CA2214565C - Nouvelles cryptophycines obtenues par synthese - Google Patents
Nouvelles cryptophycines obtenues par synthese Download PDFInfo
- Publication number
- CA2214565C CA2214565C CA002214565A CA2214565A CA2214565C CA 2214565 C CA2214565 C CA 2214565C CA 002214565 A CA002214565 A CA 002214565A CA 2214565 A CA2214565 A CA 2214565A CA 2214565 C CA2214565 C CA 2214565C
- Authority
- CA
- Canada
- Prior art keywords
- cryptophycin
- taken together
- unit
- compound
- methyl
- 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.)
- Expired - Lifetime
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- 229930188224 Cryptophycin Natural products 0.000 title claims abstract description 346
- 230000015572 biosynthetic process Effects 0.000 title claims description 32
- 108010002156 Depsipeptides Proteins 0.000 title abstract description 118
- 238000003786 synthesis reaction Methods 0.000 title description 27
- PSNOPSMXOBPNNV-VVCTWANISA-N cryptophycin 1 Chemical class C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H]2[C@H](O2)C=2C=CC=CC=2)C/C=C/C(=O)N1 PSNOPSMXOBPNNV-VVCTWANISA-N 0.000 claims abstract description 322
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 81
- 239000003814 drug Substances 0.000 claims abstract description 45
- 210000004962 mammalian cell Anatomy 0.000 claims abstract description 28
- PSNOPSMXOBPNNV-UHFFFAOYSA-N cryptophycin-327 Natural products C1=C(Cl)C(OC)=CC=C1CC1C(=O)NCC(C)C(=O)OC(CC(C)C)C(=O)OC(C(C)C2C(O2)C=2C=CC=CC=2)CC=CC(=O)N1 PSNOPSMXOBPNNV-UHFFFAOYSA-N 0.000 claims description 274
- 150000001875 compounds Chemical class 0.000 claims description 263
- 108010006226 cryptophycin Proteins 0.000 claims description 232
- 229910052739 hydrogen Inorganic materials 0.000 claims description 217
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 163
- -1 monoalkylamino Chemical group 0.000 claims description 114
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 69
- 239000001257 hydrogen Substances 0.000 claims description 64
- 150000002431 hydrogen Chemical group 0.000 claims description 49
- 150000002118 epoxides Chemical group 0.000 claims description 48
- 229910052760 oxygen Inorganic materials 0.000 claims description 46
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 45
- 239000001301 oxygen Substances 0.000 claims description 45
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 37
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 34
- 239000002246 antineoplastic agent Substances 0.000 claims description 28
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 22
- 229940034982 antineoplastic agent Drugs 0.000 claims description 22
- 230000035755 proliferation Effects 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 238000011282 treatment Methods 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 229910052757 nitrogen Chemical group 0.000 claims description 14
- 150000003553 thiiranes Chemical group 0.000 claims description 14
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 13
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 12
- 125000004069 aziridinyl group Chemical group 0.000 claims description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000006289 hydroxybenzyl group Chemical group 0.000 claims description 11
- 230000003463 hyperproliferative effect Effects 0.000 claims description 11
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 11
- 229910019142 PO4 Inorganic materials 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 10
- 210000004072 lung Anatomy 0.000 claims description 10
- 230000001575 pathological effect Effects 0.000 claims description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 10
- 239000010452 phosphate Substances 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000006307 alkoxy benzyl group Chemical group 0.000 claims description 9
- 125000003282 alkyl amino group Chemical group 0.000 claims description 9
- 125000004414 alkyl thio group Chemical group 0.000 claims description 9
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- 125000005208 trialkylammonium group Chemical group 0.000 claims description 9
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 8
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 7
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- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 230000002496 gastric effect Effects 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
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- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 230000000955 neuroendocrine Effects 0.000 claims description 3
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- 201000002094 pancreatic adenocarcinoma Diseases 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
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- 125000001544 thienyl group Chemical group 0.000 claims description 3
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- 125000005843 halogen group Chemical group 0.000 claims 1
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- 238000000034 method Methods 0.000 abstract description 64
- 238000006257 total synthesis reaction Methods 0.000 abstract description 7
- 230000009826 neoplastic cell growth Effects 0.000 abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 183
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 162
- 239000000243 solution Substances 0.000 description 107
- 210000004027 cell Anatomy 0.000 description 100
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 94
