JP5149168B2 - Lfmauおよびldtを用いる癌および他の症状または病状の処置方法 - Google Patents
Lfmauおよびldtを用いる癌および他の症状または病状の処置方法 Download PDFInfo
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- JP5149168B2 JP5149168B2 JP2008515801A JP2008515801A JP5149168B2 JP 5149168 B2 JP5149168 B2 JP 5149168B2 JP 2008515801 A JP2008515801 A JP 2008515801A JP 2008515801 A JP2008515801 A JP 2008515801A JP 5149168 B2 JP5149168 B2 JP 5149168B2
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- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 108060006613 prolamin Proteins 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229940100618 rectal suppository Drugs 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 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
- 235000013874 shellac Nutrition 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 239000012748 slip agent Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 230000003381 solubilizing effect Effects 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
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000007761 synergistic anti-cancer Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 229940033123 tannic acid Drugs 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
- 229960005311 telbivudine Drugs 0.000 description 1
- 229960001355 tenofovir disoproxil Drugs 0.000 description 1
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 description 1
- KOLLFWOTBZCTDF-XFTNXAEASA-N tert-butyl (2s)-1-[(2r,3s)-3-[[(2s)-4-amino-2-(naphthalene-2-carbonylamino)-4-oxobutanoyl]amino]-2-hydroxy-4-phenylbutyl]pyrrolidine-2-carboxylate Chemical compound CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)C=1C=C2C=CC=CC2=CC=1)CC1=CC=CC=C1 KOLLFWOTBZCTDF-XFTNXAEASA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BEUUJDAEPJZWHM-COROXYKFSA-N tert-butyl n-[(2s,3s,5r)-3-hydroxy-6-[[(2s)-1-(2-methoxyethylamino)-3-methyl-1-oxobutan-2-yl]amino]-6-oxo-1-phenyl-5-[(2,3,4-trimethoxyphenyl)methyl]hexan-2-yl]carbamate Chemical compound C([C@@H]([C@@H](O)C[C@H](C(=O)N[C@H](C(=O)NCCOC)C(C)C)CC=1C(=C(OC)C(OC)=CC=1)OC)NC(=O)OC(C)(C)C)C1=CC=CC=C1 BEUUJDAEPJZWHM-COROXYKFSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 229960000838 tipranavir 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
- 239000003104 tissue culture media Substances 0.000 description 1
