Nothing Special   »   [go: up one dir, main page]

JP2005194193A - Chemokine receptor antagonistic compound - Google Patents

Chemokine receptor antagonistic compound Download PDF

Info

Publication number
JP2005194193A
JP2005194193A JP2002169884A JP2002169884A JP2005194193A JP 2005194193 A JP2005194193 A JP 2005194193A JP 2002169884 A JP2002169884 A JP 2002169884A JP 2002169884 A JP2002169884 A JP 2002169884A JP 2005194193 A JP2005194193 A JP 2005194193A
Authority
JP
Japan
Prior art keywords
group
carbon atoms
formula
atom
represented
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
JP2002169884A
Other languages
Japanese (ja)
Inventor
Masakazu Sato
正和 佐藤
Hiroki Umemiya
広樹 梅宮
Yuiko Matsunaga
結子 松永
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Taisho Pharmaceutical Co Ltd
Original Assignee
Taisho Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Taisho Pharmaceutical Co Ltd filed Critical Taisho Pharmaceutical Co Ltd
Priority to JP2002169884A priority Critical patent/JP2005194193A/en
Priority to AU2003242244A priority patent/AU2003242244A1/en
Priority to PCT/JP2003/007379 priority patent/WO2003104198A1/en
Priority to JP2004511268A priority patent/JPWO2003104198A1/en
Publication of JP2005194193A publication Critical patent/JP2005194193A/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/452—Piperidinium derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic 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
    • C07D211/36—Heterocyclic 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

<P>PROBLEM TO BE SOLVED: To provide a substance specifically inhibiting functions of a chemokine receptor. <P>SOLUTION: The compound is represented by formula A äwherein, R1 denotes an alkyl group, a cycloalkyl group, a cycloalkenyl group, a substituted cycloalkyl group, a trifluorobutyl group, a perhydronaphthyl group, a group represented by a (CH<SB>2</SB>)-C(CH<SB>3</SB>)=CH-Ph or the like; Z denotes a group represented by formula B (wherein, R19 denotes a cycloalkyl group or a cycloalkenyl group) or formula C (wherein, R19 is the same as described in formula B; R20 denotes a 1-5C alkyl group; and Y<SP>-</SP>denotes an anion)}. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

【０００１】
【発明の属する技術分野】
本発明は、白血球遊走因子であるケモカインに対する拮抗作用を有する化合物に関する。
【０００２】
【従来の技術】
Eotaxinは最も強い好酸球走化性を示すケモカインであり、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CD11b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が高親和性リガンドである。CCR3とEotaxinは、好酸球浸潤を伴うアレルギー性炎症において中心的な役割を果たしているものと考えられる。
【０００３】
気管支喘息は慢性好酸球性剥離性気管支炎として捉えられている。特徴的な好酸球の著明な浸潤以外、気管支喘息の下気道にはTリンパ球、少数ながら好塩基球の浸潤も認められている。好酸球顆粒蛋白には細胞傷害性があり、気道上皮を含む組織の傷害を惹起する。気道に集積するリンパ球は主にTh2細胞であり、Th2細胞はIL-5、IL-4などのサイトカインを産生し、好酸球増多とIgE産生を誘導することによりアレルギー性炎症の誘導、増悪化に関与していると考えられている［Crit Rev Immunol, 17, 325-52 (1997)］。
【０００４】
Eotaxinにより誘導される局所の好酸球浸潤は、IL-5の存在下で著明に増強されることが示されており、IL-5による好酸球のprimingならびにEotaxinによる好酸球遊走が気管支喘息における気道好酸球浸潤の機序である可能性が強く示唆される。また、Th2サイトカインであるIL-4によってEotaxin産生が誘導されることが報告されている。これらから、病変局所において抗原曝露により活性化されたTh2細胞からIL-4、IL-5などのサイトカインが産生され、IL-4はEotaxin産生を介して、IL-5は好酸球のprimingを介して気道好酸球浸潤に寄与している可能性が示唆される［J Immunol, 160, 3569-76 (1998); J Exp Med, 182, 1169-74,(1995); J Allergy Clin Immunol, 102, 65-74 (1998); J Immunol, 160, 60-68 (1998)］。
【０００５】
花粉症患者の鼻ポリープ及び気管支喘息患者の気道ではEotaxinの発現及びEotaxinのmRNA発現が確認されており、その産生細胞として上皮細胞、マクロファージ、Ｔ細胞、好酸球が同定されている。気管支喘息患者の気管支肺胞洗浄液では対照と比べてEotaxinが増加し、肺組織におけるEotaxin陽性細胞数は気道過敏性と有意に相関している。さらに、気管支喘息患者ではEotaxinの発現亢進と並行して、CCR3の発現も亢進している［J Clin Invest, 97, 604-12 (1996); J Immunol, 159, 4593-601 (1997); Biochem Biophys Res Commun, 236, 299-301 (1997); Eur J Immunol, 27, 3507-16 (1997)］。
【０００６】
CCR3は、特にTh2細胞に強く発現していることが知られている。鼻ポリープなどの病変部では、浸潤しているT細胞のほとんどがCCR3を発現し、その細胞が好酸球とco-localizeしている。抗原曝露により好酸球とともにCCR3陽性Th2細胞が病変局所に浸潤し、病態の増悪化につながっていることが示唆されている［Curr
Biol, 7, 836-43 (1997)］。
【０００７】
アレルギー性結膜炎の中でも重症なアトピー性角結膜炎や春季カタルでは、結膜の著明な増殖性変化による慢性的な炎症のみならず、角膜においてもしばしば上皮障害を伴う。アレルギー性結膜炎の眼瞼結膜や涙液には多数の好酸球が浸潤しており、浸潤好酸球数と重傷度との間には相関が認められている。好酸球の眼局所への浸潤には接着分子やサイトカイン、さらにケモカインの関与が考えられている。アトピー性角結膜炎や春季カタルの患者の涙液中には好酸球遊走性ケモカインであるEotaxinが検出され、Eotaxin濃度は涙液中の好酸球数と相関することが示されている［J Allergy Clin Immunol, 103, 1220-1221 (1995)］。一方、好酸球顆粒蛋白質は角膜上皮細胞への細胞障害性を有することから、角膜上皮障害の発症は、浸潤してきた好酸球などの炎症細胞による組織障害が重要な役割を担っていると考えられている。さらに、結膜及び角膜の実質細胞が、アレルギー性サイトカインであるIL-4の刺激により多量のEotaxinを産生することが報告されている［Int Arch Allergy Immunol, 121, 144-150 (2000)］。
【０００８】
従って、CCR3へのEotaxinの結合を特異的に阻害する物質は、好酸球の遊走、接着増強及び活性化を抑制し、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。
【０００９】
ケモカイン受容体の機能を阻害する物質としてはＷＯ９８／０４５５４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。
【００１０】
【発明が解決しようとする課題】
本発明は、ケモカイン受容体の機能を特異的に阻害する物質の提供を目的とする。
【００１１】
【課題を解決するための手段】
本発明者らは、課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カ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。
【００１２】
すなわち本発明は、式
【００１３】
【化１６】

