JP4937506B2 - Novel arylamidine derivatives or salts thereof - Google Patents

Description

  The present invention relates to a novel arylamidine derivative having an antifungal activity or a salt thereof. Moreover, it is related with the antifungal agent which uses them as an active ingredient.

  Severe deep mycosis, such as invasive candidiasis, is often a fatal disease. Originally, the main defense mechanism on the host organism side against fungi such as Candida is thought to be due to non-specific immunity by neutrophils, and the risk of infecting fungi when this defense mechanism is functioning normally There are few. However, in recent years, the number of patients with underlying diseases such as malignant tumors (especially acute leukemias and malignant lymphomas) that cause a decline in the immune function of the body and AIDS and other diseases, anticancer agents, immunosuppressants, etc. The risk of suffering from deep mycosis is increasing due to frequent use, frequent use of antibacterial antibiotics and steroid hormones, long-term central parenteral nutrition and use of intravenous catheters (Non-patent Document 1).

There are far fewer drugs for treatment of deep mycosis compared to antibacterial agents, and there are only six types: amphotericin B, flucytosine, miconazole, fluconazole, itraconazole and micafungin.
While amphotericin B has a very strong bactericidal action against fungi, it has a problem of strong side effects such as nephrotoxicity, and is limited in clinical use. In addition, flucytosine is rarely used alone because it has problems such as early resistance to continuous use. Micafungin is weakly active against Cryptococcus. Other drugs are collectively referred to as azole antifungal agents because of their structural characteristics, and their fungicidal action against fungi generally tends to be inferior to that of amphotericin B, but because of the balance between efficacy and safety Currently, it is most frequently used (Non-Patent Document 2).

In recent years, more than 30% of fluconazole-resistant C. albicans has been detected in the oropharyngeal candidiasis lesions of AIDS patients who received repeated doses of fluconazole, and many of the resistant strains are itraconazole. It also exhibits cross-resistance to other azole drugs. Furthermore, isolation of resistant strains has also been reported for non-AIDS patients who developed chronic mucocutaneous candidiasis or deep candidiasis (Non-patent Document 3).
If resistance problems arise with any of these very few drugs, it will inevitably have a serious impact on the management of the increasing number of patients with deep mycosis (non-patented) Reference 4).

Clinical and Microbiology, Vol. 17, p. 265, 1990 Clinical and Microbiology, Vol. 21, 277, 1994 Clinical and Microbiology, 28, 57, 2001 Clinical and Microbiology, 28, 51, 2001

  Therefore, there is a strong demand for an antifungal agent that has a different mechanism of action from existing drugs, is effective against azole-resistant fungi, and has few side effects.

「式中、Ｒ¹およびＲ^1aは、同一または異なって保護または置換されていてもよいアミジノ基を；Ｒ²およびＲ^2aは、同一または異なって水素原子、ハロゲン原子ならびに置換されていてもよいアルキル、シクロアルキルおよびアルコキシ基から選ばれる一つ以上の基を；ＸおよびＺは、同一または異なって置換されていてもよいＣ_2-6アルキレン基を；Ｙは、二価の含窒素複素環式残基または二価のアニリン残基をそれぞれ示す。」で表される新規なアリールアミジン誘導体またはその塩が優れた抗真菌活性を有することを見出し、本発明を完成した。 Under such circumstances, as a result of intensive studies, the present inventors have found that the general formula [1] in which an amidino group is introduced into the aryl ring.

“In the formula, R ¹ and R ^1a are the same or different and may be protected or substituted; R ² and R ^2a are the same or different and may be a hydrogen atom, a halogen atom or a substituted group. One or more groups selected from alkyl, cycloalkyl and alkoxy groups; X and Z are the same or different optionally substituted C _2-6 alkylene groups; Y is a divalent nitrogen-containing heterocycle A novel arylamidine derivative represented by the formula or a divalent aniline residue is shown, respectively, or a salt thereof having excellent antifungal activity, and the present invention has been completed.

  The arylamidine derivative of the general formula [1] or a salt thereof is useful as an antifungal agent because it has high safety and exhibits excellent pharmacokinetics.

Hereinafter, the compound of 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, s-butyl, A linear or branched C _1-12 alkyl group such as isobutyl, t-butyl, pentyl, isopentyl, hexyl, heptyl and octyl; a cycloalkyl group is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl And a C _3-7 cycloalkyl group such as cycloheptyl; an amino lower alkyl group is a linear or branched amino C such as, for example, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl and aminobutyl _1-6 alkyl group; and alkoxy group, for example, methoxide , Ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s- butoxy, t-butoxy, pentyloxy, isopentyloxy, hexyloxy, C _1-12 straight-chain or branched, such as heptyloxy and octyloxy An alkoxy group; a lower alkoxy group is, for example, linear or branched such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy and isopentyloxy the lower alkylene group such as methylene, ethylene, propylene, butylene, straight-chain or branched C _1-6 alkylene group such as amylene and hexylene;; C _1-6 alkoxy group C _2- the ₆ alkylene group, for example, ethylene, propylene, butylene, amylene Oyo A linear or branched C _2-6 alkylene group such as xylene; The C _2-4 alkylene group, for example, ethylene, propylene and C ₂ straight chain or branched, such as butylene _-4 alkylene group; lower alkylamino group means, for example, linear or branched mono- or di- such as methylamino, ethylamino, isopropylamino, propylamino, dimethylamino, diethylamino and methylethylamino A C _1-6 alkylamino group; a lower alkyloxycarbonyl group is, for example, a linear or branched C _1-6 alkyloxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and propoxycarbonyl An acyl group is, for example, a formyl group, acetyl, isovaleryl and Straight or branched C _2-12 alkanoyl group such as propionyl, aralkyl group such as benzylcarbonyl, heterocycles such aroyl group and nicotinoyl, thenoyl, pyrrolidinocarbonyl and furoyl groups such as benzoyl and naphthoyl A group such as a formula carbonyl group; an aryl group is an aromatic cyclic group such as phenyl and naphthyl; and a heterocyclic group is, for example, pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, Tetrahydropyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl, quinolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinuclidinyl, quinazolyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, imi 5-membered group containing one or more nitrogen atoms as a hetero atom forming the ring such as dazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, purinyl and indazolyl group, and further containing one or more oxygen atom or sulfur atom Or 6-membered, fused or bridged nitrogen-containing heterocyclic groups, and furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinoxalyl , Dihydroquinoxalinyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzopyrrolyl, 2,3-dihydro-4H-1-thianaphthyl, 2,3-dihydrobenzofuranyl, benzo [b] dioxanyl , Imidazo [2,3-a] pyridyl, ben [B] piperazinyl, chromenyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, isoindolyl and isoquinolyl groups and the like, which may contain one or more oxygen atom or sulfur atom as a hetero atom forming the ring, nitrogen, A 5- or 6-membered, fused or bridged heterocyclic group containing at least one hetero atom selected from oxygen and sulfur atoms; lower alkenyl groups include, for example, vinyl, allyl, propenyl , isopropenyl, butenyl, straight-chain and branched-chain C _2-6 alkenyl group such as isobutenyl and pentenyl; lower alkyl sulfonyl carbamoyl group, e.g., methyl sulfonylcarbamoyl, ethyl sulfonylcarbamoyl, propylsulfonyl carba mode Le, isopropylsulfonyl carbamoylmethyl, butyl sulfonylcarbamoyl, isobutyl sulfonylcarbamoyl, s- butyl sulfonylcarbamoyl, a straight-chain or branched C _1-6 alkylsulfonylcarbamoyl group such as t- butyl sulfonylcarbamoyl and pentylsulfamoyl Honi carbamoyl; The lower alkylcarbamoyl group includes, for example, a mono- or di-C _1-6 alkylcarbamoyl group such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and methylethylcarbamoyl; , Halogen atoms, alkylsulfonyloxy groups such as methanesulfonyloxy and trifluoromethanesulfonyloxy, p-toluenesulfonyl Alkoxy and groups such as an arylsulfonyloxy group and an acyloxy group such as acetyloxy and trifluoroacetyloxy such benzenesulfonyloxy means respectively.

  The divalent nitrogen-containing heterocyclic residue is, for example, a divalent heterocycle containing a nitrogen atom such as an optionally substituted divalent nitrogen-containing heterocyclic bridge, heterocyclic spiro, or cyclic amine residue. It is a residue of a cyclic group and means a residue bonded through a ring or a nitrogen atom of an amino or amino lower alkyl group which may be protected or substituted on the side chain thereof.

The cyclic amine residue may be either a saturated cyclic amine residue or an unsaturated cyclic amine residue, and further contains one or more hetero atoms such as nitrogen atom, oxygen atom, sulfur atom and the like in the ring, and It may contain a carbonyl carbon, may have a side chain, and may be monocyclic or bicyclic or tricyclic. For example, aziridine, azetidine, pyrrolidine, pyrroline, pyrrole, dihydropyridine, piperidine, dihydroazepine, perhydroazepine, imidazole, imidazolidine, imidazoline, pyrazolidine, piperazine, 1,4-dihydropyrazine, 1,2-dihydropyrimidine, perhydro Saturated or unsaturated having only nitrogen atoms such as pyrazine, homopiperazine, 1,2,4-triazole, 1,2,3-triazole, 1,2-dihydro-1,2,4-triazine and perhydro-S-triazine Saturated monocyclic 3-7 membered cyclic amine residues; nitrogen such as oxazolidine, isoxazolidine, morpholine, 1,3-oxazolidine, thiazolidine, isothiazolidine, thiomorpholine, homothiomorpholine and 1,2,4-thiadiazoline Other than atoms Monocyclic 3-7 membered cyclic amine residues having heteroatoms; isoindoline, indoline, isoquinoline, 1H-indazole, purine, tetrahydroquinoline, 3,8-diazabicyclo [4.3.0] nonane, 2,8 -Diazabicyclo [4.3.0] nonane, 5-oxa-2,8-diazabicyclo [4.3.0] nonane, 2,5,8-triazabicyclo [4.3.0] nonane, 3,7 -Diazabicyclo [3.3.0] octane, 3-azabicyclo [3.3.0] octane, 3,7-diazabicyclo [3.3.0] octene, 3,8-diazabicyclo [4.3.0] nonene And the like, and the like.
Heterocyclic spiro residues are 5-azaspiro [2.4] heptane, 2,7-diazaspiro [4.4] nonane, 2,8-diazaspiro [4.5] decane and 3,9-diazaspiro [5. .5] Residues of 5-12 membered heterocyclic spiro compounds such as undecane.
Nitrogen-containing heterocyclic bridged ring residues include 2,5-diazabicyclo [2.2.1] heptane, 2,5-diazabicyclo [2.2.2] octane, 7-azabicyclo [2.2.1] heptane, etc. And the residue of a 5- to 12-membered nitrogen-containing heterocyclic bridged ring compound of the bridge formula.

「式中、Ｒ³、Ｒ^3aは、同一または異なって、水素原子、置換されていてもよい低級アルキル基、アミノ保護基を；Ｒ⁴は、水素原子、置換されていてもよいアルキル基およびシクロアルキル基を示す。」
などで表される単環式３−７員の環状アミン残基；一般式

「式中、Ｒ³およびＲ⁴は、前記と同様の意味を示す。」
などで表される飽和または不飽和の二環式３−７員の環状アミン残基；式、

などの架橋式の５−１２員の含窒素複素架橋環残基；式

などで表される５−１２員の複素環式スピロ残基；一般式、

「式中、Ｒ³、Ｒ^3aおよびＲ⁴は、前記と同様の意味を示す。」
などで表される環状アミン環の側鎖のアミノ基またはアルキルアミノ基の窒素原子を介して結合する窒素原子以外にヘテロ原子を有していてもよい飽和または不飽和の単環式３−７員の環状アミン残基などを意味する。 More specifically, a divalent nitrogen-containing heterocyclic residue is, for example, a general formula

"Wherein R ³ and R ^3a are the same or different and each represents a hydrogen atom, an optionally substituted lower alkyl group or an amino protecting group; R ⁴ represents a hydrogen atom, an optionally substituted alkyl group or Represents a cycloalkyl group. "
A monocyclic 3-7-membered cyclic amine residue represented by the formula:

“Wherein R ³ and R ⁴ have the same meaning as described above.”
A saturated or unsaturated bicyclic 3-7 membered cyclic amine residue represented by:

A bridged 5- to 12-membered nitrogen-containing hetero-bridged ring residue;

A 5- to 12-membered heterocyclic spiro residue represented by the formula:

“Wherein R ³ , R ^3a and R ⁴ have the same meaning as described above.”
A saturated or unsaturated monocyclic 3-7 which may have a hetero atom other than the nitrogen atom bonded through the nitrogen atom of the side chain amino group or alkylamino group of the cyclic amine ring represented by Means a cyclic amine residue of a member.

「式中、Ｒ³およびＲ⁴は、前記と同様の意味を示す。」
などで表される残基などを意味する。 The divalent aniline residue is an optionally substituted divalent aniline residue in which one is bonded through the nitrogen atom of the amino group and the other is bonded through the phenyl ring, and more specifically, For example, the general formula

“Wherein R ³ and R ⁴ have the same meaning as described above.”
It means a residue represented by.

  Examples of protecting groups for amino groups include all groups that can be used as ordinary amino protecting groups, such as (mono, di, tri) chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, phthaloyl, Acyl groups such as succinyl and amino acid residues that may be protected at the N-terminus (for example, glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, Glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine, tyrosine, tryptophan, proline and hydroxyproline, etc.); methoxycarbonyl, diphenylmethoxycarbonyl, ethoxyca Alkyloxycarbonyl such as bonyl, trichloroethoxycarbonyl, tribromoethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 2-ethylhexyloxycarbonyl, t-pentyloxycarbonyl, t-butoxycarbonyl and 1-adamantyloxycarbonyl Groups; aralkyloxycarbonyl such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl and 4- (phenylazo) benzyloxycarbonyl Groups: phenyloxycarbonyl, 4-fluorophenyloxycarbonyl, 4-methoxyphenyloxycarbonyl, 8-quinolyloxyca Aryloxycarbonyl groups such as rubonyl and 2-furfuryloxycarbonyl; aralkyl groups such as benzyl, diphenylmethyl and trityl; methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, Alkoxyalkyl groups such as 2- (trimethylsilyl) ethoxymethyl and 1-ethoxyethyl; arylthio groups such as 2-nitrophenylthio and 2,4-dinitrophenylthio; alkylsulfonyl or arylsulfonyl such as methanesulfonyl and p-toluenesulfonyl Groups; dialkylaminoalkylidene groups such as N, N-dimethylaminomethylene; benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene and 2-hydro Alkylidene groups such as cis-1-naphthylmethylene; nitrogen-containing heterocyclic alkylidene groups such as 3-hydroxy-4-pyridylmethylene; cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, Cycloalkylidene groups such as 2-acetylcyclohexylidene and 3,3-dimethyl-5-oxocyclohexylidene; diaryl or dialalkylphosphoryl groups such as diphenylphosphoryl and dibenzylphosphoryl; 5-methyl-2-oxo-2H- Examples thereof include oxygen-containing heterocyclic alkyl groups such as 1,3-dioxol-4-yl-methyl; substituted silyl groups such as trimethylsilyl group.

