CH642072A5 - Process for the preparation of aminoalkylfuran derivatives - Google Patents

Abstract

Novel aminoalkylfuran derivatives of the general formula I: <IMAGE> in which the symbols have the meaning indicated in Claim 1, are prepared by reaction of a compound of the formula <IMAGE> 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

The invention relates to a process for the preparation 60 of aminoalkylfuran derivatives of the general formula I:

Rl \ / \ ^

X-AIk - <o (CH2) nX (CII2) mWI {; N-HH; s (i)

R2

642 072

4th

and their hydrates and physiologically acceptable salts, wherein R 1 and R 2, which may be the same or different, represent hydrogen, Ci_8-alkyl, cycloalkyl, C ^ -alkenyl, aralkyl or Cj_8- '

Alkyl which is represented by an oxygen atom or a group -N-

R4

is interrupted, in which R4 has the meaning hydrogen or Ci_g-alkyl, or in which Ri and R2, together with the nitrogen atom to which they are attached, can form a heterocyclic ring which, as heteroatoms O and / or -N-

r4

may contain, in which R3 furthermore represents hydrogen, Q_r alkyl, C3.fi-alkenyl or alkoxyalkyl, -X-represents-CTk-, -O- or -S-, = Yfor = S, = 0, = NR5 or = CHR6 represents Alk represents a straight-chain or branched alkylene chain with 1 to 6 5 carbon atoms, Rs represents H, nitro, cyano, C 1-6 alkyl, aryl, alkylsulfonyl or arylsulfonyl, R6 represents nitro, arylsulfonyl or alkylsulfonyl, m is an integer from 2 to 4 and n is 1 or 2, or when -X- is -S- or -CH2-, n is 0, 1 or 2, characterized in that 10 a compound of the formula:

R. R NAik x 2

/ ^ o-A

(CH2> nX (CH2> mN

(xx-l)

wherein Ri R2, Alk, ri, X and m have the meaning given above; A is hydrogen and B is hydrogen or the group CP (where P is a removable group and Q is = NRS or = CHR6, where R5 and R6 have the meaning given above), or A and B together stand for = CS; with a compound of the formula R3NZZ ', in which Z is hydrogen and Z' is hydrogen or the group -C-P, or Z 'and Z together are = CO or

= CS, where R3 has the meaning given above, if desired isolating the end product as a physiologically acceptable salt or hydrate or converting such an end product into another salt or hydrate.

The term "aryl" for a group or part of a group preferably means phenyl or phenyl which is substituted, e.g. with alkyl, alkoxy or halogen.

The compounds produced according to the invention have the advantage that they can be readily produced from readily available starting materials.

All compounds of formula I can be in tautomeric form. The formula is intended to include all tautomeric compounds. If Alk represents a branched chain alkylene group, then optical isomers can be present. In this case, the formula should include all diastereoisomers and optical enantiomers.

In a preferred class of compounds prepared according to the invention, the following groups have the following meanings:

R1 and R2 are independently hydrogen, alkyl, phenylalkyl or dialkylaminoalkyl or these substituents together with the nitrogen atom form a 5- or 6-membered saturated heterocyclic ring, e.g. a Morpholino, Piperidino, Pyrrolidino or N-alkylpiperazine ring. Alk stands for a straight-chain alkylene chain with 1 to 4 carbon atoms.

Y is = S, = 0, = CHN02 or = NR5, where R5 is hydrogen, nitro, cyano, lower alkyl, alkylsulfonyl or benzenesulfonyl.

X, m, n and R3 have the meaning given above.

In a particularly preferred class of compounds prepared according to the invention, the following groups have the following meanings:

Ri and R2 independently of one another represent hydrogen, alkyl having 1 to 3 carbon atoms or phenetyl or these substituents.

25th

30th

35

ducks form a pyrrolidine ring together with the nitrogen atom.

Alk stands for an alkylene chain with 1 to 3 carbon atoms. Y stands for = S, = CHN02 or = NR5, where R5 has the meaning nitro, cyano, methylsulfonyl or benzenesulfonyl.

R3 represents hydrogen, alkyl having 1 to 3 carbon atoms, propenyl or alkoxyalkyl having 3 carbon atoms.

n + m has the value 3 or 4 and X has the above meaning.

In a further preferred class of compounds prepared according to the invention, the following groups have the following meanings:

Ri and R2 independently of one another represent H, alkyl having 1 to 3 carbon atoms, phenetyl or these substituents together with the nitrogen atom form a pyrrolidine ring. Alk stands for an alkylene group with 1 to 3 carbon atoms. = Y stands for = S, = CHN02 or = NR5, where R5 stands for nitro, cyano, methylsulfonyl or benzenesulfonyl.

X stands for S or -CH2-40 R3 stands for hydrogen, methyl or methoxyethyl.

n is 1 and m is 2 or 3.

In a further particularly preferred class of compounds prepared according to the invention, the following groups have the following meanings:

45 Ri stands for hydrogen, methyl or ethyl.

R2 stands for methyl or ethyl.

Alk stands for a methylene group.

= Y stands for = NCN, = NN02 or = CHNOz.

R3 stands for hydrogen or methyl.

50 X stands for -S- or -CHr.

n is 1 and m is 2.

Individual compounds produced with particular preference are the following:

N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -55 ethyl] -N '- (2-methoxyethyl) thiourea; N- [2 - [[[5- (methylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-l, 1-ethylenediamine;

N- [2 - [[[5- (ethylmethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-l, 1-ethylenediamine; 60 N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-nitroguanidine;

N- [2 - [[[5- [3-dimethylamirto) propyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-l, 1-ethylenediamine; N- [4- [5- (dimethylamino) methyI-2-furanyl] butyI] -N'-methyI-65 -2-nitro-l, 1-ethylenediamine;

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

as well as their physiologically acceptable salts, especially the

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Hydrochloride.

A very particularly preferred aminoalkyl furan derivative is the N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-l, 1-ethylenediamine, as well as its physiologically acceptable salts, especially its hydrochloride.

The compounds prepared according to the invention readily form physiologically acceptable salts. Such salts are e.g. Salts with inorganic and organic acids, e.g. B. the hydrochlorides, hydrobromides and sulfates. Particularly suitable salts of organic acids are formed with aliphatic mono- or dicarboxylic acids. Examples of such salts are the acetates, maleates and fumarates. The compounds can also form hydrates.

The compounds produced according to the invention can be administered orally, topically or parenterally or in the form of suppositories. The preferred route of administration is oral administration. They can be administered in the form of the base or as physiologically acceptable salts. They are generally blended with a pharmaceutically acceptable carrier or diluent to give a drug.

The compounds produced according to the invention can be used in combination with other active ingredients, e.g. usual

R-,

R,

N-alk

I I

Antihistamines can be administered when necessary. For oral administration, the drug may most conveniently be in the form of capsules or tablets, which may also be sustained release tablets. The 5 drugs can also be in the form of coated tablets or in syrup form. Suitable topical preparations are e.g. Ointments, lotions, creams, powders and sprays.

A suitable daily dose by the oral route can e.g. B. in the range of 100 mg to 1.2 g per day, in the form of io dosage units containing 20 to 200 mg per dosage unit. A suitable administration pattern in the case of a sustained release tablet is two or three times a day.

Parenteral administration can be by injection at 15 intervals or as a continuous infusion. Injectable solutions can contain 10 to 100 mg / ml of active ingredient.

Sprays, ointments, creams or lotions can be used for topical applications. These preparations can contain an effective amount of the active ingredient, e.g. B. in the order of 20 to 2 wt .-%, based on the total composition.

Compounds of the formula are agents for carrying out the process according to the invention

(CII2) nX (CH2) nN1T ^ ~ p (IXI>

to be mentioned in which = Q stands for = NRS or = CHRé, and R1; R?, n, X and m have the meanings given above. These

Compounds are made by reacting an amine of the formula

R

N

N-alk

R

(cn2) nx (cHc,) “ra

2'm 2

(IX)

l.

with a compound of formula P

or the formula

50

p p

\ /

ÏRp in which R5 and R6 and P have the meaning given above, temperature to reflux temperature are carried out,

produced. This reaction can be carried out in a solvent, e.g. B. Treatment of the resulting compound of Formula III ether or acetonitrile at a temperature of ambient

R-,

R,

N-alk

(cii2) nx (ch2) antic-p (hi)

where Q is = NR5 or = CHR6, have meanings with a primary amine. The amine can be in the form of R3NH2 at a temperature from ambient to free base or in the form of the salt with a weak acid,

The reflux temperature provides the desired end product. AZ-Ac • Acetic acid can be used. Compounds which are amine of the formula (II) can also be used directly and are able to introduce the group -CNHR3, e.g. B. Connection can be implemented, which is able to 65 II

Group -CHNR3, where R3 and Y are the above Y

Isocyanate R3NCO, isothiocyanate R3NCS or compounds

"'842 072

6

of the formula R3NHC-P or R3NHC-P, in which P stands for a

L i

NRs CHR6

bare group stands. The reaction with the isocyanate or isothiocyanate can be carried out by allowing the amine and the isocyanate or isothiocyanate to stand in a solvent such as acetonitrile. The reaction with R3NHC-P or R3NHC-P can be carried out in this way

II II

nr5 chr6

be that the reactants at elevated temperature, for. B. 100 to 120 ° C, melts together. Alternatively, the reaction between the amine II and R3NHC-P in a nrs

Solvents, e.g. As acetonitrile, be carried out at elevated temperatures in the presence of silver nitrate. Alternatively, the amine II and the compound R3NHC-P can be stirred in a chrg aqueous solution at room temperature. If io R3 is hydrogen, then alkali metal cyanates and thiocyanates are used. Examples of cleaving groups are halogen, thiomethyl, 3,5-dimethylpyrazolyl or alkoxy, preferably thiomethyl.

Compounds of the formula are further agents for carrying out the method according to the invention

X

R,

N-alk

(CH2) nX (CH2) mNCS

(IV)

to call. An amine of formula II can be heated with carbon disulfide and then with a chloroformate ester, e.g. Ethyl chloroformate to form an isothiocyanate IV, which is then reacted with an amine R3NH2, preferably in an alkanol as solvent, e.g. Ethanol.

Products made according to the invention where Y is sulfur can be used to obtain products where = Y is a = NCN group by combining them with a heavy metal cyanamide, e.g. of silver, lead, cadmium or mercury, and preferably implemented in aqueous solution.

