CS260497B1 - New amides of lysergic acid and methods of their production as well as therapeutical means containing these compounds - Google Patents

Abstract

Es werden Verfahren zur Synthese neuer acylierter Lysergsäurealkanolamide der allgemeinen Formel I beschrieben, die zurTherapie der verschiedensten Formen verminderter cerebraler Leistungsfähigkeit, insbesondere der alterbedingten Erscheinungsformen, Anwendung finden sollen.

Die Herstellung der I erfolgt erfindungsgemäß entweder durch Acylierung der als Zwischenprodukte auftretenden Lysergsäurediethanolamide IV bzw. Lysergsäureethanolamide V in gängiger Weise z.B. mittels eines reaktiven Säurederivates in Pyridin oder durch Kopplung einer entsprechenden Lysergsäure 11, die vorher in eine aktivierte Form überführt wurde, mit einem bereits acylierten Amin VII.

Schließlich können die in 2-Stellung unsubstituierten unter Verwendung eines milden Halogenierungsmittels, wie z.B. N-Bromsuccinimid in Dichlormethan, in 2-halogenierte Derivate überführt werden.

Description

The invention relates to a process for the production of novel lysergic acid amides which can be used in general for the treatment of reduced brain activity, in particular of age-related phenomena.

In the field of ergoline, the development of nootropically active substances, in particular compounds with the structure of lyseroxesters, is currently under development. This is evidenced by the introduction of nicergoline, i.e., 11a-methoxy-1,6-dimethylergoline-8'-methanol (5'-broicnicotinate) as a cerebral v-asodilator, as well as the actual results with 1-benzylated lysergol esters.

On the other hand, certain lysergic acid amide derivatives are also known to have some effect on the central nervous system. Apart from hallucinogenic lysergic acid diethylamide (LSD), psychostimulatory effects have also been found for example for lysergic acid pyrrolidide and lysergic acid morpholide.

O-acylated lysergic alkanolamides derived from o-d 1-amino-3-allyloxypropan-2-ol as well as from nitroargininol are also known (cf. Dutch patent specification 7,506,276 and Belgian patent specification 829,518). In these publications, in addition to the potent and long-lasting serotoninantagonist effect, the antidepressant and neuroleptic properties are mentioned in particular.

Experiments by which acylated lysergic acid alkanolamides described herein were to produce nootropically active compounds have not been known.

It is an object of the present invention to provide novel nootropically active compounds that can be used to treat various forms of reduced brain activity. Consequently, on the basis of the obtained pharmacological results, it is also intended to contribute to the extension of the classical ergoline indication areas.

Accordingly, it is an object of the present invention to provide novel lysergic acid amides of formula (I)

II

C ~ N

'* 5 (u

280497 in which

A, ---- -8, represents a group

Z -CH = C \

or a group

From —CH2 — C — R3, \

R 1 represents a hydrogen atom, a C 1 -C 4 alkyl group or a benzyl group optionally monosubstituted with a halogen atom,

R2 represents a hydrogen atom or a halogen atom,

R3 represents a hydrogen atom or a methoxy group,

R a is a hydrogen atom or a C 1 -C 4 alkyl group,

R 5 represents a hydrogen atom or a group -CH 2 -1 CH 2 -O-acyl, however

Rd and R5 do not simultaneously represent hydrogen atoms and " acyl " means an aliphatic acid residue of 2 to 8 carbon atoms; a C 7 aromatic acid radical optionally substituted on the aromatic ring by fluorine, chlorine and trifluoromethyl; a 3-carbon araliphatic acid radical containing an oxygen atom in the carbon chain and optionally substituted on the aromatic ring by a chlorine atom, or · a 6-carbon heteroaromatic acid radical containing a nitrogen atom in the ring and optionally substituted in the heteroaromatic ring a bromine atom, in which, depending on the position of the two substituents on the C 6 ergoline skeleton, relative to the hydrogen atom on the C 5, both lysergic acid and the form of isolysergic acid may be present, such as by known alkanolamides of the formula IV in which

R 1, R 2 and R 3 are as defined above, optionally the alkanolamides of formula V

CH - CH - OH

O П

C - N '

in which

R 1, R 2, R 3 and R 6 are as defined above, react with a reactive acid derivative, for example an acid chloride or an acid anhydride, for example in pyridine.

In addition, the novel compounds of formula (I) can be obtained by treating compounds of formula (II)

O гч V

- Cl

R, A A.

and; !

.. Z ´ .. Z.,.

i ^! l N .......... \ in which

(IV)

R1, R2 and R3 have the meaning given above, after being converted into a reactive derivative, preferably in the form of a mixed sulfuric anhydride or in the form of the acid chloride hydrochloride, immediately reacting with the amines of the formula VII

280497

Rd

AND

CH-CH 2 -O-acyl

OF

Η — N \

R5 (VII) wherein

Rd, Ro and "acyl" are as previously defined.

In addition, the Geiger-Konig process (W. Ko.igig and R. Geiger, Chem. Ber. 103, (1970), 788) has also proved to be an advantageous method of condensation for this step.

In principle, in a similar manner, the intermediates of formula IV and formula V can of course also be obtained by reacting compounds of formula II with compounds of formula VI

Rd

CH-CH2-OH /

Η — N \

Rg (VI) in which

R 8 represents a hydrogen atom or a group

- -СНз — СНз — OH and

Rd is as defined above, and in the case of compounds of formula V, it may be advantageous to use, for example, ergometrine or methylergometrine as starting material for the next reaction leading to the compounds of formula I.

