JPH0253734A - Agent for alleviating dementia - Google Patents

Abstract

NEW MATERIAL:Peptides shown by formula I, formula II, formula III, a derivative and a salt thereof. USE:An agent for alleviating dementia having excellently improving effect on intelligence useful for preventing and treating diseases such as presbyophrenia or cerebrovascular dementia. PREPARATION:Peptides shown by formula I, formula II and formula III are obtained by a method usually used in peptide chemistry. Condensation method to form peptide bond is azide method, acid chloride method, acid anhydride method, etc. The reaction is carried out in a solvent by using chloroform or dichloromethane generally at about -30 deg.C to 50 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to an anti-dementia agent containing an effective amount of a peptide having nootropic activity.

[Prior Art] It has been known for a long time that Pap pressin has a nootropic effect, but recently peptides that can be considered to be fragments of Pap pressin, such as pGlu-Asn-(:ys-Pro-L-＾rg-G
It has been reported that the peptide represented by ly-NH2H-Cys-011 also has a nootropic effect similar to pap pressin [Science
ce) 221.1310-1312 (1983)
].

Also, (pGlu-^5n-Cys-Pro-L-^rg-G
It has also been reported that the peptide represented by IV-Nl12)2 has nootropic effects (Japanese Patent Application Laid-Open No. 59-9303
Publication No. 6).

[Problems to be Solved by the Invention] The present invention provides an anti-dementia agent containing an effective amount of a novel peptide having an even better nootropic effect than the Pap pressin and Pap pressin fragment peptides. The purpose is to

[Means for solving the problem] The present invention provides the formula (■): pGlu-Asn-Cys-Pro-D-Arg-Gl
y (I) A peptide represented by Cys, a peptide represented by the formula (■): pGlu-Asn-Cys-Pro-Arg-Gly, and a peptide represented by the formula (■): (n) pGlu-Asn-Cys-D-Pro -Arg-Gl
a peptide represented by y(III)Cys, an effective amount of a peptide selected from the group consisting of: a peptide or a derivative in its functional group, or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier or An anti-dementia drug containing a diluent.

The functional group derivatives of the peptides of formulas (I), (II) and (m) above mean the following.

a) N-acyl derivatives derived from aliphatic carboxylic acids with 1 to 6 carbon atoms, preferably acetic acid; b) amides or 1,000- or di-alkyl derivatives with alkyl groups of 1 to 6 carbon atoms; esters derived from alkyl-substituted amides and c) alcohols having 1 to 18 carbon atoms, preferably aliphatic alcohols having 1 to 6 carbon atoms.

The pharmacologically acceptable salts of the peptides or functional group derivatives thereof include acid addition salts and basic salts. Such acid addition salts include:
Examples include salts of inorganic acids (eg, hydrochloric acid, sulfuric acid, phosphoric acid) or organic acids (eg, acetic acid, propionic acid, citric acid, tartaric acid, malic acid, oxalic acid, methanesulfonic acid). Further, examples of the basic salt include sodium salt, potassium salt, triethylamine salt, and the like.

In this specification, amino acids, peptides, protecting groups, solvents, etc. are referred to by abbreviations commonly used in the technical field, or by I
The abbreviations adopted by the UPAC-I UB naming committee are used. For example, the following abbreviations are used: Furthermore, if the optical configuration is not indicated, the amino acid shall mean the L-type.

