WO2004026832A1 - Urea compound and use thereof - Google Patents

Abstract

A compound represented by the formula (I) [wherein R1 represents C1-8 alkyl or phenyl which may have a halogen, optionally halogenated C1-4 alkyl, cyano, or C1-4 alkyloxy as a substituent; and R2 represents a group represented by the formula -SO2NR3R4 (wherein R3 represents hydrogen or C1-6 alkyl and R4 represents C1-6 alkyl having as a substituent any of hydroxy, carboxy, and carbamoyl, provided that R3 may be bonded to R4 to form, in cooperation with the nitrogen atom, a nitrogenous heterocyclic group having as a substituent any of hydroxy, carboxy, and carbamoyl) or a group represented by the formula -S(O)m-W-Y (wherein Y represents hydroxy, carboxy, or carbamoyl; W represents C1-4 alkylene optionally substituted by C1-4 alkyl; and m is 0, 1, or 2)]; or a salt of the compound. They have excellent CCR5 antagonistic activity and are useful as a preventive/therapeutic agent for diseases caused by HIV infection in human peripheral blood mononuclear cells, especially AIDS.

Description

 Description ゥ Rare compounds and their uses Technical field

 'The present invention relates to a urea compound useful for treating acquired immunodeficiency syndrome and its use. Background art

 In recent years, HIV (human immunodeficiency virus) protease inhibitors have been developed as a treatment for AIDS (acquired immunodeficiency syndrome), and combined with two previously used HIV reverse transcriptase inhibitors, Although treatment for DS has progressed significantly, it is still not enough to eradicate AIDS, and the development of new anti-AIDS drugs based on another mechanism of action is desired.

 CD4 has long been known as a receptor for HIV entry into target cells, but recently a macrophage-directed HIV second receptor, called CCR5, has a seven-transmembrane form. A G-protein-coupled chemokine receptor, Yuichi, has been discovered, and it is thought that this chemokine receptor plays an essential role in the establishment and transmission of HIV infection. In fact, it has been reported that humans who exhibited resistance to HIV infection despite repeated exposure had a mutation in which the CCR5 gene was homozygously deleted. Therefore, CCR5 antagonists are expected to be new anti-HIV drugs.

Currently, chemokine receptor antagonists include piperidine derivatives (see, for example, Patent Document 1, Patent Document 2, Patent Document 3, Patent Document 4, and Patent Document 5), ureidoalkyl piperidine derivatives (for example, Patent Document 6, Patent Document 7), cyclic amide derivatives (for example, see Patent Document 8), cyclic amine derivatives (for example, see Patent Document 9), and urea derivatives (for example, see Patent Document 10) are known. There are no examples of CCR5 antagonists being launched as a treatment for AIDS. Prior art document information related to the invention of this application includes the following.

 Patent Document 1: International Publication No. WO 99/04794 pamphlet

 Patent Document 2: WO 99/38514 pamphlet

 Patent Document 3: WO 00/39125 pamphlet

 Patent Document 4: WO 00/66558 pamphlet

 Patent Document 5: WO 00/66559 pamphlet

 Patent Document 6: WO 00/35451 pamphlet

 Patent Document 7: International Publication No. 01/98269 pamphlet

 Patent Document 8: International Publication No. 00/66551 pamphlet

 Patent Document 9: International Publication No. 01/25200 pamphlet

 Patent Document 10: WO 01/25199 pamphlet Disclosure of the invention

 To search for an anti-AIDS drug based on CCR5 antagonism, the CCR5 gene is cloned from a human tissue-derived cDNA library, ligated to an animal cell expression vector, and introduced into animal cells to express CCR5. You need to obtain a cell line. This transformed cell line must then be used to screen for compounds that strongly inhibit the binding of the natural ligand CC chemokine RANTES to CCR5. The present inventors have conducted intensive studies on compounds having CCR5 antagonistic activity, particularly urea derivatives and their structural analogs described in WO01 / 25199, and as a result, a compound represented by the following general formula (I) or a salt thereof was It has excellent CCR 5 antagonism, is useful as a preventive and therapeutic agent for HIV infection of human peripheral blood mononuclear cells, especially AIDS, and is metabolically stable and has excellent oral absorption. The present invention was completed based on this.

 That is, the present invention

(1 set:

[In the formula, R ¹ represents halogen, one may be substituted by halogen _alkyl, a Shiano or a ₄ good phenylene Le group optionally having a Arukiruokishi as _ ₈ alkyl group or a substituted group, R ² the _{^{formula: - S0 2 NR 3 R 4}} ( wherein, R ³ is hydrogen atom or - C'i having ₆ alkyl group, R ⁴ is a hydroxyl group as a substituent, any force Rupokishiru group or force Rubamoiru group May represent an alkyl group, or R ³ and R ⁴ may combine with each other to form a nitrogen-containing heterocyclic group having a hydroxyl group, a sulfoxyl group or a sulfamoyl group as a substituent together with a nitrogen atom; .) a group represented by or the formula: a _{s (o) m - W- Y} ( wherein, Y represents a hydroxyl group, a carboxyl group or force Rubamoiru group, W is optionally substituted with _ ₄ alkyl group _ ₄ Al Killen group, m is represented by represents 0, 1 or 2.) Shows the that group. ] Or a salt thereof,

(2) a halogen as R ¹ is a substituted group, a halogen-substituted _ ₄ may § alkyl, Shiano or a ₄ Arukiruokishi Ru good phenyl group der may have the (1) compound according

(3) R ² has the _{^{formula: - S0 2 NR 3 R 4}} ( provided that, R ³ is a hydrogen atom or - a ₄ § alkyl group, R ⁴ is a hydroxyl group as a substituent, any force Rupokishiru group or force Rubamoiru group _ ₄ represents an alkyl group having, or R ³ and R ⁴ hydroxyl group as a substituent together with the bond to the nitrogen atom, may form a nitrogen-containing heterocyclic group having any force Rupokishiru group or force Rubamoiru group the compounds of the group represented by good _O) above (1), wherein,

(4) R ² has the formula: _S— W, — Y (where W ′ is optionally substituted with methyl C

! — Represents ₄ alkylene, and Y represents a hydroxyl group, olepoxyl group or olebamoyl group. ') The compound according to the above (1), which is a group represented by

(5) {{[4-({[[3-({[(4-chlorophenyl) amino] carbonyl} {phenyl} amido 1907

Four

 No) Propyl] _4-piperidinyl} methyl) phenyl] sulfonyl} -piperidinecarbonic acid, ({[4-(-[3-({[(4_chlorophenyl) amino] carbonyl Hphenyl) L-amino) propyl] -4-piridinyl} methyl) phenyl] sulfonyl} {methyl} amino) acetic acid, 4-({1_ [3-({[(4-chlorophenyl) amino] Carbonyl} {phenyl} amino) propyl] -4-piperidinyl} methyl) -N- (2-hydroxyshetyl) benzenesulfonamide, 2-({[4-({tolu [3-({[ (4-Chlorophenyl) amino] potanol} {phenyl} amino) propyl] -4-piperidinyl} methyl) phenyl] sulfonyl} {methyl} amino) acetamide, 2 _ ({4 -[(({3-[{[(4-chlorophenyl) amino] aminopropyl] (phenyl) amino] propyl} piperidin-4-yl) methyl] phenyl} sulfanyl)- 2-Methyl pulp Or the salt thereof according to the above (1),

 (6) a prodrug of the compound according to (1) above,

 (7) The compound according to the above (1) or a pharmaceutical composition comprising the compound thereof:

(8) The composition according to the above (7), which is a CC chemokine receptor antagonist,

 (9) The composition according to the above (7), which is a CCR 5 antagonist,

 (10) The composition according to the above (7), which is a therapeutic agent for HIV infection.

 (1 1) The composition according to the above (Ί), which is an agent for preventing or treating AIDS.

 (12) The composition according to the above (7), which is an AIDS disease progression inhibitor,

 (13) The composition according to the above (7), which is a blood or a blood product for transfusion,

 (14) The composition according to (7), which is an agent for preventing or treating graft-versus-host disease and Z or rejection during organ or bone marrow transplantation.

 (15) The composition according to the above (7), which is a preventive / therapeutic agent for rheumatoid arthritis, an autoimmune disease, an allergic disease, ischemic brain cell injury, myocardial infarction, nephritis, nephropathy or arteriosclerosis.

 (16) Use of the compound or the prodrug thereof according to (1) for the production of a CC chemokine receptor antagonist,

 (17) HIV infection treatment, AIDS prevention and treatment, AIDS disease progression inhibitor, graft-versus-host disease during organ or bone marrow transplantation and prevention or treatment of Z or rejection, or chronic Rheumatoid arthritis, autoimmune disease, allergic disease, ischemia

'' For the prevention and treatment of cerebral cell injury, myocardial infarction, nephritis, nephropathy or arteriosclerosis The use of the compound of the above (1) or a prodrug thereof, and

 (18) Treatment of HIV infection, prevention and treatment of AIDS, suppression of progression of AIDS, prevention of graft-versus-host disease and Z or rejection during organ or bone marrow transplantation, or rheumatoid arthritis, self A method for preventing or treating an immune disease, allergic disease, ischemic brain cell injury, myocardial infarction, nephritis, nephropathy or arteriosclerosis, wherein the compound described in (1) above or A method comprising administering an effective amount of a drug. BEST MODE FOR CARRYING OUT THE INVENTION,

In the above formula, the 〇 E _ ₈ alkyl group represented by R ^1, for example methyl, E Ji Le, n- propyl, i one propyl, n- butyl, i- butyl, s- butyl, t-Bed chill, n-pentyl, i-pentyl, t-pentyl, neopentyl, n-hexyl, i-hexyl, n-heptyl and n-octyl, among which methyl, ethyl, propyl, etc. Four are preferred. Also represented by R ¹ - in the "halogen as location substituent, halogen optionally substituted by _ ₄ alkyl, Shiano or ₄ a phenyl group which may have a Arukiruokishi", with substituents phenylene Le group there the halogen such as fluorine, chlorine, bromine, and iodine, as the _ ₄ alkyl optionally substituted by halogen, for example fluorine, chlorine, bromine, optionally substituted with a halogen such as iodine _ _4- alkyl (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, etc.), and the like. (Examples of _4- alkyloxy include methyloxy, ethyloxy, n-propyloxy, i monopropyloxy, n-butyloxy, i-butyloxy and the like.

The —6 alkyl group represented by R ³ includes, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t one pentyl, neopentyl, hexyl n-, like key sill can be mentioned to i one, represented by R ⁴ "hydroxyl group as a substituent, or force Rupokishiru group has any force Rubamoiru group - ₆ alkyl group" in _ ₆ alkyl groups include, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl. Tyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neopentyl, n-hexyl, i-hexyl, etc., and R ³ and R ⁴ are bonded Examples of the nitrogen-containing heterocyclic group in the `` nitrogen-containing heterocyclic group having any one of a hydroxyl group, a carboxyl group, and a carbamoyl group as a substituent together with a nitrogen atom '' include, for example, azetidinyl, pyrrolidinyl, piberidinyl, homopiperidinyl, 3- to 8-membered (preferably 4- to 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic groups (aliphatic heterocyclic groups) such as heptamethyleneimino, morpholinyl, thiomorpholinyl, piperazinyl and homopiperazinyl. Groups), among which azetidinyl, pyrrolidinyl, piberidinyl, morpholinyl, piperazini Arbitrariness is preferred.

Represented by W: in "(E _ ₄ alkyl-substituted _ ₄ may be an alkylene group with a group" - The ₄ alkylene, which methylene is continuous with one or two to four series, i.e. methylene, Examples thereof include 1,2-ethylene, 1,3-propylene and 1,4-butylene, and examples of the substituent include a _ ₄ alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl, ., such as i over blanking chill the like _ ₄ alkyl group which is the substituent lay one to four is preferred, -. ₄ may be replaced with any substitutable position of the alkylene group R ² benzene ring Is preferably para (ie, R ² is 4-position on the benzene ring) with respect to the methylene substitution.

 As the compound represented by the formula (I), the following compounds are preferable.

1- {[4- ({[[3- ({[(4-chlorophenyl) amino] aminopropyl] {phenyl} amino) propyl] -4-pyridinyl} methyl) phenyl] Sulfonyl} -4-piperidinecarboxylic acid, ({[4-({1- [3-({[(4-chlorophenyl) amino] carbonylHphenyl} amino) propyl] -4-pi] {Ridinyl} methyl) phenyl] sulfonyl} {methyl} amino) acetic acid, 4-({tri [3 _ ({[(4_chlorophenyl) amino] carbonyl] carbonyl} {phenyl} amino) propyl]- 4-piperidinyl} methyl) -N- (2-hydroxyethyl) benzenesulfonamide, 2-({[4-({tri [3-({[(4-chlorophenyl) amino] carbonyl}} L-amino) p-pyr] -4-piperidinyl} methyl) phenyl] sulfonyl} {methyl} amino) acetamide, 2-({4-[(1- {3-[{[(4- Phenyl) amino] carbonyl} (phenyl) ami [No] propyl} piperidin-4-yl) methyl] phenyl} sulfanyl) -2-methylpropanoic acid or salts thereof.

The salt of the compound represented by the formula (I) of the present invention is preferably a pharmacologically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, or an organic compound. Examples thereof include salts with acids, salts with basic or acidic amino acids, and the like. Preferable examples of the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt, ammonium salt and the like. . Preferred examples of the salt with an organic base include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, Ν, Ν'-dibenzylethylenediamine and the like. No. Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, ス ル ホ ン- Salts with toluenesulfonic acid and the like can be mentioned. Preferable examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, orditin and the like. Preferred examples of the salt with the acidic amino acid include, for example, aspartic acid, glutamic acid, and the like. And salts thereof. The compound represented by the formula (I) of the present invention may be a hydrate or a non-hydrate. Compound (I) is an isotope ^{(eg, 3 H, 1 4 C,} 3 5 S, 1 such as ^{2 5} I) may be labeled with a. When the compound represented by the formula (I) of the present invention exists as a diastereomer, a conformer, or the like, each can be isolated by a separation / purification means known per se, if desired. . The compound (I) may have one or more asymmetric carbon atoms in the molecule, but when these compounds are in a racemic form, the (S) form can be obtained by ordinary optical resolution. , And (R) -isomers, and each of the optically active isomers and racemic isomers is included in the present invention.

The compound represented by the formula (I) or a salt thereof, which is used in the present invention [hereinafter, may be referred to as compound (I). Is a compound that is converted into compound (I) by a reaction with an enzyme or stomach acid under physiological conditions in vivo, that is, Originally, a compound which undergoes hydrolysis or the like to change to the compound (I), or a compound which undergoes hydrolysis or the like due to stomach acid or the like to change to the compound (I). Examples of the prodrug of compound (I) include compounds in which the amino group of compound (I) is acylated, alkylated, or phosphorylated (eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylamino). Compounds, such as compounds which are carbonylated, (5-methyl-2-oxo-1,3, -dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, bivaloyoxymethylated, tert-butylated, etc.); Compounds in which the hydroxyl group of (I) is acylated, alkylated, phosphorylated, or borated (eg, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloyylated, succinylated, fumarylated) , Alanylated, dimethylaminomethylcarponylated compounds, etc.); the carboxyl group of compound (I) is Tellurized or amidated compounds (eg, the carboxyl group of compound (I) is ethyl-, phenyl-, methoxy-, dimethylamino-, pivaloyloxy-, x-toxic) Carbonyloxysethyl esterification, phthalidyl esterification, (5-methyl-12-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarponyl ethyl ester, methylamide And the like). These compounds can be produced from compound (I) by a method known per se.

 The prodrug of compound (I) is compounded under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Drugs,” Volume 7, Molecular Design, pp. 163-198. It may change to the object (I).

The prodrug of compound (I) may be itself or a pharmacologically acceptable salt. Examples of such salts include inorganic bases (eg, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, zinc) when the prodrug of compound (I) has an acidic group such as a carboxy group. , Iron, copper and other transition metals) and organic bases (eg, trimethylamine, triethylamine, pyridine, picolin, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'— And salts with organic amines such as dibenzylethylenediamine, and basic amino acids such as arginine, lysine and ordinine. When the prodrug of compound (I) has a basic group such as an amino group, an inorganic acid or an organic acid (eg, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonate, formic acid, acetic acid, propionic acid, trifluoroacetic acid) , Fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), and salts with acidic amino acids such as aspartic acid, glutamic acid, etc. Is mentioned. Further, the prodrug of compound (I) may be either a hydrate or a non-hydrate.

 Compound (I) can be produced, for example, by the method shown below. The compound used in each of the following production methods may form a salt similar to compound (I) as long as the reaction is not hindered.

 In each of the following reactions, when the starting compound has an amino group, a carboxyl group, or a hydroxyl group as a substituent, a protecting group generally used in peptide chemistry or the like is introduced into these groups. The target compound can be obtained by removing the protecting group as necessary after the reaction.

The protecting group of the Amino group, for example may have a substituent _ ₆ alkyl Karuponiru (e.g., Asechiru, propionyl, etc.), formyl, phenylene Rukarupo nil.丄_6- alkyloxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.), phenyloxycarbonyl (eg, benzoxycarbonyl, etc.), C ₇ _! 0 Aralkyloxycarbonyl (for example, benzyloxycarbonyl), triter, phthaloyl and the like are used. Examples of these substituents include halogen atom (e.g., fluorine, chlorine, bromine, etc. iodine), - ₆ alkyl Cal Poni Le (e.g., Asechiru, propionyl, etc. Puchiriru) and nitro groups, the number of substituents About 1 to 3 pieces.

As the carboxyl-protecting group, for example, an optionally substituted substituent such as _6- alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenyl, trityl, silyl, etc. are used. Can be Examples of these substituents include halogen atom (e.g., fluorine, chlorine, bromine, iodine), (: E _ ₆ alkylene Rukaruponiru (e.g., Asechiru, propionyl, etc. Puchiriru), formyl, such as a secondary preparative port group is used The number of substituents is about 1 to 3. Examples of the protecting group for the hydroxy group include, for example, an optionally substituted substituent such as ₆ -alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, and C ₇ -phenyl. Ararukiru (e.g., benzyl, etc.), - ₆ § Rukirukaruponiru (e.g., Asechiru, propionyl, etc.), formyl, phenyl O alkoxycarbonyl, C ₇ _! 0 Aralkyloxycarponyl (eg, benzyl xycarponyl, etc.), pyranyl, fluel, silyl and the like are used. These substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C

! _ ₆ alkyl, phenyl, C ₇ _. Aralkyl or nitro groups are used, and the number of substitution groups is about 1 to 4.

 In addition, as a method for introducing and removing a protecting group, a method known per se or a method analogous thereto [for example, Protective Group's 'in' organic chemistry]

(The method described in JFW McOmie et al., Plenum Press Co.) is used. The removal method is, for example, acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, N-methyldithiocarpamine A method of treating with sodium acid, tetrabutylammonium fluoride, palladium acetate or the like is used.

 In the following description, the compounds represented by the formulas (I), (II), (V), (VII) and (VIII) include the compounds (I), (Π), Compound (V), compound (VII) and compound (VIII). The compounds represented by the formulas (III), (IV), (VI) and (IX) may be simply referred to as compound (III), compound (IV), compound (VI) and compound (IX), respectively. .

 Manufacturing method 1

 As shown in the following formula, compound (I) can be produced by reacting compound (II) with compound (III).

 R1— N = C = 0 + ^

 (III)

 (Wherein the symbols are as defined above.)

This reaction is usually performed in a solvent inert to the reaction. Examples of the solvent include ether solvents (eg, ethyl ether, diisopropyl ether, dimethoxy ether). , Tetrahydrofuran, dioxane, etc.), halogenated solvents (eg, dichloromethane, dichloroethane, chloroform, etc.), aromatic solvents (eg, toluene, benzene, xylene, etc.), acetonitrile, NN-dimethylformamide (eg, DMF), acetone, methyl ethyl ketone, dimethyl sulfoxide (DMSO), water, etc. can be used alone or in combination. Of these, preferred are acetonitrile, dichloromethane, and chloroform. This reaction is generally carried out by reacting compound (III) with 1 to 5 equivalents, preferably 1 to 3 equivalents, of compound (II). The reaction temperature is from −20 ° C. to 50 ° C., preferably from 0 ° C. to room temperature, and the reaction time is usually from 5 minutes to 100 hours. In this reaction, the reaction may proceed more smoothly by coexisting a base. As the base, both inorganic bases and organic bases are effective. Examples of inorganic bases include hydroxides, hydrides, carbonates, hydrogencarbonates of alkali metal alkali earth metals, among which potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide Preferred are sodium hydrogen carbonate and potassium hydrogen oxy. Tertiary amines such as triethylamine are preferred as the organic base.

 The compound (II) used in this method can be produced, for example, by the method described in Synthetic Comm., 1991 20, 3167-3180. That is, it can be produced by the following method utilizing an addition reaction of an amine to an unsaturated bond.

/ NH ₂

(Wherein each symbol is as defined above.)

