CN101208303A - Cgrp受体拮抗剂 - Google Patents
Cgrp受体拮抗剂 Download PDFInfo
- Publication number
- CN101208303A CN101208303A CNA2006800080832A CN200680008083A CN101208303A CN 101208303 A CN101208303 A CN 101208303A CN A2006800080832 A CNA2006800080832 A CN A2006800080832A CN 200680008083 A CN200680008083 A CN 200680008083A CN 101208303 A CN101208303 A CN 101208303A
- Authority
- CN
- China
- Prior art keywords
- independently
- replace
- alkyl
- substituting group
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 108010078311 Calcitonin Gene-Related Peptide Receptors Proteins 0.000 title claims abstract description 8
- 102000008323 calcitonin gene-related peptide receptor activity proteins Human genes 0.000 title claims description 6
- 229940044551 receptor antagonist Drugs 0.000 title description 5
- 239000002464 receptor antagonist Substances 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 171
- 238000011282 treatment Methods 0.000 claims abstract description 62
- 239000000203 mixture Substances 0.000 claims abstract description 61
- 239000005557 antagonist Substances 0.000 claims abstract description 26
- 208000019695 Migraine disease Diseases 0.000 claims abstract description 21
- 206010027599 migraine Diseases 0.000 claims abstract description 21
- 206010019233 Headaches Diseases 0.000 claims abstract description 20
- 231100000869 headache Toxicity 0.000 claims abstract description 17
- 208000006561 Cluster Headache Diseases 0.000 claims abstract description 16
- 208000018912 cluster headache syndrome Diseases 0.000 claims abstract description 16
- 230000002265 prevention Effects 0.000 claims abstract description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 71
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 64
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 63
- 125000003118 aryl group Chemical group 0.000 claims description 61
- 229910052799 carbon Inorganic materials 0.000 claims description 61
- 125000000623 heterocyclic group Chemical group 0.000 claims description 61
- -1 pyrrolidyl Chemical group 0.000 claims description 57
- 150000003839 salts Chemical class 0.000 claims description 57
- 238000000034 method Methods 0.000 claims description 54
- 229910052736 halogen Inorganic materials 0.000 claims description 48
- 150000002367 halogens Chemical class 0.000 claims description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 44
- 239000003814 drug Substances 0.000 claims description 43
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 35
- 150000003851 azoles Chemical class 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 18
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 15
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 14
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 13
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 13
- 150000002460 imidazoles Chemical class 0.000 claims description 13
- 150000003217 pyrazoles Chemical class 0.000 claims description 13
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 11
- 239000003112 inhibitor Substances 0.000 claims description 11
- 125000002393 azetidinyl group Chemical group 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 150000003053 piperidines Chemical class 0.000 claims description 9
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 8
- 125000005936 piperidyl group Chemical group 0.000 claims description 8
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 7
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 7
- 230000008485 antagonism Effects 0.000 claims description 7
- 150000002240 furans Chemical class 0.000 claims description 7
- 150000002475 indoles Chemical class 0.000 claims description 7
- 125000002757 morpholinyl group Chemical group 0.000 claims description 7
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 claims description 7
- 125000004193 piperazinyl group Chemical group 0.000 claims description 7
- 150000003233 pyrroles Chemical class 0.000 claims description 7
- 150000003527 tetrahydropyrans Chemical class 0.000 claims description 7
- 229930192474 thiophene Natural products 0.000 claims description 7
- 150000003852 triazoles Chemical class 0.000 claims description 7
- 241000124008 Mammalia Species 0.000 claims description 6
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims description 6
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 5
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 5
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 claims description 4
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 claims description 4
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 4
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 claims description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000480 calcium channel blocker Substances 0.000 claims description 4
- 239000003402 opiate agonist Substances 0.000 claims description 4
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 claims description 4
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 claims description 4
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 claims description 4
- 239000000952 serotonin receptor agonist Substances 0.000 claims description 4
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 claims description 4
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 claims description 3
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims description 3
- 239000002126 C01EB10 - Adenosine Substances 0.000 claims description 3
