AU727939B2 - A method of treating cancer - Google Patents

A method of treating cancer Download PDF

Info

Publication number: AU727939B2
Authority: AU; Australia
Prior art keywords: substituted; glycyl; aryl; unsubstituted; pyrrolidin
Prior art date: 1996-04-03
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Ceased

Application number

AU27221/97A

Other languages

English (en)

Other versions

AU2722197A (en

Inventor

David C. Heimbrook

Allen I. Oliff

Steven M. Stirdivant

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Merck and Co Inc

Original Assignee

Merck and Co 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.)

1996-04-03

Filing date

1997-03-31

Publication date

2001-01-04

1996-06-28 Priority claimed from GBGB9613599.1A external-priority patent/GB9613599D0/en

1997-03-31 Application filed by Merck and Co Inc filed Critical Merck and Co Inc

1997-10-22 Publication of AU2722197A publication Critical patent/AU2722197A/en

2001-01-04 Application granted granted Critical

2001-01-04 Publication of AU727939B2 publication Critical patent/AU727939B2/en

2017-03-31 Anticipated expiration legal-status Critical

Status Ceased legal-status Critical Current

Links

238000000034 method Methods 0.000 title claims description 53
206010028980 Neoplasm Diseases 0.000 title claims description 27
201000011510 cancer Diseases 0.000 title claims description 13
125000003118 aryl group Chemical group 0.000 claims description 312
125000000623 heterocyclic group Chemical group 0.000 claims description 292
GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 195
-1 1-imidazolyl Chemical group 0.000 claims description 173
229910052739 hydrogen Inorganic materials 0.000 claims description 172
239000001257 hydrogen Substances 0.000 claims description 164
150000001875 compounds Chemical class 0.000 claims description 159
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 144
125000000217 alkyl group Chemical group 0.000 claims description 126
PFMUCCYYAAFKTH-YFKPBYRVSA-N Gly-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)CN PFMUCCYYAAFKTH-YFKPBYRVSA-N 0.000 claims description 117
125000000753 cycloalkyl group Chemical group 0.000 claims description 95
150000002431 hydrogen Chemical class 0.000 claims description 90
235000001014 amino acid Nutrition 0.000 claims description 78
150000001413 amino acids Chemical class 0.000 claims description 72
229910052801 chlorine Inorganic materials 0.000 claims description 72
229910052794 bromium Inorganic materials 0.000 claims description 71
229910052731 fluorine Inorganic materials 0.000 claims description 71
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 63
150000003839 salts Chemical class 0.000 claims description 61
125000001072 heteroaryl group Chemical group 0.000 claims description 49
150000004702 methyl esters Chemical class 0.000 claims description 49
125000001424 substituent group Chemical group 0.000 claims description 49
229960004452 methionine Drugs 0.000 claims description 47
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 44
229910052757 nitrogen Inorganic materials 0.000 claims description 44
102000004357 Transferases Human genes 0.000 claims description 41
108090000992 Transferases Proteins 0.000 claims description 41
125000003107 substituted aryl group Chemical group 0.000 claims description 41
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 39
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 38
125000003342 alkenyl group Chemical group 0.000 claims description 35
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 35
125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 34
125000005010 perfluoroalkyl group Chemical group 0.000 claims description 32
125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 claims description 30
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 29
QEFRNWWLZKMPFJ-UHFFFAOYSA-N L-methionine sulphoxide Natural products CS(=O)CCC(N)C(O)=O QEFRNWWLZKMPFJ-UHFFFAOYSA-N 0.000 claims description 29
125000004432 carbon atom Chemical group C* 0.000 claims description 29
150000002460 imidazoles Chemical class 0.000 claims description 29
230000002401 inhibitory effect Effects 0.000 claims description 29
239000005557 antagonist Substances 0.000 claims description 28
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 28
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 27
229910052799 carbon Inorganic materials 0.000 claims description 22
QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 20
235000004279 alanine Nutrition 0.000 claims description 20
229910052760 oxygen Inorganic materials 0.000 claims description 20
JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
125000001088 1-naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 claims description 19
125000006239 protecting group Chemical group 0.000 claims description 19
229910052717 sulfur Inorganic materials 0.000 claims description 19
229910052720 vanadium Inorganic materials 0.000 claims description 19
239000002253 acid Substances 0.000 claims description 17
125000005842 heteroatom Chemical group 0.000 claims description 17
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
125000002950 monocyclic group Chemical group 0.000 claims description 17
