WO2006011499A1 - Novel arylamidine derivative, salt thereof, and antifungal containing these - Google Patents

Abstract

An arylamidine derivative represented by the general formula (wherein R1 represents optionally protected or substituted amidino; and R2 and R3 are the same or different and each represents hydrogen or halogeno) or a salt of the derivative. The derivative and salt have potent activity against fungi including ones having tolerance to azole type drugs and further have high safety and excellent properties in a repeated dose toxicity test. They are hence useful as an excellent antifungal. In addition, they have excellent activity against protozoans and are useful also as an antiprotozoal agent.

Description

 Specification

 Novel arylamidine derivatives and salts thereof, and antifungal agents containing them

 Technical field

 The present invention relates to a novel arylamidine derivative having antifungal activity, a salt thereof, and an antifungal agent containing them as an active ingredient.

 Background art

 [0002] Serious deep mycosis such as invasive candidiasis is often a fatal disease. Originally, the main defense mechanism of host organisms against fungi such as Candida is thought to be due to nonspecific immunity by neutrophils. If this defense mechanism is functioning normally, there is little risk of infection with fungi. However, in recent years, the number of patients with underlying diseases such as malignant tumors and AIDS, which cause a decrease in the immune function of this living body, increased use of carcinostatic agents and immunosuppressive agents, antibacterial antibiotics The risk of suffering from deep mycosis has increased due to heavy use, long-term central vein nutrition and the use of intravenous catheters (Non-patent Document 1).

 [0003] There are only six drugs for such deep mycosis: amphotericin B, flucytosine, miconazole, fluconazole, itraconazole and micafungin. Amphotericin B has a very strong bactericidal action, but there are side effects such as nephrotoxicity, which limits its clinical use. Because flucytosine has problems such as resistance, it is rarely used alone. Micafungin is weakly active against the genus Talyptococcus. All other drugs are collectively referred to as azole antifungal agents, and their fungicidal action against fungi is currently the most commonly used due to the balance between efficacy and safety, which tends to be generally inferior to that of amphotericin B. (Non-patent document 2).

[0004] Currently, Candida albicans is also frequently detected in the oropharyngeal candidiasis focus of AIDS patients receiving repeated doses of fluconazole. Moreover, many resistant strains are also cross-resistant to itraconazole and other azole drugs. In addition, chronic mucocutaneous candidiasis or deep candida Isolation of resistant strains has also been reported in non-AIDS patients who have developed complications (Non-patent Document 3). The problem of resistance has a serious impact on the management of patients with deeply growing mycosis (Non-Patent Document 3).

[0005] Non-Patent Document 1: Clinical and Microorganism, Vol.17, pp.265-266, 1990

 Non-Patent Document 2: Clinical and Microorganisms, Vol. 21, pp. 277-283, 1994

 Non-Patent Document 3: Clinical and Microorganisms, 28th, 51-58, 2001

 Disclosure of the invention

 Problems to be solved by the invention

[0006] An antifungal agent that has a different mechanism of action from existing drugs, is effective against azole drug-resistant fungi, and has few side effects is strongly desired. WO03 / 074476 discloses that allylamidine derivatives have strong antifungal activity and are useful as antifungal agents, but the side effects are further reduced, such as hygroscopicity and deliquescence. A compound with improved physical properties is desired.

 Means for solving the problem

[0007] Under such circumstances, the present inventors have conducted intensive studies, and as a result, the general formula [1]

Wherein R ¹ is an amidino group which may be protected or substituted; R ² and R ³ are the same or different and each represents a hydrogen atom or a halogen atom, or a salt thereof, or an azole The compound of general formula [1] in which R ¹ is an amidino group, R ² is a hydrogen atom and R ³ is a fluorine atom is an azole drug. It has strong activity against fungi including resistant fungi, exhibits high safety, does not exhibit deliquescence and hygroscopicity at all, has excellent chemical stability, and is suitable as a pharmaceutical drug substance. In addition, the present invention was completed by finding that it has an excellent activity against protozoa.

 The invention's effect

[0008] The compound of the present invention has strong activity against fungi including azole drug-resistant fungi, It exhibits high safety and excellent physical properties and is useful as an antifungal agent. In addition, it has excellent activity against protozoa and is also useful as an antiprotozoal drug.

 BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in detail.

 In this specification, unless otherwise specified, a halogen atom is a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; an alkyl group is, for example, methyl, ethyl, propyl, isopropyl, butyl, sec butyl A linear or branched C alkyl group such as butyl, isobutyl, tert butyl, pentyl, isopentyl, hexyl, heptyl and octyl; a lower alkyl group is, for example, methyl, ethyl, propyl, isopropyl

2

 A linear or branched C alkyl group such as butyl, sec butyl, isobutyl, tert butyl, pentyl and isopentyl;

 1-6

 Linear or branched C alkke such as Ninole, Arinole, Propeninole, Isopropeninole, Buteninole, Isobuteninole, Penteninole, Hexayl, Heptyl and Otatenyl

 2-12

An aryl group means, for example, a group such as fur and naphthyl; an alkyl group means an alkyl alkyl group such as, for example, benzyl, diphenylmethyl, trityl, phenethyl and naphthylmethyl; Examples of alkoxy groups include methoxy and eth

 1-6

 A linear or branched C alkyloxy group such as xoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec butoxy, tert butoxy, pentyloxy and isopentyloxy; an aralkyloxy group is, for example, Benzyloxy, Dihue

6

 An alkyl-alkyloxy group such as -methyloxy, trityloxy, phenethyloxy and naphthylmethyloxy; an alkoxyalkyl group is, for example, methoxymethyl

 1-6

 And C 1 alkyloxy C alkyl groups such as 1 and ethoxyethyl;

 1-6 1-6

 Examples of the alkyloxy group include C cycloalkyloxy groups such as cyclopropoxy, cyclobutoxy, cyclopentyloxy and cyclohexyloxy;

 3-8

 A ruoxyalkyl group is, for example, an al C alkyloxy C alkyl group such as benzyloxymethyl and phenethyloxymethyl;

 1-6 1-6

[0010] The acyl group is, for example, a linear or branched C alkanoyl group such as formyl group, acetyl, propiol and isovaleryl, or an al Cyl group such as benzyl carboyl. Alkylcarbol groups, aroyl groups such as benzoyl and naphthoyl, nicotine

1 -6

 Heterocyclic carbocyclic groups such as thiol, tenol, pyrrolidino carboyl and furoyl, and carboxy C alkyl such as 3 carboxypropanol and 4 carboxybutanol.

 C 6 alkyloxycarbons such as 1-6 alkyl carboyl groups, 3- (methoxy carbol) propanol and 4 (methoxy carbol) butanols.

 1 -6 1 -6

 , Succiol group, glutaryl group, maleoyl group, phthaloyl group and amino acids (for example, glycine, alanine, norin, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, Linear, branched or branched at the N-terminus derived from glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine, tyrosine, tryptophan, proline and hydroxyproline) A chained OC aminoalkanoyl group;

[0011] Alkyloxycarbonyl groups include, for example, methoxycarbon, ethoxycarbol, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 2-ethylhexyloxycarbonyl, tertbutoxycarbonyl and a straight-chain or branched C-alkyloxycarbonyl group such as tert-pentyloxypol;

 1-12

 An oral alkyloxycarbon group refers to, for example, a C cycloalkyloxycarbon group such as cyclopentyloxycarbon and cyclohexyloxycarbon.

 3-8

 An aralkyloxycarboxyl group refers to, for example, an aralkyloxycarboxyl group such as benzyloxycarbol and phenoxycarboxyl;

 1 -6

 For example, a carboxy group is a group such as a phenoxy carboxy group, and an alkoxy group is a linear or branched C alkanoyl group such as an acetyloxy and propio-oxy group. And alloys such as benzoyloxy

 2-6

 A ruoxy group;

 [0012] The arylthio group is, for example, a group such as phenolthio; the alkanesulfol group is, for example, C such as methanesulfol, ethanesulfol, and propanesulfol.

1-6 Alkanesulfol group; for example, arylsulfonyl group is a group such as benzenesulfonyl, toluenesulfol and naphthalenesulfol; for example, alkanesulfooxyl group is, for example, methanesulfoloxyl And ethanesulfoloxy c An alkanesulfo-oxy group; an arylsulfo-oxy group is, for example,

1 -6

 Groups such as benzenesulfuroxy and toluenesulfuroxy;

 [0013] An alkylthiocarbonyl group refers to, for example, a C alkylthiocarbonyl group such as methylthiocarbonyl and ethylthiocarbonyl; a cycloalkylidene group refers to

 1 -6

 For example, a group such as cyclopentylidene and cyclohexylidene; an alkylidene group such as benzylidene and naphthylmethylene; a dialkylaminoalkylidene group such as N, N dimethylaminomethylene and N, N a group such as a jetylaminomethylene; a dialalkylphosphoryl group, for example, a group such as dibenzylphosphoryl; a dialylphosphoryl group, for example, a group such as diphenylphosphoryl

[0014] The oxygen-containing heterocyclic group is, for example, a group such as tetrahydrofuryl and tetrahydrobiranyl; and the oxygen-containing heterocyclic alkyl group is, for example, 5-methyl-2-oxo-2H-1,3-dioxole-4 A group such as ethylmethyl; a sulfur-containing heterocyclic group, for example, a group such as tetrahydrocarbyl; a heterocyclic hydroxyl group, for example, 2-furfuroxycarboxyl And a group such as 8-quinolyloxycarbonyl; a nitrogen-containing bicyclic alkylidene group such as 3-hydroxy-4-pyridylmethylene; a substituted silyl group such as trimethylsilyl and triethylsilyl And a group such as tributylsilyl.

 Each of the above groups further includes a halogen atom, an amino group that may be protected, a hydroxyl group that may be protected, a nitro group, a lower alkyl group, an alkyl group, an alkoxy group, an alkyloxy group, an aryl. A group, an acyl group, or an oxo group may be substituted with one or more groups selected.

[0016] The amino protecting group includes all groups that can be used as protecting groups for ordinary amino groups. For example, W. Green et al., Protective 'Groups' In 'Organic' Synthesis (Protective Groups in Organic Synthesis) 3rd edition, 494-653, 1999, John Wiley & Sons, INC. Specifically, for example, an acyl group, an alkyl carboxy group, an aralkyl carboxy group, an aryl carboxy group, an aralkyl group, an alkoxy group. Sialkyl group, alkyloxyalkyl group, arylthio group, alkanesulfonyl group, arylaryl group, dialkylaminoalkylidene group, alkylidene group, nitrogen-containing heterocyclic alkylidene group, cycloalkylidene group, diarylphosphoryl group And a dialkyl phosphoryl group, an oxygen-containing heterocyclic alkyl group, and a substituted silyl group.

 [0017] The hydroxyl protecting group includes all groups that can be used as protecting groups for ordinary hydroxyl groups. For example, W. Green et al., Protective 'Groups' In 'Organic' Synthesis ( Protective Groups in Organic Synthesis) 3rd edition, pages 17-245, 1999, John Wiley & Sons JNC. Specifically, for example, an acyl group, an alkyloxycarbon group, an aralkyloxycarbonyl group, a heterocyclic oxycarbon group, an alkyl group, an alkenyl group, an aralkyl group, an oxygen-containing heterocyclic group And sulfur-containing heterocyclic groups, alkoxyalkyl groups, aralkyloxyalkyl groups, alkanesulfonyl groups, arylsulfonyl groups and substituted silyl groups.

 [0018] The amidino protecting group includes all groups that can be used as a protecting group for ordinary amidino groups. For example, an asilino group, an alkyloxycarbonyl group, an aralkyloxycarbonyl group , Aryloxycarboro group, cycloalkyloxycarboxyl group, alkyl group, alkoxyalkyl group, aralkyloxyalkyl group, allylthio group, alkanesulfol group, allylsulfonyl group, alkylthiocarboxyl And -alkyl group, a dialkylaminoalkylidene group, an alkylidene group, a nitrogen-containing heterocyclic alkylidene group, a cycloalkylidene group, an oxygen-containing heterocyclic alkyl group, and a substituted silyl group.

 [0019] Examples of the substituent of the amidino group include a hydroxyl group which may be substituted with an acyl group, and an alkoxy and aralkyloxy group which may be substituted.

[0020] Examples of the leaving group include a halogen atom, an alkanesulfoxy group, an arylsulfonyl group, and an acyloxy group.

