JP2017533185A - 癌の治療のための治療薬としての4−オキソ−n−(4−ヒドロキシフェニル)レチナミド誘導体 - Google Patents
癌の治療のための治療薬としての4−オキソ−n−(4−ヒドロキシフェニル)レチナミド誘導体 Download PDFInfo
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- JP2017533185A JP2017533185A JP2017515241A JP2017515241A JP2017533185A JP 2017533185 A JP2017533185 A JP 2017533185A JP 2017515241 A JP2017515241 A JP 2017515241A JP 2017515241 A JP2017515241 A JP 2017515241A JP 2017533185 A JP2017533185 A JP 2017533185A
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000001946 anti-microtubular Effects 0.000 description 1
- 230000002927 anti-mitotic effect Effects 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- SJSWRKNSCWKNIR-UHFFFAOYSA-N azane;dihydrochloride Chemical compound N.Cl.Cl SJSWRKNSCWKNIR-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004305 biphenyl Chemical group 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000025084 cell cycle arrest Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 210000003793 centrosome Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- XBPOBCXHALHJFP-UHFFFAOYSA-N ethyl 4-bromobutanoate Chemical compound CCOC(=O)CCCBr XBPOBCXHALHJFP-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000007479 molecular analysis Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- MECRKILGNPUEFQ-UHFFFAOYSA-N o-(2-aminoethyl)hydroxylamine Chemical compound NCCON MECRKILGNPUEFQ-UHFFFAOYSA-N 0.000 description 1
- VAWHTWXBNQFBAJ-UHFFFAOYSA-N o-(2-aminoethyl)hydroxylamine;dihydrochloride Chemical compound Cl.Cl.NCCON VAWHTWXBNQFBAJ-UHFFFAOYSA-N 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 201000002513 peritoneal mesothelioma Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 230000001855 preneoplastic effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 238000012342 propidium iodide staining Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000006950 reactive oxygen species formation Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 208000016691 refractory malignant neoplasm Diseases 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000003938 response to stress Effects 0.000 description 1
- 229960003471 retinol Drugs 0.000 description 1
- 235000020944 retinol Nutrition 0.000 description 1
- 239000011607 retinol Substances 0.000 description 1
- 150000004609 retinol derivatives Chemical class 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000020347 spindle assembly Effects 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 231100000338 sulforhodamine B assay Toxicity 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 150000002266 vitamin A derivatives Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/32—Oximes
- C07C251/50—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals
- C07C251/60—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/20—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by carboxyl groups or halides, anhydrides, or (thio)esters thereof
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- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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- Hematology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Xは、−COOHまたはNH2、好ましくは、−COOHであり;
Rは、直鎖もしくは分岐鎖のC1−C10アルキレン鎖、好ましくは、直鎖もしくは分岐鎖のC1−C6アルキレン鎖、より好ましくは、−CH2であり;
R1は、H、直鎖もしくは分岐鎖のC1−C10アルキル、好ましくは、C1−C6、アリール、またはR2CO−であり、ここで、R2は、直鎖もしくは分岐鎖のC1−C10アルキル、好ましくは、C1−C6、またはアリールである。
化合物1a:
ナトリウム2−[3−[(1E,3E,5E,7E)−9−(4−ヒドロキシアニリノ)−3,7−ジメチル−9−オキソ−ノナ−1,3,5,7−テトラエニル]−2,4,4−トリメチル−シクロヘキサ−2−エン−1−イリデン]アミノ]オキシアセテート(ナトリウム4−アミノオキシアセテート−4−HPR);
化合物1b(LOM1098):
ナトリウム2−[3−[(1E,3E,5E,7E)−9−(4−ヒドロキシアニリノ)−3,7−ジメチル−9−オキソ−ノナ−1,3,5,7−テトラエニル]−2,4,4−トリメチル−シクロヘキサ−2−エン−1−イリデン]アミノ]オキシブチレートまたはブタノエート(ナトリウム4−アミノオキシブチレート−4−HPR);
化合物1c(LOM1133):
ナトリウム2−[3−[(1E,3E,5E,7E)−9−(4−ヒドロキシアニリノ)−3,7−ジメチル−9−オキソ−ノナ−1,3,5,7−テトラエニル]−2,4,4−トリメチル−シクロヘキサ−2−エン−1−イリデン]アミノ]オキシヘキサノエート(ナトリウム4−アミノオキシヘキサノエート−4−HPR);
スキーム1:
スキーム2:
スキーム4
50%EtOH水溶液中、NH2OCH2COOH・1/2HCl(3a、410mg、3.75ミリモル)およびCH3COONa(166mg、2.39ミリモル)の溶液17mLを、EtOH(11mL)中、化合物2(4−オキソ−4−HPR、700mg、1.73ミリモル)の懸濁液に加えた。この反応物を室温で24時間、撹拌下で維持した。その後、溶媒を低圧で除去し、残渣を冷H2O(20mL)で希釈し、粉砕し、最後に、真空下で濾過した。739mg(1.54ミリモル)の化合物4a(4−(カルボキシメトキシイミノ)フェンレチニド)を得た。収率:89%。
50%EtOH水溶液中、3b(17mg、0.11ミリモル)およびCH3COONa(5mg、0.07ミリモル)の溶液0.5mLを、EtOH(0.5mL)中、化合物2(20mg、0.05ミリモル)の懸濁液に加えた。この反応物を室温で24時間、撹拌下で維持した。溶媒を低圧で除去し、残渣を酢酸エチルで溶解し、溶液をH2Oで洗浄し、Na2SO4で乾燥させた。次いで、粗生成物を、CH2Cl2:CH3OH 95:5での分取クロマトグラフィーにより精製した。20mg(0.04ミリモル)の
化合物4bを得た。
エチル4−(1,3−ジオキソ−1,3−ジヒドロイソインドール−2−イルオキシ)ブチレート。
N−ヒドロキシフタルイミド(1.11g、6.64ミリモル)およびK2CO3(1.84g、13.28ミリモル)を、無水DMF(6.5mL)中、4−ブロモ酪酸エチル(1mL、6.64ミリモル)の溶液に加えた。この溶液を室温で一晩撹拌下に置いた。溶媒を蒸発させた後、反応混合物を酢酸エチルで溶解し、NaCl飽和溶液で洗浄した。有機相をNa2SO4で乾燥させ、溶媒を蒸発させた。生成物をイソプロパノールから結晶化させた(1.67g)。収率:91%。
エタノール(5.8mL)およびH2O(5.8mL)中、LiOH・H2O(0.8g、19.1ミリモル)の溶液を、THF(18mL)中、4−(1,3−ジオキソ−1,3−ジヒドロイソインドール−2−イルオキシ)−酪酸エチル(1.65g、5.97ミリモル)の溶液に加え、この溶液を室温で一晩反応させた。溶媒を蒸発させた後、6N HCl溶液(6mL)を加え、粗生成物を酢酸エチルで抽出した。合わせた有機相をNaCl飽和溶液で洗浄し、Na2SO4で乾燥させた。その後、生成物を酢酸エチルから結晶化させた。1.1gの生成物を得た。収率:74%。
50%EtOH水溶液中、3c(27mg、0.15ミリモル)およびCH3COONa(7mg、0.1ミリモル)の溶液0.65mLを、EtOH(0.56mL)中、化合物2(30mg、0.07ミリモル)の懸濁液に加えた。この反応物を室温で24時間撹拌下に置いた。溶媒を低圧で除去し、残渣を酢酸エチルで溶解し、溶液をH2Oで洗浄し、Na2SO4で乾燥させた、次いで、粗生成物を、CH2Cl2:CH3OH 95:5での分取クロマトグラフィーにより精製した。16mg(0.03ミリモル)の化合物4c(4−(カルボキシペントキシイミノ)フェンレチニド)を得た。収率:43%
6−(1,3−ジオキソ−1,3−ジヒドロ−イソインドール−2−イルオキシ)−ヘキサン酸。 N−ヒドロキシ−フタルイミド(2.44g、15ミリモル)およびトリエチルアミン(6.3ml、45ミリモル)を、無水DMF(30mL)中、6−ブロモヘキサン酸(3g、15ミリモル)の溶液に加えた。この溶液を周囲温度で48時間、撹拌下に置いた。生成した沈殿物を濾過し、溶媒を蒸発させた後、粗生成物を、Sephadex LH−20でヘキサン:アセトン:エチルエーテルの3:1:1混合物を用いて精製した。2.2gの生成物を得た。収率:53%。
エタノール(500μL)中、化合物2(23mg、0.05ミリモル(mmoli))の懸濁液を、50%エタノール水溶液(500μL)中、2−アミノエトキシアミン二塩酸塩(16mg、0.11ミリモル)および無水酢酸ナトリウム(6mg、0.07ミリモル)の溶液で処理した。得られた混合物を室温で24時間撹拌した。溶媒を減圧下で除去し、粗生成物をCH3OH/H2O 9:1での分取RP−18クロマトグラフィーにより精製し、18mgの化合物1dを得た。収率:76%。融点134℃。