150000002148 esters Chemical class 0.000 claims description 16
125000003710 aryl alkyl group Chemical group 0.000 claims description 15
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 15
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 14
125000004093 cyano group Chemical group *C#N 0.000 claims description 14
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 claims description 14
229910052736 halogen Inorganic materials 0.000 claims description 14
150000002367 halogens Chemical class 0.000 claims description 14
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
229920006395 saturated elastomer Polymers 0.000 claims description 14
125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 13
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 12
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 12
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
229930182817 methionine Natural products 0.000 claims description 12
239000001301 oxygen Substances 0.000 claims description 12
239000011593 sulfur Substances 0.000 claims description 12
FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 11
125000000304 alkynyl group Chemical group 0.000 claims description 11
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 11
DWKPPFQULDPWHX-VKHMYHEASA-N l-alanyl ester Chemical compound COC(=O)[C@H](C)N DWKPPFQULDPWHX-VKHMYHEASA-N 0.000 claims description 11
125000005843 halogen group Chemical group 0.000 claims description 10
125000004446 heteroarylalkyl group Chemical group 0.000 claims description 10
101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 0.000 claims description 9
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 8
KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 7
125000004356 hydroxy functional group Chemical group O* 0.000 claims description 7
125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 claims description 7
125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 6
125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 6
125000003545 alkoxy group Chemical group 0.000 claims description 6
125000004391 aryl sulfonyl group Chemical group 0.000 claims description 6
125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 6
125000000547 substituted alkyl group Chemical group 0.000 claims description 6
RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
125000004429 atom Chemical group 0.000 claims description 5
GCFAUZGWPDYAJN-UHFFFAOYSA-N cyclohexyl 3-phenylprop-2-enoate Chemical compound C=1C=CC=CC=1C=CC(=O)OC1CCCCC1 GCFAUZGWPDYAJN-UHFFFAOYSA-N 0.000 claims description 5
239000003814 drug Substances 0.000 claims description 5
ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 5
125000004475 heteroaralkyl group Chemical group 0.000 claims description 5
125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 5
UIHPNZDZCOEZEN-YFKPBYRVSA-N methyl (2s)-2-amino-4-methylsulfanylbutanoate Chemical compound COC(=O)[C@@H](N)CCSC UIHPNZDZCOEZEN-YFKPBYRVSA-N 0.000 claims description 5
FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
125000003435 aroyl group Chemical group 0.000 claims description 4
125000005002 aryl methyl group Chemical group 0.000 claims description 4
JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 4
125000000392 cycloalkenyl group Chemical group 0.000 claims description 4
208000021045 exocrine pancreatic carcinoma Diseases 0.000 claims description 4
125000006413 ring segment Chemical group 0.000 claims description 4
238000006467 substitution reaction Methods 0.000 claims description 4
208000010507 Adenocarcinoma of Lung Diseases 0.000 claims description 3
208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 claims description 3
206010041067 Small cell lung cancer Diseases 0.000 claims description 3
210000004556 brain Anatomy 0.000 claims description 3
125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
210000000867 larynx Anatomy 0.000 claims description 3
210000004072 lung Anatomy 0.000 claims description 3
201000005249 lung adenocarcinoma Diseases 0.000 claims description 3
210000004324 lymphatic system Anatomy 0.000 claims description 3
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
201000006845 reticulosarcoma Diseases 0.000 claims description 3
208000029922 reticulum cell sarcoma Diseases 0.000 claims description 3
208000000587 small cell lung carcinoma Diseases 0.000 claims description 3
210000002784 stomach Anatomy 0.000 claims description 3
150000003457 sulfones Chemical class 0.000 claims description 3
125000004173 1-benzimidazolyl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N1* 0.000 claims description 2
125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 2
206010006187 Breast cancer Diseases 0.000 claims description 2
208000026310 Breast neoplasm Diseases 0.000 claims description 2
101100521345 Mus musculus Prop1 gene Proteins 0.000 claims description 2
108700017836 Prophet of Pit-1 Proteins 0.000 claims description 2
OITGWZQOTKBNHC-MHAHJAEUSA-N [(3s)-4-[(2r)-2-amino-3-hydroxyheptadecyl]-3-butylpiperazin-1-yl]-naphthalen-1-ylmethanone Chemical compound C1[C@H](CCCC)N(C[C@@H](N)C(O)CCCCCCCCCCCCCC)CCN1C(=O)C1=CC=CC2=CC=CC=C12 OITGWZQOTKBNHC-MHAHJAEUSA-N 0.000 claims description 2
