JP2014129427A - 腫瘍の治療のためのピペリジンおよびピペラジン誘導体 - Google Patents
腫瘍の治療のためのピペリジンおよびピペラジン誘導体 Download PDFInfo
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- JP2014129427A JP2014129427A JP2014079895A JP2014079895A JP2014129427A JP 2014129427 A JP2014129427 A JP 2014129427A JP 2014079895 A JP2014079895 A JP 2014079895A JP 2014079895 A JP2014079895 A JP 2014079895A JP 2014129427 A JP2014129427 A JP 2014129427A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/26—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
- C07D249/18—Benzotriazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
【解決手段】式Iの化合物(式中、R1、R2、R3、D、G、QおよびWは請求項1に示した意味を有する)は、腫瘍を治療するために使用することができる。
【選択図】なし
Description
本発明は、有益な特性を有する新規な化合物、特に医薬品の製造に用いることができる化合物を見出す目的に基づいた。
オートタキシンを阻害できる化合物が、Pengら、Bioorganic & Medicinal Chemistry(Letters 17、2007、1634−1640頁)(非特許文献1)に記載されている。そこに記載されている化合物は脂質類似物であるが、これらは、本発明による化合物と共通する構造的特徴をなんら有していない。
R1は、置換されていないか、またはA、Hal、NR2、(CR2)nCN、OR5および/または=O(カルボニル酸素)で一置換、二置換または三置換されていてよい、1〜4個のN、Oおよび/またはS原子を有する二環式不飽和または芳香族複素環を表し、
DはCまたはSを表し、
GはNまたはCを表し、
G=Nである場合、
R2は存在せず、
G=Cである場合、
R2はHまたはAr1を表すか、
または、
それにR2が結合しているC原子と一緒になって、かつE−Wと一緒になって、基
Qは、その1〜5個のH原子がA、(CR2)n[X(CR2)n]p−Y、Fおよび/またはClで置き換えられていてよい、1、2、3または4個のC原子を有する非分岐状もしくは分岐状アルキレンを表し、
R3は、H、A、Ar、OR、SR、NR2、Hal、NO2、CNまたは(CR2)n[X(CR2)n]p−Yを表し、
Xは、O、NRまたはCR2を表し、
YはORまたはNR2を表し、
R5は、H、またはその1〜7個のH原子がFおよび/またはClで置き換えられていてよい、1、2、3、4、5もしくは6個のC原子を有する非分岐状もしくは分岐状アルキルを表し、
Eは、COO(CR2)n、COO(CRR4)、CO(CR2)mO、CONH(CR2)n、C(=S)NH(CR2)n、S(O)qNH(CR2)n、S(O)q(CR2)n、CO(CR2)n、(CR2)n、CO(CR2)mO(CR2)n、CO(CR2)mNH(CR2)n、CO(CH2)nCO、COCHR6CHR7、C(=S)O(CR2)n、CO(CRR4)(CR2)n、COO(CRR4)、(CRR4)(CR2)n、S(O)qCR=CR、COCR=CR、(CR2)mCO、CONH(CR2)mCRR4または(CR2)mCONRを表し、
R4は、COOR5、Ar1、NRCOOR8、(CR2)nNR2またはNRCOOAを表し、
R6、R7は一緒になって(CH2)1〜4を表し、
R8は、フェニル、ナフチルまたはフオレニル(fuorenyl)を表し、
Rは、H、または1、2、3、4、5もしくは6個のC原子を有する非分岐状もしくは分岐状アルキルを表し、
Wは、ArまたはHetを表し、
Arはフェニル、インダニル、ナフチルまたはビフェニルを表し、そのそれぞれは、置換されていないか、またはHal、A、(CR2)nOR、O(CR2)nAr1、(CR2)nNR2、SR、NO2、CN、COOR、CONR2、NRCOA、NRSO2A、SO2NR2、S(O)qA、CO−Het、(CR2)nHet、O(CR2)nNR2、O(CR2)nHet、NHCOOA、NHCONR2、NHCOO(CR2)nNR2、NHCOO(CR2)nHet、CR5=CR5Ar1、SO2Het、NHCONH(CR2)nNR2、NHCONH(CR2)nHet、OCONH(CR2)nNR2、OCONH(CR2)nHet、CONR(CR2)nNR2、CONR(CR2)nHetおよび/またはCOAで一置換、二置換、三置換、四置換または五置換されており、
Hetは、置換されていないか、またはHal、A、(CR2)nAr1、O(CR2)nAr1、(CR2)nOR、(CR2)nNR2、SR、NO2、CN、COOR、CONR2、NRCOA、NRSO2A、SO2NR2、S(O)qA、CO−Het1、(CR2)nHet1、O(CR2)nNR2、O(CR2)nHet1、NHCOOA、NHCONR2、NHCOO(CR2)nNR2、NHCOO(CR2)nHet1、NHCONH(CR2)nNR2、NHCONH(CR2)nHet1、OCONH(CR2)nNR2、OCONH(CR2)nHet1、CO−Het1、CHO、COA、=S、=NH、=NAおよび/または=O(カルボニル酸素)で一置換、二置換または三置換されていてよい、1〜4個のN、Oおよび/またはS原子を有する単環式、二環式または三環式飽和、不飽和または芳香族複素環を表し、
