JP5474820B2 - アルテミシニンの二量体誘導体、および抗癌療法における用途 - Google Patents
アルテミシニンの二量体誘導体、および抗癌療法における用途 Download PDFInfo
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- JP5474820B2 JP5474820B2 JP2010538786A JP2010538786A JP5474820B2 JP 5474820 B2 JP5474820 B2 JP 5474820B2 JP 2010538786 A JP2010538786 A JP 2010538786A JP 2010538786 A JP2010538786 A JP 2010538786A JP 5474820 B2 JP5474820 B2 JP 5474820B2
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- 125000002757 morpholinyl group Chemical group 0.000 description 1
- PQYGBJHVVYREGU-UHFFFAOYSA-N n,n'-dimethyl-n'-[3-(methylamino)propyl]propane-1,3-diamine Chemical compound CNCCCN(C)CCCNC PQYGBJHVVYREGU-UHFFFAOYSA-N 0.000 description 1
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- CPQCSJYYDADLCZ-UHFFFAOYSA-N n-methylhydroxylamine Chemical compound CNO CPQCSJYYDADLCZ-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- ZJLMKPKYJBQJNH-UHFFFAOYSA-N propane-1,3-dithiol Chemical compound SCCCS ZJLMKPKYJBQJNH-UHFFFAOYSA-N 0.000 description 1
- SXYFKXOFMCIXQW-UHFFFAOYSA-N propanedioyl dichloride Chemical compound ClC(=O)CC(Cl)=O SXYFKXOFMCIXQW-UHFFFAOYSA-N 0.000 description 1
- 125000006410 propenylene group Chemical group 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- ZISJLHQNEVGTIU-RFEYTNPVSA-M sodium 4-oxo-4-[[(1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecan-10-yl]oxy]butanoate Chemical compound [Na+].C[C@@H]1CC[C@H]2[C@@H](C)[C@H](OC(=O)CCC([O-])=O)O[C@@H]3O[C@@]4(C)CC[C@@H]1[C@@]23OO4 ZISJLHQNEVGTIU-RFEYTNPVSA-M 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 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
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000006068 taste-masking agent Substances 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
- ZFQWJXFJJZUVPI-UHFFFAOYSA-N tert-butyl n-(4-aminobutyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCCN ZFQWJXFJJZUVPI-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- CXVCSRUYMINUSF-UHFFFAOYSA-N tetrathiomolybdate(2-) Chemical compound [S-][Mo]([S-])(=S)=S CXVCSRUYMINUSF-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- 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
