JP5593380B2 - 11−β−ヒドロキシステロイドデヒドロゲナーゼ1型の阻害化合物 - Google Patents
11−β−ヒドロキシステロイドデヒドロゲナーゼ1型の阻害化合物 Download PDFInfo
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- JP5593380B2 JP5593380B2 JP2012513645A JP2012513645A JP5593380B2 JP 5593380 B2 JP5593380 B2 JP 5593380B2 JP 2012513645 A JP2012513645 A JP 2012513645A JP 2012513645 A JP2012513645 A JP 2012513645A JP 5593380 B2 JP5593380 B2 JP 5593380B2
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- DRRCILYQTPWXFW-UHFFFAOYSA-N s-[4-(3,4,4a,5,6,7,8,8a-octahydro-1h-isoquinolin-2-yl)-4-oxobutyl] n-cycloheptylcarbamothioate Chemical compound C1CC2CCCCC2CN1C(=O)CCCSC(=O)NC1CCCCCC1 DRRCILYQTPWXFW-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 229910052717 sulfur Chemical group 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000001585 trabecular meshwork Anatomy 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
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- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
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- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
- C07D215/08—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms with acylated ring nitrogen atom
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- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
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- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
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Description
式(I)の化合物
sおよびpは、sが1の場合はpが0であり(ペルヒドロキノリンを形成する)、sが0の場合はpが1である(ペルヒドロイソキノリンを形成する)ように、逆の方式で0〜1から選択される整数であり、
Yは、CO、CSおよびSO2から選択されるビラジカルであり、
W1およびW2は、独立に、結合またはO、SおよびNR1から選択されるビラジカルであってよく、R1は、場合により、H、C1〜4アルキルまたはC3〜10シクロアルキルであり、
nは、0、1、2、3および4から選択される整数であり、
Vは、-CO-T、-CS-Tおよび-SO2-Tから選択されるラジカル、または
Tは、NR2R3、R2、OR2およびSR2から選択される基、または
R2およびR3は、独立に、H、COR4、SO2R4、C1〜4アルキル、アリール、ベンジル、フェネチル、C2〜4アルケニル、C2〜4アルキニル、C3〜10シクロアルキルまたは複素環から選択され、
R2またはR3が、アルキルまたはアルケニルである場合、これらは、F、OR4、NR4R5、COOR4、CONR4R5、C3〜10シクロアルキル、アリールおよび複素環から独立に選択される1つまたは複数の置換基により場合により置換されていてよく、
