DE2124640A1 - Process for the production of dihydrolysergic acid, dihydroisolysergic acid and dihydrolysergic acid and dihydroisolysergic acid derivatives as well as dihydrolysergic acid and dihydroisolysergic acid derivatives and their use - Google Patents

Description

DR. STEPHAN G. BESZEDES PATENT ADVOCATE

ÖÜ6 DACHAU near MUNICH

BOX 1168

AM HEIDEWEG 2

TELEPHONE: DACHAU 43 71

Post shock account Munich 1368 71 Bank account no. 90 637 at the district and city savings bank Dachau-Indersdorf

P 328

Description

for patent application

JUDGE GEI) EON VEGIE3ZETI GIAR R.T,

Budapest, Hungary

concerning

Method r herstel lung of D ihydrol y Serg acid, dihydroiso lys ergsäure and Dihydr o lysergsäure- and dihydroergotamine droisolysergsäurederiva th and Dihydrol7 / "s e rp; acid- and Dihydroisolysergsäurederivate and their use

The invention relates to a method for the production of dihydrolysergic acid, dihydroisolysergic acid and dihydrolysergic acid and dihydroisolysergic acid derivatives and their salts with inorganic and organic acids as well as new dihydrolysergic acid and dihydroisolysergic acid derivatives and their use, in particular as anti-serotonin drugs, sedatives, anti-histamine drugs and antihypertensive agents.

209845/1159

BATH ORIGINAL

It is known that the compounds with an ergole skeleton have played a very useful role in therapy for decades. The most intensive research in the whole world is directed towards the synthesis of the so-called natural derivatives and their manufacture the amides of lysergic acid formed mainly with amino alcohols. These compounds have multiple 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 undesirable and pathological effects on the nervous system Cause vascular changes.

With those in the derzi ^ 'position due to saturation Unsaturated double bond obtained dihydroIysergic acid derivatives on the other hand, no such side effects were recorded even in the course of long clinical experience. In The hydrogenation of the double bond in the 9, 10-position of the ergole skeleton has therefore been the first priority for a long time strives for; Valuable dihydro derivatives were produced especially in the peptide alkaloid series, such as dihydroergotamine, Dihydroergocryptine, dihydroergocristine and dihydroergocornine, respectively. According to the manufacture of the 9,10-Dihydrolysergsäurederivate known processes are the corresponding lysergic acid derivatives catalytically hydrogenated, the catalyst being palladium sponge or palladium with animal charcoal is used (Stoll and Hofmann, HeIv, Chim. Acta, 26, 922

As the starting substance of the semi-synthetic dihydr ο lysergic acid derivatives Serving dihydrolysergic acid, dihydroisolysergic acid and their amides were from Stoll, Hofmann and Petrzilka by catalytic hydrogenation either above mentioned natural series belonging to lysergic acid peptides and subsequent hydrolysis of the peptide part (HeIv.

BATH ORIGINAL 209845/1169

Chim. Acta 29, 635 [1946]; Swiss patents 232 366 and 232 390; Jacobs and Craig, J. Biol. Chem. Ri_5, 227 [1937]).

The same as the starting substance for the semi-synthetic derivatives serving

were prepared according to the currently known process in such a way that any lysergic acid peptide belonging to the natural series is catalytically hydrogenated in the 9 »10-position, then alkylated in the 1-position and finally hydrolyzed (British patent 988 001; Swiss patent 386 MA-O ) . According to Swiss Patent 386 439, the 1-alkyldihydrolysergic acid derivatives were obtained by reducing the 1-alkyllysergic acid derivatives in the presence of palladium.

The disadvantage of the specified process for the preparation of dihydrolysergic acid and its derivatives is that for Production of the basic body dihydrolysergic acid is in any case a well-defined and also well applicable in medicine Compound (for example dihydroergotamine or 1-methyldihydroergotamine) must be hydrolyzed φ Die previously known methods are therefore only suitable for the production of laboratory samples, but in no way for the technical realization. Because of this, the expansion of the research area of dihydrolysergic acids was also hindered.

