SK52003A3 - Colchinol derivatives as angiogenesis inhibitors, method for their preparation and pharmaceutical composition comprising the same - Google Patents
Colchinol derivatives as angiogenesis inhibitors, method for their preparation and pharmaceutical composition comprising the same Download PDFInfo
- Publication number
- SK52003A3 SK52003A3 SK5-2003A SK52003A SK52003A3 SK 52003 A3 SK52003 A3 SK 52003A3 SK 52003 A SK52003 A SK 52003A SK 52003 A3 SK52003 A3 SK 52003A3
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- SK
- Slovakia
- Prior art keywords
- group
- alkyl
- carbon atoms
- amino
- compound
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 9
- HSDSUBIABLFGDX-AWEZNQCLSA-N (7s)-7-amino-1,2,3-trimethoxy-6,7-dihydro-5h-dibenzo[5,3-b:1',2'-e][7]annulen-9-ol Chemical class C1C[C@H](N)C2=CC(O)=CC=C2C2=C1C=C(OC)C(OC)=C2OC HSDSUBIABLFGDX-AWEZNQCLSA-N 0.000 title abstract description 3
- 238000000034 method Methods 0.000 title description 43
- 239000004037 angiogenesis inhibitor Substances 0.000 title description 4
- 229940121369 angiogenesis inhibitor Drugs 0.000 title description 2
- -1 hydroxy, phosphoryloxy Chemical group 0.000 claims abstract description 138
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 59
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 50
- 239000001257 hydrogen Substances 0.000 claims abstract description 48
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 22
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 21
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 15
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 10
- 150000002148 esters Chemical class 0.000 claims abstract description 8
- 238000001727 in vivo Methods 0.000 claims abstract description 8
- 125000002883 imidazolyl group Chemical group 0.000 claims abstract description 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 157
- 125000000217 alkyl group Chemical group 0.000 claims description 146
- 125000004432 carbon atom Chemical group C* 0.000 claims description 139
- 150000003839 salts Chemical class 0.000 claims description 72
- 229910052757 nitrogen Inorganic materials 0.000 claims description 62
- 229940002612 prodrug Drugs 0.000 claims description 55
- 239000000651 prodrug Substances 0.000 claims description 55
- 239000012453 solvate Substances 0.000 claims description 50
- 125000003545 alkoxy group Chemical group 0.000 claims description 35
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 34
- 125000001424 substituent group Chemical group 0.000 claims description 34
- 125000000623 heterocyclic group Chemical group 0.000 claims description 33
- 125000003277 amino group Chemical group 0.000 claims description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
- 241001465754 Metazoa Species 0.000 claims description 25
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 23
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 21
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 16
- 125000006239 protecting group Chemical group 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 14
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 14
- 125000005842 heteroatom Chemical group 0.000 claims description 14
- 239000001301 oxygen Substances 0.000 claims description 14
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 12
- 125000001589 carboacyl group Chemical group 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 10
- 230000000254 damaging effect Effects 0.000 claims description 10
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 9
- 125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 claims description 9
- 125000004193 piperazinyl group Chemical group 0.000 claims description 9
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 8
- 125000002757 morpholinyl group Chemical group 0.000 claims description 8
- 125000004043 oxo group Chemical group O=* 0.000 claims description 8
- 125000005936 piperidyl group Chemical group 0.000 claims description 8
- 230000002792 vascular Effects 0.000 claims description 8
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 7
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 7
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 7
