KR101491624B1 - Composition comprising an ALLN derivative as an active ingredient for preventing and treating malaria infection - Google Patents

Abstract

The present invention relates to an anti-malarial composition comprising an ALLN derivative compound as an active ingredient, and the compounds of the present invention are useful as an anti-malarial composition containing a ALLN (N-acetyl-L-Leucyl-Lleucyl-L-norleucinal) And can be used as a pharmaceutical composition for prevention and treatment of diseases.

Description

The present invention relates to a composition for preventing or treating a malaria infectious disease containing an ALLN (N-acetyl-L-Leucyl-Lleucyl-L-norleucinal)

The present invention relates to a composition for preventing or treating a malaria infectious disease containing an ALLN (N-acetyl-L-Leucyl-Lleucyl-L-norleucinal) derivative compound as an active ingredient.

[Document 1] WHO. World Malaria Report 2011; World Health Organization: Geneva, 2011, pp 278.

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The present invention relates to a composition for preventing or treating a malaria infectious disease containing an ALLN (N-acetyl-L-Leucyl-Lleucyl-L-norleucinal) derivative compound as an active ingredient.

Malaya causes substantial public health and financial burdens. (1) In 2011, about $ 2 billion was spent on malaria control. Despite the worldwide burden of malaria control, after centuries of research, the present inventors have not yet fully elucidated the mechanistic link between environmental variables of temperature and the incidence of naliria. (2,3,4)

Malaria causes serious, health-related health problems that cause more than one million casualties a year (5). The number of malaria patients decreased by more than 50% in 43 countries in peak intensity (6). About 300-500 million patients and 2-3 million deaths occurred each year (7). Funds for the fight against malaria have increased by about 15 times from about US $ 100 million in 2003 to US $ 1.6 billion in 2010 (8)

Malaria is caused by the genus Plasmodium- derived organism and Plasmodium falciparum , a major malaria parasite in the human body, infecting about 200 million people each year, causing back infection and 600,000 casualties (9).

Since the malaria vaccine is not available, chemotherapy is the main treatment. Chloroquine (CQ) has been used for centuries as a major drug in the treatment of malaria (10). However, artemisinin-based combination therapies, which have lost their efficacy due to the rapid development of drug-resistant strains of chloroquine drugs, are currently being offered as standard worldwide therapies (11). In recent years, resistance to artemisinins has led to the development of new anti-malarials (12).

Artemisinin-based combination therapies have been rapidly increasing globally in the genus Plasmodium , which is resistant to chloroquine and sulfadoxine / pyrimethamine, which have been used as frontline treatments 13). However, resistance to artemisinins is increasing (12, 14-16) and the development of new anti-malaiases with different mechanisms of action is required. In this regard, the development of new calpain inhibitors may provide another way of developing anti-malaria drugs.

Plasmodium Plasmodium falciparum calpain; Pf-calpain genes are significantly different from those found in spinal cord animals (17). Pf-calpain is considered to be an essential mediator of merozoite entry based on the phenomenon that calpain inhibitors block infection (18). Alln (N-acetyl-L-Leucyl-Lleucyl-L-norleucinal) is a peptide aldehyde inhibitor of calpain (19), which means that ALLN inhibits cysteine protease activity. In previous studies, the calpain inhibitor ALLN has been shown to exhibit anti-malarial activity through calpain inhibition in the erythrocytic stages of plasmodium arsipamil (19).

The inventors have novel structures of ALLN (N-acetyl-L- Leucyl-Lleucyl-L-norleucinal) derivatives thereof and the synthetic anti-malarial activity P. falciparum FCR3 strain inhibitory activity and cytotoxicity test for HeLa cell growth and Plasmodium berghei ), it was confirmed that the novel compounds showed strong anti-malarial activity, such as not only remarkably reducing blood parasitemia but also prolonging the survival rate of mice. Thus, the present invention was completed Respectively.

In order to achieve the above object, the present invention provides an ALLN derivative compound represented by the following general formula (I), an isomer thereof or a pharmacologically acceptable salt thereof:

(I)

In this formula,

R 1 and R 2 are each independently at least one substituent selected from the group consisting of a hydrogen atom, a halogen atom selected from F, Cl, Br or I, a hydroxyl group, a C ₁ to C ₁₂ alkyl group and a C ₁ to C ₁₂ alkoxy group,

R3, R4 are each independently a hydrogen atom, a hydroxy group, C ₁ to C ₂₀ alkyl group, C ₁ to C ₂₀ alkoxy group, Z 'substituent and at least one R' a substituted or one or more substituents selected from the group consisting of groups unsubstituted benzyl (Wherein R 'is at least one substituent selected from the group consisting of a hydrogen atom, a halogen atom selected from F, Cl, Br or I, a hydroxyl group, a C ₁ to C ₁₂ alkyl group and a C ₁ to C ₁₂ alkoxy group)

Z, Z 'substituents are each independently selected from Bz, Boc, Ac, Cbz, or formyl.

m is an integer of 1 to 4;

In a preferred group of compounds belonging to the general formula (Ⅰ) is in the formula, R1, R2 are each independently a hydrogen atom, C ₁ to C ₉ alkyl group and a C ₁ to C ₉ Al kokgi, Z 'substituent and at least one R' A substituted or unsubstituted benzyl group wherein the Z 'protecting group is a protecting group selected from Bz, Boc, Ac, Cbz, or formyl group, and R' is a hydrogen atom, a C ₁ to C ₉ alkyl group And a C ₁ to C ₉ alkoxy group, Z is a protecting group selected from Bz, Boc, Ac, Cbz, or formyl group, and m is an integer of 1 to 3.

A more preferred group of compounds belonging to the general formula (Ⅰ) is wherein R, R1, R2 are each independently a hydrogen atom, C ₁ to C ₆ alkyl group and C ₁ to C ₆ Al kokgi, Z 'substituent and at least one R' Wherein the Z 'protecting group is a protecting group selected from the group consisting of Bz, Boc, Ac, Cbz, or formyl, and R' is a hydrogen atom, C ₁ to C ₆ An alkyl group and a C ₁ to C ₆ alkoxy group, Z is a protecting group selected from Bz, Boc, Ac, Cbz, or formyl group, and m is an integer of 1 to 2.

As a first preferred embodiment of the present invention, the present invention provides an ALLN derivative compound represented by the following general formula (Ia), an isomer thereof or a pharmacologically acceptable salt thereof:

(Ia)

In this formula,

R 1 and R 2 are each independently at least one substituent selected from the group consisting of a hydrogen atom, a hydroxyl group, a C ₁ to C ₁₂ alkyl group and a C ₁ to C ₁₂ alkoxy group,

Z, Z 'substituents are each independently selected from Bz, Boc, Ac, Cbz, or formyl.

Also as a second preferred embodiment of the present invention, the present invention provides an ALLN derivative compound represented by the following general formula (Ib), an isomer thereof or a pharmacologically acceptable salt thereof:

(Ib)

In this formula,

R 1 and R 2 are each independently at least one substituent selected from the group consisting of a hydrogen atom, a hydroxyl group, a C ₁ to C ₁₂ alkyl group and a C ₁ to C ₁₂ alkoxy group,

Z, and Z 'substituents are each independently a protecting group selected from Bz, Boc, Ac, Cbz, or formyl.

As a third preferred embodiment of the present invention, the present invention provides an ALLN derivative compound represented by the following formula (Ic), an isomer thereof or a pharmacologically acceptable salt thereof:

(Ic)

In this formula,

R3, R4 are each independently a hydrogen atom, a hydroxy group, C ₁ to C ₂₀ alkyl group, C ₁ to C ₂₀ alkoxy group, Z 'protecting group and at least one R' a substituted or one or more substituents selected from the group consisting of groups unsubstituted benzyl (Wherein R 'is at least one substituent selected from the group consisting of a hydrogen atom, a hydroxy group, a C ₁ to C ₁₂ alkyl group and a C ₁ to C ₁₂ alkoxy group)

Z, and Z 'substituents are each independently a protecting group selected from Bz, Boc, Ac, Cbz, or formyl.

As the most preferred compound among the compounds belonging to the general formula (Ia)

( E ) - [4- (1-benzyl-4-oxo-4-pyrrolidin- 1 -yl- - acetic acid benzyl ester (5a); ( E ) - [4- (1-Benzyl-3-dimethylcarbamoyl-allylcarbamoyl) -4-tert-butoxycarbonylamino-butylamino] -acetic acid benzyl ester (5b); ( E ) - [4- (1-Benzyl-3-methylcarbamoyl-allylcarbamoyl) -4-tert-butoxycarbonylamino-butylamino] -acetic acid benzyl ester (5c); ( E ) - [4- (1-benzyl-3-ethylcarbamoyl-allylcarbamoyl) -4-tert-butoxycarbonylamino-butylamino] -acetic acid benzyl ester (5d); ( E ) - [4- (1-benzyl-3-isopropylcarbamoyl-allylcarbamoyl) -4-tert-butoxycarbonylamino-butylamino] -acetic acid benzyl ester (5e) .

