JP4309761B2 - アンドロゲン依存性疾患の治療を目的とする17βヒドロキシステロイドデヒドロゲナーゼ3型の阻害剤としてのピペリジンアセトアミンおよびピペラジンアセトアミン - Google Patents
アンドロゲン依存性疾患の治療を目的とする17βヒドロキシステロイドデヒドロゲナーゼ3型の阻害剤としてのピペリジンアセトアミンおよびピペラジンアセトアミン Download PDFInfo
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- JP4309761B2 JP4309761B2 JP2003536227A JP2003536227A JP4309761B2 JP 4309761 B2 JP4309761 B2 JP 4309761B2 JP 2003536227 A JP2003536227 A JP 2003536227A JP 2003536227 A JP2003536227 A JP 2003536227A JP 4309761 B2 JP4309761 B2 JP 4309761B2
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- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960002110 vincristine sulfate Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- 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
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- A61P5/00—Drugs for disorders of the endocrine system
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- A61P5/28—Antiandrogens
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Description
本出願は、2001年10月17日に出願された米国仮特許出願第60/330,066号に対する優先権を主張する。
(1.発明の分野)
本発明は、3型17β−ヒドロキシステロイドデヒドロゲナーゼの新規阻害剤、前記化合物を含有する薬学的組成物、アンドロゲン依存性疾患の治療または予防を目的とする前記化合物の使用に関する。
アンドロゲン依存性疾患、例えばその発症または進行がアンドロゲン活性によって促進される疾患はよく知られている。これらの疾患として、限定はしないが、前立腺癌、良性前立腺過形成、アクネ、脂漏症、多毛症、アンドロゲン性脱毛症、早発思春期、副腎過形成、および多嚢胞卵巣症候群が挙げられる。エストロゲン依存性疾患、すなわち、その発症または進行がエストロゲン活性によって促進される疾患もまた、よく知られている。これらとして、限定はしないが、乳癌、子宮内膜症、平滑筋腫および早発思春期が挙げられる。
本発明は、式(I):
R1は、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキルおよびジフェニルアルキルよりなる群から選択され、各々が、
a) ハロゲン;
b) −OCF3または−OCHF2;
c) −CF3;
d) −CN;
e) アルキルまたはR18−アルキル;
f) ヘテロアルキルまたはR18−ヘテロアルキル;
g) アリールまたはR18−アリール;
h) ヘテロアリールまたはR18−ヘテロアリール;
i) アリールアルキルまたはR18−アリールアルキル;
j) ヘテロアリールアルキルまたはR18−ヘテロアリールアルキル;
k) ヒドロキシ;
l) アルコキシ;
m) アリールオキシ;
n) −SO2−アルキル;
o) −NR11R12;
p) −N(R11)C(O)R13;
q) メチレンジオキシ;
r) ジフルオロメチレンジオキシ;
s) トリフルオロアルコキシ;
t) −SCH3または−SCF3;および
u) −SO2CF3または−NHSO2CF3、
よりなる群から選択される1つから6つの基で任意に置換されており;
R2およびR3は、XがNの場合、R2およびR3がそれぞれ−OH、アルコキシ、アリールアルコキシまたはヘテロアリールアルコキシではないという条件で、H、−OH、アルコキシ、アルキル、シクロアルキル、ヘテロシクロアルキル、シクロアルキルアルキル、トリフルオロアルキル、ヘテロアルキル、アリールアルキル、ヘテロアリールアルキル、アリールアルコキシ、ヘテロアリールアルコキシ、−(CH2)n−NR11R12および−(CH2)n−SR11よりなる群からそれぞれ独立して選択され;
R4、R5、R7およびR8は、Zおよび/またはXがNの場合、R4、R5、R7およびR8は、それぞれ−OR14−NR11R12または−N(R11)C(O)R13ではないという条件で、H、−OR14、−NR11R12、−N(R11)C(O)R13、アルキル、アリール、シクロアルキル、アリールアルキル、ヘテロアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクロアルキル、
R6は、−C(O)R15および−SO2R15よりなる群から選択され;
