DE1051861B - Process for the preparation of amide-like derivatives of lysergic acid and isolysergic acid - Google Patents

Description

GERMAN

It has been found that hitherto unknown amide-like derivatives of lysergic acid and isolysergic acid can be obtained the general formula

/ CH ₂ .

C ₁₅ H ₁₅ N ₂ -CO-N: T ^ TR

CH ₂

arrives, in the R the same

- CH ₂ . - CH

- CH ₂ - CH ₂ - CH

or

CH ₂

means by taking isolysergic acid azide with amines of the general formula

hn:

.CH,
CH ₂

in the R has the above meaning, converts and the resulting mixture of lysergic acid and isolysergic acid amide broken down into the individual components in a known manner.

Amide-like derivatives of lysergic acid and isolysergic acid have been known for a long time (see A. Stoll, Oesterreichische Chemiker-Zeitung, Vol. 53, 1952, p. 73 and 101). So are z. B. the natural ergot alkaloids of the ergotamine and ergotoxin groups and theirs dextrorotatory isomers amide-like derivatives of the acids mentioned, in which the free amino group is one of three Amino acids built-up peptide residue is linked acid amide-like with the carboxyl group of the acid residue. While the ergot alkaloids mentioned are synthetic up to now because of their intricate structure of the peptide residue are not accessible, acid amide-like mono-, di- and tri-peptides of lysergic acids could be constructed more simply already set up (see A. Stoll, A. Hofmann,

E. Jucker, Th. Petrzilka, J. Rutschmann and

F. Troxler, Helvetica Chimica Acta, Vol. 33, 1950, p. 108). In other synthetically accessible amides the lysergic acid series, e.g. B. in Ergobasin, its isomers, homologues and derivatives (cf. A. Stoll and A. Hofmann, Helvetica Chimica Acta, Vol. 26, 1943, p. 944) the basic component is an aliphatic or arylaliphatic Amino alcohol or an aliphatic amine. All listed, previously known amide-like derivatives of the lysergic acids have in common that the carboxyl group of the acid residue with an openly bonded Amino group is linked acid amide. On the other hand, amide-like derivatives of lysergic acids are previously unknown in which the carboxyl group is linked to an amino group, which is a ring member of a heterocyclic Connection forms. Such amides have only become accessible through the process of the invention.

Method of manufacture

of amide-like derivatives

lysergic acid and isolysergic acid

Applicant:
Sandoz AG, Basel (Switzerland)

Representative: Dr. W. Schalk, Dipl.-Ing. P. Wirth,

Dipl.-Ing. G. E. M. Dannenberg

and Dr. V. Schmied-Kowarzik, patent attorneys,

Frankfurt / M., Große Eschenheimer Str. 39

Claimed priority:
Switzerland from January 21st and December 7th, 1955

Dr. Arthur Stoll, Ariesheim,

and Dr. Albert Hofmann, Bottmingen (Switzerland),

have been named as inventors

The method is carried out, for example, that isolysergic acid, dissolved in an organic Solvent, with an amine of the formula

.CH ₂ .

HNC " ^ R

CH ₂

can react at room temperature or slightly elevated temperature. Not only inert solvents can be used as solvents organic liquids, but the reacting amine itself can also be used in this Case is to be added in excess. The end product, a mixture of lysergic acid and isolysergic acid amide, is obtained by evaporation of the solvent or the excess amine in vacuo and in known Way, e.g. B. by chromatography on aluminum oxide, broken down into the individual components. That as a starting material Isolysergic acid azide is used according to the method of A. Stoll and A. Hofmann, Helvetica Chimica Acta, Vol. 26, 1943, p. 944.