- 102100022630 Glutamate receptor ionotropic, NMDA 2B Human genes 0.000 claims description 3
- 229940121832 Granzyme B inhibitor Drugs 0.000 claims description 3
- 108010038912 Retinoid X Receptors Proteins 0.000 claims description 3
- 229940094948 Sigma receptor agonist Drugs 0.000 claims description 3
- 229960005305 adenosine Drugs 0.000 claims description 3
- 239000000730 antalgic agent Substances 0.000 claims description 3
- 230000003474 anti-emetic effect Effects 0.000 claims description 3
- 239000001961 anticonvulsive agent Substances 0.000 claims description 3
- 239000000935 antidepressant agent Substances 0.000 claims description 3
- 239000002111 antiemetic agent Substances 0.000 claims description 3
- 239000002249 anxiolytic agent Substances 0.000 claims description 3
- 230000000949 anxiolytic effect Effects 0.000 claims description 3
- 239000002876 beta blocker Substances 0.000 claims description 3
- 239000002308 endothelin receptor antagonist Substances 0.000 claims description 3
- 229960002748 norepinephrine Drugs 0.000 claims description 3
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000002243 precursor Substances 0.000 claims description 3
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 claims description 3
- 230000001519 thymoleptic effect Effects 0.000 claims description 3
- 229940123413 Angiotensin II antagonist Drugs 0.000 claims description 2
- 102400000344 Angiotensin-1 Human genes 0.000 claims description 2
- 101800000734 Angiotensin-1 Proteins 0.000 claims description 2
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 claims description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 claims description 2
- 239000002461 renin inhibitor Substances 0.000 claims description 2
- 229940086526 renin-inhibitors Drugs 0.000 claims description 2
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 claims description 2
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 claims description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims 4
- 208000028017 Psychotic disease Diseases 0.000 claims 4
- MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 claims 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 2
- 108010062745 Chloride Channels Proteins 0.000 claims 2
- 102000011045 Chloride Channels Human genes 0.000 claims 2
- 229940123921 Nitric oxide synthase inhibitor Drugs 0.000 claims 2
- 229940087098 Oxidase inhibitor Drugs 0.000 claims 2
- 101710182223 Toxin B Proteins 0.000 claims 2
- 108010057266 Type A Botulinum Toxins Proteins 0.000 claims 2
- 229940097320 beta blocking agent Drugs 0.000 claims 2
- 230000002496 gastric effect Effects 0.000 claims 2
- 229960001340 histamine Drugs 0.000 claims 2
- 239000000236 nitric oxide synthase inhibitor Substances 0.000 claims 2
- 230000008855 peristalsis Effects 0.000 claims 2
- 239000012745 toughening agent Substances 0.000 claims 2
- 239000005541 ACE inhibitor Substances 0.000 claims 1
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 claims 1
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 claims 1
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims 1
- 108090000932 Calcitonin Gene-Related Peptide Proteins 0.000 abstract description 41
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 18
- 201000010099 disease Diseases 0.000 abstract description 17
- 102100025588 Calcitonin gene-related peptide 1 Human genes 0.000 abstract description 3
- 102000014468 Calcitonin Gene-Related Peptide Receptors Human genes 0.000 abstract description 2
- 229910052796 boron Inorganic materials 0.000 abstract description 2
- 229910052721 tungsten Inorganic materials 0.000 abstract description 2
- 230000006806 disease prevention Effects 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 102000004414 Calcitonin Gene-Related Peptide Human genes 0.000 description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- 239000003735 calcitonin gene related peptide receptor antagonist Substances 0.000 description 25
- 239000000243 solution Substances 0.000 description 25
- 239000002253 acid Substances 0.000 description 21
- 238000002360 preparation method Methods 0.000 description 21
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 19
- 125000004429 atom Chemical group 0.000 description 18
- 229940127597 CGRP antagonist Drugs 0.000 description 17
- 229940079593 drug Drugs 0.000 description 17
- 239000000543 intermediate Substances 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000003795 chemical substances by application Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 230000003203 everyday effect Effects 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 10
- 239000011737 fluorine Substances 0.000 description 10
- 239000000370 acceptor Substances 0.000 description 9
- 238000006243 chemical reaction Methods 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
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 8
- 208000002193 Pain Diseases 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 8
- 239000000556 agonist Substances 0.000 description 7
- 238000010511 deprotection reaction Methods 0.000 description 7
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 239000002953 phosphate buffered saline Substances 0.000 description 7
- 239000003981 vehicle Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 239000007900 aqueous suspension Substances 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 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 6
- 239000000376 reactant Substances 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 5
