TW200403994A

TW200403994A - Oral administration of EPOTHILONES

Oral administration of EPOTHILONES Download PDF

Info

Publication number: TW200403994A
Authority: TW; Taiwan
Prior art keywords: group; alkyl; substituted; fluorene; aryl
Prior art date: 2002-04-04

Application number

TW092107147A

Other languages

English (en)

Chinese (zh)

Inventor

Francis Y Lee

Original Assignee

Bristol Myers Squibb Co

Priority date

2002-04-04

Filing date

2003-03-28

Publication date

2004-03-16

2003-03-28 Application filed by Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co

2004-03-16 Publication of TW200403994A publication Critical patent/TW200403994A/zh

Links

229930013356 epothilone Natural products 0.000 title claims abstract description 11
HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical compound C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 title abstract description 10
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 60
238000000034 method Methods 0.000 claims abstract description 53
239000002552 dosage form Substances 0.000 claims abstract description 41
150000001875 compounds Chemical class 0.000 claims description 111
125000000217 alkyl group Chemical group 0.000 claims description 97
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 93
239000000203 mixture Substances 0.000 claims description 92
239000002253 acid Substances 0.000 claims description 88
239000000872 buffer Substances 0.000 claims description 85
125000000547 substituted alkyl group Chemical group 0.000 claims description 84
125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 72
150000003839 salts Chemical class 0.000 claims description 72
239000007788 liquid Substances 0.000 claims description 69
229910052740 iodine Inorganic materials 0.000 claims description 66
NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 65
239000000651 prodrug Substances 0.000 claims description 62
229940002612 prodrug Drugs 0.000 claims description 62
230000003472 neutralizing effect Effects 0.000 claims description 60
239000012453 solvate Substances 0.000 claims description 57
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 54
-1 substituted vanillyl Chemical group 0.000 claims description 51
239000002904 solvent Substances 0.000 claims description 49
125000003118 aryl group Chemical group 0.000 claims description 48
239000006186 oral dosage form Substances 0.000 claims description 45
125000003107 substituted aryl group Chemical group 0.000 claims description 39
239000003814 drug Substances 0.000 claims description 38
229940079593 drug Drugs 0.000 claims description 37
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
125000000623 heterocyclic group Chemical group 0.000 claims description 26
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 24
239000007787 solid Substances 0.000 claims description 24
229910052736 halogen Inorganic materials 0.000 claims description 23
150000002367 halogens Chemical class 0.000 claims description 23
125000004429 atom Chemical group 0.000 claims description 19
229910052799 carbon Inorganic materials 0.000 claims description 18
150000004677 hydrates Chemical class 0.000 claims description 14
239000008363 phosphate buffer Substances 0.000 claims description 13
239000007937 lozenge Substances 0.000 claims description 12
239000003795 chemical substances by application Substances 0.000 claims description 11
238000000354 decomposition reaction Methods 0.000 claims description 11
238000006386 neutralization reaction Methods 0.000 claims description 11
239000000126 substance Substances 0.000 claims description 10
229910019142 PO4 Inorganic materials 0.000 claims description 9
239000007979 citrate buffer Substances 0.000 claims description 9
229910052757 nitrogen Inorganic materials 0.000 claims description 9
125000005843 halogen group Chemical group 0.000 claims description 8
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 8
239000010452 phosphate Substances 0.000 claims description 8
125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 6
125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 6
239000011734 sodium Substances 0.000 claims description 6
125000004434 sulfur atom Chemical group 0.000 claims description 6
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
229910052708 sodium Inorganic materials 0.000 claims description 5
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
