JP5001832B2 - ヌクレオシド誘導体およびそれらの治療用途 - Google Patents
ヌクレオシド誘導体およびそれらの治療用途 Download PDFInfo
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- JP5001832B2 JP5001832B2 JP2007506347A JP2007506347A JP5001832B2 JP 5001832 B2 JP5001832 B2 JP 5001832B2 JP 2007506347 A JP2007506347 A JP 2007506347A JP 2007506347 A JP2007506347 A JP 2007506347A JP 5001832 B2 JP5001832 B2 JP 5001832B2
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- 239000008101 lactose Substances 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical compound [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 208000010492 mucinous cystadenocarcinoma Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- CJYQZTZSYREQBD-UHFFFAOYSA-N n-fluorobenzenesulfonamide Chemical compound FNS(=O)(=O)C1=CC=CC=C1 CJYQZTZSYREQBD-UHFFFAOYSA-N 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
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- 230000001537 neural effect Effects 0.000 description 1
- 208000014500 neuronal tumor Diseases 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 210000003300 oropharynx Anatomy 0.000 description 1
- 208000021284 ovarian germ cell tumor Diseases 0.000 description 1
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 201000005528 peripheral nervous system neoplasm Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
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- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- HBEFYGYBMKPNSZ-UHFFFAOYSA-N s-phenyl chloromethanethioate Chemical compound ClC(=O)SC1=CC=CC=C1 HBEFYGYBMKPNSZ-UHFFFAOYSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
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- 208000017520 skin disease Diseases 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 208000002918 testicular germ cell tumor Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- LALRXNPLTWZJIJ-UHFFFAOYSA-N triethylborane Chemical compound CCB(CC)CC LALRXNPLTWZJIJ-UHFFFAOYSA-N 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
本願は、ヌクレオシド化合物、関連した合成方法、組成物、およびヌクレオシド化合物を投与することにより過増殖性障害(癌を含めて)を処置する治療方法に関する。
癌のような障害を処置するための治療用分子として、新規ヌクレオシド化合物が必要とされている。公知ヌクレオシド化合物および新規ヌクレオシド化合物の両方を使用して特定の障害を処置する方法が必要である。
