SE454882B - PROCEDURE FOR THE PREPARATION OF AMINOAL COOLING RANGE DERIVATIVES WITH THERAPEUTIC EFFECT - Google Patents

Abstract

Novel aminoalkylfuran derivatives of the general formula I: in which the symbols have the meaning indicated in Claim 1, are prepared by reaction of a compound of the formula with a compound of the formula R3NZZ'. A, B, Z and Z' have the meaning indicated in Claim 1. The aminoalkylfuran derivative can be used in the form of the free base or in the form of a physiologically acceptable salt or a hydrate. These novel aminoalkylfuran derivatives exhibit inhibition of gastric acid secretion if they are stimulated via histamine H2 receptors.

Description

454 882 Y II (C fi2) nx (cnâmuucmmj (1) R1 \ N-Auc / ao Re and physiologically acceptable salts and hydrates thereof, wherein the symbols R1 and R2, which may be the same or different, each represent a hydrogen atom, a lower alkyl group, an aralkyl group or a lower alkyl group interrupted by a group -§-, where R4 represents an H4 hydrogen atom or a lower alkyl group, or where the symbols R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic ring, which may additionally contain a oxygen atom or a group -h-; where R 3 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or an alkoxyalkyl group; where X represents CH 2, O or S; where Y represents = S, = Y, = NR 5 or = CHR6; where Alk represents a straight or branched alkylene chain containing 1-6 carbon atoms; where R5 represents a hydrogen atom, a nitro group, a cyano group, a lower alkyl group, an alkylsulfonyl group or an arylsulfonyl group; where 'R6 represents a nitro group; denotes an integer from 2 to 4, and where n denotes kn 1 or 2, or where n represents 0, 1 or 2, when X represents S or CH 2; with the proviso that Y cannot represent the group CHNO 2 when R 1, R 2 and R 3 represent methyl, Alk represents methylene, X represents S, n represents 1 and m represents 2.

When the term "low" is used in connection with alkyl groups, these groups preferably contain 1-8 carbon atoms, and when the term is used in connection with alkenyl groups, these groups preferably contain 3-6 carbon atoms. By the term "aryl" is preferably meant phenyl or phenyl substituted with, for example, alkyl, alkoxy or halogen.

H 454 882 The new compounds of the formula I have the advantage that they are easy to prepare from readily available starting materials.

All of the compounds of formula I may exhibit tautomerism, and the formula is intended to cover all tautomers. When Alk represents a branched alkylene chain, optical isomers may be present, and the formula is intended to cover all diastereoisomers and optical enantiomers.

In a preferred class of compounds of formula I, the various symbols have the following meanings: The symbols R1 and R2 each represent a hydrogen atom, an alkyl group, a phenylalkyl group or a dialkylaminoalkyl group or together with the nitrogen atom they form a 5- or 6 led saturated heterocyclic ring such as morpholino, piperidino, pyrrolidino or N-alkylpiperazino; Alk denotes a straight alkylene chain containing 1-4 carbon atoms; Y represents an = S, = O, = CHNO 2 or = NR 5, where R 5 represents hydrogen, nitro, cyano, lower alkyl, alkylsulfonyl or benzenesulfonyl; and X, m, n and R 3 have the meanings given above.

In a particularly preferred class of compounds of formula I, the various symbols have the following meanings: The symbols R1 and R2 independently of one another denote a hydrogen atom, an alkyl group containing 1 to 3 carbon atoms or a phenethyl group or together with the nitrogen atom form a pyrrolidine ring; Alk denotes an alkylene chain containing 1-3 carbon atoms; Y represents = S, = CHNO 2 or = NR 5, where R 5 represents nitro, cyano, methylsulfonyl or benzenesulfonyl; R 3 represents a hydrogen atom, an alkyl group containing 1-3 carbon atoms, a propenyl group or an alkoxyalkyl group containing 3 carbon atoms; n + m is 3 or 4, and X has the meaning given above. In another preferred class of compounds of formula I, the various symbols have the following meanings: The symbols R1 and R2 independently of one another denote a hydrogen atom, an alkyl group containing 1 to 3 carbon atoms or a phenethyl group, or together with the nitrogen atom they form a pyrrolidine ring; Alk denotes an alkylene chain containing 1-3 carbon atoms; Y represents an = S, = CENO2 or = NR5, where R5 represents nitro, cyano, methylsulfonyl or benzenesulfonyl; X represents S or CH 2; R 3 represents a hydrogen atom, a methyl group or a methoxyethyl group PP; n denotes 1, and m denotes 2 or 3.

In another particularly preferred class of compounds of formula I, the various symbols have the following meanings: R 1 represents a hydrogen atom, a methyl group or an ethyl group; R 2 represents a methyl group or an ethyl group; Alk represents a methylene group Y represents an = NCN, = NNO2 or = CHNO2; R 3 represents S or CH 2; n represents 1 and m represents 2. represents a hydrogen atom or a methyl group; Specific examples of preferred compounds of formula I are given below: N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methylthiourea N '- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thioethyl] -N "-methylguanidine.

N-Cyano-N '- [2-I [[5- (methylamino) -methyl-2-furanylmethyl] -thio] ethyl] -N "-methylguanidine N- [2 - [[[5- (diethylamino) methyl- 2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine N- [2 - [[1- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] - -N '- (2-methoxyethyl) -2-nitro-1,1-ethenediamine N- [2 - [[1- (methylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl -2-nitro-1,1-ethylenediamine N- [3 - [[5- (dimethylamino) methyl-2-furanyl] thio] propyl] -N'- -methyl-2-nitro-1,1-ethylenediamine N- [2- [1- [5- (ethylmethylamino) methyl-2-furanyl] methyl] thio] -ethyl] -N'-methyl-2-nitro-1,1-ethenediamine N- [2 - [[[5- ( dimethylamino) methyl-2-furanyl] methyl] thioethyl] -N'-nitroguanidine N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methanesulfonyl- N "-methylguanidine N- [4- [5- (dimethylamino) methyl-2-furanyl] butyl} -N'-methyl-thiourea N-benzenesulfonyl-N '- [2 - [[[5- (dimethylamino)) methyl-2-furanylmethyl] thio] ethyl] -N "-methylguanidine N- [5- [5- (dimethylamino) methyl-2-furanyl] pentyl] -N'-methyl--2-nitro-1,1- ethanediamine and m »454 882 N-cyano-N '- [5- [5- (dimethylamino) methyl-2-fur anyl] pentyl] -N'-methylguanidine N- [4- [5- (dimethylamino) methyl-2-furanyl] butyl] -N'-methyl-2-nitro-1,1-ethenediamine N-cyano-N '- [4- [5- (dimethylamino) methyl-2-furanyl] butyl] -N "- -methylguanidine N- [2 - [[[5- [3- (dimethylamino) propyl] -2-furanyl] methyl] thio] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethanediamine N- [2 - [[[5 - [[2- (dimethylamino) ethyl] amino] methyl-2-furanyl ] - methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine.

The compounds of formula I form readily physiologically acceptable salts. Such salts may be salts with either inorganic or organic acids, such as hydrochlorides, hydrobromides or sulfates. Particularly useful salts of organic acids are formed with aliphatic mono- or dicarboxylic acids.

Examples of such salts are acetates, maleates and fumarates.

The compounds may also form hydrates. As stated above, the novel compounds also include N-oxides, when both R 1 and R 2 have a meaning other than hydrogen.

The compounds of formula I may be administered orally, topically or parenterally, or they may be administered in the form of suppositories. Preferably, oral administration is used.

The compounds can be used either in the form of base or in the form of physiologically acceptable salt. The compounds are usually mixed with pharmaceutically acceptable carriers or diluents to form pharmaceutical compositions.

The compounds of formula I may be administered in combination with other active substances, for example conventional antihistamines. For oral administration, the pharmaceutical compositions are suitably in the form of capsules or tablets, which may be long-acting tablets. The compositions may also be in the form of dragees or in the form of syrup. Examples of suitable compositions for topical administration are ointments, tinctures, creams, powders and sprays.

A suitable daily dose for oral administration is from 100 mg to 1.2 g per day, usually in the form of dosage units containing 20-200 mg of active compound per dosage unit. When using tablets with a long excretion time, administration is preferably done two or three times a day.

Parenteral administration can be by repeated injections or by continuous infusion. Injection solutions may contain from 10 to 100 mg of active ingredient per ml.

For topical application, you can use sprays, ointments, creams or tinctures. These compositions contain an effective amount of the active ingredient, for example of the order of 1.5-2% by weight, based on the total weight of the composition.

The compounds of formula I can be prepared according to the invention by a primary amine of formula I R 1, where R 1, R 2, X, n and m have the meanings given above, are reacted with a compound which can introduce the group -fi NHR 3, where R 3 and Y have the meanings given above. The amine of formula II can be used either as a free base or in the form of a salt with a weak acid, such as acetic acid Compounds which can introduce the group -% NHR 3 are isocyanates R3NCO, isothiocyanates R3NCS and Y compounds of formula R3NH% -P or RBNHÉ- P, where P represents NR 5 CHR 6 halogen, 3,5-dimethylpyrazolyl, methylthio or alkoxy, preferably methylthio The reaction with an isocyanate or isothiocyanate can take place by allowing the amine and the isocyanate or isothiocyanate to stand in a solvent such as acetonitrile.

The reaction with a compound of the formula R3NH% -P or R3NH fi-P NR5 CHR6 can take place by melting the reactants at elevated temperature, eg 100-120 ° C. Alternatively, the reaction between the amine of formula II and the compound of formula R3NH% fP can be carried out in NR5 in a solvent, eg acetonitrile, at elevated temperature and in the presence of silver nitrate. According to another alternative, the amine of formula II and a compound of the formula R3NH% -P is stirred in an aqueous solution at room CHR6 temperature. When R3 represents hydrogen, alkali metal cyanates and alkali metal thiocyanates are used. The introduction of the group -% NHR3 Y can also be done by first reacting the amine of formula II with a compound of the formula e \\ Cl / PP \\ ó / F || ll Cans _ NRS or where P has the meaning given above. This reaction can be carried out in a solvent, for example ether or acetonitrile, at a temperature between room temperature and the reflux temperature. When the resulting compound of the formula 1 \ N-Aik.il '1- (cnz) among) mNH fi- P (III) ~ o RQ \ where Q represents = NR5 or = CHR6, is treated with a primary amine with the formula R3NH2 at a temperature between ru temperature and reflux temperature, the desired end product is obtained.

According to an alternative method for the preparation of the compounds of formula I, wherein Y represents sulfur, the amine of formula II is heated with carbon disulfide and then reacted with one chloroformate ester, eg ethyl chloroformate, to give an isothiocyanate of formula R 1> N This isothiocyanate is then reacted with an amine R 3 NH 2, preferably in a solvent such as an alkanol, eg ethanol.

The compounds of formula I, where X represents sulfur and n represents 1, and where Y has a meaning other than = CHNO 2 when both R 1 and R represent hydrogen, can also be prepared starting from a compound of any of the following formulas: Wherein R7 represents a hydrogen atom or an acyl group, such as acetyl or p-nitrobenzyl. If O1 "| V1 H1 '\ i kan-L i cn2ci \ / 0 N-An: H20F7 \ / ° o (V) (VI) both R 1 and R 2 in the product represent hydrogen, these hydrogen atoms can be protected in a compound of formula V, for example in the form of a phthalimido group- The compound of formula V or the compound of formula VI is reacted with a thiol of the formula nsmnzrril Nncán When using a compound protecting group, using a compound of formula V, the reaction is preferably carried out at 0 DEG C. in concentrated hydrochloric acid. When using a compound of formula VI, the reaction is carried out at room temperature in an organic solvent, eg dimethylformamide.

The chloromethyl compound of formula VI can be prepared from the corresponding alcohol, for example using thionyl chloride or concentrated hydrochloric acid.

The compounds of formula I in which Y represents a group NCN can also be prepared by heating a compound of formula I in which Y represents sulfur together with a heavy metal cyanamide such as silver cyanamide, lead cyanamide, cadmium cyanamide or mercury cyanamide, preferably in an aqueous - containing solution.

