JP2019518715A - ベンゼンスルホニル非対称尿素とその医学的利用 - Google Patents
ベンゼンスルホニル非対称尿素とその医学的利用 Download PDFInfo
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- JP2019518715A JP2019518715A JP2018549890A JP2018549890A JP2019518715A JP 2019518715 A JP2019518715 A JP 2019518715A JP 2018549890 A JP2018549890 A JP 2018549890A JP 2018549890 A JP2018549890 A JP 2018549890A JP 2019518715 A JP2019518715 A JP 2019518715A
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- 0 CCC=CC=C([C@@](C)N(C(NCC(CCC*(*(CCC=C*(CNCC1)=*1C=N)=O)=C1)=C1OC)=O)O)C=C Chemical compound CCC=CC=C([C@@](C)N(C(NCC(CCC*(*(CCC=C*(CNCC1)=*1C=N)=O)=C1)=C1OC)=O)O)C=C 0.000 description 2
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Abstract
Description
本発明は、新規な非対称尿素化合物と、その医学的利用、特にグレリン受容体によって調節される病状を処置するときの医学的利用に関する。
成長ホルモン分泌促進受容体(GHS-R)は、多数の生理学的プロセス(その中には成長ホルモン(GH)放出、代謝、食欲が含まれる)を調節している。グレリン(胃の中にある内分泌細胞によって主に産生されて循環するホルモン)は、その内在性リガンドである。グレリンは28個のアミノ酸からなるペプチドであり、生物活性であるにはアシル側鎖を必要とする(Kojima他、Nature、第402巻、656〜660ページ、1999年)。グレリンは成長ホルモン(GH)の放出を促進することと、中枢に投与されたときと末梢に投与されたときの両方で食事の摂取を増加させることが示されている(Wren他、Endocrinology、第141巻、4325〜4328ページ、2000年)。
本発明の発明者は、精力的な研究と実験を通じ、グレリン受容体に対する逆アゴニスト活性を有する一連の新規な化合物を予期せず発見するに至った。
本発明の化合物、組成物、物品、装置、方法を開示して説明する前に、これらは、特に断わらない限り、具体的な合成法または具体的な処置法に限定されないことや、特に断わらない限り、特定の試薬に限定されないことを理解すべきである。そのためこれらはもちろん変更することができる。本明細書で用いる用語は個々の実施態様を説明することだけを目的としているため、制限することは意図していないことも理解すべきである。
点線は、場合によっては存在する結合を表わし;
Wは、C、N、Oのいずれかであり;
Xは、結合、CO、CR7R8のいずれかであり;
kは0〜2であり;
Rは、C1-6アルキルまたはCy1であり、そのC1-6アルキルまたはCy1は、場合によっては、ハロ、ヘテロアリール、C1-6アルコキシ、C1-6アルキル、ヘテロシクロアルキル、CO2(C1-6アルキル)、CO(C1-6アルキル)から選択された1〜3個の置換基で置換されており;
R1とR2は、それぞれ独立に、H、C1-3アルキル、メトキシ、ハロ、OHのいずれかであり、
あるいはR1とR2は、それらが結合している原子と合わさって5〜6員の環を形成し;
あるいはR1とXは、それらが結合している原子と合わさって5〜6員の環を形成し;
あるいはR1とXとRは、それらが結合している原子と合わさって二環構造を形成し;
R3は、H、C1-3アルキル、メトキシ、ハロ、OH、COOR12、CR13R14OH、COHNR15、シクロアルキル、ヘテロアリールのいずれかであり;
R4は、結合、NR6、CR9R10のいずれかであり;
あるいはR3とR4は、それらが結合している原子と合わさって3〜6員の環を形成し;
