JPS5936612B2 - Dipeptide derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The dipeptide derivative according to the invention is derived from histidylproline, in which one or two amino acids may be optically active or racemic. Yes, but especially in the L-configuration.

The present invention relates to dipeptides of general formula 1 and their hydrates and salts of these compounds with pharmaceutically usable acids.

In the above formula, R and R2 are the same or different,
It can represent a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or together these groups can represent an additional bond between both carbon atoms.

R3 means a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. z is a bridged chain suitable for forming a 5- to 6-membered ring, i.e. an NH- group or a group of the formula 1N=C- or -NH-CO-, 1C-S- or -C-O1 (in the formula R4 and R5 are the same or different and represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.

) means a group. Preferably, the carboxylic acid of the formula to be bonded to the dipeptide is orotic acid, imidazolidine mono(2)
~on-1(4)-carboxylic acid and thiomorpholine-(5
)-one-(3) monocarboxylic acid.

Other suitable acids of the general formula are, for example, morpholin-(5)-one-(3)-monocarboxylic acid, thiomorpholin-(5)-one(2.2)-dimethyl-(3)-monocarboxylic acid, 4-carboxy-one-(3)-monocarboxylic acid, imidazol-2-one, thiomorpholine mono(6)-methyl-(5)-one-(3) monocarboxylic acid,
5-methyl-, 5-ethyl- or 5-propyl-orotic acid and other corresponding compounds.

If sec, and R2 together do not represent a bond between the hydrocarbon atoms bearing these groups and/or if R4 and R5 are different from each other, the acid radicals of the formula can also be used in compounds of the formula I. It can exist in racemic or optically active form, preferably in the L-form.

A particularly preferred representative of the compounds of formula I is orotyl-histidyl-prolinamide and its salts, in which especially the two amino acids are present in the L-form.

The basicity of the histidine residue confers on the compounds of formula I the ability to form salts with acids.

The subject of the present invention therefore includes these compounds and drugs (
Inorganic or organic acids which can be used (in the form of salts) such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, benzoic acid, salicylic acid, phenylacetic acid, benzolsulfonic acid, etc. salts and the manufacture and use of such salts. The compounds obtained according to the invention exhibit surprising biological properties, which are generally referred to as "thyrotropin-releasing hormones" [TyrOtrOpin-Rel.
Although the properties and efficacy characteristics of pyroglutamyl histidyl prolinamide, also known as TRH, are strikingly similar,
It is significantly more durable than the properties of known products. It is of therapeutic significance that the relationship between central stimulant action and endocrine effects of the compounds of the invention favors the advantage of pharmacologically important properties compared to known products (TRH). It is a certain thing. The compounds are effective upon parenteral and oral administration, with the onset of effect being rapid, for example after about 10 minutes when administered enterally. The main symptoms correspond to central stimulation in pharmacological tests.

When test animals are treated with equal amounts of TRH or orotyl-L-histidyl-L-prolinamide, it is found that the product obtained according to the invention has a central stimulant effect that is approximately 5 times more potent and several times longer than that of TRH. . The toxicity of this compound is very low, so that the compound can be used, for example, as a psychostimulant or an antidepressant.

This product can be used in both humans and animals. Suitable finished forms which can be used as pharmaceuticals are tablets, dragees, granules, capsules, drops, juices or syrups and sprays for nasal or bronchial delivery, as well as sterile solutions for enteral administration. be.

The preparation of compounds of general formula 1 can be carried out by reacting a histidylprolinamide with the desired optical configuration with an acid of formula in the presence of a water-absorbing agent, in particular a carbodiimide (especially synchhexylcarbodiimide), or by e.g. This is effectively carried out by reacting with a functional derivative of the acid, such as an acid monohalokenide, anhydride or mixed anhydride, azide or activated ester.

Instead of an acid of formula a or a functional derivative thereof, a compound of formula a (wherein R
1 to R3 and z have the same meanings as above, and Y represents a group cleavable by hydrogenolysis, in particular a carbobenzoxy group or a substituted carbobenzoxy group.

) or functional derivatives of acids of the formula, such as, for example, acid halogenides, anhydrides or mixed anhydrides, azides or activated esters, can also be used. In the reaction of histidylprolinamide with an acid of formula or a or a derivative thereof, the 1-(3)-1 position of the imidazole group in the histidyl group is protected against attack by the acylating agent. I can do it.

