CA2286239A1 - Procede de traitement du cancer - Google Patents
Procede de traitement du cancer Download PDFInfo
- Publication number
- CA2286239A1 CA2286239A1 CA002286239A CA2286239A CA2286239A1 CA 2286239 A1 CA2286239 A1 CA 2286239A1 CA 002286239 A CA002286239 A CA 002286239A CA 2286239 A CA2286239 A CA 2286239A CA 2286239 A1 CA2286239 A1 CA 2286239A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- aryl
- substituted
- unsubstituted
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 101
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 28
- 201000011510 cancer Diseases 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 182
- 229940123038 Integrin antagonist Drugs 0.000 claims abstract description 34
- 239000003112 inhibitor Substances 0.000 claims abstract description 22
- 241000124008 Mammalia Species 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 14
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 566
- 125000003118 aryl group Chemical group 0.000 claims description 426
- -1 heteroaroyl Chemical group 0.000 claims description 177
- 229910052739 hydrogen Inorganic materials 0.000 claims description 152
- 239000001257 hydrogen Substances 0.000 claims description 151
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 131
- 125000000623 heterocyclic group Chemical group 0.000 claims description 129
- 102200160920 rs35304565 Human genes 0.000 claims description 119
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 111
- 150000002431 hydrogen Chemical class 0.000 claims description 110
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 97
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 92
- 125000003545 alkoxy group Chemical group 0.000 claims description 80
- 125000001424 substituent group Chemical group 0.000 claims description 72
- 229910052760 oxygen Inorganic materials 0.000 claims description 67
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 66
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 64
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 63
- 125000005842 heteroatom Chemical group 0.000 claims description 61
- 102220389089 c.33G>T Human genes 0.000 claims description 57
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 56
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 56
- 125000003107 substituted aryl group Chemical group 0.000 claims description 56
- 125000004432 carbon atom Chemical group C* 0.000 claims description 55
- 125000002947 alkylene group Chemical group 0.000 claims description 54
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 claims description 54
- 229910052757 nitrogen Inorganic materials 0.000 claims description 53
- 229910052717 sulfur Inorganic materials 0.000 claims description 52
- 229910052731 fluorine Inorganic materials 0.000 claims description 48
- 229910052736 halogen Inorganic materials 0.000 claims description 48
- 150000002367 halogens Chemical class 0.000 claims description 48
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 46
- 229910052799 carbon Inorganic materials 0.000 claims description 46
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 44
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 43
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 claims description 42
- 125000004949 alkyl amino carbonyl amino group Chemical group 0.000 claims description 39
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 39
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 38
- 229910052794 bromium Inorganic materials 0.000 claims description 38
- 229910052801 chlorine Inorganic materials 0.000 claims description 38
- 102000006495 integrins Human genes 0.000 claims description 38
- 108010044426 integrins Proteins 0.000 claims description 38
- 125000001072 heteroaryl group Chemical group 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 36
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 35
