AT368484B - METHOD FOR PRODUCING NEW SUBSTITUTED 3- (3'-AMINO-2'-HYDROXYPROPOXYPHENYL) ACRYLS [UREDERIVATIVES - Google Patents

Description

  

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 EMI1.1
 
 EMI1.2
 wherein R 'and R * independently of one another hydrogen, an alkyl or alkoxy group with 1 to
4 carbon atoms which represent allyl group, a halogen or the nitro group,
R3 is hydrogen, a phenylalkylene group with 1 to 3 carbon atoms in the alkyl part, the
Phenyl group can be mono- or disubstituted by alkoxy groups having 1 to 3 carbon atoms and / or the benzyloxy group or by the methylenedioxy group means, R '* is hydrogen, a C 1 -C 4 -alkyl group, optionally a lower one
Alkyl or alkoxy-substituted aryl or aryl-lower alkyl group,
R represents hydrogen or an alkyl group with 1 to 8 carbon atoms and R represents the nitrile, carboxyl or a lower alkoxycarbonyl or aryl lower alkoxycarbonyl group,

   as well as their physiologically tolerated acid addition salts.



   The invention comprises the preparation of both the racemic mixtures and the individual optically active isomers of the formula (I).



   Of the substituents mentioned, the following are preferred:
For R'and R ':
Hydrogen, alkyl and alkoxy radicals with 1 to 3 carbon atoms, fluorine, chlorine and the nitro group.



   For R3:
Dialkoxyphenylethylidenreste, especially the 5 ', 4'-Dimethoxyphenyläthyliden- and the
 EMI1.3
 Ethyl radical and the phenyl radical.



   For RI:
Hydrogen, an alkyl radical with 1 to 4 carbon atoms.



   For R.:
Alkoxycarbonyl with 1 to 4 carbon atoms in the alkoxy group, in particular methoxycarbonyl, ethoxycarbonyl and tert. Butoxycarbonyl and the benzyloxycarbonyl group.



   The essence of the process according to the invention consists in that a compound of the general formula is used
 EMI1.4
 wherein
R ', R2, R3, R4, RS and R6 have the meaning given above,

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X is hydrogen or the benzyl group and
Y is hydrogen or the benzyl group,
X and Y, however, cannot simultaneously mean hydrogen, split off the benzyl group (s) by catalytic hydrogenation in the presence of noble metal and, if appropriate, convert a base obtained into a physiologically tolerated acid addition salt.



   The new process products are thus obtained according to the invention by
 EMI2.1
 



   The corresponding benzyl compounds of the formula (II) can be prepared by one of the following methods, using the corresponding benzylated starting materials.



   One can a) a compound of the formula
 EMI2.2
 wherein R1, R2, R4, R5 and R6 have the meaning given for formula (I), with an amine of the formula
 EMI2.3
 wherein
Ra has the meaning given for the formula (I) and
Y has the meaning given above for formula (II), or b) a compound of the formula
 EMI2.4
 wherein R1, R, R ".

   R and R have the meaning given for the formula (I),
X has the meaning given for the formula (II) and
Z is a halogen atom, the sulfuric acid or a sulfonic acid residue, react with an amine of the formula (IV) or c) a compound of the formula

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 EMI3.1
 wherein
RI, R ', R4, R5 and R6 have the meaning given for the formula (I) and
X has the meaning given for the formula (II), with a compound of the formula Z-R3, (VII) in which
Ra to formulas (I) and
Z have the meaning given for the formula (V), or d) a phenol of the formula
 EMI3.2
 wherein R ', R2, R4, R5 and R6 have the meaning given for the formula (I), with a compound of the formula
 EMI3.3
 wherein
Ra has the meaning given for the formula (I),
Y to the formula (II)

   has the meaning given and
Z has the meaning given for the formula (V), in the presence of an acid-binding agent, or e) a compound of the formula (VI) or
 EMI3.4
 

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 wherein
Rl, R2, R '*, R and RI have the meaning given for the formula (I), react with a suitable ketone and reduce the condensation product, or f) a compound of the formula
 EMI4.1
 wherein
Rl, R2, R, R ″, R and R have the meaning given for the formula (I), or g) a compound of the formula
 EMI4.2
 wherein
R ', R2, R3, R4 R and R have the formula (I)

   have the meaning given and
Z is a carbonyl group or one optionally with a
Phenyl group or one or two lower alkyl radicals substituted methylene group, hydrolyze.



   If starting materials of the formula (II) are to be prepared in which X is the benzyl radical, the corresponding hydroxy compound can be benzylated, for example. If it is desired to start from compounds of the formula (II) in which Y is the benzyl radical, the appropriate N-benzyl compounds can be used instead of the primary amines according to procedures a), b), f) or d).



   In the process according to the invention, it can sometimes be advantageous to combine the preparation of the starting compounds directly with the further reaction, ie. H. not to isolate the raw materials separately.



   The process products can be obtained as a free base or in the form of their salts and, if necessary, can be purified by the customary workup methods, for example by recrystallization or, if appropriate, conversion to the free base and subsequent treatment with a suitable acid. The process products can, if appropriate, be converted into the salts of physiologically compatible organic or inorganic acids.



