JP2001122868A - Chromone derivatives or salts thereof and antifungal agents containing them - Google Patents

Abstract

(57) [Object] To provide a novel compound useful for prevention and treatment of fungal diseases in humans and animals. SOLUTION: [Formula 1] General formula [Formula 1] Wherein R ³ is an optionally substituted aryl, heteroaryl, acyl, alkylthio, arylamino,
A heteroarylamino, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl or heteroarylsulfonyl group;
¹ , R ² , R ⁴ and A are as described in the specification ”or a salt thereof and an antifungal agent containing them have excellent antifungal activity and have fungicidal properties in humans and animals. Useful for prevention and treatment of disease.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to the following general formula [1]

Embedded image Wherein R ³ is an optionally substituted aryl, heteroaryl, acyl, alkylthio, arylamino,
A heteroarylamino, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl or heteroarylsulfonyl group;
¹ , R ² and R ⁴ are the same or different and each represents a hydrogen atom,
A halogen atom, a nitro group, a nitrile group, an optionally protected hydroxyl group or an optionally substituted alkyl, cycloalkyl, alkenyl, alkylene, alkoxy, alkylamino, acylamino, aryl, heteroaryl, alkylthio, arylamino, A represents a heteroarylamino, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylsulfonyl or heteroarylsulfonyl group;
A nitrile group, an optionally substituted alkenyl or heterocyclic group,

Embedded image"Where R⁵Is a hydrogen atom, an optionally substituted
Kill, cycloalkyl, aryl or heteroaryl
Group, optionally protected hydroxyl, carboxy
, Amino, hydroxyamino, alkylamino, cyclic
Amino, arylamino, heteroarylamino or
Is an acylamino group or-(Z) p-R⁷  Wherein Z is an amino acid residue;⁷Is a hydroxyl
P represents 1 or 2, respectively;
You. Y is an oxygen atom, a sulfur atom or NR⁶  "Where R⁶Is a hydrogen atom, an optionally protected
Roxyl or amino group or optionally substituted
Alkylamino, alkoxycarbonylamino or
Shows an acylamino group. ] Respectively. Or

Embedded image Wherein R ⁵ ′ represents a hydrogen atom or an optionally substituted alkyl, aryl or heteroaryl group;
¹ represents an alkoxy group, respectively. Or a salt thereof, and an antifungal agent containing them.

[0002]

BACKGROUND OF THE INVENTION Severe deep mycosis, such as invasive candidiasis, is often a fatal disease. Originally, it is thought that the main defense mechanism of the host organism against fungi such as Candida is nonspecific immunity by neutrophils, and if this defense mechanism functions normally, there is a risk of infection with fungi. Is less. However, in recent years, the number of patients with malignant tumors (in particular, hematopoietic malignant tumors such as acute leukemia, malignant lymphoma, etc.) and AIDS and the like that cause a decrease in the immune function of the living body has increased, and anticancer drugs, immunosuppressants, etc. Frequent use of
The risk of developing deep mycosis is increasing due to increased use of antibacterial antibiotics and steroid hormones, prolonged central parenteral nutrition and use of intravenous catheters (Clinical and Microbiological Sciences, Vol. 17, p. 265, 1990) ). The number of drugs for which such treatment of deep mycosis has been applied is far less than that of antibacterial agents, and is only six of amphotericin B, flucytosine, miconazole, ketoconazole, fluconazole and itraconazole.

[0003]

SUMMARY OF THE INVENTION Amphotericin B is
Although it has a very strong bactericidal action against fungi, it has a problem of strong side effects such as nephrotoxicity, and its clinical use is limited. Further, flucytosine has a problem such as early resistance due to continuous use, and is rarely used alone at present. Other drugs are generally referred to as azole antifungals because of their structural characteristics, and their fungicidal activity on fungi generally tends to be inferior to that of amphotericin B, but from the viewpoint of a balance between efficacy and safety , Currently most used (Clinical and Microbial Science, Vol. 21, p. 277, 199
4 years). On the other hand, recently, it has been reported that fungi isolated from AIDS patients to whom an azole antifungal agent has been administered for a long time show resistance to the azole antifungal agent (Infectious Disease, Vol. 24, 61, 1994). Therefore, there is a strong demand for an antifungal agent that has a different action mechanism from existing drugs, has an effect on azole-resistant bacteria, and has few side effects.

[0004]

Under such circumstances, the present inventors have conducted intensive studies and as a result, the novel compound represented by the general formula [1] or a salt thereof has a strong antifungal activity. Thus, the present invention was found to be effective for the prevention and treatment of fungal diseases in humans and animals, and completed the present invention.
Hereinafter, the present invention will be described in detail.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION Unless otherwise specified in this specification
Halogen atom means fluorine atom, chlorine atom, bromine atom
Alkyl or iodine; alkyl is methyl, ethyl
, N-propyl, isopropyl, n-butyl, isobutyl
Butyl, sec-butyl, tert-butyl and pentyl
Chain or branched C_1-6An alkyl group; an alkenyl group
Means linear or branched such as vinyl and allyl
C_2-6An alkenyl group; a cycloalkyl group is cyclo
Such as propyl, cyclopentyl and cyclohexyl
C _3-6A cycloalkyl group; an alkylene group is
C, such as ethylene, ethylene and propylene_1-6Alkylene group
An alkoxy group means methoxy, ethoxy, n-propo
Xy, isopropoxy, n-butoxy, isobutoxy, se
c-butoxy, tert-butoxy and pentyloxy, etc.
Linear or branched C_1-6An alkoxy group;
A luthio group is defined as methylthio, ethylthio, n-propylthio.
E, isopropylthio, n-butylthio, isobutylthio
E, sec-butylthio, tert-butylthio and pentyl
Linear or branched C such as thio_1-6Alkylthio group
An alkylamino group means methylamino, ethylamino
No, propylamino, butylamino, pentylamino,
Hexylamino, dimethylamino, diethylamino,
Tylethylamino, dipropylamino, dibutylamino
And branched C such as dipentylamino
_1-6An amino group substituted with an alkyl group;
Is, for example, phenyl, tolyl, naphthyl;
A reel group is a heterocyclic group such as pyridinyl and quinolinyl.
An arylamido group having an aromatic ring;
A group is an aryl group such as anilino or naphthylamino
An amino group substituted with; a heteroarylamino group
Is a heterogen such as pyridinylamino and quinolinylamino
An amino group substituted with an aryl group; an aryloxy group
Means, for example, phenoxy, tolyloxy, naphthyl
An aryl-O- group such as xy;
A group is a heteroant such as pyridinoxy or quinolinoxy.
Arylthio group means, for example, phenyl
Aryl-S-groups such as ruthio, naphthylthio, etc .;
Phenylsulfinyl group means phenylsulfinyl, naph
An aryl-SO- group such as tylsulfinyl;
An arylsulfinyl group is pyridinylsulfinyl
And heteroaryl-S such as quinolinylsulfinyl
An aryl-sulfonyl group is a phenylsulfo group;
Aryl-SO such as nyl, naphthylsulfonyl, etc.₂-Group
A heteroarylsulfonyl group is pyridinylsulfon
Heteroaryl such as honyl and quinolinylsulfonyl;
SO₂A heteroarylthio group, for example,
Heteroaryl such as ridinylthio and quinolinylthio;
A heterocyclic group includes, for example, azetidinyl,
Enyl, furyl, pyrrolyl, imidazolyl, pyrazoly
, Thiazolyl, isothiazolyl, oxazolyl, iso
Oxazolyl, furazanil, pyrrolidinyl, pyrrolini
, Imidazolidinyl, imidazolinyl, imidazolidin
Nil, pyrazolidinyl, pyrazolinyl, oxazolidinyl
, Thiazolidinyl, 1,3,4-oxadiazolyl,
1,2,3-thiadiazolyl, 1,2,4-thiadiazol
1,3,4-thiadiazolyl, 1,2,3-triazolyl
1,2,4-triazolyl, tetrazolyl, thiatri
Azolyl, pyridyl, pyrazinyl, pyrimidinyl, pyri
Dazinyl, piperidinyl, piperazinyl, pyranyl, m
Rufolinyl, 1,2,4-triazinyl, benzothienyl
, Naphthothienyl, benzofuryl, isobenzofuryl
, Chromenil, indolizinyl, isoindolyl, i
Ndrill, indazolyl, purinyl, quinolyl, isokil
Noryl, phthalazinyl, naphthyridinyl, quinoxalini
, Quinazolinyl, cinnolinyl, phteridinyl,
Lysinyl, isochromanil, chromanil, indolini
, Isoindolinyl, benzoxazolyl, triazo
Lopyridyl, tetrazolopyridazinyl, tetrazolopyri
Midinyl, thiazolopyridazinyl, thiadiazolopyrida
Zinyl, triazolopyridazinyl, benzimidazoli
, Benzthiazolyl, benzothiadiazolyl, 1,2,
3,4-tetrahydroquinolyl, imidazo [1,2-b]
[1,2,4] triazinyl, 1,3-dioxonyl and
Oxygen, nitrogen and quinuclidinyl, etc.
And at least one heteroatom selected from sulfur and sulfur.
Having a 4-7 membered or fused heterocyclic group;
Is, for example, a formyl group, acetyl or propioni
C such as _2-12Alkanoyl group, benzoyl or
Are aroyl groups such as naphthoyl and nicotinoyl,
Noyl, pyrrolidinocarbonyl or furoyl group
An acyl group such as a heterocyclic carbonyl group; a cyclic amino group
Is pyrrolidinyl, piperidinyl, piperazinyl,
4- to 7-membered ring having a nitrogen atom such as rufolinyl in the ring
An amino group; an acylamino group is acetyl or benzoy;
Amino group substituted with an acyl group such as
Alkoxycarbonylamino group is methoxycarbonyl
Such as bonylamino and ethoxycarbonylamino;
Amino groups substituted with alkoxy-CO-;
Or trialkylammonio group is methylammonium
E, dimethylammonio, trimethylammonio and
Groups such as triethylammonio are meant respectively.

The term "leaving group" means a group which functions as a leaving group in a nucleophilic substitution reaction. Means an alkoxy group such as an alkylsulfonyloxy or arylsulfonyloxy group such as a group, a methoxy group and an ethoxy group.

[0007] The amino acid residue, amino acid loses a water molecule to form a peptide bond, -NHCHR ^a CO- portion when incorporated into a protein or peptide ^{(R a} is a. Showing the amino acid side chains) to means. Here, amino acids include, for example, glycine, alanine, valine, leucine,
Isoleucine, serine, threonine, asparagine, aspartic acid, cysteine, homocysteine, β-alanine, γ-aminobutyric acid, ornithine, methionine, glutamic acid, lysine, arginine, tyrosine, histidine, proline, tryptophan, phenylalanine and 3,4-dihydroxy A compound having a carboxyl group and an amino group in the same molecule, such as phenylalanine.

Aryl, heteroaryl, R ³ ,
Acyl, alkylthio, arylamino, heteroarylamino, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl or heteroarylsulfonyl groups; alkyl in R ¹ , R ² and R ⁴ ; Cycloalkyl, alkenyl,
Alkylene, alkoxy, alkylamino, acylamino, aryl, heteroaryl, alkylthio, arylamino, heteroarylamino, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylsulfonyl or heteroarylsulfonyl group; R ⁵ , R ⁵ ′ , R ^5a , R ^5a ′, R ^5b , R
Alkyl, cycloalkyl, aryl or heteroaryl groups at ^5b ′ and R ^5c ; R ⁶ and R
An alkylamino, alkoxycarbonylamino, cyclic amino or acylamino group for ^6a ; an alkenyl or heterocyclic group for A is, for example, a halogen atom,
Nitro group, cyano group, carbamoyl group, acyl group, alkyl, alkoxy, alkylthio, aryl, aryloxy, alkylamino, mono, di or trialkylammonio and heterocyclic group optionally substituted with a halogen atom and protection May be substituted with one or more groups selected from an optionally substituted hydroxyl, amino or carboxyl group.

When the compound of the present invention and an intermediate for the production thereof have a hydroxyl group, an amino group, a cyclic amino group, an aldehyde group or a carboxyl group, these substituents are
It may be protected by a known protecting group.

Here, the hydroxyl-protecting group includes all groups that can be used as ordinary hydroxyl-protecting groups, for example, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl , 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, te
rt-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,
2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, 2- (phenylsulfonyl)
Ethoxycarbonyl, 2- (triphenylphosphonio)
Ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl Acyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl and benzoyl; lower groups such as methyl, tert-butyl, 2,2,2-trichloroethyl and 2-trimethylsilylethyl Alkyl groups; lower alkenyl groups such as allyl; ar lower alkyl groups such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl and trityl; tetrahydric Oxygen- and sulfur-containing heterocyclic groups such as rofuryl, tetrahydropyranyl and tetrahydrothiopyranyl; methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, (Trimethylsilyl) lower alkoxy- and lower alkylthio-lower alkyl groups such as ethoxymethyl and 1-ethoxyethyl; alkane- or arene-sulfonyl groups such as methanesulfonyl and p-toluenesulfonyl; trimethylsilyl, triethylsilyl, triisopropylsilyl, diethyl Isopropylsilyl, tert-
And substituted silyl groups such as butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.

The protecting groups for amino, hydroxyamino, alkylamino, alkylamino, cyclic amino, arylamino, heteroarylamino and acylamino groups include all groups which can be used as ordinary amino protecting groups. For example, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o
-Bromobenzyloxycarbonyl, (mono-, di-,
Tri-) chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert
-Amyloxycarbonyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-
Dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1
Acyl groups such as dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl and 8-quinolyloxycarbonyl; lower alkyl groups such as benzyl, diphenylmethyl and trityl; 2-nitro Arylthio groups such as phenylthio and 2,4-dinitrophenylthio; alkane- or arene-sulfonyl groups such as methanesulfonyl and p-toluenesulfonyl; di-lower alkylamino-lower alkylidene groups such as N, N-dimethylaminomethylene; Benzylidene, 2-hydroxybenzylidene, 2-
Al-lower alkylidene groups such as hydroxy-5-chlorobenzylidene and 2-hydroxy-1-naphthylmethylene; nitrogen-containing heterocyclic alkylidene groups such as 3-hydroxy-4-pyridylmethylene; cyclohexylidene;
Cycloalkylidene groups such as 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene and 3,3-dimethyl-5-oxocyclohexylidene; diaryls such as diphenylphosphoryl and dibenzylphosphoryl -Or a dialle lower alkyl-phosphoryl group;
Examples include an oxygen-containing heterocyclic alkyl group such as 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl and a lower alkyl-substituted silyl group such as trimethylsilyl.

