DE2124640C2 - 1-methyl-9,10-dihydrolysergyl-omega-nitro-L-argininol and its salts and medicinal products containing these compounds - Google Patents

Description

as well as its salts with inorganic or organic acids.
2. Medicaments containing one or more compounds according to Claim 1 as active ingredients and customary auxiliaries and carriers.

33

The invention relates to the new 1-methyl-9,10-dihydrolysergyl-c .'-niiru-L-argininoI as well as its salts with inorganic and organic acids and medicaments containing these compounds, in particular Anti-serotonin agents.

It is known that the compounds with ergolenic skeleton have played such a useful role in therapy for decades. The most intensive research is directed in all over the world on the synthesis of the so-called natural derivatives and the manufacture of above all Amides of lysergic acid formed with amino alcohols. Dice compounds have a wide range of effects. the Lysergic acid amido alcohols generally show a strongly specific serotonin counteracting effect or antiserotonin effect. However, it is known that they also often have adverse effects on the nervous system and are pathological Cause vascular changes.

In the case of the saturation in the /! "" "Position On the other hand, the dihydrolysergic acid derivatives obtained from the double bond were themselves in the course Long clinical experience has not seen such side effects. An even better serotonin however, a counteracting effect than with the known compounds of this type was desirable.

In the first place, the hydrogenation of the double bond in the 9.10-position of the ergole skeleton has long been sought; Valuable dihydro derivatives such as dihydroergotamine were produced especially in the peptide alkaloid series. Dihydroergocryptine, dihydroergocristine and dihydroergocornine, respectively. According to the processes known for the preparation of the 9,10-dihydrolysergic acid derivatives, the corresponding lysergic acid derivatives are catalytically hydrogenated, using palladium or palladium with animal charcoal as the catalyst (Sloll and Hofmann, HeIν.Chim / Äcla, 26,922 [1943]).

As the starting subslani of the semi-synthetic Dihydrolysergsäuredcrivatc serving Dihydrölysergjäurc, Dihydroisolysergic acid or its amides were carried out by Sloll, Hofmann and Petrzilka catalytic hydrogenation of a genome over a period of time

50

55

60

65 th natural series belonging I.ysergic acid peptides and subsequent hydrolysis of the peptide part obtained (HeIv. Chim. Acta 29.635 [1946]; CH 2 32 366 and 2 32 390; [acobs and Craig. J. Biol. Chem. 115, 227 [1937 ]).

The I-alkyldihydrolysergsäu, which are also used as the starting substance for the semi-synthetic derivatives Ren or 1-Alkar \ ldihydrolysergsäuren were according to the known method in the way produced that any lysergic acid epidemic belonging to the natural series is in the 9.10 position catalytically hydrogenated, then alkylated in the 1-position or aralkylated and finally hydrolyzed (BG 9 88 001: CH 3 86 440). According to CH 3 86 439, the I-Alkyldihydrolysergsäurederivate were by in Reduction of the 1-alkyllysergic acid derivatives carried out in the presence of palladium.

The disadvantage of the procedure outlined for preparing the DihycJrolysergsäure and their derivatives is that a defined for the manufacture of the basic body dihydrolysergic good in every case and is also well applicable in medicine compound (e.g., dihydroergotamine 1-Methyldihydroergotamin respectively) hy ^J must be jolysiert. The previously known methods are therefore only available for c! ·? Production of laboratory samples suitable, in no way abjr for technical realization. Because of this, the expansion of the research area of dihydrolysergic acids was also hindered.

The invention is based on the object of having a superior pharmacological effect with less Toxicity exhibiting new 9.10-Dihydrolysergsäuredenvat including its salts and medicinal products containing them.

The above has surprisingly been made possible by the subject matter of the claims Invention achieved. · '"

The compounds according to the invention can be prepared in such a way that Lyscrgyl-w-nitro-L ^ argininol or l-methyllysergyl-oj-nilro-L-argiriiriöl the general formula

H ₁ C-OH

NH

Il Ί Il

H C-NH-CH-CH ₃ -Ch-CH ₂ -NH-C-NH-NO ₃

N-CH ₃

R ₁ -N

where Ri stands for a hydrogen atom or a methyl radical, or a salt thereof in liquid ammonia or in liquid ammonia and an organic solvent is hydrogenated with an alkali metal, preferably sodium and / or potassium, and the compound obtained in which Ri stands for a hydrogen atom , is methylated in the presence of a strong base, followed by base optionally dip obtained mi ¹ iiöerführt inorganic or organic acids into a salt or is liberated the free base from an obtained salt.