Figure 2005194193
【００１４】
｛式中ｍは０〜２の整数を示し、
Ｒ1は
・炭素原子数３〜８個の直鎖状、分岐鎖状の飽和または不飽和のアルキル基、
・炭素原子数５〜８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、
・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、
・トリフルオロブチル基、
・ペルヒドロナフチル基、
・-(CH2)-C(CH3)=CH-Ph で示される基、
・シンナミル基
・式
【００１５】
【化１７】
Figure 2005194193
【００１６】
（式中、ｎ２は０〜３の整数を示し、Ｒ2、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はフェニル基、ナフチル基または炭素原子数１〜４の直鎖状、分岐鎖状の飽和もしくは不飽和のアルキル基を示し、Ｘ１は酸素原子、硫黄原子、カルボニル基またはカルボニルオキシ基を示す。）で示される基、
・式
【００１７】
【化１８】
Figure 2005194193
【００１８】
（式中ｎ３およびｎ４は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、分岐鎖状の飽和もしくは不飽和のアルキル基、炭素原子数１〜６のアルコキシ基、フェニル基、ハロゲンで置換されたフェニル基、炭素原子数３〜８のシクロアルキル基またはアリル基を示し、
【００１９】
【化１９】
Figure 2005194193
【００２０】
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」、「アダマンチル基」、「式
【００２１】
【化２０】
Figure 2005194193
【００２２】
（式中、ｎ５は１または２を示し、Ａ１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 -CH(CH3)- で示される基を示す。）で示される基」、「式
【００２３】
【化２１】
Figure 2005194193
【００２４】
（Ｒ６〜Ｒ10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、トリフルオロメチル基、トリフルオロメチルオキシ基、ベンジル基、フェネチル基、スチリル基、フェノキシ基、ベンジルオキシ基、フェニル基または炭素原子数１〜３のアルコキシカルボニル基を示す。）で示される基」または「式
【００２５】
【化２２】
Figure 2005194193
【００２６】
（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、
・式
【００２７】
【化２３】
Figure 2005194193
【００２８】
[式中、ｎ６は０〜３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
【００２９】
【化２４】
Figure 2005194193
【００３０】
（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 -CH2-O-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、
・式
【００３１】
【化２５】
Figure 2005194193
【００３２】
[式中、ｎ１０は０〜２の整数を示し、
【００３３】
【化２６】
Figure 2005194193
【００３４】
は式
【００３５】
【化２７】
Figure 2005194193
【００３６】
（式中、ｎ１１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
【００３７】
【化２８】
Figure 2005194193
【００３８】
（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、
Ｚは式
【００３９】
【化２９】
Figure 2005194193
【００４０】
または式
【００４１】
【化３０】
Figure 2005194193
【００４２】
（式中Ｒ19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のシクロアルケニル基を示し、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。
【００４３】
【発明の実施の形態】
本発明において、直鎖状、分岐鎖状の飽和または不飽和のアルキル基とは、たとえばメチル基、エチル基、n-プロピル基、イソプロピル基、n-ブチル基、イソブチル基、tert-ブチル基、n-ペンチル基、イソペンチル基、ネオペンチル基、tert-ペンチル基、n-ヘキシル基、n-ヘプチル基、n-オクチル基、ビニル基、アリル基、イソプロペニル基、ブテニル基、イソブチレニル基、イソプレニル基、アセチレニル基などの炭化水素基である。
【００４４】
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、シクロヘキシル基、シクロヘプチル基、シクロオクチル基などの環状飽和炭化水素基である。
【００４５】
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、シクロヘキセニル基、シクロヘキサジエニル基などの環状不飽和炭化水素基である。
【００４６】
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、tert-ブトキシ基、ペンチルオキシ基、ヘキシルオキシ基、アリルオキシ基などの基である。
【００４７】
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）
【００４８】
【化３１】
Figure 2005194193
【００４９】
で表される化合物と下記式（ｂ）
Ｒ19-ＣＨＯ （ｂ）
（式中、Ｒ19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）
【００５０】
【化３２】
Figure 2005194193
【００５１】
（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）
【００５２】
【化３３】
Figure 2005194193
【００５３】
（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）
【００５４】
【化３４】
Figure 2005194193
【００５５】
（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）
【００５６】
【化３５】
Figure 2005194193
【００５７】
（式中、ｍ、Ｒ19は前記と同義）で表される化合物を得、下記式（ｇ）
Ｒ1-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）
【００５８】
【化３６】
Figure 2005194193
【００５９】
（式中、ｍ、Ｒ1，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。
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）
Ｒ1-Ｌ （ｉ）
（式中、Ｒ1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、メタンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基等のアルキルスルホニルオキシ基、アリールスルホニルオキシ基等が挙げられる）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。
【００６０】
更に、上記式（ｈ）で表される化合物と下記式（ｊ）
Ｒ20-Y （ｊ）
（式中、Ｒ20およびYは前記と同義である）で表される化合物を反応させることによって下記式（ｋ）
【００６１】
【化３７】
Figure 2005194193
【００６２】
（式中、ｍ、Ｒ1，Ｒ19、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、ピペリジンの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cis体、高極性の化合物をtrans体と命名する。
【００６３】
本発明の化合物は、その置換の態様によって、光学異性体、ジアステレオ異性体、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。
【００６４】
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トリウム、炭酸カリウム、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、ジムシルナトリウム、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、トリエチルアミン、ジイソプロピルアミン、ピロリジン、ピペリジン等のアミン類、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、よう化水素酸、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、トリフルオロ酢酸等であり、還元剤とは例えば水素化ホウ素ナトリウム、シアノ水素化ホウ素ナトシウム、水素化リチウムアルミニウム、トリア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、tert−ブチルアルコール等のアルコール類、ジオキサン、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、クロロホルム、アセトン、酢酸等の反応に不活性な溶媒を用いることができる。
【００６５】
本発明の化合物は常用の増量剤、ｐＨ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。
【００６６】
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１〜１０００ｍｇを１回〜数回に分けて投与することができる。
【００６７】
【発明の効果】
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ＣＣＲ３等のケモカイン受容体に対して高い親和性を有し、ＣＣＲ３等の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ＣＣＲ３等のケモカインの受容体が関わる疾患、例えば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に対する治療又は予防のために使用することができる。
【００６８】
【実施例】
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。
実施例１
化合物８１，化合物８１'の合成
【００６９】
【化３８】
Figure 2005194193
【００７０】
（１）ピペリジン４−イル−カルバミックアシッド tert-ブチルエステル（6.00g）のテトラヒドロフラン（以下ＴＨＦと略す）（120ml）溶液にシクロオクト−１−エンカルバアルデヒド（4.97g）と酢酸（1.72ml）を加え、さらにトリア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、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。
【００７１】
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ーで酢酸エチルとヘキサンの混合溶媒を用いて精製し、（１−シクロオクト−１−エニル−メチル−ピペリジン−４−イル）−カルバミックアシッド tert-ブチルエステル（3.86g）を得た。
【００７２】
（２）（１−シクロオクト−１−エニル−メチル−ピペリジン−４−イル）−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）溶液にトリフルオロ酢酸（15ml）を氷冷下加え、室温で２時間攪拌した。溶媒を留去後、クロロホルムで希釈し、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−シクロオクト−１−エニル−メチル−ピペリジン−４−イルアミン（2.66g）を得た。
【００７３】
（３）１−シクロオクト−１−エニル−メチル−ピペリジン−４−イルアミン（2.66g）と２−ヒドロキシフェニル酢酸（2.18g）と１−ヒドロキシベンゾトリアゾール１水和物（2.75g）のジメチルホルムアミド（30ml）溶液に塩酸１−エチル−３−（３−ジメチル）カルボジイミド（3.44g）を加え、80℃で３時間攪拌した。溶媒を留去後、酢酸エチルで希釈し、食塩水で３回洗浄した。有機層を無水硫酸マグネシウムで乾燥後、溶媒を留去した。得られた残渣をＮＨ型のシリカゲル（富士シリシア化学株式会社製 Chromatorex）カラムクロマトグラフィーでメタノールとクロロホルムの混合溶媒を用いて精製し、Ｎ−（１−シクロオクト−１−エニル−メチル−ピペリジン−４−イル）−２−（２−ヒドロキシフェニル）アセトアミド（3.88g）を得た。
【００７４】
（４）フェネチルアルコール（183mg）とトリフェニルホスフィン（393mg）と40％ジエチルアゾジカルボキシレート トルエン溶液（653mg）のＴＨＦ（20ml）溶液にＮ−（１−シクロオクト−１−エニル−メチル−ピペリジン−４−イル）−２−（２−ヒドロキシフェニル）アセトアミド（357mg）を氷冷下加え、室温で３時間攪拌した。さらに、フェネチルアルコール（183mg）とトリフェニルホスフィン（393mg）と40％ジエチルアゾジカルボキシレート トルエン溶液（653mg）のＴＨＦ（10ml）溶液を加え、室温で２時間攪拌した。
【００７５】
溶媒を留去後、酢酸エチルで希釈し、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ＳＣＸ（VARIAN社製固相抽出用充填剤 BondesilＳＣＸ）に吸着させ、メタノールとクロロホルムの混合溶媒で洗浄した後、7mol/lアンモニアのメタノール溶液とクロロ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エチルとヘキサンの混合溶媒を用いて精製し、Ｎ−（１−シクロオクト−１−エニル−メチル−ピペリジン−４−イル）−２−（２−フェネチルオキシフェニル）アセトアミド（402ｍg）を得た。
【００７６】
