JP2011088826A - Aromatic carboxylic acid compound - Google Patents

Aromatic carboxylic acid compound Download PDF

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Publication number
JP2011088826A
JP2011088826A JP2008022136A JP2008022136A JP2011088826A JP 2011088826 A JP2011088826 A JP 2011088826A JP 2008022136 A JP2008022136 A JP 2008022136A JP 2008022136 A JP2008022136 A JP 2008022136A JP 2011088826 A JP2011088826 A JP 2011088826A
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Japan
Prior art keywords
compound
formula
acid
reaction
alkyl
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JP2008022136A
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Japanese (ja)
Inventor
Tadatsugu Terasaka
忠嗣 寺坂
Hiroshi Matsuda
博 松田
Shinji Ito
真二 伊藤
Shirabe Tazaki
調 田▲崎▼
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Astellas Pharma Inc
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Astellas Pharma Inc
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Priority to JP2008022136A priority Critical patent/JP2011088826A/en
Priority to TW098103153A priority patent/TW200951122A/en
Priority to PCT/JP2009/051587 priority patent/WO2009096526A1/en
Publication of JP2011088826A publication Critical patent/JP2011088826A/en
Withdrawn legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/29—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
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    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C275/36—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with at least one of the oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. N-aryloxyphenylureas
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    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound exhibiting a CRTH2 inhibiting action, useful as a prophylactic and/or therapeutic agent for an inflammatory disease such as asthma and allergic rhinitis. <P>SOLUTION: The present invention is accomplished as a result of studying compounds exhibiting a CRTH2 inhibiting action to confirm that a class of aromatic carboxylic acid compounds suitably exhibit a CRTH2 inhibiting action. The aromatic carboxylic compounds exhibit a CRTH2 inhibiting action and can be used as a prophylactic and/or therapeutic agent for an inflammatory disease such as asthma and allergic rhinitis. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

本発明は医薬組成物、殊に炎症性疾患治療用医薬組成物の有効成分として有用な芳香族カルボン酸化合物に関する。   The present invention relates to an aromatic carboxylic acid compound useful as an active ingredient of a pharmaceutical composition, particularly a pharmaceutical composition for treating inflammatory diseases.

アレルギー炎症のコンダクター細胞として知られる肥満細胞は、その細胞表面のFc epsilon RIを介して抗原特異的IgEと結合している。生体内に侵入した抗原がこの細胞表面上の特異的IgEに結合することにより肥満細胞は活性化され、様々な炎症性メディエーターを産生し、アレルギー炎症を誘発する(非特許文献１)。 Mast cells, known as conductor cells for allergic inflammation, bind to antigen-specific IgE via Fcepsilon RI on the cell surface. Mast cells are activated when antigens that have entered the body bind to specific IgE on the cell surface, produce various inflammatory mediators, and induce allergic inflammation (Non-patent Document 1).

プロスタグランジンD2(PGD2)は活性化された肥満細胞が産生する主要なプロスタノイドである。これまでに喘息患者気道では抗原暴露によりPGD2の顕著な産生亢進が数分以内に認められること(非特許文献２、非特許文献３)や、アレルギー性鼻炎患者の鼻粘膜やアトピー皮膚炎患者の皮膚に抗原を暴露すると炎症局所でのPGD2産生が亢進することが報告されている(非特許文献４)。また、PGD2をヒトに皮内投与すると紅斑が発症し、ラットにおいては血管透過性が亢進し浮腫が形成され(非特許文献５)、イヌ気管においてもPGD2が好酸球の蓄積を誘発すること(非特許文献６)が以前から報告されていた。Fujitaniらは抗原誘発喘息モデルを用い、正常マウスに比べPGD2産生が増加したPGD2合成酵素トランスジェニックマウスでは気道における好酸球浸潤及びTh2サイトカイン産生が亢進していることを報告し(非特許文献７)、PGD2がアレルギー炎症を促進することを示した。このようにPGD2はアレルギー炎症部位での産生が亢進し、アレルギー反応を促進しうることから、アレルギー疾患の発症及び増悪に密接に関与していると考えられてきた。 Prostaglandin D 2 (PGD 2 ) is the major prostanoid produced by activated mast cells. So far, in the respiratory tract of asthmatic patients, a significant increase in PGD2 production has been observed within a few minutes due to antigen exposure (Non-patent document 2, Non-patent document 3), and nasal mucosa of allergic rhinitis patients and atopic dermatitis patients. It has been reported that when an antigen is exposed to the skin, PGD2 production in the inflamed area is enhanced (Non-patent Document 4). In addition, when PGD2 is administered intradermally to humans, erythema develops, vascular permeability is increased and edema is formed in rats (Non-patent Document 5), and PGD2 also induces eosinophil accumulation in canine trachea. (Non-Patent Document 6) has been reported previously. Using an antigen-induced asthma model, Fujitani et al. Reported that eosinophil infiltration and Th2 cytokine production in the respiratory tract were enhanced in PGD2 synthase transgenic mice with increased PGD2 production compared to normal mice (Non-patent Document 7). ), PGD2 has been shown to promote allergic inflammation. Thus, PGD2 has been considered to be closely involved in the onset and exacerbation of allergic diseases because production at allergic inflammation sites is enhanced and allergic reactions can be promoted.

当初、PGD2受容体としてはG蛋白共役型受容体(GPCR)の一つであるDP(D type prostanoid receptor)が知られていた。しかしながら、モルモットにおいてPGD2は眼圧低下作用及び結膜における炎症誘発作用(特に好酸球浸潤)を示すが、DP選択的作動薬であるBW245Cは眼圧低下作用を示すものの結膜への好酸球浸潤を誘発せず、PGD2の好酸球浸潤誘発作用はDPを介していないことが示唆された(非特許文献８)。さらに、2001年にMonneretらは、ヒト血液から単離した好酸球を用い、PGD2は好酸球を活性化するがDP選択的作動薬であるBW245Cは好酸球を活性化しないこと及びDP拮抗薬であるBWA868CはPGD2による好酸球活性化を阻害しないことからPGD2の好酸球活性化作用は新規のPGD2受容体を介していることを提唱した(非特許文献９)。同時期にHiraiらはPGD2が、CRTH2(chemoattractant receptor-homologous molecule expressed on Th2 cells)のリガンドとして作用することにより、Th2細胞、好酸球、好塩基球の遊走を誘発することを報告した(非特許文献１０)。もともと、CRTH2はTh1細胞には発現が認められず、Th2細胞選択的に発現しているケモアトラクタント様受容体としてクローニングされたG蛋白共役型のオーファン受容体であり、活性化した肥満細胞の培養上清中にそのリガンド活性が存在すること及びTh2細胞以外にも好酸球、好塩基球といったアレルギー反応に関与する炎症性細胞に発現していることが報告されていた(非特許文献１１、非特許文献１２)。このようなことから現在、PGD2はCRTH2とDPの2種類の受容体を介してその生物活性を発揮していると考えれている。 Initially, DP (D type prostanoid receptor), one of G protein-coupled receptors (GPCR), was known as a PGD2 receptor. However, in guinea pigs, PGD2 exhibits an intraocular pressure-lowering effect and inflammation-inducing action in the conjunctiva (especially eosinophil infiltration), while DP selective agonist BW245C exhibits an intraocular pressure-lowering action but eosinophil infiltration into the conjunctiva. It was suggested that PGD2 does not induce DP through eosinophil infiltration (Non-patent Document 8). Furthermore, in 2001 Monneret et al. Used eosinophils isolated from human blood, PGD2 activates eosinophils but the DP selective agonist BW245C does not activate eosinophils and DP Since the antagonist BWA868C does not inhibit the activation of eosinophils by PGD2, it was proposed that the eosinophil activation action of PGD2 is mediated by a novel PGD2 receptor (Non-patent Document 9). At the same time, Hirai et al. Reported that PGD2 induces migration of Th2 cells, eosinophils, and basophils by acting as a ligand for CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells). Patent Document 10). Originally, CRTH2 is a G protein-coupled orphan receptor cloned as a chemotractant-like receptor that is not expressed in Th1 cells but is selectively expressed in Th2 cells, and activated mast cells In addition to Th2 cells, it was reported that the ligand activity is present in the culture supernatant and expressed in inflammatory cells involved in allergic reactions such as eosinophils and basophils (non-patent literature). 11, Non-Patent Document 12). For this reason, PGD2 is currently considered to exert its biological activity via two types of receptors, CRTH2 and DP.

CRTH2はcAMPを上昇させるGsカップル型GPCRであり、DPはcAMP上昇を阻害するGiカップル型GPCRであることから、細胞内シグナル伝達系が異なり、違った機能を有する。これまでのCRTH2及びDPに対する作動薬、拮抗薬を用いた検討から、CRTH2の機能としては細胞遊走活性化(Th2細胞、好酸球、好塩基球)、接着分子発現促進(Th2細胞、好酸球)、Th2サイトカイン産生促進(Th2細胞)などが報告されている。一方、DPの機能としては血小板凝集抑制、血管拡張、平滑筋弛緩、細胞遊走抑制(DP発現細胞、好酸球、樹状細胞)、好酸球アポトーシス誘導、睡眠誘導などが報告されている。PGD2は、DPの作用により局所での血管拡張を誘発し血管透過性を亢進させる一方、CRTH2の作用により炎症性細胞浸潤及び活性化を惹起することでアレルギー炎症を促進する考えられる。これらの点についてはNagataら及びPettipherらの総説に詳細に述べられている((非特許文献１３、非特許文献１４)。 Since CRTH2 is a Gs-coupled GPCR that increases cAMP and DP is a Gi-coupled GPCR that inhibits cAMP increase, the intracellular signal transduction system is different and has different functions. Based on previous studies using agonists and antagonists for CRTH2 and DP, CRTH2 functions include cell migration activation (Th2 cells, eosinophils, basophils), adhesion molecule expression promotion (Th2 cells, eosinophils) Sphere) and Th2 cytokine production (Th2 cells) have been reported. On the other hand, as functions of DP, platelet aggregation suppression, vasodilation, smooth muscle relaxation, cell migration suppression (DP-expressing cells, eosinophils, dendritic cells), eosinophil apoptosis induction, sleep induction and the like have been reported. PGD2 is thought to promote allergic inflammation by inducing inflammatory cell infiltration and activation by the action of CRTH2, while inducing local vasodilation and enhancing vascular permeability by the action of DP. These points are described in detail in the review by Nagata et al. And Pettipher et al. ((Non-patent Documents 13 and 14).

以上から、抗原刺激により活性化された肥満細胞が産生する主要なプロスタノイドであるPGD2はCRTH2を介してTh2細胞や好酸球などの炎症性細胞を活性化し、炎症部位への遊走を促進し、さらにTh2細胞からのTh2サイトカイン産生を促進させることによりアレルギー炎症における中心的な役割を担っていると考えられ、CRTH2拮抗薬はアレルギー炎症に対する治療薬としてその開発が切望される。 From the above, PGD2, the main prostanoid produced by mast cells activated by antigen stimulation, activates inflammatory cells such as Th2 cells and eosinophils via CRTH2 and promotes migration to the inflammatory site. Furthermore, it is thought that it plays a central role in allergic inflammation by promoting Th2 cytokine production from Th2 cells, and CRTH2 antagonists are eagerly developed as therapeutic agents for allergic inflammation.

例えば、CRTH2受容体拮抗作用を有し、抗喘息作用を有する化合物として、下記式(A)、(B)、(C)および(D)で示される化合物が知られている(それぞれ特許文献１、２、３、４)。

Figure 2011088826

［式中の記号は、それぞれ当該公報を参照のこと。］ For example, compounds represented by the following formulas (A), (B), (C) and (D) are known as compounds having CRTH2 receptor antagonistic activity and anti-asthma activity (each of Patent Document 1). 2, 3, 4).
Figure 2011088826
[Refer to the official gazette for the symbols in the formula. ]

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本発明者らは、CRTH2受容体拮抗作用に基づく、喘息やアレルギー性鼻炎等の炎症性疾患などの予防及び／または治療に有用な医薬組成物を提供すること、さらには、これらを含有する医薬を提供することを目的として研究を行った。   The present inventors provide a pharmaceutical composition useful for the prevention and / or treatment of inflammatory diseases such as asthma and allergic rhinitis based on antagonistic action of CRTH2 receptor, and further a medicament containing these Research was conducted with the aim of providing

本発明者らは、CRTH2受容体拮抗作用を有する化合物につき鋭意検討した結果、式(I)の化合物が、CRTH2受容体拮抗作用として有用であることを見出し、本発明を完成した。
即ち、本発明は、式(I)の化合物またはその塩、並びに、式(I)の化合物またはその塩、及び賦形剤を含有する医薬組成物に関する。 As a result of intensive studies on compounds having CRTH2 receptor antagonistic activity, the present inventors have found that the compound of formula (I) is useful as CRTH2 receptor antagonistic activity and completed the present invention.
That is, the present invention relates to a pharmaceutical composition containing a compound of formula (I) or a salt thereof, and a compound of formula (I) or a salt thereof, and an excipient.

