CS250240B2 - Method of ethandiimidamide's derivatives production - Google Patents

Description

The invention relates to a process for the preparation of ethanediimidamide derivatives of the general formula II

HN HN

() where

R1 represents a hydrogen atom, a straight or branched chain alkyl of 1 to 6 carbon atoms, a group

or where

R ⁵ represents a hydrogen atom or an alkyl of 1 to 4 carbon atoms, or m represents an integer of 0 or 1, n represents an integer of 2 or 3,

Z represents an oxygen atom or a sulfur atom; and

And means one of the groups

R ⁶ and R ⁷ independently represent C 1 -C 4 alkyl radicals or form R ⁶ and R ⁷ together with the nitrogen atom to which they are attached a pyrrolidine, piperidine or 1,2,2,6-tetrahydropyridyl ring,

In the compounds of formula (II), R @ ¹ is preferably hydrogen or C1 -C4 alkyl, especially hydrogen or methyl, most preferably R @ ¹ is hydrogen. The substituent A is preferably a substituted phenyl group, a substituted furyl residue or a substituted thienyl residue, preferably a substituted phenyl residue.

Preferably, Z is a sulfur atom or an oxygen atom, and when A is a substituted phenyl radical, Z is preferably an oxygen atom. When A is a substituted phenyl radical, Z is preferably an oxygen atom. In case that A is a substituted phenyl moiety, m is preferably 0 ans preferably 3; R ⁵ is preferably hydrogen or methyl, especially hydrogen. R ⁶ and R ⁷ are preferably lower alkyl or form, with the nitrogen atom to which they are attached, a pyrrolidine or piperidine ring.

Compounds of formula II are valuable intermediates for the preparation of 3,4-diamino-1,2,5-thiadiazole derivatives of formula I

where

A, m, Z, N ¹ are as defined above; these compounds are antihistamines.

The intermediates of formula (II) used to produce the compounds of formula (I) may be obtained in various ways. In one of these processes, the corresponding 3- (amino or substituted amino) -4- (substituted amino) -1,2,5-thiadiazole-1-oxide of formula III is reacted with a strong inorganic acid, preferably hydrochloric acid. to form a compound of formula II according to the following reaction scheme:

HC! V

NH NH (N

The reaction may be carried out in an inert solvent, preferably methanol. The reaction temperature is not critical, the procedure is usually carried out at room temperature. The compounds of formula (III) are known or can be obtained in a known manner, for example according to British Patent Specification 2,067,987.

The invention therefore relates to a process for the preparation of novel ethanediimidamide derivatives of the general formula II

A- (Cry _Z (CH _{2) n} NHR .NH ^1/4

HN NH (H) wherein each substituent is as defined above, or a process for making salts, hydrates or solvates thereof.

According to a preferred embodiment of the process according to the invention, compounds of the formula II can be obtained from A

() where

R1 is hydrogen or C1-C4alkyl, m is an integer of 0 or 1, n is an integer of 2 or 3,

Z represents an oxygen or sulfur atom; and

And means one of the groups

where

is hydrogen or methyl, and and R ⁷ are independently of each other or ethyl or are taken together with ato R ^{5 to} form together

^Rc methyl MEM nitrogen to which they are attached form a pyrrolidino or piperidino ring new and nontoxic pharmaceutically acceptable salts, hydrates or solvates thereof.

According to another preferred embodiment, intermediates of formula IIIa are of the general sample

R 1 represents an atom, hydrogen or methyl,

R ⁶ and R 7 represent methyl or form together with the nitrogen atom to which they are attached a pyrrolidine or piperidine ring as well as salts of the compounds.

According to a further preferred embodiment, the intermediates of formula IIb are hydrates or solvates of these embodiments

ethyl or ethyl, as well as salts, hydrates or solvates of these compounds.

According to another preferred embodiment, intermediates of formula IIc wherein:

R ¹ and R ⁵ are each independently hydrogen or methyl and

R ⁽ i and R7 ⁾ are independently

^ CH ^ CH ^ SCH NH _χ,. HN NH

(.Me) where

R ¹ and R ⁵ are each independently hydrogen or methyl and

R 6 and R 7 are each independently methyl or ethyl, as well as salts, hydrates or solvates thereof.

