CA2586679A1

CA2586679A1 - Combined use of vitamin d derivatives and anti-proliferative agents for treating bladder cancer

Combined use of vitamin d derivatives and anti-proliferative agents for treating bladder cancer Download PDF

Info

Publication number: CA2586679A1
Authority: CA; Canada
Prior art keywords: vitamin; compound; hexane; methyl; ethyl acetate
Prior art date: 2004-11-12
Legal status : Abandoned

Application number

CA002586679A

Other languages

English (en)

French (fr)

Inventor

Luciano Adorini

Giuseppe Penna

Current Assignee

Bioxell SpA

Original Assignee

Individual

Priority date

2004-11-12

Filing date

2005-11-11

Publication date

2006-05-18

2004-11-12 Priority claimed from GB0424965A external-priority patent/GB0424965D0/en

2005-11-11 Application filed by Individual filed Critical Individual

2006-05-18 Publication of CA2586679A1 publication Critical patent/CA2586679A1/en

Status Abandoned legal-status Critical Current

Links

239000003795 chemical substances by application Substances 0.000 title claims abstract description 112
230000001028 anti-proliverative effect Effects 0.000 title claims abstract description 99
206010005003 Bladder cancer Diseases 0.000 title claims abstract description 72
208000007097 Urinary Bladder Neoplasms Diseases 0.000 title claims abstract description 72
201000005112 urinary bladder cancer Diseases 0.000 title claims abstract description 69
150000003710 vitamin D derivatives Chemical class 0.000 title claims abstract description 50
150000001875 compounds Chemical class 0.000 claims abstract description 157
239000000203 mixture Substances 0.000 claims abstract description 154
QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 claims abstract description 153
-1 vitamin D compound Chemical class 0.000 claims abstract description 143
229930003316 Vitamin D Natural products 0.000 claims abstract description 132
235000019166 vitamin D Nutrition 0.000 claims abstract description 132
239000011710 vitamin D Substances 0.000 claims abstract description 132
229940046008 vitamin d Drugs 0.000 claims abstract description 132
238000000034 method Methods 0.000 claims abstract description 44
GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 claims description 83
229960005084 calcitriol Drugs 0.000 claims description 73
235000020964 calcitriol Nutrition 0.000 claims description 72
239000011612 calcitriol Substances 0.000 claims description 72
AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 60
238000011282 treatment Methods 0.000 claims description 42
AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 37
HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 36
229960001904 epirubicin Drugs 0.000 claims description 36
229910052739 hydrogen Inorganic materials 0.000 claims description 36
229960004679 doxorubicin Drugs 0.000 claims description 29
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
239000001257 hydrogen Substances 0.000 claims description 27
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 27
229940045799 anthracyclines and related substance Drugs 0.000 claims description 25
239000008194 pharmaceutical composition Substances 0.000 claims description 20
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
230000002265 prevention Effects 0.000 claims description 17
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
208000014794 superficial urinary bladder carcinoma Diseases 0.000 claims description 13
239000003814 drug Substances 0.000 claims description 12
150000002431 hydrogen Chemical group 0.000 claims description 12
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UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
239000000969 carrier Substances 0.000 claims description 7
229960000653 valrubicin Drugs 0.000 claims description 7
ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 claims description 7
STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims description 4
XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 claims description 4
XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 claims description 4
KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 claims description 4
USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 claims description 4
229960004176 aclarubicin Drugs 0.000 claims description 4
CIDNKDMVSINJCG-GKXONYSUSA-N annamycin Chemical compound I[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(=O)CO)C1 CIDNKDMVSINJCG-GKXONYSUSA-N 0.000 claims description 4
STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims description 4
229960000908 idarubicin Drugs 0.000 claims description 4
238000004519 manufacturing process Methods 0.000 claims description 4
229960001156 mitoxantrone Drugs 0.000 claims description 4
KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 claims description 4
229960001221 pirarubicin Drugs 0.000 claims description 4
238000011260 co-administration Methods 0.000 claims description 3
229960000975 daunorubicin Drugs 0.000 claims description 3
CTMCWCONSULRHO-UHQPFXKFSA-N nemorubicin Chemical compound C1CO[C@H](OC)CN1[C@@H]1[C@H](O)[C@H](C)O[C@@H](O[C@@H]2C3=C(O)C=4C(=O)C5=C(OC)C=CC=C5C(=O)C=4C(O)=C3C[C@](O)(C2)C(=O)CO)C1 CTMCWCONSULRHO-UHQPFXKFSA-N 0.000 claims description 2
229940070710 valerate Drugs 0.000 claims description 2
YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims 1
229910052731 fluorine Chemical group 0.000 claims 1
239000011737 fluorine Chemical group 0.000 claims 1
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 269
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 267
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XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 149
239000011647 vitamin D3 Substances 0.000 description 137
229940021056 vitamin d3 Drugs 0.000 description 137
229910001868 water Inorganic materials 0.000 description 117
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 81
239000012267 brine Substances 0.000 description 71
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 71
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 64
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 62
230000015572 biosynthetic process Effects 0.000 description 58
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VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 48
210000003932 urinary bladder Anatomy 0.000 description 47
210000004027 cell Anatomy 0.000 description 45
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QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 34
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FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 32
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101150041968 CDC13 gene Proteins 0.000 description 28
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