（５）Ｎ−（１−シクロオクト−１−エニル−メチル−ピペリジン−４−イル）−２−（２−フェネチルオキシフェニル）アセトアミド（2.15g）にヨウ化メチル（20ml）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ーでメタノールとクロロ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８１）（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８１'）（0.38g）を得た。
化合物８１ 1H NMR (300 MHz, CHLOROFORM-D) d ppm 1.35-1.72 (m, 8 H) 1.78-1.94 (m, 2 H) 2.11-2.41 (m, 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８１' 1H NMR (200 MHz, CHLOROFORM-D) d ppm 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)
【００７７】
実施例
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体の化合物のデーターを示した。
【００７８】
【表１】
Figure 2005194193
【００７９】
【表２】
Figure 2005194193
【００８０】
【表３】
Figure 2005194193
【００８１】
【表４】
Figure 2005194193
【００８２】
【表５】
Figure 2005194193
【００８３】
【表６】
Figure 2005194193
【００８４】
【表７】
Figure 2005194193
【００８５】
【表８】
Figure 2005194193
【００８６】
【表９】
Figure 2005194193
【００８７】
【表１０】
Figure 2005194193
【００８８】
【表１１】
Figure 2005194193
【００８９】
【表１２】
Figure 2005194193
【００９０】
【表１３】
Figure 2005194193
【００９１】
【表１４】
Figure 2005194193
【００９２】
【表１５】
Figure 2005194193
【００９３】
【表１６】
Figure 2005194193
【００９４】
【表１７】
Figure 2005194193
【００９５】
【表１８】
Figure 2005194193
【００９６】
【表１９】
Figure 2005194193
【００９７】
【表２０】
Figure 2005194193
【００９８】
【表２１】
Figure 2005194193
【００９９】
【表２２】
Figure 2005194193
【０１００】
【表２３】
Figure 2005194193
【０１０１】
【表２４】
Figure 2005194193
【０１０２】
【表２５】
Figure 2005194193
【０１０３】
【表２６】
Figure 2005194193
【０１０４】
【表２７】
Figure 2005194193
【０１０５】
【表２８】
Figure 2005194193
【０１０６】
【表２９】
Figure 2005194193
【０１０７】
【表３０】
Figure 2005194193
【０１０８】
【表３１】
Figure 2005194193
【０１０９】
【表３２】
Figure 2005194193
【０１１０】
【表３３】
Figure 2005194193
【０１１１】
試験例１
CCR3受容体結合阻害試験
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、室温で遠心し、多核球層を得た。この多核球層をPBS(−)で希釈し、1200rpm、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(−)／2mM EDTA／0.5% BSAに懸濁し、CD16マイクロビーズ（第一化学社製）を添加して、6〜12℃で30分間インキュベートした後、MACSカラム（第一化学製）に流して、通過した細胞液を回収し、好酸球を得た。
【０１１２】
ヒト末梢血から分離した好酸球、0.1nM [125I] human Eotaxin（2000Ci/mmol、Amersham Biosciences 製）及び被験化合物を0.1mlの50mM HEPES／5mM MgCl2／1mM CaCl2／0.5% BSA（pH 7.2）に懸濁し、37℃、90分間インキュベートした後、予め0.5%ポリエチレンイミン（pH 7.2）に浸しておいたグラスフィルターGF/Cにて濾過を行い、1.5mlのPBS(−)／0.5M 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（IC50値）を算出した。
【０１１３】
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。
【０１１４】
試験例２
ラット好酸球遊走試験
Brown Norway Ratの腹腔にウマ血清を1ml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ー（ポアアイズ5μm、家田貿易 製）の下室にヒトEotaxin（100nM）及び被験化合物を30μlのRPMI1640／1% FCSに調製し、フィルターをのせ、上室に50μlのRPMI1640／1% FCSに懸濁したラット好酸球を添加した。37℃、2時間インキュベートした後、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。
【０１１５】
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（100nM）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。
【０１１６】
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。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a compound having an antagonistic action against a chemokine that is a leukocyte migration factor.
[0002]
[Prior art]
Eotaxin is a chemokine that exhibits the strongest eosinophil chemotaxis, not only acting on the mobilization of eosinophils from bone marrow to peripheral blood, but also eosinophils such as eosinophil degranulation and active enzyme production Promote the activation. It also induces the expression of eosinophil adhesion molecule receptor CD11b and the expression of vascular endothelial cell adhesion molecules ICAM-1 and VCAM-1 to enhance the adhesion of eosinophils. On the other hand, CCR3 is a G protein-coupled receptor cloned from eosinophils and expressed in eosinophils, basophils, and Th2 cells, and Eotaxin is a high affinity ligand. CCR3 and Eotaxin are thought to play a central role in allergic inflammation with eosinophil infiltration.
[0003]
Bronchial asthma is seen as chronic eosinophilic exfoliative bronchitis. In addition to the characteristic infiltration of eosinophils, infiltration of T lymphocytes and a small number of basophils is also observed in the lower respiratory tract of bronchial asthma. Eosinophil granule proteins are cytotoxic and cause damage to tissues including airway epithelium. Lymphocytes that accumulate in the respiratory tract are mainly Th2 cells, which produce cytokines such as IL-5 and IL-4, and induce allergic inflammation by inducing eosinophilia and IgE production, It is thought to be involved in exacerbations [Crit Rev Immunol, 17, 325-52 (1997)].
[0004]
Eotaxin-induced local eosinophil infiltration has been shown to be markedly enhanced in the presence of IL-5, and eosinophil priming by IL-5 and eosinophil migration by Eotaxin The possibility of airway eosinophil infiltration in bronchial asthma is strongly suggested. It has also been reported that Eotaxin production is induced by IL-4, a Th2 cytokine. From these, cytokines such as IL-4 and IL-5 are produced from Th2 cells activated by antigen exposure in the lesion area, IL-4 is mediated by Eotaxin production, IL-5 is eosinophil priming This suggests that it may contribute to airway eosinophil infiltration [J Immunol, 160, 3569-76 (1998); J Exp Med, 182, 1169-74, (1995); J Allergy Clin Immunol, 102, 65-74 (1998); J Immunol, 160, 60-68 (1998)].
[0005]
Eotaxin expression and Eotaxin mRNA expression have been confirmed in nasal polyps of hay fever patients and bronchial asthma patients, and epithelial cells, macrophages, T cells, and eosinophils have been identified as production cells. Eotaxin increased in bronchoalveolar lavage fluid of patients with bronchial asthma compared to controls, and the number of Eotaxin positive cells in lung tissue was significantly correlated with airway hyperresponsiveness. Furthermore, in patients with bronchial asthma, the expression of CCR3 is also enhanced in parallel with the increased expression of Eotaxin [J Clin Invest, 97, 604-12 (1996); J Immunol, 159, 4593-601 (1997); Biochem Biophys Res Commun, 236, 299-301 (1997); Eur J Immunol, 27, 3507-16 (1997)].
[0006]
CCR3 is known to be particularly strongly expressed in Th2 cells. In lesions such as nasal polyps, most infiltrating T cells express CCR3, which co-localize with eosinophils. It has been suggested that CCR3-positive Th2 cells infiltrated with lesions together with eosinophils due to antigen exposure, leading to aggravation of the disease state [Curr
Biol, 7, 836-43 (1997)].
[0007]
