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JPWO2006041197A1 - Activator of peroxisome proliferator activated receptor δ - Google Patents

Activator of peroxisome proliferator activated receptor δ Download PDF

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JPWO2006041197A1
JPWO2006041197A1 JP2006541003A JP2006541003A JPWO2006041197A1 JP WO2006041197 A1 JPWO2006041197 A1 JP WO2006041197A1 JP 2006541003 A JP2006541003 A JP 2006541003A JP 2006541003 A JP2006541003 A JP 2006541003A JP WO2006041197 A1 JPWO2006041197 A1 JP WO2006041197A1
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佐久間 詔悟
詔悟 佐久間
望月 信孝
信孝 望月
理恵 高橋
理恵 高橋
ユカ 田中
ユカ 田中
山川 富雄
富雄 山川
増井 誠一郎
誠一郎 増井
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Nippon Chemiphar Co Ltd
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Abstract

次の一般式(II)、(式中、B1はメチレン又はエチレン等を表し、W1は酸素原子又は硫黄原子を表し、X1は窒素原子又はCHを表し、Z1は酸素原子又はCH2を表し、R11及びR12は共に水素原子又は炭素数1〜3のアルキル基を表し、そして、R14、R15及びR16は同一又は異なっても良く、水素原子、ハロゲン原子、炭素数1〜8のアルキル基又はハロゲン原子で置換された炭素数1〜8のアルキル基等を表す。)で表される化合物又はその塩をPPARδの活性化剤として使用する。The following general formula (II), wherein B1 represents methylene or ethylene, W1 represents an oxygen atom or a sulfur atom, X1 represents a nitrogen atom or CH, Z1 represents an oxygen atom or CH2, R11 And R12 both represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R14, R15 and R16 may be the same or different, and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms or a halogen atom. Or a salt thereof is used as an activator of PPARδ.

Description

本発明はペルオキシソーム増殖剤活性化受容体(PPAR)δの活性化剤に関する。The present invention relates to an activator of peroxisome proliferator activated receptor (PPAR) δ.

ペルオキシソーム増殖剤活性化受容体(peroxisome proliferator activated receptor:PPAR)はこれまで大きく分けて3つのサブタイプの存在が知られており、PPARα、PPARγ及びPPARδと称せられている。(Proc.Natl.Acad.Sci.USA,91,p7335−7359,1994(非特許文献1))
そして、これまで種々の化合物について、PPAR各サブタイプの転写活性化作用、さらには血糖降下、脂質代謝改善作用等に関する報告がなされている。
たとえばWO 97/28115(特許文献1)には、L−165041(メルク)の糖尿病治療剤や抗肥満薬としての使用が記載され、WO 99/04815(特許文献2)には、YM−16638(山之内)が血清コレステロール低下作用、LDL−コレステロール低下作用を有する旨の記載がなされており、WO 2004/7439(特許文献3)では、ビアリール誘導体の血中HDLを上昇させる薬物としての使用が記載され、その他、WO 2003/84916(特許文献4)(フェノキシ酢酸誘導体)、WO 2004/315(特許文献5)(フェノキシ酢酸誘導体)、WO 01/40207(特許文献6)(GW−590735)他多数の特許が出願されている。
そしてWO 01/603(特許文献7)記載の次式、

Figure 2006041197
で表されるGW−501516(GSK)については、現在、脂質代謝改善剤として開発が進行中である旨の報告がなされている。
一方、本発明者らも既にPPARδの転写活性化作用を有する化合物につき、特許出願している。(WO 03/16291(特許文献8)他)
後記一般式(I)で表される本発明化合物と上記GW−501516等とは、構造上の明確な相違がある。Peroxisome proliferator activated receptors (PPARs) have been broadly classified into three subtypes so far, and are called PPARα, PPARγ and PPARδ. (Proc. Natl. Acad. Sci. USA, 91, p7335-7359, 1994 (Non-Patent Document 1))
So far, various compounds have been reported on the transcriptional activation action of each subtype of PPAR, as well as the hypoglycemic effect, the lipid metabolism improving action and the like.
For example, WO 97/28115 (Patent Document 1) describes the use of L-165041 (Merck) as a therapeutic agent for diabetes or an anti-obesity agent, and WO 99/04815 (Patent Document 2) describes YM-16638 (Patent Document 2). Yamanouchi) describes that it has a serum cholesterol lowering action and an LDL-cholesterol lowering action, and WO 2004/7439 (Patent Document 3) describes the use of a biaryl derivative as a drug that increases blood HDL. In addition, WO 2003/84916 (patent document 4) (phenoxyacetic acid derivative), WO 2004/315 (patent document 5) (phenoxyacetic acid derivative), WO 01/40207 (patent document 6) (GW-590735) and many others A patent has been filed.
And the following formula described in WO 01/603 (Patent Document 7):
Figure 2006041197
As for GW-501516 (GSK) represented by the formula, it has been reported that development is ongoing as a lipid metabolism improving agent.
On the other hand, the present inventors have already filed a patent application for a compound having the transcriptional activation effect of PPARδ. (WO 03/16291 (Patent Document 8) and others)
The compound of the present invention represented by the following general formula (I) and the above GW-501516 have a clear structural difference.

本発明の目的はペルオキシソーム増殖剤活性化受容体の活性化作用を有する下記一般式(I)で表される化合物を提供することにある。
即ち、本発明は、次の一般式(I)

Figure 2006041197
(式中、Aは結合手、酸素原子、硫黄原子、C(=O)、C(=CH)、(CH又はN(R)を表し、ここで、mは1又は2を表し、Rは、水素原子又は炭素数1〜8のアルキル基を表し、
Bは置換基として炭素数1〜8のアルキル基、3〜8員環のシクロアルキル基、ハロゲン原子で置換された炭素数1〜8のアルキル基、炭素数1〜8のアルコキシ基、炭素数2〜8のアルケニル基、ハロゲン原子、アラルキル基(アリール部分の炭素数は6〜10で、アルキル部分の炭素数は1〜3)、複素環で置換された炭素数1〜3のアルキル基から選ばれる基又は原子を有していても良いメチレン、エチレン又はビニレンを表し、
Wは酸素原子、硫黄原子、(CH又はN(R)を表し、ここで、nは1又は2を表し、Rは水素原子又は炭素数1〜8のアルキル基を表し、
X及びYは同一又は異なっても良く、窒素原子又はCHを表し、
Zは、酸素原子又はCHRを表し、ここで、Rは、水素原子又は炭素数1〜8のアルキル基を表し、
及びRは同一又は異なっても良く、水素原子、炭素数1〜8のアルキル基又はハロゲン原子で置換された炭素数1〜8のアルキルを表し、
はカルボキシル基、炭素数2〜8のアルコキシカルボニル基、カルバモイル基、アラルキルオキシカルボニル基(アリール部分の炭素数は6〜10で、アルキル部分の炭素数は1〜3)、スルホン酸基、ホスホン酸基、シアノ基又はテトラゾリル基を表し、
そして、R、R及びRは、同一又は異なっても良く、水素原子、ハロゲン原子、炭素数1〜8のアルキル基、ハロゲン原子で置換された炭素数1〜8のアルキル基、3〜8員環のシクロアルキル基、炭素数1〜8のアルコキシ基で置換された炭素数1〜8のアルキル基、炭素数1〜8のアルコキシ基、ハロゲン原子で置換された炭素数1〜8のアルコキシ基、炭素数2〜8のアルケニル基、炭素数2〜8のアルキニル基、ヒドロキシル基、ニトロ基、炭素数2〜8のアシル基、炭素数7〜11のアリールカルボニル基、炭素数6〜10のアリール基又は複素環を表す。
なお、上記のアリール及び複素環には、置換基として炭素数1〜8のアルキル基、炭素数1〜8のアルコキシ基、ハロゲン原子、ハロゲン原子で置換された炭素数1〜8のアルキル基、ヒドロキシル基、ニトロ基、アミノ基、フェニル基又は複素環から選ばれる基又は原子を有していても良い。)
で表される化合物又はその塩に関する。
また、本発明は、次の一般式(II)、
Figure 2006041197
(式中、Bはメチレン、エチレン又はCH=CH(ビニレン)を表し、
は酸素原子又は硫黄原子を表し、
は窒素原子又はCHを表し、
は酸素原子又はCHを表し、
11及びR12は共に水素原子又は炭素数1〜3のアルキル基を表し、
そして、R14、R15及びR16は同一又は異なっても良く、水素原子、ハロゲン原子、炭素数1〜8のアルキル基、ハロゲン原子で置換された炭素数1〜8のアルキル基、炭素数1〜8のアルコキシ基、又はハロゲン原子で置換された炭素数1〜8のアルコキシ基を表す。)
で表される化合物又はその塩に関する。
また本発明は上記一般式(I)又は(II)で表される化合物又はその塩を有効成分として含有するペルオキシソーム増殖剤活性化受容体δの活性化剤に関する。An object of the present invention is to provide a compound represented by the following general formula (I) having an activation action of a peroxisome proliferator-activated receptor.
That is, the present invention provides the following general formula (I)
,
Figure 2006041197
(In the formula, A represents a bond, an oxygen atom, a sulfur atom, C (═O), C (═CH 2 ), (CH 2 ) m or N (R 7 ), where m is 1 or 2 R 7 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms,
B is a C1-C8 alkyl group, a 3- to 8-membered cycloalkyl group, a C1-C8 alkyl group substituted with a halogen atom, a C1-C8 alkoxy group, or a carbon number as a substituent. From an alkenyl group having 2 to 8 carbon atoms, a halogen atom, an aralkyl group (the aryl moiety has 6 to 10 carbon atoms and the alkyl moiety has 1 to 3 carbon atoms), an alkyl group having 1 to 3 carbon atoms substituted with a heterocyclic ring Represents methylene, ethylene or vinylene which may have a selected group or atom,
W represents an oxygen atom, a sulfur atom, (CH 2 ) n or N (R 8 ), wherein n represents 1 or 2, R 8 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms,
X and Y may be the same or different and each represents a nitrogen atom or CH;
Z represents an oxygen atom or CHR 9 , where R 9 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms,
R 1 and R 2 may be the same or different and each represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or an alkyl having 1 to 8 carbon atoms substituted with a halogen atom,
R 3 is a carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms, a carbamoyl group, an aralkyloxycarbonyl group (the aryl moiety has 6 to 10 carbon atoms and the alkyl moiety has 1 to 3 carbon atoms), a sulfonic acid group, Represents a phosphonic acid group, a cyano group or a tetrazolyl group,
R 4 , R 5 and R 6 may be the same or different, and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, 3 ˜8-membered cycloalkyl group, C 1-8 alkyl group substituted with C 1-8 alkoxy group, C 1-8 alkoxy group, C 1-8 substituted with halogen atom Alkoxy groups, alkenyl groups having 2 to 8 carbon atoms, alkynyl groups having 2 to 8 carbon atoms, hydroxyl groups, nitro groups, acyl groups having 2 to 8 carbon atoms, arylcarbonyl groups having 7 to 11 carbon atoms, and 6 carbon atoms. Represents 10 to 10 aryl groups or heterocyclic rings.
In the above aryl and heterocycle, the alkyl group having 1 to 8 carbon atoms, the alkoxy group having 1 to 8 carbon atoms, the halogen atom, and the alkyl group having 1 to 8 carbon atoms substituted with a halogen atom as a substituent, You may have a group or an atom chosen from a hydroxyl group, a nitro group, an amino group, a phenyl group, or a heterocyclic ring. )
Or a salt thereof.
Further, the present invention provides the following general formula (II),
Figure 2006041197
(Wherein B 1 represents methylene, ethylene or CH═CH (vinylene);
W 1 represents an oxygen atom or a sulfur atom,
X 1 represents a nitrogen atom or CH,
Z 1 represents an oxygen atom or CH 2 ,
R 11 and R 12 both represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,
R 14 , R 15 and R 16 may be the same or different, and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, or a carbon number. An alkoxy group having 1 to 8 carbon atoms or a C 1-8 alkoxy group substituted with a halogen atom is represented. )
Or a salt thereof.
The present invention also relates to an activator for peroxisome proliferator-activated receptor δ containing the compound represented by the above general formula (I) or (II) or a salt thereof as an active ingredient.