- 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
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
B1およびB2は同一かまたは異なっており、C=O、CHOH、およびCH2から、有利にはC=OおよびCH2から選択され、好ましくはそれぞれCH2基を表し、
Aは、−S−、−S−S−、−SO−、−SO2−、−Se−Se−、−O−P(O)(OR1)−O−、−NR2−、−O−R4−、および−O−NR2−から、好ましくは−S−、−S−S−、−SO−、−SO2−、−Se−Se−、−O−P(O)(OR1)−O−、および−O−NR2−から選択される二価の基を表すか(ここで、
R1は、水素、炭素数1〜6のアルキル基、または置換されていてもよいアリール基を表し、
R2は、水素、NH2基で置換されていてもよいC1−C6のアルキル基、C2−C6のアルケニル基、C2−C6のアルキニル基、C3−C8のシクロアルキル基、アリール−(C1−C6)−アルキレン基、置換されていてもよいアリール基、または、−COR3基、−CO2R3基、もしくは−SO2R3基を表し、
R3は、水素、C1−C6のアルキル基、C3−C8のシクロアルキル基、アリール−(C1−C6)−アルキレン基、または置換されていてもよいアリール基を表し、
R4は、C1−C6のアルキレン基、C2−C6のアルケニレン基、またはC2−C6のアルキニレン基を表す)、または
X−Y−Z基を表す(ここで、
XおよびZは同一かまたは異なっており、O、S、NR2(R2は上記定義のとおりである)、および、B1またはB2に結合した窒素原子を少なくとも1つ含んでなる複素環から選択され、
Yは、C1−C6のアルキレン基、C3−C8のシクロアルキレン基、およびC2−C6のアルケニレン基、
−CO−Y1−CO基(Y1は、NHR2基(R2は上記定義のとおりである)で置換されていてもよいC1−C6のアルキレン基を表し、好ましくは、Y1は−(CH2)q−基(qは1、2、3、または4の整数を表す)を表す)、
式−[(CH2)n−NR2−(CH2)m]p−のポリアミン基(R2は上記定義のとおりであり、n、m、およびpは互いに独立して1、2、3、または4の整数を表す)、ならびに
−(CO)r−(CH2)s−Y2−(CH2)t−(CO)u−基(ここで、
rおよびuは互いに独立して0または1の整数を表し、
sおよびtは互いに独立して0、1、2、3、または4の整数を表し、r、uがそれぞれ0である場合には、s、tはそれぞれ0であることはできず(s, respectively t, cannot be equal to 0 if r, respectively u, is equal to 0)、
Y2は−S−、−S−S−、−SO−、−SO2−、−Se−Se−、−O−P(O)(OR1)−O−(R1は上記定義のとおりである)、−NR2−(R2は上の定義のとおりである)、C3−C8のシクロアルキレン基、および置換されていてもよい芳香族複素環または芳香族環から選択される)から選択される)]。
本発明において、「C3−C8のシクロアルキル」基は、例えばシクロプロピル基、シクロヘキシル基、シクロペンチル基等のように、3〜8個の炭素原子を含む飽和環式炭化水素基を意味する。
好ましくは、YはC2−C6のアルケニレン基を表さない。
−CO−Y1−CO−基(Y1は上記定義のとおりである)、または
−CO−(CH2)S−Y2−(CH2)t−CO−基(s、t、およびY2は上記定義のとおりである)
を表す。
B1およびB2は同一であり、それぞれCH2基を表すのが好ましい。
Xおよび/またはZは複素環を表し、および/または、
Yは−(CO)r−(CH2)s−Y2−(CH2)t−(CO)u−基を表し、この場合のr、s、t、およびuは上記定義のとおりであり、Y2は、置換されていてもよい芳香族複素環を表す。
すなわち、溶解性を向上させることができる塩基付加塩を本発明の分子によって得てよい。
(i)上記定義した式(I)の化合物のうち少なくとも1種類と、
(ii)癌の治療に特に有用な有効成分の少なくとも1種類と、
を含んでなる、同時に、別々に、または時間的に間隔を置いて使用する(spread out over time use)ための合剤としての医薬組成物である。
また、本発明は、医薬、具体的には癌の治療を目的とした医薬を作るための上記組成物として、ある組成物を使用することにも関する。
B1およびB2はそれぞれCH2基を表し、
