WO1998044797A1 - Procede de traitement du cancer - Google Patents
Procede de traitement du cancer Download PDFInfo
- Publication number
- WO1998044797A1 WO1998044797A1 PCT/US1998/006823 US9806823W WO9844797A1 WO 1998044797 A1 WO1998044797 A1 WO 1998044797A1 US 9806823 W US9806823 W US 9806823W WO 9844797 A1 WO9844797 A1 WO 9844797A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- aryl
- substituted
- unsubstituted
- amino
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 99
- 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 181
- 229940123038 Integrin antagonist Drugs 0.000 claims abstract description 36
- 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 758
- 125000003118 aryl group Chemical group 0.000 claims description 474
- 229910052739 hydrogen Inorganic materials 0.000 claims description 152
- 239000001257 hydrogen Substances 0.000 claims description 152
- -1 heteroaroyl Chemical group 0.000 claims description 145
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 143
- 125000000623 heterocyclic group Chemical group 0.000 claims description 128
- 125000003545 alkoxy group Chemical group 0.000 claims description 120
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 110
- 150000002431 hydrogen Chemical class 0.000 claims description 109
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 99
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 84
- 125000003282 alkyl amino group Chemical group 0.000 claims description 76
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 76
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 71
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 71
- 125000001424 substituent group Chemical group 0.000 claims description 71
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 69
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 66
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 62
- 229910052760 oxygen Inorganic materials 0.000 claims description 62
- 125000005842 heteroatom Chemical group 0.000 claims description 61
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 60
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 56
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 55
- 125000003107 substituted aryl group Chemical group 0.000 claims description 55
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 54
- 125000002947 alkylene group Chemical group 0.000 claims description 54
- 125000004432 carbon atom Chemical group C* 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
- 229910052717 sulfur Inorganic materials 0.000 claims description 51
- 229910052757 nitrogen Inorganic materials 0.000 claims description 49
- 229910052799 carbon 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
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 46
- 229910052731 fluorine Inorganic materials 0.000 claims description 46
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 45
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 43
- 125000004949 alkyl amino carbonyl amino group Chemical group 0.000 claims description 43
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 claims description 43
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 40
- 125000004390 alkyl sulfonyl 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
- 125000001072 heteroaryl group Chemical group 0.000 claims description 38
- 235000001014 amino acid Nutrition 0.000 claims description 37
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 37
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 36
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 36
- 108010044426 integrins Proteins 0.000 claims description 36
- 102000006495 integrins Human genes 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 36
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 34
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 34
- 150000001413 amino acids Chemical class 0.000 claims description 32
- 125000004122 cyclic group Chemical group 0.000 claims description 31
- 150000001721 carbon Chemical group 0.000 claims description 30
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 29
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 29
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 28
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 28
- 150000002460 imidazoles Chemical class 0.000 claims description 27
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 27
- 125000002950 monocyclic group Chemical group 0.000 claims description 26
- 125000004442 acylamino group Chemical group 0.000 claims description 24
- 125000005195 alkyl amino carbonyloxy group Chemical group 0.000 claims description 24
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 24
- 101000581118 Homo sapiens Rho-related GTP-binding protein RhoC Proteins 0.000 claims description 23
- 102100027610 Rho-related GTP-binding protein RhoC Human genes 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 23
- 101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 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
- 230000001225 therapeutic effect Effects 0.000 claims description 21
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 19
- 102000004169 proteins and genes Human genes 0.000 claims description 19
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 18
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 18
- 125000002883 imidazolyl group Chemical group 0.000 claims description 18
- 235000018102 proteins Nutrition 0.000 claims description 18
- 239000005557 antagonist Substances 0.000 claims description 17
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 125000004435 hydrogen atom Chemical group [H]* 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
- 125000004043 oxo group Chemical group O=* 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 14
- 125000005100 aryl amino carbonyl group Chemical group 0.000 claims description 14
- 235000004279 alanine Nutrition 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
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 150000001408 amides Chemical class 0.000 claims description 11
- 239000011737 fluorine Chemical group 0.000 claims description 11
- 229920006395 saturated elastomer Chemical group 0.000 claims description 11
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 10
- 235000019260 propionic acid Nutrition 0.000 claims description 10
- 229910052720 vanadium Inorganic materials 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 9
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N methylimidazole Natural products CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 claims description 9
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 claims description 9
- 102200029256 rs121964925 Human genes 0.000 claims description 9
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 9
- 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
- 125000000304 alkynyl 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
- 125000001769 aryl amino group Chemical group 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 8
- 230000005764 inhibitory process Effects 0.000 claims description 8
- 125000004076 pyridyl 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 7
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 claims description 7
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- 229930195733 hydrocarbon Natural products 0.000 claims description 7
- 102200160920 rs35304565 Human genes 0.000 claims description 7
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 6
- 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
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 6
- 235000010290 biphenyl Nutrition 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
- 102220092886 rs143733205 Human genes 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
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000003277 amino 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
- 230000003287 optical effect Effects 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 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
- 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
- 108091008648 NR7C Proteins 0.000 claims description 4
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 4
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 4
- 125000004691 alkyl thio carbonyl group Chemical group 0.000 claims description 4
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 4
- 125000006598 aminocarbonylamino group Chemical group 0.000 claims description 4
- 125000004658 aryl carbonyl amino 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
- 125000005162 aryl oxy carbonyl amino group Chemical group 0.000 claims description 4
- 125000004657 aryl sulfonyl amino 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
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 4
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 4
- 102220389089 c.33G>T Human genes 0.000 claims description 3
- 229940125898 compound 5 Drugs 0.000 claims description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 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
- 125000006823 (C1-C6) acyl group Chemical group 0.000 claims description 2
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 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
- PQAMFDRRWURCFQ-UHFFFAOYSA-N 2-ethyl-1h-imidazole Chemical compound CCC1=NC=CN1 PQAMFDRRWURCFQ-UHFFFAOYSA-N 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
- 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
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 2
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
- 125000005140 aralkylsulfonyl group Chemical group 0.000 claims description 2
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 2
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
- 230000002860 competitive effect Effects 0.000 claims description 2
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 claims description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims 2
- PDTLSIUBYNDOHS-LBPRGKRZSA-N (2S)-4-hydroxy-2-(5-pentoxypentanoylamino)butanoic acid Chemical compound CCCCCOCCCCC(=O)N[C@@H](CCO)C(O)=O PDTLSIUBYNDOHS-LBPRGKRZSA-N 0.000 claims 1
- OBYQMBFNBMSVLI-LWKPJOBUSA-N (2s)-4-hydroxy-2-[(2-methyl-3-phenylpropanoyl)-pentylsulfonylamino]butanoic acid Chemical compound CCCCCS(=O)(=O)N([C@@H](CCO)C(O)=O)C(=O)C(C)CC1=CC=CC=C1 OBYQMBFNBMSVLI-LWKPJOBUSA-N 0.000 claims 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- XYLKCEJPBKWBSJ-UHFFFAOYSA-N 4-[[5-[(n-butyl-4-phenylsulfanylanilino)methyl]imidazol-1-yl]methyl]benzonitrile Chemical compound C=1C=C(SC=2C=CC=CC=2)C=CC=1N(CCCC)CC1=CN=CN1CC1=CC=C(C#N)C=C1 XYLKCEJPBKWBSJ-UHFFFAOYSA-N 0.000 claims 1
- MRYODMJBNXKLHJ-JIDHJSLPSA-N C(#N)C1=CC=C(CC2=CN=C(N2)C(C)N2CC(N(CC2)C2=CC(=CC=C2)Cl)=O)C=C1.C(#N)C1=CC=C(CC=2C=NC=CC2N2CC(N(C[C@@H]2CCS(=O)(=O)C)C2=CC(=CC=C2)Cl)=O)C=C1 Chemical compound C(#N)C1=CC=C(CC2=CN=C(N2)C(C)N2CC(N(CC2)C2=CC(=CC=C2)Cl)=O)C=C1.C(#N)C1=CC=C(CC=2C=NC=CC2N2CC(N(C[C@@H]2CCS(=O)(=O)C)C2=CC(=CC=C2)Cl)=O)C=C1 MRYODMJBNXKLHJ-JIDHJSLPSA-N 0.000 claims 1
- QDVKETOAAQPNNT-ZSXSBBPPSA-N [(3s)-4-[3-amino-2-(naphthalen-2-ylmethylamino)propyl]-3-butylpiperazin-1-yl]-naphthalen-1-ylmethanone Chemical compound C1=CC=C2C(C(=O)N3C[C@@H](N(CC3)CC(CN)NCC=3C=C4C=CC=CC4=CC=3)CCCC)=CC=CC2=C1 QDVKETOAAQPNNT-ZSXSBBPPSA-N 0.000 claims 1
- 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 claims 1
- HKRYNIPYCZALEH-QFIPXVFZSA-N methyl (2s)-2-benzamido-3-[4-[4-(pyrimidin-2-ylamino)butoxy]phenyl]propanoate Chemical compound C([C@@H](C(=O)OC)NC(=O)C=1C=CC=CC=1)C(C=C1)=CC=C1OCCCCNC1=NC=CC=N1 HKRYNIPYCZALEH-QFIPXVFZSA-N 0.000 claims 1
- APVPOHHVBBYQAV-UHFFFAOYSA-N n-(4-aminophenyl)sulfonyloctadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 APVPOHHVBBYQAV-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 38
- 102000004357 Transferases Human genes 0.000 abstract description 27
- 108090000992 Transferases Proteins 0.000 abstract description 27
- 238000006243 chemical reaction Methods 0.000 description 113
- 239000000543 intermediate Substances 0.000 description 109
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 83
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 70
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 50
- 238000003786 synthesis reaction Methods 0.000 description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 230000015572 biosynthetic process Effects 0.000 description 39
- 229960005141 piperazine Drugs 0.000 description 38
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 37
- 150000001299 aldehydes Chemical class 0.000 description 36
- 239000000047 product Substances 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 229940024606 amino acid Drugs 0.000 description 30
- 235000019439 ethyl acetate Nutrition 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
- 238000005481 NMR spectroscopy Methods 0.000 description 28
- 238000005804 alkylation reaction Methods 0.000 description 28
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- RYGIHSLRMNXWCN-UHFFFAOYSA-N quinoline-3-carbaldehyde Chemical compound C1=CC=CC2=CC(C=O)=CN=C21 RYGIHSLRMNXWCN-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000004620 quinolinyl-N-oxide group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
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- 201000006845 reticulosarcoma Diseases 0.000 description 1
- 208000029922 reticulum cell sarcoma Diseases 0.000 description 1
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- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
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- 125000006413 ring segment Chemical group 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
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- 210000002784 stomach Anatomy 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
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- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000006089 thiamorpholinyl sulfoxide group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000004589 thienofuryl group Chemical group O1C(=CC2=C1C=CS2)* 0.000 description 1
- 125000004587 thienothienyl group Chemical group S1C(=CC2=C1C=CS2)* 0.000 description 1
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 239000003558 transferase inhibitor Substances 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 125000000169 tricyclic heterocycle group Chemical group 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 150000003668 tyrosines Chemical class 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- GSQBIOQCECCMOQ-UHFFFAOYSA-N β-alanine ethyl ester Chemical compound CCOC(=O)CCN GSQBIOQCECCMOQ-UHFFFAOYSA-N 0.000 description 1
Classifications
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Definitions
- the present invention relates to methods of treating cancer using a combination of a compound which is an integrin antagonist and a compound which is a inhibitor of farnesyl-protein transferase.