As the most preferred compound among the group of compounds belonging to the general formula (Ib)

Benzyl-tert-butyl (5-oxo-5 - ((( 3E , 5E ) -7-oxo-1-phenyl- 7- (pyrrolidin- 1 -yl) hepta-3,5- -Yl) amino) pentane-1, 4-diyl) dicarbonate (9a); Benzyl 3-butyl (5 - ((3 E , 5 E ) -7- (dimethylamino) -7-oxo-1-phenylhept- Pentane-1,4-diyl) dicarbamate (9b); Benzyl tert-butyl (5 - ((3 E , 5 E ) -7- (methylamino) -7-oxo-1-phenylhept- Pentane-1,4-diyl) dicarbamate (9c); Benzyl tert-butyl (5-oxo-5 - (((3 E , 5 E ) -7-oxo-1-phenyl- 7- (piperidin- 1 -yl) hepta-3,5- -Yl) amino) pentane-1,4-diyl) dicarbamate (9d).

As the most preferred compound among the group of compounds belonging to the above general formula (Ic)

( E ) - [4-benzylamino-4- (1-benzyl-3-methylcarbamoyl-allylcarbamoyl) -butylamino] -acetic acid benzyl ester (10a); ( E ) - [4- (1-benzyl-3-methylcarbamoyl-allylcarbamoyl) -4- (3,5-methoxy-benzylamino) -butylamino] -acetic acid benzyl ester (10b); ( E ) - [4- (1-benzyl-3-methylcarbamoyl-allylcarbamoyl) -4- (4-methoxy-benzylamino) -butylamino] -acetic acid benzyl ester (10c); ( E ) - [4- (1-benzyl-3-methylcarbamoyl-allylcarbamoyl) -4- (3-methyl-benzylamino) -butylamino] -acetic acid benzyl ester (10d); ( E ) - [4- (1-benzyl-3-methylcarbamoyl-allylcarbamoyl) -4-isopropylamino-butylamino] -acetic acid benzyl ester (10e).

The compounds of the present invention represented by the above structural formula (I) may be prepared as pharmaceutically acceptable salts and solvates according to methods conventional in the art.

The compounds of the present invention represented by the above structural formula (I) may be prepared as pharmaceutically acceptable salts and solvates according to methods conventional in the art.

Salts are useful as acid addition salts formed by pharmaceutically acceptable free acids. The acid addition salt is prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be subjected to suction filtration.

As the free acid, organic acids and inorganic acids can be used. As the inorganic acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like can be used. Examples of the organic acids include methanesulfonic acid, p- toluenesulfonic acid, acetic acid, trifluoroacetic acid, Citric acid, lactic acid, glycollic acid, gluconic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt in particular, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

The pharmaceutically acceptable salt of the pyridinecarboxylic acid compound having the structure of the general formula (I) above may be an acidic compound which may exist in the pyridinecarboxylic acid compound having the structure of the general formula (I) Or a salt of a basic group. For example, pharmaceutically acceptable salts include the sodium, calcium, and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate rate, methane sulfonate (mesylate) and p - toluene sulfonate (tosylate) and a salt, the salt manufacturing method or manufacturing process known in the art ≪ / RTI >

The pyridinecarboxylic acid compound having the structure of the general formula (I) may exist in different enantiomeric forms because it has an asymmetric center, and all the optically active compounds of the pyridinecarboxylic acid compound having the structure of the general formula (I) Isomers and R or S type stereoisomers and mixtures thereof are also intended to be included within the scope of the present invention. The present invention includes the use of racemates, one or more enantiomeric forms, one or more diastereoisomeric forms, or mixtures thereof, and includes methods and processes for the isolation and isomerization of isomers known in the art.

Another object of the present invention is to provide a process for producing the compound represented by the general formula (I), which can be chemically synthesized by the method shown in the following reaction formulas, but is not limited thereto.

The following reaction schemes illustrate the preparation of representative compounds of the present invention according to the preparation steps. Various compounds of the present invention can be prepared by small modifications such as changing reagents, solvents and reaction sequence used in the synthesis of Reaction Schemes 1 to 3 have. Some of the compounds of the present invention were synthesized according to procedures not included in the scope of the reaction formulas, and detailed synthesis procedures for these compounds are described in each of these examples.

Another object of the present invention is to provide a process for preparing a compound of the present invention which can be prepared by a synthetic method known in the art and can be chemically synthesized by the method shown in the following reaction formulas, no.

[Reaction Scheme 1]

As described in Reaction Scheme 1, α, β-unsaturated ethyl ester (Emmons-Horner-Wadsworth olefination product), which is prepared by using BocNH-Phe-OH as disclosed in the existing literature (21) ethyl ester 1 ); In order to couple the unsaturated ethyl ester 1 with the carboxylic acid of ornithine, the Boc protecting group of an unsubstituted ethyl ester ( 1 ) Is deprotected with trifluoroacetic acid in a dichloromethane solvent to produce a yuryanic acid ( 2 ); Coupling with Boc-orn (Z) -OH using 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide to form dipeptidyl ester 3 ; (5a-5e) of the general formula (Ia) is obtained by coupling the?,? - unsaturated acid (Unsaturated acid 4 ) obtained by hydrolyzing the ester compound ( 3 ) with lithium hydroxide, .

[Reaction Scheme 2]

Except for the step of synthesizing a 2,4-dienyl ester (7) using Emmons-Horner-Wadsworth olefination as described in Reaction Scheme 2 above, As a reaction analogous to Scheme 1, the 2,4-dienyl ester (7) is prepared by reacting the aldehyde (6) described in the literature with ( E ) -ethyl (diethoxyphosphoryl) - (diethoxyphosphoryl) but-2- enoate) and potassium tert-step of the synthesis by treatment with butoxide (potassium tert -butoxide); The major trans-geometry isomers are separated by column chromatography. After deprotecting the Boc group of compound (7), converting the free amine group with Boc-orn (Z) -OH to convert to amide derivative (8) to prepare dienyl amide 8; The carboxylic acid obtained by hydrolyzing the compound (8) with LiOH is reacted with four amines such as pyroolidine, dimethylamine, methylamine and piperidine, It is possible to prepare the derivatives (9a-9d) of the formula (Ib).

[Reaction Scheme 3]

Deprotecting the Boc group of compound (5c) under normal acid conditions (TFA in DCM) to produce the free amine group as described in Scheme 3 above; (Ic) derivatives (10a-10e) were prepared by introducing five alkyl groups through reductive amination using sodium triacetoxyborohydride to the amine compound It is possible.

Accordingly, the present invention provides a process for preparing the derivatives of general formula (Ia), (Ib) and (Ic).

Wherein the ALLN (N-acetyl-L- Leucyl-Lleucyl-L-norleucinal) derivatives of the novel structure of the present invention prepared by the above method for producing a target-malarial activity P. falciparum FCR3 protozoa inhibitory activity and cytotoxicity test for Hela cell growth. In animal experiments using mice infected with Plasmodium berghei, not only did they significantly reduce parasitemia in the blood (parasitemia) Prolonging the survival rate and confirming the potent anti-malarial activity of the novel compounds.

Accordingly, the present invention provides an anti-malarial agent containing an ALLN derivative compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a pharmaceutical composition for treating and preventing a malaria infectious disease, comprising an ALLN derivative compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

The malaria as defined herein includes Plasmodium falciparum , Plasmodium vivax , Plasmodium ovale , or Plasmodium malariae .

The composition of the present invention contains 0.01 to 99% by weight of the compound, based on the total weight of the composition.

However, the composition is not limited thereto, and may vary depending on the condition of the patient, the type of disease, and the progress of the disease.

The compositions comprising the compounds of the present invention may further comprise suitable carriers, excipients and diluents conventionally used in the manufacture of pharmaceutical compositions.

The composition containing the compound according to the present invention may be formulated in the form of powders, granules, tablets, capsules, oral preparations such as suspensions, emulsions, syrups and aerosols, external preparations, suppositories and sterilized injection solutions, Examples of carriers, excipients and diluents that can be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium Silicates, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, magnesium stearate and mineral oil. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient, such as starch, calcium carbonate, sucrose, Or lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of suppository bases include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like.

The preferred dosage of the compound of the present invention varies depending on the condition and the weight of the patient, the degree of disease, the type of drug, the route of administration and the period of time, but can be appropriately selected by those skilled in the art. However, for the desired effect, the compound is preferably administered at 0.01 mg / kg to 10 g / kg per day, preferably 1 mg / kg to 1 g / kg per day. The administration may be carried out once a day or divided into several doses. Therefore, the dose is not intended to limit the scope of the present invention in any aspect.

The composition of the present invention may be administered to mammals such as rats, mice, livestock, humans, and the like in various routes. All modes of administration may be expected, including, for example, oral and rectal, or intravenous.

Wherein a target of ALLN (N-acetyl-L- Leucyl-Lleucyl-L-norleucinal) derivatives of the novel structure according to the invention the active malaria P. falciparum FCR3 protozoa inhibitory activity and cytotoxicity test for HeLa cell growth In animal experiments using mice infected with Plasmodium berghei , not only the blood parasitemia was markedly reduced but also the survival rate of mice was prolonged Malaria activity of the above-mentioned novel compounds. Therefore, the compounds can be usefully used in pharmaceutical compositions for the treatment and prevention of malaria infectious diseases.

FIG. 1 is a graph showing the cumulative survival probability of mice according to the flow of dates. FIG.

Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples.

It is to be understood, however, that the present invention is not limited to the embodiments.

