SK2292003A3 - Tricyclic antitumor compounds being farnesyl protein transferase inhibitors - Google Patents

Tricyclic antitumor compounds being farnesyl protein transferase inhibitors Download PDF

Info

Publication number: SK2292003A3
Authority: SK; Slovakia
Prior art keywords: compound; mmol; solution; preparation; compounds
Prior art date: 2000-08-30

Application number

SK229-2003A

Other languages

English (en)

Slovak (sk)

Inventor

George F Njoroge

Bancha Vibulbhan

Alan B Cooper

Timothy Guzi

Dinanath F Rane

Keith P Minor

Ronald J Doll

Viyyoor Moopil Girijavallabhan

Bama Santhanam

Patrick A Pinto

Hugh Y Zhu

Kartik M Keertikar

Carmen S Alvarez

Robert W Bishop

James Wang

Jagdish A Desai

John J Baldwin

Ge Li

Chia-Yu Huang

Ray A James

Original Assignee

Schering Corp

Pharmacopeia Inc

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2000-08-30

Filing date

2001-08-28

Publication date

2003-08-05

2001-08-28 Application filed by Schering Corp, Pharmacopeia Inc filed Critical Schering Corp

2003-08-05 Publication of SK2292003A3 publication Critical patent/SK2292003A3/sk

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 814
230000000259 anti-tumor effect Effects 0.000 title description 2
239000003528 protein farnesyltransferase inhibitor Substances 0.000 title 1
150000003839 salts Chemical class 0.000 claims abstract description 21
239000012453 solvate Substances 0.000 claims abstract description 3
229910052799 carbon Inorganic materials 0.000 claims description 33
229910052757 nitrogen Inorganic materials 0.000 claims description 29
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 24
238000002360 preparation method Methods 0.000 abstract description 303
238000000034 method Methods 0.000 abstract description 60
206010028980 Neoplasm Diseases 0.000 abstract description 28
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 18
201000010099 disease Diseases 0.000 abstract description 16
230000002062 proliferating effect Effects 0.000 abstract description 16
230000002401 inhibitory effect Effects 0.000 abstract description 15
201000011510 cancer Diseases 0.000 abstract description 11
125000004030 farnesyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 abstract description 9
102000004357 Transferases Human genes 0.000 abstract description 8
108090000992 Transferases Proteins 0.000 abstract description 8
239000008194 pharmaceutical composition Substances 0.000 abstract description 3
239000000651 prodrug Substances 0.000 abstract 2
229940002612 prodrug Drugs 0.000 abstract 2
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 693
239000000243 solution Substances 0.000 description 415
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 321
238000001819 mass spectrum Methods 0.000 description 234
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 213
238000006243 chemical reaction Methods 0.000 description 202
239000000203 mixture Substances 0.000 description 173
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 165
239000012044 organic layer Substances 0.000 description 103
239000011541 reaction mixture Substances 0.000 description 99
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 92
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 91
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 90
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 90
239000003480 eluent Substances 0.000 description 84
239000007787 solid Substances 0.000 description 84
239000000047 product Substances 0.000 description 79
125000000217 alkyl group Chemical group 0.000 description 77
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
235000019439 ethyl acetate Nutrition 0.000 description 76
-1 R 31 Chemical compound 0.000 description 75
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 72
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 66
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 66
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 64
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 64
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 59
239000012043 crude product Substances 0.000 description 59
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 52
125000001424 substituent group Chemical group 0.000 description 52
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
238000003756 stirring Methods 0.000 description 49
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238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 42
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 36
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 36
239000012267 brine Substances 0.000 description 35
125000000592 heterocycloalkyl group Chemical group 0.000 description 35
239000012948 isocyanate Substances 0.000 description 35
229920006395 saturated elastomer Polymers 0.000 description 35
238000010898 silica gel chromatography Methods 0.000 description 35
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 35
150000002513 isocyanates Chemical class 0.000 description 34
DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 33
125000001072 heteroaryl group Chemical group 0.000 description 32
238000003818 flash chromatography Methods 0.000 description 31
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 30
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 30
239000000741 silica gel Substances 0.000 description 30
229910002027 silica gel Inorganic materials 0.000 description 30
239000012299 nitrogen atmosphere Substances 0.000 description 29
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 29
125000004446 heteroarylalkyl group Chemical group 0.000 description 28
238000010992 reflux Methods 0.000 description 28
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 27
239000002904 solvent Substances 0.000 description 27
GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 26
125000004432 carbon atom Chemical group C* 0.000 description 25
229910052739 hydrogen Inorganic materials 0.000 description 24
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 23
150000001412 amines Chemical class 0.000 description 23
HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 23
229910052736 halogen Inorganic materials 0.000 description 23
XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical compound CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 22
125000003118 aryl group Chemical group 0.000 description 22
150000002367 halogens Chemical class 0.000 description 21
239000010410 layer Substances 0.000 description 21
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 20
239000002253 acid Substances 0.000 description 20
