JP5080973B2 - Rna依存性rnaウイルスの感染を処置するためのヌクレオシドアリールホスホルアミダート - Google Patents
Rna依存性rnaウイルスの感染を処置するためのヌクレオシドアリールホスホルアミダート Download PDFInfo
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- JP5080973B2 JP5080973B2 JP2007518162A JP2007518162A JP5080973B2 JP 5080973 B2 JP5080973 B2 JP 5080973B2 JP 2007518162 A JP2007518162 A JP 2007518162A JP 2007518162 A JP2007518162 A JP 2007518162A JP 5080973 B2 JP5080973 B2 JP 5080973B2
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- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 208000025223 poliovirus infection Diseases 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 238000003345 scintillation counting Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 229910052717 sulfur Chemical group 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 208000011479 upper respiratory tract disease Diseases 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- 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
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/14—Pyrrolo-pyrimidine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Virology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Saccharide Compounds (AREA)
Description
YはCR9またはNであり;
Arは非置換フェニルであるか、または、ハロゲン、C1−4アルキル、C1−4アルコキシ、C1−4アルキルチオ、シアノ、ニトロ、アミノ、カルボキシ、トリフルオロメチル、C1−4アルキルアミノ、ジ(C1−4アルキル)アミノ、C1−4アルキルカルボニル、C1−4アルキルカルボニルオキシおよびC1−4アルキルオキシカルボニルからなる群から独立して選択される1個から3個の置換基により置換されたフェニルであり;
R1は、水素、フルオロ、アジド、アミノ、ヒドロキシ、C1−3アルコキシ、メルカプトおよびC1−3アルキルチオからなる群から選択され;
R2およびR3はそれぞれが独立して、水素、メチル、C1−16アルキルカルボニル、C2−18アルケニルカルボニル、C1−10アルキルオキシカルボニル、C3−6シクロアルキルカルボニルおよびC3−6シクロアルキルオキシカルボニルからなる群から選択され;
R4は、水素、ハロゲン、メチル、アジドまたはアミノであり;
R5およびR6はそれぞれが独立して、水素、ヒドロキシ、ハロゲン、C1−4アルコキシ、アミノ、C1−4アルキルアミノ、ジ(C1−4アルキル)アミノ、C3−6シクロアルキルアミノ、ジ(C3−6シクロアルキル)アミノ、ベンジルアミノ、ジベンジルアミノまたはC4−6ヘテロシクロアルキルからなる群から選択され、この場合、アルキル、シクロアルキル、ベンジルおよびヘテロシクロアルキルは非置換であるか、または、ハロゲン、ヒドロキシ、アミノ、C1−4アルキルおよびC1−4アルコキシからなる群から独立して選択される1個から5個の基により置換され;
R7は、水素、C1−5アルキル、フェニルまたはベンジルであり、