In the above description of the processes available for the preparation of the compounds prepared according to the invention, primary amines of the formula II were mentioned. These products can be made by a number of methods, which are discussed in more detail below.

25th

can in the resulting compound of formula VII

0

30th

35

CH, S (CH2) mN

for example by a Mannich reaction.

Removal of the protective group by reaction with, for example, hydrazine hydrate gives an amine of the formula II. 40 In an aging process to give amines of the formula II,

where X is S and n is 1, 2-furfuryl chloride amines of the formula II, in which X is S and n is 1, can be used as the starting material. The implementation between

can from the furfurylthiol of the formula (V)

45

I I

iL

see furfuryl chloride and a co-aminoalkylthiol in which the amine group, for example as phthalimide VIII

0

-CH2SH

(V3

HS (CH2) mN

by reaction with a co-bromoalkyl phthalimide VI

0

50

Br (CH2)

getting produced. The group

0

tvO

is protected provides an intermediate of formula VII. This .5S is treated in the manner described above to give an amine of formula II.

Another method for amines II, in which X is S and n is 1, uses a starting material of the formula

60

R,

L \

R,

R,

N-alk

: N-Alk

65

R,

/

0

-CH20H

(.ix)

Under acidic conditions, this compound can be ct> -

7

rr #> 42 Q72

Aminoalkylthiol are treated, in which the amine group can be protected if desired. Alternatively, the compound of formula IX can be converted into the corresponding acetate before the reaction under basic conditions with the co-aminoalkylthiol.

Primary amines of the formula II (with the exception of those in which X is S and n has the value 0) can be prepared by reacting furan with butyllithium to form a lithio derivative X

•O

Li

(x)

which is then reacted in succession with (1) a cc, co-dihalogen compound Hal (CH2) nX (CH2) mHal (in which shark represents chlorine, bromine or iodine) and (2) potassium phthalimide. The reaction product of formula XI

(CH2) nS (CH,) “N

2'm

(x? J

is then subjected, for example, to a Mannich reaction, in which X is S and n is 0 and the protective group is reacted with, for example, hydrazine hydrate can be split off from a furan of the formula XII.

Ri

N-alk

R;

I I

^ 0

{XII)

wherein none of the substituents Rj and R2 react to the meaning water-co-bromoalkylphthalimide VI. The resulting substance has to be prepared by reacting this compound with product of formula XIII lithium and elemental sulfur and then with a

0

R,

N-alk

R,

/

0

'S (CH2) mN

(xiii)

can then be used to split off the protective group with hydrazinhy intermediates of the formula II, in which m has the value 2 and third. 45 X for S or O can also be used using

In the manufacture of an intermediate in which X is made for an ethyleneimine. This compound is oxygen and n is 1, an alcohol of a compound of formula (IX) or the isosteric thiol formula (IX) is reacted in a solvent such as dimethylformamide.

with a compound Hal (CH2) mNH2, in which shark is a halo-amine of the formula II can also be prepared in the manner of a genatom, preferably a chlorine atom, in the presence of a 50 that base from a compound of the formula XIV, in particular of potassium tert-butoxide.

. (CH2) nX (CH2) n ^ CN

(rrv)

wherein n, m and X have the meanings given above, a compound of formula II reduced.

going out. A Mannich reaction is carried out with this nitrile compound. When using a Mannich reaction, the group can be carried out, followed by 60 with lithium aluminum hydride

alk be introduced at any suitable stage, but the XVI is carried out

Reaction preferably with compounds of the formula XV or

642 072

-CHgOH

r

(XV)

(XîVl) 0

The Mannich reaction, using an appropriate 10 methylene, uses furan-2-carboxylic acid as the starting aldehyde and amine is used to make compounds. This compound is prepared with an amine of the formula in which Alk for a methylene group or a R 2 R 2 NH 2 is converted to an amide of the formula XVII, which is then a branched chain alkylene group. If Alk stands for methylene with, for example, lithium aluminum hydride, then formaldehyde is used. tion of the formula XVIII is reduced

... An alternative approach to connections where Alk for 15

. (XVUJ)

In order to convert a compound of formula XVIII to a compound of formula (IX), the hydroxymethyl group can be introduced using formaldehyde and acetic acid. If both R 1 and R 2 are hydrogen, the amino group is protected as phthalimide during hydroxymethylation. The protective group is then split off using hydrazine hydrate.

Alternatively, if none of the substituents R 1 or R 2 is hydrogen, the hydroxymethylation can be effected using butyllithium and subsequent reaction with formaldehyde.

When Alk represents a straight chain alkylene group containing 2 or more carbon atoms, the following two methods are applicable.

In a suitable process for the preparation of ethylene derivatives which are analogous to the above-mentioned methylene derivatives, the carboxylic acid XIX

25th

HOOCCH--

(XIX)

Amines of the formula n, in which n has the value 2, can be prepared by starting with a compound of the formula XX

30th

I I

■ ch2ch2z

(XX)

used instead of furan-2-carboxylic acid.

If the alkylene chain Alk is longer than 2 carbon atoms, the lithio derivative of the formula X can be reacted in succession with (1) a dihaloalkane of the formula Hai Alk Hai, in which Hai is chlorine, bromine or iodine, and (2) an amine RjR2NH, whereby a compound of formula XII is obtained in which Alk contains 3 to 6 carbon atoms.

If R 1 and R 2 are hydrogen, the amine RXR2NH is replaced by potassium phthalimide in the two reactions above. The product of both reactions is hydroxymethylated as described above, after which a protective group is optionally removed to obtain a compound of the formula IX.

If compounds in which Rx and R2 have a meaning other than hydrogen are required, then the free amino compounds can be converted into suitably substituted amino groups, for example by using formaldehyde and formic acid, according to the Eschweiler-Clarke process, whereby the Dimethylamino compounds can be obtained. However, it is preferred to use the substituted amine in an appropriate stage of the reaction.

35 wherein Z is a leaving group, e.g. Toxyloxy, Mesyloxy or Bromin, means used. This compound is reacted with a co-phthalimidoalkylthiol of the formula VIII. The resulting compound is then subjected to a Mannich reaction and the protective group is then split off, whereby the desired amine of the formula II is obtained.

The invention is illustrated in the examples. Preparation examples 1 to 4 are given before the examples, which describe the preparation of the starting materials. Examples A to L describe the preparation of amines of the formula II and related intermediates. Examples 1 to 25 finally describe compounds of the formula I. •

Production Example 1

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

A mixture of 2-furanmethanol (49 g), methylaminohydrochloride (51.5 g) and a 36% formaldehyde solution (50 ml) was stirred at 0 to 3 ° C. for 3 hours and left to stand for 16 hours. Excess sodium carbonate was added and the slurry was extracted with ethyl acetate. After removal of the solvent, the residue was distilled to give 5- (methylamino) methyl-2-furanmethanol (36.2 g), bp 111 to 113 ° C (0.2 mm).

The following substances were prepared in a similar manner from 2-furanmethanol and the corresponding amine hydrochloride:

b) 5 - [(2-phenylethyl) amino] methyl-2-furanmethanol. Oil RF value 0.45 (silica / acetone). NMR (CC14) 7.29, br.s (4H); 6.8 s (2H); 6.40 s (2H); 5.62 s (2H); 4.0 br (2H); 2.87 s (5H).

c) 5 - [(l-Methylethyl) amino] methyl-2-furanmethanol. Oil Rf 0.55 (silica / methanol). Found: C63.35; H 8.78; N 8.09. C9H15N02 theoretical values: C63.88; H8.94; N 8.28%.

65

d) 5- (ethylmethylamino) methyl-2-furanmethanol. Rf 0.32 (silica / acetone). NMR (CDC13) 8.931 (3H); 7.80 s (3H); 7.55 q (2H); 6.50 s (2H); 6.33 br.s (IH); 5.47 s (2H); 3.80 m (2H).

e) 5 - [[2- (dimethylamino) ethyl] amino] methyl-2-furanme-methanol-bismaleate salt, mp 119 to 121 ° C.

Production Example 2

5- [2- (N, N-Dimethylamino) ethyl] -2-furanmethanol: N, N-Dimethyl-2-furanethanolamine (9.8 g), 30% aqueous formaldehyde (17.5 g) and glacial acetic acid (18 ml) were heated to 70 ° C for 5 h. The reaction mixture was cooled, made alkaline with sodium hydroxide and extracted with ether. The organic extracts were distilled to give an oil, bp 90-100 ° C (0.5mm). Found: C 64.0; H 8.9; N 8.0. Theoretical values for G, H15N02: C 63.9; H 8.9; N 8.2%.

Production Example 3

2- [l- (4-bromobutyl) furan:

n-Butyllithium (1.6M in hexane, 375 ml) was added to a solution of furan (40.8 g) in dry tetrahydrofuran (375 ml) and the mixture was stirred at 40 ° C for 3 h. 1,4-Dibromobutane (129.6g) was then added at -30 ° C and the reaction mixture was stirred at room temperature for 4 hours. Water was added and the mixture was extracted with ethyl acetate. The distillation of the extract gave a clear colorless liquid, bp 60 to 62 ° C (0.5 mm Hg).

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

Dimethylamine (56 g) was added to a solution of 2- [1- (4-bromobutyl)] furan (82 g) in toluene (500 ml). The resulting solution was stirred at room temperature for 2 days and then acidified with hydrochloric acid. The acidic layer was separated, washed with ether, made alkaline with sodium hydroxide and extracted with ether. The ether extract was distilled to give a clear, colorless oil, bp 55-58 ° C, 0.8mm Hg. Hydrochloride salt mp 133 to 136 ° C. Found: C 59.01; H 9.02; N 6.87; Theoretical values for C10H17NO.HC1: C 58.96; H 8.91; N 6.88%.

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

a) n-Butyllithium (1.6M in n-hexane, 125 ml) was converted into an ice-cooled solution of N, N-dimethyl-4- (2-furanyl) butane-amine (33.4 g) in dry tetrahydrofuran (125 ml). The mixture was stirred at room temperature for 4 hours. Parafor maldehyde (6.0 g) was then added and the mixture was stirred for an additional 1 h. The reaction mixture was quenched with water and extracted with chloroform. The organic extracts were distilled to give a colorless, clear oil, bp 100-105 ° C, 0.1 mm Hg, mp 26-28.5 ° C. Found: C67.09; H10.01; N7.06; theoretical values for C "H19N02: C 66.97; H 9.71; N 7.10%.

