JP4856638B2 - 3−β−D−リボフラノシルチアゾロ[4,5−d]ピリミジンヌクレオシドおよびその使用 - Google Patents
3−β−D−リボフラノシルチアゾロ[4,5−d]ピリミジンヌクレオシドおよびその使用 Download PDFInfo
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- JP4856638B2 JP4856638B2 JP2007527161A JP2007527161A JP4856638B2 JP 4856638 B2 JP4856638 B2 JP 4856638B2 JP 2007527161 A JP2007527161 A JP 2007527161A JP 2007527161 A JP2007527161 A JP 2007527161A JP 4856638 B2 JP4856638 B2 JP 4856638B2
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- ribofuranosyl
- thiazolo
- amino
- compound
- mmol
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- NHKZSTHOYNWEEZ-AFCXAGJDSA-N taribavirin Chemical compound N1=C(C(=N)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NHKZSTHOYNWEEZ-AFCXAGJDSA-N 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 1
- 229960002871 tenoxicam Drugs 0.000 description 1
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 description 1
- 229960002722 terbinafine Drugs 0.000 description 1
- RXGFTUPFXKYRMW-UHFFFAOYSA-N tert-butyl 4-hydroxybutanoate Chemical compound CC(C)(C)OC(=O)CCCO RXGFTUPFXKYRMW-UHFFFAOYSA-N 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- TXEYQDLBPFQVAA-UHFFFAOYSA-N tetrafluoromethane Chemical compound FC(F)(F)F TXEYQDLBPFQVAA-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- OTVAEFIXJLOWRX-NXEZZACHSA-N thiamphenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CO)NC(=O)C(Cl)Cl)C=C1 OTVAEFIXJLOWRX-NXEZZACHSA-N 0.000 description 1
- 229960003053 thiamphenicol Drugs 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- VZYCZNZBPPHOFY-UHFFFAOYSA-N thioproperazine Chemical compound C12=CC(S(=O)(=O)N(C)C)=CC=C2SC2=CC=CC=C2N1CCCN1CCN(C)CC1 VZYCZNZBPPHOFY-UHFFFAOYSA-N 0.000 description 1
- 229960003397 thioproperazine Drugs 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- JJSHYECKYLDYAR-UHFFFAOYSA-N thozalinone Chemical compound O1C(N(C)C)=NC(=O)C1C1=CC=CC=C1 JJSHYECKYLDYAR-UHFFFAOYSA-N 0.000 description 1
- 229960005138 tianeptine Drugs 0.000 description 1
- 229950004626 tiazesim Drugs 0.000 description 1
- QJJXOEFWXSQISU-UHFFFAOYSA-N tiazesim Chemical compound C1C(=O)N(CCN(C)C)C2=CC=CC=C2SC1C1=CC=CC=C1 QJJXOEFWXSQISU-UHFFFAOYSA-N 0.000 description 1
- VAMSVIZLXJOLHZ-QWFSEIHXSA-N tigemonam Chemical compound O=C1N(OS(O)(=O)=O)C(C)(C)[C@@H]1NC(=O)C(=N/OCC(O)=O)\C1=CSC(N)=N1 VAMSVIZLXJOLHZ-QWFSEIHXSA-N 0.000 description 1
- 229950010206 tigemonam Drugs 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- 229940035289 tobi Drugs 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- PNYKGCPSFKLFKA-UHFFFAOYSA-N tofenacin Chemical compound C=1C=CC=C(C)C=1C(OCCNC)C1=CC=CC=C1 PNYKGCPSFKLFKA-UHFFFAOYSA-N 0.000 description 1
- 229950010076 tofenacin Drugs 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 229960003991 trazodone Drugs 0.000 description 1
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 1
- AYNNSCRYTDRFCP-UHFFFAOYSA-N triazene Chemical compound NN=N AYNNSCRYTDRFCP-UHFFFAOYSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 description 1
- 229960003962 trifluridine Drugs 0.000 description 1
- 229960004161 trimethobenzamide Drugs 0.000 description 1
- FEZBIKUBAYAZIU-UHFFFAOYSA-N trimethobenzamide Chemical compound COC1=C(OC)C(OC)=CC(C(=O)NCC=2C=CC(OCCN(C)C)=CC=2)=C1 FEZBIKUBAYAZIU-UHFFFAOYSA-N 0.000 description 1
- 229960002431 trimipramine Drugs 0.000 description 1
- ZSCDBOWYZJWBIY-UHFFFAOYSA-N trimipramine Chemical compound C1CC2=CC=CC=C2N(CC(CN(C)C)C)C2=CC=CC=C21 ZSCDBOWYZJWBIY-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- JEJAMASKDTUEBZ-UHFFFAOYSA-N tris(1,1,3-tribromo-2,2-dimethylpropyl) phosphate Chemical compound BrCC(C)(C)C(Br)(Br)OP(=O)(OC(Br)(Br)C(C)(C)CBr)OC(Br)(Br)C(C)(C)CBr JEJAMASKDTUEBZ-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- ZNRGQMMCGHDTEI-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CNC2=C1 ZNRGQMMCGHDTEI-ITGUQSILSA-N 0.000 description 1
- 229960003688 tropisetron Drugs 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 230000005951 type IV hypersensitivity Effects 0.000 description 1
- 208000027930 type IV hypersensitivity disease Diseases 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
- 229940049588 velosef Drugs 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 229960003636 vidarabine Drugs 0.000 description 1
- 229960001255 viloxazine Drugs 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 201000002498 viral encephalitis Diseases 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000008136 water-miscible vehicle Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- 229940051021 yellow-fever virus Drugs 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
- 229960005332 zileuton Drugs 0.000 description 1
- OYPPVKRFBIWMSX-SXGWCWSVSA-N zimeldine Chemical compound C=1C=CN=CC=1C(=C/CN(C)C)\C1=CC=C(Br)C=C1 OYPPVKRFBIWMSX-SXGWCWSVSA-N 0.000 description 1
- 229960002791 zimeldine Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Images
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
- C07H19/24—Heterocyclic radicals containing oxygen or sulfur as ring hetero atom
-
- 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
- A61P35/00—Antineoplastic agents
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Virology (AREA)
- Immunology (AREA)
- Oncology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Communicable Diseases (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Hematology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
R2はH、OR5、またはN(R6)2であり;
R3はC1−18アルキルであり;
R4はH、−C(O)CH(C1−6アルキル)NH2、または−C(O)CH(CH2−アリール)NH2であり;
R5は独立にH、C1−6アルキル、C3−7アルケニル、C3−7アルキニル、−(CR7R8)t(C6−C10アリール)、−(CR7R8)t(C3−C10シクロアルキル)、−(CR7R8)t(C4−C10複素環式)、−(CR7R8)t>1OH、−(CR7R8)t>0CO2C1−18アルキル、および−(CR7R8)t>0N(R9)CO2C1−18アルキル、およびSO2(アリール)であり、ここでtは特に断りのない限り0〜6の整数であり、前記の基のアルキル、アルケニル、アルキニル、アリール、シクロアルキル、および複素環式部分は、ハロ、シアノ、ニトロ、トリフルオロメチル、トリフルオロメトキシ、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、ヒドロキシ、C1−C6アルコキシ、−NH2、−NH−アルキル、−N(アルキル)2、−NH−アリール、−N(アルキル)(アリール)、−N(アリール)2、−NHCHO、−NHC(O)アルキル、−NHC(O)アリール、−N(アルキル)C(O)H、−N(アルキル)C(O)アルキル、−N(アリール)C(O)H、−N(アリール)C(O)アルキル、−NHCO2アルキル、−N(アルキル)CO2アルキル、−NHC(O)NH2、−N(アルキル)C(O)NH2、−NHC(O)NH−アルキル、−NHC(O)N(アルキル)2、−N(アルキル)C(O)NH−アルキル、N(アルキル)C(O)N(アルキル)2、−NHSO2−アルキル、−N(アルキル)SO2−アルキル、−C(O)アルキル、−C(O)アリール、−OC(O)アルキル、−OC(O)アリール、−CO2−アルキル、−CO2−アリール、−CO2H、−C(O)NH2、−C(O)NH−アルキル、−C(O)N(アルキル)2、−C(O)NH−アリール、−C(O)N(アリール)2、−C(O)N(アルキル)(アリール)、−S(O)アルキル、−S(O)アリール、−SO2アルキル、−SO2アリール、−SO2NH2、−SO2NH−アルキル、および−SO2N(アルキル)2から独立に選択される置換基で任意に置換されていてもよく;
R6は独立にH、C1−6アルキル、C3−C10シクロアルキルであるか、または窒素と一緒になって5員または6員の複素環式環を形成し;
R7およびR8は独立にH、C1−6アルキル、C2−6アルケニル、またはC2−6アルキニルであり;そして
R9はH、C1−6アルキル、または−CH2−アリールである]
で示される化合物に関する。
図1はマウスにおけるイサトリビン(isatoribine)(1)およびインターフェロンαの血漿レベルを示したグラフである。
図2はイサトリビン(1)を服用しているHCV感染患者におけるウイルス量の変化を示したグラフである。
本明細書において以下の用語が用いられる場合、それらは以下に定義されるものとして使用される。
(i)疾病、疾患および/または状態に対して素因を持ち得るが、そうであるとはまだ診断されていない動物において、疾病、疾患および/または状態の発生を防ぐこと;
(ii)疾病、疾患、または状態を抑制すること、すなわち、その発症を阻止すること;
(iii)疾病、疾患、または状態を軽減すること、すなわち、疾病、疾患、または状態を退縮させること
を指す。
本発明は、それを必要とする患者においてC型肝炎ウイルス感染を処置または予防するための方法を提供する。
本発明の化合物の毒性および有効性は、例えば、LD50(集団の50%致死量)およびED50(集団の50%で治療上有効な量)など、細胞培養および実験動物における標準的な薬学的手順により判定することができる。有毒作用と治療作用の間の用量比が治療係数であり、LD50/ED50比として表すことができる。
本発明の特定の方法はさらに、付加的な治療薬(すなわち、本発明の化合物以外の治療薬)の投与を含む。本発明のある実施形態では、本発明の化合物は少なくとも1種類の他の治療薬と併用することができる。治療薬としては、限定されるものではないが、抗生物質、制吐薬、抗鬱薬、および抗真菌薬、抗炎症薬、抗ウイルス薬、抗癌薬、免疫調節剤、β−インターフェロン、アルキル化剤、ホルモンまたはサイトカインが挙げられる。好ましい実施形態では、本発明は、HCV特異的であるか、または抗HCV活性を示す付加的治療薬の投与を包含する。
本発明の式Iの化合物、またはその医薬上許容される塩もしくは水和物を含む医薬組成物および単位投与形もまた本発明に包含される。本発明の個々の投与形は経口投与、粘膜投与(舌下、頬側、直腸、鼻腔、または膣投与を含む)、非経口投与(皮下、筋肉内、ボーラス注射、動脈内、または静脈内投与を含む)、経皮投与、または局所投与に好適であり得る。本発明の医薬組成物および投与形は一般に1以上の医薬上許容される賦形剤も含む。無菌投与形も意図される。
経口投与に好適な本発明の医薬組成物は、限定されるものではないが、錠剤(例えば、チュアブル錠)、カプレット、カプセル剤、および液体(例えば、フレーバーを加えたシロップ)などの個別投与形として提供することができる。このような投与形は所定量の有効成分を含有し、当業者に周知の製薬法によって製造することができる。一般に、Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990)参照。
本発明の有効成分は、当業者に周知の徐放性手段または送達装置によって投与することができる。例としては、限定されるものではないが、米国特許第3,845,770号;同第3,916,899号;同第3,536,809号;同第3,598,123号;および同第4,008,719号、同第5,674,533号、同第5,059,595号、同第5,591,767号、同第5,120,548号、同第5,073,543号、同第5,639,476号、同第5,354,556号、および同第5,733,566号に記載されているものが挙げられ、これらは各々出典明示により本明細書の一部とされる。このような投与形は、例えば、ヒドロプロピルメチルセルロース、他の高分子マトリックス、ゲル、透過性膜、浸透圧系、多層コーティング、微粒子、リポソーム、ミクロスフェア、またはその組合せを所望の放出特性を得るために様々な割合で用いて1以上の有効成分の緩慢放出または徐放性を提供するために使用できる。本明細書に記載のものを含め、本発明の有効成分と併用するための、当業者に公知の好適な徐放性製剤は容易に選択することができる。よって、本発明は、限定されるものではないが、徐放性に適合された錠剤、カプセル剤、ゲルキャップ、およびカプレットなどの経口投与に好適な単位投与形を包含する。