The compounds of formula I, wherein Y represents = NR 5 and Alk represents a methylene group or branched alkylene chain, can also be prepared by subjecting a compound of formula I 10 Lo J. (cnzgnxwuahnnnlclmmj NR (VIII) 5 using a Mannich reaction using a the appropriate aldehyde and a secondary amine or a salt of a primary amine or a secondary amine. The group (CH3) 2NCH2- can be introduced, for example, using dimethylamine and formaldehyde. compound of formula VIII or by boiling the amine salt under reflux together with para-formaldehyde and a compound of formula VIII.

The primary amines of formula II used as starting materials are novel compounds which can be prepared according to a number of different methods, which are described below.

The amines of formula II, where X represents sulfur and n represents 1, can be prepared by furfurylthiol of formula 454 882 10 í || (Ix) is reacted with a w-bromoalkylphthalimide of the formula O / / Bz- (c1¶2) m 'NI \ (X) OI the resulting compound of the formula o 1 l in an s (cn ) (XI) [Q / r 2 zmw / Q _ O, the group N-Alk can be introduced by, for example, a Manních reaction.

R1 / Rz After removal of the protecting group by reaction with, for example, nydrazine hydrate, an amine of the formula II is obtained.

The amines of formula II, where X represents sulfur and n represents 1, can be prepared according to an alternative method using 2-furfuryl chloride as starting material. By reaction between furfuryl chloride and an m-aminoalkylthiol in which the amino group is protected, for example as a phthalimide of the formula o "P ~ (ÛH) Nß 2 m (XII) o 1, an intermediate of formula XI is obtained. This intermediate is treated in the same way as above to form an amine of formula II. The amines of formula II, where X represents sulfur and n represents 1, can also be prepared by a compound of \ N-Aik -Ü- en ou in 2 IOIR / The XIII () 2 formula under acidic conditions is treated with a one-aminoalkylthiol, in protected form, Alternatively, the compound of formula XIII may be converted to the corresponding acetate which the amino group is optionally before the reaction with α-aminoalkylthiol under basic conditions.

The primary amines of formula II (except those compounds where X represents sulfur and n represents 0) can be prepared by reacting the furan with butyllithium to give a lithium derivative of the formula flm \ O / (XIV). This lithium derivative is then first reacted with a a, w ~ dihalo compound of the formula Hal (CH2) nX (CH2) mHa1, where Hal represents chlorine, bromine or iodine, and then with potassium phthalimide. The resulting product of the formula O || o / Q 1, .. ~ \: = 10 (XV) is then subjected to, for example, a Mannich reaction, and the protecting group is removed in a reaction with, for example, hydrazine hydrate. The intermediates of formula II, where X represents sulfur and n represents 0, can also be prepared by reacting a: n-Anfw furan of formula H1 (XVI) Ra where neither R1 nor R2 can represent hydrogen, with lithium and elemental sulfur and then with a w-bromoalkylphthalimide of formula X. The resulting compound of formula nl. i \ N-A11 <-Ll o l s (crxe) muå \ | '\ _ \ / (XVII) Ra' 1 can then be reacted with hydrazine hydrate to remove the protecting group.

The intermediates of formula II, wherein X represents an oxygen atom and n represents 1, can be prepared by reacting an alcohol of formula XIII in a solvent such as dimethylformamide with a compound of the formula Hal (CH2) mNH2, where Hal represents a halogen atom, preferably chlorine, in the presence of a base, in particular potassium tert-butoxide.

The intermediates of formula II, where n represents 2 and X represents oxygen or sulfur, can also be prepared using ethyleneimine. This compound is hereby reacted with a compound of formula XIII or with the isosteric thiol.

The amines of formula II can also be prepared by subjecting a compound of formula 454 882 13 where n, m and X have the meanings given above, to a Mannich reaction and subsequent reduction with lithium aluminum hydride. When a Mannich reaction is used, the group R 1 \ N-Alk may be introduced in any suitable step, but R 2 / this introduction is preferably carried out on compounds of any of the following formulas: I i ßf, LO I cngo fl | \ o (c fl ynxwnaimu 0 (xxx) (xx) To prepare compounds, where Alk represents a methylene group or a branched alkylene group, a Mannich reaction is carried out using a suitable aldehyde and a suitable amine. When Alk represents methylene, formaldehyde is used.

According to an alternative method for the preparation of compounds in which Alk represents methylene, furan-2-carboxylic acid was used as starting material. This acid is reacted with an amine of the formula R1R2NH to form an amide of the following formula XXI, after which this amide is reduced with, for example, lithium aluminum hydride to form a compound of the following formula XXII: R1 \ N h R1 \ NcH2-Ü To convert a compound of formula XXII to a compound of formula XIII, the hydroxymethyl group may be introduced using formaldehyde and acetic acid. If both R 1 and R 2 represent hydrogen, the amino group is protected as a phthalimide during the hydroxymethylation. In a final step, the protecting group is then removed using hydrazine hydrate.

If neither R 1 nor R 2 represents hydrogen, the hydroxymethylation can alternatively be carried out by reaction with butyllithium and then with formaldehyde.

When Alk represents a straight alkylene group containing 2 or more carbon atoms, the following two methods can be applied.

According to a suitable method for the preparation of ethylene derivatives analogous to the method described above for the preparation of methylene derivatives, a carboxylic acid of the formula [mu] l HOOCCHQ 10 (XXIII) was used instead of furan-2-carboxylic acid.

When the alkylene chain Alk contains more than two carbon atoms, the lithium derivative of formula XIV can be reacted first with a dihaloalkane of the formula Hal Alk Hal, where Hal represents chlorine, bromine or iodine, and then with an amine R1R2NH to form a compound of formula XVI, where Alk contains 3-6 carbon atoms.

When R 1 and R 2 represent hydrogen, potassium phthalium imide was used instead of the amine R 1 R 2 NH in the above reactions. The resulting product is hydroxymethylated in the same manner as described above, after which the protecting group is removed to give a compound of formula XIII.

If aman desires compounds where R 1 and R 2 have other meanings than hydrogen, the free amino compounds can be converted to compounds containing appropriately substituted amino groups, for example by using formaldehyde and formic acid according to Eschweiler-Clarke's method, whereby dimethylamine compounds are obtained. However, it is preferred to use a substituted amine in a suitable reaction step.

The amines of formula II, where n represents 2, can be prepared by reacting a compound of formula [I IL-c fl ac fi zz (xxlv) \\ o, / where Z represents a leaving group, for example tosyloxy, mesyloxy or bromine, with a --Phthalimidoalkylthiol of the formula XII. The resulting compound is subjected to a Mannich reaction, after which the protecting group is removed to give the desired amine of formula II. For the preparation of compounds of formula I, a compound of formula V can be reacted with a thiol of formula VII, where Y may, inter alia, represent = CHNO2. The compounds of formula VII, where Y represents = CHNO 2 can be prepared by a thiazolidine intermediate having form and m represents 2, are new compounds which are reacted between CHNOQ (xxv) with an amine of the formula R 3 NH 2. The thiazolidine of formula XXV can be prepared from cysteamine and a bis-methylthio compound of formula CH 3 SCSCH 3 (XXVI) in CHNO 2 454 882 16 H.

The invention is illustrated by the following non-limiting examples. Examples d-6 describe the preparation of starting materials. Examples A-L describe the preparation of amines of formula II and related intermediates. Examples 1-27 describe the preparation of compounds of formula I. Example 28 exemplifies pharmaceutical compositions.

Example a (a) 5- (methylamino) methyl 2-furanmethanol A mixture of 49 g of 2-furanmethanol, 51.5 g of methylamine hydrochloride and 50 ml of a 36% formaldehyde solution was stirred at 0-3 ° C for 3 hours. h and then allowed to stand for 16 h. An excess of sodium carbonate was added, and the slurry was extracted with ethyl acetate. After removal of the solvent, the residue was distilled to give 36.2 g of 5- (methylamino) methyl-2-furanmethanol having a boiling point of 111-11306 at 0.2 mm Hg.

Starting from 2-furanmethanol and suitable amine hydrochlorides, the following compounds were also prepared: (b) 5 - [(2-phenylethyl) amino] -2-furanmethanol; oil. Rf 0.45 (silica / acetone). NMR (CCl 4): 7.29, br s (4H); 6.8 s (2 H); 6.40 S (2H); 5.62 S (2H); 4.0 br (2H); 2.87 s (SH). (c) 5 - [(1-methylethyl) amino] methyl-2-furanethanol; oil. Rf 0.55 (silica / methanol). Analysis: Found: C 63.35; H 8.78; N 8.09. Calculated for C 9 H 15 NO 2: C 63.88; H 8.94; N 8.28%. (d) 5- (ethylmethylamino) methyl-2-furanmethanol. Rf 0.32 (silica / acetone). NMR (CDCl 3): 8.93 t (3H); 7.80 s (3 H); 7.55 kv (28): 6.50 s (28): 6.33 br s (1H); 5.47 s (2 H); 3.80 m (ZH). (e) 5 - [[2- (dimethylamino) ethyl] amino] methyl-2-furanmethanol-bis-maleate salt; amp 119-121 ° c. 454 882 17 Exemgel ß 5- [2- (N, N-dimethylamino) ethyl] -2-furanmethanol. ' A mixture of 9.8 g of N, N-dimethyl-2-furanetanamine, 17.5 g of a 30% aqueous solution of formaldehyde and 18 ml of glacial acetic acid was heated at 70 ° C for 5 h. The reaction mixture was then cooled, alkalized with sodium hydroxide and extracted with ether. The organic extract was distilled to give an oil having a boiling point of 90-100 ° C at 0.5 mm Hg.

Found: C 64.0; H 8.9: N 8.0. Calculated for C 9 H 15 NO 2: C 63.9; H 8.9; N 8.2%.

Exemgel I 211- (4-bromobutyl)] furan. 375 ml of a 1.6 M hexane solution of n-butyllithium was added to a solution of 40.8 g of furan in 375 ml of dry tetrahydrofuran, after which the resulting mixture was stirred at 40 ° C for 3 hours. Then 129.6 g of 1 , 4-dibromobutane at -30 ° C, and the reaction mixture was stirred at room temperature for 4 hours.

Then water was added, and the reaction mixture was extracted with ethyl acetate. After distilling off the extract, a clear, colorless liquid with a boiling point of 60-62 ° C at 0.5 mm Hg was obtained.

N, N-dimethyl-4- (2-furanyl) butanamine. 56 g of dimethylamine were added to a solution of 82 g of 2- [1- (4-bromobutyl)] furan in 500 ml of toluene. The resulting solution was stirred at room temperature for 2 days and then acidified with hydrochloric acid. The acid layer was separated, washed with ether, alkalized with sodium hydroxide and extracted with ether. The ether extract was distilled to give a clear colorless oil having a boiling point of 55-58 ° C at 0.8 mm Hg.

The compound's nyarokioriasait melt at 133-1ase ° C.

Found: C 59.01; H 9.02; H 6.87. Calculated for C 10 H 17 NO.HCl: C 58.96; H 8.91; N 6.88%. 454 882 18 S- [4- (dimethylamino) butyl] -2-furanmethanol. 125 ml of a 1.6 M n-hexane solution of n-butyllithium was added to a quenched solution of 33.4 g of N, N-dimethyl-4- (2-furanyl) butanamine in 125 ml of dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 4 hours. Then 6.0 g of paraformaldehyde was added, and the resulting mixture was stirred for another 1 hour. The reaction was quenched by the addition of water, and the reaction mixture was extracted with chloroform. The organic extract was distilled to give a clear, colorless oil having a boiling point of 100-105 ° C at 0.1 mm Hg. The product had a melting point of 26-2a, s ° c.

Found: C 67.09; H 10.01; N 7.06. Calculated for H NO C 66.97; H 9.71; N 7.10%. In a similar manner, 5- [3- (dimethylamino) -C11 propyl] -2-furanmethanol was also prepared, which had a boiling point of 160 ° C at 0.08 mm Hg and a melting point of about 24 ° C.