一連のヌクレオシド化合物が合成され、そして治療活性(抗癌活性を含めて)について分析された。本発明のヌクレオシド化合物は、過増殖性障害(乳癌、結腸癌、肺癌および胃癌のような腫瘍を含めて)を処置するのに有用であることが立証されている。
(定義)
用語「ヌクレオシド」、「ヌクレオシド化合物」、および「ヌクレオシド誘導体」は、本願において交換可能に使用されて、以下に定義されるような式Iまたは式IIの化合物を意味する。本願において使用される全ての科学用語および技術用語は、他に特定されない限り、当該分野において一般的に使用される意味を有する。本願において使用される場合、以下の語もしくは語句は、特定された意味を有する。
本発明の方法で有用な化合物には、式Iを有するヌクレオシドが挙げられる:
本発明の化合物は、本明細書中で定義した本発明の化合物の治療有効量と薬学的に受容可能なキャリアまたは希釈剤とで調製された薬学的組成物として、有用である。
代表的な実施態様では、このヌクレオシド化合物は、治療が望まれる細胞(例えば、ヒトの癌細胞)に標的される。この化合物は、所望の細胞を特異的に結合する標的部分に結合体化することにより、それにより、結合体分子の投与を指示することにより、所望の細胞に標的される。有用な標的部分には、細胞の抗原または細胞表面の配位子(例えば、B細胞抗原、CD19(例えば、B43)など)に特異的に結合する配位子がある。
全ての無水溶媒(例えば、アセトニトリル、メタノール、エタノール、酢酸エチル、テトラヒドロフラン、クロロホルムおよび塩化メチレン)は、使用前に、CaH2またはP2O5またはNa/ベンゾフェノンで蒸留した。全ての化学物質は、試薬等級であり、そしてAldrich Chemical Company(Milwaukee,Wis.)またはSigma Chemical Company(St.Louis,Mo.)から購入した。
プロトンNMRスペクトルは、重水素化溶媒(例えば、DMSO−d6、CDCl3、アセトニトリル−d3またはアセトン−d6)中にて、Varian−400 MHz分光器で記録した。化学シフトは、0ppmでの内部標準としてのテトラメチルシラン(TMS)を使って、百万分率(ppm)で報告する。カップリング定数(J)は、ヘルツで示し、また、略語s、d、t、qおよびmは、それぞれ、一重項、二重項、三重項、四重項および多重項を意味する。TLCは、Merckプレコート60F254プレートで実行した。カラムクロマトグラフィーは、シリカゲル60(230〜400メッシュ、Merck)を使用して、実行した。
スキーム1で概説したように、イソプロピリド−D−リボース1から、適当に置換したフルオロシクロペンタノールを調製した。
イソプロピリデン−D−リボース1(10g、52.58mmol)および塩化トリチル(21.95g、78.88mmol)のピリジン(250mL)溶液を、室温で、20時間撹拌した。水を加えた後、その反応混合物を酢酸エチルで抽出し、乾燥し、濾過し、そして真空中で蒸発させた。得られた残渣得られた残渣をシリカゲルカラムクロマトグラフィー(これは、溶離液として、ヘキサンおよび酢酸エチル(4:1)を使用する)で精製して、無色油状物として、トリチルエーテル2(21.53g、95%)を得た;
臭化メチルトリフェニルホスホニウム(32.28g、90.36mmol)のテトラヒドロフラン(300mL)撹拌懸濁液に、0℃で、カリウム第三級ブトキシド(10.79g、88.26mmol、試薬の純度:95%)を加え、その混合物を、室温で、1時間撹拌した。この混合物を再度0℃まで冷却した後、ラクトール2(18.18g、42.03mmol)のテトラヒドロフラン(50mL)溶液を加えた。その反応混合物を、0℃で、3時間、そして室温で、4時間撹拌した。この反応混合物を水と酢酸エチルとの間で分配し、ブラインで洗浄し、乾燥し、濾過し、そして真空中で蒸発させた。得られた残渣をシリカゲルカラムクロマトグラフィー(これは、溶離液として、ヘキサンおよび酢酸エチル(8:1)を使用する)で精製して、白色固形物として、オレフィン3(15.20g、82%)を得た;
(COCl)2(28.69mL、57.38mmol、2M CH2Cl2溶液)のCH2Cl2(200mL)撹拌溶液に、−78℃で、DMSO(8.9mL、125.51mmol)のCH2Cl2(30mL)溶液を加え、その反応混合物を、同じ温度で、30分間撹拌した。アルコール3(15.44g、35.86mmol)のCH2Cl2(30mL)を加え、この反応混合物を、−78℃で、1時間撹拌した。次いで、−78℃で、トリエチルアミン(32.99mL、236.68mmol)を加え、この反応混合物を室温まで温め、そして1時間撹拌した。0℃で、飽和塩化アンモニウム溶液を慎重に加え、この反応混合物をCH2Cl2と水との間で分配した。有機層を乾燥し、濾過し、そして減圧下にて蒸発させた。その残渣をシリカゲルカラムクロマトグラフィー(これは、ヘキサンおよび酢酸エチル(6:1)を使用する)で精製して、白色固形物として、ケトン4(13.83g、90%)を得た;
