HU185001B - Process for preparing pharmaceutically active amino-alkyl-furane derivatives - Google Patents

Abstract

New furan derivs. of formula (I), and their N-oxides, hydrates and salts: (where R1 andR2 are H, lower alkyl, cycloalkyl, lower alkenyl, aralkyl, or a lower alkyl gp. interrupted by O or NR4, or NR1R2 is a heterocyclic ring opt. contg. an O atom or NR4 gp; A is 1-6C alkylene; R3 is H, lower alkyl, lower alkenyl or alkoxyalkyl; R4 is H or lower alkyl; X is CH2, O or S; Y is S, O, NR5 or CHR6; R5 is H, NO21 CN, lower alkyl, aryl, alkylsulphonyl or arylsulphonyl; R6 is NO2, arylsulphonyl or alkylsulphonyl; m = 2-4, n = 1 or 2 or can be O when X is S or CH2). (I) are histamine H2 receptor antagonists. They inhibit histamine-induced gastric hypersecretion without affecting smoth-muscle contraction induced by histamine. They can also be used to treat allergic symptoms, e.g. urticaria.

Description

This invention relates to new (1) aminoalkyl furan derivatives of the formula, pharmaceutically acceptable acid addition salts and hydrates thereof, wherein R, and R ~ is hydrogen, ^4] C4 alkyl, phenyl (C 1-4) independently of one another - an alkyl group or a group of the general formula -N (R 1, j) -carbon atoms

C 1 -C 4 alkyl, where R 4 is hydrogen, or C 1 -C 4 alkyl, or

Rj and R2 together with the adjacent nitrogen atom to ^four 5-6 membered heterocyclic group having oxygen atom as a further heteroatom and / or N (R, contain a radical of formula J-offers awkward wherein Κ4 are as defined above,

R₁ is hydrogen, C1-4alkyl ^J C3-6 alkenyl, or C1-4 alkoxy (Cl-C4) alkyl,

X is methylene, oxygen or sulfur, Y is oxygen or sulfur, or a group of the formula = NR 1 or = CHR 4,

Alk is a linear or branched alkyl group containing from 1 to 6 carbon atoms,

Rr is hydrogen, nitro, cyano, (C1-C4) alkyl, (C1-C4) alkylsulfonyl or benzenesulfonyl;

R 1 is nitro, m is an integer from 24, n is 1 or 2, or when X is sulfur or methylene, n is 0.1 or 2.

The compounds of formula (I) act selectively on histamine receptors.

The division of histamine receptors (H receptors) into two groups (H and H receptors) is described by Ash and Schild (Brit. J. Pharmacol. Chemother., 27, 427 (1966)) and Black et al. 236, 385 (1972)). Stimulation of bronchial and gastrointestinal smooth muscle is mediated by H 1 receptors and these effects may be inhibited by known histamine antagonists, such as mepiramine. While gastric acid secretion and cardiac pacing are mediated through H2 receptors, these effects are unaffected by mepiramine, while they provide inhibition or reduction of H _? antagonists such as methamide. Histamine stimulates both H 1 and L 1 receptors.

It has now been found that the novel aminoalkyl furyl derivatives of formula (I) are selective H 1 antagonists, i.e., they inhibit gastric acid secretion when stimulated through the histamine Lk receptors. (See Ash and Schild's communication below). The inhibitory effect of the compounds on gastric acid secretion can be demonstrated in the rat perfusion assay using the method of Gosh and Schild (British J. Pharmacol. (see above). The compounds of the present invention do not interfere with histamine-induced contractions of isolated gastrointestinal smooth muscle.

Histamine Iκ-blocking compounds are useful in the treatment of conditions in which there is excessive secretion of gastric acid, such as gastric ulcer, and in the treatment of allergic conditions in which histamine is a known mediator. The compounds may be used alone or in combination with other active ingredients for the treatment of allergic and inflammatory conditions such as urticaria.

The substituents of formula (I) are preferably lower alkyl and lower alkenyl are preferably lower alkenyl and lower alkenyl.

The aryl group, alone or as part of another group, preferably represents a phenyl group optionally substituted with, for example, an alkyl or alkoxy group or a halogen atom.

A further advantage of the compounds of formula I is that they are readily prepared from readily available starting materials.

The compounds of formula (1) are characterized by tautomerism and include all tautomers. In the case where Alk is a branched alkylene group, optical isomers are possible, and all diastereoisomers and optical enantiomers of formula (I) are included.

A preferred group of novel compounds of the present invention are those compounds of formula I wherein R1 and R2 are independently hydrogen, alkyl, phenylalkyl or dialkylaminoalkyl, or R1 and R2 together with the nitrogen atom Forms a 5- or 6-membered saturated heterocyclic group such as morpholino, piperidino, pyrrolidino or N-alkylpiperazino, Alk represents a C 14 straight alkylene group, Y represents sulfur or oxygen, or = NRc general wherein R 1 is hydrogen, nitro, cyano, lower alkyl, alkylsulfonyl, or benzenesulfonyl, X, m, n and R 1 are as defined above.

A particularly preferred group of compounds of the invention are those compounds of formula I wherein R 1 and R 1 are each independently hydrogen, C 1 -C 4 alkyl or phenethyl, or R 1 and R 6 together with the nitrogen atom forms a pyrrolidino group, Alk represents a C10 alkylene group, Y represents a sulfur atom, -CHNO2 or = NRj wherein Rj represents a nitro, cyano, methylsulfonyl or benzenesulfonyl group, Rj represents a hydrogen atom, 1 C 3 alkyl, propenyl or C 3 alkoxyalkyl, n and m together are 3 or 4 and X is as defined above.

A further preferred group of compounds of the present invention are those compounds of formula I wherein R1 and IX are independently hydrogen, C1-C3 alkyl or phenethyl, or R1 and R2 together with the nitrogen atom form a pyrrolidine group, Alk. is a C 1-3 alkylene group, Y is a sulfur atom, = CHNC 2 or = NR j, wherein R j is a nitro, cyano, methylsulfonyl or benzenesulfonyl group, X is a sulfur atom, or a methylene group R 1 is hydrogen, methyl or methoxy-ol, n is 1, m is 2 or 3.

Another particularly preferred group of compounds of the present invention are those compounds of formula I wherein R is hydrogen, methyl or ethyl, R is methyl or ethyl, Alk is methylene, Y is = NCN = NNO ₇ or OHNCri group, R₁ is hydrogen, or methyl-port tube, the value of X is sulfur or methylene, n is 1, the level the second

Particularly preferred compounds of formula (0) are:

N- (2- (5- / Dimethylamino / methyl-2-furyl-methylthio) ethyl) -N'-methyl-thiourea

N-Cyano-N '- (2- (5- (dimethylamino) -methyl-2-furylmethyl-thio) -ethyl) -N' -methyl-guanidine,

N- (2- (5-Dimethyl-amino / methyl-2-furylmethylthio) -ethyl) -N '

-methyl-2-nitro-1,1-ethylenediamine, N-cyano-N '- (2- (5- (diethylamino) methyl-2-furylmethylthio) ethyl) -N', - methyl-guanidine,

N- (2- (5- (Diethylamino) -methyl-2-furylmethylthio) retyl) -N'-.

-methyl-2-nitro-1,1-ethylenediamine, N- (2- (5- (dimethylamino) methyl-2-furylmethylthio) ethyl) -N '- 2-methoxyethyl -2-nitro-1,1-ethylenediamine, N- (2- (5- (dimethylamino) methyl-2-furylmethylthio) ethyl) -N'-methyl-2-nitro-1 , 1-ethylenediamine, N- (3- (5- (dimethylamino) methyl-2-furylthio) propyl) -N'-methyl-2-nitro-1,1-ethylenediamine, N- (2- (5- (ethylmethylamino) methyl-2-furylmethylthio) ethyl) -N'-methyl-2-nitro-1,1-ethylenediamine,

N- (2- (5- (Di-methylamino-methyl-2-furylmethylthio) -ethyl) -N'-nitroguanidine,

N- (2- (5- (Dimethylamino) methyl-2-furylmethylthio) ethyl) -N-methanesulfonyl-N ', methylguanidine, N- (4- (5- / Dimethylamino / methyl-2-furyl) butyl) -N'-methyl-thiourea

N-benzenesulfonyl-N '- (2- (5- (di-methylamino-methyl-2-furylmethylthio) ethyl) -N' -methyl guanidine,

N- (5- (5- (Dimethylamino-methyl-2-furyl) -pentyl) -N-methyl-2-nitro-1,1-ethylenediamine, N-Cyano-N '- (5 - (5- (dimethylamino) methyl-2-furyl) pentyl) -N'-methyl guanidine,

N- (4- (5- / Dimethylamino / methyl-2-furyl) butyl) -N'-methyl-2-nitro-1,1-ethylenediamine,

N-cyano-N '~ (4- (5- / dimethyl amine / methyl-2-furyl) butyl) -N "-methyl-guanidine,

N-2- (5- (3- (dimethylamino-propyl) -2-furanylmethylthio) ethyl-N'-methyl-2-nitro-1,1-ethenediamine,

N-2- (5- (2- (Dimethylamino) ethyl) aminomethyl-2-furanylmethylthio) ethyl-N'-methyl-2-nitro-1,1-ethylenediamine.

The compounds of general formula (I) may be converted into pharmaceutically acceptable acid addition salts. The acid addition salts may be salts with inorganic or organic acids, for example hydrochloride, hydrobromides or sulphates. Particularly preferred organic salts are salts with aliphatic mono- or dicarboxylic acids, such as acetates, maleates or fumarates.

The compounds of formula (I) may also be converted into hydrates.

The invention also relates to the preparation of N-oxides of the compounds of formula I wherein R 1 and R 1 are other than hydrogen.

The compounds of formula (I) may be administered orally, topically, parenterally, or in the form of suppositories, preferably oral administration. The compounds may be administered in the form of a base or a pharmaceutically acceptable acid addition salt. In general, the compounds of formula (I) or their salts are formulated with pharmaceutical excipients conventionally known in the art.

The compounds of the invention may be administered in combination with other active ingredients, such as, if desired, known antihistanes. For oral administration, it is preferable to use capsules or tablets, which may be sustained release tablets. The pharmaceutical composition may be, for example, a dragee or a syrup.

Topically, the compounds may be formulated as ointments, solutions, creams, powders or aerosols.

The usual daily dose for oral administration is 0.1-1.2 g. preferably in dosage units containing from 20 to 200 mg of active ingredient. The prolonged-release tablet should preferably be taken two or three times daily.

Parenteral administration can be by injection at regular intervals or by continuous infusion. The injectable solution will generally contain from 10 to 100 mg / ml of active ingredient.

For topical application, an aerosol, ointment, cream or solution may be used. These pharmaceutical compositions generally contain from 1.5 to 2% by weight of the active ingredient, based on the total amount.

Compounds of formula (I) may be prepared from a primary amine of formula (II) wherein R 1, R 1, Alk, η, X and m are as defined above, which is reacted with a compound of formula (I) wherein R 1 and Y are as defined above. The amine of formula (II) may be used in the form of the free base or of a salt with a weak acid such as acetic acid. THE? (1) capable of introducing a group of formula The compounds of formula RjNCO isocyanates, isothiocyanates RjNCS the formula or (2) or (3) a compound of formula wherein R ₃ and R _$ are as defined above, P is a leaving group.

The reaction with the isocyanate or isothiocyanate can be carried out by leaving the amine and the isocyanate or the amine and the isothiocyanate in the presence of a solvent such as acetonitrile.

The reaction of the primary amine of formula (II) with the reagents of formula (2) or (3) is carried out by melting the reaction components at a higher temperature, for example 100-120 ° C.

The reaction of the amine (II) with the reagent (2) can also take place in a solvent such as acetonitrile at elevated temperature in the presence of silver nitrate.

Alternatively, the amine of formula (01) and the compound of formula (3) are stirred in aqueous solution at room temperature.

In the case where R 1 is hydrogen, the reactant is an alkali metal cyanate and a thiocyanate.

In the formulas (2) and (3), P, which is a cleavable group, can be, for example, halogen, thiomethyl, 3,5-dimethyl-prazolyl or alkoxy, preferably methylthio.

The group of formula (1) may also be introduced into the compound of formula (II) by reaction with a compound of formula (4) or (5) wherein R 1, R 2 and P are nti. The reaction may be carried out in a solvent such as ether or acetonitrile at a temperature between ambient temperature and the boiling point of the solution. The reaction is an intermediate of formula 011

185,001 is obtained wherein R 1, R 1, Alk, X, n, m and P are as defined above, O is = NR- or = CHR 2, which is used for the primary amine of formula RoNFL where Rt is above, is converted to the product of formula (I). The reaction is carried out at ambient temperature to the reflux temperature of the reaction mixture.

In another embodiment of the invention, compounds of formula I wherein Y is sulfur, wherein R 1, R 1, Alk, R ₂ , X, n and m are as defined above, may be prepared by reacting a compound of formula (II). The primary amine of formula IIa is heated with carbon disulfide and then reacted with an acetic acid ester, such as ethyl chloroformate, to give the isothiocyanate of formula IV, wherein R 1, R 1, Alk, X, n and m are as defined above with an amine of formula wherein R ₃ is as defined above, conveniently as a solvent in the presence of an alkanol such as ethanol.

