JP4471653B2 - ホルモン作用を有する17α−ヒドロキシ−14β−ステロイド - Google Patents
ホルモン作用を有する17α−ヒドロキシ−14β−ステロイド Download PDFInfo
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- JP4471653B2 JP4471653B2 JP2003526937A JP2003526937A JP4471653B2 JP 4471653 B2 JP4471653 B2 JP 4471653B2 JP 2003526937 A JP2003526937 A JP 2003526937A JP 2003526937 A JP2003526937 A JP 2003526937A JP 4471653 B2 JP4471653 B2 JP 4471653B2
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- hydroxy
- compounds
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0062—Estrane derivatives substituted in position 17 alfa not substituted in position 17 beta
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/16—Masculine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/26—Androgens
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Endocrinology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Reproductive Health (AREA)
- Diabetes (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
i)ビス(トリメチルシリル)アミドリチウム(55.5mmol)テトラヒドロフラン(96ml)溶液を−40℃に冷却した。(7α,14β)−3−メトキシ−7−メチルエストラ−1,3,5(10)−トリエン−17−オン(WO 00/53619;15.0g)の無水テトラヒドロフラン(66ml)溶液を滴下し、反応混合物を45分間撹拌した。次に、−30℃にてヨードメタン(6.3ml)を添加し、撹拌を1時間にわたり継続した(−30<T −20℃)。この混合物を塩化アンモニウムの飽和水溶液に注ぎ、生成物を酢酸エチルに抽出した。1つに合わせた有機相を水および食塩水で洗浄し、硫酸ナトリウムで乾燥し、減圧下で濃縮して、(7α,14β,16β)−3−メトキシ−7,16−ジメチルエストラ−1,3,5(10)−トリエン−17−オン(17.33g)を得た。この生成物を、更なる精製を行わずに次の工程で用いた。
i)ビス(トリメチルシリル)アミドリチウム(29mmol)のテトラヒドロフラン(45ml)溶液を−40℃に冷却した。(7α,14β,16β)−3−メトキシ−7,16−ジメチルエストラ−1,3,5(10)−トリエン−17−オン(実施例1、工程i;6.0g)の無水テトラヒドロフラン(24ml)溶液を滴下し、この反応混合物を1時間撹拌した。次に、それを塩化アンモニウムの飽和水溶液の添加により反応停止させ、生成物を酢酸エチルに抽出した。1つに合わせた有機相を塩化アンモニウムの飽和水溶液、水および食塩水で洗浄し、硫酸ナトリウムで乾燥し、減圧下で濃縮して、(7α,14β,16α)−3−メトキシ−7,16−ジメチルエストラ−1,3,5(10)−トリエン−17−オン(6.82g)を得た。この生成物を、更なる精製を行わずに次の工程で用いた。
i)実施例1のiに記載されているものと同様の手順に従って、(7α,14β,16β)−3−メトキシ−7,16−ジメチルエストラ−1,3,5(10)−トリエン−17−オン(実施例1、工程i;6.0g)を(7α,14β)−3−メトキシ−7,16,16−トリメチルエストラ−1,3,5(10)−トリエン−17−オン(5.99g)に変換した。
(a)(7α,14β,16β,17α)−16−エチル−17−ヒドロキシ−7−メチルエストロ−4−エン−3−オン、[α]D20=+109°(c=1.00、ジオキサン)
(b)(7α,14β,16β,17α)−16−エチル−17−ヒドロキシ−7,16−ジメチルエストロ−4−エン−3−オン、[α]D20=+89°(c=1.00、ジオキサン)[出発物質をヨードメタンでアルキル化し、続いてヨードエタンでアルキル化することによる]
i)4℃に冷却した(7α,14β)−3−メトキシ−7−メチルエストラ−1,3,5(10)−トリエン−17−オン(WO 00/53619;2.8g)の無水エタノール(100ml)溶液を水素化ホウ素ナトリウム(0.70g)で処理した。1時間撹拌した後、追加の水素化ホウ素ナトリウム(0.35g)を添加し、撹拌を3時間にわたって継続した。酢酸水溶液(50%、10ml)を滴下し、この反応混合物を水に注いだ。生成物をジクロロメタンに抽出し、1つに合わせた有機相を炭酸水素ナトリウムの飽和水溶液および食塩水で洗浄し、硫酸ナトリウムで乾燥し、減圧下で濃縮して、(7α,14β,17α)−3−メトキシ−7−メチルエストラ−1,3,5(10)−トリエン−17−オール(2.93g)を得た。この生成物を、更なる精製を行わずに次の工程で用いた。
本発明の化合物の、転写活性化を起こすことができるアンドロゲン活性は、ヒト・アンドロゲン受容体(hAR)ならびにマウス乳癌ウイルス(MMTV)およびルシフェラーゼ受容体遺伝子でトランスフェクトしたチャイニーズハムスター卵巣細胞(CHO)において測定し(インキュベーション時間は16時間、37℃の温度)、5α−ジヒドロテストステロンの活性[Schoonen,W.G.E.J.;de Ries,R.J.H.;Joosten,J.W.H.;Mathijssen−Mommers,G.J.W.;Kloosterboer,H.J.,Analyt.Biochem.261,222−224(1998)]と比較した。結果を表1にまとめて示す。
