CA1064942A - Pyroglutamy compounds having antidepressive activity and process for their manufacture - Google Patents
Pyroglutamy compounds having antidepressive activity and process for their manufactureInfo
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- CA1064942A CA1064942A CA227,255A CA227255A CA1064942A CA 1064942 A CA1064942 A CA 1064942A CA 227255 A CA227255 A CA 227255A CA 1064942 A CA1064942 A CA 1064942A
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- pyroglutamyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06173—Dipeptides with the first amino acid being heterocyclic and Glp-amino acid; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT
This invention is directed to novel compounds of the formula wherein X represents hexyl or alkyl of 2 to 3 carbon atoms which is substituted in the .omega.-position by a carboxamido or carboxyl group, and to processes for the preparation of these compounds.
The compounds may be used in the treatment of psychotic diseases.
This invention is directed to novel compounds of the formula wherein X represents hexyl or alkyl of 2 to 3 carbon atoms which is substituted in the .omega.-position by a carboxamido or carboxyl group, and to processes for the preparation of these compounds.
The compounds may be used in the treatment of psychotic diseases.
Description
6~9~Z
The present invention relates to pyroglutamyl compounds having antidepressive activity and a process for their manu~
facture.
It is known that the tripeptide amide L-pyroglutamyl-L-histidyl-L-prolinamide (TRH) ~hich is thyrotropic hormone re-leasing factor also has an antidepressive effect. However, in its use as antidepressive agent, this peptide has the drawback stimulating the secretion of thyrotropic hormone.
It was surprisingly found that simple pyroglutamyl amides show a high antidepressive effect in the dopa potentiating test (cf. Everett, Fed. Proc. 23, 198 (1964) while completely lacking stimulation of thyrotropic hormone secretion.
The present invention provides pyroglutamyl compounds of the formula I
U C - N - X
wherein X is hexyl or an alkyl of 2 to 3 carbon atoms which is substituted in the ~-position by a carboxamido or carboxyl group.
This invention also relates to a process for the manuacture of these compounds, wherein eith~r a) a pyroglutamic acid optionally substituted on the nitrogen atom by a benæyloxycarbonyl radical is reacted in the form of an active ester, a mixed anhydride or by means of a carbodiimide with a primary amine of the general formula II
H2N - X (II) ~1~6~94Z
wherein X is defined as above, however, carboxyl groups, if present, can be protected by suitable groups used in peptide chemistry, and thereafter, the protective groups, if pre-sent, are split off in usual manner, or b) glutamine derivatives of the formula III
H2N -jCH -CH2 - CO - NH2 (III) ~ -NH - X
wherein X is defined as above, are cyclized to the com-pounds of the formula I of the invention by boiling in tri-fluoroacetic acid or by allowing them to dwell over a pro-longed period of time in aqueous solvents.
In method a), an active ester of the pyroglutamic acid is advantageously reacted with a corresponding primary amine.
Suitable active esters are the 4-nitrophenyl, 2,4,5-trichloro-phenyl or pentachlorophenyl ester. Suitable esters or theprotection of the carboxyl groups by which the amines can be substituted are the tertiary butyl ester which can be split off by an acid, the benzyl or 4-nitrobenzyl ester which can be split off by an alkaline agent or by catalytic hydrogena-tion or the alkyl esters which can be saponified by an alka-line agent, for example methyl or ethyl esters. The reaction ls preferably carried out in a ~trongly polar solvent, for example dimethyl formamide, dimethyl acetamide or dimethyl sulfoxide, and it can be accelerated by the addition of l-hy-droxybenzotriazole or similar compounds (cf. German Patent No.2,202,613). The pyroglutamyl derivatives still containing carboxyl protecting groups are then converted into the com-pounds of the invention by splitting off these groups in usual manner. For example, tertiary butyl esters are split off by .
106~94LZ
acids, alkyl or aralkyl esters by bases or esters of the ben-zyl type by catalytic hydrogenation.
In method b), glutaminyl derivatives are advantageously used as intermediates which can easily be cyclisized to the pyroglutamyl compounds of the invention after splitting off the protective groups by boiling in trifluoroacetic acid or by allowing the products to stand over a prolonged period of time in aqueous solvents. The glutaminyl derivatives themselves can be manufactured according to the usual methods of peptide chemistry by reacting glutamine derivatives protected on the amino group and optionally also on the carboxamido group with thq corresponding amino component, in which case carboxyl groups of the amino components, if present, are blocked by the tertiary butyl radical. For example, the aminolysis of carbobenzoxy or tertiary butyloxy-carbonylglutamine-p-nitro-phenyl ester yields the protected glutaminyl derivatives. By add ng suitable N-hydroxy compounds, for example l-hydroxy-benzotriazole or l-hydroxy-pyridone-2 the aminolysis can high-ly be accelerated. Protective groups on the carboxamido group of flutamine, for example, the ~,~'-dimethoxyben~hydryl radical, render the glutaminyl derivatives water-insoluble.
They can be isolated well.
The process of the invention allows for example the manu-facture of the following compounds:
L-pyroglutamic acid n-butyl amide, L-pyroglutamic acid iso-butyl amide, L-pyroglutamic acid n-pentyl amide, L-pyroglu-tamic acid n-hexyl amide, L-pyroglutamyl-alanin amide, L-py-roglutamyl-L-leucin amide, L-pyroglutamyl-L-norleucin amide, L-~yroglutamyl-L-valin amide, L-pyroglutamyl-L-isoleucin ami-_ ,~ _ ,, 1~6499~Z
de, L-pyroglutamyl-~-alanine, L-pyroglutamyl-~-alanine amide, L~pyroglutamyl-4-amino butyric acid, L-pyroglutamyl-4-amino-bu-tyric acid amide, L-pyroglutamyl- ~-aminovaleric acid, L-pyro-glutamyl- ~-aminovaleric acid amide, L-pyroglutamyl-6-amino~
hexanoic acid, L-pyroglutamyl-6-aminohexanoic acid amide.
In the dopa potentiating test in mice the compounds of formula I show an effect similar to that of the known TRH.
For this reason, the pharmaceutical preparations of the in-vention may be used for the treatment of psychotic diseases, especially depressive illnesses.
