JP5864590B2 - がん治療で使用するためのゲムシタビンのアミド亜リン酸エステル誘導体 - Google Patents
がん治療で使用するためのゲムシタビンのアミド亜リン酸エステル誘導体 Download PDFInfo
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- JP5864590B2 JP5864590B2 JP2013532258A JP2013532258A JP5864590B2 JP 5864590 B2 JP5864590 B2 JP 5864590B2 JP 2013532258 A JP2013532258 A JP 2013532258A JP 2013532258 A JP2013532258 A JP 2013532258A JP 5864590 B2 JP5864590 B2 JP 5864590B2
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- ester
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- alaninyl
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- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229960000310 isoleucine Drugs 0.000 description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 2
- 229960003136 leucine Drugs 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 229960003646 lysine Drugs 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 229960004452 methionine Drugs 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229960005190 phenylalanine Drugs 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 150000008299 phosphorodiamidates Chemical class 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 229960001153 serine Drugs 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 229960002898 threonine Drugs 0.000 description 2
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 description 2
- 229960004799 tryptophan Drugs 0.000 description 2
- 229960004441 tyrosine Drugs 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 229960004295 valine Drugs 0.000 description 2
- 239000004474 valine Substances 0.000 description 2
- 125000006702 (C1-C18) alkyl group Chemical group 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- NZVORGQIEFTOQZ-UHFFFAOYSA-N 9-[2-(phosphonomethoxy)ethyl]guanine Chemical compound N1C(N)=NC(=O)C2=C1N(CCOCP(O)(O)=O)C=N2 NZVORGQIEFTOQZ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229940122029 DNA synthesis inhibitor Drugs 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- CIVPHSHEDKDWJW-UHFFFAOYSA-N O1C(NC(C1)=O)=O.N1=CNC2=C1C=CC=C2 Chemical group O1C(NC(C1)=O)=O.N1=CNC2=C1C=CC=C2 CIVPHSHEDKDWJW-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229920001577 copolymer Chemical group 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 125000000332 coumarinyl group Chemical