非経口投与形は、限定されるものではないが、皮下、静脈内(ボーラス注射)、筋肉内、および動脈内をはじめとする種々の経路によって患者に投与することができる。それらの投与は一般に混入物に対する患者の生得的防御を迂回するので、非経口投与形は患者に投与する前に無菌であるか、または滅菌できることが好ましい。非経口投与形の例としては、限定されるものではないが、調製済み注射液、医薬上許容される注射用ビヒクルに溶解または懸濁させるだけの乾燥および/または凍結乾燥製品(再構成粉末)、調製済み注射懸濁液、およびエマルションが挙げられる。
経皮投与形としては、皮膚に貼り付け、所望の量の有効成分を浸透させる特定時間の間装着することができる「リザーバー型」または「マトリックス型」パッチが挙げられる。
本発明の局所投与形としては、限定されるものではないが、クリーム、ローション、軟膏、ゲル、溶液、エマルション、懸濁液、または当業者に公知の他の形態が挙げられる。例えば、Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton PA (1990);およびIntroduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985)参照。
本発明の粘膜投与形としては、限定されるものではないが、眼用の溶液、スプレーおよびエアゾール、または当業者に公知の他の形態が挙げられる。例えば、Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton PA (1990);およびIntroduction to Pharmaceutical Dosages, 4th ed., Lea & Febiger, Philadelphia (1985)参照。口腔内の粘膜組織を処置するのに好適な投与形は口内洗浄剤としてまたは口内用ゲルとして処方することができる。一実施形態では、エアゾールは担体を含む。他の実施形態では、エアゾールは担体を含まない。
本発明は、C型肝炎ウイルス感染の処置または予防に有用な式Iの化合物を含む1以上の容器を含んだ医薬パックまたはキットを提供する。他の実施形態では、本発明は、C型肝炎ウイルス感染の処置または予防に有用な式Iの化合物を含む1以上の容器と、限定されるものではないが、上記の第5.2.2節に挙げたもの、特に抗ウイルス薬、インターフェロン、ウイルス酵素を阻害する薬剤、またはウイルス複製を阻害する薬剤をはじめとする付加的な治療薬(好ましくは、この付加的な治療薬はHCV特異的であるか、または抗HCV活性を示す)を含む1以上の容器とを含んだ医薬パックまたはキットを提供する。
下記の合成スキームでは、特に断りのない限り、温度は全て摂氏で示し、部およびパーセンテージは全て重量に対するものである。試薬はAldrich Chemical CompanyまたはLancaster Synthesis Ltd.などの商業的供給者から購入し、特に断りのない限りさらに精製することなく使用した。テトラヒドロフラン(THF)およびN,N−ジメチルホルムアミド(DMF)はAldrichから密封瓶(Sure Seal bottle)で購入し、そのまま使用した。特に断りのない限り、以下の溶媒および試薬は、乾燥窒素ブランケット下で蒸留した。THFおよびEt2OはNa−ベンゾフェノンケチルから蒸留し;CH2Cl2、ジイソプロピルアミン、ピリジンおよびEt3NはCaH2から蒸留し;MeCNはまずP2O5から蒸留した後にCaH2から蒸留し;MeOHはMgから蒸留し;PhMe、EtOAcおよびi−PrOAcはCaH2から蒸留し;TFAAは乾燥アルゴン下で単に大気圧蒸留することにより精製した。
250mLのモートンフラスコに入った、アセトン(40mL)中、1(5.37g、17.0mmol、出典明示によりそのまま本明細書の一部とされる米国特許第5,041,426号(実施例2)に示されている手順に従って製造されたもの)の不均一な混合物に、室温で2,2−DMP(6.26mL、50.9mmol)、DMSO(6.6mL)およびMeSO3H(220μL、3.39mmol)を連続的に加えた。反応混合物を激しく攪拌すると、ジオールが消費されるにつれ均一で黄金色になった。TLC分析(SiO2、10%MeOH−CHCl3)により、反応の完了が6時間後であることが示された。溶解していない固体を溝付きのワットマン1型濾紙を用いて重力濾過により除去した。この後、濾液を10倍量の氷水(〜400mL)中に注ぎ込んだところ、すぐに白色固体が沈澱した。短時間攪拌した後、水(10mL)に溶解させたNaHCO3(285mg、3.39mmol)を加えてこのMeSO3Hを中和した。モートン反応器中で激しく15分間攪拌を続けた後、この混合物を目の粗い焼結ガラス漏斗で濾過した。固体材料を氷水(100mL)で洗浄し、風乾させた後、高真空下65℃でさらに乾燥させ、5.36g(88%)のアセトニド2を白色固体として得た。融点280〜81℃。1H (DMSO-d6) δ1.28 (s, 3H), 1.47 (s, 3H), 3.43-3.55 (m, 2H), 3.95-3.99 (m, 1H), 4.77-4.80 (m, 1H), 4.88-4.91 (m, 1H), 5.24-5.26 (m, 1H), 5.99 (s, 1H), 6.97 (br s, 2H), 11.25 (s, 1H)。
THF(9mL)中、N−ブトキシカルボニル−(L)−バリン(671mg、2.81mmol)の溶液に、0℃でEDC(588mg、3.07mmol)を加えた。得られた不均一混合物を0℃で45分攪拌したところ、その時点で均一になり、上記工程1の固体アセトニド2(1.00g、2.81mmol)を一度に加えた。その後、固体DMAP(522mg、4.27mmol)を加えた。反応混合物を室温にし、さらに5時間攪拌し、その後、25℃にてロータリーエバポレーターで濃縮して黄色シロップとした。残渣をEtOAc(50mL)に溶解させ、1N HCl(10mL)で分液した後、飽和NaHCO3水溶液(10mL)で酸を中和した。酸性水相をさらにEtOAc(2×50mL)で抽出した後、塩基性水相で分液した。合わせた有機相をNa2SO4で乾燥させ、SiO2のショートパッドで濾過し、濃縮し、1.480g(96%)のBoc−保護アミノ酸エステル4を泡沫としてを得た。融点158℃(分解)。1H (CDCl3)δ0.86 (d, J = 7.0, 3H), 0.95 (d, J = 7.0, 3H), 1.35 (s, 3H), 1.44 (s, 9H), 1.56 (s, 3H), 1.75 (br s, 1H), 2.08-2.19 (m, 1H), 4.20-4.24 (m, 2H), 4.30-4.37 (m, 1H), 4.56 (dd, J = 11.0, 5.9, 1H), 4.96 (dd, J = 6.2, 3.7, 1H), 5.11 (br d, J = 8.8, 1H), 5.29 (br d, J = 6.6, 1H), 5.88 (br s, 2H), 6.23 (s, 1H)。
HClガス流を濃H2SO4のバブラーに通した後、0℃で、飽和溶液が得られるまで乾燥酢酸イソプロピル(80mL)の入った250mlの三つ口モートンフラスコ中へ(フリット付き散布管を介して)送った。これに、酢酸イソプロピル(30mL)中、上記工程2から得られたBoc−アミノ酸エステル(5.53g,9.95mmol)の溶液を加えると、5分以内に白色固体沈澱が生じた。これに10%(v/v)IPA(11mL)を加えた。反応混合物を室温まで昇温した後、12時間攪拌した。この不均一な反応混合物を乾燥トルエン(100mL)で希釈した。N2下で、空隙が中程度の焼結ガラス漏斗を用いて濾過することで灰白色の非晶質固体を得た。この固体を乾燥THF中でトリチュレーションした後、濾過し、65℃で真空乾燥させ、3.677g(81%)の標題化合物3を白色固体として得た。融点166〜68℃(分解)。1H (DMSO-d6) δ0.90 (d, J = 7.0, 3H), 0.94 (d, J = 7.0, 3H), 2.14-2.18 (m, 1H), 3.83-3.85 (m, 1H), 3.96-4.00 (m, 1H), 4.23-4.28 (m, 2H), 4.42 (dd, J = 11.7, 3.4, 1H), 4.75 (dd, J = 10.3, 5.5, 1H), 5.81 (d, J = 4.4, 1H), 6.46 (br s, 3H), 7.23 (br s, 2H), 8.47 (s, 3H), 11.5 (br s, 1H)。C15H21N5O7S・2HClに関する元素分析:理論値: C, 36.89; H, 4.75; Cl, 14.52; N, 14.34; S, 6.57; 実測値: C, 37.03: H, 4.74; Cl, 14.26; N, 14.24; S, 6.42。
実施例1の工程2と同様の方法で、5−アミノ−3−(2',3'−O−イソプロピリデン−β−D−リボフラノシル)−チアゾロ[4,5−d]ピリミジン−2,7−ジオン2およびN−tert−ブトキシ−L−イソロイシン7から、5−アミノ−3−(2',3'−O−イソプロピリデン−5'−N−tert−ブトキシカルボニル−L−イソロイシル)−β−D−リボフラノシル)−チアゾロ[4,5−d]ピリミジン−2,7−ジオン6を収率93%で灰白色の泡沫として製造した。1H NMR (400 MHz, d6-DMSO)δ11.29 (s, 1H), 7.09 (d, J = 8.0, 1H), 7.02 (br s, 1H), 6.02 (s, 1H), 5.28 (d, J = 6.2, 1H), 5.06 (br s, 1H), 4.16-4.22 (m, 2H), 3.85 (dd, J = 8.0, 6.6, 1H), 1.68 (br s, 1H), 1.47 (s, 3H), 1.34 (s, 9H), 1.29 (s, 3H), 0.71-0.89 (m, 5H)。
実施例2の工程3と同様の方法で、標題化合物を上記中間体から収率80%で白色固体として製造した。融点173〜174℃(分解)。1H NMR (400 MHz, d6-DMSO)δ11.41 (br s, 1H), 8.41 (br s, 3H), 7.15 (br s, 2H), 5.82 (d, J = 4.8, 1H), 4.50-5.00 (m, 2H), 4.40 (dd, J = 11.7, 3.3, 1H), 4.21-4.30 (m, 2H), 3.91-4.0 (m, 2H), 1.84-1.91 (m, 1H), 1.37-1.44 (m, 1H), 1.19-1.27 (m, 1H), 0.80-0.87 (m, 6H)。C16H23N5O7S・3/2HClに関する元素分析:理論値: C, 39.69; H, 5.10; N, 14.47; Cl, 10.98; S, 6.62; 実測値: C, 39.05; H, 5.13; N, 13.73; Cl, 11.08; S, 6.02。
実施例1の工程2と同様の方法で、5−アミノ−3−(2,3−O−イソプロピリデン−β−D−リボフラノシル)−チアゾロ[4,5−d]ピリミジン−2,7−ジオン2およびN−α−L−tert−ブトキシグリシンから、5−アミノ−3−(2',3'−O−イソプロピリデン−5'−N−tert−ブトキシカルボニル−[α−L−tert−ブチルグリシニル]−β−D−リボフラノシル)−チアゾロ[4,5−d]ピリミジン−2,7−ジオン10を収率66%で灰白色の泡沫として製造した。1H NMR (400 MHz, d6-DMSO)δ11.28 (br s, 1H), 6.70-7.40 (m, 3H), 6.02 (s, 1H), 5.30 (d, J = 6.2, 1H), 5.05 (br s, 1H), 4.17-4.24 (m, 3 H), 3.77 (d, J = 8.4, 1H), 1.47 (s, 3H), 1.33 (s, 9H), 1.29 (s, 3H), 0.85 (s, 9H)。
実施例1の工程3と同様の方法で、標題化合物8を上記中間体から収率80%で白色固体として製造した。融点202〜203℃(分解)。1H NMR (400 MHz, d6-DMSO)δ11.35 (br s, 1H), 8.31 (br s, 3H), 7.08 (br s, 2H), 5.83 (d, J = 4.0, 1H), 5.45 (br s, 1H), 5.21 (br s, 1H), 4.77-4.82 (m, 1H), 4.42 (dd, J = 11.4, 2.6, 1H), 4.23-4.28 (m, 1H), 3.96-4.04 (m, 1H), 3.74 (s, 1H), 0.97 (s, 9H)。 C16H23N5O7S・HClに関する元素分析:理論値: C, 41.25; H, 5.19; N, 15.03; Cl, 7.61; S, 6.88; 実測値: C, 40.41; H, 5.41; N, 14.16; Cl, 7.01; S, 6.23。
実施例1の工程2と同様の方法で、5−アミノ−3−(2',3'−O−イソプロピリデン−β−D−リボフラノシル)−チアゾロ[4,5−d]ピリミジン−2,7−ジオン2およびN−tert−ブトキシ−L−N−メチルバリン13から、5−アミノ−3−(2',3'−O−イソプロピリデン−5'−N−tert−ブトキシカルボニル−[α−L−N−メチルバリニル]−β−D−リボフラノシル)−チアゾロ[4,5−d]ピリミジン−2,7−ジオン12を収率63%で灰白色の泡沫として製造した。1H NMR(400MHz, d6-DMSO)回転異性体のカルバミン酸δ11.28 (br s, 1H), 7.00 (br s, 2H), 6.02 (s, 1H), 5.27 (d, J = 6.6, 1H), 5.04 (br s, 1H), 4.14-4.28 (m, 3H), 3.91 (d, J = 9.5, 1H), 2.79 (br s, 3H), 2.09 (br s, 1H), 1.46 (s, 3H), 1.36 (s, 4.5H), 1.32 (s, 4.5H), 1.28 (s, 3H), 0.78-0.89 (m, 6H)。
実施例1の工程3と同様の方法で、標題化合物11を上記中間体から収率60%でわずかに不純物を含んだ白色固体として製造した。融点>180℃(分解)。1H NMR (400 MHz, d6-DMSO)δ11.31 (br s, 1H), 9.05 (br s, 2H), 7.05 (br s, 2H), 5.83 (d, J = 4.4, 1H), 5.46 (br s, 1H), 5.21 (br s, 1H), 4.76-4.82 (m, 1H), 4.42-4.48 (m, 1H), 4.28-4.38 (m, 1H), 4.22-4.28 (m, 1H), 3.94-4.04 (m, 2H), 2.54 (br s, 3H), 2.23 (br s, 1H), 0.98 (d, J = 7.0, 3H), 0.88 (d, J = 7.0, 3H)。C16H23N5O7S・HClに関する元素分析: 理論値: C, 41.25; H, 5.02; N, 15.03; S, 6.88; Cl, 7.61;実測値: C, 40.57; H, 5.37; N, 13.57; S, 6.16; Cl, 7.29。
スキーム2は、5−アミノ−7−メトキシ−3−β−D−リボフラノシルチアゾロ[4,5−d]ピリミジン−2−オンおよび5,7−ジアミノ−3−β−D−リボフラノシルチアゾロ[4,5−d]ピリミジン−2−オンを製造するための一般的な手順を示している。
無水の1(2.0g、6.3mmol)をアルゴン雰囲気下で乾燥ピリジンに溶解させた。この溶液を0℃に冷却し、その混合物にTFAA(13.3g、63mmol)を滴下した。5分後、この反応物を60℃の油浴中に1.5時間入れ、ピリジニウム陽イオンが形成されているかどうかをTLC(SiO2、20%MeOH−CHCl3)によりモニタリングした。0.2Rfの出発材料は、254nmのUV光を当てた際に青色の蛍光を発するベースラインスポットに変換されていた。活性型の中間体へ変換されたところで、その反応物に新しく調製したナトリウムメトキシド(1.8gNa、78mmol、300mlメタノール)溶液を0℃で加えた。この反応物を室温まで昇温し、2日間反応を進行させた。その後、この混合物を1M NH4Cl(100mL)でクエンチし、25%IPA−CHCl3(5×100mL)で抽出した。この粗材料をシリカゲルプラグで濾過した後、濃縮し、1.6g(75%)の標題化合物14を得た。分析用サンプルは分取TLC(SiO2;水:メタノール:酢酸エチル 5:10:85)によって白色固体として得た。融点>160℃(分解)。[M+H]+ 330.9, [2M+H]+ 661.1, [3M+H]+ 991.0; Rf = 0.6 (20% MeOH-CHCl3); 融点200.4℃〜200.9℃; 1H NMR (400MHz, d6-DMSO)δ6.92 (s, 2H), 5.86 (d, J = 5.2, 1H), 5.28 (d, J = 5.6, 1H), 4.96 (d, J = 5.2, 1H), 4.78 (dd, J = 10.8, 5.6, 1H), 4.67 (t, J = 6.0, 1H), 4.07-4.10 (m, 1H), 3.91 (s, 3H), 3.70-3.80 (m, 1H), 3.55-3.60 (m, 1H), 3.40-3.45 (m, 1H)。C11H14N4O6Sに関する元素分析: 理論値: C, 40.00; H, 4.27; N, 16.96; S, 9.71; 実測値: C, 40.07; H, 4.43; N, 16.71; S, 9.53。
無水の1(0.3g、0.9mmol)をアルゴン雰囲気下で乾燥ピリジンに溶解させた。この溶液を0℃に冷却した後、その混合物にTFAA(1.2mL、9.5mmol)を滴下した。5分後、この反応物を60℃の油浴中に1.5時間入れ、ピリジニウム陽イオンが形成されているかどうかをTLC(20%MeOH−CHCl3)によりモニタリングした。0.2Rfの出発材料は、254nmのUV光を当てた際に青色の蛍光を発するベースラインスポットに変換されていた。活性型の中間体へ変換されたところで、この反応フラスコを氷浴中に入れた。温度が平衡状態になった後、30%NH3水溶液(25mL)を、発熱が終わるまで滴下し、その後残りを加えた。分析TLC Rf0.25(SiO2、20%MeOH−CHCl3)により示されるように、数分以内に生成物が生じていた。このフラスコを室温まで30分かけて温めた後、この水溶液を回転真空下で脱気し、その後、25%IPA−CHCl3(5×100mL)で抽出した。この生成物をフラッシュクロマトグラフィー(SiO2、10%MeOH−CHCl3)に付し、55mg(17%)の、わずかに不純物を含んだ標題化合物15を得た。分析用サンプルは分取TLC(SiO2;水−MeOH−EtOAc、5:10:85)により白色固体として得た。融点>155℃(分解)。[M+H]+ 316.0; Rf = 0.25 (SiO2, 20% MeOH-CHCl3); 1H NMR (400MHz, d6-DMSO)δ6.76 (s, 2H), 6.14(s, 2H), 5.85 (d, J = 5.2, 1H), 5.22 (d, J = 4.8, 1H), 4.92 (d, J = 2.8, 1H), 4.70-4.83 (m, 2H), 4.05-4.10 (m, 1H), 3.65-3.80 (m, 1H), 3.52-3.62 (m, 1H) 3.40-3.50 (m, 1H)。C10H13N5O5S・1/2H2Oに関する元素分析: 理論値: C, 37.03; H, 4.35; N, 21.59; S, 9.89; 実測値: C, 37.27; H, 4.32; N, 20.43; S, 10.11。