The following is a list of values obtained in the dopa potentiating test for a number of compounds of the invention.
The numbers are a combination of values obtained after 15 to 30 minutes after administration:
Dopa potentiating test Superexcitation in ~ depending on the dose (mg/kg) 0.5 1 2 5 T~H 130 186 267 239 Pyroglutamic acid n-butyl amide 145 111 165 159 pyroglutamic acid n-hexyl amide 217 186 188 182 pyroglutamyl-alanin amide 178 132 137 151 pyroglutamyl-~-alanin 192 167 162 204 pyroglutamyl-4-aminobutyric acid 140 125 255 245 pyroglutamyl-4-aminobutyric acid amide 183 233 160 198 control 100 100 100 100 The pharmaceutical preparations of the invention may be in a form suitable for oral administration, for example ta-blets, dragées or capsules, they may also be in a form sui-_ 5 ~6,4942 table for intravenous, intramuscular or subcutaneous admini-stration, for example dissolved in physiologically acceptable sodium chloride solution, and they may also be administered via the intranasal route in the form of drops or sprays. The content of active substance is within the range of from 1 to 100% by weight, in solutions from 0.1 to 10 g/100 ml.
Depending on the disease to be treated the unit dose for oral preparations is generally within the range of from 10 to 1000 mg. For intravenous administration the unit dose is usu-ally from 0.05 to 5 mg and for intranasal administration from0.1 to 10 mg. The daily dosage unit for human beings of 75 kg weight is one time to five times this amount.
The following Examples illustrate the invention:
Manufacture of new pyroglutamyl derivatives of the formula I^
E X A M P L E 1:
a) L-Pyroglutamic acid-pentachlorophenyl ester 129 g (1 mol) of L-pyxoglutamic acid were finely mortared and suspended in 2 1 of tetrahydrofurane. 319 g (1.2 mol) of pentachlorophenol and at 0C 220 g (1.06 mol) of dicyclohexyl-carbodiimide dissolved in 300 ml of tetrahydrofurane wereadded. The mixture was stirred for 1 hour at 0C and for 5 hours at room temperature. The dicyclohexyl urea was Eiltered off, and reextracted with a small amount of warm tetrahydro~
furane. The solvent was distilled off in vacuum, the residue was boiled with isopropanol and filtered off after cooling.
After drying under vacuum over P2O5 and KOH, 175 g material wexe obtained which melted at 198Ct []D=+18.6 (c=l, dimethyl formamide).
. ' . ' ' ' b) L-Pyroglutamic acid n-butyl amide .
7.5 g (20 mmols) of L-pyroglutamic acid pentachlorophenyl ester and 1.75 g (2.4 mmols) of n-butyl amine were stirred in 100 ml of tetrahydrofurane for 5 hours, the solvent was di-stilled off, the residue was dissolved in methanol and treat-ment with strongly basic and then with strongly acid ion ex-changer followed. ~fter filtration, methanol was distilled off, the oily residue was dissolved and precipitated with petroluem ether. After a prolonged period of time, the pro-duct which had precipitated in oily form became solid. It wasfiltered off, washed with petroleum ether and dried under vacuum.
Yield: 2.95 g without sharp melting point.
CgH16N2O2 ~184.2) Calculated: C H N
58.67 8.75 15.20 Found: 58~6 8.8 14.9 E X A M P L E 2:
L-Pyroglutamic acid n-hexyl amide 4 ml of n-hexyl amine were added at 0C to a solution of 3.1 g of L-pyroglutamic acid 2,4,5-trichlorophenyl ester in 10 ml of di~ethyl ~ormamide and the solution was allowea to dwell at room temperature for 20 hours. Dlstillation followed under vacuum at room temperature, the residue was taken up in 90%
aqueous methanol, and the solution was filtered successively 2S over 200 ml of Levatit S 100 (H~ form) and Serdolit Blau(OH
form). Subsequently the ion exchanger columns were washed with 200 ml of 90% methanol, the eluate and washing solution were combined and concentrated under vacuum. The L-pyro-glutamic acid n-hexyl amide obtained as colorless solid was recrystallized rom ethyl acetate.
Yield: 1.33 g, m.p.: 95 [a]D = ~19.8 (c=l, dimethyl formamide) E X A M P L E 3:
L-pyroglutamyl-L-alanine amide 3.75 g (10 mmols) of L-pyroglutamic acid pentachlorophe-nyl esterwere stirred in 40 ml of dimethyl formamide with 1.5 g (12 mmols) of L-alanin amide-hydrochloride and 1.54 ml (12 mmols) of N-ethylmorpholine for 4 hours, the solvent was distilled off under vacuum, the residue was dissolved in methanol and the solution was stirred successively with strongly basic and strongly acid ion exchanger, the exchan-ger was filtered off and the solution concentrated. The re-sidue was digested with ethyl acetate, dissolved in a little ethanol and precipitated with petroleum ether in the form of a resin that solidiied under petroleum ether.
Yield: 1.2 g, chromatographically uniform without sharp mel-ting point.
Calculated: N 21.0 Found: 21.2 E X A M P L E 4:
., ~ .
,. ~ . .
6.75 g (0.05 mol) of l-hydroxybenztriazole and 6.5 g of L-pyroglutamic acid in the form of a fine powder were added to a solution of 9.05 g (0.05 mol? of ~-alanin tert.butyl es~er-hydrochloride and 6.32 ml (0.05 1) of N-ethyl morpho-line in 75 ml of dimethyl formamide, the solution was cooled to -5C to which 11.3 g (0.054 mol) of dicyclohexyl-carbodi-imide dissolved in 25 ml of ~imethyl formamide were adaed.
.
~L~6~94Z
The solution was again stirred at 0C for 6 hours and it was left for another 16 hours at ~4C. The precipitated dicyclo-hexyl urea was suction-iltered, the filtrate was concen-trated under vacuum at room temperature until it turned to a syrup. The residue was triturated twice wit~ 180 ml of ab-solute ether, dissolved in 80% methanol and filtered over 200 ml of Serdolit-slau (OH -form). After-washing followed with 350 ml of 80% methanol, the eluate and washing solutions were combined and evaporated at room temperature, the re-maining oil was dissolved in 30 ml of 90% trifluoroacetic acid and the solution was stirred for 1 hour at room tempera-ture. The trifluoroacetic acid was evaporated under vacuum and the residue was d;.gested with absolute ether.