Further, as the protecting group for the carboxyl group,
Includes all groups that can be used as usual protecting groups for carboxyl groups, for example, methyl, ethyl, n-propyl, i
lower alkyl groups such as so-propyl, 1,1-dimethylpropyl, n-butyl and tert-butyl; aryl groups such as phenyl and naphthyl; benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl and bis Ar-lower alkyl groups such as (p-methoxyphenyl) methyl; acyl-lower alkyl groups such as acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl and p-methanesulfonylbenzoylmethyl; 2-tetrahydropyrani Oxygen-containing heterocyclic groups such as phenyl and 2-tetrahydrofuranyl; halogeno lower alkyl groups such as 2,2,2-trichloroethyl; lower alkylsilylalkyl groups such as 2- (trimethylsilyl) ethyl; acetoxymethyl;
Alkylcarbonyloxyalkyl groups such as propionyloxymethyl and pivaloyloxymethyl; nitrogen-containing heterocyclic-lower alkyl groups such as phthalimidomethyl and succinimidomethyl; cycloalkyl groups such as cyclohexyl; methoxymethyl, methoxyethoxymethyl and Lower alkoxy lower alkyl groups such as (trimethylsilyl) ethoxymethyl; al-lower alkoxy lower alkyl groups such as benzyloxymethyl; lower alkylthio lower alkyl groups such as methylthiomethyl and 2-methylthioethyl; arylthio lower alkyl groups such as phenylthiomethyl Lower alkenyl groups such as 1,1-dimethyl-2-propenyl, 3-methyl-3-butynyl and allyl, and trimethylsilyl, triethylsilyl, triiyl; Isopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and
and substituted silyl groups such as tert-butylmethoxyphenylsilyl.

Further, as the protecting group for the aldehyde group,
Including all groups that can be used as ordinary protecting groups for aldehyde groups, examples include dialkyl acetals such as dimethyl acetal and 5- or 6-membered cyclic acetals such as 1,3-dioxolan and 1,3-dioxane. Can be

Examples of the salt of the compound represented by the general formula [1] include commonly known salts of a basic group such as an amino group or an acidic group such as a carboxyl group. Salts in the basic group include, for example, salts with mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, oxalic acid, fumaric acid, maleic acid, citric acid and tartaric acid A salt with an organic carboxylic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid; and a salt with an acidic group such as sodium and potassium. Salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine , Dicyclohexylamine, dibe And salts with nitrogen-containing organic bases such as benzylamine, pyridine, guanidine, hydrazine and quinine. As a salt of the compound of the general formula [1], preferably, a pharmacologically used salt such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, oxalic acid, fumaric acid, maleic acid, citric acid, sulfonic acid and tartaric acid is used. Acceptable salts are included.

Among the compounds of the present invention, preferred compounds are those wherein A is a nitrile group, an optionally substituted alkenyl or heterocyclic group,

Embedded image"Where R^5aRepresents a hydrogen atom, an optionally substituted
Alkyl, aryl or heteroaryl groups or protection
Hydroxyl, carboxyl, amino
No, hydroxyamino, alkylamino, cyclic amino,
Arylamino, heteroarylamino or acyl
An amino group;^aIs an oxygen atom, a sulfur atom or NR
^6a  "Where R^6aIs a hydrogen atom, an optionally protected
Droxyl or amino group or substituted
Alkylamino, alkoxycarbonylamino, cyclic
Indicates an amino or acylamino group. "
You. Or

Embedded image "Wherein R ^5a ′ represents a hydrogen atom or an optionally substituted alkyl, aryl or heteroaryl group;
Y ^1a represents an alkoxy group, respectively. ".

Further preferred compounds include R ¹ and R
² and R ⁴ are the same or different and are a hydrogen atom, a halogen atom, a nitro group, a nitrile group, an optionally protected hydroxyl group or an optionally substituted alkyl,
A cycloalkyl, alkenyl, alkylene, alkoxy, alkylamino, acylamino or alkylthio group; A is a nitrile group, an optionally substituted alkenyl or heterocyclic group,

Embedded image"Where R^5bRepresents a hydrogen atom, an optionally substituted
Alkyl, aryl or heteroaryl groups or protection
Hydroxyl, carboxyl, amino
No, arylamino or heteroarylamino group
; Y^bIs an oxygen atom, a sulfur atom or NR^6b  "Where R^6bIs a hydrogen atom, an optionally protected
Droxyl or amino group or substituted
Alkylamino, cyclic amino or acylamino groups
Is shown. ] Respectively. Or

Embedded image "Wherein, R ^5b ′ represents a hydrogen atom or an optionally substituted alkyl, aryl or heteroaryl group;
Y ^1b represents an alkoxy group, respectively. ".

Still more preferred compounds include R³
Is optionally substituted aryl, heteroaryl,
Arylamino, heteroarylamino, aryloxy
Si, arylthio, arylsulfinyl, or ant
Rsulfonyl group; R¹, R ²And R⁴But the same
A hydrogen atom or a halogen atom;
Tolyl group, optionally substituted alkenyl or
A cyclic group,

Embedded image"Where R^5cRepresents a hydrogen atom, an optionally substituted
Alkyl, aryl or heteroaryl groups or protection
Hydroxyl, carboxyl or
Amino group; Y^cIs an oxygen atom or NR^6c  "Where R^6cIs a hydrogen atom, an optionally protected
Droxyl or amino group or substituted
A cyclic amino or acylamino group. "It
Shown respectively. Or

Embedded image In the formula, R ^5c ′ represents a hydrogen atom; and Y ^1c represents an alkoxy group, respectively.

Representative compounds among the compounds of the present invention include:
For example, the compounds described in Tables 1 to 10 below can be mentioned. In the table, Me represents a methyl group; Et represents an ethyl group;
iPr represents an isopropyl group; Ph represents a phenyl group.

[0019]

[Table 1]

[0020]

[Table 2]

[0021]

[Table 3]

[0022]

[Table 4]

[0023]

[Table 5]

[0024]

[Table 6]

[0025]

[Table 7]

[0026]

[Table 8]

[0027]

[Table 9]

[0028]

[Table 10]

[0029]

[Table 11]

When isomers (for example, optical isomers, geometric isomers, tautomers, etc.) are present in the compound of the general formula [1] or a salt thereof, the present invention relates to the isomers. As well as solvates, hydrates, and crystals of various shapes.

[0031]

[Production method] Next, the production method of the compound of the present invention will be described. The compound of the present invention is produced by a combination of methods known per se. For example, it can be synthesized by the following production method.

[0032]

(Equation 1) "Wherein R represents an alkyl group; R ¹ , R ² , R ³ ,
R ⁴ , R ⁵ and R ⁶ have the same meaning as described above. "

[0033]

(Equation 2)"Where R^5zIs an aryl or heteroaryl group
; R^6zIs a hydrogen atom or alkyl, aryl,
Heteroaryl group or-(Z)_p-R⁷  Wherein Z, p and R⁷Has the same meaning as above
Show. ]; R⁸Represents an optionally substituted alkyl or
Or a carboxyl group; R⁹Is an optionally substituted
Alkyl, aryl, heteroaryl or carboxyl
A group; Y²And Y³Are the same or different nitrogen sources
An oxygen atom or a sulfur atom; n is 0 or 1;
R, R¹, R², R³And R⁴Is similar to
Meaningful. "

[0034]

(Equation 3) Wherein X is a leaving group; R ¹ ′, R ² ′ and R ⁴ ′
Are the same or different and are a hydrogen atom, a nitro group, a nitrile group, an optionally protected hydroxyl group or an optionally substituted alkyl, cycloalkyl, alkenyl, alkylene, alkoxy, alkylamino, acylamino, aryl, heteroaryl An alkylthio, arylamino, heteroarylamino, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylsulfonyl or heteroarylsulfonyl group; R ¹ , R ² , R ³ , R ⁴ and R
⁵ has the same meaning as described above. "

Production Method 1 The compound of the general formula [1b] can be obtained by subjecting the compound of the general formula [1a] and the compound of the general formula [2] to a dehydration condensation reaction. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and Ethers such as dimethyl cellosolve; alcohols such as methyl alcohol and ethyl alcohol; nitriles such as acetonitrile; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; water; And these may be used as a mixture. The amount of the compound of the general formula [2] used in this reaction may be at least equimolar to the compound of the general formula [1a], and is preferably 1 to 5 moles. This reaction is usually carried out at room temperature to the boiling point of the solvent to be used for 10 minutes to 24 hours.

The compound of the general formula [1c] has the general formula [1c]
It can be produced by subjecting a compound of the formula b) wherein R ⁵ is a hydrogen atom and R ⁶ is a hydroxyl group to a dehydration reaction in the presence or absence of a dehydrating agent. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and Ethers such as dimethyl cellosolve; alcohols such as methyl alcohol and ethyl alcohol; nitriles such as acetonitrile; N, N
Amides such as -dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide, and the like, and these may be used as a mixture. Dehydrating agents desired as needed in this reaction include, for example, acetic anhydride, thionyl chloride, phosphate, titanium tetrachloride, phenyl isocyanate, sodium formate, sodium acetate, sodium hydroxide, and the like. The use amount thereof may be at least equimolar to the compound of the general formula [1b], and preferably 2 to 5 times. This reaction is usually carried out at room temperature to the boiling point of the solvent to be used for 10 minutes to 24 hours.

The compound of the general formula [1d] has the general formula [1d]
The compound [c] can be produced by treating the compound with hydrogen chloride-alcohol. Solvents used in this reaction include:
There is no particular limitation as long as it does not adversely affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; methylene chloride and Examples include halogenated hydrocarbons such as chloroform; and sulfoxides such as dimethyl sulfoxide. These may be used as a mixture. Examples of the alcohol used in this reaction include methyl alcohol and ethyl alcohol. The concentration of hydrogen chloride used in this reaction is
It may be 1 mol / L to saturation, and the amount used is at least equimolar to the compound of the general formula [1c], preferably,
What is necessary is just 2 moles or more. This reaction may be usually performed at room temperature for 1 to 5 days.

The compound of the general formula [1e] has the general formula [1e]
The solvent used in this reaction, which can be produced by reacting the compound of formula c) with an inorganic azide compound in the presence of a Lewis acid, is not particularly limited as long as it does not adversely affect the reaction. And aromatic hydrocarbons such as xylene; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; halogenated hydrocarbons such as methylene chloride and chloroform; and sulfoxides such as dimethyl sulfoxide. These may be used as a mixture. As the Lewis acid used in this reaction, any of the normally usable ones can be used, for example, aluminum chloride, boron trifluoride / ether complex salt, boron trichloride, boron tribromide, titanium tetrachloride, etc. And the amount of use is 1 mole or more, preferably 1 to 2 moles, per 1 mole of the compound of the general formula [1c]. Examples of the inorganic azide used in this reaction include lithium azide, sodium azide, potassium azide, and the like, and the amount of the azide is at least equimolar to the compound of the general formula [1c], preferably 3 to 10 What is necessary is just a double mole. This reaction is usually carried out at a temperature between room temperature and the boiling point of the solvent used.
It may be performed for 3 to 24 hours.

Production Method 1a The compound of the general formula [1f] and the compound of the general formula [1g] are subjected to a dehydration condensation reaction of the compound of the general formula [1a '] and the compound of the general formula [3] in the presence or absence of an acid. Can be obtained. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and Ethers such as dimethyl cellosolve; N,
Amides such as N-dimethylformamide and N, N-dimethylacetamide; alcohols such as methyl alcohol and ethyl alcohol; and sulfoxides such as dimethylsulfoxide. Good. The acids used in this reaction include all acids usually used, for example, mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid; methanesulfonic acid, benzenesulfonic acid and p- Examples thereof include sulfonic acids such as toluenesulfonic acid and sulfonic acid salts such as pyridinium / p-toluenesulfonic acid. The amount of the sulfonic acid is 0.05 to 5 times, preferably 5 to 5 times, the molar amount of the compound of the formula [1a ']. , 0.1-1
What is necessary is just a double mole. The amount of the compound of the general formula [3] used in this reaction may be 1 to 50 times, preferably 2 to 10 times the mol of the compound of the general formula [1a ']. This reaction may be carried out usually at room temperature to the boiling point of the solvent used for 30 minutes to 24 hours.

The compound of the general formula [1h] has the general formula [1h]
a ′] can be obtained by subjecting the compound to a Wittig reaction with various phosphoranes or an Emmons-Honer reaction with various phosphonates, or by reacting with malonic acid in the presence of a base. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and Ethers such as dimethyl cellosolve; halogenated hydrocarbons such as methylene chloride and chloroform; nitriles such as acetonitrile; N, N
Amides such as -dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide, and the like, and these may be used as a mixture. The amount of phosphorane or phosphonate used in this reaction is determined by the general formula [1]
a ′] with respect to the compound,
It may be up to 5 times mol. The amount of malonic acid to be used in this reaction may be at least equimolar, preferably at least 2 times the molar amount of the compound of the general formula [1a ']. Examples of the base used in this reaction include trialkylamines such as triethylamine and pyridine. The amount of the base used is at least equimolar, preferably at least 5 times the molar amount of the compound of the general formula [1a ']. All that is required is the above. This reaction is usually carried out at a temperature between room temperature and the boiling point of the solvent used.
It may be carried out for 30 minutes to 24 hours.

The compound of the general formula [1i] is
a ′] can be obtained by subjecting the compound to an oxidation reaction. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and Ethers such as dimethyl cellosolve; halogenated hydrocarbons such as methylene chloride and chloroform; nitriles such as acetonitrile; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; And water. These may be used as a mixture. Examples of the oxidizing agent used in this reaction include all oxidizing agents commonly used.
Chromic acid, hydrogen peroxide, organic peracid, silver oxide, chlorite, and the like are used.
May be at least equimolar, preferably 1 to 5 moles, per 1 mole of the compound. This reaction is usually carried out at 0 ° C to 50 ° C for 30 minutes.
It may be carried out for minutes to 6 hours.

The compound of the general formula [1j] can be obtained by subjecting the compound of the general formula [1i] and the compound of the general formula [2a] to a dehydration condensation reaction in the presence of a condensing agent. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and Ethers such as dimethyl cellosolve; halogenated hydrocarbons such as methylene chloride and chloroform; nitriles such as acetonitrile; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide. And the like, and these may be used as a mixture. Examples of the condensing agent used in this reaction include all commonly used condensing agents. For example, carbodiimides such as N, N-dicyclohexylcarbodiimide or N, N-diisopropylcarbodiimide, oxalyl chloride, thionyl chloride and 2 -Chloro-1,3-dimethylimidazolinium chloride and the like, and the amount of use thereof may be at least equimolar to the compound of the general formula [1i], preferably 1 to 5 moles. As the compound of the general formula [2a] used in this reaction, a resin obtained by condensing one or two amino acids used for solid-phase synthesis of an amino compound or a peptide can be used.
It may be at least equimolar, preferably 1 to 5 moles, per mole of the compound of the general formula [1i]. This reaction is usually 0
The reaction may be carried out for 30 minutes to 24 hours at a temperature of from ° C to the boiling point of the solvent used.

