JP4580932B2 - 有糸分裂キネシン阻害剤のプロドラッグ - Google Patents
有糸分裂キネシン阻害剤のプロドラッグ Download PDFInfo
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- JP4580932B2 JP4580932B2 JP2006533588A JP2006533588A JP4580932B2 JP 4580932 B2 JP4580932 B2 JP 4580932B2 JP 2006533588 A JP2006533588 A JP 2006533588A JP 2006533588 A JP2006533588 A JP 2006533588A JP 4580932 B2 JP4580932 B2 JP 4580932B2
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- alkyl
- dihydro
- phenyl
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Description
aは、0又は1であり;
bは、0又はlであり;
mは、0、1又は2であり;
nは、0又はlであり;
rは、0又はlであり;
sは、0又はlであり;
uは、2、3、4又は5であり;
破線は、必要に応じて存在する二重結合を表し(但し、環には、二重結合が一つだけ存在する。);
R1は、
1)(C1−C6−アルキレン)n(C=X)C1−C10アルキル、
2)(C1−C6−アルキレン)n(C=X)アリール、
3)(C1−C6−アルキレン)n(C=X)C2−C10アルケニル、
4)(C1−C6−アルキレン)n(C=X)C2−C10アルキニル、
5)(C1−C6−アルキレン)n(C=X)C3−C8シクロアルキル、
6)(C1−C6−アルキレン)n(C=X)ヘテロシクリル、
7)(C1−C6−アルキレン)n(C=X)NRcRc’、
8)(C1−C6−アルキレン)nSO2NRRcRc’、
9)(C1−C6−アルキレン)nSO2C1−C10アルキル、
10)(C1−C6−アルキレン)nSO2C2−C10アルケニル、
11)(C1−C6−アルキレン)nSO2C2−C10アルキニル、
12)(C1−C6−アルキレン)nSO2−アリール、
13)(C1−C6−アルキレン)nSO2−ヘテロシクリル、
14)(C1−C6−アルキレン)nSO2−C3−C8シクロアルキル、
15)(C1−C6−アルキレン)nP(=O)RdRd’、
16)アリール、
17)ヘテロシクリル、及び
18)C1−C10アルキル、
から選択され;
前記アルキル、アリール、アルケニル、アルキニル、シクロアルキル、アルキレン、ヘテロアリール及びヘテロシクリルは、R10から選択される一又は複数の置換基で必要に応じて置換され;
R2及びR6は、
1)アリール
2)C1−C6アラルキル、
3)C3−C8シクロアルキル、及び
4)ヘテロシクリル、
から独立に選択され;
前記アリール、シクロアルキル、アラルキル及びヘテロシクリルは、R10から選択される一又は複数の置換基で必要に応じて置換され;
R3、R4、R5、R7、R8及びR9は、
1)H、
2)C1−C10アルキル、
3)アリール、
4)C2−C10アルケニル、
5)C2−C10アルキニル、
6)C1−C6ペルフルオロアルキル、
7)C1−C6アラルキル、
8)C3−C8シクロアルキル、及び
9)ヘテロシクリル、
から独立に選択され;
前記アルキル、アリール、アルケニル、アルキニル、シクロアルキル、アラルキル及びヘテロシクリルは、R10から選択される一又は複数の置換基で必要に応じて置換され;又は
同一の炭素原子に結合したR4及びR5又はR8及びR9は両者で、−(CH2)u−を形成し、炭素原子の一つが、O、S(O)m、−N(Ra)C(O)−、−N(Rb)及び−N(CORa)−から選択される部分によって必要に応じて置換されており;
R10 は、
1)(C=O)aObC1−C10アルキル、
2)(C=O)aObアリール、
3)C2−C10アルケニル、
4)C2−C10アルキニル、
5)(C=O)aObヘテロシクリル、
6)CO2H、
7)ハロ、
8)CN、
9)OH、
10)ObC1−C6ペルフルオロアルキル、
11)Oa(C=O)bNR12R13、
12)S(O)mRa、
13)S(O)2NR12R13、
14)オキソ、
15)CHO、
16)(N=O)R12R13、
17)(C=O)aObC3−C8シクロアルキル、及び
18)−OPO(OH)2;
から独立に選択され;
前記アルキル、アリール、アルケニル、アルキニル、ヘテロシクリル及びヘテロアルキルは、R11から選択される一又は複数の置換基で必要に応じて置換され;
R11は、
1)(C=O)rOs(C1−C10)アルキル、
2)Or(C1−C3)ペルフルオロアルキル、
3)(C0−C6)アルキレン−S(O)mRa、
4)オキソ、
5)OH、
6)ハロ、
7)CN、
8)(C=O)rOs(C2−C10)アルケニル、
9)(C=O)rOs(C2−C10)アルキニル、
10)(C=O)rOs(C3−C6)シクロアルキル、
11)(C=O)rOs(C0−C6)アルキレン−アリール、
12)(C=O)rOs(C0−C6)アルキレン−ヘテロシクリル、
13)(C=O)rOs(C0−C6)アルキレン−N(Rb)2、
14)C(O)Ra、
15)(C0−C6)アルキレン−CO2Ra、
16)C(O)H、
17)(C0−C6)アルキレン−CO2H、
18)C(O)N(Rb)2、
19)S(O)mRa、
20)S(O)2N(Rb)2、及び
21)−OPO(OH)2;
から選択され;
前記アルキル、アルケニル、アルキニル、シクロアルキル、アリール、アルキレン及びヘテロシクリルは、Rb、OH、(C1−C6)アルコキシ、ハロゲン、CO2H、CN、O(C=O)C1−C6アルキル、オキソ及びN(Rb)2から選択される最大三個の置換基で必要に応じて置換されており;
R12及びR13は、
1)H、
2)(C=O)ObC1−C10アルキル、
3)(C=O)ObC3−C8シクロアルキル、
4)(C=O)Obアリール、
5)(C=O)Obヘテロシクリル、
6)C1−C10アルキル、
7)アリール、
8)C2−C10アルケニル、
9)C2−C10アルキニル、
10)ヘテロシクリル、
11)C3−C8シクロアルキル、
12)SO2Ra、及び
13)(C=O)NRb 2、
から独立に選択され;
前記アルキル、シクロアルキル、アリール、ヘテロシクリル、アルケニル及びアルキニルは、R11から選択される一又は複数の置換基で必要に応じて置換され;又は
R12及びR13は、それらが結合している窒素とともに、各環が3員から7員を有し、N、O及びSから選択される1又は2個の追加の複素原子を前記窒素の他に必要に応じて含有する単環式又は二環式複素環を形成することができ、前記単環式又は二環式複素環は、R11から選択される一又は複数の置換基で必要に応じて置換されており;
R14は、
1)(C=O)aObC1−C10アルキル、
2)(C=O)aObアリール、
3)C2−C10アルケニル、
4)C2−C10アルキニル、
5)(C=O)aObヘテロシクリル、
6)CO2H、
7)ハロ
8)CN、
9)OH、
10)ObCl−C6ペルフルオロアルキル、
11)Oa(C=O)bNR12R13、
12)S(O)mRa、
13)S(O)2NR12R13、
14)オキソ、
15)CHO、
16)(N=O)R12R13、
17)(C=O)aObC3−C8シクロアルキル、及び
18)−OPO(OH)2;
から独立に選択され;
前記アルキル、アリール、アルケニル、アルキニル、ヘテロシクリル及びシクロアルキルは、R11から選択される一又は複数の置換基で必要に応じて置換され;
Raは、R14から選択される1から3個の置換基で必要に応じて置換された、(Cl−C6)アルキル、(C3−C6)シクロアルキル、アリール又はヘテロシクリルであり、
Rbは、H、R14から選択される1から3個の置換基で必要に応じて置換された、(Cl−C6)アルキル、アリール、ヘテロシクリル、(C3−C6) シクロアルキル、(C=O)OCl−C6アルキル、(C=O)Cl−C6アルキル又はS(O)2Raであり、
Rc及びRc’は、H、R10から選択される1、2又は3個の置換基で必要に応じて置換された、Cl−C6アルキル、アリール、ヘテロシクリル及び(C3−C6) シクロアルキルから独立に選択され、又は
RC及びRc’は、それらが結合している窒素とともに、各環中に3から7員を有し、前記窒素の他に、N、O及びSから選択される1又は2個の追加の複素原子を必要に応じて含有する単環式若しくは二環式複素環を形成することができ、前記単環式若しくは二環式複素環は、R11から選択される1、2又は3個の置換基で必要に応じて置換されており;
Rd及びRd’は、(Cl−C6)アルキル、(Cl−C6)アルコキシ及びNRb 2から独立に選択され、又は
Rd及びRd’は、それらが結合しているリンとともに、前記リンの他に、NRe、O及びSから選択される1又は2個の追加の複素原子を必要に応じて含有する、5から7員環の単環式複素環を形成することができ、前記単環式複素環は、R11から選択される1、2又は3個の置換基で必要に応じて置換されており;
Reは、H及び(Cl−C6)アルキルから選択され;並びに
Xは、O、NRe及びSから選択され;
但し、少なくとも1つの置換基−OPO(OH)2が式Iの化合物中に存在する。)
aは、0又は1であり;
bは、0又はlであり;
mは、0、1又は2であり;
nは、0又はlであり;