Found: C 64.66; H 9.36; N 7.39. Calculated for 1 C10H17N02.šH2p. C 64.28, H 9.39, N 7.50%.

Example Gel 6 [5- [4- [N, N-dimethylaminolbutyl] -2-furanylmethylethanoate.

A mixture of 4.9 g of S- [4- (dimethylamino) butyl] -2- -furanmethanol, 25 g of acetic anhydride and 10 g of molten and powdered sodium acetate in 25 ml of benzene was stirred at room temperature for 24 hours. The reaction mixture was then diluted with 100 ml of water and extracted with ethyl acetate. The combined extracts were distilled to give a clear, colorless oil having a boiling point of 100 ° C at 0.5 mm Hg. Found: C 65.62; H 9.03; N 5.95. Calculated for CH NO C 65.24; H 8.85; N 5.85%. 13 21 3 * 454 882 19 "Exemgel A (a) 2 - [[15- (dimethylamino) methyl-2-furanyl] methyl] thioletanamine. 15.5 g of 5- (dimethylamino) methyl-2-furanmethanol were added dropwise to a stirred and ice-cooled solution of 11.36 g of cysteamine hydrochloride in 40 ml of concentrated hydrochloric acid. After allowing the reaction mixture to stand at 0 ° C for 18 hours, an excess of anhydrous sodium carbonate was added, and the resulting solid was extracted with diethyl ether. After removal of the solvent and subsequent distillation of the residue, 11.6 g of 2 - [[15- (dimethylamino) methyl-2-furanyllmethyl] thio] -ethanamine with a boiling point of 104-106 ° C at 0.1 mm Hg were obtained. The picrate salt of the compound melted at 142-144 ° C.

Starting from cysteamine hydrochloride and suitable furan methanols, the following compounds were also prepared: (b) 2f [[[5- (methylamino) methyl-2-furanyl] methyl] thio] ethanamine.

The monopicrate salt of the compound melted at 116-118 ° C. (c) 2-II [5 - [(1-methylethyl) amino] methyl-2-furanyl] methyl] thio] ethanamine. Oil with an Rf value of 0.4 in thin-layer chromatography on silica; eluting with a mixture of methanol and ammonia (0.880) in a volume ratio of 79: 1. (d) 2 - [[[5- (diethylaminomethyl) -2-furanyl] methyl] thio] ethanamine; boiling point 134-13s ° c at 1 mm Hg. (e) 2 - [[[5- (1-piperidinyl) methyl-2-furanyl] methyl] thio] ethanamine. Oil with an Rf value of 0,37 by thin layer chromatography on silica; eluting with a mixture of methanol and ammonia (0.880) in a volume ratio of 79: 1. (f) 2 - [[[5- (aminomethyl) -2-furanyl] methyl] thio] ethanamine dihydrochloride; melting point 222-224 ° C during decomposition. (9) N- [5- [II (2-aminoethyl) thio] methyl] -2-furanyl] methyl] benzenethanamine. Oil with an Rf value of 0.33 by thin layer chromatography on silica; eluting with a mixture of methanol and ammonia (0.880) in a volume ratio of 79: 1. (h) 2- [1- [5- [2- (dimethylamino) ethyl] -2-furanyl] methyl] thio] ethanamine; xokpumxr 150-1ss ° c via 0.4 mm ng. (i) 2 - [[[5- [3- (dimethylamino) propyl] -2-furanyl] methyl] thio] ethamamine; boiling point 1000 ° C at 0.05 mm Hg. 454 882 20 (j) 2 - [[1- (ethylmethylamino) methyl-2-furanyl] methyl] thio] ethanamine. Rf = 0.34 by thin layer chromatography on silica; eluting with a mixture of methanol and ammonia (0.8B0) in a volume ratio of 79: 1. (k) 2- [IIS - [(2-dimethylaminoethyl) amino] methyl-2-furanyl] methylthioletanamine. The trismaleate salt melts at 132-135 ° C. (1) 2 - [[[5- (1-pyrrolidino) methyl-2-furanyl] methylthioletanamine. The bisoxalate salt melts at 136.5-138 ° C.

Example B 2 - [[1S- [4- (dimethylamino) butyl] -2-furanylmethyl] thio] ethanamine. 4.5 g of cysteamine hydrochloride were added to a cooled solution of 8.98 g of potassium t-butoxide in 125 ml of dry dimethylformamide.

The mixture was stirred for 20 minutes, after which 9.6 g of [5- [4- (dimethylamino) butyl] -2-furanyl] methyl ethanoate were added. The reaction mixture was heated at 90 ° C for 4 hours, then poured into a mixture of ice and water and extracted with chloroform.

After distilling off the organic extract, a yellow oil was obtained, which was chromatographed on a column of silica, using as eluent a mixture of methanol and ammonia (0.880) in a volume ratio of 9: 1. After further distillation, a colorless oil with a boiling point of 140 DEG C. at 0.05 mm Hg was obtained.

Found: C 60.81; H 9.86; N 10.44. Calculated for H H OS: C 60.91; H 9.44; N 10.93%.

C13 24 2 Example gel C 2 - [[2- (2-furanyl) ethyl] thio] ethyl-1H-isoindole-1,3 (2H ¥ dione. 0.155 g of 80% sodium hydride was added portionwise to a solution of 1.03 g 2-Phthalimido-ethanethiol in dry dimethylformamide at 0 [deg.] C. After 20 minutes, a solution of 1.33 g of 2-furanethanol-4-methylbenzenesulfonate in dry dimethylformamide was added dropwise, and the resulting solution was stirred overnight at room temperature. The reaction mixture was then poured into a mixture of ice and water, 1.3 g of 2 - [[2- (2-furanyl) ethyl] thio] ethyl-1H-isoindole-1,3 (2H) -dione being isolated as a white solid with a melting point of 53-55 ° C. 454 882 21 Example D (a) 2- [2-II (2-furanyl) methyl] thio] ethyl] -1H-isoindole-1,3 (2H) - - 1.58 g of 80% sodium hydride were added in portions to a solution of 6 g of furfuryl mercaptan in 50 ml of dry dimethylformamide, and after 30 minutes a solution of 16.71 g of 2-bromoethylphthalimide in 65 ml of dry dimethylformamide was added. and the resulting solution was heated at 110 ° C for 2 days After removal of loose The residue was washed with water and extracted with ethyl acetate. The ethyl acetate extracts were combined, the solvent was removed, and the residue was recrystallized from cyclohexane.

7.8 g of 2- [2 * [[(2-furanyl) methyl] thio] ethyl] -1H-isoindole-1,3 (1H) -dione with a melting point of 62-63 ° C were obtained.

In a similar manner, the following compound was prepared from furfuryl mercaptan and suitable n-bromoalkylphthalimidez (b) 2- [3- [1- (2-furanyl) methylthiolpropyl] -1H-isoindole-1,3- (ZH) -dione ; NMR (CDCl 3): 7.7-8.3 m (2H); 7.2 - 7.7 m (2H); 6.29 s (2 H); 6.23 t (2 H); 2.7 m (1H); 2.4 m (4H).

(C) 2- [4 - [[(2-furanyl) methyl] thio] butyl] -1H-isoindole-1,3 (2H) -dione; NMR (cDc13) = 8-8.5 m (4H); 7.49 t (2 H); 6.33 (4H), 3.7 n (25): 2.7 m (18): 2.3 m (4H).

Example gel E (a) 2- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -1H-isoindole-1,3 (2H) -dione.

A mixture of 2- [2- [1- (2-furanyl) -methyl] thio] ethyl] -1H-isoindole-1,3 (2H) -dione, 3.1 g of dimethylammonium chloride and 3 ml of 36% formaldehyde solution in 50 ml of acetic acid was heated on a meadow bath for 9 hours. The reaction mixture was then cooled and the solvent was removed in vacuo. The residue was alkalized with a 5 N sodium hydroxide solution and extracted with ethyl acetate. The organic phase was treated with charcoal, dried and evaporated to give an oil. This oil was purified by column chromatography on silica, eluting with a mixture of equal volumes of ethanol and ethyl acetate. 5.7 g of product with an Rf value of 0.4 were obtained. NMR (CDCl 3 / bMSO): 7.71 S (5H) δ 7.22 t (2H) δ 5:52 δ (za), 6.2 S (zu), 6.1 (2n) 3.8 m (2a); 2.2 m (4n).

In a similar manner, the following compounds were prepared from formaldehyde, a suitable amine and a suitable 2- [w- [1- (2-furanyl) methyl] thio] alkyl] -1H-isoindole-1,3 (2H) - dione: (b) 2- [2 * [1 [(1-pyrrolidinylmethyl] -2-furanyl] methyl] thio] ethyl-1H-isoindole-1,3 (2H) -dione NMR (CDCl 3): 8- 8.4 m (4H); 7-7.6 m (6H); 6-6.5 m (6H): 3.7-4.0 m (2H): 2-2.4 m (4H).

(C) 2- [3 - [[[5- (dimethylamino) methyl-2-furanylmethyl] thio] propyl] -1H-isoindole-1,3 (2H) -dione. Rf 0.45 (silica / methanol (6) 2- [4 - [[[5- (dimethylamino) methyl-2-furanylmethyl] thio] -butyl] -1H-isoindole-1,3 (2H) -dione. 0.26 (silica / methanol).

NMR (CDCl 3): 8.85 m (4H); 7.7 S (63): 7.42 t (2H); 6.52 S (23): 6.29 m (45): 3.9 m (2H); 2-2.4 m IÅH). (e) 2- [2- [1 [S - [(4-methyl-1-piperazinyl) methyl] -2-furanyl] -methylthiolethyl] -1H-isoindole-1,3 (2H) -dione. NMR (CDCl 3) 7.75 S (33): 7.52 S (8H); 7-7.5 m (2H): 6.5 S (2H); 6-6.3 m (49): 3.85 m (2H): 2-2.4 m (4H). (f) 2- [2-II [5 - [(4-morpholinyl) methyl] -2-furanylmethyl] thio] ethyl] -15-isoindole-1,3 (2H) -dione. NMR (CDCl 3): 7.54 m (49): 7.24 m (2H); 6.50 S (28): 6.22 m (8H); 3.8 m (2H); 2.0-2.4 m (OH).

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

A mixture of 0.5 g of 2 - [[2- (2-furanyl) ethyl] thio] ethyl-1H-isoindole-1,3 (2H) -dione, 0.27 g of dimethylamine hydrochloride and 0.102 g of paraformaldehyde was boiled. under reflux in ethanol. After 5 hours, an additional 0.27 g of dimethylamine hydrochloride and 0.102 g of paraformaldehyde were added, and boiling was continued for another 16 hours.

The solvent was then removed, and the residue was alkalized and extracted with ethyl acetate. An oil was recovered, which was subjected to column chromatography on silica with methanol as eluent. This gave 0.43 g of 2- [2 - [[2- [5- (dimethylamino) methyl-2-furanyl] ethyl] thio] ethyl] -1H-isoindole-1,3 (2H) -dione as a light oil.

Found: C 61.48; H 6.13; N 7.63. Calculated for 454 882 23 C 19 H 22 N 2 O 3 S.3 / 4H 2 O: C 61.35; H 6.37; N 7.53%.

Example gel G 2 - [[5- (dimethylamino) methyl-2-furanylmethoxylethanamine.

Method 1 To a solution of 6.2 g of S- (dimethylamino) methyl-2-furan-methanol and 2.82 g of ethyleneimine in dry tetrahydrofuran was added a solution of 11.6 g of methanesulfonic acid in 40 ml of tetrahydrofuran.