The crude product so obtained was recrystallized from ethanol/ether.
Yield: 6.4 g, m.p.: 199C [a]22 - -8.3 ~c=l, methanol).
E X A M P L E 5:
-L-Pyroglutamyl-4-aminobutyric acid a) Benzyloxycarbonyl-4-aminobutyric acid tert. butyl ester .
600 ml of liquefied isobutylene and 6 ml o~ conc. H~SO~
were added to a solution of 172 g of benzyloxycarbonyl-4-amino-butyric acid in 600 ml of methylene chloride, the solution was shaken for 3 days at room temperature in an autoclave, the isobutylene was distilled off, the methylene chloride solution was washed twice with 10% sodium carbonate solution and once with water, dried over sodium sulfate and concen-trated under vacuum. The residue was dissolved in ether and chromatographed over 620 g of basic A12O3. Elution with ether followed.
_ g _ -1~6494Z
Yield: 161.9 g (oil) b) 4-Aminobuty-ric-acid tert.-butyl ester hydrochloride A solution of 161.5 g of benzyloxycarbonyl-4-aminobutyric acid tert.-butyl ester in 500 ml of methanol was catalytically hydrogenated after the addition of Pd-catalyst and methanolic HCl at pH 4.5 (autotitrator). The reaction being finished ~no further consumption of methanolic HC1) the catalyst was suction-filtered and the filtrate was concentrated. The re-sidue was dissolved in ether and cooled. After some time, a precipitate appeared which was suction-filtered.
Yield: 78.2 g, m.p.: 82-84C.
c) L-Pyroglutamyl-4-aminobutyric acid tert.-butyl ester 1.3 ml o~ N-ethylmorpholine and 3.08 g of L-pyroglutamic acid 2,4,5-trichlorophenyl ester were added to a solution of 1.95 g (10 mmols) of 4-aminobutyric acid tert.-butyl ester-hydrochloride ih 20 ml of dimethylformamide. The solution was left overnight at room temperature, concentrated, the residue was dissolved in a mixture of ethyl acetate and water, the ethyl acetate was separated and shaken with sodium bicar-bonate solution, KHSO4-solution and NaCl solution, dried with Na2~O4 and concentrated. The residue was triturated with petxoleum ether.
Yield: 2.1 g, m~p. : 68C.
d) L-Pyroglutamyl-4-aminobutyric acid -
The present invention relates to pyroglutamyl compounds having antidepressive activity and a process for their manu~
facture.
It is known that the tripeptide amide L-pyroglutamyl-L-histidyl-L-prolinamide (TRH) ~hich is thyrotropic hormone re-leasing factor also has an antidepressive effect. However, in its use as antidepressive agent, this peptide has the drawback stimulating the secretion of thyrotropic hormone.
It was surprisingly found that simple pyroglutamyl amides show a high antidepressive effect in the dopa potentiating test (cf. Everett, Fed. Proc. 23, 198 (1964) while completely lacking stimulation of thyrotropic hormone secretion.
The present invention provides pyroglutamyl compounds of the formula I
U C - N - X
wherein X is hexyl or an alkyl of 2 to 3 carbon atoms which is substituted in the ~-position by a carboxamido or carboxyl group.
This invention also relates to a process for the manuacture of these compounds, wherein eith~r a) a pyroglutamic acid optionally substituted on the nitrogen atom by a benæyloxycarbonyl radical is reacted in the form of an active ester, a mixed anhydride or by means of a carbodiimide with a primary amine of the general formula II
H2N - X (II) ~1~6~94Z
wherein X is defined as above, however, carboxyl groups, if present, can be protected by suitable groups used in peptide chemistry, and thereafter, the protective groups, if pre-sent, are split off in usual manner, or b) glutamine derivatives of the formula III
H2N -jCH -CH2 - CO - NH2 (III) ~ -NH - X
wherein X is defined as above, are cyclized to the com-pounds of the formula I of the invention by boiling in tri-fluoroacetic acid or by allowing them to dwell over a pro-longed period of time in aqueous solvents.
In method a), an active ester of the pyroglutamic acid is advantageously reacted with a corresponding primary amine.
Suitable active esters are the 4-nitrophenyl, 2,4,5-trichloro-phenyl or pentachlorophenyl ester. Suitable esters or theprotection of the carboxyl groups by which the amines can be substituted are the tertiary butyl ester which can be split off by an acid, the benzyl or 4-nitrobenzyl ester which can be split off by an alkaline agent or by catalytic hydrogena-tion or the alkyl esters which can be saponified by an alka-line agent, for example methyl or ethyl esters. The reaction ls preferably carried out in a ~trongly polar solvent, for example dimethyl formamide, dimethyl acetamide or dimethyl sulfoxide, and it can be accelerated by the addition of l-hy-droxybenzotriazole or similar compounds (cf. German Patent No.2,202,613). The pyroglutamyl derivatives still containing carboxyl protecting groups are then converted into the com-pounds of the invention by splitting off these groups in usual manner. For example, tertiary butyl esters are split off by .
106~94LZ
acids, alkyl or aralkyl esters by bases or esters of the ben-zyl type by catalytic hydrogenation.
In method b), glutaminyl derivatives are advantageously used as intermediates which can easily be cyclisized to the pyroglutamyl compounds of the invention after splitting off the protective groups by boiling in trifluoroacetic acid or by allowing the products to stand over a prolonged period of time in aqueous solvents. The glutaminyl derivatives themselves can be manufactured according to the usual methods of peptide chemistry by reacting glutamine derivatives protected on the amino group and optionally also on the carboxamido group with thq corresponding amino component, in which case carboxyl groups of the amino components, if present, are blocked by the tertiary butyl radical. For example, the aminolysis of carbobenzoxy or tertiary butyloxy-carbonylglutamine-p-nitro-phenyl ester yields the protected glutaminyl derivatives. By add ng suitable N-hydroxy compounds, for example l-hydroxy-benzotriazole or l-hydroxy-pyridone-2 the aminolysis can high-ly be accelerated. Protective groups on the carboxamido group of flutamine, for example, the ~,~'-dimethoxyben~hydryl radical, render the glutaminyl derivatives water-insoluble.