The amide-like derivatives of lysergic acid and isolysergic acid obtainable by the process of the invention are solid, mostly crystallized compounds at room temperature, certain of which crystallized with acids Form salts. They are characterized by special pharmacodynamic properties in that they have a have a pronounced effect on vegetative nerves. In particular, the vascular tone and the Centers of the elongated medulla regulating the breathing

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dulla oblongata) and probably also higher in addition to the antihypertensive effect of these amide centers of the brain stem. In the case of animal experiments, the symptoms of lysergic acid pyrrolinide and lysergic acid pyrrolidide of the vegetative nervous system, which are best interpreted in the sense of a central sympathetic stimulation in dogs and cats, are best interpreted in the sense of a central sympathetic stimulation given intravenously in amounts of 10 to 20y per kg to an immediately onset and 5 (dilation of the pupil, increase in the body sustained lowering of blood pressure and to slow down temperature and blood sugar, piloerection), against the heartbeat. In the anesthetized dog, the reserpine effect is consistently characterized by an attenuation of pyrrolidide in an amount of 30 μg per kg intravenously of the central sympathetic tone.
given a decrease in blood pressure of 32% and a decrease in the number of heartbeats per minute by 12%. Respiration, which is superior to the new amides of lysergic acid in this respect, is only impaired after doses of 50 per kg or more, as it impairs a lowering of blood pressure and a prolonged heartbeat. In the anesthetized cat, administration of samung, without at the same time having a calming effect of 10y per kg given intravenously, reduces blood pressure by 15%, which in occupational hypertension sufferers 20% per kg, 50y per kg by 42%; in this amount is particularly advantageous, since the therapeutic amount is the drop in pulse beats per minute 15%. The action of no impairment of breathing capacity is associated with intravenous doses of 50y per kg,
given only slightly decreased, while higher Beismel 1
Quantities a significant decrease in tidal volume

condition. The antihypertensive effect is central. A solution of, prepared ^{at O 0 C, is heated}

conditional, because on the "spinal cat" (with destroyed brain 20 10 g isolysergic acid azide in 50 ecm pyrrolidine 1 hour

and preserved spinal cord) on the contrary a low to 60 ° C, the excess pyrrolidine evaporates in a vacuum

Increase in blood pressure is observed. off, the solution of the residue in chloroform is shaken off

The morpholide and the piperidide of lysergic acid with aqueous sodium bicarbonate solution and evaporated

act in the same direction, but weaker. To the chloroform solution dried over sodium sulfate

conversely, however, these derivatives have a stronger effect on the 25 in a vacuum. The residue (10.5 g) is dissolved in water

Breathing; Amounts of 50 to 100 y per kg of intravenous free chloroform dissolved and applied to a column of 500 g

given inhibit breathing, the administration given alumina. When washing the column with

Particularly of the morpholide, 7.5 g of lysergic acid pyrro-

slowing and shallowing of breathing. The lidid washed out.

vegetative irritation symptoms due to the abovementioned 3 ° The compound crystallizes from benzene in flaky

Compounds also express themselves by influencing crystals containing crystal solvents from F. = 100 to

the body temperature, which, depending on the species, is increased to 110 ⁰ C or from acetic acid ethyl ester in pointed

or is lowered. Higher quantities can also use prisms that ^{melt at 181 0} C; [a] ² S = + 25 ° (c = 1.2

Irritate the vomiting center; the intravenous administration of in pyridine).
100 y pyrrolidide per kg dog vomits regularly 35

result. C ₂₀ H ₂₃ ON ₃ ; Molecular weight = 321.4;

A notable adrenolytic effect (peripheral calculated C 74.73, H 7.21, N 13.08%;

Inhibition of the effect of adrenaline) these found C 74.87, H 7.16, N 13.16%.

Lysergic acid derivatives, but they have a labor-inducing effect, which is, however, weaker than 40. The compound is very sparingly soluble in water, forms those of the ergobasin or the methylergobasin. however, readily soluble, readily crystallizing salts, e.g. B.