≪ Reference Example 1 >

Starting materials and reagents were purchased from Aldrich Chemical Co., Junsei or others and used without further purification. Thin-layer chromatography (TLC) and column chromatography (CC) were carried out using Kieselgel 60 F ₂₅₄ (Merck) and silica gel (Kieselgel 60,230-400 mesh, Merck) Were visualized on TLC plates with UV light (both short and long wavelengths). ¹ H-NMR and ¹³ C-NMR were performed using a JEOL ECLITSE-500 spectrometer. Chemical shifts measured migration from TMS. (Chemical shifts ( ? ) In ppm and coupling constants ( J ) in Hz). Melting points were used without calibration with open capillary tubes with electrothermal 1A9100 digital melting point apparatus. The IR spectrum was measured using a Perkin Elmer Spectrum One FT-IR Spectrometer and Miracle STatr (ZnSe)

All the anhydrous solvents were distilled under a suitable dehydrating agent under argon gas. All necessary reagents were purchased from Sigma-Aldrich Corp.

≪ Example 1 > E ) -4-amino-5-phenyl-pent-2-enoic acid ethyl ester (( E ) -4-Amino-5-phenyl-pent-2-enoic acid ethyl ester, 2) Synthesis of intermediate

(E) - to 4-tert-Butoxycarbonylamino-5- phenyl-pent-2-enoic acid ethyl ester, 1 (0.4 g, 1.252 mmol) prepared by dissolving in anhydrous DCM (10 mL) and TFA (0.30 mL, 3% mmol), and the mixture is allowed to react at room temperature for 36 hours. After the reaction was completed, the solvent was blown off with a vacuum pump to obtain ( E ) -4-amino-5-phenyl-pent-2-enoic acid ethyl ester (2) in a yield of 99%.

^{1 H-NMR (500 MHz,} CDCl 3) δ 8.26 (bs, 2H), 7.33-7.14 (m, 5H), 6.86 (dd, 1H, J = 16.0, 7.8 Hz), 5.94 (d, 1H, J = 16.0 Hz), 4.12 (q, 1H, J = 7.4 Hz), 3.15 (dd, 1H, J = 14.2, 6,9 Hz), 3.01 (dd, 1H, J = 14.2, 6,9 Hz), 1.22 ( m, 3H).

< Example  2> ( E ) -Ethyl 4- (5 - ((( Benzyloxy ) Carbonyl) amino) -2 - ((tert- Butoxycarbonyl ) Amino) Pentanamido ) -5- Phenylpent -2- Enolate (( E ) - ethyl  Synthesis of Intermediates 4- (5 - ((benzyloxy) carbonyl) amino) -2 - ((tert-butoxycarbonyl) amino) pentanamido) -5-phenylpent-

(E) - 4-Amino- 5-phenyl-pent-2-enoic acid ethyl ester 2 (881.78 mg, 4.09 mmol) the preparation was dissolved in anhydrous DCM, and Boc-orn (Z) -OH ( 1.00 g, 2.73 mmol ). 4-dimethylaminopyridine (32.70 mg, 0.27 mmol) and EDACHCl (784.10 mg, 4.09 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 4 hours. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and then filtered. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate ( E ) -ethyl 4- (5 - (((benzyloxy) carbonyl) amino) -2 - (( Tert-butoxycarbonyl) amino) pentanamido) -5-phenylpent-2-enolate ( 3 ) was obtained in a yield of 72.3%.

^{1 H-NMR (500 MHz,} CDCl 3) δ 7.39-7.10 (m, 10H), 6.89 (dd, 1H, J = 15.6, 5.1 Hz), 5.82 (d, 1H, J = 5.1 Hz), 5.13-4.96 (m, 2H), 4.90 (m, 1H), 4.23-4.07 (m, 3H), 3.48-2.70 (m, 4H), 1.59 (s, 9H), 1.23 (m, 4H).

&Lt; Example 3 > ( E ) -4- (5 - ((benzyloxy) carbonyl) amino) -2 - ((tert-butoxycarbonyl) amino) pentanamide) -5-phenylpent-2-enoic acid E ) -4 - (5 - ((benzyloxy) carbonyl) amino) -2 - ((tert-butoxycarbonyl) amino) pentanamido) -5-phenylpent-2-enoic acid,

( E ) -ethyl 4- (5 - ((benzyloxy) carbonyl) amino) -2 - ((tert-butoxycarbonyl) amino) pentanamido) -5-phenylpent-2-enoate, 3 (1.00 g, 1.85 mmol) Dissolved in anhydrous THF, lithium hydroxide (1.85 mL, 1.85 mmol) was added, and the mixture was reacted at room temperature for 36 hours. After the reaction was completed, pH was adjusted to 4 with 1N HCl, and the organic layer was separated into an aqueous layer and an organic layer by dissolving in water (10 mL) and ethyl acetate (20 mL). The organic layer was washed with brine (20 mL) After drying with anhydrous sodium sulfate, the solvent was blown off with a vacuum pump to obtain ( E ) -4- (5 - (((benzyloxy) carbonyl) amino) -2 - ((tert- butoxycarbonyl ) Amino) pentanamido) -5-phenylpent-2-enoic acid ( 4 ) was obtained in a yield of 98%.

^{1 H-NMR (500 MHz,} CDCl 3) δ 7.34-7.09 (m, 10H), 6.97 (m, 1H), 5.82 (d, 1H, J = 5.1 Hz), 5.27-4.82 (m, 4H), 4.33 (m, 1H), 3.30-2.83 (m, 4H), 1.97-1.54 (m, 4H), 1.43 (s, 9H).

< Example  4> E ) - [4- (1-benzyl-4-oxo-4- Pyrrolidine -1 day- Boot -2- Enylcarbamoyl ) -4-3 Class - Ethoxycarbonylamino - Butylamino ] -Acetic acid benzyl ester (( E ) - [4- (1- Benzyl -4- oxo -4- pyrrolidine -One- yl - but -2-enylcarbamoyl) -4-tert-butoxycarbonylamino-butylamino] -acetic acid benzyl ester , 5a) Synthesis of

5-phenyl-pent-2-enoic acid 4 (1.00 g, 1.85 mmol) was dissolved in anhydrous DCM to prepare a solution of ( E ) -4- [5- (Benzyloxycarbonylmethylamino) -2-tert-butoxycarbonylamino-pentanoylamino] pyrrolidine (0.23 mL, 2.78 mmol). 4-dimethylaminopyridine (22.59 mg, 0.19 mmol) and EDACHCl (532.00 mg, 2.78 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 4 hours. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and then filtered. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate ( E ) - [4- (1-benzyl-4-oxo-4-pyrrolidin-1-yl- But-2-enylcarbamoyl) -4-tert-butoxycarbonylamino-butylamino] -acetic acid benzyl ester (5a) was obtained in a yield of 60.1%.

^{1 H-NMR (500 MHz,} CDCl 3) δ 7.41-7.09 (m, 10H), 6.96 (m, 1H), 5.82 (d, 1H, J = 15.6 Hz), 5.22-4.73 (m, 3H), 4.27 (m, 1H), 3.45-2.57 (m, 8H), 1.95-1.43 (m, 8H), 1.41 (s, 9H).

< Example  5> E ) - [4- (1-benzyl-3- Dimethylcarbamoyl - Allylcarbamoyl ) -4-3-tert- Butoxycarbonylamino - Butylamino ] -Acetic acid benzyl ester (( E ) - [4- (1- Benzyl -3- dimethylcarbamoyl - allylcarbamoyl )-4- tert -butoxycarbonylamino-butylamino] -acetic &lt; / RTI &gt; acid benzyl ester , 5b) Synthesis of

5-phenyl-pent-2-enoic acid 4 (1.00 g, 1.85 mmol) was dissolved in anhydrous DCM to prepare a solution of ( E ) -4- [5- (Benzyloxycarbonylmethylamino) -2-tert-butoxycarbonylamino-pentanoylamino] dimethylamine (2.78 mL, 2.78 mmol). 4-dimethylaminopyridine (22.59 mg, 0.19 mmol) and EDACHCl (532.00 mg, 2.78 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 4 hours. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and then filtered. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate ( E ) - [4- (1-benzyl-3-dimethylcarbamoyl-allylcarbamoyl) -4- Tert-butoxycarbonylamino-butylamino] -acetic acid benzyl ester (5b) was obtained in 63.5% yield.

^{1 H-NMR (500 MHz,} CDCl 3) δ 7.39-7.11 (m, 10H), 6.75 (m, 1H), 6.23 (d, 1H, J = 15.0 Hz), 5.13-4.77 (m, 3H), 4.16 (bs, 1 H), 3.38-3.01 (m, 4H), 2.91 (bs, 6H), 1.41 (s, 9H), 1.24 (m, 4H).

< Example  6> E ) - [4- (1-benzyl-3- Methylcarbamoyl - Allylcarbamoyl ) -4-3-tert- Butoxycarbonylamino - Butylamino ] -Acetic acid benzyl ester (( E ) - [4- (1- Benzyl -3- 메틸 카르amoyl - allylcarbamoyl )-4- tert -butoxycarbonylamino-butylamino] -acetic &lt; / RTI &gt; acid benzyl ester  Synthesis of 5c)

5-phenyl-pent-2-enoic acid 4 (1.00 g, 1.85 mmol) was dissolved in anhydrous DCM to prepare a solution of ( E ) -4- [5- (Benzyloxycarbonylmethylamino) -2-tert-butoxycarbonylamino-pentanoylamino] methylamine (0.68 mL, 2.78 mmol). 4-dimethylaminopyridine (22.59 mg, 0.19 mmol) and EDACHCl (532.00 mg, 2.78 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 4 hours. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and then filtered. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate ( E ) - [4- (1-benzyl-3-methylcarbamoyl-allylcarbamoyl) -4 &lt; RTI ID = 0.0 &gt; -3-tert-butoxycarbonylamino-butylamino] -acetic acid benzyl ester (5c) was obtained in 66.8% yield.