Suitable protecting groups are known from peptide chemistry. In this connection, in particular carbobenzoxy groups or substituted carbobenzoxy groups, trityl groups, o-nitrophenoxyacetyl groups, tertiary butyloxycarbonyl groups and also those which can be separated after reactions taking place by hydrolysis or hydrogenolysis. Residues known per se come into consideration. Instead of a histidylprolinamide with an optionally protected imidazole group, according to the invention, a histidylprolinamide derived from a trialkylsilanol or dialkylsilane diol (having 1 to 3 carbon atoms in each alkyl group) is used. silylated histidylprolinamide derivatives obtained from histidylprolinamide by reaction with silylating agents such as, for example, hexamethyldisilazane, trimethyldichlorosilane, trimethylsilylacetamide, dimethyldichlorosilane, etc., in a known manner. can also be used. After completion of the reaction, which is carried out in the presence of a non-proton-active solvent, the silyl group is then cleaved by hydrolysis or alcoholysis under mild conditions. To prepare compounds of formula 1, the formula has the formula and X represents a hydrogen atom or a group Y as defined above.

) - the 1-(3)-1 position of its imidazole group can be reversibly protected as described above - with a water-absorbing agent, in particular a carbodiimide, in particular synchrohexylcarbodiimide, or, for example, an acid. It is also possible to react with the prolinamide in the presence of a functional derivative of the compound of the formula, such as a halide, mixed anhydride or activated ester, and optionally then to remove the protecting group of the imidazole group. Formula (wherein R, to R3, X and z have the same meanings as above, and w is a hydroxyl or acyloxy group, p
- nitrophenoxy, tri or pentachlorophenoxy, pentafluorophenoxy, biridyloxy, phenylmercapto, p-nitrophenylmercapto or cyanomethyloxy groups or residues of N-oxysuccinimide; means.

It is also possible to obtain compounds of formula I by reacting a compound of ) with ammonia or a substance which gives rise to ammonia under the reaction conditions, such as, for example, ammonium carbonate. In this method as well, in the compound of the formula, the 1-(3)-1 position of the imidazole group can be reversibly protected as described above prior to the reaction. orotyl-histidyl-prolinamide, in which one or two amino acids are optically active or racemic, and especially L
- can exist in the form of

) is first prepared by converting histidyl-prolinamide in the desired optical configuration into the formula (in the formula H
al means a chlorine atom or a bromine atom.

) or functional derivatives of such acids of formula V, such as acid halides, anhydrides or mixed anhydrides, azides or activated esters, and then in the next step the obtained It can also be obtained particularly well by removing halogen atoms from intermediate products by hydrogenolysis. During the reaction of histidyl-prolinamide with an acid of formula V or a derivative thereof, the 1-(3)-1 position of the imidazole group in the histidyl group is protected against attack by the acylating agent. can. Suitable protecting groups are the groups already listed in the previous section and customary in peptide chemistry. In particular, such groups come into consideration in this case, which can be removed by hydrogenolysis (such as, for example, a carbobenzoxy group or a substituted carbobenzoxy group or an o-nitrophenoxyacetyl group). In such cases, the cleavage of the protecting group is advantageously carried out simultaneously with the hydrogenation of the halogen atom from the acylation product of the first stage. However, of course, after the reaction has taken place, a group that can be separated by hydrolysis (e.g. trityl group, tertiary butyloxycarboxyl group, etc.) is bonded to the imidazole group in one histidyl group, and then this protecting group is After the coupling reaction, but immediately after hydrogenolysis of the rogen atom, it can be split by a conventional method. ...The hydrogenolysis of rogens atoms takes place with catalytically activated hydrogen, in particular catalysts such as charcoal, barium sulfate, aluminum oxide, calcium carbonate or baradium and/or platinum on barium carbonate. ) Noble metal hydrogenation catalysts and other precious metal catalysts are used.

Hydrogenolysis can be carried out under normal pressure or under increased pressure, especially at room temperature. In particular, water or a mixture of water and lower alcohols (methanol, ethanol) or tetrahydrofuran, dioxane or the like is used as a solvent. However, it is also possible, for example, to work in ice vinegar as a solvent. Produced during hydrogen cracking...
For the binding of hydrohalic acid, the treatment is particularly carried out in the presence of a substance with an affinity for hydrogen halides. When using those listed as effective above or other non-acid-reactive solvents, e.g. magnesium oxide,
Also considered are barium oxide, alkali hydroxide, ammonia or ammonium hydroxide, triethylamine or the salts of these substances with the resulting acids, such as alkali carbonates or alkali acetates, which are clearly weaker than hydrologonic acid. . For example, alkali acetate in acetic acid, alkaline earth acetate, ammonium acetate or amine acetate are also suitable media for carrying out the hydrogenolysis. expression, a, or v
As mixed anhydrides of acids, monoesters of carbonic acid with alcohols containing 1 to 4 aliphatic hydrocarbons or those derived from trimethyl acid (pivalic acid) come into particular consideration.

