WO2008067270A1 - Inhibiteurs de liaison au domaine grb2 sh2 macrocyclique - Google Patents
Inhibiteurs de liaison au domaine grb2 sh2 macrocyclique Download PDFInfo
- Publication number
- WO2008067270A1 WO2008067270A1 PCT/US2007/085562 US2007085562W WO2008067270A1 WO 2008067270 A1 WO2008067270 A1 WO 2008067270A1 US 2007085562 W US2007085562 W US 2007085562W WO 2008067270 A1 WO2008067270 A1 WO 2008067270A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- compound
- pharmaceutically acceptable
- solvate
- hydrate
- Prior art date
Links
- 239000003112 inhibitor Substances 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 96
- -1 azido, amino Chemical group 0.000 claims abstract description 79
- 150000003839 salts Chemical class 0.000 claims abstract description 49
- 239000012453 solvate Substances 0.000 claims abstract description 48
- 238000000034 method Methods 0.000 claims abstract description 28
- 102000014400 SH2 domains Human genes 0.000 claims abstract description 27
- 108050003452 SH2 domains Proteins 0.000 claims abstract description 27
- 125000003118 aryl group Chemical group 0.000 claims abstract description 27
- 239000001257 hydrogen Substances 0.000 claims abstract description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 25
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 25
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 24
- CMPQUABWPXYYSH-UHFFFAOYSA-N phenyl phosphate Chemical compound OP(O)(=O)OC1=CC=CC=C1 CMPQUABWPXYYSH-UHFFFAOYSA-N 0.000 claims abstract description 21
- 230000003278 mimic effect Effects 0.000 claims abstract description 19
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 18
- 150000001413 amino acids Chemical class 0.000 claims abstract description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 16
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 38
- 125000003545 alkoxy group Chemical group 0.000 claims description 31
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
- 235000018102 proteins Nutrition 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 23
- 101100015729 Drosophila melanogaster drk gene Proteins 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 101150098203 grb2 gene Proteins 0.000 claims description 19
- 229940024606 amino acid Drugs 0.000 claims description 16
- 235000001014 amino acid Nutrition 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 16
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 16
- 206010028980 Neoplasm Diseases 0.000 claims description 15
- 102000004495 STAT3 Transcription Factor Human genes 0.000 claims description 12
- 108010017324 STAT3 Transcription Factor Proteins 0.000 claims description 12
- 102000007982 Phosphoproteins Human genes 0.000 claims description 11
- 108010089430 Phosphoproteins Proteins 0.000 claims description 11
- 102100033019 Tyrosine-protein phosphatase non-receptor type 11 Human genes 0.000 claims description 11
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 10
- 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 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims description 9
- 101710116241 Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 claims description 9
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 9
- 229960001230 asparagine Drugs 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 235000009582 asparagine Nutrition 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 241000124008 Mammalia Species 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims description 6
- WOXWUZCRWJWTRT-UHFFFAOYSA-N 1-amino-1-cyclohexanecarboxylic acid Chemical compound OC(=O)C1(N)CCCCC1 WOXWUZCRWJWTRT-UHFFFAOYSA-N 0.000 claims description 5
- 208000023275 Autoimmune disease Diseases 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 230000001404 mediated effect Effects 0.000 claims description 5
- PECYZEOJVXMISF-UHFFFAOYSA-N 3-aminoalanine Chemical compound [NH3+]CC(N)C([O-])=O PECYZEOJVXMISF-UHFFFAOYSA-N 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 4
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 4
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 3
- 206010025323 Lymphomas Diseases 0.000 claims description 3
- 208000008589 Obesity Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- 208000016097 disease of metabolism Diseases 0.000 claims description 3
- 208000027866 inflammatory disease Diseases 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 208000030159 metabolic disease Diseases 0.000 claims description 3
- 235000020824 obesity Nutrition 0.000 claims description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 2
- OCLLVJCYGMCLJG-CYBMUJFWSA-N (2r)-2-azaniumyl-2-naphthalen-1-ylpropanoate Chemical compound C1=CC=C2C([C@@](N)(C(O)=O)C)=CC=CC2=C1 OCLLVJCYGMCLJG-CYBMUJFWSA-N 0.000 claims description 2
- QFQYGJMNIDGZSG-YFKPBYRVSA-N (2r)-3-(acetamidomethylsulfanyl)-2-azaniumylpropanoate Chemical compound CC(=O)NCSC[C@H]([NH3+])C([O-])=O QFQYGJMNIDGZSG-YFKPBYRVSA-N 0.000 claims description 2
- BFNDLDRNJFLIKE-ROLXFIACSA-N (2s)-2,6-diamino-6-hydroxyhexanoic acid Chemical compound NC(O)CCC[C@H](N)C(O)=O BFNDLDRNJFLIKE-ROLXFIACSA-N 0.000 claims description 2
- BVAUMRCGVHUWOZ-ZETCQYMHSA-N (2s)-2-(cyclohexylazaniumyl)propanoate Chemical compound OC(=O)[C@H](C)NC1CCCCC1 BVAUMRCGVHUWOZ-ZETCQYMHSA-N 0.000 claims description 2
- DWKNTLVYZNGBTJ-IBGZPJMESA-N (2s)-2-amino-6-(dibenzylamino)hexanoic acid Chemical compound C=1C=CC=CC=1CN(CCCC[C@H](N)C(O)=O)CC1=CC=CC=C1 DWKNTLVYZNGBTJ-IBGZPJMESA-N 0.000 claims description 2
- FNRJOGDXTIUYDE-ZDUSSCGKSA-N (2s)-2-amino-6-[benzyl(methyl)amino]hexanoic acid Chemical compound OC(=O)[C@@H](N)CCCCN(C)CC1=CC=CC=C1 FNRJOGDXTIUYDE-ZDUSSCGKSA-N 0.000 claims description 2
- WAMWSIDTKSNDCU-ZETCQYMHSA-N (2s)-2-azaniumyl-2-cyclohexylacetate Chemical compound OC(=O)[C@@H](N)C1CCCCC1 WAMWSIDTKSNDCU-ZETCQYMHSA-N 0.000 claims description 2
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 claims description 2
- KNQHBAFIWGORKW-UHFFFAOYSA-N 2,3-diamino-3-oxopropanoic acid Chemical compound NC(=O)C(N)C(O)=O KNQHBAFIWGORKW-UHFFFAOYSA-N 0.000 claims description 2
- VHVGNTVUSQUXPS-UHFFFAOYSA-N 2-amino-3-hydroxy-3-phenylpropanoic acid Chemical compound OC(=O)C(N)C(O)C1=CC=CC=C1 VHVGNTVUSQUXPS-UHFFFAOYSA-N 0.000 claims description 2
- JINGUCXQUOKWKH-UHFFFAOYSA-N 2-aminodecanoic acid Chemical compound CCCCCCCCC(N)C(O)=O JINGUCXQUOKWKH-UHFFFAOYSA-N 0.000 claims description 2
- YXDGRBPZVQPESQ-QMMMGPOBSA-N 4-[(2s)-2-amino-2-carboxyethyl]benzoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(C(O)=O)C=C1 YXDGRBPZVQPESQ-QMMMGPOBSA-N 0.000 claims description 2
- CMUHFUGDYMFHEI-QMMMGPOBSA-N 4-amino-L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N)C=C1 CMUHFUGDYMFHEI-QMMMGPOBSA-N 0.000 claims description 2
- GTVVZTAFGPQSPC-UHFFFAOYSA-N 4-nitrophenylalanine Chemical compound OC(=O)C(N)CC1=CC=C([N+]([O-])=O)C=C1 GTVVZTAFGPQSPC-UHFFFAOYSA-N 0.000 claims description 2
- 239000004475 Arginine Substances 0.000 claims description 2
- NIGWMJHCCYYCSF-UHFFFAOYSA-N Fenclonine Chemical compound OC(=O)C(N)CC1=CC=C(Cl)C=C1 NIGWMJHCCYYCSF-UHFFFAOYSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 claims description 2
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 claims description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 2
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 2
- JTTHKOPSMAVJFE-VIFPVBQESA-N L-homophenylalanine Chemical compound OC(=O)[C@@H](N)CCC1=CC=CC=C1 JTTHKOPSMAVJFE-VIFPVBQESA-N 0.000 claims description 2
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 claims description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 2
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 claims description 2