group O1C(=O)C(=CC2=CC=CC=C12)* 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229940043351 ethyl-p-hydroxybenzoate Drugs 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical group CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 238000002663 nebulization Methods 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 235000011962 puddings Nutrition 0.000 description 1
- 150000003254 radicals Chemical group 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 150000003902 salicylic acid esters Chemical class 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 239000000080 wetting agent Substances 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
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine 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
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
R2は、CR5R6CO2R7及びC1〜C6のアルキル基からなる群から選ばれ、R1は、H及びC1〜C6のアルキル基からなる群から選ばれるか、
又は、
R1及びR2は、それらが結合しているN原子とともに、5ないし8個の環原子からなる環部分を形成し、
R4は、CR5R6CO2R7及びC1〜C6のアルキル基からなる群から選ばれ、R3は、H及びC1〜C6のアルキル基からなる群から選ばれるか、
又は、
R3及びR4は、それらが結合しているN原子とともに、5ないし8個の環原子からなる環部分を形成し、
R2及びR4の各々と独立して:
R5及びR6は、独立して、天然のアルファ−アミノ酸の側鎖からなる群から選 ばれ、そして、
R7は、C1〜C18のアルキル基からなる群から選ばれ、
Yは、H、及び、C(O)R(Rは、C1〜C18のアルキル基)からなる群から選ばれ、
Zは、H、及び、C(O)R(Rは、C1〜C18のアルキル基)からなる群から選ばれる。
アルギニン中に存在する、 H2NC(=NH)NH[CH2]3−、
アスパラギン中に存在する、 NH2C(O)CH2−、
アスパラギン酸中に存在する、 HO2CH2−、
システイン中に存在する、 HSCH2−、
シスチン中に存在する、 HO2CH(NH2)CH2SSCH2−、
グリシン中に存在する、 H−、
グルタミン酸中に存在する、 HO2CH2CH2−、
グルタミン中に存在する、 H2N(O)CCH2CH2−、
ヒスチジン中に存在する、 C3N2HCH2−、
ヒドロキシリジン中に存在する、 H2NCH2CH(OH)CH2CH2−、
ヒドロキシプロリン中に存在する、 −CH2CH(OH)CH2−、
イソロイシン中に存在する、 CH3CH2CH(CH3)−、
ロイシン中に存在する、 (CH3)2CHCH2−、
リジン中に存在する、 H2NCH2(CH2)3−、
メチオニン中に存在する、 CH3SCH2CH2−、
フェニルアラニン中に存在する、 PhCH2−、
プロリン中に存在する、 −CH2CH2CH2−、
セリン中に存在する、 OHCH2−、
スレオニン中に存在する、 CH3CH(OH)−、
トリプトファン中に存在する、 C8NH6CH2−、
チロシン中に存在する、 HOC6H4CH2−、
バリン中に存在する、 (CH3)2CH−。
ビス(エトキシ−L−アラニニル)リン酸2’−デオキシ−2’,2’−ジフルオロ−D−シチジン−5’−Oエステル、
ビス(ベンゾキシ−L−アラニニル)リン酸2’−デオキシ−2’,2’−ジフルオロ−D−シチジン−5’−Oエステル、
ビス(シクロヘキソキシ−L−アラニニル)リン酸2’−デオキシ−2’,2’−ジフルオロ−D−シチジン−5’−Oエステル、
ビス(2,2−ジメチルプロポキシ−L−アラニニル)リン酸2’−デオキシ−2’,2’−ジフルオロ−D−シチジン−5’−Oエステル、及び、
ビス(イソ−プロポキシ−L−アラニニル)リン酸2’−デオキシ−2’,2’−ジフルオロ−D−シチジン−5’−Oエステルを含む。
ゲムシタビンのジアミダートの調製
