CN1123548A - 喜树碱衍生物及其制备方法 - Google Patents
喜树碱衍生物及其制备方法 Download PDFInfo
- Publication number
- CN1123548A CN1123548A CN95190093A CN95190093A CN1123548A CN 1123548 A CN1123548 A CN 1123548A CN 95190093 A CN95190093 A CN 95190093A CN 95190093 A CN95190093 A CN 95190093A CN 1123548 A CN1123548 A CN 1123548A
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- CN
- China
- Prior art keywords
- camptothecine
- methyl
- group
- amino
- imino
- 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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- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims description 15
- 238000002360 preparation method Methods 0.000 title claims description 6
- 239000002246 antineoplastic agent Substances 0.000 title abstract 2
- -1 benzoyloxy, amino, hydroxy Chemical group 0.000 claims abstract description 99
- 239000001257 hydrogen Substances 0.000 claims abstract description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 38
- 150000007524 organic acids Chemical class 0.000 claims abstract description 11
- 125000005843 halogen group Chemical group 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 7
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 7
- 239000001301 oxygen Chemical group 0.000 claims abstract description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 4
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000005864 Sulphur Chemical group 0.000 claims abstract description 3
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 77
- 241000790917 Dioxys <bee> Species 0.000 claims description 32
- 150000002431 hydrogen Chemical group 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 150000002500 ions Chemical class 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 5
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- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 4
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 4
- 150000001555 benzenes Chemical group 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 150000003053 piperidines Chemical class 0.000 claims description 4
- NDSOYQZHNCXWRA-UHFFFAOYSA-N 2-propoxypropan-2-yl hypofluorite Chemical compound CCCOC(C)(C)OF NDSOYQZHNCXWRA-UHFFFAOYSA-N 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 3
- GLGSZERYOLHNML-UHFFFAOYSA-N $l^{1}-oxidanyl(phenyl)methanone Chemical compound [O]C(=O)C1=CC=CC=C1 GLGSZERYOLHNML-UHFFFAOYSA-N 0.000 claims description 2
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- 125000004423 acyloxy group Chemical group 0.000 abstract description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 3
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- 150000001450 anions Chemical class 0.000 abstract 1
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- 150000007522 mineralic acids Chemical class 0.000 abstract 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 abstract 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
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- 239000000243 solution Substances 0.000 description 16
