JP2000204078A - Type i protein, geranylgeranyltransferase inhibitory compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having an excellent type I protein geranylgeranyltransferase inhibitory activity and useful as an antifungal agent having a new action mechanism. SOLUTION: This type I protein geranylgeranyltransferase inhibitory compound is a compound of formula I (X is O or NH; W is carbonyl or methylene; R is a non-aromatic heterocyclic ring, an aliphatic ring, a 7-12C aralkyl or the like; Y is an aryl substitutable with a halogen; B is H, carbamoyl or an amino 1-3C alkylcarbamoyl), e.g. a compound of formula II. The compound of the formula I is obtained by performing a condensation reaction of a compound of formula III (Tr is trityl) obtained from histamine wish a compound of formula IV [e.g.; N-(1-indanecarbonyl)-D-1-naphthylalanine] in an inert solvent such as dimethylformamide, in the presence of a base such as hydrazine- monohydrate preferably at 20-60 deg.C for 1-12 hr and then de-blocking.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention is useful in the field of medicine, and more specifically, relates to an antifungal agent based on a novel action.

[0002]

2. Description of the Related Art In the field of antifungal agents, many compounds have already been put into practical use as pharmaceuticals. For example, flucytosine is known as a less toxic antifungal agent because it is specifically taken up by certain fungi and exerts antifungal activity. Amphotericin B acts on the fungal membrane sterol to exhibit antifungal activity, and is therefore an antifungal agent that has a strong antifungal activity and a wide variety of fungal species. In view of the above-mentioned disadvantages of flucytosine and amphotericin B, azole antifungal agents such as miconazole, fluconazole, and itraconazole, which inhibit fungal ergosterol synthesis pathway and exhibit antifungal activity, are now widely used. Recently, in fungi such as the budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe, the cytoskeletal regulatory genes RHO1 and CDC42 have been identified.
Have been reported to be essential for growth for these fungi [NakanoK. et al. (Nakano Kake et al.), Genes to Cells. (jeans·
Two Cells) Volume 2, Issue 11, 679-694
, 1997] and [Miller P. et al. J. et
al. (Mirror jay, etc.), Molecula
r & Cellular Biology (Molecular and Cellular Biology) Vol. 14, No. 2
Pp. 1075-11083, 1994]. Rho1
Proteins and Cdc42 proteins belong to the Rho protein group of cytoskeletal regulation-related proteins [Tanak
a K. and Takai Y. (Tanaka K
And Takai Wai), Current Opinio
n in Cell Biology (Current Opinion in Cell Biology) Vol. 10, No. 1
112-116, 1998], type I protein geranylgeranyltransferase (GGTase
It functions only when the C-terminal is geranylgeranylated according to I) [Ohya Y .; et al. (Oya Wai et al.) Mol. Gen. Genet. (Molecular and General Genetics) 252
Vol., Pp. 1-10, 1996]. Candida albicans, a pathogenic fungus
There is no report on an enzyme that transfers a geranylgeranyl group to a protein in ns).

A compound structurally similar to the compound of the present invention is disclosed in Japanese Patent Application Laid-Open Publication No. Hei 10-182697 and has an effect as an NK-1 receptor antagonist. However, the compounds only disclose only compounds in which R in the general formula [I-1] is limited to a 3,5-bis (trifluoromethyl) benzoyl group. Further, the mechanism of action of the compounds is based on the fact that the 3,5-bis (trifluoromethyl) benzoyl group is bonded to the N-terminal amino group of the peptide, and NK-1
It merely describes the action as a receptor antagonist.

[0004] Published Japanese Patent Application No. 2-256658 discloses compounds which are structurally similar to the compounds of the present application as renin inhibitors. However, in the general formula [I-1], B is a compound in which an alkyl group having 10 or more carbon atoms is substituted with a carbamoyl group, and only those compounds that require the alkyl group to be substituted with a hydroxyl group are essential. It is only disclosed and differs from the compounds of the present invention. Further, only the action of the compounds as a renin inhibitor is disclosed.

[0005] Published Japanese Patent Application No. 3-127732 discloses compounds which are structurally similar to the compounds of the present application as vasopressin antagonists. However, the compounds only disclose compounds in which Y is an indolyl group in the general formula [I-1], and are different from the compounds of the present invention. Furthermore, only the action of the compounds as vasopressin antagonists is disclosed.

That is, in the compound of the formula [I-1] of the present invention, wherein X represents an oxygen atom or a group represented by NH for a bond, and W represents a carbonyl group or a methylene group for a bond. , R represents an unsubstituted, non-aromatic heterocyclic group, aliphatic cyclic group, C ₇ -C _{1 2} aralkyl group or C ₆
-C ₁₂ aryl group or halogen atom, cyano group, hydroxy group, amino group, carboxyl group, sulfo group, C _1-
One or two substituents selected from the group consisting of a C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a C ₆ -C ₁₂ aryl group, a C ₇ -C ₁₀ aralkyl group and a C ₆ -C ₁₂ aryloxy group A C ₇ -C ₁₂ aralkyl group, Y represents an aryl group optionally having a halogen atom substituent, and B represents a hydrogen atom, a carbamoyl group or an amino C ₁ -C ₃ alkylcarbamoyl group]. The compound to be prepared is a novel compound not described in the literature.

[0007]

The said flucytosine is:
The types of fungi that can exert their effects are limited, and have the drawback that they must be used in combination with other antifungal agents at present because of the rapid emergence of resistant bacteria (Reference A, No. 156).
-157 pages) [Iwata Kazuo, Fungi / mycosis / chemotherapy,
129-130 (1994) Soft Science, Inc.] (hereinafter referred to as Reference A), Amphotericin B
Has the disadvantage of being highly toxic because it also acts on human cell membrane sterols (Reference A, pp. 156-157).
Various azole antifungal agents that appeared to overcome the drawbacks of flucytosine and amphotericin B have been used extensively for the treatment and prevention of mycosis, resulting in the emergence of resistant bacteria to azole antifungal agents ( Reference A,
123-135). In addition, the emergence of resistant bacteria is due to the fact that azole antifungals have the same mechanism of action and similar chemical structure. Has become a serious problem that the azole antifungal agents of the present invention cannot exert a sufficient effect [Denning DW. et al. (Denning
Etc.), European Journal
of Clinical Microbiology &
Infectious Disease, (European Journal of Clinical Microbiology and Infectious Digis) No. 16
Vol. 4, No. 26, pp. 261-280, 1997]. Therefore, development of an antifungal agent with a new mechanism of action is desired.

[0008]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, have found that the above-mentioned general formula [I-1]
Have been found to have excellent inhibitory activity on type I protein geranylgeranyltransferase (GGTaseI), and completed the present invention. More specifically, the present invention relates to a compound having a type I protein geranylgeranyltransferase (GGTase I) inhibitory activity of a pathogenic fungus, and represented by the general formula [I-1]:

Embedded image [Wherein, X represents an oxygen atom or a group represented by NH for the bond, W represents a carbonyl group or a methylene group for the bond, R represents an unsubstituted non-aromatic heterocyclic group, an aliphatic ring group, A C ₇ -C ₁₂ aralkyl group or a C ₆ -C ₁₂ aryl group or a halogen atom, a cyano group, a hydroxy group, an amino group, a carboxyl group, a sulfo group, a C ₁ -C ₆ alkyl group,
C ₁ -C ₆ alkoxy group, C ₆ -C ₁₂ aryl group, C ₇ -C
C _7- having one or two substituents selected from the group consisting of a ₁₀ aralkyl group and a C ₆ -C ₁₂ aryloxy group.
A C ₁₂ aralkyl group, Y represents an aryl group which may have a substituent of a halogen atom, and B represents a hydrogen atom, a carbamoyl group or an amino C ₁ -C ₃ alkylcarbamoyl group]. It relates to the described novel compounds.

