JPS6183182A - N-(n-substituted histidil)-omega-(2-oxo-1-pyrrolidinyl) lower alkylamine - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [Het is formula VII (m is 1-3; X is 0 imino), 1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinyl/ R<1> is formula VII (R<2> is H, lower alkyl); n is 2-5] and its salt. EXAMPLE:N-[N''-Benzyloxycarbonyl-L-histidyl]-3-(2-oxo-1-pyrro-lidinyl) propyl amine. USE:Improve for troubles in consciousness such as shizophreinia, melancholia, cerebrovascular disorder sequela and senile dementia and improver for hypobulia, depression, hypomnesia, PREPARATION:A compound of formula II and a compound of formula III are allowed to react according to the reaction equations to effect peptide synthessis to give a compound of formula IV. Then. the product is allowed to react with a compound of formula V to give the compound of formula I. The reaction is usually carried out using a condensation agent such as dicyclohexylcarbodiimide.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention relates to a (2-oxo-1-pyrrolidinyl)-N-substituted lower alkylamine or Regarding the salt.

1 (wherein, Het is a heptadylarylic quin-4-pyrimita group represented by the formula (γ (in the formula, 2m means 1, 2 or 3, and X means an oxygen atom or an imino group).

R1 is expressed by formula 8. -6 or Tohama R'c In the formula, R2 means a hydrogen atom or a lower alkyl group).

n means an integer from 2 to 5. ) (Detailed Description of the Invention) To further explain the above definition, the heterocyclic group included in formula 2 (=tsu) is, for example, a 5-okino-2-tetrahydrofuryl group (.

6-oxo-2-tetrahydropyranyl group (.0).

4-Oquino 2-azetidinyl group (C" 5-Oquine-2-pyrrolidinyl group (.q), 6-Oquino "Lower alkyl group" in "lower alkyl group" refers to a linear or branched chain having 1 to 5 carbon atoms. carbon chains such as methyl group, ethyl group, propyl group, butyl group, Inglovir M
+5ee-butyl group, etc.

Further, examples of the alkylene group included in -(CH,)n- include ethylene group, propylene group, and tetramethylene group.

The salts contained in the target compound (υ) are salts with non-toxic acids. Typical salts include inorganic acid salts such as hydrochloride and sulfate, and citrate.

Examples include organic acid salts such as acetate and tartrate.

Furthermore, the two target compounds of the present invention are stereoisomers based on asymmetric carbon atoms and prototropes.

There are several isomers. The target compounds of the present invention include separated and mixtures of these isomers.

The object compound (1) of the present invention can be prepared as it is or mixed with appropriate pharmacologically acceptable carriers, excipients, and diluents to form powders, granules, tablets, capsules, injections (intravenous, subcutaneous, It can be administered intramuscularly), orally or parenterally in the form of suppositories and the like.

The dosage of the compound (i) of the present invention varies depending on the type of compound (1), age, body weight, symptoms, route of administration, etc.
For example, for injection, about 0.001-10 mg, preferably 0.01-0.1 mg (single dose);
For oral administration: about 0.05-500 mg, preferably 0.1
~lOfftg (single dose).

Compounds related to the object compound (I) of the present invention include:
Also known as thyrotropin-releasing hormone (TR) I) -pyroglutamyl-L-histidyl-glolinamide (pGlu-Hi 5-Pro-NH)
It has been known.

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

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

Lancet 2.999 (1972)]. Smell it,
In addition to TSH-releasing activity, TRH also reduces the duration of sleep induced by barbiturates and alcohol.

Suppressing hypothermia symptoms stimulated by various drugs, increasing motor activity, preventing general tonicity caused by haloperidol, or enhancing memory.

CNS K, such as improvement of symptoms of schizophrenia, antidepressant effect, etc.
It is known to have an effect on

Furthermore, TRH improves consciousness disorders 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.
It has also been found to be a therapeutic agent (Japanese Unexamined Patent Publication No. 51-1
No. 18841). In terms of clinical treatment, there has been a demand for a TRH derivative that exhibits weaker or almost no TSH-releasing activity than TRH, and that has the same or greater effect on the CNS than TRH. Various TRH derivatives have been synthesized for such purposes.

