WO2003072545A1 - Cyclic amine compound and ccr3 inhibitory drug containing the same as active ingredient - Google Patents

Abstract

A cyclic amine compound represented by the general formula (1): [wherein A is a group which is selected from the group consisting of substituted aryls, substituted heterocyclic groups, and substituted cycloalkyls, has at least one substituent X, and may have at least one substituent Y (wherein the substituent X is selected from the group consisting of HO-(C1-6 alkyl), HO-(C2-6 alkyl)-O-(C1-6 alkyl), HOOC-(C1-6 alkyl), (C1-6 alkyl)-OCO-(C1-6 alkyl), NH2CO-(C1-6 alkyl), (C1-3 alkyl)2NCO-(C1-6 alkyl), (C1-3 alkyl)-CONH-(C1-6 alkyl), HOOC-(C1-6 alkyl)-O-(C1-6 alkyl), etc., and the substituent Y is selected from the group consisting of halogeno, C1-3 alkyl, OH, methoxy, CN, and CF3)] or a pharmaceutically acceptable salt of the compound.

Description

 Description Cyclic amine compound and CCR3 inhibitor containing it as active ingredient

 The present invention relates to a cyclic amine compound or a pharmaceutically acceptable salt thereof, and a medicament containing these as an active ingredient, particularly a CCR3 inhibitor. Background art

Diseases in inflammatory diseases, such as bronchial asthma, allergic rhinitis, atopic dermatitis, allergic bronchopulmonary aspergillosis, Jiagu-Strauss syndrome, hypereosinophilic syndrome, parasitosis, or ulcerative colitis One of the physical characteristics is the accumulation of eosinophils in the inflamed area (eg, "Samter's Immunologic Diseases", (USA), 1995, Chapter 29, p. .501—527; "See The Journal of Allergy and Clinical Immunology '\ (USA), 2000, vol. 106, p. 1033-1042.) Eosinophils. In the cytoplasm, granules composed mainly of basic proteins called major basic prot ein (MBP), eosinophil cationic protein (ECP), eosi hito derived neuroto xin (EDN), and eosinophil peroxidase (EPO) are contained. Exist These proteins show potent cytotoxic activity and stimulate basophils, mast cells, platelets, or eosinophils themselves to produce histamine, serotonin, reactive oxygen, or interleukin-8. It is known to induce the release of inflammatory mediators (eg, "The Journal of Experimental Medicine", (USA), 1983, Vol. 157, p. 1981). — 1991; "See The Journal of Immunology '(USA), 1995, 154, p. 4749-4758.). Eosinophils accumulated in the inflamed area play an important role in the development of the above-mentioned inflammatory diseases by releasing such granule proteins. Therefore, drugs that suppress tissue accumulation of eosinophils are It is thought to contribute to the treatment of such diseases.

 Steroidal anti-inflammatory drugs are clinically used as effective therapeutic agents for many chronic inflammatory diseases, including eosinophilic inflammatory diseases, and are known to strongly suppress eosinophil tissue accumulation. I have. However, various side effects such as adrenal atrophy, growth inhibition, weakening of connective tissue due to inhibition of collagen synthesis, etc., and problems such as a gradual increase in the amount used due to the acquisition of resistance have been pointed out with steroids. The development of eosinophil accumulation inhibitors with few side effects is desired.

 In recent years, a group of proteinaceous mediators called chemokines have been discovered as cytokins that induce leukocyte migration and activation. Leukocytes express a chemokine receptor on their cell surface, and the binding of the chemokine to the receptor induces a leukocyte migration reaction—a mediae overnight release reaction. Among them, eosinophils mainly express CCR3 as a chemokine receptor (for example, "The European Respiratory Journal", (Denmark), 1996, Vol. 9, p.2454—2460; “See The Journal of Clinical Investigation” (USA), 1997, Vol. 99, pp. 926—936), and its ligands. RANTES, MCP-3, MCP-4, and eotaxin have been reported to be produced at high levels from the respiratory epithelium in human asthma (see, for example, "The Journal of Clinical Medicine, (The Journal of Clinical Investigation) ">

(USA), 1997, Vol. 99, .926-936; "American Journal of Respiratory and Critical Care Medicine (USA), 2000, Vol. 162, ρ · 723—732; "The Journal of Allergy and Clinical Immunology" \ (USA), 1999, Volume 103, .476-483; "American Journal of Allergy and Clinical Immunology""American Journal of Responsible and Critical Care Medicine", (USA), 1996, Vol. 154, p. 1804-1811; "American Journal of Respoiratory and Critical Care Medicine", "American Journal of Respoiratory and Critical Care Medicine". Respiratory Cell and Mo lecular Biology) ", (USA), 1996, Vol. 14, p. 27-35.) In addition, infiltration of activated eosinophils was observed in the tissue extract of nasal polyps (chronic sinusitis). CCR3 ligands eotaxin, eotaxin-2 and MCP-4 are significantly increased (eg,

"See The Journal of Immunology '(USA), 1999, Vol. 163, p. 1545-1551.), CCR3-positive mononuclear cells in peripheral blood of RA patients (See, for example, "Arthritis and Rheumatism" (USA), 2001, Vol. 44, p. 1022-1032). I have. In addition, among these chemokines, eotaxin is also known to induce eosinophil degranulation.

(For example, "The Journal of Allergy and Clinical Immunology

(The Journal of Allergy and Clinical Immunology) '\ (USA), 2000, vol. 106, p. 507—513. ). Thus, CCR3 is considered to be an effective target in controlling eosinophilic inflammation (eg, "Nature Reviews. Immunology" '(UK), 2001, (See Volume 1, p.108-116.) In addition, TCR type 2 helper T (Th2) cells, which control airway inflammation, also express CCR3, CCR4, CXC4, and CCR8. CCR5 and CXCR3 are expressed in T helper type 1 (Thl) cells that act in the direction of suppressing Th2 cell response (see, for example, "The Journal of Experimental Medicine"). '\ (United States), 1998, Volume 187, p. 875—883; "European Journal of I tung unology" (Germany), 1999, Volume 29, p. 2037 _ 2 045; "The Journal of Immunology Immunology), (United States), 1998, Vol. 161, p.5111-5115; "Folia Histochemica et Cytobiologica", (Poland), 2000, Vol. 38, p. Therefore, inhibitors of chemokine receptors expressed on Τ1ι2 cells may be important targets in controlling airway inflammation seen in asthma.

Based on the above findings, various chemokine receptors are involved in the development of inflammatory diseases, and among them, eosinophilic inflammation, which is the main inflammatory response, or the involvement of Τ1ι2 cells CCR3 inhibitors are thought to be effective in controlling inflammatory diseases. On the other hand, CCR5 is expressed on Till cells and macrophages, but few reports suggest the involvement of the ligand in the inflammatory disease and the importance of CCR5. It is easily speculated that CCR3 inhibitors are a better choice than CCR5 inhibitors.

 As a compound having a CCR3 antagonistic activity, a piperazine, piperidine or pyrrolidine derivative (for example, International Publication No. 00Z10439; pamphlet of International Publication No. 00Z143333); No. 0/310, 32), but the structure is different from the compound of the present invention.

Further, compounds represented by the following general formula are known to have CCR5 antagonistic activity (see, for example, International Publication No. 01Z8739 pamphlet).

(In the formula, X - C0_, - S0 ₂ -, etc., R ¹ is such as alkyl (which may have a substituent such as Ariru group), R ² is hydrogen, alkyl, etc., R ³ is alkyl, cycloalkyl , NR ⁴ ¾ ^{46 etc., R 4, R 5, R} 6, R 7 is hydrogen, alkyl, etc., R ⁴⁵ is hydrogen or the like, R ⁴⁶ is a halogen as Ariru like (substituent, hydroxy, NR ²⁸ R ^29, C ( ^{0) NR 39 R 40, C0} 2 R 42, alkyl, alkoxy, full Eniru, phenylalanine alkoxy, Heteroariru may have a hetero § reel alkoxy, etc.), m, p represents 0 to 2. More See the official gazette.)

However, although the substance claims in this publication are extensive, the structures of the substituents which the group represented by R ⁴⁶ of this publication may have and the structures of the substituents X of the cyclic amine compound represented by the general formula (1) Are different from each other in the structure of the cyclic amine compound represented by the general formula (1) and the substance claim in the publication. In addition, there is no disclosure in this publication about CCR3 antagonism.

Further, the cyclic amine compound represented by the general formula (1) of the present invention is included in the compound represented by the following general formula described in a document published after the filing date of the priority application of the present application, The following compounds are known to have CCR3 antagonism (for example, see WO 02/183335).

(In the formula, A Ariru which may be substituted, etc., X is - C0_, - S0 ₂ -, etc., D is a monocyclic or bicyclic Ariru, n represents shows the 0-2.)

 The substance claims in this publication are extensive, and include the cyclic amine compound represented by the general formula (1). Specific examples of compounds and examples include descriptions of the cyclic amine compound represented by the general formula (1). There is no.

 The following compounds are known to have a factor Xa inhibitory action (see, for example, International Publication No. 01Z64642 pamphlet).

 A-Q-D-E-G-J-X

(In the formula, A alkyl, phenyl, heterocycle and the like, Q is _{- 0_, - S0 2 -,} -CO- , etc., D is Hue sulfonyl, including C5-10 membered ring (hetero atom), E is alkyl, - S0 ₂ -, Urea, etc., G is an alkenyl, phenyl or the like; [is - CH ₂ -, -S0 ₂ -, etc., X is phenyl, shows a naphthyl details, reference can be made to the publication)..

 However, there is no disclosure in this publication about CCR3 antagonism and treatment of inflammatory diseases. In addition, the substance claims in this publication are extensive, and include the cyclic amine compound represented by the general formula (1), but specific examples of compounds and working examples do not describe the cyclic amine compound represented by the general formula (1). Not at all. Disclosure of the invention

 The problem to be solved by the present invention is to provide a medicament capable of preventing and treating inflammatory diseases caused by leukocyte accumulation such as lymphocytes, eosinophils and basophils by finding a CCR3 inhibitor. Is to do.

The present inventors have conducted intensive studies and found that the cyclic amine compound represented by the general formula (1) shows a strong inhibitory activity against CCR3, and that, in an asthma model using an animal, It has been found that the cyclic amine compound represented by the formula (1) exhibits excellent effects. Furthermore, in an oral absorption test using an animal, the cyclic amine compound represented by the general formula (1) was found to exhibit excellent bioavailability, thereby completing the present invention. I came to.

 The present invention includes the following inventions

(1) Equation 1:

 (In Formula 1, A is a group selected from the group consisting of an aryl group, a heterocyclic group, and a cycloalkyl group, and has at least one substituent X and at least one substituent Y. May be

Substituent X is substituted with 0H ₍₆ alkyl, (0- (C ₂ substituted by 0H - ₆ alkyl)) _ ₆ alkyl substituted with, - substituted with C00H ₍₆ alkyl, - C00 ( (V ₆ alkyl) _ ₆ alkyl substituted by, - alkyl substituted by C0Nh _2, - CON (CH alkyl) _ ₆ alkyl substituted by _2, - substituted with NHCiHCni alkyl) _(alkyl, ( 0 _ ₆ alkyl substituted with (substituted _(C6 alkyl) by C00H), - substituted with (0 (COOO e alkyl) by substitution have been c ₆ alkyl)) ₍₆ alkyl, (o- ((o-(substituted by _{alkyl) (alkyl))} _ ₆ alkyl substituted with, 0- ((0- C w alkyl substituted by alkyl)), o - ((o-halogen in substituted with substituted _{(3-alkyl) (6} Aruki Le), 0- (substituted with 0H (^ alkyl), 0- ((0- (substituted with 0H a C ₂ - ₆ Arukiru)) In substituted ₍₆ alkyl), 0- (N (substituted by C ₂ _ ₃ alkyl) ₂ substituted with 0H ₍₆ § alkyl), C _M alkyl substituted with 0- (CN), 0 - (C _M Aruki Le substituted with Okiso group), 0 - (C _H alkyl substituted with C00H), 0- _ ₆ alkyl substituted with (COOO e alkyl)), substituted with 0- (C0Nh ₂ Alkyl), 0- (alkyl substituted with S0 ₂ NH ₂ ), 0- (CONOs alkyl) ₂ substituted ( ₆ alkyl) and 0-CH (_ ₂ alkyl substituted with 0H) Selected from the group consisting of ₂ ,

Substituent Y is halogen, alkyl, 0H, methoxy, selected from the group consisting of CN and CF _3. )

Or a pharmaceutically acceptable salt thereof.

(2) the substituent X is - substituted with C00H - ₆ alkyl, - substituted with C0Nh ₂ a t ₆ alkyl le, 0- ((0- ₆₎ alkyl substituted with) and 0 - in (0H substituted C ₂ _ ₆ § [0302227] The cyclic amine compound or the pharmaceutically acceptable salt thereof according to the above (1), which is selected from the group consisting of:

 (3) The cyclic amine compound or the pharmaceutically acceptable salt thereof according to the above (2), wherein the substituent Y is selected from the group consisting of F, Cl, 0H, methyl and CN.

 (4) A pharmaceutical composition comprising, as an active ingredient, the cyclic amine compound according to any one of (1) to (3) or a pharmaceutically acceptable salt thereof.

 (5) A CCR3 inhibitor comprising, as an active ingredient, the cyclic amine compound or the pharmaceutically acceptable salt thereof according to any of (1) to (3).

 (6) A therapeutic drug for an inflammatory disease, comprising as an active ingredient the cyclic amine compound or the pharmaceutically acceptable salt thereof according to any of (1) to (3).

 (7) A therapeutic drug for a disease derived from inflammatory cell infiltration, comprising as an active ingredient the cyclic amine compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (3).

 (8) A therapeutic agent for a disease derived from eosinophil infiltration, comprising as an active ingredient the cyclic amine compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (3) as described above. The cyclic amine compound of the present invention is represented by the above formula 1.

 In the above formula 1, the aryl group represented by A represents an aryl group having 6 to 14 carbon atoms, preferably a monocyclic or bicyclic aryl having 6 to 10 carbon atoms, and more preferably a phenyl group.

The heterocyclic group represented by A is a 4- to 14-membered monocyclic to tricyclic heterocyclic group having 1 to 4 heteroatoms selected from 0, S and N, and a saturated ring. , An aromatic ring, and a partially hydrogenated ring group thereof. For example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, benzimidazolyl, pyrrolyl, pyrrolidinyl, chenyl, furyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolyl, isoquinolyl, isoquinolyl, isoquinolyl Quinazolinyl, quinoxalinyl, phthalazinyl, piperidyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, morpholinyl, indolyl, isoindolyl, indolinyl, indazolyl, tetra 03 02227 Hydrobenzoimidazolyl, chromanyl, chromonyl (4-oxo-4H-tobenzopyranyl), benzimidazolonyl (2,3-dihydro-2-oxobenzimidazolyl). The heterocyclic group is preferably an unsaturated heterocyclic group, more preferably pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, benzimidazolyl, pyrazolyl, indolyl, and indazolyl.

 The cycloalkyl group represented by A represents, for example, a cyclic alkyl group having 3 to 10 carbon atoms, preferably 5 to 8 carbon atoms, more preferably cyclohexyl, cycloheptyl and cyclooctyl.

In the present specification, “halogen” represents F, CL Br and I. The term "alkyl" may be linear or branched, as a "_ ₆ alkyl", for example methyl, E chill, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, I Sopenchiru, neopentyl, Hexyl and the like, "[;! _ ₃ alkyl" is an alkyl group having 1 to 3 carbon atoms of the above-mentioned "CH alkyl", and "C _M alkyl" is the above-mentioned "(V ₆ alkyl) . among them, an alkyl group having 2 to 6 carbon atoms, - the term "C _{2 3} alkyl" rc, _ ₆ alkyl "of, refers to an alkyl group having 2 to 3 carbon atoms" (: Bok ₆ alkyl " Preferably ( ₃ alkyl, more preferably methyl.

`` Halogen-substituted ( ₃ alkyl) '' is one or more halogen, preferably F-substituted ( ₃ alkyl, such as fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, and the like, Preferably, it is trifluoromethyl.

 In the above formula 1, the aryl group, heterocyclic group and cycloalkyl group represented by A may have at least one substituent X and may further have at least one substituent Y.

Substituent X is substituted with 0H ₍₆ alkyl, (0 (as substitution with C ₂ _ ₆ alkyl)) substituted with 0H ₍₆ alkyl, - CH alkyl substituted with C00H, - C00 O ₆ alkyl) in replacement alkyl, - C0Nh alkyl substituted with _2, - C0N O ₃ alkyl) ₂ in replacement has been _ ₆ alkyl, - NHC0 0 ₃ alkyl) _alkyl substituted with, (0 - substituted with (substituted with _(alkyl) C00H) ₍₆ alkyl, (ο- ιοο Β alkyl) C _H alkyl substituted with)) CH alkyl substituted with, (0- ((0- (V ₆ alkyl) Has been ₍₆ alkyl)) C _M alkyl substituted with 0 - in substituted with ((0 _ ₆ alkyl) _(alkyl), o- ((substituted with o- halogen _(3-alkyl) substituted ₍₆ Al kill), 0 - (C substituted by 0H ₂ - ₆ alkyl), 0 - ((0- (substituted by alkyl)) substituted with 0H ₍₆ alkyl), 0- (N (substituted by C ₂ _ ₃ alkyl) ₂ substituted with 0H ₍₆ alkyl), 0- (substituted with CN ₍₆ alkyl), substituted with 0 (Okiso group ₍₆ Al kill ), 0 (substituted with C00H ₍₆ alkyl), 0- (C00 ((substituted with V ₆ alkyl) - ₆ alkyl), 0- (CH alkyl substituted with C0Nh _2), 0_ (S0 ₂ is substituted with NH _{2 (6} Al kill), selected from 0- (CON 0 ₃₎ alkyl substituted with ₂₎ and 0-CH (been _ ₂ alkyl) group consisting of _{2-substituted} with 0H. 2 or more substituents X Case, these may be the same or different.

As the substituent X '_ ₆ alkyl substituted with 0H "is preferably cyclohexyl hydroxy methylation, hydroxy E chill, hydroxypropyl, hydroxybutyl, hydroxy pentyl, hydroxy.

Substituent X as the "(0- (C ₂ _ ₆ alkyl substituted with 0H)) _ ₆ alkyl mud substituted with carboxymethyl-butoxymethyl, hydroxypentyl Ruo carboxymethyl, carboxymethyl Ruokishimechiru to hydroxy, hydroxyethoxy E chill, Hydroxypropoxyshetyl, hydroxybutoxyl, hydroxypentyloxethyl, hydroxyhexoxyl, hydroxyethoxypropyl, hydroxypropoxypropyl

ロキシプロポキシ プチル、 ヒドロキシブ卜キシブチル、 ヒ ヒド Π キシへキシルォキシブチル、 ヒド ヒドロキシプロポキ シペンチル、 ヒドロキシブトキシペンチル、 ヒ , Hydroxybutyl pill, hydroxyhexyloxy

Roxypropoxybutyl, hydroxybutoxybutyl, hydroxyhexyloxybutyl, hydroxypropoxypentyl, hydroxybutoxypentyl,

, Hexyl-hydroxy O carboxymethyl pentyl, hexyl hydroxy E butoxy, hexyl hydroxy Shipuropokishi, hexyl hydroxybutoxy, as hydroxypentyl Ruo key substituents X "- substituted with C00H ₍₆ alkyl" preferably Karupokishi methyl , Lipoxoxytil, carboxypropyl, carboxybutyl, Cipentyl and lipoxyhexyl.

 The “alkyl substituted with —COO Os alkyl) as the substituent X is preferably methoxycarbonylmethyl, methoxycarbonylmethyl, propoxycarbonylmethyl, butoxycarbonylmethyl, pentyloxycarbonylmethyl, hexyl Oxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl, propoxylponylethyl, butoxycarbonylethyl, pentyloxycarbonylethyl, hexyloxycarbonylethyl, methoxycarbonylpropyl, ethoxycarbonylpropyl, propoxycarbonylpropyl, butoxy Xycarbonylpropyl, pentyloxycarbonylpropyl, hexyloxycarbonylpropyl, methoxycarbonylbutyl, ethoxycarbonylbutyl, Ropoxycarbonylbutyl, butoxycarbonylbutyl, pentyloxyponylbutyl, hexoxyloxylponylbutyl, methoxycarbonylpentyl, ethoxycarbonylpentyl, propoxycarbonylpentyl, butoxycarbonylpentyl, pentyloxycarbonylpentyl, hexyloxycarbyl Nylpentyl, methoxycarbonylhexyl, ethoxycarbonylhexyl, propoxycarbonylhexyl, butoxycarbonylhexyl, pentyloxycarbonyl hexyl, and hexylcarbonylcarbonylhexyl.