More specifically, the present invention relates to an excellent fungal I
Type protein geranylgeranyltransferase (G
General formula [I-2] having GTase I) inhibitory activity

Embedded image [Wherein, B, W and R mean the above description, Y ₁ represents a naphthyl group, and X ₁ represents an oxygen atom] and a general formula [I-4]

Embedded image [Wherein, B, R and Y have the meanings described above, X ₂ represents NH involved in the bond, and W ₁ represents a carbonyl group involved in the bond]. Things.

[0010] The symbols and terms described in this specification will be described. The C ₁ -C ₆ alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec- Butyl, tert-butyl, pentyl, isopentyl, neopentyl and the like.

The C ₆ -C ₁₂ aryl group means a monocyclic or polycyclic aryl group having 6 to 12 carbon atoms, such as a phenyl group and a naphthyl group.

The C ₁ -C ₆ alkoxy group means a group in which an oxygen atom is substituted by the above-mentioned C ₁ -C ₆ alkyl group, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group. Group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group and the like.

The C ₆ -C ₁₂ aryloxy group means a group in which an oxygen atom is substituted by the C ₆ -C ₁₂ aryl group,
Examples include a phenoxy group and a naphthyloxy group.

A C ₇ -C ₁₂ aralkyl group is the same as the aforementioned C ₁ -C 12
_{A 3-} alkyl group substituted with the above-mentioned C ₆ -C ₁₂ aryl group, which means an aralkyl group having 7 to 12 carbon atoms as a whole, such as a benzyl group, a phenethyl group, a phenylpropyl group, a phenylbutyl group, a naphthyl group; Examples include a methyl group and a naphthylethyl group.

A C ₇ -C ₁₀ aralkyl group is the same as the aforementioned C ₇ -C 10
₁₂ aralkyl groups having 7 to 10 carbon atoms as a whole
Means an aralkyl group of

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The non-aromatic heterocyclic group is a 5- to 7-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, or the monocyclic heterocyclic group. means a heterocyclic group and the C ₃ -C ₆ cycloalkyl group, the C ₆ -C ₁₂ aryl group or the same or different from monocyclic fused heterocyclic group which heterocyclic group is fused,
For example, a dihydrothienyl group, a tetrahydropyranyl group,
Tetrahydrofuranyl group, tetrahydrothienyl group, pyrrolinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, dihydrothiopyranyl group, tetrahydrothiopyranyl group, thiomorpholinyl group, morpholinyl group, indolinyl group, chromanyl group, isochromanyl group, thiochromanyl group, Examples include a xanthenyl group and a benzodioxanyl group.

The aliphatic ring group is a 5- to 7-membered non-aromatic ring group or the monocyclic ring group and the C ₃ -C ₆ cycloalkyl group, the C ₆ -C ₁₂ aryl group or the same or different. Means a fused cyclic group to which another monocyclic group is fused,
Examples include an indanyl group, a tetrahydronaphthyl group, a trihydronaphthyl group, a dihydronaphthyl group, a fluorene group and the like.

An amino C ₁ -C ₃ alkyl group is one having 1 carbon atom.
Represents a group in which an amino group is substituted on an alkyl group of 1 to 3,
Examples include an aminomethyl group, an aminoethyl group, an aminopropyl group and the like.

Amino C₁-C_ThreeAlkylcarbamoyl group and
Represents the amino C ₁-C_ThreeAlkyl group
A substituted group means an aminomethylcarbamoyl group,
Minoethylcarbamoyl group, aminopropylcarbamoy
And the like.

B is a compound represented by a hydrogen atom, a carbamoyl group or an amino C ₁ -C ₃ alkylcarbamoyl group. Preferably, B is a compound represented by a hydrogen atom, a carbamoyl group or an aminoethylcarbamoyl group.

X is a compound represented by an oxygen atom or a group represented by NH for bonding.

W is a compound represented by a carbonyl group or a methylene group for the bond.

Y is a compound represented by an aryl group.
The aryl group may be unsubstituted or may have a halogen atom substituent.

Specific examples of Y include, for example, a phenyl group,
Naphthyl group, fluorophenyl group, chlorophenyl group,
Examples thereof include a dichlorophenyl group, a fluoronaphthyl group and a chloronaphthyl group.

Among them, for example, a naphthyl group or a dichlorophenyl group is preferable.

R is an unsubstituted compound represented by a non-aromatic heterocyclic group, an aliphatic ring group, a C ₇ -C ₁₂ aralkyl group or a C ₆ -C ₁₂ aryl group. The non-aromatic heterocyclic group, the aliphatic ring group or the C ₇ -C ₁₂ aralkyl group may be unsubstituted or a halogen atom, a cyano group, a hydroxy group, an amino group, a carboxyl group, a sulfo group, ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₆ -C ₁₂ aryl group, substituted C ₇ -C ₁₀ 1 or 2 selected from aralkyl and C ₆ -C ₁₂ group consisting of aryloxy groups It may have a group.

Specific examples of R include, for example, benzodioxy
Sanyl group, thiochromanyl group, xanthene group, phenyl
Group, naphthyl group, phenylmethyl group, indanyl group,
Examples include a trahydronaphthyl group or a fluorene group.
The benzodioxanyl group, the thiochromanyl group,
Phenyl, naphthyl, phenylmethyl,
A tyl group, the indanyl group, the tetrahydronaphthyl group,
Alternatively, the fluorene group may be unsubstituted or halo.
Gen atom, cyano group, hydroxy group, amino group, carbo
Xyl group, sulfo group, C₁-C₆Alkyl group, C₁-C₆A
Lucoxy group, C ₆-C₁₂Aryl group, C₇-C_TenAralki
And C₆-C₁₂Having a substituent of an aryloxy group
May be.

Among them, for example, R is an unsubstituted benzodioxanyl group having a benzodioxanyl group, a thiochromanyl group, a xanthene group, a naphthyl group, a phenylmethyl group, an indanyl group, a tetrahydronaphthyl group, a fluorene group or a phenyl group. Groups, a thiochromanyl group, a xanthene group, a naphthyl group, a phenylmethyl group, an indanyl group, a tetrahydronaphthyl group or a fluorene group.

The compound of the formula [I-1] of the present invention will be described. Among the compounds of the general formula [I-1], a compound of the general formula [I-2] or a compound of the general formula [I-4] is preferable.

Of the compounds of the general formula [I-2], the compounds of the general formula [I-3] are more preferred. The general formula [I-
Among the compounds of the formula [4], the compound of the formula [I-5] is more preferred, and the compound of the formula [I-6] is most preferred.

The compound represented by the general formula [I-1] may have any steric structure. For example, a compound having a steric structure represented by the following general formula [I-7] is mentioned as a preferred compound. Can be

Embedded image

Examples of the hydroxy-protecting group include lower alkylsilyl groups such as trimethylsilyl and tert-butyldimethylsilyl; methoxymethyl,
Lower alkoxymethyl group such as 2-methoxyethoxymethyl group; for example, tetrahydropyranyl group; for example, benzyl group, p-methoxybenzyl group, p-nitrobenzyl group,
An aralkyl group such as a trityl group; examples thereof include an acyl group such as a formyl group and an acetyl group, and particularly, a methoxymethyl group, a tetrahydropyranyl group, a trityl group, and a tert- group;
A butyldimethylsilyl group, an acetyl group and the like are preferred.