¹ H-NMR (500 MHz, CDCl ₃ )? 7.42-7.05 (m, 10H), 6.80 (m, 1H), 6.30 , 3.35-2.81 (m, 4H), 2.75 (d, 3H, J = 6.0 Hz), 1.85-1.46 (m, 4H), 1.42 (s, 9H).

< Example  7> E ) - [4- (1-benzyl-3- Ethyl carbamoyl - Allylcarbamoyl ) -4-3-tert- Butoxycarbonylamino - Butylamino ] -Acetic acid benzyl ester (( E ) - [4- (1- Benzyl -3- ethylcarbamoyl - allylcarbamoyl )-4- tert -butoxycarbonylamino-butylamino] -acetic &lt; / RTI &gt; acid benzyl ester  (5d) Synthesis of

(E) -4- [5- (Benzyloxycarbonylmethyl -amino) -2-tert-butoxycarbonylamino-pentanoylamino] -5-phenyl-pent-2-enoic acid (1.00 g, 1.85 mmol) the preparation was dissolved in anhydrous DCM and ethylamine (0.21 mL, 2.78 mmol). 4-dimethylaminopyridine (22.59 mg, 0.19 mmol) and EDACHCl (532.00 mg, 2.78 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 4 hours. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and then filtered. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate ( E ) - [4- (1-benzyl-3-ethylcarbamoyl-allylcarbamoyl) -4H-pyrazolecarboxamide] was obtained by column chromatography (hexane / ethyl acetate = 1/1) -3-tert-butoxycarbonylamino-butylamino] -acetic acid benzyl ester (5d) was obtained in 78% yield.

¹ H-NMR (500 MHz, CDCl ₃ )? 7.41-7.10 (m, 10H), 6.81 (m, , 3.96 (m, 2H), 3.33-2.61 (m, 6H), 1.85-1.45 (m, 4H), 1.42 (s, 9H), 1.10 (t, 3H).

< Example  8> E ) - [4- (1-benzyl-3- Isopropylcarbamoyl - Allylcarbamoyl ) -4-3-tert- Butoxycarbonylamino -Butylamino] -acetic acid benzyl ester (( E ) - [4- (1- Benzyl -3- isopropylcarbamoyl - allylcarbamoyl ) -4-tert-butoxycarbonylamino-butylamino] -acetic acid benzyl ester , 5e) Synthesis of

Phenyl-pent-2-enoic acid (1.00 g, 1.85 mmol) was dissolved in anhydrous DCM to prepare an isopropylamine ( E ) -4- [5- (benzyloxycarbonylmethyl- amino) -2- tert -butoxycarbonylamino-pentanoylamino] (0.25 mL, 2.78 mmol). 4-dimethylaminopyridine (22.59 mg, 0.19 mmol) and EDACHCl (532.00 mg, 2.78 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 4 hours. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and then filtered. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate ( E ) - [4- (1-benzyl-3-isopropylcarbamoyl-allylcarbamoyl) - &lt; / RTI &gt; 4-tert-butoxycarbonylamino-butylamino] -acetic acid benzyl ester (5e) was obtained in a yield of 75.2%.

¹ H-NMR (500 MHz, CDCl ₃ )? 7.40-7.11 (m, 10H), 6.78 (m, IH), 6.23 (bs, , 4.13 (m, 1H), 3.99 (m, 1H), 3.41-2.63 (m, 4H), 1.83-1.47 (m, 4H), 1.42 (s, 9H), 1.13 (m, 6H).

< Example  9> (2 E ,4 E ) -Ethyl 6 - ((tert- Butoxycarbonyl ) Amino) -7- Phenyl hepta -2,4-dienolate ((2 E ,4 E ) -ethyl 6 - (( tert - butoxycarbonyl ) amino ) -7- phenylhepta -2,4- dienoate , 7) Synthesis of

( E ) -ethyl 4- (diethoxyphosphoryl) but-2-enoate (0.893 g, 3.98 mmol) was dissolved in anhydrous THF (10 mL) at 0 ° C and potassium tert-butoxide (2.23 mL, 2.23 mmol) . The reaction mixture was allowed to react at room temperature for 1 hour and then reacted with tert-butyl (1-oxo-3-phenylpropan-2-yl) carbamate 6 (264.60 mg, 1.06 mmol) at 0 ° C for 3 hours. The reaction was quenched with water (10 mL) and dissolved in ethyl acetate (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate The residue was purified by column chromatography (hexane / ethyl acetate = 3/1) to give (2 E , 4 E ) -ethyl 6 - ((tert- butoxycarbonyl) amino) 7-phenylhepta-2,4-dienolate (7) was obtained in a yield of 65.3%.

^{1 H-NMR (500 MHz,} CDCl 3) δ 7.31-7.13 (m, 6H), 6.19 (dd, 1H, J = 15.1, 13.5 Hz), 6.01 (dd, 1H, J = 15.1, 5.0 Hz), 5.82 (d, 1H, J = 15.0 Hz), 4.53 (bs, 1H), 4.18 (q, 2H, J = 7.4 Hz), 2.92-2.80 (m, 2H), 1.40 (s, 9H), 1.28 (t, 3H, J = 7.4 Hz).

< Example  10> (2 E ,4 E ) Ethyl 6- (5 - ((( Benzyloxy ) Carbonyl) amino) -2 - ((tert- Butoxycarbonyl ) Amino) Pentanamido ) -7- Phenyl hepta -2,4- Dienolate  ( (2 E ,4 E ) - ethyl  6- (5 - ((( benzyloxy ) carbonyl ) amino ) -2 - ((tert-butoxycarbonyl) amino) pentanamido) -7-phenylhepta-2,4-dienoate, 8)

(2 E, 4 E) -ethyl 6 - prepared by dissolving the ((tert-butoxycarbonyl) amino) -7-phenylhepta-2,4-dienoate, 7 (1.00 g, 2.90 mmol) in anhydrous DCM (20 mL) and TFA (0.50 mL, 3% mmol) was added and the reaction was allowed to proceed at room temperature for 36 hours. After the reaction was completed and the solvent blown into the vacuum pump (2 E, 4 E) - ethyl 6-amino-2,4-diethoxy-7-phenyl-heptanoic obtain a play rate to a 95% yield.

(Z) -OH (284 mg, 1.16 mmol) was prepared by dissolving (2 E , 4 E ) -ethyl 6-amino- , 0.77 mmol). EDICHCl (223 mg, 1.16 mmol) was added to the reaction mixture, and the reaction was carried out at room temperature for 4 hours. Then, the solvent was distilled off. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and then filtered. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate substances obtained away the solvent with a vacuum pump is purified by column chromatography (hexane / ethyl acetate = 1/1) and (2 E, 4 E) - ethyl 6- (5 - (((benzyloxy) carbonyl) amino) - Pentanamido) -7-phenylhepta-2,4-dienolate (8) was obtained in a yield of 79.6%.

^{1 H-NMR (500 MHz,} CDCl 3) δ 7.39-7.11 (m, 11H), 6.26 (dd, 1H, J = 15.1, 11.0 Hz), 5.97 (dd, 1H, J = 15.1, 6.0 Hz), 5.80 (d, 1H, J = 15.1 Hz), 5.11-4.95 (m, 2H), 4.93-4.78 (m, 2H), 4.17 (q, 2H, J = 7.4 Hz), 3.16-2.79 (m, 4H), 1.80-1.45 (m, 4H), 1.43 (s, 9H), 1.27 (t, 3H, J = 7.4 Hz).

< Example  11> benzyl tert-butyl (5-oxo-5 - (((3 E , 5 E ) -7-oxo-1- Phenyl -7- ( Pyrrolidine -1 day) Hepta -3,5- Dien Yl) amino) pentane-l, 4- Dill ) Dicarbonate  ( benzyl tert - butyl  (5- oxo -5 - (((3 E , 5 E ) -7- oxo -One- phenyl (Pyrrolidin-1-yl) hepta-3,5-dien-2-yl) amino) pentane-1,4-diyl) dicarbamate 9a)

(2 E , 4 E ) -ethyl 6- (5 - ((benzyloxy) carbonyl) amino) -2 - ((tert-butoxycarbonyl) amino) pentanamido) -7-phenylhepta-2,4-dienoate, g, 1.65 mmol) was dissolved in anhydrous THF, lithium hydroxide (1.65 mL, 1.65 mmol) was added, and the mixture was reacted at room temperature for 36 hours. After the reaction was completed, pH was adjusted to 4 with 1N HCl, and the organic layer was separated into an aqueous layer and an organic layer by dissolving in water (10 mL) and ethyl acetate (20 mL). The organic layer was washed with brine (20 mL) It was dried with sodium (anhydrous sodium sulfate), filter and blow the solvent with a vacuum pump (2 E, 4 E) -6- (5 - ((( benzyloxy) carbonyl) amino) -2 - ((tert- Butoxycarbonyl) amino) pentanamido) -7-phenylhepta-2,4-dienoic acid was obtained in a yield of 96.5%. This carboxylic acid was used in the synthesis of compounds 9b, 9c and 9d.

^{1 H-NMR (500 MHz,} CDCl 3) δ 7.39-7.11 (m, 11H), 6.19 (dd, 1H, J = 15.1, 11.0 Hz), 6.02 (dd, 1H, J = 15.1, 6.0 Hz), 5.80 (d, 1H, J = 15.1 Hz), 5.14-4.79 (m, 4H), 3.40-2.81 (m, 4H), 1.79-1.42 (m, 4H), 1.43 (s, 9H).