Het1は、A、OA、OH、Halおよび/または=O(カルボニル酸素)で一置換または二置換されていてよい、1〜2個のNおよび/またはO原子を有する単環式飽和複素環を表し、
Ar1は、置換されていないか、またはHal、CN、Aおよび/または(CR2)nORで一置換、二置換、三置換、四置換または五置換されたフェニルを表し、
Aは、その1〜7個のH原子がOR、CN、NR2、Fおよび/またはClで置き換えられていてよく、かつ/または、1つもしくは2つの非隣接CH2基が、O、NH、S、SO、SO2および/またはCH=CH基で置き換えられていてよい、1〜10個のC原子を有する非分岐状もしくは分岐状アルキル、
または、
3〜7個のC原子を有する環状アルキルを表し、
mは、1、2、3、4、5または6を表し、
nは、0、1、2、3、4、5、6、7または8を表し、
pは、1、2、3、4、5または6を表し、
qは、0、1または2を表し、
Halは、F、Cl、BrまたはIを表す)
ならびに薬剤として使用可能なその互変異性体、塩およびそれらの立体異性体、ならびにすべての比のそれらの混合物、に関する。
a)式IIの化合物
を次の式IIIの化合物
Lは、Cl、Br、I、または遊離OH基もしくは反応的官能的に改変されたOH基を表す)
と反応させるか、
または、
b)式IVの化合物
G=Nである)
を、次の式Vの化合物
L−E−W V
(式中、
EおよびWは請求項1に示した意味を有し、
Lは、Cl、Br、I、または遊離OH基もしくは反応的官能的に改変されたOH基を表す)
と反応させ、
かつ/または式Iの塩基もしくは酸をその塩の1つに転換させることを特徴とする、
特許請求の範囲による式Iの化合物、ならびに薬剤として使用可能なその塩および立体異性体の製造方法に関する。
R2は好ましくは、
G=Nである場合、存在せず、
G=Cである場合、Hを表す、
R3は好ましくはHを表す、
Qは好ましくは、メチレンまたはエチレンを表す、
R5は好ましくは、H、またはその1〜5個のH原子がFで置き換えられていてよい1、2、3もしくは4個のC原子を有する非分岐状もしくは分岐状アルキルを表す、
Dは好ましくはCを表す、
Rは好ましくは、H、メチルまたはエチルを表し、特に好ましくはHを表す。
Ar1は好ましくは、置換されていないか、またはHal、CN、Aおよび/または(CR2)nОRで一置換、二置換、三置換、四置換または五置換されたフェニルを表す。
mは1、2、3または4、
nは0、1、2、3または4、
pは1、2、3または4、
qは0、1または2
を有する。
Iaにおいて、R1は以下の群、
から選択される二環式不飽和または芳香族複素環を表し、
Ibにおいて、R1は以下の群、
から選択される二環式不飽和または芳香族複素環を表し、
Icにおいて、
G=Nである場合、R2は存在せず、
G=Cである場合、R2はHを表し、
Idにおいて、R3はHを表し、
Ieにおいて、Qは、非分岐状もしくは分岐状のメチレン、エチレン、プロピレンまたはブチレンを表し、
Ifにおいて、R5はH、または1、2、3または4個のC原子を有する非分岐状もしくは分岐状アルキルを表し、その1〜5個のH原子はFで置き換えられていてよく、
Igにおいて、DはCを表し、
Ihにおいて、RはH、メチルまたエチルを表し、
Iiにおいて、RはHを表し、
Ijにおいて、Arはフェニル、インダニル、ナフチルまたはビフェニルを表し、そのそれぞれは置換されていないか、またはHal、A、(CR2)OR、O(CR2)nAr1、(CR2)nNR2、SR、NO2、CN、COOR、CONR2、NRCOA、NRSO2A、SO2NR2、S(O)qA、CO−Het、(CR2)nHet、O(CR2)nNR2、CR5=CR5Ar1および/またはSO2Hetで一置換、二置換、三置換、四置換または五置換されており、
Ikにおいて、Hetは、置換されていないか、またはHal、A、Ar1および/または=O(カルボニル酸素)で一置換または二置換されていてよい1〜3個のN、Oおよび/またはS原子を有する単環式または二環式飽和、不飽和または芳香族複素環を表し、
Ilにおいて、Hetは、ピペリジニル、ピペラジニル、ピロリジニル、モルホリニル、フリル、チエニル、ピロリル、イミダゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、ピリジル、ピリミジニル、トリアゾリル、テトラゾリル、オキサジアゾリル、チアジアゾリル、ピリダジニル、ピラジニル、ベンズイミダゾリル、ベンゾトリアゾリル、インドリル、ベンゾ−1,3−ジオキソリル、インダゾリル、2,3−ジヒドロベンゾ−1,4−ジオキシニル、クロマニルまたはベンゾ−2,1,3−チアジアゾリルを表し、そのそれぞれは置換されていないか、またはHal、A、Ar1および/または=O(カルボニル酸素)で一置換または二置換されており、
Imにおいて、Aは、1〜10個のC原子を有する非分岐状もしくは分岐状アルキルを表し、その1〜7個のH原子はFおよび/またはClで置き換えられていてよく、
Inにおいて、
mは1、2、3または4を表し、
nは0、1、2、3または4を表し、
pは1、2、3または4を表し、
qは0、1または2を表し、
Ioにおいて、R1は以下の群、