- 229940022663 acetate Drugs 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 235000008504 concentrate Nutrition 0.000 description 5
- 239000007859 condensation product Substances 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 150000002632 lipids Chemical class 0.000 description 5
- 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 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 210000000427 trigeminal ganglion Anatomy 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 239000007995 HEPES buffer Substances 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 206010070834 Sensitisation Diseases 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 4
- 208000006673 asthma Diseases 0.000 description 4
- 229940098773 bovine serum albumin Drugs 0.000 description 4
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 238000013016 damping Methods 0.000 description 4
- 230000001815 facial effect Effects 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 4
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-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
- 239000007788 liquid Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 231100000956 nontoxicity Toxicity 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 230000008313 sensitization Effects 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 210000003901 trigeminal nerve Anatomy 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- 244000215068 Acacia senegal Species 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 102100024654 Calcitonin gene-related peptide type 1 receptor Human genes 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 229920000084 Gum arabic Polymers 0.000 description 3
- 101000760563 Homo sapiens Calcitonin gene-related peptide type 1 receptor Proteins 0.000 description 3
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 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 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- 208000007920 Neurogenic Inflammation Diseases 0.000 description 3
- 108090000189 Neuropeptides Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 235000019483 Peanut oil Nutrition 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000021355 Stearic acid Nutrition 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
- 235000010489 acacia gum Nutrition 0.000 description 3
- 239000000205 acacia gum Substances 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 238000005576 amination reaction Methods 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 229960002802 bromocriptine Drugs 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 108010050923 calcitonin gene-related peptide (8-37) Proteins 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- LUZRJRNZXALNLM-JGRZULCMSA-N dihydroergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2[C@@H](C=3C=CC=C4NC=C(C=34)C2)C1)C)C1=CC=CC=C1 LUZRJRNZXALNLM-JGRZULCMSA-N 0.000 description 3
- 229960004704 dihydroergotamine Drugs 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 description 3
- 238000010494 dissociation reaction Methods 0.000 description 3
- 230000005593 dissociations Effects 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- XCGSFFUVFURLIX-VFGNJEKYSA-N ergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2C(C=3C=CC=C4NC=C(C=34)C2)=C1)C)C1=CC=CC=C1 XCGSFFUVFURLIX-VFGNJEKYSA-N 0.000 description 3
- 229960004943 ergotamine Drugs 0.000 description 3
- XCGSFFUVFURLIX-UHFFFAOYSA-N ergotaminine Natural products C1=C(C=2C=CC=C3NC=C(C=23)C2)C2N(C)CC1C(=O)NC(C(N12)=O)(C)OC1(O)C1CCCN1C(=O)C2CC1=CC=CC=C1 XCGSFFUVFURLIX-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000001530 fumaric acid Substances 0.000 description 3
- 229960002598 fumaric acid Drugs 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 235000012204 lemonade/lime carbonate Nutrition 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 229960005181 morphine Drugs 0.000 description 3
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 3
- 239000012053 oil suspension Substances 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000000312 peanut oil Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 210000000664 rectum Anatomy 0.000 description 3
- 230000000452 restraining effect Effects 0.000 description 3
- 238000004007 reversed phase HPLC Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 229940095064 tartrate Drugs 0.000 description 3
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- 230000001196 vasorelaxation Effects 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 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
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine Chemical compound C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 description 2
- CNIIGCLFLJGOGP-UHFFFAOYSA-N 2-(1-naphthalenylmethyl)-4,5-dihydro-1H-imidazole Chemical compound C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 CNIIGCLFLJGOGP-UHFFFAOYSA-N 0.000 description 2
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- OFUFXTHGZWIDDB-UHFFFAOYSA-N 2-chloroquinoline Chemical compound C1=CC=CC2=NC(Cl)=CC=C21 OFUFXTHGZWIDDB-UHFFFAOYSA-N 0.000 description 2
- APIXJSLKIYYUKG-UHFFFAOYSA-N 3 Isobutyl 1 methylxanthine Chemical compound O=C1N(C)C(=O)N(CC(C)C)C2=C1N=CN2 APIXJSLKIYYUKG-UHFFFAOYSA-N 0.000 description 2
- CAAMSDWKXXPUJR-UHFFFAOYSA-N 3,5-dihydro-4H-imidazol-4-one Chemical compound O=C1CNC=N1 CAAMSDWKXXPUJR-UHFFFAOYSA-N 0.000 description 2