Examples of the amino-protecting group include aralkylidene groups such as benzylidene group, p-chlorobenzylidene group and p-nitrobenzylidene group;
aralkyl groups such as p-methoxybenzyl group, p-nitrobenzyl group, benzhydryl group and trityl group; for example, formyl group, acetyl group, propionyl group, butyryl group,
Lower alkanoyl group such as pivaloyl group; lower haloalkanoyl group such as trifluoroacetyl group; lower alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, tert-butoxycarbonyl group; Lower haloalkoxycarbonyl group such as 2-trichloroethoxycarbonyl group; alkenyloxycarbonyl group such as 2-propenyloxycarbonyl group; aralkyloxycarbonyl group such as benzyloxycarbonyl group and p-nitrobenzyloxycarbonyl group; Groups, lower alkylsilyl groups such as tert-butyldimethylsilyl group, etc., and particularly, acetyl group, trifluoroacetyl group, tert-butoxycarbonyl group, benzyl group and the like. Butoxycarbonyl group and the like.

Examples of carboxyl-protecting groups include methyl, ethyl, propyl, isopropyl, t
lower alkyl groups such as tert-butyl group;
Lower haloalkyl groups such as 2-trichloroethyl group; lower alkenyl groups such as 2-propenyl group; aralkyl groups such as benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, benzhydryl group and trityl group; And particularly preferably a methyl group, an ethyl group, a tert-butyl group, a 2-propenyl group, a benzyl group, a p-methoxybenzyl group, a benzhydryl group and the like.

The salt of the compound represented by the general formula [I-1] means a conventional pharmaceutically acceptable salt. For example, when the compound has a carboxyl group or another acidic group, a base in the acidic group is used. Salts of an acid addition salt in the amino group or the basic heteroaromatic ring in the case of having an amino group or a basic heterocyclic ring in the case of having an amino group can be exemplified.

Examples of the base addition salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt, dicyclohexylamine salt And organic amine salts such as ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt and N, N'-dibenzylethylenediamine salt.

The acid addition salts include, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, perchlorate, etc .; for example, maleate, fumarate, tartrate, citrate, ascorbin Organic acid salts such as acid salts and trifluoroacetic acid salts; and sulfonic acid salts such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate.

The ester of the compound represented by the general formula [I-1] means a conventional pharmaceutically acceptable carboxyl group having a carboxyl group, such as a methyl group or an ethyl group. , Propyl, isopropyl, butyl, sec-butyl, tert
-Butyl group, pentyl group, isopentyl group, neopentyl group, cyclopropyl group, cyclobutyl group, esters with lower alkyl groups such as cyclopentyl group, benzyl group,
Esters with aralkyl groups such as phenethyl group, esters with lower alkenyl groups such as aryl group and 2-butenyl group, esters with lower alkoxyalkyl groups such as methoxymethyl group, 2-methoxyethyl group and 2-ethoxyethyl group An acetoxymethyl group, a pivaloyloxymethyl group, an ester with a lower alkanoyloxyalkyl group such as a 1-pivaloyloxyethyl group, a methoxycarbonylmethyl group, a lower alkoxycarbonylalkyl group such as an isopropoxycarbonylmethyl group. Esters, esters with a lower carboxyalkyl group such as a carboxymethyl group, 1- (ethoxycarbonyloxy) ethyl group,
(Cyclohexyloxycarbonyloxy) an ester with a lower alkoxycarbonyloxyalkyl group such as an ethyl group, an ester with a lower carbamoyloxyalkyl group such as a carbamoyloxymethyl group, an ester with a phthalidyl group, (5-methyl-2-oxo- Esters with a (5-substituted-2-oxo-1,3-dioxol-4-yl) methyl group such as a 1,3-dioxol-4-yl) methyl group.

Next, a method for producing the compound of the present invention will be described. The compound of the general formula [I-1] of the present invention can be produced by the following production methods.

Manufacturing method [Wherein, Tr represents a trityl group, and B, R, W, X, Y
Means the above description] The compound of the present invention is obtained by condensing a known compound or a compound (II) and a compound (III) produced by a known method in the presence of a base and then deprotecting the compound (I- 1) can be manufactured. The reaction is carried out in an inert organic solvent, optionally in the presence of a base (II)
The compound of the formula (III) is used in an amount of at least 1 mol, preferably 1 to 10 mol, more preferably 2 to 5 molar equivalents to the compound of the formula (1). The amount of each reagent used is not particularly limited, and can be varied over a wide range depending on the type of the compound, reaction conditions, and the like.

Examples of the inert organic solvent include dimethylformamide, methylene chloride, and a mixed solvent thereof.

The reaction can be carried out usually at a temperature in the range of about -20 ° C. to the boiling point of the solvent, and if necessary, it can be carried out at a lower temperature.
° C to 60 ° C.

The reaction time can be generally from 10 minutes to 24 hours, and can be longer or shorter as necessary, but is preferably 1 hour to 12 hours.

At this time, it is preferred that the functional groups not involved in the reaction are protected if necessary, and deprotected after the reaction.
In introducing these substituents, well-known methods for introducing substituents in the field of chemistry, for example, alkylation, alkenylation, alkynylation, aralkylation, alkanoylation, arylation, thiocarbonylation, sulfonylation, carbamate And carbamidation. These terms are to be interpreted in a broad sense. For example, alkanoylation means introduction of a substituted or unsubstituted alkanoyl group included in the present invention, and a substituent is introduced into the compound of the present invention of the general formula [I-1]. Means all reactions that are performed.

In the above-mentioned method, examples of the protecting group for the functional group which does not participate in the reaction include the above-mentioned protecting group for the hydroxy group, protecting group for the amino group, and protecting group for the carboxyl group, and the like.

The introduction and removal of the protecting group can be carried out, for example, by the method described in the literature [Protective Gross in Organic Synthesis (Protective Gross).
upsin Organic Synthesis),
T. W. JW by TW Greene
n Wiley & Sons (1981)]
Alternatively, it can be carried out using any ordinary method widely known in the field of chemistry, such as a method analogous thereto.

The isolation and purification of the compound produced by the above reaction can be performed by a method known per se in the field of organic chemistry,
For example, it can be performed by a precipitation method, a solvent extraction method, recrystallization, chromatography or the like.

Next, in order to show the usefulness of the compound of the present invention, the type I protein geranylgeranyltransferase inhibitory activity of the compound of the present invention was measured.

The general formula [I-1] provided by the present invention
Exhibit excellent fungal GGTase I inhibitory activity, as seen in the following biological activities: Table 1 shows the 50% inhibitory concentration (IC50).

