DK142874B - Analogous process for the preparation of dihydrolyseric acid derivatives or acid addition salts thereof. - Google Patents

Description

(11) PUBLICATION REPUBLIC 1 ^ 2874 DENMARK (51), ntCl · 3 c 07 D 457/06 '(21.) Application No 2385/71 (22) Filed on 17 May, 1971 (24) Running' 17 May 1971 (44) The application submitted and the petition published on 1 O · Feb. 1 981

DIRECTORATE OF

THE PATENT AND TRADEMARK BASIS (30> P "0" ** requested from the

May 18, 1970, GO 1135 * HU

<71) JUDGE GEDEON VEGYESZETI GYAR R.T., Gyoemroel u. 21, Budapest X, HU.

(72) Inventor: Erzsebet Mago, Karinthy F.u.18, Budapest XI, HU: Jozsef Borsi, Bartok B.u. 1 "9, Budapest XI, HU: Tibor Balogh, Robert K.krt.

T2 / c, Budapest XIII, HU: Lajos Wclf, NemetvoeTgyi u. 28 / b, Buda = Plague XII, HU. - (74) Plenipotentiary in the process of blessing:

The engineering company Budde, Schou & Co.

(64) Analogous process for the preparation of dihydrolyseric acid derivatives or acid addition salts thereof.

The present invention relates to an analogous process for the preparation of novel dihydrolyseric acid derivatives of the general formula o ch2oh nh H C-NH-CH-CH 2 -CH 2 -CH 2 -NH-C-NH-NO 2

Xl o.

CU3

TT

R 2 -N_ 1 2 2874 in which is a hydrogen atom or a methyl group, or acid addition salts thereof.

Connections with ergol structure have played an important role as therapeutics. Throughout the world, great emphasis has been placed on the synthesis of the so-called natural derivatives and on the preparation of hydrochloric acid amides, mainly formed with amino alcohols. These compounds have many and extremely varied effects. As a rule, lysergic acid amino alcohols have a pronounced specific antiserotonic effect, but they are known to cause undesirable side effects on the nervous system and pathological changes in the arteries.

This type of side effect has not been found with the dihydrolysergic acid derivatives prepared by saturating the unsaturated double bond in the A9.1 ° position in lysergic acid, even after extensive clinical use. This is the main reason why it has been repeatedly tried to hydrogenate the double bond at the 9.10 position in the ergole skeleton. Valuable dihydro derivatives have been prepared, especially of the peptide alkaloid series, such as dihydroergotamine, dihydroergocryptin and dihydroergochristine. In the known processes for preparing 9,10-dihydro-lysergic acid derivatives, the corresponding lysergic acid derivatives are catalytically hydrogenated using palladium as a catalyst, e.g. palladium charcoal, cf. Stoll and Hofmann, Helv. Chiro.

Acta 26, 922 (1943).

The starting materials for the semi-synthetic dihydrolyseric acid derivatives, i.e. dihydrolysergic acid, dihydroisolysergic acid and their amides have been prepared by Stoll, Hofmann and Petrzilka by catalytic hydrogenation of a lysergic acid peptide belonging to one of the above natural series, with subsequent hydrolysis of the peptide backbone, cf. Helv. Chim. Aeta 29, 635 (1946), Swiss Patent Nos. 232,366 and 232,390, and Jacobs and Craig, J. Biol. Chem. 115, 227 (1937).

The 1-Alkyl (aryl) dihydro-lysergic acid, which is also a starting material for the semisynthetic derivatives, is prepared by some of the known methods of catalytic hydrogenation of a lysergic acid peptide of the natural series at the 9 * 10 position followed by alkylation. in the 1-position, which is subsequently hydrolyzed, cf. English Patent No. 988,001 and Swiss Patent No. 386,440. According to Swiss Patent No. 386,439, 1-alkyl dihydro-lysergic acid derivatives are prepared by reducing the 1-alkyl-lysergic acid derivative in the presence of palladium.

