TWI535722B - 用於腫瘤適應徵及與mTOR/PI3K/AKT/路徑相關之疾病之mTOR激酶抑制劑 - Google Patents
用於腫瘤適應徵及與mTOR/PI3K/AKT/路徑相關之疾病之mTOR激酶抑制劑 Download PDFInfo
- Publication number
- TWI535722B TWI535722B TW104115102A TW104115102A TWI535722B TW I535722 B TWI535722 B TW I535722B TW 104115102 A TW104115102 A TW 104115102A TW 104115102 A TW104115102 A TW 104115102A TW I535722 B TWI535722 B TW I535722B
- Authority
- TW
- Taiwan
- Prior art keywords
- pyridin
- dihydropyridyl
- methyl
- substituted
- compound
- Prior art date
Links
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 53
- 201000010099 disease Diseases 0.000 title description 47
- 230000037361 pathway Effects 0.000 title description 26
- 108091008611 Protein Kinase B Proteins 0.000 title description 14
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 title description 3
- 101150097381 Mtor gene Proteins 0.000 title 1
- -1 alkylsulfonyl Amine Chemical class 0.000 claims description 335
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 272
- 150000001875 compounds Chemical class 0.000 claims description 116
- 125000000217 alkyl group Chemical group 0.000 claims description 106
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 42
- 125000004076 pyridyl group Chemical group 0.000 claims description 41
- 125000000623 heterocyclic group Chemical group 0.000 claims description 36
- 229910052736 halogen Inorganic materials 0.000 claims description 35
- 125000001072 heteroaryl group Chemical group 0.000 claims description 35
- 150000002367 halogens Chemical class 0.000 claims description 34
- 125000001424 substituent group Chemical group 0.000 claims description 34
- 150000003839 salts Chemical class 0.000 claims description 31
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 24
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 17
- 150000001412 amines Chemical class 0.000 claims description 15
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 15
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000002950 monocyclic group Chemical group 0.000 claims description 9
- 125000001425 triazolyl group Chemical group 0.000 claims description 9
- 239000003981 vehicle Substances 0.000 claims description 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 8
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 239000004202 carbamide Substances 0.000 claims description 5
- 229910052707 ruthenium Inorganic materials 0.000 claims description 5
- 125000003367 polycyclic group Chemical group 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 229940124530 sulfonamide Drugs 0.000 claims description 4
- 150000003456 sulfonamides Chemical class 0.000 claims description 4
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
- 125000005262 alkoxyamine group Chemical group 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 150000002081 enamines Chemical class 0.000 claims description 3
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 3
- 150000002466 imines Chemical class 0.000 claims description 3
- 239000012948 isocyanate Substances 0.000 claims description 3
- 150000002513 isocyanates Chemical class 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 3
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 3
- RSPCKAHMRANGJZ-UHFFFAOYSA-N thiohydroxylamine Chemical compound SN RSPCKAHMRANGJZ-UHFFFAOYSA-N 0.000 claims description 3
- 150000003573 thiols Chemical class 0.000 claims description 3
- 239000005864 Sulphur Substances 0.000 claims description 2
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 2
- 150000001540 azides Chemical class 0.000 claims description 2
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 claims description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 2
- 150000002540 isothiocyanates Chemical class 0.000 claims description 2
- 150000004060 quinone imines Chemical group 0.000 claims description 2
- 150000003568 thioethers Chemical group 0.000 claims description 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims 2
- 150000001204 N-oxides Chemical class 0.000 claims 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 2
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims 2
- 125000003396 thiol group Chemical class [H]S* 0.000 claims 2
- IWJBAPBRVCEPOG-UHFFFAOYSA-N (decylamino)phosphonic acid Chemical group C(CCCCCCCCC)NP(O)(O)=O IWJBAPBRVCEPOG-UHFFFAOYSA-N 0.000 claims 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims 1
- HAGNOTPFDLDDCR-UHFFFAOYSA-N cyanic acid;isothiocyanic acid Chemical compound N=C=S.OC#N HAGNOTPFDLDDCR-UHFFFAOYSA-N 0.000 claims 1
- DHIGSAXSUWQAEI-UHFFFAOYSA-N hydrazine azide Chemical compound NNN=[N+]=[N-] DHIGSAXSUWQAEI-UHFFFAOYSA-N 0.000 claims 1
- 229910052741 iridium Inorganic materials 0.000 claims 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims 1
- 229910052762 osmium Inorganic materials 0.000 claims 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 133
- 206010028980 Neoplasm Diseases 0.000 description 96
- 239000000203 mixture Substances 0.000 description 81
- 238000000034 method Methods 0.000 description 64
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 55
- 235000019439 ethyl acetate Nutrition 0.000 description 54
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 49
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- 201000011510 cancer Diseases 0.000 description 43
- 239000002585 base Substances 0.000 description 41
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- 239000002904 solvent Substances 0.000 description 36
- 208000024891 symptom Diseases 0.000 description 36
- 210000004027 cell Anatomy 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 31
- 108091000080 Phosphotransferase Proteins 0.000 description 30
- 102000020233 phosphotransferase Human genes 0.000 description 30
- 239000013543 active substance Substances 0.000 description 28
- 239000007787 solid Substances 0.000 description 28
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- 229910052757 nitrogen Inorganic materials 0.000 description 27
- 229910052763 palladium Inorganic materials 0.000 description 27
- 239000000047 product Substances 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 239000003112 inhibitor Substances 0.000 description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 230000002829 reductive effect Effects 0.000 description 23
- 238000011282 treatment Methods 0.000 description 23
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 22
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 22
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 22
- 125000003118 aryl group Chemical group 0.000 description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 22
- 108091007960 PI3Ks Proteins 0.000 description 21
- 102000038030 PI3Ks Human genes 0.000 description 21
- 239000003054 catalyst Substances 0.000 description 21
- 239000003795 chemical substances by application Substances 0.000 description 21
- 102000001253 Protein Kinase Human genes 0.000 description 20
- 108060006633 protein kinase Proteins 0.000 description 20
- 125000004429 atom Chemical group 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 17
- 206010039491 Sarcoma Diseases 0.000 description 16
- 208000032839 leukemia Diseases 0.000 description 16
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 15
- 206010025323 Lymphomas Diseases 0.000 description 14
- 208000009956 adenocarcinoma Diseases 0.000 description 14
- 230000002265 prevention Effects 0.000 description 14
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 13
- 239000002253 acid Substances 0.000 description 13
- 239000003814 drug Substances 0.000 description 13
- 210000004072 lung Anatomy 0.000 description 13
- 201000001441 melanoma Diseases 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 108010050904 Interferons Proteins 0.000 description 12
- 102000014150 Interferons Human genes 0.000 description 12
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 12
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 230000037396 body weight Effects 0.000 description 12
- 230000003211 malignant effect Effects 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 239000003826 tablet Substances 0.000 description 12
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 11
- 208000008770 Multiple Hamartoma Syndrome Diseases 0.000 description 11
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 11
- 238000009472 formulation Methods 0.000 description 11
- 230000002757 inflammatory effect Effects 0.000 description 11
- 229910052742 iron Inorganic materials 0.000 description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 206010041823 squamous cell carcinoma Diseases 0.000 description 11
- 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 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- 208000014674 injury Diseases 0.000 description 10
- 229940079322 interferon Drugs 0.000 description 10
- 210000003734 kidney Anatomy 0.000 description 10
- 229940002612 prodrug Drugs 0.000 description 10
- 239000000651 prodrug Substances 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 210000003491 skin Anatomy 0.000 description 10
- 229940083542 sodium Drugs 0.000 description 10
- 229910052708 sodium Inorganic materials 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 208000011580 syndromic disease Diseases 0.000 description 10
- ZHGNHOOVYPHPNJ-UHFFFAOYSA-N Amigdalin Chemical compound FC(F)(F)C(=O)OCC1OC(OCC2OC(OC(C#N)C3=CC=CC=C3)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C2OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C1OC(=O)C(F)(F)F ZHGNHOOVYPHPNJ-UHFFFAOYSA-N 0.000 description 9
- 201000009030 Carcinoma Diseases 0.000 description 9
- 206010018338 Glioma Diseases 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- 230000001154 acute effect Effects 0.000 description 9
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 9
- 239000002775 capsule Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 206010012601 diabetes mellitus Diseases 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- 210000004185 liver Anatomy 0.000 description 9
- 210000000496 pancreas Anatomy 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- 125000003226 pyrazolyl group Chemical group 0.000 description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 description 9
- DIIIISSCIXVANO-UHFFFAOYSA-N 1,2-Dimethylhydrazine Chemical compound CNNC DIIIISSCIXVANO-UHFFFAOYSA-N 0.000 description 8
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 8
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 8
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 8
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 8
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 8
- 208000008589 Obesity Diseases 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- 206010057190 Respiratory tract infections Diseases 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical class O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 210000000481 breast Anatomy 0.000 description 8
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 8
- 230000000155 isotopic effect Effects 0.000 description 8
- 235000020824 obesity Nutrition 0.000 description 8
- 210000001672 ovary Anatomy 0.000 description 8
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 8
- 229960004889 salicylic acid Drugs 0.000 description 8
- 239000012453 solvate Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 8
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 7
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 description 7
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 7
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 7
- 206010060862 Prostate cancer Diseases 0.000 description 7
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 7
- 229920002472 Starch Polymers 0.000 description 7
- 238000006619 Stille reaction Methods 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 7
- 238000006069 Suzuki reaction reaction Methods 0.000 description 7
- 239000005557 antagonist Substances 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 7
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 230000001900 immune effect Effects 0.000 description 7
- 229910052740 iodine Inorganic materials 0.000 description 7
- 229940043355 kinase inhibitor Drugs 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 230000004770 neurodegeneration Effects 0.000 description 7
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 description 7
- 239000008107 starch Substances 0.000 description 7
- 235000019698 starch Nutrition 0.000 description 7
- 210000002784 stomach Anatomy 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- OQANPHBRHBJGNZ-FYJGNVAPSA-N (3e)-6-oxo-3-[[4-(pyridin-2-ylsulfamoyl)phenyl]hydrazinylidene]cyclohexa-1,4-diene-1-carboxylic acid Chemical compound C1=CC(=O)C(C(=O)O)=C\C1=N\NC1=CC=C(S(=O)(=O)NC=2N=CC=CC=2)C=C1 OQANPHBRHBJGNZ-FYJGNVAPSA-N 0.000 description 6
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 6
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 6
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 6
- 108010035532 Collagen Proteins 0.000 description 6
- 102000008186 Collagen Human genes 0.000 description 6
- 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 6
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 6
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 6
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 6
- 206010052178 Lymphocytic lymphoma Diseases 0.000 description 6
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 6
- 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 6
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 6
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- 208000006265 Renal cell carcinoma Diseases 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 208000027418 Wounds and injury Diseases 0.000 description 6
- 230000032683 aging Effects 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 229960000590 celecoxib Drugs 0.000 description 6
- 210000003679 cervix uteri Anatomy 0.000 description 6
- 210000001072 colon Anatomy 0.000 description 6
- 239000003246 corticosteroid Substances 0.000 description 6
- 229960001334 corticosteroids Drugs 0.000 description 6
- 230000006378 damage Effects 0.000 description 6
- 125000003963 dichloro group Chemical group Cl* 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 229960001123 epoprostenol Drugs 0.000 description 6
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 description 6
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 229960001929 meloxicam Drugs 0.000 description 6
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 6
- 208000015122 neurodegenerative disease Diseases 0.000 description 6
- 229960000435 oblimersen Drugs 0.000 description 6
- MIMNFCVQODTQDP-NDLVEFNKSA-N oblimersen Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(S)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)CO)[C@@H](O)C1 MIMNFCVQODTQDP-NDLVEFNKSA-N 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 210000002307 prostate Anatomy 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 230000002441 reversible effect Effects 0.000 description 6
- 238000006798 ring closing metathesis reaction Methods 0.000 description 6
- WVYADZUPLLSGPU-UHFFFAOYSA-N salsalate Chemical compound OC(=O)C1=CC=CC=C1OC(=O)C1=CC=CC=C1O WVYADZUPLLSGPU-UHFFFAOYSA-N 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 6
- 229910000080 stannane Inorganic materials 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 229960001940 sulfasalazine Drugs 0.000 description 6
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 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 6
- 208000006542 von Hippel-Lindau disease Diseases 0.000 description 6
- PGDIPOWQYRAOSK-UHFFFAOYSA-N 1,3-dihydroimidazo[4,5-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)NC2=C1 PGDIPOWQYRAOSK-UHFFFAOYSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- 208000003174 Brain Neoplasms Diseases 0.000 description 5
- 206010009944 Colon cancer Diseases 0.000 description 5
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 5
- 108010036949 Cyclosporine Proteins 0.000 description 5
- 102000004127 Cytokines Human genes 0.000 description 5
- 108090000695 Cytokines Proteins 0.000 description 5
- 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 5
- 206010058314 Dysplasia Diseases 0.000 description 5
- 206010014733 Endometrial cancer Diseases 0.000 description 5
- 206010014759 Endometrial neoplasm Diseases 0.000 description 5
- 201000008808 Fibrosarcoma Diseases 0.000 description 5
- 208000032612 Glial tumor Diseases 0.000 description 5
- 108010002350 Interleukin-2 Proteins 0.000 description 5
- 229930195725 Mannitol Natural products 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 5
- 208000012902 Nervous system disease Diseases 0.000 description 5
- 208000025966 Neurological disease Diseases 0.000 description 5
- 229930012538 Paclitaxel Natural products 0.000 description 5
- 206010035226 Plasma cell myeloma Diseases 0.000 description 5
- 241000282849 Ruminantia Species 0.000 description 5
- 102100026715 Serine/threonine-protein kinase STK11 Human genes 0.000 description 5
- 235000010443 alginic acid Nutrition 0.000 description 5
- 229920000615 alginic acid Polymers 0.000 description 5
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 5
- 229960003805 amantadine Drugs 0.000 description 5
- 230000033115 angiogenesis Effects 0.000 description 5
- 210000000988 bone and bone Anatomy 0.000 description 5
- 210000001185 bone marrow Anatomy 0.000 description 5
- 239000001913 cellulose Substances 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 230000001684 chronic effect Effects 0.000 description 5
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 5
- 229960001265 ciclosporin Drugs 0.000 description 5
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 5
- 229920001436 collagen Polymers 0.000 description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 5
- 229930182912 cyclosporin Natural products 0.000 description 5
- 230000001419 dependent effect Effects 0.000 description 5
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 5
- BSHICDXRSZQYBP-UHFFFAOYSA-N dichloromethane;palladium(2+) Chemical compound [Pd+2].ClCCl BSHICDXRSZQYBP-UHFFFAOYSA-N 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 230000002526 effect on cardiovascular system Effects 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 5
- 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 5
- 210000002216 heart Anatomy 0.000 description 5
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 5
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 229960002411 imatinib Drugs 0.000 description 5
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound 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 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 5
- 229960004592 isopropanol Drugs 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 239000000594 mannitol Substances 0.000 description 5
- 235000010355 mannitol Nutrition 0.000 description 5
- 210000000066 myeloid cell Anatomy 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 125000002971 oxazolyl group Chemical group 0.000 description 5
- 229960001592 paclitaxel Drugs 0.000 description 5
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 5
- 210000003800 pharynx Anatomy 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 235000000346 sugar Nutrition 0.000 description 5
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 5
- 229960000894 sulindac Drugs 0.000 description 5
- 238000001356 surgical procedure Methods 0.000 description 5
- 210000003932 urinary bladder Anatomy 0.000 description 5
- 210000004291 uterus Anatomy 0.000 description 5
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 4
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 4
- HDBQZGJWHMCXIL-UHFFFAOYSA-N 3,7-dihydropurine-2-thione Chemical compound SC1=NC=C2NC=NC2=N1 HDBQZGJWHMCXIL-UHFFFAOYSA-N 0.000 description 4
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 4
- 229940122361 Bisphosphonate Drugs 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 4
- 206010009900 Colitis ulcerative Diseases 0.000 description 4
- 208000012609 Cowden disease Diseases 0.000 description 4
- 201000002847 Cowden syndrome Diseases 0.000 description 4
- 208000011231 Crohn disease Diseases 0.000 description 4
- 201000004624 Dermatitis Diseases 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- 208000021309 Germ cell tumor Diseases 0.000 description 4
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 4
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 4
- 108060003951 Immunoglobulin Proteins 0.000 description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 4
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 4
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 4
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 4
- 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 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- 102000008135 Mechanistic Target of Rapamycin Complex 1 Human genes 0.000 description 4
- 108010035196 Mechanistic Target of Rapamycin Complex 1 Proteins 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 208000034578 Multiple myelomas Diseases 0.000 description 4
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 4
- 102000007530 Neurofibromin 1 Human genes 0.000 description 4
- 108010085793 Neurofibromin 1 Proteins 0.000 description 4
- 108091034117 Oligonucleotide Proteins 0.000 description 4
- 206010033128 Ovarian cancer Diseases 0.000 description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 description 4
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 4
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 4
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 208000024770 Thyroid neoplasm Diseases 0.000 description 4
- 206010052779 Transplant rejections Diseases 0.000 description 4
- 201000006704 Ulcerative Colitis Diseases 0.000 description 4
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 4
- 208000036142 Viral infection Diseases 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 4
- 125000003943 azolyl group Chemical group 0.000 description 4
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 150000004663 bisphosphonates Chemical class 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 235000013877 carbamide Nutrition 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 229960005091 chloramphenicol Drugs 0.000 description 4
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 4
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 4
- 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 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 229960003957 dexamethasone Drugs 0.000 description 4
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 4
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 229960005277 gemcitabine Drugs 0.000 description 4
- 229940045109 genistein Drugs 0.000 description 4
- TZBJGXHYKVUXJN-UHFFFAOYSA-N genistein Natural products C1=CC(O)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O TZBJGXHYKVUXJN-UHFFFAOYSA-N 0.000 description 4
- 235000006539 genistein Nutrition 0.000 description 4
- ZCOLJUOHXJRHDI-CMWLGVBASA-N genistein 7-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 ZCOLJUOHXJRHDI-CMWLGVBASA-N 0.000 description 4
- 208000005017 glioblastoma Diseases 0.000 description 4
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 4
- 239000003102 growth factor Substances 0.000 description 4
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 4
- 229940088597 hormone Drugs 0.000 description 4
- 239000005556 hormone Substances 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 125000002883 imidazolyl group Chemical group 0.000 description 4
- 102000018358 immunoglobulin Human genes 0.000 description 4
- 239000002955 immunomodulating agent Substances 0.000 description 4
- 229940121354 immunomodulator Drugs 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 230000000968 intestinal effect Effects 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 229960004752 ketorolac Drugs 0.000 description 4
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- 201000005202 lung cancer Diseases 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 230000001394 metastastic effect Effects 0.000 description 4
- 206010061289 metastatic neoplasm Diseases 0.000 description 4
- 229920000609 methyl cellulose Polymers 0.000 description 4
- 235000010981 methylcellulose Nutrition 0.000 description 4
- 239000001923 methylcellulose Substances 0.000 description 4
- 210000000214 mouth Anatomy 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 239000011368 organic material Substances 0.000 description 4
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 4
- 229960005489 paracetamol Drugs 0.000 description 4
- 229960002895 phenylbutazone Drugs 0.000 description 4
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 description 4
- 235000011009 potassium phosphates Nutrition 0.000 description 4
- 229960004618 prednisone Drugs 0.000 description 4
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 4
- 238000002953 preparative HPLC Methods 0.000 description 4
- 230000002062 proliferating effect Effects 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 4
- 125000000168 pyrrolyl group Chemical group 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 4
- 229960003147 reserpine Drugs 0.000 description 4
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 4
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 4
- 210000000952 spleen Anatomy 0.000 description 4
- 150000008163 sugars Chemical class 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 229960001603 tamoxifen Drugs 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 201000002510 thyroid cancer Diseases 0.000 description 4
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 4
- 229960002066 vinorelbine Drugs 0.000 description 4
- 230000009385 viral infection Effects 0.000 description 4
- 239000003039 volatile agent Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 3
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 3
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 3
- VYOKOQDVBBWPKO-UHFFFAOYSA-N 1-nitro-9h-carbazole Chemical compound N1C2=CC=CC=C2C2=C1C([N+](=O)[O-])=CC=C2 VYOKOQDVBBWPKO-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- PLLBRTOLHQQAQQ-UHFFFAOYSA-N 8-methylnonan-1-ol Chemical compound CC(C)CCCCCCCO PLLBRTOLHQQAQQ-UHFFFAOYSA-N 0.000 description 3
- JAJIPIAHCFBEPI-UHFFFAOYSA-N 9,10-dioxoanthracene-1-sulfonic acid Chemical compound O=C1C2=CC=CC=C2C(=O)C2=C1C=CC=C2S(=O)(=O)O JAJIPIAHCFBEPI-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 208000024827 Alzheimer disease Diseases 0.000 description 3
- RLFWWDJHLFCNIJ-UHFFFAOYSA-N Aminoantipyrine Natural products CN1C(C)=C(N)C(=O)N1C1=CC=CC=C1 RLFWWDJHLFCNIJ-UHFFFAOYSA-N 0.000 description 3
- RMMXTBMQSGEXHJ-UHFFFAOYSA-N Aminophenazone Chemical compound O=C1C(N(C)C)=C(C)N(C)N1C1=CC=CC=C1 RMMXTBMQSGEXHJ-UHFFFAOYSA-N 0.000 description 3
- 208000035143 Bacterial infection Diseases 0.000 description 3
- 108010062877 Bacteriocins Proteins 0.000 description 3
- 201000007815 Bannayan-Riley-Ruvalcaba syndrome Diseases 0.000 description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 3
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 3
- 206010006895 Cachexia Diseases 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- 201000003883 Cystic fibrosis Diseases 0.000 description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 3
- 108010008165 Etanercept Proteins 0.000 description 3
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 3
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- 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 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 3
- 208000017604 Hodgkin disease Diseases 0.000 description 3
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 3
- 101000628562 Homo sapiens Serine/threonine-protein kinase STK11 Proteins 0.000 description 3
- 208000023105 Huntington disease Diseases 0.000 description 3
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 3
- 108010047761 Interferon-alpha Proteins 0.000 description 3
- 102000006992 Interferon-alpha Human genes 0.000 description 3
- 239000004440 Isodecyl alcohol Substances 0.000 description 3
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 102000009308 Mechanistic Target of Rapamycin Complex 2 Human genes 0.000 description 3
- 108010034057 Mechanistic Target of Rapamycin Complex 2 Proteins 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- RTGDFNSFWBGLEC-UHFFFAOYSA-N Mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1CC=C(C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-UHFFFAOYSA-N 0.000 description 3
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 3
- WUKZPHOXUVCQOR-UHFFFAOYSA-N N-(1-azabicyclo[2.2.2]octan-3-yl)-6-chloro-4-methyl-3-oxo-1,4-benzoxazine-8-carboxamide Chemical compound C1N(CC2)CCC2C1NC(=O)C1=CC(Cl)=CC2=C1OCC(=O)N2C WUKZPHOXUVCQOR-UHFFFAOYSA-N 0.000 description 3
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 3
- 208000033014 Plasma cell tumor Diseases 0.000 description 3
- 208000007452 Plasmacytoma Diseases 0.000 description 3
- 102100036143 Polycystin-1 Human genes 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- OTKJDMGTUTTYMP-ROUUACIJSA-N Safingol ( L-threo-sphinganine) Chemical compound CCCCCCCCCCCCCCC[C@H](O)[C@@H](N)CO OTKJDMGTUTTYMP-ROUUACIJSA-N 0.000 description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 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 3
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 3
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 3
- 239000004473 Threonine Substances 0.000 description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 3
- 108091008605 VEGF receptors Proteins 0.000 description 3
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 3
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 210000002945 adventitial reticular cell Anatomy 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 description 3
- 229960000212 aminophenazone Drugs 0.000 description 3
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 3
- LSNWBKACGXCGAJ-UHFFFAOYSA-N ampiroxicam Chemical compound CN1S(=O)(=O)C2=CC=CC=C2C(OC(C)OC(=O)OCC)=C1C(=O)NC1=CC=CC=N1 LSNWBKACGXCGAJ-UHFFFAOYSA-N 0.000 description 3
- 229950011249 ampiroxicam Drugs 0.000 description 3
- 229960002932 anastrozole Drugs 0.000 description 3
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 3
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 3
- 239000001961 anticonvulsive agent Substances 0.000 description 3
- VEQOALNAAJBPNY-UHFFFAOYSA-N antipyrine Chemical compound CN1C(C)=CC(=O)N1C1=CC=CC=C1 VEQOALNAAJBPNY-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- AUJRCFUBUPVWSZ-XTZHGVARSA-M auranofin Chemical compound CCP(CC)(CC)=[Au]S[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O AUJRCFUBUPVWSZ-XTZHGVARSA-M 0.000 description 3
- 229960005207 auranofin Drugs 0.000 description 3
- 229960001671 azapropazone Drugs 0.000 description 3
- WOIIIUDZSOLAIW-NSHDSACASA-N azapropazone Chemical compound C1=C(C)C=C2N3C(=O)[C@H](CC=C)C(=O)N3C(N(C)C)=NC2=C1 WOIIIUDZSOLAIW-NSHDSACASA-N 0.000 description 3
- 229950005951 azasetron Drugs 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 208000022362 bacterial infectious disease Diseases 0.000 description 3
- 229960004669 basiliximab Drugs 0.000 description 3
- WHQCHUCQKNIQEC-UHFFFAOYSA-N benzbromarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(Br)=C(O)C(Br)=C1 WHQCHUCQKNIQEC-UHFFFAOYSA-N 0.000 description 3
- 229960002529 benzbromarone Drugs 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 3
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 210000000601 blood cell Anatomy 0.000 description 3
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 3
- 229960001467 bortezomib Drugs 0.000 description 3
- 229960002092 busulfan Drugs 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000001506 calcium phosphate Substances 0.000 description 3
- 235000011010 calcium phosphates Nutrition 0.000 description 3
- 229960004117 capecitabine Drugs 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 201000010881 cervical cancer Diseases 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 229960004316 cisplatin Drugs 0.000 description 3
- 229960002626 clarithromycin Drugs 0.000 description 3
- 229960001338 colchicine Drugs 0.000 description 3
- 206010009887 colitis Diseases 0.000 description 3
- 229960005188 collagen Drugs 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- 238000011443 conventional therapy Methods 0.000 description 3
- 229960004397 cyclophosphamide Drugs 0.000 description 3
- 229960000684 cytarabine Drugs 0.000 description 3
- 229960002806 daclizumab Drugs 0.000 description 3
- 230000007850 degeneration Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 3
- KXZOIWWTXOCYKR-UHFFFAOYSA-M diclofenac potassium Chemical compound [K+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KXZOIWWTXOCYKR-UHFFFAOYSA-M 0.000 description 3
- 229960004515 diclofenac potassium Drugs 0.000 description 3
- 229960001193 diclofenac sodium Drugs 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000002934 diuretic Substances 0.000 description 3
- 229940030606 diuretics Drugs 0.000 description 3
- 229960003668 docetaxel Drugs 0.000 description 3
- 229960003722 doxycycline Drugs 0.000 description 3
- OEHFRZLKGRKFAS-UHFFFAOYSA-N droxicam Chemical compound C12=CC=CC=C2S(=O)(=O)N(C)C(C2=O)=C1OC(=O)N2C1=CC=CC=N1 OEHFRZLKGRKFAS-UHFFFAOYSA-N 0.000 description 3
- 229960001850 droxicam Drugs 0.000 description 3
- HCZKYJDFEPMADG-UHFFFAOYSA-N erythro-nordihydroguaiaretic acid Natural products C=1C=C(O)C(O)=CC=1CC(C)C(C)CC1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-UHFFFAOYSA-N 0.000 description 3
- 210000003238 esophagus Anatomy 0.000 description 3
- IIUMCNJTGSMNRO-VVSKJQCTSA-L estramustine sodium phosphate Chemical compound [Na+].[Na+].ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)OP([O-])([O-])=O)[C@@H]4[C@@H]3CCC2=C1 IIUMCNJTGSMNRO-VVSKJQCTSA-L 0.000 description 3
- 239000000328 estrogen antagonist Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 229960005293 etodolac Drugs 0.000 description 3
- XFBVBWWRPKNWHW-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 description 3
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 3
- 229960005420 etoposide Drugs 0.000 description 3
- 229960000390 fludarabine Drugs 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- 125000002541 furyl group Chemical group 0.000 description 3
- 201000010175 gallbladder cancer Diseases 0.000 description 3
- 206010017758 gastric cancer Diseases 0.000 description 3
- 229940080856 gleevec Drugs 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 210000003128 head Anatomy 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 229960001680 ibuprofen Drugs 0.000 description 3
- 125000001041 indolyl group Chemical group 0.000 description 3
- 229960000905 indomethacin Drugs 0.000 description 3
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 3
- 210000000936 intestine Anatomy 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229960004768 irinotecan Drugs 0.000 description 3
- 230000000622 irritating effect Effects 0.000 description 3
- 229960003299 ketamine Drugs 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 3
- 229960000991 ketoprofen Drugs 0.000 description 3
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 3
- 229960000681 leflunomide Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 206010025135 lupus erythematosus Diseases 0.000 description 3
- 229960003951 masoprocol Drugs 0.000 description 3
- HCZKYJDFEPMADG-TXEJJXNPSA-N masoprocol Chemical compound C([C@H](C)[C@H](C)CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-TXEJJXNPSA-N 0.000 description 3
- 229960003464 mefenamic acid Drugs 0.000 description 3
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 229960001047 methyl salicylate Drugs 0.000 description 3
- 125000002757 morpholinyl group Chemical group 0.000 description 3
- 201000006417 multiple sclerosis Diseases 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 208000010125 myocardial infarction Diseases 0.000 description 3
- 229960004270 nabumetone Drugs 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- CDBRNDSHEYLDJV-FVGYRXGTSA-M naproxen sodium Chemical compound [Na+].C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CDBRNDSHEYLDJV-FVGYRXGTSA-M 0.000 description 3
- 229960003940 naproxen sodium Drugs 0.000 description 3
- 230000009826 neoplastic cell growth Effects 0.000 description 3
- 208000016065 neuroendocrine neoplasm Diseases 0.000 description 3
- 201000011519 neuroendocrine tumor Diseases 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- QQBDLJCYGRGAKP-FOCLMDBBSA-N olsalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=C(C(O)=CC=2)C(O)=O)=C1 QQBDLJCYGRGAKP-FOCLMDBBSA-N 0.000 description 3
- 229960004110 olsalazine Drugs 0.000 description 3
- 229960005343 ondansetron Drugs 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 201000008482 osteoarthritis Diseases 0.000 description 3
- 201000008968 osteosarcoma Diseases 0.000 description 3
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 3
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 229960005222 phenazone Drugs 0.000 description 3
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 description 3
- 229960002702 piroxicam Drugs 0.000 description 3
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 3
- 208000010626 plasma cell neoplasm Diseases 0.000 description 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- 235000011056 potassium acetate Nutrition 0.000 description 3
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 3
- 229960003081 probenecid Drugs 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 210000000664 rectum Anatomy 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 208000037803 restenosis Diseases 0.000 description 3
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 229960000953 salsalate Drugs 0.000 description 3
- 208000011581 secondary neoplasm Diseases 0.000 description 3
- 229950003647 semaxanib Drugs 0.000 description 3
- WUWDLXZGHZSWQZ-WQLSENKSSA-N semaxanib Chemical compound N1C(C)=CC(C)=C1\C=C/1C2=CC=CC=C2NC\1=O WUWDLXZGHZSWQZ-WQLSENKSSA-N 0.000 description 3
- 230000011664 signaling Effects 0.000 description 3
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical class C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 3
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 3
- WFITUPFQQAGOBI-UHFFFAOYSA-M sodium;carbonochloridate Chemical compound [Na+].[O-]C(Cl)=O WFITUPFQQAGOBI-UHFFFAOYSA-M 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 201000011549 stomach cancer Diseases 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- MBGGBVCUIVRRBF-UHFFFAOYSA-N sulfinpyrazone Chemical compound O=C1N(C=2C=CC=CC=2)N(C=2C=CC=CC=2)C(=O)C1CCS(=O)C1=CC=CC=C1 MBGGBVCUIVRRBF-UHFFFAOYSA-N 0.000 description 3
- 229960003329 sulfinpyrazone Drugs 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 229960001967 tacrolimus Drugs 0.000 description 3
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229940063683 taxotere Drugs 0.000 description 3
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 3
- 229960002871 tenoxicam Drugs 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 3
- 125000003831 tetrazolyl group Chemical group 0.000 description 3
- 125000000335 thiazolyl group Chemical group 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- 229960001196 thiotepa Drugs 0.000 description 3
- 210000001685 thyroid gland Anatomy 0.000 description 3
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 3
- 229960001017 tolmetin Drugs 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- 229960001727 tretinoin Drugs 0.000 description 3
- 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 3
- 229960001099 trimetrexate Drugs 0.000 description 3
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 3
- ZNRGQMMCGHDTEI-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CNC2=C1 ZNRGQMMCGHDTEI-ITGUQSILSA-N 0.000 description 3
- 229960003688 tropisetron Drugs 0.000 description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 3
- 238000003828 vacuum filtration Methods 0.000 description 3
- ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N verteporfin Chemical compound C=1C([C@@]2([C@H](C(=O)OC)C(=CC=C22)C(=O)OC)C)=NC2=CC(C(=C2C=C)C)=NC2=CC(C(=C2CCC(O)=O)C)=NC2=CC2=NC=1C(C)=C2CCC(=O)OC ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N 0.000 description 3
- 229960003895 verteporfin Drugs 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- 229940075420 xanthine Drugs 0.000 description 3
- 229960005332 zileuton Drugs 0.000 description 3
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 3
- HZSBSRAVNBUZRA-RQDPQJJXSA-J (1r,2r)-cyclohexane-1,2-diamine;tetrachloroplatinum(2+) Chemical compound Cl[Pt+2](Cl)(Cl)Cl.N[C@@H]1CCCC[C@H]1N HZSBSRAVNBUZRA-RQDPQJJXSA-J 0.000 description 2
- FUKOTTQGWQVMQB-UHFFFAOYSA-N (2-bromoacetyl) 2-bromoacetate Chemical compound BrCC(=O)OC(=O)CBr FUKOTTQGWQVMQB-UHFFFAOYSA-N 0.000 description 2
- IVTMXOXVAHXCHI-YXLMWLKOSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid;(2s)-3-(3,4-dihydroxyphenyl)-2-hydrazinyl-2-methylpropanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1.NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 IVTMXOXVAHXCHI-YXLMWLKOSA-N 0.000 description 2
- MKJIEFSOBYUXJB-HOCLYGCPSA-N (3S,11bS)-9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one Chemical compound C1CN2C[C@H](CC(C)C)C(=O)C[C@H]2C2=C1C=C(OC)C(OC)=C2 MKJIEFSOBYUXJB-HOCLYGCPSA-N 0.000 description 2
- SWXOGPJRIDTIRL-DOUNNPEJSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s)-1-amino-3-(1h-indol-3-yl)-1-oxopropan-2-yl]-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-pent Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 SWXOGPJRIDTIRL-DOUNNPEJSA-N 0.000 description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 2
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 2
- BGRJTUBHPOOWDU-NSHDSACASA-N (S)-(-)-sulpiride Chemical compound CCN1CCC[C@H]1CNC(=O)C1=CC(S(N)(=O)=O)=CC=C1OC BGRJTUBHPOOWDU-NSHDSACASA-N 0.000 description 2
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 2
- OWXJKYNZGFSVRC-NSCUHMNNSA-N (e)-1-chloroprop-1-ene Chemical compound C\C=C\Cl OWXJKYNZGFSVRC-NSCUHMNNSA-N 0.000 description 2
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 2
- 101710175516 14 kDa zinc-binding protein Proteins 0.000 description 2
- FILKGCRCWDMBKA-UHFFFAOYSA-N 2,6-dichloropyridine Chemical compound ClC1=CC=CC(Cl)=N1 FILKGCRCWDMBKA-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- QXLQZLBNPTZMRK-UHFFFAOYSA-N 2-[(dimethylamino)methyl]-1-(2,4-dimethylphenyl)prop-2-en-1-one Chemical compound CN(C)CC(=C)C(=O)C1=CC=C(C)C=C1C QXLQZLBNPTZMRK-UHFFFAOYSA-N 0.000 description 2
- YZEUHQHUFTYLPH-UHFFFAOYSA-N 2-nitroimidazole Chemical compound [O-][N+](=O)C1=NC=CN1 YZEUHQHUFTYLPH-UHFFFAOYSA-N 0.000 description 2
- SOSPMXMEOFGPIM-UHFFFAOYSA-N 3,5-dibromopyridine Chemical compound BrC1=CN=CC(Br)=C1 SOSPMXMEOFGPIM-UHFFFAOYSA-N 0.000 description 2
- GIJXKZJWITVLHI-UHFFFAOYSA-N 3-(diphenylmethyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane Chemical compound CN1C(C2)CCC1CC2OC(C=1C=CC=CC=1)C1=CC=CC=C1 GIJXKZJWITVLHI-UHFFFAOYSA-N 0.000 description 2
- UZFPOOOQHWICKY-UHFFFAOYSA-N 3-[13-[1-[1-[8,12-bis(2-carboxyethyl)-17-(1-hydroxyethyl)-3,7,13,18-tetramethyl-21,24-dihydroporphyrin-2-yl]ethoxy]ethyl]-18-(2-carboxyethyl)-8-(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid Chemical compound N1C(C=C2C(=C(CCC(O)=O)C(C=C3C(=C(C)C(C=C4N5)=N3)CCC(O)=O)=N2)C)=C(C)C(C(C)O)=C1C=C5C(C)=C4C(C)OC(C)C1=C(N2)C=C(N3)C(C)=C(C(O)C)C3=CC(C(C)=C3CCC(O)=O)=NC3=CC(C(CCC(O)=O)=C3C)=NC3=CC2=C1C UZFPOOOQHWICKY-UHFFFAOYSA-N 0.000 description 2
- QNKJFXARIMSDBR-UHFFFAOYSA-N 3-[2-[bis(2-chloroethyl)amino]ethyl]-1,3-diazaspiro[4.5]decane-2,4-dione Chemical compound O=C1N(CCN(CCCl)CCCl)C(=O)NC11CCCCC1 QNKJFXARIMSDBR-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- CLPFFLWZZBQMAO-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 description 2
- AKJHMTWEGVYYSE-AIRMAKDCSA-N 4-HPR Chemical compound C=1C=C(O)C=CC=1NC(=O)/C=C(\C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C AKJHMTWEGVYYSE-AIRMAKDCSA-N 0.000 description 2
- RJYQLMILDVERHH-UHFFFAOYSA-N 4-Ipomeanol Chemical compound CC(O)CCC(=O)C=1C=COC=1 RJYQLMILDVERHH-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- GIYAQDDTCWHPPL-UHFFFAOYSA-N 4-amino-5-bromo-N-[2-(diethylamino)ethyl]-2-methoxybenzamide Chemical compound CCN(CC)CCNC(=O)C1=CC(Br)=C(N)C=C1OC GIYAQDDTCWHPPL-UHFFFAOYSA-N 0.000 description 2
- BVPWJMCABCPUQY-UHFFFAOYSA-N 4-amino-5-chloro-2-methoxy-N-[1-(phenylmethyl)-4-piperidinyl]benzamide Chemical compound COC1=CC(N)=C(Cl)C=C1C(=O)NC1CCN(CC=2C=CC=CC=2)CC1 BVPWJMCABCPUQY-UHFFFAOYSA-N 0.000 description 2
- 102100036009 5'-AMP-activated protein kinase catalytic subunit alpha-2 Human genes 0.000 description 2
- FDERMDFQPSEUMV-UHFFFAOYSA-N 5-(4-bromo-3-methylphenyl)-1h-1,2,4-triazole Chemical compound C1=C(Br)C(C)=CC(C2=NNC=N2)=C1 FDERMDFQPSEUMV-UHFFFAOYSA-N 0.000 description 2
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 2
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 2
- IZSHZLKNFQAAKX-UHFFFAOYSA-N 5-cyclopenta-2,4-dien-1-ylcyclopenta-1,3-diene Chemical group C1=CC=CC1C1C=CC=C1 IZSHZLKNFQAAKX-UHFFFAOYSA-N 0.000 description 2
- XKFPYPQQHFEXRZ-UHFFFAOYSA-N 5-methyl-N'-(phenylmethyl)-3-isoxazolecarbohydrazide Chemical compound O1C(C)=CC(C(=O)NNCC=2C=CC=CC=2)=N1 XKFPYPQQHFEXRZ-UHFFFAOYSA-N 0.000 description 2
- PXBZKHOQHTVCSQ-QZTJIDSGSA-N 5-nitro-2-[(2r)-1-[2-[[(2r)-2-(5-nitro-1,3-dioxobenzo[de]isoquinolin-2-yl)propyl]amino]ethylamino]propan-2-yl]benzo[de]isoquinoline-1,3-dione Chemical compound [O-][N+](=O)C1=CC(C(N([C@@H](CNCCNC[C@@H](C)N2C(C=3C=C(C=C4C=CC=C(C=34)C2=O)[N+]([O-])=O)=O)C)C2=O)=O)=C3C2=CC=CC3=C1 PXBZKHOQHTVCSQ-QZTJIDSGSA-N 0.000 description 2
- KXBCLNRMQPRVTP-UHFFFAOYSA-N 6-amino-1,5-dihydroimidazo[4,5-c]pyridin-4-one Chemical compound O=C1NC(N)=CC2=C1N=CN2 KXBCLNRMQPRVTP-UHFFFAOYSA-N 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- RTHKPHCVZVYDFN-UHFFFAOYSA-N 9-amino-5-(2-aminopyrimidin-4-yl)pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-4-ol Chemical compound NC1=NC=CC(C=2C3=C(O)C=CN=C3N3C(N)=NC=CC3=2)=N1 RTHKPHCVZVYDFN-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 229930024421 Adenine Natural products 0.000 description 2
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 2
- 241000321096 Adenoides Species 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- QGZKDVFQNNGYKY-OUBTZVSYSA-N Ammonia-15N Chemical compound [15NH3] QGZKDVFQNNGYKY-OUBTZVSYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 2
- 206010003571 Astrocytoma Diseases 0.000 description 2