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 claims description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 2
- VHVGNTVUSQUXPS-YUMQZZPRSA-N L-threo-3-phenylserine Chemical compound [O-]C(=O)[C@@H]([NH3+])[C@@H](O)C1=CC=CC=C1 VHVGNTVUSQUXPS-YUMQZZPRSA-N 0.000 claims description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004472 Lysine Substances 0.000 claims description 2
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 2
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 2
- 239000004473 Threonine Substances 0.000 claims description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 2
- 235000004279 alanine Nutrition 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- JINBYESILADKFW-UHFFFAOYSA-N aminomalonic acid Chemical compound OC(=O)C(N)C(O)=O JINBYESILADKFW-UHFFFAOYSA-N 0.000 claims description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 0.000 claims description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 2
- 235000018417 cysteine Nutrition 0.000 claims description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 2
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 claims description 2
- 235000013922 glutamic acid Nutrition 0.000 claims description 2
- 239000004220 glutamic acid Substances 0.000 claims description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 2
- QNRXNRGSOJZINA-UHFFFAOYSA-N indoline-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)CC2=C1 QNRXNRGSOJZINA-UHFFFAOYSA-N 0.000 claims description 2
- 235000014705 isoleucine Nutrition 0.000 claims description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 2
- 229960000310 isoleucine Drugs 0.000 claims description 2
- 229930182817 methionine Natural products 0.000 claims description 2
- 229960003104 ornithine Drugs 0.000 claims description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 2
- FVZVCSNXTFCBQU-UHFFFAOYSA-N phosphanyl Chemical group [PH2] FVZVCSNXTFCBQU-UHFFFAOYSA-N 0.000 claims description 2
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 2
- BJBUEDPLEOHJGE-IMJSIDKUSA-N trans-3-hydroxy-L-proline Chemical compound O[C@H]1CC[NH2+][C@@H]1C([O-])=O BJBUEDPLEOHJGE-IMJSIDKUSA-N 0.000 claims description 2
- PMMYEEVYMWASQN-IMJSIDKUSA-N trans-4-Hydroxy-L-proline Natural products O[C@@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-IMJSIDKUSA-N 0.000 claims description 2
- 239000004474 valine Substances 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 22
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 17
- 238000011282 treatment Methods 0.000 description 16
- 238000009472 formulation Methods 0.000 description 15
- 125000005843 halogen group Chemical group 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- 150000002678 macrocyclic compounds Chemical class 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 201000011510 cancer Diseases 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 239000012267 brine Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 230000019491 signal transduction Effects 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000007832 Na2SO4 Substances 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 235000014113 dietary fatty acids Nutrition 0.000 description 7
- 239000000194 fatty acid Substances 0.000 description 7
- 229930195729 fatty acid Natural products 0.000 description 7
- 125000005647 linker group Chemical group 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 101100180319 Mus musculus Itk gene Proteins 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 239000003599 detergent Substances 0.000 description 6
- 238000006798 ring closing metathesis reaction Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 108010016626 Dipeptides Proteins 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- 108090000695 Cytokines Proteins 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 4
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 4
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 150000004677 hydrates Chemical class 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 101150118364 Crkl gene Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 102000015617 Janus Kinases Human genes 0.000 description 3
- 108010024121 Janus Kinases Proteins 0.000 description 3
- 240000007472 Leucaena leucocephala Species 0.000 description 3
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 3
- 229910010084 LiAlH4 Inorganic materials 0.000 description 3
- 102000014384 Type C Phospholipases Human genes 0.000 description 3
- 108010079194 Type C Phospholipases Proteins 0.000 description 3
- 102000035181 adaptor proteins Human genes 0.000 description 3
- 108091005764 adaptor proteins Proteins 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 230000002018 overexpression Effects 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- UVBBCQLPTZEDHT-UHFFFAOYSA-N pent-4-en-1-amine Chemical class NCCCC=C UVBBCQLPTZEDHT-UHFFFAOYSA-N 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- DCWXELXMIBXGTH-UHFFFAOYSA-N phosphotyrosine Chemical compound OC(=O)C(N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-UHFFFAOYSA-N 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 230000002062 proliferating effect Effects 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical group N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- DSLBDPPHINVUID-REOHCLBHSA-N (2s)-2-aminobutanediamide Chemical compound NC(=O)[C@@H](N)CC(N)=O DSLBDPPHINVUID-REOHCLBHSA-N 0.000 description 2
- XUHRVZXFBWDCFB-QRTDKPMLSA-N (3R)-4-[[(3S,6S,9S,12R,15S,18R,21R,24R,27R,28R)-12-(3-amino-3-oxopropyl)-6-[(2S)-butan-2-yl]-3-(2-carboxyethyl)-18-(hydroxymethyl)-28-methyl-9,15,21,24-tetrakis(2-methylpropyl)-2,5,8,11,14,17,20,23,26-nonaoxo-1-oxa-4,7,10,13,16,19,22,25-octazacyclooctacos-27-yl]amino]-3-[[(2R)-2-[[(3S)-3-hydroxydecanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoic acid Chemical compound CCCCCCC[C@H](O)CC(=O)N[C@H](CC(C)C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H]1[C@@H](C)OC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CO)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC1=O)[C@@H](C)CC XUHRVZXFBWDCFB-QRTDKPMLSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- XDOFQFKRPWOURC-UHFFFAOYSA-N 16-methylheptadecanoic acid Chemical compound CC(C)CCCCCCCCCCCCCCC(O)=O XDOFQFKRPWOURC-UHFFFAOYSA-N 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N 2,4-diaminobutyric acid Chemical compound NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 101100149252 Caenorhabditis elegans sem-5 gene Proteins 0.000 description 2
- 108010001857 Cell Surface Receptors Proteins 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 101150069913 Csk gene Proteins 0.000 description 2
- 101100314281 Danio rerio trappc11 gene Proteins 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 101000652725 Drosophila melanogaster Transcription initiation factor TFIID subunit 5 Proteins 0.000 description 2
- 101100484539 Drosophila melanogaster Vav gene Proteins 0.000 description 2
- 101150036586 FES gene Proteins 0.000 description 2
- 101150040897 Fgr gene Proteins 0.000 description 2
- 102000018898 GTPase-Activating Proteins Human genes 0.000 description 2
- 108091006094 GTPase-accelerating proteins Proteins 0.000 description 2
- 101000752722 Homo sapiens Apoptosis-stimulating of p53 protein 1 Proteins 0.000 description 2
- 101001120056 Homo sapiens Phosphatidylinositol 3-kinase regulatory subunit alpha Proteins 0.000 description 2
- 101001120097 Homo sapiens Phosphatidylinositol 3-kinase regulatory subunit beta Proteins 0.000 description 2
- 101001116549 Homo sapiens Protein CBFA2T2 Proteins 0.000 description 2
- 101001000998 Homo sapiens Protein phosphatase 1 regulatory subunit 12C Proteins 0.000 description 2