Figure 2011088826
[式中、
R1は、-(C1-6アルキレン)-COOHまたは-Hであり、
１)R1が、-(C1-6アルキレン)-COOHの場合、
R2は、ハロゲン、または-H、
R3は、ハロゲン、C1-6アルキル、-O-(C1-6アルキル)、または-H、
２)R1が、-Hの場合、
R2とR3が一体となって、それらが結合するベンゼン環とともに式(II)
Figure 2011088826
で示される基を形成する、
Vは、=CH-または=N-、
mは、１から6の整数を示す；
R4は、ハロゲン、または-H、
ただし、R3が-Hの場合、R4はハロゲンである、
R5は、-H、ハロゲンまたはC1-6アルキル、
R6は、それぞれ置換されていてもよいアリール、ヘテロアリール、ヘテロシクロアルキルまたは-N(R6a)(R6b)、
R6aは、-(C1-6アルキレン)-アリール、-(C1-6アルキレン)-ヘテロアリール、-(C1-6アルキレン)-ヘテロシクロアルキル、
R6bは、-HまたはC1-6アルキル、
Aは、-O-または-S-、
Dは、-C(=O)-、または-S(=O)2-
Eは、結合、C1-6アルキレン、またはC2-6アルケニレン、
Yは、-C(R5a)=または-N=、
R5aは、-H、ハロゲンまたはC1-6アルキル、
Zは、=CH-または=N-。
Uは、-C(R5b)=または-N=、
R5bは、-H、ハロゲンまたはC1-6アルキル。]
なお、特に記載がない限り、本明細書中のある化学式中の記号が他の化学式においても用いられる場合、同一の記号は同一の意味を示す。
Figure 2011088826
 [Where
R 1 is-(C 1-6 alkylene) -COOH or -H;
1) When R 1 is-(C 1-6 alkylene) -COOH,
R 2 is halogen or -H,
R 3 is halogen, C 1-6 alkyl, —O— (C 1-6 alkyl), or —H,
2) When R 1 is -H,
R 2 and R 3 together, together with the benzene ring to which they are attached, formula (II)
Figure 2011088826
To form a group represented by
V is = CH- or = N-,
m represents an integer from 1 to 6;
R 4 is halogen or -H,
Provided that when R 3 is -H, R 4 is halogen,
R 5 is -H, halogen or C 1-6 alkyl,
Each R 6 is optionally substituted aryl, heteroaryl, heterocycloalkyl or -N (R 6a ) (R 6b ),
R 6a is- (C 1-6 alkylene) -aryl,-(C 1-6 alkylene) -heteroaryl,-(C 1-6 alkylene) -heterocycloalkyl,
R 6b is -H or C 1-6 alkyl,
A is -O- or -S-,
D is -C (= O)-, or -S (= O) 2-
E is a bond, C 1-6 alkylene, or C 2-6 alkenylene,
Y is -C (R 5a ) = or -N =,
R 5a is -H, halogen or C 1-6 alkyl,
Z is = CH- or = N-.
U is -C (R 5b ) = or -N =,
R 5b is —H, halogen or C 1-6 alkyl. ]
Unless otherwise specified, when a symbol in a chemical formula in this specification is also used in another chemical formula, the same symbol indicates the same meaning.

また、本発明は、式(I)の化合物またはその塩を含有する炎症性疾患治療用医薬組成物、即ち、式(I)の化合物またはその塩を含有する炎症性疾患治療剤に関する。
また、本発明は、炎症性疾患治療用医薬組成物の製造のための式(I)の化合物またはその塩の使用、並びに、式(I)の化合物またはその塩の有効量を患者に投与することからなる炎症性疾患治療方法に関する。 The present invention also relates to a pharmaceutical composition for treating inflammatory diseases comprising a compound of formula (I) or a salt thereof, that is, a therapeutic agent for inflammatory diseases comprising a compound of formula (I) or a salt thereof.
The present invention also provides the use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for the treatment of inflammatory diseases, and administering to a patient an effective amount of a compound of formula (I) or a salt thereof. The present invention relates to a method for treating inflammatory diseases.

式(I)の化合物またはその塩は、CRTH2受容体阻害作用を有し、喘息、アレルギー性鼻炎、アレルギー性皮膚炎、結膜炎、じんましん、好酸球性気管支炎、食物アレルギー、副鼻腔炎、多発性硬化症、血管炎及び慢性閉塞性肺疾等の予防及び／または治療剤として使用できる。   The compound of formula (I) or a salt thereof has an inhibitory action on CRTH2 receptor, and has asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, urticaria, eosinophilic bronchitis, food allergy, sinusitis, frequent occurrence It can be used as a preventive and / or therapeutic agent for systemic sclerosis, vasculitis and chronic obstructive pulmonary disease.

以下、本発明を詳細に説明する。   Hereinafter, the present invention will be described in detail.

「C1-6アルキル」は、直鎖または分枝状の炭素数が1から6のアルキルであり、例えばメチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、tert-ブチル、n-ペンチル、n-ヘキシル等である。別の態様としては、C1-4アルキルである。さらに別の態様としては、メチル、エチルである。 “C 1-6 alkyl” is linear or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- Butyl, n-pentyl, n-hexyl and the like. In another embodiment, it is C 1-4 alkyl. Yet another embodiment is methyl or ethyl.

「C1-6アルキレン」は、直鎖または分枝状の炭素数が1から6のアルキレンであり、例えばメチレン、エチレン、トリメチレン、プロピレン、テトラメチレン、ペンタメチレンまたはヘキサメチレン等である。別の態様としては、C1-4アルキレンである。さらに別の態様としては、メチレン、エチレンである。 “C 1-6 alkylene” is a linear or branched alkylene having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene or the like. Another embodiment is C 1-4 alkylene. Yet another embodiment is methylene or ethylene.

「C2-6アルケニレン」は、直鎖または分枝状の炭素数が2から6のアルケニレンであり、例えばビニレン、プロピレン、ブテニレン、ペンテニレンまたはヘキセニレン等である。別の態様としては、C2-4アルケニレンである。 “C 2-6 alkenylene” is a linear or branched alkenylene having 2 to 6 carbon atoms, such as vinylene, propylene, butenylene, pentenylene, hexenylene or the like. In another embodiment, C 2-4 alkenylene.

「ハロゲン」は、F、Cl、Br、Iである。別の態様としては、F、Clである。   “Halogen” is F, Cl, Br, I. In another embodiment, F and Cl.

「アリール」とは、C6-14の単環から三環式芳香族炭化水素環基であり、例えばフェニル、ナフチルであり、別の態様としてはフェニルである。 The “aryl” is a C 6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, for example, phenyl or naphthyl, and in another embodiment, phenyl.

「ヘテロアリール」とは、窒素、酸素、及び硫黄からなる群より選択された同一または異なるヘテロ原子を１個以上有する5または6員環芳香族へテロ環を意味し、これらは、シクロペンタン環またはベンゼン環と縮合していてもよい。別の態様としては、チエニル、トリアゾリル、ピリジル、インドリル、ベンゾフラニル、ベンゾチエニル、ベンゾオキサゾリル、ベンゾチアゾリル、ベンゾイミダゾリル、イミダゾピリジニルまたはキノリルなどである。別の態様としては、インドリルである。   “Heteroaryl” means a 5- or 6-membered aromatic heterocycle having one or more of the same or different heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, which are cyclopentane rings Or it may be condensed with a benzene ring. Other embodiments include thienyl, triazolyl, pyridyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, imidazopyridinyl or quinolyl. Another embodiment is indolyl.

「ヘテロシクロアルキル」とは、窒素、酸素、及び硫黄からなる群より選択された同一または異なるヘテロ原子を１個以上有する5から7員環の非芳香環を意味し、これらは部分的に不飽和結合を有していてもよく、ベンゼン環と縮合していてもよい。別の態様としては、ピペリジニル、イソインダニル、テトラヒドロキノリル、テトラヒドロイソキノリル、2,3,4,5-テトラヒドロ-1H-3-ベンゾアゼピニルなどである。さらに別の態様としては、テトラヒドロイソキノリルである。 “Heterocycloalkyl” means a 5- to 7-membered non-aromatic ring having one or more of the same or different heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, which are partially non-substituted. It may have a saturated bond and may be condensed with a benzene ring. Other embodiments include piperidinyl, isoindanyl, tetrahydroquinolyl, tetrahydroisoquinolyl, 2,3,4,5-tetrahydro-1H-3-benzoazepinyl and the like. Yet another embodiment is tetrahydroisoquinolyl.

本明細書において、「置換されていてもよい」とは、無置換、若しくは置換基を1から6個有していることを意味する。なお、複数個の置換基を有する場合、それらの置換基は同一であっても、互いに異なっていてもよい。   In the present specification, “optionally substituted” means unsubstituted or having 1 to 6 substituents. In addition, when it has a some substituent, those substituents may be the same or may mutually differ.

本明細書中、R6の、「それぞれ置換されていてもよいアリール、ヘテロアリールまたはヘテロシクロアルキル」における置換基としては、ハロゲン、C1-6アルキル、ハロゲン-C1-6アルキル、-O-(C1-6アルキル)、-O-(C1-6アルキル)-(ハロゲン、-S-(C1-6アルキル)、-N-(C1-6アルキル)2、アリール、-アリール-O-(C1-6アルキル)または-アリール‐N(C1-6アルキル)2であり、別の態様としては、ハロゲン、C1-6アルキル、ハロゲン-C1-6アルキルが挙げられる。別の態様としては、ハロゲンまたはC1-6アルキルである。 In the present specification, the substituent in R 6 "aryl, heteroaryl or heterocycloalkyl each optionally substituted" may be halogen, C 1-6 alkyl, halogen-C 1-6 alkyl, -O -(C 1-6 alkyl), -O- (C 1-6 alkyl)-(halogen, -S- (C 1-6 alkyl), -N- (C 1-6 alkyl) 2 , aryl, -aryl -O- (C 1-6 alkyl) or -aryl-N (C 1-6 alkyl) 2 , and other embodiments include halogen, C 1-6 alkyl, halogen-C 1-6 alkyl In another embodiment, it is halogen or C 1-6 alkyl.

本発明のある態様を以下に示す。
(1)R1が-(C1-6アルキレン)-COOHである式(I)の化合物。
(2)R2が-Hである式(I)の化合物。
(3)R3がハロゲン、C1-6アルキルまたは-O-(C1-6アルキル)である式(I)の化合物。
(4)R4が-Hである式(I)の化合物。
(5)R5が-Hである式(I)の化合物。
(6)R6がそれぞれ置換されていてもよいヘテロアリールまたはヘテロシクロアルキルである式(I)の化合物。
(7)Aが-O-であるである式(I)の化合物。
(8)Dが-C(=O)-である式(I)の化合物。
(9)Eが結合である式(I)の化合物。
(10)Yが=C(-H)-または=C(-F)-である式(I)の化合物。
(11)Zが=CH-である式(I)の化合物。
(12)Uが-CH=である式(I)の化合物。
(13)上記(1)から(12)のうち、二以上の組み合わせである式(I)の化合物。 Certain embodiments of the present invention are shown below.
(1) A compound of formula (I) wherein R 1 is-(C 1-6 alkylene) -COOH.
(2) A compound of formula (I) wherein R 2 is —H.
(3) A compound of formula (I) wherein R 3 is halogen, C 1-6 alkyl or —O— (C 1-6 alkyl).
(4) A compound of formula (I) wherein R 4 is -H.
(5) The compound of formula (I), wherein R 5 is —H.
(6) Compounds of formula (I) wherein R 6 is each optionally substituted heteroaryl or heterocycloalkyl.
(7) A compound of formula (I) wherein A is -O-.
(8) A compound of formula (I) wherein D is -C (= O)-.
(9) A compound of formula (I) wherein E is a bond.
(10) A compound of formula (I) wherein Y is = C (-H)-or = C (-F)-.
(11) A compound of formula (I) wherein Z is = CH-.
(12) A compound of formula (I) wherein U is -CH =.
(13) A compound of the formula (I) which is a combination of two or more of the above (1) to (12).