[0021] Examples of the salt of the compound of the general formula [1] include hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid. Salts with mineral acids such as L; tartaric acid, formic acid, acetic acid, citrate, L lactic acid, succinic acid, maleic acid, fumaric acid, trichlorodiacetic acid and trifluoroacetic acid, and salts with organic carboxylic acids; and methanesulfone And salts with sulfonic acids such as acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.

 Preferable salts of the compound of the general formula [1] include pharmacologically acceptable salts, and hydrochloride is more preferable.

[0022] In the compound of the present invention, preferable compounds include the following compounds.

R ¹ may be substituted with an acyl group, substituted with a hydroxyl group, or a compound that is an amidino group is preferred, or a compound that is an amidino group is more preferred. More preferred are compounds that are amidino groups.

A compound in which R ² and R ³ are the same or different and is a hydrogen atom or a fluorine atom is preferred. A compound in which one of R ² and R ³ is a hydrogen atom, and the other is a fluorine atom. More preferred is a compound wherein R ² is a hydrogen atom and R ³ is a fluorine atom.

As a salt of a compound in which R ¹ is an amidino group, R ² or R ³ hydrogen atom, trihydrochloride is preferable.

 As said trihydrochloride, a monohydrate is preferable.

[0023] Next, a method for producing the compound of the present invention will be described.

 The compound of the present invention is produced by a combination of methods known per se. For example, the compound of the present invention can be produced by the following production method.

[0024] [Production method 1]

[3] um salt

“In the formula, R ⁴ represents a lower alkyl group; R ² and R ³ have the same meaning as described above.” [0025] The compound of the general formula [la] is generally the compound of the general formula [2]. It can be produced by reacting with a compound of the formula [4] and converting it to a compound of the general formula [3], and then reacting the compound of the general formula [3] with ammonia or an ammonium salt. This reaction is carried out according to the method described in the W096 / 16947 publication and the journal 'Ob' Organic 'Chemistry (J. Org. Chem.), Vol. 64, pp. 12-13, 1999, or the like. Just do it.

 Next, this series of reactions will be described in detail.

[0026] (1-1)

 The compound of the general formula [3] can be produced by reacting the compound of the general formula [2] with the compound of the general formula [4] in the presence of an acid.

The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; N, N — Amides such as dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; Halogenated hydrocarbons such as methylene chloride, cycloform and dichloroethane; Fragrances such as benzene, toluene and xylene Group hydrocarbons; ethers such as dioxane, tetrahydrofuran, azole, diethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol monomethyl ether; sulfoxides such as dimethyl sulfoxide; acetone and 2-butano Ketones such as; E, such as acetic acid Echiru Examples include stealth and carboxylic acids such as acetic acid, and these may be used in combination. In addition, the compound of the general formula [4] can also be used as a solvent.

[0027] Examples of the acid used in this reaction include hydrogen chloride, hydrogen bromide, perchloric acid, p-toluenesulfonic acid, methanesulfonic acid, and the like.

It may be 1 to 200 times mol, preferably 5 to 100 times mol for the compound of 2].

 In this reaction, the amount of the compound represented by the general formula [4] is preferably 2 to 1000 times that of the compound represented by the general formula [2].

 This reaction may be carried out at 30 to 150 ° C, preferably 10 to 50 ° C for 30 minutes to 24 hours.

 [0028] (1-2)

 The compound of the general formula [la] can be produced by reacting the compound of the general formula [3] with ammonia or an ammonium salt.

 The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; N, N Amides such as dimethylformamide, N, N dimethylacetamide and 1-methyl-2-pyrrolidone; Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Aromatic carbonization such as benzene, toluene and xylene Hydrogens; ethers such as dioxane, tetrahydrofuran, azole, diethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol monomethyl ether; -tolyls such as acetonitrile; sulfoxides such as dimethyl sulfoxide Examples include heteroaromatics such as pyridine and water, and these may be used as a mixture.

[0029] Examples of the ammonium salt include ammonium chloride, ammonium bromide and ammonium acetate, and the amount of ammonia or ammonium salt used is generally It may be 3 to 100 times mol, preferably 3 to 10 times mol for the compound of formula [3]. This reaction may be carried out at 0 to 150 ° C, preferably 20 to 120 ° C for 1 minute to 24 hours.

[0030] [Production method 2] [2]

H. NOH or its salt

兀

“Wherein R ⁵ represents an optionally substituted acyl, lower alkyl or aralkyl group; R ² and R ³ have the same meaning as described above.”

 [0031] The compound of the general formula [lb] can also produce the compound power of the general formula [2]. Next, a compound of the general formula [lc] can be produced by alkylating or acylating the compound of the general formula [lb]. Furthermore, the compound of general formula [la] can be produced by reducing the compound of general formula [lc]. Further, the compound of the general formula [la] can be produced by reducing the compound of the general formula [lb]. These reactions are described in Tetrahedron, 51st, 12047-12068, 1995; Synthetic Communication, 26th, 4351-4367, 1996; Synthesis ( Synthesis), Vol. 16, pp. 2467-2469, 2003; Heterocycles, Vol. 60, pp. 1133-1145, 2003 and Bioorganic and Medicinal Letter (Bioorganic and Medicinal) Chemistry Letter), verse 12, pages 1203-1208, 2002, etc., or a method similar thereto.

 Next, this series of reactions will be described in detail.

 [0032] (2-1)

The compound of the general formula [lb] is a compound of the general formula [2] in the presence or absence of a base, It can be produced by reacting with hydroxylamine or a salt thereof.

 The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; N, N — Amides such as dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; Halogenated hydrocarbons such as methylene chloride, cycloform and dichloroethane; Fragrances such as benzene, toluene and xylene Group hydrocarbons; ethers such as dioxane, tetrahydrofuran, azole, diethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol monomethyl ether; sulfoxides such as dimethyl sulfoxide; acetone and 2-butano Ketones such as; and hetero aromatics and water, such as pyridine and the like, may be used which are mixed.

[0033] Bases optionally used in this reaction include, for example, metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert-butoxide and sodium tert-butoxide; sodium hydroxide, sodium hydroxide, potassium hydroxide Inorganic salts such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride and potassium hydride, and organic bases such as tritylamine and pyridine.

 The amount of the base used may be 2 to 100 times mol, preferably 2 to 20 times monole to the compound of the general formula [2].

 Examples of the salt of hydroxylamine include hydrochloride and sulfate. The amount of hydroxylamine or a salt thereof used may be 2 to 100 times mol, preferably 2 to 20 times mol, of the compound of the general formula [2].

 This reaction may be carried out at 0 to 150 ° C., preferably 30 to 150 ° C. for 1 minute to 24 hours.

[0034] (2-2)

The compound of the general formula [lc] can be produced by reacting the compound of the general formula [lb] with a reactive derivative or an alkylating agent in the presence or absence of a base. The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidone, etc. Amides; methylene chloride, black mouth form and Halogenated hydrocarbons such as dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, azole, diethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol monomethyl ether; -Tolyls such as acetonitrile; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and 2-butanone; esters such as ethyl acetate; carboxylic acids such as acetic acid; heteroaromatics such as pyridine; These may be used as a mixture.

[0035] Examples of the reactive derivative include acid anhydrides such as acetylylformyloxide, acetic anhydride, trifluoroacetic anhydride, and trifluoroacetic anhydride; organic carboxylic acids such as acetic acid, chloroethyl carbonate, and isobutyl carbonate. Mixed acid anhydrides with monoalkyl esters of carbonic acid such as; Acid anhydrides of mixed acid anhydrides of organic carboxylic acids such as acetic acid with organic acids such as pivalic acid; Acid bromides such as acetyl chloride; and ρ Nitrophenyl ester, N hydroxy And active esters such as succinimide ester and N-hydroxyphthalimide ester. These reactive derivatives may be used without isolation.

 [0036] A reactive derivative may be generated in the system using a coupling reagent! Coupling reagents include, for example, carbodiimides such as N, N, monodicyclohexylcarbodiimide and Nethyl N ′-(3-dimethylaminopropyl) carbodiimide; carbo-diimidazole and other carbodiimides. Acid azides such as diphenyl phosphoryl azide; acid cyanides such as jetyl phosphoryl cyanide; 2-ethoxy 1 ethoxycarbonyl 1, 2 dihydroquinoline; O benzotriazole 1-yl 1, 1, 3, 3—Tetramethyluronium hexafluorophosphate; and O— (7-azabenzotriazole 1-yl) -1, 1, 3, 3—Tetramethylol-um-hexa Examples include fluorophosphate.

[0037] Examples of the alkylating agent include alkyl halides such as methyl iodide and thiol iodide; aralkyl halides such as benzyl chloride and benzyl bromide; and sulfate esters such as dimethyl sulfate. It is done. [0038] Bases optionally used in this reaction include, for example, metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert butoxide and sodium tert butoxide; sodium hydroxide, potassium hydroxide, carbonate, Examples include inorganic salts such as sodium hydride, sodium carbonate, potassium carbonate, sodium hydride and potassium hydride, and organic bases such as tritylamine and pyridine.

 The amount of the reactive derivative, coupling reagent, alkylating agent and base used is 2 to 100 times mol, preferably 2 to 10 times mol, of the compound of the general formula [lb].

 This reaction may be carried out at 20-100 ° C, preferably 0-50 ° C for 1 minute to 24 hours.

[0039] (2-3)

 The compound of the general formula [la] can be produced by subjecting the compound of the general formula [lb] to a reduction reaction. The compound of the general formula [la] can be produced by subjecting the compound of the general formula [lc] to a reduction reaction.

 Examples of the reduction reaction used here include a catalytic hydrogenation reaction using a metal catalyst and a reduction using a metal and an acid such as zinc acetate.

[0040] When the compound of the general formula [lb] or the compound of the general formula [lc] is subjected to the catalytic hydrogenation reaction, the solvent used is not particularly limited as long as it does not adversely affect the reaction. Alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; amides such as N, N dimethylformamide, N, N dimethylacetamide and 1-methyl-2-pyrrolidone; methylene chloride, black mouth form And halogenated hydrocarbons such as dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, azole, diethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol monomethyl ether ; -Tolyls such as tonitrile; ketones such as acetone and 2-butanone; esters such as ethyl acetate; forces such as acetic acid; rubonic acids; heteroaromatics such as pyridine; and water. You may use together.

[0041] Examples of the metal catalyst include palladium-carbon, palladium oxide, and palladium hydroxide. Palladium catalysts such as nickel and palladium black, nickel catalysts such as Raney nickel, and acid-platinum, etc., and the amount used is 0.001 to the amount of the compound of the general formula [lb] or the compound of the general formula [lc]. The amount is 1 time (wZw), preferably 0.01 to 0.5 times (wZw).

 Examples of reducing agents other than hydrogen include formic acid; formate salts such as sodium formate, ammonium formate, and triethylammonium formate; cyclohexene, and cyclohexadiene. The amount may be 2 to 100 times mol, preferably 2 to 10 times mol, of the compound of the general formula [lb] or the compound of the general formula [lc].

 When the compound of the general formula [lb] is subjected to a catalytic hydrogenation reaction, the hydrogen pressure thereof may be normal pressure to 30 atm, preferably 2 to 10 atm.

 When the compound of the general formula [lc] is subjected to a catalytic hydrogenation reaction, the hydrogen pressure may be normal pressure.

 This reaction may be carried out at 0 to 200 ° C., preferably at 0 to 100 ° C. for 1 minute to 24 hours.

[Production method 3]

“Wherein R ⁶ represents an optionally substituted lower alkyl or aralkyl group; RR ³ and R ⁴ have the same meaning as described above.

 The compound of general formula [Id] can also produce the compound power of general formula [3]. Subsequently, the compound of general formula [la] can be produced by reducing the compound of general formula [Id].

Next, this series of reactions will be described in detail. [0044] (3-1)

 The compound of the general formula [Id] can be produced by reacting the compound of the general formula [3] with the compound of the general formula [5] or a salt thereof.

 Examples of the compound of the general formula [5] include O-methylhydroxylamine and O-benzylhydroxylamine.

 Examples of the salt of the compound of the general formula [5] include hydrochloride and sulfate.

 This reaction may be carried out according to production method 1-2.

[0045] (3- 2)

 The compound of the general formula [la] can be produced by reducing the compound of the general formula [Id]. This reaction can be carried out according to production method 2-3.

[0046] [Production Method 4]

“Wherein R ⁷ represents an optionally substituted lower alkyl, aralkyl, aryl, alkoxy, cycloalkyloxy or aralkyloxy group; R ² and R ³ have the same meaning as described above. "

 [0047] The compound of the general formula [le] can be produced by reacting the compound of the general formula [la] with a reactive derivative in the presence or absence of a base.