As the substituent X "- substituted with C0Nh _{2 (6} alkyl" is preferably cyclohexyl are Karubamo Irumechiru force Rubamoiruechiru force Luba moil propyl, force Rubamoirubuchiru force Luba moil pentyl, to force Rubamoiru.

“-C0N ((V ₃ alkyl) ₂ -substituted ( ₆ alkyl)” as a substituent X is preferably <dimethylcarbamoylmethyl, getylcarbamoylmethyl, dipropyl-capable rubamoylmethyl, dimethylcarbamoylethyl, dimethylcarbamoyl Ethyl, dipropyl carbamoyl propyl, dimethyl carbamoyl propyl, getyl carbamoyl propyl, dipropyl rubamoyl propyl, dimethyl carbamoyl butyl, getyl carbamoyl butyl, dipropyl carb amoyl butyl, dimethyl dimethyl carbamoyl pentyl, dipropyl carbamo getyl carbamoyl hexyl Dipropyl potash is rubamoylhexyl. As PT / JP03 / 02227 substituents x "- _ ₆ alkyl substituted with dish co ₃ alkyl)" refers preferably <is § cetyl aminomethyl, propionylaminomethyl, Petit Lil aminomethyl, § cetyl aminoethyl, Propionylaminoethyl, butyrylaminoethyl, acetylaminopropyl, propionylaminopropyl, propylylaminopropyl, acetylaminobutyl, propionylaminobutyl, petyrylaminobutyl, acetylaminopentyl, propionylamino Pentyl, butyrylaminopentyl, acetylaminohexyl, propionylaminohexyl, and butyrylaminohexyl.

As a substituent X '(0 (_ ₆ alkyl Le substituted with substituted _(alkyl)) in C00H "preferably carboxymethyl methoxymethyl, carboxymethyl ethoxymethyl, force Lupo carboxymethyl Provo carboxymethyl, carboxyethyl butoxy Methyl, carboxypentyloxymethyl, carboxyhexyloxymethyl, carboxymethoxyethyl, carbyl, carboxypentyloxethyl, carboxyhexyloxyshetyl, carboxymethoxypropyl, carboxyethoxy Propyl, carboxypropoxypropyl, carboxybutoxypropyl, carboxypentyloxypropyl, carboxyhexyloxypropyl, carboxymethoxybutyl, carboxyethoxybutyl, carboxypropoxybutyl, carboxybutoxybutyl, Rupoxypentyloxybutyl, carboxyhexyloxybutyl, carboxyl, carboxyptoxypentyl, carboxypentyloxypentyl, propyloxyhexyloxypentyl, propyloxymethoxyhexyl, propyloxytoxy Hexyl, carboxypropoxyhexyl, carboxybutoxyhexyl, hexoxypentyloxyhexyl, hexoxyhexyloxyhexyl, and substituted with “(0- (COO α ₆ alkyl)” as the substituent X. ₍₆ alkyl)) _ ₆ alkyl substituted with "preferably methoxycarbonyl methoxymethyl, methoxycarbonyl ethoxymethyl, methoxycarbonylmethyl Provo carboxymethyl, main Bok Kishika Lupo sulfonyl-butoxymethyl, methoxy carbonylation Le pliers Ruo carboxymethyl , Metoki Hexyl O carboxymethyl into force Lupo two Le, methoxycarbonyl ethoxy E chill, methoxide Methoxycarbonylpropoxyshetyl, methoxycarboxybutoxyl, methoxycarbonyldipentoxyl, methoxycarboxylhexoxyl, methoxycarbonyloxypropyl, methoxycarbonylpropoxypropyl, methoxycarbonyl Butoxypropyl, methoxycarbonylpentyloxypropyl Mouth pill, methoxycarbonylhexyloxypropyl, methoxycarbonylethoxybutyl, methoxycarbonylpropoxybutyl, methoxycarbonylbutoxybutyl, methoxycarbonylpentyloxy Xybutyl, methoxycarbonylhexyloxybutyl, methoxycarbonylethoxypentyl, methoxycarbonylpropoxypentyl, methoxycarbonylbutoxypentyl, methoxycarbonyl Cicarbonylethoxyhexyl, methoxycarbonylpropoxyhexyl, methoxycarbonylbutoxyhexyl, methoxycarboxylpentyloxyhexyl, methoxycarbonylhexyloxyhexyl, ethoxycarponylmethoxymethyl, propoxylmethoxylmethyl, butoxy Carbonylmethoxymethyl, pentyloxycarbonylmethoxymethyl, hexoxyloxylponylmethoxymethyl, ethoxycarbonylethoxymethyl, ethoxycarbonylpropoxymethyl, X-ethoxycarbonylbutoxymethyl, propoxycarbonylethoxymethyl, butoxycarbonylethoxymethyl, pentyloxy Carbonyloxyxethyl, hexyloxycarponyl ethoxyxyl.

The “_ ₆ alkyl substituted with (0- (CH alkyl substituted with (OC B alkyl)))” as the substituent X is preferably methoxymethoxymethyl, methoxyethoxymethyl, methoxypropoxymethyl. , Methoxybutoxymethyl, methoxypentyloxymethyl, methoxyhexyloxymethyl, methoxymethoxyl, methoxyethoxyl, methoxypropoxyl, methoxybutoxyl, methoxypentoxyl, methoxyl Xyloxyshethyl, methoxymethoxypropyl, methoxyethoxypropyl, methoxypropoxypropyl, methoxybutoxypropyl, methoxypentyloxypropyl, methoxyhexyloxypropyl, methoxymethoxybutyl, methoxyethoxybutyl, methoxypro Boxybutyl, methoxybutoxybutyl, methoxypentyloxybutyl, methoxy ', Methoxymethoxypentyl,

Methoxypropoxypentyl, methoxybutoxypentyl, methoxypentyloxypentyl, methoxyhexyloxypentyl, methoxymethoxyhexyl

Ethoxymethoxymethyl, ethoxyethoxymethyl, propoxyethoxymethyl, butoxyethoxymethyl, pentyloxyethoxymethyl, hexyloxyshethoxymethyl, ethoxymethoxyethyl, ethoxyethoxyshethyl, ethoxypropoxymethyl, ethoxybutoxymethyl Ethoxypentyloxymethyl, ethoxyhexyloxymethyl, ethoxypropoxyshetyl, propoxyethoxyl, propoxypropoxyl, and propoxybutoxyl. As the substituent X '0- ((OC H alkyl) substituted with _(alkyl) "is rather preferably the methoxymethoxy, E Bok Kishimetokishi, Purobokishime Bok alkoxy, Butokishime Bok alkoxy, pliers Ruo carboxymethyl methoxy, to Xyloxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, butoxyshethoxy, pentyloxyshethoxy, hexyloxyethoxy, methoxypropoxy, ethoxypropoxy, propoxypropoxy, butoxypropoxy, pentyloxypropoxy, hexyl Oxypropoxy, methoxybutoxy, X toxic butoxy, propoxybutoxy, butoxybutoxy, pentyloxybutoxy, hexyloxybutoxy, methoxypentyloxy, ethoxypentyloxy, propoxypentyloxy Butoxypentyloxy, pentyloxypentyloxy, hexyloxypentyloxy, methoxyhexyl, ethoxyhexyloxy, propoxyhexyloxy, butoxyhexyloxy, pentyloxyhexyloxy, hexyloxyhexyloxy. .

“0- (t ₆ alkyl substituted with (alkyl substituted with 0-halogen))” as the substituent X is preferably trifluoromethoxymethoxy, trifluoromethoxymethoxy, trifluoromethoxypropyl, Methoxy, trifluoromethoxybutoxy, trifluoromethoxypentyloxy and trifluoromethoxyhexyloxy. As the substituent X '0- (C ₂ _ ₆ alkyl substituted with OH) "is preferably Kishiruokishi is hydroxy Shietokishi, hydroxy Provo, hydroxy butoxy, hydroxypentyl Okishi, the hydroxy.

As the substituent X _{'0- ((0- (C 2 _} 6 alkyl substituted with 0H)) CH substituted by; al kill) "preferably hydroxyethoxy methoxy, hydroxy Provo Kishime Bok, hydroxy Butoxymethoxy, hydroxypentyloxymethoxy, hydroxypoxyethoxy, hydroxybutoxyethoxy, hydroxypentyloxyethoxy, hydroxyhexylethoxyethoxy, hydroxyethoxypropoxy, hydroxypropoxypropoxy, hydroxybutoxypropoxy, hydroxy. Hydroxypropoxy, hydroxyhexyloxypropoxy, hydroxyethoxybutoxy, hydroxypropoxybutoxy, hydroxybutoxybutoxy

Roxybutoxypentyloxy, hydroxypentyloxypentyloxy, hydroxypropoxyhexyloxy, hydroxybutoxyhexyloxy, hydroxypentyloxyhexyloxy, and hydroxyhexyloxyhexyloxy.

As the substituent X '0- (N (C substituted by 0H ₂ - ₃ alkyl) CH alkyl Le substituted by ₂₎ "preferably bis (hydroxymethyl E chill) amino methoxy, bis (hydroxypropyl) Aminomethoxy, bis (hydroxyethyl) aminoethoxy, bis (hydroxypropyl) aminoethoxy, bis (hydroxyethyl) aminopropoxy, bis (hydroxypropyl) aminopropoxy, bis (hydroxyethyl) aminobutoxy, bis (hydroxy) Propyl) aminobutoxy, bis (hydroxyethyl) aminopentyloxy, bis (hydroxypropyl) aminopentyloxy, bis (hydroxyethyl) aminohexyloxy, and bis (hydroxypropyl) aminohexyloxy.

“0-(_ ₆ alkyl substituted with CN)” as the substituent X is preferably a cyanome / 02227 Toxi, cyanoethoxy, cyanopropoxy, cyanobutoxy, cyanopentyloxy, cyanohexyloxy.

“0-(_ ₆ alkyl substituted with an oxo group)” as the substituent X is preferably methoxy substituted with an oxo group, ethoxy substituted with an oxo group, propoxy substituted with an oxo group, or oxo. A butoxy substituted with an oxo group, a pentyloxy substituted with an oxo group, and a hexyloxy substituted with an oxo group.

As the substituent X "0_ (substituted with C00H ₍₆ alkyl)" is preferably Kishiruokishi is carbo Kishimetokishi, Cal Po ethoxy, Cal Po carboxymethyl Provo carboxymethyl force Rupokishibutoki shea, carboxypentyl Ruo alkoxy, to carboxy.

As the substituent X '0- (C00 ((substituted with V ₆ alkyl) _(alkyl) "is favored properly methoxy Cal Poni Le methoxy, ethoxy Cal Poni Le methoxy, Purobokishi carbonyl methoxy, butoxide deer Lupo methoxy, pliers Ruo carboxymethyl Cal Poni Le Methoxy, hexyloxyl-proponylmethoxy, methoxycarbonylethoxy,

X ethoxycarbonylethoxy, propoxycarbonylethoxy, butoxycarbonylethoxy, pentyl xycarbonyloxy, hexoxycarbonylethoxy, methoxycarbonylpropoxy, ethoxycarbonylpropoxy, propoxycarbonylpropoxy, butoxycarbonyl Proboxy, Pentyloxycarbonylpropoxy, Hexyloxycarbonylpropoxy, Methoxycarponylbutoxy, Ethoxycarponylbutoxy, Propoxycarponylbutoxy, Butoxycarponylbutoxy, Pentyloxycarbonylbutoxy, Hexyloxycarbonylbutoxy, Methoxycarboxylpentyloxy Ponyl pentyloxy, propoxycarbonyl pentyloxy, butoxycarbo Lepentyloxy, pentyloxycarbonylpentyloxy, hexyloxycarboxylpentyloxy, methoxycarboxyhexyloxy, ethoxyloxyloxyloxy, propoxycarboxylhexyloxy, butoxycarbonylhexyloxy, pentyloxyloxyloxy And hexyloxycarponyl hexyloxy.

“0-(_ ₆ alkyl substituted with C0NH ₂ )” as the substituent X is preferably rubamoylmethoxy, rubamoylethoxy, Ruptoxy, carbamoylpentyloxy, carbamoylhexyloxy, “alkyl substituted with 0-0 ^” as the substituent X is preferably sulfamoylmethoxy, sulfamoylethoxy, sulfamoylpropoxy. , Suroxy.

“0- (C0N (( ₆ alkyl) substituted with (V ₃ alkyl) ₂ )” as the substituent X is preferably dimethylcarbamoylmethoxy, getylcarbamoylmethoxy, dimethylcarbamoylmethoxy, dimethylcarbamoylethoxy. , Getyl carbamoyl, getyl carbamoyl propoxy, dipropyl carbamoyl propoxy, dimethyl carbamoyl butoxy, dimethyl carbamoyl butoxy, dipropyl propyl rubamoyl butoxy, dimethyl carbamoyl pentyloxy, dimethyl carbamoyl pentyl oxy, dipropyl propyl rubamoyl Pentyloxy, dimethyl carb

 'Oxy, dipropylcal

^: Yes.

“0-CH (C ₂ alkyl substituted with 0H) ₂ ” as the substituent X is preferably bis (hydroxymethyl) methoxy, bis (hydroxyethyl) methoxy.

Examples of the substituent X include, in particular, lipoxymethyl, lipoxyxetil, lipoxypoxy pill, carboxybutyl, carboxypentyl, carboxyhexyl, lipamoyl methyl, lipamoylethyl, lipamoylpropyl, lipamoylbutyl, lipamoylpentyl, Powerbamoylhexyl, methoxymethoxy, ethoxymethoxy, propoxymethoxy, butoxymethoxy, pentyloxymethoxy, hexoxymethoxy, methoxyxoxy, ethoxyethoxy, propoxyethoxy, butoxyxoxy, pentyloxyx Ethoxy, hexoxyloxy, methoxypropoxy, ethoxypropoxy, propoxypropoxy, butoxypropoxy, pentyloxypropoxy, hexoxypropoxy, Toki Shipu Bok alkoxy, E WINCH Kishibu Bok alkoxy, Puropokishipu Bok alkoxy, blanking Bok Kishibu Bok alkoxy, pen Chiruokishibu Bok alkoxy, hexyl O carboxymethyl butoxy, main Bok carboxymethyl pliers Ruo alkoxy; eth Xypentyloxy, propoxypentyloxy, butoxypentyloxy, pentoxypentyloxy, hexyloxypentyloxy, methoxyhexyloxy, ethoxyhexyloxy, propoxyhexyloxy, butoxyhexyl hydroxy Ethoxy, hydroxypropoxy, hydroxybutoxy, hydroxypentyloxy and hydroxyhexyloxy are preferred.

Substituent Y is a halogen, ₍₃ alkyl, 0H, methoxy barrel selected from the group consisting of CN and CF _3. Substituents if group there are two or more Y, these are as substituent Y which be the same or different Halogen is preferably F, C1 ( ₃ alkyl as substituent Y is preferably methyl, tyl, propyl.

 As the substituent Y, F, Cl, 0H, methyl and CN are particularly preferred.

 Specific compounds of the present invention include, for example, the compounds shown in Table 1.

 table 1

以下に式 1で示される化合物等 （以下、 例えば 「式 1等で示される化合物」 等を 単に 「式 1」 等のように表すことがある） の製造法を示すが、 各化合物の製造法は

The method for producing the compound represented by Formula 1 and the like (hereinafter, for example, “the compound represented by Formula 1 and the like” may be simply represented as “Formula 1” and the like) is described below. Is

However, it is not limited to them. In various production methods, reaction conditions are appropriately selected from those described below.

When the amine compound used in the present invention has one or more asymmetric carbon atoms, racemic forms, diastereoisomers and individual optical isomers can exist, but the present invention uses all of them. be able to. Equation 1 becomes Equation 2

Is reacted with 4-nitrophenyl chloroformate and phenyl chloroformate in a solvent such as acetonitrile-dichloromethane in the presence of a base such as sodium bicarbonate and tertiary amine (first step), and then I, liethylamine, diisopropyl In the presence or absence of tertiary amines such as ethylamine, DBU (1,8-diazavic mouth [5.4.0] -7-indene), substituted arylamine, substituted heterocyclic amine, substituted cyclopentylamine It can be produced by reacting with a corresponding amine, such as amine, substituted cyclohexylamine, substituted cycloheptylamine, or substituted cyclooctylamine (second step). The amount of 4-ditrophenylchloroformate-phenylphenylformate used in the first step of the present production method is not particularly limited, but is usually about 1 to 5 equivalents to the formula 2. The amount of the base used in the first step, such as sodium hydrogencarbonate and tertiary amine, is not particularly limited, but is usually 1 to 4 parts by weight of 4-nitrophenyl chloroformate to phenyl chloroformate. Equivalent to about 20 equivalents. The amount of the tertiary amine used in the second step is not particularly limited, but is usually about 1 to 20 equivalents to the formula 2. The reaction temperature of the first-stage formula 2 with 4-nitrophenyl chloroformate-phenyl chloroformate is not particularly limited, but is about 0 ° C. to room temperature, and the reaction temperature of the second step is 4-nitrophenyl chloroformate. In this case, the temperature is usually about 0 ° C. to 50 ° C., and in the case of phenyl chloroformate, it is about room temperature to about the heating reflux temperature.

 In addition, in a solvent such as acetonitrile-dichloromethane, in the presence of a base such as sodium bicarbonate or tertiary amamine, substituted arylamine, substituted heterocyclic amine, substituted cyclopentylamine, substituted cyclohexylamine, substituted cycloheptylamine, substituted After reacting the corresponding amine, such as cyclooctylamine, with 4-ditrophenyl chloroformate, phenyl chloroformate, etc. (first step), in the presence of tertiary amines, such as triethylamine, diisopropylethylamine, DBU, or It can also be produced by reacting with Formula 2 in the absence (second stage). The amount of 4-nitrophenyl chloroformate used in the first step of the present production method is not particularly limited, but is usually, substituted arylamine, substituted heterocyclic amine, substituted cyclopentylamine, substituted cyclohexylamine, It is about 1 to 5 equivalents to the substituted cycloheptylamine and the substituted cyclooctylamine. The amount of the base such as sodium hydrogencarbonate and tertiary amine used in the first step of the present production method is not particularly limited, but is usually 1 to 20 equivalents based on 4-nitrophenyl chloroformate and phenyl chloroformate. It is about. The amount of the tertiary amine used in the second step is not particularly limited, but is usually a substituted arylamine, a substituted heterocyclic amine, a substituted cyclopentylamine, a substituted cyclohexylamine, a substituted cycloheptylamine, a substituted cyclooctyl. It is about 1 to 20 equivalents to the amine. Amines such as substituted arylamines, substituted heterocyclic amines, substituted cyclopentylamines, substituted cyclohexylamines, substituted cycloheptylamines, substituted cyclooctylamines, etc. in the first step, and chloroformate 4-nitrophenyl chloroformate The reaction temperature with phenyl is not particularly limited, but is about 0 ° C. to room temperature.The reaction temperature of the second step is usually about 0 ° C. to 50 ° C. for 4-nitrophenyl chloroformate. In the case of chloroformate, the temperature is from room temperature to the heating reflux temperature.

In addition, formula 2 is converted to dichloromethane, chloroform, tetrahydrofuran, and acetonitrile. In solvents such as ril, usually 0.5 to 2.0 equivalents of diphosgene, triphosgene, 1,1-potassyldiimidazole, 1, tricarponylbisbenzotriazole, N, N-disuccinimide After treatment with zircarbonate, bis (4-nitrophenyl carbonate), etc., substituted arylamine, substituted heterocyclicamine, substituted cyclopentylamine, substituted cyclohexylamine, substituted cycloheptylamine, substituted cyclooctyl It can also be produced by reacting with a corresponding amine such as an amine. The ratio (mol ratio) of Formula 2 to the substituted arylamine, substituted heterocyclicamine, substituted cyclopentylamine, substituted cyclohexylamine, substituted cycloheptylamine, or substituted cyclooctylamine is not particularly limited, but is usually The reaction is performed at a temperature of about 0 ° (about 50 ° C) for about 1 to 24 hours.

 In addition, the corresponding amines such as substituted arylamine, substituted heterocyclicamine, substituted cyclopentylamine, substituted cyclohexylamine, substituted cycloheptylamine, substituted cyclooctylamine, and the like can be dissolved in a solvent such as dichloromethane, chloroform, tetrahydrofuran, and acetonitrile. Normally 0.5 to 2.0 equivalents of diphosgene, triphosgene, 1,1-potassyldiimidazole, 1,1-carbonylbisbenzotriazole, N, N-disuccinimidyl , Bis (4-nitrophenol-one), etc., and then reacting with formula 2. The ratio (molar ratio) between the substituted arylamine, the substituted heterocyclic amine, the substituted cyclopentylamine, the substituted cyclohexylamine, the substituted cycloheptylamine, the substituted cyclooctylamine and the formula 2 is not particularly limited. : 1 to 1: 2. Usually, the reaction is carried out at 0 ° (at a temperature of about 50) for about 1 to 24 hours.

