CS200506B2 - Process for preparing 9,10-dohydroergosine and physiological additive salts with acids - Google Patents

Abstract

(I) and its acid addn. salts are prepd. by hydrogenation of ergosine in dimethylformamide with shaking, at normal press., in the dark using a 10% Pd/C catalyst and opt. converting (I) to its salts. (I) is used to treat arterial hypertension, peripheral angiopathy, cerebral circulatory troubles, cardiac arrythmia and migraine. It is administered parenterally or enterally in daily doses of 0.3-10 7g/70 kg Acute toxicity (methanesulphonate i.p. in mice LD50=72.2 mg/kg, i.p. in rats=N400mg/kg) and pharmacological tests (arterial press., effect on heart, antiadrenaline effect, antiserotonin effect) are described. The reaction is effected rapidly reducing by-prods. due to degradation and giving high yields of (I).

Description

The invention relates to a process for the preparation of 9,10-dihydroergosine and its physiologically acceptable acid addition salts.

9,10-Dihydroergosine is a natural substance obtainable by extracting sclerotia of Spbaelia SorgiMcRae, where it is contained in very small amounts [cf. P. G. Mantle and E. S. Weight, Nature, 218, 581 (1968)]. Therefore, its semi-synthetic or synthetic preparation is desirable. A synthetic preparation, which has so far been very difficult, is described in Belgian patent 689,619, which describes the preparation of ergosine and 9,10-dihydroergosine by condensation of d-lysergic acid or 9,10-dihydro-d-lysergic acid with 2-amino hydrochloride. -2-methyl-5-isobutyl-10b-hydroxy-3,6-dioxo-octahydro-oxazolo [3,2-a] pyrrolo [2,1-c] pyrazine in anhydrous methylene chloride and in the presence of pyridine.

It is also possible to obtain 9,10'-dihydroergosine by catalytic hydrogenation of the double bond at position 9, 10- in synthetic ergosine as described. The hydrogenation is carried out using a 5-why palladium catalyst on alumina and lasts 4 hours at atmospheric pressure and room temperature. The yield of the reaction is not indicated.

According to another procedure described by A, Stoll and A. Hofmann in Helv. Chim.

Acta, 26, p. 2070 [1943], the hydrogenation was carried out using a palladium sponge catalyst and lasted for 2 hours at 3.5 MPa at 60 ° C. The reaction yield was 79.5%.

A disadvantage of the known methods is that very low yields are obtained when using natural products, i.e. very large amounts of this natural material are required. In the synthetic method, the preparation of the starting material is very complex, it is carried out only for this purpose and with very low yields (agi 5%). Hydrogenation yields more by-products than the process according to the invention, since the former takes longer. The yield is lower due to the less active catalyst and the less suitable solvent. The purpose of the invention is to hydrogenate the double bond at position 9, 10 of natural ergosine under conditions such that the reaction lasts only a short time, thereby substantially reducing the formation of degradation products.

According to the invention, this is achieved by a process for the preparation of 9,10-dlhydroergosine and its physiologically acceptable acid addition salts, in which it is catalytically hydrogenated with hydrogen at atmospheric pressure ergosine in dlmethylformamide as the reaction medium, which process is referred to as " · that . .katalyzátoru formed using 'a charcoal content .. · 10 · ^7% of palladium, from 15 to 25 weight why., based on the weight of ergosine, and the reaction is conducted at a temperature ranging from 20 to 40 ° C for stirring at a speed of from 200 'to 400 ^min-1 in the absence of actinic radiation, whereupon the obtained

The 9,10-dihedroergosine optionally converts to its physiologically acceptable acid addition salt.

In the process according to the invention, ergosin obtained as a by-product in the extraction of rice ergot is used as starting material.