[0051]

[Table 1]

Method for Measuring Fungal Type I Protein Geranylgeranyltransferase Activity Preparation of Enzyme Bacterial Solution Candida albicans
ans) ATCC 90028 was shake-cultured at 30 ° C in a YPD medium (1% yeast extract, 2% peptone, 2% glucose), and the cells were precipitated and recovered by centrifugation in the late logarithmic growth phase. Equivalent amount of cell lysate (50 mM Tris-HCl pH 7.5, 1 mM ethylenediaminetetraacetic acid, 1 m)
M ethylene glycol bis (2-aminoethyl ether) tetraacetic acid, 5 mM dithiothreitol (DTT),
0.1 mM leupeptin, 0.1 μM pepstatin A,
0.2 mM phenylmethylsulfonyl fluoride,
0.1 mM Nα-tosyl-L-lysyl chloromethyl ketone, 0.1 mg / ml soybean trypsin inhibitor, 2 μg / ml aprotinin, 2.5 μg /
ml antipine) and twice the amount of glass beads having a diameter of 0.5 mm were added, and the cells were disrupted by sonication and stirring under ice cooling. After removing unbroken cells by centrifugation at 10,000 × g for 10 minutes, a cytoplasmic fraction was prepared by centrifugation at 100,000 g for 60 minutes, and further, ammonium sulfate precipitate obtained by 30-70% saturated ammonium sulfate. Then, collect the column equilibration solution (20 mM Tris-HCl pH 7.5 (4 ° C.), 1 mM
Dialysis against dithiothreitol, 20 μM zinc chloride). This was combined with MonoQ (Amersha) previously equilibrated against the column equilibration solution.
mPharmacia Biotech)) was applied to an anion exchange column and fractions eluted with a 0-0.5M sodium chloride gradient were fractionated. GGTase
I activity eluted at 0.36 M sodium chloride.

Measurement of GGTase I enzyme activity White polystyrene 96-well plate (Optiplat
e, Packard) with solution A [50 mM Hepes (Hepe
s) pH 7.5 (30-C), 12.5 mM DTT,
25 mM magnesium chloride (MgCl ₂ ), 125 μM
Zinc chloride (ZnCl ₂ ), 9.25 μM biotin-CO
NH- (CH ₂ ) ₅ -CO-TRERRKKKKCVIL
(Sawaddy Technology Co., Ltd.)] was dispensed in 20 μl aliquots, and the solution B [50 mM Hepes pH 7.5 (30-C),
0.1% Triton X-100, 0.1%
15 μM [ ³ H] geranylgeranyl pyrophosphate (GGP
P) 814GBq / mmol] was dispensed in 10 μl portions. Thereafter, the test compound dissolved in dimethyl sulfoxide (DMSO) (D was adjusted to 50 times the measured concentration.
(A dilution series was prepared with MSO) in 1 μl portions, and after stirring, the mixture was kept at 30 ° C. for 10 minutes. 50 mM Hepes (H
epes) The reaction was started by dispensing 19 μl of an enzyme solution of an appropriate concentration diluted at pH 7.5 (30-C), and the mixture was stirred and kept at 30-C for 20 minutes. Liquid C [pH 3.5
80 mM phosphoric acid, 600 mM magnesium chloride (M
gCl ₂ ), 1.25% skim milk
lk), 2.5% bovine serum (Bovine Serum)
Albumin) and SPA beads coated with streptavidin [streptavidin-
coated SPA beads (Amersham
Pharmacia Biotech)] 7.5m
g / ml], and the mixture was stirred at room temperature for 60 minutes to terminate the reaction.
After binding to PA beads, top count (Topc
The radioactivity of the reaction product was measured using “out” (Packard).

Therefore, the final concentration of the reaction solution was 50 mM Hepes pH 7.5 (30-C), 5 mM dithiothreitol,
0 mM magnesium chloride (MgCl ₂ ), 50 μM zinc chloride (ZnCl ₂ ), 0.02% Triton (Tri
ton) X-100, 3.7 μM biotin-CONH—
(CH ₂ ) ₅ —CO-TRERRKKKKCVIL, 0.
03 μM [ ³ H] geranylgeranyl pyrophosphate (GGP
P) 814 GBq / mmol, 2% dimethylsulfoxide (DMSO) and enzyme fraction. The amount of the enzyme is within a range where the amount of the enzyme is proportional to the GGTase I activity, and the GGTase I activity is 1000 Topcount.
It was determined to be around t-SPA-cpm. For each measurement, instead of the solution A, a solution D (a 9.25 μM biotin-CONH- (CH ₂ ) ₅ -CO-TRERRKK from the solution A) was used.
The well using KKCVIL) was used as a blank, and the difference from the count of the group (vehicle control) to which DMSO containing no test compound was added and solution A (vehicle control) was defined as 100% activity, and the inhibition value of GGTase I activity was determined. Was determined, and the IC ₅₀ value was determined by probit plotting based on the obtained% inhibition value.

The compound of the present invention is a compound having a completely different mechanism of action from conventional antifungal agents, has the characteristic of inhibiting the type I protein geranylgeranyltransferase, which is essential for fungal growth, and has a low Since it has inhibitory activity at a concentration, it is extremely useful as an antifungal agent.

Compounds of the invention or fungal GGTase I
The inhibitory composition can be administered orally or parenterally when used clinically, and if necessary, various pharmaceutically acceptable additives can be added and formulated according to the dosage form. Can be used as an antifungal agent. Examples of the dosage form upon formulation include solid preparations such as tablets, capsules, granules, pills, troches, powders and suppositories, such as syrups, elixirs, suspensions and injections. In addition to liquid formulations, aerosols,
Examples include eye drops, ointments, eye ointments, emulsions, creams, liniments, lotions, and the like, which can be prepared according to ordinary methods in the field of pharmaceuticals.

As the additives, various additives usually used in the field of pharmaceutical preparations can be used. For example, sugars such as lactose or glucose, for example, starches such as corn, wheat or rice, for example, soybean oil, peanut oil or Vegetable oils such as sesame oil; fatty acids such as stearic acid; inorganic salts such as magnesium metasilicate aluminate or anhydrous calcium phosphate; synthetic polymers such as polyvinylpyrrolidone or polyalkylene glycol; fatty acid salts such as calcium stearate or magnesium stearate For example, alcohols such as stearyl alcohol or benzyl alcohol, for example, methylcellulose, carboxymethylcellulose, ethylcellulose or hydroxypropylmethylcellulose Synthetic cellulose derivatives, other,
Water, gelatin, talc, gum arabic and the like.

The liquid preparation may be in the form of being dissolved or suspended in water or another suitable medium at the time of use. In particular, in the case of administration by intramuscular injection, intravenous injection, subcutaneous injection, etc., suitable vehicles for the injection include distilled water for injection, aqueous lidocaine hydrochloride (for intramuscular injection), physiological saline, aqueous glucose, ethanol Liquid for intravenous injection (for example, aqueous solution of citric acid and sodium citrate) or electrolyte solution (for intravenous drip and intravenous injection)
Or a mixed solution thereof, and a buffer or a preservative may be further added.

These preparations can contain 0.1 to 100% by weight, preferably 5 to 100% by weight, of the active ingredient in the case of the above solid preparations.
It may contain from 0.1 to 10% by weight, preferably from 1 to 5% by weight, of active ingredient. Actually preferred dosages of the compounds or antifungal compositions of the invention will depend on the type of compound used, the type of composition formulated, the sex, age, weight, severity of the condition and the specific site to be treated. In general, the daily dose for oral administration is 0.1
１００100 mg / kg, and for parenteral administration, 0.0
1 to 100 mg / kg. The number of administrations varies depending on the administration method and symptoms, but it is preferable to administer the administration once to five times a day.

As described above, according to the present invention, useful antifungal agents can be provided, and needless to say, new methods for treating fungal infections using these can be provided.