The reaction mixture was evaporated, and the oily residue was heated at 98-100 ° C for 10 minutes. After 18 hours, 60 ml of 5 N sodium hydroxide solution was added, and the solution was evaporated to dryness. Anhydrous sodium sulfate and 150 ml of ethyl acetate were added, and after 2 hours, the resulting suspension was filtered. The filtrate was treated with decolorizing charcoal and evaporated. The resulting oil was chromatographed on silica, eluting first with a 79: 1 by volume mixture of ethanol and ammonia (0.88). The eluate thus obtained was discarded. The mixture was then eluted with a mixture of methanol and ammonia (0.88) in a volume ratio of 19: 1. The eluate thus obtained was evaporated to give an oil.

This oil was treated with an ethanolic solution of oxalic acid to give 0.2 g of bisoxalate salt of 2-I [5- (dimethylamino) methyl-2-furanylmethoxylethanamine, m.p. 125-128 ° C.

Method 2 A solution of 6.25 g of 2-chloroethylamine hydrochloride in dry dimethylformamide was added dropwise to a stirred and cooled solution of 8.96 g of potassium text-butoxide and 0.4 g of 5- (dimethylamino) methyl-2-chloroformamide. furanmethanol in the same solvent. After 2 h, the solvent was removed, and the residue was alkalized and extracted with ethyl acetate. After removal of the solvent, the residue was treated with an ethanolic solution of oxalic acid. The crystalline salt formed was recrystallized from ethanol to give 3.05 g of 2 - 1- [5- (dimethylamino) methyl 2-furanylmethoxylethaneamine bisoxalate, m.p. 130-133 ° C.

In the same manner as in Method 2 above, 2 - [[5- (methylamino) methyl 2-furanylmethoxylethanamine bisoxalate with a melting point of 162-164 ° C was also prepared. 454 882 24 Example gel H 2- [4- (2-furanyl) butyl] 18-isoindole-1,3 (2H) -dione. 406 mg of 2- [1- (4-bromobutyl)] furan were stirred together with 370 mg of potassium phthalimide in dry dimethylformamide at room temperature overnight. The reaction solution was then poured into ice water, and the resulting white solid was filtered off, dried and recrystallized from a mixture of chloroform and petroleum ether (b.p. 60-80 ° C). 430 mg of 2- [4- (2-furanyl) butyl] 1H-isoindole-1,3 (2H) -dione were obtained as white microcrystals, m.p. 61-63 ° C.

In a similar manner, 2- [S- (2-furanyl) pentyl] -1H-isoindole-1,3 (2H) -dione with a melting point of 54-56 ° C was also prepared.

Example Gel I 2- [4- [5- (Dimethylamino) methyl-2-furanylbutyl] -1H-isoindole-1,3 (2H) -dione.

A mixture of 5.38 g of 2- [4- (2-furanyl) butyl] -1H-isoindole-1,3 (2H) -dione, 1.2 g of paraformaldehyde and 3.26 g of dimethylamine hydrochloride in 100 ml of absolute ethanol was boiled under reflux. After 6 hours, an additional 0.6 g of paraformaldehyde and 1.6 g of dimethylamine hydrochloride were added, then boiling was continued for another 20 hours. The solvent was then evaporated, the residue was made strongly basic with 5 N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was evaporated. The crude product thus obtained was purified by column chromatography to give 3.25 g of an amber oil.

Rf 0.4 (silica / methanol). NMR (CDCl 3); 3-3.5 m (4H>; 7.7s s (6H>; 7.3 m (za), 6.55 s (za), 6.3 m (za), 4.0 m (2H); 1.9 - 2.4 m (4H).

In a similar manner, 2- [5- [5- (dimethylamino) methyl-2-furanyl] pentyl] -15-isoindole-1,3 (2H) dione was also prepared.

TLC: Rf 0.4 (silica / methanol). NMR: 8.0-8.8 m (6H): 7.70 m (en), 7.37 t (2n); 6.52 s (za), 6.30 t (zu), 4.0 m (zu), 2.2 m (4H). 454 882 ExemRe1J g 5- (dimethylamino) methyl-2-furanpropanamine.

A mixture of 1.21 g of furanproprionitrile, 1.62 g of dimethylamine hydrochloride and 0.7 g of paraformaldehyde in 20 ml of ethanol was refluxed for 24 hours. The solvent was then evaporated, and the residue was alkalized to pH 12 and extracted with After evaporation of the solvent, the residual oil was purified by column chromatography on silica, using methanol as eluent.

0.6 g of 5- (dimethylamino) methyl-2-furan-proprionitrile was isolated. Rf 0.55 (silica / methanol).

A solution of 6.0 g of a nitrile prepared as above in 40 ml of dry ether was added dropwise with stirring to 2.0 g of lithium aluminum hydride in ether at 0 ° C. Then water was added, after which the solvents were removed. After purification by column chromatography, 3.33 g of 5- (dimethylamino) methyl-2-furan-propanamine were obtained as a light oil.

NMR (CDCl 3): 8.2 m (25): 7.6 br (2H); 7.75 s (6 H); 7.30 m (4H); 6.60 s (2 H); 4.0 m (2H).

Example 2- [3 - [[5- (dimethylamino) methyl-2-furanyl] thio] propyl] -1-1H-isoindole-1,3 (2H) -Gion. 1.9 g of sulfur was added in portions to a solution of 7.5 g of lithium derivative of N, N-dimethylfuranmethanamine at -40 ° C.

The reaction mixture was stirred at -10 ° C for 20 minutes, then 16 g of 2- (3-bromopropyl) -1H-isoindole-1,3 (2H) -dione was added.

The reaction mixture was allowed to stand at 0 ° C overnight, after which the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate, filtered off and extracted with 2 N sulfuric acid.

The aqueous layer was alkalized and re-extracted with ethyl acetate, after which the organic phase was dried. After removal of the solvent, a crystalline solid was obtained, which was recrystallized from ethanol. This gave 7.59 g of 2- [3- [1- [5- (dimethylamino) methyl-2-furanylthiolpropyl]] - 1H-isoindole-1,3 (2H) -dione, m.p. 64-65 ° C. . 454 882, 26 Example gel L (a) 4- [S- (dimethylaminolmethyl-2-furanyl] butanamine 2.9 g of 2-1 [4- (5-dimethylamino) methyl-2-furanyl] butyl] -1H- isoindole-1,3 (2H) -dione and 0.55 ml of hydrazine hydrate were refluxed in ethanol for 6 hours. The solvent was then removed, and the crystalline residue was dissolved in 5 N sodium hydroxide solution, and the resulting solution was extracted with ethyl acetate. After evaporation of the solvent from the organic phase, 1.68 g of product were obtained as a mobile yellow oil, and by thin layer chromatography on silica using methanol as eluent, a single spot was obtained at Rf 0.15.

NMR (CDCl 3): δ 8.0-8.8 m (4H); 7.7 s (6 H); 7.6 br (2H); 7.3 m (4 H); 6.58 s (2 H); 4.0 m (ZH).

In a similar manner the following compounds were also prepared: (b) 5- [5- (dimethylamino) methyl-2-furanyl pentanamine. NMR (CDCl 3): δ 8.0-8.8 m (6H); 7.75 s (6 H); 7.0-7.6 m (4H); 6.60 s (2 H); 4.0 m (ZH). (c) 5- [1- (3-Aminopropyl) thio] methyl] -N, N-dimethylfuran-2-methanamine. NMR (CDCl 3): 8-8.5 m (2H); 7.75 δ (6 H); 7.42 t (2 H); 7.25 (2 H); 6.58 s (2 H); 6.3 s (2 H); 3.88 s (2H).

Example 1 (a) N- [2 * [II5- (dimethylamino) methyl-2-furanylmethyl] thio] ethyl] -N'-methylthiourea.

A mixture of 5.3 g of 2- [2 * [1- [5- (dimethylamino) methyl] -2- -furanylmethyl] thioethyl] -1H-isoindole-1,3 (2H) -dione and 0.85 g of hydrazine hydrate in ethanol was boiled under reflux for 30 hours. After evaporation of the solvent, the phthalhydrazide salt of 2 - [[15- (dimethylamino) methyl-2-furanylmethyl] thioletanamine was obtained. 1 g of the resulting salt was suspended in acetonitrile, and 0.21 g of methyl isothiocyanate was added. The suspension was stirred at room temperature for 5 hours and at 60 ° C for 2 hours, after which it was filtered and the filtrate was evaporated. This gave an oil which was purified by column chromatography on silica using. methanol as eluent. 0.3 g of N- [2 - [[[5- (dimethylamino) methyl-2-furanyllmethyl] thioethyl] -N'-methylthiourea was obtained as a light oil. 454 882 27 ~ - v Analysis: Found: C 49.68; H 7.52; N 14.22. Calculated for c12n21n3os2 = c 50.14; H 7.37; N 14, s2%. In a similar manner the following compounds were also prepared: (b) N-methyl-N '-12-1I [5- (5% urinidinyl) methyl-2-furanyl] methyl] thio] ethyl] thiourea. Analysis: Found: C 52.33; H 7.12; N 13.17. Calculated for C 14 H 23 N 3 OS 2.1 / 2 H 2 O: C 52.14; H 7.50; N 13.03%. (c) N- [4- [1- [15- (dimethylamino) methyl-2-furanyl] methylthio] -butyl] -N'-methylthiourea. Analysis: Found: C 51.69; H 8.53; N 12.83. Calculated for C 14 H 25 N 3 OS 2: C 51.82; H 8.08; N 12.95%. (d) N- [3 - [[5- (dimethylamino) methyl-2-furanyl] thio] propyl] -N'-methylthiourea. Analysis: Found: C 49.71; H 7.33; N 14.35.

Calculated for C 12 N 21 N 3 OS 2: C 50.10; H 7.30; N 14.62%. (e) N-methyl-N '- [Zα] [5 {(4-morpholinyl) methyl] -2-furanyl] -methyl] thio] ethyl] thiourea. Analysis: Found: C 51.26; H 7.08; N 12.51. Calculated for C 14 H 23 N 3 O 2 S 2: C 51.03; H 7.04; N 12.75%. (f) N-methyl-N '- [2 - [[[5 - [(4-methyl-piperazinyl) methyl] -2-furanylmethyl] thio] ethyl] thiourea. Analysis: Found: C 50.93; H 7.74; N 15.82. Calculated for C 15 H 26 N 4 OS 2: C 51.25; H 8.03; N 15.94%. (9) N- [2- [2- [5- (dimethylamino) methyl-2-furanyl] ethyl] thio] ethyl] -N'-methylthiourea. Analysis: Found: C 50.19; H 7.20; N 13.18. Calculated for C 13 H 23 N 3 O 2 O.1 / 2 H 2 O: C 50.32; H 7.74; N 13.54%.

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

A mixture of 0.5 g of 5- [5- (dimethylamino) methyl-2-furanyl pentanamine and 0.25 g of methyl isothiocyanate was mixed in acetonitrile at room temperature for 24 hours. The solvent was then removed, and the product was purified by column chromatography. chromatography on silica using methanol as eluent. After trituration with ether, N- [5- [5- (dimethylamino) methyl-2-furanyl] pentyl] -N'-methylthiourea was obtained as white crystals with a melting point of ss-e9 ° c. starting from methyl isothiocyanate and suitable amines, the following compounds were also prepared: (b) N- [3 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -propyl] -N'-methylthiourea. Analysis: Found: C 51.38; H 7.93; N 13.41. Calculated for C 13 H 23 N 2 OS 2: C 51.79; B 7.69; N 13.94%. (c) N-1- [5- (5- (dimethylamino) methyl-2-furanylbutyl] -N'-methyl-fiourea. NMR (cnc13) = 8-8.6 m (4H); 7.72 s (6 H); 7.35 t (2 H); 6.98 d (3 H); 6.2-6.8 m (48): 4.0 Å (2H); 3-3.8 m (ZH). (d) N- [2 - [[5- (dimethylamino) methyl-2-furanylmethoxy] ethyl] -N'-methylthiourea. Analysis: Found: C 51.91; H 8.14; N 14.98.

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

Example 3 (a) N- [2 - [[[5- (dimethylamino) methyl-2-phenanyl] methyl] thio] ethyl] -N '- (2-methoxyethyl) thiourea.