In the reaction, dimethylformamide is used as the solvent. The reaction is carried out at all times in the absence of actinic radiation at a temperature in the range of from 20 to 40 ° C. At 20 ° C the reaction is complete after 1 hour, at 30 ° C after 30 minutes and only 0.5%, the starting material is not hydrogenated. Hydrogen is supplied with stirring. a stirrer, rotating at a speed of from 200 to 400 min, which also allows the recycle of the hydrogen above the reaction mixture.

The catalyst was filtered off and the reaction mixture was concentrated under reduced pressure. · Dihydroergotoxin methanesulfonate dihydroergocristir methanesulfonate ergosine methanesulfonate dihydroergosine methanesulfonate

2. Effect of dihydroergism on arterial blood pressure

This effect is investigated by administering normotensive rats weighing 180-250 g in urethane narcosis with dihydroergosmate methanesulfonate. In several rats, the spinal cord is cut at the level of the second cervical vertebra (spinal rat). After insertion of the cannula into the carotid artery, the arterial pressure is registered by the dynograph using the arterial pressure sensor. The effect of dihydroergosine mesylate on the blood pressure of hypertensive rats is also investigated.

a) Dihydroergosine mesylate, administered intravenously to normotensive rats with intact spinal cord, causes a decrease in arterial blood pressure. The minimum effective dose is 0.01 mg / kg and causes a 15% reduction in mean arterial pressure compared to the control rat. The dose is effective for about 60 minutes. The maximum pressure reduction is induced by a dose of 1.5 mg / kg, which achieves a 40% reduction over the control rat. This dose is effective for several hours.

b) Induces intravenous in spinal rats

Crystallization of the residue from ethyl acetate yields pure crystalline 9,10-dihydroergosine. Since 9,10-dihydroergosine is only slightly soluble in water and therefore not pharmacologically effective, it can optionally be converted into its addition salt with a physiologically acceptable acid. For this purpose, 9,10-dihydroergosine can be dissolved in, for example, anhydrous ethanol, an equivalent amount of acid is added to the solution, and the resulting salt is precipitated with anhydrous ether.

9,10-011 ^ 6 6 0810 prepared by the process according to the invention is characterized by the toxicological and pharmacological properties listed below.

and. Acute toxicity

The method described by JT Litchfield and F. Wilcoxon in J. Pharmacol. · Exp. Ther. 96, pp. 99 (1949] and G. Karber, Arch. Exp. Path. Pharmacol., 162 ,. p. 480 (1931] ^in! On mice and rats mean value determined lethal dose DLso mesylate dihydroergosinu. Results are shown in in the table below compared to the results obtained using several other ergot alkaloids.

DL 50 in mg / kg on mice i. p. (18-24 g) on rats (200-260 g) 175 240 234 430.4 (Karber) 162 about 400 72.2 about 400

a 0.15 mg / kg dose of dihydroergosine methanesulfonate administered first, a blood pressure reduction of 2 to 3 minutes followed by an increase in the average arterial pressure of 40 to 60% for 60 to 90 minutes.

Results in spinal rats and intact spinal cord rats indicate that the reduction in arterial pressure is of central origin. The effect of this dose in normotersive and spinal rats is accompanied by bradycardia. In most cases, the hypertensive reflex of the carotid artery is partially reduced.

(c) Viiv dihydroergosulfonate methanesulfonate for hypertensive rat blood pressure is examined in spontaneously hypertensive Akamoto-Aoki · rats (29th generation). Blood pressure is measured using a cuff on the tail of the animal in the waking state. Dihydroergosine methanesulfonate also causes a decrease in mean arterial pressure in hypertensive rats.

3. Influence on heart

Metharsulforate ОШ-Ог ^^^ го induces an increase in the amplitude of contractions on the isolated guinea pig heart (modified Langendorf's preparation, described by Zalar et al. In Bolí. Chim. Pharm. 114, 146 (1975)) at a dose of 0.005 mg / g. heart rate by about 80%, decreases heart rate by about 20% and decreases coronary artery flow by about 10% Higher doses of dihydroergosine methanesulfonate in the range of 0.025 to 0.05 mg / g of heart cause first increasing the amplitude of the contractions by more than 150%, after which the amplitude decreases to 50% of the control value, the frequency decreases by about 33%, the coronary vessel flow by about 50%, and signs of cardiac muscle damage appear on the electrocardiogram.

