JP2014141522A - エストロゲン関連受容体モジュレータ化合物及びその使用 - Google Patents
エストロゲン関連受容体モジュレータ化合物及びその使用 Download PDFInfo
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- JP2014141522A JP2014141522A JP2014080342A JP2014080342A JP2014141522A JP 2014141522 A JP2014141522 A JP 2014141522A JP 2014080342 A JP2014080342 A JP 2014080342A JP 2014080342 A JP2014080342 A JP 2014080342A JP 2014141522 A JP2014141522 A JP 2014141522A
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- cycloalkyl
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- CXGTZJYQWSUFET-IBGZPJMESA-N tesaglitazar Chemical compound C1=CC(C[C@H](OCC)C(O)=O)=CC=C1OCCC1=CC=C(OS(C)(=O)=O)C=C1 CXGTZJYQWSUFET-IBGZPJMESA-N 0.000 description 1
- 229950004704 tesaglitazar Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000037426 transcriptional repression Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 229960001641 troglitazone Drugs 0.000 description 1
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 1
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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Abstract
【解決手段】式Iの化合物、その薬学的に許容される塩、又はその立体異性体。
(A,B,D,及びEは独立にCH又はN;nは0〜2;a,bは0又は1;R1はH、ハロゲン、水酸基、ニトロ基、カルボキシル基、シアノ基、エステル基、置換されていてもよいアミド基等;R2はH、アルキル基、アリル基、複素環;R3はH、ハロゲン、水酸基、ニトロ基、カルボキシル基、シアノ基、エステル基、置換されていてもよいアミド基)
【選択図】図1
Description
nは0、1又は2であり、
以下のaは0又は1,bは0又は1であり、
R1は下記から選択され、
1) H;
2) ハロゲン化物(F,Cl,Br,I);
3) OH;
4) NO2;
5) CO2H;
6) (C=O)aObC1〜C8アルキル;
7) (C=O)aObアリル;
8) (C=O)aObC2〜C8アルケニル;
9) (C=O)aObC2〜C8アルキニル;
10) ObC1〜C8フルオロアルキル;
11) (C=O)aNR6R5;
12) CN;
13) (C=O)aObC3〜C8シクロアルキル;
14) (C=O)aObヘテロサイクル;
15) SO2NR6R5;
16) SO2C1〜C8アルキル;
17) (C=O)aObC0〜C8−NR6R5;
上記のアルキル、アリル、アルケニル、アルキニル、シクロアルキル、及びヘテロサイクル基は、R4から独立して選択される置換基により0又は1以上置換され、
R2は下記から選択され、
1) H;
2) C1〜C8アルキル:
3) アリル:
4) C3〜C8アルケニル;
5) C3〜C8アルキニル;
6) C1〜C8フルオロアルキル;
7) C1〜C6アリルアルキル;
8) C3〜C6シクロアルキル;
9) ヘテロサイクル;
上記のアルキル、アリル、アルケニル、アルキニル、シクロアルキル、及びヘテロサイクル基は、R4から独立して選択される置換基により0又は1以上置換され、
R3は下記から選択され、
1) (C=O)aObC1〜C8アルキル;
2) (C=O)aObアリル(フェニル基ではないアリル)、ここでaは0,bは0であり、A,B,D,及びEはそれぞれCHであり;
