JPS6178785A - Novel 4-oxo-2-azetidinecarboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [R<1> is azido, amino, etc.; R<2> is imidazoyl shown by the formula II or formula III (R<3> is H, or loweralkyl); Y is OH, lower alkoxy, etc.] and its salt. EXAMPLE:N<alpha>-[(2S,3R)-3-Azido-4-oxo-2-azetidinylcarbonyl]-L--h-ist idyl-L-prolin amide. USE:An improver for disturbance of consciousness in schizophrenia, depression, etc., an improver for hypobulia, etc. PREPARATION:For example, a compound shown by the formula IV and a compound shown by the formula V as starting raw materials are reacted, the prepared intermediate and a compound shown by the formula VI are subjected to peptide synthesis reaction preferably by a method wherein dicylohyxyl carbodiimide is used as a condensation agent.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a 4-okino-2-azetidi/carboxylic acid derivative represented by the following general formula [I] and a salt thereof, which is useful as a medicine.

(In the formula, R1 represents an azide group, an amino group, a lower acylamino group, a mercapto group, or a lower alkylthio group.

R2 is 1 type R8-) or sha- NR' (in the formula.

R3 means a hydrogen atom or a lower alkyl group. )
) for an imidazolyl group.

Y means a hydroxyl group, a lower alkyl group, an amine group, or a mono- or di-lower alkylamino group. ) <Specific Description of the Invention> The object compound [I] of the present invention will be further explained as follows.

In the "lower acylamino group" and "lower alkylthio group" meant by R1, and the "lower alkyl group" meant by R3, "lower" means a straight chain or branched carbon chain having 1 to 5 carbon atoms. do. Therefore, what is a lower acylamino group?

Acetylamino group, propionylamino group.

Butyrylamino group, pentanoylamino group.

Examples of the lower alkylthio group include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, a pentylthio group, and the lower alkyl group is a methyl group.

Ethyl group, globyl group, butyl group, inopropyl group,
5ec-butyl group, etc.

The lower alkoxy group represented by Y is as follows.

Methoxy group, ethoxy group, guaboxy group, impropoxy group, butoxy group, tert-butoxy group.

It is a linear or branched lower alkoxy group having 1 to 5 carbon atoms such as a pentyloxy group.

The object compound [1] of the present invention has at least three asymmetric carbon atoms, and stereoisomers based on this exist. The target compounds of the present invention include separated and mixtures of these isomers.

Further, the object compound [■] of the present invention forms a salt with an acid or a base. Salts encompassed by the invention include salts with non-toxic acids, such as inorganic acid salts such as hydrochlorides, sulfates, and citrates, acetates.

salts with non-toxic bases (e.g. salts with inorganic bases such as sodium salts, potassium salts, and ammonium salts).

salts with organic bases such as trimethylamine salts).

The object compound [I] of the present invention can be prepared by mixing it alone or with appropriate pharmacologically acceptable carriers, excipients, and diluents, and preparing powders, granules, tablets, capsules, injections (intravenous, It can be administered subcutaneously, intramuscularly), orally or parenterally in the form of suppositories.

<Effects and uses of the invention> The dosage of the compound m of the present invention is as follows: Type 1 of compound [1)
Although it varies depending on age, body weight, symptoms, route of administration, etc., for example, in the case of injection, it is about 0.001 to 10 cm, preferably 0.
．． 0.01 to 0.1 square meters (one time dose), and in the case of oral administration, it is 0.05 to 500 da, preferably o, i to 10 square meters (one time dose).

Compounds related to the object compound CI of the present invention are:
It is also known as "thyrotropin-releasing hormone" (TRH), and pyroglutamyl-L-histidyl-L-prolinamide (pGlu-His-Pro-NH2) is known.

The existence of TRH has been known since the 1960s, but its structure was confirmed in 1970 (Endocr).
ino-1ogy, 86.1143 (1970)
). TRH was originally thought to be a hormone that regulates the release of thyrotropin (TSH) in the pituitary gland of mammalian mammals. but.

Subsequent studies revealed that the biological function of this tripeptide TRI is not limited to the regulation of TS)f release, but that it acts broadly on the central nervous system (CNS), and this discovery has led to new research. [5science, 178.417 (1972)].