- 101000927796 Homo sapiens Rho guanine nucleotide exchange factor 7 Proteins 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- 108010032107 Non-Receptor Type 11 Protein Tyrosine Phosphatase Proteins 0.000 description 2
- 101100381429 Oryza sativa subsp. japonica BADH2 gene Proteins 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- 102000002727 Protein Tyrosine Phosphatase Human genes 0.000 description 2
- 102100037787 Protein-tyrosine kinase 2-beta Human genes 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 102000003901 Ras GTPase-activating proteins Human genes 0.000 description 2
- 108090000231 Ras GTPase-activating proteins Proteins 0.000 description 2
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 2
- 101710100968 Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 2
- 102000000395 SH3 domains Human genes 0.000 description 2
- 108050008861 SH3 domains Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 2
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 2
- 102100024547 Tensin-1 Human genes 0.000 description 2
- 108010088950 Tensins Proteins 0.000 description 2
- 102100021125 Tyrosine-protein kinase ZAP-70 Human genes 0.000 description 2
- 101150042678 VAV1 gene Proteins 0.000 description 2
- 108010046882 ZAP-70 Protein-Tyrosine Kinase Proteins 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 238000001815 biotherapy Methods 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 238000010265 fast atom bombardment Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000000122 growth hormone Substances 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000003463 hyperproliferative effect Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 102000006240 membrane receptors Human genes 0.000 description 2
- 238000005649 metathesis reaction Methods 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 239000008180 pharmaceutical surfactant Substances 0.000 description 2
- DCWXELXMIBXGTH-QMMMGPOBSA-N phosphonotyrosine Chemical group OC(=O)[C@@H](N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-QMMMGPOBSA-N 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- 108020000494 protein-tyrosine phosphatase Proteins 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- 239000000344 soap Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 239000003039 volatile agent Substances 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- NEBPTMCRLHKPOB-UHFFFAOYSA-N 2,2-diphenylacetonitrile Chemical compound C=1C=CC=CC=1C(C#N)C1=CC=CC=C1 NEBPTMCRLHKPOB-UHFFFAOYSA-N 0.000 description 1
- HJJWTYHOHXVVSP-UHFFFAOYSA-N 2,2-diphenylpent-4-en-1-amine Chemical compound C=1C=CC=CC=1C(CC=C)(CN)C1=CC=CC=C1 HJJWTYHOHXVVSP-UHFFFAOYSA-N 0.000 description 1
- AVMSWPWPYJVYKY-UHFFFAOYSA-N 2-Methylpropyl formate Chemical compound CC(C)COC=O AVMSWPWPYJVYKY-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 1
- MOQVHOPVBREXLY-UHFFFAOYSA-N 3h-dioxol-4-ylmethanol Chemical compound OCC1=COOC1 MOQVHOPVBREXLY-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- 108010013238 70-kDa Ribosomal Protein S6 Kinases Proteins 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000018262 Arachis monticola Nutrition 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 102100026596 Bcl-2-like protein 1 Human genes 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 101100503636 Danio rerio fyna gene Proteins 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 101100001675 Emericella variicolor andJ gene Proteins 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 101150018272 FYN gene Proteins 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 102100037759 GRB2-associated-binding protein 2 Human genes 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 102000018997 Growth Hormone Human genes 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 102100033067 Growth factor receptor-bound protein 2 Human genes 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 101001024902 Homo sapiens GRB2-associated-binding protein 2 Proteins 0.000 description 1
- 101000871017 Homo sapiens Growth factor receptor-bound protein 2 Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 101150028321 Lck gene Proteins 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 1
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 1
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 108091005682 Receptor kinases Proteins 0.000 description 1
- 102100028516 Receptor-type tyrosine-protein phosphatase U Human genes 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 101150001535 SRC gene Proteins 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- 235000003434 Sesamum indicum Nutrition 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- ULUAUXLGCMPNKK-UHFFFAOYSA-N Sulfobutanedioic acid Chemical class OC(=O)CC(C(O)=O)S(O)(=O)=O ULUAUXLGCMPNKK-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000000887 Transcription factor STAT Human genes 0.000 description 1
- 108050007918 Transcription factor STAT Proteins 0.000 description 1
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 150000001508 asparagines Chemical class 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 108700000711 bcl-X Proteins 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000001743 benzylic group Chemical group 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- FCDPQMAOJARMTG-UHFFFAOYSA-L benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichlororuthenium;tricyclohexylphosphane Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1.CC1=CC(C)=CC(C)=C1N(CCN1C=2C(=CC(C)=CC=2C)C)C1=[Ru](Cl)(Cl)=CC1=CC=CC=C1 FCDPQMAOJARMTG-UHFFFAOYSA-L 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000010001 cellular homeostasis Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 230000007073 chemical hydrolysis Effects 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 125000005046 dihydronaphthyl group Chemical group 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000002621 immunoprecipitating effect Effects 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000007257 malfunction Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 230000002297 mitogenic effect Effects 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 230000006548 oncogenic transformation Effects 0.000 description 1
- 235000015205 orange juice Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- LQAVWYMTUMSFBE-UHFFFAOYSA-N pent-4-en-1-ol Chemical compound OCCCC=C LQAVWYMTUMSFBE-UHFFFAOYSA-N 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 238000000252 photodiode array detection Methods 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- 229920001469 poly(aryloxy)thionylphosphazene Polymers 0.000 description 1
- 229920005606 polypropylene copolymer Polymers 0.000 description 1
- 230000017363 positive regulation of growth Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 208000023958 prostate neoplasm Diseases 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical class S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 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 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 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
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- Signal transduction is critical to normal cellular homeostasis and is the process of relaying extracellular messages, e.g., chemical messages in the form of growth factors, hormones and neurotransmitters, via receptors, e.g., cell-surface receptors, to the interior of the cell.
- Protein-tyrosine kinases play a central role in this biological function. Among others, these enzymes catalyze the phosphorylation of specific tyrosine residues to form tyrosine phosphorylated residues.