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- FUXVKZWTXQUGMW-FQEVSTJZSA-N 9-Aminocamptothecin Chemical compound C1=CC(N)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 FUXVKZWTXQUGMW-FQEVSTJZSA-N 0.000 description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 6
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 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
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 229910017604 nitric acid Inorganic materials 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 6
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
本发明涉及新的式(I)喜树碱衍生物或其可药用盐:
其中B为基团B′或B″
其中(X)和(Y)每个为单键或双键,
R1和R2各自独立为氢,C1-C6烷基,C3-C7环烷基,苯基C1-C6烷基或未取代的或取代的苯环,
R3和R4为
(a)具有与R1和R2相同意义的每个独立取代基或
(b)与同它们相连的氮原子一起形成3-7员饱和,未取代或取代杂单环,其可再含另一种选自氮,氧和硫的杂原子,
A为可药用无机或有机酸的可药用阴离子,条件是
(i)当(X)为双健时,(Y)为单键,
当(Y)为双键时,(X)为单键,
(ii)当B为B′基团时,那么R2,R3和R4之一不存在;R6为氢或C1-C6烷基;
X为氢,C1-C6烷基,C1-C6烷氧基,C1-C6酰氧基,C3-C7环烷基,C3-C7环烷氧基,苯甲酰基氧基,氨基,羟基,硝基,卤原子,或连到分子10和11位上的亚甲基二氧基。
本发明的喜树碱衍生物作为抗癌药在治疗中是有用的。
Description
本发明涉及新的喜树碱衍生物,其制备方法及含有它们的药物组合物。
喜树碱及其一些类似物如9—氨基喜树碱通过抑制局部异构酶1表现出强抗癌活性,该酶是与一些重要细胞功能及细胞生长有关的单节显性酶(例如见:Wani等人,J.Med.Chem.1987,30,1774;Hsiang等人,Cancer,Res.1989,49,4385和Cancer Res.1989,49,1465)。
不幸的是,喜树碱及其一些衍生物如上述9—氨基喜树碱在水溶液中溶解度低。这个缺点使得含它们的可药用配制剂的制备和给药非常难(例如见:W.J.Slichenmyer等人,Joural of the National Can-cer Institure,85卷,4期,1993,271—291页,尤其是关于9—氨基喜树碱的275页)。
因此需要找到新的喜树碱衍生物,在保持或增加喜树碱生物活性的同时,赋与使这些衍生物适于包括在可药用配制剂中的水溶性和/或物理化学特征。
本发明的化合物满足这种需要。
因此,本发明涉及式(I)的喜树碱衍生物:其中B是基团B’或B”其中(X)和(Y)每个为单键或双键,R1和R2各自独立为氢,C1—C6烷基,C3—C7环烷基,苯基C1—C6烷基或未取代的或取代的苯环,R3和R4为(a)具有与R1和R2相同意义的每个独立取代基或(b)与同它们相连的氮原子一起形成3—7员饱和,未取代或取代杂单环,其可再含另一种选自氮,氧和硫的杂原子,A-为可药用无机或有机酸的可药用阴离子,条件是(i)当(X)为双键时,(Y)为单键,
当(Y)为双键时,(X)为单键,(ii)当B为B’基团时,那么R2,R3和R4之一不存在;R6为氢或C1—C6烷基;X为氢,C1—C6烷基,C1—C6烷氧基,C1—C6酰氧基,C3—C7环烷基,C3—C7环烷氧基,苯甲酰基氧基,氨基,羟基,硝基,卤原子,或连到分子10和11位上的亚甲基二氧基。
在本说明书中,烷基,烷氧基和酰基氧基的碳氢链可以为直链或支链。
优选B连到分子的9或10位。
优选C1—C6烷基为甲基,乙基,正—丙基,异丙基,正丁基,异丁基,仲丁基或叔丁基。优选C3—C7环烷基为环丙基,环丁基,环戊基或环己基。优选苯基C1—C6烷基为苄基,苯基—乙基或苯基丙基。优选C1—C6烷氧基为甲氧基,乙氧基,正丙氧基,异丙氧基,或正丁氧基。优选C3—C7环烷氧基为环丙氧基,环丁氧基,环戊氧基,或环己氧基。优选C1—C6酰基氧基为乙酰氧基,丙酰氧基,或丁酰氧基。卤原子为氯,溴,氟或碘,优选氯和溴。
当R1,R2,R3和R4之一为不饱和或饱和苯环时,它可由下面基团表示:其中Q为氢,C1—C6烷基,C1—C6烷氧基,C1—C6酰氧基,或卤原子。
优选Q为氢,C1—C4烷基,尤其是甲基,乙基,正丙基,异丙基,正丁基,异丁基或仲丁基;C1—C4烷氧基,尤其是甲氧基,乙氧基,或丙氧基;或卤素,尤其是氯。尤其优选的Q值为氢,甲基,乙基,正丙基,异丙基,甲氧基,和氯。
当R3和R4及与它们相连的氮原子一起形成3—7员饱和,取代或未取代杂单环时,该环可由下面基团表示:其中Y为—O—,—S—,—CH2—,或>NR5,其中R5为氢,C1—C6烷基,或由上面基表示的苯环,其中Q如上定义,m和n每个独立表示O或1—5的整数,条件是,当m和n之一为零时,其它的不为零,及m+n不超过5。优选R5为氢或甲基。
优选R3和R4及与它们相连的氮原子一起形成氮丙啶,氮杂环丁烷,吡咯烷,哌啶,六亚甲基亚胺,哌嗪,甲基哌嗪或吗啉,尤其是吡咯烷,哌啶,六亚甲基亚胺,哌嗪,甲基哌嗪或吗啉。A-为可药用酸,无机酸如盐酸,硫酸,磷酸,二磷酸,氢溴酸或硝酸,和有机酸如柠檬酸,富马酸,马来酸,苹果酸,抗坏血酸,琥珀酸,酒石酸,苯甲酸,乙酸,苯基乙酸,甲磺酸,乙磺酸,苯磺酸,或对—甲苯磺酸的可药用阴离子。
优选A-为卤化物,乙酸根,苯甲酸根,甲磺酸根或对甲苯磺酸根阴离子,尤其是氯,乙酸根,甲磺酸根或对甲苯磺酸根阴离子。
优选R6为氢,甲基或乙基。
优选X为氢,羟基,氨基,硝基,卤原子,甲氧基,乙酰氧基,丙酰氧基,苯甲酰氧基,10,11亚甲基二氧基,尤其是氢,羟基,甲氧基或10,11亚甲基二氧基。
如已叙述的,本发明包括游离碱形式及与可药用无机酸和有机酸所成可药用盐形式的式(I)的喜树碱衍生物。
本发明的优选盐为与可药用无机酸如盐酸,硫酸,磷酸,二磷酸,氢溴酸或硝酸和有机酸如柠檬酸,富马酸,马来酸,苹果酸,抗坏血酸,琥珀酸,酒石酸,苯甲酸,乙酸,苯基乙酸,甲磺酸,乙磺酸,苯磺酸,或对甲苯磺酸所成的盐。
可药用季铵盐即其中B为B”基团的式(I)化合物也打算包含在本发明式(I)化合物的一般定义“可药用盐”当中。
R1,R2,R3和R4每个独立为氢,甲基,乙基,正丙基,异丙基,正丁基,异丁基,仲丁基,叔丁基,环丁基,环戊基,环己基,苄基,苯基乙基,或下面基团表示的未取代或取代苯环其中Q为氢,甲基,乙基,正丙基,异丙基,正丁基,异丁基,仲丁基,甲氧基,乙氧基,正丙氧基,异丙氧基,氟,氯或溴,
A-为选自氯化物,乙酸根,甲磺酸根和对甲苯磺酸根的可药用无机或有机酸的可药用阴离子,条件是(i)当(X)为双键时,(Y)为单键,
当(Y)为双键时,(X)为单键,(ii)当B为基团B’时,R2,R3和R4之一不存在;
R6为氢,甲基,或乙基;
X为氢,羟基,甲氧基,或连到分子10和11位的亚甲基二氧基,