- Osteoclasts are multinucleated cells of up to 400 ⁇ m in diameter that resorb mineralized tissue, chiefly calcium carbonate and calcium phosphate, in vertebrates. They are actively motile cells that migrate along the surface of bone. They can bind to bone, secrete necessary acids and proteases and thereby cause the actual resorption of mineralized tissue from the bone.
- osteoclasts are believed to exist in at least two physiological states.
- the secretory state osteoclasts are flat, attach to the bone matrix via a tight attachment zone (sealing zone), become highly polarized, form a ruffled border, and secrete lysosomal enzymes and acid to resorb bone.
- the adhesion of osteoclasts to bone surfaces is an important initial step in bone resorption.
- the osteoclasts migrate across bone matrix and do not take part in resorption until they attach again to bone.
- Integrins are transmembrane, heterodimeric, glycoproteins which interact with extracellular matrix and are involved in osteoclast attachment, activation and migration.
- the most abundant integrin in osteoclasts (rat, chicken, mouse and human) is the vitronectin receptor, or ⁇ v ⁇ 3, thought to interact in bone with matrix proteins that contain the RGD sequence.
- Antibodies to ⁇ v ⁇ 3 block bone resorption in vitro indicating that this integrin plays a key role in the resorptive process.
- ⁇ v ⁇ 3 ligands can be used effectively to inhibit osteoclast mediated bone resoption in vivo in mammals.
- a second integrin vitronectin receptor, ⁇ v ⁇ 5 has also been identified.
- a monoclonal antibody for ⁇ v ⁇ 5 has been shown to inhibit VEGF-induced angiogenesis in rabbit cornea and the chick chorioallantoic membrane model. See M.C. Friedlander, et al., Science 270, 1500-1502, 1995, which is incorporated by reference herein in its entirety.
- Two collagen receptor integrins, ⁇ l ⁇ l and ⁇ 2 ⁇ l, have also been proposed to mediate VEGF-induced mitogenesis in a mouse Matrigel implant model. See D.R. Senger, et al, Proc. Natl. Acad. Sci 94, 13612-13617, 1997, which is incorporated by reference herein in its entirety.
- ⁇ v ⁇ 3 ligands have been found to be useful in treating and/or inhibiting restenosis (recurrence of stenosis after corrective surgery on the heart valve), artherosclerosis, diabetic retinopathy, macular degeneration, and angiogenesis (formation of new blood vessels).
- restenosis currence of stenosis after corrective surgery on the heart valve
- artherosclerosis diabetic retinopathy
- macular degeneration macular degeneration
- angiogenesis formation of new blood vessels.
- ⁇ v ⁇ 3 antagonists which inhibit angiogenesis, are therefore useful in the treatment of cancer for inhibiting tumor growth and metastasis. ⁇ See e.g., Brooks et al., Cell, 79:1157-1164 (1994)).
- Prenylation of proteins by intermediates of the isoprenoid biosynthetic pathway represents a class of post-translational modification (Glomset, J. A., Gelb, M. H., and Farnsworth, C. C. (1990). Trends Biochem. Sci. 15, 139-142; Maltese, W. A. (1990). FASEB J. 4, 3319-3328). This modification typically is required for the membrane localization and function of these proteins.
- Prenylated proteins share characteristic C-terminal sequences including CaaX (C, Cys; a, usually aliphatic amino acid; X, another amino acid), XXCC, or XCXC.
- Some proteins may also have a fourth modification: palmitoylation of one or two Cys residues N-terminal to the farnesylated Cys. While some mammalian cell proteins terminating in XCXC are carboxymethylated, it is not clear whether carboxy methylation follows prenylation of proteins terminating with a XXCC motif (Clarke, S. (1992). Annu. Rev. Biochem. 61, 355-386). For all of the prenylated proteins, addition of the isoprenoid is the first step and is required for the subsequent steps (Cox, A. D. and Der, C. J. (1992a). Critical Rev. Oncogenesis 3:365-400; Cox, A. D. and Der, C. J. (1992b) Current Opinion Cell Biol. 4: 1008-1016).
- FPTase farnesyl-protein transferase
- GGPTase-I geranylgeranyl- protein transferase type I
- Rab GGPTase geranylgeranyl-protein transferase type-II
- Each of these enzymes selectively uses farnesyl diphosphate or geranyl- geranyl diphosphate as the isoprenoid donor and selectively recognizes the protein substrate.
- FPTase farnesylates CaaX-containing proteins that end with Ser, Met, Cys, Gin or Ala.
- CaaX tetrapeptides comprise the minimum region required for interaction of the protein substrate with the enzyme.
- the enzymological characterization of these three enzymes has demonstrated that it is possible to selectively inhibit one with little inhibitory effect on the others (Moores, S. L., Schaber, M. D., Mosser, S. D., Rands, E., O ⁇ ara, M. B., Garsky, V.
- Ras protein is part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
- Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein.
- Ras In the inactive state, Ras is bound to GDP.
- Ras Upon growth factor receptor activation, Ras is induced to exchange GDP for GTP and undergoes a conformational change.
- the GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M. Willumsen, Ann.
- Ras Activation of Ras leads to activation of multiple intracellular signal transduction pathways, including the MAP Kinase pathway and the Rho/Rac pathway (Joneson et al, Science 277:810-812).
- Mutated ras genes are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias.
- the protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.
- the Ras protein is one of several proteins that are known to undergo post-translational modification.
- Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et al, Cell, 62:81-88 (1990); Schaber et al, J. Biol Chem., 265: 14701-14704 (1990); Schafer et al, Science, 249: 1133-1139 (1990); Manne et al, Proc. Natl Acad. Sci USA, 87:7541-7545 (1990)). Ras must be localized to the plasma membrane for both normal and oncogenic functions.
- Ras C-terminus contains a sequence motif termed a "CAAX” or "Cys-Aaal-Aaa ⁇ -Xaa” box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al, Nature 570:583-586 (1984)).
- this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C20 isoprenoid, respectively.
- farnesylated proteins include the Ras-related GTP- binding proteins such as RhoB, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above.
- FPTase farnesyl-protein transferase
- the first class includes analogs of farnesyl diphosphate (FPP), while the second is related to protein substrates (e.g., Ras) for the enzyme.
- FPP farnesyl diphosphate
- the peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al, ibid; Reiss et. al, ibid; Reiss et al, PNAS, 88:732-736 (1991)).
- Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141,851, University of Texas; N.E. Kohl et al, Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
- Mammalian cells express four types of Ras proteins (H-, N-, K4A-, and K4B-Ras) among which K-Ras4B is the most frequently mutated form of Ras in human cancers.
- Inhibition of farnesyl-protein transferase has been shown to block the growth of H-ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of the H-Ras oncoprotein intracellularly (N.E. Kohl et al, Science, 260: 1934- 1937 (1993) and G.L. James et al, Science, 260:1937-1942 (1993).
- a pharmaceutically effective combination of an integrin antagonist and a farnesyl-protein transferase inhibitor are used in the present invention to treat cancer, such as in tumor cells that are less susceptable to treatment by an integrin antagonist or a farnesyl-protein transferase inhibitor when administered alone.
- a method of treating cancer is disclosed which is comprised of administering to a mammalian patient in need of such treatment an effective amount of a combination of an integrin antagonist and a farnesyl protein transferase inhibitor.
- a selective integrin antagonist and a selective farnesyl protein transferase inhibitor are used in such a combination.
- the present invention relates to a method of treating cancer which is comprised of admininstering to a mammalian patient in need of such treatment an effective amount of a combination of an integrin antagonist and a farnesyl-protein transferase inhibitor.
- the present method of treating cancer by simultaneously inhibiting farnesyl-protein transferase and binding to either or both of the ⁇ v ⁇ 3 integrin and ⁇ v ⁇ 5 integrin offers advantages over previously disclosed methods which utilize a prenyl-protein transferase inhibitor or an integrin antagonist alone, in that the inhibitory activity of the instant combination of inhibitors against FPTase or integrin activity can be varied by formulation depending on the nature of the cancer cells to be treated.