 This reaction may be carried out according to production method 2-2.

[0048] For each compound in the above production methods 1 to 4, a salt thereof can also be used, and examples of the salt include the same salts as those described for the compound of the general formula [1].

 Each of the production intermediates obtained in the above production methods 1 to 4 can be used for the next reaction without isolation.

Thus obtained compounds of the general formulas [la], [lb], [lc], [Id] and [le] These salts may be converted into other salts by subjecting them to known reactions such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis, or by appropriately combining these reactions. It can be derived into a compound of the general formula [1] or a salt thereof.

 [0049] In addition, when there are isomers (for example, optical isomers, geometric isomers, tautomers, etc.) in the above-described production method, these isomers may also be used. Also, solvates, hydrates and various forms of crystals can be used.

 [0050] Next, a method for producing the compound of general formula [2], which is a raw material for producing the compound of the present invention, will be described. The compound of the general formula [2] is produced by a combination of methods known per se, and can be produced, for example, by the production method shown below.

 [0051] [Production method A]

“Wherein R ⁸ is an amino protecting group; L ¹ and L ² are leaving groups; R ² and R ³ have the same meaning as described above.

 [0052] Examples of the compound of the general formula [6] include tert butyl = 4 (bromomethyl) 1 piperidine carboxylate. It can also be produced by combining known methods using 4-piperidinemethanol and tert butyl = 4 (hydroxymethyl) 1-piperidinecarboxylate as raw materials.

Examples of the compound of the general formula [8] include, for example, 4 cyanophenol and 4-cyanol 3 Examples include fluorophenol.

 [0053] (A- 1)

 The compound of the general formula [7] can be produced by reacting the compound of the general formula [6] with the compound of the general formula [8] in the presence or absence of a base and then deprotecting the compound. .

 The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; N, N Amides such as dimethylformamide, N, N-dimethylacetamide, and 1-methyl-2-pyrrolidone; Halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane; Aromatics such as benzene, toluene, and xylene Hydrocarbons; ethers such as dioxane, tetrahydrofuran, azole, diethylene glycol dimethyl ether, diethylene glycol jetyl ether and ethylene glycol monomethyl ether; -tolyls such as acetonitrile; sulfoxy such as dimethyl sulfoxide S; ketones such as acetone and 2-butanone; esters such as acetic Echiru; etc. hetero aromatics and water, such as pyridine and the like, may be used which are mixed.

[0054] Bases optionally used in this reaction include, for example, metal alkoxides such as sodium methoxide, sodium metoxide, potassium tert butoxide and sodium tert butoxide; sodium hydroxide, potassium hydroxide, hydrogen carbonate Examples thereof include inorganic bases such as sodium, sodium carbonate, potassium carbonate, sodium hydride and potassium hydride, and organic bases such as triethylamine, N, N diisopropylethylamine and pyridine.

 [0055] The amount of the base used may be 1 to 10 times mol, preferably 1 to 3 times mono to the compound of the general formula [6].

 The amount of the compound of general formula [8] used in this reaction is 1 for the compound of general formula [6].

It is -20 times mole, Preferably, it is 1-5 times mole.

This reaction may be carried out at 0 to 200 ° C, preferably 0 to 150 ° C for 1 minute to 24 hours. In addition, the removal of the amino protecting group represented by R ⁸ is, for example, protected group in organic synthesis, brother 3fe, 494: If you follow the method described on page 653, 1999, etc. or a method similar to it.

[0056] (A-2)

 The compound of the general formula [2] can be produced by reacting the compound of the general formula [7] with the compound of the general formula [9]. This reaction may be performed according to production method A-1.

[0057] [Production method B]

“Wherein R ⁹ is a hydroxyl protecting group; L ³ is a leaving group; R ² , R ³ and L ² have the same meaning as above.

 [0058] The compound of the general formula [11] can be produced, for example, by using 4-piperidinemethanol as a raw material and combining known methods.

[0059] (B- 1)

 The compound of the general formula [10] can be produced by reacting the compound of the general formula [9] with the compound of the general formula [11], followed by deprotection. This reaction may be performed according to production method A-1.

The removal of the hydroxyl protecting group represented by R ⁹ is, for example, in Protective groups in organic syntnesis 3rd edition, ¾¾ 丄 7-245, 1999, etc. If you follow the method described or similar to it. [0060] (B-2)

 The compound of the general formula [12] can be produced by converting the hydroxyl group of the compound of the general formula [10] into a leaving group by a conventional method.

 When the leaving group is an alkyl sulfo-loxy group or an aryl sulfo-loxy group, the compound of the general formula [10] can be prepared in the presence or absence of a base, for example, methane sulfol chloride. The reaction may be carried out with an arylsulfuric chloride such as alkanesulfochloride or p-toluenesulfonic acid chloride.

[0061] Bases optionally used in this reaction include, for example, metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert butoxide and sodium tert butoxide; sodium hydroxide, potassium hydroxide, hydrogen carbonate Examples thereof include inorganic bases such as sodium, sodium carbonate, potassium carbonate, sodium hydride and potassium hydride, and organic bases such as triethylamine, N, N diisopropylethylamine and pyridine.

 The amount of the alkylsulfonyl chloride or arylsulfuryl chloride and the base used may be 1 to 10 times mol, preferably 1 to 3 times mol, of the compound of the general formula [10].

 This reaction may be carried out at 0 to 200 ° C, preferably 0 to 150 ° C for 1 minute to 24 hours.

[0062] When the leaving group is a halogen atom, the compound of the general formula [10] can be converted to, for example, a salt of sodium chloride, thionyl bromide, boron tribromide and carbon tetrabromide trif-phosphine. You can react with them.

 The amount of these reagents to be used may be 1 to 10 times mol, preferably 1 to 3 times mol, of the compound of the general formula [10].

[0063] The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, N, N dimethylformamide, N, N dimethylacetamide and 1-methyl-2-pyrrolidone Amides such as; Halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane; Aromatic hydrocarbons such as benzene, toluene, and xylene; Dioxane, Tetrahydrofuran, Carsol, Diethylene glycol dimethyl ether, Diethylene glycol jetyl Ether and ethylene glycol Examples include ethers such as coal monomethyl ether; -tolyls such as acetonitrile; sulfoxides such as dimethyl sulfoxide, and heteroaromatics such as pyridine. These may be used as a mixture.

 This reaction may be carried out at 0 to 200 ° C, preferably 0 to 150 ° C for 1 minute to 24 hours.

[0064] (B— 3)

 The compound of the general formula [2] can be produced by reacting the compound of the general formula [12] with the compound of the general formula [8]. This reaction may be performed according to production method A-1.

[0065] [Production method C]

“Wherein L ⁴ represents a leaving group; R ² and L ² have the same meaning as described above.” [0066] Examples of the compound of the general formula [13] include 4 cyanophanol and 4-cyanol 3 —Fluorophenol and the like.

 Examples of the compound of the general formula [15] include 3 bromo-1 propanol.

[0067] (C 1)

 The compound of the general formula [14] can be produced by reacting the compound of the general formula [13] with the compound of the general formula [15]. This reaction may be performed according to production method A-1.

[0068] (C 2)

 The compound of the general formula [9] can be produced by converting the hydroxyl group of the compound of the general formula [14] into a leaving group. This reaction may be performed according to production method B-2.

[0069] When the compound of the present invention is used as a pharmaceutical, excipients and carriers usually used for formulation These can be mixed with formulation adjuvants such as diluents, etc. according to conventional methods. Tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, liquids, powders It can be administered orally or parenterally in the form of suppositories, suppositories, eye drops, nasal drops, ear drops, patches, ointments or injections. In addition, the administration method, the dosage, and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient. In general, for adults, 0.01 to 1000 mg / kg is divided into several doses once a day by oral or parenteral (eg injection, infusion, rectal administration, etc.) It should be administered once a day.

 [0070] In order to clarify the usefulness of the compound of the present invention, antifungal action, repeated toxicity test, Vero cell growth inhibition test, hygroscopicity test and antiprotozoal action test were performed.

 [0071] Test Example 1 Antifungal activity

 The compound of Example 6 was selected as the compound of the present invention. As a comparative compound, the compound described in the example of WO03 / 074476, which has the most similar structure to the compound of the present invention, was selected. Their chemical structural formulas are shown below.

[Example 6]

[Comparative compound]

 HCI salt

The susceptibility test against fungi was performed using a micro liquid dilution method. RPMI1640 (RPMI / MOPS) adjusted to PH 7.0 with 0.165 mol / L morpholine propanesulfonic acid (MOPS) and 1.0 mol / L sodium hydroxide was used as the medium for the sensitivity test. Test substances were dissolved in sterile water and diluted 2-fold serially with 100 L RPMI / MOPS on 96-well round bottom plates. Candida albicans TIMM1623 cultured in Sabouraud agar at 35 ° C overnight was suspended in sterile physiological saline. Count the number of cells with a biological microscope, prepare the inoculum (2 X 10 ³ cells / mL) with RPMI / MOPS, and dispense 100 L of each well into the wells. Then, a microplate containing a medium and cells was prepared. The plate was incubated at 35 ° C for 48 hours. After incubation, absorb 630 nm The light intensity was measured with an automatic spectrophotometer. IC was defined as the lowest concentration at which 50% growth inhibition was observed compared to the growth control without addition of the test substance. The results are shown in Table 1.

 50

 [0072] [Table 1] Compound Example 6 Comparative compound

IC ₅₀ (jt g / mL) 0.002 0.0039 *

* Values described in WO03 / 074476

[0073] The compound of Example 6 was stronger than the comparative compound and showed antifungal activity.

[0074] Test Example 2 Repeated dose toxicity test in mice (1)

 The compound of Example 6 was selected as the compound of the present invention. As a comparative compound, the compound described in the example of WO03 / 074476, which has the most similar structure to the compound of the present invention, was selected. Their chemical structural formulas are shown below.

[Example 6]

[Comparative compound]

 HCI salt

 Repeated dose toxicity was examined using 6-week-old male ICR mice (weight range: 30.6 to 34.8 g, number of animals allocated per group: 5). Each test substance solution was prepared by dissolving in distilled water. The dose was 6.25 mg / kg and administered subcutaneously once a day for 7 days. Sterile saline was administered to the control group. At the end of the dosing period, each mouse was anesthetized with ether. Abdominal vena cava force was also collected using a syringe containing heparin solution (Novo'Heparin Injection 1000, Aventis Pharma Co., Ltd.) as a blood coagulation inhibitor. Hematology was performed on the following items. Table 2 shows the values when the control group is 100.

 (Hematology test items and measurement method)

 Red blood cell count (RBC): 2-angle laser flow cytometry

 Reticulocyte: flow cytometry by RNA staining

[0075] [Table 2] Compound Example 6 Comparative compound Red blood cell count (RBC) 96 105 Reticulocyte count 100 62 *

 * p <0.01

[0076] The compound of Example 6 had higher safety than the comparative compound that did not reduce the reticulocyte count.

 [0077] Test Example 3 Repeated dose toxicity test in mice (2)

 The compound of Example 3 was selected as the compound of the present invention. As a comparative compound, a compound having a structure most similar to the compound of the present invention was selected from the compounds described in Examples of WO03 / 074476. Their chemical structural formulas are shown below.

[Example 3]

[Comparative compound]

 Repeated dose toxicity was examined using 6-week-old male ICR mice (weight range: 29.8-33.2 g, number of animals allocated per group: 5). Each test substance solution was prepared by dissolving in O.lmol / L hydrochloric acid. It was administered subcutaneously once daily for 14 days at a dose of 6.25 or 3.13 mg / kg. Sterile saline was administered to the control group. At the end of the dosing period, each mouse was anesthetized with ether. Abdominal vena cava force was also collected using a syringe containing heparin solution (Novo'Heparin Injection 1000, Aventis Pharma Co., Ltd.) as a blood coagulation inhibitor. Hematological examinations were performed on the following items. The values when the control group is 100 are shown in Table 3.

 (Hematology test items and measurement method)

 Red blood cell count (RBC): 2-angle laser flow cytometry

 Reticulocyte: flow cytometry by RNA staining

[0078] [Table 3] Compound Example 3 Comparative compound

 Dose (mg / kg) 6.25 3.1 3 3.1 3 Red blood cell count (RBC) 1 01 .1 1 02.1 96.2 Reticulocyte count 87.5 91.7 76.7 *

 * p <0.01

[0079] The comparative compound decreased the reticulocyte count at the dose of 3.13 mg / kg. On the other hand, the compound of Example 3 was much safer than the comparative compound that did not decrease the reticulocyte count even at the dose of 6.25 mg / kg.