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 89
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 83
- 238000005481 NMR spectroscopy Methods 0.000 description 79
- 239000000203 mixture Substances 0.000 description 79
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 76
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 74
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 69
- 229910001868 water Inorganic materials 0.000 description 69
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 65
- 101150041968 CDC13 gene Proteins 0.000 description 60
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 55
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 50
- 229910052799 carbon Inorganic materials 0.000 description 50
- QCHPKSFMDHPSNR-UHFFFAOYSA-N 3-aminoisobutyric acid Chemical compound NCC(C)C(O)=O QCHPKSFMDHPSNR-UHFFFAOYSA-N 0.000 description 48
- 230000000694 effects Effects 0.000 description 47
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 43
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 42
- 229960003048 vinblastine Drugs 0.000 description 42
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 42
- 108010089438 cryptophycin 1 Proteins 0.000 description 41
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 40
- 229940079593 drug Drugs 0.000 description 38
- 239000002243 precursor Substances 0.000 description 37
- 102000029749 Microtubule Human genes 0.000 description 35
- 108091022875 Microtubule Proteins 0.000 description 35
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- 150000001261 hydroxy acids Chemical group 0.000 description 34
- 125000000217 alkyl group Chemical group 0.000 description 33
- 235000019439 ethyl acetate Nutrition 0.000 description 32
- 239000007787 solid Substances 0.000 description 31
- 239000002904 solvent Substances 0.000 description 29
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 28
- 229940024606 amino acid Drugs 0.000 description 28
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 26
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 25
- 125000001309 chloro group Chemical group Cl* 0.000 description 25
- 238000003756 stirring Methods 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
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- LVRFTAZAXQPQHI-RXMQYKEDSA-N (R)-2-hydroxy-4-methylpentanoic acid Chemical compound CC(C)C[C@@H](O)C(O)=O LVRFTAZAXQPQHI-RXMQYKEDSA-N 0.000 description 21
- 229930012538 Paclitaxel Natural products 0.000 description 20
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 20
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 20
- TVIRNGFXQVMMGB-OFWIHYRESA-N (3s,6r,10r,13e,16s)-16-[(2r,3r,4s)-4-chloro-3-hydroxy-4-phenylbutan-2-yl]-10-[(3-chloro-4-methoxyphenyl)methyl]-6-methyl-3-(2-methylpropyl)-1,4-dioxa-8,11-diazacyclohexadec-13-ene-2,5,9,12-tetrone Chemical class C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H](O)[C@@H](Cl)C=2C=CC=CC=2)C/C=C/C(=O)N1 TVIRNGFXQVMMGB-OFWIHYRESA-N 0.000 description 19
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- YFGZFQNBPSCWPN-UHFFFAOYSA-N cryptophycin 52 Chemical class C1=CC(OC)=CC=C1CC1C(=O)NCC(C)C(=O)OC(CC(C)C)C(=O)OC(C(C)C2C(O2)C=2C=CC=CC=2)CC=CC(=O)N1 YFGZFQNBPSCWPN-UHFFFAOYSA-N 0.000 description 15
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- PMXCMJLOPOFPBT-HNNXBMFYSA-N purvalanol A Chemical compound C=12N=CN(C(C)C)C2=NC(N[C@@H](CO)C(C)C)=NC=1NC1=CC=CC(Cl)=C1 PMXCMJLOPOFPBT-HNNXBMFYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
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- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- JREYOWJEWZVAOR-UHFFFAOYSA-N triazanium;[3-methylbut-3-enoxy(oxido)phosphoryl] phosphate Chemical compound [NH4+].[NH4+].[NH4+].CC(=C)CCOP([O-])(=O)OP([O-])([O-])=O JREYOWJEWZVAOR-UHFFFAOYSA-N 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- ZBZJXHCVGLJWFG-UHFFFAOYSA-N trichloromethyl(.) Chemical compound Cl[C](Cl)Cl ZBZJXHCVGLJWFG-UHFFFAOYSA-N 0.000 description 1
- VYNGFCUGSYEOOZ-UHFFFAOYSA-N triphenylphosphine sulfide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=S)C1=CC=CC=C1 VYNGFCUGSYEOOZ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
Abstract
L'invention concerne de nouveaux composés de cryptophycines ainsi que des procédés de production de cryptophycines obtenus par synthèse totale. L'invention traite également de procédés d'utilisation de ces cryptophycines comme produits pharmaceutiques pour inhiber la prolifération des cellules de mammifères et pour traiter les néoplasies.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/400,057 | 1995-03-07 | ||
| US08/400,057 US6013626A (en) | 1993-12-21 | 1995-03-07 | Cryptophycins from synthesis |
| US08/482,141 | 1995-06-07 | ||
| US08/482,141 US5952298A (en) | 1993-12-21 | 1995-06-07 | Cryptophycins |
| PCT/US1996/003246 WO1996040184A1 (fr) | 1995-03-07 | 1996-03-07 | Nouvelles cryptophycines obtenues par synthese |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2214565A1 CA2214565A1 (fr) | 1996-12-19 |
| CA2214565C true CA2214565C (fr) | 2007-05-29 |
Family
ID=38147734
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002214565A Expired - Lifetime CA2214565C (fr) | 1995-03-07 | 1996-03-07 | Nouvelles cryptophycines obtenues par synthese |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2214565C (fr) |
-
1996
- 1996-03-07 CA CA002214565A patent/CA2214565C/fr not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CA2214565A1 (fr) | 1996-12-19 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20160307 |