The compound of the general formula [1k] has the general formula [1k]
After reacting the compound of formula [i] with an activator,
a) and a coupling reaction in the presence of a palladium catalyst. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and Ethers such as dimethyl cellosolve; and halogenated hydrocarbons such as methylene chloride and chloroform, and the like, and these may be used as a mixture. The activator used in this reaction includes thionyl chloride, oxalyl chloride, and the like.
1 to 20 moles, preferably 1 to 20 moles, based on the compound of i)
It only has to be 5 times mol. This reaction may be carried out usually at 0 ° C. to the boiling point of the solvent used for 30 minutes to 10 hours. The solvent used in the subsequent coupling reaction is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, and diethylene glycol diethyl. Ethers such as ether and dimethyl cellosolve; nitriles such as acetonitrile; halogenated hydrocarbons such as methylene chloride and chloroform; amides such as N, N-dimethylformamide and N, N-dimethylacetamide;
And sulfoxides such as dimethyl sulfoxide. These may be used as a mixture. Examples of the palladium catalyst used in this reaction include palladium-activated carbon, metal palladium such as palladium black; inorganic palladium salts such as palladium chloride;
Organic palladium salts such as palladium acetate; tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, bis
Organic palladium complexes such as (tricyclohexylphosphine) palladium (II) chloride and 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride are exemplified. The amount of the palladium catalyst used is determined by the general formula [1i]
It may be 0.00001 times or more moles of the compound of
Preferably, it may be 0.001 to 0.05 times mol. The amount of the organotin compound represented by the general formula [4a] is determined by the general formula [1i]
It is sufficient that it is at least equimolar to the compound of the formula (1), and preferably 1.0 to 2.0 times. This coupling reaction is
Usually, it may be carried out at 50 to 170 ° C. for 1 minute to 24 hours under an atmosphere of an inert gas (for example, argon and nitrogen).

Production Method 2 The compound of the general formula [1a] can be obtained by reacting the compound of the general formula [5] with phosphorus oxychloride in N, N-dimethylformamide. In this reaction, usually, after dropping phosphorus oxychloride at −20 ° C. or lower, the temperature is gradually raised to 50 ° C., and thereafter, 10 minutes to 24 hours, preferably 1 to 5 hours.
It may be carried out for a time. The amount of phosphorus oxychloride used in this reaction is at least equimolar, preferably 3 to 5 moles, per mole of the compound of the general formula [5].

The compound of the general formula [1a] can be obtained by subjecting the compound of the general formula [6] to a coupling reaction using a compound of the general formula [4] with a palladium catalyst. The solvent used in this coupling reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, and diethylene glycol diethyl. Ethers such as ether and dimethyl cellosolve;
Nitriles such as acetonitrile; halogenated hydrocarbons such as methylene chloride and chloroform; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethylsulfoxide. These may be used as a mixture. Examples of the palladium catalyst used in this reaction include palladium-active carbon, metal palladium such as palladium black; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium acetate; tetrakis (triphenylphosphine) palladium (0 ), Bis (triphenylphosphine) palladium (II)
And organic palladium complexes such as chloride, bis (tricyclohexylphosphine) palladium (II) chloride, and 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride. The amount of the palladium catalyst used may be 0.00001 times or more, and preferably 0.001 to 0.05 times, the molar amount of the compound of the general formula [6]. The amount of the organotin compound represented by the general formula [4] is:
It may be at least equimolar to the compound of the general formula [6], preferably 1.0 to 2.0 times. This reaction may be carried out usually at 50 to 170 ° C. for 1 minute to 24 hours under an inert gas (eg, argon and nitrogen) atmosphere.

The compound of the general formula [1a]
To a formic acid derivative in the presence of an acid or a base. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and Ethers such as dimethyl cellosolve; nitriles such as acetonitrile; halogenated hydrocarbons such as methylene chloride and chloroform; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide. And the like,
These may be used as a mixture. Formic acid derivatives used in this reaction include: acetal such as N, N-dimethylformamide dimethyl acetal; formate;
Orthoformates and chloroformates are used, and the amount of use thereof may be at least equimolar to the compound of the general formula [7], and preferably 1 to 10 moles. Good. Acids used in this reaction include all acids commonly used, for example, mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid; methanesulfonic acid, benzenesulfonic acid and p-toluene Examples thereof include sulfonic acids such as sulfonic acids and sulfonic acid salts such as pyridinium / p-toluenesulfonic acid, and the amount of the acid used may be 0.1 times or more mol of the compound of the general formula [7]. Preferably, it may be 0.1 to 1 mole. The base used in this reaction includes all commonly used bases, and includes, for example, sodium carbonate, potassium carbonate, sodium hydride and metal alkoxides such as sodium methoxide and potassium t-butoxide. The amount of the base used is determined by the general formula [7]
It is sufficient that it is at least equimolar to the compound of the formula (1), and preferably 2 to 5 times. This reaction may be carried out usually at a temperature between room temperature and the boiling point of the solvent used for 1 to 24 hours.

[0047]

(Equation 4) "Wherein R, R ¹ , R ¹ ′, R ² , R ² ′, R ³ , R ⁴ ,
R ⁴ ′, X and A have the same meaning as described above. "

[0048]

(Equation 5) Wherein R, R ¹ ′, R ² ′, R ³ , R ⁴ ′, X and A
Has the same meaning as described above. "

Production Method 3 The compound of the general formula [11] can be obtained by reacting the compound of the general formula [8] with a formic acid derivative in the presence of an acid or a base. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and Ethers such as dimethyl cellosolve; nitriles such as acetonitrile; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethylsulfoxide. May be used. The formic acid derivative used in this reaction is:
Acetals such as N, N-dimethylformamide dimethyl acetal; formate esters; orthoformate esters and chloroformate esters; the amount of the formic acid derivative used is based on the compound of the general formula [8]. It is sufficient that it is at least equimolar, and preferably 1 to 10 times.
Acids used in this reaction include all acids that can be used normally, for example, mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid; methanesulfonic acid,
Examples thereof include sulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid, and sulfonic acid salts such as pyridinium / p-toluenesulfonic acid. It is sufficient if it is at least mol, and preferably from 0.1 to equimolar. The base used in this reaction includes all bases that can be generally used, and examples thereof include sodium carbonate, potassium carbonate, sodium hydride and metal alkoxides such as sodium methoxide and potassium t-butoxide. The amount of the base used may be at least equimolar to the compound of the general formula [8], and is preferably 2 to 5 moles. This reaction may be carried out usually at room temperature to the boiling point of the solvent used for 1 to 24 hours.

The compound of the general formula [1l] is obtained by a coupling reaction between the compound of the general formula [9] and the compound of the general formula [4] using a palladium catalyst in the presence or absence of silver oxide. Obtainable. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; dioxane,
Ethers such as tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; nitriles such as acetonitrile; halogenated hydrocarbons such as methylene chloride and chloroform;
Examples include amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethylsulfoxide. These may be used as a mixture. Examples of the palladium catalyst used in this reaction include palladium-active carbon, metal palladium such as palladium black; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium acetate; tetrakis (triphenylphosphine)
Organic palladium such as palladium (0), bis (triphenylphosphine) palladium (II) chloride, bis (tricyclohexylphosphine) palladium (II) chloride, 1,1′-bis (diphenylphosphino) ferrocene palladium (II) chloride Complexes. The amount of the palladium catalyst to be used may be 0.00001 times mol or more, preferably 0.001 to 0.05 times mol, of the compound of the general formula [9]. When silver oxide is used in this reaction, the amount of the silver oxide used may be at least equimolar to the compound of the general formula [9], preferably 1 to 10 times the molar amount. This coupling reaction is usually carried out under an atmosphere of an inert gas (for example, argon and nitrogen).
It may be carried out at ~ 170 ° C for 1 minute to 24 hours.

Production Method 4 The compound of the general formula [11] can be obtained by subjecting a compound of the general formula [10] and a compound of the general formula [11] to a coupling reaction in the presence of a palladium catalyst. The solvent used in this coupling reaction is not particularly limited as long as it does not adversely affect the reaction.
For example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; nitriles such as acetonitrile; halogenated hydrocarbons such as methylene chloride and chloroform; Examples include amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethylsulfoxide. These may be used as a mixture. Examples of the palladium catalyst used in this reaction include palladium-active carbon, metal palladium such as palladium black; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium acetate; tetrakis (triphenylphosphine) palladium (0) ,Screw
Organic palladium complexes such as (triphenylphosphine) palladium (II) chloride, bis (tricyclohexylphosphine) palladium (II) chloride, and 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride. The amount of the palladium catalyst used is represented by the general formula [1]
0] or more, and preferably 0.001 to 0.05 times the mol of the compound of formula [0]. The amount of the organotin compound represented by the general formula [11] is determined by the general formula [10]
It is sufficient that it is at least equimolar to the compound of the formula (1), and preferably 1.0 to 2.0 times. This coupling reaction is
Usually, it may be carried out at 50 to 170 ° C. for 1 minute to 24 hours under an atmosphere of an inert gas (for example, argon and nitrogen). Further, the compound of the general formula [11] has the general formula [1]
2] and a compound of the general formula [13] can be obtained by subjecting the compound to a coupling reaction in the presence of a palladium catalyst. The solvent used in this coupling reaction is not particularly limited as long as it does not adversely affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl Ethers such as ether and dimethyl cellosolve; nitriles such as acetonitrile; halogenated hydrocarbons such as methylene chloride and chloroform;
Amides such as -dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide, and the like, and these may be used as a mixture. Examples of the palladium catalyst used in this reaction include palladium-active carbon, metal palladium such as palladium black; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium acetate; tetrakis (triphenylphosphine)
Organic palladium such as palladium (0), bis (triphenylphosphine) palladium (II) chloride, bis (tricyclohexylphosphine) palladium (II) chloride, 1,1′-bis (diphenylphosphino) ferrocene palladium (II) chloride Complexes. The amount of the palladium catalyst used is 0.00001 with respect to the compound of the general formula [12].
It is sufficient if it is at least twice the molar amount, and preferably 0.001 to 0.05 times the molar amount. The amount of the compound of the general formula [13] to be used may be at least equimolar to the compound of the general formula [12], and is preferably 1.0 to 2.0 moles. This coupling reaction is usually performed under an inert gas (eg, argon and nitrogen) atmosphere at 50 to 170 ° C. for 1 minute to 24 hours.
It may be carried out for a time.

In each of the production methods described above, each compound can be used in the form of a salt thereof. Examples of the salt include those similar to those described as the salt of the compound of the general formula [1]. Can be The thus obtained compound of the general formula [1] or a salt thereof is subjected to a reaction known per se such as, for example, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis, or The compound of the general formula [1] or a salt thereof can be derived by appropriately combining these reactions.

The general formula [2] shown in production methods 1 to 4,
As the compounds of [2a], [3] and [12], those known per se were used. In addition, general formulas [4], [4a],
The compounds of [5], [6], [7], [8], [9], [10] and [11] are known per se or produced by a combination of per se known methods, For example, it can be synthesized by the following production method.

[0054]

(Equation 6) "Wherein R, R ³ and X have the same meaning as described above."

Production Method A The compound of the general formula [4] can also be obtained by subjecting the compound of the general formula [14] to a coupling reaction of a bis (trialkyltin) with a palladium catalyst. The solvent used in this coupling reaction is not particularly limited as long as it does not adversely affect the reaction.
For example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; nitriles such as acetonitrile; halogenated hydrocarbons such as methylene chloride and chloroform; Examples include amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethylsulfoxide. These may be used as a mixture. Examples of the palladium catalyst used in this reaction include palladium-active carbon, metal palladium such as palladium black; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium acetate; tetrakis (triphenylphosphine) palladium (0) ,Screw
Organic palladium complexes such as (triphenylphosphine) palladium (II) chloride, bis (tricyclohexylphosphine) palladium (II) chloride, and 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride. The amount of the palladium catalyst used is represented by the general formula [1]
It may be at least 0.00001 times mol, preferably 0.001 to 0.05 times mol, of the compound of 4). The bis (trialkyltin) used in this reaction includes
For example, bis (tributyltin) and the like can be mentioned, and the amount of the compound used may be at least equimolar to the compound of the general formula [14], preferably 1.0 to 2.0 times. This reaction is usually carried out under an inert gas (eg,
50-170 under an atmosphere including argon and nitrogen)
C. for 1 minute to 24 hours.

Compounds of general formulas [4a] and [11] can be obtained in the same manner as in production method A.

[0057]

Equation 7 "Wherein R ¹⁰ represents a hydrogen atom or a protecting group; R ¹ , R
² , R ⁴ and X have the same meaning as described above. "

Production Method B The compound of the general formula [16] can be obtained by subjecting a known phenol derivative represented by the general formula [15] to Fries transfer or Friedel-Crafts acylation reaction. Among these, the Fries transfer reaction can be performed by reacting an acetate derivative represented by the general formula [15] in the presence of a Lewis acid. The Lewis acid used in this reaction includes all Lewis acids that can be generally used, and examples thereof include aluminum chloride and titanium tetrachloride.
1] to 5 times that of the compound of [5]. This reaction may be carried out without solvent at 50 to 150 ° C. for 10 minutes to 2 hours. The Friedel-Crafts acylation reaction can be performed by reacting an anisole derivative represented by the general formula [15] with an acetic acid derivative in the presence of a Lewis acid. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include halogenated hydrocarbons such as methylene chloride and chloroform; nitrobenzene and carbon disulfide; These may be used as a mixture. The Lewis acid used in this reaction includes all commonly used Lewis acids, and examples thereof include aluminum chloride and titanium tetrachloride. , 1 to 20 times mol, preferably 1 to 5 times mol. The acetic acid derivative used in this reaction includes, for example, acetyl chloride and acetic anhydride. What is necessary is just a double mole. The reaction is carried out between 0 ° C. and the boiling point of the solvent used,
It may be carried out for up to 12 hours.

The compound represented by the general formula [5]
Can be obtained by subjecting a compound of the formula (1) to a substitution reaction with an amine, alcohol or thiol corresponding to R ³ in the presence of a base. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran,
Ethers such as anisole, diethylene glycol diethyl ether and dimethyl cellosolve; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethylsulfoxide. May be used. The amine, alcohol and thiol corresponding to R ³ used in this reaction include all alkyl thiols, arylamines, heteroarylamines, arylols, heteroarylols, which can be produced by a method known per se or a combination of methods known per se.
It contains an arylthiol and a heteroarylthiol, and the amount of use thereof may be at least equimolar to the compound of the general formula [16], preferably 2 to 5 times the molar amount. The base used in this reaction includes all commonly used bases, and includes, for example, sodium carbonate, potassium carbonate, sodium hydride and metal alkoxides such as sodium methoxide and potassium t-butoxide. The amount of the base used may be at least equimolar to the compound of the general formula [16], and is preferably 2 to 5 moles. This reaction may be carried out usually at room temperature to the boiling point of the solvent used for 1 to 24 hours.