- KYJUBVYOOBEASB-UHFFFAOYSA-N 5-phenyl-3-piperidin-1-ium-4-yl-1h-imidazol-2-one;chloride Chemical compound [Cl-].O=C1NC(C=2C=CC=CC=2)=CN1C1CC[NH2+]CC1 KYJUBVYOOBEASB-UHFFFAOYSA-N 0.000 description 2
- 102000004379 Adrenomedullin Human genes 0.000 description 2
- 101800004616 Adrenomedullin Proteins 0.000 description 2
- WKEMJKQOLOHJLZ-UHFFFAOYSA-N Almogran Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1CS(=O)(=O)N1CCCC1 WKEMJKQOLOHJLZ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000972773 Aulopiformes Species 0.000 description 2
- 206010066091 Bronchial Hyperreactivity Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000000094 Chronic Pain Diseases 0.000 description 2
- 229940093444 Cyclooxygenase 2 inhibitor Drugs 0.000 description 2
- FFEARJCKVFRZRR-SCSAIBSYSA-N D-methionine Chemical compound CSCC[C@@H](N)C(O)=O FFEARJCKVFRZRR-SCSAIBSYSA-N 0.000 description 2
- 206010012434 Dermatitis allergic Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010013754 Drug withdrawal syndrome Diseases 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 206010015150 Erythema Diseases 0.000 description 2
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010060800 Hot flush Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 206010065390 Inflammatory pain Diseases 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- WVVSZNPYNCNODU-XTQGRXLLSA-N Lysergic acid propanolamide Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@H](CO)C)C2)=C3C2=CNC3=C1 WVVSZNPYNCNODU-XTQGRXLLSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 238000007126 N-alkylation reaction Methods 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-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
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 206010039361 Sacroiliitis Diseases 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 208000008548 Tension-Type Headache Diseases 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- HUCJFAOMUPXHDK-UHFFFAOYSA-N Xylometazoline Chemical compound CC1=CC(C(C)(C)C)=CC(C)=C1CC1=NCCN1 HUCJFAOMUPXHDK-UHFFFAOYSA-N 0.000 description 2
- ZALMZWWJQXBYQA-UHFFFAOYSA-N [N].[Cl] Chemical compound [N].[Cl] ZALMZWWJQXBYQA-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- XBMIVRRWGCYBTQ-UHFFFAOYSA-N acetylmethadol Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(OC(C)=O)CC)C1=CC=CC=C1 XBMIVRRWGCYBTQ-UHFFFAOYSA-N 0.000 description 2
- 229950005506 acetylmethadol Drugs 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- ULCUCJFASIJEOE-NPECTJMMSA-N adrenomedullin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC(=O)N[C@@H]1C(N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)NCC(=O)N[C@H](C(=O)N[C@@H](CSSC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)[C@@H](C)O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 ULCUCJFASIJEOE-NPECTJMMSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 229960002133 almotriptan Drugs 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 229940124433 antimigraine drug Drugs 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 239000000305 astragalus gummifer gum Substances 0.000 description 2
- 201000008937 atopic dermatitis Diseases 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 2
- VPSRQEHTHIMDQM-FKLPMGAJSA-N benazepril hydrochloride Chemical compound Cl.C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 VPSRQEHTHIMDQM-FKLPMGAJSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 239000012148 binding buffer Substances 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 230000036427 bronchial hyperreactivity Effects 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 229960004349 candesartan cilexetil Drugs 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 229960000590 celecoxib Drugs 0.000 description 2
- 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 2
- 230000001684 chronic effect Effects 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 238000006880 cross-coupling reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 125000005331 diazinyl group Chemical group N1=NC(=CC=C1)* 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- SOHCKWZVTCTQBG-UHFFFAOYSA-N donitriptan Chemical compound C1=C2C(CCN)=CNC2=CC=C1OCC(=O)N(CC1)CCN1C1=CC=C(C#N)C=C1 SOHCKWZVTCTQBG-UHFFFAOYSA-N 0.000 description 2
- 229950010344 donitriptan Drugs 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 230000005611 electricity Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 206010014599 encephalitis Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000002532 enzyme inhibitor Substances 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 229960001405 ergometrine Drugs 0.000 description 2
- 231100000321 erythema Toxicity 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229960002428 fentanyl Drugs 0.000 description 2
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- XPSQPHWEGNHMSK-SECBINFHSA-N frovatriptan Chemical compound N1C2=CC=C(C(N)=O)C=C2C2=C1CC[C@@H](NC)C2 XPSQPHWEGNHMSK-SECBINFHSA-N 0.000 description 2
- 229960002284 frovatriptan Drugs 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000003365 glass fiber Substances 0.000 description 2
- 229960002989 glutamic acid Drugs 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229920000591 gum Polymers 0.000 description 2
- 230000012447 hatching Effects 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- YQYJSBFKSSDGFO-FWAVGLHBSA-N hygromycin A Chemical compound O[C@H]1[C@H](O)[C@H](C(=O)C)O[C@@H]1Oc1ccc(\C=C(/C)C(=O)N[C@@H]2[C@@H]([C@H]3OCO[C@H]3[C@@H](O)[C@@H]2O)O)cc1O YQYJSBFKSSDGFO-FWAVGLHBSA-N 0.000 description 2
