DE1233407B - Process for the production of new dihydro-D-lysergic acid-alpha-hydroxyaethylamide-deriva - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

PATENT LETTERING

Int. Cl .:

CO7d

German class: 12 ρ-11/01

Number:

File number:

Registration date:

1 233 407
S93873IVd / 12p

October 23, 1964
February 2nd, 1967

August 24, 1967

Display day:
Issue date:
The patent specification corresponds to the patent specification

The invention relates to a method of manufacture new dihydro-D-lysergic acid-a-hydroxyethylamide derivatives the general formula

CH ₃

CO - NH - CH - OR

N-CH ₃

in which R is a 5- or 6-membered cycloalkyl radical, a hydroxypropyl radical or a through Halogen atom, an aryl, amino or acylamino group-substituted alkyl radical with 1 to 6 carbon atoms means in which the acyl group is the residue of a saturated aliphatic organic Represents acid with 1 to 9 carbon atoms or the benzoyl radical.

These compounds act on the central nervous system and cause hypotensive, vasodilatory effects and anti-teramine effects and are only slightly toxic. In humans, they can either administered orally, intramuscularly, subcutaneously or intravenously. You will be special with everyone Forms of hypertension, heart disease, blood vessel disorders, tachycardia, migraines and headaches applied.

They can also be used in psychiatry as an antidepressant soothing and for the psychological Balance useful tool, preferably for endogenous depression in the depressed phase mental illnesses and psychasthenic and neurotic depression.

When used as antienteraminics, the products of the process have more favorable therapeutic properties Indices than the well-known ergometrine maleate, as can be seen from the following results of comparative tests:

Checked connections Anti
enteramine
effect LDa,
mg / kg Ergometrine maleate
Dihydro-D-lysergic acid-a- (2'-chloro-
ethoxy) ethylamide (mixture
of isomers) 1
3 3.5
15th

Method of making new

Dihydro-D-lysergic acid-a-hydroxyethylamide-

derivatives

Patented for:

Societä Farmaceutici Italia, Milan (Italy)

Representative:

Dr. Dr. J. Reitstötter and Dr.-Ing. W. Bunte,

Patent Attorneys, Munich 15, Haydnstr. 5

Named as inventor:

Federico Arcamone, Milan (Italy)

Claimed priority:

Italy of October 28, 1963 (22 092)

Checked connections Anti
enteramine
effect LDm
mg / kg Dihydro-D-lysergic acid-a-cyclo-
hexyloxyethylamide (mixture
of isomers)
Dihydro-D-lysergic acid-a-benzyl-
oxyäthylamid (mixture of
Isomers)
Dihydro-D-lysergic acid-a- (2'-acet-
amidoethoxy) ethylamide
(Stereoisomer A)
Dihydro-D-lysergic acid-a- (2'-benz-
amidoethoxy) ethylamide
(Mixture of isomers)
Dihydro-D-lysergic acid-a- (3'-hy-
droxypropoxy) ethylamide
(Mixture of isomers) 3
1
1
3
3 10.5
17th
20th
15th
10

The anti-teramine activity was determined in vitro on the rat uterus according to the method from Arch. Exp.

path. Pharmak., 196 (1940), p. 343, known method. The anti-teramine effectiveness of the Process products were related to that of ergometrine maleate, which was set equal to 1. the Toxicity (LD50) was determined after intravenous administration in rabbits.

The compounds of general formula I are prepared by being known per se

709 656/242

Way Dihydro-D-lysergic acid-a-hydroxyethylamide with a compound of the general formula

RAW

II

reacts in the presence of an organic acid and, if appropriate, then the resulting mixture of stereoisomers separates into the components by fractional crystallization.

The etherification is z. B. in the presence of maleic acid, oxalic acid or tartaric acid at a Temperature between 50 and 120 ° C within 30 minutes to 4 hours and optionally in the presence run by solvents.

The reaction mixture is then evaporated to dryness in vacuo, the residue under Adding a little alkali slurried in water and the suspension with an organic solvent, such as chloroform, methylene chloride or butanol, extracted. The extract thus obtained contains two steroisomers of the product of the general formula I, which are used as stereoisomers A and B to be designated; the stereoisomer A is in organic Solvents less and the stereoisomer B more soluble. The two stereoisomers can be separated by fractional crystallization; by focusing the excerpt on one Tenth. of the original volume, the stereoisomer A falls and after further concentration the stereoisomer B from.

