AU709409B2

AU709409B2 - Thiadioxobenzodiazepine inhibitors of farnesyl protein transferase

Thiadioxobenzodiazepine inhibitors of farnesyl protein transferase Download PDF

Info

Publication number: AU709409B2
Authority: AU; Australia
Prior art keywords: dioxide; tetrahydro; imidazol; ylmethyl; benzothiadiazepine
Prior art date: 1996-07-15
Legal status : Ceased

Application number

AU38808/97A

Other languages

English (en)

Other versions

AU3880897A (en

Inventor

Charles Z. Ding

Current Assignee

Bristol Myers Squibb Co

Original Assignee

Bristol Myers Squibb Co

Priority date

1996-07-15

Filing date

1997-07-08

Publication date

1999-08-26

1997-07-08 Application filed by Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co

1998-02-09 Publication of AU3880897A publication Critical patent/AU3880897A/en

1999-08-26 Application granted granted Critical

1999-08-26 Publication of AU709409B2 publication Critical patent/AU709409B2/en

2017-07-08 Anticipated expiration legal-status Critical

Status Ceased legal-status Critical Current

Links

102000004357 Transferases Human genes 0.000 title claims description 12
108090000992 Transferases Proteins 0.000 title claims description 12
125000004030 farnesyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 title claims description 10
239000003112 inhibitor Substances 0.000 title description 5
150000001875 compounds Chemical class 0.000 claims description 101
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 41
-1 methyl 1,2,5- benzothiadiazepine Chemical compound 0.000 claims description 39
125000000217 alkyl group Chemical group 0.000 claims description 31
125000003118 aryl group Chemical group 0.000 claims description 27
JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 24
238000000034 method Methods 0.000 claims description 23
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 19
KAOYLRLQZXRRBD-UHFFFAOYSA-N 1,2,3-benzothiadiazepine Chemical compound S1N=NC=CC2=CC=CC=C12 KAOYLRLQZXRRBD-UHFFFAOYSA-N 0.000 claims description 18
125000003710 aryl alkyl group Chemical group 0.000 claims description 18
125000000547 substituted alkyl group Chemical group 0.000 claims description 18
206010028980 Neoplasm Diseases 0.000 claims description 17
239000004305 biphenyl Substances 0.000 claims description 15
239000001257 hydrogen Chemical group 0.000 claims description 15
229910052739 hydrogen Inorganic materials 0.000 claims description 15
201000010099 disease Diseases 0.000 claims description 14
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
150000003839 salts Chemical class 0.000 claims description 14
150000002431 hydrogen Chemical class 0.000 claims description 11
229910052757 nitrogen Inorganic materials 0.000 claims description 11
108090000623 proteins and genes Proteins 0.000 claims description 11
102000004169 proteins and genes Human genes 0.000 claims description 10
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
229940002612 prodrug Drugs 0.000 claims description 9
239000000651 prodrug Substances 0.000 claims description 9
DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 8
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
239000001301 oxygen Substances 0.000 claims description 8
229910052760 oxygen Inorganic materials 0.000 claims description 8
125000003107 substituted aryl group Chemical group 0.000 claims description 8
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
125000002837 carbocyclic group Chemical group 0.000 claims description 7
229910052717 sulfur Inorganic materials 0.000 claims description 7
102000004190 Enzymes Human genes 0.000 claims description 6
108090000790 Enzymes Proteins 0.000 claims description 6
125000004093 cyano group Chemical group *C#N 0.000 claims description 6
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
239000011593 sulfur Substances 0.000 claims description 6
KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 5
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
PCTMTFRHKVHKIS-BMFZQQSSSA-N (1s,3r,4e,6e,8e,10e,12e,14e,16e,18s,19r,20r,21s,25r,27r,30r,31r,33s,35r,37s,38r)-3-[(2r,3s,4s,5s,6r)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-19,25,27,30,31,33,35,37-octahydroxy-18,20,21-trimethyl-23-oxo-22,39-dioxabicyclo[33.3.1]nonatriaconta-4,6,8,10 Chemical compound C1C=C2C[C@@H](OS(O)(=O)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2.O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 PCTMTFRHKVHKIS-BMFZQQSSSA-N 0.000 claims description 4
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
125000003342 alkenyl group Chemical group 0.000 claims description 4
125000000304 alkynyl group Chemical group 0.000 claims description 4
229910052799 carbon Inorganic materials 0.000 claims description 4
CKVJNSMWIVPHRB-UHFFFAOYSA-N 1,2,3-benzothiadiazepin-7-amine Chemical compound S1N=NC=CC2=CC(N)=CC=C21 CKVJNSMWIVPHRB-UHFFFAOYSA-N 0.000 claims description 3
ILPFXWWJPKBEQR-UHFFFAOYSA-N 2-[3-benzyl-8-bromo-5-(1h-imidazol-5-ylmethyl)-3,4-dihydro-1,2,5-benzothiadiazepin-2-yl]acetic acid Chemical compound C1C(CC=2C=CC=CC=2)N(CC(=O)O)SC2=CC(Br)=CC=C2N1CC1=CNC=N1 ILPFXWWJPKBEQR-UHFFFAOYSA-N 0.000 claims description 3
WYJMLILRJURLBD-UHFFFAOYSA-N 3-benzyl-8-bromo-5-(1h-imidazol-5-ylmethyl)-2-methyl-3,4-dihydro-1,2,5-benzothiadiazepine Chemical compound C1C(CC=2C=CC=CC=2)N(C)SC2=CC(Br)=CC=C2N1CC1=CNC=N1 WYJMLILRJURLBD-UHFFFAOYSA-N 0.000 claims description 3
UCDFLGARBPQRLO-UHFFFAOYSA-N 5-(1h-imidazol-5-ylmethyl)-2-(naphthalen-1-ylmethyl)-3,4-dihydro-1,2,5-benzothiadiazepine Chemical compound C1CN(CC=2C3=CC=CC=C3C=CC=2)SC2=CC=CC=C2N1CC1=CNC=N1 UCDFLGARBPQRLO-UHFFFAOYSA-N 0.000 claims description 3
ROTRIHULNACPAI-UHFFFAOYSA-N 8-bromo-5-(1h-imidazol-5-ylmethyl)-2-(2-phenylethyl)-3,4-dihydro-1,2,5-benzothiadiazepine Chemical compound C1CN(CCC=2C=CC=CC=2)SC2=CC(Br)=CC=C2N1CC1=CNC=N1 ROTRIHULNACPAI-UHFFFAOYSA-N 0.000 claims description 3
102000019337 Prenyltransferases Human genes 0.000 claims description 3
108050006837 Prenyltransferases Proteins 0.000 claims description 3
125000000753 cycloalkyl group Chemical group 0.000 claims description 3
230000019491 signal transduction Effects 0.000 claims description 3
239000012453 solvate Substances 0.000 claims description 3
125000005017 substituted alkenyl group Chemical group 0.000 claims description 3
125000004426 substituted alkynyl group Chemical group 0.000 claims description 3
RGICCULPCWNRAB-UHFFFAOYSA-N 2-[2-(2-hexoxyethoxy)ethoxy]ethanol Chemical compound CCCCCCOCCOCCOCCO RGICCULPCWNRAB-UHFFFAOYSA-N 0.000 claims description 2
AJABEHDAANEOFM-UHFFFAOYSA-N 5-(1h-imidazol-5-ylmethyl)-n,n-dimethyl-2-(2-phenylethyl)-3,4-dihydro-1,2,5-benzothiadiazepin-7-amine Chemical compound C1CN(CC=2N=CNC=2)C2=CC(N(C)C)=CC=C2SN1CCC1=CC=CC=C1 AJABEHDAANEOFM-UHFFFAOYSA-N 0.000 claims description 2
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
108010006731 Dimethylallyltranstransferase Proteins 0.000 claims description 2
102000005454 Dimethylallyltranstransferase Human genes 0.000 claims description 2