- 229960004801 imipramine Drugs 0.000 description 2
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 208000002551 irritable bowel syndrome Diseases 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 229940045996 isethionic acid Drugs 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 210000004731 jugular vein Anatomy 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 229960001848 lamotrigine Drugs 0.000 description 2
- PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- AMKVXSZCKVJAGH-UHFFFAOYSA-N naratriptan Chemical compound C12=CC(CCS(=O)(=O)NC)=CC=C2NC=C1C1CCN(C)CC1 AMKVXSZCKVJAGH-UHFFFAOYSA-N 0.000 description 2
- 229960005254 naratriptan Drugs 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 230000001272 neurogenic effect Effects 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- ITIXDWVDFFXNEG-JHOUSYSJSA-N olcegepant Chemical compound C([C@H](C(=O)N[C@@H](CCCCN)C(=O)N1CCN(CC1)C=1C=CN=CC=1)NC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2C1)=O)C1=CC(Br)=C(O)C(Br)=C1 ITIXDWVDFFXNEG-JHOUSYSJSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- WYWIFABBXFUGLM-UHFFFAOYSA-N oxymetazoline Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C)=C1CC1=NCCN1 WYWIFABBXFUGLM-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229960004662 parecoxib Drugs 0.000 description 2
- TZRHLKRLEZJVIJ-UHFFFAOYSA-N parecoxib Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 TZRHLKRLEZJVIJ-UHFFFAOYSA-N 0.000 description 2
- 229940000596 parlodel Drugs 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- CPJSUEIXXCENMM-UHFFFAOYSA-N phenacetin Chemical compound CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 238000012545 processing Methods 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
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 230000001185 psoriatic effect Effects 0.000 description 2
- 125000004309 pyranyl group Chemical class O1C(C=CC=C1)* 0.000 description 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 238000005932 reductive alkylation reaction Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- ULFRLSNUDGIQQP-UHFFFAOYSA-N rizatriptan Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1CN1C=NC=N1 ULFRLSNUDGIQQP-UHFFFAOYSA-N 0.000 description 2
- 229960000425 rizatriptan Drugs 0.000 description 2
- 239000011435 rock Substances 0.000 description 2
- 229960000371 rofecoxib Drugs 0.000 description 2
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 2
- 235000019515 salmon Nutrition 0.000 description 2
- WVYADZUPLLSGPU-UHFFFAOYSA-N salsalate Chemical compound OC(=O)C1=CC=CC=C1OC(=O)C1=CC=CC=C1O WVYADZUPLLSGPU-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 2
- 229960003708 sumatriptan Drugs 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YRCWQPVGYLYSOX-UHFFFAOYSA-N synephrine Chemical compound CNCC(O)C1=CC=C(O)C=C1 YRCWQPVGYLYSOX-UHFFFAOYSA-N 0.000 description 2
- 239000012747 synergistic agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 description 2
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 2
- 229930101283 tetracycline Natural products 0.000 description 2
- 229960002180 tetracycline Drugs 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 208000004371 toothache Diseases 0.000 description 2
- 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 2
- NDACAFBDTQIYCQ-YVQXRMNASA-N val(8)-phe(37)-cgrp Chemical compound C([C@@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)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](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)[C@@H](C)O)C1=CN=CN1 NDACAFBDTQIYCQ-YVQXRMNASA-N 0.000 description 2
- 229960002004 valdecoxib Drugs 0.000 description 2
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 2
- 235000013311 vegetables Nutrition 0.000 description 2
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 1
- HMJIYCCIJYRONP-UHFFFAOYSA-N (+-)-Isradipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC2=NON=C12 HMJIYCCIJYRONP-UHFFFAOYSA-N 0.000 description 1
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 description 1
- 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 1
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 1
- KPJZHOPZRAFDTN-ZRGWGRIASA-N (6aR,9R)-N-[(2S)-1-hydroxybutan-2-yl]-4,7-dimethyl-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@H](CO)CC)C2)=C3C2=CN(C)C3=C1 KPJZHOPZRAFDTN-ZRGWGRIASA-N 0.000 description 1
- UNBRKDKAWYKMIV-QWQRMKEZSA-N (6aR,9R)-N-[(2S)-1-hydroxybutan-2-yl]-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@H](CO)CC)C2)=C3C2=CNC3=C1 UNBRKDKAWYKMIV-QWQRMKEZSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 1
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-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
- PPKXEPBICJTCRU-XMZRARIVSA-N (R,R)-tramadol hydrochloride Chemical compound Cl.COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 PPKXEPBICJTCRU-XMZRARIVSA-N 0.000 description 1
- UUDAMDVQRQNNHZ-UHFFFAOYSA-N (S)-AMPA Chemical compound CC=1ONC(=O)C=1CC(N)C(O)=O UUDAMDVQRQNNHZ-UHFFFAOYSA-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
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 description 1
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- ZHYMGSPDEVXULU-UHFFFAOYSA-N 1,2-benzodiazepin-3-one Chemical compound N1=NC(=O)C=CC2=CC=CC=C21 ZHYMGSPDEVXULU-UHFFFAOYSA-N 0.000 description 1
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 1
