JP2000204087A - Inhibitor against geranylgeranyl transferase, i-type protein - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound useful as an antifungal agent, excellent in inhibiting activity against geranylgeranyl transferase, a fungous I-type protein, and having a new mode of action. SOLUTION: A compound of formula I (B is a 1-3C alkylene optionally having a 6-12C aryl or a single bond; Z is O, S or a single bond; R1 is a non-aromatic heterocycle, an aliphatic ring, a 6-12C aryl or the like; Y is a carbonyl or methylene; A is O or NH; X1 is a 2-5C alkylene, a 3-7C cycloalkylene, a 2-5C alkenylene or the like), for example, a compound of formula II The compound of formula I is obtained by condensing, for example, a compound of formula III [e.g. 2-(1,4-benzodioxan)carboxylic acid] with a compound of the formula: HAX1STr (Tr is trityl) (e.g. the compound of formula IV) in an inert solvent such as dimethylformamide in the presence of a base such as dimethylaminopyridine preferably at 20-60 deg.C for 1-12 hr followed by deblocking.

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. (Naka Koke et al.), Genes to Cells. (Jeans to Cells) Vol. 2, No. 11, pp. 679-694,
1997] and [Miller P. et al. J. et a
l. (Mirror jay, etc.), Molecular
& Cellular Biology (Molecular ・
And Cellular Biology) Volume 14, Issue 2,
Pp. 1075-1083, 1994]. Rho1 protein and Cdc42 protein belong to the Rho protein group of cytoskeletal regulation-related proteins [Tanaka
K. and TakaiY. (Tanaka K and Takai Wai), Current Opinion in C
Cell Biology (Current Opinion in Cell Biology), Vol. 10, No. 1, 112-
116, 1998], by the type I protein geranylgeranyltransferase (GGTaseI),
It functions only when the terminal is geranylgeranylated [Ohya Y. et al. et al. (Oya Wai, etc.) Mo
l. Gen. Genet. (Molecular and General Genetics) Vol. 252, Vol. 1-10
, 1996]. There is no report on an enzyme that transfers a geranylgeranyl group to a protein in Candida albicans, a pathogenic fungus.

Compounds that are structurally similar to the compounds of the present invention are described in Fisher, L .; Mark et al. (Fisher El Mark, etc.), Biochemistry
(Biochemistry) Vol. 24, No. 13, No. 319
9-3207, 1985 and Riordan, Ja.
mes M et al. (Riodan James M., etc.), Journal Medical Chemi
story (Journal Medical Chemistry) No. 26
Winding, No. 6, pp. 884-891, are disclosed in 1983, the structure of the synthesized compounds dithiazole skeleton described and bleomycin A ₂ for the mechanism of action of bleomycin A ₂ to phenylene over thiazole skeleton is disclosed I have. However, such compounds have the general formula [I-
Only the compounds in which R ₁ is a phenyl group in [1] are disclosed. Moreover, the mechanism of action of the compounds merely describes bleomycin-induced cleavage of gene bases.

[0004] Published Japanese Patent Application No. Hei 2-289579 discloses a compound similar in structure to the compound of the present application as a thromboxane antagonist. However, such compounds only disclose compounds in which B is an epoxycyclohexane and Z is a lower alkylene group in the general formula [I-1], and are different from the compounds of the present invention. Further, only the action of the compound as a thromboxane antagonist is disclosed.

That is, the compound represented by the general formula [I-1] of the present invention
In the compound, wherein B is C₆-C₁₂Has an aryl group
C₁-C_ThreeAlkylene group or C₁-C_ThreeAlkylene
Z represents an oxygen atom or a sulfur atom
Or a single bond;₁Is unsubstituted, non-aromatic heterocycle
Group, aliphatic ring group or C₆-C₁₂Aryl group or halo
Gen atom, cyano group, hydroxy group, amino group, carbo
Xyl group, sulfo group, C ₁-C₆Alkyl group, C₁-C₆A
Lucoxy group, C₆-C₁₂Aryl group, C₇-C_TenAralki
And C₆-C₁₂Select from the group consisting of aryloxy groups
Non-aromatic heterocyclic ring having one or two substituents
Group, aliphatic ring group or C₆-C₁₂Represents an aryl group,
Y represents a carbonyl group or a methylene group for the bond,
A represents an oxygen atom for bonding or a group represented by NH
Then X₁Is unsubstituted, C_Two-C_FiveAlkylene group, C_Three-C₇
Cycloalkylene group or C_Two-C_FiveAlkenylene group
Is a halogen atom, a cyano group, a hydroxy group, an amino group,
Selected from the group consisting of carboxyl and mercapto groups
Having one or two substituents,_Two-C_FiveAlkylene
Group, C_Three-C₇Cycloalkylene group or C_Two-C_FiveAl
Represents a kenylene group]
It is a reference compound.

[0006]

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 ClinicalMicrobiology & I
nfectious Disease, (European Journal of Clinical Microbiology and Infectious Digis), Volume 16,
4, pp. 261-280, 1997]. Therefore, development of an antifungal agent with a new mechanism of action is desired.

[0007]

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, B is C ₁ having a substituent of C ₆ -C ₁₂ aryl group -
A C ₃ alkylene group or a C ₁ -C ₃ alkylene group or a single bond, Z represents an oxygen atom or a sulfur atom or a single bond, and R ₁ is an unsubstituted, non-aromatic heterocyclic group, aliphatic ring group or C ₆ -C ₁₂ aryl group or a halogen atom,
Cyano group, hydroxy group, amino group, carboxyl group,
1 selected from the group consisting of a sulfo group, a C ₁ -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
Or a non-aromatic heterocyclic group, aliphatic ring group or C ₆ -C ₁₂ aryl group having 2 substituents, Y represents a carbonyl group or a methylene group for the bond, and A represents an oxygen atom or NH for the bond. Wherein X ₁ is an unsubstituted C ₂ -C ₅ alkylene group, C ₃ -C ₇ cycloalkylene group or C ₂ -C ₅ alkenylene group or halogen atom, cyano group, hydroxy group, amino group, having 1 or 2 substituents selected from the group consisting of carboxyl group and mercapto group, C ₂ -C ₅ alkylene group, C ₃ -
C ₇ cycloalkylene group or C ₂ -C ₅ alkenylene group].

[0008] 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 ₁ -C ₃ alkylene group refers to the above C ₁ -C ₆ alkylene group.
Among the alkyl groups, it means a linear or branched alkylene group having 1 to 3 carbon atoms, and examples thereof include a methylene group, an ethylene group, a propylene group, a methylmethylene group, an ethylmethylene group, and a dimethylmethylene group.

The C ₂ -C ₅ alkylene group refers to the above-mentioned C ₁ -C ₆
It means a linear or branched alkylene group having 2 to 3 carbon atoms among the alkyl groups, such as ethylene group, propylene group, methylmethylene group, ethylmethylene group, dimethylmethylene group, butylene group and 3-methylpropylene group. , 2
-Methylpropylene group, 3-methylbutylene group, 2-methylbutylene group, 3-ethylpropylene group, 2-ethylpropylene group and the like.

The C ₂ -C ₅ alkenylene group means a linear or branched alkenylene group having 2 to 5 carbon atoms.
Examples include a propenylene group, a 2-butenylene group, a 3-butenylene group, a 3-pentenylene group, 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, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy. Group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group and the like.

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

The C ₃ -C ₇ cycloalkylene group means a cycloalkylene group having 3 to 7 carbon atoms, such as a cyclopropylene group, a cyclobutylene group, a cyclopentylene group and a cyclohexylene group.

A C ₇ -C ₁₀ aralkyl group refers to the above-mentioned C ₁ -C
_{A 3-} alkyl group substituted with the above-mentioned C ₆ -C ₁₂ aryl group, which means an aralkyl group having 7 to 10 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.

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.

[0020] B is a compound represented by C ₁ -C ₃ alkylene group or a C ₁ -C ₃ alkylene group or a single bond having a substituent of C ₆ -C ₁₂ aryl group. Preferably, B is a compound represented by a methylene group having a phenyl group substitution or a methylene group or a single bond.