RHJVIGLEIFVHIJ-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1[CH]CCCC1 RHJVIGLEIFVHIJ-UHFFFAOYSA-N 0.000 claims description 2
XNKOSKYHFBCHNM-UHFFFAOYSA-N n-[3-benzyl-5-(1h-imidazol-5-ylmethyl)-3,4-dihydro-2h-1,2,5-benzothiadiazepin-7-yl]cyclohexanecarboxamide Chemical compound C1CCCCC1C(=O)NC(C=C1N(CC=2N=CNC=2)C2)=CC=C1SNC2CC1=CC=CC=C1 XNKOSKYHFBCHNM-UHFFFAOYSA-N 0.000 claims description 2
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
CICPSCXBPAGDJY-UHFFFAOYSA-N 1,2,5-benzothiadiazepine Chemical compound S1N=CC=NC2=CC=CC=C12 CICPSCXBPAGDJY-UHFFFAOYSA-N 0.000 claims 6
230000002401 inhibitory effect Effects 0.000 claims 6
150000001555 benzenes Chemical class 0.000 claims 2
ZXGMOXWPHIOFPF-UHFFFAOYSA-N 2-[5-(1h-imidazol-5-ylmethyl)-3,4-dihydro-1,2,5-benzothiadiazepin-2-yl]benzoic acid Chemical compound OC(=O)C1=CC=CC=C1N1SC2=CC=CC=C2N(CC=2N=CNC=2)CC1 ZXGMOXWPHIOFPF-UHFFFAOYSA-N 0.000 claims 1
PIWSMVNNPWKMEQ-UHFFFAOYSA-N 3-[5-(1h-imidazol-5-ylmethyl)-3,4-dihydro-1,2,5-benzothiadiazepin-2-yl]benzoic acid Chemical compound OC(=O)C1=CC=CC(N2SC3=CC=CC=C3N(CC=3N=CNC=3)CC2)=C1 PIWSMVNNPWKMEQ-UHFFFAOYSA-N 0.000 claims 1
PHBCTPWQJCMVDN-UHFFFAOYSA-N 3-[5-(1h-imidazol-5-ylmethyl)-3,4-dihydro-1,2,5-benzothiadiazepin-2-yl]benzonitrile Chemical compound N#CC1=CC=CC(N2SC3=CC=CC=C3N(CC=3N=CNC=3)CC2)=C1 PHBCTPWQJCMVDN-UHFFFAOYSA-N 0.000 claims 1
NPJLRFNSCACJLF-UHFFFAOYSA-N 5-(1h-imidazol-5-ylmethyl)-2-(2-phenylethyl)-4,7,8,9-tetrahydro-3h-cyclopenta[h][1,2,5]benzothiadiazepine Chemical compound C1CN(CC=2N=CNC=2)C2=CC=3CCCC=3C=C2SN1CCC1=CC=CC=C1 NPJLRFNSCACJLF-UHFFFAOYSA-N 0.000 claims 1
BHQQULCGBKNHGT-UHFFFAOYSA-N 7,8-dibromo-2-(2-bromo-6-phenylphenyl)-5-(1h-imidazol-5-ylmethyl)-3,4-dihydro-1,2,5-benzothiadiazepine Chemical compound C1=2C=C(Br)C(Br)=CC=2SN(C=2C(=CC=CC=2Br)C=2C=CC=CC=2)CCN1CC1=CNC=N1 BHQQULCGBKNHGT-UHFFFAOYSA-N 0.000 claims 1
SZODLDYQKPAGTR-UHFFFAOYSA-N 7-bromo-5-(1h-imidazol-5-ylmethyl)-2-(2-phenylethyl)-3,4-dihydro-1,2,5-benzothiadiazepine Chemical compound C1CN(CC=2N=CNC=2)C2=CC(Br)=CC=C2SN1CCC1=CC=CC=C1 SZODLDYQKPAGTR-UHFFFAOYSA-N 0.000 claims 1
MSQBELVVUUYZCR-UHFFFAOYSA-N 8-bromo-5-(1h-imidazol-5-ylmethyl)-2-(2-phenylmethoxyphenyl)-3,4-dihydro-1,2,5-benzothiadiazepine Chemical compound C1CN(C=2C(=CC=CC=2)OCC=2C=CC=CC=2)SC2=CC(Br)=CC=C2N1CC1=CNC=N1 MSQBELVVUUYZCR-UHFFFAOYSA-N 0.000 claims 1
NLGBGQICXHKWEY-UHFFFAOYSA-N 8-bromo-5-(1h-imidazol-5-ylmethyl)-n,n-dimethyl-2-(2-phenylethyl)-3,4-dihydro-1,2,5-benzothiadiazepin-7-amine Chemical compound C1CN(CCC=2C=CC=CC=2)SC=2C=C(Br)C(N(C)C)=CC=2N1CC1=CNC=N1 NLGBGQICXHKWEY-UHFFFAOYSA-N 0.000 claims 1
MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 claims 1
125000002686 geranylgeranyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
125000001475 halogen functional group Chemical group 0.000 claims 1
MSVXDIMVHKZAAX-UHFFFAOYSA-N n,5-bis(1h-imidazol-5-ylmethyl)-2-(2-phenylphenyl)-3,4-dihydro-1,2,5-benzothiadiazepin-7-amine Chemical compound C=1NC=NC=1CNC(C=C12)=CC=C1SN(C=1C(=CC=CC=1)C=1C=CC=CC=1)CCN2CC1=CNC=N1 MSVXDIMVHKZAAX-UHFFFAOYSA-N 0.000 claims 1
YJEPPYBRXTYBBV-UHFFFAOYSA-N n-benzyl-2-[3-benzyl-8-bromo-5-(1h-imidazol-5-ylmethyl)-3,4-dihydro-1,2,5-benzothiadiazepin-2-yl]-n-methylacetamide Chemical compound S1C2=CC(Br)=CC=C2N(CC=2N=CNC=2)CC(CC=2C=CC=CC=2)N1CC(=O)N(C)CC1=CC=CC=C1 YJEPPYBRXTYBBV-UHFFFAOYSA-N 0.000 claims 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
239000000243 solution Substances 0.000 description 59
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
239000000203 mixture Substances 0.000 description 31
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 26
229940126062 Compound A Drugs 0.000 description 22
NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 22
239000003960 organic solvent Substances 0.000 description 21
239000007787 solid Substances 0.000 description 20
238000011282 treatment Methods 0.000 description 18
239000012044 organic layer Substances 0.000 description 15
238000002360 preparation method Methods 0.000 description 14
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 13
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
229920006395 saturated elastomer Polymers 0.000 description 12
239000002904 solvent Substances 0.000 description 12
102000016914 ras Proteins Human genes 0.000 description 11
108010014186 ras Proteins Proteins 0.000 description 11
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
239000002585 base Substances 0.000 description 10
125000004432 carbon atom Chemical group C* 0.000 description 10
JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 10
ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 10
125000005843 halogen group Chemical group 0.000 description 10
125000001072 heteroaryl group Chemical group 0.000 description 9
125000000623 heterocyclic group Chemical group 0.000 description 9
125000001424 substituent group Chemical group 0.000 description 9
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
235000018102 proteins Nutrition 0.000 description 8
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
125000003545 alkoxy group Chemical group 0.000 description 7
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
239000002253 acid Substances 0.000 description 6
229910052786 argon Inorganic materials 0.000 description 6
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
239000011734 sodium Substances 0.000 description 6
229940124530 sulfonamide Drugs 0.000 description 6
150000003456 sulfonamides Chemical class 0.000 description 6
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
125000005236 alkanoylamino group Chemical group 0.000 description 5
150000001412 amines Chemical class 0.000 description 5
235000010290 biphenyl Nutrition 0.000 description 5
239000012267 brine Substances 0.000 description 5
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
229910052794 bromium Inorganic materials 0.000 description 5
150000001732 carboxylic acid derivatives Chemical group 0.000 description 5
238000006243 chemical reaction Methods 0.000 description 5
125000005842 heteroatom Chemical group 0.000 description 5
125000004356 hydroxy functional group Chemical group O* 0.000 description 5
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
239000000047 product Substances 0.000 description 5
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 5
ZQEXIXXJFSQPNA-UHFFFAOYSA-N 1h-imidazole-5-carbaldehyde Chemical compound O=CC1=CNC=N1 ZQEXIXXJFSQPNA-UHFFFAOYSA-N 0.000 description 4
WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical compound BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 4
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
125000004423 acyloxy group Chemical group 0.000 description 4
125000003282 alkyl amino group Chemical group 0.000 description 4
125000004414 alkyl thio group Chemical group 0.000 description 4
150000001408 amides Chemical class 0.000 description 4
201000011510 cancer Diseases 0.000 description 4
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 4