リン酸トリエチル(1.0mL)中に懸濁された3’−Boc−ゲムシタビン(1.0当量)の攪拌溶液が0°Cに冷却された後、これに、POCl3(2.0当量)がAr雰囲気下で滴加された。この反応混合物が、0°C−4°Cで16時間攪拌された。粗精製(crude)混合物が無水DCM(10mL)で希釈され、適当なアミノ酸エステル(5.0当量)が添加され、その後に−78°CでDIPEA(10.0当量)が滴加された。前記反応混合物は96時間攪拌された。前記粗精製混合物は水で希釈され、DCM(20mLで6回)で抽出された。抽出後の有機相が合わされて、MgSO4下で乾燥され、粗精製残渣を生成するために溶媒留去され、前記粗精製残渣は溶離液の濃度勾配(DCM/MeOH:99:1〜97:3〜95:5)を用いてシリカゲルで精製された。(過剰のアミノ酸エステルは、溶離液としてDCM/MeOH 95/5を用いて分取(preparative)TLC精製によって除去された。)
リン酸トリエチル(1.0mL)中に懸濁されたゲムシタビン(1.0当量)の攪拌溶液が0°Cに冷却された後、これに、POCl3(2.0当量)がAr雰囲気下で滴加された。この反応混合物が、0°C−4°Cで16時間攪拌された。粗精製混合物が無水DCM(10mL)で希釈され、適当なアミノ酸エステル(5.0当量)が添加され、その後に−78°CでDIPEA(10.0当量)が滴加された。前記反応混合物は、0°C−4°CでAr雰囲気下で96時間攪拌された。前記粗精製混合物は水で希釈され、DCM(20mLで6回)で抽出された。抽出後の有機相が合わされて、MgSO4下で乾燥され、粗精製残渣を生成するために溶媒留去され、前記粗精製残渣は溶離液の濃度勾配(DCM/MeOH:99:1〜97:3〜95:5)を用いてシリカゲルで精製された。(過剰のアミノ酸エステルは、溶離液としてDCM/MeOH 95/5を用いて分取TLC精製によって除去された。)
TFA/DCM(1:1)中の3’位をBOC基で保護されたジアミダートの混合物が、0°Cで2時間攪拌された。溶媒は溶媒留去され、残渣は飽和NaHCO3で処理され、EtOAcで抽出された。有機相(layers)が混ぜ合わされ、(MgSO4で)乾燥され、濾過され、蒸発乾固(reduced to dryness)され、溶離液の濃度勾配(DCM/MeOH:99:5〜92:8)を用いてシリカゲルで精製された。
31P-NMR (MeOD, 202 MHz) (13.90
19F-NMR (MeOD, 121 MHz) (-115.35 (d, J = 251 Hz), -119.19 (d, ブロードシグナル, J = 249 Hz)
1H-NMR (MeOD, 500 MHz) (7.71 (1H, d, J= 8.16 Hz, H-塩基), 6.34 (1H, t, J= 9.27 Hz, H-l'), 6.00 (1H, d, J = 8.16 Hz, H-塩基), 5.27 - 5.22 (1H, m, H-3'), 4.37 - 4.33 (2H, m, 1 x H-5', H-4'), 4.29 - 4.23 (1H, m, 1 x H-5'), 4.22 - 4.16 (4H, m, 2 x CH 2CH3), 3.97 - 3.90 (2H, m, 2 x CHCH3), 1.52 (9H, s, C(CH 3)3), 1.40 (6H, d, J = 7.23 Hz, 2 x CHCH 3), 1.28 (6H, 明瞭なtd, J = 7.23 Hz, 2 x CH2CH 3)
13C-NMR (MeOD, 125 MHz) (175.64 (d, 3JC-P = 5.70 Hz, C=0, エステル), 167.76 (C=O, C-Ar, 塩基), 157.60 (C-Ar, 塩基), 153.18 (C=O, 3'-Boc), 143.02 (CH-Ar, 塩基), 123.53 (明瞭なt, lJC-F = 260 Hz, CF2), 96.86 (CH-Ar, 塩基), 86.20 - 85.81 (m, ブロードシグナル, C-1'), 85.19 (C(CH3)3), 78.82 (d, 3JC-F = 6.50 Hz, C-4'), 74.16, 73.84 (2 x d, 2JC-F = 18.0 Hz, 17.53 Hz, C-3'), 64.45 (d, 2JC-P = 3.91 Hz, C-5'), 62.37 (CH2CH3), 51.10 (d, 2JC-P = 3.90 Hz, CHCH3), 27.87 (C(CH3)3), 20.86, 20.75 (2 x d, 3JC-P = 5.43 Hz, CHCH3), 14.53 (CH2 CH3)
MS (ES+) m/e: 664 (MNa+, 100%), 精密質量分析: C24H38F2N5O11P 理論値 641.56 実測値 642.24 (13%)
31P-NMR (MeOD, 202 MHz) (13.91
19F-NMR (MeOD, 121 MHz) (-118.39 (d, J = 239 Hz), -119.83 (d, J = 239 Hz)
1H-NMR (MeOD, 500 MHz) (7.70 (1H, d, J= 7.41 Hz, H-塩基), 6.29 (1H, t, J= 8.35 Hz, H-l'), 6.01 (1H, d, J = 7.41 Hz, H-塩基), 4.36 - 4.22 (3H, m, 2 x H-5', H-3'), 4.19 - 4.17 (4H, m, 2 x CH 2CH3), 4.07 - 4.05 (1H, m, H-4'), 3.96 - 3.89 (2H, m, 2 x CHCH3), 1.40 (6H, d, J = 7.23 Hz, 2 x CHCH 3), 1.30 - 1.27 (6H, m, 2 x CH2CH 3)