Lancet, Z 999 (1972)). Thus,
In addition to its TSH-releasing activity, TRH also reduces the duration of sleep caused by barbiturates and alcohol9 and suppresses hypothermia symptoms stimulated by various drugs.

It is known to have effects on the CNS, such as promoting motor activity, preventing generalized tonicity caused by loberidol, enhancing memory, improving symptoms of schizophrenia, and acting as an antidepressant. Furthermore, TRH has been found to be an ameliorating and therapeutic agent for disorders of consciousness caused by functional or organic disorders in the brain, such as head trauma, brain surgery, cerebrovascular disorders, brain tumors, etc., especially acute or subacute disorders of consciousness. (Japanese Unexamined Patent Publication No. 118841/1984).

In terms of clinical treatment, there is a desire for the emergence of TRH derivatives that exhibit weak or almost no TSH release activity and that have the same or even greater effects on the CNS than TRH. was. Various TRH derivatives have been synthesized for such purposes, and their effects on the CNS have further expanded.

Examples of compounds synthesized for this purpose include:

TRH has weak TSH release activity, but has an anesthetic antagonistic effect.

Increased locomotor activity or dopamine-like effects, resulting in severe addiction to sleeping pills, impaired consciousness, hyperactive children, and schizophrenia.

TRH derivatives that are said to be useful for improving treatment of depression and Parkinson's disease (Japanese Patent Application Laid-open No. 116465/1983)
.

Hexopalpital has an effect on disturbance of consciousness after head trauma, reduces sleep duration due to hexopalpital, and is used for the treatment of patients with disturbance of consciousness caused by organic or functional disorders in the brain, patients with senility or mental fatigue. TRH derivatives that are said to be useful in treating depression, etc.
No. 59714) is known.

The target compound of the present invention is pyroglutamyl (p
4-
TRI converted into an oxo-2-azetidinyl carbonyl structure (β-lactam structure) (has chemical structural characteristics in that it is a derivative, and has pharmacological effects such as the above-mentioned TP, H
and conventionally known TRH derivatives, which are also significantly more potent in CNS.
It has an action and is useful as a medicine. For example, schizophrenia.

It is useful as an agent for improving consciousness disturbance in depression, sequelae of cerebrovascular accident 1, head trauma, senile dementia, epilepsy, etc., or as an agent for improving motivation, depression, memory loss, etc.

<Production method> According to the present invention, the target compound is produced by the following route.

[■1] [■,] That is, according to the present invention, the target compound [■] is obtained by reacting (a) compound (n) and compound CI] to form compound (IV
) and then react this compound [■] with compound [v], or.

(b) It can be produced by reacting compound [■] with compound [■] to form compound [VI], and then reacting the obtained compound [■] with compound [■].

In addition, the target compound thus obtained (ll is a substituent Y
It is also possible to lead to other target compound [■2] by converting .

Compound employed in (a) or (b) above [■1]
The production reaction is a peptide synthesis reaction, and a method known per se is used. Commonly used methods include a method using gin-20hexylcarbodiimide as a condensing agent, an azide method, and an acid arid method.

Examples include acid anhydride method and active ester method. To carry out these methods,9 usually, prior to the peptide formation reaction in each step, functional groups such as amino groups, imino groups, carboxyl groups, etc. that do not participate in the reaction of the raw material compound are protected, and, amine groups involved in peptide formation reactions,
The imino group or carboxyl group is activated if necessary.

A compound in which an amine group, an imino group, or a carboxyl group is activated, such as an active ester, may be once isolated and then subjected to a peptide synthesis reaction, or may be subjected to a peptide synthesis reaction without being isolated.

Examples of protecting groups for amine groups include benzyloxycarbonyl group, t-butyloquinecarbonyl group, p-methoxybenzyloquinecarbonyl group, phthaloyl group, trifluoroacetyl group, and as protecting groups for imino groups. Examples are evatosyl group and benzyloxycarbonyl group.

Examples include p-)toxypenzyloxycarbonyl group, benzyl group, and 4-dinitrophenyl group.