125000001589 carboacyl group Chemical group 0.000 description 4
239000003638 chemical reducing agent Substances 0.000 description 4
125000002541 furyl group Chemical group 0.000 description 4
125000002883 imidazolyl group Chemical group 0.000 description 4
239000010410 layer Substances 0.000 description 4
229910052943 magnesium sulfate Inorganic materials 0.000 description 4
235000019341 magnesium sulphate Nutrition 0.000 description 4
HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 4
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
239000002244 precipitate Substances 0.000 description 4
125000004076 pyridyl group Chemical group 0.000 description 4
125000000714 pyrimidinyl group Chemical group 0.000 description 4
229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
235000017557 sodium bicarbonate Nutrition 0.000 description 4
125000000335 thiazolyl group Chemical group 0.000 description 4
125000001544 thienyl group Chemical group 0.000 description 4
150000003573 thiols Chemical class 0.000 description 4
AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 4
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
WPHUUIODWRNJLO-UHFFFAOYSA-N 2-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=CC=C1S(Cl)(=O)=O WPHUUIODWRNJLO-UHFFFAOYSA-N 0.000 description 3
KRMAQXPTWQHXJX-UHFFFAOYSA-N 5-(1h-imidazol-5-ylmethyl)-2-(2-phenylethyl)-3,4-dihydro-1,2,5-benzothiadiazepine Chemical compound C1CN(CC=2N=CNC=2)C2=CC=CC=C2SN1CCC1=CC=CC=C1 KRMAQXPTWQHXJX-UHFFFAOYSA-N 0.000 description 3
108010007508 Farnesyltranstransferase Proteins 0.000 description 3
102000007317 Farnesyltranstransferase Human genes 0.000 description 3
241000724709 Hepatitis delta virus Species 0.000 description 3
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
230000001476 alcoholic effect Effects 0.000 description 3
150000001299 aldehydes Chemical class 0.000 description 3
125000004390 alkyl sulfonyl group Chemical group 0.000 description 3
229940024606 amino acid Drugs 0.000 description 3
235000001014 amino acid Nutrition 0.000 description 3
125000003277 amino group Chemical group 0.000 description 3
239000002246 antineoplastic agent Substances 0.000 description 3
230000006907 apoptotic process Effects 0.000 description 3
125000001691 aryl alkyl amino group Chemical group 0.000 description 3
125000002619 bicyclic group Chemical group 0.000 description 3
229940127089 cytotoxic agent Drugs 0.000 description 3
239000002254 cytotoxic agent Substances 0.000 description 3
231100000599 cytotoxic agent Toxicity 0.000 description 3
230000018109 developmental process Effects 0.000 description 3
125000004663 dialkyl amino group Chemical group 0.000 description 3
238000003818 flash chromatography Methods 0.000 description 3
150000002430 hydrocarbons Chemical group 0.000 description 3
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
150000004702 methyl esters Chemical class 0.000 description 3
125000002950 monocyclic group Chemical group 0.000 description 3
NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [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 3
125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
238000010992 reflux Methods 0.000 description 3
239000012321 sodium triacetoxyborohydride Substances 0.000 description 3
238000003756 stirring Methods 0.000 description 3
RNQZJVDOUDYBNX-ZDUSSCGKSA-N (2s)-2-[(2,4-diaminophenyl)sulfonylamino]-3-phenylpropanoic acid Chemical compound NC1=CC(N)=CC=C1S(=O)(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 RNQZJVDOUDYBNX-ZDUSSCGKSA-N 0.000 description 2
SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 2
MQEZYLMJQKBGHE-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine Chemical compound S1NCCNC2=CC=CC=C21 MQEZYLMJQKBGHE-UHFFFAOYSA-N 0.000 description 2
MEMDTLINFSXDKE-UHFFFAOYSA-N 2-[5-[[8-bromo-1,1-dioxo-2-(2-phenylethyl)-3,4-dihydro-1$l^{6},2,5-benzothiadiazepin-5-yl]methyl]imidazol-1-yl]acetamide Chemical compound NC(=O)CN1C=NC=C1CN1C2=CC=C(Br)C=C2S(=O)(=O)N(CCC=2C=CC=CC=2)CC1 MEMDTLINFSXDKE-UHFFFAOYSA-N 0.000 description 2
VWFJDQUYCIWHTN-YFVJMOTDSA-N 2-trans,6-trans-farnesyl diphosphate Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CO[P@](O)(=O)OP(O)(O)=O VWFJDQUYCIWHTN-YFVJMOTDSA-N 0.000 description 2
UMQJOCAXLMBHCW-UHFFFAOYSA-N 4-[5-(1h-imidazol-5-ylmethyl)-3,4-dihydro-1,2,5-benzothiadiazepin-2-yl]benzonitrile Chemical compound C1=CC(C#N)=CC=C1N1SC2=CC=CC=C2N(CC=2N=CNC=2)CC1 UMQJOCAXLMBHCW-UHFFFAOYSA-N 0.000 description 2
FOIWREMBRDMFDU-UHFFFAOYSA-N 5-(1h-imidazol-5-ylmethyl)-8-phenyl-2-(2-phenylethyl)-3,4-dihydro-1,2,5-benzothiadiazepine Chemical compound C1CN(CC=2N=CNC=2)C2=CC=C(C=3C=CC=CC=3)C=C2SN1CCC1=CC=CC=C1 FOIWREMBRDMFDU-UHFFFAOYSA-N 0.000 description 2
USQCUKQZXOWUDF-YWZLYKJASA-N 6-chloro-n-[(3s)-1-[(2s)-1-(4-methyl-5-oxo-1,4-diazepan-1-yl)-1-oxopropan-2-yl]-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide Chemical compound O=C([C@@H](N1C([C@@H](NS(=O)(=O)C=2C=C3C=CC(Cl)=CC3=CC=2)CC1)=O)C)N1CCN(C)C(=O)CC1 USQCUKQZXOWUDF-YWZLYKJASA-N 0.000 description 2
208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
208000032467 Aplastic anaemia Diseases 0.000 description 2
201000001320 Atherosclerosis Diseases 0.000 description 2
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
201000009030 Carcinoma Diseases 0.000 description 2
PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
VWFJDQUYCIWHTN-UHFFFAOYSA-N Farnesyl pyrophosphate Natural products CC(C)=CCCC(C)=CCCC(C)=CCOP(O)(=O)OP(O)(O)=O VWFJDQUYCIWHTN-UHFFFAOYSA-N 0.000 description 2
206010018364 Glomerulonephritis Diseases 0.000 description 2
208000037262 Hepatitis delta Diseases 0.000 description 2
206010025323 Lymphomas Diseases 0.000 description 2
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
239000012359 Methanesulfonyl chloride Substances 0.000 description 2
201000003793 Myelodysplastic syndrome Diseases 0.000 description 2
208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
201000004681 Psoriasis Diseases 0.000 description 2
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
208000036142 Viral infection Diseases 0.000 description 2
125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
230000004075 alteration Effects 0.000 description 2
239000000908 ammonium hydroxide Substances 0.000 description 2
238000004458 analytical method Methods 0.000 description 2
HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 2
150000001448 anilines Chemical class 0.000 description 2
230000001093 anti-cancer Effects 0.000 description 2
239000012736 aqueous medium Substances 0.000 description 2
206010003246 arthritis Diseases 0.000 description 2
125000001769 aryl amino group Chemical group 0.000 description 2
125000004391 aryl sulfonyl group Chemical group 0.000 description 2
125000004104 aryloxy group Chemical group 0.000 description 2
UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
210000000481 breast Anatomy 0.000 description 2
238000005893 bromination reaction Methods 0.000 description 2