 [0080] Test Example 4 Vero cell growth inhibition test

 The compound of Example 6 was selected as the compound of the present invention. As a comparative compound, a compound having a structure most similar to the compound of the present invention was selected from the compounds described in Examples of WO03 / 074476. Their chemical structural formulas are shown below.

[Example 6]

[Comparative compound]

 HCI salt

 Compound cytotoxicity was assessed using Vero cells. Each test substance was dissolved in dimethyl sulfoxide (DMSO), serially diluted with E'MEM containing 10% FBS, and added to a 96-well plate. The cells were suspended in E'MEM supplemented with 10% FBS, inoculated with 3000 cells / well (96 well plate), and cultured in a CO incubator at 37 ° C for 3 days. The degree of growth of Vero cells

 2

 2, 3-bis (2-methoxy 4--tro 5-5-sulfophenol) 1-5- [(Phenolamino) carbonyl] -2H-tetrazolium = inner salt = mononatrium salt (XTT) evaluated by Atsy . That is, add XTT solution containing lmg / mL XTT and 25 / z mol / L phenazine = methosulphate (PMS) to each well, and in a CO incubator for 2 hours.

 2

After the incubation, the absorbance at 450 nm (reference: 655 nm) of each weinole was measured with a microplate reader. The absorbance ratio of the control (no compound added) and each well was calculated, and the concentration of the compound that inhibits cell growth by 50% (CC; μg / mL) was calculated. Result The results are shown in Table 4.

[Table 4] Compound Example 6 Comparative compound

(CC _{50 g} / mL) 25 6

[0082] The compound of Example 6 had higher safety than the comparative compound.

 [0083] Test Example 5 Hygroscopicity test (1)

 The compound of Example 10 was selected as the compound of the present invention. As a comparative compound, a compound having a structure most similar to the compound of the present invention was selected from the compounds described in Examples of WO03 / 0 74476. Their chemical structural formulas are shown below.

[Example 1 0]

[Comparative compound]

 [0084] The compound of Example 10 and the comparative compound were stored for one week under conditions of room temperature and relative humidity of 75%. As a result, the compound of Example 10 was a powder with no change in appearance. On the other hand, the comparative compound changed into a paste.

 The compound of Example 10 had higher stability than the comparative compound.

[0085] Test Example 6 Hygroscopicity test (2)

 The compound of Example 10 was selected as the compound of the present invention. As a comparative compound, a compound having a structure most similar to the compound of the present invention was selected from the compounds described in Examples of WO03 / 0 74476. Their chemical structural formulas are shown below.

[Example 1 0]

[Comparative compound]

HCI salt The compound of Example 10 and the comparative compound were stored for 10 days under conditions of room temperature and 75% relative humidity, and the weight was measured. The results are shown in Table 5.

 [0086]

 Compound Example 1 0 Comparative compound Weight increase rate (%) 0 25

[0087] The compound of Example 10 did not absorb moisture at all, and had higher stability than the comparative compound.

[0088] Test Example 7 Antiprotozoal action

 The antiprotozoal activity of the compound of Example 6 was measured.

Trichomonas vaginalis CDC337 is cultured with Diamond's trypticase-yeast-maltose medium (pH6.8) containing 8% fetal Bovine Serum (FBS). It was. 3 Centrifuge the worms cultured at 7 ° C for 2 days (1500 rpm, 10 minutes), change the medium with fresh medium, adjust to 2 X 10 ⁴ worms / mL, and add 100 μL / well to the microplate (96 Dispensing into holes, flat bottom). The test substance was dissolved in sterilized distilled water, diluted to a predetermined concentration in the medium, and 100 L / well was dispensed onto a microplate. After culturing at 37 ° C under anaerobic conditions for 2 days, the minimum test substance concentration at which no insect movement was observed was defined as MIC.

 The MIC of the compound of Example 6 was g / mL.

[0089] Test Example 8 Candida infection model test in mice (oral administration)

 The compound of Example 37 was selected as the compound of the present invention. Its chemical structural formula is shown below.

[Example 37]

[0090] Candida albicans TIMM1 623 on an SDA plate cultured overnight at 35 ° C was suspended in sterile physiological saline and diluted to prepare an inoculum. In order to transiently infect mice (5 animals per group), cyclophosphamide 200 mg / kg 4 days before infection and cyclophosphamide 100 mg / kg intraperitoneally the day after infection Administered. Inoculated 0.2 mL of the prepared Candida albicans TIMM1623 inoculum into the tail vein of mice to induce infection (approximately 3 X 10 ⁴ CFU / mouse). Suspend the test substance in 0.5% methylcellulose, Mice were orally administered at 0.57 mol / kg. Treatment began 7 hours after infection and lasted for 7 days. The number of surviving mice was observed and recorded for 8 days after infection.

 As a result, all mice died in the test substance non-administered group, but 60% of mice survived in the compound-administered group of Example 37.

 The compound of Example 37 showed an excellent therapeutic effect even after oral administration.

[0091] In in vitro and in vivo tests, the compounds of the present invention had much superior antifungal activity than the comparative compounds. In the repeated dose toxicity test, the compound of the present invention did not decrease the reticulocyte count and had higher safety than the comparative compound. In addition, the comparative compound was hygroscopic and difficult to control the quality, but the compound of the present invention was not hygroscopic and was far superior to the comparative compound as an active pharmaceutical ingredient. . Further, the compound of the present invention showed an excellent effect against protozoa.

 Example

 Next, the present invention will be described with reference to reference examples and examples, but the present invention is not limited to these examples.

 The mixing ratios in the eluent are all volume ratios, and B.W.silica gel and BW-127ZH (Fuji Silicon Chemical Co., Ltd.) were used as the carriers in column chromatography unless otherwise specified.

 In each example, each abbreviation has the following meaning.

 Ac: acetylene, Boc: tert butoxycanoleboninole, tBu: tert-butinole, Et: ethinole, Me: methyl, Ms: methanesulfol

 DMSO-d: Heavy dimethyl sulfoxide

 6

[0093] Reference Example 1

tert-Butyl = 4 (Bromomethyl) 1-piperidinecarboxylate 0.75 g of 2-butanone in 7.5 mL was charged with 0.56 g of potassium carbonate and 0.32 g of 4 cyanophenol at room temperature and heated to reflux for 4 hours. After adding 3.0 mL of 2-butanone, the mixture was further heated under reflux for 1.5 hours. After cooling to room temperature, insolubles were removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue It was dissolved in ethyl acetate, washed successively with 10% aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 10: 1], and colorless oily tert-butyl = 4-[(4-cyanophenoxy) methyl] -1-piperi 0.46 g of gincarboxylate was obtained.

 1H-NMR (CDC1) δ fg: 1.20-1.35 (2H, m), 1.47 (9H, s), 1.75-2.10 (3H, m), 2.65-2.82 (2H,

 Three

 m), 3.84 (2H, d, J = 6.3Hz), 4.05-4.25 (2H, m), 6.93 (2H, d, J = 8.8Hz), 7.58 (2H, d, J = 8.8Hz).

[0094] Reference Example 2

 tert butyl = 4 [(4-cyanophenoxy) methyl] 1-piperidinecarboxylate 0.45 g of Kuroguchi form in 4.5 mL solution was prepared at room temperature with 1 mL of trifluoroacetic acid. The mixture was stirred at the same temperature for 2 hours, and the solvent was distilled off under reduced pressure. Toluene was added to the obtained residue and the solvent was distilled off under reduced pressure, and then the same operation was repeated. To the obtained residue, black mouth form and water were added, and the pH was adjusted to 13.0 with a 5.0 mol / L aqueous sodium hydroxide solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 4- (4 piberidinylmethoxy) benzo-tolyl as a yellow oil. got g

1H-NMR (CDC1) δ value: 1.15— 1.35 (2H, m), 1.70—2.05 (3H, m), 2.55—2.72 (2H, m), 3.05—3.2

 Three

 0 (2H, m), 3.83 (2H, d, J = 6.3Hz), 6.93 (2H, d, J = 8.9Hz), 7.58 (2H, d, J = 8.9Hz).

[0095] Reference Example 3

4- (4Piberidyl-methoxy) benzo-tolyl 0.25 g of N, N-dimethylformamide 2.5 mL of potassium carbonate 0.24 g and 4- (3-bromopropoxy) benzo-tolyl 0.28 g are added at room temperature. The mixture was stirred at 40-50 ° C for 2 hours. The reaction mixture was cooled to room temperature and added to the ethyl acetate and water mixture. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Residue obtained Diisopropyl ether was added to the solution, and the solid substance was collected by filtration to obtain 0.39 g of 4-({1 [3- (4 cyanophenoxy) propyl] 4 piveridyl-methoxy} benzo) tolyl as a white solid. 1H-NMR (CDC1) δ value: 1.35- 1.48 (2H, m), 1.77-1.89 (3H, m), 1.93-2.06 (4H, m), 2.52 (2H,

 Three

t, J = 7.4Hz), 2.93-3.02 (2H, m), 3.84 (2H, d, J = 6.1Hz), 4.07 (2H, t, J = 6.3Hz), 6.93 (2H, d, J = 8 8Hz), 6.95 (2H, d, J = 8.8Hz), 7.57 (4H, d, J = 8.8Hz).

Reference example 4

 4- (4Piveridylmethoxy) benzo-tolyl 0.29g of N, N-dimethylformamide 2. To a 9mL solution, add 0.28g of potassium carbonate and 0.35g of 4 (3-bromopropoxy) -2-fluorinated benzonitrile at room temperature. For 4 hours 30 minutes. The reaction mixture was added to the ethyl acetate and water mixture. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; black form: methanol = 8: 1], diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to give a pale orange solid. 4- (3- {4 -— [(4 cyanophenoxy) methyl] 1 piveridyl-propoxy) 2 Fluoro-Benzonitrile 0.27 g was obtained.

 'H-NMRCCDCl) δ value: 1.32- 1.51 (2H, m), 1.73- 2.11 (7H, m), 2.50 (2H, t, J = 6.8Hz), 2.88-3

 Three

 .05 (2H, m), 3.85 (2H, d, J = 5.9Hz), 4.07 (2H, t, J = 6.3Hz), 6.71-6.77 (2H, m), 6.93 (2H, d, J = 8 9Hz), 7.48-7.52 (lH, m), 7.58 (2H, d, J = 8.9Hz).

Reference Example 5

tert Butyl = 4 (Bromomethyl) 1-piperidinecarboxylate 6.40 g of dimethyl sulfoxide in 52 mL solution was charged with 4.77 g of potassium carbonate and 3.15 g of 2 fluoro-4-hydroxybenzo-tolyl at room temperature, and stirred at 40 ° C for 18 hours. did. The reaction mixture was added to a mixture of ethyl acetate and ice water. Separate the organic layer, add water, and adjust to pHll.O with potassium carbonate. It was adjusted. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 4: 1], hexane was added to the obtained residue, and the solid was collected by filtration to give a white solid. Thus, 5.66 g of tert butyl = 4 [(4-cyanol-3-fluorophenoxy) methyl] 1-piperidinecarboxylate was obtained.

 1H-NMR (CDC1) δ fg: 1.20-1.36 (2H, m), 1.47 (9H, s), 1.76-2.08 (3H, m), 2.65-2.85 (2H,

 Three

 m), 3.84 (2H, d, J = 6.3Hz), 4.07-4.29 (2H, m), 6.67-6.76 (2H, m), 7.49-7.53 (lH, m).

[0098] Reference Example 6

tert-Butyl = 4 — [(4 Cyano 3 fluorophenoxy) methyl] 1 piperidine carboxylate To a solution of 6.24 g of Kuroguchi form was added 14.5 mL of trifluoroacetic acid under ice cooling. The mixture was stirred at room temperature for 2 hours, and the solvent was distilled off under reduced pressure. Toluene was added to the obtained residue and the solvent was distilled off under reduced pressure, and then the same operation was performed twice. To the obtained residue, chloroform and ice water were added, and the pH was adjusted to 13.0 with a 5.0 mol / L aqueous sodium hydroxide solution. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 4.47 g of 2-fluoro-4- (4-piveridylmethoxy) benzo-tolyl was obtained as a pale yellow solid. Obtained.