無水の1(8.0g、39.5mmol)を乾燥ピリジン(65mL)に溶解させた。DMAP(3.1g、25.3mmol)および無水酢酸(19.1mL、202.4mmol)を順次加えた。室温で2時間反応を進行させたところで、飽和NaHCO3(100mL)でクエンチし、DCM(3×200mL)で抽出した。有機相を濃縮した後、エーテルでトリチュレーションした。これにより12.5g(103%)の、わずかに不純物を含む5−アセチルアミノ−3−(2,3,5−トリ−O−アセチル−β−D−リボフラノシル)チアゾロ−[4,5−d]ピリミジン−2,7(6H)−ジオン(16)を白色固体として得た。融点246.7〜248.1℃; Rf = 0.20 (SiO2, 50% EtOAc-CHCl3); 1H NMR (400MHz, d6-DMSO)δ12.23 (s, 1H), 11.85 (s, 1H), 5.97 (m, 2H), 5.48 (t, J = 6, 1H), 4.35-4.40 (m, 1H), 4.25-4.31 (m, 1H), 4.08-4.18 (m, 1H), 2.49 (s, 3H), 2.07 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H)。
上記工程1から得られた中間体(500mg、0.98mmol)を周囲温度でDCM(15mL)に溶解させた。この溶液にDMAP(7.3mg、0.06mmol)およびTEA(16ml、11mmol)を加えた後に2,4,6−トリイソプロピルベンゼンスルホニルクロリド(454mg、1.5mmol)を加えた。1時間後反応は完了し、この粗混合物を濃縮した後、フラッシュクロマトグラフィー(SiO2,10%EtOAc−CHCl3)により精製し、690mg(92%)の5−アセチルアミノ−7−(2,4,6−トリイソプロピル−ベンゼンスルホニルオキシ)−3−(2',3',5'−トリ−O−アセチル−β−D−リボフラノシル)チアゾロ[4,5−d]ピリミジン−2−オンを泡状の白色固体17として得た。74.5〜76.3℃; Rf = 0.7 (SiO2, 20% EtOAc-CHCl3); 1H (400MHz, d6-DMSO)δ10.83 (s, 1H), 7.39 (s, 2H), 6.03 (d, J = 4.0, 1H), 5.91-5.96 (m, 1H), 5.69 (t, J = 6.4, 1H), 4.30-4.70 (m, 1H), 4.22-4.26 (m, 1H), 4.16-4.20 (m, 1H), 3.90-4.00 (m, 2H), 2.97-3.01 (m, 1H), 2.07 (s, 3H), 2.06 (s, 3H), 2.04 (s, 3H), 1.88 (s, 3H), 1.17-1.25 (m, 18H)。
上記工程2から得られた中間体(1.7g、2.27mmol)を周囲温度でジオキサン(20mL)に溶解させた。これにメタノール中2.0Mのメチルアミン溶液(3.4mL、6.8mmol)を加えた。2時間後、出発材料が消費された。この反応混合物を濃縮した後、フラッシュクロマトグラフィー(SiO2、勾配溶出、20〜80%EtOAc−CHCl3)により精製し、945mg(83%)の純粋な標題化合物を黄色オイル状物として得た。[M+H]+ 498.2, [2M+H]+ 995.4; Rf = 0.55 (10% CH3OH-CHCl3); 1H NMR (400MHz, d6-DMSO)δ10.13 (s, 1H), 7.70 (d, J = 4.41, 1H), 5.95-6.02 (m, 2H), 5.69 (s, 1H), 4.35-4.39 (m, 1H), 4.16-4.23 (m, 2H), 2.90 (d, J = 4.8, 3H), 2.20 (s, 3H), 2.07 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H)。
上記工程3から得られた中間体(420mg、0.85mmol)をジオキサン(4mL)に溶解させ、この溶液に1M LiOH(8.5mL、8.5mmol)を加えた。O−アセチル基を40分以内に除去し、Rf=0.15(SiO2,5%MeOH−EtOAc)で中間体を得た。2時間後、TLC Rf=0.20(SiO2,5%MeOH−EtOAc)に示されたように、N−アセチル基が除去されていた。この反応混合物を化学量論量の酢酸で中和し、25%IPA−CHCl3で抽出した後に濃縮し、195mg(70%)の18を得た。標題化合物18の分析用サンプルは分取TLC(SiO2;水−MeOH−EtOAc、10:20:70)により白色固体として得た。[M+H]+ 330.0; Rf = 0.20 (5% MeOH-EtOAc);融点>108℃;1H NMR (400MHz, d6-DMSO)δ7.06 (d, J = 3.6, 1H), 6.24 (s, 2H), 5.85 (d, J = 5.2, 1H), 5.22 (d, J = 4.8, 1H), 4.93 (d, J = 5.2, 1H), 4.70-4.80 (m, 2H), 4.07 (d, J = 4.8, 1H), 3.75 (d, J = 4.4, 1H), 3.5-3.6 (m, 1H), 3.40-3.50 (m, 1H), 2.82 (d, J = 4.4, 3H)。
実施例7の工程2と同様の方法で、5−アセチルアミノ−7−ジメチルアミノ−3−(2',3',5'−トリ−O−アセチル−β−D−リボフラノシル)−チアゾロ[4,5−d]ピリミジン−2−オンを収率80%で黄色オイル状物として得た。M+ 511.14; Rf = 0.70 (SiO2, 10% MeOH-CHCl3); 1H NMR (400MHz, d6-DMSO)δ10.15 (s, 1H), 6.10-6.15 (m, 1H), 5.98-6.09 (m, 1H), 5.5.66-5.70 (m, 1H), 4.35-4.40 (m, 1H), 4.22-4.27 (m, 1H), 4.14-4.08 (m, 1H), 3.18 (s, 6H), 2.19 (s, 3H), 2.08 (s, 3H), 2.06 (s, 3H), 1.99 (s, 3H)。
実施例7の工程3と同様の方法で、標題化合物20を収率82%で得た。分析用サンプルは分取TLC(SiO2;水−MeOH−EtOAc,10:20:70)により白色固体として得た。[M+H]+ 344.0; [2M+H]+ 687.4;融点>112℃;Rf = 0.20 (5% MeOH-EtOAc); 1H NMR (400MHz, d6-DMSO)δ6.27 (s, 2H), 5.91 (d, J = 4.8, 1H), 5.22 (d, J = 6.0, 1H), 4.93 (d, J = 5.2, 1H), 4.71-4.76 (m, 2H), 4.07-4.09 (m, 1H), 3.7-3.8 (m, 1H), 3.5-3.6 (m, 1H), 3.5-3.6 (m, 1H), 3.09 (s, 6H)。C12H17N5O5Sに関する元素分析:理論値: C, 41.98; H, 4.99; N, 20.40; 実測値: C, 41.32; H, 5.14; N, 18.59。
実施例3の工程2と同様の方法で、5−アセチルアミノ−7−シクロプロピルアミノ−3−(2',3',5'−トリ−O−アセチル−β−D−リボフラノシル)チアゾロ[4,5−d]ピリミジン−2−オンを収率80%で黄色オイル状物として得た。Rf = 0.45 (SiO2, 75% EtOAc-CHCl3); 1H NMR (400MHz, D6-DMSO)δ10.11 (s, 1H), 7.87 (d, J = 2.8, 1H), 5.98-6.01 (m, 1H), 5.70-5.76 (s, 1H), 4.32-4.39 (m, 1H), 4.16-4.30 (m, 2H), 3.85 (s, 1H), 2.87 (s, 1H), 2.25 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H), 1.98 (s, 3H), 0.73-0.76 (m, 2H), 0.57-0.60 (m, 2H)。
実施例7の工程3と同様の方法で、5−アミノ−7−シクロプロピルアミノ−3−β−D−リボフラノシルチアゾロ[4,5−d]ピリミジン−2−オンを収率79%で得た。分析用サンプルは分取TLC(SiO2;水−MeOH−EtOAc,10:20:70)により白色固体として得た。Rf = 0.20 (5% MeOH-EtOAc);融点>100℃;[M+H]+ 356.0; 1H (400MHz, d6-DMSO)δ7.24 (s, 1H), 6.28 (s, 2H), 5.86 (d, J = 5.6, 1H), 5.22 (d, J = 6, 1H), 4.92 (d, J = 5.2, 1H), 4.70-4.80 (m, 2H), 4.05-4.10 (m, 1H), 3.7-3.8 (m, 1H), 3.5-3.6 (m, 1H), 3.45-3.50 (m, 1H), 2.8 (s, 1H), 0.68-0.70 (m, 2H), 0.54-0.57 (m, 2H)。
激しく攪拌しているジオキサン中4MのHClに上記工程2で製造した固体材料を添加することにより標題化合物を白色固体として得た。融点>99℃;1H NMR (400MHz, d6-DMSO)δ7.25 (d, 1H, J = 2.8, 1H), 6.23 (s, 2H), 5.87 (d, J = 5.2, 1H), 5.21 (bs, 1H), 4.98 (bs, 1H), 4.73-4.79 (m, 2H), 4.09 (t, J = 5.6, 1H), 3.72-3.79 (m, 1H), 3.55-3.60 (m, 1H), 3.45-3.37 (m, 1H), 2.75-2.82 (m, 1H), 0.72-0.79 (m, 2H), 0.55-0.63 (m, 2H)。C13H17N5O5S・HClに関する元素分析:理論値: C, 39.85; H, 4.63; N, 17.87; Cl, 9.05;実測値: C, 39.66; H, 4.85; N, 16.57; Cl, 8.13。
実施例7の工程2と同様の方法で、5−アセチルアミノ−7−ピロリジノ−3−(2',3',5'−トリ−O−アセチル−β−D−リボフラノシル)−チアゾロ[4,5−d]ピリミジン−2−オンを収率70%で得た。分析用サンプルは分取TLC(SiO2;水−MeOH−EtOAc,10:20:70)により白色固体として得た。融点>108℃(分解)。Rf = 0.80(酢酸エチル中、水10%およびメタノール20%);[M+H]+ 384.0; 1H NMR (400MHz, d6-DMSO)δ7.00 (d, J = 7.2, 1H), 6.17 (s, 2H), 5.18 (d, J = 5.2, 1H), 5.21 (d, J = 5.6, 1H), 4.92 (d, J = 5.6, 1H), 4.74-4.80 (m, 2H), 4.30-4.35 (m, 1H), 4.05-4.10 (m, 1H), 3.70-3.80 (m, 1H), 3.55-3.60 (m, 1H), 3.30-3.45 (m, 1H), 1.40-2.0 (m, 8H)。
実施例7の工程3と同様の方法で、標題化合物22を収率70%で得た。分析用サンプルは分取TLC(SiO2;水−MeOH−EtOAc,10:20:70)により白色固体として得た。融点>108℃(分解); Rf = 0.80 (酢酸エチル中、水10%およびメタノール20%);[M+H]+ 384.0; 1H NMR (400MHz, d6-DMSO)δ7.00 (d, J = 7.2, 1H), 6.17 (s, 2H), 5.18 (d, J = 5.2, 1H), 5.21 (d, J = 5.6, 1H), 4.92 (d, J = 5.6, 1H), 4.74-4.80 (m, 2H), 4.30-4.35 (m, 1H), 4.05-4.10 (m, 1H), 3.70-3.80 (m, 1H), 3.55-3.60 (m, 1H), 3.30-3.45 (m, 1H), 1.40-2.0 (m, 8H)。
実施例7の工程2と同様の方法で、5−アセチルアミノ−7−ピロリジノ−3−(2,3,5−トリ−O−アセチル−β−D−リボフラノシル)チアゾロ[4,5−d]ピリミジン−2−オンを収率79%で黄色オイル状物として得た。[M+H]+ 538.1; Rf = 0.80 (SiO2, 水-MeOH-EtOAc, 10:20:70); 1H (400MHz, D6-DMSO)δ10.04 (s, 1H), 5.97-6.02 (m, 2H), 5.68 (s, 1H), 4.38 (dd, J = 11.6, 3.6, 1H), 4.15-4.23 (m, 2H), 3.58 (s, 4H), 2.23 (s, 3H), 2.08 (s, 3H), 2.05 (s, 3H), 1.98 (s, 3H), 1.89 (s, 4H)。
実施例7の工程3と同様の方法で、標題化合物23を収率81%で得た。分析用サンプルは分取TLC(SiO2;水−MeOH−EtOAc,10:20:70)により白色固体として得た。融点>112.4℃(分解);[M+H]+ 370.3; 1H NMR (400 MHz, d6-DMSO)δ6.22 (s, 2H), 5.90 (d, J = 4.8, 1H), 5.23 (d, J = 5.2, 1H), 4.94 (d, J = 4.4, 1H), 4.68-4.75 (m, 2H), 4.08 (d, J = 4.8, 1H), 3.71-3.76 (m, 1H), 3.55 (bs, 5H), 3.38-3.54 (m, 1H), 1.87 (s, 4H)。
酢酸イソプロピル中、無水塩化水素の溶液に、0℃で激しく攪拌しながら、中間体Bを溶解させ、室温まで昇温する。この不均一混合物に酢酸イソプロピルを追加する。この反応混合物をさらに12時間攪拌する。トルエンを加え、生成物を濾過し、真空乾燥させ、目的の二塩酸塩24を得る。
5−アミノ−7−シクロペンチルアミノ−3−(2',3'−O−イゾプロピリデン−B−D−リボフラノシル)チアゾロ[4,5−d]ピリミジン−2−オン(A)
化合物Aは、Kiniらの手順に従い、5−アミノ−7−シクロペンチルアミノ−3−B−D−リボフラノシルチアゾロ[4,5−d]ピリミジン−2−オン22とアセトン、DMSO、メタンスルホン酸および過剰量のジメトキシプロパンの混合物を、出発材料が消費されるまで0℃で攪拌することにより製造する。この反応混合物を氷水に加え、飽和NaHCO3でpH7まで中和し、EtOAcで抽出する。有機層を濃縮し、シリカカラムクロマトグラフィーに付し、2',3'−保護ジオール生成物を得る。
0℃下、THF中、1.0当量の(N−tert−ブトキシカルボニル)−L−バリンの溶液に1.1当量のEDCを加える。30分攪拌した後、1.0当量の5−アミノ−7−シクロペンチルアミノ−3−(2',3'−O−イゾプロピリデン−β−D−リボフラノシル)チアゾロ[4,5−d]ピリミジン−2−オンAと1.5当量のDMAPを加える。この反応混合物を室温まで昇温し、5時間攪拌し、濃縮する。残渣をEtOAcに溶解させ、1N HClで分液し、飽和NaHCO3水溶液(10mL)で中和する。水相をさらにEtOAcで抽出する。合わせた有機層をNa2SO4で乾燥させ、濾過し、減圧下で蒸発させて中間体Bを得、これをシリカカラムクロマトグラフィーにより精製する。
スキーム9
スキーム10
無水の1(8.17g、25.7mmol)およびDMAP(3.13g、25.7mmol)を乾燥アセトニトリル(125ml)に懸濁させた。この懸濁液に無水酢酸(24.5ml、257mmol)をゆっくり加えた。この反応フラスコに水冷還流冷却器を取り付け、4.5時間還流させた。次に、この反応混合物を水600ml中に注ぎ込んだ。1時間固体を析出させた。この固体を回収し、乾燥させ、エチルエーテル(80ml)中で18時間トリチュレーションを行った。これにより10.3g(82.5%)の化合物16を黄褐色固体として得た。1H NMR (400 MHz, d6-DMSO)δ12.19 (s, 1H), 11.81 (s, 1H), 5.95 (m, 2H), 5.49 (m, 1H), 4.38 (m, 1H), 4.25 (m, 1H), 4.07 (m, 1H), 2.20 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H), 2.00 (s, 3H); MS (+)-ES [M+H]+ m/z 485。Rf = 0.45 (75%酢酸エチル-CHCl3)。C18H20N4O10Sに関する元素分析:理論値: C, 44.63; H, 4.16; N, 11.57; S, 6.62。実測値: C, 44.40; H, 4.18; N, 11.58; S, 6.56。
乾燥窒素雰囲気下、火炎乾燥したフラスコに化合物16(650mg、1.34mmol)およびアルゴノート(Argonaut)PS−トリフェニルホスフィン樹脂(4.02mmol、1.86g)を入れた後、乾燥THF(20ml)を加えた。次に、このフラスコを氷浴中で0℃まで冷却した。イソプロパノール(IPA)(0.20ml、2.68mmol)を加えた後、アゾジカルボン酸ジエチル(DEAD)(0.366ml、2.0mmol)を滴下した。氷浴からフラスコを取り出し、周囲温度まで昇温した。この反応混合物を化合物16が消失したかどうかTLCによりモニタリングした。16が消費されたところで、この固相支持材料を濾去した。粗反応混合物を、クロロホルム中15〜60%の酢酸エチル勾配を用い、フラッシュクロマトグラフィーにより精製した。溶媒を除去し、460mg(64.9%)の27を白色泡沫として得た。MS (+)-ES [M+H]+ m/z 527。Rf = 0.7 (75%酢酸エチル-CHCl3)。