rは、0又はlであり;
sは、0又はlであり;
破線は、必要に応じて存在する二重結合を表し(但し、環には、二重結合が一つだけ存在する。);
R1は、
1)(C1−C6−アルキレン)n(C=O)C1−C10アルキル、
2)(C1−C6−アルキレン)n(C=O)アリール、
3)(C1−C6−アルキレン)n(C=O)C2−C10アルケニル、
4)(C1−C6−アルキレン)n(C=O)C2−C10アルキニル、
5)(C1−C6−アルキレン)n(C=O)C3−C8シクロアルキル、
6)(C1−C6−アルキレン)n(C=O)ヘテロシクリル、
7)(C1−C6−アルキレン)n(C=O)NRcRc’、
8)(C1−C6−アルキレン)nSO2NRcRc’、
9)(C1−C6−アルキレン)nSO2C1−C10アルキル、
10)(C1−C6−アルキレン)nSO2−アリール、
11)(C1−C6−アルキレン)nSO2−ヘテロシクリル、
12)(C1−C6−アルキレン)nSO2−C3−C8シクロアルキル、
13)(C1−C6−アルキレン)nP(=O)RdRd’、
14)アリール、
15)ヘテロシクリル、及び
16)C1−C10アルキル、
から選択され;
前記アルキル、アリール、アルケニル、アルキニル、シクロアルキル、アルキレン、ヘテロアリール及びヘテロシクリルは、R10から選択される一又は複数の置換基で必要に応じて置換され;
R2及びR6は、
1)アリール
2)C1−C6アラルキル、
3)C3−C8シクロアルキル、及び
4)ヘテロシクリル、
から独立に選択され;
前記アリール、シクロアルキル、アラルキル及びヘテロシクリルは、R10から選択される一又は複数の置換基で必要に応じて置換され;
R3、R4及びR8は、
1)H、
2)C1−C10アルキル、
3)アリール、
4)C2−C10アルケニル、
5)C2−C10アルキニル、
6)C1−C6ペルフルオロアルキル、
7)C1−C6アラルキル、
8)C3−C8シクロアルキル、及び
9)ヘテロシクリル、
から独立に選択され;
前記アルキル、アリール、アルケニル、アルキニル、シクロアルキル、アラルキル及びヘテロシクリルは、R10から選択される一又は複数の置換基で必要に応じて置換され;
R10 は、
1)(C=O)aObC1−C10アルキル、
2)(C=O)aObアリール、
3)C2−C10アルケニル、
4)C2−C10アルキニル、
5)(C=O)aObヘテロシクリル、
6)CO2H、
7)ハロ、
8)CN、
9)OH、
10)ObC1−C6ペルフルオロアルキル、
11)Oa(C=O)bNR12R13、
12)S(O)mRa、
13)S(O)2NR12R13、
14)オキソ、
15)CHO、
16)(N=O)R12R13、
17)(C=O)aObC3−C8シクロアルキル、及び
18)−OPO(OH)2;
から独立に選択され;
前記アルキル、アリール、アルケニル、アルキニル、ヘテロシクリル及びシクロアルキルは、R11から選択される1、2又は3個の置換基で必要に応じて置換され;
R11は、
1)(C=O)rOs(C1−C10)アルキル、
2)Or(C1−C3)ペルフルオロアルキル、
3)オキソ、
4)OH、
5)ハロ、
6)CN、
7)(C2−C10)アルケニル、
8)(C2−C10)アルキニル、
9)(C=O)rOs(C3−C6)シクロアルキル、
10)(C=O)rOs(C0−C6)アルキレン−アリール、
11)(C=O)rOs(C0−C6)アルキレン−ヘテロシクリル、
12)(C=O)rOs(C0−C6)アルキレン−N(Rb)2、
13)C(O)Ra、
14)(C0−C6)アルキレン−CO2Ra、
15)C(O)H、
16)(C0−C6)アルキレン−CO2H、及び
17)C(O)N(Rb)2、
18)S(O)mRa、
19)S(O)2N(Rb)2、及び
20)−OPO(OH)2、
から選択され;
前記アルキル、アルケニル、アルキニル、シクロアルキル、アリール、アルキレン及びヘテロシクリルは、Rb、OH、(C1−C6)アルコキシ、ハロゲン、CO2H、CN、O(C=O)C1−C6アルキル、オキソ及びN(Rb)2から選択される最大三個の置換基で必要に応じて置換されており;
R12及びR13は、
1)H、
2)(C=O)ObC1−C10アルキル、
3)(C=O)ObC3−C8シクロアルキル、
4)(C=O)Obアリール、
5)(C=O)Obヘテロシクリル、
6)C1−C10アルキル、
7)アリール、
8)C2−C10アルケニル、
9)C2−C10アルキニル、
10)ヘテロシクリル、
11)C3−C8シクロアルキル、
12)SO2Ra、及び
13)(C=O)NRb 2、
から独立に選択され;
前記アルキル、シクロアルキル、アリール、ヘテロシクリル、アルケニル及びアルキニルは、R11から選択される1、2又は3個の置換基で必要に応じて置換され;又は
R12及びR13は、それらが結合している窒素とともに、各環が5員から7員を有し、N、O及びSから選択される1又は2個の追加の複素原子を前記窒素の他に必要に応じて含有する単環式又は二環式複素環を形成することができ、前記単環式又は二環式複素環は、R11から選択される1、2又は3個の置換基で必要に応じて置換されており;
Raは、(Cl−C6)アルキル、(C3−C6)シクロアルキル、アリール又はヘテロシクリルであり、
Rbは、H、(Cl−C6)アルキル、アリール、ヘテロシクリル、(C3−C6)シクロアルキル、(C=O)O、C1−C6アルキル、(C=O)C1−C6アルキル又はS(O)2Raであり、
Rc及びRc’は、H、(Cl−C6)アルキル、アリール、ヘテロシクリル及び(C3−C6) シクロアルキルから独立に選択され、又は
Rc及びRc’は、それらが結合している窒素とともに、各環中に5から7員を有し、前記窒素の他に、N、O及びSから選択される1又は2個の追加の複素原子を必要に応じて含有する単環式若しくは二環式複素環を形成することができ、前記単環式若しくは二環式複素環は、R11から選択される1、2又は3個の置換基で必要に応じて置換されており;
Rd及びRd’は、(Cl−C6)アルキル、(Cl−C6)アルコキシ及びNRb2から独立に選択され、又は
Rd及びRd’は、それらが結合しているリンとともに、前記リンの他に、NRe、O及びSから選択される1又は2個の追加の複素原子を必要に応じて含有する、5から7員環の単環式複素環を形成することができ、前記単環式複素環は、R11から選択される1、2又は3個の置換基で必要に応じて置換されており;
Reは、H及び(Cl−C6)アルキルから選択され;
但し、少なくとも1つの置換基−OPO(OH)2が式IIの化合物中に存在する。)
式IIIの化合物、又は、薬学的に許容されるその塩若しくは立体異性体によって表される。
aは、0又は1であり;
bは、0又はlであり;
mは、0、1又は2であり;
rは、0又はlであり;
sは、0又はlであり;
R1は、
1)(C=O)C1−C10アルキル、
2)(C=O)アリール、
3)(C=O)C3−C8シクロアルキル、
4)(C=O)ヘテロシクリル、
5)(C=O)NRcRc’、
6)(C=S)NRcRc’、
7)SO2NRcRc’、
8)SO2C1−C10アルキル、
9)SO2−アリール、及び
10)SO2−ヘテロシクリル、
から選択され;
前記アルキル、アリール、シクロアルキル及びヘテロシクリルは、R10から選択される一又は複数の置換基で必要に応じて置換され;又は
R3、R4及びR8は、
1)H、
2)C1−C10アルキル、及び
3)C1−C6ペルフルオロアルキル、
から独立に選択され;
前記アルキルは、R10から選択される一又は複数の置換基で必要に応じて置換され;
R10 及びR10bは、
1)(C=O)aObC1−C10アルキル、
2)(C=O)aObアリール、
3)C2−C10アルケニル、
4)C2−C10アルキニル、
5)(C=O)aObヘテロシクリル、
6)CO2H、
7)ハロ、
8)CN、
9)OH、
10)ObC1−C6ペルフルオロアルキル、
11)Oa(C=O)bNR12R13、
12)S(O)mRa、
13)S(O)2NR12R13、
14)オキソ、
15)CHO、
16)(N=O)R12R13、
17)(C=O)aObC3−C8シクロアルキル、及び
18)−OPO(OH)2;
から独立に選択され;
前記アルキル、アリール、アルケニル、アルキニル、ヘテロシクリル及びシクロアルキルは、R11から選択される1、2又は3個の置換基で必要に応じて置換され;
R10aは、ハロゲンであり;
R11は、
1)(C=O)rOsC(C1−C10)アルキル、
2)Or(C1−C3)ペルフルオロアルキル、
3)オキソ、
4)OH、
5)ハロ、
6)CN、
7)(C2−C10)アルケニル、
8)(C2−C10)アルキニル、
9)(C=O)rOs(C3−C6)シクロアルキル、
10)(C=O)rOs(C0−C6)アルキレン−アリール、
11)(C=O)rOs(C0−C6)アルキレン−ヘテロシクリル、
12)(C=O)rOs(C0−C6)アルキレン−N(Rb)2、
13)C(O)Ra、
14)(C0−C6)アルキレン−CO2Ra、
15)C(O)H、
16)(C0−C6)アルキレン−CO2H、
17)C(O)N(Rb)2、
18)S(O)mRa、
19)S(O)2N(Rb)2、及び
20)−OPO(OH)2、
から選択され;
前記アルキル、アルケニル、アルキニル、シクロアルキル、アリール及びヘテロシクリルは、Rb、OH、(C1−C6)アルコキシ、ハロゲン、CO2H、CN、O(C=O)C1−C6アルキル、オキソ及びN(Rb)2から選択される最大三個の置換基で必要に応じて置換されており;
R12及びR13は、
1)H、
