JP2022512736A - 重水素を含有する化合物 - Google Patents
重水素を含有する化合物 Download PDFInfo
- Publication number
- JP2022512736A JP2022512736A JP2021521145A JP2021521145A JP2022512736A JP 2022512736 A JP2022512736 A JP 2022512736A JP 2021521145 A JP2021521145 A JP 2021521145A JP 2021521145 A JP2021521145 A JP 2021521145A JP 2022512736 A JP2022512736 A JP 2022512736A
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- JP
- Japan
- Prior art keywords
- deuterium
- melphalan
- mol
- melflufen
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229910052805 deuterium Inorganic materials 0.000 title claims abstract description 149
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 title claims abstract description 147
- 150000001875 compounds Chemical class 0.000 title claims abstract description 84
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- 239000003814 drug Substances 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 15
- 206010028980 Neoplasm Diseases 0.000 claims description 14
- 201000011510 cancer Diseases 0.000 claims description 11
- 230000002265 prevention Effects 0.000 claims description 8
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 7
- 208000034578 Multiple myelomas Diseases 0.000 claims description 6
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 6
- 229940100198 alkylating agent Drugs 0.000 claims description 6
- 239000002168 alkylating agent Substances 0.000 claims description 6
- 229940124597 therapeutic agent Drugs 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 206010025323 Lymphomas Diseases 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 208000032839 leukemia Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000002955 immunomodulating agent Substances 0.000 claims description 3
- 229940121354 immunomodulator Drugs 0.000 claims description 3
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 claims 3
- 230000002584 immunomodulator Effects 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 2
- 238000010586 diagram Methods 0.000 abstract 1
- 229960001924 melphalan Drugs 0.000 description 80
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 78
- YQZNKYXGZSVEHI-VXKWHMMOSA-N ethyl (2s)-2-[[(2s)-2-amino-3-[4-[bis(2-chloroethyl)amino]phenyl]propanoyl]amino]-3-(4-fluorophenyl)propanoate Chemical compound C([C@@H](C(=O)OCC)NC(=O)[C@@H](N)CC=1C=CC(=CC=1)N(CCCl)CCCl)C1=CC=C(F)C=C1 YQZNKYXGZSVEHI-VXKWHMMOSA-N 0.000 description 61
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 57
- 241000282472 Canis lupus familiaris Species 0.000 description 28
- 238000001802 infusion Methods 0.000 description 28
- 239000002207 metabolite Substances 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000002347 injection Methods 0.000 description 19
- 239000007924 injection Substances 0.000 description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 239000000203 mixture Substances 0.000 description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 15