- any compound which acts as an integrin antagonist and any compound which inhibits farnesyl protein transferase can be used in the instant method.
- the compounds utilized in the instant combination are a selective integrin antagonist and a selective farnesyl-protein transferase inhibitor.
- the integrin antagonist and the inhibitor of farnesyl-protein transferase may be administered either sequentially in any order or simultaneously.
- the therapeutic effect of the instant compositions may be achieved with smaller amounts of either or both of the integrin antagonist and farnesyl-protein transferase inhibitor than would be required if such an integrin antagonist and a selective farnesyl- protein transferase inhibitor were administered alone, thereby avoiding any non-mechanism-based adverse toxicity effects which might result from administration of an amount of the integrin antagonist or farnesyl- protein transferase inhibitor sufficient to achieve the same therapeutic effect. It is also anticipated that the instant compositions will achieve a synergistic therapeutic effect or will exhibit unexpected therapeutic advantage over the effect of either of the component compounds if administered alone.
- an integrin antagonist refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ v ⁇ 3 integrin, which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ v ⁇ 5 integrin, which antagonize, inhibit or counteract binding of a physiological ligand to both the v ⁇ 3 integrin and the ⁇ v ⁇ 5 integrin, or which antagonize, inhibit or counteract the activity of the particular integrin or integrins expressed on capillary endothelial cells.
- the term also refers to a combination of a selective antagonist of the ⁇ v ⁇ 3 integrin and a selective antagonist of the ⁇ v ⁇ 5 integrin.
- the term also refers to antagonists of the l ⁇ l and ⁇ 2 ⁇ l integrins.
- farnesyl protein transferase (FPTase) inhibiting compound likewise refers to compounds which antagonize, inhibit or counteract the activity of the gene coding farnesyl-protein transferase or the protein produced in response thereto.
- the terms selective and selectively as used herein refer to the antagonistic activity of the particular compound against either an integrin or integrins or the inhibitory activity of the compound against FPTase activity.
- a selective compound exhibits at least 20 times greater activity against either an single integrin, a group of integrins or all of the integrins which have been demonstrated as being important for angiogenesis when comparing its activity against other integrins.
- integrins which have been demonstrated as being important for angiogenesis include, but are not limited to, ⁇ v ⁇ 3, ⁇ v ⁇ 5, ⁇ l ⁇ l and ⁇ 2 ⁇ l integrins. More preferably the selectivity is at least 100 times or more.
- a selective FPTase inhibitor may also be an inhibitor of geranylgeranyl-pro ein transferase.
- the extent of selectivity of the two or more inhibitors that comprise the method of the instant invention effects the advantages that the method of treatment claimed herein offers over previously disclosed methods of using a single integrin antagonist or FPTase inhibitor for the treatment of cancer.
- use of two independent pharmaceutically active components that have complementary, essentially non-overlapping activities allows the person utilizing the instant method of treatment to independently and accurately vary the inhibitory activity of the combination without having to synthesize a single drug having a particular pharmaceutical activity profile.
- the preferred therapeutic effect provided by the instant composition is the treatment of cancer and specifically the inhibition of cancerous tumor growth and/or the regression of cancerous tumors.
- Cancers which are treatable in accordance with the invention described herein include cancers of the brain, breast, colon, genitourinary tract, lymphatic system, pancreas, rectum, stomach, larynx, liver and lung. More particularly, such cancers include histiocytic lymphoma, lung adenocarcinoma, pancreatic carcinoma, colo-rectal carcinoma, small cell lung cancers and neurological tumors.
- compositions include inhibiting: bone resorption mediated by osteoclast cells, restenosis, artherosclerosis, diabetic retinopathy, macular degeneration and angiogenesis in animals, preferably mammals, especially humans.
- the instant composition may also be useful for preventing or treating osteoporosis.
- Additional illustrations of the invention are methods of treating hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia, and glucocorticoid treatment in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above.
- composition of this invention is also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the instant composition to a mammal in need of such treatment.
- a component of NF-1 is a benign proliferative disorder.
- the composition of the instant invention is also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature medicine, 1:541-545(1995).
- the instant composition may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaffner et al. American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et ⁇ I.FASEB Journal, 2: A3160 (1988)).
- the pharmaceutical composition of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice.
- the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
- the selected combination or compounds may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension.
- carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added.
- useful diluents include lactose and dried corn starch.
- aqueous suspensions are required for oral use, the active ingredients are combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added.
- sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.
- the total concentration of solutes should be controlled in order to render the preparation isotonic.
- the combinations of the instant invention may also be co-administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
- the instant combinations may be useful in combination with other known anti-cancer and cytotoxic agents.
- compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may be introduced into a patient's blood-stream by local bolus injection.
- the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
- a suitable amount of an integrin antagonist(s) and a farnesyl-protein transferase inhibitor are administered to a mammal undergoing treatment for cancer.
- Administration occurs in an amount of each type of inhibitor of between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
- a particular therapeutic dosage that comprises the instant composition includes from about O.Olmg to about 500mg of an integrin antagonist and from about O.Olmg to about 500mg of a farnesyl-protein transferase inhibitor.
- the dosage comprises from about lmg to about lOOmg of an integrin antagonist and from about lmg to about lOOmg of a farnesyl- protein transferase inhibitor.
- the integrin antagonist component of the instant invention may be selected from the following: (a) a compound of the formula I-a:
- Aryl is a 6-membered aromatic ring containing 0, 1, 2 or 3 nitrogen atoms and either unsubstituted or substituted with R ⁇ and R9;
- X is selected from
- polycyclic ring system a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted with Rl, R2, R3 and R 4 ;
- Y is selected from
- Z and A are each independently selected from
- p is an integer from 1 to 3;
- Rl, R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , Rl°> Rl l and R 2 are each independently selected from hydrogen, halogen,
- R6 is selected from hydrogen, fluorine, Cl-8 alkyl, hydroxyl, hydroxy Cl-6 alkyl, carboxy C ⁇ -6 alkyl,
- C ⁇ -6 alkylamino CQ-6 alkyl selected from hydrogen, C ⁇ -6 alkylamino CQ-6 alkyl, C ⁇ -6 dialkylamino C ⁇ -6 alkyl, aryl C ⁇ -6 alkyloxycarbonylamino C ⁇ -6 alkyl, aryl C ⁇ -6 alkylsulfonylamino C ⁇ -6 alkyl and aryl C ⁇ -6 alkylcarbonylamino C ⁇ -6 alkyl; C7-20 polycyclyl C ⁇ -8 alkylsulfonylamino C ⁇ -6 alkyl;
- Rl3 is selected from hydroxy
- R 4, R!5, R16 an( i R17 are each independently selected from hydrogen, halogen, Cl-l ⁇ alkyl, C3-8 cycloalkyl, oxo, aryl, aryl Cl-8 alkyl, amino, amino Cl-8 alkyl, Cl-3 acylamino, Cl-3 acylamino Cl-8 alkyl, Cl-6 alkylamino, Cl-6 alkylamino-
- Ar is a 4- to 10-membered mono- or polycyclic aromatic or non- aromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S and wherein the mono- or polycyclic aromatic or non- aromatic ring system is either unsubstituted or substituted with Rl, R2, R3 and R 4 ;
- Rl, R2, R3 and R 4 are each independently selected from hydrogen, hydroxyl, Cl-8 alkyl, halogen, aryl C ⁇ -8 alkyl, oxo, thio, amino- C ⁇ -8 alkyl, Cl_3 acylamino C ⁇ -8 alkyl, Cl-6 alkylamino C ⁇ -8 alkyl, Cl-6 dialkylamino C ⁇ -8 alkyl, aryl C ⁇ -6 alkylamino C ⁇ -6 alkyl, Cl-4 alkoxyamino C ⁇ -8 alkyl, hydroxy Cl-6 alkylamino C ⁇ -8 alkyl, Cl-4 alkoxy C ⁇ -8 alkyl, carboxy C ⁇ -8 alkyl, Cl-4 alkoxycarbonyl- C ⁇ -8 alkyl, carboxy C ⁇ -8 alkoxy, hydroxy C ⁇ -8 alkyl or C3-8 cycloalkyl C ⁇ -6 alkyl;