本发明另一类优选化合物是式(1)化合物及其可药用盐,其中
B为基团B’或B”其中(X)和(Y)每个为单键或双键,R1和R2每个独立为氢,甲基,乙基,正丙基,异丙基,正丁基,异丁基,仲丁基,叔丁基,环丁基,环戊基,环己基,苄基,苯基—乙基,或由下面基团表示的未取代或取代苯环其中Q为氢,甲基,乙基,正丙基,异丙基,正丁基,异丁基,仲丁基,甲氧基,乙氧基,正丙氧基,异丙氧基,氟,氯,或溴,
R3和R4及与它们相连的氮原子一起形成吡咯烷,哌啶,六亚甲基亚胺,哌嗪,甲基哌嗪,或吗啉,
A-为选自氯化物,乙酸根,甲磺酸根和对甲苯磺酸根的可药用无机或有机酸的可药用阴离子,条件是(i)当(X)为双键时,(Y)为单键,
当(Y)为双键时,(X)为单键,(ii)当B为基团B’时,R2,R3和R4之一不存在;
R6为氢,甲基或乙基;
X为氢,羟基,甲氧基或连到分子10和11位的亚甲基二氧基。
本发明优选化合物的具体实施例如下:(1)9—(亚氨基甲基—氨基)—喜树碱;(2)9—(1—亚氨基—乙基氨基)—喜树碱;(3)9—(甲基亚氨基—甲基氨基)—喜树碱;(4)9—(二甲基氨基—亚甲基氨基)—喜树碱;(5)9—(二甲基氨基—环己基—亚甲基氨基)—喜树碱;(6)9—[(亚氨基—苯基—甲基)—氨基]—喜树碱;(7)9—(1—苯基亚氨基—乙基氨基)—喜树碱;(8)9—(1—吗啉—4—基—亚乙基氨基)—喜树碱;(9)10—(亚氨基甲基—氨基)—喜树碱;(10)10—(1—亚氨基—乙基氨基)—喜树碱;(11)10—(甲基亚氨基—甲基氨基)—喜树碱;(12)10—(二甲基氨基—亚甲基氨基)—喜树碱;(13)10—(二甲基氨基—环己基—亚甲基氨基)—喜树碱;(14)10—[(亚氨基—苯基—甲基)—氨基]—喜树碱;(15)10—(1—苯基亚氨基—乙基氨基)—喜树碱;(16)10—(1—吗啉—4—基—亚乙基氨基)—喜树碱;(17)10—羟基—9—(亚氨基甲基—氨基)—喜树碱;(18)10—羟基—9—(1—亚氨基—乙基氨基)—喜树碱;(19)10—羟基—9—(1—二甲基氨基—亚乙基氨基)—喜树碱;(20)11—羟基—9—(亚氨基甲基—氨基)—喜树碱;(21)11—羟基—9—[(亚氨基—苯基—甲基)—氨基]—喜树碱;(22)11—羟基—9—(1—苯基—亚氨基—乙基氨基)—喜树碱;(23)10—羟基—9—(1—吗啉—4—基—亚乙基氨基)—喜树碱;(24)10,11—亚甲基二氧基—9—(亚氨基甲基—氨基)—喜树碱;(25)10,11—亚甲基二氧基—9—(1—亚氨基—乙基氨基)—喜树碱;(26)10,11—亚甲基二氧基—9—[(甲基亚氨基—甲基)氨基]—喜树碱;(27)10,11—亚甲基二氧基—9—(1—亚氨基—丙基氨基)—喜树碱;(28)10,11—亚甲基二氧基—9—(1—甲基亚氨基—乙基氨基)—喜树碱;(29)10,11—亚甲基二氧基—9—[(乙基—甲基—氨基)—亚甲基氨基]—喜树碱;(30)10,11—亚甲基二氧基—9—[(环己基—甲基亚氨基—甲基)—氨基]—喜树碱;(31)9—[1—(4—甲基—哌嗪—1—基)—亚甲基氨基]—喜树碱;(32)10—甲氧基—9—(亚氨基甲基—氨基)—喜树碱;(33)10—甲氧基—9—(1—亚氨基—乙基氨基)—喜树碱;(34)10—甲氧基—9—(1—亚氨基—戊基氨基)—喜树碱;(35)10—甲氧基—9—{[亚氨基—(4—甲氧基—苯基)—甲基]—氨基}—喜树碱;(36)10—甲氧基—9—[(苯基亚氨基—甲基)—氨基]—喜树碱;(37)10—甲氧基—9—(二甲基氨基—亚甲基氨基)—喜树碱;(38)10—甲氧基—9—(亚氨基甲基—甲基氨基)—喜树碱;(39)9—(2—甲基—1—亚氨基—丙基氨基)—喜树碱;(40)10—甲氧基—9—(2—甲基—1—甲基亚氨基—丙基氨基)—喜树碱;(41)10—羟基—9—(2,2—二甲基—1—亚氨基—丙基氨基)—喜树碱;(42)10—甲氧基—9—(吡咯烷—1—基—亚甲基氨基)—喜树碱;(43)10,11—二甲基二氧基—9—[(叔丁基—亚氨基—甲基)氨基]—喜树碱;(44)9—[(异丙基亚氨基—甲基)—氨基]—喜树碱;(45)7—乙基—9—(亚氨基甲基—氨基)—喜树碱;
上面列举化合物的结构式参考式(I)在下表1中举例说明:
表1
表1(续)
表1(续)
在表1中,符号Et,i—Pr,n—Bu,t—Bu和Cy分别表示乙基,异丙基,正丁基,叔丁基和环己基。
上面表1中列举的化合物1—45也可以呈可药用盐形式。
本发明的化合物可由包括下面步骤的方法制备:1)式(II)的化合物其中R2,R6和X如上定义,与式(III)的化合物反应其中R1,R3和R4如上定义,A1 -或为上面定义的可药用阴离子A-,或为任何其它适当的阴离子,Z为离去基团,这样得到其中R6和X如上定义且其中按反应条件B为上面定义的基团B’或B”的式(1)化合物;且如果需要,2)其中R6和X如上定义且B为如上定义其中R2,R3和R4之一为氢的基团B”的式(I)化合物转变成其中R6和X如上定义且B为上面定义基团B’的相应式(I)化合物,且如果需要,3)盐化其中R6和X如上定义且B为上面定义基团B’的式(I)化合物,这样得到可药用盐形式的式(I)化合物。
式(II)的起始化合物在生成式(I)化合物的整个过程中保持20(s)—构型。
式(II)化合物一般不包括相应的20(R)—异构体。
然而,该方法可应用于式(II)化合物与相应(20R)—异构体的外消旋混合物。在这种情况下,得到式(I)化合物及式(I)化合物的20(R)—异构体的外消旋混合物。
在式(III)化合物中,离去基团Z可为C1—C6烷氧基,C3—C7环烷氧基,C1—C6酰氧基,苯甲酰氧基,C3—C7环酰基氧基,卤原子,三氟甲磺酰基氧基,对甲苯磺酰基氧基或甲磺酰基氧基。
Z可设定的优选意义包括甲氧基,乙氧基,丙氧基,异丙氧基,乙酰氧基,丙酰氧基,苯甲酰氧基,氟,氯,溴,碘,三氟甲磺酰氧基,对甲苯磺酰氧基,或甲磺酰氧基。
Z可设定的尤其优选意义包括甲氧基,乙氧基,丙氧基,异丙氧基,乙酰氧基,丙酰氧基,苯甲酰氧基,氯,溴,三氟甲磺酰氧基,对甲苯磺酰氧基,或甲磺酰氧基。
在式(III)化合物中,A1 -优选为上述定义的可药用阴离子A-。
上面1)项下报导的反应可任选在适当的无机或有机碱存在下于约-20℃至100℃,优选从约0℃至约80℃的温度下通过溶于适当溶剂中的式(II)化合物与从化学计量量到大量过量的式(III)化合物反应一段时间来进行,反应时间可从几分钟到几天例如5分钟到3天,优选从约1小时到约1天。
当1)项的反应在无适当无机或有机碱存在下进行时,可得到其中R6和X如上定义且其中B为上面定义B”基团的式(I)化合物。当1)项的反应在有适当无机或有机碱存在下进行时,可得到其中R6和X如上定义且其中B为上面定义B’基团的式(I)化合物。
适当的溶剂包括二甲基甲酰胺(DMF),水,CH3OH,乙酸,CHCl3,二噁烷,四氢呋喃(THF)和其混合物。
适当的无机碱例如可以是与碱金属或碱土金属成的盐如NaOH,NaHCO3,Na2CO3或CaCO3。
适当的有机碱例如可以是三烷基胺如三乙胺或二异丙基乙基胺;或杂芳碱如吡啶或2,6—C1—C6烷基取代的吡啶如2,6—二甲基吡啶。
可在常规步骤后进行上面2)项下报导的转化;例如可在适当的含水溶剂中通过加入从化学计量量到稍过量的有机或无机碱进行转化。可在2)项下使用的有机或无机碱例如可选自在1)项上任选使用的那些。