[0060]

(Equation 8)"In the formula, R" represents a hydrogen atom or an alkyl group;
R¹, R², R³, R⁴, R ⁵, A and X are as described above.
Has the same meaning as "

Production Method C The compound of the general formula [7] can be obtained by reacting the compound of the general formula [5] with the compound of the general formula [17] in the presence of a base. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, and diethylene glycol diethyl ether. And ethers such as dimethyl cellosolve; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethylsulfoxide. Good. As the compound of the general formula [17] used in this reaction, acid halides which can be produced by a method known per se or a method known per se,
Examples thereof include acid anhydrides and esters, and the amount thereof is 1 to 50 moles, preferably 2 to 10 moles, based on the compound of the formula [5]. The base used in this reaction includes all bases that can be generally used, and examples thereof include sodium carbonate, potassium carbonate, sodium hydride and metal alkoxides such as sodium methoxide and potassium t-butoxide. , The amount of use thereof, relative to the compound of the general formula [5]
It is 1 to 10 moles, preferably 2 to 5 moles. The reaction is usually carried out between room temperature and the boiling point of the solvent used, from 1 to 24.
It may be carried out for a time.

The compound of the general formula [8] can be obtained by reacting the compound of the general formula [5] with the compound of the general formula [13] in the presence of a base. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and Ethers such as dimethyl cellosolve; N, N-dimethylformamide and N, N;
Examples thereof include amides such as N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide. These may be used as a mixture. Examples of the compound of the general formula [13] used in this reaction include halide, tosylate, mesylate and triflate which can be produced by a method known per se or a combination of methods known per se, and the amount of the compound represented by the general formula [5] Is 1 to 50 times, preferably 2 to 10 times the mole of the compound of formula (I). The base used in this reaction includes all bases that can be generally used, and examples thereof include sodium carbonate, potassium carbonate, sodium hydride and metal alkoxides such as sodium methoxide and potassium t-butoxide. And the amount thereof is 1 to 10 moles, preferably 2 moles per mole of the compound of the formula [5].
~ 5 times mol. This reaction is usually carried out at a temperature between room temperature and the boiling point of the solvent used, for 1 to 24 hours.

[0063]

[Equation 9] Wherein R ¹ , R ² , R ⁴ , R ⁵ , R ¹⁰ , A and X
Has the same meaning as described above. "

Production Method D The compounds of the general formulas [6] and [9] are converted to compounds of the general formula [16]
Can be obtained from the compound of the general formula [5] shown in the production method 2 according to the production method of obtaining the compound of the general formula [1a].

[0065]

(Equation 10) “Wherein R ¹ , R ² , R ³ , R ⁴ and R have the same meaning as described above.”

Production Method E The compound of the general formula [10] can be obtained by treating the compound of the general formula [5] with N, N-dimethylformamide dimethyl acetal and then reacting with iodine. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and Ethers such as dimethyl cellosolve; halogenated hydrocarbons such as methylene chloride and chloroform; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide. These may be used as a mixture. N, N- used in this reaction
The amount of dimethylformamide dimethyl acetal used is
It may be at least equimolar to the compound of the general formula [5], and preferably 1 to 2 moles. The amount of iodine used in this reaction is equimolar to the compound of the general formula [5]. This reaction may be carried out usually at a temperature between room temperature and the boiling point of the solvent used for 1 to 24 hours.

The compound represented by the general formula [12]
0] to the same coupling reaction as in production method A.

As the compound in the above-mentioned production method, a salt thereof can also be used, and examples of the salt include the same salts as described in the general formula [1]. Further, in the compound in the above-mentioned production method, isomers (for example,
When optical isomers, geometric isomers and tautomers are present, these isomers can also be used, and solvates, hydrates and crystals of various shapes can also be used. it can.

Among the compounds in the above-mentioned production method, those having an amino group, a cyclic amino group, a hydroxyl group, an aldehyde group or a carboxyl group may be protected by a conventional protecting group in advance, These protecting groups can be eliminated by a method known per se.

When the compound of the present invention is used as a medicament, formulation aids such as excipients, carriers and diluents which are usually used for formulation may be appropriately mixed. Preparations, powders, syrups, granules, pills, suspensions, emulsions, solutions, powders, suppositories, eye drops, nasal drops, ear drops, patches, ointments, injections, etc. Can be administered orally or parenterally. In addition, the administration method, dosage and number of administration can be appropriately selected according to the age, weight, and condition of the patient.Generally, for adults, oral or parenteral (e.g., injection, infusion and administration to rectal site) Administration, etc.)
It is sufficient to administer ~ 500 mg / kg once to several times.

Next, the pharmacological action of the representative compound of the present invention will be described.

Antifungal activity [Test method] Antifungal susceptibility test method proposed by the Japanese Society for Medical Mycology Antifungal Susceptibility Testing Subcommittee (Japanese Journal
of Medical Mycology, Vol. 36, No. 1, pp. 62-64, 19
(1995), the 75% growth inhibitory concentration (IC ₇₅ ) was measured by a microfluidic dilution method. The sensitivity measurement medium contains 2% glucose-added 0.67% yeast nitrogen base (YNB:
Difco). Sabouraud agar plate medium (Eiken Chemical)
Then, Candida albicans TIMM 1623 and Cryptococcus neoformans TIMM 0354 cultured overnight at 30 ° C. were suspended in sterile physiological saline, and then diluted with a measurement medium to 1 × 10 ⁵ cells / mL to obtain an inoculum. Aspergillus fumigatus TIMM 0
After culturing 063 in potato dextrose agar (Nissui Pharmaceutical) slant at 30 ° C. for 10 days, conidia were scraped into sterile physiological saline containing 0.05% Tween 80 (manufactured by Difco), and 1 × 10 ⁵ cells / mL
To obtain an inoculated conidia solution. 96
Medium 175 in a well microplate (flat bottom: Corning)
μL, 5 μL of test drug (drug dilution solvent for growth control well), 20 μL of bacterial solution, pulverize with a mixer, and measure initial turbidity at 630 nm wavelength using well reader SME3400 (manufactured by Cynics Corporation) did. After culturing at 35 ° C, one day after C. albicans TIMM 1623, A. fumigatus T
For IMM 0063 and C. neoformans TIMM 0354, the terminal turbidity was measured similarly after 3 days. In the dilution series of the drug, of the values obtained by subtracting the initial turbidity from the terminal turbidity, 25% of the value obtained by subtracting the initial turbidity from the terminal turbidity of the growth control (IC ₇₅
The value of the lowest drug concentration of IC ₇₅ in test drug concentrations showing a calculation value) equal to or less turbidity. For each strain
The results of the IC ₇₅ values are shown in Table 12.

[0073]

[Table 12] ―――――――――――――――――――――――――――― Example No. A.fumigatus C.albicans C.neoformans ―――――― ――――――――――――――――――――― 1 5 2.5 0.313 1 (5) 5 0.625 0.156 2 5 1.25 0.156 3 2.5 10 0.313 4 0.625 1.25 1.25 4 (2) 0.156 2.5 2.5 6 0.625 0.313 ≦ 0.078 6 (5) 0.625 0.625 ≦ 0.078 6 (7) 5 1.25 0.625 10 10 2.5 0.156 ――――――――――――――――――――――――― ―――

[0074]

EXAMPLES Next, the present invention will be described with reference to Reference Examples and Examples, but the present invention is not limited thereto. Unless otherwise specified, anhydrous magnesium sulfate was used for drying the solvent extract, and a rotary evaporator was used for distilling off the solvent. The mixing ratios in the eluents were all volume ratios, and BW silica gel and BW-127ZH (manufactured by Fuji Silysia Chemical Ltd.) were used as carriers in column chromatography.

Reference Example 1 (1) 31.0 g of 3-fluorophenol, 150 m of acetic anhydride
Heat a mixture of L, 15 mL of pyridine at reflux for 1 hour. The reaction mixture was returned to room temperature, the solvent was distilled off under reduced pressure, and the obtained residue was heated to an external bath at 140 ° C, and then 73.7 g of aluminum chloride was added.
And stir for 15 minutes. The reaction mixture is added to ice water, extracted with ethyl acetate, and the obtained organic layer is washed successively with water and saturated saline. The obtained organic layer is dried, and the solvent is distilled off under reduced pressure. The obtained residue is subjected to silica gel chromatography [eluent; hexane: ethyl acetate = 5:
1] to give 22.2 g of colorless oily 4-fluoro-2-hydroxyacetophenone. (2) The obtained 4-fluoro-2-hydroxyacetophenone is dissolved in 100 mL of N, N-dimethylformamide, 20.3 mL of dimethyl sulfate and 29.7 g of potassium carbonate are added, and the mixture is stirred at room temperature for 1 hour. To the reaction mixture is added 10% aqueous hydrochloric acid to adjust the pH to 2 or less, followed by extraction with ethyl acetate. The obtained organic layer is sequentially washed with water and saturated saline, dried, and the solvent is distilled off. The obtained residue is purified by silica gel chromatography [eluent; hexane: ethyl acetate = 9: 1] to obtain 20.2 g of colorless oily 4-fluoro-2-methoxyacetophenone. (3) Dissolve 8.9 g of phenol in 40 mL of N, N-dimethylformamide, add 3.8 g of sodium hydride under ice cooling, and stir at room temperature for 30 minutes. Under ice-cooling, add 4-
8.0 g of fluoro-2-methoxyacetophenone N, N-
A 40 ml solution of dimethylformamide is added dropwise, and the mixture is heated and stirred at 100 ° C. for 2 hours. The reaction mixture is returned to room temperature, diluted with ethyl acetate, and washed successively with water and saturated saline. The obtained organic layer is dried, and the solvent is distilled off under reduced pressure. The obtained residue is purified by silica gel chromatography [eluent: hexane: ethyl acetate = 9: 1] to obtain 8.2 g of 2-methoxy-4-phenoxyacetophenone as a colorless oil. (4) 2-methoxy-4-phenoxyacetophenone
Dissolve 7.1 g in 70 mL of methylene chloride, add aluminum chloride
Add 7.9 g and stir at room temperature for 3 hours. The reaction mixture is added to ice water, extracted with chloroform, and the organic layer is washed successively with water and saturated saline. The obtained organic layer is dried, and the solvent is distilled off under reduced pressure. The obtained residue is purified by silica gel chromatography [eluent: hexane: ethyl acetate = 5: 1] to obtain 5.0 g of colorless crystals of 2-hydroxy-4-phenoxyacetophenone. ¹ H-NMR (CDCl ₃ ) δ value: 2.57 (3H, s), 6.4-6.6 (2H, m), 7.0
-7.7 (6H, m), 12.60 (1H, s)

The following compounds of Reference Examples 1 (2) and 1 (3) are obtained in the same manner as in Reference Example 1. 1 (2) 2-hydroxy-4- (phenylsulfanyl)
Acetophenone ¹ H-NMR (CDCl ₃ ) δ value: 2.55 (3H, s), 6.6-6.7 (2H, m), 7.3
-7.7 (6H, m), 12.40 (1H, s) 1 (3) 4-bromo-2-hydroxyacetophenone ¹ H-NMR (CDCl ₃ ) δ value: 2.59 (3H, s), 7.0-7.2 (2H, m), 7.5
6 (1H, d, J = 8.5Hz), 12.33 (1H, s)

REFERENCE EXAMPLE 2 (1) 4.43 g of 3,4-difluoroanisole and 2.29 mL of acetyl chloride were dissolved in 50 mL of methylene chloride, and 4.30 g of aluminum chloride was added with stirring under ice-cooling.
Stir for minutes. The reaction mixture is returned to room temperature, and after 3 hours, 4.30 g of aluminum chloride is added and stirred for 17 hours. The reaction mixture is poured into ice water, the organic layer is separated and washed with water. After drying the obtained organic layer, the solvent is distilled off to obtain 5.08 g of 4,5-difluoro-2-hydroxyacetophenone. (2) In the same manner as in Reference Example 1, 5.05 g of the obtained 4,5-difluoro-2-hydroxyacetophenone was obtained to obtain 5.15 g of 5-fluoro-2-hydroxy-4- (phenylsulfanyl) acetophenone as a pale yellow oil. . _{^{1 H-NMR (CDCl 3)}} δ value: 2.56 (3H, s), 6.32 (1H, d, J = 6.6H
z), 7.3-7.7 (6H, m), 12.10 (1H, s)

In the same manner as in Reference Example 2, the following compounds of Reference Examples 2 (2) and 2 (3) are obtained. 2 (2) 5-Fluoro-2-hydroxy-4-phenoxyacetophenone ¹ H-NMR (CDCl ₃ ) δ value: 2.57 (3H, s), 6.36 (1H, d, J = 7.1H)
z), 7.1-7.6 (6H, m ), 12.35 (1H, s) 2 (3) 5- fluoro-2-hydroxy-4- (phenylsulfonyl) acetophenone _{^{1 H-NMR (CDCl 3)}} δ value: 2.61 ( 3H, s), 7.2-8.1 (7H, m), 11.
94 (1H, s)

Reference Example 3 (1) To a solution of 1.0 g of bromobenzene in 10 mL of toluene were added 1.6 mL of bis (tributyltin) and 80 mg of dichlorobis (triphenylphosphine) -palladium (II), and the mixture was heated under reflux for 2 hours. The reaction mixture is returned to room temperature, and the solvent is distilled off under reduced pressure. The obtained residue is purified by silica gel chromatography [eluent: hexane] to obtain 0.8 g of colorless oily tributyl (phenyl) tin.