3) (C=O)aObC2〜C8アルケニル;
4) (C=O)aObC2〜C8アルキニル;
5) C1〜C8フルオロアルキル;
6)Ob(C=O)aNR6R5;
7) (C=O)aObC3〜C8シクロアルキル;
8) (C=O)aObヘテロサイクル;
9) (C=O)aObC3〜C6シクロアルキル;
上記のアルキル、アリル、アルケニル、アルキニル、シクロアルキル、及びヘテロサイクル基は、R4から独立して選択される置換基により0又は1以上置換され、
R4は下記から選択され、
1) H;
2) ハロゲン化物(F,Cl,Br,I);
3) OH;
4) NO2;
5) CO2H;
6) (C=O)aObC1〜C8アルキル;
7) (C=O)aObアリル;
8) (C=O)aObC2〜C8アルケニル;
9) (C=O)aObC2〜C8アルキニル;
10) ObC1〜C8フルオロアルキル;
11) (C=O)aNR6R5;
12) CN;
13) (C=O)aObC3〜C8シクロアルキル;
14) (C=O)aObヘテロサイクル;
15) SO2NR6R5;
16) SO2C1〜C8アルキル;
上記のアルキル、アリル、アルケニル、アルキニル、シクロアルキル、及びヘテロサイクル基は、R5、OH、(C1〜C6)アルコキシ、ハロゲン化物、COOH、CN、O(C=O)C1〜C6アルキル、又はNR5R6基から独立して選択される置換基により3まで置換され、
R5及びR6は下記から選択され、
1) H;
2) (C=O)aObC1〜C8アルキル;
3) (C=O)aObアリル;
4) (C=O)aObC2〜C8アルケニル;
5) (C=O)aObC2〜C8アルキニル;
6) ObC1〜C8フルオロアルキル;
7) (C=O)aObC3〜C8シクロアルキル;
8) (C=O)aObヘテロサイクル;
9) SO2C1〜C8アルキル;
10) (C=O)aObC0〜C8−NR6R5;
上記のアルキル、アリル、アルケニル、アルキニル、シクロアルキル、及びヘテロサイクル基は、R6から独立して選択される置換基により3まで置換され、R6及びR5は4〜7原子環又は4〜7原子によって形成される二環状環であり、前記原子環又は二環状環は、N、O又はS原子から選択される1、2又は3ヘテロ原子を含み、前記原子環又は二環状環は、R5から独立して選択される置換基により1以上置換される。
R3は下記から選択され、
1) (C=O)aObC1〜C8アルキル;
2) (C=O)aObアリル;
3) (C=O)aObC2〜C8アルケニル;
4) (C=O)aObC2〜C8アルキニル;
5) C1〜C8フルオロアルキル;
6)Ob(C=O)aNR6R5;
7) (C=O)aObC3〜C8シクロアルキル;
8) (C=O)aObヘテロサイクル;
9) (C=O)aObC3〜C6シクロアルキル;
上記のアルキル、アリル、アルケニル、アルキニル、シクロアルキル、及びヘテロサイクル基は、R4から独立して選択される置換基により0又は1以上置換され、
R5及びR6は請求項1と同様に定義される。
m、nは独立して0、1、又は2から選択され、
Arは、N、S、又はOからなるヘテロ原子を含む芳香族環であり、
R1及びR7は独立して下記から選択され、
1) H;
2) ハロゲン化物(F,Cl,Br,I);
3) OH;
4) NO2;
5) CO2H;
6) (C=O)aObC1〜C8アルキル;
7) (C=O)aObアリル;
8) (C=O)aObC2〜C8アルケニル;
9) (C=O)aObC2〜C8アルキニル;
10) ObC1〜C8フルオロアルキル;
11) (C=O)aNR6R5;
12) CN;
13) (C=O)aObC3〜C8シクロアルキル;
14) (C=O)aObヘテロサイクル;
15) SO2NR6R5;
16) SO2C1〜C8アルキル;
17) (C=O)aObC0〜C8−NR6R5;
上記のアルキル、アリル、アルケニル、アルキニル、シクロアルキル、又はヘテロサイクル基は、R4から独立して選択される置換基により1以上置換され、
R2は下記から選択され、
1) H;
2) C1〜C8アルキル;
3) アリル;
4) C3〜C8アルケニル;
5) C3〜C8アルキニル;
6) C1〜C8フルオロアルキル;
7) C1〜C6アリルアルキル;
8) C3〜C6シクロアルキル;
9) ヘテロサイクル;
上記のアルキル、アリル、アルケニル、アルキニル、シクロアルキル、又はヘテロサイクル基は、R4から独立して選択される置換基により1以上置換され、