2)(C=O)ObC1−C10アルキル、
3)(C=O)ObC3−C8シクロアルキル、
4)(C=O)Obアリール、
5)(C=O)Obヘテロシクリル、
6)C1−C10アルキル、
7)アリール、
8)C2−C10アルケニル、
9)C2−C10アルキニル、
10)ヘテロシクリル、
11)C3−C8シクロアルキル、
12)SO2Ra、及び
13)(C=O)NRb 2、
から独立に選択され;
前記アルキル、シクロアルキル、アリール、ヘテロシクリル、アルケニル及びアルキニルは、R11から選択される1、2又は3個の置換基で必要に応じて置換され;又は
R12及びR13は、それらが結合している窒素とともに、各環が5員から7員を有し、N、O及びSから選択される1又は2個の追加の複素原子を窒素の他に必要に応じて含有する単環式又は二環式複素環を形成することができ、前記単環式又は二環式複素環は、R11から選択される1、2又は3個の置換基で必要に応じて置換されており;
Raは、(Cl−C6)アルキル、(C3−C6)シクロアルキル、アリール及びヘテロシクリルから独立に選択され、
Rbは、H、(Cl−C6)アルキル、アリール、ヘテロシクリル、(C3−C6) シクロアルキル、(C=O)OC1−C6アルキル、(C=O)C1−C6アルキル又はS(O)2Raから独立に選択され、
Rc及びRc’は、H、(C1−C6)アルキル、アリール、ヘテロシクリル及び(C3−C6) シクロアルキルから独立に選択され、又は
Rc及びRc’は、それらが結合している窒素とともに、各環中に5から7員を有し、前記窒素の他に、N、O及びSから選択される1又は2個の追加の複素原子を必要に応じて含有する単環式若しくは二環式複素環を形成することができ、前記単環式若しくは二環式複素環は、R11から選択される1、2又は3個の置換基で必要に応じて置換されており;
但し、少なくとも1つの置換基−OPO(OH)2が式IIIの化合物中に存在する。)
式IVの化合物、又は、薬学的に許容されるその塩若しくは立体異性体によって表される。
aは、0又は1であり;
bは、0又はlであり;
mは、0、1又は2であり;
rは、0又はlであり;
sは、0又はlであり;
R1は、
1)(C=O)C1−C10アルキル、
2)(C=O)アリール、
3)(C=O)C3−C8シクロアルキル、
4)(C=O)ヘテロシクリル、
5)(C=O)NRcRc’、
6)(C=S)NRcRc’、
7)SO2NRcRc’、
8)SO2C1−C10アルキル、
9)SO2−アリール、及び
10)SO2−ヘテロシクリル、
から選択され;
前記アルキル、アリール、シクロアルキル及びヘテロシクリルは、R10から選択される一又は複数の置換基で必要に応じて置換され;
R3、R4及びR8は、
1)H、
2)C1−C10アルキル、及び
3)C1−C6ペルフルオロアルキル、
から独立に選択され;
前記アルキルは、R10から選択される一又は複数の置換基で必要に応じて置換され;
R10は、
1)(C=O)aObC1−C10アルキル、
2)(C=O)aObアリール、
3)C2−C10アルケニル、
4)C2−C10アルキニル、
5)(C=O)aObヘテロシクリル、
6)CO2H、
7)ハロ、
8)CN、
9)OH、
10)ObC1−C6ペルフルオロアルキル、
11)Oa(C=O)bNR12R13、
12)S(O)mRa、
13)S(O)2NR12R13、
14)オキソ、
15)CHO、
16)(N=O)R12R13、
17)(C=O)aObC3−C8シクロアルキル、及び
18)−OPO(OH)2;
から独立に選択され;
前記アルキル、アリール、アルケニル、アルキニル、ヘテロシクリル及びシクロアルキルは、R11から選択される1、2又は3個の置換基で必要に応じて置換され;
R10aは、ハロゲンであり;
R11は、
1)(C=O)rOs(C1−C10)アルキル、
2)Or(C1−C3)ペルフルオロアルキル、
3)オキソ、
4)OH、
5)ハロ、
6)CN、
7)(C2−C10)アルケニル、
8)(C2−C10)アルキニル、
9)(C=O)rOs(C3−C6)シクロアルキル、
10)(C=O)rOs(C0−C6)アルキレン−アリール、
11)(C=O)rOs(C0−C6)アルキレン−ヘテロシクリル、
12)(C=O)rOs(C0−C6)アルキレン−N(Rb)2、
13)C(O)Ra、
14)(C0−C6)アルキレン−CO2Ra、
15)C(O)H、
16)(C0−C6)アルキレン−CO2H、
17)C(O)N(Rb)2、
18)S(O)mRa、
19)S(O)2N(Rb)2、及び
20)−OPO(OH)2、
から選択され;
前記アルキル、アルケニル、アルキニル、シクロアルキル、アリール及びヘテロシクリルは、Rb、OH、(C1−C6)アルコキシ、ハロゲン、CO2H、CN、O(C=O)C1−C6アルキル、オキソ及びN(Rb)2から選択される最大三個の置換基で必要に応じて置換されており;
R12及びR13は、
1)H、
2)(C=O)ObC1−C10アルキル、
3)(C=O)ObC3−C8シクロアルキル、
4)(C=O)Obアリール、
5)(C=O)Obヘテロシクリル、
6)C1−C10アルキル、
7)アリール、
8)C2−C10アルケニル、
9)C2−C10アルキニル、
10)ヘテロシクリル、
11)C3−C8シクロアルキル、
12)SO2Ra、及び
13)(C=O)NRb2、
から独立に選択され;
前記アルキル、シクロアルキル、アリール、ヘテロシクリル、アルケニル及びアルキニルは、R11から選択される1、2又は3個の置換基で必要に応じて置換され;又は
R12及びR13は、それらが結合している窒素とともに、各環が5員から7員を有し、N、O及びSから選択される1又は2個の追加の複素原子を前記窒素の他に必要に応じて含有する単環式又は二環式複素環を形成することができ、前記単環式又は二環式複素環は、R11から選択される1、2又は3個の置換基で必要に応じて置換されており;
Raは、(Cl−C6)アルキル、(C3−C6)シクロアルキル、アリール及びヘテロシクリルから独立に選択され;
Rbは、H、(Cl−C6)アルキル、アリール、ヘテロシクリル、(C3−C6) シクロアルキル、(C=O)OCl−C6アルキル、(C=O)Cl−C6アルキル又はS(O)2Raから独立に選択され;、
Rc及びRc’は、H、(Cl−C6)アルキル、アリール、ヘテロシクリル及び(C3−C6) シクロアルキルから独立に選択され、又は
RC及びRc’は、それらが結合している窒素とともに、各環中に5から7員を有し、前記窒素の他に、N、O及びSから選択される1又は2個の追加の複素原子を必要に応じて含有する単環式若しくは二環式複素環を形成することができ、前記単環式若しくは二環式複素環は、R11から選択される1、2又は3個の置換基で必要に応じて置換されている。)
R1は、
1)(C=O)NRcRc’、
2)SO2NRcRc’、及び
3)SO2C1−C10アルキル、
から選択され、
前記アルキルは、R10から選択される1、2又は3個の置換基で必要に応じて置換され;
R3、R4及びR8は、
1)H、及び
2)C1−C10アルキル、
から独立に選択され、
前記アルキルは、R10から選択される1又は複数の置換基で必要に応じて置換され;
R10、R10a、R11、R12、R13、Ra、Rb、Rc及びRc’は、直前に記載されているとおりである。)
3−{(2S)−4−(2,5−ジフルオロフェニル)−1−[(ジメチルアミノ)カルボニル]−2,5−ジヒドロ−1H−ピロール−2−イル}フェニル 二水素リン酸塩;
3−[(2S)−1−[(2S)−2−シクロプロピル−2−ヒドロキシエタノイル]−4−(2,5−ジフルオロフェニル)−2,5−ジヒドロ−1H−ピロール−2−イル]フェニル 二水素リン酸塩;
3−((2S)−4−(2,5−ジフルオロフェニル)−1−{[メチル(テトラヒドロフラン−3−イル)アミノ]カルボニル−2,5−ジヒドロ−1H−ピロール−2−イル)フェニル 二水素リン酸塩;
3−{(2S)−4−(2,5−ジフルオロフェニル)−1−[(2S)−2−ヒドロキシ−3,3−ジメチルブタノイル]−2,5−ジヒドロ−1H−ピロール−2−イル}フェニル 二水素リン酸塩;
2−(ホスホノオキシ)エチル(1S)−1−{[(2S)−4−(2,5−ジフルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−イル]カルボニル−2,2−ジメチルプロピルカルバメート;及び
(1S)−1−シクロプロピル−2−[(2S)−4−(2,5−ジフルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−イル]−2−オキソエチル 二水素リン酸塩;
又は薬学的に許容されるその塩若しくは立体異性体、が含まれる。
a)1−シクロプロピル−2−オキソエタナミン又は1−t−ブチル−2−オキソエタナミン(アミン窒素は、必要に応じて、R12及びR13で置換されている。)、
b)N,N−ジメチルカルボキサミド、及び
c)N−メチル−N−(1−メチルピペリジン−4−イル)カルボキサミド
から選択される。
スキームAに示されているように、中心的な役割のジヒドロピロール中間体A−4は、容易に入手可能な、適切に置換されたアニリン及びN−保護されたジヒドロピロールから得ることができる。その後、環窒素の脱保護により、適切に置換された求電子試薬(例示されている、ジアルキルカルバモイル・クロリドなど)による官能基の付与が可能となり、本発明の化合物A−6が得られる。スキームA−1は、A−4中間体の別の合成法を示している。