13C-NMR (MeOD, 125 MHz) (175.71 (d, 3JC-P = 4.15 Hz, C=0, エステル), 167.70 (C=O, C-Ar, 塩基), 157.79 (C-Ar, 塩基), 142.67 (CH-Ar, 塩基), 124.69 (明瞭なt, lJC-F = 259 Hz, CF2), 96.77 (CH-Ar, 塩基), 86.15 - 85.80 (m, ブロードシグナル, C-1'), 80.40 (ブロードシグナル, C-4'), 71.32, 71.13 (2 x d, 2JC-F = 22.80 Hz, C-3'), 64.38 (d, 2JC-P = 5.41 Hz, C-5'), 62.34 (CH2CH3), 51.10 (d, 2JC-P = 3.90 Hz, CHCH3), 20.85, 20.70 (2 x d, 3JC-P = 5.79 Hz, CHCH3), 14.47 (CH2 CH3)
HPLCb(H2O/MeOH 35分間で100/0から0/100まで)Rt24.21分
31P-NMR (MeOD, 202 MHz) (13.87
19F-NMR (MeOD, 121 MHz) (-118.14 (d, J = 239 Hz), -119.70 (d, ブロードシグナル, J = 239 Hz)
1H-NMR (MeOD, 500 MHz) (7.67 (1H, d, J= 7.53 Hz, H-塩基), 7.38 - 7.31 (10H, m, H-Ar), 6.27 (1H, t, J= 8.05 Hz, H-l'), 5.97 (1H, d, J = 7.51 Hz, H-塩基), 5.18 - 5.10 (4H, m, 2 x CH 2Ph), 4.31 - 4.17 (3H, m, H-5', H-3' H-5'), 4.02 - 3.95 (3H, m, H-4', 2 x CHCH3), 1.38, 1.36 (6H, 2 x d, J = 7.14 Hz, 2 x CHCH 3)
13C-NMR (MeOD, 125 MHz) (175.43 (d, 3JC-P = 5.40 Hz, C=0, エステル), 167.68 (C=O, C-Ar, 塩基), 157.81 (C-Ar, 塩基), 142.63 (CH-Ar, 塩基), 137.29, 137.28 (C-Ar), 129.85, 129.66, 129.65, 129.40, 129.39, 129.32, 127.02 (CH-Ar), 123.69 (明瞭なt, lJC-F = 258 Hz, CF2), 96.87 (CH-Ar, 塩基), 86.02 (明瞭なt, ブロードシグナル, 2JC-F = 27.0 Hz, C-1'), 80.46 (明瞭なt, 3JC-F = 8.20 Hz, C-4'), 71.28 (明瞭なt, 2JC-F = 23.44 Hz, C-3'), 68.00, 67.99 (CH2Ph), 64.52 (d, 2JC-P = 4.78 Hz, C-5'), 51.15 (d, 2JC-P = 5.41 Hz, CHCH3), 20.78, 20.67 (2 x d, 3JC-P = 5.53 Hz, CHCH3).
MS (ES+) m/e: 688.21 (MNa+, 100%), 精密質量分析: C29H34F2N5O9P 理論値 665.58 実測値 666.22 (3%)
HPLCb(H2O/MeOH 35分間で100/0から0/100まで)Rt24.15分
31P-NMR (MeOD, 202 MHz) (13.94
19F-NMR (MeOD, 121 MHz) (-118.30 (d, J = 241 Hz), -119.78 (d, ブロードシグナル, J = 245 Hz)
1H-NMR (MeOD, 500 MHz) (7.70 (1H, d, J= 7.15 Hz, H-塩基), 6.29 (1H, t, J = 7.97 Hz, H-l'), 6.01 (1H, d, J = 7.51 Hz, H-塩基), 4.79 - 4.73 (2H, m, 2 x CH-シクロヘキシル), 4.37 - 4.33 (1H, m, H-5'), 4.32 - 4.22 (2H, m, H-3', H-5'), 4.08 - 4.06 (1H, m, H-4'), 3.93 - 3.89 (2H, m, 2 x CHCH3), 1.87 - 1.84 (4H, m, 2 x CH 2, シクロヘキシル), 1.77 - 1.74 (4H, m, 2 x CH 2, シクロヘキシル), 1.58 - 1.56 (2H, m, 2 x CH2-シクロヘキシルのCH), 1.48 - 1.33 (16H, m, 10H, CH 2-シクロヘキシル; 6H, 2 x CHCH 3)