The invention is based primarily on a new method for the direct production of the Provide dihydrolysergic acid, dihydroisolysergic acid and their derivatives from lysergic acid and isolysergic acid. Lysergic acid and isolysergic acid are already available in any quantity today, as their microbiological production is based on has been resolved satisfactorily. Another object of the invention is the simple solution of the K-alkylation of the di-

~ yes ί ü ^ L ct. λ u U- r <_> L u j -ν ν ^r ä

⁷ Z * / V '/ _— * Γ_ ν

2 0 9845/1169 ^U

BATH ORIGINAL

hydrolysergic acid, dihydroisolysergic acid or derivatives of the same, as this is because of various, in some cases already mentioned therapeutic benefits is necessary. Finally, the invention is based on the object, in particular as Serotonin antagonists or serotonin antagonists to provide highly effective dihydrolysergic acid derivatives which do not cause any toxic symptoms in the central nervous system and In the area of the vital organs (heart, kidneys) and the large arteries, no pathological damage to the organ function Bring about change.

One of the findings on which the invention is based "is that from lysergic acid and isolysergic acid 9» 10- -Dihydrolysergic acid and 9 »10-Dihydroisolysergic acid can be obtained directly and even their derivatives from Amide type in dihydro- or 1-alkyldihydrolysergic acid derivatives and dihydro- or 1-alkyldihydroisolysergic acid derivatives Can be converted if any of these starting substances are dissolved in liquid ammonia and using of an alkali metal is hydrogenated.

Another finding is that the dihydrolysergic acid, dihydroisolysergic acid and dihydrolysergic acid obtained in this way, respectively Derivatives of the same in the same liquid ammoniacal solution with alkylating agents in the 1-A1-alkyl derivative can be transferred if an alkali metal amide or alcoholate is formed in the solution.

The invention therefore provides a process for the production of dihydrolysergic acid, dihydroisolysergic acid and dihydrolysergic acid and dihydroisolysergic acid derivatives of the general formula

9845/115 9

BATH ORIGINAL

N- OH,

where R ^ is hydrogen or a methyl radical and R _{2 is} a hydroxyl or amino group or a straight-chain or branched alkylamino or aralkylamino group substituted by at least 1 hydroxyl group or a group of the formulas

- OH

NCCC II Hp H, HH ^ '

CN H ₂ I H

H I

Il -c-

H I

N - NO,

III

H
I.
N - C - C - C - /
\ C - \ C - C - OH H ₂ H ₂ \ Xl i ~ \ C - OH H ₂

IV

20984 S / 1159

-N-C-C-C-N N-C-C-OH

/ Λ

-N N - C -.C - CH,

VI,

- OH

CC
H

I.
R.

1
CH, VH

-N NC
\ /H.

VIII,

Cl

H H

I.

N-N

IX,

'Cl

845/1159

HH ₀ G - OH H

- N

CH

NO,

HH ₂ C - OH

N C

I.
R.

XI

respectively

HH ₂ C - OH

XII

where R ^ is as defined above, and their salts with inorganic or organic acids, which is characterized is that a compound of the general formula

209845/116 9

- CH-

wherein R ,. and Rp are ^as defined above, or their salts in liquid ammonia or in liquid ammonia and an organic solvent with an alkali metal, preferably sodium and / or potassium, is hydrogenated and optionally methylated in the presence of a strong base, whereupon the base obtained with Inorganic or organic acids are converted into a salt or the free base is liberated from a salt obtained.

Some of the starting compounds of the general formula II of the process according to the invention are known and some New. The new compounds of these can be prepared in the manner described in Hungarian patent specification 156,385 produced v / earth.

Some of the compounds of the formula I are new and have valuable pharmacological effects.

The invention therefore also relates to dihydrolysergic acid and dihydroisolysergic acid derivatives in general formula

20984S / 1159

N - GH,

wherein R. is hydrogen or a methyl radical and Rp is one substituted by at least 2 hydroxyl groups straight-chain or branched alkylamino group or one substituted by at least 1 hydroxyl group straight-chain or branched aralkylamino group or a group of the formulas

Η ₂ ( σ - G C. - N - H
ι H
I. NO H ₂ " H I.
N
Il I.
N - N
ι - < II
- C - I.
H I. 3 - OH ; - σ - ι ²

III

CC H ₂ H

-C-N.