AはX−Y−Z基を表し、この場合のX、Y、およびZは上記定義のとおりである)の化合物の製造方法であって、
2モル当量の下式(II)の化合物と、少なくとも1モル当量の下式(III)の化合物とをカップリングすることを含んでなる方法である:
Z2−Y−Z3 (III)
(式中、Z2およびZ3は互いに独立してOH基、SH基、もしくはNHR2基、または、NH基を含む複素環を表し、YおよびR2は、上記定義のとおりである)。
B1およびB2はそれぞれCH2基を表し、
AはX−Y−Z基を表し、
XおよびZは同一であり、O、S、NR2(R2は上記定義のとおりである)から選択され、
Yは上記定義のとおりである)の化合物の製造方法であって、
2モル当量の下式(IV)の化合物と、少なくとも1モル当量の下式(V)の化合物とをカップリングすることを含んでなる方法である:
Z5−Y−Z6 (V)
(式中、Z5およびZ6は互いに独立して、塩素または臭素のようなハロゲン原子、好ましくは塩素を表し、Yは上記定義のとおりである)。
AはX−Y−Z基を表し、
XおよびZは同一であり、O、S、およびNR2(R2は上記定義のとおりである)から選択され、
Yは−CO−Y1−CO−または−CO−(CH2)s−Y2−(CH2)t−CO−(Y1、Y2、s、およびtは上記定義のとおりである)を表す) の化合物の製造方法であって、
2モル当量の下式(IV)の化合物と、少なくとも1モル当量の下式(VI)の化合物とをカップリングすることを含んでなる方法である:
HO−Y−OH (VI)
(式中、Yは上記定義のとおりである)。
この反応は、溶媒としてのジクロロメタン中にて、特に室温で行ってよい。
AはX−Y−Z基(X、Y、およびZは上で定義したようなものである)を表す)の化合の製造方法であって、
2モル当量の下式(VII)の化合物と、少なくとも1モル当量の下式(III)の化合物とをカップリングすることを含んでなる方法である:
Z2−Y−Z3 (III)
(式中、Z2およびZ3は互いに独立してOH基、SH基、もしくはNHR2基、またはNH基を含む複素環を表し、YおよびR2は上記定義のとおりである)。
共通の方法A:ジメチルスルホキシド(c=0.25)にNaH(60%油性、1eq.)を懸濁させた懸濁液に、リンカー(0.5eq.)をジメチルスルホキシド(c=0.5)に溶かした溶液を加える。30分、室温で攪拌後、臭素化誘導体A(1eq.)とヨウ化カリウム(0.1eq.)を加える。反応混合物を室温で(0.5〜3時間)攪拌してから、酢酸エチルで希釈する。有機相を飽和塩化ナトリウム溶液で洗浄してから、硫酸マグネシウムで乾燥する。濾過後、溶媒を減圧下で蒸発させる。得られた粗生成物をシリカゲルクロマトグラフィー(シクロヘキサン/酢酸エチル、90:10)で精製する。
共通の方法B:アセトニトリル(c=1)にK2CO3(0.5eq.)を懸濁させた懸濁液に、ジアミンリンカー(0.5eq.)を加える。5分間、室温で攪拌後、臭素化誘導体A(1eq.)を加える。反応混合物を室温で(18〜48時間)攪拌してから、ジクロロメタンで希釈する。有機相を飽和炭酸水素ナトリウム溶液で洗浄してから、硫酸マグネシウムで乾燥する。濾過後、溶媒を減圧下で蒸発させる。得られた粗生成物をシリカゲルクロマトグラフィー(シクロヘキサン/酢酸エチル、75:25)で精製する。
共通の方法C:ジクロロメタン(c=0.04)に中間体B(1eq.)を溶かした溶液に、4−ジメチルアミノピリジン(1.15eq.)を加える。この混合物を0℃まで冷却してから、アシルビス−クロリド(0.5eq.)を加える。室温に戻した後、反応混合物を16時間攪拌してから、溶媒を減圧下で蒸発させる。得られた粗生成物をシリカゲルクロマトグラフィー(シクロヘキサン/酢酸エチル、90:10)で精製する。
共通の方法D:テトラヒドロフラン(c=0.045)に中間体B(1eq.)を溶かした0℃の溶液に、ヘキサメチルジシラザンナトリウム(2M THF溶液、1eq.)を加える。混合物を0℃で10分間、攪拌してから、ジクロロホスフェート(0.5eq.)を加える。0℃で1時間後、反応混合物を加水分解させてから、酢酸エチルで抽出する。有機相を飽和塩化ナトリウム溶液で洗浄し、硫酸マグネシウムで乾燥し、濾過してから、減圧下で濃縮する。得られた粗生成物をシリカゲルクロマトグラフィー(シキロヘキサン/酢酸エチル、勾配:90:10〜80:20)で精製する。
共通の方法E:臭素化誘導体A(1eq.)をアセトニトリル(c=1)に溶かした溶液に、アミノ試薬(0.5eq.)を加えてから、K2CO3(1eq.)を加える。反応混合物を室温で(18〜48時間)攪拌してから、飽和炭酸水素ナトリウム溶液で希釈し、続いて、酢酸エチルで抽出する。有機相を飽和NaCl溶液で洗浄してから、硫酸マグネシウムで乾燥する。濾過後、溶媒を減圧下で蒸発させる。粗生成物をシリカゲルクロマトグラフィー(シクロヘキサン:酢酸エチル 75:25)で精製する。
