JP4694529B2 - 選択的アンドロゲン受容体調節剤及びその使用方法 - Google Patents
選択的アンドロゲン受容体調節剤及びその使用方法 Download PDFInfo
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- JP4694529B2 JP4694529B2 JP2007121464A JP2007121464A JP4694529B2 JP 4694529 B2 JP4694529 B2 JP 4694529B2 JP 2007121464 A JP2007121464 A JP 2007121464A JP 2007121464 A JP2007121464 A JP 2007121464A JP 4694529 B2 JP4694529 B2 JP 4694529B2
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- QTVIMMQJFZSVSB-YJYWNOLNSA-N C/C(/C=N)=C/NC Chemical compound C/C(/C=N)=C/NC QTVIMMQJFZSVSB-YJYWNOLNSA-N 0.000 description 1
- UTKUVRNVYFTEHF-UHFFFAOYSA-N Nc(cc1)cc(C(F)(F)F)c1[N+]([O-])=O Chemical compound Nc(cc1)cc(C(F)(F)F)c1[N+]([O-])=O UTKUVRNVYFTEHF-UHFFFAOYSA-N 0.000 description 1
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Description
ただし、Xは、O、CH2、NH、Se、PR、NO又はNRであり、
Tは、OH、OR、NHCOCH3又はNHCORであり、
Zは、CN、COOH、COR、NHCOR又はCONHRであり、
Yは、CF3、I、Br、Cl、CN、CR3又はSnR3である。
Rは、アルキル、ハロアルキル、ジハロアルキル、トリハロアルキル、CH2F、CHF2、CF3、CF2CF3、アリル、フェニル、F、Cl、Br、I、アルケニル又はOHであり、
R1は、CH3、CH2F、CHF2、CF3、CH2CH3又はCF2CF3である。
ただし、Xは、O、CH2、NH、Se、PR、NO又はNRであり、
Tは、OH、OR、NHCOCH3又はNHCORであり、
Zは、H、F、Cl、Br又はIであり、
Yは、CF3、I、Br、Cl、CN、CR3又はSnR3であり、
Qは、アルキル、F、I、Br、Cl、CF3、CN、CR3、SnR3、NR2、NHCOCH3、NHCOCF3、NHCOR、NHCONH2、NHCONHR、NHCONR2、NHCOOR、OCONHR、CONHR、NHCSCH3、NHCSCF3、NHCSR、NHCSNH2、NHCSNHR、NHCSR2、NHSO2CH3、NHSO2R、OR、COR、OCOR、OSO2R、SO2R又はSRである。或いは、Qは、次の化学構造式A、B又はCで表される縮合環システムと結合するようなものからなる。
Rは、アルキル、ハロアルキル、ジハロアルキル、トリハロアルキル、CH2F、CHF2、CF3、CF2CF3、アリル、フェニル、F、Cl、Br、I、アルケニル又はOHであり、
R1は、CH3、CH2F、CHF2、CF3、CH2CH3又はCF2CF3である。
ただし、Xは、O、CH2、NH、Se、PR、NO又はNRであり、
Tは、OH、OR、NHCOCH3又はNHCORであり、
Zは、NO2、CN、COOH、COR、NHCOR又はCONHRであり、
Yは、CF3、I、Br、Cl、CN、CR3又はSnR3である。
Rは、アルキル、ハロアルキル、ジハロアルキル、トリハロアルキル、CH2F、CHF2、CF3、CF2CF3、アリル、フェニル、F、Cl、Br、I、アルケニル又はOHであり、
R1は、CH3、CH2F、CHF2、CF3、CH2CH3又はCF2CF3である。
(ただし、QがFのときは、ZはNO2ではないという条件付である)。
ただし、Xは、O、CH2、NH、Se、PR、NO又はNRであり、
Tは、OH、OR、NHCOCH3又はNHCORであり、
Zは、H、F、Cl、Br又はIであり、
Yは、CF3、I、Br、Cl、CN、CR3又はSnR3であり、
Qは、アルキル、F、I、Br、Cl、CF3、CN、CR3、SnR3、NR2、NHCOCH3、NHCOCF3、NHCOR、NHCONH2、NHCONHR、NHCONR2、NHCOOR、OCONHR、CONHR、NHCSCH3、NHCSCF3、NHCSR、NHCSNH2、NHCSNHR、NHCSR2、NHSO2CH3、NHSO2R、OR、COR、OCOR、OSO2R、SO2R又はSRである。或いは、Qは、次の化学構造式A、B又はCで表される縮合環システムと結合するようなものからなる。