Furthermore, in a solvent such as acetone, tetrahydrofuran, and toluene, in the presence or absence of a tertiary amine such as triethylamine, diisopropylethylamine, and DBU, substituted arylalkyl carboxylic acid, substituted heterocyclic carboxylic acid, and substituted cyclopentyl carboxyl. Acid and substituted cyclohexyl carboxylic acid, substituted cycloheptyl carboxylic acid, substituted cyclooctyl carboxylic acid, etc. and the corresponding carboxylic acids with ethyl ethyl formate, etc. (first stage) It can also be produced by reacting sodium azide, diphenylphosphoryl azide and the like (second step), heating the resulting azide to form an isocyanate, and then reacting with isocyanate 2 (third step). First stage of the manufacturing method The amount of ethyl chloroformate used for the above is not particularly limited, but is usually a substituted aryl carboxylic acid, a substituted heterocyclic carboxylic acid, a substituted cyclopentyl carboxylic acid, a substituted cyclohexyl carboxylic acid, a substituted cycloheptyl carboxylic acid, It is about 1 to 2 equivalents to cyclooctylcarboxylic acid. The amount of the base such as tertiary amine used in the first step of the present production method is not particularly limited, but is usually about 1 equivalent to 20 equivalents to ethyl chloroformate. The amount of sodium azide and diphenylphosphoryl azide used in the second step is not particularly limited, but is usually a substituted aryl alcohol, a substituted heterocyclic carboxylic acid, a substituted cyclopentyl carboxylic acid, a substituted cycle hexyl carboxylic acid. It is about 1 to 10 equivalents to the substituted cycloheptyl carboxylic acid and the substituted cyclooctyl carboxylic acid. The amount of Formula 2 used in the third step is not particularly limited, but is usually a substituted aryl carboxylic acid, a substituted heterocyclic carboxylic acid, a substituted cyclopentyl carboxylic acid, a substituted cyclohexyl carboxylic acid, a substituted cyclo heptyl carboxylic acid. It is about 1 to 5 equivalents to the acid and substituted cyclooctylcarboxylic acid. Step 1 Reaction of substituted aryl carboxylic acid, substituted heterocyclic carboxylic acid, substituted cyclopentyl carboxylic acid, substituted cyclohexyl carboxylic acid, substituted cycloheptyl carboxylic acid, substituted cyclooctyl carboxylic acid with ethyl chloroformate The temperature is not particularly limited, but is about 0 ° C to room temperature.The reaction temperature of the second step with sodium azide and diphenylphosphoryl azide is usually about 0 ° C to room temperature, and the third step The reaction temperature of the isocyanate-forming reaction is usually from room temperature to about 150 ° C.

Formula 1 can also be produced by the following steps.

Four

(In the formula, represents a protecting group for a nitrogen atom, and A has the same meaning as described above.)

In the above formula, represents a nitrogen atom protecting group, the type of the protecting group, and the introduction thereof The method is described, for example, in Greene and Wuts, Protec tive Groups in Organic Synthes is (Third Edition). What is necessary is just to carry out suitably according to these reaction conditions.

 Step 1 is a step of producing urea. After reacting formula 3 with 4-ditrophenyl chloroformate or phenyl chloroformate in a solvent such as acetonitrile-dichloromethane in the presence of a base such as sodium bicarbonate or tertiary amine (first step), triethylamine置換 Substituted arylamine, substituted heterocyclicamine, substituted cyclopentylamine, substituted cyclohexylamine, substituted cycloheptylamine, substituted cyclooctylamine in the presence or absence of a tertiary amine such as diisopropylethylamine or DBU It can be produced by reacting with the corresponding amine (step 2). The amount of 4-ditrophenylchloroformate-chloroformate used in the first step of the production method is not particularly limited, but is usually about 1 to 5 equivalents to the formula 3. The amount of the base such as sodium bicarbonate tertiary amine used in the first step is not particularly limited, but is usually about 1 to 20 equivalents to 4-nitrophenyl chloroformate to phenyl chloroformate. The amount of the tertiary amine used in the second step is not particularly limited, but is usually about 1 to 20 equivalents based on the formula 3. The reaction temperature of the first-stage formula 3 with 4-nitrophenyl chloroformate-phenylphenyl chloroformate is not particularly limited, but is about 0 ° C. to room temperature, and the reaction temperature of the second step is the reaction temperature of 4_nitrophenyl chloroformate. In this case, the temperature is usually about 0 ° C. to 50 ° C., and in the case of phenyl chloroformate, it is about room temperature to about the heating reflux temperature.

 Step 2 is a step of removing a protecting group for a nitrogen atom. The removal method is described in the above-mentioned rProtective Groups in Organic Synthesis (third edition). What is necessary is just to carry out suitably according to these reaction conditions.

Step 3 is a step of condensing Formula 5 and Formula 6. Reaction of Formula 5 with Formula 6 in a solvent such as acetonitrile, dimethylformamide, or dichloromethane in the presence of a tertiary amine such as triethylamine diisopropylethylamine or a base such as carbon dioxide or sodium bicarbonate. It can be manufactured by Although the reaction of Formulas 5 and 6 is not particularly limited, it can be usually carried out by reacting at a temperature of about 0 ° C to 80 ° C for about 1 hour to 24 hours. The mixing ratio (molar ratio) of Formula 5 and Formula 6 is not particularly limited. However, it is usually about 3: 1 to 1: 3, and the amount of the tertiary amine or base is not particularly limited, but is usually about 1 to 20 equivalents to the formula 5.

 Formula 2 can be manufactured by the following steps.

工程 2

Process 2

(In the formula, P ₂ represents a protecting group for a nitrogen atom.)

P ₂ in the above formula represents a protecting group for a nitrogen atom, and the type of the protecting group and the method of introducing it are described in, for example, “Protective Group in Greene and Wuts”. Organic Synthes is (3rd edition) ". What is necessary is just to carry out suitably according to these reaction conditions.

Step 1 is a step of condensing Formula 7 and Formula 6. Reaction of Formula 7 with Formula 6 in a solvent such as acetonitrile, dimethylformamide, or dichloromethane in the presence of a tertiary amine such as triethylamine / diisopropylethylamine, or a base such as carbon dioxide or sodium bicarbonate. It can be manufactured by Although the reaction of the formulas 7 and 6 is not particularly limited, it can be usually performed by reacting at a temperature of about 0T to about 80T for about 1 hour to 24 hours. The mixing ratio (molar ratio) of Formula 7 and Formula 6 is not particularly limited, but is usually about 3: 1 to 1: 3, and the amounts of tertiary amine and base are not particularly limited. It is about 1 to 20 equivalents to the formula 7. Step 2 is a step of removing the protective group P ₂ of the nitrogen atoms. The removal method is described in the above-mentioned “Protective Groups in 0 rganic Synthes is (3rd edition).” The method may be appropriately performed according to these reaction conditions.

The reaction product obtained by each of the above production methods is isolated and purified as various solvates such as a free compound, a salt thereof or a hydrate. The salt can be produced by subjecting the salt to a usual salt-forming treatment. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, and various column chromatography.

 Various isomers can be isolated by a conventional method utilizing the physicochemical difference between the isomers. The optical isomers can be separated by a general optical resolution method, for example, fractional crystallization or chromatography. Further, the optical isomer can also be produced using a suitable optically active compound as a raw material.

 Pharmaceutically acceptable salts of the compound represented by Formula 1 include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, boric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, tartaric acid, and succinic acid. Acid addition salts with organic acids such as malic acid, lactic acid, cunic acid, malonic acid, benzoic acid, paratoluenesulfonic acid, and methylsulfonic acid; amino acids such as lysine, glycine, phenylalanine, asparagine, and glutamic acid; And the like. Furthermore, the present invention also includes various hydrates and solvates of the compound of the present invention (Formula 1) and salts thereof.

The cyclic amine compound represented by the formula 1 or a pharmaceutically acceptable salt thereof inhibits the action of chemokines mediated by CCR3, as specifically shown in Examples below. The cyclic amine compound of the present invention or a pharmaceutically acceptable salt thereof can be used for various allergic diseases represented by asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, and chronic sinuses involving CCR3. Inflammation, ulcerative colitis, Crohn's disease, pulmonary aspergillosis, Cyaug-Strauss syndrome, eosinophilia, parasitic infections, self-immune disease, rheumatoid arthritis, nephritis, arteriosclerosis, virus It is useful as a preventive and therapeutic agent for inflammatory diseases such as infectious diseases, bacterial infections, hepatitis, and chronic lung disease.In particular, diseases derived from inflammatory cell infiltration, specifically, asthma and allergic rhinitis , Allergic unilateral conjunctivitis, various allergic diseases represented by atopic dermatitis, chronic sinusitis, ulcerative colitis, Crohn's disease, autoimmune disease, rheumatoid arthritis, Flame, arterial sclerosis, viral infection, bacterial infection, hepatitis, chronic lung disease, prevention of such eosinophilia, are useful as therapeutic agents. Further, the compound of the present invention or a pharmaceutically acceptable salt thereof is represented by a disease derived from eosinophil infiltration, specifically, asthma, allergic rhinitis, allergic conjunctivitis, and atopic dermatitis. As a preventive and therapeutic agent for various allergic diseases, chronic sinusitis, ulcerative colitis, Crohn's disease, eosinophilia, etc. More useful. In addition, it can be used as a prophylactic and therapeutic agent for various diseases involving chemokine via CCR3.

 The inflammatory disease referred to in the present invention refers to a disease in which invasion or injury of a tissue induced as a result of an excessive self-defense reaction causes the onset of symptoms. In addition, the disease derived from inflammatory cell infiltration referred to in the present invention refers to a disease derived from inflammatory cell infiltration among inflammatory diseases, for example, neutrophil, eosinophil, basophil, mast cell It is a disease in which invasion or injury of the tissue is induced as a result of excessive infiltration or accumulation of lymphocytes, macrophages, etc. into the local area. The disease derived from eosinophil infiltration as referred to in the present invention particularly refers to a disease derived from eosinophil infiltration among diseases derived from inflammatory cell infiltration, and a part of inflammatory cells excessively accumulated. It is a disease when is an eosinophil.

 The cyclic amine compound of the present invention or a pharmaceutically acceptable salt thereof is a compound that is particularly excellent in an inhibitory effect on inflammatory cell infiltration. The cyclic amine compound of the present invention inhibits the infiltration of inflammatory cells into the lung using the ovalbumin-induced mouse asthma model.

I Examples 43 and 44 are shown. Compared with the number of inflammatory cell infiltration in animals to which PBS was administered, the number of inflammatory cell infiltration in animals to which the compound of Example 18 which is the cyclic amine compound of the present invention was administered was reduced to half or less. In the asthma model, the cyclic amine compound represented by the general formula (1) is included in the claims of International Publication No. 01 Z878339, but is not specifically disclosed. For example,

) Compound 9)

 It shows an excellent effect as compared with.

Further, the cyclic amine compound of the present invention or a pharmaceutically acceptable salt thereof is a compound having excellent oral absorbability especially in mammals. The results of an oral absorption evaluation test of the cyclic amine compound of the present invention are shown in Example 45. The bioavailability of the compound of Example 10 which is the cyclic amine compound of the present invention is as high as 19%, and the excellent oral absorbability of the cyclic amine compound of the present invention is excellent in this example. You can confirm. The compound represented by the formula 1 or a pharmaceutically acceptable salt thereof is directly used as a powder.

Alternatively, it can be administered orally or parenterally (for example, transdermally, intravenously, rectally, or by inhalation) to mammals as a pharmaceutical composition in a suitable dosage form. Specific examples of dosage forms for administration include tablets, powders, pills, capsules, granules, syrups, solutions, injections, emulsions, suspensions, suppositories, and the like. Such a dosage form is produced by a method known per se and contains various carriers usually used in the field of pharmaceuticals. Examples include excipients, lubricants, binders, disintegrants in solid preparations, solvents, dissolution aids, suspending agents, soothing agents and the like in liquid preparations. If necessary, additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can also be used.

Excipients include, for example, lactose, D-mannitol, starch, sucrose, corn starch, crystalline cellulose, light caffeic anhydride, and the like. Lubricants include, for example, magnesium stearate, calcium stearate, talc, colloidal silicic acid and the like. Examples of the binder include crystalline cellulose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, and sodium carboxymethylcellulose. Disintegrators include, for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylsuccinate sodium, L-hydroxypropylcellulose, and the like. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Examples of the dissolution aid include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalcodium chloride, benzethonium chloride, glyceryl monostearate, and polyvinyl alcohol, Polyvinylpyrrolidone, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcell And hydrophilic polymers such as loin. Examples of the tonicity agent include glucose, sodium chloride, D-sorbitol, D-mannitol and the like. Examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Examples of the soothing agent include benzyl alcohol and the like. Examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Examples of the antioxidant include sulfite, ascorbic acid and the like.

 The cyclic amine compound of the present invention or a pharmaceutically acceptable salt thereof can be used as a medicine. For example, it can be used as a CCR3 inhibitor, specifically as a prophylactic and therapeutic agent for inflammatory diseases, and particularly preferably used for diseases derived from inflammatory cell infiltration, and for eosinophil infiltration. It can be more preferably used for diseases of origin.

 The effective dose and frequency of administration of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof will vary depending on the dosage form, the age and weight of the patient, the nature or severity of the condition to be treated, but is usually adult 1 to 1000 mg, preferably 1 to 300 mg, can be administered once or several times a day.

Each of the above-mentioned dosage forms may contain or be used in combination with other active ingredients for treatment as long as undesired interaction is not caused by compounding with the compound represented by the formula 1 or a salt thereof. For example, steroids, non-steroidal anti-inflammatory drugs, lipoxygenase inhibitors, leukotriene antagonists, bronchodilators, tropoxane synthesis inhibitors, tropoxan antagonists, histamine antagonists, histamine release inhibitors, platelet activating factor (PAF) Antagonists, serotonin antagonists, adenosine receptor antagonists, adrenaline i3 stimulants, immunosuppressants, immunomodulators and the like. This description includes the contents described in the specifications of Japanese Patent Application No. 2000-510900 and Japanese Patent Application No. 2003-200882 which are the basis of the priority of the present application. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited to the following Examples. The method for synthesizing the starting compounds is shown in Reference Examples.

(R)-[[(6-Fluoronaphthalene-2-yl) methyl] pia-lysine-3-ylamine ω

 (R) -3- (tert-butoxycarbonylamino) pyrrolidine (7.8 g), 2-bromomethyl-6-fluoronaphthalene (12 g) and potassium carbonate (6.9 g) were added to acetonitrile (200 ml). The mixture was stirred at room temperature for 5 hours. The reaction solution was filtered, and the filtrate was concentrated. A 10% methanol solution of hydrogen chloride (125 ml) was added to the residue, and the mixture was stirred at 55 ° C for 1 hour and concentrated. The residue was washed with an aqueous solution of potassium carbonate and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography column chromatography for amines (ethyl acetate: methanol = 10: 1) to give (R) -l _ [(6-fluoronaphthalene-2-ifle) methyl] pia lysine-3-ylamine (7.3 g) was obtained as an oil (yield 71%).

MS (m / z): 245 ((M + H) +)

IR (neat): 2959, 2804, 1610, 1577, 1510, 1478 cm " ¹

Ή one NMR (300 negation _{z, CDC1 3) δ:.} .. 1. 40-1 55 (lH, m), 2. 10-2 36 (2H, m), 2. 45-2 55 (1H, m ), 2.68-2.80 (2H, m), 3.45-3.54 (1H, m), 3.72 (1H, d, J = 9.8), 3.77 (1H, d) , J = 9.8), 7.20-7.27 (1H, πι), 7.43 (1H, dd, J-9.9, 2.7), 7.51 (1H, d, J = 8.4), 7.72-7.81 (3H, m).

Reference Example 2 6-Methoxycarbonylmethoxypyridine-2-carboxylate benzyl ester (2) ( ₂₎

Triethylamine (4.2 ml) and benzyl bromide (3.6 ml) were added to a solution of 6-hydroxypicolinic acid (2.8 g) in ethyl acetate (30 ml), and the mixture was heated under reflux for 3 hours. An aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. Dried and concentrated. The obtained solid was washed with ethyl acetate (2.56 g). 1.15 g of this was dissolved in dimethylformamide (10 ml), potassium carbonate (0.90 g) and methyl bromoacetate (0.62 ml) were added, and the mixture was stirred at room temperature overnight. An aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate-1: 1) to give 6-methoxycarbonylmethoxypyridine-2-carboxylate benzyl ester (1.23 g) (yield 45%). .

Ή one NMR (270 negation _{z, CDC1 3) δ: 3.} 70 (3Η, s), 4. 98 (2H, s), 5. 37 (2H, s), 7. 07

(1H, dd, J = 7.6, 1.1.7), 7.28-7.50 (5H, m), 7.67-7.82 (2H, m).

Example 1 11 (R)-卜 [(6-Fluoronaphthalene-2-yl) methyl] pipalysin-3-yl 3--[6- (2-hydroxyethoxy) pyridine-2_ Ill] ゥ rea (3)

To a solution of 6-methoxycarbonylmethyl I, benzyloxybenzene-2-carboxylate (1.21 g) in methanol (12 ml) was added 10% palladium on carbon (50% water, 120 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere. Stirred overnight. The palladium carbon was filtered, and the solvent was distilled off (850 mg). 422 mg of this was dissolved in acetone (2 ml), cooled on ice, and a solution of triethylamine (0.32 ml) and ethyl ethyl chloroformate (0.21 ml) in acetone (2 ml) was added. An aqueous solution (2 ml) of sodium (260 mg) was added. After stirring for 2 hours, toluene was added to the reaction solution for extraction. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was added to benzene heated to 60 ° C and stirred for 1 hour, and then the solvent was distilled off (420 mg). Of these, 200 mg was dissolved in ethyl acetate (5 ml), (R) -tri [(6-fluoronaphthalen-2-yl) methyl] pyrrolidine-3-ylamine (125 mg) was added, and the mixture was stirred at room temperature for one hour. An aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in methanol, sodium borohydride (190 mg) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue is purified by silica gel column chromatography. Purification by filtration (ethyl acetate: methanol = 20: 1) yields i (R) -tri [(6-fluoronaphthalene-2-yl) methyl] pyrrolidine-3-yl 3_ [6- (2- Hydroxyethoxy) pyridine-2-yl] peria (133 mg) was obtained (63% yield).

MS (m / z): 425 (麵) ⁺ ), 423 ((MH)-)

IR (neat): 3257, 2954 , 2810, 1672, 1591, 1549, 1460, 1423, 1228 cm '1 Ή-NMR (300丽_{z, CDC1 3) δ: 1.66-1.82} (1H, m), 2.20-2.33 (1H, m), 2.38-2.5 1 (1H, m), 2.58-2.68 (1H, m), 2.72-2.84 (1H, in), 2.95-3.06 (1H, m), 3.69

(1H, d, J = 12.6), 3.79 (1H, d, J = 12.6), 3.76-3.84 (2H, m), 4.18-4.28 (1H, ni), 4.35-4.46 (1H, m), 4.62- 4.76 (1H, m), 6.27-6.35 (2H, m), 7.20-7.28

(1H, m), 7.39-7.54 (3H, m), 7.71-7.81 (3H, m), 8.38 (1H, br s), 9.31 (1H, d, J = 8.7).

Reference Example 3 (3_Nitropyridine-2-hydroxy) acetic acid methyl ester (4)

(Four)

 2-Hydroxy-3-nitropyridine (1.40 g) was dissolved in dimethylformamide (15 ml), potassium carbonate (1.8 g) and methyl bromoacetate (1.23 ml) were added, and the mixture was stirred at room temperature for 4 hours. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. When the precipitated solid was washed with ethyl acetate, methyl (3-ditropyridine-2-hydroxy) acetate (680 mg) was obtained (yield: 32%).

 Ή-NMR (300 t z, CDCI3) δ: 3.82 (3Η, s), 4.78 (2H, s), 6.38 (1H, dd, J = 7.9, 7.2), 7.64 (1H, dd, J = 7.2) , 2.0), 8.40 (1H, dd, J = 7.9, 2.0).

