DE2343037A1 - MEDICINAL PRODUCTS WITH ANTIDEPRESSIVE EFFECT - Google Patents

Description

FARBWERKE HOECHST AKTIENGESELLSCHAFT

formerly Master Lucius & Brüning 0 * 5 / Q Π Q Π

File number: HOE 73 / F 253

Dr.HG / ka

Date: August 23, 1973

Medicines with an antidepressant effect

From US Pat. No. 3,737.5 ^ 9 it is already known that the tripeptide amide L-pyroglutamyl-L-histidyl-L-prolinamide (TRH) not only causes the release of thyrotropic hormone, but also has an antidepressant effect. TRH has at his Use as an antidepressant, however, has the disadvantage of the strong thyrotropin-releasing effect.

Surprisingly, it has now been found that in compounds with little modification of the TRH molecule, the antidepressant Effect remains almost unchanged although the TRH effect is low or no longer present.

The invention relates to drugs against neurotic and psychotic diseases, in particular depression, characterized in that they contain L-pyroglutamyl peptides of the general Formula I.

L Giu-

GIu-X (i)

where X denotes the L-histidine, the L-histidine pyrrolidide, the L-histidyl-L-proline, the L-histidyl-L-trypthophanamid-, the L-phenylalanyl-L-prolinamid-, the L-methionyl-L-prolinamid- or denotes the L-lysyl-L-prolinamide residue.

509810/0935

The substances of the general formula I are known and can be prepared in a manner known per se by the methods of peptide chemistry will.

L-pyroglutamyl-L-histidine, of which no biological activity was known, was synthesized as an intermediate for the synthesis of LH-RH (Chem. Ber. 105 , 2872 (1972)). L-pyroglutamyl-L-histidine-pyrrolidide (Chem. Ber. J_0J5, 2872 (1972), L-pyroglutamyl-L-histidyl-L-proline (HeIv. Chem. Acta £ 3, 63 (197O)), L-pyroglutamyl -L-phenylalanyl-L-prolinamide ("T. Med. Chem. _1_5_, 219 (1972)), L-pyroglutamyl-L-methionyl-L-prolinamide (j. Med. Chem. _P5, 479 (1972)) and L-pyroglutamyl-L-lysyl-L-prolinamide (HeIv. Chim. Acta % k_, 135 (1971) have a weakened TRH effect. These substances also show a weak prolactin-releasing effect.

All compounds of formula I show in the dopa potentiation test (Everett, Fed. Proc. _2J3, 198 (1964)) one comparable to the TRH antidepressant effect:

Percentage of overexcitation depending on the dose (mg / kg)

0.5

TRH

-His-OH LGIu-His-pyrrolidide LGlu-His-Pro ~ 0H LGlu-His-Trp-NH ι-ι <* ■

I-Glu-Phe-Pro-NH ₂

LG.lu-Met-Pro-NH _Q '-GIu-Ly s-Pro-NH "Control

130 186 267 239 216 229 270 262 155 206 184 213 200 237 268 243 151 214 242 232 239 270 238 100 100 100 100

509810/0935

When using these substances for the treatment of ηeurotic and psychotic illnesses, especially depression, is in contrast to TRH in the products according to the invention not to worry about hyperthyroidism. Also the prolactin-releasing one Effect of TRII (BeIg. Patent No. 790 851) is both compounds according to the invention weakened.

The medicinal preparations according to the invention can, for. B. in shape a tablet or pill, as a capsule or drop, or yellow in a physiological saline solution administered intravenously or intramuscularly. In a suitable preparation they can also be administered intranasally will. The dose to be administered orally ranges between 10 and 1000 mg, depending on the particular disease. Intravenously applied, 0.1 to 10 mg of active substance are sufficient.

Abbreviation:

I-GIu = pyroglutamic acid

509810/0935

Examples:

example Λ ;

500 g of an active ingredient are mixed with 282 g of potato starch and 56Ο g of lactose mixed, the mixture with an alcoholic Solution of 8 g of gelatin moistened and granulated. After drying, mix 60 g potato starch, 10 g magnesium stearate, 20 g of highly disperse silicon oxide and 60 g of talc are added and the mixture is pressed into 10000 tablets, each weighing 150 mg. Each tablet contains 50 mg of active ingredient.

Example 2:

50 g of active ingredient are mixed with k96 g of lactose. The mixture is moistened uniformly with an aqueous mixture of k g of gelatin and granulated. The dried granules, mixed with 20 g of potato starch and 30 g of talc, are evenly filled into 2000 size 1 hard gelatine capsules. Each capsule contains 25 mg of active ingredient.

example 3:

9 liters of distilled water are heated to the boil and 20 g of methyl p-hydroxybenzoate are dissolved in it. Mine cools down to about 30 ° C, gives 89.58 g Na ₂ HPO ^, 35 ^ g citric acid,

10 g of sodium chloride and 25Ο g of mannitol and then dissolve in it 50 g of active ingredient. It is filled with distilled water to 10 1 and filtered the solution. This liquid can be used as a nose drop.

509810/0935

Claims (1)

Claim; Medicines with an antidepressant effect characterized by a content of L-pyroglutamyl peptides of the general formula I. L-GIu - X (l) where X denotes the L-histidine, the L-histidine pyrrolidide, the L-histidyl-L-proline, the L-histidyl-L-trypthopanamide, the L-phenylalanyl-L-prolinamide, means the L-methionyl-L-prolinamide or the L-lysyl-L-prolinamide residue. 509810/0935