It can be obtained by reacting acrolein (VI) with compound (V), and then reacting the product with compound (VI II) under reducing conditions. Compound (VI) and Compound (V) Is generally carried out in a solvent inert to the reaction in the presence of a base. Examples of the base include 1) a strong base, for example, a hydride of an alkali metal or an alkaline earth metal (eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), an alkali metal or an alkaline earth metal Amides (eg, lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, etc.) Or lower alkoxides of alkaline earth metals (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.) 2) Inorganic salts such as water of alkaline metal or alkaline earth metal Oxides (eg, sodium hydroxide, potassium hydroxide, hydroxide Titanium, τ-barium oxide, etc.), alkali metal or alkaline earth metal carbonates (eg, sodium carbonate, carbonated carbonate, cesium carbonate, etc.), alkali metal or alkaline earth metal bicarbonates (eg, 3) Organic bases such as triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, DBU (1,8-diazabicyclo [5.4] 0]-7-Pendecene), amines such as DBN (1,5-diazabicyclo [4.3.0] non-5-ene) or basic such as pyridine, imidazole, 2,6-lutidine And heterocyclic compounds. Examples of the solvent include the solvents described in the reaction of the compound (II) with the compound (III), and these can be used alone or as a mixture. In this reaction, compound (VII) is obtained.

 As a reduction method in the reaction between compound (VII) and aniline (VIII), a reducing agent can be used or a catalytic reduction method can be used. Examples of the reducing agent include sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like. The amount of these reducing agents to be used is generally 1 to 10 equivalents, preferably 1 to 4 equivalents, relative to compound (VII). The reaction temperature is from 120 to 50 ° (: preferably from 0 ° C to room temperature, and the reaction time is from 0.5 to 24 hours.

The catalytic reduction method uses a catalytic amount of a metal catalyst such as Raney nickel, platinum oxide, metallic palladium, palladium monocarbon and an inert solvent (eg, methanol, ethanol, It can be obtained by reacting at room temperature to 100, hydrogen pressure of 1 to 100 atm and room temperature to 100 atm for 1 to 48 hours.

 The compound (V) used in this method can be synthesized by a known general method.

Manufacturing method 2

As shown in the following formula, compound (I) can be produced by reacting compound (IV) with compound (V).

 (IV)

 (Wherein the symbols are as defined above.)

 This reaction can be seen, for example, in Organic Functional Group Preparations

(ORGAN IC FUNCTIONAL GROUP PREPARAT IONS) 2nd edition, Academic Press (in ACADEMIC PRESS, IN).

 This reaction is usually performed in a solvent inert to the reaction. As such a solvent, an alcohol solvent, an ether solvent, a halogen solvent, an aromatic solvent, acetonitrile, Ν, Ν-dimethylformamide (DMF), acetone, methyl ethyl ketone, dimethyl sulfoxide (DMS0) or the like may be used alone or in combination. Can be used in combination. Of these, acetonitrile, dimethylformamide, acetone, ethanol and the like are preferable. The reaction temperature is usually from room temperature to 10Ot: preferably from room temperature to 50 ° C, and the reaction time is usually from 0.5 to 1 day. This reaction is usually, but not always, required to add 1 to 3 equivalents of the base to the compound (IV). As the base, the base used in the reaction between compound (II) and compound (III) can be used.

 Compound (IV) used as a starting material in this reaction can be synthesized by a known general method using compound (III) as a starting material.

Manufacturing method 3

Compound (I) can be produced by reacting a compound represented by formula (IX) with a compound represented by formula (V) under reducing conditions as shown in the following formula.

 (IX)

 (Wherein the symbols are as defined above.)

 For this reaction, compound (IX) and compound (V) are usually required in an appropriate solvent (eg, water, alcohol, ether, halogen, acetonitrile, a mixed solvent of two or more of these). The reaction is carried out in the presence of 1 to 5 equivalents, preferably 1 to 1.5 equivalents of a reducing agent by adding an acidic substance such as acetic acid or trifluoroacetic acid. The method described in Production Method 1 can be used for the reducing agent and other conditions.

 Compound (IX) used as a raw material in this reaction can be produced by a known general method using compound (III) as a raw material.

Depending on the type of the substituent R ² of the compound (I), the compounds produced by the methods analogous thereto or the above-mentioned production method 1-3 as a starting material, producing a compound (I) Te cowpea its substituent conversion can do. For the substituent conversion, a known general method is used. Conversion of groups. In the case of the compound (I) having a hydroxy group in the substituent R ² , the compound is produced by the above production method 1 to 3 or a method analogous thereto in a form in which the hydroxy group is protected, and then the protective group is added. The compound (I) can be produced by removing. A known general protecting group can be used, and a method for removing the protecting group can be performed by a known general method.

 Since the compound (I) of the present invention has an excellent CCR antagonism, particularly a strong CCR5 antagonism, the compound (I) is a prophylactic / therapeutic agent for HIV infections in humans, such as AIDS.

It can be used as an agent for inhibiting the progression of AIDS and as a preventive and therapeutic agent for various other diseases. The compound (I) of the present invention has low toxicity and can be used safely.

The above compound (I) can be used alone or in a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, for example, a solid preparation such as tablets, capsules, granules and powders; or a liquid preparation such as syrups and injections. It can be administered orally or parenterally as a formulation. Parenteral administration forms include injections, infusions, suppositories, vaginal suppositories, and the like. In particular, vaginal suppositories are useful for prevention of HIV infection.

Pharmaceutically acceptable carriers include various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients, lubricants, binders, and disintegrants in solid preparations; solvents and dissolution aids in liquid preparations. Formulation, suspending agent, tonicity agent, buffering agent, soothing agent, etc. If necessary, pharmaceutical additives such as preservatives, antioxidants, coloring agents and sweeteners can be used. Preferred examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light caffeic anhydride and the like. Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferred examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like. Preferred examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethylsulfate and the like. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferred examples of the solubilizing agent include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Is mentioned. Preferred examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; Examples include hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Suitable examples of the tonicity agent include, for example, sodium chloride, glycerin, D-mannitol and the like. Preferred examples of the buffer include buffer solutions such as phosphate, acetate, carbonate, and citrate. Preferred examples of the soothing agent include, for example, benzyl alcohol And the like. Preferred examples of preservatives include, for example, esters of paraoxybenzoic acid, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid. Suitable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like.

 For example, a pharmaceutical composition containing the compound (I) of the present invention can be used as a CCR5 antagonist, for example, an AIDS prophylactic or therapeutic agent and an AIDS disease progression inhibitor.

 The compound (I) of the present invention may be used in combination with other prophylactic / therapeutic agents for HIV infectious diseases (in particular, prophylactic / therapeutic agents for AIDS). In this case, these drugs can be formulated separately or simultaneously and mixed with pharmacologically acceptable carriers, excipients, binders, diluents, etc., to prevent or treat HIV infection. It can be administered orally or parenterally as a pharmaceutical composition. When the drugs are formulated separately, the separately formulated ones can be mixed and administered using a diluent at the time of use, but the separately formulated individual products can be administered simultaneously or with a time lag. And may be administered separately to the same subject. A kit product for administering separately formulated products using a diluent or the like at the time of use (for example, an ampoule containing a powdered individual drug and two or more drugs mixed at the time of use and dissolved Kit products for administration of the same formulation to the same subject at the same time or separately at different times, such as injection kits containing diluents for Tablets in the same or separate bags and, if necessary, a column for the time of drug administration is provided.For tablets for administering two or more tablets simultaneously or separately with a time lag. Kits) are also included in the pharmaceutical composition of the present invention.

Specific examples of other prophylactic / therapeutic agents for HIV infection used in combination with the compound (I) of the present invention include zidovudine, didanosine, and zalci tabine. ), Lamivudine (l amivudine), stavudine (s tavudine), abavirvir (abacavir), adefovir (adefovir), adefovir dipipoxyle adefovir dipivoxil), fozivudine tidoxyle (foz ivudine tidoxil), tenofir Nucleic acid reverse transcriptase inhibitors such as: nevirapine (nevi rapine), delahiriresino (delavi rdine), efavirenz (efavi renz), Antioxidant activity such as non-nucleic acid reverse transcriptase inhibitors such as oral viride (loviride), imnocal (istitute Unocal), oltipraz (oltipraz), and oltibraz (o 1 tipr az) Including saquinavir, ritonavir, indinavir, nelfinavir, nelf inavir, amprenavir (amprenavir re, parinavir (pal inavir), lashina hill (lasinavir), and mouth pinavir (lopinavir) Protease inhibitors; and the like.

 As a nucleic acid reverse transcriptase inhibitor, zidovudine (zidovudine), didanosine (didanosine), zalcitabine (zalcitabine), lamivudine (lamivudine), stavudine (stavudine) and the like are preferable. Are preferably nevirapine (nevirapine), aravirirezine (delavirdine), efavirenz efavirenz) and the like. .

 The compound (I) of the present invention may be, for example, an antagonist of CXCR4, which is a second receptor for T cell-directed HIV-1, in addition to the above-mentioned protease inhibitor, nucleic acid reverse transcriptase inhibitor and the like (eg, AMD — 3100), can be used in combination with antibodies against HIV-1 surface antigens and HIV-1 vaccines.

 The daily dose of Compound (I) varies depending on the condition and weight of the patient, and the method of administration. In the case of oral administration, about 5 to 5 active ingredients per adult (body weight 5 OKg) [Compound (I)] 100 mg, preferably about 10 to 60 mg, more preferably about 10 to 30 mg, particularly preferably about 15 to 150 mg, administered once or twice to three times a day. I do.

When compound (I) is used in combination with a reverse transcriptase inhibitor or Z and a protease inhibitor, the dose of the reverse transcriptase inhibitor or the protease inhibitor is, for example, about 1 / It is appropriately selected within the range of 200 to 1/2 or more and about 2 to 3 times or less. In addition, when two or more drugs are used in combination, when one drug affects the metabolism of another drug, the dose of each drug is appropriately adjusted. The dose at the time of single drug administration is used. Typical dosages of typical reverse transcriptase inhibitors and protease inhibitors are eg It is as shown below.

Zidovudine: 10 Omg

Didanosine: 125-20 Omg

Zarshi Evening Bottle: 0.75mg

Lamivudine: 15 Omg

Stavudine: 30-4 Omg

Saquinavir: 60 Omg

Ritonavir: 60 Omg

Indinavir: 80 Omg

Nelfinavir: 75 Omg

 Further, specific embodiments when the compound (I) and a reverse transcriptase inhibitor or Z and a protease inhibitor are used in combination are shown below.

 (i) About 10 to 30 Omg of compound (I) is administered to the same subject in combination with about 50 to 20 Omg of zidovudine per adult (body weight 5 OKg). The individual drugs may be administered at the same time, or may be administered with a stagger of 12 hours or less.

 (ii) For each adult (body weight 5 OKg), about 10 to 30 Omg of compound (I) is administered to the same subject in combination with about 300 to 120 Omg of saquinavir. Each drug may be administered at the same time, or may be administered with a time lag within 12 hours.

 Further, a pharmaceutical composition containing the compound (I) of the present invention can be used as a preventive or therapeutic agent for graft-versus-host disease and Z or rejection, rheumatoid arthritis, autoimmune disease, allergic disease, ischemic brain. It can be used as a preventive / therapeutic agent for various disorders such as cell damage, myocardial infarction, chronic nephritis and arteriosclerosis.

The diseases targeted by the above preventive and therapeutic agents of the present invention include, for example, graft rejection (rejection after transplantation, erythrocytosis after transplantation, hypertension, organ disorders, vascular hypertrophy, graft versus host disease, etc. ), Arthritis bone diseases such as meningitis, etc. (rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, osteoporosis, abnormal proliferation of cells, fractures, refractures, osteomalacia, bone Petiet's disease, rigidity) Destruction of joint tissue in myelitis, knee osteoarthritis and similar diseases, etc.), autoimmune diseases (collagenous disease, systemic lupus erythematosus, strong Dermatosis, polyarteritis, myasthenia gravis, multiple sclerosis, etc.), allergic diseases (allergic rhinitis, conjunctivitis, gastrointestinal allergies, hay fever, anaphylaxis, atopic dermatitis, bronchial asthma , Etc.), inflammatory bowel disease (ulcerative colitis, Crohn's disease, gastritis, stomach ulcer, stomach cancer, gastric surgery post-disorder, dyspepsia, esophageal ulcer, tengitis, colon polyp, cholelithiasis, hemorrhoidal disease, peptic Ulcers, local ileitis, etc.), inflammatory diseases (retinopathy, inflammation after surgery and trauma, remission of swelling, pharyngitis, cystitis, meningitis, inflammatory eye diseases, etc.), respiratory tract diseases (Cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombus' pulmonary embolism, pulmonary sarcoid-cis, pulmonary tuberculosis, interstitial pneumonia, silicosis, adult respiratory distress syndrome, chronic obstructive pulmonary disease, etc.), infectious diseases (Cytomegalu Virus, flu, influenza virus, herpes virus, rickettsial infection, bacterial infection, sexually transmitted disease, carinii pneumonia, helicobacter pylori infection, systemic fungal infection, tuberculosis, invasive grape Staphylococcal infections, acute viral encephalitis, acute bacterial meningitis, AIDS encephalopathy, sepsis, sepsis, severe sepsis, septic shock, endotoxin shock, toxin shock syndrome, etc.), cancer and associated cachexia , Cancer metastasis (bladder cancer, ¥ L cancer, cervical cancer, ovarian cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, rectal cancer, colon cancer, multiple myeloma, malignant myeloma, prostate cancer, Lung cancer, stomach cancer, Hodgkin's disease, melanoma, malignant lymphoma, etc.), non-Hodgkin's lymphoma, non-small cell lung cancer, evil Melanoma, neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's chorea, diabetic neuropathy, Creutzfeldt-Jakob disease, etc.), mental disorders (depression, epilepsy, Alcoholism, etc.), schizophrenia, venous dysfunction, central nervous system disorders (disorders such as cerebral hemorrhage and cerebral infarction and their sequelae-complications, head trauma, spinal injury, brain edema, sensory dysfunction, sensory dysfunction , Autonomic nervous dysfunction, autonomic nervous dysfunction, etc.) central injury (head trauma, spinal cord injury, whiplash, etc.), vascular dementia (multi-infarct dementia, Binswanger's disease, etc.), cerebrovascular disorder (asymptomatic) Cerebrovascular disorder, transient ischemic attack, stroke, cerebral vascular dementia, hypertensive encephalopathy, etc.), recurrence and sequelae of cerebrovascular disorder (neurological symptoms, psychiatric symptoms, Subjective symptoms, impaired activities of daily living, etc.), cerebrovascular dementia, central dysfunction after cerebral vascular occlusion, impaired or abnormal cerebral circulation, automatic regulation of renal circulation, impaired brain-blood barrier, anxiety symptoms, instability Acute coronary artery syndrome such as angina, discomfort mental state, amnesia, trigeminal neuralgia, ENT diseases (Mennell syndrome, Tinnitus, taste disorder, dizziness, imbalance, dysphagia, etc.), migraine, chronic pain, skin diseases (keloid, hemangiomas, psoriasis, etc.), arteriosclerosis obliterans, thrombosed vasculitis, peripheral arterial obstruction , Post-ischemic reperfusion injury, Reino's disease, Baja's disease, myocarditis, myocardial ischemia, myocardial infarction, progression of heart failure after myocardial infarction, cardiomyopathy, cardiac hypertrophy, chronic heart failure including acute heart failure and congestive disorders, narrow Heart disease, arrhythmia, tachycardia, abnormal circadian blood pressure, abnormal properties of blood and blood cell components (enhanced platelet aggregation, abnormal erythrocyte deformability, increased leukocyte adhesion, increased blood viscosity, erythrocytosis, vascularity Purpura, autoimmune hemolytic anemia, disseminated intravascular coagulation, multiple myelosis, etc., arteriosclerosis including atherosclerosis (aneurysm, coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis) What Revascularization after bypass surgery-Restenosis, Restenosis, Intervention (percutaneous coronary angioplasty, stent placement, coronary endoscopy, intravascular ultrasound, coronary thrombolysis, etc.) And organ damage, production and hyperactivity of vasoactive substances and thrombogenic substances (endothelin, thromboxane A2, etc.), angiogenesis (abnormal vascularization in abnormal capillary network formation of atherosclerotic lesion outer membrane) ), Thrombosis, accelerated fat deposition, eye diseases (glaucoma, ocular hypertension, etc.), hypertension, hypertensive tinnitus, dialysis hypotension, endothelial cells and organ disorders, endocrine diseases (Addison's disease, Cushing's syndrome, brown cells) Species, primary aldosteronism, etc.), nephritis, renal diseases (nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy, complications of dialysis, radiation Organ disorders including nephropathy, diabetic nephropathy, diabetic diseases (insulin-dependent diabetes, diabetic complications, diabetic retinopathy, diabetic microvascular disease, diabetic neuropathy, etc.), Impaired glucose tolerance, liver disease (hepatitis including chronic, cirrhosis, etc.), interstitial liver disease, chronic inflammation, portal hypertension, obesity, male infertility, gynecological disorders (menopause, pregnancy poisoning, uterus Endometriosis, uterine fibroids, ovarian disease, mammary gland disease, etc.), edema, chronic fatigue syndrome, benign prostatic hypertrophy, peetet's disease, Hodgkin's disease, racne infarction, impaired consciousness, psoriasis, environmental and occupational factors (radiation damage) , Ultraviolet rays-infrared rays-laser beam damage, altitude sickness, etc.), intermittent claudication, and the like.

 The dose of the pharmaceutical composition of the present invention can be appropriately selected depending on the administration subject, age and weight of the administration subject, symptoms, administration time, administration method, dosage form, and the like.

The dosage for a particular patient will depend on age, weight, general health, gender, diet, time of administration, mode of administration, rate of excretion, and the extent of the condition the patient is treating at the time. The decision is made in consideration of these and other factors.

The pharmaceutical composition containing the compound (I) of the present invention varies depending on the kind of the target disease, but may be used in combination with another drug. Such other drugs include, for example, HDL enhancers [squalene synthase inhibitors, CETP inhibitors, LPL activators, etc.], NMG-CoA reductase inhibitors: seribas-utin, Atoguchi bath Evening Chin, Prabas Evening Chin, Simbas Evening Chin, Itabasu Evening Chin, Mouth Bath Evening Chin, Full Bath Evening Chin, (+)-3R, 5S-7- [4- (4-Fluorophenyl) -6f 2- (N-methyl N-methanesulfonylamino) pyrimidine-5-yl] _3,5-dihydroxy-6 (E) monoheptenoic acid, etc. Atopic dermatitis drug [Sodium cromoglycate] And allergic rhinitis treatment [sodium cromoglycate, chlorpheniramine maleate, alimemazine tartrate, clemastine fumarate, homochlor cyclidine hydrochloride, terfenadine, mequitazine, etc.], imidenem shirasu Evening sodium, endotoxin antagonist or antibody, oxidized squalene-lanosterol cyclase [eg decalin derivative, azaderic phosphorus derivative and indane derivative], calcium antagonist (diltiazem etc.), glycerol, cholinesterase inhibitor (eg, Alicebut (donebezil), a compound that suppresses cholesterol absorption [eg, sitosterol and neomycin, etc.], a compound that inhibits cholesterol biosynthesis [eg, oral bath, simbas, pravas HM G—Co A reducing enzyme inhibitors], cyclohexoxygenase inhibitors [(Cox-I, Cox-II inhibitors) For example, salicylic acid derivatives such as celecoxib, oral fuecoxib, aspirin, diclofenac , Indomethacin, loxoprofen, etc.], signal transduction Pests, squalene epoxidase inhibitors [e.g., NB-598 and related compounds, etc.], steroid drugs [dexamethasone, hexestrol, methimazol, besa methasone, triamcinolone, triamcinolone acetonide, fluocinonide, Fluocinolone acetonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometron, vec- methasone propionate, estriol, etc.], diacerin, nicotinic acid, derivatives and analogs thereof [eg, acypimox and propecolin], Niselogin syndrome Therapeutic agents: prednisolone (predonin), prednisolone sodium succinate (prednin), methyl succinate Antiplatelet drugs such as redonizolone sodium (sol'medrol), betamethasone (linderone), dipyridamole (versantin), dilazeb hydrochloride (comerian), ticlopidine, clopidogrel, FXa inhibitor, anticoagulants, valpital anticonvulsants Drugs or anesthetics (phenobarbital, mehobarbital, metal bital, etc.), drugs for Parkinson's disease (eg, L-dopa), histamine receptor blockers (cimetidine, famotidine, etc.), hydantoin Anticonvulsants (phenytoin, mephenitin, ethotoin, etc.), piroxicam, fibrates [eg, clofibrate, benzafibrate, gemfiprodil, etc.], prostaglandins, megestrol acetic acid, gastric / duodenal ulcer drug Therapeutic agent: antacid [Example Histamine H2 antagonists (cimetidine, etc.), proton pump inhibitors (lansoprazole, etc.), inflammatory mediator action inhibitors, coronary vasodilators: diphedipine, diltiazem, nicorazil, nitric acid, etc. : [Examples: antibiotics (cefatiam hydrochloride, cefozopran hydrochloride, ampicillin, etc.), chemotherapeutics (sulfur, synthetic antibacterial, antiviral, etc.), biologicals (vaccines, blood products such as immunoglobulins, etc.) Drugs for treating liver diseases: glycyrrhizin preparations [eg, strong minophagen, etc.], liver hydrolyzate, SH compounds [eg, daltathione, etc.], special amino acid preparations [eg, aminolevan, etc.], phospholipids [eg, PO Lin phosphatidylcholine, etc.], vitamins [e.g., _{vitamin, B 2, B 6, 2} , C , etc.], Adrenocortical hormones [eg, dexamezozone, betamethasone, etc.], interferon [eg, interferon, etc.] 3, etc., drugs for treating hepatic encephalopathy [eg, lactulose, etc.], esophagus, used for rupture of gastric varices Anti-arthritic drugs, muscle relaxants [pridinol, ppocurarine, panclodium, tolperisone hydrochloride, chlorphenesin carbamate, baclofen, chlormezanone, mephenesin, clozoxazone, e.g. , Tizanidine, etc.), vasodilators [oxifedrin, diltiazem, tolazoline, hexobendine, bamethane, clonidine, methyldopa, guanabenz, etc.], vasoconstrictors [dopamine, doptamine denopamine, etc.], platelet aggregation Inhibitors (such as ozadarrel), Antithrombotic and therapeutic agents: anticoagulants [eg, heparin sodium, heparin calcium, perhalin calcium (perfurin), Xa inhibitor], thrombolytics [eg, tPA, perokinase], anti- Platelet drug [eg, ass Pilin, sulfinpyrazone (anlan), dipyridamole (persantin), ticlovidine (panaldine), cilostazol (pletal), GPII b / II