R2またはR3が、アリール、ベンジル、フェネチル、シクロアルキルまたは複素環である場合、これらは、NH2、F、Cl、CN、NO2、COOH、R4、COOR4、OR4、OCF3、SH、SR4、CONR4R5、SO2NR4R5、COR4、NR1COR4、OCOR4、SOR4、SO2R4および複素環から独立に選択される1つまたは複数の置換基により場合により置換されていてよく、
R2またはR3がシクロアルキルである場合、これは、シクロアルキルと縮合した1つまたは複数のベンゼン環により場合により置換されていてよく、前記ベンゼンは、アルキル、アルコキシドまたはハロゲンから独立に選択される1つまたは複数の置換基により場合により置換されていてよく、
R4およびR5は、独立に、H、C1〜4アルキル、アリール、ベンジル、フェネチル、C2〜4アルケニル、C2〜4アルキニル、C3〜10シクロアルキルおよび複素環から選択され、
場合により、R4およびR5は、互いに結合して3〜8員環を形成することができ、
R6、R7、R8およびR9は、独立に、H、OR4、FおよびClから選択され、
R10は、独立に、H、OH、F、C1〜4アルキル、COOR11、COR11、フェニル、ベンジル、ベンズヒドリル、C2〜4アルケニル、C2〜4アルキニル、C3〜10シクロアルキルおよび複素環から選択され、前記アルキル、フェニル、ベンジル、ベンズヒドリル、シクロアルキルまたは複素環は、NH2、F、Cl、NO2、COOH、COOR4、OR4、CF3、SH、SR4、CONR4R5、SO2NR4R5、COR4、NR1COR4、OCOR4、SOR4、SO2R4およびC1〜4アルキルから独立に選択される1つまたは複数の置換基により場合により置換されていてよく、
R11は、H、C1〜4アルキル、アリールおよびC3〜10シクロアルキルから選択される]
に言及する。
AcOEt 酢酸エチル
Brine 飽和NaCl溶液
DCM ジクロロメタン
DMF ジメチルホルムアミド
DMSO ジメチルスルホキシド
EDC 1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド
Et3N トリエチルアミン
EtOH エタノール
HOBT 1-ヒドロキシベンゾトリアゾール
HPLC 高速液体クロマトグラフィー
MeOH メタノール
MS 質量分析
m/z 質量/電荷比
rt 室温
THF テトラヒドロフラン
TLC 薄層クロマトグラフィー
tr 保持時間
UV 紫外線
可変波長のUV検出器および質量分析計モデル1100VLを備えたAgilent HPLC-UV-MS装置を使用して、生成物を分析した。UV検出に使用した波長は210nmであり、MS検出器は、陽イオンエレクトロスプレーイオン化モードで操作し、100〜700m/zの走査を実施した。クロマトグラフィーによる分離に関して、使用したカラムは、Kromasil 100 C18、40×4.0mm、3.5μmであり、2〜5μlを注入した。溶出に関して、以下に記載の2つの溶媒勾配の一方に従った。
3-アミノプロピオン酸メチルエステル塩酸塩0.5g(3.5mmol)を、無水THF5mLおよびEt3N0.9mLに溶解する。溶解したら、1-クロロカルボニルオクタヒドロキノリン650mgをゆっくり添加し、18時間還流にする。次いで、AcOEtを添加し、得られた溶液を、水、1NのHClおよびブラインで逐次的に洗浄する。有機相を無水Na2SO4で乾燥させ、濾過し、溶媒を減圧下で蒸発させて、580mgの中間体IIIb.1を得る。
2-クロロカルボニルオクタヒドロイソキノリン1g(5mmol)を、ピリジン10mL中3-メルカプトプロピオン酸メチルエステル0.55mL(5mmol)の0℃の溶液に添加する。添加後、rtで18時間撹拌する。次いで、AcOEtを反応混合物に添加し、NaHCO3の5%溶液、1NのHClおよびブラインで逐次的に洗浄する。有機相を無水Na2SO4で乾燥させ、濾過し、溶媒を減圧下で蒸発させ、シリカゲルカラムクロマトグラフィーによってヘキサン:AcOEt(1:1)混合物を溶離液として使用して精製して、中間体IIIb.5と同定される残渣1.17gおよびビス-(オクタヒドロイソキノリン-2-イル)メタノン(Vb.1)と同定される固体210mgを得る。
塩化スルフリル4.48mL(55.9mmol)を、3-メルカプトプロピオン酸メチル2.47mL(22.4mmol)および硝酸カリウム5.64g(55.9mmol)によって形成された0℃に冷却した混合物に、滴下添加する。添加後、rtにして10時間撹拌し続ける。飽和NaHCO3溶液を添加し、有機相を分離し、その後NaHCO3、次いで、ブラインで再度洗浄する。有機相を無水Na2SO4で乾燥させ、濾過し、溶媒を減圧下で蒸発させて、3-クロロスルホニルプロピオン酸メチルエステルと同定される油2.6gを得る。