In addition to the liquid ammonia, alcohol and / or ether are preferably used as the organic solvent used.

It is advantageous to proceed in such a way that lysergyl-oj-nitro-L-argininol or methyllysergyl-w-nitro-L-argininol of the general formula II at a temperature of at most - 40 ° C in liquid Ammonia is dissolved, optionally alcohol, ether or tetrahydrofuran is added and then the Solution after adding crushed alkali metal to saturation of the double bond in the 9.10 position is stirred. The temperature of the reaction mixture can either be reduced by external cooling or ensured by continuous evaporation of the ammonia. The course of the reaction can be followed for example by means of thin-layer chromatographic analysis.

After the end of the reaction, the product can be obtained from the reaction mixture in the manner that the solution contains a solvent which reacts with the excess alkali metal (for example alcohol or acetone) is added and the ammonia is evaporated by gentle heating under vacuum.

Methylation is preferred with a methyl halide. especially methyl iodide. carried out and an alkali metal amide, especially sodium amide, as the base. or an alkali metal alcoholate. especially a natural alcoholate. most notably Sodium ethylate. used.

The methylation is particularly preferably carried out in such a way that the reduction with a made large excess of alkali metal and after completion of the reduction the excess alkali tall converted to an alkali metal amide by any known method (for example, by Addition of ammonium chloride. Iron nitrate or metal powder) or by adding alcohol Alkali alcoholate is generated. The discoloration of the previously blue solution also indicates the formation of the Alkaliamidcs or alcoholates. The reaction mixture if a corresponding 'time' is stirred, then a methyl halide, especially methyl iodide, alone or in solution, for example in ether, poured in and the mixture is again vigorously stirred. To When the 'Meihylielung' ends, the reaction mixture is worked up in the manner described The methylation reaction also proceeds when the

η necessary for the methylation base not im Reaction mixture formed, but ready to be added to the reaction mixture. For this implementation are 3 to 6 mol alkali metal amide or alkali metal alcoholate necessary and it is also expedient to use the methyl iodide

to use in the same excess. It's going to be Make sure that the liquid ammonia does not fall below -40 ° C during the reaction with the alkali metal cools down.

The starting compounds of the general formula II can be prepared in the manner described in HU 1 56 385 have been made.

The compounds of the invention can also be prepared in such a way that lysergic acid in the is hydrogenated to 9,10-dihydrolysergic acid and the latter in the manner indicated above Way methylated to l-methyl-9.10-dihydroIysergic acid and then the λ> obtained l-methyl-9,10-dihydrolysergic acid chlorinated to l-methyl-9,10-dihydrolysergic acid chloride hydrochloride, the latter with ω-nitro-L-arginine methyl ester hydrochloride to 1-methyl-9,10-dihydroysergyl-tü-nitro-L-arginine methyl ester implemented and the latter to l-methyl-9,10-dihydro! ysergyl-w-nitro-L-argininol is reduced, which can be converted into a salt with an acid.

The lysergic acid used as the starting material is available in any quantity, as its microbiological Manufacturing has been solved in a satisfactory manner.

For the purpose of obtaining highly pure substances, the products are chromatographed on a Purified silica gel column. The elution can for example with a mixture of alcohol, water and Chloroform can be carried out.

The inventive 1-methyl-9,10-dihydrolysergyl ω-nitro-L argininol of the formula I forms in oily or crystalline form with inorganic or organic acids salts that are rigidly crystalline. To the Salt formation can occur with mineral acids (e.g. sulfuric acid or hydrobromic acid)

Vi and strong organic acids (e.g. tartaric acid. Maleic acid or ethanesulfonic acid) can be used.

The process according to the invention is also suitable for technical implementation.

hi Furthermore, according to the invention, medicaments which I or contain several of the above compounds as active ingredient or active ingredients,

, see.

The compounds according to the invention have the following

6) lent valuable therapeutic,

especially serotonin counteracting effects.

The comparison substance was used in all experiments

1-MethyI-b-iysefgsäufebütähöiämid, which for his

good serotonir. - M counteracting H · "effect is known, used

The subcutaneous LD ₅ o value of the compound according to the invention l-methyl-9,10-dihydrolysergyI-cu-nitro-L-argininolbimaleinat in mice was mg / kg determined at 400 and the subcutaneous LD ₅ o-value of the reference compound 1-MethyI- D-lysergic acid butanolamide in mice was also found to be 400 mg / kg.