Ia antagonist (Leopro)], antidepressant [imipramine, clomipramine, noxiptilin, phenelzine, amitriptyline hydrochloride, nortriptyline hydrochloride, amoxapine, mianserin hydrochloride, maprotiline hydrochloride, sulpiride, alpoxamine maleate, trazodone hydrochloride, etc. Antiepileptic drugs [Gyabapentin, phenytoin, ethosuximide, acesuximide, chlorezazepoxide, trimetadione, kylarva mazepine, phenovalpital, primidone, sultiam, sodium parbroate, clonazepam, diazepam, nitrazepam, etc.] Allergic drugs [diphenhydramine, chlorpheniramine, triberenamine, methdilamine, clemizole, diphenylpyralin, methoxyphenamine, cromoglycic acid Thorium, tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine, acelastine, epinastine, ozadarrel hydrochloride, pranlukast hydrate, seratrodust, fexofenadine, ebastine, bucillamine, oxamide Minophagenic acid, tranexamic acid, ketotifen fumarate, etc.), anticholinergic agents (for example, iprat pap bromide, furt papium bromide, oxytropium bromide, etc.), anti-parkinson drugs (dopamine, levodopa, etc.), anti- Rheumatic drugs, anti-inflammatory drugs (eg, aspirin, acetaminophen, diclofenac sodium, ibuprofen, indomethacin, loxoprofen sodium, dexamethasone, etc.), anticoagulant Blood and antiplatelet drugs (sodium citrate, activated protein C, tissue factor pathway inhibitor, antithrombin III, dalteparin sodium, argatroban, gabexate, ozacrel sodium, ethyl icosaventate, beraprost) Sodium, alprosyl, pentoxifylline, thixokinase, streptokinase, hevalin, etc.), anticoagulant [dipyridamole (versantin), dilazep hydrochloride (comerian), ticlopidine, clovidogrel, Xa inhibitor], antibacterial Drugs [(i) sulfa drugs [sulfamethizole, sulfisoxazole, sulfamonomethoxine, sulfamethizole, salazosulfapyridine, silver sulfadiazine, etc.], (ii) quinoline antibacterial drugs [nalidixic acid, Dimidic acid trihydrate, eno Oxacin, norfloxacin, ofloxacin, tosfloxa tosylate Synth, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin hydrochloride, fleroxacin, etc.), (iii) antituberculous drugs [isodiazide, utambutol (ethambutanol hydrochloride), paraaminosalicylic acid (calcium paraaminosalicylate), pyrazinamide , Etyonamide, prothonamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine, etc.), (iv) mycobacterials [diaphenylsulfone, rifampicillin, etc.], (V) antivirals [idoxperidine, ashikokubir, pitarabin, etc.] Ganciclovir, etc.), (vi) anti-HIV drugs [zidovudine, didanosine, zalsipine, indinavir sulfate ethanolate, ritonavir, etc.], (vi i) anti-spiro overnight, (vi ii) antibiotics [tetracycline hydrochloride , Ampicillin, piperacillin, genyumycin, dibekacin, canendomycin, ribidomycin, dopramycin, amikacin, fradiomycin, sisomicin, tetracycline, oxytetracycline, lolitetracycline, doxycycline, ampicillin, piperacillin, ticarcillin , Cephalotin, cephapirin, cephaloridine, cefaclor, cephalexin, cefloxazine, cephadroxil, cef amandole, cefotiam, cefuroxime, cefotiam, cefotiam hexetil, cefuroxime axetil, cefdinil, cefdinil fipirozine, cefdinil, cefdinilpiphidine , Cefmenoxime, cefpodoxime proxetil, cefpirom, cefozopran, Cefepime, cefsulodin, cefumezinol, cefminox, cefoxitin, cefupperazone, ratamoxef, flomoxef, cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam, chenamycin, sulfazecin, aztreginam, ochanacin, azulvin sulphine, or aztregonam Antibiotics (J. Ant ibiotics), 38, 877-885 (19985)], etc.] Cefixime, repo-floxacin], antithrombotics (eg argatroban), antiprotozoal drugs [ Metronidazole, tinidazole, getylcarbamazine quenate, quinine hydrochloride, quinine sulfate, etc.], antitumor drugs [6--1- (N-chloroacetylcarbamoyl) fumagillol, bleomaisin, methotrexate, a Chinomaishin], mitomycin C, Daunorubi Singh, adriamycin, Neokaruchinosu evening Chin, cytosine § Rabbi Bruno Sid, Furuo Rourashiru, tetrahydrofuryl one 5- Furuorourashiru, picibanil, wrench Nan, Levamisole, Vesutin, Azimexone, Glycyrrhizin, Doxorubicin hydrochloride, Aclarubicin hydrochloride, Bleomycin hydrochloride, Pebromycin sulfate, Vincristine sulfate, Vinplastin sulfate, Irinotecan hydrochloride, Cyclophosphamide, Melphalan, Busulfan, Thiotepa, Procarbazine hydrochloride, cisplatin, azathioprine, mercaptopurine, tegafur, carmofur, cysteine rabin, methyltestosterone, testosterone propionate, testosterone enanthate, mepithiostane, phosphfestrol, chlormadinone acetate, lupusulin acetate acetate, buserelin acetate, etc. ], Antifungals [(i) polyethylene antibiotics (eg, amphotericin 8, nice quintin, tricomycin), (ii) glycemic (Iii) cytosine antimetabolites (eg, flucytosine, (iv) imidazole derivatives (eg, econazole, clotrimazole, miconazole nitrate, pifonazole, croconazole) such as fluvin and pyrrole ditolin; (V) Triazole derivatives (eg, fluconazole, itraconazole, azole compounds [2-[(1R, 2R) -2- (2,4-difluorophenyl) -1-2-hydroxy-1-methyl-3- ( 1 H _ 1, 2,4 _triazol-1-yl) propyl] 1 4— [4 1 (2,2,3,3-tetrafluoropropoxy) phenyl— 3— (2H, 4 H) -1,2,4-triazolone], (vi) thiocarbamic acid derivatives (eg, trinaphthol), (vi i) echinocandin derivatives (eg, casbofungin, FK-463, V-echinocandin), etc. ], Antipsychotics [chlorpromazi hydrochloride , Prochlorperazine, trifluoroperazine, thioridazine hydrochloride, perphenazine maleate, fluphenazine enanthate, prochlorperazine maleate, lepomepromazine maleate, promethazine hydrochloride, haloperidol, properidol, spiperone, reserpine, chlorcapramine Sulpiride, zotepine, etc.), anti-ulcer drugs [metaclopromide, histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine, ゥ rogastrine, oxesazein, proglumide, omebrazole, sucralphate sulphate sulphate sulphate sulphate sulpharthur sulphate sulphate sulphate sulphate sulphate sulphate sulphate sulphate sulphate sulphate sulphate sulphate sulphate sulphate sulphate sulphate sulpharthur , Argioxa, Teprenone, Pros evening glandin, etc.), antidiabetic agents (eg, , Nafglinide, pog lipose, acarpose, etc.), anti-obesity drugs (such as mazindol), anti-rheumatic drugs, etc., anxiolytics [dazepam, lorazepam, oxazepam, chlordazeboxide, Medazepam, oxazolam, cloxazolam, clotiazepam, promazepam, etizolam, fludiazepam, hydroxyzine, etc.], antiarrhythmic drugs: disopyramide, lidocaine, quinidine sulfate, flecainide acetate, mexiletine hydrochloride, amidalone hydrochloride, amidalone a) Drugs, etc. Anti-asthmatic drugs [Isoprenaline hydrochloride, salbutamol sulfate, propotanol hydrochloride, terbutaline sulfate, trimethoxynol hydrochloride, rlobbuterol hydrochloride, orciprenaline sulfate, phenothrol hydrobromide, efuedrine hydrochloride, iprotropium bromide , Platinum fluodium, Fium fluodium bromide, Theophylline, Aminophylline, Sodium cromoglycate, Tranilast, Repirinast, Amlexanox, Ibudilast, Ketotiff , Terfenadine, mexidin, alastin, epinastine, ozadarel hydrochloride, pranlukast hydrate, serratrodast, dexamethasone, prednisolone, hydrocortisone, veclotazone propionate, flutizone of propionate, propionic acid Beclomethasone, pro-power terol, etc.], hypothyroid drug Beggar thyroid (thyreoid), repothiloxine sodium (thyradin S), liothyronidine sodium (thyronine, thyronine); drug for nephrotic syndrome : Prednisolone (prednin), prednisolone sodium succinate (prednin), methylprednisolone sodium succinate (sol * medrol), betamethasone (lindelone), antihypertensive drug [(i) sympathomimetic [bistimulant] E.g., clonidine, guanabenes, guanfacine, methyldopa, etc.), ganglionic blockers (e.g., hexamethonium, trimetaphane, etc.), presynaptic blockers (e.g., alsaroxylone, dimethylaminoreserpinate) , Resinamine, reserpine, syrosingopine, etc.), neuron blocker (eg, betadidine, guanethidine, etc.), 1 blocker (eg, bunazosin, doxazosin, prazosin, terazosin, perapidil, etc.),) 3 blocker (eg, probranolol) , Nadolol, timolol, nipradilol, bunitrolol, indenolol, embbutol, carteolol, carvedilol, pindolol, acebutolol, atenolol, pisoprolol, metoprolol, labequinolol, amoslorol, aro Etc. Nororu etc.), (ii) vasodilators [calcium channel antagonists (e.g., manidipine, Two Karujipin, Two Rubajipin, Two Sorujipin, nitrendipine, Beni adipic, amlodipine, etc. Aranijipin), phthalazine derivatives (e.g., Budoraraji Iii) ACE inhibitors [alasepril, captopril, cilazapril, delapril, enalapril, lisinopril, temocapril, trandolapril, quinapril, imidabril, benlabrilリ ル, etc.), (iv) AII antagonists [oral sultan, force desartan, valsartan, telmisartan, irbesartan, forasartan, etc.], (V) diuretics (for example, the above diuretics etc.)], antihypertensive drugs: diuretics [ For example, furosemide (Rasix), bumetaed (Lunetron), azosemide (Diaart)], antihypertensive drugs [eg, ACE inhibitors, (enalapril maleate (renipace), etc.) and Ca antagonists (manidipine, amlodipine, etc.), Hi or / 3 Blockers, etc.), hyperlipidemia treatments [HMG-Co A reductase inhibitors (eg, flubasitin, ceribastin, atorvastatin, etc.), fibrate drugs (eg, synfibrate, clofibrate aluminum) , Clinofibrate, phenofibrate, etc.), anion exchange resin (eg, cholestyramide, etc.), nicotinic acid preparations (eg, nicomol, niceritrol, tocopherol nicotinate, etc.), polyunsaturated fatty acid derivatives (eg, ethyl icosapentate) , Polyenphosphatidylcholine, melinamide, etc.), plant sterols (eg, gamma-oryzanol, soysterol, etc.), elastase, dextran sodium sulfate, squalene synthase inhibitor, CETP inhibitor, 2-chloro-3 [4- (2-Methyl-2-phenylpropoxy) Nil] propionate ethyl ester [Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull), 38, 2792-2796 (1990)], etc., and bone disease drugs: calcium preparations (eg, calcium carbonate etc.), calcitonin preparations, the active vitamin D ₃ preparations (e.g., such as alfacalcidol (Alfarol), calcitriol (mouth cull trawl), etc.), sex hormones (e.g., estrogens, Esutoranjio Ichiru etc.), hormones formulation example, conjugated estrogen (Premarin), etc.], (such Osten) Ivry flavone formulation, vitamin K _2, vitamin kappa ₂ formulation example, Menate Bok Lennon (cod cable), etc.], bisphosphonic acid-based formulations (such as Echidoroneto; ), Prostaglandin Ε2, fluorine compounds (eg, sodium fluoride, etc.), bone formation protein (BMP), wire Fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming follower one timing growth factor (TGF_i3), insulin-like growth factor one 1 and 2 (I GF- 1, 1-2), parathyroid hormone (PTH), compounds described in European Patent Publications EP-A1-376691, EP-A1-460488 and EP-A1_719782 (eg, ( 2R, 4S) 1 (1) — N— [4- (diethoxyphosphorylmethyl) phenyl] —1,2,4,5-tetrahydro-4-methyl_7,8-methylenedioxy-5-oxo—3-benzobenzoin Rupokisamido etc.), etc., fat-soluble vitamins drugs [(i) vitamin A: vitamin, vitamin A ₂ Contact and palmitic acid Retino Ichiru, (ii) vitamin D: vitamin, D _2, D _3, D ₄ and D ₅ , (Iii) Vitamin Es: α-tocopherol,] 3-tocopherol, r-tocopherol, δ-tocopherol, nicotinic acid d1-hitocopherol, (iv) Vitamin Ks: vitamins, K ₂ , K ₃ and Κ, (ν) folic acid (vitamin Μ) etc.] Various conductors of vitamin derivatives [vitamins, for example, 5, 6 Toransuko Leka Rushifu Errol, 2, 5-hydroxy-cholecalciferol Schiff Errol, l «- vitamin D ₃ derivatives such as hydro Toxicogenomics Leka Rushifu Errol, 5, 6 ―Vitamin D ₂ derivatives such as trans-ergo calcipherol etc.], disease-modifying anti-rheumatic drugs and immunosuppressive drugs [eg, methotrexate, leflunomide, prograf, sulfasalazine, D-penicillamine, oral gold drugs], vasopressors [Dopamine, dobutamine, denopamine, digitoxin, digoxin, methyl digoxin, lanatoside (:, G-strophanthin, etc.), cardioprotective drugs: cardiac ATP-K opener, Na-H exchange inhibitor, endothelin antagonist , Perotinsin antagonists, etc. for the treatment of heart failure [Inotropic drugs (eg digitoxin) Digoxin, methyldigoxin, lanatoside C, prossilaridine, etc.), a, i3 stimulants (eg, epinephrine, norlepinephrine, isoproterenol, dopamine, docarpamine, dobutamine, denopamine), phosphodiesterase inhibitors (eg, , Amrinone, milrinone, olprinone hydrochloride, etc.) Calcium channel sensitivity enhancers (eg, pimoventan, etc.), nitrates (eg, nitroglycerin, isosorbide dinitrate, etc.), ACE inhibitors (eg, the above ACE inhibitors, etc.), diuretics (For example, the above diuretics), carperitide, ubidecarenone, vesnarinone, aminophylline, etc.), neurotrophic factor, renal failure, nephropathy drug, biological preparation [for example, monoclonal antibody (eg, anti-TNF-α antibody) , Anti-IL-12 antibody, anti-IL-6 antibody, I CAM-I antibody, anti-CD 4 antibodies, etc.), soluble receptors (e.g., soluble TNF- Les Seppu Yuichi, etc.), proteinaceous ligand (IL-I receptor antagonist, etc.)], bile acid binding resin [eg, cholestyramine, cholestibol, etc.], Biliary disease drug: bile drug [eg, dehydrocholic acid, etc.] ], Cholesterol [eg, magnesium sulfate, etc.], central nervous system drugs: anti-anxiety drugs, hypnotics, anesthetics, anticonvulsants, autonomic drugs, antiparkinson drugs and other psychiatric drugs Antitussive and antiseptic drugs (ephedrine hydrochloride, noseptic hydrochloride, codine phosphate, dihydrocodine phosphate, isoproterenol hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, alochlamide, clofenolanol, picoperidamine, cloperastine, protokyrol , Isoproterenol, salbutamol, terbutaline, oximetebanol, morphine hydrochloride , Dextromethorphan hydrobromide, Oxycodone hydrochloride, Dimemorphan phosphate, Tipididine hibenzanate, Pentoxeverine quenate, Clofuedanol hydrochloride, Benzonate, Guaiphenesin, Bromhexine hydrochloride, Amproxol hydrochloride, Acetyl cysteine hydrochloride, Hydrochloride Tilcysteine, carbocysteine, etc.), sedatives [chlorpromazine hydrochloride, acetobarite, phenobarbite, valpital, amobarbital, pentobarbital, tiopentanal sodium, thiamylal sodium, nitrazepam, estazolam, flurazapam, haloxazolam , Triazolam, flunitrazepam, bromperylurea, clonal hydrate, triclofos sodium, etc.), analgesics and anti-inflammatory agents [eg, central analgesia (Eg, morphine, codin, penzozocine, etc.), steroids (eg, prednisolone, dexamethasone, betamethasone, etc.), anti-inflammatory enzymes (eg, bromelain, lysozyme, proctase, etc.)], diabetes treatment [sulfonylurea agent] (Eg, tolptamide, chlorpropamide, glicloviramide, acetohexamide, tolazamide, dalibenclamide, gribizol), biguanides (eg, metformin hydrochloride, pformin hydrochloride, etc.), α-dalcosidase inhibitors (eg, poglipoise) , Acarpoise, etc.), insulin sensitizers (eg, pioglitazone, troglitazone, etc.), insulin, glucagon, drugs for treating diabetic complications (eg, epalrestat, thioctoic acid, etc.), actos, rosiglitazone, kineda Click, Benfiru, Hiyumarin, Oidarukon, Darimikuron, Doni Le, Noporin, mono- evening over de, insulin compounds, Darukobai, Jimerin, Rasuchinon, Bashirukon, Damerin, etc. Isujirin acid], brain function enhancers (eg, Idebe non, Vinpocetine, etc.), Urinary and male genital disorders: [Examples: Prostate hypertrophy treatments (such as mucus mouth hydrochloride, prazosin hydrochloride, chrommadinone acetate), prostate cancer treatments (reuprorelin acetate, goserelin acetate, chlormadinone acetate) Non-steroidal anti-inflammatory drugs [acetoaminophen, phenacetin, ethenzamide, sulpyrine, antipyrine, migrenine, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, fenilbutazone, indomestic evening Syn, ibuprofen, ketoprofen, ketoprofen, naproxen, oxaprozin, flurpiprofen, fenbufen, pranoprofen, flok fenin, epirizole, tiaramid hydrochloride, the Toprofen, gabexate mesylate, mosquito acid mesylate, perinastatin, colchicine, probenedide, sulfinvirazone, benzpromalone, aloprinol, sodium gold thiomalate, sodium hyaluronate, sodium salicylate , Morphine hydrochloride, salicylic acid, atotopin, scopolamine, morphine, pethidine, lepolfuinol, ketoprofen, naproxen, oxymorphone or a salt thereof], treatment for pollakiuria and urinary incontinence [flavoxitol hydrochloride, etc.] Stable plaque stabilizers [MMP inhibitors, chymase inhibitors, etc.], arrhythmic drugs [sodium channel blockers (eg, quinidine, proforce iminamide, disopyramide, adimarin, cibenzoline, lidocaine, diphenylhydantoin, mexican) Retin, propafenone, flecainide, pilgi kainide, phenytoin, etc.],] 3 blockers (eg, propranolol, alprenolol-pufetrol, oxprenolol, athenol, aseptol, metopro-l, pisoprolol, pindolol, force Luteo oral, arrotirol, etc.) Potassium channel blockers (eg, amiodarone), calcium channel blockers (eg, verapamil, diltiazem, etc.), etc., Gynecological drugs: [eg, menopause drugs] (Conjugated estrogens, estradiol, testosterone enanthate, estradiol valerate, etc.), drugs for treating breast cancer (such as moxifen citrate), drugs for treating endometriosis and uterine fibroids (such as leuprorelin acetate, danazol)], etc. , Hemp Intoxicants [a. Local anesthetics [cocaine hydrochloride, proforce hydrochloride, lidocaine, dibu hydrochloride power-in, te small labourin hydrochloride, mepiva-force hydrochloride, bupiva-force hydrochloride, oxybium hydrochloride pro-in, aminobenzoic acid Etc.], b. General anesthetic [(i) Inhaled anesthetics (eg, ether, octatan, nitrous oxide, influrane, enflurane), (ii) intravenous anesthetics (eg, ketamine hydrochloride, droperidol, thiopental sodium, thiamylal sodium, pentobarbi), etc. ]], Anesthetic antagonists [levalorphan, nalorphine, naloxone or a salt thereof], drugs for chronic heart failure: inotropic drugs [eg, cardiac glycosides (digoxin, etc.), jS receptor stimulants (denovamin, dobu yumin, etc.) Catecholamine preparations) and PDE inhibitors etc.), diuretics [eg, flosemid (Lasix), spironolactone (aldactone), bumeyumid (Luneto mouth), azosemide (diart), etc.], ACE inhibitors, [examples , Enala prill maleate (Renibeis) etc.], Ca antagonist [eg, amlodipine, ma Nisipin etc.) and immunomodulatory drugs such as jS receptor blockers [cyclosporine, evening crolimus, guslimus, azathioprine, anti-lymph serum, dried sulfonated immunoglobulin, erythrocyte boyetin, colony stimulating factor, interleukin, interferon Etc.), diuretics [thiazide diuretics (bentil hydrochloride thiazide, cyclobenchazide, ethiazide, hydrochloride thiazide, hydroflumethiazide, methyclothiazide, penfluthiazide, polythiazide, trichlormethiazide, etc.), loop Diuretics (chloryl lidone, clofenamide, indapamide, mefluzide, methicran, sotrazone, tribamide, kinesuizon, metrazone, furosemide, mefluside, etc.), potassium-sparing diuretics (spironolacto) And triamterene)], erectile dysfunction drugs (Viagra, etc. Apomorufuin) and the like.

