DE1443376C3 - Process for the preparation of 2-amino-alpha-substituted benzylideneamines, as well as new 2-amino-alpha-substituted benzylideneamines as such - Google Patents

Description

in which Y is halogen, A is hydrogen, lower alkyl, lower acyl, halo-lower acyl and W is phenyl or Halophenyl mean, with an amine of the general formula

FN H2

in which F is hydroxy-lower alkyl, morpholino-lower alkyl or phenyl-lower alkyl, heated and here a product of the general formula

NHA

C = N-F

obtained, in which A, W, Y and F have the above meaning and, if F in the end product, one Hydroxyalkyl radical means this optionally in a manner known per se into the lower acyloxyalkyl radical converts and, if desired, separating the stereoisomers of the product.

2. The method according to claim 1, characterized in that the reaction is carried out in an inert Solvent carries out.

3. The method according to claim 2, characterized in that the solvent used is xylene, toluene or hexanol is used.

4. New compounds of the general formula

NHA

C = O

in which Y is halogen, A is hydrogen, lower alkyl, lower acyl, halo-lower acyl, W is phenyl or halophenyl mean, with an amine of the general formula

FNH2

in which F denotes hydroxy-lower alkyl, morpholino-lower alkyl or phenyl-lower alkyl, heated and this a Product of the general formula

NHA

Y C = N-F

obtained, in which A, W, Y and F have the above meaning and, if F in the end product, one Hydroxyalkyl radical means this optionally in a manner known per se into the lower acyloxyalkyl radical converts and, if desired, separating the stereoisomers of the product.

The process proceeds according to the following, schematic formula equation, in which the substituents are the have the meaning described above.

NHA

Y C = O
I. I.
W. FNH ₂ • Λ NHA
/ I. Y \
C = NF W.

55

wherein A is hydrogen, lower alkyl, acetyl, chloroacetyl, W is phenyl, o-Chlo ^r phenyl and F hydroxyloweralkyl, acetoxyethyl, acetoxypropyl, Morpholinoäthyl, morpholinopropyl mean.

The inventive method for the preparation of 2-amino-α-substituted benzylideneamines is A substituted phenone is condensed with a substituted primary amine by heating. Optionally, the process can be carried out in an inert solvent such as xylene, toluene or hexanol and if desired with a catalytic amount of an acidic catalyst such as zinc chloride or toluenesulfonic acid be performed. On cooling, the mixture is diluted with water and the product failed. The product can be purified by recrystallization from a water-alcohol mixture and then from a benzene-hydrocarbon mixture. In the special case where you are called amine If benzylamine is used, the reaction product is made

usually from a mixture of N- (2-amino-5-chloro- <x-phenylbenzylidene) -benzylamine and its tautomer, N- (2-amino-5-chloro-a-phenylbenzyl) benzaldehyde imine.

As a result of the formation of a carbon-nitrogen double bond, the process leads to the possible formation of two stereoisomers (λ- and / 3-form). In the event that both isomers are stable and can be isolated, both forms can of course be produced within the scope of the present invention. The <x isomers can be separated off from the β isomers by known processes, such as fractional crystallization.

The substituted 2-aminobenzylideneamines obtainable according to the invention have valuable pharmacological properties Properties. They make effective antispasmodics, sedatives and muscle relaxants In addition, these compounds have disinhibiting and libido-increasing properties. Certain compounds are also more pharmacologically active as intermediates in the manufacture of others Connections useful. Because of these properties, their low toxicity and as a result of the low The compounds obtainable according to the invention represent valuable side effects during their administration Pharmaceuticals for humans and animals.

The pharmacologically active compounds obtainable according to the invention can be used in conventional Dosage forms such as tablets, powders and injection liquids can be administered.

The invention also relates to new compounds of the general formula

Cl

NHA

C = N-F

wherein A is hydrogen, lower alkyl, acetyl, chloroacetyl, W phenyl, o-chlorophenyl, F hydroxy-lower alkyl, Mean acetoxyethyl, acetoxypropyl, morpholinoethyl, morpholinopropyl.

These compounds have proven themselves on the basis of comparative tests, compared to sodium diphenylhydantoin and phenylethylbarbituric acid, which are known anticonvulsant compounds, as proven superior.

The following specific examples serve to illustrate the invention.

example 1

A mixture of 3.0 g of 2-amino-5-chlorobenzophenone and 30 ml of ethanolamine is refluxed for 4 hours cooked. On cooling, the reaction mixture is diluted with water and the product which precipitates out is diluted from water - alcohol and then benzene - cyclohexane recrystallized and this pure 2- (2-amino-5-chloro- «-phenylbenzylideneamino) ethanol (1.0 g) from Melting point 122 to 124 ° C obtained.

Analysis for C15H15CIN2O, molecular weight 274.75.

Calculated: C 65.56, H 5.50, N 10.20, Cl 12.90%;
Found: C 65.55, H 5.44, N 10.40, Cl 11.90%.

