DE2423390A1 - PYROGLUTAMYL COMPOUNDS WITH ANTIDEPRESSIVE EFFECT AND PROCESS FOR THEIR PRODUCTION - Google Patents

Abstract

Novel pyroglutamyl compounds of the formula I <IMAGE> in which X denotes an optionally branched alkyl radical having 2 to 6 carbon atoms or an optionally branched alkyl radical having 2 to 6 carbon atoms which is either substituted in the alpha -position by a carbamoyl group or in the omega -position by a carbamoyl group or a carboxyl group, are prepared by reaction of a pyroglutamic acid, which is optionally substituted on the nitrogen by a benzyloxycarbonyl radical, or of a reactive derivative thereof with a primary amine which introduces the group X and subsequent removal of possible carboxyl protective groups. The novel compounds are useful therapeutics for the treatment of psychic disorders, in particular of depressions.

Description

FARBWERKE HOECHST AKTIENGESELLSCHAFT
formerly Master Lucius & Brüning

File number: HOE 7 ^z f / ^1P 130

Date: 13- May 197 ² ^ Dr. HG / vL

Pyroglutarnyl compounds with antidepressant effects and Process for their manufacture

From US Pat. No. 3,737-5 ^ 9 it is already known that the tripeptide L-pyroglutamyl-L-histidyl-L-proline unide (TKIl) does not only causes the release of thyrotropic hormone but also has antidepressant effects. TRII has in its application as an antidepressant, however, the disadvantage of the strong thyrootropin-releasing Effect.

Surprisingly, it has now been found that "even simple pyroglutamylamides in the dopa potentiation test (Everett, Fed. Proc. 23 > 198 (1964)) show a strong antidepressant effect, while the TRH effect has completely disappeared.

The invention relates to pyroglutainyl compounds in general Formula I.

H
- N - X (l)

O "H

in which X is an optionally branched alkyl radical of k - carbon atoms or an optionally branched alkyl radical of 2-6 carbon atoms, which is optionally either at the ^ -position

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through a carboxainido group or at the CJ position, a Carboxamido or carboxyl group is substituted, represents and a process for the preparation of these compounds, which is characterized in that one

a) optionally on nitrogen by a benzyloxycarbonyl radical substituted pyroglutamic acid as an active ester, as a mixed anhydride or by means of a carbodiimide with a primary amine of the general formula II

H ₂ N - X (II)

in which X has the abovementioned meaning, but with existing Carboxyl groups can be protected by suitable protective groups customary in peptide chemistry, and then reacted the protective grips that may be present in the usual way, or that one

b) Glutamine derivatives of the general formula III

'H ₂ N - CH - CH ₂ - CH ₂ - CO - NH _£ (ill) CO - NH - * X

in which X has the stated meaning, by boiling in trifluoroacetic acid or by prolonged standing in aqueous solvents to give the compounds according to the invention of formula I cyclized.

According to procedure a) it is advantageous to use an active ester the pyroglutamic acid with a corresponding primary amine. The active esters are, for example, 4-nitrophenyl, the 2,4,5-trichlorophenyl or pentachlorophenyl ester in question. As carboxyl protection for those through the carboxyl group Substituted amines can be the more fully cleavable tert-butyl ester, the alkaline or by catalytic hydrogenation

/ 3 509849 / 09Ü2

Cleavable benzyl or 4-nitrobenzyl esters or the alkaline Use saponifiable alkyl esters such as methyl or ethyl esters. The implementation is preferably carried out in a strong polar solvents such as dimethylformamide, dirnethylacetamide or dimethylsilfoxide. To speed up the response you can also use 1-hydroxybenzotriazole or similar N-hydroxy compounds (see DBP 2 202 613). The Pyroglutamy! Derivatives, which still contain carboxyl protecting groups are then by splitting off the protective groups in the customary manner in the according to the invention Connections transferred. For example, tert-butyl esters split off by acids, alkyl esters or aralkyl esters by bases or esters of the benzyl type by catalytic hydrogenation.

