JP5278983B2 - New uses of amide compounds - Google Patents
New uses of amide compounds Download PDFInfo
- Publication number
- JP5278983B2 JP5278983B2 JP32641699A JP32641699A JP5278983B2 JP 5278983 B2 JP5278983 B2 JP 5278983B2 JP 32641699 A JP32641699 A JP 32641699A JP 32641699 A JP32641699 A JP 32641699A JP 5278983 B2 JP5278983 B2 JP 5278983B2
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- JP
- Japan
- Prior art keywords
- ring
- substituent
- monocyclic
- optionally substituted
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- -1 amide compounds Chemical class 0.000 title claims description 116
- 150000001875 compounds Chemical class 0.000 claims abstract description 80
- 125000001424 substituent group Chemical group 0.000 claims abstract description 62
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 49
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 49
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims abstract description 33
- 230000014509 gene expression Effects 0.000 claims abstract description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 21
- 239000001257 hydrogen Substances 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 102000005666 Apolipoprotein A-I Human genes 0.000 claims abstract description 14
- 108010059886 Apolipoprotein A-I Proteins 0.000 claims abstract description 14
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000001301 oxygen Substances 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical group 0.000 claims description 41
- 101100379247 Salmo trutta apoa1 gene Proteins 0.000 claims description 26
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 125000002252 acyl group Chemical group 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 239000003623 enhancer Substances 0.000 claims description 19
- 125000002619 bicyclic group Chemical group 0.000 claims description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 125000004423 acyloxy group Chemical group 0.000 claims description 12
- 210000004369 blood Anatomy 0.000 claims description 12
- 239000008280 blood Substances 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 125000004414 alkyl thio group Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 8
- 125000004429 atom Chemical group 0.000 claims description 8
- 150000002632 lipids Chemical class 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 230000005856 abnormality Effects 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 229940124597 therapeutic agent Drugs 0.000 claims description 4
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 239000000460 chlorine Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Chemical group 0.000 claims description 2
- 150000004677 hydrates Chemical class 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 2
- 230000000069 prophylactic effect Effects 0.000 claims description 2
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims 1
- 125000001288 lysyl group Chemical group 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
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- 239000000651 prodrug Substances 0.000 abstract description 14
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- 238000000034 method Methods 0.000 description 18
- 239000002904 solvent Substances 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 150000002431 hydrogen Chemical class 0.000 description 10
- 239000004215 Carbon black (E152) Substances 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 235000012000 cholesterol Nutrition 0.000 description 9
- 229930195733 hydrocarbon Natural products 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- 229910052709 silver Inorganic materials 0.000 description 7
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 6
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 208000029078 coronary artery disease Diseases 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 125000000168 pyrrolyl group Chemical group 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 108010007622 LDL Lipoproteins Proteins 0.000 description 5
- 102000007330 LDL Lipoproteins Human genes 0.000 description 5
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 5
- 230000002708 enhancing effect Effects 0.000 description 5
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 5
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 description 4
- 206010003210 Arteriosclerosis Diseases 0.000 description 4
- 108010028554 LDL Cholesterol Proteins 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 102000001494 Sterol O-Acyltransferase Human genes 0.000 description 4
- 108010054082 Sterol O-acyltransferase Proteins 0.000 description 4
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- 239000002775 capsule Substances 0.000 description 4
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- 230000000694 effects Effects 0.000 description 4
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- 125000002541 furyl group Chemical group 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 125000001041 indolyl group Chemical group 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 125000005493 quinolyl group Chemical group 0.000 description 4
- XOPHQUWQRVLDOP-VOTSOKGWSA-N (e)-3-(furan-2-yl)-n-pyridin-2-ylprop-2-enamide Chemical compound C=1C=COC=1/C=C/C(=O)NC1=CC=CC=N1 XOPHQUWQRVLDOP-VOTSOKGWSA-N 0.000 description 3
- RVXPELZCAVYGPX-UHFFFAOYSA-N 3-phenyl-n-quinoxalin-2-ylprop-2-enamide Chemical compound C=1N=C2C=CC=CC2=NC=1NC(=O)C=CC1=CC=CC=C1 RVXPELZCAVYGPX-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 102000004895 Lipoproteins Human genes 0.000 description 3
- 108090001030 Lipoproteins Proteins 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 125000003435 aroyl group Chemical group 0.000 description 3
- XNNQFQFUQLJSQT-UHFFFAOYSA-N bromo(trichloro)methane Chemical compound ClC(Cl)(Cl)Br XNNQFQFUQLJSQT-UHFFFAOYSA-N 0.000 description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 3
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- 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
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000004525 thiadiazinyl group Chemical group S1NN=C(C=C1)* 0.000 description 1
- 125000005304 thiadiazolidinyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005458 thianyl group Chemical group 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- 125000001730 thiiranyl group Chemical group 0.000 description 1
- 125000001166 thiolanyl group Chemical group 0.000 description 1
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- 238000011830 transgenic mouse model Methods 0.000 description 1
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- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
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Abstract
Description
本発明はアポリポタンパクAI発現亢進剤およびその作用を有する新規化合物に関する。 The present invention relates to an apolipoprotein AI expression enhancer and a novel compound having the action.
重篤な心疾患などの原因となる動脈硬化症の主要な成因としてコレステロールの関与は広く知られている。特に低比重リポタンパク(LDL)の血中濃度が増加する高LDL血症は、冠動脈疾患(CHD:coronary heart diseases)の明らかな危険因子とされ、スタチン類を用いて血漿中のLDLコレステロール(LDL−C)値を下げるLDL−C低下療法は、高コレステロール血症患者におけるCHDの発症および病状や生存率の改善などに著明な臨床効果をあげている。しかし、CHD患者の約40%はLDL−C値が正常であり、これらの患者にはLDL−C低下療法は必ずしも有効ではない。一方LDL−C値が正常な患者の半数は高比重リポタンパク(HDL)コレステロール(HDL−C)値が低いといわれている。
近年、この低HDL−C血症がCHDの初発・再発の別の危険因子であることが明らかにされつつある。Cholesterol is widely known as a major cause of arteriosclerosis that causes serious heart diseases. In particular, high LDLemia in which the blood concentration of low density lipoprotein (LDL) increases is regarded as an obvious risk factor for coronary heart diseases (CHD), and LDL cholesterol (LDL) in plasma using statins -C) LDL-C lowering therapy that lowers the value has a significant clinical effect on the onset of CHD and improvement of disease state and survival rate in patients with hypercholesterolemia. However, about 40% of CHD patients have normal LDL-C values, and LDL-C lowering therapy is not always effective for these patients. On the other hand, it is said that half of patients with normal LDL-C values have low high density lipoprotein (HDL) cholesterol (HDL-C) values.
In recent years, it has been clarified that this low HDL-C blood disease is another risk factor for the initial onset and recurrence of CHD.
HDLは、細胞中の過剰なコレステロールを肝臓に回収し、生体のコレステロール値を正常に維持するための生体機構として知られるコレステロール逆転送系で重要な役割を果たしている。
HDLなどのリポタンパクは一般に脂質とアポタンパクと呼ばれるタンパク成分から構成されており、HDLではアポリポタンパクAI(以下アポAIと略す)と呼ばれるアポタンパクが主要な構成成分となっている。
遊離したアポAIは細胞の特異的部位に結合し、細胞から過剰なコレステロール(FC)とリン脂質を引き出して結合し、preβ−HDLと呼ばれるリポタンパクとなる。preβ−HDL内部に多量に取り込まれたFCはレシチン:コレステロールアシルトランスフェラーゼ(LCAT)によりコレステリルエステル(CE)に変換されるとともに粒子サイズが増大し球状のHDL(HDL3)へと成熟する。成熟HDLは比重によって種々の亜分画が存在するが、これらの粒子はさらに集まりHDL2にかわる。引き続き血中に存在するコレステリルエステル転送タンパク(CETP)の作用を受け、CEはVLDやLDLなどへと転送される。CEを取り込んだこれらリポタンパクは最終的に受容体を介して肝臓に取り込まれる。この過程でアポAIは再生され、再び末梢細胞との相互作用によってコレステロールの引き抜きとpreβ−HDLの再生が繰り返される。HDL plays an important role in a reverse cholesterol transfer system known as a biological mechanism for recovering excess cholesterol in cells to the liver and maintaining normal cholesterol levels in the living body.
Lipoproteins such as HDL are generally composed of lipids and protein components called apoproteins. In HDL, apoproteins called apolipoprotein AI (hereinafter abbreviated as apoAI) are the main components.
The released apo AI binds to a specific site of the cell, draws excess cholesterol (FC) and phospholipid from the cell and binds to a lipoprotein called preβ-HDL. FC that is incorporated in a large amount inside preβ-HDL is converted to cholesteryl ester (CE) by lecithin: cholesterol acyltransferase (LCAT) and increases in particle size to mature into spherical HDL (HDL3). Although mature HDL has various subfractions depending on specific gravity, these particles further gather and replace HDL2. Subsequent to the action of cholesteryl ester transfer protein (CETP) present in the blood, CE is transferred to VLD, LDL and the like. These lipoproteins that have taken up CE are finally taken up by the liver via the receptor. In this process, Apo AI is regenerated, and cholesterol withdrawal and preβ-HDL regeneration are repeated again by interaction with peripheral cells.
HDLはコレステロール逆転送系において中心的役割を果たしており、HDLが動脈硬化の防御因子の一つであることは現在広く認識されている。すなわちHDL機能を増強させる医薬品は動脈硬化性疾患治療薬として臨床上極めて重要な役割を担うことが予想され、血漿中のHDLレベルを上げる物質の探索研究は様々な角度から進められている。
その中でも最も効果的と思われる方法の一つは、HDLの主要な構成成分である血中アポAI濃度を増加させる方法である。HDLの増加は必ずしもアポAIの増加を意味するものではないが、アポAIの増加はHDL機能増強に直接的に寄与するであろうことは、コレステロール逆転送系におけるアポAIの役割を見ても明らかである。事実アポAIの肝臓でのmRNAレベルと血中アポAIタンパク質およびHDLレベルと直接の相関があることが明らかにされている。従ってアポAI遺伝子発現を亢進させることで、血中アポAI濃度を上昇させることができれば、結果的にHDL機能を向上させ、コレステロール逆転送系の活性化につながると考えられる。事実アポAIトランスジェニックマウスやアポAIを投与したウサギ病態モデルでは抗動脈硬化作用が示されている。
これらのことから、アポAIを活性化させる物質は血中脂質異常、動脈硬化性疾患、その他HDLが関与する様々な疾患に対する全く新規な医薬の創製につながると考えられる。HDL plays a central role in the reverse cholesterol transport system, and it is now widely recognized that HDL is one of the protective factors for arteriosclerosis. In other words, pharmaceuticals that enhance HDL function are expected to play an extremely important role clinically as therapeutic agents for arteriosclerotic diseases, and search research for substances that increase HDL levels in plasma has been promoted from various angles.
One of the most effective methods among them is a method of increasing the blood apo AI concentration which is a main component of HDL. Although an increase in HDL does not necessarily mean an increase in apo AI, an increase in apo AI will directly contribute to the enhancement of HDL function, even in view of the role of apo AI in the reverse cholesterol transport system it is obvious. In fact, it has been shown that there is a direct correlation between the liver mRNA level of ApoAI and the blood ApoAI protein and HDL levels. Therefore, if the apoAI gene expression is increased to increase the blood apoAI concentration, it is considered that the HDL function is improved and the cholesterol reverse transfer system is activated as a result. In fact, anti-arteriosclerotic effects have been shown in Apo AI transgenic mice and rabbit pathological models administered with Apo AI.
From these facts, it is considered that a substance that activates apo AI leads to the creation of a completely new medicine for blood lipid abnormalities, arteriosclerotic diseases, and other various diseases involving HDL.