As a protecting group for carboxyl group, methyl ester, ethyl ester, benzyl ester.

Ester forms such as p-nitrobenzyl ester and t-butyl ester are used.

The groups involved in the reaction can be activated by using the phosphazo method using phosphorus trichloride, the isocyanate method using phosgene, or the phosphite method when the group is an amine group or an imino group, or when the group is a carboxyl group. When.

Active ester (2,4-nitrophenol ester,
N-hydroquine succinimide ester, etc.), azide, or carboxylic acid anhydride. Among these, the azide method or the method using dicyclohexylcarpodiimide as a condensing agent is preferred for synthesizing compounds [■] and [■]. It is also possible to use a method of directly preparing a peptide using an N-carboxylic anhydride of an amino acid without using a protecting group.

Next, the peptide formation reaction is carried out in an inert solvent by a conventional method.
It is carried out by cooling or heating. A suitable solvent is dimethylformamide (DMF).

Ethyl acetate, dichloromethane (methylene chloride).

Tetrahydrofuran and the like are used.

When it is necessary to remove protecting groups from the reaction product, for example by ITi catalytic reduction in the case of benzyl esters, anhydrous hydrogen fluoride in the case of p-toluenesulfonyl groups, HOBT or hydrogen succinate-pyridine complexes. When the protecting group is an alkyl ester, the protecting group is removed by hydrolysis, and when the protecting group is benzyloxy7carbonyl or p-methoxypenzyloxycarbonyl, the protecting group is removed by catalytic reduction or hydrobromic acid-acetic acid treatment. When it is a t-butyloxycarbonyl group, it can be easily removed by acid decomposition.

Next, in the reaction of converting the substituent Y of the object compound [I] of the present invention to lead to another object compound, appropriate reaction conditions are adopted depending on the properties of the compounds involved in the reaction.

<Example-> The present invention will be further explained below with reference to Examples.

Note that a reference example shows a method for producing a raw material compound that can be used in the examples.

The abbreviations used in Examples and Reference Examples have the following meanings.

NMR nuclear magnetic resonance spectrum IR infrared absorption spectrum Mass mass spectrometry spectrum mp Melting point His Histidine Pro Proline DMF Dimethylformamide HOBT 1-Hydroxy-1,2,3,-benzotriazole THF Tetrahydrofuran DCC Synchhexylcarbodiimide Reference Example 1 (Example 1) (raw material) (s)-1-t-butyldimethylsilyl-4-oxo-
2-Azetidinecarboxylic acid 1 3.1' dried in THF
This is added to a solution of 30.6 mmol lithium diinopropylamide in dry THF22rnt at O'C. After removing the cooling bath and stirring for 35 minutes, cool to -70 °C and add THF 18-
A solution of 3.51 g of p-1-luenesulfonyl azide dissolved in the solution is added dropwise. This is stirred for 1 hour at -50°C and cooled again to -70°C.

40 after adding trimethylsilyl chloride 4.811
Warm to ℃ and stir for 6 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added 3.7 f of sodium bicarbonate and 100 g of water.
Add the solution dissolved in - and adjust the pH with 10 citric acid aqueous solution.
Adjust to 3. This aqueous solution is extracted three times with ether, and the ether layers are combined and dried over anhydrous sulfate. After filtration, the liquid is concentrated to give 3.22 oil. This was subjected to column chromatography on 7 lica gel (100 IF).

(2S, 3R)-1-t-butyldimethylsilyl-3-azido-4-okino-2-azetidinecarboxylic acid 2 by elution with n-hexane-ethyl acetate (4:1) and (2:1) 1.6f is obtained as a colorless solid.

(i) NMR (CD(J3)δppm: 0.1
8 (3H,s, CH3), 0.32(3H,8
, CH3) + 0” (9H+ s+ tBu)
+ 4.00 (LH+d, J=3Hz), 4
．． 71 (IH, d, J=3Hz) Compound j 1.
Dissolve 78f in methanol 39fnt.