In another embodiment of the invention, compounds of Formula I wherein X is S, R and R are H, wherein Y is other than CHNO0, n is 1, Rt, Alk, and m are as defined above. (V) or (VI) may be prepared from a compound of formula wherein R, R _2, Alk is as defined above, R₁ is hydrogen or an acyl group such as acetyl or p-nitrobenzoyl group, if R, and R ₂ is a hydrogen atom, a protecting group (A is provided on a compound of formula V, such as a phthalimido group. The starting compounds of formula V or VI are reacted with a thiol of formula VII wherein Y, R, and m is as defined above and optionally deprotected When the compound of formula (V) is used as starting material, the reaction is conveniently carried out at 0 ° C. k of concentrated hydrochloric acid. When using the compound of formula (VI), the reaction is carried out at room temperature in an organic solvent, for example in the presence of dimetilforamid. The chloromethyl compound of formula (VI) may be prepared from the corresponding alcohol, for example, with thionyl chloride or concentrated hydrochloric acid.

Compounds of formula (I) wherein Y = NCN, wherein R 1, R 1, R 1, Alk, X m and n may also be prepared from the corresponding compound of formula (I) wherein Y is sulfur the latter is heated with a heavy metal cyanamide such as silver, lead, cadmium or mercury cyanamide, preferably in aqueous solution.

Compounds of formula (I) wherein Y = NR 1 and Alk is methylene or branched alkylene chain, wherein R 1, R 1, R 1, R 1, X, m and n are as defined above, may be prepared by: reacting a compound of Formula (VIII) wherein R 1, R 1, X, n and m are as defined above, with the appropriate aldehyde and secondary amine or a salt of a primary or secondary amine. For example, the ((.sub.1-N) -CH.sub.HCH.sub.2 group may be introduced using dimethylamine and formaldehyde. The process may be carried out by reacting the amine salt with aqueous formaldehyde and a compound of formula VIII or the amine salt with paraformaldehyde and boiling with a compound of formula (VIII).

The primary amine starting compounds of formula (II) are novel and are also within the scope of the invention. They can be prepared as follows.

Compounds of formula (II) wherein X is sulfur, wherein n is 1, R 1, R _2> Alk, and m are as defined above, can be prepared by treating furfurylthiol (IX) with an ω-bromine of formula (X) alkyl phthalimide, where m is as defined above, and the resulting compound of formula XI, where m is as described above, for example by Mannich reaction, is introduced into the group of formula (6) wherein R 1, R ₂ and Alk are above. The protecting group is then removed, for example, with hydrazine hydrate to give the amine of formula II.

Alternatively, the starting compounds of formula (II) wherein X is sulfur, wherein n is 1, R 1, R _2> Alk and m are as defined above, are prepared from rurfuryl chloride and protected by a protected amylamino group. with a ω-aminoalkylthiol group, such as a compound of formula XII, wherein m is as defined above, and the resulting compound of formula XI is obtained as described above to give the primary amine of formula II.

Alternatively, compounds of formula II wherein X is sulfur, wherein n is 1, R p R t, Alk and m are as described above, may be prepared by further reacting a compound of formula ΧΠΙ wherein R 1, R t and Alk The above acidic reaction conditions are reacted with an optionally protected amino group ω-aminoalkylthiol. Alternatively, the compound of formula (XIII) is first converted to the corresponding acetate and then reacted with ω-aminoalkylthiol under basic reaction conditions.

The primary amines of formula (II), wherein X is methylene or oxygen, n is 1 or 2, R 1, R _2> Alk and m are as defined above, can be prepared by reacting furan with butyllithium. A lithium derivative of the formula (XIV) first with an α · ω-dihalo Compound of the formula Hal (CH ₂ ) _n X (CH ₂ ) _m Hal wherein Hal is chlorine, bromine or iodine, n and m are as defined above, followed by reaction with phthalimide potassium. The resulting compound of formula XV, wherein X, n and m are as defined above, is then subjected to, for example, a Mannich reaction and the protecting group is removed, for example, with hydrazine hydrate.

Compounds of formula II wherein X is sulfur, wherein n is zero, R 1, R ₂ , Alk and m are as defined above, may be prepared by reacting a furyl derivative of formula XVI wherein R p R ₂ and Alk is as defined above, but other than R ₁ and R ₂ , with lithium and elemental kennel and then with a ω-bromoalkylphthalimide of formula (X). The resulting compound of formula XVII, wherein R 1, R ₂ , Alk and m are as defined above, is then reacted with a hydrazine hydrate wall to remove the protecting group.

Compounds of formula (II) wherein X is oxygen, wherein n is 1, R 1, R 1, Alk and m are as defined above, may be prepared by reacting an alcohol of formula (XIII) in a solvent such as diraethylformamide with a Hal. CH 2) -NH-, wherein Hal is ^z , preferably chlorine, m is as defined above, in the presence of a base, preferably potassium tert-butylate.

Compounds of formula II wherein X is sulfur or oxygen, wherein m is 2, R 1, R 1, Alk and n are as defined above, may also be prepared using ethylene min. This compound is reacted with a compound of formula XIII or the isostere thiol.

The amines of formula II may also be prepared from a compound of formula XV11I wherein X, n and m are as defined above by Mannich reaction followed by reduction with lithium aluminum hydride.

When a Mannich reaction is employed, the group of formula (6) may be introduced at any convenient step, but preferably the compound of formula (XIX) or the compound of formula (XX), wherein X, n and m are as defined above.

The Mannich reaction is used, using the appropriate aldehyde and amine, to prepare compounds of formula II wherein Alk is methylene or branched alkylene. Formaldehyde is used to prepare compounds having a methylene group in place of Alk.

Alternatively, furyl 2-carboxylic acid is used as starting material for the preparation of compounds of formula II wherein Alk is methylene. This is reacted with an amine of formula RpRjNII whereofR1 and 1% are as defined above, and the resulting amide of formula (XXI) where R6 and R6 are as defined above is reduced. The reduction is carried out, for example, with lithium aluminum hydride. The resulting compound of formula (XXII), wherein R 1 and R 1 are as defined above, is hydroxymethylated using formaldehyde and acetic acid. In the case where R 1 and R 1 are both hydrogen, the arruno group is reaction. The resulting compound of formula (XIII) is then deprotected with hydrazine.

When both Rp and R6 in formula (XXII) are other than hydrogen, the hydroxymethylation can be performed using butyllithium followed by formaldehyde.

The following two methods are useful for the preparation of compounds of formula C 2 or more wherein R 1, R 1, X, n and m are as defined above.

For the preparation of ethylene derivatives, it is preferable to use a method analogous to the synthesis of methylene derivatives, except that the carboxylic acid of formula XXIII is used instead of furyl-2-carboxylic acid.

When the alkyl alkylene chain of Alk has more than 2 carbon atoms, the lithium derivative of formula XIV is sequentially substituted with a dihaloalkane of the formula Hal-Alk-Hal wherein Hal is chlorine, bromine or iodine, Alk is 3-6. a straight alkylene chain containing carbon atoms and then reacting with an amine of formula R.R.NHH, where R1 and R1 are as defined above, to form a compound of formula XVI.

In the case where R 1 and R 1 are hydrogen, phthalic potassium is used instead of the amine R 1 R 1 NH in the above two methods. In both methods, the reaction rooms are hydroxymethylated as described above and optionally deprotected to give a compound of formula XIII.

When it is necessary to prepare compounds of formula (II) wherein R 1 and R 1 are other than hydrogen, compounds containing the free arrino group may be converted to the corresponding substituted amino group, for example, using the formaldehyde and formic acid according to the Eschweiler-Clarke reaction. In this case, dimethylamino compounds are obtained. However, it is preferable to use the substituted amine in the appropriate step of the synthesis.

Compounds of formula (II) wherein n is 2 may be prepared starting from a compound of formula (XXIV) wherein R is a cleavable group such as ρ-toluene, sulfonyloxy, methanesulfonyloxy or bromine. The compound is reacted with a ω-phthalimidoalkylthiol of formula XII, the product obtained is subjected to a Mannich reaction, and the protecting group is finally removed.

The compounds of the invention may also be prepared by reacting a compound of formula (V) with a compound of formula (VII) wherein Y may be, inter alia, = CHNOt. Compounds of formula (VII) wherein Y is = CHNO 2 and m is 2 may be prepared from a thiazoline derivative of formula (XXV) with an amine of formula R 1 NH 2 where R 1 is as defined above. The thiazolidine derivative (XXV) can be prepared from cysteamine (2-aminoethane thiol) and a bis (methylthio) compound (XXV).

Compounds of formula (VII) wherein Y is = CHNOt, wherein m is 2, Rt is as described above, are new and therefore are also included in the present invention.

The following examples illustrate the invention. I-IV. Examples A to M are examples of the preparation of materials for the preparation of starting compounds. Examples 1 to 6 illustrate the preparation of amines of formula II. 1 to 32. Examples 1 to 4 illustrate the preparation of compounds of formula (I) and finally Example 33 illustrates the preparation of pharmaceutical compositions.

Example I (a) A mixture of -5- (methylamino) -methyl-2-furylmethanol (g) 2-furylmethanol (51.5 g) in methylene amine hydrochloride and 50 ml of 36% formaldehyde solution for 3 hours stir at 0-3 ° C and allow to stand for 16 hours. Excess sodium carbonate was added and the suspension was extracted with ethyl acetate. The solvent was evaporated and the residue was fractionated in vacuo. 36.2 g of N-methylamino-methyl-2-furylmethanol are obtained, m.p. 1 III at 3 ° C / 0.2 mm Hg.

In a similar manner, the following compounds were prepared from 2-furylmethanol and the corresponding amine hydrochloride:

(b) 5 - ((2-Phenylethyl) amino) methyl-2-furylmethanol Oil. R _f = 0.45 (silica gel, acetone).

MMR spectrum: carbon tetrachloride: δ values:

7.29 (broad singlet, 4H), 6.8 (singlet, 2H),

6.40 (singlet, 2H), 5.62 (singlet, 2H),

185,001

4.0 (broad, 2H); 2.87 (singlet, 5H).

(c) 5 - ((1-Methyl-ethyl-amino) -methyl-2-furyl-methanol

Oil. Rf = 0.55 (silica gel, methanol). 5

Analysis of C _q H, <-ΝΟ _? H, 8.94; N, 8.28. Found: C, 63.35; H, 8.78; N, 8.09.

(d) 5- (ethylmethylamino) -methyl-2-furylmethanol,

Rf = 0.32 (silica gel, acetone).

MMR Spectrum: (deuterochloroform) δ values: J θ

8.93 (triplet, 3H): 7.80 (singlet, 3H), 7.55 (quartet, 2H), 6.50 (singlet, 2H), 6.33 (broad singlet, 1H), 5.47 ( singlet, 2H), 3.80 (m, 2H), (e) 5- (2- / dimethyl-aminobenzoic ethylamino) _{methyl-2-furyl-Me-1-butanol} bis maleate, mp. 119-121 ° C.

II. example

5- (2- (N, N-Dimethylamino) ethyl) -2-furylmethanol

A mixture of 9.8 g of N, N-dimethyl-2-furylethylamine, 17.5 g of 30% aqueous formaldehyde and 18 ml of glacial acetic acid is heated at 70 ° C for 5 hours. The reaction mixture was cooled, basified with sodium hydroxide and extracted with ether.

The organic extracts were concentrated in vacuo after evaporation. We get oil, fp. 90-100 ° C, 5 mmHg.

Analysis of C _Q H, _S NO _? H, 8.9; N, 8.2; Found: C, 64.0; H, 8.9; N, 8.0.

III. example

A solution of 2- (1- (4-bromobutyl-furan) -n-butyl-lithium in 1.6 M hexane (375 ml) was added to a solution of furan (40.8 g) in dry tetrahydrofuran (375 ml) and the mixture was stirred for 3 hours. stirred at 40 ^° C. 129.6 g of 1,4-dibromobutane are then added at -30 ° C and the reaction mixture is stirred for 4 hours at room temperature. Water was added to the mixture and extracted with ethyl acetate. The extract was evaporated and the residue fractionated in vacuo. A clear, colorless liquid is obtained, b.p. 60-62 ° C / 0.5 mm Hg.

H, H-Dimethyl-4- (2-furyl) -butylamine g dimethylamine is added to a solution of 82 g of 2- (1- (4-bromo-4'-butyl) furan) in 500 ml of toluene. The resulting solution was stirred at room temperature for 2 days and then acidified with hydrochloric acid. The acidic phase is separated off, washed with ether, basified with sodium hydroxide, and extracted with ether. The ether extract was evaporated and the residue was fractionated in vacuo. Colorless, clear oil is obtained fp. 55-58 ° C /

0.8 mmHg. Hydrochloride, op. 133-136 ° C.

Analysis for C, nH. No. ₇ based HC1 Calculated: V 58.96%, H 8.91%, N 6.88% Found: C 59.01%, H 9.02%, N 6.87%.

A solution of 5- (4- (dimethylamino) -butyl) -2-furylmethanol (a) in 1.6M (125 mL) of n-butyllithium in n-hexane was added to 33.4 g of dry tetrahydrofuran (125 mL). N, N-dimethyl-4- / 2-furyl / butylamine. The reaction mixture was stirred for 4 hours at room temperature. Paraformaldehyde (6.0 g) was added and the mixture was stirred for an additional hour. The reaction was quenched with water and extracted with chloroform. The organic extracts were concentrated in vacuo after evaporation. Obtain a clear, colorless oil, b.p. 100-105 ° C / 0.1 mm Hg, m.p. 26 to 28.5 ° C.

Analysis for C, H. According to the formula qN0 ₇ :

Found: C, 66.97; H, 9.71; N, 7.10; Found: C, 67.09; H, 10.01; N, 7.06.

Compound prepared in a similar manner:

(b) 5- (3- (Dimethylamino) propyl) -2-furylmethanol, m.p. 160 ° C / 0.08 mmHg, m.p. about 24 ° C.