The effects on the CNS have also been further expanded. Compounds synthesized for this purpose include 2, for example, T from TRH.
SH release activity is weak, but it has anesthetic antagonism, increases locomotor activity, or has a dopamine-like effect, and is useful for sleeping drug addiction, consciousness disorders, etc. in humans.
TRH derivatives (Japanese Patent Application Laid-Open No. 1983-1992
No. 2-116465).

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

The target compound of the present invention has a chemical structural feature in that it is a derivative of TRH diamide, and in terms of pharmacological action, it has a significantly stronger CNS effect than the above-mentioned TRH and conventionally known TRH derivatives. has.

It is useful as a medicine. For example, schizophrenia, depression, sequelae of cerebrovascular accident 1 extracephalic disorder, and senile dementia.

Ameliorating agent for consciousness disorder or loss of motivation in epilepsy, etc.
It is useful as an ameliorating agent for depression, memory loss, etc.

(Manufacturing method) The object compound of the present invention is produced by the first route.

(In the formula, Het, R' and n have the above-mentioned meanings.) That is, according to the present invention, the target compound (1) is (a
t Compound (■) is reacted with compound (III) to prepare compound (1■), and then this compound (rV) is reacted with compound (V), or.

(bl) Compound (III) and compound (V) are reacted to form compound (Vl).
) and compound (It).

The reaction for producing compound (1) employed in (a) or (bl) above is a peptide synthesis reaction, and a method known per se is used.As a commonly used method, cyclohekiflucarpodiimide is Condensing agent method, AND method, acid chloride method.

Examples include acid anhydride method and active ester method. To carry out these methods, prior to the peptide formation reaction in each step, functional groups such as amine groups, imino groups, carboxyl, etc. of the compound that do not participate in the reaction are usually protected, and, The amine group, imino group, or carboxyl group involved in the peptide-forming reaction 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 amino groups include benzyloxycarbonyl group, t-butylox7carbonyl group, p-methoxybenzyloxy7carbonyl group, phthaloyl group, trifluoroacetyl group, etc. Protecting groups for imino groups include: Example 1-1') Syl group, benzyloxycarbonyl group.

Examples include p-methoxybenzyloxycarbonyl group, benzyl group, and 2,4-dinitrophenyl group.

Protecting groups for carboxyl groups include methyl ester, ethyl ester, and benzyl ester.

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

When the group involved in the reaction is an amine group or an imino group, the group is activated by, for example, the phosphazo method using phosphorus trichloride, the removal of ynonanate using phosgene, or the phosphite method.

In addition, when it is a carboxyl group, active ester (2,4
-dinitrophenol ester, N-hydroxysuccinimide ester), azide, carboxylic acid anhydride. Among these, compounds (IV) and (V)
For the synthesis of , the AND method or the method using cyclohexylcarbodiimide as a condensing agent is preferred. 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 the protecting group from the reaction product, for example, in the case of benzyl esters, by catalytic reduction,
In the case of p-toluenesulfonyl group, anhydrous hydrogen fluoride,
By using HOBT or hydrogen fluoride-pyridine/complex, etc., when the protecting group is an alkyl ester, it is hydrolyzed, and when the protecting group is benzyloxycarbonyl/l/honyl, p-methoxybenzyloxy7carbonyl, it is catalyzed. When the protecting group is a t-butyloxycarbonyl group, it can be easily removed by acid decomposition by reduction or hydrobromic acid-acetic acid treatment.

(Example) Hereinafter, the object compound of the present invention and the method for producing the same will be further explained with reference to Examples. In addition.

Abbreviations used in the examples have the following meanings.