为盐化3)项上报导的式(I)化合物可使用常用方法。尤其是,可通过相应的式(II)化合物(其中R6如上定义,R2为氢和X为10—或12—羟基)与上面定义的式(III)化合物就地反应来制备其中B为连到分子(其中R1,R3,R4,(X),(Y)和A-如上定义且R2为氢)9位的基团B’或B”且其中R6如上定义且X为10—或12—羟基的式(I)化合物,不需从通过还原式(IV)化合物(其中R6如上定义,且羟基连到分子的10位或12位)得到的反应混合物中分离式(II)的化合物。
例如用适当还原剂或在适当还原剂存在下用适当催化剂通过催化还原来进行式(IV)化合物的还原。例如可按J.March,AdvancedOrganic Chemistry,第三版,1103中描述进行还原。例如,在大约—20℃到大约60℃在适当溶剂如稀含水HCl,稀含水质子酸,水,乙醇,甲醇,或其混合物中用还原剂如SnCl2,或其它金属或金属盐和Zn或Fe及其盐可进行还原几分钟到几天的一段时间如从大约5分钟到大约3天,如从4小时到24小时;或在大约0℃到大约100℃的某一温度下在大约1atm到大约100atm的压力下在适当溶剂如二甲基甲酰胺(DMF),CH3OH,乙酸,CHCl3,二噁烷或其混合物中在氢分子或氢源如甲酸三乙基铵,甲酸,三丁基氢化锡,环己二烯,聚甲基氢化硅氧烷等存在下,通过使用还原硝基的催化量金属如钯,氧化铂,铂,铑或钌,PdL2(其中L为乙酸根或卤原子)来还原1小时到3天的一段时间来进行还原。
式(II)和(II)化合物是已知化合物或可用已知方法得到。
可在大约-20℃到大约100℃的某一温度下例如通过10—羟基或12—羟基喜树碱与适当的常用硝化试剂如硝酸,硝酸和硫酸的混合物或其它硝化试剂如硝酸钾或硝酸和三氟化硼如三氟化硼单水合物(例如见Olah,G.A.等Synthesis 1085,1992),或硝酸/三氟甲磺酸酐(出处同上,1087,1992)反应一段时间来得到式(IV)的化合物,时间可以从几分钟到几天,如从大约5分钟到大约3天,如从4小时到24小时。
例如通过已知方法从喜树碱得到10—羟基和12—羟基喜树碱(例如见JP—A—59—51288;JP—A—5951299;J.Med.Chem.34,98,1991;和Chem.pharm.Bull.39,3183,1991)。
特别是,10—羟基喜树碱是在与喜树碱相同植物上发现的天然产物(例如见Wani等人,J.Org.Chem.,34,1364,1969)。借助于由可与可药用无机或有机酸形成盐的碱性基团B表示的碱性侧链,式(I)化合物是水溶的。式(I)化合物在水中的溶解性是尤其重要的,因为它使这些化合物能在含水药物组合物中给药。本发明的化合物具有抗癌活性,例如它们能有效地对抗白血病和实体癌如结肠癌和直肠癌。
本发明化合物的抗癌活性例如由它们被发现“体外”细胞毒性及“体内”抗白血病活性的事实来表明。作为实例,按照下面方法(a)和(b)试验9—(亚氨基甲基—氨基)—喜树碱(内部编码PCE28536)和9—(二甲基氨基—亚甲基氨基)—喜树碱(内部编码PCE29006)的活性。方法(a)细胞毒性活性评价
在补充有10%小牛血清,2mM L—谷氨酰胺,10μmM B—巯基乙醇,100UI/ml青霉素和100μg链霉素的RPMI1640培养基中以稳定悬浮液形式在体外培养L1210鼠白血病细胞。为测定细胞毒性活性,按指数增长的细胞以1×105个细胞/ml浓度种植,且在5%湿气氛下于37℃与要评价化合物的分级剂量作用48小时。用库尔特计数器测量存活细胞数;结果表示成IC50(处理48小时后相对于未处理的对照在处理的培养基中引起细胞生长50%抑制的剂量)。
在该测试中试验9—(亚氨基甲基—氨基)—喜树碱(内部编码PCE28536)和9—(二甲基氨基—亚甲基氨基)—喜树碱(内部编码PCE29006),所得结果(其表示3个不同实验的平均值)报导在下表1中
表1
方法(b):抗癌活性评价
化合物 | IC50(nM) |
FCE28536 | 82 |
FCE29006 | 120 |
L1210鼠白血病通过每周腹内移植105细胞/鼠而保持在DBA2中。为测定抗白血病活性,105个细胞/鼠腹内种植到CD2F1小鼠中;在第一天种植癌细胞后24小时腹内给入要评价化合物的分级剂量。通过评价每组小鼠的平均存活时间(MST)来测定药物活性。
以%T/C表示的所得结果示于下表2中。
表2
%TC=MST 治疗鼠/MST 对照鼠X100
化合物 | 剂量(mg/kg) | %T/C |
28536 | 51015 | 150-163188219-213 |
29006 | 51015 | 150163175 |
人体或动物体因此可通过包括向其给入药用有效量的式(I)化合物或其盐的方法得到治疗。因此可改善人或动物的病情。
本发明化合物可以不同剂型给药,例如以片剂,胶囊,锭剂,液体溶液或悬浮液形式口服;以栓剂形式直肠给药;非肠道给药如肌内,静脉内,皮内或皮下给药,或局部应用。剂量例如取决于所用喜树碱衍生物,该喜树碱衍生物的效能,年龄,体重,病情和给药路线;基于个别需要和给入或监督给人上述化合物的人的职业判断,具体剂量范围可以适于任何特定患者。例如,给成年人的剂量范围对每kg体重可以是0.1—60mg喜树碱衍生物;对每kg体重尤其优选的剂量范围为1—40mg喜树碱衍生物。
剂量可一次给入或可分成几个小剂量以不同时间间隔给入。含式(I)化合物或其可药用盐作为活性成分以及可药用载体和稀释剂的药物组合物也在本发明的范围内。这些药物组合物含一定量对抗白血病和/或抗癌活性表现出治疗有效的活性成分。作为本发明药物组合物的一部分,也可以包括可药用粘合剂和/或赋形剂。活性成份也可以与其它不施予所需作用和/或补充所需作用的活性要素混合。含本发明化合物的药物组合物通常按常规方法制备,且可以药物适用形式给药。
例如,固体口服剂型可与活性化合物一起含有稀释剂如乳糖,右旋糖,蔗糖,纤维素,玉米淀粉,或土豆淀粉;润滑剂如硅石,滑石粉,硬脂酸,硬脂酸镁或硬脂酸钙,和/或聚乙二醇;粘合剂如淀粉,阿拉伯胶,明胶,甲基纤维素,微晶纤维素,羧甲基纤维素或聚乙烯基吡咯烷酮;崩解剂(diaggregating agent)如淀粉,藻酸,藻酸盐或淀粉乙二醇钠;泡腾混合物;颜料;增甜剂如蔗糖或糖精;调味剂如薄荷,水杨酸甲酯或橙调味品;润湿剂如卵膦脂,多乙氧基醚,硫酸月桂酯;及用于药物制剂的一般无毒且药理上无活性物质。
当剂型为胶囊时,除上述类型材料之外,它可含有液体载体如脂肪油。该药物制剂可按已知方法如借助于混合,粒化,压片,涂糖或涂膜方法来生产。口服给药的液体分散液例如可以是糖浆,乳液和悬浮液。糖浆例如可含有蔗糖或与甘油和/或甘露糖和/或山梨糖醇一起的蔗糖作为载体;尤其是,给糖尿病病人的糖浆可仅含不能代谢成葡萄糖或非常少量代谢成葡萄糖的产品如山梨糖醇。
悬浮液和乳液可含例如天然胶,琼脂,藻酸钠,果胶,甲基纤维素,羧甲基纤维素,或聚乙烯基醇作为载体。
肌内注射的悬浮液或溶液可含与活性化合物一起的可药用载体如无菌水,橄榄油,油酸乙酯,二醇类如丙二醇,且如果需要,适量的盐酸利多卡因。
静脉内注射或输注的溶液可含例如无菌水作为载体,或优选它们可呈无菌的等渗盐水溶液形式。
非肠道治疗给药的溶剂或悬浮液也可含抗菌剂如苄醇或对羟苯甲酸甲酯;抗氧剂如抗坏血酸或连二亚硫酸钠;螯合剂如乙二胺四乙酸;缓冲剂如乙酸盐,柠檬酸盐或磷酸盐及增强调节剂如氯化钠或右旋糖。非肠道给药制剂可包封于安瓿,可随着处理的注射器或由玻璃或塑料制多剂小瓶中。