  Examples of the protecting group for the amidino group include all groups that can be used as a protecting group for an ordinary amidino group, such as an acyl group; an alkyloxycarbonyl group; an aralkyloxycarbonyl group; an aryloxycarbonyl group; an aralkyl group; An arylthio group; an arylsulfonyl group; a cycloalkyloxycarbonyl group such as cyclopentyloxycarbonyl and cyclohexyloxycarbonyl; an alkylthiocarbonyl group such as ethylthiocarbonyl; a dialkylaminoalkylidene group; an alkylidene group; Examples thereof include a nitrogen heterocyclic alkylidene group; a cycloalkylidene group; an oxygen-containing heterocyclic alkyl group; and a substituted silyl group.

  Examples of the protecting group for the hydroxyl group include all groups that can be used as a protecting group for a normal hydroxyl group, such as an acyl group; an alkyloxycarbonyl group; an aralkyloxycarbonyl group; an aryloxycarbonyl group; an alkyl group; Alkenyl groups such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl and trityl; oxygen-containing and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl and tetrahydrothiopyranyl Groups; alkoxyalkyl groups such as methoxymethyl, methoxyethoxymethyl and 2- (trimethylsilyl) ethoxymethyl; aralkoxyalkyl groups such as benzyloxymethyl; low groups such as methylthiomethyl and 2-methylthioethyl Alkylthioalkyl groups; alkylsulfonyl or arylsulfonyl groups such as methanesulfonyl and p-toluenesulfonyl groups; and trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, t-butyldimethylsilyl, t-butyl Examples thereof include substituted silyl groups such as diphenylsilyl group, diphenylmethylsilyl group, and t-butylmethoxyphenylsilyl group.

  Examples of the protecting group for the carboxyl group include all groups that can be used as a protecting group for a normal carboxyl group, such as an alkyl group; an aryl group; an aralkyl group; acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p Acylalkyl groups such as -bromobenzoylmethyl and p-methanesulfonylbenzoylmethyl; oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl and 2-tetrahydrofuranyl; halogenoalkyl groups such as 2,2,2-trichloroethyl; Alkylsilylalkyl groups such as 2- (trimethylsilyl) ethyl; acyloxyalkyl groups such as acetoxymethyl, propionyloxymethyl and pivaloyloxymethyl; nitrogen-containing heterocyclic alkyl groups such as phthalimidomethyl and succinimidomethyl; Kill group; an alkoxyalkyl group; aralkyl alkoxyalkyl group; a lower alkylthioalkyl group; an alkenyl group; arylthioalkyl groups such as phenylthiomethyl and substituted silyl group such as and trimethylsilyl group.

  Examples of the salt of the compound represented by the general formula [1] include generally known salts in basic groups such as amino groups or acidic groups such as hydroxyl or carboxyl groups. Salts in basic groups include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; organics such as tartaric acid, formic acid, acetic acid, citric acid, fumaric acid, maleic acid, trichloroacetic acid and trifluoroacetic acid And salts with carboxylic acids; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. Examples of the salt in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, With nitrogen-containing organic bases such as N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine and N, N′-dibenzylethylenediamine A salt etc. can be mentioned. Furthermore, among the above salts, preferred salts of the compound of the general formula [1] include pharmacologically acceptable salts.

Each substituent of R ¹ and R ^1a is further substituted with one or more groups selected from an optionally protected hydroxyl group, lower alkenyl group, lower alkoxy group, lower alkyloxycarbonyl group, aryl group, and the like. It may be.
R ² , R ^2a , R ³ , R ^3a , R ⁴ , X, Y and Z each further includes a nitro group, a halogen atom, an optionally protected amino, hydroxyl, carboxyl, carbamoyl, hydroxycarbamoyl and One or more selected from a lower alkylamino group, acyl group, aryl group, heterocyclic group, cycloalkyl group, lower alkenyl group, lower alkylsulfonylcarbamoyl group, lower alkylcarbamoyl group, lower alkoxy group and lower alkyloxycarbonyl group It may be substituted with a group.

The substituent in each of the above substituents may be further substituted with a group exemplified as the substituent of each substituent.
Moreover, the heterocyclic group in the substituent of each substituent may be further substituted with a keto group.

In the compound of the present invention, preferred compounds include the following compounds.
A compound in which R ¹ is an optionally protected amidino group is preferred, and a compound in which R ¹ is an amidino group is more preferred.
A compound in which R ^1a is an amidino group which may be protected is preferable, and a compound in which R a is an amidino group is more preferable.
A compound in which R ² is a hydrogen atom or a halogen atom is preferable, and a compound in which R ² is a hydrogen atom is more preferable.
A compound in which R ^2a is a hydrogen atom or a halogen atom is preferable, and a compound in which R ^2a is a hydrogen atom is more preferable.
A compound in which X is a C _2-6 alkylene group is preferable, and a compound in which X is a C _2-4 alkylene group is more preferable.
A compound in which Z is a C _2-6 alkylene group is preferable, and a compound in which Z is a C _2-4 alkylene group is more preferable.

「式中、Ｒ³およびＲ⁴は、それぞれ前記と同様の意味を示す。」で表される単環式５または６員環の環状アミン残基；一般式、

「式中、Ｒ³、Ｒ^3aおよびＲ⁴は、それぞれ前記と同様の意味を示す。」で表される環の側鎖のアルキルアミノ基の窒素原子を介して結合するピペラジンまたはモルホリン残基；式、

；または一般式、

「式中、Ｒ³およびＲ⁴は、それぞれ前記と同様の意味を示す。」で表されるアニリン残基である化合物が好ましく、よりさらに、式、

である化合物が好ましい。 Y represents a divalent nitrogen-containing heterocyclic bridged ring residue, a divalent aniline residue, a divalent heterocyclic spiro residue, a divalent monocyclic 3-7 membered cyclic amine residue and a cyclic amine ring Saturated monocyclic 3-7 membered cyclic amine which may have a hetero atom selected from an oxygen atom and a sulfur atom in addition to the nitrogen atom bonded through the nitrogen atom of the side chain amino group or alkylamino group A compound which is a residue is preferred, and further a general formula

A monocyclic 5- or 6-membered cyclic amine residue represented by the formula: wherein R ³ and R ⁴ each have the same meaning as described above;

A piperazine or morpholine residue bonded through the nitrogen atom of the alkylamino group in the side chain of the ring represented by “wherein R ³ , R ^3a and R ⁴ each have the same meaning as described above; formula,

Or a general formula,

A compound which is an aniline residue represented by “in the formula, R ³ and R ⁴ each have the same meaning as described above” is preferable.

Is preferred.

  Among the compounds of the present invention, representative compounds include, for example, compounds described in Tables 1 to 5 below.

  In the compound of the general formula [1] or a salt thereof, when there are isomers (for example, optical isomers, geometric isomers, tautomers, etc.), the present invention includes those isomers, In addition, solvates, hydrates and crystals of various shapes are included.

「式中、Ｒ¹、Ｒ^1a、Ｒ²、Ｒ^2a、Ｘ、ＹおよびＺは、それぞれ前記と同様の意味を；Ｌ¹およびＬ²は、脱離基を；Ｒ^aは、ヒドロキシル基の保護基を示す。」 Next, the manufacturing method of this invention compound is demonstrated.
The compound of the general formula [1] of the present invention can be produced by a combination of methods known per se, and can be produced, for example, by the production method shown below.
[Production Method 1]

“Wherein R ¹ , R ^1a , R ² , R ^2a , X, Y and Z have the same meanings as described above; L ¹ and L ² represent a leaving group; R ^a represents a hydroxyl group Indicates a protecting group. "

(1-a)
The compound of the general formula [4] can be produced by reacting the compound of the general formula [2] with the compound of the general formula [3] in the presence or absence of a base and then deprotecting the compound.
The solvent used in these reactions is not particularly limited as long as it does not adversely affect the reaction. For example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; N, Amides such as N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Aromatic hydrocarbons such as benzene, toluene and xylene Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and ethylene glycol monomethyl ether; nitriles such as acetonitrile; ketones such as acetone and 2-butanone; and dimethyl sulfone It is like sulfoxides such as SID, may be used which are mixed.
Bases optionally used in this reaction include, for example, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide and sodium t-butoxide; sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate Inorganic bases such as potassium carbonate, sodium hydride and potassium hydride; organic bases such as triethylamine, N, N-diisopropylethylamine and pyridine. The amount of the base used is the amount of the compound of the general formula [2] It may be at least equimolar, preferably 1 to 3 moles.
The amount of the compound of the general formula [3] used in this reaction may be equimolar or more with respect to the compound of the general formula [2], and preferably 1 to 5 times mol.
This reaction may be carried out at 0 to 200 ° C., preferably 0 to 150 ° C. for 1 minute to 2 days.
The removal of the protecting group for the hydroxyl group represented by ^Ra may be carried out by a known method.

(1-b)
The compound of general formula [6] can be manufactured by making the compound of general formula [4] react with the compound of general formula [5] according to manufacturing method 1-a.

(1-c)
The compound of the general formula [1] can be produced by amidinating the compound of the general formula [6].

Amidinization is described in International Publication No. WO96 / 16947; Journal of Medicinal Chemistry (J. Med. Chem.), 36, 1811-1819, 1993; Journal of Organic Chemistry (J. Org. Chem.), 64, 12-13, 1999 and J. Am. Chem. Soc., 107, 2743-2748, 1985 What is necessary is just to carry out by the method according to the method described in a year etc. or it.
More specifically, for example, a method (Pinner method) in which a benzonitrile derivative is converted into a benzamidine derivative via a benzimide ester derivative.
(1-c-1)
A benzimide ester derivative can be produced by, for example, reacting a benzonitrile derivative with an alcohol in the presence of an acid.
Alcohols used in this reaction may be used as a solvent, and examples thereof include alcohols such as methanol, ethanol, propanol and butanol. Further, for example, ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether; ketones such as acetone and 2-butanone; and halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, etc. A solvent that does not affect the solvent may be mixed and used.
Examples of the acid used in this reaction include hydrogen chloride, hydrobromic acid, perchloric acid, p-toluenesulfonic acid, methanesulfonic acid, and the like, and the amount used is 1 to 200 with respect to the benzonitrile derivative. Double moles, preferably 5 to 100 moles.
In this reaction, the amount of alcohol used may be 1 to 1000 times mol, preferably 10 to 100 times mol for the benzonitrile derivative.
This reaction is usually carried out at −30 to 150 ° C., preferably 10 to 50 ° C. for 30 minutes to 24 hours.
(1-c-2)
A benzamidine derivative can be produced by reacting a benzimide ester derivative with ammonia, an amine or a salt thereof in the presence or absence of a base.
The solvent used in this reaction may be any solvent that does not adversely influence the reaction. For example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; dioxane, tetrahydrofuran, anisole, Ethers such as diethylene glycol diethyl ether and ethylene glycol monomethyl ether; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide, which may be used in admixture. Also good.
Examples of the amine or a salt thereof include ammonium chloride, ammonium bromide, and ammonium acetate.
Examples of the amine include aliphatic amines such as methylamine, ethylamine, allylamine, and methoxyamine; hydroxylamine, and the amount used thereof is 1 to 100 times that of the benzimide ester derivative or a salt thereof. Mole, preferably 1 to 10 moles.
This reaction is usually carried out at 0 to 150 ° C., preferably 20 to 120 ° C. for 1 minute to 24 hours.

  Separately, when going through amidoxime or its analog, Tetrahedron, 51, 12047-12068, 1995; Synthetic Communication, 26, 4351-4367, 1996; Journal of Medicinal Chemistry (J. Med. Chem.), 43, 4063-4070, 2000; 44, 1217-1230, 2001; Chemical and The method described in Pharmaceutical Bulletin (Chem. Pharm. Bull.), Vol. 49, pp. 268-277, 2001, or the like may be used.

  The compound of the general formula [3] is, for example, diethyl 2,5-pyrrolidinedicarboxylate, diethyl 2,3-pyrrolidinedicarboxylate (Liebigs. Ann. Chem.), Pp. 1177-1119, 1987. Year], Diethyl 2,4-pyrrolidinedicarboxylate [Tetrahedron Letters, Vol. 22, No. 29, pp. 2727-2730, 1981], Diethyl 3,4-pyrrolidinedicarboxylate [Chemical And Pharm. Bull., Vol. 33, No. 7, pp. 2762-2766, 1985], Diethyl 2,3-piperidinedicarboxylate [Journal of Medicinal Chemistry] (J. Med. Chem.), 39, 2178-2187, 1996], diethyl 2,4-piperidinedicarboxylate (US Pat. No. 5,610,165), diethyl 2,5-piperidinedicarboxylate [Journal Of america・ Chemical Society (J. Am. Chem. Soc), Vol. 97, No. 1, pp. 159-167, 1975], Dimethyl 2,5-piperazinedicarboxylate [Journal of Medicinal Chemistry (J Med. Chem.), 28, 1228-1234, 1985], diethyl 3,5-piperidinedicarboxylate [Bioorganic & Medicinal Chemistry Letters, Volume 10, 12, 1381-1384, 2000], diethyl 3,4-pyridinedicarboxylate, diethyl 2,3-pyrazinedicarboxylate [SYNLETT, 734-736, 1996], 2,6 It can be synthesized by combining known methods using pyridine dimethanol as a raw material.

「式中、Ｒ¹、Ｒ²、Ｌ¹、Ｘ、ＹおよびＺは、それぞれ前記と同様の意味を示す。」 [Production Method 2]

“Wherein R ¹ , R ² , L ¹ , X, Y and Z each have the same meaning as described above.”

(2-a)
The compound of the general formula [6a] can be produced by reacting the compound of the general formula [2] with the compound of the general formula [7] in the presence or absence of a base.
This reaction may be performed according to production method 1-a. Moreover, the usage-amount of the compound of General formula [2] should just be 2 mol or more with respect to the compound of General formula [7], Preferably, it is 2-5 times mole.

(2-b)
The compound of the general formula [1a] can be produced by amidinating the compound of the general formula [6a]. The amidination may be performed according to production method 1-c.
Examples of the compound of the general formula [7] include 3- [5- (3-hydroxypropyl) -2-pyrrolidinyl] -1-propanol [Journal of Organic Chemistry, J. Org. Chem. 63, 6016-6020, 1998].