Analysis for CjQHpNOj. Based on 1 formula:

H, 9.39; N, 7.50. Found: C, 64.66; H, 9.36; N, 7.39.

ARC. example

- (5- (4- / N ₎ N-Dimethylamino-butyl) -2-furyl) methylacetate

A mixture of 4.9 g of 5- (4- (dimethylamino) -butyl-2-furylmethanol, 25 g of acetic anhydride, 10 g of bulk and powdered sodium acetate and 25 ml of benzene is stirred at room temperature for 24 hours. The combined extracts were concentrated and the residue was fractionated in vacuo to give a clear colorless oil, b.p.

Analysis calculated for C, olh, 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-furyl) -methyl-ethyl) -amine

15.5 g of 5-dimethylamino-methyl-2-furylmethanol are added dropwise to a solution of 11.36 g of cysteamine in 40 ml of concentrated hydrochloric acid with stirring and ice-cooling. After allowing the reaction mixture to stand at 0 ° C for 18 hours, excess sodium carbonate was added and the resulting solid was extracted with diethyl ether. After evaporation of the solvent, the residue is distilled in vacuo. 11.6 g of 2 - ((5- (di-methylamino) -methyl-2-furyl) methylthio) ethylamine are obtained, m.p. 104-106 ° C / mmHg. Picasso Op. 142-144 ° C.

In a similar manner, the following compounds were prepared from the corresponding furylmethanol derivatives and cysteamine hydrochloride:

(b) 2 - ((5- (Methylamino) -methyl-2-furyl) methylthio) ethylamine

Monopyrrate salt op. 116-118 ° C.

(c) 2 - ((5- (1-Methyl-ethylamino) -methyl-2-furyl) -methylthio) -ethylamine.

oil, Rj = 0.4 (silica gel, methanol: 0.880 ammonia 79: 1).

(d) 2 - ((5- (Diethylaminomethyl) -2-furyl) methylthio) ethylamine

Mp: 134-135 ° C / 1 mm Hg.

c- (e) 2 - ((5- (1-Piperidinyl) methyl-2-furyl) methyllo) ethylamine.

Oil, Rf = 0.37 (79: 1 silica gel, methanol: 0.880 ammonia) (f) 2 - ((5- (aminomethyl) -2-furyl) methylthio) ethylamine. Dihydrochloride, op. 222-224 ° C (with decomposition).

(g) N- (5,2-Aminoethyl) thiomethyl) -2-furylmethyl-phenylethylamine.

Oil, Rf = 0.33 (silica gel, methanol: 0.880 ammonia 79: 1). (H) 2 - ((5- (2-Dimethylaminoethyl) -2-furyl) methylthio) ethylamine. Fp. 150-155 ° C (0.04 mm Hg).

(i) 2 - ((5- / 3-Dimethylamino-propyl / -2-furyl) -methylthio) -61

ethyl aniline. Fp. 150 ° C / 0.05 mmHg.

O) 2 - ((5- (Ethyl-methyl-methyl-2-furyl) -methylthio) -ethylamine.

R '= 0.34 (silica gel, methanol: 0.880 ammonia 79: 1).

(k) 2 - ((5/2-Dimethylaninoethyl / aminomethyl-2-furyl) -ethylthio) -ethylamine. Tris-maleate salt op. 132-135 ° C.

O) 2 - ((5- (1-Pyrrolidino) -methyl-2-furyl) -methyl-ethyl-amine. Bis-oxalate salt mp 136.5-138.5 ° C).

Example B.

2 - ((5/4-Dinethylamino-butyl / -2-furyl) -methylthio) -ethylamine

4.5 g of cysteamine hydrochloride are added to a solution of 8.98 g of potassium tert-butylate in 125 ml of dry dimethylformamide under cooling. The reaction mixture was stirred for 20 minutes and 9.6 g of - (5- (4- (dimethylamino-butyl) -2-furcyl) methyl acetate) was added. The reaction mixture was heated to 90 ° C for 4 hours, then poured into ice / water and extracted with chloroform. Evaporation of the organic extract and fractionation of the residue afforded a yellow oil which was chromatographed on a silica gel column. The eluent was a 9: 1 mixture of methanol and 0.880 ammonia. A further distillation gives a colorless oil, fp. 140 ° C / 0.05 mmHg. Analysis based on the formula C ₃ H ₄ N ~ OS:

H, 9.44; N, 90.93. Found: C, 60.81; H, 9.86; N, 10.44.

Example C

2- (2- (2-Furyl) -ethylthioethyl) -1H-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-furyl ethanol (4-methylbenzenesulfonic acid) ester in dry dimethylformamide was added dropwise and the solution was stirred overnight at room temperature. The mixture was poured into ice water and the white precipitate was collected. 1.3 g of 2- (2- (2-furyl) -ethyloxyethyl) -1H-isoindole-1,3 (2H) -dione are obtained, m.p. 53-55 ° C.

Example D (a) 2- (2- (2-Furyl) -methylthioethyl) -1H-isoindole-1,3 (2H) -dione

1.58 g of 80% sodium hydride are added portionwise to a solution of 6 g of furfuryl mercaptan in 50 ml of dry dimethylformamide. After 30 minutes, a solution of 16.71 g of 2-bromoethylphthalimide in 65 ml of dry dimethylformamide was added and the solution was heated at 110 ° C for 2 days. The solvent was evaporated and the residue was washed with water and extracted with ethyl acetate. The ethyl acetate extracts were combined, the solvent was evaporated, and the residue was recrystallized from cyclohexane. 7.8 g of 2- (2- (2-furyl) -methylthioethyl) -1H-isoindole-1,3,2H-dlonone are obtained, m.p. 62-63 ° C.

In a similar manner, the following compounds were prepared from bromoalkylphthalimide and furfuryl mercaptan:

(b) 2- (3- / 2-Furyl / methylthio-propyl) -1H-isoindole-1,3 / 2H / -dione

MMR Spectrum: (deuterochloroform) δ values:

7.7 8.3 (multiplet, 2H), 7.2-7.8 (multiplet, 2H),

6.29 (singlet, 2H), 6.23 (triplet, 2H), 3.7 (multiplet, 2H), 2.7 (multiplet, 1H), 2.4 (multiplet, 41f), (c) 2 (4- (2-Furyl) -methylthio-butyl) -1H-isoindole-1,3 / 2H / -dione

MMR Spectrum: (deuterochloroform) δ values:

8-8.5 (multiplet, 4H), 7.49 (triplet, 2H), 6.33 (multiplet, 4H), 3.7 (multiplet, 2H), 2.7 (multiplet, 2H), 2.3 (multiplet, 4H).

Example E (a) 2- (2- / 5-Dimethylaminomethyl / -2-furylmethylthioethyl) -1H-isoindole-1,3 / 2H / -dione g 2- (2- / 2) -furylmethylthio (ethyl) -1H-isoindole-1,3- (2H) -dione, 3.1 g dimethylammonium chloride, 3 ml

A mixture of 36% formaldehyde solution and 50 ml of acetic acid was heated in a water bath for 9 hours. The solution was then cooled and the solvent evaporated in vacuo. The residue was basified with 5N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic phase was clarified with charcoal, dried and evaporated. The residual oil was purified by column chromatography (silica gel, ethanol: ethyl acetate = 1: 1). 5.7 g of the title compound are obtained, Rf = 0.4.

MMR Spectrum: (deuterochloroform-dimethylsulfuric-Λ-Prt ·

7.71 (singlet, 6H), 7.22 (triplet, 2H), 6.52 (singlet, 2H), 6.2 (singlet, 2H), 6.1 (triplet, 2H), 3.8 (multiplet) , 2H), 2.2 (multiplet, 4H).

The following compounds were prepared in a similar manner

From 2- (co- (2-furyl) -methylthioalkyl) -1H-isoindol-1,3 / 2H / dione, the corresponding amine and formaldehyde:

(b) 2- (2- (5- / 1-Pyrrolidinyl) methyl-2-furylmethylthio) ethyl) -1H-isoindole-1,3 / 2H / dione.

MMR Spectrum: (deuterochloroform) δ values:

8-8.4 (multiplet, 4H), 7-7.6 (multiplet, 6H),

6-6.5 (multiplet, 6H), 3.7-4.0 (multiplet, 2H), 2-2.4 (multiplet, 4H).

(c) 2- (3- (5-dimethylaminomethyl-2-furylmethylthio) -propyl) -1H-isoindole-1,3,2H-dione.

Rf = 0.45 (silica gel, methanol).

(a) 2- (4- / 5-Dimethylaminomethyl-2-furylmethylthio-butyl) -1H-isoindole-1,3 / 2H-dione.

R f = 0.26 (silica gel, methanol).

MMR Spectrum: (deuterochloroform) δ values:

8.85 (multiplet, 4H), 7.7 (singlet, 6H), 7.42 (triplet, 2H), 6.52 (singlet, 2H), 6.29 (multiplet, 4H), 3.9 (multiplet) , 2H), 2.2 - 2.4 (multiplet, 4H).

(e) 2- (2- (5- (4-Methyl-1-piperazinyl) methyl-2-furylmethylthio) ethyl) -1H-isoindole-1,3 (2H) -dione.

MMR Spectrum: (deuterochloroform) δ values:

7.75 (singlet, 3H), 7.52 (singlet, 8H), 7—

7.5 (multiplet, 2H), 6.5 (singlet, 2H), 6-6.3 (multiplet, 4H), 3.85 (multiplet, 2H), 2-2.4 (multiplet, 4H).

(f) 2- (2- (5- (4-Morpholinyl) methyl-2-furylmethylthio) ethyl) -1H-isoindole-1,3 / 2H-dione.

MMR Spectrum: (deuterochloroform) δ values:

7.54 (multiplet, 4H), 7.24 (multiplet, 2H), 6.50 (singlet, 2H), 6.22 (multiplet, 8H),

3.8 (multiplet, 2H); 2.4 - 2.4 (multiplet, 4H).

Example F.

2- (3- (3- (5-Dimethylaminomethyl-2-furyl-ethylthio) -ethyl) -1H-isoindole-1,5 (2H) -dione

0.5 g of 2- (2- (2-furylethylthio) ethyl) -1H-isoindole-1,3 (2H) -dione, 0.27 g of dimethylamine hydrochloride, 0.102 g of para-71 formaldehyde and ethanol the mixture is refluxed. After 5 hours, 0.27 g of dimethylamine hydrochloride and 0.102 g of paraformaldehyde are added and the reaction mixture is heated for an additional 16 hours. The solvent was evaporated, the residue basified and extracted with ethyl acetate. The oil obtained by evaporation of the extract was subjected to column chromatography (silica gel, methanol). 0.43 g of a pale yellow oil is obtained, which is 2- (2- (5-dimethylaminomethyl-2-furyl-ethylthio) -ethyl) -1H-isoindole-1,3,2H / dione.

Analysis of ^c J9 ^H 22 ^N 2 O 3 ^S 2 ^{H 3 O} 4 ° Calculated: C 61.35%, H 6.36%, N 7.53%, · Found: C 61.48%, H: 6, 13%, N 7.63%,

Example G

2- (5-ÍDimetil-methyl / -2-furyl methoxy) ethylamine

Method 1

To a solution of 6.2 g of 5-dimethylamino-methyl-2-furylmethanol in 6.2 g of dry tetrahydrofuran and 2.82 g of ethyleneimine are added a solution of 11.6 g of methanesulfonic acid in 40 ml of tetrahydrofuran. The solution was evaporated and the residual oil was heated at 98-100 ° C for 10 minutes. After 18 hours, 60 ml of 5N sodium hydroxide was added and the solution was evaporated to dryness. Anhydrous sodium sulfate and 150 mL ethyl acetate were added, and after 2 hours the suspension was filtered, clarified with charcoal and evaporated. The resulting oil was chromatographed on silica gel. The elution was first carried out with a 79: 1 mixture of methanol and 0.88 ammonia, the eluate was discarded, and then a 19: 1 mixture of methanol and 0.88 ammonia was used. The eluate was evaporated and the residual oil was converted to the bis-oxalate salt. 0.2 g of 2- (5- (dimethylaminomethyl) -2-furylmethoxy) ethylamine bisoxalate are obtained, m.p. 125-128 ° C (ethanol).

Method 2

A solution of 6.25 g of 2-chloroethylamine hydrochloride in dry dimethylformamide was added dropwise to 8.96 g of potassium tert-butylate and 12.4 g of 5-dimethylamino-methyl-2-furylmethanol in the same solvent. solution while stirring and cooling. After 2 hours, the solvent was evaporated, the residue basified and extracted with ethyl acetate. After removal of the solvent, the residue is treated with ethanolic oxalic acid in the presence of ethanol. The crystalline salt is recrystallized from ethanol. 3.05 g of 2- (5- (dimethylaminomethyl) -2-furylmethoxy) ethylamine bisoxalate are obtained, m.p. 130-133 ° C.

In a similar manner, 2- (5- (methylaminomethyl) -2-furylmethoxy) ethylamine bisoxalate was prepared by method 2. 162-164 ° C.

Example H (a) 2- (4- (2-Furyl-butyl) -1H-isoindole-1,3,2H) -dione

A mixture of 0.406 g of 2- (1- (4-bromobutyl) furan, 0.370 g of phthalimide potassium and dry dimethylformamide was stirred overnight. The solution was poured into ice / water, and the resulting white solid was filtered, dried and recrystallized from chloroform / petroleum ether (b.p. 60-80 ° C). 0.430 g of 2- (4- / 2-furyl-butyl) -1H-isoindole-1,3 (2H) -dione was obtained as white microcrystalline substance _Q , m.p. 61 -63

In a similar manner, the following compound is prepared:

(b) 2- (5- (2-Furyl) -pentyl) -1H-isoindole-1,3 (2H) -dione, m.p. 54-60 ° C.

