WO2000024392A1

WO2000024392A1 - β-AMYLOID FORMATION INHIBITORS

Info

Publication number: WO2000024392A1
Application number: PCT/JP1999/005871
Authority: WO
Inventors: Shinichi Kojima; Yasushi Tsutsumi; Hiroshi Yamaga; Toshio Nishihara; Tomohiro Toyoda; Akira Ito
Original assignee: Sumitomo Pharmaceuticals Company, Limited
Priority date: 1998-10-26
Filing date: 1999-10-25
Publication date: 2000-05-04
Also published as: AU6229699A

Abstract

Compounds represented by the following general formula which are useful in treating Alzheimer's disease, etc. because of having an effect of inhibiting the formation of β-amyloid: R1-Y-NH-A-CO-R2 wherein R1 represents optionally substituted aryl, an optionally substituted unsaturated heterocycle or optionally substituted alkyl; R2 represents optionally substituted amino, optionally substituted alkoxy or hydroxy; -Y- represents -CO-, etc.; and -A- represents a group of formula (I), etc. wherein one of R?3 and R4¿ represents hydrogen, halogeno, -S(O)¿n?-X (wherein n is 0, 1 or 2; and X represents optionally substituted alkyl, optionally substituted aryl or an optionally substituted unsaturated heterocycle), optionally substituted alkyl or optionally substituted aryl, while the other one of R?3 and R4¿ represents optionally substituted aryl or an optionally substituted unsaturated heterocycle.

Description

Description β-amyloid formation inhibitor

Technical field

The present invention relates to a [3] amyloid production inhibitor useful as a therapeutic agent for Alzheimer's disease and the like.

Background art

In recent years, with the increase in the elderly population, there is a strong demand for the development of pharmaceuticals effective for treating senile dementia. Alzheimer's disease, a representative disease of senile dementia, is a neurodegenerative disease characterized by brain atrophy, senile plaque deposition and neurofibrillary tangles, and the loss of nerve cells causes dementia. In patients with Alzheimer's disease, histopathological studies show that senile plaques are deposited, which results in neuronal loss and brain atrophy.

Amyloid, a major component of senile plaques, has a cytotoxic effect and is one of the causes of neuronal cell death in Alzheimer's disease (Yankner, B. et al. Science, 245, 417-420). (1989); Cai. X., Gold, T. & Younkin, S. Science, 259, 514-516 (1993); Rose, A. Nature Med. 2, 267-269 (1996); Scheuner, D. et. al. Nature Med. 2, 864-869 (1996)).

(3) Amyloid is an agglutinating peptide consisting of 39 to 43 amino acids, and is produced by processing the precursor amyloid protein (Haass, & Selkoe, D. et al. Cell 75, 1039-1042 (1993)); Roher, AE, et al. Proc. Natl. Acad. Sci. USA 90, 10836-10840 (1993)).

The amyloid precursor protein is a protein with a transmembrane site (Kang, J. et al. Nature, 325, 733-736 (1987)), which is cleaved at the site near residue 17 of 3 amyloid, A fragment with a molecular weight of about 120 kDa containing the N-terminus is secreted extracellularly (Seubert, P. et al.

Nature, 361, 260-262 (1993)) ₀ On the other hand,] 3 amyloid is present in the C-terminal region of the amyloid precursor protein and is produced by cleavage at both ends of J3 amyloid. Secreted.

Drugs that suppress amyloid production are therapeutic agents for Alzheimer's disease or It is expected as a drug to control.

Therefore, research on drugs that suppress the production of [3] amyloid is also in progress, for example, rhodanin derivatives (US 5523314), benzimidazole derivatives (US 5552426), serotonin reuptake inhibitors (W097 / 10816), sill amino alcohol derivative (W0 / 391 ⁹ 4), vinpocetine derivative (tO% / 25161) is that known. However, not enough has yet been obtained.

Disclosure of the invention

An object of the present invention is to provide a novel i3 amyloid production inhibitor useful as a therapeutic agent for Alzheimer's disease and the like. Another object of the present invention is to provide a novel compound useful as an amyloid production inhibitor or the like.

The present invention is a novel] 3 amyloid production inhibitor. That is, the present invention is a therapeutic agent for a neurodegenerative disease by inhibiting β-amyloid production. In other words, the present invention relates to an agent for inhibiting neuronal cell death by inhibiting the production of] 3 amyloid. Specifically, the 13-amyloid production inhibitor of the present invention is a therapeutic agent, a prophylactic agent, an inhibitor of progress, an inhibitor of senile plaque production, and an inhibitor of neuronal loss due to the deposition of senile plaques, for Alzheimer's disease.

The gist of the present invention is as follows.

[1] Formula 1: R ^1-丫 -A-CO-R ²

[Wherein, R ¹ represents a substituted or unsubstituted aryl, a substituted or unsubstituted unsaturated heterocyclic ring or a substituted or unsubstituted alkyl, and R ² represents a substituted or unsubstituted amino, substituted or unsubstituted Represents an alkoxy or hydroxyl group,

—Y— and — A—

(1) — Y— represents one C O—

— A— is the formula:

(Wherein one of R ³ and R ⁴ is a hydrogen atom, a halogen atom, one S (O) _n -X (n represents 0, 1 or 2; X represents a substituted or unsubstituted alkyl; Or an unsubstituted aryl or a substituted or unsubstituted unsaturated heterocyclic ring.). Represents a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, and the other of R ³ and R ⁴ is Represents a substituted or unsubstituted aryl or a substituted or unsubstituted unsaturated heterocycle.) Represents a group represented by

(2) - Y- is one CO- or a S0 ₂ - represents,

— A— is the formula:

(In the formula, R represents a substituted or unsubstituted aryl or a substituted or unsubstituted unsaturated heterocycle, _m represents 0, 1 or 2, R ⁶ represents a hydrogen atom or an alkyl. Represents a group represented by. ]

Or a pharmaceutically acceptable salt thereof.

[2] R ² is one N (R ⁷ ) R ⁸ or one OR ⁹ [wherein, one of R ⁷ and R ⁸ represents a hydrogen atom or lower alkyl, and the other represents a substituted or unsubstituted unsaturated group. R ⁹ represents a hydrogen atom or a substituted or unsubstituted lower alkyl, or represents a hydrogen atom or a substituted or unsubstituted lower alkyl; ] The amyloid production inhibitor according to [1].

[3] R ⁷ and R ⁸ are each a hydrogen atom or a lower alkyl and the other is 2-thiazolyl, or both are independently a hydrogen atom or a substituted or unsubstituted lower alkyl; Is a hydrogen atom or substituted or unsubstituted lower [3] The amyloid formation inhibitor according to [2], which is an alkyl.

[4] The amyloid production inhibitor according to any one of [1] to [3], wherein R ¹ is a substituted or unsubstituted aryl or a substituted or unsubstituted phenyl.

[5] Equation 1a:

[Wherein, R ¹ R, R ^3, and R are the same as defined in [1]. ] The amyloid formation inhibitor according to [1], which is a compound represented by the formula:

[6] R ³ is a hydrogen atom, a halogen atom, one S (O) _n -X (n and X have the same meanings as defined in [1]), substituted or unsubstituted alkyl or substituted or unsubstituted The i3 amyloid production inhibitor according to [5], wherein R ⁴ is a substituted or unsubstituted aryl or a substituted or unsubstituted unsaturated heterocycle.

[7] R ³ is a halogen atom or one S—X (X is as defined in [1].), And R ⁴ is a substituted or unsubstituted aryl or a substituted or unsubstituted unsaturated heteroaryl. The / 3 amyloid formation inhibitor according to [5], which is a ring.

[8] One of R ³ and R ⁴ is one S—X (X is as defined in [1].), And the other is a substituted or unsubstituted aryl. Amyloid production inhibitor.

[9] wherein R ^{2 is} -N (R ⁷ ) R ⁸ or one OR ^{9 wherein} R ⁷ , R ⁸ and R "are as defined in [2]. ] The J3 amyloid production inhibitor according to any one of [1] to [4].

[10] R ^{2 is} —N (R ⁷ ) R ⁸ [wherein, R ⁷ and R ⁸ each represent a hydrogen atom or lower alkyl, and the other represents substituted or unsubstituted lower alkyl. ] The J3 amyloid production inhibitor according to any one of [5] to [8].

[1 1] R ^{2 is} —OR ⁹ [wherein, R ⁹ represents substituted lower alkyl. The amyloid production inhibitor according to any one of [5] to [8]. [1 2] R ⁷ and R ⁸ are each a hydrogen atom or a lower alkyl and the other is 2-thiazolyl, or both are independently a hydrogen atom or a substituted or unsubstituted lower alkyl. Wherein R ⁹ is a hydrogen atom or a substituted or unsubstituted lower alkyl. [3] The amyloid formation inhibitor according to [9].

[1 3] R ¹ force;, i3 amyloid production inhibitor of any one of [1 2] from a Ariru or substituted or unsubstituted thienyl, substituted or unsubstituted [5].

[14] The i3 amyloid production inhibitor according to any one of [1] to [13], which is a therapeutic agent for a disease caused by 3 amyloid.

[15] The / 3 amyloid production inhibitor according to any one of [1] to [13], which is a therapeutic agent for Alzheimer's disease.

[16] Equation 1 ':

R ¹⁰ -Y ¹ -NH-A ¹ -CO-R ¹¹ [wherein, R ¹⁰ represents a substituted or unsubstituted aryl, a substituted or unsubstituted unsaturated heterocyclic ring or a substituted or unsubstituted alkyl. ,

— Y ¹ —,! ^^ Povyachi ¹ "^^,

(1) — Y ¹ — represents one CO—,

R ¹¹ represents a substituted or unsubstituted amino, a substituted or unsubstituted alkoxy or a hydroxyl group,

— A ¹ — is the formula:

(Wherein, and ^one of R ¹³ is a hydrogen atom, a halogen atom, one S (Ο) _η — X (where η and X are the same as defined in [1].), Substituted or unsubstituted alkyl. Or a substituted or unsubstituted aryl, and the other represents a substituted or unsubstituted aryl or a substituted or unsubstituted unsaturated heterocycle. R ¹³ does not become a hydrogen atom or a halogen atom. ) Represents a group represented by

(2) — Y ¹ — represents one CO— or one S0 ₂ —,

R ¹¹ represents a substituted or unsubstituted unsaturated heterocyclic amino,

— A ¹ — is the formula:

(Wherein, R ¹⁴ represents a hydrogen atom or an alkyl, R ^{l Q} represents a substituted or unsubstituted aryl or a substituted or unsubstituted unsaturated heterocyclic ring, and m represents 0, 1 or 2 Represents a group represented by. ]

Or a pharmaceutically acceptable salt thereof.

[17] Equation 1, a:

[Wherein, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are the same as defined in [16]. ]

Or a pharmaceutically acceptable salt thereof according to [16].

[18] The compound according to [17], wherein R ¹² is a halogen atom or one S—X (X is as defined in [1]), or a pharmaceutically acceptable salt thereof.

[1 9] One of R ¹² and R ¹³ is one S—X (X has the same meaning as defined in [1].), And the other is a substituted or unsubstituted aryl. 1

[7] The compound of the above or a pharmaceutically acceptable salt thereof.

[20] The compound of [18], wherein X is pyridyl, or a pharmaceutically acceptable salt thereof.

[21] R ^{11 is} —N (R ⁷ ) R ⁸ or one OR ⁹ [wherein R ⁷ , R ⁸ and R ⁹ is as defined in [2]. ] The compound according to any one of [17] to [20] or a pharmaceutically acceptable salt thereof.

[22] R ^{11 is} —N (R ⁷ ) R ⁸ [wherein, R ⁷ and R ⁸ each represent a hydrogen atom or lower alkyl, and the other represents a substituted or unsubstituted lower alkyl. [17] The compound according to any one of [17] to [21] or a pharmaceutically acceptable salt thereof.

[23] R ^{11 is} —OR ⁹ [wherein, R ⁹ represents substituted lower alkyl. ] The compound according to any one of [17] to [21] or a pharmaceutically acceptable salt thereof.

[24] R ′ and R ⁸ are each a hydrogen atom or a lower alkyl and the other is 2-thiazolyl, or both are independently a hydrogen atom or a substituted or unsubstituted lower alkyl Or the pharmaceutically acceptable salt thereof, wherein R ⁹ is a hydrogen atom or a substituted or unsubstituted lower alkyl.

[25] The compound according to any one of [17] to [24], wherein R ¹⁰ is a substituted or unsubstituted aryl or a substituted or unsubstituted phenyl, or a pharmaceutically acceptable salt thereof.

[26] Equation 1 'b:

[Wherein, R ¹⁰ , R ¹⁴ , R ¹⁵ and m are the same as defined in [16]. One Y ² — represents —CO— or one S0 ₂ —. R ^1. Represents a substituted or unsubstituted unsaturated heterocyclic amino. ]

Or a pharmaceutically acceptable salt thereof according to [16].

[27] The compound according to [26], wherein R ¹⁶ is 2-thiazolylamino, or a pharmaceutically acceptable salt thereof.

[28] The compound of [26] or [27], or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is a substituted or unsubstituted aryl or a substituted or unsubstituted phenyl. [29] The compound according to any one of [26] to [28], wherein m is 1, or a pharmaceutically acceptable salt thereof.

[30] A medicament comprising the compound according to any one of [16] to [29] or a pharmaceutically acceptable salt thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present invention, examples of unsubstituted aryl include aryl having 6 to 10 carbon atoms, and specific examples include phenyl, 1-naphthyl, and 2-naphthyl.

In the present invention, examples of the unsubstituted unsaturated hetero ring include a monocyclic 5-cyclic monocyclic ring containing 13 atoms independently and arbitrarily selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. And a 5- or 6-membered unsaturated heterocyclic ring in which a benzene ring is fused to the 5- or 6-membered ring. Preferred examples of the unsaturated heterocyclic ring include an aromatic heterocyclic ring. Specific examples of the 5-membered unsaturated hetero ring include a nitrogen atom such as pyrrole, thiophene, furan, imidazone, pyrazole, thiazole, oxazoline, isothiazole, isoxazole, and triazole, and sulfur. Monocyclic 5-membered unsaturated heterocycles containing 1 to 3 atoms arbitrarily selected independently from the group consisting of atoms and oxygen atoms. As the 6-membered unsaturated hetero ring, specifically, arbitrarily selected independently from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom such as pyridine, pyrazine, pyrimidine, pyridazine and triazine 1 And 6-membered unsaturated heterocycles containing one to three atoms. Specific examples of the bicyclic unsaturated heterocyclic ring in which a benzene ring is condensed with a 5-membered ring include benzenethiazol, indole, and other nitrogen, sulfur, and oxygen atoms. Bicyclic unsaturated heterocyclic rings containing one or two atoms optionally selected. Specific examples of the unsaturated bicyclic heterocyclic ring in which a benzene ring is fused to a 6-membered ring are arbitrarily selected independently from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom such as quinazoline. A two-ring unsaturated heterocyclic ring containing one to three atoms is exemplified.

In the present invention, examples of the substituent in the substituted aryl and the substituted unsaturated hetero ring include a halogen atom, cyano, nitro, substituted or unsubstituted alkyl, Alkene / re, a / rexyl, alkoxy, anoreoxycarbonyl, hydroxyl group, anore force yl, amino, alkylamino, dialkylamino, alkanoylamino, olevoxil, olevamoyl, alkyl olevamoyl, dialkyl Rubamoyl, sulfamoyl and the like, which may be independently substituted one or more times. Preferred substituents include a halogen atom, cyano, nitro, substituted or unsubstituted a / re / n / a, a / lekeninole, anorequininole, anoreoxy, alkoxyl repoyl, amino, alkylamino, dialkylamino, alkynoamino, Carboxyl and the like. More specifically, examples thereof include a fluorine atom, a chlorine atom, cyano, nitro, methyl, ethyl, propyl, vinyl, ethynyl, methoxy, ethoxy, methoxycarbonyl, amino, methylamino, dimethylamino, acetoamino, carboxyl and the like.

In the present invention, examples of the unsubstituted alkyl include straight-chain or branched alkyl having 1 to 10 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, and the like. Specifically, examples of straight-chain or branched alkyl include methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, pentyl, 1-methylbutizure, 2-methyl / lebutinole, 3-methylinobutynole, 1-ethyl / repropinole, hexyl, 1-methyl / lepentyl, 2-methylpentinole, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylinobutyl, octyl, decyl and the like. Specific examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

In the present invention, examples of the unsubstituted lower alkyl include straight-chain or branched alkyl having 1 to 6 carbon atoms. Specifically, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, pentyl, 1-methyl / rebutyl, 2-methylbutyl, 3-methylbutyl, 1-methylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl and the like. In the present invention, examples of the substituent in the substituted alkyl and the substituted lower alkyl include a halogen atom, an aryl, an unsaturated hetero ring, a saturated hetero ring, cyano, nitro, cycloalkyl, alkoxy, alkoxycarbonyl, a hydroxyl group, and an alkyl group. Noyl, amino, alkylamino, dialkylamino, alkanoylamino, potassium ruboxil, potassium rubamoyl, alkyl potassium rubamoyl, dialkylcabamoyl, sulfamoyl, trialkylsilyl, etc., and one or more of them independently It may be substituted. Preferred substituents include a halogen atom, aryl, an unsaturated hetero ring, a saturated hetero ring, dialkylamino, carboxyl, trialkylsilyl and the like. More specifically, a fluorine atom, a chlorine atom, phenyl, pyridyl, phenyl, pyrrolidyl, dimethylamino, carboxyl, trimethylsilyl and the like can be mentioned. Here, the unsaturated heterocyclic ring is the same as described above, and is, for example, a monocyclic ring containing 1-3 atoms independently selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. Examples thereof include a 5-membered or 6-membered unsaturated hetero ring, and a 2-ring unsaturated hetero ring in which a benzene ring is fused to the 5- or 6-membered ring. Preferred examples of the unsaturated hetero ring include an aromatic hetero ring.

Aryl, unsaturated heterocycle, saturated heterocycle, anolequinole, anorekeninole, anolequininole, anorecoxy, anorecoxy / repo force exemplified as the substituent in the above-mentioned substituted aryl, substituted unsaturated heterocycle, substituted alkyl and substituted lower alkyl. Specific examples of Ninore, anore canol, alkylamino, dialkylamino, alkyl rubamoyl, dialkyrubambayl, alkanoylamino and trialkylsilyl include the following.

Examples of aryl, unsaturated heterocycle and alkyl include the same as described above.

Examples of the saturated hetero ring include a 5 to 7 ring hetero ring containing 1 to 2 nitrogen atoms and 0 to 1 oxygen atom. Specific examples include pyrrolidine, piperidine, piperazine, morpholine and the like.

Examples of the alkenyl include a linear or branched alkenyl having 2 to 10 carbon atoms. Specific examples include bur, 1-prodenyl, 2-prodenyl, and 31-pentyl.

Examples of the alkynyl include straight-chain or branched alkynyl having 2 to 10 carbon atoms. Specifically, ethinyl, 1-propynyl, 2-propiel, 3 boutles and the like.

Examples of the alkoxy include linear or branched alkoxy having 1 to 10 carbon atoms. Specifically, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 1-ethylpropoxy, hexo Xy, 1-methylpentoxy, 2-methylpentoxy, 1-ethylbutoxy and the like.

Examples of the alkoxycarbonyl include, for example, a carbon atom substituted with a linear or branched alkoxy having 1 to 6 carbon atoms. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like.

Examples of the alkanoyl include linear or branched alkanols having 1 to 10 carbon atoms. Specific examples include formyl, acetyl, propanoyl, butanol, isobutanol, valeryl, isovaleryl, vivaloyl, 2-methinolevtanyl, hexanoyl and the like.

Examples of the alkylamino include an amino substituted with a straight-chain or branched alkyl having 1 to 6 carbon atoms. Specific examples include methylamino, ethylamino, propylamino and the like.

Examples of the dialkylamino include amino substituted with the same or different linear or branched alkyl having 1 to 6 carbon atoms. Specifically, dimethylamino, acetylamino, ethylmethylamino, dipropylamino and the like can be mentioned.

Examples of the alkyl rubamoyl include alkyl rubamoyl substituted with linear or branched alkyl having 1 to 6 carbon atoms. Specific examples include methylcarbamoyl, ethylcarbamoyl, and propylamine.

Examples of the dialkyl rubamoyl include rubamoyl substituted with the same or different linear or branched alkyl having 1 to 6 carbon atoms. Specific examples include dimethi / lecanolevamoyl, jeti / lecan / rebamoy / le, eti / lemethinorecanolebamoyl, and dipropyl lubamoyl.

Alkanoylamino includes, for example, those substituted with alkanoyl having 1 to 6 carbon atoms. Amino. Specific examples include formylamino, acetylamino, propanoylamino, and the like.

Examples of the trialkylsilinole include silyl substituted with the same or different three or more straight-chain or branched alkyl having 1 to 6 carbon atoms. Specific examples include trimethylsilyl, triethylsilyl, ethyldimethylsilyl, t-butyldimethylsilyl and the like.

In the present invention, examples of the unsubstituted alkoxy include the same as those described above. The substituted alkoxy includes, for example, methoxy substituted with azyloxy, and specific examples include acetoxymethoxy, bivaloyloxymethoxy, 1-ethoxycarboxy-methoxy, phthalidyloxymethoxy and the like. In the present invention, examples of the substituent in the substituted amino include a substituted or unsubstituted unsaturated hetero ring, a substituted or unsubstituted saturated hetero ring, a substituted or unsubstituted aryl, a substituted or unsubstituted alkyl, and an alkenyl. And alkynyl and the like. Any one or two of these may be substituted with amino. Here, the substituted or unsubstituted unsaturated heterocyclic ring is the same as described above, for example, one to three atoms independently and arbitrarily selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. And a monocyclic 5- or 6-membered unsaturated heterocyclic ring or a 2-ring unsaturated heterocyclic ring in which a benzene ring is fused to the 5- or 6-membered ring. Preferred examples of the unsaturated heterocyclic ring include an aromatic heterocyclic ring. The same applies to substituted or unsubstituted aryl, substituted or unsubstituted alkyl, alkenyl, alkynyl and the like.

Examples of the unsubstituted saturated hetero ring include a 5- to 7-membered hetero ring including 1 to 2 nitrogen atoms and 0 to 1 oxygen atom. Specific examples include pyrrolidine, piperidine, piperazine, morpholine and the like. Examples of the substituent of the substituted saturated hetero ring include the same substituents as those of the substituted unsaturated hetero ring. Further, the substituted amino may take a cyclic structure containing a nitrogen atom such as piperidino, for example, and may be a substituted or unsubstituted nitrogen-containing heterocyclic group.

Here, the unsubstituted nitrogen-containing heterocyclic group includes, for example, one nitrogen atom and is arbitrarily selected independently from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. May contain one or two atoms, a monocyclic 5- or 6-membered nitrogen-containing nitrogen-containing ring, or the 5- or 6-membered ring has another 5- or 6-membered ring. And condensed two-ring nitrogen-containing heterocycles. Preferably, it is a monocyclic 5-membered or 6-membered ring containing one nitrogen atom, and optionally containing one or two atoms independently selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. And a membered saturated nitrogen-containing heterocyclic group. Specific examples include a monocyclic 5-membered saturated nitrogen-containing heterocyclic group such as pyrrolyl, and a monocyclic 6-membered saturated nitrogen-containing heterocyclic group such as morpholyl and piperazinyl. Examples of the substituent in the substituted nitrogen-containing heterocyclic group include the same substituents as those in the substituted unsaturated heterocyclic ring.

Preferred substituents in substituted amino include substituted or unsubstituted alkyl and substituted or unsubstituted unsaturated heterocycle.

Preferred examples of the substituted or unsubstituted unsaturated hetero ring include a substituted or unsubstituted nitrogen-containing unsaturated hetero ring. Particularly preferred are a substituted or unsubstituted 2-thiazolyl, a substituted or unsubstituted. 2-benzothiazolyl and the like. Here, the nitrogen-containing unsaturated hetero ring includes, for example, one nitrogen atom, and one or three atoms independently selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom. And a monocyclic 5- or 6-membered nitrogen-containing unsaturated heterocyclic ring, or a 2- or 5-membered ring in which another 5- or 6-membered ring is fused to the 5- or 6-membered ring. And a nitrogen-unsaturated heterocyclic ring.

In the present invention, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Preferred examples of the halogen atom include a chlorine atom and a bromine atom.

In the present invention, examples of the substituted or unsubstituted unsaturated heterocyclic amino include amino substituted by the same substituted or unsubstituted unsaturated heterocyclic ring as described above. As the pharmaceutically acceptable salt, when the compound of the formula 1 has a basic group, for example, an inorganic acid salt such as hydrochloride, hydrogen bromide, sulfate, phosphate, nitrate, or an acetate; Organic salts such as propionate, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate When the compound of the formula 1 has an acidic group, In this case, inorganic base salts such as sodium salt, calcium salt and potassium salt, and organic base salts such as triethylammonium salt and lysine salt are exemplified.