[0061]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described more specifically with reference to Examples, Preparation Examples and Reference Examples, but the present invention is not limited thereto. NM below
The meaning of the symbol in R measurement is shown. s: singlet d: doublet t: triplet q: quartet m: multiplet br: blade J: coupling constant Hz: hertz

Embodiment 1

Embedded image Production of the compound represented by Histamine (1.1 g) was dissolved in dimethylformamide (20 ml), 2-acetyldimedone (2 g) was added, and the mixture was stirred at room temperature for 24 hours. The solvent was concentrated under reduced pressure, the residue was poured into water, and extracted with ethyl acetate.
The organic layer was dried and concentrated, and the residue was purified using silica gel chromatography (chloroform-methanol = 20: 1) to obtain 850 mg of an adduct. 400 mg of adduct
Was dissolved in 10 ml of benzene, 853 mg of triphenylmethyl chloride and 0.53 ml of triethylamine were added, and the mixture was heated under reflux for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified using thin-layer silica gel chromatography (chloroform-methanol = 5: 1) to obtain 540 mg of a trityl compound.
I got The obtained trityl compound was converted to dimethylformamide 4
hydrazine monohydrate (0.08 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure, and the residue was purified using thin-layer silica gel chromatography (chloroform-methanol = 5: 1).
g was obtained. 42 mg of the amine compound is 18 mg of N- (1-indanecarbonyl) -D-1-naphthylalanine, 24 mg of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (EDC), 18 mg of N-hydroxybenzotriazole is dimethylformamide Dissolved in 0.5 ml and stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure,
The residue was dissolved in 50% trifluoroacetic acid-5% triisopropylsilane-45% dichloromethane (1 ml) and stirred at room temperature for 5 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified using thin-layer silica gel chromatography (chloroform-methanol = 4: 1) to obtain 6 mg of the desired compound (1).
I got Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
CDCl ₃ ): δ 7.08-8.12 (12H, m),
6.69-6.76 (1H, m), 6.51-6.63
(2H, m), 4.704.80 (1H, m), 2.3
8-3.57 (11H, m) mass spectrometry; [FAB-MS] m / z: 453 [M + H]
⁺

Embodiment 2

Embedded image Production of a compound represented by the following formula: The compound was produced by the method shown in the following step (2-1) and step (2-2).

Embedded image Step (2-1) 1.2 g of the acetyldimedone adduct obtained in Example 1, 1.5 ml of triethylamine and 10 ml of benzene were dissolved in
4-methoxychlorotrityl resin (0.7 mmol /
g, 1 g) and stirred at 80 ° C. for 15 hours. Resin is dimethylformamide, dimethylformamide-
5 times each in the order of water mixture, methanol and dichloromethane
Washed one by one. 1 g of the obtained resin is suspended in 7 ml of dimethylformamide, and 0.7 m of hydrazine monohydrate is suspended.
and stirred at room temperature for 2 hours. The resin was washed four times each in the order of dimethylformamide, a dimethylformamide-water mixture, methanol and dichloromethane to obtain 1 g of the desired resin. Infrared absorption spectrum; ν _max (KBr) cm ^-1 : 16
52, 1508, 1276, 1246, 1176, 82
7,700 Step (2-2) 100 mg of the resin (29) obtained in the step (2-1) is suspended in 3 ml of dimethylformamide, and N-Fmoc-D-
1-Naphthylalanine (Novabiochem) 6
1 mg (Fmoc is a 9-fluorenemethyloxycarbonyl group, the same applies hereinafter), 1,3-diisopropylcarbodiimide 0.02 ml, and N-hydroxybenzotriazole 16 mg were added, and the mixture was stirred at room temperature for 16 hours. The resin was washed three times in the order of dimethylformamide, methanol and dichloromethane. A 20% piperidine-dimethylformamide solution (3 ml) was added to 100 mg of the obtained resin, followed by stirring at room temperature for 20 minutes.
The resin was washed three times in the order of dimethylformamide, methanol and dichloromethane. 100 mg of the obtained resin was suspended in 3 ml of dimethylformamide,
32 mg of xanthene-9-carboxylic acid, 0.02 ml of 1,3-diisopropylcarbodiimide and 16 mg of N-hydroxybenzotriazole were added, and the mixture was stirred at room temperature for 22 hours. Resin is dimethylformamide, methanol,
Washing was performed three times in the order of dichloromethane. 50% trifluoroacetic acid-5% to 100 mg of the obtained resin
Triisopropylsilane-45% dichloromethane (1 m
l) was added and the mixture was stirred at room temperature for 5 minutes. The resin was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using thin-layer silica gel chromatography (chloroform-methanol = 4: 1) to obtain 6 mg of the desired compound (2). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
CD ₃ OD): δ 8.13 (1H, d, J = 8.5H)
z), 7.85 (1H, d, J = 8.2 Hz), 7.7
6 (1H, d, J = 7.5 Hz), 7.54 (1H,
s), 6.81-7.48 (13H, m), 4.91.
(1H, s), 4.66-4.71 (1H, m), 3.
51 (1H, dd, J = 12, 6.9 Hz), 3.38
(1H, dd, 12, 8.5 Hz), 3.27-3.3
5 (2H, m), 2.56 (2H, td, J = 7.0,
2.2Hz)

Embodiment 3

Embedded image Production of the compound represented by the formula: 100 mg of the resin (29) obtained in the step (2-1) was suspended in 3 ml of dimethylformamide, and N-Fmoc-D-
(3,4-dichlorophenyl) alanine (Watanabe Chemical) 6
8 mg, 1,3-diisopropylcarbodiimide 0.0
2 ml and 16 mg of N-hydroxybenzotriazole were added, and the mixture was stirred at room temperature for 16 hours. The resin was washed three times in the order of dimethylformamide, methanol and dichloromethane. 20% for 100 mg of the obtained resin
Add 3 ml of piperidine-dimethylformamide solution,
Stirred at room temperature for 20 minutes. The resin was washed three times in the order of dimethylformamide, methanol and dichloromethane. The obtained resin (100 mg) was suspended in dimethylformamide (3 ml), and xanthene-9-carboxylic acid (32 mg) and 1,3-diisopropylcarbodiimide (0.1 mg) were suspended.
02 ml, N-hydroxybenzotriazole 16 mg
Was added and stirred at room temperature for 22 hours. The resin was washed three times in the order of dimethylformamide, methanol and dichloromethane. 50 to 100 mg of resin obtained
% Trifluoroacetic acid-5% triisopropylsilane-4
5% dichloromethane (1 ml) was added, and the mixture was stirred at room temperature for 5 minutes. The resin was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to thin-layer silica gel chromatography (chloroform-
Purification was performed using methanol (4: 1) to obtain 3.8 mg of the target compound (4). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
CD ₃ OD): δ 7.61 (1H, s), 6.78 −
7.37 (12H, m), 4.89 (1H, s), 4.
55 (1H, dd, J = 9.4, 5.6 Hz), 3.3
9 (2H, t, 6.9 Hz), 3.05 (1H, dd,
J = 14.2, 5.6 Hz), 2.86 (1H, dd,
14.2, 9.4 Hz), 2.70 (2H, t, J =
6.9 Hz)