These drugs can be formulated separately or simultaneously and mixed with pharmacologically acceptable carriers, excipients, binders, diluents and the like, and administered orally or parenterally. When the drugs are formulated separately, the separately formulated ones can be mixed with a diluent at the time of use and administered, but the individually formulated separately can be administered simultaneously or with a time lag. And may be administered separately to the same subject. A kit product for administering separately formulated products using a diluent or the like at the time of use (for example, mixing an ampoule containing individual powdered drugs with two or more drugs at the time of use) Kit products for the administration of the same formulation to the same subject at the same time or separately at different times, such as injection kits containing diluents for dissolution, etc.) Put the disintegrant containing the drug in the same or separate bags, Where necessary, a column for describing the time for administering the drug, a kit for tablets for administering two or more tablets simultaneously or separately with a time lag, etc.) may be included in the pharmaceutical composition of the present invention. included.

 When a pharmaceutical composition containing the compound (I) of the present invention is used as a therapeutic agent for preventing graft-versus-host disease and / or rejection when transplanting an organ such as heart, kidney, liver, or bone marrow, It is administered 3 days before transplantation and continuously after transplantation. The daily dose of the pharmaceutical composition of the present invention varies depending on the condition and weight of the patient and the method of administration. In the case of oral administration, the active ingredient per adult (body weight 50 kg) [Compound (I)] About 5 to 1000 mg, preferably about 10 to 60 Omg, more preferably about 10 to 30 Omg, particularly preferably about 15 to 150 mg, once or twice to three times a day. Is administered. In this case, it may be used in combination with an agent for suppressing graft-versus-host disease and / or rejection during other organ transplantation. Specific examples of inhibitors of graft-versus-host disease and Z or rejection at the time of organ transplantation used in combination with the above compound (I) include cyclosporin, evening chlorimus, rapamycin, steroids, azathioprine, and Mico Mofethyl phenolate, mizoribine and the like. When these drugs are used in combination, when one drug affects the metabolism of another drug, the dose of each drug is adjusted appropriately, but generally, the dose of each drug as a single drug is The current dose is used.

Use of a pharmaceutical composition containing the compound (I) of the present invention for a prophylactic / therapeutic agent for AIDS, an agent for suppressing the progression of AIDS pathology, a graft-versus-host disease at the time of organ transplantation, and a target disease other than an agent for suppressing Z or rejection. The daily dose depends on the type of target disease, the condition and weight of the patient, and the method of administration. In the case of oral administration, an adult (body weight of 5 O kg) is used as an active ingredient [Compound (I)] per person 5 to 100 Omg, preferably about 10 to 600 mg, more preferably about 10 to 300 mg, particularly preferably about 15 to 15 Omg, administered once or twice to three times a day I do. When used in combination with another drug, the dose of the other drug is appropriately selected, for example, in the range of about 1/200 to 1/2 or more and about 2 to 3 times or less of the usual dose. In addition, when two or more drugs are used in combination In addition, when one drug affects the metabolism of another drug, the dose of each drug is adjusted as appropriate, but generally, the dose of each drug at the time of single drug administration is used. The compound (I) of the present invention can also be contained in or used in combination with blood for transfusion or blood products. Transfusion blood or blood products are usually produced by mixing blood from multiple people, which may contain cells infected with the HIV virus and cells not infected. Yes, in this case, it may infect uninfected cells. By incorporating the compound (I) of the present invention, infection and proliferation of these viruses can be prevented or suppressed. In particular, it is effective to mix compound (I) when storing blood products in order to prevent or suppress viral infection and proliferation. In addition, when blood or blood products for transfusion contaminated with the HIV virus are administered, compound (I) can be added to the blood to give the body of the person who received the blood or blood products for transfusion. Can prevent HIV transmission and proliferation. For example, when administered orally to an adult (body weight of about 60 kg) to prevent HIV infection during transfusion and use of blood products, a single dose of about 0.02 to 5 Omg / kg as a CCR antagonist is usually given. The dose is preferably about 0.05 to 30 mgZkg, more preferably about 0.1 to 1 OmgZkg, and it is desirable to administer these doses about once to three times a day. Of course, these dose ranges can be adjusted on a unit basis needed to divide up the daily dose, but as noted above, the dose may vary depending on the nature and extent of the disease, the age of the patient, weight, general health, Gender, diet, time of administration, mode of administration, rate of excretion, and other factors may be considered. In this case, the administration method can also be appropriately selected.The HIV infection preventive agent of the present invention described above may be directly added to the blood or blood product to be transfused before blood transfusion or before use of the blood product. It is desirable to mix immediately before to 24 hours, preferably immediately before to 12 hours, more preferably immediately before to 6 hours.

When administering the preventive agent for HIV infection of the present invention separately from blood or blood products to be transfused at the time of blood transfusion or use of blood products, it is desirable to administer it 1 hour before or simultaneously with the use of blood transfusion or blood products, and more preferably It is desirable to continue administration once to three times a day for 4 weeks. Example

 Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, Test Examples, and Formulation Examples. However, these are merely examples and do not limit the present invention in any way. The genetic manipulation method described below is based on the method described in a companion book (Maniatis et al., Molecular Cloning, Cold Spring Harbor Laboratory, 1989) or the protocol described in the reagent attached protocol. Followed.

 In the following Reference Examples and Examples, silica gel 60 (70-230 or 230-400 mesh) or Fuji Silica Chemical NH-silica gel (100-200 mesh) was used as a filler for column chromatography. ^ NMR spectra were measured using Varian Gemini-200 (200 MHz) or Varian Mercury (300 MHz) with tetramethylsilane as the internal standard.

Example 1-1

 N- [3- (4- {4-[(4-{[tert-butyl (dimethyl) silyl] oxy] -topidridinyl) sulfonyl] benzyl-topiperidinyl) propyl] -N'-ethyl-N Ethyl isocyanate (0.112 mL, 1.42 t) was added dropwise to a solution of the compound (416 mg, 0.710 t) in dichloromethane (10 mL) obtained in Reference Example 1-3, and the mixture was stirred for 23 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate (40 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline. After drying over anhydrous magnesium sulfate and evaporation under reduced pressure, the residue was purified by column chromatography (hexane / ethyl acetate = 1/1) to obtain the title compound (449 mg, 96%) as a colorless oil.

'Mandial R (CDC1 ₃ ) δ-0.03 (6Η, s), 0.77 (9H, s), 1.03 (3H, t, J = 7.2Hz), 1.18-1.36 (2H, m), 1.45-1.89 (13H , m), 2.27-2.35 (2H, m), 2.58 (2H, d, J = 6.6Hz), 2.79-2.90 (2H, m), 2.98-3.15 (2H, m), 3.19 (2H, dq, J = 7.2, 5.7Hz), 3.70 (2H, t, J = 7.Hz), 3.74-3.82 (1H, m), 4.48 (1H, t, J = 5.7Hz), 7.18-7.23 (2H, m), 7.25-7.33 (3H, m), 7.37-7.44 (2H, m), 7.63-7.68 (2H, m).

Example 1-2

 N'-Ethyl-N- [3- (4- {4 _ [(4-hydroxy-1-piberidinyl) sulfonyl] benzyl] -topiperidinyl) propyl] -N-phenylperylene

Compound (449 mg, 0.683 bandol) obtained in Example 1-1 was dissolved in tetrahydrofuran (5 mL). To the solution was added a 1M tetrabutylammonium fluoride / tetrahydrofuran solution (1.0 mL, 1.0 mL), and the mixture was stirred for 4 hours. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (hexane / ethyl acetate = 1/1 → 0/1). The desired fraction was concentrated under reduced pressure to give a colorless oil (299 mg, 81 »).

_{Ή NMR (CDC1 3) (51.02} (3H, t, J = 7.2Hz), 1.16-1.34 (2H, m), 1.47-1.75 (7H, m), 1.78-1.98 (4H, m), 2.27-2.34 ( 2H, m), 2.59 (2H, d, J = 6.3Hz), 2.80-2.92 (4H, ra), 3.19 (2H, dq, J = 7.2, 5.4Hz), 3.27-3.37 (2H, m), 3.65 -3.81 (3H, m), 4.47 (1H, brt, J = 5.4Hz), 7.18-7.23 (2H, m), 7.24-7.33 (3H, m), 7.37-7.44 (2H, m), 7.64- 7.68 (2H, m).

Example 2-1

 N- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -4 _ {[1_ (3 _ {[(ethylamino) capillonyl] anilino} propyl) -4-piperidinyl] methyl} benzenesulfone ^ ^

 The title compound was synthesized in the same manner as in Example 1-1 using the compound obtained in Reference Example 2-3. Yield 89%.

_{^{L H NMR (CDC1 3) άθ.00}} (6Η, s), 0.84 (9H, s), 1.03 (3H, t, J = 7.5Hz), 1.18-1.34 (2H, m), 1.44-1.75 (5H, m), 1.77-1.89 (2H, m), 2.27-2.35 (2H, m), 2.58 (2H, d, J = 6.6Hz), 2.80-2.89 (2H, m), 3.02-09 (2H, m) , 3.19 (2H, dq, J = 7.5, 6.0Hz), 3.61 (2H, t, J = 5.1Hz), 3.69 (2H, t, J = 7.5Hz), 4.43-4.51 (1H, m), 4.75 ( Example 2-2 1H, t, J = 6.0Hz), 7.18-7.33 (5H, m), 7.37-7.44 (2H, m), 7.73-7.78 (2H, m).

 4-{[l- (3-{[(ethylamino) potrol] anilino} propyl) -4-Piperidinyl] methyl N- (2-hydroxyethyl) benzenesulfonamide hydrochloride

 Using the compound obtained in Example 2-1 and in the same manner as in Example 1-2, 4-{[1- (3-{[(ethylamino) potassyl] anilino} propyl) -4-pi ぺRidinyl] methyl} -N_ (2-hydr

_{Ή NMR (CDC1 3) δ 1.02} (3Η, t, J = 7.2Hz), 1.16-1.34 (2H, m), 1.39-1.89 (7H, m), 2.26-2.35 (2H, m), 2.58 (2H, d, J = 6.6Hz), 2.80-2.89 (2H, m), 3.06-3.11 (2H, m), 3.19 (2H, dq, J = 7.2, 5.7Hz), 3.27-3.35 (1H, m), 3.64 -3.72 (4H, m), 4. 9-4.58 (1H, m), 7.18-7.34 (5H, m), 7.37-7.44 (2H, m), 7.76-7.81 (2H, m). 4N in a solution of the above compound in methanol (5 mL) A hydrochloric acid / ethyl acetate solution (0.3 mL) was added, and the mixture was stirred for 1 hour. The powder obtained by distilling off the solvent was washed with disopropyl ether to give the title compound (254 mg, 80%) as colorless powdery crystals.

Example 3-1

（({4-[(ト {3 _ [{[(4-chlorophenyl) amino] aminopropyl] (phenyl) amino] propyl} piperidine-4-yl) methyl] phenyl} sulfonyl Piperidine-4-ethyl carboxylate

To a dichloromethane (15 mL) solution of the compound obtained in Reference Example 3-3 (1583 mg, 3.00 mmol) was added 4-chlorophenylisocyanate (599 mg, 3.90 mmol) with stirring, and the mixture was stirred at room temperature for 18 hours. Stirred. After the reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the insolubles were filtered off. After the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, ethyl acetate / methanol = 1/0 → 4/1), and then column chromatography (NH silica gel 80 g, hexane / ethyl acetate) ^ / 1 → 1/3) to give the title compound (1840 _mg , 2.70 bandages 01, yield 90).

_{'Η NMR (CDC1 3) δ} 1.1-2.05 (13H, m), 1.21 (3H, t, J = 7.2Hz), 2.15-2.35 (1H, m), 2.36 (2H, t, J = 7.3Hz), 2.48 (2H, td, J-11.4, 2.9Hz), 2.58 (2H, d, J = 6.2Hz), 2.87 (2H, br d, J = 11.4Hz), 3.63 (2'H, dt, J-11.9 , 3.9Hz), 3.76 (2H, t, J = 7.3Hz), 4.10 (2H, q, J = 7.2Hz), 6.51 (1H, s), 7.1-7.55 (11H, m), 7.65 (2H, d , J = 8.4Hz). Example 3-2

 1_ ({4- [({{3- [{[(4-chlorophenyl) amino] aminopropyl] (phenyl) amino] propyl} piperidin-4-yl) methyl] phenyl} Sulfonyl) piperidine-4-carboxylic acid To a solution of the compound obtained in Example 3-1 (681 mg, 1.OO mmol) in methanol (lOmL) was added a 1N aqueous sodium hydroxide solution (2.OOmL), and the mixture was added at 50 ° C. Stirred for hours. The reaction mixture was added with 1N hydrochloric acid (oOmL) and concentrated under reduced pressure. Water (15 mL) was added to the residue, and extracted with dichloromethane (20 mL, 10 mL × 2). The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, dichloromethane / methanol = 1/0-2/1) to give the title compound (541 mg, 0.83 bandat 01, yield 83) as a colorless amorphous As obtained.

1 R (CDC1 ₃ ) 51.05-1.35 (2Η, m), 1.4-1.6 (6H, m), 1.6-2.0 (3H, m), 2.1-2.4 (3H, m), 2.6-2.85 (6H, i), 3.05-3.4 (4H, m), 3.72 (2H, t, J = 6.8Hz), 6.11 (1H, s), 7.1-7.55 (11H, m ), 7.70 (2H, d, J = 7.8Hz).

Example 4-1

 1- (U-[(({{3-[(adilinolecapillon) (phenyl) amino] propyl} piperidin-4-yl) methyl] phenyl} sulfonyl) piperidine-4-carboxylate

 The title compound was synthesized in the same manner as in Example 3-1 using phenyl isocyanate. 82% yield.

_{lE NMR (CDC1 3) 5 1.1-2.05} (13H,), 1.21 (3H, t, J = 7.3Hz), 2.15-2.35 (1H, m), 2.36 (2H, t, J = 7.5Hz), 2.47 ( 2H, td, J = 11.3, 2.9Hz), 2.58 (2H, d, J = 6.2Hz), 2.87 (2H, br d, J = 11.8Hz), 3.63 (2H, dt, J-11.9, 3.7Hz) , 3.78 (2H, t, J = 7.2Hz), .10 (2H, q, J = 7.3Hz), 6.44 (1H, s), 6.9-7.05 (1H, m), 7.15-7.55 (11H, m) , 7.65 (2H, d, J = 8.6Hz).

Example 4-2

卜 (U-[({{3-[(adilinolecapillon) (phenyl) amino] propyl} piperidin-4-yl) methyl] phenyl} sulfonyl) piperidine-4-carbonic acid

 The title compound was synthesized in the same manner as in Example 3-2, using the compound obtained in Example 4-1. Yield 99%.

_{Ή NMR (CDC1 3) δ 1.15-2.05} (11H, m), 2.1-2.45 (3H, m), 2.6-2.9 (6H, m), 3.05-3.25 (2H, m), 3.36 (2H, br d, J = 11.6Hz), 3.74 (2H, t, J-6.6Hz), 6.11 (1H, s), 6.9-7.1 (1H, m), 7.1-7.55 (11H, m), 7.70 (2H, d, J -8.0Hz).

Example 5-1.

G ({4-[(gamma {3-[{[(4-methylphenyl) amino] aminopropyl] (phenyl) amino] propyl} piperidine-4-yl) methyl] phenyl} sulfonyl) piperidine -Ethyl 4-carboxylate

 The title compound was synthesized in the same manner as in Example 3-1 using 4-methylphenylisocyanate. Yield 89%.

_{Ή NMR (CDC1 3) 5 1.15-2.05} (13H, m), 1.21 (3H, t, J = 7.2Hz), 2.15-2.35 (1H, m), 2.26 (3H, s), 2.38 (2H, t, J = 7.3Hz), 2.48 (2H, td, J = 11.3, 2.5Hz), 2.58 (2H, d, J = 6.6Hz), 2.88 (2H, br d, J = 11.4Hz), 3.63 (2H, dt , J = 11.6, 3.7Hz), 3.77 (2H, t, J = 7.1Hz), 4.10 (2H, q, J = 7.2Hz), 6.36 (1H, s), 7.03 (2H, d, J = 8.6Hz), 7.16 (2H, d, J = 8.6Hz), 7.2-7.55 (7H, m), 7.65 (2H, d, J = 8.6Hz). Example 5-2

 1-({4-[(({3-[{[(4-Methylphenyl) amino] phenyl] (phenyl) amino] propyl} piperidin-4-yl) methyl] phenyl} sulfonyl) Piperidine-4-carboxylic acid The title compound was synthesized in the same manner as in Example 3-2, using the compound obtained in Example 5-1. Yield 91%.

¹謹_{R (CDC1 3) 81.1-2.05 (11H} , m), 2.1-2.45 (3H, m), 2.26 (3H, s), 2.65-2.85 (6H, m), 3.05-3.3 (2H, m), 3.35 (2H, br d, J = 10.8Hz), 3.73 (2H, t, J = 6.8Hz), 6.03 (1H, s), 6.95-7.55 (11H, m), 7.70 (2H, d, J = 8.2 Hz).

Example 6-1

 1- (U- [α- {3-[{[(4-Fluorophenyl) amino] carbonyl] (phenyl) amino] propyl} piperidine-4-yl) methyl] phenyl} sulfonyl) Piperidine-4-carboxylate

 The title compound was synthesized in the same manner as in Example 3-1 using 4-fluorophenyl isocyanate. 87% yield.

_{Ή NR (CDC1 3) δ 1.1-2.05} (13H, m), 1.21 (3H, t, J = 7.2Hz), 2.25 (1H, tt, J = 10.3, 4.0Hz), 2.36 (2H, t, J = 7.4Hz), 2.48 (2H, td, J = 11.5, 2.9Hz), 2.58 (2H, d, J = 6.2Hz), 2.86 (2H, br d, J = 11.4Hz), 3.63 (2H, dt, J = 11.7, 3.8Hz), 3.77 (2H, t, J = 7.3Hz), 4.10 (2H, q, J = 7.2Hz), 6.48 (1H, s), 6.85-7.0 (2H, m), 7.15-7.55 (9H, m), 7.65 (2H, d, J = 8.4Hz).

Example 6-2

（({4- [({{3- [{[(4-fluorophenyl) amino] aminopropyl] (phenyl) amino] pulp}} piperidine-4-yl) methyl] phenyl} sulfonyl ) Piperidine-4-carboxylic acid

 The title compound was synthesized in the same manner as in Example 3-2 using the compound obtained in Example 6-1. Yield 91%.

_{^{! H NMR (CDC1 3) δ}} 1.1-2.05 (11H, m), 2.1-2.45 (3H, m), 2.65-2.9 (6H, m), 3.05-3.25 (2H, m), 3.35 (2H, br d , J = 12.2Hz), 3.73 (2H, t, J = 6.8Hz), 6.07 (1H, s), 6.85-7.0 (2H, m), 7.05-7.55 (9H, m), 7.70 (2H, d, J = 8.6Hz).

Example 7-1

 1-({4-[(1- {3-[{[(4-Cyanophenyl) amino] potanol} (phenyl) amino] propyl} piperidin-4-yl) methyl] phenyl} sulfonyl ) Piperidine-4-ethyl carboxylate

 The title compound was synthesized in the same manner as in Example 3-1 using 4-cyanophenyl isocyanate. Yield 88%.