「式中、Ｒ¹、Ｒ^1a、Ｒ²、Ｒ^2a、Ｒ^a、Ｘ、Ｙ、Ｚ、Ｌ¹およびＬ²は、それぞれ前記と同様の意味を示す。」 [Production Method 3]

“In the formula, R ¹ , R ^1a , R ² , R ^2a , R ^a , X, Y, Z, L ¹ and L ² each have the same meaning as described above.”

(3-a)
The compound of general formula [4] can be produced by reacting the compound of general formula [9] with the compound of general formula [8] according to production method 1-a.

(3-b)
The compound of general formula [10] can be produced from the compound of general formula [4].
This reaction may be carried out, for example, by the method described in “New Experimental Chemistry Course 14, Synthesis and Reaction I of Organic Compounds I” edited by The Chemical Society of Japan (Maruzen Co., Ltd.), pages 361 to 369 or a method analogous thereto.

(3-c)
The compound of the general formula [6] can be produced by reacting the compound of the general formula [9a] with the compound of the general formula [10] according to the production method 1-a.

(3-d)
The compound of the general formula [1] can be produced by amidinating the compound of the general formula [6]. The amidination may be performed according to production method 1-c.

「式中、Ｒ¹、Ｒ²、Ｌ¹、Ｌ²、Ｘ、ＹおよびＺは、それぞれ前記と同様の意味を示す。」 [Production Method 4]

“Wherein R ¹ , R ² , L ¹ , L ² , X, Y and Z each have the same meaning as described above.”

(4-a)
The compound of the general formula [6a] can be produced by reacting the compound of the general formula [9] with the compound of the general formula [11] in the presence or absence of a base.
This reaction may be performed according to production method 1-a. Moreover, the usage-amount of the compound of General formula [9] should just be 2 mol or more with respect to the compound of General formula [11], Preferably, it is 2-5 times mole.

(4-b)
The compound of the general formula [1a] can be produced by amidinating the compound of the general formula [6a]. The amidination may be performed according to production method 1-c.

「式中、Ｒ¹、Ｒ^1a、Ｒ²、Ｒ^2a、Ｌ¹、Ｌ²、Ｘ、ＹおよびＺは、それぞれ前記と同様の意味を；Ｒ^bは、アミノ基の保護基を示す。」 [Production Method 5]

“Wherein R ¹ , R ^1a , R ² , R ^2a , L ¹ , L ² , X, Y and Z each have the same meaning as described above; R ^b represents an amino-protecting group.

(5-a)
The compound of general formula [14] can be deprotected according to production method 1-a by reacting the compound of general formula [12] with the compound of general formula [13] in the presence or absence of a base. Can be manufactured.

(5-b)
The compound of general formula [1] can be produced by reacting the compound of general formula [14] with the compound of general formula [15] according to production method 1-a.
Examples of the compound of the general formula [13] include 2-aminomethyl-4-benzyloxycarbonylmorpholine (International Publication No. WO01 / 00214), 8-benzyl-2,8-diazabicyclo [4.3.0] nonane 2003-48890).

「式中、Ｒ¹、Ｒ²、Ｘ、ＹおよびＬ¹は、それぞれ前記と同様の意味を示す。」 [Production Method 6]

“Wherein R ¹ , R ² , X, Y and L ¹ each have the same meaning as described above.”

(6-a)
The compound of the general formula [1b] can be produced by reacting the compound of the general formula [12] with the compound of the general formula [16] according to the production method 1-a.
The amount of the compound of the general formula [12] may be 2 mol or more, preferably 2 to 5 times the mol of the compound of the general formula [16].
The compound of the general formula [16] is, for example, (1S, 4S) -2,5-diazabicyclo [2.2.1] heptane, 1,2,3,4,5,6-hexahydropyrrolo [3,4-c ] Pyrrole (European Patent Publication No. 424850), 2-Oxa-5,8-diazabicyclo [4.3.0] nonane (Japanese Patent Laid-Open No. 2003-48890), 3,9-Diazaspiro [5.5] Undecane [Journal of Medicinal Chem. (J. Med. Chem.), 8, 62-73, 1965 and J. Heterocyclic Chemistry, Vol. 1, No. 3, 125- 127, 1964], 2,7-Diazaspiro [4.4] Nonane [J. Org. Chem., 46, 2757-2764, 1981 and Journal of Medicinal Chemistry (J. Med. Chem.), 33, 2270-2275, 1990].

「式中、Ｒ¹、Ｒ^1a、Ｒ²、Ｒ^2a、Ｒ^b、Ｌ¹、Ｌ²、Ｘ、ＹおよびＺは、それぞれ前記と同様の意味を示す。」 [Production Method 7]

“In the formula, R ¹ , R ^1a , R ² , R ^2a , R ^b , L ¹ , L ² , X, Y and Z each have the same meaning as described above.”

(7-a)
The compound of the general formula [18] can be produced by reacting the compound of the general formula [17] with the compound of the general formula [13] and then deprotecting according to the production method 1-a.

(7-b)
The compound of the general formula [6] can be produced by reacting the compound of the general formula [18] with the compound of the general formula [19] according to the production method 1-a.

(7-c)
The compound of the general formula [1] can be produced by amidinating the compound of the general formula [6] according to the production method 1-c.

「式中、Ｒ¹、Ｒ²、Ｌ¹、ＸおよびＹは、それぞれ前記と同様の意味を示す。」 [Production Method 8]

“Wherein R ¹ , R ² , L ¹ , X and Y each have the same meaning as described above.”

(8-a)
The compound of the general formula [6b] can be produced by reacting the compound of the general formula [17] with the compound of the general formula [16] according to the production method 1-a.
The amount of the compound of the general formula [17] may be 2 mol or more, preferably 2 to 5 times the mol of the compound of the general formula [16].

(8-b)
The compound of the general formula [1b] can be produced by amidinating the compound of the general formula [6b] according to production method 1-c.

Each of the compounds in the above production methods 1 to 8 can also use a salt thereof, 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 8 can be used for the next reaction without isolation.
In each compound in the above production methods 1 to 8, a compound having a functional group, for example, an amino group, a cyclic amine residue, a hydroxyl group, a formyl group, or a carboxyl group, is usually selected in advance. These protecting groups can also be deprotected by a method known per se after the reaction.

  The compounds of the general formulas [1], [1a] and [1b] thus obtained or their salts are, for example, condensed, added, oxidized, reduced, rearranged, substituted, halogenated, dehydrated or hydrolyzed. Can be derived into other compounds of the general formulas [1], [1a] and [1b] or salts thereof by subjecting them to a reaction known per se, or by appropriately combining these reactions.

Moreover, in the compound in the above production method, when there are isomers (for example, optical isomers, geometric isomers, tautomers, etc.), these isomers can also be used, and solvates. Hydrates and crystals of various shapes can also be used.
When the compound of the present invention is used as a pharmaceutical, formulation adjuvants such as excipients, carriers, and diluents usually used for formulation may be mixed as appropriate, and these may be mixed in accordance with conventional methods, such as tablets, capsules, Oral in the form of powder, syrup, granule, pill, suspension, emulsion, liquid, powder formulation, suppository, eye drop, nasal drop, ear drop, patch, ointment or injection Or it can be administered parenterally. The administration method, dosage and number of administration can be appropriately selected according to the age, weight and symptoms of the patient. Usually, for adults, oral or parenteral (for example, injection, infusion and rectal site) The administration may be carried out by administering 0.01 to 1000 mg / kg divided into 1 to several times a day.

Next, the pharmacological action of the representative compounds of the present invention will be described.
Test Example 1 Antifungal activity The antifungal activity was measured with reference to the standard method M27-A of the National Committee for Clinical Laboratory Standards (NCCLS), and the 50% growth inhibitory concentration (IC ₅₀ ) was measured by the micro liquid dilution method. The sensitivity measurement medium was prepared by adding 3- (N-morpholino) propanesulfonic acid (MOPS, final concentration 0.165M) to RPMI1640 as a buffer, and adjusting to pH 7.0 by adding 1 mol / L sodium hydroxide. Was used. Candida albicans TIMM1623 cultured overnight at 35 ° C. was suspended in the medium and then diluted with the measurement medium to 1 × 10 ⁴ cells / mL to obtain an inoculum. To a 96-well microplate (flat bottom: manufactured by Iwaki Glass Co., Ltd.), add 175 μL of medium, 5 μL of test drug (drug-diluting solvent for growth control wells), 20 μL of bacterial solution, and stir with a mixer. ) Was used to measure the initial turbidity at a wavelength of 630 nm. After culturing at 35 ° C., the terminal turbidity was measured 48 hours later. In the dilution series of drugs, the value obtained by subtracting the initial turbidity from the terminal turbidity is equal to or less than the 50% value (IC ₅₀ calculated value) of the value obtained by subtracting the initial turbidity from the terminal turbidity of growth control. The value of the lowest drug concentration at the test drug concentration showing the turbidity was IC ₅₀ . The results of IC ₅₀ values for each strain are shown in Table 5.

Test Example 2 Therapeutic effect of Candida albicans on systemic infection of mice Candida albicans TIMM1623 was cultured overnight at 35 ° C on Sabouraud's agar plate (Eiken Chemical Co., Ltd.) and suspended in sterile physiological saline. A bacterial solution for infection corresponding to 10 ⁵ cells / mL was prepared. 0.2 mL of this bacterial solution was inoculated into the tail vein of 5 ICR male mice (4 weeks old). In order to make mice susceptible to infection, cyclophosphamide was administered intraperitoneally at 200 mg / kg 4 days before infection and 100 mg / kg 1 day after infection. 0.2 mL of a test compound solution prepared to a concentration of 0.1 mg / mL with sterile physiological saline was administered subcutaneously in the back part once 2 hours after infection, once a day for 6 days from the next day, a total of 7 times. Mice in the control group were administered the same amount of sterile physiological saline, and the number of surviving animals until the 28th day of infection was observed.
As a result, all the control groups died by the 28th day of infection, whereas the compound administration groups of Example 1 and Example 2 survived 4/5 cases and 2/5 cases, respectively. In addition, all of the compound administration groups of Example 3, Example 4 (2) and Example 5 survived.

Next, the present invention will be described with reference examples and examples, but the present invention is not limited thereto.
The mixing ratios in the eluent are all volume ratios, and BW silica gel and BW-127ZH (manufactured by Fuji Silysia Chemical Co., Ltd.) were used as the carriers in column chromatography unless otherwise specified.
In each example, each abbreviation has the following meaning.
d ₆ -DMSO: heavy dimethyl sulfoxide
Me: methyl
Et: ethyl
Bn: benzyl
Cbz: benzyloxycarbonyl
Boc: t-Butoxycarbonyl

1,2,3,4,5,6-ヘキサヒドロピロロ[3,4-c]ピロール350mgをN,N-ジメチルホルムアミド13mLに溶解させ、この溶液に室温で4-(3-ブロモプロポキシ)ベンゾニトリル191mgおよび無水炭酸カリウム439mgを順次加え、同温で20時間攪拌した。減圧下で溶媒を留去し、残留物をシリカゲルカラムクロマトグラフィー［シリカゲル：ＹＭＣ社製ＯＤＳ−ＡＭ １２０−Ｓ５０、溶離液；エタノール：水＝１：１］で精製し、無色油状の4-{3-[3,4,5,6-テトラヒドロピロロ[3,4-c]ピロール-2(1H)-イル]プロポキシ}ベンゾニトリル130mgを得た。
¹H-NMR(CDCl₃)δ値：1.90-2.10(2H,m), 2.30-2.80(1H,brs), 2.90(2H,t,J=7.0Hz), 3.30-3.80(8H,m), 4.11(2H,t,J=6.3Hz), 6.96(2H,d,J=8.8Hz), 7.58(2H,d,J=8.8Hz) Reference example 1

350 mg of 1,2,3,4,5,6-hexahydropyrrolo [3,4-c] pyrrole is dissolved in 13 mL of N, N-dimethylformamide and 4- (3-bromopropoxy) benzoyl is added to this solution at room temperature. Nitrile 191 mg and anhydrous potassium carbonate 439 mg were sequentially added, and the mixture was stirred at the same temperature for 20 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [silica gel: YMC ODS-AM 120-S50, eluent: ethanol: water = 1: 1] to give colorless oil 4- { 130 mg of 3- [3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] propoxy} benzonitrile was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.90-2.10 (2H, m), 2.30-2.80 (1H, brs), 2.90 (2H, t, J = 7.0Hz), 3.30-3.80 (8H, m), 4.11 (2H, t, J = 6.3Hz), 6.96 (2H, d, J = 8.8Hz), 7.58 (2H, d, J = 8.8Hz)

4-{3-[3,4,5,6-テトラヒドロピロロ[3,4-c]ピロール-2(1H)-イル]プロポキシ}ベンゾニトリル130mgをN,N-ジメチルホルムアミド3.0mLに溶解させ、この溶液に室温でトリエチルアミン67μLおよび4-(3-ブロモプロポキシ)ベンゾニトリル116mgを順次加え、同温で21時間攪拌した。減圧下で溶媒を留去後、得られた残留物に水、クロロホルムおよび無水炭酸カリウムを加え有機層を分取し、更に水層をクロロホルムで抽出した。合わせた有機層を無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をクロロホルム−エタノールの混合溶媒に溶解させ、次いで2.6mol/L塩化水素エタノール溶液を加え、減圧下で濃縮後、析出した固体を2-プロパノールに加えた後、濾取し、白色固形の4-{3-[5-[3-(4-シアノフェノキシ)プロピル]-3,4,5,6-テトラヒドロピロロ[3,4-c]ピロール-2(1H)-イル]プロポキシ}ベンゾニトリル塩酸塩150mgを得た。
¹H-NMR(d₆-DMSO)δ値： 2.00-2.30(4H,m), 3.30-3.60(4H,m), 3.90-4.15(4H,m), 4.19(4H,t,J=6.0Hz), 4.25-4.50(4H,m), 7.12(4H,d,J=8.4Hz), 7.80(4H,d,J=8.4Hz) Reference example 2

4- {3- [3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] propoxy} benzonitrile (130 mg) is dissolved in N, N-dimethylformamide (3.0 mL), To this solution, 67 μL of triethylamine and 116 mg of 4- (3-bromopropoxy) benzonitrile were sequentially added at room temperature, followed by stirring at the same temperature for 21 hours. After evaporating the solvent under reduced pressure, water, chloroform and anhydrous potassium carbonate were added to the obtained residue, the organic layer was separated, and the aqueous layer was further extracted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in a mixed solvent of chloroform-ethanol, and then a 2.6 mol / L hydrogen chloride ethanol solution was added. After concentration under reduced pressure, the precipitated solid was added to 2-propanol, and then collected by filtration. White solid 4- {3- [5- [3- (4-cyanophenoxy) propyl] -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] propoxy } 150 mg of benzonitrile hydrochloride was obtained.
¹ H-NMR (d ₆ -DMSO) δ value: 2.00-2.30 (4H, m), 3.30-3.60 (4H, m), 3.90-4.15 (4H, m), 4.19 (4H, t, J = 6.0Hz ), 4.25-4.50 (4H, m), 7.12 (4H, d, J = 8.4Hz), 7.80 (4H, d, J = 8.4Hz)