この場合、アルキルは非置換であるか、または、ヒドロキシ、メトキシ、アミノ、カルボキシ、カルバモイル、グアニジノ、メルカプト、メチルチオ、1H−イミダゾリルおよび1H−インドール−3−イルからなる群から選択される1個の置換基により置換され、フェニルおよびベンジルは非置換であるか、または、ハロゲン、ヒドロキシおよびメトキシからなる群から独立して選択される1個から2個の置換基により置換され;
R8は、水素、C1−6アルキル、C3−6シクロアルキル、フェニルまたはベンジルであり、
この場合、アルキルおよびシクロアルキルは非置換であるか、または、ハロゲン、ヒドロキシ、カルボキシ、C1−4アルコキシからなる群から独立して選択される1個から3個の置換基により置換され、フェニルおよびベンジルは非置換であるか、または、ハロゲン、ヒドロキシ、シアノ、C1−4アルコキシおよびトリフルオロメチルからなる群から独立して選択される1個から3個の置換基により置換され;
R9は、水素、フッ素、シアノ、C1−3アルキル、NHCONH2、CONR10R10、CSNR10R10、COOR10、C(=NH)NH2、ヒドロキシ、C1−3アルコキシ、アミノ、C1−4アルキルアミノおよびジ(C1−4アルキル)アミノからなる群から選択され;
各R10は独立して、水素またはC1−6アルキルであり;および
R11は水素またはメチルである。
YはCR9またはNであり;
Arは非置換フェニルであるか、または、ハロゲン、C1−4アルキル、C1−4アルコキシ、C1−4アルキルチオ、シアノ、ニトロ、アミノ、カルボキシ、トリフルオロメチル、C1−4アルキルアミノ、ジ(C1−4アルキル)アミノ、C1−4アルキルカルボニル、C1−4アルキルカルボニルオキシおよびC1−4アルキルオキシカルボニルからなる群から独立して選択される1個から3個の置換基により置換されたフェニルであり;
R1は、水素、フルオロ、アジド、アミノ、ヒドロキシ、C1−3アルコキシ、メルカプトおよびC1−3アルキルチオからなる群から選択され;
R2およびR3はそれぞれが独立して、水素、メチル、C1−16アルキルカルボニル、C2−18アルケニルカルボニル、C1−16アルキルオキシカルボニル、C3−6シクロアルキルカルボニルおよびC3−6シクロアルキルオキシカルボニルからなる群から選択され;
R4は、水素、ハロゲン、メチル、アジドまたはアミノであり;
R5およびR6はそれぞれが独立して、水素、ヒドロキシ、ハロゲン、C1−4アルコキシ、アミノ、C1−4アルキルアミノ、ジ(C1−4アルキル)アミノ、C3−6シクロアルキルアミノ、ジ(C3−6シクロアルキル)アミノ、ベンジルアミノ、ジベンジルアミノまたはC4−6ヘテロシクロアルキルからなる群から選択され、この場合、アルキル、シクロアルキル、ベンジルおよびヘテロシクロアルキルは非置換であるか、または、ハロゲン、ヒドロキシ、アミノ、C1−4アルキルおよびC1−4アルコキシからなる群から独立して選択される1個から5個の基により置換され;
R7は、水素、C1−5アルキル、フェニルまたはベンジルであり、
この場合、アルキルは非置換であるか、または、ヒドロキシ、メトキシ、アミノ、カルボキシ、カルバモイル、グアニジノ、メルカプト、メチルチオ、1H−イミダゾリルおよび1H−インドール−3−イルからなる群から選択される1個の置換基により置換され、フェニルおよびベンジルは非置換であるか、または、ハロゲン、ヒドロキシおよびメトキシからなる群から独立して選択される1個から2個の置換基により置換され;
R8は、水素、C1−6アルキル、C3−6シクロアルキル、フェニルまたはベンジルであり、
この場合、アルキルおよびシクロアルキルは非置換であるか、または、ハロゲン、ヒドロキシ、カルボキシ、C1−4アルコキシからなる群から独立して選択される1個から3個の置換基により置換され、フェニルおよびベンジルは非置換であるか、または、ハロゲン、ヒドロキシ、シアノ、C1−4アルコキシおよびトリフルオロメチルからなる群から独立して選択される1個から3個の置換基により置換され;
R9は、水素、フッ素、シアノ、C1−3アルキル、NHCONH2、CONR10R10、CSNR10R10、COOR10、C(=NH)NH2、ヒドロキシ、C1−3アルコキシ、アミノ、C1−4アルキルアミノおよびジ(C1−4アルキル)アミノからなる群から選択され;
各R10は独立して、水素またはC1−6アルキルであり;および
R11は水素またはメチルである。
上記で指定されたアルキル基は、直鎖形態または分枝形態のいずれかである示された長さのこのようなアルキル基を包含することが意図される。このようなアルキル基の例には、メチル、エチル、プロピル、イソプロピル、ブチル、sec−ブチル、第三級ブチル、ペンチル、イソペンチル、ヘキシルおよびイソヘキシルなどがある。