Suitable activated esters of the acids mentioned are, for example, p-nitrophenol, tri- or pentachlorophenol, pentafluorophenol, N-hydroxysuccinimide, 2- or 4-hydroxypyridine, thiophenol, p-nitrophenol, Thiophenol, nitrile glycolate, 1-hydroxybenzotriazole and others are derived from the conventional hydroxy- or mercapto compounds in peptide chemistry for the formation of activated esters.

The compounds according to the invention are relatively stable and can therefore be purified, for example, by dissolution-reprecipitation, recrystallization, but also by column chromatography, countercurrent partitioning, etc.

Examples for products according to the invention are as follows: (
All temperature entries are uncorrected.

) Synthesis example (a) of the compound according to the present invention (T. Shiba
etal. Bull, Chem. SOc. Japan,
412748-53 (1968))N
-benzyloxycarbonyl-L-2-oxoimidazolidine-79.2 t of 4-carboxylic acid and 38.11 t of N-hydroxysuccinimide were dissolved in dimethylformamide 2
Dissolves in 00d.

Cool to 0°C and add 100 ml of dimethylformamide 11:P
N-N'-dicyclohexylcarbodiimide 61.8y
and stirred at this temperature for 1 hour, then stirred for a further 12 hours and slowly warmed to room temperature. The precipitated synchhexyl urea is then separated out, the oral liquid is evaporated under reduced pressure to a small volume, and 600 ml of hot isopropanol are added. After cooling to room temperature, the crystals that form (melting point of the crude product: 178-181 DEG C.) are filtered off with suction and used without further purification in the next process step.
(b) 40.51 r of L-histidine and 21.9 r of sodium bicarbonate were added to 1.9 r of water. The crude product 94 obtained in (a) in dioxane 11 was dissolved in e and at room temperature.
．． Purify in a 2V solution.

The reaction solution was stirred at room temperature for 24 hours and then concentrated under reduced pressure. After incorporating into 300 mt of water, the pH value is adjusted to 7 and the mixture is kept at 0°C.

At this time, N-benzyloxycarbonyl-L-2-oxoimidazolidine-4-carbonyl-L-histidine is precipitated. Filter through a suction port and recrystallize from 1.71 boiling water. Dry edge yield on phosphorus pentoxide is 66.9?
=64% of the theoretical value. Melting point: 180-182℃, [
α〕曾=-18.9. (C-1, dimethylformamide). c) 60.2f7 of the substance obtained in b) above and 21.61 f of 1-hydroxy-benzotriazole and 22.5f of L-prolinamide hydrochloride.
is suspended in 200 ml of dimethylformamide and, after cooling to -10 DEG C., 16.5 ml of N-methylmorpholine are added with stirring.

A solution of 50.9 V of synchhexylcarbodiimide in 50 ml of dimethylformamide was then added and 24
Stir for an hour while slowly raising the temperature to room temperature. The resulting precipitate is passed through a suction port and the oral fluid is concentrated under reduced pressure. Place the residue in 100ml of water and add 1
Store at 0°C for 2 hours. Pass through the mouth and then remove the solvent from the oral fluid under reduced pressure. 1 l of n-butano/
Subject to countercurrent distribution in an aqueous system. The combined fractions containing the main product are evaporated under reduced pressure. Further purification can be carried out by chromatography on silicon gel 60 (0.2-0.5 nm). For this purpose, for example, 1 portion of the product 3.5V is dissolved in water and silicon gel 180F7 is added.
column. In the subsequent elution with water, firstly the separation of impurities - this completeness is achieved at 254 nm (254 nm) of the eluent
-2.54c7n-5) confirmed by measuring the ultraviolet absorption spectrum of -. will be carried out. The main product is then eluted with a mixture of water/dioxane (2:1). The collected fractions containing the pure product were purified after evaporating the solvent under reduced pressure and drying the residue over phosphorus pentoxide to yield 19.9y (27% of theory) of N-benzyloxycarbonyl-L- 2-Oxoimide ψ゛zolidine-4-carbonyl-L-histidyl-L-prolinamide, melting point 169-173°C: [a] Z = -87.7 mol. (C = 0.
36, methanol). It is also possible to carry out the procedure according to Example 1c, using 20.9 ml of triethylamine instead of N-methylmorpholine, and otherwise proceeding as described above.

The material obtained by countercurrent partitioning can also be purified by column chromatography over basic aluminum oxide using methanol/chloroform (3:1) as solvent and eluent.

(d) 19.91 of the product obtained in (Example 1c) in a mixture of equal parts water and tetrahydrofuran 20.
0 ml and palladium-2-chloride 4
Treat with water for 5 hours in the presence of palladium black prepared from Y.