栓剂可含同活性化合物一起的可药用载体如可可脂,聚乙二醇,聚氧乙烯疏水山梨醇脂肪酸酯表面活性剂或卵膦脂。
局部应用的组合物如霜,洗剂或糊剂例如可通过将活性成分与常用的油状的或可乳化的赋形剂混合来制备。
下面实施例说明但不限制本发明。
在按照下面实施例制备的化合物的化学名后报导的括号内数相应于本说明书11,12和13页上列的优选化合物数。实施例19—(亚氨基甲基—氨基)—喜树碱(1);
室温下向9—氨基喜树碱(0.5g)在DMF(100ml)中的搅拌溶液中加入乙基亚甲胺化物盐酸盐(ethyl forminidate hydrochloride)(2.5g),所得混合物搅拌过夜。滤出固体,真空蒸发滤液。残余物溶于水,所得溶液pH调到大约6.5。通过过滤收集沉淀的固体,用几小份冷水仔细洗,然后干燥得到标题化合物(0.25g)。1NMR(DMSO-d6),δppm:0.87(3H,t,J=7.3Hz);1.85(2H,m);5.27(2H,s);5.41(2H,s);6.50(1H,broad signal);7.04(1H,d,J=7.3Hz);7.10(2H,broad signal);7.31(1H,s);7.67(1H,dd,J=7.3,8.5Hz);7.73(1H,d,J=8.5Hz);7.79(1H,m);8.94(1H,s).MS(FD):390.
标题化合物(0.1g)悬浮在水(2ml)中,加入1NHCl(0.3ml)。然后冷冻干燥所得的黄色溶液,得到标题化合物的盐酸盐。
按类似步骤可制备下面列举的化合物及其盐酸盐:10,11—亚甲基二氧基—9—(亚氨基甲基—氨基)—喜树碱(24);10—甲氧基—9—(亚氨基甲基—氨基)—喜树碱(32);10—(亚氨基甲基—氨基)—喜树碱(9);11—羟基—9—(亚氨基甲基—氨基)—喜树碱(20)和7—乙基—9—(亚氨基甲基—氨基)—喜树碱(45)。实施例210—羟基—9—(亚氨基甲基—氨基)—喜树碱(17)。
于室温大气压下在10%Pd/C(0.05g)存在下氢化10—羟基—9—硝基喜树碱(0.5g)在DMF(100ml)中的溶液直到H2停止消耗。过滤所得的溶液,然后用乙基亚甲胺化物盐酸盐(1.5g)处理。溶液搅拌过夜,按实施例1描述处理,得标题化合物(0.1g)。实施例39—(1—亚氨基—乙基氨基)—喜树碱(2)。向9—氨基喜树碱(0.5g)在DMF(100ml)的搅拌溶液中加入乙基乙胺化物盐酸盐(ethyl acetamidate hydrochloride)(2.5g),所得混合物于80℃搅拌过夜且按实施例1所述处理,得到标题化合物(0.2g)。
按类似步骤制备下面列出的化合物及其盐酸盐:10,11—亚甲基二氧基—9—(1—亚氨基—乙基氨基)—喜树碱(25);10—甲氧基—9—(亚氨基甲基—甲基氨基)—喜树碱(38);10—甲氧基—9—(1—亚氨基—乙基氨基)—喜树碱(33);10—(1—亚氨基—乙基氨基)—喜树碱(10);9—[(亚氨基—苯基—甲基)—氨基]—喜树碱(6);10—[(亚氨基—苯基—甲基)氨基]—喜树碱(14);11—羟基—9—[(亚氨基—苯基—甲基)—氨基]—喜树碱(21);10,11—亚甲基二氧基—9—(1—亚氨基—丙基氨基)—喜树碱(27);10—甲氧基—9—(1—亚氨基—戊基氨基)—喜树碱(34);10—甲氧基—9—{[亚氨基—(4—甲氧基—苯基)—甲基]—氨基}—喜树碱(35);和9—(2—甲基—1—亚氨基—丙基氨基)—喜树碱(39)。实施例1410—羟基—9—(1—亚氨基—乙基氨基)—喜树碱(18)。
于室温大气压下在10%Pd/C(0.01g)存在下氢化10—羟基—9—硝基喜树碱(0.5g)在DMF(100ml)中的溶液直到H2停止消耗。用乙基乙胺化物盐酸盐(2.0g)处理所得溶液,溶液在室温下搅拌过夜。按前面实施例描述处理,得标题化合物(0.2g)。按类似步骤可得到下面列举的化合物:10—羟基—9—(2,2—二甲基—1—亚氨基—丙基氨基)—喜树碱(41);10—羟基—9—(1—二甲基氨基—亚乙基氨基)—喜树碱(19);和10—羟基—9—(1—吗啉—4—基—亚乙基氨基)—喜树碱(23)。实施例5
类似于前面实施例1通过用适当的亚胺化物(imidate),可制备下面化合物:9—(甲基亚氨基—甲基氨基)—喜树碱(3);9—(二甲基氨基—亚甲基氨基)—喜树碱(4);9—(二甲基氨基—环己基—亚甲基氨基)—喜树碱(5);9—(1—苯基亚氨基—乙基氨基)—喜树碱(7);9—(1—吗啉—4—基—亚乙基氨基)—喜树碱(8);10—(甲基亚氨基—甲基氨基)—喜树碱(11);10—(二甲基氨基—亚甲基氨基)—喜树碱(12);10—(二甲基氨基—环己基—亚甲基氨基)—喜树碱(13);10—(1—苯基亚氨基—乙基氨基)—喜树碱(15);10—(1—吗啉—4—基—亚乙基氨基)—喜树碱(16);11—羟基—9—(1—苯基—亚氨基—乙基氨基)—喜树碱(22);10,11—亚甲基二氧基—9—[(甲基亚氨基—甲基)氨基]—喜树碱(26);10,11—亚甲基二氧基—9—(1—甲基亚氨基—乙基氨基)—喜树碱(28);10,11—亚甲基二氧基—9—[(乙基—甲基—氨基)—亚甲基氨基]—喜树碱(29);10,11—亚甲基二氧基—9—[(环己基—甲基亚氨基—甲基)—氨基]—喜树碱(30);9—[1—(4—甲基—哌嗪—1—基)—亚甲基氨基]—喜树碱(31);10—甲氧基—9—[(苯基亚氨基—甲基)—氨基]—喜树碱(36);10—甲氧基—9—(二甲基氨基—亚甲基氨基)—喜树碱(37);10—甲氧基—9—(2—甲基—1—甲基亚氨基—丙基氨基)—喜树碱(40);10—甲氧基—9—(吡咯烷—1—基—亚甲基氨基)—喜树碱(42);10,11—二甲基二氧基—9—[(叔丁基—亚氨基—甲基)氨基]—喜树碱(43);和9—[(异丙基氨基—甲基)—氨基]—喜树碱(44)。实施例69—(二甲基氨基—亚甲基氨基)—喜树碱(4)。
于40℃向二甲基甲酰胺(1ml)在乙醚(50ml)中的搅拌溶液中加入在乙醚(5ml)中的草酰氯(1.15ml)。然后于室温搅拌混合物3小时。过滤沉淀,用乙醚洗沉淀,并于室温下加到9—氨基喜树碱(150mg)在DMF(20ml)中的溶液中。于室温搅拌混合物过夜。然后“真空”蒸发反应混合物,残余物溶于水。然后用CH2Cl2洗水溶液两次,弃去有机层。通过加NaHCO3调节水层pH,直到观察到棕黄色固体完全沉淀。过滤收集固体,细心用水洗。用反相色谱法通过用酸性水/丙酮混合物洗脱纯化粗产物。收集适当的级分,冷冻干燥。
残余物溶于水(3ml),加入NaHCO3直到观察到完全沉淀。过滤收集沉淀,细心用水洗,干燥,得到标题化合物(90mg)。NMR(DMSO-d6)δ(ppm):0.87(3H,T,J=7.3Hz);1.85(2H,m);3.10(6H,s);5.27(2H,s);5.41(2H,s);6.50(1H,s);7.08(1H,m); 7.31(1H,s);7.68(2H,m);7.94(1H,s);9.04(1H,s).MS(FD):418
上述沉淀(80mg)再悬浮在水(2ml)中,加入1N HCl(0.2ml)。冷冻干燥沉淀,得到盐酸盐形式的沉淀。实施例79—(1—亚氨基—乙基氨基)—喜树碱(2)。
按实施例3中描述进行反应,但是使用二甲基乙酰胺。常规处理后得到0.1g标题化合物。
Claims (9)