- R5 is selected from hydrogen, Cl-6 alkyl, C ⁇ -6 alkylaryl, aryl or C3-8 cycloalkyl C ⁇ -6 alkyl;
- R6, R7, R8 and R9 are each independently selected from hydrogen, fluorine, Cl-8 alkyl, hydroxyl, hydroxy Cl-6 alkyl, carboxy- C ⁇ -6 alkyl, Cl-6 alkoxy, Cl-6 alkylcarbonyl, aryl C ⁇ -6 alkylcarbonyl, Cl-6 alkylcarbonyloxy, aryl C ⁇ -6 alkylcarbonyloxy, Cl-6 alkylamino- carbonyloxy, C3-8 cycloalkyl, aryl C ⁇ -6 alkyl, C ⁇ -6 alkylamino- C ⁇ -6 alkyl, C ⁇ -6 dialkylamino C ⁇ -6 alkyl, Cl-8 alkylsulfonylamino- C ⁇ -6 alkyl, aryl C ⁇ -6 alkylsulfonylamino C ⁇ -6 alkyl, C ⁇ -8 alkyl- S ⁇ 2NR 3 -C ⁇ -8 alkyl, aryl C ⁇ -8 alkoxycarbonylamino C ⁇ -8 alkyl, ary
- RIO is selected from hydroxyl, Cl-8 alkoxy, aryl C ⁇ -6 alkoxy, Cl-8 alkylcarbonyloxy Cl-4 alkoxy, aryl Cl-8 alkylcarbonyloxy- Cl-4 alkoxy, Cl-6 dialkylaminocarbonylmethoxy, aryl Cl-6 dialkylaminocarbonylmethoxy or an L- or D-amino acid joined by an amide linkage and wherein the carboxylic acid moiety of the amino acid is as the free acid or is esterified by Cl-6 alkyl; and
- each n is independently an integer from 0 to three; provided that when R5 is hydrogen and X is Ar and Ar is a 6-membered monocyclic non-aromatic ring system containing one nitrogen atom and R6 and R 7 are each hydrogen, and R 8 is selected from hydrogen or Cl-6 alkyl, and RlO is selected from hydroxyl, Cl-8 alkoxy, Cl-8 alkylcarbonyloxy Cl-4 alkoxy or an L- or D-amino acid joined by an amide linkage and wherein the carboxylic acid moiety of the amino acid is as the free acid or is esterified with Cl-6 alkyl, then R9 is selected from fluorine, hydroxyl, hydroxy Cl-6 alkyl, carboxy-C ⁇ -6 alkyl, Cl-6 alkoxy, Cl-6 alkylcarbonyl, aryl C ⁇ -6 alkylcarbonyl, Cl-6 alkylcarbonyloxy, aryl C ⁇ -6 alkylcarbonyloxy, Cl-6 alkylamino- carbonyloxy, C3
- R7 and R& are each hydrogen, and RlO is selected from hydroxyl and Cl-8 alkoxy, then R9 is selected from fluorine, Cl-8 alkyl, hydroxyl, hydroxy Cl-6 alkyl, carboxy CO-6 alkyl, Cl-6 alkoxy, Cl-6 alkylcarbonyl, aryl C ⁇ -6 alkylcarbonyl, Cl-6 alkylcarbonyloxy, aryl C ⁇ -6 alkylcarbonyloxy, Cl-6 alkylamino- carbonyloxy, C3-8 cycloalkyl, aryl C ⁇ -6 alkyl, C ⁇ -6 alkylamino- C ⁇ -6 alkyl, C ⁇ -6 dialkylamino C ⁇ -6 alkyl, Cl-8 alkylsulfonylamino- C ⁇ -6 alkyl, C ⁇ -8 alkyl-S ⁇ 2NR3-C ⁇ -8 alkyl, aryl C ⁇ -8 alkoxycarbonylamino C ⁇ -8 alkyl, Cl-8 alkoxycarbonylamino C ⁇ C ⁇
- X is selected from
- polycyclic ring system a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted with Rl and R 2 ;
- Y is selected from
- Z is a 5-11 membered aromatic or nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, O and S, and wherein the ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups independently selected from R4, R5 5 R6 and R 7 ; provided that Z is not a 6-membered monocyclic aromatic ring system; preferably, Z is a 5-11 membered nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, O and S, and wherein the ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups independently selected from R 4 , R5 , R6 and R7 ;
- Rl, R2, R4, R5 5 R13 and R 14 are each independently selected from hydrogen, halogen, Cl-10 alkyl, C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, amino, amino Cl-8 alkyl, Cl-3 acylamino, Cl-3 acylamino Cl-8 alkyl, Cl-6 alkylamino, Cl-6 alkylamino- Cl-8 alkyl, Cl-6 dialkylamino, Cl-6 dialkylamino Cl-8 alkyl, Cl-4 alkoxy, Cl-4 alkoxy Cl-6 alkyl, hydroxycarbonyl, hydroxycarbonyl Cl-6 alkyl, Cl-3 alkoxycarbonyl,
- R6, R7, R8 ? R9 ? RIO a nd RU are each independently selected from hydrogen, aryl,
- Cl-8 alkyl either unsubstituted or substituted, with one or more groups selected from: halogen, hydroxyl, Cl-5 alkylcarbonylamino, aryl Cl-5 alkoxy, Cl-5 alkoxycarbonyl, aminocarbonyl, Cl-5 alkylaminocarbonyl, Cl-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, Cl-3 alkylamino, amino Cl-3 alkyl, arylaminocarbonyl, aryl Cl-5 alkylaminocarbonyl, aminocarbonyl, aminocarbonyl Cl-4 alkyl, hydroxycarbonyl, or hydroxycarbonyl Cl-5 alkyl,
- Cl-6 alkylsulfonyl Cl-6 alkylsulfonyl, Cl-6 alkylsulfonyl Cl-6 alkyl, arylsulfonyl Cl-6 alkyl, aryl Cl-6 alkylsulfonyl, aryl Cl-6 alkylsulfonyl Cl-6 alkyl, Cl-6 alkylcarbonyl,
- Rl2 is selected from hydrogen, Cl-8 alkyl, aryl, aryl Cl-8 alkyl, hydroxy,
- n is an integer from 1 to 3
- p is an integer from 1 to 4
- q is an integer from 0 to 2
- r is an integer from 0 to 6
- s is an integer from 0 to 3;
- Ring is a 4- to 10-membered mono- or polycyclic aromatic or nonaromatic ring system containing 0, 1 , 2, 3 or 4 heteroatoms selected from N, O and S, and either unsubstituted or substituted with R27 and R28;
- X is selected from
- Y is selected from C ⁇ -8 alkylene, C3-10 cycloalkyl,
- n are each independently an integer from 0 to 6;
- A is selected from
- Rl, R2, R3, R4 R5, R6, R7, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27 ⁇ R28, R29 a nd R30 are each independently selected from hydrogen, halogen,
- R° " , R9, RIO ⁇ and RU are each independently selected from hydrogen, fluorine, Cl-8 alkyl, hydroxyl, hydroxy Cl-6 alkyl, carboxy C ⁇ -6 alkyl,
- Rl2 is selected from hydroxy
- Rl3, R14 ; R15 an d R16 a re each independently selected from hydrogen
- Ring is not a 6-membered monocyclic aromatic ring
- Ring is selected from isoxazole, isoxazoline, imidazole, imidazoline, benzofuran, benzothiophene, benzimidazole, indole, benzothiazole, benzoxazole,
- Y is selected from C ⁇ -8 alkylene
- Z is (CH2)m where m is an integer from 0 to 3; preferably, m is zero; and all other variables are as defined above;
- a 9- to 10-membered polycyclic ring system wherein one or more of the rings is aromatic, and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, and wherein the polycyclic ring system is either unsubstituted or substituted on a carbon atom with Rl and R2;
- Y is selected from
- Z is absent or is a 4- to 11 -membered aromatic or nonaromatic mono- or polycyclic ring system containing 0 to 6 double bonds, and containing 0 to 6 heteroatoms chosen from N, O and S, and wherein the ring system is either unsubstituted or substituted on a carbon or nitrogen atom with one or more groups independently selected from R 4, Rl ? R16 a nd Rl7; preferably, Z is not a 6-membered monocyclic aromatic ring system;
- Rl, R2, R3, R4, R5, R11, R12, R13, R16 an d Rl7 are each independently selected from hydrogen, halogen, Cl-l ⁇ alkyl, C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, amino, amino Cl-8 alkyl, Cl-3 acylamino, Cl-3 acylamino Cl-8 alkyl, Cl-6 alkylamino, Cl-6 alkylamino- Cl-8 alkyl, Cl-6 dialkylamino, Cl-6 dialkylamino Cl-8 alkyl, Cl-4 alkoxy, Cl-4 alkoxy Cl-6 alkyl, hydroxycarbonyl, hydroxycarbonyl Cl-6 alkyl, Cl-3 alkoxycarbonyl, Cl-3 alkoxycarbonyl Cl-6 alkyl, hydroxycarbonyl- Cl-6 alkyloxy, hydroxy or hydroxy Cl-6 alkyl;
- R 6 > R 7 , R 8 , R 9 , Rl4 and Rl5 are each independently selected from hydrogen, aryl, -(CH2)p-aryl, hydroxyl, Cl-8 alkylcarbonylamino, aryl Cl-5 alkoxy, Cl-5 alkoxycarbonyl, aminocarbonyl, Cl-8 alkylaminocarbonyl, Cl-6 alkylcarbonyloxy,
- Cl-8 alkyl either unsubstituted or substituted, with one or more groups selected from: halogen, hydroxyl, Cl-5 alkylcarbonylamino, aryl Cl-5 alkoxy,
- -(CH2)r CH CH Cl-6 alkylaryl, -(CH 2 )r S02Cl-6 alkyl, -(CH2) r S02Cl-6 alkylaryl, Cl_6 alkoxy, aryl Cl-6 alkoxy, aryl Cl-6 alkyl, Cl-6 alkylamino C 1 -6 alkyl, arylamino, arylamino Cl-6 alkyl, aryl Cl-6 alkylamino, aryl Cl-6 alkylamino Cl-6 alkyl, arylcarbonyloxy, aryl Cl-6 alkylcarbonyloxy, Cl-6 dialkylamino,
- RlO is selected from hydrogen
- Cl-8 alkyl aryl, aryl Cl-8 alkyl, aryl Cl_6 alkoxy, Cl-8 alkylcarbonyloxy Cl-4 alkyl, aryl Cl-8 alkylcarbonyloxy Cl-4 alkyl, Cl-8 alkylaminocarbonylmethylene, or Cl-8 dialkylaminocarbonylmethylene;
- n, n and r are each independently an integer from 0 to 3; p is an integer from 1 to 4; and q is an integer from 0 to 2;
- Examples of farnesyl protein transferase inhibiting compounds and in particular selective farnesyl protein transferase inhibiting compounds include the following:
- Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
- R2 and R are independently selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle,
- substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) Cl-4 alkyl,
- R2 and R3 are attached to the same C atom and are combined to form (CH2)u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(CORIO)- ;
- R4 and R5 are independently selected from H and CH3; and any two of R2, R3, R4 and R ⁇ are optionally attached to the same carbon atom;
- R6, R7 and R ⁇ are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
- R6 and R7 may be joined in a ring
- R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
- RIO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
- RU is independently selected from C1-C6 alkyl and aryl
- V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(0)m;
- W is a heterocycle
- Y is aryl, heterocycle, unsubstituted or substituted with one or more of:
- Cl-4 alkyl unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR6R7 ? c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(0) m R6, or g) -C(0)NR6R7,
- n 0, 1, 2, 3 or 4
- p 0, 1, 2, 3 or 4
- Rla, Rib, RlO, Rl l, m , R2, R3, R6, R7, p> R7a, u , R 8, A l, A2, V, W, X, n, p, r, s, t and u are as defined above with respect to formula (Il-a);
- R4 is selected from H and CH3;
- R2, R3 and R4 are optionally attached to the same carbon atom;
- R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0)m-, R 10 C(O)NRl0-, CN, NO2,
- G is H2 or O
- Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following: 1) Cl-4 alkyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(0) m R 6 , or g) -C(0)NR6R7,
- Rla, Rib, RlO, Rl l, m , R 2, R3, R6, R7, p , u , R 7a, R 8, Al, A , V, W, X, n, r and t are as defined above with respect to formula (Il-a);
- R4 is selected from H and CH3; and any two of R2, R3 and R4 are optionally attached to the same carbon atom;
- Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following:
- s 1;
- Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
- R2, R3, R4 and R ⁇ are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
- R6a, R6b, R6C, R6d an d R6e arc independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
- R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RHS(0) m -,
- R9 is independently selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0)m-, R 10 C(O)NRl0_, (Rl0)2NC(O)-, Rl 2N-C(NRlO)-, CN, N ⁇ 2, Rl°C(0)-, N3, -N(RlO)2, or RHOC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, RlOC(0)NRlO-, (Rl0) 2 NC(O)-, Rl0 2 N-C(NRlO)-, CN,
- RlO is independently selected from hydrogen, C1-C6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
- Rl l is independently selected from C1-C6 alkyl and aryl;
- Rl2 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
- V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(0) m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(0)m; W is a heterocycle;
- Rla, Rib, R2, R3, R4, R5, R7, R8, R9, RlO, Rl l, A l, A2, V, W, m, n, p, q, r and t are as previously defined with respect to formula (Il-d);
- f(s) are independently N, and the remaining f s are independently CR 6 ;
- each R 6 is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
- R3, R4, R5, R6a-e, R 7, R8, R9, RIO, Rl l, A l, A , V, W, m, n, p, q, r and t are as previously defined with respect to formula (Il-d);
- f(s) are independently N, and the remaining f s are independently CH;
- Rl and R2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rl O-, RHS(0) m -, R 10 C(O)NRl0-,
- R3, R4, R5, R7, R8, R9, RIO, Rl 1, Al, A2, V, W, m, n, p, q, r and t are as previously defined with respect to formula (Il-d);
- f(s) are independently N, and the remaining f s are independently CH;
- g(s) are independently N, and the remaining g's are independently CR 6 ;
- Rl and R2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rl O-, Rl lS(0) m -, R 10 C(O)NRl0 .
- each R 6 is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
- Rl lS(0)m- R 10 C(O)NRl0-, (RlO) 2 NC(0)-, RHC(0)0-, Rl ⁇ 2N-C(NRlO)-, CN, N02, Rl°C(0)-, N3, -N(RlO) 2 , or RHOC(O)NRl0-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rl2 ⁇ -, Rl lS(0)m-, R 0C(O)NRl0-, (RlO) 2 NC(0)-, Rl0 2 N-C(NRlO)-, CN, RlOC(O)-, N
- R c is selected from:
- Rl is hydrogen, an alkyl group, an aralkyl group, an acyl group, an aracyl group, an aroyl group, an alkylsulfonyl group, aralkylsulfonyl group or arylsulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms;
- R2 and R3 are the side chains of naturally occurring amino acids, including their oxidized forms which may be methionine sulfoxide or methionine sulfone, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substitutents may be substituted with an aromatic or heteroaromatic ring;
- R4 is hydrogen or an alkyl group, wherein the alkyl group comprises straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms;
- R5 is selected from: a) a side chain of naturally occurring amino acids, b) an oxidized form of a side chain of naturally occurring amino acids selected from methionine sulfoxide and methionine sulfone, c) substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl, or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substituent is optionally substituted with an aromatic or heteroaromatic ring, and d) -CH2CH2 ⁇ H or -CH2CH2CH2 ⁇ H;
- R6 is a substituted or unsubstituted aliphatic, aromatic or heteroaromatic group such as saturated chains of 1 to 8 carbon atoms, which may be branched or unbranched, wherein the aliphatic substituent may be substituted with an aromatic or heteroaromatic ring;
- Rl and Ri are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R80-, R9s(0)m-, R8C(0)NR8-, CN, N ⁇ 2, (R S )2N-C(NR8)-,
- R2a, R2b and R3 are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, R80-, R9s(0)m-, R S C(0)NR8-, CN, N3, (R S )2N-C(NR8)- , R8C(0)-, R8 ⁇ C(0)-, -N(R8)2, or R9 ⁇ C(0)NR8-, c) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted cycloalkyl, alkenyl, R 0-, R 9 S(0) m -, R8C(0)NR8-, CN, NO2, (R8)2N-C(NR8)-, R8c(0)-, R8 ⁇ C(0)-, N3, -N(R8)2, halogen or R90C(0)NR8-, and d) Cl-C6 alkyl substituted with
- R4 and R ⁇ are independently selected from: a) hydrogen, and
- R6 is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Br, R80-, R9s(0) m -, R8C(0)NR8-,
- CN N02, R 8 2N-C(NR8)-, R ⁇ C(O)-, R80C(0)-, N3, - N(R8)2, or R9 ⁇ C(0)NR8-, and c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Br, R80-, R9S(0)m-, R 8 C(0)NH-, CN, H2N-C(NH)-, R8c(0)- , R80C(0)-, N3, -N(R8)2, or R8 ⁇ C(0)NH-;
- R7 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Br, R80-, R9s(0)m-, R8C(0)NR8-, CN, N ⁇ 2, (R8) N-C-(NR8)-, R8C(0)-, R8 ⁇ C(0)-, N3, -N(R8)2, or R90C(0)NR8-, and c) Cl-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, Br, R80-, R 9 S(0) m -, R S C(0)NR8-, CN, (R8)2N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, N3, -N(R8) 2J or R90C(0)NR8- ;
- R8 is independently selected from hydrogen, C1-C6 alkyl, substituted or unsubstituted C1-C6 aralkyl and substituted or unsubstituted aryl;
- R9 is independently selected from C1-C6 alkyl and aryl
- RlO is independently selected from hydrogen, C1-C6 alkyl, substituted or unsubstituted C1-C6 aralkyl and substituted or unsubstituted aryl;
- V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, provided that V is not hydrogen if Al is S(0) m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(0)m;
- W is a heterocycle
- Z is H2 or O
- n 0, 1, 2, 3 or 4
- p 0, 1, 2, 3 or 4
- r 0 to 5, provided that r is 0 when V is hydrogen; and u is 0 or 1;
- Y is a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 3 carbon atoms are replaced by a heteroatom selected from N, S and O, and wherein Y is attached to Q through a carbon atom;
- Rl and R2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
- R3, R4 and R ⁇ are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
- R7 is selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) aryl or heterocycle, R 11
- R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, RlOC(0)NRlO-, (RlO) 2 NC(0)-, Rl lS(0)2NRlO-,
- R9 is independently selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RIOO-, Rl lS(0) m -, R 10 C(O)NRl0-, (R10) 2 NC(0)-, R10 2 N-C(NR10)-, CN, N02, R 10 C(O)-, N3, -N(RlO) , or RHOC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl,
- RlO is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trif ⁇ uoroethyl and aryl;
- Rl 1 is independently selected from C1-C6 alkyl and aryl
- Rl2 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl,
- Rl3 is selected from hydrogen, C1-C6 alkyl, cyano, C1-C6 alkylsulfonyl and C1-C6 acyl;
- V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C 1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(0) m and V is not hydrogen if A 1 is a bond, n is 0 and A2 is S(0)m" >
- W is a heterocycle
- Rl, R2, R3, R4, R5, R 6a-e, R 7, R 8, R9, RIO, Rl l, R12, R13, A l, A , V, W, m, n, p, q, r and t are as previously defined with respect to formula (II-m);
- Y is a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 3 carbon atoms are replaced by a heteroatom selected from N, S and O, and wherein Y is attached to Q through a carbon atom;
- Examples of compounds which selectively inhibit farnesyl protein transferase include the following: 2(S)-Butyl-l-(2,3-diaminoprop-l-yl)-l-(l-naphthoyl)piperazine;
- alkyl shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range (i.e., methyl, ethyl, 1 -propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.).
- alkenyl shall mean straight or branched chain alkenes of two to ten total carbon atoms, or any number within this range.
- alkynyl shall mean straight or branched chain alkynes of two to ten total carbon atoms, or any number within this range.
- cycloalkyl shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
- alkoxy refers to straight or branched chain alkoxides of the number of carbon atoms specified (e.g., Cl-5 alkoxy), or any number within this range (i.e., methoxy, ethoxy, etc.).