201000008275 breast carcinoma Diseases 0.000 claims description 2
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
150000001768 cations Chemical class 0.000 claims description 2
125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 2
238000004519 manufacturing process Methods 0.000 claims description 2
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
125000004546 quinazolin-4-yl group Chemical group N1=CN=C(C2=CC=CC=C12)* 0.000 claims description 2
125000005493 quinolyl group Chemical group 0.000 claims description 2
125000004434 sulfur atom Chemical group 0.000 claims description 2
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
229910052727 yttrium Inorganic materials 0.000 claims description 2
IPSFOLSLIUIMKK-LURJTMIESA-N methyl (2s)-2-[(2-aminoacetyl)amino]-4-methylsulfanylbutanoate Chemical compound CSCC[C@@H](C(=O)OC)NC(=O)CN IPSFOLSLIUIMKK-LURJTMIESA-N 0.000 claims 4
MGIYRDNGCNKGJU-UHFFFAOYSA-N isothiazolinone Chemical compound O=C1C=CSN1 MGIYRDNGCNKGJU-UHFFFAOYSA-N 0.000 claims 3
SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims 3
HCUOEKSZWPGJIM-YBRHCDHNSA-N (e,2e)-2-hydroxyimino-6-methoxy-4-methyl-5-nitrohex-3-enamide Chemical compound COCC([N+]([O-])=O)\C(C)=C\C(=N/O)\C(N)=O HCUOEKSZWPGJIM-YBRHCDHNSA-N 0.000 claims 1
KKKDZZRICRFGSD-UHFFFAOYSA-N 1-benzylimidazole Chemical compound C1=CN=CN1CC1=CC=CC=C1 KKKDZZRICRFGSD-UHFFFAOYSA-N 0.000 claims 1
125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims 1
SURCGQGDUADKBL-UHFFFAOYSA-N 2-(2-hydroxyethylamino)-5-nitrobenzo[de]isoquinoline-1,3-dione Chemical compound [O-][N+](=O)C1=CC(C(N(NCCO)C2=O)=O)=C3C2=CC=CC3=C1 SURCGQGDUADKBL-UHFFFAOYSA-N 0.000 claims 1
125000001216 2-naphthoyl group Chemical group C1=C(C=CC2=CC=CC=C12)C(=O)* 0.000 claims 1
125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims 1
ANPPJNRSHQGSIR-UHFFFAOYSA-N 4-[2-(4-methylsulfanylphenyl)-4-naphthalen-2-yl-1h-imidazol-5-yl]pyridine Chemical compound C1=CC(SC)=CC=C1C1=NC(C=2C=C3C=CC=CC3=CC=2)=C(C=2C=CN=CC=2)N1 ANPPJNRSHQGSIR-UHFFFAOYSA-N 0.000 claims 1
IJEKVOJHPYSPSL-UHFFFAOYSA-N 4-[2-(4-methylsulfinylphenyl)-4-naphthalen-2-yl-1h-imidazol-5-yl]pyridine Chemical compound C1=CC(S(=O)C)=CC=C1C1=NC(C=2C=C3C=CC=CC3=CC=2)=C(C=2C=CN=CC=2)N1 IJEKVOJHPYSPSL-UHFFFAOYSA-N 0.000 claims 1
WEIMNUYTUJXDSU-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-2-(2-methylsulfanylphenyl)-1h-imidazol-5-yl]pyridine Chemical compound CSC1=CC=CC=C1C1=NC(C=2C=CC(F)=CC=2)=C(C=2C=CN=CC=2)N1 WEIMNUYTUJXDSU-UHFFFAOYSA-N 0.000 claims 1
OJHOIAOSQSNDFE-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-2-(3-methylsulfanylphenyl)-1h-imidazol-5-yl]pyridine Chemical compound CSC1=CC=CC(C=2NC(=C(N=2)C=2C=CC(F)=CC=2)C=2C=CN=CC=2)=C1 OJHOIAOSQSNDFE-UHFFFAOYSA-N 0.000 claims 1
RWCZEVLEBFONQN-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-2-(3-methylsulfinylphenyl)-1h-imidazol-5-yl]pyridine Chemical compound CS(=O)C1=CC=CC(C=2NC(=C(N=2)C=2C=CC(F)=CC=2)C=2C=CN=CC=2)=C1 RWCZEVLEBFONQN-UHFFFAOYSA-N 0.000 claims 1
XBOAMGVRMOKHNU-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-2-(4-methoxyphenyl)-1h-imidazol-5-yl]pyridine Chemical compound C1=CC(OC)=CC=C1C1=NC(C=2C=CC(F)=CC=2)=C(C=2C=CN=CC=2)N1 XBOAMGVRMOKHNU-UHFFFAOYSA-N 0.000 claims 1
LFPRICXNGTVKHB-UHFFFAOYSA-N 4-[5-(4-fluorophenyl)-3-methyl-2-(4-methylsulfinylphenyl)imidazol-4-yl]pyridine Chemical compound CN1C(C=2C=CC(=CC=2)S(C)=O)=NC(C=2C=CC(F)=CC=2)=C1C1=CC=NC=C1 LFPRICXNGTVKHB-UHFFFAOYSA-N 0.000 claims 1
101100162200 Aspergillus parasiticus (strain ATCC 56775 / NRRL 5862 / SRRC 143 / SU-1) aflD gene Proteins 0.000 claims 1
101100334009 Caenorhabditis elegans rib-2 gene Proteins 0.000 claims 1
101100360207 Caenorhabditis elegans rla-1 gene Proteins 0.000 claims 1
102000007317 Farnesyltranstransferase Human genes 0.000 claims 1
108010007508 Farnesyltranstransferase Proteins 0.000 claims 1
HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 claims 1
101100371353 Streptomyces fradiae tylN gene Proteins 0.000 claims 1
SFMJVGMTFJODNJ-CGAIIQECSA-N [(3s)-4-[2-amino-3-(2-hydroxyphenyl)propyl]-3-butylpiperazin-1-yl]-naphthalen-1-ylmethanone Chemical compound C([C@@H]1CCCC)N(C(=O)C=2C3=CC=CC=C3C=CC=2)CCN1CC(N)CC1=CC=CC=C1O SFMJVGMTFJODNJ-CGAIIQECSA-N 0.000 claims 1
AVXFQBJAVCGIFW-FLDQDSGZSA-N [(3s)-4-[2-amino-3-(2-phenylmethoxyphenyl)propyl]-3-butylpiperazin-1-yl]-naphthalen-1-ylmethanone Chemical compound C([C@@H]1CCCC)N(C(=O)C=2C3=CC=CC=C3C=CC=2)CCN1CC(N)CC1=CC=CC=C1OCC1=CC=CC=C1 AVXFQBJAVCGIFW-FLDQDSGZSA-N 0.000 claims 1
XSAJRSTXUWYGPC-KGLYDCNGSA-N [(3s)-4-butan-2-yl-3-[(2r)-3-hydroxy-2-[(4-nitrophenyl)methylamino]propyl]piperazin-1-yl]-naphthalen-1-ylmethanone Chemical compound N([C@@H](CO)C[C@H]1CN(CCN1C(C)CC)C(=O)C=1C2=CC=CC=C2C=CC=1)CC1=CC=C([N+]([O-])=O)C=C1 XSAJRSTXUWYGPC-KGLYDCNGSA-N 0.000 claims 1
ZFVNRRWIZWCNRG-UHFFFAOYSA-N chembl17346 Chemical compound C1=CC(C(=NO)N)=CC=C1C1=NC(C=2C=CC(F)=CC=2)=C(C=2C=CN=CC=2)N1 ZFVNRRWIZWCNRG-UHFFFAOYSA-N 0.000 claims 1
125000004494 ethyl ester group Chemical group 0.000 claims 1
125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 claims 1
JWZLBIGUTOVRMZ-QWRGUYRKSA-N methyl (2s)-2-[[(2s)-1-ethylpyrrolidine-2-carbonyl]amino]-4-methylsulfanylbutanoate Chemical compound CCN1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)OC JWZLBIGUTOVRMZ-QWRGUYRKSA-N 0.000 claims 1