Example 2 1-l (R) _1-[(6-Fluoronaphthalene-2-yl) methyl] pyrrolidine-3-yl 1-3-3- [2- (2-hydroxyethoxy) pyridine-3 -Yl] ゥ rare (5)

Methanol (5 ml) of methyl 3- (3-nitropyridine-2-hydroxy) acetate (212 mg) 10) Palladium carbon (containing 50 mg of water, 20 mg) was added to the solution, and the mixture was stirred at room temperature for 30 minutes under a hydrogen atmosphere. The palladium carbon was filtered, and the solvent was distilled off (180 mg). Of these, 92 mg was dissolved in acetonitrile (4 ml), sodium hydrogencarbonate (68 mg) was added, the mixture was ice-cooled, 4-nitrophenyl chloroformate (100 mg) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was cooled on ice, (R) _l-[(6-fluoronaphthylene-2-yl) methyl] pyrrolidine-3-ylamine (125 mg) and triethylamine (0.21 ml) were added, and the mixture was added at room temperature. Stirred. An aqueous potassium carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in tetrahydrofuran (2 ml) and added to a solution of lithium aluminum hydride (38 mg) in tetrahydrofuran (2 ml). Anhydrous magnesium sulfate (300 mg) was added to the reaction solution, and a saturated aqueous solution of sodium sulfate was added dropwise. After adding ethyl acetate and filtering the mixture, the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 20: 1) to give 1-)-tri [(6-fluoronaphthalene-2-yl) methyl] pipalysin-3-yl 1-3- [2- (2-Hydroxyethoxy) pyridin-3-yl] peryl (102 mg) was obtained (yield 47%). MS (m / z): 425 (麵 "), 423 ((MH)-)

I (neat): 3332, 2956 , 2810, 1682, 1643, 1556, 1369, 1219 cm one ¹

• H-NMR (300 MHz, CDC 1 3) <3:... 1. 56-1 72 (1H, m), 2. 22-2 41 (2H, m), 2. 66-2 8 3 ( 2H, m), 2.95-3.06 (1H, m), 3.72 (1H, d, J = 12.9), 3.84 (1H, d, J = 12.9), 3. 75-3.85 (2H, m), 3.94-4.16 (2H, m), 4.40-4.56 (1H, m), 6.17-6.25 (1H, m), 6.56-6.70 (1H, m), 6.85-6.90 (1H, m), 7.19-7.29 (1H, m), 7.37-7.50

(2H, m), 7.69-7.81 (3H, m), 8.08-8.15 (1H, m), 8.44 (1H, s).

Reference Example 4 (3-Nitropyridine-4-methoxy) acetic acid methyl ester (6)

 Using 4-hydroxy-3-ditropyridine as a raw material, methyl (3-ditropyridine-4-hydroxy) acetate was synthesized using the same method as in Reference Example 3.

- NMR (300 MHz, CDC 1 3) δ: 3. 89 (3Η, s), 4. 65 (2H, s), 6. 71 (. 1Η, d, J = 7 9), 7. 24 (1H , dd, J = 7.9, 2.3), 8.49 (1H, d, J = 2.3). Example 3 1-i (R) -tri [(6-fluoronaphthylene-2-yl) methyl] pyrrolidine-3-yl 3- [4- (2-hydroxyethoxy) pyridine-3-yl ] ゥ Rare (7)

 Using methyl 3- (3-nitropyridine-4-hydroxy) acetate as a raw material l_i (R) -tri [(6-fluoronaphthalene-2-yl) using the same method as in Example 2. ) Methyl] pyrrolidine_3-yl} -3- [4- (2-hydroxyethoxy) pyridin-3-yl] perylene was synthesized.

 MS (m / z): 425 (麵) +), 423 ((M-H)-)

IR (neat): 3274, 2953 , 2808, 1680, 1628, 1556, 1487, 1383, 1219 cm "1 ^ -NMR (270 negation _{z, CDC1 3) δ:.} 1. 58-1 78 (1H, m) , 2.10-2.32 (1H, m), 2.34-2.60 (2H, m), 2.62-2.88 (2H, m), 3.67 (2H, s), 3.70-4.10 (5H, m), 6.08 (1H, d, J = 6.9), 7.01 (1H, d, 1 = 2.0), 7.14-7.30 (1H, m), 7.32-7.54 (2H, m), 7.62-7.80 (3H, m), 8.49 (1H, s), 8.58 (1H, d, J = 6.5), 9.09 (1H, s).

Reference Example 5 (2_Nitropyridine-3-dihydroxy) acetic acid methyl ester (8) (8)

 Using 3-hydroxy-2-nitropyridine as a raw material, methyl 2- (2-nitropyridine-3-hydroxy) acetate was synthesized using the same method as in Reference Example 3.

Ή-NMR (300 MHz, CDC1 3) δ: 3. 82 (3Η, s), 4. 82 (2H, s), 7. 45 (. 1H, dd, J = 8 4, 1. 2), 7 55 (1H, dd, J = 8.4, 4.7), 8.18 (1H, dd, J = 4.7, 1.2).

Reference Example 6 3- [2- (tert-butyldimethylsilanyloxy) ethoxy] pyridine-2-ylamine (9) (9)

To a solution of lithium aluminum hydride (250 mg) in tetrahydrofuran (6 ml) was added (2- A solution of methyl nitropyridine-3- (hydroxy) acetic acid (705 mg) in tetrahydrofuran (6 ml) was added, and the mixture was stirred at room temperature for 1 hour. Anhydrous magnesium sulfate was added to the reaction solution, and a saturated aqueous solution of sodium sulfate was added dropwise. After filtering the mixture, the mixture was washed with ethyl acetate, and the filtrate was concentrated. The residue was dissolved in tetrahydrofuran (6 ml), imidazole (300 mg) and tert-butyldimethylsilyl chloride (580 mg) were added, and the mixture was stirred for 2 hours. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in methanol (10 ml), 10% palladium carbon (containing 50% water, 50 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 30 minutes. The palladium solvent was filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to give 3_ [2- (tert-butyldimethylsilanyloxy) ethoxy] pyridine-2-ylamine (290 mg). (Yield 33%).

MS (m / z): 269 ((M + H) ⁺ )

Ή-NMR (300 MHz, CDC 1 3) δ:. 0. 10 (6Η, s), 0. 91 (9H, s), 3. 94-4 00 (2H, m), 4. 03-4. 08 (2H, m), 4.64-4.74 (2H, br s), 6.59 (1H, dd, J = 7.8, 5.1), 6.94 (1H, dd, J = 7.8, 1.3), 7.66 (1H, dd, J = 5.1, 1.3).

Example 4 l-i (R) -tri [(6-fluoronaphthylene-2-yl) methyl] pyrrolidine-3-yl 3- [3- (2-hydroxyethoxy) pyridine-2-yl] Perrea (10)

To a solution of (R) -tri [(6-fluoronaphthalene-2_yl) methyl] pyrrolidine-3-ylamine (125 mg) in acetonitrile (4 ml) was added sodium hydrogencarbonate (68 mg), and the mixture was cooled on ice. After adding 4-nitrophenylchloroformate (100 mg), the mixture was stirred at room temperature for 2 hours. To this, 3- [2- (tert-butyldimethylsilanyloxy) ethoxy] pyridine-2-ylamine (135 nig) and triethylamine (0.21 ml) were added, and the mixture was stirred at 50 ° C. overnight. An aqueous solution of potassium carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in tetrahydrofuran (3 ml), and tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 1 ml) was added. The mixture was stirred for 02227. An aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (ethyl acetate: methanol = 6: 1) to give 1-i (R) -tri [(6-fluoronaphthalene-2-yl) methyl] pyrrolidine-3-y 3- (2-Hydroxyethoxy) pyridine-2-yl] ィ rea (20 mg) was obtained (10% yield).

MS (m / z): 425 (麵 "), 423 ((M-H Square)

IR (neat): 3239, 2952, 2804, 1656, 1552, 1483, 1255, 1226 cm " ¹

Ή-NMR (270丽_{z, CDC1 3) <3:} ... 1. 72-1 87 (1H, m), 2. 27-2 42 (1H, m), 2. 43-2 5 7 (1H , M), 2.61-2.70 (1H, m), 2.75-2.94 (2H, m), 3.76 (1H, d, J = 13.0), 3.83 (IE d, J = 13.0), 3.90-4.01 (2H, m), 4.03-4.10 (2H, m), 4.39-4.53 (1H, m), 6. 78-6.88 (1H, m), 7.03 (1H, d, J = 7.9), 7.18-7.30 (1H, m), 7.42 (1H, dd, J = 9.9, 2.6), 7.56 (1H, d, J = 8.6) 7.67-7.85 (4H, m), 8.28 (1H, s), 9.98 (1H , d, J = 5.9).

Reference Example 7 3-amino-4-chlorophenoxyacetic acid methyl ester (11) (ID

 4-Chloro-3-nitrophenol (500 nig) was dissolved in acetonitrile (3 ml), lithium carbonate (478 mg) and methyl bromoacetate (0.33 ml) were added, and the mixture was stirred at room temperature for 1.5 hours. An aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in methanol (5 ml), 10% palladium carbon (containing 50% water, 30 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 40 minutes. The palladium solvent was filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 2) to give methyl 3-phenamino-4-chlorophenoacetate (201 mg) (yield 32%).

Ή-NMR (300 MHz, CDC1 3) <5: 3. 80 (3H, s), 4. 57 (2H, s), 6. 24 (. 1H, dd, J = 8 7, 3. 0), 6.35 (1H, d, J = 3.0), 7.13 (1H, d, J = 8.7).

Example 5 1-((R) -1-([6_fluoronaphthalen-2-yl) methyl] pyrrolidine-3-yl) -3- 3- [2-chloro-5- (2-hydroxyethoxy) ) Phenyl] ゥ rare (12)

 Dissolve methyl 3-amino-4-chlorophenoxyacetate (100 mg) in acetonitrile (3 ml), add sodium bicarbonate (47 mg), cool on ice, and add 4-nitrophenyl chloroformate (99 mg). Stirred at room temperature for 2 hours. The reaction solution was cooled on ice, and (R) -1-[(6_fluoronaphthyl-2-yl) methyl] pyrrolidine-3-ylamine (126 mg) and triethylamine (0.13 ml) were added. And stirred overnight. An aqueous potassium carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in tetrahydrofuran (5 ml) and added to a solution of lithium aluminum hydride (24 mg) in tetrahydrofuran (5 ml). Anhydrous magnesium sulfate (1 g) was added to the reaction solution, and a saturated aqueous solution of sodium sulfate was added dropwise. After adding ethyl acetate and filtering the mixture, the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 15: 1) to give 1-ί (R) -tri [(6-fluoronaphthalen-2-yl) methyl] pyrrolidine-3-yl ) -3- [2-Chloro-5- (2-hydroxyethoxy) phenyl] peryl (97 mg) was obtained (yield 45%).

MS (m / z): 458 ("")

IR (neat): 2944, 2807 , 1658, 1589, 1538, 1427, 1307, 1139, 1083 cm "1 Ή-NMR (300 negation _{z, CDC1 3) δ:.} 1. 65-2 96 (6Η, m) , 3.70 (2H, d, J = 12.9), 3.74 (2H, d, J = 12.9), 3.86 (2H, t, J = 4.5), 4.01 ( 2H, t, J = 4.5), 4.26-4.38 (1H, in), 5.74 (1H, d, J = 7.5), 6.48 (2H, dd, J = 8 7, 2, 7), 7.11-7.42 (4H, m), 7.66-7.79 (4H, m).

Reference Example 8 2-Aminobenzyloxyacetic acid-tert-butyl ester (13)

2-Nitrobenzyl alcohol (500 mg) was dissolved in toluene (30 ml), sodium hydroxide aqueous solution (10 N, 20 ml), tert-butyl bromoacetate (1.5 ml), and Monium bromide (736 mg) was added. The reaction was stirred at room temperature for 3 hours and washed with water. The organic layer was concentrated, and the residue was dissolved in tetrahydrofuran (10Omi). After methanol (20 ml), water (20 ml), iron powder (737 mg), and ammonium chloride (lg) were added to the reaction solution, the mixture was stirred at 80 ° C. for 4 hours. The solid was filtered and the filtrate was concentrated. An aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the organic solvent was distilled off, and the precipitated solid was collected by filtration to obtain 2-aminoaminobenzyloxyacetic acid-tert-butyl ester (687 mg) (89%).

'H-NMR (300 negation _{z, CDC1 3) δ:.} 1. 49 (9Η, s), 4. 00 (2H, s), 4. 55 (2H, s), 6. 64 -6 70 (2Η , m), 7.04-7.17 (2Η, m).

Example 6 1-i (R) _ [[6-fluoronaphthylene-2-yl) methyl] pyrrolidine-3-yl 3- [2- (2-hydroxyethoxymethyl) phene,

 Using 2-aminoaminobenzyloxyacetic acid-tert-butyl ester as a raw material and using the same method as in Example 5, tri (R) -tri [(6-fluoronaphthylene-2-yl) methyl] pyrrolidine -3-yl 3- [2- (2-hydroxyethoxymethyl) phenyl] urea was synthesized. MS (m / z): 438 (picture +)

IR (neat): 1668, 1612, 1589, 1538, 1479, 1454, 1249, 1103, 869 cm " ¹

¾ one NMR (300 negation _{z, CDC1 3) δ:.} . 1. 45-2 93 (6Η, m), 3. 60-3 77 (4H, m), 3. 70 (2Η

, s), 4.35-4.45 (1Η, m), 4.49 (2H, s), 5.93 (1H, d, J = 8.1), 6.90-7.47 (5

H, m), 7.68-8.02 (4H, m), 8.17 (1H, s).

Reference Example 9 3-Aminobenzyloxyacetic acid-tert-butyl ester (15)

 Using 3-nitrobenzoyl alcohol and tert-butyl bromoacetate as starting materials, 3-aminoaminobenzyloxyacetic acid-tert-butyl ester was synthesized in the same manner as in Reference Example 8.

Ή-NMR (300 MHz, CDC1 3) 6: 1. 48 (9H, s), 3. 68 (2H, br s), 3. 97 (2H, s), 4 .54 (2H, s), 6.60-6.75 (3H, m), 7.13 (1H, t, J = 7.8).

EXAMPLE 7 i (R) -1-[(6-Fluoronaphthalene-2-yl) methyl] pyrrolidine-3-yl 3- [3- (2-hydroxyethoxymethyl) phenyl] ゥ rea ( 16)

Using 3-aminoaminobenzyloxyacetic acid-tert-butyl ester as a raw material, tri (R) -tri [(6-fluoronaphthalen-2-yl) methyl] pyrrolid was obtained in the same manner as in Example 5. Zin-3-yl j-3- [3- (2-hydroxyethoxymethyl) phenyl] urea was synthesized. MS (m / z): 438 ((M + H) ⁺ ), 436 ((MH)-)

IR (neat): 1665, 1612, 1522, 1446, 1355, 1295, 1101 cm— ¹

Ή-NMR (300 thigh _{z, CDC1 3) δ: 1.55-3.00} (6Η, m), 3.49-3.53 (2H, m), 3.64-3.6 9 (4Η, m), 4.20-4.36 (1Η, m), 4.39 (1H, d, J = 12.0), 4.44 (1H, d, J = 12.0), 5.95 (1H, d, J = 8.1), 6.87 (1H, d, J = 7.5), 7.14-7.80 (9H, m).

Example 8 1-R) -Tri [(6-fluoronaphthylene-2-yl) methyl] pyrrolidine-3-yl 3_ [5-fluoro-2_ (2-hydroxyethoxy) phenyl] ゥ rea ( 17)

 Using 4-fluoro-2-ditrophenol as a raw material and using the same method as in Reference Example 7 and Example 5, tri (R) -tri [(6-fluoronaphthalene-2-yl) Methyl] piper lysine 1-3-yl 1-3- [5-fluoro-2_ (2-hydroxyethoxy) phenyl] urea was synthesized.

MS (m / z): 442 ((M + H) +), 440 ((M-H) one)

IR (neat): 2945, 2814, 1673, 1615, 1543, 1480, 1441, 1247 cm- ¹

¾-NMR (300 negation _{z, CDC1 3) <5:} 1.45-2.90 (6H, m), 3.65 (1H, d, J = 12.9), 3.71 (1H, d, J = 12.9), 3.75-3.92 (4H , m), 4.23-4.40 (1H, m), 5.84 (1H, d, 1 = 1.9), 6.45-6.70 (2H, m), 7.16-7.95 (7H, m). Example 9 l-((R) -l-[(6-2-yl) methyl] pipalysin-3-yl 3_ [3-fluoro-2- (2-hydrophenyl)} rea (18)

 Using 2-fluoro-6-ditrophenol as a raw material, using the same method as in Reference Example 7 and Example 5, tri (R) -tri [(6-fluoronaphthalene-2-yl) Methyl] pyrrolidine-3-yl 3- [3-fluoro-2- (2-hydroxyethoxy) phenyl] urea was synthesized.

MS (m / z): 442 (Picture) ⁺ ), 440 ((MH)-)

IR (neat): 1682, 1600, 1557, 1479, 1251, 1170, 1140 cm ' ¹

• H-NMR (300 thigh _{z, CDC1 3) <5:} 1.50-2.95 (6H, m), 3.68 (1H, d, J = 12.9), 3.73

(1H, d, J = \ 2.9), 3.75-4.15 (4H, m), 4.30-4.45 (1H, m), 5.54 (1H, d, J = 7.

9), 6.64-7.95 (9H, m), 8.10 (1H, s).

Reference Example 10 3-Aminophenoxyacetic acid methyl ester (19)

 Methyl 3-aminophenoxyacetic acid was synthesized in the same manner as in Reference Example 7, using 3-ditrophenol as a raw material.

ΐ-NMR (300 thigh _{z, CDC1 3) δ: 3.69} (2Η, br s), 3.80 (3Η, s), 4.60 (2Η, s), 6 .24-6.36 (3Η, in), 7.02-7.10 ( 1Η, m).

Example 10 卜 ((R)-卜 [(6-Fluoronaphthylene-2-yl) methyl] pyrrolidine-3-yl 3_ _ (2-hydroxyethoxy) phenyl] ゥ rea (20)

Using 3-aminophenoxyacetic acid methyl ester as a raw material and using the same method as in Example 5, 1-100-1-[(6-fluoronaphthyl-2-yl) methyl] pyrrolidine-3- 3- [3- (2-Hydroxyethoxy) phenyl] urea was synthesized.

MS (m / z): 424 (image ⁺ ), 422 ((MH)-)

IR (KBr): 1639, 1565, 1477, 1442, 1292, 1240, 867 cm " ¹

Ή-NMR (300 MHz, CDC1 3) δ:. 1. 60-3 01 (6Η, m), 3. 77 (2H, s), 3. 87 (2H, t,

J = 4.8), 4.05 (2H, t, J = 4.8), 4.32-4.40 (1H, m), 6.50-6.80 (2H, m), 7. Ten-

7.49 (5H, m), 7.73-7.82 (3H, m).

Reference Example 11 3- (2-methoxyethoxy) phenylamine (21)

 Using 3-nitrophenol as a raw material, 3-nitrophenoxyacetic acid methyl ester (220 mg) obtained in the same manner as in Reference Example 3 was dissolved in methanol (5 ml), and sodium borohydride (100 mg) was added. For 15 minutes. The solvent was distilled off, and the residue was washed with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in tetrahydrofuran (2 ml), sodium hydride (43 mg) and methyl iodide (0.067 ml) were added, and the mixture was stirred at room temperature. The reaction solution was washed with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in methanol (10 ml), and thereto was added 10% palladium ion (50% water, 15 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. After filtering the reaction solution, 1 M hydrochloric acid was added to the filtrate, and the mixture was washed with ethyl acetate. The aqueous layer was neutralized with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 3- (2-methoxyethoxy) phenylamine (yield 76%).

Ichi匪_{R (300 MHz, CDC1 3)} δ:. 3. 44 (3Η, s), 3. 65 (2H, br s), 3. 67-3 73 (2H, m), 4. 07-4. 10 (2H, m), 6.27-6.36 (3H, m), 7.05 (1H, t, J = 8.0).

Example 11 1-((R) -tri [(6-fluoronaphthalene-2-yl) methyl] pipalysin-3-yl 3- [3- (2-methoxyethoxy) phenyl] ゥ rea (twenty two)

(twenty two)

Dissolve 3- (2-methoxyethoxy) phenylamine (39mg) in acetonitrile (2ml) Then, sodium hydrogen carbonate (17 nig) was added thereto, and the mixture was ice-cooled. 4-Nitrophenyl chloroformate (37 mg) was added, followed by stirring at room temperature for 1 hour. The reaction solution was cooled on ice, (R) -1-[(6-fluoronaphthalene-2-yl) methyl] pyrrolidine-3-ylamine (46 mg) and triethylamine (0.048 ml) were added, and the mixture was allowed to stand at room temperature overnight. Stirred. An aqueous potassium carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give 1-ί (R) -tri [(6-fluoronaphthalene-2-yl) methyl] pipa-lysine- 3-Yield 3- [3- (2-methoxyethoxy) phenyl] ゥ rea (66 mg) was obtained (88% yield).

