DE2131674A1 - 3,4,5-Trialkoxybenzoylaminoalkanecarboxylic acids and their salts and medicinal preparations - Google Patents

Description

IS'i.'J'.vU'iO CHSHIO [PKRZiPlCO XSAlIANO S.p.A. , Milan, Italy.

¹¹ 3 _i 4,5-Ti ^> ialko.xvbenzoylaminoalkancarbon £; acids and their salts as well as medicinal preparations "

Priority: June 26, 1970, V.St.A., Ur, 50 329

The prophylaxis and treatment of heart diseases, such as iHchaemia, thrombosis, heart attack, rhythm and heating disorders, i: .'t a worthy task. Numerous investigations have been carried out to look for the causes of the disease and to find a method of prevention or treatment for these ilrankhoites, in particular for heart failure and heart disease. For the prophylaxis of Hera infarction, drugs have been administered to lower the elutcholesterol level, to relax the arteries and anticoagulants. Ventricles flicker in a very dangerous condition that is treated by electroshocking the heart muscle. Other arrhythmias and irritation disorders are treated with the use of pacemakers.

Although these procedures improve the prognosis of heart disease patients

to have, /

largely improved / heart diseases remain in general

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The problems, especially the heart attack, continue to be severe

The invention relates to new 3,4,5-trialkoxybcnzoylaminoalkanecarboxylic acids of the general formula I.

C-III- (OHp) ₁ -COOH

in which R _1, R ₂ and R * *, which are identical or different, each represent a methyl, ethyl or Prοpylgruppe, η ψ a whole number having a value of 3 to 8 and at least one of R ^ · , R ₂ and R _{7 is} a group other than the ethyl group, and their salts.

The compounds of general formula I can be prepared by known methods by reacting the corresponding ^{3,4,5- r} i'i "ialkozybenzoylchlorids with the corresponding aminoalkanecarboxylic acid at temperatures of about -5 to +5 C in the presence of an acid

h ο rg ο 31 e 11 ζ vie rö e η.
acceptox-s / In practice, the procedure is carried out in such a way that

that the free amino acid is suspended in about the same weight of water and neutralized with about 30 percent by weight! Excess sodium hydroxide solution is used ειΐβ ■ hydrogen halide acceptor. The mixture is cooled to -5 ° to + 5 ° C. and the 3,4,5-tria3-koxybenzoyl chloride is added while stirring. The temperature is kept below 5 ° C. during the addition. The I-lol ratio of amino acid to 3,4 »5-2rialkoxybenzoyl chloride is generally about 1 to 1.5: 1. The resulting solution is stirred for 2 to 4 days. After the reaction has ended, the reaction mixture can be decolorized with activated charcoal Acidification with diluted salt

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acid or sulfuric acid to · a ρ ,, - value of about 3 is the precipitated out filtered off or centrifuged, washed with water, dried and recrystallized from water or methanol.

The invention also relates to medicinal preparations which contain a compound of the general formula I or its pharmacologically acceptable salt. The medicinal preparations of the invention are administered for the treatment of cardiac ischemia, either before or after a cardiac ulcer, rhythm disturbances which may be associated with the infarction, and disturbances of the conduction of stimuli. The administration of the medicinal preparations of the invention constitutes an effective prophylaxis in cases of impending myocardial infarction and a v / irk game treatment after an infarction has occurred. The medicinal preparations of the invention can also be used in veterinary medicine, mainly in the treatment of domestic animals, in particular dogs which heart diseases occur frequently, can be used.

The heart attack often occurs without any previous symptoms or it occurs before the patient has undergone treatment to eliminate the symptoms. The doctors are, however often able to relieve the symptoms of an impending crisis ascertain. The administration of the medicinal preparations of the invention can then be started immediately in order to prevent a prophylactic treatment To make an impact.

Clinical research has shown that the toxicity of the Compounds of general formula I is low and no side effects appear. Pharnialcological examinations show

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that the main action of the compounds occurs on the heart. 'The only effect observed on the circulatory system is one Static blood pressure increase without significant change in mean arterial pressure.

The dosage der.Arzneipreparate the invention can be strong vary. Good results have been obtained with drug doses ranging from 25 rag / kg / day to 500 mg / kg / day. In humans it is with a daily dose of 2 to 8 g per person, preferably about 6 g, is generally effective for all disorders mentioned. These

"Dosage relates to an average body weight of 60 to 70 kg and thus corresponds to a dose of 25 to 200 mg / kg / day. Doses in the range of about 40 to 100 ng / kg / day are preferred. The treatment can consist in the administration of a single daily dose or in partial doses, which are administered at intervals throughout the day.For the treatment of heart attacks and associated disorders, a single daily dose is generally preferred, while for prophylaxis smaller doses given at intervals, e.g. six times a day 500 mg, preferably v / earth.