Rは、アルキル、ハロアルキル、ジハロアルキル、トリハロアルキル、CH2F、CHF2、CF3、CF2CF3、アリル、フェニル、F、Cl、Br、I、アルケニル又はOHであり、
R1は、CH3、CH2F、CHF2、CF3、CH2CH3又はCF2CF3である。
ただし、Xは、O、CH2、NH、Se、PR、NO又はNRであり、
Tは、OH、OR、NHCOCH3又はNHCORであり、
Zは、NO2、CN、COOH、COR、NHCOR又はCONHRであり、
Yは、F、Cl、Br又はIであり、
Qは、F、Cl、Br又はIであり、
Rは、アルキル、ハロアルキル、ジハロアルキル、トリハロアルキル、CH2F、CHF2、CF3、CF2CF3、アリル、フェニル、F、Cl、Br、I、アルケニル又はOHであり、
R1は、CH3、CH2F、CHF2、CF3、CH2CH3又はCF2CF3である。
ただし、Xは、O、CH2、NH、Se、PR、NO又はNRであり、
Tは、OH、OR、NHCOCH3又はNHCORであり、
Zは、H、F、I、Br、Cl、NO2、CN、COOH、COR、NHCOR又はCONHRであり、
Yは、CF3、F、I、Br、Cl、CN、CR3又はSnR3である。
Rは、アルキル、ハロアルキル、ジハロアルキル、トリハロアルキル、CH2F、CHF2、CF3、CF2CF3、アリル、フェニル、F、Cl、Br、I、アルケニル又はOHであり、
R1は、CH3、CH2F、CHF2、CF3、CH2CH3又はCF2CF3である。
ここでは、置換基Rは、アルキル、ハロアルキル、ジハロアルキル、トリハロアルキル、CH2F、CHF2、CF3、CF2CF3、アリル、フェニル、F、Cl、Br、I、アルケニル、又はヒドロキシル(OH)基と定義する。
選択型アンドロゲン調節剤化合物は、前述した次の(a)〜(g)に有効なアンドロゲン受容体標的物質(androgen receptor targeting agent:ARTA)の新しい種類である。(a)男性の避妊。(b)様々なホルモンに関連する病気(例えば、高齢男性におけるアンドロゲン減少(Androgen Decline in Aging Male:ADAM)に関連する病気)の治療。ADAMに関連する病気としては、例えば、けん怠感、憂うつ、性欲減退、性的不全、勃起不全、性腺機能低下症、骨粗鬆症、脱毛症、肥満、筋肉減少症、骨減少症、良性前立腺肥大症、気分・認識力の変調、及び前立腺癌などがある。(c)女性におけるアンドロゲン減少(Androgen Decline in Female:ADIF)に関連する病気の治療。ADIFに関連する病気としては、例えば、性的不全、性欲減退、性腺機能低下症、筋肉減少症、骨減少症、骨粗鬆症、気分・認識力の変調、貧血、憂うつ、脱毛症、肥満、子宮内膜症、乳ガン、子宮癌、及び卵巣癌などがある。(d)急性及び/又は慢性の筋萎縮症の治療及び/又は予防。(e)ドライアイの治療及び/又は予防。(f)経口アンドロゲン補充療法。(g)前立腺癌の発病率の減少、又は前立腺癌の停止又は退行。(h)癌細胞のアポトーシスの促進。
本発明に係る治療方法は、一実施形態では、SARM化合物、及び/又はその類似体、誘導体、異性体、代謝産物、薬学的に許容される塩、医薬品、水和物、N酸化物、プロドラッグ、多形体、結晶或いはこれらの任意の組み合わせと、薬学的に許容される担体とを含んでいる医薬組成物を投与する過程を含む。
選択する環BがF、Cl、Br又はI化されたSARMの結合親和力を表1に示す。
動物について。体重90〜100gの未成熟なオスのSD(Sparague-Dawley)ラットを米国インディアナポリス州のハーラン・バイオサイエンス社(Harlan Biosciences; Indianapolis, IN)から購入した。動物は、食料と水を適宜与えながら12時間の明暗サイクルで飼育された。動物実験計画書は、研究機関内の動物の管理及び使用に関する委員会(Institutional Laboratory Animal Care and Use Committee)によって審査及び承認されたものである。
去勢ラットモデルについて、化合物1〜4のアンドロゲン活性及びタンパク同化作用を、投与した14日後に調べた。結果を無損傷対照(去勢されていない、未治療)の割合として図1に示す。0mg/日は、去勢対照(去勢されている、未治療)である。
選択する化合物5の結合親和力を表2に示す。
選択する化合物6の結合親和力を表4に示す。
他のSARM化合物のインビトロアンドロゲン受容体結合親和力が研究された。その結果を表5に示す。
ラット中の4つの非ステロイド性アンドロゲン(化合物1、21、22、23)のインビボ有効性及び急性毒性が調べられた。インビトロでの分析は、これらの化合物が非常に高い親和力でアンドロゲン受容体を結合することを証明した。4つの化合物の構造及び名称を以下に示す。
化合物1 R=F
化合物21 R=NHCOCH
化合物22 R=COCH3
化合物23 R=COC2H5