- 108010004586 Ataxia Telangiectasia Mutated Proteins Proteins 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- XHVAWZZCDCWGBK-WYRLRVFGSA-M Aurothioglucose Chemical compound OC[C@H]1O[C@H](S[Au])[C@H](O)[C@@H](O)[C@@H]1O XHVAWZZCDCWGBK-WYRLRVFGSA-M 0.000 description 2
- 208000003950 B-cell lymphoma Diseases 0.000 description 2
- 206010004146 Basal cell carcinoma Diseases 0.000 description 2
- 208000033929 Birt-Hogg-Dubé syndrome Diseases 0.000 description 2
- 108010006654 Bleomycin Proteins 0.000 description 2
- 108030001720 Bontoxilysin Proteins 0.000 description 2
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 2
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 2
- 244000056139 Brassica cretica Species 0.000 description 2
- 235000003351 Brassica cretica Nutrition 0.000 description 2
- 235000003343 Brassica rupestris Nutrition 0.000 description 2
- CIUUIPMOFZIWIZ-UHFFFAOYSA-N Bropirimine Chemical compound NC1=NC(O)=C(Br)C(C=2C=CC=CC=2)=N1 CIUUIPMOFZIWIZ-UHFFFAOYSA-N 0.000 description 2
- LDZJNMJIPNOYGA-UHFFFAOYSA-N C1=C(OC(C)=O)C(OC)=CC=C1C1=C2C3=CC(OC)=C(OC(C)=O)C=C3C=CN2C2=C1C(C=C(OC)C(OC(C)=O)=C1)=C1OC2=O Chemical compound C1=C(OC(C)=O)C(OC)=CC=C1C1=C2C3=CC(OC)=C(OC(C)=O)C=C3C=CN2C2=C1C(C=C(OC)C(OC(C)=O)=C1)=C1OC2=O LDZJNMJIPNOYGA-UHFFFAOYSA-N 0.000 description 2
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 2
- KORNTPPJEAJQIU-KJXAQDMKSA-N Cabaser Chemical compound C1=CC([C@H]2C[C@H](CN(CC=C)[C@@H]2C2)C(=O)N(CCCN(C)C)C(=O)NCC)=C3C2=CNC3=C1 KORNTPPJEAJQIU-KJXAQDMKSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 201000000274 Carcinosarcoma Diseases 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- 102000053642 Catalytic RNA Human genes 0.000 description 2
- 108090000994 Catalytic RNA Proteins 0.000 description 2
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 241000191368 Chlorobi Species 0.000 description 2
- 241000272194 Ciconiiformes Species 0.000 description 2
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 2
- GDLIGKIOYRNHDA-UHFFFAOYSA-N Clomipramine Chemical compound C1CC2=CC=C(Cl)C=C2N(CCCN(C)C)C2=CC=CC=C21 GDLIGKIOYRNHDA-UHFFFAOYSA-N 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 2
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 2
- VWLHWLSRQJQWRG-UHFFFAOYSA-O Edrophonum Chemical compound CC[N+](C)(C)C1=CC=CC(O)=C1 VWLHWLSRQJQWRG-UHFFFAOYSA-O 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- LMHIPJMTZHDKEW-XQYLJSSYSA-M Epoprostenol sodium Chemical compound [Na+].O1\C(=C/CCCC([O-])=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 LMHIPJMTZHDKEW-XQYLJSSYSA-M 0.000 description 2
- 241000283086 Equidae Species 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108060006662 GSK3 Proteins 0.000 description 2
- 102000001267 GSK3 Human genes 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- 208000007882 Gastritis Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 108010024636 Glutathione Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- 208000009329 Graft vs Host Disease Diseases 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 208000023329 Gun shot wound Diseases 0.000 description 2
- 101000783681 Homo sapiens 5'-AMP-activated protein kinase catalytic subunit alpha-2 Proteins 0.000 description 2
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 2
- 101000864057 Homo sapiens Serine/threonine-protein kinase SMG1 Proteins 0.000 description 2
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 2
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 2
- 206010060708 Induration Diseases 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- UBORTCNDUKBEOP-UHFFFAOYSA-N L-xanthosine Natural products OC1C(O)C(CO)OC1N1C(NC(=O)NC2=O)=C2N=C1 UBORTCNDUKBEOP-UHFFFAOYSA-N 0.000 description 2
- 201000005099 Langerhans cell histiocytosis Diseases 0.000 description 2
- 208000007177 Left Ventricular Hypertrophy Diseases 0.000 description 2
- 208000018142 Leiomyosarcoma Diseases 0.000 description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 2
- 108010000817 Leuprolide Proteins 0.000 description 2
- 208000022010 Lhermitte-Duclos disease Diseases 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 108091054455 MAP kinase family Proteins 0.000 description 2
- 102000043136 MAP kinase family Human genes 0.000 description 2
- 108010074954 MP4 maleimide-polyethylene glycol-modified hemoglobin Proteins 0.000 description 2
- 229930126263 Maytansine Natural products 0.000 description 2
- OCJYIGYOJCODJL-UHFFFAOYSA-N Meclizine Chemical compound CC1=CC=CC(CN2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC(Cl)=CC=2)=C1 OCJYIGYOJCODJL-UHFFFAOYSA-N 0.000 description 2
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 2
- 208000003351 Melanosis Diseases 0.000 description 2
- 206010027406 Mesothelioma Diseases 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 208000034486 Multi-organ failure Diseases 0.000 description 2
- 208000010718 Multiple Organ Failure Diseases 0.000 description 2
- 208000014767 Myeloproliferative disease Diseases 0.000 description 2
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 2
- LYPFDBRUNKHDGX-SOGSVHMOSA-N N1C2=CC=C1\C(=C1\C=CC(=N1)\C(=C1\C=C/C(/N1)=C(/C1=N/C(/CC1)=C2/C1=CC(O)=CC=C1)C1=CC(O)=CC=C1)\C1=CC(O)=CC=C1)C1=CC(O)=CC=C1 Chemical compound N1C2=CC=C1\C(=C1\C=CC(=N1)\C(=C1\C=C/C(/N1)=C(/C1=N/C(/CC1)=C2/C1=CC(O)=CC=C1)C1=CC(O)=CC=C1)\C1=CC(O)=CC=C1)C1=CC(O)=CC=C1 LYPFDBRUNKHDGX-SOGSVHMOSA-N 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- 206010052399 Neuroendocrine tumour Diseases 0.000 description 2
- 208000003019 Neurofibromatosis 1 Diseases 0.000 description 2
- 208000024834 Neurofibromatosis type 1 Diseases 0.000 description 2
- 239000008979 Niprisan Substances 0.000 description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 2
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 description 2
- 206010053159 Organ failure Diseases 0.000 description 2
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 description 2
- 102000014160 PTEN Phosphohydrolase Human genes 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 206010033645 Pancreatitis Diseases 0.000 description 2
- DPWPWRLQFGFJFI-UHFFFAOYSA-N Pargyline Chemical compound C#CCN(C)CC1=CC=CC=C1 DPWPWRLQFGFJFI-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 206010034764 Peutz-Jeghers syndrome Diseases 0.000 description 2
- RMUCZJUITONUFY-UHFFFAOYSA-N Phenelzine Chemical compound NNCCC1=CC=CC=C1 RMUCZJUITONUFY-UHFFFAOYSA-N 0.000 description 2
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 2
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 208000008601 Polycythemia Diseases 0.000 description 2
- 208000007541 Preleukemia Diseases 0.000 description 2
- 206010036790 Productive cough Diseases 0.000 description 2
- 229940123924 Protein kinase C inhibitor Drugs 0.000 description 2
- 208000007531 Proteus syndrome Diseases 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- 206010063837 Reperfusion injury Diseases 0.000 description 2
- 208000007014 Retinitis pigmentosa Diseases 0.000 description 2
- 206010039085 Rhinitis allergic Diseases 0.000 description 2
- OWPCHSCAPHNHAV-UHFFFAOYSA-N Rhizoxin Natural products C1C(O)C2(C)OC2C=CC(C)C(OC(=O)C2)CC2CC2OC2C(=O)OC1C(C)C(OC)C(C)=CC=CC(C)=CC1=COC(C)=N1 OWPCHSCAPHNHAV-UHFFFAOYSA-N 0.000 description 2
- 206010039203 Road traffic accident Diseases 0.000 description 2
- 206010040070 Septic Shock Diseases 0.000 description 2
- 101710181599 Serine/threonine-protein kinase STK11 Proteins 0.000 description 2
- 102100023085 Serine/threonine-protein kinase mTOR Human genes 0.000 description 2
- 208000004346 Smoldering Multiple Myeloma Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
- 108010050144 Triptorelin Pamoate Proteins 0.000 description 2
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 description 2
- 108010004977 Vasopressins Proteins 0.000 description 2
- 102000002852 Vasopressins Human genes 0.000 description 2
- 241000863480 Vinca Species 0.000 description 2
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 2
- UBORTCNDUKBEOP-HAVMAKPUSA-N Xanthosine Natural products O[C@@H]1[C@H](O)[C@H](CO)O[C@H]1N1C(NC(=O)NC2=O)=C2N=C1 UBORTCNDUKBEOP-HAVMAKPUSA-N 0.000 description 2
- YYBNDIVPHIWTPK-KYJQVDHRSA-N [(3as,8bs)-3,4,8b-trimethyl-1,2,3,3a-tetrahydropyrrolo[2,3-b]indol-3-ium-7-yl] n-methylcarbamate;sulfate Chemical compound [O-]S([O-])(=O)=O.C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CC[NH+]2C.C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CC[NH+]2C YYBNDIVPHIWTPK-KYJQVDHRSA-N 0.000 description 2
- QPWBZVAOCWJTFK-UHFFFAOYSA-L [2-(azanidylmethyl)-3-hydroxy-2-(hydroxymethyl)propyl]azanide;cyclobutane-1,1-dicarboxylate;platinum(4+) Chemical compound [Pt+4].[NH-]CC(C[NH-])(CO)CO.[O-]C(=O)C1(C([O-])=O)CCC1 QPWBZVAOCWJTFK-UHFFFAOYSA-L 0.000 description 2
- ODEDPKNSRBCSDO-UHFFFAOYSA-N [2-(hexadecylsulfanylmethyl)-3-methoxypropyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCCSCC(COC)COP([O-])(=O)OCC[N+](C)(C)C ODEDPKNSRBCSDO-UHFFFAOYSA-N 0.000 description 2
- IKWTVSLWAPBBKU-UHFFFAOYSA-N a1010_sial Chemical compound O=[As]O[As]=O IKWTVSLWAPBBKU-UHFFFAOYSA-N 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 2
- 229960004176 aclarubicin Drugs 0.000 description 2
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 2
- SMPZPKRDRQOOHT-UHFFFAOYSA-N acronycine Chemical compound CN1C2=CC=CC=C2C(=O)C2=C1C(C=CC(C)(C)O1)=C1C=C2OC SMPZPKRDRQOOHT-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 229960000643 adenine Drugs 0.000 description 2
- 210000002534 adenoid Anatomy 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 125000002877 alkyl aryl group Chemical group 0.000 description 2
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 description 2
- 201000010105 allergic rhinitis Diseases 0.000 description 2
- 229960000473 altretamine Drugs 0.000 description 2
- WOLHOYHSEKDWQH-UHFFFAOYSA-N amantadine hydrochloride Chemical compound [Cl-].C1C(C2)CC3CC2CC1([NH3+])C3 WOLHOYHSEKDWQH-UHFFFAOYSA-N 0.000 description 2
- 229960001280 amantadine hydrochloride Drugs 0.000 description 2
- 229960000836 amitriptyline Drugs 0.000 description 2
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 2
- 229960000528 amlodipine Drugs 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 229960001220 amsacrine Drugs 0.000 description 2
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 238000002399 angioplasty Methods 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 229940125681 anticonvulsant agent Drugs 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 2
- 229960002594 arsenic trioxide Drugs 0.000 description 2
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- AYJRCSIUFZENHW-DEQYMQKBSA-L barium(2+);oxomethanediolate Chemical compound [Ba+2].[O-][14C]([O-])=O AYJRCSIUFZENHW-DEQYMQKBSA-L 0.000 description 2
- XFILPEOLDIKJHX-QYZOEREBSA-N batimastat Chemical compound C([C@@H](C(=O)NC)NC(=O)[C@H](CC(C)C)[C@H](CSC=1SC=CC=1)C(=O)NO)C1=CC=CC=C1 XFILPEOLDIKJHX-QYZOEREBSA-N 0.000 description 2
- 229950001858 batimastat Drugs 0.000 description 2
- 229940049706 benzodiazepine Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000005874 benzothiadiazolyl group Chemical group 0.000 description 2
- JSZILQVIPPROJI-UHFFFAOYSA-N benzquinamide Chemical compound C1CC2=CC(OC)=C(OC)C=C2C2N1CC(C(=O)N(CC)CC)C(OC(C)=O)C2 JSZILQVIPPROJI-UHFFFAOYSA-N 0.000 description 2
- 229940087430 biaxin Drugs 0.000 description 2
- 229960000997 bicalutamide Drugs 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 2
- 229950008548 bisantrene Drugs 0.000 description 2
- 229950002370 bisnafide Drugs 0.000 description 2
- 206010006007 bone sarcoma Diseases 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- GJPICJJJRGTNOD-UHFFFAOYSA-N bosentan Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 GJPICJJJRGTNOD-UHFFFAOYSA-N 0.000 description 2
- 229940053031 botulinum toxin Drugs 0.000 description 2
- 229940077737 brain-derived neurotrophic factor Drugs 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 229960001034 bromopride Drugs 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 229950009494 bropirimine Drugs 0.000 description 2
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 2
- 229960004596 cabergoline Drugs 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 239000000480 calcium channel blocker Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 229940097217 cardiac glycoside Drugs 0.000 description 2
- 239000002368 cardiac glycoside Substances 0.000 description 2
- BBZDXMBRAFTCAA-AREMUKBSSA-N carzelesin Chemical compound C1=2NC=C(C)C=2C([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)C3=CC4=CC=C(C=C4O3)N(CC)CC)=C2C=C1OC(=O)NC1=CC=CC=C1 BBZDXMBRAFTCAA-AREMUKBSSA-N 0.000 description 2
- 229950007509 carzelesin Drugs 0.000 description 2
- 210000002421 cell wall Anatomy 0.000 description 2
- 230000033077 cellular process Effects 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- NQGMIPUYCWIEAW-OVCLIPMQSA-N chembl1834105 Chemical compound O/N=C/C1=C(SC)C(OC)=CC(C=2N=CC=CC=2)=N1 NQGMIPUYCWIEAW-OVCLIPMQSA-N 0.000 description 2
- UKTAZPQNNNJVKR-KJGYPYNMSA-N chembl2368925 Chemical compound C1=CC=C2C(C(O[C@@H]3C[C@@H]4C[C@H]5C[C@@H](N4CC5=O)C3)=O)=CNC2=C1 UKTAZPQNNNJVKR-KJGYPYNMSA-N 0.000 description 2
- 239000007910 chewable tablet Substances 0.000 description 2
- 229960003260 chlorhexidine Drugs 0.000 description 2
- 229920005556 chlorobutyl Polymers 0.000 description 2
- 229960003677 chloroquine Drugs 0.000 description 2
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 2
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 2
- 229960001076 chlorpromazine Drugs 0.000 description 2
- 210000000349 chromosome Anatomy 0.000 description 2
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 2
- 229960002436 cladribine Drugs 0.000 description 2
- 229960001791 clebopride Drugs 0.000 description 2
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical class C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 2
- BTFHLQRNAMSNLC-UHFFFAOYSA-N clorgyline Chemical compound C#CCN(C)CCCOC1=CC=C(Cl)C=C1Cl BTFHLQRNAMSNLC-UHFFFAOYSA-N 0.000 description 2
- 229960004022 clotrimazole Drugs 0.000 description 2
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 2
- 229960003920 cocaine Drugs 0.000 description 2
- 239000000501 collagen implant Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000007819 coupling partner Substances 0.000 description 2
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 2
- 230000001351 cycling effect Effects 0.000 description 2
- 229960003564 cyclizine Drugs 0.000 description 2
- UVKZSORBKUEBAZ-UHFFFAOYSA-N cyclizine Chemical compound C1CN(C)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 UVKZSORBKUEBAZ-UHFFFAOYSA-N 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- ZQSIJRDFPHDXIC-UHFFFAOYSA-N daidzein Chemical compound C1=CC(O)=CC=C1C1=COC2=CC(O)=CC=C2C1=O ZQSIJRDFPHDXIC-UHFFFAOYSA-N 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 229960003603 decitabine Drugs 0.000 description 2
- 230000003412 degenerative effect Effects 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- RWZVPVOZTJJMNU-UHFFFAOYSA-N demarcarium Chemical compound C=1C=CC([N+](C)(C)C)=CC=1OC(=O)N(C)CCCCCCCCCCN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 RWZVPVOZTJJMNU-UHFFFAOYSA-N 0.000 description 2
- 229960004656 demecarium Drugs 0.000 description 2
- 229950010621 dezaguanine Drugs 0.000 description 2
- WVYXNIXAMZOZFK-UHFFFAOYSA-N diaziquone Chemical compound O=C1C(NC(=O)OCC)=C(N2CC2)C(=O)C(NC(=O)OCC)=C1N1CC1 WVYXNIXAMZOZFK-UHFFFAOYSA-N 0.000 description 2
- 229950002389 diaziquone Drugs 0.000 description 2
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 2
- 125000005047 dihydroimidazolyl group Chemical group N1(CNC=C1)* 0.000 description 2
- OTKJDMGTUTTYMP-UHFFFAOYSA-N dihydrosphingosine Natural products CCCCCCCCCCCCCCCC(O)C(N)CO OTKJDMGTUTTYMP-UHFFFAOYSA-N 0.000 description 2
- MZDOIJOUFRQXHC-UHFFFAOYSA-N dimenhydrinate Chemical compound O=C1N(C)C(=O)N(C)C2=NC(Cl)=N[C]21.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 MZDOIJOUFRQXHC-UHFFFAOYSA-N 0.000 description 2
- 229960004993 dimenhydrinate Drugs 0.000 description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- OGAKLTJNUQRZJU-UHFFFAOYSA-N diphenidol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)CCCN1CCCCC1 OGAKLTJNUQRZJU-UHFFFAOYSA-N 0.000 description 2
- 229960003520 diphenidol Drugs 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 2
- VZFDRQUWHOVFCA-UHFFFAOYSA-L disodium;2-sulfanylbutanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CC(S)C([O-])=O VZFDRQUWHOVFCA-UHFFFAOYSA-L 0.000 description 2
- 229960003413 dolasetron Drugs 0.000 description 2
- 229960001253 domperidone Drugs 0.000 description 2
- FGXWKSZFVQUSTL-UHFFFAOYSA-N domperidone Chemical compound C12=CC=CC=C2NC(=O)N1CCCN(CC1)CCC1N1C2=CC=C(Cl)C=C2NC1=O FGXWKSZFVQUSTL-UHFFFAOYSA-N 0.000 description 2
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 2
- 229940115080 doxil Drugs 0.000 description 2
- 229950004203 droloxifene Drugs 0.000 description 2
- 229960001776 edrecolomab Drugs 0.000 description 2
- 229960003748 edrophonium Drugs 0.000 description 2
- 210000004696 endometrium Anatomy 0.000 description 2
- JRURYQJSLYLRLN-BJMVGYQFSA-N entacapone Chemical compound CCN(CC)C(=O)C(\C#N)=C\C1=CC(O)=C(O)C([N+]([O-])=O)=C1 JRURYQJSLYLRLN-BJMVGYQFSA-N 0.000 description 2
- 229960003337 entacapone Drugs 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 2
- 229940011871 estrogen Drugs 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 229960000403 etanercept Drugs 0.000 description 2
- WCDWBPCFGJXFJZ-UHFFFAOYSA-N etanidazole Chemical compound OCCNC(=O)CN1C=CN=C1[N+]([O-])=O WCDWBPCFGJXFJZ-UHFFFAOYSA-N 0.000 description 2
- 229950006566 etanidazole Drugs 0.000 description 2
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 2
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 2
- 229960000752 etoposide phosphate Drugs 0.000 description 2
- 210000001508 eye Anatomy 0.000 description 2
- 229950011548 fadrozole Drugs 0.000 description 2
- NMUSYJAQQFHJEW-ARQDHWQXSA-N fazarabine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-ARQDHWQXSA-N 0.000 description 2
- 229950005096 fazarabine Drugs 0.000 description 2
- 229950003662 fenretinide Drugs 0.000 description 2
- 230000004761 fibrosis Effects 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 2
- 229960004039 finasteride Drugs 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- HKQYGTCOTHHOMP-UHFFFAOYSA-N formononetin Chemical compound C1=CC(OC)=CC=C1C1=COC2=CC(O)=CC=C2C1=O HKQYGTCOTHHOMP-UHFFFAOYSA-N 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 229960002870 gabapentin Drugs 0.000 description 2
- 201000007487 gallbladder carcinoma Diseases 0.000 description 2
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 description 2
- 229960002963 ganciclovir Drugs 0.000 description 2
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000009395 genetic defect Effects 0.000 description 2
- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
- 229940084910 gliadel Drugs 0.000 description 2
- 229960003180 glutathione Drugs 0.000 description 2
- 208000024908 graft versus host disease Diseases 0.000 description 2
- MFWNKCLOYSRHCJ-BTTYYORXSA-N granisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 description 2
- 229960003727 granisetron Drugs 0.000 description 2
- 210000003714 granulocyte Anatomy 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000000122 growth hormone Substances 0.000 description 2
- 229960004198 guanidine Drugs 0.000 description 2
- 230000003394 haemopoietic effect Effects 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 238000005534 hematocrit Methods 0.000 description 2
- 201000005787 hematologic cancer Diseases 0.000 description 2
- 208000014951 hematologic disease Diseases 0.000 description 2
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 2
- 230000002008 hemorrhagic effect Effects 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 231100000283 hepatitis Toxicity 0.000 description 2
- 125000005343 heterocyclic alkyl group Chemical group 0.000 description 2
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229960001330 hydroxycarbamide Drugs 0.000 description 2
- 229960000930 hydroxyzine Drugs 0.000 description 2
- ZQDWXGKKHFNSQK-UHFFFAOYSA-N hydroxyzine Chemical compound C1CN(CCOCCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZQDWXGKKHFNSQK-UHFFFAOYSA-N 0.000 description 2
- 229950006905 ilmofosine Drugs 0.000 description 2
- 125000005945 imidazopyridyl group Chemical group 0.000 description 2
- 230000002519 immonomodulatory effect Effects 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 2
- 239000000411 inducer Substances 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 229940047124 interferons Drugs 0.000 description 2
- YOSHYTLCDANDAN-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2NN=NN=2)C(CCCC)=NC21CCCC2 YOSHYTLCDANDAN-UHFFFAOYSA-N 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 229960002672 isocarboxazid Drugs 0.000 description 2
- 229960003350 isoniazid Drugs 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 229960000448 lactic acid Drugs 0.000 description 2
- 108010021336 lanreotide Proteins 0.000 description 2
- 210000000867 larynx Anatomy 0.000 description 2
- 201000010260 leiomyoma Diseases 0.000 description 2
- 229960003881 letrozole Drugs 0.000 description 2
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 2
- 229960004338 leuprorelin Drugs 0.000 description 2
- 229960004502 levodopa Drugs 0.000 description 2
- 206010024627 liposarcoma Diseases 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 210000001165 lymph node Anatomy 0.000 description 2
- 208000019420 lymphoid neoplasm Diseases 0.000 description 2
- 229940124302 mTOR inhibitor Drugs 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 210000001161 mammalian embryo Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 2
- 229960001474 meclozine Drugs 0.000 description 2
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 206010027191 meningioma Diseases 0.000 description 2
- LWYJUZBXGAFFLP-OCNCTQISSA-N menogaril Chemical compound O1[C@@]2(C)[C@H](O)[C@@H](N(C)C)[C@H](O)[C@@H]1OC1=C3C(=O)C(C=C4C[C@@](C)(O)C[C@H](C4=C4O)OC)=C4C(=O)C3=C(O)C=C12 LWYJUZBXGAFFLP-OCNCTQISSA-N 0.000 description 2
- 229950002676 menogaril Drugs 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- XMQICEWOKPEQRG-UHFFFAOYSA-N methallatal Chemical compound CC(=C)CC1(CC)C(=O)NC(=S)NC1=O XMQICEWOKPEQRG-UHFFFAOYSA-N 0.000 description 2
- 229950010373 methallatal Drugs 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- IYETZZCWLLUHIJ-UHFFFAOYSA-N methyl-(1-phenylpropan-2-yl)-prop-2-ynylazanium;chloride Chemical compound Cl.C#CCN(C)C(C)CC1=CC=CC=C1 IYETZZCWLLUHIJ-UHFFFAOYSA-N 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 229960000282 metronidazole Drugs 0.000 description 2
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229960004857 mitomycin Drugs 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- JFOHFDSMPQIOES-UHFFFAOYSA-N motexafin Chemical compound C1=NC2=CC(OCCOCCOCCOC)=C(OCCOCCOCCOC)C=C2N=CC(C(=C2CCCO)C)=NC2=CC(C(CC)=C2CC)=NC2=CC2=C(CCCO)C(C)=C1N2 JFOHFDSMPQIOES-UHFFFAOYSA-N 0.000 description 2
- 229950011637 motexafin Drugs 0.000 description 2
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 235000010460 mustard Nutrition 0.000 description 2
- 206010028537 myelofibrosis Diseases 0.000 description 2
- 208000025113 myeloid leukemia Diseases 0.000 description 2
- NJSMWLQOCQIOPE-OCHFTUDZSA-N n-[(e)-[10-[(e)-(4,5-dihydro-1h-imidazol-2-ylhydrazinylidene)methyl]anthracen-9-yl]methylideneamino]-4,5-dihydro-1h-imidazol-2-amine Chemical compound N1CCN=C1N\N=C\C(C1=CC=CC=C11)=C(C=CC=C2)C2=C1\C=N\NC1=NCCN1 NJSMWLQOCQIOPE-OCHFTUDZSA-N 0.000 description 2
- NFVJNJQRWPQVOA-UHFFFAOYSA-N n-[2-chloro-5-(trifluoromethyl)phenyl]-2-[3-(4-ethyl-5-ethylsulfanyl-1,2,4-triazol-3-yl)piperidin-1-yl]acetamide Chemical compound CCN1C(SCC)=NN=C1C1CN(CC(=O)NC=2C(=CC=C(C=2)C(F)(F)F)Cl)CCC1 NFVJNJQRWPQVOA-UHFFFAOYSA-N 0.000 description 2
- JTSLALYXYSRPGW-UHFFFAOYSA-N n-[5-(4-cyanophenyl)-1h-pyrrolo[2,3-b]pyridin-3-yl]pyridine-3-carboxamide Chemical compound C=1C=CN=CC=1C(=O)NC(C1=C2)=CNC1=NC=C2C1=CC=C(C#N)C=C1 JTSLALYXYSRPGW-UHFFFAOYSA-N 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- GECBBEABIDMGGL-RTBURBONSA-N nabilone Chemical compound C1C(=O)CC[C@H]2C(C)(C)OC3=CC(C(C)(C)CCCCCC)=CC(O)=C3[C@@H]21 GECBBEABIDMGGL-RTBURBONSA-N 0.000 description 2
- 229960002967 nabilone Drugs 0.000 description 2
- 210000003739 neck Anatomy 0.000 description 2
- OSZNNLWOYWAHSS-UHFFFAOYSA-M neostigmine methyl sulfate Chemical compound COS([O-])(=O)=O.CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 OSZNNLWOYWAHSS-UHFFFAOYSA-M 0.000 description 2
- 201000008383 nephritis Diseases 0.000 description 2
- 210000003757 neuroblast Anatomy 0.000 description 2
- 229940072228 neurontin Drugs 0.000 description 2
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 2
- 229960001597 nifedipine Drugs 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
- LVRLSYPNFFBYCZ-VGWMRTNUSA-N omapatrilat Chemical compound C([C@H](S)C(=O)N[C@H]1CCS[C@H]2CCC[C@H](N2C1=O)C(=O)O)C1=CC=CC=C1 LVRLSYPNFFBYCZ-VGWMRTNUSA-N 0.000 description 2
- 239000000082 organ preservation Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229950008017 ormaplatin Drugs 0.000 description 2
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 229960001779 pargyline Drugs 0.000 description 2
- 229960001744 pegaspargase Drugs 0.000 description 2
- 108010001564 pegaspargase Proteins 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- VPAWVRUHMJVRHU-VGDKGRGNSA-N perfosfamide Chemical compound OO[C@@H]1CCO[P@@](=O)(N(CCCl)CCCl)N1 VPAWVRUHMJVRHU-VGDKGRGNSA-N 0.000 description 2
- 229950009351 perfosfamide Drugs 0.000 description 2
- UWCVGPLTGZWHGS-ZORIOUSZSA-N pergolide mesylate Chemical compound CS(O)(=O)=O.C1=CC([C@H]2C[C@@H](CSC)CN([C@@H]2C2)CCC)=C3C2=CNC3=C1 UWCVGPLTGZWHGS-ZORIOUSZSA-N 0.000 description 2
- NDTYTMIUWGWIMO-UHFFFAOYSA-N perillyl alcohol Chemical compound CC(=C)C1CCC(CO)=CC1 NDTYTMIUWGWIMO-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229960000964 phenelzine Drugs 0.000 description 2
- 229960001847 physostigmine sulfate Drugs 0.000 description 2
- OSJJYEUEJRVVOD-UHFFFAOYSA-N pipamazine Chemical compound C1CC(C(=O)N)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 OSJJYEUEJRVVOD-UHFFFAOYSA-N 0.000 description 2
- 229950008580 pipamazine Drugs 0.000 description 2
- 230000003169 placental effect Effects 0.000 description 2
- 150000003058 platinum compounds Chemical class 0.000 description 2
- 208000030761 polycystic kidney disease Diseases 0.000 description 2
- 229960004293 porfimer sodium Drugs 0.000 description 2
- 229960002652 pramipexole dihydrochloride Drugs 0.000 description 2
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 2
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 2
- 229960000624 procarbazine Drugs 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- WIKYUJGCLQQFNW-UHFFFAOYSA-N prochlorperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 WIKYUJGCLQQFNW-UHFFFAOYSA-N 0.000 description 2
- 229960003111 prochlorperazine Drugs 0.000 description 2
- 229960003910 promethazine Drugs 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 239000003881 protein kinase C inhibitor Substances 0.000 description 2
- 201000003456 pulmonary hemosiderosis Diseases 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 125000006085 pyrrolopyridyl group Chemical group 0.000 description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- 125000005493 quinolyl group Chemical group 0.000 description 2
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 2
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000000306 recurrent effect Effects 0.000 description 2
- 229940118867 remodulin Drugs 0.000 description 2
- OWPCHSCAPHNHAV-LMONGJCWSA-N rhizoxin Chemical compound C/C([C@H](OC)[C@@H](C)[C@@H]1C[C@H](O)[C@]2(C)O[C@@H]2/C=C/[C@@H](C)[C@]2([H])OC(=O)C[C@@](C2)(C[C@@H]2O[C@H]2C(=O)O1)[H])=C\C=C\C(\C)=C\C1=COC(C)=N1 OWPCHSCAPHNHAV-LMONGJCWSA-N 0.000 description 2
- 108091092562 ribozyme Proteins 0.000 description 2
- 229960004641 rituximab Drugs 0.000 description 2
- MOCVYVBNJQIVOV-TVQRCGJNSA-N rohitukine Chemical compound O[C@@H]1CN(C)CC[C@@H]1C1=C(O)C=C(O)C2=C1OC(C)=CC2=O MOCVYVBNJQIVOV-TVQRCGJNSA-N 0.000 description 2
- 229950008902 safingol Drugs 0.000 description 2
- CGFVUVWMYIHGHS-UHFFFAOYSA-N saintopin Chemical compound C1=C(O)C=C2C=C(C(=O)C=3C(=C(O)C=C(C=3)O)C3=O)C3=C(O)C2=C1O CGFVUVWMYIHGHS-UHFFFAOYSA-N 0.000 description 2
- 229930182490 saponin Natural products 0.000 description 2
- 235000017709 saponins Nutrition 0.000 description 2
- 229960003678 selegiline hydrochloride Drugs 0.000 description 2
- 229960003440 semustine Drugs 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 2
- 229960002930 sirolimus Drugs 0.000 description 2
- 208000010721 smoldering plasma cell myeloma Diseases 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 229940063675 spermine Drugs 0.000 description 2
- PFNFFQXMRSDOHW-UHFFFAOYSA-N spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 description 2
- 229950006050 spiromustine Drugs 0.000 description 2
- 208000024794 sputum Diseases 0.000 description 2
- 210000003802 sputum Anatomy 0.000 description 2
- 238000011301 standard therapy Methods 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 229930002534 steroid glycoside Natural products 0.000 description 2
- 150000008143 steroidal glycosides Chemical class 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 229960004940 sulpiride Drugs 0.000 description 2
- 239000002511 suppository base Substances 0.000 description 2
- 229960005314 suramin Drugs 0.000 description 2
- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 229960001685 tacrine Drugs 0.000 description 2
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 2
- WOXKDUGGOYFFRN-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 WOXKDUGGOYFFRN-IIBYNOLFSA-N 0.000 description 2
- 229960001674 tegafur Drugs 0.000 description 2
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 2
- 229940061353 temodar Drugs 0.000 description 2
- 229960002197 temoporfin Drugs 0.000 description 2
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 2
- 229960001278 teniposide Drugs 0.000 description 2
- VQMNWIMYFHHFMC-UHFFFAOYSA-N tert-butyl 4-hydroxyindole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC(C)(C)C)C=CC2=C1O VQMNWIMYFHHFMC-UHFFFAOYSA-N 0.000 description 2
- 229960005333 tetrabenazine Drugs 0.000 description 2
- 229960002180 tetracycline Drugs 0.000 description 2
- 229930101283 tetracycline Natural products 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- VZYCZNZBPPHOFY-UHFFFAOYSA-N thioproperazine Chemical compound C12=CC(S(=O)(=O)N(C)C)=CC=C2SC2=CC=CC=C2N1CCCN1CCN(C)CC1 VZYCZNZBPPHOFY-UHFFFAOYSA-N 0.000 description 2
- 229960003397 thioproperazine Drugs 0.000 description 2
- 210000001541 thymus gland Anatomy 0.000 description 2
- MIQPIUSUKVNLNT-UHFFFAOYSA-N tolcapone Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC(O)=C(O)C([N+]([O-])=O)=C1 MIQPIUSUKVNLNT-UHFFFAOYSA-N 0.000 description 2
- 229960004603 tolcapone Drugs 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 2
- 229960000303 topotecan Drugs 0.000 description 2
- TVPNFKRGOFJQOO-UHFFFAOYSA-N topsentin b1 Chemical compound C1=CC=C2C(C3=CN=C(N3)C(=O)C=3C4=CC=C(C=C4NC=3)O)=CNC2=C1 TVPNFKRGOFJQOO-UHFFFAOYSA-N 0.000 description 2
- 229960005267 tositumomab Drugs 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
- 230000008736 traumatic injury Effects 0.000 description 2
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 2
- 229960005032 treprostinil Drugs 0.000 description 2
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 description 2
- IQKAWAUTOKVMLE-ZSESPEEFSA-M treprostinil sodium Chemical compound [Na+].C1=CC=C(OCC([O-])=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 IQKAWAUTOKVMLE-ZSESPEEFSA-M 0.000 description 2
- FEZBIKUBAYAZIU-UHFFFAOYSA-N trimethobenzamide Chemical compound COC1=C(OC)C(OC)=CC(C(=O)NCC=2C=CC(OCCN(C)C)=CC=2)=C1 FEZBIKUBAYAZIU-UHFFFAOYSA-N 0.000 description 2
- 229960004161 trimethobenzamide Drugs 0.000 description 2
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 2
- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 description 2
- 229960004824 triptorelin Drugs 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
- 229960002730 vapreotide Drugs 0.000 description 2
- 108700029852 vapreotide Proteins 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 229960003726 vasopressin Drugs 0.000 description 2
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 2
- 229960003048 vinblastine Drugs 0.000 description 2
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 2
- QMSXPSURJTUZMP-UHFFFAOYSA-N vincine Chemical compound COC1=CC=C2C(CCN3CCC4)=C5C3C4(CC)CC(O)(C(=O)OC)N5C2=C1 QMSXPSURJTUZMP-UHFFFAOYSA-N 0.000 description 2
- 229960004528 vincristine Drugs 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 2
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 2
- UBORTCNDUKBEOP-UUOKFMHZSA-N xanthosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(NC(=O)NC2=O)=C2N=C1 UBORTCNDUKBEOP-UUOKFMHZSA-N 0.000 description 2
- 229950003017 zeniplatin Drugs 0.000 description 2
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 2
- 229960004276 zoledronic acid Drugs 0.000 description 2
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical class C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 1
- OPFTUNCRGUEPRZ-UHFFFAOYSA-N (+)-beta-Elemen Natural products CC(=C)C1CCC(C)(C=C)C(C(C)=C)C1 OPFTUNCRGUEPRZ-UHFFFAOYSA-N 0.000 description 1
- BMKDZUISNHGIBY-ZETCQYMHSA-N (+)-dexrazoxane Chemical compound C([C@H](C)N1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-ZETCQYMHSA-N 0.000 description 1
- XEEQGYMUWCZPDN-DOMZBBRYSA-N (-)-(11S,2'R)-erythro-mefloquine Chemical compound C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-DOMZBBRYSA-N 0.000 description 1
- OPFTUNCRGUEPRZ-QLFBSQMISA-N (-)-beta-elemene Chemical compound CC(=C)[C@@H]1CC[C@@](C)(C=C)[C@H](C(C)=C)C1 OPFTUNCRGUEPRZ-QLFBSQMISA-N 0.000 description 1
- GCPUVEMWOWMALU-HZMBPMFUSA-N (1s,3s)-1-hydroxy-8-methoxy-3-methyl-1,2,3,4-tetrahydrobenzo[a]anthracene-7,12-dione Chemical compound C1[C@H](C)C[C@H](O)C2=C1C=CC1=C2C(=O)C(C=CC=C2OC)=C2C1=O GCPUVEMWOWMALU-HZMBPMFUSA-N 0.000 description 1
- QOWBXWFYRXSBAS-UHFFFAOYSA-N (2,4-dimethoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C(OC)=C1 QOWBXWFYRXSBAS-UHFFFAOYSA-N 0.000 description 1
- PNVPNXKRAUBJGW-UHFFFAOYSA-N (2-chloroacetyl) 2-chloroacetate Chemical compound ClCC(=O)OC(=O)CCl PNVPNXKRAUBJGW-UHFFFAOYSA-N 0.000 description 1
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- BUSGWUFLNHIBPT-XYBORKQMSA-N (2e,4e,6e)-7-[(1r,5r,6s)-3-[[(2e,4e)-5-cyclohexylpenta-2,4-dienoyl]amino]-5-hydroxy-2-oxo-7-oxabicyclo[4.1.0]hept-3-en-5-yl]hepta-2,4,6-trienoic acid Chemical compound C([C@]([C@H]1O[C@H]1C1=O)(O)/C=C/C=C/C=C/C(=O)O)=C1NC(=O)\C=C\C=C\C1CCCCC1 BUSGWUFLNHIBPT-XYBORKQMSA-N 0.000 description 1
- LCADVYTXPLBAGB-AUQKUMLUSA-N (2e,4e,6z,8e,10e,14e)-13-hydroxy-n-(1-hydroxypropan-2-yl)-2,10,12,14,16-pentamethyl-18-phenyloctadeca-2,4,6,8,10,14-hexaenamide Chemical compound OCC(C)NC(=O)C(\C)=C\C=C\C=C/C=C/C(/C)=C/C(C)C(O)C(\C)=C\C(C)CCC1=CC=CC=C1 LCADVYTXPLBAGB-AUQKUMLUSA-N 0.000 description 1
- VLPIATFUUWWMKC-SNVBAGLBSA-N (2r)-1-(2,6-dimethylphenoxy)propan-2-amine Chemical compound C[C@@H](N)COC1=C(C)C=CC=C1C VLPIATFUUWWMKC-SNVBAGLBSA-N 0.000 description 1
- FKHUGQZRBPETJR-RXSRXONKSA-N (2r)-2-[[(4r)-4-[[(2s)-2-[[(2r)-2-[(3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxypropanoyl]amino]propanoyl]amino]-5-amino-5-oxopentanoyl]amino]-6-(octadecanoylamino)hexanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(=O)NCCCC[C@H](C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](C)O[C@H]1[C@H](O)[C@@H](CO)OC(O)[C@@H]1NC(C)=O FKHUGQZRBPETJR-RXSRXONKSA-N 0.000 description 1
- SWTGJCNCBUCXSS-ISUZDFFFSA-N (2r)-3,4-dihydroxy-2-[(4s)-2-phenyl-1,3-dioxolan-4-yl]-2h-furan-5-one Chemical compound OC1=C(O)C(=O)O[C@@H]1[C@H]1OC(C=2C=CC=CC=2)OC1 SWTGJCNCBUCXSS-ISUZDFFFSA-N 0.000 description 1
- RCGXNDQKCXNWLO-WLEIXIPESA-N (2r)-n-[(2s)-5-amino-1-[[(2r,3r)-1-[[(3s,6z,9s,12r,15r,18r,19s)-9-benzyl-15-[(2r)-butan-2-yl]-6-ethylidene-19-methyl-2,5,8,11,14,17-hexaoxo-3,12-di(propan-2-yl)-1-oxa-4,7,10,13,16-pentazacyclononadec-18-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxopent Chemical compound N([C@@H](CCCN)C(=O)N[C@H]([C@H](C)CC)C(=O)N[C@H]1C(N[C@@H](C(=O)N[C@@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)NC(/C(=O)N[C@H](C(=O)O[C@H]1C)C(C)C)=C\C)C(C)C)[C@H](C)CC)=O)C(=O)[C@H]1CCCN1C(=O)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](NC(=O)CCCC(C)C)C(C)C)[C@@H](C)O)C(C)C)C(C)C RCGXNDQKCXNWLO-WLEIXIPESA-N 0.000 description 1
- PAYBYKKERMGTSS-MNCSTQPFSA-N (2r,3r,3as,9ar)-7-fluoro-2-(hydroxymethyl)-6-imino-2,3,3a,9a-tetrahydrofuro[1,2][1,3]oxazolo[3,4-a]pyrimidin-3-ol Chemical compound N=C1C(F)=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 PAYBYKKERMGTSS-MNCSTQPFSA-N 0.000 description 1
- NDQQRRVKUBPTHQ-QBIQUQHTSA-N (2r,3r,4r,5s)-6-(methylamino)hexane-1,2,3,4,5-pentol Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO NDQQRRVKUBPTHQ-QBIQUQHTSA-N 0.000 description 1
- WDQLRUYAYXDIFW-RWKIJVEZSA-N (2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-4-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1 WDQLRUYAYXDIFW-RWKIJVEZSA-N 0.000 description 1
- NOENHWMKHNSHGX-IZOOSHNJSA-N (2s)-1-[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-6-(ca Chemical compound C([C@H](C(=O)N[C@H](CCCCNC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 NOENHWMKHNSHGX-IZOOSHNJSA-N 0.000 description 1
- ZZKNRXZVGOYGJT-VKHMYHEASA-N (2s)-2-[(2-phosphonoacetyl)amino]butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)CP(O)(O)=O ZZKNRXZVGOYGJT-VKHMYHEASA-N 0.000 description 1
- XDZGQQRZJDKPTG-HBNQUELISA-N (2s)-2-[(3s,6s)-6-[2-[(1r,2r,4as,8as)-1-hydroxy-2,4a,5,5,8a-pentamethyl-2,3,4,6,7,8-hexahydronaphthalen-1-yl]ethyl]-6-methyldioxan-3-yl]propanoic acid Chemical compound O1O[C@H]([C@H](C)C(O)=O)CC[C@@]1(C)CC[C@]1(O)[C@@]2(C)CCCC(C)(C)[C@]2(C)CC[C@H]1C XDZGQQRZJDKPTG-HBNQUELISA-N 0.000 description 1
- CUCSSYAUKKIDJV-FAXBSAIASA-N (2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-[[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1h-indol-3-yl)propanoyl]-methylamino]-3-phenylpropanoyl]amino]-3-(1h-indol-3-yl)propanoyl]amino]-n-[(2s)-1-amino-4-methylsulfanyl-1-oxobutan-2-yl]-4-methylpent Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)N(C)C(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CUCSSYAUKKIDJV-FAXBSAIASA-N 0.000 description 1
- ZUQBAQVRAURMCL-DOMZBBRYSA-N (2s)-2-[[4-[2-[(6r)-2-amino-4-oxo-5,6,7,8-tetrahydro-1h-pyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl]amino]pentanedioic acid Chemical compound C([C@@H]1CC=2C(=O)N=C(NC=2NC1)N)CC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZUQBAQVRAURMCL-DOMZBBRYSA-N 0.000 description 1
- JRBXPUUAYKCCLQ-QMMMGPOBSA-N (2s)-2-amino-2-[3-hydroxy-4-(hydroxymethyl)phenyl]acetic acid Chemical compound OC(=O)[C@@H](N)C1=CC=C(CO)C(O)=C1 JRBXPUUAYKCCLQ-QMMMGPOBSA-N 0.000 description 1
- HJNZCKLMRAOTMA-BRBGIFQRSA-N (2s)-n-[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2r)-1-[[(2s)-1-[[(2s)-5-(diaminomethylideneamino)-1-[(2s)-2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(2-methyl-1h-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(4-hydr Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=C(C)NC2=CC=CC=C12 HJNZCKLMRAOTMA-BRBGIFQRSA-N 0.000 description 1
- NAALWFYYHHJEFQ-ZASNTINBSA-N (2s,5r,6r)-6-[[(2r)-2-[[6-[4-[bis(2-hydroxyethyl)sulfamoyl]phenyl]-2-oxo-1h-pyridine-3-carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC(O)=CC=1)C(=O)C(C(N1)=O)=CC=C1C1=CC=C(S(=O)(=O)N(CCO)CCO)C=C1 NAALWFYYHHJEFQ-ZASNTINBSA-N 0.000 description 1
- RDIMTXDFGHNINN-UHFFFAOYSA-N (3R,9R,10R)-1-heptadecen-4,6-diyne-3,9,10-triol Natural products CCCCCCCC(O)C(O)CC#CC#CC(O)C=C RDIMTXDFGHNINN-UHFFFAOYSA-N 0.000 description 1
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 description 1
- BXBSPTIDIMGJNO-YZPBMOCRSA-N (3r,4s,5s,6r,7r,9r,11r,12r,13s,14r)-6-[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-7,12,13-trihydroxy-4-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-dione;hydro Chemical compound Cl.O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 BXBSPTIDIMGJNO-YZPBMOCRSA-N 0.000 description 1
- FRCJDPPXHQGEKS-BCHFMIIMSA-N (4S,5R)-N-[4-[(2,3-dihydroxybenzoyl)amino]butyl]-N-[3-[(2,3-dihydroxybenzoyl)amino]propyl]-2-(2-hydroxyphenyl)-5-methyl-4,5-dihydro-1,3-oxazole-4-carboxamide Chemical compound C[C@H]1OC(=N[C@@H]1C(=O)N(CCCCNC(=O)c1cccc(O)c1O)CCCNC(=O)c1cccc(O)c1O)c1ccccc1O FRCJDPPXHQGEKS-BCHFMIIMSA-N 0.000 description 1
- GTEXXGIEZVKSLH-YPMHNXCESA-N (4as,12br)-8,10-dihydroxy-2,5,5,9-tetramethyl-3,4,4a,12b-tetrahydronaphtho[2,3-c]isochromene-7,12-dione Chemical compound O=C1C2=CC(O)=C(C)C(O)=C2C(=O)C2=C1[C@@H]1C=C(C)CC[C@@H]1C(C)(C)O2 GTEXXGIEZVKSLH-YPMHNXCESA-N 0.000 description 1
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 1
- PUDHBTGHUJUUFI-SCTWWAJVSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-p Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 PUDHBTGHUJUUFI-SCTWWAJVSA-N 0.000 description 1
- WTSKMKRYHATLLL-UHFFFAOYSA-N (6-benzoyloxy-3-cyanopyridin-2-yl) 3-[3-(ethoxymethyl)-5-fluoro-2,6-dioxopyrimidine-1-carbonyl]benzoate Chemical compound O=C1N(COCC)C=C(F)C(=O)N1C(=O)C1=CC=CC(C(=O)OC=2C(=CC=C(OC(=O)C=3C=CC=CC=3)N=2)C#N)=C1 WTSKMKRYHATLLL-UHFFFAOYSA-N 0.000 description 1
- MSTNYGQPCMXVAQ-RYUDHWBXSA-N (6S)-5,6,7,8-tetrahydrofolic acid Chemical compound C([C@H]1CNC=2N=C(NC(=O)C=2N1)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-RYUDHWBXSA-N 0.000 description 1
- YSGQGNQWBLYHPE-CFUSNLFHSA-N (7r,8r,9s,10r,13s,14s,17s)-17-hydroxy-7,13-dimethyl-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-one Chemical compound C1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2[C@H](C)CC3=CC(=O)CC[C@@H]3[C@H]21 YSGQGNQWBLYHPE-CFUSNLFHSA-N 0.000 description 1
- LKBBOPGQDRPCDS-YAOXHJNESA-N (7s,9r,10r)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-9-ethyl-4,6,9,10,11-pentahydroxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound O([C@H]1C[C@]([C@@H](C2=C(O)C=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)O)(O)CC)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 LKBBOPGQDRPCDS-YAOXHJNESA-N 0.000 description 1
- GYPCWHHQAVLMKO-XXKQIVDLSA-N (7s,9s)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-[(e)-n-[(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-ylidene)amino]-c-methylcarbonimidoyl]-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical group Cl.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(\C)=N\N=C1CC(C)(C)N(O)C(C)(C)C1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 GYPCWHHQAVLMKO-XXKQIVDLSA-N 0.000 description 1
- RCFNNLSZHVHCEK-YGCMNLPTSA-N (7s,9s)-7-[(2s,4r,6s)-4-amino-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.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[C@H](C)O1 RCFNNLSZHVHCEK-YGCMNLPTSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- VHZXNQKVFDBFIK-NBBHSKLNSA-N (8r,9s,10r,13s,14s,16r)-16-fluoro-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one Chemical compound C1CCC[C@]2(C)[C@H]3CC[C@](C)(C([C@H](F)C4)=O)[C@@H]4[C@@H]3CC=C21 VHZXNQKVFDBFIK-NBBHSKLNSA-N 0.000 description 1
- MHFRGQHAERHWKZ-HHHXNRCGSA-N (R)-edelfosine Chemical compound CCCCCCCCCCCCCCCCCCOC[C@@H](OC)COP([O-])(=O)OCC[N+](C)(C)C MHFRGQHAERHWKZ-HHHXNRCGSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 1
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 description 1
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- BWDQBBCUWLSASG-MDZDMXLPSA-N (e)-n-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1h-indol-3-yl)ethyl]amino]methyl]phenyl]prop-2-enamide Chemical compound C=1NC2=CC=CC=C2C=1CCN(CCO)CC1=CC=C(\C=C\C(=O)NO)C=C1 BWDQBBCUWLSASG-MDZDMXLPSA-N 0.000 description 1
- OJRZEKJECRTBPJ-NGAMADIESA-N (z,5s)-5-acetamido-1-diazonio-6-hydroxy-6-oxohex-1-en-2-olate Chemical compound CC(=O)N[C@H](C(O)=O)CC\C([O-])=C\[N+]#N OJRZEKJECRTBPJ-NGAMADIESA-N 0.000 description 1
- RHUYHJGZWVXEHW-UHFFFAOYSA-N 1,1-Dimethyhydrazine Chemical compound CN(C)N RHUYHJGZWVXEHW-UHFFFAOYSA-N 0.000 description 1
- XMKLTEGSALONPH-UHFFFAOYSA-N 1,2,4,5-tetrazinane-3,6-dione Chemical compound O=C1NNC(=O)NN1 XMKLTEGSALONPH-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- FONKWHRXTPJODV-DNQXCXABSA-N 1,3-bis[2-[(8s)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydro-3h-pyrrolo[3,2-e]indole-6-carbonyl]-1h-indol-5-yl]urea Chemical compound C1([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C4=CC(O)=C5NC=C(C5=C4[C@H](CCl)C3)C)=C2C=C(O)C2=C1C(C)=CN2 FONKWHRXTPJODV-DNQXCXABSA-N 0.000 description 1
- OUPZKGBUJRBPGC-HLTSFMKQSA-N 1,5-bis[[(2r)-oxiran-2-yl]methyl]-3-[[(2s)-oxiran-2-yl]methyl]-1,3,5-triazinane-2,4,6-trione Chemical compound O=C1N(C[C@H]2OC2)C(=O)N(C[C@H]2OC2)C(=O)N1C[C@H]1CO1 OUPZKGBUJRBPGC-HLTSFMKQSA-N 0.000 description 1
- YQYBWJPESSJLTK-HXFLIBJXSA-N 1-(2-chloroethyl)-3-[(2r,3s,4r,6s)-3-hydroxy-2-(hydroxymethyl)-6-methoxyoxan-4-yl]-1-nitrosourea Chemical compound CO[C@@H]1C[C@@H](NC(=O)N(CCCl)N=O)[C@H](O)[C@@H](CO)O1 YQYBWJPESSJLTK-HXFLIBJXSA-N 0.000 description 1
- RCLLNBVPCJDIPX-UHFFFAOYSA-N 1-(2-chloroethyl)-3-[2-(dimethylsulfamoyl)ethyl]-1-nitrosourea Chemical compound CN(C)S(=O)(=O)CCNC(=O)N(N=O)CCCl RCLLNBVPCJDIPX-UHFFFAOYSA-N 0.000 description 1
- JQJSFAJISYZPER-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-(2,3-dihydro-1h-inden-5-ylsulfonyl)urea Chemical compound C1=CC(Cl)=CC=C1NC(=O)NS(=O)(=O)C1=CC=C(CCC2)C2=C1 JQJSFAJISYZPER-UHFFFAOYSA-N 0.000 description 1
- SNYUHPPZINRDSG-UHFFFAOYSA-N 1-(oxiran-2-ylmethyl)-4-[1-(oxiran-2-ylmethyl)piperidin-4-yl]piperidine Chemical compound C1CC(C2CCN(CC3OC3)CC2)CCN1CC1CO1 SNYUHPPZINRDSG-UHFFFAOYSA-N 0.000 description 1
- ZKFNOUUKULVDOB-UHFFFAOYSA-N 1-amino-1-phenylmethyl phosphonic acid Chemical compound OP(=O)(O)C(N)C1=CC=CC=C1 ZKFNOUUKULVDOB-UHFFFAOYSA-N 0.000 description 1
- JBSWLQWGIZUKCI-UHFFFAOYSA-N 1-benzyl-1-methylhydrazine;hydrochloride Chemical compound Cl.CN(N)CC1=CC=CC=C1 JBSWLQWGIZUKCI-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 1
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 description 1
- GPVGDGBVGWUGAL-UHFFFAOYSA-N 1-cyclohexyl-1-nitrosourea Chemical compound NC(=O)N(N=O)C1CCCCC1 GPVGDGBVGWUGAL-UHFFFAOYSA-N 0.000 description 1
- 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 description 1
- WRGQSWVCFNIUNZ-GDCKJWNLSA-N 1-oleoyl-sn-glycerol 3-phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)COP(O)(O)=O WRGQSWVCFNIUNZ-GDCKJWNLSA-N 0.000 description 1
- LEZWWPYKPKIXLL-UHFFFAOYSA-N 1-{2-(4-chlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound C1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 LEZWWPYKPKIXLL-UHFFFAOYSA-N 0.000 description 1