(1S,4S)-(+)-2,5-ジアザビシクロ[2.2.1]ヘプタン二臭化水素酸塩1000mgにクロロホルム、水酸化ナトリウム水溶液および塩化ナトリウムを順次加え、有機層を分取した。分取した有機層を無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、無色油状の(1S,4S)-(+)-2,5-ジアザビシクロ[2.2.1]ヘプタン110mgを得た。これをジメチルスルホキシド3.0mLに溶解させ、この溶液に室温でN,N-ジイソプロピルエチルアミン390μLおよび4-(3-クロロプロポキシ)ベンゾニトリル438mgを加え、85〜90℃で8時間攪拌した。反応混合物を室温迄冷却し、水、クロロホルムおよび無水炭酸カリウムを加え、有機層を分取し、更に水層をクロロホルムで2回抽出した。合わせた有機層を無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：エタノール＝100：15］で精製し、淡褐色油状の4-(3-{(1S,4S)-5-[3-(4-シアノフェノキシ)プロピル]-2,5-ジアザビシクロ[2.2.1]ヘプト-2-イル}プロポキシ)ベンゾニトリル170mgを得た。
¹H-NMR(CDCl₃) δ値： 1.72(2H,s), 1.80-2.00(4H,m), 2.50-2.90(8H,m), 3.32(2H,s), 4.09(4H,t,J=6.2Hz), 6.94(4H,d,J=8.9Hz), 7.57(4H,d,J=8.9Hz) Reference example 3

Chloroform, sodium hydroxide aqueous solution and sodium chloride were sequentially added to 1000 mg of (1S, 4S)-(+)-2,5-diazabicyclo [2.2.1] heptane dihydrobromide, and the organic layer was separated. The separated organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 110 mg of colorless oily (1S, 4S)-(+)-2,5-diazabicyclo [2.2.1] heptane. . This was dissolved in dimethyl sulfoxide (3.0 mL), and N, N-diisopropylethylamine (390 μL) and 4- (3-chloropropoxy) benzonitrile (438 mg) were added to the solution at room temperature, followed by stirring at 85 to 90 ° C. for 8 hours. The reaction mixture was cooled to room temperature, water, chloroform and anhydrous potassium carbonate were added, the organic layer was separated, and the aqueous layer was extracted twice with chloroform. The combined organic layers were 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: chloroform: ethanol = 100: 15] to give 4- (3-{(1S, 4S) -5- [3- (4- 170 mg of cyanophenoxy) propyl] -2,5-diazabicyclo [2.2.1] hept-2-yl} propoxy) benzonitrile were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.72 (2H, s), 1.80-2.00 (4H, m), 2.50-2.90 (8H, m), 3.32 (2H, s), 4.09 (4H, t, J = 6.2Hz), 6.94 (4H, d, J = 8.9Hz), 7.57 (4H, d, J = 8.9Hz)

2-(アミノメチル)-4-モルホリンカルボン酸ベンジル880mgをN,N-ジメチルホルムアミド7.0mLに溶解させ、この溶液に室温で無水炭酸カリウム990mgおよび4-(3-ブロモプロポキシ)ベンゾニトリル920mgを加え、同温で26時間攪拌した。反応混合物に水およびクロロホルムを加え、有機層を分取し、分取した有機層を無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝50：1］で精製し、淡黄色油状の2-({[3-(4-シアノフェノキシ)プロピル]アミノ}メチル)-4-モルホリンカルボン酸ベンジル630mgを得た。
¹H-NMR(CDCl₃)δ値： 1.86(1H,brs), 1.90-2.10(2H,m), 2.50-3.10(4H,m), 3.20-4.20(7H,m), 4.08(2H,t,J=6.2Hz), 5.14(2H,s), 6.93(2H,d,J=8.8Hz), 7.20-7.50(5H,m), 7.57(2H,d,J=8.8Hz) Reference example 4

880 mg of benzyl 2- (aminomethyl) -4-morpholinecarboxylate is dissolved in 7.0 mL of N, N-dimethylformamide, and 990 mg of anhydrous potassium carbonate and 920 mg of 4- (3-bromopropoxy) benzonitrile are added to this solution at room temperature. The mixture was stirred at the same temperature for 26 hours. Water and chloroform were added to the reaction mixture, the organic layer was separated, the separated organic layer was 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: chloroform: methanol = 50: 1] to give 2-({[3- (4-cyanophenoxy) propyl] amino} methyl)-pale yellow oil. 630 mg of benzyl 4-morpholinecarboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.86 (1H, brs), 1.90-2.10 (2H, m), 2.50-3.10 (4H, m), 3.20-4.20 (7H, m), 4.08 (2H, t , J = 6.2Hz), 5.14 (2H, s), 6.93 (2H, d, J = 8.8Hz), 7.20-7.50 (5H, m), 7.57 (2H, d, J = 8.8Hz)

2-({[3-(4-シアノフェノキシ)プロピル]アミノ}メチル)-4-モルホリンカルボン酸ベンジル620mgをクロロホルム6.0mLに溶解させ、この溶液に室温で二炭酸ジ-t-ブチル390mgおよびトリエチルアミン210μLを加え、同温で2時間攪拌した。反応混合物を減圧下で濃縮し、得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝1：1］で精製し、無色油状の2-({(t-ブトキシカルボニル)[3-(4-シアノフェノキシ)プロピル]アミノ}メチル)-4-モルホリンカルボン酸ベンジル360mgを得た。
¹H-NMR(CDCl₃) δ値： 1.41(9H,s), 1.90-2.10(2H,m), 2.50-4.20(13H,m), 5.14(2H,s), 6.92(2H,d,J=8.8Hz), 7.20-7.40(5H,m), 7.57(2H,d,J=8.8Hz) Reference Example 5

620 mg of benzyl 2-({[3- (4-cyanophenoxy) propyl] amino} methyl) -4-morpholinecarboxylate was dissolved in 6.0 mL of chloroform, and 390 mg of di-t-butyl dicarbonate and triethylamine were dissolved in this solution at room temperature. 210 μL was added and stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 1: 1] to give 2-({(t-butoxycarbonyl) [ 360 mg of benzyl 3- (4-cyanophenoxy) propyl] amino} methyl) -4-morpholinecarboxylate were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.41 (9H, s), 1.90-2.10 (2H, m), 2.50-4.20 (13H, m), 5.14 (2H, s), 6.92 (2H, d, J = 8.8Hz), 7.20-7.40 (5H, m), 7.57 (2H, d, J = 8.8Hz)

2-({(t-ブトキシカルボニル)[3-(4-シアノフェノキシ)プロピル]アミノ}メチル)-4-モルホリンカルボン酸ベンジル360mgをエタノール7.1mLに溶解させ、室温で5％パラジウム−炭素210mgを加え、水素雰囲気下、常温常圧で12.5時間攪拌した。触媒を濾去後減圧下で溶媒を留去し、淡褐色油状の3-(4-シアノフェノキシ)プロピル(2-モルホリニルメチル)カルバミド酸t-ブチル280mgを得た。
¹H-NMR(CDCl₃)δ値： 1.42(9H,s), 1.90-2.10(2H,m), 2.70-3.60(9H,m), 3.80-4.20(5H,m), 6.93(2H,d,J=8.8Hz), 7.58(2H,d,J=8.8Hz) Reference Example 6

Benzyl 2-({(t-butoxycarbonyl) [3- (4-cyanophenoxy) propyl] amino} methyl) -4-morpholinecarboxylate 360 mg was dissolved in ethanol 7.1 mL, and 5% palladium-carbon 210 mg was dissolved at room temperature. In addition, the mixture was stirred at room temperature and normal pressure for 12.5 hours in a hydrogen atmosphere. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure to obtain 280 mg of t-butyl 3- (4-cyanophenoxy) propyl (2-morpholinylmethyl) carbamate as a pale brown oil.
¹ H-NMR (CDCl ₃ ) δ value: 1.42 (9H, s), 1.90-2.10 (2H, m), 2.70-3.60 (9H, m), 3.80-4.20 (5H, m), 6.93 (2H, d , J = 8.8Hz), 7.58 (2H, d, J = 8.8Hz)

3-(4-シアノフェノキシ)プロピル(2-モルホリニルメチル)カルバミド酸t-ブチル280mgをN,N-ジメチルホルムアミド2.1mLに溶解させ、この溶液に室温で無水炭酸カリウム200mgおよび4-(3-ブロモプロポキシ)ベンゾニトリル190mgを加え、同温で17時間攪拌した。反応混合物を水と酢酸エチルの混合溶媒に加え有機層を分取し、更に水層を酢酸エチルで抽出した。合わせた有機層を水および飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝50：1］で精製し、無色油状の3-(4-シアノフェノキシ)プロピル({4-[3-(4-シアノフェノキシ)プロピル]-2-モルホリニル}メチル)カルバミド酸t-ブチル210mgを得た。
¹H-NMR(CDCl₃)δ値： 1.42(9H,s), 1.70-2.20(6H,m), 2.40-2.60(2H,m), 2.60-2.90(4H,m), 3.00-3.20(1H,m), 3.30-3.90(6H,m), 4.01(2H,t,J=5.9Hz), 4.06(2H,t,J=6.3Hz), 6.88-6.94(4H,m), 7.56-7.61(2H,m) Reference Example 7

280 mg of t-butyl 3- (4-cyanophenoxy) propyl (2-morpholinylmethyl) carbamate was dissolved in 2.1 mL of N, N-dimethylformamide, and 200 mg of anhydrous potassium carbonate and 4- (3 -Bromopropoxy) benzonitrile (190 mg) was added, and the mixture was stirred at the same temperature for 17 hours. The reaction mixture was added to a mixed solvent of water and ethyl acetate, the organic layer was separated, and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with water 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: chloroform: methanol = 50: 1] to give 3- (4-cyanophenoxy) propyl ({4- [3- (4-cyanophenoxy) as colorless oil. 210 mg of t-butyl)] propyl] -2-morpholinyl} methyl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.42 (9H, s), 1.70-2.20 (6H, m), 2.40-2.60 (2H, m), 2.60-2.90 (4H, m), 3.00-3.20 (1H , m), 3.30-3.90 (6H, m), 4.01 (2H, t, J = 5.9Hz), 4.06 (2H, t, J = 6.3Hz), 6.88-6.94 (4H, m), 7.56-7.61 ( 2H, m)

水素化アルミニウムリチウム440mgをテトラヒドロフラン15mLに懸濁させ、氷冷下、これに3-[5-(3-メトキシ-3-オキソプロピル)-2-ピロリジニル]プロピオン酸メチル700mgのテトラヒドロフラン(13mL)溶液を滴下し、同温にて40分間攪拌した。反応混合物に水1.2mLおよび水酸化ナトリウム水溶液1.2mLを滴下し、反応混合物を濾過後減圧下で濃縮し、淡黄色油状の3-[5-(3-ヒドロキシプロピル)-2-ピロリジニル]-1-プロパノール750mgを得た。これをクロロホルム5.8mLに溶解させ、この溶液に室温でベンジルクロロホルメート490μLおよびトリエチルアミン800μLを加え、同温にて２時間攪拌した。反応混合物に水および酢酸エチルを加え、有機層を分取した。分取した有機層を飽和炭酸水素ナトリウム水溶液および飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：エタノール＝10：1］で精製し、無色油状の2,5-ビス(3-ヒドロキシプロピル)-1-ピロリジンカルボン酸ベンジル380mgを得た。
¹H-NMR(CDCl₃)δ値： 1.30-2.10(12H,m), 2.30-2.60(2H,brs), 3.40-3.80(4H,m), 3.80-4.00(2H,m), 5.12(2H,s), 7.20-7.40(5H,m) Reference Example 8

440 mg of lithium aluminum hydride was suspended in 15 mL of tetrahydrofuran, and under ice cooling, a solution of 700 mg of methyl 3- [5- (3-methoxy-3-oxopropyl) -2-pyrrolidinyl] propionate in tetrahydrofuran (13 mL) was added thereto. The solution was added dropwise and stirred at the same temperature for 40 minutes. To the reaction mixture, 1.2 mL of water and 1.2 mL of an aqueous sodium hydroxide solution were added dropwise. The reaction mixture was filtered and concentrated under reduced pressure to give 3- [5- (3-hydroxypropyl) -2-pyrrolidinyl] -1 as a pale yellow oil. -750 mg of propanol was obtained. This was dissolved in 5.8 mL of chloroform, 490 μL of benzyl chloroformate and 800 μL of triethylamine were added to this solution at room temperature, and the mixture was stirred at the same temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The separated organic layer was washed 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. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: ethanol = 10: 1] to obtain 380 mg of colorless oily benzyl 2,5-bis (3-hydroxypropyl) -1-pyrrolidinecarboxylate. It was.
¹ H-NMR (CDCl ₃ ) δ value: 1.30-2.10 (12H, m), 2.30-2.60 (2H, brs), 3.40-3.80 (4H, m), 3.80-4.00 (2H, m), 5.12 (2H , s), 7.20-7.40 (5H, m)

2,5-ビス(3-ヒドロキシプロピル)-1-ピロリジンカルボン酸ベンジル320mgをテトラヒドロフラン10mLに溶解させ、この溶液に室温で四臭化炭素990mgおよびトリフェニルホスフィン790mgを加え、同温で6時間攪拌した。反応混合物を濾過後、減圧下で溶媒を留去し、これにジエチルエーテルを加え再度濾過した。減圧下で溶媒を留去し、残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝5：1］で精製し、無色油状の2,5-ビス(3-ブロモプロピル)-1-ピロリジンカルボン酸ベンジル340mgを得た。
¹H-NMR(CDCl₃)δ値： 1.30-2.10(12H,m), 3.20-3.60(4H,m), 3.80-4.00(2H,m), 5.12(2H,s), 7.20-7.40(5H,m) Reference Example 9

Dissolve 320 mg of benzyl 2,5-bis (3-hydroxypropyl) -1-pyrrolidinecarboxylate in 10 mL of tetrahydrofuran, add 990 mg of carbon tetrabromide and 790 mg of triphenylphosphine to this solution, and stir at the same temperature for 6 hours. did. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and diethyl ether was added thereto, followed by filtration again. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 5: 1] to give colorless oily 2,5-bis (3-bromopropyl) -1- 340 mg of benzyl pyrrolidinecarboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.30-2.10 (12H, m), 3.20-3.60 (4H, m), 3.80-4.00 (2H, m), 5.12 (2H, s), 7.20-7.40 (5H , m)