They can be isolated well.
The process of the invention allows for example the manu-facture of the following compounds:
L-pyroglutamic acid n-butyl amide, L-pyroglutamic acid iso-butyl amide, L-pyroglutamic acid n-pentyl amide, L-pyroglu-tamic acid n-hexyl amide, L-pyroglutamyl-alanin amide, L-py-roglutamyl-L-leucin amide, L-pyroglutamyl-L-norleucin amide, L-~yroglutamyl-L-valin amide, L-pyroglutamyl-L-isoleucin ami-_ ,~ _ ,, 1~6499~Z
de, L-pyroglutamyl-~-alanine, L-pyroglutamyl-~-alanine amide, L~pyroglutamyl-4-amino butyric acid, L-pyroglutamyl-4-amino-bu-tyric acid amide, L-pyroglutamyl- ~-aminovaleric acid, L-pyro-glutamyl- ~-aminovaleric acid amide, L-pyroglutamyl-6-amino~
hexanoic acid, L-pyroglutamyl-6-aminohexanoic acid amide.
In the dopa potentiating test in mice the compounds of formula I show an effect similar to that of the known TRH.
For this reason, the pharmaceutical preparations of the in-vention may be used for the treatment of psychotic diseases, especially depressive illnesses.
The following is a list of values obtained in the dopa potentiating test for a number of compounds of the invention.
The numbers are a combination of values obtained after 15 to 30 minutes after administration:
Dopa potentiating test Superexcitation in ~ depending on the dose (mg/kg) 0.5 1 2 5 T~H 130 186 267 239 Pyroglutamic acid n-butyl amide 145 111 165 159 pyroglutamic acid n-hexyl amide 217 186 188 182 pyroglutamyl-alanin amide 178 132 137 151 pyroglutamyl-~-alanin 192 167 162 204 pyroglutamyl-4-aminobutyric acid 140 125 255 245 pyroglutamyl-4-aminobutyric acid amide 183 233 160 198 control 100 100 100 100 The pharmaceutical preparations of the invention may be in a form suitable for oral administration, for example ta-blets, dragées or capsules, they may also be in a form sui-_ 5 ~6,4942 table for intravenous, intramuscular or subcutaneous admini-stration, for example dissolved in physiologically acceptable sodium chloride solution, and they may also be administered via the intranasal route in the form of drops or sprays. The content of active substance is within the range of from 1 to 100% by weight, in solutions from 0.1 to 10 g/100 ml.
Depending on the disease to be treated the unit dose for oral preparations is generally within the range of from 10 to 1000 mg. For intravenous administration the unit dose is usu-ally from 0.05 to 5 mg and for intranasal administration from0.1 to 10 mg. The daily dosage unit for human beings of 75 kg weight is one time to five times this amount.
The following Examples illustrate the invention:
Manufacture of new pyroglutamyl derivatives of the formula I^
E X A M P L E 1:
a) L-Pyroglutamic acid-pentachlorophenyl ester 129 g (1 mol) of L-pyxoglutamic acid were finely mortared and suspended in 2 1 of tetrahydrofurane. 319 g (1.2 mol) of pentachlorophenol and at 0C 220 g (1.06 mol) of dicyclohexyl-carbodiimide dissolved in 300 ml of tetrahydrofurane wereadded. The mixture was stirred for 1 hour at 0C and for 5 hours at room temperature. The dicyclohexyl urea was Eiltered off, and reextracted with a small amount of warm tetrahydro~
furane. The solvent was distilled off in vacuum, the residue was boiled with isopropanol and filtered off after cooling.
After drying under vacuum over P2O5 and KOH, 175 g material wexe obtained which melted at 198Ct []D=+18.6 (c=l, dimethyl formamide).
. ' . ' ' ' b) L-Pyroglutamic acid n-butyl amide .
7.5 g (20 mmols) of L-pyroglutamic acid pentachlorophenyl ester and 1.75 g (2.4 mmols) of n-butyl amine were stirred in 100 ml of tetrahydrofurane for 5 hours, the solvent was di-stilled off, the residue was dissolved in methanol and treat-ment with strongly basic and then with strongly acid ion ex-changer followed. ~fter filtration, methanol was distilled off, the oily residue was dissolved and precipitated with petroluem ether. After a prolonged period of time, the pro-duct which had precipitated in oily form became solid. It wasfiltered off, washed with petroleum ether and dried under vacuum.
Yield: 2.95 g without sharp melting point.
CgH16N2O2 ~184.2) Calculated: C H N
58.67 8.75 15.20 Found: 58~6 8.8 14.9 E X A M P L E 2:
L-Pyroglutamic acid n-hexyl amide 4 ml of n-hexyl amine were added at 0C to a solution of 3.1 g of L-pyroglutamic acid 2,4,5-trichlorophenyl ester in 10 ml of di~ethyl ~ormamide and the solution was allowea to dwell at room temperature for 20 hours. Dlstillation followed under vacuum at room temperature, the residue was taken up in 90%
aqueous methanol, and the solution was filtered successively 2S over 200 ml of Levatit S 100 (H~ form) and Serdolit Blau(OH
form). Subsequently the ion exchanger columns were washed with 200 ml of 90% methanol, the eluate and washing solution were combined and concentrated under vacuum. The L-pyro-glutamic acid n-hexyl amide obtained as colorless solid was recrystallized rom ethyl acetate.
Yield: 1.33 g, m.p.: 95 [a]D = ~19.8 (c=l, dimethyl formamide) E X A M P L E 3:
L-pyroglutamyl-L-alanine amide 3.75 g (10 mmols) of L-pyroglutamic acid pentachlorophe-nyl esterwere stirred in 40 ml of dimethyl formamide with 1.5 g (12 mmols) of L-alanin amide-hydrochloride and 1.54 ml (12 mmols) of N-ethylmorpholine for 4 hours, the solvent was distilled off under vacuum, the residue was dissolved in methanol and the solution was stirred successively with strongly basic and strongly acid ion exchanger, the exchan-ger was filtered off and the solution concentrated. The re-sidue was digested with ethyl acetate, dissolved in a little ethanol and precipitated with petroleum ether in the form of a resin that solidiied under petroleum ether.