The synthesis of the O-acylated amines of formula (VII) may conveniently be carried out using nitrogen protecting groups exemplified in peptide chemistry (cf. Houben-Weyl, Vol. 15/1) or following the special procedures described in the literature as is disclosed, for example, for 2,2'-diacetoxydiethylammonium chloride (cf. CW Crane and HN Rydon, J. Chem. Soc., 1947, 527).

The preparation of 1-aralkylated derivatives of formula V is possible in a mixture of dimethylformamide and potassium hydroxide under ice-cooling when R1 is a hydrogen atom and simultaneously represents a group of the formula “ ^Сн г ^с х e

(cf. European Published Patent Application 0 029 082).

The following acylation, carried out in a conventional manner, affords the corresponding compounds of the general formula (I).

In addition, it is also possible to start immediately with the desired 1-substituted compounds of the general formula II, which is particularly advantageous when

S, means group /

—CH-C \

When introducing the alkoxy substituent into the ipa 10a, for example, 10a-methoxy-9,10-dihydrolyseric acid, which is a compound readily available from the methyl ester in a known manner, is preferably used. However, the photochemical addition of the alkanols to the 9,10 double bond can also be carried out in the step of the compound of formula V.

In order to prepare the 2-halogenated derivatives of the compounds of the formula I, the halogenation can in principle be carried out in each reaction step. Preferably, however, the halogenation is carried out by halogenating the esters of formula I as the last reaction step, for example by bromination in dichloromethane with N-bromosuccinimide.

The compounds obtained by the process of the invention are preferably converted into acid addition salts which are physiologically acceptable. Suitable acids which are physiologically acceptable are, for example:

hydrochloric acid, phosphoric acid or maleic acid, tartaric acid as well as methanesulfonic acid.

The preparation of these acid addition salts is carried out in a manner known per se by mixing the free base or solutions of this base with the corresponding acid or its solutions in an organic solvent, for example a lower alcohol, a lower ketone or an ether. To improve the crystallization of the salts, mixtures of the solvents mentioned are also recommended. Further, it is possible to obtain pharmaceutically acceptable aqueous acid addition salt solutions by dissolving the free base of formula I in an aqueous acid solution.

Therapeutic application of the novel compounds i ^;

The 2604S7 is carried out in conventional solid or liquid galenic dosage forms, such as tablets, capsules, dragees, or solutions, which are manufactured in conventional manner. Preferred formulations are, however, dosage forms suitable for oral administration, such as dragees or corresponding depot-like forms. In addition, parental preparations such as injectable solutions are also contemplated.

The dosage of the compounds of the invention depends on the age, condition and weight of the patients as well as the dosage form. Generally, a single dose for oral administration is between 1 and 10 mg.

The pharmacological activity of the compounds of the formula I according to the invention is illustrated by the following experiments:

Ni-methylated as well as Ni-unsubstituted 9,10-dihydrolysergic acid diethanolamide or 9,10-dihydrolysergic acid diethanolamides or diethanolamides are already known from Swiss Patent No. 463,525. Furthermore, said compounds have some constrictor effect on vascular smooth muscle and it is proposed to use said compounds for the treatment of vascular headaches.

Based on this state of knowledge, a significant nootropic effect of the compounds of the formula I obtained by acylation of the compounds of the formula IV is surprising in animal experiments. Also in the case of the compounds of formula V, although the cerebral efficacy data for several 1-benzylated ergometrines (cf. European Game, Patent Application No. 0 029 082) is indicated, the potency of the esterification of the compounds of formula V cannot be considered as obvious.

Furthermore, no side effects have been found to limit therapeutic use. Also interesting is the fact that α-adrenolysis, which occurs in some ergolines, occurs in this case only on an inferior scale. In addition, it should be emphasized that certain pharmacologically valuable side effects, such as vein toning, occur with certain compounds, such as compound 1a. These pharmacological effects, which occur in addition to the nocturnal major effect, can be considered to be a welcome addition to the pharmacological effects profile of this class of substances in the treatment of brain damage, especially the elderly.

The selection of pharmacological properties of these novel compounds found in in vivo and in vitro model models is presented below.

1. Active conditional escape reaction (W. Hoffmann and A. Rostock, Pharmazie 38 (1983), 869)

The effect of retrograded amnesia induced by electroconvulsive shock in an active conditional escape response model is expressed by the number of conditional escape reactions (%).

x + sx, * ip <0.05, ** p <0.01, rat

Substance Dose

Day 1 Control i.

i. p. la 3 mg / kg control i. p. nicergoline

1 mg / kg p. o control.