次に本発明を詳細に説明する。
上記一般式(I)においてR、R、R、R、R、R、R、R並びにBのメチレン、エチレン又はビニレンが有していても良い置換基、及びアリール及び複素環基が有していても良い置換基の炭素数1〜8のアルキル基としてはメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、i−ブチル基、t−ブチル基、ペンチル基又はヘキシル基が挙げられる。
、R及びR並びにBのメチレン、エチレン又はビニレンが有していても良い置換基の3〜8員環のシクロアルキル基としてはシクロプロピル基、シクロペンチル基又はシクロヘキシル基等が挙げられる。
、R、R、R、R並びにBのメチレン、エチレン又はビニレンが有していても良い置換基、及びアリール及び複素環基が有していても良い置換基のハロゲン原子で置換された炭素数1〜8のアルキル基としては、1〜3個のフッ素原子、塩素原子若しくは臭素原子等のハロゲン原子により置換されたメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、またはt−ブチル基が挙げられ、好ましくはトリフルオロメチル基、クロロメチル基、2−クロロエチル基、2−ブロモエチル基、2−フルオロエチル基等が挙げられる。
、R及びR並びにBのメチレン、エチレン又はビニレンが有していても良い置換基、アリール及び複素環基が有していても良い置換基の炭素数1〜8のアルコキシ基としてはメトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、i−ブトキシ基、t−ブトキシ基、ペンチルオキシ基又はヘキシルオキシ基等が挙げられる。
、R及びRのハロゲン原子で置換された炭素数1〜8のアルコキシ基としては1〜3個のフッ素原子、塩素原子若しくは臭素原子等のハロゲン原子により置換されたメトキシ基、エトキシ基、プロポキシ基、イソプロピルオキシ基、ブチルオキシ基、またはt−ブチルオキシ基が挙げられ、好ましくはトリフルオロメチルオキシ基、クロロメチルオキシ基、2−クロロエチルオキシ基、2−ブロモエチルオキシ基、2−フルオロエチルオキシ基等が挙げられる。
、R及びRの炭素数1〜8のアルコキシ基で置換された炭素数1〜8のアルキル基としては、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、i−ブトキシ基、t−ブトキシ基、ペンチルオキシ基又はヘキシルオキシ基等で置換されたメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、i−ブチル基、t−ブチル基、ペンチル基又はヘキシル基が挙げられる。
、R及びR並びにBのメチレン、エチレン又はビニレンが有していても良い置換基の炭素数2〜8のアルケニル基としては、ビニル基、アリル基が挙げられる。
、R及びRの炭素数2〜8のアルキニル基としては、プロパルギル基が挙げられる。
、R及びR並びにBのメチレン、エチレン又はビニレンが有していても良い置換基、アリール及び複素環基が有していても良い置換基のハロゲン原子としては、フッ素原子、塩素原子、又は臭素原子等が挙げられる。
の炭素数2〜8のアルコキシカルボニル基としては、メトキシカルボニル基、エトキシカルボニル基等が挙げられる。
、R及びRの炭素数2〜8のアシル基としては、アセチル基又はプロピオニル基等が挙げられる。
Bのメチレン、エチレン又はビニレンが有していても良い置換基のアラルキル基(アリール部分の炭素数は6〜10で、アルキル部分の炭素数は1〜3)としては、ベンジル基又はフェネチル基等が挙げられる。
のアラルキルオキシカルボニル基(アリール部分の炭素数は6〜10で、アルキル部分の炭素数は1〜3)としては、ベンジルオキシカルボニル基等が挙げられる。
、R及びRの炭素数7〜11のアリールカルボニル基としては、ベンゾイル基等が挙げられる。
、R及びRの炭素数6〜10のアリール基としては、フェニル基等が挙げられる。
、R、Rの複素環、並びにアリール及び複素環が有していても良い置換基の複素環、及びBのメチレン、エチレン又はビニレンが有していても良い置換基である複素環で置換された炭素数1〜3のアルキル基中の複素環としては、ピリジル基等が挙げられる。
一般式(II)中の、R14、R15及びR16のハロゲン原子、炭素数1〜8のアルキル基、ハロゲン原子で置換された炭素数1〜8のアルキル基、炭素数1〜8のアルコキシ基及びハロゲン原子で置換された炭素数1〜8のアルコキシ基は上記一般式(I)のR、R及びRで挙げたものと同じものが挙げられる。
なお、上記一般式(I)のR、R及びR並びに上記一般式(II)中の、R14、R15及びR16については、ベンゼン環等に同一又は異なったものが1〜3個存在しても良い。
(1)本発明化合物としては、上記一般式(I)の化合物で、Aが結合手である化合物又はその塩が好ましい。
(2)本発明化合物としては、上記一般式(I)の化合物又は上記(1)で、フェニル基に対し、C(=Z)とWの配置がメタ位又はパラ位である化合物又はその塩が好ましい。
(3)本発明化合物としては、上記一般式(I)の化合物又は上記(1)、(2)でBがメチレン又はエチレンである化合物又はその塩が好ましい。
(4)本発明化合物としては、上記一般式(I)の化合物又は上記(1)〜(3)でWが酸素原子又は硫黄原子である化合物又はその塩が好ましい。
(5)本発明化合物としては、上記一般式(I)の化合物又は上記(1)〜(4)でX及びYが共にCHである化合物又はその塩が好ましい。
(6)本発明化合物としては、上記一般式(I)の化合物又は上記(1)〜(5)でZが酸素原子である化合物又はその塩が好ましい。
(7)本発明化合物としては、上記一般式(I)の化合物又は上記(1)〜(6)でR及びRが共に水素原子又はメチル基である化合物又はその塩が好ましい。
(8)本発明化合物としては、上記一般式(I)の化合物又は上記(1)〜(7)でRがカルボキシル基、炭素数2〜8のアルコキシカルボニル基、カルバモイル基又はアラルキルオキシカルボニル基(アリール部分の炭素数は6〜10で、アルキル部分の炭素数は1〜3)である化合物又はその塩が好ましい。
(9)本発明化合物としては、上記一般式(I)の化合物又は上記(1)〜(7)でRがカルボキシル基である化合物又はその塩が好ましい。
(10)本発明化合物としては、上記一般式(II)の化合物でBがメチレン又はエチレンである化合物又はその塩が好ましい。
上記一般式(I)で表される化合物は、薬理学的に許容される塩であってもよく、例えばナトリウム、カリウム、リチウム等のアルカリ金属塩が挙げられる。
次に上記一般式(II)で表される化合物の合成スキームを以下に示す。
(i)B =エチレンで、Z =Oで、かつW =Oの場合

