WO2003104198A1 - Chemokine receptor antagonist - Google Patents

Chemokine receptor antagonist Download PDF

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WO2003104198A1
WO2003104198A1 PCT/JP2003/007379 JP0307379W WO03104198A1 WO 2003104198 A1 WO2003104198 A1 WO 2003104198A1 JP 0307379 W JP0307379 W JP 0307379W WO 03104198 A1 WO03104198 A1 WO 03104198A1
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group
carbon atoms
atom
formula
represented
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PCT/JP2003/007379
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French (fr)
Japanese (ja)
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正和 佐藤
広樹 梅宮
結子 松永
哲男 高山
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大正製薬株式会社
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Priority to JP2004511268A priority Critical patent/JPWO2003104198A1/en
Priority to AU2003242244A priority patent/AU2003242244A1/en
Publication of WO2003104198A1 publication Critical patent/WO2003104198A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4523Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/452Piperidinium derivatives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4523Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4523Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4523Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4523Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/06Antiasthmatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • A61P27/14Decongestants or antiallergics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/08Antiallergic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56Nitrogen atoms
    • C07D211/58Nitrogen atoms attached in position 4

Definitions

  • the present invention relates to a compound having an antagonistic effect on a receptor of a chemokine which is a leukocyte chemotactic factor.
  • Chemokines have been discovered as factors that act primarily on neutrophils and monocytes, and their role in inflammatory diseases has been studied. However, recently discovered new chemokines have been shown to target lymphocyte-dendritic cells as the primary target cells. These chemokines are thought to play a role in the formation of immune system tissues, homeostasis, and immune response. In addition, chemokines have been shown to play important roles not only in cell migration in inflammation and the immune response, but also in various fields such as development, differentiation, viral infection, and cancer.
  • Eot axin a type of chemokine, exhibits strong eosinophil chemotaxis and not only acts on the recruitment of eosinophils from the bone marrow to peripheral blood, but also has favorable effects such as eosinophil degranulation and active enzyme production. Promotes activation of acid spheres. In addition, it induces expression of CD1 lb of eosinophil adhesion molecule receptor and expression of adhesion molecules ICAM-1 and VCAM-1 of vascular endothelial cells, and enhances eosinophil adhesion.
  • CCR3 is a G protein-coupled receptor cloned from eosinophils, is expressed on eosinophils, basophils, and Th2 cells, and is a ligand with high affinity for Eotaxin.
  • a substance that specifically inhibits the binding of Eotaxin to CCR3 is considered to be useful as a medicament for treating or preventing allergic diseases such as bronchial asthma and allergic conjunctivitis.
  • An object of the present invention is to provide a compound that specifically inhibits the function of a chemokine receptor.
  • the present inventors have conducted various studies to solve the problem 3, and as a result, have found that a certain compound specifically inhibits the function of a chemoforce-in receptor, and completed the present invention.
  • a cycloalkyl group having 5'8 carbon atoms having 5'8 carbon atoms
  • n 7 represents an integer of 0 to 3
  • R 2 and R 3 each represent a hydrogen atom or a carbon atom
  • R4 represents a phenyl group, a naphthyl group, a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkyl group having 2 to 4 carbon atoms.
  • R 5 is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and a straight-chain or branched alkyl group having 1 to 4 carbon atoms.
  • n 5 is 1 or 2
  • methylene groups or - represents a group represented by
  • a 2 represents a methylene group, an ethylene group, a vinylene group or a methyl methylene group - C (C) 2.
  • R 6 to R 10 are each a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms. An alkoxy group having 1 to 5 carbon atoms., An alkylthio group having 1 to 3 carbon atoms, trifluoromethyl group, trifluoromethyloxy group, benzyl group, phenethyl group, styryl group, phenoxy group, benzyloxy group, It represents a phenyl group or an alkoxyl group having 2 to 4 carbon atoms. ) Or a formula
  • R11 and R 12 are each a hydrogen atom, an alkyl group or an off Eniru group having 1 to 3 carbon atoms
  • X 3 is an oxygen source Or a sulfur atom or a nitrogen atom.
  • n 6 represents an integer of 1 to 3
  • X 4 represents an oxygen atom or a sulfur atom
  • R 13 to R 15 are each a hydrogen atom, a halogen atom, an alkoxy group having 1 to 3 carbon atoms or a carbon atom number.
  • n 8 and n 9 each represent 0 or 1
  • R 16 represents an alkyl group having 1 to 3 carbon atoms or a group represented by —C 0 -C3 ⁇ 4-Ph.) Is shown.
  • nu represents 1 or 2
  • X 5 and X 6 represent a methylene group or an oxygen atom, respectively.
  • 11 12 represents an integer of 1 to 5
  • R 17 and R 18 each represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms
  • a 4 represents a methylene group or an oxygen atom.
  • R 19 represents a cycloalkyl group having 3 to 10 carbon atoms or a cycloalkenyl group having 3 to 10 carbon atoms
  • R20 represents an alkyl group having 1 to 5 carbon atoms
  • Y— is Represents an anion.
  • a linear or branched alkyl group is, for example, a methyl group or an ethyl group.
  • the linear or branched alkenyl group is, for example, a hydrocarbon group such as a vinyl group, an aryl group, an isopropyl group, a butenyl group, an isobutylenyl group, and an isoprenyl group.
  • a hydrocarbon group such as a vinyl group, an aryl group, an isopropyl group, a butenyl group, an isobutylenyl group, and an isoprenyl group.
  • the cycloalkyl group is a cyclic saturated hydrocarbon group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.
  • the cycloalkenyl group is a cyclic unsaturated hydrocarbon group such as a cyclopentenyl group, a cyclohexenyl group, a cyclohexenyl group, a cycloheptenyl group, and a cyclooctenyl group.
  • the alkoxy group means a methoxy group, an ethoxy group, a propoxy group, a butoxy group, an isopropoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, a hexyloxy group, an aryloxy group, or the like.
  • the anion means a halide ion and the like, and specifically includes a chloride ion, a bromide ion, an iodide ion, a methanesulfonate ion, a monomethylsulfonate ion and the like.
  • the compound of the present invention can be synthesized, for example, by the following method. That is, the following equation (a)
  • the compound of the present invention represented by the above formula (h) is a compound represented by the above formula (f) Or a salt thereof, and the following formula (i)
  • R 1 has the same meaning as described above, and L represents a leaving group.
  • the leaving group is, for example, a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, a methanesulfonyloxy group, p —A sulfonyloxy group such as a toluenesulfonyloxy group, etc.), and reacting in the presence of a base.
  • cis and trans isomers are generated at the 1- and 4-positions of piperidine.
  • a low-polarity compound is named a cis-form and a high-polarity compound is named a trans-form.
  • the compound of the present invention may have stereoisomers such as optical isomers, diastereoisomers, and geometric isomers depending on the mode of substitution. And mixtures thereof.
  • examples of the base include sodium carbonate, carbonated carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, gymnyl sodium, sodium hydride, sodium amide, tert-butyl potassium and the like.
  • Alkali metal salts, amines such as triethylamine, diisopropylamine, pyrrolidine, piperidine, etc .; sodium acetate, potassium acetate, etc .; and mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid.
  • the organic acid is, for example, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, etc.
  • the reducing agent is, for example, sodium hydrogen borohydride, cyano hydrogen borohydride. Nato shim, hydrogenation Lithium aluminum, sodium triacetoxyborohydride and the like.
  • reaction solvent examples include water, alcohols such as methanol, ethanol, isopropyl alcohol and tert-butyl alcohol, ethers such as dioxane and tetrahydrofuran, dimethylformamide, dimethylsulfoxide, pyridine, methylene chloride, chloroform and acetone.
  • alcohols such as methanol, ethanol, isopropyl alcohol and tert-butyl alcohol
  • ethers such as dioxane and tetrahydrofuran
  • dimethylformamide dimethylsulfoxide
  • pyridine pyridine
  • methylene chloride chloroform and acetone
  • the compound of the present invention may contain a conventional bulking agent, a pH regulator, a solubilizer, etc., and tablets, granules, pills, capsules, powders, solutions, suspensions, injections, It can be adjusted to ophthalmic preparations and administered by oral, injection, ophthalmic routes.
  • the dose of the compound of the present invention when used as a chemokine receptor action inhibitor varies depending on body weight, age, sex, etc., but is usually 1 to 100 mg / day for an adult patient once per day. It can be administered in several divided doses.
  • N- (1-cyclooct-1-ene) was added to a THF (20 ml) solution of phenylethyl alcohol (183 mg), triphenylphosphine (393 mg) and a 40% tert-butyl hexyl azodicarboxylate toluene solution (653 mg).
  • Rumethyl-piperidine-14-yl) -12- (2-hydroxyphenyl) acetamide (357 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours.