, C-C-OH

C-C-OH

IV,

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209845/1150

21246

C. C. - C - / \ C. C. -C- OH -C- 2 ^E 2 N N - 2 ^Η 2 H ₂ Λ /

- N N - C - C - CH-

\ / = ² in ''

VI,

HH ₂ C - OH

- N-

-C-C

^Η ;

I R,

1 CH,

-N N-C

VH,

VIII,

Cl

H H I N-N

Cl IX,

209845/1159

HH ₀ G - OH H

OH

-NO,

- OH

H,

XI

respectively

H HpC - OH

N C

XIl

209845/1159 - 12 -

where Ry, as defined above, means, as well as their salts with inorganic or organic acids.

Furthermore, according to the invention, medicaments which 1 or contain several of the above compounds as an active ingredient or active ingredients or from this or these exist, provided.

As therapeutic effects of the new compounds according to the invention have been carried out in the course of in vitro and in vivo For example, investigations found the following. Those compounds in which Rp is a group of formulas III and VII means are characterized by a significant serotonin counteracting effect respectively Antiserotonic effect from; a mild calming effect or tranquilizer effect was in those compounds in which Rp denotes a group of formula VI, to observe; a histamine counteracting or antihistamine effect was shown by those compounds in which Rp is a group of the formula IX; antihypertensive those compounds worked in which R2 is a group of formulas IV and V means.

But also, for example, the compounds prepared according to the invention in which Rp is an amino group or means a 1,4-aminobutanol group, according to the in vitro and investigations carried out in vivo show a significant anti-serotonin counteracting effect or antiserotonin effect.

According to an advantageous embodiment of the method according to the invention, the procedure is that a Compound of the general formula II is dissolved in liquid ammonia at a temperature of at most -40 G, if appropriate Alcohol, ither or tetrahydrofuran is added and then the solution after adding crushed alkali metal up to

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2 Q 9 8 4 S / 115 9

Saturation of the double bond in the 9-10 position is stirred. The temperature of the reaction mixture can be adjusted either by external cooling or by continuous evaporation of ammonia can be ensured. 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 same way as the solution a solvent which reacts with the excess alkali metal (for example alcohol or acetone) is added and that Ammoniac is evaporated by gentle heating under vacuum.

The methylation is preferably carried out in such a way that the reduction is carried out with a large excess of alkali metal and after the completion of the reduction, the excess alkali metal is added by any known method converted to an alkali metal amide (for example by adding ammonium chloride, iron nitrate or metal powder) or else an alkali alcoholate is produced by adding alcohol. The discoloration of the previously blue solution also indicates the Formation of the alkali amide or alcoholate. The reaction mixture is stirred for an appropriate time, then a Methyl halide, preferably methyl iodide, alone or in solution, for example in ether, poured in and the mixture is again intensively stirred. After the methylation is complete the reaction mixture worked up in the manner described. In this way, the methylation can be carried out not only of the dihydrolysergic acid, dihydroisolysergic acid, prepared according to the invention and their derivatives, but also the compounds produced in other ways.

The methylation is preferably carried out in the presence of sodium amide or sodium ethylate. The reaction runs even if the base necessary for the alkylation

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209845/1159

is not formed in the reaction mixture, but is added to the reaction mixture ready-made. For this reaction 3 to 6 mol of alkali metal amide or alkali metal alcoholate are necessary and it is also expedient to use the same excess of methyl iodide. It is important to ensure that the liquid ammonia is not cooled during the reaction with the alkali metal below -40 ⁰ C.

In order to obtain highly pure substances, the products are purified by chromatography on a silica gel acid. Elution can be carried out, for example, with a mixture of alcohol, water and chloroform. Becomes a 9,10-dihydro derivative from isolysergic acid or from isolysergic acid derivatives produced, then in each case 2 stereoisomeric dihydroisolysergic acids or dihydroisolysergic acid derivatives are formed (in the literature these are referred to as I and II), because on the carbon atom in the 10-position forms a new asymmetry center as a result of the hydrogenation. The dihydroisolysergic acid I or its derivatives can using known methods to dihydrolysergic acid respectively their derivatives are isomerized.