(2 E , 4 E ) -6- (5 - ((benzyloxy) carbonyl) amino) -2 - ((tert-butoxycarbonyl) amino) pentanamido) 1.68 mmol) was dissolved in anhydrous DCM and pyrrolidine (0.21 mL, 2.52 mmol) was added. 4-dimethylaminopyridine (20.52 mg, 0.17 mmol) and EDACHCl (483.11 mg, 2.52 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 4 hours. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL), washed with 1N HCl and 15% NaOH, The solvent was distilled off under reduced pressure and the residue was purified by column chromatography (hexane / ethyl acetate = 1/1) to obtain benzyl tert-butyl (5-oxo-5 - ((( 3E , 5E ) Yl) amino) pentane-1,4-diyl) dicarbonate (9a) was obtained in a yield of 59.3% .

^{1 H-NMR (500 MHz,} CDCl 3) δ 7.38-7.10 (m, 11H), 6.77 (bs. 1H), 6.28-5.71 (m, 3H), 5.22-4.76 (m, 4H), 4.23 (bs, 1H), 3.41-3.00 (m, 4H), 2.96-2.72 (m, 4H), 1.95-1.40 (m, 8H), 1.42 (s, 9H).

< Example  12> benzyl tert-butyl (5 - (((3 E , 5 E ) -7- (dimethylamino) -7-oxo-1- Phenyl hepta -3,5- Dien Yl) amino) -5- Oxopentane -1,4- Dill ) Dicarbamate  ( benzyl tert - butyl  (5 - (((3 E , 5 E ) -7- ( dimethylamino ) -7-oxo-1-phenylhepta-3,5-dien-2-yl) amino) -5-oxopentane-1,4-diyl) dicarbamate, 9b)

(2 E , 4 E ) -6- (5 - ((benzyloxy) carbonyl) amino) -2 - ((tert-butoxycarbonyl) amino) pentanamido) 1.68 mmol) was dissolved in dry DCM and dimethylamine (0.85 mL, 2.52 mmol) was added. 4-dimethylaminopyridine (20.52 mg, 0.17 mmol) and EDACHCl (483.11 mg, 2.52 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 4 hours. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and then filtered. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and substances derived away the solvent with a vacuum pump is purified by column chromatography (hexane / ethyl acetate = 1/1) and benzyl tert-butyl (5 - (((3 E , 5 E) -7- ( dimethylamino) -7 -1-phenylhepta-3,5-dien-2-yl) amino) -5-oxopentane-1,4-diyl) dicarbamate (9b) in 71.2% yield.

^{1 H-NMR (500 MHz,} CDCl 3) δ 7.37-7.11 (m, 11H), 6.62 (bs, 1H), 6.33-5.87 (m, 3H), 5.19-4.76 (m, 4H), 4.18 (bs, 1H), 3.39-2.80 (m, 10H), 1.81-1.40 (m, 4H), 1.42 (s, 9H).

< Example  13> benzyl tert-butyl (5 - (((3 E , 5 E ) -7- ( Methyl amino ) -7-oxo-1- Phenyl hepta  -3,5- Dien Yl) amino) -5- Oxopentane -1,4- Dill ) Dicarbamate  ( benzyl tert - butyl  (5 - (((3 E , 5 E ) -7- ( methylamino ) -7-oxo-1-phenylhepta-3,5-dien-2-yl) amino) -5-oxopentane-1,4-diyl) dicarbamate, 9c)

(2 E , 4 E ) -6- (5 - ((benzyloxy) carbonyl) amino) -2 - ((tert-butoxycarbonyl) amino) pentanamido) 1.68 mmol) was dissolved in anhydrous DCM and methylamine (5.1 mL, 2.52 mmol) was added. 4-dimethylaminopyridine (20.52 mg, 0.17 mmol) and EDACHCl (483.11 mg, 2.52 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 4 hours. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and then filtered. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate (3 E , 5 E ) -7- (methylamino) -7 (3-methylpiperazin-1-yl) 1-phenylhept-3,5-dien-2-yl) amino) -5-oxopentane-1,4-diyl) dicarbamate (9c) was obtained in 70.9% yield.

^{1 H-NMR (500 MHz,} CDCl 3) δ 7.38-7.08 (m, 11H), 6.49 (bs, 1H), 6.15-5.72 (m, 3H), 5.15-4.76 (m, 4H), 4.20 (bs, 1H), 3.20-2.72 (m, 7H), 1.82-1.43 (m, 4H), 1.41 (s, 9H).

< Example  14> benzyl tert-butyl (5-oxo-5 - (((3 E , 5 E ) -7-oxo-1- Phenyl -7- (piperidin-1-yl) Hepta -3,5- Dien Yl) amino) pentane-l, 4- Dill ) Dicarbamate  ( benzyl tert - butyl  (5- oxo -5 - (((3 E , 5 E ) -7- oxo 1-yl) hepta-3,5-dien-2-yl) amino) pentane-1,4-diyl) dicarbamate, 9d)

(2 E , 4 E ) -6- (5 - ((benzyloxy) carbonyl) amino) -2 - ((tert-butoxycarbonyl) amino) pentanamido) 1.68 mmol) was dissolved in dry DCM and piperidine (0.25 mL, 2.52 mmol) was added. 4-dimethylaminopyridine (20.52 mg, 0.17 mmol) and EDACHCl (483.11 mg, 2.52 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 4 hours. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and then filtered. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and substances derived away the solvent with a vacuum pump is purified by column chromatography (hexane / ethyl acetate = 1/1) and benzyl tert-butyl (5-oxo -5 - (((3 E, 5 E) -7- oxo- (Piperidin-1-yl) hepta-3,5-dien-2-yl) amino) pentane-1,4-diyl) dicarbamate (9d) was obtained in 62.8% yield.

^{1 H-NMR (500 MHz,} CDCl 3) δ 7.40-7.09 (m, 11H), 6.77 (bs, 1H), 6.33-5.69 (m, 3H), 5.27-4.75 (m, 4H), 4.23 (bs, 1H), 3.42-2.79 (m, 8H), 1.85-1.30 (m, 10H), 1.43 (s, 9H).

< Example  15> E )-[4- Benzylamino -4- (l-benzyl-3- Methylcarbamoyl - Allylcarbamoyl ) - Butylamino ] -Acetic acid benzyl ester (( E )-[4- Benzylamino -4- (1- benzyl -3- 메틸 카르amoyl - allylcarbamoyl ) -butylamino] -acetic acid benzyl ester , 10a) Synthesis of

( E ) - [4- (1-Benzyl-3-methylcarbamoyl-allylcarbamoyl) -4-tert-butoxycarbonylamino-butylamino] -acetic acid benzyl ester, 5c (1.00 g, 1.81 mmol) was dissolved in anhydrous DCM , TFA (0.50 mL, 3% mmol) was added, and the mixture was reacted at room temperature for 36 hours. After the reaction was completed, the solvent was blown off with a vacuum pump to obtain ( E ) -benzyl (4-amino-5 - ((5- (methylamino) ) -5-oxopentyl) carbamate in 97% yield, which was used in the synthesis of compounds 9a-9e.

( E ) -benzyl (4-amino-5 - ((5- (methylamino) -5-oxo-1-phenylpent-3-en- 2- yl) amino) -5- oxopentyl) carbamate (1.00 g, 1.82 mmol ) Was dissolved in anhydrous DCM and benzaldehyde (0.19 mL, 5.78 mmol) was added. Sodium triacetoxyborohydride (1.15 g, 5.45 mmol) was added and the mixture was reacted at room temperature for 12 hours and then the solvent was distilled off. After separating into an aqueous layer and an organic layer using ethyl acetate (20 mL) and water, the organic layer was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered, The material was purified by column chromatography (hexane / ethyl acetate = 1/1) to give ( E ) - [4-benzylamino- Acetic acid benzyl ester (10a) was obtained in a yield of 56.8%.

^{1 H-NMR (500 MHz,} CDCl 3) δ 8.12 (bs, 1H), 7.42-7.13 (m, 15H), 6.56 (dd, 1H, J = 15.1, 6.0 Hz), 5.82 (d, 1H, J = 2H), 2.60 (d, 3H, J &lt; RTI ID = 0.0 &gt; = 4.6 Hz), 1.78-1.36 (m, 4H).

< Example  16> E ) - [4- (1-benzyl-3- Methylcarbamoyl - Allylcarbamoyl ) -4- (3,5- Methoxy - Benzylamino ) - Butylamino ] -Acetic acid benzyl ester (( E ) - [4- (1- Benzyl -3- 메틸 카르amoyl - allylcarbamoyl ) -4- (3,5-methoxy-benzylamino) -butylamino] -acetic acid benzyl ester , 10b) Synthesis of

( E ) -benzyl (4-amino-5 - ((5- (methylamino) -5-oxo-1-phenylpent-3-en- 2- yl) amino) -5- oxopentyl) carbamate (1.00 g, 1.82 mmol ) Was dissolved in anhydrous DCM, and 3,5-methoxybenzaldehyde (291.53 mg, 1.82 mmol) was added thereto. Sodium triacetoxyborohydride (1.15 g, 5.45 mmol) was added and the mixture was reacted at room temperature for 12 hours and then the solvent was distilled off. After separating into an aqueous layer and an organic layer using ethyl acetate (20 mL) and water, the organic layer was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered, ( E ) - [4- (1-benzyl-3-methylcarbamoyl-allylcarbamoyl) -4- (3,5-methoxy -Benzylamino) -butylamino] -acetic acid benzyl ester (10b) was obtained in a yield of 60.1%.