  • the residue was diluted with ethyl acetate and washed sequentially with a 2 mol / l aqueous sodium hydroxide solution and brine. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. Obtained The residue was adsorbed on SCX, washed with a mixed solvent of methanol and chloroform, and eluted with a mixed solvent of 7mo1 / 1 ammonia in methanol and chloroform.
  • Example 11 The same operation as in Example 1 was performed using the corresponding raw materials to obtain the compounds shown in the following table. In the table, the data of cis compounds are shown. Table 11
  • Test example 1 CCR3 receptor binding inhibition test
  • Test Example 2 Rat eosinophil migration test
  • Lml of poma serum was administered to the abdominal cavity of Brown Norway Rat, and 48 hours later, the abdominal cavity was washed with HBSS to collect the cells. 65% Percoll (manufactured by Amersham Biosciences), 50% Percoll, and the collected cells in the peritoneal cavity were layered in this order and centrifuged at 2500 rpm for 10 minutes to obtain a polynuclear cell layer. This polynuclear cell layer was washed once with HBSS, and suspended in RPMI1640 / 1% FCS to obtain rat eosinophils.
  • the compound of the present invention has a high affinity for a chemokine receptor which plays an important role in eosinophil infiltration, and inhibits the action of the chemokine receptor to thereby inhibit the chemokine receptor in humans and animals. It can be used for treating or preventing diseases associated with, for example, allergic diseases such as bronchial asthma and allergic conjunctivitis.

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  • Immunology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

A compound represented by the formula (1) wherein m is 1 or 2; R1 represents linear or branched C3-8 (un)saturated alkyl, C5-8 cycloalkyl, C5-8 cycloalkenyl, C1-6 alkyl, C3-8 cycloalkyl, C5-8 cycloalkyl substituted by phenyl, trifluorobutyl, perhydronaphthyl, -(CH2)-C(CH3)=CH-Ph, cinnamyl, or other substituent; and Z represents, e.g., a group represented by the formula (2) (wherein R19 represents C3-10 cycloalkyl or C3-10 cycloalkenyl). The compound has a high affinity for chemokine receptors, which play an important role in eosinophilic infiltration, and inhibits the function of chemokine receptors. The compound is hence usable for treatments for or prevention of human and animal diseases in which chemokine receptors participate, such as bronchial asthma and allergic diseases including allergic conjunctivitis.

Description

明細書  Specification
ケモカイン受容体拮抗化合物 技 分野  Chemokine receptor antagonist compounds
本発明は、 白血球遊走因子であるケモカインの受容体に対する拮抗作用を有する 化合物に関する。 背景技術  The present invention relates to a compound having an antagonistic effect on a receptor of a chemokine which is a leukocyte chemotactic factor. Background art
ケモカインは主に好中球や単球に作用する因子として発見され、 主に炎症性疾患 における役割が研究されてきた。 しかし、 最近発見された新しいケモカインは、 リ ンパ球ゃ樹状細胞を主な標的細胞とすることが明らかになった。 これらのケモカイ ンは免疫系組織の形成、 恒常性維持、 免疫応答、 などの役割をはたすと考えられて いる。 さらに、 ケモカインは炎症や免疫応答での細胞遊走にとどまらず、 発生、 分 化、 ウィルス感染、 癌などのさまざまな分野でも重要な役割をはたしていることが わかってさた。  Chemokines have been discovered as factors that act primarily on neutrophils and monocytes, and their role in inflammatory diseases has been studied. However, recently discovered new chemokines have been shown to target lymphocyte-dendritic cells as the primary target cells. These chemokines are thought to play a role in the formation of immune system tissues, homeostasis, and immune response. In addition, chemokines have been shown to play important roles not only in cell migration in inflammation and the immune response, but also in various fields such as development, differentiation, viral infection, and cancer.
ケモカインの一種である Eot axinは強い好酸球走化性を示し、 骨髄から末梢血へ の好酸球の動員に作用するだけでなく、 好酸球脱顆粒 ·活性酵素産生などのような 好酸球の活性化を促進する。 また、 好酸球の接着分子受容体 CD1 lbの発現や血管内 皮細胞の接着分子 ICAM- 1、 VCAM-1の発現を誘導し、 好酸球の接着を増強させる。 一方、 CCR3は好酸球よりクローニングされた G蛋白質共役型受容体であり、 好酸 球や好塩基球、 Th2細胞に発現しており、 Eotaxinと高い親和性を有するリガンドで ある。  Eot axin, a type of chemokine, exhibits strong eosinophil chemotaxis and not only acts on the recruitment of eosinophils from the bone marrow to peripheral blood, but also has favorable effects such as eosinophil degranulation and active enzyme production. Promotes activation of acid spheres. In addition, it induces expression of CD1 lb of eosinophil adhesion molecule receptor and expression of adhesion molecules ICAM-1 and VCAM-1 of vascular endothelial cells, and enhances eosinophil adhesion. On the other hand, CCR3 is a G protein-coupled receptor cloned from eosinophils, is expressed on eosinophils, basophils, and Th2 cells, and is a ligand with high affinity for Eotaxin.
したがって、 Eotaxinの CCR3への結合を特異的に阻害する物質は、 気管支喘息や アレルギー性結膜炎をはじめとするアレルギー性疾患などに対する治療又は予防の ための医薬品として有用であると考えられる。  Therefore, a substance that specifically inhibits the binding of Eotaxin to CCR3 is considered to be useful as a medicament for treating or preventing allergic diseases such as bronchial asthma and allergic conjunctivitis.
ケモカイン受容体の機能を阻害する物質としては WO 9 8 / 0 4 5 5 4号明細書 などに記載されているが、 本発明の化合物は知られていない。  Substances that inhibit the function of chemokine receptors are described in WO98 / 054554 and the like, but the compounds of the present invention are not known.
本発明は、 ケモカイン受容体の機能を特異的に阻害する化合物の提供を目的とす る。 発明の開示 An object of the present invention is to provide a compound that specifically inhibits the function of a chemokine receptor. You. Disclosure of the invention
本発明者らは、 課 3題を解決するために種々検討した結果、 ある種の化合物がケモ 力イン受容体の機能を特異的に阻害することを見出し本発明を完成した。  The present inventors have conducted various studies to solve the problem 3, and as a result, have found that a certain compound specifically inhibits the function of a chemoforce-in receptor, and completed the present invention.
すなわち本発明は、  That is, the present invention
Expression
Figure imgf000004_0001
Figure imgf000004_0001
{式中 mは 1または 2を示し、  {Where m represents 1 or 2,
R1は R1
•炭素原子数 3· 8個の直鎖状、 分岐鎖状のアルキル基、  • A linear or branched alkyl group having 3.8 carbon atoms,
-炭素原子数 3· 8個の直鎖状、 分岐鎖状のアルケニル基、  -A linear or branched alkenyl group having 3.8 carbon atoms,
•炭素原子数 5' 8のシクロアルキル基、  A cycloalkyl group having 5'8 carbon atoms,
•炭素原子数 5 8のシクロアルケニル基、  A cycloalkenyl group having 58 carbon atoms,
•炭素原子数 1 6のアルキル基、 炭素原子数 3〜 8のシクロアルキル基またはフ ェニル基で置換された炭素原子数 5〜 8のシク口アルキル基、  An alkyl group having 16 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms or a cycloalkyl group having 5 to 8 carbon atoms substituted with a phenyl group,
• トリフルォロブチル基、  • trifluorobutyl group,
•ペルヒドロナフチル基、  Perhydronaphthyl group,
- -CH2-C(CH3)=CH-Ph で示される基、 式
Figure imgf000004_0002
-A group represented by -CH 2 -C (CH 3 ) = CH-Ph, a formula
Figure imgf000004_0002