R4は下記から選択され、
1) H;
2) ハロゲン化物(F,Cl,Br,I);
3) OH;
4) NO2;
5) CO2H;
6) (C=O)aObC1〜C8アルキル;
7) (C=O)aObアリル;
8) (C=O)aObC2〜C8アルケニル;
9) (C=O)aObC2〜C8アルキニル;
10) ObC1〜C8フルオロアルキル;
11) (C=O)aNR6R5;
12) CN;
13) (C=O)aObC3〜C8シクロアルキル;
14) (C=O)aObヘテロサイクル;
15) SO2NR6R5;
16) SO2C1〜C8アルキル;
上記のアルキル、アリル、アルケニル、アルキニル、シクロアルキル、又はヘテロサイクル基は、R5、OH、(C1〜C6)アルコキシ、ハロゲン化物、COOH、CN、O(C=O)C1〜C6アルキル、又はNR5R6基から独立して選択される置換基により3まで置換され、
R5及びR6は下記から選択され、
1)H;
2)(C=O)aObC1〜C8アルキル;
3)(C=O)aObアリル;
4)(C=O)aObC2〜C8アルケニル;
5)ObC1〜C8フルオロアルキル;
6)(C=O)aObC3〜C8シクロアルキル;
7)(C=O)aObヘテロサイクル;
8)SO2C1〜C8アルキル;
9)(C=O)aObC0〜C8−NR6R5;
上記のアルキル、アリル、アルケニル、アルキニル、シクロアルキル、及びヘテロサイクル基は、R6から独立して選択される置換基により3まで置換され、R6及びR5は4〜7原子環又は4〜7原子によって形成される二環状環であり、前記原子環又は二環状環は、N、O又はS原子から選択される1、2又は3ヘテロ原子を含み、前記原子環又は二環状環は、R5から独立して選択される置換基により1以上置換される。
哺乳類、特にヒトに対する適切な投薬は、本発明の化合物を効果的に投与することである。例えば、経口、直腸、表面、非経口、眼球、肺、鼻等に用いられる。調剤は、錠剤、トローチ、粉剤、懸濁液、溶液、カプセル、クリーム、軟膏、エアロゾル等を含む。好ましくは式Iの化合物は経口投与される。
本発明の他の側面により、式Iの化合物及びその薬学的に許容される担体を含む薬学的組成物が得られる。本発明の薬学的組成物は、薬学的に許容される担体及び他の最適な治療学的成分同様、活性成分として式Iの化合物又はその薬学的に許容される塩を含む。“薬学的に許容される塩”の文言は、無機塩基又は酸及び有機塩基又は酸を含む薬学的に許容される非毒性の塩基又は酸から調製される塩を意味する。プロドラッグが認可されている場合、薬学的組成物は、プロドラッグ又はその薬学的に許容される塩をも包含しても良い。
請求項に記載された発明の範囲に代謝物自身が入る場合は、治療学的に活性な代謝物も本発明の化合物である。患者に投与され又は患者に投与された後に請求項に記載された発明に変換される化合物であるプロドラッグもまた本発明の化合物である。
式Iの化合物は、式Iの化合物が有益である病気又は状態の治療又は改善に有益である他の薬剤と組み合わせて使用することができる。このような他の薬剤は、通常使用されているルート及び量にて、式Iの化合物と同時に又は連続して投与される。式Iの化合物が1以上の他の薬剤と同時に使用される場合、一つの調剤中の薬学的組成に、このような他の薬剤と式Iの化合物とを包含していることが好ましい。しかしながら、組み合わせ治療は、式Iの化合物と1以上の他の薬剤とが異なって重なるスケジュールにて投薬される治療をも包含する。1以上の他の活性成分と組み合わせで使用される場合、本発明の化合物及び他の活性成分は、各々が単一で使用される場合よりも少ない投与量にて使用されることが意図される。従って、本発明の薬学的組成物は、式Iの化合物に加えて1以上の他の活性成分を含む。
2)メトホルミン及びフェンホルミンのようなビグアニド;
3)プロテインチロシンホスファターゼ−IB(PTP−1B)抑制剤;
4)ジペプチジルペプチダーゼIV(DP−IV)抑制剤;
5)インスリン又はインスリン模倣薬
6)トルブタミド及びグリピザイド、又は関連する材料のようなスルホニル尿素
7)α−グルコシダーゼ抑制剤(アカルボースのような)