- 230000008467 tissue growth Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000005454 tryptophanyl group Chemical group 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 150000003673 urethanes Chemical class 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- MJIBOYFUEIDNPI-HBNMXAOGSA-L zinc 5-[2,3-dihydroxy-5-[(2R,3R,4S,5R,6S)-4,5,6-tris[[3,4-dihydroxy-5-(3,4,5-trihydroxybenzoyl)oxybenzoyl]oxy]-2-[[3,4-dihydroxy-5-(3,4,5-trihydroxybenzoyl)oxybenzoyl]oxymethyl]oxan-3-yl]oxycarbonylphenoxy]carbonyl-3-hydroxybenzene-1,2-diolate Chemical class [Zn++].Oc1cc(cc(O)c1O)C(=O)Oc1cc(cc(O)c1O)C(=O)OC[C@H]1O[C@@H](OC(=O)c2cc(O)c(O)c(OC(=O)c3cc(O)c(O)c(O)c3)c2)[C@H](OC(=O)c2cc(O)c(O)c(OC(=O)c3cc(O)c(O)c(O)c3)c2)[C@@H](OC(=O)c2cc(O)c(O)c(OC(=O)c3cc(O)c(O)c(O)c3)c2)[C@@H]1OC(=O)c1cc(O)c(O)c(OC(=O)c2cc(O)c([O-])c([O-])c2)c1 MJIBOYFUEIDNPI-HBNMXAOGSA-L 0.000 description 1
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Description
本出願は2005年6月7日に出願した米国仮出願番号US60/688,159および2005年12月2日に出願した米国仮出願番号US60/741,728の優先権の恩典を主張するものであり、これら出願の全文を参照により本明細書の一部とする。
Handschumacher, R. and Cheng, Y., "Purine and Pyrimidine Antimetabolites (プリンおよびピリミジン代謝拮抗剤)", Cancer Medicine, Chapter XV−1, 3rd Edition, Edited by J. Holland, et al., Lea and Febigol, publishers
XはHまたはFである;
R1およびR2は独立してH、アシル基、C1−C20アルキルもしくはエーテル基、リン酸、二リン酸、三リン酸もしくはホスホジエステル基、式:
で示される基である]
で示される化合物および医薬的に許容されるその塩、溶媒和物および多形相の使用に関する。本発明の好ましい側面においては、R1はH、C2−C18アシル基またはリン酸基でありR2はHである。
好適なアシル基は、R4がC1〜C10のアルキル基である。本発明によるアシル基は、多くのものの中でも、例えば、安息香酸および関連する酸、3−クロロ安息香酸、コハク酸、カプリン酸およびカプロン酸、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸およびオレイン酸基、アミノ酸から由来するアシル基であり、ある特定の医薬的に許容されるスルホン酸基も本発明の目的ではアシル基と考えられる。当業者は目標の医薬化合物を合成するために、または本発明によるヌクレオシドのプロドラッグの形状として本発明にて用途をもつアシル基を認識するであろう。
“過剰増殖疾患状態”という用語は、細胞が制御不能様式で増殖する疾患状態をいい、その増殖が癌性であるかないかは関係ない。かかる疾患状態は、乾癬、性器ゆうぜい、または他の過剰増殖細胞増殖疾患、例えば、過剰増殖角化細胞疾患、例えば、角質増殖、魚りんせん、角皮または扁平苔癬に反映され得るものであり、その疾患のすべてが本発明による化合物を用いて処置し得る。“抗過剰増殖性”とは、化合物がこの記載に従って過剰増殖性疾患状態または症状を治療するように作用することをいう。非常に毒性の低い、または毒性のない抗癌性化合物は、本明細書にいう抗増殖性化合物とも考えられる。
遊離の二級ヒドロキシル基を用いるアタザナビル(BMS−232632);
遊離アミン基を用いるビス(POM)−PMEA(アデフォビル・ジピボキシル):
遊離アミン基を用いるビス(POC)−PMPA(テノフォビル・ジソプロキシル):
炭素環状糖シントン上に一級ヒドロキシル基を用いるエテカビル;
遊離の二級ヒドロキシル基を用いるインディナビル(クリキシバン、MK−639L−735,524;メルク);
遊離の二級ヒドロキシル基を用いるKHI−227(日光共同(株)のキノスタチン);
遊離の二級ヒドロキシル基を用いる2−[3−[3−(S)−[[(テトラヒドロフラニルオキシ)カルボニル]アミノ]−4−フェニル−2(R)−ヒドロキシブチル]]−N−(1,1−ジメチルエチル)デカヒドロ−3−イソキノリンカルボキサミド(イソキンCONフラニルウレタン類似体;メルク);
カルバミン酸、[3−{[(4−メトキシフェニル)スルフォニル](シクロメチル)アミノ}]−2−ヒドロキシ−1−(フェニルメチル)プロピル]−、遊離第二水酸基を用いたテトラヒドロフラニルエステル(VB−11、バルテックス328)。
遊離の二級ヒドロキシル基を用いるVal−Val−Sta(サンド;オーストリア);
遊離の二級ヒドロキシル基を用いるCPG53820(チバ−ガイギー);