Et3N2.1mL(15.3mmol)、その後3-クロロスルホニルプロピオン酸メチルエステル1.3g(7mmol)を、AcOEt70mL中デカヒドロキノリン1.1mL(7.6mmol)によって形成された溶液に滴下添加する。混合物を70℃に加熱し、その温度を12時間維持する。次いで、冷却し、水を添加し、有機相を分離し、重炭酸ナトリウムの5%溶液、2NのHClおよびブラインで逐次的に洗浄する。有機相を無水Na2SO4で乾燥させ、濾過し、溶媒を減圧下で蒸発させて、中間体IIIm.1と同定される赤色がかった油1.32gを得る。
中間体IVc.1:4-アジド-1-(オクタヒドロキノリン-1-イル)ブタン-1-オン
トランスフェクトしたHEK293細胞のミクロソーム画分における11-β-HSD1の阻害活性の決定
アッセイバッファー(50mMのHEPES、100mMのKCl、5mMのNaCl、2mMのMgCl2/100mLのH2O)に溶解した、80nM[3H]-コルチゾン、1mMのNADPHおよび11-β-HSD1クローンを安定にトランスフェクトした40μg/mLのHEK-293細胞ミクロソーム調製物を含有する反応混合物99μLを、96ウェルプレートに添加した。分析する阻害剤を100%DMSOに溶解し、反応物の最終濃度を1%とした。
反応混合物59μLを、96ウェルプレートに添加した。これは、アッセイバッファー(50mMのHEPES、100mMのKCl、5mMのNaCl、2mMのMgCl2/100mLのH2O)に溶解した、1mMのNAD+および11-β-HSD2クローンを安定にトランスフェクトした80μg/mLのHEK-293細胞ミクロソーム調製物を含有していた。分析する阻害剤を100%DMSOに溶解し、反応物の最終濃度を1%とした。反応混合物を、撹拌しながら37℃で30分間プレインキュベートした。アッセイバッファーに溶解した反応基質の3.2nM[3H]-コルチゾール40μLを添加した。撹拌しながら37℃で2時間インキュベートした。停止溶液を、rtで2時間インキュベートし、光から保護しながら同時に調製した。これが終了した後、停止溶液50μLを添加して反応を停止させ、撹拌しながらrtで2時間インキュベートし、光から保護した。SPAビーズ-コルチゾール複合体によって放出されたシグナルを、1450 Microbeta Tritalux(Wallac(登録商標))シンチレーションカウンターでウェル1個あたり30秒間測定した。この場合は、基質との結合を測定するものであり、1型アイソザイムについてのアッセイのように生成物との結合を測定するものではない。
Claims (16)
- 式(I)の化合物
sおよびpは、sが1の場合はpが0であり(ペルヒドロキノリンを形成する)、sが0の場合はpが1である(ペルヒドロイソキノリンを形成する)ように、逆の方式で0〜1から選択される整数であり、
Yは、CO、CSおよびSO2から選択されるビラジカルであり、
W1およびW2は、独立に、結合またはO、SおよびNR1から選択されるビラジカルであってよく、R1は、H、C1〜4アルキルおよびC3〜10シクロアルキルから選択され、
nは、0、1、2、3および4から選択される整数であり、
Vは、-CO-T、-CS-Tおよび-SO2-Tから選択されるラジカル、または
Tは、NR2R3、OR2およびSR2から選択される基であり、
R2およびR3は、独立に、H、COR4、SO2R4、C1〜4アルキル、アリール、ベンジル、フェネチル、C2〜4アルケニル、C2〜4アルキニル、C3〜10シクロアルキルまたは複素環から選択され、
R2またはR3が、アルキルまたはアルケニルである場合、これらは、F、OR4、NR4R5、COOR4、CONR4R5、C3〜10シクロアルキル、アリールおよび複素環から独立に選択される1つまたは複数の置換基により任意選択により置換されていてよく、
R2またはR3が、アリール、ベンジル、フェネチル、シクロアルキルまたは複素環である場合、これらは、NH2、F、Cl、CN、NO2、COOH、R4、COOR4、OR4、OCF3、SH、SR4、CONR4R5、SO2NR4R5、COR4、NR1COR4、OCOR4、SOR4、SO2R4および複素環から独立に選択される1つまたは複数の置換基により任意選択により置換されていてよく、
R2またはR3がシクロアルキルである場合、これは、1つまたは複数の縮合ベンゼン環により任意選択により置換されていてよく、前記ベンゼンは、アルキル、アルコキシドまたはハロゲンから独立に選択される1つまたは複数の置換基により任意選択により置換されていてよく、
R4およびR5は、独立に、H、C1〜4アルキル、アリール、ベンジル、フェネチル、C2〜4アルケニル、C2〜4アルキニル、C3〜10シクロアルキルおよび複素環から選択され、
任意選択により、R4およびR5は、互いに結合して3〜8員環を形成することができ、
R6、R7、R8およびR9は、独立に、H、OR4、FおよびClから選択される]。 - Yが、COおよびSO2から選択される、請求項1に記載の化合物。
