JP5240927B2 - 代謝障害の処置のための化合物 - Google Patents
代謝障害の処置のための化合物 Download PDFInfo
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- JP5240927B2 JP5240927B2 JP2008540343A JP2008540343A JP5240927B2 JP 5240927 B2 JP5240927 B2 JP 5240927B2 JP 2008540343 A JP2008540343 A JP 2008540343A JP 2008540343 A JP2008540343 A JP 2008540343A JP 5240927 B2 JP5240927 B2 JP 5240927B2
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- GORAEMYVEJOQSA-UHFFFAOYSA-N 2-[3-[(2,6-dimethylphenyl)methoxy]phenyl]propanoic acid Chemical group OC(=O)C(C)C1=CC=CC(OCC=2C(=CC=CC=2C)C)=C1 GORAEMYVEJOQSA-UHFFFAOYSA-N 0.000 claims description 9
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- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 1
- 229940039781 leptin Drugs 0.000 description 1
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- 108020001756 ligand binding domains Proteins 0.000 description 1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
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- 239000007800 oxidant agent Substances 0.000 description 1
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
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- 235000019515 salmon Nutrition 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000000891 standard diet Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
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- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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Description
本出願は、米国仮特許出願第60/734,803号(2005年11月9日出願)に対する優先権を主張し、その内容は、本明細書中で参考として援用される。
糖尿病は、罹患率及び死亡率の主因である。慢性的な血糖上昇が以下の消耗性合併症につながる:透析又は腎移植が必要になることが多い腎症;末梢腎症;失明につながる網膜症;切断につながる下肢の潰瘍形成;肝硬変に進行することがある脂肪肝疾患;並びに冠動脈疾患及び心筋梗塞に対する脆弱性。
本発明は、以下に記載の生物活性剤を提供する。本発明は、インスリン抵抗性症候群、糖尿病、悪液質、高脂血症、脂肪肝疾患、肥満、アテローム性動脈硬化症又は動脈硬化症を処置する医薬品の製造における、以下に記載の生物活性剤の使用を提供する。本発明は、インスリン抵抗性症候群、糖尿病、悪液質、高脂血症、脂肪肝疾患、肥満、アテローム性動脈硬化症又は動脈硬化症を有する哺乳動物の被験体を処置する方法であって、以下に記載の生物活性剤の有効量を被験体に投与することを含む、方法を提供する。本発明は、以下に記載の生物活性剤を含む薬学的組成物、及び薬学的に許容される担体を提供する。
本明細書で使用される「アルキル」は、直鎖又は分岐鎖アルキル基を意味する。特定の炭素原子数を有するものとして同定されるアルキル基は、所定の炭素数を有するアルキル基を意味する。例えば、3個の炭素原子を有するアルキルは、プロピル又はイソプロピルであってよく、4個の炭素原子を有するアルキルは、n−ブチル、1−メチルプロピル、2−メチルプロピル又はt−ブチルであってよい。
CW 2−(3−(2,6−ジメチルベンジルオキシ)−フェニル)−2−(R,S)−メチル酢酸
CX 2−(3−(2,6−ジメチルベンジルオキシ)−フェニル)−2−(R,S)−エチル酢酸
DP 3−(3−(2,6−ジメチルベンジルオキシ)−フェニル)−2−(R,S)−メチルプロパン酸
本明細書で使用される「含む(comprising)」という移行句は、オープンエンド形式である。この用語を使用する請求項は、このような請求項において列挙されるものに加えて複数の要素を含有してよい。
上記の化学式Iの図のアスタリスクは、キラル中心を示す。本発明は、化学式Iの化合物のラセミ体、(R)型鏡像異性体、及び(S)型鏡像異性体を提供し、これらは全て活性である。これらの鏡像異性体の混合物は、例えば、Chirality 11:420−425 (1999)に記載の通り、HPLCを使用することによって分離してもよい。
本発明の生物活性剤を、以下の反応スキームに従い作製することができる。
化学式Iの化合物であって、式中、mが0であり、xが0又は1であり、qが0又は1であり、tが0又は1であり、nが1又は2であり、R2が、1〜3個の炭素原子を有するアルキルであり、R3が水素、ハロ、1〜3個の炭素原子を有するアルコキシ、又は1〜3個の炭素原子を有するアルキルであり、R4及びR5が、1〜3個の炭素原子を有するアルキルであり、他方が、水素、又は1〜3個の炭素原子を有するアルキルであり;R1が、水素、又は1〜2個の炭素原子を有するアルキルである、化合物、即ち、以下の化学式の化合物:
A−(CH2)t+n−OH
及び化学式XXIであって、式中、tが0又は1であり、nが1又は2である、化合物、即ち、以下の化学式の化合物:
A−(CH2)t+n−Y
は、スキーム7の反応スキームを介して調製することができる。
1.3−BrまたはF−2−OHC6H3CO2H
Canadian Journal of Chemistry(2001),79(11)1541−1545.