^{1 H-NMR (500 MHz,} CDCl 3) δ 7.33-7.12 (m, 10H), 7.01 (d, 2H, J = 2.3 Hz), 6.90 (m, 1H), 6.70 (t, 1H, J = 2.3 Hz ), 5.88 (m, 1H) , 5.10-4.98 (m, 3H), 3.93-3.89 (m, 2H), 3.87 (s, 6H), 3.19-2.85 (m, 4H), 2.79 (d, 3H, J = 4.6 Hz), 1.80-1.35 (m, 4H).

< Example  17> E ) - [4- (1-benzyl-3- Methylcarbamoyl - Allylcarbamoyl ) -4- (4- Methoxy - Benzylamino ) - Butylamino ] -Acetic acid benzyl ester (( E ) - [4- (1- Benzyl -3- 메틸 카르amoyl - allylcarbamoyl ) -4- (4-methoxy-benzylamino) -butylamino] -acetic acid benzyl ester , 10c) Synthesis

( E ) -benzyl (4-amino-5 - ((5- (methylamino) -5-oxo-1-phenylpent-3-en- 2- yl) amino) -5- oxopentyl) carbamate (1.00 g, 1.82 mmol ) Was dissolved in anhydrous DCM and p-anisolaldehyde (0.22 mL, 1.82 mmol) was added. Sodium triacetoxyborohydride (1.15 g, 5.45 mmol) was added and the mixture was reacted at room temperature for 12 hours and then the solvent was distilled off. After separating into an aqueous layer and an organic layer using ethyl acetate (20 mL) and water, the organic layer was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered, The material was purified by column chromatography (hexane / ethyl acetate = 1/1) to obtain ( E ) - [4- (1-benzyl-3- methylcarbamoyl-allylcarbamoyl) -4- (4-methoxy- Amino) -butylamino] -acetic acid benzyl ester (10c) was obtained in 62.5% yield.

^{1 H-NMR (500 MHz,} CDCl 3) δ 7.37-7.12 (m, 10H), 7.09 (d, 2H, J = 8.7 Hz), 6.84 (d, 2H, J = 8.7 Hz), 6.81 (m, 1H ), 5.55 (m, IH), 5.38 (d, IH, J = 15.0 Hz), 5.07 (s, 2H), 4.96 (m, , 3.41 (ABq, 2H, J = 13.3 Hz), 3.19-2.93 (m, 4H), 2.81 (d, 3H, J = 4.6 Hz), 1.86-1.49 (m, 4H).

< Example  18> E ) - [4- (1-benzyl-3- Methylcarbamoyl - Allylcarbamoyl ) -4- (3- methyl - Benzylamino ) - Butylamino ] - Acetic acid  Benzyl ester (( E ) - [4- (1- Benzyl -3- 메틸 카르amoyl - allylcarbamoyl ) -4- (3-methyl-benzylamino) -butylamino] -acetic &lt; / RTI & acid benzyl ester , 10d) Synthesis of

( E ) -benzyl (4-amino-5 - ((5- (methylamino) -5-oxo-1-phenylpent-3-en- 2- yl) amino) -5- oxopentyl) carbamate (1.00 g, 1.82 mmol ) Was dissolved in anhydrous DCM and m-tolualdehyde (0.21 mL, 1.82 mmol) was added. Sodium triacetoxyborohydride (1.15 g, 5.45 mmol) was added and the mixture was reacted at room temperature for 12 hours and then the solvent was distilled off. After separating into an aqueous layer and an organic layer using ethyl acetate (20 mL) and water, the organic layer was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered, The material was purified by column chromatography (hexane / ethyl acetate = 1/1) to give ( E ) - [4- (1-benzyl-3-methylcarbamoyl-allylcarbamoyl) -4- ) -Butylamino] -acetic acid benzyl ester (10d) was obtained in 58.2% yield.

^{1 H-NMR (500 MHz,} CDCl 3) δ 7.50-6.90 (m, 14H), 6.78 (m, 1H), 5.55 (bs, 1H), 5.48 (d, 1H, J = 15.1 Hz), 5.06 (s , 2H), 4.96 (m, 1H), 3.47 (s, 2H), 3.22-2.78 (m, 4H), 2.80 (d, 3H, J = 4.6 Hz), 2.32 (s, 3H), 1.82-1.44 ( m, 4H).

< Example  19> E ) - [4- (1-benzyl-3- Methylcarbamoyl - Allylcarbamoyl )-4- Isopropylamino - Butylamino ] -Acetic acid benzyl ester (( E ) - [4- (1- Benzyl -3- 메틸 카르amoyl - allylcarbamoyl ) -4-isopropylamino-butylamino] -acetic acid benzyl ester , 10e) Synthesis of

( E ) -benzyl (4-amino-5 - ((5- (methylamino) -5-oxo-1-phenylpent-3-en- 2- yl) amino) -5- oxopentyl) carbamate (1.00 g, 1.82 mmol ) Was dissolved in anhydrous DCM and isopropylaldehyde (1.00 g, 1.82 mmol) was added. Sodium triacetoxyborohydride (1.15 g, 5.45 mmol) was added and the mixture was reacted at room temperature for 12 hours and then the solvent was distilled off. After separating into an aqueous layer and an organic layer using ethyl acetate (20 mL) and water, the organic layer was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered, The material was purified by column chromatography (hexane / ethyl acetate = 1/1) to give ( E ) - [4- (1-benzyl-3-methylcarbamoyl-allylcarbamoyl) -4- -Acetic acid benzyl ester (10e) was obtained in 59% yield.

^{1 H-NMR (500 MHz,} CDCl 3) δ 7.37-7.12 (m, 10H), 6.80 (dd, 1H, J = 15.6, 5.0 Hz), 6.03 (d, 1H, J = 15.6 Hz), 5.08-4.99 (m, 2H), 4.89 ( m, 1H), 3.14-2.97 (m, 3H), 2.84-2.73 (m, 2H), 2.78 (d, 3H, J = 5.1 Hz), 1.83-1.35 (m, 4H ), 1.09 (m, 6H).

< Experimental Example  1 > anti- Malia  Search for efficacy

In order to confirm the anti-malaria efficacy of the compounds of the above examples, the inhibitory effect on Plasmodium falciparum was tested in accordance with the method described in the literature (Jung SY, Zheng B, Choi L-leucyl-L-norleucine by the inhibition of Plasmodium falciparum calpain. Arch Pharm Res. 2009 Jun; 32 (6): 899-906).

1.1. Cells and reagents

HeLA cells were maintained in RPMI 1640 medium (Roswell Park Memorial Institute, 10% fetal bovine serum, and 0.01% antibiotic-antimycotic supplemented) and RPMI 1640 medium was supplied from Gibco BRL, Grand Island, NY, USA. Tissue culture plates were purchased from Sigma-Aldrich Corp. (St. Louis, Mo., USA) using DMSO (Dimethyl sulfoxide) for the company (Falcon, BD Biosciences, Franklin Lakes, NJ, USA).

HeLa cells were cultured in ES medium supplemented with 2% heat-inactivated fetal bovine serum (FBS) (Nissui Pharmaceuticals, Tokyo, Japan) supplied by Gibco BRL (Grand Island, in the plastic barrel 37 ° C, were incubated in suspension culture under 5% CO ₂ atmosphere. tissue culture plates were purchased from companies (Falcon, BD Biosciences, Franklin Lakes , NJ, USA) using CQ and ALLN as a positive control .

1.2. Malaria culture

P. falciparum FCR-3 strain (American Type Culture Collection (ATCC 50005 Manassas, VA, USA) by the application of method described in the literature heat-inactivated 10% human serum type A the addition of the type O red blood cells were suspended in RPMI 1640 medium (Jensen, JB and Trager, W., Plasmodium falciparum in culture: establishment of additional strains, Am. J. Trop. Med. Hyg., 27, 743-746, 1978).

The plates were placed under a CO ₂ O ₂ N ₂ incubator (5% CO ₂ , 5% O ₂ , 90% N ₂ atmosphere) at 37 ° C and the medium was replaced with 5% parasitemia (5 parasitic infections in 100 red blood cells Which means the presence of red blood cells).

1.3. Experimental course

(200 μL) were added to a 48-well plate using an asynchronously cultivated strain ( P. falciparum ) at a concentration ranging from 5-100 μM, and 200 μL of P was added thereto using DMSO or RPMI-1640 medium as a solvent falciparum infected red blood cells (0.5% parasitemia and 2% hematocrit). The appropriate solvent control was used and the culture plates were incubated in a CO ₂ O ₂ N ₂ multiple gas incubator at 37 ° C for 72 hours without medium change. To determine the anti-malarial activity, P. falciparum FCR-3 strain wells were cultured using FACSCalibur (BD Biosciences; San Jose, CA, USA) using optical microscopy (AXIOVERT10, ZEISS, Germany) and flow cytometry assays and the parasitemia ratio per well was measured.

Blood smears were prepared for each well and Diff-Quick strain was performed for microscopic observation. A total of 1000 red blood cells / 1 thin blood film was examined under a microscope and the parasitemia ratio of the control group was adjusted to range from 4% to 5% for 72 hours. In a flow cytometric assay, 2 μL blood per well was diluted in 200 μL PBS and mixed with 3 mL solution (1 μM SYTOX green solution). IC ₅₀ Means the compound concentration required to inhibit a 50% increase over the parasite density at the 72 hour parasite density.