R9およびR10は、ZがNの場合、R9およびR10はそれぞれ、F、ヒドロキシ、アルコキシ、アリールオキシ、−NR11R12または−N(R11)C(O)R13ではないという条件で、H、F、−CF3、−CHF2、アルキル、シクロアルキル、アリールアルキル、ヘテロアルキル、ヘテロアリールアルキル、ヘテロシクロアルキル、ヒドロキシ、アルコキシ、アリールオキシ、−NR11R12、−N(R11)C(O)R13よりなる群から、それぞれ独立して選択され;
R11は、H、アルキル、アリールおよびヘテロアリールよりなる群から選択され;
R12は、H、アルキル、アリールおよびヘテロアリールよりなる群から選択され;
R13は、アルキル、アルコキシおよびアリールオキシよりなる群から選択され;
R14は、H、アルキル、アリールおよびヘテロアリールよりなる群から選択され;
R15は、R18によってそれぞれ任意に置換されている−NR16R17、−OR16、アルキル、シクロアルキル、ヘテロシクロアルキル、アリール、アリールアルキル、およびヘテロアリールアルキルよりなる群から選択され;
R16およびR17は、R15が−OR16の場合、R16はHではないという条件で、それぞれR18およびHによって任意に置換されているアルキル、アリール、アリールアルキル、ヘテロアルキルおよびヘテロアリールよりなる群から、それぞれ独立して選択され;
R18は、低級アルキル、ハロ、シアノ、ニトロ、ハロアルキル、ヒドロキシ、アルコキシ、カルボキシ、カルボキシアルキル、カルボキサミド、メルカプト、アミノ、アルキルアミノ、ジアルキルアミノ、スルホニル、スルホンアミド、アリールおよびヘテロアリールよりなる群からそれぞれ独立して選択される1つから4つの置換基であり;
XおよびZは、CおよびNよりなる群からそれぞれ独立して選択され;そして
nは1〜4である。
他に指示しない限り、本明細書および特許請求の範囲を通して以下の定義が適用される。これらの定義は、用語がそれだけで用いられる場合または他の用語と組合わせて用いられる場合にかかわらず適用される。したがって「アルキル」の定義は、「アルキル」にも、また「アルコキシ」などの「アルキル」部分にも適用される。
「少なくとも1つ」とは、「1つまたはそれ以上」、好ましくは1つから12、より好ましくは1つから6つ、最も好ましくは1つ、2つまたは3つである。
「併用して」とは、同時に、を意味し;そして
「連続的に」とは、複数成分を含む治療法の1つの成分を投与した後に他の成分を投与することを意味する。すなわち、ある成分の投与後、第2の成分を第1の成分の実質的にすぐ後に投与できるか、または第2の成分を第1の成分の投与後、ある効果的な時間をおいてから投与でき、効果的な時間とは、第1の成分の投与から最大利益が認められると考えられる時間量である。
化学療法剤(抗腫瘍剤)として利用できる化合物の種類としては、アルキル化剤、代謝拮抗物質、天然物およびそれらの誘導体、ホルモンとステロイド(合成類似体を含む)および合成物質が挙げられる。これらの種類に入る化合物の例を以下に提供する。
本明細書に用いられる微小管作用剤は、微小管形成および/または微小管の働きに作用することにより、細胞の有糸分裂を妨害する、すなわち、抗有糸分裂作用を有する化合物である。このような薬剤は、例えば、微小管安定化剤または微小管形成を撹乱する薬剤であり得る。
R1は、例えば、フェニルおよび、例えばピリジル、ナフチル(napthyl)、イミダゾリル、チアゾリル、チエニル、ベンゾチエニル、フラニル、ベンゾフラニル、キノリニル、イソキノリニル、およびインドリルなどのヘテロアリールなどのアリールから選択され、各々が、以下の:
a) ハロゲン、例えばCl、F、Br、I;
b) −OCF3;
c) −CF3;
d) −CN;
e) (C1〜C20)アルキルまたはR18−(C1〜C20)アルキル;
f) ヘテロアルキル、例えば、NHR11またはR18−ヘテロアルキル;
g) アリールまたはR18−アリール;
h) ヘテロアリールまたはR18−ヘテロアリール;
i) アリールアルキル、例えば、ベンジル、またはR18−アリールアルキル;
j) ヘテロアリールアルキルまたは;R18−ヘテロアリールアルキル;
k) ヒドロキシ;
l) アルコキシ;
m) アリールオキシ;
n) −SO2−アルキル;
o) −NR11R12;
p) −N(R11)C(O)R13;
q) メチレンジオキシ;
r) ジフルオロメチレンジオキシ;
s) トリフルオロアルコキシ、例えば、−O−(C1〜C20)アルキルCF3;
t) −SCH3;および
u) −SO2CF3;
から選択される1つから6つの基で任意に置換されており;
R4、R5、R7およびR8は、Zおよび/またはXがNの場合、R4、R5、R7およびR8は、それぞれOR14でもNR11R12でもないという条件で、H、アルキル、ヘテロアルキル、アリール、シクロアルキル、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクロアルキル、
R1は、アリールおよびヘテロアリールから選択され、各々が、以下の:
a) ハロゲン;
b) −OCF3;
c) −CF3;
d) トリフルオロアルコキシ;
e) (C1〜C6)アルキルまたはR18−(C1〜C6)アルキル;
f) ヘテロアルキルまたはR18−ヘテロアルキル;
g) アリールまたはR18−アリール;
h) アリールアルキルまたはR18−アリールアルキル;
i) ヘテロアリールアルキルまたは;R18−ヘテロアリールアルキル;および
j) アルコキシ;
