DE2019468A1 - Novel antihypertensive compounds and methods of making them - Google Patents

Description

Patent Attorneys Dlpl.-Ing. R. Π ': K TZ sen. DIpI-Inn- K. LA . "> 1. ZCHT

Dr.-lng. R. D - - ::. Z jr.
β Munich 22, Steinsdoifstr. 10 96-I5.6I2P 22.4 1970

ORSYMONDB, Paris (France)

Novel antihypertensive compounds and methods of making them

The invention relates to new therapeutically effective ones, in particular in the treatment of arterial hypertension Mandelic acid derivatives of the formula

CHOH - Cl

in which R ₁ and Rp can be identical or different and each represent a hydrogen atom, a hydroxyl group or an -O-alkyl group, in the latter case the two oxygen atoms of R- and R ₂ . cyclic over a

96- (H 6552-cas 52b) -NöE (6)

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2013468

Alkylene groups can be connected to one another and R ₁ and Rp then together form an alkylenedioxy group and in which R, and R ₁ ,, which can be the same or different, stand for a hydrogen atom, an alkyl, aryl or alkylaryl group or for a hydroxyl or -O-alkyl group and their addition salts formed with physiologically acceptable acids, according to patent ... (patent application P 18 11 804.2- ^ 2), in which the radicals R ,, Rp located on the benzene nucleus in the 3- and 4-positions are also lower Alkyl radicals, such as the isopropyl group, and lower alkoxy and alkylenedioxy radicals such as methoxy and methylenedioxy radicals are possible as alkoxy and alkylenedioxy radicals and R., equal to hydrogen or a lower alkyl radical, such as the ethyl or isopropyl group or a phenyl radical and R. ₁ , a hydroxyl group, a lower alkyl group having at least two carbon atoms or a phenyl group; Rj can also be a hydrogen atom or a methyl radical if R _{2 is} a hydroxyl group or a lower alkoxy radical and R is hydrogen or if Rp is a hydroxyl group and R _{1 is} a lower alkoxy radical or R ₁ and R ₂ together form an alkylenedioxy group.

The designation lower alkyl radical means a radical with a maximum of three carbon atoms. The present additional application also relates, of course, to the nontoxic acid addition salts of these compounds and their optical isomers.

It has been found that the compounds corresponding to the formula given above have an effect on the cardiovascular system act and are of particular interest for the treatment of arterial hypertension.

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The process for the preparation of the mandelic acid amidines of the formula (I) comprises the following steps:

1) Reaction of a lower aliphatic alcohol with a nandelsonitrile of the formula:

CHOH - CsN

in which R ,, R ^ have the meaning already given to the corresponding iminoester;

c) Implementation of this imino ester with an amine of the formula:

at the R. ,, .Rj. each is a hydrogen atom or a lower one Denote an alkyl radical or a phenyl radical, the corresponding mandelic acid amidines of the formula (I) being formed will; and

3) Reaction of a mandelic acid amide of the formula (I) ₄ where R 1, R 1 are hydrogen atoms and which was obtained by the above procedure, with hydroxylamine, if mandelic acid amidines of the formula (I) are to be obtained

109808/2291

where R _{1 is} an OH group (ie almond acid eamidoxime).

To prepare the 3, k- methylenedioxymandelonitrile used as starting material, piperonal is allowed to react with potassium cyanide in an aqueous medium in the presence of sodium bisulfite as a catalyst and hydrochloric acid diluted to about pH 4.0 to 5 * 0, for which purpose a sealed reaction apparatus is used.

The following are non-limiting examples to illustrate the invention.

example 1

Production of 3,4-methylenedioxy-mandelic acid amidoxime hydrochloride

A hydroxylamine solution is slowly added to a solution of 10 g of 3,4-methylenedioxy-mandelic acid amidine hydrochloride (0.04 mol) in 70 ml of methanol, 4 g of hydroxyl amine hydrochloride (0.063 mol) had been obtained in a methanolic medium and filtration after stirring for > 0 minutes.

1 C 9 8 0 8/229 '.

After leaving to stand for 48 hours, the mixture is evaporated in vacuo and the residue is taken up again in water, filtered and the pesticide obtained is filtered off with suction or spun off, which is dried in vacuo. This gives 7.3 g of 3,4-Methylendioxymandelsäureamidoxim (Pp: 103 ⁰ C), which is converted in ethanolic solution into the hydrochloride.

The hydrochloride is precipitated by adding ethyl ether and then purified by recrystallization from a mixture of ethanol and ethyl acetate. That with a yield 3,4-methylenedioxyraandelic acid amidoxime hydrochloride obtained from 8o # (8.5 g) is a white powder that is soluble in water (about 20 #) as well as in methanol and ethanol and in ethyl ether, Petroleum ether, benzene and ethyl acetate are insoluble. The instant melting point is 105 ° C.