_{Ή NMR (CDC1 3) δ 1.15-2.1} (13H, m), 1.21 (3H, t, J = 7.2Hz), 2.15-2.35 (1H, m), 2.37 (2H, t, J = 7.3Hz), 2.48 (2H, td, J = ll.3, 2.9Hz), 2.59 (2H, d, J = 6.2Hz), 2.87 (2H, br d, J = 10.6Hz), 3.63 (2H, dt, J = 11.6, 3.8Hz), 3.77 (2H, t, J = 7.4Hz), 4.10 (2H, q, J = 7.2Hz), 6.74 (1H, br s), 7.2-7.6 (11H, m), 7.65 (2H, d , J = 8.4Hz). Example 7-2

 1-({4- [α- {3-[{[(4-Cyanophenyl) amino] carbonyl} (phenyl) amino] propyl} piperidine-4-yl) methyl] phenyl} sulfonyl) piperidine -4-Carboxylic acid Using the compound obtained in Example 7-1, the title compound was synthesized in the same manner as in Example 3-2. Yield 91%.

_{'Η NMR (CDC1 3) δ} 1.1-2.05 (11H, m), 2.1-2.45 (3H, m), 2.65-2.95 (6H, m), 3.05-3.25 (2H, m), 3.34 (2H, br d , J-12.0Hz), 3.74 (2H, t, J = 6.6Hz), 6.39 (1H, s), 7.1-7.55 (11H, m), 7.71 (2H, d, J = 8.0Hz).

Example 8-1

 [({4-[(卜 {3- [{[(4-chlorophenyl) amino] amino] phenyl] (phenyl) amino] propyl} piperidine-4-yl) methyl] phenyl } Sulfonyl) (methyl) amino] ethyl acetate

 Using the compound obtained in Reference Example 4-3, the title compound was synthesized in the same manner as in Example 3-1. 82% yield.

'H MR (CDC1 ₃ ) δ 1.1-1.95 (9Η, m), 1.21 (3Η, t, J = 7.2Hz), 2.36 (2H, t, J = 7.3Hz), 2.58 (2H, d, J = 6.6 Hz), 2.86 (2H, br d, J = 12.2Hz), 2.89 (3H, s), 3.77 (2H, t, J = 7.3Hz), 3.97 (2H, s), 4.11 (2H, q, J = 7.2Hz), 6.52 (1H, s), J.1-7.55 (11H, m), 7.72 (2H, d, J = 8.4Hz). Example 8-2

 [({4- [α-{3-[{[(4-Chlorophenyl) amino] carbonyl] (phenyl) amino] propyl} piperidin-4-yl) methyl] phenyl} sulfonyl ) (Methyl) amino] acetic acid The title compound was synthesized in the same manner as in Example 3-2, using the compound obtained in Example 8-1. 79% yield.

_{'HNMR (CDC1 3) 61.45-1.8 (} 5Η, m), 1.8-2.05 (2H, m), 2.25-2.5 (2H, m), 2.5-2.7 (2H, m), 2.75-2.95 (2H, m) , 2.84 (3H, s), 3.38 (2H, br d, J = 11.8Hz), 3.76 (2H, t, J = 6.6Hz), 3.80 (2H, s), 6.19 (1H, s), 7.1-7.6 (11H, m), 7.82 (2H, d, J = 8.4Hz).

Example 9-1

 [({4- [(卜 {3- [{[(4-chlorophenyl) amino] carbonyl] (phenyl) amino] propyl] piperidin-4-yl) methyl] phenyl} Sulfonyl) amino] ethyl acetate

 Using the compound obtained in Reference Example 5-3, the title compound was synthesized in the same manner as in Example 3-1. Yield 41%.

_{'HNMR (CDC1 3) 51.1-2.0 (} 9Η, m), 1.19 (3H, t, J = 7.1Hz), 2.38 (2H, t, J = 7.3Hz), 2.57 (2H, d, J = 6.2Hz) , 2.87 (2H, br d, J = 11.4Hz), 3.76 (2H, t, J = 7.3Hz), 3.78 (2H, s), 4.08 (2H, q, J = 7.1Hz), 4.9-5.2 (1H , br), 6.51 (1H, br s), 7.1-7.55 (11H, m), 7.76 (2H, d, J = 8.4Hz).

Example 9-2

[({4-[(卜 {3- [{[(4-chlorophenyl) amino] carbonyl] (phenyl) amino] propyl] piperidin-4-yl) methyl] phenyl} sulfonyl) Amino] acetic acid

 Using the compound obtained in Example 9-1, the title compound was synthesized in the same manner as in Example 3-2. 97% yield.

 'H MR (CDCI3) δ 1.4-2.05 (7Η, m), 2.3-2.65 (4H, m), 2.8-3.05 (2H, 111), 3.3-3.55 (4H, m), 3.77 (2H, t, J = 6.3Hz), 5.4-5.65 (1H, br), 6.14 (1H, s), 7.1-7.6 (11H, m), 7.82 (2H, d, J = 8.0Hz).

Example 10-1

[({4- [(tri {3-[(adilinocarbonyl) (phenyl) amino] propyl} piperidin-4-yl) methyl] phenyl} sulfonyl) (methyl) amino] ethyl acetate The title compound was synthesized in the same manner as in Example 3-1 using the compound obtained in Reference Example 4-3 and phenyl isocyanate. 87% yield.

'H MR (CDC1 ₃ ) 51.1-2.0 (9Η, m), 1.21 (3H, t, J = 7.2Hz), 2.36 (2H, t, J = 7.4Hz), 2.58 (2H, d, J = 6.6Hz) ), 2.86 (2H, br d, J = 11.4Hz), 2.89 (3H, s), 3.78 (2H, t, J = 7.1Hz), 3.96 (2H, s), 4.11 (2H, q, J = 7.2 Hz), 6.45 (1H, s), 6.9-7.05 (1H, m), 7.15-7.55 (11H, m), 7.72 (2H, d, J = 8.4Hz).

Example 10-2

 [({4- [G- {3- [(anilinocarbonyl) (phenyl) amino] propyl] piperidin-4-yl) methyl] phenyl} sulfonyl) (methyl) amino] acetic acid

 Using the compound obtained in Example 10-1, the title compound was synthesized in the same manner as in Example 3-2. Yield 71%. ,

_{'HNMR (CDC1 3) 81.45-1.8 (} 5Η, m), 1.8-2.05 (2H, m), 2.25-2.5 (2H, m), 2.5-2.7 (2H, m), 2.75-2.95 (2H, m) , 2.85 (3H, s), 3.37 (2H, br d, J = 10.6 Hz), 3.76 (2H, t, J = 6.6 Hz), 3.82 (2H, s), 6.17 (1H, s), 6.9-7.1 (1H, m), 7.1-7.6 (11H, m), 7.84 (2H, d, J = 8.4Hz).

Example 11-1

 2-[({4- [a-{3- [{[(4-chlorophenyl) amino] phenyl] (phenyl) amino] pill} piperidine-4-yl) methyl] phenyl Le} sulfonyl) amino] -2-methylethyl propanoate

 Using the compound obtained in Reference Example 6-3, the title compound was synthesized in the same manner as in Example 3-1. Yield 82. '

'Η Marauder R (CDC1 ₃ ) δ 1.1-2.0 (9Η, m), 1.24 (3H, t, J = 7.2Hz), 1.44 (6H, s), 2.40 (2H, t, J = 7.3Hz), 2.56 (2H, d, J = 6.2Hz), 2.89 (2H, br d, J = 11.4Hz), 3.77 (2H, t, J = 7.1Hz), 4.10 (2H, q, J = 7.2Hz), 5.35 ( 1H, s), 6.55 (1H, brs), 7.1-7.55 (11H, m), 7.77 (2H, d, J = 8.4Hz).

Example 11-2

2-[({4-[(1- {3-[{[(4-Chlorophenyl) amino] phenyl] (phenyl) amino] py} pyridin-4-yl) methyl ] Fenyl} sulfonyl) amino] -2-methylpropanoic acid The title compound was synthesized in the same manner as in Example 3-2, using the compound obtained in Example 11-1. Yield 91%.

_{Ή NMR (CDC1 3) δ 1.37} (6Η, s), 1.5-1.85 (5H, ra), 1.9-2.15 (2H, m), 2.35-2.65 (4H ,, i), 2.9-3.1 (2H, m) , 3.4-3.6 (2H, m), 3.80 (2H, t, J = 6.2Hz), 6.13 (1H, s), 6.67 (1H, br s), 7.1-7.6 (11H, m), 7.83 (2H, d, J = 8.2Hz).

Example 12_1

 2-[({4- [a- {3-[{[(4-Chlorophenyl) amino] phenol] (phenyl) amino] pyr} pyridin-4-yl) methyl] phenyl L} sulfonyl) amino] ethyl propanoate

 Using the compound obtained in Reference Example 7-3, the title compound was synthesized in the same manner as in Example 3-1. Yield 64.

¹謹_{R (CDC1 3) 81.1-1.95 (9H} , m), 1.13 (3H, t, J-7.1Hz), 1.39 (3H, d, J = 7.0Hz), 2.35 (2H, t, J = 7.5Hz ), 2.56 (2H, d, J = 6.6Hz), 2.86 (2H, br d, J = 11.8Hz), 3.76 (2H, t, J = 7.4Hz), 3.85-4.05 (1H, m), 3.96 ( 2H, q, J = 7.1Hz), 5.21 (1H, d, J = 8.4Hz), 6.52 (1H, br s), 7.1-7.55 (11H, ra), 7.74 (2H, d, J = 8.4Hz) Example 12-2

 2-[({4-[(1- {3-[{[(4-chlorophenyl) amino] aminopropyl] (phenyl) amino] -propyl} piperidin-4-yl) methyl] phen [{Sulfonyl) amino] propanoic acid The title compound was synthesized in the same manner as in Example 3-2, using the compound obtained in Example 12-1. Yield quantitative.

_{Ή NMR (CDC1 3) δ 1.3-2.05} (7Η, m), 1.36 (3H, d, J = 7.2Hz), 2.3-2.7 (4H, in), 2.8-3.0 (2H, m), 3.3-3.6 ( 3H, m), 3.76 (2H, t, J = 6.4Hz), 6.01 (1H, br), 6.10 (1H, s), 7.1-7.6 (11H, m), 7.82 (2H, d, J = 8.4Hz) ).

Example 13-1

N- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -4-[(1- {3-[{[(4-chlorophenyl) amino] potanol} (phenyl) Amino] propyl} piperidine-4-yl) methyl] benzenesulfonamide.

The title compound was synthesized in the same manner as in Example 3-1 using the compound obtained in Reference Example 2-3. 90% yield. Ή NMR (CDCI3) δθ.00 (6H, s), 0.84 (9H, s), 1.20-1.30 (2H, m), 1.45-2.03 (7H, m), 2.35-2.47 (2H, m), 2.58 ( 2H, d, J = 5.8Hz), 2.83-2.98 (2H, m), 3.06 (2H, q, J = 5.2Hz), 3.62 (2H, t, J = 5.2Hz), 3.78 (2H, t, J -7.2Hz), 4.78 (1H, t, J = 5.8Hz), 6.52 (1H, brs), 7.15-7.56 (11H, m), 7.76 (2H, d, J = 8.6Hz). Example 13-2

 4-[(1_ {3-[{[(4-Chlorophenyl) amino] aminopropyl] (phenyl) amino] propyl} piperidin-4-yl) methyl] -N- (2- Hydroxyethyl) benzenesulfonamide hydrochloride

 To a solution of the compound (233 mg, 0.333 mmol) obtained in Example 13-1 in tetrahydrofuran (4 mL) was added 1 M tetrabutylammonium fluoride / tetrahydrofuran (0.6 mL) under ice cooling, followed by stirring for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate → methyl alcohol / ethyl acetate = 1/10). A colorless oil obtained by concentrating the target fraction was dissolved in ethyl acetate (lOmL), and a 4N hydrochloric acid / ethyl acetate solution (lmL) was added. The residue obtained by evaporation of the solvent was washed with diisopropyl ether to give the title compound (152 mg, 73%) as a colorless amorphous.

Free _{^{base: 1 HNMR (CDC1 3) (}} 51.15-1.38 (2H, m), 1.42-2.18 (7H, m), 2.37 (2H, i, J = 7.3Hz), 2: 58 (2H, d, J = (6.6Hz), 2.80-2.95 (2H, m), 3.03-3.15 (2H, m), 3.67 (2H, t, J = 4.8Hz), 3.77 (2H, t, J = 7.3Hz), 5.00-5.22 ( 1H, br), 6.56 (1H, brs), 7.15-7.35 (8H, m), 7.35-7.55 (3H, m), 7.76 (2H, d, J = 8.4Hz).

Example 14-1

 4-[(卜 {3- [(adilinolecapillonyl) (phenyl) amino] propyl} piperidin-4-yl) methyl] (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) benzene Sulfonamide

 The title compound was synthesized in the same manner as in Example 4-1 using the compound obtained in Reference Example 2-3. Yield 92%.

_{Ή NMR (CDC1 3) (50.00} (6H, s), 0.84 (9H, s), 1.22-1.42 (2H, m), 1.47-1.64 (3H, m), 1.73-1.95 (4H, m), 2.40 ( 2H, t, J = 7.5Hz), 2.59 (2H, d, J = 6.6Hz), 2.85-2.95 (2H, m), 3.05 (2H, q, J = 5.4Hz), 3.61 (2H, i, J = 5.4Hz), 3.78 (2H, t, J = 7.2Hz), 4.78 (1H, t, J = 6.0Hz), 6.44 (1H, brs), 6.95-7.02 (1H, m), 7.19-7.40 (9H, m), 7.44-7.52 (2H , m), 7.75 (2H, d, J = 8.4Hz).

Example 14-2

 4-[(1- {3-((adilinolephinyl) (phenyl) amino] propyl} piperidin-4-yl) methyl] -N- (2-hydroxyethyl) benzenesulfonamide hydrochloride

 Using the compound obtained in Example 14-II, the title compound was synthesized in the same manner as in Example 13-2. Yield 75%.

Free base: ¹ Eta negation _{R (CDC1 3) δ 1.15-1.40 (} 2H, m), 1.44-1.95 (7H, m), 2.37 (2H, t, J = 7.5Hz), 2.58 (2H, d, J = (5.8Hz), 2.80-2.95 (2H, m), 3.03-3.15 (2H, m), 3.60-3.70 (2H, m), 3.77 (2H, t, J = 7.2Hz), 4.93-5.22 (1H, br ), 6.48 (1H, brs), 6.94-7.04 (1H, m), 7.15-7.35 (8H, m), 7.35-7.55 (3H, m), 7.76 (2H, d, J = 8.4Hz). 15-1

 N- (2-{[tert-butyl (dimethyl) silyl] ethyl} ethyl) -4--4-[(1- {3-[{[(4-cyanophenyl) amino] carbonyl} (phenyl) [Amino] propyl} piperidin-4-yl) methyl Using the compound obtained in Reference Example 2-3, the title compound was synthesized in the same manner as in Example 7-1. 94% yield.

_{Ή NMR (CDC1 3) (50.00} (6H, s), 0.84 (9H, s), 1.18-1.40 (2H, m), 1.45-2.10 (7H, m), 2.40 (2H, t, J = 7.2Hz) , 2.59 (2H, d, J = 6.2Hz), 2.83-2.95 (2H, m), 3.06 (2H, q, J = 5.2Hz), 3.62 (2H, t, J = 5.2Hz), 3.78 (2H, t, J = 7.2Hz), 4.79 (1H, t, J = 6.0Hz), 6.75 (1H, br), 7.20-7.63 (11H, m), 7.76 (2H, d, J = 8.4Hz). 15-2

 4-[({{3- [{[(4_cyanophenyl) amino] aminopropyl] (phenyl) amino] propyl} piperidin-4-yl) (2-hydroxyethyl) benzenesulfonamide

To a solution of the compound obtained in Example 15-1 (357 mg, 0.517 mol) in tetrahydrofuran (5 mL) was added 1M tetrabutylammonium fluoride / tetrahydrofuran (0.52 mL) under ice-cooling, followed by stirring for 1 hour. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate-methyl alcohol / ethyl acetate = 1/10). did. The target fraction was concentrated to give the title compound (220 mg, 7 «) as a colorless amorphous. _{'H MR (CDC1 3) δ} 1.20-1.38 (2Η, m), 1.45-1.93 (7H, m), 2.37 (2H, t, J = 7.3Hz), 2.59 (2H, d, J = 6.6Hz), 2.83-2.94 (2H, m), 3.06-3.15 (2H, m), 3.70 (2H, t, J = 5.1Hz), 3.77 (2H, t, J = 7.5Hz), 4.85-4.95 (1H, br) , 6.63-6.80 (1H, br), 7.25-7.33 (4H, m), 7.36-7.45 (3H, m), 7.45-7.53 (4H, m), 7.76 (2H, d, J = 8.4Hz) Example 16

 2-[({4-[(卜 {3-[{[(4_Chlorophenyl) amino] carbonyl] (phenyl) amino] p-pyr} Piperidin-4-yl) methyl] phenyl } Sulfonyl) (methyl) amino] acetamide

 A solution of the compound (491 mg, 0.80 mmol) obtained in Example 8-2 and 1-hydroxybenzotriazole (108 mg, 0.801MQ1) in N, N-dimethylformamide (5 mL) was stirred under ice-cooling with stirring. Add ammonium chloride (64 mg, 1.2 mmol), triethylamine (0.167 mL, 1.2 bandol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (230 mg, 1.2πιπιο1) in that order. The reaction mixture was concentrated under reduced pressure, ethyl acetate (40 mL) was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate (1 (ML X 3) and saturated saline (10 mL). The organic layer was concentrated under reduced pressure. After that, the residue was subjected to column chromatography (NH silica gel, ethyl acetate / methanol = 100 / 0-90 / 10) .The fraction containing the target compound was collected and concentrated under reduced pressure.The residue was dissolved in dichloromethane (1 OmL). And add 4-cloth phenylisocyanate (49 mg) at room temperature for 18 hours The reaction mixture was concentrated under reduced pressure, dichloromethane was added to the residue, and the insoluble material was separated by filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel, ethyl acetate / methanol = 100/0). The title compound (383 mg, 0.63 mol, yield 78) was obtained as a colorless amorphous.

1請_{R (CDC1 3) 81.1-2.0 (9H} , m), 2.37 (2H, t, J = 7.5Hz), 2.60 (2H, d, J = 6.6Hz), 2.82 (3H, s), 2.88 (2H , br d, J = 11.4Hz), 3.61 (2H, s), 3.77 (2H, t, J = 7.lHz), 5.63 (1H, br s), '6.50 (1H, br s), 6.61 ( 1H, br s), 7.1-7.55 (11H, m), 7.70 (2H, d, J = 8.4Hz).

Example 17-1

（(-[({{3-[{[(4-Chlorophenyl) amino] potassium] (phenyl) amino] propyl} piperidin-4-yl) methyl] phenyl} sulfonyl) azetidine -3-carboxylic acid Etil

 Using the compound obtained in Reference Example 8-3, the title compound was synthesized in the same manner as in Example 3-1. Yield 54%.

¹ thigh _{R (CDC1 3) 51.1-1.95 (9Η} , in), 1.18 (3H, t, J = 7.1Hz), 2.36 (2H, t, J-7.3Hz), 2.61 (2H, d, J = 6.4Hz ), 2.87 (2H, br d, J = 11.4Hz), 3.1-3.35 (1H, m), 3.77

(2H, t, J = 7.1Hz), 3.85-4.1 (4H, m), 4.06 (2H, q, J = 7.1Hz), 6.52 (1H, br s),

7.1-7.55 (11H, m), 7.75 (2H, d, J = 8.4Hz).

Example 17-2

（({4_ [({{3-[{[(4-chlorophenyl) amino] aminopropyl] (phenyl) amino] propyl} piperidin-4-yl) methyl] phenyl} sulfonyl) Azetidine-3-carboxylic acid The title compound was synthesized in the same manner as in Example 3-2, using the compound obtained in Example 17-1. Yield 92%. '

_{Ή NMR (CDC1 3) 8 1.3-2.1} (7Η, m), 2.3-2.55 (2H, m), 2.7-3.0 (5H, m), 3.39 (2H, br d, J ^ ll.OHz), 3.55 ( 2H, dd, J = 7.4, 9.3Hz), 3.70 (2H, t, J = 6.4Hz), 4.05 (2H, dd, J = 9.3, 9.3Hz), 6.07 (1H, s), 7.05-7.55 (11H , m), 7.78 (2H, d, J = 8.4Hz).

Example 18-1

 ({4-[(卜 {3-[{[(4-chlorophenyl) amino] carbonyl] (phenyl) amino] propyl} piperidin-4-yl) methyl] phenyl} sulfanyl ) Ethyl acetate

 Using the compound obtained in Reference Example 9-3, the title compound was synthesized in the same manner as in Example 3-1. Yield 9 «.

'H MR (CDC1 ₃ ) 51.1-1.95 (9Η, m), 1.22 (3H, t, J = 7.1Hz), 2.36 (2H, t, J = 7.5Hz), 2.48 (2H, d, J = 6.6Hz) ), 2.86 (2H, br d, J = 12.2Hz), 3.60 (2H, s), 3.76 (2H, t, J = 7.3Hz), 4.16 (2H, q, J = 7.1Hz), 6.63 (1H, s), 7.06 (2H, d, J = 8.4Hz), 7.1-7.55 (11H, m).

Example 18-2

 ({4-[(卜 {3-[{[(4-Clo-phenyl) amino] carbonyl] (phenyl) amino] propyl} piperidin-4-yl) methyl] phenyl} sulfanyl ) Acetic acid

Using the compound obtained in Example 18-1, the title compound was prepared in the same manner as in Example 3-2. Was synthesized. 82% yield.