から選択される1つから6つの基で任意に置換されており;
R4、R5、R7およびR8は、Zおよび/またはXがNの場合、R4、R5、R7およびR8は、OR14でもNR11R12でもないという条件で、H、−OR14、NR11R12、アルキル、アリール、シクロアルキル、アリールアルキル、ヘテロアルキル、ヘテロアリールアルキル、ヘテロシクロアルキル、
a) ハロゲン;
b) −OCF3;
c) −CF3;
d) アルコキシ;
e) トリフルオロアルコキシ;および
f) (C1〜C6)アルキルまたはR18−(C1〜C6)アルキル;
から選択される1つから6つの基で任意に置換されており;
R2およびR3は、H、アルキルおよびヘテロアルキルからそれぞれ独立して選択され;
R4、R5、R7およびR8は、Zおよび/またはXがNの場合、R4、R5、R7およびR8は、OR14でもNR11R12でもないという条件で、H、アルキル、ヘテロアルキル、アリール、シクロアルキル、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクロアルキル、OR14、NR11R12、
a) ハロゲン;
b) −OCF3;
c) −CF3;
d) アルコキシ;および
e) トリフルオロアルコキシ;
から選択される1つから6つの基で任意に置換されており;
R2はアルキルであり;
R3はHであり;
R4およびR5は、以下のH、(C1〜C6)アルキル、ヘテロアルキル、および
R7は、XがNの場合、R7は、−OR14でもNR11,R12でもないという条件で、H、NR11R12、OR14およびアルキルから選択され;
R8は、それぞれ置換されてもよいH、アルキル、アリールおよびヘテロアリールから選択され;
R11は、Hおよびアルキルから選択され;
ZはCである、
式(I)の化合物がさらによりもっと好ましい。
a) Br、FまたはCl;
b) −OCF3;
c) −CF3;
d) メトキシ;
e) エトキシ;
f) シクロプロピルメトキシ;および
g) −OCH2CF3;
から選択される1つから6つの基で任意に置換されており;
R2は、メチル、エチル、プロピル、シクロプロピルメチルおよびt−ブチルから選択され;
R3はHであり;
R4およびR5は、H、メチル、エチル、イソプロピルおよびt−ブチルからそれぞれ独立して選択され;
R7は、H、OR14およびアルキルから選択され;
R8、R9、R10、R11、R12およびR14は、Hおよびアルキルからそれぞれ独立して選択され;
R13は、アルキルであり;
R15は、NR16R17、OR16およびアルキルから選択され;
R16およびR17は、R15がOR16である場合、R16がHでないという条件でHおよびアルキルからそれぞれ独立して選択され;および
ZはCである、
式(I)の化合物が最も好ましい。
(17β−ヒドロキシステロイドデヒドロゲナーゼ阻害データ)
方法:
ヒト組換え3型17β−ヒドロキシステロイドデヒドロゲナーゼ酵素を調製するために、ヒト17β−HSD3型により安定にトランスフェクションしたHEK−293細胞をコンフルエンシーまで培養し、酵素を得た。単離緩衝液(20mM KH2PO4、1mM EDTA、0.25Mスクロース、1mM PMSF、5μg/ml ペプスタチンA、5μg/ml アンチペインおよび5μg/ml ロイペプチン)中、5.0×106細胞/mlと1.0×107細胞/mlとの間の濃度まで、この細胞を懸濁した。この細胞を、マイクロ超音波細胞撹乱器を用いて40番の設定出力で10秒間の噴射を4回氷上で行って音波処理した。次に破壊された細胞を4℃、100,000×gで60分、遠心分離し、生じたペレットを再懸濁し、ミクロフュージ管に分割し、−80℃で保管した。
表1.0
例示的な化学療法剤の投薬量および投薬レジメン
スキーム1
表1、2欄のアミノ酸類を代わりに用いて、調製実施例1に記載されたものと本質的に同じ手法により、表1、3欄の表題化合物を調製した:
(表1)
調製実施例1〜4からピペラジンジオン(2欄)を代わりに用いて、調製実施例5に記載されたものと本質的に同じ手法により、3欄の化合物を調製した:
(表2)
表3の2欄の市販されているハロゲン化アルキルマグネシウムおよび3欄のアリールアルデヒドを代わりに用いるだけで、調製用実施例15に記載されたものと本質的に同じ手法により、4欄の化合物を調製した。
調製用実施例21に記載されたものと本質的に同じ手法により、表4、3欄の化合物を2欄の対応するアルコール体から調製した。
調製用実施例27に記載されたものと本質的に同じ手法により、表5、3欄の化合物を2欄の対応するアルデヒドから調製した:
(表5)
表7、2欄の化合物を代わりに用いて、調製用実施例46に記載されたものと本質的に同じ手法により、3欄の化合物を調製した(CMPD)。
(実施例100〜102)
表6、2欄の塩化物および3欄のピペラジンを代わりに用いるだけで、調製用実施例41に記載されたものと本質的に同じ手法により、4欄の生成物を調製した。
表8、2欄に示された調製用実施例47〜54を代わりに用いるだけで、実施例103に記載されたものと本質的に同じ手法により、3欄に示された化合物を調製した:
(表8)
表9、2欄に示された調製用実施例47、49〜50および53〜54の生成物を代わりに用いるだけで、実施例112に記載されたものと本質的に同じ手法により、3欄(CMPD)に示された化合物を調製した:
(表9)
Claims (9)
- 式(I):
R1は、
a) Br、F、またはCl;