4(14.66g、34.22mmol)のテトラヒドロフラン(150mL)撹拌溶液に、−78℃で、臭化ビニルマグネシウム(68.44mL、68.44mmol、1.0Mテトラヒドロフラン溶液)を滴下し、その反応混合物を、同じ温度で、1時間撹拌した。この反応混合物を飽和塩化アンモニウム溶液およびブラインでクエンチし、そして酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濾過し、そして蒸発させた。得られた油状物をカラムクロマトグラフィー(ヘキサン:酢酸エチル=9:1)で精製して、白色半固形物として、5(15.62g、100%)を得た;
5(14.55g、31.86mmol)の塩化メチレン(100mL)撹拌溶液に、トリシクロヘキシルホスフィン[1,3−ビス(2,4,6−トリメチルフェニル)−4,5−ジヒドロイミダゾール−2−イリデン]−[ベンジリジン]二塩化ルテニウム(VI)(270mg、0.32mmol)を加え、その反応混合物を、室温で、2日間撹拌した。減圧下にて揮発性物質を除去し、その残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=5:1)で精製して、白色半固形物として、6(12.83g、94%)を得た;
6(12.17g、28.40mmol)、4Åモレキュラーシーブ(14.2g)および二クロム酸ピリジニウム(32.05g、85.20mmol)のDMF(100mL)溶液を、室温で、2日間撹拌した。その混合物をジエチルエーテルおよび酢酸エチルで希釈した後、シリカとセライトの混合物のショートパッドで濾過した。その濾液を蒸発させ、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=4:1)で精製して、白色固形物として、ケトン7(11.14g、92%)を得た;
7(17.19g、40.30mmol)およびヨウ素(12.27g、48.36mmol)の塩化メチレン(80mL)撹拌溶液に、窒素雰囲気下にて、0℃で、ピリジン(3.0mL、36.27mmol)を加え、その反応混合物を、室温で、6時間撹拌した。この混合物を塩化メチレンで希釈し、そして有機層を、水、飽和チオ硫酸ナトリウム溶液、ブラインで洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を蒸発させた後、その残渣をフラッシュシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=7:1)で精製して、白色固形物として、8(16.03g、72%)を得た;
8(8.97g、16.25mmol)および塩化セシウム(III)七水和物(6.66g、17.88mmol)のメタノール(80mL)撹拌溶液に、0℃で、水素化ホウ素ナトリウム(676mg、17.88mmol)を加え、その混合物を、同じ温度で、1時間撹拌した。この混合物をブラインで希釈し、そして酢酸エチルで抽出した。有機層をブラインで洗浄し、無水硫酸マグネシウムで乾燥し、そして蒸発させた。その残渣をフラッシュシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=6:1)で精製して、白色固形物として、9(8.56g、95%)を得た;
9(8.53g、15.39mmol)およびイミダゾール(3.14g、46.17mmol)の無水N,N−ジメチルホルムアミド(70mL)撹拌溶液に、室温で、窒素雰囲気下にて、TBDPSCl(4.80mL、18.47mmol)を加え、その反応混合物を、同じ温度で、一晩撹拌した。この混合物を水でクエンチし、ジエチルエーテルで抽出し、無水硫酸マグネシウムで乾燥し、そして蒸発させた。その残渣をフラッシュシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=30:1)で精製して、無色油状物として、10(11.66g、96%)を得た;
10(11.66g、14.71mmol)およびN−フルオロベンゼンスルホンアミド(5.566g、17.65mmol)の乾燥テトラヒドロフラン(100mL)撹拌溶液に、−78℃で、窒素雰囲気下にて、n−ブチルリチウム(27.6mL、44.13mmol、1.6Mヘキサン溶液)をゆっくりと加え、その反応混合物を、同じ温度で、1時間撹拌した。この混合物を飽和塩化アンモニウム溶液でクエンチし、そして酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、そして蒸発させた。その残渣をフラッシュシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=6:1)で精製して、白色固形物として、11(7.35g、73%)を得た;
11(7.35g、10.73mmol)のテトラヒドロフラン(50mL)撹拌溶液に、フッ化テトラ−n−ブチルアンモニウム(12.88mL、12.88mmol、テトラヒドロフラン中で1.0M)を滴下し、その混合物を、室温で、1時間撹拌した。溶媒を除去した後、その残渣をフラッシュシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=4:1)で精製して、無色油状物として、12(4.31g、90%)を得た;