< Experimental Example  2> Cytotoxicity detection

In order to confirm the cytotoxicity of the compounds of the above examples, the cytotoxicity against HeLa cells was assayed according to the method described in the literature as follows (Jung SY, Zheng B, Choi YY, Soh BY, Kim SY, Park KI, Park H. Antimalarial effect of N-acetyl-L-Leucyl-L-leucyl-L-norleucinal by the inhibition of Plasmodium falciparum calpain. Arch Pharm Res. 2009 Jun; 32 (6): 899-906)

200 [mu] L cell suspension was dispensed into 96-well cell culture plates. The medium treated with 200 μL of various concentrations of the medium was changed after 2 hours and the plate was incubated for 48 hours at 37 ° C under 5% CO ₂ atmosphere. All test compounds were tested in duplicate at individual concentrations and cell counts were measured with a cell reader (cell counter CC-130; Toa Medical Electric Co., Japan). All data points represent the mean of three experiments and CC ₅₀ (50% cytotoxicity concentration) means the compound concentration required to inhibit 50% increase in cell density at 48 hours compared to the control. The TI (Therapeutic index) means the CC ₅₀ number average for Hela cells per IC ₅₀ value average for P. falciparum .

As shown in Table 1, the compounds according to the present invention exhibited an IC _{50 of} 0.64 μM, a CC _{50 of} 25.10 μM and a TI of 39.21, respectively, and inhibition of Plasmodium falciparum was confirmed , ALLN controls were IC ₅₀ (0.64 μM), CC ₅₀ (25.10 [mu] M) and TI (39.21) (Table 1). Among the five compounds of type I, compound 5c exhibited the most potent anti-malarial activity with IC ₅₀ (5 μM) and 50% cytotoxicity concentration (CC ₅₀ - 1063 μM) , TI; 157), the most safe compound. Compounds 5b and 5e also exhibited excellent anti-malarial activity (IC ₅₀ : 6 μM and 9.29 μM, respectively). Two new compounds, 5c and 11d, exhibited strong antiallergic activity.

Anti-malaria activity and cytotoxicity Compounds Inhibition of P. falciparum FCR3 strain growth (IC ₅₀ , uM) Inhibition of HeLa cell growth (CC ₅₀ , μM) Therapeutic index = CC ₅₀ / IC ₅₀ ALLN 0.64 + 0.11 25.10 ± 0.16 39.21 5a 11.40 ± 0.13 152.86 ± 0.08 13.41 5b 6.00 + - 0.01 207.09 ± 0.15 34.52 5c 5.00 0.41 1063.00 ± 0.14 157.24 5d > 100 1998.00 ± 0.09 > 19.98 5e 9.29 + 0.14 314.33 + - 0.14 33.84 9a > 100 53.05 + 0.14 > 0.53 9b > 100 116.85 ± 0.12 > 1.17 9c 23.64 + 0.14 281.16 ± 0.16 11.89 9d 15.69 + - 0.17 175.14 + 0.14 11.16 10a 15.30 ± 0.13 252.84 + - 0.01 16.53 10b 16.35 + - 0.10 258.62 ± 0.08 15.82 10c 16.70 + 0.04 461.26 + 0.07 27.62 10d 5.00 + 0.09 241.68 ± 0.21 48.34 10e 56.28 ± 0.01 610.90 ± 0.13 10.85

&Lt; Experimental Example 3 >

In order to confirm the anti-malarial activity of the compounds of the above-mentioned Examples in mice, the effect on the survival rate of parasitemia and mice in mouse blood infected with Plasmodium berghei was determined according to the method described in the literature Experiments were performed (24)

3.1. Preparation for experiment

Seven-week-old ICR female mice (ORIENT BIO CO., LRD from South Korea) were raised and maintained according to the provisions of the animal experimentation at the Wonkwang University School of Medicine.

Protozoa mouse (Plasmodium berghei NK65 (10 infected by malaria ^six channels on mouse red blood cells through the administration intraperitoneally into ATCC 30090 ^™) were separated by 8-10 mouse 100 positive control (positive control-CQ, SigmaAldrich; . St (Vehicle control-1% DMSO solution), and derivatives 10a and 10d were intravenously administered once daily for 4 days from the 5th day after infection (5-10% parasitemia). The amount of each sample was suspended in saline with 0.5 mg / kg or 6 mg / kg of CQ, 0.5 mg / kg or 5 mg / kg of ALLN and 0.5 mg / kg or 5 mg / kg of derivatives 10a and 10d respectively . After parasitemia, the cells were stained with Diff-Quick strain until day 12 and examined microscopically and analyzed by in-vivo method using a Cytometer (Beckton-Dickinson, FACS Calibur ^TM ) (FACS) were performed. The survival rate was measured until the same day after infection It was.

3.2. Flow cytometry assay (FACS) assay

Two different flow cytometric assay (FACS) assays were performed, including in - vitro and in - vivo assays. The cell signals of the two experiments were analyzed using a program (CellQuest software; Beckton-Dickinson) on a FACS Calibur ^™ flow cytometer.

In the Plasmodium berghei NK65 Infection Model, two blood samples recovered from the tail vein of the recipient mouse were fixed with 2 ml of ultra-cold methanol. Samples were stored at -80 ° C for 30 to 45 minutes before the experiment. The fixed cells were washed with methanol and the blood cells were washed twice with PBS. For analysis, 200 μL of fixed blood cell suspension in 1 ml FACS buffer was added to a 96-well plate for cell culture and centrifuged at 2000 rpm for 2 minutes. The supernatant was removed and a working RNAse solution (RNAse 1 diluted in FACS buffer 30) was added to each well of the experimental plate and incubated at room temperature for 30 to 45 minutes. After washing the cells twice with PBS, the supernatant was aspirated and a cold 30 solution (PI 1 diluted in FACS buffer 5) was added to each well of the experimental plate in a dark place for FACS analysis . Individual well blood samples were analyzed by flow cytometer with an average ratio of 600 erythrocytes per second until 19000 erythrocytes were recovered.

FACS PI staining assays in vivo ( in-vivo ) Assay method In a variable signal value (drug-untreated and treated infected group), the background value (normal mouse group; normal mice group ) Responses were observed as a parasitemia percentage.

3.3. Experiment result

10 ⁶ Plasmodium kg, 5 mg / kg, 10 mg / kg, 10 mg / kg, 10 mg / kg, and 0.5 mg / kg, respectively) of the parasitemia after 5 days of infusion of the berghei NK65 / kg, ALLN 0.5 mg / kg, 5 mg / kg intravenously once a day for 4 days, and the survival rate of the mice and the survival rate of parasitemia from the blood collected from the mouse tail were observed for 15 days.

<Influence on the number of parasitemia in blood>

We examined the number of changes in parasitemia on the first day of drug administration and the number of days of parasitemia on the 8th day of drug administration.

On the first day of dosing, on day 5, parasitemia is present in the blood at an approximate level of about 9 on average, but the number of parasitemia varies depending on the drug on the last day of dosing.

In particular, 10a 5 mg / kg averaged 3.5725, which was slightly higher than 6 mg / kg CQ with the lowest number of parasitemia, but the standard error was only about 6 mg / kg CQ, Which is less than 4.98. Thus, 10a 5mg / kg seems to work more effectively in the blood of mice. (See Table 2)

Plasmodium Anti-malarial efficacy of 10a in berghei -infected mice N Average Standard
Deviation Standard
error 95% confidence interval for the mean Minimum value Maximum value Lower limit value Upper limit value 5 days Control 7 8.5914 3.03760 1.14810 5.7821 11.4007 4.09 12.83 10a 0.5 mg / kg 8 8.8763 2.54053 0.89821 6.7523 11,0002 5.62 13.01 10a 5mg / kg 8 9.2287 2.63348 0.93108 7.0271 11.4304 5.23 13.09 10a 10 mg / kg 8 9.7738 2.59250 0.91659 7.6064 11.9411 5.52 13.05 ALLN (0.5 mg / kg) 8 10.9038 3.40628 1.20430 8.0560 13.7515 5.60 14.61 ALLN (5 mg / kg) 8 9.1312 3.78847 1.33942 5.9640 12.2985 2.35 14.00 CQ 6 mg / kg 8 8.9936 3.88768 1.37450 5.7461 12.2464 1.10 13.04 CQ 0.5 mg / kg 8 8.6675 4.96016 1.75368 4.5207 12.8143 0.00 16.58 Sum 63 9.2819 3.32961 0.41949 8.4434 10.1205 0.00 16.58 8 days Control 6 3.6800 1.08333 0.44227 2.5431 4.8169 2.84 5.57 10a 0.5 mg / kg 5 5.0280 2.43570 1.08928 2.0037 8.0523 2.19 8.89 10a 5mg / kg 8 3.5725 0.76122 0.26913 2.9631 4.2089 2.48 4.98 10a 10 mg / kg 6 4.0417 0.78853 0.32192 3.2142 4.8692 3.06 5.16 ALLN (0.5 mg / kg) 4 3.8500 1.17771 0.58885 1.9760 5.7240 2.43 5.22 ALLN (5 mg / kg) 5 5.4160 2.85439 1.27652 1.8718 8.9602 3.03 9.66 CQ 6 mg / kg 7 2.5071 1.54624 0.58442 1.0771 3.9372 1.03 5.34 CQ 0.5 mg / kg 5 4.2040 2.40219 1.07429 1.2213 7.1867 2.14 8.18 Sum 46 3.9370 1.78919 0.26380 3.4056 4.4683 1.03 9.66

&Lt; Effect on survival rate of mouse &

As a result of examining the confidence interval for the survival rate of each drug-specific mouse, the survival period of each mouse was found to be different depending on the drug.