2.4−Br−2−OHC6H3CO2H
WO 9916747またはJP 04154773.
3.2−Br−6−OHC6H3CO2H
JP 47039101.
4.2−Br−3−OHC6H3CO2H
WO 9628423.
5.4−Br−3−OHC6H3CO2H
WO 2001002388.
6.3−Br−5−OHC6H3CO2H
Journal of labelled Compounds and Radiopharmaceuticals(1992),31(3),175−82.
7.2−Br−5−OHC6H3CO2Hおよび3−Cl−4−OHC6H3CO2H
WO 9405153およびUS 5519133.
8.2−Br−4−OHC6H3CO2Hおよび3−Br−4−OHC6H3CO2H
WO 20022018323
9.2−Cl−6−OHC6H3CO2H
JP 06293700
10.2−Cl−3−OHC6H3CO2H
Proceedings of the Indiana Academy of Science(1983),Volume date 1982,92,145−51.
11.3−Cl−5−OHC6H3CO2H
WO 2002000633およびWO 2002044145.
12.2−Cl−5−OHC6H3CO2H
WO 9745400.
13.5−I−2−OHC6H3CO2Hおよび3−I,2−OHC6H3CO2H
Z.Chem.(1976),16(8),319−320.
14.4−I−2−OHC6H3CO2H
Journal of Chemical Research,Synopses(1994),(11),405.
15.6−I−2−OHC6H3CO2H
US 4932999.
16.2−I−3−OHC6H3CO2Hおよび4−I−3−OHC6H3CO2H
WO 9912928.
17.5−I−3−OHC6H3CO2H
J.Med.Chem.(1973),16(6),684−7.
18.2−I−4−OHC6H3CO2H
Collection of Czechoslovak Chemical Communications,(1991),56(2),459−77.
19.3−I−4−OHC6H3CO2,
J.O.C.(1990),55(18),5287−91.
化学式XXXIの化合物であって、式中、R3が1〜3個の炭素原子を有するアルコキシである、化合物、即ち、以下の化学式の化合物:
1. 2−OMe−4−OHC6H3CO2H
US 2001034343またはWO 9725992.
2. 5−OMe−3−OHC6H3CO2H
J.O.C(2001),66(23),7883−88.
3. 2−OMe−5−OHC6H3CO2H
US 6194406(P.96)およびJournal of the American Chemical Society(1985),107(8),2571−3.
4. 3−OEt−5−OHC6H3CO2H
Taiwan Kexue(1996),49(1),51−56.
5.4−OEt−3−OHC6H3CO2H
WO 9626176
6.2−OEt−4−OHC6H3CO2H
Takeda Kenkyusho Nempo(1965),24,221−8.
JP 07070025.
7.3−OEt−4−OHC6H3CO2H
WO 9626176.
8.3−OPr−2−OHC6H3CO2H
JP 07206658,DE 2749518.
9.4−OPr−2−OHC6H3CO2H
Farmacia(Bucharest)(1970),18(8),461−6.
JP 08119959.
10.2−OPr−5−OHC6H3CO2Hおよび2−OEt−5−OHC6H3CO2H
ヨウ化プロピルおよびヨウ化エチルを用いることによって、US 6194406(P.96)からの合成に適合させる。
11.4−OPr−3−OHC6H3CO2H
WO 9626176からの合成に適合させる。
12.2−OPr−4−OHC6H3CO2H
ハロゲン化プロピルを用いることによって、Takeda Kenkyusho Nempo(1965),24,221−8からの合成に適合させる。
13.4−OEt−3−OHC6H3CO2H
Biomedical Mass Spectrometry(1985),12(4),163−9.
14.3−OPr−5−OHC6H3CO2H
ハロゲン化プロピルを用いることによって、Taiwan Kexue(1996),49(1),51−56からの合成に適合させる。
1.5−Me−3−OHC6H3CO2Hおよび2−Me−5−OHC6H3CO2H
WO 9619437.
J.O.C.2001,66,7883−88.
2.2−Me−4−OHC6H3CO2H
WO 8503701.
3.3−Et−2−OHC6H3CO2Hおよび5−Et−2−OHC6H3CO2H
J.Med.Chem.(1971),14(3),265.
4.4−Et−2−OHC6H3CO2H
Yaoxue Xuebao(1998),33(1),67−71.
5.2−Et−6−OHC6H3CO2Hおよび2−n−Pr−6−OHC6H3CO2H
J.Chem.Soc.,Perkin Trans 1(1979),(8),2069−78.
6.2−Et−3−OHC6H3CO2H
JP 10087489およびWO 9628423.
7.4−Et−3−OHC6H3CO2H
J.O.C.2001,66,7883−88.
WO 9504046.
8.2−Et−5−OHC6H3CO2H
J.A.C.S(1974),96(7),2121−9.