- W1およびW2が、独立に、結合、SおよびNR1から選択される、請求項1に記載の化合物。
- R1がHである、請求項3に記載の化合物。
- Vが、-CO-T、-CS-Tおよび-SO2-Tから選択される、請求項1に記載の化合物。
- R2およびR3が、独立に、H、COR4、SO2R4、C1〜4アルキル、フェニル、ナフチル、ベンジル、フェネチル、C2〜4アルケニル、C3〜10シクロアルキルおよび複素環、特に、2-フラニル、2-チオフェニル、2-(1-メチルインドール)、キノリン、イソキノリンおよび2-ベンゾフラニルから選択される、請求項1に記載の化合物。
- R2およびR3が、独立に、C1〜4アルキルおよびC2〜4アルケニルから選択される、請求項7に記載の化合物。
- R2およびR3が、F、OR4、NR4R5、COOR4、CONR4R5、フェニル、C3〜10シクロアルキル、ヘキセニル、ナフチルおよび複素環、から独立に選択される1つまたは複数の置換基により任意選択により置換されている、請求項8に記載の化合物。
- R2およびR3が、独立に、フェニル、ベンジル、フェネチルおよびC3〜10シクロアルキルから選択される、請求項7に記載の化合物。
- R6、R7、R8およびR9が、独立に、H、OR4、FおよびClから選択される、請求項1に記載の化合物。
- sが1であり、pが0である、請求項1から11のいずれかに記載の化合物。
- 11-β-HSD1関連障害によって引き起こされる疾患の予防または治療を意図した医薬品の製造のための、請求項1から13のいずれかに記載の化合物の使用。
- 11-β-HSD1関連障害によって引き起こされる前記疾患が、緑内障、眼圧上昇、代謝性障害、肥満、メタボリック症候群、脂質異常症、高血圧、糖尿病、アテローム性動脈硬化症、クッシング症候群、乾癬、関節リウマチ、認知障害、アルツハイマー病または神経変性である、請求項14に記載の使用。
- 11-β-HSD1関連障害によって引き起こされる前記疾患が、緑内障またはメタボリック症候群である、請求項14に記載の使用。
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Publication number | Publication date |
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ES2350077B1 (es) | 2011-11-04 |
CN102834385B (zh) | 2016-03-09 |
EA201171410A1 (ru) | 2012-06-29 |
MX2011012984A (es) | 2012-01-12 |
CA2764214A1 (en) | 2010-12-09 |
AU2010255653A1 (en) | 2012-01-12 |
US8524894B2 (en) | 2013-09-03 |
AU2010255653B2 (en) | 2015-01-15 |
US20130303522A1 (en) | 2013-11-14 |
EP2439202A1 (en) | 2012-04-11 |
WO2010139827A1 (es) | 2010-12-09 |
PT2439202T (pt) | 2016-07-15 |
DK2439202T3 (en) | 2016-08-01 |
ES2582585T3 (es) | 2016-09-13 |
KR101732989B1 (ko) | 2017-05-08 |
CN102834385A (zh) | 2012-12-19 |
PL2439202T3 (pl) | 2016-12-30 |
EP2439202B1 (en) | 2016-04-20 |
US20120071466A1 (en) | 2012-03-22 |
CY1117790T1 (el) | 2017-05-17 |
JP2012528836A (ja) | 2012-11-15 |
CA2764214C (en) | 2017-08-29 |
US8822452B2 (en) | 2014-09-02 |
KR20120027402A (ko) | 2012-03-21 |
ES2350077A1 (es) | 2011-01-18 |
BRPI1012963A2 (pt) | 2016-03-29 |
NZ596896A (en) | 2013-02-22 |
EA020794B1 (ru) | 2015-01-30 |
MX340804B (es) | 2016-07-27 |
HUE029756T2 (en) | 2017-03-28 |
EP2439202A4 (en) | 2012-12-12 |
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