 1H-NMR (CDC1) δ value: 1.20-1.45 (2H, m), 1.76- 2.10 (3H, m), 2.60-2.75 (2H, m), 3.08-3.3

 Three

 0 (2H, m), 3.82 (2H, d, J = 6.3Hz), 6.68-6.76 (2H, m), 7.48-7.53 (lH, m).

[0099] Reference Example 7

2 Fluoro-4-(4piveridylmethoxy) benzo-tolyl To a solution of 4.42 g of N, N dimethylformamide in 45 mL, add 3.92 g of potassium carbonate and 4.54 g of (3-bromopropoxy) benzonitrile and stir at room temperature for 14 hours. did. The reaction mixture was added to a mixture of ethyl acetate and ice water. The solid matter was collected by filtration, and the white solid 4 1 ({1 1 [3— (4-Cyanofeno 4.10 g of (xy) propyl] —4-piveridyl} methoxy) -2 fluorobenzobenzotolyl was obtained.

 1H-NMR (CDC1) δ value: 1.34- 1.48 (2H, m), 1.76- 1.90 (3H, m), 1.94-2.06 (4H, m), 2.52 (2H

 Three

t, J = 7.2Hz), 2.92-3.03 (2H, m), 3.84 (2H, d, J = 6.1Hz), 4.07 (2H, t, J = 6.2Hz), 6.67-6.75 (2H, m), 6.94 (2H, d, J = 8.8Hz), 7.49-7.52 (lH, m), 7.58 (2H, d, J = 8.8Hz).

Reference Example 8

 2 Fluoro 4 -— (4-Pyveridylmethoxy) benzo-tolyl 0.40 g of N, N dimethylformamide in 4.0 mL was charged with 0.35 g of potassium carbonate and 4 (3-bromopropoxy) 2 After stirring, the mixture was stirred at room temperature for 3 hours and 30 minutes. The reaction mixture was added to a mixture of ethyl acetate and ice water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 8: 1], diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to give a white solid. 4-({1- [3— (4 cyano 3 fluorophenoxy) propyl] 4 piperidinyl} methoxy) 2-fluorine benzonitrile (0.39 g) was obtained.

 'H-NMRCCDCl) δ value: 1.35- 1.48 (2H, m), 1.77-1.90 (3H, m), 1.93-2.06 (4H, m), 2.51 (2H,

 Three

t, J = 7.2Hz), 2.93-3.02 (2H, m), 3.84 (2H, d, J = 5.9Hz), 4.07 (2H, t, J = 6.3Hz), 6.68-6.77 (4H, m), 7.49-7.53 (2H, m).

Reference Example 9

To a suspension of 2-butanone in 50.0 g of 3-fluoro-4-cyanophenol and 60.5 g of potassium carbonate was added 57.4 g of 1-bromo-3-chloropropane, and the mixture was heated to reflux for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature and water was added. The organic layer was separated, washed with l.Omol / L aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [eluent: hexane: ethyl acetate]

= 4: 1] to obtain 62.2 g of 4- (3-chloropropoxy) -2 fluorobenzo-tolyl as a slightly yellow solid.

 1H-NMR (CDC1) δ value: 2.22- 2.32 (2H, m), 3.74 (2H, t, J = 6.2Hz), 4.17 (2H, t, J = 5.9Hz), 6.70

 Three

 -6.80 (2H, m), 7.53 (lH, dd, J = 8.7,7.4Hz)

Reference Example 10

 4-Cyanphenol 45.3 g of dimethyl sulfoxide in 400 mL was added with potassium carbonate 105 g and tert butyl = 4 methanesulfonoxymethyl-1-piperidinecarboxylate 112 g, and stirred at 70 to 80 ° C. for 4 hours and 20 minutes. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the solid was collected by filtration. The organic layer of the filtrate was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue and the previously obtained solid were combined and washed with hexane to obtain 117 g of white solid tert-butyl = 4 [(4-cyanophenoxy) methyl] -1 piperidinecarboxylate .

¹ ! ”I-NMR in CDC1 was consistent with Reference Example 1.

 Three

Reference Example 11

4 -— (4-piveridylmethoxy) benzo-tolyl 25.8 g of dimethyl sulfoxide in 150 mL solution, 4-— (3-chloropropoxy) 2 fluo-benzoyl tolyl 25.5 g of dimethyl sulfoxide in lOOmL, N, N diisopropyl Ethylamine (104 mL) was added and stirred at 85 to 90 ° C. for 7 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 10: 1], diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to give a pale orange solid. 4— (3— {4 — [(4 cyanophenoxy) methyl] -1 piberidyl-l} propoxy) 2 fluobenzoyl tolyl 26.5 g was obtained. ¹ ! "I-NMR in CDC1 was consistent with Reference Example 4.

 [0104] Example 1

 4— ({1— [3— (4 Cyanophenoxy) propyl] — 4 Piberidyl} methoxy) benzol-tolyl 0.20 g of ethanol in 10 mL suspension of hydrogen chloride under ice-cooling, then the same temperature Stir for 15 minutes. After standing at room temperature for 13 hours, the solvent was distilled off under reduced pressure, ethanol was further added, and the solvent was distilled off under reduced pressure. The obtained residue was suspended in 10 mL of ethanol, and 0.41 g of ammonium acetate was added and heated to reflux for 1 hour and 30 minutes. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was purified by reversed-phase silica gel column chromatography [silica gel; YDS ODS-A, eluent; water], and the resulting white solid was dissolved in water to give 5.0 mol / L hydroxy acid. The pH was adjusted to 12.5 with sodium hydroxide aqueous solution. The solid product was collected by filtration to obtain 0.16 g of 4-solid solid (4- {[1— (3— {4— [amino (imino) methyl] phenoxy} pill) -4-piberidyl] methoxy} benzamidine. It was.

 'H-NMRCDMSO-d) δ value: 1.20— 1.37 (2H, m), 1.65— 1.80 (3H, m), 1.84— 1.93 (4H, m), 2.42 (

 6

 2H, t, J = 7.2Hz), 2.85-2.95 (2H, m), 3.85 (2H, d, J = 5.6Hz), 4.03 (2H, t, J = 6.3Hz), 6.10-6.45 (4H, broad ), 6.92 (2H, d, J = 8.8Hz), 6.92 (2H, d, J = 8.8Hz), 7.70 (2H, d, J = 8.8Hz), 7.71 (2H, d, J = 8.8Hz).

 [0105] Example 2

4- (3- {4- [(4-Cyanofenoxy) methyl] 1 piveridyl-propoxy 2- fluo-benzoyl tolyl Hydrogen chloride was introduced into 0.25 g of ethanol in 13 mL suspension under ice-cooling. Then, the mixture was stirred at the same temperature for 30 minutes. After standing at room temperature for 15 hours and 30 minutes, the solvent was distilled off under reduced pressure, ethanol was further added, and the solvent was distilled off under reduced pressure. The obtained residue was suspended in 15 mL of ethanol, 0.49 g of ammonium acetate was added, and the mixture was heated to reflux for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by reversed-phase silica gel column chromatography [silica gel; YDS ODS-A, eluent: water]. . The obtained white solid was dissolved in water and adjusted to pH 3.0 with a 5.0 mol / L aqueous sodium hydroxide solution. The solid was collected by filtration, and the white solid 4— {3— [4— ({4— [amino-imino] methyl] phenoxy} methyl) — 1-piveridyl-propoxy} — 2-fluorbenzenes 0.12 g of amidine was obtained.

 ^ -NMRCDMSO-d) δ value: 1.20— 1.38 (2H, m), 1.65— 1.95 (7H, m), 2.40 (2H, t, J = 7.1Hz), 2.8

 6

 5-2.95 (2H, m), 3.86 (2H, d, J = 5.6Hz), 4.04 (2H, t, J = 6.2Hz), 6.08-6.58 (4H, broad), 6.77-6.85 (2H, m), 6.93 (2H, d, J = 8.7Hz), 7.49-7.53 (lH, m), 7.71 (2H, d, J = 8.7Hz).

Example 3

4— ({1— [3— (4 Cyanophenoxy) propyl] — 4 Piveridyl-methoxy} 2-Fluorobenzoyl Tolyl Hydrogen chloride was introduced into a suspension of 0.25 g ethanol in 13 mL under ice-cooling. Then, the mixture was stirred at the same temperature for 12 minutes. After standing at room temperature for 15 hours and 30 minutes, the solvent was distilled off under reduced pressure, ethanol was further added, and the solvent was distilled off under reduced pressure. The obtained residue was suspended in 15 mL of ethanol, 0.49 g of ammonium acetate was added, and the mixture was heated to reflux for 1 hour and 30 minutes. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by reversed-phase silica gel column chromatography [silica gel; YDS ODS-A, eluent: water]. . The obtained solid was dissolved in water and adjusted to pH 13.0 with a 5.0 mol / L aqueous sodium hydroxide solution. The solid was collected by filtration to give a white solid 4— {[1— (3— {4— [Amino (imino) methyl] phenoxy} propyl) 4 piberidyl] methoxy} 2 fluorobenzamidine 0.12 g

 mm ^ [solo]

^{• (s'HI) 0S'6 '(s} ' HI) W

6 '( ^ζ Η8 ・ 8 = ΓΡΉ2) 83 ・'(ω'Ηΐ) 2 ^ ·-ε ・ '(ζΗ8 ・ 8 = ΓΡΉ2) ΐ6 ・ 9'(ω'Η2) 58 ・ 9-9 9 '( ω'Η ^

) 1 '(ω'Ηε) ΟΟ — 08 · ΐ'(ω'Ηε) 08 · ΐ— 39 · ΐ '(ω) 9ε · ΐ— OS'I: Army 9 (OS) Η 顺 — Η _τ

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,% Os ¾, ^ 继 鼸 疆 τ¾ε, ^ ^) ^§ οζ · ε / fH-: ^ ΰ /

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) ΐ '(ω'Η) S6'I- 08 · ΐ'(ω'Ηε) 08 · ΐ— 39 · ΐ '(ω'Η 3ε · ΐ— OS'I: Army 9 (P-OS a) H NH _T

Z0.CT0 / S00Zdf / X3d 9ε 66 Ϊ0 / 900Ζ OAV 4- {[l-(3- {4- [Amino (hydroxyimino) methyl] phenoxy} propyl) 4-piberidyl-methoxy} 2-fluoro-N, -hydroxybenzamidine 4.00 g in 40 mL of acetic acid To the solution, 2.5 mL of acetic anhydride was added at room temperature and stirred at the same temperature for 30 minutes. To this mixture, 0.40 g of 5% palladium-carbon was added and stirred for 4 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in water and adjusted to PH13.0 with a 3.0 mol / L aqueous sodium hydroxide solution. The solid was collected by filtration to obtain 3.80 g of 4 {[1— (3— {4— [amino (imino) methyl] phenoxy} propyl) 4 piberidyl] methoxy} 2 fluoro oral benzamidine as a pale yellow solid. .

 'H-NMRCDMSO-d) δ value: 1.20— 1.35 (2H, m), 1.65— 1.80 (3H, m), 1.80— 1.96 (4H, m), 2.41 (

 6

 2H, t, J = 7.1Hz), 2.85-2.95 (2H, m), 3.86 (2H, d, J = 5.9Hz), 4.03 (2H, t, J = 6.3Hz), 6.30-6.80 (4H, broad ), 6.77-6.85 (2H, m), 6.93 (2H, d, J = 8.7Hz), 7.48-7.53 (lH, m), 7.71 (2H, d, J = 8.7H z).

Example 6

 4- {[l-(3- {4- [Amino (imino) methyl] phenoxy} propyl) 4-piveridyl] methoxy} 2 Fluorobenzamidine 3.50 g water in 18 mL suspension at room temperature 1.0 Mol / L Hydrochloric acid 33mL was added, and it stirred at the same temperature for 1 hour and 30 minutes. The operation of distilling off the solvent under reduced pressure, adding ethanol and distilling off the solvent under reduced pressure were repeated three times. Ethanol was added to the obtained residue, and the solid matter was collected by filtration and purified by reverse phase silica gel chromatography [silica gel; YMC ODS-A, eluent; water] to obtain a white solid 4- {[ 1- (3- {4 -— [Amino (imino) methyl] phenoxy} propyl) 4piveridyl-methoxy} 2 fluorobenzamidine hydrochloride (3.04 g) was obtained.