リン酸化反応のためのヌクレオシド中間体の調製が国際特許出願公開WO02/057287(2002年7月25日)および同WO02/57425(2002年7月25日)に記載される。リン酸化反応のためのアリールホスホロクロリダートを、米国特許第6,455,513号に記載される方法に従って調製した(この内容はこの全体が参照により本明細書中に組み込まれる)。本発明のアリールホスホロアミダートを作製するためのリン酸化反応を、米国特許第6,455,513号およびC.McGuiganら、J.Med.Chem.、36:1048(1993)に記載される方法に従って行った。
2’−C−メチルアデノシン5’−[フェニル メトキシ−(S)−アラニルホスファート]
2’−C−メチルグアノシン5’−[フェニル メトキシ−(S)−アラニルホスファート]
4−アミノ−7−(2−C−メチル−β−D−リボフラノシル)−7H−ピロロ[2,3−d]ピリミジン5’−[フェニル メトキシ−(S)−アラニルホスファート]
1H NMR(CD3OD,500MHz):異性体A:δ0.80(s,3H),1.30(d,3H),3.66(s,3H),および6.30(s,1H);異性体B:δ0.84(s,3H),1.34(d,3H),3.62(s,3H),および6.28(s,1H)。
2−アミノ−7−(2−C−メチル−β−D−リボフラノシル)−7H−ピロロ[2,3−d]ピリミジン−4(3H)−オン5’−[フェニル メトキシ−(S)−アラニルホスファート]
1H NMR(CD3OD,500MHz):異性体A:δ0.85(s,3H),1.31(d,3H),3.67(s,3H),および6.10(s,1H);異性体B:δ0.87(s,3H),1.35(d,3H),3.63(s,3H),および6.05(s,1H)。
2,4−ジアミノ−7−(2−C−メチル−β−D−リボフラノシル)−7H−ピロロ[2,3−d]ピリミジン5’−[フェニル メトキシ−(S)−アラニルホスファート]
1H NMR(CD3OD,500MHz):異性体A:δ0.89(s,3H),1.32(d,3H),3.64(s,3H),および6.12(s,1H);異性体B:δ0.91(s,3H),1.35(d,3H),3.62(s,3H),および6.10(s,1H)。
HCVのNS5BポリメラーゼおよびHCVの複製の阻害を測定するために用いたアッセイを下記に記載する。
このアッセイは、ヘテロマーRNAテンプレートに対するC型肝炎ウイルス(HCV)のRNA依存性RNAポリメラーゼ(NS5B)の酵素活性を阻害する本発明のヌクレオシドアリールホスホルアミダートの能力を測定するために使用された。
アッセイ緩衝液条件(50μL総量/反応)
20mM Tris(pH7.5)
50μM EDTA
5mM DTT
2mM MgCl2
80mM KCl
0.4U/μLのRNAsin(Promega、ストック溶液は40ユニット/μLである)
0.75μgのt500(C型肝炎ゲノムのNS2/3領域からの配列を用いてT7ランオフ転写を使用して作製された500ntのRNA)
1.6μgの精製されたC型肝炎NS5B(21アミノ酸がC末端から短縮された形態)
1μMのATP/CTP/UTP/GTP(ヌクレオシド三リン酸のミックス)
[α−32P]−GTPまたは[α−33P]−GTP
化合物を100μMまでの最終濃度の様々な濃度で調べた。
%阻害=[1−(試験反応でのcpm−ブランクでのcpm)/(コントロール反応でのcpm−ブランクでのcpm)]x100。
本発明の化合物はまた、サブゲノムのHCVレプリコンを含有する培養された肝ガン(HuH−7)細胞におけるC型肝炎ウイルスRNAの複製に影響を及ぼすこの能力についても調べられた。アッセイの詳細を下記に記載する。このレプリコンアッセイは、V.Lohmann、F.Korner、J−O.Koch、U.Herian、L.TheilmannおよびR.Bartenschlager、「肝ガン細胞株におけるサブゲノムのC型肝炎ウイルスRNAの複製」、Science、285:110(1999)に記載されるアッセイの改変である。
このアッセイは、インシトゥーリボヌクレアーゼ保護、シンチレーション近接に基づくプレートアッセイ(SPA)である。10,000個から40,000個の細胞を、96ウエルのcytostarプレート(Amersham)で、0.8mg/mLのG418を含有する100μLから200μLの培地において置床した。化合物を、0時間から18時間の時間で、1%DMSOにおける100μMまでの様々な濃度で細胞に加え、この後、24時間から96時間培養した。細胞を固定し(20分間、10%ホルマリン)、予備透過処理し(20分間、0.25%Triton X−100/PBS)、RNAウイルスゲノムに含有される(+)鎖NS5B(または他の遺伝子)に対して相補的な一本鎖の33P−RNAプローブを用いてハイブリダイゼーションした(一晩、50℃)。細胞を洗浄し、RNAseで処理し、洗浄し、65℃に加熱し、Top−Countで計数した。複製の阻害をカウント/分(cpm)での減少として読み取った。