229910021529 ammonia Inorganic materials 0.000 description 20
125000005885 heterocycloalkylalkyl group Chemical group 0.000 description 19
GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 18
229910052801 chlorine Inorganic materials 0.000 description 18
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 18
239000012359 Methanesulfonyl chloride Substances 0.000 description 17
239000002246 antineoplastic agent Substances 0.000 description 17
125000003710 aryl alkyl group Chemical group 0.000 description 17
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 17
210000004027 cell Anatomy 0.000 description 17
238000004128 high performance liquid chromatography Methods 0.000 description 17
239000000543 intermediate Substances 0.000 description 17
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 17
102000016914 ras Proteins Human genes 0.000 description 17
108010014186 ras Proteins Proteins 0.000 description 17
229910000104 sodium hydride Inorganic materials 0.000 description 17
238000004440 column chromatography Methods 0.000 description 16
235000017557 sodium bicarbonate Nutrition 0.000 description 16
229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
229910052794 bromium Inorganic materials 0.000 description 14
230000008018 melting Effects 0.000 description 14
238000002844 melting Methods 0.000 description 14
KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 14
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 14
108091022875 Microtubule Proteins 0.000 description 13
102000029749 Microtubule Human genes 0.000 description 13
239000003795 chemical substances by application Substances 0.000 description 13
GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 13
238000000354 decomposition reaction Methods 0.000 description 13
125000004447 heteroarylalkenyl group Chemical group 0.000 description 13
210000004688 microtubule Anatomy 0.000 description 13
LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 12
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 12
229930012538 Paclitaxel Natural products 0.000 description 12
125000004429 atom Chemical group 0.000 description 12
125000000753 cycloalkyl group Chemical group 0.000 description 12
229960001592 paclitaxel Drugs 0.000 description 12
238000000926 separation method Methods 0.000 description 12
DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 12
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
INLLPKCGLOXCIV-UHFFFAOYSA-N bromoethene Chemical compound BrC=C INLLPKCGLOXCIV-UHFFFAOYSA-N 0.000 description 11
FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 11
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239000000706 filtrate Substances 0.000 description 11
229910052731 fluorine Inorganic materials 0.000 description 11
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 11
238000000746 purification Methods 0.000 description 11
125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 11
239000002585 base Substances 0.000 description 10
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125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 9
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238000002953 preparative HPLC Methods 0.000 description 9
238000012746 preparative thin layer chromatography Methods 0.000 description 9
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KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
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206010061902 Pancreatic neoplasm Diseases 0.000 description 7
KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 7
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 7
238000000262 chemical ionisation mass spectrometry Methods 0.000 description 7
229940125833 compound 23 Drugs 0.000 description 7
238000010265 fast atom bombardment Methods 0.000 description 7
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
208000015486 malignant pancreatic neoplasm Diseases 0.000 description 7
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MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 6
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NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 6
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FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 6
231100000590 oncogenic Toxicity 0.000 description 6
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NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
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FRACPXUHUTXLCX-BELIEFIBSA-N tert-butyl N-{1-[(1S)-1-{[(1R,2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-2-cyclopropylethyl]-2-oxopyridin-3-yl}carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CN(C1=O)[C@@H](CC2CC2)C(=O)N[C@@H](C[C@@H]3CCNC3=O)[C@H](C(=O)NCC4=CC=CC=C4)O FRACPXUHUTXLCX-BELIEFIBSA-N 0.000 description 1
IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
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BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
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229960003604 testosterone Drugs 0.000 description 1
229960003087 tioguanine Drugs 0.000 description 1
XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
229960005026 toremifene Drugs 0.000 description 1
229960000575 trastuzumab Drugs 0.000 description 1
150000004654 triazenes Chemical class 0.000 description 1
125000001425 triazolyl group Chemical group 0.000 description 1
DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
NVLRFXKSQQPKAD-UHFFFAOYSA-N tricarbon Chemical group [C]=C=[C] NVLRFXKSQQPKAD-UHFFFAOYSA-N 0.000 description 1
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150000008648 triflates Chemical class 0.000 description 1
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
229960001055 uracil mustard Drugs 0.000 description 1
150000003672 ureas Chemical class 0.000 description 1
VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
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229960004982 vinblastine sulfate Drugs 0.000 description 1
JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
KDQAABAKXDWYSZ-JKDPCDLQSA-N vincaleukoblastine sulfate Chemical compound OS(O)(=O)=O.C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 KDQAABAKXDWYSZ-JKDPCDLQSA-N 0.000 description 1
229960002110 vincristine sulfate Drugs 0.000 description 1
HHJUWIANJFBDHT-KOTLKJBCSA-N vindesine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(N)=O)N4C)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 HHJUWIANJFBDHT-KOTLKJBCSA-N 0.000 description 1
229960004355 vindesine Drugs 0.000 description 1
229940033942 zoladex Drugs 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