'OMR (DMS0-d ₆ ) δ 1.0-1.75 (7Η, m), 1.9-2.1 (2Η, m), 2.3-2.55 (4H, m), 2.89 (2H, br d, J = 10.8Hz), 2.5 -2.8 (4H, m), 7.07 (2H, d, J = 8.0Hz), 7.15-7.5 (11H, m), 8.22 (1H, s).

Example 19-1

 3 _ ({4_ [α- {3-[{[(4-Chlorophenyl) amino] carbonyl] (phenyl) amino] propyl} piperidin-4-yl) methyl] phenyl} sulfanyl) propane Ethyl acid Using the compound obtained in Reference Example 10-3, the title compound was synthesized in the same manner as in Example 3-1. Yield 99%.

【Thigh R (CDC1 ₃ ) δ 1.1― 2.0 (9Η, m), 1.25 (3H, t, J = 7.1Hz), 2.37 (2H, t, J = 7.5Hz), 2.48 (2H, d, J = 6.4Hz), 2.60 (2H, t, J = 7.5Hz), 2.87 (2H, br d, J = 11.4Hz), 3.13 (2H, t, J = 7.5Hz), 3.77 (2H, t, J = 7.1) Hz), 4.14 (2H, q, J = 7.1Hz), 6.63 (1H, br s), 7.06 (2H, d, J = 8.0Hz), 7.1-7.55 (11H, m).

Example 19-2

3-({4- [α- {3-[{[(4-Chlorophenyl) amino] phenyl] (phenyl) amino] propyl} piperidine-4-yl) methyl] phenyl} Sulfanyl) propanoic acid

 Using the compound obtained in Example 19-1, the title compound was synthesized in the same manner as in Example 3-2. Yield 72%.

'H MR (CDC1 ₃ ) δ 1.4-1.8 (5Η, m), 1.8-2.05 (2H, m), 2.15-2.4 (2H, m), 2.4-2.55 (2H, m), 2.49 (2H, t, J = 7.5Hz), 2.65-2.85 (2H, m), 3.11 (2H, t, J = 7.5Hz), 3.30 (2H, br d, J = 11.8Hz), 3.77 (2H, t, J = 6.7Hz) ), 6.27 (1H, s), 7.00 (2H, d, J = 8.0Hz), 7.1-7.55 (11H, m).

Example 20

 2-({4-[(卜 {3-[{[(4-chlorophenyl) amino] aminopropyl] (phenyl) amino] propyl} piperidin-4-yl) methyl] phenyl} Sulfanyl) acetoamide

To a solution of the compound (276 mg, 0.50 mmol) obtained in Example 18-2 and 1-hydroxybenzotriazole (10 mg, 0.75 mmol) in Ν, Ν-dimethylformamide (5 mL) was stirred with ammonium chloride (54 mg, 1 mg). .OOmmol), benzotriazole-trioxytripyrrolidinophosphonium hexafluorophosphato (390mg, 0.75mmol), N-ethyldiiso Propylamine (0.348 mL, OO mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Water (30 mL) and saturated aqueous sodium hydrogen carbonate (30 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layer was washed with a saturated aqueous solution of sodium bicarbonate (10 mL × 2) and a saturated saline solution (10 mL) in that order, and then concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, hexane / ethyl acetate = 50/50 → 0/100), and then re-purified by column chromatography (silica gel, ethyl acetate / methanol = 100 / 0-50 / 50). Purification gave the title compound (172 mg, 0.31 mmol, 62% yield) as a colorless amorphous.

¹ thigh _{R (CDC1 3) δ 1.1-1.95 (} 9Η, m), 2.38 (2H, t, J = 7.5Hz), 2.48 (2H, d, J = 6.4Hz), 2.88 (2H, br d, J- 11.6Hz), 3.60 (2H, s), 3.77 (2H, t, J = 7.1Hz), 5.52 (1H, br s), 6.60 (1H, br s), 6.71 (1H, br s), 7.07 (2H , d, J = 8.6Hz), 7.1-7.55 (11H, m).

Example 21

 4-[(l- {3 _ [{[(4-Coural phenyl) amino] carbonyl] (phenyl) amino] propyl} piperidin-4-yl) methyl] -N- (2-hydroxyethyl)- N-methylbenzenesulfonamide.

 A solution of the compound obtained in Example 8-2 (245 mg, 0.40 mmol) and triethylamine (0.112 mL, 0.80 mmol) in tetrahydrofuran (10 mL) was stirred at −20 ° C. with ethyl chlorocarbonate (0.076 mL, (0.79 mmol) and stirred at -20 ° C to -10 ° C for 30 minutes. An aqueous solution (0.4 mL) of sodium borohydride (61 mg, 1.6Π1) was added to the reaction mixture while stirring at -IO, and the mixture was stirred at -10 ° C to 0 ° C for 1 hour. To the reaction mixture was added 1N hydrochloric acid (1.6 mL) under ice cooling and stirring, the organic solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate (20 mL, 10 mL X2). The organic layer was washed with saturated saline (5 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate / methanol = 100/0 → 50/50) to give the title compound (83 mg, O.Hmmol, yield 35%) as a colorless amorphous.

_{[H NMR (CDC1 3) δ} 1.15-2.2 (9Η, m), 2.41 (2H, br t, J = 7.3Hz), 2.60 (2H, d, J = 6.2Hz), 2.84 (3H, s), 2.91 (2H, br d, J = 9.6Hz), 3.17 (2H, t, J = 5.3Hz), 3.77 (2H, t, J = 5.3Hz), 3.77 (2H, t, J = 6.9Hz), 6.48 ( 1H, br s), 7.1-7.55 (11H, m), 7.71 (2H, d, J-8.4Hz) .Example 22-1 4-({4-[(卜 {3-[{[(4-chlorophenyl) amino] aminopropyl] (phenyl) amino] propyl} piperidin-4-yl) methyl] phenyl Le} sulfanyl) ethyl ester

 Using the compound obtained in Reference Example 11-3, the title compound was synthesized in the same manner as in Example 3-1. Yield 88%.

_{Ή NMR (CDC1 3) δ 1.1-2.05} (11H, m), 1.25 (3H, t, J = 7.2Hz), 2.36 (2H, t, J = 7.5Hz), 2.45 (2H, t, J = 7.2Hz ), 2.47 (2H, d, J-7.0Hz), 2.86 (2H, br d, J-12.8Hz), 2.93 (2H, t, J = 7.1Hz), 3.77 (2H, t, J = 7.1Hz) , 4.12 (2H, q, J = 7.2Hz), 6.64 (1H, br s), 7.04 (2H, d, J = 8.0Hz), 7.1-7.55 (11H, m).

Example 22-2

4-({4- [a- {3-[{[(4-Chlorophenyl) amino] phenyl] (phenyl) amino] propyl} piperidine-4-yl) methyl] phenyl} Sulfanyl) butanoic acid

 Using the compound obtained in Example 22-1, the title compound was synthesized in the same manner as in Example 3-2. Yield 94¾.

_{Ή NMR (CDC1 3) δ 1.3-1.75} (5Η, m), 1.75-2.0 (4H, ra), 2.1-2.35 (2H, m), 2.30 (2H, t, J-7.0Hz), 2.4-2.55 ( 2H, m), 2.6-2.8 (2H, m), 2.92 (2H, t, J = 7.3Hz), 3.23 (2H, br d, J = 11.4Hz), 3.75 (2H, t, J = 6.8Hz) , 6.25 (1H, s), 6.98 (2H, d, J = 8.4Hz), 7.1-7.55 (11H, m).

Example 23-1

 2-({4-[(1-{3-[{[(4-chlorophenyl) amino] aminopropyl] (phenyl) amino] propyl} piperidin-4-yl) methyl] phen Nyl} sulfanyl) tert-butyl-2-methylpropanoate

 Using the compound obtained in Reference Example 12-3, the title compound was synthesized in the same manner as in Example 3-1. Yield 85.

Negation _{R (CDC1 3) 8 1.1-2.0 (} 9H, m), 1.41 (9H, s), 1.42 (6H, s), 2.36 (2H, t, J = 7.3Hz), 2.50 (2H, d, J = 6.6Hz), 2.86 (2H, br d, J = 11.0Hz), 3.77 (2H, t, J = 7.1Hz), 6.60 (1H, br s), 7.06 (2H, d, J = 8.0Hz), 7.1 -7.55 (11H, m).

Example 23-2

2-({4-[(卜 {3-[{[(4-Coufenphenyl) amino] carbonyl] (phenyl) amino] propyl} piperidin-4-yl) methylyl] phenyl {Sulfanyl) -2-methylpropanoate To a solution of the compound obtained in Example 23-1 (495 mg, 0.78 mmol) in dichloromethane (5 mL) was added 4N hydrogen chloride (ethyl acetate solution, 5 mL), and the mixture was stirred at room temperature for 24 hours. After the reaction mixture was concentrated under reduced pressure, getyl ether was added to the residue, and the precipitate was collected by filtration. The precipitate was washed with diethyl ether and dried under reduced pressure to give the title compound (426 mg, 0.69 ol, yield 89%) as a colorless amorphous.

_{Ή NMR (CDC1 3) 51.47 (} 6Η, s), 1.6-2.3 (7H, m), 2.45-2.75. (2H, m), 2.61 (2H, d, J = 6.6Hz), 2.95-3.2 (2H, m), 3.56 (2H, br d, J = 11.0Hz), 3.80 (2H, t, J = 6.2Hz), 6.17 (1H, s), 7.06 (2H, d, J = 8.0Hz), 7.1-7.6 (11H, m), 11.76 (1H, br s).

 4-{[tert-butyl (dimethyl) silyl] oxy} -tri [[4-{[tri (trifluoroacetyl) -4-piperidinyl] methyl} phenyl) sulfonyl] piperidine

 4-{[1- (Trifluoroacetyl) piperidin-4-yl] methyl} benzenesulfonyl chloride (1.70 g, 4.59 mmol) in tetrahydrofuran (40 mL) was added to 4-hydroxypyridine (0.696 mL, 6.89 marl ol) and triethylamine (L16mL, 8.26 marl 01) were added and stirred for 30 minutes. Water (40 mL) was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / hexane = 5/1) and purified by 1-[(4-{[ 1- (Trifluoroacetyl) piperidin-4-yl] methyl} phenyl) sulfonyl] piperidin-4-ol (1.85 g, 93%) was obtained as a colorless amorphous.

_{Ή NMR (CDC1 3) δΐ.19-1.35 (} 2Η, m), 1.42 (1H, d, J = 3.6Hz), 1.57-2.00 (7H, m), 2.60-2.78, (3H, m), 2.87- 2.98 (2H, m), 3.01-3.13 (1H, m), 3.24-3.35 (2H, m), 3.73-3.86 (1H, m), 3.93-4.06 (1H, m), 4.48-4.60 (1H, m ), 7.26-7.32 (2H, HI), 7.67-7.76 (2H, m).

The above [(4-m- (trifluoroacetyl) piperidin-4-yl] methyl} phenyl) sulfonyl] piperidin-4-ol (1.85 g, 4.26 t ol) and tertbutylchlorodimethylsilane (772 mg, 5.11 mol) and a solution of imidazole (348 mg, 5.11 marl) in N, N-dimethylformamide (40 mL) were stirred for 3.5 hours. After the solvent was distilled off, ethyl acetate and water were added to the residue, and the separated organic layer was washed with saturated saline. Reduced after drying with anhydrous magnesium sulfate The residue was purified by pressure chromatography (hexane / ethyl acetate = 5/1 → 2/1) to give the title compound (1.82 g, 78%) as a colorless oil.

_{Ή NMR (CDC1 3) δ-} 0.03 (6Η, s), 0.76 (9H, s), 1.17-1.35 (2H, m), 1.53-1.66 (2H, m), 1.68-1.94 (5H, m), 2.61 -2.77 (3H, m), 2.99-3.14 (5H, m), 3.76-3.84 (1H, m), 3.94-4.05 (1H, m), 4.49-4.59 (1H, m), 7.26-7.32 (2H, m), 7.67-7.72 (2H, m).

Reference example 1 -2

 4-{[tert-butyl 1 (dimethyl) silyl] oxy} -l-{[4- (4-piberidinylmethyl) phenyl] sulfonyl} piperidine

To a methanol (40) solution of the compound (1.S, 3.32 thigh (1)) obtained in Reference Example 6 was added dropwise an aqueous solution of 1.1 carbon dioxide (6.6 mL), and the mixture was stirred for 30 minutes. Saturated saline (10 mL) was added and the organic solvent was distilled off, followed by extraction with ethyl acetate to give the title compound (1.49 g, 99%) as a colorless powder. _{Ή NMR (CDC1 3) (5-0.03} (6H, s), 0.77 (9H, s), 1.08-1.25 (2H, m), 1.54-1.86 (7H, m), 2.49-2.60 (2H, m), 2.60 (2H, d, J = 7.2Hz), 3.01-3.10 (6H, m), 3.75-3.83 (1H, m), 7.26-7.32 (2H, m), 7.64-7.69 (2H, m).

Reference example 1-3

 N- [3- (4- {4-[(4-{[tert-butyl (dimethyl) silyl] oxy] -topiperidinyl) sulfonyl] benzyl} -1-piperidinyl) propyl] aniline

 The compound obtained in Reference Example 1-2 (1.49 g, 3.29) and N- (3-chloropropyl) -N-phenylamine hydrochloride (678 mg, 3.29 pt. Ol) and potassium iodide (546 mg, 3.29 mmol) and potassium carbonate (1.82 g, 13.2 iM01) in acetonitrile (20 mL) and N, N-dimethylformamide (lOmL) were stirred at 75 ° C for 17 hours. After evaporating the solvent, ethyl acetate and water were added, and the separated organic layer was washed with saturated saline. The residue was purified by column chromatography (hexane / ethyl acetate = 6/1 → 2/1) to give the title compound (1.79 g, 93%) as a colorless oil. Was.

_{^ NMR (CDC1 3) δ-} 0.03 (6Η, s), 0.77 (9H, s), 1.24-1.40 (2H, m), 1.49-1.68 (5H, m), 1.73-1.92 (7H, m), 2.44 (2H, t, J = 6.6Hz), 2.62 (2H, d, J = 6.6Hz), 2.89-2.97 (2H, m), 3.03-3.11 (3H, m), 3.17 (2H, t, J = 6.6 Hz), 3.74-3.83 (1H, m), 6.56-6.62 '(2H, m), 6.64-6.71 (1H, m), 7.13-7.21 (2H, m), 7.27-7.33 (2H, m m), 7.65-7.70 (2H, m).

Reference Example 2-1

 N- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -4-([1- (trifluoroacetyl N- (2-hydroxyethyl) -4 {[1- (trifluoroacetyl) The title compound was synthesized using piperidine-4-yl] methyl} benzenesulfonamide in the same manner as in Reference Example 6. Yield 94%.

_{Ή NMR (CDC1 3) 50.00 (} 6Η, s), 0.84 (9H, s), 1.13-1.40 (2H, m), 1.67-1.99 (3H, m), 2.60-2.79 (1H, m), 2.65 (2H , d, J = 7.0Hz), 2.97-3.14 (3H, m), 3.63 (2H, d, J = 5.2Hz), 3.91-4.08 (1H, m), 4.46-4.61 (1H, m), 4.78 ( 1H, t, J = 5.8Hz), 7.23-7.33 (2H, m), 7.75-7.84 (2H, m).

Reference Example 2-2

 N- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -4- (4-piridinylmethyl) Same as Reference Example 1-2 using the compound obtained in Reference Example 2-1. The title compound was synthesized in a yield of 98%.

_{Ή NMR (CDC1 3) (5-0.01} (6H ,. s), 0.84 (9H, s), 1.08-1.26 (2H, m), 1.55-1.73 (3H, m), 2.49-2.60 (2H, m) , 2.60 (2H, d, J = 6.9Hz), 3.01-3.09 (4H, m), 3.61 (2H, t, J = 4.8Hz), 7.25-7.31 (2H, m), 7.74-7.79 (2H, m ).

Reference example 2-3

 4-m- (3-anilinopropyl) -4-piberidinyl] methyl} -N- (2-([tert-butyl (dimension) The compound obtained in Reference Example 2-2 was used in the same manner as Reference Example 3). To give the title compound, yield 94%.

_{Ή NMR (CDC1 3) δ 1.24-1.40} (2Η, m), 1.48-1.69 (3H, m), 1.74-1.92 (4H, m), 2.44 (2H, t, J = 6.6Hz), 2.62 (2H, d, J = 6.9Hz), 2.89-2.98 (2H, m), 3.06 (2H, dt, J = 4.8, 6.0Hz), 3.17 (2H, t, J = 6.6Hz), 3.61 (2H, t, J = 4.8Hz), 4.75 (1H, t, J = 6.0Hz), 6.56-6.63 (2H, m), 6.65-6.72 (1H, m), 7.13-7.21 (2H, m), 7.26-7.33 (2H, m), 7.74-7.80 (2H, m). Reference example 3-1

[[4-{[1- (Trifluoroacetyl) piperidin-4-yl] methyl} phenyl) sulfonyl] piperidine-4-carboxylate

 4-{[1- (Trifluoromethylacetyl) piperidin-4-y] was stirred in a solution of ethyl isodipecotinate (3.77 g, 24.0 liters) and triethylamine (4.18 mL, 30.Ommol) in tetrahydrofuran (20 mL) with stirring. [R] methylile} benzenesulfonyl cuff lide (7.40 g, 20.0 marl) was added to a tetrahydrofuran (40 mL) solution, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed with water (20 mL;), 1N hydrochloric acid (20 mL), and saturated saline (20 mL) in that order. After the organic layer was concentrated under reduced pressure, the residue was subjected to column chromatography (150 g of silica gel, hexane / ethyl acetate = 4 / 1—1 / 1). After the target fraction was concentrated under reduced pressure, disopropyl ether was added to the residue, and the precipitate was collected by filtration and dried under reduced pressure to give the title compound (8.52 g, 17.4 mmol, yield 87%) as a white solid.

_{Ή NMR (CDC1 3) 51.1-1.4 (} 2Η, m), 1.22 (3H, t, J = 7.2Hz), 1.65-2.05 (7H, m), 2.27 (1H, tt, J = 10.2, 4.2Hz), 2.52 (2H, id, J = 11.2, 2.9Hz), 2.6-2.8 (1H, m), 2.65 (2H, d, J = 6.8Hz), 2.95-3.2 (1H, ni), 3.63 (2H, dt, J = 11.8, 3.9Hz), 3.9-4.1 (1H, m), 4.10 (2H, q, J = 7.2Hz), 4.45-4.65 (1H, m), 7.30 (2H, d, J = 8.5Hz), 7.69 (2H, d, J = 8.5Hz).

Reference example 3-2

l-{[4- (Pyridine-4-ylmethyl) phenyl] sulfonyl} piperidine -4.

 A solution of the compound (7.85 g, 16. Ommol) obtained in Reference Example 3-1 in ethanol (80 mL) -tetrahydrofuran (80 mL) was stirred under ice-cooling with sodium borohydride a.21 g, 32 321). In addition, the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was added dropwise to 1N hydrochloric acid (64 mL) under ice-cooling and stirring. The obtained mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate (200 mL) was added, and the mixture was extracted with dichloromethane (200 mL, 50 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (6.10 g, 15.5 mmol, yield 97%) as a white solid.

Image _{R (CDC1 3) 81.05-1.3 (2Η} , m), 1.21 (3H, t, J = 7.2Hz), 1.5-2.05 (9H, m), 2.25 (1H, tt, J = 10.4, 4.1Hz), 2.4-2.6 (2H, m), 2.60 (2H, d, J = 7.0Hz), 3.06 (2H, br d, J-12.2Hz), 3.63 (2H, dt, J = 12.0, 4.0Hz), 4.10 ( 2H, q, J = 7.2Hz), 7.29 (2H, d, J = 8.4Hz), 7.66 (2H, d, J = 8.4Hz).

Reference Example 3-3

 1-[(4-{[1- (3-anilinopropyl) piperidin-4-yl] methyl} phenyl) sulfonyl] piperidine-4-carboxylate

 N- (3-clopropylpropyl) aniline hydrochloride (1.81 g, 8.8 t ol), the compound obtained in Reference Example 3-2 (3.16 g, 8.0 marauder. 1), potassium iodide (1.46 g, 8.8 mg) 1), a mixture of potassium carbonate (4.42 g, 32.0 marl), acetonitrile (16 mL), and Ν, Ν-dimethylformamide (16 mL) were stirred at 100 ° C. for 6 hours. After the reaction mixture was concentrated under reduced pressure, water (100 mL) was added, and the mixture was extracted with a mixed solvent of ethyl acetate-tetrahydrofuran (2/1) (150 mL, 75 mL × 2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel 100 g, ethyl acetate / methanol = 1 / 0-4 / 1), and the target fraction was concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether-ethyl acetate to give the title compound (3.43 g, 6.5 mmol, yield 81%) as a white solid.