B是基团B’或B”其中(X)和(Y)每个为单键或双键,R1和R2各自独立为氢,C1—C6烷基,C3—C7环烷基,苯基C1—C6烷基或未取代的或取代的苯环,R3和R4为(a)具有与R1和R2相同意义的每个独立取代基或(b)与同它们相连的氮原子一起形成3—7员饱和,未取代或取代杂单环,其可再含另一种选自氮,氧和硫的杂原子,A为可药用无机或有机酸的可药用阴离子,条件是(i)当(X)为双键时,(Y)为单键,
当(Y)为双键时,(X)为单键,(ii)当B为B’基团时,那么R2,R3和R4之一不存在;R6为氢或C1—C6烷基;X为氢,C1—C6烷基,C1—C6烷氧基,C1—C6酰氧基,C3—C7环烷基,C3—C7环烷氧基,苯甲酰基氧基,氨基,羟基,硝基,卤原子,或连到分子10和11位上的亚甲基二氧基。
2.按照权利要求1的式(I)喜树碱衍生物或其可药用盐,其中B为基团B’或B”
其中(X)和(Y)每个为单键或双键,
R1,R2,R3和R4每个独立为氢,甲基,乙基,正丙基,异丙基,正丁基,异丁基,仲丁基,叔丁基,环丁基,环戊基,环己基,苄基,苯基乙基,或下面基团表示的未取代或取代苯环其中Q为氢,甲基,乙基,正丙基,异丙基,正丁基,异丁基,仲丁基,甲氧基,乙氧基,正丙氧蜞,异丙氧基,氟,氯或溴,
A-为选自氯化物,乙酸根,甲磺酸根和对甲苯磺酸根的可药用无机或有机酸的可药用阴离子,条件是(i)当(X)为双键时,(Y)为单键,
当(Y)为双键时,(X)为单键,(ii)为B为基团B’时,R2,R3和R4之一不存在;
R6为氢,甲基,或乙基;
X为氢,羟基,甲氧基,或连到分子10和11位的亚甲基二氧基,
其中
(X)和(Y)每个为单键或双键,R1和R2每个独立为氢,甲基,乙基,正丙基,异丙基,正丁基,异丁基,仲丁基,叔丁基,环丁基,环戊基,环己基,苄基,苯基—乙基,或由下面基团表示的未取代或取代苯环其中Q为氢,甲基,乙基,正丙基,异丙基,正丁基,异丁基,仲丁基,甲氧基,乙氧基,正丙氧基,异丙氧基,氟,氯,或溴,
R3和R4及与它们相连的氮原子一起形成吡咯烷,哌啶,六亚甲基亚胺,哌嗪,甲基哌嗪,或吗啉,
A-为选自氯化物,乙酸根,甲磺酸根和对甲苯磺酸根的可药用无机或有机酸的可药用阴离子,条件是(i)当(X)为双键时,(Y)为单键,
当(Y)为双键时,(X)为单键,
(ii)当B为基团B’时,R2,R3和R4之一不存在;
R6为氢,甲基或乙基;
X为氢,羟基,甲氧基或边到分子10和11位的亚甲基二氧基。
4.选自下面的喜树碱衍生物或其可药用盐:(1)9—(亚氨基甲基—氨基)—喜树碱;(2)9—(1—亚氨基—乙基氨基)—喜树碱;(3)9—(甲基亚氨基—甲基氨基)—喜树碱;(4)9—(二甲基氨基—亚甲基氨基)—喜树碱;(5)9—(二甲基氨基—环己基—亚甲基氨基)—喜树碱;(6)9—[(亚氨基—苯基—甲基)—氨基]—喜树碱;(7)9—(1—苯基亚氨基—乙基氨基)—喜树碱;(8)9—(1—吗啉—4—基—亚乙基氨基)—喜树碱;(9)10—(亚氨基甲基—氨基)—喜树碱;(10)10—(1—亚氨基—乙基氨基)—喜树碱;(11)10—(甲基亚氨基—甲基氨基)—喜树碱;(12)10—(二甲基氨基—亚甲基氨基)—喜树碱;(13)10—(二甲基氨基—环己基—亚甲基氨基)—喜树碱;(14)10—[(亚氨基—苯基—甲基)—氨基]—喜树碱;(15)10—(1—苯基亚氨基—乙基氨基)—喜树碱;(16)10—(1—吗啉—4—基—亚乙基氨基)—喜树碱;(17)10—羟基—9—(亚氨基甲基—氨基)—喜树碱;(18)10—羟基—9—(1—亚氨基—乙基氨基)—喜树碱;(19)10—羟基—9—(1—二甲基氨基—亚乙基氨基)—喜树碱;(20)11—羟基—9—(亚氨基甲基—氨基)—喜树碱;(21)11—羟基—9—[(亚氨基—苯基—甲基)—氨基]—喜树碱;(22)11—羟基—9—(1—苯基—亚氨基—乙基氨基)—喜树碱;(23)10—羟基—9—(1—吗啉—4—基—亚乙基氨基)—喜树碱;(24)10,11—亚甲基二氧基—9—(亚氨基甲基—氨基)—喜树碱;(25)10,11—亚甲基二氧基—9—(1—亚氨基—乙基氨基)—喜树碱;(26)10,11—亚甲基二氧基—9—[(甲基亚氨基—甲基)氨基]—喜树碱;(27)10,11—亚甲基二氧基—9—(1—亚氨基—丙基氨基)—喜树碱;(28)10,11—亚甲基二氧基—9—(1—甲基亚氨基—乙基氨基)—喜树碱;(29)10,11—亚甲基二氧基—9—[(乙基—甲基—氨基)—亚甲基氨基]—喜树碱;(30)10,11—亚甲基二氧基—9—[(环己基—甲基亚氨基—甲基)—氨基]—喜树碱;(31)9—[1—(4—甲基—哌嗪—1—基)—亚甲基氨基]—喜树碱;(32)10—甲氧基—9—(亚氨基甲基—氨基)—喜树碱;(33)10—甲氧基—9—(1—亚氨基—乙基氨基)—喜树碱;(34)10—甲氧基—9—(1—亚氨基—戊基氨基)—喜树碱;(35)10—甲氧基—9—{[亚氨基—(4—甲氧基—苯基)—甲基]—氨基}—喜树碱;(36)10—甲氧基—9—[(苯基亚氨基—甲基)—氨基]—喜树碱;(37)10—甲氧基—9—(二甲基氨基—亚甲基氨基)—喜树碱;(38)10—甲氧基—9—(亚氨基甲基—甲基氨基)—喜树碱;(39)9—(2—甲基—1—亚氨基—丙基氨基)—喜树碱;(40)10—甲氧基—9—(2—甲基—1—甲基亚氨基—丙基氨基)—喜树碱;(41)10—羟基—9—(2,2—二甲基—1—亚氨基—丙基氨基)—喜树碱;(42)10—甲氧基—9—(吡咯烷—1—基—亚甲基氨基)—喜树碱;(43)10,11—二甲基二氧基—9—[(叔丁基—亚氨基—甲基)氨基]—喜树碱;(44)9—[(异丙基亚氨基—甲基)—氨基]—喜树碱;(45)7—乙基—9—(亚氨基甲基—氨基)—喜树碱。
5.制备权利要求1中定义的式(I)喜树碱衍生物或其可药用盐的方法,该方法包括1)式(II)的化合物其中R2,R6和X如权利要求1定义,与式(III)的化合物反应其中R1,R3和R4如权利要求1定义,A1 -或为上面定义的可药用阴离子A-,或为任何其它适当的阴离子,Z为离去基团,这样得到其中R6和X如上定义且其中按反应条件B为权利要求1定义的基团B’或B”的式(I)化合物;且如果需要,2)其中R6和X如权利要求1定义且B为权利要求1定义其中R2,R3和R4之一为氢的基团B”的式(I)化合物转变成其中R6和X如权利要求1定义且B为权利要求1定义基团B’的相应式(I)化合物,且如果需要,3)盐化其中R6和X如权利要求1定义且B为权利要求1定义基团B’的式(I)化合物。
6.含权利要求1中定义的式(I)喜树碱衍生物或其可药用盐作为活性成分及可药用载体和/或稀释剂的药物组合物。
7.用于治疗人体或动物体的治疗方法的权利要求1定义的式(I)喜树碱衍生物或其可药用盐。
8.用作抗癌药物的权利要求7中要求的化合物。
9.权利要求1中定义的式(I)化合物或其可药用盐在制备用作抗癌药的药物组合物中的用途。
Applications Claiming Priority (2)
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GB9402934.5 | 1994-02-16 | ||
GB9402934A GB9402934D0 (en) | 1994-02-16 | 1994-02-16 | Camptothecin derivatives and process for their preparation |