本発明に係る化合物と類似の構造を有する化合物がGB2327675、WO99/07669、WO99/24404、US5670066、DE19734438、特開平6−41118、特開平3−14568、特開平4−253974、特開平11−147874、Journal of Pharmaceutical Sciences vol.68, No.7, 827-832等に記載されているが、これらはいずれも全く作用が異なるものである。
本発明に係る化合物と類似の構造を有し、高脂血症、動脈硬化、内臓脂肪症候群等に有効であるとされる化合物が既にいくつか知られている。
特開平3−68592には血漿中のトリグリセライドを低下させ、結果的にHDL−Cレベルを上昇させる化合物が記載されているが、その作用はリポタンパク質リパーゼ活性化である(Chem. Pharm. Bull., 44(3), 547 (1996))。また、WO98/39280およびWO98/02412に記載の化合物はアシルCoAコレステロールアシルトランスフェラーゼ(ACAT)を阻害し、マクロファージにおけるコレステロールの蓄積を阻害する。特開平11−171848に記載の化合物はアセチルCoAカルボキシラーゼを阻害し、トリグリセライドの生合成を抑制する。WO99/07382に記載の化合物はマクロファージスカベンジャー受容体拮抗作用を有する。特開平11−158133に記載の化合物はLDL酸化抑制およびACAT阻害作用を有する。
しかし、これらはいずれも本発明に係る化合物とは作用メカニズムが全く異なるものである。
アポAIの増加作用を有する化合物が特開平5−221959、特開平8−291094号公報、WO97/09048号公報等に記載されているが、いずれも本発明に係る化合物とは構造が異なる。Compounds having a structure similar to that of the compound according to the present invention are GB2327675, WO99 / 07669, WO99 / 24404, US5670066, DE19734438, JP-A-6-41118, JP-A-3-145568, JP-A-4-253974, JP-A-11-147874. , Journal of Pharmaceutical Sciences vol. 68, No. 7, 827-832, etc., all of which have completely different actions.
Several compounds that have a structure similar to that of the compound according to the present invention and are effective for hyperlipidemia, arteriosclerosis, visceral fat syndrome and the like are already known.
Japanese Patent Application Laid-Open No. 3-65892 describes a compound that lowers triglyceride in plasma and consequently increases HDL-C level, and its action is activation of lipoprotein lipase (Chem. Pharm. Bull. , 44 (3), 547 (1996)). In addition, the compounds described in WO98 / 39280 and WO98 / 02412 inhibit acyl CoA cholesterol acyltransferase (ACAT) and inhibit cholesterol accumulation in macrophages. The compound described in JP-A-11-171848 inhibits acetyl CoA carboxylase and suppresses triglyceride biosynthesis. The compound described in WO99 / 07382 has a macrophage scavenger receptor antagonistic action. The compounds described in JP-A-11-158133 have LDL oxidation suppression and ACAT inhibitory action.
However, all of these are completely different in action mechanism from the compound according to the present invention.
Compounds having an increasing action of apo AI are described in JP-A-5-221959, JP-A-8-291094, WO97 / 09048, etc., but all of them are different in structure from the compound according to the present invention.
本発明の目的は、優れたアポAI発現亢進剤およびその作用を有する新規化合物を提供することにある。 An object of the present invention is to provide an excellent apoAI expression enhancer and a novel compound having the action thereof.
本発明は、
1)式(I):
環Bは置換基を有していてもよい単環の非芳香族炭化水素環式基または置換基を有していてもよい単環の非芳香族複素環式基であり、
Rは水素または置換基を有していてもよい低級アルキルであり、
Zは酸素または硫黄であり、
Y1およびY2は各々独立して水素、ハロゲン、置換基を有していてもよい低級アルキル、カルボキシ、置換基を有していてもよい低級アルコキシカルボニル、シアノ、置換基を有していてもよいフェニルまたは置換基を有していてもよい単環の芳香族複素環式基であり、
2以上のY1および2以上のY2はそれぞれ異なっていてもよく、
nは0〜2の整数であり、
破線は各々独立して結合の存在または不存在を示し、
波線は二重結合に関するシスまたはトランス幾何異性を示す)
で示される化合物、そのプロドラッグ、それらの製薬上許容される塩またはそれらの水和物を含有するアポAI発現亢進剤、The present invention
1) Formula (I):
Ring B is a monocyclic non-aromatic hydrocarbon cyclic group which may have a substituent or a monocyclic non-aromatic heterocyclic group which may have a substituent,
R is hydrogen or optionally substituted lower alkyl,
Z is oxygen or sulfur;
Y 1 and Y 2 each independently represent hydrogen, halogen, optionally substituted lower alkyl, carboxy, optionally substituted lower alkoxycarbonyl, cyano, or optionally substituted. A monocyclic aromatic heterocyclic group optionally having phenyl or a substituent,
Two or more Y 1 and two or more Y 2 may be different from each other,
n is an integer from 0 to 2,
Each dashed line independently indicates the presence or absence of a bond,
(The wavy line shows the cis or trans geometric isomerism for the double bond)
ApoAI expression-enhancing agent comprising a compound represented by the following: a prodrug thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof,
2)Ar1が、置換基を有していてもよく、結合手を有する環構成原子の隣接位が窒素原子である単環または二環の芳香族複素環式基である、1)記載のアポAI発現亢進剤、
3)Ar1がそれぞれ置換基を有していてもよい2−ピリジル、2−キノリル、2−キノキサリル、2−ベンゾイソキサゾリル、2−ベンゾチアゾリルまたは2−ベンゾイミダゾリルである、1)記載のアポAI発現亢進剤、
4)環Bと縮合しているAr2が置換基を有していてもよいベンゼン環または置換基を有していてもよい単環の芳香族複素環である、1)〜3)のいずれかに記載のアポAI発現亢進剤、
5)環Aが置換基を有していてもよいフェニルまたは置換基を有していてもよい単環の芳香族複素環式基である、1)〜3)のいずれかに記載のアポAI発現亢進剤、2) Ar 1 is a monocyclic or bicyclic aromatic heterocyclic group which may have a substituent and the adjacent position of the ring-constituting atom having a bond is a nitrogen atom, Apo AI expression enhancer,
3) The apo described in 1), wherein Ar 1 is each optionally substituted 2-pyridyl, 2-quinolyl, 2-quinoxalyl, 2-benzisoxazolyl, 2-benzothiazolyl, or 2-benzimidazolyl. AI expression enhancer,
4) Ar 2 condensed with ring B is a benzene ring which may have a substituent or a monocyclic aromatic heterocyclic ring which may have a substituent, any of 1) to 3) An apoAI expression enhancer according to claim 1,
5) ApoAI according to any one of 1) to 3), wherein ring A is phenyl optionally having substituent (s) or monocyclic aromatic heterocyclic group optionally having substituent (s). Expression enhancer,
6)環Aがそれぞれ置換基を有していてもよいフェニルまたは単環の芳香族複素環式基(ここで置換基とはハロゲン;ハロゲンもしくは低級アルコキシで置換されていてもよい低級アルキル;ヒドロキシ;低級アルコキシ;フェノキシ;ナフチルオキシ;アシルオキシ;カルボキシ;低級アルコキシカルボニル;低級アルキルもしくは低級アシルで置換されていてもよいアミノ;低級アルコキシで置換されていてもよいフェニル;ニトロ;低級アルキルチオ;シアノ;単環の複素環式基;またはアルキレンジオキシ)である、5)記載のアポAI発現亢進剤、
7)Y1および/またはY2が水素である、1)〜6)のいずれかに記載のアポAI発現亢進剤、
8)Zが酸素である、1)〜7)のいずれかに記載のアポAI発現亢進剤、
9)nが1または2であり、破線が全て結合の存在を示す、1)〜8)のいずれかに記載のアポAI発現亢進剤、
10)nが1であり、かつ破線が結合の存在を示す場合には波線がNRCZおよび環Aの関係がトランス配置であることを示し、nが2であり、かつそれぞれの破線が結合の存在を示す場合には波線がNRCZおよびCY2の関係並びに/またはCY1および環Aの関係がトランス配置である、9)記載のアポAI発現亢進剤、
11)血中脂質異常または動脈硬化性疾患の予防剤および/または治療剤である、1)〜10)のいずれかに記載のアポAI発現亢進剤、6) Each ring A may have a phenyl or monocyclic aromatic heterocyclic group which may have a substituent (wherein the substituent is halogen; lower alkyl which may be substituted with halogen or lower alkoxy; hydroxy Alkoxy; carboxy; lower alkoxycarbonyl; amino optionally substituted with lower alkyl or lower acyl; phenyl optionally substituted with lower alkoxy; nitro; lower alkylthio; cyano; simple; An apoAI expression enhancer according to 5), which is a heterocyclic group of a ring; or alkylenedioxy),
7) The apoAI expression enhancer according to any one of 1) to 6), wherein Y 1 and / or Y 2 is hydrogen,
8) The apoAI expression enhancer according to any one of 1) to 7), wherein Z is oxygen,
9) The apoAI expression enhancer according to any one of 1) to 8), wherein n is 1 or 2, and all broken lines indicate the presence of a bond,
10) When n is 1 and the broken line indicates the presence of a bond, the wavy line indicates that the relationship between NRCZ and ring A is a trans configuration, n is 2, and each broken line indicates the presence of a bond The apoAI expression enhancer according to 9), wherein the wavy line represents the relationship between NRCZ and CY 2 and / or the relationship between CY 1 and ring A is in the trans configuration,
11) The apoAI expression enhancer according to any one of 1) to 10), which is a prophylactic and / or therapeutic agent for blood lipid abnormality or arteriosclerotic disease,
12)式(II):
Rは水素または低級アルキルであり、
W1はCR3またはNであり、
R1、R2、R3、R4およびR5は各々独立して水素、ヒドロキシ、低級アルキル、低級アルコキシ、カルボキシ、低級アルコキシカルボニル、アミノ、低級アルキルアミノまたはアシルである)
で示される化合物、そのプロドラッグ、それらの製薬上許容される塩またはそれらの水和物、12) Formula (II):
R is hydrogen or lower alkyl;
W 1 is CR 3 or N;
R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, hydroxy, lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, lower alkylamino or acyl)
A compound thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof,
13)式(III):
Rは水素または置換基を有していてもよい低級アルキルであり、
W2はCR8またはNであり、
Y1およびY2は各々独立して水素、ハロゲン、置換基を有していてもよい低級アルキル、カルボキシ、置換基を有していてもよい低級アルコキシカルボニル、シアノ、置換基を有していてもよいフェニルまたは置換基を有していてもよい単環の芳香族複素環式基であり、
R6、R7、R8、R9およびR10は各々独立して水素、ハロゲン、ヒドロキシ、置換基を有していてもよい低級アルキル、置換基を有していてもよい低級アルコキシ、カルボキシ、置換基を有していてもよい低級アルコキシカルボニル、置換基を有していてもよいアミノまたは置換基を有していてもよいアシルであり、
R6、R7およびR8のいずれか2つは一緒になって環を形成してもよく、
mは1または2であり、
破線は各々独立して結合の存在または不存在を示し、
波線は二重結合に関するシスまたはトランス幾何異性を示す)
で示される化合物、そのプロドラッグ、それらの製薬上許容される塩またはそれらの水和物、
14)W2がCHであり、Rが水素または低級アルキルであり、破線が全て結合の存在を示す、13)記載の化合物、そのプロドラッグ、それらの製薬上許容される塩またはそれらの水和物
を提供する。13) Formula (III):
R is hydrogen or optionally substituted lower alkyl,
W 2 is CR 8 or N,
Y 1 and Y 2 each independently represent hydrogen, halogen, optionally substituted lower alkyl, carboxy, optionally substituted lower alkoxycarbonyl, cyano, or optionally substituted. A monocyclic aromatic heterocyclic group optionally having phenyl or a substituent,
R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, carboxy A lower alkoxycarbonyl optionally having a substituent, an amino optionally having a substituent, or an acyl optionally having a substituent,
Any two of R 6 , R 7 and R 8 may be taken together to form a ring;
m is 1 or 2,
Each dashed line independently indicates the presence or absence of a bond,
(The wavy line shows the cis or trans geometric isomerism for the double bond)
A compound thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof,
14) The compound according to 13), a prodrug thereof, a pharmaceutically acceptable salt thereof or a hydration thereof, wherein W 2 is CH, R is hydrogen or lower alkyl, and all broken lines indicate the presence of a bond Offer things.