Figure 2006041197
(式中、Qはハロゲン原子等の脱離基を表し、R13は、炭素数1〜3のアルキル基を表し、そしてR11、R12、R14、R15、R16及びXは前記と同じ)
一般式(c)で表される化合物は、一般式(a)で表されるフェノール誘導体と一般式(b)で表される酢酸誘導体を、炭酸カリウム等の塩基の存在下、反応に関与しない溶媒中で、反応させることで得ることができる。
ここで、得られた一般式(c)で表される化合物を、水酸化ナトリウム、炭酸カリウム等の塩基の存在下、加水分解反応に付すことにより一般式(d)で表される本発明化合物を得ることができる。
原料である一般式(a)で表されるフェノール誘導体は、例えば以下の反応スキームにより得ることができる。
Figure 2006041197
(式中、Q及びQはハロゲン原子を表し、R14、R15、R16及びXは前記と同じ)
(ii)B =メチレンで、Z =Oの場合
Figure 2006041197
(式中、Qはハロゲン原子を表し、R13は、炭素数1〜3のアルキル基を表し、そしてR11、R12、R14、R15、R16、W及びXは前記と同じ)
一般式(g)で表される化合物は、一般式(f)で表される化合物にアセチルハライド誘導体(e)を反応させることで得ることができる。(Friedel−Crafts反応)
ここで、得られた一般式(g)で表される化合物を水酸化ナトリウム、炭酸カリウム等の塩基の存在下、加水分解反応に付すことにより一般式(h)で表される本発明化合物を得ることができる。
原料であるアセチルハライド誘導体(e)は、例えば以下の反応スキームにより得ることができる。
Figure 2006041197
(式中、Qは、ハロゲン原子を表し、R14,R15及びXは前記と同じ)
(iii)B =エチレンで、Z =Oで、かつW =Oの場合
Figure 2006041197
(式中、Qは、ハロゲン原子を表し、R13は、炭素数1〜3のアルキル基を表し、そしてR11、R12,R14,R15,R16及びXは前記と同じ)
一般式(k)で表されるビアリール化合物は一般式(i)で表されるフェニルボロン酸誘導体と一般式(j)をカップリング反応を行なうことで構築できる。アリール−アリールクロスカップリング反応(Suzuki Coupling Reaction)は溶媒中、塩基の存在下または非存在下で、パラジウム、ロジウム、ニッケル触媒を用いこれに必要に応じて添加剤を加えることで進行する。溶媒としてはDMF,DMA,DMSO,HMPAに代表される高極性非プロトン性溶媒、さらにはTHF、1,2−ジメトキシエタン、ジオキサン、ジエチルエーテルに代表されるエーテル溶媒、メタノール、エタノール、イソプロピルアルコールなどのアルコール系の溶媒、水あるいはこれらの混合溶媒を用いる。また塩基として炭酸カリウム、炭酸ナトリウム、炭酸セシウムあるいは水酸化ナトリウム、水酸化リチウム、トリエチルアミン、リン酸カリウム等をを用いる。また、触媒としてホスフィンリガンドを有したパラジウム化合物(例えばテトラキス(トリフェニルホスフィン)パラジウム、[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]、[1,1’−ビス(ジフェニルホスフィノ)エタン]ジクロロパラジウム、[1,1’−ビス(ジフェニルホスフィノ)プロパン]ジクロロパラジウム)や酢酸パラジジウム、パラジジウムブラックを更には[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロニッケル、[1,1’−ビス(ジフェニルホスフィノ)エタン]ジクロロニツケル、[1,1’−ビス(ジフェニルホスフィノ)プロパン]ジクロロニツケル、塩化ニッケル等のニッケル触媒を用いる。また、必要に応じてトリフェニルホスフィン等の有機リン試薬、臭化テトラブチルアンモニウム等の相関移動触媒を用いる。
ここで、得られた一般式(k)で表される化合物を、水酸化ナトリウム、炭酸カリウム等の塩基の存在下、加水分解反応に付すことにより一般式(l)で表される本発明化合物を得ることができる。
原料である一般式(i)で表される化合物は例えば以下の反応スキームにより得ることができる。
Figure 2006041197
(式中、Qはハロゲン原子を表し、Qはハロゲン原子等の脱離基を表し、R11、R12、R13、R15、R16、Q及びXは前記と同じ)
(iv)B =エチレンで、Z =Oで、かつW =Oの場合
Figure 2006041197
(式中、R13は、炭素数1〜3のアルキル基を表し、そしてR11、R12、R14、R15、R16及びXは前記と同じ)
(V)B =エチレンで、Z =CH で、かつW =Oの場合
Figure 2006041197
(式中、R13は、炭素数1〜3のアルキル基を表し、そしてR11、R12、R14、R15、R16及びXは前記と同じ)
一般式(I)で表される本発明化合物も前記の特許文献1〜8,本発明の実施例及び公知文献等を参考にして製造することができる。
斯くして得られた本発明化合物例を表1〜24に示す。
(1)次の一般式、
Figure 2006041197
で表される本発明化合物(式中、R11、R12、R15、R16及びWは表1〜3記載のもの)。
Figure 2006041197
Figure 2006041197
Figure 2006041197
(2)次の一般式、
Figure 2006041197
で表される本発明化合物(式中、R11、R12、R15、R16及びWは表4〜6記載のもの)。
Figure 2006041197
Figure 2006041197
Figure 2006041197
(3)次の一般式、
Figure 2006041197
で表される本発明化合物(式中、R11、R12、R15、R16及びWは表7〜9記載のもの)。
Figure 2006041197
Figure 2006041197
Figure 2006041197
(4)次の一般式、
Figure 2006041197
で表される本発明化合物(式中、R11、R12、R15、R16及びWは表10〜12記載のもの)。
Figure 2006041197
Figure 2006041197
Figure 2006041197
(5)次の一般式、
Figure 2006041197
で表される本発明化合物(式中、R11、R12、R14、R15、R16及びWは表13〜15記載のもの)。
Figure 2006041197
Figure 2006041197
Figure 2006041197
(6)次の一般式、
Figure 2006041197
で表される本発明化合物(式中、R11、R12、R14、R15、R16及びWは表16〜18記載のもの)。
Figure 2006041197
Figure 2006041197
Figure 2006041197
(7)次の一般式、
Figure 2006041197
で表される本発明化合物(式中、R11、R12、R14、R15、X及びZは表19〜21記載のもの)。
Figure 2006041197
Figure 2006041197
Figure 2006041197
(8)次の一般式、
Figure 2006041197
で表される本発明化合物(式中、R11、R12、R14、R15及びX及びZは表22〜24記載のもの)。
Figure 2006041197
Figure 2006041197
Figure 2006041197
次に本発明の薬理効果について述べる。
本発明化合物のPPARδ活性化作用は、試験化合物(実施例化合物)のPPAR活性化作用を以下のように測定した。
CV−1細胞(ATCC(American Type Culture Collection))に受容体発現プラスミド(pSG5−GAL4−hPPARα or γ or δ(LBD),ルシフェラーゼ発現プラスミド(pUC8−MH100×4−TK−Luc)及びβ−ガラクトシダーゼ(pCMX−β−GAL)発現プラスミド(Kliewer,S.A.et.al.,(1992) Nature,358:771−774)を導入した。リポフェクション試薬DMRIE−C又はLipofectamin 2000(Invitrogen)を用いて遺伝子導入を行った後,供試化合物存在下で42時間培養した。可溶化細胞をルシフェラーゼ活性及びβ−GAL活性測定に用いた。ルシフェラーゼ活性はβ−GAL活性で補正し,PPARαはGW−590735(PPARα選択的agonist)を、PPARγはRosiglitazoneを、PPARδはGW−501516で処理した細胞のルシフェラーゼ活性値を100%として,相対的なリガンド活性を算出した。(後記の実施例10)
表25から明らかなように本発明化合物は優れたPPARδ活性化作用を示した。
従って、本発明の一般式(I)で表される化合物は、優れたPPARδ活性化作用を有することから、血糖降下剤、肥満、シンドロームX,高コレステロール血症、高リポ蛋白血症等の代謝異常疾患、高脂血症、動脈硬化症、循環器系疾患、過食症、虚血性疾患、肺ガン、乳がん、結腸ガン、大腸ガン、卵巣ガン等の悪性腫瘍、アルツハイマー病、炎症性疾患等の予防、あるいは治療剤として期待される。
本発明化合物は、ヒトに対して一般的な経口投与又は非経口投与のような適当な投与方法によって投与することができる。
製剤化するためには、製剤の技術分野における通常の方法で錠剤、顆粒剤、散剤、カプセル剤、懸濁剤、注射剤、坐薬等の剤型に製造することができる。
これらの調製には、通常の賦形剤、崩壊剤、結合剤、滑沢剤、色素、希釈剤などが用いられる。ここで、賦形剤としては、乳糖、D−マンニトール、結晶セルロース、ブドウ糖などが、崩壊剤としては、デンプン、カルボキシメチルセルロースカルシウム(CMC−Ca)などが、滑沢剤としては、ステアリン酸マグネシウム、タルクなどが、結合剤としては、ヒドロキシプロピルセルロース(HPC)、ゼラチン、ポリビニルピロリドン(PVP)などが挙げられる。
投与量は通常成人においては、注射剤で有効成分である本発明化合物を1日約0.1mg〜100mg,経口投与で1日1mg〜2000mgであるが、年齢、症状等により増減することができる。
次に、実施例を挙げ本発明を更に詳細に説明するが本発明はこれらに限定されるものではない。Next, the present invention will be described in detail.
In the above general formula (I), R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and the substituent which B methylene, ethylene or vinylene may have, and aryl In addition, the alkyl group having 1 to 8 carbon atoms of the substituent that the heterocyclic group may have includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl group, and pentyl. Group or hexyl group.
Examples of the 3- to 8-membered cycloalkyl group of the substituent which may be possessed by R 4 , R 5 and R 6 and B methylene, ethylene or vinylene include a cyclopropyl group, a cyclopentyl group or a cyclohexyl group. .
R 1 , R 2 , R 4 , R 5 , R 6 and the halogen atom of the substituent which the methylene, ethylene or vinylene of B may have, and the substituent which the aryl and heterocyclic group may have As the alkyl group having 1 to 8 carbon atoms substituted with 1 to 3, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a butyl group substituted with 1 to 3 halogen atoms such as a fluorine atom, a chlorine atom, or a bromine atom Or t-butyl group, preferably trifluoromethyl group, chloromethyl group, 2-chloroethyl group, 2-bromoethyl group, 2-fluoroethyl group and the like.
R 4 , R 5 and R 6 as well as the substituent that the methylene, ethylene or vinylene of B may have, the aryl group and the substituent that the heterocyclic group may have have 1 to 8 carbon atoms as the alkoxy group Includes a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an i-butoxy group, a t-butoxy group, a pentyloxy group or a hexyloxy group.
Examples of the alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom of R 4 , R 5 and R 6 include a methoxy group substituted with a halogen atom such as 1 to 3 fluorine atoms, a chlorine atom or a bromine atom, ethoxy Group, propoxy group, isopropyloxy group, butyloxy group, or t-butyloxy group, preferably trifluoromethyloxy group, chloromethyloxy group, 2-chloroethyloxy group, 2-bromoethyloxy group, 2- Examples include a fluoroethyloxy group.
Examples of the alkyl group having 1 to 8 carbon atoms substituted by the alkoxy group having 1 to 8 carbon atoms of R 4 , R 5 and R 6 include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, i- Methyl group, ethyl group, propyl group, isopropyl group, butyl group, i-butyl group, t-butyl group, pentyl group or hexyl group substituted with butoxy group, t-butoxy group, pentyloxy group or hexyloxy group Is mentioned.
Examples of the alkenyl group having 2 to 8 carbon atoms of the substituents which R 4 , R 5 and R 6 and B methylene, ethylene or vinylene may have include a vinyl group and an allyl group.
A propargyl group is mentioned as a C2-C8 alkynyl group of R < 4 >, R < 5 > and R < 6 >.
R 4 , R 5 and R 6 and the halogen atom of the substituent which the methylene, ethylene or vinylene of B may have, the aryl and heterocyclic group which may have, include a fluorine atom, chlorine An atom, a bromine atom, etc. are mentioned.
Examples of the alkoxycarbonyl group having 2 to 8 carbon atoms of R 3 include a methoxycarbonyl group and an ethoxycarbonyl group.
Examples of the acyl group having 2 to 8 carbon atoms of R 4 , R 5 and R 6 include an acetyl group or a propionyl group.
The aralkyl group of the substituent which may be possessed by the methylene, ethylene or vinylene of B (the aryl moiety has 6 to 10 carbon atoms and the alkyl moiety has 1 to 3 carbon atoms) includes a benzyl group or a phenethyl group Is mentioned.
Examples of the aralkyloxycarbonyl group of R 3 (the aryl moiety has 6 to 10 carbon atoms and the alkyl moiety has 1 to 3 carbon atoms) include a benzyloxycarbonyl group.
A benzoyl group etc. are mentioned as a C7-C11 arylcarbonyl group of R < 4 >, R < 5 > and R < 6 >.
Examples of the aryl group having 6 to 10 carbon atoms of R 4 , R 5 and R 6 include a phenyl group.
The heterocycle of R 4 , R 5 , R 6 , the heterocycle of the substituent that aryl and heterocycle may have, and the heterocycle of the substituent that methylene, ethylene, or vinylene of B may have A pyridyl group etc. are mentioned as a heterocyclic ring in a C1-C3 alkyl group substituted by the ring.
In general formula (II), R 14 , R 15 and R 16 halogen atoms, alkyl groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with halogen atoms, and those having 1 to 8 carbon atoms. Examples of the alkoxy group having 1 to 8 carbon atoms substituted with an alkoxy group and a halogen atom include the same groups as those described above for R 4 , R 5 and R 6 in formula (I).
In addition, about R < 4 >, R < 5 > and R < 6 > of the said general formula (I), and R <14> , R <15> and R < 16 > in the said general formula (II), what is the same or different in a benzene ring etc. is 1- There may be three.
(1) The compound of the present invention is preferably a compound of the above general formula (I) or a salt thereof wherein A is a bond.
(2) As the compound of the present invention, the compound of the above general formula (I) or the above (1), wherein C (= Z) and W are in the meta position or para position with respect to the phenyl group, or a salt thereof Is preferred.
(3) As the compound of the present invention, a compound of the above general formula (I) or a compound or a salt thereof in which B is methylene or ethylene in the above (1) and (2) is preferable.
(4) As this invention compound, the compound or its salt whose W is an oxygen atom or a sulfur atom in the said general formula (I) or said (1)-(3).
(5) As the compound of the present invention, a compound of the above general formula (I), a compound of the above (1) to (4) wherein X and Y are both CH or a salt thereof is preferable.
(6) As the compound of the present invention, a compound of the above general formula (I), a compound in which Z is an oxygen atom in the above (1) to (5), or a salt thereof is preferable.
(7) The compound of the present invention is preferably a compound of the above general formula (I) or a compound or a salt thereof in which R 1 and R 2 are both a hydrogen atom or a methyl group in the above (1) to (6).
(8) As the compound of the present invention, the compound of the above general formula (I) or the above (1) to (7), wherein R 3 is a carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms, a carbamoyl group or an aralkyloxycarbonyl group. A compound or a salt thereof in which the aryl moiety has 6 to 10 carbon atoms and the alkyl moiety has 1 to 3 carbon atoms is preferable.
(9) As the compound of the present invention, a compound of the above general formula (I), a compound of the above (1) to (7) wherein R 3 is a carboxyl group, or a salt thereof is preferable.
(10) As the compound of the present invention, a compound of the above general formula (II) wherein B 1 is methylene or ethylene or a salt thereof is preferable.
The compound represented by the general formula (I) may be a pharmacologically acceptable salt, and examples thereof include alkali metal salts such as sodium, potassium and lithium.
Next, a synthesis scheme of the compound represented by the general formula (II) is shown below.
(I) B 1 = ethylene, Z 1 = O, and W 1 = O
Figure 2006041197
(In the formula, Q 1 represents a leaving group such as a halogen atom, R 13 represents an alkyl group having 1 to 3 carbon atoms, and R 11 , R 12 , R 14 , R 15 , R 16 and X 1. Is the same as above)
The compound represented by the general formula (c) does not participate in the reaction of the phenol derivative represented by the general formula (a) and the acetic acid derivative represented by the general formula (b) in the presence of a base such as potassium carbonate. It can be obtained by reacting in a solvent.
Here, the compound represented by the general formula (c) is subjected to a hydrolysis reaction in the presence of a base such as sodium hydroxide or potassium carbonate to give the compound of the present invention represented by the general formula (d). Can be obtained.
The phenol derivative represented by the general formula (a) as a raw material can be obtained, for example, by the following reaction scheme.
Figure 2006041197
(Wherein Q 2 and Q 3 represent a halogen atom, and R 14 , R 15 , R 16 and X 1 are the same as above)
(Ii) When B 1 = methylene and Z 1 = O
Figure 2006041197
Wherein Q 4 represents a halogen atom, R 13 represents an alkyl group having 1 to 3 carbon atoms, and R 11 , R 12 , R 14 , R 15 , R 16 , W 1 and X 1 are Same as)
The compound represented by the general formula (g) can be obtained by reacting the compound represented by the general formula (f) with the acetyl halide derivative (e). (Friedel-Crafts reaction)
Here, the compound of the present invention represented by the general formula (h) is obtained by subjecting the obtained compound represented by the general formula (g) to a hydrolysis reaction in the presence of a base such as sodium hydroxide or potassium carbonate. Obtainable.
The raw material acetyl halide derivative (e) can be obtained, for example, by the following reaction scheme.
Figure 2006041197
(Wherein Q 5 represents a halogen atom, and R 14 , R 15 and X 1 are the same as above)
(Iii) When B 1 = ethylene, Z 1 = O, and W 1 = O
Figure 2006041197
Wherein Q 6 represents a halogen atom, R 13 represents an alkyl group having 1 to 3 carbon atoms, and R 11 , R 12 , R 14 , R 15 , R 16 and X 1 are the same as above. )
The biaryl compound represented by the general formula (k) can be constructed by performing a coupling reaction between the phenylboronic acid derivative represented by the general formula (i) and the general formula (j). The aryl-aryl cross-coupling reaction proceeds in a solvent in the presence or absence of a base using a palladium, rhodium, or nickel catalyst and adding additives as necessary. Solvents include highly polar aprotic solvents represented by DMF, DMA, DMSO, HMPA, and ether solvents represented by THF, 1,2-dimethoxyethane, dioxane, diethyl ether, methanol, ethanol, isopropyl alcohol, etc. Alcohol-based solvents, water, or a mixed solvent thereof. Further, potassium carbonate, sodium carbonate, cesium carbonate or sodium hydroxide, lithium hydroxide, triethylamine, potassium phosphate, or the like is used as the base. Further, palladium compounds having a phosphine ligand as a catalyst (for example, tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocenedichloropalladium], [1,1′-bis (diphenylphosphino)) Ethane] dichloropalladium, [1,1′-bis (diphenylphosphino) propane] dichloropalladium), paradidium acetate, and paradidium black, and [1,1′-bis (diphenylphosphino) ferrocene] dichloronickel, [ A nickel catalyst such as 1,1′-bis (diphenylphosphino) ethane] dichloronickel, [1,1′-bis (diphenylphosphino) propane] dichloronickel or nickel chloride is used. Further, if necessary, an organic phosphorus reagent such as triphenylphosphine and a phase transfer catalyst such as tetrabutylammonium bromide are used.
Here, the compound represented by the general formula (k) is subjected to a hydrolysis reaction in the presence of a base such as sodium hydroxide or potassium carbonate to give the compound represented by the general formula (l). Can be obtained.
The compound represented by the general formula (i) as a raw material can be obtained, for example, by the following reaction scheme.
Figure 2006041197
(Wherein Q 7 represents a halogen atom, Q 8 represents a leaving group such as a halogen atom, and R 11 , R 12 , R 13 , R 15 , R 16 , Q 6 and X 1 are the same as above)
(Iv) When B 1 = ethylene, Z 1 = O, and W 1 = O
Figure 2006041197
(Wherein R 13 represents an alkyl group having 1 to 3 carbon atoms, and R 11 , R 12 , R 14 , R 15 , R 16 and X 1 are the same as above)
(V) In the case of B 1 = ethylene, Z 1 = CH 2 and W 1 = O
Figure 2006041197
(Wherein R 13 represents an alkyl group having 1 to 3 carbon atoms, and R 11 , R 12 , R 14 , R 15 , R 16 and X 1 are the same as above)
The compounds of the present invention represented by the general formula (I) can also be produced with reference to the above-mentioned Patent Documents 1 to 8, Examples of the present invention, known documents and the like.
Examples of the compound of the present invention thus obtained are shown in Tables 1-24.
(1) The following general formula:
Figure 2006041197
The present compound represented by the formula (wherein R 11 , R 12 , R 15 , R 16 and W 1 are those described in Tables 1 to 3).
Figure 2006041197
Figure 2006041197
Figure 2006041197
(2) The following general formula:
Figure 2006041197
The present compound represented by the formula (wherein R 11 , R 12 , R 15 , R 16 and W 1 are those described in Tables 4 to 6).
Figure 2006041197
Figure 2006041197
Figure 2006041197
(3) The following general formula:
Figure 2006041197
The present invention compound represented by the formula (wherein R 11 , R 12 , R 15 , R 16 and W 1 are those described in Tables 7 to 9).
Figure 2006041197
Figure 2006041197
Figure 2006041197
(4) The following general formula:
Figure 2006041197
The present compound represented by the formula (wherein R 11 , R 12 , R 15 , R 16 and W 1 are those described in Tables 10 to 12).
Figure 2006041197
Figure 2006041197
Figure 2006041197
(5) The following general formula:
Figure 2006041197
The present invention compound represented by the formula (wherein R 11 , R 12 , R 14 , R 15 , R 16 and W 1 are those described in Tables 13 to 15).
Figure 2006041197
Figure 2006041197
Figure 2006041197
(6) The following general formula:
Figure 2006041197
The present compound represented by the formula (wherein R 11 , R 12 , R 14 , R 15 , R 16 and W 1 are those described in Tables 16 to 18).
Figure 2006041197
Figure 2006041197
Figure 2006041197
(7) The following general formula:
Figure 2006041197
The present invention compound represented by the formula (wherein R 11 , R 12 , R 14 , R 15 , X 1 and Z 1 are those described in Tables 19 to 21).
Figure 2006041197
Figure 2006041197
Figure 2006041197
(8) The following general formula:
Figure 2006041197
The present compound represented by the formula (wherein R 11 , R 12 , R 14 , R 15 and X 1 and Z 1 are those described in Tables 22 to 24).
Figure 2006041197
Figure 2006041197
Figure 2006041197
Next, the pharmacological effect of the present invention will be described.
The PPARδ activation action of the compound of the present invention was measured as follows by the PPAR activation action of the test compound (Example compound).
Receptor expression plasmid (pSG5-GAL4-hPPARα or γ or δ (LBD), luciferase expression plasmid (pUC8-MH100 × 4-TK-Luc) and β-galactosidase in CV-1 cells (ATCC (American Type Culture Collection)) (PCMX-β-GAL) expression plasmid (Kliewer, SA et al., (1992) Nature, 358: 771-774) was introduced using lipofection reagent DMRIE-C or Lipofectamine 2000 (Invitrogen). After the gene transfer, the cells were cultured for 42 hours in the presence of the test compound, and the solubilized cells were used for the measurement of luciferase activity and β-GAL activity, which was corrected with β-GAL activity, The relative ligand activity was calculated with PPARα as GW-590735 (PPARα selective agonist), PPARγ as Rosiglitzone, and PPARδ as luciferase activity value of cells treated with GW-501516 as 100% (Examples described later). 10)
As is apparent from Table 25, the compound of the present invention showed an excellent PPARδ activation action.
Therefore, since the compound represented by the general formula (I) of the present invention has an excellent PPARδ activation action, metabolism such as hypoglycemic agent, obesity, syndrome X, hypercholesterolemia, hyperlipoproteinemia and the like. Abnormal diseases, hyperlipidemia, arteriosclerosis, cardiovascular disease, bulimia, ischemic disease, lung cancer, breast cancer, colon cancer, colon cancer, ovarian cancer and other malignant tumors, Alzheimer's disease, inflammatory diseases, etc. Expected to be a preventive or therapeutic agent.
The compound of the present invention can be administered to humans by an appropriate administration method such as general oral administration or parenteral administration.
For formulation, it can be produced into a dosage form such as a tablet, granule, powder, capsule, suspension, injection, suppository and the like by a conventional method in the technical field of formulation.
For these preparations, usual excipients, disintegrants, binders, lubricants, dyes, diluents and the like are used. Here, as the excipient, lactose, D-mannitol, crystalline cellulose, glucose and the like, as the disintegrant, starch, carboxymethylcellulose calcium (CMC-Ca), etc., as the lubricant, magnesium stearate, Examples of binders include talc and the like, and hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP), and the like.
The dosage is usually about 0.1 mg to 100 mg of the compound of the present invention, which is an active ingredient in injections, and 1 mg to 2000 mg per day by oral administration in adults, but may be increased or decreased depending on age, symptoms, etc. .
Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