Asn: asparagine Arg: arginine (:ys nigistein cty nigericin pGlu: pyroglutamic acid Pro nibroline Boc: t-butoxycarbonyl Z: penzyloxycarbonyl Mbs: p-methoxybenzenesulfonyl MBzl
: p-methoxybenzyl Acm : acetamidomethyl 5ctn : carbomethoxysulfenyl O5u : N-
Hydroxysuccinimide ester DCC: N, N'
-dicyclohexylcarbodiimide DCUrea:
N,N'-Dicyclohexylurea 110Bt: 1-hydroxybenzotriazole NMM: N-methylmorpholine TFA: Trifluoroacetic acid MS^: Methanesulfonic acid THF: Tetrahydrofuran Ac0Et: Ethyl acetate Ac011: Acetic acid DMF: N,N-dimethylformamide MeOH: methanol The peptide, which is the active ingredient of the anti-dementia agent of the present invention, can be prepared by a method commonly used in peptide chemistry, for example, 5chr.
5der and Libke, “The Peptide (Th
e Peptides)” Volume -, Academ
ic Press, New York, U.S.A.
(1965), "Fundamentals and Experiments of Peptide Synthesis" by Nobuo Izumiya et al. can.

Condensation methods for forming peptide bonds include azide method, acid chloride method, acid anhydride method, mixed acid anhydride method, N
, N'-dicyclohexylcarbodiimide method, N,N
Examples include the -dicyclohexylcarbodiimide additive method, the active ester method, the carbonyldiimidazole method, the redox method, and the method using Woodward's reagent.

Among the amino acids constituting the peptides in the anti-dementia agent of the present invention in the condensation reaction, the cystine site can be converted to cystine by using a cystine derivative, or by forming a peptide chain as a cysteine residue and then converting it into cystine by a known method. It is.

Before carrying out the condensation reaction, carboxyl groups, amino groups, etc. that do not participate in the reaction may be protected, or carboxyl groups, amino groups that participate in the reaction may be activated by means known per se.

Examples of carboxyl-protecting groups include esters such as methyl, ethyl, benzyl, p-nitrobenzyl, t-butyl, and cyclohexyl.

Examples of protecting groups for amino groups include benzyloxycarbonyl group, t-butoxycarbonyl group, isobornyloxycarbonyl group, and 9-fluorenylmethyloxycarbonyl group.

Examples of the protecting group for the guanidino group include a nitro group, a benzyloxycarbonyl group, a tosyl group, a p-methoxybenzenesulfonyl group, and a mesitylenesulfonyl group.

Examples of protecting groups for mercapto groups include trityl group,
Examples include acetamidomethyl group, benzyl group, p-methoxybenzyl group, 3-nitro-2- and lysine sulfenyl group.

Examples of activated carboxyl groups include:
Corresponding acid anhydrides, azides, active esters [alcohols (e.g., pentachlorophenol, 2,4-dinitrophenol, cyanomethyl alcohol, P-nitrophenol, N-hydroxy-5-norbornene-2,3-dicarboximide) , N-hydroxysuccinimide, N-
esters with hydroxytetraphthalimide, 1-hydroxybenzotriazole), and the like. Examples of activated amino groups include the corresponding phosphoric acid amides.

The reaction is usually carried out in a solvent, such as chloroform, dichloromethane, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, pyridine, dioxane, tetrahydrofuran, water, methanol, etc.
Alternatively, it can be carried out in a mixture of these.

The reaction temperature can be within the commonly used range of about -30°C to about 50°C.

The peptide protecting group removal reaction in the anti-dementia agent of the present invention varies depending on the type of protecting group used, but it is necessary that the protecting group be removed without affecting the peptide bond.

Examples of the method for removing the protecting group include acid treatment with hydrogen chloride, hydrogen bromide, anhydrous hydrogen fluoride, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, or a mixture thereof. Other examples include reduction with sodium in liquid ammonia and palladium on carbon. In the deprotection reaction by acid treatment, it is effective to add a cation scavenger such as anisole, phenol, and thioanisole.

After the reaction, the peptide in the anti-dementia agent of the present invention produced in this way can be obtained by known peptide separation means such as extraction, distribution, reprecipitation, recrystallization, column chromatography, etc. can.

Furthermore, the peptide in the anti-dementia agent of the present invention can be made into a derivative in its functional group or a pharmacologically acceptable salt thereof, as described above, by a method known per se.