To this was added 9.85% of IN hydrochloric acid, and the mixture was stirred at room temperature for 1.75 hours. The reaction mixture is cooled to 0° C., 9.85 rIlt of IN-sodium hydroxide is added and concentrated to dryness under reduced pressure to give an oil. Dissolve this in DMF 10-3
After adding A-molekino sieve and allowing it to stand overnight, the solvent was distilled off under reduced pressure to obtain (2S,3R)-3-azido-4.
- Okino 2-azetidine carboxylic acid was obtained. This compound was used as it was in the first Example 1.

Example 1 Compound 3 obtained in Reference Example 1(b) was dissolved in a mixed solvent of 15 ml of DMF and 15 ml of methylene chloride.
Add 1.06F and cool on ice. This has DCC1,62
After adding g, stir at 0°C for 40 minutes. (Reaction solution A)
On the other hand, L-histidyl-L-glory/amide dihydrobromide λ711 was dissolved in DMF 32-.

Add triethylamine 27 at -15°C. This-
Stir at 5° C. for 20 minutes and remove the precipitated salt to obtain a DMF solution of the free base (reaction solution B). Add reaction IB to reaction solution A and stir at 0-5°C for 20 hours. After removing the insoluble materials, the P solution was concentrated under reduced pressure and the resulting oil was subjected to column chromatography on 7 lica gel (1 sot).

Chloroform-methanol-ammonia water (80:2
0:2) When eluted, Na-[(2s,
3R)-3-azido-4-oxo-2-azetidinylcarbonyl]-L-histidyl-L-7” lolinamide
5 was obtained and lyophilized to give 58■ as a colorless solid.

(i) NMR (d'-DMSO) δppm: 1.
86 (4H, m), Z85~3.00 (2H
, m) 4.08 (IH, d, J=2Hz), 4
．． 6-8.78 (IH) (ii) IR (KBr) cm-': 3400.
2110.1765.1620~1680 (Broad) (f!ri Mass (FAB)”!/, : 390
(M+ 1), 36λ307 Reference Example 2 (raw material of Example 2) Compound 920'N! Dissolved in dry THF 8-.

This is added at 0° C. to a solution of 8.28 mmol of lithium diingrobilamide in THF.

Then, the cooling bath was removed, the mixture was stirred for 35 minutes, and then cooled to -70°C.

Add 0.47 fnt of dimethyl disulfide and add -7θ~-
Stir at 60° C. for 30 minutes and then at -SO″C for 1 hour.

Remove the cooling bath, continue stirring, and when the temperature reaches 0°C, add 5 ml of 10% citric acid aqueous solution, 30 ice water, and 5 ml of ether.
Inject into the mixed solution of 0-. pH with 10 cicitric acid aqueous solution
3 to 4 and separate the aqueous layer and organic layer. The aqueous layer is extracted with ether 30, and the organic layers are combined and washed with water. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to obtain a pale yellow oil.

This is purified by column chromatography on silica gel (80f). Elution with n-hexane-ethyl acetate (4:1) gave 272 mg of (2R,3R)-t-t-butyldimethylsilyl-3-methylthio-4-okino 2-azetidinecarbo/acid i as a white solid. .

(i) NMR (cpc13) δppm: 0.16
(3H, *, CH3), 0.32 (3H, s,
CH3), 0697 (9H,s), 119
(3H, s.

5CH3), 4.00 (IH, d, J=3Hz),
4.27 (IH, d.

J=3Hz).

Compound 569~ was dissolved in methanol 12rnt.

Add IN hydrochloric acid 3- and stir at room temperature for 1.75 hours.

The reaction solution was cooled to 0°C, IN-sodium hydroxide 3- was added, and the mixture was concentrated to dryness under reduced pressure. When this is freeze-dried as an aqueous solution, (2fk, 3R)-3-methylthio-
A white powder containing 4-okino-2-azetine/carboxylic acid was obtained. This was used as a raw material for the next example without purification.

Example 2 The white powder containing the reverse obtained in Reference Example 2(b) was mixed with DMF.
5- and methylene chloride 5-.

Add HOBT324my and DC to primary E'c' under ice cooling.
Add C618ay and stir for 40 minutes.

To this reaction mixture is added a DMF solution of 2 mmol of mono-histidyl-L-prolinamide (free base) prepared as in Example 1.

After stirring overnight at 0-5°C, insoluble matter is removed.