125000001246 bromo group Chemical group Br* 0.000 description 2
239000003054 catalyst Substances 0.000 description 2
239000003153 chemical reaction reagent Substances 0.000 description 2
239000003795 chemical substances by application Substances 0.000 description 2
239000000460 chlorine Chemical group 0.000 description 2
UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 2
210000001072 colon Anatomy 0.000 description 2
238000004440 column chromatography Methods 0.000 description 2
238000001816 cooling Methods 0.000 description 2
239000013256 coordination polymer Substances 0.000 description 2
QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
125000004122 cyclic group Chemical group 0.000 description 2
239000012024 dehydrating agents‎ Substances 0.000 description 2
230000001419 dependent effect Effects 0.000 description 2
238000013461 design Methods 0.000 description 2
238000011161 development Methods 0.000 description 2
238000009509 drug development Methods 0.000 description 2
238000010828 elution Methods 0.000 description 2
PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 2
238000001704 evaporation Methods 0.000 description 2
230000008020 evaporation Effects 0.000 description 2
239000000284 extract Substances 0.000 description 2
230000006126 farnesylation Effects 0.000 description 2
239000000706 filtrate Substances 0.000 description 2
238000009472 formulation Methods 0.000 description 2
239000012458 free base Substances 0.000 description 2
230000006130 geranylgeranylation Effects 0.000 description 2
125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 2
150000004820 halides Chemical class 0.000 description 2
238000010438 heat treatment Methods 0.000 description 2
201000005787 hematologic cancer Diseases 0.000 description 2
208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 2
208000029570 hepatitis D virus infection Diseases 0.000 description 2
229910000042 hydrogen bromide Inorganic materials 0.000 description 2
125000001041 indolyl group Chemical group 0.000 description 2
INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 2
210000004072 lung Anatomy 0.000 description 2
239000002609 medium Substances 0.000 description 2
229910052751 metal Inorganic materials 0.000 description 2
239000002184 metal Substances 0.000 description 2
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
230000004048 modification Effects 0.000 description 2
238000012986 modification Methods 0.000 description 2
230000035772 mutation Effects 0.000 description 2
125000001624 naphthyl group Chemical group 0.000 description 2
208000015122 neurodegenerative disease Diseases 0.000 description 2
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
210000001672 ovary Anatomy 0.000 description 2
229910000027 potassium carbonate Inorganic materials 0.000 description 2
230000008569 process Effects 0.000 description 2
230000005855 radiation Effects 0.000 description 2
108700042226 ras Genes Proteins 0.000 description 2
239000011369 resultant mixture Substances 0.000 description 2
239000000741 silica gel Substances 0.000 description 2
229910002027 silica gel Inorganic materials 0.000 description 2
238000010898 silica gel chromatography Methods 0.000 description 2
BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
239000000725 suspension Substances 0.000 description 2
GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 2
SFLXUZPXEWWQNH-UHFFFAOYSA-K tetrabutylazanium;tribromide Chemical compound [Br-].[Br-].[Br-].CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC SFLXUZPXEWWQNH-UHFFFAOYSA-K 0.000 description 2
210000001685 thyroid gland Anatomy 0.000 description 2
QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
230000004614 tumor growth Effects 0.000 description 2
230000009385 viral infection Effects 0.000 description 2
MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
ABJUJBDQZJNGRW-LBPRGKRZSA-N (2s)-2-[(2,4-dinitrophenyl)sulfonylamino]-3-phenylpropanoic acid Chemical compound C([C@@H](C(=O)O)NS(=O)(=O)C=1C(=CC(=CC=1)[N+]([O-])=O)[N+]([O-])=O)C1=CC=CC=C1 ABJUJBDQZJNGRW-LBPRGKRZSA-N 0.000 description 1
JXBSHSBNOVLGHF-BUJBXKITSA-N (6E,10E)-2,6,10-trimethyldodeca-2,6,10-triene Chemical compound C\C=C(/C)CC\C=C(/C)CCC=C(C)C JXBSHSBNOVLGHF-BUJBXKITSA-N 0.000 description 1
LMCFKRVBKDIKBO-UHFFFAOYSA-N 1,2,3-benzothiadiazepine-8-carbonitrile Chemical compound C1=CN=NSC2=CC(C#N)=CC=C21 LMCFKRVBKDIKBO-UHFFFAOYSA-N 0.000 description 1
KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 description 1
SSFSNKZUKDBPIT-UHFFFAOYSA-N 2,4-dinitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C([N+]([O-])=O)=C1 SSFSNKZUKDBPIT-UHFFFAOYSA-N 0.000 description 1
VCSVNFSQYJECDE-UHFFFAOYSA-N 2-(naphthalen-1-ylmethyl)-4,5-dihydro-3h-1,2,5-benzothiadiazepine Chemical compound C1CNC2=CC=CC=C2SN1CC1=CC=CC2=CC=CC=C12 VCSVNFSQYJECDE-UHFFFAOYSA-N 0.000 description 1
LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
KKRUQRAUMBARKN-UHFFFAOYSA-N 2-benzyl-5-(1h-imidazol-5-ylmethyl)-3,4-dihydro-1,2,5-benzothiadiazepine Chemical compound C=1NC=NC=1CN(C1=CC=CC=C1S1)CCN1CC1=CC=CC=C1 KKRUQRAUMBARKN-UHFFFAOYSA-N 0.000 description 1
WJAXXWSZNSFVNG-UHFFFAOYSA-N 2-bromoethanamine;hydron;bromide Chemical compound [Br-].[NH3+]CCBr WJAXXWSZNSFVNG-UHFFFAOYSA-N 0.000 description 1
ZSZKAQCISWFDCQ-UHFFFAOYSA-N 2-fluorobenzenesulfonyl chloride Chemical compound FC1=CC=CC=C1S(Cl)(=O)=O ZSZKAQCISWFDCQ-UHFFFAOYSA-N 0.000 description 1
125000004635 2-oxazepinyl group Chemical group O1N(CC=CC=C1)* 0.000 description 1
125000004638 2-oxopiperazinyl group Chemical group O=C1N(CCNC1)* 0.000 description 1
125000004637 2-oxopiperidinyl group Chemical group O=C1N(CCCC1)* 0.000 description 1
125000006087 2-oxopyrrolodinyl group Chemical group 0.000 description 1
ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 1
125000004610 3,4-dihydro-4-oxo-quinazolinyl group Chemical group O=C1NC(=NC2=CC=CC=C12)* 0.000 description 1
PFCMMUMYYZBPKE-UHFFFAOYSA-N 3-benzyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-7-amine Chemical compound C1NC2=CC(N)=CC=C2SNC1CC1=CC=CC=C1 PFCMMUMYYZBPKE-UHFFFAOYSA-N 0.000 description 1
ZCDMPBKLNQMCGD-UHFFFAOYSA-N 3-benzyl-2-methylsulfonyl-4,5-dihydro-3h-1,2,5-benzothiadiazepine Chemical compound CS(=O)(=O)N1SC2=CC=CC=C2NCC1CC1=CC=CC=C1 ZCDMPBKLNQMCGD-UHFFFAOYSA-N 0.000 description 1
MWHBYHBPQZYXHN-UHFFFAOYSA-N 3-benzyl-5-(1h-imidazol-5-ylmethyl)-2-methylsulfonyl-3,4-dihydro-1,2,5-benzothiadiazepine Chemical compound C1C(CC=2C=CC=CC=2)N(S(=O)(=O)C)SC2=CC=CC=C2N1CC1=CNC=N1 MWHBYHBPQZYXHN-UHFFFAOYSA-N 0.000 description 1
BEXQLXWKYHRKGE-UHFFFAOYSA-N 3-benzyl-8-bromo-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine Chemical compound N1SC2=CC(Br)=CC=C2NCC1CC1=CC=CC=C1 BEXQLXWKYHRKGE-UHFFFAOYSA-N 0.000 description 1
HGKAWZWOUSSYKV-UHFFFAOYSA-N 3-benzyl-8-bromo-5-(1h-imidazol-5-ylmethyl)-2-(2-phenylethyl)-3,4-dihydro-1,2,5-benzothiadiazepine Chemical compound C1C(CC=2C=CC=CC=2)N(CCC=2C=CC=CC=2)SC2=CC(Br)=CC=C2N1CC1=CNC=N1 HGKAWZWOUSSYKV-UHFFFAOYSA-N 0.000 description 1