In another preferred embodiment, intermediates of formula IId can be obtained

where

R ¹ and R ⁵ are each independently hydrogen or methyl and

R ⁶ and R 7 are each independently methyl or ethyl or form, with the nitrogen atom to which they are attached, a piperidine ring, as well as salts, hydrates or solvates thereof.

To date, the most preferred intermediates of formula (II) are:

1) N- [3- (3-piperidinomethylphenoxy) propyl] ethanediimidamide,) N- [2 - [(5-piperidinomethyl-13-henyl) methylthio] ethyl] ethanediimidamide,

7) N- [3- (6-piperidinomethyl-2-pyridyloxy) propyl] ethanediimidamide and] N- [3- (4-piperidinomethyl-2-pyridyloxy) propyl] ethanediimidamide, as well as salts, hydrates or solvates thereof.

The invention will be illustrated by the following examples.

Example 1

2) N- [2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethyl] ethanediimidamide;

3) N- | 2 - [(5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio] ethyl] ethanediimidamide;

4) N- [3- (3-pyrrolidinomethylphenoxy) propyl] ethanediimidamide;

5) N- [2 - [(5-dimethylaminomethyl-3-thienyl) methylthio] ethyl] ethanediimidamide;

N- [3- (3-piperidinomethylphenoxy) propyl] ethanediimidamide trihydrochloride

A suspension of 17.1 g (47.0 mmol) of 3-amino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-hiadiazole-1-oxide (prepared according to British Pat. 2.077.987) in 450 ml of methanol are mixed with 38 ml of concentrated hydrochloric acid. The resulting solution was stirred at room temperature for 3 hours. The solution is concentrated and the water is removed by azeotropic distillation with absolute e

220 DEG C. with decomposition. Recrystallization from 50% methanol in ethyl acetate gave the product, m.p. 210-221 ° C with decomposition.

thanol, whereby colorless crystals are obtained. The crystals were suspended in 200 ml of absolute ethanol, filtered, and dried in vacuo to give 16.6 g (82.6%) of the title compound, m.p. 205 DEG-222 DEG C. with decomposition. Recrystallization from 50% methanol in ethyl acetate gave an analytical sample, m.p. 206 DEG-216 DEG C. with decomposition.

Analysis for C ₁₇ H ₂₁ N ₅ O. 3 HC1:

calculated:

% C, 47.84;% H, 7.08;% N, 16.41.

H, 7.18; N, 16.75.

Example 2

N-H (5-dimethylammomethyl-2-furyl) methylthio] ethyl-ethanediimidamide trihydrochloride hydrate

A suspension of 6.59 g (20.0 mmol) of 33-amino-4- [2 - [(S-dimethylaninomethyl-4-furyl) methylthio] ethylamino] -1,5,5-thiadiazol-4-olide prepared according to British patent specification The solution was stirred at room temperature for 2.5 hours, then the solution was evaporated to dryness and the residue was triturated with 70 ml. The crystals were collected by filtration and dried in vacuo to give 4.3 g (52%) of the title compound, m.p. 166-169 ° C with decomposition.

Analysis for C ^ HH ^O OS. 3 HCl. H> O calculated:

H, 6.38; N, 17.05. S, 7.80. Found:

% C, 34.85;% H, 6.24;% N, 17.45.

Example 3

N-2 - [(5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio] ethyl 1-ethanediimidamide trihydrochloride

A solution of 17.9 g (50.0 mmol) of 3faminof4f - (2 - [(5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio] ethylamino) -1,2,5-thiadiazole-1-oxide prepared according to the British method No. 2,067,987 in 500 ml of methanol is mixed with stirring

33.3 ml of concentrated hydrochloric acid. After stirring for 3 hours, the mixture was concentrated and excess water was removed by azeotropic distillation with absolute ethanol to give an almost colorless crystalline residue. The residue is treated with 200 ml of absolute ethanol at 0 DEG C., filtered and dried to give 16.9 g (80%) of the title compound, m.p.