A mixture of 1.17 g of 1- (isothiocyanato) -2-methoxyethane and 2.14 g of 2- [1- [5- (dimethylamino) methyl-2-furanyl] methylthioletanamine in acetonitrile was allowed to stand overnight. The solvent was then evaporated, and the residual oil was chromatographed on silica using methanol as eluent.

There was obtained N- [2 - [[15- (dimethylamino) methyl-2-furanyl] methylthioethyl] -N '- (2-methoxyethyl) thiourea as a light oil (Rf 0.45).

Analysis: Found: C 50.64; H 7.51; N 12.58. Calculated for C 14 H 25 N 3 O 2 S 2: C 50.75; H 7.55; N 12.69%.

Starting from 2 - [[1- (dimethylamino) methyl-2-furanyl] -methyl] thio] ethanamine and suitable isothiocyanates, the following compounds were also prepared: (b) N- [2-I [[5- (dimethylamino) - methyl-2-furanylmethyl] thio] ethyl] -N '- (2-propenyl) thiourea. Analysis: Found: C 52.68; N 7.58; N 13.16. Calculated for C 14 H 23 N 3 OS 2.1 / 2H 2 O: C 52.14; H 7.50; N 13.03%.

(C) N- [2 - [[5- (dimethylamino) methyl-2-furanylmethyl] thioethyl] -N- (1-methylethyl) thiourea. Analysis: Found: C 51.84; H 7.88; N 13.00. Calculated for c14n25N3os2. 1 / 2n 2 O = c 51.90; H 8.09; N 12.97%. Example 454 N- [2 - [[[5- (methylamino) methyl-2-furanyl] methylthioethyl] -N'-methylurea.

To a stirred solution of 1.5 g of 2 - [[[5- (methylamino) methyl-2-furanyl] methyl] thio] ethanamine in 24 ml of acetonitrile was added dropwise a solution of 0.45 g of methyl isocyanate in 15 ml of acetonitrile. tonitrile. After 30 minutes, the solution was evaporated to dryness to give an oil. This oil was subjected to column chromatography, first on silica, using as eluent a mixture of methanol and ammonia (0.88), 79: 1 by volume, and then on alumina, using methanol as eluent. There was thus obtained 0.25 g of N- [2-III5- (methylamino) methyl-2-furanyl] methyl] thio] ethyl11- '-N'-methylurea in the form of an oil. Analysis: Found: C 51.00; H 7.38; N 15.91. Calculated for C 11 H 19 N 3 O 2 S: C 51.33; H 7.44; N 16.33%.

Example 5 (a) N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methylurea. 0.33 g of methyl isocyanate was added to a suspension of 2 g of 2-1115- (dimethylamino) methyl-2-furanylmethyl] thio] ethanamine-phthalhydrazide complex in 50 ml of acetonitrile. After 2 hours, the solution was filtered, and the filtrate was evaporated. This gave an oil which was purified by column chromatography on silica using methanol as eluent. There was obtained the desired product N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methylurea. Analysis: Found: C 52.38; H 7.61; N 15.25. Calculated for C12H21N3O2S. 1 / 4H 2 O: C 52.24: H 7.76; N 15.32%.

In a similar manner the following compound was also prepared: (b) N-methyl-N '- [2-II [5- (1-pyrrolidinyl) methyl] -2-furanyl] -methylthioethyl] urea. Analysis: Found: C 54.70; H 7.33; N 14.07. Calculated for C14H23N3O2S. 1 / 2H 2 O: C 54.87; H 7.89; N 13.71%. Example 4 (a) N- [2 * [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N '- (1-methylethyl) urea. 2.14 g of 2-IIis- (dimethylamino) methyl-2-furanylmethyl] thio] -ethanamine and 0.89 g of isopropyl isocyanate were dissolved in acetonitrile, after which the resulting solution was allowed to stand overnight. The solvent was then removed, and the residue was recrystallized from a mixture of methanol and ether. 2.8 g of N- [2- [II5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'- - (1-methylethyl) urea were obtained as crystals having a melting point of ss-67 ° c.

In a similar manner the following compound was also prepared: (b) N- [3- [1- [5- (dimethylamino) methyl-2-furanylmethyl] thiolpropyl] -N'-methylurea; mp 69-69.5 ° C.

Example 7 N- [2- [1- [S- (dimethylamino) methyl-2-furanylmethyl] thio] ethyl] urea.

A solution of 2.8 g of 2- [1- [5- (dimethylamino) methyl-2-furanylmethyl] thio] ethanamine dihydrochloride and 3.75 g of potassium cyanate in 50 ml of water was heated on a steam bath for 8 ILs. of solid sodium carbonate was then added, and the organic material was extracted continuously with diethyl ether.

The extracts were evaporated and the residue was purified by column chromatography. There was obtained 1.28 N- [2- [1- [5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] urea as a waxy solid. Analysis: Found: C 48.22; H 7.50; N 15.61. Calculated for C11H19N3O2S. H 2 O: C 48.00; H 7.65; N 15.27%.

Example 8 N-I2-III5- (dimethylamino) methyl-2-furanylmethyl] thio] -ethyl-N'-nitroguanidine.

A solution of 1, 2-III5- (dimethylamino) methyl-2-furanylmethylthioletanamine and 1.5 g of S-methyl-N-nitroisothiourea in 10 ml of ethanol was heated to 40 ° C for 5 minutes. The resulting precipitate was filtered off and recrystallized from ethyl acetate and petroleum ether (b.p. 80-100 ° C). N- [2- [1- [5- (dimethylamino) methyl-2-furanylmethyl] thio] ethyl] -N'-nitroguanidine with a melting point of 103-104 ° C was obtained.

(I 454 882 Example 9 (a) N-cyano-N '- [2- [II5- (methylamino) methyl-2-furanylmethyl] thioethyl] -N "-methylguanidine.

A mixture of 2.0 g of 2 - [[5- (methylamino) methyl-2-furanyl] methylthioletanamine and 1.25 g of N-cyano-N'-methylcarbamimidothioic acid methyl ester was heated on a steam bath for 6.5 hours.

The mixture was subjected to vacuum at regular intervals to remove methanethiol. The crude product was purified by column chromatography on silica using a mixture of methanol and ammonia 79: 1 (Rf 0.65) as eluent. This gave 1.05 g of N-cyano-N '- [2-I [[5- (methylamino) methyl-2-furanyl] methyl] thio] ethyl] -N "-methylguanidine, m.p. 85 ° C.

Starting from N-cyano-N'-methylcarbamimidothioic acid methyl ester and suitable amines, the following compounds were also prepared: (b) N-cyano-N '- [2- [1 [5- [N-methylethyl) amino] methyl -2-furanyl] -methylthioethyl] -N "-methylguanidine. Analysis: Found: C 54.73; H 7.82; N 22.31. Calculated for C 14 H 23 N 5 OS: C 54.34; H 7.49; N 22, 64% (c) N-cyano-N '- [2 - [[S- (dimethylamino) methyl-2-furanyl] methyl] thioethyl] -N "-methylguanidine. Analysis: Found: C 53.54; H 7.82; N 20.65. Calculated for C. OS.3 / 4 H O: C 53.46; H 7.70; N 20.78%. (d) N-cyano-N '- [2- [1- [5- (1-pyrrolidinyl) methyl-2-furanyl] -methylthioethyl] -N "-methylguanidine. Analysis: Found: C 53.97; H 6, 87; N 21.06 Calculated for C 15 H 23 N 5 OS 3 / 4H 2 O: C 53.79; H 7.37; N 20.91%. 1sH 2 N 5s 2 (e) N-cyano-N '- [3-IIIS- (dimethylamino ) methyl-2-furanylmethylthiolpropyl-1 "-N" -methylguanidine. Analysis: Found: C 52.86; H 7.49; N 20.64. Calculated for C 14 H 23 N 5 OS.1 / 2820: C 52.80: H 7.59; N 21.20%. 454 882 32 ~ a Exemgel 10 N-cyano-N '- [2- [1- [S- (dimethylamino) methyl-2-furanyl] methyl] -ethyl] -N "-methylguanidine.

To a stirred suspension of 20.7 g of potassium carbonate in a solution of 10.7 g of 2- [1- [5- (dimethylamino) methyl-2-furanyl] -methylthiolethanamine and 7.1 g of N-cyano-N'-methylcarbamimidothioic acid methyl ester in 107 ml of acetonitrile was added at 70 ° C for a period of 1 hour a solution of 9.35 g of silver nitrate in 20 ml of acetonitrile.

The reaction mixture was stirred for 16 hours, after which the solid was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in 250 ml of ethyl acetate. 10.5 ml of the resulting solution were washed with 6 ml of water, after which the ethyl acetate layer was evaporated. This gave a solid which was crystallized from 1.75 ml of isopropyl acetate. 0.35 g of N-cyano-N '- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N "-methylguanidine with a melting point of 79-81, 5 ° C.

To another portion (225 ml) of the ethyl acetate solution was added a solution of 9.09 g of sebacic acid in 30 ml of ethanol. After filtration, 13.74 g of sebacate salt with a melting point of 92.5-94 ° C were obtained. Analysis: Found: C 54.91; H 7.94; N 14.02. Calculated for C 13 H 21 N 5 OS.C 10 H 18 O 4: C 55.51; H 7.90; N 14.07%.

Example 11 N-cyano-N '- (2-methoxyethyl) carbamimidothioic acid methyl ester. 4.2 g of powdered cyanamide was added to a stirred solution of 2.3 g of sodium in absolute ethanol. After 30 minutes, a solution of 11.7 g of methoxyethyl isothiocyanate in absolute ethanol was added to the cooled solution. After an additional 1 hour at room temperature, 12.66 g of dimethyl sulfate were added over a period of 30 minutes, after which the resulting mixture was stirred overnight.

The solvent was then removed, and the residual solid was washed thoroughly with water. 12.37 g of N-cyano-N '- (2-methoxyethyl) carbamidimedioic acid methyl ester were obtained in the form of a white crystalline solid with a melting point of 94.5-9s, s ° c.

In a similar manner, cyano-N '- (2-propenyl) carbamimidothioic acid methyl ester with a melting point of 109-110 ° C was also prepared. 454 882 33 (a) N-cyano-N '- [2- [IIS- (dimethylamino) methyl-2-furanylmethyl] thioethyl] -N "- (2-methoxyethyl) 9uanidine. A mixture of 2.14 g 2-III5- (dimethylamino) methyl-2-furanylmethylthioletanamine and 1.73 g of N-cyano-N '- (2-methoxyethyl) carbamimidothioic acid methyl ester were heated on a steam bath for 6.5 n. The mixture was then subjected to vacuum and The crude product: was prepared by chromatography on silica gel using methanol as eluent to give 1.4 g of N-cyano-N '- [2 - [[[5- - (dimethylamino) methyl]. 2-furanylmethyl] thio] ethyl] -N "- (2-methoxyethyl) guanidine. Analysis: Found: C 50.51; H 7.20; N 19.41. Calculated for C 15 H 25 N 5 O 2 S.H 2 O: C 50.42; H 7.50; N 19.50%.

Starting from 2- [II5- (dimethylamino) methyl-2-furanyl] -methylthioletanamine and suitable N-alkyl-N'-cyanecarbamimidothioic acid methyl esters, the following compounds were also prepared in a similar manner: (b) N-cyano-N '- [2 - 1 [[5- (dimethylamino) methyl-2-furanylmethyl] thioethyl] -N "- (2-propenyl) guanidine. Analysis: Found: C 53.33; H 7.01; N 20.70 Calculated for C 15 H 23 N 5 OS.H 2 O: C 53.09; H 7.37; N 20.64% (c) N-cyano-N '- [2- [1- [5- (dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N "- (1-methylethyl) guanidine. Analysis: Found: C 52.97; H 7.70; N 20.57. Calculated for C15H25N5OS. H 2 O: C 52.78; H 7.91; N 20.52%.

Example Gel 12 (a) N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methylguanidine.