9.2−Et−4−OHC6H3CO2Hおよび3−Et−4−OHC6H3CO2H
JP 04282345.
10.3−n−Pr−2−OHC6H3CO2H
J.O.C(1991),56(14),4525−29.
11.4−n−Pr−2−OHC6H3CO2H
EP 279630.
12.5−n−Pr−2−OHC6H3CO2H
J.Med.Chem(1981),24(10),1245−49.
13.2−n−Pr−3−OHC6H3CO2H
WO 9509843およびWO 9628423.
14.4−n−Pr−3−OHC6H3CO2H
WO 9504046.
15.2−n−Pr−5−OHC6H3CO2H
αホルミル吉草酸エチルを用いることによってJ.A.C.S(1974),96(7),2121−9からの合成に適合させる。
16.3−n−Pr−4−OHC6H3CO2H
Polymer(1991),32(11)2096−105.
17.2−n−Pr−4−OHC6H3CO2H
3−プロピルフェノールは、メチル化されて3−プロピルアニソールになり得、これは、次いでホルミル化されて、4−メトキシ−3−ベンズアルデヒドになり得る。このアルデヒドは、Jone’s試薬によって酸化されて、対応する酸を生じ得、そしてBBr3によるメチル基の脱保護は、表題化合物を生じる。
18.1.3−Et−5−OHC6H3CO2Hおよび3−Pr−n−5−OHC6H3CO2H
2−エチルアクロレインおよび2−プロピルアクロレインを用いることによって、J.O.C.2001,66,7883−88からの合成に適合させる。
Ph3P+−(CH2)PCO2R1}Br−
は、スキーム10の反応を介して調製することができる。
本発明は、インスリン抵抗性症候群、糖尿病(I型糖尿病又はII型糖尿病等の一次性本態性糖尿病及び二次性非本態性糖尿病)及び多嚢胞性卵巣症候群からなる群から選択される病態を有する哺乳動物の被験体を処置する方法であって、被験体に病態の処置に有効な本明細書に記載の生物活性剤の有効量を投与することを含む、方法を提供する。本発明の方法において、糖尿病又は、各症状が糖尿病に関連する、アテローム動脈硬化症、肥満、高血圧、高脂質血症、脂肪肝症候群、腎症、神経障害、網膜症、下肢潰瘍及び白内障の症状等の糖尿病の症状を進行させる可能性を軽減することができる。本発明は又、高脂血症を処置する方法であって、病態の処置に有効な本明細書に記載の生物活性剤の一定量を被験体に投与することを含む、方法も提供する。実施例に示す通り、化合物は、高脂血症動物の血清トリグリセリド及び遊離脂肪酸を減少させる。本発明は又、悪質液を処置する方法であって、悪質液の治療に有効な本明細書に記載の生物活性剤の一定量を被験体に投与することを含む、方法も提供する。本発明は又、肥満を処置する方法であって、病態の処置に有効な本明細書に記載の生物活性剤の一定量を被験体に投与することを含む、方法も提供する。本発明は又、アテローム性動脈硬化症又は動脈硬化症から選択される病態を処置する方法であって、病態の処置に有効な本明細書に記載の生物活性剤の一定量を被験体に投与することを含む、方法も提供する。本発明の活性剤は、被験体が糖尿病又はインスリン抵抗性症候群を有するにかかわらず、高脂血症、脂肪肝疾患、悪質液、肥満、アテローム性動脈硬化症又は動脈硬化症の治療に有効である。本薬剤を何れかの従来の全身投与経路により投与することができる。好ましくは、本薬剤を経口投与する。更に、医薬品を経口投与用に配合するのが好ましい。本発明において、使用することができる他の投与経路には、経腸、非経口、注射(例えば、静脈内、皮下、筋肉中又は腹腔内注射)又は経鼻が含まれる。
本発明は、本明細書に記載の生物活性剤を含む医薬生成物及び薬学的に許容される担体を提供する。本発明の薬学的組成物の更なる実施形態は、上記の生物活性剤の実施形態の何れか1つを含む。不必要な冗長を避ける目的において、このような薬剤及び薬剤群を、それぞれ繰り返さないが、繰り返す場合と同じく、薬学的組成物を本説明に組み込む。
手順A:3−ヒドロキシフェニル酢酸エチルの調製:
無水エタノール(250ml)中3−ヒドロキシフェニル酢酸(25g、164.31mmol)及びp−トルエンスルホン酸一水和物(3.49g、18.3mmol)溶液を4時間又は出発材料全てを消費するまで還流した。反応混合物を濃縮し、酢酸エチルで希釈し、水で洗浄した。有機層をNa2SO4上で乾燥させ、濾過し、濃縮し、シリカゲルカラムのフラッシュクロマトグラフィーにより精製し(ヘキサン:酢酸エチル2:1)、表題化合物を得た。
1H NMR (270 MHz, CDCl3): 1.2 (t, 3H); 3.5 (s, 2H); 4.1 (q, 2H); 6.6−7.2 (m, 4H).