Embodiment 4

Embedded image Preparation of the compound represented by Am. Chem. Soc. (journal
Of American Chemical Socieati) No. 53
According to page 26, 1964, 900 mg of D-2-hydroxy-3- (1-naphthyl) propionic acid was obtained from 2.15 g of D-1-naphthylalanine. 450 mg of the obtained crude crystals were dissolved in a mixed solvent of 3 ml of methanol and 3 ml of benzene, and a hexane solution of 2N-trimethylsilyldiazomethane was added until the reaction solution became yellow. The mixture was stirred at room temperature for 30 minutes, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane-ethyl acetate = 2: 1) to obtain 300 mg of the corresponding methyl ester (yield 2).
6%). Subsequently, 10 mg of NaH (60%) was suspended in 1 ml of dimethylformamide, and after cooling with ice, a solution of 46 mg of the above methyl ester in 1.0 ml of dimethylamide and 2
66.3 mg of -naphthylmethyl bromide were added sequentially.
After stirring at room temperature overnight, the mixture was partitioned between water and ethyl acetate, and the organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate = 4: 1) to obtain 50 mg of the corresponding 2-naphthyl methyl ether (yield 50%). The obtained ether was dissolved in a mixed solvent of 0.5 ml of 1,4-dioxane and 0.5 ml of methyl alcohol, and 1.5 ml of 1N-NaOH was added dropwise. After stirring at room temperature overnight, the mixture was made weakly acidic with 1N-HCl and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried and concentrated to obtain 60 mg of a crude product. The above crude crystal 30
mg and N (im) -tritylhistamine 42 mg, N-
Hydroxybenzoliazole (18.4 mg) was dissolved in dimethylformamide (2 ml), and after cooling with ice, 15.3-mg of 1,3-diisopropylcarbodiimide was added, followed by stirring at room temperature overnight. Partition with water-ethyl acetate and separate the organic layer with 1N-HC.
After washing with 1, the mixture was dried and concentrated. Thin layer silica gel chromatography (chloroform-methyl alcohol = 20:
Purification in 1) gave the corresponding amide. This amide was dissolved in 4 ml of 5% triethylsilane-50% trifluoroacetic acid-methylene chloride and stirred at room temperature for 2 hours. After concentration under reduced pressure, the mixture was partitioned with saturated aqueous sodium hydrogen carbonate-chloroform, and the organic layer was dried and concentrated. The residue is subjected to thin-layer silica gel chromatography (chloroform-methyl alcohol =
5: 1) to give 8.0 mg of the target compound (5) (yield 28%). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
CDCl ₃ ): δ 8.10-8.20 (1H, m),
7.70-7.89 (3H, m), 7.53-7.68
(2H, m), 7.30-7.50 (8H, m), 7.
10-7.20 (1H, m), 6.67 (1H, S),
4.42 (1H, d, J = 11.8 Hz), 4.20−
4.30 (2H, m), 3.77 (1H, dd, J =
3.1, 14.3 Hz), 3.48-3.52 (2H,
m), 3.25 (1H, dd, J = 9.0, 14.3H
z), 2.62-2.82 (2H, m) mass spectrometry; [FAB-MS] m / z: 450 [M + H].
⁺

Embodiment 5

Embedded image Production of D-2-hydroxy-3- (1-naphthyl) propionic acid 200 mg and N (im) -tritylhistamine 390
mg and N-hydroxybenzotriazole (207 mg) were dissolved in dimethylformamide (4 ml).
212 ml of diisopropylcarbodiimide was added, and the mixture was stirred at room temperature overnight. Partition with water-ethyl acetate and separate the organic layer with 1N
After washing with -HCl, dried and concentrated. Purification by silica gel column chromatography (chloroform-methyl alcohol = 20: 1) gave 450 mg of the corresponding amide (91% yield). Subsequently, 55 mg of this amide and 34 mg of 9-xanthenecarboxylic acid were added to dimethylformamide 3
dissolved in N, N-dimethylaminopyridine 18m
g, EDC. HCl (29 mg) was added sequentially. The mixture was stirred overnight at room temperature, partitioned with saturated aqueous sodium hydrogen carbonate-ethyl acetate, and the organic layer was washed with 1N-HCl, dried and concentrated.
Purification by thin layer silica gel chromatography (hexane-ethyl acetate = 1: 2) gave 23.4 mg of the ester (30% yield). This ester was dissolved in 3 ml of 5% -triethylsilane-50% trifluoroacetic acid-methylene chloride and stirred at room temperature for 2 hours. After concentration under reduced pressure, the mixture was partitioned with saturated aqueous sodium hydrogen carbonate-chloroform and the organic layer was dried.
Concentrated. The residue was purified by thin-layer silica gel chromatography (chloroform-methyl alcohol = 10: 1) to obtain 11.0 mg of the desired compound (6) (yield 70%). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
CDCl ₃ ): 8.04 (1H, d, J = 8.0H)
z), 7.80 (1H, d, J = 8.0 Hz), 7.7
4 (1H, d, J = 8.0 Hz), 7.40-7.52
(3H, m), 7.35 (1H, t, J = 8.0H
z), 6.95-7.20 (8H, m), 6.71 (1
H, d, J = 8.0 Hz), 6.57 (1H, S),
5.57-5.67 (1H, m), 5.51 (1H, d
d, J = 3.6, 9.0 Hz), 4.90 (1H,
S), 3.65 (1H, dd, J = 3.6, 14.6H)
z), 3.20-3.35 (2H, m), 3.00-
3.10 (1H, m), 2.28-2.52 (2H,
m) Mass spectrometry; [FAB-MS] m / z: 518 [M + H]
⁺

Embodiment 6

Embedded image Production of a compound represented by the following procedure was repeated, except that 9-xanthencarboxylic acid of Example 5 was replaced with 2-indanecarboxylic acid, to thereby obtain 4.2 mg of the target compound (7) (yield 9%). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
CDCl ₃ ): 8.12 (1H, d, J = 7.6H)
z), 7.85 (1H, d, J = 8.2 Hz), 7.7
5 (1H, d, J = 7.6 Hz), 7.42-7.53
(2H, m), 7.30-7.40 (3H, m), 7.
13 (4H, m), 6.61-6.80 (2H, m),
5.48 (1H, dd, J = 4.6, 8.1 Hz),
3.81 (1H, dd, J = 4.7, 14.4 Hz),
3.35-3.58 (3H, m), 3.16-3.30
(1H, m), 2.82-3.10 (4H, m), 2.
65 (2H, t, J = 6.2 Hz) mass spectrometry; [FAB-MS] m / z: 454 [M + H]
⁺

Embodiment 7

Embedded image Production of Compound Represented by Replacing 2-Naphthylmethylbromide of Example 4 with 1-naphthylmethylbromide and performing the same operation,
6.3 mg of the target compound (8) was obtained (yield 23%). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
_{CDCl 3): 8.10-8.20 (1H,} m), 7.
69-7.89 (3H, m), 7.32-7.58 (4
H, m), 7.18-7.29 (2H, m), 7.03
−7.09 (1H, m), 6.90-6.98 (1H,
m), 6.67 (1H, s), 4.32-4.38 (1
H, m), 3.86-4.18 (2H, m), 3.76
(1H, dd, J = 3.1, 14.3 Hz), 3.36
-3.45 (2H, m), 3.22 (1H, dd, J =
9.0, 14.3 Hz), 2.43-2.62 (2H,
m) Mass spectrometry; [FAB-MS] m / z: 450 [M + H]
⁺

Embodiment 8

Embedded image Production of a compound represented by the following procedure: The 9-xanthenecarboxylic acid of Example 5 was replaced with 1-naphthalenecarboxylic acid, and the same operation was carried out to obtain 3.5 mg of the target compound (9) (yield: 7%). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
CDCl ₃ ): 8.69 (1H, t, J = 4.5H)
z), 8.23 (1H, d, J = 7.5 Hz), 8.0
0-8.03 (2H, m), 7.86-7.88 (2
H, m), 7.76 (1H, d, J = 9.0 Hz),
7.34-7.55 (7H, m), 7.08 (1H,
s), 6.59-7.08 (1H, m), 6.59 (1
H, s), 5.78-5.82 (1H, m), 4.98
(1H, dd, J = 4.8, 14.7 Hz), 3.71
(1H, dd, J = 7.8, 14.8 Hz), 3.45
-3.53 (2H, m), 2.64-2.68 (2H,
m) Mass spectrometry; [FAB-MS] m / z: 464 [M + H]
⁺