The present invention also includes hydrates of the compound of the formula 1 or a pharmaceutically acceptable salt thereof, and solvates such as ethanol solvate.

The compound of the formula 1 of the present invention can be divided into compounds represented by the following formulas la and 1b according to the definition of 1Y- and 1A-.

R ¹ — CONH eight

1 a l b

[Wherein I ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , one Y— and m are the same as those in the above [1]. ]

Among the compounds of the formula 1 of the present invention, the compounds of the above formula 1 are novel compounds, and the new compounds are represented by the above formulas 1, a and 1 ′ according to the definitions of 1 and 1A. It is divided into compounds represented by b.

The compound of Formula 1 (compounds represented by Formula 1a and Formula 1b) can be produced, for example, by the following method.

1. Method for producing compound of formula 1a

[Wherein, R ¹ R ″, R ³ and R ⁴ are the same as defined in the above [1].]

The compound of formula 1a can be produced by reacting the 5-oxazolidinone of formula 2 with the compound of formula 3. When the compound of the formula 3 is an amine, for example, the 5-oxazolidinone of the formula 2 and the amine of the formula 3 may be converted to a hydrocarbon solvent such as toluene or an ether such as tetrahydrofuran (hereinafter sometimes abbreviated as THF). The compound of formula 1a can be produced by reacting in an inert solvent such as a solvent at a temperature from room temperature to the boiling point of the solvent. When the amine of the formula 3 is an amine having low reactivity such as an arylamine or an unsaturated heterocyclic amine, the amine of the formula 3 is reacted with a metal base such as sodium hydride to form a metal amide, Can be reacted with 5_oxazolidinone.

When the compound of the formula 3 is a substituted or unsubstituted alcohol, the 5-oxazolidinone of the formula 2 is subjected to alcoholysis by a conventional method to obtain a compound of the formula 1a wherein R is a substituted or unsubstituted alkoxy. Can be produced. For example, a compound of formula 2 is reacted with an alcohol in the presence of a metal alkoxide such as t-butoxy potassium, or an alcohol of formula 3 is reacted with a metal base such as sodium hydride in an ether solvent such as THF to form a metal alkoxide. The reaction can be carried out by reacting with 5-oxazolidinone of the formula 2. Further, for example, a compound of the formula 1a in which R ² is a hydroxyl group is reacted with a corresponding substituted or unsubstituted alkyl halide in the presence of a base to esterify the compound, whereby R ² is substituted or unsubstituted alkoxy. Certain compounds of formula 1a can also be prepared. Here, the alkyl halide is an alkyl substituted with a halogen atom such as a chlorine atom.

When the compound of the formula 3 is water, the compound of the formula 1a in which R ² is a hydroxyl group can be produced by hydrolyzing the 5-oxazolidinone of the formula 2 by an ordinary method. For example, it can be carried out by hydrolyzing the compound of the formula 2 using an aqueous sodium hydroxide solution in an alcohol solvent. Further, the compound of the formula 1a in which R ² is a hydroxyl group can be produced by converting the compound of the formula 1a in which R ² is an alkoxy to a carboxylic acid by hydrolysis, reduction, oxidation or the like.

A compound of the formula la wherein R ³ or R ^{4 is} —S (O) _n — X (n and X have the same meanings as defined in the above [1]), wherein R ³ or R ⁴ is a chlorine atom, a bromine atom, etc. The compound of the formula la is converted to 1,8-diazabicyclo [5.4.0] —7-undecene (hereinafter referred to as DBU) in an ethereal solvent such as THF from room temperature to the boiling point of the solvent. Or a metal base such as sodium hydride. In the presence of a base, the compound can be produced by reacting with the formula: H—SX (X has the same meaning as defined in the above [1]) and, if necessary, oxidizing it.

Some compounds of the 5-oxazolidinone of formula 2 can be prepared as follows.

R-CONHCH ₂ C0 ₂ H

Four

[Wherein, R ¹ has the same meaning as defined in the above [1]. R ¹⁷ represents a substituted or unsubstituted aryl or a substituted or unsubstituted unsaturated heterocycle. R ¹⁸ represents a chlorine atom, a bromine atom or one S (O) _n —X (n and X have the same meanings as defined in the above [1]). ]

By reacting the compound of Formula 4 with the aldehyde of Formula 5, 5-oxazolidinone of Formula 6 can be produced. As the reaction conditions, for example, the reaction can be carried out at 50 to 140 ° C. in the presence of sodium acetate using acetic anhydride as a reaction solvent. The compound of formula 4 can be easily produced by N-acylation of glycine or a glycine derivative by a known method.

The 5-oxazolidinone of the formula 7 in which R ¹⁸ is a chlorine atom or a bromine atom can be produced by chlorinating or brominating the 5-oxazolidinone of the formula 6. Reaction conditions include, for example, reacting chlorine or bromine in an inert organic solvent such as a halogenated solvent such as black form at 0 ° C. to room temperature, followed by reacting a base such as triethylamine or DBU. Can be chlorinated or brominated.

1 ¹⁸ is 1 3 (O) _n -X (n and X are as defined in the above [1]). The 5-oxazolidinone of the formula 7 is, for example, a compound of the formula wherein R ¹⁸ is a chlorine atom or a bromine atom. Reaction of the compound of formula 7 with a compound of formula H-SX (X is as defined in the above [1]) in an ether solvent such as THF at 0 ° C to room temperature in the presence of an amine salt such as DBU. It can be manufactured by oxidizing if necessary. In many cases, the 5-oxazolidinone of formula 7 is obtained as a mixture of geometric isomers of double bonds, for example, silica gel forces. The two geometrical isomers can be separated and purified respectively by ordinary purification means such as column chromatography.

Compounds of formula 3 are known and can be easily prepared by known methods. Other compounds of the 5-oxazolidine of formula 2 can be prepared as follows.

[Wherein, R ¹ has the same meaning as defined in the above [1]. R ^1. And one of R ²⁰ represents a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted unsaturated heterocycle, and the other represents a substituted or unsubstituted aryl or substituted or unsubstituted Represents an unsaturated heterocyclic ring. ]

By reacting 5-oxazolidinone of formula 8 with a ketone of formula 9 according to the method described in Belgian Patent 903194, 5-oxazolidinone of formula 10 can be produced. As a specific reaction condition, for example, it can be produced by reacting in an inert organic solvent such as an ether solvent such as THF in the presence of pyridine / titanium tetrachloride.

Alternatively, according to the method described in Synthesis, 832 (1978), N-acylglycine and arylalkylketone can be produced as a mixture of geometric isomers by cyclization and dehydration condensation in THF in the presence of acetic anhydride and lead tetraacetate.

The compound represented by the formula 1'a of the present invention can be produced in the same manner by the production method described above.

2. Preparation of Compound of Formula 1b

R.

R ¹ -Y-H +

+ H-R "R ^1- Y-To NH CO-R ²

11 12 3 1b [Wherein, RR ² , R ⁵ , R ⁶ , one Y— and m are the same as defined in the above [1]. ]

In the case where one Y— in the formula 11 represents —CO—, the carboxylic acid of the formula 11 and the amino acid of the formula 12 are optionally subjected to an amidation reaction with the compound of the formula 3 to obtain Compounds of formula 1b can be produced. Examples of the amidation reaction include ordinary methods, for example, a method of activating a carboxylic acid to react with an amine, and a method of using a condensing agent. As a method of activating a carboxylic acid and reacting it with an amine, for example, the carboxylic acid is converted into an acid anhydride, and the carboxylic acid is reacted in an inert organic solvent such as a halogenated solvent such as dichloromethane in the presence of a base such as an amine such as triethylamine. It can react at 0 ° C to room temperature. Examples of the condensing agent in the method using a condensing agent include condensing agents such as dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride.

Further, a compound of the formula 1b can also be produced by subjecting a compound of the formula 1a in which one of R ³ and R ⁴ is a hydrogen atom to a hydrogenation reaction.

When Y represents 1 S 0 ₂ — in the formula 11, the compound of the formula 1b can be produced by converting the sulfonic acid of the formula 11 into a chloride and reacting in the same manner as described above. The compounds of formula 11 and formula 12 are known and can be produced by known methods.

The compound represented by the formula 1′b can be produced in the same manner by the above-mentioned production method.

The compound included in the present invention may have asymmetry or may have a substituent having an asymmetric carbon, and such a compound has an optical isomer. The compounds of the present invention include mixtures of these isomers and isolated ones. A method for obtaining such an optical isomer purely includes, for example, optical resolution.

As the optical resolution method, the compound of the present invention or an intermediate thereof is dissolved in an inert solvent (for example, an alcohol solvent such as methanol, ethanol, or 2-propanol, an ether solvent such as dimethyl ether, or an ester solvent such as ethyl acetate). Solvents, aromatic hydrocarbon solvents such as toluene, etc., acetonitrile, etc. and their mixed solvents), optically active acids (for example, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine, lactic acid) Acids, tartaric acid, dicarboxylic acids such as o-diisopropylidene tartaric acid, malic acid, and sulfonic acids such as camphors / lefonic acid and bromocamphorsulfonic acid).

When the compound of the present invention or an intermediate thereof has an acidic substituent such as a carboxyl group, a salt is formed with an optically active amine (for example, organic amines such as α-phenethylamine, cun, quinidine, cinchonidine, cinchonine, strychnine). It can also be done.

The temperature for forming the salt includes a range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent. Before the precipitated salt is collected by filtration, the salt can be cooled, if necessary, to improve the yield. The amount of the optically active acid or amine used is in the range of about 0.5 to about 2.0 equivalents, preferably about 1 equivalent, relative to the substrate. If necessary, crystallize in an inert solvent (for example, alcohol solvents such as methanol, ethanol, and 2-propanol; ether solvents such as getyl ether; ester solvents such as ethyl acetate; and aromatic hydrocarbon solvents such as toluene. , Acetonitrile and the like and a mixed solvent thereof) to obtain a high-purity optically active salt. If necessary, the obtained salt can be treated with an acid or a base in a usual manner to obtain a free compound.

The compound of formula 1 of the present invention has an action of suppressing the production of amyloid 3, and is useful as a therapeutic agent for Alzheimer's disease and the like. It can be confirmed that the compound of formula 1 has a] 3 amyloid production inhibitory effect by performing, for example, the following test.

For example, in the case of an in vitro test, a neuroglia mixed primary culture is established from guinea pig fetal brain in the same manner as in the method of Clarke et al. (FEBS Letters 430 (1998), 419-423). A DMS0 solution of the compound of the present invention was added to the culture solution containing the cultured cells, and after a certain period of time, the amount of amyloid in the culture supernatant was quantified using an ELISA method using an anti-] 3 amyloid antibody and used as a control. By comparison, it can be confirmed that the compound has an action of inhibiting] 3 amyloid production.

In the case of an in vivo test, a solution of the compound of the present invention was orally administered to a single guinea pig in the same manner as in Eckman <7) (Neurobiology of Aging supp. 17 (1996) S68). Or intravenously. After a certain period of time, the amount of / 3 amino acid in the blood or cerebrospinal fluid is quantified by ELISA, etc., and compared with a control to confirm that it has an inhibitory effect on amyloid production be able to.

In addition, genes encoding i3 amyloid precursors (for example, APP-695 gene (Nature, 325, 733-736 (1987)), APP-751 gene (Nature, 331, 525-527 (1988); Nature, 331) , 528-530 (1988)), APP-770 gene (Nature, 331, 530-532 (1988)) or a modified form of these genes, etc.) and Chinese hamster ovary cells, rat cerebral cortical neuronal primary cells , Etc., and the amount of [3] amyloid produced from the cells in the presence of the compound of the present invention is quantified by ELISA or the like, and compared with a control. It can be confirmed by performing the action of suppressing.

The [3] amyloid production inhibitor of the present invention can be administered orally or parenterally. When administered orally, it can be administered in a commonly used dosage form. Parenterally, it can be administered in the form of topical administration, injection, transdermal, nasal, and the like. Examples of the oral or rectal preparation include capsules, tablets, pills, powders, cachets, suppositories, and liquid preparations. Examples of the injection include a sterile solution or suspension. Examples of the topical preparation include creams, ointments, mouthwashes, transdermal agents (ordinary patches, matrixes) and the like.

The above-mentioned dosage forms are formulated in a conventional manner together with pharmaceutically acceptable excipients and additives. Pharmaceutically acceptable excipients and additives include carriers, binders, flavors, buffering agents, thickeners, coloring agents, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, etc. No.

Pharmaceutically acceptable carriers include, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, Low melting point wax, cocoa butter and the like. Capsules can be formulated by incorporating a compound of the present invention together with a pharmaceutically acceptable carrier. The compounds of the present invention can be mixed with pharmaceutically acceptable excipients or placed in a capsule without excipients. Cassiers can be produced in a similar manner. Solutions for injection, solutions, suspensions,? And the like. For example, an aqueous solution, a water-propylene glycol solution and the like can be mentioned. The solution may also be prepared in the form of a solution of polyethylene glycol or / and propylene dalicol, which may contain water. A liquid preparation suitable for oral administration can be produced by adding the compound of the present invention to water and adding a coloring agent, a flavor, a stabilizer, a sweetening agent, a solubilizing agent, a thickening agent and the like as necessary. Liquid preparations suitable for oral administration can also be produced by adding the compound of the present invention to water together with a dispersant to make it viscous. Examples of the thickener include a pharmaceutically acceptable natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or a known suspending agent.

Examples of the topical preparation include the above-mentioned liquid preparations, creams, aerosols, sprays, powders, lotions, ointments and the like. The above-mentioned topical preparation can be prepared by mixing with a pharmaceutically acceptable diluent and carrier usually used with the compound of the present invention. Ointments and creams are obtained, for example, by formulating an aqueous or oily base with a thickener and / or a gelling agent. Examples of the base include water, liquid paraffin, and vegetable oils (peanut oil, castor oil, etc.). Examples of the thickener include soft paraffin, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycol, lanolin, hydrogenated lanolin, honey, and the like.

Lotions may be added to an aqueous or oily base with one or more pharmaceutically acceptable stabilizers, suspending agents, emulsifiers, diffusing agents, thickeners, coloring agents, fragrances, etc. it can.

The powder is formulated with a pharmaceutically acceptable powder base. Examples of the base include talc, lactose, starch and the like. Drops can be formulated with an aqueous or non-aqueous base and one or more pharmaceutically acceptable diffusing, suspending, or dissolving agents.

The topical preparation may contain, if necessary, a preservative such as methyl hydroxybenzoate, propyl hydroxybenzoate, cresol closol, benzalconidum chloride, and a bacterial growth inhibitor.

A liquid spray, powder or drop product containing the compound of the present invention as an active ingredient The agent can be administered nasally.

The dosage and frequency of administration vary depending on the symptoms, age, body weight, dosage form, etc., but in the case of oral administration, it is usually in the range of about 1 to about 100 mg / day, preferably about 5 to 50 mg / day for adults. About 500 mg, particularly preferably in the range of about 10 to about 200 mg, can be administered once or in several divided doses. When administered as an injection, it can be administered in the range of about 0.1 to about 30 Omg, preferably in the range of about 1 to about 10 Omg, once or several times. Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. Example 1

(E)-2-(4-Fuzoleo benzoyl) 3-amino- _ 3-phenylphenyl pentic acid 2-thiazolylamide

(1) N- (4-fluorobenzoyl) glycine

Dissolve 7.5 g (0.1 mo 1) of glycine in a mixture of 100 ml of 1,4-dioxane and 50 ml of 2N aqueous sodium hydroxide solution, cool with ice, and add 4-fluorobenzoyl chloride. 9 g (0.1 mo 1) and 50 ml of a 2 N aqueous sodium hydroxide solution were simultaneously added dropwise. After stirring for 1.5 hours, dioxane was distilled off under reduced pressure, and the remaining aqueous layer was washed with ether and acidified with concentrated hydrochloric acid. The resulting crystals were collected by filtration, washed with water, and dried under reduced pressure to give 18.2 g (yield 92%) of the title compound.

1 H-NMR 5 (d ₆ -DMS0, 270 MHz) 3.91 (2H, d, J = 6 Hz), 7.32 (2H, t, J = 9 Hz), 7.94 (2H, dd, J = 6, 9 Hz), 8.87 (1H, t, J = 6Hz), 12.7 (1H, br). (2) (Z) -4-1-phenylmethylene-1-2- (4-fluorophenyl) oxazolidin-1-5-one

4-Fluorobenzoylglycine 18 g (91 mmo 1), benzaldehyde 9.7 g (91 mmo 1), anhydrous sodium acetate 7.5 g (91 mmo 1) in 75 ml of anhydrous acetic acid The mixture was stirred at 100 ° C for 3 hours. After allowing the reaction solution to cool, 5 mL of ethanol was added, and the mixture was stirred for 15 minutes. The resulting crystals are collected by filtration, and cold ethanol (50 The mixture was washed successively with mix 2) and warm water (50 ml) and dried under reduced pressure to obtain 14.3 g (yield: 59%) of the title compound.

^{1 H - NM R δ (CDC1} 3, 270 MHz) 7.23 (2H, t, J = 8Hz), 7.26 (1Η, s), 7.47-7.51 (3H, m), 8.18-8.23 (4H, m).

(3) (E), (Z) _4-—Fjürk-mouth romethylene-1-2- (4-fluorophenyl) oxazolidin-5-one

(Z) —4-pheninolemethylene 1 2 -— (4-fuzoleo mouth feni / re) oxazolidin-5-one 1.5 g (5.6 mmo 1), calcium carbonate 0.45 g (4.5 mmo 1), a few drops of water were added to the black-mouthed form 4 Om 1, and after stirring, chlorine gas was blown for 15 minutes. After stirring the reaction solution overnight, insolubles were removed by filtration and concentrated under reduced pressure. The residue was dissolved in 30 ml of THF, 3 ml of triethylamine was added, and the mixture was heated under reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure, diluted with chloroform, washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography (hexane: toluene = 2: 1-1: 1) to give 65 mg (yield 4%) of the title compound E (low-polar isomer) and Z-form (Highly polar isomer) 55 mg (yield 3%) was obtained.

_{1 H-NMR δ (CDC1 3} , 270 MHz)

E-form: 7.20 (2H, t, J = 8.6Hz), 7.47-7.53 (3H, m), 8.12 (2H, dd, J = 5.3, 8.9 Hz), 8.18-8.24 (2H, m).

Z form: 7.21 (2H, t, J = 8.6Hz), 7.44-7.53 (3H, m), 7.69 (2H, d, J = 8.2Hz), 8.17 (2H, dd, J = 5.3, 8.9Hz).

(4) (E) —2— (4-fluorobenzoyl) amino-3-chloro-3-phenylpropenoic acid 2-thiazolylamide

(E) —4-Phenylchloromethylene-1- (4-fluorophenyl) oxazolidine-5-one 2 Omg (0.066 mmo 1) and 13 mg of 2-aminothiazol (0.13 mmo 1) The mixture was stirred for 2 hours at 100 ° C in 1 ml of toluene. After allowing the reaction solution to cool, toluene was distilled off, and the residue was crystallized from chloroform to give 13 mg (yield 49%) of the title compound.

¹ H-NMR 6 (d ₆ -DMS0, 270 MHz) 7.27-7.48 (6H, m), 7.53-7.57 (3H, m), P 9 571

twenty four

87 (2H, dd, J = 5.3, 8.9 Hz), 10.2 (1H, s), 12.8 (1H, s).

Example 2

(Z) -2- (4-Fluorobenzoyl) amino 3- 3-chloro _ 3-phenylphenic acid Penic acid 2-thiazolylamide

The title compound was obtained from (Z) _4-phenylphenylmethylene-2- (4-fluorophenyl) oxazolidine- _5- one obtained in Example 1 (3) in the same manner as in Example 1 (4). Compounds were synthesized.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 7.17 (1H, d, J = 3.6 Hz), 7.33-7.42 (8H, m), 7.47-7.65 (5H, m), 8.10 (2H, dd, J = 5.6, 8.9Hz), 10.6 (1H, s), 12.7 (1H, s).

(E)-2-(2,4 dicyclomethyl benzoyl) amino-3-chloro-3 phenylpropenoic acid 2-thiazolylamide

(1) N- (2, 4-dichlorobenzene)

The title compound was synthesized using 2,4-dichlorobenzoylglycine in the same manner as in Example 1 (1).

¹ H-NMR δ (d ₆ -D S0, 270 MHz) 3.79 (2H, d, J = 6 Hz), 7.49-7.50 (2H, m), 7.68 (1H, s), 8.52 (1H, t, J = 6Hz).

(2) (Z) —4-Phenylmethylene-1- 2- (2,4-dichlorophenyl) oxosazolidine-1—one

Using N- (2,4-dichlorobenzoyl) glycine obtained in (1), the title compound was synthesized in the same manner as in Example 1 (2).

1 H - NM R δ (CDC1 3, 270 MHz) 7.34 (1H, s), 7.42 (1H, dd, J = 2, 8.6Hz), 7.47-7.50 (3H, m), 7.61 (1H, d, J = 2Hz), 8.06 (1H, d, J = 8.6Hz), 8.20-8.23 (2H, m).

(3) (E), (Z) —4-Phenylchloromethylene-1-2- (2,4-dichlorophenyl) oxazolidin-5-one (Z) — 4-Phenylmethylene-1- (2,4-dichlorophenyl) oxazolidin-5-one In a solution of 2.0 g (6.3 mm o 1) of chloroform (40 ml) in solution Blowed chlorine gas for 15 minutes. After stirring the reaction solution overnight, it was concentrated under reduced pressure. The residue was dissolved in 50 ml of THF, 10 ml of diisopropylethylamine was added, and the mixture was heated under reflux for 1.5 hours. After allowing the reaction mixture to cool, it is concentrated under reduced pressure and purified by silica gel column chromatography (hexane: toluene = 3: 1 to 2: 1) to give the title compound E (low-polar isomer) 41 Omg ( Y-form (highly polar isomer) 17 Omg (yield 8%) was obtained.

E ^{_{isomer; 1 H- NMR δ (CDC1 3}} , 270 MHz), 7.39 (1H, dd, J = 2, 8.6Hz), 7.48-7.52 (3H, ra), 7.58 (1H, d, J = 2Hz), 7.98 (1H, d, J = 8.6Hz), 8.25- 8.29 (2H, m).

Z _{isomer; - NMR δ (CDC1 3,} 270 MHz) 7.40 (1H, dd, J = 2, 8.6Hz), 7.48-7.54 (3H, m), 7.58 (1H, d, J = 2Hz), 7.71-7.74 (2H, m), 8.03 (1H, d, J = 8.6Hz).

(4) (E) -2- (2,4-dichlorobenzoyl) amino-3—clo-3-3-phenylpropenoic acid 2-thiazolylamide

Using the (E) —4-phenylchloromethylene-1-2- (2,4-dichlorophenyl) oxazolidin-5-one obtained in (3), the title compound was obtained in the same manner as in Example 1 (4). Synthesized.

1 H-NMR 6 (d ₆ -DMS0, 270 MHz) 7.29 (1H, d, J = 3.6 Hz), 7.38-7.52 (5H, m), 7.54-7.58 (3H, m), 7.68 (1H, d, J = 2Hz), 10.4 (1H, s), 12.9 (1H, s).

(Z) — 2: (2,4-dichlorobenzoyl) amino 3 _ chloro-1 3-phenylpropenoic acid 2-thiazolylamide

Example 3 Using (E) —4-fuunylchloromethylene-1-2- (2,4-dichlorophenyl) oxazolidine-15-one obtained in Example 3 (3), the title was obtained in the same manner as in Example 2. Was synthesized.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 7.17 (1H, d, J = 3.6 Hz), 7.32-7.41 (6H, m), 7.57 (1H, dd, J = 2, 8.6Hz), 7.63 (1H, d, J = 8.6Hz), 7.76 (1H, d, J = 2Hz), 10.6 (1H, s), 12.4 (1H , S).

Example 5

(E) —2— (3-chlorobenzene) amino-3 _cloth-3-phenylpropenoic acid 2-thiazolylamide

(1) N- (3-black benzoyl) glycine

The title compound was synthesized in the same manner as in Example 1 (1) using 3-benzolipid.

1 H-NMR δ (d ₆ -DMS0, 270 MHz) 3.90 (2H, d, J = 6 Hz), 7.37-7.52 (4H, t, m), 8.75 (1H, t, J = 6 Hz), 12.6 (1H , br).

(2) (Z) —4-Phenylmethylene-1- (3-chlorophenyl) oxazolidin-5-one

The title compound was synthesized in the same manner as in Example 1 (2), using N- (3-benzolipoyl) glycine obtained in (1).

^{_{1 H-NMR 6 (CDC1 3}} , 270 MHz) 7.29 (1H, s), 7.45-7.54 (4H, m), 7.57- 7.61 (1H, m), 8.05 (1H, td, J = 1.3, 8Hz), 8.17-8.22 (3H, m).

(3) (E), (Z) —4-Phenylchloromethylene-2- (3-chlorophenyl) oxazolidine-1 5-one

The title compound was prepared in the same manner as in Example 1 (3) using the (Z) —4_phenylmethylene-1- (3-chlorophenol) oxazolidin-15-one obtained in (2). The compound was synthesized.