According to procedure b), glutaminyl derivatives are advantageously used as intermediate product, which, after splitting off the protective groups, can easily be cyclized to the P3 ^ roglutamyl compounds according to the invention by boiling in trifluoroacetic acid or by prolonged standing in aqueous solvents. The glutaminyl derivatives themselves can be prepared by the usual methods of peptide chemistry by reacting glutamine derivatives protected on the amino group and optionally also on the carboxamido group with the corresponding amino component, with any carboxyl groups present in the amino component being blocked by the tert-butyl radical. For example, by aminolysis of carbobenzoxy or tert.-Butyloxycarbonylglutamin p-nitrophenyl ester, the protected Glutamin3 ^r lderivate be prepared. The aminolysis can be greatly accelerated by adding suitable N-hydroxy bonds such as 1-hydroxybenzotriazole or 1-hydroxy-pyridon-2. The glutaminyl derivatives become insoluble in water and can be easily isolated by protecting the carboxamido group of the glutamine, such as, for example, the ^, 4'-dirnethoxybenzhydryl radical.

The process according to the invention can be used, for example, to produce will:

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L-pyroglutamic acid n-butylamide, L-pyroglutaric acid iso-butylamide, L-Pyroglutamic acid-n-pentylamide, L-P3rroglutamine.Päiire-nliexylamid, L-pyroglutamyl-alaninamide, L-pyroglutamyl-L-leucinamide, L-pyroglutamyl-L-norleucinamide, L-pyroglutamyl-L ~ valinamide, L-pyroglutamyl-L-iso-leucinamide, L-pyroglutamyl-ß-alanln, L-pyroglutaniyl-ß-alauinamide, L-pyroglutamyl-4-aminobutyric acid, L-pyroglutamyl-4-aniiiiobutyric acid, L-pyroglxitamyl- γ- aniinovaleric acid, L-pyroglutarayl-V-arainovaleric acid, L-pyroglutamyl-6-aminohexanoic acid, L-pyroglutamyl-6-aminoliexansätiroainid.

The compounds according to the invention unfold in the dopa potentiation test similar effect to the well-known TRH. They serve as valuable therapeutics for the treatment of physical Illnesses, especially depression.

The following are values obtained in the dopa potentiation test given for some erf indxmgs according to en Vex ^ bindings. The payment are a combination of values obtained after 15 fc ** 30 minutes nachji application.

Percentage of overexcitation in relation to dependency on the dose (mg / kg)

0.5 1 2 5 TRH 130 186 267 239 Pyroglutamic acid-n-butyl-
amide 145 11 1 165 159 Pyrroglutaminesäxxre-n-hexyl-
amide 217 186 188 182 Pyroglutamyl alanine amide 178 132 137 151 Pyroglutamyl-ß-alanine 192 167 162 204 Pyroglutamyl-4-aminobut ter- i4o 125 255 245

acid

Pyroglutamyl-4-aminobutyric acid amide

control

183

100

233

100

160

100

198

100

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The pyroglutaineous compounds according to the invention are in shape of drops, tablets, pills or capsules orally or dissolved in physiological saline solution, also intravenously, intramuscularly or can be administered subcutaneously. Also intranasally in the form of Nasal drops or nasal spray should apply this substance.

The dose to be administered orally varies as a function of the respective diseases between 10 mg and 1000 mg of active substance. When administered intravenously, 0.05 to approx. 5 mg are sufficient and intranasally 0.1 to 10 mg of active substance.