The products of the process are crystal powder and soluble in common organic solvents.

The dihydro-D-lysergic acid-a-hydroxyethylamide required as a starting material is made by catalytic hydrogenation of D-lysergic acid-a-hydroxyethylamide in acidic aqueous solution in the presence of a hydrogenation catalyst, e.g. B. platinum oxide or palladium on charcoal.

The following examples illustrate the invention.

For example

Dihydro-D-lysergic acid-a- (2 ^/ -acetamidoethoxy) -ethylamide

A mixture of 10 g of dihydro-D-lysergic acid a-hydroxyethylamide, 55 g of N-acetylaminoethanol and 4.5 g of maleic acid is stirred at 75 ° C. for 1 hour. After cooling, it is diluted with 250 ml of water and made alkaline with sodium bicarbonate. It is then extracted with methylene chloride; the extract is evaporated in a vacuum. The residue is recrystallized from acetone. 1.6 g of isomer A, which melts at 227 to 230 ° C., are obtained. If the filtrate is concentrated further, 1.7 g of isomer B, which ^{melts at 205 to 210 °} C., are obtained.

Example 2

(Mixture of isomers A and B) are obtained 350 mg dihydro-D-lysergic acid-a- (2'-phenyläthoxy) -äthylamid which melts to IJO ⁰ C at 167; [a] T = -54 ° (c = 1 in 96% ethanol).

In a manner analogous to that given in the preceding examples, the following compounds manufactured:

Dihydro - D - lysergic acid - α - (3 '- hydroxypropoxy) ethylamide (mixture of isomers), m.p. 182 to 183 ⁰ C; [a] f ° = -61 ° (c = 1 in 96% ethanol);

Dihydro - D - lysergic acid - a - cyclohexyloxyethylamide (mixture of isomers), mp 181 to 182 ° C;

Dihydro - D - lysergic acid - a - benzyloxyethylamide (mixture of isomers), mp 164 to 166 ° C; [a] l °° = -62 ° (c = 1 in 96% ethanol);

Dihydro - D - lysergic acid - α - (2 '- formylamidoethoxy) ethylamide (IsomeresB), mp 130 to 135 ° C; [ _α ] ΐ °° = -51 ° (c = 1 in 96% ethanol);

Dihydro-D-lysergic acid-a- (2'-benzamidoethoxy) ethylamide (mixture of isomers), mp 193 to 195 ° C; Hr = -53 ° (c = 1 in 96 ° / _o sodium ethanol).

Claims (1)

Claim: Process for the production of new dihydro-D - lysergic acid - α - hydroxyethylamide - derivatives of general formula CH ₃ 55 Dihydro-D-lysergic acid-a- (2'-phenylethoxy} ethylamide A mixture of 1 g dihydro-D-lysergsäurea-hydroxyäthylamid, 10 ml of 2-phenylethyl alcohol and 0.6 g of maleic acid is stirred for I ¹ J ₂ hours at 70 ° C. After cooling, the reaction mixture is shaken three times with a little ethyl ether and the solvent is decanted off. The remaining oil is dissolved in 20 ml of 5% strength aqueous sodium bicarbonate solution and extracted with methylene chloride. The organic solution is evaporated in vacuo. The residue is recrystallized from ethyl ether. NH - CH - OR N-CH ₃ in which R is a 5- or 6-membered cycloalkyl radical, a hydroxypropyl radical or a through Halogen atom, an aryl, amino or acylamino group substituted alkyl radical with 1 to 6 carbon atoms means in which the acyl group is the residue of a saturated aliphatic organic acid with 1 to 9 carbon atoms or · represents the benzoyl radical, thereby characterized in that dihydro-D-lysergic acid-a-hydroxyethylamide is used in a manner known per se with a compound of the general formula RAW reacts in the presence of an organic acid and optionally then the obtained The mixture of stereoisomers is separated into components by fractional crystallization. Considered publications:
German Auslegeschrift No. 1 015 807;
Notice of Documentation of Belgian Patent No. 601 154;
Monthly books for chemistry, 78 (1948), pp. 172/173.