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It has now been found that the novel dihydrolysergic acid derivatives of the above formula I prepared by the process of the invention have a specific, pronounced serotonin antagonistic effect, are without toxic effects on the central nervous system, do not attack the heart or kidneys, and do not induce pathological changes in the area of the major arteries.

The process according to the invention is characterized in that a compound of the general formula 0

II

ir C-Cl l I (II) 3 4I |

R N_U

in which R1 is as defined above is reacted with a compound of the formula

COOCH, NH

VOn H 2N-CH-CH 2 -CH 2 -CH 2 -NH-C-NH-NO 2 (III) whereupon the -COOCH 3 group is reduced with an alkali metal borohydride, whereupon the compound formed is optionally N-methylated and the compound formed is optionally converted to a syreadditionssalt.deraf.

The starting materials of formula II are known compounds or can be prepared in the manner described in Hungarian Patent No. 156,385.

According to a preferred method, a compound of the general formula II is prepared from the corresponding unsaturated compound which is dissolved in liquid ammonia at a temperature of not more than -40 ° C and then, if desired, alcohol, ether or tetrahydrofuran is added and the mixture is stirred with a finely divided alkali metal until the double bond at the 9.10 position is saturated. The temperature of the reaction mixture is controlled by external cooling or by continuous evaporation of the ammonia. The course of the reaction can be followed, e.g. by thin layer chromatography. Upon completion of the reaction, the product can be obtained from the reaction mixture by adding to the reaction mixture a solvent which reacts with excess alkali metal, e.g. alcohol, acetone or the like, whereupon the ammonia is evaporated under low heat in vacuo and the product is separated from the reaction mixture using conventional methods.

The N-methylation step of the process according to the invention is preferably carried out by using a large excess of the alkali metal for the reduction and after the reduction, transfer excess alkali metal in a known manner to an alkali metal amide, e.g. by adding ammonium chloride and iron nitrate or a metal powder, or by preparing an alkali metal alcoholate by the addition of alcohol. The decolorization of the previous blue solution also indicates the formation of alkali metal amine or alcoholate. The reaction mixture is stirred for a suitable period of time, after which a methyl halide, preferably methyl iodide as such or dissolved in e.g. ether. The solution is stirred vigorously again. After completion of the methylation, the reaction mixture is worked up as described.

The methylation is preferably carried out in the presence of the base sodium amide or sodium ethylate. The reaction takes place, although the base needed for the alkylation is not formed in the reaction mixture, but is prepared beforehand and added to the mixture. For this reaction, 5-6 moles of alkali metal amide or alkali metal alcoholate are required and it is advised to use the methyl iodide in the same excess. Care must be taken that the liquid ammonia does not cool down during the alkali metal reduction to a temperature below -40 ° C.

To obtain the substances in high purity, the product is purified by chromatography on a silica gel column. The elution may e.g. is made with a mixture of alcohol, water and chloroform.

The compounds of general formula I, when treated with inorganic or organic acids in oily or crystalline state, usually form salts which are always crystalline. For the formation of salt, mineral acids such as sulfuric acid and hydrobromic acid, as well as strong organic acids, e.g. tartaric acid, maleic acid and ethanesulfonic acid.

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In the experiments below, N-methyl-9,10-dihydro-D-lys-ergyl-nitro-1-argininol, hereinafter referred to as compound A, is used to illustrate the effect of the compounds of this invention.

The experiments and results are as follows.

The in vitro experiments are performed on isolated rat uterus sensitized with 1 mg / kg of subcutaneously administered diethylstylboestrol (Caddum, J. H. and Hammed, L.A.: Brit. J. Pharmacol. 9, 240 (1954),

Lanz, U., Cerletti, A. and Rothlin, E.: Hell. Physiol. Acta 13, 207 (1955)). The dose that induces 50 $ inhibition is determined according to the probit analysis of Miller, Becker, and Tainter (J. of Pharm. Exp. Ther. 92, 260 (1948)).