(式中、 n7は 0〜3の整数を示し、 R2、 R 3はそれぞれ水素原子または炭素原子 数 1〜 3のアルキル基を示し、 R4はフエニル基、 ナフチル基、 炭素原子数 1〜4 の直鎖状もしくは分岐鎖状のアルキル基または炭素原子数 2〜 4の直鎖状もしくは 分岐鎖状のアルケニル基を示し、 は酸素原子、 硫黄原子、 力ルポニル基または 力ルポ二ルォキシ基を示す。 ) で示される基、 (In the formula, n 7 represents an integer of 0 to 3, R 2 and R 3 each represent a hydrogen atom or a carbon atom R4 represents a phenyl group, a naphthyl group, a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkyl group having 2 to 4 carbon atoms. Represents an alkenyl group of, and represents an oxygen atom, a sulfur atom, a liponyl group or a liponyloxy group. ),
.式 一 (CH2) n厂.Formula 1 (CH 2 ) n factory
Figure imgf000005_0001
Figure imgf000005_0001
(式中 n3および n4はそれぞれ 0〜3の整数を示し、 R 5は水素原子、 炭素原子数 1 〜 4の直鎖状もしくは分岐鎖状のアルキル基、 炭素原子数 2〜 4の直鎖状もしくは 分岐鎖状のアルケニル基、 炭素原子数 1〜 6のアルコキシ基、 フエニル基、 ハロゲ ンで置換されたフエニル基、 または炭素原子数 3〜 8のシクロアルキル基を示し、 環 C 1は 「無置換または炭素原子数 1〜 3のアルキル基で 1〜 3個置換された炭素 原子数 3〜 8のシクロアルキル基」 、 「炭素原子数 5〜 8のシクロアルケニル基」 、 「無置換または炭素原子数 1〜 3のアルコキシ基で置換されたナフチル基」 、 「 ァダマンチル基」 、 「式 (Wherein n 3 and n 4 each represent an integer of 0 to 3, R 5 is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and a straight-chain or branched alkyl group having 1 to 4 carbon atoms. A linear or branched alkenyl group, an alkoxy group having 1 to 6 carbon atoms, a phenyl group, a phenyl group substituted with a halogen atom, or a cycloalkyl group having 3 to 8 carbon atoms; `` Unsubstituted or substituted with 1 to 3 alkyl groups having 1 to 3 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms '', `` cycloalkenyl group having 5 to 8 carbon atoms '', `` unsubstituted or A naphthyl group substituted with an alkoxy group having 1 to 3 carbon atoms "," adamantyl group ",
Figure imgf000005_0002
Figure imgf000005_0002
(式中、 n5は 1または 2を示し、 はメチレン基または - C (C ) 2 -で示される 基を示し、 A 2 はメチレン基、 エチレン基、 ビニレン基またはメチルメチレン基を 示す。 ) で示される基」 、 「式 (Wherein, n 5 is 1 or 2, methylene groups or - represents a group represented by, A 2 represents a methylene group, an ethylene group, a vinylene group or a methyl methylene group - C (C) 2.) A group represented by
Figure imgf000005_0003
Figure imgf000005_0003
(R 6〜R 10はそれぞれ水素原子、 ハロゲン原子、 炭素原子数 1〜6のアルキル基 、 炭素原子数 1〜5のアルコキシ基.、 炭素原子数 1〜3のアルキルチオ基、 トリフ ルォロメチル基、 トリフルォロメチルォキシ基、 ベンジル基、 フエネチル基、 スチ リル基、 フエノキシ基、 ベンジルォキシ基、 フエニル基または炭素原子数 2〜4の アルコキシ力ルポ二ル基を示す。 ) で示される基」 または 「式
Figure imgf000006_0001
(R 6 to R 10 are each a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms. An alkoxy group having 1 to 5 carbon atoms., An alkylthio group having 1 to 3 carbon atoms, trifluoromethyl group, trifluoromethyloxy group, benzyl group, phenethyl group, styryl group, phenoxy group, benzyloxy group, It represents a phenyl group or an alkoxyl group having 2 to 4 carbon atoms. ) Or a formula
Figure imgf000006_0001
(式中、 R11と R 12はそれぞれ水素原子、 炭素原子数 1〜3のアルキル基またはフ ェニル基を示し、 X2 は窒素原子または =CH-で示される基を示し、 X3 は酸素原 子、 硫黄原子または窒素原子を示す。 ) で示される基」 で示される基、 (Wherein, R11 and R 12 are each a hydrogen atom, an alkyl group or an off Eniru group having 1 to 3 carbon atoms, X 2 represents a group represented nitrogen atom or = CH- with, X 3 is an oxygen source Or a sulfur atom or a nitrogen atom.) A group represented by)
•式  • Expression
— A3— X4— (CH2)— A 3 — X 4 — (CH 2 )
Figure imgf000006_0002
Figure imgf000006_0002
[式中、 n6は 1〜3の整数を示し、 X4 は酸素原子または硫黄原子を示し、 R13〜 R15はそれぞれ水素原子、 ハロゲン原子、 炭素原子数 1〜3のアルコキシ基または 炭素原子数 1〜 3のアルキル基を示し、 A3 は -(CH2)n7- (式中 n7 は 0〜5の 整数を示す。 ) で示される基、 -CH2 - CH=CH-C -で示される基または式
Figure imgf000006_0003
[Wherein, n 6 represents an integer of 1 to 3, X 4 represents an oxygen atom or a sulfur atom, and R 13 to R 15 are each a hydrogen atom, a halogen atom, an alkoxy group having 1 to 3 carbon atoms or a carbon atom number. 1 shows three of the alkyl group, a 3 is - (CH 2) n 7 - group (wherein n 7 is an integer of 0-5.) represented by, -CH 2 - CH = CH- C - A group or a formula represented by
Figure imgf000006_0003
(式中、 n8、 n9はそれぞれ 0または 1を示し、 R16は炭素原子数 1〜3のアルキ ル基または - C -0- C¾- Ph で示される基を示す。 ) で示される基を示す。 ]で示さ れる基、 (In the formula, n 8 and n 9 each represent 0 or 1, and R 16 represents an alkyl group having 1 to 3 carbon atoms or a group represented by —C 0 -C¾-Ph.) Is shown. A group represented by
.式
Figure imgf000006_0004
.formula
Figure imgf000006_0004
[式中、 。は 0〜2の整数を示し、
Figure imgf000007_0001
[Where,. Represents an integer of 0 to 2,
Figure imgf000007_0001
(式中、 n uは 1または 2を示し、 X 5および X 6 はそれぞれメチレン基または酸 素原子を示す。 ) で示される基、 または式 (In the formula, nu represents 1 or 2, and X 5 and X 6 represent a methylene group or an oxygen atom, respectively.)
Figure imgf000007_0002
Figure imgf000007_0002
(式中、 11 1 2は1〜5の整数を示し、 R 17、 R 18はそれぞれ水素原子または炭素原 子数 1〜 3のアルキル基を示し、 A4 はメチレン基または酸素原子を示す。 ) ]で 示される基を示し、 (In the formula, 11 12 represents an integer of 1 to 5, R 17 and R 18 each represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and A 4 represents a methylene group or an oxygen atom. )] Represents a group represented by
Zは式 9 Z is Equation 9
Figure imgf000007_0003
Figure imgf000007_0003
または式
Figure imgf000007_0004
Or expression
Figure imgf000007_0004
(式中 R 19は炭素原子数 3〜1 0のシクロアルキル基または炭素原子数 3〜1 0の シクロアルケ二ル基を示し、 R20は炭素原子数 1〜 5のアルキル基を示し、 Y—は 陰イオンを示す。 ) で示される基を示す。 } で表される化合物およびその医薬上許 容される塩である。  (Wherein R 19 represents a cycloalkyl group having 3 to 10 carbon atoms or a cycloalkenyl group having 3 to 10 carbon atoms, R20 represents an alkyl group having 1 to 5 carbon atoms, and Y— is Represents an anion.) Represents a group represented by. And a pharmaceutically acceptable salt thereof.
本発明において、 直鎖状、 分岐鎖状のアルキル基とは、 たとえばメチル基、 ェチ ル基、 n-プロピル基、 イソプロピル基、 n-ブチル基、 イソブチル基、 ter t-ブチル 基、 n-ペンチル基、 イソペンチル基、 ネオペンチル基、 ter t -ペンチル基、 n-へキ シル基、 n-ヘプチル基、 n-ォクチル基などの炭化水素基である。 In the present invention, a linear or branched alkyl group is, for example, a methyl group or an ethyl group. , N-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, n -A hydrocarbon group such as a heptyl group and an n-octyl group.
本発明において、 直鎖状、 分岐鎖状のアルケニル基とは、 たとえばビニル基、 ァ リル基、 イソプロぺニル基、 ブテニル基、 イソプチレニル基、 イソプレニル基など の炭化水素基である。  In the present invention, the linear or branched alkenyl group is, for example, a hydrocarbon group such as a vinyl group, an aryl group, an isopropyl group, a butenyl group, an isobutylenyl group, and an isoprenyl group.
本発明においてシクロアルキル基とは、 シクロプロピル基、 シクロブチル基、 シ クロペンチル基、 シクロへキシル基、 シクロへプチル基、 シクロォクチル基などの 環状飽和炭化水素基である。  In the present invention, the cycloalkyl group is a cyclic saturated hydrocarbon group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.
本発明においてシクロアルケニル基とは、 シクロペンテニル基、 シクロへキセニ ル基、 シクロへキサジェニル基、 シクロヘプテニル基、 シクロォクテニル基などの 環状不飽和炭化水素基である。  In the present invention, the cycloalkenyl group is a cyclic unsaturated hydrocarbon group such as a cyclopentenyl group, a cyclohexenyl group, a cyclohexenyl group, a cycloheptenyl group, and a cyclooctenyl group.
本発明においてアルコキシ基とはメトキシ基、 エトキシ基、 プロポキシ基、 ブト キシ基、 イソプロポキシ基、 イソブトキシ基、 sec-ブトキシ基、 t er t-ブトキシ基 、 ペンチルォキシ基、 へキシルォキシ基、 ァリルォキシ基などの基である。  In the present invention, the alkoxy group means a methoxy group, an ethoxy group, a propoxy group, a butoxy group, an isopropoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, a hexyloxy group, an aryloxy group, or the like. Group.
