CS210394B1 - Formamidine derivatives and processes for their preparation - Google Patents

Abstract

The invention concerns formamidine derivatives and methods for their preparation. Formamidines with an unsubstituted hydrogen atom on carbon are prepared by the reaction of ethyl orthoformate with amines, if this hydrogen atom is replaced by a benzyl group, the corresponding phenylacetamidines are prepared by the reaction of amines with ethylphenylacetimidate, and if the formamidine molecule contains a phenyl group instead of this hydrogen atom, the desired benzamidines are obtained by the reaction of amines with N-phenylbenzimidoyl chloride. The substances were tested for anti-inflammatory efficacy and in comparative tests with the preparation Brufen, some of the substances showed significant efficacy in the kaolin and adjuvant models of experimental inflammation

Description

The invention relates to formamidine derivatives of the general formula I,

in which r 'is hydrogen, benzyl or phenyl, o

R is hydrogen, 3- (5-methyl) isoxazolyl or phenyl substituted in any position by trifluoromethyl, methoxy, ethoxycarbonyl or 3,4-methylenedioxy,

2 1 1 3

R is the same as R when R is hydrogen, when R is other than hydrogen, R is 1,1,2,2-tetramethylpropyl or phenyl substituted at the 4-position by chlorine, methoxy, ethoxycarbonyl or 3, 4-methylenedioxy.

The invention also relates to processes for the production of these novel, hitherto undisclosed derivatives of general formula I having interesting pharmacodynamic properties, in particular anti-inflammatory, analgesic and antipyretic effects. Typical compounds of the invention are N, N'-bis-3,4-methylenedioxyphenylformamidine, N, N'-bis-3-trifluoromethylphenylformamidine, N-3,4-ethylenedioxyphenylacetamidine and N-phenyl-N * -1,1,2 , 2-tetramethylpropylbenzamidine.

These compounds showed significant efficacy in both the kaolin and adjuvant models of experimental inflammation compared to the known formulation of brufen at 100 mg / kg. The toxicity of all evaluated substances is very low, expressed as greater than 1 g / kg (mouse).

According to the invention, the novel formamide derivatives of the formula I can be prepared, for example, by reacting ethyl orthoformate with an amino compound of the formula II r ² nh ₂ (IX) in which R denotes the same as in formula I; it is further possible to react the ethylphenylacetimidate of formula III

oc ₂ h ₅ (III) with an amino compound of the formula IV,

R ³ NH "(IV) wherein R ^J denotes the same as in formula I or can be treated with N-phenylbenzimidoyl chloride of formula V

Cl to the amino compound of formula IV

R ³ NH "(IV) wherein R ^J denotes the same as in formula I.

Indicates if R ¹ in formula I is hydrogen, the desired compound are prepared so that a mixture of ethyl orthoformate and the amino compound of formula II is heated in the presence of

2.0394 of acetic acid for 5 minutes to 2 hours at boiling point and after removal of the volatiles, the crude product is recrystallized.

When R @ ¹ in the formula I is a benzyl group, the desired compounds are obtained by heating a mixture of ethyl phenylacetimidate of formula III and an amine compound of formula IV for 3 hours at 100 DEG C. and crystallizing the precipitated crystalline material.

When the formula (I) is a phenyl group, the compounds are prepared by reacting an N-phenylbenzimidoyl chloride of formula V with an amino compound of formula IV in dimethylformamide at room temperature for 48 hours. The crystalline product is washed with aqueous ammonia solution and purified by crystallization.

Further details can be seen from the examples.

Example l

A mixture of 3.7 g of ethyl orthoformate, 6.48 g of 3,4-methylenedioxyaniline and 1.6 ml of acetic acid is heated to boiling for 45 minutes, the volatiles are distilled off under reduced pressure and the residue is recrystallized from isopropanol. 3 g of N, N'-bis-3,4-methylenedioxyphenylformamidine of melting point 164 DEG-65 DEG C. are obtained.

In the same way:

N, N ^{'-bis-2-methoxyfenylformamidin,} tt, 05 to, 06 ° C, and N, N'-bis-4-Ethoxycarbonylphenyl nylformamidín, mp, 97-198 ° C.

Analogously, but with an extension of the reaction time to 2 hours, N, N'-bis-3-trifluoromethylphenylformamidine, mp 120-122 ° C, was prepared and shortened to 5 minutes with N, N'-bis-3- (5-methylDisoxazolylformamidine, mp. Mp 180-182 ° C.

Example 2

A mixture of 8.25 g of ethylphenylacetimidate and 6.23 g of 4-methoxyaniline was first heated at 100 ° C for 3 hours and then left at room temperature for 12 hours. The precipitated crystalline solid is filtered off with suction and recrystallized from toluene. 4.3 g of N-4-methoxyphenylacetamidine are obtained, m.p. 06-107 ° C.

In the same manner, N-3,4-methylenedioxyphenylacetamidine, m.p. 04-105 ° C, was prepared from ethylphenylacetimidate and 3,4-methylenedioxyaniline.

Example 3

To a mixture of 5.38 g of N-phenylbenzimidoyl chloride in 10 ml of dimethylformamide was added 2.88 g

1,1,2,2-tetramethylpropylamine and the mixture is left at room temperature for 48 hours. The precipitated crystalline solid is filtered off with suction, stirred with 40 ml of 15% aqueous ammonia for 1 hour, the crystalline solid is filtered off with suction and recrystallized. 3 g of N-phenyl-N'-1,1,2,2-tetramethylpropylbenzamidine are obtained, m.p. 155-157 ° C (nitromethane).

In the same way prepare:

N-phenyl-N'-4-chlorophenylbenzamidine, mp 122-123 ° C (cyclohexane),

N-phenyl-N-S, 4-methylednioxyphenylbenzamidine, m.p. 126-127 ° C (isopropyl alcohol); and

K-phenyl-N'-4-ethoxycarbonylphenylbenzamidine, m.p. 14 DEG-42 DEG C. (ethanol-water, 7: 3).

Claims (4)

SUBJECT OF THE INVENTION A formamidine derivative of the formula I, NR ² in which r 1 represents a hydrogen atom, a benzyl or a phenyl group, p R is hydrogen, 3- (5-methyl) isoxazolyl or phenyl substituted in any position by trifluoromethyl, methoxy, ethoxycarbonyl or 3,4-methylenedioxy R ^{3 is the} same as R ² when R ¹ is hydrogen, if R ^{1 is} different from hydrogen, R ³ 1,1,2,2-tetramethylpropyl or phenyl substituted in the 4-position by chlorine, methoxy, ethoxycarbonyl or 3,4-methylenedioxy. 2. The method of formamidine derivatives of general formula I according to claim 1, wherein reacting ethyl orthoformate with an amino compound of formula II R ² -NH ₂ (II) in which R represents reins as in formula I. 3. A process for the preparation of formamidine derivatives of the formula I as claimed in claim 1, characterized in that ethylphenylacetimidate of the formula III is reacted. O ~ ^ch2C C NH OC ₂ H ₅ (III) with an amino compound of formula IV, R ³ NH., (IV) wherein R ³ denotes the same in formula I. by 4. A process for the preparation of the formamidine derivatives of the formula I as claimed in claim 1, which comprises treating with N-phenylbenzimidoyl chloride of the formula: Cl (V) to an amino compound of formula IV r ³ nh ₂ (IV) wherein R is the same as in formula I.