The substances of the general formula I form in oily ode? crystalline physical state with inorganic or organic acids, generally salts, which are always crystalline. To the Mineral acids (for example sulfuric acid or hydrobromic acid) as well as strong ones can form salts Organic acids (for example tartaric acid, maleic acid or ethanesulfonic acid) can be used.

The main advantages of the method according to the invention are as follows:

209845/1159

a) Dihydrolysergic acid and dihydrolysergic acid can be obtained directly from lysergic acid and isolysergic acid in 1 stage N-methyldihydrolysergic acid or dihydroisolysergic acid and N-methyldihydroisolysergic acid getting produced.

b) Also the hydrogenation of the double bond in the 9,10-position and the formation of the N-methyl derivatives from lysergic acid amides or isolysergic acid amides can be carried out.

c) The already known compounds can also be used by the process according to the invention can be produced more economically.

d) The process is suitable for technical implementation.

The process according to the invention is explained in more detail with reference to the following examples, which are not to be interpreted as limiting

example 1
Production of dihydrolysergic acid

3 3 g of metallic sodium in about 300 cnr

dissolved liquid ammonia and 2 cm ethanol and after dissolving at about -30 to -40 ⁰ C 2.68 g of lysergic acid were added. The reaction mixture was stirred at this temperature for hours and then 20 cnr of absolute ethanol was added dropwise. The ammonia was driven off and the dry residue was dissolved in 30 cnr v / water. The pH of the solution was adjusted to 7 "to 8 while cooling with acetic acid. The dihydrolysergic acid was left to crystallize in the refrigerator for several days, then filtered, with water and acetone

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8/1159

washed and finally dried under vacuum.
Melting point: 318 ° C; W ^ ⁰ = -122 ° (c = 1, in fyridine).

Example 2
Production of dihydroisolysergic acids

The procedure described in Example 1 was repeated, with the difference that isolysergic acid was used as the starting substance. Melting point of dihydroisolysergic acid-I: 272 ° C; W ^ ⁰ = -82 ° (c = 1, in lyridine).
Melting point of dihydroisolysergic acid-II: 306 ⁰ C;
Wd ° ^{= +15} ° (c = 1, in pyridine).

Example 3
Production of 1-methyldihydrolysergic acid

3 grams of metallic sodium was dissolved in about 300 cubic meters of liquid ammonia and then 2.68 grams were thoroughly dissolved
powdered and dried lysergic acid added. The reaction mixture was stirred for 3 to 4 hours at -30 to -40 ⁰ C. The progress of the hydrogenation could be followed by means of thin-layer chromatographic analysis (an
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

7th

disappeared; then a solution of H3 g of methyl iodide, prepared with 5 cm of absolute ether, was added dropwise. The mixture was stirred for an additional 10-15 minutes and then evaporated to dryness in vacuo. The residue was 5 cm ^
Moistened with ethanol and diluted with 20 cm ^ of water. Of the

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? 09845/1 1 59

" ¹⁷ " 21246-0

The pH of the solution was adjusted to 7 bis with cooling with acetic acid. The 1-methyldihydrolysergic acid was allowed 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); Μ J " ⁰ = (c = 1, in pyridine).

Example 4
Production of 1-methyldihydroisolysergic acid-I

The product was exactly as given in Example 3 Made from isolygic acid. Melting point: 217 ° C.

Example 5

Preparation of dihydrolysergic acid amide 2.6 g of metallic sodium in

7th

300 cnr of liquid ammonia was dissolved and 2.6 g of dried and thoroughly powdered lysergic acid amide were added to the solution. The solution was stirred for a further 4 hours, then were 25 cnr of absolute ethanol was added and the solution was under

Evaporated to dryness in vacuo. The residue was 50 cnr 1% sodium thiosulphate solution and 100 cnr chloroform were added. The pH of the aqueous solution was adjusted to 8 with hydrochloric acid and, after shaking, became organic

7th

Phase separated. The extraction was repeated with 5 x 50 cur chloroform. The combined organic phases were dried over anhydrous sodium sulfate and then evaporated to dryness. The residue was dissolved in ethanol and a salt formed with maleic acid; the crystallization of the salt was encouraged by adding a small amount of ether. Characteristic data of the base dihydrolysergic acid amide: Melting point: 276 ^° C.; ° ° (c = 1, in pyridine).