8)以下のような患者の脂質プロファイルを向上させる薬剤、即ち(i)HMG−CoAレダクターゼ抑制剤(ロバスタチン、シンバスタチン、ロスバスタチン、プラバスタチン、フルバスタチン、アトルバスタチン、リバスタチン、イタバスタチン、ZD−4522及び他のスタチン)、(ii)胆汁酸抑制剤(コレスチラミン、コレスチポール、及び架橋デキストランのジアルキルアミノアルキル誘導体)、(iii)ニコチニルアルコール、ニコチン酸又はその塩、(iv)フェノフィブリン酸誘導体(ゲムフィブロジル、クロフィブレート、フェノフィブレート、及びベザフィブラート)のようなPPARγアゴニスト、(v)例えばエゼチミブのようなコレステロール吸収阻害剤、(vi)アシルCoA:アバシミブのようなコレステロールアシルトランスフェラーゼ(ACAT)阻害剤、(vii)CETP阻害剤、及び(viii)プロブコールのようなフェノール性アンチ酸化剤;
9)KRP−297、ムラグリタザル、テサグリタザル、ファルグリタザル、及びJT−501のようなPPARα/γデュアルアゴニスト;
10)WO1997/028149に開示されているようなPPARα/γデュアルアゴニスト
11)フェンフルラミン、デクスフェンフルラミン、フェンチラミン、シブトラミン、オルリスタット、ニューロペプチドY5阻害剤、Mc4rアゴニスト、カンナビノイド受容体(CB−1)アンタゴニスト/インバース アゴニスト、及びベータ3アドレナリン受容体アゴニストのような抗肥満化合物;
12)回腸胆汁酸輸送抑制剤;
13)アスピリン、非ステロイド抗炎症剤、グルココルチコイド、アザルフィジン、及びシクロオキシゲナーゼ2選択的抑制剤のような、炎症状態での使用が意図される試薬
14)グルカゴン受容体アンタゴニスト;
15)エキセニチドのようなGLP−1及びその類似物;
16)GIP−1
17)GLP−1受容体アゴニスト
上述の組み合わせは、一つの他の活性化合物のみならず2以上の他の活性化合物と、本発明化合物との組み合わせを含む。非制限的な具体例には、式Iの化合物と、ビグアニド、スルホニル尿素、HMG−CoAレダクターゼ抑制剤、他のPPARアゴニスト、PTP−1B阻害剤、DP−IV阻害剤、及び抗肥満化合物から選択される2以上の活性化合物との組み合わせが含まれる。
(7−メトキシ−3−メチル−2−フェニルキナゾリン−4(3H)−ワン)の調製
ピリジン(10ml)中の2−アミノ−4−メトキシ安息香酸(1.67g,10mmol)溶液が、ピリジン(5ml)中の塩化ベンゾイル(1.4g,10mmol)溶液に、敵状にて室温で加えられた。次に、混合物が氷水(50g)に注ぎ込まれ、酢酸エチルにて抽出され、Na2SO4にて乾燥され、濾過された。濾過物は、真空内で濃縮され、更にシリカゲル(20%エチル酢酸/石油エーテル)上でフラッシュ・クロマトグラフィーにて精製され、白色固体として表題の化合物(1.96g,77.5%)が得られた。
ステップ1で得られた化合物(0.253g、1.0mol)とメチルアミン塩酸塩(0.675g、10mmol)とがDMF(10mL)中にて混合され、そして5hの間加熱還流した。次に、混合物が氷水(50g)に注ぎ込まれ、酢酸エチルにて抽出され、Na2SO4にて乾燥され、濾過された。濾過物は、真空内で濃縮され、更にシリカゲル(エチル酢酸:石油エーテル=1:1)上でフラッシュ・クロマトグラフィーにて精製され、白色固体として表題の化合物(0.14g,51%)が得られた。
MS(ESI),m/z: 266 (M+).
《実施例2》
(2−(4−クロロフェニル)−7−メトキシ−3−メチルキナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI),m/z: 300 (M+).
《実施例3》
(2−(4−フルオロフェニル)−7−メトキシ−3−メチルキナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI),m/z: 285 (M+H) +.
《実施例4》
(2−(4−ブロモフェニル)−7−メトキシ−3−メチルキナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI),m/z: 345 (M) +.
《実施例5》
(2−(3−フルオロフェニル)−7−メトキシ−3−メチルキナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI),m/z: 284 (M) +.
《実施例6》
(2−(4−ブロモフェニル)−7−ヒドロキシ−3−メチルキナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI), m/z: 331 (M) +, 333(M+2H) +.
《実施例7》
(7−メトキシ−3−メチル−2−(ピリジン−3−イル)キナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI), m/z: 267 (M) +.