The peptide in the anti-dementia agent of the present invention exhibits a strong nootropic effect in a passive avoidance test in rats.

Useful target disease groups for the anti-dementia agent of the present invention include, for example, senile dementia (Alzheimer's dementia), cerebrovascular dementia, Alzheimer's disease, Bick's disease, Huntington's chorea, Kreiffert-Jakob disease, and Parkinson's disease. ,
Myelin degeneration of the cerebellum, dementia, etc. can be mentioned, and it can be used for the prevention or treatment of these diseases.

The toxicity of the peptide in the anti-dementia agent of the present invention is extremely low, and there have been no cases of death even at doses far exceeding the medicinally effective dose.

The peptide in the anti-dementia agent of the present invention can be administered as a free form, a derivative at its functional group, or a salt thereof. The dosage is generally lng to 1 mg/kg of body weight as the amount of the free form for any type of grass.
A daily range of amounts is appropriate. In particular, for parenteral administration and nasal administration, 10 ng to 100 μg/kg/day is preferable.
In oral administration and rectal administration, it is preferable to administer 10 to 100 times as much as parenteral administration. The peptide in the anti-dementia agent of the present invention is mainly administered parenterally (e.g., intravenous or subcutaneous injection, intraventricular or m-cavity administration, nasal administration, rectal administration), but in some cases, oral administration is may be administered.

Examples of dosage forms include injections, suppositories, powders, nasal sprays,
Examples include pills and tablets. The peptide in the anti-dementia agent of the present invention can be stored as a solution in physiological saline, but it can also be prepared into a freeze-dried ampoule by adding mannitol and sorbitol, and dissolved at the time of use.

Examples of synthesis of peptides used in the anti-dementia agent of the present invention are shown below.

In each synthesis example, the developing solvent for thin layer chromatography was as follows, and Merck & Co. TLC plate silica gel 60 F 254 was used.

R,': Chloroform-methanol-°acetic acid-water (80
:20:2.5:5) Lower layer R, 2: Chloroform-methanol-water (70:30:
5) R (3:n-butanol-acetic acid-water (2:l:], )
In addition, a special column made using high performance liquid chromatography is: μBondapak C, 1,9X15
cm mobile phase: A) 0.0596 TFA, B) Acetonitrile.

[Synthesis Example 1] pGIu-Asn-Cys-Pro-D-Arg-Gl
y-Nl12 acetate H-Cys-OH (1) Z-D-Arg(Mbs)-Gly-NH27
, -D-Arg (Mbs) - 30g of dicyclohexylamine salt to cOEt500rnft + 5% citric acid water 200mj! After stirring and dissolving in the solution, the AcoEL layer was washed with water and dried over anhydrous sodium sulfate.

The solvent was distilled off, the resulting residue was dissolved in 300 m2 of DMF, and 5 g of 1l-Guy-NH2 hydrochloride, N
M15ml! , HOBt 8g and DCII: 9.8
g was added. After the mixture was stirred at room temperature for 18 hours,
DCIIrea was filtered off and DMF was distilled off.

The residue was diluted with 2-butanol-CHzC12 (5:1 v
/v), washed successively with saturated aqueous sodium bicarbonate, saturated aqueous dilute hydrochloric acid, and saturated brine, and then dried over anhydrous sodium sulfate.

After evaporating the solvent, the residue was crystallized from MeOH-ether and the title compound was collected by filtration.

Yield: 14.6g Melting point: 194-196°C Ftr': 0.24 Rr': o, 52[
α]o Knee 2.9° (c-0,5,DMF) (2)
Boc-Pro-D-Arg(Mbs)-Gly-N
ll□Z-D-Arg(Mbs)-Gly-Nf121
0.7 g in 80% Ac011200mjZ
% palladium on carbon and stirred in a hydrogen stream for 6 hours.