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 34
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 31
- 150000001413 amino acids Chemical class 0.000 claims description 31
- 125000004122 cyclic group Chemical group 0.000 claims description 31
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 30
- 150000001721 carbon Chemical group 0.000 claims description 30
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 28
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 27
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 27
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 26
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 26
- 125000002950 monocyclic group Chemical group 0.000 claims description 26
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 25
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 24
- 125000005195 alkyl amino carbonyloxy group Chemical group 0.000 claims description 23
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 22
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 22
- 150000002460 imidazoles Chemical class 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 108090000623 proteins and genes Proteins 0.000 claims description 22
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 21
- 125000000304 alkynyl group Chemical group 0.000 claims description 21
- 230000001225 therapeutic effect Effects 0.000 claims description 21
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 20
- 125000004442 acylamino group Chemical group 0.000 claims description 20
- 125000003342 alkenyl group Chemical group 0.000 claims description 20
- 239000005557 antagonist Substances 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 19
- 125000003282 alkyl amino group Chemical group 0.000 claims description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 19
- 102000004169 proteins and genes Human genes 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 18
- 125000002883 imidazolyl group Chemical group 0.000 claims description 18
- 102220517591 Methyl-CpG-binding domain protein 3-like 2B_R11C_mutation Human genes 0.000 claims description 17
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 17
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 16
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 16
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 16
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 15
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 125000004043 oxo group Chemical group O=* 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 13
- 150000001732 carboxylic acid derivatives Chemical group 0.000 claims description 13
- 125000003367 polycyclic group Polymers 0.000 claims description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 12
- 125000005100 aryl amino carbonyl group Chemical group 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 11
- 150000001408 amides Chemical class 0.000 claims description 11
- 239000011737 fluorine Chemical group 0.000 claims description 11
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 11
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 10
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 10
- 229920006395 saturated elastomer Chemical group 0.000 claims description 10
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 8
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 claims description 8
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 claims description 8
- 150000008574 D-amino acids Chemical class 0.000 claims description 8
- 125000001931 aliphatic group Chemical group 0.000 claims description 8
- 125000000033 alkoxyamino group Chemical group 0.000 claims description 8
- 229910052786 argon Inorganic materials 0.000 claims description 8
- 125000003435 aroyl group Chemical group 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 8
- 230000005764 inhibitory process Effects 0.000 claims description 8