《実施例8》
(7−メトキシ−3−メチル−2−(ピリジン−4−イル)キナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI),m/z: 268 (M+H) +.
《実施例9》
(3−メチル−2−フェニルピリド[2,3−d]ピリミジン−4(3H)−ワン)の調製
MS(ESI),m/z: 236 (M) +- H+.
《実施例10》
(3−メチル−2−フェニルピリド[4,3−d]ピリミジン−4(3H)−ワン)の調製
《実施例11》
(3−メチル−2−フェニルキナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI), m/z: 235 (M) +- H+,236 (M) +.
《実施例12》
(7−ヒドロキシ−3−メチル−2−フェニルキナゾリン−4(3H)−ワン)の調製
化合物12は、HBr−HOAc溶液において、実施例1の化合物の脱メチル化により合成された。
MS(ESI), m/z: 251 (M) +- H+,252 (M) +.
《実施例13》
(7−エトキシ−3−メチル−2−フェニルキナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI),m/z: 279 (M) +- H+,280 (M) +.
《実施例14》
(7−イソプロポキシ−3−メチル−2−フェニルキナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI),m/z: 294 (M) +.
《実施例15》
(2−(3−クロロフェニル)−7−メトキシ−3−メチルキナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI),m/z: 301 (M+H) +, 303 (M+3H) +.
《実施例16》
(7−メトキシ−3−メチル−2−(ナフタリン−1−イル)キナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI), m/z: 317 (M+H) +, 318 (M+2H)+.
《実施例17》
(7−メトキシ−3−(2−モルホリノエチル)−2−フェニルキナゾリン−4(3H)−ワン)の調製
MS(ESI),m/z: 366 (M+H) +.
《実施例18》
(2−(4−フルオロフェニル)−7−メトキシ−3−(2−モルホリノエチル)キナゾリン−4(3H)−ワン)の調製
MS(ESI),m/z: 384 (M+H) +.
《実施例19》
(2−(4−クロロフェニル)−7−メトキシ−3−(2−モルホリノエチル)キナゾリン−4(3H)−ワン)の調製
MS(ESI),m/z: 400 (M+H) +, 402 (M+3H) +.
《実施例20》
(7−クロロ−3−メチル−2−フェニルキナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI),m/z: 271 (M+H) +, 273 (M+3H) +.
《実施例21》
(7−クロロ−3−(2−モルホリノエチル)−2−フェニルキナゾリン−4(3H)−ワン)の調製
MS(ESI),m/z: 370 (M+H) +, 373 (M+3H) +.
《実施例22》
(7−クロロ−2−(4−クロロフェニル)−3−メチルキナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI),m/z: 305 (M) +.
《実施例23》
(7−クロロ−2−(4−フルオロフェニル)−3−メチルキナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI), m/z: 288 (M) +, 287 (M+ - H+).
《実施例24》
(6−メトキシ−3−メチル−2−フェニルキナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI), m/z: 266 (M) +,265 (M+ - H+).
《実施例25》
(2−(4−クロロフェニル)−6−メトキシ−3−メチルキナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI), m/z: 301 ( M++ H+), 303 (M+ + 3H+).
《実施例26》
(2−(4−フルオロフェニル)−6−メトキシ−3−メチルキナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI), m/z: 284 ( M+).
《実施例27》
(6−ヨード−7−メトキシ−3−メチル−2−フェニルキナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI), m/z: 392 ( M+).
《実施例28》
(3,4−ジヒドロ−7−メトキシ−3−メチル−N−(2−モルホリノエチル)−4−オキソ−2−フェニルキナゾリン−6−カルボキサミド)の調製
MS(ESI), m/z: 423 ( M++ H+).
《実施例29》
(6−ヒドロキシ−7−メトキシ−3−メチル−2−フェニルキナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI), m/z: 281 (M+- H+).
《実施例30》
(6−(2−モルホリノエトキシ)−7−メトキシ−3−メチル−2−フェニルキナゾリン−4(3H)−ワン)の調製
化合物30は化合物29から合成された。
MS(ESI), m/z: 396 (M++ H+).
《実施例31》
(2−シクロヘキシル−7−メトキシ−3−メチルキナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI), m/z: 273 (M++ H+).