2,5-ビス(3-ブロモプロピル)-1-ピロリジンカルボン酸ベンジル200mgをアセトン4.5mLに溶解させ、この溶液に室温で4-シアノフェノール130mgおよび無水炭酸カリウム250mgを加え、8時間加熱還流した。反応混合物を室温迄冷却し、水およびクロロホルムを加え、有機層を分取した。分取した有機層を飽和炭酸水素ナトリウム水溶液および飽和塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝2：1］で精製し、無色油状の2,5-ビス[3-(4-シアノフェノキシ)プロピル]-1-ピロリジンカルボン酸ベンジル200mgを得た。
¹H-NMR(CDCl₃)δ値： 1.40-2.10(12H,m), 3.80-4.20(6H,m), 5.12(2H,s), 6.70-7.00(4H,m), 7.30-7.40(5H,m), 7.55(4H,d,J=8.5Hz) Reference Example 10

200 mg of benzyl 2,5-bis (3-bromopropyl) -1-pyrrolidinecarboxylate was dissolved in 4.5 mL of acetone. To this solution was added 130 mg of 4-cyanophenol and 250 mg of anhydrous potassium carbonate at room temperature, and the mixture was heated to reflux for 8 hours. . The reaction mixture was cooled to room temperature, water and chloroform were added, and the organic layer was separated. The separated organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride and then 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 = 2: 1], and colorless oily 2,5-bis [3- (4-cyanophenoxy) propyl] -1-pyrrolidine 200 mg of benzyl carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.40-2.10 (12H, m), 3.80-4.20 (6H, m), 5.12 (2H, s), 6.70-7.00 (4H, m), 7.30-7.40 (5H , m), 7.55 (4H, d, J = 8.5Hz)

6-ベンジルオクタヒドロ-1H-ピロロ[3,4-b]ピリジン730mgをテトラヒドロフラン10mLに溶解させ、この溶液に室温で4-(3-ブロモプロポキシ)ベンゾニトリル810mgおよび無水炭酸カリウム466mgを加え、４時間加熱還流した。反応混合物を室温迄冷却後濾過し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝20：1］で精製し、灰色油状の4-[3-(6-ベンジルオクタヒドロ-1H-ピロロ[3,4-b]ピリジン-1-イル)プロポキシ]ベンゾニトリル900mgを得た。
¹H-NMR(CDCl₃)δ値： 1.50-3.30(16H,m), 3.70-4.00(2H,m), 4.00-4.20(2H,m), 6.95(2H,d,J=8.9Hz), 7.20-7.50(5H,m), 7.58(2H,d,J=8.9Hz) Reference Example 11

730 mg of 6-benzyloctahydro-1H-pyrrolo [3,4-b] pyridine is dissolved in 10 mL of tetrahydrofuran, and 810 mg of 4- (3-bromopropoxy) benzonitrile and 466 mg of anhydrous potassium carbonate are added to this solution at room temperature. Heated to reflux for hours. The reaction mixture was cooled to room temperature and filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 20: 1] to give 4- [3- (6-benzyloctahydro-1H-pyrrolo [3,4-b] ] 900 mg of [pyridin-1-yl) propoxy] benzonitrile were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.50-3.30 (16H, m), 3.70-4.00 (2H, m), 4.00-4.20 (2H, m), 6.95 (2H, d, J = 8.9Hz), 7.20-7.50 (5H, m), 7.58 (2H, d, J = 8.9Hz)

4-[3-(6-ベンジルオクタヒドロ-1H-ピロロ[3,4-b]ピリジン-1-イル)プロポキシ]ベンゾニトリル900mgをメタノール10.0mLに溶解させ、この溶液に室温で10％パラジウム−炭素300mgを加え、水素雰囲気下、常圧、35℃で27時間攪拌した。触媒を濾去後、減圧下で溶媒を留去し、白色固形の4-[3-(オクタヒドロ-1H-ピロロ[3,4-b]ピリジン-1-イル)プロポキシ]ベンゾニトリル630mgを得た。
¹H-NMR(d₆-DMSO)δ値： 1.30-1.70(4H,m), 1.70-1.95(2H,m), 1.95-2.10(1H,m), 2.20-2.40(2H,m), 2.60-2.90(3H,m), 3.00-3.30(4H,m), 4.11(2H,t,J=6.5Hz), 7.13(2H,d,J=8.8Hz), 7.77(2H,d,J=8.8Hz), 8.80-9.30(1H,brd) Reference Example 12

900 mg of 4- [3- (6-benzyloctahydro-1H-pyrrolo [3,4-b] pyridin-1-yl) propoxy] benzonitrile was dissolved in 10.0 mL of methanol, and 10% palladium- 300 mg of carbon was added, and the mixture was stirred for 27 hours at 35 ° C. under normal pressure in a hydrogen atmosphere. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure to obtain 630 mg of white solid 4- [3- (octahydro-1H-pyrrolo [3,4-b] pyridin-1-yl) propoxy] benzonitrile. .
¹ H-NMR (d ₆ -DMSO) δ value: 1.30-1.70 (4H, m), 1.70-1.95 (2H, m), 1.95-2.10 (1H, m), 2.20-2.40 (2H, m), 2.60 -2.90 (3H, m), 3.00-3.30 (4H, m), 4.11 (2H, t, J = 6.5Hz), 7.13 (2H, d, J = 8.8Hz), 7.77 (2H, d, J = 8.8 Hz), 8.80-9.30 (1H, brd)

4-[3-(オクタヒドロ-1H-ピロロ[3,4-b]ピリジン-1-イル)プロポキシ]ベンゾニトリル610mgをN,N-ジメチルホルムアミド6.0mLに溶解させ、この溶液に室温で4-(3-ブロモプロポキシ)ベンゾニトリル770mgおよび無水炭酸カリウム450mgを加え、同温で22時間攪拌した。反応混合物を氷水と酢酸エチルの混合液に加え、有機層を分取した。分取した有機層を水で2回洗浄し、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝30：1］で精製し、淡褐色油状の4-(3-{6-[3-(4-シアノフェノキシ)プロピル]オクタヒドロ-1H-ピロロ[3,4-b]ピリジン-1-イル}プロポキシ)ベンゾニトリル540mgを得た。
¹H-NMR(CDCl₃)δ値： 1.50-1.75(4H,m), 1.85-2.05(4H,m), 2.10-2.20(1H,m), 2.25-3.10(11H,m), 3.90-4.20(4H,m), 6.92(2H,d,J=8.8Hz), 6.94(2H,d,J=8.8Hz), 7.54(2H,d,J=8.8Hz), 7.58(2H,d,J=8.8Hz) Reference Example 13

610 mg of 4- [3- (octahydro-1H-pyrrolo [3,4-b] pyridin-1-yl) propoxy] benzonitrile is dissolved in 6.0 mL of N, N-dimethylformamide, and 4- (3- ( 3-Bromopropoxy) benzonitrile (770 mg) and anhydrous potassium carbonate (450 mg) were added, and the mixture was stirred at the same temperature for 22 hours. The reaction mixture was added to a mixture of ice water and ethyl acetate, and the organic layer was separated. The separated organic layer was washed twice with water, 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: chloroform: methanol = 30: 1] to give 4- (3- {6- [3- (4-cyanophenoxy) propyl] octahydro as a light brown oil. -1H-pyrrolo [3,4-b] pyridin-1-yl} propoxy) benzonitrile (540 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.50-1.75 (4H, m), 1.85-2.05 (4H, m), 2.10-2.20 (1H, m), 2.25-3.10 (11H, m), 3.90-4.20 (4H, m), 6.92 (2H, d, J = 8.8Hz), 6.94 (2H, d, J = 8.8Hz), 7.54 (2H, d, J = 8.8Hz), 7.58 (2H, d, J = (8.8Hz)

5-ブロモ-1,3-ジヒドロ-2H-イソインドール-2-カルボン酸t-ブチル300mgをN,N-ジメチルアセトアミド3.0mLに溶解させ、アルゴン雰囲気下、この溶液に室温でアクリル酸エチル320μL、トリ-o-トリルホスフィン90mg、酢酸パラジウム（II）20mgおよびトリブチルアミン360μLを順次加え、7時間加熱還流した。反応混合物を室温迄冷却し、減圧下でアクリル酸エチルを留去し、残留物に水およびトルエンを加え、有機層を分取した。分取した有機層を1.0mol/L硫酸水素カリウム水溶液および飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝2：1］で精製後、ジイソプロピルエーテルを加えて濾取し、白色固形の5-[(E)-3-エトキシ-3-オキソ-1-プロペニル]-1,3-ジヒドロ-2H-イソインドール-2-カルボン酸t-ブチル220mgを得た。
¹H-NMR(CDCl₃)δ値： 1.30-1.38(3H,m), 1.52(9H,s), 4.20-4.32(2H,m), 4.66(2H,s), 4.69(2H,s), 6.42(0.5H,d,J=16.0Hz), 6.43(0.5H,d,J=16.0Hz) 7.10-7.50(3H,m), 7.68(1H,d,J=16.0Hz) Reference Example 14

Dissolve 300 mg of t-butyl 5-bromo-1,3-dihydro-2H-isoindole-2-carboxylate in 3.0 mL of N, N-dimethylacetamide and add 320 μL of ethyl acrylate at room temperature under an argon atmosphere. 90 mg of tri-o-tolylphosphine, 20 mg of palladium (II) acetate and 360 μL of tributylamine were sequentially added, and the mixture was heated to reflux for 7 hours. The reaction mixture was cooled to room temperature, ethyl acrylate was distilled off under reduced pressure, water and toluene were added to the residue, and the organic layer was separated. The separated organic layer was washed with 1.0 mol / L aqueous potassium hydrogen sulfate 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: hexane: ethyl acetate = 2: 1], added with diisopropyl ether and collected by filtration to give white solid 5-[(E) -3-ethoxy- 220 mg of t-butyl 3-oxo-1-propenyl] -1,3-dihydro-2H-isoindole-2-carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.30-1.38 (3H, m), 1.52 (9H, s), 4.20-4.32 (2H, m), 4.66 (2H, s), 4.69 (2H, s), 6.42 (0.5H, d, J = 16.0Hz), 6.43 (0.5H, d, J = 16.0Hz) 7.10-7.50 (3H, m), 7.68 (1H, d, J = 16.0Hz)

5-[(E)-3-エトキシ-3-オキソ-1-プロペニル]-1,3-ジヒドロ-2H-イソインドール-2-カルボン酸t-ブチル600mgを酢酸エチル3.0mLに溶解させ、室温で5％パラジウム−炭素60mgを加え、水素雰囲気下、常温常圧で6時間攪拌した。触媒を濾去後、減圧下で溶媒を留去し、白色固形の5-(3-エトキシ-3-オキソプロピル)-1,3-ジヒドロ-2H-イソインドール-2-カルボン酸t-ブチル480mgを得た。
¹H-NMR(CDCl₃)δ値： 1.24(3H,t,J=7.1Hz), 1.51(9H,s), 2.61(2H,t,J=7.8Hz), 2.95(2H,t,J=7.8Hz), 4.13(2H,q,J=7.1Hz), 4.61(2H,s), 4.65(2H,s), 7.00-7.30(3H,m) Reference Example 15

600 mg of t-butyl 5-[(E) -3-ethoxy-3-oxo-1-propenyl] -1,3-dihydro-2H-isoindole-2-carboxylate was dissolved in 3.0 mL of ethyl acetate, and 5% Palladium-carbon (60 mg) was added, and the mixture was stirred at room temperature and normal pressure for 6 hours under a hydrogen atmosphere. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure to obtain 480 mg of t-butyl 5- (3-ethoxy-3-oxopropyl) -1,3-dihydro-2H-isoindole-2-carboxylate as a white solid. Got.
¹ H-NMR (CDCl ₃ ) δ value: 1.24 (3H, t, J = 7.1Hz), 1.51 (9H, s), 2.61 (2H, t, J = 7.8Hz), 2.95 (2H, t, J = 7.8Hz), 4.13 (2H, q, J = 7.1Hz), 4.61 (2H, s), 4.65 (2H, s), 7.00-7.30 (3H, m)

水素化アルミニウムリチウム90mgをテトラヒドロフラン8.6mLに懸濁させ、氷冷下、この溶液に5-(3-エトキシ-3-オキソプロピル)-1,3-ジヒドロ-2H-イソインドール-2-カルボン酸t-ブチル550mgのテトラヒドロフラン(8.6mL)溶液を滴下した。同温で30分間攪拌し、さらに同温にて水および1.0mol/L水酸化ナトリウム水溶液を滴下した。反応液を濾過後減圧下で溶媒を留去し、得られた残留物にヘキサン−ジイソプロピルエーテルの混合溶媒を加え濾取し、淡褐色固形の5-(3-ヒドロキシプロピル)-1,3-ジヒドロ-2H-イソインドール-2-カルボン酸t-ブチル410mgを得た。
¹H-NMR(CDCl₃)δ値： 1.30(1H,t,J=5.3Hz), 1.52(9H,s), 1.80-2.00(2H,m), 2.72(2H,t,J=7.7Hz), 3.60-3.80(2H,m), 4.62(2H,s), 4.66(2H,s), 7.00-7.30(3H,m) Reference Example 16

90 mg of lithium aluminum hydride was suspended in 8.6 mL of tetrahydrofuran, and this solution was added to 5- (3-ethoxy-3-oxopropyl) -1,3-dihydro-2H-isoindole-2-carboxylic acid t under ice cooling. A solution of butyl 550 mg in tetrahydrofuran (8.6 mL) was added dropwise. The mixture was stirred at the same temperature for 30 minutes, and water and a 1.0 mol / L sodium hydroxide aqueous solution were added dropwise at the same temperature. The reaction solution was filtered and the solvent was distilled off under reduced pressure. A mixed solvent of hexane-diisopropyl ether was added to the resulting residue, and the mixture was collected by filtration to give a pale brown solid of 5- (3-hydroxypropyl) -1,3- 410 mg of t-butyl dihydro-2H-isoindole-2-carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.30 (1H, t, J = 5.3Hz), 1.52 (9H, s), 1.80-2.00 (2H, m), 2.72 (2H, t, J = 7.7Hz) , 3.60-3.80 (2H, m), 4.62 (2H, s), 4.66 (2H, s), 7.00-7.30 (3H, m)

5-(3-ヒドロキシプロピル)-1,3-ジヒドロ-2H-イソインドール-2-カルボン酸t-ブチル400mgをテトラヒドロフラン4.0mLに溶解させ、この溶液に室温で四臭化炭素720mgおよびトリフェニルホスフィン570mgを加え、同温で10時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液および酢酸エチルを加え、有機層を分取した。分取した有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；トルエン：酢酸エチル＝30：1］で精製し、白色固形の5-(3-ブロモプロピル)-1,3-ジヒドロ-2H-イソインドール-2-カルボン酸t-ブチル360mgを得た。
¹H-NMR(CDCl₃) δ値： 1.52(9H,s), 2.00-2.20(2H,m), 2.78(2H,t,J=7.3Hz), 3.39(2H,t,J=6.5Hz), 4.62(2H,s), 4.66(2H,s), 7.00-7.30(3H,m) Reference Example 17