Z is a compound represented by an oxygen atom, a sulfur atom or a single bond.

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

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

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

Specific examples of R ₁ include a benzodioxanyl group, a thiochromanyl group, a xanthene group, a phenyl group, an indanyl group, a tetrahydronaphthyl group and a fluorene group. The benzodioxanyl group, the thiochromanyl group, the xanthene group, the phenyl group, the indanyl group, the tetrahydronaphthyl group or the fluorene group may be unsubstituted or a halogen atom, a cyano group, a hydroxy group. , an amino group, a carboxyl group, a sulfo group, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group,
It may have a substituent of a C ₆ -C ₁₂ aryl group, a C ₇ -C ₁₀ aralkyl group or a C ₆ -C ₁₂ aryloxy group.

Among them, for example, R ₁ has an unsubstituted benzodioxanyl group, thiochromanyl group, xanthene group, phenyl group, indanyl group, tetrahydronaphthyl group or fluorene group or C ₁ -C ₆ alkoxy group.
Preferred are a benzodioxanyl group, a thiochromanyl group, a xanthene group, a phenyl group, an indanyl group, a tetrahydronaphthyl group, a fluorene group and the like.

X ₁ is a C ₂ -C ₅ alkylene group, C ₃ -C ₇
It represents a cycloalkylene group or a C ₂ -C ₅ alkenylene group. The C ₂ -C ₅ alkylene group, the C ₃ -C ₇ cycloalkylene group or the C ₂ -C ₅ alkenylene group may be unsubstituted or a halogen atom, a cyano group, a hydroxy group, an amino group, a carboxyl group. Or a substituent of a mercapto group.

Specific examples of X ₁ include a C ₂ -C ₅ alkylene group, a C ₃ -C ₇ cycloalkylene group and a C ₂ -C ₅ alkenylene group. The C ₂ -C ₅ alkylene group, the C ₃ -C ₇ cycloalkylene group or the C ₂ -C ₅ alkenylene group may be unsubstituted or have a hydroxy group or a mercapto group. Is also good.

Among them, for example, X ₁ is an unsubstituted propylene, butylene, 3 or 3 substituent having one or two substituents selected from propylene, butylene, cyclohexylene or butenyl or hydroxy and thiol. Compounds represented by a methylpropylene group, a cyclohexylene group or a butenyl group are preferred.

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 compound of the formula [I-5], the compound of the formula [I-5] or the compound of the formula [I-6] is more preferable, and the most preferable compound is the compound represented by the formula [I-7].

[0031] Among the compounds of the general formula [I-1], B, Z or R ₁ or Y may be bonded to any position of the thiazole skeleton, B, Z or R ₁ is a thiazole skeleton 2
A compound bonded to the position is mentioned as a suitable compound. Further preferred compounds include those in which B, Z or R ₁ is bonded to the 2-position of the thiazole skeleton, and Y is bonded to the 4-position of the thiazole skeleton.

Examples of the hydroxy-protecting group include lower alkylsilyl groups such as trimethylsilyl group and tert-butyldimethylsilyl group;
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 the carboxyl-protecting group include methyl, ethyl, propyl, isopropyl and 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 of the addition salt or the amino group having an amino group or the basic heteroaromatic ring having a basic heterocyclic ring can be exemplified.

The base addition salt includes, for example, alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt and magnesium salt; for example ammonium salt; for example, 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. Examples of the acid addition salt include inorganic salts such as hydrochloride, sulfate, nitrate, phosphate, and perchlorate; for example, maleate, fumarate, tartrate, citrate, ascorbate, and the like. Organic acid salts such as trifluoroacetate; and sulfonates such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate.

The ester of the compound represented by the formula [I-1] means, when having a carboxyl group, a conventional pharmaceutically acceptable 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, the 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 method A or production method B.

Production method A [Wherein, Tr represents a trityl group, and R ₁ , Z, B, A,
X ₁ has the meaning described above. The compound of the present invention can be 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 ( Ia)
(Compound of general formula [I-1] wherein Y is a carbonyl group)
Can be manufactured. The reaction is carried out in an inert organic solvent,
(II) to the compound of (II) in the presence of a base as appropriate
The compound of I) is used at least 1 mol or more, preferably 1 to 10 mol, more preferably 2 to 5 mol equivalent. The amount of each reagent used is not particularly limited,
It 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 functional group-protecting group that does not participate in the reaction include the above-described hydroxy-protecting group, amino-protecting group, and carboxyl-protecting group, and the like.

The introduction and removal of the protecting group may 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)] or a method analogous thereto or the like, using any ordinary method widely known in the field of chemistry.

The isolation and purification of the compound formed 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.

Manufacturing method B [Wherein R ₁ , Z, B, A, X ₁ , S, and Tr have the meanings described above]. Compound (V) of the present invention (wherein Y is a methylene group;
-1] can be obtained by converting compound (II) into an amine of compound (IV) by a known method, and converting compound (IV) to a known compound or compound (Ib) produced by a known method to form a reductive alkyl. It can be produced by performing deprotection reaction and then deprotecting.

The reaction includes, for example, methanol, ethanol, propanol, toluene, tetrahydrofuran, toluene, acetic acid, methylene chloride, dimethylformamide or a mixed solvent thereof in the above-mentioned inert solvent.

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 can be carried out at a temperature lower than this if necessary.
To 60 ° C.

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

The introduction of a functional group which does not participate in the reaction, the introduction and removal of a protecting group, and the isolation and purification of a product can be carried out in the same manner as in Production method A.

The thiazole derivative of compound (II), which is the starting compound, is a known compound. et al. (Such as Dew Jay),
Tetrahedron Lett. (Tetrahedron Letter) Vol. 36, No. 45, No. 8167-8170
Page, 1995 and Shin, C .; et al. (Shinshi et al.) Chem. Lett. (Chemical Letter), Vol. 1, pp. 45-46, 1995].

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).

[0055]

[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 antipain) and twice the amount of glass beads having a diameter of 0.5 mm were added thereto. Under cooling, the cells were disrupted by ultrasonic waves and stirring. 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 ammonium sulfate obtained with 30-70% saturated ammonium sulfate. The precipitated fractions are collected and dialyzed against a column equilibration solution (20 mM Tris-HCl pH 7.5 (4 ° C.), 1 mM dithiothreitol, 20 μM zinc chloride). This was combined with Mono Q (Amersham) previously equilibrated against the column equilibration solution.
(Pharmacia Biotech)) was applied to an anion exchange column, and the fraction eluted with a 0-0.5 M sodium chloride gradient was 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, 2
5 mM magnesium chloride (MgCl ₂ ), 125 μM zinc chloride (ZnCl ₂ ), 9.25 μM biotin-CON
H- (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 a G.out (Packard).

Therefore, the final concentration of the reaction solution is 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 (Trit
on) 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. 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 commonly 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, methyl cellulose, carboxymethyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, etc. 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 usually contain 0.1 to 100% by weight, preferably 5 to 100% by weight, of the active ingredient in the case of the solid preparation, and 0.1 to 10% by weight in the case of other preparations. , Preferably 1 to 5% by weight of active ingredient.
The practically preferred dosage of a compound or antifungal composition 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 dose is 0.1 to 100 mg / kg per day for an adult and 0.01 to 100 mg / kg for a parenteral administration, depending on the like. 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.