本発明の化合物はまた、ヒト肝ガン細胞株の中に入り、対応するヌクレオシド5’−モノホスファート、ヌクレオシド5’−ジホスファートおよびヌクレオシド5’−トリホスファートに細胞内で変換されるこの能力についても評価された。
ヒトのDNAポリメラーゼを阻害する本発明のヌクレオシドアリールホスホルアミダートの能力を下記のアッセイで測定した。
反応条件:
50μLの反応体積
反応緩衝液の構成成分:
20mM Tris−HCl(pH7.5)
200μg/mL ウシ血清アルブミン
100mM KCl
2mM β−メルカプトエタノール
10mM MgCl2
1.6μMのdATP/dGTP/dCTP/dTTP
α−33P−dATP
酵素およびテンプレート:
0.05mg/mLのギャップ化処理されたサカナ精子DNAテンプレート
0.01U/μLのDNAポリメラーゼαまたはβ
ギャップ化処理されたサカナ精子DNAテンプレートの調製:
5μLの1M MgCl2を500μLの活性化されたサカナ精子DNA(USB70076)に加える;
37℃に加温し、30μLの65U/μLのエキソヌクレアーゼIII(GibcoBRL18013−011)を加える;
37℃で5分間インキュベーションする;
反応を65℃での10分間の加熱によって停止させる;
50μLから100μLの量を、20mMのTris−HCl(pH7.5)で平衡化されたBio−spin6クロマトグラフィーカラム(Bio−Rad732−6002)に負荷する;
1,000Xgでの4分間の遠心分離によって溶出する;
溶出液をプールし、吸光度を260nmで測定して、濃度を求める。
ヒトDNAポリメラーゼγの阻害についての可能性を、0.5ng/μLの酵素;10μLのdATP、dGTP、dCTPおよびTTP;2μCi/反応の[α−33P]−dATP、および、0.4μg/mLの活性化されたサカナ精子DNA(US Biochemicalsから購入)を、20mMのTris(pH8)、2mMのβ−メルカプトエタノール、50mMのKCl、10mMのMgCl2および0.1μg/mLのBSAを含有する緩衝液に含む反応液において測定した。反応を37℃で1時間行わせ、0.5M EDTAを142mMの最終濃度に加えることによって停止させた。生成物の形成を、アニオン交換フィルターへの結合およびシンチレーション計数によって定量した。化合物を50μMまでの濃度で調べた。
アッセイを、低いバックグラウンドのβ−ガラクトシダーゼ(β−gal)発現のために選択された、CXCR4およびCCR5の両方を発現するHeLa Magi細胞の変化体を用いて行った。細胞を48時間感染させ、組み込まれているHIV−1のLTRプロモーターからのβ−gal産生を、化学発光基質(Galactolight Plus、Tropix、Bedford、MA)を用いて定量した。阻害剤を、100μMから出発する2倍連続希釈物において(二連で)力価測定した。各濃度における阻害率をコントロールの感染に関して計算した。
ヒト免疫不全症ウイルス(HIV)の拡大を阻害する本発明の化合物の能力を、米国特許第5,413,999号(1995年5月9日)およびJ.P.Vaccaら、Proc.Natl.Acad.Sci.、91:4096−4100(1994)(これらはこの全体が参照により組み込まれる)に記載される方法によって測定した。
細胞培養物を、3日間のインキュベーションでの懸濁培養物については約1.5x105細胞/mLの濃度で、また、3日間のインキュベーションでの接着性培養物については5.0x104細胞/mLの濃度で適切な培地において調製した。99μLの細胞培養物を96ウエルの組織培養処理プレートのウエルに移し、DMSOにおける100倍の最終濃度の試験化合物の1μLを加えた。プレートを指定された期間にわたって37℃および5%CO2でインキュベーションした。インキュベーション期間の後、20μLのCellTiter 96 Aqueous One Solution Cell Proliferation Assay試薬(MTS)(Promega)を各ウエルに加え、プレートを3時間までのさらなる期間にわたって37℃および5%CO2でインキュベーションした。プレートを振とうして十分に混合し、490nmにおける吸光度を、プレートリーダーを使用して読み取った。懸濁培養細胞の標準曲線を、MTS試薬添加直前の既知の細胞数を用いて調製した。代謝活性な細胞はMTSをホルマザンに還元する。ホルマザンは490nmで吸収する。化合物の存在下での490nmにおける吸光度を、化合物が何ら添加されていない細胞における吸光度と比較した。