The in vitro investigations were carried out on the isolated uterus of rats, which were exposed to a subcutaneous A dose of 1 mg / kg diethylstilbestrol was sensitized (Gaddum, J. H. and

Hammed, LA .: Brit. J. Pharmacol. 9 [1954], 240 and Lanz, U. Cerletti A. and Rothlin, E .: Helvet. Physiol. Acta 13 [1955], 207). The one 50% inhibition-inducing doses were after the method of Miller, Becker and Tainter (J. of Pharm. Exp. Ther. 92 [1948], 260). The blocking of the effects of serotonin on the vessels was examined according to the method of Page (Amer. (. Physiol. 174 [1953], 436).

The results of the tests are compiled in Tables 1 to 3 below.

Table 1

Serotonin counteracting efficacy in vivo and in vitro

link

ED ₅₀ -WeH in g / cm ¹
on the isolated rat uterus (in vitro)

Percentage inhibition of by subkuUuie administration of
1 mg / kg serotonin-induced edema (rats) (in vivo)

1 -M ethyl-9,10-dihydrolysergy I-
«A-nitro-L-argininol-bimaleate

1-methyl-D-lysergic acid butanolamide
f comparison substance)

3X10 "" 5x10 "'67.0
76.0

Table 2

Serotonin counteracting activity in the isolated rat uterus in vitro

link concentration Number of animals inhibition ED 50 value in, ag / cm ³ with positive in % in;, xg / cm ³ Address / number of examined animals l-Metbvl ^ lO-dihydroJysergyl- 0.01 12/22 54.7 6) -nitro-L-arginino-birmleinat 0.02 12/15 80.0 0.01 l-methyl-D-lysergic acid ^e- butanolamide 0.01 4/17 23.6 (Comparison substance) 0.02 6/9 66.6 0.017

Table 3

Effect on serotonin vessel pressure when examined in cats with ganglia blocking Means a blood pressure (hypotension) was caused

link

l-methyl ^ .lO-dihydrolysergyl- (y-nitro-L-arginino-bimaleate

1-methyl-D-lysergic acid butanolamide
(Comparison substance)

* Tables 1 to 3 above show the superiority of the comparison substance. Especially is much stronger of the compound according to the invention compared to 65 the effect of the compound according to the invention

Number ι ^Λ -χ animals Intravenous dose Percentage inhibition in, uig / kg of vascular pressure 4th 100.0 39.9 4th 250.0 85.3 4th 100.0 17.7 4th 250 _s 0 48.1

gg

Comparative substance shows, so is serotonin counteracting efficacy both in vivo and In vitro, the inhibition of the compound according to the invention is higher than that of the comparative substance the effectiveness of serotonin on the vascular base pertaining to this inhibition in the cases of

21 24 64Ö

compound according to the invention is up to 2 times as large as in the case of the reference substance. Simultaneously with it the therapeutic index of the compound according to the invention is also higher than that of the comparison substance, since the toxicities of the two are about the same.

The compounds according to the invention do not cause any toxic symptoms in the central nervous system In the area of the vital organs (heart, kidneys) and the large arteries, they do not cause any damage to the organ function cause pathological changes. Compared to the known 1-alkyllysergic acid derivatives also lead the compounds according to the invention does not bring about any fibrotic changes in the organism.

The compounds according to the invention can be used with great advantage in any disorders in which Serotonin plays a pathophysiological role (for example in carcinoid syndromes as well as in inflammatory, allergic and anaphylaxis reactions). You can especially in the Therapy νυίϊ migrant "uses" 'Orders.

The preparation of the compounds according to the invention is illustrated in more detail by means of the following example explained

example

Production of 1-methyl-9.10-dihydrolysergyl-

ω-nitro-L-argininolbimaleate

a) Production of 1 -methyl-'UO-dihydro-

l \ sergic acid

25th

30th

3 g of metallic sodium were dissolved in about 300 cm ^{3 of} liquid ammonia and then 2.68 g of thoroughly powdered and dried lysergic acid were added. The reaction mixture was stirred at -30 to -40 for 3 to 4 hours. The progress of the hydrogenation could be followed by means of thin-layer chromatographic analysis (on a silica gel plate: elution with a mixture of chloroform, water and methanol in a ratio of 10: 1: 5); the hydrogenated product showed no fluorescence in UV light. After the end of the reaction, absolute ethanol was allowed to flow into the mixture until the blue color of the solution disappeared; Then a solution of 4.8 g of methyl iodide prepared with 5 cm ^{3 of} absolute ether was added dropwise. The mixture was stirred for a further 10 to 15 minutes and then evaporated to dryness in vacuo. The residue was ^{moistened with 5 cm 3 of} ethanol and diluted with 20 cm ^{1 of water} The pH of the solution was adjusted to 7 to 8 while cooling with acetic acid. The 1-methyl-9,10-dihydrolysergic acid was left to crystallize in the refrigerator for several days, then filtered, washed with water and acetone and dried in a vacuum drying cabinet; Melting point: 235 ° C (with decomposition); [α] f = 111 " (c - i.in pyridine).