In particular, 10a 5 mg / kg is estimated to be 14.375 times longer than other drugs, and the standard error is less than 1/3 of the control, which is much lower than the control. (See Table 3).

Plasmodium The mean for mouse survival time in mice infected with berghei reagent Average ^a Estimate Standard error 95% confidence interval Lower limit maximum control 11.375 1.731 7.981 14.769 10a 0.5 mg / kg 10.500 1.392 7.772 13.228 10a 5mg / kg 14.375 0.585 13.229 15.521 10a 10 mg / kg 12,000 1.311 9.430 14.570 ALLN (0.5 mg / kg) 9.375 1.571 6.297 12.453 ALLN (5 mg / kg) 9.875 1.304 7.319 12.431 CQ 6 mg / kg 13.500 1.031 11.480 15.520 CQ 0.5 mg / kg 10.125 1.246 7.684 12.566 all 11.391 0.506 10.399 12.383

1, which shows the cumulative survival probability of mice according to the date,

The higher the cumulative probability, the more mice were alive. That is, during the 15-day experimental period, 10 a 5 mg / kg showed the most survival. (See Fig. 1)

Hereinafter, formulation examples of the composition containing the compound of the present invention will be described, but the present invention is not intended to be limited thereto but is specifically described.

Formulation example  One. Sanje  Produce

Compound 5c 200 mg

Lactose ----------------------------------------------- 100 mg

Talc ----------------------------------------------- 10 mg

The above components are mixed and filled in airtight bags to prepare powders.

Formulation example  2. Preparation of tablets

Compound 5a 200 mg

Corn starch ----------------------------------------- 100 mg

Lactose ----------------------------------------------- 100 mg

Magnesium stearate -------------------------------- 2 mg

After mixing the above components, tablets are prepared by tableting according to the usual preparation method of tablets.

Formulation example  3. Preparation of capsules

Compound 5b 200 mg

Crystalline cellulose - 3 mg

Lactose ------------------------------------------- 14.8 mg

Magnesium stearate ------------------------------ 0.2 mg

The above components are mixed in accordance with a conventional method for producing a capsule, and filled in a gelatin capsule to prepare a capsule.

Formulation example  4. Preparation of injections

Compound 5e 200 mg

Mannitol --------------------------------------------- 180 mg

Sterile sterile distilled water for injection --------------------------------- 2974 mg

Na ₂ HPO _{4 ,} 12H ₂ O ---------------------------------------- 26 mg

(2 ml) per ampoule in accordance with the usual injection method.

Formulation example  5. Liquid  Produce

Compound 9c 200 mg &lt; RTI ID = 0.0 &gt;

Isolation Party ------------------------------------------- 10 g

Mannitol --------------------------------------------- 5 g

Purified water ---------------------------------------------

Each component was added and dissolved in purified water according to the usual liquid preparation method, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed, and purified water was added thereto. The whole was added with purified water to adjust the total volume to 100 ml, And sterilized to prepare a liquid preparation.

Claims (11)

An ALLN derivative compound represented by the following general formula (I), an isomer thereof, or a pharmacologically acceptable salt thereof:

(I)
In this formula,
R 1 and R 2 are each independently at least one substituent selected from the group consisting of a hydrogen atom, a halogen atom selected from F, Cl, Br or I, a hydroxyl group, a C ₁ to C ₁₂ alkyl group and a C ₁ to C ₁₂ alkoxy group,
R3, R4 are each independently a hydrogen atom, a hydroxy group, C ₁ to C ₂₀ alkyl group, C ₁ to C ₂₀ alkoxy group, Z 'substituent and at least one R' a substituted or one or more substituents selected from the group consisting of groups unsubstituted benzyl Wherein R 'is a hydrogen atom, at least one substituent selected from the group consisting of a halogen atom selected from F, Cl, Br or I, a hydroxy group, a C ₁ to C ₁₂ alkyl group and a C ₁ to C ₁₂ alkoxy group,
Z and Z 'substituents are each independently a protecting group selected from Bz, Boc, Ac, Cbz, or formyl group, and m is an integer of 1 to 4. The method of claim 1 wherein the general formula (Ⅰ) of R3, R4 each independently represent a hydrogen atom, C ₁ to C ₉ alkyl group and a C ₁ to C ₉ Al kokgi, Z is substituted by, a substituent and at least one R 'or unsubstituted Wherein the Z 'substituent is a protecting group selected from Bz, Boc, Ac, Cbz, or formyl, and R' is a hydrogen atom, a C ₁ to C ₉ alkyl group, and a C ₁ to C ₉ alkyl group, C ₉ alkoxy group is one or more substituents selected from the group consisting of; The Z substituent is a protecting group selected from Bz, Boc, Ac, Cbz, or formyl; m is an integer of 1 to 3, an isomer thereof, or a pharmacologically acceptable salt thereof. 2. The compound according to claim 1, which is represented by the following general formula (Ia), an isomer thereof or a pharmacologically acceptable salt thereof:

In this formula,
R 1 and R 2 are each independently at least one substituent selected from the group consisting of a hydrogen atom, a hydroxyl group, a C ₁ to C ₁₂ alkyl group and a C ₁ to C ₁₂ alkoxy group,
Z, Z 'substituents are each independently selected from Bz, Boc, Ac, Cbz, or formyl. 4. The compound according to claim 3, which is ( E ) - [4- (1-benzyl-4-oxo-4-pyrrolidin- Butylamino] -acetic acid benzyl ester (5a); ( E ) - [4- (1-Benzyl-3-dimethylcarbamoyl-allylcarbamoyl) -4-tert-butoxycarbonylamino-butylamino] -acetic acid benzyl ester (5b); ( E ) - [4- (1-Benzyl-3-methylcarbamoyl-allylcarbamoyl) -4-tert-butoxycarbonylamino-butylamino] -acetic acid benzyl ester (5c); ( E ) - [4- (1-benzyl-3-ethylcarbamoyl-allylcarbamoyl) -4-tert-butoxycarbonylamino-butylamino] -acetic acid benzyl ester (5d); Or ( E ) - [4- (1-benzyl-3-isopropylcarbamoyl-allylcarbamoyl) -4-tert-butoxycarbonylamino-butylamino] -acetic acid benzyl ester (5e). The ALLN derivative compound represented by the following general formula (Ib), an isomer thereof or a pharmacologically acceptable salt thereof according to claim 1:

(Ib)
In this formula,
R 1 and R 2 are each independently at least one substituent selected from the group consisting of a hydrogen atom, a hydroxyl group, a C ₁ to C ₁₂ alkyl group and a C ₁ to C ₁₂ alkoxy group,
Z, and Z 'substituents are each independently a protecting group selected from Bz, Boc, Ac, Cbz, or formyl. 6. The compound of claim 5, which is selected from the group consisting of benzyl t-butyl (5-oxo-5 - ((( 3E , 5E ) -7-oxo-1-phenyl- 7- (pyrrolidin- , 5-dien-2-yl) amino) pentane-1,4-diyl) dicarbonate (9a); Benzyl 3-butyl (5 - ((3 E , 5 E ) -7- (dimethylamino) -7-oxo-1-phenylhept- Pentane-1,4-diyl) dicarbamate (9b); Benzyl tert-butyl (5 - ((3 E , 5 E ) -7- (methylamino) -7-oxo-1-phenylhept- Pentane-1,4-diyl) dicarbamate (9c); Benzyl or tert-butyl (5-oxo -5 - (((3 E, 5 E) -7-oxo-1-phenyl-7- (piperidin-l-yl) hepta-3,5-diene- Yl) amino) pentane-1,4-diyl) dicarbamate (9d). The alln derivative compound represented by the following formula (Ic), an isomer thereof or a pharmacologically acceptable salt thereof according to claim 1:

In this formula,
The definitions of substituents R3, R4 and Z are the same as those described in claim 1. 8. The method of claim 7,
( E ) - [4-benzylamino-4- (1-benzyl-3-methylcarbamoyl-allylcarbamoyl) -butylamino] -acetic acid benzyl ester (10a); ( E ) - [4- (1-benzyl-3-methylcarbamoyl-allylcarbamoyl) -4- (3,5-methoxy-benzylamino) -butylamino] -acetic acid benzyl ester (10b); ( E ) - [4- (1-benzyl-3-methylcarbamoyl-allylcarbamoyl) -4- (4-methoxy-benzylamino) -butylamino] -acetic acid benzyl ester (10c); ( E ) - [4- (1-benzyl-3-methylcarbamoyl-allylcarbamoyl) -4- (3-methyl-benzylamino) -butylamino] -acetic acid benzyl ester (10d); Or ( E ) - [4- (1-benzyl-3-methylcarbamoyl-allylcarbamoyl) -4-isopropylamino-butylamino] -acetic acid benzyl ester (10e). An anti-malarial agent comprising an ALLN derivative compound represented by the general formula (I) of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition for treating and preventing a malaria infectious disease comprising an ALLN derivative compound represented by the general formula (I) of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 11. The method of claim 10, wherein the malaria is selected from the group consisting of Plasmodium falciparum , Plasmodium vivax , Plasmodium ovale , or Plasmodium malariae .

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