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical class C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 description 1
- VKDGNNYJFSHYKD-UHFFFAOYSA-N 2,5-diamino-2-(difluoromethyl)pentanoic acid;hydron;chloride Chemical compound Cl.NCCCC(N)(C(F)F)C(O)=O VKDGNNYJFSHYKD-UHFFFAOYSA-N 0.000 description 1
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- PDWUPXJEEYOOTR-UHFFFAOYSA-N 2-[(3-iodophenyl)methyl]guanidine Chemical compound NC(=N)NCC1=CC=CC(I)=C1 PDWUPXJEEYOOTR-UHFFFAOYSA-N 0.000 description 1
- ACTOXUHEUCPTEW-BWHGAVFKSA-N 2-[(4r,5s,6s,7r,9r,10r,11e,13e,16r)-6-[(2s,3r,4r,5s,6r)-5-[(2s,4r,5s,6s)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[(2s,5s,6r)-5-(dimethylamino)-6-methyloxan-2-yl]oxy-4-hydroxy-5-methoxy-9,16-dimethyl-2-o Chemical compound O([C@H]1/C=C/C=C/C[C@@H](C)OC(=O)C[C@@H](O)[C@@H]([C@H]([C@@H](CC=O)C[C@H]1C)O[C@H]1[C@@H]([C@H]([C@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(O)C2)[C@@H](C)O1)N(C)C)O)OC)[C@@H]1CC[C@H](N(C)C)[C@@H](C)O1 ACTOXUHEUCPTEW-BWHGAVFKSA-N 0.000 description 1
- KPRFMAZESAKTEJ-UHFFFAOYSA-N 2-[1-amino-4-[2,5-dioxo-4-(1-phenylethyl)pyrrolidin-3-yl]-1-oxobutan-2-yl]-5-carbamoylheptanedioic acid;azane Chemical compound [NH4+].[NH4+].C=1C=CC=CC=1C(C)C1C(CCC(C(CCC(CC([O-])=O)C(N)=O)C([O-])=O)C(N)=O)C(=O)NC1=O KPRFMAZESAKTEJ-UHFFFAOYSA-N 0.000 description 1
- XXVLKDRPHSFIIB-UHFFFAOYSA-N 2-[2-(dimethylamino)ethyl]-5-nitrobenzo[de]isoquinoline-1,3-dione Chemical compound [O-][N+](=O)C1=CC(C(N(CCN(C)C)C2=O)=O)=C3C2=CC=CC3=C1 XXVLKDRPHSFIIB-UHFFFAOYSA-N 0.000 description 1
- MHXVDXXARZCVRK-WCWDXBQESA-N 2-[2-[4-[(e)-3,3,3-trifluoro-1,2-diphenylprop-1-enyl]phenoxy]ethylamino]ethanol Chemical compound C1=CC(OCCNCCO)=CC=C1C(\C=1C=CC=CC=1)=C(C(F)(F)F)/C1=CC=CC=C1 MHXVDXXARZCVRK-WCWDXBQESA-N 0.000 description 1
- CQVKMVQRSNNAGO-UHFFFAOYSA-N 2-[4-formyl-3-methyl-n-(2-methylsulfonyloxyethyl)anilino]ethyl methanesulfonate Chemical compound CC1=CC(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)=CC=C1C=O CQVKMVQRSNNAGO-UHFFFAOYSA-N 0.000 description 1
- HYHJFNXFVPGMBI-UHFFFAOYSA-N 2-[[2-chloroethyl(nitroso)carbamoyl]-methylamino]acetamide Chemical compound NC(=O)CN(C)C(=O)N(CCCl)N=O HYHJFNXFVPGMBI-UHFFFAOYSA-N 0.000 description 1
- QCXJFISCRQIYID-IAEPZHFASA-N 2-amino-1-n-[(3s,6s,7r,10s,16s)-3-[(2s)-butan-2-yl]-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-10-propan-2-yl-8-oxa-1,4,11,14-tetrazabicyclo[14.3.0]nonadecan-6-yl]-4,6-dimethyl-3-oxo-9-n-[(3s,6s,7r,10s,16s)-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-3,10-di(propa Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N=C2C(C(=O)N[C@@H]3C(=O)N[C@H](C(N4CCC[C@H]4C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]3C)=O)[C@@H](C)CC)=C(N)C(=O)C(C)=C2O2)C2=C(C)C=C1 QCXJFISCRQIYID-IAEPZHFASA-N 0.000 description 1
- VDCRFBBZFHHYGT-IOSLPCCCSA-N 2-amino-9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-enyl-3h-purine-6,8-dione Chemical compound O=C1N(CC=C)C=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O VDCRFBBZFHHYGT-IOSLPCCCSA-N 0.000 description 1
- NIXVOFULDIFBLB-QVRNUERCSA-N 2-amino-9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purine-6-sulfinamide Chemical compound C12=NC(N)=NC(S(N)=O)=C2N=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NIXVOFULDIFBLB-QVRNUERCSA-N 0.000 description 1
- PPDPUIRKDSCCFN-UHFFFAOYSA-N 2-benzofuran-1,3-diimine Chemical compound C1=CC=C2C(=N)OC(=N)C2=C1 PPDPUIRKDSCCFN-UHFFFAOYSA-N 0.000 description 1
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 description 1
- GPQFKEBVVIMFMN-UHFFFAOYSA-N 2-decyl-1,3-dioxole Chemical compound CCCCCCCCCCC1OC=CO1 GPQFKEBVVIMFMN-UHFFFAOYSA-N 0.000 description 1
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 1
- CQOQDQWUFQDJMK-SSTWWWIQSA-N 2-methoxy-17beta-estradiol Chemical compound C([C@@H]12)C[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CCC1=C2C=C(OC)C(O)=C1 CQOQDQWUFQDJMK-SSTWWWIQSA-N 0.000 description 1
- MFNXWZGIFWJHMI-UHFFFAOYSA-N 2-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)NC(C)(C)C(O)=O MFNXWZGIFWJHMI-UHFFFAOYSA-N 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- DSWLRNLRVBAVFC-UHFFFAOYSA-N 2-methylsulfinyl-1-pyridin-2-ylethanone Chemical compound CS(=O)CC(=O)C1=CC=CC=N1 DSWLRNLRVBAVFC-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- VEWXIPUUQVLOKQ-UHFFFAOYSA-N 3-(4-bromo-3-methylphenyl)-4-(oxan-2-yl)-1,2,4-triazole Chemical compound C1=C(Br)C(C)=CC(C=2N(C=NN=2)C2OCCCC2)=C1 VEWXIPUUQVLOKQ-UHFFFAOYSA-N 0.000 description 1
- GTJXPMSTODOYNP-BTKVJIOYSA-N 3-[(e)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 GTJXPMSTODOYNP-BTKVJIOYSA-N 0.000 description 1
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- WUIABRMSWOKTOF-OYALTWQYSA-N 3-[[2-[2-[2-[[(2s,3r)-2-[[(2s,3s,4r)-4-[[(2s,3r)-2-[[6-amino-2-[(1s)-3-amino-1-[[(2s)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[(2r,3s,4s,5s,6s)-3-[(2r,3s,4s,5r,6r)-4-carbamoyloxy-3,5-dihydroxy-6-(hydroxymethyl)ox Chemical compound OS([O-])(=O)=O.N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C WUIABRMSWOKTOF-OYALTWQYSA-N 0.000 description 1
- WELIVEBWRWAGOM-UHFFFAOYSA-N 3-amino-n-[2-[2-(3-aminopropanoylamino)ethyldisulfanyl]ethyl]propanamide Chemical compound NCCC(=O)NCCSSCCNC(=O)CCN WELIVEBWRWAGOM-UHFFFAOYSA-N 0.000 description 1
- NYPYPOZNGOXYSU-UHFFFAOYSA-N 3-bromopyridine Chemical compound BrC1=CC=CN=C1 NYPYPOZNGOXYSU-UHFFFAOYSA-N 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- KTBHYBVDGHMPBO-UHFFFAOYSA-N 3-propylpyrrolidin-2-one Chemical compound CCCC1CCNC1=O KTBHYBVDGHMPBO-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin 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-VTZDEGQISA-N 0.000 description 1
- KCHQXPGUJBVNTN-UHFFFAOYSA-N 4,4-diphenylbut-3-en-2-one Chemical compound C=1C=CC=CC=1C(=CC(=O)C)C1=CC=CC=C1 KCHQXPGUJBVNTN-UHFFFAOYSA-N 0.000 description 1
- LIETVYHJBSLSSW-UHFFFAOYSA-N 4,6,9-trihydroxy-8-methyl-3,4-dihydro-2h-anthracen-1-one Chemical compound OC1CCC(=O)C2=C1C=C1C=C(O)C=C(C)C1=C2O LIETVYHJBSLSSW-UHFFFAOYSA-N 0.000 description 1
- JARCFMKMOFFIGZ-UHFFFAOYSA-N 4,6-dioxo-n-phenyl-2-sulfanylidene-1,3-diazinane-5-carboxamide Chemical compound O=C1NC(=S)NC(=O)C1C(=O)NC1=CC=CC=C1 JARCFMKMOFFIGZ-UHFFFAOYSA-N 0.000 description 1
- GIKNHHRFLCDOEU-UHFFFAOYSA-N 4-(2-aminopropyl)phenol Chemical compound CC(N)CC1=CC=C(O)C=C1 GIKNHHRFLCDOEU-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- HQFSNUYUXXPVKL-UHFFFAOYSA-N 4-[(4-fluorophenyl)methyl]-2-[1-(2-phenylethyl)azepan-4-yl]phthalazin-1-one Chemical compound C1=CC(F)=CC=C1CC(C1=CC=CC=C1C1=O)=NN1C1CCN(CCC=2C=CC=CC=2)CCC1 HQFSNUYUXXPVKL-UHFFFAOYSA-N 0.000 description 1
- OUQPTBCOEKUHBH-LSDHQDQOSA-N 4-[2-[4-[(e)-2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)prop-1-enyl]phenoxy]ethyl]morpholine Chemical compound C=1C=C(C(CCC2(C)C)(C)C)C2=CC=1C(/C)=C/C(C=C1)=CC=C1OCCN1CCOCC1 OUQPTBCOEKUHBH-LSDHQDQOSA-N 0.000 description 1
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 1
- SKXUZFJOLNNWIG-UHFFFAOYSA-N 4-bromo-3-methylbenzonitrile Chemical compound CC1=CC(C#N)=CC=C1Br SKXUZFJOLNNWIG-UHFFFAOYSA-N 0.000 description 1
- SGOOQMRIPALTEL-UHFFFAOYSA-N 4-hydroxy-N,1-dimethyl-2-oxo-N-phenyl-3-quinolinecarboxamide Chemical compound OC=1C2=CC=CC=C2N(C)C(=O)C=1C(=O)N(C)C1=CC=CC=C1 SGOOQMRIPALTEL-UHFFFAOYSA-N 0.000 description 1
- NMILGIZTAZXMTM-UHFFFAOYSA-N 4-propylmorpholine Chemical compound CCCN1CCOCC1 NMILGIZTAZXMTM-UHFFFAOYSA-N 0.000 description 1
- NSUDGNLOXMLAEB-UHFFFAOYSA-N 5-(2-formyl-3-hydroxyphenoxy)pentanoic acid Chemical compound OC(=O)CCCCOC1=CC=CC(O)=C1C=O NSUDGNLOXMLAEB-UHFFFAOYSA-N 0.000 description 1
- PXLPCZJACKUXGP-UHFFFAOYSA-N 5-(3,4-dichlorophenyl)-6-ethylpyrimidine-2,4-diamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C(Cl)=C1 PXLPCZJACKUXGP-UHFFFAOYSA-N 0.000 description 1
- APNRZHLOPQFNMR-WEIUTZTHSA-N 5-[(e)-5-[(1s)-2,2-dimethyl-6-methylidenecyclohexyl]-3-methylpent-2-enyl]phenazin-1-one Chemical compound C12=CC=CC=C2N=C(C(C=CC=2)=O)C=2N1C\C=C(/C)CC[C@@H]1C(=C)CCCC1(C)C APNRZHLOPQFNMR-WEIUTZTHSA-N 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- GJOHLWZHWQUKAU-UHFFFAOYSA-N 5-azaniumylpentan-2-yl-(6-methoxyquinolin-8-yl)azanium;dihydrogen phosphate Chemical compound OP(O)(O)=O.OP(O)(O)=O.N1=CC=CC2=CC(OC)=CC(NC(C)CCCN)=C21 GJOHLWZHWQUKAU-UHFFFAOYSA-N 0.000 description 1
- ATCGGEJZONJOCL-UHFFFAOYSA-N 6-(2,5-dichlorophenyl)-1,3,5-triazine-2,4-diamine Chemical compound NC1=NC(N)=NC(C=2C(=CC=C(Cl)C=2)Cl)=N1 ATCGGEJZONJOCL-UHFFFAOYSA-N 0.000 description 1
- VJXSSYDSOJBUAV-UHFFFAOYSA-N 6-(2,5-dimethoxy-benzyl)-5-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine Chemical compound COC1=CC=C(OC)C(CC=2C(=C3C(N)=NC(N)=NC3=NC=2)C)=C1 VJXSSYDSOJBUAV-UHFFFAOYSA-N 0.000 description 1
- LRHPCRBOMKRVOA-UHFFFAOYSA-N 6-[2-(2-hydroxyethylamino)ethyl]indeno[1,2-c]isoquinoline-5,11-dione Chemical compound C12=CC=CC=C2C(=O)N(CCNCCO)C2=C1C(=O)C1=CC=CC=C12 LRHPCRBOMKRVOA-UHFFFAOYSA-N 0.000 description 1
- LJIRBXZDQGQUOO-KVTDHHQDSA-N 6-amino-3-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,4-dihydro-1,3,5-triazin-2-one Chemical compound C1NC(N)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 LJIRBXZDQGQUOO-KVTDHHQDSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- GOYNNCPGHOBFCK-UHFFFAOYSA-N 7-[4-(dimethylamino)-5-[(2,9-dimethyl-3-oxo-4,4a,5a,6,7,9,9a,10a-octahydrodipyrano[4,2-a:4',3'-e][1,4]dioxin-7-yl)oxy]-6-methyloxan-2-yl]oxy-9-ethyl-4,6,9,10,11-pentahydroxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound O=C1C2=C(O)C=CC=C2C(=O)C2=C1C(O)=C1C(OC3OC(C)C(OC4OC(C)C5OC6OC(C)C(=O)CC6OC5C4)C(C3)N(C)C)CC(CC)(O)C(O)C1=C2O GOYNNCPGHOBFCK-UHFFFAOYSA-N 0.000 description 1
- GOJJWDOZNKBUSR-UHFFFAOYSA-N 7-sulfamoyloxyheptyl sulfamate Chemical compound NS(=O)(=O)OCCCCCCCOS(N)(=O)=O GOJJWDOZNKBUSR-UHFFFAOYSA-N 0.000 description 1
- OQLZINXFSUDMHM-UHFFFAOYSA-N Acetamidine Chemical compound CC(N)=N OQLZINXFSUDMHM-UHFFFAOYSA-N 0.000 description 1
- 206010000599 Acromegaly Diseases 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 206010001233 Adenoma benign Diseases 0.000 description 1
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 1
- 108010023728 Alloderm Proteins 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 208000031277 Amaurotic familial idiocy Diseases 0.000 description 1
- ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical compound [Cl-].CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCC[NH+](CC)CC)C(I)=C1 ITPDYQOUSLNIHG-UHFFFAOYSA-N 0.000 description 1
- 239000004251 Ammonium lactate Substances 0.000 description 1
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=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 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 1
- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical compound C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- NQGMIPUYCWIEAW-UHFFFAOYSA-N Antibiotic SF 2738 Natural products COc1cc(nc(C=NO)c1SC)-c1ccccn1 NQGMIPUYCWIEAW-UHFFFAOYSA-N 0.000 description 1
- MJINRRBEMOLJAK-DCAQKATOSA-N Arg-Lys-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCN=C(N)N MJINRRBEMOLJAK-DCAQKATOSA-N 0.000 description 1
- DRCNRVYVCHHIJP-AQBORDMYSA-N Arg-Lys-Glu-Val-Tyr Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 DRCNRVYVCHHIJP-AQBORDMYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 108700032558 Aspergillus restrictus MITF Proteins 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
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- 241001263178 Auriparus Species 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 108010044811 Autologen Proteins 0.000 description 1
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 description 1
- 208000023328 Basedow disease Diseases 0.000 description 1
- CULUWZNBISUWAS-UHFFFAOYSA-N Benznidazole Chemical compound [O-][N+](=O)C1=NC=CN1CC(=O)NCC1=CC=CC=C1 CULUWZNBISUWAS-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000019838 Blood disease Diseases 0.000 description 1
- 206010073106 Bone giant cell tumour malignant Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010006143 Brain stem glioma Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- CSWHWHFXQGBAOZ-JUDXGUMMSA-N C(C)[C@@]1([C@]([C@@](O[C@@H]1CO)(N1C(=S)NC(=O)C=C1)CC)(O)CC)O Chemical compound C(C)[C@@]1([C@]([C@@](O[C@@H]1CO)(N1C(=S)NC(=O)C=C1)CC)(O)CC)O CSWHWHFXQGBAOZ-JUDXGUMMSA-N 0.000 description 1
- AJYHXPCQMCTGTE-UHFFFAOYSA-N C(CCC)CC([CH2-])=O Chemical compound C(CCC)CC([CH2-])=O AJYHXPCQMCTGTE-UHFFFAOYSA-N 0.000 description 1
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 1
- GKAVVZRJXDUXLO-UHFFFAOYSA-N CC(C)(C1=NC=C(C=C1)C2=CC(CC=N2)CC3CC3)O Chemical compound CC(C)(C1=NC=C(C=C1)C2=CC(CC=N2)CC3CC3)O GKAVVZRJXDUXLO-UHFFFAOYSA-N 0.000 description 1
- CJXUSMWVXFLYDY-UHFFFAOYSA-N CC(C)(C1=NC=C(C=C1)C2=CC(CC=N2)CC3CCOC3)O Chemical compound CC(C)(C1=NC=C(C=C1)C2=CC(CC=N2)CC3CCOC3)O CJXUSMWVXFLYDY-UHFFFAOYSA-N 0.000 description 1
- XOGDEUJMELKUKJ-PUODRLBUSA-N CC(C)(C1=NC=C(C=C1)C2=C[C@@H](CC=N2)C3CCOC3)O Chemical compound CC(C)(C1=NC=C(C=C1)C2=C[C@@H](CC=N2)C3CCOC3)O XOGDEUJMELKUKJ-PUODRLBUSA-N 0.000 description 1
- XOGDEUJMELKUKJ-NBFOIZRFSA-N CC(C)(C1=NC=C(C=C1)C2=C[C@H](CC=N2)C3CCOC3)O Chemical compound CC(C)(C1=NC=C(C=C1)C2=C[C@H](CC=N2)C3CCOC3)O XOGDEUJMELKUKJ-NBFOIZRFSA-N 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010031425 Casein Kinases Proteins 0.000 description 1
- 102000005403 Casein Kinases Human genes 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 208000015879 Cerebellar disease Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229920002567 Chondroitin Polymers 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 102000011022 Chorionic Gonadotropin Human genes 0.000 description 1
- 108010062540 Chorionic Gonadotropin Proteins 0.000 description 1
- 244000045195 Cicer arietinum Species 0.000 description 1
- 235000010523 Cicer arietinum Nutrition 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- PPASFTRHCXASPY-UHFFFAOYSA-N Cl.Cl.NCCCNc1ccc2c3c(nn2CCNCCO)c4c(O)ccc(O)c4C(=O)c13 Chemical compound Cl.Cl.NCCCNc1ccc2c3c(nn2CCNCCO)c4c(O)ccc(O)c4C(=O)c13 PPASFTRHCXASPY-UHFFFAOYSA-N 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102400000739 Corticotropin Human genes 0.000 description 1
- 101800000414 Corticotropin Proteins 0.000 description 1
- DFDTZECTHJFPHE-UHFFFAOYSA-N Crambescidin 816 Natural products C1CC=CC(CC)OC11NC(N23)=NC4(OC(C)CCC4)C(C(=O)OCCCCCCCCCCCCCCCC(=O)N(CCCN)CC(O)CCN)C3(O)CCC2C1 DFDTZECTHJFPHE-UHFFFAOYSA-N 0.000 description 1
- 208000009798 Craniopharyngioma Diseases 0.000 description 1
- 208000025962 Crush injury Diseases 0.000 description 1
- CWNYOIZMJBDEML-UHFFFAOYSA-N Cryptosin Natural products CC12CCC(CC1CC3OC34C2C(O)C(=O)C5(C)C(CCC45O)C6OC(=O)C=C6)OC7CC(O)C(O)C(CO)O7 CWNYOIZMJBDEML-UHFFFAOYSA-N 0.000 description 1
- LUEYTMPPCOCKBX-KWYHTCOPSA-N Curacin A Chemical compound C=CC[C@H](OC)CC\C(C)=C\C=C\CC\C=C/[C@@H]1CSC([C@H]2[C@H](C2)C)=N1 LUEYTMPPCOCKBX-KWYHTCOPSA-N 0.000 description 1
- LUEYTMPPCOCKBX-UHFFFAOYSA-N Curacin A Natural products C=CCC(OC)CCC(C)=CC=CCCC=CC1CSC(C2C(C2)C)=N1 LUEYTMPPCOCKBX-UHFFFAOYSA-N 0.000 description 1
- 206010011686 Cutaneous vasculitis Diseases 0.000 description 1
- 102000016736 Cyclin Human genes 0.000 description 1
- 108050006400 Cyclin Proteins 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010085626 Cymetra Proteins 0.000 description 1
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 1
- SPKNARKFCOPTSY-UHFFFAOYSA-N D-asperlin Natural products CC1OC1C1C(OC(C)=O)C=CC(=O)O1 SPKNARKFCOPTSY-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 208000011518 Danon disease Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- GJKXGJCSJWBJEZ-XRSSZCMZSA-N Deslorelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CNC2=CC=CC=C12 GJKXGJCSJWBJEZ-XRSSZCMZSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KYHUYMLIVQFXRI-SJPGYWQQSA-N Didemnin B Chemical compound CN([C@H](CC(C)C)C(=O)N[C@@H]1C(=O)N[C@@H]([C@H](CC(=O)O[C@H](C(=O)[C@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N2CCC[C@H]2C(=O)N(C)[C@@H](CC=2C=CC(OC)=CC=2)C(=O)O[C@@H]1C)C(C)C)O)[C@@H](C)CC)C(=O)[C@@H]1CCCN1C(=O)[C@H](C)O KYHUYMLIVQFXRI-SJPGYWQQSA-N 0.000 description 1
- 208000002699 Digestive System Neoplasms Diseases 0.000 description 1
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.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 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 1
- CYQFCXCEBYINGO-DLBZAZTESA-N Dronabinol Natural products C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@H]21 CYQFCXCEBYINGO-DLBZAZTESA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 208000006402 Ductal Carcinoma Diseases 0.000 description 1
- VQNATVDKACXKTF-UHFFFAOYSA-N Duocarmycin SA Natural products COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C(C64CC6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-UHFFFAOYSA-N 0.000 description 1
- DYEFUKCXAQOFHX-UHFFFAOYSA-N Ebselen Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=CC=CC=C1 DYEFUKCXAQOFHX-UHFFFAOYSA-N 0.000 description 1
- 108050009340 Endothelin Proteins 0.000 description 1
- 102000002045 Endothelin Human genes 0.000 description 1
- NBEALWAVEGMZQY-UHFFFAOYSA-N Enpromate Chemical compound C=1C=CC=CC=1C(C#C)(C=1C=CC=CC=1)OC(=O)NC1CCCCC1 NBEALWAVEGMZQY-UHFFFAOYSA-N 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- VAPSMQAHNAZRKC-PQWRYPMOSA-N Epristeride Chemical compound C1C=C2C=C(C(O)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)NC(C)(C)C)[C@@]1(C)CC2 VAPSMQAHNAZRKC-PQWRYPMOSA-N 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 description 1
- 208000036566 Erythroleukaemia Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 208000032027 Essential Thrombocythemia Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 description 1
- ITIONVBQFUNVJV-UHFFFAOYSA-N Etomidoline Chemical compound C12=CC=CC=C2C(=O)N(CC)C1NC(C=C1)=CC=C1OCCN1CCCCC1 ITIONVBQFUNVJV-UHFFFAOYSA-N 0.000 description 1
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 201000001342 Fallopian tube cancer Diseases 0.000 description 1
- 208000013452 Fallopian tube neoplasm Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
- 108010029961 Filgrastim Proteins 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 description 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 241000237858 Gastropoda Species 0.000 description 1
- 208000032320 Germ cell tumor of testis Diseases 0.000 description 1
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 1
- 101001114134 Gloydius halys Neutral phospholipase A2 agkistrodotoxin Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 208000001500 Glycogen Storage Disease Type IIb Diseases 0.000 description 1
- 102000019058 Glycogen Synthase Kinase 3 beta Human genes 0.000 description 1
- 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 description 1
- 208000035148 Glycogen storage disease due to LAMP-2 deficiency Diseases 0.000 description 1
- 206010053185 Glycogen storage disease type II Diseases 0.000 description 1
- 239000004378 Glycyrrhizin Substances 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 101150113453 Gsk3a gene Proteins 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- FOHHNHSLJDZUGQ-VWLOTQADSA-N Halofantrine Chemical compound FC(F)(F)C1=CC=C2C([C@@H](O)CCN(CCCC)CCCC)=CC3=C(Cl)C=C(Cl)C=C3C2=C1 FOHHNHSLJDZUGQ-VWLOTQADSA-N 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 206010019668 Hepatic fibrosis Diseases 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000897035 Homo sapiens Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Proteins 0.000 description 1
- 101000582950 Homo sapiens Platelet factor 4 Proteins 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 1
- JJKOTMDDZAJTGQ-DQSJHHFOSA-N Idoxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN2CCCC2)=CC=1)/C1=CC=C(I)C=C1 JJKOTMDDZAJTGQ-DQSJHHFOSA-N 0.000 description 1
- 208000010159 IgA glomerulonephritis Diseases 0.000 description 1
- 206010021263 IgA nephropathy Diseases 0.000 description 1
- 206010021450 Immunodeficiency congenital Diseases 0.000 description 1
- 101000668058 Infectious salmon anemia virus (isolate Atlantic salmon/Norway/810/9/99) RNA-directed RNA polymerase catalytic subunit Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000005726 Inflammatory Breast Neoplasms Diseases 0.000 description 1
- 206010021980 Inflammatory carcinoma of the breast Diseases 0.000 description 1
- 102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 description 1
- 101710184277 Insulin-like growth factor 1 receptor Proteins 0.000 description 1
- 102100040018 Interferon alpha-2 Human genes 0.000 description 1
- 108010079944 Interferon-alpha2b Proteins 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108010002616 Interleukin-5 Proteins 0.000 description 1
- 208000037396 Intraductal Noninfiltrating Carcinoma Diseases 0.000 description 1
- 206010073086 Iris melanoma Diseases 0.000 description 1
- 208000009164 Islet Cell Adenoma Diseases 0.000 description 1
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 description 1
- 229940124091 Keratolytic Drugs 0.000 description 1
- 206010023439 Kidney transplant rejection Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- KJQFBVYMGADDTQ-CVSPRKDYSA-N L-buthionine-(S,R)-sulfoximine Chemical compound CCCCS(=N)(=O)CC[C@H](N)C(O)=O KJQFBVYMGADDTQ-CVSPRKDYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 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
- NHTGHBARYWONDQ-JTQLQIEISA-N L-α-methyl-Tyrosine Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C=C1 NHTGHBARYWONDQ-JTQLQIEISA-N 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 description 1
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 1
- ZHTRILQJTPJGNK-FYBAATNNSA-N Leinamycin Chemical compound N([C@@H](C=1SC=C(N=1)\C=C/C=C/C(=O)[C@H](O)/C=C(C)/CC1)C)C(=O)C[C@@]21S(=O)SC(=O)[C@]2(C)O ZHTRILQJTPJGNK-FYBAATNNSA-N 0.000 description 1
- ZHTRILQJTPJGNK-UHFFFAOYSA-N Leinamycin Natural products C1CC(C)=CC(O)C(=O)C=CC=CC(N=2)=CSC=2C(C)NC(=O)CC21S(=O)SC(=O)C2(C)O ZHTRILQJTPJGNK-UHFFFAOYSA-N 0.000 description 1
- 108010062867 Lenograstim Proteins 0.000 description 1
- 235000014647 Lens culinaris subsp culinaris Nutrition 0.000 description 1
- 244000043158 Lens esculenta Species 0.000 description 1
- LMVRPBWWHMVLPC-KBPJCXPTSA-N Leptolstatin Natural products CC(CC=CC(=CC(C)C(=O)C(C)C(O)C(C)CC(=CCO)C)C)C=C(C)/C=C/C1CC=CC(=O)O1 LMVRPBWWHMVLPC-KBPJCXPTSA-N 0.000 description 1
- 208000009625 Lesch-Nyhan syndrome Diseases 0.000 description 1
- 102000004058 Leukemia inhibitory factor Human genes 0.000 description 1
- 108090000581 Leukemia inhibitory factor Proteins 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 206010049287 Lipodystrophy acquired Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010025219 Lymphangioma Diseases 0.000 description 1
- 208000010423 Lymphatic Vessel Tumors Diseases 0.000 description 1
- 101710126949 Lysin Proteins 0.000 description 1
- 229940126560 MAPK inhibitor Drugs 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010026673 Malignant Pleural Effusion Diseases 0.000 description 1
- 208000030070 Malignant epithelial tumor of ovary Diseases 0.000 description 1
- 206010061269 Malignant peritoneal neoplasm Diseases 0.000 description 1
- 208000032271 Malignant tumor of penis Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000009018 Medullary thyroid cancer Diseases 0.000 description 1
- 208000037196 Medullary thyroid carcinoma Diseases 0.000 description 1
- 229920000877 Melamine resin Polymers 0.000 description 1
- JCYZMTMYPZHVBF-UHFFFAOYSA-N Melarsoprol Chemical compound NC1=NC(N)=NC(NC=2C=CC(=CC=2)[As]2SC(CO)CS2)=N1 JCYZMTMYPZHVBF-UHFFFAOYSA-N 0.000 description 1
- 101710170181 Metalloproteinase inhibitor Proteins 0.000 description 1
- 108700021154 Metallothionein 3 Proteins 0.000 description 1
- 102100028708 Metallothionein-3 Human genes 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 206010059282 Metastases to central nervous system Diseases 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 206010073101 Mucinous breast carcinoma Diseases 0.000 description 1
- 208000002678 Mucopolysaccharidoses Diseases 0.000 description 1
- 206010028289 Muscle atrophy Diseases 0.000 description 1
- 208000021642 Muscular disease Diseases 0.000 description 1
- HFPXYDFQVINJBV-UHFFFAOYSA-N Mycaperoxide B Natural products O1OC(C(C)C(O)=O)CCC1(C)CCC1(O)C2(C)CCCC(C)(C)C2CCC1C HFPXYDFQVINJBV-UHFFFAOYSA-N 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 206010028561 Myeloid metaplasia Diseases 0.000 description 1
- 201000009623 Myopathy Diseases 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- USVMJSALORZVDV-SDBHATRESA-N N(6)-(Delta(2)-isopentenyl)adenosine Chemical compound C1=NC=2C(NCC=C(C)C)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O USVMJSALORZVDV-SDBHATRESA-N 0.000 description 1
- HRNLUBSXIHFDHP-UHFFFAOYSA-N N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide Chemical compound NC1=CC=CC=C1NC(=O)C(C=C1)=CC=C1CNC1=NC=CC(C=2C=NC=CC=2)=N1 HRNLUBSXIHFDHP-UHFFFAOYSA-N 0.000 description 1
- BNQSTAOJRULKNX-UHFFFAOYSA-N N-(6-acetamidohexyl)acetamide Chemical compound CC(=O)NCCCCCCNC(C)=O BNQSTAOJRULKNX-UHFFFAOYSA-N 0.000 description 1
- CGCZBEPAJSUCCZ-UHFFFAOYSA-N N-(methyldiazenyl)-N-(N-phenylanilino)methanamine Chemical compound CN(N=NC)N(C1=CC=CC=C1)C1=CC=CC=C1 CGCZBEPAJSUCCZ-UHFFFAOYSA-N 0.000 description 1
- QJMCKEPOKRERLN-UHFFFAOYSA-N N-3,4-tridhydroxybenzamide Chemical compound ONC(=O)C1=CC=C(O)C(O)=C1 QJMCKEPOKRERLN-UHFFFAOYSA-N 0.000 description 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 1
- MHXGEROHKGDZGO-UHFFFAOYSA-N N-[(1-methyl-4-piperidinyl)methyl]-3-[3-(trifluoromethoxy)phenyl]-6-imidazo[1,2-b]pyridazinamine Chemical compound C1CN(C)CCC1CNC1=NN2C(C=3C=C(OC(F)(F)F)C=CC=3)=CN=C2C=C1 MHXGEROHKGDZGO-UHFFFAOYSA-N 0.000 description 1
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-UHFFFAOYSA-N N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine Chemical compound C=1C=CC=CC=1C(CCNC)OC1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-UHFFFAOYSA-N 0.000 description 1
- 108010021717 Nafarelin Proteins 0.000 description 1
- GTEXXGIEZVKSLH-UHFFFAOYSA-N Naphterpin Natural products O=C1C2=CC(O)=C(C)C(O)=C2C(=O)C2=C1C1C=C(C)CCC1C(C)(C)O2 GTEXXGIEZVKSLH-UHFFFAOYSA-N 0.000 description 1
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- 201000004404 Neurofibroma Diseases 0.000 description 1
- 208000002537 Neuronal Ceroid-Lipofuscinoses Diseases 0.000 description 1
- ARFHIAQFJWUCFH-IZZDOVSWSA-N Nifurtimox Chemical compound CC1CS(=O)(=O)CCN1\N=C\C1=CC=C([N+]([O-])=O)O1 ARFHIAQFJWUCFH-IZZDOVSWSA-N 0.000 description 1
- BUSGWUFLNHIBPT-UHFFFAOYSA-N Nisamycin Natural products O=C1C2OC2C(C=CC=CC=CC(=O)O)(O)C=C1NC(=O)C=CC=CC1CCCCC1 BUSGWUFLNHIBPT-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- KYRVNWMVYQXFEU-UHFFFAOYSA-N Nocodazole Chemical compound C1=C2NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CS1 KYRVNWMVYQXFEU-UHFFFAOYSA-N 0.000 description 1
- 206010029488 Nodular melanoma Diseases 0.000 description 1
- UMDBGTRUNWFBPE-UHFFFAOYSA-N O.Cl.Cl.CNCCNc1ccc2c3c(nn2CCNCCO)c4c(O)ccc(O)c4C(=O)c13 Chemical compound O.Cl.Cl.CNCCNc1ccc2c3c(nn2CCNCCO)c4c(O)ccc(O)c4C(=O)c13 UMDBGTRUNWFBPE-UHFFFAOYSA-N 0.000 description 1
- 229960005524 O6-benzylguanine Drugs 0.000 description 1
- KRWMERLEINMZFT-UHFFFAOYSA-N O6-benzylguanine Chemical compound C=12NC=NC2=NC(N)=NC=1OCC1=CC=CC=C1 KRWMERLEINMZFT-UHFFFAOYSA-N 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010030216 Oesophagitis Diseases 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- VTAZRSXSBIHBMH-UHFFFAOYSA-N Ophiocordin Natural products OC1=CC(C(=O)O)=CC(O)=C1C(=O)C1=C(O)C=CC=C1C(=O)NC1C(OC(=O)C=2C=CC(O)=CC=2)CCCNC1 VTAZRSXSBIHBMH-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 201000000023 Osteosclerosis Diseases 0.000 description 1
- 208000007571 Ovarian Epithelial Carcinoma Diseases 0.000 description 1
- 206010061328 Ovarian epithelial cancer Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- LKBBOPGQDRPCDS-UHFFFAOYSA-N Oxaunomycin Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC=C4C(=O)C=3C(O)=C2C(O)C(CC)(O)CC1OC1CC(N)C(O)C(C)O1 LKBBOPGQDRPCDS-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- OYONTEXKYJZFHA-SSHUPFPWSA-N PHA-665752 Chemical compound CC=1C(C(=O)N2[C@H](CCC2)CN2CCCC2)=C(C)NC=1\C=C(C1=C2)/C(=O)NC1=CC=C2S(=O)(=O)CC1=C(Cl)C=CC=C1Cl OYONTEXKYJZFHA-SSHUPFPWSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- VYOQBYCIIJYKJA-UHFFFAOYSA-N Palauamine Natural products C1N2C(=O)C3=CC=CN3C3N=C(N)NC32C2C1C(CN)C(Cl)C12NC(N)=NC1O VYOQBYCIIJYKJA-UHFFFAOYSA-N 0.000 description 1
- 206010033701 Papillary thyroid cancer Diseases 0.000 description 1
- FRCJDPPXHQGEKS-UHFFFAOYSA-N Parabactin Natural products CC1OC(=NC1C(=O)N(CCCCNC(=O)c1cccc(O)c1O)CCCNC(=O)c1cccc(O)c1O)c1ccccc1O FRCJDPPXHQGEKS-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- 206010034299 Penile cancer Diseases 0.000 description 1
- BYPFEZZEUUWMEJ-UHFFFAOYSA-N Pentoxifylline Chemical compound O=C1N(CCCCC(=O)C)C(=O)N(C)C2=C1N(C)C=N2 BYPFEZZEUUWMEJ-UHFFFAOYSA-N 0.000 description 1
- 108010057150 Peplomycin Proteins 0.000 description 1
- 229940083963 Peptide antagonist Drugs 0.000 description 1
- 208000009565 Pharyngeal Neoplasms Diseases 0.000 description 1
- 206010034811 Pharyngeal cancer Diseases 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- APNRZHLOPQFNMR-UHFFFAOYSA-N Phenazinomycin Natural products C12=CC=CC=C2N=C(C(C=CC=2)=O)C=2N1CC=C(C)CCC1C(=C)CCCC1(C)C APNRZHLOPQFNMR-UHFFFAOYSA-N 0.000 description 1
- QZVCTJOXCFMACW-UHFFFAOYSA-N Phenoxybenzamine Chemical compound C=1C=CC=CC=1CN(CCCl)C(C)COC1=CC=CC=C1 QZVCTJOXCFMACW-UHFFFAOYSA-N 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 229940122907 Phosphatase inhibitor Drugs 0.000 description 1
- PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 description 1
- 240000007643 Phytolacca americana Species 0.000 description 1
- 206010050487 Pinealoblastoma Diseases 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-O Piperidinium(1+) Chemical compound C1CC[NH2+]CC1 NQRYJNQNLNOLGT-UHFFFAOYSA-O 0.000 description 1
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)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]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 1
- 208000010067 Pituitary ACTH Hypersecretion Diseases 0.000 description 1
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 1
- 208000020627 Pituitary-dependent Cushing syndrome Diseases 0.000 description 1
- 102000010752 Plasminogen Inactivators Human genes 0.000 description 1
- 108010077971 Plasminogen Inactivators Proteins 0.000 description 1
- 102100030304 Platelet factor 4 Human genes 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 101710146367 Polycystin-1 Proteins 0.000 description 1
- 102100037935 Polyubiquitin-C Human genes 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 1
- 102000003946 Prolactin Human genes 0.000 description 1
- 108010057464 Prolactin Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- KNAHARQHSZJURB-UHFFFAOYSA-N Propylthiouracile Chemical compound CCCC1=CC(=O)NC(=S)N1 KNAHARQHSZJURB-UHFFFAOYSA-N 0.000 description 1
- 101800004937 Protein C Proteins 0.000 description 1
- 102100032420 Protein S100-A9 Human genes 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000052575 Proto-Oncogene Human genes 0.000 description 1
- 108700020978 Proto-Oncogene Proteins 0.000 description 1
- PICZCWCKOLHDOJ-UHFFFAOYSA-N Pseudoaxinellin Natural products N1C(=O)C2CCCN2C(=O)C(CC(N)=O)NC(=O)C(C(C)C)NC(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C(C(C)C)NC(=O)C1CC1=CC=CC=C1 PICZCWCKOLHDOJ-UHFFFAOYSA-N 0.000 description 1
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 1
- 229940123827 Purine nucleoside phosphorylase inhibitor Drugs 0.000 description 1
- XESARGFCSKSFID-UHFFFAOYSA-N Pyrazofurin Natural products OC1=C(C(=O)N)NN=C1C1C(O)C(O)C(CO)O1 XESARGFCSKSFID-UHFFFAOYSA-N 0.000 description 1
- 206010063562 Radiation skin injury Diseases 0.000 description 1
- 208000034541 Rare lymphatic malformation Diseases 0.000 description 1
- 102000003901 Ras GTPase-activating proteins Human genes 0.000 description 1
- 108090000231 Ras GTPase-activating proteins Proteins 0.000 description 1
- 229940078123 Ras inhibitor Drugs 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010038019 Rectal adenocarcinoma Diseases 0.000 description 1
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 1
- 229930189077 Rifamycin Natural products 0.000 description 1
- GCPUVEMWOWMALU-UHFFFAOYSA-N Rubiginone B1 Natural products C1C(C)CC(O)C2=C1C=CC1=C2C(=O)C(C=CC=C2OC)=C2C1=O GCPUVEMWOWMALU-UHFFFAOYSA-N 0.000 description 1
- 208000008620 Ruvalcaba syndrome Diseases 0.000 description 1
- 108010005173 SERPIN-B5 Proteins 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- 108010084592 Saporins Proteins 0.000 description 1
- 101800001700 Saposin-D Proteins 0.000 description 1
- 102400000827 Saposin-D Human genes 0.000 description 1
- YADVRLOQIWILGX-MIWLTHJTSA-N Sarcophytol A Chemical compound CC(C)C/1=C/C=C(C)/CC\C=C(C)\CC\C=C(C)\C[C@@H]\1O YADVRLOQIWILGX-MIWLTHJTSA-N 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 101710142052 Serine/threonine-protein kinase mTOR Proteins 0.000 description 1
- 102100030333 Serpin B5 Human genes 0.000 description 1
- 229920000519 Sizofiran Polymers 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 102100038803 Somatotropin Human genes 0.000 description 1
- 208000029033 Spinal Cord disease Diseases 0.000 description 1
- 239000004187 Spiramycin Substances 0.000 description 1
- 201000002661 Spondylitis Diseases 0.000 description 1
- UIRKNQLZZXALBI-MSVGPLKSSA-N Squalamine Chemical compound C([C@@H]1C[C@H]2O)[C@@H](NCCCNCCCCN)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CC[C@H](C(C)C)OS(O)(=O)=O)[C@@]2(C)CC1 UIRKNQLZZXALBI-MSVGPLKSSA-N 0.000 description 1
- UIRKNQLZZXALBI-UHFFFAOYSA-N Squalamine Natural products OC1CC2CC(NCCCNCCCCN)CCC2(C)C2C1C1CCC(C(C)CCC(C(C)C)OS(O)(=O)=O)C1(C)CC2 UIRKNQLZZXALBI-UHFFFAOYSA-N 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 241001505901 Streptococcus sp. 'group A' Species 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- NINIDFKCEFEMDL-AKLPVKDBSA-N Sulfur-35 Chemical compound [35S] NINIDFKCEFEMDL-AKLPVKDBSA-N 0.000 description 1
- 206010042553 Superficial spreading melanoma stage unspecified Diseases 0.000 description 1
- 108010021188 Superoxide Dismutase-1 Proteins 0.000 description 1
- 102100038836 Superoxide dismutase [Cu-Zn] Human genes 0.000 description 1
- 208000031673 T-Cell Cutaneous Lymphoma 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
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229940123582 Telomerase inhibitor Drugs 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- WXZSUBHBYQYTNM-UHFFFAOYSA-N Tetrazomine Natural products C1=CC=2CC(N34)C(N5C)C(CO)CC5C4OCC3C=2C(OC)=C1NC(=O)C1NCCCC1O WXZSUBHBYQYTNM-UHFFFAOYSA-N 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000009470 Theobroma cacao Nutrition 0.000 description 1
- 108010078233 Thymalfasin Proteins 0.000 description 1
- 208000033781 Thyroid carcinoma Diseases 0.000 description 1
- 102000011923 Thyrotropin Human genes 0.000 description 1
- 108010061174 Thyrotropin Proteins 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- IWEQQRMGNVVKQW-OQKDUQJOSA-N Toremifene citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 IWEQQRMGNVVKQW-OQKDUQJOSA-N 0.000 description 1
- 208000035317 Total hypoxanthine-guanine phosphoribosyl transferase deficiency Diseases 0.000 description 1
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 1
- 108010074506 Transfer Factor Proteins 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 108010009583 Transforming Growth Factors Proteins 0.000 description 1
- 102000009618 Transforming Growth Factors Human genes 0.000 description 1
- 206010060872 Transplant failure Diseases 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 206010073104 Tubular breast carcinoma Diseases 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 108010040002 Tumor Suppressor Proteins Proteins 0.000 description 1
- 102000001742 Tumor Suppressor Proteins Human genes 0.000 description 1
- VGQOVCHZGQWAOI-UHFFFAOYSA-N UNPD55612 Natural products N1C(O)C2CC(C=CC(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 206010046798 Uterine leiomyoma Diseases 0.000 description 1
- 201000005969 Uveal melanoma Diseases 0.000 description 1
- 229940127538 Vascular Endothelial Growth Factor Receptor Inhibitors Drugs 0.000 description 1
- 102000016549 Vascular Endothelial Growth Factor Receptor-2 Human genes 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- 102100026383 Vasopressin-neurophysin 2-copeptin Human genes 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 201000008803 Wolff-Parkinson-white syndrome Diseases 0.000 description 1
- 201000006083 Xeroderma Pigmentosum Diseases 0.000 description 1
- 208000012018 Yolk sac tumor Diseases 0.000 description 1
- MHDDZDPNIDVLNK-ZGIWMXSJSA-N Zanoterone Chemical compound C1C2=NN(S(C)(=O)=O)C=C2C[C@]2(C)[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CC[C@H]21 MHDDZDPNIDVLNK-ZGIWMXSJSA-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
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- OGQICQVSFDPSEI-UHFFFAOYSA-N Zorac Chemical compound N1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C(SCCC2(C)C)C2=C1 OGQICQVSFDPSEI-UHFFFAOYSA-N 0.000 description 1
- ZMQRJWIYMXZORG-GZIFKOAOSA-N [(1e,3r,4r,6r,7z,9z,11e)-3,6,13-trihydroxy-3-methyl-1-[(2s)-6-oxo-2,3-dihydropyran-2-yl]trideca-1,7,9,11-tetraen-4-yl] dihydrogen phosphate Chemical compound OC/C=C/C=C\C=C/[C@H](O)C[C@@H](OP(O)(O)=O)[C@@](O)(C)\C=C\[C@@H]1CC=CC(=O)O1 ZMQRJWIYMXZORG-GZIFKOAOSA-N 0.000 description 1
- ZZWKZQDOSJAGGF-VRSYWUPDSA-N [(1s,2e,7s,10e,12r,13r,15s)-12-hydroxy-7-methyl-9-oxo-8-oxabicyclo[11.3.0]hexadeca-2,10-dien-15-yl] 2-(dimethylamino)acetate Chemical compound O[C@@H]1\C=C\C(=O)O[C@@H](C)CCC\C=C\[C@@H]2C[C@H](OC(=O)CN(C)C)C[C@H]21 ZZWKZQDOSJAGGF-VRSYWUPDSA-N 0.000 description 1
- VUPBDWQPEOWRQP-RTUCOMKBSA-N [(2R,3S,4S,5R,6R)-2-[(2R,3S,4S,5S,6S)-2-[(1S,2S)-3-[[(2R,3S)-5-[[(2S,3R)-1-[[2-[4-[4-[[4-amino-6-[3-(4-aminobutylamino)propylamino]-6-oxohexyl]carbamoyl]-1,3-thiazol-2-yl]-1,3-thiazol-2-yl]-1-[(2S,3R,4R,5S,6S)-5-amino-3,4-dihydroxy-6-methyloxan-2-yl]oxy-2-hydroxyethyl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-hydroxy-5-oxopentan-2-yl]amino]-2-[[6-amino-2-[(1S)-3-amino-1-[[(2S)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-1-(1H-imidazol-5-yl)-3-oxopropoxy]-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]oxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl] carbamate Chemical compound C[C@@H](O)[C@H](NC(=O)C[C@H](O)[C@@H](C)NC(=O)[C@@H](NC(=O)c1nc(nc(N)c1C)[C@H](CC(N)=O)NC[C@H](N)C(N)=O)[C@H](O[C@@H]1O[C@@H](CO)[C@@H](O)[C@H](O)[C@@H]1O[C@H]1O[C@H](CO)[C@@H](O)[C@H](OC(N)=O)[C@@H]1O)c1cnc[nH]1)C(=O)NC(O[C@@H]1O[C@@H](C)[C@@H](N)[C@@H](O)[C@H]1O)C(O)c1nc(cs1)-c1nc(cs1)C(=O)NCCCC(N)CC(=O)NCCCNCCCCN VUPBDWQPEOWRQP-RTUCOMKBSA-N 0.000 description 1
- SPKNARKFCOPTSY-XWPZMVOTSA-N [(2r,3s)-2-[(2s,3r)-3-methyloxiran-2-yl]-6-oxo-2,3-dihydropyran-3-yl] acetate Chemical compound C[C@H]1O[C@@H]1[C@H]1[C@@H](OC(C)=O)C=CC(=O)O1 SPKNARKFCOPTSY-XWPZMVOTSA-N 0.000 description 1
- IFJUINDAXYAPTO-UUBSBJJBSA-N [(8r,9s,13s,14s,17s)-17-[2-[4-[4-[bis(2-chloroethyl)amino]phenyl]butanoyloxy]acetyl]oxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] benzoate Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@H]4OC(=O)COC(=O)CCCC=1C=CC(=CC=1)N(CCCl)CCCl)C)CC2=CC=3OC(=O)C1=CC=CC=C1 IFJUINDAXYAPTO-UUBSBJJBSA-N 0.000 description 1
- KMLCRELJHYKIIL-UHFFFAOYSA-N [1-(azanidylmethyl)cyclohexyl]methylazanide;platinum(2+);sulfuric acid Chemical compound [Pt+2].OS(O)(=O)=O.[NH-]CC1(C[NH-])CCCCC1 KMLCRELJHYKIIL-UHFFFAOYSA-N 0.000 description 1
- JJULHOZRTCDZOH-JGJFOBQESA-N [1-[[[(2r,3s,4s,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]oxy-3-octadecylsulfanylpropan-2-yl] hexadecanoate Chemical compound O[C@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(CSCCCCCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)O[C@H]1N1C(=O)N=C(N)C=C1 JJULHOZRTCDZOH-JGJFOBQESA-N 0.000 description 1
- PNDPGZBMCMUPRI-XXSWNUTMSA-N [125I][125I] Chemical compound [125I][125I] PNDPGZBMCMUPRI-XXSWNUTMSA-N 0.000 description 1
- XSMVECZRZBFTIZ-UHFFFAOYSA-M [2-(aminomethyl)cyclobutyl]methanamine;2-oxidopropanoate;platinum(4+) Chemical compound [Pt+4].CC([O-])C([O-])=O.NCC1CCC1CN XSMVECZRZBFTIZ-UHFFFAOYSA-M 0.000 description 1
- AYVGBNGTBQLJBG-UHFFFAOYSA-N [3-(hydroxymethyl)cyclopentyl]methanol Chemical compound OCC1CCC(CO)C1 AYVGBNGTBQLJBG-UHFFFAOYSA-N 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- NAFFDQVVNWTDJD-UHFFFAOYSA-L [4-(azanidylmethyl)oxan-4-yl]methylazanide;cyclobutane-1,1-dicarboxylate;platinum(4+) Chemical compound [Pt+4].[NH-]CC1(C[NH-])CCOCC1.[O-]C(=O)C1(C([O-])=O)CCC1 NAFFDQVVNWTDJD-UHFFFAOYSA-L 0.000 description 1
- XEIPQVVAVOUIOP-UHFFFAOYSA-N [Au]=S Chemical compound [Au]=S XEIPQVVAVOUIOP-UHFFFAOYSA-N 0.000 description 1
- GZOSMCIZMLWJML-VJLLXTKPSA-N abiraterone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CC[C@H](O)CC3=CC2)C)CC[C@@]11C)C=C1C1=CC=CN=C1 GZOSMCIZMLWJML-VJLLXTKPSA-N 0.000 description 1
- 229960000853 abiraterone Drugs 0.000 description 1
- 206010059394 acanthoma Diseases 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- RUGAHXUZHWYHNG-NLGNTGLNSA-N acetic acid;(4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5, Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1.C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 RUGAHXUZHWYHNG-NLGNTGLNSA-N 0.000 description 1
- IGCAUIJHGNYDKE-UHFFFAOYSA-N acetic acid;1,4-bis[2-(2-hydroxyethylamino)ethylamino]anthracene-9,10-dione Chemical compound CC([O-])=O.CC([O-])=O.O=C1C2=CC=CC=C2C(=O)C2=C1C(NCC[NH2+]CCO)=CC=C2NCC[NH2+]CCO IGCAUIJHGNYDKE-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 229960004150 aciclovir Drugs 0.000 description 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- QAWIHIJWNYOLBE-OKKQSCSOSA-N acivicin Chemical compound OC(=O)[C@@H](N)[C@@H]1CC(Cl)=NO1 QAWIHIJWNYOLBE-OKKQSCSOSA-N 0.000 description 1
- 229950008427 acivicin Drugs 0.000 description 1
- 229950000616 acronine Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 229940112258 acular Drugs 0.000 description 1
- 208000021841 acute erythroid leukemia Diseases 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
- DPGOLRILOKERAV-AAWJQDODSA-N adecypenol Chemical compound OC1C(CO)=CCC1(O)N1C(N=CNC[C@H]2O)C2N=C1 DPGOLRILOKERAV-AAWJQDODSA-N 0.000 description 1
- WJSAFKJWCOMTLH-UHFFFAOYSA-N adecypenol Natural products OC1C(O)C(CO)=CC1N1C(NC=NCC2O)=C2N=C1 WJSAFKJWCOMTLH-UHFFFAOYSA-N 0.000 description 1
- 201000008395 adenosquamous carcinoma Diseases 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 206010001323 adrenal adenoma Diseases 0.000 description 1
- 208000015234 adrenal cortex adenoma Diseases 0.000 description 1
- 208000020990 adrenal cortex carcinoma Diseases 0.000 description 1
- 201000005188 adrenal gland cancer Diseases 0.000 description 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 1
- 239000000695 adrenergic alpha-agonist Substances 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 229940062527 alendronate Drugs 0.000 description 1
- 229920000180 alkyd Polymers 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 239000002160 alpha blocker Substances 0.000 description 1
- 229940061720 alpha hydroxy acid Drugs 0.000 description 1
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 229950010949 ambamustine Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- JKOQGQFVAUAYPM-UHFFFAOYSA-N amifostine Chemical compound NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 description 1
- 229960001097 amifostine Drugs 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229940059265 ammonium lactate Drugs 0.000 description 1
- 235000019286 ammonium lactate Nutrition 0.000 description 1
- 229940025084 amphetamine Drugs 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound 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 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- 229960003942 amphotericin b Drugs 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960002550 amrubicin Drugs 0.000 description 1
- VJZITPJGSQKZMX-XDPRQOKASA-N amrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC=C4C(=O)C=3C(O)=C21)(N)C(=O)C)[C@H]1C[C@H](O)[C@H](O)CO1 VJZITPJGSQKZMX-XDPRQOKASA-N 0.000 description 1
- 206010002022 amyloidosis Diseases 0.000 description 1
- 229940025141 anafranil Drugs 0.000 description 1
- 229960001694 anagrelide Drugs 0.000 description 1
- OTBXOEAOVRKTNQ-UHFFFAOYSA-N anagrelide Chemical compound N1=C2NC(=O)CN2CC2=C(Cl)C(Cl)=CC=C21 OTBXOEAOVRKTNQ-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 108010070670 antarelix Proteins 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- VGQOVCHZGQWAOI-HYUHUPJXSA-N anthramycin Chemical compound N1[C@@H](O)[C@@H]2CC(\C=C\C(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-HYUHUPJXSA-N 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000003432 anti-folate effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 229940125683 antiemetic agent Drugs 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 229940127074 antifolate Drugs 0.000 description 1
- 229940082992 antihypertensives mao inhibitors Drugs 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- ZDINGUUTWDGGFF-UHFFFAOYSA-N antimony(5+) Chemical compound [Sb+5] ZDINGUUTWDGGFF-UHFFFAOYSA-N 0.000 description 1
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- IOASYARYEYRREA-LQAJYKIKSA-N aphidicolin glycinate Chemical compound C1[C@]23[C@]4(C)CC[C@H](O)[C@](C)(CO)[C@H]4CC[C@@H]3C[C@@H]1[C@@](COC(=O)CN)(O)CC2 IOASYARYEYRREA-LQAJYKIKSA-N 0.000 description 1
- 235000015197 apple juice Nutrition 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 108010055530 arginyl-tryptophyl-N-methylphenylalanyl-tryptophyl-leucyl-methioninamide Proteins 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 230000003140 astrocytic effect Effects 0.000 description 1
- TWHSQQYCDVSBRK-UHFFFAOYSA-N asulacrine Chemical compound C12=CC=CC(C)=C2N=C2C(C(=O)NC)=CC=CC2=C1NC1=CC=C(NS(C)(=O)=O)C=C1OC TWHSQQYCDVSBRK-UHFFFAOYSA-N 0.000 description 1
- 229950011088 asulacrine Drugs 0.000 description 1
- PEPMWUSGRKINHX-TXTPUJOMSA-N atamestane Chemical compound C1C[C@@H]2[C@@]3(C)C(C)=CC(=O)C=C3CC[C@H]2[C@@H]2CCC(=O)[C@]21C PEPMWUSGRKINHX-TXTPUJOMSA-N 0.000 description 1
- 229950004810 atamestane Drugs 0.000 description 1
- 229960003159 atovaquone Drugs 0.000 description 1
- KUCQYCKVKVOKAY-CTYIDZIISA-N atovaquone Chemical compound C1([C@H]2CC[C@@H](CC2)C2=C(C(C3=CC=CC=C3C2=O)=O)O)=CC=C(Cl)C=C1 KUCQYCKVKVOKAY-CTYIDZIISA-N 0.000 description 1
- 229950006933 atrimustine Drugs 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- 229940000201 avapro Drugs 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- 108010093161 axinastatin 1 Proteins 0.000 description 1
- PICZCWCKOLHDOJ-GHTSNYPWSA-N axinastatin 1 Chemical compound C([C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)N2CCC[C@H]2C(=O)N[C@H](C(N[C@@H](CC(N)=O)C(=O)N2CCC[C@H]2C(=O)N1)=O)C(C)C)C(C)C)C(C)C)C1=CC=CC=C1 PICZCWCKOLHDOJ-GHTSNYPWSA-N 0.000 description 1