Example 2

Production of (-) - and (+) - 3,4-methylenedioxy-mandelic acid amidine hydrochloride

29 g of 3 * 4-methylenedioxyraandelic acid amidine hydrochloride (0.125 mol) suspended in 30 ml of water are treated in the cold with a solution of 6 g of sodium hydroxide (0.125 mol) in 30 ml of water. The released insoluble amidine base is quickly isolated by filtration, filtered off with suction or centrifuged and dried in vacuo.

The yield of 80 # (19 * 5 g) obtained raoemische 3,4-methylenedioxy-mandelsäureamldin has a Momentanschraelzpunkt of 118 ⁰ C.

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^{15.2 g of L-almond acid (0.1 mol; * ^ 0} = -156 ° 5; c = 5 # in water) are added to a solution of this product (0.1 mol) in 80 ml of ethanol. For complete dissolution, the mixture is heated to 50 ° C. and then allowed to crystallize out and filtered. 17.5 g of a product Ia, the instantaneous melting point of which is 160-2 ° C., are obtained.

When the filtrate is evaporated to dryness, a remains Residue, which is taken up in 100 ml of a mixture of equal volumes of acetone and ethyl ether after filtering 20 g of a product Ha, the instantaneous melting point of which is 152-4 ° C.

The product Ia recrystallized from ethanol (17.3 g) gives 13 g of a product Ib (pp 168-9 ° C.). The evaporated piltrate leaves a residue which, when treated with a mixture of acetone and ethyl ether, gives 3.2 g of a product Hb (pp 132 ^° C.).

The treated with acetone in the heat product Ha leaves an insoluble product Ic (5g; Pp 165-6 ⁰ C). After recrystallization from acetone solution, 14 g of a compound Hc (pp 135-7 ° C.) are obtained.

The products Ib (I3 g) and Ic (5 g) give by recrystallization from ethanol 16.2 g of (-) - mandelate of (-) - 3.4 methylenedioxy-mandelic acid amidine (compound I), the instantaneous melting point of which is 168-9 ° C, with an optical rotatability Oi. _D = + 8 ° (c = 0.5Ji in methanol).

Production of (-) - 3,4 »methylenedioxy-mandelic acid amidine hydrochloride

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The (-) - 3j ^ -Methylendloxy-mandelic acid amidine hydrochloride is prepared starting from the compound I, which is suspended treated in 30 ml of water with an excess of 5N hydrochloric acid will.

The released mandelic acid is extracted 3 times with 100 ml of ethyl ether. The aqueous solution evaporated in vacuo leaves a residue which is purified by recrystallization of a mixture of ethanol and ethyl ether. This gives 9, £ g (yield 63 #) (-) - 3,4-methylenedioxy-mandelsäureamidin hydroehlorid, which in the form of a crystalline white powder is present and has an instantaneous melting point of 160 ⁰ C, and an op
(c = 0.5% in methanol).

g p

160 ⁰ C, and an optical rotation capacity ot ^ = -71 °

Preparation of (+) - j5,4-methylenedioxy-mandelic acid amidine hydrochloride

The (+) - 3 »4-methylenedioxy-mandelic acid amidine hydrochloride is prepared starting from the compound II (12.5 g), which, as was written for the compound I, is treated. 7 * 2 g of (+) - 3,4-methylenedioxy-mandelic acid amidine hydrochloride are obtained with a yield of 50 $ in the form of prismatic, white crystals, the instantaneous melting point of which is ITE ⁰ C and which have an optical rotatability of <X ^ ° = + 69 ° (c = 0.5 # in methanol).

Example 3

Production of (-) - 3,4-methylenedioxy-mandelic acid amidoxime hydrochloride

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A hydroxylamine solution prepared from 4.2 g of hydroxylamine hydrochloride (0.06 mol) and 3.25 g of sodium methylate (0.06 mol) in 50 ml of methanol becomes a solution of 9.2 g (-) -?> ^ -Methylenedioxy-mandelic acid amidine hydrochloride ⁱⁿ 50 ml of methanol, which had been prepared according to Example 2, was added.

After 48 hours of resting, it is acidified with an ethanolic hydrochloric acid solution and evaporated in vacuo, the residue was taken up again with water and the base was precipitated by adding acidic sodium carbonate. After filtering 7.4 g of Amidoxlm base with an instantaneous melting point of 114 ° C. are obtained.

