CH437252A - Process for the preparation of catechol-O-methyltransferase inhibitors - Google Patents

Description

  

  



  Process for the preparation of catechol-O-methyltransferase inhibitors
The present invention relates to a process for the production of catechol-O-methyltransferase inhibitors of the formula:
EMI1.1
 in which formula X has the meaning given below, and is characterized in that a compound with the formula
EMI1.2
 where R and Rl represent ether or ester groups which can be converted into hydroxyl groups, Hal represents a halogen atom and X represents the group -CnH2n-, where n is an integer from 1 to 3,

   is subjected to an amidation reaction with ammonia or ammonium salts and then the radicals R and R1 are converted into the corresponding phenolic hydroxyl groups by hydrogenolysis or hydrolysis.



   These compounds show an inhibitory effect on one of the enzymes which degrade adrenaline and other cate cholamine, with z. B. the bronchodilator effect of isoprenaline is prolonged and a stimulation of the central nervous system is obtained with simultaneous administration of the noradrenalinprekur- sors 1-dopa.

   The two main ways in which
Adrenaline and nearby catecholamines are broken down in the mammalian organism, consist of oxidative deamination by means of monoamine oxidase (MAO) and
3-O-methylation under the action of catechol O-methylztransferase (COMT). The substance most widely used to date to inhibit COMT, PyrogaNdl, has pronounced poisonous effects (including metaemoglobinemia) which greatly impair its use as a COMT inhibitor.



   It has now been found that compounds with the above-mentioned form have more favorable properties than COMT-Inhi'i'bv'tar and at the same time are much less toxic.



   Example 1 a) 3,4-Dibenzyloxyphenylacetyl chloride
21.0 g of 3,4-dibenzyloxyphenylacetic acid, 70 ml of benzene and 30 ml of thionyl chloride were refluxed for 3 hours. The oily residue obtained after evaporation in vacuo was processed further directly. b) 3,4-dibenzyloxyphenylacetamide
20 g of the obtained acid chloride were in 50 ml
Dissolved benzene and shaken for 3 hours with 100 ml of 15 percent ammonia solution. The amide was filtered off and recrystallized from methanol-water.



   M.p. 136 C. Yield 18 g. c) 3,4-dihydroxyphenylacetamide
2.3 g of 3, 4-dibenzyloxyphenylacetamide were in
100 ml of ethanol in the presence of 0.5 g of Pd-C catalytically hydrogenated. After absorption of 2 moles of hydrogen was filtered and evaporated. The residue was recrystallized from acetone-benzene. M.p.



     147 C. Yield 1.1g.



   Example 2 a) 3,4-Diacetoxyphenylacetic acid
2 g of 3,4-dihydroxyphenylacetic acid were dissolved in 10 ml of anhydrous pyridine, and 5 g of acetic anhydride were added. After standing for 12 hours at room temperature, the solution was evaporated at 20 ° C. in vacuo. The residue did not crystallize. b) 3,4-diacetoxyphenylacetyl chloride
2 g of 3, 4-diacetoxyphenylacetic acid and 5 ml of thionyl chloride were cooled in an ice bath and with
3 drops of pyridine added.

   After 1/2 hour at 0 ° C. and 3 hours at 20 ° C., the reaction mixture was evaporated at 20 ° C. in vacuo. Of the
The residue was triturated with petroleum ether to remove thionyl chloride. c) 3,4-dihydroxyphenylacetamide
To 2 g of 3, 4-diacetoxyphenylacetyl chloride were added 7 ml of concentrated NH40H and while cooling with ice
Given 0.1 g of sodium sulfite. After 1 hour at room temperature, the solution became 50 percent
Bred sulfuric acid to pH 6 and extracted four times with ethyl acetate.

   The ethyl acetate solutions were dried over sodium sulphate and evaporated.



   The residue was recrystallized from acetone-benzene. M.p. 147 C. Yield 1.1g.



   Ce (3, 4-dihydroxyphenyl) propionic acid amide, m.p. = 139 C, and z- (3, 4-dihydroxyphenyl) isobutyric acid amide, m.p. = 139 C, were prepared by the same process.



   Biological studies
The testing of the compounds for their COM-inhibiting effect was carried out in vivo on mice (6 per group).



   The test substances were injected intraperitoneally (i.p.) in modified amounts. When testing the COMT activity in the brain, a monoamine oxidase inhibitor (nialamide, that is N-benzyl-fl- (isonicotincyl-hydrozino) -propionamide, 100 mg per kg i.p.) Was administered first. After half an hour the test substances and after a further half hour Dopaa a = 3,4-dihydroxyphenylalanine), the latter in an amount of 7.5 mg per kg i. p. injected.



  After a further hour, the animals were sacrificed and the content of dopamine (3,4-dihydroxy-ss-phenylethylamine) and 3 methoxytyramine in their brains was determined. A reduced level of 3-methoxytyramine, with an unchanged or increased level of dopamine, was regarded as a criterion for COM-inhibiting activity.



   It was found that even 500 mg of 3,4-dihydroxyphenylacetamide per kg of animal reduced the 3-methoxytyramine content in the brain to 0.2 y per g compared with 0.7 y per g in control animals. 2 g of the compound per kg of animal did not show any toxic symptoms and was well tolerated. To achieve the same effect, about 300 mg of pyrogallol is required per kg of animal, but the lethal dose (LDUo) for pyrogallol is 520 mg per kg of animal.



   In order to reduce the content of 0.7 y 3-methoxytyramine per kg mouse brain to 0.1 y per kg, the following amounts were required:
3,4-Dihydroxyphenylacetamide 2 g per kg animal a- (Dihydroxyphenyl) propionic acid amide 1 g per kg animal a- (3,4-Dihydroxyphenyl) -n-butyric acid amide 0.8 g per kg animal α- (3, SDihydroxyphenyl) isobutyric acid amide 1 g per kg animal
Preparations of the compounds for the treatment of mammals which can be prepared by the process of the invention are expediently prepared by dissolving or suspending one or more of the active compounds in a water-containing physiological carrier.



   This solution can be made isotonic with the blood in a manner known per se and adjusted to a suitable pH.

 

Claims (1)

PATENT CLAIM Process for the preparation of catechol-O-methyl transferase inhibitors of the formula EMI2.1 in which formula X has the meaning given below, characterized in that a connec tion with the formula EMI2.2 where R and RI mean ether or ester groups which can be converted into hydroxyl groups, Hal stands for a halogen atom and X means the group-C "H2", where n is an integer from 1 to 3, is subjected to an amidation reaction with ammonia or ammonium salts and then the R and Rl radicals are converted into the corresponding phenolic hydroxyl groups by hydrogenolysis or hydrolysis. SUBClaims 1. Process according to patent claim, characterized in that the radicals R and Rl are converted into the corresponding hydroxyl groups by hydrogenation in the presence of Pd C as a catalyst. 2. The method according to claim, characterized in that the radicals R and Ri are converted into the corresponding phenolic hydroxyl groups by saponification with acid.