4. Antiadrenaline effect

a) Protective effect against lethal dose of adrenaline

The anti-adrenaline effect was tested in rats weighing 180-240 g and administered dihydroergosine methanesulfonate 70-90 minutes prior to intravenous injection of adrenaline at a dose of 1 mg / kg corresponding to DL95. The results are summarized in the table below as compared to those obtained using some other ergot alkaloids.

Ш50 in mg / kg ergotamine methanesulfonate30.0 dihydroergotamine methanesulfonate30.0 ergosine methanesulfonate 6.5 dihydroergosine methanesulfonate 5.2 ^x KSrber (see above)

(b) In rat arterial pressure tests as described in paragraph 2, dihydroergosine methanesulfonate at a dose of 0,01 mg / kg iv reduces the hypertensive response to intravenous injection of adrenaline and noradrenaline. Higher doses ranging from 0.02 to 0.15 mg / kg

iv block norepinephrine-induced hypertension and induce adrenaline efficacy. Dihydroergosine methanesulfonate administered intravenously at doses of 0.02 to 0.05 mg / kg reduces the hypertension induced by the intravenous administration of physostigmine salicylate by 30 to 75%. Hypertense due to physostigmine salicylate represents the consequence of an indirect ¹ stimulating effect on the central sympathetic system [Varagič, Br.

J. Pharmacol. 10, p. 349 (1955)].

c) Dihydroergosine methanesulfonate at a dose of 0.02 mg / kg reduces the hypertensive response to intransferable. injection of canine angiotensirm by 20% and at a higher dose of 0.05 to 0.15 mg / kg

by about 50%.

d) The anti-adrenaline effect on the isolated vas deferens is investigated by the method described by G. D. H. Leach in J. Pharm. Pharmacol. 8, p. 501, (1956). Dihydroergosine methanesulfonate prevents adrenaline and noradrenaline-induced contractions. The degree of antagonism is determined by the pA? Value method described by H. O. Schild in Brit. J. Pharmacol. 2, p. 189, (1947).

If the agonist is adrenaline, the ω-value of dihydroergosine mesylate is 7.84; if the agonist is noradrenaline, this value is 8.79. This means that in the presence of mesylate dihydroergosinu as antagonists at a concentration of 9.3 x 10 ^{5 * * * 9} g / m, or 1.0 xx 10 ^-9 g / m, it is necessary to double the amount of the agonist (epinephrine and norepinephrine) to elicit the same organ response as in the absence of this antagonist. The results obtained are summarized in the table below as compared to those obtained using several other ergot alkaloids.

PAz agonist dihydroergotoxin methanesulfonate dihydroergocristine methanesulfonate dihydroergosine methanesulfonate

adrenaline 7.82 noradrenaline 8.47 adrenaline 7.42 noradrenaline 8.56 adrenaline 7.84 noradrenaline 8.79

5. Antiserotonin effect

(a) This effect is determined on the isolated rat uterus according to the methods of Dejalon, Bajo and Dejalon described in Pharmacoter. Act. 3, p. 313 (1945).

Dihydroergosine methanesulfonate prevents serotonin-induced contractions. The degree of antagonism is determined according to the pAz assay method described by H. 0. Schild in Brit. J. Pharmacol. 2, p.189 (1947). If the agonist is serotine, the pAž value is dihydroergosine methanesulfonate

8.62. Thus, in the presence of 1.6 x 10 ⁹ g / ml dihydroergosine methanesulfonate as an antagonist, twice the dose of serotonin is required to elicit the same organ response than in the absence of the antagonist.

b) Dihydroergosine methanesulfonate at a dose of 0.1 mg / kg i. v. blocks in the guinea pig the bronchial spasm induced by an intravenous injection of 0.005 to 0.06 mg / kg serotonin. The method of Konzett and Rbssler described in Arch. exp. Path. Pharmak. 195, p. 171 (1940).