WIAUBSGALLIFJD-UHFFFAOYSA-N 4-(4,5-dihydro-3h-1,2,5-benzothiadiazepin-2-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1N1SC2=CC=CC=C2NCC1 WIAUBSGALLIFJD-UHFFFAOYSA-N 0.000 description 1
HQSCPPCMBMFJJN-UHFFFAOYSA-N 4-bromobenzonitrile Chemical compound BrC1=CC=C(C#N)C=C1 HQSCPPCMBMFJJN-UHFFFAOYSA-N 0.000 description 1
125000005986 4-piperidonyl group Chemical group 0.000 description 1
ROMFZTLZHPEJQU-UHFFFAOYSA-N 7-amino-3-benzyl-3,5-dihydro-2h-1,2,5-benzothiadiazepin-4-one Chemical compound O=C1NC2=CC(N)=CC=C2SNC1CC1=CC=CC=C1 ROMFZTLZHPEJQU-UHFFFAOYSA-N 0.000 description 1
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 description 1
OGRNGGVOVKELSL-UHFFFAOYSA-N 8-bromo-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine Chemical compound N1CCNSC2=CC(Br)=CC=C21 OGRNGGVOVKELSL-UHFFFAOYSA-N 0.000 description 1
HMLQQCZJXICZJT-UHFFFAOYSA-N 8-bromo-2-(2-phenylethyl)-5-[(1-tritylimidazol-4-yl)methyl]-3,4-dihydro-1,2,5-benzothiadiazepine Chemical compound C1CN(CCC=2C=CC=CC=2)SC2=CC(Br)=CC=C2N1CC(N=C1)=CN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 HMLQQCZJXICZJT-UHFFFAOYSA-N 0.000 description 1
CJOMKZRAXXXTTH-UHFFFAOYSA-N 8-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine Chemical compound C1=C2SNCCNC2=CC=C1C1=CC=CC=C1 CJOMKZRAXXXTTH-UHFFFAOYSA-N 0.000 description 1
208000030507 AIDS Diseases 0.000 description 1
206010065040 AIDS dementia complex Diseases 0.000 description 1
208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
208000024827 Alzheimer disease Diseases 0.000 description 1
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
239000004475 Arginine Substances 0.000 description 1
BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
206010003571 Astrocytoma Diseases 0.000 description 1
208000023275 Autoimmune disease Diseases 0.000 description 1
208000003950 B-cell lymphoma Diseases 0.000 description 1
208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
201000004569 Blindness Diseases 0.000 description 1
OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
206010058019 Cancer Pain Diseases 0.000 description 1
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
239000005749 Copper compound Substances 0.000 description 1
QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 1
239000005751 Copper oxide Substances 0.000 description 1
229910021590 Copper(II) bromide Inorganic materials 0.000 description 1
XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
201000003883 Cystic fibrosis Diseases 0.000 description 1
XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
206010014824 Endotoxic shock Diseases 0.000 description 1
201000006107 Familial adenomatous polyposis Diseases 0.000 description 1
201000008808 Fibrosarcoma Diseases 0.000 description 1
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
102000020897 Formins Human genes 0.000 description 1
108091022623 Formins Proteins 0.000 description 1
102000004437 G-Protein-Coupled Receptor Kinase 1 Human genes 0.000 description 1
108091004242 G-Protein-Coupled Receptor Kinase 1 Proteins 0.000 description 1
102000013446 GTP Phosphohydrolases Human genes 0.000 description 1
102100039788 GTPase NRas Human genes 0.000 description 1
108091006109 GTPases Proteins 0.000 description 1
208000032612 Glial tumor Diseases 0.000 description 1
206010018338 Glioma Diseases 0.000 description 1
208000017604 Hodgkin disease Diseases 0.000 description 1
208000021519 Hodgkin lymphoma Diseases 0.000 description 1
208000010747 Hodgkins lymphoma Diseases 0.000 description 1
101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 1
101000610550 Homo sapiens Opiorphin prepropeptide Proteins 0.000 description 1
101001002066 Homo sapiens Pleiotropic regulator 1 Proteins 0.000 description 1
101000830696 Homo sapiens Protein tyrosine phosphatase type IVA 1 Proteins 0.000 description 1
101000686227 Homo sapiens Ras-related protein R-Ras2 Proteins 0.000 description 1
101000667821 Homo sapiens Rho-related GTP-binding protein RhoE Proteins 0.000 description 1
241000701044 Human gammaherpesvirus 4 Species 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
150000000994 L-ascorbates Chemical class 0.000 description 1
FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
239000004472 Lysine Substances 0.000 description 1
FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
125000004633 N-oxo-pyridyl group Chemical group 0.000 description 1
206010029260 Neuroblastoma Diseases 0.000 description 1
208000009905 Neurofibromatoses Diseases 0.000 description 1
208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
208000001132 Osteoporosis Diseases 0.000 description 1
229910019142 PO4 Inorganic materials 0.000 description 1
229930012538 Paclitaxel Natural products 0.000 description 1
206010061902 Pancreatic neoplasm Diseases 0.000 description 1
208000018737 Parkinson disease Diseases 0.000 description 1
108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
108010064071 Phosphorylase Kinase Proteins 0.000 description 1
102000014750 Phosphorylase Kinase Human genes 0.000 description 1
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
108010029485 Protein Isoforms Proteins 0.000 description 1
102000001708 Protein Isoforms Human genes 0.000 description 1
102100024599 Protein tyrosine phosphatase type IVA 1 Human genes 0.000 description 1
101150040459 RAS gene Proteins 0.000 description 1
102100025003 Ras-related protein R-Ras2 Human genes 0.000 description 1
206010063837 Reperfusion injury Diseases 0.000 description 1
208000007014 Retinitis pigmentosa Diseases 0.000 description 1
102100039640 Rho-related GTP-binding protein RhoE Human genes 0.000 description 1
101150054980 Rhob gene Proteins 0.000 description 1
108090000799 Rhodopsin kinases Proteins 0.000 description 1
201000010208 Seminoma Diseases 0.000 description 1
206010040070 Septic Shock Diseases 0.000 description 1
MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
241000710960 Sindbis virus Species 0.000 description 1
206010041067 Small cell lung cancer Diseases 0.000 description 1
208000006011 Stroke Diseases 0.000 description 1
206010042971 T-cell lymphoma Diseases 0.000 description 1
208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
229940123237 Taxane Drugs 0.000 description 1
102000006612 Transducin Human genes 0.000 description 1
108010087042 Transducin Proteins 0.000 description 1
102000004243 Tubulin Human genes 0.000 description 1
108090000704 Tubulin Proteins 0.000 description 1
206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
241000700605 Viruses Species 0.000 description 1
GELXFVQAWNTGPQ-UHFFFAOYSA-N [N].C1=CNC=N1 Chemical compound [N].C1=CNC=N1 GELXFVQAWNTGPQ-UHFFFAOYSA-N 0.000 description 1
229960001138 acetylsalicylic acid Drugs 0.000 description 1
239000013543 active substance Substances 0.000 description 1
230000001154 acute effect Effects 0.000 description 1
230000010933 acylation Effects 0.000 description 1
238000005917 acylation reaction Methods 0.000 description 1