NMR nuclear magnetic resonance spectrum IR infrared absorption spectrum Mass Mass spectrometry spectrum mp Melting point AnaL Elemental analysis value His Histidine pGlu Pyroglutamic acid DMF Dimethylformamide HOBT 1-Hydroxy-1,2,3-benzitriazole DCC Dicyclohexylcarbodiimide Ph Phenylz Benzyl Oxycarbonyl Example l 14 g of Na-benzylox7carbonyl-L-histidine hydrazide are dissolved in 40 ml of IN-hydrochloric acid and 60 mt of ethyl acetate are added. The mixture is cooled in a water bath and a solution of 111 g of IJum 911 dissolved in 4 ml of water is added. After stirring for 3 minutes, 50%
Add 16 ml of potassium carbonate aqueous solution. The organic and aqueous layers are separated and the aqueous layer is extracted once with ethyl acetate.

The organic layers are combined and dried over anhydrous sodium sulfate while cooling with water. After r-filtration, 1-(3-aminopropyl)-2- is added to P solution.
Add 21.6 g of oxinovirolidine.

This mixture is stirred in a water bath for 3 hours. The solvent was removed under reduced pressure and the resulting residue was purified with silica gel (300 mt).
column chromatography. Elution with methanol-chloroform (15:85) yields N-[Na
-benzyloxycarbonyl-L-histidyl]-3-
(2-oxo-l-pyrrolidinyl)propylamine 3
3.30 g is obtained.

(il NMR (CD, OD) δppm: 7.
6 (IH, imidazole).

7.30 (5H, s, Ph), 6.84 (IH, imidazole).

5.04 (2H9s, PhC!i2), 4.30 (
lH,q, Hisα-(!!l IR(KBr)Cm
-' : 3250.1710.1650.1520°125(L (jjl Mass m/z : 414(M+1
), 346.306.262°225, 194°Compound 3920■ was dissolved in 15 ml of methanol.

Hydrogenate in the presence of 10% Pd-C. Work-up is carried out in a conventional manner to obtain N-L-histidyl-3-(2-oquino-1-pyrrolidinyl)propylamine 4 as a foam in quantitative yield. This will be used as is in the next reaction.

N-benzyloxy7carbonyl-pyroglutamic acid 5 586mg topentachlorophenol 713ff1
Dissolve g in 3 m4 of dry DMF and cool on ice.

3. After adding 111 g of DCC505, the mixture was cooled with water.
Stir for 5 hours. After removing the insoluble matter from F, the P solution is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel (200+nt).

N-[N-benzyloxycarbonyl-
6690 ml of pyroglutamyl-L-histidyl]-3-(2-oxo-1-pyrrolidinyl)propylamine is obtained.

(o NMR (CD, OD) δppm
: 7.56 (IH, Imidan-ru)
), 7.30 (5H, S, ph),
6.84 (IH, imidazole), 5.1
6 (2H,!l+phcdan,), 1.44~2.6
81ii) IR(KBr)c+++-':
3250.1780,1720,1650°1540,
1290 (i!!I Massm/z: 506
(M-)1,0), 430. 416. 395° 690 mg of Compound 6 was dissolved in 15 ml of methanol and hydrogenated in the presence of 10% Pd-C by a conventional method.

After removing the catalyst and solvent, the residue was triturated with ether to obtain 7335 mg of N-(L-pyroglutamyl-pyrodinyl)propylamine in the form of a white powder.

m NMR (CD, OD) δ ppm
: 7.92 (IH, I mida so °
-L'), 7.0 (IH, imidazole),
4.60 (IH, q, 4Gluα-CH),
4.20 (IH, t, Hisα-CH), 1
．． 5-2.6 (IOH.

(!IR(KBr)cm-': 3250.1
640 (Broad).

1530, 1420.1270 (iii) Mass m/z: 390 (M”
), 372, 306, 264.

Example 2 Example 1 [In cl, -15 instead of compound 50]
-Oxo 2-tetrahydrofurancarboxylic acid grass 26
The target compound N-[Na-[(S,)me-5-oxo-2-tetrahydrofuroyl]-L-histidyl]-3-(2-oxo-l) was treated in the same manner using 0 mg. -pyrrolidinyl)propylamine 9260M is obtained.