In the same manner as in Reference Example 3, the following Reference Examples 3 (2) to
3 (9) is obtained. 3 (2) Tributyl (4-ethoxycarbonylphenyl)
Tin 3 (3) Tributyl (2-naphthyl) tin 3 (4) Tributyl (1-naphthyl) tin 3 (5) Tributyl (3-pyridyl) tin 3 (6) Tributyl (3-thienyl) tin 3 (7) Tributyl (3-quinolinyl) tin 3 (8) 7-phenoxy-3- (tributylstannyl)-
4H-chromen-4-one 3 (9) N, 2,2-trimethyl-N- [3-methyl-5
-(Tributylstannyl) -2-pyridinyl] propionamide

Reference Example 4 (1) 0.46 g of 2-hydroxy-4-phenoxyacetophenone was dissolved in 5 mL of toluene, 0.32 g of sodium hydride and 0.85 mL of ethyl nicotinate were added at room temperature, and the mixture was heated under reflux for 20 minutes. After cooling, water and hydrochloric acid are added to the reaction mixture to make it neutral, and ethyl acetate and dry ice are sequentially added to adjust the pH to 6, and then the organic layer is separated. The obtained organic layer is washed successively with water and saturated saline, dried, and the solvent is distilled off under reduced pressure. The obtained residue is purified by silica gel column chromatography [eluent; n-hexane: ethyl acetate = 10: 1] to give 1- (2-hydroxy-4-phenoxyphenyl) -3- (3-pyridinyl)-. 0.45 g of 1,3-propanedione is obtained. ¹ H-NMR (CDCl ₃ ) δ value: 6.44 (1 H, d, J = 2.4 Hz), 6.58 (1 H, d
d, J = 2.4,8.8Hz), 6.74 (1H, s), 7.0-7.5 (6H, m), 7.73 (1
H, d, J = 8.8Hz), 8.1-8.3 (1H, m), 8.7-8.8 (1H, m), 9.12 (1
(H, d, J = 2.2Hz), 12.31 (1H, s)

In the same manner as in Reference Example 4, the following Reference Examples 4 (2) to
The compound of 4 (11) is obtained. 4 (2) 1- (2-hydroxy-4-phenoxyphenyl) -1,3-butanedione 4 (3) 1- (2-hydroxy-4-phenoxyphenyl) -1,3-pentanedione 4 (4) 1 -(2-hydroxy-4-phenoxyphenyl) -4-methyl-1,3-pentanedione 4 (5) 1- (6-fluoro-2-hydroxy-4-phenoxyphenyl) -1,3-butanedione 4 ( 6) 1- (2-hydroxy-4-phenoxyphenyl)
-4,4-difluoro-1,3-butanedione 4 (7) 1- [2-hydroxy-4- (phenylsulfanyl) phenyl] -1,3-butanedione 4 (8) ethyl 6- (2-hydroxy-4 -Phenoxyphenyl) -4,6-dioxohexanoate 4 (9) ethyl 4- (2-hydroxy-4-phenoxyphenyl) -2,4-dioxobutanoate 4 (10) 1- [2- Hydroxy-4- (phenylsulfanyl) phenyl] -3- (3-pyridinyl) -1,3-
Propanedione 4 (11) 1- (2-hydroxy-4-phenoxyphenyl) -3-phenyl-1,3-propanedione 4 (12) 1- (5-Fluoro-2-hydroxy-4-phenoxyphenyl)- 3- (2-fluorophenyl)-
1,3-propanedione

Reference Example 5 (1) To a solution of 0.65 g of 2-hydroxy-4-phenoxyacetophenone in 5 mL of xylene was added 0.42 mL of N, N-dimethylformaldehyde dimethylacetal, and the mixture was added at 130 ° C.
Heat and stir for hours. The reaction mixture is returned to room temperature, diluted with ethyl acetate, and washed successively with water and saturated saline. The obtained organic layer is dried, and the solvent is distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography [eluent: hexane: ethyl acetate = 5: 1] to give a colorless oily 3- (dimethylamino) -1- (2-hydroxy-4-).
0.67 g of (phenoxyphenyl) -2-propen-1-one are obtained. (2) The obtained 3- (dimethylamino) -1- (2-
0.53 g of (hydroxy-4-phenoxyphenyl) -2-propen-1-one was dissolved in 5 mL of chloroform, and iodine was dissolved.
Add 0.71 g and stir at room temperature for 2 hours. The reaction mixture is diluted with ethyl acetate and washed successively with water and saturated saline.
The obtained organic layer is dried, and the solvent is distilled off under reduced pressure.
The obtained residue is purified by silica gel chromatography [eluent: hexane: ethyl acetate = 5: 1] to give 0.58 g of 3-iodo-7-phenoxy-4H-chromen-4-one as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ value: 6.44 (1 H, d, J = 2.4 Hz), 6.58 (1 H, d
d, J = 2.4,8.8Hz), 6.74 (1H, s), 7.0-7.5 (6H, m), 7.73 (1
H, d, J = 8.8Hz), 8.1-8.3 (1H, m), 8.7-8.8 (1H, m), 9.12 (1
(H, d, J = 2.2Hz), 12.31 (1H, s)

Reference Example 6 (1) 4-bromo-2-hydroxyacetophenone 2
To a solution of 2.2 g of N, N-dimethylformamide in 220 mL is added dropwise 38.5 mL of phosphorus oxychloride at -15 ° C. Heat to 50 ° C. over 1 hour and heat and stir at 50 ° C. for 1 hour. The reaction mixture was returned to room temperature, added to ice water, and the deposited precipitate was collected by filtration and dried to give a pale yellow solid, 7-bromo-4.
-Oxo-4H-chromene-3-carbaldehyde 20.2 g are obtained. ¹ H-NMR (DMSO-d ₆ ) δ value: 7.8-8.1 (3H, m), 8.92 (1H, s), 1
0.10 (1H, s)

Reference Example 7 The following compounds were obtained in the same manner as in Reference Example 1. 2-hydroxy-4- (4-methoxyphenoxy) acetophenone

Reference Example 8 The following compound was obtained in the same manner as in Reference Example 2. 2-hydroxy-5-nitro-4-phenoxyacetophenone

Reference Example 9 The following compounds of Reference Examples 9 (1) to 9 (3) were obtained in the same manner as in Reference Example 3. 9 (1) tributyl (3-formylaminophenyl) tin 9 (2) tributyl [(1R) -2- (2,2-dimethylpropanoyl) -1-methyl-2,3-dihydro-1H
-Isoindol-5-yl] tin 9 (3) tributyl (5-pyrimidinyl) tin

Reference Example 10 In the same manner as in Reference Example 4, the following compounds of Reference Examples 10 (1) to 10 (8) are obtained. 10 (1) 1- (2-hydroxy-4-phenoxyphenyl) -3- (4-pyridinyl) -1,3-propanedione 10 (2) 1- (2-hydroxy-4-phenoxyphenyl) -3- (2-pyridinyl) -1,3-propanedione 10 (3) 1- (2-hydroxy-4-phenoxyphenyl) -3- (6-methyl-3-pyridinyl) -1,3-
Propanedione 10 (4) 1- (2-hydroxy-4-phenoxyphenyl) -3- (2-methyl-3-pyridinyl) -1,3-
Propanedione 10 (5) 1- [2-hydroxy-4- (4-methoxyphenoxy)]-1,3-butanedione 10 (6) 3-cyclopropyl-1- (2-hydroxy-
4-phenoxyphenyl) -1,3-propanedione 10 (7) 3- (3-dimethylaminophenyl) -1-
(2-hydroxy-4-phenoxyphenyl) -1,3
-Propanedione 10 (8) 1- (2-hydroxy-5-nitro-4-phenoxyphenyl) -1,3-butanedione

REFERENCE EXAMPLE 11 3-acetyl-7-bromo-4H-chromen-4-one was obtained in the same manner as in Example 3.

Example 1 1.63 g of 2-hydroxy-4-phenoxyacetophenone
Was dissolved in 10 mL of N, N-dimethylformamide, and -15
At 2 ° C., 2 mL of phosphorus oxychloride was added dropwise, the temperature was raised to 50 ° C. over 1 hour, and the mixture was further stirred at 50 ° C. for 1 hour. The reaction mixture is returned to room temperature, added to ice water and extracted with ethyl acetate. The organic layer is washed successively with water and saturated saline, dried, and the solvent is distilled off. The obtained residue is purified by silica gel chromatography [eluent: hexane: ethyl acetate = 5: 1] to give a colorless solid, 4-oxo-7-phenoxy-4H.
1.62 g of chromene-3-carbaldehyde are obtained. FT-IR (K
Br): 1702, 1645, 1624cm -1 1 H-NMR (CDCl 3) δ value: 6.93 (1H, d, J = 2.4Hz), 7.00-7.60
(6H, m), 8.25 (1H, d, J = 8.8Hz), 8.46 (1H, s), 10.39 (1H,
s)

In the same manner as in Example 1, the following Examples 1 (2) to
1 (8) is obtained. 1 (2) 4-oxo-7-anilino-4H-chromene-3
−Carbaldehyde FT-IR (KBr): 1694, 1652, 1609cm^-1  1 (3) 6-fluoro-4-oxo-7-phenoxy-4
H-chromen-3-carbaldehyde¹ H-NMR (CDCl_Three) δ value: 6.91 (1H, d, J = 6.6Hz), 7.1-7.6 (5
H, m), 8.03 (1H, d, J = 10.0Hz), 8.44 (1H, s), 10.36 (1H,
s). 1 (4) 7- (2-Naphthyloxy) -4-oxo-4H-
Chromen-3-carbaldehyde FT-IR (KBr): 1694, 1654, 1617cm^{-1 1} H-NMR (CDCl_Three) δ value: 6.9-8.0 (9H, m), 8.26 (1H, d, J = 8.8
Hz), 8.44 (1H, s), 10.38 (1H, s) 1 (5) 4-oxo-7- (phenylsulfanyl) -4H
-Chromen-3-carbaldehyde¹ H-NMR (CDCl_Three) δ value: 7.00-7.38 (2H, m), 7.40-7.75 (5H,
m), 8.11 (1H, d, J = 8.1 Hz), 8.42 (1H, s), 10.35 (1H, s) 1 (6) 6-fluoro-4-oxo-7- (phenylsulfur
Fanyl) -4H-chromen-3-carbaldehyde¹ H-NMR (CDCl_Three) δ value: 6.80 (1H, d, J = 5.9Hz), 7.3-7.7 (5
H, m), 7.87 (1H, d, J = 9.0Hz), 8.39 (1H, s), 10.33 (1H, s) .1 (7) 6-Fluoro-4-oxo-7- (phenylsulfur
(Honyl) -4H-chromen-3-carbaldehyde¹ H-NMR (CDCl_Three) δ value: 7.5-7.8 (3H, m), 7.9-8.1 (3H, m),
8.37 (1H, d, J = 5.4Hz), 8.60 (1H, s), 10.33 (1H, s)

Example 2 0.8 g of tributyl (phenyl) tin was dissolved in 8 mL of toluene, and 7-bromo-4-oxo-4H-chromene-3- was dissolved.
0.38 g of carbaldehyde and 19 mg of dichlorobis (triphenylphosphine) -palladium (II) are added, and the mixture is heated under reflux for 2 hours. The reaction mixture is returned to room temperature, and the solvent is distilled off under reduced pressure. The obtained residue is subjected to silica gel chromatography [eluent; hexane to hexane: ethyl acetate =
9: 1] to give 4-oxo-7- as a colorless solid.
Phenyl-4H-chromen-3-carbaldehyde 0.52 g
Get. ¹ H-NMR (DMSO-d ₆ ) δ value: 7.4-7.9 (8H, m), 8.96 (1H, s), 1
0.14 (1H, s)

In the same manner as in Example 2, the following Examples 2 (2) to 2
2 (7) is obtained. 2 (2) 7- (4-ethoxycarbonylphenyl) -4-oxo-4H-chromene-3-carbaldehyde 2 (3) 7- (2-naphthyl) -4-oxo-4H-chromene-3-carbaldehyde ¹ H-NMR (DMSO-d ₆ ) δ value: 7.5-8.
5 (10H, m), 8.97 (1H, s), 10.15 (1H, s) 2 (4) 7- (1-Naphthyl) -4-oxo-4H-chromene-3-carbaldehyde 2 (5) 4- Oxo-7- (3-pyridyl) -4H-chromen-3-carbaldehyde ¹ H-NMR (DMSO-d ₆ ) δ value: 7.5-7.
6 (2H, m), 7.9-8.3 (3H, m), 8.67 (1H, d, J = 3.2Hz), 8.99 (1
H, s), 10.14 (1H, s) 2 (6) 4-oxo-7- (3-thienyl) -4H-chromene-3-carbaldehyde ¹ H-NMR (DMSO-d ₆ ) δ value: 7.7- 7.
8 (2H, m), 7.9-8.2 (4H, m), 8.93 (1H, s), 10.13 (1H, s) 2 (7) 4-oxo-7- (3-quinolinyl) -4H-chromene-3 -Carbaldehyde ¹ H-NMR (DMSO-d ₆ ) δ value: 7.4-8.4 (9H, m), 8.93 (1H, s), 1
0.10 (1H, s)

Example 3 1- (2-hydroxy-4-phenoxyphenyl)-
0.13 g of 1,3-butanedione was dissolved in 1.5 mL of N, N-dimethylformamide, and 0.22 mL of N, N-dimethylformaldehyde dimethyl acetal and 0.1 mL of acetic acid were added.
Stir at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, washed successively with water and saturated saline, dried, and the solvent is distilled off. The obtained residue was purified by silica gel chromatography [eluent: hexane: ethyl acetate = 5: 1] to give 3-acetyl-7-phenoxy- as a colorless solid.
0.11 g of 4H-chromen-4-one is obtained. FT-IR (KBr): 1684, 1651, 1626 cm ^{-1 1} H-NMR (CDCl ₃ ) δ value: 2.74 (3H, s), 6.90 (1H, d, J = 2.2H
z), 7.0-7.5 (6H, m), 8.23 (1H, d, J = 8.5Hz), 8.51 (1H, s)

In the same manner as in Example 3, the following Examples 3 (2) to
3 (8) compound is obtained. 3 (2) 7-phenoxy-3-propionyl-4H-chromen-4-one ¹ H-NMR (CDCl ₃ ) δ value: 1.16 (3H, t, J = 7.3 Hz), 3.19 (2H, q,
J = 7.3Hz), 6.90 (1H, d, J = 2.4Hz), 7.0-7.5 (6H, m), 8.22
(1H, d, J = 8.8Hz), 8.49 (1H, s) 3 (3) 3-isobutyryl-7-phenoxy-4H-chromen-4- ^one 1H-NMR (CDCl ₃ ) δ value: 1.17 (6H , d, J = 6.8Hz), 3.91 (1H,
m), 6.90 (1H, d, J = 2.2Hz), 7.0-7.5 (6H, m), 8.23 (1H, d, J =
9.0Hz), 8.43 (1H, s) 3 (4) 3-acetyl-6-fluoro-7-phenoxy-
4H-chromen-4-one ¹ H-NMR (CDCl ₃ ) δ value: 2.73 (3H, s), 6.86 (1H, d, J = 2.0H)
z), 6.9-7.6 (5H, m), 8.01 (1H, d, J = 10.5Hz), 8.49 (1H, s) 3 (5) 3- (2,2-difluoroacetyl) -7-phenoxy-4H - chromen-4-one FT-IR (KBr): 1708 , 1655, 1622cm -1 1 H-NMR (CDCl 3) δ value: 6.30-7.60 (8H, m), 8.22 (1H, d, J =
8.8Hz), 8.56 (1H, s) 3 (6) 3-acetyl-7- (phenylsulfanyl) -4
H-chromen-4-one ¹ H-NMR (CDCl ₃ ) δ value: 2.72 (3H, s), 7.1-7.3 (2H, m), 7.4
-7.7 (5Hm), 8.11 (1H, d, J = 8.6Hz), 8.48 (1H, s) .3 (7) 4-oxo-4- (4-oxo-7-phenoxy-4H-chromene-3- Yl) butanoic acid ¹ H-NMR (CDCl ₃ ) δ value: 2.75 (2H, t, J = 6.4 Hz), 3.51 (2H, t,
J = 6.4Hz), 6.90 (1H, d, J = 2.2Hz), 7.0-7.5 (6H, m), 8.23
(1H, d, J = 9.0Hz), 8.53 (1H, s) .3 (8) 2-oxo-2- (4-oxo-7-phenoxy-4H-chromen-3-yl) acetic acid FT-IR ( KBr): 3081, 1720, 1649, 1621cm ^-1