- 108010093000 axinastatin 2 Proteins 0.000 description 1
- OXNAATCTZCSVKR-AVGVIDKOSA-N axinastatin 2 Chemical compound C([C@H]1C(=O)N[C@H](C(=O)N[C@H](C(N2CCC[C@H]2C(=O)N[C@@H](C(=O)N[C@@H](CC(N)=O)C(=O)N2CCC[C@H]2C(=O)N1)C(C)C)=O)CC(C)C)C(C)C)C1=CC=CC=C1 OXNAATCTZCSVKR-AVGVIDKOSA-N 0.000 description 1
- UZCPCRPHNVHKKP-UHFFFAOYSA-N axinastatin 2 Natural products CC(C)CC1NC(=O)C2CCCN2C(=O)C(NC(=O)C(CC(=O)N)NC(=O)C3CCCN3C(=O)C(Cc4ccccc4)NC(=O)C(NC1=O)C(C)C)C(C)C UZCPCRPHNVHKKP-UHFFFAOYSA-N 0.000 description 1
- 108010092978 axinastatin 3 Proteins 0.000 description 1
- ANLDPEXRVVIABH-WUUSPZRJSA-N axinastatin 3 Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CC(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C(=O)N[C@@H](CC(N)=O)C(=O)N2CCC[C@H]2C(=O)N1)C(C)C)=O)[C@@H](C)CC)C1=CC=CC=C1 ANLDPEXRVVIABH-WUUSPZRJSA-N 0.000 description 1
- RTGMQVUKARGBNM-UHFFFAOYSA-N axinastatin 3 Natural products CCC(C)C1NC(=O)C(CC(C)C)NC(=O)C2CCCN2C(=O)C(NC(=O)C(CC(=O)N)NC(=O)C3CCCN3C(=O)C(Cc4ccccc4)NC1=O)C(C)C RTGMQVUKARGBNM-UHFFFAOYSA-N 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- OPWOOOGFNULJAQ-UHFFFAOYSA-L azane;cyclopentanamine;2-hydroxybutanedioate;platinum(2+) Chemical compound N.[Pt+2].NC1CCCC1.[O-]C(=O)C(O)CC([O-])=O OPWOOOGFNULJAQ-UHFFFAOYSA-L 0.000 description 1
- KLNFSAOEKUDMFA-UHFFFAOYSA-N azanide;2-hydroxyacetic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OCC(O)=O KLNFSAOEKUDMFA-UHFFFAOYSA-N 0.000 description 1
- RZOBLYBZQXQGFY-HSHFZTNMSA-N azanium;(2r)-2-hydroxypropanoate Chemical compound [NH4+].C[C@@H](O)C([O-])=O RZOBLYBZQXQGFY-HSHFZTNMSA-N 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 150000004200 baccatin III derivatives Chemical class 0.000 description 1
- 229960000794 baclofen Drugs 0.000 description 1
- XYUFCXJZFZPEJD-PGRDOPGGSA-N balanol Chemical compound OC(=O)C1=CC=CC(O)=C1C(=O)C1=C(O)C=C(C(=O)O[C@H]2[C@H](CNCCC2)NC(=O)C=2C=CC(O)=CC=2)C=C1O XYUFCXJZFZPEJD-PGRDOPGGSA-N 0.000 description 1
- 208000003373 basosquamous carcinoma Diseases 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 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
- 229960004001 benznidazole Drugs 0.000 description 1
- 229950005567 benzodepa Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- NDTSRXAMMQDVSW-UHFFFAOYSA-N benzthiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1N=C2CSCC1=CC=CC=C1 NDTSRXAMMQDVSW-UHFFFAOYSA-N 0.000 description 1
- 229960001541 benzthiazide Drugs 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
- VFIUCBTYGKMLCM-UHFFFAOYSA-N benzyl n-[bis(aziridin-1-yl)phosphoryl]carbamate Chemical compound C=1C=CC=CC=1COC(=O)NP(=O)(N1CC1)N1CC1 VFIUCBTYGKMLCM-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- NPSOIFAWYAHWOH-UHFFFAOYSA-N bistratene A Natural products O1C(CC(=O)C=CC)CCC(O2)(O)CC(C)C2CCCNC(=O)C(C)C2OC(CCC(C)C=C(C)C(C)O)CCCCC(C)C1CC(=O)NC2 NPSOIFAWYAHWOH-UHFFFAOYSA-N 0.000 description 1
- 229950006844 bizelesin Drugs 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 229960004395 bleomycin sulfate Drugs 0.000 description 1
- 239000003633 blood substitute Substances 0.000 description 1
- 208000018420 bone fibrosarcoma Diseases 0.000 description 1
- 238000010322 bone marrow transplantation Methods 0.000 description 1
- 229960003065 bosentan Drugs 0.000 description 1
- 230000006931 brain damage Effects 0.000 description 1
- 231100000874 brain damage Toxicity 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 201000007476 breast mucinous carcinoma Diseases 0.000 description 1
- 201000000135 breast papillary carcinoma Diseases 0.000 description 1
- PZOHOALJQOFNTB-UHFFFAOYSA-M brequinar sodium Chemical compound [Na+].N1=C2C=CC(F)=CC2=C(C([O-])=O)C(C)=C1C(C=C1)=CC=C1C1=CC=CC=C1F PZOHOALJQOFNTB-UHFFFAOYSA-M 0.000 description 1
- 229960002624 bretylium tosilate Drugs 0.000 description 1
- KVWNWTZZBKCOPM-UHFFFAOYSA-M bretylium tosylate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1.CC[N+](C)(C)CC1=CC=CC=C1Br KVWNWTZZBKCOPM-UHFFFAOYSA-M 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 229940045348 brown mixture Drugs 0.000 description 1
- 229950002361 budotitane Drugs 0.000 description 1
- 229960003150 bupivacaine Drugs 0.000 description 1
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 description 1
- 229960002495 buspirone Drugs 0.000 description 1
- QWCRAEMEVRGPNT-UHFFFAOYSA-N buspirone Chemical compound C1C(=O)N(CCCCN2CCN(CC2)C=2N=CC=CN=2)C(=O)CC21CCCC2 QWCRAEMEVRGPNT-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229950009908 cactinomycin Drugs 0.000 description 1
- 108700002839 cactinomycin Proteins 0.000 description 1
- ATZQZZAXOPPAAQ-UHFFFAOYSA-M caesium formate Chemical compound [Cs+].[O-]C=O ATZQZZAXOPPAAQ-UHFFFAOYSA-M 0.000 description 1
- 229960002882 calcipotriol Drugs 0.000 description 1
- LWQQLNNNIPYSNX-UROSTWAQSA-N calcipotriol Chemical compound C1([C@H](O)/C=C/[C@@H](C)[C@@H]2[C@]3(CCCC(/[C@@H]3CC2)=C\C=C\2C([C@@H](O)C[C@H](O)C/2)=C)C)CC1 LWQQLNNNIPYSNX-UROSTWAQSA-N 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 229960004015 calcitonin Drugs 0.000 description 1
- 229960005084 calcitriol Drugs 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
- 239000001354 calcium citrate Substances 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Inorganic materials [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- LSUTUUOITDQYNO-UHFFFAOYSA-N calphostin C Chemical compound C=12C3=C4C(CC(C)OC(=O)C=5C=CC=CC=5)=C(OC)C(O)=C(C(C=C5OC)=O)C4=C5C=1C(OC)=CC(=O)C2=C(O)C(OC)=C3CC(C)OC(=O)OC1=CC=C(O)C=C1 LSUTUUOITDQYNO-UHFFFAOYSA-N 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
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 229950005155 carbetimer Drugs 0.000 description 1
- 229960004205 carbidopa Drugs 0.000 description 1
- TZFNLOMSOLWIDK-JTQLQIEISA-N carbidopa (anhydrous) Chemical compound NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 TZFNLOMSOLWIDK-JTQLQIEISA-N 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 150000001722 carbon compounds Chemical class 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- YAYRGNWWLMLWJE-UHFFFAOYSA-L carboplatin Chemical compound O=C1O[Pt](N)(N)OC(=O)C11CCC1 YAYRGNWWLMLWJE-UHFFFAOYSA-L 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 230000002612 cardiopulmonary effect Effects 0.000 description 1
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin Chemical class C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003543 catechol methyltransferase inhibitor Substances 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 229950010667 cedefingol Drugs 0.000 description 1
- 229940047495 celebrex Drugs 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000006369 cell cycle progression Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 201000007455 central nervous system cancer Diseases 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 108700008462 cetrorelix Proteins 0.000 description 1
- SBNPWPIBESPSIF-MHWMIDJBSA-N cetrorelix Chemical compound C([C@@H](C(=O)N[C@H](CCCNC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 SBNPWPIBESPSIF-MHWMIDJBSA-N 0.000 description 1
- 229960003230 cetrorelix Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- HZCWPKGYTCJSEB-UHFFFAOYSA-N chembl118841 Chemical compound C12=CC(OC)=CC=C2NC2=C([N+]([O-])=O)C=CC3=C2C1=NN3CCCN(C)C HZCWPKGYTCJSEB-UHFFFAOYSA-N 0.000 description 1
- DCKFXSZUWVWFEU-JECTWPLRSA-N chembl499423 Chemical compound O1[C@@H](CC)CCCC[C@]11NC(N23)=N[C@]4(O[C@H](C)CCC4)[C@@H](C(=O)OCCCCCCCCCCCCCCCC(=O)N(CCCN)C[C@@H](O)CCN)[C@@]3(O)CC[C@H]2C1 DCKFXSZUWVWFEU-JECTWPLRSA-N 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 230000002113 chemopreventative effect Effects 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 229940068682 chewable tablet Drugs 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- DLGJWSVWTWEWBJ-HGGSSLSASA-N chondroitin Chemical compound CC(O)=N[C@@H]1[C@H](O)O[C@H](CO)[C@H](O)[C@@H]1OC1[C@H](O)[C@H](O)C=C(C(O)=O)O1 DLGJWSVWTWEWBJ-HGGSSLSASA-N 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- 208000024207 chronic leukemia Diseases 0.000 description 1
- 201000010902 chronic myelomonocytic leukemia Diseases 0.000 description 1
- 229940117229 cialis Drugs 0.000 description 1
- ARUGKOZUKWAXDS-SEWALLKFSA-N cicaprost Chemical compound C1\C(=C/COCC(O)=O)C[C@@H]2[C@@H](C#C[C@@H](O)[C@@H](C)CC#CCC)[C@H](O)C[C@@H]21 ARUGKOZUKWAXDS-SEWALLKFSA-N 0.000 description 1
- 229950000634 cicaprost Drugs 0.000 description 1
- 229960004588 cilostazol Drugs 0.000 description 1
- RRGUKTPIGVIEKM-UHFFFAOYSA-N cilostazol Chemical compound C=1C=C2NC(=O)CCC2=CC=1OCCCCC1=NN=NN1C1CCCCC1 RRGUKTPIGVIEKM-UHFFFAOYSA-N 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- JKNIRLKHOOMGOJ-UHFFFAOYSA-N cladochrome D Natural products COC1=C(CC(C)OC(=O)Oc2ccc(O)cc2)c3c4C(=C(OC)C(=O)c5c(O)cc(OC)c(c45)c6c(OC)cc(O)c(C1=O)c36)CC(C)OC(=O)c7ccc(O)cc7 JKNIRLKHOOMGOJ-UHFFFAOYSA-N 0.000 description 1
- SRJYZPCBWDVSGO-UHFFFAOYSA-N cladochrome E Natural products COC1=CC(O)=C(C(C(OC)=C(CC(C)OC(=O)OC=2C=CC(O)=CC=2)C2=3)=O)C2=C1C1=C(OC)C=C(O)C(C(C=2OC)=O)=C1C=3C=2CC(C)OC(=O)C1=CC=CC=C1 SRJYZPCBWDVSGO-UHFFFAOYSA-N 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 229960003608 clomifene Drugs 0.000 description 1
- 229960004606 clomipramine Drugs 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 230000037011 constitutive activity Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 210000004246 corpus luteum Anatomy 0.000 description 1
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 1
- 229960000258 corticotropin Drugs 0.000 description 1
- 229940072645 coumadin Drugs 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- CEJANLKHJMMNQB-UHFFFAOYSA-M cryptocyanin Chemical compound [I-].C12=CC=CC=C2N(CC)C=CC1=CC=CC1=CC=[N+](CC)C2=CC=CC=C12 CEJANLKHJMMNQB-UHFFFAOYSA-M 0.000 description 1
- NRBYBABUHKEQNM-QCJAYSJESA-N cryptosin Chemical compound O([C@@H]1C[C@H]2C[C@@H]3O[C@@]33[C@@]4(O)CC[C@@H]([C@]4(C([C@H](O)[C@@H]3[C@@]2(C)CC1)=O)C)C=1COC(=O)C=1)[C@H]1C[C@@H](O)[C@H](O)[C@@H](CO)O1 NRBYBABUHKEQNM-QCJAYSJESA-N 0.000 description 1
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000004367 cycloalkylaryl group Chemical group 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
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000002243 cyclohexanonyl group Chemical group *C1(*)C(=O)C(*)(*)C(*)(*)C(*)(*)C1(*)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexyloxide Natural products O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 208000002445 cystadenocarcinoma Diseases 0.000 description 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 235000007240 daidzein Nutrition 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin 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(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229960003109 daunorubicin hydrochloride Drugs 0.000 description 1
- 229940026692 decadron Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229960000958 deferoxamine Drugs 0.000 description 1
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 1
- 229940075894 denatured ethanol Drugs 0.000 description 1
- 229940089052 depakene Drugs 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 108700025485 deslorelin Proteins 0.000 description 1
- 229960005408 deslorelin Drugs 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- VPOCYEOOFRNHNL-RQDPQJJXSA-J dexormaplatin Chemical compound Cl[Pt](Cl)(Cl)Cl.N[C@@H]1CCCC[C@H]1N VPOCYEOOFRNHNL-RQDPQJJXSA-J 0.000 description 1
- 229950001640 dexormaplatin Drugs 0.000 description 1
- 229960000605 dexrazoxane Drugs 0.000 description 1
- 229960001985 dextromethorphan Drugs 0.000 description 1
- SGTNSNPWRIOYBX-HHHXNRCGSA-N dexverapamil Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCC[C@@](C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-HHHXNRCGSA-N 0.000 description 1
- 229950005878 dexverapamil Drugs 0.000 description 1
- 201000010064 diabetes insipidus Diseases 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- DIXBSCZRIZDQGC-UHFFFAOYSA-N diaziridine Chemical compound C1NN1 DIXBSCZRIZDQGC-UHFFFAOYSA-N 0.000 description 1
- 125000002720 diazolyl group Chemical group 0.000 description 1
- KYHUYMLIVQFXRI-UHFFFAOYSA-N didemnin B Natural products CC1OC(=O)C(CC=2C=CC(OC)=CC=2)N(C)C(=O)C2CCCN2C(=O)C(CC(C)C)NC(=O)C(C)C(=O)C(C(C)C)OC(=O)CC(O)C(C(C)CC)NC(=O)C1NC(=O)C(CC(C)C)N(C)C(=O)C1CCCN1C(=O)C(C)O KYHUYMLIVQFXRI-UHFFFAOYSA-N 0.000 description 1
- 108010061297 didemnins Proteins 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 1
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 1
- 229960005156 digoxin Drugs 0.000 description 1
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 1
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- 125000005052 dihydropyrazolyl group Chemical group N1(NCC=C1)* 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 125000005054 dihydropyrrolyl group Chemical group [H]C1=C([H])C([H])([H])C([H])([H])N1* 0.000 description 1
- 229940064790 dilantin Drugs 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- CZLKTMHQYXYHOO-QTNFYWBSSA-L disodium;(2s)-2-[(2-phosphonatoacetyl)amino]butanedioic acid Chemical compound [Na+].[Na+].OC(=O)C[C@@H](C(O)=O)NC(=O)CP([O-])([O-])=O CZLKTMHQYXYHOO-QTNFYWBSSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 229940052760 dopamine agonists Drugs 0.000 description 1
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 229960005426 doxepin Drugs 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 1
- NOTIQUSPUUHHEH-UXOVVSIBSA-N dromostanolone propionate Chemical compound C([C@@H]1CC2)C(=O)[C@H](C)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](OC(=O)CC)[C@@]2(C)CC1 NOTIQUSPUUHHEH-UXOVVSIBSA-N 0.000 description 1
- 229960004242 dronabinol Drugs 0.000 description 1
- RMEDXOLNCUSCGS-UHFFFAOYSA-N droperidol Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CC=C(N2C(NC3=CC=CC=C32)=O)CC1 RMEDXOLNCUSCGS-UHFFFAOYSA-N 0.000 description 1
- 229960000394 droperidol Drugs 0.000 description 1
- 229950004683 drostanolone propionate Drugs 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 229950005133 duazomycin Drugs 0.000 description 1
- 229930192837 duazomycin Natural products 0.000 description 1
- 208000028715 ductal breast carcinoma in situ Diseases 0.000 description 1
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 description 1
- 229960005510 duocarmycin SA Drugs 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 229950010033 ebselen Drugs 0.000 description 1
- 229950005678 ecomustine Drugs 0.000 description 1
- 229960003913 econazole Drugs 0.000 description 1
- FSIRXIHZBIXHKT-MHTVFEQDSA-N edatrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CC(CC)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FSIRXIHZBIXHKT-MHTVFEQDSA-N 0.000 description 1
- 229950006700 edatrexate Drugs 0.000 description 1
- 229950011461 edelfosine Drugs 0.000 description 1
- 229940098766 effexor Drugs 0.000 description 1
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 1
- 229960002759 eflornithine Drugs 0.000 description 1
- 229960002046 eflornithine hydrochloride Drugs 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- 229940011681 elavil Drugs 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- MGQRRMONVLMKJL-KWJIQSIXSA-N elsamitrucin Chemical compound O1[C@H](C)[C@H](O)[C@H](OC)[C@@H](N)[C@H]1O[C@@H]1[C@](O)(C)[C@@H](O)[C@@H](C)O[C@H]1OC1=CC=CC2=C(O)C(C(O3)=O)=C4C5=C3C=CC(C)=C5C(=O)OC4=C12 MGQRRMONVLMKJL-KWJIQSIXSA-N 0.000 description 1
- 229950002339 elsamitrucin Drugs 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 201000002246 embryonal cancer Diseases 0.000 description 1
- 229940000733 emcyt Drugs 0.000 description 1
- 229950005450 emitefur Drugs 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 229940073621 enbrel Drugs 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 201000002491 encephalomyelitis Diseases 0.000 description 1
- 208000001991 endodermal sinus tumor Diseases 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 1
- JOZGNYDSEBIJDH-UHFFFAOYSA-N eniluracil Chemical compound O=C1NC=C(C#C)C(=O)N1 JOZGNYDSEBIJDH-UHFFFAOYSA-N 0.000 description 1
- 229950010625 enloplatin Drugs 0.000 description 1
- 229950001022 enpromate Drugs 0.000 description 1
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 229950004926 epipropidine Drugs 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 208000010932 epithelial neoplasm Diseases 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 229950009537 epristeride Drugs 0.000 description 1
- 229940082789 erbitux Drugs 0.000 description 1
- 229950001426 erbulozole Drugs 0.000 description 1
- KLEPCGBEXOCIGS-QPPBQGQZSA-N erbulozole Chemical compound C1=CC(NC(=O)OCC)=CC=C1SC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C=CC(OC)=CC=2)OC1 KLEPCGBEXOCIGS-QPPBQGQZSA-N 0.000 description 1
- GTTBEUCJPZQMDZ-UHFFFAOYSA-N erlotinib hydrochloride Chemical compound [H+].[Cl-].C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 GTTBEUCJPZQMDZ-UHFFFAOYSA-N 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 208000006881 esophagitis Diseases 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- HYSIJEPDMLSIQJ-UHFFFAOYSA-N ethanolate;1-phenylbutane-1,3-dione;titanium(4+) Chemical compound [Ti+4].CC[O-].CC[O-].CC(=O)[CH-]C(=O)C1=CC=CC=C1.CC(=O)[CH-]C(=O)C1=CC=CC=C1 HYSIJEPDMLSIQJ-UHFFFAOYSA-N 0.000 description 1
- XPGDODOEEWLHOI-GSDHBNRESA-N ethyl (2s)-2-[[(2s)-2-[[(2s)-2-amino-3-(4-fluorophenyl)propanoyl]amino]-3-[3-[bis(2-chloroethyl)amino]phenyl]propanoyl]amino]-4-methylsulfanylbutanoate Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)OCC)NC(=O)[C@@H](N)CC=1C=CC(F)=CC=1)C1=CC=CC(N(CCCl)CCCl)=C1 XPGDODOEEWLHOI-GSDHBNRESA-N 0.000 description 1
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- DBPFRRFGLYGEJI-UHFFFAOYSA-N ethyl glyoxylate Chemical compound CCOC(=O)C=O DBPFRRFGLYGEJI-UHFFFAOYSA-N 0.000 description 1
- HZQPPNNARUQMJA-IMIWJGOWSA-N ethyl n-[4-[[(2r,4r)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methylsulfanyl]phenyl]carbamate;hydrochloride Chemical compound Cl.C1=CC(NC(=O)OCC)=CC=C1SC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 HZQPPNNARUQMJA-IMIWJGOWSA-N 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 229940009626 etidronate Drugs 0.000 description 1
- 229960005167 everolimus Drugs 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 208000024519 eye neoplasm Diseases 0.000 description 1
- 210000003195 fascia Anatomy 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 229940126864 fibroblast growth factor Drugs 0.000 description 1
- 201000008825 fibrosarcoma of bone Diseases 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 229960004177 filgrastim Drugs 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 229950006000 flezelastine Drugs 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- FEBLZLNTKCEFIT-VSXGLTOVSA-N fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 description 1
- 238000002376 fluorescence recovery after photobleaching Methods 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 229950005682 flurocitabine Drugs 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229950004217 forfenimex Drugs 0.000 description 1
- 229960004421 formestane Drugs 0.000 description 1
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- RIKPNWPEMPODJD-UHFFFAOYSA-N formononetin Natural products C1=CC(OC)=CC=C1C1=COC2=CC=CC=C2C1=O RIKPNWPEMPODJD-UHFFFAOYSA-N 0.000 description 1
- UXTSQCOOUJTIAC-UHFFFAOYSA-N fosquidone Chemical compound C=1N2CC3=CC=CC=C3C(C)C2=C(C(C2=CC=C3)=O)C=1C(=O)C2=C3OP(O)(=O)OCC1=CC=CC=C1 UXTSQCOOUJTIAC-UHFFFAOYSA-N 0.000 description 1
- 229950005611 fosquidone Drugs 0.000 description 1
- 229950010404 fostriecin Drugs 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 229960002258 fulvestrant Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 description 1
- 229940044658 gallium nitrate Drugs 0.000 description 1
- 229950004410 galocitabine Drugs 0.000 description 1
- 108010074605 gamma-Globulins Proteins 0.000 description 1
- 108700032141 ganirelix Proteins 0.000 description 1
- GJNXBNATEDXMAK-PFLSVRRQSA-N ganirelix Chemical compound C([C@@H](C(=O)N[C@H](CCCCN=C(NCC)NCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN=C(NCC)NCC)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 GJNXBNATEDXMAK-PFLSVRRQSA-N 0.000 description 1
- 229960003794 ganirelix Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229960005144 gemcitabine hydrochloride Drugs 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 108010020199 glutaraldehyde-cross-linked collagen Proteins 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 208000007345 glycogen storage disease Diseases 0.000 description 1
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 description 1
- 229960002867 griseofulvin Drugs 0.000 description 1
- 229960003602 guanethidine Drugs 0.000 description 1
- ACGDKVXYNVEAGU-UHFFFAOYSA-N guanethidine Chemical compound NC(N)=NCCN1CCCCCCC1 ACGDKVXYNVEAGU-UHFFFAOYSA-N 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 229960003242 halofantrine Drugs 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000025750 heavy chain disease Diseases 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 201000002222 hemangioblastoma Diseases 0.000 description 1
- 208000018706 hematopoietic system disease Diseases 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 208000029824 high grade glioma Diseases 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 229940084986 human chorionic gonadotropin Drugs 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 description 1
- 229960001410 hydromorphone Drugs 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- 229960004171 hydroxychloroquine Drugs 0.000 description 1
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- MPGWGYQTRSNGDD-UHFFFAOYSA-N hypericin Chemical compound OC1=CC(O)=C(C2=O)C3=C1C1C(O)=CC(=O)C(C4=O)=C1C1=C3C3=C2C(O)=CC(C)=C3C2=C1C4=C(O)C=C2C MPGWGYQTRSNGDD-UHFFFAOYSA-N 0.000 description 1
- 229940005608 hypericin Drugs 0.000 description 1
- PHOKTTKFQUYZPI-UHFFFAOYSA-N hypericin Natural products Cc1cc(O)c2c3C(=O)C(=Cc4c(O)c5c(O)cc(O)c6c7C(=O)C(=Cc8c(C)c1c2c(c78)c(c34)c56)O)O PHOKTTKFQUYZPI-UHFFFAOYSA-N 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 229960005236 ibandronic acid Drugs 0.000 description 1
- 229950002248 idoxifene Drugs 0.000 description 1
- TZBDEVBNMSLVKT-UHFFFAOYSA-N idramantone Chemical compound C1C(C2)CC3CC1(O)CC2C3=O TZBDEVBNMSLVKT-UHFFFAOYSA-N 0.000 description 1
- 229950009926 idramantone Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- NITYDPDXAAFEIT-DYVFJYSZSA-N ilomastat Chemical compound C1=CC=C2C(C[C@@H](C(=O)NC)NC(=O)[C@H](CC(C)C)CC(=O)NO)=CNC2=C1 NITYDPDXAAFEIT-DYVFJYSZSA-N 0.000 description 1
- 229960003696 ilomastat Drugs 0.000 description 1
- 229960002240 iloprost Drugs 0.000 description 1
- HIFJCPQKFCZDDL-ACWOEMLNSA-N iloprost Chemical compound C1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)C(C)CC#CC)[C@H](O)C[C@@H]21 HIFJCPQKFCZDDL-ACWOEMLNSA-N 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- XZZXIYZZBJDEEP-UHFFFAOYSA-N imipramine hydrochloride Chemical compound [Cl-].C1CC2=CC=CC=C2N(CCC[NH+](C)C)C2=CC=CC=C21 XZZXIYZZBJDEEP-UHFFFAOYSA-N 0.000 description 1
- 229960002751 imiquimod Drugs 0.000 description 1
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 239000000677 immunologic agent Substances 0.000 description 1
- 229940124541 immunological agent Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 229960001438 immunostimulant agent Drugs 0.000 description 1
- 239000003022 immunostimulating agent Substances 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 201000004653 inflammatory breast carcinoma Diseases 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 201000002696 invasive tubular breast carcinoma Diseases 0.000 description 1
- 229960003795 iobenguane (123i) Drugs 0.000 description 1
- 229940044173 iodine-125 Drugs 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 229950010897 iproplatin Drugs 0.000 description 1
- 229960002198 irbesartan Drugs 0.000 description 1
- 229960000779 irinotecan hydrochloride Drugs 0.000 description 1
- 229950000855 iroplact Drugs 0.000 description 1
- 229950010984 irsogladine Drugs 0.000 description 1
- HUOOMAOYXQFIDQ-UHFFFAOYSA-N isoginkgetin Chemical compound C1=CC(OC)=CC=C1C1=CC(=O)C2=C(O)C=C(O)C(C=3C(=CC=C(C=3)C=3OC4=CC(O)=CC(O)=C4C(=O)C=3)OC)=C2O1 HUOOMAOYXQFIDQ-UHFFFAOYSA-N 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 229960005280 isotretinoin Drugs 0.000 description 1
- RWXRJSRJIITQAK-ZSBIGDGJSA-N itasetron Chemical compound C12=CC=CC=C2NC(=O)N1C(=O)N[C@H](C1)C[C@H]2CC[C@@H]1N2C RWXRJSRJIITQAK-ZSBIGDGJSA-N 0.000 description 1
- 229950007654 itasetron Drugs 0.000 description 1
- 229960004130 itraconazole Drugs 0.000 description 1
- GQWYWHOHRVVHAP-DHKPLNAMSA-N jaspamide Chemical compound C1([C@@H]2NC(=O)[C@@H](CC=3C4=CC=CC=C4NC=3Br)N(C)C(=O)[C@H](C)NC(=O)[C@@H](C)C/C(C)=C/[C@H](C)C[C@@H](OC(=O)C2)C)=CC=C(O)C=C1 GQWYWHOHRVVHAP-DHKPLNAMSA-N 0.000 description 1
- 108010052440 jasplakinolide Proteins 0.000 description 1
- GQWYWHOHRVVHAP-UHFFFAOYSA-N jasplakinolide Natural products C1C(=O)OC(C)CC(C)C=C(C)CC(C)C(=O)NC(C)C(=O)N(C)C(CC=2C3=CC=CC=C3NC=2Br)C(=O)NC1C1=CC=C(O)C=C1 GQWYWHOHRVVHAP-UHFFFAOYSA-N 0.000 description 1
- 208000017476 juvenile neuronal ceroid lipofuscinosis Diseases 0.000 description 1
- 201000008632 juvenile polyposis syndrome Diseases 0.000 description 1
- 108010091711 kahalalide F Proteins 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 235000015141 kefir Nutrition 0.000 description 1
- 230000001530 keratinolytic effect Effects 0.000 description 1
- 239000003410 keratolytic agent Substances 0.000 description 1
- FPCCSQOGAWCVBH-UHFFFAOYSA-N ketanserin Chemical compound C1=CC(F)=CC=C1C(=O)C1CCN(CCN2C(C3=CC=CC=C3NC2=O)=O)CC1 FPCCSQOGAWCVBH-UHFFFAOYSA-N 0.000 description 1
- 229960005417 ketanserin Drugs 0.000 description 1
- BWHLPLXXIDYSNW-UHFFFAOYSA-N ketorolac tromethamine Chemical compound OCC(N)(CO)CO.OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 BWHLPLXXIDYSNW-UHFFFAOYSA-N 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 description 1
- 229960001848 lamotrigine Drugs 0.000 description 1
- 229960002437 lanreotide Drugs 0.000 description 1
- 229960001739 lanreotide acetate Drugs 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 1
- 208000003849 large cell carcinoma Diseases 0.000 description 1
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 description 1
- 229960001160 latanoprost Drugs 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- 229960002618 lenograstim Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- GZQKNULLWNGMCW-PWQABINMSA-N lipid A (E. coli) Chemical compound O1[C@H](CO)[C@@H](OP(O)(O)=O)[C@H](OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC)[C@@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H]1OC[C@@H]1[C@@H](O)[C@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](OP(O)(O)=O)O1 GZQKNULLWNGMCW-PWQABINMSA-N 0.000 description 1
- 208000006132 lipodystrophy Diseases 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- RBBBWKUBQVARPL-SWQMWMPHSA-N lissoclinamide 7 Chemical compound C([C@H]1C(=O)N2CCC[C@H]2C2=N[C@@H]([C@H](O2)C)C(=O)N[C@@H](C=2SC[C@H](N=2)C(=O)N[C@H](CC=2C=CC=CC=2)C=2SC[C@H](N=2)C(=O)N1)C(C)C)C1=CC=CC=C1 RBBBWKUBQVARPL-SWQMWMPHSA-N 0.000 description 1
- 108010020270 lissoclinamide 7 Proteins 0.000 description 1
- RBBBWKUBQVARPL-UHFFFAOYSA-N lissoclinamide 7 Natural products N1C(=O)C(N=2)CSC=2C(CC=2C=CC=CC=2)NC(=O)C(N=2)CSC=2C(C(C)C)NC(=O)C(C(O2)C)N=C2C2CCCN2C(=O)C1CC1=CC=CC=C1 RBBBWKUBQVARPL-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 229950008991 lobaplatin Drugs 0.000 description 1
- 229950000909 lometrexol Drugs 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 229960003538 lonidamine Drugs 0.000 description 1
- WDRYRZXSPDWGEB-UHFFFAOYSA-N lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 description 1
- YROQEQPFUCPDCP-UHFFFAOYSA-N losoxantrone Chemical compound OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO YROQEQPFUCPDCP-UHFFFAOYSA-N 0.000 description 1
- 229950008745 losoxantrone Drugs 0.000 description 1
- XDMHALQMTPSGEA-UHFFFAOYSA-N losoxantrone hydrochloride Chemical compound Cl.Cl.OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO XDMHALQMTPSGEA-UHFFFAOYSA-N 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 229940083747 low-ceiling diuretics xanthine derivative Drugs 0.000 description 1
- 229950005634 loxoribine Drugs 0.000 description 1
- RVFGKBWWUQOIOU-NDEPHWFRSA-N lurtotecan Chemical compound O=C([C@]1(O)CC)OCC(C(N2CC3=4)=O)=C1C=C2C3=NC1=CC=2OCCOC=2C=C1C=4CN1CCN(C)CC1 RVFGKBWWUQOIOU-NDEPHWFRSA-N 0.000 description 1
- 229950002654 lurtotecan Drugs 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 208000019053 lymphatic vessel neoplasm Diseases 0.000 description 1
- 201000011649 lymphoblastic lymphoma Diseases 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- FXBYOMANNHFNQV-UHFFFAOYSA-L magnesium;hydrogen sulfate Chemical compound [Mg+2].OS([O-])(=O)=O.OS([O-])(=O)=O FXBYOMANNHFNQV-UHFFFAOYSA-L 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 229950001474 maitansine Drugs 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
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 201000002350 malignant ciliary body melanoma Diseases 0.000 description 1
- 201000004593 malignant giant cell tumor Diseases 0.000 description 1
- 201000011614 malignant glioma Diseases 0.000 description 1
- 208000006178 malignant mesothelioma Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 229950008959 marimastat Drugs 0.000 description 1
- OCSMOTCMPXTDND-OUAUKWLOSA-N marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- QZIQJVCYUQZDIR-UHFFFAOYSA-N mechlorethamine hydrochloride Chemical compound Cl.ClCCN(C)CCCl QZIQJVCYUQZDIR-UHFFFAOYSA-N 0.000 description 1
- 208000030163 medullary breast carcinoma Diseases 0.000 description 1
- 229960001962 mefloquine Drugs 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- JDSHMPZPIAZGSV-UHFFFAOYSA-N melamine Chemical compound NC1=NC(N)=NC(N)=N1 JDSHMPZPIAZGSV-UHFFFAOYSA-N 0.000 description 1
- 229960001728 melarsoprol Drugs 0.000 description 1
- 229960003846 melengestrol acetate Drugs 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000003475 metalloproteinase inhibitor Substances 0.000 description 1
- 229940126170 metalloproteinase inhibitor Drugs 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 208000010658 metastatic prostate carcinoma Diseases 0.000 description 1
- 108700025096 meterelin Proteins 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- HRHKSTOGXBBQCB-VFWICMBZSA-N methylmitomycin Chemical compound O=C1C(N)=C(C)C(=O)C2=C1[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N(C)[C@H]3CN12 HRHKSTOGXBBQCB-VFWICMBZSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- VQJHOPSWBGJHQS-UHFFFAOYSA-N metoprine, methodichlorophen Chemical compound CC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C(Cl)=C1 VQJHOPSWBGJHQS-UHFFFAOYSA-N 0.000 description 1
- 229960003404 mexiletine Drugs 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- VKHAHZOOUSRJNA-GCNJZUOMSA-N mifepristone Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@@]([C@]3(C2)C)(O)C#CC)=CC=C(N(C)C)C=C1 VKHAHZOOUSRJNA-GCNJZUOMSA-N 0.000 description 1
- 229960003248 mifepristone Drugs 0.000 description 1
- 229950008541 mirimostim Drugs 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- DRCJGCOYHLTVNR-ZUIZSQJWSA-N mitindomide Chemical compound C1=C[C@@H]2[C@@H]3[C@H]4C(=O)NC(=O)[C@H]4[C@@H]3[C@H]1[C@@H]1C(=O)NC(=O)[C@H]21 DRCJGCOYHLTVNR-ZUIZSQJWSA-N 0.000 description 1
- 229950001314 mitindomide Drugs 0.000 description 1
- 229950002137 mitocarcin Drugs 0.000 description 1
- 229950000911 mitogillin Drugs 0.000 description 1
- 229960003539 mitoguazone Drugs 0.000 description 1
- MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 0.000 description 1
- VFKZTMPDYBFSTM-GUCUJZIJSA-N mitolactol Chemical compound BrC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-GUCUJZIJSA-N 0.000 description 1
- 229950010913 mitolactol Drugs 0.000 description 1
- 108010026677 mitomalcin Proteins 0.000 description 1
- 229950007612 mitomalcin Drugs 0.000 description 1
- 229950001745 mitonafide Drugs 0.000 description 1
- 229950005715 mitosper Drugs 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- ZAHQPTJLOCWVPG-UHFFFAOYSA-N mitoxantrone dihydrochloride Chemical compound Cl.Cl.O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO ZAHQPTJLOCWVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004169 mitoxantrone hydrochloride Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229950008012 mofarotene Drugs 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229960003063 molgramostim Drugs 0.000 description 1
- 108010032806 molgramostim Proteins 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 210000000865 mononuclear phagocyte system Anatomy 0.000 description 1
- FOYWNSCCNCUEPU-UHFFFAOYSA-N mopidamol Chemical compound C12=NC(N(CCO)CCO)=NC=C2N=C(N(CCO)CCO)N=C1N1CCCCC1 FOYWNSCCNCUEPU-UHFFFAOYSA-N 0.000 description 1
- 229950010718 mopidamol Drugs 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 229960004715 morphine sulfate Drugs 0.000 description 1
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 description 1
- 230000001002 morphogenetic effect Effects 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 208000005264 motor neuron disease Diseases 0.000 description 1
- 206010028093 mucopolysaccharidosis Diseases 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- 201000000585 muscular atrophy Diseases 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 201000005962 mycosis fungoides Diseases 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- PAVKBQLPQCDVNI-UHFFFAOYSA-N n',n'-diethyl-n-(9-methoxy-5,11-dimethyl-6h-pyrido[4,3-b]carbazol-1-yl)propane-1,3-diamine Chemical class N1C2=CC=C(OC)C=C2C2=C1C(C)=C1C=CN=C(NCCCN(CC)CC)C1=C2C PAVKBQLPQCDVNI-UHFFFAOYSA-N 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- CRJGESKKUOMBCT-PMACEKPBSA-N n-[(2s,3s)-1,3-dihydroxyoctadecan-2-yl]acetamide Chemical compound CCCCCCCCCCCCCCC[C@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-PMACEKPBSA-N 0.000 description 1
- NKFHKYQGZDAKMX-PPRKPIOESA-N n-[(e)-1-[(2s,4s)-4-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1h-tetracen-2-yl]ethylideneamino]benzamide;hydrochloride Chemical compound Cl.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(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 NKFHKYQGZDAKMX-PPRKPIOESA-N 0.000 description 1
- TVYPSLDUBVTDIS-FUOMVGGVSA-N n-[1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]-3,4,5-trimethoxybenzamide Chemical compound COC1=C(OC)C(OC)=CC(C(=O)NC=2C(=CN(C(=O)N=2)[C@H]2[C@@H]([C@H](O)[C@@H](C)O2)O)F)=C1 TVYPSLDUBVTDIS-FUOMVGGVSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- ARKYUICTMUZVEW-UHFFFAOYSA-N n-[5-[[5-[(3-amino-3-iminopropyl)carbamoyl]-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-4-[[4-[bis(2-chloroethyl)amino]benzoyl]amino]-1-methylpyrrole-2-carboxamide Chemical compound C1=C(C(=O)NCCC(N)=N)N(C)C=C1NC(=O)C1=CC(NC(=O)C=2N(C=C(NC(=O)C=3C=CC(=CC=3)N(CCCl)CCCl)C=2)C)=CN1C ARKYUICTMUZVEW-UHFFFAOYSA-N 0.000 description 1
- RWHUEXWOYVBUCI-ITQXDASVSA-N nafarelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 RWHUEXWOYVBUCI-ITQXDASVSA-N 0.000 description 1
- 229960002333 nafarelin Drugs 0.000 description 1
- 229960004127 naloxone Drugs 0.000 description 1
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 1
- JZGDNMXSOCDEFQ-UHFFFAOYSA-N napavin Chemical compound C1C(CC)(O)CC(C2)CN1CCC(C1=CC=CC=C1N1)=C1C2(C(=O)OC)C(C(=C1)OC)=CC2=C1N(C)C1C2(C23)CCN3CC=CC2(CC)C(O)C1(O)C(=O)NCCNC1=CC=C(N=[N+]=[N-])C=C1[N+]([O-])=O JZGDNMXSOCDEFQ-UHFFFAOYSA-N 0.000 description 1
- 229950007221 nedaplatin Drugs 0.000 description 1
- 229960001800 nefazodone Drugs 0.000 description 1
- VRBKIVRKKCLPHA-UHFFFAOYSA-N nefazodone Chemical compound O=C1N(CCOC=2C=CC=CC=2)C(CC)=NN1CCCN(CC1)CCN1C1=CC=CC(Cl)=C1 VRBKIVRKKCLPHA-UHFFFAOYSA-N 0.000 description 1
- DYCKFEBIOUQECE-UHFFFAOYSA-N nefazodone hydrochloride Chemical compound [H+].[Cl-].O=C1N(CCOC=2C=CC=CC=2)C(CC)=NN1CCCN(CC1)CCN1C1=CC=CC(Cl)=C1 DYCKFEBIOUQECE-UHFFFAOYSA-N 0.000 description 1
- CTMCWCONSULRHO-UHQPFXKFSA-N nemorubicin Chemical compound C1CO[C@H](OC)CN1[C@@H]1[C@H](O)[C@H](C)O[C@@H](O[C@@H]2C3=C(O)C=4C(=O)C5=C(OC)C=CC=C5C(=O)C=4C(O)=C3C[C@](O)(C2)C(=O)CO)C1 CTMCWCONSULRHO-UHQPFXKFSA-N 0.000 description 1
- 229950010159 nemorubicin Drugs 0.000 description 1
- 208000025440 neoplasm of neck Diseases 0.000 description 1
- 229960002253 neostigmine methylsulfate Drugs 0.000 description 1
- PUUSSSIBPPTKTP-UHFFFAOYSA-N neridronic acid Chemical compound NCCCCCC(O)(P(O)(O)=O)P(O)(O)=O PUUSSSIBPPTKTP-UHFFFAOYSA-N 0.000 description 1
- 229950010733 neridronic acid Drugs 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000000276 neural tube Anatomy 0.000 description 1
- 208000007538 neurilemmoma Diseases 0.000 description 1
- 201000007607 neuronal ceroid lipofuscinosis 3 Diseases 0.000 description 1
- 239000003900 neurotrophic factor Substances 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 229960002644 nifurtimox Drugs 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- 201000001705 nipple carcinoma Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229940125745 nitric oxide modulator Drugs 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical compound NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 description 1
- 239000001272 nitrous oxide Substances 0.000 description 1
- 229950006344 nocodazole Drugs 0.000 description 1
- 201000000032 nodular malignant melanoma Diseases 0.000 description 1
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 description 1
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 230000000683 nonmetastatic effect Effects 0.000 description 1
- 230000001254 nonsecretory effect Effects 0.000 description 1
- 229960001158 nortriptyline Drugs 0.000 description 1
- 208000020205 notochordal tumor Diseases 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 229960000988 nystatin Drugs 0.000 description 1
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound 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/CC/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)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 1
- 229960002700 octreotide Drugs 0.000 description 1
- 201000008106 ocular cancer Diseases 0.000 description 1
- 201000002575 ocular melanoma Diseases 0.000 description 1
- 210000004248 oligodendroglia Anatomy 0.000 description 1
- 229950000973 omapatrilat Drugs 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 229940127240 opiate Drugs 0.000 description 1
- 239000000014 opioid analgesic Substances 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000015205 orange juice Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- ZLLOIFNEEWYATC-XMUHMHRVSA-N osaterone Chemical compound C1=C(Cl)C2=CC(=O)OC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 ZLLOIFNEEWYATC-XMUHMHRVSA-N 0.000 description 1
- 229950006466 osaterone Drugs 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- CTRLABGOLIVAIY-UHFFFAOYSA-N oxcarbazepine Chemical compound C1C(=O)C2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 CTRLABGOLIVAIY-UHFFFAOYSA-N 0.000 description 1
- 229950000370 oxisuran Drugs 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 1
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 1
- VYOQBYCIIJYKJA-VORKOXQSSA-N palau'amine Chemical compound N([C@@]12[C@@H](Cl)[C@@H]([C@@H]3[C@@H]2[C@]24N=C(N)N[C@H]2N2C=CC=C2C(=O)N4C3)CN)C(N)=N[C@H]1O VYOQBYCIIJYKJA-VORKOXQSSA-N 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 229940055692 pamelor Drugs 0.000 description 1
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 1
- 229960003978 pamidronic acid Drugs 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- RDIMTXDFGHNINN-IKGGRYGDSA-N panaxytriol Chemical compound CCCCCCC[C@H](O)[C@@H](O)CC#CC#C[C@H](O)C=C RDIMTXDFGHNINN-IKGGRYGDSA-N 0.000 description 1
- ZCKMUKZQXWHXOF-UHFFFAOYSA-N panaxytriol Natural products CCC(C)C(C)C(C)C(C)C(C)C(O)C(O)CC#CC#CC(O)C=C ZCKMUKZQXWHXOF-UHFFFAOYSA-N 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 208000022102 pancreatic neuroendocrine neoplasm Diseases 0.000 description 1
- 229950003440 panomifene Drugs 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 208000004019 papillary adenocarcinoma Diseases 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- LPHSYQSMAGVYNT-UHFFFAOYSA-N pazelliptine Chemical compound N1C2=CC=NC=C2C2=C1C(C)=C1C=CN=C(NCCCN(CC)CC)C1=C2 LPHSYQSMAGVYNT-UHFFFAOYSA-N 0.000 description 1
- 229950006361 pazelliptine Drugs 0.000 description 1
- DOHVAKFYAHLCJP-UHFFFAOYSA-N peldesine Chemical compound C1=2NC(N)=NC(=O)C=2NC=C1CC1=CC=CN=C1 DOHVAKFYAHLCJP-UHFFFAOYSA-N 0.000 description 1
- 229950000039 peldesine Drugs 0.000 description 1
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-N pemetrexed Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-N 0.000 description 1
- GJVFBWCTGUSGDD-UHFFFAOYSA-L pentamethonium bromide Chemical compound [Br-].[Br-].C[N+](C)(C)CCCCC[N+](C)(C)C GJVFBWCTGUSGDD-UHFFFAOYSA-L 0.000 description 1
- 229950000494 pentamethonium bromide Drugs 0.000 description 1
- 229960004448 pentamidine Drugs 0.000 description 1
- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 description 1
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 1
- 229960005301 pentazocine Drugs 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 229960001476 pentoxifylline Drugs 0.000 description 1
- QIMGFXOHTOXMQP-GFAGFCTOSA-N peplomycin Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCN[C@@H](C)C=1C=CC=CC=1)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C QIMGFXOHTOXMQP-GFAGFCTOSA-N 0.000 description 1
- 229950003180 peplomycin Drugs 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 229940023041 peptide vaccine Drugs 0.000 description 1
- WTWWXOGTJWMJHI-UHFFFAOYSA-N perflubron Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br WTWWXOGTJWMJHI-UHFFFAOYSA-N 0.000 description 1
- 229960001217 perflubron Drugs 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 201000002524 peritoneal carcinoma Diseases 0.000 description 1
- 229960002087 pertuzumab Drugs 0.000 description 1
- LCADVYTXPLBAGB-GNCBHIOISA-N phenalamide A1 Natural products CC(CO)NC(=O)C(=CC=CC=C/C=C/C(=C/C(C)C(O)C(=CC(C)CCc1ccccc1)C)/C)C LCADVYTXPLBAGB-GNCBHIOISA-N 0.000 description 1
- 229960003418 phenoxybenzamine Drugs 0.000 description 1
- MRBDMNSDAVCSSF-UHFFFAOYSA-N phentolamine Chemical compound C1=CC(C)=CC=C1N(C=1C=C(O)C=CC=1)CC1=NCCN1 MRBDMNSDAVCSSF-UHFFFAOYSA-N 0.000 description 1
- 229960001999 phentolamine Drugs 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 description 1
- 208000028591 pheochromocytoma Diseases 0.000 description 1
- 239000011990 phillips catalyst Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 229960004838 phosphoric acid Drugs 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 229960001697 physostigmine Drugs 0.000 description 1
- 239000003075 phytoestrogen Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229940023488 pill Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- XESARGFCSKSFID-FLLFQEBCSA-N pirazofurin Chemical compound OC1=C(C(=O)N)NN=C1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 XESARGFCSKSFID-FLLFQEBCSA-N 0.000 description 1
- 229950001030 piritrexim Drugs 0.000 description 1
- 208000031223 plasma cell leukemia Diseases 0.000 description 1
- 229940012957 plasmin Drugs 0.000 description 1
- 239000002797 plasminogen activator inhibitor Substances 0.000 description 1
- CLSUSRZJUQMOHH-UHFFFAOYSA-L platinum dichloride Chemical compound Cl[Pt]Cl CLSUSRZJUQMOHH-UHFFFAOYSA-L 0.000 description 1
- JKPDEYAOCSQBSZ-OEUJLIAZSA-N plomestane Chemical compound O=C1CC[C@]2(CC#C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 JKPDEYAOCSQBSZ-OEUJLIAZSA-N 0.000 description 1
- 229950004541 plomestane Drugs 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 208000015768 polyposis Diseases 0.000 description 1
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 description 1
- 229960000688 pomalidomide Drugs 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 239000012254 powdered material Substances 0.000 description 1
- 229940089484 pravachol Drugs 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229940096112 prednisol Drugs 0.000 description 1
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 1
- 229960001233 pregabalin Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 229960005179 primaquine Drugs 0.000 description 1
- 208000016800 primary central nervous system lymphoma Diseases 0.000 description 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 229960005385 proguanil Drugs 0.000 description 1
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940095574 propionic acid Drugs 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 150000003815 prostacyclins Chemical class 0.000 description 1
- UQOQENZZLBSFKO-POPPZSFYSA-N prostaglandin J2 Chemical compound CCCCC[C@H](O)\C=C\[C@@H]1[C@@H](C\C=C/CCCC(O)=O)C=CC1=O UQOQENZZLBSFKO-POPPZSFYSA-N 0.000 description 1
- 239000002089 prostaglandin antagonist Substances 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 208000023958 prostate neoplasm Diseases 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 229960000856 protein c Drugs 0.000 description 1
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 230000009822 protein phosphorylation Effects 0.000 description 1
- 229940126731 protein tyrosine phosphatase inhibitor Drugs 0.000 description 1
- 239000003806 protein tyrosine phosphatase inhibitor Substances 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 229940035613 prozac Drugs 0.000 description 1
- SSKVDVBQSWQEGJ-UHFFFAOYSA-N pseudohypericin Natural products C12=C(O)C=C(O)C(C(C=3C(O)=CC(O)=C4C=33)=O)=C2C3=C2C3=C4C(C)=CC(O)=C3C(=O)C3=C(O)C=C(O)C1=C32 SSKVDVBQSWQEGJ-UHFFFAOYSA-N 0.000 description 1
- 210000001147 pulmonary artery Anatomy 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 239000000784 purine nucleoside phosphorylase inhibitor Substances 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- MKSVFGKWZLUTTO-FZFAUISWSA-N puromycin dihydrochloride Chemical compound Cl.Cl.C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO MKSVFGKWZLUTTO-FZFAUISWSA-N 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- WKSAUQYGYAYLPV-UHFFFAOYSA-N pyrimethamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1 WKSAUQYGYAYLPV-UHFFFAOYSA-N 0.000 description 1
- 229960000611 pyrimethamine Drugs 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- NTHPAPBPFQJABD-LLVKDONJSA-N ramosetron Chemical compound C12=CC=CC=C2N(C)C=C1C(=O)[C@H]1CC(NC=N2)=C2CC1 NTHPAPBPFQJABD-LLVKDONJSA-N 0.000 description 1