 'H-NMRCDMSO-d) δ value: 1.65— 1.85 (2H, m), 1.90— 2.15 (3H, m), 2.20— 2.35 (2H, m), 2.90—

 6

3.05 (2H, m), 3.10-3.24 (2H, m), 3.50-3.60 (2H, m), 3.99 (2H, d, J = 6.3Hz), 4.20 (2H, t, J = 6.1 Hz), 6.99-7.01 (lH, m), 7.10-7.20 (lH, m), 7.17 (2H, d, J = 9.0Hz), 7.63-7.67 (lH, m), 7.87 (2 H, d, J = 9.0Hz), 8.96-9.10 (2H, m), 9.16-9.39 (6H, m), 10.85-11.00 (lH, broad).

 [0110] Example 7

 4— ({1— [3— (4 cyano 3 fluorophenoxy) propyl] — 4 piveridyl-methoxy) -2-fluorobenzo-tolyl in a solution of 0.35 g of dimethyl sulfoxide at room temperature A 50% aqueous hydroxylamine solution (0.52 mL) was added, and the mixture was stirred at 40 ° C for 4 hours. After cooling the reaction mixture to room temperature, 7.0 mL of water was added dropwise over 3 minutes and stirred at the same temperature for 40 minutes. The solid was collected by filtration to give a white solid 4 {[1 (3— {4 [Amino (hydroxyimino) methyl] 3 —fluorophenoxy} propyl) 4 piveridyl-methoxy] 2 fluoro-N, -0.39 g of hydroxybenzamidine was obtained.

 'H-NMRCDMSO-d) δ value: 1.21— 1.35 (2H, m), 1.66— 1.78 (3H, m), 1.81— 1.95 (4H, m), 2.40 (

 6

 2H, t, J = 7.1Hz), 2.85-2.93 (2H, m), 3.86 (2H, d, J = 5.9Hz), 4.03 (2H, t, J = 6.3Hz), 5.64-5.73 (4H, m ), 6.76-6.85 (4H, m), 7.37-7.42 (2H, m), 9.50 (2H, s).

 [0111] Example 8

4- {[l-(3- {4- [Amino (hydroxyimino) methyl] 3-fluorophenoxy} propyl) -4piberidyl] methoxy} 2 fluoro-N, monohydroxybenzamidine To 35 g of acetic acid 5.3 mL solution, acetic anhydride 0.21 mL was added at room temperature and stirred at the same temperature for 1 hour. To this mixture was added 0.04 g of 5% palladium-carbon, and the mixture was stirred for 3 hours under a hydrogen atmosphere. Bad Ninth Region [επο]

(s'HT) 0e-6 '( ^s ' HT) ^-

6 '( ^ζ Η8 ・ 8 = ΓΡΉ2) 83 ・'(ω'Ηΐ) ^ ・ -9ε ・ '(ζΗ0 ・ 6 = Γ'ΡΉ2) ΐ6 ・ 9'(ω'Η2) 98 (Ρ ^ΏΟ ^

'H) rS— 9'S'(ZHS'9 = l ^ 'HS) Wr ( ^z H6'S = f'P'HS) 8'S'(ra'HS) S6 — S8 '(ra'HS) SfS — S 2' ( UI'H) S6'I- Ζ8 · ΐ '(ω'Ηε) 08 · ΐ- 39 · ΐ'(ω'Η 3ε · ΐ- 0 ^: 119 (P-OS a) H NH _T

 . ¾¾ 9'S be; ^^ X be: ^ / ^^

氺

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 6th category [mo]

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) 0S'9— 0ΐ · 9 '( ^ζ Ηε · 9 = ί ^' Η Μ) · ( ^ζ Η6 · 3 = ί "'Ρ'Η 98 · ε'(ω'Ηζ ^ 6 — '( ^z HrZ = l ^ 'HS

) 0 '(ω'Η) 96 · ΐ- 08 · ΐ'(ω'Ηε) 08 · ΐ-9 · ΐ '(ω'Η 9ε · ΐ-: Army 9 (P-OS a) H NH _T

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 4- {[l-(3- {4- [Amino (hydroxyimino) methyl] phenoxy} propyl) 4-piberidyl-methoxy} 2 fluoro-N, -hydroxybenzamidine 1.14 g of acetic acid in 12 mL suspension To the liquid, 0.59 mL of acetic anhydride and 0.10 g of 5% palladium carbon were added at room temperature, and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. The insoluble material was removed by filtration, and the filter cake was washed with 6 mol / L hydrochloric acid. The filtrate and washings were combined and concentrated to about 10 mL under reduced pressure. After adjusting to pH12 with 5mol / L sodium hydroxide aqueous solution, the solid was collected by filtration, dissolved with lmol / L hydrochloric acid, and reverse phase silica gel column chromatography [silica gel; YDS ODS-A, elution Liquid; water]. The obtained white solid was suspended in a mixture of water and 2-propanol and stirred at room temperature for 45 minutes and ice-cooled for 2 hours. The solid was collected by filtration, and the white solid 4— {[1— (3— {4— [Amino (imino) methyl] phenoxy} propyl) 4 piberidyl] methoxy} 2 fluorobenzamidine trihydrochloride water 1.04 g of Japanese product was obtained.

Moisture: 3.8%

¹ H-NMR in DMSO-d was consistent with the value of Example 6.

 6

Example 11

4- (3- {4- [(4- {[(Acetyloxy) imino] (amino) methyl} phenoxy) methyl] 1 piperidinyl} propoxy) 2-Fluorobenzamide = O Acetyloxime 2.78 g of 2 propanol and 8 mL To a suspension of 8 mL of water, 0.30 g of 5% palladium carbon and 3 mL of formic acid were added at room temperature, followed by stirring at 25 to 35 ° C. for 3 hours and 50 minutes. Acetic anhydride at 25 ° C 0.3 mL and 1 mL of formic acid were added, and the mixture was stirred at 20 to 25 ° C. for 1 hour and 15 minutes. Insolubles were removed by filtration, and the filtrate was adjusted to pH 13 with 20% aqueous sodium hydroxide solution. The solid was collected by filtration, washed with water and 2-propanol, and light gray solid 4— {3— [4— ({4— [amino (imino) methyl] phenoxy} methyl) -1 piberidyl] Propoxy} 2 1.98 g of fluorobenzamidine was obtained.

¹ H-NMR in DMSO-d was consistent with the value of Example 2.

 6

Example 12

 In the same manner as in Example 11, 4-68- {1-[3-- ({4 [amino] methyl] phenoxy} propyl) -4-piveridyl-methoxy} 2 fluorobenzamidine 1.68 g was obtained as a light gray solid. Obtained.

¹ H-NMR in DMSO-d was consistent with the value of Example 3.

 6

Example 13

4— ({1-[3- (4 Cyanophenoxy) propyl] — 4 piveridyl-methoxy) 2— Fluoro-benzo-tolyl Hydrogen chloride was introduced into 0.3 mL of ethanol in 10 mL suspension under ice-cooling. And left at room temperature overnight. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in 20 mL of ethanol. To this suspension, 0.64 g of O-methylhydroxylamine hydrochloride and 3.18 mL of triethylamine were sequentially added, stirred for 2 hours and 30 minutes, and then allowed to stand overnight. The solvent was distilled off under reduced pressure, and black residue was added to the resulting residue to obtain a 1.0 mol / L aqueous sodium hydroxide solution. The solution was adjusted to pHIO. The organic layer was separated, washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 10: 1], diisopropyl ether was added, the solid was collected by filtration, and a white solid 4 {[ 1- (3- {4- [Amino (methoxyimino) methyl] phenoxy} propyl) -4-piveridyl-methoxy} 2 -fluorine benzamide = 0-methyloxime 0.29 g was obtained.

 'H-NMRCCDCl) δ value: 1.34- 1.48 (2H, m), 1.74- 1.88 (3H, m), 1.92- 2.04 (4H, m), 2.46-2.5

 Three

 6 (2H, m), 2.94-3.02 (2H, m), 3.80 (2H, d, J = 5.9Hz), 3.90 (3H, s), 3.90 (3H, s), 4.03 (2H, t, J = 6.3Hz), 4.70-4.80 (2H, broad), 4.90-5.10 (2H, broad), 6.61 (lH, dd, J = 13.7, 2.6Hz), 6.69 (lH, dd, J = 8.8, 2.6Hz) 6.90 (2H, d, J = 8.9Hz), 7.55 (2H, d, J = 8.9Hz), 7.63 (lH, t, J = 8.8Hz).

 [0117] Example 14

 In the same manner as in Example 13, white solid 4— {3— [4— ({4 [Amino (methoxyimino) methyl] phenoxy} methyl) — 1-piveridyl] propoxy} — 2-fluorobenzamide = 0.24 g of O-methyloxime was obtained.

 'H-NMRCCDCl) δ value: 1.34- 1.48 (2H, m), 1.76- 1.88 (3H, m), 1.94-2.04 (4H, m), 2.45-2.5

 Three

 4 (2H, m), 2.93-3.01 (2H, m), 3.82 (2H, d, J = 6.1Hz), 3.90 (3H, s), 3.90 (3H, s), 4.02 (2H, t, J = 6.3Hz), 4.65-4.80 (2H, broad), 4.90-5.10 (2H, broad), 6.63 (lH, dd, J = 13.7,2.4Hz), 6.70 (lH, dd, J = 8.8,2.4Hz) 6.89 (2H, d, J = 8.8Hz), 7.55 (2H, d, J = 8.8Hz), 7.63 (lH, t, J = 8.8Hz).

 [0118] Example 15

4— ({1-[3- (4 Cyanophenoxy) propyl] — 4 piveridyl-methoxy) 2— Fluoro-benzo-tolyl Hydrogen chloride was introduced into 0.3 mL of ethanol in 10 mL suspension under ice-cooling. And left at room temperature overnight. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in 20 mL of ethanol. To this suspension, 0.74 g of oxyethyl hydroxylamine hydrochloride and 3.18 mL of triethylamine were sequentially added, stirred for 4 hours, and left overnight. The solvent was distilled off under reduced pressure, and chloroform was added to the obtained residue, and the pH was adjusted to 1.0 with 1.0 mol / L sodium hydroxide aqueous solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 20: 1], and isopropyl ether was added to the obtained residue, and the solid was collected by filtration. 0.13 g of white solid 4 {[1— (3 -— {4 [amino (ethoxyimino) methyl] phenoxy} propyl) 4 piveridyl] methoxy} 2 fluoro-bensamide = ethyl etheroxime was obtained.

 ^ -NMRCCDCl) δ value: 1.32 (3H, t, J = 7.0Hz), 1.32 (3H, t, J = 7.0Hz), 1.36-1.50 (2H, m), 1.75

 Three

 -1.88 (3H, m), 1.94-2.08 (4H, m), 2.50-2.58 (2H, m), 2.95-3.05 (2H, m), 3.80 (2H, d, J = 5.9H z), 4.03 ( 2H, t, J = 6.3Hz), 4.13 (2H, q, J = 7.0Hz), 4.14 (2H, q, J = 7.0Hz), 4.70-4.80 (2H, broad), 4.95-5.05 (2H, broad ), 6.61 (lH, dd, J = 13.7,2.6Hz), 6.68 (lH, dd, J = 8.8,2.6Hz), 6.90 (2H, d, J = 8.9Hz), 7.56 (2H, d, J = 8.9Hz), 7.63 (lH, t, J = 8.8Hz).

Example 16

 In the same manner as in Example 15, 4- {3 -— [4 — ({4- (amino (ethoxyimino) methyl] phenoxy} methyl) —1-piveridyl-propoxy} —2-fluoroben 0.41 g of zamide = O ethyloxime was obtained.