手順B:3−(2,6−ジメチルベンジルオキシ)フェニル酢酸エチルの調製:
THF(30ml)及びDMF(13ml)中2,6−ジメチルベンジルアルコール(5.25g、38.6mmol)及びジイソプロピルアゾジカルボキシレート(DIAD、8.49g、42mmol)溶液をTHF(100ml)中3−ヒドロキシフェニル酢酸エチル(手順A、6.66g、37mmol)及びトリフェニルホスフィン(11g、42mmol)溶液に滴加した。反応混合物を室温にて4時間撹拌し、エーテルで希釈し、水で洗浄した。有機層をNa2SO4上で乾燥させ、濾過し、濃縮し、シリカゲルカラムのフラッシュクロマトグラフィーにより精製し(ヘキサン:酢酸エチル4:1)、表題化合物を得た。
1H NMR (270 MHz, CDCl3): 1.2 (t, 3H); 2.4 (s, 6H); 3.5 (s, 2H); 4.1 (q, 2H); 5.1 (s, 2H); 6.9 (m, 2H); 7.15−7.35 (m, 5H).
手順C:2−(3−(2,6−ジメチルベンジルオキシ)フェニル)−2−メチル酢酸エチルの調製:
乾燥アルゴン雰囲気下において、−68℃にて、乾燥THF(30ml)中3−(2,6−ジメチルベンジルオキシ)フェニル酢酸エチルの撹拌溶液(手順B、4g、13.6mmol)にLiHMDS(THF中1M溶液、17.45ml、17.4mmol)を滴加し、得られた橙色溶液を低温にて30分間撹拌し、その後、CH3I(5.71g、40.26mmol)を添加した。反応混合物を室温まで緩徐に加温し、15時間撹拌した。反応は、氷でクエンチし、生成物をEtOAc(2回)で抽出し、有機相をブラインで洗浄し、Na2SO4上で乾燥させ、濾過し、濃縮し、シリカゲルカラムのフラッシュクロマトグラフィーにより精製し(ヘキサン:エーテル5:1)、表題化合物を得た。
1H NMR (270 MHz, CDCl3): 1.2 (t, 3H); 1.5 (t, 3H); 2.4 (s, 6H); 3.7 (m, 1H); 4.1 (q, 2H); 5.0 (s, 2H); 6.9 (m, 2H); 7.15−7.35 (m, 5H).
手順D:2−(3−(2,6−ジメチルベンジルオキシ)フェニル)−2−メチル酢酸の調製:
無水エタノール(60ml)中2−(3−(2,6−ジメチルベンジルオキシ)フェニル)−2−メチル酢酸の撹拌溶液(手順C、3g、9.6mmol)に室温にて1N NaOH(20ml)を添加した。反応混合物を3時間撹拌し、1N HClによりpH3.5〜4.0に酸性化し、濃縮した。残留物をクロロホルムに入れ、0.1N HCl、ブラインで洗浄し、Na2SO4上で乾燥させ、濾過し、濃縮し、シリカゲルカラムのフラッシュクロマトグラフィーにより精製し(クロロホルム:メタノール95:5酢酸を使用してスパイク)、表題化合物を得た。
1H NMR (270 MHz, CDCl3): 1.5 (t, 3H); 2.4 (s, 6H); 3.7 (m, 1H); 5.0 (s, 2H); 6.9 (m, 2H); 7.15−7.35 (m, 5H).
(実施例2)
手順A:3−ヒドロキシフェニル酢酸エチルの調製:
実施例1、手順Aの方法を使用して、表題化合物を得た。
1H NMR (270 MHz, CDCl3): 1.2 (t, 3H); 3.5 (s, 2H); 4.1 (q, 2H); 6.6−7.2 (m, 4H).
手順B:3−(2,6−ジメチルベンジルオキシ)フェニル酢酸エチルの調製:
実施例1、手順Bの方法を使用して、表題化合物を得た。
1H NMR (270 MHz, CDCl3): 1.2 (t, 3H); 2.4 (s, 6H); 3.5 (s, 2H); 4.1 (q, 2H); 5.1 (s, 2H); 6.9 (m, 2H); 7.15−7.35 (m, 5H).