A mixture of 2.14 g of 2-II [5- (dimethylamino) methyl-2-furanylmethyl] thioletanamine and N, S-dimethylisothiouronium iodide was heated on a steam bath for 3 hours. The residue was chromatographed on the ion exchanger Amberlyst nA26, eluting with methanol. . There was thus obtained 1.5 g of N- [2-1 [5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methylguanidine as an amber oil. Analysis: Found: C 50.92; H 8.23; N 19.90. Calculated for c121a22N4os.3 / 4H2o = c 50.76; H 8.34: N 19.749 In a similar manner the following compound was also prepared: (b) 'N- [2-III5- (dimethylaminolmethyl-2-furanylmethylthiolethyl] -N' -, N "-dimethylguanidine. NMR (CDCl 3) = 7.75 s (6H): 6.8-7.3 m (an), 6.5 m 1411); 6.22 s (211): 3.80 m 12H>; - 2.0-3.S br ( 211) - 454 882 34 Example 13 N-methyl-1-methylthio-2-nitroethenamine.

A solution of methylamine in a mixture of ethanol and ethylene dichloride (112.5 ml of a 33% ethanol solution of methylamine in 0.8 l of ethylene dichloride (0.94 mol)) was added over a period of 5.5 n via 70 ° C. In a solution of 99.0 g (0.6 mol) of 1,1-bismethylthio-2-nitroethylene in 1.5 l of ethylene dichloride. The reaction mixture was heated to boiling and 0.7 l of solvent was distilled off. After cooling, the reaction mixture was washed with 0.25 L of 2 N hydrochloric acid and then with 0.25 L of brine. The solvent was evaporated, and the residue was crystallized from 0.5 l of isopropyl acetate, the hot solution being treated with 10.0 g of charcoal. 35.0 g of product were obtained in the form of yellow prisms with a melting point of 114 ° C. 'N- [2- [1- [5- (methylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine hydrochloride.

A solution of 10 g (0.05 mol) of 2-I [[5- (methylamino) methyl-2-furanyl] methyl] thio] ethanamine and 7.4 g of N-methyl-1-methylthio-2-nitroethenamine in 25 ml of water was stirred at 50 ° C for 2 hours. 350 ml of acetone were then added, and the solvent was distilled off at atmospheric pressure until 275 ml of distillate had been collected. To the residue was added 27.5 ml of a 2 M ethanolic solution of hydrogen chloride, and the solution was stirred overnight at room temperature. 11.0 g of product with a melting point of 161 ° C were collected. This product was recrystallized from ethanol to give 10.1 g of a colorless microcrystalline solid, m.p. 162 ° C. Analysis: Found: C 42.6; H 6.3; N 16.4. Calculated for C 12 H 20 N 4 O 3 S.HCl: C 42.8; H 6.2; N 16.68.

Example 14 (a) N- [2- [1- [5- (methylamino) methyl-2-furanylmethyl] thio] ethyl1- -N'-methyl-2-nitro-1,1-ethenediamine.

A mixture of 0.9 g of 2- [1- {5- (methylamino) methyl-2-furanylmethyl] thioletanamine and 0.6 g of N-methyl-1-methylthio-2-nitroethenamine was heated at 100-120 ° C for 30 hours. min, using a water pump to adjust the reaction pressure.

The residue was purified by column chromatography on silica, eluting with a mixture of methanol and ammonia (0.88). After recrystallization from acetonitrile, 0.65 9 454 882 35 .. was obtained.

N- [2-III5- (methylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl--2-nitro-1,1-ethenediamine, m.p. 106-10806.

In a similar manner the following compounds were also prepared: (b) N- [2- [1- [5 - [(Phentyl] amino] methyl-2-furanyl] -methyl] thio] -ethyl] -N'-methyl-2-nitro-1 .1-ethylenediamine Analysis: Found: C 49.75; H 7.21; N 16.36 Calculated for C 14 H 24 N 4 O 3 S.1 / 2H 2 O: C 49.83; H 7.47; N 16.60%. (C ) N-methyl-2-nitro-N '- [2-IIIS-1- (2-phenylethyl) amino] methyl-2-furanylmethylthioethyl] -1,1-ethenediamine Analysis: Found: C 57.19; H 6 .53; N 13.83 Calculated for C 19 H 26 N 4 O 3 S.1 / 2H 2 O: C 57.12; H 6.81; N 14.02%. (D) N-methyl-fl-fl ifro-IW-1z-11 [sI t upiperidinynmethyl 1-2- -furanyl] methyl] thio] ethyl] -1,1-ethenediamine Analysis: Found: c 53.36; H 7.51; N 14.23 Calculated for c 16 H 26 N 4 O 3 S.1 / 4H 2 O = C 53 .33; H 7.44; N 15.61%. (E) N- [2 - 1 [[5- [2- (dimethylamino) ethyl] -2-furanyl] methyl] thio] ethyl] -N ' -methyl-2-nitro-1,1-ethenediamine, mp 95.5-96 ° C. (f) N- [2 - [[15- [3- (dimethylamino) propyl] -2-furanyl] methyl] - thioethyl] -N'-methyl-2-nitro-1,1-ethylenediamine NMR 1 C (CDCl 3): 8.1-7.1 m (6H); 7.65 s (6H); 7.1 s (3H ); 6.5 m (28): 6.28 s (2H); 4.0 m (2H); 3.38 s (1H). (9) N- [2- [II5 - (4-Dimethylaminolbutyl) -2-furanyl] methyl] thio] ethyl] -N-methyl-2-nitro-1,1-ethenediamine; waxy solid. Analysis: Found: C 53.90; B 7.95; N 15.64. Calculated for c16H28N4O3s} c 53.91; H 7.92; N 1s, 72%. (h) N- [2-III5- (ethylmethylamino) methyl-2-furanylmethylthiol-ethyl] -N'-methyl-2-nitro-1,1-ethenediamine. NMR + (CDCl 3): 8.90 t (3H); 7.76 S (3H): 6.8-7.5 m (7H) 7 6.5 br (281: 6.42 S (2H); 6.25 s (2H); 3.77 s (2H) 3.35 s (1H). (I) N- [2 - [[[5-I [2- (dimethylamino) ethyl] amino] methyl-2-furanylmethyl] thioethyl] -N'-methyl-2-nitro- 1,1-ethenediamine.

NMRT (cnc13n 7.79 s (en), 7-7, sm nom; 6.6 m (zu), 6.22 s (2H); 3.85 m (2H): 3.37 s (1H); 2-3.2 br (1H); 0.8-0.2 br (1H) (j) N- [2- [5- (dimethylamino) methyl-2-furanylmethoxy] ethyl] -N'- -methyl -2-nitro-1,1-ethenediamine, mp 110-112 ° C. 454 882 36 Example 15 N-methyl-2-nitro-N '- [2-II [5 - [(1-pyrrolidinyl) methyl] - 2-furanylmethyl] thio] ethyl] -1,1-ethenediamine.

A mixture of 2.1 g of 2 - [[5- (1-pyrrolidino) methyl-2-furanylmethyl] thio] ethanamine bisoxalate salt. 1.12 g of potassium hydroxide and 0.9,9 N-methyl- (1-methylthio) -2-nitroethanamine were stirred in 9 ml of water at room temperature for 18 hours. The water was removed by evaporation under reduced pressure, and the residue was extracted with ethyl acetate in presence of an excess of anhydrous sodium carbonate. After evaporation of the solvent, a residue was obtained, which was crystallized from isopropyl acetate.

This gave 0.9 g of product as a white crystalline solid, m.p. 79-82 ° C. Analysis: Found: C 52.78; H 7.05; N 16.57. Calculated for C 15 H 24 N 4 O 3 S: C 52.92; H 7.11; N 16.46%. Example 16 N- [2 - [[[S- (methylamino) methyl-2-furanyl] methyl] thio] ethyl1- -N'-methylurea.

To a stirred solution of 2.0 g of N- [2-mercaptoethyl] -N'- -methyl urea in concentrated hydrochloric acid was added dropwise at 0 ° C a solution of 2.0 g of 5- (methylamino) methyl 42-furanmethanol in 3 ml of water . After 24 hours, 100 ml of ethyl acetate and an excess of anhydrous sodium carbonate were added. The suspension was filtered, the filtrate was evaporated to dryness, and the oily residue was subjected to column chromatography on silica, eluting with a mixture of methanol and ammonia (0.88) in a volume ratio of 79: 1. The eluate fractions containing the desired product were evaporated to dryness. This gave 0.42 g of an oil which was identical to the product prepared in Example 4.

Example 17 N-cyano-N '- [2- [II5- (dimethylamino) methyl-2-furanyl] methyl] -thio] ethyl] -N "-methylguanidine.

To a stirred solution of 1 g of N-cyano-N '- (2-mercaptoethyl) -N "-methylguanidine in concentrated hydrochloric acid was added at 0 DEG C. 0.98 g of 5- (dimethylamino) -2-furanmethanol dropwise over a period of After 3 hours at room temperature, the few 454 882 37 "solution were neutralized with an excess of anhydrous sodium carbonate, and the resulting solid was extracted with ethyl acetate. After evaporation of the solvent, an oil was obtained which, after purification by column chromatography, gave a product identical to the product prepared in Example 10.

Example 18 N- [2 - [[5- (aminomethyl) -2-furanylmethyl] thio] ethyl] -N "-cyano- -N'-methylguanidine. 2- (5-chloromethyl-2-furanylmethyl) -1H-isoindole -1,3- (2H) -dione 10 g of 2- (hydroxymethyl-2-furanylmethyl) -1H-isoindole-1,3- - (ZH) -dione was dissolved in 15 ml of thionyl chloride under gentle heating. evaporated to dryness, and the solid residue was taken up in a mixture of equal volumes of cyclohexane and benzene, after which it was again evaporated to dryness, the residue thus obtained was suspended in ether, the suspension was filtered off and the filtered substance was washed with ether and dried. This gave 10.1 g of 2- (5-chloromethyl-2-furanylmethyl) -1H-isoindole-1,3- (2H) -dione, m.p. 119 DEG-180 DEG C. (decomposition). c 61.32; u 3.71; N 5.00 Calculated for C 14 H 10 ClNO 4: C 60.99; H 3.66; N 5.08%.

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

To a stirred solution of 1.0 g of N "-cyan-N- (2-mercaptoethyl) -N'-methylguanidine and 0.152 g of sodium hydride in 4 ml of dry dimethylformamide was slowly added at room temperature a solution of 1.74 g of 2- (5-Chloromethyl-2-furanylmethyl) -1H-isoindole-1,3- (2H) -dione in 8 ml of dry dimethylformamide After stirring for 2 hours, the reaction mixture 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 formed was filtered off and recrystallized from methanol to give 1.4 g of the desired compound, m.p. 179-182 ° C.

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

A suspension of 4.45 g of N "-cyan-N- [2 - [[5 - [(1,3-dioxo-2H-isoindol-yl) methyl] -2-furanylmethylthioethyl] -N'-methylguanidine and 0.6 g of hydrazine hydrate in 35 ml of methanol was refluxed for 45 hours. The suspension was then evaporated to dryness, and the residue was dissolved in 15 ml of water at 0 ° C and neutralized with 5 N hydrochloric acid. was filtered, an excess of anhydrous sodium carbonate was added, and the solution was evaporated to dryness, the residue was mixed with anhydrous sodium sulfate and the solid mass was extracted with ethanol.After evaporation of the extract a semi-solid was obtained which was mixed with anhydrous sodium sulfate and extracted 2.12 g of an oil were obtained, which was subjected to column chromatography on silica, eluting with a mixture of methanol and ammonia (0.88) in a volume ratio of 79: 1, and the fractions containing it were evaporated. desired product, thereby obtaining an oil which slowly solidified. This gave 1.88 g of the desired product, m.p. 80-82 ° C.

Analysis: Found: C 49.57; H 6.66; N 25.93. Calculated for C 11 H 17 N 5 OS: C 49.41; H 6.41; N 26.20%.

Example 19 N-cyano-N '- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thioethyl] -N "-methylguanidine.