本発明で陰イオンとはハロゲン化物イオンなどのことであり、 具体的には塩化物 イオン、 臭化物イオン、 ヨウ化物イオン、 メタンスルホネートイオン、 モノメチル スルホネートイオンなどがあげられる。  In the present invention, the anion means a halide ion and the like, and specifically includes a chloride ion, a bromide ion, an iodide ion, a methanesulfonate ion, a monomethylsulfonate ion and the like.
本発明の化合物は、 例えば以下に示す方法によって合成することができる。 すな わち、 下記式 (a ) The compound of the present invention can be synthesized, for example, by the following method. That is, the following equation (a)
Figure imgf000008_0001
Figure imgf000008_0001
で表される化合物と下記式 (b ) And a compound represented by the following formula (b):
R 19-C HO ( b ) R 19-C HO (b)
(式中、 R 19は前記と同義) で表される化合物を還元剤の存在下、 還元的アルキル 化反応を行い、 下記式 (c )
Figure imgf000009_0001
(Wherein, R 19 is as defined above) in a reductive alkylation reaction in the presence of a reducing agent to obtain a compound represented by the following formula (c):
Figure imgf000009_0001
(式中、 R19は前記と同義) で表される化合物を得、 更に、 鉱酸、 有機酸処理など の通常用いられる方法により加水分解することにより、 下記式 (d)
Figure imgf000009_0002
(Wherein R19 is as defined above), and the compound is hydrolyzed by a commonly used method such as treatment with a mineral acid or an organic acid to obtain a compound represented by the following formula (d)
Figure imgf000009_0002
(式中、 R19は前記と同義) で表される化合物もしくはそれらの塩とした後、 下記 式 (e)
Figure imgf000009_0003
(Wherein R19 is as defined above) or a salt thereof, and then represented by the following formula (e)
Figure imgf000009_0003
(式中、 mは前記と同義) で表される化合物もしくはそれらの塩を用いてアミド結 合を形成する通常の方法により縮合し、 下記式 (f)
Figure imgf000009_0004
(Wherein m is as defined above) or a salt thereof, and condensed by an ordinary method of forming an amide bond,
Figure imgf000009_0004
(式中、 m、 R19は前記と同義) で表される化合物を得、 下記式 (g)  (Wherein, m and R19 are as defined above), and a compound represented by the following formula (g):
Rl-OH (g) Rl-OH (g)
(式中、 R1は前記と同義) で表される化合物と光延反応によりエーテル結合を形 成することによって、 下記式 (h)  (Wherein R1 is as defined above) to form an ether bond by a Mitsunobu reaction, thereby obtaining the following formula (h)
Figure imgf000009_0005
Figure imgf000009_0005
(式中、 m、 Rl, R19は前記と同義) で表される本発明化合物を合成することが できる。  (Wherein, m, Rl, and R19 are as defined above) can be synthesized.
また、 上記式 (h) で示される本発明の化合物は、 上記式 (f) で表される化合 物もしくはそれらの塩と、 下記式 (i ) Further, the compound of the present invention represented by the above formula (h) is a compound represented by the above formula (f) Or a salt thereof, and the following formula (i)
R l-L ( i ) R l-L (i)
(式中、 R 1は前記と同義であり、 Lは脱離基を表す。 ここで脱離基とは、 例えば 塩素原子、 臭素原子、 ヨウ素原子等のハロゲン原子、 メタンスルホニルォキシ基、 p—トルエンスルホニルォキシ基等のスルホニルォキシ基などがあげられる) で表 される化合物を塩基存在下反応させることによって合成することもできる。  (Wherein, R 1 has the same meaning as described above, and L represents a leaving group. Here, the leaving group is, for example, a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, a methanesulfonyloxy group, p —A sulfonyloxy group such as a toluenesulfonyloxy group, etc.), and reacting in the presence of a base.
更に、 上記式 (h) で表される化合物と下記式 (j )  Further, the compound represented by the above formula (h) and the following formula (j)
R20-Y ( j ) R20-Y (j)
(式中、 R 20および Yは前記と同義) で表される化合物を反応させることによって 下記式 (k )  (Wherein R 20 and Y are as defined above) by reacting a compound represented by the following formula (k)
Figure imgf000010_0001
Figure imgf000010_0001
(式中、 m、 R l, R 19、 R20は前記と同義) で表される本発明化合物を合成する ことができる。 この際、 ピぺリジンの 1位と 4位に cis, transの異性体が生じるが 、 便宜上、 低極性の化合物を c is体、 高極性の化合物を trans体と命名する。  (Wherein, m, R 1, R 19 and R 20 have the same meanings as described above). At this time, cis and trans isomers are generated at the 1- and 4-positions of piperidine. For convenience, a low-polarity compound is named a cis-form and a high-polarity compound is named a trans-form.
本発明の化合物は、 その置換の態様によって、 光学異性体、 ジァステレオ異性体 、 幾何異性体等の立体異性体が存在することがあるが、 本発明の化合物はこれら全 ての立体異性体及びそれらの混合物をも包含する。  The compound of the present invention may have stereoisomers such as optical isomers, diastereoisomers, and geometric isomers depending on the mode of substitution. And mixtures thereof.
上記反応で塩基を用いる場合の塩基としては例えば炭酸ナ卜リゥム、 炭酸力リゥ ム、 炭酸水素ナトリウム、 炭酸水素カリウム、 水酸化ナトリウム、 ジムシルナトリ ゥム、 水素化ナトリウム、 ナトリウムアミド、 tert—ブチルカリウム等のアルカリ 金属塩類、 トリェチルァミン、 ジイソプロピルァミン、 ピロリジン、 ピぺリジン等 のァミン類、 酢酸ナトリウム、 酢酸カリウム等を用いることができ、 鉱酸とは例え ば塩酸、 臭化水素酸、 ヨウ化水素酸、 硝酸、 硫酸等であり、 有機酸とは例えば、 酢 酸、 メタンスルホン酸、 p—トルエンスルホン酸、 トリフルォロ酢酸等であり、 還 元剤とは例えば水素ィ匕ホウ素ナトリウム、 シァノ水素ィ匕ホウ素ナ卜シゥム、 水素化 リチウムアルミニウム、 トリァセトキシ水素化ホウ素ナトリウム等である。 反応溶 媒としては、 水、 メタノール、 エタノール、 イソプロピルアルコール、 ter t—プチ ルアルコール等のアルコール類、 ジォキサン、 テトラヒドロフラン等エーテル類、 ジメチルホルムアミド、 ジメチルスルホキシド、 ピリジン、 塩化メチレン、 クロ口 ホルム、 ァセ卜ン、 酢酸等の反応に不活性な溶媒を用いることができる。 When a base is used in the above reaction, examples of the base include sodium carbonate, carbonated carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, gymnyl sodium, sodium hydride, sodium amide, tert-butyl potassium and the like. Alkali metal salts, amines such as triethylamine, diisopropylamine, pyrrolidine, piperidine, etc .; sodium acetate, potassium acetate, etc .; and mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid. , Nitric acid, sulfuric acid, etc., and the organic acid is, for example, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, etc., and the reducing agent is, for example, sodium hydrogen borohydride, cyano hydrogen borohydride. Nato shim, hydrogenation Lithium aluminum, sodium triacetoxyborohydride and the like. Examples of the reaction solvent include water, alcohols such as methanol, ethanol, isopropyl alcohol and tert-butyl alcohol, ethers such as dioxane and tetrahydrofuran, dimethylformamide, dimethylsulfoxide, pyridine, methylene chloride, chloroform and acetone. A solvent inert to the reaction, such as toluene or acetic acid, can be used.
本発明の化合物は常用の増量剤、 p H調節剤、 溶解剤などを添加し、 常用の製剤 技術によって錠剤、 顆粒剤、 丸剤、 カプセル剤、 粉剤、 液剤、 懸濁剤、 注射剤、 点 眼剤などに調整し、 経口、 注射、 点眼などの経路で投与することができる。  The compound of the present invention may contain a conventional bulking agent, a pH regulator, a solubilizer, etc., and tablets, granules, pills, capsules, powders, solutions, suspensions, injections, It can be adjusted to ophthalmic preparations and administered by oral, injection, ophthalmic routes.
本発明の化合物を、 ケモカイン受容体作用阻害剤として用いる場合の投与量は、 体重、 年齢、 性別などにより異なるが、 通常成人の患者に対して 1日あたり 1〜1 0 0 O m gを 1回〜数回に分けて投与することができる。 発明を実施するための最良の形態  The dose of the compound of the present invention when used as a chemokine receptor action inhibitor varies depending on body weight, age, sex, etc., but is usually 1 to 100 mg / day for an adult patient once per day. It can be administered in several divided doses. BEST MODE FOR CARRYING OUT THE INVENTION
以下、 実施例および試験例により本発明をさらに詳細に説明する。  Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples.