さらに、上記化合物、そのプロドラッグ、その製薬上許容される塩またはそれらの水和物を投与することを特徴とする、アポAI発現を亢進させる方法並びに血中脂質異常または動脈硬化性疾患の治療方法および/または予防方法を提供する。別の態様として、アポAI発現を亢進させるための医薬または血中脂質異常もしくは動脈硬化性疾患の治療および/または予防のための医薬を製造するための、上記化合物、そのプロドラッグ、その製薬上許容される塩またはそれらの水和物の使用を提供する。 Furthermore, a method for enhancing the expression of apoAI, which comprises administering the above compound, a prodrug thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof, and a treatment for abnormal blood lipid or arteriosclerotic disease Methods and / or prevention methods are provided. In another embodiment, the above-mentioned compound, its prodrug, its pharmacological agent for producing a medicament for enhancing apoAI expression or a medicament for treating and / or preventing blood lipid abnormality or arteriosclerotic disease Use of acceptable salts or hydrates thereof is provided.
本明細書中において、nが2の場合、2つのY1および2つのY2はそれぞれ異なっていてもよい。
「ハロゲン」とは、フッ素、塩素、臭素およびヨウ素を包含する。
「低級アルキル」とは、炭素数1〜6、好ましくは炭素数1〜3の直鎖および分枝状のアルキルを包含し、例えばメチル、エチル、n−プロピル、イソプロピル、n−ブチル、イソブチル、sec−ブチル、tert−ブチル、n−ペンチル、イソペンチル、ネオペンチル、ヘキシルおよびイソヘキシル等が挙げられる。
「置換基を有していてもよい低級アルキル」とは、任意の位置が1以上の置換基で置換されていてもよい低級アルキルを包含し、その置換基としてはハロゲン、ヒドロキシ、低級アルコキシ、単環または二環の炭化水素環式基、アシル、アシルオキシ、カルボキシ、低級アルコキシカルボニル、アミノ、低級アルキルアミノ、ニトロ、および単環または二環の複素環式基等が挙げられる。
「低級アルコキシ」、「低級アルキルチオ」および「低級アルキルアミノ」のアルキル部分は上記「低級アルキル」と同様である。In the present specification, when n is 2, two Y1 and two Y2 may be different from each other.
“Halogen” includes fluorine, chlorine, bromine and iodine.
“Lower alkyl” includes linear and branched alkyl having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl and isohexyl.
The “lower alkyl optionally having substituent (s)” includes lower alkyl optionally substituted with one or more substituents at any position, such as halogen, hydroxy, lower alkoxy, Examples include monocyclic or bicyclic hydrocarbon cyclic groups, acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino, lower alkylamino, nitro, and monocyclic or bicyclic heterocyclic groups.
The alkyl part of “lower alkoxy”, “lower alkylthio” and “lower alkylamino” is the same as the above “lower alkyl”.
「アルキレンジオキシ」とは、具体的にはメチレンジオキシおよびエチレンジオキシ等を包含する。
「置換基を有していてもよい低級アルコキシ」の置換基は上記「置換基を有していてもよい低級アルキル」の置換基と同様である。
「低級アルコキシカルボニル」の低級アルキル部分は上記「低級アルキル」と同様であり、「置換基を有していてもよい低級アルコキシカルボニル」の置換基は上記「置換基を有していてもよい低級アルキル」の置換基と同様である。
「アシル」とはアロイルおよび炭素数1〜7の脂肪族アシルを包含する。ここで「アロイル」とは、芳香族炭化水素環式基または芳香族複素環式基にカルボニル基が結合した基を意味する。具体的には、ホルミル、アセチル、プロピオニル、ブチリル、イソブチリル、バレリル、ピバロイル、ヘキサノイル、アクリロイル、プロピオロイル、メタクリロイル、クロトノイルおよびベンゾイル等が例示される。「アシルオキシ」のアシル部分も同様である。“Alkylenedioxy” specifically includes methylenedioxy, ethylenedioxy, and the like.
The substituent of “lower alkoxy optionally having substituent” is the same as the substituent of “lower alkyl optionally having substituent”.
The lower alkyl moiety of “lower alkoxycarbonyl” is the same as the above “lower alkyl”, and the substituent of “optionally substituted lower alkoxycarbonyl” is the above “optionally substituted lower alkyl”. The same as the substituent of “alkyl”.
“Acyl” includes aroyl and aliphatic acyl having 1 to 7 carbon atoms. Here, “aroyl” means a group in which a carbonyl group is bonded to an aromatic hydrocarbon cyclic group or an aromatic heterocyclic group. Specific examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioroyl, methacryloyl, crotonoyl and benzoyl. The same applies to the acyl moiety of “acyloxy”.
「置換基を有していてもよいアシル」の置換基としては上記「置換基を有していてもよい低級アルキル」と同様のものが挙げられ、アロイルは低級アルキルで置換されていてもよい。アシルの1以上の任意の位置がこれらの置換基で置換されていてもよい。
「置換基を有していてもよいアミノ」とは非置換、モノ置換またはジ置換のアミノを包含し、その置換基として上記「置換基を有していてもよい低級アルキル」の置換基および低級アルキル等が挙げられる。Examples of the substituent of “acyl optionally having substituent (s)” include those similar to the above-mentioned “lower alkyl optionally having substituent (s)”, and aroyl may be substituted with lower alkyl. . One or more arbitrary positions of acyl may be substituted with these substituents.
The “optionally substituted amino” includes unsubstituted, mono-substituted, or di-substituted amino, and the substituent of the above-mentioned “lower alkyl optionally having substituent” as the substituent, and And lower alkyl.
「単環の非芳香族炭化水素環式基」とは、炭素数3〜10、好ましくは炭素数5〜8の環状基であり、任意の位置に1以上の二重結合を有していてもよい非芳香族環式基を包含する。具体的には、シクロプロピル、シクロブチル、シクロペンチル、シクロペンテニル、シクロヘキシル、シクロヘキセニル、シクロヘプチル、シクロヘプテニル、シクロヘプタジエニル、シクロオクチル、シクロオクテニル、シクロオクタジエニル、シクロノニルおよびシクロデシル等が挙げられる。
「単環の炭化水素環式基」とは、炭素数3〜10、好ましくは炭素数5〜8の環状基であり、上記「単環の非芳香族炭化水素環式基」およびフェニルを包含する。
「単環の芳香族炭化水素環式基」とは、フェニル(またはベンゼン環)を意味する。The “monocyclic non-aromatic hydrocarbon cyclic group” is a cyclic group having 3 to 10 carbon atoms, preferably 5 to 8 carbon atoms, and having one or more double bonds at any position. Including non-aromatic cyclic groups. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, cyclononyl and cyclodecyl.
The “monocyclic hydrocarbon cyclic group” is a cyclic group having 3 to 10 carbon atoms, preferably 5 to 8 carbon atoms, and includes the above “monocyclic non-aromatic hydrocarbon cyclic group” and phenyl. To do.
“Monocyclic aromatic hydrocarbon cyclic group” means phenyl (or benzene ring).
「単環の芳香族複素環式基」とは、N、SおよびOから任意に選択されるヘテロ原子を環内に1以上包含している芳香族環式基を包含し、具体的にはピロリル、イミダゾリル、ピラゾリル、ピリジル、ピリダジル、ピリミジル、ピラジニル、トリアゾリル、トリアジニル、テトラゾリル、イソキサゾリル、オキサゾリル、オキサジアゾリル、イソチアゾリル、チアゾリル、チアジアゾリル、フリルおよびチエニル等が挙げられる。
「単環の非芳香族複素環式基」とは、上記「単環の非芳香族炭化水素環式基」の置換可能な一個以上の炭素原子をN、SおよびOから任意に選択されるヘテロ原子で置換した非芳香族の環状基を包含する。具体的にはジオキサニル、ジオキサジニル、ジオキソラニル、ジオキソリル、ジチアジニル、イミダゾリジニル、イミダゾリニル、モルホリル、オキサジニル、オキサジアジル、フラザリル、オキサチアニル、オキサチアジニル、オキサチオラニル、オキサゾリジニル、オキサゾリニル、ピペラジニル、ピペリジニル、ピラニル、ピラゾリジニル、ピラゾリニル、ピロリジニル、ピロリニル、テトラヒドロピラニル、チアジアゾリジニル、チアニル、チアジニル、チアジアジニル、チイラニルおよびチオラニル等を包含する。
「単環の複素環式基」とは、上記「単環の芳香族複素環式基」および「単環の非芳香族複素環式基」を包含し、好ましくはピリジル、ピリミジニル、ピロリル、フリル、チエニルまたはチアゾリル等である。
「単環の芳香族複素環オキシ」の複素環部分は上記芳香族複素環式基と同様である。The “monocyclic aromatic heterocyclic group” includes an aromatic cyclic group containing one or more hetero atoms arbitrarily selected from N, S and O in the ring, specifically, Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl and thienyl.
The “monocyclic non-aromatic heterocyclic group” is arbitrarily selected from N, S, and O at least one substitutable carbon atom of the above “monocyclic non-aromatic hydrocarbon cyclic group”. Includes non-aromatic cyclic groups substituted with heteroatoms. Specifically, dioxanyl, dioxazinyl, dioxolanyl, dioxolyl, dithiazinyl, imidazolidinyl, imidazolinyl, morpholyl, oxazinyl, oxadiazyl, furazalyl, oxathianyl, oxathiazinyl, oxathiolanyl, oxazolidinyl, oxazolinyl, piperazinyl, pyridinyl, pyranyl, pyrazolidyl , Tetrahydropyranyl, thiadiazolidinyl, thianyl, thiazinyl, thiadiazinyl, thiiranyl, thiolanyl and the like.
“Monocyclic heterocyclic group” includes the above “monocyclic aromatic heterocyclic group” and “monocyclic non-aromatic heterocyclic group”, preferably pyridyl, pyrimidinyl, pyrrolyl, furyl. , Thienyl or thiazolyl and the like.
The heterocyclic moiety of “monocyclic aromatic heterocyclic oxy” is the same as the above aromatic heterocyclic group.
「二環の炭化水素環式基」とは、二つの環が縮合した炭素数6〜12の芳香族または非芳香族環式基を包含する。具体的にはナフチル、インダニル、インデニル、ジヒドロナフチルおよびテトラヒドロナフチル等を包含する。好ましくはナフチルである。
「二環の芳香族炭化水素環式基」とは、ナフチル(またはナフタレン環)を意味する。
「二環の複素環式基」とは、上記「二環の炭化水素環式基」の置換可能な一個以上の炭素原子をN、SおよびOから任意に選択されるヘテロ原子で置換した環状化合物を包含する。例えばインドリル、イソインドリル、インドリジニル、ベンズイミダゾリル、インダゾリル、シンノリニル、フタラジニル、ベンズオキサゾリル、ベンズイソキサゾリル、ベンズオキサジアゾリル、ベンゾチアゾリル、ベンズイソチアゾリル、ベンゾチアジアゾリル、ベンゾフリル、イソベンゾフリル、ベンゾチエニル、ベンゾトリアゾリル、イミダゾピリジル、トリアゾロピリジル、イミダゾチアゾリル、ピラジノピリダジニル、キナゾリニル、キノリル、イソキノリル、キノキサリニル、プリニル、プテリジニル、ナフチリジニルおよびピラジノピリダジニル等の芳香族複素環式基並びにクロマニル、2H-クロメニル、クマリニル、クマラノニル、1,3-ジオキサインダニル、インドリニル、イソインドリニル、ジヒドロキノリル、ジヒドロイソキノリル、テトラヒドロキノリル、テトラヒドロイソキノリル、6,7-ジヒドロ-5H-[1]ピリミジニル、ベンゾチアジニル、テトラヒドロキノキサリル、シクロペンテノピリジニル、4,5,6,7-テトラヒドロ-1H-インドリル、4−オキソクロメニル、3,4-ジヒドロ-2H-ベンゾ[1,4]オキサジニルおよびピロリジニル等の非芳香族複素環式基等が挙げられる。好ましくはインドリル、ベンズイミダゾリル、ベンズオキサゾリル、ベンズオキサジアゾリル、ベンゾチアゾリル、ベンズチアジアゾリル、ベンゾフリル、ベンゾチエニル、イミダゾピリジル、トリアゾロピリジル、キノリル、イソキノリルおよびキノキサリニル等である。
「二環の芳香族複素環式基」とは、上記「二環の複素環式基」のうち、芳香族複素環式基のみを包含する。The “bicyclic hydrocarbon cyclic group” includes an aromatic or non-aromatic cyclic group having 6 to 12 carbon atoms in which two rings are condensed. Specifically, naphthyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl and the like are included. Naphthyl is preferable.