MS (m / z): 438 (麵) +)

IR (KBr): 2925, 2805, 1650, 1606, 1554, 1290, 1 126 cm " ¹

Ή-NMR (300丽_{z, CDC1 3) δ:.} . 1. 58-1 65 (1H, m), 2. 20-2 97 (5H, m), 3. 42 (3Η, s), 3. 65-3.77 (4H, m), 4.02-4.30 (3H, m), 5.54 (1H, d, J = 8.1), 6.60-6.81 (2H, m ), 7.05-7.75 (8H, m).

Reference Example 12 Ν, Ν-Dimethyl-2- (2-nitrophenoxy) acenamide (23)

 2, Ν-Dimethyl-2- (2-nitrophenoxy) acetamide was synthesized in the same manner as in Reference Example 3, using 2-ditrophenol as a raw material.

-ΝΜ] 300丽_{z, CDC 1 3) δ:} 2. 98 (3Η, s), 3. 14 (3Η, s), 4. 85 (2Η, s), 7. 05-

7.21 (2Η, m), 7.53 (1Η, m), 7.85 (1Η, m).

Reference Example 13-(2-aminophenoxy) -N, N-dimethylacetamide (24)

N, N_dimethyl-2- (2-nitrophenoxy) acetamide OOOnig) was dissolved in methanol (10 ml), 10% palladium carbon (50% water content, 90 mg) was added, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The palladium carbon was filtered and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 1- (2-Aminophenoxy) _N, N-dimethylacetamide (768 mg) was obtained (yield 98%).

MS (ιη / ζ): 195 (picture ⁺ )

IR (KBr): 2924, 1665, 1619, 1511, 1461, 1229 cm " ¹

'H-NMR (300 MHz, CDC1 3) δ:. 2. 99 (3Η, s), 3. 06 (3Η, s), 4. 72 (2Η, s), 6. 66-6 86 (4Η, m).

Example 12 2- (2- (3-((R) -tri [(6-fluoronaphthalen-2-yl) methyl] pyrrolidin-3-yljureido) phenoxyl N, N-dimethylacetami Do (25)

 Using 2- (2-aminophenoxy) -N, N-dimethylacetamide as a raw material and using the same method as in Example 11, 2- (2- (3-((R) -tri [(6- Fluoronaphthalene-2-yl) methyl] pyrrolidine-3-yl 1-reido) phenoxyl N, N-dimethylacetamide was synthesized.

MS (m / z): 465 ((M + H) ⁺ )

IR (neat): 3057, 2956, 2802, 1654, 1604, 1541, 1453, 1248 cur ¹

¾- NMR (300 negation _{z, CDC 1 3) δ:} ... 1. 64-1 76 (1H, m), 2. 26-2 47 (2H, m), 2. 61-2 89

(3H, m), 2.96 (3H, s), 2.99 (3H, s), 3.76 (2H, s), 4.41 (1H, m), 4.68 (2H, s) , 5.59 (1H, d, J = 7.3), 6.87-8.53 (11H, m).

Reference Example 14 (4-7 minophenoxy) acetic acid methyl ester (26) (26)

 Using 4-ditrophenol as a raw material, (4-aminophenoxy) acetic acid methyl ester was synthesized in the same manner as in Reference Example 7.

MS (ιη / ζ): 182 (麵 ")

IR (KBr): 3464, 3369, 2794, 1743, 1514, 1441, 1223, 1093, 825, 783 cm " ¹ Example 13 [4- (3-((R) -tri [(6-fluoronaphthalene) -2 -yl) methyl] pyrrolidine-3 -Yl 1-Reido) phenoxy] acetic acid methyl ester (27)

 Using (4-aminophenoxy) acetic acid methyl ester as a raw material, [4- (3-R) -tri [(6-fluoronaphthalen-2-yl) methyl] pi was obtained in the same manner as in Example 11. Mouth lyzin-3-yl} perido) phenoxy] acetic acid methyl ester was synthesized.

MS (m / z): 452 (麵 ")

IR (KBr): 3313, 2794, 1751, 1633, 1564, 1508, 1211, 1074, 827 cm- ¹

Ή-NMR (300 negation _{z, CDC1 3) δ:.} . 1. 66 (1H, m), 2. 20-2 35 (2H, m), 2. 52-2 55 (1Η, m), 2. 67 (1Η, d, J = 12.8), 2.90 (1H, t, J = 8.5), 3.69 (2H, s), 3.77 (3H, s), 4.21 ( 1H, m), 4.58 (2H, s), 5.00 (1H, m), 6.82 (2H, d, J = 8.8), 7.14 (2H, d, J = 8. 8), 7.22 (1H, m), 7.38 (2H, m), 7.64-7.71 (3H, m).

Example 14 tri ((R) -tri [(6-fluoronaphthalene-2-yl) methyl] pyrrolidine-3-yl 3-tri [4- (2-hydroxyethoxy) phenyl] ゥ rea (28)

 Methyl [4- (3-1 (R) -1-[(6-fluoronaphthylene-2-yl) methyl] pyrrolidine-3-yl 1-reid) phenoxy] acetic acid (74 mg) in methanol (5 ml) ), And sodium borohydride (140 mg) was added, followed by stirring at room temperature for 2 hours. Methanol was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. Purification of the residue by chromatography column chromatography for amines (ethyl acetate: ethanol = 10: 1) yields: i (R) -tri [(6-fluoronaphthylene-2-yl) methyl] pyrrolidine -3-yl 3- [4- (2-hydroxyethoxy) phenyl] フ rea (58 mg) was obtained (yield 84%).

MS (m / z): 424 (麵 "), 422 ((M-H wide)

IR (KBr): 3317, 2800, 1635, 1566, 1510, 1234, 1055, 835 cm ^-1

Ή one NMR (300 thigh _{z, CDC1 3) δ: 1.} 64 (1H, m), 2. 25 (2H, m), 2. 53 (1Η, m), 2. 66 (1H, m), 2.89 (1H, m), 3.69 (2H, s), 3.92 (2H, t, J = 4.7), 4.01 (2H, t, J = 4 7), 4.23 (1H, m), 5.00 (1H, d, J = 7.4), 6.82 (2H, d, J = 8.8), 7.12 (2H, d , J = 8.8), 7.17 (IE m), 7.38 (2H, d, J = 8.5), 7.73-7.71 (3H, m).

Reference Example 15 (4-Amino-2-methoxycarbonylmethoxyphenoxy) acetic acid methyl ester (29)

(29)

 Methyl (4-amino-2-methoxycarbonylmethoxyphenoxy) acetate was synthesized using 3,4-dihydroxynitrobenzene as a raw material and in the same manner as in Reference Example 7.

MS (m / z): 270 ((M + H) ⁺ )

IR (KBr): 3419, 3350, 2962, 1749, 1518, 1441, 1282, 1217, 1173, 1142, 106 3, 829 cm " ¹

Example 15 (4- (3- [tri (6-fluoronaphthalene-2-ylmethyl) pipalysin-3-yl]} reido 1-2-methoxycarbonylmethoxyphenoxy) acetic acid methyl ester ( 30)

(30)

 Using (4-amino-2-methoxycarbonylmethoxyphenoxy) acetic acid methyl ester as a raw material, and using the same method as in Example 11, (4-[1- (6-Fluoronaphthalen-2-ylmethyl) pyrrolidine) -3-yl] peridot 2-methylcarbonylmethoxyphenoxy) acetic acid methyl ester was synthesized.

MS (m / z): 540 (麵) +)

IR (KBr): 3303, 2852 , 1747, 1641, 1568, 1514, 1441, 1215, 1065, 804 cm- 1 Ή-NMR (300 MHz, CDC1 3) δ: 1. 73 (1H, m), 2. 30 (2H, m), 2.57 (1H, m), 2.73 (1H, m), 2.96 (1H, m), 3.75 (3H, s), 3.78 (2H, s ), 3.79 (3H, s), 3.96 (2H, m), 4.22 (1H, m), 4.68 (2H, s), 4.70 (1H, m), 5.08 (1H, m), 6.71 (1H, d, J = 8.8), 6.84 (1H, d, J = 8.8), 7.00 (1H, s), 7.24 (1H , t, J = 8.8), 7.4 1 (2H, d, J = 8.9), 7.69-7.76 (3H, m).

Example 16 1- [3,4-Bis (2-hydroxyethoxy) phenyl] -3-((R) -1-[(6-fluoro-naphthalene-2-yl) methyle] pi-lysine-3 -Ill 1 rare (31)

 Using methyl 4- (13- [2- (6-fluoronaphthalene-2-ylmethyl) pipalysine_3-yl]} reido-2-methoxycarbonylmethoxyphenoxy) acetate as the starting material, Using a similar method, 1-, 4-bis (2-hydroxyethoxy) phenyl] -3-((R) -l-[(6-fluoronaphthylene-2-yl) methyl] pyrrolidine-3 -Yl) Urea was synthesized.

 MS (m / z): 484 ((M + H) +), 482 ((M-H) one)

I (KBr): 3305, 2933 , 1635, 1560, 1512, 1225, 1136, 1080, 1043, 902cm "1 Ή-NMR (300 negation _{z, CDC1 3) (5:} 1. 68 (1H, m), 2 32 (2H, m), 2.57 (1H, m), 2.80 (1H, m), 3.02 (1H, m), 3.77 (2H, s), 3.84 (4H, m), 3.96 (2H, m), 4.04 (2H, m), 4.29 (1H, m), 5.56 (1H, m), 6.74 (1H, m), 6. 82 (1H, d, J = 8.5), 7.00 (1H, s), 7.22 (1H, m), 7.44 (2H, m), 7.70-7.77 (3H, m).

Reference Example 16 3- (tert-butyldimethylsilanyloxymethyl) phenylamine (32)

 3-Aminobenzyl alcohol (827 mg) was dissolved in tetrahydrofuran (10 ml), imidazole (924 mg) and tert-butyldimethylsilyl chloride (320 mg) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1.3) to give 3- (tert-butyldimethylsilanyloxymethyl) phenylamine (1.52 g) (96% yield). .

MS (m / z): 238 ((M + H) ⁺ )

IR (KBr): 3367, 2956, 2856, 1622, 1464, 1255, 1093, 839, 777 cm " ¹

Ή 匪 匪 R (300 匪 z, CDC I3) δ: 0.06 (6Η, s), 0.90 (9Η, s), 3.61 (2Η, s), 4.62 (2H, br s), 6.52 (1H, d, J = 7.0), 6.64 (1H, s), 6.66 (1H, d, J = 7.0), 7.07 ( 1H, t, 1 = 1. 0).

Example 17 (R) -1 _ [(6-Fluoronaphthalene-2-yl) methyl] pipalysine-3- (3- (3- (hydroxymethyl) phenyl]) rea (33)

Example 1 Using 3_ (tert-butyldimethylsilanyloxymethyl) phenylamine instead of 3- [2- (tert-butyldimethylsilanyloxy) ethoxy] pyridine-2-ylamine as a raw material, Using the same method as in 4, convert l-i (R) -l _ [(6-fluoronaphthalene-2-ylyl) methyl] pyrrolidine-3-yl 3 [3- (hydroxymethyl) phenyl] ゥ rea Synthesized.

MS (ffl / z): 394 ((M + H) ⁺ ), 392 ((MH)-)

IR (KBr): 3309, 2949, 2796, 1633, 1566, 1483, 1242, 1136, 1010, 869, 796 cm— ¹

'H-NMR (300 MHz, CDC 1 3) <5:. 1. 66 (1H, m), 2. 12-2 80 (5H, m), 3. 68 (2H, s), 4. 23 ( 1H, m), 4.51 (2H, m), 6.24 (1H, m), 6.85 (1H, d, 1 = 1.6), 7.12 (1H, t, J = 8. 0), 7.18 (1H, t, J = 8.8), 7.34-7.44 (3H, m), 7.65-7.75 (3H, m), 8.40 (1H, m).

Reference Example 17 2- (3-Aminophenyl) -N, N_dimethylacetamide (34)

3-Ditrophenylacetic acid (396 mg) was dissolved in dichloromethane (8 ml), and Bop reagent (986 mg), dimethylamine hydrochloride (350 mg), diisopropylethylamine (1.2 ml) were added, and the mixture was stirred at room temperature overnight. did. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 4: 1) (513 mg). 472 mg of the solution was dissolved in ethanol (20 ml), and 10% palladium carbon (50% water content, 67 mg) was added. After stirring overnight under a hydrogen atmosphere, the palladium carbon was filtered off and concentrated. The residue is chromatolex column chromatography for amine (ethyl acetate: ethanol)

= 10: 1) to give 312 mg of 2- (3-aminophenyl) -N, N_dimethylacetamide (80% yield).

MS (m / z): 179 (picture +)

IR (KBr): 3462, 3357, 2936, 1631, 1495, 1402, 1 135, 846 cm- ¹

Ή-NMR (300 MHz, CDC 1 3) <5: 2. 92 (3H, s), 2. 94 (3H, s), 3. 59 (2H, s), 6. 52 (1H, d, J = 7.9.), 6.58 (2H, m), 7.05 (1H, t, 1 = 1.9)-Example 18 2- [3- (3- ((R)-[[(6 -Fluoronaphthalene-2-yl) methyl] pyrrolidine) -3-yl iureido) phenyl] -N, N-dimethylacetamide (35)

Using 2- (3-aminophenyl) -N, N-dimethylacetamide as a raw material, 2- [3- (3-1-1 (R) -tri [(6 -Fluoronaphthylene-2-yl) methyl] pyrrolidine-3-yl 1-reido) phenyl] -N, N-dimethylacetamide was synthesized. MS (m / z): 449 ((M + H) +)

IR (KBr): 3340, 2794, 1622, 1554, 1485, 1228, 1 136, 872, 771 cm " ¹

Ή-NMR (300 MHz, CDC 1 3) δ:. 1. 65 (1H, m), 1. 97-2 38 (2H, m), 2. 60 (2H, m), 2. 83 (1H, m), 2.90 (3H, s), 2.96 (3H, s), 3.59 (2H, s), 3.70 (2H, s), 4 • 22 (1H, m), 5. 36 (1H, m), 6.79 (1H, d, J = 7.0), 7.00-7.25 (4H, m), 7.36-7.43 (2H, m), 7. 65-7.73 (3H, m).

 Reference Example 18 N- (4-Aminobenzyl) asemidamide (36) 6)

4_Nitoguchi benzylamine hydrochloride (421 mg) was added to dichloromethane (8 ml), diisopropylethylamine (lml) and acetic anhydride (0.5 ml) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer is treated with sulfuric anhydride: After drying, it was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: ethanol = 10: 1) (435 mg). 230 mg of the solution was dissolved in tetrahydrofuran (20 inl), 10% palladium carbon (50% water content, 30 mg) was added, and the mixture was stirred under a hydrogen atmosphere for one hour. Then, the palladium carbon was filtered off and concentrated. The residue was purified by chromatography column chromatography for amine (ethyl acetate) to obtain 194 mg of N- (4-aminobenzyl) acetamide (yield: 95%).

MS (m / z): 165 (麵 ")

I (neat): 3396, 3240, 1643, 1556, 1514, 1271, 823 cm- ¹

'H-NMR (300 Keio _{z, CDC1 3) (5:} . 1. 95 (3H, s), 3. 64 (2H, s), 4. 25 (2H, d, J = 5 6

), 5.57 (1H, m), 6.61 (2H, d, J = 8.5), 7.03 (2H, d, J = 8.5).

Example 19 N- [4- (3-i (R) -tri [(6-fluoronaphthalen-2-yl) methyl] pyrrolidine

-3 -yl} ゥ Reid) benzyl] acetamide (37)

 Using N- (4-aminobenzyl) acetamide as a raw material, N- [4- (3-1 (R) -l-[(6-fluoronaphthalene-2-y) was obtained in the same manner as in Example 11. L) methyl] pyrrolidine-3-yl 1-reido) benzyl] acetamide was synthesized.

MS (m / z): 435 (麵) +)

IR (KBr): 3467, 3330 , 2794, 1641, 1562, 1246, 868, 756 cm one ¹

H_ 丽 R (300 MHz, CDC I 3) δ: 1.74 (1H, m), 2.00 (3H, s), 2.20-2.42 (2H, m), 2.60- 2.78 (2Η, m), 2.90-3.00 (1Η, m), 3.74 (2Η, s), 4.41 (2Η, d, J-7.6), 4.63 ( 1H, m), 5.87 (1H, m), 6.61 (1H, d, J = 8.2), 7.17-7.45 (4H, m), 7.46 (1H, d, J = 8.5), 7.58 (1H, d, J = 7.0), 7.63 (1H, s), 7.69-7.77 (3H, m). Reference example 193-[ 3- (tert-Butyldimethylsilanyloxy) propoxy] phenylamine (38)

1-Fluoro-3-nitrobenzene (1.39 g) and 1,3-propanediol (1.5 ml) / 02227 was dissolved in formamide (4 ml), sodium hydride (400 mg) was added, the mixture was stirred at 80 ° C for 1 hour, and concentrated. Water was added to the residue and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in ethanol (20 ml), 10% palladium carbon (containing 50% water, 49 mg) was added, and the mixture was stirred under a hydrogen atmosphere under reduced pressure. Then, the palladium carbon was separated by filtration and concentrated. The residue was dissolved in tetrahydrofuran (20 ml), imidazole (214 mg) tert-butyldimethylsilyl chloride (320 mg) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give 3- [3_ (tert-butyldimethylsilanyloxy) propoxy] phenylamine (496 mg) (18% yield).

MS (m / z): 282 ((M + H) ⁺ )

 IR (neat) 3372, 2952, 2856, 1496, 1471, 1290, 1255, 1190, 1150, 1097, 83 7, 775 cm

Ή-NMR (300 negation _{z CDC1 3) δ 0. 06 (} 6Η, s), 0. 90 (9H, m), 1. 97 (2Η, m), 3. 64

(2Ηm), 3.77 (2Η, m), 4.02 (2Η, m), 6.43-6.51 (3Η, m) 7.10-7.26 (1H, m).

Reference Example 20 1-13- [3- (tert-butyldimethylsilanyloxy) propoxy] phenyl} -3-1 ()-tri [(6-fluoronaphthalen-2-yl) methyl] pi Lysine-3-yl 1 rare (39)

Using 3- [3- (tert-butyldimethylsilanyloxy) propoxy] phenylamine as a raw material, and using the same procedure as in Example 11, 1- [3- (tert-butyldimethylsilanyloxy) propoxy] Phenyl 1-3-I (R) -1-[(6-fluoronaphthalene-2-yl) methyl] pyrrolidine-3-yl 1 urea was synthesized.

MS (m / z) 552 (麵) +)

IR (KBr) 3319, 2953, 1641, 1608, 1551, 1481, 1250, 1101, 841, 773 cm- 1 Ή-NMR (300 MHz, CDC1 3) ά 0. 03 (6Η, s), 0. 88 ( 9H, s), 1.72 (1H, m), 1.95 (2H, Quint, J = 6.2), 2.30 (2H, m), 2.54-3.03 (3H, m), 3.79 (4H, m), 4.02 (2H, t, J = 6.2), 4.27 (1H, m) , 5.21 (1H, d, J = 8.5), 6.63 (1H, d, J = 8.2), 6.78 (1H, d, J = 8.1), 6.97 (1H, s), 7.16 (1H, d, J = 8.0) ), 7.19-7.24 (1H, m), 7.40-7.46 (2H, m), 7.60-7.76 (3H, m).

Example 20 [(10-tri [(6-fluoronaphthalene-2_yl) methyl] pyrrolidine-3-yl] -3- [3- (3-hydroxypropoxy) phenyl] ゥ rea (40 )

1-13- [3- (tert-butyldimethylsilanyloxy) propoxy] phenyl j -3- ί (R) -tri [(6-fluoronaphthylene-2-yl) methyl] pyrrolidine-3--3-y Toluene (87 mg) was dissolved in tetrahydrofuran (4 ml), and tetrabutylammonium fluoride (0.16 ml of a 1 M solution in tetrahydrofuran) was added, followed by stirring at room temperature for 2 hours. The tetrahydrofuran was distilled off, and the residue was purified by chromatography column chromatography for amines (ethyl acetate: ethanol = 20: 1) to obtain R) -1-[(6-fluoronaphthalene-2-yl). ) Methyl] pyrrolidine-3-yl 3- [3- (3-hydroxypropoxy) phenyl] ゥ rare (62 mg) was obtained (89% yield).