- 230000036470 plasma concentration Effects 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 13
- 229940079593 drug Drugs 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- -1 amino acids Chemical class 0.000 description 12
- 125000004429 atom Chemical group 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- 239000012071 phase Substances 0.000 description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 230000009885 systemic effect Effects 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 8
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 231100000331 toxic Toxicity 0.000 description 7
- 230000002588 toxic effect Effects 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 230000000144 pharmacologic effect Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- LFQSCWFLJHTTHZ-LIDOUZCJSA-N ethanol-d6 Chemical compound [2H]OC([2H])([2H])C([2H])([2H])[2H] LFQSCWFLJHTTHZ-LIDOUZCJSA-N 0.000 description 5
- 235000011007 phosphoric acid Nutrition 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- 238000000825 ultraviolet detection Methods 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 230000002503 metabolic effect Effects 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- XWHHYOYVRVGJJY-QMMMGPOBSA-N 4-fluoro-L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(F)C=C1 XWHHYOYVRVGJJY-QMMMGPOBSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 108090000371 Esterases Proteins 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 3
- 108091005804 Peptidases Proteins 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
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- 238000004519 manufacturing process Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 3
- 235000019833 protease Nutrition 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000002110 toxicologic effect Effects 0.000 description 3
- 231100000027 toxicology Toxicity 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- LHUVSBBFFSLTHN-HNNXBMFYSA-N (2s)-3-[4-[bis(2-chloroethyl)amino]phenyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C(N(CCCl)CCCl)C=C1 LHUVSBBFFSLTHN-HNNXBMFYSA-N 0.000 description 2
- CHADEQDQBURGHL-UHFFFAOYSA-N (6'-acetyloxy-3-oxospiro[2-benzofuran-1,9'-xanthene]-3'-yl) acetate Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(OC(C)=O)C=C1OC1=CC(OC(=O)C)=CC=C21 CHADEQDQBURGHL-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 2
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
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Abstract
Description
各R1~R30は、独立して、Hおよび重水素からなる群から選択され、R1~R30のうちの少なくとも1つは、重水素の天然に生じる存在量よりも多い存在量レベルを有する重水素である。
各R1~R30は、独立して、Hおよび重水素からなる群から選択され、R1~R30のうちの少なくとも1つは、重水素の天然に生じる存在量よりも多い存在量レベルを有する重水素である。
一般的な実験の詳細
別段明記されない限り、全ての試薬および溶媒を、商業的供給業者から購入し、さらなる精製なく使用した。メルフルフェンおよびメルフルフェン中間体は、WO2016/180740またはWO01/96367に記載される合成方法を使用して調製され得る。