R5は、Cy2、CO(C1-6アルキル)、C1-6アルキルのいずれかであり、そのCy2、CO(C1-6アルキル)、C1-6アルキルは、場合によっては、ハロ、C1-6アルキルアミン、COR11、SO2R11、ヘテロシクロアルキル、CO2R11、C1-6ヒドロキシアルキル、ヘテロアリール、CH2CO2R11、C1-6アルコキシ、OH、CN、R11、CH2OSO3H、ベンジル、CH2SO3H、CH2CN、NHCH2シクロアルキルから選択された1〜3個の置換基で置換されており;
R6は、結合、H、CH3のいずれかであり;
R7とR8は、それぞれ独立に、H、C1-3アルキル、CONH2のいずれかであり、そのC1-3アルキルは、場合によってはハロで置換されており;
R9とR10は、それぞれ独立に、HまたはC1-3アルキルであり、そのC1-3アルキルは、場合によってはハロで置換されており;
R11は、H、NH2、場合によっては置換されたC1-6アルキルのいずれかであり;
R12は、HまたはC1-3アルキルであり;
R13とR14は、それぞれ独立に、HまたはC1-3アルキルであり;
R15は、HまたはC1-3アルキルである。
X、W、R1〜R4、kは上に定義した通りであり;
Cy1は、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキルからなる群から選択された環状部分であり、その環状部分は、場合によっては、ハロ、ヘテロアリール、C1-6アルコキシ、C1-6アルキル、ヘテロシクロアルキル、CO2(C1-6アルキル)、CO(C1-6アルキル)から選択された1〜3個の置換基で置換されており;
Cy2は、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキルからなる群から選択された環状部分であり、その環状部分は、場合によっては、ハロ、C1-6アルキルアミン、COR11、SO2R11、ヘテロシクロアルキル、CO2R11、C1-6ヒドロキシアルキル、ヘテロアリール、CH2CO2R11、C1-6アルコキシ、OH、CN、R11、CH2OSO3H、ベンジル、CH2SO3H、CH2CN、NHCH2シクロアルキルから選択された1〜3個の置換基で置換されている。
X、R1〜R4、kは上に定義した通りであり;
点線は、場合によっては存在する結合を表わし;
Uは、C、N、S、Oのいずれかであり;
Bは、5〜7員の環構造または二環構造であり、その5〜7員の環構造または二環構造は、場合によっては、COR11、SO2R11、ヘテロシクロアルキル、CO2R11、C1-6ヒドロキシアルキル、ヘテロアリール、CH2CO2R11、C1-6アルコキシ、OH、CN、R11、CH2OSO3H、ベンジル、CH2SO3H、CH2CNのいずれかで置換されており;
Yは、それぞれ独立にCまたはNであり;
Zは、ハロ、メトキシ、場合によってはハロで置換されたC1-3アルキルのいずれかであり;
R'は、ハロ、ヘテロアリール、C1-6アルコキシ、C1-6アルキル、ヘテロシクロアルキル、CNシクロアルキル、CO2(C1-6アルキル)、CO(C1-6アルキル)のいずれかであり;
あるいは2つのR'は、それらが結合している原子と合わさって5〜6員の環を形成し;
lは0〜3であり;
mは0〜3であり;
nは0〜3である。
H0937の合成
H1027とH1071の合成
H1060の合成
H1148とH1194の合成
1.試験化合物貯蔵溶液:10 mMのデキストロメトルファン(Dtr)を含むDMSO溶液、10 mMのジフェンヒドラミン(DPA)を含むDMSO溶液、10 mMのオメプラゾール(Ome)を含むDMSO溶液、10 mMのベラパミル(Ver)を含むDMSO溶液、10 mMの逆アゴニスト化合物を含むDMSO溶液を、アセトニトリル/水(70/30)を用いてそれぞれ0.25 mM溶液に希釈する。
2.緩衝液:pH7.4の100 mMリン酸カリウム緩衝液(PBS)
3.肝臓ミクロソーム(20 mg/ml):37℃の水浴の中で素早く解凍する
4.2000μlのNADPH再生系(1.3 mM)。使用する前にこの系を氷の上に置く:
330μlの100 mM G6P
1300μlの10 mM NADP
5μlの1200 U/ml G6PD
365μlのPBS緩衝液
5.クエンチ溶液:LC-MS/MS分析のための、ISを含むアセトニトリル。
Claims (92)
- 式(I):
点線は、場合によっては存在する結合を表わし;
Wは、C、N、Oのいずれかであり;
