JP4267447B2 - 細胞増殖抑制作用を有するランタン化合物 - Google Patents
細胞増殖抑制作用を有するランタン化合物 Download PDFInfo
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- JP4267447B2 JP4267447B2 JP2003521240A JP2003521240A JP4267447B2 JP 4267447 B2 JP4267447 B2 JP 4267447B2 JP 2003521240 A JP2003521240 A JP 2003521240A JP 2003521240 A JP2003521240 A JP 2003521240A JP 4267447 B2 JP4267447 B2 JP 4267447B2
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- Prior art keywords
- alkylene
- general formula
- substituted
- sub
- alkyl
- 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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- 150000002604 lanthanum compounds Chemical class 0.000 title abstract description 3
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- 230000002401 inhibitory effect Effects 0.000 title description 2
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- 206010028980 Neoplasm Diseases 0.000 claims abstract description 7
- 238000011282 treatment Methods 0.000 claims abstract description 7
- 201000011510 cancer Diseases 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 15
- 229940079593 drug Drugs 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000001450 anions Chemical class 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims 5
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- 125000003545 alkoxy group Chemical group 0.000 claims 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 2
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims 2
- 125000003282 alkyl amino group Chemical group 0.000 claims 2
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
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- 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 3
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- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 description 2
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- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
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- 239000000305 astragalus gummifer gum Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
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- 239000003086 colorant Substances 0.000 description 2
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000004976 cyclobutylene group Chemical group 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
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- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
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- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229940116357 potassium thiocyanate Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/06—Aluminium compounds
- C07F5/069—Aluminium compounds without C-aluminium linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyridine Compounds (AREA)
Description
式中、Rは一般式(A)の基であり、
式中、
R1及びR3は互いに独立して、それぞれ置換または非置換のC1-C10アルキル、C3-C6シクロアルキル、C3-C6シクロアルケニル、C2-C10アルケニル、C6-C14アリール及び複素環、並びに水素からなる群より選択され;
R2はそれぞれ置換または非置換のC1-C6アルキレン、C3-C6シクロアルキレン、C3-C6シクロアルケニレン、C2-C6アルケニレン、C6-C14アリーレン、または複素環であり;並びに
R1及びR2並びに/またはR2及びR3は、適用可能な場合には、さらに窒素原子を含むことができる複素環を形成することができ;
Yは生理学上許容される陰イオンであり;
i及びnは互いに独立して、1以上の自然数であり;
ただし、Rは
ではない。
塩化物、臭化物、リン酸塩、炭酸塩、硝酸塩、過塩素酸塩、硫酸塩、クエン酸塩、乳酸塩、酒石酸塩、マレイン酸塩、フマル酸塩、マンデル酸塩、安息香酸塩、アスコルビン酸塩、ケイ皮酸塩、グリコール酸塩、メタンスルホン酸塩、ギ酸塩、マロン酸塩、ナフタリン-2-スルホン酸塩、サリチル酸塩、及び/または酢酸塩。
式中、Rは一般式(A)の基であり、
式中、
R1及びR3は互いに独立して、それぞれ置換または非置換のC1-C10アルキル、C3-C6シクロアルキル、C3-C6シクロアルケニル、C2-C10アルケニル、C6-C14アリール及び複素環、並びに水素からなる群より選択され;
R2はそれぞれ置換または非置換のC1-C6アルキレン、C3-C6シクロアルキレン、C3-C6シクロアルケニレン、C2-C6アルケニレン、C6-C14アリーレン、または複素環であり;並びに
R1及びR2、並びに/またはR2及びR3は、適用可能な場合には、さらに窒素原子を含むことができる複素環を形成することができ;
Yは生理学上許容される陰イオンであり;並びに
i及びnは互いに独立して、1以上の自然数である。
式中、Rbは一般式(B)の基であり;
式中、
R1'およびR3'は置換または非置換のC1-C10アルキル、C3-C6シクロアルキル、C2-C10アルケニル、C6-C14アリールもしくは複素環、または水素であり;
R2'はそれぞれ置換または非置換のC1-C6アルキレン、C3-C6シクロアルキレン、C2-C6アルケニレン、C6-C14アリーレンまたは複素環であり;並びに
R1'及びR2'またはR2'及びR3'は、適用可能な場合には、さらに窒素原子を含むことができる複素環を形成することができ;並びに