本発明の別の態様を以下に示す。
R1が-(C1-6アルキレン)-COOHであり、R2が-Hであり、R3が-F、-Clまたは-Brである式(I)の化合物。 Another embodiment of the present invention is shown below.
A compound of formula (I) wherein R 1 is — (C 1-6 alkylene) -COOH, R 2 is —H, and R 3 is —F, —Cl or —Br.

本発明に包含される具体的化合物の例として、以下の化合物(1)から(3)、それぞれの塩およびそれぞれのプロドラッグが挙げられる。
(1)(3-クロロ-4-{4-[(3,4-ジヒドロイソキノリン-2(1H)-イルカルボニル)アミノ]フェノキシ}フェニル)酢酸。
(2)(3-クロロ-4-{2-フルオロ-4-[(1H-インドール-2-イルカルボニル)アミノ]フェノキシ}フェニル)酢酸。
(3)[3-クロロ-4-(4-{[(1-メチル-1H-インドール-2-イル)カルボニル]アミノ}フェノキシ)フェニル]酢酸。 Examples of specific compounds included in the present invention include the following compounds (1) to (3), respective salts and respective prodrugs.
(1) (3-Chloro-4- {4-[(3,4-dihydroisoquinolin-2 (1H) -ylcarbonyl) amino] phenoxy} phenyl) acetic acid.
(2) (3-Chloro-4- {2-fluoro-4-[(1H-indol-2-ylcarbonyl) amino] phenoxy} phenyl) acetic acid.
(3) [3-Chloro-4- (4-{[(1-methyl-1H-indol-2-yl) carbonyl] amino} phenoxy) phenyl] acetic acid.

式(I)の化合物には、置換基の種類によって、互変異性体や幾何異性体が存在しうる。本明細書中、式(I)の化合物が異性体の一形態のみで記載されることがあるが、本発明は、それ以外の異性体も包含し、異性体の分離されたもの、あるいはそれらの混合物も包含する。
また、式(I)の化合物には、不斉炭素原子を有する場合があり、これに基づく光学異性体が存在しうる。本発明は、式(I)の化合物の光学異性体の分離されたもの、あるいはそれらの混合物も包含する。 The compound of formula (I) may exist as a tautomer or a geometric isomer depending on the kind of the substituent. In the present specification, the compound of the formula (I) may be described in only one form of an isomer, but the present invention also includes other isomers, separated isomers, or those isomers. And mixtures thereof.
In addition, the compound of formula (I) may have an asymmetric carbon atom, and optical isomers based on this may exist. The present invention also includes separated optical isomers of the compound of formula (I) or a mixture thereof.

さらに、本発明は、式(I)で示される化合物の製薬学的に許容されるプロドラッグも包含する。製薬学的に許容されるプロドラッグとは、加溶媒分解によりまたは生理学的条件下で、アミノ基、水酸基、カルボキシル基等に変換されうる基を有する化合物である。プロドラッグを形成する基としては、例えば、Prog. Med., 5, 2157-2161(1985)や、「医薬品の開発」(廣川書店、1990年)第7巻、分子設計163-198に記載の基が挙げられる。   Furthermore, the present invention includes a pharmaceutically acceptable prodrug of the compound represented by the formula (I). A pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985), and `` Development of pharmaceuticals '' (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. Groups.

また、式(I)の化合物の塩とは、式(I)の化合物の製薬学的に許容される塩であり、置換基の種類によって、酸付加塩または塩基との塩を形成する場合がある。具体的には、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸等の無機酸や、ギ酸、酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、乳酸、リンゴ酸、マンデル酸、酒石酸、ジベンゾイル酒石酸、ジトルオイル酒石酸、クエン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、アスパラギン酸、グルタミン酸等の有機酸との酸付加塩、ナトリウム、カリウム、マグネシウム、カルシウム、アルミニウム等の無機塩基、メチルアミン、エチルアミン、エタノールアミン、リシン、オルニチン等の有機塩基との塩、アセチルロイシン等の各種アミノ酸及びアミノ酸誘導体との塩やアンモニウム塩等が挙げられる。   The salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I), and may form an acid addition salt or a salt with a base depending on the type of the substituent. is there. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition with organic acids such as lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid Salts, salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine, salts with various amino acids and amino acid derivatives such as acetylleucine and ammonium salts Etc.

さらに、本発明は、式(I)の化合物及びその塩の各種の水和物や溶媒和物、及び結晶多形の物質も包含する。また、本発明は、種々の放射性または非放射性同位体でラベルされた化合物も包含する。   Furthermore, the present invention also includes various hydrates and solvates of the compound of the formula (I) and salts thereof, and polymorphic substances. The present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.

本明細書中における略号は以下のとおりである。
AcOEtまたはEtOAc：酢酸エチル、brine: 飽和食塩水、BuOH：ブタノール、Cs2CO3：炭酸セシウム、CHCl3：クロロホルム、CuCl2：塩化銅、DCM：ジクロロメタン、DCC：ジシクロヘキシルカルボジイミド、DEAD：ジエチルアゾジカルボキシレート、DMSO：ジメチルスルホキシド、DMF：N,N-ジメチルホルムアミド、DMAP：4-ジメチルアミノピリジン、DIPEA：ジイソプロピルエチルアミン、DPPA：ジフェニルリン酸アジド、EtOH：エタノール、HOBt：N-ヒドロキシベンズトリアゾール、IPE：ジイソプロピルエーテル、K2CO3：炭酸カリウム、KOH：水酸化カリウム、mCPBA：メタクロロ過安息香酸、MeCN:アセトニトリル、MeOH：メタノール、MgSO4：無水硫酸マグネシウム、Na2CO3：炭酸ナトリウム、NaHCO3：炭酸水素ナトリウム、NaOH：水酸化ナトリウム、NMM：N-メチルモルホリン、TEA：トリエチルアミン、THF：テトラヒドロフラン、PdCl2(PPh3)2：ジクロロビス(トリフェニルホスフィン)パラジウム、Pd(PPh3)4：テトラキス(トリフェニルホスフィン)パラジウム(0)、WSC・HCl：N-エチル-N'-(3-ジメチルアミノプロピル)-カルボジイミド 塩酸塩、Zn(CN)2：ジンクシアニド、ESI-MS：electrospray ionization mass spectrometry (電子スプレーイオン化法質量分析)。 Abbreviations in the present specification are as follows.
AcOEt or EtOAc: ethyl acetate, brine: saturated sodium chloride solution, BuOH: butanol, Cs 2 CO 3: Cesium carbonate, CHCl 3: chloroform, CuCl 2: Copper chloride, DCM: dichloromethane, DCC: dicyclohexylcarbodiimide, DEAD: Jiechiruazoji Carboxylate, DMSO: dimethyl sulfoxide, DMF: N, N-dimethylformamide, DMAP: 4-dimethylaminopyridine, DIPEA: diisopropylethylamine, DPPA: diphenylphosphate azide, EtOH: ethanol, HOBt: N-hydroxybenztriazole, IPE : Diisopropyl ether, K 2 CO 3 : Potassium carbonate, KOH: Potassium hydroxide, mCPBA: Metachloroperbenzoic acid, MeCN: Acetonitrile, MeOH: Methanol, MgSO 4 : Anhydrous magnesium sulfate, Na 2 CO 3 : Sodium carbonate, NaHCO 3 : Sodium bicarbonate, NaOH: Sodium hydroxide, NMM: N-Methylmorpholine , TEA: triethylamine, THF: tetrahydrofuran, PdCl 2 (PPh 3 ) 2 : dichlorobis (triphenylphosphine) palladium, Pd (PPh 3 ) 4 : tetrakis (triphenylphosphine) palladium (0), WSC · HCl: N- Ethyl-N ′-(3-dimethylaminopropyl) -carbodiimide hydrochloride, Zn (CN) 2 : zinc cyanide, ESI-MS: electrospray ionization mass spectrometry (electrospray ionization mass spectrometry).

(製造法)
式(I)の化合物及びその塩は、その基本構造あるいは置換基の種類に基づく特徴を利用し、種々の公知の合成法を適用して製造することができる。その際、官能基の種類によっては、当該官能基を原料から中間体へ至る段階で適当な保護基(容易に当該官能基に転化可能な基)に置き換えておくことが製造技術上効果的な場合がある。このような保護基としては、例えば、ウッツ(P. G. M. Wuts)及びグリーン(T. W. Greene)著、「Greene's Protective Groups in Organic Synthesis(第4版、2006年)」に記載の保護基等を挙げることができ、これらの反応条件に応じて適宜選択して用いればよい。このような方法では、当該保護基を導入して反応を行なった後、必要に応じて保護基を除去することにより、所望の化合物を得ることができる。
また、式(I)の化合物のプロドラッグは、上記保護基と同様、原料から中間体へ至る段階で特定の基を導入、あるいは得られた式(I)の化合物を用いてさらに反応を行なうことで製造できる。反応は通常のエステル化、アミド化、脱水等、当業者に公知の方法を適用することにより行うことができる。
以下、式(I)の化合物の代表的な製造法を説明する。各製法は、当該説明に付した参考文献を参照して行うこともできる。なお、本発明の製造法は以下に示した例には限定されない。 (Production method)
The compound of the formula (I) and salts thereof can be produced by applying various known synthetic methods utilizing characteristics based on the basic structure or the type of substituent. At that time, depending on the type of functional group, it is effective in terms of production technology to replace the functional group with an appropriate protecting group (a group that can be easily converted into the functional group) at the stage from the raw material to the intermediate. There is a case. Examples of such protecting groups include protecting groups described in “Greene's Protective Groups in Organic Synthesis (4th edition, 2006)” by PGM Wuts and TW Greene. These may be appropriately selected according to the reaction conditions. In such a method, after carrying out the reaction by introducing the protecting group, the desired compound can be obtained by removing the protecting group as necessary.
In addition, the prodrug of the compound of formula (I) introduces a specific group at the stage from the raw material to the intermediate, or reacts further using the obtained compound of formula (I), like the above-mentioned protecting group. Can be manufactured. The reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
Hereinafter, typical production methods of the compound of the formula (I) will be described. Each manufacturing method can also be performed with reference to the reference attached to the said description. In addition, the manufacturing method of this invention is not limited to the example shown below.

(第一製法)
式（I）の化合物は、保護されたカルボン酸を脱保護して製造できる。当該脱保護は、加水分解、加水素分解または触媒的脱保護等により製造することができる。アルカリ加水分解の場合、無機塩基(例えばNaOH、KOH、NaHCO3、Cs2CO3等)を用いる事ができる。酸加水分解の場合、塩酸等を用いることができる。いずれも反応温度は氷冷下から還流条件下で、基質が分解しない条件で反応を行うことができる。溶媒としては、アルコール(MeOH、EtOH等)、DMFまたはDMSO等の有機溶媒や、水あるいはそれらの混合溶媒を用いることができる。加水素分解の場合、通常パラジウム触媒の存在下、水素雰囲気下で反応させることができる。DMF、MeOH等の溶媒中、室温から還流までの反応温度で製造できる。触媒的脱保護の場合、パラジウム等の触媒と塩基性条件下で製造できる。 (First manufacturing method)
Compounds of formula (I) can be prepared by deprotecting the protected carboxylic acid. The deprotection can be produced by hydrolysis, hydrogenolysis or catalytic deprotection. In the case of alkaline hydrolysis, an inorganic base (for example, NaOH, KOH, NaHCO 3 , Cs 2 CO 3 etc.) can be used. In the case of acid hydrolysis, hydrochloric acid or the like can be used. In either case, the reaction can be carried out under conditions where the reaction temperature is from ice-cooling to reflux conditions and the substrate is not decomposed. As the solvent, an organic solvent such as alcohol (MeOH, EtOH, etc.), DMF or DMSO, water, or a mixed solvent thereof can be used. In the case of hydrogenolysis, the reaction can usually be carried out in a hydrogen atmosphere in the presence of a palladium catalyst. It can be produced at a reaction temperature from room temperature to reflux in a solvent such as DMF or MeOH. In the case of catalytic deprotection, it can be produced under basic conditions with a catalyst such as palladium.