実施例1
2−[2−メチル−4−[3−(4’−トリフルオロメチルビフェニル−3−イル)プロピオニル]フェノキシ]−2−メチルプロピオン酸
(1)3−(3−ブロモフェニル)−1−(4−ヒドロキシ−3−メチルフェニル)プロパン−1−オン
窒素雰囲気下、60%水素化ナトリウム(200mg,5.00mmol)をテトラヒドロフラン(20mL)に懸濁後、氷冷下、3−(4−ベンジルオキシ−3−メチルフェニル)−3−オキソプロピオン酸エチル(1.56g,4.99mmol)のテトラヒドロフラン(10mL)溶液を10分間かけて滴下し、室温で30分間撹拌した。次に、氷冷下、3−ブロモベンジル ブロミド(1.25g,5.00mmol)を加え、18時間加熱還流した。室温まで放冷後、反応混合物を減圧下に濃縮し、得られた残留物に酢酸(12mL)及び濃塩酸(3mL)を加え、100℃で5時間加熱撹拌した。室温まで放冷後、氷水(50mL)及び飽和重曹水を加え、pH7とした。酢酸エチル(100mLx2)で抽出後、有機層を水(50mL)で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去後、得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/4〜1/2)で精製することにより、表題化合物を白色結晶として1.60g(収率100%)得た。
H NMR(CDCl,400MHz):
δ=
2.28(3H,s),
3.02(2H,t,J=8Hz),
3.23(2H,t,J=8Hz),
5.47(1H,bs),
6.80(1H,d,J=8Hz),
7.1−7.2(2H,m),
7.3−7.4(1H,m),
7.40(1H,s),
7.7−7.8(2H,m)
(2)2−[4−[3−(3−ブロモフェニル)プロピオニル]−2−メチルフェノキシ]−2−メチルプロピオン酸エチル
上記で得た3−(3−ブロモフェニル)−1−(4−ヒドロキシ−3−メチルフェニル)プロパン−1−オン(800mg,2.51mmol)及び炭酸カリウム(1.40g,10.1mmol)を2−ブタノン(35mL)に懸濁後、2−ブロモイソ酪酸エチル(1.48mL,10.1mmol)を加え、16時間加熱還流した。室温まで放冷後、不溶物を濾過し、濾液を減圧下に濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/10)で精製することにより、表題化合物を無色油状物として706mg(収率65%)得た。
H NMR(CDCl,400MHz):
δ=
1.22(3H,t,J=7Hz),
1.65(6H,s),
2.26(3H,s),
3.01(2H,t,J=8Hz),
3.21(2H,t,J=8Hz),
4.22(2H,q,J=7Hz),
6.61(1H,d,J=9Hz),
7.1−7.2(2H,m),
7.3−7.4(1H,m),
7.40(1H,s),
7.7−7.8(2H,m)
(3)2−[2−メチル−4−[3−(4’−トリフルオロメチルビフェニル−3−イル)プロピオニル]フェノキシ]−2−メチルプロピオン酸エチル
4−(トリフルオロメチル)フェニルボロン酸(125mg,0.66mmol)、上記で得た2−[4−[3−(3−ブロモフェニル)プロピオニル]−2−メチルフェノキシ]−2−メチルプロピオン酸エチル(237mg,0.55mmol)及びテトラキス(トリフェニルホスフィン)パラジウム(20mg,0.017mmol)を1,4−ジオキサン(3mL)に溶解後、炭酸カリウム(250mg,1.81mmol)水溶液(0.5mL)を加え、4時間加熱還流した。室温まで放冷後、飽和重曹水を加え、酢酸エチル(50mLx2)で抽出した。有機層を飽和食塩水(50mL)で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/20〜1/10)で精製することにより、表題化合物を無色油状物として249mg(収率91%)得た。
H NMR(CDCl,400MHz):
δ=
1.21(3H,t,J=7Hz),
1,65(6H,s),
2.25(3H,s),
3.12(2H,t,J=8Hz),
3.29(2H,t,J=8Hz),
4.21(2H,q,J=7Hz),
6.61(1H,d,J=9Hz),
7.2−7.3(1H,m),
7.3−7.5(3H,m),
7.6−7.7(5H,m),
7.78(1H,s)
(4)2−[2−メチル−4−[3−(4’−トリフルオロメチルビフェニル−3−イル)プロピオニル]フェノキシ]−2−メチルプロピオン酸
上記で得た2−[2−メチル−4−[3−(4’−トリフルオロメチルビフェニル−3−イル)プロピオニル]フェノキシ]−2−メチルプロピオン酸エチル(240mg,0.481mmol)をエタノール(10mL)に溶解後、氷冷下、1M水酸化ナトリウム水溶液(2.25mL)を加え、室温で40時間撹拌した。反応混合物を減圧下に濃縮後、得られた残留物に氷水及び1M塩酸水溶液を加え、pH3とした。酢酸エチル(30mLx2)で抽出後、有機層を水(30mL)及び飽和食塩水(20mL)で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去することにより、表題化合物を白色アモルファスとして125mg(収率55%)得た。
FAB−MS(m/e):471(M+1)
H NMR(CDCl,400MHz):
δ=
1.68(6H,s),
2.26(3H,s),
3.12(2H,t,J=8Hz),
3.29(2H,t,J=8Hz),
6.74(1H,d,J=9Hz),
7.2−7.3(1H,m),
7.3−7.5(3H,m),
7.6−7.7(4H,m),
7.7−7.8(2H,m)
IR(KBr,cm−1):3304,2943,2345,1740,1716,1676,1601,1500,1400,1327,1259,1165,1126,1072,1016,972,845,796,702,606
実施例2
[2−メチル−4−[3−(4’−トリフルオロメチルビフェニル−3−イル)プロピオニル]フェノキシ]酢酸
(1)[4−[3−(3−ブロモフェニル)プロピオニル]−2−メチルフェノキシ]酢酸エチル
3−(3−ブロモフェニル)−1−(4−ヒドロキシ−3−メチルフェニル)プロパン−1−オン(320mg,1.00mmol)及び炭酸カリウム(415mg,3.00mmol)をアセトン(30mL)に懸濁後、ブロモ酢酸エチル(0.34mL,3.07mmol)を加え、24時間加熱還流した。室温まで放冷後、反応混合物を減圧下に濃縮し、得られた残留物に水(100mL)を加えた。酢酸エチル(50mLx2)で抽出後、有機層を水(50mL)及び飽和食塩水(30mL)で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去後、得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン1/10)で精製することにより、表題化合物を無色油状物として406mg(収率100%)得た。
H NMR(CDCl,400MHz):δ=
1.29(3H,t,J=7Hz),
2.32(3H,s),
3.02(2H,t,J=8Hz),
3.22(2H,t,J=8Hz),
4.27(2H,q,J=7Hz),
4.70(2H,s),
6.70(1H,d,J=8Hz),
7.1−7.2(2H,m),
7.3−7.4(1H,m),
7.40(1H,s),
7.7−7.8(2H,m)
(2)[2−メチル−4−[3−(4’−トリフルオロメチルビフェニル−3−イル)プロピオニル]フェノキシ]酢酸
4−(トリフルオロメチル)フェニルボロン酸(222mg,1.17mmol)、上述で得た[4−[3−(3−ブロモフェニル)プロピオニル]−2−メチルフェノキシ]酢酸エチル(394mg,0.972mmol)及びテトラキス(トリフェニルホスフィン)パラジウム(35mg,0.017mmol)を1,4−ジオキサン(5mL)に溶解後、炭酸カリウム(444mg,3.21mmol)水溶液(1mL)を加え、4時間加熱還流した。室温まで放冷後、飽和重曹水を加え、酢酸エチル(50mLx2)で抽出した。有機層を飽和食塩水(50mL)で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。得られた残留物を酢酸エチル/ヘキサン中で撹拌後、濾過することにより、表題化合物のナトリウム塩330mgを得た。次に、このナトリウム塩(250mg,0.538mmol)を水(10mL)に懸濁後、1M塩酸水溶液を加え、pH2とし、酢酸エチル(10mLx2)で抽出した。有機層を水(10mL)及び飽和食塩水(10mL)で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去することにより、表題化合物を白色結晶として85mg(収率36%)得た。
mp:136−139℃
FAB−MS(m/e):443(M+1)
H NMR(CDCl,400MHz):
δ=
2.31(3H,s),
3.13(2H,t,J=7Hz),
3.30(2H,t,J=7Hz),
4.76(2H,d,J=1Hz),
6.74(1H,d,J=8Hz),
7.3−7.5(4H,m),
7.6−7.7(4H,m),
7.8−7.9(2H,m)
IR(KBr,cm−1):2927,2592,2345,1770,1747,1678,1643,1601,1578,1504,1435,1421,1400,1331,1257,1203,1165,1130,1072,1016,989,891,845,798,700,663,604
実施例3
2−[2−メチル−4−[3−(4−メチル−4’−トリフルオロメチルビフェニル−3−イル)プロピオニル]フェノキシ]−2−メチルプロピオン酸
(1)1−(4−ヒドロキシ−3−メチルフェニル)−3−(4−メチル−4’−トリフルオロメチルビフェニル−3−イル)プロパン−1−オン
(4−メチル−4’−トリフルオロメチルビフェニル−3−イル)メタノール(212mg,0.796mmol)をベンゼン(5mL)に溶解後、氷冷下、塩化チオニル(0.09mL,1.23mmol)を滴下し、室温で5時間撹拌した。反応混合物を減圧下に濃縮することにより、3−クロロメチル−4−メチル−4’−トリフルオロメチルビフェニルを得た。
以下、実施例1(1)と同様の手法を用いて表題化合物を得た。
白色結晶
収率48%
H NMR(CDCl,400MHz):
δ=
2.28(3H,s),
2.40(3H,s),
3.1−3.2(2H,m),
3.2−3.3(2H,m),
5.24(1H,s),
6.80(1H,d,J=8Hz),
7.2−7.3(1H,m),
7.36(1H,dd,J=2,8Hz),
7.42(1H,d,J=2Hz),
7.6−7.7(4H,m),
7.7−7.8(2H,m)
(2)2−[2−メチル−4−[3−(4−メチル−4’−トリフルオロメチルビフェニル−3−イル)プロピオニル]フェノキシ]−2−メチルプロピオン酸エチル
実施例1(2)と同様の手法を用いて表題化合物を得た。
無色油状物
収率89%
H NMR(CDCl,400MHz):
δ=
1.21(3H,t,J=7Hz),
1.65(6H,s),
2.25(3H,s),
2.40(3H,s),
3.0−3.2(2H,m),
3.2−3.3(2H,m),
4.22(2H,q,J=7Hz),
6.61(1H,d,J=9Hz),
7.2−7.3(1H,m),
7.3−7.5(2H,m),
7.6−7.7(4H,m),
7.7−7.8(2H,m)
(3)2−[2−メチル−4−[3−(4−メチル−4’−トリフルオロメチルビフェニル−3−イル)プロピオニル]フェノキシ]−2−メチルプロピオン酸
実施例1(4)と同様の手法を用いて表題化合物を得た。
白色アモルファス
収率91%
FAB−MS(m/e):485(M+1)
H NMR(CDCl,400MHz):
δ=
1.68(6H,s),
2.26(3H,s),
2.39(3H,s),
3.10(2H,t,J=7Hz),
3.23(2H,t,J=7Hz),
6.75(1H,d,J=8Hz),
7.2−7.3(1H,m),
7.3−7.5(2H,m),
7.6−7.7(4H,m),
7.7−7.8(2H,m)
実施例4
[2−メチル−4−[3−(4−メチル−4’−トリフルオロメチルビフェニル−3−イル)プロピオニル]フェノキシ]酢酸
(1)[2−メチル−4−[3−(4−メチル−4’−トリフルオロメチルビフェニル−3−イル)プロピオニル]フェノキシ]酢酸エチル
実施例2(1)と同様の手法を用いて表題化合物を得た。
白色結晶
収率92%
H NMR(CDCl,400MHz):
δ=
1.29(3H,t,J=7Hz),
2.31(3H,s),
2.40(3H,s),
3.11(2H,t,J=7Hz),
3.24(2H,t,J=7Hz),
4.26(2H,q,J=7Hz),
4.70(2H,s),
6.70(1H,d,J=9Hz),
7.2−7.3(1H,m),
7.3−7.5(2H,m),
7.6−7.7(4H,m),
7.7−7.8(2H,m)
(2)[2−メチル−4−[3−(4−メチル−4’−トリフルオロメチルビフェニル−3−イル)プロピオニル]フェノキシ]酢酸
実施例1(4)と同様の手法を用いて表題化合物を得た。
白色結晶
収率81%
mp:158−161℃
FAB−MS(m/e):457(M+1)
H NMR(CDCl,400MHz):
δ=
2.31(3H,s),
2.40(3H,s),
3.11(2H,t,J=7Hz),
3.24(2H,t,J=7Hz),
4.76(2H,s),
6.74(1H,d,J=9Hz),
7.2−7.3(1H,m),
7.3−7.5(2H,m),
7.65(4H,s),
7.8−7.9(2H,m)