化合物27(600mg、1.14mmol)を乾燥窒素雰囲気下でメタノール(15ml)に溶解させた。K2CO3(31.5mg、0.2mmol)を加え、この混合物を、定期的にTLC(1:1 THF:クロロホルム)によりモニタリングしながら、18時間攪拌した。反応混合物を真空濃縮し、フラッシュカラムクロマトグラフィー(クロロホルム中3%メタノール)により精製した。単離した固体をエチルエーテルでトリチュレーションし、210mg(51%)の純粋な28を白色固体として得た。1H NMR (400 MHz, d6-DMSO)δ6.83 (s, 2H), 5.86 (d, J = 5.2 Hz, 1H), 5.34 (m, 1H), 5.26 (d, J = 5.6 Hz, 2H), 4.95 (d, J = 5.6 Hz, 1H), 4.77 (m, 1H), 4.67 (m, 1H), 4.09 (m, 1H), 3.75 (m, 1H), 3.58 (m,1H), 3.43 (m,1H), 1.29 (d, J = 6.4 Hz, 6H); MS (+)-ES [M+H]+ m/z 359, [2M+H]+ m/z 717.3。Rf = 0.2 (50% THF-CHCl3)。C13H18N4O16Sに関する元素分析:理論値: C, 43.57; H, 5.06; N, 15.63; S, 8.95。実測値: C, 43.39; H, 5.07; N, 15.45; S, 8.82。
実施例13工程2と同様の方法で、16およびエタノールから29を収率72%で白色泡沫として製造した。MS (+)-ES [M+H]+ m/z 513。Rf = 0.45 (75%酢酸エチル-CHCl3)。
実施例13工程3と同様の方法で、29から標題化合物を収率65%で白色固体として製造した。1H NMR (400 MHz, d6-DMSO)δ6.87 (s, 2H), 5.85 (d, J = 4.8 Hz, 1H), 5.27 (d, J = 5.6 Hz, 1H), 4.96 (d, J = 5.2 Hz, 1H), 4.78 (m, 1H), 4.66 (m, 1H), 4.36 (m, 2H), 4.09 (m, 1H), 3.74 (m, 1H), 3.58 (m,1H), 3.40 (m, 1H), 1.29 (m, 3H); MS (+)-ES [M+H]+ m/z 445, [2M+H]+ m/z 689。Rf = 0.2 (50% THF-CHCl3)。C12H16N4O6S・0.25 H2Oに関する元素分析:理論値: C, 41.31; H, 4.77; N, 16.06; S, 9.19。実測値: C, 41.24; H, 4.71; N, 15.89; S, 9.06。
実施例13工程2と同様の方法で、16およびベンジルアルコールから31を収率77%で白色泡沫として製造した。MS (+)-ES [M+H]+ 575。Rf = 0.55 (75%酢酸エチル-CHCl3)。
実施例13工程3と同様の方法で、31から標題化合物を収率62%で白色固体として製造した。1H NMR (400 MHz, d6-DMSO)δ7.39 (bm, 5H), 6.95 (s, 2H), 5.86 (d, J = 4.8 Hz, 1H), 5.43 (s, 2H), 5.28 (d, J = 5.2 Hz, 1H), 4.96 (d, J = 5.2 Hz, 1H), 4.80 (m, 1H), 4.66 (m,1H), 4.09 (m, 1H), 3.76 (m, 1H), 3.42 (m, 1H); MS (+)-ES [M+H]+ 407, [2M+H] 813。Rf = 0.15 (50% THF-CHCl3)。C17H18N4O16Sに関する元素分析:理論値: C, 50.24; H, 4.46; N, 13.79; S, 7.89。実測値: C, 49.97; H, 4.55; N, 13.44; S, 7.70。
実施例13工程2と同様の方法で、16および4−メトキシル−ベンジルアルコールから33を収率72%で白色泡沫として得た。[M+H]+ 605。Rf = 0.5 (75%酢酸エチル-CHCl3)。
実施例13工程3と同様の方法で、33から標題化合物を収率68%で白色固体として製造した。1H NMR (400 MHz, d6-DMSO)δ7.38 (dd, J = 8,4, 2.0 Hz, 2H), 6.93 (s, 2H), 6.91 (dd, J = 6.8, 2.0 Hz, 2H), 5.85 (d, J = 5.2 Hz, 1H), 5.35 (s, 2H), 5.27 (d, J = 5.6 Hz, 1H), 4.96 (d, J = 5.2, 1H), 4.78 (m, 2H), 4.65 (m, 1H), 4.09 (m, 1H), 3.75 (m, 1H), 3.74 (m, 3H), 3.55 (m, 1H), 3.41 (m, 1H); MS (+)-ES [M+H]+ 437, [2M+H]+ 873。Rf = 0.3 (50% THF-CHCl3)。C18H20N4O7S・1.0 H2Oに関する元素分析:理論値: C, 47.57; H, 4.88; N, 12.33; S, 7.06。実測値: C, 47.28; H, 4.91; N, 12.36; S, 7.10。
実施例13工程2と同様の方法で、16およびアリルアルコールから35を収率73%で白色泡沫として製造した。[M+H]+ 525。Rf = 0.6 (75%酢酸エチル/CHCl3)。
実施例13工程3と同様の方法で、35から収率69%で標題化合物白色泡沫として製造した。1H NMR (400 MHz, d6-DMSO)δ6.90 (s, 2H), 6.04 (m, 1H), 5.86 (d, J = 8.0 Hz, 1H), 5.26 (m, 2H), 4.96 (d, J = 5.6 Hz, 1H), 4.86 (m, 1H), 4.79 (m, 2H), 4.66 (m, 1H), 4.08 (m, 1H), 3.76 (m, 1H), 3.58 (m, 1H), 3.45 (m, 1H); MS (+)-ES [M+H]+ 357, [2M+H]+ 713。Rf = 0.3 (50% THF-CHCl3)。C13H16N4O6Sに関する元素分析:理論値: C, 43.82; H, 4.53; N, 15.72; S, 9.00。実測値: C, 43.65; H, 4.65; N, 15.64; S, 8.96。
実施例13工程2と同様の方法で、16および3−メチル−ブト−2−エン−1−オールから37を収率76%で白色泡沫として製造した。MS (+)-ES [M+H]+ 553。Rf = 0.8 (75%酢酸エチル-CHCl3)。
実施例13工程3と同様の方法で、37から標題化合物を収率68%で白色固体として製造した。1H NMR (400 MHz, d6-DMSO)δ6.86 (s, 1H), 5.85 (d, J = 4.8 Hz, 1H), 5.41 (m, 1H), 5.27 (d, J = 5.6 Hz, 1H), 4.96 (d, J = 5.2 Hz, 1H), 4.86 (d, J = 6.8 Hz, 1H), 4.78 (m, 1H), 4.66 (m, 1H), 4.08 (m, 1H), 3.75 (m, 1H), 3.56 (m, 1H), 3.41 (m, 2H), 1.73 (s, 3H), 1.70 (s, 3H); MS (+)-ES [M+H]+ 385。Rf = 0.35 (50% THF-CHCl3)。C15H20N4O6Sに関する元素分析:理論値: C, 46.87; H, 5.24; N, 14.57; S, 8.34。実測値: C, 46.86; H, 5.24; N, 14.62; S, 8.34。
実施例13工程2と同様の方法で、16およびプロパルギルアルコールから39を収率62%で白色泡沫として製造した。MS (+)-ES [M+H]+ 523。Rf = 0.7 (75%酢酸エチル-CHCl3)。
実施例13工程3と同様の方法で、39から標題化合物を収率68%で白色固体として製造した。1H NMR (400 MHz, d6-DMSO)δ6.99 (s, 2H), 5.86 (d, J = 5.2 Hz, 1H), 5.29 (d, J = 5.6 Hz, 1H), 5.04 (s, 2H), 4.97 (d, J = 5.6 Hz, 1H), 4.78 (m, 1H), 4.65 (m, 2H), 4.08 (m, 1H), 3.76 (m, 1H), 3.58 (m, 1H), 3.28 (m, 1H); MS (+)-ES [M+H]+ 355。Rf = 0.25 (50% THF-CHCl3)。C13H14N4O6S・0.5 H2Oに関する元素分析:理論値: C, 42.97; H, 4.16; N, 15.42; S, 9.82; 実測値: C, 43.22; H, 4.27; N, 14.80; S, 8.47。
実施例13工程2と同様の方法で、16およびヒドロキシル−酢酸メチルエステルから41を収率58%で白色泡沫として製造した。MS (+)-ES [M+H]+ 556。Rf = 0.45 (75%酢酸エチル-CHCl3)。
実施例13工程3と同様の方法で、41から標題化合物を収率57%で白色固体として製造した。1H NMR (400 MHz, d6-DMSO)δ6.93 (s, 3H), 5.86 (d, J = 5.6 Hz, 1H), 5.28 (m, 1H), 4.99 (s, 2H), 4.95 (s, 1H), 4.80 (m, 1H), 4.65 (m, 1H), 4.09 (m, 1H), 3.76 (m, 1H), 3.67 (s, 3H), 3.55 (m, 1H), 3.42 (m, 1H); MS (+)-ES [M+H]+ 389, [2M+H]+ 777.3。Rf = 0.15 (75% THF-CHCl3)。C13H16N4O8Sに関する元素分析:理論値: C, 40.21; H, 4.15; N, 14.43; S, 8.26。実測値: C, 40.07; H, 4.25; N, 14.20; S, 8.11。
実施例13工程2と同様の方法で、16および(±)2−ヒドロキシ−プロピオン酸メチルエステルから43を収率55%で白色固体として製造した。MS (+)-ES [M+H]+ 571。Rf = 0.4 (75%酢酸エチル-CHCl3)。
実施例13工程3と同様の方法で、43から収率63%で白色固体として標題化合物を製造した。1H NMR (400 MHz, d6-DMSO)δ6.88 (s, 2H), 5.84 (d, J = 4.0 Hz, 1H), 5.39 (m, 1H), 5.29 (d, J = 5.6 Hz, 1H), 4.97 (d, J = 5.6 Hz, 1H), 4.80 (m, 1H), 4.66 (m, 1H), 4.10 (m, 1H), 3.76 (m, 1H), 3.66 (s, 3H), 3.56 (m, 1H), 3.43(m, 1H), 1.51 (d, J = 6.8 Hz, 3H); MS (+)-ES [M+H]+ 403, [2M+H]+ 805。Rf = 0.15 (50% THF-CHCl3)。C14H18N4O8Sに関する元素分析:理論値: C, 41.79; H, 4.51; N, 13.92; S, 7.97。実測値: C, 41.77; H, 4.50; N, 13.88; S, 7.94。
実施例13工程2と同様の方法で、16およびメタノールから45を収率65%で白色泡沫として製造した。MS (+)-ES [M+H]+ 499。Rf = 0.5 (75%酢酸エチル-CHCl3)。
実施例13工程3と同様の方法で、45から標題化合物を収率78%で白色固体として製造した。1H NMR (400 MHz, d6-DMSO)δ6.91 (s, 2H), 5.86 (d, J = 5.2 Hz, 1H), 5.28 (d, J = 5.2 Hz, 1H), 4.96 (d, J = 5.2 Hz, 1H), 4.77 (m, 1H), 4.66 (m, 1H), 4.09 (m, 1H), 3.90 (s, 3H), 3.75 (m, 1H), 3.56 (m, 1H), 3.43 (m, 1H); MS (+)-ES [M+H]+ 331。Rf = 0.2 (50% THF-CHCl3)。C11H14N4O6S・0.25 H2Oに関する元素分析:理論値: C, 39.46; H, 4.37; N, 16.73; S, 9.58。実測値: C, 39.59; H, 4.17; N, 16.55; S, 9.52。
実施例13工程2と同様の方法で、16およびN−プロパノールから46を収率65%で白色泡沫として製造した。MS (+)-ES [M+H]+ 527。Rf = 0.55 (75%酢酸エチル-CHCl3)。
実施例13工程3と同様の方法で、47から標題化合物を収率70%で白色固体として製造した。1H NMR (400 MHz, d6-DMSO)δ6.87 (s, 2H), 5.85 (J = 5.2 Hz, 1H), 5.28 (d, J = 5.6 Hz, 1H), 4.96 (d, J = 1.2 Hz, 1H), 4.80 (m, 1H), 4.66 (m, 1H), 4.29 (m, 2H), 4.08 (m, 1H), 3.75 (m, 1H), 3.56 (m, 1H), 3.42 (m, 1H), 1.71 (m, 2H), 0.92 (m, 3H); MS (+)-ES [M+H]+ 359。Rf = 0.3 (50% THF-CHCl3)。C13H18N4O6Sに関する元素分析:理論値: C, 43.57; H, 5.06; N, 15.63; S, 8.95。実測値: C, 43.77; H, 5.29; N, 15.39; S, 8.81。
実施例13工程2と同様の方法で、16およびN−ブタノールから48を収率64%で白色ペーストとして製造した。MS (+)-ES [M+H]+ 541。Rf = 0.65 (75%酢酸エチル-CHCl3)。
実施例13工程3と同様の方法で、48から標題化合物を収率72%で白色固体として製造した。1H NMR (400 MHz, d6-DMSO)δ6.87 (s, 2H), 5.85 (d, J = 4.8 Hz, 1H), 5.28 (d, J = 5.2 Hz, 1H), 4.95 (d, J = 5.6 Hz, 1H), 4.77 (m, 1H), 4.34 (m, 1H), 4.07 (m, 1H), 3.74 (m, 1H), 3.58 (m, 1H), 3.41 (m, 1H), 1.63 (m, 2H), 1.31 (m, 2H), 0.92 (m, 3H); MS (+)-ES [M+H]+ 373。Rf = 0.25 (50% THF-CHCl3)。C14H20N4O6Sに関する元素分析:理論値: C, 45.15; H, 5.41; N, 15.04; S, 8.61。実測値: C, 44.79; H, 5.34; N, 15.02; S, 8.60。
実施例13工程2と同様の方法で、16および4−フルオロベンジルアルコールから50を製造した。1H NMR (400 MHz, CDCl3)δ8.20 (m, 1H), 7.44 (m, 1H), 7.06 (m, 1H), 6.10 (d, J = 3.2 Hz, 1H), 6.02 (dd, J = 3.0, 6.0 Hz, 1H), 5.92 (t, J = 5.0 Hz, 1H), 5.48 (s, 2H), 4.51 (dd, J = 4.0, 6.0 Hz, 1H), 4.34 (m, 1), 4.23 (dd, J = 4.0, 8.0 Hz, 1H), 2.44 (s, 3H), 2.13 (s, 3H), 2.11 (s, 3H), 2.04 (s, 3H)。
実施例13工程3と同様の方法で、50から標題化合物を製造した。1H NMR (400 MHz, d6-DMSO)δ7.50 (m, 2H), 7.19 (m, 2H), 6.96 (s, 2H), 5.86 (d, J = 4.8 Hz, 1H), 5.41 (s, 2H), 5.28 (d, J = 5.6 Hz, 1H), 4.96 (d, J = 5.6 Hz, 1H), 4.78 (q, J = 5.2 Hz, 1H), 4.66 (t, J = 6.0 Hz, 1H), 4.09 (q, J = 5.2 Hz, 1H), 3.75 (q, J = 4.8 Hz, 1H), 3.57 (m, 1H), 3.42 (m, 1H)。
実施例13工程2と同様の方法で、16および1,3−プロパンジオールモノアセテート(Dittmer, JACS, 79, 4431-35) (1957))から52を製造した。1H NMR (400 MHz, CDCl3)δ8.17 (s, 1H), 6.10 (d, J = 3.2 Hz, 1H), 6.02 (dd, J = 2.8, 6.0 Hz, 1H), 5.89 (t, J = 6.8 Hz, 1H), 4.56-4.89 (m, 3H), 4.34 (m, 1H), 4.26-4.20 (m, 3H), 2.46 (s, 3H), 2.15 (m, 2H), 2.13 (s, 3H), 2.11 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H)。
実施例13工程3と同様の方法で、52から標題化合物を製造した。1H NMR (400 MHz, d6-DMSO)δ6.87 (s, 2), 5.86 (d, J = 5.2 Hz, 1H), 5.28 (d, J = 5.6 Hz, 1H), 4.96 (d, J = 5.2 Hz, 1H), 4.78 (q, J = 5.6 Hz, 1H), 4.67 (t, J = 5.6 Hz, 1H), 4.53 (t, J = 5.2 Hz, 1H), 4.40 (t, J = 6.8 Hz, 2H), 4.09 (q, J = 5.2 Hz, 1H), 3.75 (q, J = 4.8 Hz, 1H), 3.57 (m, 1H), 3.50 (q, J = 6.4 Hz, 2H), 3.42 (m, 1H), 1.83 (m, 2H)。
実施例13工程2と同様の方法で、16および1,4−ブタンジオールモノアセテート(Clarke, Tet. Lett., 43(27), 4761-64 (2002))から54を製造した。1H NMR (400 MHz, CDCl3)δ8.15 (s, 1H), 6.10 (d, J = 3.2 Hz, 1H), 6.02 (dd, J = 3.2, 6.4 Hz, 1H), 5.89 (t, J = 6.4 Hz, 1H), 4.50 (m, 3H), 4.32 (m, 1H), 4.24 (dd, J = 6.4, 12.0 Hz, 1H), 4.13 (t, J = 6.4 Hz, 1H), 2.45 (s, 3H), 2.13 (s, 3H), 2.10 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H), 1.88 (s, 3H), 1.78 (m, 2H).
