CA2548951A1

CA2548951A1 - Kinase inhibitor phosphonate conjugates

Kinase inhibitor phosphonate conjugates Download PDF

Info

Publication number: CA2548951A1
Authority: CA; Canada
Prior art keywords: compound; formula; substituted; kinase; alkyl
Prior art date: 2003-12-22
Legal status : Abandoned

Application number

CA002548951A

Other languages

English (en)

French (fr)

Inventor

William J. Watkins

Current Assignee

Gilead Sciences Inc

Original Assignee

Individual

Priority date

2003-12-22

Filing date

2004-12-22

Publication date

2005-07-14

2004-04-26 Priority claimed from PCT/US2004/013062 external-priority patent/WO2004096234A2/en

2004-12-22 Application filed by Individual filed Critical Individual

2005-07-14 Publication of CA2548951A1 publication Critical patent/CA2548951A1/en

Status Abandoned legal-status Critical Current

Links

UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 title description 97
229940043355 kinase inhibitor Drugs 0.000 title description 11
239000003757 phosphotransferase inhibitor Substances 0.000 title description 11
150000001875 compounds Chemical class 0.000 claims abstract description 326
238000000034 method Methods 0.000 claims abstract description 194
239000000203 mixture Substances 0.000 claims abstract description 91
108091000080 Phosphotransferase Proteins 0.000 claims abstract description 57
102000020233 phosphotransferase Human genes 0.000 claims abstract description 57
230000002401 inhibitory effect Effects 0.000 claims abstract description 30
229910052760 oxygen Inorganic materials 0.000 claims description 102
229910052757 nitrogen Inorganic materials 0.000 claims description 86
125000004432 carbon atom Chemical group C* 0.000 claims description 64
125000000217 alkyl group Chemical group 0.000 claims description 63
125000006239 protecting group Chemical group 0.000 claims description 55
239000004480 active ingredient Substances 0.000 claims description 47
125000003118 aryl group Chemical group 0.000 claims description 39
239000003814 drug Substances 0.000 claims description 38
229910052717 sulfur Inorganic materials 0.000 claims description 36
238000009472 formulation Methods 0.000 claims description 35
125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 35
206010028980 Neoplasm Diseases 0.000 claims description 34
150000003839 salts Chemical class 0.000 claims description 33
125000003710 aryl alkyl group Chemical group 0.000 claims description 31
125000000623 heterocyclic group Chemical group 0.000 claims description 31
229910052739 hydrogen Inorganic materials 0.000 claims description 30
239000001257 hydrogen Substances 0.000 claims description 27
238000011282 treatment Methods 0.000 claims description 27
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
125000003107 substituted aryl group Chemical group 0.000 claims description 22
241001465754 Metazoa Species 0.000 claims description 21
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108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 19
125000005842 heteroatom Chemical group 0.000 claims description 19
201000011510 cancer Diseases 0.000 claims description 18
125000003342 alkenyl group Chemical group 0.000 claims description 17
239000000546 pharmaceutical excipient Substances 0.000 claims description 17
125000000547 substituted alkyl group Chemical group 0.000 claims description 14
ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 13
125000000753 cycloalkyl group Chemical group 0.000 claims description 13
238000001727 in vivo Methods 0.000 claims description 13
239000008194 pharmaceutical composition Substances 0.000 claims description 13
229910052801 chlorine Inorganic materials 0.000 claims description 11
229910052731 fluorine Inorganic materials 0.000 claims description 11
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229910052794 bromium Inorganic materials 0.000 claims description 9
229910052740 iodine Inorganic materials 0.000 claims description 9
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HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
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125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
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229910052698 phosphorus Inorganic materials 0.000 abstract description 5
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OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 abstract description 3
239000011574 phosphorus Substances 0.000 abstract description 3
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239000000047 product Substances 0.000 description 105
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NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 70
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125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 23
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JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 17
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238000005859 coupling reaction Methods 0.000 description 16
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 16
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 16
KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 15
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XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
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