in vitro試験
種々の腫瘍細胞株に対する様々な化合物1a〜cの(単独療法および併用療法の両方の)抗増殖活性を、72時間の処理後にスルホローダミンBアッセイにより評価し、単独療法については、増殖を50%阻害することができる用量(IC50)を算出し(結果は表1および表3にまとめる)、併用療法については、相乗作用/拮抗作用屈折率としてケルン指数(Kern Index)(KI)を決定した(結果は図2に示している)。
塩1aの血漿レベルを評価するために、4−オキソ−4−HPR(120mg/kg)および塩1a(ナトリウム4−アミノオキシアセテート−4−HPR)(60mg/kgおよび100mg/kg)を、ヌードマウスに連続4日間(1日1回)i.p.投与し、最後の投与から5時間後にHPLCにより血漿レベルを評価した(結果は表2にまとめる)。
塩1a:5%DMSO、H2O。
Claims (15)
- 下式(I)の化合物またはその薬学上許容される塩:
Xは、−COOHまたはNH2であり;
Rは、直鎖もしくは分岐鎖のC1−C10アルキレン鎖であり;かつ
R1は、H、直鎖もしくは分岐鎖のC1−C10アルキル、アリール、またはR2CO−であり、ここで、R2は、直鎖もしくは分岐鎖のC1−C10アルキルである]。 - Xは−COOHである、請求項1に記載の式(I)の化合物またはその薬学上許容される塩。
- アルカリ金属もしくはアルカリ土類金属、有機アミンまたはアミノ酸との、請求項2に記載の式(I)の化合物の塩。
- ナトリウム、カリウム、リチウム、カルシウムまたはマグネシウムとの、請求項3に記載の式(I)の化合物の塩。
- XはNH2である、請求項1に記載の式(I)の化合物またはその薬学上許容される塩。
- Rは直鎖もしくは分岐鎖のC1−C6アルキレン鎖である、請求項1〜5のうちいずれか一項に記載の式(I)の化合物またはその薬学上許容される塩。
- R1はHである、請求項1〜6のうちいずれか一項に記載の式(I)の化合物またはその薬学上許容される塩。
- ナトリウム2−[3−[(1E,3E,5E,7E)−9−(4−ヒドロキシアニリノ)−3,7−ジメチル−9−オキソ−ノナ−1,3,5,7−テトラエニル]−2,4,4−トリメチル−シクロヘキサ−2−エン−1−イリデン]アミノ]オキシアセテート(化合物1a);
ナトリウム2−[3−[(1E,3E,5E,7E)−9−(4−ヒドロキシアニリノ)−3,7−ジメチル−9−オキソ−ノナ−1,3,5,7−テトラエニル]−2,4,4−トリメチル−シクロヘキサ−2−エン−1−イリデン]アミノ]オキシブチレート(化合物1b);
ナトリウム2−[3−[(1E,3E,5E,7E)−9−(4−ヒドロキシアニリノ)−3,7−ジメチル−9−オキソ−ノナ−1,3,5,7−テトラエニル]−2,4,4−トリメチル−シクロヘキサ−2−エン−1−イリデン]アミノ]オキシヘキサノエート(化合物1c)
からなる群から選択される、請求項1に記載の式(I)の化合物。 - 医薬としての使用のための、請求項1〜8のうちいずれか一項に記載の式(I)の化合物またはその薬学上許容される塩。
- 抗腫瘍薬または化学的予防薬としての使用のための、請求項1〜8のうちいずれか一項に記載の式(I)の化合物またはその薬学上許容される塩。
- 固形または血液系の(転移性および非転移性)腫瘍の治療における、請求項10に記載の使用のための式(I)の化合物またはその薬学上許容される塩。
- 乳癌、卵巣癌、前立腺癌、結腸直腸癌、中皮腫および他の肉腫、神経芽腫、リンパ腫、白血病および黒色腫の治療における、請求項11に記載の使用のための式(I)の化合物またはその薬学上許容される塩。
- 請求項1〜8のうちいずれか一項に記載の式(I)の化合物と、抗有糸分裂薬、標準的な化学療法に使用される化合物、天然もしくは合成のレチノイド類、エピジェネティック薬、または(腫瘍性もしくは非腫瘍性)標的特異的医薬からなる群から選択される1種以上の医薬との組合せ。
- 式(I)の化合物および前記のさらなる医薬は、同時にまたは任意の順序で逐次的に投与される、請求項13に記載の組合せ。
- 有効成分としての請求項1〜8のうちいずれか一項に記載の式(I)の化合物の少なくとも1つ、および薬学上許容される担体および/または溶出剤を含む医薬組成物。
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ITMI2014A001603 | 2014-09-17 | ||
ITMI20141603 | 2014-09-17 | ||
PCT/EP2015/071178 WO2016042010A1 (en) | 2014-09-17 | 2015-09-16 | 4-oxo-n-(4-hydroxyphenyl)retinamide derivatives as therapeutic agents for the treatment of cancer |
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US10093621B2 (en) | 2018-10-09 |
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EP3194360B1 (en) | 2018-06-27 |
CN107001258A (zh) | 2017-08-01 |
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CN107001258B (zh) | 2019-03-19 |
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HUE039947T2 (hu) | 2019-02-28 |
DK3194360T3 (en) | 2018-09-03 |
AU2015316886B2 (en) | 2019-02-21 |
US20170253560A1 (en) | 2017-09-07 |
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