実施例 1 Example 1
化合物 8 1 , 化合物 8 の合成 Synthesis of Compound 8 1 and Compound 8
Figure imgf000011_0001
Figure imgf000011_0001
( 1 ) ピぺリジン 4ーィルーカルパミックアシッド ter t-ブチルエステル (6. 00g ) のテトラヒドロフラン (以下 TH Fと略す) (120ml) 溶液にシクロォクトー 1 一ェンカルバアルデヒド (4. 97g) と酢酸 (1. 72ml) を加え、 さらにトリァセトキ シ水素化ホウ素ナトリウム (8. 25g) を氷冷下加え、 室温で 2時間攪拌した。 溶媒 を留去後、 エーテルで希釈し、 2mo l/l水酸化ナトリウム水溶液、 食塩水で順次洗浄 した。 有機層を無水硫酸マグネシウムで乾燥後、 溶媒を留去した。 得られた残渣をシリカゲルフラッシュカラムクロマトグラフィ一で酢酸ェチルと へキサンの混合溶媒を用いて精製し、 (1ーシクロォクト— 1—ェニルーメチルー ピぺリジン一 4一ィル) 一力ルバミックアシッド tert-ブチルエステル (3. 86g) を得た。 (1) A solution of piperidine 4-pyrucalmic acid tert-butyl ester (6.00 g) in tetrahydrofuran (hereinafter abbreviated to THF) (120 ml) was mixed with cyclooct-1-enecarbaldehyde (4.97 g). Acetic acid (1.72 ml) was added, and sodium triacetoxyborohydride (8.25 g) was further added under ice-cooling, followed by stirring at room temperature for 2 hours. After distilling off the solvent, the residue was diluted with ether and washed successively with a 2 mol / l aqueous sodium hydroxide solution and brine. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. The obtained residue was purified by silica gel flash column chromatography using a mixed solvent of ethyl acetate and hexane, and (1-cyclooct-1-enyl-methyl-piperidine-1-41-yl) rubactic acid tert-butyl ester was used. (3.86 g) was obtained.
( 2 ) ( 1—シクロォクトー 1—ェニル一メチルーピペリジン一 4—ィル) 一カル バミックアシッド tert-ブチルエステル (3. 86g) の塩化メチレン (15ml) 溶液に トリフルォロ酢酸 (15ml) を氷冷下加え、 室温で 2時間攪拌した。 溶媒を留去後、 クロ口ホルムで希釈し、 2mol/l水酸化ナトリウム水溶液で洗浄した。 有機層を無水 硫酸マグネシウムで乾燥後、 溶媒を留去し、 未精製の 1ーシクロォクトー 1ーェニ ル—メチルーピペリジン一 4一ィルァミン (2. 66g) を得た。  (2) (1-Cyclooct-1-enyl-1-methyl-piperidine-14-yl) carboxyacid tert-butyl ester (3.86 g) in methylene chloride (15 ml) solution and trifluoroacetic acid (15 ml) in ice The mixture was added under reduced pressure and stirred at room temperature for 2 hours. After evaporating the solvent, the residue was diluted with chloroform and washed with a 2 mol / l aqueous sodium hydroxide solution. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off to obtain unpurified 1-cyclooct-1-enyl-methyl-piperidine-14-ylamine (2.66 g).
( 3 ) 1ーシクロォクトー 1—ェニル一メチル一ピペリジン一 4一ィルァミン (2. 66g) と 2—ヒドロキシフエニル酢酸 (2. 18g) と 1—ヒドロキシベンゾトリアゾ一 ル 1水和物 (2. 75g) のジメチルホルムアミド (30ml) 溶液に塩酸 1—ェチルー 3 ― ( 3—ジメチル) カルポジイミド (3. 44g) を加え、 80でで 3時間攪拌した。 溶 媒を留去後、 酢酸ェチルで希釈し、 食塩水で 3回洗浄した。 有機層を無水硫酸マグ ネシゥムで乾燥後、 溶媒を留去した。 得られた残渣を NH型のシリカゲルカラムク 口マトグラフィ一でメタノールとクロ口ホルムの混合溶媒を用いて精製し、 N— ( 1ーシクロォクト _ 1 —ェニル—メチルーピペリジン一 4一ィル) 一 2— (2—ヒ ドロキシフエニル) ァセトアミド (3. 88g) を得た.。  (3) 1-cyclooct-1-enyl-methyl-piperidine-14-ylamine (2.66 g), 2-hydroxyphenylacetic acid (2.18 g) and 1-hydroxybenzotriazole monohydrate (2.75 g) 1) -Ethyl-3- (3-dimethyl) carboimide (3.44 g) was added to a solution of the above) in dimethylformamide (30 ml), and the mixture was stirred at 80 for 3 hours. After the solvent was distilled off, the residue was diluted with ethyl acetate and washed three times with saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. The obtained residue was purified by NH-type silica gel column chromatography using a mixed solvent of methanol and chloroform, to give N- (1-cyclooct_1-enyl-methyl-piperidine-14-yl) 12. — (2-Hydroxyphenyl) acetamide (3.88 g) was obtained.
( 4 ) フエネチルアルコール (183mg) とトリフエニルホスフィン (393mg) と 40% ジェチルァゾジカルポキシレート トルエン溶液 (653mg) の TH F (20ml) 溶液に N— ( 1—シクロォクトー 1—ェニルーメチルーピペリジン一 4—ィル) 一 2— ( 2—ヒドロキシフエニル) ァセトアミド (357mg) を氷冷下加え、 室温で 3時間攪 拌した。 さらに、 フエネチルアルコ一ル (183mg) とトリフエニルホスフィン (393 mg) と 40%ジェチルァゾジカルボキシレート トルエン溶液 (653mg) の TH F (10 ml) 溶液を加え、 室温で 2時間攪拌した。  (4) N- (1-cyclooct-1-ene) was added to a THF (20 ml) solution of phenylethyl alcohol (183 mg), triphenylphosphine (393 mg) and a 40% tert-butyl hexyl azodicarboxylate toluene solution (653 mg). Rumethyl-piperidine-14-yl) -12- (2-hydroxyphenyl) acetamide (357 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Furthermore, a THF (10 ml) solution of phenethyl alcohol (183 mg), triphenylphosphine (393 mg) and a 40% getyl azodicarboxylate toluene solution (653 mg) was added, and the mixture was stirred at room temperature for 2 hours.
溶媒を留去後、 酢酸ェチルで希釈し、 2mol/l水酸化ナトリウム水溶液、 食塩水で 順次洗浄した。 有機層を無水硫酸マグネシウムで乾燥後、 溶媒を留去した。 得られ た残渣を S C Xに吸着させ、 メ夕ノ一ルとクロ口ホルムの混合溶媒で洗浄した後、 7mo 1/1ァンモニァのメタノール溶液とク口口ホルムの混合溶媒で溶出させた。 溶媒 を留去し、 残渣を NH型のシリカゲルフラッシュカラムクロマトグラフィーで酢酸 ェチルとへキサンの混合溶媒を用いて精製し、 N— (1—シクロォクトー 1—ェニ ルーメチルーピペリジン一 4一ィル) 一 2— (2—フエネチルォキシフエニル) ァ セトアミド (402mg) を得た。 After evaporating the solvent, the residue was diluted with ethyl acetate and washed sequentially with a 2 mol / l aqueous sodium hydroxide solution and brine. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. Obtained The residue was adsorbed on SCX, washed with a mixed solvent of methanol and chloroform, and eluted with a mixed solvent of 7mo1 / 1 ammonia in methanol and chloroform. The solvent was distilled off, and the residue was purified by flash column chromatography using NH-type silica gel with a mixed solvent of ethyl acetate and hexane to give N- (1-cyclooct-1-enylmethyl-piperidine-14-yl). One 2- (2-phenethyloxyphenyl) acetamide (402 mg) was obtained.
(5) N— (1ーシクロォクトー 1—ェニル—メチルーピペリジン一 4一ィル) 一 2— (2—フエネチルォキシフエニル) ァセトアミド (2.15g) にヨウ化メチル (2 Oml) を加え、 室温で一晩攪拌した。 溶媒を留去し、 残渣をシリカゲルカラムクロ マトグラフィ一でメタノールとクロ口ホルムの混合溶媒を用いて精製し、 Rf値の高 い低極性の化合物 (cis体) を含むフラクションの溶媒を留去し、 標題化合物 (表 中の化合物 8 1) (2.25g) を得た。 また、 Rf値の低い高極性の化合物 (trans体) を含むフラクションの溶媒を留去し、 標題化合物 (表中の化合物 8 1') (0.38g) を得た。  (5) N- (1-cyclooct-1-enyl-methyl-piperidine-14-yl) -1-2- (2-phenethyloxyphenyl) acetamide (2.15 g) was added with methyl iodide (2 Oml), Stirred overnight at room temperature. The solvent is distilled off, and the residue is purified by silica gel column chromatography using a mixed solvent of methanol and chloroform. The solvent of the fraction containing a low-polar compound (cis-form) having a high Rf value is distilled off. The title compound (compound 81 in the table) (2.25 g) was obtained. Further, the solvent of a fraction containing a highly polar compound having low Rf value (trans form) was distilled off to obtain the title compound (compound 81 ′ in the table) (0.38 g).