Example 2

3-aminopropanol (60 ml) is according to the procedure described in Example 1 with 2-amino-5-chlorobenzophenone reacted (11.0g) and this 3- (2-amino-5-chloro-Ä-phenylbenzylideneamino) propanol (3.0 g) with a melting point of 107-109 ° C.

Analysis for CieH 17CIN2O

Calculated: C 66.50, H 5.92, N 9.70%;
found: C 66.26, H 5.96, N 9.66%.

Example 3

A solution of 3- (2-amino-5-chloro - «- phenylbenzylideneamino) propanol (0.85 g) in pyridine was treated with acetic anhydride and the reaction mixture diluted with water. The resulting precipitate was filtered and 3- (2-acetami-

do-S-chloro-ot-phenylbenzylideneaminoJ-propyl acetate
(0.4 g) of melting point 122-124 ° C.

Analysis for C20H21CIN2O3

Calculated: C 64.42, H 5.81, N 7.52, Cl 9.51%;
found: C 64.77, H 5.73, N 7.79, Cl 9.70%.

Example 4

2-Amino-2 ', 5-dichlorobenzophenone (8.0 g) was prepared according to the procedure described in Example 1 with Ethanolamine (50 ml) reacted and this 2- [2-amino-5-chloro-a- (o-chlorophenyl) benzylideneamino] ethanol (5.0 g) with a melting point of 123-125 ° C.

40 Analysis for C15H14CI2N2O

Calculated: C 58.27, H 4.56, N 9.06, Cl 22.93%;
Found: C 58.54, H 4.62, N 9.25, Cl 22.70%.

Example 5

2-methylamino-5-chlorobenzophenone (12.0 g) was refluxed with ethanolamine (80 ml) and the The resulting reaction mixture was poured into water. The aqueous phase was obtained from the insoluble oil is decanted off and the oil washed several times with water, then dissolved in the ether dried ethereal solution and the ether removed in vacuo, with 2- (2-methylamino-5-chloro - «- phenylbenzylideneamino) ethanol remained as a viscous oil (4.5 g).

45 Analysis for C16H17CIN2O

Calculated: C 66.54, H 5.94, N 9.70%;
Found: C 66.23, H 5.75, N 10.09%.

Example 6

2-Amino-5-chlorobenzophenone (6.0 g) was prepared according to the procedure described in Example 1 with Benzylamine reacted and this N- (2-amino-5-chloro (X-phenylbenzylidene) benzylamine from melting point 122 to 124 ° C and its tautomer N- (2-amino-5-chloro-a-phenylbenzyl) benzaldehyde imine obtained (2.5 g).

Analysis for C20H17CIN2

Calculated: C 75.89, H 5.34, N 8.74, Cl 11.07%;
found: C 74.80, H 5.44, N 8.93, Cl 11.10%.

Example 7

A solution of 23.1 g of 2-amino-5-chlorobenzophenone, 45 g of 4- (2-aminoethyl) morpholine in 100 ml of xylene and a catalytic amount of zinc chloride were refluxed for 3 hours until the theoretical had deposited the calculated amount of water. The solvent was removed in vacuo, the remaining one The residue was recrystallized from heptane and then from ethanol and this resulted in the α-isomer of N- [2- (2-amino-S-chloro-a-phenylbenzylideneaminoJ-ethylj-morpholine) (7.8 g) having a melting point of 140 to 142 ° C.

Analysis for C19H22CIN3O

Calculated: C 66.36, H 6.45, Cl 10.32, N 12.22%; Found: C 66.13, H 6.29, Cl 10.40, N 12.09%.

The above heptane filtrate was concentrated to a small volume and the solid substance which precipitated out in the process recrystallized from cyclohexane and then from alcohol-water, resulting in the j9-form of N- [2- (2-amino-5-chloro-a-phenylbenzylideneamino) ethyl] morpholine (2.4 g) having a melting point of 112 to 114 ° C.

Analysis for C19H22CIN3O

Calculated: C 66.36, H 6.45, Cl 10.32, N 12.22%; Found: C 66.17, H 6.50, Cl 10.35, N 12.40%.

Example 8

2-Amino-5-chlorobenzophenone (23 g) was prepared according to the procedure described in Example 7 with 4- (3-aminopropyl) morpholine (45 g) reacted and the α- and /? - isomers of N- [3- (2-amino-5-

obtained chlor-a-phenylbenzylidenamino) propyl] morpholine.

Analysis for C20H24CIN3O

Example 10

2- (2-Amino-5-chloro-a-phenylbenzylideneamino) -ethanol (13 g) was reacted with acetic anhydride according to the method described in Example 3 and 2- (2-acetamido-5-chloro-a-phenylbenzylideneamino) - Ethyl acetate (13.6 g) of melting point 99 to 101 of ⁰ C.

Analysis for C19H19CIN2O2

Calculated: C 66.55, H 4.10, N 10.35%;
Found: C 66.45, H 4.03, N 10.55%.