(原料合成)

Figure 2011088826

[R1'、R2'、R3'は、いずれかに保護されたカルボキシ基を示し、脱保護によりそれぞれR1、R2、R3へと変換できる基を示す。] (Raw material synthesis)
Figure 2011088826
[R 1 ′, R 2 ′ and R 3 ′ each represent a protected carboxy group, and represents a group which can be converted to R 1 , R 2 or R 3 by deprotection, respectively. ]

化合物(2a)は、化合物(1)のアミノ基と対応するカルボン酸とを縮合させて製造できる(Step1-1)。この反応では、化合物(1)と対応するカルボン酸とを等量若しくは一方を過剰量用い、これらの混合物を縮合剤の存在下、反応に不活性な溶媒中、冷却下から加熱下、好ましくは-20℃から60℃で、0.1時間から5日間撹拌する。溶媒の例としては、特に限定はされないが、芳香族炭化水素類(ベンゼン、トルエンまたはキシレン等)、ハロゲン化炭化水素類(例えばジクロロメタン、1,2-ジクロロエタン若しくはクロロホルム等)、エーテル類(ジエチルエーテル、テトラヒドロフランまたはジオキサン等)、DMF、DMSO、EtOAc、MeCNまたは水、及びこれらの混合溶媒が挙げられる。縮合剤の例としては、WSC、DCC、DPPA、オキシ塩化リンが挙げられるが、これらに限定されるものではない。添加剤(例えばHOBt等)を用いることが反応に好ましい場合がある。有機塩基(例えばTEA、DIPEAまたはNMM等)、または無機塩基(例えば、K2CO3またはKOH等)の存在下で反応を行うことが、反応を円滑に進行させる上で有利な場合がある。 Compound (2a) can be produced by condensing the amino group of compound (1) with the corresponding carboxylic acid (Step 1-1). In this reaction, an equivalent amount of compound (1) and the corresponding carboxylic acid or an excess of one of them is used, and a mixture of these in the presence of a condensing agent, in a solvent inert to the reaction, from cooling to heating, preferably Stir at -20 ° C to 60 ° C for 0.1 hour to 5 days. Examples of the solvent include, but are not limited to, aromatic hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, 1,2-dichloroethane, chloroform, etc.), ethers (diethyl ether). , Tetrahydrofuran or dioxane, etc.), DMF, DMSO, EtOAc, MeCN or water, and mixed solvents thereof. Examples of condensing agents include, but are not limited to, WSC, DCC, DPPA, phosphorus oxychloride. It may be preferable for the reaction to use an additive (eg HOBt). It may be advantageous to carry out the reaction in the presence of an organic base (such as TEA, DIPEA or NMM) or an inorganic base (such as K 2 CO 3 or KOH) in order to facilitate the reaction.

また、化合物(2a)は、カルボン酸を反応性誘導体へ変換した後に、化合物(1)と反応させて得ることができる。カルボン酸の反応性誘導体の例としては、ハロゲン化剤(例えばオキシ塩化リン、塩化チオニル等)と反応して得られる酸ハロゲン化物、クロロギ酸イソブチル等と反応して得られる混合酸無水物、HOBt等と縮合して得られる活性エステル等が挙げられる。化合物(1)と反応性誘導体との反応は、ハロゲン化炭化水素類、芳香族炭化水素類、エーテル類等の反応に不活性な溶媒中、冷却下から加熱下、好ましくは、-20℃から60℃で行うことができる。なお、反応に際して塩基（例えば、NMM、TEA、DIPEA、DMAP、ピリジン、ピコリン、ルチジン等）の存在下に反応させるのが、反応を円滑に進行させる上で有利な場合がある。また、ピリジンは溶媒と兼ねることもできる。
[文献]S. R. Sandler及びW. Karo著、「Organic Functional Group Preparations」、第2版、第1巻、Academic Press Inc.、1991年
日本化学会編「実験化学講座(第5版)」16巻(2005年)(丸善) Compound (2a) can be obtained by converting carboxylic acid into a reactive derivative and then reacting with compound (1). Examples of reactive derivatives of carboxylic acids include acid halides obtained by reaction with halogenating agents (for example, phosphorus oxychloride, thionyl chloride, etc.), mixed acid anhydrides obtained by reaction with isobutyl chloroformate, HOBt Active esters obtained by condensation with the like. The reaction between the compound (1) and the reactive derivative is carried out in a solvent inert to the reaction of halogenated hydrocarbons, aromatic hydrocarbons, ethers, etc., under cooling to heating, preferably from −20 ° C. Can be performed at 60 ° C. In the reaction, it may be advantageous to carry out the reaction in the presence of a base (for example, NMM, TEA, DIPEA, DMAP, pyridine, picoline, lutidine, etc.) in order to facilitate the reaction. Pyridine can also serve as a solvent.
[Literature] SR Sandler and W. Karo, "Organic Functional Group Preparations", 2nd edition, 1st volume, Academic Press Inc., 1991, "Chemical Chemistry Course (5th edition)" volume 16 ( (2005) (Maruzen)

化合物(2b)は、Step1-1の条件を援用して製造できる。すなわち、試薬のカルボン酸遊離酸またはその反応性誘導体を用いる代わりに、スルホン酸の遊離酸またはその反応性誘導体を用いることにより化合物(Ib)が製造できる(Step1-2)。   Compound (2b) can be produced with the aid of the conditions of Step 1-1. That is, instead of using a carboxylic acid free acid or a reactive derivative thereof as a reagent, compound (Ib) can be produced by using a sulfonic acid free acid or a reactive derivative thereof (Step 1-2).

化合物(2c)は、化合物(1)にトリホスゲン等とHN(R6a)(R6b)とを反応させて製造できる。反応は、通常塩基（例えば、NMM、TEA、DIPEA、DMAP、ピリジン、ピコリン、ルチジン等）の存在下で行う。溶媒はハロゲン化炭化水素類、芳香族炭化水素類、エーテル類、エステル類、MeCN、DMFまたはDMSO等の反応に不活性な有機溶媒、またはそれらの混合溶媒が用いられる。また、反応は冷却下、冷却から室温下、あるいは室温から加熱下に行われる。 Compound (2c) can be produced by reacting compound (1) with triphosgene or the like and HN (R 6a ) (R 6b ). The reaction is usually performed in the presence of a base (for example, NMM, TEA, DIPEA, DMAP, pyridine, picoline, lutidine, etc.). As the solvent, halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, MeCN, DMF, DMSO and other organic solvents inert to the reaction, or a mixed solvent thereof are used. The reaction is carried out under cooling, from cooling to room temperature, or from room temperature to heating.

Figure 2011088826

［式中、Xはハロゲン等の脱離基を意味する。］
化合物(5)は、アルコールまたはチオールの化合物(3)と化合物(4)とをカップリングさせて、製造できる(Step2-1)。塩基としては、無機塩基(例えばNaOH、KOH、NaHCO3、Cs2CO3等)を用い、反応溶媒は、ハロゲン化炭化水素類、芳香族炭化水素類、エーテル類、EtOAc等のエステル類、MeCN、DMFまたはDMSO等の反応に不活性な有機溶媒、または、それらの混合溶媒が用いられる。また、反応は室温から加熱下に行われる。
Figure 2011088826
[Wherein X represents a leaving group such as halogen. ]
Compound (5) can be produced by coupling alcohol or thiol compound (3) and compound (4) (Step 2-1). As the base, an inorganic base (e.g., NaOH, KOH, NaHCO 3 , Cs 2 CO 3 etc.) is used, and the reaction solvent is halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters such as EtOAc, MeCN, etc. , DMF or DMSO, or an inert organic solvent or a mixed solvent thereof is used. The reaction is carried out from room temperature under heating.

化合物(1)は、化合物(4)のニトロ基を還元して製造できる(Step2-2)。反応は、芳香族ニトロ基の還元方法が用いられ、通常、塩酸条件下で鉄粉末を反応、または接触還元等によって製造することができる。
なお、上述の製造法および中間体製造法に記載した以外の実施例化合物および中間体を製造する場合には、本明細書の参考例、もしくは実施例に記載の方法、またはそれに準じた方法を採用することもでき、さらに、公知の方法、当業者にとって自明である方法により製造することができる。 Compound (1) can be produced by reducing the nitro group of compound (4) (Step 2-2). For the reaction, a method for reducing an aromatic nitro group is used. Usually, iron powder can be produced by reaction or catalytic reduction under hydrochloric acid conditions.
In addition, when producing Example compounds and intermediates other than those described in the above-mentioned production methods and intermediate production methods, the methods described in the Reference Examples of the present specification, the Examples, or methods according thereto are used. Further, it can be produced by a known method or a method obvious to those skilled in the art.

さらに、式(I)で示されるいくつかの化合物は、以上のように製造された本発明化合物から、公知のアルキル化、アシル化、置換反応、酸化、還元、加水分解、脱保護など当業者が通常採用しうる工程を任意に組み合わせることにより製造することもできる。   Further, some compounds represented by the formula (I) can be obtained from the compounds of the present invention produced as described above by known alkylation, acylation, substitution reaction, oxidation, reduction, hydrolysis, deprotection and the like. Can be produced by arbitrarily combining the processes that can normally be employed.

式(I)の化合物は、遊離化合物、その塩、水和物、溶媒和物、あるいは結晶多形の物質として単離され、精製される。式(I)の化合物の塩は、常法の造塩反応に付すことにより製造することもできる。
単離、精製は、抽出、分別結晶化、各種分画クロマトグラフィー等、通常の化学操作を適用して行なわれる。
各種の異性体は、適当な原料化合物を選択することにより製造でき、あるいは異性体間の物理化学的性質の差を利用して分離することができる。例えば、光学異性体は、ラセミ体の一般的な光学分割法(例えば、光学活性な塩基または酸とのジアステレオマー塩に導く分別結晶化や、キラルカラム等を用いたクロマトグラフィー等)により得られ、また、適当な光学活性な原料化合物から製造することもできる。 The compounds of formula (I) are isolated and purified as free compounds, their salts, hydrates, solvates, or crystalline polymorphic substances. The salt of the compound of the formula (I) can also be produced by subjecting it to a conventional salt formation reaction.
Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
Various isomers can be produced by selecting an appropriate raw material compound, or can be separated by utilizing a difference in physicochemical properties between isomers. For example, optical isomers can be obtained by general optical resolution of racemates (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Further, it can also be produced from a suitable optically active raw material compound.

式(I)の化合物の薬理活性は、以下の試験により確認した。
試験例1-1：膜標本の調製
ヒトCRTH2 cDNAを持続的に発現させたHEK293細胞をバッファー(10 mM BES(N,N-bis (2-hydroxyethyl)-2-amino-ethane-sulfonic acid)、1 mM EDTA、10 mM MnCl2、pH=7.0、以下アッセイバッファーと記す)中で26ゲージ注射針内をすばやく通過させ破砕することにより調製した細胞膜を含む懸濁液を膜標本として-80℃で保存した。以後、用時融解して試験を行った。 The pharmacological activity of the compound of formula (I) was confirmed by the following test.
Test Example 1-1: Preparation of membrane specimen HEK293 cells continuously expressing human CRTH2 cDNA were buffered (10 mM BES (N, N-bis (2-hydroxyethyl) -2-amino-ethane-sulfonic acid), (1 mM EDTA, 10 mM MnCl 2 , pH = 7.0, hereinafter referred to as assay buffer)) A suspension containing a cell membrane prepared by rapidly passing through a 26 gauge needle and crushing was used as a membrane specimen at -80 ° C. saved. Thereafter, the test was conducted after melting at the time of use.