- CZSRXHJVZUBEGW-UHFFFAOYSA-N 1,2-thiazolidine Chemical compound C1CNSC1 CZSRXHJVZUBEGW-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- JQSAYKKFZOSZGJ-UHFFFAOYSA-N 1-[bis(4-fluorophenyl)methyl]-4-[(2,3,4-trimethoxyphenyl)methyl]piperazine Chemical compound COC1=C(OC)C(OC)=CC=C1CN1CCN(C(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 JQSAYKKFZOSZGJ-UHFFFAOYSA-N 0.000 description 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 1
- ACOQCRWPQYUNSU-UHFFFAOYSA-N 1-benzyl-4-(2-chloroquinolin-3-yl)piperidin-4-ol Chemical compound C1CC(O)(C=2C(=NC3=CC=CC=C3C=2)Cl)CCN1CC1=CC=CC=C1 ACOQCRWPQYUNSU-UHFFFAOYSA-N 0.000 description 1
- 125000004806 1-methylethylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- OHUCGNJZMRINKX-UHFFFAOYSA-N 1-piperidin-1-ium-4-yl-3h-imidazo[4,5-b]pyridin-4-ium-2-one;dichloride Chemical compound Cl.Cl.O=C1NC2=NC=CC=C2N1C1CCNCC1 OHUCGNJZMRINKX-UHFFFAOYSA-N 0.000 description 1
- LRRMJTIYKJNZFB-UHFFFAOYSA-N 2,3,4,5,6-pentabromopyridine;hydrobromide Chemical compound Br.BrC1=NC(Br)=C(Br)C(Br)=C1Br LRRMJTIYKJNZFB-UHFFFAOYSA-N 0.000 description 1
- KWJQWQPCFHIXJD-UHFFFAOYSA-N 2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride Chemical compound Cl.Cl.C1=CN=C2NCNC2=C1 KWJQWQPCFHIXJD-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- CYENWLQMKHLYKF-UHFFFAOYSA-N 2-[carboxymethyl(3-sulfopropyl)amino]acetic acid Chemical compound OC(=O)CN(CC(O)=O)CCCS(O)(=O)=O CYENWLQMKHLYKF-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- SPCKHVPPRJWQRZ-UHFFFAOYSA-N 2-benzhydryloxy-n,n-dimethylethanamine;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 SPCKHVPPRJWQRZ-UHFFFAOYSA-N 0.000 description 1
- KHEVPDFAQFJIGK-UHFFFAOYSA-N 2-sulfooxyethanesulfonic acid Chemical compound OS(=O)(=O)CCOS(O)(=O)=O KHEVPDFAQFJIGK-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- JXZZEXZZKAWDSP-UHFFFAOYSA-N 3-(2-(4-Benzamidopiperid-1-yl)ethyl)indole Chemical group C1CN(CCC=2C3=CC=CC=C3NC=2)CCC1NC(=O)C1=CC=CC=C1 JXZZEXZZKAWDSP-UHFFFAOYSA-N 0.000 description 1
- YDUGVOUXNSWQSW-UHFFFAOYSA-N 3-bromo-1h-pyridin-2-one Chemical compound OC1=NC=CC=C1Br YDUGVOUXNSWQSW-UHFFFAOYSA-N 0.000 description 1
- RBCARPJOEUEZLS-UHFFFAOYSA-N 3-bromopyridin-2-amine Chemical compound NC1=NC=CC=C1Br RBCARPJOEUEZLS-UHFFFAOYSA-N 0.000 description 1
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 1
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 description 1
- GUUULVAMQJLDSY-UHFFFAOYSA-N 4,5-dihydro-1,2-thiazole Chemical compound C1CC=NS1 GUUULVAMQJLDSY-UHFFFAOYSA-N 0.000 description 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 1
- MDMJLMDBRQXOOI-UHFFFAOYSA-N 4-fluoro-n-[3-(1-methylpiperidin-4-yl)-1h-indol-5-yl]benzamide Chemical group C1CN(C)CCC1C(C1=C2)=CNC1=CC=C2NC(=O)C1=CC=C(F)C=C1 MDMJLMDBRQXOOI-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- WAAWMJYYKITCGF-WTPIMUJOSA-N 5alpha-ergostane Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CC[C@H](C)C(C)C)[C@@]2(C)CC1 WAAWMJYYKITCGF-WTPIMUJOSA-N 0.000 description 1
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 description 1
- OBYJTLDIQBWBHM-UHFFFAOYSA-N 6-chloropyridin-2-amine Chemical compound NC1=CC=CC(Cl)=N1 OBYJTLDIQBWBHM-UHFFFAOYSA-N 0.000 description 1
- 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 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 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
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- 239000002080 C09CA02 - Eprosartan Substances 0.000 description 1
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 1
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 1
- 239000005537 C09CA07 - Telmisartan Substances 0.000 description 1
- YURNUQQDKASIIJ-UHFFFAOYSA-N CCOClC Chemical compound CCOClC YURNUQQDKASIIJ-UHFFFAOYSA-N 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 description 1
- AKJDEXBCRLOVTH-UHFFFAOYSA-N Carbetapentane citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C1(C(=O)OCCOCCN(CC)CC)CCCC1 AKJDEXBCRLOVTH-UHFFFAOYSA-N 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 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
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 1
- 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 1
- 206010011224 Cough Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 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 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
- 229930182818 D-methionine Natural products 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- NESVMZOPWPCFAU-UHFFFAOYSA-N Ergoclavinine Natural products C1=CC(C=2C(N(C)CC(C=2)C(=O)NC2(C(=O)N3C(C(N4CCCC4C3(O)O2)=O)CC(C)C)C)C2)=C3C2=CNC3=C1 NESVMZOPWPCFAU-UHFFFAOYSA-N 0.000 description 1
- UJYGDMFEEDNVBF-UHFFFAOYSA-N Ergocorninine Natural products C1=CC(C=2C(N(C)CC(C=2)C(=O)NC2(C(=O)N3C(C(N4CCCC4C3(O)O2)=O)C(C)C)C(C)C)C2)=C3C2=CNC3=C1 UJYGDMFEEDNVBF-UHFFFAOYSA-N 0.000 description 1
- 108010008165 Etanercept Proteins 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 108091008681 GABAA receptors Proteins 0.000 description 1
- 102000027484 GABAA receptors Human genes 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
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 238000007341 Heck reaction Methods 0.000 description 1
- 101000741445 Homo sapiens Calcitonin Proteins 0.000 description 1
- 101000932890 Homo sapiens Calcitonin gene-related peptide 1 Proteins 0.000 description 1
- 101000584583 Homo sapiens Receptor activity-modifying protein 1 Proteins 0.000 description 1
- 208000004454 Hyperalgesia Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 108010041872 Islet Amyloid Polypeptide Proteins 0.000 description 1