Among allergic conjunctivitis, severe atopic keratoconjunctivitis and spring catarrh are often accompanied by epithelial damage not only in chronic inflammation due to proliferative changes in the conjunctiva but also in the cornea. Many eosinophils infiltrate the eyelid conjunctiva and tears of allergic conjunctivitis, and there is a correlation between the number of infiltrating eosinophils and the degree of serious injury. Involvement of eosinophils into the local area of the eye is thought to involve adhesion molecules, cytokines, and chemokines. Eotaxin, an eosinophil migrating chemokine, was detected in tears of patients with atopic keratoconjunctivitis and spring catarrh, and Eotaxin concentration has been shown to correlate with the number of eosinophils in tears [J Allergy Clin Immunol, 103, 1220-1221 (1995)]. On the other hand, since eosinophil granule protein has cytotoxicity to corneal epithelial cells, the onset of corneal epithelial disorder is due to tissue damage caused by inflammatory cells such as infiltrating eosinophils. It is considered. Furthermore, it has been reported that conjunctival and corneal parenchymal cells produce a large amount of Eotaxin by stimulation with IL-4, an allergic cytokine [Int Arch Allergy Immunol, 121, 144-150 (2000)].
[0008]
Therefore, a substance that specifically inhibits the binding of Eotaxin to CCR3 suppresses eosinophil migration, adhesion enhancement and activation, and is used to treat or prevent allergic diseases such as bronchial asthma and allergic conjunctivitis. Therefore, it is considered useful as a pharmaceutical product.
[0009]
Although the substance which inhibits the function of a chemokine receptor is described in WO98 / 04554 etc., the compound of this invention is not known.
[0010]
[Problems to be solved by the invention]
An object of the present invention is to provide a substance that specifically inhibits the function of a chemokine receptor.
[0011]
[Means for Solving the Problems]
As a result of various studies to solve the problems, the present inventors have found that certain compounds specifically inhibit the function of chemokine receptors, and completed the present invention.
[0012]
That is, the present invention has the formula
Embedded image
Figure 2005194193
[0014]
{Wherein m represents an integer of 0 to 2,
R1 is a linear or branched saturated or unsaturated alkyl group having 3 to 8 carbon atoms,
A cycloalkyl group having 5 to 8 carbon atoms,
A cycloalkenyl group having 5 to 8 carbon atoms,
A C1-C6 alkyl group, a C3-C8 cycloalkyl group, or a C5-C8 cycloalkyl group substituted with a phenyl group,
・ Trifluorobutyl group,
A perhydronaphthyl group,
A group represented by-(CH 2 ) -C (CH 3 ) = CH-Ph,
・ Cinnamil group ・ Formula [0015]
Embedded image
Figure 2005194193
[0016]
(Wherein, n 2 represents an integer of 0 to 3, R2, R3 indicates each hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R4 is a phenyl group, a naphthyl group or a 1 to 4 carbon atoms A linear or branched saturated or unsaturated alkyl group, and X 1 represents an oxygen atom, a sulfur atom, a carbonyl group or a carbonyloxy group).
・ Formula 【0017】
Embedded image
Figure 2005194193
[0018]
(Wherein n 3 and n 4 represent an integer of 0 to 3, R 5 represents a hydrogen atom, a linear or branched saturated or unsaturated alkyl group having 1 to 4 carbon atoms, 1 to 6 an alkoxy group, a phenyl group, a phenyl group substituted with a halogen, a cycloalkyl group having 3 to 8 carbon atoms, or an allyl group,
[0019]
Embedded image
Figure 2005194193
[0020]
Is “unsubstituted or substituted with 1 to 3 carbon atoms alkyl group having 1 to 3 carbon atoms”, “cycloalkenyl group with 5 to 8 carbon atoms”, “unsubstituted Or a naphthyl group substituted with an alkoxy group having 1 to 3 carbon atoms ”,“ adamantyl group ”,“ formula
Embedded image
Figure 2005194193
[0022]
(In the formula, n 5 represents 1 or 2, A 1 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 —CH (CH 3 ) a group represented by-), a group represented by the following formula:
Embedded image
Figure 2005194193
[0024]
(R6 to R10 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, and trifluoromethyl. An oxy group, a benzyl group, a phenethyl group, a styryl group, a phenoxy group, a benzyloxy group, a phenyl group, or an alkoxycarbonyl group having 1 to 3 carbon atoms)) or a group represented by the formula:
Embedded image
Figure 2005194193
[0026]
(Wherein, R11 and R12 each represent a hydrogen atom, an alkyl group or a phenyl group having 1 to 3 carbon atoms, X 2 represents a group represented nitrogen atom or = CH- with, X 3 is an oxygen atom, a sulfur A group represented by “a group represented by an atom or a nitrogen atom”),
・ Formula [0027]
Embedded image
Figure 2005194193
[0028]
[Wherein n 6 represents an integer of 0 to 3, X 4 represents an oxygen atom or a sulfur atom, R 13 to R 15 represent a hydrogen atom, a halogen atom, an alkoxy group having 1 to 3 carbon atoms, or the number of carbon atoms, respectively. 1 to 3 alkyl groups, A 3 is a group represented by — (CH 2 ) n 7 — (wherein n 7 represents an integer of 0 to 5), —CH 2 —CH═CH—CH 2 A group represented by the formula:
Embedded image
Figure 2005194193
[0030]
(Wherein n 8 and n 9 each represents 0 or 1, and R 16 represents an alkyl group having 1 to 3 carbon atoms or a group represented by —CH 2 —O—CH 2 —Ph). Indicates a group. A group represented by
・ Formula [0031]
Embedded image
Figure 2005194193
[0032]
[Wherein n 10 represents an integer of 0 to 2,
[0033]
Embedded image
Figure 2005194193
[0034]
Is the formula
Embedded image
Figure 2005194193
[0036]
Wherein n 11 represents 1 or 2, and X 5 and X 6 each represent a methylene group or an oxygen atom, or a group represented by the formula:
Embedded image
Figure 2005194193
[0038]
(Wherein n 12 represents an integer of 1 to 5, R 17 and R 18 each represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and A 4 represents a methylene group or an oxygen atom)]. Group
Z is the formula [0039]
Embedded image
Figure 2005194193
[0040]
Or the formula [0041]
Embedded image
Figure 2005194193
[0042]
(In the formula, R 19 represents a cycloalkyl group having 3 to 10 carbon atoms or a cycloalkenyl group having 3 to 10 carbon atoms, R 20 represents an alkyl group having 1 to 5 carbon atoms, and Y − represents an anion. )). } And pharmaceutically acceptable salts thereof.
[0043]
DETAILED DESCRIPTION OF THE INVENTION
In the present invention, a linear or branched saturated or unsaturated alkyl group is, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, tert-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, vinyl group, allyl group, isopropenyl group, butenyl group, isobutenyl group, isoprenyl group, A hydrocarbon group such as an acetylenyl group;
[0044]
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.
[0045]
In the present invention, the cycloalkenyl group is a cyclic unsaturated hydrocarbon group such as a cyclopentenyl group, a cyclohexenyl group, or a cyclohexadienyl group.