遊離の二級ヒドロキシル基を用いるビス−Val HOEt−N2アザ−ペプチド等配電子体;
遊離アミン基を用いるC2−Symホスフィン酸アミド誘導体(ヘキストAG);
遊離の二級ヒドロキシル基を用いる2,5−ジアミノ−N,N’−ビス(N−ベンジルオキシカルボニルウエリル)−1,6−ジフェニル−3(S),4(S)−ヘキサンジオールBzOCValPhe[ジCHOH(SS]PheValBzOC(アボット);
遊離の二級ヒドロキシル基を用いる2,5−ジアミノ−N,N’−ビス(N−ベンジルオキシカルボニルウエリル)−1,6−ジフェニル−3(R),4(R)−ヘキサンジオールBzOCValPhe[ジCHOH(RR]PheValBzOC(アボット);
遊離アミンを用いるddAまたは[ビス(SATE)ddAMP]のビス(S−アセチル−2−チオエチル)ホスホトリエステル;
遊離の二級ヒドロキシル基を用いるBILA2186BS(バイオ−メガ/ベーリンガー・インゲルハイム);
遊離の二級ヒドロキシルまたはアミン基でのアゲネラーゼ(アンプレナビル;VX−478;141W94)、ベルテックス/キッセイ/グラクソ・ウエルカム;
遊離の二級ヒドロキシル基またはフェノール性ヒドロキシル基を用いるA−98881(アザサイクリック尿素誘導体)、アボット;
遊離の二級ヒドロキシル基を用いるA−80987(リホナビル誘導体)、アボット;
遊離の二級ヒドロキシルを用いる(2−ナルタルカルボニル)Asn[デカルボニルPhe−ヒドロキシエチル]ProOtertブテルまたは2NaphCOAsnPhe[CHOHCH2]Pro−OtBu、ロシュ;
遊離の二級ヒドロキシルまたはアミンを用いる2−アミノベンジルスタチン・バリルCbz誘導体、サンド;
遊離ヒドロキシを用いる2−アミノベンジルスタチン・バリルCbz誘導体、サンド;
遊離の二級ヒドロキシルを用いる10H−2(Cbz−ValNH)3PhPr[14]パラシクロファン誘導体、サンド;
遊離の二級ヒドロキシルを用いる10H−2(Cbz−ValNH)3PhPr[13]パラシクロファン誘導体、サンド;
遊離の二級ヒドロキシルを用いる10H−2(Cbz−ValNH)3PhPr[13]メタシクロファン誘導体、サンド;
遊離の二級ヒドロキシルを用いる10H−2(Cbz−Tle)3PhPr[14]パラシクロファン誘導体、サンド;
遊離の二級ヒドロキシル基を用いる1−(20HPr)−4−置換ピペラジン(シクロプロピル)、カルバミン酸チエネイル誘導体(メルクから);
遊離の二級ヒドロキシル基を用いる1−(20HPr)−4−置換ピペラジン(3−ペンチル)、カルバミン酸チエニル誘導体(メルクから);
遊離の二級ヒドロキシル基を用いる10H−2(Cbz−ValNH)3PhPr[17]パラシクロファン誘導体(サンドから);
遊離の二級ヒドロキシル基を用いるA−81525(アボットから);
遊離の一級または二級ヒドロキシル基を用いるXM323(DMP−323;デュポン・メルクから);
フェノール性ヒドロキシル基を用いるチプラナビル(U−140690またはPHU−140690;ファルマシア&アップジョンから);
遊離の二級ヒドロキシル基を用いるチエノピリドCONチエニルウレタン誘導体(リリーからのHOCH2CH2等配電子体)(ベンジル置換誘導体またはメチルメルカプトフェニル置換誘導体);
遊離の二級ヒドロキシル基を用いるSDZPRI053(サンド);
遊離の二級ヒドロキシル基またはアミンを用いるテリナビル(SC−52151;サール/モンサントから);
遊離の二級ヒドロキシル基またはアミンを用いる(R)2QuinCOAsnPhe[CHOHCH2]PipCONHtBu(ロシュから);
遊離の二級ヒドロキシル基またはアミンを用いるサキナビル(インビラーゼまたはRO31−8959;ロシュから);
遊離の二級ヒドロキシル基を用いるサキナビル/メルフィナビル誘導体(リリーから);
遊離の二級ヒドロキシル基を用いるイソキンCON Thf−Thfウレタン類似体(メルクから);
遊離の二級ヒドロキシル基を用いるイソキンCONチエニルウレタン類似体(メルクから);
遊離アミン基を用いるR−87366(AHPBA類似体;三共から);
遊離の二級ヒドロキシル基またはいずれかのアニリンアミン基を用いるDMP460(デュポン・メルク/アビド);
遊離の二級ヒドロキシル基を用いるL685,434(メルク);
遊離の二級ヒドロキシル基を用いるL685,434−6−ヒドロキシル誘導体(メルク);
遊離の二級ヒドロキシル基を用いるL685,434−OEtNMe2(メルク);
遊離の二級ヒドロキシル基を用いるL689,502(メルク);
遊離の二級ヒドロキシル基を用いるラシナビル(CGP61755;チバ/ノバルティスから);
遊離の二級ヒドロキシル基を用いるアルビラン(ロピナビル、ABT−378、RS−346A157378;アボット);
遊離の二級ヒドロキシル基を用いるネルフィナビル−オクタヒドロ−チエノピリジン類似体(リリーから);
遊離の二級ヒドロキシル基のいずれかを用いるP9941(デュポン・メルクから);
遊離の二級ヒドロキシル基を用いるパリナビル(BILA2011BS;バイオ−メガ/ベーリンガーインゲルハイムから);
数ある中で、遊離の二級ヒドロキシル基を用いるペニシリン、2イソキン−OHPrNH2類似体(グラクソウエルカムから)。
XはHまたはFである;
R1およびR2は独立してH、アシル基、C1−C20アルキルもしくはエーテル基、リン酸、二リン酸、三リン酸もしくはホスホジエステル基、式:
で示される基である]