(it NMR(CDCI,+C8D)δppm
: 7.76 (LH.

imidazole), 6.90 (IH, imidazole).

4.96 (I H,., 1 move), 4.64 (I H
, Hisα-CH).

■ 1ri IR (KBr) cm-': 3250,177
0.1650,1520゜1430,1170 (!Iri Mass rnlz: 3!N (M
+), 373.306.293゜Example 3 Orotic acid 10351 mg and HOBT 415 fag
is mixed with dry DMF8oIt and cooled to 0-4°C.

After adding 1 g of DCC633I and stirring for 20 minutes, a solution of compound 42.04/17 mol in DMF (10 m4) is added. The mixture was stirred at 50 ml of water for 40 hours. After removing the insoluble matter, the P solution was concentrated under reduced pressure and the residue was subjected to column chromatography on silica gel (150 mt). Chloroform-methanol-
By elution with aqueous ammonia (70:30:2), 3-(2-oxo-1-pyrrolidinyl)-N-[N“
11,514 mg of -(uracil-6-carbonyl)-L-histidyl]propylamine are obtained. This is triturated with methanol to remove insoluble matter, the methanol solution is concentrated, and ethanol is added to the residue to crystallize it.

fl mp 250~251'C 11Anal, (as CI8H23N?0.) (C
) (H) (N) Calculated value egg 51.79 s, 5s, 23.
49 Experimental value% 51.55 5.58 23.
48 (Song NMR (D20) δppm: 8.0
4 (IH, imidazole).

7.12 (IH, imidazole), 6.20 (I
H, s, uracil).

QVI IR(KBr)l-': 3270.3
150.3070.1630-1710 (Broad)
, 1540.1420M Mass rn//z:
417 (M"), 399.330.319.305°247, 231 Example 4 20 rnl of 0.1N sodium hydroxide is cooled to 0-5°C.

■ N”-[4j-4-oxo-2-azetidinylcarbonyl]-L-histidine methyl ester 12 532m
g was added thereto, and the mixture was stirred at the same temperature for 1.5 hours. Next, 760 mg of para-toluenesulfonic acid monohydrate was added at the same temperature, and water was distilled off under reduced pressure. Acetonitrile the residue.

It was azeotropically dehydrated using benzene and dried under reduced pressure.

The obtained powder was dissolved in 20 m of DMF, 2285 cm of 1-(3-aminopropyl)-2-oxopyrrolidine was added, and then 412 mg of DCC was added under water cooling at 0 to 5°C.
The mixture was stirred overnight. The reaction mixture was filtered, the P solution was concentrated under reduced pressure, and the residue was subjected to column chromatography using silica gel (200 g). Elution was performed with chloroform-methanol-concentrated aqueous ammonia (80:20:2). 550ff1g of crude product was obtained.

This was recrystallized from 4 ml of methanol to yield 240,111 g.
3-(2-oxo-1-pyrrolidinyl)-N-[N'-[(S)-4-oxo-2-azetidylcarbonyl]-L-histidyl]globylamine as colorless crystals of
] I got 3.

11 mp 120-123°C (jil NMR (d”-DMSO) δppm:
1.49 (2H, m), 1.94 (2H, m)
, 2.16 (2H, m), 2.7-3.4 (IOH
, m).

3,! 19 (IH, dd J=10Hz, 3Hz)
, 4.44 (IH, m).

61゛7 (1'H), 7.53 (IH), 7.89 (I
H, t, J = 10Hz).

Claims (1)

[Claims] General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, Het is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
((In the formula, m means 1, 2, or 3, and X means an oxygen atom or an imino group)) Heterocyclic group or formula ▲ Numerical formula, chemical formula, table, etc. ▼ 1, 2 , 3,6-tetrahydro-2,6-dioxo-4-pyrimidinyl group, R^1 is the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ ((In the formula, R^2 means a hydrogen atom or a lower alkyl group)) An imidazolyl group, n means an integer from 2 to 5. ) N-(N^α-substituted histidyl)-ω-(2
-oxo-1-pyrrolidinyl) lower alkylamine or a salt thereof.