509849/0942

Example 1;

L — Pyx'of;.! utamiric acid-n-butylamine

a) Pentachlorophenyl L-pyroglitamic acid

129 g (1 mol) of L-pyroglutaric acid are finely ground in a mortar and suspended in 2 l of tetrahydrofuran. 3 "19 g (1.2 mol) of pentachlorophenol and 220 g (1.06 mol) of dicyc3ohexylcarbodiimide, dissolved in 300" ¹ l of tetrcihydrofuran, are added and the mixture is stirred at 0 for 1 hour and at room temperature for 5 hours, then filtered from dicyclohexyl urea, which is extracted again with a little warm tetrahydrofuran. The solvent is distilled off in vacuo, the residue is boiled with isopropanol and filtered off after cooling. Yield after drying in VaIc. via P ₀ (V ^and KOH 175 g, melting point 19S °, [<x] f ° = + 18.6 ° (c = 1, dimethylformamide)

b) L-pyroglutamic acid n-butylamide

7> 5 S (20 mmol) LP ^^ roglutamic acid-pentachlorophen ^ '- lestex "and 1> 75 g (24 mmol) 11-butylamine are stirred in 100 ml tetrahydrofuran for 5 hours. The solvent is distilled off and the residue is dissolved in methanol and treated successively with strongly basic and strongly acidic ion exchangers. After filtration, the methanol is distilled off, the oily residue is dissolved and precipitated with petroleum ether. The initially oily product becomes solid after standing for a long time. It is filtered off, washed with petroleum ether and im Yak. Dried. Yield 2.95 g (no sharp melting point)

^C 9 ^H 16 ^N 2 ° 2 (184.2) calc. C 58.67 H 8.75 N 15.20

Found C 58.6 II '8.8 N ΛΗ.9

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Example 2;
L-pyroglutamic acid n-hexylantide

To a solution of 3.1 g of L-pyroglutanic acid 2, 4, 5-trichloroplieri3'lester in 10 ml of dirnetliylformamide is added at 0 C ^ 1 ml of n-hexylamine, and the solution is allowed to emperatxvr for 20 hours stand. The mixture is then distilled off in vacuo at room temperature, the residue is taken up in 90 percent methanol, the solution is filtered successively through 200 ml Lewatit S 100 (il - form) and Serdolite blue (oil "" - form) each. The ion exchange oils are rewashed with 200 ml of 90% methanol, and the elution and washing solution are brought together to dryness under vacuum. The L-pyroglutamic acid-n-hexylamide obtained as a colorless solid was recrystallized from ethyl acetate.
Yield: 1.33 S mp: 95 ° C ^ J ^ = + 19.8 ° (c = 1, DMF)

Example 3t
L-pyroglutamyl ~ L-alanine amide

3 »75 g (IO.H1M0I) of L-pyroglutamic acid pentachlorophenyl ester are dissolved in h0 ml of dimethylforranide with 1.5 g (12 mmol) of L-alanine amide hydrochloride and 1.5 ml (12 mmol) of N-ethylmorpholine for 4 hours . touched. The solvent is distilled in vacuo. from, dissolves the residue in methanol and stirs one after the other with "strongly basic and strongly acidic ion exchanger, the exchanger is filtered off and brought to dryness. The residue is digested with ethyl acetate, dissolved in a little ethanol and initially precipitated as a resin with petroleum ether Standing under petroleum ether, it becomes solid, yield 1.2 g, chromatographically uniform, (no sharp melting point) N Ber. 21.0 Found 21.2

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Beisn: i el / l [:
L-pyroglutamyl-ß-a3 anine