Embodiment 9

Embedded image Production of the compound represented by the formula: 9-xanthencarboxylic acid in Example 5 was replaced with 2-naphthalenecarboxylic acid, and the same operation was carried out to obtain 4.5 mg of the target compound (36) (yield: 10%). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
CDCl ₃ ): 8.43 (1H, s), 8.25 (1
H, d, J = 8.4 Hz), 7.82-7.95 (5
H. m), 7.75 (1 Hd, J = 8.1 Hz),
7.44-7.64 (6H, m), 7.36 (1H,
t, J = 8.1 Hz), 7.04-7.10 (2H,
m), 6.60 (1H, s), 5.77 (1H, dd,
J = 4.5, 7, 7 Hz), 3.95 (1H, dd, J)
= 4.8, 14.5 Hz), 3.73 (1H, dd, J)
= 7.2, 14.4 Hz), 3.44-3.56 (2
H, m), 2.56-2.72 (2H, m) mass spectrometry; [FAB-MS] m / z: 464 [M + H].
⁺

Embodiment 10

Embedded image Production of compound represented by the formula: Linkamide MBHA resin (Novabiochem)
After adding 2 ml of dimethylformamide to 20 mg (0.01 mmol) to swell the resin, the dimethylformamide was filtered off. To this, 2 ml of 20% piperidine / dimethylformamide was added, and after stirring for 5 minutes, the piperidine / dimethylformamide solution was filtered off. again,
After adding 2 ml of 20% piperidine / dimethylformamide, the mixture was stirred for 5 minutes, and then filtered off. The resin was washed with dimethylformamide to remove piperidine. Fmoc-D
-His (Tr) 31.0 mg (0.05 mmol),
7.7 mg (0.05 mmol) of N-hydroxybenzotriazole (HOBt or less) and 26.0 mg (0.05 mmol) of benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP or less). Dissolved in 2 ml of dimethylformamide, combined with 17 μl (0.1 mmol) of diisopropylethylamine and added to the resin,
Stir for 3 hours. After the dimethylformamide solution was filtered off, the resin was further washed with dimethylformamide. To the obtained Fmoc-amino acid-resin, 2 ml of 20% piperidine / dimethylformamide was added, and the mixture was stirred for 5 minutes and filtered off twice. Then, the resin was washed with dimethylformamide. Fmoc-D-1-naphthylalanine 2
1.9 mg (0.05 mmol), HOBt 7.7 mg
(0.05 mmol), PyBOP 26.0 mg (0.
Was dissolved in 2 ml of dimethylformamide, and 17 μl of diisopropylethylamine (0.1 mm
ol), and the mixture was added to the amino acid-resin and stirred for 3 hours. After the dimethylformamide solution was filtered off, the resin was further washed with dimethylformamide. Obtained F
After 2 ml of 20% piperidine / dimethylformamide was added to the moc-peptide-resin, the mixture was stirred for 5 minutes and filtered off, and then the resin was washed with dimethylformamide. 11.3 mg of xanthene-9-carboxylic acid (0.
05 mmol), 7.7 mg of HOBt (0.05 mmol)
1) 26.0 mg (0.05 mmol) of PyBOP was dissolved in 2 ml of dimethylformamide, combined with 17 μl (0.1 mmol) of diisopropylethylamine, added to the peptide-resin, and stirred for 3 hours. After the dimethylformamide solution was filtered off, the resin was further washed with dimethylformamide and dichloromethane, and dried under reduced pressure.
The resulting dipeptide-resin was treated with 2 ml of 5% triisopropylsilane / trifluoroacetic acid for 10 minutes, and the filtrate was collected. The resin was washed with 2 ml of 5% triisopropylsilane / trifluoroacetic acid, and the washing was combined with the filtrate. The trifluoroacetic acid solution is concentrated under reduced pressure to obtain the desired compound (11).
5.2 mg (9.3 mol) were obtained (93% of yield). Mass spectrometry; [FAB-MS] m / z: 560 [M + H]
⁺ HPLC retention time; 19.5 min HPLC conditions (hereinafter, measurement conditions by HPLC are the same); Column: CapcellPak ODS-UG120A
(2.0 × 150 mm) Mobile phase: 5-95% acetonitrile / 0.1% trifluoroacetic acid (30 min), gradient Flow rate: 0.2 ml / min Detection: UV 220 nm

Embodiment 11

Embedded image Production of a compound represented by the formula: Linkamide MBHA resin 20 mg (0.01 mmol)
After adding 2 ml of dimethylformamide to 1) to swell the resin, dimethylformamide was removed by filtration. This is 2
Add 2 ml of 0% piperidine / dimethylformamide,
After stirring for 5 minutes, the piperidine / dimethylformamide solution was filtered off. Again, 2 ml of 20% piperidine / dimethylformamide was added, stirred for 5 minutes, and filtered off. The resin was washed with dimethylformamide to remove piperidine. Fmoc-D-His (Trt) 31.0m
g (0.05 mmol), HOBt 7.7 mg (0.0
5 mmol), 26.0 mg of PyBOP (0.05 mm
ol) was dissolved in 2 ml of dimethylformamide, combined with 17 μl (0.1 mmol) of diisopropylethylamine, added to the resin, and stirred for 3 hours. After the dimethylformamide solution was filtered off, the resin was further washed with dimethylformamide. To the obtained Fmoc-amino acid-resin, 2 ml of 20% piperidine / dimethylformamide was added, and the mixture was stirred for 5 minutes and filtered off twice. Then, the resin was washed with dimethylformamide. Fmoc-D-1
-Naphthylalanine 21.9mg (0.05mmo
l), HOBt 7.7 mg (0.05 mmol), Py
26.0 mg (0.05 mmol) of BOP was dissolved in 2 ml of dimethylformamide, added to 17 μl (0.1 mmol) of diisopropylethylamine, added to the amino acid-resin, and stirred for 3 hours. After the dimethylformamide solution was filtered off, the resin was further washed with dimethylformamide. In the obtained Fmoc-peptide-resin, 2
Add 2 ml of 0% piperidine / dimethylformamide,
After the operation of stirring for 5 minutes and filtering off was performed twice, the resin was washed with dimethylformamide. Diphenylacetic acid 10.6
mg (0.05 mmol), HOBt 7.7 mg (0.
05 mmol), 26.0 mg of PyBOP (0.05 m
mol) was dissolved in 2 ml of dimethylformamide, added to 17 μl (0.1 mmol) of diisopropylethylamine, added to the peptide-resin, and stirred for 3 hours.
After the dimethylformamide solution was filtered off, the resin was further washed with dimethylformamide and dichloromethane, and dried under reduced pressure. The resulting dipeptide-resin was treated with 2 ml of 5% triisopropylsilane / trifluoroacetic acid for 10 minutes, and the filtrate was collected. The resin was washed with 2 ml of 5% triisopropylsilane / trifluoroacetic acid, and the washing was combined with the filtrate. The trifluoroacetic acid solution was concentrated under reduced pressure to obtain 5.5 mg (10 μmol) of the target compound (12) (yield: 10).
0%). Mass spectrometry; [FAB-MS] m / z: 546 [M + H]
⁺ HPLC retention time: 19.6 min