本発明の化合物は、様々な用途に用いられる。当業者であれば自明であるように、有糸分裂は様々な態様で変化させることができる。すなわち、有糸分裂経路中の要素の活性を増加又は減少させることによって、有糸分裂に影響を与えることができる。換言すれば、有糸分裂は、ある種の要素を阻害又は活性化することにより均衡を崩壊させることによって、影響を与える(例えば、崩壊させる)ことができる。類似のアプローチは、減数分裂を変化させるためにも使用し得る。
意味を有する。
3−フェニル−4−(4−(メチルスルホニル)フェニル)−2−(5H)−フラノン;及び
実施例に記載されている本発明の化合物は、以下に記載されているアッセイによって検査され、キネシン阻害活性を有することが見出された。その他のアッセイが文献において公知であり、当業者によって容易に実施され得る(例えば、PCT 公開WO 01/30768、2001年5月3日、18−22ページ)。
ヒトポリヒスチジンタグ化KSPモータードメイン(KSP(367H))のクローニング及び発現
pBluescript完全長ヒトKSP構築物をテンプレートとして使用し、ヒトKSPモータードメイン構築物を発現するためのプラスミドを、PCRによってクローニングした(Blangy et al., Cell, vol. 83, ppll59−1169, 1995)。 モータードメインとネックリンカー領域を増幅するために、N末端プライマー
細胞ペレットを氷上で融解し、溶解緩衝液(50mM K−HEPES, pH 8.0、250mM KCl、0.1% Tween、10mM イミダゾール、0.5mM Mg−ATP、1mM PMSF、2mM ベンズイミジン、1×完全プロテアーゼ阻害カクテル(Roche))中に再懸濁した。1mg/ml リゾチーム及び5mM β−メルカプトエタノールとともに、細胞懸濁物を10分間インキュベートした後、音波処理を行った(3×30秒)。その後の操作は全て、4℃で行った。溶解液を40,000×gで40分間遠心した。上清を希釈し、緩衝液A(50mM K−HEPES、pH6.8、1mM MgCl2、1mM EGTA、10μM Mg−ATP、1mM DTT)中のSP Sepharoseカラム(Pharmacia, 5ml カートリッジ)にかけ、緩衝液A中の0から750mM KClグラジエントで溶出した。KSPを含有する画分をプールし、Ni−NTA樹脂(Qiagen)とともに1時間インキュベートした。緩衝液B(溶解緩衝液からPMSFとプロテアーゼ阻害剤カクテルを除去したもの)で、この樹脂を三回洗浄した後、15分のインキュベーションと緩衝液Bでの洗浄とを三回行った。最後に、この樹脂をインキュベートし、緩衝液C(pH6.0であることを除き、緩衝液Bと同じ。)で15分間、3回洗浄し、カラムの中に注いだ。溶出緩衝液でKSPを溶出した(150mM KCl及び250mM イミダゾールであることを除き、緩衝液Bと同じ。)KSP含有画分をプールし、スクロース中で10%として、−80℃で保存した。
24、48及び72時間にわたって対数増殖が可能な密度で、96ウェル組織培養皿の上に細胞を播種し、一晩付着させる。翌日、10ポイントの半対数滴定で、全てのプレートに化合物を添加する。各滴定系列は、三つ組みで実施され、アッセイを通じて、0.1%の一定のDMSO濃度を維持する。0.1%DMSOのみの対照も含める。各化合物希釈系列は、血清なしの溶媒中で作製される。アッセイ中の血清の最終濃度は、200μL容量の溶媒中で、5%である。薬物添加から24、48又は72時間後の時点で、Alamarブルー染色試薬20μLを、滴定プレート上の各試料及び対照ウェルに添加し、37℃でのインキュベーションに戻す。530−560ナノメーターの波長励起、590ナノメータの発光を使用して、CytoFluor IIプレートリーダー上で、6から12時間後にAlamarブルー蛍光を分析する。
%細胞毒性:(蛍光対照)−(蛍光試料)×100×(蛍光対照)−1
として定義される。変曲点は、細胞毒性EC50として報告される。
細胞の被処理集団中のDNA含量を測定することによって、化合物が、化合物が有糸分裂中の細胞を停止させる能力とアポトーシスを誘導する能力を評価するために、FACS分析を使用する。1.4×106細胞/6cm2組織培養皿の密度で細胞を播種し、一晩付着させる。次いで、ビヒクル(0.1% DMSO)又は化合物の滴定系列で、8から16時間、細胞を処理する。処理に引き続き、表記の時点で、トリプシン処理によって細胞を採集し、遠心によって沈降させる。細胞ペレットをPBS中でリンスし、70%エタノール中で固定し、4℃で一晩以上保存した。
DNA、チュブリン、及びペリセントリンの免疫蛍光染色のための方法は、実質的に、「Kapoor et al. (2000) J. Cell Biol. 159:975−988」に記載されているとおりである。細胞培養研究のために、組織培養で処理されたガラス試験容器スライド上に細胞を播種し、一晩付着させる。次いで、目的の化合物とともに、4から16時間、細胞をインキュベートする。インキュベーションが完了したら、溶媒と薬物を吸引し、チャンバーとガスケットをガラススライドから取り出す。次いで、参照されたプロトコールに従って、細胞を透過化し、固定し、洗浄し、非特異抗体の結合に対してブロックする。パラフィン包埋された腫瘍切片のパラフィンをキシレンで除去し、ブロッキングの前に、エタノールの系列を通して再水和させる。一次抗体(マウスモノクローナル抗α−チュブリン抗体、Sigmaから購入したクローンDM1A、1:500希釈;Covanceから購入したウサギポリクローナル抗ペリセントリン抗体、1:2000希釈)中において、一晩、4℃でスライドをインキュベートする。洗浄後、15μg/mLに希釈された、包合二次抗体(チュブリンに対するFITC包合ロバ抗マウスIgG;ペリセントリンに対するテキサスレッド包合ロバ抗ウサギIgG)とともに、スライドを1時間、室温でインキュベートする。次いで、スライドを洗浄し、ヘキスト33342で対比染色し、DNAを可視化する。Metamorph逆重畳・画像化ソフトウェアを使用して、免疫染色された試料をNikon落射蛍光顕微鏡上の100倍油浸対物レンズで画像化する。
2−クロロ−5−フルオロアニリン(1.00g、6.87mmol)のアセトニトリル溶液(50mL)に、0℃で、ニトロソニウム テトラフルオロボレート(802mg、6.87mmol)を添加した。得られた混合物を1時間攪拌した後、エチルエーテル(150mL)で希釈した。沈殿を濾過し、風乾して、2−クロロ−5−フルオロベンゼンジアゾニウム テトラフルオロボレート(1−1)を灰白色固体として得た。1H NMR(300MHz,CD3OD)δ8.66(ddd,1H,J=6.7,2.1,1.0Hz),8.16(m,2H)。
激しく攪拌された、水及び四塩化炭素(1;1、50mL)中の、tert−ブチル 2,5−ジヒドロ−1H−ピロール−1−カルボキシレート(900mg、5.32mmol)と2−クロロ−5−フルオロベンゼンジアゾニウムテトラフルオロボレート(1−1,1.30g,5.32mmol)の脱酸素化された混合物に、23℃で、酢酸パラジウム(II)(24mg、0.11mmol、0.020当量)を添加し、得られた混合物を20時間攪拌した。この反応混合物を、飽和炭酸水素ナトリウム水溶液(150mL)と酢酸エチル(2×150mL)の間に、分配した。合わせた有機層を硫酸ナトリウム上で乾燥し、濃縮した。残留物をトルエン(100mL)中に溶かし、得られた溶液を真空中で濃縮して、残留水の共沸除去を促進した。続いて、2,6−ルチジン(1.24mL、10.6mmol、2.00当量)及びトリフルオロ酢酸無水物(0.558mL、2.66mmol、0.500当量)を、前記残留物のトルエン溶液(100mL)に、0℃で、順次添加した。この反応混合物を0℃で8時間維持した後、23℃まで8時間加温し、さらに8時間攪拌した。この反応混合物を1時間還流して加熱した後、23℃まで冷却し、濃縮した。この残留物を、酢酸エチル(100mL)と飽和炭酸水素ナトリウム水溶液(100mL)との間に、分配した。有機層を硫酸ナトリウム上で乾燥し、濃縮した。フラッシュカラムクロマトグラフィー(ヘキサンから始まり、ヘキサン中の60% EtOAcまで段階的に増加)によって、残留物を精製して、オレンジ色の油として、tert−ブチル 3−(2−クロロ−5−フルオロフェニル)−2,3−ジヒドロ−1H−ピロール−1−カルボキシレート(1−2)を得た。LRMS m/z(M+H−CH3)実測値283.0、理論値283.1。
アセトニトリル(20mL)中の、tert−ブチル 3−(2−クロロ−5−フルオロフェニル)−2,3−ジヒドロ−1H−ピロール−1−カルボキシレート(1−2、330mg、1.11mmol、1当量)、ベンゼンジアゾニウム テトラフルオロボレート(1−3、1−1について記載した方法によってアニリンから調製、1.213mg、1.11mmol、1.00当量)及び酢酸ナトリウム・三水和物(459mg、3.32mmol、3.00当量)の脱酸素化混合物に、トリス(ジベンジリデンアセトン)ジパラジウム(0)(20mg、0.22mmol、0.020 equiv)を、23℃で添加した。この反応混合物を、16時間攪拌し、飽和炭酸水素ナトリウム水溶液(50mL)と酢酸エチル(2×70mL)の間に、分配した。
合わせた有機層を硫酸ナトリウム上で乾燥し、濃縮した。フラッシュカラムクロマトグラフィー(ヘキサンから始まり、EtOAc中の40%ヘキサンまで段階的に増加)によって、残留物を精製して、濃いオレンジ色の油として、tert−ブチル 4−(2−クロロ−5−フルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−カルボキシレート(1−4)を得た。LRMS m/z (M+H−CH3)実測値359.0、理論値359.1。