The administration of the medicinal preparations of the invention can be oral, subeutane, intravenous or intraperitoneal. With subeutaner, intraperitoneal or intravenous injection the compounds of general formula I in the form of their water-soluble ones neutral salts are used. All soluble, pharmacologically acceptable salts are suitable for this purpose. Preferably be the liatrium and potassium salts used. The sodium salts are particularly preferred. For oral administration, the

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Free acids prefer / ends, but it can also 'pharma-' ecologically compatible salts, e.g. the ammonium, sodium, potassium, magnesium or calcium salts are used. the Free acids can optionally be mixed with an equimolar amount of sodium or potassium bicarbonate. peritoneal administration, the drugs ground as urodium salts ends, as these can easily be handled in an aqueous solution. When administered orally, usually Tablets with 500 mg active ingredient, the © in the usual binder included, used.

Tablets for administration to humans or animals can usually 50 to 500 mg of a compound of the general formula I either in the form of the free acid or a pharmacological contain compatible salt. Tablets with 50 mg of active ingredient are suitable for oral administration, especially for children and toddlers and in veterinary medicine for small animals. Tablets with less than 50 mg of active ingredient can be produced are and are valuable in special cases, but in general a dose of less than 50 mg is too low because of the number of the tablets per Ts.g required for the average patient would be too high. Tablets with more than 500 mg of active ingredient can also be made, but prepare large tablets most patients have difficulty swallowing.

The examples illustrate the invention.

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Example 1,.

7 g of b-aminocaproic acid are suspended in 7 nil of water and Neutralized with 10 percent sodium hydroxide solution. After that, the Solution with 4.1 g of ΙΓ-atriumhydr oxide in 20 ml V / ater added. On that at 5 to 10 C slowly 11.5 g of 3,5-diethoxy-4-methoxy ~ ·

lcl-ujorfri registered. The mixture is stirred for 16 to 18 hours and then acidified with dilute hydrochloric acid. The precipitate is filtered off and washed with water and P & trol ether. The 3,5-diethGxy - / - methoxybenzoyl-E-amino acid spray obtained is recrystallized from water. P. 105 to 106 ⁰ C.

Example 2

14 g of 95 percent pure £ -aminocaproic acid are mixed with 14 r _; J. Water is added and the mixture is neutralized with 10 percent sodium hydroxide solution. Thereafter, "the solution with 8.2 g of sodium hydroxide in 80 ml Vvasser added. Thereupon, at 10 ° C 9 bic lan. ^ Srun 22 g 3,4,5-'i ¹ riäthoxybönzoylo} ilorid entered, and DAU mixture 3 to 4 hours at room temperature .gorüLrt, The solution is decolorized with charcoal, filtered uno with dilute hydrochloric acid to a p ,, - \, ^r 3 ert acidified The precipitated crystals filtered off, "Ausbeutο 30 g of crude 3j4,5-Triäthoxybcnsoy. 1- £ -aminocaproic acid from P. 115 to 116 C. After recrystallization from a mixture of 7130 ml of water and 250 ml of ethanol, the compound melts at 120 to 122 °.

Example 3

53.4 S (0.2 mol) e-amnocaproic acid hydrochloride in 20 ml v / water dissolved are neutralized with 50 percent sodium hydroxide solution

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and then do verse with a solution of 12 g sodium hydroxide in 120 ml Vaster. The solution is cooled 8 ⁰ C to 5 ms and treated slowly with 38 g of 3,5-DirrK:; thoxy-4-äthoxybenzoylchlorid, stirred for 16 to 18 hours and then acidified with dilute hydrochloric acid. The precipitated crystals of 4-ethoxy-3, S-dimothoxybenzoyl - ^ - asnnocaproic acid are uncrystallinated from 3 liters V / acr. ] ?. 125 to 126 ⁰ C.

Example 4

11 g of fc-aminocaproic acid hydrooliloride are dissolved in 15 ml of water, with lOprosenti ^ ea? ITatronlau ^ e neutral J yaw and anr.chlicfjoend with 5 g liatriui-.hydro; -: id in 15 ril .water added,! Lach eng cooling to 5 ° C the solution is at 5 to 8 ⁰ C with 19 g 3, 4,5-tripropo>: benzoyl chloride and at the same time slowly added uit 2Oi ■ ml of V. 'asücx'. The mixture is stirred for 16 to 18 hours, then decolorized with active charcoal and acidified with dilute hydrochloric acid. The precipitated crystals of 3,4,5-tripropoxylbenzoyl-t-ciminocaproic acid were recrystallized from 100 ml of a mixture of equal parts of ethanol and water. Yield 21 g with a melting point of 110 to 111 ^° C.