E _{isomer; ifi- NMR δ (CDC1 3,} 270 MHz) 7.43-7.60 (4H, m), 7.98 (1H, td, J = 1.3, 8Hz), 8.09 (1H, t, J = 2Hz), 8, 17 —8.22 (3H, m).

Z _{isomer; if - NMR δ (CDC1 3} , 270 MHz) 7.44-7.54 (4H, m), 7.57-7.61 (1H, m), 7.69-7.73 (2H, m), 8.03 (1H, td, J = 1.3 , 8Hz), 8.15 (1H, t, J = 2Hz).

(4) (E) -2- (3-chlorobenzoyl) amino-3-chloro-1-3-phenylpropionic acid 2-thiazolylamide

(E) obtained from (3) —4—Füyrk-mouth lomethylene-1 2- (3-chlorofu The title compound was synthesized in the same manner as in Example 1 (4) using oxazolidin-5-one.

¹ H-NMR 6 (d ₆ -DMS0, 270 MHz) 7.28 (1H, d, J = 3.6Hz), 7.40-7.57 (7H, m), 7.64 (1H, d, J = 8Hz), 7.75 (1H, d, J = 8Hz), 7.86 (1H, t, J = 2Hz), 10.3 (1H, s), 12.8 (1H, s).

(Z) I 2— (3—Brozen Benzoinole) Amino I 3—Brozen J_ 1-Feninolepropenoic acid 2-Thiazolylamide

Example 5 The title compound was obtained in the same manner as in Example 2 using (Z) —4-phenylchloromethylene-12- (3-chlorophenyl) oxazolidin-5-one obtained in (3). Was synthesized.

^ -NMR δ (d ₆ -DMS0, 270 MHz) 7.17 (1H, d, J = 3.6 Hz), 7.34-7.42 (6H, m), 7.58 (1H, t, J = 8 Hz), 7.70 (1H, d , 8Hz), 7.95 (1H, d, J = 8Hz), 8.11 (1H, t, J = 2Hz), 10.5 (1H, s), 12.4 (1H, s).

(E)-2-(2-benzoyl) amino-1-chloro-3-phenylpropionic acid 2-thiazolylamide

(1) N— (2-black benzoyl) glycine

The title compound was synthesized in the same manner as in Example 1 (1) using 2-benzolipid.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 3.90 (2H, d, J = 6 Hz), 7.37-7.52 (4H, m), 8.75 (1H, t, J = 6 Hz), 12.6 (1H, br ).

(2) (Z) —4-phenylmethylene-1-2- (2-chlorophenyl) oxazolidin-5-one

The title compound was synthesized in the same manner as in Example 1 (2) using the N- (2-cyclobenzoyl) glycine obtained in (1).

¹ H-NMR δ (CDC13, 270 MHz) 7.33 (1H, s), 7.40-7.54 (5H, m), 7.59 T 71

28

(1H, dd, J = 1.3, 8Hz), 8.11 (1H, dd, J = 1.6, 8Hz), 8.20-8.25 (2H, m).

(3) (E), (Z) —4-Fumuric-mouth romethylene-2- (2-cyclohexyl) oxazolidin-1-5-one

The title compound was prepared in the same manner as in Example 1 (3) using the (Z)-(4-phenylmethylene) 2- (2-chloromouth phenyl) oxazolidin-15-one obtained in (2). The compound was synthesized.

E _{isomer; i fi- NMR δ (CDC1 3} , 270 MHz) 7.38-7.58 (6H, m), 8.04 (1H, dd, J two 1.6, 8Hz), 8.27-8.31 (2H , m).

Z _{isomer; 1 H- NMR δ (CDC1 3} , 270 MHz) 7.38-7.58 (6H, m), 7.71-7.75 (2H, m), 8.07 (1H, dd, J = 1.6, 8Hz).

(4) (E) I-2- (2-chlorobenzoyl) amino-3-chloro-1-phenylpropenoic acid 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 1 (4) using (E) -4-phenylchloromethylene-1-2- (2-chlorophenyl) oxazolidin-15-one obtained in (3). did.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 7.29 (1H, d, J = 3.6 Hz), 7.36-7.50 (7H, m), 7.54-7.60 (3H, m), 10.4 (1H, s) , 12.8 (1H, s).

Example 8

(Z)-2-(2-benzobenzene) amino-3-chloro-3-phenylphenylenoic acid 2-thiazolylamide

Example 7 The title compound was obtained in the same manner as in Example 2 using (Z) -4-fuunylchloromethylene-1- (2-chlorophenyl) oxazolidin-1-5-one obtained in (3). Was synthesized.

1 H-NM R 6 (d ₆ -DMS0, 270 MHz) 7.17 (1H, d, J = 3.3Hz), 7.31-7.61

(10H, m), 10.5 (1H, s), 12.3 (1H, s).

Example 9

(E) —2— (4-methoxybenzoinole) 1-amino-3—cloth 3—Feuerp Penic acid 2-thiazolylamide

(1) N- (4-Methoxybenzoyl) glycine

4-Methoxybenzoyl chloride was added to a mixture of 12.5 g (0.1 mol) of glycine methyl ester hydrochloride and 20.2 g (0.2 mol) of triethylamine in dichloromethane (20 Om1) under ice-cooling. 17.1 g (0.1 mo 1) was added dropwise. The reaction solution was stirred at room temperature for 4 hours, diluted with chloroform, washed successively with water and 1N hydrochloric acid, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained crystals were dissolved in methanol (10 Oml), 2N aqueous sodium hydroxide solution (10 Om1) was added, and the mixture was stirred at room temperature for 30 minutes. The methanol was distilled off under reduced pressure, and the remaining aqueous layer was washed with ether and then acidified with concentrated hydrochloric acid. The resulting crystals were collected by filtration, washed with water, and dried under reduced pressure to give the title compound (21 g, yield quantitative).

¹ H-NMR δ (d ₆ -DMSO, 270 MHz) 3.81 (3H, s), 3.89 (2H, d, J = 6 Hz), 7.01 (2H, d, J = 9 Hz), 7.85 (2H, d, J = 9Hz), 8.68 (1H, t, J = 6Hz), 12.6 (1H, br).

(2) (Z) — 4-phenylmethylene-1- 2- (4-methoxyphenyl) oxazolidin-5-one

Example 1 was performed using the N- (4-methoxybenzoyl) glycine obtained in (1).

The title compound was synthesized in the same manner as in (2).

¹ H-NMR δ (CDC13, 270 MHz) 3.91 (3H, s), 7.03 (2H, d, J = 9 Hz), 7.19 (1H, s), 7.43-7.51 (3H, m), 8.14 (2H, d , J = 9Hz), 8.17-8.22 (2H, m).

(3) (E), (Z) —4-Phenylchloromethylene-1-2- (4-methoxyphenyl) oxazolidine-1-one

Using (Z) -4-phenylphenylmethylene-2- (4-methoxyphenyl) oxazolidin-5-one obtained in (2), the title compound was synthesized in the same manner as in Example 1 (3). Was synthesized.

E ^{isomer; 1 H-NMR δ (CDC1} 3, 270 MHz) 3.90 (3H, s), 7.00 (2H, d, J = 9Hz), 7.47-7.51 (3H, m), 8.06 (2H, d, J = 9Hz), 8.20-8.23 (2H, m).

Z ^{_{isomer; 1 H- NMR 6 (CDC1 3}} , 270 MHz) 3.91 (3H, s), 7.01 (2H, d, J = 9Hz), 7.46-7.51 (3H, m), 7.67-7.70 (2H, m) , 8.11 (2H, d, J = 9 Hz). (4) (E) — 2- (4-Methoxybenzoyl) amino-3-chloro-3-phenylpropionic acid 2-thiazolylamide

The title compound was obtained in the same manner as in Example 1 (4), using (E) — 4_phenylchloromethylene-1- (4-methoxyphenyl) oxazolidin-15-one obtained in (3). Was synthesized.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 3.80 (3H, s), 6.98 (2H, d, J = 9 Hz), 7.27 (1H, d, J = 3.6 Hz), 7.39-7.47 (3H, m), 7.53-7.57 (3H, m), 7.78 (2H, d, J = 9Hz), 10.0 (1H, s), 12.8 (1H, s).

(Z) -2- (4-Methoxybenzoyl) amino-3-chloro-3-phenylphenyl penic acid 2-thiazolylamide

Example 9 The title compound was prepared in the same manner as in Example 2 by using (Z) —4-furycyl romethylene 1-2- (4-methoxyphenyl) oxazolidin-5_one obtained in (3) in the same manner as in Example 2. Synthesized.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 3.84 (3H, s), 7.07 (2H, d, J = 9 Hz), 7.16 (1H, d, J = 3.3 Hz), 7.32-7.42 (6H, m), 8.01 (2H, d, J = 9Hz), 10.1 (1H, s), 12.3 (1H, s).

(E) — 2-benzoylamino-3-chloro-3 _-phenylpropenoic acid 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 1 (1)-(4) using hippuric acid.

1 H-NMR 6 (dg-DMSO, 270 MHz) 7.28 (1H, d, J = 3.6 Hz), 7.45 (5H, m), 7.53 (1H, d, J = 3.6 Hz), 7.56 (3H, m) , 7.79 (2H, d, J = 7 Hz), 10.2 (1H, s), 12.8 (1H, s). (Z) — 2-Benzylamino-3-3-chloro-3, -phenylpropenoic acid 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 1 (1)-(3) and Example 2 using hippuric acid.

1 H-NMR 6 (d ₆ -DMS0, 270 MHz) 7.17 (1H, d, J = 3.6Hz), 7.33-7.43 (6H, m), 7.54 (2H, t, J = 7Hz), 7.63 (1H, t, J = 7Hz), 8.02 (2H, d, J = 8Hz), 10.3 (1H, s), 12.4 (1H, s).

(E) — 2- (2,2-dichloro-1-hexanoyl) amino-3-chloro-3-monophenylpropenoic acid 2-thiazolylamide

(1) N- (1-hexanoyl) glycine

Glycine methyl ester hydrochloride 12.5 g (0.1 mol), 1-hexanoic acid 11.6 g (0.1 mol), 1-hydroxybenzotriazo mono 13.5 g (0.1 mo 1), triethylamine 12.1 g (0.12 mol 1) in dichloromethane (200 ml) 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide Hydrochloride (19.2 g, 0.1 mmo 1) was added, and the mixture was stirred for 3 hours. After evaporating the solvent, the residue was diluted with ethyl acetate, washed successively with water, saturated aqueous sodium bicarbonate, 1 N hydrochloric acid and saturated aqueous sodium bicarbonate, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was dissolved in methanol (15 Om 1), 1 N aqueous sodium hydroxide solution (15 Om 1) was added, and the mixture was stirred at room temperature for 2 hours. The methanol was distilled off under reduced pressure, the remaining aqueous layer was acidified with concentrated hydrochloric acid, and then extracted with ethyl acetate. After the extract layer was washed with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained solid was washed with ether and dried under reduced pressure to obtain 12.3 g (yield: 11%) of the title compound.

_{1 H- NMR δ (CDC1 3,} 270 MHz) 0.89 (3H, t, J = 6.6Hz), 1.28-1.36 (4H, m), 1.59-1.70 (2H, m), 2.28 (2H, t, J = 8Hz), 4.06 (2H, d, J = 5Hz), 6.43 (1H, brt), 9.08 (1H, br).

(2) (Z) —4-Phenylmethylene-1-2- (1-pentyl) oxazolidine-5-one 1.Add 1.73 g (l Ommo l) of hexanoylglycine, 1.1 g (1 Ommo 1) of benzaldehyde and 0.82 g (l Ommo l) of anhydrous sodium acetate to 1 Om 1 of acetic anhydride. The mixture was stirred at 60 ° C for 7 hours. After evaporating acetic anhydride under reduced pressure, the residue was diluted with ethyl acetate, washed sequentially with water and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent and the remaining benzaldehyde were distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: toluene = 1: 1) to give 0.96 g (yield 40%) of the title compound as an oil. Obtained as a product.

¹ H-NMR 6 (CDC13, 270 MHz) 0.93 (3H, t, J = 7Hz), 1.32—1.48 (4H, m), 1.76-1.87 (2H, m), 2.66 (2H, t, J = 7.6Hz) ), 7.15 (1H, s), 7.40-7.47 (3H, m), 8.06-8.11 (2H, m).

(3) (E), (Z) —4-Phenylchloromethylene-1- 2- (1,1-dichloro-1-pentyl) oxazolidin-5-one

The title compound was synthesized in the same manner as in Example 1 (3) using (Z) —4-phenylmethylene-1- (1-pentyl) oxosazolidine-1-one obtained in (2). Done.

E _{isomer; i fi- NMR δ (CDC1 3} , 270 MHz) 0,97 (3H, t, J = 7Hz), 1.37-1.52 (2H, m), 1.62-1.76 (2H, m), 2.58 (2H, m), 7.45-7.56 (3H, m), 8.11 (2H, d, J = 9Hz).

Z _{isomer; - NMR 6 (CDC1 3,} 270 MHz) 0.99 (3H, t, J = 7Hz), 1.40-1.55 (2H, m), 1.67-1.78 (2H, m), 2.63 (2H, m), 7.45 -7.59 (3H, ra), 7.70 (2H, d, J = 9Hz).

(4) (E) -2- (2,2-dichloro-1-hexanoyl) amino-3-chloro-1--3-phenylpropenoic acid 2-thiazolylamide

Using (E) — 4-Feyluc mouth romethylene 1-2- (1,1-dichloro-1-pentyl) oxazolidin-5-one obtained in (3), in the same manner as in Example 1 (4) The title compound was synthesized.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 0.85 (3H, t, J = 7Hz), 1.23--1.40 (4H, m), 2.35 (2H, m), 7.29 (1H, d, J = 3.6 Hz), 7.33-7.55 (6H, m), 10.2 (1H, s), 12.8 (1H, s). Example 14

(Z) -2-(2,2-Dichloro-1-hexanoyl) amino-3 -chloro-3 -phenylpropenoic acid 2-thiazolylamide

Example 13 A method similar to that of Example 2 using (Z) —4_Fjürk-mouthed romethylene 1-2- (1,1-dichloro-1-pentyl) oxazolidin-1-5-one obtained in 3 (3). Was used to synthesize the title compound.

丄 H— NMR 6 (d ₆ -DMS0, 270 MHz) 0.91 (3H, t, J = 7Hz), 1.33—1.54 (4H, m), 2.50 (2H, m), 7.18 (1H, d, J = 3.6 Hz), 7.33-7.41 (6H, m), 10.3 (1H, s), 12.3 (1H, s).

(Z) —2-benzoylamino-3- (4-cyanophenyl) propenoic acid 2-thiazolylamide

(1) (Z) -4- (4-Cyanophenyl) methylene-1 2-phenyloxazolidin-1 5-one

The title compound was synthesized in the same manner as in Example 1 (2) using hippuric acid and 4-cyanobenzaldehyde.

¹ H-NMR 6 (CDC13, 270 MHz) 7.19 (1H, s), 7.57 (2H, t, J = 7 Hz), 7.68 (1H, t, J = 7 Hz), 7.76 (2H, d, J = 8.3 Hz), 8.21 (2H, d, J = 8 Hz), 8.30 (2H, d, J = 8.2 Hz).

(2) (Z) _ 2-benzoylamino-3- (4-cyanophenyl) propenoic acid 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 1 (4) using (Z) -4-1- (4-cyanophenyl) methylene-12-phenyloxazolidin-15-one obtained in (1). .

¹ H-NMR 6 (d ₆ -DMS0, 270 MHz) 7.24 (1H, d, J = 3.3 Hz), 7.31 (1H, s), 7.52 (1H, d, J = 3.3 Hz), 7.50-7.66 (3H, m), 7.92 (2H, d, J = 8 Hz), 7.85 (2H, d, J = 8 Hz), 8.02 (2H, d, J = 8 Hz), 10.37 (1H, br s), 12.57 (1H , br s).

Example 16

(E)-2-Benzoinoleamino-3- (4-Fe / Leno-propane) propenoic acid 2-thiazolylamide

Using a Pyrex photoreactor, (Z) —2-benzoylamino-3- (4-cyanophenyl) propenoic acid 2-thiazolylamide 50 Omg (1.3 mmo

A solution of 1) in 300 ml of acetone was irradiated for 1.5 hours with a 100 W high-pressure mercury lamp under a nitrogen atmosphere. Acetone was distilled off under reduced pressure, and a small amount of methanol was added to the residue. The resulting crystals (raw materials) were filtered off, the mother liquor was concentrated, and the residue was crystallized with ethyl acetate-ether to give 16 Omg (containing 20% of the raw materials) of the title compound.

¹ H-NMR 6 (d ₆ -DMS0, 270 MHz) 7.27 (1H, d, J = 3.3 Hz), 7.47 (1H, d, J = 3.3 Hz), 7.50-7.65 (5H, m), 7.74 (2H, d, J = 9 Hz), 7.90-7.98 (3H, m), 10.65 (1H, s), 12.62 (1H, s).

(Z) — 2-benzoylamino-3 _ (2-pyridyl) propenoic acid 2-thiazolylamide

(1) (E, Z) -4- (2-pyridyl) methylene- 1- 2-phenyl-oxazolidin-5-one

Add 5.0 g (28 mmo 1) of hippuric acid, 2.6 m 1 (28 mmo 1) of nicotine aldehyde and 2.29 g (28 mmo 1) of sodium acetate anhydride to 8 m 1 of acetic anhydride and bring it to 100 ° C. And stirred for 3 hours. Acetic anhydride was distilled off under reduced pressure, and the residue was poured into saturated aqueous sodium hydrogen carbonate. The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give 4.39 g (yield 63%) of the title compound as a brown solid (Z: E = 3: 1).

Z _{isomer; i H- NMR 6 (CDC1 3} , 270MHz) 7.23 (1Η, s), 7.42-7.70 (4H, m), 8.20 (2H, d, 6.9 Hz), 8.66 (1H, dd, J = 5.0, 1.7 Hz), 8.71 (1H, dt, J = 10, 1.9 Hz), 9.21 (1H, d, 2 Hz).

(2) (Z) -2—Benzoylamino-3- (2-pyridyl) propenoic acid 2— Thiazolyl amide

(E, Z) —4- (2-pyridyl) methylene-1-2-phenyloxazolidin-5-one 500 mg (2 mmo 1), 2-aminothiazole 30 Omg (3 mmo 1) solution in toluene 10 ml Was heated to reflux for 3 hours. After distilling off the toluene under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to obtain the title compound (178 mg, yield 25%) as a white powder. .

¹ H-NMR δ (d ₆ -DMS 0, 270 MHz) 7.27 (1 H, d, J = 3.6 Hz), 7.35 (1 H, s), 7.43 (1 H, dd, J = 8.3, 5.0 Hz), 7.50-7.66 ( 3H, m), 7.53 (1H, d, J = 3.6 Hz), 7.99-8.07 (3H, m), 8.50 (1H, dd, J = 4.6, 1.7 Hz), 8.79 (1H, d, J = 2.0 Hz) ), 10.31 (1H, br s), 12.60 (1H, br s)

(E) —2-benzoylamino-3- (2-pyridyl) propenoic acid 2_thiazolinoleamide,

Example 17 The title compound was obtained in the same manner as in Example 16 by using 2-thiazolylamide (Z) -2_benzoylamino-3- (2-pyridyl) propenoic acid obtained in (2). Synthesized.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 6.79 (1H, s), 7.25 (1H, d, J = 3.6 Hz), 7.30 (2H, dd, J = 8.3, 5.0 Hz), 7.46 (1H, d, J = 3.6 Hz), 7.50-7.66 (3H, m), 7.92-7.98 (2H, m), 8.38 (1H, dd, J = 4.6, 1.3 Hz), 8.43 (1H, d, J = 2.3 Hz) ), 10.63 (1H, br s), 12.57 (1H, br s).

Example 19

(Z) 2-benzoylamino-3- (3-Chenyl) propenoic acid 2-thiazolylamide

(1) (Z) —4— (3-Chenyl) methylene-1-2-phenyloxazolidine-1-one

As in Example 1 (2), using hippuric acid and 3-thiophenecarboxyaldehyde The title compound was synthesized by a simple method.

^{_{1 H-NMR δ (CDC1 3}} , 270MHz) 7.30 (1H, s), 7.42 (1H, dd, J = 4.6, 3.0 Hz), 7.49-7.65 (3H, m), 7.95 (1H, dd, J = 4.6 , 1.7 Hz), 8.14-8.21 (3H, m). (2) (Z) — 2-benzoylamino-3- (3-chenyl) propenoic acid 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 1 (4), using (Z) -4--(3-Chenyl) methylene-2-phenylazozolidine-15-one obtained in (1). did.

¹ H-NMR 6 (d ₆ -DMS0, 270 MHz) 7.24 (1H, d, J = 3.6 Hz), 7.39 (1H, dd, J = 5.3, 1.0 Hz), 7.51 (1H, d, J = 3.6 Hz) , 7.50-7.66 (6H, m), 7.92 (1H, d, J = 2.0 Hz), 8.09 (2H, d, 6.9 Hz), 10.11 (1H, s), 12.43 (1H, s).

(E) — 2-benzoylamino-3- (3-Chenyl) propenoic acid 2-thiazolylamide

Example 19 The title compound was obtained in the same manner as in Example 16 using (Z) -2-benzoylamino-3- (3-phenyl) propenoic acid 2-thiazolylamide obtained in (2). Synthesized.

¹ H-NMR 5 (d ₆ -DMS0, 270 MHz) 6.76 (1H, s), 6.98 (1H, t, J = 3.3 Hz), 7.26 (1H, d, J = 3.3 Hz), 7.45-7.65 (6H, m), 7.95 (1H, d, J = 6.9 Hz), 10.43 (1H, s), 12.54 (1H, s).

Example 2 1

(Z) — 2-Benzylamino _ 3 — (2-Chenyl) propenoic acid 2-thiazolinole

(1) (Z) -4--(2-Chenyl) methylene-1-2-phenyloxazolidine-1-one

The title compound was synthesized in the same manner as in Example 1 (2) using hippuric acid and 2-thiophene carboxyaldehyde. ^{_{1 H-NMR 6 (CDC1 3}} , 270MHz) 7.17 (1H, dd, J = 5.0, 3.6 Hz), 7.46-7.65 (5H, m). 7.73 (1H, d, J = 5.3 Hz), 8.17 (2H, m).

(2) (Z) —2-benzoylamino-3- (2-Chenyl) propenoic acid 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 1 (4) using (Z) —4— (2-Chenyl) methylene-12-phenyloxysazolidin-1-5-one obtained in (1). did.

¹ H-NMR 6 (d ₆ -DMS0, 270 MHz) 7.15 (1H, dd, J = 5.3, 4.0 Hz), 7.25 (1H, d, J = 3.6 Hz), 7.52 (1H, d, J = 3.6 Hz) , 7.50-7.67 (3H, m), 7.73 (1H, d, J = 5.3 Hz), 7.96 (1H, s), 8.11 (2H, d, J = 6.6 Hz), 9.94 (1H, s), 12.46 ( 1H, s). Example 22

(E) — 2-benzoylamino-3- (2-phenyl) propenoic acid 2-thiazolylamide,

Using the (Z) -2-benzoylamino-3- (2-phenyl) propenoic acid ₂ -thiazolylamide obtained in Example 21 (2), the title compound was prepared in the same manner as in Example 16. Synthesized.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 6.97 (1H, s), 7.01 (1H, dd, J = 5.3, 3.6 Hz), 7.13 (1H, d, J = 3.3 Hz), 7.27 (1H, d, J = 3.3 Hz), 7.46-7.55 (5H, m), 7.95 (2H, d, J = 6.6 Hz), 10.43 (1H, s), 12.62 (1H, s).

(E) _ 2—Benzoylamino 3- 3-promo 3-phenylphenylenoic acid 2-thiazolyl amide

(1) 4-Bromo-4_Fenii / Reb Moutine 1-Feninoleoxazolidine 1-one

(Z) —4-Phenylmethylene-1-2-phenyloxazolidin-1-5-one A solution of 2.0 g (8 mmo 1) of formaldehyde 3 Om 1 in bromine 0.5 ml (1 0 mm o 1) was added and stirred for 19 hours. 1.5 ml of bromine was further added to the reaction solution, and the mixture was stirred for 24 hours. The reaction solution was concentrated under reduced pressure to dryness to give the title compound (3.19 g) as a pale-yellow solid.

^{1 H- NMR 6 (CDC13, 270MHz} ) 5.54 (1H, s), 7.40-7.83 (8H, m), 8.18- 8.24 (2H, m).