[0046]
In the present invention, the alkoxy group is a group such as 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, and an allyloxy group. is there.
[0047]
The compound of this invention is compoundable by the method shown below, for example. That is, the following formula (a)
[0048]
Embedded image
Figure 2005194193
[0049]
And a compound represented by the following formula (b)
R19-CHO (b)
(Wherein R19 is as defined above), a reductive alkylation reaction is carried out in the presence of a reducing agent, and the following formula (c):
[0050]
Embedded image
Figure 2005194193
[0051]
(Wherein R19 is as defined above), and further hydrolyzed by a commonly used method such as mineral acid or organic acid treatment, whereby the following formula (d)
[0052]
Embedded image
Figure 2005194193
[0053]
(Wherein R19 is as defined above) or a salt thereof, and then the following formula (e)
[0054]
Embedded image
Figure 2005194193
[0055]
(Wherein m is as defined above) or a salt thereof is used for condensation by an ordinary method for forming an amide bond, and the following formula (f)
[0056]
Embedded image
Figure 2005194193
[0057]
(Wherein, m and R19 are as defined above) to obtain a compound represented by the following formula (g)
R1-OH (g)
(Wherein R1 is as defined above) and an ether bond formed by Mitsunobu reaction with the compound represented by the following formula (h)
[0058]
Embedded image
Figure 2005194193
[0059]
(Wherein m, R 1 and R 19 are the same as defined above) can be synthesized.
In addition, the compound of the present invention represented by the above formula (h) includes the compound represented by the above formula (f) or a salt thereof, and the following formula (i):
R1-L (i)
(Wherein R1 has the same meaning as described above, and L represents a leaving group, where 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-toluene). It can also be synthesized by reacting in the presence of a base a compound represented by an alkylsulfonyloxy group such as a sulfonyloxy group, and an arylsulfonyloxy group.
[0060]
Furthermore, the compound represented by the above formula (h) and the following formula (j)
R20-Y (j)
(Wherein R20 and Y have the same meanings as described above) to react with a compound represented by the following formula (k)
[0061]
Embedded image
Figure 2005194193
[0062]
(Wherein m, R 1, R 19 and R 20 have the same meanings as described above) can be synthesized. At this time, cis and trans isomers are generated at the 1- and 4-positions of piperidine. For convenience, a low-polar compound is named cis-form and a high-polar compound is named trans-form.
[0063]
The compound of the present invention may have stereoisomers such as optical isomers, diastereoisomers, geometric isomers and the like depending on the mode of substitution. And mixtures thereof.
[0064]
Examples of the base when a base is used in the above reaction include alkali metal salts such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, dimmyl sodium, sodium hydride, sodium amide, tert-butyl potassium, etc. , Amines such as triethylamine, diisopropylamine, pyrrolidine and piperidine, sodium acetate, potassium acetate and the like, and the mineral acid is, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, etc. Examples of the organic acid include acetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, and the like. Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, triacetoxyhydrogenation. Sodium boron and the like. Reaction solvents include water, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and other alcohols, dioxane, tetrahydrofuran and other ethers, dimethylformamide, dimethyl sulfoxide, pyridine, methylene chloride, chloroform, acetone, acetic acid and the like. An inert solvent can be used.
[0065]
The compound of the present invention is added with a usual bulking agent, pH adjusting agent, solubilizing agent, and the like, and tablets, granules, pills, capsules, powders, liquids, suspensions, injections, eye drops by conventional pharmaceutical techniques. And can be administered by routes such as oral, injection, and eye drops.
[0066]
When the compound of the present invention is used as a chemokine receptor action inhibitor, the dose varies depending on body weight, age, sex, etc., but is usually 1 to 1000 mg per day for adult patients once to several times. Can be administered separately.
[0067]
【The invention's effect】
The compound of the present invention has a high affinity for chemokine receptors such as CCR3, which play an important role in eosinophil infiltration, and inhibits the action of chemokine receptors such as CCR3. It can be used for the treatment or prevention of diseases involving chemokine receptors such as CCR3 in animals, such as bronchial asthma and allergic conjunctivitis.
[0068]
【Example】
Hereinafter, the present invention will be described in more detail with reference to examples and test examples.
Example 1
Synthesis of Compound 81 and Compound 81 ′
Embedded image
Figure 2005194193
[0070]
(1) Piperidine-4-yl-carbamic acid tert-butyl ester (6.00 g) in tetrahydrofuran (hereinafter abbreviated as THF) (120 ml) was added cyclooct-1-enecarbaldehyde (4.97 g) and acetic acid (1.72 ml). Furthermore, sodium triacetoxyborohydride (8.25 g) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off, the residue was diluted with ether and washed successively with 2 mol / l aqueous sodium hydroxide solution and brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off.
[0071]
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-piperidin-4-yl) -carbamic acid tert-butyl ester ( 3.86 g) was obtained.
[0072]
(2) (1-Cyclooct-1-enyl-methyl-piperidin-4-yl) -carbamic acid tert-butyl ester (3.86 g) in methylene chloride (15 ml) with trifluoroacetic acid (15 ml) under ice cooling The mixture was further stirred at room temperature for 2 hours. After the solvent was distilled off, the residue was diluted with chloroform and washed with a 2 mol / l aqueous sodium hydroxide solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain unpurified 1-cyclooct-1-enyl-methyl-piperidin-4-ylamine (2.66 g).
[0073]
(3) Dimethylformamide of 1-cyclooct-1-enyl-methyl-piperidin-4-ylamine (2.66 g), 2-hydroxyphenylacetic acid (2.18 g) and 1-hydroxybenzotriazole monohydrate (2.75 g) ( 30 ml) 1-ethyl-3- (3-dimethyl) carbodiimide hydrochloride (3.44 g) was added to the solution and stirred at 80 ° C. for 3 hours. After the solvent was distilled off, it was diluted with ethyl acetate and washed 3 times with brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by NH-type silica gel (Chromatorex, manufactured by Fuji Silysia Chemical Ltd.) column chromatography using a mixed solvent of methanol and chloroform, and N- (1-cyclooct-1-enyl-methyl-piperidine-4). -Il) -2- (2-hydroxyphenyl) acetamide (3.88 g) was obtained.