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209845/1159

Example 6

■ Production of 1-methyldihydrolysergic acid amide

bimaleinat

There were dissolved 2.6 g of metallic sodium at a temperature below ⁰ C in 300 cur -4o liquid ammonia and 2.6 g of lysergic acid amide added. After stirring for about 4 hours, the blue solution was decolorized by adding ethanol. A solution of 1.2 g of methyl iodide prepared with 5% absolute ether was added dropwise and, after standing for 5 minutes, the mixture was evaporated in vacuo. The residue was worked up in W as shown in Example 5 manner, then the residue after the Äbtreiben Chloroformes was taken up in a little chloroform and again precipitated with petroleum ether. For purification, the crude product was chromatographed on a silica gel column; elution was carried out with a mixture of chloroform, water and ethanol. After evaporation of the solvent, a salt was formed from the residue with an ethanolic maleic acid solution. Characteristics of the Base! Et
20th

1-methyldihydrolysergic acid amide: melting point: 256 ° C .; = -135 ° (c = 1, in pyridine).

Example 7

Production of dihydrolysergic acid (4-hydroxybut-1-yl) amide bimaleate

The compound was prepared from 3.38 g of lysergic acid (4-hydroxybut-1-yl) amide in the manner described in Example 5. Melting point: 132 to 134 ^O C; M ^ ° = -50.7 ° (c = 0.5, in 50% aqueous ethanol).

209845 / 11S9

Example 8

Production of 1-methyldihydrolysergic acid - (4-hydroxybut-1-yl) amide bimaleate

The compound was prepared in the procedure described in Example 6 from 3.38 g of lysergic acid (4-hydroxybut-1-yl) amide. Melting point: 123 to 125 ° C; M ^ ⁰ = -51.7 ° (c = 0.5 »in 50% aqueous ethanol).

Example 9

Production of dihydrolysergic acid ~ (2-ethyl- -1,3-dihydroxyprop-2-yl) amide bimaleate

The compound was prepared with 2.3 S metallic sodium from 3 »95 B lysergic acid (2-ethyl-1,3-dihydroxyprop-2-yl) - amide by means of the procedure given in Example 5. Melting point: 118 to 120 ⁰ C; (c = 0.5 »in 50% aqueous ethanol).

Example 10

Production of 1-methyldihydrolysergyl-ui-nitro- -L-argininolbimaleinate

a) Production of 1-methyldihydrolyseric acid chloride hydrochloride

There were 2.81 g prepared according to Example 3 dried 1-methyldihydrolysergic acid with cooling in a solution of 3.5 g of phosphorus pentachloride sprinkled in a mixture of 60 cirrs of acetonitrile and 60 cnr of phosphorus trichloride. It made up temporarily found a solution and then divorced

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209845/1159

further stirring the formed I-methyldihydrolysergic acid chloride hydrochloride .aus. The suspension was stirred at a temperature of 0 to 5 ° C for 30 minutes, then the Reaktionsgeinisch under vacuum eingedanpft to dryness, the residue was suspended in 30 cm * tetrahydrofuran, petroleum ether repeatedly washed through and at 4-0 ⁰ C under vacuum dried.

b) Production of 1-Methyldihydrolysergyl- -ω-nitro-L-arginine methyl ester

There were 3j1 g of o-nitro-L-arginine methyl ester hydrochloride dissolved with stirring in 50 cm / dimethylformamide. The solution was Diluted with 100% chloroform and there were 8.4 cnr triethylamine added. Then, while cooling in ice water, the 1-methyldihydrolysergic acid chloride hydrochloride prepared according to point a) was obtained admitted. The acylation reaction proceeded in 1 hour. The reaction mixture was under vacuum at low

7th

evaporated to dryness ger temperature and then in 100 cnr 1% aqueous tartaric acid solution and 200 cnr of a mixture suspended by chloroform and isopropanol in a ratio of 4: 1. The pH of the mixture was adjusted to 8 with aqueous ammonium hydroxide solution. After shaking the separated organic phase and the extraction was carried out with 4 × 50 cnr of a mixture of chloroform and isopropanol 4: 1 ratio repeated. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness after filtering in vacuo. The residue was dissolved in chloroform and washed with petroleum ether pleases. The precipitate was filtered off, washed with petroleum ether and dried under vacuum to constant weight.