- Protein-tyrosine phosphorylation is known to be involved in modulating the activity of some target enzymes as well as in generating specific complex networks involved in signal transduction via various proteins containing a specific amino acid sequence called an Src homology region or SH2 domain (see, e.g., Proc. Natl. Acad. Sd. USA, 90, 5891 (1990)).
- a malfunction in this protein-tyrosine phosphorylation through tyrosine kinase overexpression or deregulation is manifested by various oncogenic and (hyper-) proliferative disorders such as cancer, inflammation, autoimmune disease, hyper-proliferative skin disorders, such as psoriasis, and allergy/asthma.
- SH2- and/or SH3- comprising proteins that play a role in cellular signaling and transformation include, but are not limited to, the following: Src, Lck, Eps, ras GTPase-activating protein (GAP), phospholipase C, phosphoinositol-3 (PI-3) kinase, Fyn, Lyk, Fgr, Fes, ZAP-70, Sem-5, p85, SHPTPl, SHPTP2, corkscrew, Syk, Lyn, Yes, Hck, Dsrc, Tec, Atk/Bpk, Itk/Tsk, Arg, Csk, tensin, Vav, Emt, Grb2, BCR-AbI, She, Nek, Crk, CrkL, Syp, BIk, 113TF, 91TF, Tyk2, especially Src, phospholipase c, phoshoinositol-3 (PI-3) kinase, Grb
- the invention provides macrocyclic compounds that inhibit the binding of a phosphoprotein with a Grb2 SH2 domain-containing protein.
- the invention provides macrocyclic compounds of formula (I):
- R and R are the same and are hydrogen or aryl which is optionally substituted;
- R 2 in combination with the phenyl ring, is a phenylphosphate mimic group or a protected phenylphosphate mimic group;
- R 3 is hydrogen, azido, amino, oxalylamino, carboxy C 1 -Ce alkyl, Ci-C 6 alkoxycarbonyl Ci-C ⁇ alkyl, aminocarbonyl Cj-C 6 alkyl, or Ci-C 6 alkyl carbonylamino; wherein the alkyl portion of R 3 is optionally substituted;
- R 6 is a linker;
- AA is an amino acid;
- m is 1 to 6; and
- n is 1 to 6; or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.
- the invention further provides pharmaceutical compositions and methods of use of such compounds, for example, in the treatment of cancer.
- Figure 1 illustrates a method of preparing achiral alkenyl amines 9a and 9f, which are intermediates in the synthesis of compounds in accordance with an embodiment of the invention.
- Reagents and conditions (i) CH 3 SO 2 Cl, NEt 3 , CH 2 Cl 2 , room temp, 3 h; then NaN 3 , DMF-H 2 O, 50 0 C, overnight; (ii) LiAlH 4 , Et 2 O, 0 0 C, 1 h then (Boc) 2 O, Et 2 O - H 2 O, room temp, overnight; (iii) CF 3 CO 2 H, Et 3 SiH, CH 2 Cl 2 , room temp, 2 h; (iv) NaH, DMF 0 0 C to room temp, overnight; (vii) LiAlH 4 , Et 2 O.
- Figure 2 illustrates a method of preparing N-Boc protected asparagine alkenylamides 10a and 1Of, which are intermediates in the synthesis of compounds in accordance with an embodiment of the invention.
- Reagents and conditions (i) 4- methylmorpholine, Z-BuOC(O)Cl, DMF, 0 0 C 10 min then (ii) ra-Boc-L-Asn(Trt), room temperature, overnight.
- Figure 3 illustrates a method of preparing compound 18, which is an intermediate in the synthesis of compounds in accordance with an embodiment of the invention.
- Reagents and conditions (i) AUyI bromide, K 2 CO 3 , DMF, room temp, 2 days; (ii) CF 3 CO 2 H, Et 3 Si, CH 2 Cl 2 , room temp, 2 h; (iii) HOAt, EDCI, NEt(Z-Pr) 2 , DMF, room temp, 2 days; (iv) Pd(PPh 3 ) 4 , morpholine, THF, room temp, 30 min.
- Figure 4 illustrates a method of preparing compounds of formula (Ilia) and (HIb) (5a and 5b, respectively) in accordance with an embodiment of the invention.
- Reagents and conditions (i) HOAt, EDCI, NEt(Z-Pr) 2 , DMF, room temp, 2 days; (ii) 1,2-dichloroethane, reflux, 2 days; (iii) CF 3 CO 2 H, Et 3 Si, CH 2 Cl 2 , room temp, 2 h.
- the invention provides macrocyclic compounds of formula (I):
- R 1 and R 1 are the same and are hydrogen or aryl which is optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, carboxyl, amino, amino Ci-C 6 alkyl, Ci-C 6 alkyl, and Ci-C 6 alkoxy;
- R 2 in combination with the phenyl ring, is a phenylphosphate mimic group or a protected phenylphosphate mimic group;
- R 3 is hydrogen, azido, amino, oxalylamino, carboxy Ci-C 6 alkyl, Ci-C 6 alkoxycarbonyl Ci-C 6 alkyl, aminocarbonyl Ci-C 6 alkyl, or Ci-C 6 alkyl carbonylamino; wherein the alkyl portion of R 3 is optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, carboxyl, amino, amino Ci-C 6 alkyl, C]-C 6 alkyl, Ci-C 6 alkoxy
- the macrocyclic compounds of formula (I) can be of a suitable ring size.
- m is from 1 to 4, more preferably, m is 1 or 2, and in a particular embodiment, m is 1.
- n is from 2 to 4, more preferably, n is 2 or 3, and in particularly, n is 2.
- the amino acids of (AA) n are incorporated, to arrive at the compounds of formula I, such that the N- and C-termini of (AA) n form amide linkages.
- n is 2 and the amino acids of AA are ⁇ -aminocyclohexane carboxylic acid and asparagine, wherein each of the amino and carboxyl groups of the N- and C-termini of AA have been reacted to form amide linkages.
- the amino acid or amino acids of (AA) n can be any suitable amino acids, natural or synthetic.
- the amino acids can be selected from the group consisting of glycine, alanine, valine, norvaline, leucine, iso-leucine, norleucine, ⁇ -amino n-decanoic acid, serine, homoserine, threonine, methionine, cysteine, S-acetylaminomethyl-cysteine, proline, trans-3- and trans-4-hydroxyproline, phenylalanine, tyrosine, 4-aminophenylalanine, 4-nitrophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine, ⁇ -phenylserine, ⁇ -hydroxyphenylalanine, phenylglycine, ⁇ -naphthylalanine, cyclohexylalanine, cyclohe
- R 1 and R 1 are the same and can be either hydrogen or aryl.
- the carbon atom to which R 1 and R 1 are attached is achiral.
- R 1 and R 1 can be introduced, to prepare compounds of the invention, using any suitable method such as, for example, using achiral alkenyl amines as depicted in Figures 1-4.
- R and R of formula (I) can be any suitable aryl group.
- Aryl groups are well-known to the skilled artisan and include, for example, phenyl, naphthyl, anthracenyl, fluorenyl, biphenyl, dihydronaphthyl, tetrahydronaphthyl, heteroaryl, and the like.