LC-MS(条件#1):tR 2.28分(純度>97%)、m/z[M+H]505。LC-MS(条件#2):tR 2.63分(純度>98%)、m/z[M+H]505。1H NMR(400MHz,MeOD):δ/ppm;2.92-2.97(m,1H),3.01-306(m,1H),3.16-3.21(dd,2H),3.67-3.71(m,4H),3.78-3.81(m,4H),4.02-4.05(m,1H),4.69-4.73(m,1H),6.78-6.82(d,0.25H),7.02-7.07(t,2H),7.19(s,2H),7.24-7.28(m,2H)。
蛍光マイクロカルチャー細胞毒性アッセイ(FMCA)(Larsson, R., et al-1992: Int J Cancer, 50,177-185)が、化合物を評価するために使用される。簡単に説明すると、96ウェルマイクロタイタープレート(NUNC, Roskilde, Denmark)は、20μlの薬液を所望の濃度の10倍で調製され、-70℃で最大2か月間保管される。一般に、物質は、最初に無水または酸性エタノールに4.0~8.2mMの濃度に溶解され、さらに無菌水または無菌リン酸緩衝生理食塩水で希釈される。水での全ての希釈は、マスタード加水分解の影響を最小化するために実験の直前に行われる。最終エタノール濃度は、1%v/vを超えない。実験のゼロ日目に、適切な濃度の細胞懸濁液180μLを解凍したプレートのウェルに添加し、6つのウェルを対照(細胞懸濁液のみ)として、6つのウェルをブランク(細胞培地のみ)として供する。72時間のインキュベーション後、細胞がPBSで1回洗浄され、生理学的緩衝液中の100μLのフルオレセインジアセテート(10μg/ml)が添加される。さらに45分後、生成した蛍光(ex 485 rim ; em 528 nm)は、96ウェルスキャニング蛍光光度計(Fluoroscan II, Labsystems Oy, Helsinki, Finland)で測定される。生成した蛍光は生細胞の数に比例し、データは生存指数(ブランク値が差し引かれた対照ウェルのパーセントでの試験ウェルにおける蛍光)およびIC50(ソフトウェアGraphPad Prism@(Graphpad Software Inc., San Diego, CA, USAによって計算された場合、阻害濃度50%)として提示される。成功したアッセイのための品質基準は、トリパンブルー排除試験によって判断された場合、それぞれブランク(6ウェル)、対照(6ウェル)、試験ウェル(3)において30%未満の変動係数、ブランクの10倍超の対照信号、および最後に70%(初代ヒト腫瘍培養物)または90%(細胞株)超の初期細胞生存率を含む。
実施例(a)イヌにおけるインビボ研究
イヌにおける30分の注入としてのメルフルフェン-d5(III)またはメルフルフェン単回静脈内投与後に、イヌにおける比較単回用量毒性試験を実行し、メルフルフェン-d5(III)およびメルフルフェンを比較して、メルフルフェンおよびメルフルフェン-d5(III)ならびにそれらの代謝物であるデスエチル-メルフルフェンおよびメルファランの毒物動態を調査した。
この研究は、メルフルフェン-d5(III)およびメルフルフェンの潜在的な急性毒性を比較することを目的とした。メルフルフェン-d5(III)、メルフルフェンならびにそれらの代謝物であるデスエチル-メルフルフェンおよびメルファランの毒物動態を、イヌにおける30分の注入としての単回静脈内投与後に評価した。
血液試料を、1日目の投与前、15分、30分(注入終了直前)、注入開始後40分、1時間、2時間、4時間および6時間に末梢静脈から回収した。
メルフルフェン-d5(III)、メルフルフェンならびにその代謝物である、デスエチル-メルフルフェンおよびメルファランの血漿毒物動態分析を、Phoenix WinNonlin(v. 6.3, Certara Company, USA)を使用する標準的非コンパートメントアプローチに従って実施した。
終末相の半減期であるt1/2,zを、次の式に従って自然対数濃度対時間の曲線の線形回帰分析によって計算し、
メルフルフェン-d5(III)、メルフルフェンならびにそれらの代謝物であるデスエチル-メルフルフェンおよびメルファランは、対照群(群1)の血漿試料、同様に治療群2、3および4の投与前において測定されなかった。
組み合わされた雄および雌のビーグル犬におけるメルフルフェン-d5(III)(群3、2.5mg/kg)およびメルフルフェン(群4、2.5mg/kg)の個々および平均(±SD)全身曝露パラメータの比較が、図2(C最大)および図3(AUC最後)に示される。
組み合わされた雄および雌のビーグル犬におけるメルフルフェン-d5(III)(群3、2.5mg/kg)およびメルフルフェン(群4、2.5mg/kg)の注入後のデスエチル-メルフルフェンの個々および平均(±SD)全身曝露パラメータの比較が、図4(C最大)および図5(AUC最後)に示される。
組み合わされた雄および雌のビーグル犬ビーグル犬におけるメルフルフェン-d5(III)(群3、2.5mg/kg)およびメルフルフェン(群4、2.5mg/kg)の注入後のメルファランの個々および平均(±SD)全身曝露パラメータの比較が、図9(C最大)および図10(AUC最後)に示される。t1/2,zおよびAUC∞の結果はまた、図11および図12に示される。
メルフルフェン-d5(III)(1.25および2.5mg/kg)またはメルフルフェン(2.5mg/kg)の単回30分注入後の、メルフルフェン-d5(III)、メルフルフェンならびにそれらの代謝物であるデスエチル-メルフルフェンおよびメルファランの全身曝露記述子は、雄および雌において同様であった。
Claims (23)
- R1~R30のうちの少なくとも1つが、少なくとも1mol%、5mol%、10mol%、50mol%、90mol%、または98mol%の重水素の、重水素存在量レベルを有する、請求項1に記載の化合物。
- R1~R8のうちの少なくとも1つが、少なくとも5mol%の存在量レベルを有する重水素である、請求項1および2に記載の化合物。
- R9~R15のうちの少なくとも1つが、少なくとも5mol%の存在量レベルを有する重水素である、請求項1および2に記載の化合物。
- R16~R18のうちの少なくとも1つが、少なくとも5mol%の存在量レベルを有する重水素である、請求項1および2に記載の化合物。
- R19~R25のうちの少なくとも1つが、少なくとも5mol%の存在量レベルを有する重水素である、請求項1および2に記載の化合物。
- R26~R30のうちの少なくとも1つが、少なくとも5mol%の存在量レベルを有する重水素である、請求項1および2に記載の化合物。