c) Production of 1-methyldihydrolysergyl-G) - -nitro-L-argininolbimaleate

5.0 g of powdered calcium chloride were dissolved in 200 cm ^{5 of} absolute ethanol with stirring. After solving the

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209845/1 159

ester compound prepared according to point b) was added. The solution was cooled to 0 ° to 2 ° C. with ice water and under intensive With stirring, 2.5 6 sodium borohydride was added. The reaction proceeded in 4 hours; then the pH of the solution adjusted to 6 with 5 η hydrochloric acid. The solution was at evaporated to syrup thickness under vacuum at low temperature. The residue was dissolved in 100 cnr water with ammonium hydroxide made alkaline to a pH of 8 and then

7th

extracted with 8 χ 50 cnr of a mixture of chloroform and isopropanol in the ratio of 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; the elution took place with a mixture of chloroform, water and ethanol in the ratio of 90: 4.5 'x 30. A salt was formed from the purified product with an ethanolic maleic acid solution. Melting point: 144 to 145 ° C; [Vj ^ ⁰ = -49 ° (c = 0.5 i in 50% aqueous ethanol).

Example 11

Manufacture of Dihydrolysergyl- £ 3 - (nitrophenyl) -1,3-o ^ bydiaxyprop-2-ylj -amidbimal inat

The compound was prepared from 4.4 g of lysergyl-3- (nitrophenyl) -1,3-dihydroxyprop-2-yl3-amide in the procedure described in Example 5; a salt was formed from the base with an ethanolic maleic acid solution. Melting point: 114 to 115 ° C; Mj ⁰ = -69.6 ° (c = 0.5, in 50% aqueous ethanol).

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- ²² - 21246A0

Example 12

Preparation of 1-methyldihydrolysergyl- [3- - (nitrophenyl) -i, 3-dihydroxyprop-2-yl] -amidebimaleate

The compound was prepared from 4.4 g of lysergyl- [3- (nitrophenyl) -1,3-dihydroxyprop-2-yl3-amide prepared according to Example 6]. Melting point: 121 to 123 ° C; [<*] ²⁰ = -74-, 2 ° (c = 0.5j in 50% aqueous ethanol).

Example 15

Production of 1-methyldihydrolysergic acid - (+) - Dl -hydroxybut-2-yfJ amide tartrate

a) Production of lysergic acid-2-amidobutyric acid emethyle st he

A mixture of 150 cur absolute chloroform and

50 cur tert-butanol while stirring 1.54 g (+) - 2-amino butter-

7th

acid methyl ester hydrochloride and 5 »6 cnr triethylamine added. Then, while cooling in ice water, 2.68 g of lysergic acid were prepared in the manner described in Example 10 a). Lysergic acid chloride hydrochloride added. The coupling reaction proceeded in about JO minutes. That

7th
The reaction mixture was diluted with 150 cn chloroform and shaken with 100 cn 2% aqueous hydrochloric acid. The separated aqueous phase was extracted with a further 3 × 100 cm- ^ chloroform at a pH of 8. The combined organic phases were dried over anhydrous sodium sulfate and, after filtration, evaporated to dryness under vacuum. The residue was dried over phosphorus pentoxide.

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209845/115 3

b) Production of lysergic acid - (+) - [i-hydroxybut-2-yl]] amide

The connection was made from that according to point a) Ester compound prepared in the manner indicated in Example 10 c). The reaction was carried out using 3 »5 S Calcium chloride and 1.75 6 sodium borohydride.

c) Production of 1-methyldihydrolysergic acid - (+) - [i-Hydroxybut-2-yl3-amide tartrate

The compound was prepared in the manner described in Example 6 from the compound prepared according to point b). Melting point: 14-3 to 145 ° C; [«] ^ ⁰ » -50 ° (c = 0.5, in V / water).