   Examples of organic acids are:
Acetic acid, malonic acid, propionic acid, lactic acid, succinic acid, tartaric acid, maleic acid, fumaric acid, citric acid, malic acid, benzoic acid, salicylic acid, oxyethanesulfonic acid, acetic acid, ethylenediaminetetraacetic acid, embonic acid and synthetic resins containing acidic groups.



   Examples of suitable inorganic acids are:
Hydrogen halide acids, such as hydrochloric acid or hydrobromic acid, sulfuric acid, phosphoric acid and amidosulfonic acid.

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   The optically active isomers of the racemic, basic substituted phenol ethers of the formula (I) can be obtained if the latter are broken down into their components using optically active acids.



   Examples of acids which can be used for the production of optically active salts are:
 EMI5.1
 Ven salts can be made in water, water-containing or water-free organic solvents.



  The use of alcohols or esters of organic carboxylic acids has proven to be advantageous.



   To prepare optically active compounds, the racemate of the base is reacted in a solvent, preferably in molar proportions, with an optically active acid and the optically active salt of the compounds of the formula (I) is isolated. In certain cases, it is also possible to use only half an equivalent of the optically active acid in order to remove the one optically active antipode from the racemate, just as one can also use excess amounts of optically active acid.



   Depending on the type of optically active acid, the desired antipode can be obtained either directly or from the mother liquor of the first crystals. The optically active base can then be released from the salt in a conventional manner and this optically active base can be converted into a salt of one of the physiologically compatible organic or inorganic acids mentioned.



   The compounds of formula (I) or their physiologically tolerable acid addition salts have shown valuable therapeutic, in particular ss-adrenolytic, ss 1 -adrenolytic and / or hypotensive and / or antiarrhythmic properties in animal experiments on dogs and can therefore be used, for example, for treatment or prophylaxis of diseases of the coronary arteries, for the treatment of cardiac arrhythmias and for the treatment of high blood pressure in human medicine.



   The following should be emphasized in particular:
The compounds of the formula (I) show a therapeutically favorable split between ss 1 and ss 2 receptor blocking action, the ss2 receptors not being blocked.
 EMI5.2
 Tablets or dragees, optionally mixed with conventional pharmaceutical carriers and / or stabilizers, or administered parenterally in the form of solutions in ampoules. Milk sugar, starch, tragacanth and / or magnesium stearate, for example, are suitable as carrier substances for tablets.



   A dose of about 2 to 20 mg can be used for injections, while the oral dose is about between 6 and 150 mg: a single tablet or a coated tablet can contain about 5 to 50 mg of active ingredient.



   For example:
A solution of 5.42 g of [D, L] -3- [4- (3-3 *, 4 * -Dimethoxyphenäthyl-benzylamino-2-hydroxy-prop-oxy) -phenyl] -crotonsonitrile in 100 ml of methanol is in Hydrogenated the presence of 1.0 g of prehydrogenated 10% in accordance with the palladium-activated carbon catalyst. After 450 ml of hydrogen have been taken up, the hydrogenation is interrupted. The catalyst is filtered off and the filtrate is evaporated to dryness, dissolved in ethanol, adjusted to pH 4 by dropwise addition of concentrated HCl and then evaporated to dryness in vacuo. The distillation residue is dried by repeated evaporation in vacuo with toluene and then recrystallized from a little ethanol and ether and then again from ethanol.

   After repeated recrystallization of the hydrochloride, finally, 1.47 g of sufficiently pure [D, L] -3- [4- (3-3 *, 4 * -dimethoxyphenethyl-amino-2-hydroxy-propoxy) -phenyl] -crotononitrile hydrochloride obtained from mp 148 to 149 C.

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   The [D, L] -3- [4- (3-3 *, 4 * -dimethoxyphenethyl-benzylamino--2-hydroxy-propoxy) -phenyl] -crotononitrile used as the starting material can be reacted with 10 g of [D, L ] -3- [4- (2-Hydroxy-3-chloro-propoxy) -phenyl] -crotonitrile with 24 g of benzylhomoveratrylamine.

 

Claims (1)

 PATENT CLAIM:  EMI6.1     (3'-Amino-2'-hydroxypropoxyphenyl) acrylic acid derivatives of the general formula  EMI6.2  wherein R 1 and Ra independently of one another are hydrogen, an alkyl or alkoxy group 1 to 4 carbon atoms, which represent allyl groups, a halogen or the nitro group, R is hydrogen, a phenylalkylene group with 1 to 3 carbon atoms in the alkyl part, the phenyl group of which is mono- or disubstituted by alkoxy groups with 1 to 3 carbon atoms and / or the benzyloxy group or by which methylenedioxy group can be substituted means, R "is hydrogen, a C 1 -C 4 -alkyl group, an aryl or aryl-lower alkyl group which is optionally substituted by lower alkyl or alkoxy,    Rs represent hydrogen or an alkyl group having 1 to 8 carbon atoms and R represents the nitrile, carboxyl or a lower alkoxycarbonyl or aryl lower alkoxycarbonyl group, and also of their physiologically tolerable acid addition salts, characterized in that the compound general formula  EMI6.3  wherein R1-, R2, R3, R '*, Rs and R have the meaning given above, X is hydrogen or the benzyl group and Y is hydrogen or the benzyl group, However, X and Y cannot simultaneously be hydrogen, the benzyl group (s) is eliminated by catalytic hydrogenation in the presence of noble metal and the base obtained is converted, if appropriate, into a physiologically compatible acid addition salt.