置換されていないか、またはA、Hal、NR2、(CR2)nCN、OR5および/または=O(カルボニル酸素)で一置換、二置換または三置換されていてよい、基
GはNまたはCを表し、
G=Nである場合、
R2は存在せず、
G=Cである場合、
R2はHまたはAr1を表すか、
または、
それにR2が結合しているC原子と一緒になって、かつE−Wと一緒になって、基
Qは、非分岐状もしくは分岐状のメチレン、エチレン、プロピレンまたはブチレンを表し、
R3はHを表し、
R5は、H、またはその1〜5個のH原子がFで置き換えられていてよい、1、2、3もしくは4個のC原子を有する非分岐状もしくは分岐状アルキルを表し、
Eは、COO(CR2)n、COO(CRR4)、CO(CR2)mO、CONH(CR2)n、S(O)q(CR2)n、CO(CR2)n、(CR2)n、CO(CR2)mO(CR2)p、CO(CR2)mNH(CR2)p、C(=S)O(CR2)n、CO(CRR4) (CR2)n、COO(CRR4)、(CRR4) (CR2)n、S(O)qCR=CR、COCR=CR、(CR2)mCOまたは(CR2)mCONRを表し、
R4は、COOR5、Ar1、(CR2)nNR2またはNRCOOAを表し、
Rは、H、または1、2、3、4、5もしくは6個のC原子を有する非分岐状もしくは分岐状アルキルを表し、
WはArまたはHetを表し、
Arは、フェニル、インダニル、ナフチルまたはビフェニルを表し、そのそれぞれは、置換されていないか、またはHal、A、(CR2)nOR、O(CR2)nAr1、(CR2)nNR2、SR、NO2、CN、COOR、CONR2、NRCOA、NRSO2A、SO2NR2、S(O)qA、CO−Het、(CR2)nHet、O(CR2)nNR2、CR5=CR5Ar1および/またはSO2Hetで一置換、二置換、三置換、四置換または五置換されており、
Hetは、置換されていないか、またはHal、A、Ar1および/または=O(カルボニル酸素)で一置換または二置換されていてよい、1〜3個のN、Oおよび/またはS原子を有する単環式または二環式飽和、不飽和または芳香族複素環を表し、
Ar1は、Hal、CN、Aおよび/または(CR2)nORで一置換、二置換、三置換、四置換または五置換されたフェニルを表し、
Aは、その1〜7個のH原子がFおよび/またはClで置き換えられていてよい、1〜10個のC原子を有する非分岐状もしくは分岐状アルキルを表し、
mは、1、2、3または4を表し、
nは、0、1、2、3または4を表し、
pは、1、2、3または4を表し、
qは、0、1または2を表し、
Halは、F、Cl、BrまたはIを表し、
Ipにおいて、R1は、
DはCを表し、
GはNまたはCを表し、
G=Nである場合、R2は存在せず、
G=Cである場合、R2はHまたはAr1を表すか、
または、
それにR2が結合しているC原子と一緒になって、かつE−Wと一緒になって、基
Qは、メチレン、エチレン、プロピレンまたはブチレンを表し、
R3はHを表し、
R5は、H、またはその1〜5個のH原子がFで置き換えられていてよい、1、2、3もしくは4個のC原子を有する非分岐状もしくは分岐状アルキルを表し、
Eは、COO(CR2)n、COO(CRR4)、CO(CR2)mO、CONH(CR2)n、S(O)q(CR2)n、CO(CR2)n、(CR2)n、CO(CR2)mO(CR2)p、CO(CR2)mNH(CR2)p、C(=S)O(CR2)n、CO(CRR4)(CR2)n、COO(CRR4)、(CRR4)(CR2)n、S(O)qCR=CR、COCR=CR、(CR2)mCOまたは(CR2)mCONRを表し、
R4は、COOR5、Ar1、(CR2)nNR2またはNRCOOAを表し、
Rは、H、メチルまたはエチルを表し、
WはArまたはHetを表し、
Arは、フェニル、インダニル、ナフチルまたはビフェニルを表し、そのそれぞれは、置換されていないか、またはHal、A、(CR2)nOR、O(CR2)nAr1、(CR2)nNR2、SR、NO2、CN、COOR、CONR2、NRCOA、NRSO2A、SO2NR2、S(O)qA、CO−Het、(CR2)nHet、O(CR2)nNR2、CR5=CR5Ar1および/またはSO2Hetで一置換、二置換、三置換、四置換または五置換されており、
Hetは、ピペリジニル、ピペラジニル、ピロリジニル、モルホリニル、フリル、チエニル、ピロリル、イミダゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、ピリジル、ピリミジニル、トリアゾリル、テトラゾリル、オキサジアゾリル、チアジアゾリル、ピリダジニル、ピラジニル、ベンズイミダゾリル、ベンゾトリアゾリル、インドリル、ベンゾ−1,3−ジオキソリル、インダゾリル、2,3−ジヒドロベンゾ−1,4−ジオキシニル、クロマニルまたはベンゾ−2,1,3−チアジアゾリルを表し、そのそれぞれは、置換されていないか、またはHal、A、Ar1および/または=O(カルボニル酸素)で一置換または二置換されており、
Ar1は、Hal、CN、Aおよび/または(CR2)nORで一置換、二置換、三置換、四置換または五置換されたフェニルを表し、
Aは、その1〜7個のH原子がFおよび/またはClで置き換えられていてよい、1〜10個のC原子を有する非分岐状もしくは分岐状アルキルを表し、
mは、1、2、3または4を表し、
nは、0、1、2、3または4を表し、
pは、1、2、3または4を表し、
qは、0、1または2を表し、
Halは、F、Cl、BrまたはIを表す。
(a)有効量の式Iの化合物および/または薬剤として使用可能なその誘導体、溶媒和物およびすべての比のその混合物を含む立体異性体