Yield: 1.2 g, chromatographically uniform without sharp mel-ting point.
Calculated: N 21.0 Found: 21.2 E X A M P L E 4:
., ~ .
,. ~ . .
6.75 g (0.05 mol) of l-hydroxybenztriazole and 6.5 g of L-pyroglutamic acid in the form of a fine powder were added to a solution of 9.05 g (0.05 mol? of ~-alanin tert.butyl es~er-hydrochloride and 6.32 ml (0.05 1) of N-ethyl morpho-line in 75 ml of dimethyl formamide, the solution was cooled to -5C to which 11.3 g (0.054 mol) of dicyclohexyl-carbodi-imide dissolved in 25 ml of ~imethyl formamide were adaed.
.
~L~6~94Z
The solution was again stirred at 0C for 6 hours and it was left for another 16 hours at ~4C. The precipitated dicyclo-hexyl urea was suction-iltered, the filtrate was concen-trated under vacuum at room temperature until it turned to a syrup. The residue was triturated twice wit~ 180 ml of ab-solute ether, dissolved in 80% methanol and filtered over 200 ml of Serdolit-slau (OH -form). After-washing followed with 350 ml of 80% methanol, the eluate and washing solutions were combined and evaporated at room temperature, the re-maining oil was dissolved in 30 ml of 90% trifluoroacetic acid and the solution was stirred for 1 hour at room tempera-ture. The trifluoroacetic acid was evaporated under vacuum and the residue was d;.gested with absolute ether.
The crude product so obtained was recrystallized from ethanol/ether.
Yield: 6.4 g, m.p.: 199C [a]22 - -8.3 ~c=l, methanol).
E X A M P L E 5:
-L-Pyroglutamyl-4-aminobutyric acid a) Benzyloxycarbonyl-4-aminobutyric acid tert. butyl ester .
600 ml of liquefied isobutylene and 6 ml o~ conc. H~SO~
were added to a solution of 172 g of benzyloxycarbonyl-4-amino-butyric acid in 600 ml of methylene chloride, the solution was shaken for 3 days at room temperature in an autoclave, the isobutylene was distilled off, the methylene chloride solution was washed twice with 10% sodium carbonate solution and once with water, dried over sodium sulfate and concen-trated under vacuum. The residue was dissolved in ether and chromatographed over 620 g of basic A12O3. Elution with ether followed.
_ g _ -1~6494Z
Yield: 161.9 g (oil) b) 4-Aminobuty-ric-acid tert.-butyl ester hydrochloride A solution of 161.5 g of benzyloxycarbonyl-4-aminobutyric acid tert.-butyl ester in 500 ml of methanol was catalytically hydrogenated after the addition of Pd-catalyst and methanolic HCl at pH 4.5 (autotitrator). The reaction being finished ~no further consumption of methanolic HC1) the catalyst was suction-filtered and the filtrate was concentrated. The re-sidue was dissolved in ether and cooled. After some time, a precipitate appeared which was suction-filtered.
Yield: 78.2 g, m.p.: 82-84C.
c) L-Pyroglutamyl-4-aminobutyric acid tert.-butyl ester 1.3 ml o~ N-ethylmorpholine and 3.08 g of L-pyroglutamic acid 2,4,5-trichlorophenyl ester were added to a solution of 1.95 g (10 mmols) of 4-aminobutyric acid tert.-butyl ester-hydrochloride ih 20 ml of dimethylformamide. The solution was left overnight at room temperature, concentrated, the residue was dissolved in a mixture of ethyl acetate and water, the ethyl acetate was separated and shaken with sodium bicar-bonate solution, KHSO4-solution and NaCl solution, dried with Na2~O4 and concentrated. The residue was triturated with petxoleum ether.
Yield: 2.1 g, m~p. : 68C.
d) L-Pyroglutamyl-4-aminobutyric acid -
2 g o~ L-pyroglutamyl-4-aminobutyric acid tert.-butyl ester were dissolved in 20 ml of trifluoroacetic acid with warming, the solution was left at room temperature for 30 minutes, the trifluoroacetic acid was removed under vacuum and the residue was triturated with ether and suction-filtered.
-k9~2 The product was dissolved in water, insoluble substances were removed by filtration over active charcoal and the solution was lyophilized.
Yield: 760 mg, m.p.: 117 - 120 , 1]D = -11.3 (C=1, me-thanol).
CgH14N2O4(214.2) Calculated: C 50.42 H 6.58 N 13.08 Foun~: C 50.6 H 5.5 N 13.2 E X A M P L E 6:
L-Pyroglutamyl-4-aminobutyric acid a) Na-Benzyloxycarbonyl-N ~-4,4'-dimethoxybenzhydryl-L-glut-, aminyl-4-aminobutyric acid tert.-butyl ester 2.53 g (5 mmols) of Na benzyloxycarbonyl--N ~-4,4'-di-methoxybenzhydryl-L-glutamine, 975 mg of 4-aminobutyric acid tert.-butyl ester hydrochloride and 675 mg of l-hydroxybenzo-triazole were dissolved in 10 ml of dimethyl formamide. 0.65 ml of N-ethylmorpholine and, at 0C, a solution of 1.1 g of dicyclohexylcarbodiimide in dimethyl formamide were added. The solution was stirred for 1 hour at 0C and left overnight at room temperature. The precipitate was suction-~iltered and the ~iltrate was concentrated. The residue was triturated with sodium bicarbonate solution and water, suction-Eiltered and dried over P2O5. The ~olid wa~ boiled with acetone, cooled to 0C, suction-filtered and washed with acetone and petro-leum ether.