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N methylimidazole Natural products CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 7
- 229930195733 hydrocarbon Natural products 0.000 claims description 7
- 125000001963 4 membered heterocyclic group Chemical group 0.000 claims description 6
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 6
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 6
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 6
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 6
- 125000001960 7 membered carbocyclic group Chemical group 0.000 claims description 6
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 6
- 101150020251 NR13 gene Proteins 0.000 claims description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000001769 aryl amino group Chemical group 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 235000019260 propionic acid Nutrition 0.000 claims description 6
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 6
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 6
- 229910052720 vanadium Inorganic materials 0.000 claims description 6
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 5
- 125000006560 (C1-C5)alkylcarbonylamino group Chemical group 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 5
- 150000002430 hydrocarbons Chemical class 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 239000000758 substrate Substances 0.000 claims description 5
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 5
- 230000004614 tumor growth Effects 0.000 claims description 5
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 4
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 4
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 4
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 4
- QEFRNWWLZKMPFJ-ZXPFJRLXSA-N L-methionine (R)-S-oxide Chemical compound C[S@@](=O)CC[C@H]([NH3+])C([O-])=O QEFRNWWLZKMPFJ-ZXPFJRLXSA-N 0.000 claims description 4
- UCUNFLYVYCGDHP-BYPYZUCNSA-N L-methionine sulfone Chemical compound CS(=O)(=O)CC[C@H](N)C(O)=O UCUNFLYVYCGDHP-BYPYZUCNSA-N 0.000 claims description 4
- QEFRNWWLZKMPFJ-UHFFFAOYSA-N L-methionine sulphoxide Natural products CS(=O)CCC(N)C(O)=O QEFRNWWLZKMPFJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004691 alkyl thio carbonyl group Chemical group 0.000 claims description 4
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 4
- 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 4
- 125000005002 aryl methyl group Chemical group 0.000 claims description 4
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 4
- 235000010290 biphenyl Nutrition 0.000 claims description 4
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 4
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 4
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 230000003287 optical effect Effects 0.000 claims description 4
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 4
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 3
- QOHNKSGSGSZCNK-UHFFFAOYSA-N 4-[[5-[(3-methoxy-4-phenylanilino)methyl]imidazol-1-yl]methyl]benzonitrile Chemical compound C=1C=C(C=2C=CC=CC=2)C(OC)=CC=1NCC1=CN=CN1CC1=CC=C(C#N)C=C1 QOHNKSGSGSZCNK-UHFFFAOYSA-N 0.000 claims description 3
- 108091008648 NR7C Proteins 0.000 claims description 3
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 3
- 229940125898 compound 5 Drugs 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 3
- 229930192474 thiophene Natural products 0.000 claims description 3
- SIEXHGZWGJLLAC-OSTWSGHESA-N (2s)-2-[[(2s)-2-[(2s,3s)-2-[[(2r)-2-amino-3-sulfanylpropyl]amino]-3-methylpentoxy]-3-phenylpropanoyl]amino]-4-methylsulfonylbutanoic acid Chemical compound SC[C@H](N)CN[C@@H]([C@@H](C)CC)CO[C@H](C(=O)N[C@@H](CCS(C)(=O)=O)C(O)=O)CC1=CC=CC=C1 SIEXHGZWGJLLAC-OSTWSGHESA-N 0.000 claims description 2