Example 14

Production of dihydrolysergic acid dichlorophenyl

hydrazide

The compound was prepared from 4.27 S lysergic acid dichlorophenyl hydrazide in the manner indicated in Example 5. Melting point: 202 to 204 ⁰ C; [«] ^ ⁰ = -47.9 ° (c = 0.5, in 50% aqueous ethanol).

Example 15

Production of 1-methyldihydrolysergic acid dichlorophenyl hydrazide

The compound was prepared from 2.47 g of lysergic acid dichlorophenyl hydrazide in the manner described in Example 3, melting point: 256 to 258 ° C.; - [«] p ⁰ = -70.6 ° (c = 0.5, in pyridine).

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209845/1159

Example 16

Production of 1-methyldihydrolysergic acid (1-hydroxy-3-indolylprop-2-yl) amide binaleinate

The compound was prepared from 2.82 g of 1-methyldihydrolysergic acid and 2.6 g of tryptophan methyl ester hydrochloride in the manner described in Example 10. 4.5 g calcium chloride and 2.25% sodium borohydride were used for the reduction. Melting point: 140 to 142 ⁰ C; [Xj ² , ⁰ - (c = 0.5, in 50% aqueous ethanol).

Example 17

Preparation of 1-methyldihydrolysergic acid- (1- -hydroxy-3-imidazolylprop-2-yl) -amidebimaleate

The compound was made from 2.82 g of 1-methyldihydrolysergic acid and 1.8 g of histidine methyl ester in the procedure described in Example 10 prepared. For the reduction, 4.0 g of calcium chloride were used and 2.0 g of sodium borohydride are used. Melting point:

, g
139 to 141 ° C; [<x] ²⁰ = -55.1 ° (c = 0.5, in 50% aqueous ethanol).

Example 18

Production of dihydrolysergic acid-N- [2- (hydroxy) - -propylj -piperazidbimaleinat

The compound was prepared from 3> 95 g of lysergic acid-N- £ 2- (hydroxy) -propylj-piperazid in the manner described in Example 5, but with the difference that the hydrogenation was carried out with 3 * 9 g of metallic potassium. Melting point 206-207 ° C; [oCj ^ ⁰ = -47.5 ° (c = 0.5, in 50% aqueous ethanol).

- 25 209845/1 1 $ 9l

Example 19

Preparation of dihydrolysergic acid [j! I- (hydroxyethylpiperazino) -N · prop-1-ylj-amide bimaleate

The compound was prepared from 4.35 6 lysergic acid-fN- (hydroxyethylpiperazino) -N'-prop-1-yl [{- amide in the manner described in Example 5, with the difference that 6.8 g Sodium alcoholate were used. Melting point: 158 to 160 ° C; Mp ⁰ = -29.45 ° (c = 0.5, in 50% aqueous ethanol).

Example 20

Production of dihydrolysergic acid (3-diethanoliminoprop-1-yl) amide

About 300 cm ^ of liquid ammonia with 2 cm ^ absolute Ethanol mixed and then 4.15 S lysergic acid (3-diethanoliminoprop-1-yl) amide starting substance were sprinkled in. Then 4 g of metallic sodium was added in small portions with stirring and the solution became still Stirred for 2 hours. Then 15 cur of absolute ethanol poured in and the solution was evaporated to dryness in vacuo. The dry residue was in 100 cm 2% Dissolved sodium bisulfite solution, the pH of the solution was adjusted with diluted hydrochloric acid adjusted to 8 and then was with

7th

7 x 50 cur of a mixture of chloroform and isopropanol in a ratio of 4: 1 extracted. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The crude product was purified by chromatography on a silica gel column. Melting point: 119 ° CM ^ ⁰ = -90.4 ° (c = 0.5, in pyridine).

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209845/115 9

Example 21

Production of dihydrolysergic acid - [_ 1- (hydroxy) - _3_ (4 - «_ hydroxy-3 'j 5' -dibromophen-1 '-yl) -prop- -2-ylJ-amide tartrate

The compound was prepared from 5 »1 g of lysergic acid [1- (hydroxy) -I- - (V-hydroxy-3 ¹ , 5'-dibromophen-1 * -yl) -prop-2-yI-amide with the help of the Procedure given in Example 20 produced. A salt was prepared from the base with methanolic tartaric acid solution. Melting point: 164- 162 ⁰ C; L ⁰ O? ° = -4-2.7 ° (c = 0.5, in 50% aqueous ethanol).