- Heteroaryl groups are well-known to the skilled artisan and include, for example, pyrrolyl, furanyl, pyrenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, imidazolyl, pyradazinyl, pyrimidinyl, triazinyl, pyranyl, thiazolyl, isothiazolyl, pteridinyl, piperonyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, and the like.
- aryl and heterocyclyl moieties may be fused, such as, e.g., indole, isoindole, benzimidazole, quinoline, isoquinolinyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, carbazolyl, benzodioxolyl, and the like.
- R 1 and R 1 are aryl, which is optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, carboxyl, amino, amino Ci-Ce alkyl, Ci-C 6 alkyl, and Ci-C 6 alkoxy.
- halo refers to any suitable halogen atom, including, for example, fluoro, chloro, bromo, iodo, and any combinations thereof.
- the substituent can be located at any suitable position which is available for substitution, for example, in phenyl, the phenyl ring can be substituted at, for example, the 2, 3, 4, and/or 5 positions.
- the aryl groups may be substituted by more than one substituent as appropriate.
- R 2 in formula (I), in combination with the phenyl ring is a phenylphosphate mimic group or protected phenylphosphate mimic group.
- a phenylphosphate mimic group can be one that has the functional property of the phosphorylated side chain of tyrosine-phosphorylated sequences, e.g., it can replicate the interaction of phenylphosphate side chain with proteins. The interaction may involve any number of mechanisms, including geometry, size, and/or charge.
- a protected phenylphosphate mimetic is a phenylphosphate mimic that contains a protecting group that releases the mimetic, e.g., in a biological environment, such as due to chemical or enzymatic hydrolysis.
- the protecting groups can be esters or amides.
- R 2 can be hydroxyl, carboxyl, formyl, carboxy Ci-C 6 alkyl, carboxy Ci-C 6 alkoxy, dicarboxy Ci-C 6 alkyl, dicarboxy C]-C 6 alkyloxy, dicarboxyhalo Ci-C 6 alkyl, dicarboxyhalo Ci-C 6 alkyloxy, phosphono, phosphono Cj-C 6 alkyl, phosphonohalo Ci-C 6 alkyl, phosphoryl, phosphoryl Ci-C 6 alkyl, and phosphoryl Ci-C 6 alkoxy, carboxy Ci-C 6 alkylamino, oxalylamino, C 6 -Ci 4 aryl Ci-C 6 alkyl, phosphino Cj-C 6 alkyl, Ci-C 6 alkyl phosphino C]-C 6 alkyl, C 6 -Ci 4 aryl, or RSO 2 NH- wherein R can be
- R 2 is dicarboxy Ci-C 6 alkyl, e.g., dicarboxymethyl.
- R 2 is phosphono Ci-C 6 alkyl, e.g., phosphonomethyl.
- R 3 of formula (I) can be hydrogen, azido, amino, oxalylamino, carboxy Ci-C 6 alkyl, Ci-C 6 alkoxycarbonyl Ci-C 6 alkyl, aminocarbonyl Ci-C 6 alkyl, or Ci-C 6 alkyl carbonylamino; wherein the alkyl portion of R 3 is optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, carboxyl, amino, amino Ci-C 6 alkyl, Ci-C 6 alkyl, Ci-C 6 alkoxy, and formyl.
- R 3 is carboxy Ci-C 6 alkyl, e.g., carboxy methyl.
- the invention provides compounds of formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof:
- R 1 and R 1 are the same and are hydrogen or aryl which is optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, carboxyl, amino, amino Ci-C 6 alkyl, Ci-C 6 alkyl, and Ci-C 6 alkoxy;
- R 2 in combination with the phenyl ring, is a phenylphosphate mimic group or a protected phenylphosphate mimic group;
- R 3 is hydrogen, azido, amino, oxalylamino, carboxy Ci-C 6 alkyl, Ci-C 6 alkoxycarbonyl Ci-C 6 alkyl, aminocarbonyl C]-C 6 alkyl, or Ci-C 6 alkyl carbonylamino; wherein the alkyl portion of R 3 is optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, carboxyl, amino, amino Ci-C 6 alkyl, Cj-C 6 alkyl, Ci-C
- R and R independently, can be hydrogen, Ci-C 6 alkyl, C 4 -C 8 cycloalkyl, or heterocyclyl, or R 4 and R 5 together can form a C 4 -C 8 cycloalkyl or heterocyclyl.
- heterocyclyl is heterocycloalkyl.
- R and R together form a C 4 -C 8 cycloalkyl, e.g., a cyclohexyl group.
- R 6 is a linker.
- the linker R 6 connects the benzylic carbon of the phenylphosphate mimic or protected phenylphosphate mimic group (i.e., the carbon atom of the macrocycle to which the R 2 -phenyl group is attached) to the carbon atom bearing R 1 and R 1 .
- the bond connecting the linker to the linking sites can have any suitable configuration (R, S, or R/S).
- the linking site at R 1 and R 1 has a R/S configuration.
- the linker R 6 can be a bond or a group having 1-6 carbon atoms and can be optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, carboxyl, amino, aminoalkyl, Ci-C 6 alkyl, Ci-C 6 alkoxy, and formyl.
- R 6 is a C 2 -CO alkenylenyl or C 2 -C 6 alkynylenyl group, optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, carboxyl, amino, aminoalkyl, Ci-C 6 alkyl, Ci-C 6 alkoxy, and formyl.
- R 6 is a C 2 -C 6 alkenylenyl.
- R 6 is propenylenyl.
- R 6 can be a C 2 -C 6 alkenylenyl or C 2 -C 6 alkynylenyl group, preferably C 3 alkenylenyl or C 3 alkynylenyl.
- R 6 can be optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, carboxyl, amino, aminoalkyl, C]-C 6 alkyl, Ci-C 6 alkoxy, and formyl.
- m can be 1 or 2.
- R 6 can be C 3 alkenylenyl or
- C 3 alkynylenyl optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, carboxyl, amino, aminoalkyl, Cj-C 6 alkyl, Ci-C 6 alkoxy, and formyl.
- R and R 1 are hydrogen and m is 2, R can be C 3 alkenylenyl or
- C 3 alkynylenyl optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, carboxyl, amino, aminoalkyl, Ci-C 6 alkyl, Ci-C 6 alkoxy, and formyl.
- the present invention provides compounds of formula (II), wherein R 1 and R 1 are hydrogen, R 2 is dicarboxymethyl, R 3 is carboxy methyl, R 4 and R 5 together form a cyclohexyl, R is propenylenyl, and m is 1.
- the present invention provides compounds of formula (II), wherein R 1 and R 1 are hydrogen, R 2 is phosphonomethyl, R 3 is carboxy methyl, R 4 and R 5 together form a cyclohexyl, R 6 is propenylenyl, and m is 1.
- the present invention provides compounds of formula (II), wherein R 1 and R 1 are phenyl, R 2 is dicarboxymethyl, R 3 is carboxy methyl, R 4 and R 5 together form a cyclohexyl, R 6 is propenylenyl, and m is 1.