[0074]
(4) Phenethyl alcohol (183 mg), triphenylphosphine (393 mg) and 40% diethyl azodicarboxylate Toluene solution (653 mg) in THF (20 ml) was added N- (1-cyclooct-1-enyl-methyl-piperidine- 4-yl) -2- (2-hydroxyphenyl) acetamide (357 mg) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. Further, phenethyl alcohol (183 mg), triphenylphosphine (393 mg) and a 40% diethylazodicarboxylate toluene solution (653 mg) in THF (10 ml) were added, and the mixture was stirred at room temperature for 2 hours.
[0075]
After the solvent was distilled off, the residue was diluted with ethyl acetate and washed successively with 2 mol / l aqueous sodium hydroxide solution and brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was adsorbed on SCX (Varians' solid phase extraction filler Bondesil SCX), washed with a mixed solvent of methanol and chloroform, and then eluted with a mixed solvent of 7 mol / l ammonia in methanol and chloroform. The solvent was distilled off, and the residue was purified by NH-type silica gel flash column chromatography using a mixed solvent of ethyl acetate and hexane, and N- (1-cyclooct-1-enyl-methyl-piperidin-4-yl)- 2- (2-phenethyloxyphenyl) acetamide (402 mg) was obtained.
[0076]
(5) Methyl iodide (20 ml) was added to N- (1-cyclooct-1-enyl-methyl-piperidin-4-yl) -2- (2-phenethyloxyphenyl) acetamide (2.15 g) and mixed at room temperature. Stir overnight. The solvent was distilled off, the residue was purified by silica gel column chromatography using a mixed solvent of methanol and chloroform, the solvent of the fraction containing a low-polarity compound (cis form) having a high Rf value was distilled off, and the title compound ( Compound 81) (2.25 g) in the table was obtained. Further, the solvent of the fraction containing a highly polar compound (trans form) having a low Rf value was distilled off to obtain the title compound (compound 81 ′ in the table) (0.38 g).
Compound 81 1H NMR (300 MHz, CHLOROFORM-D) d ppm 1.35-1.72 (m, 8 H) 1.78-1.94 (m, 2 H) 2.11-2.41 (m, 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 81 '1H NMR (200 MHz, CHLOROFORM-D) d ppm 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)
[0077]
The same operations as in Example 1 were performed using the corresponding raw materials, and the compounds shown in the following table were obtained. The table shows data for cis compounds.
[0078]
[Table 1]
Figure 2005194193
[0079]
[Table 2]
Figure 2005194193
[0080]
[Table 3]
Figure 2005194193
[0081]
[Table 4]
Figure 2005194193
[0082]
[Table 5]
Figure 2005194193
[0083]
[Table 6]
Figure 2005194193
[0084]
[Table 7]
Figure 2005194193
[0085]
[Table 8]
Figure 2005194193
[0086]
[Table 9]
Figure 2005194193
[0087]
[Table 10]
Figure 2005194193
[0088]
[Table 11]
Figure 2005194193
[0089]
[Table 12]
Figure 2005194193
[0090]
[Table 13]
Figure 2005194193
[0091]
[Table 14]
Figure 2005194193
[0092]
[Table 15]
Figure 2005194193
[0093]
[Table 16]
Figure 2005194193
[0094]
[Table 17]
Figure 2005194193
[0095]
[Table 18]
Figure 2005194193
[0096]
[Table 19]
Figure 2005194193
[0097]
[Table 20]
Figure 2005194193
[0098]
[Table 21]
Figure 2005194193
[0099]
[Table 22]
Figure 2005194193
[0100]
[Table 23]
Figure 2005194193
[0101]
[Table 24]
Figure 2005194193
[0102]
[Table 25]
Figure 2005194193
[0103]
[Table 26]
Figure 2005194193
[0104]
[Table 27]
Figure 2005194193
[0105]
[Table 28]
Figure 2005194193
[0106]
[Table 29]
Figure 2005194193
[0107]
[Table 30]
Figure 2005194193
[0108]
[Table 31]
Figure 2005194193
[0109]
[Table 32]
Figure 2005194193
[0110]
[Table 33]
Figure 2005194193
[0111]
Test example 1
CCR3 receptor binding inhibition test Mono-poly separation liquid (manufactured by Dainippon Pharmaceutical Co., Ltd.) was layered with human peripheral blood, and centrifuged at 1500 rpm for 20 minutes at room temperature to obtain a multinucleated cell layer. This polynuclear sphere layer was diluted with PBS (−), centrifuged at 1200 rpm for 5 minutes, and the precipitated cells were suspended in sterile water for hemolysis. The same amount of 1.8% NaCl aqueous solution as sterilized water was added, centrifuged at 1200 rpm for 5 minutes, and the precipitated cells were washed once with PBS (−). After suspending in ice-cooled PBS (−) / 2 mM EDTA / 0.5% BSA, adding CD16 microbeads (Daiichi Kagaku) and incubating at 6-12 ° C. for 30 minutes, MACS column (Daiichi Kagaku) And passed cell fluid was collected to obtain eosinophils.
[0112]
Eosinophils isolated from human peripheral blood, 0.1nM [125 I] human Eotaxin (2000Ci / mmol, Amersham Biosciences Ltd.) and test compounds in 0.1ml 50mM HEPES / 5mM MgCl 2 / 1mM CaCl 2 /0.5% BSA (pH 7.2) and incubated at 37 ° C. for 90 minutes, followed by filtration with a glass filter GF / C previously soaked in 0.5% polyethyleneimine (pH 7.2), and 1.5 ml of PBS (−) / 0.5M After washing with NaCl / 0.05% BSA, the radioactivity on the glass filter was measured. For binding affinity for CCR3, 50% binding inhibitory concentration (IC 50 value) of [ 125 I] human Eotaxin by various concentrations of compounds was calculated.
[0113]
As a result, it was found that the compound of the present invention has an excellent effect.
[0114]
Test example 2
Rat eosinophil migration test
1 ml of horse serum was administered to the abdominal cavity of Brown Norway Rat, and after 48 hours, the abdominal cavity was washed with HBSS to collect cells. 65% Percoll (manufactured by Amersham Biosciences), 50% Percoll, and the collected intraperitoneal cells 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 then suspended in RPMI 1640/1% FCS to obtain rat eosinophils.
Prepare human Eotaxin (100 nM) and test compound in 30 μl RPMI1640 / 1% FCS in the lower chamber of a 96-well chemotaxis chamber (Pore Eyes 5 μm, manufactured by Ieda Trading Co., Ltd.) Rat eosinophils suspended in% FCS were added. After incubating at 37 ° C. for 2 hours, the filter was removed, and the number of cells migrated to the lower chamber was measured.
[0115]
The effect of the test compound on the migration of rat eosinophils was calculated as the inhibition rate (%) of migration into the lower chamber by adding the test compound to human Eotaxin (100 nM).
[0116]
As a result, it was found that the compound of the present invention has an excellent effect.