試験例1-2：CRTH2結合実験
膜標本(1アッセイ当たり蛋白量として50 μg使用)、被験化合物及びトリチウムラベルされたPGD2(最終濃度：2 nM)を0.2 mLのアッセイバッファー中で4℃にて2時間インキュベートした後、反応液をGF/Bプレート(PerkinElmer)のフィルター上に吸引濾過し、洗浄用バッファー(10mM BES、0.01% BSA)で3回洗浄後、フィルターに吸着した放射活性をTopCount(PerkinElmer)で測定した。尚、CRTH2特異的な結合は10 μMのDK-PGD2を添加した際に阻害される放射活性部分として求めた。 Test example 1-2: CRTH2 binding experiment Membrane specimen (50 μg of protein used per assay), test compound and tritium-labeled PGD2 (final concentration: 2 nM) in 0.2 mL of assay buffer at 4 ° C After incubating for 2 hours, the reaction solution was suction filtered onto a filter on a GF / B plate (PerkinElmer), washed 3 times with a washing buffer (10 mM BES, 0.01% BSA), and then the radioactivity adsorbed on the filter was measured by TopCount ( PerkinElmer). CRTH2-specific binding was determined as a radioactive moiety that was inhibited when 10 μM DK-PGD2 was added.

その結果、本発明化合物である以下の実施例化合物はそれぞれ以下の活性値(IC50値、単位nM)を示した。実施例化合物1：9.1、実施例化合物30：2.9、実施例化合物34：10、実施例化合物35：5.6、実施例化合物37：4.8、実施例化合物55：4.1、実施例化合物56：8.7、実施例化合物109：4.9、実施例化合物140：0.53、実施例化合物151:1.0。 As a result, the following Example compounds which are the compounds of the present invention exhibited the following activity values (IC 50 values, unit nM). Example compound 1: 9.1, Example compound 30: 2.9, Example compound 34: 10, Example compound 35: 5.6, Example compound 37: 4.8, Example compound 55: 4.1, Example compound 56: 8.7, Example compound Example compound 109: 4.9, Example compound 140: 0.53, Example compound 151: 1.0.

試験例2：モルモット抗原誘発気道反応性亢進モデル
本発明化合物の抗喘息作用はBurgessらの方法(非特許文献15)に若干の変更を加えたモルモット抗原誘発気道反応性亢進モデルにより評価した。
即ち、雄性Hartley系モルモットに20 mg/mLの卵白アルブミン(以下、OVAと記す)生理食塩液を1 mL腹腔内投与(初回感作，Day 0とする)し、さらにDay 2に1 mg/mLのOVA生理食塩液を1 mL腹腔内投与することにより能動的に抗原感作を行った。Day 14から21に超音波ネブライザ(オムロン)を用いて、動物に0.5 % OVA生理食塩液を1日1回10分間吸入曝露(生理食塩液対照群は生理食塩液を吸入曝露)した。被験化合物は抗原吸入曝露開始の1時間前に経口投与した。また、アナフィラキシーを防ぐために吸入曝露開始の30分前にピリラミンを10 mg/kgにて腹腔内投与した。
Day 22にウレタン(1.5 g/kg、腹腔内投与)麻酔下で動物の気管に人工呼吸器(Model 683，Harvard社)に接続されたカニューレを挿入し、ガラミン(6 mg/kg、腹腔内投与)で自発呼吸を停止させ、機械的換気(換気速度：毎分60ストローク，換気量：体重100 g当たり1 mL)下でメサコリン(0、2、4、6、8、10、12、14 μg/kg)を3分間隔で順次静脈内投与した。圧トランスデューサーにより気道内圧の上昇を測定し、メサコリン投与量と気道内圧上昇をプロットした際の濃度曲線下面積(AUC)を算出した。 Test Example 2: Guinea Pig Antigen-Induced Airway Reactivity Model The anti-asthmatic effect of the compound of the present invention was evaluated by a guinea pig antigen-induced airway responsiveness model obtained by slightly modifying the method of Burgess et al. (Non-patent Document 15).
Specifically, 20 mg / mL ovalbumin (hereinafter referred to as OVA) physiological saline was administered intraperitoneally to male Hartley guinea pigs (first sensitization, referred to as Day 0), and further on Day 2, 1 mg / mL Antigen sensitization was actively performed by intraperitoneally administering 1 mL of OVA physiological saline. From Day 14 to 21, using an ultrasonic nebulizer (OMRON), the animals were exposed to inhalation of 0.5% OVA physiological saline once a day for 10 minutes (in the physiological saline control group, the physiological saline was inhaled). The test compound was orally administered 1 hour before the start of antigen inhalation exposure. To prevent anaphylaxis, pyriramine was intraperitoneally administered at 10 mg / kg 30 minutes before the start of inhalation exposure.
On Day 22, urethane (1.5 g / kg, intraperitoneal administration) Under anesthesia, a cannula connected to a ventilator (Model 683, Harvard) was inserted into the trachea of the animal, and gallamine (6 mg / kg, intraperitoneal administration) ) To stop spontaneous breathing and methacholine (0, 2, 4, 6, 8, 10, 12, 14 μg under mechanical ventilation (ventilation rate: 60 strokes per minute, ventilation: 1 mL per 100 g body weight) / kg) was intravenously administered sequentially at 3-minute intervals. The increase in airway pressure was measured with a pressure transducer, and the area under the concentration curve (AUC) when the mesacholine dose and the increase in airway pressure were plotted was calculated.

その結果、本発明化合物中、例えば実施例化合物34、55は有効な活性を示すことが判明した。   As a result, among the compounds of the present invention, for example, Example compounds 34 and 55 were found to show effective activity.

上記試験の結果、式(I)の化合物はCRTH2に対しアンタゴニスト活性作用を有することが確認された。従って、喘息、アレルギー性鼻炎、アレルギー性皮膚炎、結膜炎、じんましん、好酸球性気管支炎、食物アレルギー、副鼻腔炎、多発性硬化症、血管炎及び慢性閉塞性肺疾患等の治療等に使用できる。   As a result of the above test, it was confirmed that the compound of formula (I) has an antagonistic activity on CRTH2. Therefore, used for the treatment of asthma, allergic rhinitis, allergic dermatitis, conjunctivitis, hives, eosinophilic bronchitis, food allergy, sinusitis, multiple sclerosis, vasculitis, chronic obstructive pulmonary disease, etc. it can.

式(I)の化合物またはその塩の１種または２種以上を有効成分として含有する医薬組成物は、当分野において通常用いられている賦形剤、即ち、薬剤用賦形剤や薬剤溶担体等を用いて、通常使用されている方法によって調製することができる。
投与は錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤等による経口投与、または、関節内、静脈内、筋肉内等の注射剤、坐剤、点眼剤、眼軟膏、経皮用液剤、軟膏剤、経皮用貼付剤、経粘膜液剤、経粘膜貼付剤、吸入剤等による非経口投与のいずれの形態であってもよい。 A pharmaceutical composition containing one or more compounds of the formula (I) or a salt thereof as an active ingredient is an excipient normally used in the art, that is, a pharmaceutical excipient or a drug-soluble carrier. Can be prepared by a commonly used method.
Administration is orally by tablets, pills, capsules, granules, powders, liquids, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.

経口投与のための固体組成物としては、錠剤、散剤、顆粒剤等が用いられる。このような固体組成物においては、1種または2種以上の有効成分を、少なくとも1種の不活性な賦形剤、例えば乳糖、マンニトール、ブドウ糖、ヒドロキシプロピルセルロース、微結晶セルロース、デンプン、ポリビニルピロリドン、及び／またはメタケイ酸アルミン酸マグネシウム等と混合される。組成物は、常法に従って、不活性な添加剤、例えばステアリン酸マグネシウムのような滑沢剤やカルボキシメチルスターチナトリウム等のような崩壊剤、安定化剤、溶解補助剤を含有していてもよい。錠剤または丸剤は必要により糖衣または胃溶性若しくは腸溶性物質のフィルムで被膜してもよい。
経口投与のための液体組成物は、薬剤的に許容される乳濁剤、溶液剤、懸濁剤、シロップ剤またはエリキシル剤等を含み、一般的に用いられる不活性な希釈剤、例えば精製水またはエタノールを含む。当該液体組成物は不活性な希釈剤以外に可溶化剤、湿潤剤、懸濁剤のような補助剤、甘味剤、風味剤、芳香剤、防腐剤を含有していてもよい。 As a solid composition for oral administration, tablets, powders, granules and the like are used. In such solid compositions, one or more active ingredients are combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. And / or mixed with magnesium aluminate metasilicate. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, or a solubilizing agent according to a conventional method. . If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or contains ethanol. The liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.

非経口投与のための注射剤は、無菌の水性または非水性の溶液剤、懸濁剤または乳濁剤を含有する。水性の溶剤としては、例えば注射用蒸留水または生理食塩液が含まれる。非水性の溶剤としては、例えばプロピレングリコール、ポリエチレングリコールまたはオリーブ油のような植物油、エタノールのようなアルコール類、またはポリソルベート80(局方名)等がある。このような組成物は、さらに等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤、または溶解補助剤を含んでもよい。これらは例えばバクテリア保留フィルターを通す濾過、殺菌剤の配合または照射によって無菌化される。また、これらは無菌の固体組成物を製造し、使用前に無菌水または無菌の注射用溶媒に溶解または懸濁して使用することもできる。   Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of the aqueous solvent include distilled water for injection or physiological saline. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol or vegetable oils such as olive oil, alcohols such as ethanol, or polysorbate 80 (a pharmacopeia name). Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.

外用剤としては、軟膏剤、硬膏剤、クリーム剤、ゼリー剤、パップ剤、噴霧剤、ローション剤、点眼剤、眼軟膏等を包含する。一般に用いられる軟膏基剤、ローション基剤、水性または非水性の液剤、懸濁剤、乳剤等を含有する。例えば、軟膏またはローション基剤としては、ポリエチレングリコール、プロピレングリコール、白色ワセリン、サラシミツロウ、ポリオキシエチレン硬化ヒマシ油、モノステアリン酸グリセリン、ステアリルアルコール、セチルアルコール、ラウロマクロゴール、セスキオレイン酸ソルビタン等が挙げられる。   External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like. Contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like. For example, ointment or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. Can be mentioned.

吸入剤や経鼻剤等の経粘膜剤は固体、液体または半固体状のものが用いられ、従来公知の方法に従って製造することができる。例えば公知の賦形剤や、更に、pH調製剤、防腐剤、界面活性剤、滑沢剤、安定剤や増粘剤等が適宜添加されていてもよい。投与は、適当な吸入または吹送のためのデバイスを使用することができる。例えば、計量投与吸入デバイス等の公知のデバイスや噴霧器を使用して、化合物を単独でまたは処方された混合物の粉末として、もしくは医薬的に許容し得る担体と組み合わせて溶液または懸濁液として投与することができる。乾燥粉末吸入器等は、単回または多数回の投与用のものであってもよく、乾燥粉末または粉末含有カプセルを利用することができる。あるいは、適当な駆出剤、例えば、クロロフルオロアルカン、ヒドロフルオロアルカンまたは二酸化炭素等の好適な気体を使用した加圧エアゾールスプレー等の形態であってもよい。   Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semi-solid form and can be produced according to conventionally known methods. For example, known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added. For administration, an appropriate device for inhalation or insufflation can be used. For example, using a known device such as a metered dose inhalation device or a nebulizer, the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to. The dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable gas such as a suitable propellant such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.

通常経口投与の場合、1日の投与量は、体重当たり約0.001から100 mg/kg、好ましくは0.1から30 mg/kg、更に好ましくは0.1から10 mg/kgが適当であり、これを1回であるいは2回から4回に分けて投与する。静脈内投与される場合は、1日の投与量は、体重当たり約0.0001から10 mg/kgが適当で、1日1回から複数回に分けて投与する。また、経粘膜剤としては、体重当たり約0.001から100 mg/kgを1日1回から複数回に分けて投与する。投与量は症状、年令、性別等を考慮して個々の場合に応じて適宜決定される。   In the case of oral administration, the appropriate daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Or in 2 to 4 divided doses. When administered intravenously, the daily dose is suitably about 0.0001 to 10 mg / kg per body weight, and is administered once a day or in multiple doses. In addition, as a transmucosal agent, about 0.001 to 100 mg / kg per body weight is administered once a day or divided into multiple times. The dosage is appropriately determined according to the individual case in consideration of symptoms, age, sex and the like.