~5 Yield: 3.45 g, m.p.: 178C.
b)_ L Pyroglutamyl-4-aminobutyric acid 2.5 g of Na-benzyloxycarbonyl-N ~-4,4'-dimethoxybenzhydryl-L-glutaminyl-4-aminobutyric acid tert.-butyl ester were boiled under reflux for 100 minutes with 2 ml of anisole in 20 ml of - HOE 74~ 13~
~4~3142 triflouroacetic acid. Concentration followed and the residue was dissolved in a mixture of water and ether. The aqueous phase was clarified with active charcoal and lyophilized. The oily residue was recrystallized from methanol/ether.
Yield: 410 mg (about 50%). m.p.: 123-124. Chromatographi-cally identical with the material obtained according to Example 5d).
E X A M P: L E 7:
L-Pyroglutamyl-4-aminobutyric acid amide a) Benzyloxycarbonyl-4-aminobutyric acid amide 4.2 ml of triethylamine were added to a solution of 7.12 g (30 mmols) of benzyloxycarbonyl-4-aminobutyric acid in 50 ml of tetrahydrourane. The solution was cooled to -10C' and 2.9 ml of ethyl chloroformate dissolved in 10 ml of absolute tetrahydro-furane were added dropwise. The solution was stirred for 10 minutes at -10C and for l hour at room temperature and the precipitate was suction-filtered. The filtrate was concentrated and the residue was dissolved in a mixture of ethyl acetate and water. The ethyl acetate phase was washed with sodium bicarbo-nate solution and water, dried with sodium sulfate and concentrated. The residue was triturated with petroleum ether.
Yield: 5~4 g ~76%); m.p.: 131 - 132C.
b) 4-~minobutyric acid amide-hydrochloride 4 g (16.9 mmols) of benzyloxycarbonyl-4-aminobutric acid amide were catalytically hydrogenated in methanol in a manner analogous to Example 5 b . The product crystallized a~ter addition of ether.
29 Yield: 1.81 g (78%), m.p.: 137 - 138C.
.
c) L-Pyroglutamyl-4-aminobutyric acid amide
-k9~2 The product was dissolved in water, insoluble substances were removed by filtration over active charcoal and the solution was lyophilized.
Yield: 760 mg, m.p.: 117 - 120 , 1]D = -11.3 (C=1, me-thanol).
CgH14N2O4(214.2) Calculated: C 50.42 H 6.58 N 13.08 Foun~: C 50.6 H 5.5 N 13.2 E X A M P L E 6:
L-Pyroglutamyl-4-aminobutyric acid a) Na-Benzyloxycarbonyl-N ~-4,4'-dimethoxybenzhydryl-L-glut-, aminyl-4-aminobutyric acid tert.-butyl ester 2.53 g (5 mmols) of Na benzyloxycarbonyl--N ~-4,4'-di-methoxybenzhydryl-L-glutamine, 975 mg of 4-aminobutyric acid tert.-butyl ester hydrochloride and 675 mg of l-hydroxybenzo-triazole were dissolved in 10 ml of dimethyl formamide. 0.65 ml of N-ethylmorpholine and, at 0C, a solution of 1.1 g of dicyclohexylcarbodiimide in dimethyl formamide were added. The solution was stirred for 1 hour at 0C and left overnight at room temperature. The precipitate was suction-~iltered and the ~iltrate was concentrated. The residue was triturated with sodium bicarbonate solution and water, suction-Eiltered and dried over P2O5. The ~olid wa~ boiled with acetone, cooled to 0C, suction-filtered and washed with acetone and petro-leum ether.
~5 Yield: 3.45 g, m.p.: 178C.
b)_ L Pyroglutamyl-4-aminobutyric acid 2.5 g of Na-benzyloxycarbonyl-N ~-4,4'-dimethoxybenzhydryl-L-glutaminyl-4-aminobutyric acid tert.-butyl ester were boiled under reflux for 100 minutes with 2 ml of anisole in 20 ml of - HOE 74~ 13~
~4~3142 triflouroacetic acid. Concentration followed and the residue was dissolved in a mixture of water and ether. The aqueous phase was clarified with active charcoal and lyophilized. The oily residue was recrystallized from methanol/ether.
Yield: 410 mg (about 50%). m.p.: 123-124. Chromatographi-cally identical with the material obtained according to Example 5d).
E X A M P: L E 7:
L-Pyroglutamyl-4-aminobutyric acid amide a) Benzyloxycarbonyl-4-aminobutyric acid amide 4.2 ml of triethylamine were added to a solution of 7.12 g (30 mmols) of benzyloxycarbonyl-4-aminobutyric acid in 50 ml of tetrahydrourane. The solution was cooled to -10C' and 2.9 ml of ethyl chloroformate dissolved in 10 ml of absolute tetrahydro-furane were added dropwise. The solution was stirred for 10 minutes at -10C and for l hour at room temperature and the precipitate was suction-filtered. The filtrate was concentrated and the residue was dissolved in a mixture of ethyl acetate and water. The ethyl acetate phase was washed with sodium bicarbo-nate solution and water, dried with sodium sulfate and concentrated. The residue was triturated with petroleum ether.
Yield: 5~4 g ~76%); m.p.: 131 - 132C.
b) 4-~minobutyric acid amide-hydrochloride 4 g (16.9 mmols) of benzyloxycarbonyl-4-aminobutric acid amide were catalytically hydrogenated in methanol in a manner analogous to Example 5 b . The product crystallized a~ter addition of ether.
29 Yield: 1.81 g (78%), m.p.: 137 - 138C.
.
c) L-Pyroglutamyl-4-aminobutyric acid amide
3.9 g (12.65 mmols) of L-pyxoglutamic acid 2,4,5-tri-chlorophenyl ester were added to a solution of 1.76 g (12.9 mmols) of 4-aminobutyric acid amide-hydrochloride and 1.72 g (12.75 mmols) of l-hydroxybenzotriazole and 1.65 ml of N-ethylmorpholine in 40 ml of dimethyl formamide. The solution was left for 1 hour at room temperature, concentrated and triturated with ether. The substance was suction-filtered and chromatographed in methanol/water (1:1) on Serdolit Blau.
The eluate was concentrated and the residue was triturated with ether and suction-filtered.
Yield: 1.6 g (58%). For further purification, the product ,-~can be recrystallized from ethanol. M.p.: 159 - 160C, ~ 20 =.-1.9 ~c=l, methanol).