The following substances were prepared in a similar manner:

b) 5- [3- (Dimethylamino) propyl] -2-furanmethanoI, bp 160 ° C / 0.08 mm Hg, m.p. 24 ° C. Found: C 64.66; H 9.36; N 7.39: theoretical values for C10H17NOvl / 5H2O: C 64.28; H 9.39; N 7.50%.

Production Example 4

[5- [4- [N, N-Dimethylamino] butyl] -2-furanyl] methyl ether noate:

A mixture of 5- [4- (dimethylamino) butyl] -2-furanmethanol (4.9 g), acetic anhydride (25 g) and melted and powdered sodium acetate (10 g) in benzene (25 ml) was stirred at room temperature for 24 h . The reaction mixture was with

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Diluted water (100 ml) and extracted with ethyl acetate. The combined extracts were distilled to give a clear, colorless oil, bp 100 ° C, 0.5 mm Hg. Found: C 65.62; H 9.03; N 5.95; theoretical values for Cx3H23N03: C 65.24; H 8.85; N 5.85%.

Example A

a) 2 - [[[5- (Dimethylamino) methyl-2-furanyl] methyl] thio] ethanolamine:

5- (Dimethylamino) methyl-2-furanmethanol (15.5 g) was added dropwise to a stirred ice-cold solution of cystamine hydrochloride (11.36 g) in concentrated hydrochloric acid (40 ml). After standing at 0 ° C for 18 hours, excess anhydrous sodium carbonate was added and the resulting solid was extracted with diethyl ether. Removal of the solvent and subsequent distillation of the residue gave 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanolamine (11.6 g), bp 104 to 106 ° C (0.1 mm ). Picrate salt mp 142 to 144 ° C.

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

b) 2 - [[[5- (Methylamino) methyl-2-furanyl] methyl] thio] ether anamine. Monopicrate salt mp 116-118 ° C.

c) 2 - [[[5 - [(l-methylethyl) amino] methyl-2-furanyl] methyl] thio] ethanolamine. Oil Rf 0.4 (silica / methanol 0.880, ammonia 79: 1).

d) 2 - [[[5- (diethylaminomethyl) -2-furanyl] methyl] thio] ether anamine, bp 134 to 135 ° C (1mm).

e) 2 - [[[5- (l-piperidinyl) methyl-2-furanyl] methyl] thio] etha-namine. Oil RF 0.37 (silica / methanol: 0.880 ammonia 79: 1).

f) 2 - [[[5- (aminomethyl) -2-furanyl] methyl] thio] ethanolamine, dihydrochloride, mp 222 to 224 ° C (dec.).

g) N- [5 - [[((2-aminoethyl) thio] methyl] -2-furanyl] methyl] benzeneethanolamine, oil Rf value 0.33 (silica / methanol: 0.880 ammonia 79: 1) .

h) 2 - [[[5- [2- (dimethylamino) ethyl] -2-furanyl] methyl] thio] ethanolamine, bp 150 to 155 ° C (0.04mm).

i) 2 - [[[5- (ethylmethylamino) methyl-2-furanyl] methyl] thio] ethanolamine, bp 150 ° C (0.05mm).

j) 2 - [[[5- (dimethylamino) propyl] -2-furanyl] methyl] thio] ethanolamine, Rf value 0.34 (silica / methanol: 0.880 ammonia 79: 1).

k) 2 - [[[5 - [(2-dimethylaminoethyl) amino] methyl-2-furanyl] methyl] thio] ethanolamine. Trismaleate salt mp 132 to 135 ° C.

l) 2 - [[[5- (l-pyrrolidino) methyl-2-furanyl] methyl] thio] ether anamine. Bisoxalate salt mp 136.5 to 138.5 ° C.

Example B

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

Cysteamine hydrochloride (4.5 g) was added to a chilled solution of potassium t-butoxide (8.98 g) in dry dimethylformamide (125 ml). The mixture was stirred for 20 min and [5- [4- (dimethylamino) butyl] -2-furanyl] methyl ethanoate (9.6 g) was added. The reaction mixture was heated to 90 ° C. for 4 h, poured into an ice / water mixture and extracted with chloroform. Distillation of the organic extract gave a yellow oil which, after column chromatography on silica using methanol / 0.880 ammonia (9: 1) as the eluent and, by subsequent distillation, a colorless oil with a bp of 140 ° C./0.05 mm Hg revealed. Found: C 60.81; H 9.86; N 10.44; theoretical values for C13H24N2OS: C 60.91; H 9.44; N 10.93%.

9

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

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40

Example C

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

Example D

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

80% sodium hydride (1.58 g) was added in portions to a solution of furfuryl mercaptan (6 g) in dry dimethylformamide (50 ml). After 30 minutes, a solution of 2-bromoethyl phthalimide (16.71 g) in dry dimethylformamide (65 ml) was added and the solution was heated to 110 ° C for 2 days. After removing the solvents, the residue was washed with water and extracted with ethyl acetate. The ethyl acetate extracts were combined and the solvent was removed. The residue was recrystallized from cyclohexane, giving 2- [2 - [[(2-furanyl) methyl] thio] ethyl] -IH-isoindole-1,3, (2H) -dione, mp 62 to 63 ° C, (7.8 g) was obtained.

The following substances were similarly prepared from the co-bromoalkyl phthalimide and furfuryl mercaptan:

b) 2- [3 - [[(2-furanyl) methyl] thio] propyl] -1 H-isoindole-1,3 (2H) -dione, NMR (CDC13) 7.7 to 8.3 m ( 2H); 7.2 to 7.7m (2H); 6.29s (2H); 6.23t (2H); 3.7m (2H); 2.7m (1H); 2.4m (4H).

c) 2- [4 - [[(2-furanyl) methyl] thio] butyl] -1 H-isoindole-1,3 (2H) -dione, NMR (CDC13) 8 to 8.5 m (4H); 7.49t (2H); 6.33m (4H); 3.7n (2H); 2.7m (1H); 2.3m (4H).

Example E

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

A mixture of 2- [2 - [[(2-furanyl) methyl] thio] ethyl] -1 H-isoindole-1,3 (2H) -dione (10 g), dimethylammonium chloride (3.1 g). and 36% formaldehyde solution (3 ml) in acetic acid (50 ml)

is heated for 9 hours in a steam bath. The solution was cooled and the solvent was removed in vacuo. The residue was made alkaline with 5N sodium hydroxide solution and extracted with ethyl acetate. The organic phase was treated with charcoal, dried and evaporated to give an oil which was purified by column chromatography (silica / ethanol: ethyl acetate 1: 1) (5.7 g). Rf value 0.4. NMR (CDCl3 / DMSO) 7.71s (6H); 7.22t (2H); 6.52s (2H); 6.2s (2H); 6.1t (2H); 3.8m (2H); 2.2m (4H).

Similarly, the following substances were prepared from 2- [o) - [[(2-furanyl) methyl] thio] alkyl] 1H isoindole-1,3, 2H) dione, the corresponding amine and formaldehyde .:

b) 2- [2 - [[[5 - [(l-pyrrolidinyl) methyl] -2-furanyl] methyl] thio] ethyl] -IH-isoindole-1,3 (2H) -dione. NMR (CDC13) 8 to 8.4m (4H); 7 to 7.6m (6H); 6 to 6.5 m (6H); 3.7 to 4.0 m (2H); 2 to 2.4m (4H).

c) 2- [3 - [[[5- (Dimethylamino) methyl-2-furanyl] methyl] thio] propyI] -lH-isoindole-1,3 (2H) -dione. Rf 0.45 (silica / methanol).

d) 2- [4 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] butyl] -IH-isoindole-1,3 (2H) -dione. Rf 0.26 (silica / methanol). NMR (CDC13) 8.85m (4H); 7.7s (6H); 7.42t (2H); 6.52s (2H); 6.29 m (4H); 3.9 m (2H); 2 to 2.4m (4H).

e) 2- [2 - [[[5 - [(4-methyl-l-piperazinyl) methyl] -2-furanyl] -me-

thyl] -thio] -ethyl] -lH-isoindole-1,3, (2H) -dione. NMR (CDC13) 7.75s (3H); 7.52s (8H); 7 to 7.5 m (2H); 6.5 s (2H); 6 to 6.3 m (4H); 3.85 m (2H); 2 to 2.4m (4H). f) 2- [2 - [[[5 - [(4-morpholinyl) methyl] -2-furanyl] methyl] thio] -5 ethyl] -lH-isoindole-1,3 (2H) -dione. NMR (CDC13) 7.54m (4H); 7.24m (2H); 6.50s (2H); 6.22m (8H); 3.8m (2H); 2.0 to 2.4m (4H).

10 Example F

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

2 - [[2- (2-furanyl) ethyl] thio] ethyl-1H-isoindole-1,3, (2H) -dione (0.5 g), dimethylamine hydrochloride (0.27 g) and paraformaldehyde (0.102 g) were heated together in reflux in ethanol. After 5 hours additional dimethylamine hydrochloride (0.27 g) and paraformaldehyde (0.102 g) were added and heating was continued for a further 16 hours. The solvent was removed and the residue was made alkaline and extracted with ethyl acetate 20 to give an oil which, after column chromatography (silica / methanol), was 2- [2 - [[2- [5- (dimethylamino) methyl -2-furanyl] -ethyl] -thio] -ethyl] -lH-isoindole-1,3 (2H) -dione as a light oil (0.43g).

25 Analysis found: C61.48; H6.13; N7.63; theoretical values for C19H22N203S-3 / 4H20: C 61.35; H 6.37; N 7.53%.

15

Example G

2 - [[5- (Dimethylamino) methyl-2-furanyl] methoxy] ethane-30 amine:

Way (1):

To a solution of 5- (dimethylamino) methyl-2-furanme-35 ethanol (6.2 g) and ethylenimine (2.82 g) in dry tetrahydrofuran was added a solution of methanesulfonic acid (11.6 g) in tetrahydrofuran (40 ml). The solution was evaporated and the oily residue was heated at 98 to 100 ° C for 10 min. After 16 h, 5N sodium hydroxide solution (60 ml) 40 was added and the solution was evaporated to dryness. Anhydrous sodium sulfate and ethyl acetate (150 ml) were added. After 2 hours the suspension was filtered, treated with decolorizing charcoal and evaporated. The resulting oil was chromatographed on silica first with methanol-ammonia (0.88 79/45 l), discarding the eluate, and then with methanol-ammonia (0.8819: 1). This eluate was evaporated to give an oil from which the bisoxalate salt of 2 - [[5- (dimethylamino) methyl-2-furanyl] methoxy] ethanolamine (from ethanol), 0.2 g, mp 125-128 ° C, was obtained.