《実施例32》
(2−イソプロピル−7−メトキシ−3−メチルキナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI), m/z: 232 (M+).
《実施例33》
(2,3−ジメチル−7−メトキシキナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI), m/z: 204 (M+).
《実施例34》
(2−tertブチル−7−メトキシ−3−メチルキナゾリン−4(3H)−ワン)の調製
実施例1と同様の合成方法が用いられた。
MS(ESI), m/z: 246 (M+).
《実施例35》
本実施例によって、本発明の上記の化合物(例えば化合物1、DK3とも命名された、7−メトキシ−3−メチル−2−フェニルキナゾリン−4(3H)−ワン)、並びに、DK6とも命名された2−(4−ブロモフェニル)−7−メトキシ−3−メチルキナゾリン−4(3H)−ワンである化合物4、及び、DK7とも命名された2−(4−フルオロフェニル)−7−メトキシ−3−メチルキナゾリン−4(3H)−ワンである化合物3のような式Iのコア構造を有するその他の化合物が、ヒーラ細胞においてERRαによって調整されたレポーター遺伝子の発現を効果的に上昇させることが説明される。そのため、これらの化合物はERRαの機能を効果的に上昇させることができる。
本実施例によって、DK3のような本発明における上記化合物がヒーラ細胞においてPGC−1αプロモータレポータ遺伝子の発現を効果的に向上させることが説明される。
本実施例によって、DK3のような本発明における上記化合物が、筋芽細胞L6におけるインスリン依存性グルコース摂取を効果的に向上させることが説明される。
インスリンは、放射性グルコースを取り込む筋管能力を誘起する。抗糖尿病薬ロシグリタゾンはグルコースの摂取を向上させる。DK1は、陽性コントロールロシグリタゾンと比較して、筋管におけるインスリン依存性グルコース摂取を向上させる(図5参照)。
本実施例によって、DK3のような本発明における上記化合物が、高脂食マウスにおいてグルコース耐性を効果的に向上させることが説明される。
てプロットされ、カーブ下の領域が異なるグループごとに計算された。
本実施例によって、DK3のような本発明における上記化合物が、高脂食により誘起された脂肝臓の範囲を効果的に減少させることが説明される。
Claims (7)
- 下記化学式Iで示される化合物、その薬学的に許容される塩、又はその立体異性体。
nは0、1又は2であり、
以下のaは0又は1,bは0又は1であり、
R1は下記から選択され、
1) H;
2) ハロゲン化物;
3) OH;
4) NO2;
5) CO2H;
6) (C=O)aObC1〜C8アルキル;
7) (C=O)aObアリル;
8) (C=O)aObC2〜C8アルケニル;
9) (C=O)aObC2〜C8アルキニル;
10) ObC1〜C8フルオロアルキル;
11) (C=O)aNR6R5;
12) CN;
13) (C=O)aObC3〜C8シクロアルキル;
14) (C=O)aObヘテロサイクル;
15) SO2NR6R5;
16) SO2C1〜C8アルキル;
17) (C=O)aObC0〜C8−NR6R5;
上記のアルキル、アリル、アルケニル、アルキニル、シクロアルキル、及びヘテロサイクル基は、R4から独立して選択される置換基により0又は1以上置換され、
R2は下記から選択され、
1) H;
2) C1〜C8アルキル:
3) アリル:
4) C3〜C8アルケニル;
5) C3〜C8アルキニル;
6) C1〜C8フルオロアルキル;
7) C1〜C6アリルアルキル;
8) C3〜C6シクロアルキル;
9) ヘテロサイクル;
上記のアルキル、アリル、アルケニル、アルキニル、シクロアルキル、及びヘテロサイクル基は、R4から独立して選択される置換基により0又は1以上置換され、
R3は下記から選択され、
1) (C=O)aObC1〜C8アルキル;
2) (C=O)aObアリル(フェニル基ではないアリル)、ここでaは0,bは0であり、A,B,D,及びEはそれぞれCHであり;
3) (C=O)aObC2〜C8アルケニル;
4) (C=O)aObC2〜C8アルキニル;
5)C1〜C8フルオロアルキル;
6) Ob(C=O)aNR6R5;
7) (C=O)aObC3〜C8シクロアルキル;