This product, brought into solution in ethyl ether, is treated with an ethanolic solution of hydrochloric acid. The isolated hydrochloride is purified by crystallization from a mixture of ethanol and ethyl acetate.

The 8j5 in a yield of # (8.2 g) obtained (-) - 3,4-methylenedioxy-mandelsäureamidoxim hydrochloride is in the form of white crystals whose instantaneous melting point of 138-9 ⁰ C and in water, methanol and ethanol are soluble and insoluble in ethyl ether, petroleum ether, benzene and ethyl acetate. It has an optical rotatability oi. * ° = -42 ° (c = 0.5 # in methanol).

Example 4

Production of (+) - 3,4-methylenedioxy-mandelic acid amide oxide hydrochloride

Z 9 8 0 δ / 2 2 9 1

The (+) - 3,4-methylenedioxy-mandelic acid amidoxime hydrochloride was prepared in the manner described in Example 3 using 7 * 7 g of that obtained in Example 2 (+) - 3, 4-Methylenedioxy-mandelic acid amidine hydrochloride.

The product obtained in a yield of $ 76 (6.2 g) is a white powder with an instantaneous melting point of 9 ^° C., which is soluble in water, methanol and ethanol and in

Ethyl ether, petroleum ether, benzene and ethyl acetate are insoluble. It has an optical rotatability Of = + 46 (c = 5 0.5 # in methanol).

In addition, the following connections were made:

4-hydroxy-3-methoxy-mandelsäureamidin, HCl (bp 200 ⁰ C) 4-Methoxy-mandelsäureamidin, HCl (Pp 246 ° C) N-diethyl-mandelsäureamidin, HCl (Pp 167 ⁰ C) N-phenyl-mandelsäureamidin, HCl (Pp 128-13O ⁰ C) N-isopropyl-3-hydroxy-mandelic acid amidine, HCl (Pp 212-3 ⁰ C) N-isopropyl ^^ - dihydroxy-mandelic acid amidine, HCl (Pp 173 ° C) 3-hydroxy-mandelic acid amidoxime, HCl (pp 184 ° C).

The products according to the invention give addition salts with acids and, in particular, the hydrochlorides are in the form of white crystals which are soluble in water, methanol and ethanol and insoluble in ethyl ether, petrol, benzene and ethyl acetate are.

The following is a description of the pharraacological properties of the products according to the invention.

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Example A.

Mode of action of 3,4-methylenedioxy-mandelsaureainidoximhydrochlorlds (example 1)

I - test of acute toxicity of convulsive properties

a) With the mouse

Intravenous administration; At 800 mg / kg the death of 12 animals tested is found. The symptoms observed are: Severe clonic convulsions that last for 24 hours in some animals without causing death.

Bukkaie administration: No mortality up to a dose of JJ g / kg. From 2 g / kg onwards, the animals show an excitation phase without convulsion followed by sedation.

b) In the rat

Bukkai : a dose of 500 mg / kg leads to convulsions in 2 out of 5 rats and to ftosis in 4 out of 5 rats; no mortality.

Bukkai: A dose of 1 g / kg leads to ptosis, cramps, hypotension, paralysis of the hind parts (de l'arridre-train) and hypothermia. The animal is dead 24 hours after administration of this dose.

II - Cardiovascular Properties a) Isolated Rabbit Heart:

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- li -

Without barium chloride: Bel leads to a dose of 100 JfVmI the product with 2 hearts to:

a small increase in the coronary throughput and a positive inotropic effect. The heart rhythm is not changed.

Opposite barium chloride: The examinations were on 3 hearts performed, using the following doses:

- 100 y / ml (1 attempt)

Increase in throughput by $ 33. Increase in amplitude by $ 28. Decrease in rhythm by $ 33

- 500 jf / ml (2 attempts)

Throughput increased by $ 35 and $ 66

Variable effect on amplitude, -40 $ to + 14 $

The rhythm is not changed.

- 1 mg / ml (1 attempt)

Throughput increased by $ 82 Decrease in amplitude by $ 69. The rhythm has not changed.

b) Arterial pressure in the awakened rat

Intramuscular administration: In 3 rats (1 hypertensive and 2 with normal pressure) the product administered at a dose of 185 mg / kg lowered the arterial pressure by $ 40.

The effects start in 10 to 30 minutes. Even after No return to normal is observed for 6 hours.