The new derivatives of lysergic acid also show a bimaleate; this crystallizes when they are brought together

significant inhibitory effect on 5-oxytryptamine equimolecular amounts of the base and the acid in the

(Serotonin). The serotonin effect on the exposed rat - five times the amount of methanol in elongated prisms;

uterus is replaced by the pyrrolidide, morpholide or piperi 45 F. = 204 to 206 ⁰ C; \ d \ ² g = + 35 ° (c = 0.5 in water).

did still in a dilution of 1 · 10 ~ ⁷ , i.e. when developing the chromatogram with

1: 10000000, inhibited. Chloroform, which contains 1% ethanol, is 2.3 g

Washed out the isolysergic acid pyrrolidide produced by the process of the invention. This crystalline

New compounds can be used in therapy to be based on acetone in plates from F. = 202 to 203 ⁰ C;

Treatment of high blood pressure (hypertension) treats 50 [α] o ° = + 193 ° (c = 0.5 in pyridine).
be turned.

The good resorbability of the C ₂₀ H ₂₃ ON ₃ ; Molecular weight = 321.4;

To highlight connections as particularly important. The calculated ... C 74.73, H 7.21, N 13.08%;

The effective individual amount for parenteral tests is C 74.95, H 7.25, N 13.26 / ₀ .

administration 0.2-0.3 mg, while for the same 55 The compound is difficult in water, in dilute

Effect with oral intake only about twice as much as aqueous acids, but easily soluble,

necessary is. .

The new amides of lysergic acid differ in Example 2

basically from the antihypertensive rau- Man adds 10 g isolysergic acid azide to the solution

wolfial alkaloids. The blood pressure caused by reserpine was heated in 50 ecm tetrahydrofuran with 2 ecm piperidine

Lowering and slowing down of the heartbeat (Brady- the mixture 2 hours at 50 ⁰ C, the solution evaporates

cardia) set in slowly and decrease in the course of the medium and shake the solution of the residue in

■ first hours, while in these lysergic acid ethyl acetate with aqueous sodium bicarbonate

■ use derivatives immediately. Reserpine also causes a solution. The evaporation residue of the dried

progressive calming with constriction of the pupils 65 acetic acid ester solution (11 g) is dissolved in benzene and

(Miosis) and lowering of the body temperature, while chromatographed on a column of aluminum oxide.

these amides tend to have a stimulating effect, dilate the pupils. With anhydrous benzene, 7.2 g of lysergic acid piperi

(Mydriasis) and - at least in part - the body did out of the column. Lysergic acid piperidide

increase temperature. In contrast to reserpine, they cannot be obtained in crystalline form as a free base,

■ also effective serotonin antagonists. 70 The amorphous compound is in most organic

Solvents very easily, but not at all soluble in water. It forms crystallized water-soluble salts.

Lysergic acid piperidide-d-tartrate; on combining equivalent amounts of Lysergsäurepiperidid and d-tartaric acid in five times the amount of methanol, the d-tartrate crystallizes in needles, mp = 145 to 15O ⁰ C; [a] ² S = + 15 ° (c = 0.4 in water).

(C ₂₁ H ₂₅ ON ₃ ) ₂ ■ C ₄ H ₆ O ₆ ; Molecular weight = 820.9;
Calculated .... C 67.29, H 6.88, N 10.24%;
found C 67.58, H 7.10, N 10.35%.

Lysergic acid piperidide can be obtained from the tartrate in an amorphous but pure state; [a] ² S = + 18 ° (c = 0.5 in pyridine).

When developing the chromatogram with benzene containing 5% methanol, 3.0 g of isolysergic acid piperidide are washed out. This crystallized from methanol in kristaUösungsmittelhaltigen polyhedra, mp = 137 to 14O ⁰ C; [a] ² S = + 190 ° (c = 0.5 in pyridine).

C ₂₁ H ₂₅ ON ₃ ; Molecular weight = 335.4;

Calculated .... C 75.18, H 7.52, N 12.54%;
found C 75.29, H 7.82, N 12.38%.

Example 3

The solution, prepared at 0 ° C., of 10 g of isolysergic acid azide in 50 ecm of morpholine is left in for 10 hours Stand at room temperature, the excess morpholine evaporates in vacuo, the solution of the shakes Residue in chloroform with aqueous sodium bicarbonate solution and the dried chloroform solution is evaporated in a vacuum. The residue (10.5 g), consisting of a mixture of lysergic acid and Isolysergic acid morpholide, is dissolved in anhydrous chloroform and applied to a column of aluminum oxide brought. 7.0 g of lysergic acid morpholide are washed out with anhydrous chloroform, which is obtained from benzene in Crystallized plates containing crystalline benzene with a melting point of 116 ° C .; [α]!? = + 44 ° (c = 0.2 in chloroform).