および
(b)有効量の他の医薬品活性成分
の個別のパックからなるセット(キット)にも関する。
FAB(高速原子衝撃)(M+H)+
ESI(エレクトロスプレーオン化)(M+H)+
APCI−MS(大気圧化学イオン化−質量分析)(M+H)+
LC/MS法:
溶媒A:水+0.1%のTFA
溶媒B:アセトニトリル+0.1%のTFA
流量:2.4ml/分
勾配:0.0分 4%のB
2.6分 100%のB
カラム:Chromolith(登録商標)Speed ROD RP−18e 50−4、6mm
HPLC法:
溶媒A:水+0.1%のTFA
溶媒B:アセトニトリル+0.08%のTFA
流量:1.5ml/分
勾配:0.0分 20%のB
6.0分 100%のB
7.0分 100%のB
8.0分 20%のB
9.0分 20%のB
カラム:Chromolith(登録商標)RP18e 100−4、6mm。
4−クロロベンジル4−[3−オキソ−3−(2−オキソ−2,3−ジヒドロベンズオキサゾール−6−イル)プロピル]ピペラジン−1−カルボキシレート(「A1」)の合成を以下のスキームと同様にして実施する。
d.4−クロロベンジルアルコール(10.0g、70.1ミリモル)をDCM(200ml)に溶解し、1,1’−カルボニルジイミダゾール(11.9g、73.6ミリモル)を加え、撹拌をRTで3時間続行する。tert−ブチル1−ピペラジン−N−カルボキシレート(14.4g、77.1ミリモル)をこの混合物に加える。撹拌をRTで18時間続行する。反応混合物をDCM(100ml)で希釈し、水で2回洗浄し、有機相を硫酸ナトリウムで脱水し、ろ別し、乾燥するまで蒸発させる。乾燥した粗製物質5(24.5g、69.0ミリモル、98%)を、さらに精製することなく反応させる。
6−(3−{4−[2−(4−クロロフェノキシ)アセチル]ピペラジン−1−イル}プロピオニル)−3H−ベンズオキサゾール−2−オン(「A2」)の合成を以下のスキームと同様にして実施する。
j.4−クロロフェノキシアセチルクロリド(0.50g、2.44ミリモル)をDMF(10ml)に溶解し、化合物3(0.76g、2.44ミリモル)をRTで加えた。撹拌をRTで18時間続行した。水(10ml)を反応混合物に加え、生成した沈殿物をろ別した。後者を水で洗浄し、乾燥(真空乾燥器)した。得られた無色固体は化合物「A2」と同様のもの(0.96g、2.16ミリモル、89%)であった。1H−NMR(DMSO−d6):δ[ppm]=2.37〜243(m、2H)、2.43〜2.48(m、2H)、2.71(t、2H)、3.15〜3.21(m、2H)、3.34〜3.45(m、4H)、4.81(s、2H)、6.93(d、2H)、7.17(d、1H)、7.30(d、2H)、7.83〜7.88(m、2H)、11.72(s(b)、1H)。
6−(3−{4−[2−(4−クロロフェニル)エチルスルホニル]ピペラジン−1−イル}プロピオニル)−3H−ベンズオキサゾール−2−オン(「A3」)、
N−(4−トリフルオロメトキシベンジル)4−[3−オキソ−3−(2−オキソ−2,3−ジヒドロベンズオキサゾール−6−イル)−プロピル]ピペラジン−1−カルボキサミド(「A4」)、
6−(3−{4−[3−(4−トリフルオロメチルフェニル)プロピオニル]ピペラジン−1−イル}プロピオニル)−3H−ベンズオキサゾール−2−オン(「A5」)の調製を、以下のスキームと同様にして実施する。
1H−NMR(DMSO−d6):δ[ppm]=2.34(s(b)、4H)、2.63〜2.71(m、4H)、2.90(t、2H)、3.13〜3.20(m、2H)、3.35〜3.46(m、4H)、7.17(d、1H)、7.47(d、2H)、7.62(d、2H)、7.83〜7.88(m、2H)、11.95(s、1H)。
4−クロロベンジル4−[2−オキソ−2−(2−オキソ−2,3−ジヒドロベンズオキサゾール−6−イル)エチル]ピペラジン−1−カルボキシレート(「A6」)の調製を、以下のスキームと同様にして実施する。
N−(4−クロロベンジル)−1−[3−オキソ−3−(2−オキソ−2,3−ジヒドロベンズオキサゾール−6−イル)プロピル]ピペリジン−4−カルボキサミド(「A7」)の調製を、以下のスキームと同様にして実施する。
を同様にして得る。
3,5−ジクロロベンジル4−[2−(3H−ベンゾトリアゾール−5−スルフィニル)エチル]ピペラジン−1−カルボキシレート(「B48」);塩酸塩8の合成
試験の説明
オートタキシン活性を、Amplex Red試薬を用いて間接的に測定する。ここではAmplex Redを、生成したH2O2についての蛍光指示薬として測定を行う。詳細には、オートタキシンが、基質リゾホスファチジルコリン(LPC)をホスホコリンおよびリゾホスファチジン酸(LPA)へ転換させる。この反応の後、ホスホコリンをアルカリ性ホスファターゼと反応させて無機リン酸塩とコリンを得る。次のステップで、コリンをコリンオキシダーゼで酸化させて、H2O2の生成を伴って、ベタインにする。1:1の化学量論比でのペルオキシダーゼ(西洋ワサビペルオキシダーゼ)の存在下、H2O2をAmplex Red試薬と反応させ、高度に蛍光性のレゾルフィンを生成する。反応に関わっていない可能性のある他の蛍光性物質からの蛍光シグナルを修正するために、蛍光を反応依存性動態モードで測定する。