- 229950001588 ramosetron Drugs 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 108091006082 receptor inhibitors Proteins 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001281 rectum adenocarcinoma Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229940116176 remicade Drugs 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 235000021283 resveratrol Nutrition 0.000 description 1
- 229940016667 resveratrol Drugs 0.000 description 1
- 230000003307 reticuloendothelial effect Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 229940061341 retisert Drugs 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 229960004356 riboprine Drugs 0.000 description 1
- 229960003292 rifamycin Drugs 0.000 description 1
- HJYYPODYNSCCOU-ODRIEIDWSA-N rifamycin SV Chemical compound OC1=C(C(O)=C2C)C3=C(O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O HJYYPODYNSCCOU-ODRIEIDWSA-N 0.000 description 1
- 229950003733 romurtide Drugs 0.000 description 1
- 108700033545 romurtide Proteins 0.000 description 1
- 229960003522 roquinimex Drugs 0.000 description 1
- YADVRLOQIWILGX-UHFFFAOYSA-N sarcophytol N Natural products CC(C)C1=CC=C(C)CCC=C(C)CCC=C(C)CC1O YADVRLOQIWILGX-UHFFFAOYSA-N 0.000 description 1
- 229960002530 sargramostim Drugs 0.000 description 1
- 108010038379 sargramostim Proteins 0.000 description 1
- 239000000565 sealant Substances 0.000 description 1
- 201000008407 sebaceous adenocarcinoma Diseases 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 230000009758 senescence Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229940099190 serzone Drugs 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- 210000001013 sinoatrial node Anatomy 0.000 description 1
- 208000037968 sinus cancer Diseases 0.000 description 1
- 229950005143 sitosterol Drugs 0.000 description 1
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 description 1
- 229950001403 sizofiran Drugs 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 238000010321 sleep therapy Methods 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 201000009295 smoldering myeloma Diseases 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 229940125794 sodium channel blocker Drugs 0.000 description 1
- 239000003195 sodium channel blocking agent Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 235000010268 sodium methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229940006198 sodium phenylacetate Drugs 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- WGIKUIATRROGSN-UHFFFAOYSA-M sodium;4-hydroxy-4-oxo-2-sulfanylbutanoate Chemical compound [Na+].OC(=O)CC(S)C([O-])=O WGIKUIATRROGSN-UHFFFAOYSA-M 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
- 229950004225 sonermin Drugs 0.000 description 1
- 229950004796 sparfosic acid Drugs 0.000 description 1
- 229950009641 sparsomycin Drugs 0.000 description 1
- XKLZIVIOZDNKEQ-CLQLPEFOSA-N sparsomycin Chemical compound CSC[S@](=O)C[C@H](CO)NC(=O)\C=C\C1=C(C)NC(=O)NC1=O XKLZIVIOZDNKEQ-CLQLPEFOSA-N 0.000 description 1
- XKLZIVIOZDNKEQ-UHFFFAOYSA-N sparsomycin Natural products CSCS(=O)CC(CO)NC(=O)C=CC1=C(C)NC(=O)NC1=O XKLZIVIOZDNKEQ-UHFFFAOYSA-N 0.000 description 1
- 230000001148 spastic effect Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- YBZRLMLGUBIIDN-NZSGCTDASA-N spicamycin Chemical compound O1[C@@H](C(O)CO)[C@H](NC(=O)CNC(=O)CCCCCCCCCCCCC(C)C)[C@@H](O)[C@@H](O)[C@H]1NC1=NC=NC2=C1N=CN2 YBZRLMLGUBIIDN-NZSGCTDASA-N 0.000 description 1
- YBZRLMLGUBIIDN-UHFFFAOYSA-N spicamycin Natural products O1C(C(O)CO)C(NC(=O)CNC(=O)CCCCCCCCCCCCC(C)C)C(O)C(O)C1NC1=NC=NC2=C1NC=N2 YBZRLMLGUBIIDN-UHFFFAOYSA-N 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 229960001294 spiramycin Drugs 0.000 description 1
- 235000019372 spiramycin Nutrition 0.000 description 1
- 229930191512 spiramycin Natural products 0.000 description 1
- 229950004330 spiroplatin Drugs 0.000 description 1
- 108010032486 splenopentin Proteins 0.000 description 1
- ICXJVZHDZFXYQC-UHFFFAOYSA-N spongistatin 1 Natural products OC1C(O2)(O)CC(O)C(C)C2CCCC=CC(O2)CC(O)CC2(O2)CC(OC)CC2CC(=O)C(C)C(OC(C)=O)C(C)C(=C)CC(O2)CC(C)(O)CC2(O2)CC(OC(C)=O)CC2CC(=O)OC2C(O)C(CC(=C)CC(O)C=CC(Cl)=C)OC1C2C ICXJVZHDZFXYQC-UHFFFAOYSA-N 0.000 description 1
- HAOCRCFHEPRQOY-JKTUOYIXSA-N spongistatin-1 Chemical compound C([C@@H]1C[C@@H](C[C@@]2(C[C@@H](O)C[C@@H](C2)\C=C/CCC[C@@H]2[C@H](C)[C@@H](O)C[C@](O2)(O)[C@H]2O)O1)OC)C(=O)[C@@H](C)[C@@H](OC(C)=O)[C@H](C)C(=C)C[C@H](O1)C[C@](C)(O)C[C@@]1(O1)C[C@@H](OC(C)=O)C[C@@H]1CC(=O)O[C@H]1[C@H](O)[C@@H](CC(=C)C(C)[C@H](O)\C=C\C(Cl)=C)O[C@@H]2[C@@H]1C HAOCRCFHEPRQOY-JKTUOYIXSA-N 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 229950001248 squalamine Drugs 0.000 description 1
- 102000009076 src-Family Kinases Human genes 0.000 description 1
- 108010087686 src-Family Kinases Proteins 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 1
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 229960004306 sulfadiazine Drugs 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- YZMCKZRAOLZXAZ-UHFFFAOYSA-N sulfisomidine Chemical compound CC1=NC(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 YZMCKZRAOLZXAZ-UHFFFAOYSA-N 0.000 description 1
- 229960001975 sulfisomidine Drugs 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical compound S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 description 1
- 229950007841 sulofenur Drugs 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 208000030457 superficial spreading melanoma Diseases 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 229960005566 swainsonine Drugs 0.000 description 1
- FXUAIOOAOAVCGD-FKSUSPILSA-N swainsonine Chemical compound C1CC[C@H](O)[C@H]2[C@H](O)[C@H](O)CN21 FXUAIOOAOAVCGD-FKSUSPILSA-N 0.000 description 1
- FXUAIOOAOAVCGD-UHFFFAOYSA-N swainsonine Natural products C1CCC(O)C2C(O)C(O)CN21 FXUAIOOAOAVCGD-UHFFFAOYSA-N 0.000 description 1
- 201000008759 sweat gland cancer Diseases 0.000 description 1
- 206010042863 synovial sarcoma Diseases 0.000 description 1
- 201000008753 synovium neoplasm Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- VAZAPHZUAVEOMC-UHFFFAOYSA-N tacedinaline Chemical compound C1=CC(NC(=O)C)=CC=C1C(=O)NC1=CC=CC=C1N VAZAPHZUAVEOMC-UHFFFAOYSA-N 0.000 description 1
- 229960000835 tadalafil Drugs 0.000 description 1
- 108700003774 talisomycin Proteins 0.000 description 1
- 229950002687 talisomycin Drugs 0.000 description 1
- 108010021891 tallimustine Proteins 0.000 description 1
- 229950005667 tallimustine Drugs 0.000 description 1
- 229950007866 tanespimycin Drugs 0.000 description 1
- AYUNIORJHRXIBJ-TXHRRWQRSA-N tanespimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(NCC=C)C(=O)C=C1C2=O AYUNIORJHRXIBJ-TXHRRWQRSA-N 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229950010168 tauromustine Drugs 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 229960000565 tazarotene Drugs 0.000 description 1
- URLYINUFLXOMHP-HTVVRFAVSA-N tcn-p Chemical compound C=12C3=NC=NC=1N(C)N=C(N)C2=CN3[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O URLYINUFLXOMHP-HTVVRFAVSA-N 0.000 description 1
- 229940090016 tegretol Drugs 0.000 description 1
- 239000003277 telomerase inhibitor Substances 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 1
- 208000001608 teratocarcinoma Diseases 0.000 description 1
- 231100000378 teratogenic Toxicity 0.000 description 1
- 230000003390 teratogenic effect Effects 0.000 description 1
- 229950008703 teroxirone Drugs 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 230000002381 testicular Effects 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 208000002918 testicular germ cell tumor Diseases 0.000 description 1
- MJNHIYILRDOOTC-UHFFFAOYSA-N tetrachlorophosphanium Chemical compound Cl[P+](Cl)(Cl)Cl MJNHIYILRDOOTC-UHFFFAOYSA-N 0.000 description 1
- 239000005460 tetrahydrofolate Substances 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- WXZSUBHBYQYTNM-WMDJANBXSA-N tetrazomine Chemical compound C=1([C@@H]2CO[C@@H]3[C@H]4C[C@@H](CO)[C@H](N4C)[C@@H](N23)CC=1C=C1)C(OC)=C1NC(=O)C1NCCC[C@H]1O WXZSUBHBYQYTNM-WMDJANBXSA-N 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- NZVYCXVTEHPMHE-ZSUJOUNUSA-N thymalfasin Chemical compound CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NZVYCXVTEHPMHE-ZSUJOUNUSA-N 0.000 description 1
- 229960004231 thymalfasin Drugs 0.000 description 1
- 229950010183 thymotrinan Drugs 0.000 description 1
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 1
- 208000013818 thyroid gland medullary carcinoma Diseases 0.000 description 1
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 description 1
- YFTWHEBLORWGNI-UHFFFAOYSA-N tiamiprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC(N)=NC2=C1NC=N2 YFTWHEBLORWGNI-UHFFFAOYSA-N 0.000 description 1
- 229950011457 tiamiprine Drugs 0.000 description 1
- 229960003723 tiazofurine Drugs 0.000 description 1
- FVRDYQYEVDDKCR-DBRKOABJSA-N tiazofurine Chemical compound NC(=O)C1=CSC([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=N1 FVRDYQYEVDDKCR-DBRKOABJSA-N 0.000 description 1
- 229950002376 tirapazamine Drugs 0.000 description 1
- QVMPZNRFXAKISM-UHFFFAOYSA-N tirapazamine Chemical compound C1=CC=C2[N+]([O-])=NC(=N)N(O)C2=C1 QVMPZNRFXAKISM-UHFFFAOYSA-N 0.000 description 1
- XFYDIVBRZNQMJC-UHFFFAOYSA-N tizanidine Chemical compound ClC=1C=CC2=NSN=C2C=1NC1=NCCN1 XFYDIVBRZNQMJC-UHFFFAOYSA-N 0.000 description 1
- 229960000488 tizanidine Drugs 0.000 description 1
- 229940041597 tofranil Drugs 0.000 description 1
- ONYVJPZNVCOAFF-UHFFFAOYSA-N topsentin Natural products Oc1ccc2cc([nH]c2c1)C(=O)c3ncc([nH]3)c4c[nH]c5ccccc45 ONYVJPZNVCOAFF-UHFFFAOYSA-N 0.000 description 1
- 229960004167 toremifene citrate Drugs 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 229940118436 tracleer Drugs 0.000 description 1
- 229960004380 tramadol Drugs 0.000 description 1
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 229960003991 trazodone Drugs 0.000 description 1
- 229950005609 trestolone Drugs 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 229960004319 trichloroacetic acid Drugs 0.000 description 1
- 229950003873 triciribine Drugs 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 229940061414 trileptal Drugs 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- CCRMAATUKBYMPA-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C.C[Sn](C)C CCRMAATUKBYMPA-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- WMPQMBUXZHMEFZ-YJPJVVPASA-N turosteride Chemical compound CN([C@@H]1CC2)C(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)N(C(C)C)C(=O)NC(C)C)[C@@]2(C)CC1 WMPQMBUXZHMEFZ-YJPJVVPASA-N 0.000 description 1
- 229950007816 turosteride Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 229940045136 urea Drugs 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 208000037965 uterine sarcoma Diseases 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-M valinate Chemical compound CC(C)C(N)C([O-])=O KZSNJWFQEVHDMF-UHFFFAOYSA-M 0.000 description 1
- 229940124676 vascular endothelial growth factor receptor Drugs 0.000 description 1
- 230000004218 vascular function Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 229950000578 vatalanib Drugs 0.000 description 1
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 1
- LLDWLPRYLVPDTG-UHFFFAOYSA-N vatalanib succinate Chemical compound OC(=O)CCC(O)=O.C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 LLDWLPRYLVPDTG-UHFFFAOYSA-N 0.000 description 1
- 229950008261 velaresol Drugs 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- XLQGICHHYYWYIU-UHFFFAOYSA-N veramine Natural products O1C2CC3C4CC=C5CC(O)CCC5(C)C4CC=C3C2(C)C(C)C21CCC(C)CN2 XLQGICHHYYWYIU-UHFFFAOYSA-N 0.000 description 1
- 229940094720 viagra Drugs 0.000 description 1
- 229940065658 vidaza Drugs 0.000 description 1
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 1
- 229960004982 vinblastine sulfate Drugs 0.000 description 1
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 1
- 229960002110 vincristine sulfate Drugs 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- BCXOZISMDZTYHW-IFQBWSDRSA-N vinepidine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@H](C2)CC)N2CCC2=C1NC1=CC=CC=C21 BCXOZISMDZTYHW-IFQBWSDRSA-N 0.000 description 1
- 229960002166 vinorelbine tartrate Drugs 0.000 description 1
- GBABOYUKABKIAF-IWWDSPBFSA-N vinorelbinetartrate Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC(C23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IWWDSPBFSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 229960001771 vorozole Drugs 0.000 description 1
- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 229940009065 wellbutrin Drugs 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- QDLHCMPXEPAAMD-QAIWCSMKSA-N wortmannin Chemical compound C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O QDLHCMPXEPAAMD-QAIWCSMKSA-N 0.000 description 1
- QDLHCMPXEPAAMD-UHFFFAOYSA-N wortmannin Natural products COCC1OC(=O)C2=COC(C3=O)=C2C1(C)C1=C3C2CCC(=O)C2(C)CC1OC(C)=O QDLHCMPXEPAAMD-UHFFFAOYSA-N 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
- 229950005561 zanoterone Drugs 0.000 description 1
- BPKIMPVREBSLAJ-QTBYCLKRSA-N ziconotide Chemical compound C([C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]2C(=O)N[C@@H]3C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CSSC2)C(N)=O)=O)CSSC[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CSSC3)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(N1)=O)CCSC)[C@@H](C)O)C1=CC=C(O)C=C1 BPKIMPVREBSLAJ-QTBYCLKRSA-N 0.000 description 1
- 229960002811 ziconotide Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229940072168 zocor Drugs 0.000 description 1
- 229940020965 zoloft Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Pain & Pain Management (AREA)
- Pulmonology (AREA)
- Hematology (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Obesity (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Urology & Nephrology (AREA)
- Psychology (AREA)
- Endocrinology (AREA)
- Transplantation (AREA)
- Oncology (AREA)
- Vascular Medicine (AREA)
- Emergency Medicine (AREA)
Description
本文中所提供者為某些雜芳基化合物,包含有效量之一或多種此類化合物之組合物,及用於治療或預防癌症、炎性症狀、免疫學症狀、代謝症狀及可藉由抑制激酶路徑而被治療或預防之症狀之方法,其包括對有需要之病患投予有效量之雜芳基化合物。
本申請案係主張2008年10月27日提出申請之美國臨時申請案號61/108,627之權益,其全部內容均併於本文供參考。
在異常蛋白質磷醯化作用與疾病之原因或結果間之連接係被知曉超過20年。因此,蛋白質激酶已變成一組極重要之藥物標的。參閱Cohen,Nature,1:309-315(2002)。各種蛋白質激酶抑制劑已於臨床上被使用於治療極多種疾病,譬如癌症與慢性炎性疾病,包括糖尿病與中風。參閱Cohen,Eur.J.Biochem.,268:5001-5010(2001)。
蛋白質激酶為大的且多樣之酵素族群,其會催化蛋白質磷醯化作用,且在細胞發出訊息上扮演一個關鍵角色。蛋白質激酶可施加正面或負面調節作用,依其標的蛋白質而定。蛋白質激酶係涉及會調節細胞功能之特定發出訊息路徑,譬如但不限於新陳代謝作用、細胞循環
進展、細胞黏連、血管功能、細胞凋零及血管生成。細胞發出訊息之功能障礙係與許多疾病有關聯,其中最具特徵者係包括癌症與糖尿病。訊息轉導藉由細胞活素之調節,及訊息分子與原致癌基因及腫瘤抑制基因之締合已被充分記載。同樣地,在糖尿病及相關症狀與蛋白質激酶之失調含量間之連接已被証實。參閱,例如Sridhar等人醫藥研究,17(11):1345-1353(2000)。病毒感染及與其有關聯之症狀亦與蛋白質激酶之調節有關聯。Park等人Cell 101(7):777-787(2000)。
蛋白質激酶可被區分成寬廣組群,以其作為標的之胺基酸身分為基礎(絲胺酸/蘇胺酸、酪胺酸、離胺酸及組胺酸)。例如,酪胺酸激酶包括受體酪胺酸激酶(RTK),譬如生長因子,與非受體酪胺酸激酶,譬如src激酶族群。亦有以酪胺酸與絲胺酸/蘇胺酸兩者為標的之雙專一蛋白質激酶,譬如環素依賴性激酶(CDK)與有絲分裂原活化之蛋白質激酶(MAPK)。
由於蛋白質激酶係調節幾乎每個細胞過程,包括新陳代謝作用、細胞增生、細胞分化及細胞存活,故其係為關於各種疾病狀態之治療介入之吸引人標的。例如,其中蛋白質激酶係扮演一項樞紐角色之細胞循環控制與血管生成,係為與許多疾病症狀有關聯之細胞過程,該疾病症狀譬如但不限於癌症、炎性疾病、異常血管生成及與其有關聯之疾病、動脈粥瘤硬化、斑點變性、糖尿病、肥胖及疼痛。
蛋白質激酶已變成關於治療癌症之吸引人標的。Fabbro等人,藥理學與治療學93:79-98(2002)。已被提出的是,蛋白質激酶涉及人類惡性病症之發展可藉由以下而發生:(1)基因組重排(例如在慢性骨髓性白血病中之BCR-ABL),(2)導致構成上活性之激酶活性之突變型,譬如急性骨髓性白血病與胃腸腫瘤,(3)激酶活性因致癌基因之活化作用或腫瘤抑制劑功能損失之失調,譬如在具有致癌性RAS之癌症中,(4)激酶活性因過度表現之失調,如在EGFR之情況中,及(5)生長因子之
異位表現,其可助長贅瘤表現型之發展與維持。Fabbro等人,藥理學與治療學93:79-98(2002)。
蛋白質激酶路徑之錯綜複雜,及在各種蛋白質激酶與激酶路徑之中與之間之關係與交互作用之複雜性之說明,係強調發展能夠充作蛋白質激酶調制劑、調節劑或抑制劑之藥劑之重要性,其對於多重激酶或多重激酶路徑具有有利活性。因此,仍然需要新穎激酶調制劑。
被稱為mTOR(雷帕霉素之哺乳動物標的)之蛋白質,其亦被稱為FRAP、RAFTI或RAPT1),係為2549-胺基酸Ser/Thr蛋白質激酶,其已被証實係為在mTOR/PI3K/Akt路徑上最重要蛋白質之一,其會調節細胞生長與增生。Georgakis與Younes Expert Rev.Anticancer Ther.6(1):131-140(2006)。mTOR係存在於兩種複合物內,mTORC1與mTORC2。mTORC1係對雷帕霉素類似物(譬如天喜羅利莫斯(temsirolimus)或約洛利莫斯(everolimus))為敏感,而mTORC2係大部份為雷帕霉素不敏感性。數種mTOR抑制劑在關於治療癌症之臨床試驗上已被或正被評估。天喜羅利莫斯係在2007年被許可,供使用於腎細胞癌,而約洛利莫斯係在2009年被許可,供已在血管內皮生長因子受體抑制劑上進展之腎細胞癌病患用。此外,喜洛利莫斯(sirolimus)係在1999年被許可,供預防腎移植排斥。此等mTORC1化合物之令人感興趣但受到限制之臨床成功係証實mTOR抑制劑在治療癌症與移植排斥上之實用性,及關於具有mTORC1與mTORC2兩種抑制活性之化合物之經增加潛力。
在本申請案之原文段落2中任何參考資料之引用或確認,並不欲被解釋為承認該參考資料係為本申請案之先前技藝。
本文中所提供者為具有下式(I)之化合物:
及其藥學上可接受之鹽、籠合物、溶劑合物、互變異構物、立體異構物及前體藥物,其中R1-R4均如本文定義。
進一步於本文中提供者為具有下式(II)之化合物:
及其藥學上可接受之鹽、籠合物、溶劑合物、互變異構物、立體異構物及前體藥物,其中R1、R2及R3均如本文定義。
式(I)與(II)化合物,或其藥學上可接受之鹽、籠合物、溶劑合物、水合物、立體異構物、互變異構物或前體藥物(各於本文中稱為"雜芳基化合物"),係可用於治療或預防癌症、炎性症狀、免疫學症狀、神經變性疾病、糖尿病、肥胖、神經病症、與老化有關聯之疾病及心血管症狀,及可藉由抑制激酶路徑而被治療或預防之症狀。於一項具體實施例中,激酶路徑為mTOR/PI3K/Akt路徑。於另一項具體實施例中,激酶路徑為PI3Kα、PI3Kβ、PI3Kδ、KDR、GSK3α、GSK3β、ATM、ATX、ATR、cFMS及/或DNA-PK路徑。
進一步於本文中提供者為包含有效量之雜芳基化合物之組合物,及包含有效量之雜芳基化合物與藥學上可接受之載劑或媒劑之組合物。此等組合物可用於治療或預防癌症、炎性症狀、免疫學症狀、神
經變性疾病、糖尿病、肥胖、神經病症、與老化有關聯之疾病或心血管症狀,及可藉由抑制激酶路徑而被治療或預防之症狀,於一項具體實施例中,為mTOR/PI3K/Akt路徑。
進一步於本文中提供者為關於治療或預防癌症、炎性症狀、免疫學症狀、神經變性疾病、糖尿病、肥胖、神經病症、與老化有關聯之疾病或心血管症狀及可藉由抑制激酶路徑而被治療或預防之症狀之方法,於一項具體實施例中,為mTOR/PI3K/Akt路徑,該方法包括對需要治療或預防之病患投予有效量之雜芳基化合物。
亦於本文中提供者為關於在會表現激酶之細胞中抑制該激酶之方法,其包括使該細胞與有效量之如本文中所述之雜芳基化合物接觸。於一項具體實施例中,該激酶為mTOR、DNA-PK或PI3K或其組合。
本發明具體實施例可參考詳細說明與實例(意欲舉例說明非限制性具體實施例)而更完全地瞭解。
"烷基"為飽和、部份飽和或不飽和直鏈或分枝狀非環狀烴,具有1至10個碳原子,典型上為1至8個碳,或在一些具體實施例中為1至6、1至4或2至6個碳原子。代表性烷基包括-甲基、-乙基、-正-丙基、-正-丁基、-正-戊基及-正-己基;而飽和分枝狀烷基包括-異丙基、-第二-丁基、-異丁基、-第三-丁基、-異戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。不飽和烷基之實例包括但不限於其中尤其是乙烯基、烯丙基、-CH=CH(CH3)、-CH=C(CH3)2、-C(CH3)=CH2、-C(CH3)=CH(CH3)、-C(CH2CH3)=CH2、-C≡CH、-C≡C(CH3)、-C≡C(CH2CH3)、-CH2C≡CH、-CH2C≡C(CH3)及-CH2C≡C(CH7CH3)。烷基可經取代或未經取代。
"環烷基"為3至10個碳原子之飽和、部份飽和或不飽和環狀烷基,
具有單一環狀環或多重縮合或橋接環,其可視情況被1至3個烷基取代。在一些具體實施例中,環烷基具有3至8個環員,而在其他具體實施例中,環碳原子之數目係涵蓋範圍為3至5、3至6或3至7。舉例言之,此種環烷基係包括單環結構,譬如環丙基、環丁基、環戊基、環己基、環庚基、環辛基、1-甲基環丙基、2-甲基環戊基、2-甲基環辛基等,或多重或橋接環結構,譬如金剛烷基等。不胞和環烷基之實例包括其中尤其是環己烯基、環戊烯基、環己二烯基、丁二烯基、戊二烯基、己二烯基。環烷基可經取代或未經取代。舉例言之,此種經取代之環烷基係包括環己酮等。
"芳基"為6至14個碳原子之芳族碳環基團,具有單環(例如苯基)或多重縮合環(例如萘基或蒽基)。在一些具體實施例中,芳基含有6-14個碳,而在其他具體實施例中,為6至12個或甚至是6至10個碳原子在該基團之環部份中。特定芳基包括苯基、聯苯基、萘基等。芳基可經取代或未經取代。"芳基"措辭亦包括含有稠合環之基團,譬如稠合芳族-脂族環系統(例如氫茚基、四氫萘基等)。
"雜芳基"為具有一至四個雜原子在雜芳族環系統中作為環原子之芳基環系統,其中原子之其餘部份為碳原子。在一些具體實施例中,雜芳基含有5至6個環原子,而在其他具體實施例中,為6至9個或甚至是6至10個原子在該基團之環部份中。適當雜原子包括氧、硫及氮。在某些具體實施例中,雜芳基環系統為單環狀或雙環狀。非限制性實例包括但不限於以下基團,譬如吡咯基、吡唑基、咪唑基、三唑基、四唑基、唑基、異唑基、噻唑基、吡咯基、吡啶基、嗒基、嘧啶基、吡基、硫苯基、苯并硫苯基、呋喃基、苯并呋喃基(例如異苯并呋喃-1,3-二亞胺)、吲哚基、氮吲哚基(例如吡咯并吡啶基或1H-吡咯并[2,3-b]吡啶基)、吲唑基、苯并咪唑基(例如1H-苯并[d]咪唑基)、咪唑并吡啶基(例如氮苯并咪唑基、3H-咪唑并[4,5-b]吡啶基或1H-咪唑并
[4,5-b]吡啶基)、吡唑并吡啶基、三唑并吡啶基、苯并三唑基、苯并唑基、苯并噻唑基、苯并噻二唑基、異唑并吡啶基、硫萘基、嘌呤基、黃嘌呤基、腺嘌呤、鳥嘌呤、喹啉基、異喹啉基、四氫喹啉基、喹喏啉基及喹唑啉基。
"雜環基"為芳族(亦被稱為雜芳基)或非芳族環烷基,其中一至四個環碳原子係獨立被得自O、S及N所組成之組群之雜原子置換。在一些具體實施例中,雜環基包含3至10個環員,而其他此種基團具有3至5、3至6或3至8個環員。雜環基亦可在任何環原子上(意即在雜環之任何碳原子或雜原子上)結合至其他基團。雜環烷基可經取代或未經取代。雜環基涵蓋不飽和、部份飽和及飽和環系統,例如咪唑基、二氫咪唑基及四氫咪唑基。雜環基之措辭包括稠合環物種,包括含有稠合芳族與非芳族基團者,例如苯并三唑基、2,3-二氫苯并[1,4]二氧陸圜烯基及苯并[1,3]二氧伍圜烯基。該措辭亦包括含有雜原子之橋接多環狀環系統,譬如但不限於啶基。雜環基之代表性實例包括但不限於氮丙啶基、一氮四圜基、四氫吡咯基、四氫咪唑基、四氫吡唑基、噻唑啶基、四氫硫苯基、四氫呋喃基、二氧伍圜烯基、呋喃基、硫苯基、吡咯基、二氫吡咯基、咪唑基、二氫咪唑基、吡唑基、二氫吡唑基、三唑基、四唑基、唑基、異唑基、噻唑基、噻唑啉基、異噻唑基、噻二唑基、二唑基、六氫吡啶基、六氫吡基、嗎福啉基、硫代嗎福啉基、四氫哌喃基(例如四氫-2H-哌喃基)、四氫硫代哌喃基、氧硫陸圜、二氧基、二硫陸圜基、哌喃基、吡啶基、嘧啶基、嗒基、吡基、三基、二氫吡啶基、二氫二硫陸圜烯基、二氫二硫酮基、高六氫吡基、啶基、吲哚基、二氫吲哚基、異吲哚基、氮吲哚基(吡咯并吡啶基)、吲唑基、吲基、苯并三唑基、苯并咪唑基、苯并呋喃基、苯并硫苯基、苯并噻唑基、苯并二唑基、苯并基、苯并二硫陸圜烯基、苯并氧硫陸圜烯基、苯并噻基、苯并唑基、苯并噻唑基、苯并噻二唑
基、苯并[1,3]二氧伍圜烯基、吡唑并吡啶基、咪唑并吡啶基(氮苯并咪唑基;例如1H-咪唑并[4,5-b]吡啶基或1H-咪唑并[4,5-b]吡啶-2(3H)-酮基)、三唑并吡啶基、異唑并吡啶基、嘌呤基、黃嘌呤基、腺嘌呤、鳥嘌呤、喹啉基、異喹啉基、喹基、喹喏啉基、喹唑啉基、啈啉基、呔基、啶基、喋啶基、硫萘基、二氫苯并噻基、二氫苯并呋喃基、二氫吲哚基、二氫苯并二氧陸圜烯基、四氫吲哚基、四氫吲唑基、四氫苯并咪唑基、四氫苯并三唑基、四氫吡咯并吡啶基、四氫吡唑并吡啶基、四氫咪唑并吡啶基、四氫三唑并吡啶基及四氫喹啉基。代表性經取代之雜環基可為經單取代或取代超過一次,譬如但不限於吡啶基或嗎福啉基,其係被譬如列示於下文之不同取代基2-,3-,4-,5-或6-取代或二取代。
"環烷基烷基"為式:-烷基-環烷基之基團,其中烷基與環烷基係定義於上文。經取代之環烷基烷基可在該基團之烷基、環烷基或烷基與環烷基兩部份上經取代。代表性環烷基烷基包括但不限於環戊基甲基、環戊基乙基、環己基甲基、環己基乙基及環己基丙基。代表性經取代之環烷基烷基可為經單取代或取代超過一次。
"芳烷基"為式:-烷基-芳基之基團,其中烷基與芳基係定義於上文。經取代之芳烷基可在該基團之烷基、芳基或烷基與芳基兩部份上經取代。代表性芳烷基包括但不限於苄基與苯乙基,及經稠合之(環烷基芳基)烷基,譬如4-乙基-氫茚基。
"雜環基烷基"為式:-烷基-雜環基之基團,其中烷基與雜環基係定義於上文。經取代之雜環基烷基可在該基團之烷基、雜環基或烷基與雜環基兩部份上經取代。代表性雜環基烷基包括但不限於4-乙基-嗎福啉基、4-丙基嗎福啉基、呋喃-2-基甲基、呋喃-3-基甲基、吡啶-3-基甲基、(四氫-2H-哌喃-4-基)甲基、(四氫-2H-哌喃-4-基)乙基、四氫呋喃-2-基甲基、四氫呋喃-2-基乙基及吲哚-2-基丙基。
"鹵素"為氟、氯、溴或碘。
"羥烷基"為被一或多個羥基取代之如上述之烷基。
"烷氧基"為-O-(烷基),其中烷基係定義於上文。
"烷氧烷基"為-(烷基)-O-(烷基),其中烷基係定義於上文。
"胺基"為式:-NH2之基團。
"烷胺基"為式:-NH-烷基或-N(烷基)2之基團,其中各烷基係獨立如上文所定義。
"羧基"為式:-C(O)OH之基團。
"胺基羰基"為式:-C(O)N(R#)2、-C(O)NH(R#)或-C(O)NH2之基團,其中各R#係獨立為如本文定義之經取代或未經取代之烷基、環烷基、芳基、芳烷基或雜環基。
"醯基胺基"為式:-NHC(O)(R#)或-N(烷基)C(O)(R#)之基團,其中各烷基與R#係獨立如上文所定義。
"烷基磺醯基胺基"為式:-NHSO2(R#)或-N(烷基)SO2(R#)之基團,其中各烷基與R#係定義於上文。
"脲"基團為式:-N(烷基)C(O)N(R#)2、-N(烷基)C(O)NH(R#)、-N(烷基)C(O)NH2、-NHC(O)N(R#)2、-NHC(O)NH(R#)或-NH(CO)NHR#之基團,其中各烷基與R#係獨立如上文所定義。
於一項具體實施例中,當本文中所述之基團係被稱為"經取代"時,其可被任何一或多個適當取代基取代。取代基之說明例係為在本文中所揭示之舉例化合物與具體實施例中所發現者,以及鹵素(氯基、碘基、溴基或氟基);烷基;羥基;烷氧基;烷氧烷基;胺基;烷胺基;羧基;硝基;氰基;硫醇;硫醚;亞胺;醯亞胺;脒;胍;烯胺;胺基羰基;醯基胺基;膦酸基;膦;硫代羰基;磺醯基;碸;磺醯胺;酮;醛;酯;脲;胺基甲酸酯;肟;羥胺;烷氧基胺;芳烷氧基胺;N-氧化物;肼;醯肼;腙;疊氮化物;異氰酸酯;異硫氰酸酯;氰酸
鹽;硫氰酸鹽;氧(=O);B(OH)2、O(烷基)胺基羰基;環烷基,其可為單環狀或稠合或非稠合多環狀(例如環丙基、環丁基、環戊基或環己基),或雜環基,其可為單環狀或稠合或非稠合多環狀(例如四氫吡咯基、六氫吡啶基、六氫吡基、嗎福啉基或噻基);單環狀或稠合或非稠合多環狀芳基或雜芳基(例如苯基、萘基、吡咯基、吲哚基、呋喃基、硫苯基、咪唑基、唑基、異唑基、噻唑基、三唑基、四唑基、吡唑基、吡啶基、喹啉基、異喹啉基、吖啶基、吡基、嗒基、嘧啶基、苯并咪唑基、苯并硫苯基或苯并呋喃基);芳氧基;芳烷氧基;雜環基氧基;及雜環基烷氧基。
於本文中使用之"藥學上可接受之鹽"一詞,係指製自藥學上可接受之無毒性酸或鹼之鹽,包括無機酸與鹼及有機酸與鹼。雜芳基化合物之適當藥學上可接受之鹼加成鹽,包括但不限於製自鋁、鈣、鋰、鎂、鉀、鈉及鋅之金屬鹽,或製自離胺酸、N,N'-二苄基乙二胺、氯普魯卡因、膽鹼、二乙醇胺、乙二胺、甲基葡胺(N-甲基葡萄糖胺)及普魯卡因之有機鹽。適當無毒性酸包括但不限於無機與有機酸類,譬如醋酸、海藻酸、鄰胺基苯甲酸、苯磺酸、苯甲酸、樟腦磺酸、檸檬酸、乙烯磺酸、甲酸、反丁烯二酸、呋喃甲酸、半乳糖醛酸、葡萄糖酸、葡萄糖醛酸、麩胺酸、乙醇酸、氫溴酸、鹽酸、羥乙磺酸、乳酸、順丁烯二酸、蘋果酸、苯乙醇酸、甲烷磺酸、黏酸、硝酸、雙羥萘酸、泛酸、苯基醋酸、磷酸、丙酸、柳酸、硬脂酸、琥珀酸、磺胺酸、硫酸、酒石酸及對-甲苯磺酸。特定無毒酸包括鹽酸、氫溴酸、磷酸、硫酸及甲烷磺酸。因此,特定鹽之實例包括鹽酸鹽與甲烷磺酸鹽。其他係為此項技藝中所習知,參閱,例如Remington氏醫藥科學,第18版,Mack出版,Easton PA(1990)或Remington:製藥科學與實務,第19版,Mack出版,Easton PA(1995)。
當於本文中使用時,且除非另有指出,否則"籠合物"一詞係意謂
呈晶格形式之雜芳基化合物或其鹽,其含有間隙(例如溝槽),其具有被捕獲在內之賓分子(例如溶劑或水),或其中雜芳基化合物為賓分子之晶格。
當於本文中使用時,且除非另有指出,否則"溶劑合物"一詞係意謂雜芳基化合物或其鹽,其進一步包含化學計量或非化學計量之溶劑,藉由非共價分子間力結合。在一項具體實施例中,溶劑合物為水合物。
當於本文中使用時,且除非另有指出,否則"水合物"一詞係意謂雜芳基化合物或其鹽,其進一步包含化學計量或非化學計量之水,藉由非共價分子間力結合。
當於本文中使用時,且除非另有指出,否則"前體藥物"一詞係意謂雜芳基化合物衍生物,其可於生物學條件(活體外或活體內)下被水解、氧化或以其他方式反應,以提供活性化合物,特別是雜芳基化合物。前體藥物之實例包括但不限於雜芳基化合物之衍生物與新陳代謝產物,其包含生物可水解部份基團,譬如生物可水解醯胺類、生物可水解酯類、生物可水解胺基甲酸酯類、生物可水解碳酸酯類、生物可水解脲類及生物可水解磷酸鹽類似物。在某些具體實施例中,具有羧基官能基之化合物之前體藥物,係為羧酸之低碳烷基酯類。此羧酸酯可合宜地藉由酯化存在於分子上之任何羧酸部份基團而形成。前體藥物典型上可使用習知方法製備,譬如由Burger氏醫藥化學與藥物發現第6版(Donald J.Abraham編著,2001,Wiley)與前體藥物之設計與應用(H.Bundgaard編著,1985,Harwood大學出版社Gmfh)所描述者。
當於本文中使用時,且除非另有指出,否則"立體異構物"或"立體異構上純"術語係意謂雜芳基化合物之一種立體異構物,其係實質上不含該化合物之其他立體異構物。例如,具有一個對掌中心之立體異構上純化合物,係實質上不含該化合物之相反對掌異構物。具有兩個對
掌中心之立體異構上純化合物係實質上不含該化合物之其他非對映異構物。典型立體異構上純化合物係包含該化合物之大於約80重量%之一種立體異構物,及該化合物之低於約20重量%之其他立體異構物,該化合物之大於約90重量%之一種立體異構物,及該化合物之低於約10重量%之其他立體異構物,該化合物之大於約95重量%之一種立體異構物,及該化合物之低於約5重量%之其他立體異構物,或該化合物之大於約97重量%之一種立體異構物,及該化合物之低於約3重量%之其他立體異構物。雜芳基化合物可具有對掌中心,且可以外消旋物、個別對掌異構物或非對映異構物及其混合物存在。所有此種異構形式係被包含在本文中所揭示之具體實施例內,包括其混合物。此種雜芳基化合物之立體異構上純形式之用途,以及此等形式之混合物之用途,係被本文中所揭示之具體實施例涵蓋。例如,包含特定雜芳基化合物之相等或不相等量對掌異構物之混合物可被使用於本文中所揭示之方法與組合物中。此等異構物可經不對稱性地合成或使用標準技術解析,譬如對掌性管柱或對掌性解析劑。參閱,例如Jacques,J.等人,對掌異構物、外消旋物及解析(Wiley-Interscience,New York,1981);Wilen,S.H.等人,Tetrahedron 33:2725(1977);Eliel,E.L.,碳化合物之立體化學(McGraw-Hill,NY,1962);及Wilen,S.H.,解析劑與光學解析之表第268頁(E.L.Eliel編著,Notre Dame大學出版社,Notre Dame,IN,1972)。
亦應注意該雜芳基化合物可包括E與Z異構物或其混合物,及順式與反式異構物或其混合物。在某些具體實施例中,雜芳基化合物係被單離成順式或反式異構物。在其他具體實施例中,雜芳基化合物為順式與反式異構物之混合物。
"互變異構物"係指一種化合物之異構形式,其係彼此呈平衡。異構形式之濃度係依於其中發現化合物之環境而定,且可依例如該化合
物為固體抑或係在有機或水溶液中而有所不同。例如,在水溶液中,吡唑可顯示下列異構形式,其係被稱為彼此之互變異構物:
如熟諳此藝者所易於明瞭者,極多種官能基及其他結構可顯示互變異構現象,且式(I)與式(II)化合物之所有互變異構物係在本發明之範圍內。
亦應注意該雜芳基化合物可含有非天然比例之原子同位素在一或多個原子處。例如,化合物可以放射性同位素經放射性標識,例如氚(3H)、碘-125(125I)、硫-35(35S)或碳-14(14C),或可經同位素上富含,譬如以氘(2H)、碳-13(13C)或氮-15(15N)。於本文中使用之"同位素類似物"為同位素上富含之化合物。"同位素上富含"一詞係指一種原子,其具有該原子之同位素組成,而非天然同位素組成。"同位素上富含"亦可指一種化合物,其含有至少一個原子,具有該原子之同位素組成,而非天然同位素組成。"同位素組成"一詞係指關於特定原子所存在各同位素之量。經放射性標識與同位素上富含之化合物可作為治療劑使用,例如癌症與發炎治療劑,研究試劑,例如結合檢測試劑,及診斷劑,例如活體內成像劑。如本文中所述雜芳基化合物之所有同位素變型,無論具放射性與否,係意欲被涵蓋在本文中所提供具體實施例之範圍內。在一些具體實施例中,係提供雜芳基化合物之同位素類似物,例如,同位素類似物為氘、碳-13或氮-15富含之雜芳基化合物。
於本文中使用之"治療"係意謂與病症或疾病有關聯病徵之整體或部份減輕,或此等病徵之進一步進展或惡化之減緩或停止,或在有發展出該疾病或病症危險下之病患中疾病或病症之防止或預防。
連同雜芳基化合物之"有效量"一詞,係意謂一種量,其能夠整體或部份減輕與病症或疾病有關聯之病徵,或減緩或停止此等病徵之進
一步進展或惡化,或在有發展出如本文中所揭示疾病或病症危險下之病患中防止該疾病或病症或提供關於其預防,該疾病或病症譬如癌症、炎性症狀、免疫學症狀、神經變性疾病、糖尿病、肥胖、神經病症、與老化有關聯之疾病或心血管症狀,及可藉由抑制激酶路徑而被治療或預防之症狀,例如mTOR/PI3K/Akt路徑。於一項具體實施例中,雜芳基化合物之有效量係為會在細胞中抑制激酶之量,例如於活體外或活體內。於一項具體實施例中,激酶為mTOR、DNA-PK、PI3K或其組合。在一些具體實施例中,雜芳基化合物之有效量係在細胞中抑制該激酶達10%、20%、30%、40%、50%、60%、70%、80%、90%或99%,相較於未經治療細胞中之激酶之活性。雜芳基化合物之有效量,例如在醫藥組合物中,可在將行使所要作用之含量下;例如,在關於口腔與非經腸投藥兩者之單位劑量中,約0.005毫克/公斤病患體重至約100毫克/公斤病患體重。正如熟諳此藝者所明瞭,被預期的是,本文中所揭示雜芳基化合物之有效量可依被治療之適應徵而改變,例如雜芳基化合物之有效量對於治療患有或處於炎性症狀危險下之病患係可能不同,相對於關於治療患有或處於不同病症(例如癌症或代謝病症)危險下之病患之化合物之有效量。
"病患"一詞包括動物,包括但不限於譬如乳牛、猴子、馬、綿羊、豬、雞、火雞、鵪鶉、貓、狗、老鼠、大白鼠、兔子或天竺鼠之動物,於一項具體實施例中,為哺乳動物,於另一項具體實施例中,為人類。
"癌症"一詞係指任何各種惡性贅瘤,其特徵為可侵入周圍組織且轉移至新身體位置之細胞增生。良性與惡性腫瘤兩者係根據於其中發現彼等之組織類型而被分類。例如,纖維瘤為纖維狀結締組織之贅瘤,而黑色素瘤為色素(黑色素)細胞之異常生長。源自上皮組織之惡性腫瘤,例如在皮膚、枝氣管及胃中,係被稱為癌瘤。上皮腺組織之惡性病症,譬如被發現於乳房、前列腺及結腸中者,係被稱為腺癌。結締
組織之惡性生長,例如肌肉、軟骨、淋巴組織及骨頭,係被稱為肉瘤。淋巴瘤與白血病為源自於白血球中之惡性病症。經過轉移之過程,腫瘤細胞潛移至身體之其他區域係建立贅瘤在遠離最初出現位置之區域中。骨頭組織為惡性腫瘤轉移之最有利位置之一,發生於約30%之所有癌症病例中。在惡性腫瘤中,肺臟、乳房、前列腺或其類似物之癌症係特別已知可能轉移至骨頭。
就贅瘤、癌症、腫瘤生長或腫瘤細胞生長而論,抑制可藉由其中尤其是原發性或續發性腫瘤之經延遲出現,原發性或續發性腫瘤之經減緩發展,原發性或續發性腫瘤之經降低發生,疾病之續發作用之經減緩或降低嚴重性,經遏制之腫瘤生長及腫瘤退化,進行評估。於極端情況下,完全抑制於本文中係被稱為預防或化學預防。關於此點,"預防"一詞包括在處於危險下之個體中,預防全部臨床上顯著贅瘤形成之展開,或預防贅瘤形成之臨床前顯著階段之展開。亦意欲被此定義所涵蓋者係為預防轉變成惡性細胞,或遏制或逆轉惡性前細胞之進展成惡性細胞。其包括處於發展贅瘤形成危險下者之預防治療。
本文中所提供者為具有下式(I)之化合物:
及其藥學上可接受之鹽、籠合物、溶劑合物、立體異構物、互變異構物及前體藥物,其中:R1為經取代或未經取代之C1-8烷基、經取代或未經取代之芳基、經取代或未經取代之環烷基、經取代或未經取代之雜環基或經取代或
未經取代之雜環基烷基;R2為H、經取代或未經取代之C1-8烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環基、經取代或未經取代之雜環基烷基、經取代或未經取代之芳烷基或經取代或未經取代之環烷基烷基;R3與R4係各獨立為H、經取代或未經取代之C1-8烷基、經取代或未經取代之芳基、經取代或未經取代之環烷基、經取代或未經取代之雜環基、經取代或未經取代之雜環基烷基、經取代或未經取代之芳烷基、經取代或未經取代之環烷基烷基,或R3與R4和彼等所連接之原子一起形成經取代或未經取代之環烷基或經取代或未經取代之雜環基;或R2及R3與R4之一和彼等所連接之原子一起形成經取代或未經取代之雜環基;其條件是,該化合物不為下文所描繪之化合物,意即:
6-(4-羥苯基)-4-(3-甲氧基苄基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;
6-(4-(1H-1,2,4-三唑-5-基)苯基)-3-(環己基甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;或
(R)-6-(4-(1H-1,2,4-三唑-5-基)苯基)-3-(環己基甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮。
在式(I)化合物之一些具體實施例中,R1為經取代或未經取代之芳基或經取代或未經取代之雜芳基。於一項具體實施例中,R1為苯基、吡啶基、嘧啶基、苯并咪唑基、吲哚基、吲唑基、1H-吡咯并[2,3-b]吡啶基、1H-咪唑并[4,5-b]吡啶基、1H-咪唑并[4,5-b]吡啶-2(3H)-酮基、3H-咪唑并[4,5-b]吡啶基或吡唑基,各視情況經取代。在一些具體實施例中,R1為被一或多個取代基取代之苯基,取代基獨立選自下列組成之組群:經取代或未經取代之C1-8烷基(例如甲基)、經取代或未經取代之雜環基(例如經取代或未經取代之三唑基或吡唑基)、鹵素(例如氟)、胺基羰基、氰基、羥烷基(例如羥丙基)及羥基。在其他具體實施例中,R1為被一或多個取代基取代之吡啶基,取代基獨立選自下列組成之組群:經取代或未經取代之C1-8烷基、經取代或未經取代之雜環基(例如經取代或未經取代之三唑基)、鹵素、胺基羰基、氰基、羥烷基、-OR及-NR2,其中各R係獨立為H或經取代或未經取代之C1-4烷基。在又其他具體實施例中,R1為1H-吡咯并[2,3-b]吡啶基或苯并咪唑基,各視情況被一或多個取代基取代,取代基獨立選自經取代或未經取代之C1-8烷基與-NR2所組成之組群,其中各R係獨立為H或經取代或未經取代之C1-4烷基。
在式(I)化合物之一些具體實施例中,R1為
其中R在每一存在處係獨立為H或經取代或未經取代之C1-4烷基(例如甲基);R'在每一存在處係獨立為經取代或未經取代之C1-4烷基、鹵素(例如氟)、氰基、-OR或-NR2;m為0-3;且n為0-3。熟諳此藝者應明瞭的是,任何取代基R'可被連接至稠合環系統中之任何環之任何適當原子。熟諳此藝者亦應明瞭的是,R1之連接鍵結(藉由平分波狀線指定)可被連接至稠合環系統中之任何環之任何原子。
在式(I)化合物之一些具體實施例中,R1為
其中R在每一存在處係獨立為H或經取代或未經取代之C1-4烷基;R'在每一存在處係獨立為經取代或未經取代之C1-4烷基、鹵素、氰基、-OR或-NR2;m為0-3;且n為0-3。
在式(I)化合物之一些具體實施例中,R2為H、經取代或未經取代之C1-8烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環基、經取代或未經取代之C1-4烷基-雜環基、經取代或未經取代之C1-4烷基-芳基或經取代或未經取代之C1-4烷基-環烷基。例如,R2為H、甲基、乙基、正-丙基、異丙基、正-丁基、第二-丁基、異丁基、第三-丁基、正-戊基、異戊基、環戊基、環己基、四氫呋喃基、四氫哌喃基、(C1-4烷基)-苯基、(C1-4烷基)-環丙基、(C1-4烷基)-環丁基、(C1-4烷基)-環戊基、(C1-4烷基)-環己基、(C1-4烷基)-四氫吡咯基、(C1-4烷基)-六氫吡啶基、(C1-4烷基)-六氫吡基、(C1-4烷基)-嗎福啉基、(C1-4烷基)-四氫呋喃基或(C1-4烷基)-四氫哌喃基,各視情況經取代。
在其他具體實施例中,R2為H、C1-4烷基、(C1-4烷基)(OR),
其中R在每一存在處係獨立為H或經取代或未經取代之C1-4烷基(例如甲基);R'在每一存在處係獨立為H、-OR、氰基或經取代或未經取代之C1-4烷基(例如甲基);且p為0-3。
在一些此種具體實施例中,R2為H、C1-4烷基、(C1-4烷基)(OR),
其中R在每一存在處係獨立為H或經取代或未經取代之C1-2烷基;R'在每一存在處係獨立為H、-OR、氰基或經取代或未經取代之C1-2烷基;且p為0-1。
在式(I)化合物之一些其他具體實施例中,R2及R3與R4之一和彼等所連接之原子一起形成經取代或未經取代之雜環基。例如,在一些具體實施例中,式(I)化合物為
其中R在每一存在處係獨立為H或經取代或未經取代之C1-4烷基;R"為H、OR或經取代或未經取代之C1-4烷基;且R1係如本文定義。
在式(I)化合物之一些具體實施例中,R3與R4均為H。在其他具體實施例中,R3與R4之一為H,而另一個不為H。於又再其他具體實施例中,R3與R4之一為C1-4烷基(例如甲基),而另一個為H。於又再其他具體實施例中,R3與R4兩者均為C1-4烷基(例如甲基)。
在上述一些此種具體實施例中,R1為經取代或未經取代之芳基或經取代或未經取代之雜芳基。例如,R1為苯基、吡啶基、嘧啶基、苯并咪唑基、吲哚基、吲唑基、1H-吡咯并[2,3-b]吡啶基、1H-咪唑并[4,5-b]吡啶基、1H-咪唑并[4,5-b]吡啶-2(3H)-酮基、3H-咪唑并[4,5-b]吡啶基或吡唑基,各視情況經取代。在一些具體實施例中,R1為被一或多個取代基取代之苯基,取代基獨立選自下列組成之組群:經取代或未經取代之C1-8烷基、經取代或未經取代之雜環基、鹵素、胺基羰基、氰基、羥烷基及羥基。在其他具體實施例中,R1為被一或多個取代基取
代之吡啶基,取代基獨立選自下列組成之組群:氰基、經取代或未經取代之C1-8烷基、經取代或未經取代之雜環基、羥烷基、鹵素、胺基羰基、-OR及-NR2,其中各R係獨立為H或經取代或未經取代之C1-4烷基。在其他具體實施例中,R1為1H-吡咯并[2,3-b]吡啶基或苯并咪唑基,視情況被一或多個取代基取代,取代基獨立選自經取代或未經取代之C1-8烷基與-NR2所組成之組群,其中R係獨立為H或經取代或未經取代之C1-4烷基。
在某些具體實施例中,式(I)化合物具有本文所提出之R1基團與本文所提出之R2基團。
於式(I)化合物之一些具體實施例中,在濃度為10μM下之化合物會抑制mTOR、DNA-PK或PI3K或其組合達至少約50%。在任何適當檢測系統中,式(I)化合物可經証實為上述激酶之抑制劑,譬如本文實例中所述者。
在式(I)化合物之一些具體實施例中,該化合物為6-(1H-吡咯并[2,3-b]吡啶-3-基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(4-甲基-6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-4-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-4-((反式-4-甲氧基環己基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-4-((順式-4-甲氧基環己基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-4-((反式-4-甲氧基環己基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-4-((反式-4-羥基環己基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;
6-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-4-((順式-4-甲氧基環己基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-4-((反式-4-羥基環己基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-4-(順式-4-羥基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-4-((順式-4-羥基環己基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-4-(反式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-4-(反式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-4-(反式-4-羥基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-4-((順式-4-羥基環己基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-4-(順式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-4-(2-甲氧基乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-4-異丙基-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-4-(順式-4-羥基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-4-(順式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;
6-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-4-(2-甲氧基乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-4-(四氫-2H-哌喃-4-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-4-乙基-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-4-(反式-4-羥基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-4-(四氫-2H-哌喃-4-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-4-異丙基-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;4-乙基-6-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(3-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-4-(四氫-2H-哌喃-4-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(3-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-4-(順式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(3-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-4-(反式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;4-(2-甲氧基乙基)-6-(4-甲基-6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(3-(1H-1,2,4-三唑-5-基)苯基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;5-(8-(2-甲氧基乙基)-6-酮基-5,6,7,8-四氫吡并[2,3-b]吡-2-基)-4-甲基甲基吡啶醯胺;
3-(6-酮基-8-(2-(四氫-2H-哌喃-4-基)乙基)-5,6,7,8-四氫吡并[2,3-b]吡-2-基)苯甲醯胺;3-(6-酮基-8-(2-(四氫-2H-哌喃-4-基)乙基)-5,6,7,8-四氫吡并[2,3-b]吡-2-基)苯甲腈;5-(8-(反式-4-甲氧基環己基)-6-酮基-5,6,7,8-四氫吡并[2,3-b]吡-2-基)-4-甲基甲基吡啶醯胺;6-(1H-咪唑并[4,5-b]吡啶-6-基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(1H-吲唑-6-基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;4-((1R,3S)-3-甲氧基環戊基)-6-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;4-((1S,3R)-3-甲氧基環戊基)-6-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;4-((1R,3R)-3-甲氧基環戊基)-6-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;4-((1S,3S)-3-甲氧基環戊基)-6-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;4-乙基-6-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(1H-吡咯并[2,3-b]吡啶-5-基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(1H-吲哚-6-基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(1H-吲哚-5-基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;
4-(((1R,3S)-3-甲氧基環戊基)甲基)-6-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;4-(((1S,3R)-3-甲氧基環戊基)甲基)-6-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(3-氟基-2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(3-氟基-2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-4-(2-甲氧基乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;3,3-二甲基-6-(4-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-4-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-((1R,3S)-3-甲氧基環戊基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-((1S,3R)-3-甲氧基環戊基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-(((1S,3S)-3-甲氧基環戊基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-(((1R,3R)-3-甲氧基環戊基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-((1S,3S)-3-甲氧基環戊基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-((1R,3R)-3-甲氧基環戊基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-(((1R,3S)-3-甲氧基環戊基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-(((1S,3R)-3-甲氧基環戊基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;
6-(3-氟基-4-(4H-1,2,4-三唑-3-基)苯基)-4-(2-甲氧基乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(3-氟基-4-(4H-1,2,4-三唑-3-基)苯基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7'-(2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-1'-((四氫-2H-哌喃-4-基)甲基)-1'H-螺[環戊烷-1,2'-吡并[2,3-b]吡]-3'(4'H)-酮;7'-(2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-1'-((四氫-2H-哌喃-4-基)甲基)-1'H-螺[環丁烷-1,2'-吡并[2,3-b]吡]-3'(4'H)-酮;4-(環丙基甲基)-6-(6-(2-羥丙-2-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7'-(2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-1'H-螺[環戊烷-1,2'-吡并[2,3-b]吡]-3'(4'H)-酮;7'-(2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-1'H-螺[環丁烷-1,2'-吡并[2,3-b]吡]-3'(4'H)-酮;7'-(2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-1'H-螺[環丙烷-1,2'-吡并[2,3-b]吡]-3'(4'H)-酮;(R)-6-(4-(4H-1,2,4-三唑-3-基)苯基)-4-((四氫呋喃-2-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;(S)-6-(4-(4H-1,2,4-三唑-3-基)苯基)-4-((四氫呋喃-2-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(1H-吲唑-5-基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;4-(6-酮基-8-(2-(四氫-2H-哌喃-4-基)乙基)-5,6,7,8-四氫吡并[2,3-b]吡-2-基)苯甲醯胺;4-(2-甲氧基乙基)-3,3-二甲基-6-(2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;
4-乙基-3,3-二甲基-6-(2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;3,3-二甲基-6-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-4-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;(R)-6-(6-(1-羥乙基)吡啶-3-基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;3,3-二甲基-6-(2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-4-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)-4-甲基吡啶-3-基)-4-(反式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)-4-甲基吡啶-3-基)-4-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;3,3-二甲基-6-(2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;3,3-二甲基-6-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)-2-甲基吡啶-3-基)-4-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)-2-甲基吡啶-3-基)-4-(反式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;(S)-6-(6-(1-羥乙基)吡啶-3-基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;3,3-二甲基-6-(2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;
6-(6-(2-羥丙-2-基)吡啶-3-基)-3,3-二甲基-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(4-(2-羥丙-2-基)苯基)-4-(反式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(4-(2-羥丙-2-基)苯基)-4-((反式-4-甲氧基環己基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;4-(順式-4-甲氧基環己基)-6-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;4-(反式-4-甲氧基環己基)-6-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(4-(2-羥丙-2-基)苯基)-4-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;4-(2-甲氧基乙基)-6-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;9-(6-(4H-1,2,4-三唑-3-基)-3-吡啶基)-6,11,4a-三氫嗎福啉基[4,3-e]吡并[2,3-b]吡-5-酮;6-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-4-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;5-(8-(順式-4-甲氧基環己基)-6-酮基-5,6,7,8-四氫吡并[2,3-b]吡-2-基)-6-甲基甲基吡啶腈;6-(6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;9-(4-(4H-1,2,4-三唑-3-基)-2-甲基苯基)-3-(2-甲氧基乙醯基)-6,11,4a-三氫六氫吡并[1,2-e]吡并[2,3-b]吡-5-酮;9-(4-(4H-1,2,4-三唑-3-基)-2-甲基苯基)-6,11,4a-三氫六氫吡并[1,2-e]吡并[2,3-b]吡-5-酮;
9-(4-(4H-1,2,4-三唑-3-基)-2-甲基苯基)-3-(2-甲氧基乙基)-6,11,4a-三氫六氫吡并[1,2-e]吡并[2,3-b]吡-5-酮;4-(環戊基甲基)-6-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;9-(6-(4H-1,2,4-三唑-3-基)-2-甲基-3-吡啶基)-6,11,4a-三氫嗎福啉基[4,3-e]吡并[2,3-b]吡-5-酮;4-(反式-4-羥基環己基)-6-(6-(2-羥丙-2-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;4-(順式-4-羥基環己基)-6-(6-(2-羥丙-2-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-((四氫呋喃-3-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;4-(環戊基甲基)-6-(6-(2-羥丙-2-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-新戊基-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-異丁基-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;3-甲基-6-(2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-(六氫吡啶-4-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-(2-(四氫-2H-哌喃-3-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;8-(4-(4H-1,2,4-三唑-3-基)-2-甲基苯基)(3aS,2R)-2-甲氧基-5,10,3a-三氫吡并[2,3-b]四氫吡咯并[1,2-e]吡-4-酮;
8-(4-(4H-1,2,4-三唑-3-基)-2-甲基苯基)(2R,3aR)-2-甲氧基-5,10,3a-三氫吡并[2,3-b]四氫吡咯并[1,2-e]吡-4-酮;8-(4-(4H-1,2,4-三唑-3-基)-2-甲基苯基)(2S,3aR)-2-甲氧基-5,10,3a-三氫吡并[2,3-b]四氫吡咯并[1,2-e]吡-4-酮;8-(4-(4H-1,2,4-三唑-3-基)-2-甲基苯基)(2S,3aS)-2-甲氧基-5,10,3a-三氫吡并[2,3-b]四氫吡咯并[1,2-e]吡-4-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-(3-甲氧基丙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;(S)-6-(6-(2-羥丙-2-基)吡啶-3-基)-4-((四氫呋喃-2-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;(R)-6-(6-(2-羥丙-2-基)吡啶-3-基)-4-((四氫呋喃-2-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;9-(4-(4H-1,2,4-三唑-3-基)-2-甲基苯基)-3-甲基-6,11,4a-三氫六氫吡并[1,2-e]吡并[2,3-b]吡-5-酮;9-(4-(4H-1,2,4-三唑-3-基)苯基)-6,11,4a-三氫嗎福啉基[4,3-e]吡并[2,3-b]吡-5-酮;9-(4-(4H-1,2,4-三唑-3-基)-2-甲基苯基)-6,11,4a-三氫六氫吡啶并[1,2-e]吡并[2,3-b]吡-5-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-(反式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-(順式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-(2-嗎福啉基乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;
6-(6-(2-羥丙-2-基)吡啶-3-基)-4-苯乙基-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-(四氫-2H-哌喃-4-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;4-(環己基甲基)-6-(6-(2-羥丙-2-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-((反式-4-甲氧基環己基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-((順式-4-甲氧基環己基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;(R)-6-(6-(2-羥丙-2-基)吡啶-3-基)-4-(四氫呋喃-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;(S)-6-(6-(2-羥丙-2-基)吡啶-3-基)-4-(四氫呋喃-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;(S)-6-(6-(2-羥丙-2-基)吡啶-3-基)-3-甲基-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;9-[6-(1-羥基-異丙基)-3-吡啶基]-6,11,4a-三氫嗎福啉基[4,3-e]吡并[2,3-b]吡-5-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-(2-甲氧基乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(2-胺基-7-甲基-1H-苯并[d]咪唑-5-基)-4-(3-(三氟甲基)苄基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-(3-(三氟甲基)苄基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;
9-(4-(4H-1,2,4-三唑-3-基)-2-甲基苯基)-6,11,4a-三氫嗎福啉基[4,3-e]吡并[2,3-b]吡-5-酮;6-(4-甲基-2-(甲胺基)-1H-苯并[d]咪唑-6-基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;8-(4-(4H-1,2,4-三唑-3-基)-2-甲基苯基)-5,10,3a-三氫吡并[2,3-b]四氫吡咯并[1,2-e]吡-4-酮;6-(4-(4H-1,2,4-三唑-3-基)苯基)-4-乙基-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(4-(4H-1,2,4-三唑-3-基)苯基)-4-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(6-(2-羥丙-2-基)吡啶-3-基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(4-(4H-1,2,4-三唑-3-基)苯基)-4-(2-甲氧基乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(4-(4H-1,2,4-三唑-3-基)苯基)-4-(3-(三氟甲基)苄基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(4-甲基-1H-苯并[d]咪唑-6-基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;6-(4-(2-羥丙-2-基)苯基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;或6-(4-(1H-1,2,4-三唑-5-基)苯基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮。
進一步於本文中所提供者為具有下式(II)之化合物:
及其藥學上可接受之鹽、籠合物、溶劑合物、立體異構物、互變異構物及前體藥物,其中:R1為經取代或未經取代之C1-8烷基、經取代或未經取代之芳基、經取代或未經取代之環烷基、經取代或未經取代之雜環基或經取代或未經取代之雜環基烷基;R2為H、經取代或未經取代之C1-8烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環基、經取代或未經取代之雜環基烷基、經取代或未經取代之芳烷基或經取代或未經取代之環烷基烷基;R3為H或經取代或未經取代之C1-8烷基;其條件是,式(II)化合物不為7-(4-羥苯基)-1-(3-甲氧基苄基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮,描繪於下文:
在式(II)化合物之一些具體實施例中,R1為經取代或未經取代之芳基或經取代或未經取代之雜芳基。例如,R1為苯基、吡啶基、嘧啶基、苯并咪唑基、1H-吡咯并[2,3-b]吡啶基、吲唑基、吲哚基、1H-咪唑并[4,5-b]吡啶基、1H-咪唑并[4,5-b]吡啶-2(3H)-酮基、3H-咪唑并[4,5-b]吡啶基或吡唑基,各視情況經取代。在一些具體實施例中,R1為被一或多個取代基取代之苯基,取代基獨立選自下列組成之組群:經取代
或未經取代之C1-8烷基(例如甲基)、經取代或未經取代之雜環基(例如經取代或未經取代之三唑基或吡唑基)、胺基羰基、鹵素(例如氟)、氰基、羥烷基及羥基。在其他具體實施例中,R1為被一或多個取代基取代之吡啶基,取代基獨立選自下列組成之組群:經取代或未經取代之C1-8烷基(例如甲基)、經取代或未經取代之雜環基(例如經取代或未經取代之三唑基)、鹵素、胺基羰基、氰基、羥烷基(例如羥丙基)、-OR及-NR2,其中各R係獨立為H或經取代或未經取代之C1-4烷基。在一些具體實施例中,R1為1H-吡咯并[2,3-b]吡啶基或苯并咪唑基,視情況被一或多個取代基取代,取代基獨立選自經取代或未經取代之C1-8烷基與-NR2所組成之組群,其中R係獨立為H或經取代或未經取代之C1-4烷基。
在一些具體實施例中,R1為
其中R在每一存在處係獨立為H或經取代或未經取代之C1-4烷基(例如甲基);R'在每一存在處係獨立為經取代或未經取代之C1-4烷基(例如甲基)、鹵素(例如氟基)、氰基、-OR或-NR2;m為0-3;且n為0-3。熟諳此藝者應明瞭的是,任何取代基R'可被連接至稠合環系統中之任何環之任何適當原子。
在式(II)化合物之一些具體實施例中,R1為
其中R在每一存在處係獨立為H或經取代或未經取代之C1-4烷基;R'在每一存在處係獨立為經取代或未經取代之C1-4烷基、鹵素、氰基、-OR或-NR2;m為0-3;且n為0-3。
在式(II)化合物之一些具體實施例中,R2為H、經取代或未經取代之C1-8烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環基、經取代或未經取代之C1-4烷基-雜環基、經取代或未經取代之C1-4烷基-芳基或經取代或未經取代之C1-4烷基-環烷基。例如,R2為H、甲基、乙基、正-丙基、異丙基、正-丁基、第二-丁基、異丁基、第三-丁基、正-戊基、異戊基、環戊基、環己基、四氫呋喃基、四氫哌喃基、(C1-4烷基)-苯基、(C1-4烷基)-環丙基、(C1-4烷基)-環丁基、(C1-4烷基)-環戊基、(C1-4烷基)-環己基、(C1-4烷基)-四氫吡咯基、(C1-4烷基)-六氫吡啶基、(C1-4烷基)-六氫吡基、(C1-4烷基)-嗎福啉基、(C1-4烷基)-四氫呋喃基或(C1-4烷基)-四氫哌喃基,各視情況經取代。
在其他具體實施例中,R2為H、C1-4烷基、(C1-4烷基)(OR),
其中R在每一存在處係獨立為H或經取代或未經取代之C1-4烷基(例如甲基);R'在每一存在處係獨立為H、-OR、氰基或經取代或未經取代之C1-4烷基(例如甲基);且p為0-3。
在式(II)化合物之其他具體實施例中,R2為H、C1-4烷基、(C1-4烷基)(OR),
其中R在每一存在處係獨立為H或經取代或未經取代之C1-2烷基;R'在每一存在處係獨立為H、-OR、氰基或經取代或未經取代之C1-2烷基;且p為0-1。
在式(II)化合物之其他具體實施例中,R3為H。
在本文中所述之一些此種具體實施例中,R1為經取代或未經取代之芳基或經取代或未經取代之雜芳基。例如,R1為苯基、吡啶基、嘧啶基、苯并咪唑基、1H-吡咯并[2,3-b]吡啶基、吲唑基、吲哚基、1H-咪唑并[4,5-b]吡啶、吡啶基、1H-咪唑并[4,5-b]吡啶-2(3H)-酮基、3H-咪唑并[4,5-b]吡啶基或吡唑基,各視情況經取代。在一些具體實施例中,R1為被一或多個取代基取代之苯基,取代基獨立選自下列組成之組群:經取代或未經取代之C1-8烷基、經取代或未經取代之雜環基、胺基羰基、鹵素、氰基、羥烷基及羥基。在其他具體實施例中,R1為被一或多個取代基取代之吡啶基,取代基獨立選自下列組成之組群:C1-8烷基、經取代或未經取代之雜環基、鹵素、胺基羰基、氰基、羥烷基、-OR及-NR2,其中各R係獨立為H或經取代或未經取代之C1-4烷
基。於又再其他具體實施例中,R1為1H-吡咯并[2,3-b]吡啶基或苯并咪唑基,視情況被一或多個取代基取代,取代基獨立選自經取代或未經取代之C1-8烷基與-NR2所組成之組群,其中R係獨立為H或經取代或未經取代之C1-4烷基。
在某些具體實施例中,式(II)化合物具有本文所提出之R1基團與本文所提出之R2基團。
於式(II)化合物之一些具體實施例中,在濃度為10μM下之化合物會抑制mTOR、DNA-PK、PI3K或其組合達至少約50%。在任何適當檢測系統中,式(II)化合物可經証實為上述激酶之抑制劑,譬如本文實例中所述者。
在式(II)化合物之一些具體實施例中,該化合物為7-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-1-((反式-4-甲氧基環己基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-1-(順式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(1H-吡咯并[2,3-b]吡啶-3-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-1-((順式-4-甲氧基環己基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-乙基-7-(1H-吡咯并[3,2-b]吡啶-5-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-1-((順式-4-甲氧基環己基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(1H-苯并[d]咪唑-4-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(1H-吡咯并[2,3-b]吡啶-4-基)-1-(2-(四氫-2H-哌喃-4-基)乙
基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-1-((反式-4-甲氧基環己基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-1-((反式-4-羥基環己基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-1-(順式-4-羥基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-1-(順式-4-羥基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-1-(四氫-2H-哌喃-4-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-1-(2-甲氧基乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-1-乙基-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-1-((順式-4-羥基環己基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-1-(四氫-2H-哌喃-4-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(1H-吲哚-4-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-1-((反式-4-羥基環己基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-1-((順式-4-羥基環己基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-1-(反式-4-羥基環己基)-3,4-
二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-1-(反式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-1-異丙基-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-1-(反式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-1-(反式-4-羥基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-1-(2-甲氧基乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-1-異丙基-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-乙基-7-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(2-羥基吡啶-4-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-異丙基-7-(4-甲基-6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;5-(8-異丙基-7-酮基-5,6,7,8-四氫吡并[2,3-b]吡-2-基)-4-甲基甲基吡啶醯胺;7-(1H-吲唑-4-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(2-胺基嘧啶-5-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(2-胺基吡啶-4-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡
并[2,3-b]吡-2(1H)-酮;7-(6-(甲胺基)吡啶-3-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-羥基吡啶-3-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(4-(1H-吡唑-3-基)苯基)-1-(2-甲氧基乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(吡啶-3-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(1H-吲唑-4-基)-1-(2-甲氧基乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(1H-吲唑-6-基)-1-(2-甲氧基乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(嘧啶-5-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-甲氧基吡啶-3-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-(2-甲氧基乙基)-7-(1H-吡咯并[2,3-b]吡啶-5-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-乙基-7-(1H-吡咯并[2,3-b]吡啶-5-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-乙基-7-(1H-吲唑-4-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(吡啶-4-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-胺基吡啶-3-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;
1-甲基-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;2-(2-羥丙-2-基)-5-(8-(反式-4-甲氧基環己基)-7-酮基-5,6,7,8-四氫吡并[2,3-b]吡-2-基)吡啶1-氧化物;4-甲基-5-(7-酮基-8-((四氫-2H-哌喃-4-基)甲基)-5,6,7,8-四氫吡并[2,3-b]吡-2-基)甲基吡啶醯胺;5-(8-((順式-4-甲氧基環己基)甲基)-7-酮基-5,6,7,8-四氫吡并[2,3-b]吡-2-基)-4-甲基甲基吡啶醯胺;7-(1H-吡唑-4-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-(反式-4-甲氧基環己基)-7-(4-甲基-6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;3-((7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-2-酮基-3,4-二氫吡并[2,3-b]吡-1(2H)-基)甲基)苯甲腈;1-((反式-4-甲氧基環己基)甲基)-7-(4-甲基-6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;3-(7-酮基-8-(2-(四氫-2H-哌喃-4-基)乙基)-5,6,7,8-四氫吡并[2,3-b]吡-2-基)苯甲醯胺;5-(8-((反式-4-甲氧基環己基)甲基)-7-酮基-5,6,7,8-四氫吡并[2,3-b]吡-2-基)-4-甲基甲基吡啶醯胺;3-((7-(6-(2-羥丙-2-基)吡啶-3-基)-2-酮基-3,4-二氫吡并[2,3-b]吡-1(2H)-基)甲基)苯甲腈;7-(6-(2-羥丙-2-基)吡啶-3-基)-1-((1R,3R)-3-甲氧基環戊基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(2-羥丙-2-基)吡啶-3-基)-1-((1S,3R)-3-甲氧基環戊基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;
7-(6-(2-羥丙-2-基)吡啶-3-基)-1-((1S,3S)-3-甲氧基環戊基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(2-羥丙-2-基)吡啶-3-基)-1-((1R,3S)-3-甲氧基環戊基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(1H-吲唑-6-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-1-(2-嗎福啉基乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-(反式-4-羥基環己基)-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-(順式-4-羥基環己基)-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(2-羥丙-2-基)吡啶-3-基)-1-(2-嗎福啉基乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-異丙基-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(1H-咪唑并[4,5-b]吡啶-6-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-((順式-4-甲氧基環己基)甲基)-7-(2-甲基-6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-(反式-4-羥基環己基)-7-(6-(2-羥丙-2-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-(順式-4-羥基環己基)-7-(6-(2-羥丙-2-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;4-(7-酮基-8-(2-(四氫-2H-哌喃-4-基)乙基)-5,6,7,8-四氫吡并[2,3-b]吡-2-基)苯甲醯胺;
7-(1H-吲唑-5-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(1H-吡咯并[2,3-b]吡啶-5-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-1-(四氫-2H-哌喃-4-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-((1S,3R)-3-甲氧基環戊基)-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-((1R,3R)-3-甲氧基環戊基)-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-((1R,3S)-3-甲氧基環戊基)-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-((1S,3S)-3-甲氧基環戊基)-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(1H-吲哚-5-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-乙基-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(1H-吲哚-6-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(4-(2-羥丙-2-基)苯基)-1-(反式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(2-羥丙-2-基)吡啶-3-基)-1-(四氫-2H-哌喃-4-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-((反式-4-甲氧基環己基)甲基)-7-(2-甲基-6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;