Example 4 1- (2-hydroxy-4-phenoxyphenyl) -3
-(3-pyridinyl) -1,3-propanedione 0.11
g, 6 mg of p-toluenesulfonic acid monohydrate, 2 mL of ethyl orthoformate and 2 mL of toluene are mixed and heated to reflux for 1.5 hours. After cooling the reaction mixture, water and ethyl acetate are added, and the organic layer is separated. The obtained organic layer is washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and then the solvent is distilled off. The obtained residue is purified by silica gel column chromatography [eluent; n-hexane: ethyl acetate = 5: 1] to give a colorless solid, 7-phenoxy-3- (3-pyridinylcarbonyl) -4H. 0.07 g of chromen-4-one is obtained. FT-IR (KBr): 1668 , 1652, 1624cm -1 1 H-NMR (CDCl 3) δ value: 6.95 (1H, dJ = 1.9Hz ), 7.02-7.60
(7H, m), 8.00-8.38 (3H, m), 8.70-8.90 (1H, m), 8.96-9.0
3 (1H, m)

In the same manner as in Example 4, the following Examples 4 (2) to
4 (5) is obtained. 4 (2) 7- (phenylsulfanyl) -3- (3-pyridinylcarbonyl) -4H-chromen-4-one ¹ H-NMR (CDCl ₃ ) δ value: 7.1-7.6 (8H, m), 8.0 -8.1 (2H, m),
8.27 (1H, s), 8.76 (1H, dd, J = 4.9,1.9Hz), 8.96 (1H, d, J =
1.9 Hz) 4 (3) 3-benzoyl-7-phenoxy-4H-chromen-4-one ¹ H-NMR (CDCl ₃ ) δ value: 6.93 (1H, d, J = 2.2 Hz), 7.0-7.6 (10
H, m), 7.8-7.9 (2H, m), 8.19 (1H, s), 8.20 (1H, d, J = 8.8H
z) 4 (4) 6-Fluoro-3- (2-fluorobenzoyl)-
7-phenoxy-4H-chromen-4-one ¹ H-NMR (CDCl ₃ ) δ value: 6.91 (1H, d, J = 6.6 Hz), 6.9-7.9 (9
H, m), 7.95 (1H, d, J = 10.3Hz), 8.33 (1H, s) 4 (5) 3-[(4-oxo-7-phenoxy-4H-chromen-3-yl) carbonyl] pyridinium Chloride ¹ H-NMR (DMSO-d ₆ ) δ value: 7.00-7.60 (7H, m), 7.70-8.20 (2
H, m), 8.40-8.80 (3H, m)

Example 5 A mixture of 0.14 g of 4-oxo-7-phenoxy-4H-chromene-3-carbaldehyde, 0.11 g of hydroxylamine hydrochloride and 2 mL of N, N-dimethylformamide was added at room temperature to
After stirring for 0 minutes, water and ethyl acetate are added to the reaction mixture, and the organic layer is separated. The obtained organic layer is sequentially washed with water and saturated saline, and then dried. The solvent was distilled off under reduced pressure to give 4-oxo-7-phenoxy-4 as a pale yellow solid.
0.15 g of H-chromen-3-carbaldehyde oxime is obtained. FT-IR (KBr): 3272, 1648, 1622cm ^-1 .

In the same manner as in Example 5, the following Examples 5 (2) to 5
The compound of 5 (13) is obtained. 5 (2) 4-oxo-7-anilino-4H-chromene-3
−Carbaldehyde oxime FT-IR (KBr): 1568, 1613cm^-1  5 (3) 6-fluoro-4-oxo-7-phenoxy-4
H-chromen-3-carbaldehyde oxime 5 (4) 7- (2-naphthyloxy) -4-oxo-4H-
Chromene-3-carbaldehyde oxime FT-IR (KBr): 3221, 1654, 1648, 1618cm^{-1 1} H-NMR (CDCl_Three) δ value: 6.9-8.3 (12H, m), 10.62 (1H, s) 5 (5) 4-oxo-7- (phenylsulfanyl) -4H
-Chromene-3-carbaldehyde oxime 5 (6) 6-fluoro-4-oxo-7- (phenylsulfur
Fanyl) -4H-chromene-3-carbaldehyde
Shim FT-IR (KBr): 3106, 1626, 1605cm^{-1 1} H-NMR (CDCl_Three) δ value: 6.36 (1H, d, J = 6.4Hz), 7.33 (1H, d,
J = 10.0Hz), 7.3-7.7 (5H, m), 8.70 (1H, s), 8.98 (1H, s),
11.68 (1H, s) 5 (7) 4-oxo-7-phenyl-4H-chromene-3
-Carbaldehyde oxime 5 (8) 4-oxo-7- (4-ethoxycarbonyl
Nyl) -4H-chromen-3-carbaldehyde oxime 5 (9) 4-oxo-7- (2-naphthyl) -4H-chrome
3-carbaldehyde oxime 5 (10) 4-oxo-7- (1-naphthyl) -4H-chloro
Men-3-carbaldehyde oxime 5 (11) 4-oxo-7- (3-thienyl) -4H-chloro
Men-3-carbaldehyde oxime 5 (12) 4-oxo-7- (3-quinolinyl) -4H-co
Romen-3-carbaldehyde oxime 5 (13) 3-ethanimidyl-7-phenoxy-4H-
Chromen-4-one FT-IR (KBr): 1654cm^{-1 1} H-NMR (CDCl_Three) δ value: 2.29 (3H, s), 6.87 (1H, d, J = 2.5H
z), 7.00-7.60 (7H, m), 7.95 (1H, s), 8.20 (1H, d, J = 9.0H
z)

Example 6 A mixture of 0.15 g of 4-oxo-7-phenoxy-4H-chromene-3-carbaldehyde oxime, 0.05 g of sodium acetate and 1 mL of acetic acid is heated under reflux for 1 hour. After cooling the reaction mixture, water and chloroform are added, and the organic layer is separated. The obtained organic layer is washed with a saturated aqueous solution of sodium hydrogen carbonate and then dried. The solvent was distilled off under reduced pressure to obtain 0.14 g of 4-oxo-7-phenoxy-4H-chromen-3-carbonitrile as a pale yellow solid. FT-IR (KBr): 2236 , 1662, 1625cm -1 1 H-NMR (CDCl 3) δ value: 6.91 (1H, d, J = 2.2Hz), 7.00-7.60
(6H, m), 8.19 (1H, d, J = 9.0Hz), 8.32 (1H, s)

In the same manner as in Example 6, the following Examples 6 (2) to
6 (13) is obtained. 6 (2) 4-oxo-7-anilino-4H-chromene-3
−Carbonitrile FT-IR (KBr): 2246, 1656, 1624cm^-1  6 (3) 6-fluoro-4-oxo-7-phenoxy-4
H-chromen-3-carbonitrile FT-IR (KBr): 3073, 2237, 1741, 1671, 1635cm^{-1 1} H-NMR (CDCl_Three) δ value: 6.89 (1H, d, J = 6.4Hz), 7.1-7.5 (5
H, m), 7.99 (1H, d, J = 10.0Hz), 8.30 (1H, s) 6 (4) 7- (2-naphthyloxy) -4-oxo-4H-
Chromene-3-carbonitrile FT-IR (KBr): 3052, 2235, 1671, 1654, 1622cm^-1  6 (5) 4-oxo-7- (phenylsulfanyl) -4H
-Chromene-3-carbonitrile FT-IR (KBr): 2234, 1663, 1616cm^{-1 1} H-NMR (CDCl_Three) δ value: 7.0-7.3 (2H, m), 7.4-7.6 (5H, m),
8.06 (1H, d, J = 8.3Hz), 8.27 (1Hs) 6 (6) 6-Fluoro-4-oxo-7- (phenylsulfur
(Fanyl) -4H-chromen-3-carbonitrile FT-IR (KBr): 3058, 2236, 1670, 1654, 1646cm^{-1 1} H-NMR (CDCl_Three) δ value: 6.79 (1H, d, J = 5.9Hz), 7.5-7.7 (5
H, m), 7.79 (1H, d, J = 9.0Hz), 8.28 (1H, s) 6 (7) 4-oxo-7-phenyl-4H-chromene-3
−Carbonitrile FT-IR (KBr): 2237, 1679cm^{-1 1} H-NMR (DMSO-d₆) δ value: 7.4-8.0 (8H, m), 9.05 (1H, s) 6 (8) 4-oxo-7- (4-ethoxycarbonylphen)
Nyl) -4H-chromen-3-carbonitrile FT-IR (KBr): 2238,1713,1622cm^-1  6 (9) 4-oxo-7- (4-carboxyphenyl) -4
H-chromen-3-carbonitrile FT-IR (KBr): 2237, 1663cm^{-1 1} H-NMR (DMSO-d₆) δ value: 7.5-8.5 (10H, m), 9.29 (1H, s),
12.80 (1H, brs) 6 (10) 4-oxo-7- (2-naphthyl) -4H-chloro
Men-3-carbonitrile FT-IR (KBr): 2236, 1662, 1619cm^-1  6 (11) 4-oxo-7- (1-naphthyl) -4H-chloro
Men-3-carbonitrile FT-IR (KBr): 2241, 1613cm^{-1 1} H-NMR (DMSO-d₆) δ value: 7.5-8.2 (10H, m), 9.24 (1H, s) 6 (12) 4-oxo-7- (3-thienyl) -4H-chloro
Men-3-carbonitrile FT-IR (KBr): 2236, 1660, 1622cm^-1  6 (13) 4-oxo-7- (3-quinolinyl) -4H-co
Romen-3-carbonitrile FT-IR (KBr): 2237, 1664, 1617cm^{-1 1} H-NMR (DMSO-d₆) δ value: 7.5-8.4 (9H, m), 9.31 (1H, s)

Example 7 90 mg of 4-oxo-7- (phenylsulfanyl) -4H-chromene-3-carbonitrile was suspended in 1 mL of chloroform, 4 mL of saturated hydrochloric acid-ethyl alcohol was added, and the mixture was stirred at room temperature for 3 days. Evaporation of the solvent or the like under reduced pressure gives 0.1 g of light brown solid ethyl 4-oxo-7- (phenylsulfanyl) -4H-chromene-3-carboxymidate hydrochloride. ¹ H-NMR (CDCl ₃ ) δ value: 1.5-1.7 (3H, brt), 5.0-5.3 (2H, br
q), 7.1-7.7 (7H, m), 8.12 (1H, d, J = 8.8Hz), 8.7-8.9 (1H,
brs)

Example 8 6-Fluoro-4-oxo-7-phenoxy-4H-chromen-3-carbonitrile 0.20 g, sodium azide 0.2
1 g, aluminum chloride 0.10 g and tetrahydrofuran 5
After heating the mixture to reflux for 7 hours, 1m was added to the reaction mixture.
Add 5 mL of ol / L hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, and dried to give a colorless solid, 6-fluoro-7-phenoxy-3- (1H-1,2,3,4-tetrazole-).
0.22 g of 5-yl) -4H-chromen-4-one is obtained. FT-IR (KBr): 2122 , 1636cm -1 1 H-NMR (DMSO-d 6) δ value: 7.2-7.6 (7H, m), 8.10 (1H, d, J = 1
0.5Hz), 9.25 (1H, s)

Example 9 A mixture of 27 mg of 4-oxo-7-phenoxy-4H-chromene-3-carbaldehyde, 15 mg of 1-aminopiperidine and 1 mL of ethyl alcohol was allowed to stir at room temperature for 1 hour, and then water and water were added to the reaction mixture. Ethyl acetate is added, and the mixture is adjusted to acidic with 1 mol / L hydrochloric acid. The organic layer is separated, washed sequentially with water and saturated saline, and dried. When the solvent is distilled off under reduced pressure, 29 mg of 7-phenoxy-3-[(1-piperidinylimino) methyl] -4H-chromen-4-one as a pale yellow solid is obtained.
Get. FT-IR (KBr): 1639 , 1626cm -1 1 H-NMR (CDCl 3) δ value: 1.40-1.90 (6H, m), 3.10-3.30 (4H,
m), 6.86 (1H, d, J = 1.7Hz), 6.95-7.60 (6H, m), 7.70 (1H,
s), 8.21 (1H, d, J = 9.0Hz), 8.34 (1H, s)

In the same manner as in Example 9, the following Examples 9 (2)-
9 (10) compound is obtained. 9 (2) 4-oxo-7-phenoxy-4H-chromene-
3-carbaldehyde hydrazone ¹ H-NMR (CDCl ₃ ) δ value: 6.92 (1H, d, J = 2.2 Hz), 7.00-7.60
(6H, m), 8.15-8.35 (1H, m), 8.68 (1H, s), 8.85 (1H, s) 9 (3) 1- (2,4-dimethoxybenzyl) -4-
｛[(4-oxo-7-phenoxy-4H-chromene-
3-yl) methylidene] amino} -2,3-piperazinedione FT-IR (KBr): 1698,1670,1646,1625cm -1 1 H-NMR (CDCl 3) δ value: 3.50-3.70 (2H, m) , 3.80-4.00 (8H,
m), 4.68 (2H, s), 6.40-6.60 (2H, m), 6.85-5.95 (1H, m),
7.00-7.60 (7H, m), 8.20 (1H, d, J = 9.0Hz), 8.60 (1H, s),
8.65 (1H, s) 9 (4) 1-{[(4-oxo-7-phenoxy-4H-
Chromen-3-yl) methylidene] amino} -2-imidazolidinone FT-IR (KBr): 1736 , 1649, 1626cm -1 1 H-NMR (CDCl 3) δ value: 3.60-4.00 (4H, m), 4.95-5.10 (1H,
m), 6.85-7.80 (8H, m), 8.19 (1H, d, J = 8.8Hz) 9 (5) N '-[(4-oxo-7-phenoxy-4H-
Chromen-3-yl) methylidene] isonicotinohydrazide FT-IR (KBr): 1654 , 1628cm -1 1 H-NMR (DMSO-d 6) δ value: 7.00-7.60 (7H, m), 7.75-7.90 ( Two
H, m), 8.05-8.20 (1H, m), 8.62 (1H, s), 8.70-8.90 (3H, m),
12.15 (1H, s) 9 (6) 4-({2-[(4-oxo-7-phenoxy-4
H- chromen-3-yl) methylidene] hydrazino} carbonyl) benzoate FT-IR (KBr): 1701,1654,1638,1625cm -1 1 H-NMR (DMSO-d 6) δ value: 7.00-7.60 (7H , m), 7.90-8.30 (5
H, m), 8.60 (1H, s), 8.78 (1H, s), 12.06 (1H, s) 9 (7) 2-[(4-oxo-7-phenoxy-4H-chromen-3-yl) methylidene ] -1-hydrazine carboxylate FT-IR (KBr): 1750 , 1637, 1625cm -1 1 H-NMR (DMSO-d 6) δ value: 3.68 (3H, s), 7.00-7.60 (7H, m) ,
8.00-8.25 (2H, m), 8.62 (1H, s), 11.20 (1H, s) 9 (8) N, N, N-trimethyl-2-oxo-2- {2-
[(4-oxo-7-phenoxy-4H-chromene-3
- yl) methylidene] hydrazino} -1-ethanone Nami chloride FT-IR (KBr): 1706 , 1654, 1625cm -1 1 H-NMR (D 2 O) δ value: 3.30-3.60 (9H, m), 4.32 ( 2H, s), 6.8
0-7.60 (7H, m), 7.97 (1H, d, J = 9.8Hz), 8.26 (1H, s), 8.60
(1H, s) 9 (9) N, N, N-trimethyl-2-oxo-2- {2-
[(4-oxo-7-phenoxy-4H-chromene-3
-Yl) (3-pyridinyl) methylidene] hydrazino} -1
- ethanone Nami chloride FT-IR (KBr): 1707 , 1652, 1626cm -1 1 H-NMR (D 2 O) δ value: 3.07-3.40 (9H, m), 4.10 (2H, s), 6.8
0-7.80 (8H, m), 8.00-8.20 (3H, m), 8.70-8.80 (2H, m) 9 (10) N, N, N-trimethyl-2-oxo-2- {2-
[(4-oxo-7-phenoxy-4H-chromene-3
- yl) ethylidene] hydrazino} -1-ethanone Nami chloride FT-IR (KBr): 1706 , 1684, 1654cm -1 1 H-NMR (D 2 O) δ value: 2.63 (3H, s), 3.25-3.50 ( 9H, m), 4.3
0 (2H, s), 6.85-7.70 (7H, m), 7.90-8.50 (2H, m)