- the present invention provides compounds of formula (II), wherein R 1 and R 1 are phenyl, R 2 is phosphonomethyl, R 3 is carboxy methyl, R 4 and R 5 together form a cyclohexyl, R 6 is propenylenyl, and m is 1. [0036] In a specific embodiment, the invention provides a compound of formula (Ilia):
- the invention provides a compound of formula (HIb):
- the present invention also provides pharmaceutically acceptable salts, stereoisomers, solvates, or hydrates of the inventive compounds, as appropriate, including alkali or amine salts.
- Suitable pharmaceutically acceptable salts, stereoisomers, solvates, or hydrates of the inventive compounds are known to the skilled artisan.
- the acidic groups, e.g., carboxylic, phosphoric, or phosphonic groups, of the compound can be converted to salts known to those skilled in the art, for example, a salt of an alkali metal (e.g., sodium or potassium), alkaline earth metal (e.g., calcium), or ammonium salt.
- an alkali metal e.g., sodium or potassium
- alkaline earth metal e.g., calcium
- ammonium salt e.g., sodium or potassium
- compositions include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, />-toluenesulphonic acids, and arylsulphanic, for example.
- Solvates and hydrates of the present invention can be prepared using any suitable technique known in the art, for example, by crystallizing compounds of the invention in the presence of a suitable solvent, using conditions such that a solvate is formed.
- hydrates of the present invention can be prepared, for example, by crystallizing compounds of the invention in the presence of water using conditions such that a hydrate is formed.
- the present invention further provides compositions comprising a pharmaceutically acceptable carrier and an effective (e.g., therapeutically or prophylactically effective) amount of at least one of the compounds described above.
- the present invention further provides a method of inhibiting an SH2 domain from binding with a phosphoprotein comprising contacting a sample or substance containing an SH2 domain with a compound of the present invention.
- the present invention discloses the use of above compounds in the manufacture of a medicament for the treatment of a condition that responds to the inhibition of phosphoprotein binding to an SH2 domain of a mammal.
- the present invention further provides the use of the above compounds in medicine.
- the compounds can find use as an SH2 domain binding inhibitor.
- SH2 domain-containing proteins are Grb2, Shp2, and STAT3 proteins.
- the pharmaceutically acceptable (e.g., pharmacologically acceptable) carriers described herein, for example, vehicles, adjuvants, excipients, or diluents, are well known to those who are skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the active compounds and one which has no detrimental side effects or toxicity under the conditions of use.
- compositions of the present invention are merely exemplary and are in no way limiting.
- Formulations suitable for oral administration can comprise (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
- Liquid formulations can include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
- Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch.
- Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
- Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
- a flavor usually sucrose and acacia or tragacanth
- pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
- the compounds of the present invention can be made into aerosol formulations to be administered via inhalation.
- aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also can be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
- Formulations suitable for parenteral administration include aqueous and nonaqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
- the compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2,2-dimethyl-l,3-dioxolane- 4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical
- Oils which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
- Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
- suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl- ⁇ -aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.
- the parenteral formulations will typically contain from about 0.5 to about 25% by weight of the active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants. The quantity of surfactant in such formulations typically ranges from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
- parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use.
- sterile liquid carrier for example, water
- Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
- the compounds of the present invention may be made into injectable formulations.
- the requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art; see, e.g., Pharmaceutics and Pharmacy Practice, J.B. Lippincott Co., Philadelphia, PA, Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4 th ed., pages 622- 630 (1986).
- the compounds of the present invention may be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases.
- bases such as emulsifying bases or water-soluble bases.
- Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
- Suitable doses and dosage regimens can be determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
- the total daily dosage may be divided and administered in portions during the day if desired.
- the present invention provides for a wide range of responses.
- the dosages range from about 0.001 to about 1000 mg/kg body weight of the animal being treated/day.
- Preferred dosages range from about 0.01 to about 10 mg/kg body weight/day, and further preferred dosages range from about 0.01 to about 1 mg/kg body weight/day.
- Embodiments of the compounds have the advantage that they are stable to or in presence of enzymes encountered during in vivo use.
- Embodiments of the compounds can find use in in vitro and in vivo applications.
- the compounds can find use as molecular probes as well as in assays to identify, isolate, and/or quantitate receptor or binding sites in a cell or tissue.
- the compounds also can find use in vivo for studying the efficacy in the treatment of various diseases or conditions involving SH2 domains.
- the present invention further provides a method of preventing or treating a disease, state, or condition in a mammal by the use of the compounds of the present invention.
- the method involves preventing a disease, state, or condition.
- the method involves treating an existing disease, state, or condition.
- the method involves inhibition of SH2 domain binding with a phosphoprotein.
- the SH2 domain may involve one or more of the following proteins: Shp2, STAT3, Src, Lck, Eps, ras GTPase-activating protein (GAP), phospholipase C, PI-3 kinase, Fyn, Lyk, Fgr, Fes, ZAP-70, Sem-5, p85, SHPTPl, SHPTP2, corkscrew, Syk, Lyn, Yes, Hck, Dsrc, Tec, Atk/Bpk, Itk/Tsk, Arg, Csk, tensin, Vav, Emt, Grb2, BCR-AbI, She, Nek, Crk, CrkL, Syp, BIk, 113TF, 91TF, and Tyk2, especially Grb2, Shp2, and STAT3.
- GAP GTPase-activating protein
- Grb2 is an adaptor protein with N- and C-terminal src homology 3 (SH3) domains and a central src homology 2 (SH2) domain.
- SH3 domain can bind to phosphoTyr residues of receptors or other adaptor proteins, such as SHC.
- the SH3 domains bind the Ras exchange factor SOS, but can also bind to other adaptor proteins such as GABl and GAB2.
- Grb2 is involved in activation of Ras but can also play a role in other signaling pathways in mammalian cells.
- Shp2 is a tyrosine phosphatase that is recruited into tyrosine kinase signaling pathways through binding of its two amino-terminal SH2 domains to specific phosphotyrosine motifs.
- Shp2 is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation.
- Shp2 contains two tandem Src homology-2 domains, which function as phosphotyrosine binding domains and mediate the interaction with its substrates.
- Shp2 is widely expressed in most tissues and plays a regulatory role in various cell-signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration.
- STATs Signal Transducers and Activators of Transcription
- JAK kinases transcription factors that are phosphorylated by JAK kinases in response to cytokine activation of a cell surface receptor tyrosine kinases.
- the STATs dimerize and are localized to the nucleus where they activate transcription of cytokine-responsive genes.
- Cytokines that activate STAT3 include growth hormone, IL-6 family cytokines, and G-CSF.
- STAT3 induces progression through the cell cycle, prevents apoptosis and upregulates oncogenes, such as c-myc and bcl-X and may play a role in oncogenesis.
- STAT3 has been shown to play a critical role in hematopoiesis. The importance of STAT3 is underscored by the failure of mice lacking STAT3 to survive embryogenesis.
- Crosstalk from pathways other than JAK kinases also leads to phosphorylation and activation of STAT3 as indicated by a role of mTOR (mammalian target of rapamycin, or p70 S 6 kinase) and MAP kinase pathways in STAT3 activation and signaling.