7-(6-(2-羥丙-2-基)吡啶-3-基)-1-((順式-4-甲氧基環己基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-(2-甲氧基乙基)-7-(4-甲基-2-(甲胺基)-1H-苯并[d]咪唑-6-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(7-甲基-2-酮基-2,3-二氫-1H-苯并[d]咪唑-5-基)-1-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-(2-甲氧基乙基)-7-(4-甲基-6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-苄基-7-(2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(3-氟基-4-(4H-1,2,4-三唑-3-基)苯基)-1-(2-甲氧基乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(3-氟基-4-(4H-1,2,4-三唑-3-基)苯基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(3-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-1-(2-甲氧基乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-(反式-4-甲氧基環己基)-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(2-羥丙-2-基)吡啶-3-基)-1-(反式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(5-氟基-2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(3-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;
1-(2-甲氧基乙基)-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(2-羥丙-2-基)吡啶-3-基)-1-((反式-4-甲氧基環己基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-(環戊基甲基)-7-(6-(2-羥丙-2-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(4-(2-羥丙-2-基)苯基)-1-(2-甲氧基乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;(S)-7-(6-(1-羥乙基)吡啶-3-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;(R)-7-(6-(1-羥乙基)吡啶-3-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-1-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(4-(2-羥丙-2-基)苯基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(2-羥丙-2-基)吡啶-3-基)-1-(4-(三氟甲基)苄基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(2-羥丙-2-基)吡啶-3-基)-1-(3-(三氟甲基)苄基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(2-羥丙-2-基)吡啶-3-基)-1-(3-甲氧基丙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(4-甲基-6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(2-羥丙-2-基)吡啶-3-基)-1-(2-甲氧基乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;
7-(6-(2-羥丙-2-基)吡啶-3-基)-1-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(4-甲基-2-(甲胺基)-1H-苯并[d]咪唑-6-基)-1-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(2-胺基-4-甲基-1H-苯并[d]咪唑-6-基)-1-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;(R)-7-(6-(2-羥丙-2-基)吡啶-3-基)-3-甲基-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;(S)-7-(6-(2-羥丙-2-基)吡啶-3-基)-3-甲基-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(2-胺基-4-甲基-1H-苯并[d]咪唑-6-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(2-羥丙-2-基)吡啶-3-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(4-(1H-1,2,4-三唑-5-基)苯基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-(1-羥丙-2-基)-7-(2-甲基-6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;或1-(2-羥乙基)-7-(2-甲基-6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮。
代表性式(I)與(II)雜芳基化合物係列示於表1中。
雜芳基化合物可由熟諳此藝者,使用習用有機合成與市購可得物質製成。作為實例而非限制,雜芳基化合物可如下文所示圖式1-9中,以及原文段落5.1所提出實例中所概述而製成。應注意的是,熟諳此藝者可修改說明性圖式與實例中所提出之程序,以達成所要之產物。
式(I)化合物之合成係示於圖式1中。自5-溴基吡-2-胺A開始,R1基團可使用適當二羥基硼烷或硼酸酯(R+為H,或和硼原子及彼等所連接之原子一起形成環狀二羥基硼烷酯)、鈀觸媒(例如二氯[1,1'-雙(二苯基膦基)二環戊二烯鐵]鈀(II)二氯甲烷)、溶劑(譬如二甲基甲醯胺)及鹼(譬如碳酸鈉),經過Suzuki偶合,或者使用適當錫烷(R++為C1-4烷基)、鈀觸媒(譬如二氯[1,1'-雙(二苯基膦基)二環戊二烯鐵]鈀(II)二氯甲烷或鈀(dba)2/三-鄰-甲苯基膦)及溶劑(譬如二甲基甲醯胺,添加或未添加鹼,譬如三乙胺),使用Stille偶合操作法而被引進。關於Suzuki與Stille反應之典型反應條件與試劑可參閱本文(亦參閱Rossi等人,Synthesis 15:2419-2440(2004),Buchwald等人化學研究報告,41:1461-1473(2008),Fu.化學研究報告,41:1555-1564(2008)及Echavarren等人Angew.Chem.Int.Ed.,43:4704-4734(2004),及其中之參考資料)。所形成之R1胺基吡 B可使用NBS或其他標準溴化條件被溴化,而得經溴化之中間物C,然後使其與2-溴基醋酸酐反應,而得醯基化之中間物D。R2取代基係經過胺添加至D中及後續閉環作用,於胺鹼(例如三乙
胺)存在下,且在適當溶劑(譬如乙腈)中加熱而被引進,而得所要之產物。
或者,如圖式2中所示,將3,5-二溴基吡-2-胺E以如上述之2-溴基醋酸酐處理,以提供中間物F。如上文所述,R2取代基係經過胺添加至F中及後續閉環作用而被引進,而得中間物G。然後,R1基團可使用上述方法引進,意即經由與適當二羥基硼烷或硼酸酯,於鈀觸媒與鹼存在下,經過Suzuki偶合,或者與適當錫烷,於鈀觸媒存在下,使用如上述Stille偶合操作法之反應,而得所要之產物。
在另一種途徑(圖式3)中,將3,5-二溴基吡-2-胺E以2-氯醋酸酐,接著以碘化鈉處理,以提供碘基中間物F2。中間物F2係按照圖式2中關於F所概述之程序,被轉化成所要之產物。
為獲得具有對於羰基為α位之取代之類似物(圖式4),使經適當取代之胺基-保護之胺基酸H(PN為胺基之保護基,譬如Boc)與3,5-二溴基
吡-2-胺,於偶合劑例如1,1'-羰基二咪唑存在下反應。去除保護條件(例如,當PN為Boc時,去除保護係藉由例如以TFA或HCl之處理而達成),接著為鈀催化之閉環作用(使用例如碳酸氫鈉、醋酸鈀(II)及4,5-雙(二苯基膦基)-9,9-二甲基二苯并哌喃),而得中間物I。如前述,R1基團可使用適當二羥基硼烷或硼酸酯、鈀觸媒、溶劑及鹼,經過Suzuki偶合,或者使用適當錫烷、鈀觸媒及溶劑,使用Stille偶合操作法(上述)被引進,而得所要之產物。亦可使用此方法以獲得其中R2為氫之類似物。此外,可使用此途徑,以獲得其中R3與R4和彼等兩者所連接之原子一起形成螺-環狀環之化合物,經由使用適當起始胺基酸。
其中R2與R3和彼等所連接之原子一起形成環之類似物(參閱圖式5)可類似圖式4中所示之化學,以適當環狀胺基酸J開始而獲得。
為獲得所要之產物,可逆轉偶合配對物之反應性。例如,如圖式6中所示,中間物I可被轉化成其相應之錫烷K,經由與例如六甲基二錫(R++為甲基),於鈀觸媒(譬如肆(三苯膦)-鈀)存在下,且R1基團可使用適當鹵素(譬如溴化物)被引進,與溶劑,使用如上述Stille偶合操作法
之反應,而得所要之產物。或者,中間物I可被轉化成其相應之二羥基硼烷酯K2,其方式是與4,4,4',4',5,5,5',5'-八甲基-2,2'-雙(1,3,2-二氧硼伍圜),於鈀觸媒(譬如1,1'-雙(二苯基膦基)二環戊二烯鐵]鈀(II)二氯甲烷)與鹼(譬如醋酸鉀)存在下,在溶劑譬如二氧陸圜中之反應。R1基團可使用適當鹵素(譬如溴化物)、鈀觸媒及溶劑,使用如上述之Suzuki偶合操作法被引進,而得所要之產物。
式(II)化合物可按圖式7中所示獲得。3,5-二溴基吡-2-胺E以2-酮基醋酸乙酯(於例如作為還原劑之硼氫化鈉存在下)之還原胺化作用,獲得中間物L。或者,3,5-二溴基吡-2-胺E可經由與2-氯基醋酸乙酯,在鹼性條件(使用例如Cs2CO3)下之反應,而被轉化成中間物L。R2取代基係經過胺添加至L中,於胺鹼存在下,譬如二異丙基乙胺,且在適當溶劑(譬如DMSO)中加熱,及後續酸催化之閉環作用(使用例如醋酸)被引進,而得中間物M。或者,胺加成產物L之閉環作用可於鹼性催化之條件下進行,譬如以第三-丁醇鉀在適當溶劑中之處理。如前述,R1基團可使用適當二羥基硼烷或硼酸酯、鈀觸媒、溶劑及鹼,經過Suzuki偶合,或者使用適當錫烷、鈀觸媒及溶劑,使用Stille偶合操作法(上述)被引進,而得所要之產物。
替代途徑(圖式8)係以2,6-二氯吡 N與適當胺基酯(R^為C1-3烷基)
之反應開始,接著以氫,與鈀觸媒,譬如氫氧化鈀,鹼,譬如碳酸鉀,在溶劑譬如乙醇中之還原性脫鹵素作用,及經由與溴化劑譬如NBS反應之後續溴化,而產生中間物O。如上述,R2取代基係經過胺添加至O中及後續酸催化之閉環作用被引進,而得中間物P。R1基團可使用適當二羥基硼烷或硼酸酯、鈀觸媒、溶劑及鹼,經過Suzuki偶合,或者使用適當錫烷、鈀觸媒及溶劑,使用Stille偶合操作法被引進,而得所要之產物(上述)。此途徑亦允許合成具有對於羰基為α位之R3取代之類似物。
如前述,為獲得所要之產物,可逆轉偶合配對物之反應性(圖式9)。例如,中間物P可被轉化成其相應之錫烷Q,且R1基團可使用適當鹵素、鈀觸媒及溶劑,使用如上述之Stille偶合操作法被引進,而得所要之產物。或者,中間物P可被轉化成其相應之二羥基硼烷酯Q2,且R1基團可使用適當鹵素、鈀觸媒及溶劑,使用如上述之Suzuki偶合操作法被引進,而得所要之產物。
本文中所提供者為製備式(I)化合物之方法,
此方法包括使式(III)化合物
與R1-Y,在溶劑中,於鈀觸媒存在下接觸,其中該接觸係在適合提供式(I)化合物之條件下發生,其中R1,R2,R3及R4均如本文定義,且a)當X為鹵素(例如Br、Cl或I)時,則Y為B(OR+)2或Sn(R++)3;或b)當Y為鹵素(例如Br、Cl或I)時,則X為B(OR+)2或Sn(R++)3;其中各R+係獨立為氫或經取代或未經取代之C1-3烷基,或各R+與硼原子及彼等所連接之原子一起形成環狀二羥基硼烷酯;且R++為C1-4烷基。
典型上,溶劑為二甲基甲醯胺、異丙醇、二氧陸圜、甲苯、二甲基乙醯胺、四氫呋喃、乙腈、醋酸異丙酯、二甲亞碸、丙酮、甲醇、甲基第三-丁基醚或其組合,具有或未具有水之存在,且鈀觸媒為二氯[1,1'-雙(二苯基膦基)二環戊二烯鐵]鈀(II)二氯-甲烷)、鈀(dba)2/三-鄰-甲苯基膦、二氯[1,1'-雙(二-第三-丁基膦基)二環戊二烯鐵]鈀、二氯雙(對-二甲胺基苯基二第三丁基膦)鈀(II)、肆(三苯膦)鈀(0)或醋酸鈀(II)/4,5-雙(二苯基膦基)-9,9-二甲基二苯并哌喃。在一些具體實施例中,當X或Y為鹵素時,此鹵素為Br。在一些具體實施例中,當X或Y為B(OR+)2時,該接觸係於鹼存在下發生,譬如碳酸鈉、三乙胺、二異丙基乙胺、六氫吡啶、吡啶、碳酸銫、碳酸鉀、磷酸鉀或氫氧化鈉。在一些此種具體實施例中,B(OR+)2為B(OH)2或B(-OC(CH3)2C(CH3)2O-)。在其他具體實施例中,當X或Y為Sn(R++)3時,該接觸係視情況於鹼存在下發生,譬如三乙胺、碳酸鈉、二異丙基乙胺、六氫吡啶、吡啶、碳酸銫、碳酸鉀、磷酸鉀或氫氧化鈉。在
一些此種具體實施例中,R++為甲基或正-丁基。
亦提供製備式(III)化合物之方法,
此方法包括使式(IV)化合物
與R2-NH2,在溶劑中,譬如乙腈或四氫呋喃,於鹼譬如三乙胺或二異丙基乙胺存在下接觸,其中該接觸係在適合提供式(III)化合物之條件下發生,其中R2係如本文定義,R3與R4為H,X為鹵素,譬如Br,Hal為鹵素,譬如Br,且Hal2為Br或I。
亦提供製備式(III)化合物之方法,
此方法包括使式(V)化合物環化
在溶劑中,譬如乙腈,於鈀觸媒譬如醋酸鈀(II),配位體譬如4,5-雙-(二苯基膦基)-9,9-二甲基二苯并哌喃,及鹼譬如碳酸氫鈉存在下,其中該環化作用係在適合提供式(III)化合物之條件下發生,其中R2係
如本文定義,R3與R4均如本文中所述,X為鹵素,譬如Br,且Hal為鹵素,譬如Br。
亦提供製備式(II)化合物之方法,
此方法包括使式(VI)化合物
與R1-Y,在溶劑中,於鈀觸媒存在下接觸,其中該接觸係在適合提供式(I)化合物之條件下發生,其中R1、R2及R3均如本文定義,且a)當X為鹵素(例如Br、Cl或I)時,則Y為B(OR+)2或Sn(R++)3;或b)當Y為鹵素(例如Br、Cl或I)時,則X為B(OR+)2或Sn(R++)3;其中各R+係獨立為氫或經取代或未經取代之C1-3烷基,或各R+與硼原子及彼等所連接之原子一起形成環狀二羥基硼烷酯;且各R++為C1-3烷基。
典型上,溶劑為二甲基甲醯胺、異丙醇、二氧陸圜、甲苯、二甲基乙醯胺、四氫呋喃、乙腈、醋酸異丙酯、二甲亞碸、丙酮、甲醇、甲基第三-丁基醚或其組合,具有或未具有水之存在,且鈀觸媒為二氯[1,1'-雙(二苯基膦基)二環戊二烯鐵]鈀(II)二氯-甲烷)、鈀(dba)2/三-鄰-甲苯基膦、二氯[1,1'-雙(二-第三-丁基膦基)二環戊二烯鐵]鈀、二氯雙(對-二甲胺基苯基二第三丁基膦)鈀(II)、肆(三苯膦)鈀(0)或醋酸鈀(II)/4,5-雙(二苯基膦基)-9,9-二甲基二苯并哌喃。在一些具體實施例
中,當X或Y為鹵素時,此鹵素為Br。在一些具體實施例中,當X或Y為B(OR+)2時,該接觸係於鹼存在下發生,譬如碳酸鈉、三乙胺、二異丙基乙胺、六氫吡啶、吡啶、碳酸銫、碳酸鉀、磷酸鉀或氫氧化鈉。在一些此種具體實施例中,B(OR+)2為B(OH)2或B(-OC(CH3)2C(CH3)2O-)。在其他具體實施例中,當X或Y為Sn(R++)3時,該接觸係視情況於鹼存在下發生,譬如三乙胺、碳酸鈉、二異丙基乙胺、六氫吡啶、吡啶、碳酸銫、碳酸鉀、磷酸鉀或氫氧化鈉。在一些此種具體實施例中,R++為甲基或正-丁基。
亦提供製備式(VI)化合物之方法,
此方法包括使式(VII)化合物環化
於鹼譬如丁醇鉀,或酸譬如醋酸、TFA、HCl或磷酸存在下,其中該環化作用係在適合提供式(VI)化合物之條件下發生,其中R2與R3均如本文定義,Hal為鹵素,譬如Br,且R為H或C1-4烷基。典型上,環化作用係在溶劑中進行,譬如甲醇或水。
亦提供製備式(VII)化合物之方法,
此方法包括使式(VIII)化合物
與R2-NH2,在溶劑中,譬如二甲亞碸或N-甲基四氫吡咯酮,視情況於鹼譬如三乙胺或二異丙基乙胺存在下接觸,其中該接觸係在適合提供式(VII)化合物之條件下發生,其中R2與R3均如本文定義,且Hal為鹵素,譬如Br。
雜芳基化合物之藥學上可接受鹽可藉由習用及已知技術形成,譬如經由使雜芳基化合物與如上文所揭示之適當酸反應。此種鹽典型上係以高產率,在適當溫度下形成,且經常僅只是藉由在合成之最後步驟中將化合物自適當酸性洗液單離而製成。可使可形成鹽之酸溶於適當有機溶劑或含水有機溶劑中,譬如烷醇、酮或酯。另一方面,若雜芳基化合物係想要呈自由態鹼形式,則其可根據已知技術,自鹼性最後洗滌步驟單離。例如,關於製備鹽酸鹽之典型技術係使自由態鹼溶於適當溶劑中,且在使氯化氫氣體起泡經過該溶液之前,使其徹底地乾燥,如經過分子篩。
本文中所述之雜芳基化合物具有作為醫藥之利用性,以在動物或人類中治療或預防疾病。再者,本文中所述之雜芳基化合物係具抵抗激酶(例如蛋白質激酶)之活性,該激酶包括涉及癌症、炎性症狀、免疫學症狀、神經變性疾病、糖尿病、肥胖、神經病症、與老化有關聯之疾病及心血管症狀者。在未受理論限制下,雜芳基化合物係被認為有效治療與預防該疾病與症狀,此係由於其調制(例如抑制)涉及此等疾病與症狀之病因學之激酶之能力所致。因此,本文中所提供者為雜芳基化合物之許多用途,包括治療或預防下文所述之疾病。本文中所
提供之方法包括對有需要之病患投予有效量之一或多種雜芳基化合物。在一些具體實施例中,該方法另外包括投予如本文中所述之第二種活性劑。
雜芳基化合物可用於治療或預防之代表性免疫學症狀,包括但不限於風濕性關節炎、風濕性脊椎炎、骨關節炎、多發性硬化、狼瘡、炎性腸疾病、潰瘍性結腸炎、克隆氏病、重症肌無力、格雷武司氏病、腦脊髓炎、第II型糖尿病、皮肌炎及移植排斥(例如在治療以下疾病之接受者上,例如心臟、肺臟、合併之心肺、肝臟、腎臟、胰、皮膚或角膜移植;或移植物-對-宿主疾病,譬如在骨髓移植之後)。
雜芳基化合物可用於治療或預防之代表性炎性症狀,包括但不限於牛皮癬、氣喘與過敏性鼻炎、枝氣管炎、慢性阻塞肺病、囊纖維變性、炎性腸疾病、刺激性腸徵候簇、克隆氏病、黏膜結腸炎、潰瘍性結腸炎及肥胖。
雜芳基化合物可用於治療或預防之代表性心血管疾病,包括但不限於再狹窄、Wolf-Parkinson-White徵候簇、中風、心肌梗塞,或對心臟、肺臟、腸、腎臟、肝臟、胰臟、脾臟或腦部之絕血性傷害。
雜芳基化合物可用於治療或預防之代表性神經變性疾病,包括但不限於亨丁頓氏病、阿耳滋海默氏病、巴金生氏病、因τ突變所造成之癡呆症、脊髓與小腦失調類型3、因SOD1突變所造成之運動神經元疾病、神經元蠟樣脂褐質沉著病/Batten疾病(兒科神經變性)及與HIV有關聯之腦炎。
雜芳基化合物可用於治療或預防之代表性與老化有關聯之疾病,包括但不限於癌症、肥胖、第II型糖尿病、自身免疫疾病、心血管疾病及神經元退化。
於另一項具體實施例中,本文中所提供者為關於治療或預防纖維變性疾病與病症之方法。在一項特定具體實施例中,本文中所提供者
為關於治療或預防硬皮病、自發性肺纖維變性、腎纖維變性、囊纖維變性、骨髓纖維變性、肝纖維變性、皮脂腺纖維變性及皮脂腺肝炎之方法。
雜芳基化合物可用於治療或預防之代表性癌症,包括但不限於頭部、頸部、眼睛、嘴巴、喉嚨、食道、枝氣管、喉、咽、胸部、骨頭、肺臟、結腸、直腸、胃、前列腺、膀胱、子宮、子宮頸、乳房、卵巢、睪丸或其他生殖器官、皮膚、甲狀腺、血液、淋巴節、腎臟、肝臟、胰臟及腦部或中樞神經系統之癌症。雜芳基化合物亦可用於治療或預防固態腫瘤與帶血腫瘤。
在本文中所提供方法之範圍內之特定癌症,包括與涉及mTOR、PI3K或Akt激酶及其突變體或異構重組物之路徑有關聯者。在本文中所提供方法之範圍內之其他癌症,包括與下列激酶之路徑有關聯者:PI3Kα、PI3Kβ、PI3Kδ、KDR、GSK3α、GSK3β、ATM、ATX、ATR、cFMS及/或DNA-PK激酶,及其突變體或異構重組物。在一些具體實施例中,與mTOR/PI3K/Akt路徑有關聯之癌症,包括固體與帶血腫瘤,例如多發性骨髓瘤、外膜細胞淋巴瘤、擴散大B-細胞淋巴瘤、急性髓樣淋巴瘤、濾胞淋巴瘤、慢性淋巴球白血病;乳房、肺臟、子宮內膜、卵巢、胃、子宮頸及前列腺癌;神經膠質母細胞瘤;腎癌;肝細胞癌;結腸癌;神經內分泌腫瘤;頭部與頸部腫瘤;及肉瘤。
在一項特定具體實施例中,本文中所提供者為關於治療或預防與mTOR發出訊息之活化作用有關聯之疾病或病症之方法,包括但不限於直接或間接地由於PTEN(在染色體10上經刪除之磷酸酶與緊縮素同系物)、TSC1(粗隆硬結1)、TSC2(粗隆硬結2)、NF1(Neurofibromin 1)、AMPK(AMP依賴性蛋白質激酶STK11、絲胺酸/蘇胺酸激酶11)、LKB1、VHL(von Hippel-Lindau疾病)及PKD1(聚胱胺酸-1)中之基因缺陷所造成之腫瘤徵候簇。在未受理論限制下,一般認為與此等蛋白質
有關聯之基因缺陷會造成mTOR/PI3K/Akt路徑之活動過度。可經由抑制mTOR/PI3K/Akt路徑而被治療或預防之一些特定疾病,包括但不限於Cowden氏疾病、Cowden徵候簇、似Cowden徵候簇、Bannayan-Zonana徵候簇、Bannayan-Riley-Ruvalcaba徵候簇、Lhermitte-Duclos疾病、子宮內膜癌、粗隆硬結複徵、淋巴管肌瘤、神經纖維瘤病1、Peutz-Jeghers徵候簇、腎細胞癌、von Hippel-Lindau疾病、Proteus徵候簇及多囊腎臟病。
在一項特定具體實施例中,本文中所提供者為關於治療或預防與mTOR、PI3K、Akt及/或DNA-PK發出訊息有關聯之疾病或病症之方法。可藉由抑制mTOR、PI3K、Akt及/或DNA-PK發出訊息而被治療或預防之特定疾病,包括但不限於風濕性關節炎;風濕性脊椎炎;骨關節炎;痛風;氣喘、枝氣管炎;過敏性鼻炎;慢性阻塞肺病;囊纖維變性;炎性腸疾病;刺激性腸徵候簇;黏膜結腸炎;潰瘍性結腸炎;克隆氏病;亨丁頓氏病;胃炎;食管炎;肝炎;胰腺炎;腎炎;多發性硬化;紅斑性狼瘡;動脈粥瘤硬化;於血管造形術後之再狹窄;左心室肥大;心肌梗塞;中風;心臟、肺臟、腸、腎臟、肝臟、胰臟、脾臟及腦部之絕血性傷害;急性或慢性器官移植排斥;關於移植之器官保存;器官衰竭或肢體耗損(例如,包括但不限於由於絕血-再灌注損傷、外傷、全身損傷、汽車意外事故、壓碎損傷或移植失敗所造成者);移植物對宿主疾病;內毒素休克;多發性器官衰竭;牛皮癬;來自曝露至火、化學品或輻射之灼傷;濕疹;皮膚炎;皮膚移植;絕血;與手術或外傷性損傷(例如交通意外事故、槍傷或肢體壓碎)有關聯之絕血性症狀;癲癇;阿耳滋海默氏病;巴金生氏病;對細菌或病毒感染之免疫回應;惡病質;血管生成與增生疾病(包括色素性視網膜炎)、固態腫瘤,及多種組織之癌症,譬如結腸、直腸、前列腺、肝臟、肺臟、枝氣管、胰臟、腦部、頭部、頸部、胃、皮膚、腎臟、子宮頸、
血液、喉、食道、嘴巴、咽、膀胱、卵巢或子宮。
亦於本文中所提供者為關於在會表現激酶之細胞中抑制該激酶之方法,其包括使該細胞與有效量之如本文中所述之雜芳基化合物接觸。於一項具體實施例中,激酶為mTOR、DNA-PK或PI3K或其組合。在一些具體實施例中,細胞係在病患中。
亦於本文中所提供者為關於治療或預防可藉由抑制激酶路徑而被治療或預防之症狀之方法,例如mTOR/PI3K/Akt及/或DNA-PK路徑,該方法包括對有需要之病患投予有效量之如本文中所述之雜芳基化合物。在一些具體實施例中,可藉由抑制mTOR/PI3K/Akt路徑而被治療或預防之症狀,包括固體與帶血腫瘤,例如多發性骨髓瘤、外膜細胞淋巴瘤、擴散大B-細胞淋巴瘤、急性髓樣淋巴瘤、濾胞淋巴瘤、慢性淋巴球白血病;乳房、肺臟、子宮內膜、卵巢、胃、子宮頸及前列腺癌;神經膠質母細胞瘤;腎癌;肝細胞癌;結腸癌;神經內分泌腫瘤;頭部與頸部腫瘤;肉瘤;直接或間接地由於PTEN(在染色體10上經刪除之磷酸酶與緊縮素同系物)、TSC1(粗隆硬結1)、TSC2(粗隆硬結2)、NF1(Neurofibromin 1)、AMPK(AMP依賴性蛋白質激酶STK11、絲胺酸/蘇胺酸激酶11)及LKB1、VHL(von Hippel-Lindau疾病)及PKD1(polycystin-1)中之基因缺陷所造成之腫瘤徵候簇;Cowden氏疾病、Cowden徵候簇、似Cowden徵候簇、Bannayan-Zonana徵候簇、Banuayan-Riley-Ruvalcaba徵候簇、Lhermitte-Duclos疾病、子宮內膜癌、粗隆硬結複徵、淋巴管肌瘤、神經纖維瘤病1、Peutz-Jeghers徵候簇、腎細胞癌、von Hippel-Lindau疾病、Proteus徵候簇及多囊腎臟病;風濕性關節炎;風濕性脊椎炎;骨關節炎;痛風;氣喘、枝氣管炎;過敏性鼻炎;慢性阻塞肺病;囊纖維變性;炎性腸疾病;刺激性腸徵候簇;黏膜結腸炎;潰瘍性結腸炎;克隆氏病;亨丁頓氏病;胃炎;食管炎;肝炎;胰腺炎;腎炎;多發性硬化;紅斑性狼瘡;動脈粥瘤
硬化;於血管造形術後之再狹窄;左心室肥大;心肌梗塞;中風;心臟、肺臟、腸、腎臟、肝臟、胰臟、脾臟及腦部之絕血性傷害;急性或慢性器官移植排斥;關於移植之器官保存;器官衰竭或肢體耗損(例如,包括但不限於由於絕血-再灌注損傷、外傷、全身損傷、汽車意外事故、壓碎損傷或移植失敗所造成者);移植物對宿主疾病;內毒素休克;多發性器官衰竭;牛皮癬;來自曝露至火、化學品或輻射之灼傷;濕疹;皮膚炎;皮膚移植;絕血;與手術或外傷性損傷(例如交通意外事故、槍傷或肢體壓碎)有關聯之絕血性症狀;癲癇;阿耳滋海默氏病;巴金生氏病;對細菌或病毒感染之免疫回應;惡病質;血管生成與增生疾病,包括色素性視網膜炎,固態腫瘤,及多種組織之癌症,譬如結腸、直腸、前列腺、肝臟、肺臟、枝氣管、胰臟、腦部、頭部、頸部、胃、皮膚、腎臟、子宮頸、血液、喉、食道、嘴巴、咽、膀胱、卵巢或子宮。
更特定言之,可藉由本文中所提供之方法與組合物治療或預防之癌症及相關病症,包括但不限於下列:白血病,譬如但不限於急性白血病、急性淋巴球白血病,急性骨髓細胞白血病,譬如骨髓胚細胞、前骨髓細胞、骨髓單核血球、單核血球、紅白血病、白血病及脊髓發育不良徵候簇(或其病徵,譬如貧血、血小板減少症、嗜中性白血球減少症、兩種血球減少或全部血球減少)、反拗貧血(RA)、具有環狀鐵芽球之RA(RARS)、具有過量胚細胞之RA(RAEB)、於轉變中之RAEB(RAEB-T)、預白血病與慢性骨髓單核血球白血病(CMML),慢性白血病,譬如但不限於慢性骨髓細胞(粒性細胞)白血病(CML)、慢性淋巴球白血病(CLL)、有毛細胞白血病;真性紅血球增多症;淋巴瘤,譬如但不限於霍奇金(Hodgkin)氏疾病、非霍奇金(non-Hodgkin)氏疾病;多發性骨髓細胞瘤,譬如但不限於悶燒多發性骨髓瘤、非分泌性骨髓細胞瘤、骨硬化骨髓細胞瘤、漿細胞白血病、孤立漿細胞腫瘤及骨髓外漿
細胞腫瘤;Waldenström氏巨球蛋白血症;未測得重要性之單株γ-球蛋白病;良性單株γ-球蛋白病;重鏈疾病;骨頭與結締組織肉瘤,譬如但不限於骨頭肉瘤、骨肉瘤、軟骨肉瘤、Ewing氏肉瘤、惡性巨細胞腫瘤、骨頭之纖維肉瘤、脊索瘤、骨膜肉瘤、柔軟組織肉瘤、血管肉瘤(血管內瘤)、纖維肉瘤、卡波西氏肉瘤、平滑肌肉瘤、脂肉瘤、淋巴管肉瘤、轉移性癌症、神經鞘肉瘤、橫紋肌肉瘤、滑膜肉瘤;腦部腫瘤,譬如但不限於神經膠質瘤、星細胞瘤、腦幹神經膠瘤、室管膜瘤、寡樹突膠質瘤、非神經膠質腫瘤、聽神經纖維瘤、顱咽管瘤、神經管胚細胞瘤、腦膜瘤、松果體細胞瘤、松果體胚細胞瘤、原發性腦部淋巴瘤;乳癌,包括但不限於腺癌、小葉性(小細胞)癌瘤、管內癌瘤、髓質乳癌、黏液素乳癌、管狀乳癌、乳頭乳癌、原發性癌症、柏哲德氏病及炎性乳癌;腎上腺癌,譬如但不限於親鉻細胞瘤與腎上腺皮質癌瘤;甲狀腺癌,譬如但不限於乳頭狀或濾胞甲狀腺癌、髓質甲狀腺癌及退變甲狀腺癌;胰癌,譬如但不限於胰島腺瘤、胃胰瘤、胰高血糖瘤、蛇狀瘤、生長激素釋放抑制因子分泌之腫瘤及輕癌或胰島細胞腫瘤;垂體癌,譬如但不限於Cushing氏病、催乳激素分泌之腫瘤、肢端肥大病及尿崩症;眼睛癌症,譬如但不限於眼睛黑色素瘤,譬如虹膜黑色素瘤、脈絡膜黑色素瘤及睫狀體黑色素瘤,與視網膜胚細胞瘤;陰道癌,譬如鱗狀細胞癌、腺癌及黑色素瘤;女陰癌症,譬如鱗狀細胞癌、黑色素瘤、腺癌、基底細胞癌、肉瘤及柏哲德氏病;子宮頸癌,譬如但不限於鱗狀細胞癌與腺癌;子宮癌,譬如但不限於子宮內膜癌瘤與子宮肉瘤;卵巢癌,譬如但不限於卵巢上皮癌、邊界腫瘤、生殖細胞腫瘤及基質腫瘤;食管癌,譬如但不限於鱗狀癌、腺癌、腺樣膽囊癌、黏膜表皮樣癌、腺鱗狀癌、肉瘤、黑色素瘤、漿細胞腫瘤、疣性癌瘤及燕麥細胞(小細胞)癌;胃癌,譬如但不限於腺癌、變成蕈狀(息肉狀)、形成潰瘍、表面擴展、滲出擴展、惡性淋巴瘤、脂肉瘤、纖維
肉瘤及癌肉瘤;結腸癌;直腸癌;肝癌,譬如但不限於肝細胞癌與肝胚細胞瘤,膽囊癌,譬如腺癌;膽管癌,譬如但不限於乳頭狀、結狀及擴散;肺癌,譬如非小細胞肺癌、鱗狀細胞癌(表皮樣癌)、腺癌、大細胞癌及小細胞肺癌;睪丸癌,譬如但不限於胚腫瘤、精細胞瘤,退變、古典(典型)、精母細胞、非精細胞瘤,胚胎癌、畸胎生成癌、絨毛膜癌(卵黃囊腫瘤),前列腺癌,譬如但不限於腺癌、平滑肌肉瘤及橫紋肌肉瘤;陰莖癌;口腔癌,譬如但不限於鱗狀細胞癌;基底癌症;唾液腺癌,譬如但不限於腺癌、黏膜表皮樣癌及腺樣膽囊癌;咽癌,譬如但不限於鱗狀細胞癌與疣;皮膚癌,譬如但不限於基底細胞癌、鱗狀細胞癌及黑色素瘤、表面擴展黑色素瘤、結狀黑色素瘤、雀斑惡性黑色素瘤、肢端雀斑黑色素瘤;腎臟癌,譬如但不限於腎細胞癌、腺癌、腎上腺樣瘤、纖維肉瘤、轉移細胞癌(腎盂及/或子宮);Wilm氏腫瘤;膀胱癌,譬如但不限於轉移細胞癌、鱗狀細胞癌、腺癌、癌肉瘤。此外,癌症包括黏液肉瘤、成骨質肉瘤、內皮肉瘤、淋巴管-內皮肉瘤、間皮瘤、滑膜瘤、血管母細胞瘤、上皮癌、囊腺癌、枝氣管原癌、汗腺癌、皮脂腺癌、乳頭癌及乳頭腺癌(關於此種病症之回顧,參閱Fishman等人,1985,Medicine,第2版,J.B.Lippincott公司,Philadelphia與Murphy等人,1997,通知之決定:癌症診斷、治療及恢復之完整書籍,Viking Penguin,Penguin圖書U.S.A.公司,美國)。
因此,本文中所提供之方法與組合物亦可用以治療或預防多種癌症或其他異常增生疾病,包括(但不限於)下列:癌瘤,包括膀胱、乳房、結腸、腎臟、肝臟、肺臟、卵巢、胰臟、胃、子宮頸、甲狀腺及皮膚者;包括鱗狀細胞癌;淋巴樣血統之造血腫瘤,包括白血病、急性淋巴球白血病、急性淋巴胚細胞白血病、B-細胞淋巴瘤、T-細胞淋巴瘤、Berketts淋巴瘤;髓樣血統之造血腫瘤,包括急性與慢性骨髓性白血病與前骨髓細胞白血病;間葉來源之腫瘤,包括纖維肉瘤與橫紋
肌肉瘤;其他腫瘤,包括黑色素瘤、生殖細胞瘤、四癌瘤、神經胚細胞瘤及神經膠質瘤;中樞與末梢神經系統之腫瘤,包括星細胞瘤、多形神經膠質母細胞瘤、神經胚細胞瘤、神經膠質瘤及神經鞘瘤;固體與帶血腫瘤;間葉來源之腫瘤,包括纖維肉瘤、橫紋肌肉瘤及骨肉瘤;及其他腫瘤,包括黑色素瘤、著色性乾皮症、角質棘皮瘤、生殖細胞瘤、甲狀腺濾胞癌及畸胎癌。亦意欲涵蓋的是,因細胞凋零中之迷行所造成之癌症亦藉由本文中所揭示之方法與組合物治療。此種癌症可包括但不限於濾胞淋巴瘤、具有p53突變之癌瘤,乳房、前列腺及卵巢之激素依賴性腫瘤,及癌前損傷,譬如家族腺瘤息肉病、幼年息肉病徵候簇、Birt-Hogg-Dubé徵候簇(BHD)及脊髓發育不良徵候簇。在特殊具體實施例中,惡性或不良增生變化(譬如化生與發育異常)或過高增生病症,係在卵巢、膀胱、乳房、結腸、肺臟、皮膚、胰臟、腎臟或子宮中被治療或預防。在其他特殊具體實施例中,肉瘤、黑色素瘤或白血病係經治療或預防。
在一項特定具體實施例中,本文中所提供之方法與組合物亦可用以治療、預防或處理各種類型之淋巴瘤(意即源自於網狀內皮與淋巴系統中之贅瘤之異質組群),譬如非霍奇金(Non-Hodgkin)氏淋巴瘤(NHL)(意即,在免疫系統位置中之淋巴樣細胞之惡性單株增生,包括淋巴節、骨髓、脾臟、肝臟及胃腸道)。雜芳基化合物可用於治療或預防之NHL,包括但不限於外膜細胞淋巴瘤、MCL、中間分化之淋巴球淋巴瘤、中間淋巴球淋巴瘤、ILL、擴散不良分化淋巴球淋巴瘤、PDL、中央細胞淋巴瘤、擴散小分裂細胞淋巴瘤、DSCCL、濾胞淋巴瘤,及可在顯微鏡下見及之任何類型之外膜細胞淋巴瘤(結狀、擴散、胚及外膜區帶淋巴瘤)。
於另一項具體實施例中,本文中所提供之方法與組合物亦可用以投予需要治療惡性疾病之病患(例如,患有急性淋巴球白血病、急性骨
髓性白血病、慢性骨髓性白血病、慢性淋巴球白血病、脊髓發育不良徵候簇("預白血病")、單核糖體7徵候簇、非霍奇金(non-Hodgkin)氏淋巴瘤、神經胚細胞瘤、腦部腫瘤、多發性骨髓瘤、睪丸生殖細胞腫瘤、乳癌、肺癌、卵巢癌、黑色素瘤、神經膠質瘤、肉瘤或其他固態腫瘤之病患),以及需要治療非惡性疾病者(例如患有血液學病症、先天性免疫不全、黏多醣症、脂肪代謝障礙、骨質疏鬆症、Langerhan氏細胞組織細胞症、Lesch-Nyhan徵候簇或糖原儲存疾病之病患)。
於另一項具體實施例中,本文中所提供者為關於治療骨髓增生病症或脊髓發育不良徵候簇之方法,其包括對有需要之病患投予有效量之雜芳基化合物或其組合物。在某些具體實施例中,骨髓增生病症為真性紅血球過病;原發性血小板增多症;慢性骨髓性白血病;急性或慢性粒性細胞白血病;急性或慢性骨髓單核血球白血病;骨髓纖維化紅白血病;或血管生成髓樣化生。
於另一項具體實施例中,本文中所提供者為關於治療對其他激酶抑制劑(譬如愛馬汀尼伯(imatinib)甲烷磺酸鹽(STI-571或GleevecTM)治療)具抗藥性之癌症或腫瘤之方法,其包括對有需要之病患投予有效量之雜芳基化合物或其組合物。在一項特定具體實施例中,本文中所提供者為關於治療白血病之方法,包括但不限於對愛馬汀尼伯(imatinib)甲烷磺酸鹽(STI-571或GleevecTM)治療具抗藥性之胃腸基質腫瘤(GIST)、急性淋巴球白血病或慢性骨髓細胞白血病,該方法包括對有需要之病患投予有效量之雜芳基化合物或其組合物。
在一項特殊具體實施例中,本文中所提供者為關於治療或預防白血病(意即形成血液組織之惡性贅瘤)之方法,包括但不限於慢性淋巴球白血病、慢性骨髓細胞白血病、急性淋巴胚細胞白血病、急性骨髓性白血病及急性骨髓胚細胞白血病。白血病可經復發、反拗或對習用療法具抗藥性。"復發"一詞係指以下狀況,其中在治療之後已具有白
血病之減輕之病患,係具有白血病細胞在骨髓中之恢復,及降低正常血球。"反拗或抗藥性"一詞係指其中病患即使是在密集治療之後仍具有殘留白血病細胞在其骨髓中之情況。
各種類型之癌症係被描述於2004年2月12日公告之美國專利申請案公報2004/0029832中,其係以全文併於本文供參考(參閱,例如段落2.2.癌症之類型)。特定癌症包括但不限於白血病,譬如慢性淋巴球白血病、慢性骨髓細胞白血病、急性淋巴胚細胞白血病、急性骨髓性白血病及急性骨髓胚細胞白血病;已進展之惡性病症、澱粉樣變性病、神經胚細胞瘤、腦膜瘤、血管外皮細胞瘤、多重腦部轉移、多形神經膠質母細胞瘤、神經膠質母細胞瘤、腦幹神經膠瘤、不良預後惡性腦部腫瘤、惡性神經膠質瘤、復發惡性神經膠質瘤、星細胞退變瘤、退變寡樹突膠質瘤、神經內分泌腫瘤、直腸腺癌、Dukes C & D結腸直腸癌、不可切除結腸直腸癌、轉移性肝細胞癌、卡波西氏肉瘤、核型急性骨髓胚細胞白血病、霍奇金(Hodgkin)氏淋巴瘤、非霍奇金(non-Hodgkin)氏淋巴瘤、皮膚T-細胞淋巴瘤、皮膚B-細胞淋巴瘤、擴散大B-細胞淋巴瘤、輕度濾胞淋巴瘤、惡性黑色素瘤、惡性間皮瘤、惡性胸膜滲液間皮瘤徵候簇、腹膜癌瘤、乳頭漿癌瘤、婦科肉瘤、柔軟組織肉瘤、皮膚脈管炎、Langerhan氏細胞組織細胞症、平滑肌肉瘤、進行性骨化纖維發育異常、激素反拗前列腺癌、經切除之高危險柔軟組織肉瘤、不可切除肝細胞癌、Waldenstrom氏巨球蛋白血症、悶燒骨髓細胞瘤、無痛骨髓細胞瘤、輸卵管癌、雄激素無關之前列腺癌、雄激素依賴性第IV期非轉移性前列腺癌、激素不敏感性前列腺癌、化學療法不敏感性前列腺癌、乳頭甲狀腺癌瘤、濾胞甲狀腺癌瘤、髓質甲狀腺癌瘤及平滑肌瘤。於一項具體實施例中,癌症為原發性或轉移性。於另一項具體實施例中,癌症為復發、反拗或對化學療法或放射具抵抗性;特定言之,對酞胺哌啶酮為反拗。
進一步於本文中提供者為關於治療已於先前經治療關於癌症但對標準療法無回應性之病患以及先前尚未被治療者之方法。亦於本文中提供者為關於治療病患而不管病患年齡之方法,惟一些癌症係在某些年齡組群中較常見。又進一步於本文中提供者為關於治療已接受手術以企圖治療討論下之癌症之病患以及尚未接受者之方法。由於具有癌症之病患具有異質臨床表象與不同臨床結果,故給予病患之治療可依其預後而改變。熟練臨床家係能夠容易地決定可有效地用以治療具有癌症之個別病患之特定二次藥劑、手術類型及非藥物為基礎標準療法之類型,無需過度實驗。
再者,於本文中所提供者為關於治療或預防病症之方法,譬如肺高血壓、Carney複徵、肌肉消耗(萎縮、惡病質),肌病,譬如Danon氏疾病,及細菌、真菌及病毒感染(包括結核分枝桿菌、組群A鏈球菌屬、HSV類型I及HIV感染)。
雜芳基化合物可與其他藥理學活性化合物("第二種活性劑")合併在本文所述之方法與組合物中。咸認某些組合可發生作用,以治療特定型式之疾病或病症,及與此種疾病或病症有關聯之症狀與病徵。雜芳基化合物亦可發生作用以減輕伴隨著某些第二種活性劑之不利作用,而反之亦然。
一或多種第二種活性成份或藥劑可被使用於本文中所述之方法與組合物中。第二種活性劑可為大分子(例如蛋白質)或小分子(例如合成無機、有機金屬或有機分子)。
大分子第二種活性劑之實例包括但不限於造血生長因子、細胞活素及單株與多株抗體。活性劑之特殊實例為抗-CD40單株抗體(例如SGN-40);組織蛋白脫乙醯胺抑制劑(例如MGCD0103、SAHA及LAQ 824);低甲基化劑(譬如Vidaza);IMiD®品牌之免疫調制產物(譬如酞胺哌啶酮、連那利多麥(lenalidomide)及波馬利多醯胺(pomalidomide));
熱震蛋白質-90抑制劑(例如17-AAG);似胰島素生長因子-1受體激酶抑制劑;血管內皮生長因子受體激酶抑制劑(例如PTK787);胰島素生長因子受體抑制劑;溶血磷脂酸醯基轉移酶抑制劑;IkB激酶抑制劑;p38MAPK抑制劑;Pim激酶抑制劑(例如SGI-1776或WO/2008/106692中所揭示者);EGFR抑制劑(例如吉非汀尼伯(gefitinib)與婀羅提尼伯(erlotinib)HCL);HER-2抗體(例如搓史圖諸馬伯(trastuzumab)(Herceptin®)與柏圖祖馬伯(pertuzumab)(OmnitargTM)),以及HER-2激酶抑制劑(譬如拉巴提尼伯(Lapatinib));VEGFR抗體(例如貝發西馬伯(bevacizumab)(AvastinTM));VEGFR抑制劑(例如flk-1特定激酶抑制劑、SU5416及ptk787/zk222584);P13K抑制劑(例如華特曼寧(wortmannin));C-Met抑制劑(例如PHA-665752);抗雌激素劑(例如列特羅唑(Letrozo1e)、弗爾威斯傳(Fulvestrant)、他摩西吩(tamoxifen));單株抗體(例如利圖西馬伯(rituximab)(Rituxan®)、托西圖莫伯(tositumomab)(Bexxar®)、艾卓可羅伯(edrecolomab)(Panorex®)及G250);及抗-TNF-α抗體。小分子活性劑之實例包括但不限於小分子抗癌劑與抗生素(例如克拉利霉素(clarithromycin))。
可與雜芳基化合物併用之特定第二種活性化合物係依欲被治療、預防或處理之特定適應徵而改變。
例如,關於癌症之治療、預防或處理,第二種活性劑包括但不限於:抗葉酸鹽,譬如PremetrexedTM;些馬山尼伯(semaxanib);環孢質;恩塔臬西伯(etanercept);強力霉素;博替左米(bortezomib);阿西文辛(acivicin);阿可拉紅菌素(aclarubicin);阿可達唑(acodazole)鹽酸鹽;阿克羅寧(acronine);阿多傑利辛(adozelesin);阿迪斯白血球素(aldesleukin);阿催塔胺(altretamine);偶氮霉素;阿美坦酮(ametantrone)醋酸鹽;阿姆薩素(amsacrine);安那史唑(anastrozole);安刷霉素(anthramycin);天冬醯胺酶;阿斯伯林(asperlin);氮西替定
(azacitidine);阿皆帖巴(azetepa);含固氮霉素;貝替制菌素(batimastat);苯并地巴(benzodepa);二卡如醯胺(bicalutamide);雙安催(bisantrene)鹽酸鹽;雙那非得(bisnafide)二甲烷磺酸鹽;必皆列辛(bizelesin);博來霉素硫酸鹽;布瑞奎那(brequinar)鈉;布羅吡胺(bropirimine);白血福恩(busulfan);卡提諾霉素(cactinomycin);二甲睪酮;卡拉謝醯胺(caracemide);卡貝提莫(carbetimer);碳氯胺鉑;亞硝基脲氮芥;卡紅菌素(carubicin)鹽酸鹽;卡皆列辛(carzelesin);謝迪吩果(cedefingol);塞拉庫西比(celecoxib);苯丁酸氮芥(chlorambucil);西羅里霉素;順氯胺鉑;克拉利賓(cladribine);克利斯那托(crisnatol)甲烷磺酸鹽;環磷醯胺;阿糖胞苷;氮烯咪胺;達克汀霉素;道諾紅菌素鹽酸鹽;得西塔賓(decitabine);多索馬胺鉑(dexormaplatin);迪札鳥嘌呤(dezaguanine);迪札鳥嘌呤(dezaguanine)甲烷磺酸鹽;迪阿濟醌(diaziquone);多謝他索(docetaxel);多克索紅菌素;多克索紅菌素鹽酸鹽;卓洛西吩(droloxifene);卓洛西吩(droloxifene)檸檬酸鹽;卓莫史坦酮(dromostanolone)丙酸鹽;迪烏偶氮霉素(duazomycin);伊達催克沙特(edatrexate);艾弗洛尼辛(eflornithine)鹽酸鹽;約薩米如辛(elsamitrucin);恩若胺鉑(enloplatin);恩普洛美特(enpromate);表普比啶(epipropidine);表紅菌素鹽酸鹽;阿布羅唑(erbulozole);約索紅菌素(esorubicin)鹽酸鹽;雌氮芥(estramustine);雌氮芥(estramustine)磷酸鹽鈉;安他尼達唑(etanidazole);衣托糖苷(etoposide);衣托糖苷(etoposide)磷酸鹽;衣托普林(etoprine);發德羅唑(fadrozole)鹽酸鹽;發雜拉賓(fazarabine);吩瑞亭奈德(fenretinide);5-氟脫氧尿苷;弗達拉賓(fludarabine)磷酸鹽;氟尿嘧啶;弗洛西塔賓(flurocitabine);弗斯奎酮(fosquidone);弗三約辛(fostriecin)鈉;真西塔賓(gemcitabine);真西塔賓(gemcitabine)鹽酸鹽;羥基脲;依達紅菌素鹽酸鹽;依發斯醯胺(ifosfamide);依莫弗辛(ilmofosine);衣普氯胺鉑
(iproplatin);伊利諾提肯(irinotecan);伊利諾提肯(irinotecan)鹽酸鹽;蘭瑞歐太得(lanreotide)醋酸鹽;列特羅唑(letrozole);留普內酯(leuprolide)醋酸鹽;利洛唑(liarozole)鹽酸鹽;羅美催索(lometrexol)鈉;環己亞硝脲;洛索山酮(losoxantrone)鹽酸鹽;馬索普洛可(masoprocol);美坦生(maytansine);氮芥鹽酸鹽;甲地孕酮醋酸鹽;甲連孕酮(melengestrol)醋酸鹽;苯丙胺酸氮芥;門諾加利(menogaril);巰基嘌呤;胺甲喋呤;胺甲喋呤鈉;美托普林(metoprine);雙二甲磷醯胺乙酯;米亭多醯胺(mitindomide);絲裂卡辛(mitocarcin);絲裂可洛林(mitocromin);絲裂吉林(mitogillin);絲裂麻辛(mitomalcin);絲裂霉素;絲裂史伯(mitosper);米托坦(mitotane);絲裂黃酮(mitoxantrone)鹽酸鹽;霉菌酚酸;諾可達唑(nocodazole);諾加拉霉素;歐馬胺鉑(ormaplatin);歐西蘇蘭(oxisuran);培克里他索(paclitaxel);佩加斯巴酶(pegaspargase);佩里霉素;五氮芥;佩普羅霉素(peplomycin)硫酸鹽;伯弗斯發醯胺(perfosfamide);雙溴丙基哌;哌醯硫烷;皮若山酮(piroxantrone)鹽酸鹽;普利卡霉素;普羅美斯坦(plomestane);波非莫(porfimer)鈉;甲基絲裂霉素;潑尼氮芥(prednimustine);鹽酸甲基苄肼;嘌呤霉素;嘌呤霉素鹽酸鹽;吡唑呋喃菌素;利玻普林(riboprine);沙吩果(safingol);沙吩果(safingol)鹽酸鹽;賽氮芥(semustine);二甲二苯四氮烯;史巴弗賽特(sparfosate)鈉;稀疏霉素;螺鍺鹽酸鹽;螺氮芥(spiromustine);螺胺鉑(spiroplatin);鏈黑菌素;鏈霉亞硝基素;速洛非諾(sulofenur);塔利索霉素(talisomycin);提可加蘭(tecogalan)鈉;紅豆杉帖里(taxotere);提佳弗(tegafur);提洛山酮(teloxantrone)鹽酸鹽;提莫波吩(temoporfin);天尼苷(teniposide);提洛西隆(teroxirone);睪丸內脂;噻米普林(thiamiprine);硫基鳥嘌呤;噻替哌(thiotepa);提偶氮呋林(tiazofurin);提拉巴胺(tirapazamine);托里米吩(toremifene)檸檬酸鹽;催史托隆(trestolone)醋酸鹽;三西利賓
(triciribine)磷酸鹽;胺三甲喋呤(trimetrexate);胺三甲喋呤(trimetrexate)醛糖酸鹽;三普托瑞林(triptorelin);圖布羅唑(tubulozole)鹽酸鹽;尿嘧啶芥;尿烷亞胺;發普瑞太(vapreotide);維替波吩(verteporfin);長春花鹼硫酸鹽;長春新鹼硫酸鹽;長春花素;長春花素硫酸鹽;長春比啶(vinepidine)硫酸鹽;長春甘胺酸酯(vinglycinate)硫酸鹽;環氧長春鹼硫酸鹽;威諾賓(vinorelbine)酒石酸鹽;異長春鹼硫酸鹽;長春唑利啶(vinzolidine)硫酸鹽;波羅唑(vorozole);間尼胺鉑(zeniplatin);吉諾制菌素;及唑紅菌素(zorubicin)鹽酸鹽。
其他第二種藥劑包括但不限於:20-表-1,25-二羥維生素D3;5-乙炔基尿嘧啶;阿必拉特酮(abiraterone);阿可拉紅菌素(aclarubicin);醯基弗烯;阿迭西片醇(adecypenol);阿多傑利辛(adozelesin);阿迪斯白血球素(aldesleukin);ALL-TK拮抗劑;阿催塔胺(altretamine);恩巴氮芥(ambamustine);阿米多斯(amidox);亞米弗斯亭(amifostine);胺基乙醯丙酸;阿姆紅菌素(amrubicin);阿姆薩素(amsacrine);安那瑞利得(anagrelide);安那史唑(anastrozole);穿心蓮內酯;血管生成抑制劑;拮抗劑D;拮抗劑G;安塔瑞利斯(antarelix);抗背側化形態發生蛋白質-1;抗雄激素劑、前列腺腫瘤;抗雌激素劑;抗新伯拉斯東(antineoplaston);反有意義寡核苷酸;阿菲地可林(aphidicolin)甘胺酸鹽;細胞凋零基因調制劑;細胞凋零調節劑;以新陳代謝作用作為標的之化合物,譬如白藜蘆醇;無嘌呤核酸;ara-CDP-DL-PTBA;精胺酸脫胺酶;阿蘇拉可林(asulacrine);阿塔美斯坦(atamestane);阿三氮芥(atrimustine);阿克西那制菌素(axinastatin)1;阿克西那制菌素(axinastatin)2;阿克西那制菌素(axinastatin)3;氮謝特隆(azasetron);氮毒素;氮酪胺酸;漿果赤霉素III衍生物;巴蘭醇(balanol);貝替制菌素(batimastat);BCR/ABL拮抗劑;苯并二氫卟酚;苯甲醯基星形孢素;β內醯胺衍生物;β-阿列辛(alethine);β可列霉素(betaclamycin)B;
樺木醇酸;bFGF抑制劑;二卡如醯胺(bicalutamide);雙安催(bisantrene);雙氮丙啶基精胺;雙那非得(bisnafide);雙催提臬(bistratene)A;必皆列辛(bizelesin);布瑞弗列特(breflate);布羅吡胺(bropirimine);布多提坦(budotitane);丁噻寧磺醯胺(buthionine sulfoximine);鈣波三醇(calcipotriol);鈣磷汀(calphostin)C;喜樹鹼衍生物;卡配西塔賓(capecitabine);羧醯胺-胺基-三唑;羧基醯胺三唑;CaRest M3;CARN 700;軟骨衍生抑制劑;卡皆列辛(carzelesin);酪蛋白激酶抑制劑(ICOS);卡斯坦精胺(castanospermine);塞可洛品B;西左釋放素(cetrorelix);可洛林斯(chlorlns);氯基喹啉磺醯胺;西卡普斯特(cicaprost);順式-卟啉;克拉利賓(cladribine);克拉霉素(clathromycin);可洛米吩(clomifene)類似物;克羅三馬唑(clotrimazole);可利斯霉素(collismycin)A;可利斯霉素(collismycin)B;風車子制菌素A4;風車子制菌素類似物;可那基寧(conagenin);可蘭貝西定(crambescidin)816;克利斯那托(crisnatol);隱藻素8;隱藻素A衍生物;苦拉辛(curacin)A;環戊蒽醌;環普拉坦(cycloplatam);西佩霉素(cypemycin);阿糖胞苷歐可弗斯特(ocfosfate);溶細胞因子;細胞制菌素;達可利西馬(dacliximab);得西塔賓(decitabine);脫氫迪蘭寧(didemnin)B;迪斯若瑞林(deslorelin);地塞米松;得西磷醯胺(dexifosfamide);得拉唑山(dexrazoxane);得維拉巴密(dexverapamil);迪阿濟醌(diaziquone);迪蘭寧(didemnin)B;迪多克斯(didox);二乙基正精胺;二氫-5-氮胞苷;9-二氫紅豆杉醇;二氧霉素;二苯基螺氮芥;多謝他索(docetaxel);廿二烷醇;多拉西從(dolasetron);多西弗利叮(doxifluridine);多克索紅菌素;卓洛西吩(droloxifene);卓那賓諾(dronabinol);都卡霉素(duocarmycin)SA;阿貝西連(ebselen);也可氮芥(ecomustine);艾迪弗辛(edelfosine);艾卓可羅伯(edrecolomab);艾弗洛尼辛(eflornithine);欖香烯;艾米提弗(emitefur);表紅菌素;約
利史特來(epristeride);雌氮芥(estramustine)類似物;雌激素催動劑;雌激素拮抗劑;安他尼達唑(etanidazole);衣托糖苷(etoposide)磷酸鹽;約克美斯烷(exemestane);發德羅唑(fadrozole);發雜拉賓(fazarabine);吩瑞亭奈德(fenretinide);非葛拉亭(filgrastim);菲那史替來(finasteride);黃酮吡啶醇;弗列吉史汀(flezelastine);弗史特隆(fluasterone);弗達拉賓(fludarabine);氟基道諾如尼辛(daunorunicin)鹽酸鹽;發吩尼美斯(forfenimex);弗美斯烷(formestane);弗三約辛(fostriecin);弗提氮芥(fotemustine);釓提沙啡啉(texaphyrin);硝酸鎵;加洛西塔賓(galocitabine);甘尼瑞利斯(ganirelix);明胺酶抑制劑;真西塔賓(gemcitabine);谷胱甘肽抑制劑;庚蘇汎(hepsulfam);遺傳素;六亞甲基雙乙醯胺;金絲桃蒽酮;愛邦宗(ibandronic)酸;依達紅菌素;愛多西吩(idoxifene);愛卓滿酮(idramantone);依莫弗辛(ilmofosine);衣洛馬制菌素(ilomastat);愛馬汀尼伯(imatinib)(Gleevec®)、依米奎莫得(imiquimod);免疫刺激劑肽;似胰島素生長因子-1受體抑制劑;干擾素催動劑;干擾素;間白血球活素;愛歐苯胍(iobenguane);碘基多克索紅菌素;4-愛波明醇(ipomeanol);愛洛普拉特(iroplact);俄索葛拉定(irsogladine);異苯加唑(isobengazole);異高哈利軟骨素B;愛塔西從(itasetron);加普拉金來(jasplakinolide);卡哈拉來得(kahalalide)F;拉美拉林(lamellarin)-N三醋酸鹽;蘭瑞歐太得(lanreotide);列因那霉素(leinamycin);列諾拉斯亭(lenograstim);香菇糖硫酸鹽;列普托制菌素(leptolstatin);列特羅唑(letrozole);白血病抑制因子;白血球α干擾素;留普內酯(leuprolide)+雌激素+黃體酮;留普瑞林(leuprorelin);左旋四咪唑;利洛唑(liarozole);線性聚胺類似物;親脂性雙醣肽;親脂性鉑化合物;利索可醯胺(lissoclinamide)7;羅巴鉑胺(lobaplatin);胍乙基磷酸絲胺酸;羅美催索(lometrexol);洛尼達胺(lonidamine);洛索山酮(losoxantrone);洛索利賓(loxoribine);留托提
肯(lurtotecan);鎦提沙啡啉(texaphyrin);來索非林(lysofylline);溶解肽;美坦新(maitansine);甘露制菌素A;馬利制菌素(marimastat);馬索普洛可(masoprocol);馬斯平(maspin);間質溶素抑制劑;間質金屬蛋白酶抑制劑;門諾加利(menogaril);莫巴酮(merbarone);美特瑞林(meterelin);甲硫胺酸酶;胃復安(metoclopramide);MIF抑制劑;米非普利史東(mifepristone);米提弗辛(miltefosine);米利莫斯亭(mirimostim);絲裂胍腙(mitoguazone);絲裂乳酸萘酚(mitolactol);絲裂霉素類似物;絲裂那伐(mitonafide);絲裂毒素成纖維細胞生長因子-沙孢素(saporin);絲裂黃酮(mitoxantrone);莫發洛亭(mofarotene);莫葛拉莫亭(molgramostim);鄂比圖斯(Erbitux)、人類絨毛膜促性腺激素;單磷醯基脂質A+分枝桿菌細胞壁sk;莫皮達莫(mopidamol);芥末抗癌劑;麥卡過氧化物(mycaperoxide)B;分枝桿菌細胞壁萃取物;麥利波隆(myriaporone);N-乙醯基二那林(acetyldinaline);N-取代之苯甲醯胺;那發瑞林(nafarelin);那葛瑞提普(nagrestip);那諾松(naloxone)+戊唑星(pentazocine);那巴文(napavin);那夫特平(naphterpin);那托拉斯亭(nartograstim);臬達鉑胺(nedaplatin);內莫紅菌素(nemorubicin);臬利宗(neridronic)酸;尼如醯胺(nilutamide);尼沙霉素(nisamycin);氧化氮調制劑;氧化氮抗氧化劑;尼出林(nitrullyn);歐利莫森(oblimersen)(Genasense®);O6-苄基鳥嘌呤;八瑞歐肽(octreotide);歐吉西酮(okicenone);寡核苷酸;翁那普利史東(onapristone);翁丹西從(ondansetron);澳拉辛(oracin);口服細胞活素誘發物;歐馬胺鉑(ormaplatin);歐沙特酮(osaterone);草酸鉑;氧幽諾霉素(oxaunomycin);培克里他索(paclitaxel);培克里他索(paclitaxel)類似物;培克里他索衍生物;巴老胺(palauamine);棕櫚醯基利坐素(rhizoxin);帕米宗(pamidronic)酸;巴那西三醇(panaxytriol);巴諾米吩(panomifene);巴拉菌素(parabactin);帕拮利普汀(pazelliptine);佩
加斯巴酶(pegaspargase);配爾地辛(peldesine);五醣多硫酸鈉;戊托制菌素(pentostatin);片特羅唑(pentrozole);伯弗玻隆(perflubron);伯弗斯發醯胺(perfosfamide);紫蘇醇;吩霉素(phenazinomycin);醋酸苯酯;磷酸酶抑制劑;皮西班尼(picibanil);氫氯化毛果芸香鹼;皮拉紅菌素(pirarubicin);皮利催新(piritrexim);普拉西汀(placetin)A;普拉西汀(placetin)B;血纖維蛋白溶酶原活化劑抑制劑;鉑複合物;鉑化合物;鉑-三胺複合物;波非莫(porfimer)鈉;甲基絲裂霉素;潑尼松;丙基雙-吖啶酮;前列腺素J2;蛋白質降解體抑制劑;蛋白質A為基礎之免疫調制劑;蛋白質激酶C抑制劑;蛋白質激酶C抑制劑、微阿加爾(microalgal);蛋白質酪胺酸磷酸酶抑制劑;嘌呤核苷磷酸化酶抑制劑;羥基茜草素;吡唑并吖啶;吡啶氧基化血紅素聚氧化乙烯共軛物;raf拮抗劑;瑞提崔斯得(raltitrexed);拉莫西從(ramosetron);ras法呢基蛋白質轉移酶抑制劑;ras抑制劑;ras-GAP抑制劑;去甲基化瑞提利汀(retelliptine);乙底宗酸(etidronate)錸Re 186;利坐素(rhizoxin);核糖酵素;RII視黃醯胺;洛西圖激素(rohitukine);羅莫太得(romurtide);洛奎尼美斯(roquinimex);如必金酮(rubiginone)B1;如玻西爾(ruboxyl);沙吩果(safingol);沙因托平(saintopin);SarCNU;沙可植醇(sarcophytol)A;沙葛拉莫斯亭(sargramostim);Sdi 1擬似物;賽氮芥(semustine);衰老衍生抑制劑1;有意義寡核苷酸;訊息轉導抑制劑;西坐非蘭(sizofiran);索布唑山(sobuzoxane);硼卡普特酸鈉(sodium borocaptate);苯基醋酸鈉;索維醇(solverol);促生長因子結合蛋白質;索能明(sonermin);史巴發席克酸(sparfosicacid);史比卡霉素(spicamycin)D;螺氮芥(spiromustine);脾潘亭(splenopentin);史豐吉制菌素(spongistatin)1;角鯊胺;史替皮醯胺(stipiamide);基質溶素抑制劑;硫吩諾辛(sulfinosine);超活性影響血管腸肽拮抗劑;蘇拉迪斯塔(suradista);蘇拉明(suramin);史萬松寧(swainsonine);塔利氮芥
(tallimustine);他摩西吩(tamoxifen)碘化甲烷;道羅氮芥(tauromustine);塔雜若汀(tazarotene);提可加蘭(tecogalan)鈉;提佳弗(tegafur);碲吡錠;調聚酶抑制劑;提莫波吩(temoporfin);天尼苷(teniposide);四氯癸氧化物;四唑明(tetrazomine);唐松草胞生素;硫可拉林(coraline);血栓造血素;血栓造血素擬似物;席嗎發辛(thymalfasin);胸腺造血素受體催動劑;胸腺三南(thymotrinan);促甲狀腺激素;錫乙基本羥基茜草素;提拉巴胺(tirapazamine);二氯化二環戊二烯鈦;托普仙亭(topsentin);托里米吩(toremifene);轉譯抑制劑;崔替諾因(tretinoin);三乙醯基脲嘧啶核苷;三西利賓(triciribine);胺三甲喋呤(trimetrexate);三普托瑞林(triptorelin);搓比西從(tropisetron);圖洛史得來(turosteride);酪胺酸激酶抑制劑;提發史亭(tyrphostins);UBC抑制劑;由苄尼梅斯(ubenimex);泌尿生殖器竇房結衍生之生長抑制因子;尿激酶受體拮抗劑;發普瑞太(vapreotide);發利歐林(variolin)B;維拉瑞索(velaresol);維拉胺(veramine);勃定斯(verdins);維替波吩(verteporfin);威諾賓(vinorelbine);溫沙亭(vinxaltine);維他克辛(vitaxin);波羅唑(vorozole);占諾特隆(zanoterone);間尼胺鉑(zeniplatin);吉拉可伯(zilascorb);及吉諾制菌素史替馬拉莫(stimalamer)。
特定第二種活性劑包括但不限於2-甲氧雌二醇、調聚制菌素、在多發性骨髓瘤細胞中之細胞凋零之誘發物(例如TRAIL)、博替左米(bortezomib)、制菌素、些馬山尼伯(semaxanib)、環孢質、恩塔臬西伯(etanercept)、強力霉素、博替左米(bortezomib)、歐利莫森(oblimersen)(Genasense®)、瑞米卡得(remicade)、多謝他索(docetaxel)、塞拉庫西比(celecoxib)、苯丙胺酸氮芥、地塞米松(Decadron®)、類固醇、真西塔賓(gemcitabine)、順氯胺鉑、天莫洛醯胺(temozolomide)、衣托糖苷(etoposide)、環磷醯胺、提莫達(temodar)、碳氯胺鉑、甲基
苄肼、葛來迪爾(gliadel)、他摩西吩(tamoxifen)、拓波提肯(topotecan)、胺甲喋呤、Arisa®、紅豆杉醇、紅豆杉帖里(taxotere)、氟尿嘧啶、甲醯四氫葉酸、伊利諾提肯(irinotecan)、愛西若達(xeloda)、CPT-11、干擾素α、經PEG化之干擾素α(例如PEG INTRON-A)、卡配西塔賓(capecitabine)、順氯胺鉑、噻替哌(thiotepa)、弗達拉賓(fludarabine)、碳氯胺鉑、微脂粒道諾紅菌素、阿糖胞苷、多謝他索(doxetaxol)、巴西他索(pacilitaxel)、長春花鹼、IL-2、GM-CSF、氮烯咪胺、威諾賓(vinorelbine)、卓列宗(zoledronic)酸、棕櫚宗酸鹽(palmitronate)、必阿克辛(biaxin)、白血福恩(busulphan)、潑尼松、雙膦酸鹽、三氧化二砷、長春新鹼、多克索紅菌素(Doxil®)、培克里他索(paclitaxel)、建西環維爾(ganciclovir)、亞德里亞霉素、雌氮芥(estramustine)磷酸鈉(Emcyt®)、沙林達克(sulindac)及衣托糖苷(etoposide)。
同樣地,根據欲被治療、預防或處理之適應徵之特定第二種藥劑,其實例可參閱下列參考資料,其全部均以其全文併於本文:美國專利案號5,635,517、6,281,230及7,189,740;與美國專利申請案公報2004/0029832、2004/0087546、2004/0091455、2005/0100529、2005/0214328、2005/0239842、2006/0122228、2006/0143344、2006/0154880及2006/0188475。
其他第二種活性劑之實例包括但不限於用以治療或預防疼痛之習用治療劑,譬如抗抑鬱劑、抗搐搦藥、抗高血壓劑、解焦慮劑、鈣通道阻斷劑、肌肉鬆弛劑、非麻醉性止痛劑、類阿片止痛劑、消炎劑、cox-2抑制劑、免疫調制劑、α-腎上腺素能受體催動劑或拮抗劑、免疫壓抑劑、皮質類固醇、高比重氧、氯胺酮、其他麻醉劑、NMDA拮抗劑,及例如在醫師之桌上參考資料2003中所發現之其他治療劑。特殊實例包括但不限於柳酸醋酸鹽(Aspirin®)、塞拉庫西比(celecoxib)(Celebrex®)、Enbrel®、氯胺酮、加巴潘亭(gabapentin)
(Neurontin®)、苯妥英(Dilantin®)、胺甲醯氮(Tegretol®)、羧咪(Trileptal®)、法普酸(Depakene®)、嗎啡硫酸鹽、氫莫風(hydromorphone)、潑尼松、灰黃霉素、片松尼恩(penthonium)、阿連宗酸鹽(alendronate)、地吩醯胺(dyphenhydramide)、胍乙啶、酮洛拉克(ketorolac)(Acular®)、降血鈣素、二甲亞碸(DMSO)、可樂寧(clonidine)(Catapress®)、布瑞替林(bretylium)、凱坦斯林(ketanserin)、利血平(reserpine)、達哌啶酮(droperidol)、阿托品、酚妥拉明(phentolamine)、丁哌卡因(bupivacaine)、利多卡因、乙醯胺吩(acetaminophen)、諾三替林(nortriptyline)(Pamelor®)、阿米替林(amitriptyline)(Elavil®)、丙咪(Tofranil®)、多慮平(doxepin)(Sinequan®)、可洛米胺(clomipramine)(Anafranil®)、氟西汀(fluoxetine)(Prozac®)、色他林(sertraline)(Zoloft®)、那發坐酮(nefazodone)(Serzone®)、溫拉發辛(venlafaxine)(Effexor®)、搓唑酮(trazodone)(Desyrel®)、丁胺苯丙酮(Wellbutrin®)、慢心利(mexiletine)、硝苯吡啶(nifedipine)、丙喏羅(propranolol)、搓馬哚(tramadol)、拉莫三金(lamotrigine)、吉康諾太得(ziconotide)、氯胺酮、右美沙芬(dextromethorphan)、苯并二氮七圜類、氯苯胺丁酸(baclofen)、太札尼定(tizanidine)及苯氧苄胺。
其他第二種活性劑之實例包括但不限於類固醇、光敏化劑、整合素、抗氧化劑、干擾素、黃嘌呤衍生物、生長激素、神經營養因子、新血管生成作用之調節劑、抗-VEGF抗體、前列腺素、抗生素、植物雌激素、消炎化合物或抗血管生成化合物或其組合。特殊實例包括但不限於維替波吩(verteporfin)、嘌利亭(purlytin)、制血管類固醇、rhuFab、干擾素-2α、己酮可可豆鹼、錫本羥基茜草素、莫提沙吩(motexafin)鎦、9-氟基-11,21-二羥基-16,17-1-甲基乙川-雙(氧基)孕-1,4-二烯-3,20-二酮、拉塔諾斯特(latanoprost)(參閱美國專利6,225,348)、四
環素及其衍生物、利福霉素及其衍生物、大環內酯類、滅滴靈(metronidazole)(美國專利案號6,218,369與6,015,803)、金雀異黃素、金雀黃素、6'-O-Mal金雀黃素、6'-O-Ac金雀黃素、大豆黃素、黃苷、6'-O-Mal黃苷、6'-O-Ac黃苷、黃豆黃素、黃豆素、6'-O-Mal黃豆素、雞豆黃素A、芒柄花素(美國專利6,001,368)、氟羥脫氫皮質甾醇乙醯胺、地塞米松(美國專利5,770,589)、酞胺哌啶酮、谷胱甘肽(美國專利5,632,984)、鹼性成纖維細胞生長因子(bFGF)、轉變生長因子b(TGF-b)、腦部衍生之神經營養因子(BDNF)、血纖維蛋白溶酶原活化劑因子類型2(PAI-2)、EYE101(Eyetech醫藥)、LY333531(Eli Lilly)、Miravant及RETISERT植入物(Bausch & Lomb)。所有上文引述之參考資料均以其全文併於本文供參考。
其他第二種活性劑之實例包括但不限於角質溶解劑、類視色素、α-羥基酸類、抗生素、膠原、肉毒毒素、干擾素及免疫調制劑。特殊實例包括但不限於5-氟尿嘧啶、馬索普洛可(masoprocol)、三氯醋酸、柳酸、乳酸、乳酸銨、尿素、崔替諾因(tretinoin)、異崔替諾因(isotretinoin)、抗生素、膠原、肉毒毒素、干擾素、皮質類固醇、反視黃酸,及膠原,譬如人類胎盤膠原、動物胎盤膠原、Dermalogen、AlloDerm、Fascia、Cymetra、Autologen、Zyderm、Zyplast、Resoplast及Isolagen。
其他第二種活性劑之實例包括但不限於抗凝血劑、利尿劑、心糖苷、鈣通道阻斷劑、血管擴張劑、前列環素類似物、內皮肽拮抗劑、磷酸二酯酶抑制劑(例如PDE V抑制劑)、內肽酶抑制劑、脂質降低劑、前列凝素抑制劑及其他已知會降低肺動脈壓力之治療劑。特殊實例包括但不限於哇華靈(warfarin)(Coumadin®)、利尿劑、心糖苷、地高辛(digoxin)-氧、迪耳替阿簡(diltiazem)、硝苯吡啶(nifedipine),血管擴張劑,譬如前列環素(例如前列腺素I2(PGI2)),衣波普提諾
(epoprostenol)(EPO,Floran®)、催普斯尼爾(treprostinil)(Remodulin®)、氧化氮(NO)、伯仙坦(bosentan)(Tracleer®)、胺若地平(amlodipine)、衣波普提諾(epoprostenol)(Floran®)、催普斯尼爾(treprostinil)(Remodulin®)、前列環素、塔達拉費(tadalafil)(Cialis®)、辛伐制菌素(simvastatin)(Zocor®)、歐馬巴列特(omapatrilat)(Vanlev®)、愛貝沙坦(irbesartan)(Avapro®)、普拉伐制菌素(pravastatin)(Pravachol®)、地高辛(digoxin)、L-精胺酸、衣洛普斯特(iloprost)、β普斯特(betaprost)及席墊那費(sildenafil)(Viagra®)。
其他第二種活性劑之實例包括但不限於蒽環素、鉑、烷基化劑、歐利莫森(oblimersen)(Genasense®)、順氯胺鉑、環磷醯胺、提莫達(temodar)、碳氯胺鉑、甲基苄肼、葛來迪爾(gliadel)、他摩西吩(tamoxifen)、拓波提肯(topotecan)、胺甲喋呤、紅豆杉帖里(taxotere)、伊利諾提肯(irinotecan)、卡配西塔賓(capecitabine)、順氯胺鉑、噻替哌(thiotepa)、弗達拉賓(fludarabine)、碳氯胺鉑、微脂粒道諾紅菌素、阿糖胞苷、多謝他索(doxetaxol)、巴西他索(pacilitaxel)、長春花鹼、IL-2、GM-CSF、氮烯咪胺、威諾賓(vinorelbine)、卓列宗(zoledronic)酸、棕櫚宗酸鹽(palmitronate)、必阿克辛(biaxin)、白血福恩(busulphan)、潑尼松、雙膦酸鹽、三氧化二砷、長春新鹼、多克索紅菌素(Doxil®)、培克里他索(paclitaxel)、建西環維爾(ganciclovir)、亞德里亞霉素、博來霉素、玻尿酸酵素、絲裂霉素C、阿的平、噻替哌(thiotepa)、四環素及真西塔賓(gemcitabine)。
其他第二種活性劑之實例包括但不限於氯喹(chloroquine)、奎寧、奎尼定、乙胺嘧啶、磺胺嘧啶、強力霉素、克森達霉素、甲氟喹、鹵凡特寧(halofantrine)、普來馬昆(primaquine)、羥氯喹、普胍尼爾(proguanil)、阿特瓦醌(atovaquone)、阿濟霉素(azithromycin)、蘇拉明(suramin)、戊烷脒、美拉索普(melarsoprol)、尼弗提莫(nifurtimox)、苯
并尼達唑(benznidazole)、兩性霉素B、五價銻化合物(例如銻醛糖酸鈉)、干擾素γ、依康唑(itraconazole)、死亡鞭毛原菌與BCG之組合、甲醯四氫葉酸、皮質類固醇、磺醯胺、螺旋霉素、IgG(血清學)、三甲氧苄二胺嘧啶及磺胺甲基異唑。
其他第二種活性劑之實例包括但不限於:抗生素(治療或預防),譬如但不限於胺苄青霉素、克拉利霉素(clarithromycin)、四環素、青霉素、頭孢菌素、鏈霉素、康霉素及紅霉素;抗病毒劑,譬如但不限於金剛胺、金剛烷乙胺、阿環維爾(acyclovir)及三唑核苷;免疫球蛋白;血漿;免疫學增強藥物,譬如但不限於左旋四咪唑與異丙肌苷;生物製劑,譬如但不限於γ球蛋白、轉移因子、間白血球活素及干擾素;激素,譬如但不限於胸腺;及其他免疫學劑,譬如但不限於B細胞刺激子(例如BAFF/BlyS)、細胞活素(例如IL-2、IL-4及IL-5)、生長因子(例如TGF-β)、抗體(例如抗-CD40與IgM)、含有未甲基化CpG主體之寡核苷酸,及疫苗(例如病毒與腫瘤肽疫苗)。
其他第二種活性劑之實例包括但不限於:多巴胺催動劑或拮抗劑,譬如但不限於左旋多巴、L-DOPA、古柯鹼、α-甲基-酪胺酸、利血平(reserpine)、四苯拿(tetrabenazine)、苯并多平(benzotropine)、巴吉林(pargyline)、非諾多片(fenodolpam)甲烷磺酸鹽、卡伯哥林(cabergoline)、普拉米佩索(pramipexole)二鹽酸鹽、洛平諾羅(ropinorole)、金剛胺鹽酸鹽、西列葛林(selegiline)鹽酸鹽、卡比多巴、伯郭內酯(pergolide)甲烷磺酸鹽、西內美特(Sinemet)CR及金剛烷胺;MAO抑制劑,譬如但不限於異丙異菸肼、可洛葛林(clorgyline)、苯乙肼及異羧吉得(isocarboxazid);COMT抑制劑,譬如但不限於托卡朋(tolcapone)與恩塔卡朋(entacapone);膽鹼酯酶抑制劑,譬如但不限於毒扁豆鹼柳酸鹽、毒扁豆鹼硫酸鹽、溴化毒扁豆鹼、溴化美史替明(meostigmine)、甲基硫酸新斯的明、氯化安朋諾寧(ambenonim)、氯化
約卓風寧(edrophonium)、塔克林(tacrine)、氯磷定、氯化雙異煙醛肟甲醚、溴化雙解磷、二乙醯基單克辛(monoxim)、安卓風寧(endrophonium)、吡啶斯的明及去甲卡利姆(demecarium);消炎劑,譬如但不限於那丙新(naproxen)鈉、二氯苯胺苯乙酸鈉、二可吩拿克(diclofenac)鉀、塞拉庫西比(celecoxib)、普羅辛(oxaprozin)、二氟苯柳酸、依托多拉克(etodolac)、美氧胺(meloxicam)、異丁苯丙酸(ibuprofen)、酮基丙吩(ketoprofen)、那布美東(nabumetone)、瑞非庫西比(refecoxib)、胺甲喋呤、列弗諾醯胺(leflunomide)、硫酸沙(sulfasalazine)、金鹽、Rho-D免疫球蛋白、分枝酚酸莫非替(mycophenylate mofetil)、環孢質、硝基脒唑硫嘌呤、塔可利馬斯(tacrolimus)、巴西利馬伯(basiliximab)、達可利諸伯(daclizumab)、柳酸、乙醯柳酸、柳酸甲酯、二氟苯柳酸、沙沙雷特(salsalate)、歐沙(olsalazine)、硫酸沙(sulfasalazine)、乙醯胺吩(acetaminophen)、吲哚美薩辛(indomethacin)、沙林達克(sulindac)、甲滅酸、甲氯滅酸鈉、四苯醯吡咯乙酸(tolmetin)、酮洛拉克(ketorolac)、二氯吩那克(dichlofenac)、弗賓丙吩(flurbinprofen)、普羅辛(oxaprozin)、吡氧胺(piroxicam)、美氧胺(meloxicam)、安比氧胺(ampiroxicam)、卓克氧胺(droxicam)、吡弗氧胺(pivoxicam)、天氧胺(tenoxicam)、苯基保泰松(phenylbutazone)、氧基苯基保泰松、安替比林、胺基比林、炎爽痛(apazone)、吉留通(zileuton)、金硫葡萄糖、硫基蘋果酸金鈉、歐蘭諾吩(auranofin)、胺甲喋呤、秋水仙素、異嘌呤醇、羧苯磺胺(probenecid)、沙芬吡宗(sulfinpyrazone)及苯并溴阿酮(benzbromarone)或β-美塞松及其他類皮質糖;及止吐劑,譬如但不限於美托環丙胺(metoclopromide)、冬培利酮(domperidone)、普氯伯(prochlorperazine)、異丙(promethazine)、氯丙(chlorpromazine)、三甲苯甲醯胺(trimethobenzamide)、翁丹西從(ondansetron)、葛來尼西
從(granisetron)、羥(hydroxyzine)、乙醯基白胺酸單乙醇胺、阿利札賴得(alizapride)、氮謝特隆(azasetron)、苯喹醯胺、二伊坦諾汀(bietanautine)、溴普來得(bromopride)、氯苯丁、可列玻普得(clebopride)、環利(cyclizine)、乘暈寧(dimenhydrinate)、二苯尼多(diphenidol)、多拉西從(dolasetron)、敏克靜(meclizine)、美索列托(methallatal)、甲磺哌丙、那比隆(nabilone)、氧伯恩迪(oxyperndyl)、派巴馬(pipamazine)、莨菪胺、蘇必利(sulpiride)、四氫大麻油醇、唑乙伯、硫丙伯(thioproperazine)、搓比西從(tropisetron)及其混合物。
其他第二種活性劑之實例包括但不限於免疫調制劑、免疫壓抑劑、抗高血壓劑、抗搐搦藥、纖維蛋白溶解劑、破壞血小板劑、抗精神病藥、抗抑鬱劑、苯并二氮七圜類、丁螺旋酮(buspirone)、金剛胺,及用於具有CNS損傷/傷害及相關徵候簇之病患之其他已知或習用藥劑。特殊實例包括但不限於:類固醇(例如類皮質糖,譬如但不限於甲基氫化潑尼松、地塞米松及β-美塞松);消炎劑,包括但不限於那丙新(naproxen)鈉、二氯苯胺苯乙酸鈉、二可吩拿克(diclofenac)鉀、塞拉庫西比(celecoxib)、普羅辛(oxaprozin)、二氟苯柳酸、依托多拉克(etodolac)、美氧胺(meloxicam)、異丁苯丙酸(ibuprofen)、酮基丙吩(ketoprofen)、那布美東(nabumetone)、瑞非庫西比(refecoxib)、胺甲喋呤、列弗諾醯胺(leflunomide)、硫酸沙(sulfasalazine)、金鹽、RHo-D免疫球蛋白、分枝酚酸莫非替(mycophenylate mofetil)、環孢質、硝基脒唑硫嘌呤、塔可利馬斯(tacrolimus)、巴西利馬伯(basiliximab)、達可利諸伯(daclizumab)、柳酸、乙醯柳酸、柳酸甲酯、二氟苯柳酸、沙沙雷特(Salsalate)、歐沙(olsalazine)、硫酸沙(sulfasalazine)、乙醯胺吩(acetaminophen)、吲哚美薩辛(indomethacin)、沙林達克(sulindac)、甲滅酸、甲氯滅酸鈉、四苯醯吡咯乙酸(tolmetin)、酮洛拉克
(ketorolac)、二氯吩那克(dichlofenac)、弗賓丙吩(flurbinprofen)、普羅辛(oxaprozin)、吡氧胺(piroxicam)、美氧胺(meloxicam)、安比氧胺(ampiroxicam)、卓克氧胺(droxicam)、吡弗氧胺(pivoxicam)、天氧胺(tenoxicam)、苯基保泰松(phenylbutazone)、氧基苯基保泰松、安替比林、胺基比林、炎爽痛(apazone)、吉留通(zileuton)、金硫葡萄糖、硫基蘋果酸金鈉、歐蘭諾吩(auranofin)、胺甲喋呤、秋水仙素、異嘌呤醇、羧苯磺胺(probenecid)、沙芬吡宗(sulfinpyrazone)及苯并溴阿酮(benzbromarone);cAMP類似物,包括但不限於db-cAMP;一種包含吩奈酸甲酯藥物之藥劑,其包括l-異赤蘚式-吩奈酸甲酯、d-異赤蘚式-吩奈酸甲酯、dl-異赤蘚式-吩奈酸甲酯、l-赤蘚式-吩奈酸甲酯、d-赤蘚式-吩奈酸甲酯、dl-赤蘚式-吩奈酸甲酯及其混合物;及利尿劑,譬如但不限於甘露醇、利尿磺胺、甘油及尿素。
其他第二種活性劑之實例包括但不限於三環抗抑鬱劑劑、選擇性血清素再攝取抑制劑、抗癲癇藥劑(加巴潘亭(gabapentin)、普瑞加巴林(pregabalin)、胺甲醯氮、羧咪、列維提拉坦(levitiracetam)、托皮拉美(topiramat))、抗節律不齊劑、鈉通道阻斷劑、選擇性炎性介體抑制劑、類阿片劑、第二種免疫調制化合物、組合劑及用於睡眠療法之其他已知或習用藥劑。特殊實例包括但不限於神經素(Neurontin)、甲硝噠唑、嗎啡、托皮拉美(topiramat)、阿米催替林(amitryptiline)、正色醯素、胺甲醯氮、左旋多巴、L-DOPA、古柯鹼、α-甲基-酪胺酸、利血平(reserpine)、四苯拿(tetrabenazine)、苯并多平(benzotropine)、巴吉林(pargyline)、非諾多片(fenodolpam)甲烷磺酸鹽、卡伯哥林(cabergoline)、普拉米佩索(pramipexole)二鹽酸鹽、洛平諾羅(ropinorole)、金剛胺鹽酸鹽、西列葛林(selegiline)鹽酸鹽、甲基多巴肼、伯郭內酯(pergolide)甲烷磺酸鹽、西內美特(Sinemet)CR、金剛烷胺、異丙異菸肼、可洛葛林(clorgyline)、苯乙肼、異羧吉得(isocarboxazid)、
托卡朋(tolcapone)、恩塔卡朋(entacapone)、毒扁豆鹼柳酸鹽、毒扁豆鹼硫酸鹽、溴化毒扁豆鹼、溴化美史替明(meostigmine)、甲基硫酸新斯的明、氯化安朋諾寧(ambenonim)、氯化約卓風寧(edrophonium)、塔克林(tacrine)、氯磷定、氯化雙異煙醛肟甲醚、溴化雙解磷、二乙醯基單克辛(monoxim)、安卓風寧(endrophonium)、吡啶斯的明、去甲卡利姆(demecarium)、那丙新(naproxen)鈉、二氯苯胺苯乙酸鈉、二可吩拿克(diclofenac)鉀、塞拉庫西比(celecoxib)、沙林達克(sulindac)、普羅辛(oxaprozin)、二氟苯柳酸、依托多拉克(etodolac)、美氧胺(meloxicam)、異丁苯丙酸(ibuprofen)、酮基丙吩(ketoprofen)、那布美東(nabumetone)、瑞非庫西比(refecoxib)、胺甲喋呤、列弗諾醯胺(leflunomide)、硫酸沙(sulfasalazine)、金鹽、RHo-D免疫球蛋白、分枝酚酸莫非替(mycophenylate mofetil)、環孢質、硝基脒唑硫嘌呤、塔可利馬斯(tacrolimus)、巴西利馬伯(basiliximab)、達可利諸伯(daclizumab)、柳酸、乙醯柳酸、柳酸甲酯、二氟苯柳酸、沙沙雷特(salsalate)、歐沙(olsalazine)、硫酸沙(sulfasalazine)、乙醯胺吩(acetaminophen)、吲哚美薩辛(indomethacin)、沙林達克(sulindac)、甲滅酸、甲氯滅酸鈉、四苯醯吡咯乙酸(tolmetin)、酮洛拉克(ketorolac)、二氯吩那克(dichlofenac)、弗賓丙吩(flurbinprofen)、普羅辛(oxaprozin)、吡氧胺(piroxicam)、美氧胺(meloxicam)、安比氧胺(ampiroxicam)、卓克氧胺(droxicam)、ö吡弗氧胺(pivoxicam)、天氧胺(tenoxicam)、苯基保泰松(phenylbutazone)、氧基苯基保泰松、安替比林、胺基比林、炎爽痛(apazone)、吉留通(zileuton)、金硫葡萄糖、硫基蘋果酸金鈉、歐蘭諾吩(auranofin)、胺甲喋呤、秋水仙素、異嘌呤醇、羧苯磺胺(probenecid)、沙芬吡宗(sulfinpyrazone)、苯并溴阿酮(benzbromarone)、β-美塞松及其他類皮質糖、美托環丙胺(metoclopromide)、冬培利酮(domperidone)、普氯伯
(prochlorperazine)、異丙(promethazine)、氯丙(chlorpromazine)、三甲苯甲醯胺(trimethobenzamide)、翁丹西從(ondansetron)、葛來尼西從(granisetron)、羥(hydroxyzine)、乙醯基白胺酸單乙醇胺、阿利札賴得(alizapride)、氮謝特隆(azasetron)、苯喹醯胺、二伊坦諾汀(bietanautine)、溴普來得(bromopride)、氯苯丁、可列玻普得(clebopride)、環利(cyclizine)、乘暈寧(dimenhydrinate)、二苯尼多(diphenidol)、多拉西從(dolasetron)、敏克靜(meclizine)、美索列托(methallatal)、甲磺哌丙、那比隆(nabilone)、氧伯恩迪(oxyperndyl)、派巴馬(pipamazine)、莨菪胺、蘇必利(sulpiride)、四氫大麻油醇、唑乙伯、硫丙伯(thioproperazine)、搓比西從(tropisetron)及其混合物。
其他第二種活性劑之實例包括但不限於:間白血球活素,譬如IL-2(包括重組IL-II("rIL2")與卡那利伯斯(canarypox)IL-2)、IL-10、IL-12及IL-18;干擾素,譬如干擾素α-2a、干擾素α-2b、干擾素α-n1、干擾素α-n3、干擾素β-Ia及干擾素γ-Ib;及G-CSF;羥基脲;丁酸鹽或丁酸鹽衍生物;氧化亞氮;HEMOXINTM(NIPRISANTM;參閱美國專利案號5,800,819);Gardos通道拮抗劑,譬如克羅三馬唑(clotrimazole)與三芳基甲烷衍生物;去鐵胺;蛋白質C;及血液或血液代用品之輸血劑,譬如HemospanTM或HemospanTMPS(Sangart)。
雜芳基化合物與第二種活性劑對病患之投藥可同時或相繼地藉由相同或不同投藥途徑發生。供特定活性劑所採用之特定投藥途徑之適合性係依活性劑本身(例如,其是否可在進入血流之前,以經口方式投予而不會分解)與被治療之疾病而定。關於雜芳基化合物之一種投藥途徑為口腔。關於本發明第二種活性劑或成份之較佳投藥途徑係為一般熟諳此項技藝者所已知。參閱,例如醫師之桌上參考資料(Physicians' Desk Reference),1755-1760(第56版,2002)。
於一項具體實施例中,第二種活性劑係以靜脈內方式或皮下方式且每日投予一次或兩次,其量為約1至約1000毫克,約5至約500毫克,約10至約350毫克,或約50至約200毫克。第二種活性劑之特定量係依所使用之特定藥劑、被治療或處理之疾病類型、疾病之嚴重性與病期,及共同地投予病患之雜芳基化合物與任何選用其他活性劑之量而定。
進一步於本文中提供者為降低、治療及/或預防伴隨著習用療法之不利或不想要作用之方法,該習用療法包括但不限於手術、化學療法、放射療法、激素療法、生物學療法及免疫療法。雜芳基化合物及其他活性成份可在伴隨著習用療法之不利作用存在之前、期間或之後被投予病患。
本文中所提供者為包含有效量之雜芳基化合物之組合物,及包含有效量之雜芳基化合物與藥學上可接受載劑或媒劑之組合物。在一些具體實施例中,本文中所述之醫藥組合物係適用於口腔、非經腸、黏膜、經皮或局部投藥。
雜芳基化合物可以經口方式或非經腸方式投予病患,呈習用製劑形式,譬如膠囊、微膠囊、片劑、顆粒、粉末、錠劑、丸劑、栓劑、注射、懸浮液及糖漿。適當配方可藉由常用方法製成,使用習用、有機或無機添加劑,譬如賦形劑(例如蔗糖、澱粉、甘露醇、花楸醇、乳糖、葡萄糖、纖維素、滑石、磷酸鈣或碳酸鈣)、黏合劑(例如纖維素、甲基纖維素、羥甲基纖維素、聚丙基四氫吡咯酮、聚乙烯基四氫吡咯酮、明膠、阿拉伯膠、聚乙二醇、蔗糖或澱粉)、崩解劑(例如澱粉、羧甲基纖維素、羥丙基澱粉、低取代之羥丙基纖維素、碳酸氫鈉、磷酸鈣或檸檬酸鈣)、潤滑劑(例如硬脂酸鎂、輕質無水矽酸、滑石或月桂基硫酸鈉)、矯味劑(例如檸檬酸、醇、甘胺酸或橘色粉末)、防腐劑(例如苯甲酸鈉、亞硫酸氫鈉、對羥基苯甲酸甲酯或對羥基苯甲酸丙
酯)、安定劑(例如檸檬酸、檸檬酸鈉或醋酸)、懸浮劑(例如甲基纖維素、聚乙烯基四氫吡咯酮或硬脂酸鋁)、分散劑(例如羥丙甲基纖維素)、稀釋劑(例如水)及基質蠟(例如可可豆脂、白蠟油或聚乙二醇)。雜芳基化合物在醫藥組合物中之有效量可在將行使所要作用之含量下;例如,約0.005毫克/公斤病患體重至約10毫克/公斤病患體重,呈供口服與非經腸投藥兩者之單位劑量。
欲被投予病患之雜芳基化合物之劑量係頗為廣泛地可改變,且可容許保健執行者之判斷。一般而言,雜芳基化合物可於病患中一天投予一至四次,在約0.005毫克/公斤病患體重至約10毫克/公斤病患體重之劑量中,但上述劑量可適當地依病患之年齡、體重及醫療症狀,及投藥型式而改變。於一項具體實施例中,劑量為約0.01毫克/公斤病患體重至約5毫克/公斤病患體重、約0.05毫克/公斤病患體重至約1毫克/公斤病患體重、約0.1毫克/公斤病患體重至約0.75毫克/公斤病患體重或約0.25毫克/公斤病患體重至約0.5毫克/公斤病患體重。於一項具體實施例中,一份劑量係每天給予。在任何特定情況中,所投予雜芳基化合物之量係依一些因素而定,譬如活性成份之溶解度、所使用之配方及投藥途徑。
於另一項具體實施例中,本文中所提供者為關於治療或預防疾病或病症之方法,其包括對有需要之病患投予約0.375毫克/天至約750毫克/天、約0.75毫克/天至約375毫克/天、約3.75毫克/天至約75毫克/天、約7.5毫克/天至約55毫克/天或約18毫克/天至約37毫克/天之雜芳基化合物。
於另一項具體實施例中,本文中所提供者為關於治療或預防疾病或病症之方法,其包括對有需要之病患投予約1毫克/天至約1200毫克/天、約10毫克/天至約1200毫克/天、約100毫克/天至約1200毫克/天、約400毫克/天至約1200毫克/天、約600毫克/天至約1200毫克/天、約400
毫克/天至約800毫克/天或約600毫克/天至約800毫克/天之雜芳基化合物。在一項特定具體實施例中,於本文中所揭示之方法包括對有需要之病患投予400毫克/天、600毫克/天或800毫克/天之雜芳基化合物。
於另一項具體實施例中,本文中所提供者為單位劑量配方,其包含約1毫克與約2000毫克、約1毫克與200毫克、約35毫克與約1400毫克、約125毫克與約1000毫克、約250毫克與約1000毫克或約500毫克與約1000毫克間之雜芳基化合物。
在一項特定具體實施例中,本文中所提供者為單位劑量配方,其包含約100毫克或400毫克之雜芳基化合物。
於另一項具體實施例中,本文中所提供者為單位劑量配方,其包含1毫克、2.5毫克、5毫克、10毫克、15毫克、20毫克、30毫克、35毫克、50毫克、70毫克、100毫克、125毫克、140毫克、175毫克、200毫克、250毫克、280毫克、350毫克、500毫克、560毫克、700毫克、750毫克、1000毫克或1400毫克之雜芳基化合物。
雜芳基化合物可每日投予一、二、三、四或更多次。
雜芳基化合物可由於方便性而以經口方式投予。於一項具體實施例中,當經口投予時,雜芳基化合物係與餐飲及水一起投予。於另一項具體實施例中,雜芳基化合物係被分散於水或汁液(例如蘋果汁或橘子汁)中,且以經口方式,以懸浮液投予。於另一項具體實施例中,當經口投予時,雜芳基化合物係在斷食狀態中被投予。
雜芳基化合物亦可以皮內方式、肌內方式、腹膜腔內方式、經皮、靜脈內方式、皮下方式、鼻內方式、硬膜外方式、舌下方式、大腦內方式、陰道內方式、經皮方式、直腸方式、黏膜方式,藉吸入或以局部方式投予至耳朵、鼻子、眼睛或皮膚。投藥模式係留待保健執行者之判斷,且可部份依醫療症狀之位置而定。
於一項具體實施例中,本文中所提供者為含有雜芳基化合物而無
另一種載劑、賦形劑或媒劑之膠囊。
於另一項具體實施例中,本文中所提供者為組合物,其包含有效量之雜芳基化合物,與藥學上可接受之載劑或媒劑,其中藥學上可接受之載劑或媒劑可包括賦形劑、稀釋劑或其混合物。於一項具體實施例中,組合物為醫藥組合物。
組合物可呈片劑、可咀嚼片劑、膠囊、溶液、非經腸溶液、錠劑、栓劑及懸浮液等形式。組合物可經調配以包含日服劑量或日服劑量之合宜分率,在劑量單位中,其可為單一片劑或膠囊或合宜體積之液體。於一項具體實施例中,溶液係製自水溶性鹽,譬如其鹽酸鹽。一般而言,所有組合物係根據醫藥化學中之已知方法製成。膠囊可經由將雜芳基化合物與適當載劑或稀釋劑混合,且將適當量之混合物裝填於膠囊中而製成。一般載劑與稀釋劑包括但不限於惰性粉末狀物質,譬如許多不同種類之澱粉,粉末狀纖維素,尤其是結晶性與微晶性纖維素,糖類,譬如果糖、甘露醇及蔗糖,穀物粉末及類似可食用粉末。
片劑可藉由直接壓縮,藉由濕式造粒,或藉由乾式造粒而製成。其配方除了該化合物之外,通常摻有稀釋劑、黏合劑、潤滑劑及崩解劑。典型稀釋劑包括例如各種類型之澱粉、乳糖、甘露醇、高嶺土、磷酸鈣或硫酸鹽,無機鹽,譬如氯化鈉,及粉末狀糖。亦可使用粉末狀纖維素衍生物。於一項具體實施例中,醫藥組合物係不含乳糖。典型片劑黏合劑為以下物質,譬如澱粉、明膠及糖類,譬如乳糖、果糖、葡萄糖等。天然與合成膠質亦為合宜,包括阿拉伯膠、海藻酸鹽、甲基纖維素、聚乙烯基四氫吡咯等。聚乙二醇、乙基纖維素及蠟類亦可充作黏合劑。
潤滑劑在片劑配方中可能為必須,以防止片劑與衝模黏附在孔模中。潤滑劑可選自一些光滑固體,譬如滑石、硬脂酸鎂與鈣、硬脂酸及氫化植物油。片劑崩解劑為當被潤濕時會膨脹以分解片劑且釋出化
合物之物質。其包括澱粉、黏土、纖維素、藻膠及膠質。更特定言之,除了月桂基硫酸鈉以外,可使用例如玉米與馬鈴薯澱粉、甲基纖維素、瓊脂、膨土、木纖維素、粉末狀天然海綿、陽離子交換樹脂、海藻酸、瓜爾膠、柑橘漿粕及羧甲基纖維素。片劑可以作為矯味劑與密封劑之糖或以可形成薄膜之保護劑塗覆,以修改片劑之溶解性質。組合物亦可被調配成可咀嚼片劑,例如在配方中利用譬如甘露醇之物質。
當期望投予雜芳基化合物作為栓劑時,可使用典型基料。可可豆脂為傳統栓劑基料,其可藉由添加蠟類以稍微地提升其熔點而被改變。水可溶混栓劑基料,包括特別是各種分子量之聚乙二醇,係廣泛使用。
雜芳基化合物之作用可藉由適當配方而被延遲或延長。例如,雜芳基化合物之緩慢溶解丸粒可被製成,且摻入片劑或膠囊中,或作為緩慢釋出可植入裝置。此技術亦包括製造數種不同溶解速率之丸粒,且以丸粒之混合物充填膠囊。片劑或膠囊可以會阻止溶解,歷經一段可預期時間之薄膜塗覆。甚至非經腸製劑可被製成長效,其方式是使雜芳基化合物溶解或懸浮於油性或乳化媒劑中,其係允許其慢慢地分散在血清中。
Chem-4D Draw(ChemInnovation軟體公司,San Diego,CA)或ChemDraw Ultra(Cambridgesoft,Cambridge,MA)係用以產生關於化學結構之名稱。
下列縮寫係被使用於說明例與實例中:
AmPhos:對-二甲胺基苯基二第三丁基膦
Boc:第三-丁氧羰基
dba:二苯亞甲基丙酮
DMSO:二甲亞碸
ESI:電子噴霧離子化作用
HPLC:高性能液相層析法
mp:熔點
MS:質量光譜法
NBS:N-溴基琥珀醯亞胺
NMR:核磁共振
TFA:三氟醋酸
TLC:薄層層析法
MTBE:甲基第三-丁基醚
下述實例係藉由說明方式提出,而非限制。
實例1:7-(2-胺基-4-甲基-1H-苯并[d]咪唑-6-基)-1-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡
并[2,3-b]吡
-2(1H)-酮
A. 2-(6-氯基吡 -2-基胺基)醋酸乙酯. 於2,6-二氯吡(50克,336毫莫耳)與2-胺基醋酸乙酯(34.6克,336毫莫耳)中,添加三乙胺(140毫升,1007毫莫耳)與乙腈(350毫升)。將反應物在80℃下加熱3天。藉過濾移除已沉澱之三乙胺鹽,並以醋酸乙酯與己烷(1:1)洗滌多次。合併濾液與洗滌溶劑,及濃縮。過濾所形成之白黃色沉澱物,且以己烷中之20%醋酸乙酯洗滌,獲得灰白色固體。使濾液接受相同方法,而得另一批次之灰黃色固體。合併批料,而得標題化合物(35.5克,164毫莫耳,49%產率)。MS(ESI)m/z 216.11M+1]+。
B. 2-(吡 -2-基胺基)醋酸乙酯. 使2-(6-氯基吡-2-基胺基)醋
酸乙酯(23.6克,109毫莫耳)溶於非變性乙醇(250毫升)中,並添加碳酸鉀(15.13克,109毫莫耳)。將反應物置於氮氣下,且添加氫氧化鈀(3.84克,5.47毫莫耳)。將反應物於氫大氣下攪拌18小時。添加另外之氫氧化鈀(3.84克,5.47毫莫耳),並於反應物中添加另外之氫,且將其攪拌過夜。經過矽藻土過濾反應物,及在減壓下移除溶劑,而得標題化合物(15.13克,84毫莫耳,76%產率)。MS(ESI)m/z 182.3[M+1]+。
C. 2-(3,5-二溴基吡 -2-基胺基)醋酸乙酯. 使2-(吡-2-基胺基)醋酸乙酯(7.6克,41.9毫莫耳)溶於二甲亞碸(80毫升)與水(4.00毫升)中,並冷卻至0℃。慢慢添加N-溴基琥珀醯亞胺(18.66克,105毫莫耳),歷經15分鐘,且使反應物溫熱至室溫,及攪拌48小時。添加另外1.5當量N-溴基琥珀醯亞胺,並將其攪拌過夜。將反應混合物倒入冰水(200毫升)中,且以醋酸乙酯(150毫升)萃取。以碳酸鈉慢慢地使水層中和,直到pH~7為止,並以醋酸乙酯(3x150毫升)萃取。匯集有機層,以鹽水洗滌,以硫酸鎂脫水乾燥,過濾,及在減壓下濃縮。將殘留物以己烷中之25-33%醋酸乙酯研製,並過濾所形成之沉澱物,而得黃色固體。將其餘褐色殘留物使用Biotage矽膠層析純化(0-60%醋酸乙酯在己烷中),獲得另一批次之灰黃色固體。合併兩種批料,而得24克標題化合物(24克,71毫莫耳,75%產率)。MS(ESI)m/z 338.1[M]+,340.1[M+2]+,342.1[M+4]+。
D. 2-(5-溴基-3-((四氫-2H-哌喃-4-基)甲胺基)吡 -2-基胺基)醋酸乙酯. 將2-(3,5-二溴基吡-2-基胺基)醋酸乙酯(2.00克,5.90毫莫耳)、(四氫-2H-哌喃-4-基)甲胺(0.713克,6.19毫莫耳)、N,N-二異丙基乙胺(3.08毫升,17.70毫莫耳)及二甲亞碸(4毫升)在具有攪拌棒之微波小玻瓶中合併,且在Biotage Emrys Optimizer微波反應器中於150℃下加熱1小時。將所形成之混合物轉移至具有甲醇之圓底燒瓶。在減壓下移除甲醇與N,N-二異丙基乙胺,並將殘留物使用Biotage急驟式層析純
化(5-100%醋酸乙酯在己烷中)。將含有所要產物之溶離份在分液漏斗中合併,且以水洗滌兩次,及以鹽水一次。使有機物質以硫酸鎂脫水乾燥,過濾,及在減壓下濃縮。使殘留物在高真空及50℃下乾燥,獲得不純所要之產物(1.578克),為琥珀色蠟狀固體,將其取至下一步驟無需進一步純化。MS(ESI)m/z 373.4[M]+,375.4[M+2]+。
E. 7-溴基-1-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將2-(5-溴基-3-((四氫-2H-哌喃-4-基)甲胺基)吡-2-基胺基)醋酸乙酯(1.474克,3.95毫莫耳)在醋酸(13毫升)中之經攪拌溶液,於密封容器中,在120℃下,於油浴中加熱2小時。在減壓下移除醋酸。使殘留物於醋酸乙酯與飽和碳酸氫鈉水溶液之間作分液處理,振盪,並分離液層。將水層以醋酸乙酯萃取兩次。使合併之有機物質以硫酸鎂脫水乾燥,過濾,及在減壓下濃縮。使殘留物溶於二氯甲烷與己烷中,並藉真空過濾收集所形成之固體。將固體以己烷洗滌,及在真空下乾燥,而得所要之產物(0.879克,2.688毫莫耳,68%產率),為紫色固體。MS(ESI)m/z 327.1[M]+,329.0[M+2]+。
F. 2-甲基-6-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧硼伍圜-2-基)苯胺. 將4-溴基-2-甲基-6-硝基苯胺(5克,21.64毫莫耳)、雙(品吶可基)二硼(5.50克,21.64毫莫耳)、醋酸鉀(6.37克,64.9毫莫耳)及N,N-二甲基甲醯胺(100毫升)合併,且在真空下脫氣。添加醋酸鈀(0.243克,1.082毫莫耳),並使系統再一次脫氣。將反應物加熱至90℃,歷經2小時。將反應物以水與二氯甲烷萃取。使有機層以無水硫酸鎂脫水乾燥,過濾,及濃縮。使殘留物藉矽膠管柱層析純化(0-30%醋酸乙酯在己烷中),獲得黃色固體(5.3克,19.0毫莫耳,88%產率)。MS(ESI)m/z 279.0[M+1]+。
G. 3-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼伍圜-2-基)苯-1,2-二胺. 將2-甲基-6-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧硼伍圜-2-基)苯胺
(5.3克,19.06毫莫耳)在甲醇(50毫升)中之溶液以氮氣滌氣。添加鈀/碳(10%重量,50毫克),並將反應混合物於氫氣瓶下攪拌16小時。經過矽藻土過濾反應物,且將濾餅以甲醇沖洗。使濾液濃縮,及使所形成之物質藉矽膠管柱層析純化(0-100%醋酸乙酯在己烷中),獲得暗色油。將此油以己烷中之10%醚研製,獲得黃褐色固體(4.2克,16.9毫莫耳,89%產率)。MS(ESI)m/z 248.9[M+1]+。
H. 7-(3,4-二胺基-5-甲基苯基)-1-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將3-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼伍圜-2-基)苯-1,2-二胺(0.523克,2.109毫莫耳)、7-溴基1-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(0.600克,1.834毫莫耳)、與二氯甲烷之[1,1'-雙(二苯基膦基)-二環戊二烯鐵]二氯鈀(II)複合物(1:1)(0.150克,0.183毫莫耳)、碳酸鈉(1M,在水中,5.50毫莫耳)、1,4-二氧陸圜(4.1毫升)及異丙醇(1.4毫升)在具有攪拌棒之可密封容器中合併。將系統以氮滌氣。將所形成之混合物密封,激烈攪拌,並在100℃下加熱3.5小時。將所形成之混合物以二氯甲烷中之20%甲醇稀釋,及在減壓下移除所有揮發性物質。使殘留物溶於二氯甲烷中之20%甲醇內,並在減壓下使用矽膠濃縮。將殘留物使用急驟式層析純化(1-10%甲醇在二氯甲烷中),而得所要之產物(0.669克,1.818毫莫耳,99%產率),為褐色固體。MS(ESI)m/z 369.1[M+1]+。
I. 7-(2-胺基-4-甲基-1H-苯并[d]咪唑-6-基)-1-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 於0℃下,將N,N-二甲基甲醯胺(0.5毫升)中之溴化氰(0.059克,0.556毫莫耳)添加至7-(3,4-二胺基-5-甲基苯基)-1-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(0.195克,0.529毫莫耳)在N,N-二甲基甲醯胺(3毫升)中之經攪拌溶液內。將所形成之深褐色混合物加蓋,並於室溫下攪拌16小
時。將所形成之混合物以甲醇稀釋,過濾,及使用逆相製備型HPLC純化(5-50%乙腈+水中之0.1% TFA+0.1% TFA,歷經30分鐘)。將含有所要產物之溶離份合併,且在減壓下移除大部份溶劑。將殘留物裝填至得自Phenomenex之Strata X-C離子交換管柱上。將管柱以水、乙腈、甲醇及甲醇中之5%氫氧化銨連續洗滌。使產物以甲醇中之5%氫氧化銨溶離劑溶離,並在減壓下濃縮,及在高真空下於50℃下乾燥,而得所要之產物(0.130克,0.331毫莫耳,62%產率),為橘色固體。1H NMR(400MHz,D2O與DMSO-d6)δ(ppm)8.13(s,1H),7.56(s,1H),7.36(s,1H),4.18(s,2H),4.03(d,J=6.64Hz,2H),3.84-3.90(m,2H),3.24(t,J=11.32Hz,2H),2.40(s,3H),2.04-2.19(m,1H),1.59(d,J=12.10Hz,2H),1.25-1.41(m,2H);MS(ESI)m/z 394.2[M+1]+。
實例2:3,3-二甲基-6-(2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡
并[2,3-b]吡
-2(1H)-酮
A. 3-(4-溴基-3-甲基苯基)-4H-1,2,4-三唑. 使4-溴基-3-甲基苯甲腈(10.0克,51.0毫莫耳)溶於乙醇(200毫升)中,並攪拌,且於氮氣下冷卻至0℃。使氯化氫氣體起泡進入反應混合物中,歷經20分鐘。將所形成之反應混合物加蓋,並攪拌,同時慢慢溫熱至室溫,歷經5.5小時。於減壓下移除溶劑,及使殘留物在真空下乾燥,獲得13.86克灰白色固體。將灰白色固體甲酸醯肼(4.48克,74.6毫莫耳)、三乙胺(28.0毫升,199毫莫耳)及乙醇(90毫升)在密封管中合併,且加熱,並在90℃下攪拌6.5小時。於減壓下移除所有溶劑,且使所形成之殘留物於醋酸乙酯與
水之間作分液處理。分離液層,並將有機物質以鹽水洗滌,以硫酸鎂脫水乾燥,過濾,及在減壓下濃縮。使殘留物溶於熱醋酸乙酯(13毫升)中,加蓋,並使其在室溫下靜置過夜。於燒瓶底部自固體傾析出溶劑。將固體以醋酸乙酯與乙醚洗滌,及在真空下於45℃下乾燥,而得所要之產物(7.47克,31.4毫莫耳,63%產率),為淡黃色固體。MS(ESI)m/z 238.2[M]+,240.3[M+2]+。
B. 3-(4-溴基-3-甲基苯基)-4-(四氫-2H-哌喃-2-基)-4H-1,2,4-三唑. 於室溫下,使3-(4-溴基-3-甲基苯基)-4H-1,2,4-三唑(2.00克,8.40毫莫耳)溶於四氫呋喃(10毫升)中,並於氮氣下攪拌。添加3,4-二氫-2H-哌喃(3.80毫升,42.0毫莫耳)與甲烷磺酸(0.027毫升,0.42毫莫耳),且將所形成之混合物在50℃下,於回流冷凝管下,在氮氣下加熱20小時。使所形成之混合物冷卻至室溫,以醋酸乙酯稀釋,並以飽和碳酸氫鈉水溶液與鹽水洗滌。使有機物質以硫酸鎂脫水乾燥,過濾,及在減壓下濃縮。急驟式層析(10-30-50%醋酸乙酯在己烷中),獲得所要之產物(2.64克,8.22毫莫耳,98%產率),為黃色油。MS(ESI)m/z 322[M]+,324[M+2]+。
C. 3-(3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼伍圜-2-基)苯基)-4-(四氫-2H-哌喃-2-基)-4H-1,2,4-三唑. 將3-(4-溴基-3-甲基苯基)-4-(四氫-2H-哌喃-2-基)-4H-1,2,4-三唑(2.294克,7.12毫莫耳)、雙(品吶可基)二硼(1.898克,7.48毫莫耳)、與二氯甲烷之[1,1'-雙(二苯基膦基)-二環戊二烯鐵]二氯鈀(II)複合物(1:1)(291毫克,0.36毫莫耳)、醋酸鉀(2.096克,21.4毫莫耳)及二甲亞碸(15毫升)在圓底燒瓶中合併,且攪拌。將燒瓶中之大氣於真空下移除,並被氮置換三次。將所形成之混合物在90℃及氮氣下加熱4小時。以醋酸乙酯稀釋所形成之混合物,並經過矽藻土過濾。以醋酸乙酯充分地洗滌濾餅。將濾液以水洗滌兩次,以鹽水一次,以硫酸鎂脫水乾燥,過濾,及在減壓下濃縮。急驟式層
析(30-50%醋酸乙酯在己烷中),獲得蠟狀半固體,將其在45℃下以己烷研製。使所形成之固體在真空下乾燥,而得所要之產物(2.10克,5.69毫莫耳,80%產率),為粉紅色粉末。MS(ESI)m/z 370[M+1]+。