共通の方法F:中間体E(1eq.)をジクロロメタン(c=0.04)に溶かした溶液に、トリエチルアミン(1eq.)を加える。5分間、室温で攪拌後、アシルビス−クロリド(0.5eq.)を加える。反応混合物を20時間攪拌してから、水洗し、酢酸エチルで抽出する。有機相をデカンテーションし、硫酸マグネシウムで乾燥してから、減圧下で蒸発させる。得られた粗生成物をシリカゲルクロマトグラフィー(シクロヘキサン/酢酸エチル、65:35)で精製する。
中間体F(0.103g、0.25mモル、1eq.)と中間体H(0.094g、0.25mモル、1eq.)との混合物を900℃で4時間、封管中で加熱する。室温に戻した後、反応媒質をシリカゲルクロマトグラフィー(シクロヘキサン/酢酸エチル、90:10〜75:25)で精製し、低極性化合物32および化合物33を単離する(合計収率48%、白色粉末、化合物32は0.032g、化合物33は0.060g)。
共通の方法G:カルボン二酸試薬(0.12mモル、0.5eq.)をジクロロメタン(5mL)に溶かした溶液に、1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミドクロルハイドレート(EDCI)(0.067g、0.91mモル、3eq.)とヒドロキシベンゾトリアゾール(HOBt)(0.047g、0.91mモル、3eq.)を加える。30分間、室温で攪拌後、中間体E(0.087g、0.25mモル、1eq.)をジクロロメタン(5mL)に溶かした溶液を加える。反応混合物を2時間、室温で攪拌する。水を加えた後、混合物をジクロロメタンで抽出する。有機相を飽和塩化ナトリウム溶液で洗浄してから、硫酸マグネシウムで乾燥する。濾過後、溶媒を減圧下で蒸発させる。粗生成物をシリカゲルクロマトグラフィー(ジクロロメタン/メタノール、96:4)で精製する。
中間体B(0.13g、0.37mモル)をDMSO(3mL)に溶かした溶液に、0.022g(0.55mモル、2.2eq.)のNaH(60%油性懸濁液)を加える。10分間、室温で攪拌後、2,6−ビス(クロロメチル)ピリジン(0.044g、0.025mモル)を加える。反応媒質を6時間攪拌してから水洗し、酢酸エチルで抽出する。有機相を飽和塩化ナトリウム溶液で洗浄してから、硫酸マグネシウムで乾燥する。濾過後、溶媒を減圧下で蒸発させる。シリカゲルクロマトグラフィー(シクロヘキサン/酢酸エチル、95:5)で精製する。化合物37を単離する(収率13%)。
中間体I(0.179g、0.38mモル、0.8eq.)をアセトニトリル(1mL)に溶かした0℃の溶液に、NaH(0.048g、1.21mモル、2.5eq)を加える。10分間攪拌し、室温に戻した後、中間体A(0.200g、0.48mモル、1eq.)をアセトニトリル(0.5mL)に溶かした溶液を加える。反応媒質を16時間、室温で攪拌する。水を加えた後、混合物を酢酸エチルで抽出する。有機相を飽和塩化ナトリウム溶液で洗浄してから、硫酸マグネシウムで乾燥する。濾過後、溶媒を減圧下で蒸発させる。シリカゲルクロマトグラフィー(ジクロロメタン/メタノール/アンモニア、97.5:2.25:0.25)で精製する。化合物38を黄白色粉末として単離する(収率19%)。
中間体F(0.048g、0.12mモル)をテトラヒドロフラン(1mL)に溶かした−78℃の溶液に、n−ブチル−リチウム(n−BuLi)(1.6Mヘキサン溶液、100μL、0.16mモル、1.3eq.)を滴下する。20分間、−78℃で攪拌後、中間体G(0.043g、0.12mモル、1eq.)をテトラヒドロフラン(1mL)に溶かした溶液を加える。続いて、反応混合物を室温に戻し、16時間攪拌する。飽和塩化アンモニウム溶液を加えた後、混合物をジクロロメタンで抽出する。続いて、有機相を硫酸マグネシウムで乾燥し、濾過してから、減圧下で濃縮する。粗生成物をシリカゲルクロマトグラフィー(シクロヘキサン/酢酸エチル、85:15)で精製する。化合物39を白色粉末として単離する(収率13%)。
中間体J(0.11g、0.30mモル)をジクロロメタン(5mL)に溶かした溶液に、1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミドクロルハイドレート(EDCI)(0.085g、0.45mモル、1.5eq.)と1−ヒドロキシベンゾトリアゾール(HOBt)(0.06g、0.45mモル、1.5eq.)を加える。30分間、室温で攪拌後、ジアミノ−1,3−プロパン(0.011g、0.15mモル、0.5eq.)をジクロロメタン(1mL)に溶かした溶液を加える。反応混合物を6時間、室温で攪拌する。水を加えた後、混合物をジクロロメタンで抽出する。有機相を飽和塩化ナトリウム溶液で洗浄してから、硫酸マグネシウムで乾燥する。濾過後、溶媒を減圧下で蒸発させる。粗生成物をシリカゲルクロマトグラフィー(ジクロロメタン/酢酸エチル、98:2〜95:5)で精製し、化合物40を単離する(収率9%、白っぽい粉末、0.010g)。