AKHWKIBLTBWRIC-ZETCQYMHSA-N methyl (2s)-4-methylsulfanyl-2-(propanoylamino)butanoate Chemical compound CCC(=O)N[C@H](C(=O)OC)CCSC AKHWKIBLTBWRIC-ZETCQYMHSA-N 0.000 claims 1
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 1
125000006178 methyl benzyl group Chemical group 0.000 claims 1
STTPMEVACJNPEF-YADHBBJMSA-N n-[[(2r)-2-amino-3-[(2s)-2-butyl-4-(naphthalene-1-carbonyl)piperazin-1-yl]propyl]sulfanylmethyl]acetamide Chemical compound C1CN(C[C@@H](N)CSCNC(C)=O)[C@@H](CCCC)CN1C(=O)C1=CC=CC2=CC=CC=C12 STTPMEVACJNPEF-YADHBBJMSA-N 0.000 claims 1
125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims 1
CLNGMCHUKJFCQJ-UHFFFAOYSA-N tert-butyl 3-[4-(4-fluorophenyl)-5-pyridin-4-yl-1h-imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC1C1=NC(C=2C=CC(F)=CC=2)=C(C=2C=CN=CC=2)N1 CLNGMCHUKJFCQJ-UHFFFAOYSA-N 0.000 claims 1
PETWPNDULASRKU-UHFFFAOYSA-N tert-butyl 4-benzyl-2-[4-(4-fluorophenyl)-5-pyridin-4-yl-1h-imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1C(C=2NC(=C(N=2)C=2C=CC(F)=CC=2)C=2C=CN=CC=2)N(C(=O)OC(C)(C)C)CCC1CC1=CC=CC=C1 PETWPNDULASRKU-UHFFFAOYSA-N 0.000 claims 1
238000006243 chemical reaction Methods 0.000 description 127
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 125
229960005141 piperazine Drugs 0.000 description 88
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 72
229940024606 amino acid Drugs 0.000 description 57
239000000047 product Substances 0.000 description 46
239000000243 solution Substances 0.000 description 43
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102000030938 small GTPase Human genes 0.000 description 1
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BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical class [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 1
239000012279 sodium borohydride Substances 0.000 description 1
229910000033 sodium borohydride Inorganic materials 0.000 description 1
235000017550 sodium carbonate Nutrition 0.000 description 1
229910000029 sodium carbonate Inorganic materials 0.000 description 1
FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
229940048086 sodium pyrophosphate Drugs 0.000 description 1
239000011343 solid material Substances 0.000 description 1
239000002195 soluble material Substances 0.000 description 1
238000003797 solvolysis reaction Methods 0.000 description 1
238000000527 sonication Methods 0.000 description 1
235000011150 stannous chloride Nutrition 0.000 description 1
230000000707 stereoselective effect Effects 0.000 description 1
238000011916 stereoselective reduction Methods 0.000 description 1
229960005322 streptomycin Drugs 0.000 description 1
125000005017 substituted alkenyl group Chemical group 0.000 description 1
125000004426 substituted alkynyl group Chemical group 0.000 description 1
125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
QQWYQAQQADNEIC-RVDMUPIBSA-N tert-butyl [(z)-[cyano(phenyl)methylidene]amino] carbonate Chemical compound CC(C)(C)OC(=O)O\N=C(/C#N)C1=CC=CC=C1 QQWYQAQQADNEIC-RVDMUPIBSA-N 0.000 description 1
MSKPKYQESULKCE-QHCPKHFHSA-N tert-butyl n-[(2s)-1-(2,3-dimethylanilino)-6-phenylmethoxyhexan-2-yl]carbamate Chemical compound CC1=CC=CC(NC[C@H](CCCCOCC=2C=CC=CC=2)NC(=O)OC(C)(C)C)=C1C MSKPKYQESULKCE-QHCPKHFHSA-N 0.000 description 1
UAEBCZDITCOVNB-WMCAAGNKSA-N tert-butyl n-[(2s)-1-oxo-5-phenylmethoxyhexan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](C=O)CCC(C)OCC1=CC=CC=C1 UAEBCZDITCOVNB-WMCAAGNKSA-N 0.000 description 1
ZUSPXVZVYRCDTB-UHFFFAOYSA-N tert-butyl n-[2-(3-chloroanilino)ethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCNC1=CC=CC(Cl)=C1 ZUSPXVZVYRCDTB-UHFFFAOYSA-N 0.000 description 1
ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 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
235000019818 tetrasodium diphosphate Nutrition 0.000 description 1
239000001577 tetrasodium phosphonato phosphate Substances 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
125000000335 thiazolyl 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
125000001544 thienyl group Chemical group 0.000 description 1
150000003568 thioethers Chemical class 0.000 description 1
125000004568 thiomorpholinyl group Chemical group 0.000 description 1
229930192474 thiophene Natural products 0.000 description 1
229960004072 thrombin Drugs 0.000 description 1
AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
238000011830 transgenic mouse model Methods 0.000 description 1
125000005270 trialkylamine group Chemical group 0.000 description 1
TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
125000000169 tricyclic heterocycle group Chemical group 0.000 description 1
JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
238000001665 trituration Methods 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
238000011144 upstream manufacturing Methods 0.000 description 1
230000003612 virological effect Effects 0.000 description 1
239000003039 volatile agent Substances 0.000 description 1
230000003442 weekly effect Effects 0.000 description 1
239000011592 zinc chloride Substances 0.000 description 1
235000005074 zinc chloride Nutrition 0.000 description 1