13C-NMR (MeOD, 125 MHz) (175.64 (d, 3JC-P = 5.37 Hz, C=0, エステル), 167.69 (C=O, C-Ar, 塩基), 157.79 (C-Ar, 塩基), 142.66 (CH-Ar, 塩基), 123.66 (明瞭なt, lJC-F = 259 Hz, CF2), 96.85 (CH-Ar, 塩基), 86.00 (明瞭なt, ブロードシグナル, 2JC-F = 30 Hz, C-1'), 80.48 (明瞭なt, 3JC-F = 8.50 Hz, C-4'), 74.66, 74.56 (2 x CH-シクロヘキシル), 71.29 (明瞭なt, 2JC-F = 25.0 Hz, C-3'), 64.54 (d, 2JC-P = 4.23 Hz, C-5'), 51.13 (d, 2JC-P = 13.0 Hz, CHCH3), 32.55, 32.53, 32.48, 32.34, 26.58, 26.44, 24.79, 24.69 (CH2-シクロヘキシル), 21.15, 20.93 (2 x d, 3JC-P = 5.52 Hz, CHCH3)
MS (ES+) m/e: 672.26 (MNa+, 100%), 精密質量分析: C27H42F2N5O9P 理論値 649.62 実測値 650.28 (33%)
HPLCb(H2O/CH3CN 35分間で100/0から0/100まで)Rt17.72分
31P-NMR (MeOD, 202 MHz) (13.93
19F-NMR (MeOD, 121 MHz) (-118.1 (d, J = 245 Hz), -119.6 (d, J = 245 Hz)
1H-NMR (MeOD, 500 MHz) (7.70 (1H, d, J= 7.58 Hz, H-塩基), 6.29 (1H, t, J = 8.20 Hz, H-l'), 6.01 (1H, d, J = 7.58 Hz, H-塩基), 4.37 - 4.33 (1H, m, H-5'), 4.30 - 4.23 (2H, m, H-5', H-3'), 4.08 - 4.06 (1H, m, H-4'), 4.03 - 3.96 (2H, 2 x CHCH3), 3.90, 3.93, 3.79, 3.73 (4H, 2 x AB, JAB = 10.55 Hz, 2 x CH 2(CH3)3), 1.45, 1.43 (6H, 2 x d, J = 7.08 Hz, 2 x CHCH 3), 0.97 (18H, s, 2 x CH2C(CH 3)3)
13C-NMR (MeOD, 125 MHz) (175.71, 175.67 (2 x d, 3JC-P = 3.44 Hz, C=0, エステル), 167.70 (C=O, C-Ar, 塩基), 157.79 (C-Ar, 塩基), 142.68 (CH-Ar, 塩基), 123.65 (明瞭なt, lJC-F = 258 Hz, CF2), 96.84 (CH-Ar, 塩基), 86.04 (明瞭なt, 2JC-F = 26 Hz, C-1'), 80.48 (明瞭なt, 3JC-F = 8.51 Hz, C-4'), 75.46, 75.43 (CH2C(CH3)3), 71.30 (t, 2JC-F = 23.0 Hz, C-3'), 64.57 (d, 2JC-P = 4.73 Hz, C-5'), 51.17 (d, 2JC-P = 7.78 Hz, CHCH3), 26.7 (CH2C(CH3)3), 21.08, 20.96 (2 x d, 3JC-P = 6.10 Hz, CHCH3)
MS (ES+) m/e: 648 (MNa+, 100%), 精密質量分析: C25H42F2N5O9P 理論値 625.60, 実測値 626.28 (2%)
HPLCb(H2O/CH3CN 35分間で100/0から0/100まで)Rt17.27分
31P-NMR (MeOD, 202 MHz) (13.97
19F-NMR (MeOD, 121 MHz) (-117.5 (d, J = 245 Hz), -120.3 (d, J = 245 Hz)
1H-NMR (MeOD, 500 MHz) (7.70 (1H, d, J= 7.20 Hz, H-塩基), 6.29 (1H, t, J = 8.0 Hz, H-l'), 6.00 (1H, d, J = 7.58 Hz, H-塩基), 5.10 - 4.98 (2H, 明瞭な7重, J = 6.40 Hz, 2 x H, CH(CH3)2), 4.36 - 4.34 (1H, m, H-5'), 4.30 - 4.22 (2H, m, H-5', H-3'), 4.09 - 4.06 (1H, m, H-4'), 3.93 - 3.86 (2H, m, 2 x CHCH3), 1.49, 1.47 (6H, 2 x d, J = 6.70 Hz, 2 x CHCH 3), 1.29 - 1.26 (12H, m, 2 x CH(CH 3)2)
