JP2017532305A - 増加した抗腫瘍効果を有する白金(iv)錯体 - Google Patents
増加した抗腫瘍効果を有する白金(iv)錯体 Download PDFInfo
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- JP2017532305A JP2017532305A JP2017512996A JP2017512996A JP2017532305A JP 2017532305 A JP2017532305 A JP 2017532305A JP 2017512996 A JP2017512996 A JP 2017512996A JP 2017512996 A JP2017512996 A JP 2017512996A JP 2017532305 A JP2017532305 A JP 2017532305A
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- NDBYXKQCPYUOMI-UHFFFAOYSA-N platinum(4+) Chemical class [Pt+4] NDBYXKQCPYUOMI-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 230000000259 anti-tumor effect Effects 0.000 title abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- 230000001613 neoplastic effect Effects 0.000 claims abstract description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 24
- 239000003446 ligand Substances 0.000 claims description 23
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 12
- MIBQYWIOHFTKHD-UHFFFAOYSA-N adamantane-1-carbonyl chloride Chemical compound C1C(C2)CC3CC2CC1(C(=O)Cl)C3 MIBQYWIOHFTKHD-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 3
- 230000000996 additive effect Effects 0.000 claims description 3
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- 125000005456 glyceride group Chemical group 0.000 claims description 3
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000005270 trialkylamine group Chemical group 0.000 claims description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 37
- 229910052697 platinum Inorganic materials 0.000 description 13
- -1 1-adamantyl groups Chemical group 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 206010028980 Neoplasm Diseases 0.000 description 9
- 229960004316 cisplatin Drugs 0.000 description 9
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical class [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000004094 surface-active agent Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 190014017285 Satraplatin Chemical compound 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 5
- 229960001756 oxaliplatin Drugs 0.000 description 5
- 229960005399 satraplatin Drugs 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 210000000170 cell membrane Anatomy 0.000 description 4
- 201000010897 colon adenocarcinoma Diseases 0.000 description 4
- 208000029742 colonic neoplasm Diseases 0.000 description 4
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 150000003057 platinum Chemical class 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
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- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 2
- 108091092356 cellular DNA Proteins 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- 229910003460 diamond Inorganic materials 0.000 description 2
- 239000010432 diamond Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000003473 lipid group Chemical group 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 239000003880 polar aprotic solvent Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 108091035539 telomere Proteins 0.000 description 2