- the method of treatment or prevention of a diseases comprises administering to the mammal one or more compounds of the present invention.
- the disease, state, condition can be a cancer, e.g., a breast cancer or an ovarian cancer, or a tumor such as a solid tumor, e.g., a brain tumor, a prostate tumor, and the like, leukemia including chronic myelocytic leukemia, lymphoma, an autoimmune disease, an inflammatory disease, a metabolic disease, diabetes, obesity, or cardiovascular disease.
- the present invention further provides a method of enhancing the therapeutic effect of a treatment rendered to a mammal comprising administering a compound in conjunction with the treatment.
- the inhibitor can be used in any suitable manner, for example, prior to, simultaneous with, or post- administration of the therapeutic agent. Synergistic effects are observed when the SH2 domain binding inhibitor is used in combination with other treatments known to those skilled in the art.
- the inhibitor enhances the cytotoxicity of the chemotherapeutic treatments. Cancer treatment is particularly suitable for this combination treatment.
- the cancer may involve any number of mechanisms.
- a majority of human breast cancers are dependent upon activation of the Ras signaling pathways through activation of growth factor receptor as the means to achieve continuous cellular proliferation.
- the cancer may involve overexpression of Her-2/neu.
- the cancer can be mediated through BCR-AbI or the expression of erbB-2 receptor.
- therapeutic agents affecting Grb2 function at its SH2 domain may interrupt the flow of signal transduction to the Ras pathway and thus result in reversal of the cancer phenotype.
- the therapeutic treatment can include chemotherapy, radiation therapy, and/or a biological therapy.
- chemotherapy include the use of cancer treatment agents such as alkylating agents, hormonal agents, antimetabolites, natural products, and miscellaneous agents.
- cancer treatment agents include paclitaxel, 5- fluoruracil, and doxorubicin.
- biological therapy include the use of a protein such as an antibody (monoclonal or polyclonal) or a recombinant protein.
- An example of an antibody is herceptin, which is targeted for inhibiting the erbB-2 receptor.
- the enhancement of the therapeutic effect comprises blocking of a cell survival factor in the mammal and/or triggering, e.g., enhancing or speeding up, of cell apoptosis.
- the treatment can be carried out in vivo and/or in vitro.
- the Grb2 SH2 binding inhibitors are effective in inhibiting the association or binding of Grb2 with activated receptor PTKs. Interaction of native Grb2 protein with phosphotyrosinylated proteins including receptor PTKs can be monitored by immunoprecipitating Grb2 and detecting the amount of phosphotyrosinylated proteins which are coprecipitated using anti-phosphotyrosine Western Blotting.
- the compounds of the present invention can be prepared by any suitable method, for example, a method that advantageously utilizes achiral alkenyl amines in a synthesis involving ring closing metathesis (RCM) reaction of asparagine pentenylamides onto a ⁇ -vinyl-containing residue; see, e.g., Figures 1-4.
- RCM ring closing metathesis
- For examples of RCM reactions see, Gao et al., Org. Lett. 2001, 3, 1617-1620; Reichwein et al., Angew. Chem., Int. Ed. 1999, 38, 3684-3687, J. Org. Chem., 2000, 65, 6187-6195; andJ. Org.
- the RCM reaction advantageously allows ring closure with retention of desired functional groups, e.g., phenylphosphate functionality or the chemical (e.g., aryl groups of R and R ) functionality at or near the site of ring juncture(s).
- desired functional groups e.g., phenylphosphate functionality or the chemical (e.g., aryl groups of R and R ) functionality at or near the site of ring juncture(s).
- desired functional groups e.g., phenylphosphate functionality or the chemical (e.g., aryl groups of R and R ) functionality at or near the site of ring juncture(s).
- desired functional groups e.g., phenylphosphate functionality or the chemical (e.g., aryl groups of R and R ) functionality at or near the site of ring juncture(s).
- the preparation of multiple analogues may be made possible through the use of solid-phase chemistries.
- macrocyclic compounds of any suitable size can be prepared.
- homologs of compounds 9a and 9f which have one or more additional methylene units between the amino group and the carbon atom bearing R 1 and R 1 (i.e., m is greater than 1), can be prepared using any suitable chemistry known in the art. These homologs can then be used to prepare macrocyclic compounds of the invention, wherein m is greater than 1, using similar chemistry as depicted in Figures 2-4.
- Another exemplary approach is varying the number of amino acids of (AA) n .
- analogs of compounds 10a, 1Of, and/or 18 can be prepared, which comprise one or more additional amino acids (i.e., n of (AA) n is greater than 2). These analogs can then be used to prepare macrocyclic compounds of the invention, wherein n is greater than 2, using similar chemistry as depicted in Figure 4. Both of these approaches can be used to vary the ring size while producing macrocyclic compounds of the invention. In accordance with the invention, one or both of these approaches can be used to prepare macrocyclic compounds of the invention with various ring sizes.
- This example demonstrates a method of preparing compounds 5a and 5f in accordance with an embodiment of the invention.
- HPLC separations are conducted using a Waters Prep LC4000 system with photodiode array detection and either a J-sphere ODS-H80 column (20 x 250 mm) with a solvent system consisting of 0.1% aqueous TFA (v/v, solvent A) / 0.1% TFA in MeCN (v/v, solvent B).
- the reaction mixtue is diluted with water (200 mL) and extracted with ether (300 mL). The ether layer is washed with water (50 mL x 2) and brine (50 mL), dried over sodium sulfate and concentrated in vacuo. The concentrated oil is dissolved in anhydrous ether (100 mL), LiAlH 4 (2.2 g, 58.1 mmol) is added in several portions at 0 0 C, and the suspension is stirred for 1 hour. Water (5.0 rnL) is carefully added to the reaction mixture at 0 0 C, which is stirred vigorously until white.
- N-Boc protected asparagines alkenylamides are prepared as depicted in Figure 2.
- ⁇ -Boc- ⁇ -aminocyclohexanecarboxylic acid 2-propenyl ester A mixture of ⁇ -Boc-l-aminocyclohexanecarboxylic acid (1.70 g, 7.00 mmol), allyl bromide (0.89 mL, 10.5 mmol) and Na 2 CO 3 (881 mg, 10.5 mmol) in DMF (20 mL) is stirred at room temperature (2 days). The reaction mixture is diluted with ethyl acetate (150 mL), washed with H 2 O (2 x 50 mL) and brine (50 mL), dried (Na 2 SO 4 ) and solvent evaporated.
- Dipeptide acid 18 To a solution of dipeptide allyl ester 17 (540 mg, 0.82 mmol) in anhydrous THF (30 mL) which has been degassed under argon for 5 minutes is added Pd(PPh 3 ) 4 (93 mg, 0.080 mmol) and morpholine (0.70 mL, 8.00 mmol). The mixture is stirred at room temperature (30 minutes) then 0.1 N HCl (100 mL) is added, THF is removed in vacuuo and the remaining residue is extracted with ethyl acetate (3 x 50 mL).