N-cyano-N '- [2 - [[[5- (methylamino) methyl-2-furanyl] methyl] thio] ethyl] carbamimidothioic acid methyl ester. 1.07 g of 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethanamine was added to a solution of 0.73 g of N-cyanimidocarbamic dithioacid dimethyl ester in ether, after which the resulting mixture the mixture was stirred overnight. The crystalline solid formed was filtered off, washed with ether and dried. There was obtained 1.14 g of N-cyano-N '- [2 - [[[5- (dimethylamino) methyl-2--furanylmethyl] thio] ethyl] carbamimidothioic acid methyl ester having a melting point of 78-79 ° C.

N'CYaU'N "[2- {[1- (dimethylamino) methyl-2-furanyl] methyl] -thioethyl] -N" -methylguanidine.

A solution of 1.06 g of N'-cyano-N- [2-I [[5- (Amethylamino] methyl-2-furanyl] methyl] thio] ethylcarbamimidothioic acid methyl ester in 10 ml of a 33% ethanol solution of methylamine was stirred at room temperature for 4 hours. The solution was then evaporated to dryness, and the oily residue was crystallized from a mixture of ethyl acetate and light gasoline (b.p. 80-100 ° C). The desired product with a melting point of 77 DEG-100 DEG C. was obtained. 'Exemgel 20 N-cyano-N '- [2- [II5- (dimethylamino) methyl-2-furanyl] methyl] -thioethyl] -N' -heptylguanidine.

A mixture of 1.15 g of heptylamine and 3.12 g of N-cyano- -N '- [2 - [1- [5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] urea thiamic acid was heated on a oil bath at 100 ° C for 12 hours. The resulting product was chromatographed on silica using methanol (Rf = 0.49). There was obtained 2.31 g of N-cyano-N '- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N "-heptylguanidine hydrate. Analysis: Found: C 56.99; H 8.32; N 17.53 Calculated for C 19 H 33 N 5 OS.H 2 O: C 57.43; H 8.81; N 17.63%. As eluent Example 21 ia) N- [2 - [[ N5- (dimethylamino) methyl-2-furanylmethyl] thio] ethyl] -N '- (2-methoxyethyl) -2-nitro-1,1-ethenediamine A mixture of 2.14 g of 2 - [[[5- ( dimethylamino) methyl-2-furanylmethylthioletanamine and 1.65 g of 1,1-bis (methylthio) -2-nitroethylene were refluxed in acetonitrile for 8 hours.

The solvent was then removed, and to the residue was added an ethanolic solution of 0.75 g of 2-methoxyethylamine. The resulting mixture was refluxed for 8 hours, after which the solvent was evaporated. This gave an oil which was purified by column chromatography. 1.0 g of N- [2 - [[[5- - (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N '- (2-methoxyethyl) -2-nitro-1, 1-ethenediamine.

NMRI (CDCl 3) 7.73 s (6H); 7-7, sm (211): δ, 2-7 m (HH) 6.23 s (2H); 3.81 s (2H): 3.42 S ( TH).

In a similar manner the following compound was also prepared: (b) N- [2- [115- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -2-nitro-1,1-ethylenediamine; mp 100-101 ° C. 454 882 Exemgel 22 (a) N- [4- [5- (dimethylamino) methyl-2-furanylbutyl] -N'-methyl--2-nitro-1,1-ethenediamine.

A mixture of 0.7 g of 4- [5- (dimethylamino) methyl-2-furanylbutanamine and 0.6 g of 1,1-bis (thiomethyl) -2-nitroethylene in 12 ml of acetonitrile was boiled under reflux for 22 hours. was removed, and to the residue was added a 33% ethanol solution of methylamine. The resulting mixture was refluxed for 2 hours. The solvent was then removed, and the residue was purified by column chromatography on silica using methanol as eluent. 310 mg of N- [4- [5- (dimethylamino) methyl-2-furanyl] butyl] -N'-methyl-2-nitro-1,1-ethylenediamine were obtained. Analysis: Found: C 55.54; H 8.23, N 17.75.

Calculated for C 14 H 24 N 4 O 3 .1 / 2H 2 O: C 55.26; H 8.22; N 18.42%.

In a similar manner the following compounds were also prepared: (b) N- [5- [5- (dimethylamino) methyl-2-furanyl] pentyl] -N'-methyl--2-nitro-1,1-ethylenediamine. Analysis: Found: C 56.76; H 8.36; N 17.37. Calculated for c15n26N4o3.1 / 2 a2o = c 56.43; M p, 46; N 17.55%. (c) N- [3 - [[5- (dimethylamino) methyl-2-furanyl] thio] propyl] -N'-methyl-2-nitro-1,1-ethenediamine. Analysis: Found: C 49.36; H 7.19; N 17.45. Calculated for C 13 H 22 N 4 O 3 S: C 49.66; H 7.05; N 17.84%. (d) N-[3- [5- (dimethylamino) methyl-2-furanyl] propyl] -N'-methyl--2-nitro-1,1-ethenediamine. Analysis: Found: C 55.09; H 7.84. Calculated for C 13 H 22 N 4 O 3: C 55.31: H 7.72%. (e) N- [2- [1- [5- (diethylamino) methyl-2-furanyl] methyl] thiol] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine. Analysis: Found: C 51.38; H 7.44; N 15.66. Calculated for C 15 H 26 N 4 O 3 S.1 / 2H 2 O: C 51.26; H 7.74; N 15.94%. (f) N- [3 * [[[5- (dimethylamino) methyl-2-furanylmethyl] thio] propyl] -N'-methyl-2-nitro-1,1-ethylenediamine. Analysis: Found: c 49.57; H 7.20; N 15.59. Calculated for c14n24N4o3s.1 / 2H2O = C 49.86; H 7.47; N 16.61%. 454 882 41 --- Example Gel 23 (a) N-cyano-N'-1- [4- (dimethylamino) methyl] -2-furanylButyl] N "-methylguanidine.

A mixture of 0.4 g of 4- [5- (dimethylamino) methyl-2-furanyl] butanamine and 0.3 g of N-cyanimidocarbamedithioic acid dimethyl ester was stirred in ethanol at room temperature for 3 hours. A 33% solution of methylamine in ethanol was then added, and the resulting mixture was refluxed for 2 hours.

The solvent was then evaporated under reduced pressure, and the product formed was purified by column chromatography on silica using methanol as eluent.

The desired product was thus obtained as a light yellow oil.

NnnT (9H); 4.0 m (2H); 2.8 - 3.7 m (2H). In a similar manner the following compound was also prepared: (b) N-cyano-N '- [5- [5- (dimethylamino) methyl-2-furanyl] pentyl] -N'-methylguanidine. NMR (CDCl 3): 8-8.7 br (63): 7.68 S (6H); 7.32 t (2 H); 7.10 d (3 H); 6.7 kv (2 H); 6.48 s (2 H); 3.8-4.3 m (45).

Example Gel 24 (a) N- [2- [1- [5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methanesulfonyl-N "-methylguanidine.

A mixture of 1.9 g of methanesulfonyliminodithiocarbamic acid dimethyl ester and 2.14 g of 2-[[5- (dimethylamino) methyl-2-furanylmethyl] thioletanamine was stirred in ethanol at room temperature for 3 hours. 20 ml of a 33% Ethanol solution of methylamine was then added, and the resulting mixture was refluxed for 16 hours. The product was purified by column chromatography on silica using methanol as eluent. This gave 2.7 g of N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methanesulfonyl-N "-methylguanidine as a light oil. Analysis: Found: C 43.54; H 7.05; N 15.48. Calculated for C 13 H 24 N 4 O 3 S.1 / ZH 2 O: C 43.70; H 7.00; N 15.69%.

In a similar manner the following compound was also prepared: (b) N-benzenesulfonyl-N '- [2 - [[1-5 (dimethylamino) methyl] -2- -furanylmethylthioethyl] fN "-methylguanidine. Analysis: Found: C 50.30; H 6 (25; N 12.93. Calculated for C 18 H 26 N 4 O 3 S. H 2 O: C 50.47; H 6.54; N 13.08%. 454 882 42 Example 25 N-cyano-N '- [2 - [[[5 - (dimethylamino) methyl-2-furanyl] methyl] -thiolethyl] -N "-methylguanidine.

A solution of 8.5 g of silver nitrate in 50 ml of dimethylformamide was added dropwise to a solution of 6.1 g of N-cyano-N'-methylcarbamimidothioic acid methyl ester, 4.8 g of triethylamine and 7.8 g of 2 - [[ [2-furanylmethyl] thioletanamine in 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 layer was dried and evaporated to give an oil. This oil gave 3.9 g of crystalline N-cyano-N'- - [2 - [[[2-furanyl] methylthioethyl] -N "-methylguanidine with a melting point of 78-82 ° C.

A solution of 4.5 g of the amine prepared, 3.1 g of dimethylamine hydrochloride and 3.16 g of a 36% aqueous solution of formaldehyde in 20 ml of ethanol was heated at 50 ° C for 60 hours. The residue was partitioned between ethyl acetate and an aqueous base. The organic extracts were combined, dried and evaporated. An oil was obtained which, on treatment with sebacic acid in isoprohanol, gave the sebacic acid salt of the desired compound. 2 g of salt with a melting point of 93-94 ° C were obtained.

Example 26 N- [2 - [[1- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methylthiourea. 1.52 g of carbon disulfide were added with stirring to a cooled solution of 0.8 g of sodium hydroxide in 1.7 ml of water. 4.28 g of 2-II [5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine were added slowly, and after the addition was complete, the resulting mixture was heated at 100 ° C for 2 hours. After cooling to a temperature below 40 ° C, 1.940 ml of ethyl chloroformate were added, and stirring was continued for another 30 minutes.

The lower thick yellow oil was extracted with chloroform, after which the chloroform extract was dried and evaporated. There was thus obtained N, N-dimethyl-5 - [[[2- (isothiocyanato) ethyl] thio] methyl] furan-methanamide as an oil. Rf = 0.43 (silica / methanol). 0.46 g of the crude isothiocyanate was dissolved in 25 ml of a 33% ethanol solution of methylamine, and the resulting solution was allowed to stand overnight. 0.16 g of N - [2 - [[[5- - (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methylthiourea was isolated as a light oil. This product was identical to a product prepared from 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine and methyl isothiocyanate.

Example 27 N-cyano-N '- [2 - [[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N "-methylguanidine.

A solution of 1.3 g of N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methylthiourea was refluxed with 1.5 g of lead cyanamide. The solution was then filtered, and the filtrate was evaporated. Upon treatment of the residue with a solution of sebacic acid in isopropanol, the desired compound was obtained in the form of monosebacate salt. 0.7 g of this salt with a melting point of 90-92 ° C was obtained.

Example 28 Pharmaceutical compositions. (a) Tablets for oral administration, each containing 50 mg of active ingredient.

For the preparation of 10,000 tablets the following substances are mixed: Active ingredient 500 g Anhydrous lactose USP 2.17 kg Starch Sta-Rx 1500 * 300 g Magnesium stearate BP 30 g * A form of directly compressible starch from AE Stanley Mfg Co (London) Limited, Orpington, Kent.

The active ingredient is sieved through a 250 μm sieve, after which the four components are intimately mixed in a mixer. The resulting mixture is compressed into tablets in a tablet machine equipped with punches with a diameter of 8.5 mm. 454 882 44 (b) Injection preparations for intravenous administration containing 200 mg of active ingredient per 2 ml.

The active ingredient is dissolved with stirring in water of a grade suitable for injection, and dilute hydrochloric acid is added until the pH becomes 5.0. The active ingredient is dissolved in such an amount that the solution will contain 10.0% by weight of active ingredient. The solution is bubbled with nitrogen and then clarified by filtration through a membrane filter with a pore size of 1.35 μm. The solution is filled into 2 ml glass ampoules (2.2 ml each), and each ampoule is sealed under a nitrogen atmosphere. The ampoules are sterilized in an autoclave at 121 ° C for 30 minutes. g (c) Oral tablets with a long excretion time each containing 150 mg of active ingredient.