MS (m / z): 438 (麵 "), 436 ((M-H) 1

IR (KBr): 3303, 2952, 1639, 1560, 1290, 1244, 1064, 870, 764 cm— ¹

Ή-NMR (300 thigh _{z, CDC1 3) δ:.} 1.74 (1H, m), 1.98 (2H, auint, J = 5.9), 2.24-2 34 (2H, m), 2.56 (1H, m), 2.76 (1H, d, J = 9.9), 2.96 (1H, m), 3.75 (2H, s), 3.79 (2H, t, J = 5.9), 4.08 (2H, t, J = 5.9), 4.26 (1H, m), 5.44 (1H, m), 6.61 (1H, d, J = 8.2), 6.72 (1H, d, 1 = 1.6), 7.08-7.26 (3H, m), 7.43 (2H, in), 7.73 ( 3H, m).

Reference Example 21 3- [4- (tert-butyldimethylsilanyloxy) butoxy] phenylamine (41)

Using 1,4-butanediol as a raw material instead of 1,3-propanediol, 3- [4- (tert-Butyldimethylsilanyloxy) butoxy] phenylamine was synthesized using the same method as in Reference Example 19.

MS (m / z): 296 ((M + H) +)

IR (neat): 3373, 2929, 2856, 1641, 1600, 1497, 1254, 1190, 1159, 1093, 83 5, 773 c ¹

Ή-NMR (300 thigh _{z, CDC1 3) 5: 0.06} (6H, s), 0.90 (9H, s), 1.67 (2H, auini, J

= 6.2), 1.82 (2H, Quint, J = 6.2), 3.63 (2H, br s), 3.67 (2H, i, J = 6.2), 3.

93 (2H, t, J = 6.2), 6.23-6.33 (3H, m), 7.04 (1H, t, J = 7.9).

Reference Example 22 1-13- [4- (tert-butyldimethylsilanyloxy) butoxy] phenyl

3-ί (R)-[[(6-Fluoronaphthalene-2-yl) methyl] piperidin-3-yl 1 ゥ rare (4

2))

Using 3- [4- (tert-butyldimethylsilanyloxy) butoxy] phenylamine as a raw material and using the same method as in Example 11, tri (3- [4- (tert-butyldimethylsilanyloxy) butoxy] Phenyl 1-3-R) -tri [(6-fluoronaphthalene-2-yl) methyl] pyrrolidine-3-yl jurea was synthesized.

MS (m / z): 566 ((M + H) +)

IR (KBr): 3317, 2953, 1641, 1610, 1550, 1440, 1297, 1249, 1112, 835, 775 cm— ¹

Ή-NM (300 MHz, CDC1 3) δ: 0.05 (6H, s), 0.89 (9H, s), 1.60-1.86 (5H, m), 2.30 (2H, m), 2.73 (1H, m), 2.73 (1H, d, J = 9.7), 2.95 (1H, in), 3.65 (2H, t, J = 6.2), 3.73 (2H, m), 3.94 (2H, t, J = 6.5), 4.26 (1H, m), 5.28 (1H, m), 6.79 (1H, d, J-8.5), 6.75 (1H, d, J = 8.2), 6.99 (1H, m), 7.13-7.20 (1 H, m), 7.20 -7.24 (1H, m), 7.40-7.47 (2H, m), 7.69-7.76 (3H, m).

Example 21 1-i (R) -1 _ [(6-fluoronaphthylene-2-yl) methyl] pyrrolidine-3-yl 3_ [3- (4-hydroxybutoxy) phenyl] ゥ rea (43)

1- (3- [4- [tert-Butyldimethylsilanyloxy) butoxy] phenyl 1-3-((R) -1-([6-fluoronaphthylene-2-yl) methyl] pyrrolidine-3 1-i (R) -1 _ [(6_fluoronaphthalene-2-yl) methyl] pyrrolidine-3-y 3_ [3- (4-Hydroxybutoxy) phenyl] ゥ rea was synthesized.

 MS (m / z): 452 (麵) +), 450 ((M-H)-)

IR (KBr): 3315, 2949, 1641, 1608, 1550, 1483, 1440, 1294, 1228, 1190, 10 49, 867, 771 cm " ¹

^J H-NMR (300丽_{z CDC1 3) δ: 1.68-1.84 (} 5Η, m) 2.24-2.34 (2H, m), 2.55 (1Η, m), 2.81 (1Η d, J = 10.5), 2.94 (1H , m), 3.68 (2H, t, J = 7.2), 3.74 (2H, s), 3.97 (2H, t, J = 6.2), 4.27 (1H, m), 5.30 (1H, m), 6.60 (1H , d 1 = 1.9), 6.72 (1H, d, J = 8.2), 7.05-7.27 (3H, m), 7.41 (2H, m) 7.71 (3H, m) .Reference example 23 2- [2- (tert -Butyldimethylsilanyloxy) ethoxy] phenylamine (44)

 2- [2- (tert-butyldimethylsilanyloxy) ethoxy] phenylamine was synthesized using 1-fluoro-2-nitrobenzene and ethylenedalicol as raw materials and using the same method as in Reference Example 19.

MS (m / z): 268 ((M + H) ⁺ )

I (neat): 3473, 3374, 2933, 2859, 1618, 1508, 1466, 1440, 1255, 1219, 11 26, 835, 779, 739cm ' ¹

Ή-NMR (300 MHz, CDC1 ₃ ) δ: 0.10 (6Η, s), 0.91 (9Η, s) 3.88 (2H, br s), 3

.99 (2H, t, J = 5.2), 4.06 (2H, t, J = 5.2), 6.67-6.85 (4H, m).

Reference Example 24 1- (2- [2- (tert-butyldimethylsilanyloxy) ethoxy] phenyl) 3-) -to [(6-Fluoronaphthalene-2-yl) methyl] pipalysin-3-yl 1 ゥ rea (45)

 Using 2- [2- (tert-butyldimethylsilanyloxy) ethoxy] phenylamine as a raw material and using the same procedure as in Example 11, tri (2- [2- (tert-butyldimethylsilanyloxy) ethoxy] Phenyl j-3-R)-[[6-fluoronaphthyl-2-yl) methyl] pyrrolidine-3-yl) urea was synthesized.

MS (m / z): 538 (麵) +)

IR (neat): 3336, 2929, 2856, 1651, 1603, 1539, 1452, 1252, 1109, 958, 835, 744 cm ^-1

Ή-NMR (300 negation _{z, CDC1 3) δ: 0.10} (6Η, s), 0.91 (9H s), 1.65 (1H, m), 2.34 (2H, m), 2.66 (2H, m) 2.86 (1H, m), 3.75 (2H s), 3.97 (2H m), 4.07 (2H, t J = 5.3), 4.40 (1H, m), 5.03 (1H, d, J = 7.9), 6.66-7.03 (3H, m ) 7.2 3-7.52 (3H, m), 7.41-7.70 (2H, ni) 7.72-7.80 (3H m), 8.03 (1H m).

Example 22 1-f (R) -tri [(6-fluoronaphthalene-2-yl) methyl] pyrrolidine-3-yl 3_ [2- (2-hydroxyethoxy) phenyl] ゥ rea (46)

 1- (2- [2- (tert-butyldimethylsilanyloxy) ethoxy] phenyl i-3-{(R) -1-[(6-fluoronaphthalen-2-yl) methyl] pi Using 1 urea of lysine-3-yl as a raw material and using the same method as in Example 20, tri-R) -tri [(6-fluoronaphthalene-2-y Mmethyl] pyrrolidine-3-yl 3- [2- (2-Hydroxyethoxy) phenyl] ゥ rea was synthesized.

MS (πι / ζ): 424 ((Μ + Η) ⁺ ), 422 ((Μ-Η 广)

IR (KBr): 3332, 2808, 1633, 1604, 1549, 1248, 1219, 748 cm- ¹

Ή over丽_{R (300 MHz, CDC1 3)} δ: 1.66 (1H, m), 2.12-2.82 (5H, m) 3.74 (2H, m) 0302227

3.85 (2H, br s), 3.86 (2H, br s), 4.38 (1H, ni), 6.06 (1H, m), 6.80 (1H, in), 6.94 (2H, m), 7.21-7.90 (8H, m).

Reference Example 25 3- (2- [2- (tert-butyldimethylsilanylyoxy) ethoxy] ethoxy 1 phenylamine (47)

 Using trifluoro-3-nitrobenzene and diethylene glycol as raw materials, 3- (2- [2- (tert-butyldimethylsilanyloxy) ethoxy] ethoxy 1 was obtained using the same method as in Reference Example 19. Phenylamine was synthesized.

MS (m / z): 312 (drawings)

 IR (neat): 3464, 3371, 2929, 2858, 1736, 1626, 1496, 1462, 1254, 1192, 11 05, 837, 777 cm "'

Reference Example 26 RR)-卜 [(6-Fluoronaphthalene-2-yl) methyl] pyrrolidine-3-yl i-3- (3- (2- [2- (tert-butyldimethylsilanyl) Ethoxy) ethoxy] ethoxy! Phenyl) ゥ rea (48)

 3- (2- [2- (tert-Butyldimethylsilanyloxy) ethoxy] ethoxy 1-phenylamine as raw material Using the same method as in Example 11, tri (R) -tri [(6- Fluoro naphthalene-2-yl) methyl] piperidin-3-yl 1-3- (3- (2- [2- (tert-butylmethylsilasiloxy) ethoxy] ethoxy) phenyl)） rea did.

MS (m / z): 582 (麵)

IR (KBr): 3319, 2933, 2862, 1641, 1608, 1551, 1246, 1144, 1109, 837, 773 cm " ¹

Ή one _{NMR (300 MHz, CDC1 3)} <5: 0.06 (6H, s), 0.89 (9H, m), 1.71 (1H, m), 1.21 -2.36 (2H, m), 2.55 (1H, m), 2.71 (1H, m), 2.96 (1H, m), 3.61 (2H, t, J = 5.5), 3.68-3.83 (6H, m), 3.07 (2H, t, J = 7.0), 4.24 (1H, m ), 5.37 (1H, d, J = 9.2), 6.63 (1H, d, J = 8.2), 6.77 (1H, d, J = 8.2), 7.01 (1H, m), 7.15 (1 2227

H, t J = 8.2), 7.24 (1H, t, J = 8.8), 7.40-7.62 (2H, m), 7.68-7.76 (3H, in) Example 23))-卜 [(6-Fluoronaphthalene-2-yl) methyl] pyrrolidine-3-yl 3- 3- [2- (2-hydroxyethoxy) ethoxy] phenyl 1 ゥ rea (49 )

 1- {00 _1-[(6-Fluoronaphthalene-2-yl) methyl] piperidin-3-yl 1 -3- (3- {2- [2_ (tert_butyldimethylsilanylo) Using xy) ethoxy] ethoxy 1 phenyl) urea as a raw material and using the same method as in Example 20, 1-ί (10-1-[(6-fluoronaphthalen-2-yl) methyl] piperidine -3-yl i-3- (3- [2- (2-hydroxyethoxy) ethoxy] phenyl 1 urea was synthesized.

MS (m / z): 468 (麵) +), 466 ((M-H)

IR (KBr): 3342, 2925, 1662, 1604, 1552, 1292, 1244, 1132, 1065, 870, 767 cm " ¹

Ή-NMR (300丽_{z CDC1 3) (5:.} . 1. 66 (1H, m), 2. 03-2 31 (2H, m), 2. 48-2 54 (1H, m), 2. 70 (1Η, m), 2.92 (1H, m), 3.59-3.78 (8H, m), 4.04 (2H, m) 4.23 (1H, m), 5.64 ( 1H, d J = 7.3), 6.53 (1H d, J = 7.9), 6.76 (1H, d, J = 8.9), 7.08 (2H, m), 7. 21 (1H m), 7.32-7.50 (2H, m), 7.67-7.75 (3H, m).

Reference Example 27 2-ί2- [2- (tert-butyldimethylsilanyloxy) ethoxy] ethoxy 1 phenylamine (50)

 Using 2-fluorobenzene and diethylene glycol as raw materials, 2-12- [2- (tert-butyldimethylsilanyloxy) ethoxy] ethoxy-1-phenylamine was synthesized using the same method as in Reference Example 19. .

IR (neat): 3373, 3367, 2929, 2856, 1616, 1506, 1460, 1277, 1253, 1221, 11 42, 1105, 835, 777 cm— ¹

Example 24 1-((R) -l-[(6-Fluoronaphthalene-2-yl) methyl] pyrrolidine-3-y 3- 3- [2- [2- (2-hydroxyethoxy) ethoxy] phenyl]] rea (51)

 Using 2- (2- [2- (tert-butyldimethylsilanyloxy) ethoxy] ethoxy 1-phenylamine as a starting material and the same method as in Example 4, tri (R) -tri [(6- Fluoro naphthalene-2-yl) methyl] pyrrolidine-3-yl 3- (2- [2- (2-hydroxyethoxy) ethoxy] phenyl) perea was synthesized.

MS (m / z): 468 (麵 "), 466 ((M-H)-)

IR (KBr): 3344, 2926 , 1660, 1603, 1547, 1447, 1249, 1118, 1067, 748 cm- 1 Ή one _{NMR (300 MHz, CDC1 3)} δ: 1. 66 (1Η, m), 2. 17-2.59 (2H, m), 2.48-2.54 (1H, m), 2.94 (1H, m), 3.10 (1H, m), 3.60-3.86 ( 8H, m), 4.05 (2H, m), 4.59 (1H, m), 6.71 (HI, d, J = 8.6), 6.82-7.04 (2H, m) , 7.23-7.27 (1H, m), 7.46 (1H, t, J = 8.2), 7.61 (1H, s), 7.74-7.83 (3H, m) , 8.24 (1H, d, J = 8.8). Reference Example 28 2- [3_ (tert-butyldimethylsilanyloxy) propoxy] phenylamine (52)

 Using 1_fluoro-2-nitrobenzene and 1,3-propanediol as raw materials, 2- [3_ (tert-butyldimethylsilanyloxy) propoxy] phenylamine was synthesized in the same manner as in Reference Example 19. .

MS (m / z): 282 ((M + H) ⁺ )

IR (neat): 2927, 1739, 1615, 1505, 1463, 1221 cm " ¹

'H-NMR (300 thigh _{z, CDC1 3) ά:.} 0. 05 (6Η, s), 0. 89 (9H, s), 1. 97-2 06 (2H, m), 3. 82 (2Η , t, J = 6.2), 4.10 (2H, t, J = 6.2), 6.70-6.82 (4H, m).

Example 25 l-i (R) -tri [(6-fluoronaphthalene-2-yl) methyl] pipalysin-3-yl 3- [2- (3-hydroxypropoxy) phenyl]ゥ rare (53)

 Using 2- [3_ (tert-butyldimethylsilanyloxy) propoxy] phenylamine as a raw material, 1-((R) -l-[(6-fluoronaphthylene- 2- [yl] methyl] pyrrolidine-3-yl 3- [2- (3-hydroxypropoxy) phenyl] urea was synthesized.

MS (m / z): 438 ((M + H) ⁺ ), 436 ((MH)

IR (KBr): 3331, 2954, 2809, 1640, 1601, 1548, 1450, 1248 cm " ¹

'H-NMR (300 MHz, CDC1 3) δ:... 1. 63-1 70 (1H, m), 1. 95-2 03 (2H, m), 2. 26-2 3 6 (2H, m), 2.60-2.72 (2H, m), 2.87-2.92 (1H, m), 3.73 (2H, s), 3.84 (2H, t, J = 5. 9), 4.09 (2H, t, J = 5.9), 4.37 (1H, m), 5.37 (1H, d, J-7.6), 6.87-7.98 ( 11H, m).

Reference Example 29 2- [4- (tert-butyldimethylsilanyloxy) butoxy] phenylamine (54)

 2- [4- (tert-butyldimethylsilanyloxy) butoxy] phenylamine was synthesized using trifluoro-2-nitrobenzene and 1,4-butanediol as raw materials and using the same method as in Reference Example 19.

MS (m / z): 296 ((M + H) ⁺ )

IR (neat): 2929, 1613, 1506, 1471, 1390, 1221 cm " ¹

Ή-NMR (300 MHz, CDC1 3) δ:.. 0. 06 (6Η, s), 0. 90 (9H, s), 1. 66-1 75 (2H, m), 1. 83-1 92 (2H, m), 3.69 (2H, t, J = 6.2), 4.02 (2H, t, J = 6.2), 6.68-6.79 (4H, m).

Example 26 RR)-卜 [(6-Fluoronaphthalen-2-yl) methyl] pipalysin-3-yl 3- [2- (4-hydroxybutoxy) phenyl] ゥ rea ( 55)

 Using 2- [4_ (tert-butyldimethylsilanyloxy) butoxy] phenylamine as a raw material and using the same method as in Example 4, tri-R) -tri [(6-fluoronaphthalene-2-yl) ) Methyl] pyrrolidine-3-yl 3- [2- (4-hydroxybutoxy) phenyl] threa was synthesized.

MS (m / z): 452 (麵) ⁺ ), 450 ((MH)-)

IR (neat): 3332, 2948, 2806, 1653, 1601, 1549, 1450, 1248 cm " ¹

Ή-NMR (300 negation _{z, CDC1 3) δ:.} .. 1. 62-1 96 (6Η, m), 2. 26-2 40 (1H, m), 2. 61-2 7

3 (2H, m), 2.85-2.94 (1H, m), 3.71 (2H, t, J-5.9), 3.75 (2H, s), 4.01 (2

H, s), 4.38 (1H, m), 5.47 (1H, d, J = 7.6), 6.80-8.03 (11H, m).

Reference Example 30 2- (2-methoxyethoxy) phenylamine (56)

(56)

 A solution of 2-methoxyethanol (1.7 ml) in dimethylformamide (20 ml) was ice-cooled, potassium tert-butoxide (800 mg) and 1-fluoro-2-nitrobenzene (1.0 g) were added, and the mixture was stirred for 12 hours. . The reaction solution was concentrated, distilled water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in methanol (50 ml), 10% palladium carbon (containing 50% water, 200 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The palladium carbon was filtered, and the filtrate was concentrated. The residue was purified by chromatography column chromatography for amine (ethyl acetate: hexane = 3: 7) to give 2- (2-methoxyethoxy) phenylamine (856 mg) (yield 72%).

MS (m / z): 168 (麵 ")

IR (neat): 3458, 3359, 2928, 2882, 1616, 1505, 1458, 1277, 1220, 1126, 74 1 cm ^-1

'H-NMR (300丽_{z, CDC1 3) δ:.} 3. 45 (3Η, s), 3. 73-3 78 (2H, m), 3. 85 (2H, br s), 4.08-4.17 (2H, m), 6.66-6.75 (2H, m), 6.78-6.84 (2H, m).

Example 27 1-((R) -tri [(6-fluoronaphthalene-2-yl) methyl] pyrrolidine-3-yl 1-3- [2- (2-methoxyethoxy) phenyl] ゥ rea (57)

 Using 2- (2-methoxyethoxy) phenylamine as a raw material and using the same method as in Example 11, 1-I (R) -tri [(6-fluoronaphthalene-2-yl) methyl] pi Mouth lysine-3-yl) -3- [2- (2-methoxyethoxy) phenyl] urea was synthesized.

MS (m / z): 438 ((M + H) ⁺ )

IR (KBr): 3331, 2940 , 2808, 1642, 1542, 1448 1246 1124, 869, 746 cm '1 Ή-NMR (300丽_{z CDC1 3) δ:. 1.} 65-1 74 (1H, m), 2.28-2.41 (2H, m), 2.68 (2Ηd, J = 4.9), 2.85-2.94 (1H, m), 3.42 (3H, s), 3 69-3.83 (4H, m), 4.09-4.18 (2H, HI), 4.35-4.44 (1H m), 5.21-5.25 (1H, m), 6.85-7.00 (3H, m) 7.2 0-7.28 (1H, in), 7.42 (1H, dd, J = 9.9, 2.6), 7.47-7 53 (1H, m), 7.71-7.80 (3H, m), 8.08 (1H, dd, J = 7.8, 1.7).

Reference Example 31 2- [2- (tert-butyldimethylsilanyloxy) ethyl] phenylamine (58)

 Using 2- (2-aminophenyl) ethanol as a raw material, 2- [2_ (tert-butyldimethylsilaeroxy) ethyl] phenylamine was synthesized in the same manner as in Reference Example 16.

 MS (m / z): 252 (麵 ")

IR (neat): 2929, 1624, 1498, 1461, 1255, 1095 cm- ¹

 — NMR (300 丽 z CDCI3) δ: 0.02 (6Η, s), 0.88 (9Η, s), 2.78 (2Η, t J = 6.2), 3.89 (2H, t, J = 6.2), 6.68-7.05 (4H, m).