- 102000036770 Islet Amyloid Polypeptide Human genes 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 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 1
- 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 1
- 239000012097 Lipofectamine 2000 Substances 0.000 description 1
- 102000003820 Lipoxygenases Human genes 0.000 description 1
- 108090000128 Lipoxygenases Proteins 0.000 description 1
- 108010007859 Lisinopril Proteins 0.000 description 1
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 108010065028 Metabotropic Glutamate 5 Receptor Proteins 0.000 description 1
- 102100038357 Metabotropic glutamate receptor 5 Human genes 0.000 description 1
- 241001092142 Molina Species 0.000 description 1
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 description 1
- IJHNSHDBIRRJRN-UHFFFAOYSA-N N,N-dimethyl-3-phenyl-3-(2-pyridinyl)-1-propanamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=CC=C1 IJHNSHDBIRRJRN-UHFFFAOYSA-N 0.000 description 1
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 description 1
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 description 1
- 102000003797 Neuropeptides Human genes 0.000 description 1
- 229940123134 Nitric oxide inhibitor Drugs 0.000 description 1
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000005480 Olmesartan Substances 0.000 description 1
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 description 1
- RMUCZJUITONUFY-UHFFFAOYSA-N Phenelzine Chemical compound NNCCC1=CC=CC=C1 RMUCZJUITONUFY-UHFFFAOYSA-N 0.000 description 1
- ISFHAYSTHMVOJR-UHFFFAOYSA-N Phenindamine Chemical compound C1N(C)CCC(C2=CC=CC=C22)=C1C2C1=CC=CC=C1 ISFHAYSTHMVOJR-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 102100030697 Receptor activity-modifying protein 1 Human genes 0.000 description 1
- 241000218998 Salicaceae Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 206010043269 Tension headache Diseases 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 240000006474 Theobroma bicolor Species 0.000 description 1
- 208000009205 Tinnitus Diseases 0.000 description 1
- KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- YEEZWCHGZNKEEK-UHFFFAOYSA-N Zafirlukast Chemical compound COC1=CC(C(=O)NS(=O)(=O)C=2C(=CC=CC=2)C)=CC=C1CC(C1=C2)=CN(C)C1=CC=C2NC(=O)OC1CCCC1 YEEZWCHGZNKEEK-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- CCCUVHHPYBWVOW-UHFFFAOYSA-K [Na+].[Na+].[Na+].[O-]S(=O)(=O)c1ccccc1.[O-]S(=O)(=O)c1ccccc1.[O-]S(=O)(=O)c1ccccc1 Chemical compound [Na+].[Na+].[Na+].[O-]S(=O)(=O)c1ccccc1.[O-]S(=O)(=O)c1ccccc1.[O-]S(=O)(=O)c1ccccc1 CCCUVHHPYBWVOW-UHFFFAOYSA-K 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- PWACSDKDOHSSQD-IUTFFREVSA-N acrivastine Chemical compound C1=CC(C)=CC=C1C(\C=1N=C(\C=C\C(O)=O)C=CC=1)=C/CN1CCCC1 PWACSDKDOHSSQD-IUTFFREVSA-N 0.000 description 1
- 229960003792 acrivastine Drugs 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 206010053552 allodynia Diseases 0.000 description 1
- YDOTUXAWKBPQJW-NSLWYYNWSA-N alpha-ergocryptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=CNC3=C1 YDOTUXAWKBPQJW-NSLWYYNWSA-N 0.000 description 1
- 229950001817 alpha-ergocryptine Drugs 0.000 description 1
- 229960004538 alprazolam Drugs 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 229960000836 amitriptyline Drugs 0.000 description 1
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229960000528 amlodipine Drugs 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical group O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 description 1
- 229960001372 aprepitant Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 229960002274 atenolol Drugs 0.000 description 1
- WRZVGHXUPBWIOO-UHFFFAOYSA-N avitriptan Chemical compound C12=CC(CS(=O)(=O)NC)=CC=C2NC=C1CCCN(CC1)CCN1C1=NC=NC=C1OC WRZVGHXUPBWIOO-UHFFFAOYSA-N 0.000 description 1
- 229950002360 avitriptan Drugs 0.000 description 1
- 229960001671 azapropazone Drugs 0.000 description 1
- 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 1
- SEBMTIQKRHYNIT-UHFFFAOYSA-N azatadine Chemical compound C1CN(C)CCC1=C1C2=NC=CC=C2CCC2=CC=CC=C21 SEBMTIQKRHYNIT-UHFFFAOYSA-N 0.000 description 1
- 229960000383 azatadine Drugs 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 235000013405 beer Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000009286 beneficial effect Effects 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
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- VZOVOHRDLOYBJX-UHFFFAOYSA-N benzyl 4-oxopiperidine-1-carboxylate Chemical compound C1CC(=O)CCN1C(=O)OCC1=CC=CC=C1 VZOVOHRDLOYBJX-UHFFFAOYSA-N 0.000 description 1
- 229950010031 beta-ergocryptine Drugs 0.000 description 1
- YYWXOXLDOMRDHW-UHFFFAOYSA-N beta-ergocryptine Natural products C1=CC(C=2C(N(C)CC(C=2)C(=O)NC2(C(=O)N3C(C(N4CCCC4C3(O)O2)=O)C(C)CC)C(C)C)C2)=C3C2=CNC3=C1 YYWXOXLDOMRDHW-UHFFFAOYSA-N 0.000 description 1
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- NUNIWXHYABYXKF-UHFFFAOYSA-N bromazine Chemical compound C=1C=C(Br)C=CC=1C(OCCN(C)C)C1=CC=CC=C1 NUNIWXHYABYXKF-UHFFFAOYSA-N 0.000 description 1
- ZDIGNSYAACHWNL-UHFFFAOYSA-N brompheniramine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Br)C=C1 ZDIGNSYAACHWNL-UHFFFAOYSA-N 0.000 description 1
- 229960000725 brompheniramine Drugs 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 1
- 229960001736 buprenorphine Drugs 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 description 1
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 1
- 229960002504 capsaicin Drugs 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 229950011546 carabersat Drugs 0.000 description 1