で示される化合物および医薬的に許容されるその塩を投与することを特徴とする方法を目的する。本発明の好適な側面においては、上記の化合物が少なくとも1種のさらなる抗癌剤または過剰増殖細胞増殖疾患に対して有効な薬剤と同時に投与される。本発明の他の好適な側面においては、R1がH、C2−C18アシル基またはリン酸基であり、R2がHである。
LFMAUまたはその誘導体は、アメリカ特許第5,565,438号;第5,808,040号;第6,894,159号;第5,558,736号;第5,587,362号;および第5,567,688号の一つ以上に詳細に記載されている方法(その関連部分を参照により本明細書の一部とする)に従い、または当業者既知の他の方法により調製し得る。LDTまたはその誘導体は当該分野で周知の方法により容易に作製し得る。2種の活性剤を含む化合物の場合には、LFMAUまたはLDTまたはその誘導体と別の活性剤との結合が、標準的な技法に従って容易に達成し得る。結合基を形成するための適切な保護基および保護剤が容易に使用できる。
静脈内投与する場合、好適な担体は生理食塩水またはリン酸緩衝食塩水(PBS)である。
広範な生物学的アッセイ法が用いられており、化合物の抗癌活性を評価するために当業者により受け容れられている。これら方法のいずれもが本明細書に開示した化合物の活性を評価するために使用することができる。
一般に、以下のプロトコールを用いて腫瘍細胞株をマウスに移植し、抗癌作用について化合物を試験した。
この腫瘍はマウスで増殖する固形腫瘍から由来する。数グラム(1mlを1グラムと仮定)を無菌のスクリーンに通し、腫瘍1g当り2mlの組織培養培地(フェノールレッドまたはウシ胎児血清を含まず;平衡塩類溶液)に懸濁する。次いで、この腫瘍懸濁液0.1mlをマウスの脇腹に埋め込む。特に断りのない限り、移植後10日目ないし2週間目に(腫瘍がカリパスで測定可能な段階)薬物療法を開始した。
これは10%FBS含有MEM中、単層として組織培養にて増殖するヒト肝細胞癌である。細胞を数個のフラスコで増殖させ、次いでパンクレアチンと共に収穫し、平衡塩類溶液中、1ml当たり108個の割合で再懸濁し、この懸濁液0.1mlをNCRヌードマウス(ヒト組織増殖のためにT細胞欠損)の脇腹に埋め込む。次いで、約10日後に、腫瘍が測定可能となった段階で、薬物処置を開始した。
腫瘍の体積は測定値から、式:長さ(mm)x幅(mm)x幅(mm)xII/6(第1日a%として)により計算する。
本実験は免疫適格マウスにて、マウス腫瘍(結腸38)の増殖に対するLMFAUの作用を測定するためにデザインした。図1はLFMAUが免疫適格マウスにおいて結腸38腫瘍の増殖を減速することを示す。この実験では対照群15匹のマウス中、14匹でその腫瘍サイズが5日間で2倍になったのに対し、LFMAU処置群では15匹のマウス中、5匹のみでその腫瘍サイズが2倍となることを証明した。
実験2では、BDF1雌マウスにおける結腸38の増殖に対する抗癌薬物(オキシプラチン)の作用増強に関わるLFMAUの効果を試験した。図2はその実験結果を示すが、LFMAUは結腸38に対するオキサリプラチンの抗腫瘍作用を明確に増強した。その作用はLFMAU処置を停止した後も相当に持続する。
実験3では、NCR Nu/Nuマウスにおける結腸38増殖に対する抗癌薬物(オキサリプラチン)の作用増強に関わるLFMAUの効果を試験した。図3はその実験結果を示すが、LFMAUはヌードマウスの結腸38に対するオキサリプラチンの抗腫瘍作用を明確に増強した。本実験はLFMAUの作用が恐らくT細胞の現象ではないことを示している。その作用はLFMAU処置を停止した後も相当に持続する。
オキサリプラチンにおけるLFMAUの抗腫瘍増強作用を他の分類の抗癌剤について試験した。本実験では、BCF1雌マウスにおける結腸38に対するFU(ハロゲン化ウラシル)、ゲムシタビン(Dヌクレオシド類似体)およびLOddC(Lヌクレオシド類似体)の増強作用に関わるLFMAUの効果を試験した。図4および5はその実験結果を示すが、LFMAUは結腸38に対するFU、LOddCおよびゲムシタビンの抗腫瘍作用を明確に増強した。FUの場合、LFMAUの作用はLFMAU処置を停止した後も相当に持続する。LOddCの場合、LFMAUは抗癌作用を増強し、ゲムシタビンではLFMAUが第1日目で腫瘍の体積をその出発レベル以下にまで低下させる。
これらの実験では、C57BL6マウスにB16メラノーマを皮下注射した;該マウスは事前に50mg/kgのLFMAU(B.I.D.)で5日間処置し、引き続きLFMAU(B.I.D.)で10日間処置し、他の抗癌性化合物は使用しなかった。本実験では、腫瘍サイズS.D.が対照では831±474.5であり、LFMAU処置マウスでは160±150.3であった。LFMAUはB156メラノーマに対し抗癌作用を示した。
本実験は免疫適格マウスにおいて、マウス腫瘍(結腸38)の増殖に対するLDTおよびLFMAU単独の作用、およびロイコボリン併用5−フルオロウラシルとの組合わせによる作用を測定するようにデザインした。薬物は以下のスケジュールに従って投与した:
対照−ビークルのみ;
5FU/LV−150mg/kg、各腹腔内、1日目に1回
LDT−100mg/kg、経口、1日2回、5日間
LFMAU−50mg/kg、経口、1日2回、5日間
組合わせ群は、上記スケジュールごとに両方の処置を受けた。