Example 28 RR)-卜 [(6-Fluoronaphthalene-2-yl) methyl] pyrrolidine-3-- ) -3- [2- (2-Hydroxyethyl) phenyl] ゥ rea (59)

 Using 2- [2- (tert-butyldimethylsilanyloxy) ethyl] phenylamine as a raw material, and using the same method as in Example 4, tri (R) -tri [(6-fluoronaphthylene -2- [yl] methyl] pyrrolidine-3-yl 3- [2- (2-hydroxyethyl) phenyl] peryl was synthesized.

MS (m / z): 408 ((M + H) ⁺ ), 406 ((MH)-)

IR (neat): 3315, 2953, 2805, 1635, 1552, 1480, 1449, 1250 cnf ¹

Ή-NMR (300丽_{z, CDC1 3) δ:.} 1. 59 (1H, m), 2. 04-2 29 (2H, m), 2. 56 (1Η, dd,

J = 6.3, 9.9), 2.70-2.91 (4H, m), 3.66-3.76 (2H, m), 3.84 (2H, t, J = 5.9 ),

4.33 (1H, m), 5.34 (1H, d, J = 8.3), 7.11-7.77 (11H, m).

Reference Example 32 3- (2-Aminophenyl) propanol (60)

(60)

 To a dichloromethane (50 ml) solution of 3- (2-nitrophenyl) acrylic acid methyl ester (2.7 g) was added dropwise diisobutylaluminum hydride (0.95 M hexane solution: 30 ml) under ice cooling, and the mixture was stirred at room temperature for 24 hours. did. Water (30 ml) was added to the reaction solution, and the mixture was stirred for 1 hour. The solid was filtered off and the filtrate was concentrated. After dissolving the residue in methanol (50 ml), 10% palladium carbon (containing 50% water, 200 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 5 hours. The reaction solution was filtered, and the filtrate was concentrated. The residue was purified by chromatography column chromatography for amine (ethyl acetate: hexane = 1: 3) to give 3- (2-aminophenyl) propanol (767 mg) (yield 39%).

MS (m / z): 152 ((M + H) ⁺ )

I (KBr): 3393, 3315, 3214, 2935, 2867, 1647, 1584, 1494, 1459, 1260, 116 0, 1054, 1027, 907 cnf ¹

Ή-NMR (300 MHz, CDC1 3) δ:. 1. 82-1 91 (2Η, in), 2. 64 (. 2H, t, J = 7 3), 2. 93 ( 2H, br s), 3.64 (2H, t, J = 6.0), 6.68-6.72 (1H, m), 6.77 (1H, dt, 7.3, 1.2) , 7.01-7.07 (2H, m).

Reference Example 33 2- [3_ (tert_butyldimethylsilanyloxy) propyl] phenylamine (61)

(61)

 Using 3- (2-aminophenyl) propanol as a raw material, 2- [3- (tert-butyldimethylsilanyloxy) propyl] phenylamine was synthesized in the same manner as in Reference Example 16.

MS (m / z): 266 ((M + H) ⁺ )

IR (neat): 3366, 2953, 2928, 1621, 1498, 1471, 1461, 1256, 1097, 966, 835 cm " ¹

'H-NMR (300 MHz, CDC1 3) δ:. 0. 07 (6H, s), 0. 92 (9H, s), 1. 76-1 84 (2H, m), 2. 61 (2H, t, J = 7.4), 3.65 (2H, t, J = 5.9), 6.64-6.74 (2H, m), 6.97-7.05 (2H, m).

Example 29 {{(R)-[[(6-Fluoronaphthylene-2-yl) methyl] pyrrolidine-3-yl 3- [2- (3-hydroxypropyl) phenyl] ゥ rea (62)

 Using 2- [3- (tert-butyldimethylsilanyloxy) propyl] phenylamine as a raw material and using the same method as in Example 4, tri ((R) -tri [(6-fluoronaphthalene-2 -(Yl) methyl] pyrrolidine-3-yl 3- [2- (3-hydroxypropyl) phenyl] ゥ rea was synthesized.

 MS (m / z): 422 (concession), 420 ((M-H Square)

IR (KBr): 3324, 2951, 2795, 1624, 1560, 1251 cm " ¹

Ή-NM (300 MHz, CDC1 ₃ ) δ 1.59-1.70 (1 m, m), 1.75-1.83 (2H, m), 2.23-2.7.4 (7H, m) , 2.87-2.95 (1H, m), 3.52-3.57 (2H, m), 3.69-3.79 (2H, m), 4.33 -4.41 (1H, m), 5.39-5.47 (1H, m), 7.04-7.11 (IE m), 7.15-7.29 (3H, m), 7. 39-7.44 (3H, m), 7.54-7.60 (1H, m), 7.66-7.77 (3H, m).

Reference Example 34 1- [2- (tert-Butyldimethylsilanyloxy) ethyl] -1H-indazole-6-ylamine (63) (63)

 To a solution of 6-nitroindazole (1.56 g) in dimethylformamide (20 ml) were added potassium carbonate (1.54 g) and methyl bromoacetate (1 ml), and the mixture was stirred at room temperature. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. 1.09 g of the residue was dissolved in ethanol (10 ml), 10% palladium carbon (containing 50% water, 81 mg) was added, and the mixture was stirred overnight under a hydrogen atmosphere. The palladium carbon was filtered off and concentrated. 400 mg of the residue was dissolved in methanol (10 ml), sodium borohydride (450 mg) was added, and the mixture was stirred for 3 hours. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. 299 mg of the residue was dissolved in tetrahydrofuran (10 ml), and imidazole (200 mg) and tert-butyldimethylsilylcyl chloride (280 mg) were added, followed by stirring for 2 hours. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 1- [2- (tert-butyldimethylsilanyloxy) ethyl] -1H-indazole-6-ylamine (473 mg) was gotten.

MS (m / z): 292 (麵 ")

'H-NMR (300 MHz, CDC1 3) δ:. 0. 19 (6Η, s), 0. 92 (9H, s), 3. 95-3 97 (2H, m), 4. 17 (2H, t, J = 5.1), 4.59 (1H, t, J = 5.1), 6.97-7.10 (1H, m), 7.61-7.63 (1H, m), 7.88-7.93 (2H, m).

Example 30 RR)-卜 [(6-Fluoronaphthylene-2-yl) methyl] pyrrolidine-3-yl 3- [1- (2-hydroxyethyl) -1H-indazole-6-yl ] ゥ Rare (64)

 l_ [2_ (tert-butyldimethylsilanyloxy) ethyl] -1H-indazol-6-ylamine as a starting material, using the same method as in Example 4, to obtain R)-([6-fluoro) [Lonaphthalene-2-yl) methyl] pyrrolidine-3-yl 1-3-[(2-hydroxyethyl) -1H-indazol-6-yl] urea was synthesized.

MS (m / z): 448 (讓) +)

IR (KBr): 3314, 1633, 1589, 1557, 1509, 1477, 1249, 1068, 868 cm— ¹

Ή-NMR (300 MHz, CDC1 3) δ: 1.48-3.11 (6Η, m), 3.77 (2H, s), 4.00-4.02 (3H, m), 4.41 (2H, t, J = 4.9), 6.74 ( 1H, d, J = 10.3), 7.20-7.90 (10H, m).

Reference Example 35 2- [2- (tert-butyldimethylsilanyloxy) -1- (tert-butyldimethylsilanyloxymethyl) ethoxy] phenylamine (65)

 Using 2-fluoro-2-benzene and 1,3-dibenzyloxy-2-propanol as raw materials, and using the same method as in Reference Example 19, 2- [2- (tert-butyldimethylsilanyloxy)- [Tert-butyldimethylsilanyloxymethyl) ethoxy] phenylamine was synthesized.

MS (m / z): 412 (Y) ⁺ )

IR (neat): 3473, 3363, 2931, 2858, 1616, 1504, 1466, 1255, 1215, 1097, 839, 777 cm— ¹

'H-NMR (300 thigh _{z, CDC1 3) δ: 0.16} (12H, s), 0.83 (18H, s), 3.74-3.78 (4H, m), 3.95 (2Η, s), 4.09 (1Η, Quint, J = 5.1), 6.60 (1H, t, J = 7.8), 6.64 (1H, d, J = 7.8), 6.77 (1H, t, 1 = 1.8), 6.84 (1H, d, 1 = 1.8).

Example 31 1-((R) -Tri [(6-fluoronaphthalene-2-yl) methyl] pipalysin-3-yl 3- [2- (2-hydroxy-1-hydroxymethyl Ethoxy) phenyl] ゥ rea (66)

 Using 2- [2- (tert-butyldimethylsilanyloxy) -tri (tert-butyldimethylsilazyloxymethyl) ethoxy] phenylamine as a starting material, tri ((R)- l-[(6-Fluoronaphthylene-2-yl) methyl] pyrrolidine-3-yl 3- [2- (2-hydroxy-1-hydroxymethylethoxy) phenyl] urea was synthesized.

MS (m / z): 454 ((M + H) ⁺ )

IR (KBr): 3325, 1668, 1603, 1549, 1448, 1250, 1043, 744 cm " ¹

.. Ή - negation _{R (300 MHz, CDC1 3)} δ: 1. 55-3 00 (6Η, m), 3. 76 (2Η, s), 3. 87-3 92 (4Η, m), 4. 17 (1H, uint, J = 4.2), 4.37-4.44 (1H, m), 5.80 (1H, d, J = 7.8), 6.91-6.99 (3H , m), 7.23-7.28 (1H, m), 7.42-7.47 (3H, m), 7.72-7.81 (3H, m), 7.94 (1H, s ), 8.00 (1H, d, J = 8.0).

Reference Example 36 [4- (2-Hydroxyethylamino) -3-nitrophenyl] carbamic acid benzyl ester (67)

To a solution of 4-fluoro-3-nitroaniline (1.88 g) in tetrahydrofuran (60 ml) were added sodium hydride (506 mg) and thiopobenzoxycyclolide (1.8 ml), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained solid was dissolved in dimethylformamide, potassium carbonate (1.80 g) and 2-aminoethanol (lml) were added, and the mixture was stirred at 80 ° C for 5 hours. The reaction solution was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give [4- (2-hydroxyethylamino) -3- (2-phenylphenyl) carbamic acid benzyl ester (1.67 g) Was obtained (yield 42%). MS (m / z): 332 ((M + H) ⁺ )

Ή-NMR (300 MHz, CDC1 3) <5: 3. 51 (. 2H, Q, J = 5 4), 3. 94 (. 2H, a, J = 5 4), 5. 20 (2H, s ), 6.89 (1H, d, J = 9.1), 7.36-7.40 (6H, m), 8.10 (1H, s).

Reference Example 37 1- [2- (tert-butyldimethylsilanyloxy) ethyl] -1H-benzoimidazole-5-ylamine (68)

 [4- (2-Hydroxyethylamino) -3_nitrophenyl] benzyl ester carbamate (660 mg) in tetrahydrofuran (7 ml), methanol (14 ml) and water (14 ml) was dissolved in a solution of ammonium chloride (460 mg) and iron powder ( 350 mg) and stirred at 80 ° C for 2 hours. The precipitate was filtered, the filtrate was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in tetrahydrofuran (10 ml), imidazole (200 mg) and tert-butyldimethylsilyl chloride (360 mg) were added, and the mixture was stirred for 2 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1), 238 mg of which was dissolved in ethyl orthoformate (5 ml) and stirred at 100 ° C for 6 hours. The reaction solution was concentrated, the residue was dissolved in ethanol (15 ml), 10% palladium carbon (containing 50% water, 19 mg) was added, and the mixture was stirred overnight under a hydrogen atmosphere. The palladium carbon was filtered off, and the filtrate was concentrated. . The residue was purified by silica gel column chromatography (ethyl acetate) to give tri- [2- (tert-butyldimethylsilanyloxy) ethyl] -1H-benzoimidazole-5-ylamine (134 mg).

MS (m / z): 292 ((M + H) +)

Ή-NMR (300 thigh _{z, CDC1 3) δ: 0.} 02 (6Η, s), 0. 96 (9H, s), 3. 62 (2H, s), 4. 04 (2H, t, J = 5.2), 4.33 (2H, t, J = 5.2), 6.87 (1H, d, J = 8.5), 7.23 (1H, s), 7.30 (1H, d, J = 8.5), 7.96 (1H, s)

Example 32 1-((R) _1-[(6-Fluoronaphthalene-2-yl) methyl] pialysin-3-yl 4- [1- (2-hydroxyethyl) -1H -Benzoimidazo- 5-yl] ゥ rea (69) (69)

 Using 1- [2- (tert-butyldimethylsilanyloxy) ethyl] -1H-benzimidazole-5-ylamine as a raw material, a method similar to that of Example 4 was used to prepare ((R) -tol [( 6-Fluoronaphthalene-2-yl) methyl] pyrrolidine-3-yl 3- [1- (2-hydroxyethyl) -1H-benzoimidazole-5-yl] urea was synthesized. .

MS (m / z): 448 (picture +)

IR (KBr): 3289, 1635, 1565, 1249, 1141, 871 cm— ¹

 Ή-Band R (300 MHz, DMS0) δ: 1.55 (1Η, m), 2.19 (1H, m), 2.37-2.49 (2H, m), 2.64-2.74 (2H, m), 3.70 (2H, Q, J = 5.1), 3.74 (2H, s), 4.12 (1H, m), 4.21 (2H, t, J = 5.1), 4.96 (1H, t, J = 5.1), 6.24 (1H, d, J = 5.4) ), 7.12 (1H, d, J = 8.5), 7.38-7.42 (2H, m), 7.58 (1H, d, J = 8.5), 7.68 (1H, d, J = 8.2), 7.72 (1H, s) , 7.84-7.99 (3H, m), 8.04 (1H, s), 8.27 (1H, s).

Reference Example 38 2- [2- (tert-butyldimethylsilanyloxy) ethoxy] -4-fluorophenylamine (70)

(70)

 Using 5-fluoro-2-nitrophenol as a raw material, 2_ [2- (tert-butyldimethylsilanylooxy) ethoxy] -4-fluorophenylamine was synthesized by the same method as in Reference Examples 3 and 6. .

MS (m / z): 286 ((M + H) ⁺ )

Ή-NMR (300 MHz, CDC1 3) δ: 0.10 (6Η, s), 0.91 (9H, s), 3.96-4.06 (4H, m), 6.49-6.65 (3H, m).

Example 33 1-((R) -tri [(6-fluoronaphthalen-2-yl) methyl] pyrrolidine-3-yl) -3- [4-fluoro-2- (2-hydroxyethoxy) Phenyl] ゥ rare (71)

 Using 2- [2- (tert-butyldimethylsilanyloxy) ethoxy] -4-fluorophenylamine as a raw material and using the same method as in Example 4, 1-i (R) -tri [(6 -Fluoro naphthylene-2-yl) methyl] pyrrolidine-3-yl 3- [4-fluoro-2- (2-hydroxyshethoxy) phenyl] urea was synthesized.

MS (m / z): 442 ((M + H) ⁺ )

Ή-NMR (300 MHz, CDC1 3) δ: 1.56 (1Η, in), 2.16-2.83 (5H, m), 3.65 (2H,), 3.78 (2H, m), 3.88 (2H, m), 4.28 ( 1H, br s), 5.73 (1H, m), 6.45-6.62 (2H, m), 7.20-7.74 (9H, m).

Reference Example 39 1- [2- (tert-butyldimethylsilanyloxy) ethyl] -1H-indole-6-ylamine (72)

1- [2- (tert-Butyldimethylsilanyloxy) ethyl] -1H-indole-6-ylamine was synthesized using 6-nitroindole as a raw material and using the same method as in Reference Example 34.

MS (m / z): 291 ((M + H) ⁺ )

Ή-丽R (300丽_{z, CDC1 3) δ -0.11 (} 6Η, s), 0.85 (9H, s), 3.88 (2H, t, J = 5.9), 4.11 (2H, t, J = 5.9), 6.34-7.40 (5H, m).

Example 34 (R) -l-[(6-Fluoronaphthalen-2-yl) methyl] pyrrolidine-3-yl 3- [H2-hydroxyethyl) -1H-indole-6-yl] ゥ rea (73 )

1- [2- (tert-ブチルジメチルシラニルォキシ）ェチル] - 1H-ィンドール- 6-ィルァ ミンを原料として用い、 実施例 4と同様の手法を用いて 卜（（R) -卜 [ (6-フルォロ ナフタレン- 2-ィル）メチル] ピロリジン- 3 -ィルト 3- [卜（2 -ヒ ドロキシェチ ル）- 1H-インドール- 6-ィル]ウレァを合成した。

Using 1- [2- (tert-butyldimethylsilanyloxy) ethyl] -1H-indole-6-ylamine as a raw material, a method similar to that of Example 4 was used to prepare the tritium ((R) -trit [( 6-Fluoronaphthalene-2-yl) methyl] pyrrolidine-3-yl-3- [tri (2-hydroxylethyl) -1H-indole-6-yl] urea was synthesized.

MS (m / z): 447 ((M + H) ⁺ )

Ή-NMR (300丽_{z CDC1 3) δ:. 1.} 68 (1H, m), 2. 17-2 94 (5H, m), 3. 70 (2H, s), 3. 81 (2H, t J = 5.1), 4.17 (2H, t J = 5.1), 4.36 (1H, brs) 5.46 (1H m) 6.48-7.72 (12H, m).

Reference Example 40 2- [2- (tert-butyldimethylsilanyloxy) ethoxy] -3- (tert-butyldimethylsilanyloxymethyl) phenylamine (74)

 Using 3-nitrosalicylic acid methyl ester as a raw material, 2- [2- (tert-butyldimethylsilanyloxy) ethoxy] -3- (tert-butyldimethyl) was obtained in the same manner as in Reference Example 36. Silanyloxymethyl) phenylamine was synthesized. MS (m / z): 412 (麵) +)

¾ -丽R (300 negation _{z CDC1 3) δ: 0. 096} (6Η, s), 0. 12 (6Η, s), 0. 93 (9Η, s), 0. 94 (9Η s), 3. 93 (4Η m) 4.14 (2Η, br s), 4.77 (2H, s), 6.64-6.94 (3H, m) · Example 35 1-((R) _ [[( 6-Fluoronaphthalene-2-yl) methyl] pyrrolidine-3-yl1-3- [2- (2-hydroxyethoxy) -3-hydroxymethylphenyl] ゥ rea (75)

Using 2- [2- (tert-butyldimethylsilanyloxy) ethoxy] -3- (tert-butyldimethylsilanyloxymethyl) phenylamine as a raw material, a method similar to that of Example 4 was used to prepare the tri (( R) -tri [(6-fluoronaphthyl-2-yl) methyl] pyrrolidine-3-yl 3_ [2- (2-hydroxyethoxy) -3-hydroxymethylphenyl] urea was synthesized. MS (m / z): 454 ((M + H) "

Ή over丽R (300 thigh _{z, CDC1 3) δ: 1.59} (1H, m), 2.26-2.95 (5H, m), 3.68-3.85 (6H, m), 4.36 (1H, br s), 4.56 (2H , s) 5.56 (1H, m), 6.86-8.21 (10H, m).

 Reference Example 41 2- [2- (tert-butyldimethylsilanyloxy) ethoxy] -5-methylphenylamine (76)

 Using 4-chloro-3-nitrotoluene and ethylene glycol as raw materials, and using the same method as in Reference Example 19, 2- [2- (tert-butyldimethylsilanyloxy) ethoxy] -5-methyl Phenylamine was synthesized.

) MS (m / z): 282 ((M + H) +)

Ή-NM (300 MHz, CDC1 3) δ: 0.09 (6H, s), 0.90 (9H, s), 2.21 (3H, s), 3.79 (2H, br s), 3.94 (2H, t, J = 5.1 ), 4.01 (2H, t, J = 5.1), 6.47 (1H, d, J = 8.0), 6.45 (1H, s), 6.61 (1H, d, J = 8.0).

 Example 36 1-((R) _tri [(6-fluoronaphthalene-2-yl) methyl] pyrrolidine-3-yl 3- [2- (2-hydroxyethoxy) -5-methylphenyl] ゥ rea (77)

 Using 2- [2- (tert-butyldimethylsilanyloxy) ethoxy] _5-methylphenylamine as a raw material, 1-((R) -1-[( 6-Fluoronaphthalene-2-yl) methyl] pyrrolidine-3-yl 3- [2- (2-hydroxyethoxy) -5-methylphenyl] urea was synthesized.

 MS (m / z): 438 ((M + H) +)

Ή-1 NMR (300 bandz, CDCI3) δ: 1.63 (1H, m), 2.24-2.90 (8H, m), 3.72 (2H, m), 3.83 (2H, m), 3.96 (2H, m), 4.35 (1H, br s), 5.86 (1H, m), 6.69-7.76 (10H, m).