- aryl refers to a mono- or polycyclic system composed of 5- and 6-membered aromatic rings containing 0, 1, 2, 3 or 4 heteroatoms chosen from N, O or S and either unsubstituted or substituted with one or more groups selected from hydrogen, halogen, Cl-io alkyl, C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, amino, amino Cl-8 alkyl, Cl-3 acylamino, Cl-3 acylamino Cl-8 alkyl, Cl-6 alkylamino, Cl-6 alkylamino Cl-8 alkyl, Cl-6 dialkylamino, Cl-6 dialkylamino Cl-8 alkyl, Cl-4 alkoxy, Cl-4 alkoxy Cl-6 alkyl, hydroxycarbonyl, hydroxycarbonyl Cl-6 alkyl, Cl-5 alkoxycarbonyl, Cl-3 alkoxycarbonyl Cl-6 alkyl, hydroxycarbonyl Cl-6 alkyloxy, hydroxy, hydroxy Cl-6 alkyl, hydroxycarbony
- aryl examples include, but are not limited to, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, benzimidazolyl, indolyl, thienyl, oxazolyl, isoxazolyl and thiazolyl, which are either unsubstituted or substituted with one or more groups selected from hydrogen, halogen, Cl-10 alkyl, C3-8 cycloalkyl, aryl, aryl Cl_8 alkyl, amino, amino Cl-8 alkyl, Cl-3 acylamino, Cl-3 acylamino Cl-8 alkyl, Cl-6 alkylamino, Cl-6 alkylamino Cl-8 alkyl, Cl-6 dialkylamino, Cl-6 dialkylamino Cl-8 alkyl, Cl-4 alkoxy, Cl-4 alkoxy Cl-6 alkyl, hydroxycarbonyl, hydroxycarbonyl Cl-6 alkyl, Cl-5 alkoxycarbonyl, Cl
- the aryl group is unsubstituted, mono-, di-, tri- or tetra-substituted with one to four of the above-named substituents; more preferably, the aryl group is unsubstituted, mono-, di- or tri-substituted with one to three of the above-named substituents; most preferably, the aryl group is unsubstituted, mono- or di-substituted with one to two of the above-named substituents.
- alkyl or aryl or either of their prefix roots appear in a name of a substituent (e.g., aryl C ⁇ -8 alkyl) it shall be interpreted as including those limitations given above for "alkyl” and "aryl.”
- Designated numbers of carbon atoms e.g., Cl-10 shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
- arylalkyl and “alkylaryl” include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above.
- arylalkyl include, but are not limited to, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl.
- alkylaryl include, but are not limited to, toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine, propylpyridine and butylpyridine.
- substituent Y, B, Rl to R28 includes the definition Co (e.g., aryl C ⁇ -8 alkyl), the group modified by Co is not present in the substituent.
- the group modified by the variable is not present; for example, when s is zero, the group "-(CH2)s C ⁇ CH" is "-C ⁇ CH".
- halogen shall include iodine, bromine, chlorine and fluorine.
- oxy means an oxygen (O) atom.
- thio means a sulfur (S) atom.
- substituted shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
- alkyl refers to a monovalent alkane
- hydrocarbon (hydrocarbon) derived radical containing from 1 to 15 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopentyl and cyclohexyl. When substituted alkyl is present, this refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups as defined with respect to each variable.
- Heteroalkyl refers to an alkyl group having from 2-15 carbon atoms, and interrupted by from 1-4 heteroatoms selected from O, S and N.
- alkenyl refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 15 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four nonaromatic (non-resonating) carbon-carbon double bonds may be present.
- alkenyl groups examples include vinyl, allyl, iso- propenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2- butenyl, isoprenyl, farnesyl, geranyl, geranylgeranyl and the like.
- Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted when a substituted alkenyl group is provided.
- alkynyl refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 15 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon- carbon triple bonds may be present.
- Preferred alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted when a substituted alkynyl group is provided.
- Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and like groups as well as rings which are fused, e.g., naphthyl and the like.
- Aryl thus contains at least one ring having at least 6 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms.
- the preferred aryl groups are phenyl and naphthyl.
- Aryl groups may likewise be substituted as defined below.
- Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups.
- aryl is intended to include any stable monocyclic, bicyclic or tricyclic carbon ring(s) of up to 7 members in each ring, wherein at least one ring is aromatic.
- aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl and the like.
- heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one additional carbon atom is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms.
- the heteroaryl group is optionally substituted with up to three groups.
- Heteroaryl thus includes aromatic and partially aromatic groups which contain one or more heteroatoms.
- this type are thiophene, purine, imidazopyridine, pyridine, oxazole, thiazole, oxazine, pyrazole, tetrazole, imidazole, pyridine, pyrimidine, pyrazine and triazine.
- partially aromatic groups are tetrahydro- imidazo[4,5-c]pyridine, phthalidyl and saccharinyl, as defined below.
- heterocycle or heterocyclic represents a stable 5- to 7- membered monocyclic or stable 8- to 11 -membered bicyclic or stable 11-15 membered tricyclic heterocycle ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
- the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
- heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydro-benzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazoly
- substituted aryl substituted heterocycle
- substituted cycloalkyl are intended to include the cyclic group which is substituted with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(Cl-C6 alkyl)2, NO2, CN, (C1-C6 alkyl)0-, - OH, (C1-C6 alkyl)S(0)m-, (C1-C6 alkyl)C(0)NH-, H2N-C(NH)-, (C1-C6 alkyl)C(O)-, (C1-C6 alkyl)OC(O)-, N3,( -C6 alkyl)OC(0)NH- and C1-C2O alkyl.
- amino acids which are disclosed are identified both by conventional 3 letter and single letter abbreviations as indicated below:
- the compounds used in the present method may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.
- named amino acids are understood to have the natural "L" stereoconfiguration With respect to the farnesyl-protein transferase inhibitors of the formulas Il-d and II-f,the substituent illustrated by the structure
- fused ring moieties may be further substituted by the remaining R 6a , R 6 b, R6c, R6d and/or R e as defined hereinabove.
- R 6 is as defined hereinabove.
- fused ring moieties may be further substituted by the remaining R 6 s as defined hereinabove.
- fused ring moieties may be further substituted by the remaining R , R 6 b, R 6 c, R6d and/or R e as defined hereinabove.
- Y represents a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 3 carbon atoms are replaced by a heteroatom selected from N, S and O, and wherein Y is attached to Q through a carbon atom and includes the following ring systems:
- Y represents a 5-, 6- or 7 -membered carbocyclic ring wherein from 0 to 3 carbon atoms are replaced by a heteroatom selected from N, S and O, and wherein Y is attached to Q through a carbon atom and includes the following ring systems:
- fused ring moieties may be further substituted by the remaining R , R b, R c, R6d and/or R 6 ⁇ as defined hereinabove.
- cyclic moieties When R2 and R3 are combined to form - (CH2)u -, cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to:
- cyclic moieties may optionally include a heteroatom(s).
- heteroatom-containing cyclic moieties include, but are not limited to:
- cyclic moieties are formed.
- examples of such cyclic moieties include, but are not limited to:
- the pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids.
- such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenyl-acetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
- any substituent or variable e.g., RlO, Z, n, etc.
- - N(RlO)2 represents -NHH, -NHCH3, -NHC2H5, etc.
- substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth below.
- the pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
- the compounds of formula (Il-h) can be synthesized from their constituent amino acids by conventional peptide synthesis techniques, and the additional methods described below. Standard methods of peptide synthesis are disclosed, for example, in the following works: Schroeder et al, "The Peptides", Vol. I, Academic Press 1965, or Bodanszky et al, “Peptide Synthesis”, Interscience Publishers, 1966, or McOmie (ed.) "Protective Groups in Organic Chemistry", Plenum Press, 1973, or Barany et al, "The Peptides: Analysis, Synthesis, Biology” 2, Chapter 1, Academic Press, 1980, or Stewart et al, "Solid Phase Peptide Synthesis", Second Edition, Pierce Chemical Company, 1984.
- compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers.
- Non-toxic salts include conventional non-toxic salts or quarternary ammonium salts formed, e.g., from non-toxic inorganic or organic acids.
- Non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
- the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt- forming inorganic or organic acid or base, in a suitable solvent or solvent combination.
- the farnesyl transferase inhibitors of formula (Il-a) through (II-c) can be synthesized in accordance with Schemes 1-22, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures.
- Substituents R, R a and Rb, as shown in the Schemes, represent the substituents R2, R3, R4, a nd R ⁇ ; however their point of attachment to the ring is illustrative only and is not meant to be limiting.
- Boc-protected amino acids I available commercially or by procedures known to those skilled in the art, can be coupled to N-benzyl amino acid esters using a variety of dehydrating agents such as DCC (dicyclohexycarbodiimide) or EDC HC1 (l-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride) in a solvent such as methylene chloride , chloroform, dichloroethane, or in dimethyl- formamide.
- dehydrating agents such as DCC (dicyclohexycarbodiimide) or EDC HC1 (l-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride) in a solvent such as methylene chloride , chloroform, dichloroethane, or in dimethyl- formamide.
- the product II is then deprotected with acid, for example hydrogen chloride in chloroform or ethyl acetate, or trifluoroacetic acid in methylene chloride, and cyclized under weakly basic conditions to give the diketopiperazine III.
- acid for example hydrogen chloride in chloroform or ethyl acetate, or trifluoroacetic acid in methylene chloride
- Reduction of III with lithium aluminum hydride in refluxing ether gives the piperazine IV, which is protected as the Boc derivative V.
- the N-benzyl group can be cleaved under standard conditions of hydrogenation, e.g., 10% palladium on carbon at 60 psi hydrogen on a Parr apparatus for 24-48 h.
- the product VI can be treated with an acid chloride, or a carboxylic acid under standard dehydrating conditions to furnish the carboxamides VII; a final acid deprotection as previously described gives the intermediate VIII
- the intermediate VIII can be reductively alkylated with a variety of aldehydes, such as IX.
- the aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses. 1988, 67, 69-75, from the appropriate amino acid (Scheme 3).
- the reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloroethane, methanol or dimethylformamide.
- the product X can be deprotected to give the final compounds XI with trifluoro- acetic acid in methylene chloride.