b) −OCF3 ;
c) −CF3;
d) メトキシ、エトキシまたはシクロプロピルメトキシ;および
e) −OCH 2 CF 3
よりなる群から選択される1つから6つの基で任意に置換されているフェニルおよびピリジルよりなる群から選択され;
R2 は、メチル、エチル、プロピル、シクロプロピルメチルおよびt−ブチルよりなる群から選択され;
R 3 は、Hであり;
R4 およびR5 は、H、メチル、エチル、イソプロピルおよびt−ブチルよりなる群からそれぞれ独立して選択され;
R6は、−C(O)R15および−SO2R15よりなる群から選択され;
R 7 は、H、−OR 14 、およびアルキルよりなる群から選択され;
R 8 、R9 、R10、R 11 、R 12 、およびR 14 は、Hおよびアルキルよりなる群から、それぞれ独立して選択され;
R13は、アルキルであり;
R15は、−NR16R17、−OR16、およびアルキルよりなる群から選択され;
R16およびR17は、Hおよびアルキルよりなる群から、それぞれ独立して選択され;
Xは、CおよびNよりなる群から各々独立して選択され;および
ZはCである、
化合物。
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US33006601P | 2001-10-17 | 2001-10-17 | |
PCT/US2002/032979 WO2003033487A1 (en) | 2001-10-17 | 2002-10-15 | Piperidine- and piperazineacetamines as 17beta hydroxysteroid dehydrogenase type 3 inhibitors for the treatment of androgen dependent diseases |
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JP4309761B2 true JP4309761B2 (ja) | 2009-08-05 |
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US (1) | US6969718B2 (ja) |
EP (1) | EP1436281B1 (ja) |
JP (1) | JP4309761B2 (ja) |
CN (1) | CN1571782A (ja) |
AR (1) | AR036812A1 (ja) |
AT (1) | ATE471315T1 (ja) |
CA (1) | CA2463626C (ja) |
DE (1) | DE60236743D1 (ja) |
ES (1) | ES2347643T3 (ja) |
MX (1) | MXPA04003611A (ja) |
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WO (1) | WO2003033487A1 (ja) |
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TW201512215A (zh) | 2013-06-25 | 2015-04-01 | Forendo Pharma Ltd | 治療活性雌三烯噻唑衍生物 |
TN2015000555A1 (en) | 2013-06-25 | 2017-04-06 | Forendo Pharma Ltd | Therapeutically active 17-nitrogen substituted estratrienthiazole derivatives as inhibitors of 17.beta.-hydroxysteroid dehydrogenase |
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CN107207561B (zh) | 2014-12-23 | 2020-03-31 | 佛恩多制药有限公司 | 17β-HSD1–抑制剂的前药 |
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CN1571782A (zh) | 2005-01-26 |
PE20030705A1 (es) | 2003-08-21 |
JP2005506356A (ja) | 2005-03-03 |
AR036812A1 (es) | 2004-10-06 |
US20030232837A1 (en) | 2003-12-18 |
ATE471315T1 (de) | 2010-07-15 |
US6969718B2 (en) | 2005-11-29 |
EP1436281A1 (en) | 2004-07-14 |
DE60236743D1 (de) | 2010-07-29 |
CA2463626C (en) | 2011-05-24 |
MXPA04003611A (es) | 2004-07-30 |
EP1436281B1 (en) | 2010-06-16 |
CA2463626A1 (en) | 2003-04-24 |
ES2347643T3 (es) | 2010-11-03 |
WO2003033487A1 (en) | 2003-04-24 |
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