The “bicyclic aromatic hydrocarbon cyclic group” means naphthyl (or naphthalene ring).
The “bicyclic heterocyclic group” is a ring in which one or more substitutable carbon atoms of the above “bicyclic hydrocarbon cyclic group” are substituted with a heteroatom optionally selected from N, S and O Includes compounds. For example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, indazolyl, cinnolinyl, phthalazinyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, Fragrances such as benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl, quinoxalinyl, purinyl, pteridinyl, naphthyridinyl and pyrazinopyridazinyl Aromatic heterocyclic groups and chromanyl, 2H-chromenyl, coumarinyl, coumaranyl, 1,3-dioxaindanyl, indolinyl, isoindolinyl, dihydroquinolyl, dihydroyl Soquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, 6,7-dihydro-5H- [1] pyrimidinyl, benzothiazinyl, tetrahydroquinoxalyl, cyclopentenopyridinyl, 4,5,6,7-tetrahydro-1H Non-aromatic heterocyclic groups such as -indolyl, 4-oxochromenyl, 3,4-dihydro-2H-benzo [1,4] oxazinyl and pyrrolidinyl. Preferred are indolyl, benzimidazolyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzthiadiazolyl, benzofuryl, benzothienyl, imidazopyridyl, triazolopyridyl, quinolyl, isoquinolyl and quinoxalinyl.
The “bicyclic aromatic heterocyclic group” includes only the aromatic heterocyclic group in the “bicyclic heterocyclic group”.
「置換基を有していてもよい単環または二環の炭化水素環式基」、「置換基を有していてもよい単環の炭化水素環式基」、「置換基を有していてもよいフェニル」および「置換基を有していてもよい単環もしくは二環の芳香族炭化水素環式基」の置換基としては、ハロゲン;ヒドロキシ;ハロゲン、ヒドロキシもしくは低級アルコキシで置換されていてもよい低級アルキル;ハロゲン、ヒドロキシ、カルボキシもしくは低級アルコキシカルボニルで置換されていてもよい低級アルコキシ;ハロゲン、ヒドロキシ、カルボキシもしくは低級アルコキシカルボニルで置換されていてもよい低級アルケニル;ハロゲンもしくはヒドロキシで置換されていてもよい低級アルケニルオキシ;低級アルキルチオ;ハロゲン、ヒドロキシもしくは低級アルキルで置換されていてもよい非芳香族炭化水素環式基;アシル;アシルオキシ;カルボキシ;低級アルコキシカルボニル;低級アルケニルオキシカルボニル;低級アルキルまたはアシルで置換されていてもよいアミノ;ヒドラジノ;ニトロ;シアノ;ハロゲン、ヒドロキシ、低級アルキルもしくは低級アルコキシで置換されていてもよい単環もしくは二環の芳香族炭化水素環式基;単環または二環の複素環式基;ハロゲン、ヒドロキシもしくは低級アルキルで置換されていてもよいフェノキシ;単環の芳香族複素環オキシ;オキソ;および低級アルキレンジオキシ等が挙げられ、1以上の任意の位置がこれらの置換基で置換されていてもよい。
好ましくはハロゲン;ヒドロキシ;ハロゲンもしくはヒドロキシで置換されていてもよい低級アルキル;ハロゲン、ヒドロキシ、カルボキシもしくは低級アルコキシカルボニルで置換されていてもよい低級アルコキシ;ハロゲン、ヒドロキシ、カルボキシもしくは低級アルコキシカルボニルで置換されていてもよい低級アルケニル;低級アルキルチオ;アシル;アシルオキシ;カルボキシ;低級アルコキシカルボニル;低級アルキルもしくはアシルで置換されていてもよいアミノ;ヒドラジノ;ニトロ;シアノ;フェニル;単環または二環の複素環式基;オキソ;および低級アルキレンジオキシである。“Monocyclic or bicyclic hydrocarbon cyclic group which may have a substituent”, “monocyclic hydrocarbon cyclic group which may have a substituent”, “having a substituent Substituents of “optionally phenyl” and “optionally substituted monocyclic or bicyclic aromatic hydrocarbon cyclic group” include halogen; hydroxy; halogen, hydroxy or lower alkoxy. Lower alkyl optionally substituted with halogen, hydroxy, carboxy or lower alkoxycarbonyl; Lower alkenyl optionally substituted with halogen, hydroxy, carboxy or lower alkoxycarbonyl; Substituted with halogen or hydroxy Optionally lower alkenyloxy; lower alkylthio; halogen, hydroxy or lower alkyl A non-aromatic hydrocarbon cyclic group optionally substituted with; acyl; acyloxy; carboxy; lower alkoxycarbonyl; lower alkenyloxycarbonyl; amino optionally substituted with lower alkyl or acyl; hydrazino; nitro; cyano; Monocyclic or bicyclic aromatic hydrocarbon cyclic group optionally substituted with halogen, hydroxy, lower alkyl or lower alkoxy; monocyclic or bicyclic heterocyclic group; substituted with halogen, hydroxy or lower alkyl Phenoxy which may be substituted; monocyclic aromatic heterocyclic oxy; oxo; and lower alkylenedioxy, and the like, and one or more arbitrary positions may be substituted with these substituents.
Preferably halogen; hydroxy; lower alkyl optionally substituted with halogen or hydroxy; lower alkoxy optionally substituted with halogen, hydroxy, carboxy or lower alkoxycarbonyl; substituted with halogen, hydroxy, carboxy or lower alkoxycarbonyl Lower alkylthio; acyl; acyloxy; carboxy; lower alkoxycarbonyl; amino optionally substituted with lower alkyl or acyl; hydrazino; nitro; cyano; phenyl; monocyclic or bicyclic heterocyclic A group; oxo; and lower alkylenedioxy.
「置換基を有していてもよい単環の芳香族複素環式基」、「置換基を有していてもよい単環の非芳香族複素環式基」、「置換基を有していてもよい単環の複素環式基」、「置換基を有していてもよい単環の芳香族複素環式基」、「置換基を有していてもよい単環もしくは二環の芳香族複素環式基」、「置換基を有していてもよい2−ピリジル」および「それぞれ置換基を有していてもよい2−ピリジル、2−キノリル、2−キノキサリル、2−ベンゾイソキサゾリル、2−ベンゾチアゾリルまたは2−ベンゾイミダゾリル」の置換基は上記「置換基を有していてもよい単環または二環の炭化水素環式基」等の置換基と同様である。好ましくはハロゲン;ヒドロキシ;低級アルコキシで置換されていてもよい低級アルキル;低級アルコキシ;低級アルケニル;低級アルキルチオ;アシル;アシルオキシ;カルボキシ;低級アルコキシカルボニル;低級アルキルで置換されていてもよいアミノ;低級アルコキシで置換されていてもよいフェニルおよび単環の複素環式基等である。 "A monocyclic aromatic heterocyclic group which may have a substituent", "A monocyclic non-aromatic heterocyclic group which may have a substituent", "A substituent May be a monocyclic heterocyclic group ”,“ optionally substituted monocyclic aromatic heterocyclic group ”,“ optionally substituted monocyclic or bicyclic aromatic group ” Group heterocyclic group "," optionally substituted 2-pyridyl "and" optionally substituted 2-pyridyl, 2-quinolyl, 2-quinoxalyl, 2-benzoisoxa The substituent of “zolyl, 2-benzothiazolyl or 2-benzimidazolyl” is the same as the substituent of the above-mentioned “monocyclic or bicyclic hydrocarbon cyclic group which may have a substituent”. Preferably halogen; hydroxy; lower alkyl optionally substituted with lower alkoxy; lower alkoxy; lower alkenyl; lower alkylthio; acyl; acyloxy; carboxy; lower alkoxycarbonyl; amino optionally substituted with lower alkyl; Such as phenyl and monocyclic heterocyclic group which may be substituted with.
「結合手を有する環構成原子の隣接位が窒素原子である単環または二環の芳香族複素環式基」とは、環を構成するN原子のオルト位にNRCZとの結合手を有する上記 単環または二環の芳香族複素環式基」を包含する。具体例としては、2−ピリジル、2−または4−ピリミジニル、3−ピリダジニル、2−ピラジニル、1,3,5−トリアジン−2−イル、2−ピロリル、1−または3−ピラゾリル、2−または4−イミダゾリル、2−または4−オキサゾリル、3−イソオキサゾリル、1,3,4−オキサジアゾール−2−イル、1,3−チアゾール−2−イル、1,3−チアゾール−4−イル、1,2,5−チアジアゾール−3−イル、1,2,3−チアジアゾール−4−イル、1,3,4−チアジアゾール−2−イル、3−イソチアゾリル、1,2,3−トリアゾール−4−イル、1H−テトラゾール−1−イル、1H−テトラゾール−5−イル等の単環の芳香族複素環式基および2−ベンズイミダゾリル、3−ベンズイソチアゾリル、3−ベンズイソキサゾリル、2−ベンズオキサゾリル、2−ベンゾチアゾリル、1−ベンゾトリアゾリル、1−または3−インダゾリル、3−シンノリニル、2−インドリル、1−または3−イソインドリル、2−ナフチリジニル、2−、4−、6−または7−プテリジニル、2−、6または8−プリニル、1−または3−イソキノリル、2−キノリル、2−または4−キナゾリニル、2−キノキサリニル等の二環の芳香族複素環式基を包含する。これらは上記「置換基を有していてもよい単環または二環の炭化水素環式基」等と同様の1以上の置換基で任意の位置が置換されていてもよい。 “A monocyclic or bicyclic aromatic heterocyclic group in which the adjacent position of the ring-constituting atom having a bond is a nitrogen atom” means the above having a bond with NRCZ at the ortho position of the N atom constituting the ring Monocyclic or bicyclic aromatic heterocyclic groups ”. Specific examples include 2-pyridyl, 2- or 4-pyrimidinyl, 3-pyridazinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 2-pyrrolyl, 1- or 3-pyrazolyl, 2- or 4-imidazolyl, 2- or 4-oxazolyl, 3-isoxazolyl, 1,3,4-oxadiazol-2-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1 , 2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,3,4-thiadiazol-2-yl, 3-isothiazolyl, 1,2,3-triazol-4-yl Monocyclic aromatic heterocyclic groups such as 1H-tetrazol-1-yl, 1H-tetrazol-5-yl and the like and 2-benzimidazolyl, 3-benzisothiazolyl, 3-benzui Xazolyl, 2-benzoxazolyl, 2-benzothiazolyl, 1-benzotriazolyl, 1- or 3-indazolyl, 3-cinnolinyl, 2-indolyl, 1- or 3-isoindolyl, 2-naphthyridinyl, 2--4 Bicyclic aromatic heterocyclic groups such as-, 6- or 7-pteridinyl, 2-, 6 or 8-purinyl, 1- or 3-isoquinolyl, 2-quinolyl, 2- or 4-quinazolinyl, 2-quinoxalinyl, etc. Is included. These may be substituted at any position with one or more substituents similar to the above-mentioned “monocyclic or bicyclic hydrocarbon cyclic group which may have a substituent”.