IR(KBr,cm−1):3066,2926,2303,1753,1676,1601,1504,1431,1329,1248,1165,1124,1120,1074,1014,993,847,818,791,679,606
実施例5
2−[4−[3−(4−イソプロピル−4’−トリフルオロメチルビフェニル−3−イル)プロピオニル]−2−メチルフェノキシ]−2−メチルプロピオン酸
(1)(5−ブロモ−2−イソプロピルフェニル)メタノール
2−イソプロピル安息香酸(1.65g,10.0mmol)のトリフルオロ酢酸(5mL)溶液に濃硫酸(1mL)を加え、次いでN−ブロモこはく酸イミド(2.67g,15.0mmol)を2時間かけて少量ずつ加えた。室温で5時間撹拌後、反応溶液を氷水(50mL)に注入し、クロロホルム(50mLx2)で抽出した。有機層を飽和食塩水(50mL)で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去することにより、5−ブロモ−2−イソプロピル安息香酸粗体2.73gを得た。
窒素雰囲気下、上記で得た5−ブロモ−2−イソプロピル安息香酸粗体(2.73g)をテトラヒドロフラン(25mL)に溶解後、氷冷下、水素化ホウ素ナトリウム(568mg,15.0mmol)を加え、15分間撹拌した。次いで、三フッ化ホウ素ジエチルエーテル錯体(1.90mL,15.0mmol)を10分間かけて滴下後、室温で18時間撹拌した。更に、氷冷下、2M水酸化ナトリウム水溶液(7.5mL)を加え、室温で5時間撹拌後、飽和重曹水(50mL)を加え、酢酸エチル(100mLx2)で抽出した。有機層を10%炭酸カリウム水溶液(50mL)及び飽和食塩水(50mL)で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/10)で精製することにより、表題化合物を無色油状物として1.60g(収率70%)得た。
H NMR(CDCl,400MHz):
δ=
1.23(6H,d,J=7Hz),
1.58(1H,t,J=6Hz),
3.1−3.2(1H,m),
4.72(2H,d,J=6Hz),
7.18(1H,d,J=8Hz),
7.40(1H,dd,J=2,8Hz),
7.52(1H,d,J=2Hz)
(2)(4−イソプロピル−4’−トリフルオロメチルビフェニル−3−イル)メタノール
4−(トリフルオロメチル)フェニルボロン酸(1.59g,8.37mmol)、上記で得た(5−ブロモ−2−イソプロピルフェニル)メタノール(1.59g,6.94mmol)及びテトラキス(トリフェニルホスフィン)パラジウム(255mg,0.221mmol)を1,4−ジオキサン(35mL)に溶解後、炭酸カリウム(3.17g,22.9mmol)水溶液(7mL)を加え、4時間加熱還流した。室温まで放冷後、飽和重曹水(100mL)を加え、酢酸エチル(100mLx2)で抽出した。有機層を飽和食塩水(50mL)で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/10〜1/5)で精製することにより、表題化合物を白色結晶として1.92g(収率94%)得た。
H NMR(CDCl,400MHz):
δ=
1.30(6H,d,J=7Hz),
1.63(1H,bs),
3.2−3.4(1H,m),
4.84(2H,s),
7.43(1H,d,J=8Hz),
7.53(1H,dd,J=2,8Hz),
7.61(1H,d,J=2Hz),
7.6−7.8(4H,m)
(3)1−(4−ヒドロキシ−3−メチルフェニル)−3−(4−イソプロピル−4’−トリフルオロメチルビフェニル−3−イル)プロパン−1−オン
実施例3(1)と同様の手法を用いて表題化合物を得た。
白色結晶
収率31%
H NMR(CDCl,400MHz):
δ=
1.29(6H,d,J=7Hz),
2.28(3H,s),
3.1−3.3(5H,m),
5.32(1H,s),
6.80(1H,d,J=9Hz),
7.3−7.5(3H,m),
7.66(4H,s),
7.7−7.8(2H,m)
(4)2−[4−[3−(4−イソプロピル−4’−トリフルオロメチルビフェニル−3−イル)プロピオニル]−2−メチルフェノキシ]−2−メチルプロピオン酸エチル
実施例1(2)と同様の手法を用いて表題化合物を得た。
無色油状物
収率62%
H NMR(CDCl,400MHz):
δ=
1.21(3H,t,J=7Hz),
1.29(6H,d,J=7Hz),
1.65(6H,s),
2.25(3H,s),
3.1−3.3(5H,m),
4.21(2H,q,J=7Hz),
6.61(1H,d,J=8Hz),
7.3−7.5(3H,m),
7.66(4H,s),
7.7−7.8(2H,m)
(5)2−[4−[3−(4−イソプロピル−4’−トリフルオロメチルビフェニル−3−イル)プロピオニル]−2−メチルフェノキシ]−2−メチルプロピオン酸
実施例1(4)と同様の手法を用いて表題化合物を得た。
白色アモルファス
収率91%
FAB−MS(m/e):513(M+1)
H NMR(CDCl,400MHz):
δ=
1.28(6H,d,J=7Hz),
1.68(6H,s),
2.25(3H,s),
3.1−3.3(5H,m),
6.73(1H,d,J=8Hz),
7.3−7.5(3H,m),
7.65(4H,s),
7.7−7.8(2H,m)
実施例6
[4−[3−(4−イソプロピル−4’−トリフルオロメチルビフェニル−3−イル)プロピオニル]−2−メチルフェノキシ]酢酸
(1)4−[3−(4−イソプロピル−4’−トリフルオロメチルビフェニル−3−イル)プロピオニル]−2−メチルフェノキシ]酢酸エチル
実施例2(1)と同様の手法を用いて表題化合物を得た。
無色油状物
収率83%
H NMR(CDCl,400MHz):
δ=
1.29(3H,t,J=7Hz),
1.29(6H,d,J=7Hz),
2.31(3H,s),
3.1−3.3(5H,m),
4.26(2H,q,J=7Hz),
4.70(2H,s),
6.70(1H,d,J=9Hz),
7.3−7.5(3H,m),
7.66(4H,s),
7.7−7.8(2H,m),
(2)[4−[3−(4−イソプロピル−4’−トリフルオロメチルビフェニル−3−イル)プロピオニル]−2−メチルフェノキシ]酢酸
実施例1(4)と同様の手法を用いて表題化合物を得た。
白色結晶
収率93%
mp:170−172℃
FAB−MS(m/e):485(M+1)
H NMR(CDCl,400MHz):
δ=
1.30(6H,d,J=7Hz),
2.31(3H,s),
3.1−3.3(5H,m),
4.76(2H,s),
6.74(1H,d,J=9Hz),
7.3−7.5(3H,m),
7.66(4H,s),
7.8−7.9(2H,m)
IR(KBr,cm−1):2966,2875,2588,2345,1749,1676,1601,1506,1458,1427,1392,1369,1325,1259,1255,1169,1167,1132,1074,1038,1016,922,877,849,825,785,681
実施例7
2−[4−[3−(4’−トリフルオロメチルビフェニル−4−イル)プロピオニル]−2−メチルフェノキシ]−2−メチルプロピオン酸
(1)1−(4−ヒドロキシ−3−メチルフェニル)−3−(4’−トリフルオロメチルビフェニル−4−イル)プロパン−1−オン
実施例3(1)と同様の手法を用いて表題化合物を得た。
白色結晶
収率98%
H NMR(CDCl,400MHz):
δ=
2.28(3H,s),
3.11(2H,t,J=7Hz),
3.28(2H,t,J=7Hz),
5.32(1H,s),
6.81(1H,d,J=8Hz),
7.36(2H,d,J=8Hz),
7.53(2H,d,J=8Hz),
7.67(4H,s),
7.7−7.8(2H,m)
(2)2−[4−[3−(4’−トリフルオロメチルビフェニル−4−イル)プロピオニル]−2−メチルフェノキシ]−2−メチルプロピオン酸エチル
実施例1(2)と同様の手法を用いて表題化合物を得た。
白色結晶
収率52%
H NMR(CDCl,400MHz):
δ=
1.21(3H,t,J=7Hz),
1.65(6H,s),
2.26(3H,s),
3.10(2H,t,J=7Hz),
3.27(2H,t,J=7Hz),
4.22(2H,q,J=7Hz),
6.61(1H,d,J=9Hz),
7.35(2H,d,J=8Hz),
7.53(2H,d,J=8Hz),
7.67(4H,s),
7.70(1H,dd,J=2,9Hz),
7.79(1H,d,J=2Hz)
(3)2−[4−[3−(4’−トリフルオロメチルビフェニル−4−イル)プロピオニル]−2−メチルフェノキシ]−2−メチルプロピオン酸
実施例1(4)と同様の手法を用いて表題化合物を得た。
白色結晶
収率66%
mp:149−151℃
FAB−MS(m/e):471(M+1)
H NMR(CDCl,400MHz):
δ=
1.69(6H,s),
2.27(3H,s),
3.10(2H,t,J=7Hz),
3.28(2H,t,J=7Hz),
6.76(1H,d,J=9Hz),
7.35(2H,d,J=8Hz),
7.52(2H,d,J=8Hz),
7.67(4H,s),
7.8−7.9(2H,m)
IR(KBr,cm−1):3151,2924,2299,1747,1641,1603,1578,1504,1439,1381,1327,1271,1269,1267,1230,1201,1165,1126,1070,1026,1005,999,968,818,814
実施例8
[4−[3−(4’−トリフルオロメチルビフェニル−4−イル)プロピオニル]−2−メチルフェノキシ]酢酸
(1)4−[3−(4’−トリフルオロメチルビフェニル−4−イル)プロピオニル]−2−メチルフェノキシ]酢酸エチル
実施例2(1)と同様の手法を用いて表題化合物を得た。
白色結晶
収率68%
H NMR(CDCl,400MHz):
δ=
1.31(3H,t,J=7Hz),
2.34(3H,s),
3.13(2H,t,J=7Hz),
3.30(2H,d,J=7Hz),
4.28(2H,q,J=7Hz),
4.72(2H,s),
6.72(1H,d,J=8Hz),
7.37(2H,d,J=8Hz),
7.54(2H,d,J=8Hz),
7.69(4H,s),
7.8−7.9(2H,m)
(2)[4−[3−(4’−トリフルオロメチルビフェニル−4−イル)プロピオニル]−2−メチルフェノキシ]酢酸
実施例1(4)と同様の手法を用いて表題化合物を得た。
白色結晶
収率81%
mp:174−175℃
FAB−MS(m/e):443(M+1)
H NMR(CDCl,400MHz):
δ=
2.32(3H,s),
3.11(2H,d,J=7Hz),
3.29(2H,d,J=7Hz),
4.77(2H,s),
6.75(1H,d,J=9Hz),
7.35(2H,d,J=8Hz),
7.53(2H,d,J=8Hz),
7.67(4H,s),
7.8−7.9(2H,m)
IR(KBr,cm−1):3115,2933,2501,1761,17403,1655,1603,1601,1578,1504,1435,1402,1371,1329,1271,1227,1184,1167,1134,1072,1018,1005,989,817
実施例9
2−[2−メチル−4−[3−(3’−トリフルオロメチルビフェニル−3−イル)プロピオニル]フェノキシ]−2−メチルプロピオン酸
(1)2−[2−メチル−4−[3−(3’−トリフルオロメチルビフェニル−3−イル)プロピオニル]フェノキシ]−2−メチルプロピオン酸エチル
実施例1(3)と同様の手法を用いて表題化合物を得た。
無色油状物
収率71%
H NMR(CDCl,400MHz):
δ=
1.21(3H,t,J=7Hz),
1.64(6H,s),
2.25(3H,s),
3.12(2H,t,J=7Hz),
3.28(2H,t,J=7Hz),
4.21(2H,q,J=7Hz),
6.61(1H,d,J=9Hz),
7.2−7.9(10H,m)
(2)2−[2−メチル−4−[3−(3’−トリフルオロメチルビフェニル−3−イル)プロピオニル]フェノキシ]−2−メチルプロピオン酸
実施例1(4)と同様の手法を用いて表題化合物を得た。
淡黄色結晶
収率80%
FAB−MS(m/e):471(M+1)
H NMR(CDCl,400MHz):
δ=
1.68(6H,s),
2.25(3H,s),
3.11(2H,t,J=7Hz),
3.28(2H,t,J=7Hz),
6.72(1H,d,J=9Hz),
7.2−7.8(10H,m)
実施例10 薬理実験
I.試験方法
試験化合物(実施例化合物)のPPAR活性化作用を以下のように測定した。
CV−1細胞(ATCC(American Type Culture Collection))に受容体発現プラスミド(pSG5−GAL4−hPPARα or γ or δ(LBD),ルシフェラーゼ発現プラスミド(pUC8−MH100×4−TK−Luc)及びβ−ガラクトシダーゼ(pCMX−β−GAL)発現プラスミド(Kliewer,S.A.et.al.,(1992) Nature,358:771−774)を導入した。リポフェクション試薬(DMRIE−C,Lipofectamin 2000(Invitrogen))を用いて遺伝子導入を行った後,供試化合物存在下で42時間培養した。可溶化細胞をルシフェラーゼ活性及びβ−GAL活性測定に用いた。ルシフェラーゼ活性はβ−GAL活性で補正し,PPARαはGW−590735(PPARα選択的agonist)を、PPARγはRosiglitazoneを、PPARδはGW−501516で処理した細胞のルシフェラーゼ活性値を100%として,相対的なリガンド活性を算出した。
II.試験結果
試験結果を表25に示す。