 'H-NMRCCDCl) δ value: 1.32 (6H, t, J = 7.0Hz), 1.36- 1.48 (2H, m), 1.76- 1.88 (3H, m), 1.94- 2

 Three

.06 (4H, m), 2.46-2.56 (2H, m), 2.94-3.04 (2H, m), 3.82 (2H, d, J = 6.1Hz), 4.02 (2H, t, J = 6.3H {^^^ i.) ^ →) -ε] -χ}) → a> ^ U ^ "^ mM ^ nm ^

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I— 08 · ΐ '(ω'Ηε) 08 · ΐ— 0Ζ · ΐ'(ω'Η 3ε · ΐ— 0Π '( ^ζ Η9 · Ζ = ί "' νΗε) 80 · ΐ '( ^ζ Η3 · Ζ = Π'Ηε) Ζ0 · ΐ: Army 9 (P-OS a) H NH _T

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 {^^^ Λ (^ Ι ^ ^ Λ ((^ (^ -Ζ-^ {Λ (-^ Λ (^ ^ Λ-

• (zH8 "8 = rVHT) 8Z" Z '(zH6 "8 = f'P'H2) ^ 9"Z' (z H6'8 = f'P'HS) 06'9 '( ^z HS'S'8' 8 = rPP'HI) Sr9 '( ^z HS'S'rSI = rPP'HI) 99'9'(PJOJq'HS) SS '

ω'ΗΖ) 00 · ε- 06 'C "' HS) SS-S S '(ra'HS) SS-SrS'WH SO-36 · ΐ'(ω'Ηε) 06 · ΐ- • I '(ra 'H0S) 0S'I— 3ε · ΐ' ( ^ζ Η8 · 9 = ί "'Ρ'Η9) 30 · ΐ' ( ^ζ Η8 · 9 = ΓΡ'Η9) ΐ0 · ΐ: Army 9 (OQDWH-H ^

Z0.CT0 / S00Zdf / X3d 917 66 Ϊ0 / 900Ζ OAV 4- (3- {4- [(4- {Amino [(23)-2- (tert-butoxycarbol) amino-1-methylbutyryloxymino] methyl} phenoxy) methyl] 1-piveridi- } Propoxy) — 2 Fluorobenzamide = 0— [(2S)-2- (tert-Butoxycarbol) amino-3-methylbutyryl] oxime 50 mol of 2-propanol in 0.5 mL suspension with 5.5 mol / L salt 1 mL of hydrogen fluoride / 2-propanol was added, and the mixture was stirred at 50 ° C for 30 minutes. The solvent was distilled off under reduced pressure, and chloroform, formaldehyde, 2-propanol and saturated aqueous sodium hydrogen carbonate solution were added to the resulting residue under ice cooling. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Jetyl ether was added to the obtained residue, and the solid was collected by filtration, washed with ethyl acetate, and then converted into a light yellow solid 4 ((3— {4 [(4 {amino [(2S) — 2 amino-3 Methylbutyryloxyimino] methyl} phenoxy) methyl] 1 piveridyl-propoxy) 2 Fluorobenzamide = 0 — [(2S) -2 amino-3-methylbutyryl] Aged xime 19 mg was obtained.

 'H-NMRCDMSO-d) δ value: 0.80-0.95 (12H, m), 1.25-1.40 (2H, m), 1.65-2.00 (13H, m), 2.3

 6

 5-2.45 (2H, m), 2.85-2.95 (2H, m), 3.15-3.25 (2H, m), 3.87 (2H, d, J = 5.9Hz), 4.07 (2H, t, J = 6.3Hz ), 6.68 (2H, s), 6.78 (2H, s), 6.83 (lH, dd, J = 8.7, 2.3Hz), 6.92 (lH, dd, J = 12.4, 2.3Hz), 6.98 (2H, d, J = 8.9Hz), 7.42 (lH, t, J = 8.7Hz), 7.65 (2H, d, J = 8.9Hz).

Example 24

 In the same manner as in Example 23, 4-({1-[3- (4-— {amino [(2S) -2 amino-3-methylbutyryloxymino] methyl} phenoxy) propyl]- 4-Pyberidyl} methoxy) 2 fluorobenzamide = 0 — [(2S) -2 amino-3-methylbutyryl] oxime 85 mg was obtained.

'H-NMRCDMSO-d) δ value: 0.80- 0.95 (12H, m), 1.20-1.40 (2H, m), 1.65- 1.95 (13H, m), 2.3 5-2.45 (2H, m), 2.85-2.95 (2H, m), 3.15-3.25 (2H, m), 3.89 (2H, d, J = 5.9Hz), 4.05 (2H, t, J = 6.

3Hz), 6.68 (2H, s), 6.77 (2H, s), 6.80-6.95 (2H, m), 6.98 (2H, d, J = 8.8Hz), 7.35-7.45 (lH, m),

7.65 (2H, d, J = 8.8Hz).

 [0128] Example 25

 To a solution of 345 mg of N- (tert-butoxycarbol) -L-isoleucine 1Z2 hydrate in 3 mL of N-methyl-2-pyrrolidone was added 349 mg of 1,1, -carbodiimidazole at room temperature, and the mixture was stirred for 30 minutes. 4— {3— [4— ({4— [Amino (hydroxyimino) methyl] phenoxy} methyl) —1-piveridyl] propoxy} — 2-fluoro-N, -hydroxybenzamidine 300 mg N— A 3 mL solution of methyl-2-pyrrolidone was prepared at room temperature and stirred for 1 hour. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue, diethyl ether was added, and the solid was collected by filtration to give a white solid 4-1- (3— {4 [(4 {amino [(2S, 3S)-2- (tert-butoxycarbo- L) amino-3-methylpentanoyloxymino] methyl} phenoxy) methyl] 1-piveridyl-propoxy) 2-fluorobenzamide = 0— [(2S, 3S)-2- (tert-butoxycarbo -(L) Amino-3-methylpentanoyl] oxime 363 mg was obtained.

 1H-NMR (CDC1) δ fg: 0.95 (6H, t, J = 7.3Hz), 1.02 (6H, d, J = 6.8Hz), 1.15-1.30 (2H, m), 1.3

 Three

 0-1.50 (20H, m), 1.50-1.65 (2H, m), 1.75-2.05 (9H, m), 2.45-2.55 (2H, m), 2.90-3.00 (2H, m), 3.82 (2H, d , J = 5.9Hz), 4.03 (2H, t, J = 6.3Hz), 4.25-4.40 (2H, m), 5.05-5.30 (4H, m), 5.46 (2 H, s), 6.65 (lH, dd , J = 13.8,2.4Hz), 6.71 (lH, dd, J = 8.8,2.4Hz), 6.89 (2H, d, J = 8.8Hz), 7.63 (2 H, d, J = 8.8Hz), 7.77 ( lH, t, J = 8.8Hz).

[0129] Example 26

1-[^ (, ^, e {^ [^ ^^ /, ^ be ^ —

£-^. ^ 4:--Z- (S £ 'ss)] ^} —)] —} —ε) —

2) ^ 9 "'(zH0" 6 = rP'H2) T6 "9' ( ^z HS-2'6" 8 = rPP'HT) 0 -9 '( ^z HS-2' -ST = rPP'HT) S9 "9 '( ^s ' H s 'S'(ui'H ^) SS'S— S0'S '(ra'HS) 0f to SS ( ^z HS'9 = f' HS) WT ( ^z H6'S = f'P'HS ) I8'S '(ωΉ2) 30 · ε-06 · 2'(ω'Η2) 3 · 2-8 ^ · 2 '(ω'Η6) 30 · 2-0 · ΐ'(ω'Η2) 0 · ΐ- 03 · ΐ '(ω'Η02) 03 · ΐ-3 ε · ΐ'(ω'Η θε · ΐ— OS 'ΐ' ( ^ζ Η9 · 9 = ί "'Ρ'Η9) Ζ0 · ΐ' ( ^Ζ Η3 · Ζ = Γ H9) S6'0: 3} 9 ODaD) H NH _T

.

Lf ^ ^ ίΛ ^ ^ · ^ Λ ^ -Ζ-iJ. ^ 4:-^ V) -Z- (SS 'SS)] — 0 =, ^ XBe: ^ ΰ / One

[

 Ｅ {i ^ y ^^ y ^ ^^ — ε—, (/ — ^ / ^^-

Z0.CT0 / S00Zdf / X3d 6a 66 Ϊ0 / 900Ζ OAV Under reduced pressure, the solvent was distilled off, and the resulting residue was cooled with ice, and then chloroform, saturated aqueous sodium hydrogen carbonate solution and 2-propanol were added. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Jetyl ether was added to the obtained residue, and the solid product was collected by filtration and washed with jetyl ether to give a light yellow solid of 4- (3— {4 ([(4 {amino [(2S, 3S ) -2 Amino 1-Methylpentanoyloxymino] methyl} phenoxy) methyl] 1-piberidyl} propoxy) -2 Fluorobenzamide = 0— [(2S, 3S) 2 Amamino 3-methylpenta 69 mg of [Neyl] oxime was obtained.

 'H-NMRCDMSO-d) δ value: 0.80- 0.95 (12H, m), 1.08-1.20 (2H, m), 1.25-1.40 (2H, m), 1.45

 6

 -2.00 (15H, m), 2.37-2.47 (2H, m), 2.85-2.95 (2H, m), 3.20-3.30 (2H, m), 3.87 (2H, d, J = 5.9

Hz), 4.07 (2H, t, J = 6.2Hz), 6.67 (2H, s), 6.77 (2H, s), 6.83 (lH, dd, J = 8.6, 2.3Hz), 6.92 (lH, dd,

J = 12.6, 2.3Hz), 6.98 (2H, d, J = 8.8Hz), 7.42 (lH, t, J = 8.6Hz), 7.65 (2H, d, J = 8.8Hz).

 [0131] Example 28

 In the same manner as in Example 27, 4-({1-[3- (4— {amino [(2S, 3S) -2-amino-3-methylpentanoyloximino] methyl} phenoxy) Propyl] —4-piberidyl} methoxy) —2 fluorobenzamide = 0 — [(2S, 3S) —2 amino-3-methylpentanoyl] oxime 112 mg was obtained.

 1H-NMR (DMSO-d) δ value: 0.80-0.90 (12H, m), 1.09- 1.20 (2H, m), 1.20-1.40 (2H, m), 1.45

 6

 -1.95 (15H, m), 2.38-2.46 (2H, m), 2.80-2.95 (2H, m), 3.20-3.30 (2H, m), 3.89 (2H, d, J = 5.9

Hz), 4.05 (2H, t, J = 6.2Hz), 6.67 (2H, s), 6.77 (2H, s), 6.80-6.95 (2H, m), 6.98 (2H, d, J = 8.8Hz)

, 7.35-7.45 (lH, m), 7.66 (2H, d, J = 8.8Hz).

[0132] Example 29

 4-Trophenol 0.20 g of N, N-dimethylformamide in 3 mL solution was charged with 0.22 mL of triethylamine and 0.21 mL of benzyl = formate at room temperature, stirred at the same temperature for 1 hour, and then mixed with 4- {3 — [4— ({4 [Imino) methyl] phenoxy} methyl) 1 piberidyl-l] propoxy} 2 Fluorobenzamidine (0.25 g) was added and stirred for 2 hours 30 minutes. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 20: 1]. Ethyl acetate was added to the obtained residue, and the solid was collected by filtration to give a white solid. 4 {3— [4— ({4— [Amino (benzyloxycarbo-luimino) methyl] phenoxy} methyl)-1-piveridyl] propoxy}-N 'monobenzyloxycarbonyl 2 Fluoroben 0.18 g of zamidine was obtained.

'H-NMRCDMSO-d) δ value: 1.20— 1.40 (2H, m), 1.65— 1.80 (3H, m), 1.80— 1.95 (4H, m), 2.35—

 6

 2.45 (2H, m), 2.85-2.95 (2H, m), 3.90 (2H, d, J = 5.9Hz), 4.08 (2H, t, J = 6.2Hz), 5.06 (2H, s), 5.0 9 ( 2H, s), 6.84 (lH, dd, J = 8.7, 2.4Hz), 6.92 (lH, dd, J = 13.4, 2.4Hz), 7.00 (2H, d, J = 8.9Hz), 7.2 5-7.45 ( 10H, m), 7.68 (lH, t, J = 8.7Hz), 7.98 (2H, d, J = 8.9Hz).

Example 30

In the same manner as in Example 29, white solid 4— {[1— (3— {4 [amino (benzyloxycarpo- limino) methyl] phenoxy} propyl) 4-piveridyl] methoxy} N, 0.15 g of ndioxycarbonyl 2 fluorobenzamidine was obtained.

 1H-NMR (DMSO-d) δ value: 1.20— 1.40 (2H, m), 1.65— 1.80 (3H, m), 1.80— 1.95 (4H, m), 2.35—

 6

 2.45 (2H, m), 2.85-2.95 (2H, m), 3.90 (2H, d, J = 5.6Hz), 4.07 (2H, t, J = 6.2Hz), 5.06 (2H, s), 5.0

9 (2H, s), 6.84 (lH, dd, J = 8.8,2.3Hz), 6.92 (lH, dd, J = 13.4,2.3Hz), 7.00 (2H, d, J = 9.0Hz), 7.2

5-7.45 (10H, m), 7.68 (lH, t, J = 8.8Hz), 7.98 (2H, d, J = 9.0Hz).