Reference Example 42 3-Amino-4_ [2- (tert-butyldimethylsilanyloxy) ethoxy] benzonitrile (78)

4_Clot mouth-3-Nitrobenzonitrile (1.00 g), ethylene glycol (0.9 ml) were dissolved in dimethylformamide (5 ml), sodium hydride (241 mg) was added, and the mixture was stirred at room temperature for 10 minutes. . Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. 625 mg of the residue was dissolved in tetrahydrofuran (6 ml), and methanol (10 ml), water (12 ml), iron powder (503 mg) and ammonium chloride (570 mg) were added, followed by stirring at 60 ° C for 4 hours. The solid was filtered off and the filtrate was concentrated. An aqueous solution of sodium hydrogen carbonate was added to the residue, and the mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the organic solvent was distilled off, and the precipitated solid was collected by filtration. 410 mg of the solution was dissolved in tetrahydrofuran (2.5 ml), imidazole (235 mg) and tert-butyldimethylsilyl chloride (381 mg) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 20) to obtain 333 mg of 3-amino-4- [2- (tert-butyldimethylsilanyloxy) ethoxy] benzonitrile. .

MS (m / z): 293 ((M + H) +)

¾- NMR (300 negation _{z, CDC1 3) 6:.} 0. 09 (6H, s), 0. 91 (9H, s), 3. 98-4 13 (6H, m), 6. 81-7. 04 (3Η, m).

Example 37 1-ί (R) -tri [(6-fluoronaphthalene-2-yl) methyl] pyrrolidine-3-yl) -3- [5-cyano-2- (2-hydroxyethoxy) Phenyl] ゥ rea (79)

 Using 3-amino-4- [2- (tert-butyldimethylsilanyloxy) ethoxy] benzonitrile as a raw material and using the same method as in Example 4, 1-i (R) -tri [(6- Fluoronaphthalene-2-yl) methyl] piperidin-3-yl j-3- [5-cyano-1- (2-hydroxyethoxy) phenyl] urea was synthesized.

MS (ni / z): 449 (picture ⁺ )

Ή-NMR (300顧_{z, CDC1 3) δ: 1.62} (1Η, m), 2.27-2.91 (5H, m), 3.72 (2H, m), 3.88 (2H, m), 3.99 (2H, m), 4.33 (1H, br s), 5.83 (1H, m), 6.73-8.38 (10H, m).

Example 38 1-ί (R) -tri [(6-fluoronaphthalene-2-yl) methyl] pyrrolidine-3-y M -3--[5-culo-2- (2-hydroxye Toxi) phenyl] rare (80)

Using 2,5-dichloronitrobenzene and ethylene glycol as raw materials, 1-((R) -toluene [(6-fluoronaphthalene-2-yl) was obtained by the same method as in Reference Example 42 and Example 4. ) Methyl] pyrrolidine-3-yl 3- -chloro-2- (2-hydroxyethoxy) phenyl] urea was synthesized.

MS (πι / ζ): 458 (Picture +)

Ή-NMR (300 MHz, CD 3 0D) δ: 1.61 (1H, m), 2.22-2.85 (5H, m), 3.66-4.25 (7H, m), 6.77-8.10 (9H, m).

Example 39 1-I (R) -tri [(6-fluoronaphthalene-2-yl) methyl] pyrrolidine-3-yl 3- [3-chloro-2- (2-hydroxyethoxy) phene two (81)

 Using 2,3-dichloronitrobenzene and ethylene glycol as raw materials and using the same method as in Reference Example 42 and Example 4, tri ((R) -1-[(6-fluoronaphthalene-2-yl) ) Methyl] pyrrolidine-3-yl 3- [3-chloro-2_ (2-hydroxyethoxy) phenyl] urea was synthesized.

MS (m / z): 458 ((M + H) ⁺ )

Ή-NMR (300 MHz, CD 3 0D) δ:.. 1. 66 (1H, m), 2. 29-2 88 (5Η, m), 3. 76-4 27 (7Η, m), 6. 96-7. 98 (9Η, m).

Reference Example 43 (3-Hydroxy-2-nitrophenoxy) acetic acid methyl ester (82)

 To a solution of 2-nitroresorcinol (3.10 g) in dimethylformamide (40 ml) were added potassium carbonate (1.45 g) and methyl bromoacetate (0.95 ml), and the mixture was stirred at room temperature. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give (3-hydroxy-2-diphenoxy) acetic acid methyl ester (591 mg) (yield 26%).

MS (m / z): 228 (drawings)

Ή-NMR (300 MHz, CDC1 3) δ 3. 82 (3Η, s), 4. 77 (2Η, s), 6. 41 (1Η, d, J = 8. 3), 6. 78 (1Η, d, J = 8.5), 7.38 (1H, t, J = 8.5), 10.12 (1H, s).

Reference Example 44 2_tert-butyldimethylsilanyloxy-6- [2- (tert-butyldimethylsilanyloxy) ethoxy] phenylamine (83)

In a solution of lithium aluminum hydride (113 mg) in tetrahydrofuran (3 ml), A solution of (3-hydroxy-2-nitrophenoxy) acetic acid methyl ester (340 mg) in tetrahydrofuran (3 ml) was added, and the mixture was stirred at room temperature for 1 hour. Anhydrous magnesium sulfate was added to the reaction solution, and a saturated aqueous solution of sodium sulfate was added dropwise. The deposited precipitate was separated by filtration and the solvent was distilled off. Dissolve the residue in methanol (10 ml) and add 10% palladium

(50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 30 minutes. After filtering off the palladium, the solvent was distilled off. The residue was dissolved in tetrahydrofuran (6 ml) and imidazole

(510 mg) and tert-butyldimethylsilyl chloride (904 mg) were added, and the mixture was stirred for 2 hours. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to give 2-tert-butyldimethylsilylyloxy-6- [2- (tert-butyldimethylsilanyloxy) ethoxy] phenylamine (161 mg) was obtained (yield 27%).

MS (m / z): 398 (麵) ⁺ )

'H-NMR (300丽_{z, CDC1 3) δ: 0.} 10 (6Η, s), 0. 23 (6H, s), 0. 91 (9H, s), 1. 02 (9H, s), 3.79 (2Η, br s), 3.96 (2H, t, J = 5.2), 4.05 (2H, t, J = 5.2), 6.44-6.54 (3H, m).

Example 40 l-{(R) -tri [(6-fluoronaphthalene-2-yl) methyl] pipalysin-3-yl 3- [2-hydroxy-6- (2-hydroxyethoxy) Phenyl] ゥ rea (84)

 Using 2-ter t-butyldimethylsilanyloxy-6- [2- (tert-butyldimethylsilanyloxy) ethoxy] phenylamine as a starting material, tri ((R)- [(6-Fluoronaphthalene-2-yl) methyl] pyrrolidine-3-yl 3- [2-hydroxy-6- (2-hydroxyethoxy) phenyl] urea was synthesized MS (m / z): 440 ((M + H) +)

IR (neat): 3347, 2943 , 2814, 1657, 1558, 1479, 1254, 1103, 1072, 735 cm "1 'H-NMR (300 MHz, CDC1 3) δ: 1. 63 (1H, m), 2 20-2. 27 (2H, m), 2.51-2.55 (1H, m), 2.81 (1H, d, J = 10.5), 2.92 (1H, t, J = 8.3), 3.72 (2H, m), 3.79-3.81 (2H, ml, 3.92-3.93 (2H, m), 4.29 (1H, br s), 6.33 (1H, d, J = 8.3), 6.58 (1H, d, J = 8.3), 6.91 (1H, t, J = 8.3) ), 7.20-7.28 (1H, m), 7.39-7.43 (2H, m), 7.68-7.75 (3H, m).

Example 41 Evaluation of intracellular Ca ²⁺ concentration using human CCR3-expressing cells (CCR3 / B300-19 cells)

実施例 42 マウス CCR3発現細胞を用いた細胞内 Ca²⁺濃度評価 A solution was prepared by adding the fluorescent indicator fura-2 AM (Dohjin Chemical Laboratory Co., Ltd.) to an RPMI 1640 medium containing 1% fetal bovine serum to a final concentration of 5 ^ M. B300-19 cells (Cell 27, 381-390, 1981) transformed with human CCR3 were suspended at ⁷ cells / ml. After allowing fura-2 AM to be taken into the cells by allowing them to stand for 30 minutes at 37, basic salt solution containing 0.1% pepsin albumin (5.4 mM KC1, 130 mM NaCL 2.5 mM CaCl ₂ , It was washed twice with ImM MgCl ₂ , 5.5 mM glucose, 20 mM HE PES, pH 7.4) and resuspended to 2 × 10 ⁶ cells / ml. Intracellular Ca ²⁺ concentration ([Ca ²⁺ ] i) was measured using CAF-110 (JASCO Corporation). When human eotaxin (Peprotech Inc., USA) was added to the cell suspension to a final concentration of 50 ng / ml, an increase in [Ca ²⁺ ] i was observed. Test compounds were added one minute before the addition of human eotaxin, by measuring the effect on the increase of by human eotaxin [Ca ^2+] i, the CCR3 inhibitory activity of a test compound IC _{5 ()} values (human eotaxin (A concentration that suppresses the increase of [Ca ²⁺ ] i caused by the addition of 50). Table 2 shows the inhibitory activities of representative compounds. Table 2

Example 42 Evaluation of intracellular Ca ²⁺ concentration using mouse CCR3-expressing cells

Suspend mouse CCR3-expressing CH0 cells in RPMI 1640 medium containing 10% fetal fetal serum at a concentration of ³ × 10 ^{5 to 5} × 10 ⁵ cells / ml, and inoculate 100 x 1 / well in a 96-well plate overnight. Cultured. After washing the cells, a solution was added to RPMI 1640 medium containing 1% fetal bovine serum and fluo-3 cliff (Dojindo Laboratories, Inc.), a fluorescent indicator, added to a final concentration of 5 μl. Each 40 / _Π was added, and the cells were further cultured for 1.5 to 2 hours. Then the fluorescence The solution containing the indicator was removed, the cells were washed, and Hank's balanced salt solution (Invitrogen, Tokyo, Japan) containing 0.1% BSA was added to IOOI. The intracellular Ca ²⁺ concentration was evaluated using a Fluorometric Imaging Plate Reader (Molecular Devices). When mouse eotaxin (Peprotech Inc., USA) was added to a final concentration of 50 ng / ml, an increase in [Ca ²⁺ ] i was observed. Test compounds were added one minute before you added Mouse eotaxin, by measuring the impact with respect to the increase of by ^{mouse eotaxin [Ca 2+] i,} CCR3 inhibitory activity IC _5Q values of the test compound (mouse eo taxin (A concentration that suppresses the increase of [Ca ²⁺ ] i by 50% caused by the addition of). Table 3 shows the inhibitory activities of typical compounds.

 Table 3

実施例 43 卵白アルブミン誘発マウス喘息モデルを用いた肺への炎症性細胞浸潤 に対する抑制作用 1

Example 43 Inhibitory effect on inflammatory cell infiltration into lung using ovalbumin-induced mouse asthma model 1

 The inhibitory effect of the compound of the present invention on inflammatory cell infiltration into the lung in a mouse asthma model using ovalbumin (0VA) as an antigen was evaluated.

After purchasing female BALB / c mice at the age of 6 weeks, they were pre-bred for 1 week before use in the experiments. The mice were sensitized on day 1 and day 14 by intraperitoneal administration of 0.2 ml of a mixture containing 20 ovalbumin (0VA) and 2 mg of aluminum hydroxide. On the 28th day, an aerosol generated by an ultrasonic nebulizer (NE_U12, OMRON, Kyoto, Japan) supplemented with 20 xg / ml OVA-PBS was inhaled for 20 minutes to induce an asthmatic response (induced group). . In the non-induced group, only PBS was inhaled for 20 minutes (non-induced group). Compound of the present invention An unresolved solvent or a drug solution containing the compound of the present invention was administered before inhaling OVA-PBS. The administration was continued from the 27th to 30th day from the start of the test by implanting two Osmotic Pumps (made of Alze earth) filled with the compound solution of the present invention subcutaneously in the back. In the non-induction group and the drug-free control group, two pumps filled with the solvent only were implanted under the skin on the back. 48 hours after the induction, the animals were exsanguinated and killed under ether anesthesia, tracheal force was inserted, and the inside of the alveolar cavity was washed four times with 0.7 ml of physiological saline, and the cells were collected. The alveolar lavage solution was transferred to a plastic tube, centrifuged, and the supernatant was removed. The cells were then reconstituted with 1 ml of Hank's balanced salt solution (Invitrogen, Tokyo, Japan). Suspended in water. The total number of leukocytes contained in this cell suspension was measured using a multi-item automatic blood cell counter (Toa Medical Co., Ltd., Hyogo, Japan).

 Most of the inflammatory cell infiltration into the lungs is eosinophils, and the average of the total leukocyte (resident cell) count in the uninduced group measured as described above is subtracted from the total leukocyte count in each individual. The inflammatory cell infiltration number was calculated by subtraction. Further,% of Control (the value when the control group was taken as 100) was calculated by dividing the number of inflammatory cell infiltration of each individual by the average value of the number of inflammatory cell infiltration in the control group. Table 4 shows the values of Control for representative compounds.

実施例 44 卵白アルブミン誘発マウス喘息モデルを用いた肺への炎症性細胞浸潤 に対する抑制作用 2 Table 4

Example 44 Inhibitory effect on inflammatory cell infiltration into lung using ovalbumin-induced mouse asthma model 2

 The inhibitory effect of the compound of the present invention on inflammatory cell infiltration into the lung in a mouse asthma model using ovalbumin (0VA) as an antigen was evaluated.

After purchasing female BALB / c mice at the age of 6 weeks, they were pre-bred for 1 week before use in the experiments. The mice were sensitized on day 1 and day 14 by intraperitoneal administration of 0.2 ml of a mixture containing 20 ovalbumin (0VA) and 2 mg of aluminum hydroxide. Day 28 On the 29th and 29th days, an aerosol generated by an ultrasonic nebulizer (NE-ϋ12, OMRON, Kyoto, Japan) supplemented with 20 zg / ml OVA-PBS was inhaled for 20 minutes to induce an asthma reaction ( Trigger group). In the non-induced group, only PBS was inhaled for 20 minutes (non-induced group). A solvent containing no compound of the present invention or a drug solution containing the compound of the present invention was administered before inhaling OVA-PBS. The administration was carried out continuously from the 27th to 30th day from the start of the test by implanting two Osmotic Pumps (manufactured by Alzet) filled with the compound solution of the present invention subcutaneously in the back. In the non-induced group and the drug-untreated control group, two pumps filled only with the solvent were implanted subcutaneously in the back. Twenty-four hours after induction, the animals were exsanguinated and killed under ether anesthesia, tracheal force was introduced, and the alveolar cavity was washed four times with 0.7 ml of physiological saline to collect cells. . The alveolar cavity washing solution was transferred to a plastic tube, centrifuged, the supernatant was removed, and the cells were suspended in 1 ml of Hank's balanced salt solution (Invitrogen Corporation, Tokyo, Japan). The total number of leukocytes contained in the cell suspension was measured using a multi-item automatic blood cell counter (Toa Medical Co., Ltd., Hyogo, Japan).

 The activity of the compound of the present invention was measured in the same manner as in Example 43, except that asthma induction by inhalation of 20 g / ml of OVA-PBS was performed on days 28 and 29. The number of inflammatory cell infiltration was calculated by the same method as in Example 43, and the number of inflammatory cell infiltration of each individual was divided by the average value of the number of inflammatory cell infiltration in the control group to obtain% of Cont. rol (value when the control group is set to 100) was calculated. Table 5 shows typical compounds and numerical values (% of Control Compound 9) of compounds (compound 9) included in the claims of International Publication No. 01/87983 9 but not specifically disclosed. ) showed that. In addition to the results of Example 43, the compound of this example was found to have a superior effect of inhibiting infiltration of inflammatory cells as compared to Compound 9.

 Table 5

実施例 45 サルにおける経口吸収性評価 被験薬剤を力二クイザルに投与 （静脈内投与： 0. 5mg/kg、 経口投与： 1. Omg/kg ) 後、 血漿を経時的に採取した。 採取した血漿を te rt-ブチルメチルエーテルを 用いて前処理後、 LC- MS/MSにより血漿中の被験薬剤濃度を測定し、 血漿中濃度時 間曲線下面積 （A U C ) を算出した。 経口投与後の A U Cを静脈内投与後の A U Cで除すことにより、 経口吸収性の指標である生物学的利用率を求めた。 表 6に 本発明の環状アミン化合物である実施例 1 0の化合物を投与した場合における血 漿中濃度から算出した生物的利用率の数値を示した。

Example 45 Evaluation of oral absorption in monkeys After the test drug was administered to cynomolgus monkeys (intravenous administration: 0.5 mg / kg, oral administration: 1. Omg / kg), plasma was collected over time. After the collected plasma was pretreated with tert-butyl methyl ether, the test drug concentration in the plasma was measured by LC-MS / MS, and the area under the plasma concentration time curve (AUC) was calculated. By dividing the AUC after oral administration by the AUC after intravenous administration, bioavailability, an indicator of oral absorbability, was determined. Table 6 shows the values of the bioavailability calculated from the plasma concentration when the compound of Example 10 which is the cyclic amine compound of the present invention was administered.

Table 6

) All publications, patents and patent applications cited herein are hereby incorporated by reference in their entirety. Industrial applicability

 The compounds of the present invention are useful as active ingredients in pharmaceutical preparations. In particular, it has a CCR3 antagonistic activity i, so it is useful as a prophylactic and therapeutic agent for inflammatory diseases and the like. It is more useful as

 Further, the compound of the present invention is a compound having excellent oral absorption in mammals and a compound having excellent drug efficacy even when administered orally.

Claims

Scope of Claim Formula 1:

 (In Formula 1, A is a group selected from the group consisting of an aryl group, a heterocyclic group, and a cycloalkyl group, and has at least one substituent X and at least one substituent Y. May be Substituent X is substituted with 0H ₍₆ alkyl, (0 (substituted by C ₂ _ ₆ alkyl)) substituted with 0H ₍₆ alkyl, - substituted with C00H ₍₆ alkyl, - (KHCH Alkyl) substituted C _1Hj alkyl, -C0NH ₂ substituted ( ₆ alkyl, -CON (Cw alkyl) ₂ substituted ( ₆ alkyl, -NHCOO ^ alkyl) substituted _ ₆ alkyl, 0 - alkyl substituted by (substituted _(C6 alkyl) by C00H), substituted with (0- (as substitution with coo ₆ alkyl) _{(alkyl)) (6} alkyl, (0 (( 0 ₍₆ alkyl) substituted by a _ ₆ alkyl)) ₆ alkyl substituted with, O-O-CH-alkyl) C Bok ₆ alkyl substituted with), is substituted with 0- ((0- halogen was substituted with _{(3-alkyl) (6} Aruki _{Le), 0 - (C 2 _} 6 alkyl substituted with 0H), 0 - substituted with ((0 ₍₆ Arukiru substituted by 0H)) _ ₆ alkyl), 0- C _M § alkyl substituted with (N (been C ₂ _ ₃ alkyl substituted by 0H) _2), 0- (substituted with CN ₍₆ alkyl), 0 - (Okiso group in substituted ₍₆ alkyl Le), 0- (substituted with C00H ₍₆ alkyl), 0- (C00O ₆ alkyl) d_ ₆ alkyl substituted with), 0 (_ ₆ substituted by C0Nh ₂ alkyl), 0 0 ₂ volumes ₂ _ ₆ Al killed substituted with), 0 - (consisting CONO ^ alkyl) substituted with ₂ (^ alkyl) and 0_CH (substituted by 0H ₍₂ alkyl) ₂ Selected from the group, Substituent Y is selected from the group consisting of halogen, _—3 alkyl, 0H, methoxy, CN and CF ₃ . ) Or a pharmaceutically acceptable salt thereof. 2. substituent X is - substituted with C00H ₍₆ alkyl, - _ ₆ alkyl substituted with C0Nh ₂ , 0- ((0 _ ₆ alkyl) with substituted alkyl) and 0- (c ₂ _ ₆ Al substituted with 0H 2. The cyclic amine compound or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the group consisting of:  3. The cyclic amine compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein the substituent Y is selected from the group consisting of F, Cl, 0H, methyl and CN.  4. A pharmaceutical composition comprising the cyclic amine compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.  5. A CCR3 inhibitor comprising the cyclic amine compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.  6. A therapeutic agent for an inflammatory disease, comprising the cyclic amine compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.  7. A therapeutic agent for a disease derived from inflammatory cell infiltration, comprising the cyclic amine compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.  8. A therapeutic agent for a disease derived from eosinophil infiltration, comprising the cyclic amine compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.