Classifications

- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents

Landscapes

Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Pharmacology & Pharmacy (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Epidemiology (AREA)
Gastroenterology & Hepatology (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Immunology (AREA)
Proteomics, Peptides & Aminoacids (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Organic Chemistry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Steroid Compounds (AREA)

AU27221/97A 1996-04-03 1997-03-31 A method of treating cancer Ceased AU727939B2 (en)

Applications Claiming Priority (5)

Application Number	Priority Date	Filing Date	Title
US1477396P	1996-04-03	1996-04-03
US60/014773		1996-04-03
GBGB9613599.1A GB9613599D0 (en)	1996-06-28	1996-06-28	A method of treating cancer
GB9613599		1996-06-28
PCT/US1997/005328 WO1997036587A1 (en)	1996-04-03	1997-03-31	A method of treating cancer

Publications (2)

Publication Number	Publication Date
AU2722197A AU2722197A (en)	1997-10-22
AU727939B2 true AU727939B2 (en)	2001-01-04

Family

ID=26309586

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
AU27221/97A Ceased AU727939B2 (en)	1996-04-03	1997-03-31	A method of treating cancer

Country Status (5)

Country	Link
EP (1)	EP0906099A4 (ja)
JP (1)	JP2000504023A (ja)
AU (1)	AU727939B2 (ja)
CA (1)	CA2250232A1 (ja)
WO (1)	WO1997036587A1 (ja)