実施例13工程3と同様の方法で、54から標題化合物を製造した。1H NMR (400 MHz, d6-DMSO)δ6.87 (s, 2H), 5.85 (d, J = 5.2 Hz, 1H), 5.29 (s, 1H), 4.98 (s, 1H), 4.79 (t, J = 5.2 Hz, 1H), 4.67 (s, 1H), 4.43 (t, J = 4.8 Hz, 1H), 4.35 (t, J = 6.8 Hz, 2H), 4.09 (t, J = 5.2 Hz, 1H), 3.75 (q, J = 4.8 Hz, 1H), 3.57 (m, 1H), 3.42 (m, 3H), 1.72 (m, 2H), 1.50 (m, 2H)。
Kelper, JOC, 52, 453-55 (1987)が報告している一般的な実験条件下で、水(480μL)中、Ba(OH)2(46.0mg、266μmol)のスラリーを、N−エチルウレタン(2.04mL、17.1mmol)と37%ホルマリン水溶液(1.28mL、17.1mmol)の混合物に攪拌しながら一度に加えた。混合物が冷めるにつれ、徐々に曇りのある溶液となった。この混合物を室温で攪拌し、N−エチルウレタンの消失をTLC分析によりモニタリングした。2時間後、固体CO2を加えることにより反応をクエンチし、30分攪拌し、濾過して沈殿した炭酸バリウムを除去した。真空下で溶媒を除去して油性の残渣を得た。ベンゼン(3×100mL)との共沸蒸留により微量の水を除去して56を透明なオイル状物として得た(2.50g、定量的)。1H NMR (400 MHz, CDCl3)δ4.88 (d, J = 7.6 Hz, 1H), 4.79 (d, J = 7.6 Hz, 2H), 4.18 (q, J = 7.6 Hz, 2H), 3.40 (q, J = 6.4 Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H), 1.19 (t, J = 7.6 Hz, 3H)。
実施例13工程2と同様の方法で、16および56から化合物57を収率24%で白色固体として製造した。Rf = 0.4 (33% EtOAc-CHCl3); 1H NMR (400 MHz, CDCl3)δ11.49 (br s, 1H), 6.08 (d, J = 4.0 Hz, 1H), 5.75 (t, J = 6.0 Hz, 1H), 5.53 (s, 2H), 4.49 (dd, J = 13.5, 8.4 Hz, 1H), 4.30 (m, 5H), 3.62 (q, J = 7.2 Hz, 2H), 2.30 (s, 3H), 2.12 (s, 3H), 2.09 (s, 3H), 2.08 (s, 3H), 1.36 (t, J = 6.8 Hz, 3H), 1.20 (t, J = 6.8 Hz, 3H); [M+H]+ 614.2。
実施例13工程3と同様の方法で、57から標題化合物を収率30%で白色固体として製造した。1H NMR (400 MHz, d6-DMSO)δ7.89 (br s, 2H), 5.82 (d, J = 4.8 Hz, 1H), 5.49 (m, 3H), 5.32 (d, J = 5.2 Hz, 1H), 5.01 (d, J = 5.6 Hz, 1H), 4.82 (q, J = 5.6 Hz, 1H), 4.69 (t, J = 5.6 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 4.11 (q, J = 5.6 Hz, 2H), 3.78 (q, J = 5.2 Hz, 1H), 3.60 (m, 1H), 3.45 (m, 1H), 1.27 (t, J = 7.2 Hz, 3H), 1.09 (t, J = 6.0 Hz, 3H); [M+H]+ 446.3。
実施例28工程1と同様の方法で、N−メチルウレタンおよびホルマリンから化合物59を定量的収率で粘稠なオイルとして製造した。1H NMR (400 MHz, CDCl3)δ5.02 (d, J = 7.6 Hz, 1H), 4.79 (d, J = 7.6 Hz, 2H), 4.18 (q, J = 4.4 Hz, 2H), 3.01 (s, 3H), 1.30 (t, J = 7.6 Hz, 3H)。
実施例13工程2と同様の方法で、16および59から化合物60を収率24%で白色固体として製造した。Rf = 0.4 (33% EtOAc-CHCl3); 1H NMR (400 MHz, CDCl3)δ11.49 (br s, 1H), 6.08 (d, J = 4.0 Hz, 1H), 5.75 (t, J = 6.0 Hz, 1H), 5.53 (s, 2H), 4.49 (dd, J = 13.5, 8.4 Hz, 1H), 4.30 (m, 5H), 3.62 (q, J = 7.2 Hz, 2H), 2.30 (s, 3H), 2.12 (s, 3H), 2.09 (s, 3H), 2.08 (s, 3H), 1.36 (t, J = 6.8 Hz, 3H), 1.20 (t, J = 6.8 Hz, 3H); [M+H]+ 614.2。
実施例13工程3と同様の方法で、60から標題化合物を収率20%で白色固体として製造した。1H NMR (400 MHz, d6-DMSO)δ7.86 (br s, 2H), 5.82 (d, J = 4.8 Hz, 1H), 5.47 (s, 2H), 5.31 (d, J = 5.2 Hz, 1H), 5.00 (d, J = 5.6 Hz, 1H), 4.82 (q, J = 5.2 Hz, 1H), 4.67 (q, J = 5.6 Hz, 1H), 4.18 (q, J = 6.4 Hz, 2H), 4.12 (m, 1H), 3.78 (q, J = 6.0 Hz, 1H), 3.60 (m, 1H), 3.47 (m, 1H), 3.30 (s, 3H), 1.27 (t, J = 6.8 Hz, 3H); [M+H]+ 432.3。
0℃下、アセトニトリル(160mL)中、1(5.00g、15.8mmol)の懸濁液にEt3N(11.0mL、79.0mmol)、DMAP(195mg、1.59mmol)、およびAc2O(4.47mL、47.4mmol)を連続的に加えた。この反応混合物を室温で2時間攪拌したところで濃縮して褐色のシロップとした。残渣をフラッシュカラムクロマトグラフィー(シリカ、MeOH/CHCl3=1〜10%)により精製し、6.22g(89%)のトリアセテート25を白色固体として得た。融点198〜199℃。1H (400 MHz, d6-DMSO)δ11.34 (s, 1H), 7.02 (br s, 2H), 5.90 (m, 2H), 5.51 (t, J = 6.0 Hz, 1H), 4.36 (dd, J = 12.4, 3.2 Hz, 1H), 4.21 (m, 1H), 4.08 (q, J = 6.0 Hz, 1H), 2.06 (s, 3H), 2.06 (s, 3H), 2.00 (s, 3H); MS (+)-ES [M+H]+ m/z 443.3。
0℃下、THF(70mL)中、上記のトリアセテート25(1.49g、3.37mmol)、アルゴノートポリマー支持トリフェニルホスフィン樹脂(5.98g、10.1mmol)、およびシクロプロピルメチルカルビノール(546μL、6.74mmol)の不均一混合物に、DEAD(742μL、4.72mmol)を加えた。この反応混合物を室温まで昇温し、16時間攪拌した後、SiO2のショートパッドで濾過した。この濃縮濾液をクロマトグラフィー(SiO2、勾配溶出、0〜5%EtOAc−CHCl3)に付し、680mg(42%)の白色固体を得た。1H (400 MHz, d6-DMSO)δ6.95 (s, 2H), 5.99 (d, J = 4.0 Hz, 1H), 5.91 (dd, J = 6.2, 4.0 Hz, 1H), 5.55 (dd, J = 6.6, 6.2 Hz, 1H), 4.37 (dd, J = 12.1, 3.7 Hz, 1H), 4.22-4.26 (m, 1H), 4.19 (d, J = 7.0 Hz, 2H), 4.09 (dd, J = 11.7, 5.9 Hz, 1H), 2.07 (s, 3H), 2.06 (s, 3H), 1.99 (s, 3H), 1.20-1.26 (m, 1H), 0.53-0.58 (m, 2H), 0.31-0.35 (m, 2H); MS (+)-ES [M+H]+ m/z 497。C20H24N4O9Sに関する元素分析:理論値: C, 48.38; H, 4.87; N, 11.28; S, 6.46。実測値: C, 48.53; H, 4.99; N, 11.27; S, 6.18。
MeOH中、62(570mg、1.18mmol)の懸濁液に、室温でK2CO3(50mg、0.36mmol)を加えた。この反応混合物を1時間攪拌し、濃縮し、20%IPA−CHCl3と水で分液した後、Et2Oでトリチュレーションし、128mg(29%)の63を白色固体として得た。1H (400 MHz, d6-DMSO)δ6.86 (s, 2H), 5.85 (d, J = 5.1 Hz, 1H), 5.27 (d, J = 5.5 Hz, 1H), 4.96 (d, J = 5.5 Hz, 1H), 4.77 (q, J = 5.5 Hz, 1H), 4.66 (t, J = 5.9 Hz, 1H), 4.18 (dd, J = 7.3, 1.1 Hz, 1H), 4.09 (q, J = 5.5 Hz, 1H), 3.75 (q, J = 5.1 Hz, 1H), 3.39-3.60 (m, 2H), 1.20-1.27 (m, 1H), 0.53-0.57 (m, 2H), 0.31-0.34 (m, 2H); MS (+)-ES [M+H]+ m/z 371。C14H18N4O6S に関する元素分析:理論値: C, 45.40; H, 4.90; N, 15.13; S, 8.66。実測値: C, 44.98; H, 4.92; N, 14.92; S, 8.49。
実施例25工程2と同様の方法で、25およびシンナミルアルコールから化合物64を収率69%で製造した。MS (+)-ES [M+H]+ m/z 601。
実施例25工程3と同様の方法で、64から標題化合物を収率19%で白色固体として製造した。1H (400 MHz, d6-DMSO)δ7.46 (d, J = 7.0 Hz, 1H), 7.34 (t, J = 7.3 Hz, 1H), 7.23-7.27 (m, 1H), 6.93 (s, 2H), 6.74 (d, J = 16.1 Hz, 1H), 6.45-6.53 (m, 1H), 5.86 (d, J = 5.1 Hz, 1H), 5.28 (d, J = 5.5 Hz, 1H), 5.04 (d, J = 6.2 Hz, 1H), 4.96 (d, J = 5.5 Hz, 1H), 4.79 (q, J = 5.5 Hz, 1H), 4.67 (t, J = 5.5 Hz, 1H), 4.09 (q, J = 5.1 Hz, 1H), 3.76 (q, J = 4.8 Hz, 1H), 3.30-3.60 (m, 2H); MS (+)-ES [M+H]+ m/z 433。C19H20N4O6Sの元素分析:理論値: C, 52.77; H, 4.66; N, 12.96; S, 7.41。実測値: C, 52.28; H, 4.66; N, 12.66; S, 7.27。
室温で、DMF(20mL)中、1(1.00g、3.16mmol)の懸濁液に、イミダゾール(753mg、11.06mmol)、DMAP(39mg、0.32mmol)、およびクロロトリエチルシラン(1.64mL、9.80mmol)を連続的に加えた。この反応混合物を室温で2時間攪拌したところで、飽和NaHCO3溶液(20mL)で反応をクエンチした。この混合物をCHCl3(3×20mL)で抽出し、MgSO4で乾燥させ、濃縮した。残渣をフラッシュカラムクロマトグラフィー(シリカ、MeOH/CHCl3=1〜5%)により精製し、1.91g(92%)の化合物26を白色固体として得た。1H (400 MHz, d6-DMSO)δ5.99 (s, 1H), 5.62 (br s, 2H), 5.19 (dd, J = 4.4, 6.0 Hz, 1H), 4.35 (dd, J = 2.8, 4.4 Hz, 1H), 3.99 (m, 1H), 3.77 (dd, J = 7.6, 10.8 Hz, 1H), 3.68 (dd, J = 4.8, 10.4 Hz, 1H), 1.10 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.1 Hz, 3H), 0.89 (t, J = 7.1 Hz, 3H), 0.68 (q, J = 7.1 Hz, 2H), 0.61 (q, J = 7.1 Hz, 2H), 0.54 (m, 2H); MS (+)-ES [M+H]+ m/z 660.0。
実施例13工程2と同様の方法で、26およびN−エチルウレタンから化合物67を収率31%で白色固体として製造した。[M+H]+ 760.5; 1H NMR (400 MHz, CDCl3)δ6.43 (br s, 2H), 6.09 (t, J = 7.6 Hz, 1H), 5.94 (d, J = 6.0 Hz, 1H), 5.31 (d, J = 4.8 Hz, 2H), 5.19 (dd, J = 6.0, 4.8 Hz, 1H), 4.35 (dd, J = 4.8, 2.8 Hz, 1H), 4.19 (q, J = 6.4 Hz, 2H), 3.98 (m, 1H), 3.76 (dd, J = 10.8, 7.6 Hz, 1H), 3.68 (dd, J = 10.4, 4.8 Hz, 1H), 1.29 (t, J = 6.8 Hz, 3H), 1.02 (t, J = 8.0 Hz, 3H), 0.96 (t, J = 7.6 Hz, 3H), 0.90 (t, J = 8.0 Hz, 3H), 0.69 (q, J = 8.0 Hz, 2H), 0.61 (q, J = 8.0 Hz, 2H), 0.55 (m, 2H); [M+H]+ 760.5。
67(244mg、321μmol)、ピリジン中5MのHF(321μL、1.60mmol)およびTHF(3.20mL)の溶液を室温で5時間攪拌した。真空下で溶媒を除去すると残渣が残り、これをフラッシュクロマトグラフィー(SiO2、10%MeOH−CHCl3)により精製し、68(119mg、90%)を白色固体として得た。1H NMR (400 MHz, d6-DMSO)δ8.43 (br s, 1H), 7.76 (br s, 2H), 5.82 (d, J = 5.2 Hz, 1H), 5.78 (s, 2H), 5.32 (d, J = 5.6 Hz, 1H), 5.24 (dd, J = 6.0, 4.8 Hz, 1H), 5.00 (d, J = 5.6 Hz, 1H), 4.82 (q, J = 5.6 Hz, 1H), 4.68 (t, J = 6.0, 1H), 4.11 (q, J = 5.2 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.78 (q, J = 5.6 Hz, 1H), 3.60 (m, 1H), 3.46 (m, 1H), 1.21 (t, J = 7.2 Hz, 3H); [M+H]+ 418.2。
実施例32と同様の方法で、26および4−ヒドロキシメチル−5−メチル−[1,3]ジオキソール−2−オンから化合物69を収率45%で白色固体として製造した。1H NMR (400 MHz, CDCl3)δ6.06 (d, J = 6.0 Hz, 1H), 5.21 (dd, J = 6.0, 4.8 Hz, 1H), 5.18 (d, J = 3.2 Hz, 2H), 4.94 (br s, 2H), 4.38 (dd, J = 4.8, 2.8 Hz, 1H), 4.00 (m, 1H), 3.79 (dd, J = 11.2, 8.0 Hz, 1H), 3.69 (dd, J = 10.8, 5.2 Hz, 1H), 2.23 (s, 3H), 1.02 (t, J = 8.0 Hz, 3H), 0.96 (t, J = 7.6 Hz, 3H), 0.89 (t, J = 8.4 Hz, 3H), 0.70 (q, J = 7.6 Hz, 2H), 0.61 (q, J = 8.0 Hz, 2H), 0.53 (m, 2H); [M+H]+ 771.5。
実施例33工程3と同様の方法で、69から標題化合物を収率89%で白色固体として製造した。1H NMR (400 MHz, d6-DMSO)δ7.03 (br s, 2H), 5.90 (d, J = 5.2 Hz, 1H), 5.33 (s, 2H), 5.02 (d, J = 4.8 Hz, 1H), 4.83 (q, J = 5.6 Hz, 1H), 4.71 (t, J = 6.0 Hz, 1H), 4.14 (q, J = 5.2 Hz, 1H), 3.80 (q, J = 4.8 Hz, 1H), 3.62 (m, 1H), 3.47 (m, 1H), 2.27 (s, 3H); [M+H]+ 429.2。
実施例13工程2と同様の方法で、26および4−ヒドロキシ−酪酸tert−ブチル−エステル(Lui, JOC, 68(17), 6679-6684 (2003))から化合物71を収率92%で白色固体として製造した。1H NMR (400 MHz, CDCl3)δ6.06 (d, J = 6.4 Hz, 1H), 5.22 (dd, J = 6.0, 4.8 Hz, 1H), 4.98 (br s, 2H), 4.42 (t, J = 6.0 Hz, 2H), 4.38 (dd, J = 6.0, 4.8 Hz, 1H), 4.00 (m, 1H), 3.80 (dd, J = 10.8, 7.6 Hz, 1H), 3.69 (dd, J = 10.8, 5.2 Hz, 1H), 2.38 (t, J = 7.2 Hz, 2H), 2.06 (quint, J = 7.2 Hz, 3H), 1.47 (s, 9H), 1.02 (t, J = 8.0 Hz, 3H), 0.96 (t, J = 8.0 Hz, 3H), 0.88 (t, J = 8.0 Hz, 3H), 0.70 (q, J = 7.6 Hz, 2H), 0.61 (q, J = 8.0 Hz, 2H), 0.53 (m, 2H); [M+H]+ 801.5。
実施例33工程3と同様の方法で、71から標題化合物を収率66%で白色固体として製造した。1H NMR (400 MHz, d6-DMSO)δ6.93 (br s, 2H), 5.90 (d, J = 4.8 Hz, 1H), 5.32 (d, J = 5.6 Hz, 1H), 5.10 (d, J = 5.6 Hz, 1H), 4.83 (q, J = 5.6 Hz, 1H), 4.71 (t, J = 5.6 Hz, 1H), 4.38 (t, J = 6.4 Hz, 2H), 4.13 (q, J = 5.6 Hz, 1H), 3.80 (q, J = 5.6 Hz, 1H), 3.62 (m, 1H), 3.47 (m, 1H), 2.35 (t, J = 7.6 Hz, 2H), 1.96 (quint, J = 6.8 Hz, 2H), 1.44 (s, 9H); [M+H]+ 459.3。