The serotonin antagonizing effect is determined under in vitro conditions by the rat potato edema test. In the study, groups of 8 rats are used and the compounds are injected subcutaneously at a dose of 1 mg / kg and the paw edema obtained during 90 minutes after this treatment is measured according to the method of Bonta (Arch. Int. Pharmacodyn. 132, 147 (1961)). The edema is induced by using 5 μg / pot dose of serotonin creatinine sulfate when administered with this substance 30 minutes after administration of the test compound. In the detailed analysis, the above test is repeated using the relevant compounds in various other dose sizes. Control experiments are performed with physiological saline and the percentage inhibition is calculated on the basis of the results found in the control group.

The blocking of the vascular effects of serotonin is investigated by the Page method, cf. Amer. J. Physiol. 174, 436 (1953) ·

The electroencephalographic tests are conducted with cats in the waking state with permanent electrodes. Bipolar chromium-nickel electrodes are inserted into two sensorimotor regions of the cortex, and on both sides of the hypocampus, nucleus caudatus, and formatio reticularis, and the signals are recorded using a Schwarzer-type electroencephalograph.

Deseryl (1-methyl-D-lysergic acid-butanolamide) is used as a reference substance.

The results of the above experiments are given in the following tables.

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Table I

Antiserotonin action in vivo and in vitro.

ED50 g / ml isolate Percent inhibition of right rat uterine edema induced by 1 mg / kg Compound __ (in vitro) serotonin (sc) (in vivo) N-methyl-9,10-dihydro-D-lysergyl-nitro-1 argininol bimaleate 3 x 10 67.0

Deseryl 5 x 1076.0

Table II

Antiserotonin effect on isolated rat uterus under in vitro conditions

Number of animals with ®tr * positive reaction Percentage of concentration / sarolate inhibition in ml / ml Compound / ml / ml_ Number of animals_ N-methyl-9,10-dihydro-D-lysergylnitro-1-argininol bimaleate 0.01 12/22 54.7 0.01 0.02 12/15 80.0

Deseryl 0.01 4/17 25.6 0.017 0.02 6/9 66.6

Table III

Antiserotonin effect in rat edema edema T? T)

Dose Percent 50

Compound Number of animals mg / kg s.c. inhibition | µg / kg __ __s.c.

N-methyl-9,10-dihydro-3 15,8 -D-lysergyl-nitro-1- 20 10 38 * 1 n -argininol bimaleate 20 30 54 3 20, 20 100 64

Deseryl 25 3 21.9 ^ 5 10 48.4 17 Ί

50 30 58.8 1 ''; L

20 100 70.0 7 142874

Table IV

Duration of anti-serotonin effects in the rat paw edema test

Percent Inhibition of Paw Edema Dose Caused by Serotonin µΒ / ΐΰ3 1 hour 2 hours 3 hours Compound _c._ after administration of serotonin_ N-methyl-9,10-dihydro-D-lysergylnitro-1-argininol bimaleate 100 64.8 43.4 40.8

Deseryl 100 70.0 52.6 43.9

Table V

Effect on serotonin invasive depression investigated on cats made hypotensive with ganglone blocking agents.

Dose pg / kg Percent inhibition

Compound_ Number of animals i.v. of vasopressone N-methyl-9,10-dihydro-D-lysergyl-nitro-1-argininol bimaleate 4 100.0 39.9 4 250.0 85.3

Deseryl 4 100.0 17.7 4 250.0 48.1 Based on the data given in the tables above, the following conclusions can be drawn.

The hydrogenation of the ergoline skeleton has no significant effect on the in vitro and in vivo effects, cf. the data listed in Table I. The in vitro effect of compound A is to some extent greater than the effect of the reference substance, cf. Table II. The compounds of this invention have a markedly antagonizing effect on the paw edema by serotonin, but this antagonizing effect is somewhat weaker than the effect of the reference substance, cf. Table III. On the other hand, the compounds of this invention antagonize the vasopressor action of serotonin twice as efficiently as deseryl in the same intravenous dose range (100-250 [Ag / kg).