After filtering off the palladium on carbon, the solvent was distilled off. After drying the residue under reduced pressure, it was dissolved in DMFlootnjZ and N
6.2 g of MM3mR1Boc-Pro-O5u was added and stirred at room temperature for 18 hours.

DMF was distilled off, and the residue was dissolved in 2-butanol-(:H2(
:12 (5:1 v/v), washed sequentially with saturated sodium bicarbonate water, salt-saturated dilute hydrochloric acid water, and saturated salt water, and then dried over anhydrous sodium sulfate.

After evaporating the solvent, ether was added to the residue to crystallize it, and the title compound was collected by filtration.

Yield: 11.9g Melting point = 108-111°C Rt': 0. 32 Rr': 0. 5
6[a]o: s, go (c-0,5,DMF)
(3) Boc-Cys (8 cm)-Pro-D-Ar
g(Mbs) -Gly-NLBoc-Pro-D-A
rg(Mbs)-Gly-NH29g, THF100
m12 and 4 NHCl-AcOEt 100 m I
After being left in a mixed solvent with t for 30 minutes at room temperature, the solvent was distilled off.

After drying the residue under reduced pressure, it was dissolved in DMFloomjl and mixed with NMM 3.3 m fl, Boc-Cys under ice cooling.
4.8 g of (Acm)-0H, 2.4 g of HOBt and 3.4 g of DCC were added, and the mixture was stirred at room temperature for 18 hours.

DCUrea was filtered off, DMF was distilled off, and the residue was
It was dissolved in butanol-CM2C12 (5:1 v/v), washed successively with saturated sodium bicarbonate water, salt-saturated dilute hydrochloric acid water, and saturated salt water, and then dried over anhydrous sodium sulfate.

After evaporating the solvent, ether was added to the residue to crystallize it, and the title compound was collected by filtration.

Yield: 9.8g Melting point = 88-90°C Rf': o, 21 Re': 0.
52 [α]. Knee 17.6° (c-0,5,DMF
)Z-pGlu-Asn-Cys (Acm)-Pr
o-D-Arg(Mbs) -Gly-NH2Boc-
Cys (Acm)-Pro-D-Arg(Mbs)-
Gly-NH26,3g 2N HC:1-AcOH
After standing in 20ml It for 30 minutes at room temperature, the solvent was distilled off.

After drying the residue under reduced pressure, it was dissolved in DMFloomJZ and 1ml of NMM, Z-pGlu-Asn-O was added under water cooling.
H3.1g, HOBt 1.3g and DCC1.8g
added.

After stirring at room temperature for 40 hours, D(:Urea was filtered off and DMF was distilled off.

The residue was dissolved in 2-butanol-CLC12 (5:1 v/
v), washed successively with saturated aqueous sodium bicarbonate, saturated aqueous dilute hydrochloric acid, and saturated brine, and then dried over anhydrous sodium sulfate.

After evaporating the solvent, ether was added to the residue to crystallize it, and the title compound was collected by filtration.

Yield: 6. Og Melting point: 161-166℃ R(': 0.05 Rr'+ 0.3
1 [a], knee 35.0° (c-0,5, DMF)
Z-pGIu-Asn-Cys(Scm)-Pro-D
-Arg(Mbs)-Gly-NH2Z-pGIu-A
sn-Cys (Acm)-Pro-D-Arg(Mb
s)-Gly-NH4I, Og of CH2Cl2-Me
OH (1:1 v/v) 50 m It was added to the hot solution (: l-5 cm 0.15 m ft) under water cooling, and the mixture was stirred for 1 hour.

The solvent was distilled off, ether was added to crystallize, and the title compound was collected by filtration.

Yield: 1. Og Melting point = 176-180°C Rf': o, 11 Rr': 0.42[α
]D knee 54.3° (c-0,5,DMF)Z-pG
lu-Asn-Cys-Pro-D-Arg (Mbs
)-Gly-NI12 hydrochloride H-(:ys-OH 2-pGlu-Asn-Cys (Scm)-Pro-
D-8rg(Mbs)-Gly-NH4I, 0 g of D
0.38 g of cysteine hydrochloride was added to 20 ml of MF solution, and the mixture was stirred at room temperature for 1 hour.