Analysis for C 13 H 23 N 5 S 2. 3 HC1:

calculated:

Found: C, 36.92; H, 6.20; N, 16.56; S, 15.17.

36.76 o / o C, 6.33 o / o H, 16.97 o / _o n, 15.54% S.

Example 4

N- [3- (3-pyrrolidinomethylphenoxy) propyl] ethanedlimidamide trihloride

A suspension of 13.4 g (38.3 mmol) of i-amino-4- [3- (3-pyrrolidinomethylphenoxy) propylamino] -1,2,5-thiadiazole-1-oxide, prepared according to British Patent Specification 2,067,987 in 350 ml of methanol are mixed with

25.5 ml of concentrated hydrochloric acid. The resulting solution was stirred at room temperature for 3 hours. The solution was concentrated by azeotropic removal of water with absolute ethanol to give the title product as a crystalline residue which was triturated with 150 ml of absolute ethanol, filtered and dried to give 10.8 g of the title compound, m.p. 195 DEG-203 DEG C. with decomposition.

Analysis for. 3 HC1:

calculated:

% C, 46.55;% H, 6.84;% N, 16.97.

H, 6.93; N, 16.93.

Example 5

N-methyl-Nf [3- (S-piperidinomethylphenoxy) propyl] ethacdiimidamide trihydride

A suspension of 4.13 g (10.9 mmol) of 33-methylamino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole-1-oxide prepared according to the method of British Patent No. 2 The mixture was stirred at room temperature for 3 hours, the solution was evaporated and the residue was triturated with acetone, the solution was filtered and the solid dried.

90.4% yield 4.35 g of the title compound. A sample of this product was recrystallized from aqueous isopropyl alcohol to give the title compound, mp 207-225 cc with decomposition.

Analysis for C, _S H _{2 Y} N-0.3 HCl:

calculated:

H, 7.33; N, 15.89. Found:

H, 7.35; N, 15.71.

(Corrected to 0.94% water content.)

Example 6

N-benzyl-N- [3- (3-piperidinomethylphenoxy) propyl] ethanediimidamide trihydrochloride

A suspension of 5.14 g (11.3 mmol) of 3-benzylamino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-hiadiazole-1-oxide, prepared according to British patent specification no. 2067987 in 100 ml of methanol are mixed

7.55 ml of concentrated hydrochloric acid. After stirring at room temperature for 3 hours, the solution was evaporated and the residue triturated with acetone, filtered and dried to give 5.16 g (88%) of the title compound, mp 178-205 ° C. for decomposition.

Analysis for C24H.KIN5O. 3 HC1:

calculated:

H, 7.03; N, 13.55; Cl, 20.57. Found:

% C, 54.88;% H, 6.75;% N, 13.33.

Example 7

N - [2 - [(5-dimethylaminomethyl-3-thienyl) methylthio] ethyl] ethanediimidamide trihydrochloride

A suspension of 7.8 g (22.6 mmol) of 3-amino-4- {2 - [(5-dimethylaminomethyl-3-thienyl) methylthio] ethyl] amino-1,2,5-thiadiazole-1-oxide prepared according to the British method No. 2,067,987 in 150 ml of methanol is mixed with 15.0 ml of concentrated hydrochloric acid. After stirring at room temperature for 3 hours, the solution was evaporated and the residue was triturated with 1-propanol, filtered and dried to give the title compound (7.38 g, 80%). A sample of this product was recrystallized from methanol / acetone to give the title compound, m.p. 190 DEG-205 DEG C. with decomposition.

Analysis for C12H21N5S2.3 HCl:

calculated:

% C, 35.25;% H, 5.92;% N, 17.13.

H, 5.93; N, 17.39.