- PSVBRVBRNCRSRH-OALUTQOASA-N (3s)-3-[[2-[(3s)-2-oxo-3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-ylmethylamino)pyrrolidin-1-yl]acetyl]amino]-3-pyridin-3-ylpropanoic acid Chemical compound C1([C@@H](NC(=O)CN2C([C@@H](NCC=3N=C4NCCCC4=CC=3)CC2)=O)CC(=O)O)=CC=CN=C1 PSVBRVBRNCRSRH-OALUTQOASA-N 0.000 claims description 2
- JLPWKVWUGXSHGX-GOTSBHOMSA-N (3s)-3-[[2-[(3s)-2-oxo-3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-ylmethylamino)pyrrolidin-1-yl]acetyl]amino]-3-quinolin-3-ylpropanoic acid Chemical compound C1=CC=CC2=CC([C@@H](NC(=O)CN3C([C@@H](NCC=4N=C5NCCCC5=CC=4)CC3)=O)CC(=O)O)=CN=C21 JLPWKVWUGXSHGX-GOTSBHOMSA-N 0.000 claims description 2
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 2
- HNZWSDHIOTWZCQ-VDZZXDNDSA-N 2-[(s)-[[2-[(3s)-2-oxo-3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-ylmethylamino)pyrrolidin-1-yl]acetyl]amino]-pyridin-3-ylmethyl]butanoic acid Chemical compound C1([C@@H](NC(=O)CN2C([C@@H](NCC=3N=C4NCCCC4=CC=3)CC2)=O)C(CC)C(O)=O)=CC=CN=C1 HNZWSDHIOTWZCQ-VDZZXDNDSA-N 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 claims description 2
- YJOMRKGHKZAPJK-DEOSSOPVSA-N 4-[2-[5-[[(2s)-4-(3-chlorophenyl)-2-(2-methylsulfonylethyl)-5-oxopiperazin-1-yl]methyl]imidazol-1-yl]propan-2-yl]benzonitrile Chemical compound C1=NC=C(CN2[C@H](CN(C(=O)C2)C=2C=C(Cl)C=CC=2)CCS(C)(=O)=O)N1C(C)(C)C1=CC=C(C#N)C=C1 YJOMRKGHKZAPJK-DEOSSOPVSA-N 0.000 claims description 2
- NLZOACWOGZPESV-UHFFFAOYSA-N 4-[[2-[1-[4-(3-chlorophenyl)-3-oxopiperazin-1-yl]ethyl]-1h-imidazol-5-yl]methyl]benzonitrile Chemical compound N=1C=C(CC=2C=CC(=CC=2)C#N)NC=1C(C)N(CC1=O)CCN1C1=CC=CC(Cl)=C1 NLZOACWOGZPESV-UHFFFAOYSA-N 0.000 claims description 2
- RZCCSBJIZHJNDF-UHFFFAOYSA-N 4-[[3-[(6-pyridin-2-ylpyridin-3-yl)methyl]imidazol-4-yl]methyl]benzonitrile Chemical compound C1=CC(C#N)=CC=C1CC1=CN=CN1CC1=CC=C(C=2N=CC=CC=2)N=C1 RZCCSBJIZHJNDF-UHFFFAOYSA-N 0.000 claims description 2
- UDFSQTKNKSQMRH-UHFFFAOYSA-N 4-[[5-(4-phenylphenoxy)imidazol-1-yl]methyl]benzonitrile Chemical compound C1=CC(C#N)=CC=C1CN1C(OC=2C=CC(=CC=2)C=2C=CC=CC=2)=CN=C1 UDFSQTKNKSQMRH-UHFFFAOYSA-N 0.000 claims description 2
- SWACOCQRVHRVTA-MHZLTWQESA-N 4-[[5-[2-[(2s)-2-butyl-4-(naphthalene-1-carbonyl)piperazin-1-yl]-2-oxoethyl]imidazol-1-yl]methyl]benzonitrile Chemical compound C([C@@H]1CCCC)N(C(=O)C=2C3=CC=CC=C3C=CC=2)CCN1C(=O)CC1=CN=CN1CC1=CC=C(C#N)C=C1 SWACOCQRVHRVTA-MHZLTWQESA-N 0.000 claims description 2
- RMZQNOARFIICNW-DEOSSOPVSA-N 4-[[5-[[(2s)-4-(2,3-dimethylphenyl)-2-(2-methoxyethyl)-5-oxopiperazin-1-yl]methyl]imidazol-1-yl]methyl]benzonitrile Chemical compound C([C@@H]1CCOC)N(C=2C(=C(C)C=CC=2)C)C(=O)CN1CC1=CN=CN1CC1=CC=C(C#N)C=C1 RMZQNOARFIICNW-DEOSSOPVSA-N 0.000 claims description 2
- JNUGFGAVPBYSHF-UHFFFAOYSA-N L-778,123 (free base) Chemical compound ClC1=CC=CC(N2C(CN(CC=3N(C=NC=3)CC=3C=CC(=CC=3)C#N)CC2)=O)=C1 JNUGFGAVPBYSHF-UHFFFAOYSA-N 0.000 claims description 2
- CNADKONKVARWGQ-UHFFFAOYSA-N O=C1N(C=CC(=C1)CN1C=NC=C1CC1=CC=C(C#N)C=C1)C1=CC=CC=C1.ClC=1C=CC(N(C1)C1=NC=C(C=C1)CN1C(=CC=C1)CC1=CC=C(C#N)C=C1)=O Chemical compound O=C1N(C=CC(=C1)CN1C=NC=C1CC1=CC=C(C#N)C=C1)C1=CC=CC=C1.ClC=1C=CC(N(C1)C1=NC=C(C=C1)CN1C(=CC=C1)CC1=CC=C(C#N)C=C1)=O CNADKONKVARWGQ-UHFFFAOYSA-N 0.000 claims description 2
- RLKCKOPHQUKVOE-UHFFFAOYSA-N O=C1N(C=CC=C1)C1=NC=C(C=C1)CN1C(=CC=C1)CC1=CC=C(C#N)C=C1.ClC=1C=CC(N(C1)C1=CC=C(CN2C(=CC=C2)CC2=CC=C(C#N)C=C2)C=C1)=O Chemical compound O=C1N(C=CC=C1)C1=NC=C(C=C1)CN1C(=CC=C1)CC1=CC=C(C#N)C=C1.ClC=1C=CC(N(C1)C1=CC=C(CN2C(=CC=C2)CC2=CC=C(C#N)C=C2)C=C1)=O RLKCKOPHQUKVOE-UHFFFAOYSA-N 0.000 claims description 2
- PVYWVOMHDKGWBJ-QFIPXVFZSA-N [(3s)-3-butyl-4-[3-(1h-imidazol-5-yl)propyl]piperazin-1-yl]-naphthalen-1-ylmethanone Chemical compound C([C@@H]1CCCC)N(C(=O)C=2C3=CC=CC=C3C=CC=2)CCN1CCCC1=CNC=N1 PVYWVOMHDKGWBJ-QFIPXVFZSA-N 0.000 claims description 2
- LJCGCTKDZDSLPX-YTTGMZPUSA-N [(3s)-3-butyl-4-[[3-[(4-phenylphenyl)methyl]imidazol-4-yl]methyl]piperazin-1-yl]-naphthalen-1-ylmethanone Chemical compound C([C@@H]1CCCC)N(C(=O)C=2C3=CC=CC=C3C=CC=2)CCN1CC1=CN=CN1CC(C=C1)=CC=C1C1=CC=CC=C1 LJCGCTKDZDSLPX-YTTGMZPUSA-N 0.000 claims description 2