そしてYbは金属ハロゲン、ハロゲン、擬ハロゲン、HCO3またはR'COOであり、ここでR'はC1-C6アルキル、C2-C6アルケニルまたはアリールであり、それぞれ、置換または非置換でありえる。
R1'及びR3'は好ましくはC1-C5アルキル、特にメチル、エチル、またはプロピルである。また、R1'及びR3'は好ましくはシクロブチル、シクロプロピルまたはC2-C5アルケニル、特にエテニル、プロペニルまたはブテニルである。さらに、R1'及びR3'はベンジルまたはピリジルでありうる。
R1'及びR3'は、特にR1'及びR2'またはR2'及びR3'が複素環を形成するときには、メチル、エチルまたはプロピルで置換されうる。
R2'は好ましくはC1-C5アルキレン、特にメチレン、エチレン、プロピレンである。また、R1'及びR3'は好ましくはシクロブチレン、シクロプロピレン、またはC2-C5アルケニレン、特にエテニレン、プロペニレンまたはブテニレンである。さらに、R2'はベンジレンまたはピリジレンでありうる。
R2'は、特にR1'及びR2'またはR2'及びR3'が複素環を形成するときには、メチル、エチルまたはプロピルで置換されうる。
[トリ(1,10-フェナントロリン)ランタン(III)]トリチオシアネートの合成
[トリ(1,10-フェナントロリン)ランタン(III)]トリチオシアネートの製造は、三塩化ランタン六水和物(LaCl36H2O)の0.05Mエタノール溶液をチオシアン酸カリウム(KSCN)の0.053Mエタノール溶液とモル比1:4で混合して行われる。生成した塩化カリウム沈殿物をろ過した後、そのろ過液に1,10-フェナントロリン一水和物の0.1Mエタノール溶液を、攪拌しながらゆっくり滴下し加える。その生成した純粋な結晶生成物をろ過し、エタノールで数回洗い、硫酸カルシウム上で真空で乾燥させる。
[トリ(1,10-フェナントロリン)ランタン(III)]トリチオシアネートの細胞増殖抑制活性
50を超えるヒト腫瘍細胞系における48時間サルファローダミンBアッセイ法(sulphurhodamine B-assay)において、下記のパラメーターで良好な効果が見出された。
平均値Gl50: 1.29μmol/l 1.10μg/ml
平均値TGl: 13.2μmol/l 11.3μg/ml
平均値LC50: 55.0μmol/l 46.9μg/ml
平均値IC50: 4.21μmol/l 3.60μg/ml
平均値IC70: 7.90μmol/l 6.74μg/ml
平均値IC90: 14.2μmol/l 12.1μg/ml
Claims (4)
- フェナントロリン残基またはビピリジン残基のそれぞれが、ヒドロキシル、アミノ、 -SO 3 H 、ハロゲン、 C 1 -C 4 アルキル、 C 2 -C 4 アルケニル、 C 3 -C 6 シクロアルキル、 C 3 -C 6 シクロアルケニル、 C 1 -C 6 アリール、 C 1 -C 4 アルコキシ、 C 1 -C 4 アルコキシ -C 1 -C 4 アルキレン、 C 1 -C 4 アルキルメルカプト、 C 1 -C 4 アルキルメルカプト -C 1 -C 4 アルキレン、ホルミル、カルボキシル、 C 1 -C 4 アルコキシカルボニル、 C 1 -C 4 アルコキシカルボニル -C 1 -C 4 アルキレン、ジ C 1 -C 4 アルキルアミノ、ジ C 1 -C 4 アルキルアミノ -C 1 -C 4 アルキレン、ジ C 1 -C 4 アルキルアミノカルボニル、ジ C 1 -C 4 アルキルアミノカルボニル -C 1 -C 4 アルキレンで置換されていてもよい、請求項1記載の薬剤。
- 請求項 1 記載の一般式( I )の化合物の、癌の予防及び/または治療のための薬剤の製造における、使用。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE10138538A DE10138538C2 (de) | 2001-08-06 | 2001-08-06 | Tumorhemmende Lanthanverbindungen |
PCT/EP2002/008770 WO2003016318A1 (de) | 2001-08-06 | 2002-08-06 | Tumorhemmende lanthanverbindungen |
Publications (3)
Publication Number | Publication Date |
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JP2005500383A JP2005500383A (ja) | 2005-01-06 |
JP2005500383A5 JP2005500383A5 (ja) | 2005-11-17 |
JP4267447B2 true JP4267447B2 (ja) | 2009-05-27 |
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US (1) | US7122643B2 (ja) |
EP (1) | EP1414830B1 (ja) |
JP (1) | JP4267447B2 (ja) |
AT (1) | ATE342907T1 (ja) |
CA (1) | CA2456551C (ja) |
DE (2) | DE10138538C2 (ja) |
WO (1) | WO2003016318A1 (ja) |
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US20050043233A1 (en) | 2003-04-29 | 2005-02-24 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis |
WO2010138686A1 (en) * | 2009-05-29 | 2010-12-02 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Mdri-inverse agents |
US7924203B2 (en) * | 2009-06-12 | 2011-04-12 | Analog Devices, Inc. | Most significant bits analog to digital converter, and an analog to digital converter including a most significant bits analog to digital converter |
-
2001
- 2001-08-06 DE DE10138538A patent/DE10138538C2/de not_active Expired - Fee Related
-
2002
- 2002-08-06 DE DE50208503T patent/DE50208503D1/de not_active Expired - Lifetime
- 2002-08-06 JP JP2003521240A patent/JP4267447B2/ja not_active Expired - Fee Related
- 2002-08-06 EP EP02767331A patent/EP1414830B1/de not_active Expired - Lifetime
- 2002-08-06 CA CA2456551A patent/CA2456551C/en not_active Expired - Fee Related
- 2002-08-06 AT AT02767331T patent/ATE342907T1/de active
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Also Published As
Publication number | Publication date |
---|---|
US20040176346A1 (en) | 2004-09-09 |
CA2456551A1 (en) | 2003-02-27 |
EP1414830B1 (de) | 2006-10-18 |
DE10138538A1 (de) | 2003-02-27 |
DE10138538C2 (de) | 2003-12-04 |
JP2005500383A (ja) | 2005-01-06 |
ATE342907T1 (de) | 2006-11-15 |
US7122643B2 (en) | 2006-10-17 |
DE50208503D1 (de) | 2006-11-30 |
EP1414830A1 (de) | 2004-05-06 |
WO2003016318A1 (de) | 2003-02-27 |
CA2456551C (en) | 2013-02-19 |
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