(2) (E), (Z) — 4-Phenylbromomethylene-1-2-phenylenoxazolin-1-5-one

4-Bromo-4-pheninoleb Mouthtinole 2-Fe / Lexazolidine-1-5-one 50 Omg (1.2 mmo 1) in THF (10 ml) solution of triethylamine 0.17 ml (1.2 mmo) 1) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was further added with 5 drops of DBU and stirred for 2.5 hours. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate. After concentration, the residue is purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to give the title compound E (low-polar isomer) 110 mg, Z-isomer (highly polar isomer) 32 Thus, 105 mg (total yield: 62%) of a mixture of E, Z and E was obtained.

¹ H-NMR δ (CDC13, 270 MHz) E form; 7.45-7.66 (6H, m), 8.17-8.25 (4H, m).

Z-form; 7.43-7.56 (5H, m), 7.60-7.68 (3H, m), 8.14-8.20 (2H, m).

(3) (E) -2-benzoylamino-3-bromo-3-phenylpropenoic acid 2-thiazolylamide

(E) of 4-phenylene ^^ bromomethylene-1 2-phenenoleoxazoline-5-one 5 Omg (0.15 mmo 1) and 18 mg of 2-aminothiazol (0.18 mmo 1) The toluene (1 ml) solution was heated under reflux for 4 hours. After allowing the reaction mixture to cool, the resulting precipitate was collected by filtration, washed with toluene, and dried under reduced pressure to give the title compound (44 mg, yield 68%) as a white powder.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 7.25 (1H, d, J = 3.6 Hz), 7.30-7.44 (3H, m), 7.50-7.69 (6H, m) 8.05 (2H, d, J = 6.9 Hz), 10.19 (1H, s), 12.50 (1H, s). 1

39 Example 24

(Z) 1-Benzoinoleamino-1-3-bromo-1-3-phen2 / reb-open-pentic acid 2-thiazolylamide

The title compound was obtained in the same manner as in Example 23 (3) using (Z) —4-phenylbromomethylene-12-phenyloxazoline-15-one obtained in Example 23 (2). Synthesized.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 7.15 (1H, d, J = 3.6 Hz), 7.26-7.42 (6H, m), 7.50-7.67 (3H, m), 8.02 (2H, d, J = 6.9 Hz), 10.20 (1H, s), 12.30 (1H, s).

(Z) 2-benzoinoleamino-3- (4-phenolic phenol) 2-propylic acid lylamide

(1) (Z) -4- (4-Funoleolopheninole) methylene-1 2-phenyloxazoline-1 5-one

The title compound was synthesized in the same manner as in Example 1 (2) using hippuric acid and 4-fluorobenzaldehyde.

¹ H-NMR δ (CDC13, 270MHz) 7.10-7.30 (3H, m), 7.50-7.70 (3H, m), 8.15-8.33 (3H, m).

(2) (Z) 1-2-Benzylamino-3- (4-fluorophenyl) propenoic acid 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 1 (4) using (Z) -4- (4-fluorophenyl) methylene-2-phenyloxazoline-15-one obtained in (1). .

1H-NMR δ (d ₆ -DMS0, 270 MHz) 7.19-7.30 (3H, m), 7.37 (1H, s), 7.49-- 7.75 (6H, m), 8.04 (2H, d, J = 7 Hz), 10.17 (1H, s), 12.46 (1H, s).

(E) _ — 2 Benzenylamino 1 3 _ (4-fluorophenyl) propenoic acid — 2 PT / JP 9/05871

40

—Thiazolylamide

Example 25 The title compound was prepared in the same manner as in Example 16 using (Z) -2-benzoylamino-3- (4-fluorophenyl) propenoic acid 2-thiazolylamide obtained in (2). Synthesized.

1 H-NMR 6 (d ₆ -DMS0, 270 MHz) 6.77 (1H, s), 7.12 (2H, t, J = 8.9 Hz), 7.23 (1H, d, J = 3.3 Hz), 7.22-7.31 (2H, m), 7.45 (1H, d, J = 3.3 Hz), 7.49-7.65 (3H, m), 7.92-7.98 (2H, m), 10.49 (1H, s), 12.49 (1H, s). 7

2-benzoylamino 3- 3-phenyl 3-methinorethiopropenoic acid 2-thiazolyl amide

2-benzoinoleamino-1-3-chloro-3-enophenylpropenoic acid 2-thiazolylamide (E: Z = 2: 1) 10 Omg (0.26 mmo1) and sodium methoxide methoxide 44 mg (0 Two drops of DBU were added to a mixed solution of 6.3 mmo 1) in methanol (1 ml) -acetonitrile (1 ml), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with a filter form, washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (46 mg, yield 45%) as a 1: 1 mixture of E and Z forms.

1 H-NMR δ (d ₆ -DMS0, 270 MHz) 1.83 and 1.94 (total 3H, s), 7.09 and 7.23 (total 1H, d, J = 3.6 Hz), 7.20-7.70 (9H, m), 8.02 (2H , d, J = 7 Hz), 9.47 and 9.90 (total 1H, s), 11.92 and 12.26 (total 1H, br s).

2-Benzoylamino 3- (4-fluorophenyl) -1-butenoic acid 2-thiazolyl amide

(1) 4- (1- (4-fluorophenyl) -1-methyl) methylene-1-phenyloxyxazoline-5-one

2—Phenyloxazoline-5-one 30 Omg (1.9 mmo 1), 4— 0.25 ml (2.Ommo 1), pyridine 0.9 ml

To a solution of (9.3 mmol) in THF (5 ml) was added dropwise 0.27 ml (2.5 mmol) of titanium tetrachloride under ice-cooling. After the temperature of the reaction solution was gradually raised to room temperature, the mixture was further stirred for 1 hour and poured into saturated aqueous sodium hydrogen carbonate. After extraction with ethyl acetate, the extracted layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 330 mg (yield 63%) of the title compound as a mixture of E and Z forms.

^{_{1 H - NMR δ (CDC1 3}} , 270MHz) 2.64 and 2.78 (total 3H, s), 7 · 05- 7.22

(3H, m), 7.45-7.65 (3H, m), 7.90-8.14 (3H, m).

(2) 2-benzoylamino-3 _ (4-fluorophenyl) mono-2-butenoic acid

2-thiazolyl amide

A method similar to that of Example 1 (4) using 4- (1- (4-fluorophenyl) -11-methyl) methylen-2-phenyloxazoline-15-one obtained in (1). Was used to synthesize the title compound.

1 H-NMR δ (d _fi -DMS0, 270MHz) 2.16 and 2.25 (total 3H, s), 7.06-7.65

Example 29 (9H, m), 7.72-7.78 and 7.98-8.04 (total 2H, m), 9.58 and 10.07 (total 1H, s), 11.95 and 12.38 (total 1H, s).

2-benzoylamine 3-phenyl-1-phenylthiopropenoic acid 2-thiazolylamide

2-benzoylamino-1-3-chloropropenoic acid 2-thiazolylamide (E: Z = 2: 1) l O Omg (0.26 mmo 1), thiophenol 35 mg (0.32 mmo 1) To a solution of 11 ml (0.78 mmo 1) of triethylamine in THF (1 ml) was added 1 drop of DBU at room temperature, followed by stirring for 5 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to obtain 107 mg (yield 90%) of the title compound as an E- or Z-form. Obtained as a mixture.

¹ H-NM R δ (d6-DMS0, 270MHz) 7.00-7.60 (15 H, m), 7.63-7.75 and 7.80—7.88 (total 2H, m), 9.89 and 10.03 (1H, br s), 12.12 and 12.59 (total 1H, br s).

(Z) — 2-benzoylamino-3- (2-naphthyl) propenoic acid 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 15 (1)-(2) using hippuric acid and 2-naphthalenecarboxyaldehyde.

¹ H-NMR 6 (d ₆ -DMS0, 270 MHz) 7.27 (1H, d, J = 3.6 Hz), 7.48-7.68 (7H, m), 7.78-7.93 (4H, m), 8.07 (1H, br d, J = 6.9 Hz), 8.19 (1H, s), 10.28 (1H, s), 12.56 (1H, s).

2-benzoylamino-3-phenyl-1-butenoic acid 2-thiazolylamide (4: 1 geometric isomer mixture)

(1) 4- (1-phenyl 1-methyl) methylene-1 2-phenyloxazoline 5-

Hippuric acid 2.0 g (ll mmo l), acetofenone 1.34 g (11 mmo 1), lead tetraacetate 2.48 g (5.6 mmo 1), acetic anhydride 3.2 m1 to THF (10 ml) ) And heated under reflux for 15 hours. After allowing the reaction solution to cool, it was poured into ice water and extracted with a black hole form. The extract layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to obtain 85 mg (yield 3%) of the title compound as a white powder.

_{1 H-NMR 6 (CDC1 3} , 270MHz) 2.80 (3Η, s), 7.40-7.60 (6H, m), 7.83- 7.90 (2H, m), 8.03-8.10 (2H, m).

(2) 2-benzoylamino-1,3-phenyl-2-butenoic acid 2-thiazolylamide (4: 1 geometric isomer mixture)

4- (1-phenyl-1-methyl) methylene-1-2-phenyl obtained in (1) 71

The title compound was synthesized in the same manner as in Example 1 (4) using 43oxazolin-1-one.

¹ H-NMR 6 (d ₆ -DMS0, 270 MHz) 2.17 and 2.27 (total 3H, s), 7.07-7.70 (10 H, m), 7.70-7.80 and 7.98-8.05 (total 2H, m), 9.52 and 10.05 (total 1H, br s), 11.91 and 12.35 (total 1H, br s).

Example 32

(Z) — 2-Benzylamino-1-3-phenylpropenoic acid 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 15 (1)-(2) using hippuric acid and benzaldehyde.

¹ H—NMR δ (d ₆ -DMS0, 270 MHz) 7.32 (1H, d, J = 3.6 Hz), 7.36 (1H, s), 7.40 (3H, m), 7.51 (1H, d, J = 3.6 Hz) , 7.60 (5H, m), 8.04 (2H, d, J = 6.9 Hz), 10.17 (1H, s), 12.48 (1H, s).

Example 33

(E) — 2-benzoylamino-3-phenylphenylenoic acid 2-thiazolylamino acid

The title compound was synthesized in the same manner as in Example 16 using the (Z) -2-benzoylamino-3-feuerup pent-2-ic acid 2-thiazolylamide obtained in Example 32.

¹ H-NMR 6 (d ₆ -DMS0, 270 MHz) 6.77 (1H, s), 6.15—6.32 (6H, m), 7.44 (1H, d, J = 3.6 Hz), 7.49—7.66 (3H, m), 7.93-7.98 (2H, m), 10.48 (1H, s), 12.47 (1H, s).

Example 34

(E) — 2-benzoylamino-3- (4-aminocarboylphenyl) propionic acid 2-thiazolylamide

(E) —2-Benzylamino-3- (4-cyanophen) obtained in Example 16 Nyl) Profenic acid 2-thiazolyl amide (5 Omg) was added little by little to concentrated sulfuric acid (0.5 ml) at room temperature, and the mixture was stirred at room temperature for 17 hours. The reaction solution was poured into water, and the resulting precipitate was collected by filtration, washed with water and dried under reduced pressure to give 45 mg (yield: 88%) of the title compound (containing 30% of Z form).

1 H-NMR δ (d ₆ -DMS0, 270 MHz) 6.73 (1H, s), 7.19 (1H, d, J = 3.6 Hz), 7.22 (2H, d, J = 9 Hz), 7.27 (1H, br s ), 7.40 (1H, d, J = 3.6 Hz), 7.44- 7.60 (3H, m), 7.68 (2H, d, J = 8 Hz), 7.86 (1H, br s), 7.86-7.94 (2H, m ), 10.51 (1H, s), 12.50 (1H, s).

(Z) — 2-benzoylamino-3- (4-aminocarboylphenyl) propionic acid 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 34, using (Z) -2-benzoylamino-3- (4-cyanophenyl) propenoic acid 2-thiazolylamide obtained in Example 15 .

¹ HN R δ (d ₆ -DMS0, 270 MHz) 7.27 (1H, d, J = 3.6 Hz), 7.36 (1H, s), 7.41 (1H, br s), 7.50-7.66 (4H, m), 7.70 ( 2H, d, J = 8 Hz), 7.86 (2H, d, J = 8 Hz), 7.98 (1H, br s), 8.04 (2H, d, J = 7 Hz), 10.25 (1H, s), 12.50 (1H, br s). Example 36

(Z) _ 2-benzoylamino-3- (4-methoxycarbophenyl) propenoic acid 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 15 (1)-(2) using hippuric acid and 4-methoxybenzaldehyde.

¹ H-NMR 6 (d ₆ -DMS0, 270 MHz) 3.84 (3H, s), 7.27 (1H, d, J = 3.6 Hz), 7.33 (1H, s), 7.53 (1H, d, J = 3.6 Hz) , 7.50-7.66 (3H, s), 7.77 (2H, d, J = 8 Hz), 7.95 (2H, d, J = 8 Hz), 8.02 (2H, d, J = 7 Hz). Example 37

(E) 1-2-Benzoylamino 3- (4-methoxycarberphenyl) propenoic acid 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 16 using (Z) -2-benzoylamino-3- (4-methoxyproponylphenyl) propenoate 2-thiazolylamide obtained in Example 36. did.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 7.26 (1H, d, J = 3.6 Hz), 7.35 (2H, d, J = 8 Hz), 7.46 (1H, d, 3.6 Hz), 7.50—7.66 (5H, m), 7.82 (2H, d, J = 8 Hz), 7.95 (2H, d, J = 8 Hz), 10.62 (1H, s), 12.67 (1H, s).

(Z) _ 2-benzoylamino-3- (4-carboxyphenyl) propenoic acid 2-thiazolylamide

10 Omg (0.25 mmo 1) of (Z) -2-benzoylamino-1- (4-methoxycarberphenyl) propenoic acid 2-thiazolinoleamide obtained in Example 36 was added to a 1 N aqueous sodium hydroxide solution. To the mixture, and the mixture was stirred at room temperature for 3 hours. The reaction solution was acidified by adding concentrated hydrochloric acid, and the resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (94 mg, yield 98%) as a white powder.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 7.27 (1H, d, J = 3.3 Hz), 7.33 (1H, s), 7.50-7.66 (4H, m), 7.74 (2H, d, J = 9 Hz), 7.93 (2H, d, J = 8 Hz), 8.03 (2H, d, J = 8 Hz), 10.30 (1H, s), 12.62 (1H, br s), 12.94 (1H, br s). Example 39

(E) — 2-benzoylamino-3- (4-carboxyphenyl) propenoic acid 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 16 using (Z) _2-benzoylamino-3- (4-carboxyphenyl) propenoic acid 2-thiazolylamide obtained in Example 38.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 6.84 (1H, s), 7.26 (2H, d, J = 3.6 Hz), 7.32 (1H, d, J = 8 Hz), 7.46 (1H, d, J = 3.6 Hz), 7.50-7.66 (3H, m), 7.80 (2H, d, J = 9 Hz), 7.95 (2H, d , J = 8 Hz), 10.62 (1H, s), 12.58 (1H, br s).

2-benzoylamino _ 3- (2-pyridylthio) -1-phenylpropenoic acid 2-thiazolylamide (E-form and Z-form)

2-benzoylamine 3-chloro-3-phenylpropenoic acid 2-thiazolylamide (E-form) (0.52 mmo 1) and 2_mercaptopyridine (0.57 mmo 1) tetrahydrofuran (5.0 m 1) To the solution was added DBU (0.81 mmo 1) at room temperature, and the reaction mixture was heated at room temperature for 2 hours at 50 °. And stirred for 1.5 hours. The reaction solution was diluted with ethyl acetate, washed sequentially with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. A small amount of methanol (1: 1) was added to the concentrated residue, and the resulting precipitate was collected by filtration, washed with chloroform and dried under reduced pressure to obtain the low-polar isomer (0.45 in. Cloth form / methanol = 20: 1)) 34 mg (14%) was obtained as a pale yellow powder. After concentrating the mother liquor, a small amount of chloroform / methanol (1: 1) was added and the resulting precipitate was collected by filtration, washed with chloroform and dried under reduced pressure to obtain the highly polar isomer (R f value). 0.30 (form: methanol / methanol = 20: 1) 33 mg (14%) was obtained as a pale yellow solid.

Low polarity isomer: ifi—NMR δ (d ₆ -DMS0, 270 MHz) 7.12 (1H, ddd, J = 7.2, 4.6, 1.0 Hz), 7.18-7.35 (4H, m), 7.41-7.50 (4H, m) , 7.52-7.63 (4H, m), 7.75-7.81 (2H, m), 8.36 (1H, ddd, J = 5.6, 2.1, 1.0 Hz), 10.20 (1H, s), 12.65 (1H, s).

Highly polar isomer: ifi—NMR δ (d ₆ -DMS0, 270 MHz) 7.05 (1H, ddd, J = 7.3,

4.6, 1.0 Hz), 7.14 (1H, d, J = 3.6 Hz), 7.16-7.27 (3H, m), 7.30-7.61 (9H, m), 7.36 (1H, d, J = 3.6 Hz), 7.81 ( Example 41 2H, d, J-7 Hz), 8.30 (1H, ddd, J = 5.4, 2.7, 1.4 Hz), 10.26 (1H, s), 12.27 (1H, s).

2-Benzylamino-3- (2-pyridylthio) _3-Furpropenoic acid Methyl ester (E-form and Z-form)

(1) 2-benzoinoleamino-1-methyl-3-pheninolepropenoate methyl ester (E-form)

(E) — One drop of a 28% sodium methoxide methanol solution was added to a solution of 4-phenylene / clomethylene-1,2-phenenoleoxazolidine-15-one (1.8 mmo 1) in methanol (1 Om 1) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the concentrated residue was suspended in getyl ether, the precipitate was collected by filtration, washed with getyl ether, and dried under reduced pressure to obtain 258 mg (47%) of the title compound as a pale yellow powder.

_{1 H-NMR δ (CDC1 3} , 270MHz) 3.96 (3H, s), 7.30-7.56 (8H, tn), 7.63 (2H, d, J = 7 Hz).

(2) 2-benzoylamino-3- (2-pyridylthio) -13-phenylproic acid methyl ester (E-form and Z-form)

(2) Benzoinoleamino-13-chloro-1-3-methynolepropenoic acid methinolester (E-form) (0.64 mmol) and 2-mercaptopyridine (0.64 mmol) in tetrahydrofuran (5 ml) solution (1.3 mmo 1) was added and the reaction mixture was stirred at room temperature for 14 hours. The reaction solution was diluted with ethyl acetate, washed sequentially with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography (ethyl ethyl hexane: hexane = 1: 2) to give 79 mg (32%) of the low-polar isomer (R 0.20) as a pale yellow solid to give the high-polar isomer ( R fj O. 15) 66 mg (27%) was obtained as a pale yellow solid.

Low polarity _{isomer: - NMR δ (CDC1 3,} 270MHz) 3.61 (3Η, s), 7.03 (1H, ddd, J = 7.6, 5.0, 1.0 Hz), 7.20-7.35 (4H, m), 7.40-7.60 ( 6H, m), 7.83 (2H, d, J = 7 Hz), 8.39 (1H, ddd, J = 5.0, 2.0, 1.0 Hz), 9.01 (1H, s). Highly polar isomer: — NMR 6 (CDC13 , 270MHz) 3.92 (3H, s), 6.95 (1H, ddd, J = 7.6, 4.9, 1.0 Hz), 7.23-7.66 (12H, m), 7.90 (1H, s), 8.34 (1H, ddd, J = (5.6, 2.4, 1.5 Hz). Example 42

2-benzoylamino 3- (2-naphthinorethio) 1-3-phenic / reb mouth penic acid 2-thiazolyl amide

The title compound was synthesized in the same manner as in Example 40 using 2-naphthalene thiol.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 7.05-8.05 (19H, m), 9.98 and 10.10 (total 1H, s), 12.17 and 12.68 (total 1H, s).

Example 43

2-benzoylamino-3- (1-octylthio) -1-phenylpropenoic acid 2-thiazolylamide

Using 1-octanethiol, the title compound was synthesized in the same manner as in Example 40.

¹ H-NMR δ (d ₆ — DMSO, 270 MHz) 0.83 (3H, t, J = 7 Hz), 1.00—1.45 (12H, m), 2.28 and 2.42 (total 2H, t, J = 7.3 Hz), 7.10 and 7.23 (total 1H, d, J = 3.6 Hz), 7.25-7.62 and 7.98-8.04 (total 10H, m), 9.46 and 9.75 (total 1H, s), 11.92 and 12.21 (total 1H, s).

Example 44

(Z) — 2-benzoylamino-3- (2-methoxycarbylphenyl) propenoic acid 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 15 using hippuric acid and 2-methoxycarbonylbenzaldehyde.

¹ H-NMR δ (d ₆ -DMSO, 270 MHz) 3.84 (3H, s), 7.27 (1H, d, J = 3.3 Hz), 7.40-7.60 (7H, m), 7.74 (1H, s), 7.88- 7.97 (3H, m), 10.03 (1H, s), 12.49 (1H, s).

Example 45

(E) _— 2—Benzoylamino-3- (2-Methoxycarboephenyl) pro Penic acid 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 16 using (Z) -2-benzoylamino-1- (2-methoxycarbonylcarbonylphenyl) propenoate 2-thiazolylamide obtained in Example 44. .

¹ H-NMR 6 (d ₆ -DMS0, 270 MHz) 3.85 (3H, s), 7.18 (1H, d, J = 3.6 Hz), 7.30-7.66 (8H, m), 7.88—8.00 (3H, m), 10.59 (1H, s), 12.35 (1H, s).

2-benzoylamino-3,3-diphenylpropenoic acid 2-thiazolylamide (1) (Z) —4-diphenylmethylene-1 2 _phenyloxazoline_ 5—one 2-phenyloxazoline 1— On 50 Omg (3.1 mmo 1), 620 mg of benzophenone (3.4 mmo 1), 1.5 ml of pyridine in THF (5 ml) and 0.45 ml of titanium tetrachloride (4. Ommol) was added dropwise, and the temperature was raised to room temperature over 1 hour. 1N Hydrochloric acid was added to the reaction solution, and extracted with getyl ether. The extract layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1) to obtain 474 mg (yield 47%) of the title compound.

¹ H-NMR δ (CDC13, 270 MHz) 7.30-7.70 (13 H, m), 8.08—8.15 (2 H, m). (2) 2-Benzylamino-3,3-diphenylpropenoic acid 2- Thiazolyl amide

The title compound was synthesized in the same manner as in Example 1 (4) using (Z) —4-diphenylmethylene-12-phenyloxazolin-15-one obtained in (1).

¹ H-NMR 6 (d ₆ -DMS0, 270 MHz) 7.10-7.60 (1δ Η, m), 7.77-7.85 (2Η, m), 9.99 (1H, br s), 12.13 (1H, br s). Example 47

(Z) 1-Benzoinoleamino -3- 3-Chloro-3-phenynolepropenoic acid

(Z) — 4-Fehlk Mouth Methylene-1 2-phenyloxazoline-1 5-one To a solution of 3 Omg (0.11 mmo 1) in methanol (4 ml) was added a 1N aqueous solution of sodium hydroxide, and the mixture was stirred for 30 minutes. After methanol was distilled off under reduced pressure, the remaining aqueous layer was acidified with 5% hydrochloric acid, and the resulting precipitate was collected by filtration and dried under reduced pressure to obtain 16 mg (yield: 48%) of the title compound.

1 H-NMR 5 (d ₆ -DMS0, 270 MHz) 7.36-7.64 (8H, m), 8.00 (2H, d, J = 7 Hz), 10.39 (1H, s), 12.9 (1H, br). Example 48

(E) 1-Benzoinoleamino-3-3-chloro-3-phenylpropenoic acid

(E) The title compound was synthesized in the same manner as in Example 47 using 14-phenyl-2-methylene-2-phenylenoxazoline-5-one.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 7.38-7.58 (8H, m), 7.76 (2H, d, J = 7 Hz), 10.05 (1H, s), 13.2 (1H, br). Example 49

(Z) — 2-Benzo / reamino-1-3-chloro-3-phenenedolepropenoic acid 2-benzothiazolylamide

(Z) 14-phenylc-l-methylene 1-2-phenyloxazoline-5-one 2 Omg (0.07 mmo 1), 2-aminoaminobenzothiazole 21 mg (0.14 mmo 1) The mixture was stirred at 100 ° C. for 2 hours in toluene (1 ml). After the toluene was distilled off under reduced pressure, the residue was crystallized from acetonitrile to obtain 19 mg (yield 63%) of the title compound.

¹ H-NMR 8 (d ₆ -DMS 0, 270 MHz) 7.25-7.45 (7H, m), 7.52-7.57 (2H, m), 7.61-7.66 (2H, m), 7.94 (1H, d, J = 7.6 Hz), 8.03 (2H, d, J = 7Hz), 10.39 (1H, s), 12.62 (1H, s).

Example 5 O

(Z)-2-Benzoinoleamino-3- 3-chloropropenoic acid 2- (4-tert-butylthiazolyl) amide The title compound was synthesized in the same manner as in Example 49 using 2-amino- 4-tert-butylthiazole.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 1.19 (9H, s), 6.71 (1H, s), 7.35-7.42 (5H, m), 7.51-7.56 (2H, m), 7.60-7.66 ( 1H, m), 8.02 (2H, d, J = 7Hz), 10.23 (1H, s), 12.36 (1H, s).