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Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Life Sciences & Earth Sciences (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Veterinary Medicine (AREA)
Pharmacology & Pharmacy (AREA)
Public Health (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Other In-Based Heterocyclic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

SK229-2003A 2000-08-30 2001-08-28 Tricyclic antitumor compounds being farnesyl protein transferase inhibitors SK2292003A3 (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US22918300P	2000-08-30	2000-08-30
PCT/US2001/026792 WO2002018368A1 (en)	2000-08-30	2001-08-28	Tricyclic antitumor compounds being farnesyl protein transferase inhibitors

Publications (1)

Publication Number	Publication Date
SK2292003A3 true SK2292003A3 (en)	2003-08-05

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US (1)	US20020198216A1 (de)
EP (1)	EP1313725B1 (de)
JP (1)	JP2004513885A (de)
KR (1)	KR20030034161A (de)
CN (1)	CN100384837C (de)
AR (1)	AR033680A1 (de)
AT (1)	ATE359281T1 (de)
AU (2)	AU2001288451C1 (de)
BR (1)	BR0113675A (de)
CA (1)	CA2420673A1 (de)
CO (1)	CO5640109A2 (de)
DE (1)	DE60127846T2 (de)
EC (1)	ECSP034494A (de)
ES (1)	ES2284686T3 (de)
HK (1)	HK1054548B (de)
HU (1)	HUP0302942A3 (de)
IL (1)	IL154528A0 (de)
MX (1)	MXPA03001849A (de)
NO (1)	NO20030918L (de)
NZ (1)	NZ524246A (de)
PE (1)	PE20020486A1 (de)
PL (1)	PL361103A1 (de)
RU (1)	RU2293734C9 (de)
SK (1)	SK2292003A3 (de)
TW (1)	TWI268280B (de)
WO (1)	WO2002018368A1 (de)
ZA (1)	ZA200301545B (de)