Xは、結合、CO、CR7R8のいずれかであり;
kは0〜2であり;
Rは、C1-6アルキルまたはCy1であり、そのC1-6アルキルまたはCy1は、場合によっては、ハロ、ヘテロアリール、C1-6アルコキシ、C1-6アルキル、ヘテロシクロアルキル、CO2(C1-6アルキル)、CO(C1-6アルキル)から選択された1〜3個の置換基で置換されており;
R1とR2は、それぞれ独立に、H、C1-3アルキル、メトキシ、ハロ、OHのいずれかであり、
あるいはR1とR2は、それらが結合している原子と合わさって5〜6員の環を形成し;
あるいはR1とXは、それらが結合している原子と合わさって5〜6員の環を形成し;
あるいはR1とXとRは、それらが結合している原子と合わさって二環構造を形成し;
R3は、H、C1-3アルキル、メトキシ、ハロ、OH、COOR12、CR13R14OH、COHNR15、シクロアルキル、ヘテロアリールのいずれかであり;
R4は、結合、NR6、CR9R10のいずれかであり;
あるいはR3とR4は、それらが結合している原子と合わさって3〜6員の環を形成し;
R5は、Cy2、CO(C1-6アルキル)、C1-6アルキルのいずれかであり、そのCy2、CO(C1-6アルキル)、C1-6アルキルは、場合によっては、ハロ、C1-6アルキルアミン、COR11、SO2R11、ヘテロシクロアルキル、CO2R11、C1-6ヒドロキシアルキル、ヘテロアリール、CH2CO2R11、C1-6アルコキシ、OH、CN、R11、CH2OSO3H、ベンジル、CH2SO3H、CH2CN、NHCH2シクロアルキルから選択された1〜3個の置換基で置換されており;
R6は、結合、H、CH3のいずれかであり;
R7とR8は、それぞれ独立に、H、C1-3アルキル、CONH2のいずれかであり、そのC1-3アルキルは、場合によってはハロで置換されており;
R9とR10は、それぞれ独立に、HまたはC1-3アルキルであり、そのC1-3アルキルは、場合によってはハロで置換されており;
R11は、H、NH2、場合によっては置換されたC1-6アルキルのいずれかであり;
R12、R13、R14、R15は、それぞれ独立に、HまたはC1-3アルキルである)。 - 式(III):
点線は、場合によっては存在する結合を表わし;
W、X、k、R1、R2、R3、R4は、請求項1で定義したのと同じであり;
Uは、C、N、S、Oのいずれかであり;
Yは、それぞれ独立にCまたはNであり;
Zはハロまたはメトキシであり;
Bは、5〜7員の環構造または二環構造であり、その5〜7員の環構造または二環構造は、場合によっては、COR11、SO2R11、ヘテロシクロアルキル、CO2R11、C1-6ヒドロキシアルキル、ヘテロアリール、CH2CO2R11、C1-6アルコキシ、OH、CN、R11、CH2OSO3H、ベンジル、CH2SO3H、CH2CNのいずれかで置換されており;
R'は、ハロ、ヘテロアリール、C1-6アルコキシ、C1-6アルキル、ヘテロシクロアルキル、CNシクロアルキル、CO2(C1-6アルキル)、CO(C1-6アルキル)のいずれかであり;
あるいは2つのR'は、それらが結合している原子と合わさって5〜6員の環を形成し;
lは0〜3であり;
mは0〜3であり;
nは0〜3である)。 - 式(IV):
点線は、場合によっては存在する結合を表わし;
W、X、k、R1、R2、R3、R4は、請求項1で定義したのと同じであり;
Uは、C、N、S、Oのいずれかであり;
R'は、ハロ、ヘテロアリール、C1-6アルコキシ、C1-6アルキル、ヘテロシクロアルキル、CNシクロアルキル、CO2(C1-6アルキル)、CO(C1-6アルキル)のいずれかであり;
あるいは2つのR'は、それらが結合している原子と合わさって5〜6員の環を形成し;
R16は、HまたはC1-3アルキルであり;
R17は、H、ハロ、C1-3アルキルのいずれかであり;
l、m、nは、請求項3で定義したのと同じであり;
pは1〜3である)。 - WがCである、請求項1に記載の化合物。
- XがCR7R8である、請求項1に記載の化合物。
- XがCOである、請求項1に記載の化合物。
- Xが結合である、請求項1に記載の化合物。
- 前記CR7R8がC1-3 アルキルである、請求項6に記載の化合物。
- 前記CR7R8がCH(CH3)である、請求項6に記載の化合物。
- 前記CR7R8がCH2である、請求項6に記載の化合物。