For the preparation of 10,000 tablets, the following substances are mixed: Active ingredient '1.50 kg Cutina HR ** 0.40 kg anhydrous lactose USP 2,060 kg Magnesium stearate BP 7 40 g ** Cutina HR is a quality of microfine, hydrogenated castor oil from Sipon Product Limited, London.

The active ingredient, the anhydrous lactose and the main part of Cutina HR are mixed intimately, whereupon the resulting mixture is moistened by adding a 10% solution of the remainder of Cutina HR in industrial methylated spirits (OP 74). The moistened mass is granulated through a sieve with an opening of 1.2 mm, after which the granules are dried at 50 ° C in a fluidized bed. The granules are then passed through a sieve with an opening of 0.85 mm and mixed with the magnesium stearate. The resulting mixture is compressed into tablets with a hardness of at least 10 kp (according to Schleuniger) on a tablet machine equipped with 12.5 mm diameter punches. fi »454 882 as (d) Syrup for oral administration. An aqueous syrup containing active ingredient is prepared in an amount of 2.0 g per 100 ml and sorbitol solution EPC in an amount of 60% by volume and the required amounts of dilute hydrochloric acid and flavors. The active ingredient is dissolved in part of the water with stirring, and hydrochloric acid is added gradually until the pH has dropped to 5.0.

Then the sorbitol solution, the flavors and the rest of the water are added, and the pH is readjusted to 5.0. The syrup is clarified by filtration through a suitable cellulose filter. (e) Capsules for oral administration, each containing 50 mg of active ingredient.

To make 10,000 capsules, the following substances are mixed: - Active ingredient 500 g Starch Sta-Rx 1500 1 700 g Magnesium stearate BP 20 mg The active ingredient is sieved through a sieve with an opening of 250 μm and then mixed with the other components.

The resulting powder mixture is filled into No. 3 hard gelatin capsules by means of a suitable machine. (f) Salva.

An ointment containing 2.0% by weight of active ingredient and 98% by weight of white soft paraffin BP is prepared. The active ingredient is sieved through a 150 μm sieve and then mixed uniformly with the paraffin in a high shear mixer. (g) Cream.

A cream containing the following substances is prepared: Active ingredient 2.0% by weight Cetomacrogol emulsifying ointment BP 30.0% by weight Chlorocresol 0.1% by weight Distilled water residue The active ingredient is sieved through a sieve with an opening of 150 μm and then mixed intimately with the Cetomacrogol ointment at 65 ° C. The chlorocresol is dissolved in water at 65 ° C, and the resulting solution is mixed with the oily drug mixture. The resulting emulsion is stirred continuously under cooling to give a cream.

The active ingredient in the above compositions is a compound of formula I. Particularly useful is the compound of Example 10.

The new compounds of formula I have been found to be able to inhibit the gastric juice secretion induced by histamine. This has been demonstrated in experiments with rats according to a modification of the method described by, among others, N Ghosh and Ii O Achild, British Journal of Pharmacology 1958, Vol 13, p. 54.

As experimental animals, female rats weighing about 150 g were used. The rats are allowed to starve overnight and then given an 8% solution of sucrose in normal saline instead of drinking water.

The rats are anesthetized by a single intraperitoneal injection of a solution containing 25 g of urethane per 100 ml.

The urethane solution is injected in an amount of 0.5 ml per 100 g body weight. After anesthesia, needles are inserted into the trachea and jugular veins.

The stomach is exposed through an incision in the middle of the abdominal wall, and the stomach is separated from the liver and spleen by cutting off the connecting tissues. A small opening is made in the upper sac-shaped enlargement of the stomach, and the stomach is washed with a 5% dextrose solution. A cannula consisting of a rubber tube is inserted into the esophagus, and the esophagus and nerves are then cut off above the cannula.

A small opening is then made in the stomach port. A large plexiglass cannula is then inserted into the stomach through the opening in the upper sac-shaped dilation of the stomach, and this cannula is positioned so that the inlet end of the cannula protrudes from the stomach through the opening in the gastric port. This cannula has such a shape that it reduces the effective volume of the stomach and causes a turbulent flow of the perfusion fluid over the mucosa. A drainage cannula is then inserted through the opening in the upper sac-shaped dilation of the stomach. Both cannulas are held in place by means of ligatures arranged in such a way that they do not come into contact with the main blood vessels. The needles skin 454 882 47 extend through holes in the body wall. Through the cannulas in the esophagus and gastric port, a 5% dextrose solution is passed through the stomach. The dextrose solution has a temperature of 39 ° C, and the flow rate through each cannula is 1.5 ml per minute.

In the starting dextrose solution, the pH value is determined.

Normal gastric juice secretion is determined by measuring the pH of the perfusion effluent. Increased gastric juice secretion is then induced by a continuous intravenous infusion of a sub-maximal dose of histamine. In this way a stable elevated level of the nasal secretion is achieved, and when this stable state has been reached, the pH value of the perfusion effluent is again measured.

The test compound is then administered by intravenous injection, and the change in gastric secretion produced by this administration is determined by measuring the change in the pH of the perfusion effluent.

Using the pH measurements, the increase in gastric juice secretion achieved by histamine is calculated, and this increase is expressed as moles of hydrogen ions per liter. The reduction in this increased gastric juice secretion, which is achieved by administering test compound, is also calculated as moles of hydrogen per liter. The percentage reduction in the elevated gastric juice secretion produced by the administration of the test compound can then be calculated.

The test compound is administered in three or more doses, using at least four rats per dose. ED50 is calculated, ie the dose of the tested compound which reduces by 50% the increased gastric juice secretion induced by histamine. The results obtained are summarized in the table below.

Compound of Example ED50 mg / kg 2 (c) 1.5 8 0.65 9 (a) 2.30 10 1.39 14 (a) 0.23 14 (f) 0.8 14 (h) 0.48 21 ( a) 22 (a) 0.55

Claims (7)

.'454 882 48 W. P a t e n t k r a v 1. Process for the preparation of compounds of the general formula} Y 11 \ \ _ ll _ =: xx-Anka> (CH¿JnX (CHQHJWICNHM; m / O H2 and physiologically acceptable salts and hydrates thereof, wherein the symbols R1 and R2, which may be the same or different, each represents a hydrogen atom, a lower alkyl group, an aralkyl group or a lower alkyl group interrupted by a group -n-, where R4 represents R4 hydrogen or lower alkyl, or where the symbols R1 and R2 together with the nitrogen atom, to to which they are attached form a heterocyclic ring, which may additionally contain an oxygen atom or a group -h-, wherein R 3 represents a hydrogen atom, a lower alkyl group, R 4 a lower alkenyl group or an alkoxyalkyl group, wherein X represents CH 2, O or S; where Y represents = S, = O, = NR 5 or = CHR 6; where Alk represents a straight or branched alkylene chain containing 1-6 carbon atoms; where R 5 represents a hydrogen atom, a nitro group, a cyano group, a lower alkyl group, an alkylsulfonyl group or an arylsulfonyl group; where R6 represents a nitro group; where mb e- represents an integer from 2 to 4 and where n represents 1 or 2, or where n represents 0, 1 or 2 when X represents S or CH 2; with the proviso that Y cannot represent the group CHNO2 when R1, R. and R2 denote S, n denotes 1 and m denotes 2, denoted denotes methyl, Alk denotes methylene, X denotes that ia) a compound having the formula / Fa n 1. \ n-Anç JN) L (<'H; ») rf <(°“ 2) ml' "12 (m - (i, v 454 882 49 ~ - where R1, R2, Alk, n, X and m have the meanings given above, are reacted with a compound which can introduce a group of the formula -CNHR where R u 3, 3 and Y have the meanings given above, Y or that (b) a compound of the formula R 1 \ NA k II (III) / - 1 i O 1- (cllâhguclxæmran fi- p H2 Q where Q represents = NR5 or = CHR6, where P represents halogen, 3,5-dimethylpyrazolyl, methylthio or alkoxy, and where R Alk, X, n and m have the meanings given above, are reacted with a primary amine of the formula RBNHZ, where R3 has the meaning given above, to give compounds of the formula I, where Y represents a group = NR5 or = CHR6; or that (c) a compound of any of the following formulas R. l ~ \\ - I n \ [Ü * N-Alk_l \\ o // __ CHÉOH7 J N_ ^ 1k // L_CHqCl /. o = n? (v) (VI) where R 1 and R 2 have the meanings given above, and R 7 represents a hydrogen atom or an acyl group, wherein in addition the symbols R 1 and R 2 may be protected when they represent hydrogen atoms, is reacted with a thiol of the formula HS (CH 2 ) mNH% NHR3 (VII) Y after which any protecting group is removed, to give compounds of formula I, where X represents sulfur and n represents 1, and where Y has a meaning other than = CHNO2 when both R 1 and R 2 represent hydrogen; or that (d) a compound of formula I, wherein Y represents sulfur, is reacted with a heavy metal cyanamide to form compounds of formula I, wherein Y represents a group NCN; or that (e) a compound of the formula L \ 0 / J .. (CH2) nX (CU2) mNHñNHR3 NR 5 (vili) is subjected to a Mannich reaction with a suitable aldehyde and a secondary amine or a salt of a primary amine or a second amine to form compounds of formula I, wherein Y represents an = NR 5 and Alk represents a methylene group or a branched alkylene group; or that (f) a compound of the formula ni - ::; N-Alu h \ 0 / J ___ (cn2) nx (cH2) mncs (mv) n. Q where R1, R2, Alk, X, m and n have the the meanings given above, are reacted with an amine of the formula R 3 NH 2, where R 3 has the meaning given above, to give compounds of the formula I, wherein Y represents sulfur; wherein in all cases the final product is optionally isolated as a physiologically acceptable salt or converted from such a salt to another. Process according to claim 1, alternative (a), characterized in that the compound which can introduce the group -fiNHR is an alkali metal cyanate, an alkali metal thiocyanate, an isocyanate of the formula R3NCO, an isothiocyanate of the formula R NCS, a compound of the formula R 3 NH 6 -P- or a compound of the formula R 3 NH 3 - P 2, where P represents halogen, 3,5-dimethylpyrazolyl, CHR 6 methylthio or alkoxy. 3. A process according to claim 1, alternative (b), characterized in that the compound of formula II is reacted with a compound of the formula wherein P, R 5 and R 6 have the meanings given in claim 1, after which the resulting compound III is reacted with a primary amine of the formula R 3 NH 2, wherein R 3 has the meaning given in claim 1. Process according to claim 1, alternative (f), characterized in that the compound of formula II is reacted with carbon disulfide and then with a chloroformate ester, after which the resulting compound IV is reacted with an amine of formula R 3 NH 2, wherein R 3 has it in claim 1 specified meaning. A process according to claim 1 for the preparation of compounds of formula I, wherein R 1 and R 2 independently represent a hydrogen atom, an alkyl group containing 1-3 carbon atoms or a phenethyl group, or wherein R 1 and R 2 together with the nitrogen atom forms a pyrrolidine ring; Alk denotes an alkylene chain containing 1-3 carbon atoms; Y represents = S, = CHNO or = NR 5, where R represents nitro, cyano, methylsulfonyl or benzenesulfonyl; R 3 represents a hydrogen atom, an alkyl group containing 1-3 carbon atoms, a propenyl group or an alkoxyalkyl group containing 3 carbon atoms; n + m is 3 or 4; and X has the meaning given in claim 1. w '454 882 _ 52 "" A process according to claim 1 for the preparation of compounds of formula I, wherein - R 1 represents a hydrogen atom, a methyl group or an ethyl group; R 2 represents a methyl group or an ethyl group; Alk represents a methylene group; Y represents a = NCN, = NNO2 or = CHNO2; R 3 represents a hydrogen atom or a methyl group; X represents S or CH 2; n denotes 1 and m denotes 2. A process according to claim 1 for the preparation of N- [2- - [1- [5- (methylamino) methyl-2-furanyl] methyl] thio] ethyl] -N '# methyl-2-nitro-1,1-ethylenediamine.