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Buccal administration: In 3 rats (with normal pressure) the product administered in a dose of 390 mg / kg orally lowers the arterial pressure by 2k% on average after 60 to 90 minutes. The effect begins in 30 to 60 minutes and ends after 90/120 minutes in two rats and lasts for more than 5 hours in the third

c) Arterial pressure in the anesthetized rabbit

The administered in a dose of 77 * 5 mg / kg (IV) Product lowers arterial pressure in 3 rabbits by an average of 49 # after 3 hours. The effects start in 15 minutes and lasts for more than 5 hours.

d) Cardiovascular effect in the anesthetized dog

That to a dog in a dose of 77 * 5 mg / kg in intravenous Perfusion administered product gives the following results:

- Temporary increase in differential arterial pressure by 25 # by increasing systolic pressure;

- very slight increase (+ 9%) in the mean arterial pressure, which rises from 80 to 87 mmHg;

- slight decrease (-14 #) in arterial pressure in the right ventricle after 15 minutes;

- decrease in heart rate by J> 2% after 15 minutes (the heart rhythm changes from 155 to 105 beats / min);

- Increase of the cardiac throughput and especially of the systolic throughput (+ 78 # after 15 min);

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r 13-

- Increase in the cardiac index (+ 20 # after 15 min);

- Increase of the "stroke volume index ^11" by 20 # at the end of the perfusion and by 77 $ after 15 min;

- 20 # increase in the work of the left ventricle during 15 minutes;

- Decrease in peripheral resistance (resistance peripherique)

at l6 # after 15 min.

Further compounds according to the invention have been examined pharmacologically. Doing this in the same way as with Properties determined in accordance with Example 1 are summarized below.

Example B. ^ -Hydroxy - ^ - roethoxy-mandelic acid amidine

The product dissolved in water has a pH of 5. The DL ₅₀ (IV) in the mouse is 400 mg / kg. The animals that die have accelerated respiration and death occurs in a few minutes.

An intramuscularly injected dose of 200 mg / kg des The product has no effect on the mouse, and neither does it detract from the vegetative nervous system, nor does it become one Tranquillizer or analgesic effects found.

Example C 4-methoxymandelic acid amidine

The product is in water at a concentration of 10980 8/229

$ 0.5 soluble. The DL ™ (IV) in the mouse is 117 mg / kg. Symptoms observed are: cramping, paleness and a prolonged bleeding time after injection; when death occurs so it happens instantly. The intramuscular administration of 60 mg / kg of the product in the mouse results severe diarrhea and mild hypothermia.

When studying cardiovascular properties, the following results were obtained:

a) Arterial pressure in the awakened rat

The five anesthetized at a dose of 60 mg / kg Product administered intramuscularly to rats results in a maximum hypotension of $ 20 between the 30th and the 120th minute. There will be no return within 6 hours observed to normal.

b) Arterial pressure in the anesthetized rabbit

The product administered intramuscularly to 10 animals at a dose of 60 mg / kg lowers the arterial pressure by YYYes after 2 hours. Hypotension begins after 50 minutes. 5 hours after the injection, the hypotension is still 29 #.

Example D N-isopropyl-3-hydroxy-mandelic acid amidine

The DL ₁₅₀ (i «v.) In the mouse is 36 mg / kg and when administered intramuscularly a value of 135 mg / kg is found. With strong doses in the vicinity of the DL _{1 -Q}

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(125 ms / kg) convulsions are observed in the treated animals.

The study of cardiovascular properties revealed the following results:

a) Arterial pressure in the awakened R-ttte

An intramuscular dose of 70 mg / kg reduced the arterial pressure in 5 rats by an average of > (with one exception); the hypotensive effect is delayed after 1 to 5 hours and the maximum effect is observed between 2 and 6 hours; the return to normal takes between 5 and 6 1/2 hours.

b) Cardiovascular effect in the cat

That of a cat intravenously at a dose of 20 mg / kg administered product lowers carotid pressure by 40 #. It does not lead to any change in the pressing effects of adrenaline, acetylcholine and tyramine. It increases the through Dimethylphenylpiperazine Induced Hypertension. No direct effect is exerted on the nictitating membrane, and it does there is no change in the contractions caused by pre- and post-ganglionic stimulation of the upper cervical nerve

The product administered intra-arterially in the area of the ganglion in doses of 166 and 530 mg / kg lowers the arterial pressure at the higher dose slightly (12Ji). It temporarily diminishes those caused by pre- and post-ganglionic ones Stimulations of the upper cervical nerve evoked contractions.

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The product was applied to humans at a dose of 25 mg per dose; 4 tablets or capsules per day give good results 70% of the time.

Example E. N-Isopropyl-3i4-dihydroxy-mandelic acid amidine

The aqueous solution of the product has a pH of 5. The DL ₅₀ (iv) in the mouse is 62.5 mg / kg, the symptoms observed are: dyspnoea, exophthalmia and peripheral vasoconstrictions.