Example 10 4-oxo-7-phenoxy-4H-chromene-3-carbaldehyde 20 mg, L-cysteine 14 mg and N, N-
Stir the mixture of 1 mL of dimethylformamide at room temperature for 1 hour. Water and ethyl acetate are added to the reaction mixture, and the organic layer is separated. The obtained organic layer is sequentially washed with water and saturated saline, and then dried. The solvent was distilled off under reduced pressure to obtain (4S) -2- (4-oxo-7-phenoxy-4H-chromen-3-yl) -1,3-thiazolidine-4-carboxylic acid (23 mg) as a pale yellow solid. Get. FT-IR (KBr): 1646cm -1 1 H-NMR (CDCl 3) δ value: 3.30-3.50 (2H, m), 4.10-4.57 (1
H, m), 5.65 (1H, s), 5.8-6.2 (br), 6.80-6.90 (1H, m), 6.
95-7.60 (6H, m), 8.00-8.20 (2H, m)

The following Example 10 was performed in the same manner as in Example 10.
The compound of (2) is obtained. 10 (2) 7-phenoxy-3- (1,3-thiazolidine-
2-yl) -4H- chromen-4-one FT-IR (KBr): 1654cm -1 1 H-NMR (D 2 O) δ value: 2.96-3.60 (4H, m), 5.56 (1H, s), 6.4
-6.6 (br), 6.85-7.60 (7H, m), 7.95 (1H, s), 8.10-8.25 (1
H, m)

Example 11 4-oxo-7-phenoxy-4H-chromene-3-carbaldehyde 100 mg, p-toluenesulfonic acid monohydrate 7 m
g, a mixture of 0.21 mL of ethylene glycol and 2 mL of benzene are heated at reflux for 30 minutes. After cooling the reaction mixture, water and ethyl acetate are added, and the organic layer is separated. The obtained organic layer is washed with a saturated aqueous solution of sodium hydrogen carbonate and dried. The solvent was distilled off under reduced pressure to obtain a pale yellow solid, 3-
110 mg of (1,3-dioxolan-2-yl) -7-phenoxy-4H-chromen-4-one are obtained. ¹ H-NMR (CDCl ₃ ) δ value: 4.00-4.20 (4H, m), 6.04 (1H, s),
6.85 (1H, d, J = 2.2Hz), 7.00-7.60 (6H, m), 8.04 (1H, s),
8.19 (1H, d, J = 8.8Hz)

The following Example 11 was performed in the same manner as in Example 11.
The compound of (2) is obtained. 11 (2) 3- (dimethoxymethyl) -7-phenoxy-4
H-chromen-4-one ¹ H-NMR (D ₂ O) δ value: 3.43 (6H, s), 5.60 (1H, s), 6.86 (1H,
d, J = 2.4Hz), 7.0-7.5 (6H, m), 8.02 (1H, s), 8.18 (1H, d, J
= 8.8Hz)

Example 12 A mixture of 27 mg of 4-oxo-7-phenoxy-4H-chromene-3-carbaldehyde, 21 mg of malonic acid and 1 mL of pyridine is stirred at 100 ° C. for 30 minutes. After cooling the reaction mixture,
Water and ethyl acetate are added, the mixture is adjusted to be acidic with 1 mol / L hydrochloric acid, and the organic layer is separated. The obtained organic layer is sequentially washed with water and saturated saline, and then dried. The solvent was distilled off under reduced pressure, diisopropyl ether and n-hexane were added to the obtained residue, and the precipitated crystals were collected by filtration to give a colorless solid (E) -3- (4-oxo-7-). Phenoxy-4H-
15 mg of (chromen-3-yl) -2-propenoic acid are obtained. FT-IR (KBr): 1697, 1654, 1618 cm ^{-1 1} H-NMR (CDCl ₃ ) δ value: 6.12 (1H, d, J = 12.9 Hz), 6.88 (1H,
d, J = 1.0Hz), 7.00-7.60 (6H, m), 8.11 (1H, d, J = 12.9Hz),
8.20 (1H, d, J = 8.8Hz), 8.91 (1H, s)

Example 13 0.53 g of 4-oxo-7-phenoxy-4H-chromene-3-carbaldehyde was dissolved in 5 mL of methylene chloride, and a solution of 0.39 g of sulfamic acid in 3 mL of water was added under ice cooling. A solution obtained by dissolving 0.27 g of sodium chlorate in 2 mL of water is sequentially added dropwise, and the mixture is stirred for 30 minutes. The precipitated crystals are collected by filtration, washed with water, and dried to obtain 0.32 g of 4-oxo-7-phenoxy-4H-chromene-3-carboxylic acid. ¹ H-NMR (DMSO-d ₆ ) δ value: 7.1-7.6 (7H, m), 8.17 (1H, d, J = 9.
5Hz), 9.05 (1H, s), 13.1-13.3 (1H, brs)

In the same manner as in Example 13, the following Example 13 (2)
Is obtained. 13 (2) 6-fluoro-4-oxo-7-phenoxy-4
H-chromen-3-carboxylic acid ¹ H-NMR (DMSO-d ₆ ) δ value: 7.1-7.6 (6H, m), 8.03 (1H, d, J = 1)
0.5Hz), 9.02 (1H, s), 13.15 (1H, brs)

Example 14 28 mg of 4-oxo-7-phenoxy-4H-chromene-3-carboxylic acid was dissolved in 2 mL of methylene chloride, 0.01 mL of oxalyl chloride and 1 drop of N, N-dimethylformamide were added. Stir for 10 minutes. Then, a solution of 17 mg of 2-aminothiazole dissolved in 2 mL of pyridine is added at room temperature, and the mixture is further stirred for 30 minutes. Water and chloroform are added to the reaction mixture, and the mixture is acidified with hydrochloric acid, and then the organic layer is separated. The obtained organic layer is washed with water and a saturated aqueous solution of sodium hydrogen carbonate and dried. The solvent is distilled off under reduced pressure,
The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to give
A colorless solid, 4-oxo-7-phenoxy-N- (1,
5 mg of 3-thiazol-2-yl) -4H-chromen-3-carboxamide are obtained. FT-IR (KBr): 1675 , 1654cm -1 1 H-NMR (CDCl 3) δ value: 6.9-7.6 (9H, m), 8.30 (1H, d, J = 8.8
Hz), 8.97 (1H, s), 12.6-12.8 (1H, br)

The following Example 14 was carried out in the same manner as in Example 14.
The compound of (2) is obtained. 14 (2) 6-Fluoro-N-hydroxy-4-oxo-7
-Phenoxy-4H-chromene-3-carboxamide FT-IR (KBr): 3412, 2224, 1654, 1589 cm ^-1

Example 15 169 mg of Rinkamide MBHA resin and 3 mL of N, N-dimethylformamide are placed in a polypropylene container with a filter, and the resin is allowed to swell for several minutes. After removing N, N-dimethylformamide by filtration, 3 mL of a 20% piperidine / N, N-dimethylformamide solution is added, and the mixture is shaken for 20 minutes. The reaction solution was removed by filtration, and the resin was washed with N, N-dimethylformamide (5m).
Wash 6 times with L. Subsequently, 94 mg of N-α-9-fluorenylmethoxycarbonylalanine, 46 mg of 1-hydroxybenzotriazole, 0.048 mL of N, N-diisopropylcarbodiimide and 2 mL of N, N-dimethylformamide are sequentially added to the resin, followed by shaking for 2 hours. The reaction solution is removed by filtration, and the resin is washed six times with 5 mL of N, N-dimethylformamide. 20% piperidine / N, N-dimethylformamide solution in resin
Add mL and shake for 20 minutes. The reaction solution is removed by filtration, and the resin is washed six times with 5 mL of N, N-dimethylformamide. Furthermore, 6-fluoro-4-oxo-7-phenoxy- is added to the resin.
75 mg of 4H-chromen-3-carboxylic acid, 4 mg of 1-hydroxy-7-azabenzotriazole, 2-chloro-1,
42 mg of 3-dimethylimidazolinium chloride, 2 mL of N-methylpyrrolidone and 0.04 mL of pyridine are sequentially added and shaken for 2 hours. The reaction solution is filtered off, and the resin is washed four times with 5 mL of N, N-dimethylformamide and three times with 5 mL of methylene chloride, and dried under reduced pressure. 5 mL of trifluoroacetic acid is added to the obtained resin and shaken for 4 hours. The insoluble material is removed by filtration, and the solvent is distilled off under reduced pressure. Diethyl ether is added to the obtained residue.
20 mL was added, and the solid matter was collected by filtration.
[(1S) -2-amino-1-methyl-2-oxoethyl] -6-fluoro-4-oxo-7-phenoxy-4
15 mg of H-chromen-3-carboxamide are obtained.

The following Example 15 was carried out in the same manner as in Example 15.
Compounds (2) and 15 (3) are obtained. 15 (2) N-[(1S) -2-amino-1- (hydroxymethyl) -2-oxoethyl] -6-fluoro-4-
Oxo-7-phenoxy-4H-chromen-3-carboxamide 15 (3) (2R) -2-[((2S) -2-｛[(4-
Oxo-7-phenoxy-4H-chromen-3-yl)
Carbonyl] amino} propanoyl) amino] propanoic acid

Example 16 0.23 g of 4-oxo-7-phenoxy-4H-chromene-3-carboxylic acid was dissolved in 2 mL of methylene chloride, 0.08 mL of oxalyl chloride, N, N-dimethylformamide 1
Add the drops and stir at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in 5 mL of chloroform.
N, 2,2-trimethyl-N- [3-methyl-5- (tributylstannyl) -2-pyridinyl] propanamide
0.43 g and dichlorobis (triphenylphosphine) -palladium (II) 15 mg are added, and the mixture is heated and stirred at 65 ° C. for 5 hours. The reaction mixture was brought to room temperature, diluted with chloroform,
After washing with water and saturated saline solution in that order, it is dried. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel chromatography [eluent: hexane: ethyl acetate = 2: 1].
Purification by colorless solid N, 2,2-trimethyl-
0.15 g of N- {3-methyl-5-[(4-oxo-7-phenoxy-4H-chromen-3-yl) carbonyl] -2-pyridinyl} propanamide is obtained. ¹ H-NMR (CDCl ₃ ) δ value: 1.08 (9H, s), 2.35 (3H, s), 3.19 (3
H, s), 6.92 (1H, d, J = 0.22Hz), 7.1-7.6 (7H, m), 7.99 (1H,
s), 8.04 (1H, s), 8.25 (1H, d, J = 8.8Hz), 8.41 (1H, s).

Example 17 N, 2,2-Trimethyl-N- {3-methyl-5
[(4-oxo-7-phenoxy-4H-chromene-3
-Yl) carbonyl] -2-pyridinyl} propanamide (15 mg) is dissolved in dioxane (0.5 mL), concentrated hydrochloric acid (0.2 mL) is added, and the mixture is heated under reflux for 2 hours. The reaction mixture was returned to room temperature and
A 10% aqueous sodium hydroxide solution is added to adjust the pH to 10, and the mixture is extracted with ethyl acetate. The obtained organic layer is sequentially washed with water and a saturated saline solution, and dried. The solvent was distilled off under reduced pressure, hexane was added to the obtained residue, and the mixture was solidified to give a colorless solid, 3-{[5-methyl-6- (methylamino)
-3-pyridinyl] carbonyl} -7-phenoxy-4
3 mg of H-chromen-4-one are obtained. ¹ H-NMR (CDCl ₃ ) δ value: 2.13 (3H, s), 3.07 (3H, s), 6.89 (1
H, d, J = 0.22Hz), 7.0-7.6 (8H, m), 7.89 (1H, s), 8.08 (1H,
d, J = 1.7Hz), 8.24 (1H, d, J = 8.8Hz)

Example 18 Under a nitrogen atmosphere, 0.11 g of 7-phenoxy-3- (tributylstannyl) -4H-chromen-4-one was dissolved in 1 mL of N, N-dimethylformamide, and methyl 5-bromo-2-amide was dissolved. After adding 0.21 g of furoate and heating to 100 ° C, 0.25 g of silver oxide (I) and 7 mg of dichlorobis (triphenylphosphine) -palladium (II) were further added.
Stir for hours. The reaction mixture is returned to room temperature, the insolubles are removed by filtration, diluted with ethyl acetate, and washed successively with water and saturated saline. The obtained organic layer is dried, and the solvent is distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography [eluent; hexane: ethyl acetate = 5: 1] to give a colorless solid, methyl 5- (4-oxo-7-phenoxy-4H-chromen-3-yl). ) -2-Floate
Obtain 50 mg. _{^{1 H-NMR (CDCl 3)}} δ value: 3.91 (3H, s), 6.91 (1H, d, J = 2.2H
z), 7.0-7.6 (8H, m), 8.25 (1H, d, J = 8.8Hz), 8.61 (1H, s)