参考文献:Cory,A.H.ら、「培養での細胞成長アッセイのための水溶性テトラゾリウム/ホルマザンアッセイの使用」、Cancer Commun.、3:207(1991)。
アッセイ条件が、SidwellおよびHuffman、「抗ウイルス誘導研究およびインターフェロン誘導研究のための使い捨てミクロ組織培養プレートの使用」、Appl.Microbiol.、22:797−801(1971)による論文に記載される。
ライノウイルス2型(RV−2)(HGP株)を、SidwellおよびHuffmanの参考文献で述べられたようにKB細胞および培地(0.1%NaHCO3、抗生物質なし)とともに使用した。このウイルスは、ATCCから得られたが、軽度の急性熱性上部気道疾患の成人男性の咽頭スワブ物に由来した。
アッセイの詳細は上記のSidwellおよびHuffmanの参考文献に示される。
デングウイルス2型(New Guinea株)を疾病対策センターから得た。2系統のアフリカミドリザル腎臓細胞を使用して、ウイルスを培養し(Vero)、また、抗ウイルス試験を行った(MA−104)。黄熱ウイルス(17D株)(これは感染マウスの脳から調製された)およびバンジウイルス(H336株)(これは南アフリカにおける熱病少年の血清から単離された)の両方をATCCから得た。Vero細胞を、これらのウイルスの両方とともに、また、アッセイのために使用した。
MA−104細胞(BioWhittaker,Inc.、Walkersville、MD)およびVero細胞(ATCC)を、5%のFBSおよび0.1%のNaHCO3を伴い、および、抗生物質を伴わない培地199において使用した。
デングウイルス、黄熱ウイルスおよびバンジウイルスについてのアッセイ培地は、2%のFBS、0.18%のNaHCO3および50μg/mLのゲンタマイシンを伴うMEMであった。
アッセイの詳細は、上記で引用されたSidwellおよびHuffmanの参考文献に示される。ウエストナイルウイルス(カラスの脳に由来するNew York単離体)を疾病対策センターから得た。Vero細胞を上記のように成長させ、使用した。試験培地は、1%のFBS、0.1%のNaHCO3および50μg/mLのゲンタマイシンを伴うMEMであった。
上記のCPE阻害アッセイを行った後、「インターフェロンについてのマイクロタイターアッセイ:細胞変性作用の微量分光光度法による定量」、Appl.Environ.Microbiol.、31:35−38(1976)に記載されるさらなる細胞変性検出法を使用した。Model EL309マイクロプレートリーダー(Bio−Tek Instruments Inc.)を使用して、アッセイプレートを読み取った。ED50およびCD50を上記のように計算した。
本発明の化合物の経口用配合物の1つの具体的な実施態様として、50mgの実施例1または実施例2の化合物が、580mgから590mgの総量を提供するための十分に細かく分割されたラクトースを用いて配合され、サイズOのハードゼラチンカプセルに充填される。
Claims (6)
- R11が水素であり、ならびにR7がメチルである、請求項1に記載の化合物。
- R8がメチルである、請求項2に記載の化合物。
- 請求項1に記載の化合物と、医薬的に許容されるキャリアとを含む医薬組成物。
- 哺乳動物におけるC型肝炎ウイルス(HCV)感染を治療するための、請求項5に記載の医薬組成物。
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EP1773355A2 (en) | 2007-04-18 |
WO2006012078A2 (en) | 2006-02-02 |
JP2008504265A (ja) | 2008-02-14 |
CN1972696A (zh) | 2007-05-30 |
AU2005267421A1 (en) | 2006-02-02 |
AU2005267421B2 (en) | 2010-06-03 |
WO2006012078A3 (en) | 2006-06-01 |
EP1773355A4 (en) | 2009-08-12 |
EP1773355B1 (en) | 2014-06-25 |
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