[0064]

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 Step (1-1)

Embedded image (Wherein Tr represents a trityl group; the same applies hereinafter). Dithiothreitol (1 g) was dissolved in anhydrous dichloromethane (10 ml), 4 equivalents of triphenylmethyl chloride (7.2 g) and 0.2 equivalents of dimethylaminopyridine (160 mg) were added, and the mixture was stirred at room temperature overnight. did. The reaction solution was poured into water and extracted with chloroform. The organic layer was washed with water and then with saturated saline, dried and concentrated, and the residue was purified using silica gel column chromatography (chloroform-methanol = 50: 1).
3.6 g of the target compound (2) was obtained (yield 87%). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
_{CDCl 3): 7.14-7.39 (30H,} m),
2.88-2.91 (2H, m), 2.24-2.34
(2H, m), 2.13 to 2.15 (2H, m), 2.
02-2.09 (2H, m)

Step (1-2) 50 mg of 2- (1,4-benzodioxane) carboxylic acid (Maybridge), compound (2) obtained in step (1-1)
243 mg, WSC.HCl 73 mg, and dimethylaminopyridine 46 mg were dissolved in dimethylformamide 3 ml, and the mixture was stirred at room temperature for 24 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried and concentrated to obtain an ester. 50% trifluoroacetic acid-
5% triisopropylsilane-45% dichloromethane 3
The mixture was dissolved in 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 (hexane-ethyl acetate = 2: 1) to obtain 23 mg of the desired compound (1). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
_{CDCl 3): 8.31 (1H,} s), 6.90-7.
05 (4H, m), 5.69 (1H, dd, J = 6.
8, 2.7 Hz), 5.27 (1H, td, J = 6.
7, 2.8 Hz), 4.68 (1H, dd, J = 11.
4, 2.76 Hz), 4.31 (1H, dd, J = 1)
1.4, 6.8 Hz), 4.11 (1H, bs), 2.
67-3.10 (4H, m), 1.58-1.68 (2
H, m) mass spectrometry; [FAB-MS] m / z: 400 [M + H]
⁺

Embodiment 2

Embedded image Production of the compound represented by Step (2-1)

Embedded image (Wherein TBS represents a t-butyldimethylsilyl group). 3.24 g of (-)-O-isopropylidene-D-threitol (Tokyo Kasei) was dissolved in 30 ml of anhydrous dimethylformamide, and 3.06 g of one equivalent of t-butyl-methylchlorosilane was added.
63 g was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 5:
1-3: 1), and the crude monosilyl compound 3.1
g was obtained. 1.5 g of the crude monosilyl compound was added to 20 m of ethyl acetate.
methanesulfonyl chloride 0.53 ml,
1.2 ml of triethylamine was added, and the mixture was stirred at room temperature for 1 hour. The precipitated white crystals were removed by filtration, and the filtrate was washed with water, dried and concentrated to obtain a crude mesylate. 0.2 g of crude mesylate was dissolved in 2 ml of dimethylformamide, 0.2 g of sodium azide was added, and the mixture was stirred at 100 ° C. for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and then with saturated saline, dried and concentrated, and the residue was taken up in tetrahydrofuran (5 ml) -water (0.1 ml).
5 ml), 0.2 g of triphenylphosphine was added, and the mixture was heated under reflux for 1.5 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to thin-layer silica gel chromatography (chloroform-
Purification was performed using methanol (5: 1) to obtain 0.1 g of a crude amine compound. 40 mg of crude amine compound, 2- (1,4-
Benzodioxane) carboxylic acid (Maybridge) 43m
g, 50 mg of WSC.HCl and 30 mg of N-hydroxybenzotriazole were dissolved in 1 ml of dimethylformamide, and the mixture was stirred at room temperature for 3.5 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to thin-layer silica gel chromatography (hexane-hexane).
Purification was performed using ethyl acetate (4: 1) to obtain 73 mg of the target compound (4). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
CDCl ₃ ): 8.15 (1H, s), 7.61 (1
H, dd, J = 5.1, 4.7 Hz), 7.01-7.
05 (1H, m), 6.92-6.94 (4H, m),
5.50 (1H, dt, J = 7.1, 2.5 Hz),
4.63 (1H, dt, J = 12.4, 2.5 Hz),
4.29 (1H, dt, J = 12.4, 7.1 Hz),
4.14-4.21 (1H, m), 3.61-3.85
(5H, m), 1.46 (3H, s), 1.42 (3
H, s), 0.91 (9H, s), 0.08 (6H,
s)

Step (2-2) 73 mg of the compound (4) obtained in the step (2-1) was dissolved in 1 ml of tetrahydrofuran, and tetra-n-butylammonium fluoride (1.0 M solution in tetrahydrofuran) was dissolved.
0.3 ml was added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried and concentrated, and the residue was purified using thin-layer silica gel chromatography (ethyl acetate) to obtain 45 mg of a crude alcohol. The crude alcohol was dissolved in 3 ml of ethyl acetate, and methanesulfonyl chloride 0.03 was dissolved.
1 ml and 0.02 ml of triethylamine were added, and the mixture was stirred at room temperature for 1 hour. The precipitated white crystals were removed by filtration, and the filtrate was washed with water, dried and concentrated to obtain a crude mesylate. The crude mesylate was dissolved in dimethylformamide (2 ml), potassium thioacetate (40 mg) was added, and the mixture was stirred at 60 ° C for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. After drying and concentration, the residue was purified by thin-layer silica gel chromatography (hexane-ethyl acetate = 1: 1) to obtain 30 mg of a crude thioacetate compound. The crude thioacetate was dissolved in 0.5 ml of methanol, and 0.07 ml of a 1N aqueous sodium hydroxide solution was added under ice cooling, followed by stirring for 10 minutes. 0.14 ml of 1N hydrochloric acid was added to the reaction solution, and the mixture was further diluted with water and extracted with ethyl acetate. After the organic layer was dried and concentrated, the residue was dissolved in methanol (0.5 ml), p-toluenesulfonic acid (12.7 mg) was added, and the mixture was stirred at room temperature for 1 hour. A 0.5N aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer is dried and concentrated, and the residue is subjected to thin-layer silica gel chromatography (ethyl acetate).
Then, 10.7 mg of the target compound (3) was obtained. Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
_{CDCl 3): 8.17 (1H,} s), 7.67-7.
74 (1H, m), 6.90-7.05 (4H, m),
5.49-5.52 (1H, m), 4.60-4.65
(1H, m), 4.28-4.34 (1H, m), 3.
42-3.90 (5H, m), 3.08-3.12 (2
H, m), 2.76 (2H, t, J = 8.6 Hz),
1.54 (1H, t, J = 9.5 Hz) mass spectrometry; [FAB-MS] m / z: 383 [M + H]
⁺

Embodiment 3

Embedded image Production of the compound represented by Dissolve 39 mg of 2- (1,4-benzodioxane) carboxylic acid (Maybridge) in 1 ml of methylene chloride, 0.3 ml of thionyl chloride and D
After adding 0.3 ml of MF and stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. The residue was dissolved in 1 ml of methylene chloride, and 180 mg of 3-mercapto-1,2-propanediol and D
The solution was added dropwise to 1 ml of a methylene chloride solution containing 40 mg of MAP.
After stirring at room temperature for 4 hours, the mixture was refluxed for 2 hours. The reaction solution was concentrated to dryness and then purified using preparative silica gel chromatography to obtain 25.2 mg of the desired compound (5). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
_{CDCl 3): 8.25 (1H,} s), 6.85-7.
05 (4H, m), 5.69 (1H, dd, J = 2.
5,6.3 Hz), 4.65 (1H, dd, J = 2.
5,11.0 Hz), 4.44 (2H, m), 4.26
(1H, dd, J = 6.3, 11.0 Hz), 4.05
(1H, m), 3.10 (1H, br), 2.65−
2.85 (2H, m), 1.58 (1H, t, J = 1
2.1 Hz) mass spectrometry; [FAB-MS] m / z: 354 [M + H]
⁺