tert−ブチル 4−(2−クロロ−5−フルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−カルボキシレート(1−4、320mg、0.856mmol、1当量)のジクロロメタン溶液(40mL)に、23℃で、トリフルオロ酢酸(10mL)を添加し、得られた混合物を30分間攪拌した後、濃縮して、4−(2−クロロ−5−フルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール(1−5)をTFA塩(茶色の油)として得た。LRMS m/z(M+H)実測値274.1、理論値274.1。
4−(2−クロロ−5−フルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール(1−5、TFA塩、0.856mmol、1当量)のジクロロメタン溶液(50mL)に、23℃で、トリエチルアミン(0.600mL、4.28mmol、5.00当量)及びジメチルカルバモイルクロリド(0.080mL、0.86mmol、1.00当量)を添加し、得られた混合物を2時間攪拌した後、濃縮した。この残留物を、飽和炭酸水素ナトリウム水溶液(75mL)と酢酸エチル(100mL)の間に、分配した。有機層を硫酸ナトリウム上で乾燥し、濃縮した。残留物をエチルエーテル(2mL)中に懸濁し、沈殿を濾過して、4−(2−クロロ−5−フルオロフェニル)−N,N−ジメチル−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−カルボキサミド(1−6)を灰白色の固体として得た。1H NMR(500MHz,CDCl3)δ7.40−7.30(m,5H),7.26(m,1H),7.03(dd,1H,J=9.0,2.9Hz),6.97(m,1H),6.24(m,1H),6.15(m,1H),4.86(ddd,1H,J=13.9,5.6,2.2Hz),4.49(dt,1H,J=13.9,2.0Hz),2.86(s,6H)。LRMS m/z (M+H−CH3)実測値345.0、理論値345.1。
2,5−ジフルオロアニリン(0.780mL、7.75mmol、1当量)のアセトニトリル溶液(50mL)に、0℃で、ニトロソニウム テトラフルオロボレート(905mg、7.75mmol、1.00当量)を添加した。得られた混合物を1時間攪拌し、次いで、エチルエーテル(150mL)で希釈した。沈殿を濾過し、風乾して、2,5−ジフルオロベンゼンジアゾニウム テトラフルオロボレート(2−1)を黄褐色の固体として得た。1H NMR(300MHz,CD3OD)δ8.54(m,1H),8.24(m,1H),7.95(m,1H)。
激しく攪拌された、水及び四塩化炭素(1:1、150mL)中の、tert−ブチル 2,5−ジヒドロ−1H−ピロール−1−カルボキシレート(2.59mL,15.0mmol、1当量)と2,5−ジフルオロベンゼンジアゾニウム テトラフルオロボレート(2−1,3.42g,15.0mmol、1.00当量)に、23℃で、酢酸パラジウム(II)(67mg、0.30mmol、0.020当量)を添加し、得られた混合物を20時間攪拌した。この反応混合物を濃縮し、残留物を酢酸エチル(300mL)と飽和炭酸水素ナトリウム水溶液(75mL)との間に、分配した。有機層を塩水で洗浄した後、硫酸ナトリウム上で乾燥し、濃縮した。残留物をトルエン(200mL)中に溶かし、得られた溶液を真空中で濃縮して、残留水の共沸除去を促進した。続いて、2,6−ルチジン(3.50mL、30.0mmol、2.00当量)及びトリフルオロ酢酸無水物(1.48mL、10.5mmol、0.700当量)を、前記残留物のトルエン溶液(100mL)に、−10℃で、順次添加した。得られた混合物を16時間かけて10℃まで加温した後、還流しながら1時間加熱した。この反応混合物を23℃まで冷却した後、濃縮した。この残留物を、酢酸エチル(300mL)と飽和炭酸水素ナトリウム水溶液(150mL)との間に、分配した。有機層を硫酸ナトリウム上で乾燥し、濃縮した。フラッシュカラムクロマトグラフィー(ヘキサンから始まり、ヘキサン中の20% EtOAcまで段階的に増加)によって、残留物を精製して、赤い油として、tert−ブチル 3−(2,5−ジフルオロフェニル)−2,3−ジヒドロ−1H−ピロール−1−カルボキシレート(2−2)を得た。1H NMR(500MHz,CDCl3)主要回転異性体:δ7.03−6.84(m,3H),6.70(brs,1H),5.01(brs,1H),4.42(m,1H),4.13(m,1H),3.60(m,1H),1.50(s,9H)。
アセトニトリル(70mL)中の、tert−ブチル 3−(2,5−ジフルオロフェニル)−2,3−ジヒドロ−1H−ピロール−1−カルボキシレート(2−2、900mg、3.20mmol、1当量)、ベンゼンジアゾニウム テトラフルオロボレート(1−3、1−1について記載した方法によって調製、614mg、3.20mmol、1.00当量)及び酢酸ナトリウム・三水和物(1.32g、9.60mmol、3.00当量)の脱酸素化混合物に、トリス(ジベンジリデンアセトン)ジパラジウム(0)(59mg、064mmol、0.020当量)を、23℃で添加した。この反応混合物を、16時間攪拌した後、飽和炭酸水素ナトリウム水溶液と酢酸エチル(2×70mL)の間に、分配した。合わせた有機層を硫酸ナトリウム上で乾燥し、濃縮した。フラッシュカラムクロマトグラフィー(ヘキサンから始まり、EtOAc中の40% ヘキサンまで段階的に増加)によって、残留物を精製して、オレンジ色の油として、tert−ブチル 4−(2,5−ジフルオロフェニル)――2−フェニル−2,5−ジヒドロ−1H−ピロール−1−カルボキシレート(2−3)を得た。LRMS m/z (M+H−CH3)実測値343.0、理論値343.1。
tert−ブチル 4−(2,5−ジフルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−カルボキシレート(2−3、700mg、1.96mmol、1当量)のジクロロメタン(50mL)溶液に、23℃で、トリフルオロ酢酸(20mL)を添加し、得られた混合物を30分間攪拌した後、濃縮して、TFA塩として4−(2,5−ジフルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール(2−4)(茶色の油)を得た。LRMS m/z (M+H−CH3)実測値258.1、理論値258.1。
4−(2,5−ジフルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール(2−4、1.96mmol)のジクロロメタン溶液(50mL)に、23℃で、トリエチルアミン(1.37mL、9.79mmol、5.00当量)及びジメチルカルバモイルクロリド(0.180mL、1.96mmol、1.00当量)を添加し、得られた混合物を2時間攪拌した後、濃縮した。得られた混合物を2時間攪拌した後、濃縮した。残留物を、飽和炭酸水素ナトリウム水溶液(75mL)と酢酸エチル(100mL)の間に、分配した。有機層を硫酸ナトリウム上で乾燥し、濃縮した。逆相LC(H2O/CH3CNグラジエントw/0.1% TFAが存在)によって、残留物を精製して、)によって、残留物を精製して、4−(2,5−ジフルオロフェニル)−N,N−ジメチル−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−カルボキサミド(2−5)を灰白色の固体として得た。1H NMR(500MHz,CDCl3)δ7.35−7.29(m,4H),7.25(m,1H),7.05(m,1H),7.00(m,1H),6.96(m,1H),6.40(brs,1H),6.13(m,1H),4.88(ddd,1H,J=13.7,5.6,2.0Hz),4.52(d,1H,J=13.7Hz),2.88(s,6H)。LRMS m/z (M+H−CH3)実測値329.1、理論値329.1。
キラル順相HPLC(Chiralcel ODカラム:40%エタノールのヘキサン溶液中の、0.1%ジエチルアミン)によって、ラセミの4−(2,5−ジフルオロフェニル)−N,N−ジメチル−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−カルボキサミド(2−5)の鏡像異性体を分割して、2−6(−)及び2−7(+)の溶出順序で得た。
水及び四塩化炭素(1:1、150mL)中の、tert−ブチル 2,5−ジヒドロ−1H−ピロール−1−カルボキシレート(4.00g、23.6mmol、1当量)と5−クロロ−2−フルオロベンゼンジアゾニウム テトラフルオロボレート(10.4g、42.5mmol、1.80当量)の激しく攪拌された脱酸素化混合物に、23℃で、酢酸パラジウム(II)(106mg、0.473mmol、0.020当量)を添加し、得られた混合物を20時間攪拌した。この反応混合物を、飽和炭酸水素ナトリウム水溶液(200mL)とジクロロメタン(2×200mL)の間に、分配した。合わせた有機層を硫酸ナトリウム上で乾燥し、濃縮した。残留物をトルエン(200mL)中に溶かし、得られた溶液を真空中で濃縮して、残留水の共沸除去を促進した。続いて、2,6−ルチジン(5.51mL、47.3mmol、2.00当量)及びトリフルオロ酢酸無水物(1.67mL、11.8mmol、0.500当量)を、前記残留物のトルエン溶液(150mL)に、−20℃で、順次添加した。得られた混合物を−20℃に5時間保った後、23℃までゆっくり加温した。23℃で16時間後、この反応混合物を還流しながら30分間加熱した。この反応混合物を23℃まで冷却した後、酢酸エチル(100mL)と飽和炭酸水素ナトリウム水溶液(100mL)との間に、分配した。有機層を硫酸ナトリウム上で乾燥し、濃縮した。フラッシュカラムクロマトグラフィー(ヘキサンから始まり、ヘキサン中の30% EtOAcまで段階的に増加)によって、残留物を精製して、オレンジ色の油として、tert−ブチル 3−(5−クロロ−2−フルオロフェニル)−2,3−ジヒドロ−1H−ピロール−1−カルボキシレート (3−1)を得た。LRMS m/z (M+H−CH3)実測値283.0、理論値283.1。