1-[(Z)-2-Benzoylamino 3- 3-chloro-3 -phenylpropanol] piperidine

The title compound was synthesized in the same manner as in Example 49 using piperidine.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 1.05-1.29 (5H, m), 3.00-3.30 (4H, m), 7.42-7.55 (7H, m), 7.62 (1H, t, J = 7Hz) ), 7.99 (2H, d, J = 7Hz), 10.14 (1H, br).

(Z) 1-Benzoylamino 3-Cro-3-3-Feninolepropenoic acid Hexylamide

The title compound was synthesized in the same manner as in Example 49 using hexylamine.

1 H-NMR δ (d ₆ -DMS0, 270 MHz) 0.74-1.11 (5H, m), 1.33-1.52 (5H, m), 3.33 (1H, m), 7.35-7.44 (5H, m), 7.52 ( 2H, t, J = 7Hz), 7.61 (1H, t, J = 7Hz), 7.81 (1H, d, J = 8Hz), 7.98 (2H, d, J = 7Hz), 9.92 (1H, br).

Example 53

(Z)-2-Benzoylamine 3 _ 1-3-ethyl propenoic acid

The title compound was synthesized in the same manner as in Example 49 using getylamine.

¹ H-NMR δ (d ₆ DMSO, 270 MHz) 0.67 (3H, t, J = 7 Hz), 0.80 (3H, t, J = 7 Hz), 3.15 (4H, m), 7.40-7.55 (7H, m ), 7,58-7.64 (1H, m), 7.98 (1H, d, 8.02 (2H, d, J = 7Hz), 10.05 (1H, br).

Example 54

(Z) _ 2-benzoylamino-3-chloro-3-phenylpropenoic acid 2-methylpropylamide

The title compound was synthesized in the same manner as in Example 49 using 2-methylpropylamine.

¹ H-NMR δ (d ₆ -DMSO, 270 MHz) 0.53 (6H, d, J = 7 Hz), 1.42 (1H, m), 2.67 (2H, t, J = 6 Hz), 7.35-7.45 (5H, m ), 7.52 (2H, t, J = 7Hz), 7.61 (1H, t, J = 7Hz), 7.98 (2H, d, J = 8Hz), 8.07 (1H, t, J = 6Hz), 9.97 (1H, br).

Example 5 5

(Z) — 2-Benzylamino-3-3-chloro-1-aniline on phenylipropenoic acid

The title compound was synthesized in the same manner as in Example 49 using aniline.

¹ H-NMR δ (d ₆ -DMSO, 270 MHz) 6.97 (1 H, t, J = 7 Hz), 7.18 (2 H, t, J = 7 Hz), 7.29-7.37 (5H, m), 7.46-7.51 (2H , m), 7.54 (2H, t, J = 7Hz), 7.63 (1H, t, J = 7Hz), 8.02 (2H, d, J = 7Hz), 10.10 (1H, s), 10.20 (1H, s) .

Example 56

(Z) — 2—Benzoylamino 3 —Chloro 3 —Phenylpropenoic acid 2- (3-Indolyl) ethylamide

The title compound was synthesized in the same manner as in Example 49 using 2- (3-indolyl) ethylamine.

1 H-NMR δ (d ₆ -DMSO, 270 MHz) 2.43 (2H, m), 3.15 (2H, m), 6.93-7.07 (3H, m), 7.31 (1H, d, J = 8 Hz), 7.37- 7.47 (5H, m), 7.50- 7.56 (2H, m), 7.59-7.64 (1H, m), 8.02 (2H, d, J = 7Hz), 8.12 (1H, t, J = 6Hz), 10.03 (1H , s), 10.75 (1H, s). Example 57

(Z) 1-2-Benzoinoleamino-13-chloro-3-3-phenylenopropenoic acid 4- (1-benzylpyridyl) amide

The title compound was synthesized in the same manner as in Example 49 using 4-amino-1-benzylpiperidine.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 1.00-1.09 (2H, rn), 1.28-1.33 (2H, m), 1.78-1.95 (4H, m), 3.25-3.45 (3H, m), 7.19-7.43 (10H, m), 7.52 (2H, t, J = 7Hz), 7.61 (1H, t, J = 7Hz), 7.89 (1H, d, J = 8Hz), 7.99 (2H, d, J = 7Hz), 9.95 (1H, br).

(Z) — 2-Benzoylamino-1- 3-cloth — 3-Aryl amide phenylpropenoate

The title compound was synthesized in the same manner as in Example 49 using arylamine.丄 H—NMR δ (d ₆ -DMS0, 270 MHz) 3.51 (2H, t, J = 6Hz), 4.81—4.89 (2H, m), 5.37-5.47 (1H, m), 7.36-7.43 (5H, m ), 7.52 (2H, t, J = 7Hz), 7.61 (1H, t, J = 7Hz), 8.00 (2H, d, J = 7Hz), 8.21 (1H, t, J = 6Hz), 10.01 (1H, br). Example 59

(Z)-2-Benzoylamino 1-3-Chloro 3-Hue / Repropenoic acid 1-decylamide

The title compound was synthesized in the same manner as in Example 49 using decylamine.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 0.84-1.25 (19H, m), 2.84 (2H, td, J = 7, 12Hz), 7.35-7.43 (5H, m), 7.52 (2H, t , J = 7Hz), 7.61 (1H, t, J = 7Hz), 7.97 (1H, t, J = 12Hz), 7.99 (2H, d, J = 7Hz), 9.92 (1H, br).

1-[(Z) _ 2-Benzoylamino 3-Black 3-Phenylpropanol 1-4-Phenylbiperazine Using 1-fluorobiperazine, the title compound was synthesized in the same manner as in Example 49.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 3.10 (1H, m), 3.20-3.33 (7H, m), 6.79 (3H, m), 7.17 (2H, t, J = 7Hz), 7.39- 7.64 (8H, m), 8.00 (2H, d, J = 7Hz), 10.26 (1H, s).

1-[(Z) — 2-Benzyramino-1--3-clo-3 -Feninolepropionyl] -4- (2-pyridyl) pidazine

The title compound was synthesized in the same manner as in Example 49 using 11- (2-pyridyl) pidazine.

¹ H-NMR 6 (dg-DMSO, 270 MHz) 3.12 (1H, t, J = 5Hz), 3.27 (6H, m), 3.65 (1H, t, J = 5Hz), 6.63 (1H, dd, J = 5, 7Hz), 6.71 (1H, d, J = 9Hz), 7.39- 7.55 (8H, m), 7.59- 7.65 (1H, m), 8.00 (2H, d, J = 7Hz), 8.06 (2H, dd , J = 5Hz), 10.27 (1H, s).

(Z) — 2-benzoylamino-3-chloro-3-phenylpropenoic acid 2-pyridinylamide

Under a nitrogen atmosphere, to a suspension of 60% sodium hydride in THF (0.5 ml) was added a solution of 2-aminoviridine 15 mg (0.16 mmo 1) in THF (1 ml), and the mixture was stirred at room temperature for 20 minutes. . To this solution was added a solution of 30 mg (0.11 mmol) of (Z) -4-phenylchloromethylene-12-phenylenoxazoline-15-one in THF (lm1), and the mixture was stirred for 1 hour. The reaction solution was diluted with ethyl acetate, washed with 1 N hydrochloric acid and saturated saline in that order, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1) to obtain the title compound (26 mg, yield 65%) as a white powder.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 7.23 (1H, ddd, J = 7.6, 4.9, 1.0 Hz), 7.25-7.37 (3H, m), 7.44-7.73 (6H, m), 7.90 (1H, d, J = 8.3 Hz), 8.01 (2H, d, J = 8 Hz), 8.15—8.20 (1H, ra) , 10.15 (1H, s), 10.53 (1H, s).

(Z)-2-benzoylamino 3- 3-clo 3- 3- pheninolepropenoic acid 2-pyrazinyl amide

The title compound was synthesized in the same manner as in Example 62 using 2-aminovirazine.

¹ H-NMR 6 (d ₆ -DMS0, 270 MHz) 7.26-7.38 (3H, m), 7.43-7.66 (5H, m), 8.02 (2H, d, J = 8 Hz), 8.25-8.30 (2h, m), 9.12 (1H, s), 10.26 (1H, s), 10.97 (1H, s).

(Z) -2-benzoylamino-3-chloro-3-phenylpropenoic acid 2-pyrimidinylamide

The title compound was synthesized in the same manner as in Example 62 using 2-aminovirimidine.

¹ H-NMR δ (d 6 -DMS0, 270 MHz) 7.10 (1H, t, J = 4.6 Hz), 7.27-7.33 (3H, m), 7.41-7.65 (5H, m), 7.92 (2H, d, J = 7 Hz), 8.54 (2H, d, J = 4.6 Hz), 10.09 (1H, s), 10.73 (1H, s).

(Z) 1-Benzoylamino 3-Cro-3-3-Phenylpropenoic acid 3-Pyrazolylamide

The title compound was synthesized in the same manner as in Example 62 using 3-aminopyrazole.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 6.38 (1H, br s), 7.30-7.65 (8H, m), 8.01 (2H, d, J = 8 Hz), 10.07 (1H, s), 10.53 (1H, s), 12.21 (1H, s). Example 66

(2) 1-Benzoylamino-13-chloro-3-phenylpropenoic acid 2- (4-ethoxycarbonylmethyl) thiazolylamide

The title compound was synthesized in the same manner as in Example 49, using 2-amino-4'-ethoxycarbonylmethylthiazole.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 1.43 (3H, t, J = 6.9 Hz), 3.61 (2H, s), 4.04 (2H, q, J = 6.9 Hz), 6.94 (1H, s ), 7.32-7.43 (5H, m), 7.53 (2H, t, J = 7 Hz), 7.63 (1H, t, J = 7 Hz), 10.29 (1H, s), 12.43 (1H, s). Example 67

(Z)-2-Benzoinoleamino-1- 3-chloro-3-phenylenopropanoic acid 2- (4-carboxylic acid) thiazolylamide

Using the (Z) —2-benzoylamino-3-chloro-3-phenylpropenoic acid 2- (4-ethoxycarbonylmethyl) thiazolylamide obtained in Example 66, the title compound was obtained in the same manner as in Example 38. Compounds were synthesized.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 3.52 (2H, s), 6.91 (1H, s), 7.33-7.43 (5H, m), 7.53 (2H, t, J = 7 Hz), 7.63 (1H, t, J = 7 Hz), 8.03 (2H, d, J = 7 Hz), 10.29 (1H, s), 12.44 (1H, br s).

(Z) — 2-Benzo / reamino _— 3-chloro-1- 3-phenylenopropenoic acid methyl amide

Using an aqueous methylamine solution, the title compound was synthesized in the same manner as in Example 49.

1 H-NMR δ (d ₆ -DMS0, 270 MHz) 2.37 and 2.70 (total 3H, d, J = 5Hz), 7.36-7.49 (5H, m), 7.52 (2H, t, J = 7Hz), 7.61 ( 1H, t, J = 7Hz), 7.75 and 7.99 (total 2H, d, J = 7Hz), 7.93 and 8.29 (total 1H, q, J = 5Hz), 9.90 and 10.00 (total 1H, br). Example 6 9

(Z) 1 2 1 Benzoylamino 3-Black 3-Phenylphenolic acid 3-Methoxyulide

The title compound was synthesized in the same manner as in Example 49 using 3-methoxyaniline.

"H-NMR δ (d ₆ -DMS0, 270 MHz) 3.65 (3H, s), 6.56 (1H, dd, J = 2, 7Hz), 6.86 (1H, d, J = 9Hz), 7.00 (1H, t , J = 2Hz), 7.08 (1H, t, J = 8Hz), 7.29-7.38 (3H, m), 7.45-7.49 (2H, m), 7.54 (2H, t, J = 7Hz), 7.63 (1H, t, J = 7Hz), 8.02 (2H, d, J = 7Hz), 10.07 (1H, s), 10.20 (1H, br).

(Z)-2-benzoylamino 3- 3-chloro-3-ene phenolepropenoic acid 3-fluoroanilide

The title compound was synthesized in the same manner as in Example 49 using 3-fluoroaniline.

丄 H—NMR δ (d ₆ -DMS0, 270 MHz) 6.56 (1H, dt, J = 2, 8Hz), 7.05 (1H, d, J = 9Hz), 7.21 (1H, q, J = 8Hz), 7.28 -7.38 (4H, m), 7.45-7.48 (2H, m), 7.54 (2H, t, J = 7Hz), 7.63 (1H, t, J = 7Hz), 8.02 (2H, d, J = 7Hz), 10.22 (1H, s), 10.30 (1H, br).

L-N-Benzoylphenylalanine 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 72 using benzoyl chloride.

¹ H-NMR S (d ₆ -DMS0, 270 MHz) 3.09 (1H, dd, J = 13.5, 10.6 Hz), 3.17 (1H, dd, J = 13.5, 4.6 Hz), 4.94 (1H, ddd, J = 10, 7.6, 4.3 Hz), 7.13-7.35 (4H, m), 7.40-7.60 (6H, ra), 7.77-7.85 (2H, m), 8.82 (1H, d, J = 7.9 Hz), 12.50 (1H , s). Example 72

L-N- (2-Fu-l-acetyl) Fenil-alanine 2-thiazolyl amide

To a solution of L-phenylalanine 2-thiazolylamide hydrochloride 284 mg (1 mmo 1) and triethylamine 0.35 ml (2.5 mmo 1) in dichloromethane (5 ml) 0.13 ml of phenylacetyl chloride (lmmol) and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed sequentially with 1 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was crystallized from chloroform to give 173 mg (yield: 47%) of the title compound.

_{1 H-NMR δ (CDC1 3} , 270 MHz) 2.94-3.13 (2H, m), 3.56 (2H, s), 5.03 (1H, q, J = 7Hz), 6.17 (1H, d, J = 8Hz), 6.90—6.93 (2H, m), 7.01 (1H, d, J = 3.6Hz), 7.12-7.18 (5H, m), 7.29—7.36 (3H, m), 7.58 (1H, d, J = 3.6Hz) , 11.6 (1H, br).

L-N- (2-furoyl) phenylalanine 2-thiazolylamide

_The title compound was synthesized in the same manner as in Example 72 using _2- furoyl chloride.

^{1 H - NM R δ (CDC1} 3, 270 MHz) 3.25 (2H, d, J = 7Hz), 5.23 (1Η, q, J = 7Hz), 6.51 (1H, dd, J = 2, 4Hz) 7.03 (1H , d, J = 3.6Hz), 7.07 (1H, br), 7.12-7.25 (6H, m), 7.45 (1H, dd, J = 1, 2Hz), 7.58 (1H, d, J = 3.6Hz). Example 74

Using L-N- (4-toluenesulfonyl) phenylalanine 2-thiazolylamide 4-toluenesulfonyl chloride, the title compound was synthesized in the same manner as in Example 72.

¹ H-NMR δ (CDC13, 270 MHz) 2.33 (3H, s), 3.00 (2H, dd, J = 2, 7Hz), 4.20 (1H, q, J-7Hz), 5.40 (1H, d, J = 8Hz), 6.90 (2H, d, J = 8Hz), 7.02 (1H, d, J = 3.6Hz), 7.08-7.17 (5H, m), 7.52 (1H, d, J = 3.6Hz), 7.57 (2H , D, (J = 8Hz).

L-N- (Isonicotinoyl) feniralanine 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 72 using isonicotinoyl chloride.

¹ H-NMR 5 (CDC1, 270 MHz) 3.30 (2H, dd, J = 3, 7Hz), 5.30 (1H, q, J = 7Hz), 7.08 (1H, d, J = 3.6Hz), 7.13-7.16 (2H, m), 7.20-7.24 (3H, m), 7.38 (1H, d, J = 8Hz), 7.60 (1H, d, J = 3.6Hz), 7.64 (2H, d, J = 6Hz), 8.76 (2H, d, J = 6Hz) .Example 76

LN- (2-pyrrolecarbonyl) phenylalanine 2-thiazolylamide L-phenylalanine 2-thiazolylamide hydrochloride 284 mg (1 mmo 1), pyrrole monol 2-pyrenoic acid 1 1 1 mg (1 mmo 1 ), 135 mg (lmmol) of 1-hydroxybenzotriazole and 120 ml (1.2 mol) of trietinoleamine in 5 ml of dichloromethane were mixed with 1-ethyl-3- (3-dimethylamine). (Minopropyl) carbodimid hydrochloride (192 mg, 1 mmo 1) was added, and the mixture was stirred for 3 hours. After the solvent was distilled off, the residue was diluted with ethyl acetate, washed sequentially with water, saturated aqueous sodium bicarbonate, 1N hydrochloric acid and saturated aqueous sodium bicarbonate, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was crystallized from ether to give the title compound (208 mg, yield 61%).

¹ H-NMR 5 (CDC13, 270 MHz) 3.26 (2H, m), 5.83 (1H, td, J = 7, 9Hz), 6.25 (1H, m), 6.71 (1H, m) 6.75 (1H, d, J = 9Hz), 6.98 (1H, d, J = 3.3Hz), 7.00 (1H, m), 7.13-7.24 (5H, m), 7.47 (1H, d, J = 3.3Hz), 12.1 (1H, br ), 12.6 (1H, br).

LN- (2-indolecarbonyl) _Fenilalanine 2-thiazolylamine Up

The title compound was synthesized in the same manner as in Example 76 using indole-12-carboxylic acid.

¹ H-NMR δ (CDC13, 270 MHz) 3.33 (2H, m), 5.88 (1H, td, J = 7, 9Hz), 7.00 (1H, s), 7.06 (1H, d, J = 3.6Hz), 7.10-7.34 (8H, m), 7.47 (1H, d, J = 9Hz), 7.66 (1H, d, J = 3.6Hz), 7.68 (1H, d, J = 9Hz), 11.8 (1H, br), 12.5 (1H, br). Example 78

L-N- (2-naphthoyl) phenylalanine 2_thiazolylamide

The title compound was synthesized in the same manner as in Example 76 using 2-naphthoic acid.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 3.10-3.26 (2H, ra), 5.03 (1H, m), 7.16-7.32 (4H, ra), 7.47 (2H, d, J = 8Hz) , 7.51 (1H, d, J = 3.6Hz), 7.56- 7.66 (2H, m), 7.89 (1H, d, J = 8Hz), 7.96-8.04 (3H, m), 8.5 (1H, s) , 8.99 (1H, d, J = 8Hz), 12.5 (1H, s).

Example 79

L-N- (2-tenol) feniralanine 2-thiazolyl amide

The title compound was synthesized in the same manner as in Example 76 using 2-thiophenecarboxylic acid.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 3.01-3.20 (2H, m), 4.91 (1H, m), 7.14-7.18 (2H, m), 7.21-7.30 (3H, m), 7.42 (2H, d, J = 7Hz), 7.50 (1H, d, J = 3.3Hz), 7.76 (1H, d, J = 5Hz), 7.88 (1H, d, J = 4Hz), 8.87 (1H, d, J = 8Hz), 12.5 (1H, s).

Example 80

L-N- (cyclohexanecarbonyl) phenylalanine 2-thiazolylami on

The title compound was prepared in the same manner as in Example 72, using a hexahedral hexanecarboyluclide. Compounds were synthesized.

¹ H-NMR 6 (d ₆ -DMS0, 270 MHz) 1.00-1.25 (5H, m), 1.49-1.65 (5H, m),

2.14 (1H, ra), 2.84 (1H, dd, J = 10.2, 14Hz), 3.05 (1H, dd, J = 4.6, 14Hz),

4.73 (1H, m), 7.16-7.33 (6H, m), 7.48 (1H, d, J = 3.6Hz), 8.09 (1H, d, J = 8Hz), 12.3 (1H, s).

L-N- (1-pentanoyl) phenylalanine 2-thiazolyl amide

The title compound was synthesized in the same manner as in Example 76 using pentanoic acid.

1 H-NMR δ (d ₆ -DMS0, 270 MHz) 0.79 (3H, t, J = 7 Hz), 1.02-1.23 (4H, m), 1.31-1.42 (2H, m), 2.04 (2H, t, J = 7Hz), 2.82 (1H, dd, J = 10, 14Hz), 3.05 (1H, dd, J = 5, 14Hz), 4.76 (1H, m), 7.16-7.34 (6H, m), 7.8 ( 1H, d, J = 3.6Hz), 8.24 (1H, d, J = 8Hz), 12.3 (1H, s).

L-N- (3-thenoyl) phenylalanine 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 76 using 3-thiophene carboxylic acid.

¹ H-NM R δ (d ₆ -DMS0, 270 MHz) 3.00-3.19 (2H, m), 4.92 (1H, m), 7.15-7.30 (4H, m), 7.42 (2H, d, J = 7Hz) , 7.47-7.51 (2H, m), 7.57 (1H, dd, J = 3, 5Hz), 8.17 (1H, d, J = 3Hz), 8.66 (1H, d, J = 8Hz), 12.5 (1H, s Example 83

The title compound was synthesized in the same manner as in Example 72, using L-N- (2-nitrobenzoyl) phenylalanine 2-thiazolylamide 2-nitrobenzoyl chloride.

¹ H-NMR δ (dg-DMSO, 270 MHz) 3.00 (1H, dd, J = 14, 10 Hz), 3.14 (1H, dd, J = 14, 5.3 Hz), 4.97 (1H, ddd, J = 10 , 7.6, 5.3 Hz), 7.08-7.39 (6H, m), 7.44 (1H, dd, J = 7.6, 1.7 Hz), 7.50 (1H, d, J = 3.6 Hz), 7.68 (1H, dt, J = 1.3, 7.6 Hz), 7.80 (1H, dt, J = 1.3, 7.6 Hz), 8.00 (1H, dd, J = 7.9,

1.0 Hz), 9.23 (1H, d, J = 7.6 Hz), 12.44 (1H, s).

Example 84

L-N- (4-cyanobenzoyl) phenylalanine 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 72, using 4-cyanobenzoyl chloride.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 3.07 (1H, dd, J = 13, 11 hz), 3.19 (1H, dd, J = 13, 4.3 Hz), 4.95 (1H, ddd, J = 11, 8.0, 4.3 Hz), 7.15-7.32 (4H, m), 7.43 (2H, d, J = 7 Hz), 7.50 (1H, d, J = 3.3 Hz), 7.96 (4H, s), 9.14 ( Example 8 5 1H, d, J = 8.0 Hz), 12.54 (1H, br s).

The title compound was synthesized in the same manner as in Example 72 using L-N- (2-fluorobenzoyl) phene / realanine 2-thiazolylamide 2-fluorobenzoyl chloride.

^A H-NMR δ (d _R -DMS0 ₍ 270 MHz) 3.03 (1H, dd, J = 14, 10 hz), 3.15 (1H, dd, J = 13, 4.6 Hz), 4.93 (1H, ddd, J = Examples: 10, 7.6, 4.6Hz), 7.18-7.42 (8H, m), 7.48-7.56 (3H, m), 8.64 (1H, dd, J = 7.9, 2.0 Hz), 12.48 (1H, br s). 86

Using L-N- (2-pyrazinecarbonyl) phenylalanine 2-thiazolylamide 2-pyrazinecarboxylic acid, the title compound was synthesized in the same manner as in Example 76.

¹ H-NMR 6 (d ₆ -DMS0, 270 MHz) 3.23 (2H, d, J = 7.6 Hz), 4.93 (1H, dt, J = 7.9, 6.3 Hz), 7.13-7.36 (6H, m), 7.50 (1H, d, J = 3.6 Hz), 8.77 (1H, dd, J = 2.6, 1.7 Hz), 8.89 (1H, d, J = 2.6 Hz), 9.10 (1H, d, J = 1.7 Hz), 12.53 (1H, br s). Example 87

I.-N- (3-Methoxycarbonylbenzoyl) phenylalanine 2-thiazolylamide

Using 3-methoxycarboxybenzoic acid, the title compound was synthesized in the same manner as in Example 76.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 3.10 (1H, dd, J = 13, 10 hz), 3.15 (1H, dd, J = 13, 4.6 Hz), 4.97 (1H, ddd, J = 10, 7.6, 4.6 Hz), 7.18 (1H, t, J = 8 Hz), 7.25 (1H, d, J = 3.3 Hz), 7.28 (2H, t, J = 7 Hz), 7.43 (2H, d, J = 7 Hz), 7.50 (1H, d, J = 3.3 Hz), 7.63 (1H, t, J = 8 Hz), 8.09 (2H, tt, J = 8.6, 1.3 Hz), 8.42 (1H, t, J = 1.7 Hz), 9.09 (1H, d, J = 7.6 Hz), 12.52 (1H, s).

L-N- (2H-pyran-1 2-one-5-pot olebonyl) Phenylalanine 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 76 using coumaric acid.