実験8では、C57BL6雌マウスにおける結腸38増殖に対する抗癌剤作用(オキサリプラチン、10mg/kg、腹腔内、1日目に1回)の増強に関するLDT(L−dT)およびLFMAU(各15mg/kg、上記同様のスケジュール)の作用を試験した。図8はその実験結果を示すが、LDTおよびLFMAUそれぞれは結腸38に対するオキサリプラチンの抗腫瘍作用(相加的または相乗的)を明確に増強した。その作用はヌクレオシドの処置を停止した後も相当に持続する。
実験9では、免疫欠損NCR Nu/Nu雄マウスにおけるHepG2に対する抗癌性薬物作用(オキサリプラチン10mg/kg、腹腔内、1日目に1回)の増強に関するLDT(15mg/kg、上記同様のスケジュール)の作用を試験した。図9はその実験結果を示すが、LDTは単独またはオキサリプラチンとの組合わせにおいて有効であり、HepG2に対するオキサリプラチンの抗腫瘍作用(相加的または相乗的)を明確に増強した。その作用はヌクレオシドの処置を停止した後も持続する。
実験10では、図10〜12に示すように、Rag1マウス(重篤な合併免疫欠損−成熟T細胞またはB細胞を産生せず)に対する抗癌性薬物作用(ゲムシタビン400mg/kg、腹腔内、1日目に1回)の増強に関するL−FMAUの作用を試験した。この実験では、マウス腫瘍結腸38をRag1マウスおよびC57B1免疫欠損(しかし、成熟T細胞は産生する)マウスに植え付けた。ゲムシタビンを1日目に1回腹腔内投与し(400mg/kg)、LFMAUは第1〜5日目に2種の異なる濃度(15+50mg/kg)で投与した。
Claims (38)
- 患者または対象での癌を処置するための医薬の製造における構造:
XはFである;
R1およびR2は独立してH、アシル基、C1−C20アルキルもしくはエーテル基、リン酸、二リン酸、三リン酸もしくはホスホジエステル基である]
で示される少なくとも1つの化合物または医薬的に許容されるその塩の使用であって、前記癌が、胃癌、結腸癌、直腸癌、膵臓癌、肺癌、乳癌、子宮頸癌、子宮体癌、卵巣癌、前立腺癌、睾丸癌、膀胱癌、腎癌、脳/CNS癌、頭頚部癌、咽頭癌、ホジキン病、非ホジキンリンパ腫、多発性骨髄腫、白血病、メラノーマ、ユーイング肉腫、小細胞肺癌、絨毛癌、横紋筋肉腫、ウイルムス腫瘍、神経芽細胞腫、毛髪細胞白血病、口腔/咽頭癌、鼻咽頭癌、食道癌、喉頭癌、腎臓癌またはリンパ腫である使用。 - 前記患者または対象がヒトであり、R 1 およびR 2 がそれぞれ独立してH、C 2 −C 18 アシル基またはリン酸基である請求項1に記載の使用。
- 前記癌が癌性腫瘍である請求項1または2に記載の使用。
- 前記癌が、結腸癌、直腸癌、膵臓癌およびメラノーマからなる群より選択されるものである請求項3に記載の使用。
- 前記癌が、膵臓癌または白血病である請求項1または2に記載の使用。
- 前記癌が膵臓癌である請求項3に記載の使用。
- 前記癌が結腸癌である請求項3に記載の使用。
- 前記癌が膀胱癌である請求項3に記載の使用。
- 前記癌が前立腺癌である請求項3に記載の使用。
- 前記癌が乳癌である請求項3に記載の使用。
- 前記癌が肺癌である請求項3に記載の使用。
- 前記癌が鼻咽頭癌である請求項3に記載の使用。
- 前記癌が卵巣癌である請求項3に記載の使用。
- 前記癌がリンパ腫である請求項3に記載の使用。
- 前記癌がメラノーマである請求項3に記載の使用。
- 癌を処置するための医薬の製造における有効量の少なくとも2種の化合物の使用であって、第一の化合物は構造:
XはHまたはFである;
R 1 およびR 2 は独立してH、アシル基、C 1 −C 20 アルキルもしくはエーテル基、リン酸、二リン酸、三リン酸もしくはホスホジエステル基である]
で示される化合物および医薬的に許容されるその塩であり、第二の化合物は追加の抗癌剤であり、前記癌が、胃癌、結腸癌、直腸癌、膵臓癌、肺癌、乳癌、子宮頸癌、子宮体癌、卵巣癌、前立腺癌、睾丸癌、膀胱癌、腎癌、脳/CNS癌、頭頚部癌、咽頭癌、ホジキン病、非ホジキンリンパ腫、多発性骨髄腫、白血病、メラノーマ、ユーイング肉腫、小細胞肺癌、絨毛癌、横紋筋肉腫、ウイルムス腫瘍、神経芽細胞腫、毛髪細胞白血病、口腔/咽頭癌、食道癌、鼻咽頭癌、喉頭癌、腎臓癌またはリンパ腫である使用。 - 前記患者または対象がヒトであり、R 1 およびR 2 がそれぞれ独立してHまたはC 2 −C 18 アシル基である請求項16に記載の使用。
- 前記患者または対象がヒトであり、R 1 およびR 2 がそれぞれHである請求項16に記載の使用。
- 前記追加の抗癌剤が、代謝拮抗剤、トポイソメラーゼIおよびIIのインヒビター、アルキル化剤または微小管インヒビターである請求項16に記載の使用。
- 前記追加の抗癌剤が、代謝拮抗剤、トポイソメラーゼIおよびIIのインヒビター、アルキル化剤または微小管インヒビターである請求項17に記載の使用。
- 前記追加の抗癌剤が、代謝拮抗剤、アルキル化剤または微小管インヒビターである請求項18に記載の使用。