Example J (a) 2- (4- (5-Dimethylaminomethyl / -2-furyl) butyl) -1H-isoindole-1,3 (2H) -dione

5.38 g of 2- (4- (2-furyl-butyl) -1H-isoindole-1,3,2H) -done,

A mixture of 1.2 g of paraformaldehyde, 3.26 g of dimethylamine hydrochloride and 100 ml of absolute ethanol is refluxed. After 6 hours, additional paraformaldehyde (0.6 g) and dimethylamine hydrochloride (1.6 g) were added and heating continued for a further 20 hours. The solvent is then evaporated, the residue is made strongly basic with 5N sodium hydroxide solution, extracted with ethyl acetate and the organic phase is evaporated. The crude product was purified by column chromatography. 3.25 g of amber color (oil, Rr = 0.4 (silica gel, methanol)).

MMR Spectrum: (deuterochloroform) δ values:

8-8.6 (multiplet, 4H), 7.75 (singlet, 6H),

7.3 (multiplet, 2H), 6.55 (singlet, 2H), 6.3 (multiplet, 2H), 4.0 (multiplet, 2H), 1.9-2.4 (multiplet, 4H).

In a similar manner, the following compound was prepared:

(b) 2- (5- (5-Dimethylaminomethyl-2-furyl) pentyl) -1H-isoindole-1,3 (2H) -dione.

TLC Rf = 0.4 (silica gel, methanol).

MMR Spectrum: (Duterochloroform) δ values:

8.0-8.8 (multiplet, 6H), 7.70 (multiplet, 6H),

7.37 (triplet, 2H), 6.52 (singlet, 2H), 6.30 (triplet, 2H), 4.0 (multiplet, 2H), 2.2 (multiplet, 4H).

Example K.

5- / Dimethylamino / methyl-2-furyl-propyl-amine

A mixture of 1.21 g of furylpropionitrile, 1.62 g of dimethylamine hydrochloride, 0.7 g of paraformaldehyde and 20 ml of ethanol is heated under reflux for 24 hours. The solvent was evaporated and the residue was basified to pH 12 and extracted with ethyl acetate. The solvent was evaporated and the residual oil was purified by column chromatography (silica gel, methanol). 0.6 g of 5- (dimethylamino) -methyl-2-furylpropionitrile is isolated. R f = 0.55 (silica gel, methanol).

ml of dry ether a solution of 6.0 grams of the nitrile was added dropwise to a suspension of 2.0 g of lithium aluminum hydride in of stirring, 0 ^° C. Water was added, the solvent was evaporated and the residue was subjected to column chromatography. 3.33 g of 5- (dimethylamino) methyl-2-furylpropylamine are obtained in the form of a pale yellow oil.

MMR Spectrum: (deuterochloroform) δ values:

8.2 (multiplet, 2H), 7.6 (broad, 2H), 7.75 (singlet, 6H), 7.30 (multiplet, 4H), 6.60 (singlet, 2H), 4.0 (multiplet) , 2 H).

Example L.

2- (3- (5-Dimethylaminomethyl-2-furylthio-piperyl) -propyl) -1H-isoindole-1,3 / 2H-dione

To a solution of 7.5 g of N, N-dimethylfurylmethylamine-lithium derivative is added 1.9 g of sulfur in portions at -40 ° C. The mixture was stirred at -10 ° C for 20 minutes and 16 g of 2- (3-bromopropyl) -1H-isoindole-1,3 (2H) -dione was added. After stirring at 0 ° C overnight, the solvent was evaporated in vacuo, the residue was dissolved in ethyl acetate, filtered and extracted with 2N sulfuric acid. The aqueous phase is dried. The crystalline material from the solvent evaporation is recrystallized from ethanol with activated carbon clarification. 7.59 g of 2- (3- (5-dimethylaminomethyl-2-furylthio) propyl) -1H-isoindole-1,3 (2H) -dione, m.p. 64-65 C.

Example M '(a) 4- (5- (Dimethylaminomethyl) -2-furyl) butylamine

2.9 g of 2- (4- (5-dimethylaminomethyl-2-furyl-butyl) -1H-isoindole-1,3 / 2H) -dione, 0.55 ml of a mixture of hydrazine hydrate and ethanol 6 reflux for an hour. The solvent was evaporated and the remaining crystalline material was dissolved in 5N sodium hydroxide solution. The solution was extracted with ethyl acetate, and the organic solution was evaporated to give 1.68 g of cirp as a mobile yellow oil. Thin layer chromatography (silica gel, methanol) gave a single spot at Rf = 0.15. MMR spectrum: δ values for (deuterochloroform)

8.0-8.8 (multiplet, 4H), 7.7 (singlet, 6H),

7.6 (broad, 2H), 7.3 (multiplet, 4H), 6.58 (singlet, 2H), 4.0 (multiplet, 2H).

In a similar manner, the following compounds were prepared from the corresponding phthalimide:

(b) 5- (5- (Dimethylaminomethyl) -2-furyl) pentylamine. Δ values for MMR spectrum (deuterochloroform):

8.0-8.8 (multiplet, 6H), 7.75 (singlet, 6H),

7.0 - 7.6 (multiplet, 4H), 6.60 (singlet, 2H),

4.0 (multiplet, 2H).

(c) 5- (3-Amino-propyl-thiomethyl) -N, N-dimethyl-furyl-2-ethyl-amine.

MMR Spectrum: (deuterochloroform) δ values:

8-8.5 (multiplet, 2H), 7.75 (singlet, 6H),

7.42 (triplet, 2H), 7.25 (multiplet, 2H), 6.58 (singlet, 2H), 6.3 (singlet, 2H), 3.88 (singlet, 2H).

Example 1 (a) N-2- / 5-Dimethylaminomethyl-2-furylmethylthio / ethyl-N '

methyl-thiourea

5.3 g of 2- (2- (5-dimethylaminomethyl-2-furylmethylthioethyl) -1H-isoindole-1,3 / 2H) -dione, 0.85 g of hydrazine hydrate and the ethanol mixture was refluxed for 30 hours. The solvent was evaporated to give the phthalic hydrazide salt of 2- (5-dimethylaminomethyl-2-furylmethylthio) -ethylamine.

The resulting salt is suspended in acetonitrile and 0.21 g of methyl isothiocyanate is added. The suspension was stirred for 5 hours at room temperature and then for 2 hours at 60 ° C. The mixture was filtered, concentrated and the residual oil was purified by column chromatography (silica gel, methanol). 0.3 g of N- (2- (5-dimethylaminomethyl-2-furylmethylthio) -ethyl) -N'-methylthiourea are isolated as a pale yellow oil.

Analysis calculated for C, ₂ H ₇ iN, OS ₇ : (750; {4%, H7.37; N, 14.62%). Found: C, 49.68; H, 7.52; 22%.

In a similar manner, the following compounds were prepared:

(b) Hydrate of N-Methyl-N '- (2- (5- (1-pyrrolidinyl) -methyl-2-furylmethylthio) ethyl) thiourea.

. Analysis ϋ ^ Η -, - based Ν-, Ο S ₂ .1 H2O Calcd: fc 57.14%, H 6.50%, N 13.03%.

Found: C, 52.33; H, 7.12; N, 3.17.

(c) N- (4/5-Dimethylaminomethyl-2-furylmethylthio-butyl) -N'-methylthiourea.

Analysis based on the formula _C14 H-rN-, OS ₇ :

N, 12.95; Found C, 51.69; H, 8.53; N, 12.83.

(d) N- (3- / 5-Dimethylaminomethyl-2-furylthio / propyl) -N '-methylthiourea.

Analysis of C _,? H _{71 according to} N ^ OS ₇ :

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

(e) N-Methyl-N '- (2- (5- (4-inorpholinyl) -methyl-2-furylmethylthio) ethyl) thiourea

Analysis by formula:

H, 7.04; N, 12.75. Found: C, 51.26; H, 7.08; N, 12.51.

(f) N-Methyl-N '- (2- (5- (4-methylpiperazinyl) -methyl-2-furylmethylthio) ethyl) thiourea.

Analysis for C 5 ^H 26 ^N 4 ^OS 2 ^O '''Η * Calculated: C 51.25%, H 8.03%, N 15.94% Found: C 50.93%, H 7.74%, N, 15.82%.

(g) Hydrate of N- (2- (2- (5-Dinethylaminomethyl-2-furyl / ethylthio) ethyl) -N'-methylthiourea.

Analysis a. By the formula 1 H ^ O:

H, 7.74; N, 13.54. Found: C, 50.19; H, 7.20; N, 13.18.

Example 2 (a) N- (5- (5-Dimethylaminomethyl-2-furyl / pentyl) -N'-methyl-urea

A mixture of 0.5 g of 5- (5-dimethylaminomethyl-2-furyl) pentylamine, 0.25 g of methyl isocyanate and acetonitrile was stirred for 24 hours at room temperature. The solvent was evaporated and the product was purified by column chromatography (silica gel, methanol). After treatment with ether, N- (5- (5-dimethylaminomethyl-2-furyl) -pentyl) -N, methyl-thiourea, m.p. 66-69 ° C.

In a similar manner, the following compounds were prepared from the corresponding amine and methyl isothiocyanate:

(b) N- (3- / 5-Dimethylaminomethyl-2-furylmethylthio / propyl) -N'-methylthiourea,

Analysis using the formula C ₁₃ H ₂₃ N ₂ OS ₂ :

Found: C, 51.79; H, 7.69; N, 13.94; Found: C, 51.38; H, 7.93; N, 13.41.

(c) N- (4- / 5-Dimethylaminomethyl-2-furyl-butyl) -N'-methylthiourea

MMR Spectrum: (deuterochloroform) δ values:

8-8.6 (multiplet, 4H), 7.72 (singlet, 6H),

7.35 (triplet, 2H), 6.98 (doublet, 3H), 6.2-6.8 (multiplet, 4H), 4.0 (doublet, 2H), 3-3.8 (multiplet, 2H) .

(d) Hydrate of N- (2- / 5-Dimethylaminomethyl-2-furylmethoxy / ethyl) -N'-methylthiourea.

Analysis for C ₁₇ H ₇₁ N 0 ₇ S. 1 H calcd ₇ 0 O: σ5Γ, 4θ% Η7,91 7Ν% 14.99% Found: C 51.91%, H 8.14%, N 14.98% ..

Example 3 (a) N- (2- (5-Dimethylaminomethyl-2-furylmethyl) -ethyl) -N '- (2-methoxy-ethyl) -thiourea

A mixture of 1.17 g of 1-isothiocyanato-2-methoxyethane, 2.14 g of 2- (5-dimethylaminomethyl-2-furylmethylthio) -ethylamine and acetonitrile is left standing overnight,

The solvent was evaporated and the residual oil was chromatographed (silica gel, methanol). N <2/5-dimethyl-amino-methyl-2-furyl] -metiItio / ethyl> N '- / 2-methoxyethyl / -tlokarbamidot pale yellow Olai or a salt _Rf = 0.45.

Calcd for ^C] 4 ^H 25 ^N 3 O 2 ^S 2 P ^{let Sa:}

H, 7.55; N, 12.69. Found: C, 50.64; H, 7.51; N, 12.58.

In a similar manner, the following compounds were prepared from the corresponding isothiocyanate and 2- (5-dimethylaminomethyl-2-furylmethylthio) ethylamine:

(b) N- (2- (5-Dimethylaminomethyl-2-furylmethylthio) -ethyl) -N '- (2-propenyl) -thiourea hydrate.

H, 7.50; N, 13.03. Found: C, 52.68; H, 7.58; N, 13.16.

(c) Hydrate of N- (2- / 5-Dimethylaminomethyl-2-furylmethylthio / ethyl) -N '- (1-methyl) ethylthiourea.

H, 8.09; N, 12.97%. Found: C, 51.84; H, 7.88; N, 13. Found: C, 51.90; 00%.

Example 4

N- (2- / 5-Methylamino-methyl-2-furyl-methylthio / ethyl) -N'-methyl-urea

To a solution of 1,5 2- (5-methylaminomethyl-2 ^: furylmethyl) -ethylamine in 24 ml of acetonitrile was added dropwise 0.45 g of methyl isocyanate in 15 ml of acetonitrile. After 30 minutes, the mixture was evaporated to dryness and the residual oil was subjected to column chromatography, first on silica gel using methanol / 0.88 ammonia 79: 1 as the eluent and then on alumina using methanol as the eluent. 0.25 g of N- (2- (5-methylaminomethyl-2-furylmethylthio) ethyl) -N'-methylcarbainide are obtained.

H, 7.44; N, 16.33. Found: C, 51.00; H, 7.38; N, 7.38%. Found: C, 51.33; H, 7.44; .

Example 5 (a) N- (2- / 5-Dimethylaminomethyl-2-furylmethylthio / ethyl) -N'-methylurea

Methyl isocyanate (0.33 g) was added to a suspension of 2 g of 2- (5-dimethylaminomethyl-2-furylmethylthioethylamine) phthalic acid hydrazine complex in 50 ml of acetonitrile. After 2 hours, the mixture was filtered and the filtrate was evaporated. The residual oil was purified by column chromatography (silica gel, methanol). N- (2- / 5-Dimethylaminomethyl-2-furylmethylthio / ethyl) -N'-methylurea is obtained.

Analysis for C ^^H ^NNjC ^S. According to the formula H ₂ O:

H, 7.76; N, 15.32. Found: C, 52.38; H, 7.61; N, 15.25.

In a similar manner, the following compound was prepared:

(b) Hydrate of N-Methyl-N '- (2- (5- / 1-pyrrolidinyl / methyl-2-furylmethyl-thio) ethyl) urea.