D. 1-(3,5-二溴基吡 -2-基胺基)-2-甲基-1-酮基丙烷-2-基胺基甲酸第三-丁酯. 於室溫下,將1,1'-羰基二咪唑(2.63克,16.24毫莫耳)添加至2-(第三-丁氧羰基胺基)-2-甲基丙酸(3.00克,14.76毫莫耳)在N,N-二甲基甲醯胺(4毫升)與二氯甲烷(8毫升)中之經攪拌溶液內。將所形成之透明無色混合物於室溫及氮氣下攪拌3小時。添加N,N-二異丙基乙胺(3.86毫升,22.14毫莫耳),接著為3,5-二溴基吡-2-胺(5.60克,22.14毫莫耳)。將所形成之混合物在50℃下,於回流冷凝管下,在氮氣下加熱71小時。在減壓下移除二氯甲烷。將殘留物以醋酸乙酯稀釋,並以水洗滌。以醋酸乙酯萃取水層。將合併之有機物質以鹽水洗滌,以硫酸鎂脫水乾燥,過濾,及在減壓下濃縮。將殘留物以己烷中之30%醋酸乙酯研製,且藉真空過濾收集固體。使濾液在減壓下濃縮,並使用急驟式層析純化(5-50%醋酸乙酯在己烷中)。將含有所要產物之溶離份與藉過濾所獲得之固體合併,及在減壓下濃縮。使殘留物在高真空下乾燥,而得所要之產物(2.38克,5.43毫莫耳,37%產率),為灰白色固體。MS(ESI)m/z 439.3[M+1]+,461.1[M+Na]+。
E. N-(3,5-二溴基吡 -2-基)-2-甲基-2-(2-(四氫-2H-哌喃-4-基)乙胺基)丙醯胺三氟醋酸鹽. 將TFA(3.66毫升,47.5毫莫耳)添加至1-(3,5-二溴基吡-2-基胺基)-2-甲基-1-酮基丙烷-2-基胺基甲酸第三-丁酯(1.04克,2.374毫莫耳)在二氯甲烷(20毫升)中之經攪拌混合物內。將所形成之透明黃色溶液於室溫下攪拌3小時。在減壓下移除所有揮發性物質,及使殘留物在高真空下乾燥,獲得黃色半固體。MS(ESI)m/z 339.1[M+1]+。
添加硫酸鈉(1.686克,11.87毫莫耳),接著為2-(四氫-2H-哌喃-4-基)乙
醛(0.396克,3.09毫莫耳)與1,2-二氯乙烷(20毫升)。將所形成之混合物激烈攪拌,並在80℃下,於回流冷凝管下,在氮氣下加熱2.5小時。添加更多2-(四氫-2H-哌喃-4-基)乙醛(0.100克,0.780毫莫耳)與硫酸鈉(1.00克,7.04毫莫耳),且於80℃下再持續加熱2小時。將所形成之黃色溶液藉由自固體硫酸鈉以吸量管吸取至裝有攪拌棒之乾燥250毫升圓底燒瓶中而移除。將所形成之混合物激烈攪拌,並於氮氣下冷卻至0℃。慢慢添加三乙醯氧基硼氫化鈉(0.553克,2.61毫莫耳)。將所形成之混合物於0℃及氮氣下激烈攪拌30分鐘。移除冷浴,且將所形成之混合物於室溫及氮氣下攪拌2小時。使混合物冷卻至0℃,並添加更多三乙醯氧基硼氫化鈉(0.250克,1.180毫莫耳)。移除冷浴,且將所形成之混合物於室溫及氮氣下攪拌1.5小時。添加更多三乙醯氧基硼氫化鈉(0.055克,0.260毫莫耳)。將所形成之混合物在室溫及氮氣下激烈攪拌1小時,然後在0℃下攪拌過夜。將所形成之混合物以甲醇稀釋,並在減壓下移除揮發性物質。使殘留物溶於甲醇中,過濾,且使用逆相製備型HPLC純化(10-40%乙腈+水中之0.1% TFA+0.1% TFA,歷經30分鐘)。將含有所要產物之溶離份合併,及在減壓下移除溶劑。使殘留物在真空下乾燥,而得所要之產物(0.890克,1.978毫莫耳,67%產率),為微黃色泡沫物-固體。MS(ESI)m/z 451.3[M+1]+。
F. 6-溴基-3,3-二甲基-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將N-(3,5-二溴基吡-2-基)-2-甲基-2-(2-(四氫-2H-哌喃-4-基)乙胺基)丙醯胺三氟醋酸鹽(0.856克,1.517毫莫耳)、N,N-二異丙基乙胺(1.321毫升,7.59毫莫耳)及1,4-二氧陸圜(25毫升)在具有攪拌棒之可密封容器中合併。將系統以氮滌氣,並將所形成之混合物密封,激烈攪拌,且於110℃下加熱2.5小時。使反應混合物在減壓下濃縮,及使用急驟式層析純化(5-50%醋酸乙酯在己烷中),而得所要之產物(0.394克,1.068毫莫耳,70%產率),為白色固體。
MS(ESI)m/z 369.4[M]+,371.3[M+2]+。
G. 3,3-二甲基-6-(2-甲基-4-(4-(四氫-2H-哌喃-2-基)-4H-1,2,4-三唑-3-基)苯基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將3-(3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼伍圜-2-基)苯基)-4-(四氫-2H-哌喃-2-基)-4H-1,2,4-三唑(1當量)、6-溴基-3,3-二甲基-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(1當量)、與二氯甲烷之[1,1'-雙(二苯基膦基)-二環戊二烯鐵]二氯鈀(II)複合物(1:1)(0.1當量)、水中之1M碳酸鈉(3當量)、1,4-二氧陸圜及異丙醇合併,且將系統以氮滌氣。將所形成之混合物激烈攪拌,並在100℃下加熱1.5小時。使所形成之混合物冷卻至室溫,以甲醇稀釋,及在減壓下移除揮發性物質。使殘留物於二氯甲烷與水之間作分液處理,振盪,並分離液層。將水層以二氯甲烷萃取。使合併之有機物質以硫酸鎂脫水乾燥,過濾,及在減壓下濃縮。將殘留物使用急驟式層析純化(己烷中之20-100%醋酸乙酯,接著為二氯甲烷中之0-10%甲醇),而得所要之產物,97%產率。MS(ESI)m/z 532.7[M+1]+。
H. 3,3-二甲基-6-(2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 於80℃下,將水中之6N鹽酸添加至3,3-二甲基-6-(2-甲基-4-(4-(四氫-2H-哌喃-2-基)-4H-1,2,4-三唑-3-基)苯基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮在乙醇中之經攪拌混合物內。將所形成之混合物激烈攪拌,並在80℃下,於回流冷凝管下,在氮氣下加熱70分鐘。過濾所形成之混合物,及使用逆相製備型HPLC純化(10-65%乙腈+水中之0.1% TFA+0.1% TFA,歷經30分鐘)。將含有所要產物之溶離份合併,以飽和碳酸氫鈉水溶液中和,且在減壓下移除乙腈。藉真空過濾收集固體,以水與乙醚充分地洗滌,及在高真空下於50℃下乾燥,而得所要之產物,48%產率。1H NMR(400MHz,
DMSO-d6)δ(ppm)11.32(寬廣s.,1H),8.44(寬廣s.,1H),7.96(s,1H),7.90(d,J=8.59Hz,1H),7.70(s,1H),7.56(d,J=7.81Hz,1H),3.78(dd,J=2.93,11.13Hz,2H),3.52-3.64(m,2H),3.23(t,J=10.93Hz,2H),2.48(s,3H),1.51-1.66(m,5H),1.49(s,6H),1.11-1.26(m,2H);MS(ESI)m/z 448.3[M+1]+。
實例3:7-(2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-3,4-二氫吡
并[2,3-b]吡
-2(1H)-酮鹽酸鹽
A. 2-(5-溴基-3-(2,4-二甲氧基苄胺基)吡 -2-基胺基)醋酸乙酯. 將2-(3,5-二溴基吡-2-基胺基)醋酸乙酯(參閱實例1.C)(1.06克,3.13毫莫耳)、(2,4-二甲氧基苯基)甲胺(0.601克,3.60毫莫耳)、N,N-二異丙基乙胺(1.63毫升,9.38毫莫耳)及二甲亞碸(1.6毫升)在具有攪拌棒之微波小玻瓶中合併,且在微波反應器中於150℃下加熱2小時。將所形成之混合物使用急驟式層析純化(5-60%醋酸乙酯在己烷中)。將含有所要產物之溶離份合併,及在減壓下幾乎濃縮至乾涸。添加醋酸乙酯(2毫升)與己烷(18毫升)。將所形成之固體藉真空過濾收集,以己烷洗滌,並在高真空下乾燥,而得所要之產物(0.636克,1.495毫莫耳,48%產率),為淡粉紅色固體。1H NMR(300MHz,DMSO-d6)δ(ppm)7.24(s,1H),7.19(d,J=8.52Hz,1H),7.11(t,J=5.63Hz,1H),6.84(t,J=4.81Hz,1H),6.59(d,J=2.47Hz,1H),6.50(dd,J=2.20,8.24Hz,1H),4.37(d,J=4.67Hz,2H),3.96-4.15(m,4H),3.81(s,3H),3.75(s,3H),1.17(t,3H);MS(ESI)m/z 425.3[M]+,426.9[M+2]+。
B. 7-溴基-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮三氟醋酸鹽. 將2-(5-溴基-3-(2,4-二甲氧基苄胺基)吡-2-基胺基)醋酸乙酯(0.484
克,1.138毫莫耳)、甲醇(0.461毫升,11.38毫莫耳)及TFA(7毫升)在具有攪拌棒之可密封容器中合併。將系統以氮滌氣。將所形成之混合物密封,激烈攪拌,並在75℃下於油浴中加熱25分鐘。將所形成之混合物以水(14毫升)稀釋,且於室溫下攪拌5分鐘。藉真空過濾收集固體,以水與乙醚洗滌,及在高真空下乾燥,而得所要之產物(0.375克,1.093毫莫耳,96%產率),為粉紅色固體。MS(ESI)m/z 229.0[M]+,231.3[M+2]+。
C. 7-(2-甲基-4-(4-(四氫-2H-哌喃-2-基)-4H-1,2,4-三唑-3-基)苯基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將3-(3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼伍圜-2-基)苯基)-4-(四氫-2H-哌喃-2-基)-4H-1,2,4-三唑(參閱實例2.C)(0.465克,1.259毫莫耳)、7-溴基-3,4-二氫吡并[2,3-b]吡-2(1H)-酮三氟醋酸鹽(0.432克,1.259毫莫耳)、與二氯甲烷之[1,1'-雙(二苯基膦基)-二環戊二烯鐵]二氯鈀(II)複合物(1:1)(0.103克,0.126毫莫耳)、碳酸鈉(1M,在水中,3.78毫升,3.78毫莫耳)、1,4-二氧陸圜(2.5毫升)及異丙醇(1毫升)在具有攪拌棒之可密封容器中合併。將系統以氮滌氣。將所形成之混合物密封,激烈攪拌,並在100℃下加熱70分鐘。將所形成之混合物以水與二氯甲烷稀釋,且經過燒結漏斗過濾。將固體以二氯甲烷中之20%甲醇洗滌。合併濾液與洗液,及在減壓下移除溶劑。將殘留物以乙腈研製。添加水。藉真空過濾收集固體,並以水與乙醚充分地洗滌。將固體以二氯甲烷中之20%甲醇洗滌。合併濾液與洗液,且在減壓下移除溶劑。使殘留物溶於熱DMSO與甲醇中,過濾,及使用逆相製備型HPLC純化(20-65%乙腈+水中之0.1% TFA+0.1% TFA,歷經30分鐘)。將含有所要產物之溶離份合併,以飽和碳酸氫鈉水溶液中和,並在減壓下幾乎濃縮至乾涸。藉真空過濾收集固體,以水洗滌,及在高真空下乾燥,而得所要之產物(0.072克,0.184毫莫耳,15%產率),為灰白色固體。MS(ESI)m/z 392.1
[M+1]+。
D. 7-(2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮鹽酸鹽. 於80℃下,將鹽酸(6N,在水中,0.149毫升,0.894毫莫耳)添加至7-(2-甲基-4-(4-(四氫-2H-哌喃-2-基)-4H-1,2,4-三唑-3-基)苯基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(0.070克,0.179毫莫耳)在乙醇(3毫升)中之經攪拌混合物內。將系統以氮滌氣。將所形成之混合物密封,並於80℃下加熱。將所形成之混合物在80℃下加熱25分鐘,然後冷卻至室溫。藉過濾收集固體,以甲醇洗滌,且在高真空下於40℃下乾燥,而得所要之產物(0.058克,0.169毫莫耳,94%產率),為白色固體。1H NMR(300MHz,DMSO-d6)δ(ppm)11.32(s,1H),8.66(s,1H),7.97(s,1H),7.92(dd,J=1.37,7.97Hz,1H),7.74(s,1H),7.50(d,J=7.97Hz,1H),4.14(s,2H),2.44(s,3H);MS(ESI)m/z 308.3[M+1]+。
實例4:6-(4-(2-羥丙-2-基)苯基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡
并[2,3-b]吡
-2(1H)-酮
A. 2-溴-N-(3,5-二溴基吡 -2-基)乙醯胺. 將2-胺基-3,5-二溴基吡(6.17克,23.7毫莫耳)與溴基醋酸酐(3.0克,11.9毫莫耳)在乙腈(40毫升)中之溶液,於70℃下攪拌。在起始物質完全消耗(藉TLC)時,使溶液濃縮,並於水與醋酸乙酯(3X)之間作分液處理。合併有機層,以硫酸鎂脫水乾燥,過濾,及在減壓下移除溶劑。將所形成之物質使用Biotage管柱層析純化(5-80%醋酸乙酯在己烷中),而得標題化合物(3.78克,10.1毫莫耳,85%產率)。MS(ESI)m/z 372.1[M-2]+,374.0[M]+,376.1[M+2]+,378.3[M+4]+。
B. 6-溴基-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將2-溴-N-(3,5-二溴基吡-2-基)乙醯胺(3.30克,8.83毫莫耳)與2-(四氫-2H-哌喃-4-基)乙胺鹽酸鹽(1.46克,8.83毫莫耳)及二異丙基乙胺(6.67毫升,35.3毫莫耳)合併,且於85℃下加熱。在起始物質完全消耗(藉TLC)時,使反應溶液濃縮,並經由Biotage層析純化(0-100%醋酸乙酯在己烷中),而得標題化合物(1.53克,4.48毫莫耳,50%產率)。MS(ESI)m/z 341.4[M]+,343.1[M+2]+。
C. 2-(4-溴苯基)丙-2-醇. 使1-(4-溴苯基)乙酮(9.25克,46.5毫莫耳)溶於四氫呋喃(200毫升)中。使溶液在-50℃浴液中冷卻。添加溴化甲基鎂(3M,在醚中,46.5毫升,139毫莫耳),歷經15分鐘期間。使反應物溫熱至室溫,然後攪拌20小時。以飽和氯化銨使反應淬滅,接著以醋酸乙酯萃取。使有機層以硫酸鎂脫水乾燥,過濾,及濃縮,而得油狀物。使此油於矽膠管柱上純化(0-20%醋酸乙酯在己烷中),獲得產物無色油(9.1克,46.2毫莫耳,91%產率)。MS(ESI)m/z 197.1[M]+,199.1[M+2]+。
D. 2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼伍圜-2-基)苯基)丙-2-醇. 將2-(4-溴苯基)丙-2-醇(4.7克,21.85毫莫耳)、雙(品吶可基)二硼(6.66克,26.2毫莫耳)、醋酸鉀(6.43克,65.6毫莫耳)及二甲亞碸(50毫升)攪拌,並在真空下脫氣10分鐘。添加與二氯甲烷之[1,1'-雙(二苯基-膦基)二環戊二烯鐵]二氯-鈀(II)複合物(1:1)(0.892克,1.093毫莫耳),且使反應物再脫氣5分鐘。然後,將反應物於氮氣下加熱至80℃,歷經2小時。使反應物冷卻至室溫,接著以1:1醚:醋酸乙酯與水萃取。使所形成之黑色乳化液經過矽藻土墊過濾,及將濾液與萃取層合併。使有機層以硫酸鎂脫水乾燥,過濾,然後於矽膠管柱上純化(0-25%醋酸乙酯在己烷中)。使產物溶離份濃縮,接著在己烷中研製,獲得白色固體(4.0克,15.3毫莫耳,70%產率)。MS(ESI)m/z 263.3[M+1]+。
E. 6-(4-(2-羥丙-2-基)苯基)-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將6-溴基-4-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(0.250克,0.733毫莫耳)、2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼伍圜-2-基)苯基)丙-2-醇(0.192克,0.733毫莫耳)及二氯[1,1'-雙(二苯基膦基)二環戊二烯鐵]鈀(II)二氯甲烷(0.030克,0.037毫莫耳)在二甲基甲醯胺(1.0毫升)中合併。添加水(0.2毫升)中之碳酸鈉(0.311克,2.93毫莫耳),然後,將反應溶液在Biotage Emrys Optimizer微波反應器中於120℃下加熱15分鐘。使已冷卻之反應溶液經過矽藻土過濾,並將濾餅以醋酸乙酯洗滌。合併濾液與醋酸乙酯洗液,且在減壓下移除溶劑。將所形成之物質使用Biotage管柱層析純化(0-5%甲醇在醋酸乙酯中),接著以二甲基甲醯胺與水研製,而得標題化合物(0.074克,0.19毫莫耳,25%)。1H NMR(400MHz,DMSO-d6)δ(ppm)12.24(s,1H),7.98(s,1H),7.89(d,J=8.39Hz,2H),7.53(d,J=8.39Hz,1H),5.04(s,1H),4.16(s,1H),3.82(dd,J=11.1,2.39Hz,2H),3.61(t,J=7.59Hz,2H),3.25(t,J=9.59Hz,3H),1.70(s,1H),1.66(s,1H),1.58(m,3H),1.44(s,6H),1.25(m,2H);MS(ESI)m/z 397.2[M+1]+;熔點210-212℃。
實例5:6-(6-(2-羥丙-2-基)吡啶-3-基)-4-(2-嗎福啉基乙基)-3,4-二氫吡
并[2,3-b]吡
-2(1H)-酮
A. 2-氯-N-(3,5-二溴基吡 -2-基)乙醯胺. 使2-胺基-3,5-二溴基吡(3.0克,11.9毫莫耳)與氯醋酸酐(4.2克,8.7毫莫耳)之溶液在乙腈(10毫升)中,於70℃下反應16小時。使溶液濃縮,並以醋酸乙酯稀釋。將有機物質以碳酸氫鈉(飽和)與碳酸鉀之1:1溶液(1.75M,在水中)
洗滌(4X)。合併有機物質,以硫酸鎂脫水乾燥,過濾,及在減壓下移除溶劑。將所形成之固體以己烷中之10%醋酸乙酯研製,而得標題化合物(3.12克,9.3毫莫耳,72%產率)。MS(ESI)m/z 328.3[M-1]+,330.4[M+1]+,332.3[M+3]+。
B. N-(3,5-二溴基吡 -2-基)-2-碘乙醯胺. 於2-氯-N-(3,5-二溴基吡-2-基)乙醯胺(3.0克,9.11毫莫耳)在丙酮(40毫升)中之溶液內,添加已溶於丙酮(20毫升)中之碘化鈉(13.65克,91毫莫耳)。將溶液於環境溫度下攪拌16小時。使溶液在減壓下濃縮,並以醋酸乙酯(500毫升)稀釋,且以水連續地洗滌(5X),以移除藍色。使有機物質以硫酸鎂脫水乾燥,過濾,及在減壓下移除溶劑,而得粗產物。將固體以己烷中之10%醋酸乙酯(40毫升)稀釋,並音振,同時將燒瓶側面刮削。然後,將溶液在加熱槍下加熱5分鐘,接著冷卻,同時於環境溫度下音振。將所形成之固體過濾,且以另外之己烷洗滌,及在真空下乾燥,而得標題化合物(3.0克,7.13毫莫耳,78%產率)。MS(ESI)m/z 420.3[M-1]+,422.0[M+1]+,424.0[M+3]+。
C. 6-溴基-4-(2-嗎福啉基乙基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將N-(3,5-二溴基吡-2-基)-2-碘乙醯胺(0.5克,1.188毫莫耳)、二異丙基乙胺(0.415毫升,2.376毫莫耳)及2-嗎福啉基乙胺(0.162克,1.248毫莫耳)在乙腈(5毫升)中合併。將溶液加熱至45℃,歷經1小時。使溶液濃縮,並以己烷中之75%醋酸乙酯稀釋。過濾所形成之固體,且收集濾液,及濃縮,接著經由Biotage層析純化(己烷中之0-75%醋酸乙酯,然後為醋酸乙酯中之0-10%甲醇),而得標題化合物(0.228克,0.67毫莫耳,56%產率)。MS(ESI)m/z 342.4[M]+,344.4[M+2]+。
D. 2-(5-溴基吡啶-2-基)丙-2-醇. 於100毫升圓底燒瓶中,使2,5-二溴基吡啶(1.04克,4.39毫莫耳)溶於甲苯(22毫升)中。使混合物冷卻至-78℃。逐滴添加正-丁基鋰(3.02毫升,4.83毫莫耳)。將混合物攪拌
30分鐘,接著添加丙酮(2毫升)。將混合物攪拌40分鐘,然後,使其溫熱至室溫。將混合物以氯化銨(5%水溶液,50毫升)、水(50毫升),接著以鹽水(50毫升)洗滌。使有機層以硫酸鈉脫水乾燥,過濾,及濃縮。使殘留物藉由Biotage純化(16%醋酸乙酯在己烷中)。濃縮所要之溶離份,獲得產物(0.82克,3.78毫莫耳,86%產率)。MS(ESI)m/z 216.0[M]+,218.1[M+2]+。
E. 2-(5-(三甲基錫烷基)吡啶-2-基)丙-2-醇. 於50毫升可再密封燒瓶中,將2-(5-溴基吡啶-2-基)丙-2-醇(0.34克,1.574毫莫耳)、1,1,1,2,2,2-六甲基二錫烷(0.361毫升,1.652毫莫耳)及肆(三苯膦)鈀(0)(0.182克,0.157毫莫耳)在甲苯(5毫升)中合併。將反應物於115℃下攪拌1.5小時。然後,使混合物濃縮至約2毫升體積。使殘留物經由Biotage純化(16%醋酸乙酯在己烷中)。濃縮所要之溶離份,獲得標題化合物(0.33克,1.10毫莫耳,70%產率)。MS(ESI)m/z 302.1[M+1]+。
F. 6-(6-(2-羥丙-2-基)吡啶-3-基)-4-(2-嗎福啉基乙基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將6-溴基-4-(2-嗎福啉基乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(0.228克,0.666毫莫耳)與2-(5-(三甲基錫烷基)吡啶-2-基)丙-2-醇(0.220克,0.733毫莫耳)在二甲基甲醯胺(3毫升)中合併。將溶液以氮氣滌氣,接著添加二氯[1,1'-雙(二苯基膦基)二環戊二烯鐵]鈀(II)二氯甲烷(0.109克,0.133毫莫耳)。將溶液加熱至100℃,歷經2小時。使溶液在減壓下濃縮,並使所形成之油經由逆相-製備型HPLC純化(5-60%乙腈+H2O中之0.1% TFA+0.1% TFA,歷經30分鐘),且將所要之溶離份裝填至Strata-XC離子交換管柱上。將管柱以水、乙腈、甲醇及甲醇中之5%氫氧化銨連續洗滌。使產物以甲醇中之5%氫氧化銨溶離,並在減壓下濃縮,及乾燥,而得標題化合物(0.070克,0.18毫莫耳,26%產率)。1H NMR(400MHz,DMSO-d6)δ(ppm)11.33(寬廣s.,1H),9.05(d,J=1.56Hz,1H),8.27(dd,J=8.59,2.34Hz,1H),
8.06(s,1H),7.72(d,J=8.59Hz,1H),5.27(s,1H),4.29(s,2H),3.71(t,J=6.44Hz,2H),3.54(t,J=4.49Hz,4H),2.62(t,J=6.44Hz,2H),2.40-2.48(m,4H),1.46(s,6H);MS(ESI)m/z 399.2[M+1]+;熔點239-241℃。
實例6:1-(((反式)-4-甲氧基環己基)甲基)-7-(4-甲基-6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡
并[2,3-b]吡
-2(1H)-酮
A. 5-溴基-4-甲基甲基吡啶腈. 將2,5-二溴基-4-甲基吡啶(5.0克,19.9毫莫耳)、氰化銅(1.43克,15.9毫莫耳)、氰化鈉(0.801克,16.3毫莫耳)及二甲基甲醯胺(30毫升)在密封反應容器中合併,且於158℃下加熱3小時。使反應混合物藉矽膠管柱層析純化(0-80%醋酸乙酯在己烷中)。使所形成之物質接受第二個矽膠管柱(0-20%甲醇在二氯甲烷中)。合併純淨溶離份,及濃縮,而得標題化合物,為白色固體(2.30克,11.6毫莫耳,58%產率)。MS(ESI)m/z 198.0[M+1]+。
B. 2-(3,5-二溴基吡 -2-基胺基)醋酸乙酯. 於2000毫升3頸圓底燒瓶中,裝填二甲基甲醯胺(860毫升)中之2-胺基-3,5-二溴基吡(172克,680毫莫耳),並冷卻至0-5℃。以一份添加碳酸銫(288克,884毫莫耳),接著,分批添加氯基醋酸乙酯(87毫升,816毫莫耳)。使溶液溫熱至20-25℃,然後加熱至55℃(發現放熱,發現最高溫度76℃)。一旦內部反應溫度消退至65℃,立即將反應物在65℃下加熱~4小時。使反應物冷卻至20-25℃,並經過濾紙過濾,以移除無機鹽,且以二甲基甲醯胺(3份體積)洗滌固體。將濾液逐滴添加至16份體積之冰水(8份體積冰/8份體積水)中,並將漿液攪拌12-24小時。在過濾之後,將所形成之褐色固體單離,且以水(10份體積)洗滌,及風乾。使粗產物溶於
甲基第三-丁基醚(3.46升,15份體積)中。添加炭(C-906,得自Ecosorb,20重量%,46.1克),並將混合物於回流下加熱1小時。在冷卻至室溫後,於矽藻土床上移除炭,且使濾液濃縮至乾涸。使粗製物溶於醋酸乙酯(576毫升,2.5份體積)中,及濃縮成濃稠漿液。添加2%醋酸乙酯在庚烷中之溶液(1.15升,5份體積),並將混合物在室溫下攪拌30-60分鐘。藉過濾收集產物,以庚烷(2-3份體積)洗滌,及在高真空下於35-40℃下乾燥16小時,而得所要之化合物,為灰白色固體(109克,47%產率)。將第二份收取產物自母液單離,如下述:使濾液濃縮,獲得粗製油。添加醋酸乙酯(1份體積)。將所形成之溶液以先前經單離之產物接種,並在0-5℃下冷卻1小時。藉過濾收集所形成之固體,且以冷醋酸乙酯:庚烷(1:1混合物,<1份體積)洗滌。按前述,使固體乾燥,及與第一份收取產物合併,以提供標題化合物(132克,57%總產率)。MS(ESI)m/z 337.8[M-1]+,339.8[M+1]+,341.8[M+3]+。
C. 7-溴基-1-(((反式)-4-甲氧基環己基)甲基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將2-(3,5-二溴基吡-2-基胺基)醋酸乙酯(500毫克,1.47毫莫耳)、((反式)-4-甲氧基環己基)甲胺(317毫克,2.21毫莫耳)及二異丙基乙胺(0.77毫升,4.42毫莫耳)在無水二甲亞碸(8.0毫升)中之溶液,置於微波容器(20毫升)中。將反應物加熱至150℃,歷經1小時。將反應物倒入水中,以醋酸乙酯(2x100毫升)萃取,以硫酸鈉脫水乾燥,過濾,及在減壓下濃縮。使所形成之物質溶於醋酸(30毫升)中,並置於密封管中。將反應物加熱至120℃過夜。使溶液冷卻,在減壓下濃縮,以飽和碳酸氫鈉中和,以醋酸乙酯(3x100毫升)萃取,以硫酸鈉脫水乾燥,過濾,及吸附至矽膠上。藉急驟式層析純化(50%醋酸乙酯在己烷中),獲得淡橘色固體(400毫克,1.12毫莫耳,76%產率)。MS(ESI)m/z 355.2[M+]+,357.2{M+2]+。
D. 1-(((反式)-4-甲氧基環己基)甲基)-7-(三甲基錫烷基)-3,4-二 氫吡 并[2,3-b]吡 -2(1H)-酮. 將7-溴基-1-(((反式)-4-甲氧基環己基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(2.71克,7.63毫莫耳)、1,1,1,2,2,2-六甲基二錫烷(3.00克,9.15毫莫耳)及肆(三苯膦)鈀(0)(882毫克,0.76毫莫耳)在裝有無水二氧陸圜(40毫升)之密封管中合併,且以氮氣滌氣。將反應物加熱至100℃,歷經4小時。將反應物以醋酸乙酯稀釋,經過矽藻土過濾,將矽藻土以醋酸乙酯洗滌,並使濾液在減壓下濃縮。使粗製物質藉急驟式層析純化(0-50%醋酸乙酯在己烷中),且將所要之溶離份合併,及濃縮,而得淡黃色固體(2.32克,5.28毫莫耳,69%產率)。MS(ESI)m/z 441.1[M+1]+。
E. 5-(8-(((反式)-4-甲氧基環己基)甲基)-7-酮基-5,6,7,8-四氫吡 并[2,3-b]吡 -2-基)-4-甲基甲基吡啶腈. 將1-(((反式)-4-甲氧基環己基)甲基)-7-(三甲基錫烷基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(0.721克,1.64毫莫耳)、5-溴基-4-甲基甲基吡啶腈(0.323克,1.64毫莫耳)、參(二苯亞甲基丙酮)二鈀(0)(0.150克,0.164毫莫耳)、三乙胺(0.687毫升,4.93毫莫耳)、三-鄰-甲苯基膦(0.100克,0.328毫莫耳)及二甲基甲醯胺(8毫升)在密封反應容器中合併。使氮起泡經過反應物,歷經5分鐘,並將反應物在100℃下加熱3小時。過濾反應物,濃縮,且藉矽膠管柱層析純化(0-80%醋酸乙酯在己烷中)。合併溶離份,及濃縮,而得粗製標題化合物,直接使用於下一步驟(0.607克,1.55毫莫耳,94%產率)。MS(ESI)m/z 393.5[M+1]+。
F. 5-(8-(((反式)-4-甲氧基環己基)甲基)-7-酮基-5,6,7,8-四氫吡 并[2,3-b]吡 -2-基)-4-甲基甲基吡啶醯胺. 將5-(8-(((反式)-4-甲氧基環己基)甲基)-7-酮基-5,6,7,8-四氫吡并[2,3-b]吡-2-基)-4-甲基甲基吡啶腈(0.607克,1.55毫莫耳)、三氟醋酸(2.0毫升,26.0毫莫耳)及硫酸(0.5毫升,9.38毫莫耳)合併,且在65℃下加熱1小時。以碳酸鈉調整反應pH值至10,並將所形成之溶液以醋酸乙酯(3 x 15毫升)萃取。收集有
機層,以硫酸鎂脫水乾燥,濃縮,及使用逆相製備型HPLC純化(10-100%乙腈+H2O中之0.1% TFA+0.1% TFA,歷經30分鐘)。合併純淨溶離份,並在減壓下濃縮,且於高真空下乾燥,而得標題化合物,為黃色固體(0.425克,1.04毫莫耳,67%產率)。MS(ESI)m/z 411.5[M+1]+。
G. (Z)-N-((二甲胺基)亞甲基)-5-(8-(((反式)-4-甲氧基環己基)甲基)-7-酮基-5,6,7,8-四氫吡 并[2,3-b]吡 -2-基)-4-甲基甲基吡啶醯胺. 將5-(8-(((反式)-4-甲氧基環己基)甲基)-7-酮基-5,6,7,8-四氫吡并[2,3-b]吡-2-基)-4-甲基甲基吡啶醯胺(0.412克,1.00毫莫耳)、二甲基甲醯胺二新戊基縮醛(1.5毫升)及四氫呋喃(10毫升)合併,且於85℃下加熱3小時。使反應物在氮氣流下濃縮,置於反應容器中。將粗產物直接使用於下一步驟(0.467克,1.00毫莫耳,100%產率)。MS(ESI)m/z 466.6[M+1]+
H. 1-(((反式)-4-甲氧基環己基)甲基)-7-(4-甲基-6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將(Z)-N-((二甲胺基)亞甲基)-5-(8-(((反式)-4-甲氧基環己基)甲基)-7-酮基-5,6,7,8-四氫吡并[2,3-b]吡-2-基)-4-甲基甲基吡啶醯胺(0.467克,1.00毫莫耳)添加至醋酸(6毫升)中。使反應物冷卻至0℃,並逐滴添加肼(1.00毫升,32毫莫耳)。將反應物攪拌,且溫熱至25℃,歷經10分鐘。使反應物在氮氣流下濃縮,置於反應容器中。添加水(5毫升),並藉過濾收集產物,且使用逆相半製備型HPLC純化(20-70%乙腈+H2O中之0.1% TFA+0.1% TFA,歷經30分鐘)。合併純淨溶離份,並於減壓下濃縮,及在高真空下乾燥,而得標題化合物,為黃色固體(0.046克,0.106毫莫耳,11%產率)。1H NMR(400MHz,甲醇-d4)δ(ppm)8.72(s,1H),8.62(s,1H),8.37(s,1H),7.93(s,1H),4.30(s,2H),3.99(d,J=7.03Hz,2H),3.32(s,3H),3.08-3.17(m,1H),2.71-2.76(m,3H),2.06(寬廣s.,2H),1.80-1.89(m,1H),1.74(寬廣s.,2H),1.09(d,J=11.32Hz,
4H);MS(ESI)m/z 435.5[M+1]+。
實例7:7-(5-氟基-2-甲基-4-(1H-1,2,4-三唑-3-基)苯基)-1-異丙基-3,4-二氫吡
并[2,3-b]吡
-2(1H)-酮
A. 2-(5-溴基-3-(異丙基胺基)吡 -2-基胺基)醋酸乙酯. 於反應小玻瓶中,將2-(3,5-二溴基吡-2-基胺基)醋酸乙酯(參閱實例6.B)(1.5克,4.43毫莫耳)、異丙胺(0.17克,4.87毫莫耳)、N,N-二異丙基乙胺(1.14克,8.84毫莫耳)及二甲亞碸(10毫升)之混合物,於150℃下之油浴中加熱16小時。於冷卻至室溫後,將所形成之混合物倒入水中,並以醋酸乙酯萃取。使有機層以硫酸鈉脫水乾燥,過濾,於減壓下蒸發,及在矽膠管柱層析上純化(10-20%醋酸乙酯在石油醚中),而得標題化合物(780毫克,55.7%產率)。MS(ESI)m/z 316.9[M+1]+。
B. 7-溴基-1-異丙基-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 於可密封容器中,將2-(5-溴基-3-(異丙基胺基)吡-2-基胺基)醋酸乙酯(780毫克,2.26毫莫耳)、甲醇(5毫升)及TFA(10毫升)之混合物以氮滌氣,密封,激烈攪拌,並在90℃下使用油浴加熱16小時。將所形成之混合物以甲醇稀釋,且於減壓下移除溶劑。添加甲醇(10毫升),並於減壓下再一次移除溶劑。添加甲醇(10毫升)與碳酸氫鈉。將所形成之混合物於室溫下攪拌,直到pH=6(在水中)為止,於減壓下移除溶劑。添加水(20毫升)。將混合物以二氯甲烷(20毫升x3)萃取。使有機層以無水硫酸鈉脫水乾燥,濃縮,而得粗產物,並於矽膠管柱層析上純化(10-20%醋酸乙酯在石油醚中),而得標題化合物(360毫克,39.4%產率)。
C. 1-異丙基-7-(三甲基錫烷基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將7-溴基-1-異丙基-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(0.5克,1.844毫莫耳)、六甲基二錫(0.725克,2.213毫莫耳)、肆(三苯膦)鈀(0)(0.213克,0.184毫莫耳)及1,4-二氧陸圜(3毫升)在具有攪拌棒之可密封容器中合併。使氮氣起泡經過此溶液。將容器密封,激烈攪拌,並在100℃下加熱2小時。將所形成之混濁黑色混合物以醋酸乙酯稀釋,過濾,且以醋酸乙酯充分地洗滌濾餅。使濾液在減壓下濃縮,及使用矽膠急驟式管柱層析純化(20-80%醋酸乙酯在己烷中),而得所要之產物(0.49克,1.38毫莫耳,75%產率),為黃白色固體。MS(ESI)m/z 357.4[M+2]+。
D. 4-溴基-2-氟基-5-甲基苯甲醯胺. 將4-溴基-2-氟基-5-甲基苯甲腈(40克,190毫莫耳)在硫酸(98%)與TFA之混合物(v/v=4:1,480毫升)中之溶液,於80℃下攪拌16小時。使混合物冷卻至室溫後,將所形成之混合物倒入冰冷水中。藉過濾收集所形成之沉澱物,以水洗滌,並在減壓下乾燥,獲得標題化合物(41克,95%產率),為白色固體。MS(ESI)m/z 232.0[M+1]+。
E. 4-溴-N-((二甲胺基)亞甲基)-2-氟基-5-甲基苯甲醯胺. 將4-溴基-2-氟基-5-甲基苯甲醯胺(20克,86毫莫耳)在N,N-二甲基-甲醯胺二甲基縮酶(200毫升)中之溶液,於100℃及氮氣下攪拌3小時。使所形成之混合物濃縮,並乾燥,而得所要之產物(24.6克,95%產率),為黃色油,將其使用於下一步驟,無需進一步純化。MS(ESI)m/z 287.0[M+1]+。
F. 3-(4-溴基-2-氟基-5-甲基苯基)-1H-1,2,4-三唑. 在0℃下,於4-溴-N-((二甲胺基)亞甲基)-2-氟基-5-甲基苯甲醯胺(24.6克,86.2毫莫耳)在醋酸(200毫升)中之溶液內,逐滴添加肼水合物(25毫升,0.70莫耳)。將反應混合物在室溫下攪拌過夜。過濾混合物,以水(500毫升x3)洗滌,並在減壓下乾燥,而得標題化合物(15克,68%產率),為白色固
體。MS(ESI)m/z 256.0[M+1]+。
G. 3-(4-溴基-2-氟基-5-甲基苯基)-1-(四氫-2H-哌喃-2-基)-1H-1,2,4-三唑. 將3-(4-溴基-2-氟基-5-甲基苯基)-1H-1,2,4-三唑(15克,60毫莫耳)、甲苯-4-磺酸(2.0克,12毫莫耳)及3,4-二氫-2H-哌喃(20克,240毫莫耳)在四氫呋喃(200毫升)中之溶液,於80℃及氮氣下攪拌15小時。使所形成之混合物濃縮,及在矽膠管柱上純化(1-25%醋酸乙酯在石油醚中),獲得經保護之三唑產物(15克,75%產率),為白色固體。1H NMR(DMSO-d6,400MHz):δ(ppm)8.83(s,1H),7.96(d,J=7.6Hz,1H),7.66(d,J=10.0Hz,1H),5.61(dd,J1=2.4Hz,J2=9.6Hz,1H),3.96(d,J=1.6Hz,1H),3.69(m,1H),2.36(s,3H),2.00(m,2H),1.70(m,2H),1.57(m,2H);MS(ESI)m/z 340.0[M+1]+。
H. 7-(5-氟基-2-甲基-4-(1-(四氫-2H-哌喃-2-基)-1H-1,2,4-三唑-3-基)苯基)-1-異丙基-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將1-異丙基-7-(三甲基錫烷基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(300毫克,0.84毫莫耳)、3-(4-溴基-2-氟基-5-甲基苯基)-1-(四氫-2H-哌喃-2-基)-1H-1,2,4-三唑(428毫克,1.26毫莫耳)及雙(三苯膦)二氯化鈀(II)(56毫克,0.08毫莫耳)在N,N-二甲基甲醯胺(5毫升)中合併。使混合物脫氣,並在140℃及氮氣下加熱3小時。於冷卻至室溫後,將反應混合物過濾,且使濾液於醋酸乙酯(15毫升)與水(15毫升)之間作分液處理。分離有機層,並將水層以醋酸乙酯(10毫升x2)萃取。使合併之有機層以硫酸鈉脫水乾燥,過濾,在減壓下濃縮,及藉製備型TLC純化(15%甲醇在二氯甲烷中),而得標題化合物(200毫克,產率52%),為固體。
I. 7-(5-氟基-2-甲基-4-(IH-1,2,4-三唑-3-基)苯基)-1-異丙基-3,4-二氫吡 并[2,3-b]吡 -2(IH)-酮. 將7-(5-氟基-2-甲基-4-(1-(四氫-2H-哌喃-2-基)-1H-1,2,4-三唑-3-基)苯基)-1-異丙基-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(200毫克,0.44毫莫耳)在甲醇性鹽酸鹽溶液(20毫
升,2M)中之溶液,於室溫下攪拌5小時。將反應物以飽和碳酸氫鈉水溶液(25毫升)稀釋,並以醋酸乙酯(25毫升x2)萃取含水混合物,使有機相以硫酸鈉脫水乾燥,過濾,於減壓下蒸發,及在矽膠管柱上純化(50-100%醋酸乙酯在石油醚中)。合併所要之溶離份,且在減壓下濃縮,而得標題化合物(75毫克,46%產率)。1H NMR(DMSO-d6,400MHz):δ(ppm)14.25(寬廣s.,1H),8.20(寬廣s.,1H),7.90(m,2H),7.58(s,1H),7.35(s,1H),5.24(m,1H),4.10(s,2H),2.43(s,3H),1.44(d,J=7.2,6H):MS(ESI)m/z 368.2[M+1]+。
實例8:7'-(2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-1'H-螺[環丙烷-1,2'-吡
并[2,3-b]吡
]-3'(4'H)-酮
A. 1-(3,5-二溴基吡 -2-基胺甲醯基)環丙基-胺基甲酸第三-丁酯. 於室溫下,將1,1'-羰基二咪唑(4.37克,27.0毫莫耳)添加至1-(第三-丁氧羰基胺基)環丙烷羧酸(4.93克,24.50毫莫耳)在N,N-二甲基甲醯胺(6毫升)與二氯甲烷(12毫升)中之經攪拌溶液內。將所形成之透明黃色混合物於室溫及氮氣下攪拌4小時。添加N,N-二異丙基乙胺(8.54毫升,49.0毫莫耳),接著為3,5-二溴基吡-2-胺(9.29克,36.8毫莫耳)。將所形成之混合物在50℃下,於回流冷凝管下,在氮氣下加熱60小時。以醋酸乙酯稀釋所形成之混合物,並以水洗滌。分離液層,且將有機層以鹽水洗滌,以硫酸鎂脫水乾燥,過濾,及在減壓下濃縮。使殘留物溶於二氯甲烷中,並使用急驟式層析純化(Biotage)(5-60%醋酸乙酯在己烷中)。將含有所要產物之溶離份合併,及在減壓下濃縮。將殘留物以己烷中之15%醋酸乙酯研製,且在高真空下乾燥,而得所要之產物(5.349克,12.27毫莫耳,50%產率),為灰白色固體。1H NMR(400
MHz,DMSO-d6)δ(ppm)9.92(寬廣s.,1H),8.76(s,1H),7.70(寬廣s.,1H),1.41(s,9H),1.34-1.40(m,2H),1.02-1.09(m,2H);MS(ESI)m/z 437.3[M+1]+,459.1[M+Na]+。
B. 1-胺基-N-(3,5-二溴基吡 -2-基)環丙烷羧醯胺雙三氟基醋酸鹽. 將TFA(6.02毫升,78毫莫耳)添加至1-(3,5-二溴基吡-2-基胺甲醯基)環丙基胺基甲酸第三-丁酯(3.410克,7.82毫莫耳)在二氯甲烷(20毫升)中之經攪拌混合物內。將所形成之透明黃色溶液於室溫下攪拌4小時。在減壓下移除所有揮發性物質,及使殘留物在高真空下於40℃下乾燥,而得所要之產物(4.42克,7.85毫莫耳,100%產率),為蠟狀黃色固體。MS(ESI)m/z 337.1[M+1]+。
C. 7'-溴基-1'H-螺[環丙烷-1,2'-吡 并[2,3-b]吡 ]-3'(4'H)-酮. 將1-胺基-N-(3,5-二溴基吡-2-基)環丙烷羧醯胺雙三氟基醋酸鹽(0.394克,0.700毫莫耳)、N,N-二異丙基乙胺(0.610毫升,3.50毫莫耳)及1,4-二氧陸圜(6毫升)在具有攪拌棒之可密封容器中合併。將系統以氮滌氣。將所形成之混合物密封,激烈攪拌,並於110℃下加熱2小時。在減壓下移除揮發性物質。使殘留物溶於DMSO與甲醇中,過濾,及使用逆相製備型HPLC純化(10-65%乙腈+水中之0.1% TFA+0.1% TFA,歷經30分鐘)。將含有所要產物之溶離份合併,以飽和碳酸氫鈉水溶液中和,並在減壓下移除大部份溶劑。藉真空過濾收集固體,以水充分地洗滌,及在高真空下乾燥,而得所要之產物(0.141克,0.553毫莫耳,79%產率),為淡黃色固體。1H NMR(400MHz,DMSO-d6)δ(ppm)11.27(s,1H),8.04(s,1H),7.46(s,1H),1.29-1.38(m,2H),0.91-1.01(m,2H);MS(ESI)m/z 255.1[M]+,257.0[M+2]+。
D. 7'-(2-甲基-4-(4-(四氫-2H-哌喃-2-基)-4H-1,2,4-三唑-3-基)苯基)-1'H-螺[環丙烷-1,2'-吡 并[2,3-b]吡 ]-3'(4'H)-酮三氟醋酸鹽. 將3-(3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼伍圜-2-基)苯基)-4-(四氫
-2H-哌喃-2-基)-4H-1,2,4-三唑(參閱實例2.C)(0.201克,0.545毫莫耳)、7'-溴基-1'H-螺[環丙烷-1,2'-吡并[2,3-b]吡]-3'(4'H)-酮(0.139克,0.545毫莫耳)、與二氯甲烷之[1,1'-雙(二苯基膦基)-二環戊二烯鐵]二氯鈀(II)複合物(1:1)(0.045克,0.054毫莫耳)、碳酸鈉(1M,在水中,1.635毫升,1.635毫莫耳)、1,4-二氧陸圜(1.2毫升)及異丙醇(0.4毫升)在具有攪拌棒之可密封容器中合併。將系統以氮滌氣。將所形成之混合物密封,激烈攪拌,並在100℃下加熱1小時。將所形成之混合物以水稀釋,且以二氯甲烷萃取三次。使合併之有機物質在減壓下濃縮。使殘留物溶於DMSO與甲醇中,過濾,及使用逆相製備型HPLC純化(20-70%乙腈+水中之0.1% TFA+0.1% TFA,歷經30分鐘)。將含有所要產物之溶離份合併,及在減壓下移除溶劑。使殘留物在高真空下乾燥,而得所要之產物(0.109克,0.205毫莫耳,38%產率),為橘色固體。MS(ESI)m/z 418.4[M+1]+。
E. 7'-(2-甲基-4-(4H-1,2,4-三唑-3-基)苯基)-1'H-螺[環丙烷-1,2'-吡 并[2,3-b]吡 ]-3'(4'H)-酮. 於80℃下,將水中之6N鹽酸(0.171毫升,1.025毫莫耳)添加至7'-(2-甲基-4-(4-(四氫-2H-哌喃-2-基)-4H-1,2,4-三唑-3-基)苯基)-1'H-螺[環丙烷-1,2'-吡并[2,3-b]吡]-3'(4'H)-酮三氟醋酸鹽(0.109克,0.205毫莫耳)在乙醇(4毫升)中之經攪拌混合物內。將所形成之混合物激烈攪拌,並在80℃下,於回流冷凝管下,在氮氣下加熱30分鐘。過濾所形成之混合物,及使用逆相製備型HPLC純化(10-60%乙腈+水中之0.1% TFA+0.1% TFA,歷經30分鐘)。將含有所要產物之溶離份合併,以飽和碳酸氫鈉水溶液中和,並在減壓下移除大部份溶劑。藉真空過濾收集固體,以水充分地洗滌,及在高真空下於45℃下乾燥,而得所要之產物(0.027克,0.079毫莫耳,39%產率),為黃色固體。1H NMR(400MHz,DMSO-d6)δ(ppm)11.22(寬廣s.,1H),8.63(寬廣s.,1H),7.93(s,1H),7.89(d,J=7.81Hz,1H),7.62(s,1H),
7.58(s,1H),7.47(寬廣s.,1H),2.43(s,3H),1.29-1.38(m,2H),0.95-1.04(m,2H);MS(ESI)m/z 334.2[M+1]+。
實例9:7-(6-(2-羥丙-2-基)吡啶-3-基)-1-((反式)-4-甲氧基環己基)-3,4-二氫吡
并[2,3-b]吡
-2(1H)-酮
A. 2-(5-溴基-3-(反式-4-甲氧基環己胺基)吡 -2-基胺基)醋酸乙酯. 將2-(3,5-二溴基吡-2-基胺基)醋酸乙酯(參閱實例6.B)(30.0克,88毫莫耳)、反式-4-甲氧基環己胺(17.15克,133毫莫耳)、N,N-二異丙基乙胺(30.8毫升,177毫莫耳)及二甲亞碸(70.8毫升)在具有攪拌棒之反應小玻瓶中合併,且於150℃下之油浴中加熱16小時,並攪拌。將所形成之混合物以醋酸乙酯稀釋,及在減壓下移除揮發性物質。將殘留物於Biotage SP1上使用矽膠層析純化(12%醋酸乙酯在己烷中)。合併含有所要產物之溶離份,且在減壓下移除有機揮發性物質。將殘留物以己烷中之5%醋酸乙酯研製。藉真空過濾收集固體,以己烷洗滌,及在真空下乾燥,而得乙基標題化合物(15.37克,39.7毫莫耳,44.8%產率),為灰白色固體。MS(ESI)m/z 387.0[M]+,389.0[M+2]+。
B. 7-溴基-1-(反式-4-甲氧基環己基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將下述反應物分配至3個各別密封管件中,並個別處理。然後,在純化之後,合併此物質。將2-(5-溴基-3-(反式-4-甲氧基環己胺基)吡-2-基胺基)醋酸乙酯(10克,25.7毫莫耳)、甲醇(10.5毫升,259毫莫耳)及TFA(100毫升)在具有攪拌棒之可密封容器中合併。將系統以氮滌氣,並將所形成之混合物密封,激烈攪拌,且在90℃下使用油浴加熱18.5小時。將所形成之混合物以甲醇稀釋,及在減壓下
移除所有溶劑。添加甲醇(100毫升),並於減壓下再一次移除所有溶劑。添加甲醇(100毫升)與碳酸氫鈉(12.4克,147毫莫耳)。將所形成之混合物於室溫下攪拌,直到pH=6(在水中)為止。使混合物幾乎濃縮至乾涸。添加水(100毫升)。藉真空過濾收集所形成之褐色固體,並以水洗滌。使褐色固體溶於熱甲醇與乙腈中,且使用逆相C18急驟式管柱層析純化(20-100%乙腈在水中)。將含有所要產物之溶離份合併,及在減壓下幾乎濃縮至乾涸。藉真空過濾收集固體,以水洗滌,並在高真空下乾燥,而得所要之產物(4.88克,14.3毫莫耳,55%產率),為淡黃褐色固體。1H NMR(400MHz,DMSO-d6)δ(ppm)7.71(s,1H),7.59(s,1H),4.66(tt,J=3.61,12.20Hz,1H),4.07(d,J=1.56Hz,2H),3.25(s,3H),3.06-3.17(m,1H),2.42(qd,J=3.51,12.89Hz,2H),2.10(d,J=10.93Hz,2H),1.61(d,J=10.93Hz,2H),1.10-1.24(m,2H);MS(ESI)m/z 341.3[M]+,343.1[M+2]+。
C. 7-(6-(2-羥丙-2-基)吡啶-3-基)-1-(反式-4-甲氧基環己基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將2-(5-(三甲基錫烷基)吡啶-2-基)丙-2-醇(參閱實例5.E)(9.43克,31.4毫莫耳)、7-溴基-1-(反式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(10.02克,29.4毫莫耳)、[1,1'-雙(二苯基-膦基)-二環戊二烯鐵]二氯鈀(II)二氯甲烷加成物(2.398克,2.94毫莫耳)及N,N-二甲基甲醯胺(25毫升)在具有攪拌棒之圓底燒瓶中合併。於真空下移除容器中之大氣,並被氮氣置換三次。將所形成之混合物激烈攪拌,且於120℃及氮氣下加熱35分鐘。將所形成之混合物使用急驟式層析純化,分配至4個各別管柱(2-15%甲醇在二氯甲烷中)中。將含有所要產物之溶離份合併,及在減壓下移除大部份溶劑。將所形成之混合物使用逆相製備型HPLC純化(20-40%乙腈+水中之0.1% TFA+0.1% TFA,歷經30分鐘),分成6次進行。將含有所要產物之溶離份合併,且於25℃下在減壓下移除所有乙腈與若干水。將殘留
黃色溶液裝填至得自Phenomenex之50克Strata X-C離子交換樹脂上。將管柱以水、乙腈、甲醇,接著以甲醇中之5%氫氧化銨連續洗滌。使產物以甲醇中之5%氫氧化銨洗液溶離,並在減壓下濃縮,及在高真空下乾燥,而得所要之產物(4.85克,12.20毫莫耳,42%產率),為粉紅色泡沫物-固體。1H NMR(400MHz,DMSO-d6)δ(ppm)9.03(d,J=1.56Hz,1H),8.28(s,1H),8.24(dd,J=2.34,8.20Hz,1H),7.74(d,J=7.81Hz,1H),7.61(s,1H),5.26(s,1H),4.90(tt,J=3.71,12.10Hz,1H),4.13(s,2H),3.28(s,3H),3.20(tt,J=4.00,10.84Hz,1H),2.58(qd,J=2.93,12.82Hz,2H),2.14(d,J=10.15Hz,2H),1.68(d,J=10.93Hz,2H),1.47(s,6H),1.17-1.35(m,2H);MS(ESI)m/z 398.3[M+1]+;熔點196-198℃(未經校正)。
D. 7-(6-(2-羥丙-2-基)吡啶-3-基)-1-(反式-4-甲氧基環己基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮(替代途徑). 將2-(3,5-二溴基吡-2-基胺基)醋酸乙酯(1當量)與反式-4-甲氧基環己胺.鹽酸鹽(1.5當量)、NMP及DIEA合併,且加熱至127℃,並在該溫度下保持18小時。於反應完成時,使混合物冷卻至35℃,歷經4小時。將此批料轉移至醋酸乙酯與5%鹽水之混合物。移除水層,及將含有批料之有機層以5%鹽水與水連續洗滌。使含有批料之有機層藉真空蒸餾濃縮至低體積,冷卻至環境溫度,並藉真空過濾收集固體。將濾餅以MTBE洗滌,且使產物在真空中乾燥,獲得41%產率之2-(5-溴基-3-(反式-4-甲氧基環己胺基)吡-2-基胺基)醋酸乙酯。將2-(5-溴基-3-(反式-4-甲氧基環己胺基)吡-2-基胺基)醋酸乙酯(1當量)、水與85%磷酸(3:1)之混合物加熱至80℃,歷經1小時。保持加熱18小時,以達成反應完成。於反應完成時,使混合物冷卻至25℃,並過濾,獲得粗產物,為黃褐色固體。將所形成之固體以水洗滌,在水中配成漿液,及過濾。將濾餅以水洗滌,直到濾液之pH值係在4與8之間為止。使所形成之物質在真空下乾燥,而
得89%產率之7-溴基-1-(反式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮、將7-溴基-1-(反式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(1當量)、5-(4,4,5,5-四甲基-1,3,2-二氧硼伍圜-2-基)-2-(2-(三甲基矽烷基氧基)丙-2-基)吡啶(1當量)、碳酸鈉(3當量)及PdCl2(AmPh0s)2(0.003當量)在異丙醇中合併,且在70℃下加熱1.5小時。標準處理及純化係獲得經保護之化合物,93%產率。使用標準條件去除保護,以移除三甲基矽烷基,及單離,獲得標題化合物。
實例10:9-(6-(4H-1,2,4-三唑-3-基)-2-甲基-3-吡啶基)-6,11,4a-三氫嗎福啉并[4,3-e]吡
并[2,3-b]吡
-5-酮
A. 5-溴基-6-甲基甲基吡啶腈. 將3,6-二溴基-2-甲基吡啶(4.9克,19.53毫莫耳)、氰化銅(I)(1.75克,19.53毫莫耳)及N,N-二甲基甲醯胺(20毫升)在具有攪拌棒之可密封容器中合併。將所形成之混合物密封,激烈攪拌,並於110℃下加熱4小時。以醋酸乙酯稀釋所形成之混合物,倒入含有水之分液漏斗中,並分離液層。以醋酸乙酯萃取水層兩次。將合併之有機物質以鹽水洗滌,以硫酸鎂脫水乾燥,過濾,及在減壓下濃縮。使所形成之固體藉矽膠層析純化(10%醋酸乙酯在己烷中),而得標題化合物,為白色固體(1.88克,9.54毫莫耳,49%產率)。MS(ESI)m/z 197.3[M]+。
B. 3-(3,5-二溴基吡 -2-基胺甲醯基)嗎福啉-4-羧酸第三-丁酯. 將4-(第三-丁氧羰基)嗎福啉-3-羧酸(1.500克,6.49毫莫耳)與1,1'-羰基二咪唑(1.578克,9.73毫莫耳)在N,N-二甲基甲醯胺(2毫升)與二氯甲烷(6毫升)中之溶液,於室溫及氮氣下攪拌4.5小時。添加N,N-二異丙基乙胺(2.260毫升,12.97毫莫耳),接著為3,5-二溴基吡-2-胺(3.28克,12.97
毫莫耳)。將所形成之混合物攪拌,並在50℃下,於回流冷凝管下,在氮氣下加熱2天。使所形成之混合物在減壓下濃縮。將殘留物以水稀釋,且以醋酸乙酯萃取3次。將合併之有機物質以水與鹽水洗滌,以硫酸鎂脫水乾燥,過濾,及在減壓下濃縮。將殘留物使用急驟式層析純化(20-30-50%醋酸乙酯在己烷中),而得所要之產物(2.136克,4.58毫莫耳,71%產率),為微黃色泡沫物-固體。MS(ESI)m/z 467[M+1]+。
C. 9-溴基-6,11,4a-三氫嗎福啉并[4,3-e]吡 并[2,3-b]吡 -5-酮. 使3-(3,5-二溴基吡-2-基胺甲醯基)嗎福啉-4-羧酸第三-丁酯(2.132克,4.57毫莫耳)溶於二氯甲烷(45毫升)中,並在室溫下攪拌。添加TFA(9毫升),且將所形成之淡黃色混合物加蓋,及在室溫下攪拌2.5小時。於減壓下移除溶劑,並使殘留物在高真空下於45℃下乾燥,獲得黏稠黃色油。使黃色油溶於異丙醇(潮濕)(50毫升)中,且在室溫下攪拌。添加碳酸氫鈉(3.84克,45.7毫莫耳)、醋酸鈀(II)(0.103克,0.457毫莫耳)及4,5-雙(二苯基膦基)-9,9-二甲基二苯并哌喃(0.239毫升,1.372毫莫耳)。將燒瓶中之大氣移除,並被氮置換。將所形成之混合物激烈攪拌,且在80℃下,於回流冷凝管下,在氮氣下加熱2小時。使所形成之混合物冷卻至室溫,並以水(30毫升)稀釋。藉真空過濾收集所形成之固體,以水與乙醚充分地洗滌,及在高真空下乾燥,而得所要之產物,~90%純度(1.441克,5.05毫莫耳,99%產率),為黃色固體。MS(ESI)m/z 285[M]+,287[M+2]+。
D. 9-(1,1-二甲基-1-錫烷乙基)-6,11,4a-三氫嗎福啉并[4,3-e]吡 并[2,3-b]吡 -5-酮. 將9-溴基-6,11,4a-三氫嗎福啉并[4,3-e]吡并[2,3-b]吡-5-酮(0.30克,1.052毫莫耳)、六甲基二錫(0.414克,1.263毫莫耳)、肆(三苯膦)鈀(0)(0.122克,0.105毫莫耳)及1,4-二氧陸圜(5毫升)在具有攪拌棒之可密封容器中合併。使氮氣起泡經過此溶液,歷經五分鐘。將容器密封,激烈攪拌,並在100℃下加熱2小時。將所形成
之混濁黑色混合物以醋酸乙酯稀釋,過濾,且以醋酸乙酯充分地洗滌濾餅。使濾液在減壓下濃縮,及使用Biotage急驟式層析純化(20-80%醋酸乙酯在己烷中),而得所要之產物(0.350克,0.948毫莫耳,90%產率),為黃白色固體。MS(ESI)m/z 369.5[M]+。
E. 6-甲基-5-(5-酮基(6,11,4a-三氫嗎福啉并[4,3-e]吡 并[2,3-b]吡 -9-基))吡啶-2-甲腈. 將5-溴基-6-甲基甲基吡啶腈(0.080克,0.406毫莫耳)、9-(1,1-二甲基-1-錫烷乙基)-6,11,4a-三氫嗎福啉并[4,3-e]吡并[2,3-b]吡-5-酮(0.150克,0.406毫莫耳)、參(二苯亞甲基丙酮)二鈀(0)(0.041克,0.045毫莫耳)、三-鄰-甲苯基膦(0.027克,0.089毫莫耳)及三乙胺(0.170毫升,1.219毫莫耳)置於密封管中,並添加N,N-二甲基甲醯胺(2毫升)。使氮氣起泡經過反應混合物,歷經五分鐘,且將反應物密封,及在100℃下加熱1小時。將所形成之混濁黑色混合物以甲醇稀釋,過濾,並將濾餅以甲醇充分地洗滌。使濾液在減壓下濃縮,且使用Biotage急驟式層析純化(50-100%醋酸乙酯在己烷中),而得所要之產物(0.117克,0.363毫莫耳,89%產率)。MS(ESI)m/z 323.5[M+1]+
F. 6-甲基-5-(5-酮基(6,11,4a-三氫嗎福啉并[4,3-e]吡 并[2,3-b]吡 -9-基))吡啶-2-羧醯胺. 將6-甲基-5-(5-酮基(6,11,4a-三氫嗎福啉并[4,3-e]吡并[2,3-b]吡-9-基))吡啶-2-甲腈(0.18克,0.558毫莫耳)置於圓底燒瓶中,並同時攪拌,添加TFA(1.6毫升)與硫酸(0.4毫升)之混合物。將所形成之懸浮液在室溫下攪拌16小時。將混合物傾倒於冰上,且以固體氫氧化鉀使過量酸小心地中和。過濾所獲得之固體,以水洗滌,及在高真空下乾燥,產生標題化合物(0.153克,0.450毫莫耳,81%產率),為紅色固體。MS(ESI)m/z 341.5[M+1]+
G. 9-(6-(4H-1,2,4-三唑-3-基)-2-甲基-3-吡啶基)-6,11,4a-三氫嗎福啉并[4,3-e]吡 并[2,3-b]吡 -5-酮. 將6-甲基-5-(5-酮基(6,11,4a-三氫嗎福啉并[4,3-e]吡并[2,3-b]吡-9-基))吡啶-2-羧醯胺(0.159克,
0.467毫莫耳)、N,N-二甲基甲醯胺二新戊基縮醛(2毫升,8.85毫莫耳)及二甲亞碸(0.5毫升)置於燒瓶中,並加熱至85℃,歷經1小時。將溶液以醋酸(5毫升,87毫莫耳)稀釋,且逐滴添加肼(0.468毫升,14.90毫莫耳)。將反應物於25℃下攪拌30分鐘。使混合物在減壓下濃縮,並以飽和碳酸鈉水溶液使殘留物小心地中和。然後,將此溶液以醋酸乙酯萃取三次,在減壓下濃縮,及使用逆相半製備型HPLC純化(5-50%乙腈+水中之0.1% TFA+0.1% TFA,歷經20分鐘),而得標題化合物(0.03克,0.082毫莫耳,17.63%產率)。1H NMR(400MHz,DMSO-d6)δ(ppm)7.96-8.04(m,2H),7.88(s,1H),4.33(dd,J=3.71,10.74Hz,1H),4.15-4.23(m,2H),3.98(dd,J=3.51,11.71Hz,1H),3.51-3.63(m,2H),2.89-2.99(m,1H),2.70(s,3H);MS(ESI)m/z 365.5[M+1]+
實例11:6-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-4-(四氫-2h-哌喃-4-基)-3,4-二氫吡
并[2,3-b]吡
-2(1H)-酮
A. 6-溴基-4-(四氫-2H-哌喃-4-基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 於N-(3,5-二溴基吡-2-基)-2-碘乙醯胺(參閱實例5.B)(6.6克,15.8毫莫耳)與二異丙基乙胺(4.0克,31.6毫莫耳)在乙腈(50毫升)中之溶液內,添加四氫-2H-哌喃-4-胺(6.4克,63.2毫莫耳),並將混合物於環境溫度下攪拌16小時。在減壓下移除溶劑,使殘留物於矽膠上藉層析純化(5-20%醋酸乙酯在石油醚中),而得標題化合物(1.98克,40%產率)。MS(ESI)m/z 313.1[M+1]+。
B. 4-(四氫-2H-哌喃-4-基)-6-(三甲基錫烷基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將6-溴基-4-(四氫-2H-哌喃-4-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(1.98克,6.35毫莫耳)、肆(三苯膦)鈀(1.45克,
1.27毫莫耳)及六甲基二錫(4.0克,12.7毫莫耳)在二氧陸圜(10毫升)中之經脫氣混合物,於氮氣下,在90℃下加熱3小時。使反應混合物在減壓下濃縮,及在矽膠管柱上純化(10-20%醋酸乙酯在石油醚中),而得產物(1.07克,42.3%產率)。MS(ESI)m/z 399.1[M+1]+。
C. 6-(6-(1-(四氫-2H-哌喃-2-基)-1H-1,2,4-三唑-3-基)吡啶-3-基)-4-(四氫-2H-哌喃-4-基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將4-(四氫-2H-哌喃-4-基)-6-(三甲基錫烷基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(1當量)、5-溴基-2-(1-(四氫-2H-哌喃-2-基)-1H-1,2,4-三唑-3-基)吡啶(1.2當量)、參(二苯亞甲基丙酮)二鈀(0.1當量)、三-鄰-甲苯基膦(0.2當量)、三乙胺(3當量)及N,N-二甲基甲醯胺之混合物,於氮氣下,在95℃下加熱3小時。濃縮及層析純化係獲得所要之產物,39%產率。MS(ESI)m/z 463.1[M+1]+。
D. 6-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-4-(四氫-2H-哌喃-4-基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將6-(6-(1-(四氫-2H-哌喃-2-基)-1H-1,2,4-三唑-3-基)吡啶-3-基)-4-(四氫-2H-哌喃-4-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮在甲醇性鹽酸鹽溶液中之混合物,於室溫下攪拌0.5小時。在減壓下蒸發溶劑,獲得粗產物,將其以N,N-二甲基甲醯胺洗滌,而得標題化合物,為鹽酸鹽,34%產率。1H NMR(DMSO-d6,400MHz)δ(ppm)11.44(s,1H),9.30(s,1H),8.59(d,J=8.4Hz,1H),8.46(s,1H),8.22(m,2H),4.70(t,J=10Hz,1H),4.16(s,1H),3.99(m,4H),3.51(t,J=11.2Hz,2H),1.86(m,2H),1.69(d,J=12.8Hz,2H);MS(ESI)m/z 379.1[M+1]+。
實例12:1-乙基-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡
并[2,3-b]吡
-2(1H)-酮
A. 7-溴基-1-乙基-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將2-(3,5-二溴基吡-2-基胺基)醋酸乙酯(參閱實例6.B)(1當量)、乙胺鹽酸鹽(3.1當量)、N,N-二異丙基乙胺(4當量)在N-甲基四氫吡咯酮中之混合物,於105℃及氮氣下加熱14小時。標準醋酸乙酯/水處理係獲得粗產物,77%產率。使用此物質無需進一步純化。將粗製2-(5-溴基-3-(乙胺基)吡-2-基胺基)醋酸乙酯與醋酸在甲醇中合併。使反應混合物在60-62℃及氮氣下回流16小時。使反應物在減壓下濃縮,並將所形成之殘留物以甲醇稀釋,及濃縮。使所形成之殘留物溶於醋酸乙酯中,以碳酸鈉處理,且攪拌10分鐘,直到pH~7為止。過濾混合物,並以醋酸乙酯洗滌。使濾液濃縮,及藉由矽膠填充柱純化法,使用(0-40%醋酸乙酯在己烷中)純化,獲得產物,為黃褐色固體。此外,使濾餅懸浮於水中,以移除碳酸鉀。將殘留固體產物藉過濾收集。此方法係以75%之合併產率獲得產物。
B. 1-乙基-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 使3-溴基-2-甲基-6-(1-(四氫-2H-哌喃-2-基)-1H-1,2,4-三唑-3-基)吡啶(1當量)、雙(品吶可基)二硼(1.05當量)、醋酸鉀(2當量)、碳酸鉀(3當量)、與二氯甲烷之[1,1'-雙(二苯基膦基)-二環戊二烯鐵]二氯鈀(II)複合物(1:1)(0.1當量)在無水二氧陸圜中之混合物脫氣,並在90℃下加熱2小時。使混合物冷卻至<40℃,並添加7-溴基-1-乙基-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(1當量)、水及與二氯甲烷之[1,1'-雙(二苯基膦基)-二環戊二烯鐵]二氯鈀(II)複合物(1:1)(0.05當量)。使混合物脫氣,且於65-70℃及氮氣下加熱1小時。使混合物冷卻至<40℃,以水與醋酸乙酯稀釋。標準醋酸乙酯/水處理,接著
為急驟式管柱層析(0-5%甲醇在二氯甲烷中),獲得標題化合物,57%產率。1H NMR(400MHz,DMSO-d6)δ(ppm)7.99(s,2H),7.93(s,1H),7.72(s,1H),4.22(s,2H),4.05(q,J=6.77Hz,2H),2.71(s,3H),1.18(t,J=7.03Hz,3H);MS(ESI)m/z 337.6[M+1]+。
實例13:4-((順式)-4-甲氧基環己基)-6-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡
并[2,3-b]吡
-2(1H)-酮
A. 5-溴基-6-甲基甲基吡啶醯胺. 將5-溴基-6-甲基甲基吡啶腈(1.8克,9.14毫莫耳)在TFA與硫酸之混合物(30毫升,4:1,v/v)中之溶液,於40℃下攪拌16小時。將反應混合物倒入冰水中。濾出所形成之固體,並以水洗滌,且乾燥,而得所要之產物,為白色固體(1.0克,4.65毫莫耳,54%產率)。MS(ESI)m/z 217.1[M+2]+。
B. 3-溴基-2-甲基-6-(1H-1,2,4-三唑-3-基)吡啶. 將5-溴基-6-甲基甲基吡啶醯胺(1克,4.65毫莫耳)與N,N-二甲基甲醯胺二甲基縮醛(20毫升)在具有攪拌棒之100毫升圓底燒瓶中合併,且在85℃下,於回流冷凝管下,在氮氣下加熱3小時。使所形成之混合物於減壓下濃縮,及在真空下乾燥,獲得黃色油,將其使用於下一步驟無需純化。以醋酸(10毫升)稀釋殘留物,並逐滴添加肼(2.5毫升,70.3毫莫耳),且將其在室溫下攪拌5小時。將反應混合物倒入冰水中。過濾所形成之固體,以水洗滌,及乾燥,而得所要之產物,為白色固體。將含水濾液以二氯甲烷萃取。使有機層在減壓下幾乎濃縮至乾涸,而產生另外之物質。合併兩份批料,獲得所要之產物(0.7克,2.9毫莫耳,63%產率)。MS(ESI)m/z 241.1[M+2]+。
C. 3-溴基-2-甲基-6-(1-(四氫-2H-哌喃-2-基)-1H-1,2,4-三唑-3- 基)吡啶. 使3-溴基-2-甲基-6-(1H-1,2,4-三唑-3-基)吡啶(0.7克,2.93毫莫耳)與3,4-二氫-2H-哌喃(0.493克,5.86毫莫耳)溶於四氫呋喃(20毫升)中。添加TFA(3.34毫克,0.029毫莫耳),並將所形成之溶液加熱至70℃,歷經16小時。使反應混合物冷卻至室溫,以醋酸乙酯稀釋,過濾,及倒入含有水與醋酸乙酯之分液漏斗中。使有機層在減壓下濃縮。急驟式層析(0-60%醋酸乙酯在己烷中),獲得所要之產物,為白色固體(0.40克,1.23毫莫耳,42%產率)。MS(ESI)m/z 325.1[M+2]+。
D. (順式)-4-甲氧基環己胺鹽酸鹽. 在氮大氣下,於圓底燒瓶中,添加(順式)-4-羥基環己基胺基甲酸第三-丁酯(7.8克,36.2毫莫耳),並懸浮於無水四氫呋喃(181.0毫升)中,且冷卻至0℃。然後添加氫化鈉(2.174克,54.3毫莫耳),並將所形成之溶液攪拌5分鐘。在氮大氣下,於第二個燒瓶中,添加碘化甲烷(2.265毫升,36.2毫莫耳),且懸浮於無水四氫呋喃(10.0毫升)中。將四氫呋喃中之碘化甲烷溶液慢慢逐滴添加至第一個燒瓶中,歷經3分鐘。將反應物在室溫下攪拌16小時。在減壓下移除有機揮發性物質,並於醋酸乙酯(3X)與水之間作分液處理。匯集有機離份,以硫酸鎂脫水乾燥,過濾,及在減壓下濃縮。使所形成之物質藉矽膠管柱層析純化(25-50%醋酸乙酯在己烷中)。合併所要之溶離份,且在減壓下移除有機揮發性物質,接著添加鹽酸(4M,在1,4-二氧陸圜中,23.5毫升)。將所形成之溶液加熱至40℃,歷經1小時,並在減壓下移除有機揮發性物質,而得標題化合物(6.0克,36.2毫莫耳,100%產率)。MS(ESI)m/z 130.1[M+1]+。
E. 6-溴基-4-((順式)-4-甲氧基環己基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 於N-(3,5-二溴基吡-2-基)-2-碘乙醯胺(參閱實例5.B)(1.0克,2.376毫莫耳)與二異丙基乙胺(1.038毫升,5.94毫莫耳)在乙腈(10毫升)中之溶液內,添加(順式)-4-甲氧基環己胺鹽酸鹽(0.413克,2.495毫莫耳)。將溶液在55℃下攪拌3小時。過濾所形成之沉澱物,並
以乙腈洗滌,且於減壓下乾燥,而得標題化合物(0.442克,1.29毫莫耳,55%產率)。MS(ESI)m/z 341.3[M]+,343.3[M+2]+。
F. 4-((順式)-4-甲氧基環己基)-6-(三甲基錫烷基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將6-溴基-4-((順式)-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(0.442克,1.295毫莫耳)、肆(三苯膦)鈀(0.225克,0.194毫莫耳)及六甲基二錫(0.322毫升,1.554毫莫耳)在二氧陸圜(5毫升)中合併。將溶液以氮氣滌氣,並在經螺帽加蓋之管件中加熱至90℃,歷經3小時。使溶液在減壓下濃縮,及使用Biotage管柱層析純化(0-50%醋酸乙酯在己烷中),而得標題化合物(0.356克,0.837毫莫耳,65%產率)。MS(ESI)m/z 426.5[M+1]+,427.5[M+1]+。
G. 4-((順式)-4-甲氧基環己基)-6-(2-甲基-6-(4-(四氫-2H-哌喃-2-基)-4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將4-((順式)-4-甲氧基環己基)-6-(三甲基錫烷基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(0.292克,0.687毫莫耳)、3-溴基-2-甲基-6-(1-(四氫-2H-哌喃-2-基)-1H-1,2,4-三唑-3-基)吡啶(0.244克,0.756毫莫耳)、參(二苯亞甲基丙酮)二鈀(0.063克,0.069毫莫耳)、三-鄰-甲苯基膦(0.042克,0.137毫莫耳)、三乙胺(0.287毫升,2.061毫莫耳)及二甲基甲醯胺(5.0毫升)在經螺帽加蓋之燒瓶中合併,且加熱至95℃,歷經1小時。使溶液在減壓下濃縮,及使用Biotage層析純化(己烷中之0-80%醋酸乙酯,接著為醋酸乙酯中之0-10%甲醇),而得標題化合物(0.279克,0.687毫莫耳,80%產率)。MS(ESI)m/z 505.6[M+1]+。
H. 4-((順式)-4-甲氧基環己基)-6-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將4-((順式)-4-甲氧基環己基)-6-(2-甲基-6-(4-(四氫-2H-哌喃-2-基)-4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(0.279克,0.553毫莫耳)以乙醇(15毫升)與氯化氫(4.0N,在二氧陸圜中,5毫升)稀釋。將
溶液在75℃下攪拌1小時,並於80℃下2小時。使溶液濃縮成漿液,且以乙醇稀釋,及音振。過濾沉澱物,並以另外之乙醇,接著以乙腈洗滌。將粗製固體使用逆相半製備型HPLC純化(10-100%乙腈+水中之0.1% TFA+0.1% TFA,歷經30分鐘),而得標題化合物(0.040克,0.095毫莫耳,17%產率)。1H NMR(400MHz,甲醇-d4)δ(ppm)7.88-8.13(m,2H),7.65(s,1H),4.58(s,1H),4.16(s,2H),3.47(寬廣s.,1H),3.22-3.32(m,66H),2.73(s,3H),2.08(寬廣s.,2H),1.91(寬廣s.,2H),1.56(寬廣s.,4H);MS(ESI)m/z 421.2[M+1]+;熔點192-195℃。
實例14:1-異丙基-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡
并[2,3-b]吡
-2(1H)-酮
A. 1-異丙基-7-(三甲基錫烷基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將7-溴基-1-異丙基-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(參閱實例7.B)(0.5克,1.844毫莫耳)、六甲基二錫(0.725克,2.213毫莫耳)、肆(三苯膦)鈀(0)(0.213克,0.184毫莫耳)及1,4-二氧陸圜(3毫升)在具有攪拌棒之可密封容器中合併。使氮氣起泡經過此溶液。將容器密封,激烈攪拌,並在100℃下加熱2小時。將所形成之混濁黑色混合物以醋酸乙酯稀釋,過濾,且以醋酸乙酯充分地洗滌濾餅。使濾液在減壓下濃縮,及使用矽膠急驟式管柱層析純化(20-80%醋酸乙酯在己烷中),而得所要之產物(2.410克,77%產率),為黃白色固體。MS(ESI)m/z 357.4[M+2]+
B. 1-異丙基-7-(2-甲基-6-(4-(四氫-2H-哌喃-2-基)-4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 於燒瓶中,添加3-溴基-2-甲基-6-(1-(四氫-2H-哌喃-2-基)-1H-1,2,4-三唑-3-基)吡啶
(0.446克,1.380毫莫耳)、1-異丙基-7-(三甲基錫烷基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(0.490克,1.380毫莫耳)、參(二苯亞甲基丙酮)二鈀(0)(0.139克,0.152毫莫耳)、三-鄰-甲苯基膦(0.092克,0.304毫莫耳)、三乙胺(0.577毫升,4.14毫莫耳)及N,N-二甲基甲醯胺(3毫升)。使氮氣起泡經過反應混合物,歷經5分鐘,並將混合物加熱至100℃,歷經1小時。於冷卻至室溫後,使反應混合物經過矽藻土過濾,以甲醇沖洗,及濃縮至乾涸。使所形成之殘留物藉由矽膠急驟式管柱層析純化(己烷中之0-80%醋酸乙酯,接著為二氯甲烷中之0-10%甲醇),而產生所要之產物(0.40克,0.921毫莫耳,66.7%產率)。MS(ESI)m/z 435.5[M+1]+。
C. 1-異丙基-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 於1-異丙基-7-(2-甲基-6-(4-(四氫-2H-哌喃-2-基)-4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(0.400克,0.921毫莫耳)在乙醇(40毫升)中之經攪拌混合物內,在50℃下,添加氯化氫(4M,在二氧陸圜中,1.381毫升,5.52毫莫耳)。將所形成之混合物在50℃及氮氣下加熱1小時。使此懸浮液在減壓下濃縮,並使所形成之固體溶於二甲亞碸中,且使用矽膠層析純化(0-10%經氨飽和之甲醇在二氯甲烷中),而得標題化合物(0.200克,0.571毫莫耳,62.0%產率),為褐紅色固體。1H NMR(400MHz,DMSO-d6)δ(ppm)8.10(寬廣s.,1H),8.01(寬廣s.,2H),7.92(s,1H),5.26(五重峰,J=6.93Hz,1H),4.14(s,2H),3.58(d,J=5.08Hz,3H),1.47(d,J=6.64Hz,6H);MS(ESI)m/z 351.5[M+1]+。
D. 1-異丙基-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮(替代途徑). 將7-溴基-1-異丙基-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(1當量)、雙(品吶可基)二硼)(1當量)、醋酸鉀(3當量)及雙(1,1'-雙(二苯基膦基)二環戊二烯鐵)鈀(0.01當量)在二
氧陸圜中合併,以氮脫氣,並於氮氣下加熱至95℃。以醋酸乙酯稀釋,經過矽藻土過濾,濃縮,以醋酸乙酯與己烷研製,過濾,及乾燥,獲得二羥基硼烷酯,60%產率。將3-(5-溴基-6-甲基吡啶-2-基)-1H-1,2,4-三唑-1-羧酸第三-丁酯(1當量)、1-異丙基-7-(4,4,5,5-四甲基-1,3,2-二氧硼伍圜-2-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(1.2當量)、肆(三苯膦)鈀(0)(0.05當量)、碳酸鈉(3當量)在(3:1)二甲基乙醯胺與水中合併。使混合物脫氣,並加熱至100℃過夜。標準醋酸乙酯/水處理,且在醋酸乙酯中之後續研製,獲得所要之產物,41%產率。
實例15:7-(1H-吡咯并[2,3-b]吡啶-5-基)-1-(2-(四氫-2h-哌喃-4-基)乙基)-3,4-二氫吡
并[2,3-b]吡
-2(1H)-酮
A. 2-(5-溴基-3-(2-(四氫-2H-哌喃-4-基)乙胺基)吡 -2-基胺基)醋酸乙酯. 將2-(3,5-二溴基吡-2-基胺基)醋酸乙酯(參閱實例6.B)(1.0克,2.95毫莫耳)與2-(四氫-2H-哌喃-4-基)乙胺(0.381克,2.95毫莫耳)置於微波小玻瓶中,添加二甲亞碸(2毫升),並將所形成之混合物在Biotage Emrys Optimizer微波反應器中於150℃下加熱3600秒。將粗製反應混合物使用矽膠層析純化(33%醋酸乙酯在己烷中),產生標題化合物(0.5克,1.3毫莫耳,44%產率)。MS(ESI)m/z 387.1[M]+,389.1[M+2]+。
B. 7-溴基-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將2-(5-溴基-3-(2-(四氫-2H-哌喃-4-基)乙胺基)吡-2-基胺基)醋酸乙酯(0.5克,1.291毫莫耳)與鹽酸(6M,在水中,0.215毫升,1.291毫莫耳)在乙醇(2毫升)中合併,並將所形成之混合物
在Biotage Emrys Optimizer微波反應器中於100℃下加熱2400秒。使反應混合物濃縮,及使用矽膠層析純化(33%醋酸乙酯在己烷中),產生標題化合物(定量產率)。MS(ESI)m/z 341.1[M]+,343.1[M+2]+。
C. 1-(2-(四氫-2H-哌喃-4-基)乙基)-7-(三甲基錫烷基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將7-溴基-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(0.4克,1.29毫莫耳)、六甲基二錫(0.57克,1.75毫莫耳)及肆(三苯膦)鈀(0)(0.2克,0.176毫莫耳)置於具有1,4-二氧陸圜(5毫升)之密封管中。將燒瓶以氮抽氣,沖洗,密封,並於110℃下加熱1小時。使反應混合物冷卻至室溫,且經過矽藻土過濾,以醋酸乙酯洗滌。使濾液濃縮,並與小體積之溶劑混合物(50%己烷在醋酸乙酯中)一起音振,及藉過濾單離,產生標題化合物(0.34克,0.8毫莫耳,54.6%產率)。MS(ESI)m/z 427[M+2]+。
D. 7-(1H-吡咯并[2,3-b]吡啶-5-基)-1-(2-(四氫-2H-哌喃-4-基)乙基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將1-(2-(四氫-2H-哌喃-4-基)乙基)-7-(三甲基錫烷基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(1.0克,2.352毫莫耳)、5-溴基-1H-吡咯并[2,3-b]吡啶(0.556克,2.82毫莫耳)、參(二苯亞甲基丙酮)鈀(0)(0.237克,0.259毫莫耳)、三-鄰-甲苯基膦(0.158克,0.518毫莫耳)及三乙胺(0.984毫升,7.06毫莫耳)在密封管中合併,添加二甲基甲醯胺(5毫升)。於真空下移除容器中之大氣,並被氮氣置換。將反應物加熱至100℃,歷經1小時。於冷卻至室溫後,使反應混合物經過矽藻土過濾。將濾餅以醋酸乙酯洗滌。合併洗液與濾液,及幾乎濃縮至乾涸。使所形成之固體溶於熱甲醇中,經過矽藻土過濾,並藉由逆相製備型HPLC純化(5-80%乙腈+水中之0.1% TFA+0.1% TFA,歷經30分鐘)。收集純淨溶離份,以氫氧化銨中和,及濃縮至乾涸。過濾所獲得之固體,以水洗滌,並在高真空下乾燥,產生標題化合物(0.10克,0.264毫莫耳,11.2%產率)。1H NMR(400MHz,
DMSO-d6)δ(ppm)11.71(寬廣s.,1H),8.81(s,1H),8.44(s,1H),8.26(s,1H),7.49(d,J=10.54Hz,2H),6.48(寬廣s.,1H),4.18(s,2H),4.13(t,J=6.44Hz,2H),3.82(d,J=12.89Hz,2H),3.27(t,J=11.13Hz,2H),1.71(d,J=12.49Hz,2H),1.60(寬廣s.,3H),1.24(d,2H);MS(ESI)m/z 379.2[M+1]+;熔點255-258℃
實例16:6-(6-(2-羥丙-2-基)吡啶-3-基)-4-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡
并[2,3-b]吡
-2(1H)-酮
A. 6-溴基-4-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將N-(3,5-二溴基吡-2-基)-2-碘乙醯胺(參閱實例5.B)(8.0克,19.01毫莫耳)、(四氫-2H-哌喃-4-基)甲胺(2.63克,22.81毫莫耳)及二異丙基乙胺(6.64毫升,38.0毫莫耳)置於250毫升圓底燒瓶中,懸浮於乙腈(80.0毫升)中,並加熱至40℃,歷經16小時。過濾所形成之白色沉澱物,以乙腈,接著以己烷洗滌,及在真空下乾燥,而得標題化合物(4.89克,14.95毫莫耳,79%產率)。MS(ESI)m/z 327.4[M]+,329.5[M+2]+。
B. 6-(6-(2-羥丙-2-基)吡啶-3-基)-4-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將6-溴基-4-((四氫-2H-哌喃-4-基)甲基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(35.98克,110毫莫耳)、2-(5-(三甲基錫烷基)吡啶-2-基)丙-2-醇(參閱實例5.E)(33.0克,110毫莫耳)及與二氯甲烷之[1,1'-雙(二苯基-膦基)二環戊二烯鐵]二氯-鈀(II)複合物(1:1)(8.05克,11.00毫莫耳)在密封管中合併,且懸浮於N,N-二甲基甲醯胺(288毫升)中。然後,將反應物加熱至125℃,歷經2小時。使反應物稍微地冷卻,並趁仍然溫熱時傾倒至矽膠管柱上,及使用
Biotage SP1純化(0-100%(5%甲醇在醋酸乙酯中)在己烷中)。合併所要之溶離份,且在減壓下移除有機揮發性物質。將殘留物以己烷中之20%醋酸乙酯研製,接著為以變性乙醇之數次洗滌。使微黃色固體在減壓下乾燥,而得所要之化合物(15.08克,39.3毫莫耳,35.8%產率)。1H NMR(400MHz,DMSO-d6)δ(ppm)11.32(s,1H),9.07(d,J=1.56Hz,1H),8.29(dd,J=8.59,2.34Hz,1H),8.05(s,1H),7.72(d,J=8.20Hz,1H),5.26(s,1H),4.21(s,2H),3.83(d,J=2.73Hz,2H),3.51(d,J=7.42Hz,2H),3.27(t,J=11.32Hz,2H),2.09(寬廣s.,1H),1.61(d,J=11.3Hz,2H),1.46(s,6H),1.24-1.38(m,2H);MS(ESI)m/z 384.2[M+1]+;熔點268-269℃。
實例17:7-(6-(2-羥丙-2-基)吡啶-3-基)-1-(2-甲氧基乙基)-3,4-二氫吡
并[2,3-b]吡
-2(1H)-酮
A. 7-溴基-1-(2-甲氧基乙基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 使2-(3,5-二溴基吡-2-基胺基)醋酸乙酯(參閱實例1.C)(1當量)、2-甲氧基乙胺(1當量)、二異丙基乙胺(3當量)懸浮於二甲亞碸中,並在Emrys Biotage微波反應器中於150℃下加熱1小時。標準醋酸乙酯/水處理係獲得粗製物質,使其懸浮於99.7%醋酸中。將反應物密封,加熱至120℃,並將其攪拌2小時。將反應物在醋酸乙酯中萃取。匯集有機層,且以飽和碳酸氫鈉,接著以鹽水洗滌,並以硫酸鎂脫水乾燥。濃縮及急驟式管柱層析(0-100%醋酸乙酯在己烷中),獲得所要之產物,27%產率,歷經兩個步驟。MS(ESI)m/z 287.4[M]+,289.4[M+2]+。
B. 7-(6-(2-羥丙-2-基)吡啶-3-基)-1-(2-甲氧基乙基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 使7-溴基-1-(2-甲氧基乙基)-3,4-二氫吡
并[2,3-b]吡-2(1H)-酮(1當量)、2-(5-(三甲基錫烷基)吡啶-2-基)丙-2-醇(參閱實例5.E)(1當量)及二氯雙(三苯膦)-鈀(II)(0.2當量)懸浮於二甲基甲醯胺中。將反應物以氮滌氣,並加熱至140℃,歷經2小時。使反應物冷卻至室溫,經過矽藻土過濾,且以醋酸乙酯洗滌。在減壓下移除揮發性物質,及將所形成之紫色漿液使用矽膠管柱層析純化(0-100%(5%甲醇在醋酸乙酯中)在己烷中)。合併所要之溶離份,且在減壓下移除有機揮發性物質。將固體在己烷中之5%醋酸乙酯內研製,並以己烷洗滌,而得所要之產物,38%產率。1H NMR(400MHz,DMSO-d6)δ(ppm)9.02(d,J=1.6Hz,1H),8.27(s,1H),8.24(dd,J=8.6,2.3Hz,1H),7.71(d,J=0.8Hz,1H),7.69(s,1H),5.25(s,1H),4.28(t,J=6.2Hz,2H),4.20(d,2H),3.60(t,J=6.2Hz,2H),3.26(s,3H),1.46(s,6H);MS(ESI)m/z 344.3[M+1]+。
實例18:7-(1H-吡咯并[2,3-b]吡啶-4-基)-1-[2-(四氫-哌喃-4-基)-乙基]-3,4-二氫-1H-吡
并[2,3-b]吡
-2-酮
A. 7-(1H-吡咯并[2,3-b]吡啶-4-基)-1-[2-(四氫-哌喃-4-基)-乙基]-3,4-二氫-1H-吡 并[2,3-b]吡 -2-酮. 將1-(2-(四氫-2H-哌喃-4-基)乙基)-7-(三甲基錫烷基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(參閱實例15.C)(1當量)、4-溴基-吡咯并[2,3-b]吡啶-1-羧酸第三-丁酯(1當量)、參(二苯亞甲基丙酮)鈀(0.13當量)、三-鄰-甲苯基膦(0.25當量)及三乙胺(2.8當量)在無水二氧陸圜中混合物滌氣,脫氣2分鐘,並於95℃及氮氣下攪拌3-4小時。在藉TLC顯示反應完成時,於減壓下移除揮發性物質,且將殘留物藉管柱層析純化,而得所要之產物,35%產率。
MS(ESI)m/z 479.7[M+1]+。將4-(7-酮基-8-(2-(四氫-2H-哌喃-4-基)乙基)-5,6,7,8-四氫吡并[2,3-b]吡-2-基)-1H-吡咯并[2,3-b]吡啶-1-羧酸第三-丁酯,在甲醇性鹽酸鹽溶液中,於室溫下攪拌。在藉TLC顯示反應完成時,於減壓下移除溶劑,並使殘留物於矽膠上純化,而得標題化合物,63%產率。1H NMR(DMSO-d6,400MHz)δ(ppm)11.72(s,1H),8.38(s,1H),8.25(d,J=4.8Hz,1H),7.79(s,1H),7.53-7.51(m,2H),6.97(q,J=1.6Hz,1H),4.23(s,2H),4.14(t,J=7.6Hz,2H),3.81(dd,J1=2.4Hz,J2=11.2Hz,2H),3.25(d,J=10.8Hz,2H),1.67(d,J=13.2Hz,2H),1.61(m,3H),1.22(m,2H);MS(ESI):m/z 379.2[M+1]+。
實例19:1-(2-甲氧基乙基)-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡
并[2,3-b]吡
-2(1H)-酮
A. 1-(2-甲氧基乙基)-7-(三甲基錫烷基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將7-溴基-1-(2-甲氧基乙基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(參閱實例17.A)(0.5克,1.741毫莫耳)、1,1,1,2,2,2-六甲基二錫烷(0.856克,2.61毫莫耳)及肆(三苯膦)鈀(0)(0.201克,0.174毫莫耳)在1,4-二氧陸圜(20毫升)中合併,且於140℃下加熱2小時。使所形成之混合物冷卻至室溫,以醋酸乙酯稀釋,並經過矽藻土過濾。使濾液在減壓下濃縮。急驟式層析(0-30%醋酸乙酯在己烷中),獲得所要之產物,為透明油(0.5克,1.34毫莫耳,77%產率)。MS(ESI)m/z 373.0[M+2]+。
B. 1-(2-甲氧基乙基)-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 將1-(2-甲氧基乙基)-7-(三甲基錫烷基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(0.5克,1.348毫莫
耳)、3-溴基-2-甲基-6-(1-(四氫-2H-哌喃-2-基)-1H-1,2,4-三唑-3-基)吡啶(0.436克,1.348毫莫耳)、參(二苯亞甲基丙酮)二鈀(0)(0.123克,0.135毫莫耳)、三-鄰-甲苯基膦(0.082克,0.270毫莫耳)、三乙胺(0.584毫升,4.04毫莫耳)及N,N-二甲基甲醯胺(10毫升)在75毫升可密封燒瓶中合併,將燒瓶中之大氣移除,並被氮置換。將混合物在130℃下攪拌3小時。使所形成之混合物冷卻至室溫,且過濾。使有機層在減壓下濃縮。將所形成之殘留物以甲醇與二甲亞碸稀釋,過濾,及使用逆相製備型HPLC純化(10-30%乙腈+水中之0.1% TFA+0.1% TFA,歷經30分鐘)。使含有純淨產物之溶離份通過Phenomenex Strata-X-C固相萃取管柱。將管柱以水、乙腈、甲醇及甲醇中之5%氫氧化銨連續洗滌。使產物以甲醇中之5%氫氧化銨溶離劑溶離,並在減壓下濃縮。將殘留物以己烷中之乙醚研製,以製成微細粉末,及在真空下於50℃下乾燥,而得所要之產物(0.05克,0.136毫莫耳,10%產率),為白色固體。1H NMR(400MHz,DMSO-d6)δ(ppm)8.10(寬廣s.,1H),7.98(寬廣s.,1H),7.94(s,1H),7.73(寬廣s.,1H),4.13-4.28(m,4H),3.55(t,J=6.25Hz,2H),3.24(s,3H),2.70(寬廣s.,3H);MS(ESI)m/z 367.2[M+1]+。
實例20:6-(4-(4H-1,2,4-三唑-3-基)苯基)-4-乙基-3,4-二氫吡
并[2,3-b]吡
-2(1H)-酮鹽酸鹽
A. 6-溴基-4-乙基-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮. 於2-溴-N-(3,5-二溴基吡-2-基)乙醯胺(參閱實例4.A)(1當量)與二異丙基乙胺(3當量)在乙腈中之溶液內,添加乙胺鹽酸鹽(1.05當量)。將溶液加熱至70℃,歷經30分鐘。使溶液在減壓下濃縮,並使用管柱層析純化(0-75%醋酸乙酯在己烷中),而得標題化合物,36%產率。MS(ESI)
m/z 257.5[M]+,259.4[M+2]+。
B. 4-乙基-6-(4-(4-(四氫-2H-哌喃-2-基)-4H-1,2,4-三唑-3-基)苯基)-3,4-二氫-吡 并[2,3-b]吡 -2(1H)-酮. 將6-溴基-4-乙基-3,4-二氫吡并[2,3-b]吡-2(1H)-酮(1.1當量)、4-(四氫-2H-哌喃-2-基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼伍圜-2-基)苯基)-4H-1,2,4-三唑(1當量)及二氯[1,1'-雙(二苯基膦基)二環戊二烯鐵]鈀(II)二氯甲烷(0.05當量)在1,4-二氧陸圜中合併,接著添加水中之碳酸鈉(3當量)。將溶液在Biotage Emrys Optimizer微波反應器中加熱至120℃,歷經30分鐘。使溶液在減壓下濃縮,並使用管柱層析純化(0-10%甲醇在醋酸乙酯中),而得標題化合物,45%產率。MS(ESI)m/z 406.6[M+1]+。
C. 6-(4-(4H-1,2,4-三唑-3-基)苯基)-4-乙基-3,4-二氫吡 并[2,3-b]吡 -2(1H)-酮鹽酸鹽. 將乙醇中之4-乙基-6-(4-(4-(四氫-2H-哌喃-2-基)-4H-1,2,4-三唑-3-基)苯基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮,以2N氯化氫,在二氧陸圜中處理。將溶液在75℃下攪拌1小時。使溶液部份濃縮,並冷卻。將冷乙醇添加至漿液中,且過濾所形成之沉澱物,及以另外之冷乙醇,接著以己烷洗滌,而得標題化合物,為其鹽酸鹽,82%產率。1H NMR(400MHz,甲醇-d4)δ(ppm)9.18(s,1H),8.22(d,J=8.59Hz,2H),8.04-8.09(m,3H),7.66-7.74(m,1H),7.58-7.64(m,1H),4.24(s,2H),3.74(q,J=7.03Hz,2H),1.29(t,J=7.03Hz,4H),0.79-0.98(m,4H);MS(ESI)m/z 322.2[M+1]+。
製成下列結構單位,且使用於如本文中所述之製備或其此項技藝中已知之變型。
4-溴基-1H-吡咯并[2,3-b]吡啶-1-羧酸第三-丁酯
A. 4-溴基-1H-吡咯并[2,3-b]吡啶. 於0℃下,將三氟甲基磺酸酐(9.3克,33毫莫耳)溶液逐滴添加至1H-吡咯并[2,3-b]吡啶7-氧化物(3克,22毫莫耳)與四丁基溴化銨(10.8克,33毫莫耳)在N,N-二甲基甲醯胺(30毫升)中之混合物內。將所形成之混合物在0℃下攪拌4小時,並於室溫下過夜。以水使反應淬滅,且以1N氫氧化鈉中和至pH=7。將所形成之混合物以二氯甲烷與異-丙醇(30毫升,Vm:Vp=4:1)之混合物萃取兩次。合併有機層,以無水硫酸鈉脫水乾燥,濃縮,及藉由逆相製備型HPLC純化(0-30%:乙腈+水中之0.1% TFA+0.1% TFA,歷經15分鐘),而得標題化合物(1.5克,34.3%產率)。MS(ESI)m/z 196.8[M+1]+,198.8[M+3]+。
B. 4-溴基-1H-吡咯并[2,3-b]吡啶-1-羧酸第三-丁酯. 將4-溴基-1H-吡咯并[2,3-b]吡啶(250毫克,1.26毫莫耳)、二碳酸二-第三-丁酯(302毫克,1.38毫莫耳)、二甲基-吡啶-4-基-胺(7.6毫克,0.06毫莫耳)及三乙胺(127毫克,1.26毫莫耳)在無水二氯甲烷(15毫升)中之混合物,於室溫下攪拌3小時。在藉TLC顯示反應完成時,於減壓下移除揮發性物質,並使殘留物於矽膠上藉管柱層析純化(9-25%醋酸乙酯在石油醚中),而得所要之產物(230毫克,61%產率),為油狀物。MS(ESI)m/z 242.9[M-56+1]+
1-(四氫-2H-哌喃-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼伍圜-2-基)-1H-吲唑
A. 4-溴基-1H-吲唑. 在0℃下,於3-溴基-2-甲基苯胺(5克,27毫莫耳)在氯仿(1毫升)中之溶液內,添加醋酸酐(5克,27毫莫耳),並將混合物於室溫下攪拌1小時。添加醋酸鉀(0.75克,7.8毫莫耳)與亞硝酸異戊酯(0.78克,58毫莫耳),且使反應混合物回流18小時。在減壓下移除揮發性物質,並添加水(0.65毫升)。使混合物濃縮,以濃鹽酸鹽(1毫升)稀釋,且在50℃下加熱2小時。於冷卻至室溫後,添加氫氧化鈉水溶液(50%),直到pH=10為止。將含水混合物以醋酸乙酯(100毫升x3)萃取。以鹽水(150毫升)洗滌合併之有機層,以無水硫酸鈉脫水乾燥,過濾,蒸發,及在矽膠管柱上純化(3%醋酸乙酯在石油醚中),而得所要之產物(2.69克,34%產率),為固體。MS(ESI):m/z 197.0[M+1]+。
B. 4-溴基-1-(四氫-哌喃-2-基)-1H-吲唑. 將4-溴基-1H-吲唑(1.82克,9.24毫莫耳)、3,4-二氫-2H-哌喃(1.55克,18.48毫莫耳)及甲苯-4-磺酸(0.26克,1.39毫莫耳)在無水四氫呋喃(40毫升)中之溶液,於80℃及氮氣下加熱過夜。於減壓下移除溶劑,並使殘留物於矽膠管柱上純化(3%醋酸乙酯在石油醚中),而得標題化合物(2.13克,81%產率),為黃色固體。MS(ESI):m/z 280.9[M+1]+。
C. 1-(四氫-哌喃-2-基)-4-(4,4,5,5-四甲基-[1,3,2]二氧硼伍圜-2-基)-1H-吲唑. 將4-溴基-1-(四氫-哌喃-2-基)-1H-吲唑(2.13克,7.45毫莫耳)、雙(品吶可基)二硼(3.73克,14.9毫莫耳)、磷酸鉀(2.70克,12.67毫莫耳)、醋酸鈀(0.174克,0.75毫莫耳)及三苯膦(0.59克,2.24毫莫耳)在1,2-二甲氧基-乙烷(50毫升)中之經脫氣混合物,於100℃及氮氣下加熱過夜。在冷卻至室溫後,將反應混合物過濾,於減壓下濃縮,及在矽膠管柱上純化(10-30%醋酸乙酯在石油醚中),獲得產物(1.83克,74%產率),為固體。MS(ESI):m/z 329.2[M+1]+。
3-(4-溴基-2-氟基-3-甲基苯基)-4-(四氫-2h-哌喃-2-基)-4H-1,2,4-三唑
A. 4-溴基-3-氟基-2-甲基苯胺. 於3-氟基-2-甲基苯胺(25克,200毫莫耳)在醋酸(140毫升)中之經攪拌溶液內,在0-5℃下,添加溴化氫(100毫升,200毫莫耳),然後慢慢逐滴添加二甲亞碸(72毫升)(反應係為放熱,且在溫度高於5-15℃下,產生二溴基異構物)。將混合物在5-15℃下攪拌12小時(混合物變成透明溶液)。使所形成之溶液冷卻至0℃,並以氫氧化鈉,接著以碳酸氫鈉中和至pH 7。將混合物以醋酸乙酯萃取。使有機層在減壓下濃縮。急驟式層析(0-10%醋酸乙酯在己烷中),獲得所要之產物,為白色固體(23.3克,114毫莫耳,57%產率)。1H NMR(400MHz,氯仿-d)δ(ppm)7.11(t,J=8.20Hz,1H),6.35(d,J=8.98Hz,1H),3.72(寬廣s.,2H),2.07(d,J=1.95Hz,3H)。
B. 4-胺基-2-氟基-3-甲基苯甲腈. 將4-溴基-3-氟基-2-甲基苯胺(23克,113毫莫耳)與氰基銅(20.19克,225毫莫耳)、N,N-二甲基甲醯胺(200毫升)之混合物加熱至140℃,歷經7小時。使混合物冷卻至室溫後,過濾,並倒入含有水與醋酸乙酯(1:1)之分液漏斗中。分離液層,且使有機層在減壓下濃縮。急驟式層析(0-50%醋酸乙酯在己烷中),獲得所要之產物(11.4克,76毫莫耳,67%產率),為褐色固體。1H NMR(400MHz,氯仿-d)δ(ppm)7.22(t,1H),6.45(d,J=8.59Hz,1H),4.23(寬廣s.,2H),2.07(s,3H);MS(ESI)m/z 151.1[M+1]+。
C. 4-溴基-2-氟基-3-甲基苯甲腈. 將二甲亞碸(400毫升)與亞硝酸鉀(22.67克,266毫莫耳)之混合物攪拌,以使亞硝酸鉀溶解,並添加4-胺基-2-氟基-3-甲基苯甲腈(10克,66.6毫莫耳)與溴化銅(I)(1.911克,13.32毫莫耳)。逐滴添加經二甲亞碸(200毫升)稀釋之48%溴化氫水溶液(33毫升,266毫莫耳),並將反應物攪拌2小時。在起始物質之完全轉
化後,將反應混合物倒入冰-冷水中,且以冷濃氫氧化鈉中和至pH 7。藉過濾收集所形成之固體,而得所要之產物(11.4克,53.3毫莫耳,80%產率),為白色固體。1H NMR(400MHz,氯仿-d)δ(ppm)7.47(d,J=9.37Hz,1H),7.33(t,1H),2.39(d,J=2.34Hz,3H)。
D. 4-溴基-2-氟基-3-甲基苯甲醯胺. 將4-溴基-2-氟基-3-甲基苯甲腈(11克,51.4毫莫耳)在TFA-硫酸(4:1,v/v)之100毫升混合物中,於40℃下攪拌16小時。在起始物質之完全轉化後,將反應混合物倒入冰-冷水中。濾出所形成之固體,並以水洗滌,且乾燥,而得所要之產物(11.24克,48.4毫莫耳,94%產率),為白色固體。MS(ESI)m/z 234.1[M+2]+。
E. 3-(4-溴基-2-氟基-3-甲基苯基)-1H-1,2,4-三唑. 將4-溴基-2-氟基-3-甲基苯甲醯胺(11克,47.4毫莫耳)與N,N-二甲基甲醯胺二甲基縮醛(60毫升)在具有攪拌棒之100毫升圓底燒瓶中合併,且在55℃下,於回流冷凝管下,在氮氣下加熱3小時。使所形成之混合物在減壓下濃縮,及在真空下乾燥,獲得黃色油,將其使用於下一步驟無需純化。在0℃下以醋酸(60毫升)稀釋殘留物,並逐滴添加肼單水合物(20毫升),且將其在室溫下攪拌5小時。在起始物質之完全轉化後,將反應混合物倒入冰-冷水中,並以冰冷濃氫氧化鈉中和至pH 7。將所形成之固體藉真空過濾收集。使固體溶於醋酸乙酯(400毫升)中,且攪拌15分鐘,過濾不溶性固體,使濾液以硫酸鎂脫水乾燥,過濾,於減壓下濃縮,及在真空下乾燥,獲得褐色純固體(4.3克,16.79毫莫耳,35%產率),將其使用於下一步驟無需純化。1H NMR(400MHz,氯仿-d)δ(ppm)8.12(s,1H),7.97(t,J=8.00Hz,1H),7.52(d,J=8.59Hz,1H),2.44(d,3H)。
F. 3-(4-溴基-2-氟基-3-甲基苯基)-4-(四氫-2H-哌喃-2-基)-4H-1,2,4-三唑. 將甲烷磺酸(0.090毫升,1.390毫莫耳)添加至3-(4-溴
基-2-氟基-3-甲基苯基)-1H-1,2,4-三唑(7.0克,27.3毫莫耳)與3,4-二氫-2H-哌喃(12.68毫升,139毫莫耳)在四氫呋喃(33毫升)中之經攪拌溶液內。將所形成之混合物在85℃下,於回流冷凝管下,在氮氣下攪拌20小時。以醋酸乙酯稀釋混合物,並以飽和碳酸氫鈉水溶液與鹽水洗滌。使有機層以硫酸鎂脫水乾燥,過濾,及在減壓下濃縮。將殘留物使用急驟式層析純化(20-30-50%醋酸乙酯在己烷中)。合併含有產物之溶離份,且在減壓下移除溶劑,而得所要之產物(8.8克,95%產率),為黃色固體。MS(ESI)m/z 340.0[M]+
3-(4-溴基-2-氟苯基)-4h-1,2,4-三唑
A. 4-溴基-2-氟基苯甲醯胺. 將4-溴基-2-氟基苯甲腈(10.0克,50.0毫莫耳)在TFA(56.0毫升,727毫莫耳)-硫酸(14.0毫升,263毫莫耳)(4:1 v/v)之70毫升混合物中之溶液,於40℃下攪拌16小時。趁仍然溫熱時,將反應物傾倒在冰水上。產物沉澱,並將固體過濾,且乾燥,獲得4-溴基-2-氟基苯甲醯胺(9.53克,43.7毫莫耳,87%產率),為白色固體。MS(ESI)m/z 218.1[M]+,220.1[M+2]+。
B. 3-(4-溴基-2-氟苯基)-4H-1,2,4-三唑. 將4-溴基-2-氟基苯甲醯胺(9.53克,43.7毫莫耳)與N,N-二甲基甲醯胺二甲基縮醛(75.0毫升)在500毫升圓底燒瓶中合併,且以氮滌氣。將反應物在85℃下加熱至回流,歷經2小時。使所形成之混合物在減壓下濃縮,及在真空下乾燥,而得黃色油。使此油懸浮於濃醋酸(75.0毫升)中,並冷卻至0℃。逐滴添加肼水合物(21.88克,437毫莫耳),且將混合物在室溫下攪拌5小時。將反應物溫熱傾倒至冷冰上,並以二氯甲烷(3x200毫升)萃取。在減壓下移除有機揮發性物質,而得3-(4-溴基-2-氟苯基)-4H-1,2,4-三唑(7.20克,29.7毫莫耳,68.1%產率),為白色固體。MS(ESI)m/z 241.9[M]+,
243.9[M+2]+。
2-(4-甲基-5-(三甲基錫烷基)吡啶-2-基)丙-2-醇
A. 2-(5-溴基-4-甲基吡啶-2-基)丙-2-醇. 使2,5-二溴基-4-甲基吡啶(4.0克,15.94毫莫耳)溶於甲苯(60.0毫升)中,並使反應物冷卻至-78℃。逐滴添加丁基鋰(7.01毫升,17.54毫莫耳),且將反應物攪拌30分鐘。然後添加丙酮(4.69毫升,63.8毫莫耳),並使反應物溫熱至室溫,且攪拌16小時。以飽和氯化銨使反應淬滅,於醋酸乙酯(3x200毫升)中萃取,及以水,接著以鹽水洗滌。使有機物質以硫酸鎂脫水乾燥,並在減壓下移除揮發性物質。使化合物於矽膠層析上純化(0-50%醋酸乙酯在己烷中),而得2-(5-溴基-4-甲基吡啶-2-基)丙-2-醇(2.33克,10.13毫莫耳,63.5%產率)。MS(ESI)m/z 230.3[M]+,232.3[M+2]+。
B. 2-(4-甲基-5-(三甲基錫烷基)吡啶-2-基)丙-2-醇. 將2-(5-溴基-4-甲基吡啶-2-基)丙-2-醇(2.33克,10.13毫莫耳)與肆(三苯膦)鈀(0)(1.045克,1.013毫莫耳)添加至耐壓管中,並懸浮於1,4-二氧陸圜(33.8毫升)中。然後添加1,1,1,2,2,2-六甲基二錫烷(2.99毫升,12.15毫莫耳),且加熱至150℃,歷經30分鐘。使反應物冷卻至室溫,並經過矽藻土過濾,且以醋酸乙酯洗滌。在減壓下移除有機揮發性物質,接著,在醋酸乙酯(3x200毫升)與水中萃取。於減壓下移除有機揮發性物質,及將化合物於Biotage管柱上使用矽膠管柱層析純化(10-50%醋酸乙酯在己烷中),而得2-(4-甲基-5-(三甲基錫烷基)吡啶-2-基)丙-2-醇(1.75克,5.57毫莫耳,55.0%產率)。1H NMR(400MHz,DMSO-d6)δ(ppm)8.31(s,1H),7.51(s,1H),5.25(寬廣s.,1H),2.37(s,3H),1.41(s,6H),0.65(寬廣s.,3H),0.34(s,6H)。
3-(5-溴基-6-甲基吡啶-2-基)-1H-1,2,4-三唑-1-羧酸第三-丁酯