最大で77%のDMSOを含む20mM Hepes pH7.2中に溶解した個々の濃度の1.5μlの標準溶液または試験物質(名称A(n)を有する物質)を、384ウェルを備えた黒色のマイクロタイタープレート中で、10μl(16ng)の高度に精製した組換えオートタキシンとともに22℃で30分間プレインキュベートする。次いで、5μlのL−a−リゾホスファチジルコリン(LPC)を加えて反応を開始させる。LPCの最終濃度は75μMである。混合物を37℃で90分間インキュベートする。インキュベーションした後、Amplex Red試薬、ペルオキシダーゼ(西洋ワサビペルオキシダーゼ)およびコリンオキシダーゼを加え、蛍光を、「Tecan Ultraマルチモード」リーダーで、485nmの励起によって直ちに612nmで測定する。オートタキシンの活性度を、生成したH2O2の検出によって間接的に算出する。
マイクロタイタープレート:PSマイクロプレート、384ウェル、小容積、黒色Corning、カタログ番号3677
タンパク質:組換えオートタキシン(バキュロウイルスHi5発現(Baculovirale Hi5 Expression))
基質:L−a−リゾホスファチジルコリン(鶏卵);Avanti Polar Lipids#830071P
標準:C14 LPA、Avanti Polar Lipids、カタログ番号857120P
検出試薬:Amplex Red試薬;Invitrogen#A12222;Sigma#P6782からの1.923mlのDMSOペルオキシダーゼ型VI−A(西洋ワサビ)に溶解;7.45mlの試験緩衝液に溶解、コリンオキシダーゼ;Sigma#C5896;2.47mlの試験緩衝液に溶解
検出試薬ミックス:Amplex Red試薬を試験緩衝液中に1:100で希釈
試験緩衝剤:200mMトリスHCl、Merck、カタログ番号1.08219、pH7.9、0.1%のBSA、脂質フリー、Rocheカタログ番号775835
以下の例は医薬品に関するものである:
例B:注入バイアル
3lの再蒸留水(bidistilled water)中の100gの式Iの活性成分および5gのリン酸1水素2ナトリウムの溶液を2N塩酸でpH6.5に調節し、注入バイアル中に滅菌ろ過して移し、無菌条件下で凍結乾燥し、無菌条件下で密封する。各注入バイアルは5mgの活性成分を含む。
20gの式Iの活性成分と100gの大豆レクチンの混合物と1400gのココアバターを溶融させ鋳型に注加し、冷却する。各坐剤は20mgの活性成分を含む。
溶液を、940mlの再蒸留水中の1gの式Iの活性成分、9.38gのNaH2PO4・2H2O、28.48gのNa2HPO4・12H2Oおよび0.1gの塩化ベンザルコニウムで調製する。pHを6.8に調節し、溶液を1lにして放射線で滅菌する。この液剤を、点眼剤の形態で使用することができる。
500mgの式Iの活性成分を無菌状態下で99.5gのワセリンと混合する。
1kgの式Iの活性成分、4kgのラクトース、1.2kgのジャガイモでんぷん、0.2kgのタルクおよび0.1kgのステアリン酸マグネシウムの混合物を慣用的な方法で圧縮し、各錠剤が10mgの活性成分を含むような形で押圧して錠剤を得る。
錠剤を例Eと同様にして押圧し、続いて慣用的な方法により、スクロース、ジャガイモでんぷん、タルク、トラガカントおよび染料からなるコーティング材でコーティングする。
2kgの式Iの活性成分を、各カプセルが20mgの活性成分を含むような形で慣用的な方法で硬質ゼラチンカプセル中に導入する。
60lの再蒸留水中の1kgの式Iの活性成分の溶液を滅菌ろ過して、アンプルに移し、無菌条件下で凍結乾燥し、無菌条件下で密封する。各アンプルは10mgの活性成分を含む。
Claims (27)
- 式Iの化合物
(式中、
R1は、置換されていないか、またはA、Hal、NR2、(CR2)nCN、OR5および/または=O(カルボニル酸素)で一置換、二置換または三置換されていてよい、1〜4個のN、Oおよび/またはS原子を有する二環式不飽和または芳香族複素環を表し、
DはCまたはSを表し、
GはNまたはCを表し、
G=Nである場合、
R2は存在せず、
G=Cである場合、
R2はHまたはAr1を表すか、
または、
それにR2が結合しているC原子と一緒になって、かつE−Wと一緒になって、基
から選択されるスピロ環基を表し、
Qは、その1〜5個のH原子がA、(CR2)n[X(CR2)n]p−Y、Fおよび/またはClで置き換えられていてよい、1、2、3または4個のC原子を有する非分岐状もしくは分岐状アルキレンを表し、
R3は、H、A、Ar、OR、SR、NR2、Hal、NO2、CNまたは(CR2)n[X(CR2)n]p−Yを表し、
Xは、O、NRまたはCR2を表し、
YはORまたはNR2を表し、
R5は、H、またはその1〜7個のH原子がFおよび/またはClで置き換えられていてよい、1、2、3、4、5もしくは6個のC原子を有する非分岐状もしくは分岐状アルキルを表し、
Eは、COO(CR2)n、COO(CRR4)、CO(CR2)mO、CONH(CR2)n、C(=S)NH(CR2)n、S(O)qNH(CR2)n、S(O)q(CR2)n、CO(CR2)n、(CR2)n、CO(CR2)mO(CR2)n、CO(CR2)mNH(CR2)n、CO(CH2)nCO、COCHR6CHR7、C(=S)O(CR2)n、CO(CRR4)(CR2)n、COO(CRR4)、(CRR4)(CR2)n、S(O)qCR=CR、COCR=CR、(CR2)mCO、CONH(CR2)mCRR4または(CR2)mCONRを表し、
R4は、COOR5、Ar1、NRCOOR8、(CR2)nNR2またはNRCOOAを表し、
R6、R7は一緒になって(CH2)1〜4を表し、
R8は、フェニル、ナフチルまたはフオレニルを表し、