13C-NMR (MeOD, 125 MHz) (175.25 (d, JC-P = 2.20 Hz, C=0, エステル), 167.70 (C=O, C-Ar, 塩基), 157.81 (C-Ar, 塩基), 142.68 (CH-Ar, 塩基), 123.38 (明瞭なt, lJC-F = 257 Hz, CF2), 96.85 (CH-Ar, 塩基), 85.94 (明瞭なt, 2JC-F = 28.7 Hz, C-1'), 80.46 (明瞭なt, 3JC-F = 8.21 Hz, C-4'), 71.28 (明瞭なt, 2JC-F = 24.0 Hz, C-3'), 70.12 (CH(CH3)2), 64.52 (d, 2JC-P = 4.77 Hz, C-5'), 51.17 (d, 2JC-P = 8.6 Hz, CHCH3), 22.07, 22.05 (CH(CH3)2), 20.91, 20.82 (2 x d, 3JC-P = 6.3 Hz, CHCH3)
MS (ES+) m/e: 592.19 (MNa+, 100%), 精密質量分析: C21H34F2N5O9P 理論値 569.49, 実測値 570.20 (10%)
HPLCb(H2O/CH3CN 35分間で100/0から0/100まで)Rt12.15分
ヒトのヒト大腸がん細胞株のHRT18が、動物培養細胞の欧州コレクション(European Collection of Animal Cell Cultures)(ECACC、英国サリスベリー)から購入された。細胞毒性(cytoxicity)アッセイは、我々が以前に報告したMTTアッセイに基づく。この方法は水溶性テトラゾリウム塩のMTT(臭化3−[4,5−ジメチルチアジド−2−イル]−2,5−ジフェニルテトラゾリウム)を不溶性ホルマザン沈殿物に変換する、生きているミトコンドリアの能力に基づき、前記沈殿物は溶解され、分光光度法によって定量される。96穴の培養細胞培養プレートが用いられた。細胞は血球計算盤(haemocytomete counting chamber)で数を数えられ、特定数の細胞(ウェル1個あたり4000個)が培養培地(DMEM)とともに各々のウェルに播種された。DMSOに溶解した本発明の化合物は、培養培地内で、順次(1:5)の割合で希釈され、最終的に0.128nMから2000nMまでの濃度範囲が網羅された。前記培養プレートは37°Cで72時間インキュベーションされた。前記細胞はBSSで2回洗浄された。培養培地中に0.5mg/mLのMTTの溶液が各々のウェルに添加された。その後、前記培養プレートは37°Cで4時間インキュベーションされた。その後、MTTが吸引によって除去された。その後、細胞内にMTT試薬によって生成した結晶が、100lLのTriton X100(水に10%)の添加によって抽出された。細胞は4°Cで24時間インキュベーションされた。その後、発色生成物の吸光度が、分光光度計(Titertecek)を用いて波長540nmで測定された。
Claims (16)
- 化学式(1)の化合物又はその薬学的に許容可能な誘導体であって、
前記化学式(1)中、
R 1 は、H、
R2は、CR5R6CO2 R 7 、
R 3 は、H、
R4は、CR5R6CO2 R 7 、
R5 は、メチル基、i−プロピル基、−CH 2 CH(CH 3 ) 2 、及び、−CH(CH 3 )(C 2 H 5 )からなる群から選ばれ、そして、
各々のR 6 は、H、
各々のR7は、分岐した又は分岐のない、C 1 〜C 18 の非環式アルキル基、及び、C 3 〜C 8 の環式アルキル基からなる群から選ばれ、
Yは、H、
Zは、Hであり、
前記R 7 は、飽和又は不飽和であってもよく、1ないし3個の置換基で置換されていてもよく、該置換基は、
F、Cl、Br及びI原子からなる群から選択されるハロゲン原子;
CF 3 基及びCCl 3 基からなる群から選択されるハロメチル基;
オキソ基、ヒドロキシ基、カルボキシ基、アルコキシ基、アルコイル基、アルコイロキシ基、アリーロキシ基、アリーロイル基及びアリーロイロキシ基からなる群から選択される酸素を含む基;
アミノ基、シアノ基、アジド基及びニトロ基からなる群から選択される窒素を含む基;
チオール基、スルホニル基及びスルホキシド基からなる群から選択される硫黄を含む基;
ピロリル基、イミダゾリル基、ピラジオリル基、チアゾリル基、イソチアゾリル基、オキサゾリル基、ピロリジニル基、ピロリニル基、イミダゾリジニル基、イミダゾリニル基、ピラゾリジニル基、テトラヒドロフラニル基、ピラニル基、ピロニル基、ピリジル基、ピラジニル基、ピラダジニル基、ピペリジル基、ピペラジニル基、モルホリニル基、チオナフチル基、ベンゾフラニル基、イソベンゾフリル基、インドリル基、オキシインドリル基、イソインドリル基、インダゾリル基、インドリニル基、7−アザインドリル基、イソインダゾリル基、ベンゾピラニル基、クマリニル基、イソクマリニル基、キノリル基、イソキノリル基、ナフチリジニル基、シンノリニル基、キナゾリニル基、ピリドピリジル基、ベンゾオキサジニル基、キノキサジニル基、クロメニル基、クロマニル基、イソクロマニル基、及び、カルボリニル基からなる群から選択される複素環基;
フェニル基、ナフチル基、ピリジル基、ピロリル基、フラニル基及びチオフェニル基からなる群から選択されるアリール基;
から選択されることを特徴とする、化学式(1)の化合物又はその薬学的に許容可能な塩、水和物又は溶媒和物。 - R2及びR4が同一であることを特徴とする、請求項1に記載の化合物。
- R7は、メチル基、エチル基、i−プロピル基、t−ブチル−CH2−、ベンジル基、及び、C3〜C6のシクロアルキル基からなる群から選ばれることを特徴とする、請求項2に記載の化合物。