実施例13工程2と同様の方法で、26および1,4−ブタンジオールモノアセテートから73を収率81%で白色固体として製造した。1H NMR (400 MHz, CDCl3)δ6.06 (d, J = 6.0 Hz, 1H), 5.23 (dd, J = 5.6, 5.2 Hz, 1H), 4.93 (br s, 2H), 4.41 (t, J = 6.4 Hz, 2H), 4.37 (dd, J = 4.8, 2.8 Hz, 1H), 4.14 (t, J = 6.4 Hz, 2H), 4.00 (m, 1H), 3.80 (dd, J = 11.2, 7.6 Hz, 1H), 3.69 (dd, J = 10.8, 4.8 Hz, 1H), 2.07 (s, 3H), 1.85 (m, 2H), 1.78 (m, 2H), 1.02 (t, J = 7.6 Hz, 3H), 0.96 (t, J = 8.0 Hz, 3H), 0.88 (t, J = 7.6 Hz, 3H), 0.70 (q, J = 7.6 Hz, 2H), 0.61 (q, J = 8.0 Hz, 2H), 0.56 (m, 2H); [M+H]+ 773.5。
アセトニトリル(1.22mL、1.22mmol)中、73(188mg、243μmol)および1M HFの溶液を室温18時間攪拌した。真空下で溶媒を除去すると残渣が残り、これをフラッシュクロマトグラフィー(SiO2、10%MeOH−CHCl3)により精製し、74(91.1mg、88%)を白色固体として得た。1H NMR (400 MHz, d6-DMSO)δ6.93 (br s, 2H), 5.90 (d, J = 5.2 Hz, 1H), 5.32 (d, J = 5.6 Hz, 1H), 5.01 (d, J = 5.6 Hz, 1H), 4.83 (q, J = 5.6 Hz, 1H), 4.71 (t, J = 6.0 Hz, 1H), 4.41 (t, J = 6.0 Hz, 2H), 4.14 (q, J = 4.8 Hz, 1H), 4.07 (t, J = 6.4 Hz, 1H), 3.80 (q, J = 6.0 Hz, 1H), 3.62 (m, 1H), 3.47 (m, 1H), 2.04 (s, 3H), 1.80 (m, 2H), 1.71 (m, 2H); [M+H]+ 431.3。
実施例13工程2と同様の方法で、26および1,3−プロパンジオールモノアセテートから75を収率70%で白色固体として製造した。1H NMR (400 MHz, CDCl3)δ6.06 (d, J = 6.4 Hz, 1H), 5.23 (dd, J = 6.4, 4.8 Hz, 1H), 4.93 (br s, 2H), 4.46 (t, J = 6.4 Hz, 2H), 4.38 (dd, J = 4.4, 2.4 Hz, 1H), 4.22 (t, J = 6.4 Hz, 2H), 4.00 (m, 1H), 3.80 (dd, J = 10.8, 7.6 Hz, 1H), 3.69 (dd, J = 10.8, 5.2 Hz, 1H), 2.12 (quint, J = 6.4 Hz, 2H), 2.08 (s, 3H), 1.02 (t, J = 8.0 Hz, 3H), 0.96 (t, J = 8.0 Hz, 3H), 0.88 (t, J = 8.0 Hz, 3H), 0.70 (q, J = 8.4 Hz, 2H), 0.61 (q, J = 8.4 Hz, 2H), 0.54 (m, 2H); [M+H]+ 759.5。
実施例36工程2と同様の方法で、75から76を収率92%で白色固体として製造した。1H NMR (400 MHz, d6-DMSO)δ6.94 (br s, 2H), 5.90 (d, J = 5.2 Hz, 1H), 5.32 (d, J = 4.8 Hz, 1H), 5.00 (d, J = 4.8 Hz, 1H), 4.83 (q, J = 4.8 Hz, 1H), 4.71 (t, J = 6.0 Hz, 1H), 4.46 (t, J = 6.4 Hz, 2H), 4.14 (t, J = 6.4 Hz, 2H), 3.80 (q, J = 5.2 Hz, 1H), 3.62 (dd, J = 11.2, 8.0 Hz, 1H), 3.47 (dd, J = 11.2, 6.0 Hz, 1H), 2.06 (quint, J = 6.4 Hz, 2H), 2.04 (s, 3H); [M+H]+ 417.2。
ピリジン(50mL)中、25(1g、2.26mmol)の溶液に室温でP2S5(2.13g、4.79mmol)を加えた。この溶液を29時間、穏やかに還流させた(浴温130〜140℃)。この反応混合物を真空下で蒸発乾固させた。60℃でH2O(40mL)を加えることによって過剰なP2S5を分解した。この混合物を60℃で1時間攪拌した後、室温まで冷却した。この混合物をCHCl3(3×40mL)で抽出した。乾燥させた(MgSO4)有機層を蒸発させてシロップを得、これをフラッシュカラムクロマトグラフィー(シリカ、アセトン/CHCl3=15%)により精製し、0.93g(90%)の77を黄色固体として得た。1H (400 MHz, d6-DMSO)δ12.50 (s, 1H), 7.35 (br s, 2H), 5.89 (m, 2H), 5.51 (t, J = 6.4 Hz, 1H), 4.36 (dd, J = 12.0, 4.0 Hz, 1H), 4.24 (m, 1H), 4.10 (q, J = 6.0 Hz, 1H), 2.07 (s, 3H), 2.06 (s, 3H), 2.01 (s, 3H); MS (+)-ES [M+H]+ m/z 459.3。
アセトン(50mL)中、ラネー(登録商標)2800ニッケル(H2O、MeOHおよびアセトンで予め洗浄したもの、スパチュラ大さじ3杯)の懸濁液を還流下で1時間攪拌した。次に、還流下で上記の懸濁液にトリアセテート77(0.93g、2.03mmol)を加えた。この混合物を5分攪拌し、30分かけて室温まで冷却した。この混合物に2時間、H2S(g)気泡を通じることにより反応をクエンチした。得られた混合物をセライト(登録商標)のショートパッドで濾過し、EtOHで洗浄した。濾液を濃縮し、フラッシュカラムクロマトグラフィー(シリカ、MeOH/CHCl3=1〜2%)により精製し、0.52g(60%)の78を白色固体として得た。融点121〜123℃。1H (400 MHz, d6-DMSO)δ8.38 (s, 1H), 6.93 (s, 2H), 6.03 (d, J = 3.6 Hz, 1H), 5.93 (dd, J = 6.4, 3.6 Hz, 1H), 5.58 (t, J = 6.0 Hz, 1H), 4.38 (dd, J = 11.6, 3.6 Hz, 1H), 4.26 (m, 1H), 4.11 (q, J = 6.0 Hz, 1H), 2.08 (s, 3H), 2.07 (s, 3H), 2.00 (s, 3H); MS (+)-ES [M+H]+ m/z 427.2。C16H18N4O8S・0.5 CH3OH・0.25 H2Oに関する元素分析:理論値: C, 44.34; H, 4.62; N, 12.54; S 7.17。実測値: C, 44.54; H, 4.88; N, 12.16; S, 7.17。
MeOH(20mL)中、78(0.52g、1.22mmol)の溶液に、K2CO3(25mg、0.18mmol)を加えた。この反応物を室温で一晩攪拌した後、AcOH(21μL、0.36mmol)で中和した。得られた混合物を室温でさらに30分攪拌し、濃縮し、H2O(2ml)でトリチュレーションし、0.33gの化合物79(89%)を白色固体として得た。融点220℃(分解)。1H (400 MHz, d6-DMSO)δ8.34 (s, 1H), 6.85 (s, 2H), 5.90 (d, J = 4.8 Hz, 1H), 5.31 (d, J = 5.6 Hz, 1H), 4.98 (d, J = 5.6 Hz, 1H), 4.81 (q, J = 5.2 Hz, 1H), 4.67 (t, J = 6.0 Hz, 1H), 4.11 (q, J = 5.2 Hz, 1H), 3.77 (dd, J = 10.8, 4.8 Hz, 1H), 3.58 (m, 1H), 3.44 (m, 1H); MS (+)-ES [M+H]+ m/z 301.1。C10H12N4O5S・0.3 H2Oに関する元素分析:理論値: C, 39.29; H, 4.15; N, 18.33; S 10.49。実測値: C, 39.51; H, 4.18; N, 17.95; S, 10.27。
別法合成経路A
工程1: 5−アミノ−7−クロロ−3−(2',3',5'−トリ−O−アセチル−β−D−リボフラノシル)−チアゾロ[4,5−d]ピリミジン−2−オン(80)の製造
CHCl3(9mL)中、25(0.84g、1.90mmol)の溶液に、トリエチルアミン(0.50mL、3.59mmol)およびPOCl3(1.60mL、17.1mmol)を加えた。16時間加熱還流した後、反応混合物を室温まで冷却し、氷と飽和NaHCO3水溶液(150mL)に注ぎ込んだ。得られた混合物をCH2Cl2(3×75mL)で抽出し、合わせた有機層を乾燥させた(MgSO4)。濃縮後にフラッシュクロマトグラフィー(9:1/CH2Cl2:EtOAc)に付し、708mg(87%)の生成物を白色固体として得た。融点101〜103℃。1H NMR (400 MHz, CDCl3)δ6.10 (d, J = 2.8 Hz, 1H), 6.01 (dd, J = 5.6, 3.2 Hz, 1H), 5.92 (t, J = 6.0 Hz, 1H), 5.42 (s, 2), 4.97 (dd, J = 11.6, 3.6 Hz, 1H), 4.32 (m, 1), 4.21 (dd, J = 12.0, 5.2 Hz, 1H), 2.12 (s, 6H), 2.06 (s, 3H)。
火炎乾燥した丸底フラスコに80(4.37g、9.48mmol)および氷酢酸(61mL)を入れた。フラスコをセプタムで密閉し、窒素でフラッシュした。亜鉛−銅合金(6.07g、Aldrich)を加え、この反応物を室温で21時間攪拌した。次に、この反応物を1時間80℃まで加熱した。この反応混合物を室温まで冷却し、セライト(登録商標)パッドで濾過し、EtOAc(200mL)で洗浄し、真空濃縮した。得られた白色固体(残渣)をCH2Cl2(250mL)で希釈し、0.5M NaOH(500mL)で洗浄した。水層をCH2Cl2(2×150mL)で抽出し、合わせた有機層を乾燥させ(MgSO4)、濾過および濃縮した。フラッシュクロマトグラフィー(SiO2、5%アセトン−CH2Cl2)により精製し、78(3.64g、90%)を、全ての点で実施例38工程2で単離された物質と一致する白色粉末として得た。
標題化合物の製造については実施例38工程3に記載されている。
別法合成経路B
工程1: 5−アセチルアミノ−7−クロロ−3−(2',3',5'−トリ−O−アセチル−β−D−リボフラノシル)−チアゾロ[4,5−d]ピリミジン−2−オン(81)の製造
窒素下、室温で、16(3.40g、7.02mmol)、トリエチルアミン(1.96mL、14.04mmol)、およびクロロホルム(14mL)の溶液にオキシ塩化リン(6.42mL、70.2mmol)を30分かけて滴下した。次に、この反応混合物を30時間70℃に加熱した。この混合物を周囲温度まで冷却し、0℃で飽和NaHCO3水溶液(500mL)に2時間かけて滴下し、さらに1時間攪拌した。層を分離し、水層を塩化メチレン(2×100mL)で逆抽出し、合わせた有機層を乾燥させ(MgSO4)、濾過および濃縮して黄色固体を得た。フラッシュクロマトグラフィー(SiO2、5%アセトン−CHCl3)により精製を行い、81(3.17g、90%)を白色固体として得た。1H NMR (400 MHz, d6-DMSO)δ11.08 (s, 1H), 6.09 (d, J = 4.0 Hz, 1H), 5.99 (dd, J = 6.0, 4.0 Hz, 1H), 5.76 (t, J = 6.8 Hz, 1H), 4.41 (dd, J = 11.2, 3.2 Hz, 1H), 4.32 (td, J = 7.2, 3.2 Hz, 1H), 4.24 (dd, J = 11.6, 6.8 Hz, 1H), 2.18 (s, 3H), 2.12 (s, 3H), 2.11 (s, 3H), 2.03 (s, 3H); [M+H]+ 503.3。
窒素下、81(2.07mg、4.12mmol)、酢酸ナトリウム(675mg、8.23mmol)および無水エタノール(100mL)の溶液に10%パラジウム/カーボン(862mg)を加えた。この混合物をボンベ内、250〜300psi H2(g)下で48時間攪拌した。この混合物をセライト(登録商標)で濾過し、酢酸エチル(200mL)で洗浄および濃縮して黄色固体を得た。この混合物をH2O(200mL)で希釈し、CH2Cl2(3×100mL)で抽出した。合わせた有機層を乾燥させ(MgSO4)、濾過および濃縮した。残渣をフラッシュクロマトグラフィー(SiO2、10%アセトン−CHCl3)により精製し、82(1.74g、90%)を白色粉末として得た。1H NMR (400 MHz, d6-DMSO)δ10.78 (s, 1H), 8.82 (s, 1H), 6.10 (d, J = 4.0 Hz, 1H), 6.04 (dd, J = 6.0, 4.0 Hz, 1H), 5.77 (t, J = 6.0 Hz, 1H), 4.41 (dd, J = 11.6, 3.2 Hz, 1H), 4.30 (m, 1H), 4.23 (dd, J = 12.0, 6.8 Hz, 1H), 2.20 (s, 3H), 2.12 (s, 3H), 2.10 (s, 3H), 2.03 (s, 3H); [M+H]+ 469.4。
実施例13工程3と同様の方法で、82から標題化合物を製造した。
別法合成経路C
工程1: N'−(7−クロロ−2−オキソ−3−(2',3',5'−トリ−O−アセチル−β−D−リボフラノシル)−2,3−ジヒドロ−チアゾロ[4,5−d]ピリミジン−5−イル)−N,N−ジメチル−ホルムアミジン(83a)の製造
N2下、室温で、CHCl3(28mL)中、16(500mg、1.03mmol)およびDMF(1.29mL、16.7mmol)の混合物に、塩化チオニル(2.58mL、35.4mmol)を1時間かけて滴下した。この反応混合物を60℃まで23時間加熱した。この混合物を氷冷飽和NaHCO3溶液に注意深く注ぎ、30分攪拌した。層を分離し、水層をCH2Cl2(2×80mL)で抽出し、合わせた有機層をMgSO4で乾燥させ、濾過および濃縮し、83a(519mg、定量的)を白色泡沫として得た。1H NMR (400 MHz, d6-DMSO)δ8.65 (s, 1H), 6.14 (d, J = 4.0 Hz, 1H), 5.97 (dd, J = 6.4, 3.6 Hz, 1H), 5.62 (t, J = 6.8 Hz, 1H), 4.43 (dd, J = 12.0, 3.6 Hz, 1H), 4.32 (m, 1H), 4.16 (dd, J = 12.0, 5.2 Hz, 1H), 3.23 (s, 3H), 3.11 (s, 3H), 2.13 (s, 3H), 2.12 (s, 3H), 2.02 (s, 3H); [M+H]+ 516.1。
N2下、室温で、16(2.34g、4.83mmol)、DMF(5.61mL、72.5mmol)、CHCl3(50mL)、およびトルエン(55mL)の混合物に、臭化チオニル(11.2mL、145mmol)を1時間かけて滴下した。この反応混合物を110℃まで20時間加熱した。この混合物を氷冷飽和NaHCO3溶液に注意深く注ぎ、1時間攪拌した。層を分離し、水層をCH2Cl2(2×80mL)で抽出し、合わせた有機層をMgSO4で乾燥させ、濾過および濃縮して黄色残渣を得た。この生成物をフラッシュクロマトグラフィー(SiO2、20%アセトン−CHCl3)により精製し、83b(1.53g、57%)を白色泡沫として得た。1H NMR (400 MHz, d6-DMSO)δ8.64 (s, 1H), 6.12 (d, J = 3.2 Hz, 1H), 5.96 (dd, J = 6.4, 3.2 Hz, 1H), 5.61 (t, J = 6.8 Hz, 1H), 4.42 (dd, J = 8.8, 3.2 Hz, 1H), 4.31 (m, 1H), 4.16 (dd, J = 12.4, 5.6 Hz, 1H), 3.23 (s, 3H), 3.11 (s, 3H), 2.13 (s, 3H), 2.12 (s, 3H), 2.02 (s, 3H); [M+H]+ 560.2。
火炎乾燥した丸底フラスコに83a(1.08g、2.11mmol)および氷酢酸(21mL)を入れた。フラスコをセプタムで密閉し、窒素でフラッシュした。亜鉛末(1.38g、21.1mmol)を加え、この反応物を80℃まで48時間加熱した。この反応混合物を室温まで冷却し、セライト(登録商標)パッドで濾過し、EtOAc(100mL)で洗浄し、真空濃縮した。得られた白色固体(残渣)をCH2Cl2(100mL)で希釈し、飽和NaHCO3水溶液(500mL)で洗浄した。水層をCH2Cl2(2×50mL)で抽出し、合わせた有機層を乾燥させ(MgSO4)、濾過および濃縮した。フラッシュクロマトグラフィー(SiO2、5%アセトン−CH2Cl2)により精製し、78(464mg、52%)を、全ての点で実施例38工程2で単離した物質と一致する白色粉末として得た。
標題化合物の製造については実施例38工程3に記載されている。
別法合成経路D
工程1: 4−クロロ−2−オキソ−2,3−ジヒドロ−チアゾール−5−カルバルデヒド(85)の製造
化合物85はBaranov, et al, Chem. Het. Compounds (Engl. Trsl.), 1975, 11, p.73により最初に合成されたものであるが、報告されている手順を改変して製造した。市販の2,4−チアゾリジンジオン84(25.0g、213mmol)を、冷却のための氷浴を用いて0℃に冷却したPOCl3(59ml、641mmol)に懸濁させた。この反応物にDMF(24.8mL、320mmol)を15分かけて滴下した。この反応物を90℃まで2時間、さらに115℃で20分加熱した。20分後、反応物を90℃まで冷却し、さらに1時間維持した。1時間後、この混合物を115℃まで15分加熱した。この熱い反応混合物を激しく攪拌しながら水1L中に注ぎ込んだ。10分後、この混合物を濾過した。水相をエチルエーテル(600mL)で5回抽出し、有機相を分離し、真空濃縮した。固体残渣を最少量の飽和NaHCO3水溶液に溶解させた。この混合物を6M HClでpH=2まで注意深く酸性化したところ、約30分後に沈殿が生じた。濾過して20.9gの化合物85を収率62%で得た。Rf = 0.3 (2%H2O, 8%メタノール, 90%酢酸エチル); 1H NMR (400 MHz, CDCl3)δ9.79 (s, 1H), 8.95 (s, 1H); MS (+)-ES [M+H]+ 164。