Analysis according to the formula I 1 I ^ O:

Found: C, 54.87; H, 7.89; N, 13.71; Found: C, 54.70; II, 7.33; N, 14.07.

Example 6 (a) N- (2- (5-Dimethylaminomethyl-2-furylmethylthio) -ethyl) -N '- (1-methylethyl) urea

2- (5-Dimethylaminomethyl-2-furylmethylthio) -ethylamine (2.14 g) and isopropyl isocyanate (0.89 g) were dissolved in acetonitrile and allowed to stand overnight. The solvent was evaporated and the residue was recrystallized from methanol / ether. 2.8 g of N- (2- (5-dimethylaminomethyl-2-furylmethylthio) ethyl) -N '- (1-methylethyl) urea are obtained in the form of crystals, m.p. 65-67 ° C.

In a similar manner, the following compound was prepared:

(b) N- (3- / 5-Dimethylaminomethyl-2-furylmethylthio / propyl) -N'-methylurea, m.p. 69-69,5oC.

Example 7

N- (2- / dimethyl-aminomethyl-2-furyl-methylthio / ethyl) urea

A solution of 2.8 g of 2- (5-dimethylaminomethyl-2-furylmethyl) -ethylamine and 3.75 g of potassium cyanate in 50 ml of water is heated on a water bath for 8 hours. Excess solid sodium carbonate was added and the organic material was extracted continuously with diethyl ether. The extracts were evaporated to give 1.28 g of N- (2- (5-dimethylaminomethyl-2-furylmethylthio) ethyl) urea as a waxy material after column chromatography.

Analysis for C, 1H. _q N ₃ O _? S. H _? H, 7.63; N, 15.27. Found: C, C; C 48.22%, H 7.50%, N 15.61%.

Example 8

A solution of N- (2- (5-dimethylaminomethyl-2-furylmethylthio) -ethylamine and 1.5 g of S-methyl-N-nitro-isothiourea in 10 ml of ethanol was heated at 40 ° C for 5 minutes. The resulting precipitate was filtered and recrystallized from ethyl acetate and petroleum ether boiling at 80-100 ° C to give N- (2- (5-dimethylaminomethyl-2-furylmethylthio) -ethyl) -N'-nitroguanidine. mp 103-104 ° C.

Example 9, (a) N-Cyano-N '- (2- [5-methyl-ethylaminomethyl-2-furylmethylthio) ethyl] -N' -methylguanidine

A mixture of 2.0 g of 2- (5-methylaminomethyl-2-furylmethylthio) ethylamine and 1.25 g of N-cyano-N'-methylisothiocarbamylmethyl ester was added for 6.5 hours. heat in a water bath. Occasionally, the methanethiol is removed by vacuum. The crude product was purified by column chromatography (silica gel, methnaol: ammonia 79: 1), Rf 0.65. 1.05 g of N-cyano-N '- (2- / 5-methylaminomethyl-2-furylmethylthio / ethyl) -N' -methyl-guanidine are obtained, m.p. 81-85 ° C.

In a similar manner, the following compounds were prepared from the corresponding amine and N-cyano-N'-methylisothiourea methyl ester:

(b) N-Cyano-N '- (2- (1-methylethyl) -aminomethyl-2-furylmethylthio) ethyl) -N' -methyl guanidine.

Analysis by C C HH ^ NNgOS:

Calculated: 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-Diethylaminomethyl-2-furylmethylthio) -ethyl) -N '' -methyl-guanidine.

Analysis for C ₅ H ₂₅ N ₅ OS. According to the formula 3 H ₂ O:

Calculated: 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-furylmethylthio) ethyl-N '-methyl guanidine.

Analysis based on the formula C ₅ H ₂ 3 ^N 5 ^OS ^ ^H 2 O:

Found: C, 53.70; H, 7.37; N, 20.91; Found: C, 53.97; H, 6.87; N, 21.06.

(e) N-Cyano-N- (3- / 5-dimethylaminomethyl-2-furylmethyl-thiopropyl) -N '-methyl-ganganine.

Calcd for C ^ H ^ O ₂ NGOs JH formula :.

Found: 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-dimethylaminomethyl-2-furylmethylthio / ethyl) -N' -methyl-guanidine

In a solution of 10.7 g of 2- (5-dimethylaminomethyl-2-furylmethylthio) -ethylamine and 7.1 g of N-cyano-N-methylisothiocarbamide methyl ester in 107 ml of acetonitrile

20.7 g of potassium carbonate are suspended and 9.35 g of silver nitrate dissolved in 20 ml of acetonitrile is added at 70 ° C over 1 hour. After stirring for 16 hours, the solid was filtered and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate (250 ml) and part of the solution was washed with water (10.5 ml), the ethyl acetate layer was evaporated and the solid residue was crystallized from isopropyl ester of acetic acid (1.75 ml). 0.35 g of N-cyano-N '- (2- / 5-dimethylaminomethyl-2-furylmethylthio / ethyl) -N' -methyl-guanidine are obtained, m.p. 79 to 81.5 ° C.

To another portion of the ethyl acetate solution (225 mL) was added 0.09 g of sebacine band dissolved in mL of ethanol. 13.74 g of sebacic acid salt, m.p. 92.5-94 ° C. Analysis using the formula C ₃ H ₂₁ NgOS:

Calculated: 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-methoxy-ethyl) -isothiourea-methyl-ester (4.2 g) was added to a stirred solution of 2.3 g of sodium cyanamide in absolute ethanol. After 30 minutes, it was dissolved in absolute ethanol

11.7 g of methoxyethyl isothiocyanate are added under cooling. After a further 1 hour at room temperature, dimethyl sulfate (12.66 g) was added over 30 minutes and the mixture was stirred overnight. The solvent was evaporated and the residual solid was washed well with water. 12.37 g of white crystals are obtained, m.p. 94.5-95.5 ° C.

In a similar manner, the following compound was prepared:

N-Cyano-N '- (2-nropenyl) -isothiocarbamide methyl ester, m.p. 109-110 ° C.

(a) N-Ciuno-N '- (2- (5-dimethylaminomethyl-2-furylmethylthio) ethyl) -N', - (2-methoxyethyl) guanidine 2.13 g. - (5-Dimethylaminomethyl-2-furylmethylthio) -ethylamine and 1.73 g of N-cyano-N '- (2-methoxyethyl) -isothiourea methyl ester for 6.5 hours The crude product is purified by chromatography (silica gel, methanol) 1.4 g of N-cyano-N '- (2- / 5-dimethylaminomethyl-2-furylmethylthio) ethyl) -N ', [2-methoxyethyl] guanidide is obtained

Analysis of C _L gH _? gNgO ₂ S. H, 7.50; N, 19.60. Found: C, 50.51; H, 7.20; N, 19.41.

In a similar manner, the following compounds were prepared from 2- (5-dimethylaminomethyl-2-furylmethylthio) ethylamine and the corresponding N-alkyl-N'-cyanoisothiourea methyl ester:

(b) N-Cyano-N '- (2- (5-dimethylaminomethyl-2-furylmethylthio) ethyl) -N' - (2-propenyl) guanidine.

Analysis for _{C? H?} -, N <.OS. Found: C, 53.33; H, 7.01; N, 20.70. Found: C, 53.33; H, 7.01;

(c) N-Cyano-N '- (2- (5-dimethylaminomethyl-2-furylmethylthio) -ethyl) -N' - (1-methylethyl) guanidine.

Analysis for C, _s H _? -NcOS. H _? H, 7.91; N, 20.52. Found: C, 52.97; H, 7.70; N, 20.57.

Example 12 (a) N- (2- / 5-Dimethylaminomethyl-2-furylmethylthio / ethyl) -N'-methylguanidine

A mixture of 2.14 g of 2- (5-dimethylaminomethyl-2-furylmethylthio) -ethylamine and N, S-dimethylisothiouronium iodide was heated on a steam bath for 3 hours. The methanolic residue was treated with Amberlyst A26 ion exchange resin. 1.5 g of N- (2- (5-dimethylaminomethyl-2-furylmethylthio) -ethyl) -N'-methylguanidine are obtained in the form of a tan oil.

Analysis using the formula ^c i2 ^H 22 ^N 4 ^OS ~ H ₂ O:

Calculated: C 50.76%, H 8.34%, N 19.74%, found C 50.92%, H 98.23%, Ν 19.90%,

In a similar manner, the following compound was prepared:

(b) N- (2- / 5-Dimethylaminomethyl-2-furylmethylthio / ethyl) -N 'N' -dimethyl-guanidine

MMR spectrum (deuterochloroform) δ values:

7.75 (singlet, 6H), 6.8-7.3 (multiplet, 8H),

6.5 (multiplet, 4H), 6.22 (singlet, 2H), 3.80 (multiplet, 2H), 2.0-3.5 (broad, 2H).

Example 13

N-methyl-l-methylthio-2-nitro-ethyl-amine

A mixture of 112.5 ml (0.94 mol) of 3% methylamine in ethanol and 800 ml of dichloroethane is added over a period of 5.5 hours with 99.0 g (0.6 mol) of 1,1-bis-methylthio-2-nitroethylene 1500. ml of dichloroethane at 70 ° C with stirring. The reaction mixture was heated to reflux and the solvent was distilled off (700 mL). The cooled solution was washed with 2N hydrochloric acid (250 mL) and brine (250 mL). The solvent was evaporated and the residue was recrystallized from 500 ml of acetic acid isopropyl ester while the hot solution was treated with 10 g of activated carbon. 35.0 g of product are obtained in the form of yellow prism crystals, m.p. 114 ° C.

N- (2- (5-Methylaminomethyl-2-furylmethylthio) ethyl) -N'-methyl-2-nitro-1,1-ethenediamine hydrochloride g (0.05 mol) A solution of 2- (5-methylaminomethyl-2-furylmethylthio) -ethylamine and 7.4 g of N-methyl-1-methylthio-2-nitroethyleneamine in 25 ml of water was stirred for 2 hours. At 50 ° C. 350 ml of acetone are added and the solvent is distilled off under atmospheric conditions until 275 ml of distillate are collected. To the residue was added 27.5 ml of 2 (hydrochloric acid ethanol) and the solution was stirred overnight at room temperature. 11.0 g of crude product (m.p. 161 ° C) were added.

-111

185 00!

we separate it. Recrystallization from ethanol gave a colorless microcrystalline material, m.p. 162 ° C.

Analysis CJ2 ^H 20 ^N 4 O 3 ^{S HC1} Pl ^{Sa et} tab 5 Calculated: C 42.8%, H 6.2%, N 16.6%. Found: C, 42.6; H, 6.3; N, 16.4.

Example 14 (a) N- (2- / 5-Methylaminomethyl-2-phenylmethylthio / ethyl) -10.

-N'-methyl-2-nitro-1,1-ethenediamine ¹

A mixture of 0.9 g of 2- (5-methylaminomethyl-2-furylmethylthio) -ethylamine and N-methyl-1-methylthio-2-nitroethylamine was heated at 100-120 ° C for 30 minutes. on vacuum produced by a water jet pump. The residue was purified by column chromatography (silica gel, methanol / 0.88 ammonia). 0.65 g of N- (2- / 5-methylaminomethyl-2-furylmethylthioethyl) -N-methyl-2-nitro-1,1-ethenediamine is obtained, which is recrystallized from acetonitrile, m.p.

106-108 ° C.

The following materials were prepared in a similar manner:

(b) N - (2- (5- (1'-Methyl-ethyl-aminomethyl-2-furylmethyl-thio) -20-ethyl) -N'-methyl-2-nitro-1,1- ethenediamine

Analysis for Cj ^ H ^^ N ^ O ^ S. J_. From the formula:

Found: C, 49.83; H, 7.47; N, 16.60; Found: C, 49.75; H, 7.21; N, 16.36. ₂₅ (c) N-Methyl-2 -nitro-N '- (2- (5- (2-phenylethyl) aminomethyl-2-furylmethylthio) ethyl) -1,1-ethenediamine.

Analysis for C ^ H ^ N ^ qSS. H, 6.81; N, 14.02. Found: C, 57.19; H, 6.53; N, 13.83. (D) N-Methyl-2-nitro- (2- (5- (1-piperidinyl) -methyl-2-furylmethyl-thio) -ethyl) -1,1-ethenediamine.

Calcd for C ₆ H ₂₆ N ₄ O ₃ S .111% O:

H, 7.44; N, 15.61. Found: C, 53.36; H, 7.51; N, 14.23. 35 (e) N- (2- (5-, 2-Dimethylamino-ethyl-2-furylmethylthio) -ethyl) -N'-methyl-2-nitro-1,1-ethenediamine, m.p. : 95.5-96 ° C.

(f) N- (2- (5- (3-Dimethylamino) -propyl-2-furylmethylthio) ethyl) -N'-methyl-2-nitro-1,1-ethenediamine. .MMR spectrum (deuterochloroform)

8.1-7.1 (multiplet, 6H), 7.65 (singlet, 6H),

7.1 (singlet, 3H), 6.5 (multiplet, 2H), 6.28 (singlet, 2H), 4.0 (multiplet, 2H), 3.38 (singlet, 1H).

(g) N - (2- (5- / 4-Dimethylamino-butyl-2-furylmethylthio) -45

-ethyl) - N'methyl-2-nitro-1,1-ethenediamine, waxy substance

Analysis using the formula C, _A H _{? R} NO, S:

H, 7.92; N, 15.72. Found: C, 53.90; H, 7.95; N, 15.64; (5-Ethylmethylaminomethyl-2-furylmethylthio) -50

ethyl) -N-methyl-2-nitrobenzenebutanamine-l, l-ethenediamine.