1 H-NMR δ (d ₆ -DMS0, 270 MHz) 3.22 (1H, dd, J = 14, 9.6 Hz), 3.33 (1H, dd, J = 14, 4.6 Hz), 4.81 (1H, br s), 5.56 (1H, d, J = 9.2 Hz), 7.14- 7.35 (7H, m), 7.45 (1H, J = 8.9 Hz), 7.54 (1H, d, J = 3.6 Hz), 7.95 (1H, d, J = 15 Hz), 9.78 (1H, dd, J = 13, 8.2 Hz), 12.75 (1H.brs).

The title compound was synthesized in the same manner as in Example 2 using L-N- (4-fluorobenzoyl) phenylalanine 2-thiazolylamide 4-fluorobenzoyl chloride.

¹ H-NMR 6 (d ₆ -DMS0, 270 MHz) 3.08 (1H, dd, J = 14, 10 hz), 3.16 (1H, dd, J = 14, 4.6 Hz), 4.92 (1H, ddd, J = 10, 7.9, 4.6Hz), 7.14-7.35 (6H, m), 7.43 (2H, d, J = 7 Hz), 7.50 (1H, d, J = 3.6 Hz), 7.89 (2H, dd, J = 8.9) , 5.6 Hz), 8.87 (1H, d, J = 7.9 Hz), 12.51 (1H, s). Example 90

The title compound was synthesized in the same manner as in Example 72 by using L-N- (4-trobenzoyl) phenylalanine 2-thiazolylamide 412 trobenzozoyl chloride.

^{1 H-NMR δ (dg-} DMSO, 270 MHz) 3.09 (1H, dd, J = 14, 11 Hz), 3.20 (1H, dd, J = 14, 4.3 Hz), 4.98 (1H, ddd, J = 11 , 7.9, 4.3Hz), 7.18 (1H, t, J = 7.3 Hz), 7, 25 (1H, d, J = 3.6 Hz), 7.28 (2H, t, J = 7 Hz), 7.43 (1H, d , J = 7 Hz), 7.51 (1H, d, J = 3.6 Hz), 8.04 (2H, d, J = 9 Hz), 8.31 (2H, d, J = 9 Hz), 9.21 (1H, d, J = 7.9 Hz), 12.56 (1H, s).

The title compound was synthesized in the same manner as in Example 72 using L-N- (3-cyanobenzoyl) phenylalanine 2-thiazolylamide 31-cyanobenzoyl chloride.

¹ H-NMR 6 (d ₆ -DMS0, 270 MHz) 3.07 (1H, dd, J = 14, 11 Hz), 3.20 (1H, dd, J = 14, 4.3 Hz), 4.97 (1H, ddd, J = 11, 7.6, 4.3Hz), 7.19 (1H, t, J = 7.3Hz), 7.25 (1H, d, J = 3.6Hz), 7.29 (2H, t, J = 7Hz), 7.42 (2H, d, J = 7 Hz), 7.50 (1H, d, J = 3.6 Hz), 7.69 (1H, t, J = 7.9 Hz), 8.01 (1H, d, J = 9.5 Hz), 8.11 (1H, d, J = 9.5 Hz), 8.27 (1H, s), 9.08 (1H, d, J = 7.6 Hz), 12.53 (1H, br s).

L-N- (4-dimethy ^^ aminobenzoy ^) phenyaralanine 2-thiazoli / reamide

The title compound was synthesized in the same manner as in Example 76 using 4-dimethylaminobenzoic acid.

¹ Η-NM R δ (d ₆ DMSO, 270 MHz) 2.96 (6H, s), 3.05-3.18 (2H, m), 4.82-4.95 (1H, m), 6.69 (2H, d, J = 8.9 Hz ), 7.17 (1H, t, J = 7.3 Hz), 7.23 (1H, d, J = 3.4 Hz), 7.27 (2H, t, J = 7 Hz), 7.43 (2H, d, J = 7 Hz), 7.49 (1H, d, J = 3.6 Hz), 7.70 ( 2H, d, J = 8.9 Hz), 8.39 (1H, d, J = 7.9 Hz), 12.41 (1H, s).

Example 93

L-N- (1-oxo-13-pyridinecarbonyl) phenylalanine 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 76 using nicotinic acid N-oxide.

1 H-NMR δ (d ₆ -DMS0, 270 MHz) 3.04 (1H, dd, J = 14, 11 Hz), 3.19 (1H, dd, J = 14, 4.3 Hz), 4.93 (1H, ddd, J = 11, 7.9, 4.3 Hz), 7.19 (1H, t, J = 7 Hz), 7.25 (1H, d, J = 3.6 Hz), 7.29 (2H, t, J = 7 Hz), 7.40 (2H, d, J = 7 Hz), 7.50 (1H, d, J = 3.6 Hz), 7.51 (1H, t, J = 7.3 Hz), 7.66 (1H, dt, J = 8, 5, 1.3 Hz), 8.35 (1H, ddd, J = 5.2, 1.7, 1.0 Hz), 8.56 (1H, t, J = 1.6 Hz), 9.16 (1H, d, J = 7.9 Hz), 12.54 (1H, s).

L-N- (3-carboxybenzoyl) phenylalanine 2-thiazolylami on

Using L-N- (3-methoxycarbonylbenzoyl) phenylalanine 2-thiazolylamide obtained in Example 87, the title compound was synthesized in the same manner as in Example 38.

¹ H-NMR 6 (d ₆ -DMS0, 270 MHz) 3.11 (1H, dd, J = 14, 10 Hz), 3.18 (1H, dd, J = 14, 4.3 Hz), 4.97 (1H, ddd, J = 10, 7.6, 4.3Hz), 7.18 (1H, t, J = 7Hz), 7.24 (1H, d, J 3.6Hz), 7.28 (2H, t, J = 7Hz), 7.43 (2H, d, J = 7 Hz), 7.50 (1H, d, J = 3.6 Hz), 7.59 (1H, t, J = 7.8 Hz), 8.07 (2H, t, J = 10 Hz), 8.43 (1H, t, J = 1.3 Hz), 9.06 (1H, d, J = 7.6 Hz), 12.51 (1H, br s). Example 95

LN- (4-aminobenzoyl) phenylalanine 2-thiazolylamide Hydrogenation reaction using palladium carbon with LN- (4-nitrobenzoyl) phenylalanine 2-thiazolylamide obtained in Example 90 By performing the above, the title compound was synthesized.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 3.00--3.20 (2H, m), 4.80-4.97 (1H, m), 6.80 (2H, d, J = 8.6 Hz), 7.13-7.32 (4H, m), 7.43 (2H, d, J = 7.3 Hz), 7.49 (1H, d, J = 3.6 Hz), 7.68 (2H, d, J = 8.6 Hz), 8.45 (1H, d, J = 8.3 Hz) , 8.52 (1H, d, J = 1.7 Hz), 8.70 (1H, s), 12.41 (1H, br s).

Using L-N- (2-methoxybenzoyl) phenylalanine 2-thiazolylamide 2-methoxybenzoyl chloride, the title compound was synthesized in the same manner as in Example 72.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 3.07 (1H, dd, J = 14, 10 Hz), 3.19 (1H, dd, J = 14, 4.6 Hz), 3.87 (3H, s), 4.94 (1H, ddd, J = 10, 6.9, 4.6 Hz), 7.03 (1H, t, J = 8 Hz), 7.15 (1H, d, J = 8.3 Hz), 7.20-7.54 (6H, m), 7.76 ( 1H, dd, J = 7.6, 2.0 Hz), 8.43 (1H, s, J = 6.9 Hz), 12.46 (1H, s).

D, L—N-benzoyltryptophan 2-thiazolylamide

(1) D, L-N-benzoyltryptophan

Dissolve 20 Omg (0.99mmo1) of D, L-tryptophan in 2N-NaOH (5m1) and add 0.15m1 (0.99mmo1) of benzoyl chloride in THF (1 ml) under ice-cooling. m 1) The solution was added dropwise. After stirring for 3 hours, the reaction solution was washed with ether, acidified with concentrated hydrochloric acid, and extracted with ether. The extract layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was crystallized from a small amount of chloroform, collected by filtration, and dried under reduced pressure to obtain 258 mg (yield: 85%) of the title compound. ¹ H-NMR δ (dg-DMSO, 270 MHz) 3.21 (1H, dd, J = 14.5, 9.9 Hz), 3.31 (1H, dd, J = 14.5, 4.6 Hz), 4.66 (1H, ddd, J = 9.9 , 7.9, 4.6 Hz), 6.98 (1H, dt, J = 1.0, 6.9 Hz), 7.06 (1H, dt, J = 1.3, 6.9 Hz), 7.21 (1H, d, J = 2.3 Hz), 7.31 (1H , d, J = 7.6 Hz), 7.40-7.56 (4H, m), 7.60 (1H, d, J = 7.9 Hz), 7.82 (2H, d, J = 6.9 Hz), 8.64 (1H, d, J = 7.9 Hz), 10.81 (1H, s), 12.72 (1H, s).

(2) D, L-N-benzoyltryptophan 2-thiazolylamide

D, L—N-benzoyltryptophan 20 Omg (0.65 mmo 1), 2-aminothiazole 72 mg (0.72 mmo 1), 1-hydroxybenzobenzotriazole 88 mg (0.65 mmo 1) To a solution of dimethinoleformamide (hereinafter sometimes abbreviated as DMF) (5 m 1) was added 1-ethyl-3- (3-dimethylaminobutene pill) carbodiimide hydrochloride 125 mg (0.65 mmo 1) The mixture was stirred for 4 hours. The reaction solution was diluted with a mixture of ethyl acetate-toluene (1: 1), washed sequentially with water and saturated aqueous sodium hydrogen carbonate, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from a small amount of chloroform, filtered, and dried under reduced pressure to obtain 186 mg (yield 73%) of the title compound.

¹ H-NMR δ (d 6 -DMS0, 270 MHz) 3.28 (1H, dd, J = 15, 8.6 Hz), 3.30 (1H, dd, J = 15, 5.3 Hz), 4.92-5.03 (1H, m) , 6.98 (1H, dt, J = 1, 7 Hz), 7.06 (1H, dt, J = 1, 7 Hz), 7.23 (1H, d, J = 3.3 Hz), 7.27-7.34 (2H, m), 7. 0-7.56 (4H, m), 7.79-7.88 (2H, m), 8.70 (1H, d, J = 7.6 Hz), 10.82 (1H, s), 12.54 (1H, s).

. L-N-Benzoyl- (2-chlorophenyl) alanine 2-thiazolylamide

(1) D, L— N-benzoyl mono (2-chlorophenyl) alanine

The title compound was synthesized in the same manner as in Example 97 (1) using D, L-β- (2-chlorophenyl) alanine.

¹ H-NMR 6 (d ₆ -DMS0, 270 MHz) 3.14 (1H, dd, J = 14, 11 Hz), 3.39 (1H, dd, J = 14, 4.3 Hz), 4.74 (1H, ddd, J = 11, 8.6, 4.3 Hz), 7.19-7.27 (2H, m), 7.38-7.56 (5H, m), 7.78 (2H, d, J = 6.6 Hz), 8.77 (1H, d, J = 8.6 Hz), 12.85 (1H, br s).

(2) D, L—N—Benzoyl] 3— (2-chloropheninole) alanine 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 97 (2) using D, LN-benzoyl-1] 3- (2-chlorophenyl) alanine obtained in (1).

1 H-NMR δ (d 6 -DMS0, 270 MHz) 3.28 (1H, dd, J = 14, 9.0 Hz), 3.32 (1H, dd, J = 14, 7.2 Hz), 4.99-5.09 (1H, ra) , 7.20-7.27 (3H, m), 7.37-7.59 (6H, m), 7.81-7.87 (2H, m), 8.81 (1H, d, J = 7.9 Hz), 12.35 (1H, s).

Example 99

D, L—N-benzoyl-1- (3-Chenyl) alanine 2-thiazolylamide

(1) (Z) —2-Benzylamino-3- (3-Chenyl) propenoic acid

(Z) -4- (3-Chenyl) methylene-1-2-phenylenoxazolidine-5-one (Example 19-l) 500 mg (2 mmo 1) of 1,4-dioxane (10 m 1) 2.4 ml of N sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 4 hours. After washing the reaction solution with ether, concentrated aqueous hydrochloric acid was added to make the aqueous layer acidic, and the resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give 437 mg (yield 81%) of the title compound.

¹ H-NMR 6 (d ₆ -DMS0, 270 MHz) 7.41 (1H, dd.J = 5.0, 1.0 Hz), 7.49-- 7.65 (5H, m), 7.94 (1H, d, J = 2.0 Hz), 8.00 (2H, d, J = 6.9 Hz), 9.88 (1H, s), 12.66 (1H, s).

(2) D, L— N—benzoyl] 3— (3-Chenyl) alanine

To a solution of 200 mg (0.73 mmo 1) of 2- (benzoylamino) propenoic acid (0.73 mmo 1) in 2-acetone (20 ml) was added 77 mg of 10% palladium on carbon, and the mixture was stirred at room temperature under a hydrogen atmosphere. Stirred for 6 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (form: methanol: Purification with acetic acid-300: 10: 1.5) yielded 122 mg (61% yield) of the title compound as a white solid.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 3.42 (1H, dd, J = 15, 10 Hz), 3.48 (1H, dd, J = 15, 5.0 Hz), 4.90 (1H, ddd, J = 10, 7.9, 5.0 Hz), 7.38 (1H, dd, J = 5.0, 1.3 Hz), 7.58 (1H, dd, J = 2.6, 0.7 Hz), 7.71-7.88 (4H, m), 8.11 (2H, d , J = 5.9 Hz), 9.00 (1H, d, J = 7.9 Hz), 13.05 (1H, s).

(3) D, L—N—Benzoyl / 3 / (3-Chenyl) alanine 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 97 (2) using D, L—N—benzoylou obtained in (2) and 3- (3-chelle) alanine.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 3.16 (2H, d, J = 7.6 Hz), 4.89 (1H, q, J = 7.6 Hz), 7.15 (1H, dd, J = 5.0, 1.0 Hz ), 7.24 (1H, d, J = 3.6 Hz), 7.34 (1H, dd, J = 2.7, 0.9 Hz), 7.43-7.58 (5H, m), 7.84 (2H, d, J = 6.6 Hz), 8.81 (1H, d, J = 7.6 Hz), 12.45 (1H, s).

2 Benzoylamino 4-phenylbutanoic acid 2-thiazolylamide

(1) 2-benzoylamino-4-phenylbutanoic acid

The title compound was synthesized in the same manner as in Example 97 (1) using 2-amino-1-phenylbutanoic acid.

¹ H-NMR δ (d 6 -DMS0, 270 MHz) 2.09 (2H, q, J = 7.3 Hz), 2.58-2.82 (2H, m), 4.33 (1H, q, 7.3 Hz), 7.15-7.32 (5H , M), 7.45-7.60 (3H, m), 7.91 (2H, d, J = 6.6 Hz), 8.70 (1H, d, J = 7.6 Hz), 12.62 (1H, s).

(2) Using 2-benzoylamino-4-phenylbutanoic acid obtained from 2-benzoylamino_4-phenylbutanoic acid 2-thiazolylamide (1), the title compound was prepared in the same manner as in Example 97 (2). Synthesized.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 2.13 (2H, q, J = 7.6 Hz), 2.59-2.90 (2H, m), 4.68 (1H, q, J = 7.3 Hz), 7.14-7.32 (6H, m), 7.47-7.61 (4H, m), 7.91-7.96 (2H, m), 8.78 (1H, d, J = 7.3 Hz), 12.33 (1H, s). Example 101

D._ L— N-benzoyl _α-methylphenylalanine 2-thiazolylamide

(1) D, L-α-methylphenylalanine methyl ester

1.3 ml of thionyl chloride was added dropwise at 110 ° C to 5 ml of methanol, stirred for 10 minutes, and then D, L-ct-methylphenylalanine 50 Omg (2.8 mmo 1) was added in small portions. Was. After the temperature of the reaction solution was gradually raised to room temperature, it was further stirred for 17 hours. Methanol was distilled off under reduced pressure, a 5% aqueous solution of calcium carbonate was added, and the mixture was extracted with ether. The extracted layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 429 mg (yield: 80%) of the title compound as a white solid.

^{_{1 H-NMR 5 (CDC1 3}} , 270 MHz) 1.40 (3H, s), 2.96 (2H, AB q, J = 13 Hz), 3.71 (3H, s), 7.10-7.33 (5H, m).

(2) D, L—N—Venzoinole a—Methinolepheninoleanine Methyl Estenole D, L—a—Metine 7 Refeninoleanine Methinoleester 20 Omg (1 mmol), Triethylamine 0.22 ml Under ice-cooling, 0.13 ml (1.1 mmol) of benzoyl chloride was added to a solution of (1.6 mmol) in dichloromethane (5 ml) and stirred for 16 hours. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 25 Omg (yield 81%) of the title compound as a white solid.

¹ H-NMR 6 (CDC13, 270 MHz) 1.80 (3H, s), 3.51 (2H, AB q, J = 13.5 Hz), 3.82 (3H, s), 6.81 (1H, br s), 7.03-7.10 ( 2H, m), 7.19-7.26 (3H, m), 7.38-7.53 (3H, m), 7.67-7.72 (2H, m).

(3) D, L— N-benzoyl _ a—methylphenylalanine

1.6 ml of a 1N aqueous solution of sodium hydroxide was added to a solution of 240 mg (0.81 mmol) of D, L—N-benzoyl-a-methylphenylalanine methyl ester in 1,4-dioxane (5 ml). The mixture was stirred at room temperature for 21 hours. After washing the reaction solution with ether, concentrated aqueous hydrochloric acid is added to make the aqueous layer acidic, and the resulting precipitate is collected by filtration, washed with water, and dried under reduced pressure. As a result, 207 mg (yield: 91%) of the title compound was obtained as a white powder.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 1.33 (3H, s), 3.26 (2H, AB q, J = 13 Hz), 7.06-7.12 (2H, m), 7.16-7.29 (3H, m ), 7.42-7.58 (3H, m), 7.76-7.82 (2H, m), 8.17 (1H, s), 12.47 (1H, s).

(4) D, L-N-benzoyl-a-methinolepheniralanine 2-thiazolinoleamide

The title compound was synthesized in the same manner as in Example 97 (2) using D, LN-benzoyl_ct-methylphenyl-2-alanine obtained in (3).

¹ H-NMR δ (d 6 -DMS0, 270 MHz) 1.33 and 1.42 (total 3H, s), 3.04- 3.58 (total 2H, AB q, J = 14 Hz), 7.00-7.08 (2H, m), 7.17 —7.28 (4H, m), 7.42-7.60 (4H, m), 7.78 and 7.91 (total 2H, d, J = 6.9 Hz), 8.22 and 8.30 (total 1H, s), 12.10 (1H, s).

Example 102

D, L—N-Benzoyl (2-Chenyl) alanine 2-Thiazolylamide Above

(1) D, L— N—benzoyl] 3— (2-Chenyl) alanine

The title compound was synthesized in the same manner as in Example 97 (1) using D, L-β- (2-phenyl) alanine.

^ -NMR δ (d ₆ -DMS0, 270 MHz) 3.31 (1H, dd, J = 15, 10 Hz), 3.43 (1H, dd, J = 15, 4.3 Hz), 4.59 (1H, ddd, J = 10 , 7.9, 4.3 Hz), 6.93 (1H, dd, J = 5.0, 3.3 Hz), 6.96 (1H, dd, J = 3.6, 1.3 Hz), 7.32 (1H, dd, J = 5.0, 1.3 Hz), 7.43 -7.58 (3H, m), 7.82-7.88 (2H, m), 8.79 (1H, d, J = 7.9 Hz), 12.87 (1H, s).

(2) D, L—N—Benzoyl] 3— (2-Chenyl) alanine 2-thiazolylamide

The title compound was synthesized in the same manner as in Example 97 (2) using D, LN-benzoyl-1] 3_ (2-phenyl) alanine obtained in (1).

1 H-NMR δ (dg-DMSO, 270 MHz) 3.39 (1H, dd, J = 15, 8.9 Hz), 3.41 (1H, dd, J = 15, 5.3 Hz), 4.92 (1H, ddd, J = 8.9, 7.9, 5.3 Hz), 6.94 (1H, dd, J = 7.9, 4.0 Hz), 7.04 (1H, dd, J = 4.3, 1.0 Hz), 7.24 (1H, d, J = 3.6 Hz), 7.33 (1H, dd, J = 5.0, 1.0 Hz), 7.44-7.60 (6H, m), 7.85-7.90 (2H, m) , 8.88 (1H, d, J = 7.9 Hz), 12.50 (1H, s).

D, L—N—Benzoylphenylalanine 2-pyrimidinyl amide

D, L—N-benzoylphenylalanine 100 mg (0.37 mmo 1), 2-aminovirimidine 35 mg (0.37 mmo l), 1-hydroxybenzotriazo mono 50 g (0.37 mmo 1) To the DMF solution (2 ml) was added 71 mg (0.37 mmo 1) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and the mixture was stirred for 16 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (chloroform: methanol = 40: 1) to obtain the title compound lOmg (yield 8%) as a white solid. .

1 H-NMR δ (d ₆ -DMS0, 270 MHz) 3.20 (1H, dd, J = 14, 9.6 Hz), 3.42 (1H, dd, J = 14, 5.3 Hz), 5.16 (1H, ddd, J = 9.6, 8.2, 5.3 Hz), 7.08 (1H, ddd, J = 7.6, 5.0, 1.3 Hz), 7.15-7.60 (H, m), 7.77 (1H, ddd, J = 9.6, 7.6, 2.0 Hz), 7.86 (2H, d, J = 6.9 Hz), 8.02 (1H, br d, J = 7.3 Hz), 8.20 (1H, d, J = 9 Hz), 8.27 (1H, ddd, J = 5.0, 2.0, 1.0 Hz ), 9.69 (1H, br s). Example 104

D, L— N—Benzoylphenylalanine 3-pyridylamide

The title compound was synthesized in the same manner as in Example 103 using 3-aminoviridine.

1 H-NMR δ (dg-DMSO, 270 MHz) 3.12 (1H, dd, J = 13.5, 9.0 Hz), 3.16 (1H, dd, J = 13.5, 3.3 Hz), 4.85 (1H, ddd, J = 9.0 , 7.9, 3.3 Hz), 7.14-7.56 (9H, m), 7.82 (2H, d, J = 8 Hz), 8.05 (1H, ddd, J = 8.3, 2.6, 1.7 Hz), 8.28 (1H, dd, J = 4.6, 1.3 Hz), 8.76 (1H, d, J = 2.0 Hz), 8.82 (1H, d, J = 7.9 Hz), 10.45 (1H, s). Example 105

D, L—N—Benzoylphenylalanine 3-quinolylamide

The title compound was synthesized in the same manner as in Example 103 using 3-aminoquinoline.

¹ H-NMR δ (d 6 -DMS0, 270 MHz) 3.17 (1H, dd, J = 13.5, 9,6 Hz), 3.22 (1H, dd, J = 13.5, 4,9 Hz), 4.92 (1H, ddd, J = 9.6, 7.9, 4.9 Hz), 7.19 (2H, t, J = 7 Hz), 7.30 (1H, t, J = 7 Hz), 7.40-7.70 (7H, ra), 7.85 (2H, d , J = 7 Hz), 7.95 (2H, t, J = 8 Hz), 8.71 (1H, d, J = 2.3 Hz), 8.87 (1H, d, J = 7.9 Hz), 8.94 (1H, d, J = 2.3 H), 10.71 (1H, s).

D, L— N—Benzoylphenylalanine 4— (1 ^ 2, 4-triazolyl) amide

The title compound was synthesized in the same manner as in Example 103 using 4-amino-1,2,4-triazole.

¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 3.14 (1H, dd, J = 13, 10 Hz), 3.25 (1H, dd, J = 13, 4.8 Hz), 4.85 (1H, ddd, J = 10, 7.9, 4.8 Hz), 7.17-7.57 (8H, m), 7.84 (2H, d, J = 6.9 Hz), 8.59 (2H, s), 8.91 (1H, d, J = 7.9 Hz), 11.90 ( 1H, s). Example 107

2-benzoylamino-3- (2-pyridylthio) -1-3-phenig! ^ Methyl amide penic acid (E-form and Z-form)

(1) (E) —2—Benzoylamino 3- 3-chloro-3-methyl phenylpropenoate

(E) 14-Feyluc mouth romethylene-12-phenyloxazolidine-15-one (0.88 mmol) was added to a 30% dimethylamineethanol solution (1 ml), and the reaction mixture was heated to 50 ° C. Stirred with C for 1.5 hours and allowed to cool. The resulting precipitate is collected by filtration, washed with ethanol, The residue was dried under reduced pressure to give the title compound (190 mg, yield 68%) as a white powder. ^{_{1 H- NMR δ (d 6 -DMS0}} , 270MHz) 2.70 and 2.71 (total 3H, s), 7.30- 7.60 (8H, m), 7.75 (2H, d, J = 7.3 Hz), 8.30 and 8.31 (total 1H , Br s), 9.92 (1H, br s).