A549細胞株(肺)、およびナマルバ細胞株(リンパ腫)のようなヒト由来の腫瘍細胞株の細胞増殖の阻害性を測定することによって、本発明に従って調製した化合物の細胞障害活性を評価した。この活性は、IC50(細胞増殖を50%阻害できる試験生成物の濃度)によって表す。用いた方法は、パーキン・エルマーから市販されている「ATPLite」キットを用いて、インキュベーションの72時間後にルミネセンスによって残存ATPを測定するものである。
Claims (13)
- 前記B 1 およびB 2 は、同一かまたは異なっており、C=OおよびCH 2 から選択される、請求項1に記載の二量体誘導体。
- 前記B 1 およびB 2 がそれぞれCH 2 基を表す、請求項1または2に記載の二量体誘導体。
- 医薬を製造するための、請求項1〜4のいずれか一項に記載の二量体誘導体の使用。
- 癌治療を意図する医薬を製造するための、請求項1〜4のいずれか一項に記載の二量体誘導体の使用。
- 請求項1〜4のいずれか一項に記載の少なくとも1種類の二量体誘導体と、少なくとも1種類の薬理学的に許容可能な担体とを含んでなる、医薬組成物。
- 別の有効成分を更に含んでなることを特徴とする、請求項7に記載の医薬組成物。
- 前記別の有効成分が、6−メルカプトプリン、フルダラビン、クラドリビン、ペントスタチン、シタラビン、5−フルオロウラシル、ゲムシタビン、メトトレキセート、ラルチトレキセド、イリノテカン、トポテカン、エトポシド、ダウノルビシン、ドキソルビシン、エピルビシン、イダルビシン、ピラルビシン、ミトキサントロン、クロルメチン、シクロホスファミド、イホスファミド、メルファラン、クロラムブシル、ブスルファン、カルムスチン、フォテムスチン、ストレプトゾシン、カルボプラチン、シスプラチン、オキサリプラチン、プロカルバジン、ダカルバジン、ブレオマイシン、ビンブラスチン、ビンクリスチン、ビンデシン、ビノレルビン、パクリタキセル、ドセタキセル、L−アスパラギナーゼ、フルタミド、ニルタミド、ビカルタミド、酢酸シプロテロン、トリプトレリン、リュープロレリン、ゴセレリン、ブセレリン、フォルメスタン、アミノグルテチミド、アナストラゾール、レトロゾール、タモキシフェン、オクトレオチド、およびランレオチドから選択される、請求項8に記載の医薬組成物。
- (i)請求項1〜4のいずれか一項に記載の式(I)のうち、少なくとも1種類の化合物と、
(ii)少なくとも1種類の他の有効成分と
を含んでなる、同時に、別々に、または時間的に間隔を置いて使用する合剤としての医薬組成物。 - 前記他の有効成分が癌の治療に有用である、請求項10に記載の医薬組成物。
- 前記他の有効成分が、6−メルカプトプリン、フルダラビン、クラドリビン、ペントスタチン、シタラビン、5−フルオロウラシル、ゲムシタビン、メトトレキセート、ラルチトレキセド、イリノテカン、トポテカン、エトポシド、ダウノルビシン、ドキソルビシン、エピルビシン、イダルビシン、ピラルビシン、ミトキサントロン、クロルメチン、シクロホスファミド、イホスファミド、メルファラン、クロラムブシル、ブスルファン、カルムスチン、フォテムスチン、ストレプトゾシン、カルボプラチン、シスプラチン、オキサリプラチン、プロカルバジン、ダカルバジン、ブレオマイシン、ビンブラスチン、ビンクリスチン、ビンデシン、ビノレルビン、パクリタキセル、ドセタキセル、L−アスパラギナーゼ、フルタミド、ニルタミド、ビカルタミド、酢酸シプロテロン、トリプトレリン、リュープロレリン、ゴセレリン、ブセレリン、フォルメスタン、アミノグルテチミド、アナストラゾール、レトロゾール、タモキシフェン、オクトレオチド、およびランレオチドから選択されることを特徴とする、請求項10に記載の医薬組成物。
- 癌治療を意図する医薬として用いられる、請求項7〜12のいずれか一項に記載の医薬組成物。
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PCT/EP2008/068133 WO2009080805A1 (en) | 2007-12-21 | 2008-12-22 | Dimeric derivatives of artemisinin and application in anticancer therapy |
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