Way (2):

A solution of 2-chloroethylamine hydrochloride (6.25 g) in dry dimethylformamide was added dropwise to a stirred and cooled solution of potassium tert-butoxide (8.96 g) and 5- (dimethylamino) methyl-2- furanmethanol (12.4g) added in the same solvent. After 2 h the solvent was removed and the residue was made alkaline and extracted with ethyl acetate. The residue after removal of the solvent was treated in ethanol with ethanolic oxalic acid. The crystalline salt was recrystallized from ethanol to give 2 - [[5- (dimethylamino) methyl-2-furanyl] methoxy] ethanolamine, bisoxalate, mp 130-133 ° C, (3.05 g).

65 In a similar way, the following connection was made according to route (2):

b) 2 - [[5- (Methylamino) methyl-2-furan] methoxy] ethane amine, bisoxalate, mp 162 to 164 ° C.

.1.1

.642.07?

Example H

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

2- [l- (4-bromobutyl)] furan (406mg) and potassium phthalimide

(370 mg) were stirred together in dry dimethylformamide at room temperature overnight. The solution was poured into ice water and the resulting white solid was filtered off, dried and recrystallized from chloroform / petroleum ether (bp 60 to 80 ° C.). In this way, 2- [4- (2-furanyl) butyl] -1H-isoindole-1,3 (2H) -dione was obtained in the form of white microcrystals (430 mg), mp 61 to 63 ° C.

The following connection was made in a similar manner:

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

Example I

a) 2- [4- [5- (Dimethylamino) methyl-2-furanyl] butyl] -1H-iso-indole-1,3 (2H) -dione:

2- [4- (2-Furanyl) butyl] -IH-isoindole-1,3, (2H) -dione (5.38 g), para-formaldehyde (1.2 g) and dimethylamine hydrochloride (3.26 g) were added in absolute ethanol (100 ml) heated to reflux. After 6 hours further paraformaldehyde (0.6 g) and dimethylamine hydrochloride (1.6 g) were added and the mixture was heated for a further 20 hours. The solvent was removed and the residue was made strongly basic with 5N sodium hydroxide solution. It was extracted with ethyl acetate and the organic layer was evaporated. The crude product was purified by column chromatography to give an amber oil (3.25 g). Rf value 0.4 (silica / methanol). NMR (CDCI3) 8 to 8.6m (4H); 7.75 s (6H); 7.3 m (2H); 6.55s (2H); 6.3 m (2H); 4.0m (2H); 1.9 to 2.4m (4H).

Similarly, the following connection was made:

b) 2- [5- [5- (Dimethylamino) methyl-2-furanyl] pentyl) -1 H-isoindole-1,3 (2H) -dione. Rf value in thin layer chromatography 0.4 (silica / methanol). NMR 8.0 to 8.8 m (6H); 7.70 m (6H); 7.37t (2H); 6.52s (2H); 6.30t (2H); 4.0m (2H); 2.2m (4H).

Example J

5- (dimethylamino) methyl-2-furanpropanamine:

Furan propionitrile (1.21 g), dimethylamine hydrochloride (1.62 g) and paraformaldehyde (0.7 g) in ethanol (20 ml) were heated under reflux for 24 hours. The solvents were removed and the residue was made alkaline to pH 12 and extracted with ethyl acetate. After removal of the solvents, the remaining oil was purified by column chromatography (silica / methanol). 5- (Dimethylamino) methyl-2-furanpropionitrile (0.6 g) Rf 0.55 (silica / methanol) was isolated.

The nitrii (6.0 g) in dry ether (40 ml) was added dropwise with stirring to lithium aluminum hydride (2.0 g) in ether at 0 ° C. The addition of water and the subsequent removal of the solvents gave 5- (dimethylamino) methyl-2-furanpropanamine as a light oil (3.33 g) after column chromatography. NMR (CDCI3) 8.2m (2H); 7.6br (2H); 7.75s (6H); 7.30 m (4H); 6.60s (2H); 4.0m (2H).

Example K

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

Sulfur (1.9 g) was added portionwise to a solution of the lithium derivative of N, N-dimethylfuranmethanamine (7.5 g) at -40 ° C. The mixture was stirred at -10 ° C. for 20 min and 2- (3-bromopropyl) -1H-isoindole-1,3 (2H) -dione (16 g) was added. The mixture was left overnight at 0 ° C and the solvent was removed in vacuo. The residue was taken up in ethyl acetate and the solution was filtered and extracted with 2N sulfuric acid. The watery

Layer was made alkaline and extracted again with ethyl acetate. The organic phase was dried. Removal of the solvent gave a crystalline solid which was recrystallized from ethanol (charcoal), giving 2- [3-5 [[[5- (dimethylamino) methyl-2-furanyl] thio] propyl]] - lH- iso-indole-1,3 (2H) -dione (7.59 g), mp 64 to 65 ° C, was obtained.

Example L

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

10 2 - [[4- (5-dimethylamino) methyl-2-furanyl] butyl] -1 H -isoin-dol-1,3, (2H) -dione (2.9 g) and hydrazine hydrate (0.55 ml ) were refluxed for 6 hours in ethanol. The solvent was removed and the crystalline residue was dissolved in 5N sodium hydroxide solution. The solution was extracted with ethyl acetate.

15 here. After removal of the solvent, the product was obtained as a mobile yellow oil (1.68 g). Single layer chromatography with silica / methanol gave a single spot with an Rf value of 0.15. NMR (CDC13) 8.0 to 8.8 m (4H); 7.7s (6H); 7.6br (2H); 7.3 m (4H); 6.58s (2H);

20 4.0m (2H).

The following substances were similarly prepared from the corresponding phthalimide:

b) 5- [5- (Dimethylamino) methyl-2-furanyl] pentanamine.

25 NMR (CDCI3) 8.0 to 8.8 m (6H); 7.75s (6H); 7.0 to 7.6 m (4H); 6.60s (2H); 4.0m (2H).

c) 5 - [[(3-aminopropyl) thio] methyl] -N, N-dimethylfuran-2-methanamine. NMR (CDC13) 8 to 8.5 m (2H); 7.75 s (6H); 7.421 (2H); 7.25 m (2H); 6.58s (2H); 6.3s (2H); 3.88s (2H).

30th

example 1

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

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

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

40 This salt (lg) was suspended in acetonitrile and methyl isothiocyanate (0.21 g) was added. The solution was stirred for 5 hours at room temperature and for 2 hours at 60 ° C. It was filtered and evaporated to give an oil which was purified by column chromatography (silica / methanol). N- [2-

45 [[[5- (Dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methylthiourea was obtained as a light oil (0.3 g). Analysis: Found: C 49.68; H 7.52; N 14.22; theoretical values for C12H2iN3OS2: C 50.14; H 7.37; n 14.62%.

The following substances were prepared in a similar manner.

50 places:

b) N-Methyl-N '- [2 - [[[5- (l-pyrrolidinyl) methyl-2-furanyl] methyl] thio] ethyl] thiourea. Found: C 52.33; H 7.12; N 13.17; theoretical values for C14H23N30S2-1 / 2H20: C 52.14; H 7.50; N 13.03%.

55 c) N- [4 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] butyl] -N'-methylthiourea. Found: C51.69; H 8.53; N 12.83; theoretical values for C ^ H ^ OS;,: C 51.82; H 8.08; N 12.95%.

6Q d) N- [3 - [[5- (dimethylamino) methyl-2-furanyl] thio] propyl] N'-methylthiourea. Found: C49.71; H7.33; N 14.35; theoretical values for C12H2iN3OS2: C50.10; H7.30; N 14.62%.

e) N-methyl-N '- [2 - [[5- (4-morpholinyl) methyl] -2-furanyI] -

65 methyl] thio] ethyl] thiourea. Found: C 51.26;

H7.08; N 12.51; theoretical values for C14H23N302S9: C51.03; H 7.04; N 12.75%.

f) N-Methyl-N '- [2 - [[[5 - [(4-methylpiperazinyl) -methyl] -2-fur-

642 072

12

anyl] methyl] thio] ethyl] thiourea. Found: C, 50.93; H 7.74; N 15.82; theoretical values for C15H26N4OS2: C 51.25; H 8.03; N 15.94%.

g) N- [2 - [[2- [5- (dimethylamino) methyl-2-furanyl] ethyl] thio] ethyl] -N'methylthiourea. Found: C50.19, H 7.20; N 13.18; theoretical values for Ci3H23N302S-1 / 2H20; C 50.32; H 7.74; N 13.54%.

Example 2

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

5- [5- (Dimethylamino) methyl-2-furanyl] pentanamine (0.5 g) and methyl isothiocyanate (0.25 g) were stirred in acetonitrile at room temperature for 24 hours. The solvent was removed and the product was purified by column chromatography (silica / methanol). After stirring with ether, N- [5- (5- (dimethylamino) methyl-2-furanyl] pentyl] -N'-methylthiourea was obtained as gray-white crystals, mp 66 to 69 ° C.

The following substances were similarly prepared from the corresponding amine and methyl isothiocyanate:

b) N- [3 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] propyl] -N'-methylthiourea. Found: C 51.38; H 7.93; N 13.41; theoretical values for C13H23N2OS2: C 51.79; H 7.69; N 13.94%.

c) N- [4- [5- (Dimethylamino) methyl-2-furanyl] butyl] -N'-methyl thiourea. NMR t (CDC13) 8 to 8.6 m (4H); 7.72s (6H); 7.35t (2H); 6.98 d (3H); 6.2 to 6.8 m (4H); 4, Od (2H); 3 to 3.8m (2H).

d) N- [2 - [[5- (dimethylamino) methyl-2-furanyl] methoxy] ethylJ-N'-methylthiourea. Found: C 51.91; H 8.14; N14.98; theoretical values for Cj2H21N302S-1 / 2H20: C 51.40; H 7.91; N 14.99%.

Example 3

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

l- (Isothiocyanato) -2-methoxyethane (1.17 g) and 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanolamine (2.14 g) in acetonitrile left overnight. The solvent was removed and the remaining oil was chromatographed (silica / methanol) to give N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N '- (2-methoxyethyl) thiourea was obtained as a light oil. Rf 0.45. Found: C, 50.64; H7.51; N 12.58; theoretical values for C14H25N302S2: C 50.75; H 7.55; N 12.69%.