The study of the cardiovascular properties gave the following results:

a) Isolated rabbit heart

With two hearts perfused with a Van Dyke-Hastings fluid without barium chloride, the following results are achieved ^{at a dose of 100 / V 111 I:}

slight increase in coronary throughput (+51 %) positive inotropic effect (+ 96 #). no change in rhythm.

b) Arterial pressure in the anesthetized rabbit

The product administered intramuscularly to five rabbits at a dose of J> \ mg / kg lowers the arterial pressure by 40 *.

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2079468

Example F 3-Hydroxy-nandelic acid amidoxime

Doses administered intravenously to the mouse up to
1 g / kg does not lead to any mortality; the animals only show a pilot erection. In mice given 1 g / kg of the product intramuscularly, the following
Symptoms observed: slight excitement, significant piloerection, slight hypothermia and no tranquillizer or analgesic effects.

The three awakened rats at a dose of 500 mg / kg Intramuscularly administered product lowers arterial pressure by an average of $ 20.

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Claims (1)

Claims 1. New therapeutically effective derivatives of mandelic acid, particularly in the treatment of arterial hypertension the formula: in which R _{1 and R 2 can be} identical or different and each represent a hydrogen atom, a hydroxyl group or an -O-alkyl group, in the latter case the two oxygen atoms of R ₁ and R ₂ can be linked to one another cyclically via an alkylene group and R . and Rp then together form an alkylenedioxy group and in which R, and R ₁ ,, which can be identical or different, stand for a hydrogen atom, an alkyl, aryl or alkylaryl group or a hydroxyl or -O-alkyl group and their addition salts formed with physiologically acceptable acids, according to patent ... (patent application P 18 11 804.2-42), characterized in that the radicals R., R _{2 located} on the benzene nucleus in the 5- and 4-positions can also be lower alkyl radicals and as Alkoxy or alkylenedioxy groups, lower alkoxy or alkylenedioxy groups come into question and R, is hydrogen or a lower alkyl or a phenyl radical and Rj, a hydroxyl group, a lower alkyl radical m it has at least two carbon atoms 109808/2291 or a phenyl radical, where Rj. can also be a hydrogen atom or a methyl radical «if R _{2 is} a hydroxyl group or a lower alkoxy radical and R. is H or if R _{2 is} a hydroxyl group and R _{1 is} a lower alkoxy radical or R-, Rp together form an alkylenedioxy group. 2. N-diethyl mandelic acid amldine and its hydrochloride as Mandelic acid derivatives according to claim 1. 2. N-Phenyi-mandelsäureamidin and its hydrochloride as Mandelic acid derivatives according to claim 1. 4. 3- ^Hydrox y ^mandels £ ^uream i ^{doxlm xma} its hydrochloride as mandelic acid derivatives according to claim 1. 5. N-isopropyl-3-hydroxy-mandelic acid amidine and its hydrochloride as mandelic acid derivatives according to claim 6. 4-Methoxymandelic acid amidine and its hydrochloride as Mandelic acid derivatives according to claim 1. 7. N-isopropyl- \ 5,4-dihydroxy-mandelic acid amidine and its hydrochloride as mandelic acid derivatives according to claim 8. ll-Hydroxy - ^ - methoxy-mandelic acid ainidine and its hydrochloride as mandelic acid derivatives according to claim 9 · 3,4-Methylenedioxy-mandelic acid amidoxime and its hydrochloride as mandelic acid derivatives according to claim 10 · (-) - 5 * 4-methylenedioxy-mandelic acid amidine and its hydrochloride as mandelic acid derivatives according to claim 109808/2291 11. (+) - 3,4-Methylenedioxy-mandelic acid amidine and its hydrochloride as mandelic acid derivatives according to claim 1. 12. (-) - 3> 4-methylenedioxy-mandelic acid amidoxime and its hydro chloride as mandelic acid derivatives according to claim 1. Process for the preparation of the mandelic acid derivatives according to one of the preceding claims, characterized in that that one has a lower aliphatic alcohol with a mandelonitrile of the formula; CHOH -CsN converts to the corresponding imino ester and allows this to react with a compound NHR, R ^, in which R, and R ^ are the same Are hydrogen or a lower alkyl or a phenyl radical and finally gfs. one that is not substituted on nitrogen Converts mandelic acid amidine with hydroxylamine into the corresponding mandelic acid amidoxime. 14. Medicines, in particular arterial pressure-lowering agents, characterized by a content of at least one of the compounds according to any one of the preceding claims. 15. Medicament according to claim \ J>, characterized by a content of 3,4-methylenedioxymandelic acid amidoxime or its hydrochloride. 109808/2291