「R6、R7およびR8のいずれか2つは一緒になって環を形成」するとは、
R6、R7、R8のいずれか2つが、結合しているピリジン環またはピリミジン環の環構成原子と一緒になって非芳香族炭化水素環式基、ベンゼン環または複素環式基を形成することを意味する。具体的には、結合しているピリジン環またはピリミジン環と共にキノリル、イソキノリル、キナゾリニル、プテリジニル、プリニル、ピリドオキサジニル、テトラヒドロキノリル、テトラヒドロイソキノリルまたはテトラヒドロキナゾリニル等を形成する場合を包含する。“Any two of R 6 , R 7 and R 8 together form a ring” means
Any two of R 6 , R 7 and R 8 together with the ring-constituting atoms of the pyridine ring or pyrimidine ring to form a non-aromatic hydrocarbon cyclic group, benzene ring or heterocyclic group It means to do. Specifically, when quinolyl, isoquinolyl, quinazolinyl, pteridinyl, purinyl, pyridooxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydroquinazolinyl, etc. are formed together with the pyridine ring or pyrimidine ring to which they are bonded. Include.
環Bとして、好ましくは
等が挙げられる。
As ring B, preferably
Etc.
環Bが縮合するAr2としては、例えばベンゼン環が挙げられる。その場合の環Aの具体例としては、1−、2−、3−または4−ジヒドロナフタレニル、1−、2−または3−インドリニル、1−または2−インダニル、1−、2−または3−インデニル、1−または2−テトラヒドロナフタレニル、2−、3−または4−1,2-ジヒドロキノリニル、3−または4−イソクロマニル、2−、3−または4−クロマニル、2−、3−または4−クロメニル、2−、3−または4−チオクロメニル、2−、3−または4−ベンゾチオピラニル、2−または3−ジヒドロベンゾチエニル、2−または3−ジヒドロベンゾフリル、2−ベンゾ[1,3]ジオキソリル、2−2,3-ジヒドロベンゾ[1,4]ジオキソニル、2−または3−3,4-ジヒドロ-2H-ベンゾ[1,4]オキサジニル、8−または9−6,7−ジヒドロ-5H-ベンゾシクロヘプテニルおよび2−、3−または4−オキソ-4H−クロメニル等が挙げられる。
環Bが縮合するAr2としてはベンゼン環の他、例えばピリジン環、ピラジン環およびピリミジン環等の6員環、ピロール環、フラン環、チオフェン環、オキサゾール環、イソキサゾール環およびチアゾール環等の5員環並びにキノリン環、イソキノリン環およびインドール環等の二環の芳香族環が挙げられ、上記環Aの具体例中のベンゼン環をこれらの環に置き換えることが可能である。
環BおよびAr2は上記「置換基を有していてもよい単環または二環の炭化水素環式基」等と同様の置換基を任意の位置に有していてもよい。Examples of Ar 2 to which ring B is condensed include a benzene ring. Specific examples of ring A in that case include 1-, 2-, 3- or 4-dihydronaphthalenyl, 1-, 2- or 3-indolinyl, 1- or 2-indanyl, 1-, 2- or 3-indenyl, 1- or 2-tetrahydronaphthalenyl, 2-, 3- or 4-1,2-dihydroquinolinyl, 3- or 4-isochromanyl, 2-, 3- or 4-chromanyl, 2- 3-, 4-chromenyl, 2-, 3- or 4-thiochromenyl, 2-, 3- or 4-benzothiopyranyl, 2- or 3-dihydrobenzothienyl, 2- or 3-dihydrobenzofuryl, 2 -Benzo [1,3] dioxolyl, 2-2,3-dihydrobenzo [1,4] dioxonyl, 2- or 3-3,4-dihydro-2H-benzo [1,4] oxazinyl, 8- or 9- 6,7-Dihydro-5H-benzocycloheptenyl Preliminary 2-, 3- or 4-oxo -4H- chromenyl and the like.
Ar 2 to which ring B is condensed includes a benzene ring, a 5-membered ring such as a pyridine ring, a pyrazine ring and a pyrimidine ring, a pyrrole ring, a furan ring, a thiophene ring, an oxazole ring, an isoxazole ring and a thiazole ring. Examples include a ring and a bicyclic aromatic ring such as a quinoline ring, an isoquinoline ring and an indole ring, and the benzene ring in the specific example of the ring A can be replaced with these rings.
Ring B and Ar 2 may have the same substituent as the above-mentioned “monocyclic or bicyclic hydrocarbon cyclic group which may have a substituent” at any position.
本発明に係る化合物には、各々の化合物の生成可能であり、製薬上許容される塩を包含する。「製薬上許容される塩」としては、例えば塩酸、硫酸、硝酸またはリン酸等の無機酸の塩;パラトルエンスルホン酸、メタンスルホン酸、シュウ酸またはクエン酸等の有機酸の塩;アンモニウム、トリメチルアンモニウムまたはトリエチルアンモニウム等の有機塩基の塩;ナトリウムまたはカリウム等のアルカリ金属の塩;ヨウ化メチル、ヨウ化エチル等のハロゲン化アルキルとの四級塩;およびカルシウムまたはマグネシウム等のアルカリ土類金属の塩等を挙げることができる。
本発明に係る化合物はその水和物を包含し、化合物(I)1分子に対し、任意の数の水分子と配位していてもよい。The compound according to the present invention includes a pharmaceutically acceptable salt capable of producing each compound. “Pharmaceutically acceptable salts” include, for example, salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid; salts of organic acids such as paratoluenesulfonic acid, methanesulfonic acid, oxalic acid or citric acid; ammonium, Salts of organic bases such as trimethylammonium or triethylammonium; salts of alkali metals such as sodium or potassium; quaternary salts with alkyl halides such as methyl iodide and ethyl iodide; and alkaline earth metals such as calcium or magnesium And the like.
The compound according to the present invention includes its hydrate, and may be coordinated with any number of water molecules per molecule of compound (I).
また、本発明に係る化合物はそのプロドラッグを包含する。プロドラッグとは、化学的または代謝的に分解できる基を有する本発明に係る化合物の誘導体であり、生体内での代謝過程で本発明に係る化合物に変換されることで薬理作用を発現する化合物である。適当なプロドラッグ誘導体を選択する方法および製造する方法は、例えばDesign of Prodrugs,Elsevier,Amsterdam 1985に記載されている。
例えば、本発明に係る化合物がカルボキシを有する場合は、カルボキシと適当なアルコールを反応させることによって製造されるエステル誘導体、またはカルボキシと適当なアミンを反応させることによって製造されるアミド誘導体のようなプロドラッグが例示される。
例えば、本発明に係る化合物がヒドロキシを有する場合は、ヒドロキシと適当なアシルハライドまたは適当な酸無水物とを反応させることにより製造されるアシルオキシ誘導体のようなプロドラッグが例示される。The compounds according to the present invention also include prodrugs thereof. A prodrug is a derivative of a compound according to the present invention having a group that can be chemically or metabolically decomposed, and a compound that exhibits a pharmacological action by being converted to the compound according to the present invention during a metabolic process in vivo. It is. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985.
For example, when the compound according to the present invention has carboxy, a compound such as an ester derivative produced by reacting carboxy with a suitable alcohol or an amide derivative produced by reacting carboxy with a suitable amine is used. Drugs are exemplified.
For example, when the compound according to the present invention has hydroxy, a prodrug such as an acyloxy derivative produced by reacting hydroxy with an appropriate acyl halide or an appropriate acid anhydride is exemplified.
例えば、本発明に係る化合物がアミノを有する場合は、アミノを有する化合物と適当な酸ハロゲン化物または適当な混合酸無水物とを反応させることにより製造されるアミド誘導体のようなプロドラッグが例示される。
本発明に係る化合物(I)が不斉炭素原子を有する場合には、ラセミ体、両対掌体および全てのジアステレオマーを含む。また、本発明に係る化合物(I)が二重結合を有する場合には、二重結合の置換基配置につき、幾何異性体が存在するときはそのいずれをも含む。For example, when the compound according to the present invention has an amino, a prodrug such as an amide derivative produced by reacting an amino-containing compound with an appropriate acid halide or an appropriate mixed acid anhydride is exemplified. The
When compound (I) according to the present invention has an asymmetric carbon atom, it includes a racemate, both enantiomers and all diastereomers. In addition, when the compound (I) according to the present invention has a double bond, the arrangement of substituents of the double bond includes any of the geometrical isomers.
本発明に係る化合物は全てアポAI発現亢進作用を有しているが、特に好ましい化合物としては、以下の化合物が挙げられる。
式(I)において
1)Ar1が置換基を有していてもよい単環もしくは二環の芳香族炭化水素環式基または置換基を有していてもよい単環もしくは二環の芳香族複素環式基(ここで置換基とはハロゲン、ハロゲンで置換されていてもよい低級アルキル、ヒドロキシ、低級アルコキシ、アリールオキシ、アシルオキシ、カルボキシ、低級アルコキシカルボニル、低級アルキルまたは低級アシルで置換されていてもよいアミノ、フェニル、ニトロ、低級アルキルチオ、シアノ、単環の複素環式基または低級アルキレンジオキシ)である(以下、Ar1がAr1−aであるとする)化合物、
Ar1が、置換基を有していてもよく、結合手を有する環構成原子の隣接位が窒素原子である単環または二環の芳香族複素環式基(ここで置換基とは上記Ar1−aと同様)である(以下、Ar1がAr1−bであるとする)化合物、All of the compounds according to the present invention have an apoAI expression enhancing action, and particularly preferable compounds include the following compounds.