- 102000055501 telomere Human genes 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 1
- COYZTUXPHRHKGV-UHFFFAOYSA-N 4-methoxy-5-[3-(2-methoxy-4-nitro-5-sulfophenyl)-5-(phenylcarbamoyl)-1h-tetrazol-2-yl]-2-nitrobenzenesulfonic acid Chemical class COC1=CC([N+]([O-])=O)=C(S(O)(=O)=O)C=C1N1N(C=2C(=CC(=C(C=2)S(O)(=O)=O)[N+]([O-])=O)OC)N=C(C(=O)NC=2C=CC=CC=2)N1 COYZTUXPHRHKGV-UHFFFAOYSA-N 0.000 description 1
- RXGJTUSBYWCRBK-UHFFFAOYSA-M 5-methylphenazinium methyl sulfate Chemical compound COS([O-])(=O)=O.C1=CC=C2[N+](C)=C(C=CC=C3)C3=NC2=C1 RXGJTUSBYWCRBK-UHFFFAOYSA-M 0.000 description 1
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 230000000970 DNA cross-linking effect Effects 0.000 description 1
- 102000009058 Death Domain Receptors Human genes 0.000 description 1
- 108010049207 Death Domain Receptors Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 102100031988 Tumor necrosis factor ligand superfamily member 6 Human genes 0.000 description 1
- 108050002568 Tumor necrosis factor ligand superfamily member 6 Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000003670 adamantan-2-yl group Chemical group [H]C1([H])C(C2([H])[H])([H])C([H])([H])C3([H])C([*])([H])C1([H])C([H])([H])C2([H])C3([H])[H] 0.000 description 1
- JIMXXGFJRDUSRO-UHFFFAOYSA-N adamantane-1-carboxylic acid Chemical compound C1C(C2)CC3CC2CC1(C(=O)O)C3 JIMXXGFJRDUSRO-UHFFFAOYSA-N 0.000 description 1
- 125000005599 alkyl carboxylate group Chemical group 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000005775 apoptotic pathway Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 238000007630 basic procedure Methods 0.000 description 1
- 238000004177 carbon cycle Methods 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 210000005095 gastrointestinal system Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- SRZWJXLDVCHJGO-UHFFFAOYSA-N methyl hydrogen sulfate;10-methyl-5h-phenazine Chemical compound COS(O)(=O)=O.C1=CC=C2N(C)C3=CC=CC=C3NC2=C1 SRZWJXLDVCHJGO-UHFFFAOYSA-N 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000011049 pearl Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000005592 polycycloalkyl group Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
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- 210000003411 telomere Anatomy 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
-
- 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
- A61K31/28—Compounds containing heavy metals
- A61K31/282—Platinum compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
式(II)及び(III)に従う白金(IV)錯体の合成
a)重要な中間体「c-t-c」PtCl2(OH)2(NH3,アルキル-若しくはシクロアルキルアミン又はポリシクロアルキルアミン)の合成
米国特許第6,503,943号、実施例2a、第4段、45行目にさらに記載されている基本手順に従って、合成を行った。
b)「c-t-c」PtCl2(アルキルカルボキシラト)2(NH3,アルキル-若しくはシクロアルキルアミン又はポリシクロアルキルアミン)、すなわち、式(II)に従う白金(IV)錯体の合成
EP0 328 274、実施例1から5、4頁に記載されている基本手順に従って合成を行った。
c)TU-31、すなわち、「c-t-c」PtCl2(1-アダマンチルカルボキシラト)2(NH3,1-アダマンチルアミン)の合成。
合成を光の非存在下で行った。純度99%(2.1mmol)の「c-t-c」PtCl2(OH)2(NH3,1-アダマンチルアミン)1.0g、純度>99%の1,4-ジオキサン20ml、純度>99%(12.9mmol)のピリジン1.05ml及び純度>95%(10.5mmol)の1-アダマンタンカルボニルクロリド2.2gを、室温で3時間撹拌した。得られた混合物を室温で8時間放置した。沈殿させたTU-31を、ろ過により分離し、水及び1,4-ジオキサンにより繰り返し洗浄し、次いで、これを真空下で45℃で乾燥した。TU-31の収率は、1.43g(理論に基づいた86%)であり、純度は、(HPLCにより)98.6%であった。