8) (C=O)aObヘテロサイクル;
9) (C=O)aObC3〜C6シクロアルキル;
上記のアルキル、アリル、アルケニル、アルキニル、シクロアルキル、及びヘテロサイクル基は、R4から独立して選択される置換基により0又は1以上置換され、
R4は下記から選択され、
1) H;
2) ハロゲン化物;
3) OH;
4) NO2;
5) CO2H;
6) (C=O)aObC1〜C8アルキル;
7) (C=O)aObアリル;
8) (C=O)aObC2〜C8アルケニル;
9) (C=O)aObC2〜C8アルキニル;
10) ObC1〜C8フルオロアルキル;
11) (C=O)aNR6R5;
12) CN;
13) (C=O)aObC3〜C8シクロアルキル;
14) (C=O)aObヘテロサイクル;
15) SO2NR6R5;
16) SO2C1〜C8アルキル;
上記のアルキル、アリル、アルケニル、アルキニル、シクロアルキル、及びヘテロサイクル基は、R5、OH、(C1〜C6)アルコキシ、ハロゲン化物、COOH、CN、O(C=O)C1〜C6アルキル、又はNR5R6基から独立して選択される置換基により3まで置換され、
R5及びR6は下記から選択され、
1) H;
2) (C=O)aObC1〜C8アルキル;
3) (C=O)aObアリル;
4) (C=O)aObC2〜C8アルケニル;
5) (C=O)aObC2〜C8アルキニル;
6) ObC1〜C8フルオロアルキル;
7) (C=O)aObC3〜C8シクロアルキル;
8) (C=O)aObヘテロサイクル;
9) SO2C1〜C8アルキル;
10) (C=O)aObC0〜C8−NR6R5;
上記のアルキル、アリル、アルケニル、アルキニル、シクロアルキル、及びヘテロサイクル基は、R6から独立して選択される置換基により3まで置換され、R6及びR5は4〜7原子環又は4〜7原子によって形成される二環状環であり、前記原子環又は二環状環は、N、O又はS原子から選択される1、2又は3ヘテロ原子を含み、前記原子環又は二環状環は、R5から独立して選択される置換基により1以上置換される。 - 請求項1記載の化合物、その薬学的に許容される塩、又はその立体異性体において、
前記化合物は、下記化学式IIで示される。
- 請求項1記載の化合物、その薬学的に許容される塩、又はその立体異性体において、
前記化合物は、下記化学式III〜VIで示される。
ここでR1、R2、n、a及びbは請求項1と同様に定義され、
R3は下記から選択され、
1) (C=O)aObC1〜C8アルキル;
2) (C=O)aObアリル;
3) (C=O)aObC2〜C8アルケニル;
4) (C=O)aObC2〜C8アルキニル;
5) C1〜C8フルオロアルキル;
6)Ob(C=O)aNR6R5;
7) (C=O)aObC3〜C8シクロアルキル;
8) (C=O)aObヘテロサイクル;
9) (C=O)aObC3〜C6シクロアルキル;
上記のアルキル、アリル、アルケニル、アルキニル、シクロアルキル、及びヘテロサイクル基は、R4から独立して選択される置換基により0又は1以上置換され、
R5及びR6は請求項1と同様に定義される。 - 請求項2記載の化合物、その薬学的に許容される塩、又はその立体異性体において、
前記化合物は、下記化学式VIIで示される。
m、nは独立して0、1、又は2から選択され、
Arは、N、S、又はOからなるヘテロ原子を含む芳香族環であり、
R1及びR7は独立して下記から選択され、
1) H;
2) ハロゲン化物;
3) OH;
4) NO2;
5) CO2H;
6) (C=O)aObC1〜C8アルキル;
7) (C=O)aObアリル;
8) (C=O)aObC2〜C8アルケニル;
9) (C=O)aObC2〜C8アルキニル;
10) ObC1〜C8フルオロアルキル;
11) (C=O)aNR6R5;
12) CN;
13) (C=O)aObC3〜C8シクロアルキル;
14) (C=O)aObヘテロサイクル;
15) SO2NR6R5;
16) SO2C1〜C8アルキル;
17) (C=O)aObC0〜C8−NR6R5;
上記のアルキル、アリル、アルケニル、アルキニル、シクロアルキル、又はヘテロサイクル基は、R4から独立して選択される置換基により1以上置換され、
R2は下記から選択され、
1) H;
2) C1〜C8アルキル:
3) アリル:
4) C3〜C8アルケニル;
5) C3〜C8アルキニル;