(2) 2-Benzylamino-3- (2-pyridylthio) -1,3-phenylpropenoic acid methyl amide (E-form and Z-form)

A solution of (Z) -2-benzoylamino-3-chloro-3-phenylpropenoic acid methylamide (0.48 mmol), 2-mercaptopyridine (0.52 mmol) and DBU (0.95 mmol) in tetrahydrofuran (5 ml) was prepared. The mixture was stirred at 50 ° C for 3.5 hours and allowed to cool. The reaction solution was diluted with ethyl acetate / toluene (1: 1), washed successively with water and saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the concentrated residue was purified by silica gel column chromatography (ethyl acetate: toluene = 2: 1) to give 77 mg of the low-polar isomer (Rf value 0.25) as a white powder to give the high-polar isomer ( 30 mg of Rf value 0.20) was obtained as a white powder, and 22 _mg (a total yield of 70%) of a mixture of both isomers was obtained.

Low polarity _{isomer:: ifi- NMR δ (d 6} -DMSO, 270MHz) 2.36 and 2.37 (total 3H, s), 7.04 (1H, ddd, J = 7.6, 4.9, 1.0 Hz), 7.18-7.32 (4H, m), 7.40-7.60 (6H, m), 7.83 (2H, d, J = 6.9 Hz), 8.30 (1H, ddd, J = 5.0, 2.0, 1.0 Hz), 10.04 (1H, s).

Highly polar isomer: ¹ H-NMR δ (d ₆ -DMSO, 270MHz) 2.65 and 2.67 (total 3H, s), 7.07 (1H, ddd, J = 7.6, 5.0, 1.0 Hz), 7.11-7.58 (10H, m), 7.71 (2H, d, J = 6.9 Hz), 8.17 and 8.18 (total 1H, s), 8.32 (1H, ddd, J: 5.6, 2.0, 1.0 Hz), 9.86 (1H, br s). Example 1 08

2-benzoylamino-3- (2-pyridylthio) -13-phenylpropenoic acid getylamide (low-polar isomer)

A solution of 4- (2-pyridylthio) phene / remethylene-1-2-phenyloxazolidin-1 51-one (highly polar isomer, 0.28 mmol) and getylamine (0.42 mmol) in tetrahydrofuran (2 ml) was added at room temperature. Stirred for hours. After evaporation of the solvent under reduced pressure, the concentrated residue The precipitate was collected by filtration, washed with getyl ether, and dried under reduced pressure to give 112 mg of the title compound (R f value 0.60 (form: methanol = 20: 1)). ( ⁹³ % yield) as a white powder.

¹ H-NMR 6 (d g-DMSO, 270 MHz) 0.73 (3H, t, J- 7.3 Hz), 0.76 (3H, t, J = 6.9 Hz), 3.20 (4H, br s), 7.08 (1H, ddd , J = 7.6, 5.0, 1.0 Hz), 7.21 (1H, d, J = 7.9 Hz), 7.24-7.34 (4H, m), 7.43-7.51 (4H, m), 7.53-7.62 (2H, m), 7.82 (2H, d, J = 6.9 Hz), 8.32 (1H, ddd,] = 7.6, 2.0, 1.0 Hz), 10.03 (1H, s).

2-benzoylamino-1- (2-pyridylthio) -3-phenylpropenoic acid jutylamide (highly polar isomer)

4- (2-Pyridylthio) phenylmethylene-1-2-phenyloxazolidine-15-one (low-polar isomer, 0.28 mmol) and tert-amine (0.42 mmol) in tetrahydrobran (2 ml) at room temperature Stir for 13 hours. After evaporating the solvent under reduced pressure, the concentrated residue is suspended in diethyl ether, the precipitate is collected by filtration, washed with dimethyl ether, and dried under reduced pressure to give the title compound (R f value 0.55 (chloroform: methanol). = 20: 1)) 99 mg (82% yield) as a white powder.

¹ H-NMR 6 (d ₆ -DMSO, 270 MHz) 1.03 (3H, t, J = 6.9 Hz), 1.08 (3H, t, J = 7.3 Hz), 3.38 (2H, q, J = 6.9 Hz), 3.54 (2H, q, J = 6.9 Hz), 7.04 (1H, ddd, J = 7.6, 4.9, 1.0 Hz), 7.15-7.35 (4H, m), 7,40-7.64 (8H, m), 7.73 (2H , d, J = 6.9 Hz), 8.28 (1H, ddd, J = 4.9, 2.0, 1.0 Hz), 10.00 (1H, s).

2-benzoylamino _ 3- (2-pyridylthio) -1-phenylpropenoic acid 2-dimethylaminoethylamide (E-form and Z-form)

(1) (Z) —2-Benzylamino-3--3-chloro-3-phenylpropenoic acid 2-dimethylaminoethylamide

(Z) Methylene-1-4-phenyleneoxazolidine-1-one (1.8 mmol) and N, N-dimethylmethylenediamine (2.1 mmol) in tetrahydrofuran (5 ml) The solution was stirred at room temperature for 15.5 hours. After the solvent was distilled off under reduced pressure, the concentrated residue was removed. The precipitate was collected by filtration, washed with getyl ether, and dried under reduced pressure to give the title compound (595 mg, yield 91%) as a white powder.

^{_{1 H- NR δ (d 6 -DMS0}} , 270MHz) 1.90 (2H, t, J = 7.3 Hz), 1.98 (6H, s), 2.95 (2H, q, J = 7.3 Hz), 7.37 (5H, s) , 7.52 (2H, t, J = 7.3 Hz), 7.61 (1H, t, J = 7.3 Hz), 7.74 (1H, t, J = 5.8 Hz), 7.99 (2H, d, J = 6.9 Hz), 9.99 (1H, br s).

(2) 2-benzoylamino-13- (2-pyridylthio) -13-phenylpropionic acid 2-dimethylaminoethylamide (E-form and isomer)

(Z) — 2-Benzylamino-1-3-chloro-1--3-phenylpropenoic acid A solution of 2-dimethylaminoethylamide (0.81 benzyl) and 2-mercaptopyridine (0.81 瞧 ol) in tetrahydrofuran (2 ml) DBU (1.6 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 15.5 hours. The reaction solution was diluted with ethyl acetate / toluene (1: 1), washed with water and saturated saline in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography (form: methanol: methanol = 20: 1, 0.5% triethylamine) to give 173 mg (48% yield) of a low-polar isomer (Rf value 0.25) as a white powder. 90 mg (yield 25%) of the polar isomer (Rf value 0.20) was obtained as a white powder, and 56 mg (yield 16%) of a mixture of both isomers was obtained as a white powder.

Less polar isomer hydrochloride: ¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 2.69 (3H, s), 2.70 (3H, s), 2.90 (2H, q, J = 5.6 Hz), 3.25 (2H, q, J = 5.6 Hz), 7.07 (1H, ddd, J = 7.6, 5.0, 1.0 Hz), 7.20-7.40 (4H, m), 7.41-7.62 (7H, m), 7.86 (2H, d, J = 6.9 Hz), 8.31 (1H, ddd, J = 5.0, 4.0, 1.0 Hz).

High polarity isomer _{hydrochloride: i H- NMR S (d 6} -DMSO, 270MHz) 2.81 (3H, s), 2.83 (3H, s), 3.20 (2H, q, J = 5.6 Hz), 3.53 (2H, q, J = 5.6 Hz), 7.10

(1H, ddd, J = 7.3, 5.0, 1.0 Hz), 7.13-7.62 (10H, m), 7.75 (2H, d, J = 6.9

Hz), 8.33 (1H, ddd, J = 5.0, 2.0, 1.0 Hz), 8.67 (1H, t, J = 5.6 Hz), 9.92 (1H, br s), 10.10 (1H, s). Example 1 10

2-benzoylamino-3- (2-pyridylthio) -1-phenylpropenoic acid (2-dimethylaminodityl) methyl amide (highly polar isomer)

Of 4- (2-pyridylthio) phenylmethylene-1-phenylphenyloxazolidin-5-one (low polar isomer, 0.42 mmol) and Ν, Ν, Ν'-trimethylethylenediamine (0.50 mmol) A solution of tetrahydrofuran (2 ml) was stirred at room temperature for 14 hours. The solvent was distilled off under reduced pressure to obtain 200 mg (quantitative yield) of the title compound as a pale yellow oil (R f value 0.40 (cloth form: methanol = 10: 1)).

Hydrochloride: ¹ H-NMR δ (d ₆ -DMS0, 270 MHz) 2.82 (3H, s), 2.84 (3H, s), 3.21 (3H, s), 3.25-3.35 (2H, m), 3.77 (2H, t, J = 6.9 Hz), 7.08 (1H, dd, J = 6.9, 5.3 Hz), 7.20-7.70 (10H, m), 7.77 (2H, s, J = 6.9 Hz), 8.30 (1H, ddd, J = 4.0, 1.7, 1.0 Hz), 10.12 (1H, br s), 10.25 (1H, s).

2-benzoylamino-3- (2-pyridylthio) -1-phenylpropenoic acid (2-dimethylaminoethyl) methylamide (low-polar isomer)

In this example, 4- (2-pyridylthio) phenylmethylene-1-2-phenyloxazolidine-15-one (highly polar isomer) and Ν, Ν, Ν'-trimethylethylenediamine were used. The title compound (R f value 0.45 (cloform form: methanol = 10: 1)) was synthesized in the same manner as described above.

Hydrochloride: ifi—NMR δ (d ₆ -DMS0, 270MHz) 2.73 (3H, s), 2.74 (3H, s), 2.79 (3H, s), 2.98 (2H, t, J = 5.3 Hz), 3.35- 3.50 (2H, m), 7.10 (1H, dd, J = 7.1, 5.1 Hz), 7.20-7.70 (10H, m), 7.84 (2H, d, J = 6.9 Hz), 8.33 (1H, d, J = 5.0 Hz), 10.25 (2H, br s).

Example 1 1 1

2-benzoylamino-1- (2-pyridylthio) -1-phenylpropenoic acid 2- (2-pyridyl) ethylamide (E-form and Z-form)

(1) (Z) —2 ^ Nzylamino-3-3-chloro-3 —Phenylpropenoic acid 2- (2-pyridyl) ethylamide

(Z) ― 4-Feum-l-octa-methylene 2- 2-phenyloxazolidine-1 5- 5 The title compound was synthesized in the same manner as in Example 109 (1) using pyridine and 2- (2-aminoethyl) pyridine.

¹ H-NMR 6 (d ₆ -DMS0, 270 MHz) 2.52 (2H, t, 6.6 Hz), 3.23 (2H, t, J = 6.6 Hz), 7.09 (1H, d, J = 7.6 Hz), 7.17 (1H , ddd, J = 7.6, 5.0, 1.0 Hz), 7.34-7.45 (5H, m), 7.52 (2H, t, J = 6.7 Hz), 7.58-7.66 (2H, m), 7.00 (2H, d, J = 6.9 Hz), 8.12 (1H, t, J 5.9 Hz), 8.41 (1H, ddd, J = 4.6, 1.7, 1.0 Hz), 10.02 (1H, s).

(2) 2-Benzylamino-3- (2-pyridylthio) -1-phenylpropenoic acid 2- (2-pyridyl) ethylamide (E-form and Z-form)

(Z) — 2—Benzoylamino-1- 3-cloth — 3—Ferpropenoic acid 2—

The title compound was synthesized in the same manner as in Example 109 (2) using (2-pyridyl) ethylamide.

Less polar isomer hydrochloride: ¹ H-NMR δ (d ₆ -D S0, 270 MHz) 3.00 (2H, t, J = 6.9 Hz), 3.33 (2H, q, J = 6.9 Hz), 7.06 (1H, ddd , J = 7.6, 4.9, 1.0 Hz), 7.16-7.27 (4H, m), 7.37-7.62 (5H, m), 7.76 (1H, d, J = 7.9 Hz), 7.82-7.89 (3H, m), 8.19 (1H, t, J = 5.9 Hz), 8.29 (1H, ddd, J = 4.6, 4.0, 1.0 Hz), 8.38 (1H, dt, J = 1.7, 7.9 Hz), 8.76 (1H, d, J = 4.6 Hz), 10.13 (1H, s). Highly polar isomer hydrochloride: i H—NMR δ (d 6 -DMS0, 270 MHz) 3.26 (2H, t, J = 5.9 Hz), 3.67 (2H, q, J = 5.9 Hz), 7.09 (1H, ddd, J = 7.6, 5.0, 1.0 Hz), 7.12-7.28 (4H, m), 7.36-7.58 (6H, m), 7.71 (2H, d, J = 6.9 Hz) , 7.73-7.88 (2H, m), 7.92 (1H, d, J = 8.3 Hz), 8.24 (1H, dd, J = 7.9, 1.3 Hz), 8.27—8.32 (1H, m), 8.54 (1H, t , J = 6.3 Hz), 8.73 (1H, d, J = 4.9 Hz), 10.13 (1H, s).

2-benzoylamino-3- (2-pyridylthio) -1-phenylpropenoic acid

3-pyridylmethylamide

Of 4- (2-pyridylthio) phenylmethylene-1 2-phenyloxazolidine-1 51-one (highly polar isomer) (0.28 mmol) and 3-picolylamine (0.31 mmol) The tetrahydrofuran (1 ml) solution was stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, the concentrated residue was suspended in getyl ether, the precipitate was collected by filtration, washed with getyl ether, and dried under reduced pressure to obtain the title compound (120 mg, yield 86%). .

Hydrochloride: — NMR δ (d ₆ -DMS0, 270 MHz) 4.28 (2H, d, J = 6.3 Hz), 7.07 (1H, ddd, J = 7.6, 5.6, 1.0 Hz), 7.18-7.24 (2H, m) , 7.26 (1H, d, J = 8.3 Hz), 8.37-8.62 (6H, m), 7.87 (2H, d, J = 6.9 Hz), 7.95 (1H, dd, J = 7.9, 6.6 Hz), 8.16 ( 1H, d, J = 8.6 Hz), 8.31 (1H, ddd, J = 5.0, 2.0, 1.0 H), 8.65 (1H, s), 8.73 (1H, t, J = 5.8 Hz), 7.78 (1H, d , J = 5.0 Hz), 10.24 (1H, s).

2-Benzoylamino-3- (2-pyridylthio) -13-phenylpropenoic acid 2-pyridylamide

A solution of 2-aminopyridine (4.2 mmol) in tetrahydrofuran (10 ml) was added dropwise to a solution of sodium hydride (3.3 mmol) in tetrahydrofuran (5 ml) under ice cooling, and the mixture was stirred for 20 minutes. Subsequently, a solution of 4- (2-pyridylthio) phenylmethylene-1-2-phenyloxazolidine-15-one (highly polar isomer) (2.8 mmol) in tetrahydrofuran (30 ml) was added dropwise under ice-cooling. The reaction mixture was stirred for 1 hour as it was, then heated to room temperature and stirred for 30 minutes. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the concentrated residue was purified by silica gel column chromatography (toluene: ethyl acetate = 1.5: 1) to obtain 525 mg (yield 42%) of the title compound as a light brown powder. .

Hydrochloride: — NMR δ (d ₆ -DMS0, 270 MHz) 7.10 (1H, ddd, J = 7.6, 5.0, 1.0 Hz), 7.13-7.27 (6H, m), 7.40 (1H, d, J = 8.3 Hz) , 8.44-8.63 (6H, m), 7.75 (1H, t, J = 8.6 Hz), 7.85 (2H, d, J = 6.9 Hz), 7.92 (1H, t, J = 7.9 Hz), 8.25 (1H, ddd, J- 5.3, 2.0, 1.0 Hz), 8.33 (1H, ddd, J = 4.6, 1.7, 0.7 Hz), 10.33 (1H, s), 11.11 (1H, s).

Example 1 1 4 2-benzoylamino-3- (2-pyridylthio) -1-phenylpropenoic acid carboxymethylamide

(1) 2-Benzoylamino-3- (2-pyridylthio) -13-phenylpropanoate t-butoxycarbonylmethylamide

4- (2-pyridylthio) phenylmethylene-1-2-phenyloxazolidine-15-one (highly polar isomer) (0.28 mmol), glycine t-butyl ester hydrochloride (0.33 mmol) and triethylamine (0.56 mmol) in tetrahydrofuran (3 ml) was stirred at room temperature for 22.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the concentrated residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1) to obtain the title compound (64 mg, yield 47%) as a white powder.

^{_{1 H-NMR δ (d 6}} -DMSO, 270MHz) 1.38 (9H, s), 3.59 (2H, d, J = 5.6 Hz), 7.04 (1H, ddd J = 7.6, 5.0, 1.0 Hz), 7.15-7.23 (4H, m), 7.42-7.60 (6H, m), 7.88 (2H, d, J = 6.9 Hz), 8.25 (1H, d, J = 5.6 Hz), 8.28 (1H, ddd, J = 4.9, 2.0 , 1.0 Hz), 10.11 (1H, s).

(2) 2-benzoylamino-3- (2-pyridinorethio) carboxymethyl amide 3-phenylpropionate

To a solution of 2-benzoylamino-3- (2-pyridylthio) -13-phenylpropenoic acid t-butoxycarbonylmethylamide (0.061 mmol) in 1,4-dioxane (1 ml) is added a 4N-hydrochloric acid-dioxane solution ( 2 ml) was added, and the reaction mixture was stirred at 50 ° C for 1 hour. After evaporating the solvent under reduced pressure, the concentrated residue was suspended in getyl ether, the precipitate was collected by filtration, washed with getyl ether, and dried under reduced pressure to obtain 34 mg (quantitative) of the title compound as a white powder. Was.

¹ H-NMR δ (d _fi -DMSO, 270MHz) 3.64 (2H, d, J = 5.6 Hz), 7.08 (1H, ddd, J = 7.3, 5.0, 1.0 Hz), 7.16-7.30 (4H, m), 7.43-7.61 (6H, m), 7.88 (2H, d, J = 6.9 Hz), 8.24 (1H, t, J = 5.6 Hz), 8.30 (1H, d, J = 4.6 Hz), 10.13 (1H, s ).

Example 1 1 5 2-benzoylamino-3- (2-pyridylthio) -3-phenylpropenoic acid 4-pyridylmethylamide

The title compound was synthesized in the same manner as in Example 112 using 4-picolylamine and 4- (2-pyridylthio) phenylmethylene-2-phenyloxyzolidine-5-one (highly polar isomer). did.

_{Hydrochloride: H- NMR δ (d 6 -DMS0} , 270MHz) 4.33 (2H, br s), 7.00-7.93 (14H, m), 8.31 (1H, br s), 8.65-8.90 (3H, m), 10.25 (1H, s).

Example 1 1 6

2-benzoylamino-3- (2-pyridylthio) -3-phenylpropenoic acid 2-pyridylmethyl ester

To a suspension of sodium hydride (0.17 ol) in tetrahydrofuran (0.5 ml) was added dropwise a solution of 2-pyridylmethanol (0.1 aramol) in tetrahydrofuran (1 ml) under ice cooling, followed by stirring for 20 minutes. Then, a solution of 4- (2-pyridylthio) phenylmethylen-1--2-phenyloxazolidin-1-5-one (highly polar isomer, 0.14 mmol) in tetrahydrofuran (2 ml) was added dropwise under ice cooling, and the reaction was continued. The mixture was stirred for 50 minutes. The reaction solution was diluted with ethyl acetate, washed sequentially with water and saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the concentrated residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1) to obtain 42 mg (yield: 64%) of the title compound as a brown oil.

_{Hydrochloride: ifi- NMR 6 (d 6 -DMS0} , 270MHz) 5.16 (2H, br s), 6.90-7.90 (15H, m), 8.11 (1H, br s), 8.28 (1H, br s), 8.66 ( 1H, br s), 10.53 (1H, s) 4.22 (2H, br s), 6.95-7.70 (11H, m), 7.89 (2H, br s), 8.29 (1H, br s), 10.53 (1H, s) s), 11.03 (1H, br s).

Example 1 1 7

2-Benzylamino-3- (2-pyridylthio) -1-phenylpropenoic acid 2- (2-pyridyl) ethyl ester (E-form and Z-form)

(1) (Z) — 2-Venzoinoleamino-3-3-chloro-3-pheninolepropenoic acid 2- (2-pyridyl) ethyl ester

Potassium was added to a tetrahydrofuran (5 ml) solution of (Z) -4 phenylcopent romethylene-1-2-phenyloxazolidine-15-one (1.1 mraol) and 2-pyridineethanol (1.3 mmol) at room temperature. t-Butoxide (1.1 mmol) was added and the reaction mixture was stirred at room temperature for 14 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline in this order, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the concentrated residue was suspended in toluene and the resulting crystals were collected by filtration, washed with hexane, and dried under reduced pressure to give the title compound (139 mg, yield 32%) as a white solid. Obtained as a solid.

^{_{1 H-NMR δ (d 6}} -DMS0, 270MHz) 2.70 (2H, t, J = 6.6 Hz), 4.27 (2H, t, J = 6.6 Hz), 7.03 (1H, d, J = 7.9 Hz), 7.17 (1H, ddd, J = 7.6, 5.0, 1.3 Hz), 7.31-7.67 (10H, m), 7.96 (2H, d, J = 6.9 Hz), 8.43 (1H, ddd, J = 4.9, 2.0, 1.0 Hz ), 10.35 (1H, s).

(2) 2-benzoylamino-3- (2-pyridylthio) -13-phenylprodonic acid 2- (2-pyridyl) ethyl ester (E-form and Z-form)

(Z) —2-Benzylamino-1-3-chloro-3-phenylphenylenoic acid 2—

To a solution of (2-pyridyl) ethyl ester (0.25 mmol) and 2-mercaptopyridine (0.25 mmol) in tetrahydrofuran (2 ml) was added DBU (0.49 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 14.5 hours. The reaction solution was diluted with ethyl acetate Z toluene (1: 1), washed with water and saturated saline in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1) to give 22 mg (19% yield) of the low-polar isomer as a pale yellow oil (low-polar isomer). (Rf value 0.15) 34 mg (29% yield) was obtained as a pale yellow oil, and 61 mg (total yield quantitative) of a mixture of both isomers was obtained as a yellow oil.

Less polar isomer hydrochloride: 1 NMR δ (d ₆ -DMS0, 270 MHz) 3.13 (2H, t, J = 5.8 Hz), 4.33 (2H, t, J = 5.9 Hz), 7.06 (1H, ddd, J = 7.6, 5.0, 1.0 Hz), 7.13 (1H, d, J = 7.9 Hz), 7.19-7.32 (5H, m), 7.44-7.83 (8H, m), 8.23-8.31 (2H, m), 8.70 (1H , dd, J = 5.6, 1.0 Hz, 10.41 (1H, s).

High polarity isomer hydrochloride: A _{NMR δ (d 6 -DMS0, 270MHz} ) 3.39 (2H, t, J = 5.6 Hz), 4.64 (2H, t, J = 5.6 Hz), 7.05-7.14 (2H, m), 7.17-7.30 (3H, m), 7.40-7.72 (10H, m), 7.88 (1H, d, J = 7.9 Hz), 8.17 (1H, t, J = 7.8 Hz), 8.28 (1H, ddd, J = 4.6, 1.6, 1.0 Hz), 8.65 (1H, dd, J = 5.9, 1.0 Hz), 10.19 (1H , s).

Example 1 1 8

2-benzoylamino-3- (2-pyridylthio) -1-phenylpropenoic acid 3- (2-pyridyl)

To a suspension of sodium hydride (0.1 mmol) in tetrahydrofuran (0.5 ml) was added dropwise a solution of 2_pyridinepropanol (0.1 mmol) in tetrahydrofuran (1 ml) under ice cooling. Stirred for minutes. Then, a solution of 4_ (2-pyridylthio) phenylmethylene-2-enephenyloxazolidin-1-5-one (highly polar isomer, 0.14 mol) in tetrahydrofuran (3 ml) was added dropwise under ice-cooling. The reaction mixture was stirred for 50 minutes. The reaction solution was diluted with ethyl acetate, washed sequentially with water and saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the concentrated residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1) to obtain the title compound (69 mg, quantitative) as a brown oil.

Oxalate: i fi— NMR δ (d 6 -DMSO, 270 MHz) 1.55-1.75 (2H, m), 2.45 (2H, t, J = 7.6 Hz), 3.88 (2H, t, J = 6.3 Hz), 7.06 (1H, dd, J = 6.6, 5.0 Hz), 7.10-7.62 (12H, m), 7.73 (1H, dt, J = 2.0, 7.6 Hz), 7.88 (2H, d, J = 7.3 Hz), 8.29 (1H, d, J = 4.4 Hz), 8.47 (1H, d, J = 4.6 Hz), 10.41 (1H, s).

2-benzoylamino-3- (2-pyridylthio) -1-phenylpropenoic acid _2- (1-pyrrolidyl) ethylester.

41 The title compound was prepared in the same manner as in Example 118 using 1- (2-pyridylthio) phenylmethylene-12-phenyloxazolidine-15-one (highly polar isomer) and topyrrolidineethanol. Synthesized. ¹ H-NMR δ (CDC13, 270MHz) 1.60-1.73 (4H, m), 2.37 (4H, br s), 2.48 (2H, t, J = 6.3 Hz), 4.17 (2H, t, J = 6.3 Hz) , 7.02 (1H, ddd, J = 7.3, 4.6, 1.0 Hz), 7.20-7.30 (4H, m), 7.40-7.57 (6H, m), 7.83 (2H, d, J = 6.9 Hz), 8.38 (1H , Ddd, J = 5.0, 2.0, 1.0 Hz), 9.01 (1H, s).