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Publication number	Priority date	Publication date	Assignee	Title
US7342016B2 (en) *	2000-08-30	2008-03-11	Schering Corporation	Farnesyl protein transferase inhibitors as antitumor agents
HU230273B1 (hu) *	2001-03-14	2015-11-30	Bristol-Myers Squibb Company	Egy epotilon analóg és kemoterápiás szerek kombinációja proliferatív betegségek kezelésére
AU2002340139A1 (en) *	2001-10-09	2003-04-22	The University Of Cincinnati	Inhibitors of the egf receptor for the treatment of thyroid cancer
CN1617755A (zh) *	2001-11-30	2005-05-18	先灵公司	法尼基蛋白转移酶抑制剂和其它抗肿瘤剂联合使用在制备抗癌症的药物中的应用
MXPA04005425A (es) *	2001-12-03	2004-10-11	Schering Corp	Uso de inhibidores de farnesil proteina transferasa y por lo menos dos agentes antineoplasicos en el tratamiento de cancer.
US20030195192A1 (en) *	2002-04-05	2003-10-16	Fortuna Haviv	Nicotinamides having antiangiogenic activity
US20040014744A1 (en) *	2002-04-05	2004-01-22	Fortuna Haviv	Substituted pyridines having antiangiogenic activity
US7714139B2 (en) *	2003-03-27	2010-05-11	Lankenau Institute For Medcial Research	IDO inhibitors and methods of use
US20060281813A1 (en) *	2003-06-05	2006-12-14	Charles Rubin	Methods of treating hyperproliferative cell disorders
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Publication number	Publication date
PE20020486A1 (es)	2002-06-14
KR20030034161A (ko)	2003-05-01
AU8845101A (en)	2002-03-13
EP1313725B1 (de)	2007-04-11
RU2293734C2 (ru)	2007-02-20
IL154528A0 (en)	2003-09-17
AR033680A1 (es)	2004-01-07
CN100384837C (zh)	2008-04-30
AU2001288451C1 (en)	2008-03-06
ATE359281T1 (de)	2007-05-15
WO2002018368A1 (en)	2002-03-07
PL361103A1 (en)	2004-09-20
US20020198216A1 (en)	2002-12-26
NO20030918L (no)	2003-04-29
HUP0302942A3 (en)	2007-02-28
TWI268280B (en)	2006-12-11
JP2004513885A (ja)	2004-05-13
BR0113675A (pt)	2003-06-24
DE60127846D1 (en)	2007-05-24
HK1054548B (en)	2007-10-18
DE60127846T2 (de)	2008-03-06
ZA200301545B (en)	2004-06-22
HK1054548A1 (en)	2003-12-05
HUP0302942A2 (hu)	2003-12-29
MXPA03001849A (es)	2003-06-04
CO5640109A2 (es)	2006-05-31
RU2293734C9 (ru)	2007-10-10
CA2420673A1 (en)	2002-03-07
CN1471524A (zh)	2004-01-28
ECSP034494A (es)	2003-04-25
ES2284686T3 (es)	2007-11-16
AU2001288451B2 (en)	2007-05-24
NO20030918D0 (no)	2003-02-27
EP1313725A1 (de)	2003-05-28
NZ524246A (en)	2004-11-26

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Publication	Publication Date	Title
SK2292003A3 (en)	2003-08-05	Tricyclic antitumor compounds being farnesyl protein transferase inhibitors
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US7342016B2 (en)	2008-03-11	Farnesyl protein transferase inhibitors as antitumor agents
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AU2001288451A1 (en)	2002-06-06	Tricyclic antitumor compounds being farnesyl protein transferase inhibitors
AU2006207300A1 (en)	2006-07-27	Substituted triazole derivatives as oxytocin antagonists
JP2005525356A5 (de)	2006-04-13
EP0989983B1 (de)	2004-08-11	Benzpyrido cycloheptan derivate mit farnesyl protein transferase inhibierender wirkung
CN113348165B (zh)	2024-06-25	用于治疗过度增殖性疾病的1,2,4-三嗪-3(2h)-酮化合物
WO2005014577A1 (en)	2005-02-17	Novel farnesyl protein transferase inhibitors as antitumor agents
US5945430A (en)	1999-08-31	Aminooxyamide tricyclic inhibitors of farnesyl-protein transferase
MX2007007078A (es)	2007-09-04	Inhibidores de farnesil-transferasa de proteina y metodos para tratar las enfermedades proliferativas.
CN114555603B (zh)	2025-03-14	制备作为食欲素受体调节剂的(2h-1,2,3-三唑-2-基)苯基化合物的改进的合成方法
AU2007202115A1 (en)	2007-05-31	Tricyclic antitumor compounds being farnesyl protein transferase inhibitors
HK40060627B (zh)	2025-01-03	用於治疗过度增殖性疾病的1,2,4-三嗪-3(2h)-酮化合物
MXPA01006241A (en)	2001-12-13	Tricyclic farnesyl protein transferase inhibitors