Claims (1)

式
Figure 2005194193
｛式中ｍは０〜２の整数を示し、
Ｒ1は
・炭素原子数３〜８個の直鎖状、分岐鎖状の飽和または不飽和のアルキル基、
・炭素原子数５〜８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、
・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、
・トリフルオロブチル基、
・ペルヒドロナフチル基、
・-(CH2)-C(CH3)=CH-Ph で示される基、
・シンナミル基
・式
Figure 2005194193
（式中、ｎ２は０〜３の整数を示し、Ｒ2、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はフェニル基、ナフチル基または炭素原子数１〜４の直鎖状、分岐鎖状の飽和もしくは不飽和のアルキル基を示し、Ｘ１は酸素原子、硫黄原子、カルボニル基またはカルボニルオキシ基を示す。）で示される基、
・式
Figure 2005194193
（式中ｎ３およびｎ４は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、分岐鎖状の飽和もしくは不飽和のアルキル基、炭素原子数１〜６のアルコキシ基、フェニル基、ハロゲンで置換されたフェニル基、炭素原子数３〜８のシクロアルキル基またはアリル基を示し、
Figure 2005194193
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」、「アダマンチル基」、「式
Figure 2005194193
（式中、ｎ５は１または２を示し、Ａ１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 -CH(CH3)- で示される基を示す。）で示される基」、「式
Figure 2005194193
（Ｒ６〜Ｒ10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、トリフルオロメチル基、トリフルオロメチルオキシ基、ベンジル基、フェネチル基、スチリル基、フェノキシ基、ベンジルオキシ基、フェニル基または炭素原子数１〜３のアルコキシカルボニル基を示す。）で示される基」または「式
Figure 2005194193
（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、
・式
Figure 2005194193
[式中、ｎ６は０〜３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
Figure 2005194193
（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 -CH2-O-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、
・式
Figure 2005194193
[式中、ｎ１０は０〜２の整数を示し、
Figure 2005194193
は式
Figure 2005194193
（式中、ｎ１１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
Figure 2005194193
（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、
Ｚは式
Figure 2005194193
または式
Figure 2005194193
（式中Ｒ19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のシクロアルケニル基を示し、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。formula
Figure 2005194193
 {Wherein m represents an integer of 0 to 2,
R1 is a linear or branched saturated or unsaturated alkyl group having 3 to 8 carbon atoms,
A cycloalkyl group having 5 to 8 carbon atoms,
A cycloalkenyl group having 5 to 8 carbon atoms,
An alkyl group having 1 to 6 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,
・ Trifluorobutyl group,
A perhydronaphthyl group,
A group represented by-(CH 2 ) -C (CH 3 ) = CH-Ph,
・ Cinnamil group ・ Formula
Figure 2005194193
 (Wherein, n 2 represents an integer of 0 to 3, R2, R3 indicates each hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R4 is a phenyl group, a naphthyl group or a 1 to 4 carbon atoms A linear or branched saturated or unsaturated alkyl group, and X 1 represents an oxygen atom, a sulfur atom, a carbonyl group or a carbonyloxy group).
·formula
Figure 2005194193
 (Wherein n 3 and n 4 represent an integer of 0 to 3, R 5 represents a hydrogen atom, a linear or branched saturated or unsaturated alkyl group having 1 to 4 carbon atoms, 1 to 6 an alkoxy group, a phenyl group, a phenyl group substituted with a halogen, a cycloalkyl group having 3 to 8 carbon atoms, or an allyl group,
Figure 2005194193
 Is “unsubstituted or substituted with 1 to 3 carbon atoms alkyl group having 1 to 3 carbon atoms”, “cycloalkenyl group with 5 to 8 carbon atoms”, “unsubstituted Or a naphthyl group substituted with an alkoxy group having 1 to 3 carbon atoms ”,“ adamantyl group ”,“ formula
Figure 2005194193
 (In the formula, n 5 represents 1 or 2, A 1 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 —CH (CH 3 ) a group represented by-), a group represented by
Figure 2005194193
 (R6 to R10 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, and trifluoromethyl. An oxy group, a benzyl group, a phenethyl group, a styryl group, a phenoxy group, a benzyloxy group, a phenyl group, or an alkoxycarbonyl group having 1 to 3 carbon atoms.
Figure 2005194193
 (Wherein, R11 and R12 each represent a hydrogen atom, an alkyl group or a phenyl group having 1 to 3 carbon atoms, X 2 represents a group represented nitrogen atom or = CH- with, X 3 is an oxygen atom, a sulfur A group represented by “a group represented by an atom or a nitrogen atom”),
·formula
Figure 2005194193
 [Wherein n 6 represents an integer of 0 to 3, X 4 represents an oxygen atom or a sulfur atom, R 13 to R 15 represent a hydrogen atom, a halogen atom, an alkoxy group having 1 to 3 carbon atoms, or the number of carbon atoms, respectively. 1 to 3 alkyl groups, A 3 is a group represented by — (CH 2 ) n 7 — (wherein n 7 represents an integer of 0 to 5), —CH 2 —CH═CH—CH 2 -Group or formula
Figure 2005194193
 (Wherein n 8 and n 9 each represents 0 or 1, and R 16 represents an alkyl group having 1 to 3 carbon atoms or a group represented by —CH 2 —O—CH 2 —Ph). Indicates a group. A group represented by
·formula
Figure 2005194193
 [Wherein n 10 represents an integer of 0 to 2,
Figure 2005194193
 Is an expression
Figure 2005194193
 (Wherein n 11 represents 1 or 2, X 5 and X 6 each represent a methylene group or an oxygen atom), or a formula
Figure 2005194193
 (Wherein n 12 represents an integer of 1 to 5, R 17 and R 18 each represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and A 4 represents a methylene group or an oxygen atom)]. Group
Z is the formula
Figure 2005194193
 Or expression
Figure 2005194193
 (In the formula, R 19 represents a cycloalkyl group having 3 to 10 carbon atoms or a cycloalkenyl group having 3 to 10 carbon atoms, R 20 represents an alkyl group having 1 to 5 carbon atoms, and Y − represents an anion. )). And a pharmaceutically acceptable salt thereof.
JP2002169884A 2002-06-11 2002-06-11 Chemokine receptor antagonistic compound Pending JP2005194193A (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2002169884A JP2005194193A (en) 2002-06-11 2002-06-11 Chemokine receptor antagonistic compound
AU2003242244A AU2003242244A1 (en) 2002-06-11 2003-06-10 Chemokine receptor antagonist
PCT/JP2003/007379 WO2003104198A1 (en) 2002-06-11 2003-06-10 Chemokine receptor antagonist
JP2004511268A JPWO2003104198A1 (en) 2002-06-11 2003-06-10 Chemokine receptor antagonist compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP2002169884A JP2005194193A (en) 2002-06-11 2002-06-11 Chemokine receptor antagonistic compound