Example 5

The effect of the compound prepared in Example 1 on de.s Hers was had by intravenous injection of 1 unit of vasopressin per kilograr-iu (Pitressin, Parke Davis Co.), an antidiuretic pituitary hormone. It is known that the administration of vasopressin causes changes in the tension and shape of T cells. Likewise will causing arrhythmia and ischemia of the kyocardium. It

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it was found that these can be detected in the ■ electrocardiogram Changes normally caused by administration of pitressin due to administration of the Connection of example 1 prevents grounding.

Example 6

The effects of the compound of Example 1 were demonstrated on hats determined in those arrhythmias caused by chloroform-epinephrine had been induced. The procedure used was the rats were anesthetized with urethane. Han left the animals for 1 minute Inhale chloroform and then administer rtravenously 100 µg / kg epinephrine hydrochloride. Electrocardiograms were taken and the extent of the arrhythmia was determined as the number of heartbeats per minute. The effect of the connection of Example 1 is that the extent of the arrhythmia substantial when administered intraperitoneally at 700 rag / kg is decreased.

Example -7

500 mg of the compound of Example 1, 50 mg of corn starch and 50 mg sucrose were mixed and placed in a '.-.' Abletting machine compressed into a tablet. It is suitable for oral administration to humans or animals suffering from cardiac disorders To suffer. It is particularly suitable for the prophylaxis of heart attacks.

The 3,4,5-trialkoxybenzoic acids used according to the process are known; See U.S. Patents 3,234,276, 3,364,249 and 3,485,865. Examples of other aminocarboxylic acids that can be used are aminovaleric acid, aminobutyric acid, aminoheptane. acid, amino octanoic acid and amino nonanoic acid. These compounds i & fi ^ ^ww 109885/1969

can be prepared by hydrolysis of the corresponding lactams.

The following dosage is used for the first 24 hours after a inf arkt recommended: '

2 to 4 g for phleboclysis; 1 to 2 ampoules (each ampoule contains 2000 mg sodium salt of the compound of Example 1, dissolved in sterilized, distilled water with a total volume of 10 ml) dissolved in 400 to 600 ml of physiological saline solution.

2 to 4 g for intravenous administration; 2 "to 4 ampoules for 2 to 4 injections (each ampoule contains 1000 mg of hatriuia salt the compound of Example 1, dissolved in sterilized, distilled water with a total volume of 10 ml).

2 g for intramuscular administration; 8 ampoules for 4 injections (Each ampoule contains 250 mg of the liatric salt of the compound of Example 1 and sterilized, distilled water

3 ml total volume).

4 to 6 g for oral administration; 8 to 12 tablets (each Tablet contains 500 mg liatric salt of the compound of Example 1 and a sufficient amount of vehicle).

4 to 6 g for oral administration; 8 to 12 tablets (each tablet contains 500 mg of the sodium salt of the compound of Example 1 and a sufficient amount of carrier).

On the third or fourth day after the start of treatment, the dosage can be can be reduced to half of the stated amounts.

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Therapy should not be discontinued before the third week after the onset of the infarction.

Both during the seizure and in the subsequent stage, therapy can be administered using one of several modes of administration be performed.

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Claims (6)

Claims 3,4,5-trialkoxybonaoylaminoalkanecarboxylic acids and their Salts of the general formula I - C-KH- (CH ₂ ) _n -COOH / ν in which R-,, R ^ and R ~, which are identical or different,, each mean a hotiiyl-, Ä'üh ^ l- oacr propyl group, η is an integer with a value of 3 to 8 and at least one of the radicals Rj, R ₀ and R-. a group other than the Hctiiy ^ group irjt., and their; ^; ale. 2. A compound according to claim 1, in which η is 5, R, and IiU are I-ietiiylijruppen and Rp is the atiiylgruppe. 3. Compound according to An.spruch 1, in which η has the V / ert 5, Ii-, and Rv i'Lthylcruppen and R _{0 is} the methyl group. 4. Compound according to claim 1, in which η has the V.'ert 5 and the Reute Ri, 'R? ^xm & ^ mean ethyl groups. ¹ J. Compound according to Claim 1, in which η is 5 and the radicals R-,, R ₀ and R- * are propyl groups. 6. Medicinal products containing a 3,4> 5-trialkoxybenzoylaminoalkanecarboxylic acid Geraäss Ansi> ruch 1 to 5 or their pharmacologically acceptable SaIs. 109885/1969