ヒト肝細胞との接触による化合物の半減期は、信頼性の高い代謝安定性の指標となっている。このクラスのステロイドの吸収が高いことは十分に知られているので、このアッセイは、ヒトにおける経口活性についてのin vitroモデルとなる。半減期が短いことは、化合物がより迅速に代謝されることを示し、その逆も成り立ち、半減期が長いほど、化合物は、経口投与された際に、その作用をより良好にヒトの身体に対して発揮し得る、と理解されよう。
本発明の化合物の代謝安定性(t1/2)を、次のスキームに従って分類した。
(+++)代謝安定性>17α−メチルテストステロン(MT)
(++)17α−メチルテストステロン>代謝安定性>80%の17α−メチルテストステロン
(+)80%の17α−メチルテストステロン>代謝安定性>テストステロン
(−)代謝安定性<テストステロン
結果を表1にまとめる。
Claims (6)
- R1がOであり、R2とR3の少なくとも一方がメチルであり、他方が水素またはメチルであることを特徴とする、請求項1に記載のステロイド化合物。
- (7α,14β,16β,17α)−17−ヒドロキシ−7,16−ジメチルエストロ−4−エン−3−オンであることを特徴とする、請求項2に記載のステロイド化合物。
- アンドロゲン関連治療において使用する医薬を製造するための、請求項1から3のいずれか一項に記載のステロイド化合物の使用。
- 前記治療が、男性避妊または男性もしくは女性のホルモン補充療法のためであることを特徴とする、請求項4に記載の使用。
- 請求項1に記載の化合物を含む医薬組成物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP01203455 | 2001-09-12 | ||
PCT/EP2002/010041 WO2003022864A1 (en) | 2001-09-12 | 2002-09-06 | 17alpha-hydroxy-14beta-steroids with hormonal effect |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2005505566A JP2005505566A (ja) | 2005-02-24 |
JP2005505566A5 JP2005505566A5 (ja) | 2006-01-05 |
JP4471653B2 true JP4471653B2 (ja) | 2010-06-02 |
Family
ID=8180920
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2003526937A Expired - Fee Related JP4471653B2 (ja) | 2001-09-12 | 2002-09-06 | ホルモン作用を有する17α−ヒドロキシ−14β−ステロイド |
Country Status (29)
Country | Link |
---|---|
US (1) | US7169769B2 (ja) |
EP (1) | EP1427748B1 (ja) |
JP (1) | JP4471653B2 (ja) |
KR (1) | KR100940054B1 (ja) |
CN (1) | CN1257913C (ja) |
AR (1) | AR036462A1 (ja) |
AT (1) | ATE395352T1 (ja) |
AU (1) | AU2002339536B2 (ja) |
BR (1) | BR0212409A (ja) |
CA (1) | CA2505575C (ja) |
CY (1) | CY1108152T1 (ja) |
DE (1) | DE60226623D1 (ja) |
DK (1) | DK1427748T3 (ja) |
EC (1) | ECSP045012A (ja) |
ES (1) | ES2305306T3 (ja) |
HK (1) | HK1063637A1 (ja) |
HR (1) | HRP20040193A2 (ja) |
HU (1) | HUP0402139A3 (ja) |
IL (2) | IL160451A0 (ja) |
IS (1) | IS2555B (ja) |
MX (1) | MXPA04002418A (ja) |
NO (1) | NO326624B1 (ja) |
NZ (1) | NZ531487A (ja) |
PL (1) | PL207493B1 (ja) |
PT (1) | PT1427748E (ja) |
RU (1) | RU2294332C2 (ja) |
TW (1) | TWI221154B (ja) |
WO (1) | WO2003022864A1 (ja) |
ZA (1) | ZA200401992B (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI221154B (en) | 2001-09-12 | 2004-09-21 | Akzo Nobel Nv | 17alpha-hydroxy-14beta-steroids with hormonal effect |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3338925A (en) * | 1965-10-25 | 1967-08-29 | Syntex Corp | 17-substituted 14beta-estr-4-enes |
EP1163259B1 (en) | 1999-03-08 | 2002-11-20 | Akzo Nobel N.V. | 14.beta.,17-alpha-hydroxymethylandrostane derivatives as androgens |
AU4299301A (en) * | 2000-02-29 | 2001-09-12 | National University Of Singapore, The | A method for modulating steroidogenic activity |