1 1 1 mg / kg control p.

lc 3 mg / kg control of p. nicergoline

p.o. 1 mg / kg

33.0 + 1.5

33.0 + 1.5

32.0 + 6.3

32.0 + 2.0

26.0 ± 1.6

28.0 + 2.0

31.0 ± 1.8

30.0 + 1.5

26.0 + 1.6

26.0 + 1.6

Day 2 Day 3 Day 4 55.0 + 3.0 * * 64.0 + 3.1 # # 64.0 + 1.6 # # 65.0 + 2.7 48.0 + 5.7 78.0 + 1.3 49.0 + 5.2 * # 84.0 + 2.2 57.0 + 5.0 # * 57.0 + 5.6 44.0 + 3.1 * # 77.0 + 4.2 57.0 + 2.6 # * 79.0 + 2.3 66.0 + 2.7 # * 60.0 + 2.6 52.0 + 2.5 # # 74.0 + 3.1 58.0 + 3.6 * * 79.0 + 3.1 66.0 + 2.2 * # 69.0 + 3.8 44.0 + 3.1 # * 76.0 + 3.1 57.0 + 2.6 * * 82.0 + 2.0 66.0 + 2.7 * 61.0 + 3.8 75.0 + 4.0 79.0 + 5.0

2. Porsolt Swimming Test (R. D. Porsolt et al., Arch.Intern. Pharmacodyn. 229, (1977) 327)

Influence of immobility time, mouse i.

Substance Dose Immobility time (s) x + sx

control - 226.3 + 1.4 la 1 mg / kg i.p. 202.6 + 1.8 control - 228.8 + 1.5 nicergoline 1 mg / kg i.p. 196.7 + 5.6 control - 226.1 + 1.2 11 1 mg / kg p. 199.4 + 2.3 control - 228.2 + 1.1 lc 3 mg / kg ip. O. 203.6 + 5.9 le 3 mg / kg ip. O. 210.0 + 3.8

3. Influencing of transallocally induced potentials

Methodology - see C. Giurgea and F. Moyersoons, Arch. Int. Pharmacodyn. (1972), 67

The experiments were performed on waking female Wistar rats fixed in a stereotactic apparatus.

application: i. p. VW = preliminary value * p <0.05

Substance

Dose mg / kg mean intensity irritation μ V (x + sx) negative positive wave wave

Influence of amplitude of maximum irritation intensity μ V (x + sx) negative positive wave wave

la 1 VW 0.18 + 0.02 60 ‘ 0.23 + 0.03 * 120 ‘ 0.25 + 0.03 nicergoline w 0.23 + 0.03 1 VW 0.23 + 0.02 60 ‘ 0.24 + 0.02 120 ‘ 0.23 + 0.02 180 ‘ 0.21 + 0.01

0.19 + 0.02

0.34 + 0.03

0.38 + 0.03

0.26 + * 0.03 0.40 * 0.03 0.42 _L · 0.03 0.27 ± « 0.03 0.40 + 0.02 0.41 ± 0.02 0.25 + 0.02 0.39 ± 0.02 0.42 + 0.02 0.23 + 0.02 0.39 + 0.02 0.39 + 0.02 0.24 + 0.01 0.41 + 0.03 0.40 + 0.02 0.22 + 0.02 0.38 + 0.02 0.36 + 0.02 0.19 + 0.02 0.39 + 0.04 0.39 + 0.04

4. SFT test (Spinal cord fixation time) - spinal cord fixation test cf. C. Giurgea and F. Mouravieff-Lesmísse Arch. Intern. Pharmacodyn. 191 (1971), 279) The number of animals with persistent asymmetry to the total number of rats used is reported.

Substance

Dose

(mg / kg)

Result la nicergoline

5/10

2/10

4/6

5. Antagonism against norepinephrine

Adrenaline antagonism on guinea pig deferens

Substance

Concentration mol / liter

Inhibition (x + sx) in% la nicergoline

10 ' ⁷ 4.4 + 9.7

10 ⁶ '14.7 + 17.0 10' ^{* 5} 60.7 + 66.7 _° ED 50 = 4.3 X 10 ' ⁸ mol / liter

6. Experiments on isolated human vascular preparations (Vena and Arteria femoralis) (cf. Glusa, E. and F. Markwardt, Pharmacology 24 (1982), 287) and Nanuyn-Schmiedebergs-Arch. Pharmacol. 323 (1983), 101 )

Substance

Vascular preparation

Concentration of ^ mol / 1% contraction based on NA

Number of vascular preparations 1h la dihydrcergotamine

Examples:

Example 1

9,10-Dihydrolysergic acid bis- (β-acetoxyethyl) amide (compound 1a)

A mixture of 9,10-dihydrolysergic acid diethanolamide (5 g) and acetic anhydride (6.6 ml) was stirred in pyridine (150 ml) for 5 hours at room temperature. 50 ml of water were added to work up the reaction mixture, the mixture was stirred for a further 15 minutes and then dried to dryness in vacuo. The viscous residue is chromatographed on a 10-fold amount of silica gel using chloroform containing 1% methanol as eluent. After about 500 ml of eluate is collected, the methanol content is increased to 3%. 5.7 g (92% of theory) of a glassy solid are obtained. Recrystallization from acetone gave the following properties:

Melting point:

142.3-143.0 ° C (bars) [α] D ²⁰ = -50.0 ° C (c = 0.5% in chloroform).