Rは、H、または1、2、3、4、5もしくは6個のC原子を有する非分岐状もしくは分岐状アルキルを表し、
WはArまたはHetを表し、
Arは、フェニル、インダニル、ナフチルまたはビフェニルを表し、そのそれぞれは、置換されていないか、またはHal、A、(CR2)nOR、O(CR2)n、Ar1、(CR2)nNR2、SR、NO2、CN、COOR、CONR2、NRCOA、NRSO2A、SO2NR2、S(O)qA、CO−Het、(CR2)nHet、O(CR2)nNR2、O(CR2)nHet、NHCOOA、NHCONR2、NHCOO(CR2)nNR2、NHCOO(CR2)n−Het、CR5=CR5Ar1、SO2Het、NHCONH(CR2)nNR2、NHCONH(CR2)nHet、OCONH(CR2)nNR2、OCONH(CR2)n−Het、CONR(CR2)nNR2、CONR(CR2)nHetおよび/またはCOAで一置換、二置換、三置換、四置換または五置換されており、
Hetは、置換されていないか、またはHal、A、(CR2)nAr1、O(CR2)nAr1、(CR2)nOR、(CR2)nNR2、SR、NO2、CN、COOR、CONR2、NRCOA、NRSO2A、SO2NR2、S(O)qA、CO−Het1、(CR2)nHet1、O(CR2)nNR2、O(CR2)nHet1、NHCOOA、NHCONR2、NHCOO(CR2)nNR2、NHCOO(CR2)n−Het1、NHCONH(CR2)nNR2、NHCONH(CR2)nHet1、OCONH(CR2)nNR2、OCONH(CR2)nHet1、CO−Het1、CHO、COA、=S、=NH、=NAおよび/または=O(カルボニル酸素)で一置換、二置換または三置換されていてよい、1〜4個のN、Oおよび/またはS原子を有する単環式、二環式または三環式飽和、不飽和または芳香族複素環を表し、
Het1は、A、OA、OH、Halおよび/または=O(カルボニル酸素)で一置換または二置換されていてよい、1〜2個のNおよび/またはO原子を有する単環式飽和複素環を表し、
Ar1は、置換されていないか、またはHal、CN、Aおよび/または(CR2)nORで一置換、二置換、三置換、四置換または五置換されたフェニルを表し、
Aは、その1〜7個のH原子がOR、CN、NR2、Fおよび/またはClで置き換えられていてよく、かつ/または1つもしくは2つの非隣接CH2基が、O、NH、S、SO、SO2および/またはCH=CH基で置き換えられていてよい、1〜10個のC原子を有する非分岐状もしくは分岐状アルキル、
または、
3〜7個のC原子を有する環状アルキルを表し、
mは、1、2、3、4、5または6を表し、
nは、0、1、2、3、4、5、6,7または8を表し、
pは、1、2、3、4、5または6を表し、
qは、0、1または2を表し、
Halは、F、Cl、BrまたはIを表す)
ならびに薬剤として使用可能なその互変異性体、塩およびそれらの立体異性体、ならびにすべての比のそれらの混合物。 - G=Nである場合、
R2が存在せず、
G=Cである場合、
R2がHを表す
請求項1から3の一項または複数項に記載の化合物、ならびに薬剤として使用可能なその互変異性体、塩およびそれらの立体異性体、ならびにすべての比のそれらの混合物。 - R3がHを表す、請求項1から4の一項または複数項に記載の化合物、ならびに薬剤として使用可能なその互変異性体、塩およびそれらの立体異性体、ならびにすべての比のそれらの混合物。
- Qが、非分岐状もしくは分岐状メチレン、エチレン、プロピレンまたはブチレンを表す、請求項1から5の一項または複数項に記載の化合物、ならびに薬剤として使用可能なその互変異性体、塩およびそれらの立体異性体、ならびにすべての比のそれらの混合物。
- R5が、H、またはその1〜5個のH原子がFで置き換えられていてよい、1、2、3または4個のC原子を有する非分岐状もしくは分岐状アルキルを表す、請求項1から6の一項または複数項に記載の化合物、ならびに薬剤として使用可能なその互変異性体、塩およびそれらの立体異性体、ならびにすべての比のそれらの混合物。
- RがH、メチルまたはエチルを表す、請求項1から7の一項または複数項に記載の化合物、ならびに薬剤として使用可能なその互変異性体、塩およびそれらの立体異性体、ならびにすべての比のそれらの混合物。
- RがHを表す、請求項1から8の一項または複数項に記載の化合物、ならびに薬剤として使用可能なその互変異性体、塩およびそれらの立体異性体、ならびにすべての比のそれらの混合物。
- Arが、フェニル、インダニル、ナフチルまたはビフェニルを表し、そのそれぞれは置換されていないか、またはHal、A、(CR2)nOR、O(CR2)nAr1、(CR2)nNR2、SR、NO2、CN、COOR、CONR2、NRCOA、NRSO2A、SO2NR2、S(O)qA、CO−Het、(CR2)nHet、O(CR2)nNR2、CR5=CR5Ar1および/またはSO2Hetで一置換、二置換、三置換、四置換または五置換されている、請求項1から9の一項または複数項に記載の化合物、ならびに薬剤として使用可能なその互変異性体、塩およびそれらの立体異性体、ならびにすべての比のそれらの混合物。
- Hetが、置換されていないか、またはHal、A、(CR2)nAr1および/または=O(カルボニル酸素)で一置換または二置換されていてよい、1〜3個のN、Oおよび/またはS原子を有する単環式または二環式飽和、不飽和または芳香族複素環を表す、請求項1から10の一項または複数項に記載の化合物、ならびに薬剤として使用可能なその互変異性体、塩およびそれらの立体異性体、ならびにすべての比のそれらの混合物。