化合物 8 1 Ή NMR (300 MHz, CDC13) δ ρπι 1.35-1.72 (m, 8 H), 1.78-1.94 (m, 2 H), 2.11-2.41 On, 6 H), 3.11 (t, J=6.84 Hz, 2 H), 3.27 (s, 3 H), 3.41-3 .67 (m, 4 H), 3.57 (s, 2 H), 4.02 (m, 1 H), 4.05 (s, 2 H), 4.20 (t, J=6.84 Hz, 2 H), 6.09 (t, J=8.00 Hz, 1 H), 6.81-7.02 (m, 3 H), 7.14-7.38 (m, 7 H) 化合物 8 1' 'Η NMR (200 MHz, CDC13) 5ppm 1.38-1.80 (m, 8 H), 1.80-2.05 (m , 2 H), 2.10-2.42 (m, 6 H), 3.04 (s, 3 H), 3.13 (t, J=6.9 Hz, 2 H), 3.35-3 .58 (m, 2 H), 3.70 (s, 2 H), 3.92-4.32 (m, 3 H), 4.21 (t, J=6.9 Hz, 2 H), 4 .27 (s, 2 H), 6.15 (t, J=8.1 Hz, 1 H), 6.80-6.96 (m, 2 H), 7.12-7.41 (m, 8 H) 実施例 Compound 8 1 Ή NMR (300 MHz, CDC1 3) δ ρπι 1.35-1.72 (m, 8 H), 1.78-1.94 (m, 2 H), 2.11-2.41 On, 6 H), 3.11 (t, J = 6.84 Hz, 2 H), 3.27 (s, 3 H), 3.41-3.67 (m, 4 H), 3.57 (s, 2 H), 4.02 (m, 1 H), 4.05 (s, 2 H), 4.20 (t, J = 6.84 Hz, 2 H), 6.09 (t, J = 8.00 Hz, 1 H), 6.81-7.02 (m, 3 H), 7.14-7.38 (m, 7 H) Compound 8 1 '' Η NMR (200 MHz, CDC1 3 ) 5ppm 1.38-1.80 (m, 8 H), 1.80-2.05 (m, 2 H), 2.10-2.42 (m, 6 H), 3.04 (s, 3 H), 3.13 ( t, J = 6.9 Hz, 2 H), 3.35-3.58 (m, 2 H), 3.70 (s, 2 H), 3.92-4.32 (m, 3 H), 4.21 (t, J = 6.9 Hz, 2 H), 4.27 (s, 2 H), 6.15 (t, J = 8.1 Hz, 1 H), 6.80-6.96 (m, 2 H), 7.12-7.41 (m, 8 H)
対応する原料を用いて実施例 1と同様の操作を行い、 以下の表に示した化合物を 得た。 表では cis体の化合物のデ一ターを示した。 表 1一 The same operation as in Example 1 was performed using the corresponding raw materials to obtain the compounds shown in the following table. In the table, the data of cis compounds are shown. Table 11
Figure imgf000014_0001
差替え用紙 (規則 26)
Figure imgf000014_0001
Replacement form (Rule 26)
t t
CO CO
Figure imgf000015_0001
Figure imgf000015_0001
O /AVεο! O / AVεο!
Figure imgf000016_0001
Figure imgf000016_0001
O /AVs/:2I/卜o 6 O / AVs /: 2I / uo 6
CO Cs3 CO Cs3
Figure imgf000017_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000020_0001
O/AVί〕i71dfc P O / AVί) i71dfc P
Figure imgf000021_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000022_0001
i
Figure imgf000023_0001
i
Figure imgf000023_0001
1 7 — 1 7 —
Figure imgf000024_0001
差替え用紙 (規則 26)
Figure imgf000025_0001
Figure imgf000024_0001
Replacement form (Rule 26)
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000026_0001
18/1 18/1
Figure imgf000027_0001
Figure imgf000027_0001
差替え用紙 (規則 26) 1 9 Replacement form (Rule 26) 1 9
Figure imgf000028_0001
差替え用紙 (規則 26) 19/1
Figure imgf000028_0001
Replacement form (Rule 26) 19/1
Figure imgf000029_0001
差替え用紙 (規則 26) 2 0
Figure imgf000029_0001
Replacement form (Rule 26) 2 0
Figure imgf000030_0001
差替え用紙 (規則 26) O
Figure imgf000030_0001
Replacement form (Rule 26) O
Figure imgf000031_0001
Figure imgf000031_0001
CO CO
Figure imgf000032_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000033_0001
2 2 twenty two
Figure imgf000034_0001
差替え用紙 (規則 26) / O卜sAV
Figure imgf000034_0001
Replacement form (Rule 26) / Oto sAV
Figure imgf000035_0001
Figure imgf000035_0001
/ O 6卜 εζ-οAV / O 6 εζ-οAV
術 S: Jutsu S:
CO CO
Figure imgf000036_0001
Figure imgf000036_0001
/ OfAVΜί / OfAVΜί
O CM O CM
Figure imgf000037_0001
Figure imgf000037_0001
i7J.pfcd/ OsAV : 寸
Figure imgf000038_0001
i7J.pfcd / OsAV: Dimensions
Figure imgf000038_0001
24/1 表 13— 2
Figure imgf000039_0001
24/1 Table 13-2
Figure imgf000039_0001
差替え用紙 (規則 26) 2 5 Replacement form (Rule 26) twenty five
一 1
Figure imgf000040_0001
One one
Figure imgf000040_0001
差替え用紙 (規則 26)
Figure imgf000041_0001
Replacement form (Rule 26)
Figure imgf000041_0001
1 2
Figure imgf000042_0001
1 2
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000043_0001
//: 6卜 CAOsdTI£ /f 0 //: 6 minutes CAOsdTI £ / f 0
9 9
Figure imgf000044_0001
Figure imgf000044_0001
2 1 / 1 2 1/1
Figure imgf000045_0001
差替え用紙 (規則 26) 2 8
Figure imgf000045_0001
Replacement form (Rule 26) 2 8
Figure imgf000046_0001
差替え用紙 (規則 26)
Figure imgf000047_0001
Figure imgf000046_0001
Replacement form (Rule 26)
Figure imgf000047_0001
τ-Ητ-Η
03 03
Figure imgf000048_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000051_0001
0 s拏  0 halla
T ε  T ε
6L£L0/£0dT/13d 86 οι/εο OAV O /AVεοΜ 6ίΧ1 6L £ L0 / £ 0dT / 13d 86 οι / εο OAV O / AVεοΜ 6ίΧ1
Figure imgf000052_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000054_0001
i:― ε z拏 /,C,0/C0df/X3d 861而 fO OAV ϋ 6卜 i:-ε zalla /, C, 0 / C0df / X3d 861 fO OAV ϋ 6
Dimension
CO  CO
Figure imgf000055_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000056_0001
/ OsAVM£i / OsAVM £ i
LO CO LO CO
Figure imgf000057_0001
Figure imgf000057_0001
3 6 3 6
表 2 5  Table 25
Figure imgf000058_0001
差替え用紙 (規則 26)
Figure imgf000059_0001
Figure imgf000058_0001
Replacement form (Rule 26)
Figure imgf000059_0001
3 7 3 7
Figure imgf000060_0001
差替え用紙 (規則 26)
Figure imgf000060_0001
Replacement form (Rule 26)
Figure imgf000061_0001
Figure imgf000061_0001
I-1
Figure imgf000062_0001
I- 1
Figure imgf000062_0001
72 溢 72 Overflow
Figure imgf000063_0001
Figure imgf000063_0001
\ 18 3 / OAVs/:2/drIo26卜 \ 18 3 / OAVs /: 2 / drIo26
Figure imgf000064_0001
Figure imgf000064_0001
iv:/ O/-pfcl£さ ϊsAV一 iv: / O / -pfcl £ sa AVsAV
Figure imgf000065_0001
Figure imgf000065_0001
o h-1 o h- 1
Figure imgf000066_0001
Figure imgf000066_0001
29
Figure imgf000067_0001
29
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000069_0001
\ 1 ^1 嫩 \ 1 ^ 1 Penn
Figure imgf000070_0001
Figure imgf000070_0001
/ O卜sAV / Oto sAV
τ τ
Dimension
Figure imgf000071_0001
Figure imgf000071_0001
/ / O 6卜 εζ-οsAV / / O 6 εζ-οsAV
CO CO
 Dimension
Figure imgf000072_0001
Figure imgf000072_0001
4 4 4 4
表 3 3 —
Figure imgf000073_0001
Table 3 3 —
Figure imgf000073_0001
差替え用紙 (規則 26) 44/1 Replacement form (Rule 26) 44/1
表 33 2  Table 33 2
Figure imgf000074_0001
試験例 1 . CCR3受容体結合阻害試験
Figure imgf000074_0001
Test example 1. CCR3 receptor binding inhibition test
• モノ ·ポリ分離液(大日本製薬製)にヒト末梢血を重層し、 1500rpm、 20分間、 室 差替え用紙(規則 26) 45 • Overlaid human peripheral blood on a mono-poly separation solution (Dainippon Pharmaceutical), 1500 rpm, 20 minutes, room replacement paper (Rule 26) 45
温で遠心し、 多核球層を得た。 この多核球層を PBS (—)で希釈し、 1200卬 m、 5分間 遠心し、 沈殿した細胞を滅菌水で懸濁して溶血した。 滅菌水と同量の 1.8% NaCl水 溶液を添加して、 1200rpm、 5分間遠心し、 沈殿した細胞を一度 PBS (—)で洗浄した 。 氷冷した PBS (—)Z2mM EDTAZO.5% BSAに懸濁し、 CD16マイクロビーズを添加し て、 6〜12°Cで 30分間インキュベートした後、 MACSカラムに流して、 通過した細胞 液を回収し、 好酸球を得た。 Centrifugation was performed at room temperature to obtain a polynuclear cell layer. This polynuclear cell layer was diluted with PBS (-), centrifuged at 1200 卬 m for 5 minutes, and the precipitated cells were suspended in sterile water and lysed. A 1.8% NaCl aqueous solution of the same volume as sterile water was added, centrifuged at 1200 rpm for 5 minutes, and the precipitated cells were washed once with PBS (-). Suspend in ice-cold PBS (-) Z2mM EDTAZO.5% BSA, add CD16 microbeads, incubate at 6 to 12 ° C for 30 minutes, flow onto a MACS column, and collect the passed cell solution. Eosinophils were obtained.