Example 2 2

Production of "dihydrolysergic acid-N- -E2- (methyl) -benzyIJ-piperazidtartrate

The compound was prepared from 4.6 g of lysergic acid-N- [2- (methyl) - -benzyl] piperazide using the method described in Example 5 Procedure prepared, but with the difference that the hydrogenation with a mixture of 2.9 g of metallic Sodium and 1.1 g metallic potassium was made. A methanolic tartaric acid solution was used from the crude product Salt made. Melting point: 169 to 171 ° C; M p ° = -30.7 ° (c = 0.5 »in 50% aqueous ethanol).

Claims

209845/115 9

Claims (5)

Claims / "} ·.) Process for the production of Dihydrolysergsöure ₅ Dihydroisolysergsäure und Dihydrolysergsllure-" and Dihydroisolysergsäurederivaten of the general ϊογι.;. Ο1 C-R, E ₁ - K ' where R ^ represents hydrogen or an IJethylrest υπΐ Rp is a hydroxyl or amino group or one through rdr'de-stens 1 hydroxyl group substituted gerodkotti ^ c; respectively branched alkylamino or aralkyla'i.ino group or a group of formulas H ₂ C - OH N H C-C-C-N HTT TT - C - N - NO, II H III -N-C-C-C-N. ^ CC-OH
'2 ^H 2 C-C-OH 209845/1159 BAD ORJGINAL - 23 - H
ι N C - C-N / \ -C- C. I.
N - \ H ₂ H ₂ \ \
N H ₂ H ₂ \ ν_ __ / / - C - \
N -C- H
ι H ₂ / H ₂ I.
C - CH ₅ I.
OH H HoG - OH C-G I ^H ; N- N
I. GH ₅ - N N-C / H. Cl VH VIII H H I I N-N IX, 'Cl -29- 209845 / 11S9 H H "0 - OH H XI "respectively HH ₂ G - OH XII 209845/1159 where Ry. as defined above, and their salts with inorganic or organic acids, characterized in that a compound of the general formula C-R. - CH, wherein R. and R "are as defined above, respectively their salts in liquid ammonia or in liquid ammonia and an organic solvent with a Alkali metal, preferably sodium and / or potassium, hydrogenated and optionally in the presence of a strong one Base methylated, whereupon if necessary the obtained Base converted into a salt with inorganic or organic acids or the free salt obtained from a salt Base releases. 2.) The method according to claim 1, characterized in that in addition to the liquid ammonia as the organic solvent Alcohol and / or ether used. 209845/1159 3.) Method according to claim 1 or 2, characterized in that that the methylation is carried out with a methyl halide, preferably methyl iodide, and as a Base an alkali metal amide, preferably sodium amide, or an alkali metal alcoholate, preferably sodium alcoholate, used. 4.) Dihydrolysergic acid and dihydroisolysergic acid derivatives the general formula N - CH- 209845 / 11FP BAD OFUGiNAL where R. is hydrogen or a methyl radical and R _{2 is} a straight-chain or branched alkylamino group substituted by at least 2 hydroxyl groups or a straight-chain or branched aralkylamino group substituted by at least 1 hydroxyl group or a group of the formulas H ₀ C - OH NH I Il I N-C-G-G-C-N-G-N-N0 ~ III Il TT TT TT ι <- I ^H 2 ^H 2 ^H 2 I.
HH H H G-C-OH ο Ho -N-C-C-C-N "IV H ₂ H, CC-OH H ₂ H ₂ 209R45 / 11SP BAD ORIGINAL -N-C-C-C-N N-C-C-OH V, - N- \ I N-C-C-CH, OH - OH CC
H - N VI, VH, VIII IX, 209845/1159 H H ~ C - OH H XI respectively XII where E ^ is defined as above, means, as well as theirs Salts with inorganic or organic acids. - 35 - 209845/1159 5.) Medicines, characterized by a content of 1 or more compounds according to claim 4 as an active ingredient or ingredients. 20984S / 11h9 OBK3INAL INSPECtEO