US6391868B2 (en) * | 2000-05-10 | 2002-05-21 | Lpt Research, Inc. | Use of 5-alpha-androst-1-en-3,17-dione to increase the level of the anabolic/androgenic hormone 17-beta-hydroxy-5-alpha-androst-1-en-3-one in humans |
TWI221154B (en) | 2001-09-12 | 2004-09-21 | Akzo Nobel Nv | 17alpha-hydroxy-14beta-steroids with hormonal effect |
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2002
- 2002-07-19 TW TW091116164A patent/TWI221154B/zh not_active IP Right Cessation
- 2002-09-06 AT AT02777036T patent/ATE395352T1/de active
- 2002-09-06 NZ NZ531487A patent/NZ531487A/en not_active IP Right Cessation
- 2002-09-06 AU AU2002339536A patent/AU2002339536B2/en not_active Expired
- 2002-09-06 ES ES02777036T patent/ES2305306T3/es not_active Expired - Lifetime
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- 2002-09-06 CN CNB02817853XA patent/CN1257913C/zh not_active Expired - Lifetime
- 2002-09-06 IL IL16045102A patent/IL160451A0/xx unknown
- 2002-09-06 HU HU0402139A patent/HUP0402139A3/hu unknown
- 2002-09-06 PT PT02777036T patent/PT1427748E/pt unknown
- 2002-09-06 US US10/489,456 patent/US7169769B2/en not_active Expired - Lifetime
- 2002-09-06 MX MXPA04002418A patent/MXPA04002418A/es active IP Right Grant
- 2002-09-06 KR KR1020047003609A patent/KR100940054B1/ko not_active IP Right Cessation
- 2002-09-06 DE DE60226623T patent/DE60226623D1/de not_active Expired - Lifetime
- 2002-09-06 RU RU2004110934/04A patent/RU2294332C2/ru not_active IP Right Cessation
- 2002-09-06 DK DK02777036T patent/DK1427748T3/da active
- 2002-09-06 EP EP02777036A patent/EP1427748B1/en not_active Expired - Lifetime
- 2002-09-06 WO PCT/EP2002/010041 patent/WO2003022864A1/en active IP Right Grant
- 2002-09-06 JP JP2003526937A patent/JP4471653B2/ja not_active Expired - Fee Related
- 2002-09-06 BR BR0212409-2A patent/BR0212409A/pt not_active IP Right Cessation
- 2002-09-06 CA CA2505575A patent/CA2505575C/en not_active Expired - Lifetime
- 2002-09-10 AR ARP020103415A patent/AR036462A1/es unknown
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2004
- 2004-02-18 IL IL160451A patent/IL160451A/en not_active IP Right Cessation
- 2004-02-26 IS IS7165A patent/IS2555B/is unknown
- 2004-02-26 HR HR20040193A patent/HRP20040193A2/hr not_active Application Discontinuation
- 2004-03-10 NO NO20041010A patent/NO326624B1/no not_active IP Right Cessation
- 2004-03-10 EC EC2004005012A patent/ECSP045012A/es unknown
- 2004-03-11 ZA ZA200401992A patent/ZA200401992B/en unknown
- 2004-08-24 HK HK04106336A patent/HK1063637A1/xx not_active IP Right Cessation
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2008
- 2008-06-19 CY CY20081100653T patent/CY1108152T1/el unknown
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