125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
239000000654 additive Substances 0.000 description 1
238000012382 advanced drug delivery Methods 0.000 description 1
229910052783 alkali metal Inorganic materials 0.000 description 1
150000001340 alkali metals Chemical class 0.000 description 1
229910052784 alkaline earth metal Inorganic materials 0.000 description 1
150000001342 alkaline earth metals Chemical class 0.000 description 1
125000006550 alkoxycarbonyl aryl group Chemical group 0.000 description 1
239000002168 alkylating agent Substances 0.000 description 1
229940100198 alkylating agent Drugs 0.000 description 1
230000029936 alkylation Effects 0.000 description 1
238000005804 alkylation reaction Methods 0.000 description 1
125000006242 amine protecting group Chemical group 0.000 description 1
150000001413 amino acids Chemical class 0.000 description 1
150000001414 amino alcohols Chemical class 0.000 description 1
206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
208000007502 anemia Diseases 0.000 description 1
238000002399 angioplasty Methods 0.000 description 1
150000008064 anhydrides Chemical class 0.000 description 1
230000003527 anti-angiogenesis Effects 0.000 description 1
239000003429 antifungal agent Substances 0.000 description 1
229940121375 antifungal agent Drugs 0.000 description 1
239000000427 antigen Substances 0.000 description 1
108091007433 antigens Proteins 0.000 description 1
102000036639 antigens Human genes 0.000 description 1
229940045985 antineoplastic platinum compound Drugs 0.000 description 1
230000005775 apoptotic pathway Effects 0.000 description 1
125000005140 aralkylsulfonyl group Chemical group 0.000 description 1
ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
125000005239 aroylamino group Chemical group 0.000 description 1
230000006793 arrhythmia Effects 0.000 description 1
206010003119 arrhythmia Diseases 0.000 description 1
125000004659 aryl alkyl thio group Chemical group 0.000 description 1
125000005110 aryl thio group Chemical group 0.000 description 1
238000006254 arylation reaction Methods 0.000 description 1
235000010323 ascorbic acid Nutrition 0.000 description 1
238000003556 assay Methods 0.000 description 1
VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
125000002785 azepinyl group Chemical group 0.000 description 1
150000001541 aziridines Chemical class 0.000 description 1
SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
229940092714 benzenesulfonic acid Drugs 0.000 description 1
125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
125000005605 benzo group Chemical group 0.000 description 1
125000004602 benzodiazinyl group Chemical group N1=NC(=CC2=C1C=CC=C2)* 0.000 description 1
125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 description 1
125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
150000001558 benzoic acid derivatives Chemical class 0.000 description 1
125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
125000004600 benzothiopyranyl group Chemical group S1C(C=CC2=C1C=CC=C2)* 0.000 description 1
125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
125000004599 benzpyrazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
125000002618 bicyclic heterocycle group Chemical group 0.000 description 1
239000012867 bioactive agent Substances 0.000 description 1
229920002988 biodegradable polymer Polymers 0.000 description 1
239000004621 biodegradable polymer Substances 0.000 description 1
125000006267 biphenyl group Chemical group 0.000 description 1
229910000085 borane Inorganic materials 0.000 description 1
150000001642 boronic acid derivatives Chemical class 0.000 description 1
230000031709 bromination Effects 0.000 description 1
244000309464 bull Species 0.000 description 1
239000011575 calcium Substances 0.000 description 1
229910052791 calcium Inorganic materials 0.000 description 1
VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
239000002775 capsule Substances 0.000 description 1
125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 1
150000001721 carbon Chemical group 0.000 description 1
125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
229960004562 carboplatin Drugs 0.000 description 1
125000004181 carboxyalkyl group Chemical group 0.000 description 1
150000001733 carboxylic acid esters Chemical class 0.000 description 1
230000003197 catalytic effect Effects 0.000 description 1
210000004027 cell Anatomy 0.000 description 1
230000030833 cell death Effects 0.000 description 1
230000024245 cell differentiation Effects 0.000 description 1
230000032823 cell division Effects 0.000 description 1
230000010261 cell growth Effects 0.000 description 1
210000000170 cell membrane Anatomy 0.000 description 1
210000003169 central nervous system Anatomy 0.000 description 1
208000025434 cerebellar degeneration Diseases 0.000 description 1
210000003679 cervix uteri Anatomy 0.000 description 1
229910052801 chlorine Inorganic materials 0.000 description 1
WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
125000004617 chromonyl group Chemical group O1C(=CC(C2=CC=CC=C12)=O)* 0.000 description 1
125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
229960004316 cisplatin Drugs 0.000 description 1
150000001860 citric acid derivatives Chemical class 0.000 description 1
208000029664 classic familial adenomatous polyposis Diseases 0.000 description 1
201000011024 colonic benign neoplasm Diseases 0.000 description 1
208000029742 colonic neoplasm Diseases 0.000 description 1
229910052802 copper Inorganic materials 0.000 description 1
239000010949 copper Substances 0.000 description 1
150000001880 copper compounds Chemical class 0.000 description 1
229910000431 copper oxide Inorganic materials 0.000 description 1
DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
125000000332 coumarinyl group Chemical group O1C(=O)C(=CC2=CC=CC=C12)* 0.000 description 1
239000012043 crude product Substances 0.000 description 1
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
RVOJTCZRIKWHDX-UHFFFAOYSA-N cyclohexanecarbonyl chloride Chemical compound ClC(=O)C1CCCCC1 RVOJTCZRIKWHDX-UHFFFAOYSA-N 0.000 description 1
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
235000018417 cysteine Nutrition 0.000 description 1
XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
230000001086 cytosolic effect Effects 0.000 description 1
238000010511 deprotection reaction Methods 0.000 description 1
125000002576 diazepinyl group Chemical group N1N=C(C=CC=C1)* 0.000 description 1
125000004598 dihydrobenzofuryl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
125000004586 dihydrobenzopyranyl group Chemical group O1C(CCC2=C1C=CC=C2)* 0.000 description 1
125000004582 dihydrobenzothienyl group Chemical group S1C(CC2=C1C=CC=C2)* 0.000 description 1
125000004597 dihydrobenzothiopyranyl group Chemical group S1C(CCC2=C1C=CC=C2)* 0.000 description 1