229960004543 anhydrous citric acid Drugs 0.000 claims description 4
125000001072 heteroaryl group Chemical group 0.000 claims description 4
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
241000124008 Mammalia Species 0.000 claims description 3
230000003139 buffering effect Effects 0.000 claims description 3
150000003883 epothilone derivatives Chemical class 0.000 claims description 3
238000004519 manufacturing process Methods 0.000 claims description 3
229910052760 oxygen Inorganic materials 0.000 claims description 3
NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 3
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims description 2
229910052717 sulfur Inorganic materials 0.000 claims description 2
150000002118 epoxides Chemical class 0.000 claims 6
125000004435 hydrogen atom Chemical group [H]* 0.000 claims 4
DVIVLYHDLNAXAT-OAQYLSRUSA-N (2R)-2-[[3-cyano-2-[4-(2-fluoro-3-methylphenyl)phenyl]-1,7-naphthyridin-4-yl]amino]butanoic acid Chemical compound CC[C@H](C(=O)O)NC1=C(C(=NC2=C1C=CN=C2)C3=CC=C(C=C3)C4=CC=CC(=C4F)C)C#N DVIVLYHDLNAXAT-OAQYLSRUSA-N 0.000 claims 2
UTEHUKGJDLVHIH-UHFFFAOYSA-N 2-(4-methylphenyl)-1h-quinazolin-4-one Chemical compound C1=CC(C)=CC=C1C1=NC(=O)C2=CC=CC=C2N1 UTEHUKGJDLVHIH-UHFFFAOYSA-N 0.000 claims 2
NUUYFIBMHLLMSL-QGZVFWFLSA-N 6-[(2R)-2-benzylpyrrolidin-1-yl]-4-morpholin-4-yl-1H-pyridin-2-one Chemical compound C(C1=CC=CC=C1)[C@@H]1N(CCC1)C1=CC(=CC(N1)=O)N1CCOCC1 NUUYFIBMHLLMSL-QGZVFWFLSA-N 0.000 claims 2
PLICJOZBQFYDQQ-UHFFFAOYSA-N C(CC(O)(C(=O)O)CC(=O)O)(=O)O.C(CC(O)(C(=O)O)CC(=O)O)(=O)O.P(=O)(O)(O)O Chemical compound C(CC(O)(C(=O)O)CC(=O)O)(=O)O.C(CC(O)(C(=O)O)CC(=O)O)(=O)O.P(=O)(O)(O)O PLICJOZBQFYDQQ-UHFFFAOYSA-N 0.000 claims 2
150000001335 aliphatic alkanes Chemical class 0.000 claims 2
125000003147 glycosyl group Chemical group 0.000 claims 2
229910052739 hydrogen Inorganic materials 0.000 claims 2
WWDRZXVUQYMTLY-RITPCOANSA-N methyl (2s,4r)-4-amino-1-methylpyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1C[C@@H](N)CN1C WWDRZXVUQYMTLY-RITPCOANSA-N 0.000 claims 2
BEGRGCCTDSKILY-ROUUACIJSA-N (2s)-1-[(2s)-6-amino-2-[(2,2,2-trifluoroacetyl)amino]hexanoyl]-n-(4-propan-2-ylphenyl)pyrrolidine-2-carboxamide Chemical compound C1=CC(C(C)C)=CC=C1NC(=O)[C@H]1N(C(=O)[C@H](CCCCN)NC(=O)C(F)(F)F)CCC1 BEGRGCCTDSKILY-ROUUACIJSA-N 0.000 claims 1
OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 1
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 1
125000003158 alcohol group Chemical group 0.000 claims 1
210000004051 gastric juice Anatomy 0.000 claims 1
239000008103 glucose Substances 0.000 claims 1
229910052735 hafnium Inorganic materials 0.000 claims 1
VBJZVLUMGGDVMO-UHFFFAOYSA-N hafnium atom Chemical compound [Hf] VBJZVLUMGGDVMO-UHFFFAOYSA-N 0.000 claims 1
229910052698 phosphorus Inorganic materials 0.000 claims 1
239000011574 phosphorus Substances 0.000 claims 1
150000003254 radicals Chemical class 0.000 claims 1
239000001509 sodium citrate Substances 0.000 claims 1
230000000144 pharmacologic effect Effects 0.000 abstract description 14
229940126062 Compound A Drugs 0.000 description 124
NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 124
206010028980 Neoplasm Diseases 0.000 description 77
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239000000243 solution Substances 0.000 description 53
238000009472 formulation Methods 0.000 description 40
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229960001592 paclitaxel Drugs 0.000 description 34
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 34
241000282414 Homo sapiens Species 0.000 description 31
241000699670 Mus sp. Species 0.000 description 30
210000004027 cell Anatomy 0.000 description 26
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 23
239000004480 active ingredient Substances 0.000 description 23
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238000004458 analytical method Methods 0.000 description 22
238000010253 intravenous injection Methods 0.000 description 18
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238000001990 intravenous administration Methods 0.000 description 14
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XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
150000001412 amines Chemical class 0.000 description 12
239000004359 castor oil Substances 0.000 description 12
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