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CN1123548A true CN1123548A (zh) | 1996-05-29 |
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CN95190093A Pending CN1123548A (zh) | 1994-02-16 | 1995-02-03 | 喜树碱衍生物及其制备方法 |
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US (2) | US5602141A (zh) |
EP (1) | EP0694035B1 (zh) |
JP (1) | JPH08509244A (zh) |
KR (1) | KR960701878A (zh) |
CN (1) | CN1123548A (zh) |
AT (1) | ATE220681T1 (zh) |
AU (1) | AU681941B2 (zh) |
CA (1) | CA2158855C (zh) |
DE (1) | DE69527400T2 (zh) |
ES (1) | ES2180625T3 (zh) |
FI (1) | FI954898A0 (zh) |
GB (1) | GB9402934D0 (zh) |
HU (1) | HUT73423A (zh) |
IL (1) | IL112622A (zh) |
MX (1) | MX9504287A (zh) |
NO (1) | NO954072L (zh) |
NZ (1) | NZ279813A (zh) |
PL (1) | PL311122A1 (zh) |
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CN100338066C (zh) * | 2001-11-30 | 2007-09-19 | 中外制药株式会社 | 六环化合物 |
CN101555250B (zh) * | 2009-05-19 | 2011-05-18 | 重庆泰濠制药有限公司 | 盐酸拓扑替康的制备方法 |
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GB9402934D0 (en) * | 1994-02-16 | 1994-04-06 | Erba Carlo Spa | Camptothecin derivatives and process for their preparation |
GB9410388D0 (en) * | 1994-05-24 | 1994-07-13 | Erba Carlo Spa | Method for the preparation of 9-amino camptothecin |
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US6096336A (en) * | 1996-01-30 | 2000-08-01 | The Stehlin Foundation For Cancer Research | Liposomal prodrugs comprising derivatives of camptothecin and methods of treating cancer using these prodrugs |
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US6043367A (en) * | 1998-09-30 | 2000-03-28 | Roffler; Steve | Proactive antitumor compounds |
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US6352996B1 (en) | 1999-08-03 | 2002-03-05 | The Stehlin Foundation For Cancer Research | Liposomal prodrugs comprising derivatives of camptothecin and methods of treating cancer using these prodrugs |
WO2001024763A2 (en) | 1999-10-01 | 2001-04-12 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
US8034831B2 (en) | 2002-11-06 | 2011-10-11 | Celgene Corporation | Methods for the treatment and management of myeloproliferative diseases using 4-(amino)-2-(2,6-Dioxo(3-piperidyl)-isoindoline-1,3-dione in combination with other therapies |
US7563810B2 (en) | 2002-11-06 | 2009-07-21 | Celgene Corporation | Methods of using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione for the treatment and management of myeloproliferative diseases |
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CZ299593B6 (cs) * | 2003-12-16 | 2008-09-10 | Pliva-Lachema A. S. | Zpusob výroby 7-ethyl-10-hydroxykamptothecinu |
CA2563502A1 (en) | 2004-04-09 | 2005-10-20 | Chugai Seiyaku Kabushiki Kaisha | Novel water-soluble prodrug |
TW200744603A (en) | 2005-08-22 | 2007-12-16 | Chugai Pharmaceutical Co Ltd | Novel anticancer concomitant drug |
JP5126900B2 (ja) * | 2009-02-24 | 2013-01-23 | 株式会社渡辺オイスター研究所 | カキ肉エキス顆粒の製造方法。 |
EP4347601A1 (en) * | 2021-05-27 | 2024-04-10 | Zymeworks BC Inc. | Camptothecin analogues, conjugates and methods of use |