Families Citing this family (72)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US5916891A (en)	1992-01-13	1999-06-29	Smithkline Beecham Corporation	Pyrimidinyl imidazoles
US6524832B1 (en)	1994-02-04	2003-02-25	Arch Development Corporation	DNA damaging agents in combination with tyrosine kinase inhibitors
US6046208A (en) *	1996-01-11	2000-04-04	Smithkline Beecham Corporation	Substituted imidazole compounds
WO1998007425A1 (en)	1996-08-21	1998-02-26	Smithkline Beecham Corporation	Imidazole compounds, compositions and use
AU7966198A (en)	1997-06-13	1998-12-30	Smithkline Beecham Corporation	Novel pyrazole and pyrazoline substituted compounds
WO1998057966A1 (en)	1997-06-19	1998-12-23	Smithkline Beecham Corporation	Novel aryloxy substituted pyrimidine imidazole compounds
US7301021B2 (en)	1997-07-02	2007-11-27	Smithkline Beecham Corporation	Substituted imidazole compounds
AU8381098A (en)	1997-07-02	1999-01-25	Smithkline Beecham Corporation	Novel cycloalkyl substituted imidazoles
US6562832B1 (en)	1997-07-02	2003-05-13	Smithkline Beecham Corporation	Substituted imidazole compounds
CA2306077A1 (en)	1997-10-08	1999-04-15	Smithkline Beecham Corporation	Novel cycloalkenyl substituted compounds
AU1924699A (en)	1997-12-19	1999-07-12	Smithkline Beecham Corporation	Compounds of heteroaryl substituted imidazole, their pharmaceutical compositionsand uses
DE69904302T2 (de) *	1998-02-02	2003-08-14	Lg Chemical Ltd	Farnesyltransferase-inhibitoren mit piperidinstruktur und verfahren zu ihrer herstellung
CN1548436A (zh)	1998-05-22	2004-11-24	ʷ��˿��ȳ�ķ��޹�˾	新的2-烷基取代咪唑化合物
US6858617B2 (en)	1998-05-26	2005-02-22	Smithkline Beecham Corporation	Substituted imidazole compounds
GB9812523D0 (en) *	1998-06-10	1998-08-05	Angeletti P Ist Richerche Bio	Peptide inhibitors of hepatitis c virus ns3 protease
FR2780892B1 (fr) *	1998-07-08	2001-08-17	Sod Conseils Rech Applic	Utilisation d'inhibiteurs de prenyltransferases pour preparer un medicament destine a traiter les pathologies qui resultent de la fixation membranaire de la proteine g heterotrimerique
WO2000016778A1 (en) *	1998-09-24	2000-03-30	Merck & Co., Inc.	A method of treating cancer
AU1909200A (en)	1998-11-04	2000-05-22	Smithkline Beecham Corporation	Pyridin-4-yl or pyrimidin-4-yl substituted pyrazines
WO2000051611A1 (en) *	1999-03-03	2000-09-08	Merck & Co., Inc.	Inhibitors of prenyl-protein transferase
US6316462B1 (en) *	1999-04-09	2001-11-13	Schering Corporation	Methods of inducing cancer cell death and tumor regression
US7122666B2 (en)	1999-07-21	2006-10-17	Sankyo Company, Limited	Heteroaryl-substituted pyrrole derivatives, their preparation and their therapeutic uses
ES2228629T3 (es)	1999-11-22	2005-04-16	Smithkline Beecham Plc	Derivados de imidazol y su uso como inhibidores de raf-quinasa.
JP2003514900A (ja)	1999-11-23	2003-04-22	スミスクライン・ビーチャム・コーポレイション	ＣＳＢＰ／ｐ３８キナーゼ阻害剤としての３，４−ジヒドロ−（１Ｈ）−キナゾリン−２−オン化合物
EP1233950B1 (en)	1999-11-23	2005-10-05	Smithkline Beecham Corporation	3,4-DIHYDRO-(1H)QUINAZOLIN-2-ONE COMPOUNDS AS CSBP/P39 kINASE INHIBITORS
US6759410B1 (en)	1999-11-23	2004-07-06	Smithline Beecham Corporation	3,4-dihydro-(1H)-quinazolin-2-ones and their use as CSBP/p38 kinase inhibitors
GB0005357D0 (en)	2000-03-06	2000-04-26	Smithkline Beecham Plc	Compounds
DE60112312T2 (de)	2000-09-21	2005-12-29	Smithkline Beecham P.L.C., Brentford	Imidazolderivate als raf-kinase-inhibitoren
WO2002026246A2 (en) *	2000-09-29	2002-04-04	Gsf-Forschungszentrum Für Umwelt Und Gesundheit, Gmbh	Pharmaceutical compositions comprising polynucleotides encoding a raf protein
EP1322334A2 (en)	2000-10-05	2003-07-02	George Q. Daley	Methods of inducing cancer cell death and tumor regression
JP2005505562A (ja) *	2001-09-05	2005-02-24	スミスクライン　ビーチャム　パブリック　リミテッド　カンパニー	Ｒａｆキナーゼ阻害剤としてのピリジルフランおよびピロール
GB0121488D0 (en)	2001-09-05	2001-10-24	Smithkline Beecham Plc	Compounds
JP2005526008A (ja) *	2001-12-04	2005-09-02	オニックスファーマシューティカルズ，インコーポレイティド	癌を処置するためのｒａｆ−ｍｅｋ−ｅｒｋ経路インヒビター
JP2005538066A (ja)	2002-07-09	2005-12-15	ベーリンガーインゲルハイムファルマゲゼルシャフトミットベシュレンクテルハフツングウントコンパニーコマンディトゲゼルシャフト	新規な抗コリン作用薬及びｐ３８キナーゼ阻害剤を用いた新規な医薬組成物
US6878731B2 (en) *	2002-08-14	2005-04-12	Pure World Botanicals, Inc.	Imidazole alkaloids from Lepidium meyenii and methods of usage
CN101899006B (zh)	2002-08-19	2013-11-06	劳洛斯治疗公司	2，4，5-三取代的咪唑及其作为抗菌剂的用途
JP4654035B2 (ja)	2002-11-05	2011-03-16	グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー	抗菌剤
EP1633758B1 (en)	2003-05-15	2011-11-23	Arqule, Inc.	Imidazothiazoles and imidazoxazole derivatives as inhibitors of p38
CA2540518A1 (en)	2003-10-02	2005-04-07	Irm Llc	Compounds and compositions as protein kinase inhibitors