400 mg of t-butyl 5- (3-hydroxypropyl) -1,3-dihydro-2H-isoindole-2-carboxylate was dissolved in 4.0 mL of tetrahydrofuran, and 720 mg of carbon tetrabromide and triphenylphosphine were added to this solution at room temperature. 570 mg was added and stirred at the same temperature for 10 hours. Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The separated organic layer was 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: toluene: ethyl acetate = 30: 1], and white solid 5- (3-bromopropyl) -1,3-dihydro-2H-isoindole- 360 mg of t-butyl 2-carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.52 (9H, s), 2.00-2.20 (2H, m), 2.78 (2H, t, J = 7.3Hz), 3.39 (2H, t, J = 6.5Hz) , 4.62 (2H, s), 4.66 (2H, s), 7.00-7.30 (3H, m)

5-(3-ブロモプロピル)-1,3-ジヒドロ-2H-イソインドール-2-カルボン酸t-ブチル340mgおよび4-シアノフェノール140mgを2-ブタノン5.0mLに溶解させ、この混合物に室温で無水炭酸カリウム280mgを加え、４時間加熱還流した。反応混合物を室温迄冷却し、トルエンおよび水を加え、有機層を分取した。分取した有機層を炭酸カリウム水溶液で３回洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にヘキサン−ジイソプロピルエーテルを加え濾取し、白色固形の5-[3-(4-シアノフェノキシ)プロピル]-1,3-ジヒドロ-2H-イソインドール-2-カルボン酸t-ブチル300mgを得た。
¹H-NMR(CDCl₃)δ値： 1.52(9H,s), 2.00-2.20(2H,m), 2.82(2H,t,J=7.6Hz), 3.99(2H,t,J=6.2Hz), 4.61(2H,s), 4.66(2H,s), 6.93(2H,d,J=8.8Hz), 7.00-7.30(3H,m), 7.58(2H,d,J=8.8Hz) Reference Example 18

340 mg of t-butyl 5- (3-bromopropyl) -1,3-dihydro-2H-isoindole-2-carboxylate and 140 mg of 4-cyanophenol are dissolved in 5.0 mL of 2-butanone, and the mixture is dehydrated at room temperature. 280 mg of potassium carbonate was added, and the mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, toluene and water were added, and the organic layer was separated. The separated organic layer was washed three times with an aqueous potassium carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane-diisopropyl ether was added to the obtained residue and collected by filtration, and white solid 5- [3- (4-cyanophenoxy) propyl] -1,3-dihydro-2H-isoindole-2-carboxylic acid t- 300 mg of butyl was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.52 (9H, s), 2.00-2.20 (2H, m), 2.82 (2H, t, J = 7.6Hz), 3.99 (2H, t, J = 6.2Hz) , 4.61 (2H, s), 4.66 (2H, s), 6.93 (2H, d, J = 8.8Hz), 7.00-7.30 (3H, m), 7.58 (2H, d, J = 8.8Hz)

5-[3-(4-シアノフェノキシ)プロピル]-1,3-ジヒドロ-2H-イソインドール-2-カルボン酸t-ブチル300mgをクロロホルム1.2mLに溶解させ、室温でトリフルオロ酢酸1.2mLを加え、同温で1.5時間攪拌した。減圧下で溶媒を留去後、得られた残留物に2.6mol/L塩化水素エタノール溶液2.0mLを加え、析出物を2-プロパノールに加えた後、濾取し、白色固形の4-[3-(2,3-ジヒドロ-1H-イソインドール-5-イル)プロポキシ]ベンゾニトリル塩酸塩220mgを得た。
¹H-NMR(d₆-DMSO)δ値： 1.90-2.10(2H,m), 2.77(2H,t,J=7.7Hz), 4.06(2H,t,J=6.3Hz), 4.40-4.50(4H,m), 7.10(2H,d,J=8.9Hz), 7.15-7.35(3H,m), 7.76(2H,d,J=8.9Hz), 9.70-10.00(1H,brs) Reference Example 19

Dissolve 300 mg of t-butyl 5- [3- (4-cyanophenoxy) propyl] -1,3-dihydro-2H-isoindole-2-carboxylate in 1.2 mL of chloroform and add 1.2 mL of trifluoroacetic acid at room temperature. The mixture was stirred at the same temperature for 1.5 hours. After distilling off the solvent under reduced pressure, 2.0 mL of a 2.6 mol / L hydrogen chloride ethanol solution was added to the obtained residue, the precipitate was added to 2-propanol, and then collected by filtration to give a white solid 4- [3 220 mg of-(2,3-dihydro-1H-isoindol-5-yl) propoxy] benzonitrile hydrochloride were obtained.
¹ H-NMR (d ₆ -DMSO) δ value: 1.90-2.10 (2H, m), 2.77 (2H, t, J = 7.7Hz), 4.06 (2H, t, J = 6.3Hz), 4.40-4.50 ( 4H, m), 7.10 (2H, d, J = 8.9Hz), 7.15-7.35 (3H, m), 7.76 (2H, d, J = 8.9Hz), 9.70-10.00 (1H, brs)

4-[3-(2,3-ジヒドロ-1H-イソインドール-5-イル)プロポキシ]ベンゾニトリル塩酸塩220mgをN,N-ジメチルホルムアミド4.9mLに懸濁させ、室温で4-(3-ブロモプロポキシ)ベンゾニトリル200mgおよび無水炭酸カリウム290mgを加え、50℃で3時間攪拌した。無水炭酸カリウム100mgを加え、50℃で1時間攪拌した。反応混合物を室温迄冷却し、水と酢酸エチルの混合液に加え、有機層を分取した。分取した有機層を水および飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；クロロヘホルム：メタノール＝50：1］で精製し、黒色固形の4-(3-{2-[3-(4-シアノフェノキシ)プロピル]-2,3-ジヒドロ-1H-イソインドール-5-イル}プロポキシ)ベンゾニトリル120mgを得た。
¹H-NMR(CDCl₃)δ値： 2.00-2.20(4H,m), 2.79(2H,t,J=7.4Hz), 2.91(2H,t,J=7.0Hz), 3.85-3.95(4H,m), 3.97(2H,t,J=6.2Hz), 4.14(2H,t,J=6.5Hz), 6.92(2H,d,J=9.0Hz), 6.96(2H,d,J=9.0Hz), 7.00-7.10(2H,m), 7.13(1H,d,J=7.3Hz), 7.57(2H,d,J=9.0Hz), 7.57(2H,d,J=9.0Hz) Reference Example 20

220 mg of 4- [3- (2,3-dihydro-1H-isoindol-5-yl) propoxy] benzonitrile hydrochloride is suspended in 4.9 mL of N, N-dimethylformamide and 4- (3-bromo 200 mg of propoxy) benzonitrile and 290 mg of anhydrous potassium carbonate were added, and the mixture was stirred at 50 ° C. for 3 hours. 100 mg of anhydrous potassium carbonate was added, and the mixture was stirred at 50 ° C. for 1 hour. The reaction mixture was cooled to room temperature, added to a mixture of water and ethyl acetate, and the organic layer was separated. The separated organic layer was washed with water 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: chloroform: methanol = 50: 1] to give 4- (3- {2- [3- (4-cyanophenoxy) propyl] -2 as a black solid. , 3-Dihydro-1H-isoindol-5-yl} propoxy) benzonitrile 120 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.00-2.20 (4H, m), 2.79 (2H, t, J = 7.4Hz), 2.91 (2H, t, J = 7.0Hz), 3.85-3.95 (4H, m), 3.97 (2H, t, J = 6.2Hz), 4.14 (2H, t, J = 6.5Hz), 6.92 (2H, d, J = 9.0Hz), 6.96 (2H, d, J = 9.0Hz) , 7.00-7.10 (2H, m), 7.13 (1H, d, J = 7.3Hz), 7.57 (2H, d, J = 9.0Hz), 7.57 (2H, d, J = 9.0Hz)

4-(3-ヒドロキシプロピル)フェニルカルバミン酸t-ブチル1.55gをテトラヒドロフラン55mLに溶解させ、この溶液に氷冷下、四臭化炭素2.89gおよびトリフェニルホスフィン2.28gを加え、同温で14時間攪拌した。反応混合物を飽和炭酸水素ナトリウム水溶液50mLおよびトルエン50mLの混合溶媒に加え、有機層を分取した。得られた有機層を水および飽和塩化ナトリウム水溶液で順次洗浄した後、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー[溶離液；ヘキサン：酢酸エチル＝10：1]で精製し、ヘキサンを加えて濾取し、白色固形の4-(3-ブロモプロピル)フェニルカルバミン酸t-ブチル1.10gを得た。
¹H-NMR (CDCl₃)δ値： 1.51(9H,s), 2.00-2.20(2H,m), 2.72(2H,t,J=7.3Hz), 3.37(2H,t,J=6.6Hz), 6.30-6.50(1H,brs), 7.12(2H,d,J=8.4Hz), 7.28(2H,d,J=8.4Hz) Reference Example 21

Dissolve 1.55 g of t-butyl 4- (3-hydroxypropyl) phenylcarbamate in 55 mL of tetrahydrofuran, add 2.89 g of carbon tetrabromide and 2.28 g of triphenylphosphine to the solution under ice cooling, and continue at the same temperature for 14 hours. Stir. The reaction mixture was added to a mixed solvent of 50 mL of saturated aqueous sodium hydrogen carbonate solution and 50 mL of toluene, and the organic layer was separated. The obtained organic layer was washed successively with water and saturated aqueous sodium chloride solution and then 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], hexane was added, and the mixture was collected by filtration to give white solid 4- (3-bromopropyl) phenylcarbamic acid t. -1.10 g of butyl were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.51 (9H, s), 2.00-2.20 (2H, m), 2.72 (2H, t, J = 7.3Hz), 3.37 (2H, t, J = 6.6Hz), 6.30-6.50 (1H, brs), 7.12 (2H, d, J = 8.4Hz), 7.28 (2H, d, J = 8.4Hz)

4-シアノフェノール0.38gを2-ブタノン3.8mLに溶解させ、この溶液に室温で無水炭酸カリウム0.66gおよび4-(3-ブロモプロピル)フェニルカルバミン酸t-ブチル1.05gを順次加え、4.5時間加熱還流した。反応混合物を室温迄冷却し、不溶物を濾去後、減圧下で溶媒を留去した。得られた残留物に酢酸エチルおよび水を加え、有機層を分取した。水層を酢酸エチルで２回抽出した後、得られた有機層を先の有機層とあわせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にヘキサンを加えて濾取し、白色固形の4-[3-(4-シアノフェノキシ)プロピル]フェニルカルバミン酸t-ブチル1.11gを得た。
¹H-NMR (CDCl₃) δ値： 1.51(9H,s), 2.00-2.20(2H,m), 2.76(2H,t,J=7.4Hz), 3.97(2H,t,J=6.3Hz), 6.30-6.50(1H,brs), 6.91(2H,d,J=8.8Hz), 7.11(2H,d,J=8.5Hz), 7.20-7.40(2H,m), 7.57(2H,d,J=8.8Hz) Reference Example 22

Dissolve 0.38 g of 4-cyanophenol in 3.8 mL of 2-butanone, add 0.66 g of anhydrous potassium carbonate and 1.05 g of t-butyl 4- (3-bromopropyl) phenylcarbamate successively to this solution, and heat for 4.5 hours. Refluxed. The reaction mixture was cooled to room temperature, insolubles were filtered off, and the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the obtained residue, and the organic layer was separated. After the aqueous layer was extracted twice with ethyl acetate, the obtained organic layer was combined with the previous organic layer, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the obtained residue and collected by filtration to obtain 1.11 g of t-butyl 4- [3- (4-cyanophenoxy) propyl] phenylcarbamate as a white solid.
¹ H-NMR (CDCl ₃ ) δ value: 1.51 (9H, s), 2.00-2.20 (2H, m), 2.76 (2H, t, J = 7.4Hz), 3.97 (2H, t, J = 6.3Hz) , 6.30-6.50 (1H, brs), 6.91 (2H, d, J = 8.8Hz), 7.11 (2H, d, J = 8.5Hz), 7.20-7.40 (2H, m), 7.57 (2H, d, J = 8.8Hz)

4-[3-(4-シアノフェノキシ)プロピル]フェニルカルバミン酸t-ブチル1.06gをクロロホルム4.2mLに溶解させ、室温でトリフルオロ酢酸4.4mLを加えた後、同温で40分間攪拌した。減圧下で溶媒を留去し、得られた残留物に2.58mol/L塩化水素エタノール溶液を加え、減圧下にて濃縮した。得られた析出物に2-プロパノールを加えて濾取し、白色固形の4-[3-(4-アミノフェニル)プロポキシ]ベンゾニトリル塩酸塩0.51gを得た。
¹H-NMR (d₆-DMSO)δ値： 1.90-2.10(2H,m), 2.70-2.90(2H,m), 3.20-3.60(3H,brs), 4.06(2H,t,J=6.2Hz), 7.10(2H,d,J=9.0Hz), 7.25(2H,d,J=8.4Hz), 7.33(2H,d,J=8.4Hz), 7.76(2H,d,J=9.0Hz) Reference Example 23

1.06 g of t-butyl 4- [3- (4-cyanophenoxy) propyl] phenylcarbamate was dissolved in 4.2 mL of chloroform, 4.4 mL of trifluoroacetic acid was added at room temperature, and the mixture was stirred at the same temperature for 40 minutes. The solvent was distilled off under reduced pressure, a 2.58 mol / L hydrogen chloride ethanol solution was added to the obtained residue, and the mixture was concentrated under reduced pressure. 2-Propanol was added to the resulting precipitate and collected by filtration to obtain 0.51 g of white solid 4- [3- (4-aminophenyl) propoxy] benzonitrile hydrochloride.
¹ H-NMR (d ₆ -DMSO) δ value: 1.90-2.10 (2H, m), 2.70-2.90 (2H, m), 3.20-3.60 (3H, brs), 4.06 (2H, t, J = 6.2Hz ), 7.10 (2H, d, J = 9.0Hz), 7.25 (2H, d, J = 8.4Hz), 7.33 (2H, d, J = 8.4Hz), 7.76 (2H, d, J = 9.0Hz)