The solvent was distilled off, and the residue was purified on a silica gel column using CHCl+MeO1+, crystallized from ether, and the title compound was collected by filtration.

Yield: 0.68g Melting point: 162-166℃ R,2:0.05 [a]D Knee 37.9° (c-0,5,DMF) f(
-Cys-OH 420mg with MSA4mffi and anisole 0.4m
l1. After stirring for 1.5 hours at room temperature, ether was added and the supernatant was removed. Dissolve the precipitate in water and
After xlx2 (acetate type) treatment, water was distilled off.

The residue was dissolved in 0.05% TFA and purified by high performance liquid chromatography using a 15 ml 11 min (flow rate), 0 to 10% B) 20 min linear gradient (mobile phase).
WexlX2 (acetate form) treatment and lyophilization gave the title compound.

Yield: 80 mg R/:0107 [α]o knee 129.1° (c-0,6, water) [Synthesis Example 2] pGlu-Asn-(:ys-Pro-Arg-Gly
-NH2 acetate (1) Z-Arg (Mbs) -G
ly-Nil□Z-Arg(Mbs,)-Kano dicyclohexylamine salt 10 g, tl-Gly-Nlh hydrochloride 1.7 g, NMM 1.7 m fl,! 10B
Synthesis Example 1 (1
), the title compound was obtained.

Yield: 5.0g Melting point: 201-202°C R,'+ 0.26 R,2: 0.55[α]o
:+2.1° (c=0.5. DMF) (2,)
Boc-Pro-8rg(Mbs)-Gly-Nl
(27, -Arg(Mbs)-Gly-NHz 20.
8 g, Boc-Pro-O5u12.1 g, and N
The title compound was obtained from 4.3 ml of MM in the same manner as in Synthesis Example 1 (2).

Yield: 21.5g Melting point: 120-126°C Rr': 0. 3 1 Rr': 0.
53 [αlo knee 26. 5° (c=1,
DMF) (3) Boc-[:ys(MBzl)-P
ro-Arg(Mbs)-Gly-NH2Boc-Pr
123.7 g of o-Arg(Mbs)-Gly-Nl,
Similarly to Synthesis Example 1 (3), cO to 4811CI-
Boc was removed by Et treatment.

The obtained 1l-Pro-Arg(Mbs)-Gly-N
Dissolve i12 hydrochloride in 30 ml of DMF and add NM under cooling.
M 0.7 ml, Boc-Cys(MBzl)-0
+12. Ig, 11OBt O, 85g and DCCl,
4 g was added. After stirring at room temperature for 18 hours, DCU
rea was filtered off, and DMF was distilled off.

The residue was dissolved in Cl1C13, washed successively with saturated aqueous sodium bicarbonate, saturated dilute hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate.

After evaporating the solvent, ether was added to the residue to crystallize it, and the title compound was collected by filtration.

Yield: 3.2g Melting point: 104-107°C Ry': o, 44 R, 2: o,
63 [a] o knee 2'7. 9° (c-0
,5,D cap→Z-pGlu-85n-Cys (MBz
l)-Pro-8rg(Mbs)-Gly-Nll□B
oc-Cys(MBzl)-Pro-Arg(Mbs)
-Gly-Nl 121.8g was added to 2Nt (CI-Ac
After standing in OH10m II for 30 minutes at room temperature, the solvent was evaporated.

After drying the residue under reduced pressure, it was dissolved in DMF30rnJZ,
NMM 0.25m II, Z-pGlu-A under water cooling
sn-0) 10.9g, HOBt O, 38g and D
5 g of CGO was added.