ヒト末梢血から分離した好酸球、 0. InM [125I] human Eotaxin (2000Ci/mmoK Am ersham Biosciences 製) 及び被験化合物を 0. lmlの 50mM HEPES/51M MgCl2/lmM Ca Cl2/0.5% BSA (pH 7.2) に懸濁し、 37°C、 90分間インキュベートした後、 予め 0.5% ポリエチレンィミン (pH 7.2) に浸しておいたグラスフィルター GF/Cにて濾過を行 レ、 1.5mlの PBS (—) Z0.5M NaCl/0.05% BSAにて洗浄した後、 グラスフィルター上 の放射活性を測定した。 CCR3に対する結合親和性は、 さまざまな濃度の化合物によ る [125I] human Eotaxinの 50%結合阻害濃度 (IC5。値) を算出した。 Human peripheral blood eosinophils isolated from, 0. InM [125 I] human Eotaxin (2000Ci / mmoK Am ersham made Biosciences) and test compounds in 0. lml 50mM HEPES / 51M MgCl 2 / lmM Ca Cl 2 /0.5% Suspend in BSA (pH 7.2), incubate at 37 ° C for 90 minutes, filter through a glass filter GF / C pre-soaked in 0.5% polyethyleneimine (pH 7.2), and add 1.5 ml of PBS. (—) After washing with Z0.5M NaCl / 0.05% BSA, the radioactivity on the glass filter was measured. Binding affinity for CCR3 was calculated Ru good in various concentrations of compound [125 I] 50% binding inhibition concentrations of human Eotaxin (IC 5. Value).
その結果、 本発明の化合物は優れた効果があることがわかった。 試験例 2 ラット好酸球遊走試験  As a result, it was found that the compound of the present invention had an excellent effect. Test Example 2 Rat eosinophil migration test
Brown Norway Ratの腹腔にゥマ血清を lml投与し、 48時間後に腹腔内を HBSSで洗 浄して細胞を回収した。 65% Percoll (Amersham Biosciences 製) 、 50% Percoll 、 回収した腹腔内細胞の順に重層し、 2500rpm、 10分間遠心し、 多核球層を得た。 この多核球層を一度 HBSSで洗浄した後、 RPMI1640/1% FCSで懸濁してラット好酸球 とした。 96穴ケモタキシスチャンバ一 (ポアアイズ 5μΐη) の下室にヒト Eotaxin (10 OnM) 及び被験化合物を 30μ1の RPMI1640/1% FCSに調製し、 フィル夕一をのせ、 上 室に 50μ1の RPMI1640Z1% FCSに懸濁したラット好酸球を添加した。 37°C、 2時間ィ ンキュペートした後、 フィルターを取り除き、 下室に移動した細胞数を測定した。 ラット好酸球の遊走に対する被験化合物の作用は、 ヒト Eotaxin (ΙΟΟηΜ) に被 験化合物を添加することによって下室への遊走の抑制率 (%) を算出した。  Lml of poma serum was administered to the abdominal cavity of Brown Norway Rat, and 48 hours later, the abdominal cavity was washed with HBSS to collect the cells. 65% Percoll (manufactured by Amersham Biosciences), 50% Percoll, and the collected cells in the peritoneal cavity were layered in this order and centrifuged at 2500 rpm for 10 minutes to obtain a polynuclear cell layer. This polynuclear cell layer was washed once with HBSS, and suspended in RPMI1640 / 1% FCS to obtain rat eosinophils. Prepare human Eotaxin (10 OnM) and the test compound in 30 μl RPMI1640 / 1% FCS in the lower chamber of a 96-well chemotaxis chamber (Pore Eyes 5μ の η). Rat eosinophils were added. After incubating at 37 ° C for 2 hours, the filter was removed, and the number of cells that moved to the lower chamber was counted. The effect of the test compound on the migration of rat eosinophils was calculated by adding the test compound to human Eotaxin (ΙΟΟηΜ) and calculating the inhibition rate (%) of migration into the lower chamber.
その結果、 本発明の化合物は優れた効果があることがわかった。 4 6 As a result, it was found that the compound of the present invention had an excellent effect. 4 6
産業上の利用可能性  Industrial applicability
本発明の化合物は、 好酸球浸潤において重要な働きを担っているケモカイン受容 体に対して高い親和性を有し、 ケモカイン受容体の作用を阻害することにより、 ヒ ト及び動物におけるケモカイン受容体が関わる疾患、 例えば気管支喘息やアレルギ —性結膜炎をはじめとするアレルギー性疾患に対する治療又は予防のために使用す ることができる。  The compound of the present invention has a high affinity for a chemokine receptor which plays an important role in eosinophil infiltration, and inhibits the action of the chemokine receptor to thereby inhibit the chemokine receptor in humans and animals. It can be used for treating or preventing diseases associated with, for example, allergic diseases such as bronchial asthma and allergic conjunctivitis.