DMF(10mL)中の、tert−ブチル 3−(5−クロロ−2−フルオロフェニル)−2,3−ジヒドロ−1H−ピロール−1−カルボキシレート(3−1、1.100g、3.69mmol、1当量)、tert−ブチル−(3−ヨードフェノキシ)ジメチルシラン(1.85g、5.54mmol、1.50当量)、トリブチルアミン(1.76mL、7.39mmol、2.00当量)、トリフェニルアルシン(0.453g、1.48mmol、0.400当量)及び酢酸パラジウム(0.166g、0.739mmol、0.200当量)を、65℃で20時間加熱した。この反応混合物を、水(100mL)と酢酸エチル(2×85mL)の間に、分配した。合わせた有機層を硫酸ナトリウム上で乾燥し、濃縮した。フラッシュカラムクロマトグラフィー(100%ヘキサンから始まり、ヘキサン中の50% 酢酸エチルまで段階的に増加)によって、残留物を精製して、オレンジ色の油として、tert−ブチル 2−(3−{[tert−ブチル(ジメチル)シリル]オキシ}フェニル)−4−(5−クロロ−2−フルオロフェニル)−2,5−ジヒドロ−1H−ピロール−1−カルボキシレート(3−2)を得た。1H NMR(300MHz,CDCl3)主要回転異性体:δ7.11−6.53(m,7H),6.11(s,1H),5.32(m,1H),4.53(m,2H),1.09(s,9H),0.79(s,9H),0.00(s,6H)。LRMS m/z (M+H)実測値504.1、理論値504.2。
DMF(10mL)中の、tert−ブチル 2−(3−{[tert−ブチル(ジメチル)シリル]オキシ}フェニル)−4−(5−クロロ−2−フルオロフェニル)−2,5−ジヒドロ−1H−ピロール−1−カルボキシレート(3−2、276mg、0.683mmol、1当量)、トリエチルアミン(277mg、2.73mmol、4当量)、PYBOP(711mg、1.37mmol、2当量)及び2−[(tert−ブトキシカルボニル)アミノ]−2−メチルプロパン酸(278mg、1.37mmol、2当量)の溶液を、60℃で18時間加熱した。この溶液を濃縮し、残留物を酢酸エチルと飽和炭酸水素ナトリウム水溶液の間に分配した。有機層を塩水で洗浄し、硫酸マグネシウム上で乾燥し、濃縮した。フラッシュカラムクロマトグラフィーによって、この残留物を精製した。10%酢酸エチル/ヘキサンから20%酢酸エチル/ヘキサンへの溶出によって、tert−ブチル 2−[2−(3{[tert−ブチル(ジメチル)シリル]オキシフェニル)−4−(5−クロロ−2−フルオロフェニル)−2,5−ジヒドロ−1H−ピロール−1−イル}−1,1−ジメチル−2−オキソエチルカルバメート(3−3)を青黄色のガムとして得た。LRMS m/z(M+H)実測値588.9、理論値589.0。
tert−ブチル 2−[2−(3{[tert−ブチル(ジメチル)シリル]オキシ}フェニル)−4−(5−クロロ−2−フルオロフェニル)−2,5−ジヒドロ−1H−ピロール−1−イル]−1,1−ジメチル−2−オキソエチルカルバメート(3−3、247mg、0.419mmol、1当量)及びトリフルオロ酢酸(4mL)の、ジクロロメタン(10mL)溶液を、周囲の条件下で、1時間攪拌した。この反応物を23℃で濃縮し、残留物を酢酸エチルと飽和炭酸水素ナトリウム水溶液の間に分配した。有機層を塩水で洗浄した後、硫酸マグネシウム上で乾燥し、濃縮して、黄色のガムを得た。このガムのメタノール溶液(5mL)を、炭酸カリウム(290mg、2.10mmol、5.00当量)及び水(1mL)で処理した。この反応混合物を、周囲の条件下で2時間攪拌した後、濃縮した。この水溶液を、1N HCl水溶液でpH8まで酸性化し、この混合物を酢酸エチルで抽出した。有機層を塩水で洗浄し、硫酸マグネシウム上で乾燥させ、濃縮して、4−(5−クロロ−2−フルオロフェニル)−2−(3−ヒドロキシフェニル)−1−(2−メチルアラニル)−2,5−ジヒドロ−1H−ピロール(3−4)をクリーム色の固体として得た。1H NMR(500MHz,CDCl3)δ7.30(dd,1H,J=6.6,2.7Hz),7.30(m,1H),7.18(t,1H,J=7.8Hz),7.05(t,1H,J=9.2Hz),6.83(brd,1H,J=7.6Hz),6.78(brs,1H),6.70(dd,1H,J=8.1,1.8Hz),6.38(s,1H),5.92(brs,1H),5.30(m,1H),5.08(m,1H),1.46(s,6H)。LRMS m/z(M+H)実測値375.0、理論値375.0。
キラル順相HPLC(Chiralcel ODカラム:10%エタノールのヘキサン溶液中の、0.1%ジエチルアミンから始まり、ヘキサン中の30%エタノールまで段階的に増加)によるラセミ4−(5−クロロ−2−フルオロフェニル)−2−(3−ヒドロキシフェニル)−1−(2−メチルアラニル)−2,5−ジヒドロ−1H−ピロール(3−4)の鏡像異性体の分割によって、最初に溶出されるマイナス(−)鏡像異性体として、(2S)−4−(5−クロロ−2−フルオロフェニル)−2−(3−ヒドロキシフェニル)−1−(2−メチルアラニル)−2,5−ジヒドロ−1H−ピロール(3−5)を得た。上記手順の単純な修飾によって、以下の化合物を調製した。別段の記載がなければ、表中の化合物を遊離の塩基として単離した。
攪拌バーを装備した、炎で乾燥されたフラスコに、tert−ブチル (2S,4S)−4−{[tert−ブチル(ジメチル)シリル]オキシ}−2−フェニルピロリジン−1−カルボキシレート(5−1、Maeda et al Synlett 2001, 1808−1810の方法によって、(S)−(−)−4−クロロ−3−ヒドロキシブチロニトリル、7.8g、20.7mmolから調製)及び無水アセトニトリル(20.0mL)を添加した。得られた溶液を、N2下で攪拌しながら、トリエチルアミン トリヒドロフッ化物(10.1mL、62.0mmol)で処理した。この反応物を40℃で12時間攪拌した。次いで、この反応混合物を、EtOAc(100mL)で希釈し、5% aq. NaHCO3中に注いだ。気体の発生が止んだら、5% aq. NaHCO3で、有機層をさらに三回洗浄した。有機層を硫酸マグネシウム上で乾燥し、濾過し、濃縮して、未精製の生成物を得た。EtOAc/ヘキサンから再結晶を行って、tert−ブチル (2S,4S)−4−ヒドロキシ−2−フェニルピロリジン−1−カルボキシレート(5−2)を白色結晶固体として得た。1H NMR(300MHz,CDCl3)回転異性体 δ7.38−7.18(m,5H),4.90(m,1H),4.42(m,1H),3.88(m,1H),3.56(dd,J=11.5,4.0Hz,1H),2.60(m,1H),2.03(m,1H),1.50及び1.20(brs,9H);MS m/z実測値208.0、理論値208.1(M−C(CH3)3)。
攪拌バーを装備した、炎で乾燥されたフラスコに、−78℃まで冷却された150mLの無水ジクロロメタンを添加した。塩化オキサリル(3.8mL、44mmol)及びDMSO(4.8mL、61mmol)を順次添加し、この反応物を10分間攪拌した。10mLの無水ジクロロメタン中のtert−ブチル (2S,4S)−4−ヒドロキシ−2−フェニルピロリジン−1−カルボキシレート(5−2、2.28g、8.73mmol)を滴下して添加し、−78℃で1時間攪拌した。トリエチルアミン(12mL、87mmol)を添加し、この反応物を1時間かけて0℃まで加温した。完了したら、反応物を5% NaHCO3、塩水で洗浄し、MgSO4上で乾燥させた。有機層を濃縮して、未精製のtert−ブチル (2S)−4−オキソ−2−フェニルピロリジン−1−カルボキシレート(5−3)を得た。EtOAC/ヘキサンで再結晶を行った。1H NMR(300MHz,CDCl3)δ7.35(m,3H),7.17(m,2H),5.38(m,1H),4.08(d,J=19.5Hz,1H),3.90(d,J=19.3Hz,1H),3.13(dd,J=18.8,9.8Hz,1H),2.58(dd,J=18.6,2.4Hz,1H),1.40(brs,9H);MS m/z(M−C(CH3)3)実測値206.0、理論値206.1。