- Hetが、ピペリジニル、ピペラジニル、ピロリジニル、モルホリニル、フラニル、チエニル、ピロリル、イミダゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、ピリジル、ピリミジニル、トリアゾリル、テトラゾリル、オキサジアゾリル、チアジアゾリル、ピリダジニル、ピラジニル、ベンズイミダゾリル、ベンゾトリアゾリル、インドリル、ベンゾ−1,3−ジオキソリル、インダゾリル、2,3−ジヒドロベンゾ−1,4−ジオキシニル、クロマニル、チアゾリジニル、イソインドリル、テトラヒドロフラニル、カルバゾリル、ベンゾ[b]チオフェニルまたはベンゾ−2,1,3−チアジアゾリルを表し、そのそれぞれは置換されていないか、またはHal、A、(CR2)nAr1および/または=O(カルボニル酸素)で一置換または二置換されている、請求項1から13の一項または複数項に記載の化合物、ならびに薬剤として使用可能なその互変異性体、塩およびそれらの立体異性体、ならびにすべての比のそれらの混合物。
- Aが、その1〜7個のH原子がFおよび/またはClで置き換えられていてよい、1〜10個のC原子を有する非分岐状もしくは分岐状アルキルを表す、請求項1から12の一項または複数項に記載の化合物、ならびに薬剤として使用可能なその互変異性体、塩およびそれらの立体異性体、ならびにすべての比のそれらの混合物。
- mが、1、2、3または4を表し、
nが、0、1、2、3または4を表し、
pが、1、2、3または4を表し、
qが、0、1または2を表す、請求項1から13の一項または複数項に記載の化合物、ならびに薬剤として使用可能なその互変異性体、塩およびそれらの立体異性体、ならびにすべての比のそれらの混合物。 - R1が、置換されていないか、またはA、Hal、NR2、(CR2)nCN、OR5および/または=O(カルボニル酸素)で一置換、二置換または三置換されていてよい、基
から選択される二環式不飽和または芳香族複素環を表し、
DがCまたはSを表し、
GがNまたはCを表し、
G=Nである場合、
R2は存在せず、
G=Cである場合、
R2がHまたはAr1を表すか、
または、
それにR2が結合しているC原子と一緒になって、かつE−Wと一緒になって、基
から選択されるスピロ環基を表し、
Qが、非分岐状もしくは分岐状メチレン、エチレン、プロピレンまたはブチレンを表し、
R3がHを表し、
R5が、H、またはその1〜5個のH原子がFで置き換えられていてよい、1、2、3もしくは4個のC原子を有する非分岐状もしくは分岐状アルキルを表し、
Eが、COO(CR2)n、COO(CRR4)、CO(CR2)mO、CONH(CR2)n、S(O)q(CR2)n、CO(CR2)n、(CR2)n、CO(CR2)mO(CR2)p、CO(CR2)mNH(CR2)p、C(=S)O(CR2)n、CO(CRR4)(CR2)n、COO(CRR4)、(CRR4)(CR2)n、S(O)qCR=CR、COCR=CR、(CR2)mCOまたは(CR2)mCONRを表し、
R4が、COOR5、Ar1、(CR2)nNR2またはNRCOOAを表し、
Rが、H、または1、2、3、4、5もしくは6個のC原子を有する非分岐状もしくは分岐状アルキルを表し、
WがArまたはHetを表し、
Arが、フェニル、インダニル、ナフチルまたはビフェニルを表し、そのそれぞれは、置換されていないか、またはHal、A、(CR2)nOR、O(CR2)nAr1、(CR2)nNR2、SR、NO2、CN、COOR、CONR2、NRCOA、NRSO2A、SO2NR2、S(O)qA、CO−Het、(CR2)nHet、O(CR2)nNR2、CR5=CR5Ar1および/またはSO2Hetで一置換、二置換、三置換、四置換または五置換されており、
Hetが、置換されていないか、またはHal、A、(CR2)nAr1および/または=O(カルボニル酸素)で一置換または二置換されていてよい、1〜3個のN、Oおよび/またはS原子を有する単環式または二環式飽和、不飽和または芳香族複素環を表し、
Ar1が、置換されていないか、またはHal、CN、Aおよび/または(CR2)nORで一置換、二置換、三置換、四置換または五置換されたフェニルを表し、
Aが、その1〜7個のH原子がFおよび/またはClで置き換えられていてよい、1〜10個のC原子を有する非分岐状もしくは分岐状アルキルを表し、
mが、1、2、3または4を表し、
nが、0、1、2、3または4を表し、
pが、1、2、3または4を表し、
qが、0、1または2を表し、
Halが、F、Cl、BrまたはIを表す
請求項1から14の一項または複数項に記載の化合物、ならびに薬剤として使用可能なその互変異性体、塩およびそれらの立体異性体、ならびにすべての比のそれらの混合物。 - R1が、A、Hal、NR2、(CR2)nCNおよび/またはOR5でさらに一置換または二置換されていてよい、基
から選択される二環式不飽和または芳香族複素環を表し、
DがCまたはSを表し、
GがNまたはCを表し、
G=Nである場合、
R2は存在せず、
G=Cである場合、
R2はHまたはAr1を表すか、
または、
それにR2が結合しているC原子と一緒になって、かつE−Wと一緒になって、基
から選択されるスピロ環基を表し、
Qが、メチレン、エチレン、プロピレンまたはブチレンを表し、
R3がHを表し、
R5が、H、またはその1〜5個のH原子がFで置き換えられていてよい、1、2、3もしくは4個のC原子を有する非分岐状もしくは分岐状アルキルを表し、