- the final product XI is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
- the product diamine XI can further be selectively protected to obtain XII, which can subsequently be reductively alkylated with a second aldehyde to obtain XIII. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XV can be accomplished by literature procedures.
- the protected piperazine intermediate VII can be reductively alkylated with other aldehydes such as l-trityl-4- imidazolyl-carboxaldehyde or l-trityl-4-imidazolylacetaldehyde, to give products such as XVI (Scheme 4).
- the trityl protecting group can be removed from XVI to give XVII, or alternatively, XVI can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole XVIII.
- the intermediate VIII can be acylated or sulfonylated by standard techniques.
- the imidazole acetic acid XIX can be converted to the acetate XXI by standard procedures, and XXI can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XXII.
- Hydrolysis and reaction with piperazine VIII in the presence of condensing reagents such as l-(3-dimethylaminopropyl)- 3-ethylcarbodiimide (EDC) leads to acylated products such as XXIV.
- the piperazine VIII is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XXV in Scheme 6, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 6, 7).
- the alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohols such as XXIX.
- the fully deprotected amino alcohol XXX can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXXI (Scheme 7), or tertiary amines.
- the Boc protected amino alcohol XXVII can also be utilized to synthesize 2-aziridinylmethylpiperazines such as XXXII (Scheme 8). Treating XXVII with l,l'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXXII. The aziridine reacted in the presence of a nucleo- phile, such as a thiol, in the presence of base to yield the ring-opened product XXXIII.
- a nucleo- phile such as a thiol
- piperazine VIII can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XXXIX.
- R' is an aryl group
- XXXIX can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XL.
- the amine protecting group in XXXIX can be removed, and O-alkylated phenolic amines such as XLI produced.
- N-Aryl piperazines can be prepared as described in Scheme
- Piperazin-5-ones can be prepared as shown in Scheme
- the isomeric piperazin-3-ones can be prepared as described in Scheme 13.
- the imine formed from arylcarboxamides LII and 2- aminoglycinal diethyl acetal (LIII) can be reduced under a variety of conditions, including sodium triacetoxyborohydride in dichloroethane, to give the amine LIV.
- Amino acids I can be coupled to amines LIV under standard conditions, and the resulting amide LV when treated with aqueous acid in tetrahydrofuran can cyclize to the unsaturated LVI.
- Catalytic hydrogenation under standard conditions gives the requisite intermediate LVII, which is elaborated to final products as described in Schemes 3-9.
- N-benzyl piperazine V can be acylated with an aryl carboxylic acid.
- the resulting N-benzyl aryl carboxamide LIX can be hydrogenated in the presence of a catalyst to give the piperazine carboxamide LX which can then be carried on to final products as described in Schemes 3-9.
- Reaction Scheme 15 provides an illustrative example the synthesis of compounds of the instant invention wherein the substituents R2 and R3 are combined to form - (CH2)u -•
- 1-aminocyclohexane-l -carboxylic acid LXI can be converted to the spiropiperazine LXVI essentially according to the procedures outlined in Schemes 1 and 2.
- the piperazine intermediate LXIX can be deprotected as before, and carried on to final products as described in Schemes 3-9.
- reagents utilized to provide the substituent Y which is 2-(naphthyl) and the imidazolylalkyl substituent may be readily replaced by other reagents well known in the art and readily available to provide other N-substituents on the piperazine.
- the aldehyde XLIX from Scheme 12 can also be reductively alkylated with an aniline as shown in Scheme 16.
- the product LXXI can be converted to a piperazinone by acylation with chloroacetyl chloride to give LXXII, followed by base-induced cyclization to LXXIII.
- LXXV Deprotection, followed by reductive alkylation with a protected imidazole carboxaldehyde leads to LXXV, which can be alkylation with an arylmethylhalide to give the imidazolium salt LXXVI.
- Scheme 17 illustrates the use of an optionally substituted homoserine lactone LXXIX to prepare a Boc-protected piperazinone LXXXII.
- Intermediate LXXXII may be deprotected and reductively alkylated or acylated as illustrated in the previous Schemes.
- intermediate LXXXII may be mesylated and displaced by a suitable nucleophile, such as the sodium salt of ethane thiol, to provide an intermediate LXXXIII.
- a suitable nucleophile such as the sodium salt of ethane thiol
- Intermediate LXXXII may also be oxidized to provide the carboxylic acid on intermediate LXXXIV, which can be utilized form an ester or amide moiety.
- Amino acids of the general formula LXXXVI which have a sidechain not found in natural amino acids may be prepared by the reactions illustrated in Scheme 18 starting with the readily prepared imine LXXXV.
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Abstract
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002286239A CA2286239A1 (fr) | 1997-04-07 | 1998-04-06 | Procede de traitement du cancer |
EP98915318A EP0973396A4 (fr) | 1997-04-07 | 1998-04-06 | Procede de traitement du cancer |
JP54301398A JP2001524079A (ja) | 1997-04-07 | 1998-04-06 | ガンの治療方法 |
AU69532/98A AU724216B2 (en) | 1997-04-07 | 1998-04-06 | A method of treating cancer |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US4192397P | 1997-04-07 | 1997-04-07 | |
US60/041,923 | 1997-04-07 | ||
GB9800976.4 | 1998-01-16 | ||
GBGB9800976.4A GB9800976D0 (en) | 1998-01-16 | 1998-01-16 | A Method of treating cancer |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998044797A1 true WO1998044797A1 (fr) | 1998-10-15 |
Family
ID=26312961
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1998/006823 WO1998044797A1 (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) |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0901373A1 (fr) * | 1996-04-10 | 1999-03-17 | Merck & Co., Inc. | ANTAGONISTES DU RECEPTEUR Alpha v Beta 3 |
EP0946164A1 (fr) * | 1996-10-30 | 1999-10-06 | Merck & Co., Inc. | Antagonistes de l'integrine |
US6096757A (en) * | 1998-12-21 | 2000-08-01 | Schering Corporation | Method for treating proliferative diseases |
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US6495540B2 (en) | 2000-03-28 | 2002-12-17 | Bristol - Myers Squibb Pharma Company | Lactams as inhibitors of A-β protein production |
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US11117870B2 (en) | 2017-11-01 | 2021-09-14 | Drexel University | Compounds, compositions, and methods for treating diseases |
US11304949B2 (en) | 2018-03-30 | 2022-04-19 | Incyte Corporation | Treatment of hidradenitis suppurativa using JAK inhibitors |
US11426473B2 (en) | 2013-09-24 | 2022-08-30 | Fujifilm Corporation | Nitrogen-containing compound or salt thereof, or metal complex thereof |
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-
1998
- 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 EP EP98915318A patent/EP0973396A4/fr not_active Withdrawn
- 1998-04-06 WO PCT/US1998/006823 patent/WO1998044797A1/fr not_active Application Discontinuation
- 1998-04-06 JP JP54301398A patent/JP2001524079A/ja active Pending
Non-Patent Citations (3)
Title |
---|
DATABASE STN WPIDS 1 January 1900 (1900-01-01), ARNAOUT M A: "In Vitro Identification of Integrin Function Antagonists", XP002911537, Database accession no. 96-371576 * |
DATABASE STN WPIDS 1 January 1900 (1900-01-01), BARBACID M, MANNE V: "Assaying Farnesyl-Protein Transferase", XP002911536, Database accession no. 91-334169 * |
See also references of EP0973396A4 * |
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US10610530B2 (en) | 2007-06-13 | 2020-04-07 | Incyte Corporation | Salts of the Janus kinase inhibitor (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
US8722693B2 (en) | 2007-06-13 | 2014-05-13 | Incyte Corporation | Salts of the Janus kinase inhibitor (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
US8829013B1 (en) | 2007-06-13 | 2014-09-09 | Incyte Corporation | Salts of the Janus kinase inhibitor (R)-3-(4-(7H-pyrrolo[2,3-D]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
US8822481B1 (en) | 2007-06-13 | 2014-09-02 | Incyte Corporation | Salts of the janus kinase inhibitor (R)-3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
US10016429B2 (en) | 2007-06-13 | 2018-07-10 | Incyte Corporation | Salts of the janus kinase inhibitor (R)-3-(4-(7H-pyrrolo[2,3-D]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
US9371311B2 (en) | 2008-06-30 | 2016-06-21 | Janssen Pharmaceutica Nv | Benzoimidazol-2-yl pyrimidine derivatives |
US8410144B2 (en) | 2009-03-31 | 2013-04-02 | Arqule, Inc. | Substituted indolo-pyridinone compounds |
US9623029B2 (en) | 2009-05-22 | 2017-04-18 | Incyte Holdings Corporation | 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]octane- or heptane-nitrile as JAK inhibitors |