MMR Spectrum: (deuterochloroform)

8.90 (triplet, 3H), 7.76 (singlet, 3H), 6.87.5 (multiplet, 7H), 6.5 (broad, 2H), 6.42 (singlet, 2H), 6.25 (singlet, 2H) ), 3.77 (singlet, -ς 2H), 3.35 (singlet, 1H). ⁰⁰ (i) N- (2- (5- (2-Dimethylamino) ethylaminomethyl-2-furylmethylthio) ethyl) -N'-methyl-2-nitro-1,1-ethene diamine

MMR Spectrum: (deuterochloroform)

7.79 (singlet, 6H), 7-7.6 (multiplet, 10H),

6.6 (multiplet, 2H), 6.26 (singlet, 2H), 6.22gQ (singlet, 2H), 3.85 (multiplet, 2H), 3.37 (singlet, 1H), 2-3 (wide, ΙΗ), 0.8-O, 2 (wide,

(5-Dimethylaminomethyl-2-furylmethoxy) -ethyl) -N'-methyl-2-nitro-1,1-ethenediamine, m.p. 110-112 ° C.

Example 15

N- (2- / 5-Dimethylaminomethyl-2-furylmethylthio / ethyl) -N'-methyl-2-nitro-1,1-ethenediamine

Mixed with 230 g of N-methyl-l-methylthio-2-nitro-ethene-amint400 ml of water at 45-50 ° C dropwise over 4 hours 321 g of 2, ^5-dimethyl-l amjno-methyl-2-furyl methylthio-ethylamine and then the reaction mixture is further stirred

Stir for 3.5 hours. The solution was then heated for 5 hours at 0 to reflux, then cooled to 70 ^ö C., and 2 liters of 4-methyl-pentan-2-one were added. The water was removed by azeotropic distillation under reduced pressure (260 mm Hg), the resulting solution was treated with 10 g of activated carbon at 50 ° C, filtered and cooled to 10 ° C. The precipitated product is filtered off and dried. 380 g of N- (2- (5-dimethylaminomethyl-2-furylmethylthio) ethyl) -N'-methyl-2-nitro-1,1-ethenediamine are obtained, m.p. 69-70 ° C.

Example 16

N-Methyl-2-nitro-N '~ (2- (5- / l-pyrrolidinyl / -methyl-2-furyl-methylthio) ethyl) -l, l-ethenediamine

2.1 g of 2- (5- (1-pyrrolidino) -methyl-2-furylmethylthio) ethylamine bis-oxalate salt, 1.12 g of potassium hydroxide, 0.9 g of N-methyl-1- -methylthio / -2-nitroethylamine and 9 ml vfz were stirred for 18 hours at room temperature. The water was evaporated under reduced pressure and the residue was extracted with ethyl acetate in the presence of excess anhydrous sodium carbonate. The solvent was evaporated and the residue was recrystallized from acetic acid isopropyl ester. 0.9 g of the title compound is obtained in the form of white crystals, m.p. 79-82 ° C.

Calcd for C, 'H, _{4 N4} O, S salt. Found: C52) 92%, H 7.11%, N 16.46% Found: C 52.78%, H 7.05%, N, 16.57%.

Example 17

N- (2- / 5-Methylamino-methyl-2-furyl-methylthio / ethyl) -N'-methyl-urea

To a solution of 2.0 g of N- (2-mercaptoethyl) -N, methyl-urea in concentrated hydrochloric acid was added dropwise, with stirring at 0 ° C, 2.0 g of 5- (methylaminomethyl) -2- furyl methanol in 3 ml water. After 24 hours, 100 mL of ethyl acetate and an excess of anhydrous sodium carbonate were added. The suspension is filtered, the filtrate is evaporated to dryness and the oily residue is subjected to column chromatography (silica gel, methanol: 0.88 ammonia 79: 1). The eluate is evaporated to dryness. The residual oil (0.42 g) was the same as that obtained in Example 4.

Example 18

N-Cyano-N '- (2- / 5-dimethylaminomethyl-2-furyl'-methylthio-thio-ethyl) -N' -methyl-guanidine g N-cyano-N '- / 2-mercapto- To a solution of ethyl N-methyl guanidine in concentrated hydrochloric acid was added dropwise 0.98 g of 5- (dimethylamino) -2-furylmethanol under stirring at 0 ° C for 10 minutes. After 3 hours, neutralize the solution at room temperature12

It is extracted with excess sodium carbonate and the resulting solid is extracted with ethyl acetate. The solvent was evaporated and the residual oil was subjected to column chromatography. The title compound is obtained which is identical to the product of Example 10.

Example 19

N- (2- / 5-Aminomethyl-2-furyl-methyl-thio-ethyl) -N '-cyano-methyl-guanidine,

2- (5-Chloromethyl-2-furylmethyl) -1H-isoindole-1,3,2H-dione g 2- / 5-hydroxymethyl-2-furylmethyl / -1H-isoindole-1 The 3 [2H] -dione was dissolved in 15 ml of thionyl chloride with gentle heating. The solution was evaporated to dryness and the resulting solid was re-evaporated after addition of a 1: 1 mixture of cyclohexane and benzene. The residue is suspended in ether, the suspension is filtered, washed with ether and dried. 10.1 g of 2- (5-chloromethyl-2-furylmethyl) -1H-isoindole-1,3 (2H) -dione are obtained, m.p. 119-122 ° C (with decomposition).

Analysis using the formula C, ₄ H. _n C10 ₄ :

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-furyl-methylthio) ethyl) -N'-methyl guanidine

To a 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 is slowly added 1.74 g of 2- / 5-chloro. -methyl-2-furylmethyl-1 H -isolide-1,3-2 H-dione in 8 ml of dry dimethylformamide. After stirring for 2 hours, the solution was evaporated to dryness and the oily residue was suspended in a mixture of 25 ml of ethyl acetate and 20 ml of water. The solid residue was filtered and recrystallized from methanol. 1.4 g of the title compound are obtained, m.p. 179-182 ° C.

N- {2- / 5-Amino-methyl-2-furyl-methylthio / ethyl) -N '-ciaro-N'-methyl guanidine

4.5 g N '-cyano-N- (2- (5- (1,3-dioxo-2H-isoindol-2-yl) methyl-2-furylmethylthio) ethyl) -N'-methyl -guanidine and 0.6 g of hydrazine hydrate in 35 ml of methanol are refluxed for 4 hours. The suspension is evaporated to dryness, the residue is dissolved in 15 ml of water at 0 ° C and neutralized with 5N hydrochloric acid. The suspension is filtered, anhydrous sodium carbonate is added and the solution is evaporated to dryness. The residue was mixed with anhydrous sodium sulfate and the solid was extracted with ethanol. Evaporation of the extract gave a semi-solid which was mixed with anhydrous sodium sulfate and extracted with ethyl acetate. 2.12 g of an oil are obtained which is subjected to column chromatography (silica gel, methanol and 0.88 g of ammonia 79: 1). Evaporation of the eluate gave an oil which slowly solidified to give 1.88 g of the title compound, m.p. 8082 ° C.

H, 6.66; N, 25.93. Found: C, 49.57; H, 6.66; N, 25.93.

Example 20

N- (2- / 5-Di-methylaminomethyl-2-furylmethylthioethyl) · -N'-methyl-2-nitro-1,1-ethenediamine 2-Nitroethane- thiazolidinedione

A mixture of 11.36 g of cysteamine hydrochloride, 5.61 g of potassium hydroxide, 16.52 g of 1,1-bis (methylthio / -2-nitroethylene), 30 ml of water and 100 ml of ethanol is refluxed for 1 hour. suspension was evaporated to dryness, the residue suspended in water, filtered, and the residue was crystallized from methanol ^, 9.2 g of 2-nitro-ethene-thiazolidine, m.p. 141 -142 C. Analysis calculated ^Ö ^ CjtLN CUS formula:. CH 4, N, 19.17%. Found: C, 32.91%; H, 4.13%; N, 19.10%.

A solution of N- (2-mercaptoethyl) -N'-methyl-2-nitro-1,1-ethenediamine g-2-nitroethylenethlazolidine-40 ml in 33% methanolic ethanol was heated for 65 hours. at room temperature. The separated solid was filtered, washed with ethanol and dried. 4.98 g of N-2 / mercaptoethyl / -N'-methyl-2-nitro-1,1'-ethenediamine are obtained, m.p. 174-175 ° C, dec. 209-211 ° C. Analysis based on the formula:

Found: C, 33.88; H, 6.26; N, 23.71; Found: C, 34.05; H, 5.87; N, 23.85.

N- (2- (5-Di-methylanaminomethyl-2-furylmethylthio) ethyl) -N'-methyl-2-nitro-1,1-ethenediamine in 0.354 g of N- 2-Mercaptoethyl-N'-methyl-2-nitro-1,1-ethenediamine was added dropwise at 0 ° C to 0.428 g of 5- (dimethylamino) -methyl-2-furylmethanol. The reaction mixture was allowed to stand at 0 ° C for 7 days, diluted with water (3 ml), excess potassium carbonate was added and the solid was extracted with ethyl acetate (50 ml). The solvent was evaporated and the residue was purified by preparative thin layer chromatography. 0.1 g of the title compound is obtained which is identical to the product of Example 15.

Example 21

N- (2- / 5-Dimethylaminomethyl-2-furylmethylthio / ethyl) -N'-methyl-2-nitro-1,1-ethenediamine

N, N-dimethyl-2-furylmethylamine (0.125 g) was dissolved in glacial acetic acid (1 ml) and paraformaldehyde (0.03 g) was added. A solution of 0.354 g of N- (2-mercaptoethyl) -N, methyl-2-nitro-1,1-ethenediamine in 1 ml of concentrated hydrochloric acid and 1 ml of glacial acetic acid was added dropwise and the reaction mixture was allowed to stand for 5 days at room temperature. . The solution was then diluted with water (30 mL), saturated with potassium carbonate, and extracted with ethyl acetate. The combined extracts were purified by preparative thin layer chromatography. 0.089 g of the title compound is obtained which is identical to the product of Example 15.

Example 22

N-cyano-N '- (2- / 5-dimethylamino-methyl-2-furyl-methylthio / ethyl) -N' - methyl-guanidine

N-cyano-N '- (2-5-dimethyl-Amimed-methyl-2-furyl-methylthio / ethyl) isothiourea ester

2- (5-Dimethylaminomethyl-2-furylmethylthio) ethylamine (1.07 g) was added to a solution of N-cyanoimidocarbamodithioic acid dimethyl ester (0.73 g) in ether and the reaction mixture was stirred overnight. . The crystalline material formed is filtered off, washed with ether and dried. 1.14 g of N-cyano-N '- (- 5-dimethylaminomethyl-2-furylmethylthio / ethyl) isothiourea methyl ester are obtained, m.p. 78-79 ° C.

N-cyano-N '- {2- / 5-dimethylamino-methyl-2-furyl metlltio / ethyl) -N' - methyl-guanidine

-131

A solution of 1.05 g of N-cyano-N- (2- / 5-dimethylaminomethyl-2-furyl-ethylthio-ethyl) -isothioureamethyl ester in 10 ml of 33% ethanol in methylamine was stirred at room temperature for 4 hours. The solution was evaporated to dryness and the oily residue was recrystallized from a mixture of ethyl acetate and light boiling point 80100v. The title compound is obtained, m.p. 77-80 ° C.

Example 23 '

N-cyano-N '- (2- / 5-dimethylamino-methyl-2-furyl-methylthio / ethyl) -N' - heptyl guanldin

A mixture of 1.15 g of heptylamine and 3.12 g of N-cyano-N '- (2- (5-dimethylaminomethyl-2-furylmethylthio) ethyl) isothiourea was heated at 100 ° C for 12 hours in an oil bath. The product is chromatographed (silica gel, methanol) to give 2.31 g of N-cyano-N '- (2- (5-dimethylaminomethyl-2-furylmethyl) ethyl) -N', _> ptil guanidine hydrate, Rf = 0.49.

Analysis for CjqHj^N NO OS. H ₂ O:

Calculated: C, 57.43; H, 8.81; N, 17.63; Found: C, 56.99; H, 8.32; Ν 17.53.

Example 24

N- (2- / 5-Dimethylaminomethyl-2-furylmethylthio / ethyl) -N'-methyl-2-nitro-1,1-ethenediamine

4.25 g of 2- (5-dimethylaminomethyl-2-furylmethylthio) ethylamine, 3.3 g of 1,1-bis (methylthio) -2-nitroethene and 50 ml of acetonitrile the mixture was refluxed for 14 hours. The solvent was evaporated and the residue was dissolved in 50 ml of a 3% methanolic methanol solution and the reaction mixture was refluxed for 8 hours. The solvent was evaporated and the residue dissolved in methanol was clarified with activated carbon. The suspension was filtered and the filtrate was evaporated to give 5.0 g of the title compound, which was identical to the product of Example 15.

Example 25 (a) N- (2- (5-Dimethylaminomethyl-2-furylmethylthio) ethyl) -N '- (2-methoxyethyl) -2-nitro-1,1-ethene diamine

A mixture of 2.14 g of 2- (5-dimethylaminomethyl-2-furylmethylthio) ethylamine, 1.65 g of 1,1-bis (methylthio) -2-nitroethylene and acetonitrile was stirred for 8 hours. bring to the boil under reflux. The solvent was evaporated and a solution of 0.75 g of 2-methoxyethylamine in ethanol was added to the residue. The mixture was refluxed for a further 8 hours and then the solvent was evaporated. The residual oil was purified by column chromatography. 1.0 g of N- (2- (5-dimethylaminomethyl-2-furylmethylthio) ethyl) -N '- (2-methoxyethyl) -2-nltro-1,1-ethenediamine we get.