C ₂₀ H ₂₃ O ₂ N ₃ ; Molecular weight = 337.4; Calculated .... C 71.19, H 6.87, N 12.46%;
found C 71.27, H 6.84, N 12.16%.

The compound is easily soluble in most organic solvents, but difficult to dissolve in water. she Forms well-crystallizing, easily water-soluble salts with acids.

Lysergic acid morpholide-d-tartrate crystallizes from methanol in needles with a melting point of 180 ° C; [α] ² g = + 23 ° (c = 0.3 η water).

When dissolving equimolecular amounts of the base and the maleic acid Bimaleinat crystallized in needles, mp = 207 ⁰ C.

C ₂₀ H ₂₃ O ₂ N ₃ • C ₄ H ₄ O ₄ ; Molecular weight = 453.48;

Calculated .... C 63.56, H 6.00, N 9.27%;

found C 63.49, H 5.99, N 9.23%.

When developing the chromatogram with chloroform, which contains 2% ethanol, 3.1 g of isolysergic acid morpholide are washed out. It crystallizes from ethyl acetate or acetone in thin platelets with a melting point of 188 ° C; [a] ² S = + 213 ° (c = 0.2 in chloroform).

C ₂₀ H ₂₃ O ₂ N ₃ ; Molecular weight = 337.4;

Calculated C 71.19, H 6.87, N 12.46%;

found C 70.90, H 6.95, N 12.51%.

Example 4

Poured over 10 g of d-Isolysergsäureazid with 20 cc pyrroline, and the mixture heated for 1 hour at 6O ⁰ C. The excess pyrroline is evaporated in vacuo, the residue dissolved in chloroform containing 0.5% ethanol, and chromatographed on 1000 g of aluminum oxide .

The d-lysergic acid pyrrolinide is first washed out with chloroform, which contains 0.5% ethanol. These Compound could not be obtained in crystallized form as the free base. In ethanol, acetone, chloroform and It is light with benzene, moderate in ether, and insoluble in water. Together with maleic acid, it forms a water-soluble one Salt.

d-Lysergic acid pyrrolinide bimaleate

When equimolar amounts of d-lysergic acid pyrrolinide and maleic acid are combined in ten times the amount of methanol, the bimaleate crystallizes out in needles or hexagonal prisms; F. = 207 to 212 ^° C. with decomposition; [a] ² = ₀ ° + 39 ° (c = 0.5 in 50% aqueous ethanol).

C ₂₀ H ₂₁ ON ₃ ■

C ₄ H ₄ O ₄ ;

Calculated. C 66.19, H 5.79, 0 18.37, N 9.65%;
Found ... C 66.31, H 5.86, O 18.40, N 9.38%.

D-Lysergic acid pyrrolinide can be obtained in an amorphous but pure state from the bimaleate; [α] 2 ° = + 57 ° (c = 0.6 in pyridine).

C ₂₀ H ₂₁ ON ₃ ;

Calculated N 13.2%;

found N 13.4%.

The isomeric d-isolysergic acid pyrrolinide is washed out with chloroform, which contains 1% ethanol.

Claims (1)

Claim: Process for the preparation of amide-like derivatives of lysergic acid and isolysergic acid in general formula . CH2 » : R in the same row -CH CH ₂ : CH ₂ or -CH ₂ -CH ₂ -CH -CH ₂ - means, characterized in that one isolysergic acid azide with amines of the general formula HN: XH,
-CH ₂ in which R has the above meaning, and the resulting mixture of lysergic acid amide and isolysergic acid amide broken down into the individual components in a known manner. 65 Publications Considered
German patent specifications No. 860 218, 818 947. © 809 768/527 2.59