Embodiment 4

Embedded image Production of the compound represented by 1.76 g of 2-butene-1,4-diol (a mixture of cis and trans) is dissolved in 10 ml of anhydrous dimethylformamide, 3.02 g of one equivalent of t-butyl-methylchlorosilane and 1.64 of imidazole are dissolved.
g was added and stirred at room temperature for 1.5 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried and concentrated, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 5:
1-3: 1), and the crude monosilyl compound 3.1
g was obtained. 0.2 g of crude monosilyl compound, 0.26 of 2- (1,4-benzodioxane) carboxylic acid (Maybridge)
g, WSC.HCl 0.23 g, and dimethylaminopyridine 0.03 g were dissolved in dimethylformamide (2 ml) and stirred at room temperature for 2 hours. Pour the reaction solution into water,
Extracted with ethyl acetate. After washing the organic layer with saturated saline,
After drying and concentration, the residue was purified using silica gel chromatography (hexane-ethyl acetate = 10: 1),
0.14 g of a crude cis ester was obtained. The crude cis ester was dissolved in 1 ml of tetrahydrofuran, 0.5 ml of tetra-n-butylammonium fluoride (1.0 M solution in tetrahydrofuran) was added, and the mixture was stirred at room temperature for 30 minutes.
The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried and concentrated, and the residue was subjected to thin-layer silica gel chromatography (hexane-ethyl acetate =
Purification was performed using 1: 1) to obtain 64 mg of a crude alcohol compound. The crude alcohol was dissolved in 3 ml of ethyl acetate, and 0.02 ml of methanesulfonyl chloride and 0.04 ml of triethylamine were added, followed by stirring at room temperature for 20 minutes. The precipitated white crystals were removed by filtration, the filtrate was washed with water, dried and concentrated, and the residue was dissolved in dimethylformamide (2 ml).
68 mg of potassium thioacetate was added, and the mixture was stirred at 60 ° C. for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. After drying and concentration, the residue was purified using thin-layer silica gel chromatography (hexane-ethyl acetate = 4: 1) to obtain 24 mg of crude thioacetate. The crude thioacetate was dissolved in 0.5 ml of methanol, and 0.07 ml of a 1N aqueous sodium hydroxide solution was added under ice cooling, followed by stirring for 10 minutes. 0.14 ml of 1N hydrochloric acid was added to the reaction solution, and the mixture was further diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated, and the residue was purified using thin-layer silica gel chromatography (hexane-ethyl acetate = 2: 1) to obtain 5.1 mg of the desired compound (6). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
_{CDCl 3): 8.23 (1H,} s), 6.90-7.
05 (4H, m), 5.79-6.05 (2H, m),
5.60 (1H, dd, J = 6.9, 2.6 Hz),
4.86 (2H, d, J = 6.2 Hz), 4.68 (1
H, dd, J = 11.4, 2.6 Hz), 4.26 (1
H, dd, J = 11.4, 6.9 Hz), 3.20 (2
H, t, J = 7.7 Hz), 1.48 (1H, t, J =
7.8 Hz) mass spectrometry; [FAB-MS] m / z: 350 [M + H]
⁺

Embodiment 5

Embedded image Production of the compound represented by Step (5-1)

Embedded image (Wherein Tr represents a trityl group; the same applies hereinafter). 3-mercapto-1-propanol 50
Was dissolved in 10 ml of anhydrous dichloromethane, 1 equivalent of triphenylmethyl chloride (1.4 g) and 0.1 equivalent of dimethylaminopyridine (66 mg) were added, and the mixture was added at room temperature.
Stirred for hours. The reaction solution was poured into water and extracted with chloroform. The organic layer was washed with water and then with saturated saline, dried and concentrated, and the residue was purified using silica gel column chromatography (chloroform-methanol = 100: 1) to obtain 1.65 g of the target compound (8) (yield). 91%). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
_{CDCl 3): 7.20-7.43 (15H,} m),
3.53-3.57 (2H, m), 2.25-2.29
(2H, m), 1.61-1.63 (2H, m)

Step (5-2) 191 mg of the compound obtained in Step (5-1), 1.5 equivalents of 2- (1,4-benzodioxane) carboxylic acid (Maybridge) 100 mg, 1.5 equivalents WSC ・ HCl 1
09 mg, 1.0 equivalent of dimethylaminopyridine 47 m
g was dissolved in 10 ml of dichloromethane and stirred at room temperature overnight. The reaction solution was poured into water and extracted with chloroform. The organic layer was washed with water and saturated saline, dried and concentrated, and the residue was purified using silica gel column chromatography (hexane-ethyl acetate = 7: 3) to obtain 130 mg of an ester. The ester (130 mg) was dissolved in dichloromethane (1 ml), and triethylsilyl hydride (100 ml) and trifluoroacetic acid (1 ml) were added, followed by stirring at room temperature for 5 minutes. After evaporating the solvent, chloroform was added, and the organic layer was washed with water and saturated saline, dried and concentrated, and the residue was purified by silica gel column chromatography (chloroform-methanol = 50: 1) to obtain the desired compound. (7) 19 mg was obtained. Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
CDCl ₃ ): 8.13 (1H, s), 7.38 (1
H, m), 6.99-7.03 (1H, m), 6.88.
−6.92 (3H, m), 5.59 (1H, dd, J =
6.9, 2.6 Hz), 4.68 (1H, dd, J = 1)
1.4, 2.7 Hz), 4.25-4.32 (3H,
m), 2.28-2.35 (2H, m), 1.79-
1.85 (2H, m) mass spectrometry; [FAB-MS] m / z: 338 [M + H].
⁺

Embodiment 6

Embedded image Production of the compound represented by Step (6-1)

Embedded image (Wherein Ac represents an acetyl group; the same applies hereinafter). After dissolving 5 g of cyclohexenone in 20 ml of anhydrous benzene, cooling the solution to 0 ° C., adding 5.7 g of 2,6-lutidine and 4.0 g of thioacetic acid, and stirring at 0 ° C. for 2 hours, And stirred at room temperature overnight. The reaction solution was poured into water and extracted with diethyl ether. The organic layer was washed with water and saturated brine, dried and concentrated, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 1).
0: 1) to give 8.8 g of the desired compound (10).
Was obtained (98% yield). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
_{CDCl 3): 3.83-3.86 (1H,} m), 2.
68-2.78 (1H, m), 2.34-2.48 (3
H, m), 2.33 (3H, s), 2.04-2.13
(2H, m), 1.79-1.89 (2H, m)

Step (6-2) 600 mg of the compound (10) obtained in the step (6-1) is dissolved in 10 ml of absolute ethanol, and the solution is cooled to 0 ° C.
Add 375 mg of 10 equivalents of sodium borohydride,
After stirring at 0 ° C. for 20 minutes, the mixture was stirred at room temperature for 2 hours.
10 ml of a saturated aqueous ammonium chloride solution was added, and the mixture was stirred at room temperature overnight. Add 1.5 equivalents of triethylamine 2 to the reaction mixture.
After adding 51 ml and stirring at room temperature for 2 hours, the mixture was extracted with chloroform. After washing the organic layer with water and saturated saline,
After drying and concentration, the resulting residue was washed with anhydrous dichloromethane 10
ml of triphenylmethyl chloride, 2.0 g of 0.2 equivalent of dimethylaminopyridine 81 m
g was added and stirred at room temperature for 2 days. The reaction solution was poured into water and extracted with chloroform. The organic layer was washed with water and then with saturated saline, dried and concentrated, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 10: 10).
Purification was performed using 1) to obtain 300 mg of a crude trityl compound. 293 mg of crude trityl compound, 1.5 equivalents of 2- (1,
4-benzodioxane) carboxylic acid 110 mg, 1.5
Equivalent amount of WSC.HCl (80 mg) and 0.5 equivalent amount of dimethylaminopyridine (17 mg) were dissolved in dichloromethane (10 ml) and stirred at room temperature overnight. Pour the reaction solution into water,
Extracted with chloroform. The organic layer was washed with water and saturated saline, dried and concentrated, and the residue was purified using silica gel column chromatography (hexane-ethyl acetate = 7: 3) to obtain 130 mg of a crude ester. 50 mg of the crude ester was dissolved in 1 ml of dichloromethane, 100 ml of triethylsilane and 1 ml of trifluoroacetic acid were added, and the mixture was stirred at room temperature for 5 minutes. After evaporating the solvent, chloroform was added, the organic layer was washed with water and saturated brine, dried and concentrated, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate = 2: 1). 22 mg of compound (9) was obtained. Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
_{CDCl 3): 8.21 (1H,} s), 6.90-7.
08 (4H, m), 6.0 (1H, dd, J = 6.9,
2.7Hz), 4.91-5.08 (1H, m), 4.
71 (1H, dd, J = 11.5, 2.6 Hz);
28 (1H, dd, J = 11.4, 7.0 Hz);
80-2.99 (1H, m), 2.45-2.55 (1
H, m), 2.20-1.21 (8H, m) mass spectrometry; [FAB-MS] m / z: 378 [M + H].
⁺