- 前記追加の抗癌剤が、アルデスロイキン、アレムツズマブ、アリトレチノイン、アロプリノール、アルトレタミン、アミフォスチン、アナストロゾール、三酸化砒素、アスパラギナーゼ、生BCG、ベキサロテンカプセル、ベキサロテンゲル、ブレオマイシン、ブスルファン静注、ブスルファン経口、カルステロン、カペシタビン、カルボプラチン、カルムスチン、ポリフェプロサン20インプラントによるカルムスチン、セレコキシブ、クロランブシル、シスプラチン、クラドリビン、シクロホスファミド、シタラビン、リポソーム・シタラビン、ダカルバジン、ダクチノマイシン、アクチノマイシンD、ダルベポエチンアルファ、リポソーム・ダウノルビシン、ダウノルビシン、ダウノマイシン、デニロイキン・ジフチトックス、デクスラゾキサン、ドセタキセル、ドキソルビシン、リポソーム・ドキソルビシン、プロピオン酸ドロモスタノロン、エリオットB溶液、エピルビシン、エポエチンアルファ・エストラムスチン、リン酸エトポシド、エトポシド(VP−16)、エクゼメスタン、フィルグラスチム、フロクスウリジン(動脈内)、フルダラビン、フルオロウラシル(5−FU)、フルベストラント、ゲムシタビン、ゲムツズマブ オゾガマイシン、グリーベック、酢酸ゴセレリン、ヒドロキシ尿素、イブリツモマブ・チウキセタン、イダルビシン、イフォスファミド、メシル酸イマチニブ、インターフェロンアルファ−2a、インターフェロンアルファ−2b、イリノテカン、レトロゾール、ロイコボリン、レバミソール、ロムスチン(CCNU)、メクロレタミン(ナイトロジェンマスタード)、酢酸メゲストロール、メルファラン(L−PAM)、メルカプトプリン(6−MP)、メスナ、メトトレキセート、メトクスサレン、マイトマイシンC、ミトタン、ミトキサントロン、フェンプロピオン酸ナンドロロン、ノフェツモマブ、LOddC、オプレルベキン、オキサリプラチン、パクリタキセル、パミドロネート、ペガデマーゼ、ペガスパルガーゼ、ペグフィルグラスチム、ペントスタチン、ピポブロマン、プリカマイシン、ミスラマイシン、ポルフィマーナトリウム、プロカルバジン、キナクリン、ラスブリカーゼ、リツキシマブ、サルグラモスチム、ストレプトゾシン、スラフェニブ、タルブビジン(LDT)、タルク、タモキシフェン、タルセバ、テモゾロミド、テニポシド(VM−26)、テストラクトン、チオグアニン(6−TG)、チオテパ、トポテカン、トレミフェン、トシツモマブ、トラスツズマブ、トレチノイン(ATRA)、ウラシルマスタード、バルルビシン、バルトルシタビン(モノバールLDC)、ビンブラスチン、ビノレルビン、ゾレドロネート、およびその混合物からなる群より選択される請求項16に記載の使用。
- 前記追加の抗癌剤が、アルデスロイキン、アレムツズマブ、アリトレチノイン、アロプリノール、アルトレタミン、アミフォスチン、アナストロゾール、三酸化砒素、アスパラギナーゼ、生BCG、ベキサロテンカプセル、ベキサロテンゲル、ブレオマイシン、ブスルファン静注、ブスルファン経口、カルステロン、カペシタビン、カルボプラチン、カルムスチン、ポリフェプロサン20インプラントによるカルムスチン、セレコキシブ、クロランブシル、シスプラチン、クラドリビン、シクロホスファミド、シタラビン、リポソーム・シタラビン、ダカルバジン、ダクチノマイシン、アクチノマイシンD、ダルベポエチンアルファ、リポソーム・ダウノルビシン、ダウノルビシン、ダウノマイシン、デニロイキン・ジフチトックス、デクスラゾキサン、ドセタキセル、ドキソルビシン、リポソーム・ドキソルビシン、プロピオン酸ドロモスタノロン、エリオットB溶液、エピルビシン、エポエチンアルファ・エストラムスチン、リン酸エトポシド、エトポシド(VP−16)、エクゼメスタン、フィルグラスチム、フロクスウリジン(動脈内)、フルダラビン、フルオロウラシル(5−FU)、フルベストラント、ゲムシタビン、ゲムツズマブ オゾガマイシン、グリーベック、酢酸ゴセレリン、ヒドロキシ尿素、イブリツモマブ・チウキセタン、イダルビシン、イフォスファミド、メシル酸イマチニブ、インターフェロンアルファ−2a、インターフェロンアルファ−2b、イリノテカン、レトロゾール、ロイコボリン、レバミソール、ロムスチン(CCNU)、メクロレタミン(ナイトロジェンマスタード)、酢酸メゲストロール、メルファラン(L−PAM)、メルカプトプリン(6−MP)、メスナ、メトトレキセート、メトクスサレン、マイトマイシンC、ミトタン、ミトキサントロン、フェンプロピオン酸ナンドロロン、ノフェツモマブ、LOddC、オプレルベキン、オキサリプラチン、パクリタキセル、パミドロネート、ペガデマーゼ、ペガスパルガーゼ、ペグフィルグラスチム、ペントスタチン、ピポブロマン、プリカマイシン、ミスラマイシン、ポルフィマーナトリウム、プロカルバジン、キナクリン、ラスブリカーゼ、リツキシマブ、サルグラモスチム、ストレプトゾシン、スラフェニブ、タルブビジン(LDT)、タルク、タモキシフェン、タルセバ、テモゾロミド、テニポシド(VM−26)、テストラクトン、チオグアニン(6−TG)、チオテパ、トポテカン、トレミフェン、トシツモマブ、トラスツズマブ、トレチノイン(ATRA)、ウラシルマスタード、バルルビシン、バルトルシタビン(モノバールLDC)、ビンブラスチン、ビノレルビン、ゾレドロネート、およびその混合物からなる群より選択される請求項17に記載の使用。
- 前記追加の抗癌剤が、アルデスロイキン、アレムツズマブ、アリトレチノイン、アロプリノール、アルトレタミン、アミフォスチン、アナストロゾール、三酸化砒素、アスパラギナーゼ、生BCG、ベキサロテンカプセル、ベキサロテンゲル、ブレオマイシン、ブスルファン静注、ブスルファン経口、カルステロン、カペシタビン、カルボプラチン、カルムスチン、ポリフェプロサン20インプラントによるカルムスチン、セレコキシブ、クロランブシル、シスプラチン、クラドリビン、シクロホスファミド、シタラビン、リポソーム・シタラビン、ダカルバジン、ダクチノマイシン、アクチノマイシンD、ダルベポエチンアルファ、リポソーム・ダウノルビシン、ダウノルビシン、ダウノマイシン、デニロイキン・ジフチトックス、デクスラゾキサン、ドセタキセル、ドキソルビシン、リポソーム・ドキソルビシン、プロピオン酸ドロモスタノロン、エリオットB溶液、エピルビシン、エポエチンアルファ・エストラムスチン、リン酸エトポシド、エトポシド(VP−16)、エクゼメスタン、フィルグラスチム、フロクスウリジン(動脈内)、フルダラビン、フルオロウラシル(5−FU)、フルベストラント、ゲムシタビン、ゲムツズマブ オゾガマイシン、グリーベック、酢酸ゴセレリン、ヒドロキシ尿素、イブリツモマブ・チウキセタン、イダルビシン、イフォスファミド、メシル酸イマチニブ、インターフェロンアルファ−2a、インターフェロンアルファ−2b、イリノテカン、レトロゾール、ロイコボリン、レバミソール、ロムスチン(CCNU)、メクロレタミン(ナイトロジェンマスタード)、酢酸メゲストロール、メルファラン(L−PAM)、メルカプトプリン(6−MP)、メスナ、メトトレキセート、メトクスサレン、マイトマイシンC、ミトタン、ミトキサントロン、フェンプロピオン酸ナンドロロン、ノフェツモマブ、LOddC、オプレルベキン、オキサリプラチン、パクリタキセル、パミドロネート、ペガデマーゼ、ペガスパルガーゼ、ペグフィルグラスチム、ペントスタチン、ピポブロマン、プリカマイシン、ミスラマイシン、ポルフィマーナトリウム、プロカルバジン、キナクリン、ラスブリカーゼ、リツキシマブ、サルグラモスチム、ストレプトゾシン、スラフェニブ、タルブビジン(LDT)、タルク、タモキシフェン、タルセバ、テモゾロミド、テニポシド(VM−26)、テストラクトン、チオグアニン(6−TG)、チオテパ、トポテカン、トレミフェン、トシツモマブ、トラスツズマブ、トレチノイン(ATRA)、ウラシルマスタード、バルルビシン、バルトルシタビン(モノバールLDC)、ビンブラスチン、ビノレルビン、ゾレドロネート、およびその混合物からなる群より選択される請求項18に記載の使用。
- 前記癌が癌性腫瘍である請求項16〜25のいずれかに記載の使用。
- 前記癌が、結腸癌、直腸癌、膵臓癌およびメラノーマからなる群より選択されるものである請求項26に記載の使用。
- 前記癌が結腸癌である請求項26に記載の使用。
- 前記癌が膀胱癌である請求項26に記載の使用。
- 前記癌が前立腺癌である請求項26に記載の使用。
- 前記癌が乳癌である請求項26に記載の使用。
- 前記癌が膵臓癌である請求項26に記載の使用。
- 前記癌が白血病である請求項26に記載の使用。
- 前記癌が肺癌である請求項26に記載の使用。
- 前記癌が鼻咽頭癌である請求項26に記載の使用。
- 前記癌が卵巣癌である請求項26に記載の使用。
- 前記癌がリンパ腫である請求項26に記載の使用。
- 前記癌がメラノーマである請求項26に記載の使用。
- 前記追加の抗癌剤が、フルオロウラシル、オキサリプラチン、ゲムシタビン、またはこれらの混合物である請求項16に記載の使用。
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US74172805P | 2005-12-02 | 2005-12-02 | |
US60/741,728 | 2005-12-02 | ||
PCT/US2006/021742 WO2006133092A1 (en) | 2005-06-07 | 2006-06-05 | Methods of treating cancer and other conditions or disease states using lfmau and ldt |
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JP5149168B2 true JP5149168B2 (ja) | 2013-02-20 |
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EP (1) | EP1890537B1 (ja) |
JP (1) | JP5149168B2 (ja) |
KR (1) | KR101298631B1 (ja) |
CN (1) | CN103735560A (ja) |
AU (1) | AU2006255125B2 (ja) |
BR (1) | BRPI0613796A2 (ja) |
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EP1990054A1 (de) * | 2007-05-11 | 2008-11-12 | Freie Universität Berlin | Polymerase-Hemmer und ihre Verwendung zur Behandlung von Tumoren |
EP2152273A2 (de) * | 2007-05-11 | 2010-02-17 | Freie Universität Berlin | Polymerase-hemmer und ihre verwendung zur behandlung von tumoren |
FR2924430B1 (fr) | 2007-11-30 | 2010-03-19 | Univ Bordeaux 2 | Procede de preparation de nanoparticules a base de molecules ou macromolecules amphiphiles fonctionnelles et leur utilisation |
US9569724B2 (en) | 2010-09-24 | 2017-02-14 | International Business Machines Corporation | Using ontological information in open domain type coercion |
US8492386B2 (en) | 2011-10-21 | 2013-07-23 | Abbvie Inc. | Methods for treating HCV |