In formula (I), 1) Ar 1 may have a monocyclic or bicyclic aromatic hydrocarbon cyclic group or monocyclic or bicyclic aromatic group which may have a substituent Heterocyclic group (wherein the substituent is halogen, lower alkyl optionally substituted with halogen, hydroxy, lower alkoxy, aryloxy, acyloxy, carboxy, lower alkoxycarbonyl, lower alkyl or lower acyl) Amino, phenyl, nitro, lower alkylthio, cyano, monocyclic heterocyclic group or lower alkylenedioxy) (hereinafter Ar 1 is Ar1-a),
Ar 1 may have a substituent, and a monocyclic or bicyclic aromatic heterocyclic group in which the adjacent position of the ring-constituting atom having a bond is a nitrogen atom (wherein the substituent is the above Ar 1 -Similar to -a) (hereinafter referred to as Ar 1 is Ar1-b),
Ar1が、低級アルキルまたはアミノで置換されていてもよく、結合手を有する環構成原子の隣接位が窒素原子である単環または二環の芳香族複素環式基である(以下、Ar1がAr1−cであるとする)化合物、
Ar1が、結合手を有する環構成原子の隣接位が窒素原子である無置換の単環または二環の芳香族複素環式基である(以下、Ar1がAr1−dであるとする)化合物、
Ar1が2−キノリル、2−キノキサリル、2−ベンズイミダゾリル、2−チアゾリル、2−ベンゾチアゾリル、2−オキサゾリル、2−ベンズオキサゾリル、2−オキサジアゾリル、2−ピリジル、2−ピリミジルまたは2−イミダゾリルである(以下、Ar1がAr1−eであるとする)化合物、Ar 1 may be substituted with lower alkyl or amino, and is a monocyclic or bicyclic aromatic heterocyclic group in which the adjacent position of the ring member atom having a bond is a nitrogen atom (hereinafter referred to as Ar 1). The compound is Ar1-c),
Ar 1 is an unsubstituted monocyclic or bicyclic aromatic heterocyclic group in which the adjacent position of the ring-constituting atom having a bond is a nitrogen atom (hereinafter referred to as Ar 1 is Ar1-d) Compound,
Ar 1 is 2-quinolyl, 2-quinoxalyl, 2-benzimidazolyl, 2-thiazolyl, 2-benzothiazolyl, 2-oxazolyl, 2-benzoxazolyl, 2-oxadiazolyl, 2-pyridyl, 2-pyrimidyl or 2-imidazolyl (Hereinafter referred to as Ar 1 is Ar1-e),
2)環Aが置換基を有していてもよい単環もしくは二環の芳香族炭化水素環式基または置換基を有していてもよい単環もしくは二環の芳香族複素環式基(ここで置換基とはハロゲン、ハロゲンで置換されていてもよい低級アルキル、ヒドロキシ、低級アルコキシ、アリールオキシ、アシルオキシ、カルボキシ、低級アルコキシカルボニル、低級アルキルまたは低級アシルで置換されていてもよいアミノ、フェニル、ニトロ、低級アルキルチオ、シアノ、単環の複素環式基または低級アルキレンジオキシ)である(以下、環AがA−aであるとする)化合物、
環Aが置換基を有していてもよい単環もしくは二環の芳香族炭化水素環式基または置換基を有していてもよい単環もしくは二環の芳香族複素環式基である(ここで置換基とはハロゲン、ハロゲンで置換されていてもよい低級アルキル、アシルオキシ、低級アルコキシ、アルキレンジオキシもしくはフェニル)である(以下、環AがA−bであるとする)化合物、
環Aが無置換の単環または二環の芳香族複素環式基である(以下、環AがA−cであるとする)化合物、
環Aがフェニル、2−ナフチル、2−もしくは3−フリル、2−もしくは3−チエニル、2−もしくは3−ピロリル、2−、3−もしくは4−ピリジル、2−インドリル、2−ベンゾフリル、6−キノリル、2−もしくは6−ベンゾチエニルまたは3−2H−クロメニルである(以下、環AがA−dであるとする)化合物、2) The ring A may have a monocyclic or bicyclic aromatic hydrocarbon cyclic group which may have a substituent or a monocyclic or bicyclic aromatic heterocyclic group which may have a substituent ( Here, the substituent is halogen, lower alkyl which may be substituted with halogen, hydroxy, lower alkoxy, aryloxy, acyloxy, carboxy, lower alkoxycarbonyl, lower alkyl or lower acyl which may be substituted with amino or phenyl Nitro, lower alkylthio, cyano, monocyclic heterocyclic group or lower alkylenedioxy) (hereinafter, ring A is Aa),
Ring A is a monocyclic or bicyclic aromatic hydrocarbon cyclic group which may have a substituent, or a monocyclic or bicyclic aromatic heterocyclic group which may have a substituent ( Here, the substituent is a halogen, lower alkyl optionally substituted with halogen, acyloxy, lower alkoxy, alkylenedioxy or phenyl) (hereinafter, ring A is assumed to be Ab),
A compound in which ring A is an unsubstituted monocyclic or bicyclic aromatic heterocyclic group (hereinafter, ring A is Ac),
Ring A is phenyl, 2-naphthyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-indolyl, 2-benzofuryl, 6- A compound which is quinolyl, 2- or 6-benzothienyl or 3-2H-chromenyl (hereinafter, ring A is Ad);
環Aが
環Aが
環Aが
環Aが
である(以下、環AがA−hであるとする)化合物、Ring A is
Ring A is
Ring A is
Ring A is
(Hereinafter, ring A is Ah),
3)Rが水素である化合物、
4)Zが酸素である化合物、3) a compound wherein R is hydrogen,
4) a compound wherein Z is oxygen,
5)Y1およびY2が各々独立して水素、ハロゲン、低級アルキルまたはシアノである(以下、Y1およびY2がY−aであるとする)化合物、
Y1およびY2が各々独立して水素または低級アルキルである(以下、Y1およびY2がY−bであるとする)化合物、
Y1およびY2が水素である(以下、Y1およびY2がY−cであるとする)である化合物、
6)nが1または2であり、破線が全て結合の存在を示す化合物、
nが1であり、破線が結合の存在を示す化合物、5) A compound in which Y 1 and Y 2 are each independently hydrogen, halogen, lower alkyl or cyano (hereinafter, Y 1 and Y 2 are assumed to be Ya),
A compound in which Y 1 and Y 2 are each independently hydrogen or lower alkyl (hereinafter, Y 1 and Y 2 are Yb),
A compound wherein Y 1 and Y 2 are hydrogen (hereinafter, Y 1 and Y 2 are Yc),
6) a compound wherein n is 1 or 2, and all broken lines indicate the presence of a bond,
a compound wherein n is 1 and the dashed line indicates the presence of a bond,
7)Rが水素であり、Zが酸素であり、nが0であり、Ar1および環Aの組み合わせ(Ar1,A)が以下のものである化合物
(Ar1,A)=(Ar1-a, A-a), (Ar1-a, A-b), (Ar1-a, A-c), (Ar1-b, A-a), (Ar1-b, A-b), (Ar1-b, A-c), (Ar1-c, A-a), (Ar1-c, A-b), (Ar1-c, A-c), (Ar1-d, A-a), (Ar1-d, A-b), (Ar1-d, A-c), (Ar1-e, A-a), (Ar1-e, A-b), (Ar1-e, A-c), (Ar1-a, A-e), (Ar1-a, A-f), (Ar1-a, A-g), (Ar1-b, A-e), (Ar1-b, A-f), (Ar1-b, A-g), (Ar1-c, A-e), (Ar1-c, A-f), (Ar1-c, A-g),(Ar1-d, A-e), (Ar1-d, A-f), (Ar1-d, A-g), (Ar1-e, A-d), (Ar1-e, A-e), (Ar1-e, A-f), (Ar1-e, A-g), (Ar1-e, A-h)7) Compound in which R is hydrogen, Z is oxygen, n is 0, and the combination of Ar 1 and ring A (Ar1, A) is as follows:
(Ar1, A) = (Ar1-a, Aa), (Ar1-a, Ab), (Ar1-a, Ac), (Ar1-b, Aa), (Ar1-b, Ab), (Ar1-b , Ac), (Ar1-c, Aa), (Ar1-c, Ab), (Ar1-c, Ac), (Ar1-d, Aa), (Ar1-d, Ab), (Ar1-d, Ac ), (Ar1-e, Aa), (Ar1-e, Ab), (Ar1-e, Ac), (Ar1-a, Ae), (Ar1-a, Af), (Ar1-a, Ag), (Ar1-b, Ae), (Ar1-b, Af), (Ar1-b, Ag), (Ar1-c, Ae), (Ar1-c, Af), (Ar1-c, Ag), (Ar1 -d, Ae), (Ar1-d, Af), (Ar1-d, Ag), (Ar1-e, Ad), (Ar1-e, Ae), (Ar1-e, Af), (Ar1-e , Ag), (Ar1-e, Ah)
8)Rが水素であり、Zが酸素であり、nが1または2であり、破線が結合の存在を示し、Ar1、Y1およびY2並びに環Aの組み合わせ(Ar1,Y,A)が以下のものである化合物
(Ar1, Y, A)=(Ar1-a, Y-c, A-a), (Ar1-a, Y-c, A-b), (Ar1-a, Y-c, A-c),
(Ar1-b, Y-c, A-a), (Ar1-b, Y-c, A-b), (Ar1-b, Y-c, A-c),
(Ar1-c, Y-c, A-a), (Ar1-c, Y-c, A-b), (Ar1-c, Y-c, A-c),
(Ar1-d, Y-c, A-a), (Ar1-d, Y-c, A-b), (Ar1-d, Y-c, A-c),
(Ar1-e, Y-c, A-a), (Ar1-e, Y-c, A-b), (Ar1-e, Y-c, A-c),
(Ar1-e, Y-c, A-d), (Ar1-e, Y-c, A-h)
(Ar1-a, Y-b, A-a), (Ar1-a, Y-b, A-b), (Ar1-a, Y-b, A-c)
(Ar1-b, Y-b, A-a), (Ar1-b, Y-b, A-b), (Ar1-b, Y-b, A-c),
(Ar1-c, Y-b, A-a), (Ar1-c, Y-b, A-b), (Ar1-c, Y-b, A-c),
(Ar1-d, Y-b, A-a), (Ar1-d, Y-b, A-b), (Ar1-d, Y-b, A-c),
(Ar1-e, Y-b, A-a), (Ar1-e, Y-b, A-b), (Ar1-e, Y-b, A-c),
(Ar1-a, Y-c, A-e), (Ar1-a, Y-c, A-f), (Ar1-a, Y-c, A-g),
(Ar1-b, Y-c, A-e), (Ar1-b, Y-c, A-f), (Ar1-b, Y-c, A-g),
(Ar1-c, Y-c, A-e), (Ar1-c, Y-c, A-f), (Ar1-c, Y-c, A-g),
(Ar1-d, Y-c, A-e), (Ar1-d, Y-c, A-f), (Ar1-d, Y-c, A-g),
(Ar1-e, Y-c, A-e), (Ar1-e, Y-c, A-f), (Ar1-e, Y-c, A-g),
(Ar1-a, Y-b, A-e), (Ar1-a, Y-b, A-f), (Ar1-a, Y-b, A-g),
(Ar1-b, Y-b, A-e), (Ar1-b, Y-b, A-f), (Ar1-b, Y-b, A-g),
(Ar1-c, Y-b, A-e), (Ar1-c, Y-b, A-f), (Ar1-c, Y-b, A-g),
(Ar1-d, Y-b, A-e), (Ar1-d, Y-b, A-f), (Ar1-d, Y-b, A-g),
(Ar1-e, Y-b, A-e), (Ar1-e, Y-b, A-f), (Ar1-e, Y-b, A-g),
である化合物、そのプロドラッグ、それらの製薬上許容される塩またはそれらの水和物が挙げられる。8) R is hydrogen, Z is oxygen, n is 1 or 2, broken lines indicate the presence of a bond, Ar 1 , Y 1 and Y 2 and ring A combination (Ar1, Y, A) Is a compound wherein
(Ar1, Y, A) = (Ar1-a, Yc, Aa), (Ar1-a, Yc, Ab), (Ar1-a, Yc, Ac),
(Ar1-b, Yc, Aa), (Ar1-b, Yc, Ab), (Ar1-b, Yc, Ac),
(Ar1-c, Yc, Aa), (Ar1-c, Yc, Ab), (Ar1-c, Yc, Ac),
(Ar1-d, Yc, Aa), (Ar1-d, Yc, Ab), (Ar1-d, Yc, Ac),
(Ar1-e, Yc, Aa), (Ar1-e, Yc, Ab), (Ar1-e, Yc, Ac),
(Ar1-e, Yc, Ad), (Ar1-e, Yc, Ah)
(Ar1-a, Yb, Aa), (Ar1-a, Yb, Ab), (Ar1-a, Yb, Ac)
(Ar1-b, Yb, Aa), (Ar1-b, Yb, Ab), (Ar1-b, Yb, Ac),
(Ar1-c, Yb, Aa), (Ar1-c, Yb, Ab), (Ar1-c, Yb, Ac),
(Ar1-d, Yb, Aa), (Ar1-d, Yb, Ab), (Ar1-d, Yb, Ac),
(Ar1-e, Yb, Aa), (Ar1-e, Yb, Ab), (Ar1-e, Yb, Ac),
(Ar1-a, Yc, Ae), (Ar1-a, Yc, Af), (Ar1-a, Yc, Ag),
(Ar1-b, Yc, Ae), (Ar1-b, Yc, Af), (Ar1-b, Yc, Ag),
(Ar1-c, Yc, Ae), (Ar1-c, Yc, Af), (Ar1-c, Yc, Ag),
(Ar1-d, Yc, Ae), (Ar1-d, Yc, Af), (Ar1-d, Yc, Ag),
(Ar1-e, Yc, Ae), (Ar1-e, Yc, Af), (Ar1-e, Yc, Ag),
(Ar1-a, Yb, Ae), (Ar1-a, Yb, Af), (Ar1-a, Yb, Ag),
(Ar1-b, Yb, Ae), (Ar1-b, Yb, Af), (Ar1-b, Yb, Ag),
(Ar1-c, Yb, Ae), (Ar1-c, Yb, Af), (Ar1-c, Yb, Ag),
(Ar1-d, Yb, Ae), (Ar1-d, Yb, Af), (Ar1-d, Yb, Ag),
(Ar1-e, Yb, Ae), (Ar1-e, Yb, Af), (Ar1-e, Yb, Ag),
Or a prodrug thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
特に好ましい化合物の例として下記をあげることができる。
Ia-1, Ia-3, Ia-4, Ia-5, Ia-6, Ia-7, Ia-9, Ia-10, Ia-16, Ia-17, Ia-18, Ia-23, Ia-27, Ia-29, Ia-30, Ia-37, Ia-38, Ia-39, Ia-42, Ia-44, Ia-45, Ia-46, Ia-48, Ia-53, Ia-54, Ia-55, Ia-59, Ia-60, Ia-61, Ia-62, Ia-63, Ia-64,Ia-69, Ia-72, Ia-95, Ia-97, Ia-104, Ia-105, Ia-112, Ia-113, Ia-118, Ia-119, Ia-144, Ia-145, Ia-146, Ia-150, Ia-152, Ia-153, Ia-156, Ia-161, Ia-162, Ia-177, Ia-204, Ib-01, Ib-3, Ib-4, Ib-6, Ib-7, Ib-8, Ib-9, Ib-11, Ib-12, Ib-13, Ib-14, Ib-144, Ib-17, Ib-18, Ib-19, Ib-20, Ib-24, Ib-25, Ib-26, Ib-28, Ib-35, Ib-73, Ib-97, Ib-102, Ib-105, Ib-131, Ib-137, Id-1および Id-11。Examples of particularly preferred compounds include the following.
Ia-1, Ia-3, Ia-4, Ia-5, Ia-6, Ia-7, Ia-9, Ia-10, Ia-16, Ia-17, Ia-18, Ia-23, Ia- 27, Ia-29, Ia-30, Ia-37, Ia-38, Ia-39, Ia-42, Ia-44, Ia-45, Ia-46, Ia-48, Ia-53, Ia-54, Ia-55, Ia-59, Ia-60, Ia-61, Ia-62, Ia-63, Ia-64, Ia-69, Ia-72, Ia-95, Ia-97, Ia-104, Ia- 105, Ia-112, Ia-113, Ia-118, Ia-119, Ia-144, Ia-145, Ia-146, Ia-150, Ia-152, Ia-153, Ia-156, Ia-161, Ia-162, Ia-177, Ia-204, Ib-01, Ib-3, Ib-4, Ib-6, Ib-7, Ib-8, Ib-9, Ib-11, Ib-12, Ib- 13, Ib-14, Ib-144, Ib-17, Ib-18, Ib-19, Ib-20, Ib-24, Ib-25, Ib-26, Ib-28, Ib-35, Ib-73, Ib-97, Ib-102, Ib-105, Ib-131, Ib-137, Id-1 and Id-11.
本発明に係る化合物(I)は、例えば次のA法〜C法に示すいずれかの方法で合成する事が出来る。以下に、その一例を挙げるが、詳しくは例えば「有機合成化学VI合成編4(1977)6,79」または「第4版実験化学講座(1992)22,138」等を参考にする事が出来る。
[A法](A−1+A−2→I)
本工程は、アミン類(A−1)と酸ハロゲン化物(A−2)の反応であり、常法に従って化合物(I)を合成することが出来る。一般に共存塩基としてトリエチルアミン、ピリジン、過剰の(A−1)またはジメチルアミノピリジン等を、また溶媒としては塩化メチレンまたはテトラヒドロフラン等を用いることができる。反応は氷冷〜溶媒の還流温度で行えばよい。Compound (I) according to the present invention can be synthesized, for example, by any of the following methods A to C. An example is given below. For example, “Organic Synthetic Chemistry VI Synthesis 4 (1977) 6, 79” or “Fourth Edition Experimental Chemistry Course (1992) 22, 138” can be referred to. .
[Method A] (A-1 + A-2 → I)
This step is a reaction of amines (A-1) and acid halides (A-2), and compound (I) can be synthesized according to a conventional method. In general, triethylamine, pyridine, excess (A-1) or dimethylaminopyridine or the like can be used as the coexisting base, and methylene chloride or tetrahydrofuran can be used as the solvent. The reaction may be carried out at an ice-cold temperature to a solvent reflux temperature.
[B法](B−1+B−2→I)
本反応も、アミド類合成の常法である。即ち、ジシクロヘキシルカルボジイミドまたは塩酸1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド等の脱水縮合剤の存在下、アミン類(B−1)とカルボン酸(B−2)を直接縮合反応させることにより化合物(I’)が得られる。反応は、ジメチルホルムアミド、塩化メチレンまたはテトラヒドロフラン等の溶媒中、室温〜溶媒の還流温度で行えばよい。[Method B] (B-1 + B-2 → I)
This reaction is also a conventional method for synthesizing amides. That is, an amine (B-1) and a carboxylic acid (B-2) are directly condensed in the presence of a dehydrating condensing agent such as dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. To obtain compound (I ′). The reaction may be carried out in a solvent such as dimethylformamide, methylene chloride or tetrahydrofuran at room temperature to the reflux temperature of the solvent.
[C法](C−1+C−2→I)
本反応も前述と同様にアミン類(C−1)とカルボン酸(C−2)の縮合反応であり、Eur. J. Med. Chem., (1994) 29, 841記載の方法によって実施出来る。即ち、例えばトリフェニルホスフィンおよびブロモトリクロロメタン等を用いてカルボン酸(C−2)を活性化後、アミンと反応させれば化合物(I’)が得られる。溶媒は、塩化メチレンまたはテトラヒドロフラン等を用いる事が出来る。反応は室温〜溶媒の還流温度で行えばよい。[Method C] (C-1 + C-2 → I)
This reaction is also a condensation reaction of amines (C-1) and carboxylic acids (C-2) as described above, and can be carried out by the method described in Eur. J. Med. Chem., (1994) 29, 841. That is, for example, after activating the carboxylic acid (C-2) using triphenylphosphine, bromotrichloromethane, or the like and then reacting with an amine, the compound (I ′) is obtained. As the solvent, methylene chloride, tetrahydrofuran or the like can be used. The reaction may be performed at room temperature to the reflux temperature of the solvent.
上記の方法で得られたRがHである化合物(I)とハロゲン化アルキルを水素化ナトリウム存在下、ジメチルホルムアミド中、室温〜80℃で反応させることにより、Rが低級アルキルである化合物(I)を得ることができる。
Zが硫黄である化合物(I)は、Zが酸素である化合物(I)をピリジンまたはトルエン等の溶媒中、五硫化リンまたはローソン試薬と共に溶媒の還流温度で加熱することにより得ることができる。The compound (I) obtained by the above method, wherein R is H and an alkyl halide are reacted in the presence of sodium hydride in dimethylformamide at room temperature to 80 ° C., whereby compound (I) wherein R is lower alkyl is reacted. ) Can be obtained.
Compound (I) in which Z is sulfur can be obtained by heating compound (I) in which Z is oxygen in a solvent such as pyridine or toluene together with phosphorus pentasulfide or Lawesson's reagent at the reflux temperature of the solvent.
本発明のアポAI発現亢進剤は、HDLのコレステロール逆転送作用、抗炎症作用および抗凝固作用等を活性化させる。従って、血清中のHDLが低下することに起因する血中脂質異常、動脈硬化性疾患およびそれに伴う様々な循環器系疾患の予防および/または治療に有用である。適応可能な疾患として具体的には、低HDL血症、高コレステロール血症、高トリグリセリド血症、動脈硬化症、心筋梗塞、高尿酸血症、冠動脈疾患、虚血性心疾患、角膜混濁、脳血管障害、遺伝性HDL欠損症(Tangier病、魚眼病等)等が挙げられる。 The apoAI expression enhancer of the present invention activates the reverse cholesterol transfer, anti-inflammatory and anticoagulant effects of HDL. Therefore, it is useful for the prevention and / or treatment of blood lipid abnormalities, arteriosclerotic diseases and various cardiovascular diseases associated therewith caused by a decrease in serum HDL. Specific applicable diseases include hypoHDLemia, hypercholesterolemia, hypertriglyceridemia, arteriosclerosis, myocardial infarction, hyperuricemia, coronary artery disease, ischemic heart disease, corneal opacity, cerebrovascular Disorders, hereditary HDL deficiency (Tangier disease, fisheye disease, etc.) and the like.
本発明に係る化合物をアポAI発現亢進剤として投与する場合、経口的、非経口的のいずれの方法でも投与することができる。経口投与は常法に従って錠剤、顆粒剤、散剤、カプセル剤、丸剤、液剤、シロップ剤、バッカル剤または舌下剤等の通常用いられる剤型に調製して投与すればよい。非経口投与は、例えば筋肉内投与、静脈内投与等の注射剤、坐剤、経皮吸収剤、吸入剤等、通常用いられるいずれの剤型でも好適に投与することができる。 When the compound according to the present invention is administered as an apoAI expression enhancer, it can be administered either orally or parenterally. Oral administration may be prepared and administered in a commonly used dosage form such as tablets, granules, powders, capsules, pills, liquids, syrups, buccals or sublinguals according to conventional methods. For parenteral administration, any commonly used dosage forms such as injections such as intramuscular administration and intravenous administration, suppositories, percutaneous absorption agents, inhalants and the like can be suitably administered.
本発明に係る化合物の有効量にその剤型に適した賦形剤、結合剤、湿潤剤、崩壊剤、滑沢剤、希釈剤等の各種医薬用添加剤とを必要に応じて混合し医薬製剤とすることができる。注射剤の場合には適当な担体と共に滅菌処理を行なって製剤とすればよい。
具体的には、賦形剤としては乳糖、白糖、ブドウ糖、デンプン、炭酸カルシウムもしくは結晶セルロ−ス等、結合剤としてはメチルセルロ−ス、カルボキシメチルセルロ−ス、ヒドロキシプロピルセルロ−ス、ゼラチンもしくはポリビニルピロリドン等、崩壊剤としてはカルボキシメチルセルロ−ス、カルボキシメチルセルロ−スナトリウム、デンプン、アルギン酸ナトリウム、カンテン末もしくはラウリル硫酸ナトリウム等、滑沢剤としてはタルク、ステアリン酸マグネシウムもしくはマクロゴ−ル等が挙げられる。坐剤の基剤としてはカカオ脂、マクロゴ−ルもしくはメチルセルロ−ス等を用いることができる。また、液剤もしくは乳濁性、懸濁性の注射剤として調製する場合には通常使用されている溶解補助剤、懸濁化剤、乳化剤、安定化剤、保存剤、等張剤等を適宜添加しても良く、経口投与の場合には嬌味剤、芳香剤等を加えても良い。An effective amount of the compound according to the present invention is mixed with excipients, binders, wetting agents, disintegrants, lubricants, diluents, and other various pharmaceutical additives suitable for the dosage form, as necessary. It can be a formulation. In the case of an injection, it may be sterilized with an appropriate carrier to form a preparation.
Specifically, the excipients are lactose, sucrose, glucose, starch, calcium carbonate or crystalline cellulose, and the binders are methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, gelatin or polyvinyl. Examples of disintegrants include pyrrolidone, carboxymethyl cellulose, sodium carboxymethyl cellulose, starch, sodium alginate, agar powder or sodium lauryl sulfate, and lubricants include talc, magnesium stearate, or macrogol. It is done. As a suppository base, cacao butter, macrogol, methyl cellulose, or the like can be used. In addition, when preparing as liquid or emulsion or suspension injections, commonly used solubilizers, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents, etc. are added as appropriate. In the case of oral administration, a flavoring agent, a fragrance or the like may be added.