4-(3-ブロモプロポキシ)ベンゾニトリル0.25gをN,N-ジメチルホルムアミド2.5mLに溶解させ、この溶液に室温で無水炭酸カリウム0.36gおよび4-[3-(4-アミノフェニル)プロポキシ]ベンゾニトリル塩酸塩0.25gを順次加え、70〜80℃で3時間攪拌した。反応混合物を室温迄冷却後、水および酢酸エチルの混合溶媒に加え、有機層を分取した。水層を酢酸エチルで２回抽出し、得られた有機層を先の有機層とあわせ、無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー[溶離液；ヘキサン：酢酸エチル＝3：1]で精製し、更にヘキサンと酢酸エチルの混合溶媒を加えて濾取し、白色固形の4-(3-{4-[3-(4-シアノフェノキシ)プロピル]アニリノ}プロポキシ)ベンゾニトリル0.21gを得た。
¹H-NMR (CDCl₃)δ値： 2.00-2.20(4H,m), 2.69(2H,t, J=7.4Hz), 3.34(2H,t,J=6.5Hz), 3.60-3.80(1H,brs), 3.98(2H,t,J=6.3Hz), 4.13(2H,t,J=6.0Hz), 6.57(2H,d,J=8.4Hz), 6.92(2H,d,J=9.0Hz), 6.95(2H,d,J=9.0Hz), 7.00(2H,d,J=8.4Hz), 7.57(2H,d,J=9.0Hz), 7.58(2H,d,J=9.0Hz) Reference Example 24

0.25 g of 4- (3-bromopropoxy) benzonitrile is dissolved in 2.5 mL of N, N-dimethylformamide, and 0.36 g of anhydrous potassium carbonate and 4- [3- (4-aminophenyl) propoxy] benzoate are added to this solution at room temperature. Nitrile hydrochloride 0.25 g was sequentially added and stirred at 70-80 ° C. for 3 hours. The reaction mixture was cooled to room temperature, added to a mixed solvent of water and ethyl acetate, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate, and the obtained organic layer was combined with the previous organic layer, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 3: 1], mixed with hexane and ethyl acetate, and collected by filtration to give 4- (3- 0.21-g of {4- [3- (4-cyanophenoxy) propyl] anilino} propoxy) benzonitrile was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.00-2.20 (4H, m), 2.69 (2H, t, J = 7.4Hz), 3.34 (2H, t, J = 6.5Hz), 3.60-3.80 (1H, brs), 3.98 (2H, t, J = 6.3Hz), 4.13 (2H, t, J = 6.0Hz), 6.57 (2H, d, J = 8.4Hz), 6.92 (2H, d, J = 9.0Hz), 6.95 (2H , d, J = 9.0Hz), 7.00 (2H, d, J = 8.4Hz), 7.57 (2H, d, J = 9.0Hz), 7.58 (2H, d, J = 9.0Hz)

4-{3-[5-[3-(4-シアノフェノキシ)プロピル]-3,4,5,6-テトラヒドロピロロ[3,4-c]ピロール-2(1H)-イル]プロポキシ}ベンゾニトリル塩酸塩0.14gをエタノール28mLに懸濁させ、氷冷下、塩化水素ガスを導入後、室温で5時間30分攪拌した。反応混合物を減圧下で濃縮し、得られた残留物をエタノール32mLに溶解させ、室温で酢酸アンモニウム0.26gを加え、2時間加熱還流した。反応混合物を室温迄冷却後、減圧下で濃縮し、残留物に2.6mol/L塩化水素エタノール溶液を加え、減圧下で再度濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル：ＹＭＣ社製ＯＤＳ−ＡＭ １２０−Ｓ５０、溶離液；水］で精製し、白色固形の4-{3-[5-(3-{4-[アミノ(イミノ)メチル]フェノキシ}プロピル)-3,4,5,6-テトラヒドロピロロ[3,4-c]ピロール-2(1H)-イル]プロポキシ}ベンズアミジン塩酸塩0.18gを得た。
¹H-NMR(CD₃OD)δ値： 2.20-2.50(4H,m), 3.50-3.90(4H,m), 4.00-5.00(14H,m), 7.20(4H,d,J=8.4Hz), 7.84(4H,d,J=8.4Hz)
¹³C-NMR(CD₃OD)δ値： 26.4, 54.5, 57.9, 66.4, 116.1, 120.9, 130.8, 135.7, 164.3, 167.0. Example 1

4- {3- [5- [3- (4-Cyanophenoxy) propyl] -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] propoxy} benzonitrile 0.14 g of hydrochloride was suspended in 28 mL of ethanol, hydrogen chloride gas was introduced under ice cooling, and the mixture was stirred at room temperature for 5 hours 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethanol (32 mL). Ammonium acetate (0.26 g) was added at room temperature, and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, a 2.6 mol / L hydrogen chloride ethanol solution was added to the residue, and the mixture was concentrated again under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel: ODS-AM 120-S50, manufactured by YMC, eluent: water], and white solid 4- {3- [5- (3- {4- [ 0.18 g of amino (imino) methyl] phenoxy} propyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] propoxy} benzamidine hydrochloride was obtained.
¹ H-NMR (CD ₃ OD) δ value: 2.20-2.50 (4H, m), 3.50-3.90 (4H, m), 4.00-5.00 (14H, m), 7.20 (4H, d, J = 8.4Hz) , 7.84 (4H, d, J = 8.4Hz)
¹³ C-NMR (CD ₃ OD) δ value: 26.4, 54.5, 57.9, 66.4, 116.1, 120.9, 130.8, 135.7, 164.3, 167.0.

4-{3-[5-(3-{4-[アミノ(イミノ)メチル]フェノキシ}プロピル)-3,4,5,6-テトラヒドロピロロ[3,4-c]ピロール-2(1H)-イル]プロポキシ}ベンズアミジン塩酸塩0.15gをメタノール5.0mLに溶解させ、室温で20％水酸化パラジウム(II)−炭素0.07gを加え、水素雰囲気下、常温常圧で13時間攪拌した。触媒を濾去後、減圧下で溶媒を留去し、残留物に2-プロパノールを加えて濾取し、白色固形の4-{3-[5-(3-{4-[アミノ(イミノ)メチル]フェノキシ}プロピル)ヘキサヒドロピロロ[3,4-c]ピロール-2(1H)-イル]プロポキシ}ベンズアミジン塩酸塩0.13gを得た。
¹H-NMR(CD₃OD)δ値： 2.20-2.50(4H,m), 3.40-4.00(14H,m), 4.26(4H,t,J=5.9Hz), 7.10-7.70(2H,brs), 7.18(4H,d,J=9.0Hz), 7.84(4H,d,J=9.0Hz)
¹³C-NMR(CD₃OD)δ値： 26.7, 41.0, 52.7, 58.4, 66.4, 116.1, 120.8, 130.8, 164.2, 167.0. Example 2

4- {3- [5- (3- {4- [Amino (imino) methyl] phenoxy} propyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1H)- [Il] propoxy} benzamidine hydrochloride (0.15 g) was dissolved in methanol (5.0 mL), 20% palladium hydroxide (II) -carbon (0.07 g) was added at room temperature, and the mixture was stirred in a hydrogen atmosphere at room temperature and normal pressure for 13 hours. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure, 2-propanol was added to the residue, and the mixture was collected by filtration. 0.13 g of [methyl] phenoxy} propyl) hexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] propoxy} benzamidine hydrochloride was obtained.
¹ H-NMR (CD ₃ OD) δ value: 2.20-2.50 (4H, m), 3.40-4.00 (14H, m), 4.26 (4H, t, J = 5.9Hz), 7.10-7.70 (2H, brs) , 7.18 (4H, d, J = 9.0Hz), 7.84 (4H, d, J = 9.0Hz)
¹³ C-NMR (CD ₃ OD) δ value: 26.7, 41.0, 52.7, 58.4, 66.4, 116.1, 120.8, 130.8, 164.2, 167.0.

4-(3-{(1S,4S)-5-[3-(4-シアノフェノキシ)プロピル]-2,5-ジアザビシクロ[2.2.1]ヘプト-2-イル}プロポキシ)ベンゾニトリル170mgをエタノール20mLに懸濁させ、氷冷下、塩化水素ガスを導入後、室温で13時間攪拌した。反応混合物を減圧下で濃縮し、得られた残留物をエタノール32mLに懸濁させ、室温で酢酸アンモニウム378mgを加え、6時間加熱還流した。反応混合物を室温迄冷却後、減圧下で濃縮し、残留物に2.6mol/L塩化水素エタノール溶液を加え、減圧下で再度濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル：ＹＭＣ社製ＯＤＳ−ＡＭ １２０−Ｓ５０、溶離液；水］で精製し、白色固形の4-{3-[(1S,4S)-5-(3-{4-[アミノ(イミノ)メチル]フェノキシ}プロピル)-2,5-ジアザビシクロ[2.2.1]ヘプト-2-イル]プロポキシ}ベンズアミジン塩酸塩225mgを得た。
¹H-NMR(d₆-DMSO)δ値： 2.00-2.80(6H,m), 3.00-4.30(12H,m), 4.65(2H,s), 7.00-7.30(4H,m), 7.80-8.00(4H,m), 9.20(4H,brs), 9.41(4H,brs), 12.08(1H,brs), 12.48(1H,brs) Example 3

4- (3-{(1S, 4S) -5- [3- (4-cyanophenoxy) propyl] -2,5-diazabicyclo [2.2.1] hept-2-yl} propoxy) benzonitrile (170 mg) in ethanol (20 mL) Then, hydrogen chloride gas was introduced under ice cooling, followed by stirring at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was suspended in 32 mL of ethanol, 378 mg of ammonium acetate was added at room temperature, and the mixture was heated to reflux for 6 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, a 2.6 mol / L hydrogen chloride ethanol solution was added to the residue, and the mixture was concentrated again under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel: ODS-AM 120-S50 manufactured by YMC, eluent: water], and 4- {3-[(1S, 4S) -5- ( 225 mg of 3- {4- [amino (imino) methyl] phenoxy} propyl) -2,5-diazabicyclo [2.2.1] hept-2-yl] propoxy} benzamidine hydrochloride was obtained.
¹ H-NMR (d ₆ -DMSO) δ value: 2.00-2.80 (6H, m), 3.00-4.30 (12H, m), 4.65 (2H, s), 7.00-7.30 (4H, m), 7.80-8.00 (4H, m), 9.20 (4H, brs), 9.41 (4H, brs), 12.08 (1H, brs), 12.48 (1H, brs)

3-(4-シアノフェノキシ)プロピル({4-[3-(4-シアノフェノキシ)プロピル]-2-モルホリニル}メチル)カルバミド酸t-ブチル200mgをエタノール7.4mLに溶解させ、氷冷下、塩化水素ガスを導入後、室温で18時間攪拌した。反応混合物を減圧下で濃縮し、得られた残留物をエタノール7.4mLに懸濁させ、室温で酢酸アンモニウム230mgを加え、1時間加熱還流した。反応混合物を室温迄冷却後、減圧下で濃縮し残留物に2.6mol/L塩化水素エタノール溶液を加え、減圧下で再度濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル：ＹＭＣ社製ＯＤＳ−ＡＭ １２０−Ｓ５０、溶離液；水］で精製し、白色固形の4-[3-({[4-(3-{4-[アミノ(イミノ)メチル]フェノキシ}プロピル)-2-モルホリニル]メチル}アミノ)プロポキシ]ベンズアミジン塩酸塩150mgを得た。
¹H-NMR(d₆-DMSO)δ値： 2.10-2.40(4H,m), 2.90-3.80(10H,m), 3.90-4.50(7H,m), 7.16(2H,d,J=8.8Hz), 7.17(2H,d,J=8.8Hz), 7.90(2H,d,J=8.8Hz), 7.90(2H,d,J=8.8Hz), 9.14(4H,brs), 9.34(4H,brs), 9.61(1H,brs), 12.06(1H,brs) Example 4 (1)

Dissolve 200 mg of t-butyl 3- (4-cyanophenoxy) propyl ({4- [3- (4-cyanophenoxy) propyl] -2-morpholinyl} methyl) carbamate in 7.4 mL of ethanol After introducing hydrogen gas, the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was suspended in 7.4 mL of ethanol, 230 mg of ammonium acetate was added at room temperature, and the mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, a 2.6 mol / L hydrogen chloride ethanol solution was added to the residue, and the mixture was concentrated again under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel: ODS-AM 120-S50, manufactured by YMC, eluent: water], and white solid 4- [3-({[4- (3- {4 -[Amino (imino) methyl] phenoxy} propyl) -2-morpholinyl] methyl} amino) propoxy] benzamidine hydrochloride 150 mg was obtained.
¹ H-NMR (d ₆ -DMSO) δ value: 2.10-2.40 (4H, m), 2.90-3.80 (10H, m), 3.90-4.50 (7H, m), 7.16 (2H, d, J = 8.8Hz ), 7.17 (2H, d, J = 8.8Hz), 7.90 (2H, d, J = 8.8Hz), 7.90 (2H, d, J = 8.8Hz), 9.14 (4H, brs), 9.34 (4H, brs ), 9.61 (1H, brs), 12.06 (1H, brs)

4-[3-({[4-(3-{4-[アミノ(イミノ)メチル]フェノキシ}プロピル)-2-モルホリニル]メチル}アミノ)プロポキシ]ベンズアミジン塩酸塩110mgを水に溶解させ、1.0mol/L水酸化ナトリウム水溶液を用いてpH13に調整し、クロロホルムを加え、水層を2回抽出した。これを無水硫酸ナトリウムで乾燥後、減圧下にて溶媒を留去した。水層に更に飽和塩化ナトリウム水溶液を加え、析出物を濾取し、これをメタノールに溶解後、減圧下にて溶媒を留去した。先に得られた残留物と合わせジイソプロピルエーテルに加えた後、濾取し、淡褐色固形の4-[3-({[4-(3-{4-[アミノ(イミノ)メチル]フェノキシ}プロピル)-2-モルホリニル]メチル}アミノ)プロポキシ]ベンズアミジン50mgを得た。
¹H-NMR(d₆-DMSO)δ値： 1.60-2.00(6H,m), 2.30-2.40(1H,m), 2.60-2.80(2H,m), 2.90-3.70(8H,m), 3.90-4.20(5H,m), 6.98(2H,d,J=9.4Hz), 7.03(2H,d,J=9.4Hz), 7.70(2H,d,J=9.4Hz), 7.73(2H,d,J=9.4Hz), 8.00-10.00(4H,brs) Example 4 (2)

4- [3-({[4- (3- {4- [Amino (imino) methyl] phenoxy} propyl) -2-morpholinyl] methyl} amino) propoxy] benzamidine hydrochloride 110 mg was dissolved in water, 1.0 mol The pH was adjusted to 13 using an aqueous / L sodium hydroxide solution, chloroform was added, and the aqueous layer was extracted twice. After drying this over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. A saturated aqueous sodium chloride solution was further added to the aqueous layer, the precipitate was collected by filtration, dissolved in methanol, and the solvent was distilled off under reduced pressure. Combined with the residue obtained above and added to diisopropyl ether, filtered and collected as a light brown solid 4- [3-({[4- (3- {4- [amino (imino) methyl] phenoxy} propyl 50 mg of) -2-morpholinyl] methyl} amino) propoxy] benzamidine were obtained.
¹ H-NMR (d ₆ -DMSO) δ value: 1.60-2.00 (6H, m), 2.30-2.40 (1H, m), 2.60-2.80 (2H, m), 2.90-3.70 (8H, m), 3.90 -4.20 (5H, m), 6.98 (2H, d, J = 9.4Hz), 7.03 (2H, d, J = 9.4Hz), 7.70 (2H, d, J = 9.4Hz), 7.73 (2H, d, J = 9.4Hz), 8.00-10.00 (4H, brs)