Example 19 The following compounds of Examples 19 (1) to 19 (3) are obtained in the same manner as in Example 2. 19 (1) 3-acetyl-7-[(1R) -2- (2,2
-Dimethylpropanoyl) -1-methyl-2,3-dihydro-1H-isoindol-5-yl] -4H-chromen-4-one ¹ H-NMR (CDCl ₃ ) δ value: 1.37 (9H, s) , 1.53 (3H, d, J = 6.4Hz),
2.74 (3H, s), 5.06-5.40 (2H, m), 5.47-5.71 (1H, m), 7.3
3-7.72 (5H, m), 8.31 (1H, d, J = 8.6Hz), 8.60 (1H, s) 19 (2)
3-acetyl-7- (5-pyrimidinyl) -4H-chromen-4-one ¹ H-NMR (CDCl ₃ ) δ value: 2.77 (3H, s), 7.6
7-7.80 (2H, m), 8.54 (1H, d, J = 8.8Hz), 8.65 (1H, s), 9.04
(1H, s), 9.31 (1H, s) 19 (3) N- [5- (3-acetyl-4-oxo-4H
-Chromen-7-yl) -3-methyl-2-pyridinyl] -N, 2,2-trimethylpropanamide

Example 20 The following compounds of Examples 20 (1) to 20 (8) are obtained in the same manner as in Example 3. 20 (1) 3- (cyclopropylcarbonyl) -7-phenoxy-4H-chromen-4-one ¹ H-NMR (CDCl ₃ ) δ value: 0.9-1.4 (4H, m), 3.2-3.5 (1H, m ),
6.9-7.6 (8H, m), 8.25 (1H, d, J = 9.0Hz), 8.44 (1H, s) 20 (2) 3- [3- (dimethylamino) benzoyl]-
7-phenoxy-4H-chromen-4-one ¹ H-NMR (CDCl ₃ ) δ value: 2.99 (6H, s), 6.9-7.6 (11H, m), 8.1
3 (1H, s), 8.20 (1H, d, J = 8.8Hz) 20 (3) 3-acetyl-6-nitro-7-phenoxy-
4H-chromen-4-one ¹ H-NMR (CDCl ₃ ) δ value: 2.73 (3H,
s), 6.8-7.6 (6H, m), 8.47 (1H, s), 8.83 (1H, s) 20 (4) 3-isonicotinoyl-7-phenoxy-4H
-Chromen-4-one ¹ H-NMR (CDCl ₃ ) δ value: 6.94 to 7.62 (9
H, m), 8.16 (1H, d, J = 8.8Hz), 8.33 (1H, s), 8.74-8.81 (2
H, s) 20 (5) 7-phenoxy-3- (2-pyridinylcarbonyl) -4H-chromen-4-one ¹ H-NMR (CDCl ₃ ) δ value: 6.92-7.54 (8H, m), 7.79-8.07 (2H,
m), 8.17 (1H, d, J = 8.8 Hz), 8.37 (1H, s), 8.60-8.66 (1H, m) 20 (6) 3-[(6-methyl-3-pyridinyl) carbonyl] -7 -Phenoxy-4H-chromen-4-one ¹ H-NMR (CDCl ₃ ) δ value: 2.64 (3H, s), 6.94-7.55 (8H, m), 7.
95-8.06 (1H, m), 8.18 (1H, d, J = 8.8Hz), 8.28 (1H, s), 8.8
8-8.90 (1H, m) 20 (7) 3-[(2-Methyl-3-pyridinyl) carbonyl] -7-phenoxy-4H-chromen-4- ^one 1H-NMR (CDCl ₃ ) δ value: 2.69 (3H, s), 6.93-7.55 (8H, m), 7.
64-7.74 (1H, m), 8.13 (1H, d, J = 8.8Hz), 8.43 (1H, s), 8.5
6-8.65 (1H, m) 20 (8) 3-acetyl-7- (4-methoxyphenoxy) -4H-chromen-4- ^one 1H-NMR (CDCl ₃ ) δ value: 2.74 (3H, s), 3.85 (3H, s), 6.82-7.
13 (6H, m), 8.21 (1H, d, J = 8.8Hz), 8.49 (1H, s)

Example 21 The following compounds of Examples 21 (1) to 21 (5) are obtained in the same manner as in Example 9. 21 (1) N, N, N-trimethyl-2-oxo-2- ｛2
-[(4-oxo-7-phenylsulfanyl-4H-
Chromen-3-yl) ethylidene] hydrazino} -1-
Ethanaminium chloride ¹ H-NMR (DMSO) δ value: 2.68 (3H, s), 3.31 (9H, s), 4.72 (2H,
s), 7.10-7.30 (2H, m), 7.59 (5H, s), 7.97 (1H, d, J = 8.3H
z), 8.37 (1H, s), 12.00 (1H, s) 21 (2) N, N-dimethyl-4-oxo-7-phenylsulfanyl-4H-chromene-3-carbaldehyde hydrazone ¹ H-NMR (CDCl ₃ ) δ value: 2.97 (6H, s), 7.1-7.7 (8H, m), 8.11
(1H, d, J = 8.1Hz), 8.29 (1H, s) 21 (3) N, N-dimethyl-2-oxo-2- ｛2-
[(4-oxo-7-phenylsulfanyl-4H-chromen-3-yl) ethylidene] hydrazino} -1-ethylammonium chloride ¹ H-NMR (DMSO) δ value: 2.85 (3H, s), 4.10 (2H, s), 7.12-8.5
1 (10H, m) 21 (4) N, N, N-trimethyl-2-oxo-2- ｛2
-[(4-oxo-7-phenoxy-4H-chromene-
3-yl) propylidene] hydrazino} -1-ethanaminium chloride 21 (5) 3- [1- (2,2-dimethylhydrazono) ethyl] -7-phenoxy-4H-chromen-4-one ¹ H-NMR (CDCl ₃ ) δ value: 2.66 (3H, s), 2.95 (6H, s), 6.82 (1
(H, d, J = 1.2Hz), 6.96-7.54 (6H, m), 7.56 (1H, s), 8.16 (1
(H, d, J = 8.8Hz)

Example 22 The following compounds of Examples 22 (1) to 22 (4) are obtained in the same manner as in Example 10. 22 (1) (4S) -2- (4-oxo-7-phenylsulfanyl-4H-chromen-3-yl) -1,3-thiazolidine-4-carboxylic acid ¹ H-NMR (DMSO) δ value: 3.3 -4.6 (4H, m), 5.65 (1H, s), 7.0-
7.7 (7H, m), 7.90-8.09 (2H, m) 22 (2) (4S) -2- (6-fluoro-4-oxo-
7-phenylsulfanyl-4H-chromen-3-yl) -1,3-thiazolidine-4-carboxylic acid ¹ H-NMR (DMSO) δ value: 2.8-4.2 (m), 5.46 (0.4H, s), 5.68
(0.6H, s), 6.92-6.99 (1H, m), 7.58 (5H, s), 7.72-7.84 (1
H, m), 8.19 (0.6H, s), 8.50 (0.4H, s) 22 (3) (4S) -2- (4-oxo-7-phenylsulfinyl-4H-chromen-3-yl) -1 , 3-thiazolidine-4-carboxylic acid ¹ H-NMR (DMSO) ^δ value: 2.8-4.2 (m), 5.5 ( 0.4H, s), 5.70 (0.
6H, s), 7.4-8.2 (8H, m), 8.33 (0.6H, s), 8.63 (0.4H, s) 22 (4) (4S) -2- (6-fluoro-4-oxo-
7-phenylsulfinyl-4H-chromen-3-yl) -1,3-thiazolidine-4-carboxylic acid ¹ H-NMR (DMSO) δ value: 2.8-4.2 (m), 5.5 (0.4H, s), 5.75 (0.
6H, s), 7.4-8.2 (8H, m), 8.38 (0.6H, s), 8.7 (0.4H, s)

Example 23 The following compounds of Examples 23 (1) to 23 (2) are obtained in the same manner as in Example 16. 23 (1) 3-[(4-oxo-7-phenoxy-4H-
Chromen-3-yl) carbonyl] phenylformamide ¹ H-NMR (CDCl ₃ ) δ value: 6.8-7.6 (11H, m), 8.12 (1H, d, J = 9.0)
Hz), 8.24 (1H, s), 9.15 (1H, s) 23 (2) 7-phenoxy-3- (5-pyrimidinylcarbonyl) -4H-chromen-4- ^one 1H-NMR (CDCl ₃ ) δ value ： 6.92-7.65 (8H, m), 8.03 (1H, s), 8.
26 (1H, d, J = 8.8Hz), 8.98 (1H, s), 9.23 (1H, s)

Example 24 0.10 g of 4-oxo-7- (phenylsulfanyl) -4H-chromene-3-carbaldehyde was dissolved in 2 mL of methylene chloride, and 96 mg of m-chloroperbenzoic acid was added under ice-cooling.
Stir for 15 minutes. Ethyl acetate is added to the reaction mixture, and the mixture is washed with saturated aqueous sodium hydrogen carbonate and saturated saline, and then dried. By distilling off the solvent under reduced pressure, 4
68 mg of -oxo-7- (phenylsulfinyl) -4H-chromen-3-carbaldehyde are obtained. ¹ H-NMR (CDCl ₃ ) δ value: 7.47-7.77 (6H, m), 7.99 (1H, s), 8.
34 (1H, d, J = 8.3Hz), 8.55 (1H, s), 10.35 (1H, s)

The following Example 24 was carried out in the same manner as in Example 24.
The compound of (2) is obtained. 24 (2) 6-Fluoro-4-oxo-7- (phenylsulfinyl) -4H-chromen-3-carbaldehyde ¹ H-NMR (CDCl ₃ ) δ value: 7.44-7.95 (6H, m), 8.22 (1H , d, J = 5.
1Hz), 8.58 (1H, s), 10.34 (1H, s)

Example 25 3-Acetyl-7- (4-methoxyphenoxy) -4H
-Dissolve 0.23 g of chromen-4-one in 2 mL of methylene chloride, add 0.8 mL of 1.0 M boron tribromide / methylene chloride solution, and stir at room temperature for 1 hour. Methylene chloride is added to the reaction solution, washed with water and saturated saline, and dried. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography [eluent; hexane: ethyl acetate = 5: 1] to give 3-acetyl-7- (4-hydroxyl) as a colorless solid. Phenoxy) -4H-chromen-4-one 0.18
get g. ¹ H-NMR (CDCl ₃ ) δ value: 2.74 (3H, s), 6.83-7.14 (6H, m), 8.
21 (1H, d, J = 9.0Hz), 8.51 (1H, s)

[0128]

The derivative represented by the general formula [1] or a salt thereof has a strong antifungal activity and is effective for prevention and treatment of fungal diseases in humans and animals.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/4433 A61K 31/4433 31/4453 31/4453 31/4709 31/4709 31/496 31/496 A61P 31/10 A61P 31/10 C07D 311/24 C07D 311/24 405/04 405/04 405/06 405/06 405/12 405/12 407/04 407/04 409/04 409/04 417/04 417 / 04 417/12 417/12 (72) Inventor Minoru Yonezawa 5321-1 Fzenme, Irizen-cho, Shimoshinagawa-gun, Toyama F-term (reference) 4C062 EE43 EE46 4C063 AA01 AA03 BB01 CC10 CC79 CC82 DD12 DD14 DD25 DD34 DD62 DD75 DD79 EE01 4C086 AA01 AA02 AA03 BA08 BC07 BC17 BC21 BC28 BC38 BC50 BC62 BC82 GA02 GA07 GA08 GA10 MA01 MA04 NA14 ZB35

Claims (4)

[Claims] 1. A compound of the general formula"Where R³Is an optionally substituted aryl,
Loaryl, acyl, alkylthio, arylamino,
Heteroarylamino, aryloxy, heteroaryl
Ruoxy, arylthio, heteroarylthio, aryl
Rusulfinyl, heteroarylsulfinyl, aryl
A rusulfonyl or heteroarylsulfonyl group;
¹, R²And R⁴Are the same or different hydrogen atoms,
Halogen, nitro, nitrile, protected
A hydroxyl group or an optionally substituted
Kill, cycloalkyl, alkenyl, alkylene, al
Coxy, alkylamino, acylamino, aryl, f
Teloaryl, alkylthio, arylamino, hetero
Arylamino, aryloxy, heteroaryloxy
Si, arylthio, heteroarylthio, arylsul
A is a honyl or heteroarylsulfonyl group;
A nitrile group, an optionally substituted alkenyl or
A heterocyclic group,"Where R⁵Is a hydrogen atom, an optionally substituted
Kill, cycloalkyl, aryl or heteroaryl
Group, optionally protected hydroxyl, carboxy
, Amino, hydroxyamino, alkylamino, cyclic
Amino, arylamino, heteroarylamino or
Is an acylamino group or-(Z) p-R⁷  Wherein Z is an amino acid residue;⁷Is a hydroxyl
P represents 1 or 2, respectively;
You. Y is an oxygen atom, a sulfur atom or NR⁶  "Where R⁶Is a hydrogen atom, an optionally protected
Roxyl or amino group or optionally substituted
Alkylamino, alkoxycarbonylamino, cyclic
Shows a mino or acylamino group. "
You. Or"Where R⁵’Is a hydrogen atom or optionally substituted
An alkyl, aryl or heteroaryl group; Y
¹Represents an alkoxy group, respectively. Compound represented by
Thing or its salt. 2. A is a nitrile group, which may be substituted
Alkenyl or heterocyclic group,"Where R^5aRepresents a hydrogen atom, an optionally substituted
Alkyl, aryl or heteroaryl groups, protected
Optionally hydroxyl, carboxyl, amino, arsenic
Droxyamino, alkylamino, cyclic amino, aryl
Ruamino, heteroarylamino or acylamino
A group; Y^aIs an oxygen atom, a sulfur atom or NR^6a  "Where R^6aIs a hydrogen atom or may be protected
Hydroxyl, amino or substituted
Alkylamino, alkoxycarbonylamino, cyclic
Shows a mino or acylamino group. "
You. Or"Where R^5a’Is a hydrogen atom or a substituted
Good alkyl, aryl or heteroaryl groups;
Y^1aRepresents an alkoxy group, respectively. "
Item 7. The compound according to Item 1 or a salt thereof. (3) R¹, R²And R⁴But the same or different
Is a hydrogen atom, a halogen atom, a nitro group, a nitrile group,
An optionally protected hydroxyl group or substituted
Alkyl, cycloalkyl, alkenyl, a
Lucylene, alkoxy, alkylamino, acylamino
Or an alkylthio group; A is a nitrile group,
An optionally substituted alkenyl or heterocyclic group,"Where R^5bRepresents a hydrogen atom, an optionally substituted
Alkyl, aryl or heteroaryl groups or protection
Hydroxyl, carboxyl, amino
No, arylamino or heteroarylamino group
; Y^bIs an oxygen atom, a sulfur atom or NR^6b  "Where R^6bIs a hydrogen atom, an optionally protected
Droxyl or amino group or substituted
Alkylamino, cyclic amino or acylamino groups
Is shown. ] Respectively. Or"Where R^5b’, Hydrogen or optionally substituted
An alkyl, aryl or heteroaryl group; Y
^1bRepresents an alkoxy group, respectively. "
3. The compound according to 1 or 2 or a salt thereof. 4. An antifungal agent comprising the compound according to any one of claims 1 to 3 or a salt thereof as an active ingredient.