Embodiment 7

Embedded image Production of the compound represented by Dissolve 7.9 g of 2- (1,4-benzodioxane) carboxylic acid in 60 ml of benzene, add 4.4 ml of thionyl chloride, heat under reflux for 3 hours, and concentrate under reduced pressure to obtain 9.3 g of a crude acid chloride. Was. Under ice cooling, a crude acid chloride derivative (1.4 g) was added to a tetrahydrofuran solution containing 190 mg of lithium aluminum hydride.
Tetrahydrofuran solution was added dropwise, and the mixture was stirred at 0 ° for 20 minutes, water was added, and the mixture was extracted with ethyl acetate, and the organic layer was dried.
After concentration, 1.2 g of a crude alcohol compound was obtained. Subsequently, 0.9 ml of triethylamine was added to a methylene chloride solution of 1.2 g of the crude alcohol compound under ice-cooling, and a methylene chloride solution of 0.46 ml of methanesulfonyl chloride was added thereto, followed by stirring for 30 minutes. This was separated with ethyl acetate-water, and the organic layer was dried and concentrated to obtain 1.7 g of a crude mesyl compound. Subsequently, 3.3 g of sodium azide was dissolved in dimethylformamide and heated at 70 ° C. for 2 hours. After liquid separation with ethyl acetate-saturated saline, the organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (chloroform) to obtain 934 mg of a crude azide compound. Next, this was reduced by catalytic hydrogenation to obtain 650 mg of a crude amino compound. After 124 mg of the crude amino compound and 86 mg of the compound (10) obtained in the step (6-1) were dissolved in dimethylformamide and stirred at room temperature for 4 hours, 148 mg of sodium triacetoxyborohydride was added, and the mixture was further stirred overnight. The mixture was separated with chloroform-water, the organic layer was dried and concentrated, and then purified by thin-layer silica gel column chromatography (chloroform: methanol = 10: 1). )
23 mg were obtained. Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
_{CDCl 3): 7.80 (1H,} s), 6.95-7.
09 (1H, m), 6.88-6.95 (3H, m),
5.5 (1H, m), 4.60-4.68 (1H,
m), 3.92 (2H, s), 3.35-3.42 (1
H, m), 2.96-3.07 (1H, m), 1.19
-1.97 (8H, m) mass spectrometry; [FAB-MS] m / z: 363 [M + H]
⁺

Embodiment 8

Embedded image Production of the compound represented by 47 mg of 2-phenoxymethylthiazole-4-carboxylic acid and 256 mg of the compound (2) obtained in the step (1-1) were dissolved in 3 ml of dichloromethane, 77 mg of WSC and 49 mg of N-hydroxybenzotriazole were sequentially added, and the mixture was stirred at room temperature for 2 hours. . This was separated with chloroform-water, the organic layer was dried and concentrated under reduced pressure, and the residue was purified by thin-layer silica gel chromatography (chloroform: methanol = 100: 1) to obtain a crude ester. The crude ester was dissolved in 2 ml of 50% trifluoroacetic acid-5% triisopropylsilane-45% dichloromethane and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure,
The residue was purified using thin-layer silica gel column chromatography (chloroform-methanol = 100: 1),
14 mg of the target compound (12) was obtained (19% yield). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
_{CDCl 3): 8.34 (1H,} s), 7.31-7.
35 (2H, m), 6.99-7.06 (3H, m),
5.40 (2H, s), 5.26-5.30 (1H,
m), 4.13 (1H, m), 2.93-3.00 (2
H, m), 2.69-2.74 (2H, dd, J = 8.
7 Hz 6.6 Hz), 1.54-1.65 (2H,
m) Mass spectrometry; [FAB-MS] m / z: 370 [M-2H
+ H] ⁺

Embodiment 9

Embedded image Production of the compound represented by 59 mg of 2-diphenylmethylthiazole-4-carboxylic acid and 256 mg of the compound (2) obtained in the step (1-1) are dissolved in 3 ml of dichloromethane, 77 mg of WSC and 49 mg of dimethylaminopyridine
Were added successively, and the mixture was stirred at room temperature for 2 hours. This was separated with chloroform-water, the organic layer was dried and concentrated under reduced pressure. The residue was purified by thin-layer silica gel chromatography (chloroform: methanol = 100: 1) to obtain a crude ester, and subsequently 50% Dissolve in fluoroacetic acid-5% triisopropylsilane-45% dichloromethane (2 ml) and add
Stirred for 0 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified using thin-layer silica gel column chromatography (chloroform-methanol = 100: 1) to obtain the target compound (1
3) 30 mg was obtained (30% yield). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
_{CDCl 3): 8.27 (1H,} s), 7.21-7.
37 (10H, m), 5.95 (1H, s), 5.20
−5.25 (1H, t, J = 6.9 Hz), 4.02
(1H, s), 2.83-2.94 (2H, m), 2.
61-2.67 (2H, dd, J = 8.4 Hz 6.6H
z) Mass spectrometry; [FAB-MS] m / z: 432 [M + H]
⁺

Embodiment 10

Embedded image Production of the compound represented by 50 mg of 2- (1-indanyl) thiazole-4-carboxylic acid and 256 mg of the compound (2) obtained in the step (1-1) were dissolved in 3 ml of dichloromethane, and 77 mg of WSC and 49 m of dimethylaminopyridine were dissolved.
g were sequentially added and the mixture was stirred at room temperature for 2 hours. This was separated with chloroform-water, the organic layer was dried and concentrated under reduced pressure. The residue was purified by thin-layer silica gel chromatography (chloroform: methanol = 100: 1) to obtain a crude ester, and subsequently 50% It was dissolved in fluoroacetic acid-5% triisopropylsilane-45% dichloromethane (2 ml) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin-layer silica gel column chromatography (chloroform-methanol = 100: 1) to obtain 11 mg of the desired compound (14). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
_{CDCl 3): 8.43 (1H,} s), 7.17-7.
33 (4H, m), 5.40-5.29 (1H, t, J
= 6.6 Hz), 3.94-4.06 (1H, m),
2.84-3.14 (4H, m), 2.56-2.82
(4H, m), 2.21-2.38 (1H, m) mass spectrometry; [FAB-MS] m / z: 382 [M + H]
⁺

Embodiment 11

Embedded image Production of the compound represented by 50 mg of 2- (2-indanyl) thiazole-4-carboxylic acid and 256 mg of the compound (2) obtained in the step (1-1) are dissolved in 3 ml of dichloromethane, and 7 mg of WSC and 49 mg of dimethylaminopyridine are dissolved.
Were added successively, and the mixture was stirred at room temperature for 2 hours. This was separated with chloroform-water, the organic layer was dried and concentrated under reduced pressure. The residue was purified by thin-layer silica gel chromatography (chloroform: methanol = 100: 1) to obtain a crude ester, and subsequently 50% Dissolve in fluoroacetic acid-5% triisopropylsilane-45% dichloromethane (2 ml) and add
Stirred for 0 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified using thin-layer silica gel column chromatography (chloroform-methanol = 100: 1) to obtain the target compound (1
5) 12 mg was obtained. Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
_{CDCl 3): 8.34 (1H,} s), 7.15-7.
26 (4H, m), 5.23-5.28 (1H, t, J
= 6.6 Hz), 4.12-4.14 (1H, t, J =
6.3 Hz), 3.97-4.02 (1H, t, J =
6.3 Hz), 3.47-3.54 (2H, m),
20-3.31 (2H, m), 2.87-2.91 (1
H, t, J = 6.6 Hz), 2.6-2.61 (2H,
t, J = 6.6 Hz) mass spectrometry; [FAB-MS] m / z: 382 [M + H]
⁺