手順C:2−(3−(2,6−ジメチルベンジルオキシ)フェニル)−2−エチル酢酸エチルの調製:
乾燥アルゴン雰囲気下において、−78℃にて、乾燥THF(60ml)及びHMPA(15ml)中3−(2,6−ジメチルベンジルオキシ)フェニル酢酸エチルの撹拌溶液(手順B、4.84g、16.2mmol)にLDA(THF中2M溶液、25ml、48.72mmol)を滴加し、得られた橙色溶液を低温にて30分間撹拌し、その後、CH3CH2I(10.13g、64.96mmol)を添加した。反応混合物を室温まで緩徐に加温し、15時間撹拌した。反応は、クエン酸水溶液でクエンチし、生成物をEtOAc(2回)で抽出し、有機相をブラインで洗浄し、Na2SO4上で乾燥させ、濾過し、濃縮し、シリカゲルカラムのフラッシュクロマトグラフィーにより精製し(ヘキサン:酢酸エチル4:1)、表題化合物を得た。
1H NMR (270 MHz, CDCl3): .9 (t, 3H); 1.2 (t, 3H); 1.8 (m, 1H); 2.1(m, 1H); 2.4 (s, 6H); 3.4 (t, 1H); 4.1 (q, 2H); 5.0 (s, 2H); 6.9 (m, 2H); 7.15−7.30 (m, 5H).
手順D:2−(3−(2,6−ジメチルベンジルオキシ)フェニル)−2−エチル酢酸の調製:
無水エタノール(60ml)中2−(3−(2,6−ジメチルベンジルオキシ)フェニル)−2−エチル酢酸エチルの撹拌溶液(手順C、3.26g、10.0mmol)に室温にて1N NaOH(20ml)を添加した。反応混合物を3時間撹拌し、1N HClにより酸性化し、濃縮した。残留物をクロロホルムに入れ、0.1N HCl、ブラインで洗浄し、Na2SO4上で乾燥させ、濾過し、濃縮し、シリカゲルカラムのフラッシュクロマトグラフィーにより精製し(クロロホルム:メタノール95:5 酢酸を使用してスパイク)、表題化合物を得た。
1H NMR (270 MHz, CDCl3): .9 (t, 3H); 1.8 (m, 1H); 2.1(m, 1H); 2.4 (s, 6H); 3.4 (t, 1H); 5.0 (s, 2H); 6.9 (m, 2H); 7.15−7.30 (m, 5H).
(実施例3)
手順A:3−(3−ヒドロキシフェニル)プロパン酸エチルの調製:
無水エタノール(250ml)中3−ヒドロキシフェニルプロパン酸(25g、150.60mmol)及びp−トルエンスルホン酸一水和物(3.80g、20mmol)溶液を4時間又は出発材料全てを消費するまで還流した。反応混合物を濃縮し、酢酸エチルで希釈し、水で洗浄した。有機層をNa2SO4上で乾燥させ、濾過し、濃縮し、シリカゲルカラムのフラッシュクロマトグラフィーにより精製し(ヘキサン:酢酸エチル2:1)、表題化合物を得た。
1H NMR (270 MHz, CDCl3): 1.2 (t, 3H); 2.6 (t, 2H); 2.8 (t, 2H); 4.2 (q, 2H); 6.7−6.8 (m, 3H); 7.2 (m, 1H).
手順B:3−(2,6−ジメチルベンジルオキシ)フェニル)プロパン酸エチルの調製:
THF(30ml)及びDMF(13ml)中2,6−ジメチルベンジルアルコール(7.71g、56.7mmol)及びジイソプロピルアゾジカルボキシレート(DIAD、11.36g、56.18mmol)溶液を0℃にてTHF(100ml)中3−(3−ヒドロキシフェニル)プロパン酸エチル(手順A、10.0g、51.5mmol)及びトリフェニルホスフィン(14.73g、56.18mmol)溶液に滴加した。反応混合物を同じ温度にて4時間撹拌し、エーテルで希釈し、水で洗浄した。有機層をNa2SO4上で乾燥させ、濾過し、濃縮し、シリカゲルカラムのフラッシュクロマトグラフィーにより精製し(ヘキサン:酢酸エチル4:1)、表題化合物を得た。
1H NMR (270 MHz, CDCl3): 1.2 (t, 3H); 2.4 (s, 6H); 2.6 (t, 2H); 3.0 (t, 2H); 4.2 (q, 2H); 5.1 (s, 2H); 6.8 (m, 3H); 7.2−7.4 (m, 4H).
手順C:3−(3−(2,6−ジメチルベンジルオキシ)フェニル)−2−メチルプロパン酸エチルの調製:
乾燥アルゴン雰囲気下において、−68℃にて、乾燥THF(30ml)中3−(2,6−ジメチルベンジルオキシ)フェニル酢酸エチルの撹拌溶液(手順B、4.53g、14.5mmol)にLiHMDS(THF中1M溶液、21.77ml、21.77mmol)を滴加し、得られた橙色溶液を低温にて30分間撹拌し、その後、CH3I(20.60g、145.2mmol)を添加した。反応混合物を室温まで緩徐に加温し、15時間撹拌した。反応は、氷でクエンチし、生成物をEtOAc(2回)で抽出し、有機相をブラインで洗浄し、Na2SO4上で乾燥させ、濾過し、濃縮し、シリカゲルカラムのフラッシュクロマトグラフィーにより精製し(ヘキサン:エーテル5:1)、表題化合物を得た。
1H NMR (270 MHz, CDCl3): 1.2 (t, 3H); 1.5 (t, 3H); 2.4 (s, 6H); 2.51−2.58 (m, 1H); 2.71 (dd, 1H); 2.88 (dd, 1H); 4.2 (q, 2H); 5.1 (s, 2H); 6.9 (m, 3H); 7.2−7.4 (m, 4H).