MMR Spectrum: (deuterochloroform)

7.73 (singlet, 6H), 7-7.5 (multiplet, 2H),

6.2 - 7 (multiplet, 81H); 6.23 (singlet, 2H),

3.81 (singlet, 2H), 3.42 (singlet, 1H).

In a similar manner, the following compound was prepared:

(b) N - (2- / 5-Dimethyl-amino-methyl-2-furylmethylthio / ethyl) -2-nitro-1,1-ethenediamine, m.p. 100-101 ° C.

Example 26 (a) N- (4- (5-Dimethylaminomethyl-2-tert-butyl) -N'-methyl-2-nitro-1,1-ethenediamine

A mixture of 0.7 g of 4- (5-dimethylaminomethyl-2-furyl-butyl) -amine, 0.6 g of 1,1'-bis (thiomethyl) -2-nitroethylene and 12 ml of acetonitrile was added. reflux for an hour. The solvent was evaporated, 33% methanolic ethanol in ethanol was added and the mixture was refluxed for 2 hours. The solvent was evaporated and the residue was purified by column chromatography (silica gel, methanol). 0.31 g of N- (4- (5-dimethylaminomethyl-2-furyl-butyl) -N'-methyl-2-nitro-1,1-ethenediamine are obtained.

Analysis a. According to the formula H1 ₂ O:

H, 8.22; N, 18.42. Found: C, 55.54; H, 8.23; N, 17.75.

In a similar manner, the following compounds were prepared:

(b) N- (5- / 5-Dimethylaminomethyl-2-furyl / pentyl) -N'-methyl-2-nitro-1,1-ethenediamine.

Calcd for C ₁₅ H ₂₆ N ₄ O ₃ H ₂ O ._1 formula:

H, 8.46; N, 17.55. Found: C, 56.76; H, 8.36; N, 17.37.

(c) N- (3- / 5-Dimethylaminomethyl-2-furylthio-propyl) -N'-methyl-2-nitro-1,1-ethenediamine.

Analysis by Cj:

Found: C, 49.66; H, 7.05; N, 17.84; Found: C, 49.36; H, 7.19; N, 17.45.

(d) N- (3- / 5-Dimethylaminomethyl-2-furyl / propyl) -N'-methyl-2-nitro-1,1-ethenediamine.

Analysis based on the formula Cj 3 ^ 22 ^ 4 ^ 3:

Found: C, 55.31; H, 7.72; Found: C, 55.09; H, 7.84.

(e) N- (2- / 5-Diethylaminomethyl-1-furylmethylthio / ethyl) -N'-methyl-2-nitro-1,1-ethenediamine.

Analysis using the formula J_H ₂ O:

H, 7.74; N, 15.94. Found: C, 51.38; H, 7.44; N, 15.66.

(f) N- (3- / 5-Dimethylaminomethyl-2-funl-methylthio-propyl) -N'-methyl-2-nitro-1,1-ethenediamine.

Analysis by the formula S. 1 H ₂ O:

H, 7.47; Ν 16.61. Found: C, 49.57; H, 7.20; N, 15.59.

Example 27 (a) N-Cyano-N '- (4- / 5-dimethylaminomethyl-2-furyl-butyl) -N' -methyl-guanidine

A mixture of 0.4 g of 4- (5-dinethylaminomethyl) -2-furyl-butylamine, 0.3 g of N-cyanoimidothiothiourothiourea dimethyl ester and ethanol was stirred for 3 hours at room temperature. A 33% solution of methamine in ethanol was added and the reaction mixture was refluxed for 2 hours. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (silica gel, methanol). The title compound was obtained as a pale yellow oil.

MMR Spectrum: (deuterochloroform)

8-8.5 (broad, 4H), 7.77 (singlet, 6H), 6.61 -

7.5 (9H), 4.0 (multiplet, 2H), 2.8-3.7 (multiplet, 2H).

In a similar manner, the following compound was prepared:

(b) N-Cyano-N '- (5- [5-dimethylaminomethyl-2-furyl] -pentyl) -N'-methyl-guanidine.

MMR spectrum (deuterochloroform)

8.0-8.7 (broad, 6H), 7.68 (singlet, 6H), 7.32 (triplet, 2H), 7.10 (doublet, 3H), 6.7 (quartet,

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Example 28 (a) N <2- (5-Dimethylaminomethyl-2-furylmethylthio) -ethyl) -N * -ethanesulfonyl-N '-methyl-guanidine

A mixture of 1.9 g of methanesulfonyl iminodithiocarbamic acid dimethyl ester, 2.14 g of 2- (5-dimethylaminomethyl-2-furylmethylthio) -ethylamine and ethanol is stirred for 3 hours at room temperature. 20 ml of a 33% solution of methylamine in ethanol are added and the reaction mixture is refluxed for 16 hours. The product was purified by column chromatography (silica gel, methanol). 2.7 g of N- (2- (5-dimethylaminomethyl-2-furylmethylthio) -ethyl-N'-methanesulfonyl-N '-methyl-guanidine are obtained in the form of a pale yellow oil.

Analysis using the formula Cj 3 ^ 24 ^ 4θ3 ^ 2 '~ ^ 2θ:

H, 7.00; N, 15.69. Found: C, 43.54; H, 7.05; N, 25.48.

(b) N-Benzoylsulfonyl-N '- (2- / 5-dimethylaminomethyl-2-ylmethylthio / ethyl) -N' -methyl-guanidine

Analysis for Cjgk ^ N ^ O ^ S. Hj O formula:

Calculated: C 50.47%, H 6.54%, N 13.08%. Found: C 50.30%, H 6.25%, N 12.93%.

Example 29

N-Cyano-N '- (2- (5-dimethylaminomethyl-2-furylmethylthio) -ethyl) -N' -methyl-guanidine

A solution of 8.25 g of silver nitrate in 50 ml of dimethylformamide is added dropwise to 6.1 g of N-cyano-N'-methylisothiourea methyl ester, 4.8 g of triethylamine, 7.8 g of 2- (2-furylmethylthio) -ethyl- amine and 150 ml of methanol. After 42 hours at 50 ° C, the reaction mixture was filtered and the filtrate was evaporated. The residue was partitioned between ethyl acetate and water. The organic layers were combined, dried and evaporated. The residual oil gave 3.9 g of crystalline N-cyano-N '- (2- (2-furylmethylthio) -ethyl) -N', methylguanidine, m.p. 78-82 ° C.

A mixture of 4.5 g of the above amine, 3.1 g of dimethylamine hydrochloride, 3.16 g of 36% aqueous formaldehyde and 20 ml of ethanol is heated at 50 ° C for 60 hours. The residue was partitioned between ethyl acetate and aqueous base. The organic extracts were combined, dried and concentrated, and the residual oil was treated with sebacic acid dissolved in isopropanol. 2 g of product are obtained, which is the sebacic acid salt of the title compound, m.p. 93-94 ° C.

Example 30

N- (2- / 5-dimethylamino-methyl-2-furyl-methylthio / ethyl) -N'-methyl-thiourea

Carbon disulfide (1.52 g) was added with stirring to a cooled solution of sodium hydroxide (0.8 g) in water (1.7 mL). 4.28 g of 2- (5-dimethylaminomethyl-2-furylmethylthio) -ethylamine (4.28 g) are then added slowly and the reaction mixture is heated at 100 ° C for 2 hours, then at 40 ° C. After cooling to a temperature below 1.94 ml of ethyl chloroformate, the mixture was stirred for an additional 30 minutes. The dense yellow oil below was extracted with chloroform, dried and evaporated. N, N-dimethyl-5- / 2-isothiocyanatoethylthiomethylfurylmethylamine was obtained as an oil, Rf =

0.43 (silica gel, methanol).

0.46 g of crude isothiodanate is dissolved in 25 ml of a 33% solution of methylamine in ethanol and allowed to stand overnight. 0.16 g of N <2- [5-dimethylaminomethyl-2-furylmethylthio] -ethyl) -N'-methylthiourea is obtained, which is identical to 2- [5-dimethylaminomethyl-2 product of furfurylmethylthioethylamine and methyl isothiodanate.

Example 31

N-cyano-N '- (2- / 5-dimethylamino-methyl-2-furyl-methylthio / ethyl) -N' - methyl-guanidine

A solution of 1.3 g of N- (2- (5-dimethylaminomethyl-2-furylmethylthio) ethyl) -N'-methylthiourea is refluxed with 1.5 g of lead cyanide. The solution was filtered, the filtrate evaporated and the residue treated with a solution of sebacic acid in isopropyl alcohol to give 0.7 g of the product, the sebacic acid salt of the title compound, m.p. 90-92 ° C.

Example 32

N- (2- (5-Dimethylaminomethyl-2-furylmethylthio) ethyl) -N, methyl-2-nitro-1,1-ethenediamine hydrochloride g (0.16 mol) N - (2- (5-Dimethylaminomethyl-2-furylmethylthio) -ethyl) -N'-methyl-2-nitro-1,1-ethenediamine is dissolved in 200 ml of industrial methyl alcohol-denatured alcohol. , Containing 16 equivalents of hydrochloric acid. Ethyl acetate (200 mL) was added slowly, the crystallized hydrochloride was filtered, washed with a mixture of denatured alcohol (50 mL) and ethyl acetate (50 mL) and dried at 50 ° C. 50 g of the title compound are obtained in the form of an off-white solid, m.p. 133-134 ° C.

Example 33

Pharmaceutical preparations (a) Oral tablets (50 gm)

Components for making 10,000 tablets: Active ingredient 500 g

Anhydrous lactose (US

State Pharmacopoeia Quality) 2.17 kg Sta-Rx 1500 Starch (directly compressed starch, manufactured by Staley Mfg.Co.Ltd.) 300 g magnesium stearate (British Pharmacopoeia quality) 30 g

The drug was sieved through a 250 micrometer sieve and the four powdered materials were thoroughly mixed in a blender and tabletted between 8.5 mm diameter die-forming tools.

(b) Injection for intravenous administration (200 mg of active ingredient in 2 ml solution)

Active ingredient 10% by weight

Water for injection.

(British Pharmacopoeia quality) up to 100% by weight

Dilute hydrochloric acid (British Pharmacopoeia quality) to pH = 5.

While stirring, the active ingredient is dissolved in water for injection and acid is added slowly until the pH is 5.0. The solution was treated with nitrogen and filtered through a 1.35 micrometer membrane filter. The solution was filled into a 2 ml glass ampoule (22 ml each) and the ampoules were soldered under a nitrogen atmosphere.

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Sterilize in a strain of 185,001 for 30 minutes.

fc) Oral prolonged-release tablet (150 mg)

Components for making 10,000 tablets Active ingredient 1.50 kg

Cutina HR (hydrogenated castor oil, manufactured by Sippon Products Ltd.) 0.40 kg

Anhydrous lactose (US

State Pharmacopoeia Quality) 2,060 kg

Magnesium stearate (British Pharmacopoeia quality 40 g

The active ingredient, most of the anhydrous lactose and most of Cutina HR are well mixed and the mixture is moistened by mixing with a 10% solution of the remaining Cutina HR in industrial denatured alcohol. The wetted mass is granulated through a 1.2 mm mesh screen and dried at 50 ° C in a fluidized bed dryer. The granules are then passed through a sieve having a mesh size of 0.85%, mixed with magnesium stearate and pressed to a hardness of at least 10 kg (Schleuniger tester) on a tableting machine with a diameter of 12.5 mm.

(d) Syrup for oral administration

Active ingredient 2% mixed

Diluted hydrochloric acid (British Pharmacopoeia grade), as required

Sorbitol solution (British Pharmacopoeia quality) 60% by volume

Flavoring, if necessary

Distilled water up to 100% w / v

The drug was dissolved in a small amount of water with gradual addition of hydrochloric acid while stirring to bring the pH to 5.0. The sorbitol solution, the flavoring and the remainder of the water are then added and the pH is again adjusted to 5.0. The syrup is clarified with a suitable cellulose filter.

(e) Oral capsule (50 mg)

Components for making 10,000 capsules Active ingredient 500 g

Sta-Rx 1500 starch 1700 g

Magnesium stearate (British Pharmacopoeia quality) 20 mg

The drug was sieved through a 250 micrometer sieve and mixed with the other powder components. The mixture is filled into size 3 hard gelatin capsules using a suitable filling machine.

(f) Ointment

Active ingredient 2.0% by weight

White soft paraffin (British Pharmacopoeia) up to 100% by weight

The drug was passed through a 150 micrometer sieve. and mix evenly with paraffin in a blender.

(g) Cream

Active ingredient 2.0% by weight

Cetomacrogol Emulsifying Ointment (British Pharmacopoeia) 20.0% by weight

Chlorcresol 0.1% by weight

Distilled water up to 100% by weight.

The drug is passed through a 150 micrometer sieve and thoroughly mixed with Cetomacrogol emulsifying ointment at 65 ° C. Chlorcresol is dissolved in water at 65 ° C and the resulting solution is mixed with the oily drug mixture. The resulting emulsion is continuously stirred under cooling until a cream is obtained.

In the above examples, a compound of the invention is used as the active ingredient. Preferably, the compounds of Examples 80 and 15 can also be used.

The compounds of formula I inhibit histamine-induced gastric acid secretion. This effect was investigated in rats by modification of the method of Ghosh and Schild (British Journal of Pharmacology, 13, 54 (1958)).

Female rats weighing approximately 150 g were fasted overnight and physiologically replaced with drinking water.

An 8% sucrose solution in saline was added to the animals.

Rats were anesthetized with 0.5 ml / 100 g of 25% w / v urethane solution; intraperitoneally, then a male was injected into the trachea and cervical veins.