WOKPSXJEBSRSAT-UHFFFAOYSA-N dihydrobenzothiopyranyl sulfone group Chemical group S1C(CCC2=C1C=CC=C2)S(=O)(=O)C2SC1=C(CC2)C=CC=C1 WOKPSXJEBSRSAT-UHFFFAOYSA-N 0.000 description 1
125000004611 dihydroisoindolyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
125000004609 dihydroquinazolinyl group Chemical group N1(CN=CC2=CC=CC=C12)* 0.000 description 1
239000003085 diluting agent Substances 0.000 description 1
125000000532 dioxanyl group Chemical group 0.000 description 1
229960003668 docetaxel Drugs 0.000 description 1
229940079593 drug Drugs 0.000 description 1
239000003814 drug Substances 0.000 description 1
239000003937 drug carrier Substances 0.000 description 1
238000009510 drug design Methods 0.000 description 1
230000000694 effects Effects 0.000 description 1
229930013356 epothilone Natural products 0.000 description 1
HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 description 1
150000002118 epoxides Chemical class 0.000 description 1
210000003238 esophagus Anatomy 0.000 description 1
125000004494 ethyl ester group Chemical group 0.000 description 1
238000001914 filtration Methods 0.000 description 1
239000011737 fluorine Substances 0.000 description 1
229910052731 fluorine Inorganic materials 0.000 description 1
125000001153 fluoro group Chemical group F* 0.000 description 1
230000003325 follicular Effects 0.000 description 1
201000003444 follicular lymphoma Diseases 0.000 description 1
125000004615 furo[2,3-b]pyridinyl group Chemical group O1C(=CC=2C1=NC=CC2)* 0.000 description 1
125000004613 furo[2,3-c]pyridinyl group Chemical group O1C(=CC=2C1=CN=CC2)* 0.000 description 1
125000004614 furo[3,1-b]pyridinyl group Chemical group 0.000 description 1
125000004612 furopyridinyl group Chemical group O1C(=CC2=C1C=CC=N2)* 0.000 description 1
210000000232 gallbladder Anatomy 0.000 description 1
SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
229960005277 gemcitabine Drugs 0.000 description 1
108010050749 geranylgeranyltransferase type-I Proteins 0.000 description 1
239000011521 glass Substances 0.000 description 1
239000008187 granular material Substances 0.000 description 1
229910052736 halogen Inorganic materials 0.000 description 1
150000002367 halogens Chemical class 0.000 description 1
208000014951 hematologic disease Diseases 0.000 description 1
230000013632 homeostatic process Effects 0.000 description 1
239000005556 hormone Substances 0.000 description 1
229940088597 hormone Drugs 0.000 description 1
150000004677 hydrates Chemical class 0.000 description 1
150000004678 hydrides Chemical class 0.000 description 1
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
229910000041 hydrogen chloride Inorganic materials 0.000 description 1
230000003301 hydrolyzing effect Effects 0.000 description 1
230000001969 hypertrophic effect Effects 0.000 description 1
125000002632 imidazolidinyl group Chemical group 0.000 description 1
125000002636 imidazolinyl group Chemical group 0.000 description 1
238000001727 in vivo Methods 0.000 description 1
125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
208000015181 infectious disease Diseases 0.000 description 1
230000002757 inflammatory effect Effects 0.000 description 1
238000007918 intramuscular administration Methods 0.000 description 1
238000007912 intraperitoneal administration Methods 0.000 description 1
238000001990 intravenous administration Methods 0.000 description 1
239000011630 iodine Chemical group 0.000 description 1
229910052740 iodine Chemical group 0.000 description 1
PGLTVOMIXTUURA-UHFFFAOYSA-N iodoacetamide Chemical compound NC(=O)CI PGLTVOMIXTUURA-UHFFFAOYSA-N 0.000 description 1
150000002500 ions Chemical class 0.000 description 1
KLEAIHJJLUAXIQ-JDRGBKBRSA-N irinotecan hydrochloride hydrate Chemical compound O.O.O.Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 KLEAIHJJLUAXIQ-JDRGBKBRSA-N 0.000 description 1
208000037906 ischaemic injury Diseases 0.000 description 1
125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 1
125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 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
125000003971 isoxazolinyl group Chemical group 0.000 description 1
125000000842 isoxazolyl group Chemical group 0.000 description 1
210000003734 kidney Anatomy 0.000 description 1
208000017169 kidney disease Diseases 0.000 description 1
210000005053 lamin Anatomy 0.000 description 1
230000003902 lesion Effects 0.000 description 1
208000032839 leukemia Diseases 0.000 description 1
239000007788 liquid Substances 0.000 description 1
229910052744 lithium Inorganic materials 0.000 description 1
239000012280 lithium aluminium hydride Substances 0.000 description 1
210000004185 liver Anatomy 0.000 description 1
208000019423 liver disease Diseases 0.000 description 1
230000004807 localization Effects 0.000 description 1
208000037841 lung tumor Diseases 0.000 description 1
239000011777 magnesium Substances 0.000 description 1
229910052749 magnesium Inorganic materials 0.000 description 1
238000012423 maintenance Methods 0.000 description 1
VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
239000011976 maleic acid Substances 0.000 description 1
239000000463 material Substances 0.000 description 1
230000001404 mediated effect Effects 0.000 description 1
201000001441 melanoma Diseases 0.000 description 1
239000012528 membrane Substances 0.000 description 1
229910001509 metal bromide Inorganic materials 0.000 description 1
229940098779 methanesulfonic acid Drugs 0.000 description 1
229930182817 methionine Natural products 0.000 description 1
SWVMLNPDTIFDDY-FVGYRXGTSA-N methyl (2s)-2-amino-3-phenylpropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=CC=C1 SWVMLNPDTIFDDY-FVGYRXGTSA-N 0.000 description 1
FBIPTCVAYJYXEB-UHFFFAOYSA-N methyl 2-(2-phenylethylamino)acetate Chemical compound COC(=O)CNCCC1=CC=CC=C1 FBIPTCVAYJYXEB-UHFFFAOYSA-N 0.000 description 1
VSDUZFOSJDMAFZ-VIFPVBQESA-N methyl L-phenylalaninate Chemical compound COC(=O)[C@@H](N)CC1=CC=CC=C1 VSDUZFOSJDMAFZ-VIFPVBQESA-N 0.000 description 1
150000007522 mineralic acids Chemical class 0.000 description 1
125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
125000002757 morpholinyl group Chemical group 0.000 description 1
201000006417 multiple sclerosis Diseases 0.000 description 1
210000002346 musculoskeletal system Anatomy 0.000 description 1
208000010125 myocardial infarction Diseases 0.000 description 1
GNMHHXWQXKIQCB-UHFFFAOYSA-N n-(3-benzyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-7-yl)cyclohexanecarboxamide Chemical compound C1CCCCC1C(=O)NC(C=C1NC2)=CC=C1SNC2CC1=CC=CC=C1 GNMHHXWQXKIQCB-UHFFFAOYSA-N 0.000 description 1
CJKUWCILEMHBSL-UHFFFAOYSA-N n-[3-benzyl-5-(1h-imidazol-5-ylmethyl)-3,4-dihydro-2h-1,2,5-benzothiadiazepin-7-yl]benzamide Chemical compound C=1C=CC=CC=1C(=O)NC(C=C1N(CC=2N=CNC=2)C2)=CC=C1SNC2CC1=CC=CC=C1 CJKUWCILEMHBSL-UHFFFAOYSA-N 0.000 description 1
125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
208000007538 neurilemmoma Diseases 0.000 description 1
201000004931 neurofibromatosis Diseases 0.000 description 1