手順D:3−(3−(2,6−ジメチルベンジルオキシ)フェニル)−2−メチルプロパン酸の調製:
無水エタノール(25ml)中3−(3−(2,6−ジメチルベンジルオキシ)フェニル)−2−メチルプロパン酸エチルの撹拌溶液(手順C、1.61g、4.9mmol)に室温にて1N NaOH(10ml)を添加した。反応混合物を3時間撹拌し、1N HClによりpH3.5〜4.0に酸性化し、濃縮した。残留物をクロロホルムに入れ、0.1N HCl、ブラインで洗浄し、Na2SO4上で乾燥させ、濾過し、濃縮し、シリカゲルカラムのフラッシュクロマトグラフィーにより精製し(クロロホルム:メタノール95:5 酢酸を使用してスパイク)、表題化合物を得た。
1H NMR (270 MHz, CDCl3): 1.5 (t, 3H); 2.4 (s, 6H); 2.51−2.58 (m, 1H); 2.71 (dd, 1H); 2.88 (dd, 1H); 5.1 (s, 2H); 6.9 (m, 3H); 7.2−7.4 (m, 4H).
以下の生物学的活性の実施例全てにおいて、化合物CWを化学合成実施例1に従い生成した。
(実施例A) db/dbマウスにおける化合物CWの抗糖尿病効果
db/dbマウスは、レプチンシグナル伝達を欠失し、過食、肥満及び糖尿病につながる。更に、C57BL/6Jバックグラウンドのob/obマウスと異なり、C57BLKSバックグラウンドのdb/dbマウスは、これらのインスリン産生膵臓ランゲルハンス島細胞の機能不全があり、高インスリン症(末梢インスリン抵抗性に関連)から低インスリン性糖尿病に進行する。
PPARαの化合物CW活性を試験するために、トランス活性化検定を使用した。トランス活性化検定は、核受容体の分子ドメイン構造を利用する。融合タンパク質をヒト又はマウスのPPARリガンド結合ドメイン(PPAR−LBD)と酵母Ga14DNA結合ドメイン(「アクチベータープラスミド」)との間で作製した。レポーター遺伝子構築物は、ルシフェラーゼレポーターを有するcisのGa14DNA結合要素からなる。作用薬がGa14/PPAR−LBDを結合する場合、融合タンパク質がレポーター遺伝子上のGa14DNA結合要素を結合し、ホタルルシフェラーゼ遺伝子の転写を生じる。ルシフェラーゼは、ATP依存性反応において基質ルシフェリンを酸化し、放出された光量は、酵素濃度及び結果的にはPPAR−LBDを結合するリガンド活性濃度を直接測定する。
Claims (10)
- インスリン抵抗性症候群、I型糖尿病及びII型糖尿病を含めた糖尿病、並びに多嚢胞性卵巣症候群からなる群から選択される病態を処置する;又はアテローム性動脈硬化症、動脈硬化症、肥満、高血圧、高脂血症、脂肪肝疾患、腎症、神経障害、網膜症、糖尿病に関連する下肢潰瘍又は白内障を処置する又は発症の可能性を低下させる;或いは高脂血症、悪液質及び肥満からなる群から選択される病態を処置する、医薬品の製造における生物活性剤の使用であって;
前記生物活性剤が2−(3−(2,6−ジメチルベンジルオキシ)−フェニル)−2−メチル酢酸である、
使用。 - 前記医薬品が経口投与用に配合される、請求項1に記載の使用。
- インスリン抵抗性症候群、糖尿病、嚢胞性卵巣症候群、高脂血症、脂肪肝疾患、悪質液、肥満、アテローム性動脈硬化症及び動脈硬化症からなる群から選択される病態を有する哺乳動物の被験体を処置するための組成物であって、生物活性剤の一定量を含み、前記生物活性剤が2−(3−(2,6−ジメチルベンジルオキシ)−フェニル)−2−メチル酢酸である、
組成物。 - 前記被験体がヒトである、請求項3に記載の組成物。
- 前記組成物が1日当たり1mg〜400mgの量で経口投与される、請求項4に記載の組成物。
- 前記病態がインスリン抵抗性症候群又はII型糖尿病である、請求項3に記載の組成物。
- 前記組成物が、糖尿病の症状又は糖尿病の症状を発症する可能性を軽減し、前記症状が、アテローム性動脈硬化症、肥満、高血圧、高脂血症、脂肪肝疾患、腎症、神経障害、網膜症、糖尿病に関連する下肢潰瘍及び白内障からなる群から選択される、請求項3に記載の組成物。
- インスリン抵抗性症候群、糖尿病、嚢胞性卵巣症候群、高脂血症、脂肪肝疾患、悪質液、肥満、アテローム性動脈硬化症、動脈硬化症からなる群から選択される病態の処置に使用し、経口投与に適合した薬学的組成物であって、薬学的に許容される担体及び1mg〜400mgの生物活性剤を含み、
前記生物活性剤が2−(3−(2,6−ジメチルベンジルオキシ)−フェニル)−2−メチル酢酸である、
薬学的組成物。 - 経口投与形態の、請求項8に記載の薬学的組成物。
- 2−(3−(2,6−ジメチルベンジルオキシ)−フェニル)−2−メチル酢酸である、
生物活性剤。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US73480305P | 2005-11-09 | 2005-11-09 | |
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EP (1) | EP1948152B1 (ja) |
JP (2) | JP5240927B2 (ja) |
KR (1) | KR101344392B1 (ja) |
CN (2) | CN101304740A (ja) |
AU (1) | AU2006311266B2 (ja) |
BR (1) | BRPI0618500A2 (ja) |
CA (1) | CA2627363C (ja) |
HK (1) | HK1119577A1 (ja) |
IL (1) | IL190920A (ja) |
NO (1) | NO20081821L (ja) |
NZ (1) | NZ568048A (ja) |
RU (1) | RU2420276C2 (ja) |
UA (1) | UA95613C2 (ja) |
WO (1) | WO2007056771A2 (ja) |
ZA (1) | ZA200803440B (ja) |
Families Citing this family (22)
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ES2530235T3 (es) * | 2003-02-13 | 2015-02-27 | Wellstat Therapeutics Corporation | Compuestos para el tratamiento de trastornos metabólicos |
AU2007212104A1 (en) * | 2006-02-02 | 2007-08-16 | Wellstat Therapeutics Corporation | Compounds for the treatment of metabolic disorders |