式(I)の化合物は、前述の式(I)の化合物が有効性を示すと考えられる疾患の種々の治療剤または予防剤と併用することができる。当該併用は、同時投与、或いは別個に連続して、若しくは所望の時間間隔をおいて投与してもよい。同時投与製剤は、配合剤であっても別個に製剤化されていてもよい。   The compound of the formula (I) can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound of the formula (I) is considered to be effective. The combination may be administered simultaneously, separately separately, or at desired time intervals. The simultaneous administration preparation may be a compounding agent or may be separately formulated.

以下、実施例に基づき、式(I)の化合物の製造法をさらに詳細に説明する。なお、本発明は、下記実施例に記載の化合物に限定されるものではない。また、原料化合物の製法を製造例にそれぞれ示す。また、式(I)の化合物の製造法は、以下に示される具体的実施例の製造法のみに限定されるものではなく、式(I)の化合物はこれらの製造法の組み合わせ、あるいは当業者に自明である方法によっても製造されうる。   Hereinafter, based on an Example, the manufacturing method of the compound of a formula (I) is demonstrated in detail. In addition, this invention is not limited to the compound as described in the following Example. Moreover, the manufacturing method of a raw material compound is shown in a manufacture example, respectively. Further, the production method of the compound of the formula (I) is not limited to the production methods of the specific examples shown below. The compound of the formula (I) may be a combination of these production methods or a person skilled in the art. It can also be produced by methods that are self-evident.

また、実施例、製造例及び後記表中において、以下の略号を用いることがある。Pr：製造例番号、Ex：実施例番号、Structure：構造式、Data：物理化学データ、NMR：1H-NMR(d6-DMSO)、NMR(CDCl3)：1H-NMR(CDCl3)、ESI：ESI-MS、Syn：製造法(数字は、当該実施例化合物がその実施例化合物と同様の製造法で製造されたことを示す)。 Moreover, the following abbreviations may be used in Examples, Production Examples, and Tables below. Pr: Production example number, Ex: Example number, Structure: Structural formula, Data: Physical chemical data, NMR: 1 H-NMR (d 6 -DMSO), NMR (CDCl 3 ): 1 H-NMR (CDCl 3 ) , ESI: ESI-MS, Syn: Production method (numbers indicate that the Example compound was produced by the same production method as the Example compound).

製造例1
3-クロロ-4-ヒドロキシフェニル酢酸エチル(5.66 g)のDMF(100 mL)溶液に、K2CO3 (4.74 g)とジメチルチオカルバモイルクロライド(3.75 g)を加え、50℃で5時間撹拌した。反応混合物を水(500 mL)に注ぎ、EtOAc(300 mL)で抽出した。有機層を水(200 mL)、飽和食塩水(200 mL)で洗浄後、MgSO4で乾燥後、ろ液を減圧濃縮することにより、3-クロロ-4-(ジメチルアミノカルボノチオニルオキシ)フェニル酢酸エチル(7.69 g)を橙色オイルとして得た。 Production Example 1
To a solution of ethyl 3-chloro-4-hydroxyphenylacetate (5.66 g) in DMF (100 mL) was added K 2 CO 3 (4.74 g) and dimethylthiocarbamoyl chloride (3.75 g), and the mixture was stirred at 50 ° C. for 5 hours. . The reaction mixture was poured into water (500 mL) and extracted with EtOAc (300 mL). The organic layer was washed with water (200 mL) and saturated brine (200 mL), dried over MgSO 4 , and the filtrate was concentrated under reduced pressure to give 3-chloro-4- (dimethylaminocarbonothionyloxy) phenyl. Ethyl acetate (7.69 g) was obtained as an orange oil.

製造例2
{3-クロロ-4-(ジメチルアミノカルボノチオニルオキシ)フェニル}酢酸エチル(7.6 g)を、外温240℃で3時間撹拌した。反応物を、シリカゲルカラムクロマトグラフィー(n-hexane/EtOAc)で精製し、(3-クロロ-4-((ジメチルカルバモイル)スルファニル)フェニル)酢酸エチル(1.65 g)を橙色オイルとして得た。 Production Example 2
Ethyl {3-chloro-4- (dimethylaminocarbonothionyloxy) phenyl} acetate (7.6 g) was stirred at an external temperature of 240 ° C. for 3 hours. The reaction product was purified by silica gel column chromatography (n-hexane / EtOAc) to obtain ethyl (3-chloro-4-((dimethylcarbamoyl) sulfanyl) phenyl) acetate (1.65 g) as an orange oil.

製造例3
{3-クロロ-4-(ジメチルカルバモイルスルファニル)フェニル}酢酸エチル(1.64 g)をMeOH(16.4 mL)に溶かし、KOH(1.52 g)の水(8.2 mL)溶液を加え、50 ℃で2時間撹拌した。反応混合物を減圧濃縮し、残渣を水(10 mL)に溶解し、室温撹拌下、1M 塩酸(40 mL)へ滴下した。30分間以上撹拌後、析出物をろ取した。ろ取物を乾燥させて、(3-クロロ-4-スルファニルフェニル)酢酸(0.93 g)を淡黄色粉末として得た。 Production Example 3
{3-Chloro-4- (dimethylcarbamoylsulfanyl) phenyl} ethyl acetate (1.64 g) is dissolved in MeOH (16.4 mL), a solution of KOH (1.52 g) in water (8.2 mL) is added, and the mixture is stirred at 50 ° C. for 2 hours. did. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (10 mL) and added dropwise to 1M hydrochloric acid (40 mL) with stirring at room temperature. After stirring for 30 minutes or more, the precipitate was collected by filtration. The filtered product was dried to obtain (3-chloro-4-sulfanylphenyl) acetic acid (0.93 g) as a pale yellow powder.

後記表に示す製造例3-1から3-2の化合物を、製造例3と同様に、対応する原料を用いて製造した。   The compounds of Production Examples 3-1 to 3-2 shown in the table below were produced using the corresponding raw materials in the same manner as Production Example 3.

製造例4
{4-(4-アミノフェノキシ)-3-クロロフェニル}酢酸エチル(1.50 g)のDCM(30 mL)溶液に3,4-ジクロロ安息香酸(1.12 g)、WSC・HCl(1.13 g)、HOBt(795 mg)を加え室温で6 時間攪拌した。反応液を水(150 mL)に注いだ後、EtOAc(300 mL)で抽出した。有機層を水(150 mL)、飽和食塩水で洗浄後、MgSO4で乾燥後、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィーを用いて精製し、3-クロロ-4-{4-(3,4-ジクロロベンゾイルアミノ)フェノキシ}フェニル酢酸エチル(1.90 g)を淡黄色固体として得た。 Production Example 4
To a solution of ethyl {4- (4-aminophenoxy) -3-chlorophenyl} acetate (1.50 g) in DCM (30 mL), 3,4-dichlorobenzoic acid (1.12 g), WSC / HCl (1.13 g), HOBt ( 795 mg) was added and stirred at room temperature for 6 hours. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (300 mL). The organic layer was washed with water (150 mL) and saturated brine, dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography to obtain ethyl 3-chloro-4- {4- (3,4-dichlorobenzoylamino) phenoxy} phenyl acetate (1.90 g) as a pale yellow solid.

後記表に示す製造例4-1から4-119の化合物を、製造例4と同様に、対応する原料を用いて製造した。   In the same manner as in Production Example 4, the compounds of Production Examples 4-1 to 4-119 shown in the table below were produced using the corresponding raw materials.

製造例5
{4-(6-アミノピリジン-3-イルオキシ)-3-クロロフェニル}酢酸エチル(150 mg)のDCM(3 mL)溶液 に3,4-ジクロロベンゾイルクロライド(108 mg)、 TEA(82 μL)、DMAP(12 mg)を加え、室温下、一晩攪拌した。 反応混合物を水に注ぎ、EtOAcで抽出した。有機層を、飽和NaHCO3水溶液、水、飽和食塩水で順次洗浄した後、MgSO4で乾燥後、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(n-hexane:EtOAc=3:1)で精製し、[3-クロロ-4-({6-[(3,4-ジクロロベンゾイル)アミノ]ピリジン-3-イル}オキシ)フェニル]酢酸エチル(209.5 mg)を無色ガム状物として得た。 Production Example 5
To a solution of ethyl {4- (6-aminopyridin-3-yloxy) -3-chlorophenyl} acetate (150 mg) in DCM (3 mL), 3,4-dichlorobenzoyl chloride (108 mg), TEA (82 μL), DMAP (12 mg) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed successively with saturated aqueous NaHCO 3 solution, water and saturated brine, dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: EtOAc = 3: 1), and [3-chloro-4-({6-[(3,4-dichlorobenzoyl) amino] pyridine-3- Ir} oxy) phenyl] ethyl acetate (209.5 mg) was obtained as a colorless gum.

後記表に示す製造例5-1から5-17の化合物を、製造例5と同様に、対応する原料を用いて製造した。   In the same manner as in Production Example 5, the compounds of Production Examples 5-1 to 5-17 shown in the table below were produced using the corresponding raw materials.

製造例6
[4-(4-アミノフェノキシ)-3-クロロフェニル]酢酸エチル(300 mg)のTHF(6 mL)溶液に氷冷下、TEA(410 μL)とトリホスゲン(146 mg)を加え１時間攪拌した後、1,2,3,4-テトラヒドロイソキノリン(137 μL)を加え、室温で終夜攪拌した。反応液をEtOAcで希釈した後、1M 塩酸、飽和食塩水で順次洗浄し、MgSO4で乾燥後、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィーを用いて精製し、(3-クロロ-4-{4-[(3,4-ジヒドロイソキノリン-2(1H)-イルカルボニル)アミノ]フェノキシ}フェニル)酢酸エチル(243 mg)を淡褐色アモルファスとして得た。 Production Example 6
TEA (410 μL) and triphosgene (146 mg) were added to a solution of ethyl [4- (4-aminophenoxy) -3-chlorophenyl] acetate (300 mg) in THF (6 mL) under ice cooling, and the mixture was stirred for 1 hour. 1,2,3,4-tetrahydroisoquinoline (137 μL) was added and stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed successively with 1M hydrochloric acid and saturated brine, dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography to obtain ethyl (3-chloro-4- {4-[(3,4-dihydroisoquinolin-2 (1H) -ylcarbonyl) amino] phenoxy} phenyl) acetate (243 mg ) Was obtained as a light brown amorphous.

後記表に示す製造例6-1から6-8の化合物を、製造例6と同様に、対応する原料を用いて製造した。   In the same manner as in Production Example 6, the compounds of Production Examples 6-1 to 6-8 shown in the table below were produced using the corresponding raw materials.

製造例7
[3-クロロ-4-(4-{(4-ニトロフェノキシカルボニル)アミノ}フェノキシ)フェニル]酢酸エチル(250 mg)とTEA(148 μL)のTHF(5 mL)溶液に氷冷下、フェネチルアミン(80.4 μL)を加え、室温で１時間攪拌した。反応液を水に注いだ後、EtOAcで抽出した。有機層を飽和NaHCO3水、水、飽和食塩水で順次洗浄後、MgSO4で乾燥後、ろ液を減圧濃縮した。残渣をIPEを用いて洗浄し、[3-クロロ-4-(4-{[(2-フェニルエチル)カルバモイル]アミノ}フェノキシ)フェニル]酢酸エチル(203 mg)を白色粉末として得た。 Production Example 7
A solution of ethyl [3-chloro-4- (4-{(4-nitrophenoxycarbonyl) amino} phenoxy) phenyl] acetate (250 mg) and TEA (148 μL) in THF (5 mL) under ice cooling with phenethylamine ( 80.4 μL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with EtOAc. The organic layer was washed successively with saturated aqueous NaHCO 3 , water and saturated brine, dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was washed with IPE to obtain ethyl [3-chloro-4- (4-{[(2-phenylethyl) carbamoyl] amino} phenoxy) phenyl] acetate (203 mg) as a white powder.