Figure 2006041197
注1)PPAR活性:対照薬を100%とした時の試験化合物 10−6Mでの相対値
対照薬 α:GW−590735 10−6
γ:Rosiglitazone 10−5
δ:GW−501516 10−7
2)GW−590735:特許文献6の実施例2
3)iaはinactiveを表す。
表25から明らかなように、実施例化合物は優れたPPARδの活性化作用を示した。Example 1
2- [2-Methyl-4- [3- (4′-trifluoromethylbiphenyl-3-yl) propionyl] phenoxy] -2-methylpropionic acid
(1) 3- (3-Bromophenyl) -1- (4-hydroxy-3-methylphenyl) propan-1-one
Under a nitrogen atmosphere, 60% sodium hydride (200 mg, 5.00 mmol) was suspended in tetrahydrofuran (20 mL), and then cooled with ice, ethyl 3- (4-benzyloxy-3-methylphenyl) -3-oxopropionate A solution of (1.56 g, 4.99 mmol) in tetrahydrofuran (10 mL) was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 30 minutes. Next, 3-bromobenzyl bromide (1.25 g, 5.00 mmol) was added under ice cooling, and the mixture was heated to reflux for 18 hours. After allowing to cool to room temperature, the reaction mixture was concentrated under reduced pressure, acetic acid (12 mL) and concentrated hydrochloric acid (3 mL) were added to the obtained residue, and the mixture was stirred with heating at 100 ° C. for 5 hr. After cooling to room temperature, ice water (50 mL) and saturated aqueous sodium hydrogen carbonate were added to adjust the pH to 7. After extraction with ethyl acetate (100 mL × 2), the organic layer was washed with water (50 mL) and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/4 to 1/2) to give 1.60 g (yield) of the title compound as white crystals. 100%).
11 H NMR (CDCl3, 400 MHz):
δ =
2.28 (3H, s),
3.02 (2H, t, J = 8 Hz),
3.23 (2H, t, J = 8 Hz),
5.47 (1H, bs),
6.80 (1H, d, J = 8 Hz),
7.1-7.2 (2H, m),
7.3-7.4 (1H, m),
7.40 (1H, s),
7.7-7.8 (2H, m)
(2) Ethyl 2- [4- [3- (3-bromophenyl) propionyl] -2-methylphenoxy] -2-methylpropionate
3- (3-Bromophenyl) -1- (4-hydroxy-3-methylphenyl) propan-1-one (800 mg, 2.51 mmol) and potassium carbonate (1.40 g, 10.1 mmol) obtained above were used. After suspending in 2-butanone (35 mL), ethyl 2-bromoisobutyrate (1.48 mL, 10.1 mmol) was added, and the mixture was heated to reflux for 16 hours. The mixture was allowed to cool to room temperature, the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/10) to give 706 mg (yield 65%) of the title compound as a colorless oil.
11 H NMR (CDCl3, 400 MHz):
δ =
1.22 (3H, t, J = 7 Hz),
1.65 (6H, s),
2.26 (3H, s),
3.01 (2H, t, J = 8 Hz),
3.21 (2H, t, J = 8 Hz),
4.22 (2H, q, J = 7Hz),
6.61 (1H, d, J = 9 Hz),
7.1-7.2 (2H, m),
7.3-7.4 (1H, m),
7.40 (1H, s),
7.7-7.8 (2H, m)
(3) 2- [2-Methyl-4- [3- (4'-trifluoromethylbiphenyl-3-yl) propionyl] phenoxy] -2-methylpropionate ethyl
4- (Trifluoromethyl) phenylboronic acid (125 mg, 0.66 mmol), 2- [4- [3- (3-bromophenyl) propionyl] -2-methylphenoxy] -2-methylpropionic acid obtained above Ethyl (237 mg, 0.55 mmol) and tetrakis (triphenylphosphine) palladium (20 mg, 0.017 mmol) are dissolved in 1,4-dioxane (3 mL), and then an aqueous potassium carbonate (250 mg, 1.81 mmol) solution (0.5 mL). ) And heated to reflux for 4 hours. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic layer was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/20 to 1/10) to give 249 mg (yield 91%) of the title compound as a colorless oil.
11 H NMR (CDCl3, 400 MHz):
δ =
1.21 (3H, t, J = 7 Hz),
1, 65 (6H, s),
2.25 (3H, s),
3.12 (2H, t, J = 8 Hz),
3.29 (2H, t, J = 8 Hz),
4.21 (2H, q, J = 7 Hz),
6.61 (1H, d, J = 9 Hz),
7.2-7.3 (1H, m),
7.3-7.5 (3H, m),
7.6-7.7 (5H, m),
7.78 (1H, s)
(4) 2- [2-Methyl-4- [3- (4'-trifluoromethylbiphenyl-3-yl) propionyl] phenoxy] -2-methylpropionic acid
Ethyl 2- [2-methyl-4- [3- (4′-trifluoromethylbiphenyl-3-yl) propionyl] phenoxy] -2-methylpropionate (240 mg, 0.481 mmol) obtained above was added to ethanol (240 mg, 0.481 mmol). 10 mL), 1M aqueous sodium hydroxide solution (2.25 mL) was added under ice cooling, and the mixture was stirred at room temperature for 40 hours. The reaction mixture was concentrated under reduced pressure, and ice water and 1M aqueous hydrochloric acid solution were added to the resulting residue to adjust to pH 3. After extraction with ethyl acetate (30 mL × 2), the organic layer was washed with water (30 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 125 mg (yield 55%) of the title compound as a white amorphous.
FAB-MS (m / e): 471 (M + 1)
11 H NMR (CDCl3, 400 MHz):
δ =
1.68 (6H, s),
2.26 (3H, s),
3.12 (2H, t, J = 8 Hz),
3.29 (2H, t, J = 8 Hz),
6.74 (1H, d, J = 9 Hz),
7.2-7.3 (1H, m),
7.3-7.5 (3H, m),
7.6-7.7 (4H, m),
7.7-7.8 (2H, m)
IR (KBr, cm-1): 3304, 2943, 2345, 1740, 1716, 1676, 1601, 1500, 1400, 1327, 1259, 1165, 1126, 1072, 1016, 972, 845, 796, 702, 606
Example 2
[2-Methyl-4- [3- (4′-trifluoromethylbiphenyl-3-yl) propionyl] phenoxy] acetic acid
(1) [4- [3- (3-Bromophenyl) propionyl] -2-methylphenoxy] ethyl acetate
3- (3-Bromophenyl) -1- (4-hydroxy-3-methylphenyl) propan-1-one (320 mg, 1.00 mmol) and potassium carbonate (415 mg, 3.00 mmol) were suspended in acetone (30 mL). After turbidity, ethyl bromoacetate (0.34 mL, 3.07 mmol) was added, and the mixture was heated to reflux for 24 hours. After allowing to cool to room temperature, the reaction mixture was concentrated under reduced pressure, and water (100 mL) was added to the obtained residue. After extraction with ethyl acetate (50 mL × 2), the organic layer was washed with water (50 mL) and saturated brine (30 mL), and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane 1/10) to give 406 mg (yield 100%) of the title compound as a colorless oil.
11 H NMR (CDCl3, 400 MHz): δ =
1.29 (3H, t, J = 7 Hz),
2.32 (3H, s),
3.02 (2H, t, J = 8 Hz),
3.22 (2H, t, J = 8 Hz),
4.27 (2H, q, J = 7Hz),
4.70 (2H, s),
6.70 (1H, d, J = 8 Hz),
7.1-7.2 (2H, m),
7.3-7.4 (1H, m),
7.40 (1H, s),
7.7-7.8 (2H, m)
(2) [2-Methyl-4- [3- (4'-trifluoromethylbiphenyl-3-yl) propionyl] phenoxy] acetic acid
4- (Trifluoromethyl) phenylboronic acid (222 mg, 1.17 mmol), ethyl [4- [3- (3-bromophenyl) propionyl] -2-methylphenoxy] acetate (394 mg, 0.972 mmol) obtained above. ) And tetrakis (triphenylphosphine) palladium (35 mg, 0.017 mmol) were dissolved in 1,4-dioxane (5 mL), an aqueous solution of potassium carbonate (444 mg, 3.21 mmol) (1 mL) was added, and the mixture was heated to reflux for 4 hours. . After cooling to room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic layer was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was stirred in ethyl acetate / hexane and then filtered to obtain 330 mg of the sodium salt of the title compound. Next, this sodium salt (250 mg, 0.538 mmol) was suspended in water (10 mL), 1M aqueous hydrochloric acid solution was added to adjust the pH to 2, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 85 mg (yield 36%) of the title compound as white crystals. .
mp: 136-139 ° C
FAB-MS (m / e): 443 (M + 1)
11 H NMR (CDCl3, 400 MHz):
δ =
2.31 (3H, s),
3.13 (2H, t, J = 7 Hz),
3.30 (2H, t, J = 7Hz),
4.76 (2H, d, J = 1 Hz),
6.74 (1H, d, J = 8 Hz),
7.3-7.5 (4H, m),
7.6-7.7 (4H, m),
7.8-7.9 (2H, m)
IR (KBr, cm-1): 2927, 2592, 2345, 1770, 1747, 1678, 1643, 1601, 1578, 1504, 1435, 1421, 1400, 1331, 1257, 1203, 1165, 1130, 1072, 1016, 989, 891, 845, 798, 700,663,604
Example 3
2- [2-Methyl-4- [3- (4-methyl-4′-trifluoromethylbiphenyl-3-yl) propionyl] phenoxy] -2-methylpropionic acid
(1) 1- (4-hydroxy-3-methylphenyl) -3- (4-methyl-4'-trifluoromethylbiphenyl-3-yl) propan-1-one
(4-Methyl-4′-trifluoromethylbiphenyl-3-yl) methanol (212 mg, 0.796 mmol) was dissolved in benzene (5 mL), and then thionyl chloride (0.09 mL, 1.23 mmol) was added under ice cooling. The solution was added dropwise and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to give 3-chloromethyl-4-methyl-4'-trifluoromethylbiphenyl.
Hereinafter, the title compound was obtained in the same manner as in Example 1 (1).
White crystals
Yield 48%
11 H NMR (CDCl3, 400 MHz):
δ =
2.28 (3H, s),
2.40 (3H, s),
3.1-3.2 (2H, m),
3.2-3.3 (2H, m),
5.24 (1H, s),
6.80 (1H, d, J = 8 Hz),
7.2-7.3 (1H, m),
7.36 (1H, dd, J = 2, 8 Hz),
7.42 (1H, d, J = 2 Hz),
7.6-7.7 (4H, m),
7.7-7.8 (2H, m)
(2) Ethyl 2- [2-methyl-4- [3- (4-methyl-4'-trifluoromethylbiphenyl-3-yl) propionyl] phenoxy] -2-methylpropionate
The title compound was obtained in the same manner as in Example 1 (2).
Colorless oil
Yield 89%
11 H NMR (CDCl3, 400 MHz):
δ =
1.21 (3H, t, J = 7 Hz),
1.65 (6H, s),
2.25 (3H, s),
2.40 (3H, s),
3.0-3.2 (2H, m),
3.2-3.3 (2H, m),
4.22 (2H, q, J = 7Hz),
6.61 (1H, d, J = 9 Hz),
7.2-7.3 (1H, m),
7.3-7.5 (2H, m),
7.6-7.7 (4H, m),
7.7-7.8 (2H, m)
(3) 2- [2-Methyl-4- [3- (4-methyl-4'-trifluoromethylbiphenyl-3-yl) propionyl] phenoxy] -2-methylpropionic acid
The title compound was obtained in the same manner as in Example 1 (4).
White amorphous
Yield 91%
FAB-MS (m / e): 485 (M + 1)
11 H NMR (CDCl3, 400 MHz):
δ =
1.68 (6H, s),
2.26 (3H, s),
2.39 (3H, s),
3.10 (2H, t, J = 7Hz),
3.23 (2H, t, J = 7 Hz),
6.75 (1H, d, J = 8 Hz),
7.2-7.3 (1H, m),
7.3-7.5 (2H, m),
7.6-7.7 (4H, m),
7.7-7.8 (2H, m)
Example 4
[2-Methyl-4- [3- (4-methyl-4′-trifluoromethylbiphenyl-3-yl) propionyl] phenoxy] acetic acid
(1) [2-Methyl-4- [3- (4-methyl-4'-trifluoromethylbiphenyl-3-yl) propionyl] phenoxy] ethyl acetate
The title compound was obtained in the same manner as in Example 2 (1).
White crystals
Yield 92%
11 H NMR (CDCl3, 400 MHz):
δ =
1.29 (3H, t, J = 7 Hz),
2.31 (3H, s),
2.40 (3H, s),
3.11 (2H, t, J = 7 Hz),
3.24 (2H, t, J = 7Hz),
4.26 (2H, q, J = 7Hz),
4.70 (2H, s),
6.70 (1H, d, J = 9 Hz),
7.2-7.3 (1H, m),
7.3-7.5 (2H, m),
7.6-7.7 (4H, m),
7.7-7.8 (2H, m)
(2) [2-Methyl-4- [3- (4-methyl-4'-trifluoromethylbiphenyl-3-yl) propionyl] phenoxy] acetic acid
The title compound was obtained in the same manner as in Example 1 (4).
White crystals
Yield 81%
mp: 158-161 ° C.
FAB-MS (m / e): 457 (M + 1)
11 H NMR (CDCl3, 400 MHz):
δ =
2.31 (3H, s),
2.40 (3H, s),
3.11 (2H, t, J = 7 Hz),
3.24 (2H, t, J = 7Hz),
4.76 (2H, s),
6.74 (1H, d, J = 9 Hz),
7.2-7.3 (1H, m),
7.3-7.5 (2H, m),
7.65 (4H, s),
7.8-7.9 (2H, m)