After stirring at room temperature for 40 hours, D(:Urea was filtered off and DMF was distilled off.

The residue was dissolved in 2-butanol-0H2CI2 (5:1 v
/v), washed successively with saturated aqueous sodium bicarbonate, saturated aqueous dilute hydrochloric acid, and saturated brine, and then dried over anhydrous sodium sulfate.

The solvent was distilled off, and the residue was purified on a silica gel column using C11 (:13-Me). Ether was added to crystallize it, and the title compound was collected by filtration.

Yield: 0.85g Melting point: 131-135°C R,l: 0. 19R,2: 0.
44 [α]. Knee 43. 3° (c-0,6,D
MF) (5) pGIu-Asn-Cys-Pro-A
rg-Gly-Nl12 acetate Z-pGlu-^5n-
(:ys (MBz l) -Pro-Arg (Mb
s)-Gly-NH□ 440 mg with MSA 4 mfi and anisole 0.25 ml and ethanedithiol 0.2
After stirring for 1 hour at room temperature in mff1, ether was added and the supernatant was removed. Dissolve the precipitate in water and dowex
After the lx2 (acetate type) treatment, water was distilled off.

The residue was dissolved in 0.05% TFA and purified by high performance liquid chromatography in a 15 ml 11 min (flow rate), 2% to 12% B) 20 min linear gradient (mobile phase).
owexlX2 (acetate form) and freeze-drying to give the title compound.

Yield: 28 mg Rr' (containing 1% ethanedithiol): 0.14 [αlo
Knee 92.8° (cJ, 5.water) [Synthesis Example 3] pGlu-Asn-Cys-D-Pro-Arg-Gl
y-Nl2 acetate H-Cys-OH (1) Boc-D-Pro-Arg(Mbs)-Gly
-Nl2Z-Arg(Mbs)-Gly-Nl25.2
The title compound was obtained from 3.1 g of Boc-D-Pro-O5u, and 2.2 m of NMM in the same manner as in Synthesis Example 1(2).

Yield: 5.7g Melting point: 288-91°C R,': 0.3 S R,2: 0.59 [a
]o: +8.7° (c=0.6, DMF) (2
) Boc-(:ys(AcII+)-D-Pro-A
rg(Mbs)-Gly-Nl2Boc-D-Pro-
Arg(Mbs)-Gly-Nl22.5g, Boc
-tl:ys (8cm) -〇〇 1.3g%)lOBt
O, 73g, DCG O, 94g and NMM 1ml
! The title compound was obtained in the same manner as in Synthesis Example 1 (3).

Yield: 2.2g Melting point = 110-114°C R,': 0.22 R,2: 0.50[α]o
: 21.9°(C~0.5.DMF)Z-pG
lu-Asn-Cys (Acm)-D-Pro-Ar
g(Mbs) -Gly-Nl-+2Boc-Cys
(Acm)-D-Pro-Arg(Mbs)-Gly-
Nll, 2 g.

Z-pGlu-Asn-OH2g, +1OBt 0
．． 5g, D(:GO,58g and NMMMO,5
The title compound was obtained from m 11 in the same manner as in Synthesis Example 1 (4).

Yield: 1.8g Melting point = 120-124°C Rr': 0.09 R,2: o, 35[αl
o Knee 23.3° (c-0,5, DMF) Z-pG
1u-Asn-11:ys (SCQI) -D-Pr
o-Arg (Mbs) -G 1y-Nl12Z-p
Glu-Asn-Cys (Acm) -D-Pro-
Arg (Mbs) -Gl,! /-NH21g and C
The title compound was obtained from 1-5 cm 0.15 ml in the same manner as in Synthesis Example 1 (5).

Yield: 0.9g Melting point: 142-147°C R,': 0.2OR, 2: 0.49[α]o Knee 40.8° (c-0,5,DMF)Z-pGIu-As
n-Cys (Scm) -D-Pro-Arg (Mb
The title compound was obtained from 20.5 g of -Gly-N)+ and 0.15 g of cysteine hydrochloride in the same manner as in Synthesis Example 1 (6).