In a similar manner, the following substances were prepared from the corresponding isothiocyanate and 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanolamine:

b) N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N '- (2-propenyl) thiourea. Found: C 52.68; H 7.58; N 13.16; theoretical values for Ci4H23N30S2-1 / 2H20: C 52.14; H 7.50; N 13.03%.

c) N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N- (l-methylethyl) thiourea £ f. Found: C51.84; H7.88; N 13.00; theoretical values for C] 4H25N3OS2-l / 2H20: C 51.90; H 8.09; N 12.97%.

Example 4

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

To a stirred solution of 2 - [[[5- (methylamino) methyl-2-furanyl] methyl] thio] ethanolamine (1.5 g) in acetonitrile (24 ml) was added a solution of methyl isocyanate (0, 45 g) in acetonitrile (15 ml). After 30 min the solution was evaporated to dryness to give an oil which

25th

was first chromatographed with silica / methanol: 0.88 ammonia 79/1 and then with aluminum oxide / methanol, whereby an oil consisting of N- [2 - [[[5- (methylamino) methyl-2-furanyl] methyl ] -thio] -ethyl] -N'-methylurea 5 (0.25 g) was obtained. Analysis found:

C 51.00; H 7.38; N 15.91; theoretical values for CnHi9N302S: C 51.33; H 7.44; N 16.33%.

N.m.r. (CDCl3) 13.85, s, (2H); 4. 3-4.8, m, (2H);

6.27, s, (4H); 6.64, q, (2H); 7.22, d, 7.32, t, 7.54,

10 s, (8H); 8.05, brs, (1H)

Example 5

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

15 Methyl isocyanate (0.33 g) was added to a suspension of 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] -ethane-amine-phthalhydrazide complex (2 g) in acetonitrile (50 ml ) given. After 2 h the solution was filtered and the filtrate was evaporated to give an oil which was purified by column 20 chromatography (silica / methanol). In this way, N- [2 - [[[5- (dimethylamino) methyl-2-furan-yl] methyl] thio] ethyl] -N'-methylurea was obtained. Found: C 52.38; H 7.61; N 15.25; theoretical values for C12H2IN3Ö2S-1 / 4H20: C 52.24; H 7.76; N 15.32%.

Similarly, the following connection was made:

b) N-Methyl-N '- [2 - [[[5- (l-pyrrolidinyl) methyl-2-furanyl] methyl] thio] urea. Found: C54.70; H7.33; N 14.07; theoretical values for CMH23N302S-1 / 2H, 0: C54.87; H 7.89; N 13.71%.

30th

Example 6

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

35 2 - [[[5- (Dimethylamino) methyl-2-furanyl] methyl] thio] ethanolamine (2.14 g) and isopropyl isocyanate (0.89 g) were dissolved in acetonitrile and left to stand overnight. The solvent was removed and the residue was recrystallized from methanol: ether to give N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl-N '- (l- methylethyl) urine-40 substance in the form of crystals, mp 65 to 67 ° C, (2.8 g) was obtained.

Similarly, the following connection was made:

b) N- [3 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] -45 thio] propyl] -N'-methylurea, mp 69 to 69.5 ° C.

Example 7

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

J0 A solution of 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanolamine dihydrochloride (2.8 g) and potassium cyanate (3.75 g) in water ( 50 ml) was heated on a steam bath for 8 hours. Excess solid sodium carbonate was added and organic material was continuously extracted with diethyl 55 ether. The extracts were evaporated and the residue provided N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] urea as a waxy solid after column chromatography (1, 28 g). Found: C 48.22; H 7.50; N 15.61; theoretical values for CnHjgNjO ^ S-60 -H20; C 48.00; H 7.63; N 15.27%.

Example 8

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

65 A solution of 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanolamine (2.14 g) and S-methyl-N-nitroisothio-urea (1.5 g) in Ethanol (10 ml) was heated to 40 ° C for 5 min. The resulting precipitate was filtered and recrystallized from ethyl acetate and petroleum ether, bp 80 to 100 ° C, whereby

13

642 072

N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-nitroguanidine, mp 103 to 104 ° C, was obtained.

Example 9

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

A mixture of 2 - [[[5- (methylamino) methyl-2-furanyl] methyl] thio] ethanolamine (2.0 g) and methyl N-cyano-N'-methylcarbamido-midothioate ( 1.25 g) was heated on a steam bath for 6.5 hours. A vacuum was applied at regular intervals to remove methanethiol. The crude product was purified by column chromatography. Rf value 0.65 (silica / methanol: ammonia 79: 1). In this way, N-cyano-N '- [2 - [[[5- (methylamino) methyl-2-furanyl] methyl] thio] ethyl] -N "methylguanidine (1.05 g ), Mp 81 to 85 ° C, obtained.

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

b) N-Cyano-N '- [2 - [[[5- (l-methylethyl) amino] methyl-2-furanyl] methyl] thio] ethyl] -N "-methylguanidine. Analysis found: C 54.73; H 7.82; N 22.31; theoretical values for Ci4H23N5OS: C 54.34; H 7.49; N 22.64%.

c) N-Cyano-N '- [2 - [[[5- (diethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N "methylguanidine. Analysis found: C 53, 54; H7.82; N 20.65; theoretical values for C15H25N5OS-3 / 4H20: C 53.46; H 7.70; N 20.78%.

d) N-Cyano-N '- [2 - [[[5- (l-pyrrolidinyl) methyl-2-furanyl] methyl] thio] ethyl] -N "methylguanidine. Analysis found: C 53.97; H6.87; N21.06; theoretical values for C15H23N5OS-3/4 H20: C 53.79; H 7.37; N 20.91%.

e) N-Cyano-N '- [3 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] propyl] -N "-methyIguanidine. Analysis found: C 52.86; H 7.49; N20.64; theoretical values for Ci4H23N5OS • 1 / 2HzO: C 52.80; H 7.59; N 21.20%.

Example 10

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

To a stirred suspension of potassium carbonate (20.7 g) in a solution of 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanolamine (10.7 g) and N-cyano-N'-methyl-carbamimidothioic acid methyl ester (7.1 g) in acetonitrile (107 ml) at 70 ° C., a solution of silver nitrate (9.35 g) in acetonitrile (20 ml) was added during one hour. The mixture was stirred for 16 hours and the solid was filtered off. The filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate (250 ml). A portion of it (10.5 ml) was washed with water (6 ml). The ethyl acetate layer was evaporated to give a solid which was crystallized from isopropyl acetate (1,751). In this way, N "-Cyano-N- [2 - [[[5- (dimethylaminomethyl) -2-furanyl] methyl] thio] ethyl] -N'-methylguanidine (0.35 g), mp 79 bis 81.5 ° C, obtained.

N.m.r. (CDC13) t3.82, s, 3.6-4.4, brm, (4H); 6.28, s, (2H); 6.57, s, 6.63, q, (4H); 7.15, d, 7.30, t, (5H); 7.65, s, (6H)

To a further portion (225 ml) was added a solution of sebacic acid (9.09 g) in ethanol (30 ml). The filtered solution provided the sebacate salt (13m, 74 g), mp 92.5 to 94 ° C. Found: C 54.91; H7.94; N 14.02; theoretical values for C13H21N5OS-C10H18O4: C 55.51; H 7.90; N 14.07%.

Example 11

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

Powdered cyanamide (4.2 g) was added to a stirred solution of sodium (2.3 g) in absolute ethanol. After 30 min, a solution of methoxyethyl isothiocyanate

25th

(11.7g) in absolute ethanol was added to the chilled solution. After another hour at room temperature, dimethyl sulfate (12.66 g) was added over 30 minutes and the mixture was stirred overnight. The solvent was removed 5 and the remaining solid was washed well with water, giving methyl N-cyano-N'-2- (methoxyethyl) caramimidothioate as a white crystalline solid (12.37 g), mp 94.5 to 95 , 5 ° C, was obtained.

The following compound was prepared in a similar manner: 10 N-cyano-N '- (2-propenyl) carbamimidothioic acid methyl ester, mp 109 to 110 ° C.

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

A mixture of 2 - [[[5- (dimethylamino) methyl-2-furanyl] -15 methyl] thio] ethanolamine (2.14g) and N-cyano-N '- (2-methoxyethyl) carbamimidothioic acid -Methyl ester (1.73 g) was heated on a steam bath for 6.5 h. Vacuum was occasionally applied to remove methanethiol. The crude product was purified by chromatography (silica gel / methanol), 20 whereby N-cyano-N '- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N "- (2-methoxyethyl) guanidine (1.4 g) was obtained. Analysis found: C50.51; H7.20; N19.41; theoretical values for C15H25N502S-H20: C 50.42; H7.50; N 19.60%.

In a similar manner, the following substances were prepared from 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanolamine and the corresponding methyl N-alkyl-N'-cyanocarbamimidothioate: 30 b) N-Cyano-N '- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N "- (2-propenyl) guanidine. Analysis found: C 53.33; H7.01; N 20.70; theoretical values for CjsH ^ NSOS-HZO: C 53.09; H 7.37; N 20.64%.

c) N-Cyano-N '- [2 - [[[5- (dimethylamino) methyl-2-furanyl] -35 methyl] thio] ethyl] -N "- (l-methylethyl) guanidine. Analysis found: C 52.97; H7.70; N 20.57; theoretical values for Ci5H25N50S-H20: C 52.78; H 7.91; N 20.52%.

Example 12

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

A mixture of 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanolamine (2.14g) and N, S-dimethylisothiouronium iodide was heated on a steam bath for 3 h. The 45 residue in methanol was eluted from an Amberlyst A-26 ion exchange resin to give N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] - N'-methylguanidine was obtained as an amber oil (1.5 g). Found: C50.92; H 8.23; N 19.90; theoretical values for 50 C12H22N4OS-3 / 4H2Ö: C 50.76; H 8.34; N 19.74%.

Similarly, the following connection was made:

b) N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N ', N "-dimethylguanidine. NMR (CDC13) 7.75 s (6H ); 6.8 to 7.3 m (8H); 6.5 m (4H); 6.22 s (2H); 3.80 m (2H); 2.0

55 to 3.5br (2H).