CN101361968B (zh) * | 2007-08-06 | 2011-08-03 | 健能隆医药技术(上海)有限公司 | 白介素-22在治疗脂肪肝中的应用 |
EP2025674A1 (de) | 2007-08-15 | 2009-02-18 | sanofi-aventis | Substituierte Tetrahydronaphthaline, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
EP2240024A4 (en) * | 2008-01-15 | 2014-05-21 | Wellstat Therapeutics Corp | COMPOUNDS FOR THE TREATMENT OF METABOLIC DISORDERS |
CN102976928B (zh) | 2008-03-13 | 2014-09-17 | 维尔斯达医疗公司 | 用于降低尿酸的化合物 |
WO2011107494A1 (de) | 2010-03-03 | 2011-09-09 | Sanofi | Neue aromatische glykosidderivate, diese verbindungen enthaltende arzneimittel und deren verwendung |
US8933024B2 (en) | 2010-06-18 | 2015-01-13 | Sanofi | Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases |
US8530413B2 (en) | 2010-06-21 | 2013-09-10 | Sanofi | Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments |
TW201215387A (en) | 2010-07-05 | 2012-04-16 | Sanofi Aventis | Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament |
TW201221505A (en) | 2010-07-05 | 2012-06-01 | Sanofi Sa | Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament |
TW201215388A (en) | 2010-07-05 | 2012-04-16 | Sanofi Sa | (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments |
WO2012033720A1 (en) | 2010-09-08 | 2012-03-15 | Wellstat Therapeutics Corporation | Benzoic acid compounds for reducing uric acid |
US8871758B2 (en) | 2011-03-08 | 2014-10-28 | Sanofi | Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof |
WO2012120052A1 (de) | 2011-03-08 | 2012-09-13 | Sanofi | Mit carbozyklen oder heterozyklen substituierte oxathiazinderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung |
WO2012120055A1 (de) | 2011-03-08 | 2012-09-13 | Sanofi | Di- und trisubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung |
WO2012120053A1 (de) | 2011-03-08 | 2012-09-13 | Sanofi | Verzweigte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung |
US8828994B2 (en) | 2011-03-08 | 2014-09-09 | Sanofi | Di- and tri-substituted oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
EP2760862B1 (en) | 2011-09-27 | 2015-10-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
CN104623637A (zh) | 2013-11-07 | 2015-05-20 | 健能隆医药技术(上海)有限公司 | Il-22二聚体在制备静脉注射药物中的应用 |
WO2017181143A1 (en) | 2016-04-15 | 2017-10-19 | Generon (Shanghai) Corporation, Ltd. | Use of il-22 in treating necrotizing enterocolitis |
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CS175831B1 (ja) * | 1974-12-17 | 1977-05-31 | ||
EP0540165A1 (en) * | 1991-10-03 | 1993-05-05 | Zeneca Limited | Alkanoic acid derivatives |
HUP0100072A3 (en) | 1997-10-27 | 2002-11-28 | Reddys Lab Ltd Dr | Phenoxazine, phenthiazine derivatives, their use in medicine; process for their preparation and pharmaceutical compositions containing them |
WO1999019313A1 (en) | 1997-10-27 | 1999-04-22 | Dr. Reddy's Research Foundation | Novel tricyclic compounds and their use in medicine; process for their preparation and pharmaceutical compositions containing them |