A. 5-溴基-6-甲基甲基吡啶腈. 於裝有機械攪拌器與氮氣入口管之1升三頸圓底燒瓶中,裝填3,6-二溴基-2-甲基吡啶(150克,0.59莫耳)、氰化銅(I)(42.8克,0.47莫耳)及氰化鈉(23克,0.47莫耳)。於混合物中,添加N,N-二甲基甲醯胺(300毫升)。將混合物加熱至95℃,並攪拌48小時。使反應混合物冷卻至環境溫度,且倒入乙醇(3升)中,同時攪拌。經過矽藻土墊過濾混合物,使濾液在減壓下濃縮,並在水(3升)與醋酸乙酯(3升)之間進行分液處理。分離有機層,且以鹽水(2 x 600毫升)洗滌,以無水硫酸鈉脫水乾燥,過濾,及濃縮。使粗產物藉由矽膠填充柱純化法純化(0-5%醋酸乙酯在己烷中),而得產物(61.5克,45%產率),為白色固體。此外,單離19.32克(14%)起始物質與產物之混合物。
B. 5-溴基-6-甲基甲基吡啶基腙醯胺. 於500毫升三頸圓底燒瓶中,裝有5-溴基-6-甲基甲基吡啶腈(101.5克,0.515莫耳)、乙醇(122毫升)及肼水合物(50毫升,1.03莫耳)。將所形成之極濃稠混合物於環境溫度下攪拌24小時。添加更多乙醇(50毫升),並將混合物攪拌度過週末。過濾混合物,且以冷乙醇(100毫升)與冷己烷(50毫升)洗滌。使固體在真空烘箱中乾燥,而得產物(110克,93%產率),為灰白色固體。
C. 3-溴基-2-甲基-6-(1H-1,2,4-三唑-3-基)吡啶. 將500毫升三頸圓底燒瓶裝上機械攪拌器、經連接至J-KEM溫度控制器之熱電偶及回流冷凝管。於燒瓶中,裝填5-溴基-6-甲基甲基吡啶基腙醯胺(100克,0.463莫耳)與甲酸(250毫升)。將所形成之溶液加熱至100℃,並攪拌48小時。在減壓下移除甲酸,且將所形成之漿液以水(1.5升)處理,同時激烈攪拌。過濾混合物,並以水(300毫升)洗滌。將固體轉移至圓底燒
瓶中,且以水(1升)與1M氫氧化鈉溶液處理,直到pH 7為止。將混合物攪拌30分鐘,過濾,以水(300毫升)洗滌,並在真空烘箱中於30-35℃下乾燥48小時,而得產物(96克,92%產率),為白色固體。
D. 3-溴基-2-甲基-6-(1-(四氫-2H-哌喃-2-基)-1H-1,2,4-三唑-3-基)吡啶. 於3-溴基-2-甲基-6-(1H-1,2,4-三唑-3-基)吡啶(96.0克,0.4莫耳)在四氫呋喃(780毫升)中之懸浮液內,添加3,4-二氫-2H-哌喃(72.5毫升,0.8莫耳)與甲烷磺酸(3.2毫升)。將混合物加熱至65℃,並將所形成之黃色溶液在65℃下攪拌6小時。使混合物冷卻至環境溫度,以三乙胺(23毫升)使反應淬滅,在減壓下濃縮,及進一步於高真空中乾燥1小時。使所形成之油溶於乙腈(250毫升)中,且將溶液添加至水(750毫升)中,同時激烈攪拌。添加更多乙腈(80毫升),並將混合物攪拌1小時。將所形成之固體過濾,以1:4乙腈/水(800毫升)洗滌,及在真空烘箱中乾燥48小時,而得產物(110克,85%產率),為白色固體。將產物進一步藉由矽膠填充柱純化法純化(1:1己烷/醋酸乙酯),獲得88克純產物,為白色固體,與16.2克較不純產物。MS(ESI)m/z 239.1[M]+,241.1[M+2]+。
E. 3-(5-溴基-6-甲基吡啶-2-基)-1H-1,2,4-三唑-1-羧酸第三-丁酯. 於3-溴基-2-甲基-6-(1H-1,2,4-三唑-3-基)吡啶(300克,1.25莫耳)在二氧陸圜(4升)中之混合物內,添加碳酸鈉(398克,3.75莫耳),接著為水(4升)。添加二碳酸二-第三-丁酯(274克,1.25莫耳),並將混合物在室溫下攪拌1小時。然後,將混合物以冷水(~10升)稀釋,且以醋酸乙酯(4升x 3)萃取。將合併之醋酸乙酯層以鹽水洗滌,以硫酸鈉脫水乾燥,過濾,及濃縮,而得產物(254克,60%產率),為微黃色固體。
4-(四氫-2H-哌喃-2-基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼伍圜-2-基)苯基)-4h-1,2,4-三唑
A. 4-溴基苯并醯亞胺酸乙酯鹽酸鹽. 使4-溴基苯甲腈(17.65克,97毫莫耳)在乙醇(500毫升)中之溶液,以氯化氫氣體,在0℃下酸化十五分鐘。將溶液攪拌16小時。使溶液在減壓下濃縮,而得標題化合物(25.35克,99%)。MS(ESI)m/z 228.1[M]+,230.4[M+2]+。
B. 3-(4-溴苯基)-4H-1,2,4-三唑. 將4-溴基苯并醯亞胺酸乙酯鹽酸鹽(35.6克,135毫莫耳)、甲酸醯肼(16.16克,269毫莫耳)及三乙胺(75毫升,538毫莫耳)在經螺帽加蓋之燒瓶中合併,且加熱至85℃,歷經16小時。使溶液在減壓下濃縮,而得固體,使其在水與醋酸乙酯(3X)之間作分液處理,以硫酸鎂脫水乾燥,並在減壓下移除溶劑。使所形成之固體與己烷中之20%醋酸乙酯一起音振,過濾,及乾燥,而得標題化合物(14.6克,65.2毫莫耳,48%產率)。MS(ESI)m/z 224.1[M]+,226.1[M+2]+。
C. 3-(4-溴苯基)-4-(四氫-2H-哌喃-2-基)-4H-1,2,4-三唑. 將3-(4-溴苯基)-4H-1,2,4-三唑(14.1克,62.9毫莫耳)、3,4-二氫-2H-哌喃(10.59毫莫耳)及甲烷磺酸(1.19克,6.29毫莫耳)在四氫呋喃(150毫升)中之溶液,於75℃下加熱2小時。使溶液濃縮,並於碳酸氫鈉溶液與醋酸乙酯(3X)之間作分液處理,使有機物質以硫酸鎂脫水乾燥,過濾,及在減壓下移除溶劑。將固體以己烷中之10%醋酸乙酯研製,而得標題化合物(8.1克,26.3毫莫耳,70%產率)。MS(ESI)m/z 308.4[M]+,310.5[M+2]+。
D. 4-(四氫-2H-哌喃-2-基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼伍圜-2-基)苯基)-4H-1,2,4-三唑. 將3-(4-溴苯基)-4-(四氫-2H-哌喃-2-基)-4H-1,2,4-三唑(8.1克,26.3毫莫耳)、雙(品吶可基)二硼(6.67克,26.3
毫莫耳)及醋酸鉀(10.32克,105毫莫耳)在二甲基甲醯胺(100毫升)中合併。將溶液以氮氣滌氣2分鐘。然後添加二氯[1,1'-雙(二苯基膦基)二環戊二烯鐵]鈀(II)二氯甲烷(1.07克,1.31毫莫耳),並將溶液加熱至100℃,歷經16小時。使溶液經過矽藻土過濾,及使濾液在減壓下濃縮,而得暗色油。使此油經由Biotage層析純化(0-70%醋酸乙酯在己烷中),於乾燥時,獲得固體。將固體以己烷稀釋,音振,過濾,並乾燥,而得標題化合物(7.1克,20.0毫莫耳,71%產率)。MS(ESI)m/z 356.5[M+1]+。
5-溴基-2-(1-(四氫-2H-哌喃-2-基)-1H-1,2,4-三唑-3-基)吡啶
A. (E)-5-溴-N-((二甲胺基)亞甲基)甲基吡啶醯胺. 將5-溴基甲基吡啶醯胺(0.500克,2.49毫莫耳)與二甲基甲醯胺二甲基縮醛(20毫升)之溶液加熱至85℃,歷經3小時。使反應物濃縮,並將產物直接使用於下一步驟(0.604克,95%產率)。MS(ESI)m/z 257.1[M+1]+。
B. 5-溴基-2-(1H-1,2,4-三唑-3-基)吡啶. 將(E)-5-溴-N-((二甲胺基)亞甲基)甲基吡啶醯胺(0.604毫克,2.36毫莫耳)與肼(2.12克,66.1毫莫耳)之溶液於25℃下攪拌3小時。使反應物濃縮,並以水稀釋。藉過濾收集所形成之沉澱物,及在真空下乾燥,而得標題化合物(0.442克,83%產率)。MS(ESI)m/z 226.1[M+1]+。
C. 5-溴基-2-(1-(四氫-2H-哌喃-2-基)-1H-1,2,4-三唑-3-基)吡啶. 將5-溴基-2-(1H-1,2,4-三唑-3-基)吡啶(0.342毫克,1.52毫莫耳)、3,4-二氫-2H-哌喃(0.256克,3.04毫莫耳)及4-甲苯磺酸(0.058克,0.30毫莫耳)在四氫呋喃中之溶液加熱至75℃,歷經6小時。使反應物濃縮,及使用Biotage管柱層析純化(0-20%甲醇在二氯甲烷中),以提供半純淨產
物,為油狀物(0.614克,1.9毫莫耳,>100%產率)。使用此物質而無需進一步純化。MS(ESI)m/z 309.4[M]+,311.1[M+2]+。
6-溴基-4-甲基-2-(甲胺基)-1H-苯并[d]咪唑-1-羧酸第三-丁酯
A. (6-溴基-4-甲基苯并咪唑-2-基)-N-甲胺. 於0℃下,將N,N-二甲基甲醯胺(1.0毫升)中之異硫氰基甲烷(0.055克,0.746毫莫耳)慢慢地逐滴添加至5-溴基-3-甲苯-1,2-二胺(0.150克,0.746毫莫耳)在N,N-二甲基甲醯胺(1.5毫升)中之經攪拌溶液內。移除冷浴,將反應混合物加蓋,並於室溫下攪拌48小時。添加N-(3-二甲胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽(0.157克,0.821毫莫耳),且將反應混合物加蓋,及在40℃下加熱過夜。將所形成之混合物以甲醇稀釋,過濾,並使用逆相製備型HPLC純化(10-50%乙腈+H2O中之0.1% TFA+0.1% TFA,歷經30分鐘)。將含有所要產物之溶離份合併,且在減壓下移除大部份溶劑。添加乙腈,並將所形成之混合物裝填在Strata離子交換管柱上。將管柱以水、乙腈、甲醇及甲醇中之5%氫氧化銨連續洗滌。使產物以甲醇中之5%氫氧化銨溶離,且於減壓下濃縮,及在高真空下乾燥,而得所要之產物(0.128克,0.53毫莫耳,72%產率),為微黃色蠟狀固體。MS(ESI)m/z 240[M]+,242[M+2]+。
B. 6-溴基-4-甲基-2-(甲胺基)-1H-苯并[d]咪唑-1-羧酸第三-丁酯. 將(6-溴基-4-甲基苯并咪唑-2-基)-N-甲胺(0.128克,0.533毫莫耳)、二異丙基乙胺(0.464毫升,2.67毫莫耳)、二碳酸二-第三-丁酯(0.349克,1.599毫莫耳)及N,N-二甲基甲醯胺(5毫升)在100毫升圓底燒瓶中合併,加蓋,並於室溫下攪拌21小時。使所形成之混合物於水與醋酸乙酯之間作分液處理。分離液層,且將有機物質以水與鹽水洗滌。使有
機物質以硫酸鎂脫水乾燥,過濾,在減壓下濃縮,及使用急驟式層析純化(10-30%醋酸乙酯在己烷中),而得所要之產物(0.092克,0.27毫莫耳,51%產率),為黃色蠟狀固體。MS(ESI)m/z 340[M]+,342[M+2]+。
6-溴基-4-甲基-2-(甲胺基)-1H-苯并[d]咪唑-1-羧酸第三-丁酯
A. 7-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼伍圜-2-基)-1H-苯并[d]咪唑-2-胺. 於室溫下,將3-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼伍圜-2-基)苯-1,2-二胺(參閱實例1.G)(500毫克,2.015毫莫耳)與溴化氰(0.484毫升,2.418毫莫耳)添加至圓底燒瓶中,懸浮於甲醇(10.0毫升)中,並將其攪拌1.5小時。在減壓下移除揮發性物質,接著添加飽和碳酸氫鈉。經由過濾收集沉澱物,以醋酸乙酯洗滌,及在減壓下乾燥,而得標題化合物(557毫克,2.039毫莫耳,定量產率)。使化合物繼續進行無需進一步純化或特徵鑒定。MS(ESI)m/z 273.8[M+1]+。
6-溴基-4-甲基-2-(甲胺基)-1H-苯并[d]咪唑-1-羧酸第三-丁酯
A. 6-溴基-4-甲基-1-(四氫-2H-哌喃-2-基)-1H-苯并[d]咪唑. 於室溫下,使6-溴基-4-甲基-1H-苯并[d]咪唑(1.02克,4.83毫莫耳)溶於四氫呋喃(10毫升)中,並在氮氣下攪拌。添加3,4-二氫-2H-哌喃(3.5毫升,38.4毫莫耳)與甲烷磺酸(0.032毫升,0.48毫莫耳),且將所形成之混合物在75℃下加熱49小時。使所形成之混合物冷卻至室溫,以醋酸乙酯稀釋,並以飽和碳酸氫鈉水溶液與鹽水洗滌。使有機物質以硫酸鎂脫水乾燥,過濾,及在減壓下濃縮。急驟式層析(50-100%醋酸乙酯在己烷中),獲得所要之產物(1.32克,4.47毫莫耳,93%產率),為淡黃色固
體。MS(ESI)m/z 295.1[M]+,297.3[M+2]+。
B. 4-甲基-1-(四氫-2H-哌喃-2-基)-6-(4,4,5,5-四甲基-1,3,2-二氧硼伍圜-2-基)-1H-苯并[d]咪唑. 將6-溴基-4-甲基-1-(四氫-2H-哌喃-2-基)-1H-苯并[d]咪唑(1.320克,4.47毫莫耳)、雙(品吶可基)二硼(1.192克,4.70毫莫耳)、與二氯甲烷之[1,1'-雙(二苯基膦基)二環戊二烯鐵]二氯鈀(II)複合物(1:1)(183毫克,0.22毫莫耳)、醋酸鉀(1.317克,13.4毫莫耳)及二甲亞碸(9毫升)在圓底燒瓶中合併,且攪拌。將燒瓶中之大氣於真空下移除,並被氮置換三次。將所形成之混合物在90℃及氮氣下加熱1.5小時。以醋酸乙酯稀釋所形成之混合物,且經過矽藻土過濾。以醋酸乙酯充分地洗滌濾餅。將濾液以水洗滌兩次,以鹽水一次,以硫酸鎂脫水乾燥,過濾,及在減壓下濃縮。急驟式層析(50-100%醋酸乙酯在己烷中),獲得所要之產物,~90%純度(1.31克,3.83毫莫耳,77%產率),為黃色黃褐色泡沫物-固體。MS(ESI)m/z 343.2[M+1]+。
mTOR HTR-FRET檢測. 下述為可用以測定待測化合物之mTOR抑制活性之檢測實例。使雜芳基化合物溶於DMSO中,並製成10mM儲備液,且經適當地稀釋以供實驗用。試劑係按下述製成:
"簡單TOR緩衝劑"(用以稀釋高甘油TOR分率):10mM Tris pH 7.4,100mM NaCl,0.1% Tween-20,1mM DTT。將Invitrogen mTOR(目錄#PR8683A)於此緩衝劑中稀釋至檢測濃度為0.200微克/毫升。
ATP/受質溶液:0.075mM ATP,12.5mM MnCl2,50mM Hepes,pH 7.4,50mMβ-GOP,250nM微胱胺酸LR,0.25mM EDTA,5mM DTT及3.5微克/毫升GST-p70S6。
偵測試劑溶液:50mM HEPES,pH 7.4,0.01% Triton X-100,0.01% BSA,0.1mM EDTA,12.7微克/毫升Cy5-αGST Amersham(目錄
#PA92002V),9毫微克/毫升α-磷醯基p70S6(Thr389)(細胞發出訊息老鼠單株#9206L),627毫微克/毫升α-老鼠Lance Eu(Perkin Elmer目錄#AD0077)。
於20微升簡單mTor緩衝劑中,添加DMSO中之0.5微升待測化合物。為引發此反應,故將5微升ATP/受質溶液添加至20微升簡單TOR緩衝溶液(對照組)中,及至上文所製成之化合物溶液中。此檢測係在60分鐘之後藉由添加5微升60mM EDTA溶液而停止;然後,添加10微升偵測試劑溶液,且在經設定以偵測LANCE Eu TR-FRET(在320毫微米下之激發及在495/520毫微米下之發射)之Perkin-Elmer Envision微板讀取器上讀取之前,使混合物靜置至少2小時。
PI3Kα與γ檢測. PI3Kα與γ檢測係使用Millipore PI3K檢測套件(目錄#33-017)中所述之程序進行。PI3Kα與γ酵素係得自Invitrogen(目錄#PV4788與PV4786)。
在此項檢測中,所選定之雜芳基化合物具有或預期具有IC50低於10μM,其中一些化合物具有IC50低於1μM,而其他具有IC50低於0.10μM。
DNA-PK檢測. DNA-PK檢測係使用Promega DNA-PK檢測套件(目錄#V7870)中所提供之程序進行。DNA-PK酵素係購自Promega(Promega目錄#V5811)。
在此項檢測中,所選定之雜芳基化合物具有或預期具有IC50低於10μM,其中一些化合物具有IC50低於1μM,而其他具有IC50低於0.10μM。
PC-3 p-S6與P-Akt MesoScale檢測. 下述為可用以測定待測化合物之抗癌活性之檢測實例。PC-3,一種前列腺腺癌細胞系(#CRL-1435),係被使用於pS6 Mesoscale檢測中。使細胞生長在經補充
10%牛胎兒血清與1%青霉素/鏈霉素之F-12 Kaighns'中。使用下列緩衝劑:完全Tris溶胞緩衝劑(關於10毫升用途:100微升磷酸酶抑制劑I(100X儲備液)、100微升磷酸酶抑制劑II(100X儲備液)、1片劑完全Mini(不含EDTA)、40微升PMSF,全部係充分地在室溫下混合5分鐘);1X Tris洗滌緩衝劑(關於250毫升用途:25毫升10X Tris洗滌緩衝劑、225毫升去離子水,儲存在室溫下);MSD阻斷溶液-A(關於20毫升用途:20毫升1X tris洗滌緩衝劑與600毫克MSD阻斷劑-A,儲存在冰上);抗體稀緩衝液(關於3毫升用途:1毫升阻斷溶液-A、1.82毫升1X tris洗滌緩衝劑、150微升2% MSD阻斷劑D-M、30微升10% MSD阻斷劑D-R,儲存在冰上)。
於第一天下午,將細胞在20,000個細胞/井下,於180微升體積中,覆蓋在96-井平底細胞培養板中。於第2天早晨,將待測化合物稀釋至所要之濃度,並添加至細胞中。將細胞在37℃,5% CO2下以化合物處理1小時。小心地移除培養基,並將50微升1X Tris溶胞緩衝劑添加至各井中,且於4℃下,將板放置在振盪器上,歷經1小時,以溶解細胞。使用得自各井之35微升溶胞產物,以檢測關於p-S6含量,使用關於MA6000磷醯基-S6RP(Ser235/236)全細胞溶胞產物套件#K110DFD-3之手冊中所述之擬案。溶胞產物係使用關於MA6000磷醯基-Akt(Ser4730)全細胞溶胞產物套件(#K111CAD-3)之手冊中所述之擬案,檢測關於p-Akt含量。將板在Sector成像器板讀取器上讀取。IC50值係計算自劑量回應曲線。
在此項檢測中,雜芳基化合物具有或預期具有IC50低於10μM,其中一些化合物具有IC50低於1μM,而其他具有IC50低於0.10μM。
Btk-PH、Akt-PH及FoxO-EGFP移位作用檢測. 下述為可用以測定待測化合物之抗癌活性之檢測實例。使BTK-PH_CHO細胞(Bioimage C007A)在經補充10%牛胎兒血清、1%青霉素/鏈霉素、0.5毫克/毫升基
因素及0.25% DMSO之Nut.MixF-12-Ham中生長。將細胞於每井12,000個細胞下,覆蓋在黑色壁透明底部96-井板中。在24小時培養之後,將細胞以細胞洗滌緩衝劑洗滌,並與細胞洗滌緩衝劑一起培養1小時。然後,在室溫下將細胞以對照/待測化合物與IGF-1(似胰島素生長因子-1)處理4分鐘。接著,將細胞固定,洗滌,及以Hoescht在含有0.5% Triton X-100之PBS中染色。將板密封,然後,於30分鐘後,在Cellomics上讀取。使Akt-PH_CHO細胞(Bioimage C006A)在如同BTK-PH_CHO細胞之相同培養基中生長。將細胞於每井10,000個細胞下,覆蓋在黑色透明底部96-井板中。擬案之其餘部份係與Btk-PH檢測(如上述)相同。
以FoxO-EGFP構造物安定地轉染之U-2 OS細胞系係為來自Gary Chiang,Burnham學會,La Jolla之贈品。使細胞在經補充10%牛胎兒血清與1%青霉素/鏈霉素之DMEM中生長。將細胞於每井20,000個細胞下,覆蓋在黑色透明底部96-井板中。在過夜培養之後,將細胞以對照/待測化合物處理,並培養2小時。將細胞固定,洗滌,及以Hoescht染色。然後,將板以PBS洗滌三次,接著,將100微升PBS添加至各井中。然後,將板以透明覆蓋片條覆蓋。於Cellomics上讀取板,且IC50值係相較於華特曼寧(wortmannin)計算而得。
在此項檢測中,所選定之雜芳基化合物具有或預期具有IC50低於30μM,其中一些化合物具有IC50低於1μM,而其他具有IC50低於0.10μM。
細胞增生檢測. 下述為可用以測定待測化合物之抗癌活性之檢測實例。此檢測係經由四銼鹽之還原成弗馬宗(formazon)鹽,以代謝活性之度量為基礎,用以定量細胞增生。WST-1(Roche目錄#11 644 807 001)係用以度量PC-3細胞之增生。將PC-3細胞於每井3000個細胞下,覆蓋在180微升生長培養基(經補充10%牛胎兒血清與1%青霉素/鏈霉素之F-12 Kaighns)中。經覆蓋之細胞係於5% CO2中,在37℃下培養過夜。
將化合物稀釋於得自10mM儲備溶液之DMSO中,然後至F-12 Kaighns培養基中。將包含DMSO對照組之20微升化合物稀釋液,以三份複製,添加至96-井板中之細胞內。將細胞與化合物在5% CO2中,於37℃下一起培養3天。將20微升WST-1添加至各井中。將板於5% CO2中,在37℃下培養兩小時。在Victor 2多標識板讀取器(Perkin Elmer)上,於450毫微米下讀取板。IC50值係相較於DMSO對照組計算而得。
在此項檢測中,雜芳基化合物具有或預期具有IC50低於30μM,其中一些化合物具有IC50低於lμM,而其他具有IC50低於0.10μM。
IL-2發炎檢測. 下述為可用以測定待測化合物之消炎活性之檢測實例。得自經刺激初生T細胞之IL-2生產係使用來自Mesoscale(MA6000#L41AHB-1)之IL-2套件檢測。將人類初生T細胞以化合物預處理30分鐘,然後,以抗人類CD3珠粒與抗CD28珠粒刺激24小時。於細胞處理之後,採集培養基。將25微升試樣或校正標準物添加至人類IL-2細胞活素Mesoscale檢測板中。將培養基培養1-2小時,並在室溫下振盪。以1XPBS將板洗滌三次。每井添加150微升2XMSD讀取緩衝劑T,且在Mesoscale Discovery Sector成像器板讀取器上分析板。
在此項檢測中,雜芳基化合物具有或預期具有IC50低於30μM,其中一些化合物具有IC50低於1μM,而其他具有IC50低於0.10μM。
延遲型過敏性(DTH)模式. 於第0天,使用3%唑酮,使CD-1老鼠敏化,塗敷在經刮毛之腹部上(激敏作用)。於第5天,將其右耳以1%唑酮塗敷,而其左耳係以媒劑(丙酮:橄欖油)(誘發)塗敷。化合物處理係於1%唑酮誘發步驟前一天開始。將化合物以經口方式、腹膜腔內方式或靜脈內方式投予,使用一次或兩次每日服藥,歷經研究期間。於第6天(誘發後24小時),未經處理動物之右耳係顯示發紅(紅斑)與腫脹(水腫)。經化合物處理動物之耳朵係於誘發後24、48及72小時度量。
在顯示DTH發展之右與左耳厚度間之差異,係藉由微測徑器度量法測得。
在此模式中,雜芳基化合物具有或預期具有ED50值<100毫克/公斤,其中一些化合物具有ED50<10毫克/公斤,而其他為ED50<1毫克/公斤。
異種移植物癌症模式.將人類癌細胞系注入SCID(嚴重合併之免疫不全)老鼠中。對於經保持在活體外之細胞,腫瘤係藉由準確地注射所測得數目之細胞至老鼠中而產生。關於最良好地於活體內繁殖之腫瘤,將得自供體老鼠之腫瘤碎片植入小數目之老鼠中,以供維持,或較大數目之老鼠,以供研究引發。典型功效研究設計係涉及投予一或多種化合物至帶有腫瘤之老鼠中。此外,參考化學治療劑(正對照組)與負對照組係以類似方式投藥與保持。投藥途徑可包括皮下(SC)、腹膜腔內(IP)、靜脈內(IV)、肌內(IM)及口腔(PO)。腫瘤度量與體重係於研究期間內採取,且記錄發病率與死亡率。驗屍、組織病理學、細菌學、寄生蟲學、血清學及PCR亦可進行,以提昇疾病與藥物作用之瞭解。
被使用於或可被使用於上述異種移植物模式中之一些典型人類癌細胞系為:關於乳癌之MDA MB-231、MCF7、MDA-MB-435及T-47D細胞系;關於結腸癌之KM 12、HCT-15、COLO 205、HCT 116及HT29細胞系;關於肺癌之NCI-H460與A549細胞系;關於前列腺癌之CRW22、LNCAP、PC-3及DU-145細胞系;關於黑色素瘤之LOX-IMVI與A375細胞系;關於卵巢癌之SK-O V-3與A2780細胞系;及關於腎癌之CAKI-I、A498及SN12C細胞系;以及關於神經膠質瘤癌症之U-87MG細胞系。
簡言之,使SCID老鼠服用範圍為例如100毫克/公斤至0.1毫克/公斤之化合物,具有不同劑量預定,包括但不限於每天(qd)、每兩天一
次(q2d)、每三天一次(q3d)、每五天一次(q5d)及每天兩次(bid)。將化合物調配在例如0.5%CMC/0.25%Tween中,並以經口方式傳輸。使老鼠服藥21天,且每三天採取腫瘤體積度量。經測試之舉例異種移植物模式包括PC-3、HCT-116、A549、MDA MB-231及U-87MG模式。
在此模式中,雜芳基化合物具有或預期具有ED50值<100毫克/公斤,其中一些化合物具有ED50<10毫克/公斤,而其他為ED50<1毫克/公斤。
在表1中之各化合物係在mTor HTR-FRET檢測中測試,且發現其中具有活性,其中在該檢測中,所有化合物具有IC50低於10μM,其中一些化合物具有IC50在0.005nM與250nM之間(活性程度D),其他具有IC50在250nM與500nM之間(活性程度C),其他具有IC50在500nM與1μM之間(活性程度B),而其他具有IC50在1μM與10μM之間(活性程度A)。
於本文中所揭示之具體實施例並非在範圍上受限於實例中所揭示之特殊具體實施例,其係意欲作為所揭示具體實施例之數種方面之說明,且於功能性上等效之任何具體實施例係被本發明揭示內容所
涵蓋。事實上,本文中所揭示具體實施例之各種修正係除了本文中所顯示與描述者以外,將為熟諳此藝者所明瞭,且係意欲落在隨文所附請求項之範圍內。
許多參考資料已被引述,其揭示內容係以其全文併於本文供參考。
Claims (21)
- 一種具有式(II)之化合物,
- 如請求項1之化合物,其中R1為經羥基烷基取代之吡啶基。
- 如請求項1之化合物,其中R1為經經取代或未經取代之三唑基及經取代或未經取代之C1-8烷基取代之吡啶基。
- 如請求項1之化合物,其中R2為:
- 如請求項4之化合物,其中R'為-OR。
- 如請求項5之化合物,其中R3為H。
- 如請求項6之化合物,其中R1為經羥基烷基取代之吡啶基。
- 如請求項6之化合物,其中R1為經經取代或未經取代之三唑基取代之吡啶基。
- 如請求項1之化合物,其係為7-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-1-(順式-4-羥基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮或其藥學上可接受之鹽、立體異構物或互變異構物。
- 如請求項1之化合物,其係為7-(6-(2-羥丙-2-基)吡啶-3-基)-1-((1R,3R)-3-甲氧基環戊基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮或其藥學上可接受之鹽、立體異構物或互變異構物。
- 如請求項1之化合物,其係為1-(反式-4-羥基環己基)-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮或其藥學上可接受之鹽、立體異構物或互變異構物。
- 如請求項1之化合物,其係為1-(反式-4-羥基環己基)-7-(6-(2-羥丙-2-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮或其藥學上可接受之鹽、立體異構物或互變異構物。
- 如請求項1之化合物,其係為1-((1S,3R)-3-甲氧基環戊基)-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮或其藥學上可接受之鹽、立體異構物或互變異構物。
- 如請求項1之化合物,其係為7-(6-(2-羥丙-2-基)吡啶-3-基)-1-((反式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮或其藥學上可接受之鹽、立體異構物或互變異構物。
- 如請求項1之化合物,其係為7-(6-(2-羥丙-2-基)吡啶-3-基)-1-((1R,3S)-3-甲氧基環戊基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮或其藥學上可接受之鹽、立體異構物或互變異構物。
- 如請求項1之化合物,其係為1-(順式-4-羥基環己基)-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮或其藥學上可接受之鹽、立體異構物或互變異構物。
- 如請求項1之化合物,其係為1-((1R,3S)-3-甲氧基環戊基)-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮或其藥學上可接受之鹽、立體異構物或互變異構物。
- 如請求項1之化合物,其中該化合物為:7-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-1-(順式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-1-(順式-4-羥基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-1-((反式-4-羥基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮; 7-(6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-1-((反式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-(反式-4-甲氧基環己基)-7-(4-甲基-6-(1H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(2-羥丙-2-基)吡啶-3-基)-1-((1R,3R)-3-甲氧基環戊基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(2-羥丙-2-基)吡啶-3-基)-1-((1S,3R)-3-甲氧基環戊基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(2-羥丙-2-基)吡啶-3-基)-1-((1S,3S)-3-甲氧基環戊基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;7-(6-(2-羥丙-2-基)吡啶-3-基)-1-((1R,3S)-3-甲氧基環戊基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-(反式-4-羥基環己基)-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-(順式-4-羥基環己基)-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-(反式-4-羥基環己基)-7-(6-(2-羥丙-2-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-(順式-4-羥基環己基)-7-(6-(2-羥丙-2-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-((1S,3R)-3-甲氧基環戊基)-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-((1R,3R)-3-甲氧基環戊基)-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-((1R,3S)-3-甲氧基環戊基)-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮; 1-((1S,3S)-3-甲氧基環戊基)-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;1-(反式-4-甲氧基環己基)-7-(2-甲基-6-(4H-1,2,4-三唑-3-基)吡啶-3-基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮;或7-(6-(2-羥丙-2-基)吡啶-3-基)-1-(反式-4-甲氧基環己基)-3,4-二氫吡并[2,3-b]吡-2(1H)-酮,或其藥學上可接受之鹽、立體異構物或互變異構物。
- 一種醫藥組合物,其包含有效量之如請求項1之化合物及藥學上可接受之載劑或媒劑。
- 一種醫藥組合物,其包含有效量之如請求項18之化合物及藥學上可接受之載劑或媒劑。
- 一種具有式(II)之化合物,
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10862708P | 2008-10-27 | 2008-10-27 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201531475A TW201531475A (zh) | 2015-08-16 |
TWI535722B true TWI535722B (zh) | 2016-06-01 |
Family
ID=41490345
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW098136346A TWI527817B (zh) | 2008-10-27 | 2009-10-27 | 用於腫瘤適應徵及與mTOR/PI3K/AKT/路徑相關之疾病之mTOR激酶抑制劑 |
TW104115101A TWI605047B (zh) | 2008-10-27 | 2009-10-27 | 用於腫瘤適應徵及與mTOR/PI3K/AKT/路徑相關之疾病之mTOR激酶抑制劑 |
TW104115102A TWI535722B (zh) | 2008-10-27 | 2009-10-27 | 用於腫瘤適應徵及與mTOR/PI3K/AKT/路徑相關之疾病之mTOR激酶抑制劑 |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW098136346A TWI527817B (zh) | 2008-10-27 | 2009-10-27 | 用於腫瘤適應徵及與mTOR/PI3K/AKT/路徑相關之疾病之mTOR激酶抑制劑 |
TW104115101A TWI605047B (zh) | 2008-10-27 | 2009-10-27 | 用於腫瘤適應徵及與mTOR/PI3K/AKT/路徑相關之疾病之mTOR激酶抑制劑 |
Country Status (35)
Country | Link |
---|---|
US (10) | US8110578B2 (zh) |
EP (5) | EP3660020B1 (zh) |
JP (3) | JP5689420B2 (zh) |
KR (2) | KR101896855B1 (zh) |
CN (3) | CN104744475B (zh) |
AR (2) | AR073995A1 (zh) |
AU (1) | AU2009320137C1 (zh) |
BR (1) | BRPI0920254A2 (zh) |
CA (1) | CA2740975C (zh) |
CO (1) | CO6501147A2 (zh) |
CR (1) | CR20110223A (zh) |
CY (2) | CY1117272T1 (zh) |
DK (2) | DK2740733T3 (zh) |
EC (1) | ECSP11011084A (zh) |
ES (4) | ES2794012T3 (zh) |
HK (3) | HK1154858A1 (zh) |
HR (2) | HRP20160084T1 (zh) |
HU (1) | HUE026834T2 (zh) |
IL (1) | IL212440A (zh) |
LT (1) | LT2740732T (zh) |
MX (2) | MX2011004401A (zh) |
MY (1) | MY159235A (zh) |
NI (1) | NI201100080A (zh) |
NZ (4) | NZ603831A (zh) |
PE (3) | PE20141197A1 (zh) |
PL (2) | PL2740732T3 (zh) |
PT (1) | PT2740732T (zh) |
RU (2) | RU2692796C2 (zh) |
SG (3) | SG10201402267VA (zh) |
SI (2) | SI2740733T1 (zh) |
SM (1) | SMT201600089B (zh) |
TW (3) | TWI527817B (zh) |
UA (1) | UA108601C2 (zh) |
WO (1) | WO2010062571A1 (zh) |
ZA (1) | ZA201102813B (zh) |
Families Citing this family (117)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009143389A1 (en) | 2008-05-21 | 2009-11-26 | Ariad Pharmaceuticals, Inc. | Phosphorous derivatives as kinase inhibitors |
US9273077B2 (en) | 2008-05-21 | 2016-03-01 | Ariad Pharmaceuticals, Inc. | Phosphorus derivatives as kinase inhibitors |
US8110578B2 (en) * | 2008-10-27 | 2012-02-07 | Signal Pharmaceuticals, Llc | Pyrazino[2,3-b]pyrazine mTOR kinase inhibitors for oncology indications and diseases associated with the mTOR/PI3K/Akt pathway |
JP5590040B2 (ja) | 2008-11-12 | 2014-09-17 | アリアド・ファーマシューティカルズ・インコーポレイテッド | キナーゼ阻害剤としてのピラジノピラジンおよび誘導体 |
DE102009043260A1 (de) | 2009-09-28 | 2011-04-28 | Merck Patent Gmbh | Pyridinyl-imidazolonderivate |
BR112012009751A2 (pt) * | 2009-10-26 | 2020-09-24 | Signal Pharmaceuticals, Llc | métodos de síntese e purificação de heteroarila |
NZ601581A (en) * | 2010-02-03 | 2014-03-28 | Signal Pharm Llc | Identification of lkb1 mutation as a predictive biomarker for sensitivity to tor kinase inhibitors |
US20110275699A1 (en) * | 2010-03-16 | 2011-11-10 | University Of California | Treatment For Obesity And Diabetes |
US20120028972A1 (en) * | 2010-07-30 | 2012-02-02 | Lilly Wong | Biomarker assays for detecting or measuring inhibition of tor kinase activity |
ES2547916T3 (es) * | 2011-02-18 | 2015-10-09 | Novartis Pharma Ag | Terapia de combinación de inhibidores de mTOR/JAK |
WO2012122405A2 (en) * | 2011-03-08 | 2012-09-13 | The Trustees Of Columbia University In The City Of New York | Screening assays using stem cells and stem cell-derived neurons from mouse models of alzheimer's disease |
MX360404B (es) | 2011-05-04 | 2018-10-31 | Ariad Pharma Inc | Compuestos para inhibir la proliferacion celular en canceres transmitidos por egfr. |
AU2012290056B2 (en) * | 2011-08-03 | 2015-03-19 | Signal Pharmaceuticals, Llc | Identification of gene expression profile as a predictive biomarker for LKB1 status |
AU2015200318B2 (en) * | 2011-10-19 | 2016-10-20 | Signal Pharmaceuticals, Llc | Treatment of cancer with TOR kinase inhibitors |
TWI758746B (zh) * | 2011-10-19 | 2022-03-21 | 美商標誌製藥公司 | 以tor激酶抑制劑治療癌症 |
AU2015201807B2 (en) * | 2011-12-02 | 2016-12-08 | Signal Pharmaceuticals, Llc | Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methocyclohexyl)-3,4-dihydropyrazino[2,3-b] pyrazin-2(1H)-one, a solid form thereof and methods of their use |
MY169749A (en) | 2011-12-02 | 2019-05-15 | Signal Pharm Llc | Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-b]pyrazin-2(1h)-one, a solid form thereof and methods of their use |
US8481498B1 (en) | 2012-01-17 | 2013-07-09 | Steven Hoffman | Pharmaceutical compositions and methods |
US10646552B2 (en) | 2012-01-17 | 2020-05-12 | Tyme, Inc. | Pharmaceutical compositions and methods |
US10272068B2 (en) | 2012-01-17 | 2019-04-30 | Tyme, Inc. | Pharmaceutical compositions and methods |
LT2804599T (lt) * | 2012-01-17 | 2019-04-10 | Tyme, Inc. | Kombinuota terapija vėžio gydymui |
US20130183263A1 (en) | 2012-01-17 | 2013-07-18 | Steven Hoffman | Pharmaceutical compositions and methods |
FR2986230B1 (fr) * | 2012-01-30 | 2014-03-07 | Univ Paris Diderot Paris 7 | Nouveaux composes et compositions utilises comme anticancereux |
ES2742398T3 (es) * | 2012-02-24 | 2020-02-14 | Signal Pharm Llc | Métodos para tratar el cáncer de pulmón no microcítico usando una terapia de combinación de inhibidores de TOR quinasa |
WO2013138556A1 (en) * | 2012-03-15 | 2013-09-19 | Signal Pharmaceuticals, Llc | Treatment of cancer with tor kinase inhibitors |
KR20210071101A (ko) * | 2012-03-15 | 2021-06-15 | 시그날 파마소티칼 엘엘씨 | Tor 키나제 억제자를 사용하는 암의 치료 |
AU2015201138B2 (en) * | 2012-03-15 | 2016-06-23 | Signal Pharmaceuticals, Llc | Treatment of cancer with TOR kinase inhibitors |
ES2678250T3 (es) * | 2012-03-15 | 2018-08-09 | Signal Pharmaceuticals, Llc | Tratamiento del cáncer con inhibidores de quinasa TOR |
EP2825171B1 (en) | 2012-03-15 | 2018-03-14 | Signal Pharmaceuticals, LLC | Treatment of cancer with tor kinase inhibitors |
AU2015213400B2 (en) * | 2012-03-15 | 2017-07-27 | Signal Pharmaceuticals, Llc | Treatment of cancer with TOR kinase inhibitors |
WO2013169401A1 (en) | 2012-05-05 | 2013-11-14 | Ariad Pharmaceuticals, Inc. | Compounds for inhibiting cell proliferation in egfr-driven cancers |
ME02651B (me) | 2012-06-13 | 2017-06-20 | Incyte Holdings Corp | Substituisana triciklična jedinjenja kao inhibitori fgfr |
EA039396B1 (ru) * | 2012-10-18 | 2022-01-24 | СИГНАЛ ФАРМАСЬЮТИКАЛЗ, ЭлЭлСи | Лечение рака молочной железы с тройным негативным фенотипом ингибиторами tor-киназы |
AU2015213397B2 (en) * | 2012-10-18 | 2017-07-27 | Signal Pharmaceuticals, Llc | Treatment of cancer with TOR kinase inhibitors |
AU2013203714B2 (en) * | 2012-10-18 | 2015-12-03 | Signal Pharmaceuticals, Llc | Inhibition of phosphorylation of PRAS40, GSK3-beta or P70S6K1 as a marker for TOR kinase inhibitory activity |
AU2013202768B2 (en) * | 2012-10-18 | 2015-11-05 | Signal Pharmaceuticals, Llc | Treatment of cancer with TOR kinase inhibitors |
TW201441227A (zh) | 2013-01-16 | 2014-11-01 | Signal Pharm Llc | 經取代吡咯并嘧啶化合物、其組合物及其治療方法 |
DK2948134T3 (da) | 2013-01-24 | 2020-06-02 | Palvella Therapeutics Inc | Sammensætninger til transdermal indgivelse af mtor-inhibitorer |
WO2014134240A1 (en) | 2013-02-28 | 2014-09-04 | Signal Pharmaceuticals, Llc | Treatment of cancer with tor kinase inhibitors |
US9611283B1 (en) | 2013-04-10 | 2017-04-04 | Ariad Pharmaceuticals, Inc. | Methods for inhibiting cell proliferation in ALK-driven cancers |
WO2014172424A1 (en) * | 2013-04-17 | 2014-10-23 | Signal Pharmaceuticals, Llc | Treatment of cancer with dihydropyrazino-pyrazines |
BR112015026257B1 (pt) * | 2013-04-17 | 2022-12-20 | Signal Pharmaceuticals, Llc | Uso de um composto dihidropirazino-pirazina e enzalutamida, composição farmacêutica que os compreende, e kit |
BR112015026247B1 (pt) * | 2013-04-17 | 2022-08-23 | Signal Pharmaceuticals, Llc | Uso de compostos em combinação com um análogo de citidina, composição farmacêutica que os compreende, e kit |
WO2014172425A1 (en) | 2013-04-17 | 2014-10-23 | Signal Pharmaceuticals, Llc | Treatment of cancer with dihydropyrazino-pyrazines |
US9358232B2 (en) | 2013-04-17 | 2016-06-07 | Signal Pharmaceuticals, Llc | Methods for treating cancer using TOR kinase inhibitor combination therapy |
EP2986298A1 (en) | 2013-04-17 | 2016-02-24 | Signal Pharmaceuticals, LLC | Treatment of cancer with dihydropyrazino-pyrazines |
AU2014254056B2 (en) * | 2013-04-17 | 2019-06-06 | Signal Pharmaceuticals, Llc | Combination therapy comprising a TOR kinase inhibitor and an IMiD compound for treating cancer |
CA2909625C (en) * | 2013-04-17 | 2021-06-01 | Signal Pharmaceuticals, Llc | Combination therapy comprising a tor kinase inhibitor and a 5-substituted quinazolinone compound for treating cancer |
SG11201508527VA (en) * | 2013-04-17 | 2015-11-27 | Signal Pharm Llc | Pharmaceutical formulations, processes, solid forms and methods of use relating to 1-ethyl-7-(2-methyl-6-(1h-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazino[2,3-b]pyrazin-2(1h)-one |
CA2909207C (en) | 2013-04-19 | 2021-11-02 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
CN113831345A (zh) | 2013-05-29 | 2021-12-24 | 西格诺药品有限公司 | 二氢吡嗪并吡嗪化合物的药物组合物、其固体形式和它们的用途 |
CN105792816A (zh) | 2013-10-04 | 2016-07-20 | 西格诺药品有限公司 | 以基因突变为特征的癌症的预防或治疗中的tor激酶抑制剂 |
US9585841B2 (en) | 2013-10-22 | 2017-03-07 | Tyme, Inc. | Tyrosine derivatives and compositions comprising them |
US9326962B2 (en) | 2013-10-22 | 2016-05-03 | Steven Hoffman | Compositions and methods for treating intestinal hyperpermeability |
US10813901B2 (en) | 2013-10-22 | 2020-10-27 | Yamo Pharmaceuticals Llc | Compositions and methods for treating autism |
US9763903B2 (en) | 2013-10-22 | 2017-09-19 | Steven Hoffman | Compositions and methods for treating intestinal hyperpermeability |
US10751313B2 (en) | 2013-10-22 | 2020-08-25 | Yamo Pharmaceuticals Llc | Compositions and methods for treating autism |
WO2015069217A1 (en) * | 2013-11-05 | 2015-05-14 | Baylor College Of Medicine | Src kinase inhibition as treatment for lympangioleiomyomatosis and tuberous sclerosis |
US9718824B2 (en) | 2014-04-16 | 2017-08-01 | Signal Pharmaceuticals, Llc | Solid forms comprising 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, and a coformer, compositions and methods of use thereof |
WO2015160869A1 (en) | 2014-04-16 | 2015-10-22 | Signal Pharmaceuticals, Llc | Methods for treating cancer using tor kinase inhibitor combination therapy |
NZ714742A (en) | 2014-04-16 | 2017-04-28 | Signal Pharm Llc | Solid forms of 1-ethyl-7-(2-methyl-6-(1h-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1h)-one, compositions thereof and methods of their use |
EP3131552B1 (en) | 2014-04-16 | 2020-07-15 | Signal Pharmaceuticals, LLC | Methods for treating cancer using tor kinase inhibitor combination therapy |
WO2015160880A1 (en) | 2014-04-16 | 2015-10-22 | Signal Pharmaceuticals, Llc | SOLID FORMS COMPRISING 1-ETHYL-7-(2-METHYL-6-(1H-1,2,4-TRIAZOL-3-YL) PYRIDIN-3-YL)-3,4-DIHYDROPYRAZINO(2,3-b)PYRAZIN-2(1H)-ONE, AND A COFORMER, COMPOSITIONS AND METHODS OF USE THEREOF |
NZ629796A (en) | 2014-07-14 | 2015-12-24 | Signal Pharm Llc | Amorphous form of 4-((4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7h-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-n-methylbenzamide, compositions thereof and methods of their use |
EA201790189A1 (ru) | 2014-07-14 | 2017-11-30 | СИГНАЛ ФАРМАСЬЮТИКАЛЗ, ЭлЭлСи | Способы лечения злокачественного новообразования с использованием замещенных пирролопиримидиновых соединений, композиции на их основе |
CN107073066B (zh) | 2014-09-11 | 2021-09-17 | 加利福尼亚大学董事会 | mTORC1抑制剂 |
US9987241B2 (en) | 2014-09-25 | 2018-06-05 | The Board Of Regents Of The University Of Oklahoma | Enzyme conjugate and prodrug cancer therapy |
US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
MA41551A (fr) | 2015-02-20 | 2017-12-26 | Incyte Corp | Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4 |
CR20170390A (es) | 2015-02-20 | 2017-10-23 | Incyte Holdings Corp | Heterociclos biciclicos como inhibidores de fgfr |
US10722484B2 (en) | 2016-03-09 | 2020-07-28 | K-Gen, Inc. | Methods of cancer treatment |
US10159665B2 (en) | 2016-03-23 | 2018-12-25 | Louis Habash | Preventing amyloid plaque formation by treating a human subject with a nitroxide |
US20180078539A1 (en) | 2016-03-23 | 2018-03-22 | Louis Habash | T-cell regulation in t-cell mediated diseases by reducing pathogenic function of th17 in a human subject through treatment with a nitroxide |
WO2017165572A1 (en) * | 2016-03-23 | 2017-09-28 | Louis Habash | Increasing expression level of apoptosis-related genes by treating a human subject with a nitroxide |
US10231959B2 (en) | 2016-03-23 | 2019-03-19 | Louis Habash | Increasing expression level of apoptosis-related genes by treating a human subject with a nitroxide |
US10818331B2 (en) | 2016-09-27 | 2020-10-27 | Spin Memory, Inc. | Multi-chip module for MRAM devices with levels of dynamic redundancy registers |
IL267869B2 (en) | 2017-01-06 | 2023-10-01 | Palvella Therapeutics Inc | Non-aqueous preparations of mTOR inhibitors and methods of use |
WO2018183868A1 (en) * | 2017-03-31 | 2018-10-04 | Bioventures, Llc | Inhibitors of dna pk and uses thereof |
AR111960A1 (es) | 2017-05-26 | 2019-09-04 | Incyte Corp | Formas cristalinas de un inhibidor de fgfr y procesos para su preparación |
AU2018289539B2 (en) | 2017-06-22 | 2024-07-04 | Celgene Corporation | Treatment of hepatocellular carcinoma characterized by hepatitis B virus infection |
WO2020032951A1 (en) | 2018-08-09 | 2020-02-13 | The Board Of Regents Of The University Of Oklahoma | Antimalarial enzyme conjugates, kits containing same, and methods of producing and using same |
KR102133794B1 (ko) * | 2017-08-24 | 2020-07-15 | 주식회사 셀투인 | 세포 소기관 내 글루타치온 측정용 실시간 형광 이미징 센서 및 이의 제조 방법 |
US10656994B2 (en) | 2017-10-24 | 2020-05-19 | Spin Memory, Inc. | Over-voltage write operation of tunnel magnet-resistance (“TMR”) memory device and correcting failure bits therefrom by using on-the-fly bit failure detection and bit redundancy remapping techniques |
MX2020004239A (es) | 2017-11-01 | 2020-09-09 | Juno Therapeutics Inc | Proceso para producir una composicion de celulas t. |
KR102083916B1 (ko) | 2017-11-23 | 2020-03-03 | 서울대학교산학협력단 | 대장암 진단을 위한 tcf7 돌연변이의 용도 및 게다토리십 약물내성을 갖는 대장암 치료용 조성물 |
RU2020121820A (ru) * | 2017-12-04 | 2022-01-10 | БИАЛ - ПОРТЕЛА ЭНД Ка, С.А. | Ингибиторы дофамин-в-гидроксилазы |
US10886330B2 (en) | 2017-12-29 | 2021-01-05 | Spin Memory, Inc. | Memory device having overlapping magnetic tunnel junctions in compliance with a reference pitch |
US10840439B2 (en) | 2017-12-29 | 2020-11-17 | Spin Memory, Inc. | Magnetic tunnel junction (MTJ) fabrication methods and systems |
US10596165B2 (en) | 2018-02-12 | 2020-03-24 | resTORbio, Inc. | Combination therapies |
ES2945560T3 (es) | 2018-05-01 | 2023-07-04 | Revolution Medicines Inc | Análogos de rapamicina unidos en C40, C28 y C-32 como inhibidores de mTOR |
IL278335B1 (en) | 2018-05-01 | 2024-05-01 | Revolution Medicines Inc | C26-linked rapamycin analogs as MTOR inhibitors |
BR112020022373A2 (pt) | 2018-05-04 | 2021-02-02 | Incyte Corporation | sais de um inibidor de fgfr |
WO2019213544A2 (en) | 2018-05-04 | 2019-11-07 | Incyte Corporation | Solid forms of an fgfr inhibitor and processes for preparing the same |
US10411185B1 (en) | 2018-05-30 | 2019-09-10 | Spin Memory, Inc. | Process for creating a high density magnetic tunnel junction array test platform |
SG11202012447YA (en) | 2018-06-15 | 2021-01-28 | Navitor Pharm Inc | Rapamycin analogs and uses thereof |
US11000513B2 (en) | 2018-07-02 | 2021-05-11 | Palvella Therapeutics, Inc. | Anhydrous compositions of mTOR inhibitors and methods of use |
US10650875B2 (en) | 2018-08-21 | 2020-05-12 | Spin Memory, Inc. | System for a wide temperature range nonvolatile memory |
JP2022500384A (ja) | 2018-09-10 | 2022-01-04 | ミラティ セラピューティクス, インコーポレイテッド | 組み合わせ療法 |
US10971680B2 (en) | 2018-10-01 | 2021-04-06 | Spin Memory, Inc. | Multi terminal device stack formation methods |
US11621293B2 (en) | 2018-10-01 | 2023-04-04 | Integrated Silicon Solution, (Cayman) Inc. | Multi terminal device stack systems and methods |
WO2020185532A1 (en) | 2019-03-08 | 2020-09-17 | Incyte Corporation | Methods of treating cancer with an fgfr inhibitor |
US11591329B2 (en) | 2019-07-09 | 2023-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
UY38806A (es) | 2019-08-01 | 2021-02-26 | Novartis Ag | Compuestos inhibidores tricíclicos de kars dependientes de akr1c3, composiciones y sus usos |
JOP20220083A1 (ar) | 2019-10-14 | 2023-01-30 | Incyte Corp | حلقات غير متجانسة ثنائية الحلقة كمثبطات لـ fgfr |
US11566028B2 (en) | 2019-10-16 | 2023-01-31 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
BR112022010664A2 (pt) | 2019-12-04 | 2022-08-16 | Incyte Corp | Derivados de um inibidor de fgfr |
JP2023505258A (ja) | 2019-12-04 | 2023-02-08 | インサイト・コーポレイション | Fgfr阻害剤としての三環式複素環 |
TW202134234A (zh) | 2019-12-05 | 2021-09-16 | 美商奈維特製藥公司 | 雷帕黴素類似物及其用途 |
WO2021146424A1 (en) | 2020-01-15 | 2021-07-22 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
CN115151532B (zh) * | 2020-04-29 | 2023-06-06 | 北京泰德制药股份有限公司 | 喹喔啉二酮衍生物作为kras g12c突变蛋白的不可逆抑制剂 |
CN115916350A (zh) * | 2020-07-22 | 2023-04-04 | 南京正大天晴制药有限公司 | Akt抑制剂的单位剂量组合物 |
WO2022166866A1 (zh) * | 2021-02-08 | 2022-08-11 | 南京明德新药研发有限公司 | 二氢吡嗪并吡嗪类大环化合物 |
AU2022224567A1 (en) | 2021-02-16 | 2023-08-24 | Barinthus Biotherapeutics North America, Inc. | Self-assembling nanoparticles based on amphiphilic peptides |
TW202313611A (zh) | 2021-06-09 | 2023-04-01 | 美商英塞特公司 | 作為fgfr抑制劑之三環雜環 |
US20240226126A1 (en) * | 2021-06-16 | 2024-07-11 | The Board Of Trustees Of The Leland Stanford Junior University | Compositions for treatment of psoriasis |
WO2023170107A1 (en) | 2022-03-07 | 2023-09-14 | Centre Hospitalier Universitaire Vaudois (Chuv) | Pi3k/akt/mtor inhibitor for improving the cellular uptake of a radiopharmaceutical |
WO2024092030A1 (en) | 2022-10-25 | 2024-05-02 | Vaccitech North America, Inc. | Self-assembling nanoparticles |
Family Cites Families (67)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE262026C (zh) | ||||
US3507866A (en) * | 1967-08-08 | 1970-04-21 | Merck & Co Inc | 1h - imidazo(4,5-b)pyrazin - 2 - one and processes for their preparation |
US3567725A (en) * | 1968-11-20 | 1971-03-02 | Merck & Co Inc | Process for preparation of 1h-imidazo-(4,5-b)pyrazin-2-ones |
US4317909A (en) * | 1980-03-24 | 1982-03-02 | Sterling Drug Inc. | Preparation of 1,3-dihydro-5-(pyridinyl)-2H-imidazo[4,5-b]pyridin-2-ones |
US4294836A (en) * | 1980-03-24 | 1981-10-13 | Sterling Drug Inc. | 1,3-Dihydro-6-(pyridinyl)-2H-imidazo[4,5-b]pyridin-2-ones and -imidazo[4,5-b]-pyridine-2-thiones and their cardiotonic use |
US4294837A (en) * | 1980-03-28 | 1981-10-13 | Sterling Drug Inc. | 1,3-Dihydro-6-(pyridinyl)-2H-imidazo[4,5-b]pyridin-2-ones and -imidazo[4,5-b]pyridine-2-thiones and their cardiotonic use |
US4309537A (en) * | 1980-03-28 | 1982-01-05 | Sterling Drug Inc. | Production of imidazo[4,5-b]pyridin-2-ones or thiones |
GB8709448D0 (en) * | 1987-04-21 | 1987-05-28 | Pfizer Ltd | Heterobicyclic quinoline derivatives |
JPS63275582A (ja) | 1987-05-02 | 1988-11-14 | Naade Kenkyusho:Kk | 2−アミノイミダゾ〔4,5−b〕ピリジン誘導体の製造方法 |
DD262026A1 (de) | 1987-07-10 | 1988-11-16 | Akad Wissenschaften Ddr | Verfahren zur herstellung von 4-substituierten 6-(pyrid-4-yl)-2,4-dihydro-1h-imidazo[4,5-b]pyrid-2-onen |
FR2643903A1 (fr) | 1989-03-03 | 1990-09-07 | Union Pharma Scient Appl | Nouveaux derives de benzimidazole, leurs procedes de preparation, intermediaires de synthese, compositions pharmaceutiques les contenant, utiles notamment pour le traitement des maladies cardiovasculaires, et des ulceres duodenaux |
US4963561A (en) * | 1990-02-28 | 1990-10-16 | Sterling Drug Inc. | Imidazopyridines, their preparation and use |
TW274550B (zh) * | 1992-09-26 | 1996-04-21 | Hoechst Ag | |
WO1995003009A1 (en) | 1993-07-22 | 1995-02-02 | Oculex Pharmaceuticals, Inc. | Method of treatment of macular degeneration |
US5770589A (en) | 1993-07-27 | 1998-06-23 | The University Of Sydney | Treatment of macular degeneration |
ATE190978T1 (de) * | 1994-11-14 | 2000-04-15 | Warner Lambert Co | 6-aryl-pyrido(2,3-d)pyrimidine und -naphthyridine zur hemmung der durch protein-tyrosin-kinase hervorgerufenen zellvermehrung |
IT1274549B (it) | 1995-05-23 | 1997-07-17 | Indena Spa | Uso di flavanolignani per la preparazione di medicamenti ad attivita' antiproliferativa nei tumori dell'utero,dell'ovaio e del seno |
DE19601627A1 (de) * | 1996-01-18 | 1997-07-24 | Bayer Ag | Heteroatomhaltige Cyclopentanopyridyl-Oxazolidinone |
US5800819A (en) | 1996-01-25 | 1998-09-01 | National Institute For Pharmaceutical Research And Development Federal Ministry Of Science And Technology | Piper guineense, pterocarpus osun, eugenia caryophyllata, and sorghum bicolor extracts for treating sickle cell disease |
US5635517B1 (en) | 1996-07-24 | 1999-06-29 | Celgene Corp | Method of reducing TNFalpha levels with amino substituted 2-(2,6-dioxopiperidin-3-YL)-1-oxo-and 1,3-dioxoisoindolines |
US6281230B1 (en) | 1996-07-24 | 2001-08-28 | Celgene Corporation | Isoindolines, method of use, and pharmaceutical compositions |
EP1017384B1 (en) * | 1997-09-26 | 2004-11-10 | Zentaris GmbH | Azabenzimidazole-based compounds for modulating serine/threonine protein kinase function |
ZA9810490B (en) * | 1997-12-03 | 1999-05-20 | Dainippon Pharmaceutical Co | 2-Aryl-8-oxodihydropurine derivative process for the preparation thereof pharmaceutical composition containing the same and intermediate therefor |
US6015803A (en) | 1998-05-04 | 2000-01-18 | Wirostko; Emil | Antibiotic treatment of age-related macular degeneration |
US6225348B1 (en) | 1998-08-20 | 2001-05-01 | Alfred W. Paulsen | Method of treating macular degeneration with a prostaglandin derivative |
US6001368A (en) | 1998-09-03 | 1999-12-14 | Protein Technologies International, Inc. | Method for inhibiting or reducing the risk of macular degeneration |
JP2003146987A (ja) | 1999-05-31 | 2003-05-21 | Dainippon Pharmaceut Co Ltd | 2−アリールプリン−9−アセトアミド誘導体 |
JP3814125B2 (ja) | 1999-06-02 | 2006-08-23 | 大日本住友製薬株式会社 | 2−アリール−8−オキソジヒドロプリン誘導体からなる医薬 |
JP4820518B2 (ja) * | 2000-01-24 | 2011-11-24 | アストラゼネカ アクチボラグ | モルホリノ置換化合物治療薬 |
JP2002167387A (ja) | 2000-11-29 | 2002-06-11 | Dainippon Pharmaceut Co Ltd | 2−(7,8−ジヒドロ−8−オキソ−9h−プリン−9−イル)酢酸誘導体 |
DE60115092T2 (de) * | 2000-12-12 | 2006-03-30 | Neurogen Corp., Brandford | Spiro[isobenzofuran-1,4'-piperidin]-3-one und 3h-spiroisobenzofuran-1,4'-piperidine |
AU2002257217A1 (en) | 2001-04-24 | 2002-11-05 | Broadcom Corporation | Alerting system, architecture and circuitry |
CA2458699C (en) | 2001-09-04 | 2010-10-19 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Novel dihydropteridinones, method for producing the same and the use thereof as medicaments |
JP2005506350A (ja) * | 2001-10-18 | 2005-03-03 | ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド | サイトカイン阻害薬としての1,4−二置換ベンゾ−縮合尿素化合物 |
US7968569B2 (en) | 2002-05-17 | 2011-06-28 | Celgene Corporation | Methods for treatment of multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione |
AU2003299531A1 (en) | 2002-08-05 | 2004-06-07 | University Of Massachusetts | Compounds for modulating rna interference |
US7189740B2 (en) | 2002-10-15 | 2007-03-13 | Celgene Corporation | Methods of using 3-(4-amino-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for the treatment and management of myelodysplastic syndromes |
US20040091455A1 (en) | 2002-10-31 | 2004-05-13 | Zeldis Jerome B. | Methods of using and compositions comprising immunomodulatory compounds for treatment and management of macular degeneration |
US7563810B2 (en) | 2002-11-06 | 2009-07-21 | Celgene Corporation | Methods of using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione for the treatment and management of myeloproliferative diseases |
EP1590341B1 (en) | 2003-01-17 | 2009-06-17 | Warner-Lambert Company LLC | 2-aminopyridine substituted heterocycles as inhibitors of cellular proliferation |
CN101200457A (zh) | 2003-02-26 | 2008-06-18 | 贝林格尔英格海姆法玛两合公司 | 二氢蝶啶酮、其制法及作为药物制剂的用途 |
GB2400101A (en) | 2003-03-28 | 2004-10-06 | Biofocus Discovery Ltd | Compounds capable of binding to the active site of protein kinases |
US20050100529A1 (en) | 2003-11-06 | 2005-05-12 | Zeldis Jerome B. | Methods of using and compositions comprising immunomodulatory compounds for the treatment and management of asbestos-related diseases and disorders |
RU2006121990A (ru) * | 2003-11-21 | 2007-12-27 | Эррэй Биофарма Инк. (Us) | Ингибиторы протеинкиназ акт |
NZ550026A (en) | 2004-03-22 | 2009-10-30 | Celgene Corp | Methods of using and compositions comprising immunomodulatory compounds for the treatment and management of skin diseases or disorders |
EP1734951A2 (en) * | 2004-04-08 | 2006-12-27 | TopoTarget A/S | Diphenyl-indol-2-on compounds and their use in the treatment of cancer |
CA2563810A1 (en) | 2004-04-23 | 2005-11-10 | Celgene Corporation | Methods of using and compositions comprising immunomodulatory compounds for the treatment and management of pulmonary hypertension |
WO2005120511A1 (en) | 2004-06-04 | 2005-12-22 | Icos Corporation | Methods for treating mast cell disorders |
DE102004029784A1 (de) * | 2004-06-21 | 2006-01-05 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue 2-Benzylaminodihydropteridinone, Verfahren zur deren Herstellung und deren Verwendung als Arzneimittel |
WO2006001266A1 (ja) | 2004-06-23 | 2006-01-05 | Banyu Pharmaceutical Co., Ltd. | 2-アリールプリン誘導体の製造方法 |
WO2006020755A2 (en) | 2004-08-10 | 2006-02-23 | Beth Israel Deaconess Medical Center, Inc. | Methods for identifying inhibitors of the mtor pathway as diabetes therapeutics |
GB0420719D0 (en) | 2004-09-17 | 2004-10-20 | Addex Pharmaceuticals Sa | Novel allosteric modulators |
WO2006036883A2 (en) | 2004-09-24 | 2006-04-06 | Janssen Pharmaceutica, N.V. | Imidazo{4,5-b}pyrazinone inhibitors of protein kinases |
MX2007005159A (es) | 2004-10-29 | 2007-06-26 | Tibotec Pharm Ltd | Derivados de pirimidina biciclicos inhibidores del vih. |
AU2005304420A1 (en) | 2004-11-12 | 2006-05-18 | Celgene Corporation | Methods and compositions using immunomodulatory compounds for treatment and management of parasitic diseases |
US20060122228A1 (en) | 2004-11-23 | 2006-06-08 | Zeldis Jerome B | Methods and compositions using immunomodulatory compounds for treatment and management of central nervous system injury |
CA2588990A1 (en) | 2004-12-01 | 2006-06-08 | Celgene Corporation | Compositions comprising immunomodulatory compounds and the use thereof for the treatment of immunodeficiency disorders |
JP5111113B2 (ja) | 2004-12-13 | 2012-12-26 | サネシス ファーマシューティカルズ, インコーポレイテッド | Rafキナーゼ阻害剤として有用なピリドピリミジノン、ジヒドロピリミドピリミジノンおよびプテリジノン |
WO2006091737A1 (en) | 2005-02-24 | 2006-08-31 | Kemia, Inc. | Modulators of gsk-3 activity |
JP2008531538A (ja) * | 2005-02-25 | 2008-08-14 | クドス ファーマシューティカルズ リミテッド | 2,4−ジアミノ−ピリドピリミジン誘導体とmTOR阻害剤としてのその使用 |
RU2007140903A (ru) | 2005-04-05 | 2009-05-20 | Фармакопия, Инк. (Us) | Производные пурина и имидазопиридина для иммуносупрессии |
RS51843B (en) * | 2005-11-17 | 2012-02-29 | Osi Pharmaceuticals Llc. | CONDENSED BICYCLIC m TOR INHIBITORS |
ES2558517T3 (es) | 2006-08-02 | 2016-02-04 | Cytokinetics, Inc. | Ciertas entidades químicas, composiciones y métodos que comprenden imidazopirimidinas |
ES2627352T3 (es) * | 2006-10-19 | 2017-07-27 | Signal Pharmaceuticals, Llc | Compuestos heteroarilo, sus composiciones y su uso como inhibidores de proteínas quinasas |
EA019951B1 (ru) | 2007-03-01 | 2014-07-30 | Новартис Аг | Ингибиторы киназы pim и способы их применения |
US8110578B2 (en) | 2008-10-27 | 2012-02-07 | Signal Pharmaceuticals, Llc | Pyrazino[2,3-b]pyrazine mTOR kinase inhibitors for oncology indications and diseases associated with the mTOR/PI3K/Akt pathway |
BR112012009751A2 (pt) * | 2009-10-26 | 2020-09-24 | Signal Pharmaceuticals, Llc | métodos de síntese e purificação de heteroarila |
-
2009
- 2009-10-26 US US12/605,791 patent/US8110578B2/en active Active
- 2009-10-27 NZ NZ603831A patent/NZ603831A/en unknown
- 2009-10-27 BR BRPI0920254-4A patent/BRPI0920254A2/pt not_active Application Discontinuation
- 2009-10-27 SI SI200931377T patent/SI2740733T1/sl unknown
- 2009-10-27 AR ARP090104139A patent/AR073995A1/es not_active Application Discontinuation
- 2009-10-27 ES ES16171709T patent/ES2794012T3/es active Active
- 2009-10-27 DK DK14158171.0T patent/DK2740733T3/en active
- 2009-10-27 CN CN201510072669.6A patent/CN104744475B/zh active Active
- 2009-10-27 AU AU2009320137A patent/AU2009320137C1/en active Active
- 2009-10-27 NZ NZ619458A patent/NZ619458A/en unknown
- 2009-10-27 PL PL14158161T patent/PL2740732T3/pl unknown
- 2009-10-27 EP EP20152165.5A patent/EP3660020B1/en active Active
- 2009-10-27 ES ES14158171.0T patent/ES2562803T3/es active Active
- 2009-10-27 PE PE2014000555A patent/PE20141197A1/es active IP Right Grant
- 2009-10-27 EP EP09759827.0A patent/EP2358718B1/en active Active
- 2009-10-27 RU RU2015105249A patent/RU2692796C2/ru active
- 2009-10-27 UA UAA201106622A patent/UA108601C2/uk unknown
- 2009-10-27 NZ NZ592278A patent/NZ592278A/xx unknown
- 2009-10-27 CA CA2740975A patent/CA2740975C/en active Active
- 2009-10-27 TW TW098136346A patent/TWI527817B/zh active
- 2009-10-27 SI SI200931697T patent/SI2740732T1/sl unknown
- 2009-10-27 CN CN200980150130.0A patent/CN102245611B/zh active Active
- 2009-10-27 EP EP14158171.0A patent/EP2740733B1/en active Active
- 2009-10-27 DK DK14158161.1T patent/DK2740732T3/en active
- 2009-10-27 KR KR1020177018241A patent/KR101896855B1/ko active IP Right Grant
- 2009-10-27 PE PE2012002515A patent/PE20130457A1/es active IP Right Grant
- 2009-10-27 TW TW104115101A patent/TWI605047B/zh active
- 2009-10-27 TW TW104115102A patent/TWI535722B/zh active
- 2009-10-27 EP EP14158161.1A patent/EP2740732B1/en active Active
- 2009-10-27 MX MX2011004401A patent/MX2011004401A/es active IP Right Grant
- 2009-10-27 PE PE2011000936A patent/PE20110575A1/es not_active Application Discontinuation
- 2009-10-27 PL PL14158171T patent/PL2740733T3/pl unknown
- 2009-10-27 CN CN201510072757.6A patent/CN104725384B/zh active Active
- 2009-10-27 SG SG10201402267VA patent/SG10201402267VA/en unknown
- 2009-10-27 ES ES14158161.1T patent/ES2633194T3/es active Active
- 2009-10-27 WO PCT/US2009/062143 patent/WO2010062571A1/en active Application Filing
- 2009-10-27 SG SG10201402273RA patent/SG10201402273RA/en unknown
- 2009-10-27 KR KR1020117012069A patent/KR101815604B1/ko active IP Right Grant
- 2009-10-27 MY MYPI2011001855A patent/MY159235A/en unknown
- 2009-10-27 EP EP16171709.5A patent/EP3103803B1/en active Active
- 2009-10-27 ES ES09759827.0T patent/ES2620774T3/es active Active
- 2009-10-27 MX MX2014000653A patent/MX361916B/es unknown
- 2009-10-27 NZ NZ708183A patent/NZ708183A/en unknown
- 2009-10-27 JP JP2011533419A patent/JP5689420B2/ja active Active
- 2009-10-27 PT PT141581611T patent/PT2740732T/pt unknown
- 2009-10-27 LT LTEP14158161.1T patent/LT2740732T/lt unknown
- 2009-10-27 SG SG2014006852A patent/SG2014006852A/en unknown
- 2009-10-27 RU RU2011121353/04A patent/RU2546658C2/ru active
- 2009-10-27 HU HUE14158171A patent/HUE026834T2/en unknown
-
2011
- 2011-04-14 ZA ZA2011/02813A patent/ZA201102813B/en unknown
- 2011-04-17 IL IL212440A patent/IL212440A/en active IP Right Grant
- 2011-04-27 NI NI201100080A patent/NI201100080A/es unknown
- 2011-04-29 CR CR20110223A patent/CR20110223A/es unknown
- 2011-05-17 CO CO11060485A patent/CO6501147A2/es not_active Application Discontinuation
- 2011-05-25 EC EC2011011084A patent/ECSP11011084A/es unknown
- 2011-08-30 HK HK11109149.8A patent/HK1154858A1/zh unknown
- 2011-11-14 US US13/295,533 patent/US8492381B2/en active Active
- 2011-11-14 US US13/295,513 patent/US8507492B2/en active Active
-
2013
- 2013-06-26 US US13/927,255 patent/US8907087B2/en active Active
-
2014
- 2014-10-31 US US14/529,261 patent/US9193692B2/en active Active
- 2014-12-10 HK HK14112450.2A patent/HK1200442A1/zh unknown
- 2014-12-10 HK HK14112447.8A patent/HK1199020A1/zh unknown
- 2014-12-19 JP JP2014257140A patent/JP6110358B2/ja active Active
-
2015
- 2015-10-05 US US14/874,524 patent/US9771371B2/en active Active
-
2016
- 2016-01-26 HR HRP20160084TT patent/HRP20160084T1/hr unknown
- 2016-03-08 CY CY20161100198T patent/CY1117272T1/el unknown
- 2016-03-29 SM SM201600089T patent/SMT201600089B/xx unknown
- 2016-08-16 JP JP2016159422A patent/JP2017014256A/ja not_active Withdrawn
-
2017
- 2017-07-12 HR HRP20171069TT patent/HRP20171069T1/hr unknown
- 2017-07-14 CY CY20171100752T patent/CY1119075T1/el unknown
- 2017-08-18 US US15/680,688 patent/US10167290B2/en active Active
- 2017-12-18 AR ARP170103549A patent/AR110388A2/es unknown
-
2018
- 2018-11-12 US US16/186,883 patent/US10683298B2/en active Active
-
2020
- 2020-05-04 US US16/865,512 patent/US11292796B2/en active Active
-
2022
- 2022-02-25 US US17/681,645 patent/US20230119470A1/en not_active Abandoned
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11292796B2 (en) | Substituted pyrazino[2,3-b]pyrazines as mTOR kinase inhibitors |