Yield: 0.46 g Melting point = 162-165°C R,2: 0.07 [α]. Knee 26. 2” (c 0.
5. DMF) (6) pGlu-^sn-Cys-
D-Pro-Arg-Gly-Nl2 Acetate H-Cys
-OH z-pGlu-Asn-Cys-D-Pro-Arg(
Mbs)-Gly-Nl2 hydrochloride H-Cys-01 (120 mg was subjected to MS in the same manner as in Synthesis Example 1 (7)).
A - After anisole treatment, 12 ml 1 minute (flow rate),
0 to 20% B) 20 minutes linear gradient (mobile phase), high performance liquid chromatography purification, DowexlX
2 (acetate type) treatment followed by lyophilization to obtain the title compound.

Yield: 53 mg R,': 0.10 [α]o knee 106.0° (c-0,5, water) Then,
An example of a pharmacological test showing the effectiveness of the peptide in the anti-dementia agent of the present invention is shown.

[Pharmacological test example] The effect on memory consolidation was determined using Wistar male rats by Burbach et al.
Science), 221.1310-1:112 (
This study was conducted using a one-trial passive avoidance experiment based on the method of [198:1 year)]. The experimental equipment consists of a bright room and a dark room.
The floor is made of stainless steel grid. Rats placed in a light room are allowed to freely move to a dark room, and when they enter the dark room, they receive a single electric shock. Retention of passive avoidance behavior in response to electric shock was determined by the time it took for the rat, placed in the light room again after a certain period of time, to enter the dark room (response latency).

1) Examination of memory promoting effect Immediately after experiencing an electric shock (0.25 mA), the peptide or physiological saline in the anti-dementia agent of the present invention obtained in Moeki Synthesis Examples 1 to 3 was administered subcutaneously. After an hour, an electric shock memory retention test was performed.

Control group rats that received only saline generally received 5
The reaction latency was around 0 seconds.

In addition, for comparison, Comparative Example 1 (the above-mentioned known peptide): pGIu-8sn-Gys-Pro-L-Arg-Gl
y-NH2H-Cys-011 Comparative Example 2 (the above-mentioned known peptide): (pGIu-8sn-Cys-Pro-L-Arg-G
A similar test was also conducted for ly-Nl2)2. The number of rats used for testing each group is 6-8. The maximum measurement time was 600 seconds.

For the peptides obtained in each synthesis example and the peptides in each comparative example, the dosage and effects (the ratio of each individual reaction latency to the reaction latency of the control group is shown in %) are shown in Table 1.

Table 1 Example Dose (ng/kg) Effect (%) Synthesis Example 1 Synthesis Example 2 Synthesis Example 3 Comparative Example 1 10 313 Comparative Example 2
10 2492) Cycloheximide (
Examination of the effect of ameliorating experimental retrograde amnesia caused by cycloheximide The peptide or physiological saline in the anti-dementia agent of the present invention was subcutaneously administered, 1 hour later an electric shock (0.5 mA) was experienced, and immediately thereafter, cycloheximide was administered subcutaneously. 2.7~3,
0 B/kg or saline was administered subcutaneously, and a memory retention test was performed 48 hours later. Rats administered only physiological saline generally exhibited a response latency of around 300 seconds, while rats in the control group administered only cycloheximide exhibited a response latency of around 50 seconds, developing retrograde amnesia.

The average response latency of the peptide-administered group and that of the control group in the anti-dementia drug of the present invention were compared. The number of rats used for testing each group is 6-8. Maximum measurement time is 6
00 seconds.

For the peptides obtained in each synthesis example and the peptides of each comparative example, the projected amount and effect (expressed as a percentage of each individual reaction latency to the reaction latency of the control group) are shown in Table 2.