Mass spectrum (m / e):

441 (M &lt; + &gt;), 381, 389, 321, 296, 252, 225, 209, 184, 167, 154;

Mnnotartrát:

C24H31N3O5. V2 С1НбОб

Molecular Weight: 516,2

Melting point:

171-173 ° C (from a mixture of methyl ethyl ketone and methanol) [α] ²⁰ ° -70.5 ° (c = 0.2% in pyridine)

The following compounds are obtained in an analogous manner:

vein 3.9 1.0 106.0 + 33.0 15 Dec 3 .1 artery 3.9 38,0+ 7,5 3 vein 3.0 70.0 + 20.0 4 1.0 65.0 + 15.0 3 0.1 45.0 -1- 17.0 5 artery 3.0 11.0 + 10.0 5 vein 1.0 61.0 + 24.0 6 0.1 52.0 + 18.0 6 artery 1.0 8.8 + 8.0 4

9,10-dihydrolysergic acid bis- (3-benzoylethyl) amide (compound 1g) citrate: melting point:

102.5 to 104 ° C [α] D ²⁰ = -59.1 ° (c = 1% in methanol) 1- (3'-fluorobenzyl) -9 bis- (3-3'-trifluoromethylbenzoylethyl) amide, 10-dihydrolysergic acid (compound 1k) mesylate: melting point:

147.9-150.4 ° C 1- (3‘-Fluorobenzyl) -9,10-dihydrolysergic acid bis- (β-acetyl-ethyl) -amide (compound 11) bitartrate: melting point:

82.8-84.9 ° C [α] D ²⁰ = -48.0 ° (δ = 1% in methanol) 1-methyl-9,10-dihydrolysergic acid bis- (β-acetoxyethyl) amide ^; (compound 1c) bitartrate: melting point:

up to 92 ° C base:

[.alpha.] D @ ²⁰ = -22.3 DEG (c = 0.5% in methanol) 1-methyl-9,10-dihydrolysergic acid bis- (β-propionylethyl) amide (compound 1e) bitartrate: melting point:

77.8 to 81.8 ° C [α] D ²⁰ = -46.2 ° (c - 10/0 in methanol).

Example 2

2-Bromo-9,10-dihydrolysergic acid bis- (z-acetoxyethyl) amide (compound 1h)

To a solution of bis - (? - acetoxyethyl) amide lig

9,10-Dihydrolysergic acid in 600 ml of dichloromethane is added with stirring and under reflux for 5 minutes a suspension of 6.05 g of N-bromosuccinimide in 150 ml of dichloromethane. The reaction mixture was then refluxed for 75 minutes, cooled and shaken twice with 500 ml of 10% sodium carbonate solution. The organic phase is then washed twice with water (500 ml), dried over sodium sulphate and dried in vacuo to dryness. 7.5 g of a light brown foam are obtained, which is taken up in 10 ml of dichloromethane and, after standing overnight at - | -3 ° C, 0.5 g of pure reaction product is obtained in the form of a light gray powder, m.p. C.

The filtrate was concentrated and then chromatographed on a 20-fold amount of silica gel eluting with dichloromethane. After collecting 200 ml of the eluate, 2% methanol is added to the dichloromethane used as eluent. 5.8 g of base are obtained, which corresponds to a yield of 49% of theory.

Mass spectrum (m / e):

521/519 (M ^& lt ^{; +} & gt ^; ), 461, 447, 388, 332, 317, 303, 289, 261, 147, 232 _? 224, 215, 190,171,154.

Monotartrate:

С24Нзоsme05Вг. С2 С4.НбОб (Molecular Weight: 595)

Melting point:

169.5-171 [deg.] C (from acetone) _([ .alpha.] D @ 20 ₌ 75.40 ₍ c0 > 10 DEG / _{o in water} ))

Example 3

9,10-Dihydrolyseric acid bis- (β-acetoxyethyl) jamide (compound 1a)

A mixture of 3.15 g of diethanolamine and 3.24 g of trimethylchlorosilane in 45 ml of anhydrous chloroform was heated to boiling in an oil bath. After about 5 minutes, the reaction mixture was cooled somewhat, and 3.03 g of triethylamine, which was dissolved in 5 ml of chloroform, was added. The reaction mixture was then refluxed for a further 30 minutes, after which the reaction mixture was cooled to room temperature. 5.65 ml of acetic anhydride is then added to the reaction mixture and stirred for a further 3 hours. After standing overnight, the reaction mixture was made basic by the careful addition of 5% sodium carbonate solution, then washed with some water and dried over sodium sulfate.

The oily substance obtained after concentration of the organic phase is then reacted with Geiger-Konig with 9,10-dihydrolysergic acid. To this end, 2.8 g of 9,10-dihydrolysergic acid suspended in a mixture of 25 ml of dimethylformamide and 25 ml of methylene chloride are added. After cooling the reaction mixture to -10 DEG C., 4.06 g of hydroxybenzotriazole are added. After stirring for 15 minutes, 2.24 g of dicyclohexylcarbodiimide is added and then the oily residue obtained above is dissolved in 5 ml of the solvent mixture at 0 ° C.

After 24 hours at room temperature, the reaction mixture is filtered and the filtrate is concentrated to dryness under reduced pressure. To the residue is added 15 ml of 5% tartaric acid. The insolubles were filtered off and the filtrate was extracted twice with 10 ml of methylene chloride. It was then basified with saturated sodium carbonate solution and extracted three times with 15 ml of ethyl acetate. The usual work-up of the ethyl acetate extract yields a product which is identical to the product obtained according to Example 1.