Example 13

N-methyl-l-methylthio-2-nitroätheneamine:

A solution of methylamine in ethanol / ethylene dichloride 6C (112.5 ml of 33% ethanolic methylamine in 0.81 ethylene dichloride; 0.9 4 mol) became a stirred solution of 1 over 5 '/ 2 h at 70 ° C , 1-Bismethylthio-2-nitroethylene (99.0 g 0.6 mol) in ethylene dichloride (1.51). The solution was heated to boiling and 0.71 solvent 65 was distilled off. The cooled solution was washed with 2N hydrochloric acid (0.251) and then with brine (0.251). The solvent was removed and the residue was crystallized from isopropyl acetate (0.51), the hot solution with

6Ï2 072

'14

Charcoal (10.0g) was treated. The product (35.0 g) formed yellow prisms, mp 114 ° C.

N- [2 - [[[5- (methylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-l, l-ethylenediamine hydrochloride:

A solution of 2 - [[[5- (methylamino) methyl I-2-furany I] methyl] thio] ethanolamine (10 g, 0.05 mol) and N-methyl-l-methyl thio-2 -nitroethylene amine (7.4 g) in water (25 ml) was stirred at 50 ° C. for 2 h. Acetone (350 ml) was added and the solvent was distilled off at atmospheric pressure until 275 ml of distillate was collected. Ethanolic hydrogen chloride (2M; 27.5 ml) was added to the residue and the solution was stirred at room temperature overnight. The product (11.0 g), mp 161 ° C., was collected and recrystallized from ethanol in the form of a colorless microcrystalline solid (10.1 g), mp 162 ° C. Found: C42.6, H6.3, N 16.4; theoretical values for C12H, 0N4O3S-HCl: C 42.8; H 6.2; N 16.6%.

Example 15

N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-l, 1-ethylenediamine: N-methyl-l - (Methylthio) -2-nitroethylene amine (230 g) in water (400 ml) was stirred and heated to 45 to 50 ° C. 2 - [[[5- (Dimethylamino) methyl-2-furanyl] methyl] thio] ethanolamine (321 g) was added dropwise over 4 hours and the resulting solution was stirred for a further 3 hours. The solution was then refluxed for one hour, cooled to 70 ° C and 4-methylpentan-2-one (21) was added. The water was removed by azeotropic distillation under reduced pressure (260 torr) and the resulting solution was treated with charcoal (10 g) at 50 ° C. The solution was filtered and cooled to 10 ° C. The N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-l, 1-ethylenediamine (380 g) was filtered off and dried, mp 69 to 70 ° C.

10th

15

Example 14

a) N- [2 - [[[5- (methylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-l, 1-ethylenediamine:

A mixture of 2 - [[[5- (methylamino) methyl-2-furanyl] methyl] thio] ethanolamine (0.9 g) and N-methyl-l-methylthio-2-nitroethylene amine ( 0.6 g) was heated at 100 to 120 ° C under water jet pressure for 30 min. The residue was purified by column chromatography (silica / methanol: 0.88 ammonia) to give N- [2 - [[[5- (methylamino) methyl-2-furanyl] methyl] thio] ethyl] -N ' -methyl-2-nitro-l, 1-ethylenediamine was obtained, which was crystallized from acetonitrile, mp 106 to 108 ° C (0.65g).

The following substances were prepared in a similar manner:

b) N- [2 - [[[5 - [(l-methylethyl) amino] methyl-2-furanyl] -me-35thyl] -thio] ethyl] -N'-methyl-2-nitro- l, 1-ethylenediamine. Found: C 49.75; H 7.21; N 16.36; theoretical values for C14H24N4O3S • 1 / 2H20: C 49.83; H 7.47; N 16.60%.

c) N-Methyl-2-nitro-N '- [2 - [[[5 - [(2-phenylethyl) amino] methyl] -2-furanyl] methyl] thio] ethyl] - l, 1-ethylenediamine. Analysis 40 found: C 57.19; H 6.53; N13.83; theoretical values for C19H26N403S-1 / 2H20: C 57.12; H6.81; N 14.02%.

d) N-Methyl-2-nitro-N '- [2 - [[[5 - [(l-piperidinyl) methyl] -2-fur-anyl] methyl] thio] ethyl] -l, 1 -ethylenediamine. Analysis found: C53.36; H7.51; N14.23; theoretical values for 45 C16H26N403S-1 / 4H20: C 53.33; H 7.44; N 15.61%. e) N- [2 - [[[5- [2- (dimethylamino) ethyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-l, 1-ethylenediamine , Mp 95.5 to 96 ° C.

f) N- [2 - [[[5- [3- (dimethylamino) propyl] -2-furanyl] methyl] - sg thio] ethyl] -N'-methyl-2-nitro-l, l- ethylene diamine. NMRx (CDCI3) 8.1 to 7.1m (6H); 7.65 s (6H); 7.1 s (3H); 6.5 m (2H); 6.28s (2H); 4.0m (2H); 3.38s (1H).

g) N- [2 - [[[5- [4- (dimethylamino) butyl] -2-furanyl] methyl] thio] ethyl] -N-methyl-2-nitro-l, 1-ethylenediamine. Waxy 55 solid; Found: C53.90; H 7.95; N 15.64; theoretical values for C16H28N403S: C 53.91; H 7.92; N 15.72%.,

h) N- [2 - [[[5- (ethylmethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-l, 1-ethylenediamine. NMR x (CDC1,) 8.901 (3H); 7.76 s (3H); 6.8 to 7.5 m (7H); 6.5 br (2H); eo 6.42 s (2H); 6.25 s (2H); 3.77 s (2H); 3.35 s (IH).

i) N- [2 - [[5 - [[2- (dimethylamino) ethyl] amino] methyl-2-fur-anyl] methyl] thio] ethyl] -N'-methyl-2 -nitro-l, 1-ethylenediamine. NMR t (CDCl-i) 7.79 s (6H); 7 to 7.6 m (10H); 6.6 m (2H); 6.26 s (2H); 6.22s (2H); 3.85 m (2H); 3.37 s (IH); 2 to 3.2 br (1H); 0.8 65 to 0.2 br (1H).

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

Example 16

, 0 N-methyl-2-nitro-N '- [2 - [[[5 - [(l-pyrrolidinyl) methyl] -2-fur-

anyl] -methyl] -thio] -ethyl] -l, 1-ethylenediamine:

A mixture of 2 - [[[5- (l-pyrrolidino) methyl-2-furanyl] methyl] thio] ethanol amine bisoxalate salt (2.1 g) potassium hydroxide (1.12 g) and N-methyl - (l-methylthio) -2-nitroethylene amine 25 (0.9 g) in water (9 ml) was stirred at room temperature for 18 h. The water was evaporated under reduced pressure and the residue was extracted with ethyl acetate in the presence of excess anhydrous sodium carbonate. Evaporation of the solvent gave a residue which was crystallized from 30 isopropyl acetate in the form of a white crystalline solid (0.9 g), mp 79 to 82 ° C. Found: C 52.78; H7.05; N 16.75; theoretical values for CI5H-> 4N403S: C 52.92; H 7.11; N 16.46%.

Example 17

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

N-Cyano-N '- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -carbamimidothioic acid methyl ester: 2 - [[[5- (dimethylamino ) -methyl-2-furanyl] -methyl] -thio] -ethane-amine (1.07 g) was added to a solution of dimethyl N-cyanoimidocarba-modithioate (0.73 g) in ether and the mixture was poured over Stirred at night. The crystalline solid formed was filtered off, washed with ether and dried, giving N-cyano-N '- [2 - [[[5- (dimethylamino) methyl-2-furan-yl] methyl] thio] ethyl] -carbamimidothioic acid methyl ester (1.14 g), mp 78 to 79 ° C, was obtained.

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

A solution of N'-cyano-N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] carbamimidothioic acid methyl ester (1.06 g) in ethanolic methylamine 33% (10ml) was stirred at room temperature for 4h. The solution was evaporated to dryness and the oily residue was crystallized from ethyl acetate / light petroleum (bp 80 to 100 ° C), whereby the above-mentioned compound, mp 77 to 80 ° C, was obtained.

Example 18

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

A mixture of heptylamine (1.15 g) and N-cyano-N '- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] carbamimidothioic acid (3rd , 12g) was heated to 100 ° C. in an oil bath. The product was subjected to chromatography (silica / methanol), whereby N-cyano-N, - [2 - [[[5- (dimethylamino) methyl-2-furan-yl] methyl] thio] ethyl] -N " -heptylguanidine hydrate (2.31 g), Rf 0.49, analysis found: C 56.99; H 8.32;

N 17.53; theoretical values for C19H33N50S-H20: C57.43; H 8.81; N 17.63%.

Example 19

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

2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanolamine (4.25 g) and l, l-bis (methylthio) -2-nitroethylene (3.3 g) 14hlangin acetonitrile (50ml) was heated to reflux. The solvent was removed and the residue was dissolved in 36% methanolic methylamine (50 ml). The solution was refluxed for 8 hours. The solvent was removed and the residue was treated with charcoal in methanol. Filtration and evaporation of the solvent gave the above compound as in Example 15 (5.0 g).

Example 20

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

2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanolamine (2.14 g) and 1,1-bis (methylthio) -2-nitroethylene (1.65 g) were refluxed in acetonitrile for 8 hours. The solvent was removed and an ethanolic solution of 2-methoxyethylamine (0.75 g) was added. After a further 8 hours of refluxing, removal of the solvent provided an oil. This was purified by column chromatography, whereby N- [2 - [[[5- (dimethylamino) methyl-2-furan-yl] methyl] thio] ethyl] -N, - (2-methoxyethyl) -2- nitro-l, l-ethylenediamine (1.0 g) was obtained. NMRx (CDC13) 7.73 s (6H); 7 to 7.5 m (2H); 6.2 to 7m (11H); 6.23 s (2H); 3.81s (2H); 3.42s (1H).

Similarly, the following connection was made:

b) N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -2-nitro-l, 1-ethylenediamine, mp 100 to 101 ° C.

Example 21

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

4- [5- (Dimethylamino) methyl-2-furanyl] butanamine (0.7 g) and l, l-bis (thiomethyl) -2-nitroethylene (0.6 g) in acetonitrile (12 ml) were 22h heated at reflux for a long time. The solvent was removed and the residue was refluxed in 33% methanolic methylamine for 2 h. The solvent was removed and the residue was purified by column chromatography (silica / methanol). In this way, N- [4- [5- (dimethylamino) methyl-2-furanyl] butyl] -N'-methyl-2-nitro-l, 1-ethylenediamine (310mg) or N- [4- Obtain [5- (dimethylamino) methyl-2-furanyl] butyl] -N'-methyl-2-nitro-l, l-ethylenediamine. Found: C 55.54; H 8.23; N 17.75; theoretical values for C14H, 4N403-1 / 2H, 0: C 55.26; H 8.22; N 18.42%.