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Abstract
L'invention concerne des procédés de traitement du cancer visant à utiliser en combinaison un composé antagoniste de l'intégrine et un composé inhibiteur de farnésyl transférase, lesdits procédés consistant à administrer à un mammifère, de manière séquentielle dans un ordre indéterminé ou simultanément, des quantités d'au moins deux agents thérapeutiques choisis dans un groupe comprenant un composé antagoniste de l'intégrine et un composé inhibiteur de farnésyle transférase. L'invention concerne aussi des procédés qui permettent d'élaborer les compositions considérées.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US4192397P | 1997-04-07 | 1997-04-07 | |
US60/041,923 | 1997-04-07 | ||
GBGB9800976.4A GB9800976D0 (en) | 1998-01-16 | 1998-01-16 | A Method of treating cancer |
GB9800976.4 | 1998-01-16 | ||
PCT/US1998/006823 WO1998044797A1 (fr) | 1997-04-07 | 1998-04-06 | Procede de traitement du cancer |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2286239A1 true CA2286239A1 (fr) | 1998-10-15 |
Family
ID=26312961
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002286239A Abandoned CA2286239A1 (fr) | 1997-04-07 | 1998-04-06 | Procede de traitement du cancer |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0973396A4 (fr) |
JP (1) | JP2001524079A (fr) |
AU (1) | AU724216B2 (fr) |
CA (1) | CA2286239A1 (fr) |
WO (1) | WO1998044797A1 (fr) |
Families Citing this family (56)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE69716900T2 (de) * | 1996-04-10 | 2003-07-03 | Merck & Co., Inc. | Alpha v Beta 3 ANTAGONISTEN |
WO1998018461A1 (fr) * | 1996-10-30 | 1998-05-07 | Merck & Co., Inc. | Antagonistes de l'integrine |
US6096757A (en) | 1998-12-21 | 2000-08-01 | Schering Corporation | Method for treating proliferative diseases |
CA2347671A1 (fr) | 1998-12-24 | 2000-07-06 | Dupont Pharmaceuticals Company | Benzodiazepines succinoylamino utilisees comme inhibiteurs de la production de proteine a.beta. |
US6960576B2 (en) | 1999-09-13 | 2005-11-01 | Bristol-Myers Squibb Pharma Company | Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production |
US6503902B2 (en) | 1999-09-13 | 2003-01-07 | Bristol-Myers Squibb Pharma Company | Hydroxyalkanoylaminolactams and related structures as inhibitors of a β protein production |
WO2001027091A1 (fr) | 1999-10-08 | 2001-04-19 | Du Pont Pharmaceuticals Company | AMINO SULFONAMIDES DE LACTAME UTILISES COMME INHIBITEURS DE LA PRODUCTION DE PROTEINE A$g(b) |
JP4039856B2 (ja) | 2000-02-03 | 2008-01-30 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | インテグリン発現阻害剤 |
JP2003523345A (ja) | 2000-02-17 | 2003-08-05 | ブリストル−マイヤーズ スクイブ ファーマ カンパニー | Aβタンパク質産生の阻害剤としてのスクシノイルアミノ炭素環および複素環 |
WO2001070670A1 (fr) | 2000-03-23 | 2001-09-27 | Ajinomoto Co., Inc. | Nouveau derive de phenylalanine |
US6495540B2 (en) | 2000-03-28 | 2002-12-17 | Bristol - Myers Squibb Pharma Company | Lactams as inhibitors of A-β protein production |
WO2001074784A1 (fr) | 2000-04-03 | 2001-10-11 | Dupont Pharmaceuticals Company | Lactames cycliques utiles en tant qu'inhibiteurs de la production de proteine a-beta |
AU2001253090A1 (en) | 2000-04-03 | 2001-10-15 | Bristol-Myers Squibb Pharma Company | Cyclic lactams as inhibitors of abeta protein production |
EP1289966A1 (fr) | 2000-04-11 | 2003-03-12 | Bristol-Myers Squibb Pharma Company | LACTAMES SUBSTITUES UTILISES EN TANT QU'INHIBITEURS DE PRODUCTION DE PROTEINE A$g(b) |
CN1386118A (zh) | 2000-06-01 | 2002-12-18 | 布里斯托尔-迈尔斯斯奎布药品公司 | 作为Aβ蛋白产生抑制剂的被环状琥珀酸酯取代的内酰胺类化合物 |
ATE350660T1 (de) * | 2001-02-21 | 2007-01-15 | Eisai Co Ltd | Verfahren zur untersuchung der wirkung eines angionegesis-hemmers unter vermittlung durch hemmung der integrin-expression |
US6770763B2 (en) | 2002-06-11 | 2004-08-03 | Bristol-Myers Squibb Company | Asymmetric synthesis of amino-pyrrolidinones |