化合物85(1.22g、7.47mmol)、塩酸グアニジン(2.13g、22.4mmol)、K2CO3(1.03g、7.47mmol)、およびNaHCO3(1.88g、22.3mmol)をDMFに懸濁させ、110℃で2日間加熱した。TLCにより判定して出発材料が消費された際に溶媒を真空除去した。この固体残渣を水でトリチュレーションした。86の分析上純粋なサンプルがHPLC(ODS−A C18;3〜97%CH3CN/H2O勾配;1.0mL/分)により得られた。黄褐色固体: HPLC Rt = 1.63分; Rf = 0.45 (2% H2O, 8%メタノール, 90%酢酸エチル);1H NMR (400 MHz, d6-DMSO)δ8.11 (s, 1H), 6.67 (s, 2H); MS (+)-ES [M+H]+ 169; C5H4N4OS・0.1 CH3CN・0.1 H2Oに関する元素分析:理論値: C, 35.88; H, 2.61; N, 32.99; S, 18.42。実測値: C, 35.96; H, 2.75; N, 32.56; S, 18.42。
化合物86(62mg、0.4mmol)、1,2,3,5−テトラ−O−アセチル−β−D−リボフラノーステトラアセテート(128mg、0.4mmol)、および触媒リン酸水素ビス(p−ニトロフェニル)(13mg、0.04mmol)を混合し、500mlフラスコ中に入れた。この反応容器を注意深く真空下(〜5.0mmHg)に置き、150℃に加熱した油浴中に10分置いた。室温まで冷却した後、その固体を酢酸エチルで洗浄した。粗生成物をフラッシュカラム(シリカ、クロロホルム中5〜35%酢酸エチル勾配)により精製し、68mgの化合物79(40%)を、全ての点で実施例38工程2で単離した物質と一致する白色固体として白色粉末として得た。
DMF(10mL)中、79(0.68g、2.28mmol)の溶液に、イミダゾール(0.54g、7.93mmol)および塩化tert−ブチルジメチルシリル(0.68g、4.56mmol)を順次加えた。この反応混合物を室温で2時間攪拌し、その時点でこれを濃縮し、フラッシュカラムクロマトグラフィー(シリカ、MeOH/CHCl3;勾配=5〜20%)により精製し、0.49g(52%)の87を白色固体として得た。1H (400 MHz, d6-DMSO)δ8.33 (s, 1H), 6.87 (s, 2H), 5.90 (d, J = 4.0 Hz, 1H), 5.33 (d, J = 5.6 Hz, 1H), 5.00 (d, J = 5.2 Hz, 1H), 4.79 (q, J = 5.2 Hz, 1H), 4.16 (q, J = 5.2 Hz, 1H), 3.77 (m, 2H), 3.64 (dd, J = 12.0, 7.2 Hz, 1H), 0.84 (s, 9H), 0.00 (s, 6H); MS (+)-ES [M+H]+ m/z 415.4。
0℃のアセトニトリル(5mL)中、87(0.20g、0.48mmol)の溶液に、Et3N(0.26mL、1.86mmol)およびAc2O(91μL、0.96mmol)を連続的に加えた。この反応混合物を室温で24時間攪拌し、この時点でこれを濃縮し、フラッシュカラムクロマトグラフィー(シリカ、アセトン/CHCl3:勾配=5〜10%)により精製し、0.22g(92%)の88を白色固体として得た。1H (400 MHz, d6-DMSO)δ8.36 (s, 1H), 6.90 (s, 2H), 6.00 (m, 2H), 5.57 (t, J = 6.0 Hz, 1H), 4.07 (q, J = 5.2 Hz, 1H), 3.77 (m, 2H), 2.07 (s, 3H), 2.06 (s, 3H), 0.83 (s, 9H), 0.00 (d, J = 2.4 Hz, 6H); MS (+)-ES [M+H]+ m/z 499.5。
プラスチックバイアル内、THF(5mL)中、88(0.22g、0.44mmol)の溶液にHF/ピリジン(0.70mL)を加えた。この反応物を2時間攪拌し、濃縮し、フラッシュカラムクロマトグラフィー(シリカ、MeOH/CHCl3:勾配=5〜10%)により精製し、0.17g(100%)の標題化合物を白色固体として得た。融点109〜111℃。1H (400 MHz, d6-DMSO)δ8.37 (s, 1H), 6.91 (s, 2H), 6.00 (m, 2H), 5.48 (t, J = 6.0 Hz, 1H), 4.91 (t, J = 6.0 Hz, 1H), 4.04 (dd, J = 10.4, 6.0 Hz, 1H), 3.64 (m, 1H), 3.52 (m, 1H), 2.08 (s, 3H), 2.05 (s, 3H); MS (+)-ES [M+H]+ m/z 385.3。C14H16N4O7S・0.5 CH3OH・0.2 CHCl3に関する元素分析:理論値: C, 41.61; H, 4.32; N, 13.21; S 7.56: 実測値: C, 41.73; H, 4.29; N, 12.86; S, 7.33。
別法合成経路A
工程1: 5−アミノ−3−(2',3'−ジ−O−アセチル−β−D−リボフラノシル)−3H−チアゾロ[4,5−d]ピリミジン−2−オン(89)の製造
アセトン(5mL)中、78(500mg)の透明溶液に、リン酸ナトリウムバッファー(pH=7.0、0.1M、25mL)を加えたところ、溶液に曇りが生じた(白色沈殿)。この混合物にカンジダ・アンタルクチカリパーゼ樹脂(250mg)を加えた後、この懸濁液を室温で10時間穏やかに振盪した。得られた透明な混合物を濾過し、真空下で有機溶媒を除去した。次に、この水溶液を酢酸エチル(3×25mL)で抽出し、有機層を合わせ、MgSO4で乾燥させ、濃縮した。得られた固体は実施例43工程3に記載したものと同様の方法でさらに精製することができた。
DMF中、1(12.0g、37.9mmol)およびイミダゾール(7.75g、114mmol)の混合物に、塩化tert−ブチルジメチルシリル1(5.72g、37.9mmol)をDMF溶液(25mL)として加えた。TLC分析(20%MeOH−CHCl3)によれば、この反応は〜60%消費まで進行していたことが示された。反応が完了するまで、追加の塩化tert−ブチルジメチルシリル(5.72g、37.9mmol)を滴下したところで、MeOH(10mL)でクエンチした後、濃縮して褐色の残渣を得た。この残渣をEtOAc(800mL)に溶解させた後、水(3×200mL)で洗浄した。有機相を無水Na2SO4−炭で乾燥させた後、SiO2のショートパッドで濾過して溶液を得、これを濃縮して黄褐色固体を得た。この粗生成物をEt2Oでトリチュレーションし、12.41g(76%)の90を白色固体として得た。1H (400 MHz, d6-DMSO)δ11.16 (s, 1H), 6.92 (br s, 2H), 5.77 (d, J = 4.4 Hz, 1H), 5.27 (d, J = 5.5 Hz, 1H), 4.95 (d, J = 5.9 Hz, 1H), 4.73 (dd, J = 9.9, 5.1 Hz, 1H), 4.11 (dd, J = 10.6, 5.1 Hz, 1H), 3.70-3.76 (m, 2H), 3.59-3.64 (m, 1H), 0.84 (s, 9H), 0.0 (s, 6H)。
MeCN(40mL)中、ジオール90(2.44g、5.67mmol)およびEt3N(2.37mL、17.0mmol)の均一な溶液に、Ac2O(1.06mL、11.3mmol)およびDMAP(69mg、0.57mmol)を順次加えた。この反応混合物を3時間攪拌した後、濃縮し、クロマトグラフィー(SiO2、勾配溶出、40〜60%EtOAc−CHCl3)に付し、1.2g(41%)の91を白色固体として得た。1H (400 MHz, d6-DMSO)δ11.25 (s, 1H), 7.96-8.00 (m, 1H), 7.54-7.57 (m, 2H), 7.24-7.28 (m, 2H) 6.96 (br s, 2H), 6.12 (s, 1H), 5.96 (s, 1H), 5.39-5.41 (m, 1H), 5.01-5.04 (m, 1H), 4.12-4.17 (m, 1H), 3.48-3.59 (m, 3H); MS (+)-ES [M+H]+ m/z 515。
THF(20mL)中、91(1.2g、2.3mmol)の均一な溶液に、THF中1.0Mのフッ化テトラブチルアンモニウム(4.7mL、4.7mmol)を加えた。この反応混合物を16時間攪拌した後、濃縮し、クロマトグラフィーに付し、800mg(86%)の白色固体を得た。1H (400 MHz, d6-DMSO)δ11.25 (s, 1H), 6.97 (br s, 2H), 5.95 (dd, J = 5.9, 4.4 Hz, 1H), 5.89 (d, J = 4.8 Hz, 1H), 5.41 (t, J = 6.2 Hz, 1H), 4.90 (t, J = 5.9 Hz, 1H), 4.00 (q, J = 5.9 Hz, 1H), 3.48-3.64 (m, 2H), 2.06 (s, 3H), 2.04 (s, 3H); MS (+)-ES [M+H]+ m/z 401。
実施例30工程1と同様の方法で、92および無水ピバル酸から化合物93を収率21%で白色固体として製造した。1H (400 MHz, d6-DMSO)δ11.27 (s, 1H), 6.98 (br s, 2H), 5.88-5.91 (m, 2H), 5.55 (dd, J = 7.0, 5.9 Hz, 1H), 4.29 (dd, J = 12.1, 4.0 Hz, 1H), 4.18-4.27 (m, 1H), 4.11 (dd, J = 12.1, 5.1 Hz, 1H), 2.06 (s, 3H), 2.05 (s, 3H), 1.13 (s, 9H); MS (+)-ES [M+H]+ m/z 485。C19H24N4O9S・0.75 H2Oに関する元素分析:理論値: C, 45.82; H, 5.16; N, 11.25; S, 6.44。実測値: C, 45.93; H, 5.20; N, 11.29; S, 6.44。
実施例30工程1と同様の方法で、92および無水ラウリン酸から化合物94を収率59%で白色固体として製造した。1H (400 MHz, d6-DMSO)δ11.26 (s, 1H), 6.97 (br s, 2H), 5.87-5.91 (m, 2H), 5.51 (t, J = 6.4 Hz, 1H), 4.36 (dd, J = 12.1, 3.5 Hz, 1H), 4.18-4.22 (m, 1H), 4.08 (dd, J = 12.1, 5.9 Hz, 1H), 2.27 (t, J = 7.3 Hz, 1H), 2.06 (s, 6H), 1.46-1.50 (m, 1H), 1.17-1.28 (m, 16H), 0.85 (t, J = 6.0 Hz, 3H); MS (+)-ES [M+H]+ m/z 583。C26H38N4O9Sに関する元素分析:理論値: C, 52.55; H, 6.49; N, 9.25; S, 5.29。実測値: C, 52.58; H, 6.57; N, 9.49; S, 5.38。
実施例30工程1と同様の方法で、1および無水酪酸から化合物95を製造した。カラムクロマトグラフィー(SiO2、40%EtOAc−CHCl3)により精製し、Et2O−ヘキサンでトリチュレーションし、収率17%で白色固体を得た。1H (400 MHz, d6-DMSO)δ11.27 (s, 1H), 6.97 (br s, 2H), 5.87-5.91 (m, 2H), 5.54 (dd, J = 12.8, 6.2 Hz, 1H), 4.37 (dd, J = 12.1, 3.7 Hz, 1H), 4.18-4.22 (m, 1H), 4.10 (dd, J = 12.1, 5.9 Hz, 1H), 2.25-2.38 (m, 6H), 1.47-1.59 (m, 6H), 0.84-0.91 (m, 9H); MS (+)-ES [M+H]+ m/z 527。C22H30N4O9Sに関する元素分析:理論値: C, 50.18; H, 5.74; N, 10.64; S, 6.09。実測値: C, 50.18; H, 5.64; N, 10.56; S, 6.02。
実施例30工程1と同様の方法で、1および無水カプリル酸から化合物96を収率30%で白色固体として製造した。1H (400 MHz, d6-DMSO)δ11.28 (s, 1H), 6.96 (br s, 2H), 5.87-5.92 (m, 2H), 5.35 (dd, J = 12.8, 6.2 Hz, 1H), 4.35 (dd, J = 11.7, 3.3 Hz, 1H), 4.17-4.21 (m, 1H), 4.09 (dd, J = 11.7, 5.9 Hz, 1H), 2.24-2.39 (m, 6H), 1.48-1.53 (m, 6H), 1.22-1.25 (m, 2H), 0.82-0.87 (m, 9H); MS (+)-ES [M+H]+ m/z 695。C34H54N4O9Sに関する元素分析:理論値: C, 58.77; H, 7.83; N, 8.06; S, 4.61。実測値: C, 58.65; N, 7.92; N, 7.98; S, 4.55。
室温で、MeCN(10mL)中、3(2.00g、4.09mmol)の懸濁液に、Et3N(1.14mL、8.19mmol)を加えた。得られた混合物を30分攪拌し、ジ−tert−ブチルジカーボネート(894mg、4.09mmol)で処理した後、16時間攪拌した。この混合物にEt3N(1.40mL、10.0mmol)およびAc2O(950μL、10.0mmol)を順次加えた。3時間後、混合物を濃縮し、EtOAc(200mL)と水(100mL)とで分液し、無水Na2SO4で乾燥させ、濃縮した後、クロマトグラフィー(SiO2、80%EtOAc−CHCl3)に付し、白色泡沫を得た。この泡沫をCHCl3−Et2O−ヘキサン中でトリチュレーションし、1.38gの二酢酸塩97を白色固体として得た。1H (400 MHz, d6-DMSO)δ11.29 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.99 (br s, 2H), 5.91 (d, J = 1.5 Hz, 1H), 5.50 (s, 1H), 4.34 (dd, J = 11.0, 2.2 Hz, 1H), 4.13-4.23 (m, 2H), 3.84 (dd, J = 8.1, 6.6 Hz, 1H), 2.06 (s, 3H), 2.06 (s, 3H), 1.97-2.03 (m, 1H), 1.35 (s, 9H), 0.82 (d, J = 6.6 Hz, 6H); MS (-)-ES [M-H]+ m/z 598。
ジオキサン(50mL)中4MのHClとi−PrOAcの混合物に固体の97(1.35g、2.25mmol)を加えた。得られた溶液は数分以内に不均一な混合物となった。1時間後、この懸濁液を濾過し、Et2Oで洗浄した後、高真空下で乾燥させ、0.66g(55%)の白色固体を得た。1H (400 MHz, d6-DMSO)δ11.46 (s, 1H), 8.40 (s, 3H), 7.19 (br s, 2H), 4.46 (dd, J = 12.5, 3.7 Hz, 1H), 4.28-4.44 (m, 2H), 3.85 (s, 1H), 3.68 (br s, 1H), 2.13-2.24 (m, 1H), 2.08 (s, 3H), 2.06 (s, 3H), 0.95 (d, J = 7.3 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H); MS (+)-ES [M+H]+ m/z 498。元素分析C19H25N5O9S・1.0 HCl・1.0 H2Oに関する理論値: C, 41.19; H, 5.09; Cl, 6.40; N, 12.64; S, 5.79.実測値: C, 41.52; H, 5.01; Cl, 6.64; N, 12.85; S, 5.85。
実施例49工程1と同様の方法で、3および無水酪酸から99を収率62%で白色蝋状固体として製造した。1H (400 MHz, d6-DMSO)δ11.27 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.97 (br s, 2H), 5.92 (dd, J = 6.6, 3.7 Hz, 1H), 5.88 (d, J = 3.7 Hz, 1H), 4.35 (dd, J = 11.7, 2.9 Hz, 1H), 4.13-4.23 (m, 2H), 3.84 (dd, J = 8.1, 6.6 Hz, 1H), 2.24-2.39 (m, 4H), 1.98-2.03 (m, 1H), 1.46-1.59 (m, 4H), 1.35 (s, 9H), 0.85-0.91 (m, 12H); MS (-)-ES [M-H]+ m/z 654。
実施例49工程2と同様の方法で、標題化合物を収率60%で白色固体として製造した。1H (400 MHz, d6-DMSO)δ11.48 (s, 1H), 8.42 (s, 3H), 7.19 (br s, 2H), 6.00 (dd, J = 6.6, 4.4 Hz, 1H), 5.92 (d, J = 4.4 Hz, 1H), 5.57 (dd, J = 12.5, 5.9 Hz, 1H), 4.47 (dd, J = 12.5, 2.9 Hz, 1H), 4.35-4.40 (m, 1H), 4.27-4.31 (m, 1H), 3.83-3.85 (m, 1H), 2.28-2.40 (m, 4H), 2.14-2.25 (m, 1H), 1.46-1.60 (m, 4H), 0.83-0.96 (m, 12H); MS (-)-ES [M-H]+ m/z 554。C23H33N5O9S・1.1 HCl・0.5 H2Oに関する元素分析:理論値: C, 45.68; H, 5.85; Cl, 6.45; N, 11.58; S, 5.30。実測値: C, 45.34; H, 5.70; Cl, 6.59; N, 11.62; S, 5.42。
実施例49工程1と同様の方法で、3およびトリホスゲンから101を収率54%で白色固体として製造した。1H (400 MHz, d6-DMSO)δ11.34 (s, 1H), 7.09 (d, J = 8.1 Hz, 1H), 7.06 (br s, 2H), 6.12 (s, 1H), 5.83 (d, J = 8.1, 1H), 5.67-5.72 (m, 1H), 4.46-4.51 (m, 1H), 4.23-4.32 (m, 2H), 3.82 (dd, J = 13.9, 5.9 Hz, 1H), 1.94-1.99 (m, 1H), 1.34 (s, 9H), 0.81 (d, J = 6.6 Hz, 6H); MS (-)-ES [M-H]+ m/z 540。