The following substances were prepared in a similar manner:

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

Found: C, 56.76; H 8.36; N 17.37; theoretical values for C15H26N403-1 / 2H2Ö: C 56.43; H 8.46; N 17.55%.

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

Found: C 49.36; H 7.19; N 17.45; theoretical values for C13H22N403S: C 49.66; H 7.05; N 17.84%.

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

Found: C, 55.09; H 7.84; theoretical values for C, 3H; 2N403: C 55.31; H 7.72%.

15 642 072

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

Analysis found: C51.38; H7.44; N15.66; theoretical values for C15H26N403S-1 / 2H20: C 51.26; H 7.74; N 15.94%.

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

Found: C49.57; H7.20; N 15.59; theoretical values for C14H24N403S-1 / 2H20: C 49.86; H 7.47; N 16.61%.

10 Example 22

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

4- [5- (Dimethylamino) methyl-2-furanyl] butanamine (0.4 g) and dimethyl N-cyanoimidocarbamodithioate (0.3 g) 15 were stirred in ethanol at room temperature for 3 hours. A solution of 33% methylamine in ethanol was then added and the mixture was refluxed for 2 hours. The solvent was removed under reduced pressure and the product was purified by column chromatography (silica / 20 methanol) to give the product as a light yellow oil. NMR x (CDC13) 8 to 8.5 br (4H); 7.77 s (6H); 6.61 to 7.5m (9H); 4.0m (2H); 2.8 to 3.7m (2H).

The following compound was prepared in a similar manner: 25 b) N-cyano-N '- [5- [5- (dimethylamino) methyl-2-furanyl] pentyl] -N'-methylguanidine. NMRx (CDC13) 8.0 to 8.7br (6H); 7.68s (6H); 7.32t (2H); 7.10d (3H), 6.7q (2H); 6.48s (2H); 3.8 to 4.3 m (4H).

30 Example 23

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

Methanesulfonyliminodithiocarbamic acid dimethyl ester (1.9g) and 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] -35 thio] ethanolamine (2.14g) was stirred in ethanol at room temperature for 3 hours. 33% ethanolic methylamine (20 ml) was added and the whole was heated to reflux for 16 hours. The product was column chromatographed (silica / methanol), whereby N- [2 - [[[5- (dimethylamino) methyl-40 2-furanyl] methyl] thio] ethyl] -N'-methanesulfonyl-N "- methyl guanidine was obtained as a light yellow oil (2.7 g) Found: C 43.54; H 7.05; N15.48; theoretical values for C13H24N403S2-1 / 2H20: C 43.70; H 7.00; N 15.69%.

The following compound was prepared in a similar manner: 45 b) N-benzenesulfonyl-N '- [2 - [[[5- (dimethylammo) methyl-2-furanyl] methyl] thio] ethyl] -N "- Found: C50.30; H6.25; N 12.93; theoretical values for C18H26N403S-H20: C 50.47; H 6.54; N 13.08%.

50 Example 24

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

Carbon disulfide (1.52 g) was added dropwise with stirring to a cooled solution of sodium hydroxide (0.8 g) in 55 water (1.7 ml). 2 - [[[5- (Dimethylamino) methyl-2-fur-anyl] methyl] thio] ethanolamine (4.28 g) was slowly added. After the addition had ended, the mixture was heated to 100 ° C. for 2 hours. After cooling to below 40 ° C, ethyl chloroformate (1.94 ml) was added and stirring was continued for 30 minutes. The lower thick yellow oil was extracted with chloroform, dried and evaporated to give N, N-dimethyl-5 - [[[[2- (isothiocyanato) ethyl] thio] methyl] furan methane amine as an oil was obtained. Rf 0.43 (silica / methanol).

f> 5 The crude isothiocyanate (0.46 g) was dissolved in 33% ethanolic methylamine (25 ml), left to stand overnight and the N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] -methyl] -thio] -ethyl] -N'-methylthiourea was as a light yellow oil

642 072

16

(0.16g) isolated. The product was identical to the material obtained from 2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanolamine and methyl isothiocyanate.

Example 25

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

A solution of N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methylthiourea (1.3 g) was treated with lead cyanamide (1 , 5 g) heated to reflux. The solution was filtered and the filtrate was evaporated. Treatment of the residue with a solution of sebacic acid in isopropanol gave the compound mentioned as monosebacate salt (0.7 g), mp 90 to 92 ° C.

Example 26

N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-l, l-ethylenediamine hydrochloride:

N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-l, 1-ethylenediamine (50 g, 0, 16 mol) was dissolved in technical denatured alcohol 74 ° C. (200 ml), which contained 0.16 of an equivalent of hydrogen chloride. Ethyl acetate (200 ml) was slowly added to the solution. The hydrochloride crystallized and was filtered off. It was washed with a mixture of technical denatured alcohol 75 ° C. (50 ml) and ethyl acetate (50 ml) and dried at 50 ° C. The product (50 g) was obtained as an off-white solid, mp 133 to 134 ° C.

Pharmaceutical preparation a) Oral tablets 50mg:

Magnesium stearate BP

40g

The active ingredient, the anhydrous lactose and most of the Cutina HR are intimately mixed together. The mixture is then moistened by mixing it with a 10% solution of the rest of the Cutina HR in technical denatured alcohol OP 74. The moistened mass is granulated through a sieve with an opening of 1.2 mm and dried in a fluid bed dryer at 50 ° C. The granules are then passed solo through a sieve with an opening of 0.85 mm, mixed with the magnesium stearate and compressed to a hardness of at least 10 kg (Schleuniger tester) on a tabletting machine with punches with a diameter of 12.5 mm. * Cutina HR is a grade of microfine hydrogenated castor oil manufactured by Sipon Products Limited, London.

15

d) Oral Syrup:

20th

Active ingredient dilute hydrochloric acid BP, as required sorbitol solution BPC 25 flavoring agent as necessary, distilled water

% Weight / volume 2.0

60 volume / vol.

100

30th

Active ingredient anhydrous lactose U.S.P. Sta-Rx 1500 starch * Magnesium stearate B.P.

for 10000 tablets 500g

2.17kg 300g 30g

35

The active ingredient is dissolved in a portion of the water with stirring, gradually adding hydrochloric acid until the pH has dropped to 5.0. The sorbitol solution, the flavoring agent and the rest of the water are added and the pH is readjusted to 5.0. The syrup is clarified by filtration through suitable cellulose filter pads, e) Oral capsules 50 mg:

The active ingredient is sieved through a 250 [xm sieve. The four powdery components are then intimately mixed in a mixer and pressed between punches with a diameter of 8.5 mm in a tabletting machine.

* A form of a directly compressible starch made by A. E. Staley Mfg. Co. (London) Limited, Orpington, Kent.

b) Injectable preparation for intravenous administration (200mg in ml):

Active ingredient Sta-Rx 1500 * 40 magnesium stearate BP

for 10000 capsules 500g 1700g 20g

Active ingredient

Water for injection BP on dilute hydrochloric acid BP

% W / w 10.0 100.0 pH 5.0

The active ingredient is dissolved in the water for injection with mixing and the acid is slowly added until the pH is 5.0. Nitrogen is passed through the solution and the solution is clarified by filtration through a membrane filter with a pore size of 1.35 μm. It is filled into 2 ml glass ampoules (2.2 ml each). Each ampoule is sealed under a nitrogen atmosphere. The ampoules are sterilized in an autoclave at 121 ° C for 30 minutes.

c) Oral sustained-release tablets 150 mg:

The active ingredient is sieved through a sieve with 250 [im and then mixed with the other powdery constituents ^. The powder is in hard gelatin capsules no. 3 filled in a 45 suitable filling machine.

f) ointment:

% By weight

Active ingredient 2.0

50 white soft paraffin BP to 100

The active ingredient is sieved through a sieve with an opening of 150 μm and then uniformly mixed with the soft white paraffin in a high shear mixer.

g) cream:

55

Active ingredient

Cetomacrogol emulsifying ointment BP 00 chlorcresol distilled water

% By weight 2.0

30.0 0.1 100

Active ingredient Cutina HR **

anhydrous lactose U.S.P.

for 1000 tablets 1.50 kg 0.40kg 2.060 kg

The active ingredient is a compound produced according to the invention. Particular examples of this are the compounds of Example 10 and Example 15. Other compounds can also be used.

The compounds of formula I have been shown to be inhibitors of gastric acid secretion induced by histamine.

17th

642 072

proven. This was described in rats using a modified method by M. N. Ghosh and H. O.

Sign shown in British Journal of Pharmacology 1958, volume 13, page 54.

Female rats weighing approximately 150 g are fasted overnight and are given an 8% sucrose solution in normal saline instead of drinking water.

The rats are anesthetized by a single intraperitoneal injection of a 25% (weight / volume) urethane solution (0.5 ml / 100 g). The trachea and jugular veins are cannulated

A midline incision is made in the abdomen wall to expose the stomach, which is separated from the liver and spleen by cutting the connective tissue. A small opening is made in the background of the stomach and the stomach is washed with a 5% dextrose solution. A rubber tube is inserted into the esophagus. The esophagus and vagus nerves are then cut off above the cannula.

A small opening is made in the pyloric area of the stomach. A large safety cannula is then inserted into the stomach through the opening in the background area in such a way that the inlet end of the cannula comes out of the stomach through the opening in the pyloric area. The cannula is designed in such a way that the effective volume of the stomach is reduced and that a turbulent flow of the fluid flowing through the mucosal surface is obtained. A drain cannula is then inserted through the opening in the background area of the stomach. Both cannulas are held in place by ligaments around the stomach and are positioned so that the main blood vessels are not touched. Knife wounds are made in the body wall and the cannula is passed through. The stomach is passed through the esophagus and pylorus cannula with a 5% dextrose solution of 39 ° C. at a rate of 1.5 ml / min for each cannula. The effluent is passed through a microflow pH electrode and recorded using a pH meter and a flatbed recorder.

The basal release of gastric acid secretion is monitored by means of the pH value of the flow through-flow.

Increased acid secretion is then induced by continuous intravenous infusion of a submaximal dose of histamine. This creates a stable plateau of acid secretion. The pH value of the flow through-flow is determined after this condition has been obtained.