To the solution of 9.0.5 g (0.05 mol) of fi-Alcmin-tert. Butyl ester hydrochloride and 6.32 ml (0.05 mol) of N-Ätliyamoi-pliolin in 75 nil dimethylformamide are added 6.75 g (0.05 mol) of 1-hydroxybenzotriazole and 6.5 g of finely powdered pyroglutamic acid. The solution is then cooled to -5 and 11.3 g (0.05 * l mol) of cyclohexylcarbodiinide, dissolved in 25 ml of dimethylformamide, are added. The mixture is stirred for a further 6 hours at 0 C and left to stand at + h ° G for a further 16 hours. Then one sucks off the precipitated dicyclohexylurea, and enr ^ L the filtrate iV at room temperature to a syrupy consistency. The residue is twice with 180 ml of abs. Ether digested, and then dissolved in 8Obigem methanol through 200 ml of scrdolite blue (OII "" form) filtered. Then it is washed with 350 ml SO percent methanol. \ ^A Bluat and washings v / ground together i.. evaporated at room temperature. The remaining oil is dissolved in 30 ml of 90 percent strength trifluoroacetic acid, and the solution is stirred for one hour at room temperature. The trifluoroacetic acid is then evaporated off iV, and the residue is digested with abs. Ether. The crude product obtained in this way is crystallized from ethanol / ether. Yield: 6, h g mp: 199 ° l ^a ~ \ y ^Z = - ⁸ »3 ° (c = 1, methanol)

Beis ] ) le.l 5?

L-Pyro glut amy l- ^ l -aminobutt er acid

a) Benzyloxycarbonyl-'j-aminobuttersäux'o-tert. -butyl ester

600 ml of liquefied isobutylene and 6 ml of conc. H ₀ SOj. It is left for 3 days at room temperature

cnQo / .Q / no /. ο

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Shake in the autoclave, then the isobutylene is distilled off, the methylene chloride solution washes two ηιειΐ with 10 percent. Sodalösimg · and. once with hater, dry over sodium sulfate and concentrated in vacuo. The residue is dissolved in ether xmd over 620.g basic Al ^ Oo chiOinatographed. With Xther is eluted. From ta. 1 61.9 g Ql.

b) ^ - aminobutyric acid tert-butyl ester hydrochloride

A solution of 161.5 g of benzyloxycarbonyl - ^ - amirio butyl acid tert-butyl ester in 500 ml of methanol was catalytically hydrogenated beforehand after the addition of Pd catalyst with the addition of inethanolic HCl at -pllh (autatitrator). After the reaction has ended (no further uptake of methanolic HCl), the catalyst is filtered off with suction and the filtrate is concentrated. The residue is dissolved in ether and kept cool. After a while, a precipitate separates out and is filtered off with suction. Yield 78 »2 g Schnip. 82 - V> k °.

c) L-pyroglutamyl - ^ - aminobutyric acid tert-butyl ester

To a solution of 1.95 g (10 mmol) of 4-amino-butyric acid tert-butyl ester hydrochloride 1.3 ml of N-Ethylmorpholiii and 3 * 08 g of L-pyroglutamic acid 2,4,5-trichlorophenyl ester are added to 20 ml of dimethylformamide » It is left to stand overnight at room temperature, concentrated, the residue is partitioned between ethyl acetate and fesser, shakes the ethyl acetate solution with sodium bicarbonate solution, KIISOj solution and NaCl solution, dried with Ne ^ SOr and concentrated. Of the The residue is triturated with petroleum ether. Yield: 2.1 g, melting point 68 C.

- 10 -

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d) L-Pyrogiutamy 1-h -ai: ': no'jut t ·' - rr>"ure

2 g L-Pyroglutarav'l- ^ aminolmtter "acid tert.-B'utylestor in 20» ti Trif luoressigsätire dissolved warm, ί-'taii can iirmtcn-i at room temperature filters' JO. Thereafter, the trifluoroacetic acid is stripped off in vacuo and the residue is triturated with ether and filtered off with suction. The product is dissolved in water, insoluble matter filtered through activated charcoal and freeze-dried. Yield 76 mg, mp 117-120 °, [a] ^ ° = -l 1, 3 ° (c = 1, in methanol)

^C 9 ^H 14 ^N 2 ° 4 ( ²¹ ^ » ² ) ^Ber * ^C 50.42 H ό, 58 Ν Ι3.Ο8

Found 50.6 .6.5 13.2

Example 6:

L-Pyr oglutamyl- ^! -aminobutic acid e

a) N -BenzyloxycarbonyI-N ^T '-'i , k ' -dimGthoxybel ^ κhydΓyl-L · -g ■ lutaminyl-4-aminobutyric acid tert-butyl ester

2.53 (5 mmol) N -Bensyloxycarbonyl-N ^ -i! _f h '-dimethoxybenzhydryl-L-glutamine, 975 mg ^ -amino butyric acid tert. butyl ester hydrochloride and 6-75 mg I-hydroxybenzotriazole are dissolved in 10 ml dimethylformamide. To this are added 0.65 ml of N-ethylmorpholine and, at 0 ° C., a solution of 1.1 g of dicyclohexylcarbodiimide in dimethylformamide. The mixture is stirred for 1 hour at 0 and left to stand at room temperature overnight. The precipitate is filtered off with suction and the filtrate is concentrated. The residue is ^{triturated with sodium carbonate 1} -bonate solution and water, in each case filtered off with suction and dried _{over P 2} O _11. It is then boiled up with acetone, cooled to 0 C and filtered off. Wash with acetone and petroleum ether.
The end. 3.5 g, melting point 178 ° C.

- 11 "~

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b) L ~ Pyrog-l utanvyl - ^ - aiiiinobutters-ilure

2.5g benzyloyycarbonyl-N * '- ¹ ! , 'Ί' -dimethoxybeuzhydryl-L-glutamiiiy.i.-4-aiuinobiitteräure-tert.-butyl ester are: boiled with 2 ml of anisole in 20 nil trifluoroacetic acid 100 mimits under reflux. Then it is concentrated and the residue is distributed between water and ether. The aqueous phase is cleared with activated charcoal and freeze-dried. The oily residue is crystallized from methanol / ether. Yield : ^ -10 mg

(approx. 50 fa) * melting point 123 - 1 2 ^. Chromatographically identical to the material obtained in Example 5 d.

Example '7 ; ■

L-pyroglutamyl-A -aminobutyric acid amide

a) Benzyloxycarbony 1 ~ k - aniinobut t er acid amide

To a solution of ■ 7 · 1 2 g (30 mmol) of benzyloxycarbonyl-'l-arainobuttersäure in 50 ml of tetrahydrofuran are one h.2 ml triethylamine. One cools down to -10. and 2.9 ml of ethyl chloroformate dissolved in 10 ml of abs. Tetrahydro

furan too. The mixture is stirred for 10 minutes at -10 and 1 hour at room temperature and the precipitate which has separated out is filtered off with suction. The piltrate is concentrated and the residue is partitioned between ethyl acetate and water. The ethyl acetate phase is washed with sodium bicarbonate solution and water, dried with sodium sulfate and concentrated. The residue is triturated with petroleum ether. Yield 5, h g (76 <fo), m.p. 131-132 ° C.

50 ¹ §849 / 0942

- 1 Z -

b) 'Ί - Aini η ο bu ι. tor s; ' ü ι ν ομ ^ iiilzl ¹ J- ν .. ^ Γ ^ ^Λ

h g (16.9 mmol) of benzyloxycirboiryl -'- J-aminobufctersiu.ii'eain.Lcl are catalytically hydrogenated in methanol analogously to Example 5b. The product crystallizes with ether. The end. 1.81 g (78%)> Schüip. 137 -

c) L-Pyx'ofyl u taniy l- ^ t -am inobut tej ^ sä

To a solution of 1.76 g (12.9 mmol) and 1.72 g (i2.75 mmol) 1 -Hy droxyb en ζ ο t ri az ο 1 and 1.65 ml N-Äthyliiiorpliol in in ^; 10 ml of dimethylformamide are added 3.9 S (12.65 mmol) of L-pyroglutamic acid-2, ^, ^ -trichloi'-phenylesfcer. It is left with llaumtonip for 1 hour. stir, concentrate and rub with ether. The substance is filtered off with suction and cbrOinatofjraphier * t in methanol / water (1: 1) over Serdolit Hlau. The elixate is concentrated and the residue is triturated with ether and filtered off with suction. iVusb. 1.6 g (; 58 ⁽ fo) . For further purification can be recrystallized from ethanol.

