JP4021327B2 - Fxrに対する作用薬としてのステロイド - Google Patents
Fxrに対する作用薬としてのステロイド Download PDFInfo
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- JP4021327B2 JP4021327B2 JP2002571512A JP2002571512A JP4021327B2 JP 4021327 B2 JP4021327 B2 JP 4021327B2 JP 2002571512 A JP2002571512 A JP 2002571512A JP 2002571512 A JP2002571512 A JP 2002571512A JP 4021327 B2 JP4021327 B2 JP 4021327B2
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- compound
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- pharmaceutically acceptable
- amino acid
- fxr
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/12—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic the nitrogen atom of the amino group being further bound to hydrocarbon groups substituted by hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
Description
3α−テトラヒドロピラニルオキシ−7−ケト−5β−コラン−24−酸
p−トルエンスルホン酸(6.0g、3.2mmol)および3,4−ジヒドロ−2H−ピラン(4.6g、54mmol)を、3α−ヒドロキシ−7−ケト−5β−コラン−24−酸(1)(6.0g、14.4mmol)のジオキサン120ml中溶液に加えた。この反応混合物を室温で15分攪拌し、次いでpHが約8〜9に達するまでアンモニアで飽和させたメタノールで処理した。真空下で溶媒を除去し、残留物をクロロホルム(200ml)で抽出し、飽和NaHCO3溶液(2×50ml)で洗浄した。無水Na2SO4で乾燥し、真空下で蒸発させた後、シリカゲルクロマトグラフィーで残留物を精製した。CHCl3:MeOH(90:10)を用いた溶出によって、化合物2を白色固体(mp:157〜159℃)で5.4g(10.4mmol、収率74%)得た。
n−ブチルリチウム(21.1ml、1.6Mヘキサン溶液)およびHMPA(4.3ml)を、ジイソプロピルアミン(4.1ml、33.7mmol)の乾燥THF250ml中溶液に−78℃で滴下して加えた。この系をさらに30分間−78℃に維持し、次いで乾燥THF50mlに溶解させた3α−テトラヒドロピラニルオキシ−7−ケト−5β−コラン−24−酸(2)(5g、10.5mmol)を−78℃に冷却し、混合物に滴下して加えた。20分後、THF(20ml)に溶解させた臭化エチル(7.8ml、105mmol)をゆっくり加え、混合物を一夜の間に室温に到達させた。真空下で溶媒を除去し、10%HClで酸性にし、酢酸エチル(5×200ml)で抽出し、飽和NaCl溶液(1×200ml)で洗浄した。無水Na2SO4で乾燥し、真空下で蒸発させた後、粗製残留物を2N HClのEtOH(50ml)溶液で12時間還流させた。真空下でこの残留物を蒸発させ、酢酸エチル(300ml)で抽出し、飽和NaHCO3溶液(2×100ml)で洗浄し、Na2SO4で乾燥し、真空下で蒸発させた。シリカゲルクロマトグラフィーで残留物を精製し、軽油:酢酸エチル(70:30)で溶出して、3α−ヒドロキシ−6α−エチル−7−ケト−5β−コラン−24−酸エチル(3)を0.57g(1.27mmol、収率12%)非晶質固体として得た。
3α−ヒドロキシ−6α−エチル−7−ケト−5β−コラン−24−酸エチル(3)(0.185g、0.4mmol)を96%EtOH30mlに溶解させ、NaBH4(30mg、0.8mmol)で処理した。この混合物を、室温で2時間攪拌した。次いで水(10ml)を加え、真空下でこの混合物を部分的に濃縮し、酢酸エチル(3×20ml)で抽出した。有機画分を合わせて飽和NaCl溶液(1×50ml)で洗浄し、Na2SO4で乾燥し、真空下で蒸発させた。3α,7α−ジヒドロキシ−6α−エチル−5β−コラン−24−酸エチル(4)(0.15g、0.33mmol、収率81%)を白色固体(mp:55〜57℃)で得た。
3α,7α−ジヒドロキシ−6α−エチル−5β−コラン−24−酸エチル(4)(0.10g、0.22mmol)を96%EtOH15mlに溶解させ、10%NaOHの96%EtOH溶液(2ml、5mmol)に加えた。この混合物を4時間還流させた。この混合物を3N HClで酸性にし、酢酸エチル(3×20ml)で抽出した。有機画分を合わせて飽和NaCl溶液(1×50ml)で洗浄し、Na2SO4で乾燥し、真空下で蒸発させた。残留物をシリカゲルカラムでクロマトグラフィーによって分離し、CHCl3:MeOH(95:5)で溶出して、3α,7α−ジヒドロキシ−6α−メチル−5β−コラン−24−酸(6)(0.04g、0.095mmol、収率43%)を得た。
Claims (14)
- 3α,7α−ジヒドロキシ−6α−エチル−5β−コラン−24−酸、あるいは、その薬剤として許容される塩、溶媒和物またはアミノ酸抱合体。
- 請求項1に記載の化合物、あるいは、その薬剤として許容される塩、溶媒和物またはアミノ酸抱合体を有効成分として含む、FXRが媒介する疾患または症状の予防剤または治療剤。