The test compound is then administered to the rat by intravenous injection. The change in gastric acid secretion is monitored by measuring the change in the pH of the flow through-flow.

io The difference in acid secretion between basal release and the histamine-stimulated plateau value is calculated as the hydrogen ion concentration in mol / 1 from the change in the pH value of the flow-through effluent. The decrease in acid secretion caused by administration of the Test-15 compound is also calculated as a change in hydrogen ion concentration in mol / 1 from the difference in the pH of the flow-through effluent. The percentage decrease in acid secretion caused by administration of the test compound can then be calculated from the two numbers obtained.

The ED so values for inhibiting acid secretion are determined by administering a dose of the test compound to a rat and repeating this in at least four rats at each of the three or more dose values. The results obtained are then used to calculate the ED50 value by the standard least squares method used for each dose response curve.

Using the above procedure, the following ED50 values are obtained:

30th

35

Connection of example no.

ED50mg / kg

2 (c)

1.5

8th

0.65

9 (a)

2.30

10th

1.39

14 (a)

0.23

14 (f)

0.8

14 (h)

0.48

15

0.18

20 (a)

1.82

21 (a)

0.55

m

Claims (14)

-> 642 072 - 2 PATENT CLAIMS 1. Process for the preparation of aminoalkyl furan derivatives of the general formula (I): Ri r \ fr " K-Alk (/ \> - (CH-) X (CH) NHCNHR- (I) / \ 0 2 n 2 m y R „/ and their hydrates and physiologically acceptable salts, which may include, wherein R3 further represents hydrogen, C 1-4 alkyl, R, and R 2, which may be the same or different, represents water C 1-4 alkenyl or alkoxyalkyl, -X- represents -CHr-, -O- or Stoff, Q_rAlkyl, Cycloalkyl, C ^ -AIkenyl, AralkyloderC ^ - -S-stands, = Y stands for = S, = 0, = NR5 oder = CHR6, Alk stands for alkyl, which is represented by an oxygen atom or a group -N- «a straight-chain or branched alkylene chain with 1 to 6 | Carbon atoms, R5 is hydrogen, nitro, cyano, Ci_8-R4 alkyl, aryl, alkylsulfonyl or arylsulfonyl, R6 is nitro, where R4 is hydrogen or Q_8-arylsulfonyl or alkylsulfonyl, m is an integer of 2 alkyl, or are Rj and R2 is together with that to 4 and n is 1 or 2, or when X is -S- or Nitrogen atom to which they are attached has a heterocyclic -0 -CHr-, n has the value 0.1 or 2, characterized in that it can form rings which are heteroatoms O and / or -N- that a compound of the formula : I. R4 (xxi) ' whereRi, R2, Alk, n, Xandm is substituted phenyl. to have; A represents hydrogen and B represents hydrogen or the 5th method according to claim 1, characterized in that Group -C-P stands in which P stands for a cleavable group that n + m has the value 3 or 4. II 35 6. The method according to claim 1, characterized in Q that Alk stands for a methylene group. and Q stands for = NR5 or = CHR6, in which R5 and R6 are the 7. Process according to claim 1, characterized in that have the meaning given, or A and B together that Rj is H or CM-alkyl and that R2 is Ci_4-alkyl = CS stand; with a compound of the formula R3NZZ '. wherein Z is hydrogen and Z 'is hydrogen or the 40 8. Process according to claim 1, characterized in that Group -C-P, or Z 'and Z with one another = CO or that Ri and / or R2 stand for methyl or ethyl. I 9. The method according to claim 1, characterized in Q that X stands for a sulfur atom. = CS, where R3 has the meaning given above, 10. The method according to claim 1, characterized in that if desired, the end product as physiological that X stands for a -CH2 group. acceptable salt or hydrate isolated or such an end pro 11. Process according to claim 1, characterized in product converted into another salt or into a hydrate. that A, ZundZ 'stand for hydrogen and that B for the 2. The method according to claim 1, characterized in that group -C-P stands. that the compound R3NZZ 'is an isocyanate of the formula || R3NCO or an isothiocyanate of the formula R3NCS or a 50 CHN02 Compound of the formula R3NHC-P or R3NHC-P used 12. The method according to claim 1, characterized in that II I that A, Bund Z stand for hydrogen, and that Z 'for the NR5 cHR6 group -C-P stands. wherein R3, R5 and R6 have the meaning given above and II P stands for a removable group. CHN02 3. The method according to claim 1, characterized in 13- The method according to claim 1, characterized in that a compound of the formula (XXI), wherein Rj and R2, that a compound of the formula (XXI) wherein A, B, X and independently of one another for hydrogen, alkyl, phenylalkyl, P have the meanings given in claim 1, where, dialkylaminoalkyl or together with the nitrogen ^ when B is the group CP, Q for = CHN02 or = NR5 tom a 5- or 6-membered group saturated heterocyclic ring II form, Alk for a straight-chain alkylene chain with 1 to 4 Q Carbon atoms, with a compound of the formula and R5 is nitro, cyano, methylsulfonyl or R3NZZ ', where Q is = NR5 or = CHNO-, in which has benzenesulfonyl, in which Ri and R2 are the same or different R5 can be hydrogen, nitro, cyano, lower alkyl, for hydrogen, alkyl having 1 to 3 carbon atoms. Has alkylsulfonyl or benzosulfonyl, and X, m, n, A, B, Z, Z ', 65 men or phenethyl or together with the nitrogen P and R3 have the meanings given in claim 1. atom form a pyrrolidine ring. Alk for an alkylene chain with 1 4. The method according to claim 1, characterized in that there is up to 3 carbon atoms, with a compound of the formula that aryl as a group or as part of a group for phenyl or R3NZZ ', in which Z is hydrogen and Z' is AoA R1R2NAik (CH2) nX (CH2) mN- a b 3rd ,, 642 072 Is hydrogen or the group -C-P or Z and Z miteman- Q which stands for = CS, where P has the meaning given in claim 1, Q stands for = CHN02 or = NR5 and R5 has the meaning nitro, cyano, methylsulfonyl or benzenesulfonyl, where R3 is hydrogen, alkyl having 1 to 3 carbon atoms, propenyl or alkoxyalkyl with 3 carbon atoms and n + m has the value 3 or 4. 14. The method according to claim 13, characterized in that R], R2, alk, A, B, P, Z, Z ', Q and R5 have the meanings given in claim 13, and that -X-for-S-or -CH2 and R3 is hydrogen, methyl or methoxyethyl, where n is 1 and m is 2 or 3. 15. The method according to claim 1, characterized in that reacting a compound of formula (XXI) with a compound of formula R3NZZ ', wherein Rx is hydrogen, methyl or ethyl, R2 is methyl or ethyl, alk is a methylene group , R3 is hydrogen or methyl, -X- is -S- or -CH2-, n is 1 and m is 2, A and Z are hydrogen and one of the groups B or Z 'is hydrogen and the other for the group -CP Q stand, where P has the meaning given in claim 1 and Q stands for = NR5 or = CHN02 where R5 has the meaning nitro or cyano. 16. The method according to claim 1, characterized in that reacting a compound of the formula (XXI) with a compound of the formula R3NZZ ', in which the Rb R2 and R3 are methyl, Alk is the methylene group, -X-is-S- , n has the value 1 and m has the value 2, A and Z represent hydrogen and one the groups B or Z 'represent hydrogen and the other the group CP, where P is the one stated in claim 1 Q Has meaning and Q stands for = CHN02, wherein if desired the end product is isolated as a physiologically acceptable salt or such an end product is converted into another physiologically acceptable salt. 17. The method according to claim 1, characterized in that reacting a compound of formula (XXI) with a compound of formula R3NZZ ', wherein Rj is hydrogen or a methyl group, R2 for a methyl or ethyl group or for a through -N - interrupted propyl group, R3 CH3 represents hydrogen, a methyl or methoxyethyl group, alk represents an alkylene chain with 1 or 3 carbon atoms, X represents CH2- or -S-, n has the value 1 and m has the value 2, either A and Z for hydrogen and one the groups B or Z 'for hydrogen and the other for the group -CP Q stand, where P has the meaning given in claim 1 and Q stands for = CHN02 or = NN02, or A and B both stand for hydrogen and Z and Z 'stand together for = CS, or A and B stand together for = CS and Z and Z 'both represent hydrogen. 18. The method according to claim 1, characterized in that the physiologically acceptable salt is a hydrochloride. 19. The method according to claim 16, characterized in that the physiologically acceptable salt is a hydrochloride. 5 20. The method according to claim 1 for the preparation of derivatives of formula I, wherein = Y is = NCN, characterized in that a derivative of formula I, wherein = Y is = S, is reacted with a heavy metal cyanide. 21. Aminoalkylfuran derivatives of the general formula I, phy-10 siologically acceptable salts and hydrates thereof, prepared by the process according to claim 1. 22. Derivatives according to claim 21, produced by the method according to claim 16. 23. Derivatives according to claim 21, produced after the expulsion according to claim 17. 24. Derivatives according to claim 21, produced by the method according to claim 19. 20th By Ashund Schild (Brit. J. Pharmacol. Chemother, 1966, 27, 427) and by Black et al. (Nature 1972, 236, 385), a division of histamine receptors (H receptors) into two groups has been proposed, which are named as Hr and H2 receptors 25. The stimulation of the bronchial and gastroin-testinal smooth muscles is mediated by HR receptors. These effects can be prevented by conventional histamine antagonists such as mepyramine. The stimulation of gastric acid secretion and heart rate is mediated by H2 receptors. These effects are not modified by mepyramine, but are prevented or eliminated by H2 antagonists such as metiamide. Histamine stimulates Hi and H2 receptors. It has now been found that certain new aminoalkylfuran derivatives are selective H2 antagonists, ie that they show an inhibition of gastric acid secretion when this is stimulated via histamine H2 receptors (cf. Ash and Schild loc. Cit .). Their ability to prevent gastric juice secretion when stimulated by histamine H2 receptors 40 may be demonstrated in the rat rat gastric flow by the method of Ghosh and Schild (Brit. J. Pharmacol. 1958, 13, 54), which-like described below-modified. This ability can also be demonstrated in conscious dogs with Heidenhain pockets and 45 using the same method described by Black et al in Nature 1972, 236, 385. The compounds according to the invention do not modify histamine-induced contractions of isolated gastrointestinal smooth muscles. 50 compounds with histamine H2 blocking activity can be used to treat conditions where gastric acid hypersecretion is present, such as gastric and peptic ulcers, and to treat allergic conditions where histamine 55 is a known cause. The compounds can also continue to be used either alone or in combination with other active ingredients for the treatment of allergic and inflammatory conditions, such as urticaria.