2,5-ビス[3-(4-シアノフェノキシ)プロピル]-1-ピロリジンカルボン酸ベンジル200mgをクロロホルム0.76mLとエタノール7.6mLの混合溶媒に溶解させ、氷冷下、塩化水素ガスを導入後、室温で２１時間攪拌した。反応混合物を減圧下で濃縮し、得られた残留物をエタノール7.6mLに懸濁させ、室温で酢酸アンモニウム240mgを加え、１時間加熱還流した。反応混合物を室温まで冷却後、減圧下で濃縮し、残留物をメタノールに溶解させ、室温で2.5mol/L塩化水素エタノール溶液を加え、減圧下で再度濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル：ＹＭＣ社製ＯＤＳ−ＡＭ １２０−Ｓ５０、溶離液；アセトニトリル：水＝95：5］で精製し、析出物にジエチルエーテルを加え濾取し、白色固形の4-{3-[5-(3-{4-[アミノ(イミノ)メチル]フェノキシ}プロピル)-2-ピロリジニル]プロポキシ}ベンズアミジン塩酸塩150mgを得た。
¹H-NMR(d₆-DMSO)δ値： 1.50-2.20(12H,m), 3.30-3.60(2H,m), 4.00-4.20(4H,m), 7.17(4H,d,J=8.7Hz), 7.88(4H,d,J=8.7Hz), 8.79(1H,brs), 9.09(4H,brs), 9.30(4H,brs), 10.11(1H,brs) Example 5

200 mg of benzyl 2,5-bis [3- (4-cyanophenoxy) propyl] -1-pyrrolidinecarboxylate was dissolved in a mixed solvent of 0.76 mL of chloroform and 7.6 mL of ethanol, and after introducing hydrogen chloride gas under ice cooling, Stir at room temperature for 21 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was suspended in 7.6 mL of ethanol, 240 mg of ammonium acetate was added at room temperature, and the mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, the residue was dissolved in methanol, a 2.5 mol / L hydrogen chloride ethanol solution was added at room temperature, and the mixture was concentrated again under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel: ODS-AM 120-S50, manufactured by YMC, eluent; acetonitrile: water = 95: 5], and diethyl ether was added to the precipitate, followed by filtration. 150 mg of solid 4- {3- [5- (3- {4- [amino (imino) methyl] phenoxy} propyl) -2-pyrrolidinyl] propoxy} benzamidine hydrochloride was obtained.
¹ H-NMR (d ₆ -DMSO) δ value: 1.50-2.20 (12H, m), 3.30-3.60 (2H, m), 4.00-4.20 (4H, m), 7.17 (4H, d, J = 8.7Hz ), 7.88 (4H, d, J = 8.7Hz), 8.79 (1H, brs), 9.09 (4H, brs), 9.30 (4H, brs), 10.11 (1H, brs)

4-(3-{6-[3-(4-シアノフェノキシ)プロピル]オクタヒドロ-1H-ピロロ[3,4-b]ピリジン-1-イル}プロポキシ)ベンゾニトリル250mgをエタノール10mLに溶解させ、氷冷下、塩化水素ガスを導入後、室温で18時間攪拌した。反応混合物を減圧下で濃縮し、得られた残留物をエタノール15mLに溶解させ、室温で酢酸アンモニウム430mgを加え、3時間加熱還流した。反応混合物を室温迄冷却し、減圧下で濃縮した。得られた残留物に水およびクロロホルムを加え、5.0mol/L水酸化ナトリウム水溶液でpH13に調整後、有機層を分取し、分取した有機層を無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物に塩化水素エタノール溶液およびメタノールを加え溶解させ、減圧下で再度濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル：ＹＭＣ社製ＯＤＳ−ＡＭ １２０−Ｓ５０、溶離液；水］で精製し、白色固形の4-{3-[6-(3-{4-[アミノ(イミノ)メチル]フェノキシ}プロピル)オクタヒドロ-1H-ピロロ[3,4-b]ピリジン-1-イル]プロポキシ}ベンズアミジン塩酸塩220mgを得た。
¹H-NMR(d₆-DMSO)δ値： 1.50-4.60(24H,m), 7.10-7.25(4H,m), 7.80-8.00(4H,m), 9.05-9.20(4H,m), 9.22-9.50(4H,m), 11.82(1H,brs), 12.12(1H,brs) Example 6

4- (3- {6- [3- (4-cyanophenoxy) propyl] octahydro-1H-pyrrolo [3,4-b] pyridin-1-yl} propoxy) benzonitrile (250 mg) was dissolved in ethanol (10 mL) and iced. After introducing hydrogen chloride gas under cooling, the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in 15 mL of ethanol, 430 mg of ammonium acetate was added at room temperature, and the mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water and chloroform are added to the obtained residue, and after adjusting the pH to 13 with a 5.0 mol / L sodium hydroxide aqueous solution, the organic layer is separated. The separated organic layer is dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure. Was distilled off. A hydrogen chloride ethanol solution and methanol were added to the obtained residue to dissolve it, and the mixture was concentrated again under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel: ODS-AM 120-S50, manufactured by YMC, eluent; water], and 4- {3- [6- (3- {4- [ Amino (imino) methyl] phenoxy} propyl) octahydro-1H-pyrrolo [3,4-b] pyridin-1-yl] propoxy} benzamidine hydrochloride 220 mg was obtained.
¹ H-NMR (d ₆ -DMSO) δ value: 1.50-4.60 (24H, m), 7.10-7.25 (4H, m), 7.80-8.00 (4H, m), 9.05-9.20 (4H, m), 9.22 -9.50 (4H, m), 11.82 (1H, brs), 12.12 (1H, brs)

4-(3-{2-[3-(4-シアノフェノキシ)プロピル]-2,3-ジヒドロ-1H-イソインドール-5-イル}プロポキシ)ベンゾニトリル110mgをクロロホルム3.0mLとエタノール6.0mLの混合溶媒に溶解させ、氷冷下、塩化水素ガスを導入後、室温で２日間攪拌した。反応混合物を減圧下で濃縮し、得られた残留物をエタノール5.0mLに溶解させ、室温で酢酸アンモニウム150mgを加え、50分間加熱還流した。反応混合物を室温迄冷却後、得られた残留物にメタノールと2.6mol/L塩化水素エタノール溶液を加えた。減圧下で濃縮し、得られた残留物をシリカゲルカラムクロマトグラフィー［シリカゲル：ＹＭＣ社製ＯＤＳ−ＡＭ １２０−Ｓ５０、溶離液：水］で精製し、灰色固形の4-{3-[2-(3-{4-[アミノ(イミノ)メチル]フェノキシ}プロピル)-2,3-ジヒドロ-1H-イソインドール-5-イル]プロポキシ}ベンズアミジン塩酸塩110mgを得た。
¹H-NMR(d₆-DMSO)δ値： 1.90-2.15(2H,m), 2.20-2.40(2H,m), 2.79(2H,t,J=7.4Hz), 3.40-3.60(2H,m), 4.10(2H,t,J=6.2Hz), 4.25(2H,t,J=6.1Hz), 4.40-4.60(2H,m), 4.70-4.90(2H,m), 7.15(2H,d,J=8.5Hz), 7.18(2H,d,J=8.5Hz), 7.20-7.40(3H,m), 7.85-7.90(4H,m), 8.90-9.10(4H,m), 9.20-9.40(4H,m), 12.21(1H,brs) Example 7

4- (3- {2- [3- (4-Cyanophenoxy) propyl] -2,3-dihydro-1H-isoindol-5-yl} propoxy) benzonitrile (110 mg) mixed with chloroform (3.0 mL) and ethanol (6.0 mL) After dissolving in a solvent and introducing hydrogen chloride gas under ice cooling, the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in 5.0 mL of ethanol, 150 mg of ammonium acetate was added at room temperature, and the mixture was heated to reflux for 50 minutes. After cooling the reaction mixture to room temperature, methanol and a 2.6 mol / L hydrogen chloride ethanol solution were added to the obtained residue. The residue obtained by concentrating under reduced pressure was purified by silica gel column chromatography [silica gel: ODS-AM 120-S50, manufactured by YMC, eluent: water] to give 4- {3- [2- ( 110 mg of 3- {4- [amino (imino) methyl] phenoxy} propyl) -2,3-dihydro-1H-isoindol-5-yl] propoxy} benzamidine hydrochloride was obtained.
¹ H-NMR (d ₆ -DMSO) δ value: 1.90-2.15 (2H, m), 2.20-2.40 (2H, m), 2.79 (2H, t, J = 7.4Hz), 3.40-3.60 (2H, m ), 4.10 (2H, t, J = 6.2Hz), 4.25 (2H, t, J = 6.1Hz), 4.40-4.60 (2H, m), 4.70-4.90 (2H, m), 7.15 (2H, d, J = 8.5Hz), 7.18 (2H, d, J = 8.5Hz), 7.20-7.40 (3H, m), 7.85-7.90 (4H, m), 8.90-9.10 (4H, m), 9.20-9.40 (4H , m), 12.21 (1H, brs)

4-(3-{4-[3-(4-シアノフェノキシ)プロピル]アニリノ}プロポキシ)ベンゾニトリル0.18gをクロロホルム7.2mLおよびエタノール7.2mLの混合溶媒に懸濁させた。この懸濁液に塩化水素を吹き込んだ後、反応混合物を室温で17時間攪拌した。減圧下で溶媒を留去した後、得られた残留物をエタノール10mLに溶解させ、室温で酢酸アンモニウム0.34gを加え2時間加熱還流した。反応混合物を室温に冷却後、減圧下で溶媒を留去し、得られた残留物に水およびクロロホルムを加え、水酸化ナトリウム水溶液を用いてpH13に調整した。析出物を濾取した後、濾液の有機層を分取した。水層をクロロホルムで抽出し、得られた有機層をあわせ、無水硫酸ナトリウムで乾燥させ、この有機層に先の析出物を加え、減圧下で溶媒を留去した。得られた残留物に2.58mol/L塩化水素エタノール溶液およびメタノールを加え、溶媒を減圧濃縮し、シリカゲルカラムクロマトグラフィー[シリカゲル：ＹＭＣ社製ＯＤＳ−ＡＭ １２０−Ｓ５０、溶離液；アセトニトリル：水＝1：9]で精製し、白色固形の4-{3-[4-(3-{4-[アミノ(イミノ)メチル]フェノキシ}プロピル)アニリノ]プロポキシ}ベンズアミジン塩酸塩0.20gを得た。
¹H-NMR (d₆-DMSO)δ値： 1.85-2.10(4H,m), 2.61(2H,t,J=7.3Hz), 3.18(2H,t,J=6.6Hz), 3.20-3.60(2H,brs), 4.06(2H,t,J=6.0Hz), 4.21(2H,t,J=6.2Hz), 6.50-6.80(2H,m), 6.98(2H,d,J=7.8Hz), 7.10-7.30(4H,m), 7.80-8.00(4H,m), 9.13(4H,brs), 9.30(4H,brs)
Example 8

4- (3- {4- [3- (4-Cyanophenoxy) propyl] anilino} propoxy) benzonitrile (0.18 g) was suspended in a mixed solvent of 7.2 mL of chloroform and 7.2 mL of ethanol. After hydrogen chloride was bubbled through the suspension, the reaction mixture was stirred at room temperature for 17 hours. After the solvent was distilled off under reduced pressure, the obtained residue was dissolved in 10 mL of ethanol, 0.34 g of ammonium acetate was added at room temperature, and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, water and chloroform were added to the resulting residue, and the pH was adjusted to 13 using an aqueous sodium hydroxide solution. After the precipitate was collected by filtration, the organic layer of the filtrate was separated. The aqueous layer was extracted with chloroform, and the obtained organic layers were combined and dried over anhydrous sodium sulfate. The previous precipitate was added to this organic layer, and the solvent was distilled off under reduced pressure. 2.58 mol / L hydrogen chloride ethanol solution and methanol were added to the obtained residue, the solvent was concentrated under reduced pressure, and silica gel column chromatography [silica gel: ODS-AM 120-S50 manufactured by YMC, eluent; acetonitrile: water = 1 9] to obtain 0.20 g of white solid 4- {3- [4- (3- {4- [amino (imino) methyl] phenoxy} propyl) anilino] propoxy} benzamidine hydrochloride.
¹ H-NMR (d ₆ -DMSO) δ value: 1.85-2.10 (4H, m), 2.61 (2H, t, J = 7.3Hz), 3.18 (2H, t, J = 6.6Hz), 3.20-3.60 ( 2H, brs), 4.06 (2H, t, J = 6.0Hz), 4.21 (2H, t, J = 6.2Hz), 6.50-6.80 (2H, m), 6.98 (2H, d, J = 7.8Hz), 7.10-7.30 (4H, m), 7.80-8.00 (4H, m), 9.13 (4H, brs), 9.30 (4H, brs)

Claims (4)

General formula

“In the formula, R ¹ and R ^1a are the same or different and may be protected or substituted; R ² and R ^2a are the same or different and may be a hydrogen atom, a halogen atom or a substituted group. One or more groups selected from alkyl, cycloalkyl and alkoxy groups; X and Z are C _2-6 alkylene groups which may be the same or differently substituted; Y is
General formula

"Wherein R ³ and R ^3a are the same or different and each represents a hydrogen atom, an optionally substituted lower alkyl group or an amino protecting group; R ⁴ represents a hydrogen atom, an optionally substituted alkyl group or Represents a cycloalkyl group. ",
General formula

“Wherein R ³ and R ⁴ have the same meaning as described above.”
formula

,
formula

,
General formula

“Wherein R ³ , R ^3a and R ⁴ have the same meaning as described above” or
General formula

“Wherein R ³ and R ⁴ have the same meaning as described above.” Or an salt thereof. R ¹ and R ^1a may be the same or differently protected amidino groups; R ² and R ^2a are the same or different, hydrogen atoms or halogen atoms; X and Z are the same or different, C _2-6 The arylamidine derivative or a salt thereof according to claim 1, which is an alkylene group. R ¹ and R ^1a are amidino groups; R ² and R ^2a are hydrogen atoms; X and Z are the same or different, and a C _2-4 alkylene group; Y is a formula

The arylamidine derivative or a salt thereof according to claim 1 or 2, wherein The antifungal agent containing the arylamidine derivative or its salt of Claims 1-3.