Example 4

10α-methoxy-9,10-dihydrolysergic acid

To a solution of 25.2 g of potassium hydroxide in a mixture of 345 ml of 96% ethanol and 175 ml of water was added 13 g of methyl 10-methoxy-9,10-dihydrolysergic acid. The reaction mixture was then stirred at reflux for 1.5 hours. The reaction mixture is then filtered and the filtrate is concentrated to dryness. The residue is taken up in water (225 ml) and the aqueous solution obtained is adjusted to pH 6.9 by addition of 20% sulfuric acid. After standing overnight at - (- 4 ° C), 11.7 g (94.4% of theory) of 10? -Methoxy-9,10-dihydrolysergic acid are obtained in the form of a white powder.

Analysis: for C17H20O3N2 (molecular weight: 300.1)

Melting point:

260 DEG C. (decomposition) [ _.alpha. ] _D @ ²⁰ = -14.9 DEG (c = 0.5 in methanol)

Content: 86.0%

Mass spectrum (m / e):

30.0 (M ^& lt ^{; +} & gt ^; ), 268, 250, 224, 221, 207, 192, 181, 167, 154.

EXAMPLE 5 1-Benzyl-10 &apos; -methoxy-9,10-dihydrolysergic acid

In a special apparatus with a solid carbon dioxide cooler pocket and a drain tube, 200 ml of ammonia are condensed after the cooling pocket is filled with a mixture of acetone and solid carbon dioxide. 180 mg of ferric nitrate is then added and 1.2 g of sodium are added in portions by continuing the addition of sodium only after the blue color has disappeared. Then 5.22 g of 10? -Methoxy-9,10-dihydrolysergic acid is added, the mixture is stirred for 10 minutes and then a solution of 12 g of benzyl bromide in 10 ml of ether is rapidly flowed. The reaction mixture was stirred at reflux for a further 10 minutes and then worked up as follows:

After complete distillation of the ammonia, the dry residue obtained is partitioned between 250 ml of ether and 400 ml of water. After filtration and phase separation, 250 mg of activated carbon are added to the aqueous phase and the mixture is stirred at room temperature for 10 minutes. It is then filtered and the filtrate is treated with 50% acetic acid using a pH meter to a pH of 6.3. Recrystallization from isopropyl alcohol gave the desired acid as a light gray powder, m.p. 169.9-173.3 ° C.

Analysis: for C 24 H 26 N 2 O 3 (molecular weight: 390.1)

Yield: 90.5% [α] 546 ²⁰ = -23 ° (c = 0.5% in methanol).

Example 6

10α-Methoxy-9,10-dihydrolysergic acid diethanolamide

7.76 g of 10α-methoxy-9,10-dihydrolysergic acid and 1.46 g of potassium hydroxide, spread in a mortar, are dissolved in 100 ml of methanol and the reaction mixture is evaporated to dryness under reduced pressure. Then, the residue is dissolved in 45 ml of methanol, 520 ml of absolute dimethylformamide are added and the above procedure is repeated except that the mixture is concentrated at 45 DEG C. under reduced pressure to a volume of about 80 ml. Then, under ice-cooling, 45 ml of a dimethylformamide-sulfur trioxide complex solution (F = 1.22) are added to the above residue and the reaction mixture is stirred for 20 minutes. The mixture was then poured into a solution of 13.6 g of diethanolamine in 28 ml of water and stirred again for 20 minutes.

For further work-up, 12 ml of water are added, the mixture is made alkaline with concentrated ammonia solution and stirred in portions with a total of 600 ml of ethyl acetate. After washing, drying and concentration of the ethyl acetate extract, 12 g of the desired product are obtained in the form of a light brown foam, which can be used for acetylation without further purification.

Mass spectrum (m / e):

387 (M ^& lt ^{; +} & gt ^; ), 369, 356, 355, 268, 223, 201, 184, 167, 154.

Example 7

10α-Methoxy-9,10-dihydrolysergic acid bis - (? - acetoxyethyl) amide (compound 1d)

A suspension of 3 g of 10α-methoxy-9,10-dihydrolysergic acid diethanolamide in a mixture of 18 ml of absolute pyridine and 42 ml of absolute chloroform was stirred for 5 hours at room temperature after addition of 9.45 ml of acetic anhydride, whereupon a clear solution was obtained. This clear solution is poured into 20 ml of water, basified with sodium carbonate solution and the phases are separated. Extraction is then carried out twice more with 30 ml of chloroform. The combined organic extracts were washed, dried over sodium sulfate and concentrated to dryness in vacuo. The bovine residue obtained is chromatographed on a 10-fold amount of silica gel using chloroform containing 3% methanol as eluent.

Mass spectrum (m / e):

471 (M ^& lt ^{; +} & gt ^; ), 440, 285, 250, 223, 207, 184, 167, 154.

Bitartrát:

C25H33N3O6. С1НбОб (Molecular Weight: 621,1)

Melting point:

97.8-98.2 ° C (from acetone) [α] 578 ²⁰ = -7.7 ° (c = 1% in methanol).

The following compounds are obtained in an analogous manner:

1-Benzyl-10α-methoxy-9,10-dihydrolysergic acid bis- (R-3‘-chlorobenzoylethyl) amide (Compound Ij)

Hydrochloride: Melting point:

93.7-97.2 ° C [α] D ²⁰ = -8.7 ° (c = 1% in methanol); 10α-Methoxy-9,10-dihydrolysergic acid bis- (3,5'-brominonicotinylethyl) amide (compound 1f) mesylate: melting point:

116.5-119 ° C.