_{Ή NMR (CDC1 3) 5 1.15-2.05} (13H, m), 1.21 (3H, t, J = 7.1Hz), 2.25 (1H, tt, J = 4.2, 10.4Hz), 2.4-2.6 (2H, m) , 2.46 (2H, t, J = 6.8Hz), 2.63 (2H, d, J = 6.2Hz), 2.96 (2H, brd, J = 12.0Hz), 3.17 (2H, t, J = 6.4Hz), 3.63 (2H, td, J = 3.8, 11.7Hz), 4.10 (2H, q, J = 7.1Hz), 6.5-6.75 (3H, m), 7.1-7.25 (2H, m), 7.30 (2H, d, J = 8.1Hz), 7,67 (2H, d, J = 8.1Hz).

Reference Example 4-1

{Methyl [(4-{[tri (trifluoroacetyl) piperidin-4-yl] methyl} phenyl) sulfonyl] amino} ethyl acetate

A mixture of sarcosine ethyl ester hydrochloride (5.53 g, 36.0 marl ol), triethylamine (12.54 mL, 90.0 marl ol), and tetrahydrofuran (150 mL) was stirred and mixed with 4-{[g (11.09 g, 30.0 gol ol). Then, ethyl acetate (150 mL) was added to the reaction mixture, and the mixture was washed with water (100 mL), IN hydrochloric acid (50 mLX2), and saturated saline (50 mLX2) in this order. The residue was purified by column chromatography (silica gel 150 g, hexane / ethyl acetate = 4/1 → 1/1) to give the title compound (13.08 g, 30.0 mmol, quantitative yield) as a colorless oil. Was. Ή NMR (CDCI3) δ 1.1-1.4 (2H, m), 1.23 (3H, t, J = 7.2Hz), 1.65-2.0 (3H, m), 2.6-2.8 (1H, m), 2.64 (2H, d , J = 7.0Hz), 2.90 (3H, s), 2.95-3.15 (1H, m), 3.9-4.1 (1H, m), 3.99 (2H, s), 4.12 (2H, q, J = 7.2Hz) , 4.45-4.65 (1H, m), 7.29 (2H, d, J = 8.6Hz), 7.76 (2H, d, J = 8.6Hz).

Reference example 4-2

 (Methyl {[4- (piperidin-4-ylmethyl) phenyl] sulfonyl} amino) ethyl acetate Reference Example 4-1 (13.04 g, 29.9 mmol) of ethanol (150 mL) -tetra: To a solution of hydrofuran (150 mL) was added sodium borohydride (2.27 g, 60.0 mL) under ice-cooling with stirring, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added dropwise to 1N hydrochloric acid (120 mL) under ice-cooling and stirring. The obtained mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate (300 mL) was added, and the mixture was extracted with dichloromethane (100 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (9.17 g, 25.9 mmol, yield 87%) as a colorless oil.

'Review R (CDC1 ₃ ) 6 1.05-1.3 (2Η, m), 1.22 (3H, t, J = 7.2Hz), 1.5-1.9 (3H, m), 2.45-2.65 (2H, m), 2.60 ( 2H, d, J = 7.0Hz), 2.90 (3H, s), 2.95-3.15 (2H, m), 3.97 (2H, s), 4.12 (2H, q, J = 7.2Hz), 7.29 (2H, d , J = 8.0Hz), 7.73 (2H, d, J = 8.0Hz).

Reference Example 4-3

 [[(4-{[tri (3-anilinopropyl) piperidine + yl] methyl} phenyl) sulfonyl] (methyl) amino] ethyl acetate

 Using the compound obtained in Reference Example 4-2, the title compound was synthesized in the same manner as in Reference Example 3-3. Yield 68%.

¹ recitation R (CDC1 ₃ ) 81.15-2.0 (9Η, m), 1.22 (3H, t, J-7.2Hz), 2.45 (2H, t, J = 6.8Hz), 2.62 (2H, d, J = 6.6Hz) ), 2.90 (3H, s), 2.95 (2H, br d, J = 11.6Hz), 3.17 (2H, t, J = 6.4Hz), 3.97 (2H, s), 4.12 (2H, q, J = 7.2) Hz), 6.5-6.75 (3H, m), 7.1-7.25 (2H, m), 7.29 (2H, d, J = 8.4Hz), 7.74 (2H, d, J = 8.4Hz).

Reference example 5-1

 {[(4- {[1- (Trifluoroacetyl) piperidin-4-yl] methyl} phenyl) sulfonyl

 'Ethyl acetate

z The title compound was prepared in the same manner as in Reference Example 4-1 using hydrochloride. Was synthesized. Yield 85%.

_{Ή NMR (CDC1 3) δ 1.1-1.4} (2Η, m), 1.20 (3H, t, J = 7.2Hz), 1.65-2.0 (3H, m), 2.6-2.8 (lH, m), 2.64 (2H, d, J = 6.8Hz), 2.95-3.15 (1H, m), 3.79 (2H, d, J = 5.6Hz), 3.9-4.1 (1H, m), 4.10 (2H, q, J = 7.2Hz), 4.45-4.65 (1H, m), 5.05 (1H, t, J = 5.6Hz), 7.29 (2H, d, J-8.6Hz), 7.80 (2H, d, J = 8.6Hz).

Reference example 5-2

 ({[4- (Pyridin-4-ylmethyl) phenyl] sulfonyl} amino) ethyl ester

 The title compound was synthesized from the compound obtained in Reference Example 5-1 in the same manner as in Reference Example 4-2. Yield 6.

_{Ή NMR (CDC1 3) δ 1.05-1.3} (2Η, m), 1.19 (3H, t, J = 7.2Hz), 1.5-1.8 (3H, m), 2.45-2.65 (2H, m), 2.59 (2H, d, J-6.6Hz), 2.95-3.2 (2H, m), 3.78 (2H, s), 4.08 (2H, q, J = 7.2Hz), 7.28 (2H, d, J = 8.4Hz), 7.77 ( (2H, d, J = 8.4Hz).

Reference Example 5-3

 {[(4-{[1- (3-anilinopropyl) piperidin-4-yl] methyl} phenyl) sulfonylyl] amino} ethyl acetate

 N- (3-chloropropyl) aniline hydrochloride (1.18 g, 5.7 mmol), the compound obtained in Reference Example 5-2 (1.62 g, 4.8 丽 .1), and potassium iodide (0.95 g, 5.7). A mixture of 1), sodium hydrogen carbonate (1.60 g, 19.0 marl) and acetonitrile (60 mL) was stirred at 100 ° C for 18 hours. After the reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 100 g, ethyl acetate / methanol = 1/0 → 4/1) to give the title compound (1.26 g, 2.7 maraud 01, yield 56¾) as a pale yellow oil.

¹ thigh _{R (CDC1 3) δ 1.1-2.0 (} 9Η, m), 1.19 (3H, t, J = 7.2Hz), 2.47 (2H, t, J = 6.7Hz), 2.63 (2H, d, J = 6.2 Hz), 2.97 (2H, br d, J = ll.2Hz), 3.17 (2H, t, J-6.2Hz), 3.78 (2H, s), 4.09 (2H, q, J = 7.2Hz), 5.04 ( 1H, br), 6.5-6.75 (3H, m), 7.1-7.25 (2H, m), 7.29 (2H, d, J = 8.2Hz), 7.78 (2H, d, J = 8.2Hz).

Reference Example 6-1

2-Methyl-2 _ {[(4-{[(trifluoro (acetyl) piperidin-4-yl] methyl} phenyl) sulfonyl] amino} ethyl propanoate Ethyl 2-aminoisobutyrate hydrochloride (2.01 g, 12.0 ol), triethylamine (4. i8 mL, 30.0 mmol), and tetrahydrofuran (50 mL) were stirred with a mixture of 4-{[tri (trifluoroacetyl) piperidine-4-y. [Methyl] benzenesulfonyl chloride (3.70 g, 10.O mmol) was added, and the mixture was stirred at room temperature for 18 hours. Add triethylamine (4.18 mL, 30.0 t) and 4-{[1- (trifluoroacetyl) piperidine-4-yl] methyl} benzenesulfonyl chloride (3.70 g, 10.0 t) and add 50 ° C. For 18 hours. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed sequentially with water (20 mL), IN hydrochloric acid (20 mL × 2), and saturated saline (20 mL × 1). After concentrating the organic layer under reduced pressure, the residue was purified by column chromatography (silica gel 100 g, hexane / ethyl acetate = 4 / 1-1 / 1) to give the title compound (4.29 g, 9.24 mmol, yield 92%). Obtained as a colorless oil.

'H MR (CDC1 ₃ ) δ 1.1-1.4 (2Η, m), 1.26 (3H, t, J = 7.2Hz), 1.45 (6H, s), 1.65-2.0 (3H, m), 2.6-2.8 (1H , m), 2.63 (2H, d, J = 7.0Hz), 2.95-3.15 (1H, m), 3.9-4.1 (1H, m), 4.13 (2H, q, J = 7.2Hz), 4.5- 4.65 (1H, m), 5.34 (1H, s), 7.25 (2H, d, J = 8.4Hz), 7.81 (2H, d, J = 8.4Hz).

Reference Example 6-2

 2-Methyl-2-({[4- (piperidin-4-ylmethyl) phenyl] sulfonyl} amino) ethyl propanoate

 The title compound was synthesized in the same manner as in Reference Example 4-2, using the compound obtained in Reference Example 6-1. 85% yield.

_{LH MR (CDC1 3) δ 1.0-1.4} (2Η, m), 1.24 (3H, t, J = 7.2Hz), 1.45 (6H, s), 1.5-1.9 (3H, m), 2.45-2.65 (2H, m), 2.58 (2H, d, J = 7.0Hz), 2.95-3.15 (2H, m), 4.10 (2H, q, J = 7.2Hz), 7.25 (2H, d, J = 8.4Hz), 7.78 ( (2H, d, J = 8.4Hz).

Reference Example 6-3

 2-{[(4-{[1- (3-anilinopropyl) piperidine + yl] methyl} phenyl) sulfonyl] amino} -ethyl 2-ethylpropanoate

 Using the compound obtained in Reference Example 6-2, the title compound was synthesized in the same manner as in Reference Example 5-3. Yield 35%.

'HNMR (CDCI3) δ 1.15-2.0 (9Η, m), 1.24 (3H, t, J = 7.2Hz), 1.45 (6H, s), 2.46 (2H, t, J = 6.7Hz), 2.61 (2H, d, J = 6.6Hz), 2.96 (2H, br d, J = 11.6Hz), 3.17 (2H, t, J-6.4Hz), 4.10 (2H, q, J = 7.2Hz), 5.34 (1H, br s), 6.5-6.75 (3H, m), 7.1-7.25 (2H, m), 7.26 (2H, d, J-8.4Hz), 7.79 (2H, d, J = 8.4Hz).

Reference example 7-1

 2-{[(4- {[1- (Trifluoroacetyl) piperidine-4_yl] methyl} phenyl) sulfonyl] amino} ethyl propane

 The title compound was synthesized in the same manner as in Reference Example 4-1 using aranineethyl ester hydrochloride. Yield 92%.

_{'HNMR (CDC1 3) δ 1.05-1.45} (2Η, m), 1.15 (3H, t, J = 7.1Hz), 1.40 (3H, d, J-7.0Hz), 1.65-2.0 (3H, m), 2.6 -2.8 (1H, m), 2.63 (2H, d, J = 7.0Hz), 2.95-3.15 (1H, m), 3.9-4.1 (4H, m), 4.45-4.65 (1H, m), 5.22 (1H , d, J = 8.4Hz), 7.27 (2H, d, J = 8.4Hz), 7.78 (2H, d, J-8.4Hz).

Reference Example 7-2

 2-({[4- (piperidin-4-ylmethyl) phenyl] sulfonyl} amino) ethyl propanoate

 Using the compound obtained in Reference Example 7-1, the title compound was synthesized in the same manner as in Reference Example 4-2. Yield 77%.

 'HNMR (CDCI3) δ 1.0-1.35 (2Η, m), 1.14 (3H, t, J = 7.2Hz), 1.39 (3H, d, J = 7.0Hz), 1.5-1.8 (3H, m), 2.45- 2.65 (2H, m), 2.59 (2H, d, J = 6.6Hz), 2.95-3.15 (2H, m), 3.9-4.05 (1H, m), 3.97 (2H, q, J = 7.2Hz), 7.26 (2H, d, J = 8.4Hz), 7.75 (, d, J = 8.4Hz).

Reference Example 7-3

 2-{[(4-{[1- (3-anilinopropyl) piperidin-4-yl] methyl} phenyl) sulfonyl] amino} ethyl propanoate

 Using the compound obtained in Reference Example 12-2, the title compound was synthesized in the same manner as in Reference Example 5-3. Yield 54%.

'H MR (CDCI3) 61.13 (3Η, t, J = 7.1Hz), 1.2-2.0 (9H, m), 1.39 (3H, d, J = 7.0Hz), 2.48 (2H, t, J = 6.6Hz) , 2.61 (2H, d, J = 6.2Hz), 2.97 (2H, br d, J = 11.8Hz), 3.17 (2H, t, J = 6.4Hz), 3.9-4.05 (1H, m), 3.97 (2H , q, J = 7.lHz), 5.20 (1H, br d, J-7.6Hz), 6.5-6.75 (3H, m), 7.1-7.25 (2H, m), 7.28 (2H, d, J = 8.4 Hz), 7.76 (2H, d, J-8.4Hz).

Reference Example 8-1

 1-[(4-{[1- (Trifluoroacetyl) piridin-4-yl] methyl} phenyl) sulfonyl] azetidine-3-carboxylate

 Thionyl chloride (4.8 mL) was added to a solution of 3-azetidine carboxylic acid (1.67 g, 16.5 wake 01) in ethanol (5 () 111) under ice-cooling and stirring, followed by stirring under heating to reflux for 5 hours. The mixture was concentrated under reduced pressure, and to the residue were added detrahydrofuran (50 mL) and trieduramine (4.18 mL), and the resulting mixture was stirred with 4-{[1- (trifluoroacetyl) piperidine- 4_ [yl] methyl} benzenesulfonyl chloride (3.70 g, lO.Ommol) and stirred at room temperature for 24 hours Ethyl acetate (50 mL) was added to the reaction mixture, and water (20 mL) and IN hydrochloric acid (20 mL X2) were added. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane / ethyl acetate = 4/1 → 3/7) to give the title compound ( 2.23 g, 4.82 mmol, 48% yield) as a colorless oil.

_{Ή NMR (CDC1 3) 5 1.1-1.4} (2Η, m), 1.19 (3H, t, J = 7.1Hz), 1.65-2.0 (3H, m), 2.6-2.8 (1H, m), 2.68 (2H, d, J = 7.4Hz), 2.95-3.15 (1H, m), 3.15-3.35 (1H, m), 3.8-4.1 (5H, m), 4.06 (2H, q, J = 7.1Hz), 4.45-4.65 (1H, m), 7.37 (2H, d, J = 8.4Hz), 7.79 (2H, d, J = 8.4Hz).

Reference Example 8-2

{{[4- (Piperidin-4-ylmethyl) phenyl] sulfonyl} azetidine-3-ethyl carboxylate

 Using the compound obtained in Reference Example 17-1, the title compound was synthesized in the same manner as in Reference Example 4-2. Yield 43¾.

_{Ή NMR (CDC1 3) 5 1.05-1.3} (2Η, m), 1.18 (3H, t, J-7.1Hz), 1.5-1.9 (3H, m), 2.45-2.65 (2H, m), 2.63 (2H, d, J = 6.8Hz), 2.95-3.15 (2H, m), 3.15-3.35 (1H, m), 3.8-4.1 (6H, m), 7.36 (2H, d, J = 8.4Hz), 7.76 (2H , d, J = 8.4Hz).

Reference Example 8-3

 {[4-({tri [3- (phenylamino) propyl] piperidin-4-yl} methyl) phenyl] sulfonyl} azetidine-3-carboxylate

Using the compound obtained in Reference Example 8-2, the title compound was obtained in the same manner as in Reference Example 5-3. Synthesized. Yield 40%.

_{lHNMR (CDC1 3) δ 1.1-2.0 (} 9Η, πι), 1.18 (3Η, t, J = 7.3Ηζ), 2.48 (2Η, t, J = 6.8Hz), 2.66 (2Η, d, J = 6.6Hz) , 2.98 (2H, br d, J = 11.0Hz), 3.1-3.35 (1H, m), 3.17 (2H, t, J = 6.4Hz), 3.85-4.1 (4H, m), 4.07 (2H, q, J = 7.3Hz), 6.5-6.75 (3H, m), 7.1-7.25 (2H, m), 7.36 (2H, d, J = 8.3Hz), 7.77 (2H, d, J = 8.3Hz).

Reference Example 9-1

 [(4-{[(Tri (trifluoroacetyl) piperidin-4-yl] methyl] phenyl) sulfanyl] ethyl ester

 A mixture of concentrated sulfuric acid (10 mL) and distilled water (50 mL) was stirred under ice-cooling, and 4 _ {[((trifluoroacetyl) piperidin-4-yl] methyl} benzenesulfonyl chloride (5.55 g, 15.0 mmol) in dichloromethane ( (15 mL) solution and zinc powder (9.81 g) were added in that order, and the mixture was stirred at 60 ° C for 6 hours. The insolubles were filtered off and washed with dichloromethane. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (X2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give crude 4-{[1- (trifluoromethylacetyl) piperidin-4-yl] methyl} benzenthiol (4.94 g) as a colorless oil. As obtained. To a solution of the obtained oil (4.94 g) in acetonitrile (30 mL) was added ethyl bromoacetate (2.16 mL, 19.5 mmol) and triethylamine (4.18 mL, 30.0 imnol) in that order under ice-cooling and stirring. For 18 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (40 mL) was added thereto, and the mixture was washed with water (aOmL), IN hydrochloric acid (1 (ML X 2), and saturated saline (1 OmL). Purification by column chromatography (NH silica gel 150 g, hexane / ethyl acetate = 1 / 0-9 / 1) gave the title compound (2.98 g, 7.65 mmol, yield 51%) as a colorless oil.

_{Ή NMR (CDC1 3) δ 1.1-1.35} (2Η, m), 1.23 (3H, t, J = 7.2Hz), 1.65-1.95 (3H, m), 2.54 (2H, d, J-7.0Hz), 2.6 -2.8 (1H, m), 2.95-3.15 (1H, m), 3.61 (2H, s), 3.9-4.1 (1H, m), 4.17 (2H, q, J = 7.2Hz), 4.45-4.6 (1H , m), 7.07 (2H, d, J = 8.1Hz), 7.35 (2H, d, J = 8.1Hz).

Reference Example 9-2

 {[4- (Piperidin-4-ylmethyl) phenyl] sulfanyl} ethyl ester

Using the compound obtained in Reference Example 9-1, the title compound was synthesized in the same manner as in Reference Example 4-2. 95% yield. ^l E NMR (CDClg) δ 1.0-1.3 (2H, m), 1.22 (3H, t, J = 7.2Hz), 1.45-1.7 (3H, m), 2.4-2.65 (2H, m), 2.49 (2H, m d, J = 6.6Hz), 2.95-3.15 (2H, m), 3.60 (2H, s), 4.16 (2H, q, J = 7.2Hz), 7.08 (2H, d, J = 8.4Hz), 7.34 ( (2H, d, J = 8.4Hz).

Reference Example 9-3

[(4-{[tri (3-anilinopropyl) piperidine-4-yl] methyl} phenyl) sulfanyl] ethyl acetate

 Using the compound obtained in Reference Example 9-2, the title compound was synthesized in the same manner as in Reference Example 5-3. Yield 64%.

 ^ NMR (CDCI3) δ 1.15-1.95 (9Η, m), 1.22 (3H, t, J = 7.2Hz), 2.43 (2H, t, J = 6.8Hz), 2.52 (2H, d, J = 6.6Hz) , 2.93 (2H, br d, J = 11.8Hz), 3.16 (2H, t, J = 6.4Hz), 3.60 (2H, s), 4.16 (2H, q, J = 7.2Hz), 6.5-6.75 (3H , m), 7.09 (2H, d, J = 8.4Hz) 7.1-7.25 (2H, m), 7.35 (2H, d, J = 8.4Hz).

Reference example 10-1

 3-[(4-{[(Trifluoroacetyl) piperidin-4-yl] methyl} phenyl) sulfanyl] ethyl propane

 The title compound was synthesized in the same manner as in Reference Example 9-1 using ethyl 3-bromopropionate. Yield 54%.

_{Ή NMR (CDC1 3) 8 1.1-1.4} (2Η, m), 1.26 (3H, t, J-7.2Hz), 1.65-1.95 (3H, m), 2.54 (2H, d, J = 7.0Hz), 2.6 -2.8 (1H, m), 2.61 (2H, i, J = 7.4Hz), 2.95-3.15 (1H, m), 3.15 (2H, t, J = 7.4Hz), 3.9-4.1 (1H, m), 4.15 (2H, q, J = 7.2Hz), 4.45-4.6 (1H, m), 7.07 (2H, d, J-8.0Hz), 7.31 (2H, d, J = 8.0Hz).

Reference example 10-2

 3-Ethyl 3-{[4- (piperidin-4-ylmethyl) phenyl] sulfanyl} propanoate The title compound was synthesized in the same manner as in Reference Example 4-2, using the compound obtained in Reference Example 10-1. did. Yield 88%.