After completion of the hydrocracking, the catalyst is separated off, the oral fluid is treated with activated carbon, and the tetrahydrofuran is then removed from the solution under reduced pressure. Freeze dry the remaining aqueous solution. Melting point 172-173°C x [a') M = -52 as described in Example 1 below
．． 12.8 V of L-2-oxoimidazolidine-4-carbonyl-L-histidyl-L-prolinamide dihydrate with 4° (C=1, methanol) - 89% of theory. Example 1 L=2-oxoimidazolidine~4-carbonyl-L
-Histidyl-L-prolinamide dihydrate Example 2 Imidazol-2-one-4-carbonyl-L-histidyl-L-prolinamide trihydrate This material begins to sinter at 189°C and upon further heating. 212
Melts at ℃.

[α] = -45.3° (c = 0.64, methanol)
. Example 3 Several points of orotyl-L-histidyl-L-prolinamide hydrate 250°C; [α] = 45.8p (c =
1, methanol) 5-methylorotyl-L-histidyl-L-prolinamide trihydrate melting point 222-
227℃ (decomposition), [α] bleached 46.8-(e=1,
Methanol) Example 5 5-Ethylorotyl-L-histidyl-L-prolinamide-hydrate Melting point: 186°C: [α] 1-46.0
(e-0.5, methanol) Example 5 -n-propyl-orotyl-L-histidyl-L-prolinamide-hydrate? Melting point 187℃: [α] 1148.6s (c-0.5,
Methanol) Example 7 L-5-oxothiomorpholine-3-carbonyl-L
-Histidyl-L-prolinamide hydrate melting point 1
55-157°C: [α] Blue = -48, 5 = 0.52, methanol) Example 8 Thiomorpholin-5-one-6(DL)-methyl-3
-(L)-carbonyl-L-histidyl-L-prolinamide-trihydrate melting point 140-142°C; [α
] Blue=33,5=1, methanol) Example 9 D-thiomorpholin-5-one-2,2-dimethyl-3
-Carbonyl-L-histidyl-L-prolinamide-
Hydrate melting point 153-155℃; [α]M=-83
L(c1, methanol) Example 10 Further compounds of the general formula 1 are also the following substances, among others.

(Unless their distinct configuration is stated, all three starting components in these compounds, i.e. prolinamide, histidine and the acid of the formula, may in each case be present as racemates, in the L- or D-form). can.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ I (In the formula, R_1 and R_2 are the same or different and are a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or together represents an additional bond between both carbon atoms with these groups, R_3 means a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, Z represents an NH- group or a formula ▲ Numerical formula, chemical formula, table etc. ▼ or -N
H-CO-, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [R_4 and R in the formula
_5 are the same or different and represent hydrogen or an alkyl group having 1 to 3 carbon atoms] Salts with usable acids. 2 General formula ▲ There are numerical formulas, chemical formulas, tables, etc. ▼ I a (In the formula, R_3 has the same meaning as in the case of formula I in claim 1, and Z_1 is an NH- group or -NH
-CO- or -N=C(OH)- group) and hydrates and/or salts of these compounds with pharmaceutically usable acids according to claim 1. . 3 The dippetide derivative is orotyl-histidyl-prolinamide. Dipeptide derivatives according to claim 1 and their hydrates and/or salts of these compounds with pharmaceutically usable acids. 4. The dipeptide derivative and its hydrate and/or these compounds and a pharmaceutically usable acid according to claim 1, wherein the dipeptide derivative is 2-oxo-imidazolidine-4-carbonyl-histidyl-prolinamide. Salt with. 5 The dipeptide derivative is 5-oxo-thiomorpholine-
3-carbonyl-histidyl-prolinamide,
Dipeptide derivatives and hydrates thereof and/or salts of these compounds and pharmaceutically usable acids according to claim 1. 6 The dipeptide derivative is orotyl-L-histidyl-L
- The dipeptide derivative according to claim 1, which is prolinamide. 7 The dipeptide derivative is L-2-oxo-imidazolidine-4-carbonyl-L-histidyl-L-prolinamide. A dipeptide derivative according to claim 1. 8 The dipeptide derivative is L-5-oxo-thiomorpholine-3
-Carbonyl-L-histyl-L-prolinamide, the dipeptide derivative according to claim 1. 9 Dipeptide derivative is thiomorpholin-5-one-6
-Methyl-3-carbonyl-histidyl-prolinamide, the dipeptide derivative according to claim 1, a hydrate thereof and/or a salt of these compounds with a pharmaceutically usable acid. 10 Dipeptide derivative is thiomorpholin-5-one-
Pharmaceutically usable with the dipeptide derivative and its hydrate and/or these compounds according to claim 1, which is 6-(D・L)-methyl-3(L)-carbonyl-histidyl-prolinamide. salts with acids.