 [0134] Example 31

 4 Add 0.22 mL of triethylamine and 0.14 mL of ethyl-chloroformate at room temperature to a solution of 0.20 g of N, N-dimethylformamide in 0.20 g of nitrophenol, and stir at that temperature for 1 hour. — [4— ({4 [Imino) methyl] phenoxy} methyl) 1 piveryl] propoxy} 2-Fluorobenzamidine (0.25 g) was stirred at room temperature and stirred at that temperature for 3 hours. . Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the solid matter was collected by filtration. 4 {3— [4 1 ({4 [Amino (ethoxycarbo-limino) methyl] phenoxy} methyl) —1— [Piberidyl] propoxy} —N, -ethoxycarbole 2 Fluorobenzamidine 0.12 g was obtained.

 ^ -NMRCDMSO-d) δ fg: 1.19 (3H, t, J = 7.1Hz), 1.21 (3H, t, J = 7.2Hz), 1.25-1.40 (2H, m),

 6

 1.70-1.80 (3H, m), 1.80-1.95 (4H, m), 2.35-2.45 (2H, m), 2.85-2.95 (2H, m), 3.90 (2H, d, J = 5.9Hz), 3.95 -4.15 (6H, m), 6.85 (lH, dd, J = 8.8,2.4Hz), 6.92 (lH, dd, J = 13.3,2.4Hz), 7.00 (2H, d, J = 9.0Hz), 7.68 ( lH, t, J = 8.8Hz), 7.97 (2H, d, J = 9.0Hz).

[0135] Example 32

 In the same manner as in Example 31, a light gray solid 4 — {[1— (3— {4 [amino (ethoxycarbodilymino) methyl] phenoxy} propyl) 4-piveridyl] methoxy} N, monoethoxycarbonyl 2 0.19 g of fluorobenzamidine was obtained.

 ^ -NMRCDMSO-d) δ value: 1.19 (3H, t, J = 7.1Hz), 1.21 (3H, t, J = 7.1Hz), 1.25-1.35 (2H, m),

 6

 1.65-1.80 (3H, m), 1.85-1.95 (4H, m), 2.40-2.45 (2H, m), 2.85-2.95 (2H, m), 3.91 (2H, d, J = 5.9Hz), 3.99 -4.10 (6H, m), 6.85 (lH, dd, J = 8.8,2.4Hz), 6.92 (lH, dd, J = 13.3,2.4Hz), 7.01 (2H, d, J = 9.0Hz), 7.68 ( lH, t, J = 8.8Hz), 7.97 (2H, d, J = 9.0Hz).

Example 33

4-Nitrophenol 0.20 g of N, N-dimethylformamide in 3 mL of solution at room temperature with 0.22 mL of triethylamine and 2,2,2-trichlorodiethyl = 0.20 mL of chloroformate at the same temperature for 1 hour After stirring, 4— {3— [4— ({4— [Amino (imino) methyl] phenoxy} methyl) 1-pivelidyl] propoxy} 2 0.25 g fluorobenzamidine at room temperature Stir at temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 20: 1], diisopropyl ether was added to the obtained residue, and the solid was collected by filtration. solid

 No. 1

• (zH0 "6 = rP'H2) 20" 8 '( ^z H8 "8 = rVHT) T Z-Z'(zH0" 6 = rP'H2) ^ 0 "Z '(zW2'S-ST = f'PP' HT) S6 "9'W2'8" 8 = rPP'HT) Z8 "9 '( ^s ' H2) 8

— _3ε · 2 '(τιι'Η) 00-38 · ΐ'(ω'Ηε) 08 · ΐ- 39 · ΐ '(ω'Η Ο · ΐ-: Military 9 (P-OS a) H NH _T

.靜

Γ0 ^^ Ο ^^ / Δ -Z- {^ — ^ C ^^ ^ C ^-Ζ 'Ζ' Ζ)- ₍ Κ- {

 First

• (zH6 "8 = rP'H2) 20" 8 '( ^z H8 "8 = rVHT) T Z-Z'(zH6" 8 = rP'H2) ^ 0 "Z '(zW2'S-ST = f'PP' HT) S6 "9'W2'8" 8 = rPP'HT) Z8 "9 '( ^s ' H2) 8

— ZS '(ω'Η) 00 — Ζ8 · ΐ'(ω'Ηε) Ζ8 · ΐ— Ζ9 · ΐ '(ω'Η Ο · ΐ— SS'I: Military 9 (P-OS a) H NH _T

. ¾¾§0 0Be; ^^ XBe: ^ cl / -Z- (/ — ^ / ^ [^ (^ / ^ / ^ é crn ^ fH— S 'Z ^] — ε} —

ZO.CTO / SOOZdf / X3d 66 Ϊ0 / 900Ζ OAV 1-Pentanol Add 0.12 mL of N, N dimethylformamide in 3 mL solution at room temperature and add 0.22 mL of triethylamine and 0.29 g of 4-tropeol black formate. After stirring at the same temperature for 2 hours, 4- {3— [4— ({4 -— [Amino (imino) methyl] phenoxy} methyl) 1 benzylidyl] propoxy} 2-Fluorobenzamidine (0.25 g) at room temperature and stirred at the same temperature for 1 hour 30 minutes did. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: black mouth form: methanol = 20: 1], ethyl acetate was added to the obtained residue, and the solid was collected by filtration to give a white solid. 4 {3— [4 ({4- (Amino (pentyloxycarbo-luimino) methyl] phenoxy} methyl)-1-piveridinyl] propoxy} -N 'pentyloxycarbonyl 2-rufluorobenz 0.03 g of amidine was obtained.

 'H-NMRCDMSO-d) δ value: 0.80- 0.95 (6H, m), 1.20-1.40 (10H, m), 1.50-1.65 (4H, m), 1.65

 6

 -1.80 (3H, m), 1.82-1.98 (4H, m), 2.38-2.44 (2H, m), 2.85-2.95 (2H, m), 3.90 (2H, d, J = 5.9H z), 3.97 ( 2H, t, J = 6.5Hz), 4.00 (2H, t, J = 6.3Hz), 4.08 (2H, t, J = 6.3Hz), 6.85 (lH, dd, J = 8.8,2.4 Hz), 6.92 ( lH, dd, J = 13.4,2.4Hz), 7.01 (2H, d, J = 9.0Hz), 7.67 (lH, t, J = 8.8Hz), 7.96 (2H, d, J = 9.0Hz).

Example 36

 In the same manner as in Example 35, white solid 4— {[1— (3— {4 [Amino (pentyloxycarpo-rimino) methyl] phenoxy} propyl) 4-piveridyl] methoxy} N, monopentyl Xycarboyl 2 Fluorobenzamidine 0.08g was obtained.

'H-NMRCDMSO-d) δ: 0.80- 0.95 (6H, m), 1.20-1.40 (10H, m), 1.50-1.65 (4H, m), 1.67 One of them. 09¾ 呦 Learning Ρ

, One

First

 z []

¾

ΐ¾ 晷 ^

缀 ^ 氺 ¾ii | ¾ ^s 0'S / — 4-Bem 呦 ^ 9ί ^ ¾ϊ

(zH8 "8 = rP'H2) e"'(zHS"8 = r HT) 09"-W'(ra'He) 8r -0r '(ra'HT) 00 "-96"9' ( ^z H

6'S = f'VHS) 6r ( ^ζ Ηε · 9 = ί "'Ρ'Η 86 · ε'(ω'Η 09 · ε— 0S'S '(ra'HS) WS— ΐ · ε'(ω'Η Μ) · Ε

- '(ra'HS) SS - OS '(ω'Ηε) ΐ - Ο6 · ΐ '(ω'Η Ο8 · ΐ- 0Ζ · ΐ: army 9 (P-OS a) H NH T

 . ¾¾S9S'0 ^ 邈 ^ Be XBe: ^ / ^^ ΰ, 3—

{Ν-

 -^) -ε)-1]} → θ) ^, ¾ difficulty 呦 ^ 圑, "¾ ^ i one,

. Times ε

¾ Bezier A) Marquis ¾

 No. 1 [ο ιο]

'(ΖΗ8 ・ 8

= f'P'H2) Z6 "Z '(zH8" 8 = f'VHT) Z9 "Z'(zH8" 8 = rP'H2) T0 "Z '(zHr2 ^" ST = rPP'HT) 26 "9 '( ^z H r2'8 "8 = rPP'HT) e8"9' ( ^z HS "9 = rVH2) 80 ^ '( ^z HS" 9 = f'VH2) 00 ^' ( ^z H9 "9 = rVH2) 96 "S '( ^z

 H9'S = f'P'HS) 06'S '(ra'HS) S6 — S8' C "'HS) — 8S' (ω'Η) 86 · ΐ— Ζ8 · ΐ '(ω'Ηε) 08 · ΐ—

Z0.CT0 / S00Zdf / X3d 99 66 Ϊ0 / 900Ζ OAV Thereafter, 70 mg of crospopidone [trade name: Kollidon CL: manufactured by BASF], 180 mg of crystalline cellulose [trade name: Avicel PH302: manufactured by Asahi Kasei Co., Ltd.] and 20 mg of magnesium stearate were mixed and mixed. No. 3 gelatin capsules were filled with 150 mg of the mixture per capsule to obtain capsules.

[0143] Formulation Example 3

 Dissolve 0.2 g of the compound obtained in Example 3 in 80 mL of water for injection (JP), add O.lmol / L potassium dihydrogen phosphate aqueous solution and 0.1 mol / L disodium hydrogen phosphate aqueous solution, pH 7. Adjusted to 5. To the solution was added sodium chloride sodium salt as an isotonic agent, and water for injection was added to make exactly 10 mL. The obtained solution was filtered through a membrane filter (pore size 0.2 μm) in an aseptic environment to obtain an eye drop solution. The obtained solution was filled in a polyethylene eye drop bottle (capacity 5 mL) in an aseptic environment and closed to obtain an eye drop.

[0144] Formulation Example 4

 500 mg of the compound obtained in Example 4, 350 mg of lactose, 250 mg of corn starch, and 400 mg of crystalline cellulose [Product name: Cerath PH101: Asahi Kasei Chemicals] were mixed and kneaded with 0.6 mL of 5% hydroxypropylcellulose aqueous solution and water. Combined. The obtained mixture was dried at 60 ° C. and then mixed with 100 mg of crospovidone [trade name: Kollidon CL: BASF], 10 mg of light anhydrous silicic acid lOO mg and 20 mg of magnesium stearate. 175 mg of the mixture was tableted as a round tablet with a diameter of 8 mm to obtain a tablet.

[0145] Formulation Example 5

 The compound obtained in Example 4 (500 mg), lactose (200 mg) and corn starch (530 mg) were mixed, and kneaded with 0.6% 5% hydroxypropylcellulose aqueous solution and water. After the resulting mixture was dried at 60 ° C, 70 mg of crospovidone [trade name: Kollidon CL: BASF], 180 mg of crystalline cellulose [trade name: Cerath PH302: Asahi Kasei Chemicals] and 20 mg of magnesium stearate were collected. Mixed. 150 mg of the mixture was filled into a No. 3 gelatin capsule to obtain a capsule.

[0146] Formulation Example 6

0.89 g of the compound obtained in Example 10 and 31.5 g of sodium chloride salt were dissolved in water for injection to make the total volume 3.5L. The solution is filtered through a 0.22 m membrane filter and the resulting drug solution 1 An ampule was filled with OmL and sealed, and then steam sterilized to obtain an injection.

Industrial applicability

 The compound of the present invention has a strong activity against fungi including azole drug-resistant fungi, and further has high safety and excellent physical properties in repeated dose toxicity tests, so it is useful as an excellent antifungal agent. .

Claims

The scope of the claims

[1] General formula

An arylamidine derivative represented by the formula: wherein R ¹ represents an amidino group which may be protected or substituted; R ² and R ³ are the same or different and each represents a hydrogen atom or a halogen atom. .

[2] The arylamidine derivative according to claim 1, wherein R ¹ is an amidino group which may be substituted with a hydroxyl group; one of R ² and R ³ is a hydrogen atom, and the other is a fluorine atom salt.

[3] The arylamidine derivative or a salt thereof according to claim 1 or 2, wherein R ¹ is an amidino group; one of R ² and R ^{3 is} a hydrogen atom, and the other is a fluorine atom.

[4] 4— {[1— (3— {4— [Amino (imino) methyl] phenoxy} propyl) 4 piveridyl] methoxy} 2-fluorobenzamidine or a salt thereof.

[5] 4— {[1— (3— {4— [Amino (hydroxyimino) methyl] phenoxy} propyl) 4 piperidyl-methoxy} — 2-fluoro-N, monohydroxybenzamidine or its salt .

[6] An antifungal agent comprising the arylamidine derivative or a salt thereof according to any one of claims 1 to 5.