The oily substance obtained by concentrating the p liquid under reduced pressure is fused with silica gel (io
o r ) column chromatography.

Chloroform-methanol-ammonia water (8°: 2
When eluted with a mixture of 0:2), Nα-((2R,
3R)-3-Methylthio-4-oxo-2-azetidinylcarfonyl]-L-histidyl-L-7'' lolinamide turf was obtained, and after freeze-drying it was 2361 as a colorless solid.
Obtain rIg. (jump 142-144℃ (iD
NMR (d'-DMSO) δppm: 1.8
5 (4H,m), 2[6(3f(,s,5C
H3), 284-Z96 (2H, m), 6.93
(IH,s), 6.98 (LH), 7.56
(IH,s)8.04(IH), &5(2H,m
).

(Song IR (KBr) cm: 3400 (7'c+-de), 1755° 1620-1680 (broad) fNMasa (FAB) m/z: 395 (M+1)
, 381.349 Reference Example 3 (Raw materials for Example 3) (t)cis-3-azido-4-oxo-2-azetidinecarbo/acid methyl ester 9 L67ji, balatoluenesulfonic acid monohydrate 1.869 in DMF50I+
1/2, add to% Pd-0400 and evaporate at room temperature to obtain a viscous oil. Chloride this.

2.89 ml of triethylamine was dissolved in 80 ml of methylene and cooled to -10°C. Acetyl chloride 0.736a/
were added one after another and stirred at the same temperature for 1 hour and 20 minutes. The reaction mixture was concentrated under reduced pressure and the residue was purified with silica gel (100,9
) column chromatography. Elution with ethyl acetate-methanol (10:1) gives (t)cis-3-acetylamino-4-okino-2-azetidinecarboxylic acid methyl ester 11 683m9 as a white solid.

(i) NMR (cDct3+cD3on) δppm:
1.98 (3H, s, CH3Co) 3.77 (3H,
S, 0CH3), 4.46(IH, d, J=6H
z).

5.45 (IH, d, J=6Hz).

(!i)IR(KBr)cm-': 3250.
3175.3080. 1745° Compound 11 497
Dissolve η in 40 ml of methanol.

Add 2.7 ml of IN-sodium hydroxide under water cooling, and stir for 25 minutes under water cooling, then remove the cooling bath and stir for 30 minutes. Cool on ice again, add 2.7 rul of IN hydrochloric acid, and concentrate to dryness under reduced pressure. The residue was azeotropically dehydrated under reduced pressure using an acetonitrile-benzene mixture to give 81:) cis-3-acetylamino-4-oxo-2-azetidinecarboxylic acid 1.
A residue containing 2 was obtained. This was used as it was in the next example.

Example 3 3b Residual product containing the compound compound obtained in Reference Example 3(b) and L-Histidyl- prepared in the same manner as in Example 1
and -prolinamide (free base) in the same manner as in Example 2. The resulting reaction mixture is purified by column chromatography on silica gel (150,9).

Ethyl acetate-methanol-ammonia water (20:10
Elute the target compound using 1), remove the solvent, and freeze-dry.

N'-((28,33) -3-'7 SELF AMY/
-4-oxo-2-azetidinylcarbonyl]-L-histidyl-prolinamide 131 and N-[(2
R, 3R) -3-acetylamino-4-okino 2-
[Azetidinylcarbonyl]-L-histidyl-prolineamide 13b is obtained as a mixture of A-274.

N) NMR (D20) δppm: 1.88~Z
IO (7H), 2.95-3.16 (2H), 3
．． 5 (IH, m), 3.8 (IH, m), 4.4 (
IH, m).

4,'u(IH,m), 4.7~5.04(IH,
m), 5.35 (IH, m).

7.08 (IH), 7.88 (IH).

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, R^1 is an azide group, an amino group, a lower acylamino group, a mercapto group, or a lower alkylthio group, and R^2 is Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^3 is
It means a hydrogen atom or a lower alkyl group. ), Y means a hydroxyl group, a lower alkoxy group, an amino group, or a mono- or di-lower alkylamino group. ) 4-oxo-2-azetidinecarboxylic acid derivatives and salts thereof