_X A M P L E 8:
L-Pyroglutamyl ~V-aminovaleric acid a) L-Pyroglutamyl- ~-aminovaleric acid ethyl ester 1.6 g (0.012 mol) of l-hydoxybenzotriazole and 7.8 g (0.025 mol) of L-pyroglutamic acid 2,4,5-trichlorophenyl ester were added to a solution of 4.25 g (0.025 mol) o~ amino-valeric acid methyl ester-hydrochloride and 3.2 ml of N-ethyl-morpholine in 15 ml of dimethyl ormamide at 0C. The solution was stir.red at 0C or 2 hours and then left for 16 hours at +4C. IT was evaporated under vacuum and the crude product was purified by fi.ltration over an acid and-a basic ion exchanger resin as has been described in the synthesis of L-pyroglutamyl n-hexyl amide in Example 2. The product was recrystallized from ethanol/ether.
Yield: 2.34 g, solidification point 74 5o ~oc~22 = +20.8 (c=l, dimethyl formamide) ~69~94Z
b) L-Pyroglutamyl-~r'-aminovaleric acid 1.13 g (5 mmols) of L-pyroglutamyl- ~ -aminovaleric acid methyl ester were added to a solution of 800 mg ~5 mmols) of bariumhydroxide-octahydrate in 35 ml of water, and the solution was stirred for 2.5 hours at room temperature. 2.5 ml (5 mmols) of 2n H2SO4 were added, the solution was filtered through a clarification layer of kieselguhr to eliminate the precipitated barium sulfate. The peptide was obtained in 80% yield as a colorless amorphous solid by lyophilization from the clear filtrate.
c~ = +793 (c=l, methanol) Preparations ~or oral administration E X A M P L E 9:
500 g of pyroglutamic acid n-hexyl amide were mixed with 15 282 g of potato starch and 560 g o~ lactose, the mi~ture was moistened with an alcoholic solution of 8 g of gelatine and granulated. After drying, 60 g of potato starch, 10 g of magnesium stearate, 20 g of highly disperse silicon oxide and 60 g of talcum were admixed and the mixture was compressed 20 into 10,000 tablets each weighing 150 mg and containing 50 mg of active substance.
.
'` -- 14 --
The eluate was concentrated and the residue was triturated with ether and suction-filtered.
Yield: 1.6 g (58%). For further purification, the product ,-~can be recrystallized from ethanol. M.p.: 159 - 160C, ~ 20 =.-1.9 ~c=l, methanol).
_X A M P L E 8:
L-Pyroglutamyl ~V-aminovaleric acid a) L-Pyroglutamyl- ~-aminovaleric acid ethyl ester 1.6 g (0.012 mol) of l-hydoxybenzotriazole and 7.8 g (0.025 mol) of L-pyroglutamic acid 2,4,5-trichlorophenyl ester were added to a solution of 4.25 g (0.025 mol) o~ amino-valeric acid methyl ester-hydrochloride and 3.2 ml of N-ethyl-morpholine in 15 ml of dimethyl ormamide at 0C. The solution was stir.red at 0C or 2 hours and then left for 16 hours at +4C. IT was evaporated under vacuum and the crude product was purified by fi.ltration over an acid and-a basic ion exchanger resin as has been described in the synthesis of L-pyroglutamyl n-hexyl amide in Example 2. The product was recrystallized from ethanol/ether.
Yield: 2.34 g, solidification point 74 5o ~oc~22 = +20.8 (c=l, dimethyl formamide) ~69~94Z
b) L-Pyroglutamyl-~r'-aminovaleric acid 1.13 g (5 mmols) of L-pyroglutamyl- ~ -aminovaleric acid methyl ester were added to a solution of 800 mg ~5 mmols) of bariumhydroxide-octahydrate in 35 ml of water, and the solution was stirred for 2.5 hours at room temperature. 2.5 ml (5 mmols) of 2n H2SO4 were added, the solution was filtered through a clarification layer of kieselguhr to eliminate the precipitated barium sulfate. The peptide was obtained in 80% yield as a colorless amorphous solid by lyophilization from the clear filtrate.
c~ = +793 (c=l, methanol) Preparations ~or oral administration E X A M P L E 9:
500 g of pyroglutamic acid n-hexyl amide were mixed with 15 282 g of potato starch and 560 g o~ lactose, the mi~ture was moistened with an alcoholic solution of 8 g of gelatine and granulated. After drying, 60 g of potato starch, 10 g of magnesium stearate, 20 g of highly disperse silicon oxide and 60 g of talcum were admixed and the mixture was compressed 20 into 10,000 tablets each weighing 150 mg and containing 50 mg of active substance.
.
'` -- 14 --
Claims (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the formula I
(I) wherein X represents hexyl or alkyl of 2 to 3 carbon atoms which is substituted in the .omega.-position by a carboxamido or carboxyl group, in which a) a pyroglutamic acid, which may be substituted by a benzyl-oxy-carbonyl radical, is reacted in the form of an active ester or a mixed anhydride, or by means of a carbodiimide with a primary amine of the formula II
H2N - X (II) wherein X is as defined above and in which any carboxyl groups present can be protected by suitable groups used in peptide chemistry and may subsequently be split off, b) a glutamine derivative of the formula III
(III) wherein X is as defined above, is cyclized to a compound of the formula I by boiling the derivative in trifluoro-acetic acid or by allowing the derivative to dwell over a prolonged period of time in an aqueous solvent.
(I) wherein X represents hexyl or alkyl of 2 to 3 carbon atoms which is substituted in the .omega.-position by a carboxamido or carboxyl group, in which a) a pyroglutamic acid, which may be substituted by a benzyl-oxy-carbonyl radical, is reacted in the form of an active ester or a mixed anhydride, or by means of a carbodiimide with a primary amine of the formula II
H2N - X (II) wherein X is as defined above and in which any carboxyl groups present can be protected by suitable groups used in peptide chemistry and may subsequently be split off, b) a glutamine derivative of the formula III
(III) wherein X is as defined above, is cyclized to a compound of the formula I by boiling the derivative in trifluoro-acetic acid or by allowing the derivative to dwell over a prolonged period of time in an aqueous solvent.