Example 8

N- {2 - [(5-piperidine (. Onethyl-3-thienyl) methylthi) ethyl] ethanediimidamide trihydride chloride

A suspension of 6.1 g (15.8 mmol) of 3-amino-4- [2 - [(5-piperidinomethyl-3-thienyl) methylthio] othylaminol-1,4-thiadiazole-1-oxide prepared according to the method of the British patent specification No. 2,067,987 in 80 ml of methanol was treated with 10.5 ml of concentrated hydrochloric acid. After stirring at room temperature for 3 hours, the solution was evaporated and the residue was triturated with 1-propanol (50 ml), filtered and dried to give 5.86 g (83%) of the product. A sample of this product was recrystallized from methanol / acetone to give the title compound, mp 201-214 ° C with decomposition.

Analysis for C15H25N5S2. 3 HCl: calculated:

H, 6.29; N, 15.60; S, 14.29. Found:

H, 6.47; N, 15.28; S, 14.63.

Example 9

3-Amino-4- [3- (6-piperidinomethyl-2-pyridyloxy) propylamino] -1,2,5-l-β-3-thiol-1-oxide

A solution of 4.65 g (18.6 mmol) of 3- (6-piperidinomethyl-4-pyridyloxy) ropine amine prepared according to British Patent Specification No. 2,098,988 in 50 ml of methanol is reacted with 2.74 g (18.6 mmol) of mmol of 3-amino-4-methoxy-1,2,5-thiadiazole-1-oxide produced by the method of British Patent Specification 2,067,987 to give a solution containing 3-amino-4- [3- (6) (piperidinomethyl-2-pyridyloxy) propylamino] -1,2,5-thiadiazole-1-oxide The pure sample had a melting point of 145-147 ° C.

Example 10

3- ((β-β-β-β-β-β-β-β-β-β-β-β-β-β-β-thiophene))

When the general procedure for the preparation of 3- (6-piperidinomrthr-2-pyridinyl-oxy) proprolidine is repeated as described in British Patent Specification 2,098,988 except that 2-chloro-6-methylpyridine is replaced by 2 4-methyl-4-methylgidinidine to give the title compound as an oil.

Analysis for C18H18N3O3:

calculated:

% C, 67.44;% H, 9.30;% N, 68%;

H, 8.98; N, 16.55.

Example 11

The procedure described in Example 9 was repeated except that the 3- (6-piperidinomethyl-pyridinyl) eropropylamine used as starting material in the above example was replaced with an equivalent amount of 3- [3- (1,2,3,6) tetramethylphenoxy] propylamine to give 2.31 g of the title compound. Crystallization from toluene gave the title product, m.p. 99.5-104 ° C.

14

Analysis for C17HH23N5OS: found:

C 58.78, H 6.71, N 19.90, S 9.26.

calculated:

59.10% C, 6.71% H, 20.27% N, 9.28% S (corrected for 2.19% H ₂ Oj

Claims (2)

A process for the preparation of ethanediimidamide derivatives of the general formula II (.ni where R 'is hydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms, or m is an integer of 0 or 1, n is an integer of 2 or 3, Z represents an oxygen atom or a sulfur atom; and A is one of the groups ^K1 N (Flg) 5 ° X ^R > r ' Ai or; Or where R ⁵ represents a hydrogen atom or an alkyl of 1 to 4 carbon atoms, R ⁶ and R 7 are each independently alkyl radicals of 1 to 4 carbon atoms or form R 6 and R 7 together with the nitrogen atom to which the pyrrolidine, piperidine or 1,2,3,6-tetrahydropyridyl ring are bonded, characterized in that a compound of formula III is reacted, preferably in an inert solvent at room temperature 7сн ₂ ^ (снру1н w II o where A, Z, R ^j, m and n have the abovementioned meanings, with a strong inorganic acid, preferably hydrochloric acid. 2. A process according to item 1 for the preparation of ethanediimidamide derivatives of the general formula II, in which the individual symbols have the meaning given in item 1, except for the groups of the symbol A which are always attached in the 2-position. a compound of formula (III) wherein each symbol is as defined above with a strong inorganic acid, preferably hydrochloric acid.