According to the experiments, compound A is suitable for therapeutic use. Compared to the known N-alkyl-lysergic acid derivatives, compound A probably does not cause fibrotic changes in the organism. This compound can be used with great advantage in all conditions where serotonin is a pathophysiological factor, e.g. in carcinoid syndromes as well as in inflammatory, allergic and anaphylactic reactions. Compound A can be used extensively in the treatment of migraine.

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The compounds of this invention can be transferred into pharmaceutical compositions suitable for oral or parenteral administration. The oral compositions may e.g. may be tablets containing 3 ~ 30 active ingredient, while for parenteral administration, subcutaneous or intramuscular injection preparations containing 1-3 mg of active substance are preferably prepared. dosage unit. The injection compositions may preferably be administered 1-3 times per day. per day, while for oral treatment, preferably one or two tablets are administered three times a day.

The process of the invention is described in more detail by the following example:

Example

Preparation of 1-methyl-dihydro-lysergyl-m-nitro-L-argininol bimaleate.

a) Preparation of 1-methyl-dihydro-lysergic acid chloride hydrochloride.

To 3.5 s of phosphorus pentahloride dissolved in a mixture of 60 ml of aeetonitrile and βθ ml of phosphorus trichloride is added 2.8 g of dried 1-methyl-dihydro-lysergic acid with m.p. 235 ° C (dec.). Gradually, a solution is formed and, after further stirring, the 1-methyl-dihydro-lysergic acid chloride hydrochloride is precipitated. The suspension is stirred for 30 minutes in the temperature range from 0 to 5 ° C, then the reaction mixture is evaporated in vacuo, the evaporation residue is suspended in 30 ml of tetrahydrofuran and washed repeatedly with petroleum ether and finally dried at 40 ° C in vacuo.

b) Preparation of 1-methyl-dihydro-lysergyl-β-nitro-L-arginine-methyl ester.

3) Dissolve 1 g of L-nitro-arginine methyl ester hydrochloride in 50 ml of dimethylformamide with stirring. Dilute the solution with 100 ml of chloroform and add 8.4 ml of triethylamine. The 1-methyl dihydrolysis ferric acid chloride hydrochloride, prepared as under a) above, is added while cooling with ice and water. The acylation reaction is completed within 1 hour. The reaction mixture is evaporated to dryness in vacuo at low temperature, then suspended in 100 ml of 1% aqueous tartaric acid solution and in 200 ml of a 4: 1 mixture of chloroform and isopropyl alcohol and the pH of the mixture is adjusted to 8 at using an aqueous ammonium hydroxide solution. After shaking, the organic phase is separated and the shaking is repeated with 4 x 50 ml of the above mixture of chloroform and isopropyl alcohol. The combined organic phases are dried over anhydrous sodium sulfate, then filtered and evaporated to dryness in vacuo. The evaporation residue is dissolved in chloroform and precipitated in petroleum ether. The precipitate is filtered off, washed with petroleum ether and dried in vacuo to constant weight.

c) Preparation of 1-methyl-dihydro-lysergyl-co-nitro-L-argininol bimaleate.

Dissolve 5.0 g of powdered calcium chloride in 200 ml of absolute ethanol with stirring. After dissolution, the ester compound prepared under b) is added. The solution is cooled with ice water to 0-2 ° C and 2.5 g of sodium borohydride are added with vigorous stirring. The reduction is completed within 4 hours. The pH of the solution is then adjusted to 6 by means of 5 N hydrochloric acid and the solution is evaporated to a low temperature syrup in vacuo. The evaporation residue is dissolved in 100 ml of water and adjusted to pH = 8 by means of ammonium hydroxide, then shaken with 8 x 50 ml of a 4: 1 mixture of chloroform and isopropyl alcohol. The combined organic phases are dried, filtered and evaporated to dryness. The isomer is removed from the crude product by silica gel chromatography. The elution is done with a 90: 4.5: 30 mixture of chloroform: water: ethanol. From the purified product, a salt is formed by the addition of alcoholic maleic acid. Mp. 144-145 ° C, (a) + - 49 ° (c = 0.5, in 50% aqueous ethanol).