Below is a blank space in Table 2. Example Dose (ng/kg) Effect (%) Synthesis Example 11 Synthesis Example 21 Synthesis Example 3.1 Comparative Example 1 10 Comparative Example 2 100 From the above test results, it is clear that the peptides in the anti-dementia agent of the present invention is 1/10 to 1/10 compared to known peptides.
It is clear that the same effect was achieved at a dose of 0, and that it exhibited an excellent memory promoting effect and an improving effect on retrograde amnesia.

Although the peptide in the anti-dementia agent of the present invention is similar in structure to known peptides, it has slight differences, and this difference has an important influence on the effect of the peptide on memory consolidation.

The superior effect of the peptide in the anti-dementia agent of the present invention due to this difference clearly demonstrates that the effect of the peptide on memory consolidation cannot be predicted from the structure of the peptide. This shows that the peptide in the anti-dementia agent of the present invention has specificity in its action and effect.

For example, although the peptide obtained in Synthesis Example 1 is the same as the peptide in Comparative Example 1 except that L-Arg is changed to D-Arg, its effect on memory consolidation is different from that in Synthesis Example 1. The peptide obtained in Synthesis Example 1 showed the same effect as the comparative peptide at a dose of 1/10, and it is clear that the peptide obtained in Synthesis Example 1 has a significantly superior effect.

Next, Examples of the anti-dementia agent of the present invention will be shown. In each example, the peptide obtained in Synthesis Example 1 is used,
Peptides obtained in other synthesis examples can also be formulated in the same manner.

[Example 1] (Injection) 0.1 mg of the peptide obtained in Synthesis Example 1 and 0.9 g of sodium chloride were contained in 100 mJJ of distilled water for injection, and the pH was adjusted to 6.0 to 8 with sodium hydroxide. An aqueous solution adjusted to .0 was prepared. After bacterial filtration, this was filled into a 1 m JZ ampoule, sealed and heat sterilized to produce an injection.

[Example 2] (Lyophilized formulation) 5 mg of the peptide obtained in Synthesis Example 1 and 5 g of D-mannitol were added to 100 mfi of distilled water for injection, and p
An aqueous solution in which H was adjusted to 6.0 to 8.0 with a phosphate buffer was prepared. This was subjected to bacterial filtration, dispensed in 1 m2 portions into vials, and then freeze-dried to produce a freeze-dried injection.

[Example 3] (Nasal Drop) 10 mg of the peptide obtained in Synthesis Example 1 was contained in 100 mfi of physiological saline, and the pH was adjusted to 3.0 with a citric acid buffer.
Adjusted to 0-6.0, 50μ in a single dose of 0.5ml
A nasal spray containing g was produced.

[Example 4] (Suppositories) Hard fat (triglyceride of saturated fatty acids) 98
．． After adding 0.5 g of egg yolk lecithin to 5 g and melting at 40 to 45°C, 5 m of the peptide obtained in Synthesis Example 1 was added.
A solution obtained by dissolving 1 g of PE0400 in 1 g of PE0400 was added thereto, stirred and dispersed, and then 1 g of the solution was poured into a suppository mold, and after assimilation, the solution was separated from the mold to produce a suppository.

[Effects of the Invention] The peptide in the anti-dementia agent of the present invention is a novel compound and has an excellent nootropic effect, and the anti-dementia agent of the present invention is an excellent anti-dementia agent.

Patent applicant: Nippon Chemifa Co., Ltd.

Claims (1)

[Claims] 1. A peptide represented by the formula (I): [There is a gene sequence] (I), a peptide represented by the formula (II): [There is a gene sequence] (II), and a peptide represented by the formula (II): III): [There is a gene sequence] (III) An effective amount of a peptide selected from the group consisting of (III) or a derivative in its functional group, or a pharmacologically acceptable salt thereof, and pharmacology An anti-dementia agent comprising a carrier or diluent that is acceptable to the public.