AU2022367142A1 (en) | 2021-10-15 | 2024-03-28 | Kunshan Xinyunda Biotech Co., Ltd. | Composition containing antitumor drug, and preparation method therefor and use thereof |
WO2023178452A1 (en) * | 2022-03-25 | 2023-09-28 | Zymeworks Bc Inc. | Antibody-drug conjugates targeting folate receptor alpha and methods of use |
TW202421137A (zh) * | 2022-10-19 | 2024-06-01 | 加拿大商酵活英屬哥倫比亞有限公司 | 靶向NaPi2b之抗體—藥物結合物及使用方法 |
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GB9402934D0 (en) * | 1994-02-16 | 1994-04-06 | Erba Carlo Spa | Camptothecin derivatives and process for their preparation |
-
1994
- 1994-02-16 GB GB9402934A patent/GB9402934D0/en active Pending
-
1995
- 1995-02-03 EP EP95908901A patent/EP0694035B1/en not_active Expired - Lifetime
- 1995-02-03 AU AU17056/95A patent/AU681941B2/en not_active Ceased
- 1995-02-03 WO PCT/EP1995/000393 patent/WO1995022549A1/en active IP Right Grant
- 1995-02-03 DE DE69527400T patent/DE69527400T2/de not_active Expired - Fee Related
- 1995-02-03 ES ES95908901T patent/ES2180625T3/es not_active Expired - Lifetime
- 1995-02-03 MX MX9504287A patent/MX9504287A/es unknown
- 1995-02-03 HU HU9503273A patent/HUT73423A/hu unknown
- 1995-02-03 NZ NZ279813A patent/NZ279813A/en unknown
- 1995-02-03 PL PL95311122A patent/PL311122A1/xx unknown
- 1995-02-03 AT AT95908901T patent/ATE220681T1/de active
- 1995-02-03 KR KR1019950704455A patent/KR960701878A/ko not_active Application Discontinuation
- 1995-02-03 CN CN95190093A patent/CN1123548A/zh active Pending
- 1995-02-03 CA CA002158855A patent/CA2158855C/en not_active Expired - Fee Related
- 1995-02-03 JP JP7521541A patent/JPH08509244A/ja not_active Ceased
- 1995-02-13 IL IL112622A patent/IL112622A/xx not_active IP Right Cessation
- 1995-02-15 ZA ZA951227A patent/ZA951227B/xx unknown
- 1995-02-15 US US08/389,190 patent/US5602141A/en not_active Expired - Fee Related
- 1995-10-13 FI FI954898A patent/FI954898A0/fi not_active Application Discontinuation
- 1995-10-13 NO NO954072A patent/NO954072L/no unknown
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100338066C (zh) * | 2001-11-30 | 2007-09-19 | 中外制药株式会社 | 六环化合物 |
CN101555250B (zh) * | 2009-05-19 | 2011-05-18 | 重庆泰濠制药有限公司 | 盐酸拓扑替康的制备方法 |
Also Published As
Publication number | Publication date |
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KR960701878A (ko) | 1996-03-28 |
EP0694035B1 (en) | 2002-07-17 |
US5602141A (en) | 1997-02-11 |
US5801167A (en) | 1998-09-01 |
IL112622A (en) | 1997-09-30 |
JPH08509244A (ja) | 1996-10-01 |
CA2158855C (en) | 2006-01-31 |
AU681941B2 (en) | 1997-09-11 |
NO954072L (no) | 1995-12-11 |
HU9503273D0 (en) | 1996-01-29 |
GB9402934D0 (en) | 1994-04-06 |
ES2180625T3 (es) | 2003-02-16 |
HUT73423A (en) | 1996-07-29 |
NO954072D0 (no) | 1995-10-13 |
PL311122A1 (en) | 1996-02-05 |
WO1995022549A1 (en) | 1995-08-24 |
MX9504287A (es) | 1997-05-31 |
DE69527400T2 (de) | 2003-03-06 |
CA2158855A1 (en) | 1995-08-24 |
IL112622A0 (en) | 1995-05-26 |
DE69527400D1 (de) | 2002-08-22 |
NZ279813A (en) | 1996-10-28 |
ATE220681T1 (de) | 2002-08-15 |
FI954898A (fi) | 1995-10-13 |
AU1705695A (en) | 1995-09-04 |
EP0694035A1 (en) | 1996-01-31 |
ZA951227B (en) | 1996-01-19 |
FI954898A0 (fi) | 1995-10-13 |
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