US7049342B2 (en) | 2000-05-29 | 2006-05-23 | Kyorin Pharmaceutical Co., Ltd. | Substituted phenylpropionic acid derivatives |
CA2410647C (en) * | 2000-05-29 | 2010-02-09 | Kyorin Pharmaceutical Co., Ltd. | Substituted phenylpropanoic acid derivatives |
US6531494B1 (en) * | 2001-08-29 | 2003-03-11 | Pharmacia Corporation | Gem-substituted αvβ3 antagonists |
WO2002083616A1 (fr) | 2001-04-10 | 2002-10-24 | Sankyo Company, Limited | DERIVE D'ACIDE GRAS φomega;-ARYLE α-SUBSTITUE |
RU2341513C2 (ru) * | 2001-06-12 | 2008-12-20 | Веллстат Терапьютикс Корпорейшн | Соединения для лечения метаболических заболеваний |
JP2004123643A (ja) * | 2002-10-04 | 2004-04-22 | Sankyo Co Ltd | ω−アリール−α−置換脂肪酸誘導体を含有する糖尿病予防剤、治療剤 |
AU2003286728A1 (en) * | 2002-11-01 | 2004-06-07 | Wellstat Therapeutics Corporation | Compounds for the treatment of metabolic disorders |
ES2530235T3 (es) * | 2003-02-13 | 2015-02-27 | Wellstat Therapeutics Corporation | Compuestos para el tratamiento de trastornos metabólicos |
CN101912380A (zh) * | 2003-04-15 | 2010-12-15 | 维尔斯达医疗公司 | 用于治疗代谢紊乱的化合物 |
ATE450496T1 (de) * | 2003-04-22 | 2009-12-15 | Wellstat Therapeutics Corp | Verbindungen zur behandlung von stoffwechselstörungen |
JP4837557B2 (ja) * | 2003-04-30 | 2011-12-14 | ウェルスタット セラピューティクス コーポレイション | 代謝障害の処置のための化合物 |
EP1660428A1 (en) | 2003-08-20 | 2006-05-31 | Eli Lilly And Company | Ppar modulators |
CN101948416A (zh) * | 2003-08-20 | 2011-01-19 | 维尔斯达医疗公司 | 用于治疗代谢紊乱的化合物 |
AU2005220728B2 (en) | 2004-02-27 | 2009-08-06 | Amgen Inc. | Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders |
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- 2006-11-09 EP EP06839799A patent/EP1948152B1/en not_active Not-in-force
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- 2006-11-09 RU RU2008123000/15A patent/RU2420276C2/ru not_active IP Right Cessation
- 2006-11-09 JP JP2008540343A patent/JP5240927B2/ja active Active
- 2006-11-09 AU AU2006311266A patent/AU2006311266B2/en not_active Ceased
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Also Published As
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RU2008123000A (ru) | 2009-12-20 |
WO2007056771A2 (en) | 2007-05-18 |
IL190920A (en) | 2013-12-31 |
AU2006311266A1 (en) | 2007-05-18 |
CN102743368A (zh) | 2012-10-24 |
US20090203793A1 (en) | 2009-08-13 |
CA2627363C (en) | 2013-08-13 |
NO20081821L (no) | 2008-07-30 |
WO2007056771A3 (en) | 2007-11-22 |
IL190920A0 (en) | 2009-09-22 |
CN101304740A (zh) | 2008-11-12 |
JP2013082753A (ja) | 2013-05-09 |
RU2420276C2 (ru) | 2011-06-10 |
EP1948152A4 (en) | 2010-07-07 |
JP2009514987A (ja) | 2009-04-09 |
CA2627363A1 (en) | 2007-05-18 |
HK1119577A1 (en) | 2009-03-13 |
KR20080074925A (ko) | 2008-08-13 |
BRPI0618500A2 (pt) | 2011-09-06 |
KR101344392B1 (ko) | 2013-12-23 |
US8178675B2 (en) | 2012-05-15 |
UA95613C2 (ru) | 2011-08-25 |
AU2006311266B2 (en) | 2011-09-29 |
EP1948152A2 (en) | 2008-07-30 |
ZA200803440B (en) | 2009-03-25 |
EP1948152B1 (en) | 2013-01-02 |
NZ568048A (en) | 2011-08-26 |
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