2. A process as claimed in claim 1 for the preparation of a compound of the formula I as defined in claim 1 in which a pyroglutamic acid, which may be substituted by a benzyloxy-carbonyl radical, is reacted in the form of an active ester or a mixed anhydride, or by means of a carbodiimide with a pri-mary amine of the formula II as defined in claim 1.
3. A process for the preparation of a compound of the formula I as defined in claim 1 in which a glutamine derivative of the formula III as defined in claim 1 is cyclized to a compound of the formula I by boiling the derivative in trifluoroacetic acid or by allowing the derivative to dwell over a prolonged period of time in an aqueous solvent.
4. A compound of the formula I as defined in claim 1, whenever obtained according to a process as claimed in claim 1, claim 2 or claim 3 or by an obvious chemical equivalent thereof.
5. A process as claimed in claim 1 for the preparation of L-pyroglutamyl-4-aminobutyric acid in which N.alpha.-benzyloxy-carbonyl-N? -4,4'-dimethoxybenzhydryl-L-glutaminyl-4-amino-butyric acid tert.-butyl ester is cyclized by boiling it under reflux in trifluoroacetic acid and the product is sub-sequently isolated.
6. L-Pyroglutamyl-4-aminobutyric acid, whenever obtained according to a process as claimed in claim 5 or by an obvious chemical equivalent thereof.
7. A process as claimed in claim 1 for the preparation of L-pyroglutamyl-4-aminobutyric acid amide in which L-pyro-glutamic acid 2,4,5-trichlorophenyl ester is reacted with 4 aminobutyric acid amide-hydrochloride and N-ethylmorpholine in the presence of 1-hydroxybenzotriazole in a solvent and the product is subsequently isolated.
8. L-Pryoglutamyl-4-aminobutyric acid amide, whenever obtained according to a process as claimed in claim 7 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2423390A DE2423390A1 (en) | 1974-05-14 | 1974-05-14 | PYROGLUTAMYL COMPOUNDS WITH ANTIDEPRESSIVE EFFECT AND PROCESS FOR THEIR PRODUCTION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1064942A true CA1064942A (en) | 1979-10-23 |
Family
ID=5915523
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA227,255A Expired CA1064942A (en) | 1974-05-14 | 1975-05-13 | Pyroglutamy compounds having antidepressive activity and process for their manufacture |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JPS50157362A (en) |
| AT (2) | AT352707B (en) |
| BE (1) | BE829059A (en) |
| CA (1) | CA1064942A (en) |
| CH (2) | CH613689A5 (en) |
| DE (1) | DE2423390A1 (en) |
| DK (1) | DK209575A (en) |
| FR (1) | FR2270866B1 (en) |
| GB (1) | GB1472154A (en) |
| IE (1) | IE41145B1 (en) |
| IL (1) | IL47258A (en) |
| LU (1) | LU72450A1 (en) |
| NL (1) | NL7505473A (en) |
| SE (1) | SE405113B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0775112A1 (en) * | 1994-08-05 | 1997-05-28 | Warwick International Group Limited | Bleach activators |
| US6420427B1 (en) * | 1997-10-09 | 2002-07-16 | Ono Pharmaceutical Co., Ltd. | Aminobutyric acid derivatives |
| RU2232578C1 (en) * | 2003-04-10 | 2004-07-20 | Ахапкина Валентина Ивановна | Substance eliciting antidepressant activity |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5220996B2 (en) * | 1972-01-14 | 1977-06-07 | ||
| JPS5015793B2 (en) * | 1972-06-07 | 1975-06-07 |
-
1974
- 1974-05-14 DE DE2423390A patent/DE2423390A1/en not_active Withdrawn
-
1975
- 1975-05-08 IL IL47258A patent/IL47258A/en unknown
- 1975-05-09 NL NL7505473A patent/NL7505473A/en not_active Application Discontinuation
- 1975-05-12 GB GB1984075A patent/GB1472154A/en not_active Expired
- 1975-05-12 CH CH85079A patent/CH613689A5/en not_active IP Right Cessation
- 1975-05-12 CH CH608075A patent/CH612180A5/en not_active IP Right Cessation
- 1975-05-12 LU LU72450A patent/LU72450A1/xx unknown
- 1975-05-13 AT AT364875A patent/AT352707B/en not_active IP Right Cessation
- 1975-05-13 CA CA227,255A patent/CA1064942A/en not_active Expired
- 1975-05-13 DK DK209575A patent/DK209575A/en not_active Application Discontinuation
- 1975-05-13 IE IE1069/75A patent/IE41145B1/en unknown
- 1975-05-14 BE BE156337A patent/BE829059A/en not_active IP Right Cessation
- 1975-05-14 JP JP50056232A patent/JPS50157362A/ja active Pending
- 1975-05-14 FR FR7515026A patent/FR2270866B1/fr not_active Expired
- 1975-05-14 SE SE7505546A patent/SE405113B/en unknown
-
1979
- 1979-01-08 AT AT0013179A patent/AT364875B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| IE41145L (en) | 1975-11-14 |
| AT352707B (en) | 1979-10-10 |
| SE405113B (en) | 1978-11-20 |
| AT364875B (en) | 1979-03-15 |
| SE7505546L (en) | 1975-11-17 |
| IE41145B1 (en) | 1979-10-24 |
| GB1472154A (en) | 1977-05-04 |
| DE2423390A1 (en) | 1975-12-04 |
| JPS50157362A (en) | 1975-12-19 |
| DK209575A (en) | 1975-11-15 |
| FR2270866B1 (en) | 1978-08-04 |
| LU72450A1 (en) | 1977-02-09 |
| IL47258A (en) | 1978-07-31 |
| IL47258A0 (en) | 1975-07-28 |
| NL7505473A (en) | 1975-11-18 |
| ATA13179A (en) | 1981-04-15 |
| CH613689A5 (en) | 1979-10-15 |
| ATA364875A (en) | 1979-03-15 |
| BE829059A (en) | 1975-11-14 |
| CH612180A5 (en) | 1979-07-13 |
| FR2270866A1 (en) | 1975-12-12 |
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