150000002823 nitrates Chemical class 0.000 description 1
231100000252 nontoxic Toxicity 0.000 description 1
230000003000 nontoxic effect Effects 0.000 description 1
150000007524 organic acids Chemical class 0.000 description 1
150000007530 organic bases Chemical class 0.000 description 1
201000008968 osteosarcoma Diseases 0.000 description 1
238000012261 overproduction Methods 0.000 description 1
125000001715 oxadiazolyl group Chemical group 0.000 description 1
125000000160 oxazolidinyl group Chemical group 0.000 description 1
125000002971 oxazolyl group Chemical group 0.000 description 1
125000003566 oxetanyl group Chemical group 0.000 description 1
125000004043 oxo group Chemical group O=* 0.000 description 1
229960001592 paclitaxel Drugs 0.000 description 1
229910052763 palladium Inorganic materials 0.000 description 1
210000000496 pancreas Anatomy 0.000 description 1
201000002528 pancreatic cancer Diseases 0.000 description 1
230000008506 pathogenesis Effects 0.000 description 1
210000001428 peripheral nervous system Anatomy 0.000 description 1
239000008194 pharmaceutical composition Substances 0.000 description 1
239000008024 pharmaceutical diluent Substances 0.000 description 1
235000021317 phosphate Nutrition 0.000 description 1
150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
125000004193 piperazinyl group Chemical group 0.000 description 1
125000003386 piperidinyl group Chemical group 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
150000003058 platinum compounds Chemical class 0.000 description 1
208000030761 polycystic kidney disease Diseases 0.000 description 1
230000004481 post-translational protein modification Effects 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
239000011591 potassium Substances 0.000 description 1
239000000843 powder Substances 0.000 description 1
210000002307 prostate Anatomy 0.000 description 1
230000013498 protein farnesylation Effects 0.000 description 1
208000005069 pulmonary fibrosis Diseases 0.000 description 1
125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
125000003373 pyrazinyl group Chemical group 0.000 description 1
125000002755 pyrazolinyl group Chemical group 0.000 description 1
125000003226 pyrazolyl group Chemical group 0.000 description 1
125000002098 pyridazinyl group Chemical group 0.000 description 1
125000004590 pyridopyridyl group Chemical group N1=C(C=CC2=C1C=CC=N2)* 0.000 description 1
125000000719 pyrrolidinyl group Chemical group 0.000 description 1
125000006085 pyrrolopyridyl group Chemical group 0.000 description 1
125000000168 pyrrolyl group Chemical group 0.000 description 1
125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
125000004620 quinolinyl-N-oxide group Chemical group 0.000 description 1
125000005493 quinolyl group Chemical group 0.000 description 1
125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
230000009467 reduction Effects 0.000 description 1
238000011160 research Methods 0.000 description 1
208000037803 restenosis Diseases 0.000 description 1
230000004276 retinal vascularization Effects 0.000 description 1
238000012552 review Methods 0.000 description 1
206010039073 rheumatoid arthritis Diseases 0.000 description 1
101150079354 rho gene Proteins 0.000 description 1
150000003902 salicylic acid esters Chemical class 0.000 description 1
239000012047 saturated solution Substances 0.000 description 1
230000036573 scar formation Effects 0.000 description 1
201000009890 sinusitis Diseases 0.000 description 1
210000003491 skin Anatomy 0.000 description 1
208000000587 small cell lung carcinoma Diseases 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
235000019345 sodium thiosulphate Nutrition 0.000 description 1
239000008259 solid foam Substances 0.000 description 1
238000007614 solvation Methods 0.000 description 1
239000011877 solvent mixture Substances 0.000 description 1
208000002320 spinal muscular atrophy Diseases 0.000 description 1
206010041823 squamous cell carcinoma Diseases 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
210000002784 stomach Anatomy 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
239000000758 substrate Substances 0.000 description 1
150000003900 succinic acid esters Chemical class 0.000 description 1
YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
201000000596 systemic lupus erythematosus Diseases 0.000 description 1
239000003826 tablet Substances 0.000 description 1
150000003899 tartaric acid esters Chemical class 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
239000003277 telomerase inhibitor Substances 0.000 description 1
208000001608 teratocarcinoma Diseases 0.000 description 1
AOCSUUGBCMTKJH-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCN AOCSUUGBCMTKJH-UHFFFAOYSA-N 0.000 description 1
IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
239000012414 tert-butyl nitrite Substances 0.000 description 1
238000012360 testing method Methods 0.000 description 1
210000001550 testis Anatomy 0.000 description 1
YJBKVPRVZAQTPY-UHFFFAOYSA-J tetrachlorostannane;dihydrate Chemical compound O.O.Cl[Sn](Cl)(Cl)Cl YJBKVPRVZAQTPY-UHFFFAOYSA-J 0.000 description 1
125000006092 tetrahydro-1,1-dioxothienyl group Chemical group 0.000 description 1
125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
125000001113 thiadiazolyl group Chemical group 0.000 description 1
125000006090 thiamorpholinyl sulfone group Chemical group 0.000 description 1
125000006089 thiamorpholinyl sulfoxide group Chemical group 0.000 description 1
125000001984 thiazolidinyl group Chemical group 0.000 description 1
125000004589 thienofuryl group Chemical group O1C(=CC2=C1C=CS2)* 0.000 description 1
125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 description 1
125000004587 thienothienyl group Chemical group S1C(=CC2=C1C=CS2)* 0.000 description 1
125000002053 thietanyl group Chemical group 0.000 description 1
125000001730 thiiranyl group Chemical group 0.000 description 1
150000003568 thioethers Chemical class 0.000 description 1
125000004568 thiomorpholinyl group Chemical group 0.000 description 1
238000011200 topical administration Methods 0.000 description 1
239000003053 toxin Substances 0.000 description 1
231100000765 toxin Toxicity 0.000 description 1
108700012359 toxins Proteins 0.000 description 1
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
230000001131 transforming effect Effects 0.000 description 1
125000004306 triazinyl group Chemical group 0.000 description 1
125000001425 triazolyl group Chemical group 0.000 description 1
IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
230000005747 tumor angiogenesis Effects 0.000 description 1
230000005748 tumor development Effects 0.000 description 1
241000701161 unidentified adenovirus Species 0.000 description 1
241001529453 unidentified herpesvirus Species 0.000 description 1
210000003932 urinary bladder Anatomy 0.000 description 1
238000007631 vascular surgery Methods 0.000 description 1
239000003981 vehicle Substances 0.000 description 1