DK1692113T3 (en) *	2003-11-14	2018-01-08	Lorus Therapeutics Inc	ARYLIMIDAZOLES AND USE THEREOF AS ANTICANCES
US7829560B2 (en)	2004-07-08	2010-11-09	Arqule, Inc.	1,4-disubstituted naphthalenes as inhibitors of P38 MAP kinase
US20060035893A1 (en)	2004-08-07	2006-02-16	Boehringer Ingelheim International Gmbh	Pharmaceutical compositions for treatment of respiratory and gastrointestinal disorders
EP2258704A1 (en)	2004-10-19	2010-12-08	ArQule, Inc.	Synthesis of imidazooxazole and imidazothiazole inhibitors of p38 map kinase
PE20060777A1 (es)	2004-12-24	2006-10-06	Boehringer Ingelheim Int	Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas
CA2611032C (en)	2005-05-25	2012-01-17	Genesense Technologies Inc.	2-indolyl imidazo[4,5-d]phenanthroline derivatives and their use in the treatment of cancer
HUE030235T2 (en)	2005-12-13	2017-04-28	Incyte Holdings Corp	Heteroaryl-substituted pyrrolo [2,3-b] pyridines and pyrrolo [2,3-b] pyrimidines as Janus kinase inhibitors
UY30639A1 (es)	2006-10-17	2008-05-31	Kudos Pharm Ltd	Derivados sustituidos de 2h-ftalazin-1-ona, sus formas cristalinas, proceso de preparacion y aplicaciones
EP1992344A1 (en)	2007-05-18	2008-11-19	Institut Curie	P38 alpha as a therapeutic target in pathologies linked to FGFR3 mutation
EP3070090B1 (en)	2007-06-13	2018-12-12	Incyte Holdings Corporation	Use of salts of the janus kinase inhibitor (r)-3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h- pyrazol-1-yl)-3- cyclopentylpropanenitrile
EP2346495B2 (en)	2008-10-07	2023-05-24	Kudos Pharmaceuticals Limited	Pharmaceutical formulation 514
EA020494B1 (ru)	2009-05-22	2014-11-28	Инсайт Корпорейшн	3-[4-(7H-ПИРРОЛО[2,3-d]ПИРИМИДИН-4-ИЛ)-1H-ПИРАЗОЛ-1-ИЛ]ОКТАН- ИЛИ ГЕПТАННИТРИЛ КАК JAK-ИНГИБИТОРЫ
AR076794A1 (es)	2009-05-22	2011-07-06	Incyte Corp	Derivados de n-(hetero)aril-pirrolidina de pirazol-4-il-pirrolo [2,3-d]pirimidinas y pirrol-3-il-pirrolo [2,3-d ]pirimidinas como inhibidores de la quinasa janus y composiciones farmaceuticas que los contienen
AR078012A1 (es)	2009-09-01	2011-10-05	Incyte Corp	Derivados heterociclicos de las pirazol-4-il- pirrolo (2,3-d) pirimidinas como inhibidores de la quinasa janus
MX347851B (es)	2010-03-10	2017-05-16	Incyte Corp	Derivados de piperidin-4-il azetidina como inhibidores de janus cinasa 1 (jak1).
EP3087972A1 (en)	2010-05-21	2016-11-02	Incyte Holdings Corporation	Topical formulation for a jak inhibitor
EP2640725B1 (en)	2010-11-19	2015-01-07	Incyte Corporation	Heterocyclic-substituted pyrrolopyridines and pyrrolopyrimidines as jak inhibitors
SG190839A1 (en)	2010-11-19	2013-07-31	Incyte Corp	Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as jak inhibitors
AR086983A1 (es)	2011-06-20	2014-02-05	Incyte Corp	Derivados de azetidinil fenil, piridil o pirazinil carboxamida como inhibidores de jak
TW201313721A (zh)	2011-08-18	2013-04-01	Incyte Corp	作為ｊａｋ抑制劑之環己基氮雜環丁烷衍生物
UA111854C2 (uk)	2011-09-07	2016-06-24	Інсайт Холдінгс Корпорейшн	Способи і проміжні сполуки для отримання інгібіторів jak
AR091079A1 (es)	2012-05-18	2014-12-30	Incyte Corp	Derivados de pirrolopirimidina y pirrolopiridina sustituida con piperidinilciclobutilo como inhibidores de jak
KR20220162825A (ko)	2012-11-15	2022-12-08	인사이트 홀딩스 코포레이션	룩솔리티니브의 서방성 제형
AU2014225938B2 (en)	2013-03-06	2018-07-19	Incyte Holdings Corporation	Processes and intermediates for making a JAK inhibitor
US9309247B2 (en)	2013-03-20	2016-04-12	Lorus Therapeutics Inc.	2-substituted imidazo[4,5-D]phenanthroline derivatives and their use in the treatment of cancer
KR20160045081A (ko)	2013-08-07	2016-04-26	인사이트 코포레이션	Jak1 억제제용 지속 방출 복용 형태
WO2015051304A1 (en)	2013-10-04	2015-04-09	Aptose Biosciences Inc.	Compositions, biomarkers and their use in treatment of cancer
WO2015184305A1 (en)	2014-05-30	2015-12-03	Incyte Corporation	TREATMENT OF CHRONIC NEUTROPHILIC LEUKEMIA (CNL) AND ATYPICAL CHRONIC MYELOID LEUKEMIA (aCML) BY INHIBITORS OF JAK1
CN111417395A (zh)	2017-10-30	2020-07-14	艾普托斯生物科学公司	用于治疗癌症的芳基咪唑
TW201924683A (zh)	2017-12-08	2019-07-01	美商英塞特公司	用於治療骨髓增生性贅瘤的低劑量組合療法
TWI797242B (zh)	2018-01-30	2023-04-01	美商英塞特公司	製備ｊａｋ抑制劑之方法及中間物
MX2022012285A (es)	2018-03-30	2023-08-15	Incyte Corp	Tratamiento de la hidradenitis supurativa mediante el uso de inhibidores de actividad de la cinasa janus (jak).
US11833155B2 (en)	2020-06-03	2023-12-05	Incyte Corporation	Combination therapy for treatment of myeloproliferative neoplasms
WO2022249192A1 (en) *	2021-05-27	2022-12-01	Ramot At Tel-Aviv University Ltd.	Broad-spectrum metastasis suppressing compounds and therapeutic uses thereof in human tumors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US5352705A (en) *	1992-06-26	1994-10-04	Merck & Co., Inc.	Inhibitors of farnesyl protein transferase