Embodiment 12

Embedded image Production of a compound represented by the formula: Fmoc-D-His (Tr) 31.0 mg (0.05
mmol), HOBt 7.7 mg (0.05 mmol)
1), 26.0 mg (0.05 mmol) of PyBOP were dissolved in 2 ml of dimethylformamide, and combined with 17 μl (0.1 mmol) of diisopropylethylamine, 40 mg (0.1 mg) of 1,2-diaminoethanetrityl resin.
01 mmol) and stirred for 3 hours. After the dimethylformamide solution was filtered off, the resin was further washed with dimethylformamide. 2 ml of 20% piperidine / dimethylformamide was added to the obtained Fmoc-amino acid-resin.
Was added, and the operation of stirring and filtering off for 5 minutes was performed twice, and then the resin was washed with dimethylformamide. Fmoc-D-
11.9 mg of 1-naphthylalanine (0.05 mmol
l), HOBt 7.7 mg (0.05 mmol), Py
26.0 mg (0.05 mmol) of BOP was dissolved in 2 ml of dimethylformamide, added to 17 μl (0.1 mmol) of diisopropylethylamine, added to the amino acid-resin, and stirred for 3 hours. After the dimethylformamide solution was filtered off, the resin was further washed with dimethylformamide. In the obtained Fmoc-peptide-resin, 2
Add 2 ml of 0% piperidine / dimethylformamide,
After the operation of stirring for 5 minutes and filtering off was performed twice, the resin was washed with dimethylformamide. Xanthen-9-carboxylic acid 11.3 mg (0.05 mmol), HOBt7.
7 mg (0.05 mmol), PyBOP 26.0 mg
(0.05 mmol) was dissolved in 2 ml of dimethylformamide, and 17 μl of diisopropylethylamine (0.1
mmol) and the mixture was added to the peptide-resin and stirred for 3 hours. After filtering off the dimethylformamide solution,
Further, the resin was washed with dimethylformamide and dichloromethane, and dried under reduced pressure. The resulting dipeptide-resin was
The mixture was treated with 2 ml of% triisopropylsilane / trifluoroacetic acid for 10 minutes, and the filtrate was collected. The resin was washed with 2 ml of 5% triisopropylsilane / trifluoroacetic acid, and the washing was combined with the filtrate. The trifluoroacetic acid solution was concentrated under reduced pressure to obtain 6.0 mg (10 μmol) of the target compound (39) (yield: 100%). Mass spectrometry; [FAB-MS] m / z: 603 [M + H]
⁺ HPLC retention time: 17.6 min

Specific examples of the preparations are shown below by way of examples, but the present invention is not limited to the following preparation examples. Formulation Example 1 10 parts of Compound 10, 15 parts of heavy magnesium oxide, and 75 parts of lactose are uniformly mixed to prepare a powdery or fine powder having a particle size of 350 μm or less. This powder was placed in a capsule container to obtain a capsule. Formulation Example 2 45 parts of compound 10, 15 parts of starch, 16 parts of lactose, 21 parts of crystalline cellulose, 3 parts of polyvinyl alcohol and 30 parts of distilled water are uniformly mixed, crushed and granulated, dried, and then sieved to obtain a diameter. Granules having a size of 1410-177 μm were obtained. Formulation Example 3 After a granule was prepared in the same manner as in Formulation Example 2, 3 parts of calcium stearate was added to 96 parts of the granule, followed by compression molding to prepare a tablet having a diameter of 10 mm. Formulation Example 4 To 90 parts of the granules obtained by the method of Formulation Example 2, 10 parts of crystalline cellulose and 3 parts of calcium stearate were added and compression-molded to obtain a tablet having a diameter of 8 mm. Sugar-coated tablets were prepared by adding a mixed calcium carbonate suspension. Formulation Example 5 1 part of Compound 10, Macrogol 4000 49.5
Part and Macrogol 4009.5 parts were mixed and kneaded well to obtain an ointment with uniform quality. Formulation Example 6 0.3 part of Compound 10, 2.4 parts of a nonionic surfactant and 97 parts of physiological saline were heated and mixed, put into an ampoule, and sterilized to prepare an injection.

[0075]

The compound of the present invention is a fungal type I protein geranylgeranyltransferase (GGTase).
I) Since it has inhibitory activity, it is useful as an antifungal agent having a new mechanism of action.

[0076]

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Takeshi Sagara 3 Okubo Tsukuba, Ibaraki Pref. Within Tsukuba Research Laboratories (72) Inventor Toshihiko Sato 3rd Okubo Tsukuba, Ibaraki Pref. Tsukuba Research Laboratories (72) Inventor Tsuyoshi Morishima 3 Okubo, Tsukuba City, Ibaraki Prefecture Banyu Pharmaceutical Co., Ltd. BA51 DA55 EA29 FA41 FA58 FA59 FA60 FA61 HA02

Claims (7)

[Claims] 1. A compound represented by the general formula [I-1] [Wherein, X represents an oxygen atom or a group represented by NH for the bond, W represents a carbonyl group or a methylene group for the bond, R represents an unsubstituted non-aromatic heterocyclic group, an aliphatic ring group, A C ₇ -C ₁₂ aralkyl group or a C ₆ -C ₁₂ aryl group or a halogen atom, a cyano group, a hydroxy group, an amino group, a carboxyl group, a sulfo group, a C ₁ -C ₆ alkyl group,
C ₁ -C ₆ alkoxy group, C ₆ -C ₁₂ aryl group, C ₇ -C
C _7- having one or two substituents selected from the group consisting of a ₁₀ aralkyl group and a C ₆ -C ₁₂ aryloxy group.
A C ₁₂ aralkyl group, Y represents an aryl group which may have a substituent of a halogen atom, and B represents a hydrogen atom, a carbamoyl group or an amino C ₁ -C ₃ alkylcarbamoyl group], A pharmaceutically acceptable salt or ester thereof. 2. A compound of the general formula [I-2] Wherein B, W and R have the meanings described above, Y ₁ represents a naphthyl group, and X ₁ represents an oxygen atom. The compound according to claim 1, which is pharmaceutically acceptable. Salt or ester. 3. A compound of the formula [I-3] [In the formula, X ₁ , W and Y ₁ represent the above description, B ₁ represents a hydrogen atom, a carbamoyl group or a 2-aminoethylcarbamoyl group, and R ₁ represents an unsubstituted xanthene group, an indanyl group or naphthyl. A pharmaceutically acceptable salt or ester thereof. 4. A compound of the formula [I-4] Wherein, B, R and Y have the meanings described above, X ₂ represents NH participating in the bond, and W ₁ represents a carbonyl group participating in the bond. A pharmaceutically acceptable salt or ester thereof. 5. A compound of the formula [I-5] [Wherein, B ₁ , X ₂ and W ₁ have the meanings described above, and R ₂ represents an unsubstituted non-aromatic heterocyclic group or aryl group or cyano group, hydroxy group, amino group, carboxyl group, C _6-
A C ₁₂ aryl group, a C ₇ -C ₁₀ aralkyl group and a C ₆ -C ₁₂
1 or 2 selected from the group consisting of aryloxy groups
A C ₆ -C ₁₂ aralkyl group having a substituent; and Y ₂ represents an aryl group having a halogen atom substituent.], A pharmaceutically acceptable salt thereof, or ester. 6. A compound of the general formula [I-6] 5. The compound according to claim 4, wherein B ₁ , X ₂ and W ₁ represent the above description, R ₃ represents a xanthene group or a diphenylmethyl group, and Y ₃ represents a naphthyl group or a dichlorophenyl group. Or a pharmaceutically acceptable salt or ester thereof. 7. A compound of the general formula [I-1] [Wherein, B, X, W, R and Y mean the above description]
A type I protein geranylgeranyltransferase inhibitor comprising, as an active ingredient, a compound represented by the formula: or a pharmaceutically acceptable salt or ester thereof.