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(c) In the test described in paragraph 2, it blocks. dihydroergosine methanesulfonate. at a dose of 0.15 m-g / kg in a spinal rat hypersensitive reaction to intravenous. injection 0.07 to. 0.15 mg / kg serotomine.

Based on the described pharmacological properties, dihydroergosine has been found to act as a catecholamine antagonist. to α-adrenergic receptors, as a serotonin antagonist to the D-receptors of serotonin, as a substance causing a decrease in arterial pressure and as a substance causing a positive inotropic effect on the heart.

Due to these properties, dihydroergosine can be used for the treatment of arterial hypertension, peripheral angiopathy, cerebral circulation disorders, cardiac arythmia and migraine.

9, 10-O-Dioydroergosine in the form of physiologically acceptable acid addition salts can be used as a medicament for ether and parenteral administration. For the manufacture of pharmaceutical compositions, inorganic or organic additives may be added to said salts. For the manufacture of tablets and dragees it is possible to add - for example, lactone, starch, - talc, stearic acid, etc. For production. solutions and emulsions may be added, for example, water, alcohols, glycerol, vegetable oils and the like. For the manufacture of suppositories it is possible, for example, to add natural oils or hardened oils and waxes. The pharmaceutical compositions may also contain suitable preservatives, stabilizers, wetting agents, solubilizers, sweeteners and colorants.

A suitable dose of 9,10-dihydroergosine in the form of a physiologically acceptable acid addition salt is in the range of 0.3 to 10 mg / 70 kg per day.

The invention is illustrated by the following examples, which are not to be construed as limiting.

He did

6.90 g of ergosine are dissolved in 120 ml of anhydrous dimethylformamide in a 800 ml dark-walled, double-walled, stirred reactor. The whole apparatus was flushed with nitrogen, and a suspension of 1.29 g of activated charcoal containing 10% palladium in 20 ml of anhydrous dimethylformamide was added. The solution was heated to 30 degrees Celsius and nitrogen was removed. replaces with hydrogen. With vigorous stirring, the hydrogynation is complete after 30 minutes. The catalyst was filtered off and the solvent was distilled off at 45 ° C under reduced pressure to dryness. After recrystallizing the residue from boiling ethyl acetate, filtering off the crystals and drying them under reduced pressure, 6.51 g of O10-dihydroergosine having a melting point of 195 DEG -19 DEG -9 DEG C. and a specific rotation of _{D20 are obtained} . = -48 ° [c = 0.5 in pyridine].

Example 2

3.0 g of 9,10-dihydroyrgosilicon are suspended in 10 ml of ethanol and 0.36 ml of distilled methanesulfonic acid are added and the mixture is stirred until complete dissolution. While stirring vigorously, the clear solution is slowly poured into 250 ml of anhydrous ether, and stirring is continued for 2 hours. Another 15 minutes. The precipitated salt is filtered off and washed thoroughly with anhydrous ether. It is then dried at room temperature. under reduced pressure to give 2.85 g of colorless 9,10-dihydroyrgosine methanesulfonate, m.p. 237 DEG C. (dec.) - and a specific rotation of ²⁰ DEG -40 DEG (c-0.5) in pyridine. ).

Claims (1)

SUBJECT A process for the preparation of 9,10-dihydroergosine and its physiologically acceptable acid addition salts, wherein ergosine is catalytically hydrogenated with hydrogen at atmospheric pressure in dimethylformamide as reaction medium, characterized in that an activated carbon catalyst of 10% is used. palladium, in an amount of the invention. 15 to 25% by weight, based on the amount of ergosine, and the reaction is carried out at a temperature in the range of -20 to 40 ° C with stirring at a speed of 200 to 400 rpm in the absence of actinic radiation. dihydroyrgosir optionally converts to its physiologically acceptable acid addition salt.