IR (KBr, cm-1): 3066, 2926, 2303, 1753, 1676, 1601, 1504, 1431, 1329, 1248, 1165, 1124, 1120, 1074, 1014, 993, 847, 818, 791, 679, 606
Example 5
2- [4- [3- (4-Isopropyl-4′-trifluoromethylbiphenyl-3-yl) propionyl] -2-methylphenoxy] -2-methylpropionic acid
(1) (5-Bromo-2-isopropylphenyl) methanol
Concentrated sulfuric acid (1 mL) was added to a solution of 2-isopropylbenzoic acid (1.65 g, 10.0 mmol) in trifluoroacetic acid (5 mL), and then N-bromosuccinimide (2.67 g, 15.0 mmol) was added for 2 hours. Added in small portions over time. After stirring at room temperature for 5 hours, the reaction solution was poured into ice water (50 mL) and extracted with chloroform (50 mL × 2). The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.73 g of a crude 5-bromo-2-isopropylbenzoic acid.
Under a nitrogen atmosphere, the 5-bromo-2-isopropylbenzoic acid crude product (2.73 g) obtained above was dissolved in tetrahydrofuran (25 mL), and then sodium borohydride (568 mg, 15.0 mmol) was added under ice cooling. And stirred for 15 minutes. Subsequently, boron trifluoride diethyl ether complex (1.90 mL, 15.0 mmol) was added dropwise over 10 minutes, followed by stirring at room temperature for 18 hours. Furthermore, 2M aqueous sodium hydroxide solution (7.5 mL) was added under ice cooling, and after stirring at room temperature for 5 hours, saturated aqueous sodium hydrogen carbonate (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic layer was washed with 10% aqueous potassium carbonate solution (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/10) to give 1.60 g (yield 70%) of the title compound as a colorless oil.
11 H NMR (CDCl3, 400 MHz):
δ =
1.23 (6H, d, J = 7 Hz),
1.58 (1H, t, J = 6Hz),
3.1-3.2 (1H, m),
4.72 (2H, d, J = 6 Hz),
7.18 (1H, d, J = 8Hz),
7.40 (1H, dd, J = 2, 8 Hz),
7.52 (1H, d, J = 2Hz)
(2) (4-Isopropyl-4'-trifluoromethylbiphenyl-3-yl) methanol
4- (trifluoromethyl) phenylboronic acid (1.59 g, 8.37 mmol), (5-bromo-2-isopropylphenyl) methanol (1.59 g, 6.94 mmol) obtained above and tetrakis (triphenylphosphine) ) Palladium (255 mg, 0.221 mmol) was dissolved in 1,4-dioxane (35 mL), potassium carbonate (3.17 g, 22.9 mmol) aqueous solution (7 mL) was added, and the mixture was heated to reflux for 4 hours. After allowing to cool to room temperature, saturated aqueous sodium hydrogen carbonate (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic layer was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/10 to 1/5) to obtain 1.92 g (yield 94%) of the title compound as white crystals.
11 H NMR (CDCl3, 400 MHz):
δ =
1.30 (6H, d, J = 7Hz),
1.63 (1H, bs),
3.2-3.4 (1H, m),
4.84 (2H, s),
7.43 (1H, d, J = 8 Hz),
7.53 (1H, dd, J = 2, 8 Hz),
7.61 (1H, d, J = 2 Hz),
7.6-7.8 (4H, m)
(3) 1- (4-Hydroxy-3-methylphenyl) -3- (4-isopropyl-4'-trifluoromethylbiphenyl-3-yl) propan-1-one
The title compound was obtained in the same manner as in Example 3 (1).
White crystals
Yield 31%
11 H NMR (CDCl3, 400 MHz):
δ =
1.29 (6H, d, J = 7 Hz),
2.28 (3H, s),
3.1-3.3 (5H, m),
5.32 (1H, s),
6.80 (1H, d, J = 9 Hz),
7.3-7.5 (3H, m),
7.66 (4H, s),
7.7-7.8 (2H, m)
(4) 2- [4- [3- (4-Isopropyl-4'-trifluoromethylbiphenyl-3-yl) propionyl] -2-methylphenoxy] -2-methylpropionate ethyl
The title compound was obtained in the same manner as in Example 1 (2).
Colorless oil
Yield 62%
11 H NMR (CDCl3, 400 MHz):
δ =
1.21 (3H, t, J = 7 Hz),
1.29 (6H, d, J = 7 Hz),
1.65 (6H, s),
2.25 (3H, s),
3.1-3.3 (5H, m),
4.21 (2H, q, J = 7 Hz),
6.61 (1H, d, J = 8 Hz),
7.3-7.5 (3H, m),
7.66 (4H, s),
7.7-7.8 (2H, m)
(5) 2- [4- [3- (4-Isopropyl-4'-trifluoromethylbiphenyl-3-yl) propionyl] -2-methylphenoxy] -2-methylpropionic acid
The title compound was obtained in the same manner as in Example 1 (4).
White amorphous
Yield 91%
FAB-MS (m / e): 513 (M + 1)
11 H NMR (CDCl3, 400 MHz):
δ =
1.28 (6H, d, J = 7 Hz),
1.68 (6H, s),
2.25 (3H, s),
3.1-3.3 (5H, m),
6.73 (1H, d, J = 8 Hz),
7.3-7.5 (3H, m),
7.65 (4H, s),
7.7-7.8 (2H, m)
Example 6
[4- [3- (4-Isopropyl-4′-trifluoromethylbiphenyl-3-yl) propionyl] -2-methylphenoxy] acetic acid
(1) 4- [3- (4-Isopropyl-4'-trifluoromethylbiphenyl-3-yl) propionyl] -2-methylphenoxy] ethyl acetate
The title compound was obtained in the same manner as in Example 2 (1).
Colorless oil
Yield 83%
11 H NMR (CDCl3, 400 MHz):
δ =
1.29 (3H, t, J = 7 Hz),
1.29 (6H, d, J = 7 Hz),
2.31 (3H, s),
3.1-3.3 (5H, m),
4.26 (2H, q, J = 7Hz),
4.70 (2H, s),
6.70 (1H, d, J = 9 Hz),
7.3-7.5 (3H, m),
7.66 (4H, s),
7.7-7.8 (2H, m),
(2) [4- [3- (4-Isopropyl-4'-trifluoromethylbiphenyl-3-yl) propionyl] -2-methylphenoxy] acetic acid
The title compound was obtained in the same manner as in Example 1 (4).
White crystals
Yield 93%
mp: 170-172 ° C
FAB-MS (m / e): 485 (M + 1)
11 H NMR (CDCl3, 400 MHz):
δ =
1.30 (6H, d, J = 7Hz),
2.31 (3H, s),
3.1-3.3 (5H, m),
4.76 (2H, s),
6.74 (1H, d, J = 9 Hz),
7.3-7.5 (3H, m),
7.66 (4H, s),
7.8-7.9 (2H, m)
IR (KBr, cm-1): 2966, 2875, 2588, 2345, 1749, 1676, 1601, 1506, 1458, 1427, 1392, 1369, 1325, 1259, 1255, 1169, 1167, 1132, 1074, 1038, 1016, 922, 877, 849, 825,785,681
Example 7
2- [4- [3- (4′-trifluoromethylbiphenyl-4-yl) propionyl] -2-methylphenoxy] -2-methylpropionic acid
(1) 1- (4-hydroxy-3-methylphenyl) -3- (4'-trifluoromethylbiphenyl-4-yl) propan-1-one
The title compound was obtained in the same manner as in Example 3 (1).
White crystals
Yield 98%
11 H NMR (CDCl3, 400 MHz):
δ =
2.28 (3H, s),
3.11 (2H, t, J = 7 Hz),
3.28 (2H, t, J = 7Hz),
5.32 (1H, s),
6.81 (1H, d, J = 8 Hz),
7.36 (2H, d, J = 8 Hz),
7.53 (2H, d, J = 8 Hz),
7.67 (4H, s),
7.7-7.8 (2H, m)
(2) 2- [4- [3- (4'-trifluoromethylbiphenyl-4-yl) propionyl] -2-methylphenoxy] -2-methylpropionate ethyl
The title compound was obtained in the same manner as in Example 1 (2).
White crystals
Yield 52%
11 H NMR (CDCl3, 400 MHz):
δ =
1.21 (3H, t, J = 7 Hz),
1.65 (6H, s),
2.26 (3H, s),
3.10 (2H, t, J = 7Hz),
3.27 (2H, t, J = 7 Hz),
4.22 (2H, q, J = 7Hz),
6.61 (1H, d, J = 9 Hz),
7.35 (2H, d, J = 8 Hz),
7.53 (2H, d, J = 8 Hz),
7.67 (4H, s),
7.70 (1H, dd, J = 2, 9 Hz),
7.79 (1H, d, J = 2Hz)
(3) 2- [4- [3- (4'-trifluoromethylbiphenyl-4-yl) propionyl] -2-methylphenoxy] -2-methylpropionic acid
The title compound was obtained in the same manner as in Example 1 (4).
White crystals
Yield 66%
mp: 149-151 ° C
FAB-MS (m / e): 471 (M + 1)
11 H NMR (CDCl3, 400 MHz):
δ =
1.69 (6H, s),
2.27 (3H, s),
3.10 (2H, t, J = 7Hz),
3.28 (2H, t, J = 7Hz),
6.76 (1H, d, J = 9 Hz),
7.35 (2H, d, J = 8 Hz),
7.52 (2H, d, J = 8 Hz),
7.67 (4H, s),
7.8-7.9 (2H, m)
IR (KBr, cm-1): 3151, 2924, 2299, 1747, 1641, 1603, 1578, 1504, 1439, 1381, 1327, 1271, 1269, 1267, 1230, 1201, 1165, 1126, 1070, 1026, 1005, 999, 968, 818, 814
Example 8
[4- [3- (4′-trifluoromethylbiphenyl-4-yl) propionyl] -2-methylphenoxy] acetic acid
(1) 4- [3- (4'-trifluoromethylbiphenyl-4-yl) propionyl] -2-methylphenoxy] ethyl acetate
The title compound was obtained in the same manner as in Example 2 (1).
White crystals
Yield 68%
11 H NMR (CDCl3, 400 MHz):
δ =
1.31 (3H, t, J = 7 Hz),
2.34 (3H, s),
3.13 (2H, t, J = 7 Hz),
3.30 (2H, d, J = 7Hz),
4.28 (2H, q, J = 7Hz),
4.72 (2H, s),
6.72 (1H, d, J = 8 Hz),
7.37 (2H, d, J = 8 Hz),
7.54 (2H, d, J = 8 Hz),
7.69 (4H, s),
7.8-7.9 (2H, m)
(2) [4- [3- (4′-trifluoromethylbiphenyl-4-yl) propionyl] -2-methylphenoxy] acetic acid
The title compound was obtained in the same manner as in Example 1 (4).
White crystals
Yield 81%
mp: 174-175 ° C
FAB-MS (m / e): 443 (M + 1)
11 H NMR (CDCl3, 400 MHz):
δ =
2.32 (3H, s),
3.11 (2H, d, J = 7 Hz),
3.29 (2H, d, J = 7 Hz),
4.77 (2H, s),
6.75 (1H, d, J = 9 Hz),
7.35 (2H, d, J = 8 Hz),
7.53 (2H, d, J = 8 Hz),
7.67 (4H, s),
7.8-7.9 (2H, m)
IR (KBr, cm-1): 3115, 2933, 2501, 1761, 17403, 1655, 1603, 1601, 1578, 1504, 1435, 1402, 1371, 1329, 1271, 1227, 1184, 1167, 1134, 1072, 1018, 1005, 989, 817
Example 9
2- [2-Methyl-4- [3- (3′-trifluoromethylbiphenyl-3-yl) propionyl] phenoxy] -2-methylpropionic acid
(1) 2- [2-Methyl-4- [3- (3'-trifluoromethylbiphenyl-3-yl) propionyl] phenoxy] -2-methylpropionate
The title compound was obtained in the same manner as in Example 1 (3).
Colorless oil
Yield 71%
11 H NMR (CDCl3, 400 MHz):
δ =
1.21 (3H, t, J = 7 Hz),
1.64 (6H, s),
2.25 (3H, s),
3.12 (2H, t, J = 7Hz),
3.28 (2H, t, J = 7Hz),
4.21 (2H, q, J = 7 Hz),
6.61 (1H, d, J = 9 Hz),
7.2-7.9 (10H, m)
(2) 2- [2-Methyl-4- [3- (3'-trifluoromethylbiphenyl-3-yl) propionyl] phenoxy] -2-methylpropionic acid
The title compound was obtained in the same manner as in Example 1 (4).
Pale yellow crystals
Yield 80%
FAB-MS (m / e): 471 (M + 1)
11 H NMR (CDCl3, 400 MHz):
δ =
1.68 (6H, s),
2.25 (3H, s),
3.11 (2H, t, J = 7 Hz),
3.28 (2H, t, J = 7Hz),
6.72 (1H, d, J = 9 Hz),
7.2-7.8 (10H, m)
Example 10 Pharmacological experiment
I. Test method
The PPAR activation action of the test compound (Example compound) was measured as follows.
Receptor expression plasmid (pSG5-GAL4-hPPARα or γ or δ (LBD), luciferase expression plasmid (pUC8-MH100 × 4-TK-Luc) and β-galactosidase in CV-1 cells (ATCC (American Type Culture Collection)) (PCMX-β-GAL) expression plasmid (Kliewer, SA et al., (1992) Nature, 358: 771-774) was introduced, and lipofection reagent (DMRIE-C, Lipofectamine 2000 (Invitrogen)) was introduced. After transfection, the cells were cultured for 42 hours in the presence of the test compound, and the solubilized cells were used to measure luciferase activity and β-GAL activity. Corrected, relative ligand activity was calculated with PPARα as GW-590735 (PPARα selective agonist), PPARγ as Rosiglitazole, and PPARδ as luciferase activity value of cells treated with GW-501516 as 100%.
II. Test results
  The test results are shown in Table 25.
Figure 2006041197
Note 1) PPAR activity: Relative value at 10-6M of test compound when the control is 100%
Control drug α: GW-590735 10-6M
γ: Rosiglitazone 10-5M
δ: GW-501516 10-7M
2) GW-590735: Example 2 of Patent Document 6
  3) ia represents inactive.
  As is apparent from Table 25, the example compounds exhibited an excellent PPARδ activation effect.