Embodiment 12

Embedded image Production of the compound represented by 2- (1- (1,2,3,4
-Tetrahydronaphthyl)) 33 mg of thiazole-4-carboxylic acid and 162 m of the compound (2) obtained in the step (1-1)
was dissolved in 3 ml of dichloromethane, and 49 mg of WSC and 31 mg of dimethylaminopyridine were sequentially added.
Stirred for hours. This was separated with chloroform-water, the organic layer was dried and concentrated under reduced pressure. The residue was purified by thin-layer silica gel chromatography (chloroform: methanol = 100: 1) to obtain a crude ester, and subsequently 50% It was dissolved in fluoroacetic acid-5% triisopropylsilane-45% dichloromethane (2 ml) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was subjected to thin-layer silica gel column chromatography (chloroform-methanol = 100: 1).
Then, 13.6 mg of the target compound (16) was obtained. Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
_{CDCl 3): 8.39 (1H,} s), 7.04-7.
23 (4H, m), 5.23-5.29 (1H, t, J
= 6.6 Hz), 4.61 (1H, t), 3.98-
4.01 (1H, t, J = 6.6 Hz), 2.81−
2.96 (4H, m), 2.62-2.69 (2H,
m), 2.19-2.28 (2H, m), 1.80-
1.89 (2H, m) mass spectrometry; [FAB-MS] m / z: 396 [M + H].
⁺

Embodiment 13

Embedded image Production of the compound represented by 28 mg of 2- (thiochroman-4-yl) thiazole-4-carboxylic acid and the step (1-
128 mg of the compound (2) obtained in 1)
Then, 38 mg of WSC and 24 mg of dimethylaminopyridine were sequentially added, and the mixture was stirred at room temperature for 2 hours. This was separated with chloroform-water, the organic layer was dried and concentrated under reduced pressure. The residue was purified by thin-layer silica gel chromatography (chloroform: methanol = 100: 1) to obtain a crude ester, and subsequently 50% It was dissolved in fluoroacetic acid-5% triisopropylsilane-45% dichloromethane (2 ml) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified using thin-layer silica gel column chromatography (chloroform-methanol = 100: 1) to obtain 16 mg of the desired compound (17). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
_{CDCl 3): 8.41 (1H,} s), 7.03-7.
19 (4H, m), 5.24-5.29 (1H, t, J
= 6.6 Hz), 4.66-4.69 (1H, t, J =
4.5 Hz), 4.00-4.08 (1H, m), 2.
81-2.95 (5H, m), 2.61-2.64 (2
H, m), 2.24-2.36 (1H, m) mass spectrometry; [FAB-MS] m / z: 414 [M + H].
⁺

Embodiment 14

Embedded image Production of the compound represented by 25 mg of 2-thiophenoxymethylthiazole-4-carboxylic acid and 128 mg of the compound (2) obtained in the step (1-1) were dissolved in 3 ml of dichloromethane, and 38 mg of WSC and dimethylaminopyridine 24 were dissolved.
mg was sequentially added, and the mixture was stirred at room temperature for 2 hours. This was separated with chloroform-water, the organic layer was dried and concentrated under reduced pressure. The residue was purified by thin-layer silica gel chromatography (chloroform: methanol = 100: 1) to obtain a crude ester.
Subsequently, it was dissolved in 50% trifluoroacetic acid-5% triisopropylsilane-45% dichloromethane (2 ml) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was subjected to thin-layer silica gel column chromatography (chloroform-
Purification was performed using methanol (100: 1) to obtain 16 mg of the desired compound (18). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
_{CDCl 3): 8.18 (1H,} s), 7.20-7.
38 (5H, m), 5.20-5.27 (1H, m),
4.42 (2H, s), 4.06-4.11 (1H,
m), 2.87-2.96 (2H, m), 2.61-
2.71 (2H, m), 1.51-1.67 (2H,
m) Mass spectrometry; [FAB-MS] m / z: 386 [M-2H
+ H] ⁺

Embodiment 15

Embedded image Production of the compound represented by 2- (2- (1,2,3,4
-Tetrahydronaphthyl)) 26 mg of thiazole-4-carboxylic acid and 128 m of compound (2) obtained in step (1-1)
was dissolved in 3 ml of dichloromethane, and 38 mg of WSC and 24 mg of dimethylaminopyridine were added sequentially.
Stirred for hours. This was separated with chloroform-water, the organic layer was dried and concentrated under reduced pressure. The residue was purified by thin-layer silica gel chromatography (chloroform: methanol = 100: 1) to obtain a crude ester, and subsequently 50% It was dissolved in fluoroacetic acid-5% triisopropylsilane-45% dichloromethane (2 ml) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was subjected to thin-layer silica gel column chromatography (chloroform-methanol = 100: 1).
Then, 17 mg of the target compound (19) was obtained. Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
CDCl ₃ ): 8.20 (1H, s), 7.10 (4
H, s), 5.24-5.29 (1H, t, J = 6.6).
Hz), 4.08-4.13 (1H, m), 3.54-
3.57 (1H, m), 3.28-3.45 (1H, d
d, J = 16.5 Hz, 4.8 Hz), 3.05-3.
14 (1H, dd, J = 16.5Hz, 10.8H
z), 2.91-3.02 (4H, m), 2.68-
2.73 (1H, t, J = 8.7 Hz), 2.38-
2.43 (1H, m), 2.02-2.12 (1H,
m), 1.60-1.66 (1H, t, J = 8.7H)
z), 1.54-1.59 (1H, t, J = 9.0H
z) Mass spectrometry; [FAB-MS] m / z: 396 [M + H]
⁺

Embodiment 16

Embedded image Production of the compound represented by 31 mg of 2- (9-fluorenemethyl) thiazole-4-carboxylic acid and step (1-
128 mg of the compound (2) obtained in 1)
Then, 38 mg of WSC and 24 mg of dimethylaminopyridine were sequentially added, and the mixture was stirred at room temperature for 2 hours. This was separated with chloroform-water, the organic layer was dried and concentrated under reduced pressure. The residue was purified by thin-layer silica gel chromatography (chloroform: methanol = 100: 1) to obtain a crude ester, and subsequently 50% It was dissolved in fluoroacetic acid-5% triisopropylsilane-45% dichloromethane (2 ml) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin-layer silica gel column chromatography (chloroform-methanol = 100: 1) to obtain 18.5 mg of the desired compound (20). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
_{CDCl 3): 7.98 (1H,} s), 7.73-7.
75 (2H, d, J = 6.0 Hz), 7.36-7.3
9 (4H, d, 7.5 Hz), 7.28-7.31 (2
H, d, J = 6.6 Hz), 5.18-5.26 (1
H, m), 4.52-4.58 (1H, t, J = 6.0).
Hz), 4.03-4.12 (1H, m), 3.71-
3.73 (1H, d, J = 6.3 Hz), 2.85 −
2.94 (2H, m), 2.63-2.71 (2H,
m), 1.56-1.64 (2H, m) mass spectrometry; [FAB-MS] m / z: 442 [M-2H
+ H] ⁺

Embodiment 17

Embedded image Production of the compound represented by 2- (2-isopropoxyphenoxymethyl) thiazole-4-carboxylic acid 112m
g, 128 mg of compound (2) obtained in step (1-1), W
SC ・ HCl 38mg and dimethylaminopyridine 2
4 mg was dissolved in dimethylformamide (2 ml) and stirred at room temperature for 18 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and then with saturated saline, dried and concentrated to obtain an ester. The ester was dissolved in 50% trifluoroacetic acid-5% triisopropylsilane-45% dichloromethane (1 ml) and stirred at room temperature for 15 minutes. The reaction solution was concentrated under reduced pressure, and the residue was subjected to thin-layer silica gel chromatography (hexane-ethyl acetate =
2: 1) to give 14 mg of the desired compound (21)
I got Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
_{CDCl 3): 8.30 (1H,} s), 6.90-7.
00 (4H, m), 5.40 (2H, s), 5.27
(1H, dt, J = 3.0, 2.6 Hz), 4.56
(1H, m), 4.10 (1H, dt, J = 3.0,
2.7 Hz), 2.68-3.05 (4H, m), 1.
48-1.63 (2H, m), 1.38 (3H, s),
1.36 (3H, s) mass spectrometry; [FAB-MS] m / z: 430 [M + H]
⁺