材料について。化合物1、21、22、23のS異性体と化合物1のR異性体は、図7に示したスキームに基づいて合成された。プロピオン酸テストステロン(TP)、ポリエチレングリコール300(PEG300、試薬等級)及び中性緩衝ホルマリン(10%w/v)は、シグマケミカル社(Sigma Chemical Company; St Louis, MO)から購入した。アルゼット浸透圧ポンプ(2002年モデル)は、アルザ社(Alza Corp; Palo Alto, CA)から購入した。
去勢ラットモデル中の化合物1、21、22、23のS異性体と化合物1のR異性体のアンドロゲン活性及びタンパク同化作用は、与薬の14日後に調べられた。プロピオン酸テストステロンは、投与量を増加しながら投与され、アンドロゲン活性及びタンパク同化作用効果の陽性対照として用いられた。
(2R)−1−メタクリロイルピロリジン−2−カルボン酸((2R)-1-Methacryloylpyrrolidin-2-carboxylic Acid)(R−129)。D−プロリン(R−128、14.93g、0.13mol)を71mLの2 N NaOHに溶解し、氷浴で冷却し、結果として得られたアルカリ溶液をアセトン(71mL)で希釈した。氷浴においてD−プロリンの水溶液に塩化メタクリロイル127のアセトン溶液(71mL)(13.56g、0.13mol)と2N NaOH溶液(71mL)とを40分間同時に加えた。混合物のpHは、塩化メタクリロイルを加える間は10〜11℃で維持した。撹拌(3時間、室温)後、混合物を温度35〜45℃で真空蒸発させ、アセトンを除去した。得られた溶液をエチルエーテルで洗浄し、濃縮HClでpH=2まで酸性化した。酸性混合物は、NaClで飽和させ、EtOAc(100mL×3)で抽出した。複合抽出物をNa2SO4で乾燥させ、セライトでろ過し、真空で蒸発させ、無色油として粗生成物を得た。エチルエーテル及びヘキサンからの油の再結晶は、16.2(68%)の所望の化合物を無色結晶として産出した。mp 102-103℃ (lit. [214] mp 102.5-103.5℃);この化合物のNMRスペクトルは、題記化合物に2つの回転異性体が存在することを証明した。1H NMR (300 MHz, DMSO-d6)δ5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (totally 1H for both rotamers, CH at the chiral canter), 3.57-3.38 (m, 2H, CH2), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH2, CH, Me); 13C NMR (75MHz, DMSO-d6)δfor major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C=O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm-1; [α]D 26+80.8°(c = 1, MeOH); Anal. Calcd. for C9H13NO3: C 59.00, H 7.15, N 7.65. Found: C 59.13, H 7.19, N 7.61.
Claims (16)
- 前記ADIFに関連する病気が、性的不全、性欲減退、性腺機能低下症、筋肉減少症、骨減少症、骨粗鬆症、気分・認識力の変調、貧血、憂うつ、脱毛症、肥満、子宮内膜症、乳ガン、子宮癌、及び卵巣癌を含むことを特徴とする請求項1に記載の医薬組成物。
- ADIF(女性におけるアンドロゲン減少)に関連する病気の治療のための医薬組成物であって、次の化学構造式IIbで表される選択的アンドロゲン受容体調節剤(SARM)化合物を含むことを特徴とする医薬組成物。
ただし、Xは、Oであり、
Zは、H、F、Cl、Br又はIであり、
Yは、CF3、I、Br、Cl、CN、C(R)3又はSn(R)3であり、
Qは、アルキル、F、I、Br、Cl、CF3、CN、C(R)3、Sn(R)3、N(R)2、NHCOCH3、NHCOCF3、NHCOR、NHCONH2、NHCONHR、NHCONR2、NHCOOR、OCONHR、CONHR、NHCSCH3、NHCSCF3、NHCSR、NHCSNH2、NHCSNHR、NHCS(R)2、NHSO2CH3、NHSO2R、OR、COR、OCOR、OSO2R、SO2R又はSRである。或いは、Qは、次の化学構造式A、B又はCで表される縮合環システムと結合するようなものからなり、
Rは、アルキル、ハロアルキル、ジハロアルキル、トリハロアルキル、CH2F、CHF2、CF3、CF2CF3、アリル、フェニル、F、Cl、Br、I、アルケニル又はOHである。 - 前記ADIFに関連する病気が、性的不全、性欲減退、性腺機能低下症、筋肉減少症、骨減少症、骨粗鬆症、気分・認識力の変調、貧血、憂うつ、脱毛症、肥満、子宮内膜症、乳ガン、子宮癌、及び卵巣癌を含むことを特徴とする請求項7に記載の医薬組成物。
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