2-benzoinoleamino-1- (2-pyridinorethio) -3-phenyl-2-enopropenoic acid 2-trimethylsilylethyl ester (E-form and Z-form)

(1) (E) — 2-Benzylamino-3-3-chloro-3, -phenylenopropenoic acid 2-trimethylsilylethyl ester

(E) -4 Potassium-t-tetrahydrofuran (3 ml) solution of 4-pheninolek-oral methylene 1-2-phenenoleoxazolidine-15-one (2.5 ol) and 2-trimethylsilylethanol (3.0 ol) at room temperature. -Butoxide (2.5 mol) was added, and the reaction mixture was heated to reflux for 1 hour and allowed to cool. After evaporating the solvent under reduced pressure, ethyl acetate was added, and the mixture was washed with 0.5N aqueous hydrochloric acid, water and saturated saline in this order, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the concentrated residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to give the title compound (649 mg, yield 65%) as a colorless solid.

¹ H-NMR 6 (CDC13, 270 MHz) 0.02 (9H, s), 1.00 (2H, t, J = 8.6 Hz), 4.27 (2H, t, J = 8.6 Hz), 7.35-7.60 (8H, m), 7.75 (2H, d, J = 8 Hz), 10.17 (1H, s).

(2) 2-Benzylamino-3- (2-pyridylthio) -1-phenylpropionic acid 2-trimethylsilylethyl ester (E-form and Z-form)

(E) — 2-Benzylamino-3-3-chloro-1--3-methylphenolepropenoic acid 2-trimethylsilylethyl ester (1.5 olol) and 2-mercaptopyridine (1.6 ol) in tetrahydrofuran (5 ml) at room temperature Then, DBU (2.2 mmol) was added thereto, and the reaction mixture was stirred at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline in that order, and dried over sodium sulfate. After distilling off the solvent under reduced pressure, the concentrated residue was subjected to silica gel column chromatography (form: chloroform). Purification in 1) gave 244 mg (34% yield) of the less polar isomer as a pale yellow powder, and 105 mg of the more polar isomer (20% of the less polar isomer, yield 15%) as a single powder. Obtained as a brown oil.

Low polarity _{isomer: ifi- NMR δ (CDC1 3,} 270MHz) 0.05 (9H, s), 0.60-0.70 (2H, m), 4.05-4.15 (2H, m), 7.02 (1H, ddd, J = 8.6, 5.6, 1.0 Hz), 7.21- 7.30 (4H, m), 7.40-7.58 (6H, m), 7.82 (2H, d, J = 8 Hz), 8.38 (1H, ddd, J = 5.0, 2.0, 1.0 Hz), 8.97 (1H, s).

Highly polar isomer: ifi- NMR δ (CDC13, 270MHz) 0.02 (9H, s), 1.00-1.10 (2H, m), 4.40-4.50 (2H, m), 7.02 (1H, ddd, J = 7.3, 4.6 , 1.0 Hz), 7.20-7.70 (12H, m), 7.89 (1H, br s), 8.34 (1H, ddd, J = 5.0, 2.0, 1.0 Hz).

2-benzoylamino 3- (2-pyridylthio) -1-phenylpropenoic acid (E-form and Z-form)

(1) 2-benzoylamino-3- (2-pyridylthio) -1-phenylproic acid (low-polar isomer)

2-Benzoylamino-1- (2-pyridylthio) -1-phenylpropenoic acid 2-trimethylsilylethyl ester (low polar isomer, 0.31 mmol) in dichloromethane (1 ml) solution at room temperature in trifluoroacetic acid (1 ml) ml) was added, and the reaction mixture was stirred at room temperature for 4 hours. After the trifluoroacetic acid was distilled off under reduced pressure, the concentrated residue was suspended with geethyl ether. The precipitate was collected by filtration, washed with geethyl ether, and evaporated under reduced pressure to give the title compound (R f value 0.55 (chloroform form). : Methanol: acetic acid = 100: 10: 1)) 117 mg (yield 99%) was obtained as a light brown powder.

¹ H-NMR δ (d ₆ -DMSO, 270 MHz) 7.06 (1H, ddd, J = 7.3, 5.0, 1.0 Hz), 7.10-7.60 (10 H, m), 7.87 (2H, d, J = 8 Hz) , 8.03 (1H, ddd, J = 7.0, 2.0, 1.0 Hz), 10.25 (1H, br s), 12.65 (1H, br s).

(2) 2-Benzoylamino-3- (2-pyridylthio) -13-phenylprodonic acid (highly polar isomer)

2-benzoylamino-3- (2-pyridylthio) -1-phenylpropenoic acid / JP

86

To a solution of 2-trimethylsilylethyl ester (highly polar isomer, 0.31 mmol) in dichloromethane (1 ml) was added trifluoroacetic acid (1 ml) at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. After trifluoroacetic acid was distilled off under reduced pressure, the concentrated residue was purified by silica gel column chromatography (chloroform: methanol: acetic acid = 100: 10: 1) to give 30 mg of the title compound (R f value 0.50) (40% yield). ) Was obtained as a light brown powder.

^{_{1 H-NMR δ (d 6}} -DMSO, 270MHz) 7.06 (1H, ddd, J = 7.6, 4.6, 1.0 Hz), 7.10-7.20 (4H, m), 7.40-7.60 (6H, m), 7.73 (2H , d, J = 8 Hz), 8.26-8.32 (1H, m), 9.96 (1H, s), 12.80 (1H, br s).

Reference example 1

4- (2-pyridylthio) phenylmethylene-1-2-phenyl / leoxazolidine-15-one (E-form and Z-form)

4-Fuelc-mouth romethylene-1-2-pheninoleoxazolidine-15-one (E: Z = 2: 1 mixture, 37.2 ol) and 2-mercaptopyridine (37.2 arm ol) in tetrahydrofuran (200 ml) at room temperature. DBU (55.8 mmol) was added, and the mixture was stirred as it was for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline in this order, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, ethyl acetate (50 ml) was added to the concentrated residue, and the resulting precipitate was collected by filtration and washed with ethyl acetate to obtain the low-polar isomer 1.21 (yield 48%) as a yellow powder. . The mother liquor was concentrated, and the concentrated residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain 580 mg (yield 23%) of a highly polar isomer as a yellow powder.

Low polarity _{isomer: - NMR δ (CDC1 3,} 270MHz) 6.98 (1Η, ddd, J = 7.6, 5.0, 1.3 Hz), 7.18 (1H, dt, J = 8.3, 1.0 Hz), 7.24 - 7.31 (4H, m), 7.36-7.60 (4H, m), 7.65-7.70 (2H, m), 8.05 (2H, d, J = 6.9 Hz), 8.31 (1H, ddd, J = 4.9, 2.0, 1.0 Hz), 8.32 (1H, s).

High polarity _{isomer: - NMR δ (CDC1 3,} 270MHz) 7.02 (1H, ddd, J = 7.3, 4.6, 1.0 Hz), 7.16 (1H, dt, J = 7.9, 1.0 Hz), 7.20-7.62 (9H, m), 8.09 (2H, d, J = 6.9 Hz), 8.37 (1H, ddd, J = 4.9, 2.0, 1.0 Hz). The structure of the compound produced in Example 121 is shown below.

Example 1

1 4—Funoleolopheninole E

2 4-Funore Talent Rohueninore Z

3 2,4-Dichloropheninole E

4 2, 4 Jikro mouth Feninore Z

5 3-cloth mouth

6 3-Black mouth Feninore Z

7 2-cloth mouth fennore E

8 2—Black mouth Feninore Z

9 4—Methoxypheno E

10 4—Methoxy Tonino Z

11 Feninore E

12 Phenyl Z

13 1, 1-Dichloropentinole E

14 1, 1-Dichloropentinole Z

CONH ヽ CONH

S]

Example 23

15 4 1-Cyanophenyl -H

16-H 4-Cyanophenyl

17 2-Pyridinole -H

18-H 2-pyridyl

19 3-Chenyl-H

20 -H 3 -Chenyl

21 2-Cheninole -H

22 -H 2—Cheninore

23 Phenyl-Br

24-Br phenyl

25 4-Fluorophenyl -H

26 -H 4-Funole

I

N,

, CONH

s

2 3 Example

30 2 -Naphthyl -H

32 Phenyl -H

33 -H Feninole 34 -H 4 -Aminocarbonyl Feninole

35 4-Aminocarbonyl -H

Phenyl

36 4-Methoxycarbonyl -H

Phenyl

37 -H 4-Methoxycarbonylphenyl

38 4-Carboxyphenol -H

39 -H 4-Carboxyphenyl

43 2-Methoxycarbinole -H

Phenyl

44 -H 2-methoxycanoleboninole phenyl

45 phenyl phenyl

twenty three

Example

27 Phenyl methylthio

28 4-Fluorophenyl methyl

29 Phenyl Feni / Retio

31 phenylmethyl

42 2-Naphthylthiophenyl

43 1-octylthiophenyl

(The above compound is a mixture of E-form and Z-form.)

Example 2 3 4

I

Feninole 2-pyridylthio 2-thiazolylamino

40

2_pyridylthio pheninole 2-thiazolylamino pheny / le 2-pyridylthio methoxy 41 J

2-pyridylthiophenyl methoxy To CONH C〇L ⁴ Example L 4

47 -O H

4 "O H

⁴⁸ (However, the double bond is in the E configuration)

49 2-Benzothiazolylamino

50 4-1-Butyl-2-thiazolylamino 51 Piperidino

52 Cyclohexylamino

53 Jethylamino

54 2-methylpropylamino

55 Fueninoleamino

56 2- (3-Indolyl) ethylamino

57 4- (1-benzylpiperidyl) amino 58 arylamino

Example

59 1 -decylamino

60 4—Feninole 1—Piura Jonore

61 4— (2-pyridinole) — 1—piperazinole 62 2-pyridylamino

63 2-Pyrazininoreamino

64 2 -Pyridimidinylamino

65 3-Virazori Norea Mi No

4- (ethoxycanoleponylmethyl)

66

Thiazolylamino

4- (carboxymethyl) thiazolyl

67

Amino

68 Methylamino

69 3 -Methoxyphenamino

70 3 -Funoleolophenylamino

And ⁵ tooth ⁵

71 Feninore 85 2 -Funenre Lofeninore

72 Benzyl 86 2 -Pirajunole

73 2-furinole 8 3

w7, -Methoxycarbonyl feninole

75 4-pyridyl

88 2H-Pyran-2-one-5-yl

76 2-pyrrolyl

89 4—Funoleolofeninole

77 2-Indone Nore

90 4--2 G

78 2-Naphthyl

91 3-Cyanophenyl

79 2—Cheninore

92 4-Dimethinoleaminophenyl

80 Cyclohexinole

93 1-oxo-3-pyridyl

81 Petil

94 3-carboxyphenyl

82 3-Cheninore

95 4-aminophenyl

83 2-Nitoguchi Feninore

96 2-Methoxyphenyl

84 4-Cyanophenyl

6

Example

97 3-Indrill

98 2-black mouth

99 3-Cheninole

100 Benzinole

102 2-Cheninore

Example

103 2-Pyrimidinyl

104 3-pyridinole

105 3-quinolyl

106 4- (1,2,4-triazo

Example 74 Example 101

Example L ⁸ 9

107-H methyl (both isomers)

108 Ethyl I-chill (both isomers)

109-H 2-Dimethylaminoethyl (both isomers)

110 Methyl 2-dimethylaminoethyl (both isomers)

111-H 2- (2-pyridyl) ethyl (both isomers)

112 -H 3-pyridylmethyl

113-H 2-pyridyl

114-H carboxymethyl

115-H 4-pyridylmethyl

(Examples 112 to 115 were synthesized from 4- (2-pyridylthio) phenyl methylene-1-phenyloxazolidin-1-5-one (highly polar isomer).)

Ten

Example

116 2-Pyridylmethyl

117 2- (2-Pyridyl) ethyl (both isomers)

118 3- (2-Pyridyl) propyl

119 2- (1-Pyrrolidyl) ethyl

120 2-Trimethylsilylethyl (both isomers)

121-H (both isomers) Example 1 16, 1 18 and 1 19 are 4- (2-pyridylthio) phen 2 • 2 phenyloxazolidin 1 5-one (highly polar isomer) More synthesized

Test example 1

13-Amyloid (Αβ) production inhibitory effect on primary cultured guinea pig neuroglial cells

1) Experimental materials and methods

Primary culture of mixed neuroglia

The cerebral cortex extracted from the guinea pig (SLC_Hartley) fetus on the 28th to 35th day of pregnancy was minced, and a single cell suspension was prepared by papain treatment and pipetting. This was dispersed in a MEM (manufactured by Gibco) medium containing 2% inactivated fetal serum, 5 mM glucose, 24 mM sodium bicarbonate, and 10 mM HEPES, and the 96-well plate was coated with poly D-lysine (Sigma). One cell (Falcon) was seeded at 6 × 10 ⁴ cells / well. After culturing in a CO ₂ incubator (5% CO ₂ , 37 ° C) for 2 hours, the medium was NBB27G medium (B27 supplement (Gibco), NEUROBASAL Medium containing 0.5πιΜglutamine (registered trademark: Gibco) )) was exchanged with, the culture was continued in C0 ₂ incubator within one. Thereafter, the medium was changed every 3 to 4 days. On the 8th day of culture, add a fresh medium containing the compound of the present invention. After 48 hours, collect the culture supernatant, evaluate cytotoxicity,

Stored at 20 ° C.

Determination of A 6 in culture supernatant (ELISA)

Anti-] 3 amyloid antibody clone 4G8 (manufactured by Senetech) dissolved in 0.1 M carbonate buffer (pH 9.6) at a concentration of 5 µg Zml was added to the ELISA plate at 50 µl / well and incubated at 4 ° C.した I left it. After washing each well twice with phosphate buffered saline (PBS), add a blocking solution (25% Block Ace (purchased from Dainippon Pharmaceutical) ZPBS) at 200 // 1 / well and add 1 well at room temperature. Left for hours. Wash each well four times with 0.02PBST (PBS containing 0.02% Tween20), and then dilute with culture supernatant or 25% Block Ace ZPBS AJ3 standard (0.3, 1, 3, 10 ng / ml from Sigma) ) Was added at 50 / il Nowell and left at 4 ° C for 2 minutes. After aspirating and removing the supernatant from each well, each well was washed four times with 0.02 PBST, and biotinylated anti-amyloid antibody clone 6E10 (manufactured by Senetech) dissolved in 10% Block Ace ZPBS at a concentration of 2.5 gZml. Was added at 50 / \ / well. After standing at 4 ° C for 1 hour, each well was washed 4 times with 0.02 PBST, and diluted with 1000% 10% Block Ace ZPBS, horseradish peroxidase (HRP) labeled store. Leptoavidin (Amersham) was added at 50 wells. After leaving at room temperature for 1 hour, each well was washed four times with 0.02 PBST, and a color reaction solution (ImmunoPure TMB substrate kit, manufactured by PIERCE) was added in 100 μl wells. After the reaction at room temperature for 8 to 10 minutes, the reaction is stopped by adding a 2Μ sulfuric acid solution to each well at 100 // 1 / ゥ, and colorimetric determination (measurement using a microplate reader (BIO-RAD)) Wavelength, 450 nm). A calibration curve was prepared from the absorbance at 450 nm of the A] 3 standard, and the amount of A] 3 in the culture supernatant was measured. As a control, the amount of A] 3 in the culture supernatant when the compound of the present invention was not added was determined. The A0 production inhibition rate by the compound of the present invention was determined by comparing with a control.

Evaluation of cytotoxicity-lactate dehydrogenase (LDH) method

20 μl of the culture supernatant was taken, and the amount of LDH leaked from the cells was measured using a reagent for microtoxicity test ΜΤΧ “LDH” (manufactured by Kyokuto Pharmaceutical). Table 1 shows the A | 3 production inhibition rate at 10 /// of the compounds obtained in the examples. The compounds listed in Table 1 were not cytotoxic at 10 μ 10

Industrial applicability

According to the present invention, novel [3] amyloid production inhibitors useful as therapeutic agents for Alzheimer's disease and the like, and novel compounds useful as [3] amyloid production inhibitors and the like can be provided.

Claims

The scope of the claims

1.Equation 1

R ¹ -Y— NH- A— CO-R ²

— Y— and — A—

(1) — Y— represents one CO—,

— A— is the formula:

(Wherein one of R ³ and R ⁴ is a hydrogen atom, a halogen atom, —S (O) _n -X (n represents 0, 1 or 2, X is a substituted or unsubstituted alkyl, Or an unsubstituted aryl or a substituted or unsubstituted unsaturated heterocycle.), Represents a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl,

^{The other of 3} and R ⁴ represents a substituted or unsubstituted aryl or a substituted or unsubstituted unsaturated heterocycle. ) Represents a group represented by

(2) - Y- is one CO- or a S0 ₂ - represents,

— A— is the formula:

(H ₂ ) _m -R,

(In the formula, R is a substituted or unsubstituted aryl or a substituted or unsubstituted unsubstituted aryl. Represents a saturated hetero ring, _m represents 0, 1 or 2, and R ⁶ represents a hydrogen atom or alkyl. ) Represents a group represented by ]

And / or a pharmaceutically acceptable salt thereof.

2. R ² is one N (R ⁷ ) R ⁸ or one OR ⁹ [wherein one of R ⁷ and R ⁸ represents a hydrogen atom or lower alkyl, and the other is a substituted or unsubstituted unsaturated heterocyclic ring Or both independently represent a hydrogen atom or a substituted or unsubstituted lower alkyl, and R ⁹ represents a hydrogen atom or a substituted or unsubstituted lower alkyl. 3. The inhibitor for amyloid formation according to claim 1, wherein

3. R ⁷ and R ⁸ forces One is a hydrogen atom or lower alkyl and the other is 2-thiazolyl, or both are independently a hydrogen atom or substituted or unsubstituted lower alkyl, and R ⁹ is 3. The J3 amyloid formation inhibitor according to claim 2, which is a hydrogen atom or a substituted or unsubstituted lower alkyl.

4. scale ¹ month, beta-amyloid production inhibitor according to claim 1 Kakara 3 is a substituted or unsubstituted Ariru or substituted or unsubstituted Choi chloride.

5. Equation 1a:

[Wherein, R ¹ R ² and R ⁴ have the same meaning as in claim 1. ]

3. The 3-amyloid production inhibitor according to claim 1, which is a compound represented by the formula:

6. R ³ is a hydrogen atom, a halogen atom, one S (O) _n — X (n and X are the same as defined in claim 1), substituted or unsubstituted alkyl or substituted or unsubstituted aryl. The / 3 amyloid formation inhibitor according to claim 5, wherein R ⁴ is a substituted or unsubstituted aryl or a substituted or unsubstituted unsaturated heterocycle.

7. R ³ is a halogen atom or one SX (X is as defined in claim 1) It is. ) Wherein R ⁴ is a substituted or unsubstituted aryl or a substituted or unsubstituted unsaturated heterocyclic ring.

8. Claim 5 wherein one of R ³ and R ⁴ is one S—X (X is the same as defined in claim 1), and the other is a substituted or unsubstituted aryl. ] 3 Amyloid production inhibitor.

9. R ² is one N (R ⁷ ) R ⁸ or one OR ⁹ [wherein R ′, R ⁸ and R ⁹ are as defined in claim 2]. 9. The / 3 amyloid production inhibitor according to any one of claims 5 to 8, wherein

10. R ² is one N (R ⁷ ) R ⁸ [wherein, R ⁷ and R ⁸ each represent a hydrogen atom or lower alkyl, and the other represents substituted or unsubstituted lower alkyl. ] The amyloid production inhibitor according to any one of claims 5 to 8].

11. R ² is one OR ⁹ [wherein R ⁹ represents substituted lower alkyl. ] The amyloid production inhibitor according to any one of claims 5 to 8].

12. R ⁷ and R ^8, one is a hydrogen atom or a lower alkyl, the other is 2 - thiazolyl or where both are independently a lower alkyl hydrogen atom or a substituted or Mu置conversion, R ⁹ 10. The 13-amyloid formation inhibitor according to claim 9, wherein is a hydrogen atom or a substituted or unsubstituted lower alkyl.

13. The amyloid formation inhibitor according to any one of claims 5 to 12, wherein R ¹ is a substituted or unsubstituted aryl or a substituted or unsubstituted phenyl.

14. The / 3 amyloid production inhibitor according to any one of claims 1 to 13, which is a therapeutic agent for a disease caused by β-amyloid.

15. The β-amyloid production inhibitor according to any one of claims 1 to 13, which is a therapeutic agent for Alzheimer's disease.

16. Equation 1 ':

11

R ¹⁰ -Y ¹ -NH-A ⁿ -CO-R

[In the formula, R ¹⁰ represents a substituted or unsubstituted aryl, a substituted or unsubstituted unsaturated heterocyclic ring or a substituted or unsubstituted alkyl, — Y ¹ —, R ^{1 1} and — A ¹ —

(1) — Y ¹ — represents one CO—,

— A ¹ — is the formula:

(In the formula, one of R ¹² and R ¹³ is a hydrogen atom, a halogen atom, one S (O) _n -X (n and X are the same as defined in claim 1), and substituted or unsubstituted Represents an alkyl or a substituted or unsubstituted aryl, and the other represents a substituted or unsubstituted aryl or a substituted or unsubstituted unsaturated heterocycle.

R ¹³ cannot be a hydrogen atom or a halogen atom. ) Represents a group represented by

(2) — Y ¹ — represents one CO— or one S0 ₂ —,

One A ¹ — is the formula:

Fifteen

(CH ₂ ) _m -R

14

R

(Wherein, R ¹⁴ represents a hydrogen atom or alkyl, R ^la represents a substituted or unsubstituted aryl or a substituted or unsubstituted unsaturated heterocyclic ring, and m represents 0, 1 or 2. ) Represents a group represented by ]

Or a pharmaceutically acceptable salt thereof.

17. Equation 1 'a:

[Wherein, R ¹⁰ , R ¹ \ R ¹² and R ¹³ are the same as defined in claim 16. ]

17. The compound according to claim 16, which is represented by the formula: or a pharmaceutically acceptable salt thereof.

18. Salts R ^{1 2} is a halogen atom or a S- X (X is the definition and a synonym. In claim 1) is a compound of claim 1 7 wherein the or a pharmaceutically acceptable.

19. One of R ¹² and R ¹³ is one S—X (X is the same as defined in claim 1), and the other is a substituted or unsubstituted aryl. Or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 18, wherein X is pyridyl, or a pharmaceutically acceptable salt thereof.

21. R ¹¹ is one N (R ⁷ ) R ⁸ or one OR ⁹ [wherein R ⁷ and R. And R ⁹ are as defined in claim 2. 21. The compound according to any one of claims 17 to 20, or a pharmaceutically acceptable salt thereof.

22. R ¹¹ is one N (R ⁷ ) R ⁸ [wherein, R ⁷ and R ⁸ each represent a hydrogen atom or a lower alkyl, and the other represents a substituted or unsubstituted lower alkyl. 22. The compound according to any one of claims 17 to 21 or a pharmaceutically acceptable salt thereof.

23. R ¹¹ is one OR ⁹ [where R. Represents a substituted lower alkyl. 22. The compound according to any one of claims 17 to 21 or a pharmaceutically acceptable salt thereof.

24. R ⁷ and R ^8, one is a hydrogen atom or a lower alkyl, the other is 2 one thiazolyl, or lower alkyl of both independently represent a hydrogen atom or a substituted or Mu置conversion, R ⁹ Is a hydrogen atom or a substituted or unsubstituted lower alkyl, or the pharmaceutically acceptable salt thereof.

25. The compound according to any one of claims 17 to 24, or a pharmaceutically acceptable salt thereof, wherein R ^{1 Q} is a substituted or unsubstituted aryl or a substituted or unsubstituted phenyl.

26. Equation 1 'b:

R ¹⁰ -Y

[Wherein, R ¹⁰ , R ¹⁴ , R ¹⁵ and m are the same as defined in claim 16. — Y ² — represents one CO— or one S0 ₂ —. R ¹⁶ represents a substituted or unsubstituted unsaturated heterocyclic amino. ]

27. The compound or a pharmaceutically acceptable salt thereof according to claim 26, wherein R ¹⁶ is 2-thiazolylamino.

28. The compound according to claim 26 or 27, or a pharmaceutically acceptable salt thereof, wherein R ^{1 Q} is a substituted or unsubstituted aryl or a substituted or unsubstituted phenyl.

29. The compound according to any one of claims 26 to 28, wherein m is 1, or a pharmaceutically acceptable salt thereof.

30. A medicament comprising the compound according to any one of claims 16 to 29 or a pharmaceutically acceptable salt thereof.