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US5563255A (en) *	1994-05-31	1996-10-08	Isis Pharmaceuticals, Inc.	Antisense oligonucleotide modulation of raf gene expression
IL117580A0 (en) *	1995-03-29	1996-07-23	Merck & Co Inc	Inhibitors of farnesyl-protein transferase and pharmaceutical compositions containing them
KR19990064117A (ko) *	1995-10-06	1999-07-26	폴락 돈나 엘.	항암 활성과 사이토킨 억제 활성을 갖는 치환된 이미다졸

1997
- 1997-03-31 WO PCT/US1997/005328 patent/WO1997036587A1/en not_active Application Discontinuation
- 1997-03-31 AU AU27221/97A patent/AU727939B2/en not_active Ceased
- 1997-03-31 EP EP97921085A patent/EP0906099A4/en not_active Withdrawn
- 1997-03-31 JP JP9535542A patent/JP2000504023A/ja active Pending
- 1997-03-31 CA CA002250232A patent/CA2250232A1/en not_active Abandoned

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US5352705A (en) *	1992-06-26	1994-10-04	Merck & Co., Inc.	Inhibitors of farnesyl protein transferase

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AU2722197A (en)	1997-10-22
JP2000504023A (ja)	2000-04-04
EP0906099A4 (en)	2001-02-07
CA2250232A1 (en)	1997-10-09
WO1997036587A1 (en)	1997-10-09
EP0906099A1 (en)	1999-04-07

Legal Events

Date	Code	Title	Description
2002-10-31	MK14	Patent ceased section 143(a) (annual fees not paid) or expired

Publication	Publication Date	Title
AU727939B2 (en)	2001-01-04	A method of treating cancer
AU701763B2 (en)	1999-02-04	Inhibitors of farnesyl protein transferase
AU3215197A (en)	1998-01-05	A method of treating cancer
US5869682A (en)	1999-02-09	Inhibitors of farnesyl-protein transferase
CA2251955A1 (en)	1997-10-23	A method of treating cancer
AU717298B2 (en)	2000-03-23	Inhibitors of farnesyl-protein transferase
AU700175B2 (en)	1998-12-24	Thiol-free inhibitors of farnesyl-protein transferase
WO1996034010A2 (en)	1996-10-31	Inhibitors of farnesyl-protein transferase
AU716153B2 (en)	2000-02-17	Inhibitors of farnesyl-protein transferase
US5627202A (en)	1997-05-06	Inhibitors of farnesyl-protein transferase
WO1997027853A1 (en)	1997-08-07	Inhibitors of farnesyl-protein transferase
AU713698B2 (en)	1999-12-09	Inhibitors of farnesyl-protein transferase
AU708620B2 (en)	1999-08-05	Inhibitors of farnesyl-protein transferase
WO1996031525A2 (en)	1996-10-10	Inhibitors of farnesyl-protein transferase
EP0837857A2 (en)	1998-04-29	Inhibitors of farnesyl-protein transferase
CA2201349A1 (en)	1996-04-04	Inhibitors of farnesyl-protein transferase
CA2201348A1 (en)	1996-04-04	Thiol-free inhibitors of farnesyl-protein transferase
AU2692599A (en)	1999-06-24	Inhibitors of farnesyl-protein transferase
JPH11502822A (ja)	1999-03-09	ファルネシル−タンパク質トランスフェラーゼ阻害剤