Example 11

N- [3- (2-Amino-5-chloro-a-phenylbenzylideneamino) propyl] morpholine (1.3 g) was prepared according to the im Example 3 described method reacted with chloroacetic anhydride and this N- [3- (2-chloroacet-

amido) -5-chloro-a-phenylbenzylidenamino) -propyl] -morpholine (1.00 g) of melting point 107 to 109 ⁰ C.

Analysis for C22H25CI2N3O2

Calculated: C 60.83, H 5.80, Cl 16.33, N 9.67%;
Found: C 60.92, H 5.85, Cl 16.30, N 9.44%.

Example 12

N- [2- (2-Amino-5-chloro-a-phenylbenzylideneamino) ethyl] morpholine (3.0 g) was according to the im The method described in Example 3 is reacted with acetic anhydride and N- [2- (2-acetamido-5-chlora-phenylbenzylideneamino) ethyl] morpholine (1.5 g) of melting point 147-149 ° C.

Analysis for C21H24CIN3O

Calculated: C 67.12, H 6.76, Cl 9.90, N 11.75%,

α-isomer (6.4 g), melting point 91-92 ° C;

found: C 67.23, H 6.76, Cl 9.84, N 11.94%,

/ Msomer (5, Og), melting point 118 to

Found: C 67.36, H 6.79, Cl 9.94, N 11.85%.

Example 9

5-Chloro-2-methylaminobenzophenone (12 g) was prepared according to the procedure described in Example 7 4- (2-Aminoethyl) morpholine (30 ml) reacted and the α- and / Msomers of N- [2- (5-chloro-2-methylamino-a-phenylbenzylideneamino) ethyl] morpholine receive.

Analysis for C20H24CIN3O

Calculated: C 67.12, H 6.76, Cl 9.90, N 11.74%,

α-form (2.6 g), melting point 100 to 102 ° C;

found: C 66.96, H 6.65, Cl 9.90, N 11.53%,

/? - form (1.8 g), melting point 123 to

found: C 66.84, H 6.61, Cl 9.80, N 11.66%.

Calculated: C 65.30, H 6.27, Cl 9.19, N 10.89%;
Found: C 65.34, H 6.13, Cl 9.30, N 10.73%.

Example 13

3.5 g of 2- (2-acetamido-5-chloro-a-phenylbenzylideneamino) ethyl acetate was in a solution of 5 ml Dissolved 4-N sodium hydroxide and 50 ml of ethanol. The solution was diluted with water and the solid recrystallized from carbon tetrachloride, wherein

2- (2-Acetamido-5-chloro-a-phenylbenzylideneamino) ethanol (1.5 g), melting point 143 to 145 ° C was obtained.

Analysis for C17H17CIN2O2

Calculated: C 64.45, H 5.41, Cl 11.19, N 8.84%;
Found: C 64.60, H 5.39, Cl 11.20, N 8.92%.

Example 14
(Comparative example)

In the following, compounds according to the invention are compared with diphenylhydantoin sodium and Phenylethylbarbituric acid, which are known anticonvulsant compounds. The connections were examined for their antagonism to the maximum electric shock, their antagonism against pentamethylene tetrazole, with regard to its antimorphine effect and with regard to its antitremorine effect.

The results obtained are shown in the table below. table

connection 1 LD50 (oral)
mg / kg EDso (oral) mg / kg antagonism Antimorphine Antitremorin 4th antagonism opposite to effect effect 10 opposite maxi Pentamethylene 13th mal electro tetrazole 2 shock 57 400 31 to 50 (tremor) Diphenylhydantoin Na 8th 400 7 *) 17th 31 to 50 16 to 30 (tremor) Phenylethylbarbituric acid 9 400 13 *) 1 to 5 Connection according to the example 11th 400 51 to 100 6 to 15 Connection according to the example 400 16 to 30 31 to 50 Connection according to the example 400 51 to 100 31 to 50 Connection according to the example 400 51 to 100 16 to 30 Connection according to the example 400 1 to 5 (tremor) Connection according to the example 400 6 to 15 (tremor) Connection according to the example 400 6 to 15 (tremor) Connection according to the example 400

·) Minimum effective oral dose, the value for EDso would be higher.

From the table above it can be seen that the compounds according to Examples 1, 4, 10 and 13 compared to the Diphenylhydantoin-Na and the compounds according to Examples 1 and 4 compared to the Phenylethylbarbituric acid with regard to its anti-penta-

methylentetrazole action are superior. The connection according to example 2 is in their antimorphine effect and the compounds of examples 8, 9 and 11 are superior to the comparison substances with regard to their antitremorin effect.

609 686/4

Claims (1)

Patent claims: 1. Process for the preparation of 2-amino- <x-substituted Benzylideneamines, characterized in that a 2-aminobenzophenone is used the general formula NHA C = O characterized in that a 2-aminobenzophenone of the general formula NHA