CN104383541A (zh) | 2011-10-21 | 2015-03-04 | 艾伯维公司 | 用于治疗hcv的包含至少两种直接抗病毒剂和利巴韦林但无干扰素的方法 |
DK2583680T1 (da) | 2011-10-21 | 2015-01-19 | Abbvie Inc | Mono (PSI-7977) eller kombinationsbehandling af DAA til anvendelse ved behandling af HCV |
US8466159B2 (en) | 2011-10-21 | 2013-06-18 | Abbvie Inc. | Methods for treating HCV |
WO2014004376A2 (en) | 2012-06-26 | 2014-01-03 | Del Mar Pharmaceuticals | Methods for treating tyrosine-kinase-inhibitor-resistant malignancies in patients with genetic polymorphisms or ahi1 dysregulations or mutations employing dianhydrogalactitol, diacetyldianhydrogalactitol, dibromodulcitol, or analogs or derivatives thereof |
KR20160061911A (ko) | 2013-04-08 | 2016-06-01 | 데니스 엠. 브라운 | 최적하 투여된 화학 화합물의 치료 효과 |
CA2969372C (en) | 2014-12-15 | 2023-05-16 | Emory University | Phosphoramidates for the treatment of hepatitis b virus |
CA3022119A1 (en) | 2016-04-28 | 2017-11-02 | Emory University | Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto |
CA3029315A1 (en) | 2016-06-24 | 2017-12-28 | Emory University | Phosphoramidates for the treatment of hepatitis b virus |
SG10201609131YA (en) | 2016-11-01 | 2018-06-28 | Xylonix Ip Holdings Pte Ltd | Zinc-pga compositions and methods for treating cancer |
SG10201708886RA (en) * | 2017-10-30 | 2019-05-30 | Xylonix Ip Holdings Pte Ltd | α-PGA-ZINC COMPOSITIONS AND METHODS FOR TREATING CANCER |
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JPS5123512B2 (ja) | 1973-09-05 | 1976-07-17 | ||
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KR20080017339A (ko) | 2008-02-26 |
CA2609343A1 (en) | 2006-12-14 |
US7879816B2 (en) | 2011-02-01 |
CA2609343C (en) | 2015-03-31 |
AU2006255125B2 (en) | 2011-12-08 |
EA200800002A1 (ru) | 2008-08-29 |
JP2008542442A (ja) | 2008-11-27 |
NZ563686A (en) | 2011-07-29 |
CN103735560A (zh) | 2014-04-23 |
KR101298631B1 (ko) | 2013-08-30 |
SG162753A1 (en) | 2010-07-29 |
WO2006133092A1 (en) | 2006-12-14 |
EP1890537A1 (en) | 2008-02-27 |
MX2007015534A (es) | 2008-02-25 |
AU2006255125A1 (en) | 2006-12-14 |
EA016838B1 (ru) | 2012-07-30 |
IL187553A0 (en) | 2008-03-20 |
EP1890537A4 (en) | 2009-11-11 |
BRPI0613796A2 (pt) | 2011-02-15 |
US20110104108A1 (en) | 2011-05-05 |
US8207143B2 (en) | 2012-06-26 |
IL187553A (en) | 2012-12-31 |
EP1890537B1 (en) | 2012-08-08 |
ES2392544T3 (es) | 2012-12-11 |
US20080292687A1 (en) | 2008-11-27 |
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