- 前記CR7R8がC(CH3)2である、請求項6に記載の化合物。
- 前記CR7R8がCHCF3である、請求項6に記載の化合物。
- 前記CR7R8がCH(CH2CH3)である、請求項6に記載の化合物。
- 前記C1-3アルキルが場合によってはハロで置換されている、請求項9に記載の化合物。
- 前記C1-3アルキルがCHCF3である、請求項15に記載の化合物。
- RがCy1である、請求項1に記載の化合物。
- 前記Cy1が、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキルからなる群から選択される、請求項17に記載の化合物。
- 前記Cy1が場合によっては置換されている、請求項18に記載の化合物。
- 前記Cy1がフェニルである、請求項17に記載の化合物。
- 前記Cy1がシクロプロパンである、請求項17に記載の化合物。
- RがC1-6アルキルである、請求項1に記載の化合物。
- 前記C1-6アルキルがCH3である、請求項23に記載の化合物。
- 前記C1-6アルキルがC(CH3)3である、請求項23に記載の化合物。
- 前記C1-6アルキルがCH(CH3)2である、請求項23に記載の化合物。
- R1がHである、請求項1に記載の化合物。
- R1がOHである、請求項1に記載の化合物。
- R1がCH3である、請求項1に記載の化合物。
- R2がHである、請求項1に記載の化合物。
- R2がCH3である、請求項1に記載の化合物。
- R3がHである、請求項1に記載の化合物。
- R3がFである、請求項1に記載の化合物。
- R3がClである、請求項1に記載の化合物。
- R3がメトキシである、請求項1に記載の化合物。
- R4が結合である、請求項1に記載の化合物。
- R4がCR9R10である、請求項1に記載の化合物。
- 前記CR9R10がCH2である、請求項37に記載の化合物。
- 前記CR9R10がCHCH3である、請求項37に記載の化合物。
- 前記CR9R10がC(CH3)2である、請求項37に記載の化合物。
- R4がNR6である、請求項1に記載の化合物。
- 前記NR6がNHである、請求項41に記載の化合物。
- 前記NR6がNCH3である、請求項41に記載の化合物。
- R4とR3が合わさって5員の複素環を形成する、請求項1に記載の化合物。
- R5がCy2である、請求項1に記載の化合物。
- 前記Cy2が、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキルからなる群から選択される、請求項45に記載の化合物。
- 前記Cy2が場合によっては置換されている、請求項45に記載の化合物。
- 前記Cy2がフェニルである、請求項45に記載の化合物。
- 前記Cy2がテトラヒドロイソキノリンである、請求項44に記載の化合物。
- 前記Cy2がシクロプロパンである、請求項44に記載の化合物。
- R5がCO(C1-6アルキル)である、請求項1に記載の化合物。
- 前記CO(C1-6アルキル)がCOCH3である、請求項58に記載の化合物。
- R5がC1-6アルキルである、請求項1に記載の化合物。
- Cy1が、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキルからなる群から選択される、請求項2に記載の化合物。
- Cy1がフェニルである、請求項2に記載の化合物。
- Cy2が、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキルからなる群から選択される、請求項2に記載の化合物。
- Cy2がイソインドリンである、請求項2に記載の化合物。
- Cy2がテトラヒドロイソキノリンである、請求項2に記載の化合物。
- Bが、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキルからなる群から選択される、請求項3に記載の化合物。
- Bが5員のヘテロシクロアルキルである、請求項3に記載の化合物。
- Bが6員のヘテロシクロアルキルである、請求項3に記載の化合物。
- pが1である、請求項4に記載の化合物。
- nが0である、請求項68に記載の化合物。
- pが2である、請求項4に記載の化合物。
- nが0である、請求項69に記載の化合物。
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