本発明に係る化合物のアポAI発現亢進剤としての投与量は、患者の年齢、体重、疾病の種類や程度、投与経路等を考慮した上で設定することが望ましいが、成人に経口投与する場合、通常1〜100mg/kg/日であり、好ましくは5〜30mg/kg/日の範囲内である。非経口投与の場合には投与経路により大きく異なるが、通常0.1〜10mg/kg/日であり、好ましく1〜5mg/kg/日の範囲内である。これを1日1回〜数回に分けて投与すれば良い。
以下に実施例を示し、本発明をさらに詳しく説明するが、これらは本発明を限定するものではない。The dose of the compound according to the present invention as an apoAI expression enhancer is preferably set in consideration of the patient's age, weight, type and degree of disease, route of administration, etc. Usually, it is 1 to 100 mg / kg / day, preferably 5 to 30 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.1 to 10 mg / kg / day, preferably 1 to 5 mg / kg / day. This may be administered once to several times a day.
The present invention will be described in more detail with reference to the following examples, but these are not intended to limit the present invention.
実施例1 4−クロロ−N−(4−トリル)ベンズアミド(Ib−17)
実施例2 チオフェン−2−カルボン酸ピリジン−2−イルアミド(Ib−122)
実施例3 N−メチル−N−フェニルベンズアミド(Ib−27)
実施例4 3−フェニル−N−キノキサリン−2−イル−アクリルアミド(Ia−9)
実施例5 3−ピリジン−3−イル−N−ピリジン−2−イル−アクリルアミド(Ia−112)
実施例6 3−フラン−2−イル−N−ピリジン−2−イル−アクリルアミド(Ia−104)
同様にしてその他の化合物を合成した。以下に構造式を示す。Example 6 3-Furan-2-yl-N-pyridin-2-yl-acrylamide (Ia-104)
Other compounds were synthesized in the same manner. The structural formula is shown below.
試験例1 ヒトアポAI産生遺伝子プロモーター機能亢進作用
ヒトアポAI産生遺伝子のプロモーター領域を単離し、それをホタルルシフェラーゼ構造遺伝子のすぐ上流につないだリポータープラスミドを作成した。それとネオマイシン耐性を付与するマーカープラスミドをヒト肝癌由来株化細胞であるHepG2細胞にコートランスフェクトし、10%牛胎児血清を含むDMEM培地にG418(最終濃度0.7mg/ml、Gibco社製)を添加した選択培地で培養することにより、そのリポーター分子の安定発現株を樹立した。この細胞株を96−ウェルの培養プレートにウェル当たり5万個となるようにシードし、48時間37℃、5%の炭酸ガス濃度下で培養した。その後、DMSOに溶解した本発明に係る化合物を終濃度0〜10μg/mlとなるように添加した。さらに24時間培養後、細胞にルシフェラーゼアッセイ用試薬(ピッカジーンLT7.5(登録商標)東洋インキ製造株式会社製)を添加、ルシフェラーゼ活性をルミノメーター(Wallac社製MicroBetaTM TRILUX, 1秒/ゥェル)にて測定した。ルシフェラーゼ活性をコントロール(本発明に係る化合物は添加せず、DMSOのみ添加)に対して2倍増強する化合物濃度を最小有効用量(MED)と設定した。結果を表25に示す。Test Example 1 Human Apo AI Production Gene Promoter Function Promoting Action A promoter region of a human apo AI production gene was isolated and a reporter plasmid was prepared by linking it to the upstream of the firefly luciferase structural gene. Then, a marker plasmid conferring neomycin resistance was co-transfected into HepG2 cells, a human hepatoma-derived cell line, and G418 (final concentration 0.7 mg / ml, manufactured by Gibco) was added to DMEM medium containing 10% fetal bovine serum. A stable expression strain of the reporter molecule was established by culturing in the added selective medium. This cell line was seeded in a 96-well culture plate at 50,000 cells per well and cultured for 48 hours at 37 ° C. under 5% carbon dioxide concentration. Thereafter, the compound according to the present invention dissolved in DMSO was added to a final concentration of 0 to 10 μg / ml. Further, after culturing for 24 hours, a luciferase assay reagent (Piccagene LT7.5 (registered trademark) manufactured by Toyo Ink Co., Ltd.) was added to the cells, and the luciferase activity was transferred to a luminometer (MicroBeta TM TRILUX, 1 sec / well manufactured by Wallac). Measured. The compound concentration at which the luciferase activity was enhanced 2-fold over the control (no addition of the compound according to the present invention but only DMSO) was set as the minimum effective dose (MED). The results are shown in Table 25.
表25から、本発明に係る化合物がアポAI発現亢進作用を有していることが分かる。 From Table 25, it can be seen that the compounds according to the present invention have an apoAI expression enhancing action.
製剤例1 錠剤
化合物(Ia−1) 15mg
デンプン 15mg
乳糖 15mg
結晶性セルロース 19mg
ポリビニルアルコール 3mg
蒸留水 30ml
ステアリン酸カルシウム 3mg
ステアリン酸カルシウム以外の成分を均一に混合し、破砕造粒して乾燥し、適当な大きさの顆粒剤とした。次にステアリン酸カルシウムを添加して圧縮成形して錠剤とした。Formulation Example 1 Tablet Compound (Ia-1) 15 mg
Starch 15mg
Lactose 15mg
Crystalline cellulose 19mg
Polyvinyl alcohol 3mg
30ml distilled water
Calcium stearate 3mg
Ingredients other than calcium stearate were uniformly mixed, crushed and granulated, and dried to give granules of an appropriate size. Next, calcium stearate was added and compression molded to obtain tablets.
製剤例2 カプセル剤
化合物(Ia−7) 10mg
ステアリン酸マグネシウム 10mg
乳糖 80mg
を均一に混合して粉末または細粒状として散剤をつくる。それをカプセル容器に充填してカプセル剤とした。Formulation Example 2 Capsule Compound (Ia-7) 10 mg
Magnesium stearate 10mg
Lactose 80mg
Are mixed uniformly to make a powder as a fine powder or powder. This was filled into a capsule container to obtain a capsule.
製剤例3 顆粒剤
化合物(Ia−1) 30g
乳糖 265g
ステアリン酸マグネシウム 5g
よく混合し、圧縮成型した後、粉砕、整粒し、篩別して適当な大きさの顆粒剤とした。Formulation Example 3 Granules Compound (Ia-1) 30 g
Lactose 265g
Magnesium stearate 5g
After thoroughly mixing and compression molding, the mixture was pulverized, sized and sieved to give granules of an appropriate size.
以上の試験例から明らかなように、本発明に係る化合物はアポAI発現亢進作用を示す。従って、本発明に係る化合物は血中脂質異常または動脈硬化性疾患の予防および/または治療剤として非常に有用である。 As is clear from the above test examples, the compound according to the present invention exhibits an apoAI expression enhancing action. Therefore, the compound according to the present invention is very useful as a preventive and / or therapeutic agent for blood lipid abnormality or arteriosclerotic disease.
Claims (5)
【化1】
(式中、環AはAr2であり、Ar1は置換基を有していてもよい単環もしくは二環の芳香族炭化水素環式基(該単環もしくは二環の芳香族炭化水素環式基は、フェニルまたはナフチルから選択される。)または置換基を有していてもよい単環もしくは二環の芳香族複素環式基(該単環もしくは二環の芳香族複素環式基は、ピリジル、ピリミジル、ピラジニル、2−キノリル、イソキノリル、キノキサリニルまたはナフチリジニルから選択される。)であり、
Ar2はメタ位の少なくともいずれか一方がメチル、トリフルオロメチル、フッ素、塩素、ヒドロキシまたはアセチルオキシで置換され、さらに置換基を有していてもよいフェニル(但し、メタ位のうち一方がメトキシ基で置換されたフェニルである場合を除く。)であり、
Rは水素であり、
Zは酸素であり、
Y1およびY2は水素であり、
nは1または2の整数であり、
破線は全て結合の存在を示し、
波線は二重結合に関するシスまたはトランス幾何異性を示し、
ここで、「置換基を有していてもよい単環もしくは二環の芳香族炭化水素環式基」、「置換基を有していてもよい単環もしくは二環の芳香族複素環式基」および「置換基を有していてもよいフェニル」の置換基は、ハロゲン;ヒドロキシ;ハロゲン、ヒドロキシもしくは低級アルコキシで置換されていてもよい低級アルキル;ハロゲン、ヒドロキシ、カルボキシもしくは低級アルコキシカルボニルで置換されていてもよい低級アルコキシ;ハロゲン、ヒドロキシ、カルボキシもしくは低級アルコキシカルボニルで置換されていてもよい低級アルケニル;ハロゲンもしくはヒドロキシで置換されていてもよい低級アルケニルオキシ;低級アルキルチオ;アシル;アシルオキシ;カルボキシ;低級アルコキシカルボニル;低級アルケニルオキシカルボニル;低級アルキルまたはアシルで置換されていてもよいアミノ;ヒドラジノ;ニトロ;シアノ;オキソ;および低級アルキレンジオキシから選択される1以上の任意の基である。)
で示される化合物、その製薬上許容される塩またはそれらの水和物を含有するアポAI発現亢進剤。
Formula (I):
[Chemical 1]
(In the formula, ring A is Ar2 and Ar1 is a monocyclic or bicyclic aromatic hydrocarbon cyclic group which may have a substituent (the monocyclic or bicyclic aromatic hydrocarbon cyclic group). it is selected from phenyl or naphthyl.) or may have a substituent mono- or bicyclic aromatic ring heterocyclic group (monocyclic or bicyclic aromatic heterocyclic groups, peak Selected from lysyl, pyrimidyl, pyrazinyl , 2 -quinolyl, isoquinolyl, quinoxalinyl or naphthyridinyl).
Ar2 is phenyl in which at least one of the meta positions is substituted with methyl, trifluoromethyl, fluorine, chlorine, hydroxy or acetyloxy, and may further have a substituent (provided that one of the meta positions is a methoxy group) Except for phenyl substituted with
R is hydrogen;
Z is oxygen,
Y1 and Y2 are hydrogen,
n is an integer of 1 or 2,
All dashed lines indicate the presence of bonds,
The wavy line shows cis or trans geometric isomerism with respect to the double bond,
Here, “monocyclic or bicyclic aromatic hydrocarbon cyclic group which may have a substituent”, “monocyclic or bicyclic aromatic heterocyclic group which may have a substituent And “optionally substituted phenyl” are substituted by halogen; hydroxy; halogen, hydroxy or lower alkyl optionally substituted by lower alkoxy; halogen, hydroxy, carboxy or lower alkoxycarbonyl substituted which do may be lower alkoxy; halogen, hydroxy, carboxy or lower alkoxycarbonyl lower alkenyl optionally substituted by carbonyl; halogen or hydroxy optionally substituted lower alkenyloxy, lower alkylthio, a sill; acyloxy; carboxy Lower alkoxycarbonyl; lower alkenyloxyca Boniru; is one or more optional group selected from and lower alkylenedioxy, lower alkyl or amino optionally substituted with acyl; hydrazino; nitro; cyano; o Kiso. )
ApoAI expression-enhancing agent comprising a compound represented by the formula: pharmaceutically acceptable salts thereof or hydrates thereof.
The apo AI according to claim 1, wherein Ar1 may have a substituent, and is a monocyclic or bicyclic aromatic heterocyclic group in which the adjacent position of the ring-constituting atom having a bond is a nitrogen atom. Expression enhancer.
Ar1 may pyridyl which may have a substituent, 2-quinolyl or 2-Kinokisari is Le, apo AI expression enhancer according to claim 1.
n is 1 and the relationship between NRCZ and ring A is in the trans configuration, or n is 2, and the relationship between NRCZ and CY2 and / or the relationship between CY1 and ring A is in the trans configuration. The apoAI expression enhancer according to any of -3.
The apoAI expression enhancer according to any one of claims 1 to 4, which is a prophylactic and / or therapeutic agent for blood lipid abnormality or arteriosclerotic disease.
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