- R7はt−ブチル−CH2−あることを特徴とする、請求項3に記載の化合物。
- R 5 はメチル基であることを特徴とする、請求項1に記載の化合物。
- R7は、メチル基、エチル基、i−プロピル基、t−ブチル−CH2−、ベンジル基、及び、C3ないしC6のシクロアルキル基からなる群から選ばれることを特徴とする、請求項5に記載の化合物。
- R7は、t−Bu−CH2−であることを特徴とする、請求項5に記載の化合物。
- 前記化合物は、*CR5R6に天然のL配置の立体化学を有することを特徴とする、請求項1ないし7のいずれか1項に記載の化合物。
- 前記化合物は、*CR5R6にD配置の立体化学を有することを特徴とする、請求項1ないし7のいずれか1項に記載の化合物。
- ビス(エトキシ−L−アラニニル)リン酸2′−デオキシ−2′,2′−ジフルオロ−D−シチジン−5′−Oエステル、
ビス(ベンゾキシ−L−アラニニル)リン酸2′−デオキシ−2′,2′−ジフルオロ−D−シチジン−5′−Oエステル、
ビス(シクロヘキソキシ−L−アラニニル)リン酸2′−デオキシ−2′,2′−ジフルオロ−D−シチジン−5′−Oエステル、
ビス(2,2−ジメチルプロポキシ−L−アラニニル)リン酸2′−デオキシ−2′,2′−ジフルオロ−D−シチジン−5′−Oエステル、及び、
ビス(イソ−プロポキシ−L−アラニニル)リン酸2′−デオキシ−2′,2′−ジフルオロ−D−シチジン−5′−Oエステルからなる群から選ばれることを特徴とする、化合物。 - がんの予防又は治療の必要な患者で、前記予防又は治療の方法で使用するための、請求項1ないし10のいずれか1項に記載の化合物。
- がんの予防又は治療のための薬剤の製造における、請求項1ないし10のいずれか1項に記載の化合物の使用。
- 請求項1ないし10のいずれか1項に記載の化合物の有効量を含むことを特徴とする、がんの予防又は治療のための医薬組成物。
- 薬学的に許容可能な担体、希釈剤又は添加剤と組み合わせることを特徴とする、請求項1ないし10のいずれか1項に記載の化合物を含む医薬組成物。
- 請求項1ないし10のいずれか1項に記載の化合物を、薬学的に許容可能な添加剤、担体又は希釈剤と組み合わせるステップを含むことを特徴とする、医薬組成物の調製方法。
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DD279248A1 (de) | 1989-01-01 | 1990-05-30 | Akad Wissenschaften Ddr | Verfahren zur herstellung von 2',3'-didesoxythymidin-5'-diamidophosphaten |
GB9708611D0 (en) * | 1997-04-28 | 1997-06-18 | Univ Cardiff | Chemical compounds |
GB0009486D0 (en) * | 2000-04-17 | 2000-06-07 | Univ Cardiff | Chemical compounds |
GB0317009D0 (en) * | 2003-07-21 | 2003-08-27 | Univ Cardiff | Chemical compounds |
GB0505781D0 (en) * | 2005-03-21 | 2005-04-27 | Univ Cardiff | Chemical compounds |
GB0623493D0 (en) * | 2006-11-24 | 2007-01-03 | Univ Cardiff | Chemical compounds |
JP2012521359A (ja) * | 2009-03-20 | 2012-09-13 | アリオス バイオファーマ インク. | 置換されたヌクレオシドアナログおよびヌクレオチドアナログ |
ES2701020T3 (es) * | 2010-09-22 | 2019-02-20 | Alios Biopharma Inc | Nucleósidos azido y análogos nucleotídicos |
WO2012048013A2 (en) | 2010-10-06 | 2012-04-12 | Inhibitex, Inc. | Phosphorodiamidate derivatives of guanosine nucleoside compounds for treatment of viral injections |
LT3447061T (lt) | 2011-03-01 | 2022-01-25 | NuCana plc | Farmacinė vaisto forma, apimanti 5-fluor-2'-deoksiuridinofosforamidato darinį, skirtą naudoti vėžio gydymui |
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US20130252918A1 (en) | 2013-09-26 |
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