- 請求項1に記載の化合物、あるいは、その薬剤として許容される塩、溶媒和物またはアミノ酸抱合体を有効成分として含む、心血管疾患の予防剤または治療剤。
- 前記心血管疾患がアテローム性動脈硬化症である、請求項9に記載の予防剤または治療剤。
- 請求項1に記載の化合物、あるいは、その薬剤として許容される塩、溶媒和物またはアミノ酸抱合体を有効成分として含む、胆汁うっ滞性肝疾患の予防剤または治療剤。
- 請求項1に記載の放射標識化合物。
- 前記化合物がトリチウム化されている、請求項9に記載の化合物。
- FXRが媒介する疾患または症状を予防または治療する医薬品を調製するための請求項1に記載の化合物、あるいは、その薬剤として許容される塩、溶媒和物またはアミノ酸抱合体の使用。
- 心血管疾患を予防または治療する医薬品を調製するための請求項1に記載の化合物、あるいは、その薬剤として許容される塩、溶媒和物またはアミノ酸抱合体の使用。
- アテローム性動脈硬化症を予防または治療する医薬品を調製するための請求項1に記載の化合物、あるいは、その薬剤として許容される塩、溶媒和物またはアミノ酸抱合体の使用。
- 胆汁うっ滞性肝疾患を予防または治療する医薬品を調製するための請求項1に記載の化合物、あるいは、その薬剤として許容される塩、溶媒和物またはアミノ酸抱合体の使用。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US27495901P | 2001-03-12 | 2001-03-12 | |
PCT/EP2002/001832 WO2002072598A1 (en) | 2001-03-12 | 2002-02-21 | Steroids as agonists for fxr |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2007162928A Division JP2007269815A (ja) | 2001-03-12 | 2007-06-20 | Fxrに対する作用薬としてのステロイド |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2004519492A JP2004519492A (ja) | 2004-07-02 |
JP4021327B2 true JP4021327B2 (ja) | 2007-12-12 |
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Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
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JP2002571512A Expired - Lifetime JP4021327B2 (ja) | 2001-03-12 | 2002-02-21 | Fxrに対する作用薬としてのステロイド |
JP2007162928A Pending JP2007269815A (ja) | 2001-03-12 | 2007-06-20 | Fxrに対する作用薬としてのステロイド |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
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JP2007162928A Pending JP2007269815A (ja) | 2001-03-12 | 2007-06-20 | Fxrに対する作用薬としてのステロイド |
Country Status (16)
Country | Link |
---|---|
US (9) | USRE48286E1 (ja) |
EP (1) | EP1392714B1 (ja) |
JP (2) | JP4021327B2 (ja) |
AT (1) | ATE303399T1 (ja) |
AU (1) | AU2002308295B2 (ja) |
BE (1) | BE2017C018I2 (ja) |
CA (1) | CA2440680C (ja) |
CY (1) | CY2017020I1 (ja) |
DE (1) | DE60205891T2 (ja) |
DK (1) | DK1392714T3 (ja) |
ES (1) | ES2248581T3 (ja) |
FR (1) | FR17C0003I2 (ja) |
IL (2) | IL157816A0 (ja) |
NL (1) | NL300877I2 (ja) |
NO (2) | NO326134B1 (ja) |
WO (1) | WO2002072598A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017170854A1 (ja) | 2016-03-31 | 2017-10-05 | 大日本住友製薬株式会社 | 有効成分の化学的安定性に優れたフィルムコーティング錠 |
WO2017170858A1 (ja) | 2016-03-31 | 2017-10-05 | 大日本住友製薬株式会社 | 溶出性に優れた経口製剤 |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2017170854A1 (ja) | 2016-03-31 | 2017-10-05 | 大日本住友製薬株式会社 | 有効成分の化学的安定性に優れたフィルムコーティング錠 |
WO2017170858A1 (ja) | 2016-03-31 | 2017-10-05 | 大日本住友製薬株式会社 | 溶出性に優れた経口製剤 |
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