- R26~R30のうちの少なくとも2つが重水素である、例えば、R26~R30のうちの2つが重水素であるか、またはR26~R30のうちの3つが重水素であるか、またはR26~R30のうちの4つが重水素であるか、またはR26~R30の各々が重水素である、請求項7に記載の化合物。
- 前記存在量レベルが、少なくとも10mol%、50mol%、90mol%、または98mol%の重水素である、請求項8に記載の化合物。
- 請求項1~15のいずれか一項に定義される化合物を、薬学的に許容される担体と一緒に、任意選択で、追加の治療薬、例えば、プロテアーゼ阻害剤(PI)、免疫調節薬(IMiD)またはアルキル化剤と一緒に含む、薬学的組成物。
- 医薬としての使用のための、請求項1~15のいずれか一項に記載の化合物、または請求項16に記載の薬学的組成物。
- 癌の治療または予防における使用のための、請求項1~15のいずれか一項に記載の化合物、または請求項16に記載の薬学的組成物。
- 多発性骨髄腫、乳癌、肺癌、卵巣癌、白血病およびリンパ腫の治療または予防における使用のための、請求項1~15のいずれか一項に記載の化合物、または請求項16に記載の薬学的組成物。
- 薬学的有効量の請求項1~15のいずれか一項に記載の化合物または請求項16に記載の薬学的組成物を投与することを含む、患者を治療するための方法。
- 有効量の請求項1~15に記載の化合物または請求項16に記載の薬学的組成物を投与することを含む、癌の治療または予防のための方法。
- 前記癌が、多発性骨髄腫、乳癌、肺癌、卵巣癌、白血病およびリンパ腫のうちのいずれか1つである、請求項21に記載の方法。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004503564A (ja) * | 2000-06-13 | 2004-02-05 | オンコペプティド アクチボラグ | メルファラン誘導体及び癌の化学療法薬としてのその使用 |
JP2014512402A (ja) * | 2011-04-28 | 2014-05-22 | オンコペプティデス エービー | 細胞毒性ジペプチドの凍結乾燥調製物 |
JP2015535243A (ja) * | 2012-10-26 | 2015-12-10 | オンコペプティデス エービーOncopeptides AB | メルファランフルフェナミドの凍結乾燥製剤 |
JP2016513084A (ja) * | 2013-02-05 | 2016-05-12 | インファール・アクティエンゲゼルシャフト | 位置特異的非対称重水素富化カテコールアミン誘導体および前記化合物を含有する医薬 |
JP2018515512A (ja) * | 2015-05-08 | 2018-06-14 | オンコペプティデス エービーOncopeptides AB | ナイトロジェンマスタード誘導体の調製方法 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010044981A2 (en) | 2008-09-18 | 2010-04-22 | Auspex Pharmaceutical ,Inc. | Benzoquinoline inhibitors of vesicular monoamine transporter 2 |
CN110229159B (zh) * | 2013-12-18 | 2021-08-24 | 康塞特医药品有限公司 | 卢索替尼的氘代衍生物 |
GB201521217D0 (en) * | 2015-12-01 | 2016-01-13 | Oncopeptides Ab | Dosage regimens |
-
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004503564A (ja) * | 2000-06-13 | 2004-02-05 | オンコペプティド アクチボラグ | メルファラン誘導体及び癌の化学療法薬としてのその使用 |
JP2014512402A (ja) * | 2011-04-28 | 2014-05-22 | オンコペプティデス エービー | 細胞毒性ジペプチドの凍結乾燥調製物 |
JP2015535243A (ja) * | 2012-10-26 | 2015-12-10 | オンコペプティデス エービーOncopeptides AB | メルファランフルフェナミドの凍結乾燥製剤 |
JP2016513084A (ja) * | 2013-02-05 | 2016-05-12 | インファール・アクティエンゲゼルシャフト | 位置特異的非対称重水素富化カテコールアミン誘導体および前記化合物を含有する医薬 |
JP2018515512A (ja) * | 2015-05-08 | 2018-06-14 | オンコペプティデス エービーOncopeptides AB | ナイトロジェンマスタード誘導体の調製方法 |
Non-Patent Citations (3)
Title |
---|
HARBESON, S.AND TUNG, R.: "Deuterium Medicinal Chemistry: A New Approach to Drug Discoveryand Development", MEDCHEM NEWS, JPN6023040163, 2014, pages 8 - 22, XP055246294, ISSN: 0005165550 * |
SAWADA, M. ET AL.: "Chiral Recognition in Host-Guest Complexation Determined by the Enantiomer-Labeled Guest Method Usin", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 117, no. 29, JPN6023040162, 1995, pages 7726 - 7736, ISSN: 0005165551 * |
TUNG, R.: "The Development of Deuterium-Containing Drugs", INNOVATIONS IN PHARMACEUTICAL TECHNOLOGY, vol. 32, JPN6023040164, 2010, pages 24 - 28, XP009148260, ISSN: 0005165549 * |
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