CA2393026A1

CA2393026A1 - Bryostatin analogues, synthetic methods and uses

Bryostatin analogues, synthetic methods and uses Download PDF

Info

Publication number: CA2393026A1
Authority: CA; Canada
Prior art keywords: mmol; compound; formula; etoac; salt
Prior art date: 1999-11-30
Legal status : Abandoned

Application number

CA002393026A

Other languages

English (en)

French (fr)

Inventor

Paul A. Wender

Blaise Lippa

Cheol-Min Park

Kevin W. Hinkle

Current Assignee

Leland Stanford Junior University

Original Assignee

Individual

Priority date

1999-11-30

Filing date

2000-11-30

Publication date

2001-06-07

2000-11-30 Application filed by Individual filed Critical Individual

2001-06-07 Publication of CA2393026A1 publication Critical patent/CA2393026A1/en

Status Abandoned legal-status Critical Current

Links

MJQUEDHRCUIRLF-TVIXENOKSA-N bryostatin 1 Chemical class C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)[C@H]([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-TVIXENOKSA-N 0.000 title claims abstract description 50
238000010189 synthetic method Methods 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims abstract description 176
238000000034 method Methods 0.000 claims abstract description 60
229960005520 bryostatin Drugs 0.000 claims abstract description 49
MUIWQCKLQMOUAT-AKUNNTHJSA-N bryostatin 20 Natural products COC(=O)C=C1C[C@@]2(C)C[C@]3(O)O[C@](C)(C[C@@H](O)CC(=O)O[C@](C)(C[C@@]4(C)O[C@](O)(CC5=CC(=O)O[C@]45C)C(C)(C)C=C[C@@](C)(C1)O2)[C@@H](C)O)C[C@H](OC(=O)C(C)(C)C)C3(C)C MUIWQCKLQMOUAT-AKUNNTHJSA-N 0.000 claims abstract description 26
229910052739 hydrogen Inorganic materials 0.000 claims description 117
150000003839 salts Chemical class 0.000 claims description 40
125000000217 alkyl group Chemical group 0.000 claims description 36
230000015572 biosynthetic process Effects 0.000 claims description 36
238000003786 synthesis reaction Methods 0.000 claims description 33
229910052717 sulfur Inorganic materials 0.000 claims description 32
229910052760 oxygen Inorganic materials 0.000 claims description 28
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 25
125000001424 substituent group Chemical group 0.000 claims description 25
125000004432 carbon atom Chemical group C* 0.000 claims description 24
125000003342 alkenyl group Chemical group 0.000 claims description 23
239000001301 oxygen Substances 0.000 claims description 23
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 21
239000001257 hydrogen Substances 0.000 claims description 19
238000011282 treatment Methods 0.000 claims description 19
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
229910052799 carbon Inorganic materials 0.000 claims description 17
125000000304 alkynyl group Chemical group 0.000 claims description 15
125000003118 aryl group Chemical group 0.000 claims description 15
239000002243 precursor Substances 0.000 claims description 11
125000004429 atom Chemical group 0.000 claims description 10
239000008194 pharmaceutical composition Substances 0.000 claims description 8
239000000546 pharmaceutical excipient Substances 0.000 claims description 8
239000003795 chemical substances by application Substances 0.000 claims description 7
125000001072 heteroaryl group Chemical group 0.000 claims description 7
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
241000124008 Mammalia Species 0.000 claims description 6
125000003710 aryl alkyl group Chemical group 0.000 claims description 6
125000004475 heteroaralkyl group Chemical group 0.000 claims description 6
230000007246 mechanism Effects 0.000 claims description 6
125000001624 naphthyl group Chemical group 0.000 claims description 6
125000004122 cyclic group Chemical group 0.000 claims description 5
230000001225 therapeutic effect Effects 0.000 claims description 4
125000003367 polycyclic group Chemical group 0.000 claims description 2
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125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
125000006850 spacer group Chemical group 0.000 abstract description 10
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HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 178
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101150041968 CDC13 gene Proteins 0.000 description 138
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ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 95
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 94
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 78
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UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 24
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 23
MJQUEDHRCUIRLF-YCVQJEHTSA-N bryostatins Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)C([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-YCVQJEHTSA-N 0.000 description 23
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RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 21
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235000017557 sodium bicarbonate Nutrition 0.000 description 21
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HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 20
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DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 16
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GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 14
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