6) C1〜C8フルオロアルキル;
7) C1〜C6アリルアルキル;
8) C3〜C6シクロアルキル;
9) ヘテロサイクル;
上記のアルキル、アリル、アルケニル、アルキニル、シクロアルキル、又はヘテロサイクル基は、R4から独立して選択される置換基により0又は1以上置換され、
R4は下記から選択され、
1) H;
2) ハロゲン化物;
3) OH;
4) NO2;
5) CO2H;
6) (C=O)aObC1〜C8アルキル;
7) (C=O)aObアリル;
8) (C=O)aObC2〜C8アルケニル;
9) (C=O)aObC2〜C8アルキニル;
10) ObC1〜C8フルオロアルキル;
11) (C=O)aNR6R5;
12) CN;
13) (C=O)aObC3〜C8シクロアルキル;
14) (C=O)aObヘテロサイクル;
15) SO2NR6R5;
16) SO2C1〜C8アルキル;
上記のアルキル、アリル、アルケニル、アルキニル、シクロアルキル、又はヘテロサイクル基は、R5、OH、(C1〜C6)アルコキシ、ハロゲン化物、COOH、CN、O(C=O)C1〜C6アルキル、又はNR5R6基から独立して選択される置換基により3まで置換され、
R5及びR6は下記から選択され、
1) H;
2) (C=O)aObC1〜C8アルキル;
3) (C=O)aObアリル;
4) (C=O)aObC2〜C8アルケニル;
5) (C=O)aObC2〜C8アルキニル;
6) ObC1〜C8フルオロアルキル;
7) (C=O)aObC3〜C8シクロアルキル;
8) (C=O)aObヘテロサイクル;
9) SO2C1〜C8アルキル;
10) (C=O)aObC0〜C8−NR6R5;
上記のアルキル、アリル、アルケニル、アルキニル、シクロアルキル、及びヘテロサイクル基は、R6から独立して選択される置換基により3まで置換され、R6及びR5は4〜7原子環又は4〜7原子によって形成される二環状環であり、前記原子環又は二環状環は、N、O又はS原子から選択される1、2又は3ヘテロ原子を含み、前記原子環又は二環状環は、R5から独立して選択される置換基により1以上置換される。 - 請求項1乃至4の何れかに記載の化合物、その薬学的に許容される塩、又はその立体異性体の何れかを含む医薬組成物並びにそのプロドラッグ及び薬学的に許容される担体若しくは賦形剤。
- 代謝性疾患の治療において、エストロゲン関連受容体又はモジュレータとして機能する、請求項1乃至4の何れかに記載の化合物、及びその薬学的に許容される塩、その立体異性体、又はそのプロドラッグの使用。
- 請求項6記載の使用であって、
前記代謝性疾患は、(1)タイプII糖尿病;(2)高血糖症;(3)グルコース耐性の低下;(4)インスリン抵抗症;(5)肥満症;(6)異常脂肪代謝症;(7)脂質異常症;(8)高脂血症;(9)高トリグリセリド血症;(10)高コレステロール血症;(11)低レベルHDL;(12)高レベルLDL;(13)アテローム性動脈硬化症;(14)血管再狭窄;(15)中心性肥満症;(16)メタボリックシンドローム;(17)脂肪肝を含む。
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CN101531638A (zh) | 2009-09-16 |
AU2009225171C1 (en) | 2014-11-27 |
EP2266962A1 (en) | 2010-12-29 |
CA2750859C (en) | 2016-05-10 |
EP2266962A4 (en) | 2011-12-07 |
WO2009111943A1 (zh) | 2009-09-17 |
IL211821A0 (en) | 2011-07-31 |
AU2009225171B2 (en) | 2014-05-01 |
JP2011513441A (ja) | 2011-04-28 |
JP5524091B2 (ja) | 2014-06-18 |
CN101531638B (zh) | 2011-12-28 |
CA2750859A1 (en) | 2009-09-17 |
US20110071148A1 (en) | 2011-03-24 |
AU2009225171A1 (en) | 2011-06-23 |
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