後記表に示す製造例7-1及び7-2の化合物を、製造例7と同様に、対応する原料を用いて製造した。   In the same manner as in Production Example 7, the compounds of Production Examples 7-1 and 7-2 shown in the table below were produced using the corresponding raw materials.

製造例8
(3-クロロ-4-ヒドロキシフェニル)酢酸(3.00 g)のEtOH(30 mL)溶液に濃硫酸(89.3 μL)を加え、室温で終夜攪拌した。反応液を水に注いだ後、EtOAcで抽出した。有機層を水、飽和NaHCO3水、水、飽和食塩水で順次洗浄した後、MgSO4で乾燥後、ろ液を減圧濃縮して(3-クロロ-4-ヒドロキシフェニル)酢酸エチル(3.30 g)を褐色油状物質として得た。 Production Example 8
Concentrated sulfuric acid (89.3 μL) was added to a solution of (3-chloro-4-hydroxyphenyl) acetic acid (3.00 g) in EtOH (30 mL), and the mixture was stirred at room temperature overnight. The reaction solution was poured into water and extracted with EtOAc. The organic layer was washed successively with water, saturated aqueous NaHCO 3 , water and saturated brine, and dried over MgSO 4 , and the filtrate was concentrated under reduced pressure to obtain ethyl (3-chloro-4-hydroxyphenyl) acetate (3.30 g). Was obtained as a brown oil.

後記表に示す製造例8-1及び8-5の化合物を、製造例8と同様に、対応する原料を用いて製造した。   In the same manner as in Production Example 8, the compounds of Production Examples 8-1 and 8-5 shown in the table below were produced using the corresponding raw materials.

製造例9
{3-クロロ-4-(4−アミノフェノキシ)フェニル}酢酸エチル(1.50 g)のDCM(30 mL)溶液に氷冷下ピリジン(1.31 mL)を加え10分間攪拌し、クロロギ酸(４−ニトロフェニル)(1.19 g)を徐々に加え室温で２時間攪拌した。反応液に水(100 mL)を加え10分間攪拌した後、EtOAcで抽出した。有機層を飽和食塩水で洗浄した後、MgSO4で乾燥しろ過後、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出液；n-hexane：EtOAc＝3:2−0:1)で精製し、得られた粗結晶を混合溶媒(DCM：IPE=1:4)で洗浄して[3-クロロ-4-(4-{[(4-ニトロフェノキシ)カルボニル]アミノ}フェノキシ)フェニル]酢酸エチル(2.36 g)を白色粉末として得た。 Production Example 9
To a solution of ethyl {3-chloro-4- (4-aminophenoxy) phenyl} acetate (1.50 g) in DCM (30 mL) was added pyridine (1.31 mL) under ice-cooling, and the mixture was stirred for 10 minutes, and chloroformate (4-nitro Phenyl) (1.19 g) was gradually added and stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction mixture, and the mixture was stirred for 10 min, and extracted with EtOAc. The organic layer was washed with saturated brine, dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane: EtOAc = 3: 2-0: 1), and the resulting crude crystals were washed with a mixed solvent (DCM: IPE = 1: 4) [ Ethyl 3-chloro-4- (4-{[(4-nitrophenoxy) carbonyl] amino} phenoxy) phenyl] acetate (2.36 g) was obtained as a white powder.

製造例10
[4-(4-{[(5-ブロモ-1-ベンゾフラン-2-イル)カルボニル]アミノ}フェノキシ)-3-クロロフェニル]酢酸エチルのDMF(5 mL)溶液に Zn(CN)2(133 mg) とPd(PPh3)4(175 mg)を加え、マイクロウェーブ照射下で 150 ℃で1時間反応させた。不溶物をろ別し、ろ液に水(50 mL)を加え、EtOAc(40 mL)で抽出した。有機層を水、飽和食塩水で順次洗浄し、MgSO4で乾燥し、ろ液を減圧濃縮し、褐色オイル(570 mg)を得た。残渣をシリカゲルカラムクロマトグラフィー(n-hexane:EtOAc=2:1)で精製し、[3-クロロ-4-(4-{[(5-シアノ-1-ベンゾフラン-2-イル)カルボニル]アミノ}フェノキシ)フェニル]酢酸エチル(199.3 mg)を白色固体として得た。 Production Example 10
[4- (4-{[(5-Bromo-1-benzofuran-2-yl) carbonyl] amino} phenoxy) -3-chlorophenyl] ethyl acetate in DMF (5 mL) solution with Zn (CN) 2 (133 mg ) And Pd (PPh 3 ) 4 (175 mg) were added, and the mixture was reacted at 150 ° C. for 1 hour under microwave irradiation. Insoluble material was filtered off, water (50 mL) was added to the filtrate, and the mixture was extracted with EtOAc (40 mL). The organic layer was washed successively with water and saturated brine, dried over MgSO 4 , and the filtrate was concentrated under reduced pressure to give a brown oil (570 mg). The residue was purified by silica gel column chromatography (n-hexane: EtOAc = 2: 1), and [3-chloro-4- (4-{[(5-cyano-1-benzofuran-2-yl) carbonyl] amino} Phenoxy) phenyl] ethyl acetate (199.3 mg) was obtained as a white solid.

製造例11
{3-クロロ-4-(4-ニトロフェノキシ)フェニル}酢酸エチル(300 mg)のDCM(6 mL)溶液にピリジン(95.2 μL)とベンゼンスルホニルクロリド(138 μL)を加え室温で終夜攪拌した。反応液を水に注いだ後、EtOAcを用いて抽出した。有機層を水、飽和食塩水で順次洗浄した後、MgSO4で乾燥ろ過し、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、(3-クロロ-4-{4-[(フェニルスルホニル)アミノ]フェノキシ}フェニル)酢酸エチル(410 mg)を白色粉末として得た。 Production Example 11
Pyridine (95.2 μL) and benzenesulfonyl chloride (138 μL) were added to a DCM (6 mL) solution of ethyl {3-chloro-4- (4-nitrophenoxy) phenyl} acetate (300 mg), and the mixture was stirred at room temperature overnight. The reaction solution was poured into water and extracted with EtOAc. The organic layer was washed successively with water and saturated brine, dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain ethyl (3-chloro-4- {4-[(phenylsulfonyl) amino] phenoxy} phenyl) acetate (410 mg) as a white powder.

後記表に示す製造例11-1の化合物を、製造例11と同様に、対応する原料を用いて製造した。   In the same manner as in Production Example 11, the compound of Production Example 11-1 shown in the table below was produced using the corresponding raw material.

製造例12
ボラン-THF錯体(1.17 M, 12.8 mL)に氷冷下、シクロヘキセン(3.04 mL)を加え５分間攪拌した後、{[2,5-ジクロロ-4-(4-ニトロフェノキシ)フェニル]エチニル}(トリメチル)シラン(1.63 g)のTHF(25 mL)溶液を加え同温で２時間攪拌した。反応液に1M NaOH水溶液(10.7 mL)とMeOH(12.5 mL)を加えた後、過酸化水素水(30%, 4.86 mL)を加え同温で１時間攪拌した。反応液を水に注いだ後、EtOAcで抽出した。有機層を飽和食塩水で洗浄後、MgSO4で乾燥し、ろ液を減圧濃縮した。残渣をEtOH(5 mL)に溶解した後、濃硫酸を１滴加え、４時間加熱還流した。反応液を室温まで冷却した後、水に注ぎ、EtOAcで抽出した。有機層を飽和食塩水で洗浄、MgSO4で乾燥し、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、[2,5-ジクロロ-4-(4-ニトロフェノキシ)フェニル]酢酸エチル(510 mg)を茶色油状物質として得た。 Production Example 12
Cyclohexene (3.04 mL) was added to borane-THF complex (1.17 M, 12.8 mL) under ice cooling, and the mixture was stirred for 5 minutes, and then {[2,5-dichloro-4- (4-nitrophenoxy) phenyl] ethynyl} ( A solution of trimethyl) silane (1.63 g) in THF (25 mL) was added and stirred at the same temperature for 2 hours. 1M NaOH aqueous solution (10.7 mL) and MeOH (12.5 mL) were added to the reaction solution, hydrogen peroxide solution (30%, 4.86 mL) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was poured into water and extracted with EtOAc. The organic layer was washed with saturated brine, dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOH (5 mL), 1 drop of concentrated sulfuric acid was added, and the mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with EtOAc. The organic layer was washed with saturated brine, dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain [2,5-dichloro-4- (4-nitrophenoxy) phenyl] ethyl acetate (510 mg) as a brown oily substance.

製造例13
1-ブロモ-2,5-ジクロロ-4-(4-ニトロフェノキシ)ベンゼン(1.85 g)とTEA(1.07 mL)のMeCN(10 mL)溶液にジクロロビス(トリフェニルホスフィン)パラジウム(358 mg)、ヨウ化銅(I)(194 mg)、(トリメチルシリル)アセチレン(2.12 mL)を加え、マイクロウェーブ照射下、80℃で２時間反応させた。反応液を水に注いだ後、EtOAcで抽出した。有機層を飽和食塩水で洗浄した後、MgSO4で乾燥し、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、{[2,5-ジクロロ-4-(4-ニトロフェノキシ)フェニル]エチニル}(トリメチル)シラン(1.63 g)を茶色油状物質として得た。 Production Example 13
To a solution of 1-bromo-2,5-dichloro-4- (4-nitrophenoxy) benzene (1.85 g) and TEA (1.07 mL) in MeCN (10 mL) was added dichlorobis (triphenylphosphine) palladium (358 mg), iodine. Copper (I) chloride (194 mg) and (trimethylsilyl) acetylene (2.12 mL) were added, and the mixture was reacted at 80 ° C. for 2 hours under microwave irradiation. The reaction solution was poured into water and extracted with EtOAc. The organic layer was washed with saturated brine, dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain {[2,5-dichloro-4- (4-nitrophenoxy) phenyl] ethynyl} (trimethyl) silane (1.63 g) as a brown oily substance.

製造例14
{3-クロロ-4-(4-ニトロフェノキシ)フェニル}酢酸エチル(2.30 g)のEtOH(46 mL)-水(11.5 mL)溶液に塩化アンモニウム(3.66 g)と鉄粉末(3.83 g)を加え、３時間加熱還流した。反応液をセライトでろ過した後、減圧濃縮し、飽和NaHCO3を加えた後、EtOAcで抽出した。有機層を飽和食塩水で洗浄した後、MgSO4で乾燥し、ろ液を減圧濃縮することにより、{4-(4-アミノフェノキシ)-3-クロロフェニル}酢酸エチル(2.30 g)を褐色油状物質として得た。 Production Example 14
Add ammonium chloride (3.66 g) and iron powder (3.83 g) to a solution of ethyl {3-chloro-4- (4-nitrophenoxy) phenyl} acetate (2.30 g) in EtOH (46 mL) -water (11.5 mL). Heated to reflux for 3 hours. The reaction mixture was filtered through celite, concentrated under reduced pressure, saturated NaHCO 3 was added, and the mixture was extracted with EtOAc. The organic layer was washed with saturated brine, dried over MgSO 4 , and the filtrate was concentrated under reduced pressure to give ethyl {4- (4-aminophenoxy) -3-chlorophenyl} acetate (2.30 g) as a brown oily substance. Got as.

後記表に示す製造例14-1から14-15の化合物を、製造例14と同様に、対応する原料を用いて製造した。   In the same manner as in Production Example 14, the compounds of Production Examples 14-1 to 14-15 shown in the table below were produced using the corresponding raw materials.

製造例15
氷冷下、(2-ブロモ-4-メトキシフェニル)酢酸エチル (4.4 g) のDCM(44 mL)溶液 に 1M BBr3の DCM溶液 (24.1 mL)を滴下した。5℃で5時間攪拌した後、反応混合物にEtOH (30 mL) を氷冷下、滴下して反応を停止し、減圧濃縮し、得られた残渣をEtOAc(150 mL)で抽出した。有機層を水(100 mL) 、飽和食塩水(100 mL)で順次洗浄し、MgSO4で乾燥し、ろ液を減圧濃縮した。残渣をn-hexane/IPEで粉末化後ろ取し、減圧乾燥することにより、 (2-ブロモ-4-ヒドロキシフェニル)酢酸エチル(2.56 g) を白色固体として得た。 Production Example 15
A solution of 1M BBr 3 in DCM (24.1 mL) was added dropwise to a solution of ethyl (2-bromo-4-methoxyphenyl) acetate (4.4 g) in DCM (44 mL) under ice cooling. After stirring at 5 ° C. for 5 hours, EtOH (30 mL) was added dropwise to the reaction mixture under ice cooling to stop the reaction, and the mixture was concentrated under reduced pressure, and the resulting residue was extracted with EtOAc (150 mL). The organic layer was washed successively with water (100 mL) and saturated brine (100 mL), dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was triturated with n-hexane / IPE and dried under reduced pressure to obtain ethyl (2-bromo-4-hydroxyphenyl) acetate (2.56 g) as a white solid.