US9216984B2 (en) | 2009-05-22 | 2015-12-22 | Incyte Corporation | 3-[4-(7H-pyrrolo[2,3-D]pyrimidin-4-yl)-1H-pyrazol-1-yl]octane—or heptane-nitrile as JAK inhibitors |
US9334274B2 (en) | 2009-05-22 | 2016-05-10 | Incyte Holdings Corporation | N-(hetero)aryl-pyrrolidine derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines and pyrrol-3-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors |
US9249145B2 (en) | 2009-09-01 | 2016-02-02 | Incyte Holdings Corporation | Heterocyclic derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors |
US10695337B2 (en) | 2010-03-10 | 2020-06-30 | Incyte Holdings Corporation | Piperidin-4-yl azetidine derivatives as JAK1 inhibitors |
US9464088B2 (en) | 2010-03-10 | 2016-10-11 | Incyte Holdings Corporation | Piperidin-4-yl azetidine derivatives as JAK1 inhibitors |
US9999619B2 (en) | 2010-03-10 | 2018-06-19 | Incyte Holdings Corporation | Piperidin-4-yl azetidine derivatives as JAK1 inhibitors |
US11285140B2 (en) | 2010-03-10 | 2022-03-29 | Incyte Corporation | Piperidin-4-yl azetidine derivatives as JAK1 inhibitors |
US10869870B2 (en) | 2010-05-21 | 2020-12-22 | Incyte Corporation | Topical formulation for a JAK inhibitor |
US11590136B2 (en) | 2010-05-21 | 2023-02-28 | Incyte Corporation | Topical formulation for a JAK inhibitor |
US11571425B2 (en) | 2010-05-21 | 2023-02-07 | Incyte Corporation | Topical formulation for a JAK inhibitor |
US10758543B2 (en) | 2010-05-21 | 2020-09-01 | Incyte Corporation | Topical formulation for a JAK inhibitor |
US11219624B2 (en) | 2010-05-21 | 2022-01-11 | Incyte Holdings Corporation | Topical formulation for a JAK inhibitor |
US8933085B2 (en) | 2010-11-19 | 2015-01-13 | Incyte Corporation | Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors |
US10640506B2 (en) | 2010-11-19 | 2020-05-05 | Incyte Holdings Corporation | Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidines derivatives as JAK inhibitors |
US9034884B2 (en) | 2010-11-19 | 2015-05-19 | Incyte Corporation | Heterocyclic-substituted pyrrolopyridines and pyrrolopyrimidines as JAK inhibitors |
US10513522B2 (en) | 2011-06-20 | 2019-12-24 | Incyte Corporation | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors |
US8691807B2 (en) | 2011-06-20 | 2014-04-08 | Incyte Corporation | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors |
US9023840B2 (en) | 2011-06-20 | 2015-05-05 | Incyte Corporation | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors |
US11214573B2 (en) | 2011-06-20 | 2022-01-04 | Incyte Holdings Corporation | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors |
US9611269B2 (en) | 2011-06-20 | 2017-04-04 | Incyte Corporation | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors |
US9359358B2 (en) | 2011-08-18 | 2016-06-07 | Incyte Holdings Corporation | Cyclohexyl azetidine derivatives as JAK inhibitors |
US9487521B2 (en) | 2011-09-07 | 2016-11-08 | Incyte Holdings Corporation | Processes and intermediates for making a JAK inhibitor |
US9718834B2 (en) | 2011-09-07 | 2017-08-01 | Incyte Corporation | Processes and intermediates for making a JAK inhibitor |
US9505725B2 (en) | 2012-05-17 | 2016-11-29 | Genentech, Inc. | Crystalline and mesomorphous forms of an AKT inhibiting pyrimidinyl-cyclopentane compound, compositions and methods thereof |
US9315471B2 (en) | 2012-05-17 | 2016-04-19 | Genetech, Inc. | Process of making hydroxylated cyclopentapyrimidine compounds and salts thereof |
US9790190B2 (en) | 2012-05-17 | 2017-10-17 | Array Biopharma Inc. | Process for making hydroxylated cyclopentylpyrimidine compounds |
US9278917B2 (en) | 2012-05-17 | 2016-03-08 | Genentech, Inc. | Process for making amino acid compounds |
US9416110B2 (en) | 2012-05-17 | 2016-08-16 | Array Biopharma Inc. | Process for making hydroxylated cyclopentylpyrimidine compounds |
US9290458B2 (en) | 2012-05-17 | 2016-03-22 | Genentech, Inc. | Amorphous form of an AKT inhibiting pyrimidinyl-cyclopentane compound, compositions and methods thereof |
US9309204B2 (en) | 2012-05-17 | 2016-04-12 | Array Biopharma Inc. | Process for making hydroxylated cyclopentylpyrimidine compounds |
US9676730B2 (en) | 2012-05-17 | 2017-06-13 | Array Biopharma Inc. | Process for making hydroxylated cyclopentylpyrimidine compounds |
US9193733B2 (en) | 2012-05-18 | 2015-11-24 | Incyte Holdings Corporation | Piperidinylcyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors |
US9889102B2 (en) | 2012-07-19 | 2018-02-13 | Drexel University | Sigma receptor ligands and methods of modulating cellular protein homeostasis using same |
US10314795B2 (en) | 2012-07-19 | 2019-06-11 | Drexel University | Sigma receptor ligands and methods of modulating cellular protein homeostasis using same |
US9388126B2 (en) | 2012-07-19 | 2016-07-12 | Drexel University | Sigma receptor ligands and methods of modulating cellular protein homeostasis using same |
US10166191B2 (en) | 2012-11-15 | 2019-01-01 | Incyte Corporation | Sustained-release dosage forms of ruxolitinib |
US11576865B2 (en) | 2012-11-15 | 2023-02-14 | Incyte Corporation | Sustained-release dosage forms of ruxolitinib |
US11337927B2 (en) | 2012-11-15 | 2022-05-24 | Incyte Holdings Corporation | Sustained-release dosage forms of ruxolitinib |
US11576864B2 (en) | 2012-11-15 | 2023-02-14 | Incyte Corporation | Sustained-release dosage forms of ruxolitinib |
US10874616B2 (en) | 2012-11-15 | 2020-12-29 | Incyte Corporation | Sustained-release dosage forms of ruxolitinib |
US11896717B2 (en) | 2012-11-15 | 2024-02-13 | Incyte Holdings Corporation | Sustained-release dosage forms of ruxolitinib |
US9663497B2 (en) | 2013-03-06 | 2017-05-30 | Janssen Pharmaceutica Nv | Benzoimidazol-2-yl pyrimidine modulators of the histamine H4 receptor |
US8859575B2 (en) | 2013-03-06 | 2014-10-14 | Janssen Pharmaceutica Nv | Benzoimidazol-2-yl pyrimidine modulators of the histamine h4 receptor |
US9278952B2 (en) | 2013-03-06 | 2016-03-08 | Janssen Pharmaceutica Nv | Benzoimidazol-2-yl pyrimidine modulators of the histamine H4 receptor |
US9714233B2 (en) | 2013-03-06 | 2017-07-25 | Incyte Corporation | Processes and intermediates for making a JAK inhibitor |
US8987443B2 (en) | 2013-03-06 | 2015-03-24 | Incyte Corporation | Processes and intermediates for making a JAK inhibitor |
US9434715B2 (en) | 2013-03-06 | 2016-09-06 | Janssen Pharmaceutica Nv | Benzoimidazol-2-yl pyrimidine modulators of the histamine H4 receptor |
US9221845B2 (en) | 2013-03-06 | 2015-12-29 | Incyte Holdings Corporation | Processes and intermediates for making a JAK inhibitor |
US11045421B2 (en) | 2013-08-07 | 2021-06-29 | Incyte Corporation | Sustained release dosage forms for a JAK1 inhibitor |
US9655854B2 (en) | 2013-08-07 | 2017-05-23 | Incyte Corporation | Sustained release dosage forms for a JAK1 inhibitor |
US10561616B2 (en) | 2013-08-07 | 2020-02-18 | Incyte Corporation | Sustained release dosage forms for a JAK1 inhibitor |
US11426473B2 (en) | 2013-09-24 | 2022-08-30 | Fujifilm Corporation | Nitrogen-containing compound or salt thereof, or metal complex thereof |
US9498467B2 (en) | 2014-05-30 | 2016-11-22 | Incyte Corporation | Treatment of chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) by inhibitors of JAK1 |
US11046685B2 (en) | 2017-02-28 | 2021-06-29 | Morphic Therapeutic, Inc. | Inhibitors of (α-v)(β-6) integrin |
US11046669B2 (en) | 2017-02-28 | 2021-06-29 | Morphic Therapeutic, Inc. | Inhibitors of (α-v)(β-6) integrin |
US11040955B2 (en) | 2017-02-28 | 2021-06-22 | Morphic Therapeutic, Inc. | Inhibitors of (alpha-v)(beta-6) integrin |
US11795167B2 (en) | 2017-02-28 | 2023-10-24 | Morphic Therapeutic, Inc. | Inhibitors of (α-v)(β-6) integrin |
US11827621B2 (en) | 2017-02-28 | 2023-11-28 | Morphic Therapeutic, Inc. | Inhibitors of (α-v)(β-6) integrin |
US11117870B2 (en) | 2017-11-01 | 2021-09-14 | Drexel University | Compounds, compositions, and methods for treating diseases |
US11278541B2 (en) | 2017-12-08 | 2022-03-22 | Incyte Corporation | Low dose combination therapy for treatment of myeloproliferative neoplasms |
US10596161B2 (en) | 2017-12-08 | 2020-03-24 | Incyte Corporation | Low dose combination therapy for treatment of myeloproliferative neoplasms |
US10899736B2 (en) | 2018-01-30 | 2021-01-26 | Incyte Corporation | Processes and intermediates for making a JAK inhibitor |
US11304949B2 (en) | 2018-03-30 | 2022-04-19 | Incyte Corporation | Treatment of hidradenitis suppurativa using JAK inhibitors |
US11739087B2 (en) | 2018-08-29 | 2023-08-29 | Morphic Therapeutic, Inc. | Inhibiting (α-v)(β-6) integrin |
US11021480B2 (en) | 2018-08-29 | 2021-06-01 | Morphic Therapeutic, Inc. | Inhibiting (α-V)(β-6) integrin |
US11833155B2 (en) | 2020-06-03 | 2023-12-05 | Incyte Corporation | Combination therapy for treatment of myeloproliferative neoplasms |
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Publication number | Publication date |
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EP0973396A4 (fr) | 2001-02-07 |
EP0973396A1 (fr) | 2000-01-26 |
JP2001524079A (ja) | 2001-11-27 |
CA2286239A1 (fr) | 1998-10-15 |
AU724216B2 (en) | 2000-09-14 |
AU6953298A (en) | 1998-10-30 |
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