_{^ NMR (CDC1 3) 8 1.0-1.3} (2Η, m), 1.26 (3H, i, J = 7.2Hz), 1.45-1.7 (3H, m), 2.45-2.65 (2H, m), 2.49 (2H, d, J = 6.6Hz), 2.60 (2H, t, J = 7.4Hz), 2.95-3.15 (2H, m), 3.13 (2H, i, J = 7.4Hz), 4.14 (2H, q, J = 7.2 Hz), 7.08 (2H, d, J-8.1Hz), 7.30 (2H, d, J = 8.1Hz). Reference Example 10-3

 3-[(4-{[tri (3-anilinopropyl) piperidin-4-yl] methyl} phenyl) sulfanyl] ethyl propane

 Using the compound obtained in Reference Example 10-2, the title compound was synthesized in the same manner as in Reference Example 5-3. Yield 72%.

¹ recitation R (CDC1 ₃ ) 51.15-1.95 (9Η, m), 1.25 (3Η, t, J = 7.2Hz), 2.44 (2H, t, J = 6.6Hz), 2.52 (2H, d, J = 6.6Hz) ), 2.61 (2H, t, J = 7.5Hz), 2.93 (2H, br d, J = 11.6Hz), 3.14 (2H, t, J-7.5Hz), 3.16 (2H, t, J = 6.2Hz) , 4.14 (2H, q, J = 7.2Hz), 6.5-6.75 (3H, m), 7.09 (2H, d, J = 8.2Hz), 7.1-7.25 (2H, m), 7.30 (2H, d, J = 8.2Hz). Reference example 1

 4-[(4-{[1- (Trifluoroacetyl) piperidin-4-yl] methyl} phenyl) sulfanyl] ethyl ester

 The title compound was synthesized in the same manner as in Reference Example 9-1 using ethyl 4-bromobutyrate. Yield 45%.

_{Ή NMR (CDC1 3) δ 1.1-1.35} (2H, m), 1.25 (3H, t, J = 7.1Hz), 1.65-1.95 (3H, m), 1.94 (2H, quint, J = 7.2Hz), 2.46 (2H, t, J = 7.2Hz), 2.53 (2H, d, J = 7.0Hz), 2.6-2.8 (1H, m), 2.94 (2H, t, J = 7.2Hz), 2.95-3.15 (1H, m), 3.9-4.1 (1H, m), 4.13 (2H, q, J = 7.1Hz), 4.45-4.6 (1H, m), 7.06 (2H, d, J = 8.0Hz), 7.28 (2H, d , J = 8.0Hz).

Reference Example 11-2

 4-{[4- (Pyridin-4-ylmethyl) phenyl] sulfanyl} ethyl ester

 Using the compound obtained in Reference Example 11-1, the title compound was synthesized in the same manner as in Reference Example 4-2. 82% yield.

_{lR NMR (CDC1 3) δ 1.0-1.3} (2Η, m), 1.25 (3H, t, J-7.2Hz), 1.45-1.75 (3H, m), 1.94 (2H, quint, J = 7.3Hz), 2.4 -2.65 (2H, m), 2.46 (2H, t, J = 7.3Hz), 2.49 (2H, d, J = 6.4Hz), 2.93 (2H, t, J = 7.3Hz), 2.95-3.15 (2H, m), 4.13 (2H, q, J = 7.2Hz), 7.06 (2H, d, J = 8.4Hz), 7.27 (2H, d, J = 8.4Hz).

Reference example 1 to 3

4-[(4-{[((3-anilinopropyl) piperidine—4-yl] methyl} phenyl) sulfa Nil] ethyl butyl

 Using the compound obtained in Reference Example 11-2, the title compound was synthesized in the same manner as in Reference Example 5-3. Yield 66%.

Ή NR (CDC1 ₃ ) δ 1.15-1.95 (9Η, m), 1.25 (3H, t, J = 7.2Hz), 1.94 (2Η, quint, J = 7.3Hz), 2.43 (2H, t, J = 6.6Hz) ), 2.46 (2H, t, J = 7.5Hz), 2.52 (2H, d, J = 6.6Hz), 2.85-3.0 (2H, m), 2.94 (2H, t, J = 7.3Hz), 3.16 (2H , t, J = 6.4Hz), 4.12 (2H, q, J = 7.2Hz), 6.5-6.75 (3H, m), 7.07 (2H, d, J = 8.2Hz), 7.1-7.25 (2H, m) , 7.27 (2H, d, J = 8.2Hz).

Reference Example 12-1

Tert-butyl 2-methyl-2-[[(4-{[1- (trifluoromethylacetyl) piperidin-4-yl] methyl} phenyl) sulfanyl] propanoate

 The title compound was synthesized in the same manner as in Reference Example 9-1 using tert-butyl 2-bromoisobutyrate. Yield 17%.

Awakening: _{R (CDC1 3) 5 1.05-1.95 (} 5Η, m), 1.43 (6H, s), 1.43 (9H, s), 2.56 (2H, d, J = 7.0Hz), 2.6-2.8 (1H, m) , 2.95-3.15 (1H, m), 3.9-4.1 (1H, m), 4.45-4.6 (1H, m), 7.08 (2H, d, J = 8.1Hz), 7.43 (2H, d, J = 8.1Hz) ).

Reference Example 12-2

 Tert-Butyl 2-methyl-2-{[4- (piperidin-4-ylmethyl) phenyl] sulfanyl} propanoate

 Using the compound obtained in Reference Example 12-1, the title compound was synthesized in the same manner as in Reference Example 4-2. Yield quantitative.

_{Ή NMR (CDC1 3) δ 1.0-1.8} (5Η, m), 1.41 (9H, s), 1.43 (6H, s), 2.4-2.65 (2H, m), 2.52 (2H, d, J = 7.0Hz) , 2.95-3.15 (2H, m), 7.09 (2H, d, J = 8.1Hz), 7.41 (2H, d, J = 8.1Hz).

Reference example 12-3.

 Tert-Butyl 2-[(4-{[tri (3-anilinopropyl) piperidin-4-yl] methyl} phenyl) sulfanyl] -2-methylpropanoate

Using the compound obtained in Reference Example 12-2, the title compound was synthesized in the same manner as in Reference Example 5-3. Yield 41%. Ή NMR (CDCI3) δ 1.15-1.95 (9H, m), 1.41 (9H, s), 1.43 (6H, s), 2.43 (2H, t, J = 6.8Hz), 2.55 (2H, d, J = 6.6 Hz), 2.93 (2H, br d, J = l 1.4Hz), 3.16 (2H, t, J = 6.4Hz), 6.5-6.75 (3H, m), 7.10 (2H, d, J = 8.0Hz), 7.1-7.25 (2H, m), 7.41 (2H, d, J = 8.0Hz).

Test example 1

 (Measurement of RANTES binding inhibitory action)

 (1) Cloning of human CCR 5 chemokine receptor Yuichi

 The CCR5 gene was cloned from human spleen cDNA by PCR. 0.5 ng of spleen cDNA (Toyobo, QUICK_Clone cDNA) was used as type III, and was prepared with reference to the CCR5 gene base sequence reported by Samson et al. (Biochemistry 35 (11), 3362-3367 (1996)). Primer set;

 SEQ ID NO: 1 described in Experimental Example (1) of WO 99/32100 [Sequence length: 34; Sequence type: nucleic acid; Number of chains: single-stranded; Topology: linear; Nucleic acid synthetic DNA]

SEQ ID NO: 2 described in Experimental Example (1) of WO 99/32100 [Sequence length: 34; Sequence type: nucleic acid; number of strands: single-stranded; topology: linear; Nucleic acid synthetic DNA]

PCR reaction was carried out in DNA Thermal Cycler 480 (Pakinkin Elma) using TaKaRa EX Taq (Takara Shuzo) at 25 pmol each (reaction conditions: 95 ° C for 1 minute, 60 minutes). 30 cycles of 1 minute at ° C and 5 minutes at 75). The PCR product was subjected to agarose gel electrophoresis, and a DNA fragment of about 1. Okb was recovered. Then, the CRC5 gene was cloned using the Original TA Cloning Kit (Funakoshi).

(2) Construction of plasmid for human CCR5 expression

The plasmid obtained above was digested with restriction enzymes Xbal (Takara Shuzo) and BamHI (Takara Shuzo), and then agarose gel electrophoresis was performed to recover a DNA fragment of about 1. Okb. The DNA fragment and the expression plasmid pcDNA3.1 (Funakoshi) for animal cells digested with Xbal and BamHI are mixed and ligated with DNA Ligation Kit Ver. The plasmid pCKR5 was obtained by the conversion. (3) Introduction and expression of human CCR5 expression plasmid into CHO-K1 cells

0.5 g / L trypsin of CHO-K1 cells grown in 750 ml tissue culture flask (Becton Dickinson) using Ham F12 medium (Nippon Pharmaceutical) containing 10% fetal serum (Lifetech Oriental) After detachment with 0.2 gZL EDTA (Lifetech Oriental), the cells were washed with PBS (Lifetech Oriental), centrifuged (100 rpm, 5 minutes), and suspended in PBS. Next, DNA was introduced into the cells using Genepulsa 1 (Bio-Rad) under the following conditions. That is, 8 × 10 6 cells and 10 pg of plasmid PCKR5 for expressing human CCR5 were added to a 0.4 cm gap cuvette, and electrolysis was performed under a voltage of 0.25 kV and a capacitance of 960 pF. Then, transfer the cells to Ham's F12 medium containing 10% Fetal Serum, and after culturing for 24 hours, detach the cells again and centrifuge, and then add dienecin (Lifetech Oriental) to 500 pg / ml. suspended in ham F 12 medium containing 10% © shea calf serum was added, 10 ⁴ were seeded into a cell Zml and such so that the dilution to 96 © El plates (Becton Dickinson), to obtain a geminal Netishin resistant strains Was.

Next, the obtained dineticin-resistant strain was cultured in a 96-L plate (Becton Dickinson), and CCR5-expressing cells were selected from the resistant strains. That is, an assay buffer (ham F12 medium containing 0.5% BSA, 2 OmM HEPES (Wako Pure Chemicals, pH 7.2)) supplemented with 200 pM of ²⁵ I] -R ANTES (Amersham) as a ligand. After binding for 40 minutes at room temperature, wash with ice-cold PBS, add 1M NaOH at 5 μΟ / well, stir, and measure the radioactivity with a γ-counter to identify the ligand. CCR5ZCHO strain was selected.

 (4) Evaluation of compounds based on CCR 5 antagonism

In 96-well microphone port plate seeded with CCR 5ZCHO strains 5x1 0 ⁴ cells / Ueru, after the medium is aspirated off and cultured for 24 hours, added the test compound (ΙμΜ) inclusive mediation Si buffer to each Ueru is the ligand after addition C ^{1 2 5} I] -RANTES the (§ Ma one sham) so that 10 ΟρΜ, was reacted at room temperature for 40 minutes. Next, the Atsushi buffer was removed by suction and washed twice with cooled PBS. Then, 200 μΐ of Micro Shin Chi 20 (Packard) was added to each well, and the radioactivity was measured with a top count (Packard).

 According to the method described above, the CCR5 binding inhibition rate of the test compound was measured. The results are shown in the table below.

Example No. 1.0% inhibition rate (%)

 1 100

 4 100

5 100

 13 97

 16 93

 17 89

 18 96

23 79

Test example 2

Growth inhibitory effect against HIV infection (MOLT-4ZCCR 5 cells used to measure anti-HIV-1 activity of test compound)

 (1) Cells and medium

 As a CCR5 expressing cell, MOLT-4 no CCR5 cell (AIDS Res. Hum. Retrovir. 16, 935-941 (2000)), which is a human lymphocyte-derived cell line reported by Baba et al. RPMI 1640 medium (Nikken Institute of Biomedical Research) containing 10% fetal bovine serum (FBS, GI BCO) and lmg / mL dieneticin (Lifetech Oriental) was used as the medium.

 (2) Test compound

The test compound was dissolved in dimethylsunoxide (DMSO) and diluted to 200 nM in RPMI 1640 medium containing 1.0% FBS and lmg ZmL dieneticin (Lifetech Oriental).

 (3) Virus

 The B a-L strain, which is a laboratory strain of R 5 H I V-1, was used.

(4) Infection MOLT-4ZCCR5 cells (4 × 10 ⁶ cells / lmL) were inoculated with R5HIV-1Ba-L strain at 1,000 CCID _{5 Q} / mL and incubated at 37 ° C for 6 hours. After incubation, suspended infected cells washing away unadsorbed virus to the cell in the medium of 2 mL, 96 well microphone port plate in infected cells 100 L, the test compound was dispensed 100 min, 5% C_〇 ₂ The cells were cultured at 37 ° C for 3 days. The concentration of the test compound was 100 nM. Three days after infection, the cells were diluted 5-fold with a medium containing the same concentration of the test compound, and cultured for another 2 days. The amount of p24 in the supernatant after the culture was measured using a commercially available ELISA kit '(ZeptoMetrix). The infection inhibition rate was calculated as the amount of P24 in the test compound-administered group relative to the amount of p24 in the control group.

 The results of measuring the infection inhibition rate of the test compound are shown in the table below.

Example number Inhibition rate in {η} (%)

 3 100

 8 100

Formulation Example 1 Capsule

 (1) {{[4-({卜 [3-({[(4-chlorophenyleneamino) carbonyl] carbonyl} {phenyl} amino) propyl] -4-piperidinyl} methyl) phenyl] sulfo Nil} -4-piperidinecarbonic acid 40mg

 (2) Lactose .6 lmg

 (3) Microcrystalline cellulose 18mg

 (4) Magnesium stearate lmg

 1 capsule (contents) 12 Omg

 After mixing (1), (2), (3) and (4), encapsulate in a gelatin capsule. Formulation Example 2 Capsule

 (1) ({[4- ({1- [3-({[(4-chlorophenyl) amino] carbonyl] {phenyl} amino) propyl] -4-piperidinyl} methyl) phenyl] sulfonyl {{Methyl} amino) acetic acid 4 Omg

 (2) Lax 1 6 lmg

 (3) Microcrystalline cellulose 18mg

(4) Magnesium stearate lmg 1 capsule (contents) 12 Omg

 After mixing (1), (2), (3) and (4), enclose in a gelatin capsule. Formulation Example 3 Capsules

 (1) 4-({tri [3-({[(4-chlorophenyl) amino] carbonyl} {phenyl} amino) pypyl] -4-piperidinyl} methyl) -N- (2-high

^ Do 4 Omg

 (2) Lactose 61 mg

 (3) Microcrystalline cellulose 18 mg

 (4) Magnesium stearate 1 mg

 1 capsule (contents) 2 Omg

 After mixing (1), (2), (3) and (4), enclose in a gelatin capsule. Formulation Example 4 Tablet

 (1) 2- ({[4--{{u [3- ({[(4-chlorophene) amino] carbonyl} {phenyl} amino) propyl] -4-piperidinyl} methyl) phenyl ] Sulfonyl} {methyl} amino) acetoamide 40 mg

 (2) Mannitol '51 .2 mg

 (3) Microcrystalline cellulose 18 mg

 (4) Hydroxypropyl cellulose 3.6 mg

 (5) Croscarmellose sodium 6mg

 (6) Magnesium stearate 1.2 mg

 1 tablet 12 Omg

 Mix (1), (2), (3) and (4) and granulate. (5) and (6) are added to the granules and pressed into tablets.

Formulation Example 5 Tablet

 (1) 2-({4-[(1-{3 _ [{[(4-chlorophenyl) amino] aminopropyl] (phenyl) amino] propyl} piperidin-4-yl) methyl] Fenyl} sulfanyl) -2-methylpropanoic acid 4 Omg

 (2) Mannitol 51.2 mg

(3) Microcrystalline cellulose 18mg (4) Hydroxypropyl cellulose 3.

 (5) Croscarmellose sodium 6 mg

 (6) Magnesium stearate 1.2 mg

 1 tablet 12 Omg

 Mix (1), (2), (3) and (4) and granulate. Add (5) and (6) to the granules of (1) and press-mold into tablets. Industrial applicability

 The compound represented by the formula (I) of the present invention or a salt thereof has an extremely strong CCR5 antagonistic effect and has good metabolic stability, so that various HIV infections in humans, for example, AIDS It can be used advantageously for prevention as well as treatment.

Claims

The scope of the claims

1 set:

[In the formula, R ¹ - ₈ halogen, may be a halogen as an alkyl group or a substituted group - shows ₄ alkyl, Shiano or (E one ₄ may have a Arukiruokishi phenylene le radical, R ² wherein: - in S_〇 ₂ NR ³ R ⁴ (wherein, R ³ is a hydrogen atom or _ ₆ alkyl group, _ R ⁴ has hydroxyl group, one of the forces Rupokishiru group or force Rubamoiru group as a substituent 6 It may represent an alkyl group, or R ³ and R ⁴ may combine to form a nitrogen-containing heterocyclic group having either a hydroxyl group, a hydroxyl group or a hydroxyl group as a substituent together with a nitrogen atom. or a group represented by the formula in): a S (0) _m _W- Y (wherein, Y represents a hydroxyl group, a force Rupokishiru group or Karupamoiru group, W is one _alkyl group is ₄ _ may be Al substituted with And m represents 0, 1 or 2.) Or a salt thereof.

2. halogen as R ¹ is a substituted group may be substituted with a halogen - ₄ Al kill, Shiano or - ₄ compound according to claim 1 have Arukiruokishi is also good phenyl group.

3. R ² has the _{^{formula: - S0 2 NR 3 R 4}} ( where the R ³ is a hydrogen atom or a ₄ Al kill group, R ⁴ is a hydroxyl group as a substituent, the have either the force Rupokishiru group or force Rubamoiru group a - ₄ represents an alkyl group, or R ³ and R ⁴ hydroxyl group as a substituent together with the bond to the nitrogen atom, may form a nitrogen-containing heterocyclic group having either a carboxyl group or force Rubamoiru group The compound according to claim 1, which is a group represented by:

4. R ² has the formula: — S— W, one Y (W 'is optionally substituted with methyl C — Represents ₄ alkylene, and Y represents a hydroxyl group, a carboxyl group, or a rubamoyl group. The compound according to claim 1, which is a group represented by the formula:

 5.1-{[4-({1- [3-({[(4-Chlorophenyl) amino] carbonyl} {phenyl} amino) propyl] -4-Piperidinyl} methyl) phenyl] sulfo Nyl} -4-piperidinecarboxylic acid, ({[4- (U-[3-({[(4-chlorophenyl) amino] amino]} {phenyl} amino) ] -4-Piperidinyl} methyl) phenyl] sulfonyl} {methyl} amino) acetic acid, 4-({tri [3-({[(4-chlorophenyl) amino] aminopropyl} {phenyl} amino) propy 4-]-Piperidinyl} methyl) -N- (2-hydroxyethyl) benzenesulfonamide, 2-({[4-({tri [3-({[(4-chlorophenyl) amino] carbonyl H Phenyl} amino) pulp] -4-4-piridinyl} methyl) phenyl] sulfonyl} {methyl} amino) acetamide, 2 _ ({4-[(tri {3-[{[(4- Phenyl) amino] potassium (phenyl) amino] propyl} pi Gin - 4 I) methyl] Hue sulfonyl} sulfa yl) - 2-Mechirupuro pan acid or compound of claim 1 which is a salt thereof.

 6. A prodrug of the compound of claim 1.

7. A medicament comprising the compound according to claim 1 or a prodrug thereof.

 8. The medicament according to claim 7, which is a CC chemokine receptor antagonist.

 9. The medicament according to claim 7, which is a CCR5 antagonist.

 10. The medicament according to claim 7, which is a therapeutic agent for HIV infection.

 11. The medicament according to claim 7, which is an agent for preventing and treating AIDS.

 12. The medicament according to claim 7, which is an AIDS disease progression inhibitor.

 13. The medicament according to claim 7, which is a blood or a blood product for transfusion.

 14. The medicament according to claim 8, which is an agent for preventing or treating graft-versus-host disease and Z or rejection during organ or bone marrow transplantation.

 15. The medicament according to claim 7, which is an agent for preventing or treating rheumatoid arthritis, an autoimmune disease, an allergic disease, ischemic brain cell injury, myocardial infarction, nephritis, nephropathy or arteriosclerosis.

16. Use of the compound according to claim 1 or a prodrug thereof for the manufacture of a CC chemokine receptor antagonist.

17. Agents for HIV infection, AIDS prevention and treatment, AIDS disease progression inhibitors, graft-versus-host disease and / or rejection during organ or bone marrow transplantation The compound according to claim 1 or a compound thereof for the manufacture of a therapeutic agent or a prophylactic / therapeutic agent for rheumatoid arthritis, autoimmune disease, allergic disease, ischemic cerebral cell disorder, myocardial infarction, nephritis, nephropathy or arteriosclerosis. Use of prodrugs.

 18 Treatment of HIV infection, prevention and treatment of AIDS, suppression of progression of AIDS, prevention of graft-versus-host disease and z or rejection during organ or bone marrow transplantation; treatment, or rheumatoid arthritis, autoimmunity A method for preventing or treating diseases, allergic diseases, ischemic brain cell injury, myocardial infarction, nephritis, nephropathy or arteriosclerosis, wherein the compound according to claim 1 or a prodrug thereof is used in a human in need thereof. Administering an effective amount of