b) Production of l-methyl-9,10-dihydrolysergic acid chloride hydrochloride

2451 g of dried 1-methyl-9,10-dihydroIysergic acid prepared according to section a) above were added with cooling to a solution of 35 g of phosphorus penene chloride in a mixture of 60 cm ^{3 of} acetonitrile and 60 cm ^{3 of} phosphorus trichloride. A solution formed temporarily and then, after further stirring, the formed 1-methyl-g.lO-dihydrolysis chloride hydrochloride separated out * The suspension was carried out slowly at a temperature of 0 to 5 ° C for 30 minutes, then the reaction mixture was submerged eiligedampft vacuum to dryness, the residue was suspended in 30 CRRI ³ of tetrahydrofuran, with petroleum ether several times by washed and dried at 4O ⁰ C under vacuum.

c) Preparation of I-MethyI-9.1 Ö-dihydrolysefgyl-tu-nitro-L-afgininine ethyl ester

3.1 g of ω-Nitro'L-arginine methyl ester hydrochloride were dissolved ^{in 50 cm 3 of dimethylformamide with stirring.} The solution was ^{diluted with 100 cm 1 of} chloroform and 8.4 cm of triethylamine were added. The l-methyl-9,10-dihydrolysergic acid chloride hydrochloride prepared in accordance with section b) above was then added while cooling in ice water. The acylation reaction proceeded in 1 hour. The RsakticriSETSrnisch W "rd ^p" NTI "r vacuum evaporated to dryness at niedrieer temperature and then cm ³ l ° / cent aqueous tartaric acid solution and 200 cm ¹ of a mixture in 100; of chloroform and tsopropanol in the ratio of 4: suspended 1 The pH. The value of the mixture was adjusted with aqueous ammonium hydroxide solution to 8. After shaking, the organic phase was separated off and the extraction was ^{repeated with 4 × 50 cm 3 of} a mixture of chloroform and isopr organic phases were dried over anhydrous sodium sulfate and, after filtration, evaporated to dryness in vacuo.The residue was dissolved in chloroform and precipitated with petroleum ether

d) Production of 1-methyl-9,10-dihydro-Iysergyi-cu-nitro-L-argininolbimaleate

5.0 g of powdered calcium chloride were dissolved in 200 cm ^{3 of} absolute ethanol with stirring. After dissolution, the 1-methyl-9,10-dihydrolysergyl-ca-nitro-L-arginine methyl ester prepared according to section c) above was added. The solution was cooled to 0 to 2 ° C. with ice water and 2.5 g of sodium borohydride were added with vigorous stirring. The reaction proceeded in 4 hours; then the pH of the solution was adjusted to pH 6 with 5N acid. The solution was evaporated to the syrup thickness at low temperature under vacuum. The residue was dissolved in 100 cm ^{3 of} water, made alkaline with ammonium hydroxide to a pH of 8 and then with 8 × 50 cm ^{3 of} a mixture of chloroform and isopropanol in the ratio extracted from 4: 1. The combined organic phases were dried, filtered and evaporated to dryness. The isomer compound was removed from the crude product by chromatography on a silica gel column; elution took place with a mixture of chloroform, water and ethanol in the ratio of 90: 4.5: 30. The salt l-methyl-9,10-dihydrolysergyl-ta-nitro-L-argininol-bimaleate was formed from the purified product with an ethanolic maleic acid solution;

Melting point: 144 to 145 ° C; [«] f = -49 ° (c = OA in 50% aqueous ethanol).

Sä; ' fr

Claims (1)

Claims: 1. l-methyl-9,10-dihydrolysergyI- (u-nitn) -L-arginol of the formula OH ₂ C-OH NH II C - NH - CH - CHj - CHj-CH ₂ -NH-C-NH-NO ₂ N-CH ₃ H ₃ CN