The abdominal wall was incised in the middle, and the stomach was separated from the liver and spleen by a cut of connective tissue. A small opening was made in the fundus of the stomach and the stomach was washed with 5% dextrose solution. A rubber tube was inserted into the esophagus as a cannula, and the esophagus and the planetary nerves were cut above the cannula.

A small opening was then made at the stomach gate. A large plexiglass cannula was inserted through the opening in the stomach of the stomach, with the inlet portion of the cannula coming out through the stomach gate. The cannula was shaped to reduce the actual volume of the stomach and to provide turbulent flow of perfusion fluid over the mucosa. A drain cannula was then inserted through the opening in the fundus. Both cannulas were secured by banding them with vascular fonaoc lacquer around the stomach.-We designed a placement to avoid major blood vessels. We pierced the body wall and passed the cannulas through the openings thus formed. Perfusion was performed through the stomach through the cannulae in the esophagus and gastric gland with 5% dextrose40 at 39 ° C at 1.5 ml / min. The removed liquid was led to a flow-through micro pH electrode and the pH was recorded using a ρΗ meter and a writing device.

By measuring the pH of the effluent perfusion fluid, gastric gastric acid secretion was checked as a baseline value, and increased gastric acid secretion was generated by continuous intravenous infusion of sub-maximal dose histamine. This triggered a constant level of maximal fasting acid secretion, and the acidity of the perfusion fluid leaving was determined when this condition was reached.

The rat was then intravenously administered the test compound of the invention and the change in gastric acid secretion was monitored by measuring the pH of the effluent perfusion effluent.

The difference between the baseline value and the peak induced by histamine in the change in pH of the effluent perfusion fluid was calculated as the hydrogen ion concentration per mol / liter. The decrease in gastric acid secretion upon administration of the test compound was also expressed as the change in hydrogen ion concentration in mole / l as a function of the pH of the perfused effluent.

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Ságéból. From these two numerical values, the percentage reduction in gastric acid secretion induced by the test compound was calculated.

Inhibition of gastric acid secretion was determined by characterizing an ED <-q by administering the test compound to a single dose in a rat and repeating the assay with at least four rats using three or more doses. From the results obtained, the least squares method was used to calculate ED ^ ^. The following EDjQ values were obtained for the various compounds of formula (1):

2 (c) 1.5 8 0.65 9 (a) 2.30 10 1.39 14 (a) 0.23 H (0 0.8 14 (h) 0.48 15 0.18 25ía) 1.82 26 (a) 0.55

PATENT CLAIMS

Claims (15)

1. Proceeded; An aminoalkyl furan derivative of formula (I), and pharmaceutically acceptable acid addition salts thereof, for the preparation of ts hydrates, R1 and R2 are independently hydrogen, (C1-C4) alkyl, phenyl (C1-C4) -alkyl, or (C1-C4) -alkyl containing a group of the carbon atoms wherein R , represents a hydrogen atom or a C 14 alkyl group, or R 1 and R ¹ together with the adjacent nitrogen atom ¹ are ² 5-6 membered heterocyclic groups which may additionally contain oxygen and / or -Nf R 1 j where R 1 is hydrogen, C 14 alkyl, 3-6 C alk alk alkalkenyl or C 14 14 alkalkoxy (C 14 14)) alkyl, X is methylene, oxygen or sulfur, Y is oxygen or sulfur, or a group of the formula = NR 1 or = CHR 4, Alk is a C 1-6 straight or branched alkylene group, Rr is hydrogen, nitro, cyano, C14 alkyl, C14 alkylsulfonyl or benzenesulfonyl, R 1 is a nitro group, m ⁰ is an integer between 24, n is 1 or 2, or when X is a sulfur atom or a methylene group, n is 0, 1 or 2, characterized in that (a) a compound of the formula wherein R1, R2, Alk, η, X and m are as defined in the foregoing, with an alkali metal cyanate, thiocyanate; or an isocyanate of the formula R 1 -NCO or an isothiocyanate of the formula R 1 NCS, or a compound of the general formula (2) or (3), wherein R 1, R 1 and R 9 are as defined herein, and Is a leaving group, reacting or (b) to form a compound of formula (I) wherein Y is = NR 1 or = CHR 9, wherein R p R _2> R j, R j, R g.X, Alk m and n are A compound of formula (III) wherein R 1, R ₂ , Alk, X, n and m are as defined above, O is a group of the formula = NR 1 or = CHR 4 wherein R 1 and R 9 are as defined above. , P is an interchangeable group, with a primary amine of the formula RjNik, wherein Rj is as defined above, or (c) to form a compound of formula I wherein X is a sulfur atom, wherein n is 1, R1, R6, Rj, Alk, Y and m are as defined herein, but when R 1 and R 6 are simultaneously hydrogen, Y is other than = CHNO 3, a compound of Formula (V) or (VI) ² wherein R 1, R 1, and Alk are above, R? is hydrogen or acyl, and when R1 and Rj are simultaneously hydrogen, the amino group may be protected with a thiol of formula VII wherein Y, Rj and m are as defined above, and optionally deprotecting, or (d) preparing a compound of formula (I) wherein Y is = NCN, wherein R 1, R 1, R 1, X, Alk, m and n are as defined in the foregoing. a compound of Formula I wherein R 1, R 1, R 1, Alk, X, m and n are as defined above, with a heavy metal cyanamide; or (e) Y is = NR 1 and Alk is for the preparation of a compound of formula (I) containing a methylene group or a branched alkylene group, wherein R 1, R 1, R 1, X, R 1, n and m are as defined above for a compound of formula (VIII) wherein X, R 1, R 1, n and m are as defined above, with an aldehyde and a secondary amine or an acid addition salt of a primary or secondary amine, or (0 for the preparation of a compound of formula I wherein Y is a sulfur atom, wherein R 1, R 1, R 1, X, Alk, n and m are as defined in the foregoing, a compound of formula (IV) wherein R 1, R 1 _? , Alk, X, n and m are as defined above, reacting an amine of formula R 1 NH 2 where R 1 is as defined above, optionally converting the resultant product to a pharmaceutically acceptable acid addition salt or converting a resulting acid addition salt to another salt. (Priority: August 3, 1977) The process of claim 1 (a), wherein the compound of formula (I) is an alkali metal cyanate or an alkali metal thiocyanate, and a R 2 -NCO, R 3 CN and a compound of formula (2) or with a compound of formula (3) wherein R3, R1 and IC are as defined in the preamble of claim 1 and P is an exchangeable group. (Priority: August 4, 1976) 3. A process for the preparation of compounds of formula I and pharmaceutically acceptable salts and hydrates thereof, wherein: R 1 and R 3 are the same or different hydrogen atoms, C 14 alkyl, C 14 alkyl interrupted by a -N (R 4) - group, wherein R ₄ is a -171 185,001 rogens or C 14 alkyl groups, R 1 and R 6 together with the adjacent nitrogen atom represent a 5-6 membered heterocyclic ring which may further comprise an oxygen atom or a -N (R 1) - group, where R is as defined above, R 1 is C 14 alkyl, X is oxygen or sulfur, Y is sulfur or oxygen, and = NRj or = CHR ^ Alk is a straight or branched C 1 -C 6 alkylene group, is hydrogen, nitro, cyano, C 14 alkyl, R 1 is nitro, m is 24, n is 1, and 11 is taken to mean a) reacting a compound of formula II wherein R 1, R a, R a, Alk, X, m and n are as defined above, with a compound of the formula K 1 CO, R 3 CN and a compound of the formula ^-5 (2) or (3) Wherein R 1, R 5, and R 8 are as defined above, or b) for the preparation of compounds of formula I wherein X is sulfur, when R 1 and R 1 are hydrogen, Y is other than CHNO 3, a compound of formula V or VI, wherein R 1 , R, and Alk are as defined above, and R? is a hydrogen atom or an acyl group which, when R 1 and R ₂ are hydrogen, may be protected with a protecting group by reaction with a thio compound of formula VII, optionally deprotecting the resulting compound and optionally converting the resulting compounds to a pharmaceutically acceptable salt over. (Priority: August 4, 1976) The process of claim 3 (a), wherein a compound of formula II wherein R 1, R a, Alk, X, m and n are as defined in claim 3 is a compound of formula (II). With an isocyanate of the formula R, NCO or an isothiocyanate of the formula RjNCS, wherein R is as defined in claim 3, or with a compound of formula (2) or (3), wherein Rj, Rj and Rg are as defined in claim 3 and P is an interchangeable group. (Priority: August 4, 1976) 5. A process for the preparation of compounds of formula I and pharmaceutically acceptable salts thereof, wherein: R and R ₂ are C 14 alkyl, Alk is CH ₂ , R 1 is CH, X is sulfur, n is 1, m is 2, Y is = CHNO ₂ , characterized in that a) a compound of Formula II wherein R 1, R 1, Alk, X, n and m are as defined above, or a compound of Formula 3 wherein R 2 is NO-, the group P is a peelable group - you are responding B) reacting a compound of formula (III) wherein R 1, R 1, Alk, X, n and m are as defined above and O is CHNO ₂ ; to a suitable salt. (Priority: 1976. 'Θ December 6) 6. Process for carrying out process b) according to claim 5 according to N - (2- (5- (dimethylamino) methyl-2-furylmethylthio) ethyl) -N-methyl-2-nitro-1 For the preparation of 1-ethylenediamine, characterized in that 2 - ((5 - (dimethyl-ylamino) -methyl-2-furyl) methylthio) ethylamine 1,1-bis / methylthio 2-nitroethene and the resulting product is treated with methylamine. (Priority: December 6, 1976) 7. The process of claim 5 a) N-2- [5- (dimethylamino) -methyl-2-furylmethylthio) 20-ethyl] -N'-methyl-2-nitro-1,1 for the preparation of ethylenediamine, characterized in that N-methyl-1- (methylthio) -2-nitroethyleneamine is 2- (5-dimethylamino-methyl-2-furyl) methylthio. ) with ethylamine. (Priority: December 6, 1976) A method of carrying out process b) according to claim 3 25 for the preparation of N-2- (5-dimethylamino-methyl-2-furylmethylthio) ethyl-N'-methyl-2-nitro-1,1-ethylenediamine, characterized in that N- (2-Mercaptoethyl) -N'-methyl-2-nitro-1,1-ethylenediamine is reacted with 5- (dimethylamino) -methyl-2-furylmethanol. (Priority: 1976. __ August 4) A variant of claim 3, variant b), which is N- (2- (5-dimethylamino-methyl-2-furylmethylthio) -ethyl) -N'-methyl-2-nitro-1,1- for the preparation of ethylenediamine, by the addition of N, N-dimethyl-2-furylmethanamine with paraformaldehyde and N- (235-mercaptoethyl) -N'-methyl-2-nitro-1, Reaction with 1-ethylenediamine. (Priority: August 4, 1976) 10. The process according to claim 1, wherein N- (2- (5- (dimethylamino) methyl-2-furylmethylthio) ethyl) -N'-methyl-2-nitro-1,1-ethylene is used. diamine hydrochloride. RID, wherein N- (240- (5- (5-dimethylanthino) methyl-2-furylmethylthio) ethyl) -N 'is prepared. reacting methyl-2-nitro-1,1-ethylenediamine with hydrochloric acid. (Priority: August 3, 1977) 11. A process for the preparation of a compound of formula (XXVII) wherein: a) a compound of formula (XXVIII) with a compound of formula (3) 45 - wherein: R 1 is methyl, R ₆ is NO 2, P is a cleavable group - or b) reacting a compound of formula (XXIX) ελ wherein P is as defined above with methylamine ^ου and converting the resulting compound into a pharmaceutically acceptable salt if desired. (Priority: May 13, 1977) 12. A process for the preparation of a pharmaceutical composition, characterized in that a compound of formula (I) or a pharmaceutically acceptable acid addition salt or hydrate thereof according to claim 1, wherein the substituents have the same meanings as defined in claim 1, acceptable 60 liquid or solid carriers and / or other -181 185,001 by mixing with known pharmaceutical excipients and optionally other pharmacologically active compounds which do not exhibit synergistic activity with the compounds of formula I for oral, rectal or parenteral administration and topical administration. (Priority: August 3, 1977) 13. A process for the preparation of a pharmaceutical composition, wherein the compound of formula (I) or a pharmaceutically acceptable acid addition salt or hydrate thereof, as claimed in claim 3, wherein the substituents are as defined in claim 3. - with pharmaceutically acceptable liquid or solid excipients and / or other known pharmaceutical excipients and optionally without synergism with other compounds of formula (I), pharmacologically active compounds, by oral or parenteral administration. and converting it to a topical formulation. (Priority: August 4, 1976) 14. A process for the preparation of a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable acid addition salt or hydrate thereof according to claim 5, wherein the substituents have the meaning given by As defined in claim 5, no synergistic effect with pharmaceutically acceptable liquid or solid carriers and / or other known pharmaceutical excipients and optionally other pharmacologically active compounds can be demonstrated by oral or parenteral administration. and converting it to a topical formulation. (Priority: December 6, 1976) 15. A process for the preparation of a pharmaceutical composition comprising the step of forming an all. A compound of formula (XXVII) or a pharmaceutically acceptable salt thereof, prepared by the process of claim 1, wherein the substituents are as defined in claim 11, with pharmaceutically acceptable liquid or solid carriers and / or other known pharmaceutical excipients; By mixing with compounds of formula XXVII which are not synergistic, pharmacologically active compounds, they are formulated for oral or parenteral administration and topical administration. (Priority: May 13, 1977) 5 pieces of drawing Published by: National Office of Inventions Responsible publisher: Zoltán Himer o.v. CODE