- 125000006699 (C1-C3) hydroxyalkyl group Chemical group 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- 125000006697 (C1-C3) aminoalkyl group Chemical group 0.000 claims description 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- 125000005242 carbamoyl alkyl group Chemical group 0.000 claims description 5
- 125000000524 functional group Chemical group 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 4
- STCOOQWBFONSKY-UHFFFAOYSA-N tributyl phosphate Chemical compound CCCCOP(=O)(OCCCC)OCCCC STCOOQWBFONSKY-UHFFFAOYSA-N 0.000 claims description 4
- IAGFPWUZTLVULW-KRWDZBQOSA-N 2-amino-n-[2-oxo-2-[[(7s)-1,2,3,9-tetramethoxy-6,7-dihydro-5h-dibenzo[5,3-b:1',2'-e][7]annulen-7-yl]amino]ethyl]acetamide Chemical compound NCC(=O)NCC(=O)N[C@H]1CCC2=CC(OC)=C(OC)C(OC)=C2C2=CC=C(OC)C=C21 IAGFPWUZTLVULW-KRWDZBQOSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 2
- LHZQBYZXLGZBJZ-UHFFFAOYSA-N cyclohept-4-en-1-amine Chemical compound NC1CCC=CCC1 LHZQBYZXLGZBJZ-UHFFFAOYSA-N 0.000 claims description 2
- ZJXZSIYSNXKHEA-UHFFFAOYSA-N ethyl dihydrogen phosphate Chemical compound CCOP(O)(O)=O ZJXZSIYSNXKHEA-UHFFFAOYSA-N 0.000 claims description 2
- 150000002440 hydroxy compounds Chemical class 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 150000008300 phosphoramidites Chemical class 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims 2
- GJVYXMVWXNYWRD-NRFANRHFSA-N 2-morpholin-4-ylethyl n-[(7s)-1,2,3,9-tetramethoxy-6,7-dihydro-5h-dibenzo[5,3-b:1',2'-e][7]annulen-7-yl]carbamate Chemical compound N([C@@H]1C=2C(C3=C(OC)C(OC)=C(OC)C=C3CC1)=CC=C(C=2)OC)C(=O)OCCN1CCOCC1 GJVYXMVWXNYWRD-NRFANRHFSA-N 0.000 claims 1
- 235000007119 Ananas comosus Nutrition 0.000 claims 1
- 244000099147 Ananas comosus Species 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 125000003275 alpha amino acid group Chemical group 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
- 206010028980 Neoplasm Diseases 0.000 description 35
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- 239000000243 solution Substances 0.000 description 21
- 238000011282 treatment Methods 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- 210000005166 vasculature Anatomy 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 150000002431 hydrogen Chemical class 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
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- MAHWPDWNBBRICZ-HNNXBMFYSA-N (7s)-1,2,3,9-tetramethoxy-6,7-dihydro-5h-dibenzo[5,3-b:1',2'-e][7]annulen-7-amine Chemical compound N[C@H]1CCC2=CC(OC)=C(OC)C(OC)=C2C2=CC=C(OC)C=C21 MAHWPDWNBBRICZ-HNNXBMFYSA-N 0.000 description 9
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- 125000002252 acyl group Chemical group 0.000 description 9
- 201000011510 cancer Diseases 0.000 description 9
- 238000000921 elemental analysis Methods 0.000 description 9
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 8
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PCT/GB2001/002964 WO2002008213A1 (en) | 2000-07-07 | 2001-07-04 | Colchinol derivatives as angiogenesis inhibitors |
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JP (1) | JP2004504391A (ko) |
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AU (2) | AU2001266232B2 (ko) |
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GB9714249D0 (en) * | 1997-07-08 | 1997-09-10 | Angiogene Pharm Ltd | Vascular damaging agents |
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KR20030022264A (ko) | 2003-03-15 |
IL153325A0 (en) | 2003-07-06 |
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NO20030055D0 (no) | 2003-01-06 |
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CA2410562A1 (en) | 2002-01-31 |
EE200300015A (et) | 2004-10-15 |
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BR0112225A (pt) | 2003-05-06 |
JP2004504391A (ja) | 2004-02-12 |
IS6668A (is) | 2003-01-03 |
EP1301498A1 (en) | 2003-04-16 |
MXPA02012903A (es) | 2004-07-30 |
CN1255392C (zh) | 2006-05-10 |
AU2001266232B2 (en) | 2005-09-15 |
HUP0301742A3 (en) | 2005-08-29 |
NO20030055L (no) | 2003-01-06 |
CN1440396A (zh) | 2003-09-03 |
WO2002008213A1 (en) | 2002-01-31 |
NZ522661A (en) | 2004-07-30 |
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