製造例16
(3-クロロ-4-ヒドロキシフェニル)酢酸エチル(2.00 g)のDMF(30 mL)溶液にK2CO3(2.58 g)と４−ニトロフルオロベンゼン(1.03 mL)を加え、60 ℃で２時間攪拌した。反応液を室温まで冷却した後、水に注ぎ、EtOAcを用いて抽出した。有機層を飽和食塩水で２回洗浄した後、MgSO4で乾燥し、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出液；n-hexane：EtOAc＝4:1)を用いて精製し、{3-クロロ-4-(4-ニトロフェノキシ)フェニル}酢酸エチル(2.30 g)を褐色油状物質として得た。 Production Example 16
To a solution of ethyl (3-chloro-4-hydroxyphenyl) acetate (2.00 g) in DMF (30 mL) was added K 2 CO 3 (2.58 g) and 4-nitrofluorobenzene (1.03 mL), and then at 60 ° C. for 2 hours. Stir. The reaction solution was cooled to room temperature, poured into water, and extracted with EtOAc. The organic layer was washed twice with saturated brine, dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane: EtOAc = 4: 1), and ethyl {3-chloro-4- (4-nitrophenoxy) phenyl} acetate (2.30 g) was brown oily Obtained as material.

後記表に示す製造例17-1から17-15の化合物を、製造例17と同様に、対応する原料を用いて製造した。   The compounds of Production Examples 17-1 to 17-15 shown in the table below were produced in the same manner as in Production Example 17 using the corresponding raw materials.

製造例17
4-ベンジロキシ-1-インドール(2.98 g)とK2CO3 (1.12 g)のDMF(30 mL)懸濁液を室温で撹拌下に、エチルブロモアセテート(1.9 mL)をすこしづつ加え、一夜室温で撹拌した。K2CO3(1.12 g)とエチルブロモアセテート(1.9 mL)を追加し、室温で更に8時間撹拌した。反応混合物に水を加えEtOAcで抽出し、有機層を飽和食塩水で洗浄後、MgSO4で乾燥し、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(トルエン)で精製し、エチル(4-ベンジロキシ-1H-インドール-1-イル)アセテート(1.66 g)を白色固体として得た。 Production Example 17
While stirring a suspension of 4-benzyloxy-1-indole (2.98 g) and K 2 CO 3 (1.12 g) in DMF (30 mL) at room temperature, ethyl bromoacetate (1.9 mL) was added a little at room temperature overnight. Stir with. K 2 CO 3 (1.12 g) and ethyl bromoacetate (1.9 mL) were added, and the mixture was further stirred at room temperature for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with EtOAc. The organic layer was washed with saturated brine, dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (toluene) to obtain ethyl (4-benzyloxy-1H-indol-1-yl) acetate (1.66 g) as a white solid.

製造例18
インドール-2-カルボン酸エチル(1 g) の DMF(10 mL) 溶液に氷冷下、 60% 水素化ナトリウム(240 mg)を加え室温で 10分間撹拌したのち、1-ブロモ-2-フルオロエタン(1 g)を加え、室温で2時間撹拌した。反応液をEtOAcで希釈したのち1M 塩酸、飽和食塩水で順次洗浄し、MgSO4で乾燥し、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィーを用いて精製し、1-(2-フルオロエチル)インドール-2-カルボン酸エチル(1.1 g)を無色オイルとして得た。 Production Example 18
To a solution of ethyl indole-2-carboxylate (1 g) in DMF (10 mL) under ice-cooling, 60% sodium hydride (240 mg) was added and stirred at room temperature for 10 minutes, and then 1-bromo-2-fluoroethane was added. (1 g) was added and stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc, washed successively with 1M hydrochloric acid and saturated brine, dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography to obtain ethyl 1- (2-fluoroethyl) indole-2-carboxylate (1.1 g) as a colorless oil.

製造例19
エチル(4-ベンジロキシ-1H-インドール-1-イル)アセテート(1.75 g)をEtOH(17.5 mL)とTHF(17.5 mL)の混合溶媒に溶かし、10%パラジウム炭素(50 %水含有)(1.2 g)を加え、水素ガス雰囲気下、室温、常圧で4時間接触還元した。反応混合物をセライトを用いてろ過し、ろ液を減圧濃縮した。エチル(4-ヒドロキシ-1H-インドール-1-イル)アセテート(1.37 g)を淡茶色オイルとして得た。 Production Example 19
Ethyl (4-benzyloxy-1H-indol-1-yl) acetate (1.75 g) is dissolved in a mixed solvent of EtOH (17.5 mL) and THF (17.5 mL), and 10% palladium on carbon (containing 50% water) (1.2 g ) Was added, and catalytic reduction was performed at room temperature and normal pressure for 4 hours under a hydrogen gas atmosphere. The reaction mixture was filtered using celite, and the filtrate was concentrated under reduced pressure. Ethyl (4-hydroxy-1H-indol-1-yl) acetate (1.37 g) was obtained as a light brown oil.

製造例20
2-ブロモ−N,N−ジメチルアニリン (500 mg)と3-エトキシカルボニルフェニルボロン酸(582 mg)の1,4-ジオキサン(10 mL)溶液に2M Na2CO3水溶液(2.75 mL)と[1,1'-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム (204 mg)を加え、窒素雰囲気下で90℃で4時間攪拌した。反応混合物を室温まで冷却したのち水に注ぎ、EtOAcで抽出した。有機層をbrineで洗浄した後、無水硫酸ナトリウムで乾燥し、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィーを用いて精製し、2'-(ジメチルアミノ)ビフェニル-3-カルボン酸エチル(620 mg)を淡黄色油状物質として得た。 Production Example 20
To a solution of 2-bromo-N, N-dimethylaniline (500 mg) and 3-ethoxycarbonylphenylboronic acid (582 mg) in 1,4-dioxane (10 mL), 2M Na 2 CO 3 aqueous solution (2.75 mL) and [ 1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (204 mg) was added, and the mixture was stirred at 90 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, poured into water, and extracted with EtOAc. The organic layer was washed with brine and then dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain ethyl 2 ′-(dimethylamino) biphenyl-3-carboxylate (620 mg) as a pale yellow oily substance.

製造例化合物の構造および物理化学的データを表１から表２８に示す。   The structures and physicochemical data of the production example compounds are shown in Tables 1 to 28.

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実施例１
(3-クロロ-4-{4-[(3,4-ジクロロベンゾイル)アミノ]フェノキシ}フェニル)酢酸エチル(210 mg)のEtOH(4.2 mL)溶液に2M NaOH水溶液(439 μL)を加え、室温で４時間攪拌した。反応液に１M塩酸を加えpHを3から4に調製した後、水で希釈し、EtOAcで抽出した。有機層を飽和食塩水で洗浄後、MgSO4で乾燥し、ろ液を減圧濃縮した。残渣をジイソプロピルエーテルで粉末化したのち乾燥し、(3-クロロ-4-{4-[(3,4-ジクロロベンゾイル)アミノ]フェノキシ}フェニル)酢酸(182 mg)を白色粉末として得た。 Example 1
2M NaOH aqueous solution (439 μL) was added to a solution of ethyl (3-chloro-4- {4-[(3,4-dichlorobenzoyl) amino] phenoxy} phenyl) acetate (210 mg) in EtOH (4.2 mL) at room temperature. For 4 hours. 1M hydrochloric acid was added to the reaction solution to adjust the pH to 3 to 4, and then diluted with water and extracted with EtOAc. The organic layer was washed with saturated brine, dried over MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was triturated with diisopropyl ether and dried to give (3-chloro-4- {4-[(3,4-dichlorobenzoyl) amino] phenoxy} phenyl) acetic acid (182 mg) as a white powder.

以下の表２９から表４９に示す実施例2から実施例134の化合物を、実施例1と同様に、対応する原料を用いて製造した。実施例化合物の構造を表２９から表４９に、物理化学的データを表５０から表６３にそれぞれ示す。
The compounds of Examples 2 to 134 shown in Table 29 to Table 49 below were produced in the same manner as in Example 1 using the corresponding raw materials. The structures of the example compounds are shown in Tables 29 to 49, and the physicochemical data are shown in Tables 50 to 63, respectively.

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Claims (2)

式(I)の化合物、その塩またはそのプロドラッグ。
Figure 2011088826
 [式中、
R1は、-(C1-6アルキレン)-COOH、または-Hであり、
１)R1が、-(C1-6アルキレン)-COOHの場合、
R2は、ハロゲンまたは-H、
R3は、ハロゲン、C1-6アルキル、-O-(C1-6アルキル)または-H、
２)R1が、-Hの場合、
R2とR3が一体となって、それらが結合するベンゼン環とともに式(II)
Figure 2011088826
で示される基を形成する、
Vは、=CH-または=N-、
mは、１から6の整数を示す；
R4は、ハロゲン、または-H、
ただし、R3が-Hの場合、R4はハロゲンである、
R5は、-H、ハロゲンまたはC1-6アルキル、
R6は、それぞれ置換されていてもよいアリール、ヘテロアリール、ヘテロシクロアルキルまたは-N(R6a)(R6b)、
R6aは、-(C1-6アルキレン)-アリール、-(C1-6アルキレン)-ヘテロアリール、-(C1-6アルキレン)-ヘテロシクロアルキル、
R6bは、-HまたはC1-6アルキル、
Aは、-O-または-S-、
Dは、-C(=O)-、または-S(=O)2-
Eは、結合、C1-6アルキレン、またはC2-6アルケニレン、
Yは、=C(R5a)-または=N-、
R5aは、-H、ハロゲンまたはC1-6アルキル、
Zは、=CH-または=N-。
Uは、-C(R5b)=または-N=、
R5bは、-H、ハロゲンまたはC1-6アルキル。] A compound of formula (I), a salt thereof or a prodrug thereof.
Figure 2011088826
 [Where
R 1 is-(C 1-6 alkylene) -COOH, or -H;
1) When R 1 is-(C 1-6 alkylene) -COOH,
R 2 is halogen or -H,
R 3 is halogen, C 1-6 alkyl, —O— (C 1-6 alkyl) or —H,
2) When R 1 is -H,
R 2 and R 3 together, together with the benzene ring to which they are attached, formula (II)
Figure 2011088826
To form a group represented by
V is = CH- or = N-,
m represents an integer from 1 to 6;
R 4 is halogen or -H,
Provided that when R 3 is -H, R 4 is halogen,
R 5 is -H, halogen or C 1-6 alkyl,
Each R 6 is optionally substituted aryl, heteroaryl, heterocycloalkyl or -N (R 6a ) (R 6b ),
R 6a is- (C 1-6 alkylene) -aryl,-(C 1-6 alkylene) -heteroaryl,-(C 1-6 alkylene) -heterocycloalkyl,
R 6b is -H or C 1-6 alkyl,
A is -O- or -S-,
D is -C (= O)-, or -S (= O) 2-
E is a bond, C 1-6 alkylene, or C 2-6 alkenylene,
Y is = C (R 5a ) -or = N-,
R 5a is -H, halogen or C 1-6 alkyl,
Z is = CH- or = N-.
U is -C (R 5b ) = or -N =,
R 5b is —H, halogen or C 1-6 alkyl. ] 式(I)において
R3が、ハロゲン、C1-6アルキルまたは-O-(C1-6アルキル)、
である請求項１記載の化合物またはその塩。 In formula (I)
R 3 is halogen, C 1-6 alkyl or —O— (C 1-6 alkyl),
The compound according to claim 1 or a salt thereof.
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