- Metathesis precursor 13a ⁇ -Boc-protected asparagine amide 10a (94 mg, 0.174 mmol) is treated with CF 3 CO 2 H (1.60 mL) and triethylsilane (0.30 mL) in CH 2 Cl 2 (1.0 mL) at room temperature (4 h). Volatiles are then removed in vaccuo and the residue is placed in vacuum (30 minutes) to yield the CF 3 CO 2 H amine salt 19a.
- Metathesis precursor 13f Deprotection of ⁇ -Boc-protected asparagine amide 1Of yields the CF 3 CO 2 H amine salt 19f, which is coupled with dipeptide acid 18 as in 13a to provide 13f in 85% yield.
- the steady state values are determined using a Biacore 2000 and S51 instruments using amine coupled surfaces as described in Oishi et al. ChemBioChem, 2005, 6, 668-674 and Oishi et al. Bioorg. Med. Chem., 2005, 13, 2431-2438.
- the binding experiment directly measures the binding of 5a and 5f to biotinylated Grb2 SH2 domain protein immobilized onto a sensor chip. Immobilization of protein is achieved either by amine coupling or by streptavidin capturing of the biotin functionality.
- the binding data is provided in Table 1.
- 5a and 5f display binding affinities of 320 nM and 72 nM, respectively.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
L'invention concerne des composés permettant d'inhiber la liaison d'une protéine contenant le domaine SH2, par exemple un composé représenté par la formule (I), dans laquelle R1 et R1'sont semblables et sont hydrogène ou aryle éventuellement substitué tel que dans la description, R2 en combinaison avec son cycle phényle est un groupe analogue phényle phosphate ou un groupe analogue phényle phosphate protégé, R3 est hydrogène, azido, amino, oxalylamino, carboxy C1-C6 alkyle, C1-C6 alkoxycarbonyle C1-C6 alkyle, aminocarbonyle C1-C6 alkyle, ou C1-C6 alkyle carbonylamino; la partie alkyle de R3 est éventuellement substituée telles que dans de la description, R6 est un lieur, AA est un acide aminé, m est compris entre 1 et 6 et n est comprise entre 1 et 6. L'invention concerne aussi un sel, un stéréoisomère, un solvate ou un hydrate de ces composés pharmaceutiquement acceptable. L'invention concerne aussi des compositions pharmaceutiques et des procédés d'utilisation de ces composés.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US86730706P | 2006-11-27 | 2006-11-27 | |
US60/867,307 | 2006-11-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2008067270A1 true WO2008067270A1 (fr) | 2008-06-05 |
Family
ID=39146974
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2007/085562 WO2008067270A1 (fr) | 2006-11-27 | 2007-11-27 | Inhibiteurs de liaison au domaine grb2 sh2 macrocyclique |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2008067270A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2567959A1 (fr) | 2011-09-12 | 2013-03-13 | Sanofi | Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs |
US11485750B1 (en) | 2019-04-05 | 2022-11-01 | Kymera Therapeutics, Inc. | STAT degraders and uses thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004003005A2 (fr) * | 2002-06-28 | 2004-01-08 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Inhibiteurs de liaison au domaine sh2 |
WO2006039527A1 (fr) * | 2004-09-30 | 2006-04-13 | Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Inhibiteurs de liaison de domaine sh2 macrocyclique |
-
2007
- 2007-11-27 WO PCT/US2007/085562 patent/WO2008067270A1/fr active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004003005A2 (fr) * | 2002-06-28 | 2004-01-08 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Inhibiteurs de liaison au domaine sh2 |
WO2006039527A1 (fr) * | 2004-09-30 | 2006-04-13 | Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Inhibiteurs de liaison de domaine sh2 macrocyclique |
Non-Patent Citations (3)
Title |
---|
LEE K ET AL: "UTILIZATION OF A BETA-AMINOPHOSPHOTYROSYL MIMETIC IN THE DESIGN AND SYNTHESIS OF MACROCYCLIC GRB2 SH2 DOMAIN-BINDING PEPTIDES", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 46, no. 13, 19 June 2003 (2003-06-19), pages 2621 - 2630, XP009063654, ISSN: 0022-2623 * |
LIU FA ET AL: "Utilization of achiral alkenyl amines for the preparation of high affinity Grb2 SH2 domain-binding macrocycles by ring-closing metathesis.", ORGANIC & BIOMOLECULAR CHEMISTRY 21 JAN 2007, vol. 5, no. 2, 4 December 2006 (2006-12-04), pages 367 - 372, XP002472708, ISSN: 1477-0520 * |
SHI Z D ET AL: "Synthesis of a C-terminally biotinylated macrocyclic peptide mimetic exhibiting high Grb2 SH2 domain-binding affinity", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER SCIENCE LTD, GB, vol. 13, no. 13, 1 July 2005 (2005-07-01), pages 4200 - 4208, XP004913665, ISSN: 0968-0896 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2567959A1 (fr) | 2011-09-12 | 2013-03-13 | Sanofi | Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs |
US11485750B1 (en) | 2019-04-05 | 2022-11-01 | Kymera Therapeutics, Inc. | STAT degraders and uses thereof |
US11746120B2 (en) | 2019-04-05 | 2023-09-05 | Kymera Therapeutics, Inc. | Stat degraders and uses thereof |
US12077555B2 (en) | 2019-04-05 | 2024-09-03 | Kymera Therapeutics, Inc. | STAT degraders and uses thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7073266B2 (ja) | Peg化薬物リンカー及びその中間体を調製するためのプロセス | |
EA019749B1 (ru) | Противовирусные соединения | |
CA3061611A1 (fr) | Modulateurs de l'interaction sestrine-gator2 et utilisations de ces derniers | |
US7825216B2 (en) | Phenylanine derivatives | |
US9458200B2 (en) | Method for producing intermediates for the production of novel macrocycles that are inhibitors of the proteasomic degradation of p27, such as argyrin and derivatives thereof, and uses of said macrocycles | |
WO2008067270A1 (fr) | Inhibiteurs de liaison au domaine grb2 sh2 macrocyclique | |
US20080139456A1 (en) | Macrocyclic Sh2 Domain Binding Inhibitors | |
US7767645B2 (en) | SH2 domain binding inhibitors | |
US6977241B2 (en) | SH2 domain binding inhibitors | |
US10905769B2 (en) | Peptide and peptide mimetic binding antagonists of polo-like kinase 1 polo box domain and methods of use | |
EP1793843A1 (fr) | Inhibiteurs de liaison de domaine sh2 macrocyclique | |
US7425537B2 (en) | SH2 domain binding inhibitors | |
US7226991B1 (en) | Phenylalanine derivatives | |
WO2004003005A2 (fr) | Inhibiteurs de liaison au domaine sh2 | |
JP7496112B2 (ja) | プロドラッグ及び医薬組成物 | |
WO2020130119A1 (fr) | Inhibiteur de la voie de signalisation wnt | |
WO2017082924A1 (fr) | Peptides et peptides mimétiques antagonistes de liaison de domaine polo-box de kinase 1 de type polo et procédé d'utilisation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 07854780 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 07854780 Country of ref document: EP Kind code of ref document: A1 |