CN101365679B - 制备cc-1065类似物的方法和化合物 - Google Patents
制备cc-1065类似物的方法和化合物 Download PDFInfo
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- CN101365679B CN101365679B CN2006800491755A CN200680049175A CN101365679B CN 101365679 B CN101365679 B CN 101365679B CN 2006800491755 A CN2006800491755 A CN 2006800491755A CN 200680049175 A CN200680049175 A CN 200680049175A CN 101365679 B CN101365679 B CN 101365679B
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- compound
- unsubstituted
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- alkyl
- aryl
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- 238000000034 method Methods 0.000 title claims abstract description 47
- 150000001875 compounds Chemical class 0.000 title claims description 145
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 93
- -1 CBI CC-1065 analogue Chemical class 0.000 claims description 65
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 49
- 125000003118 aryl group Chemical group 0.000 claims description 43
- 125000001072 heteroaryl group Chemical group 0.000 claims description 34
- 229910052757 nitrogen Inorganic materials 0.000 claims description 29
- 230000000903 blocking effect Effects 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 21
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- XLJMAIOERFSOGZ-UHFFFAOYSA-N cyanic acid Chemical compound OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 claims description 16
- 125000005842 heteroatom Chemical group 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 150000001412 amines Chemical class 0.000 claims description 10
- 150000001721 carbon Chemical group 0.000 claims description 10
- 125000004122 cyclic group Chemical group 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
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- 230000029936 alkylation Effects 0.000 claims description 5
- 238000005804 alkylation reaction Methods 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 229930195733 hydrocarbon Natural products 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 229910052710 silicon Inorganic materials 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
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- 125000001151 peptidyl group Chemical group 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 238000006073 displacement reaction Methods 0.000 claims description 3
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 claims description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims 2
- 238000010511 deprotection reaction Methods 0.000 claims 2
- 125000003545 alkoxy group Chemical group 0.000 abstract description 8
- 239000000543 intermediate Substances 0.000 abstract description 2
- 125000004093 cyano group Chemical group *C#N 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 58
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 35
- 150000001413 amino acids Chemical class 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 31
- 235000001014 amino acid Nutrition 0.000 description 31
- 150000003839 salts Chemical class 0.000 description 21
- 239000007787 solid Substances 0.000 description 21
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- 238000003756 stirring Methods 0.000 description 19
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- 235000019439 ethyl acetate Nutrition 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000002585 base Substances 0.000 description 13
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- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 125000001424 substituent group Chemical group 0.000 description 10
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical group SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- UOWVMDUEMSNCAV-WYENRQIDSA-N rachelmycin Chemical class C1([C@]23C[C@@H]2CN1C(=O)C=1NC=2C(OC)=C(O)C4=C(C=2C=1)CCN4C(=O)C1=CC=2C=4CCN(C=4C(O)=C(C=2N1)OC)C(N)=O)=CC(=O)C1=C3C(C)=CN1 UOWVMDUEMSNCAV-WYENRQIDSA-N 0.000 description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 125000002252 acyl group Chemical group 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
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- 238000011534 incubation Methods 0.000 description 8
- 125000000547 substituted alkyl group Chemical group 0.000 description 8
- 125000003107 substituted aryl group Chemical group 0.000 description 8
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
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- 108010047041 Complementarity Determining Regions Proteins 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
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- 239000012043 crude product Substances 0.000 description 6
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N isopropyl alcohol Natural products CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 229940125898 compound 5 Drugs 0.000 description 5
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- 231100000419 toxicity Toxicity 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical class [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 230000027455 binding Effects 0.000 description 4
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- HIYWOHBEPVGIQN-UHFFFAOYSA-N 1h-benzo[g]indole Chemical compound C1=CC=CC2=C(NC=C3)C3=CC=C21 HIYWOHBEPVGIQN-UHFFFAOYSA-N 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
Description
Claims (13)
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- 2006-10-18 AT AT06839458T patent/ATE534629T1/de active
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- 2006-10-18 DK DK06839458.4T patent/DK1940789T3/da active
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EA200801176A1 (ru) | 2009-02-27 |
WO2007051081A8 (en) | 2010-12-16 |
ATE534629T1 (de) | 2011-12-15 |
DK1940789T3 (da) | 2012-03-19 |
CN101365679A (zh) | 2009-02-11 |
BRPI0619331A2 (pt) | 2011-09-27 |
HK1118549A1 (en) | 2009-02-13 |
CA2627046C (en) | 2015-09-15 |
EA015324B1 (ru) | 2011-06-30 |
JP2009513676A (ja) | 2009-04-02 |
JP5116686B2 (ja) | 2013-01-09 |
SI1940789T1 (sl) | 2012-03-30 |
RS52100B (en) | 2012-06-30 |
IL190971A0 (en) | 2008-12-29 |
NO20082243L (no) | 2008-07-21 |
EP1940789B1 (en) | 2011-11-23 |
IL190971A (en) | 2013-02-28 |
ZA200804521B (en) | 2009-04-29 |
WO2007051081A1 (en) | 2007-05-03 |
PT1940789E (pt) | 2012-02-01 |
US7847105B2 (en) | 2010-12-07 |
KR20080068084A (ko) | 2008-07-22 |
CA2627046A1 (en) | 2007-05-03 |
CY1112533T1 (el) | 2015-12-09 |
US20080281102A1 (en) | 2008-11-13 |
WO2007051081B1 (en) | 2007-07-19 |
AU2006305842A1 (en) | 2007-05-03 |
EP1940789A1 (en) | 2008-07-09 |
AU2006305842B2 (en) | 2011-11-03 |
PL1940789T3 (pl) | 2012-04-30 |
ES2375843T3 (es) | 2012-03-06 |
HRP20120058T1 (hr) | 2012-02-29 |
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