Claims

4 7 請求の範囲 4 7 Claims
1 . 式  1 set
Figure imgf000077_0001
Figure imgf000077_0001
{式中 mは 1または 2を示し、  {Where m represents 1 or 2,
R 1は R 1
炭素原子数 3 8個の直鎖状、 分岐鎖状のアルキル基、  A linear or branched alkyl group having 38 carbon atoms,
炭素原子数 3 8個の直鎖状、 分岐鎖状のアルケニル基、  A linear or branched alkenyl group having 38 carbon atoms,
炭素原子数 5 8のシクロアルキル基、  A cycloalkyl group having 58 carbon atoms,
炭素原子数 5 8のシクロアルケニル基、  A cycloalkenyl group having 58 carbon atoms,
炭素原子数 1 6のアルキル基、 炭素原子数 3〜 8のシクロアルキル基またはフ ェニル基で置換された炭素原子数 5〜 8のシクロアルキル基、  An alkyl group having 16 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms or a cycloalkyl group having 5 to 8 carbon atoms substituted with a phenyl group,
トリフルォロブチル基、  Trifluorobutyl group,
ペルヒドロナフチル基、  Perhydronaphthyl group,
-CH2 -C (CH3 ) =CH-Ph で示される基、 式
Figure imgf000077_0002
-CH 2 -C (CH 3 ) = CH-Ph
Figure imgf000077_0002
(式中、 n 2は 0〜3の整数を示し、 R 2、 R3はそれぞれ水素原子または炭素原子 数 1〜 3のアルキル基を示し、 R4はフエニル基、 ナフチル基、 炭素原子数 1〜4 の直鎖状もしくは分岐鎖状のアルキル基または炭素原子数 2〜 4の直鎖状もしくは 分岐鎖状のアルケニル基を示し、 ェ は酸素原子、 硫黄原子、 カルボニル基または カルボ二ルォキシ基を示す。 ) で示される基、 (In the formula, n 2 represents an integer of 0 to 3, R 2 and R 3 each represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R 4 represents a phenyl group, a naphthyl group, or a carbon atom having 1 to 4 carbon atoms. Represents a linear or branched alkyl group or a linear or branched alkenyl group having 2 to 4 carbon atoms, and represents an oxygen atom, a sulfur atom, a carbonyl group or a carboxy group. ),
.式 4 8 .formula 4 8
Figure imgf000078_0001
Figure imgf000078_0001
(式中 n3および n4はそれぞれ 0〜3の整数を示し、 R5は水素原子、 炭素原子数 1 〜 4の直鎖状もしくは分岐鎖状のアルキル基、 炭素原子数 2〜 4の直鎖状もしくは 分岐鎖状のアルケニル基、 炭素原子数 1〜6のアルコキシ基、 フエニル基、 ハロゲ ンで置換されたフエニル基、 または炭素原子数 3〜 8のシクロアルキル基を示し、 環 C 1は 「無置換または炭素原子数 1〜 3のアルキル基で 1〜 3個置換された炭素 原子数 3〜 8のシクロアルキル基」 、 「炭素原子数 5〜 8のシクロアルケニル基」 、 「無置換または炭素原子数 1〜3のアルコキシ基で置換されたナフチル基」 、 「 ァダマンチル基」 、 「式 (Wherein n 3 and n 4 each represent an integer of 0 to 3, R 5 is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and a linear chain having 2 to 4 carbon atoms. Or a branched alkenyl group, an alkoxy group having 1 to 6 carbon atoms, a phenyl group, a phenyl group substituted with a halogen atom, or a cycloalkyl group having 3 to 8 carbon atoms. 1 to 3 unsubstituted or substituted with 1 to 3 carbon atoms, an alkyl group having 3 to 8 carbon atoms, cycloalkyl group having 3 to 8 carbon atoms, cycloalkenyl group having 5 to 8 carbon atoms, unsubstituted or carbon A naphthyl group substituted with an alkoxy group having 1 to 3 atoms ", an" adamantyl group ", a" formula
Figure imgf000078_0002
Figure imgf000078_0002
(式中、 η 5は 1または 2を示し、 はメチレン基または - C (CH3 ) 2 -で示される 基を示し、 A2 はメチレン基、 エチレン基、 ビニレン基またはメチルメチレン基を 示す。 ) で示される基」 、 「式 (In the formula, η 5 represents 1 or 2, represents a methylene group or a group represented by —C (CH 3 ) 2 —, and A 2 represents a methylene group, an ethylene group, a vinylene group or a methylmethylene group. ) Group ”,“ Formula
Figure imgf000078_0003
Figure imgf000078_0003
(R 6〜R 10はそれぞれ水素原子、 ハロゲン原子、 炭素原子数 1〜6のアルキル基 、 炭素原子数 1〜 5のアルコキシ基、 炭素原子数 1〜3のアルキルチオ基、 トリフ ルォロメチル基、 トリフルォロメチルォキシ基、 ベンジル基、 フエネチル基、 スチ リル基、 フエノキシ基、 ベンジルォキシ基、 フエニル基または炭素原子数 2〜4の アルコキシ力ルポ二ル基を示す。 ) で示される基」 または 「式 49 (R 6 to R 10 are each a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 3 carbon atoms, a trifluoromethyl group, a trifluoromethyl group. And a group represented by the formula: or a methyloxy group, a benzyl group, a phenethyl group, a styryl group, a phenoxy group, a benzyloxy group, a phenyl group or an alkoxyl group having 2 to 4 carbon atoms. 49
Figure imgf000079_0001
Figure imgf000079_0001
(式中、 R11と R12はそれぞれ水素原子、 炭素原子数 1〜 3のアルキル基またはフ ェニル基を示し、 X2 は窒素原子または =CH-で示される基を示し、 X3 は酸素原 子、 硫黄原子または窒素原子を示す。 ) で示される基」 で示される基、 (Wherein, R11 and R12 each represent a hydrogen atom, an alkyl group or an off Eniru group having a carbon number. 1 to 3, X 2 represents a group represented nitrogen atom or = CH- with, X 3 is an oxygen atom , A sulfur atom or a nitrogen atom.) A group represented by ")
.式  Expression
— A3— X厂— A 3 — X Factory
Figure imgf000079_0002
Figure imgf000079_0002
[式中、 n6は 1〜3の整数を示し、 X4 は酸素原子または硫黄原子を示し、 R13〜 R15はそれぞれ水素原子、 ハロゲン原子、 炭素原子数 1〜 3のアルコキシ基または 炭素原子数 1〜3のアルキル基を示し、 A3 は _(CH2)n7- (式中 n7 は 0〜5の 整数を示す。 ) で示される基、 -CH2-CH=CH-CH2 で示される基または式 [In the formula, n 6 represents an integer of 1 to 3, X 4 represents an oxygen atom or a sulfur atom, and R 13 to R 15 are a hydrogen atom, a halogen atom, an alkoxy group having 1 to 3 carbon atoms or a carbon atom number, respectively. shows a 1-3 alkyl group, a 3 is _ (CH 2) n 7 - group (. wherein n 7 is represents an integer of 0 to 5) represented by, -CH 2 -CH = CH-CH 2 A group or a formula represented by
H  H
— (CH2) n「C- (CH,) ng — (CH 2 ) n “C- (CH,) n g
R16  R16
(式中、 n8、 n9はそれぞれ 0または 1を示し、 R16は炭素原子数 1〜3のアルキ ル基または - C -0- CH2 -Ph で示される基を示す。 ) で示される基を示す。 ]で示さ れる基、 (Wherein, n 8, n 9 each represent 0 or 1, R16 is alkyl group or 1 to 3 carbon atoms - a group represented by C -0- CH 2 -Ph.) Represented by Represents a group. A group represented by
•式
Figure imgf000079_0003
•formula
Figure imgf000079_0003
[式中、 。は 0〜2の整数を示し, 50 [Where,. Represents an integer from 0 to 2, 50
Figure imgf000080_0001
Figure imgf000080_0001
(式中、 nuは 1または 2を示し、 X5 および; X6 はそれぞれメチレン基または酸 素原子を示す。 ) で示される基、 または式 (Wherein, nu represents 1 or 2, X 5 and X 6 each represent a methylene group or an oxygen atom.)
Figure imgf000080_0002
Figure imgf000080_0002
(式中、 n12は 1〜5の整数を示し、 R17、 R18はそれぞれ水素原子または炭素原 子数 1〜3のアルキル基を示し、 A4 はメチレン基または酸素原子を示す。 ) ]で 示される基を示し、 (Wherein, n 12 represents an integer of 1 to 5, R17, R18 each represents a hydrogen atom or an alkyl group TansoHara terminal number 1 to 3, A 4 represents a methylene group or an oxygen atom.)] In Represents the group shown,
Zは式  Z is the expression
ΊΓ ヽ R,9 または式
Figure imgf000080_0003
ΊΓ ヽ R, 9 or expression
Figure imgf000080_0003
(式中 R 19は炭素原子数 3〜10のシクロアルキル基または炭素原子数 3〜 10の シクロアルケ二ル基を示し、 R20は炭素原子数 1〜5のアルキル基を示し、 Y—は 陰イオンを示す。 ) で示される基を示す。 } で表される化合物およびその医薬上許 容される塩。  (Wherein R 19 represents a cycloalkyl group having 3 to 10 carbon atoms or a cycloalkenyl group having 3 to 10 carbon atoms, R20 represents an alkyl group having 1 to 5 carbon atoms, and Y— represents an anion. Represents a group represented by. And a pharmaceutically acceptable salt thereof.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004094381A1 (en) * 2003-04-16 2004-11-04 Celltech R & D Limited Cyclic quaternary amino derivatives as modulators of chemokine receptors
US10464896B2 (en) 2015-06-11 2019-11-05 Basilea Pharmaceutica International AG Efflux-pump inhibitors and therapeutic uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001014333A1 (en) * 1999-08-24 2001-03-01 Astrazeneca Uk Limited Substituted piperidine compounds useful as modulators of chemokine receptor activity
EP1201239A1 (en) * 1999-08-04 2002-05-02 Teijin Limited Cyclic amine ccr3 antagonists

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1201239A1 (en) * 1999-08-04 2002-05-02 Teijin Limited Cyclic amine ccr3 antagonists
WO2001014333A1 (en) * 1999-08-24 2001-03-01 Astrazeneca Uk Limited Substituted piperidine compounds useful as modulators of chemokine receptor activity

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004094381A1 (en) * 2003-04-16 2004-11-04 Celltech R & D Limited Cyclic quaternary amino derivatives as modulators of chemokine receptors
US10464896B2 (en) 2015-06-11 2019-11-05 Basilea Pharmaceutica International AG Efflux-pump inhibitors and therapeutic uses thereof

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