Publications (1)

Publication Number Publication Date
JP2005194193A true JP2005194193A (en) 2005-07-21

Family

ID=29727750

Family Applications (2)

Application Number Title Priority Date Filing Date
JP2002169884A Pending JP2005194193A (en) 2002-06-11 2002-06-11 Chemokine receptor antagonistic compound
JP2004511268A Pending JPWO2003104198A1 (en) 2002-06-11 2003-06-10 Chemokine receptor antagonist compound

Family Applications After (1)

Application Number Title Priority Date Filing Date
JP2004511268A Pending JPWO2003104198A1 (en) 2002-06-11 2003-06-10 Chemokine receptor antagonist compound

Country Status (3)

Country Link
JP (2) JP2005194193A (en)
AU (1) AU2003242244A1 (en)
WO (1) WO2003104198A1 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0308801D0 (en) * 2003-04-16 2003-05-21 Celltech R&D Ltd Chemical compounds
CN107709314A (en) 2015-06-11 2018-02-16 巴斯利尔药物国际股份公司 Efflux pump inhibitor and its therapeutic use

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100667645B1 (en) * 1999-08-04 2007-02-28 데이진 가부시키가이샤 Cyclic amine ccr3 antagonists
SE9902987D0 (en) * 1999-08-24 1999-08-24 Astra Pharma Prod Novel compounds

Also Published As

Publication number Publication date
JPWO2003104198A1 (en) 2005-12-22
WO2003104198A1 (en) 2003-12-18
AU2003242244A1 (en) 2003-12-22

Similar Documents

Publication Publication Date Title
TWI827590B (en) PRODRUGS OF FUSED-BICYCLIC C5aR ANTAGONISTS
US10676438B2 (en) KCNQ2-5 channel activator
WO2023029380A1 (en) Novel aryl ether substituted heterocyclic compound as glp1r agonist
KR20100110361A (en) Compounds having crth2 antagonist activity
JP2004307440A (en) 2-amino-1,3-propanediol derivative and its addition salt
CN1438991A (en) Cyclopentyl-substituted glutaramide derivatives as inhibitors of neutral endopeptidase
JP6529575B2 (en) Substituted oxetanes and their use as inhibitors of cathepsin C
JP2010208945A (en) Heterocyclic compound
CN103958505A (en) Disubstituted 3,4-diamino-3-cyclobutene-1,2-dione compounds for use in the treatment of chemokine-mediated pathologies
TW200305417A (en) Chemical compounds
US5703106A (en) Antagonists of endothelin receptors
JP2001089448A (en) Amide derivative
EP1238970B1 (en) Cycloamine ccr5 receptor antagonists
TW200407140A (en) Chemical compounds
JP6197971B1 (en) KCNQ2-5 channel-related disease prevention and / or treatment agent
JPH07500604A (en) Ethylalanine aminodiol compound for hypertension treatment
JPH09500656A (en) Tricyclic derivatives, pharmaceutical compositions containing them
JP2005194193A (en) Chemokine receptor antagonistic compound
JP2001520225A (en) Arylpiperazines as serotonin reuptake inhibitors and 5-HT1Dα antagonists
JPH03505583A (en) Aminoalkylaminocarbonylaminodiol amino acid derivatives as antihypertensive agents
JP2010126496A (en) Heterocyclic compound
US20030225288A1 (en) Imidazolidine compounds
JPWO2017183723A1 (en) KCNQ2-5 channel activator
KR100806478B1 (en) Formamide derivatives useful as adrenoceptor
JP6265313B1 (en) Crystalline polymorph of KCNQ2-5 channel activator