Example 8

10α-methoxy-9,10-dihydroergometrine

In special irradiation apparatus (quartz emitter S180R, VEB EGS Zella

The methanol was irradiated with 7.5 g of ergometrine dissolved in a mixture of 380 ml of methanol and 40 ml of concentrated sulfuric acid for 2.5 hours at room temperature under nitrogen purge. The reaction solution was then stirred into 450 ml of ice-water, the mixture was carefully basified with concentrated ammonia solution and extracted three times with 400 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. A mixture of methanol and ether gives a pink colored amorphous substance.

g of this material in 40 ml of acetone containing 10% methanol was stirred at 40 ° C for 30 minutes. The acetone and ether-washed product is then suitable as a raw material for further reactions. For finer purification, 10.alpha.-methoxy-9.10 dihydroergometrine is chromatographed on a 15-fold amount of silica gel using acetone containing 12% methanol as eluent.

Bitartrát:

Ό20Η27Ο3Ν3. С4НбОб (Molecular Weight: 507,4)

Melting point:

211 DEG-211.5 DEG C. (methanol / acetone bars) [.alpha.] D ^{@ 20} = + 0 DEG (c = 0.5% in methanol). With gradual heating, decomposition temperatures of 175 DEG C. occur.

Example 9 1-Methyl-10α-methoxy-9,10-dihydroergometrine

A suspension of 3.88 g of sodium hydroxide finely ground in a mortar in 40 ml of dimethylformamide is stirred for 10 minutes and then 5 g of 10α-methoxy-9,10-dihydroergometrine is added. After an additional 20 minutes of stirring, the mixture was stirred for 30 minutes. 2.43 g of methyl iodide dissolved in 5 ml of dimethylformamide were added thereto, and the reaction mixture was stirred for 45 minutes under ice-cooling. The reaction mixture was then poured into 25 ml of water and concentrated under reduced pressure. The residue was dissolved in 100 ml of 20% tartaric acid. After filtering off the precipitate, the filtrate obtained is extracted twice with 50 ml of methylene chloride. The aqueous phase is adjusted to pH 10-11 with concentrated ammonia solution and then extracted three times with 100 ml of ethyl acetate each time.

The combined ethyl acetate extracts were dried over sodium sulfate and concentrated to dryness on a rotary evaporator at 40 ° C. The residue thus obtained is then chromatographed on a 15-fold amount of silica gel using chloroform containing

3.5% methanol as eluent. After recrystallization from chloroform and acetone each time with the addition of methanol, after conversion to the tartaric acid salt, 1-methyl-10α-methoxy-9,10-dihydroergometrine bitartrate is obtained.

C21H29O3N3. С4НбОб (Molecular Weight: 521,4)

Melting point:

154 DEG-156 DEG C. [.alpha.] D @ ²⁰ = -3.9 DEG (c 1% in methanol).

Example 1-Methyl-10α-methoxy-9,10-dihydrolysergic acid (+) -2-propanolamide acetate (Compound 1r)

To a solution of 3.21 g of 1-methyl-10'-ethoxy-9,10-dihydroergometrine in 45 ml of pyridine, 9.6 ml of acetic anhydride is added dropwise with stirring, and the reaction mixture is then allowed to stir for 3 hours at room temperature. After standing overnight, 10 ml of water are added and then the mixture is concentrated under reduced pressure. Subsequent column chromatography on a 10-fold amount of silica gel using chloroform containing 3% methanol afforded a pale yellow foam which, upon conversion to. bimaleinate and recrystallized from acetone / ether to give the final product as a white powder.

Base:

Mass spectrum (m / e):

431 (M &lt; + &gt;), 382, 322, 297, 281, 265, 237, 221, 213, 199, 181, 168.

Bimaleinate:

C23H31O4N3. C4H4O4 (Molecular Weight: 529,5)

Melting point:

143.5 to 146.5 ° C [n?; | 578 ²⁰ - ^Э -17.9 (c - 1% in methanol).

The following compounds are obtained in an analogous manner:

9,10-Dihydrolvsergic acid (+) -2-p-propanolamide-3-fluoro-benzoate ⁽ tallow bitartrate compound: melting point:

133.2 to 135.6 [ce] o ²⁰ - 18, δ ³ (c - 0.5% in methanol);

(+) -2-propanolamide-4'-chloroenoxyacetate

9,10-dihydrolysergic acids (compound 1p) monotartrate: melting point:

114.3 DEG-117.1 DEG C. [ _.alpha. ] _D @ ²⁰ ₌ .delta., (C = 0.25% in water);

N -α-methoxy-9,10-dihydrolysergic acid (+) -2-propanolamide-ipropionate (compound 1q) bitartrate: melting point:

111.3-113.7 ° C [α] D ²⁰ = -4.6 ° (c = 1% in methanol);

10'a-methoxy-9,10-dihydrolysergic acid (+) -2-propanolamide-acetylsalicylate (compound 1s) bitertrate: melting point:

116.5-120.1 ° C [α] _D ²⁰ = + 8.9 ° (c = 1% in methanol);

10-a-methoxy-9,10-dihydrolysergic acid (- (-) -2-propaiiolaniid-3‘-chlorobenzoate 10) (compound lt) bitartrate: melting point:

130.1-133.3 ^° C [ _.alpha. ] _D @ ²⁰ = + 17.0 DEG (с = 1% in methanol);

10α-methoxy-9,10-dihydrolysergic acid () -2-butanolamide-2‘-fluorobenzoate (compound lu) bitartrate: melting point:

123.5-125.3 ° C.