攪拌バーを装備した、炎で乾燥されたフラスコに、tert−ブチルケトン(2S)−4−オキソ−2−フェニルピロリジン−1−カルボキシレート(5−3、2.00g、7.65mmol)及び無水THF(100mL)を添加した。得られた溶液を−78℃まで冷却し、ヘキサメチルジシリルアミドナトリウム(NaHMDS、8.42mL、1M THF中、8.42mmol)を滴下して処理した。この反応物を1時間、−78℃で攪拌し、1,1,1−トリフルオロ−N−フェニル−N−[(トリフルオロメチル)スルホニル]メタンスルホンアミド(3.01g、8.42mmol)のTHF溶液(30mL)を、カニューラを介して添加した。この反応物を0℃まで加温し、30分攪拌した。続いて、この反応混合物を、塩水(200mL)と、酢酸エチル及びヘキサンの1:1混合液(200mL)との間に、分配した。有機層を硫酸ナトリウム上で乾燥させ、濃縮して、未精製のtert−ブチル (2S)−2−フェニル−4−{[(トリフルオロメチル)スルホニル]オキシ}−2,5−ジヒドロ−1H−ピロール−1−カルボキシレート(5−4)をオレンジ色の油として得た。1H NMR(300MHz,CDCl3)主要回転異性体:δ7.30(m,5H),5.72(m,1H),5.48(m,1H),4.42(m,2H),1.18(s,9H);MS 実測値379.0、理論値379.1(M−CH3)。
ジオキサン(100mL)中の、未精製tert−ブチル (2S)−2−フェニル−4−{[(トリフルオロメチル)スルホニル]オキシ}−2,5−ジヒドロ−1H−ピロール−1−カルボキシレート(5−4、7.65mmol)、2,5−ジフルオロフェニルボロン酸(1.81g、11.5mmol)、Na2CO3水溶液(2M、11.5mL、23.0mmol)及びPd(PPh3)4(0.442g、0.383mmol)の脱酸素化された混合物を、90℃で45分間加熱した。この反応混合物を冷却した後、塩水(200mL)と、酢酸エチル及びヘキサンの1:1混合液(200mL)との間に、分配した。有機層を硫酸ナトリウム上で乾燥し、濃縮した。フラッシュカラムクロマトグラフィー(SiO2、0−50% EtOAc/ヘキサングラジエント)によって、残留物を精製して、tert−ブチル (2S)−4−(2,5−ジフルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−カルボキシレート(5−5)を白色固体として得た。LRMS m/z (M+H−CH3)実測値358.0、理論値358.2
ジクロロメタン及びトリフルオロ酢酸(20mL)の4:1混合液中の、tert−ブチル (2S)−4−(2,5−ジフルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−カルボキシレート(5−5、400mg、1.12mmol、1当量)の溶液を30分間攪拌した後、濃縮した。トルエン共沸混合物残留物(2×10mL)を介して残留物を乾燥させた後、DMT(5mL)中に溶かした。トリエチルアミン(0.780mL、5.60mmol、5.00当量)、N−(tert−ブトキシカルボニル)−3−メチル−L−バリン(388mg、1.68mmol、1.50当量)及びPYBOP(874mg、1.68mmol、1.50当量)を添加し、得られた混合物を23℃で24時間攪拌した。この反応混合物を、飽和炭酸水素ナトリウム水溶液と酢酸エチル(2×50mL)の間に、分配した。合わせた有機層を硫酸ナトリウム上で乾燥し、濃縮した。フラッシュカラムクロマトグラフィー(ヘキサンから始まり、ヘキサン中の40% EtOAcまで段階的に増加)によって残留物を精製して、所望の、カップルされた、N−Boc−保護された中間体を得、これをジクロロメタンとトリフルオロ酢酸の2:1混合物中に溶かした。得られた溶液を30分間放置した後、濃縮した。逆相LC(H2O/CH3CNグラジエント w・0.1% TFAが存在)によって、残留物を精製した。飽和炭酸水素ナトリウム水溶液と酢酸エチル(2×50ml)の間に、所望の画分を分配し、合わせた有機層を硫酸ナトリウム上で乾燥させ、濃縮して、(1S)−1−{[(2S)−4−(2,5−ジフルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−イル]カルボニル}−2,2−ジメチルプロピルアミン(6−1)を白色固体として得た。1H NMR(500MHz,CDCl3)主要回転異性体:δ7.40(t,2H,J=7.6Hz),7.31(m,1H),7.26(d,2H,J=7.8Hz),7.11−6.93(m,3H),6.38(s,1H),5.81(m,1H),4.88(m,2H),3.03(s,1H),1.00(s,9H)。LRMS m/z(M+H)実測値371.0、理論値371.2。
n−BuPH(4.0mL)中の、(1S)−1−{[(2S)−4−(2,5−ジフルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−イル]カルボニル−2,2−ジメチルプロピルアミン(6−1、325mg、0.877mmol、1当量)、ブロモ酢酸エチル(0.195mL、1.76mmol、2.00当量)及びN,N−ジイソプロピルエチルアミン(0.613mL、3.51mmol、4.00当量)の溶液を、マイクロ波照射下、150℃で15分間加熱した。この反応混合物を濃縮し、酢酸エチル(100mL)と、飽和重硫酸カリウム水溶液及び塩水の1:1混合液(100mL)との間に、残留物を分配した。有機層を飽和炭酸水素ナトリウム水溶液(100mL)と塩水(100mL)で洗浄した後、続いて、硫酸マグネシウム上で乾燥させ、濃縮して、エチル({(1S)−1−tert−ブチル−2−[(2S)−4−(2,5−ジフルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−イル]−2−オキソエチル}アミノ)アセテート(7−1)を白色固体として得た。LRMS m/z(M+H)実測値475.5.0、理論値475.2。
エチルアミンのTHF溶液中(2M、2mL)の、エチル({(1S)−1−tert−ブチル−2−[(2S)−4−(2,5−ジフルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−イル]−2−オキソエチル}アミノ)アセテート(7−1、50mg、0.11mmol)の溶液を100℃で、16時間、密封可能なチューブの中で加熱した。この反応混合物を濃縮し、フラッシュカラムクロマトグラフィー(EtOAc)によって、残留物を精製して、2−({(lS)−1−tert−ブチル−2−[(2S)−4−(2,5−ジフルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−イル−2−オキソエチル}アミノ)−N−エチルアセトアミド(7−2)を白色固体として得た。 1H NMR(500MHz,CDCl3)は、回転異性体の1:1混合物を示した;一つの回転異性体:δ7.43−7.22(m,5H),7.11−6.96(m,3H),6.89(brm,1H),6.38(brs,1H),5.94(m,1H),4.92(ddd,1H,J=14.9,4.4,1.7Hz),4.87(brd,1H,J=15.3Hz),3.42(d,1H,J=16.8Hz),3.35(m,2H),3.03(s,1H),2.88(d,1H,J=16.8Hz),2.34(brs,1H),1.18(t,3H,J=7.3Hz),1.06(s,9H)。LRMS m/z(M+H)実測値465.5、理論値465.2。
上記手順の単純な修飾によって、以下の化合物を調製した。
4:1のMeOH:シクロヘキサジエン(2mL)中に、ジベンジル 3{(2S)−4−(2,5−ジフルオロフェニル)−1−[(ジメチルアミノ)カルボニル]−2,5−ジヒドロ−1H−ピロール−2−イル}フェニルホスフェート(8−1、108mg、0.18mmol)を溶かし、10%パラジウム炭素(100mg)で処理した。反応物を15分間激しく攪拌した後、セライト上で濾過し、MeOHを使用して、セライトから完全に化合物を洗浄した。洗浄物を濃縮し、逆相カラムクロマトグラフィー(C−8、10−90% CH3CN/H2O 0.1% TFAグラジエントあり)によって精製して、3−{(2S)−4−(2,5−ジフルオロフェニル)−1−[(ジメチルアミノ)カルボニル]−2,5−ジヒドロ−1H−ピロール−2−イル}フェニル二水素リン酸(8−2)を白色固体として得た。1H NMR(300MHz,CD3OD)δ7.20(m.7H),6.42(brs,1H),6.08(m,1H),5.00(dd,J=14.0,3.6Hz,1H),4.55(d,J=14.0Hz,1H),2.92(s,6H)。LRMS m/z(M+H)実測値425.4、理論値425.3。
4−ニトロフェニルクロロホルメート(300mg、1.49mmol、1.2当量)のTHF溶液(10mL)を、(1S)−1−{[(2S)−4−(2,5−ジフルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−イル]カルボニル−2,2−ジメチルプロピルアミン(6−1、460mg、1.24mmol、1.0当量)及びトリエチルアミン(151mg,1.49mmol、1.2当量)の、攪拌されたTHF溶液(10mL)に、23℃で滴下しながら添加した。1時間後、反応物を濾過し、淡黄色のガムになるまでろ液を濃縮して、シリカゲル上のフラッシュクロマトグラフィーによってこれを精製した。3%酢酸エチル/ジクロロメタンになるまで、ジクロロメタンで溶出すると、2−ヒドロキシエチル(1S)−1−{[(2S)−4−(2,5−ジフルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−イル]カルボニル}−2,2−ジメチルプロピルカルバメート(9−1)を無色の泡として得た。LRMS m/z(M+H)実測値536.5、理論値535.2。