US7414142B2 (en) | 2005-09-19 | 2008-08-19 | Wyeth | 5-aryl-indan-1-one oximes and analogs useful as progesterone receptor modulators |
US7319152B2 (en) | 2005-09-19 | 2008-01-15 | Wyeth | 5-Aryl-indan-1-one and analogs useful as progesterone receptor modulators |
LT2474545T (lt) | 2005-12-13 | 2017-02-27 | Incyte Holdings Corporation | Heteroarilu pakeisti pirolo[2,3-b]piridinai ir pirolo[2,3-b]pirimidinai kaip janus kinazės inhibitoriai |
CN101400653A (zh) | 2006-02-07 | 2009-04-01 | 惠氏公司 | 11-βHSD1抑制剂 |
CN101460483B (zh) | 2006-03-31 | 2013-05-08 | 詹森药业有限公司 | 作为组胺h4受体调节剂的苯并咪唑-2-基嘧啶和吡嗪 |
CA2689663C (fr) | 2007-06-13 | 2016-08-09 | Incyte Corporation | Sels de l'inhibiteur (r)-3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropanenitrile de la janus kinase |
US9371311B2 (en) | 2008-06-30 | 2016-06-21 | Janssen Pharmaceutica Nv | Benzoimidazol-2-yl pyrimidine derivatives |
TW201100398A (en) | 2009-03-31 | 2011-01-01 | Arqule Inc | Substituted indolo-pyridinone compounds |
BRPI1012159B1 (pt) | 2009-05-22 | 2022-01-25 | Incyte Holdings Corporation | Compostos derivados de n-(hetero)aril-pirrolidina de pirazol-4-il-pirrolo[2,3-d] pirimidinas e pirrol-3-il-pirrolo[2,3-d] pirimidinas como inibidores de janus cinase, composições farmacêuticas compreendendo os referidos compostos e usos dos mesmos |
DK2432472T3 (da) | 2009-05-22 | 2019-11-18 | Incyte Holdings Corp | 3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl]octan- eller heptan-nitril som jak-inhibitorer |
TW201113285A (en) | 2009-09-01 | 2011-04-16 | Incyte Corp | Heterocyclic derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors |
KR20220015492A (ko) | 2010-03-10 | 2022-02-08 | 인사이트 홀딩스 코포레이션 | Jak1 저해제로서의 피페리딘4일 아제티딘 유도체 |
PL2574168T3 (pl) | 2010-05-21 | 2016-10-31 | Preparaty inhibitora kinazy janusowej do stosowania miejscowego | |
CA2818542A1 (fr) | 2010-11-19 | 2012-05-24 | Incyte Corporation | Derives pyrrolopyridine et pyrrolopyrimidine a substitution cyclobutyle utilises comme inhibiteurs des jak |
ES2536415T3 (es) | 2010-11-19 | 2015-05-25 | Incyte Corporation | Pirrolopiridinas y pirrolopirimidinas sustituidas heterocíclicas como inhibidores de JAK |
EP2721028B1 (fr) | 2011-06-20 | 2015-11-04 | Incyte Corporation | Dérivés d'azétidinyl-phényl-, de pyridyl- ou de pyrazinyl-carboxamide en tant qu'inhibiteurs des jak |
TW201313721A (zh) | 2011-08-18 | 2013-04-01 | Incyte Corp | 作為jak抑制劑之環己基氮雜環丁烷衍生物 |
UA111854C2 (uk) | 2011-09-07 | 2016-06-24 | Інсайт Холдінгс Корпорейшн | Способи і проміжні сполуки для отримання інгібіторів jak |
SG11201407616TA (en) | 2012-05-17 | 2015-03-30 | Array Biopharma Inc | Process for making hydroxylated cyclopentylpyrimidine compounds |
SG11201407591PA (en) | 2012-05-17 | 2015-01-29 | Genentech Inc | Process of making hydroxylated cyclopentapyrimidine compounds and salts thereof |
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WO2013173736A1 (fr) | 2012-05-17 | 2013-11-21 | Array Biopharma Inc. | Procédé de fabrication de composés cyclopentylpyrimidines hydroxylées |
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US11833155B2 (en) | 2020-06-03 | 2023-12-05 | Incyte Corporation | Combination therapy for treatment of myeloproliferative neoplasms |
-
1998
- 1998-04-06 WO PCT/US1998/006823 patent/WO1998044797A1/fr not_active Application Discontinuation
- 1998-04-06 CA CA002286239A patent/CA2286239A1/fr not_active Abandoned
- 1998-04-06 AU AU69532/98A patent/AU724216B2/en not_active Ceased
- 1998-04-06 JP JP54301398A patent/JP2001524079A/ja active Pending
- 1998-04-06 EP EP98915318A patent/EP0973396A4/fr not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
AU6953298A (en) | 1998-10-30 |
JP2001524079A (ja) | 2001-11-27 |
AU724216B2 (en) | 2000-09-14 |
EP0973396A4 (fr) | 2001-02-07 |
EP0973396A1 (fr) | 2000-01-26 |
WO1998044797A1 (fr) | 1998-10-15 |
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