スキーム2で概説したように、フルオロ−シクロペンタノール12を保護N3−ベンゾイル塩基とカップリングした。
フルオロ−シクロペンタノール12(800mg、1.79mmol)、トリフェニルホスフィン(1174.8mg、4.48mmol)および選択したN3−ベンゾイル塩基(ウラシル誘導体、3.58mmol)の乾燥テトラヒドロフラン(10mL)溶液に、0℃で、窒素雰囲気下にて、アゾジカルボン酸ジエチル(780mg、4.48mmol)の乾燥テトラヒドロフラン(30mL)溶液を滴下した。その反応混合物を、室温で、15時間撹拌し、次いで、減圧下にて揮発性物質を蒸発させた。その残渣をフラッシュシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=4:1)で精製して、この塩基縮合生成物を得た。
(3R,4S,6aR)−3−ベンゾイル−1−(5−フルオロ−2,2−ジメチル−6−トリチルオキシメチル−4,6a−ジヒドロ−3aH−シクロペンタ[1,3]ジオキソール−4−イル)−1H−ピリミジン−2,4−ジオン(13)。865.5mg、75%;
保護化合物13〜18(1.00mmol)を1N HCl/メタノール(2:1、v/v)10mLに溶解し、その反応混合物を、室温で、20時間撹拌した。減圧下にて溶媒を除去し、得られた残渣をフラッシュシリカゲルカラムクロマトグラフィー(塩化メチレン:メタノール=10:1)で精製して、N−ベンゾイルウラシル誘導体を得た。
(1S,4R,5S)−1−(2−フルオロ−4,5−ジヒドロキシ−3−ヒドロキシメチル−シクロペンタ−2−エニル)−1H−ピリミジン−2,4−ジオン(19、RX−3116)。170.4mg、66%;
表1のウラシル化合物19〜24(1.00mmol)の無水ピリジン(10mL)を無水酢酸(940μl、10.0mmol)で処理し、その混合物を、外界温度で、5時間撹拌した。全ての揮発性物質を蒸発した後に得られた残渣を塩化メチレンで希釈し、希HCl、飽和NaHCO3溶液およびブラインで洗浄し、乾燥し(MgSO4)、濾過し、そして蒸発させた。そのトリアセテート含有残渣を、さらに精製することなく、次の工程で使用した。
(1S,4R,5S)−4−アミノ−1−(2−フルオロ−4,5−ジヒドロキシ−3−ヒドロキシメチル−シクロペンタ−2−エニル)−1H−ピリミジン−2−オン(25、RX−3117)。133.8mg、52%;
表1のウラシル誘導体(0.50mmol)のピリジン(5mL)撹拌溶液に、外界温度で、DMAP(1.00mmol)および1,3−ジクロロ−1,1,3,3−テトライソプロピルジシロキサン(0.75mmol)を加えた。10時間後、溶媒を除去し、その残渣を、塩化メチレンと水との間で分配した。有機層をブラインで洗浄し、次いで、無水硫酸マグネシウムで乾燥した。減圧下にて溶媒を除去し、その粗残渣を、さらに精製することなく、次の工程で使用した。
(1S,4R)−1−(2−フルオロ−4−ヒドロキシ−3−ヒドロキシメチル−シクロペンタ−2−エニル)−1H−ピリミジン−2,4−ジオン(30、RX−3216)。63.0mg、52%;
表3のウラシル化合物(0.5mmol)の無水ピリジン(5mL)溶液を無水酢酸(470μl、5.0mmol)で処理し、その混合物を、外界温度で、5時間撹拌した。全ての揮発性物質を蒸発した後に得られた残渣を塩化メチレンで希釈し、希HCl、飽和NaHCO3溶液およびブラインで洗浄し、乾燥し(MgSO4)、濾過し、そして蒸発させた。そのトリアセテート含有残渣を、さらに精製することなく、次の工程で使用した。
(1S,4R)−4−アミノ−1−(2−フルオロ−4−ヒドロキシ−3−ヒドロキシメチル−シクロペンタ−2−エニル)−1H−ピリミジン−2−オン(36、RX−3217)。63.9mg、53%;
(癌細胞株の増殖)
ヌクレオシド化合物の効果を判定するための癌細胞株を、以下の供給源から得た:American Type Culture Collection(ATCC)(Manassas,VA)から、Human OVCAR−3(卵巣癌)、MCF−7(乳癌、ホルモン依存性)、MDA−MB−231乳癌)、HeLa(子宮頸癌)、PC3(前立腺癌)、LNCap(前立腺癌)、HepG2(肝臓癌)、A549(肺癌)、NCI−H226(肺癌)、HT−29(結腸癌)、HCT116(結腸癌)、SK−MEL−28(黒色腫)およびPANC−1(膵臓癌);理研(日本)から、U251(脳腫瘍);DSMZ(独国)から、MKN−45(胃癌);United States National Cancer Institute(Bethesda,MD)から、UMRC2(腎臓癌)。MDA−MB−231、HCT116、UMRC2およびPANC−1を除く全ての細胞株を、10%ウシ胎仔血清(「FBS」)、1mMピルビン酸ナトリウム、10mM HEPESならびに100U/mlペニシリンおよび100g/mlストレプトマイシン(「P/S」)を補充したRPMI1640培地(Invitrogen,Carlsbad,CA)で増殖させた。MDA−MB−231、HCT116、UMRC2およびPANC−1細胞を、10% FBS、P/S、10mM HEPESおよび2mM L−グルタミンを補充したダルベッコ改変イーグル培地(「DMEM」,Invitrogen)中で維持した。全ての細胞を、加湿した5%CO2下で、37℃でインキュベートした。