Claims (14)

次の一般式(I)、
Figure 2006041197
(式中、Aは結合手、酸素原子、硫黄原子、C(=O)、C(=CH)、(CH又はN(R)を表し、ここで、mは1又は2を表し、Rは、水素原子又は炭素数1〜8のアルキル基を表し、
Bは置換基として炭素数1〜8のアルキル基、3〜8員環のシクロアルキル基、ハロゲン原子で置換された炭素数1〜8のアルキル基、炭素数1〜8のアルコキシ基、炭素数2〜8のアルケニル基、ハロゲン原子、アラルキル基(アリール部分の炭素数は6〜10で、アルキル部分の炭素数は1〜3)、複素環で置換された炭素数1〜3のアルキル基から選ばれる基又は原子を有していても良いメチレン、エチレン又はビニレンを表し、
Wは酸素原子、硫黄原子、(CH又はN(R)を表し、ここで、nは1又は2を表し、Rは水素原子又は炭素数1〜8のアルキル基を表し、
X及びYは同一又は異なっても良く、窒素原子又はCHを表し、
Zは、酸素原子又はCHRを表し、ここで、Rは、水素原子又は炭素数1〜8のアルキル基を表し、
及びRは同一又は異なっても良く、水素原子、炭素数1〜8のアルキル基又はハロゲン原子で置換された炭素数1〜8のアルキルを表し、
はカルボキシル基、炭素数2〜8のアルコキシカルボニル基、カルバモイル基、アラルキルオキシカルボニル基(アリール部分の炭素数は6〜10で、アルキル部分の炭素数は1〜3)、スルホン酸基、ホスホン酸基、シアノ基又はテトラゾリル基を表し、
そして、R、R及びRは、同一又は異なっても良く、水素原子、ハロゲン原子、炭素数1〜8のアルキル基、ハロゲン原子で置換された炭素数1〜8のアルキル基、3〜8員環のシクロアルキル基、炭素数1〜8のアルコキシ基で置換された炭素数1〜8のアルキル基、炭素数1〜8のアルコキシ基、ハロゲン原子で置換された炭素数1〜8のアルコキシ基、炭素数2〜8のアルケニル基、炭素数2〜8のアルキニル基、ヒドロキシル基、ニトロ基、炭素数2〜8のアシル基、炭素数7〜11のアリールカルボニル基、炭素数6〜10のアリール基又は複素環を表す。
なお、上記のアリール及び複素環には、置換基として炭素数1〜8のアルキル基、炭素数1〜8のアルコキシ基、ハロゲン原子、ハロゲン原子で置換された炭素数1〜8のアルキル基、ヒドロキシル基、ニトロ基、アミノ基、フェニル基又は複素環から選ばれる基又は原子を有していても良い。)
で表される化合物又はその塩。
The following general formula (I),
Figure 2006041197
(In the formula, A represents a bond, an oxygen atom, a sulfur atom, C (═O), C (═CH 2 ), (CH 2 ) m or N (R 7 ), where m is 1 or 2 R 7 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms,
B is a C1-C8 alkyl group, a 3- to 8-membered cycloalkyl group, a C1-C8 alkyl group substituted with a halogen atom, a C1-C8 alkoxy group, or a carbon number as a substituent. From an alkenyl group having 2 to 8 carbon atoms, a halogen atom, an aralkyl group (the aryl moiety has 6 to 10 carbon atoms and the alkyl moiety has 1 to 3 carbon atoms), an alkyl group having 1 to 3 carbon atoms substituted with a heterocyclic ring Represents methylene, ethylene or vinylene which may have a selected group or atom,
W represents an oxygen atom, a sulfur atom, (CH 2 ) n or N (R 8 ), wherein n represents 1 or 2, R 8 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms,
X and Y may be the same or different and each represents a nitrogen atom or CH;
Z represents an oxygen atom or CHR 9 , where R 9 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms,
R 1 and R 2 may be the same or different and each represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or an alkyl having 1 to 8 carbon atoms substituted with a halogen atom,
R 3 is a carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms, a carbamoyl group, an aralkyloxycarbonyl group (the aryl moiety has 6 to 10 carbon atoms and the alkyl moiety has 1 to 3 carbon atoms), a sulfonic acid group, Represents a phosphonic acid group, a cyano group or a tetrazolyl group,
R 4 , R 5 and R 6 may be the same or different, and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, 3 ˜8-membered cycloalkyl group, C 1-8 alkyl group substituted with C 1-8 alkoxy group, C 1-8 alkoxy group, C 1-8 substituted with halogen atom Alkoxy groups, alkenyl groups having 2 to 8 carbon atoms, alkynyl groups having 2 to 8 carbon atoms, hydroxyl groups, nitro groups, acyl groups having 2 to 8 carbon atoms, arylcarbonyl groups having 7 to 11 carbon atoms, and 6 carbon atoms. Represents 10 to 10 aryl groups or heterocyclic rings.
In the above aryl and heterocycle, the alkyl group having 1 to 8 carbon atoms, the alkoxy group having 1 to 8 carbon atoms, the halogen atom, and the alkyl group having 1 to 8 carbon atoms substituted with a halogen atom as a substituent, You may have a group or an atom chosen from a hydroxyl group, a nitro group, an amino group, a phenyl group, or a heterocyclic ring. )
Or a salt thereof.
Aが結合手である請求の範囲第1項記載の化合物又はその塩。  The compound or a salt thereof according to claim 1, wherein A is a bond. フェニル基に対し、C(=Z)とWの配置がメタ位又はパラ位である請求の範囲第1又は2項の何れかの項に記載の化合物又はその塩。  The compound or a salt thereof according to any one of claims 1 or 2, wherein the configuration of C (= Z) and W is meta or para with respect to the phenyl group. Bがメチレン又はエチレンである請求の範囲第1〜3項の何れかの項に記載の化合物又はその塩。  The compound or a salt thereof according to any one of claims 1 to 3, wherein B is methylene or ethylene. Wが酸素原子又は硫黄原子である請求の範囲第1〜4項の何れかの項に記載の化合物又はその塩。  The compound or a salt thereof according to any one of claims 1 to 4, wherein W is an oxygen atom or a sulfur atom. X及びYが共にCHである請求の範囲第1〜5項の何れかの項に記載の化合物又はその塩。  The compound or a salt thereof according to any one of claims 1 to 5, wherein X and Y are both CH. Zが酸素原子である請求の範囲第1〜6項の何れかの項に記載の化合物又はその塩。  The compound or a salt thereof according to any one of claims 1 to 6, wherein Z is an oxygen atom. 及びRが共に水素原子又はメチル基である請求の範囲第1〜7項の何れかの項に記載の化合物又はその塩。The compound or a salt thereof according to any one of claims 1 to 7, wherein R 1 and R 2 are both a hydrogen atom or a methyl group. がカルボキシル基、炭素数2〜8のアルコキシカルボニル基、カルバモイル基又はアラルキルオキシカルボニル基(アリール部分の炭素数は6〜10で、アルキル部分の炭素数は1〜3)である請求の範囲第1〜8項の何れかの項に記載の化合物又はその塩。R 3 is a carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms, a carbamoyl group or an aralkyloxycarbonyl group (the aryl moiety has 6 to 10 carbon atoms and the alkyl moiety has 1 to 3 carbon atoms). The compound or salt thereof according to any one of items 1 to 8. がカルボキシル基である請求の範囲第1〜8項の何れかの項に記載の化合物又はその塩。The compound or a salt thereof according to any one of claims 1 to 8, wherein R 3 is a carboxyl group. 、R及びRが同一又は異なっても良く、水素原子、炭素数1〜8のアルキル基、ハロゲン原子で置換された炭素数1〜8のアルキル基又はハロゲン原子である請求の範囲第1〜8項の何れかの項に記載の化合物又はその塩。R 4 , R 5 and R 6 may be the same or different and are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, or a halogen atom. The compound or salt thereof according to any one of items 1 to 8. 次の一般式(II)、
Figure 2006041197
(式中、Bはメチレン、エチレン又はビニレンを表し、
は酸素原子又は硫黄原子を表し、
は窒素原子又はCHを表し、
は酸素原子又はCHを表し、
11及びR12は共に水素原子又は炭素数1〜3のアルキル基を表し、
そして、R14、R15及びR16は同一又は異なっても良く、水素原子、ハロゲン原子、炭素数1〜8のアルキル基、ハロゲン原子で置換された炭素数1〜8のアルキル基、炭素数1〜8のアルコキシ基又はハロゲン原子で置換された炭素数1〜8のアルコキシ基を表す。)
で表される化合物又はその塩。
The following general formula (II),
Figure 2006041197
(Wherein B 1 represents methylene, ethylene or vinylene;
W 1 represents an oxygen atom or a sulfur atom,
X 1 represents a nitrogen atom or CH,
Z 1 represents an oxygen atom or CH 2 ,
R 11 and R 12 both represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,
R 14 , R 15 and R 16 may be the same or different, and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, or a carbon number. It represents a C 1-8 alkoxy group substituted with a 1-8 alkoxy group or a halogen atom. )
Or a salt thereof.
がメチレン又はエチレンである請求の範囲第12項記載の化合物又はその塩The compound or a salt thereof according to claim 12, wherein B 1 is methylene or ethylene. 請求の範囲第1〜13項の何れかの項に記載の化合物又はその塩を有効成分として含有するペルオキシソーム増殖剤活性化受容体δの活性化剤。  An activator of peroxisome proliferator-activated receptor δ comprising the compound or salt thereof according to any one of claims 1 to 13 as an active ingredient.
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