4−ニトロフェニル(1S)−1−{[(2S)−4−(2,5−ジフルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−イル]カルボニル}−2,2−ジメチルプロピルカルバメート(9−1、27mg、0.05mmol、1.0当量)、ジベンジル 2−ヒドロキシエチルホスフェート(260mg、0.81mmol、16当量)及びトリエチルアミン(0.014mL、0.10mmol、2当量)の混合物を、100℃で1時間激しく加熱した。この反応混合物を冷却し、酢酸エチルと水の間に分配した。有機層を塩水で洗浄した後、硫酸マグネシウム上で乾燥し、濃縮した。シリカゲル上でのフラッシュクロマトグラフィーによって、この残留物を精製した。30%酢酸エチル/ジクロロメタンになるまでジクロロメタンで溶出すると、2−{[ビス(ベンジルオキシ)ホスホイル]オキシ}エチル(1S)−1−{[(2S)−4−(2,5−ジフルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−イル]カルボニル}−2,2−ジメチルプロピルカルバメート(9−2)を無色のゴムとして得た。LRMS m/z (M+H)実測値719.7、理論値718.3。
2−{[ビス(ベンジルオキシ)ホスホリル]オキシ}エチル(1S)−1−{[(2S)−4−(2,5−ジフルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−イル]カルボニル}−2,2−ジメチルプロピルカルバメート(9−2、11mg、0.015mmol、1当量)、1,4−シクロヘキサジエン(1mL、過剰)及び10% Pd/C(5mg)をメタノール(4mL)に添加し、この混合物を窒素雰囲気下で攪拌した。30分後に、さらに5mgの10% Pd/Cを添加し、さらに一時間攪拌を継続した。この反応物を濾過し、ろ液を濃縮した。逆相LC(H2O/CH3CNグラジエントw/0.1% TFAが存在)によって、残留物を精製して、2−(ホスホノオキシ)エチル (1S)−1−{[(2S)4−(2,5−ジフルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−イル]カルボニル}−2,2−ジメチルプロピルカルバメート(9−3)を無色の泡として得た。1H NMR(500MHz,CDCl3)主要回転異性体:δ7.34−7.20(m,5H),7.12−6.92(m,3H),6.38(s,1H),5.93(bs,1H),5.21(d,1H,J=14Hz),4.91(d,1H,J=14Hz),4.41(d,1H,J=10Hz),4.38−3.97(m,7H),0.91(s,9H)。LRMS m/z(M+H)実測値539.5、理論値538.2。
(1S)−1−シクロプロピル−2−[(2S)―4−(2,5−ジフルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール1−イル]−2−オキソエタノール(6−2、230mg、0.647mmol、1当量)のジクロロメタン溶液(5mL)に、チタン(IV)tert−ブトキシド(0.022mL、0.065mmol、0.100当量)を23℃で添加し、続いて、トリエチルアミン(0.271mL、1.94mmol、3.00当量)及びジメチルクロロリン酸(0.140mL、1.29mmol、2.00当量)を添加した。この反応混合物を、2時間攪拌した後、飽和炭酸水素ナトリウム水溶液(50mL)と酢酸エチル(2×50mL)の間に、分配した。合わせた有機層を硫酸ナトリウム上で乾燥し、濃縮した。残留物を硫化ジメチル(0.5mL)中に溶かし、得られた溶液にメタンスルホン酸(1mL)を添加した。得られた混合物を10時間攪拌し、次いで、アセトニトリル(3mL)で希釈した。逆相クロマトグラフィー(H2O/CH3CNグラジエントw/0.1% TFAが存在)によって、残留物を精製して、(1S)−シクロプロピル−2−[(2S)−4−(2,5−ジフルオロフェニル)−2−フェニル−2,5−ジヒドロー1H−ピロール−1−イル]−2−オキソエチル二水素リン酸(10−1)を白色固体として得た。1H NMR(500MHz,CDCl3)主要回転異性体:δ7.42−7.04(m,8H),6.46(s,1H),5.95(m,1H),5.14(brd,1H,J=14Hz),5.04(brd,1H,J=14Hz),4.46(t,1H,J=8.2Hz),1.32(m,1H),0.62(m,4H)。LRMS m/z(M+H)実測値436.4、理論値436.1。
Claims (2)
- 式IVの化合物:
(式中、
aは、0又は1であり;
bは、0又はlであり;
R 1 は、
1)(C=O)C1−C10アルキル、及び
2)(C=O)NRcRc’
から選択され;
前記アルキルは、R10から選択される一又は複数の置換基で必要に応じて置換され;
R3、R4及びR8は、
1)H、及び
2)C1−C10アルキル
から独立に選択され;
R 10 は、
1)(C=O)aObC1−C10アルキル、
2)CO2H、
3)ハロ、
4)OH、
5)Oa(C=O)bNR12R13、
6)(C=O)aObC3−C8シクロアルキル、及び
7)−OPO(OH)2;
から独立に選択され;
R 10a は、ハロゲンであり;
R 12 及びR13は、
1)H、及び
2)(C=O)ObC1−C10アルキル
から独立に選択され;
R c 及びRc’は、H、(Cl−C6)アルキル、ヘテロシクリル及び(C3−C6)シクロアルキルから独立に選択される。) - 3−{(2S)−4−(2,5−ジフルオロフェニル)−1−[(ジメチルアミノ)カルボニル]−2,5−ジヒドロ−1H−ピロール−2−イル}フェニル 二水素リン酸塩;
3−[(2S)−1−[(2S)−2−シクロプロピル−2−ヒドロキシエタノイル]−4−(2,5−ジフルオロフェニル)−2,5−ジヒドロ−1H−ピロール−2−イル]フェニル 二水素リン酸塩;
3−((2S)−4−(2,5−ジフルオロフェニル)−1−{[メチル(テトラヒドロフラン−3−イル)アミノ]カルボニル−2,5−ジヒドロ−1H−ピロール−2−イル)フェニル 二水素リン酸塩;
3−{(2S)−4−(2,5−ジフルオロフェニル)−1−[(2S)−2−ヒドロキシ−3,3−ジメチルブタノイル]−2,5−ジヒドロ−1H−ピロール−2−イル}フェニル 二水素リン酸塩;
2−(ホスホノオキシ)エチル(1S)−1−{[(2S)−4−(2,5−ジフルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−イル]カルボニル−2,2−ジメチルプロピルカルバメート;及び
(1S)−1−シクロプロピル−2−[(2S)−4−(2,5−ジフルオロフェニル)−2−フェニル−2,5−ジヒドロ−1H−ピロール−1−イル]−2−オキソエチル 二水素リン酸塩;
から選択される化合物、又は薬学的に許容されるその塩若しくは立体異性体。
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CA2576619A1 (en) | 2004-08-18 | 2006-02-23 | Altana Pharma Ag | Benzothienopyridines for use as inhibitors of eg5 kinesin |
EP1963258A4 (en) * | 2005-12-19 | 2011-06-29 | Methylgene Inc | HISTONE DEACETYLASE INHIBITORS FOR INCREASING THE ACTIVITY OF ANTIFUNGAL AGENTS |
EP1996592B1 (en) | 2006-02-22 | 2014-08-27 | 4Sc Ag | INDOLOPYRIDINES AS MODULATORS OF KINSIN EG5 |
KR20090094383A (ko) | 2006-12-19 | 2009-09-04 | 메틸진 인크. | 히스톤 탈아세틸화효소의 억제제 및 이의 프로드럭 |
US8796330B2 (en) * | 2006-12-19 | 2014-08-05 | Methylgene Inc. | Inhibitors of histone deacetylase and prodrugs thereof |
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WO2011133520A1 (en) | 2010-04-19 | 2011-10-27 | Synta Pharmaceuticals Corp. | Cancer therapy using a combination of a hsp90 inhibitory compounds and a egfr inhibitor |
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US9402831B2 (en) | 2011-11-14 | 2016-08-02 | Synta Pharmaceutical Corp. | Combination therapy of HSP90 inhibitors with BRAF inhibitors |
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EP1636182A2 (en) | 2006-03-22 |
WO2004111193A2 (en) | 2004-12-23 |
WO2004111193A3 (en) | 2005-03-24 |
JP2007505949A (ja) | 2007-03-15 |
AU2004248160B2 (en) | 2010-05-27 |
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