種々のヒト腫瘍細胞に対するヌクレオシド誘導体の増殖阻害を評価し得る。化合物における特定の置換基の相対的重要性を研究し得る。上記のように調製されたヌクレオシド誘導体を、DMSOをコントロールとして試験する。
%生存=生細胞数[試験]/生細胞数[コントロール]×100
非線形回帰分析によって、IC50値を計算した。
(ヒト癌細胞株に対するRX−3117による細胞増殖阻害(IC50、μM))
動物モデルにおける腫瘍増殖の阻害を観察するために、RX−3117を使用したヌードマウスのエキソビボ異種移植片研究を行った。適切なヒト癌細胞株は、肝細胞増殖の阻害について既に試験されている癌細胞株であり、そして特に好ましいものは、結腸癌HCT116である。RX−3117の抗腫瘍効力を、ヌードマウスにおいて皮下注射された腫瘍異種移植片に対して評価し、そしてRX−3117の処置後に、腫瘍体積を測定した。
Claims (16)
- 過増殖性障害を処置するための組成物であって、該組成物は、このような処置を必要とする被験体への投与のために適切であり、該組成物は、次式の化合物:
組成物。 - 前記化合物が、以下である:
請求項1に記載の組成物。 - 前記化合物が、以下である、請求項1に記載の組成物:
- 前記過増殖性障害が、腫瘍である、請求項1に記載の組成物。
- 前記組成物が、さらに、薬学的に受容可能なキャリアまたは希釈剤を含有する、請求項1に記載の組成物。
- 前記腫瘍が、卵巣の腫瘍、乳房の腫瘍、子宮頚部の腫瘍、前立腺の腫瘍、肝臓の腫瘍、肺の腫瘍、腎臓の腫瘍、結腸の腫瘍、膵臓の腫瘍、脳腫瘍、胃の腫瘍および黒色腫から選択される、請求項4に記載の組成物。
- 次式の化合物:
Aは、
- 次式:
を有する、請求項7に記載の化合物。 - 以下である、請求項7に記載の化合物:
- 請求項7に記載の化合物の治療有効量、またはそれらの薬学的に受容可能な塩と薬学的に受容可能なキャリアもしくは希釈剤とを含有する、薬学的組成物。
- 卵巣の腫瘍、乳房の腫瘍、子宮頚の腫瘍、前立腺の腫瘍、肝臓の腫瘍、肺の腫瘍、腎臓の腫瘍、結腸の腫瘍、膵臓の腫瘍、脳腫瘍、胃の腫瘍および黒色腫から選択される腫瘍についての少なくとも1つの細胞株に関して、10μM以下のIC50を有する、請求項7に記載の化合物。
- 前記細胞株が、卵巣の腫瘍に対するHuman OVCAR−3、乳房の腫瘍に対するMCF−7またはMDA−MB−231、子宮頚部の腫瘍に対するHeLa、前立腺の腫瘍に対するPC3またはLNCap、肝臓の腫瘍に対するHepG2、肺の腫瘍に対するA549またはNCI−H226、腎臓の腫瘍に対するUMRC2、結腸の腫瘍に対するHT−29またはHCT116、膵臓の腫瘍に対するPANC−1、脳腫瘍に対するU251、胃の腫瘍に対するMKN−45および黒色腫に対するSK−MEL−28から選択される、請求項11に記載の化合物。
- 1.0μM以下のIC50を有する、請求項11に記載の化合物。
- 0.5μM以下のIC50を有する、請求項11に記載の化合物。
- 次式の化合物:
方法。 - Bが、トリチルである、請求項15に記載の方法。
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US7405214B2 (en) | 2008-07-29 |
CN102091072A (zh) | 2011-06-15 |
AU2005230676A1 (en) | 2005-10-20 |
IN2014DN04587A (ja) | 2015-07-10 |
BRPI0509553B8 (pt) | 2021-05-25 |
JP2012107072A (ja) | 2012-06-07 |
EP1732902B1 (en) | 2009-12-30 |
MXPA06011141A (es) | 2007-08-14 |
DE602005018620D1 (de) | 2010-02-11 |
AU2005230676B2 (en) | 2010-10-07 |
US20050222185A1 (en) | 2005-10-06 |
CN1980898A (zh) | 2007-06-13 |
WO2005097757A2 (en) | 2005-10-20 |
ES2334803T3 (es) | 2010-03-16 |
WO2005097757A3 (en) | 2005-12-08 |
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