Example 11

D-lysergic acid bis- (β-acetoxyethyl) amide (compound lh / li)

Lysergic acid diethanolamide can be prepared as described in Swiss Patent Specification No. 463,525, or else according to other amidation procedures customary in ergoline chemistry, such as using a dimethylformamide-sulfur trioxide complex. Acetylation analogously to Example 1 affords a brown foam which is chromatographed on a 15-fold amount of silica gel using chloroform containing 1% methanol as eluent. After about 300 ml of eluate is collected, the methanol content of the eluent is increased to 2% and then the zone is eluted into the filtrate from which the product can be precipitated as tartrate after concentration with acetonic tartaric acid. Further elution provides a second zone which is also isolated in the form of tartrate, but the product is very difficult to crystallize.

Zone 1:

d-lysergic acid bis- (β-acetoxyethyl) amide monotartrate (molecular weight: 514.1)

C24H29N3O5. У2 С4НбОб

Melting point:

126 ^DEG- 128.5 ^DEG C. (from acetone) [.alpha ^.] D @ ²⁰ = + 14.9 DEG (c = 0.5% in methanol);

Zone 2:

d-isolysergic acid bis- (β-acetoxyethyl) amide bitartrate (molecular weight: 589.1)

C24H29N3O5. С4НбОб

Melting point:

83.5 to 86.5 ^C (from a mixture of acetone and ether) [a] _D = ^z0 4-160,5 ° (c = 0.12% in methanol).

The following compounds are obtained in an analogous manner:

lysergic acid bis- (0-3‘-fluorobenzoylethyl) amide (compound Im) mesylate: melting point:

Mp 71.5 DEG-74.1 DEG C. [.alpha.] _D @ 20 ₌ -31.2 DEG _{(c =} 0.5% in methanol);

1-methyllysergic acid bis- (β-acetoxyethyl) amide (compound 1n) bitartrate: melting point:

77.8 DEG-80.4 DEG C. [.alpha.] D @ ²⁰ = + 16 DEG (~ 0.25% in methanol).

Example 12

In an analogous manner to that described above, the following are also prepared:

9,10-dihydrolysergic acid bis - (? - capryloxyethyl) amide, molecular weight: 609 melting point:

° C (from a mixture of petroleum ether and dichloromethane).

Example 13

In an analogous manner to that described in the above examples, the molecular weight: 719.1 is also: melting point:

bis (β-capryloxyethyl) amine methanesulfonate 132-135 ° C (from isopropylalkchol) du-1-methyl-9,10-dihydrolysergic acid,

Claims (29)