Embodiment 18

Embedded image Production of the compound represented by Step (18-1) Production of the compound represented by 2.96 g of R-(+)-glycidol was dissolved in 100 ml of dimethylformamide, 13 g of t-butyldiphenylsilyl chloride and 6 g of imidazole were added, and the mixture was stirred at room temperature overnight. After partitioning with water-ethyl acetate, the organic layer was washed with 1N-HCl, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate = 6: 1) to obtain 10.1 g of a silyl compound (81%). Subsequently, 3.12 g of the silyl compound, 6.5 g of sodium azide, and 1.1 g of ammonium chloride were dissolved in a mixed solvent of 80 ml of methanol and 10 ml of water, and the mixture was stirred at 100 degrees overnight. The methanol was removed by concentration under reduced pressure, the residue was partitioned with water-ethyl acetate, and the organic layer was washed with saturated saline, dried and concentrated. The residue was purified by silica gel color chromatography (hexane-ethyl acetate = 2: 1) to obtain 2.7 g of an azide compound (78% yield). 2.7 g of the obtained azide compound is dissolved in 100 ml of dichloromethane, and 1.0 g of dihydropyran and 150 mg of p-toluenesulfonic acid are sequentially added under ice cooling, followed by stirring at room temperature overnight. The mixture was partitioned between water and ethyl acetate, and the organic layer was washed with saturated saline, dried and concentrated. The residue is subjected to silica gel column chromatography (hexane-ethyl acetate = 2
0: 1) to obtain 2.4 g of a tetrahydropyran derivative (yield 68%). 2.4 g of the above tetrahydropyran derivative
Was dissolved in 50 ml of tetrahydrofuran, 3 g of tetrabutylammonium fluoride was added, and the mixture was stirred at room temperature for 1 hour. The residue was purified by silica gel column chromatography (hexane-ethyl acetate = 2: 3) to obtain 780 mg of an alcohol (75% yield). The obtained alcohol (780 mg) was dissolved in ethyl acetate (10 ml), and triethylamine (1.0 ml) and methanesulfonyl chloride (570 mg) were sequentially added under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction mixture was filtered through celite to give crude product 1.
1 g was obtained. The above crude product was treated with dimethylformamide 10
and 350 mg of potassium thioacetate.
Stirred at 0 degrees for 2 hours. The mixture was partitioned between water and ethyl acetate, and the organic layer was washed with saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain 750 mg of a thioacetyl compound (83% yield). The obtained thioacetyl compound was converted to 1,4-
It was dissolved in dioxane, and 5.0 ml of 1N NaOH was added dropwise. After stirring at room temperature for 3 hours, 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 530 mg of a crude product. 530 mg of this crude product was dissolved in 20 ml of dichloromethane, and 2.0 g of trityl chloride and 300 mg of 4-dimethylaminopyridine were sequentially added under ice cooling, followed by stirring at room temperature overnight. The mixture was partitioned between water and ethyl acetate, and the organic layer was washed with saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to obtain 980 mg of a thiotrityl compound from which a tetrahydropyranyl group had been eliminated (yield: 63%). The obtained thiotrityl compound was dissolved in methanol, and palladium-carbon 50 was dissolved.
mg was added, hydrogenated and stirred for 3 hours. The reaction mixture was filtered through celite to give 730 mg of the desired compound (23).
Was obtained (76% yield). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
_{CDCl 3): 7.38-7.46 (6H,} m), 7.
19-7.34 (9H, m), 3.22-3.30 (1
H, m), 3.13-3.18 (2H, m), 2.40.
-2.47 (2H, m)

Step (18-2) 2-diphenylmethylthiazole-4-carboxylic acid 30
mg and 52 mg of the compound (23) obtained in the step (18-1)
Was dissolved in 3 ml of dichloromethane, 33 mg of WSC and 26 mg of dimethylaminopyridine were sequentially added, and the mixture was stirred at room temperature for 2 hours. This was separated with chloroform-water, the organic layer was dried and concentrated under reduced pressure, and the residue was purified by thin-layer silica gel chromatography (chloroform: methanol = 100: 1) to obtain an ester thereof. It was dissolved in acetic acid-5% triisopropylsilane-45% dichloromethane (2 ml) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified using thin-layer silica gel column chromatography (chloroform-methanol = 100: 1) to obtain 12 mg of the desired compound (22). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
CDCl ₃ ): 8.05 (1H, s), 7.66 (1
H, m), 7.21-7.38 (10H, m), 5.8.
0 (1H, s), 3.81-3.84 (1H, m),
3.62-3.72 (1H, m), 3.46-3.54
(1H, m), 2.60-2.70 (2H, m), 1.
51-1.57 (1H, t, J = 8.7 Hz) mass spectrometry; [FAB-MS] m / z: 385 [M + H]
⁺

Embodiment 19

Embedded image Production of the compound represented by 600 mg of the compound (10) obtained in the step (6-1) is dissolved in 10 ml of absolute ethanol, the solution is cooled to 0 ° C, and then 375 mg of 10 equivalents of sodium borohydride is added, followed by stirring at 0 ° C for 20 minutes. After that, the mixture was stirred at room temperature for 2 hours. 10 ml of a saturated aqueous ammonium chloride solution was added, and the mixture was stirred at room temperature overnight. In the reaction solution:
Add 5 equivalents of triethylamine (251 ml) and add
After stirring for an hour, the mixture was extracted with chloroform. The organic layer was washed with water and saturated saline, dried and concentrated. The resulting residue was dissolved in 10 ml of anhydrous dichloromethane, and 2.0 g of 2 equivalents of triphenylmethyl chloride and 0.2 equivalent of dimethylamino were added. Pyridine (81 mg) was added, and the mixture was stirred at room temperature for 2 days. The reaction solution was poured into water and extracted with chloroform. The organic layer was washed with water and then with saturated saline, dried and concentrated, and the residue was purified using silica gel column chromatography (hexane-ethyl acetate = 10: 1) to obtain 300 mg of a crude trityl compound. 31 mg of the crude trityl compound and 31 mg of 2- (9-fluorenemethyl) thiazole-4-carboxylic acid were dissolved in 3 ml of dichloromethane, and WS
C23 mg and dimethylaminopyridine 15 mg were sequentially added, and the mixture was stirred at room temperature for 2 hours. This was separated with chloroform-water, the organic layer was dried and concentrated under reduced pressure, and the residue was subjected to thin-layer silica gel chromatography (chloroform: methanol = 10
0: 1) to obtain a crude ester, followed by 50%
Trifluoroacetic acid-5% triisopropylsilane-45
% Dichloromethane (2 ml) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was subjected to thin-layer silica gel column chromatography (chloroform-methanol =
100: 1), and purified with the desired compound (24) 5.
8 mg were obtained. Mass spectrometry; [FAB-MS] m / z: 385 [M + H]
⁺

Embodiment 20

Embedded image Production of the compound represented by 32 mg of 2- (9-xanthenemethyl) thiazole-4-carboxylic acid and step (1-
128 mg of the compound (2) obtained in 1)
Then, 38 mg of WSC and 24 mg of dimethylaminopyridine were sequentially added, and the mixture was stirred at room temperature for 2 hours. This was separated with chloroform-water, the organic layer was dried and concentrated under reduced pressure. The residue was purified by thin-layer silica gel chromatography (chloroform: methanol = 100: 1) to obtain a crude ester, and subsequently 50% It was dissolved in fluoroacetic acid-5% triisopropylsilane-45% dichloromethane (2 ml) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin-layer silica gel column chromatography (chloroform-methanol = 100: 1) to obtain 22.4 mg of the target compound (25). Nuclear magnetic resonance spectrum; ¹ H-NMR (300 MHz,
_{CDCl 3): 8.04 (1H,} s), 7.22-7.
28 (1H, m), 7.01-7.14 (7H, m),
5.21-5.26 (1H, m), 4.58-4.62
(1H, t, J = 6.6 Hz), 4.03-4.09
(1H, m), 3.41 (2H, d, J = 6.3H
z), 2.89-2.99 (2H, m), 2.63-
2.69 (2H, dd, J = 6.6 Hz, 8.7H
z), 1.59-1.65 (1H, t, J = 9.0H
z), 1.52-1.58 (1H, t, J = 9.0H
z) Mass spectrometry; [FAB-MS] m / z: 460 [M + H]
⁺