Gelucire 50/13を含むTU-31、すなわち、「c-t-c」PtCl2(1-アダマンチルカルボキシラト)2(NH3,1-アダマンチルアミン)の医薬組成物の調製
TU-31 1.0g及びGelucire 50/13 4.0gを、65℃まで加熱して、黄色溶融液を創出した。この溶融液を、ポリプロピレン型に注ぎ、-18℃で1時間冷却した。次いで、固形組成物を、機械的に粒子にすり砕き、それぞれ、およそ5mgずつ秤量し、TU-31 20重量%を含有する。すり砕いた組成物を、ヒドロキシプロピルメチルセルロースカプセルに充てんし、その組成物の投与量1.0gは各カプセル当たり活性物質200mgを含有する。
調製された白金(IV)錯体のin vitro細胞毒性IC50の決定
用いられた化合物の略語:
DMSO:ジメチルスルホキシド
PBS:リン酸緩衝食塩水
XTT:2,3-ビス-(2-メトキシ-4-ニトロ-5-スルホフェニル)-2H-テトラゾリウム-5-カルボキサニリド塩
PMS:N-メチル-ジベンゾピラジンメチルスルフェート
FBS:ウシ胎児血清
NEAA:非必須アミノ酸
L-glu:L-グルタミン
DMEM:ダルベッコ変法イーグル培地(SigmaAldrich社)
PMS:フェナジンメトスルフェート
被験化合物:
表中の本明細書による白金(IV)錯体
用いられた腫瘍細胞系:
MCF-7乳腺癌
CaCo-2結腸腺癌
HL60前骨髄球性白血病(promyelotic leukaemia)
A2780/シス 卵巣癌シスプラチン抵抗性
LNCaP前立腺がん
COR-L23肺癌
培養の条件:37℃、5%CO2
増殖培地:DMEM、10%FBS、2mML-glut.、NEAA100×
被験化合物を、ウェル中で細胞系に加える直前にDMSOに溶解し、試験される濃度範囲までPBSにより希釈した。PBSを陽性対照として用い、最終濃度20%のDMSOを陰性対照として用いた。化合物のすべての濃度を3連でアッセイした。決定をそれぞれ2回行い、実験者に対して盲検化した。試験を96-ウェルプレートで実施した。腫瘍細胞の投与量は、ウェル当たり約2.5×104細胞であり、増殖培地の投与量は、ウェル当たり100μlであった。24時間後、増殖培地を吸引し、新鮮な増殖培地80μl及び異なる濃度の被験物質を含む溶液20μlを、ウェルに加えた。72時間後、培地を吸引し、XTT及びPMSを含有するOptimem試薬の溶液100μlをウェルに加えた。さらに4時間後、吸収度を450nmで測定した(参照は、630nmであった)。IC50としての結果を、物質の濃度の対数に対してプロットした細胞の基準化された生存率のグラフから評価した。
エカトリアルアミノリガンドA2の構造及び親油性における式(II)に従う白金(IV)錯体(R1基はメチルである)のIC50の相互依存性の試験
R1基がメチルであり、A2基が異なるアミノ-化合物である式(II)に従う白金(IV)錯体を、実施例1に従って調製した。腫瘍細胞系MCF-7(乳腺癌)及びCaCo-2(結腸腺癌)を用いた。IC50を実施例3における手順に従って測定した。市販のシスプラチン及びオキサリプラチンを参照化合物として用いた。これらの結果を表1に示す。
1. エカトリアルアミノリガンドA2のタイプ及び親油性とIC50との間で明らかな関係性が無い。
2. 最良の結果は、従来技術と一致する1-アダマンチルアミンエカトリアルリガンドを含む白金(IV)錯体を有する。
3. 1-アダマンチル骨格を3,5-ジメチル-1-アダマンチル骨格に変化させると、おそらく、1-アダマンチル基の対称性の低下により、抗腫瘍効果が低下する。ダイヤモンドのような1-アダマンタン骨格の高対称性は、白金(IV)錯体のこのタイプにおそらくは重要である。
4. 1-アダマンチル骨格を2-アダマンチル骨格に変化させると、おそらく、中心のPt(IV)-イオンの空間保護が低下することにより、抗腫瘍効果がやはり低下する。
5. 1-アダマンタン骨格と中心のPt(IV)-イオンとの間の距離が増大すると、おそらく中心のPt(IV)-イオンの空間保護が悪化することにより、抗腫瘍効果が低下する。
R1基の構造及び親油性における式(II)に従う白金(IV)錯体(エカトリアルアミノリガンドA2は、1-アダマンチルアミンである)のIC50の相互依存性の試験
1. R1基の脂肪族鎖中の炭素原子数間に明らかな関係性が無い。R1としてメチル基を有するLA-12はよい結果であったが、R1としてtert-ブチル基を有する白金錯体は、すべての被験脂肪族鎖の中で最良と思われ、従来技術と一致している(EP0328274、請求項1〜3を参照のこと)。
2. 1-アダマンチル基は、驚くべきことに、tert-ブチル基を含めたすべての被験R1基を上回っている。
より広範な腫瘍細胞系パネルにおける、TU-31、すなわち、式(III)の白金(IV)錯体の、対象白金(II)錯体オキサリプラチン及び一時的に最良の白金(IV)錯体LA-12のIC50との比較
被験腫瘍細胞系パネル:
MCF-7乳腺癌
CaCo-2結腸腺癌
HL60前骨髄球性白血病
A2780/シス 卵巣癌シスプラチン抵抗性
LNCaP前立腺がん
COR-L23肺癌
1. TU-31、すなわち、本発明による白金(IV)錯体は、6種の被験がん細胞系のうち4種において最良の白金(II)錯体オキサリプラチン及び一時的に最良の白金(IV)錯体LA-12を上回る。
2. オキサリプラチンは、腫瘍細胞系LNCaPにおいて結果が良好であり、白金錯体の親油性が高まると共に、抗腫瘍効果は低下する。
Claims (9)
- 式(III)
- 無極性の非プロトン性溶媒中で「シス-トランス-シス」PtCl2(OH)2(NH3,1-アダマンチルアミン)を1-アダマンチルカルボニルクロリド及びアミンと反応させることにより、請求項1に記載の白金(IV)錯体を調製するための方法。
- 無極性の非プロトン性溶媒が、1,4-ジオキサンである、請求項2に記載の方法。
- アミンが、ピリジン又はトリアルキルアミンである、請求項2又は3に記載の方法。
- ピリジン対1-アダマンチル-カルボニルクロリドの化学量論的な比が、ピリジン対1-アダマンチルカルボニルクロリド1〜2部対1部である、請求項2から4のいずれか一項に記載の方法。
- 腫瘍性疾患を治療する方法に用いるための、式(III)
- 請求項1に記載の白金(IV)錯体、及び少なくとも1種の親油性の薬学的に許容される添加剤を含有する、腫瘍性疾患の治療のための医薬組成物。
- 請求項1に記載の白金(IV)錯体の含有量が、組成物の総重量に対して0.5〜50重量%である、請求項7に記載の医薬組成物。
- 添加剤が、ステアロイルマクロゴール-32グリセリドである、請求項7又は8に記載の医薬組成物。
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JP7386972B2 (ja) | 2019-09-05 | 2023-11-27 | ブイユーエービー ファーマ エー.エス. | 実質的に増加した抗腫瘍効果を有する新規白金iv錯体 |
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