New lysergic acid amides of the general formula I in which 1 represents —CH = C \ or R1 represents a hydrogen atom, a C1-C4 alkyl group or a benzyl group optionally substituted once with a halogen atom, R2 represents a hydrogen atom or a halogen atom, R3 represents a hydrogen atom or a methoxy group, R4 represents a hydrogen atom or a C1-C4 alkyl group, R 5 represents a hydrogen atom or a -CH 2 -CH 2 -O-acyl group, however Rd and R5 do not simultaneously represent hydrogen atoms and &quot; acyl &quot; means an aliphatic acid residue of 2 to 8 carbon atoms; a C 7 aromatic acid radical optionally substituted on the aromatic ring by fluorine, chlorine or trifluoromethyl; an 8-carbon araliphatic acid radical containing an oxygen atom in the carbon chain and optionally substituted on the aromatic ring by a chlorine atom or a 6-atom heteroaromatic acid radical containing a nitrogen atom in the ring and optionally substituted in the heteroaromatic ring by bromine and in which, depending on the position of the two substituents on the »» ergoline skeleton, relative to the hydrogen atom on the Cs, both the lysergic acid and the isolysergic acid forms and their acid-acceptable salts can be present, which are pharmaceutically acceptable, preferably maleate, tartrate, methanesulfonate or hydrochloride. 2. 9,10-Dihydrolysergic acid bis- (β-acetoxyethyl) amide. 3. 2-Bro-m-9,10-dihydrolysergic acid bis- (β-acetoxyethyl) amide. 4. 1-Methyl-9,10-dihydrolysergic acid bis- (4-acetoxyethyl jamide). and 5. N-Methoxy-9,10-dihydrolysergic acid Bls - [(4-acetoxyethyl) amide]. 6. 1-Methyl-9,10-dihydrolysergic acid bis- (β-propionylethyl) amide. 7. α-Methoxy-9,10-dihydrolysergic acid bis - (η 3-5‘-bromonicotinylethyl jamide). 8. 9,10-Dihydrolysergic acid bis- (β-benzoylethyl) amide. 9. Lysergic acid bis- [beta-acetoxyethyl] amide. 10. Isolysergic acid bis- (β-acetoxyethyl) amide. 11. Bis- (3-3‘-chlorobenzoylethyl) amide 1- -benzyl-10α-methoxy-9,10-dihydrolysergic acid. 12. 1- (3‘-Fluorobenzyl) -9,10-dihydrolysergic acid bis- (3'-trifluoromethylbenzoylethyl) amide. 13. 1- (3‘-Fluorobenzyl) -9,10-dihydrolysergic acid bis- (1,6-acetoxyethyl) amide. 14. Lysergic acid bis - (β-3‘-fluorobenzoylethyl) amide. 15. 1-Methyllysergic acid bis- (β-acetoxyethyl) amide. 16. (+ J -2-Propanolamide-3'-fluorobenzoate) 9,10-dihydrolysergic acids. 17. () -2-Pro _; 9,10-dihydrolysergic acid panolamide-4'-chlorophenoxyacetate. 18. 4α-Methoxy-9,10-dihydrolysergic acid (4j-2-propanolamide-propionate). 19. 1-Methyl-10α-methoxy-9,10-dihydrolysergic acid (+ J-2-propanolamide acetate). 20. (+) -2-Propanolamide acetyl salicylate 10α-methoxy-9,10-dihydrolysergic acid. . 21. (+ b ² ) 10α-Methoxy-9,10-dihydrolysergic acid propanolamide-3 ^; -chlorobenzoate. 22. 10α-Methoxy-9,10-dihydrolysergic acid (+) - 2-butanolamide-2‘-fluorobenzoate. A process for the preparation of novel lysergic acid amides of the general formula I, in which R 1 to R 5 as well as "acyl" are as defined above, as well as their physiologically acceptable acid salts, preferably maleate, tartrate, methanesulfonate or hydrochloride, characterized in that the appropriately substituted lysergic acid of formula II C, L.-Cr 1 OH СИ СН ..- П, ·! in which R 1, R 2 and R 3 are as defined above, optionally of intermediates of formula V H - O 'J' in which R 1, R 2 and R 3 are as defined above, reacted with an amine of formula VI via an activated form, preferably obtained by the Geiger-Konig process or using dimethylformamide-sulfur trioxide complex R4 AND OH — CH2 — OH / Η — N \ R5 (VI) wherein R a and R 5 are as defined above, first to give intermediates of formula IV (3'‘). in which R 1, R 2, R 3 and R 4 are as defined above, which are then converted, preferably by treatment with an acid chloride or an acid anhydride in pyridine, into compounds of the general formula Ia or the obtained compounds into their pharmaceutically acceptable salts. A process for the preparation of the novel lysergic acid amides of the general formula I, in which R 1 to R 5 as well as "acyl" have the meanings given above, as well as their physiologically acceptable acid addition salts thereof, characterized in that the corresponding substituted lysergic acid of formula (II) above is activated via an activated form, preferably obtained by a process according to Geiger-Konig or using dimethylformamide-sulfur trioxide complex, reacted with an amine of formula VII Rd AND CH — CH2 — O — acyl] Η — N \ R5 (VII) wherein R 1, R 5 and "acyl" have the meanings given above and optionally convert the obtained compounds to their pharmaceutically acceptable salts. 25. A process for the preparation of the novel lysergic acid amides of formula (I), wherein the compounds of formula (I) in which R2 is a halogen atom and optionally converting the obtained compounds to their pharmaceutically acceptable salts. A process for the preparation of novel lysergic acid amides of the general formula I, in which R 1 to R 5, as well as "acyl" have the meanings given above, as well as their physiologically acceptable acid addition salts thereof, characterized in that the compounds of formula (V) as defined above in which R 1 represents a hydrogen atom and represents a group A B, R 1 to R 5 as well as "acyl" are as defined above, as well as their physiologically acceptable acid addition salts thereof, characterized in that the compounds of formula III in which: В, R 1, R 2, R 4 and "acyl" have the above meanings, they are converted by treatment with alkyl halides or benzyl halides, for example dimethylformamide / sodium hydroxide, under ice cooling using a mild halogenating agent such as N-bromosuccinimide, in methylene chloride or dioxane to compounds of formula V wherein R 1 is C 1 -C 4 alkyl or benzyl, followed by acylation to convert compounds of formula I and optionally convert them to their pharmaceutically acceptable salts. A process for the preparation of the novel lysergic acid amides of the general formula I, in which R 1 to R 5 as well as "acyl" have the above meanings, as well as their physiologically acceptable acid addition salts thereof; wherein the intermediates of formula (V) are those in which: Д —B. represents the group z -CH = C \ are converted in an acidic environment by photochemical addition of methanol to the derivatives of formula (V) in which: A β, represents a group, and Á represents a methoxy group, and these are acylated to the compounds of formula (I) by conventional methods, and the obtained compounds are optionally brought to their pharmaceutically acceptable salts. Pharmaceutical preparations comprising a lysergic acid derivative of the formula I, wherein the general substituents are as defined above, or one of its physiologically acceptable acid addition salts, as active ingredient, in particular for the treatment of post-apoptotic drugs conditions - loss of cognitive and mnestic interventions of various origins - cerebral organic psychosyndromes caused by age-related vascular cerebral functional disorders - hypoxically, neurotoxically and traumatically-related cerebral functional disorders - decreased brain activity in alcoholics and - pathologically or age-related stroke. Nootropics in the form of tablets, dragees, solutions for administration in the form of drops, ampoules or other suitable dosage forms, characterized in that they contain 0.1 to 10 mg per unit dose of a lysergic acid derivative of the formula I, wherein the general substituents or a physiologically acceptable acid addition salt thereof, as an active ingredient in addition to the usual galenic additives such as carriers, antioxidants and diluents.