Shrap. 159 - 160 ° C, [a] ^ ° = 1.9 ° (c = 1, methanol) Example 8:

L-pyr-oglutamyl- γ- amino valeric acid

a) L-Pyroglutamyl-y-aniinovaleriraisäureäthylester

To the solution of h; 2. $ G (O, O2 3 app!) Γ -amino valeriansäuremethylcster hydrochloride and 3.2 ml of N-ethylmorpholine in 15 ml of dimethylformamide, after cooling to 0 ° C 1.6 g (0.012 mol ) 1-Hydroxybenzotriazole and 7.8 g (θ, Ο25 mol) of L-pyroglutamic acid 2,4,5-trichlorophenyl ester were added. Ks is stirred at 0 C after 2 hours and then left to stand at + h ° C for 16 hours. Then it is evaporated off iV, and the crude product, as in the synthesis of L-Pyr <) gliitainyi-n-he: v '}' lamicT ^ "(T5eispiol 2) boscJiriebcn, by filtration over an acidic and basic ionic stucco.

5098i9 / 0942

liar a {coreini gfc. The En-! Nroclu! .. t Fird rais-! Vchanol / Äfchor uiiigeTfi I it Exploits 2,: ~> h g. · Fp ί 7 ^; 1.5 ° [«] ' ^? f> = ⁺ 20, fi ° (c = 1, diuiftliyl-

b.) L-P ^ / rof; lutamy 1-y-aminovaleric acid

1.13 έϊ (5 mmoles) of L-pyroglutarn3 ^r l-aminovaleriansäxircin.ethylestor 'Aiferdeii to a solution of 800 mg (5 mmol) of barium hydroxide octali hydrate in 35 ml barrels, which is stirred for 2.5 hours at room temperature. Then 2.5 ml (5 mmol) of 2N ~ HpSOj are added and the mixture is filtered through a clarifying glass of Kiose3.gur in order to remove the precipitated barium sulfate. The peptide is obtained from the cold Filtx ^ at by freeze-drying in 80 percent yield as a colorless ε ^: linear solid. [α] = + 7.3 ° (c = 1, Methano1)

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Claims (2)

- Ik - HOE 7h / F Ϊ3Ο claims 1 .B Pyroglutamy! Compounds of the general formula I IT
CNX (I) in which X is an optionally branched alkyl radical of h - 6 carbon atoms or an optionally branched alkyl radical of 2 - 6 carbon atoms, which is optionally either at the ^ position by a carboxamide group or at the Co position by a carboxamido or carboxyl group is substituted. 2.) Process for the preparation of compounds of the general formula I II
CNX (I) in which X is an optionally branched alkyl radical of 4-6 carbon atoms or "an optionally branched alkyl radical of 2-6 carbon atoms, which is optionally either at the C $ L position by a carboxamide group or at the CxJ position by a Carboxamido or carboxyl group is substituted, characterized in that one a) one optionally on the nitrogen by a benzyloxycarbonyl radical substituted pyroglutamic acid as an active ester, as a mixed anhydride or by means of a carbodiimide with a primary amine of. general formula II 509849/0942 HOE 7 * 1 / F ¹ 3O H ₂ N - X (II) in which X has the abovementioned meaning, but with existing carboxyl groups can be protected by suitable protective groups customary in peptide chemistry, implements and then any existing Splitting off protective groups in the usual way, or that one b) Glutamine derivatives of the general formula III H'N - CH - CH - CH- CO-NII (ill) CO - NH - X in which X has the meaning mentioned, by boiling in trxfluoroacetic acid or by letting it stand for a long time in aqueous solvents to those according to the invention Compounds of formula I cyclized. 509849/0942