Eが、COO(CR2)n、COO(CRR4)、CO(CR2)mO、CONH(CR2)n、S(O)q(CR2)n、CO(CR2)n、(CR2)n、CO(CR2)mO(CR2)p、CO(CR2)mNH(CR2)p、C(=S)O(CR2)n、CO(CRR4)(CR2)n、COO(CRR4)、(CRR4)(CR2)n、S(O)qCR=CR、COCR=CR、(CR2)mCOまたは(CR2)mCONRを表し、
R4が、COOR5、Ar1、(CR2)nNR2またはNRCOOAを表し、
Rが、H、メチルまたはエチルを表し、
WがArまたはHetを表し、
Arが、フェニル、インダニル、ナフチルまたはビフェニルを表し、そのそれぞれは、置換されていないか、またはHal、A、(CR2)nOR、O(CR2)nAr1、(CR2)nNR2、SR、NO2、CN、COOR、CONR2、NRCOA、NRSO2A、SO2NR2、S(O)qA、CO−Het、(CR2)nHet、O(CR2)nNR2、CR5=CR5Ar1および/またはSO2Hetで一置換、二置換、三置換、四置換または五置換されており、
Hetが、ピペリジニル、ピペラジニル、ピロリジニル、モルホリニル、フラニル、チエニル、ピロリル、イミダゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、ピリジル、ピリミジニル、トリアゾリル、テトラゾリル、オキサジアゾリル、チアジアゾリル、ピリダジニル、ピラジニル、ベンズイミダゾリル、ベンゾトリアゾリル、インドリル、ベンゾ−1,3−ジオキソリル、インダゾリル、2,3−ジヒドロベンゾ−1,4−ジオキシニル、クロマニル、チアゾリジニル、イソインドリル、テトラヒドロフラニル、カルバゾリル、ベンゾ[b]チオフェニルまたはベンゾ−2,1,3−チアジアゾリルを表し、そのそれぞれは、置換されていないか、またはHal、A、(CR2)nAr1および/または=O(カルボニル酸素)で一置換または二置換されており、
Ar1が、置換されていないか、またはHal、CN、Aおよび/または(CR2)nORで一置換、二置換、三置換、四置換または五置換されたフェニルを表し、
Aが、その1〜7個のH原子がFおよび/またはClで置き換えられていてよい、1〜10個のC原子を有する非分岐状もしくは分岐状アルキルを表し、
mが、1、2、3または4を表し、
nが、0、1、2、3または4を表し、
pが、1、2、3または4を表し、
qが、0、1または2を表し、
Halが、F、Cl、BrまたはIを表す、請求項1から15の一項または複数項に記載の化合物、ならびに薬剤として使用可能なその互変異性体、塩およびそれらの立体異性体、ならびにすべての比のそれらの混合物。 - a)式IIの化合物
(式中、R2、R3、G、EおよびWは請求項1に示した意味を有する)
を、式IIIの化合物
(式中、R1、DおよびQは請求項1に示した意味を有し、
Lは、Cl、Br、I、または遊離OH基もしくは反応的官能的に改変されたOH基を表す)
と反応させるか、
または
b)式IVの化合物
(式中、R1、R2、R3、DおよびQは請求項1に示した意味を有し、
G=Nである)
を、次の式Vの化合物
L−E−W V
(式中、EおよびWは請求項1に示した意味を有し、
Lは、Cl、Br、I、または遊離OH基もしくは反応的官能的に改変されたOH基を表す)
と反応させ、
かつ/または式Iの塩基または酸をその塩の1つに転換させることを特徴とする式Iの化合物ならびに薬剤として使用可能なその互変異性体、塩およびそれらの立体異性体、ならびにすべての比のそれらの混合物の調製方法。 - 請求項1から18に記載の少なくとも1つの式Iの化合物、および/またはならびに薬剤として使用可能なその互変異性体、塩およびそれらの立体異性体、ならびにすべての比のそれらの混合物、ならびに任意選択の賦形剤および/または補助剤を含む医薬品。
- 有糸分裂モータータンパク質Eg5の阻害、制御および/または調節が役割を果たす疾患の治療用の医薬品を製造するための、請求項1から18に記載の化合物、ならびに薬剤として使用可能なその互変異性体、塩およびそれらの立体異性体、ならびにすべての比のそれらの混合物の使用。
- 癌疾患の治療および予防用の医薬品を製造するための、請求項1から18に記載の化合物の使用。
- 前記癌疾患が、扁平上皮、膀胱、胃、腎臓、頭頸部、食道、頸部、甲状腺、腸、肝臓、脳、前立腺、尿生殖路、リンパ系、胃、喉頭および/または肺の腫瘍の群からの腫瘍と関連する、請求項22に記載の使用。
- 前記腫瘍が、単球性白血病、肺腺癌、小細胞肺癌、膵臓癌、膠芽細胞腫、乳癌および結腸癌(colocarcinoma)の群に由来する、請求項23に記載の使用。
- 治療される疾患が血液および免疫系の腫瘍である、請求項24に記載の使用。
- 前記腫瘍が、急性骨髄性白血病、慢性骨髄性白血病、急性リンパ性白血病および/または慢性リンパ性白血病の群に由来する、請求項25に記載の使用。
- 腫瘍の治療用の医薬品の製造のための、請求項1から18に記載の式Iの化合物および/または生理学的に許容されるその塩の使用であって、治療有効量の式Iの化合物を、放射線治療ならびに1)エストロゲン受容体調節物質、2)アンドロゲン受容体調節物質、3)レチノイド受容体調節物質、4)細胞傷害性作用物質、5)抗増殖性作用物質、6)プレニル化タンパク質トランスフェラーゼ阻害薬、7)HMG−CoAレダクターゼ阻害剤、8)HIVプロテアーゼ阻害剤、9)逆転写酵素阻害剤、および10)さらなる血管新生阻害剤の群からの化合物と合わせて投与する使用。
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