実施例49工程2と同様の方法で、102を収率65%で白色固体として製造した。1H (400 MHz, d6-DMSO)δ11.51 (s, 1H), 8.36 (s, 3H), 7.25 (br s, 2H), 6.13 (s, 1H), 5.88 (d, J = 7.3 Hz, 1H), 5.76-5.82 (m, 2H), 4.39 (dd, J = 10.3, 2.9 Hz, 1H), 3.86 (s, 1H), 3.41-3.54 (m, 1H), 2.01-2.32 (m, 1H), 0.91 (d, J = 7.3 Hz, 3H), 0.85 (d, J = 6.6 Hz, 3H); MS (-)-ES [M-H]+ m/z 440。C16H19N5O8S・1.1 HCl・0.5 H2O・0.75 Et2Oに関する元素分析:理論値: C, 40.21; H, 4.22; Cl, 7.42; N, 14.66; S, 6.71。実測値: C, 41.48; H, 5.08; Cl, 7.16; N, 12.75; S, 5.79。
室温で、DCE(22.5mL)中、Boc−Val−Val−OH(3.00g、9.48mmol)とEDC(1.82g、9.48mmol)の不均一な混合物にピリジン(7.5mL)を加えた。均一になったところでこの混合物を室温で1時間攪拌し、その後、0℃まで冷却した。この溶液に2(3.07g、8.62mmol)およびDMAP(1.16g、9.48mmol)を順次加えた。この反応混合物を0℃で30分攪拌した後、室温で16時間攪拌した。この混合物を蒸発乾固した後、EtOAc(200mL)と水(100mL)とで分液した。有機相を無水Na2SO4で乾燥させ、濃縮し、クロマトグラフィー(SiO2、勾配溶出60%EtOAc−CHCl3〜100%EtOAc)に付し、濃縮して粘稠な固体を得た。この固体をEt2O−CHCl3中でトリチュレーションし、2.048g(36%)の103を結晶性固体として得た。1H (400 MHz, d6-DMSO)δ11.63 (s, 1H), 11.37 (s, 1H), 11.25 (s, 1H), 7.92 (dd, J = 13.2, 8.1 Hz, 1H), 6.98 (br s, 2H), 6.61 (dd, J = 11.7, 8.8 Hz, 1H), 6.01 (s, 1H), 5.23-5.27 (m, 1H), 5.05 (br s, 1H), 4.10-4.35 (m, 3H), 3.76-3.90 (m, 2H), 3.57-3.60 (m, 1H), 1.80-2.06 (m, 2H), 1.47 (s, 3H), 1.36 (s, 3H), 1.35 (s, 3H), 1.29 (s, 3H), 0.77-0.86 (m, 12 H); [M-H]+ m/z 653。
ジオキサン中4MのHCl(50mL)とi−PrOAcの混合物に固体103(1.48g、2.26mmol)を加えた。得られた溶液は数分以内に不均一な混合物となった。1時間後、この懸濁液を濾過し、Et2Oで洗浄した後、高真空下で乾燥させ、948mg(74%)の104を白色固体として得た。1H (400 MHz, d6-DMSO)δ11.29 (s, 1H), 8.52 (d, J = 7.7 Hz, 1H), 8.06 (br s, 3H), 7.03 (br s, 2H), 5.79 (d, J = 4.0 Hz, 1H), 5.42 (d, J = 5.5 Hz, 1H), 5.13 (d, J = 5.9 Hz, 1H), 4.71 (dd, J = 9.9, 5.5 Hz, 1H), 4.35 (dd, J = 11.7, 3.3 Hz, 1H), 4.18-4.22 (m, 2H), 4.06 (dd, J = 11.7, 8.0 Hz, 1H), 3.88-3.92 (m, 1H), 3.69 (s, 1H), 2.02-2.13 (m, 2H), 0.87-0.92 (m, 12H); MS (-)-ES [M-H]+ m/z 513。
実施例52工程1と同様の方法で、標題化合物を収率64%で白色固体として製造した。1H (400 MHz, d6-DMSO)δ11.24 (s, 1H), 8.00-8.08 (m, 1H), 7.22-7.23 (m, 4H), 7.13-7.16 (m, 1H), 6.98 (br s, 2H), 6.83-6.87 (m, 1H), 6.02 (d, J = 3.7 Hz, 1H), 5.25-5.28 (m, 1H), 5.06 (s, 1H), 4.12-4.34 (m, 4H), 2.88-2.94 (m, 1H), 2.66-2.75 (m, 1H), 1.97-2.04 (m, 1H), 1.46 (d, J = 7.3 Hz, 2H), 1.17-1.28 (m, 14H), 0.77-0.85 (m, 6H); MS (-)-ES [M-H]+ m/z 701。
実施例52工程2と同様の方法で、標題化合物を収率74%で白色固体として製造した。1H (400 MHz, d6-DMSO)δ11.32 (s, 1H), 8.72 (d, J = 8.0 Hz, 1H), 8.16 (br s, 3H), 7.19-7.28 (m, 5H), 7.09 (br s, 2H), 5.79 (d, J = 4.0 Hz, 1H), 5.20 (br s, 3H), 4.70 (dd, J = 5.5, 4.4 Hz, 1H), 4.36 (dd, J = 11.7, 3.3 Hz, 1H), 4.03-4.24 (m, 3H), 3.90-3.94 (m, 1H), 3.09 (dd, J = 14.0, 5.9 Hz, 1H), 2.92 (dd, J = 14.0, 7.7 Hz, 1H), 2.01-2.10 (m, 1H), 0.89 (d, J = 6.6 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H); MS (-)-ES M+ m/z 562。
THF中、90(750mg、1.74mmol)および4−フルオロベンズアルデヒド(1.86mL、17.4mmol)の均一な溶液にH2SO4(1滴)を加えた。得られた混合物を16時間攪拌したところ沈殿が生じた。濾過し、360mg(49%)のベンジリデンアセタール107を黄色固体として得た。1H (400 MHz, d6-DMSO)δ11.24 (s, 1H), 7.96-8.00 (m, 1H), 7.54-7.57 (m, 2H), 7.24-7.28 (m, 2H), 6.96 (br s, 2H), 6.12 (s, 1H), 5.96 (s, 1H), 5.39-5.41 (m, 1H), 5.01-5.04 (m, 1H), 4.12-4.17 (m, 1H), 3.48-3.59 (m, 3H); MS (+)-ES [M+H]+ m/z 423。
MeCN(5mL)中、107(360mg、0.605mmol)、Et3N(278μL、2.00mmol)、およびDMAP(5mg、0.04mmol)の不均一な混合物に、無水カプリル酸(180μL、0.605mmol)を加えた。この反応混合物を16時間攪拌したところで、これを濃縮し、クロマトグラフィー(SiO2、勾配溶出40〜60%EtOAc−CHCl3)に付し、407mg(87%)の108を白色固体として得た。1H (400 MHz, d6-DMSO)δ11.28 (s, 1H), 7.56 (dd, J = 8.4, 6.2 Hz, 2H), 7.25 (dd, J = 9.2, 8.8 Hz, 2H), 7.00 (br s, 2H), 6.14 (s, 1H), 5.97 (s, 1H), 5.39 (d, J = 7.0 Hz, 1H), 5.15-5.18 (m, 1H), 4.27-4.35 (m, 2H), 4.14 (dd, J = 11.4, 7.7 Hz, 1H), 2.26 (t, J = 7.0 Hz, 2H), 1.45-1.47 (m, 2H), 1.20-1.23 (m, 8H), 0.82 (t, J = 5.9 Hz, 3H); MS (+)-ES [M+H]+ m/z 549。
MeOH(40mL)中、108(200mg、0.365mmol)とPPTS(5mg、0.02mmol)の混合物を45℃まで20分加熱し、濃縮し、HPLC精製を行い、69mg(43%)の標題化合物を白色固体として得た。1H (400 MHz, d6-DMSO)δ11.18 (s, 1H), 6.93 (br s, 2H), 5.77 (d, J = 4.0 Hz, 1H), 5.35 (d, J = 5.3 Hz, 1H), 5.08 (d, J = 6.0 Hz, 1H), 4.67 (dd, J = 9.9, 5.3 Hz, 1H), 4.30 (dd, J = 11.9, 3.7 Hz, 1H), 4.21 (dd, J = 12.1, 6.4 Hz, 1H), 3.98 (dd, J = 11.9, 6.8 Hz, 1H), 3.84-3.88 (m, 1H), 2.27 (t, J = 7.1 Hz, 2H), 1.47-.150 (m, 2H), 1.19-1.25 (m, 8H), 0.84 (t, J = 6.8 Hz, 3H); MS (+)-ES [M+H]+ m/z 443。C18H26N4O7S・1.0 H2Oに関する元素分析:理論値: C, 46.71; H, 5.78; N, 11.47; S, 6.56。実測値: C, 46.62; H, 6.09; N, 12.01; S, 6.89。
CH2Cl2(10mL)に化合物25(250mg、0.56mmol)を溶解させ、DMAP(3.4mg、0.028mmol)およびTEA(0.24mL、1.70mmol)を加えた。この混合物を塩化p−トルエンスルホニル(21.5mg、113mmol)を40ごとに1当量の5分の1ずつ加えた。反応の進行をTLCによりモニタリングした。3時間後、出発材料の大部分が消費された。この粗反応混合物をシリカプラグに通し、濃縮し、クロロホルム中25%の酢酸エチルを用いてフラッシュカラムにより精製した。この生成物をエチルエーテルに溶解させ、ヘキサンを加えると化合物16(190mg、0.32mmol)が白色固体として沈殿した。1H NMR (400MHz, d6-DMSO)δ8.00 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.35 (s, 2H), 5.97 (d, J = 4.0 Hz, 1H), 5.86 (m, 1H), 5.52 (m, 1H), 4.35 (m, 1H), 4.24 (m, 1H), 4.08 (m, 1H), 2.43 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H), 1.97 (s, 3H); MS (+)-ES [M+H]+ 597. Rf = 0.65 (75% 酢酸エチル-CHCl3)。C23H24N4O11Sに関する元素分析: 理論値: C, 46.30; H, 4.05; N, 9.39; S, 10.75。実測値: C, 46.54; H, 4.27; N, 9.19; S, 10.44。
式Iの化合物の、有利な経口送達特性を示す能力および選択した経路で投与した場合に免疫応答を誘導する能力は、マウスおよびビーグル犬での実験で容易に実証された。式Iの化合物に対するこのような測定の結果を、本開示中に引用されている文献(例えば、米国特許第5,041,426号および同第4,880,784号)に記載の化合物を用いた同様の実験の結果と比較して、薬物動態学的特性および薬力学的特性に関しての式Iの化合物の有利な点を明らかにすることができる。
標準マウスは、本明細書に記載の発明が1(イサトリビン)の経口送達においてどの程度の物質改善をもたらすか評価するのに有用な系を提供する。上記プロドラッグの経口投与から生じるイサトリビンの血漿濃度を測定することができるだけでなく、マウスで実施される広範囲にわたる免疫学的研究により、イサトリビンの所望の生物活性の一つを反映する、注目されるサイトカインであるインターフェロンαのレベルを測定するのに好適な試薬が提供されてきた。
NR−報告不可
BQLn−引き上げた定量限界未満<npg/mL
NR−報告不可
プロドラッグ(val−イサトリビン、3)をビーグル犬に経口投与した後の、イサトリビン(1)への全身曝露に対する効果を調べた。イサトリビンは重炭酸ナトリウム溶液として調製した。Val−イサトリビンおよびイサトリビンは、溶解性を確保するために選択した次の処方に従って調製した。
処方1:イサトリビンの重炭酸ナトリウム溶液、1mg/mLおよび4mg/mL。
処方2:リン酸緩衝生理食塩水中のval−イサトリビン、1.62mg/mLおよび6.48mg/mL(モル基準でイサトリビン1mg/mLおよび4mg/mL相当)。
また、本発明の式Iの化合物は毒性学的作用の予期しなかった、そして大幅な軽減、特にGI刺激の軽減も示す。胃腸(「GI」)管は実質的な免疫組織(例えば、パイエル板など)で覆われている。式Iの化合物は、薬剤が腸を覆うリンパ組織を通過する際に活性構造をマスクするものと期待でき、この組織の活性化が最小限となるはずであり、これによりGI刺激が軽減される。
候補薬剤化合物の、腸管上皮細胞バリアを通る吸収率を推定するためには、分化し、P−糖タンパク質を発現するCaco2細胞単層を用いたin vitro薬剤輸送アッセイが広く用いられている。例えば、Hilgers, A. R. et al., Pharm. Res., 20(8), 1149-55 (Aug. 2003)参照。
本発明の化合物は効果的なプロドラッグとして働くとすれば、体内で1に変換されなければならない。ある化合物が動物の体内で変換される程度を評価するには、肝細胞がよく用いられ、このような変換はその動物個体の代謝を反映して、異なる種に由来する肝細胞では異なり得ることが知られている。Seddon T. et al., Biochem Pharmacol., 38(10), 1657-65 (May 1989)参照。
本発明の化合物の、経口投与後に全身循環へ1を送達する能力の評価は、当技術分野で周知の方法によって行った。表9および10では、各試験化合物を、pH3のPBSなどの水性バッファーまたはCremaphor、Tween80、もしくはPEG400などの可溶化剤を含有する溶液に化合物を溶解させることにより、経口投与用の溶液として製造した。一般に、各試験につき3個体の動物群を用い、この化合物溶液をSprague−Dawleyラットまたはカニクイザルに強制経口投与により投与した。6〜24時間内のいくつかの時点(通常、6〜12時点を用いた)で各動物から血漿サンプルを採取した。これらの血漿サンプルは採取後すぐに冷凍し、生物分析用にサンプル調製する直前に解凍した。
動物PK試験またはin vitro試験で採取した各サンプルのアリコート(通常50μL)を、内部標準(通常ネブラリン)を含有するアセトニトリル(アセトニトリル:血漿比3:1)でクエンチした。この懸濁液を14,000rpmで5〜10分遠心分離した。得られた上清のアリコートを清浄なバイアルに移し、窒素下で乾燥させた。乾燥させたサンプルを再構成し、MRM(multiple reaction monitoring)法によりLC−MS/MS分析を行った。較正標準は、分析物の最初の濃縮標準を動物血漿または細胞培養培地のいずれかで連続希釈することにより調製した。較正標準は、動物PKサンプルに関して上記したLC−MS/MS分析用に調製した。LC−MS/MS分析は、試験サンプルをブラケットする(bracketing)少なくとも2セットの較正標準を用い、バッチモードで行った。分析物と内部標準の双方のLC−MS/MSトレースを積分し、それらのピーク面積の比を用いて、試験サンプルと較正標準の双方における分析物の相対的応答を算出した。較正標準から得られた応答に曲線の当てはめを行うことで合成較正曲線を作成した。当てはめた較正曲線を用いて、サンプル中の分析物の量を算出した。この較正曲線の有用な動的範囲は1〜5ng/mLから2,000〜10,000ng/mLであった。
既知用量の化合物を経口投与した後の1の血漿濃度−時間プロフィールを用い、全身循環中の1のAUC(曲線下面積(area-under-the-curve))を算出した。このAUCを、分子量に基づき、化合物中の1の総理論含量に従ってノーマライズした。表8では、AUCをさらに用量1mg/kgに対してノーマライズした。
細胞培養、動物モデル、およびヒト被験者への投与など、本発明の化合物の抗ウイルス活性の程度を判定するためには、本発明に従っていくつかのアッセイを使用することができる。本発明の化合物の存在下でウイルスの増殖特性を判定するために経時的にウイルス増殖をアッセイするには、本明細書に記載のアッセイを使用することができる。
イサトリビン治験薬品は、50mLバイアルに入った無菌の通常の生理食塩水中、1mg/mL溶液として提供した。イサトリビンは、7日間1日1回、1回当たり200、400、600または800mgを静脈注入により投与した。800mg用量は80分にわたって投与したことを除き、どの用量も60分にわたって一定速度で注入することにより投与した。各用量の流速は次の通りである:200mg用量は3.33mL/分;400mg用量は6.67mL/分;500mg用量は8.33mL/分;または600mgおよび800mg用量は10.0mL/分。
高剪断ミキサーを備えた密閉ステンレス鋼容器内でイサトリビンとトリクロロモノフルオロメタン12.6kg部とを合わせることで濃縮物を調製する。約20分間混合を行う。次に、21〜27℃に温度制御し、2.8〜4.0バールに圧力制御した大量生産タンク内で、この濃縮物と残部としての噴射剤とを合わせることにより、密閉容器内で大量の懸濁液を調製する。17ml用のエアゾール容器は、本発明の組成物100回分の吸入を提供するように設計した計量バルブを備えている。各容器には次のものが提供されている。
静脈製剤は、本発明の化合物を注射水(WFI)または5%デキストロース溶液などの適当な液体媒体で再構成することにより調製する。適当な量の本発明の化合物を適当な容量の液体媒体で再構成することにより、所望の濃度の静脈製剤を得ることができる。所望の濃度の静脈製剤は、治療上有効な量の本発明の化合物を、その静脈医薬製剤を必要とする患者、好ましくは哺乳類、より好ましくはヒトに提供し、その患者において本発明の化合物の治療上有効なレベルを維持する。治療上有効な用量は、その静脈製剤を患者に送達する速度、およびその静脈製剤の濃度によって異なる。例えば、組成物を含有するバイアル1本(例えば、バイアル1本当たり本発明の化合物50mg)を5%デキストロース溶液(バイアル1本当たり5%デキストロース溶液14ml)で再構成して総量25mLの溶液とする。この再構成溶液を点滴バッグ内のデキストロース溶液に配合して50mlとすると、静脈注入投与に好適な本発明の化合物1mg/mlを含有する溶液となる。点滴バッグ内の液体媒体中の本発明の化合物の好ましい濃度は、約0.001〜約3mg/ml、好ましくは約0.75〜約1mg/mlである。
Claims (8)
- 医薬上許容される担体と請求項1から3のいずれかに記載の化合物を含む、医薬組成物。
- 請求項1から3のいずれかに記載の化合物、またはその医薬上許容される塩もしくは溶媒和物を活性成分として含む、C型肝炎ウイルス感染症を処置するための薬剤。
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