Embodiment 21

Embedded image Production of the compound represented by 8.8 g of the compound (10) obtained in the step (6-1) was dissolved in 100 ml of tetrahydrofuran, 50 ml of K-selectride (1.0 M solution in tetrahydrofuran) was added at -78 ° C, and the mixture was stirred for 15 minutes. The reaction solution was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried and concentrated. The residue was dissolved in 20 ml of methanol, 2.3 g of sodium borohydride was added, and the mixture was heated under reflux for 20 minutes. After cooling, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was stirred at room temperature for 1.5 hours. The methanol was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was dried and concentrated, and the residue was purified using silica gel chromatography (hexane-ethyl acetate = 4: 1) to obtain 4.5 g of an alcohol. 3 g of the obtained alcohol compound was dissolved in 40 ml of chloroform, 16.4 g of triphenylmethyl chloride and 5 ml of pyridine were added, and the mixture was heated under reflux for 20 minutes. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 4: 4).
Purification was performed using 1) to obtain 4 g of an S-trityl compound. The obtained S-trityl compound was dissolved in 30 ml of dichloromethane, 1.16 ml of methanesulfonyl chloride and 2.16 ml of triethylamine were added, and the mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate.
The organic layer was washed with 0.3N hydrochloric acid and then with a saturated saline solution, dried and concentrated to obtain a crude mesylate. The crude mesylate was dissolved in 30 ml of dimethylformamide, 3.5 g of sodium azide was added, and the mixture was stirred at 120 ° C. for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried and concentrated to obtain a crude azide. The obtained crude azide was converted to tetrahydrofuran (50
ml) -water (5 ml), 5.6 g of triphenylphosphine was added, and the mixture was heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography (chloroform-methanol = 3: 1) to obtain 2.3 g of an amine compound. 220 mg of the obtained amine compound,
2- (1,4-benzodioxane) carboxylic acid 130 m
g and 100 mg of WSC.HCl were dissolved in 10 ml of pyridine and stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure,
The residue was dissolved in chloroform, washed with water and then with saturated saline, dried and concentrated to obtain a crude amide. 2 crude amides
It was dissolved in 0% trifluoroacetic acid-10% triisopropylsilane-70% dichloromethane (11 ml) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified using thin-layer silica gel chromatography (chloroform-methanol = 20: 1) to obtain the desired compound (26).
28 mg were obtained. Nuclear magnetic resonance spectrum; ¹ H-NMR (200 MHz,
CDCl ₃ ): 8.14 (1H, s), 7.15 (1
H, d, J = 3.2 Hz), 6.92-7.08 (4
H, m), 5.50 (1H, dd, J = 9.4, 4.4)
Hz), 4.62 (1H, dd, J = 15.3, 4.4)
Hz), 4.22-4.35 (1H, m), 3.86-
4.08 (1H, m), 2.80-3.00 (1H,
m), 2.35-2.48 (1H, m), 1.99-
2.13 (3H, m), 1.221.41 (6H, m) mass spectrometry; [FAB-MS] m / z: 377 [M + H].
⁺

[0091] Specific examples of the preparations are shown below with reference to 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.

[0092]

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.

[0093]

 ──────────────────────────────────────────────────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. Within the Tsukuba Research Laboratory (72) Inventor Tsuyoshi Morishima 3 Okubo, Tsukuba City, Ibaraki Pref.

Claims (8)

[Claims] 1. A compound of the general formula [I][Where B is C₆-C₁₂May have an aryl group
C₁-C_ThreeRepresents an alkylene group or a single bond, and Z is an oxygen atom
Or a sulfur atom or a single bond;₁Is unsubstituted
A non-aromatic heterocyclic group, an aliphatic ring group or C₆-C₁₂
Aryl group or halogen atom, cyano group, hydroxy
Group, amino group, carboxyl group, sulfo group, C ₁-C₆A
Alkyl group, C₁-C₆Alkoxy group, C₆-C₁₂Aryl
Group, C₇-C_TenAralkyl group and C₆-C₁₂Aryloxy
Having one or two substituents selected from the group consisting of
A non-aromatic heterocyclic group, an aliphatic ring group or C₆-C
₁₂An aryl group, Y is a carbonyl group for the bond or
Represents a methylene group, A represents an oxygen atom or N
X represents a group represented by H₁Is unsubstituted, C_Two-C_FiveAl
Kylene group, C_Three-C₇Cycloalkylene group or C_Two−
C_FiveAlkenylene or halogen atom, cyano group, hydride
Roxy, amino, carboxyl and mercapto groups
Having one or two substituents selected from the group consisting of
C_Two-C_FiveAlkylene group, C_Three-C₇Cycloalkylene
Group or C_Two-C_FiveRepresents an alkenylene group]
A compound, a pharmaceutically acceptable salt or ester thereof. 2. A compound of the general formula [I-2]Wherein B, Z, Y, A and X₁Means the above description,
R_TwoIs an unsubstituted benzodioxanyl group, thiochromani
Group, xanthene group, phenyl group, indanyl group, tet
Lahydronaphthyl group or fluorene group or halogen
Atom, cyano group, hydroxy group, amino group, carboxy
Group, sulfo group, C₁-C₆Alkyl group, C₁-C₆Arco
Xy group, C₆-C₁₂Aryl group, C₇-C_TenAralkyl group
And C₆-C ₁₂Selected from the group consisting of aryloxy groups
Benzodioxanyl having one or two substituents
Group, thiochromanyl group, xanthene group, phenyl group,
Danyl group, tetrahydronaphthyl group or fluor
A compound represented by the formula:
A chemically acceptable salt or ester. 3. A compound of the formula [I-3] Wherein B, Z, Y, A and X ₁ have the meanings described above;
R ₃ is an unsubstituted benzodioxanyl group, thiochromanyl group, xanthene group, phenyl group, indanyl group, tetrahydronaphthyl group or fluorene group or C ₁ -C ₆
A benzodioxanyl group, a thiochromanyl group, a xanthene group, a phenyl group, an indanyl group, a tetrahydronaphthyl group or a fluorene group having an alkoxy group], and a pharmaceutically acceptable compound thereof. Salt or ester. 4. A compound of the formula [I-4] [Wherein, R ₁ , B, Z, Y and A mean the above description,
X ₂ is an unsubstituted C ₂ -C ₅ alkylene group, C ₃ -C ₇ cycloalkylene group or C ₂ -C ₅ alkenylene group or 1 or 2 selected from a hydroxy group and a mercapto group
A C ₂ -C ₅ alkylene group, a C ₃ -C ₇ cycloalkylene group or a C ₂ -C ₅ alkenylene group having a substituent of the formula (I). Salt or ester. 5. A compound of the formula [I-5] The compound according to claim ₂ , wherein R ₂ , B, Z, Y, A and X ₂ have the meanings described above, or a pharmaceutically acceptable salt or ester thereof. 6. A compound of the general formula [I-6] 4. The compound according to claim 3, wherein R ₃ , B, Z, Y, A and X ₂ have the meanings described above, or a pharmaceutically acceptable salt or ester thereof. 7. A compound of the formula [I-7] [Wherein, R ₃ , B, Z, Y and A mean the above description,
X ₃ is an unsubstituted propylene, butylene, 3-methylpropylene or cyclohexylene having one or two substituents selected from a propylene group, a butylene group, a cyclohexylene group or a butenyl group, or a hydroxy group and a mercapto group. Or a butyl group or a butenyl group]], a pharmaceutically acceptable salt or ester thereof. 8. A compound of the general formula [I-1] [Wherein R ₁ , B, X, Y, A, and X ₁ have the meanings described above], and a geranylgeranyl type I protein comprising a pharmaceutically acceptable salt or ester thereof as an active ingredient Transferase inhibitors.