- OFAIGZWCDGNZGT-UHFFFAOYSA-N caramiphen Chemical compound C=1C=CC=CC=1C1(C(=O)OCCN(CC)CC)CCCC1 OFAIGZWCDGNZGT-UHFFFAOYSA-N 0.000 description 1
- 229960004160 caramiphen Drugs 0.000 description 1
- OJFSXZCBGQGRNV-UHFFFAOYSA-N carbinoxamine Chemical compound C=1C=CC=NC=1C(OCCN(C)C)C1=CC=C(Cl)C=C1 OJFSXZCBGQGRNV-UHFFFAOYSA-N 0.000 description 1
- 229960000428 carbinoxamine Drugs 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- PBKVEOSEPXMKDN-LZHUFOCISA-N chembl2311030 Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.CS(O)(=O)=O.CS(O)(=O)=O.C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)C(C)C)C(C)C)=C3C2=CNC3=C1.C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)C(C)CC)C(C)C)=C3C2=CNC3=C1.C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)CC(C)C)C(C)C)=C3C2=CNC3=C1.C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](C(N21)=O)(NC(=O)[C@H]1CN(C)[C@H]2[C@@H](C=3C=CC=C4NC=C(C=34)C2)C1)C(C)C)C1=CC=CC=C1 PBKVEOSEPXMKDN-LZHUFOCISA-N 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- 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 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 208000037516 chromosome inversion disease Diseases 0.000 description 1
- 125000000259 cinnolinyl group Chemical class N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 229960001653 citalopram Drugs 0.000 description 1
- YNNUSGIPVFPVBX-NHCUHLMSSA-N clemastine Chemical compound CN1CCC[C@@H]1CCO[C@@](C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 YNNUSGIPVFPVBX-NHCUHLMSSA-N 0.000 description 1
- 229960002881 clemastine Drugs 0.000 description 1
- 229960004606 clomipramine Drugs 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 238000006298 dechlorination reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000000850 decongestant Substances 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 229960003914 desipramine Drugs 0.000 description 1
- ZDIGNSYAACHWNL-HNNXBMFYSA-N dexbrompheniramine Chemical compound C1([C@H](CCN(C)C)C=2N=CC=CC=2)=CC=C(Br)C=C1 ZDIGNSYAACHWNL-HNNXBMFYSA-N 0.000 description 1
- 229960002691 dexbrompheniramine Drugs 0.000 description 1
- SOYKEARSMXGVTM-HNNXBMFYSA-N dexchlorpheniramine Chemical compound C1([C@H](CCN(C)C)C=2N=CC=CC=2)=CC=C(Cl)C=C1 SOYKEARSMXGVTM-HNNXBMFYSA-N 0.000 description 1
- 229960001882 dexchlorpheniramine Drugs 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- MKXZASYAUGDDCJ-NJAFHUGGSA-N dextromethorphan Chemical compound C([C@@H]12)CCC[C@]11CCN(C)[C@H]2CC2=CC=C(OC)C=C21 MKXZASYAUGDDCJ-NJAFHUGGSA-N 0.000 description 1
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 description 1
- 229960004193 dextropropoxyphene Drugs 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- PBUNVLRHZGSROC-VTIMJTGVSA-N dihydro-alpha-ergocryptine Chemical compound C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)CC(C)C)C(C)C)=C3C2=CNC3=C1 PBUNVLRHZGSROC-VTIMJTGVSA-N 0.000 description 1
- SEALOBQTUQIVGU-QNIJNHAOSA-N dihydroergocornine Chemical compound C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)C(C)C)C(C)C)=C3C2=CNC3=C1 SEALOBQTUQIVGU-QNIJNHAOSA-N 0.000 description 1
- 229960004290 dihydroergocornine Drugs 0.000 description 1
- DEQITUUQPICUMR-HJPBWRTMSA-N dihydroergocristine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](C(N21)=O)(NC(=O)[C@H]1CN(C)[C@H]2[C@@H](C=3C=CC=C4NC=C(C=34)C2)C1)C(C)C)C1=CC=CC=C1 DEQITUUQPICUMR-HJPBWRTMSA-N 0.000 description 1
- 229960004318 dihydroergocristine Drugs 0.000 description 1
- 229960002032 dihydroergocryptine Drugs 0.000 description 1
- 229940043279 diisopropylamine 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
- 238000007865 diluting Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 229960000520 diphenhydramine Drugs 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- AUZONCFQVSMFAP-UHFFFAOYSA-N disulfiram Chemical compound CCN(CC)C(=S)SSC(=S)N(CC)CC AUZONCFQVSMFAP-UHFFFAOYSA-N 0.000 description 1
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229960001253 domperidone Drugs 0.000 description 1
- 229960005426 doxepin Drugs 0.000 description 1
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 1
- HCFDWZZGGLSKEP-UHFFFAOYSA-N doxylamine Chemical compound C=1C=CC=NC=1C(C)(OCCN(C)C)C1=CC=CC=C1 HCFDWZZGGLSKEP-UHFFFAOYSA-N 0.000 description 1
- 229960005178 doxylamine 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
- 238000001035 drying Methods 0.000 description 1
- 229960002866 duloxetine Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- OROAFUQRIXKEMV-LDADJPATSA-N eprosartan Chemical compound C=1C=C(C(O)=O)C=CC=1CN1C(CCCC)=NC=C1\C=C(C(O)=O)/CC1=CC=CS1 OROAFUQRIXKEMV-LDADJPATSA-N 0.000 description 1
- 229960004563 eprosartan Drugs 0.000 description 1
- UJYGDMFEEDNVBF-OGGGUQDZSA-N ergocornine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)C(C)C)C(C)C)C2)=C3C2=CNC3=C1 UJYGDMFEEDNVBF-OGGGUQDZSA-N 0.000 description 1
- HEFIYUQVAZFDEE-MKTPKCENSA-N ergocristine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](C(N21)=O)(NC(=O)[C@@H]1C=C2C=3C=CC=C4NC=C(C=34)C[C@H]2N(C)C1)C(C)C)C1=CC=CC=C1 HEFIYUQVAZFDEE-MKTPKCENSA-N 0.000 description 1
- HEFIYUQVAZFDEE-UHFFFAOYSA-N ergocristinine Natural products N12C(=O)C(C(C)C)(NC(=O)C3C=C4C=5C=CC=C6NC=C(C=56)CC4N(C)C3)OC2(O)C2CCCN2C(=O)C1CC1=CC=CC=C1 HEFIYUQVAZFDEE-UHFFFAOYSA-N 0.000 description 1
- NESVMZOPWPCFAU-ZPRCMDFASA-N ergosine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C)C2)=C3C2=CNC3=C1 NESVMZOPWPCFAU-ZPRCMDFASA-N 0.000 description 1
- 229960003133 ergot alkaloid Drugs 0.000 description 1
- 229960004341 escitalopram Drugs 0.000 description 1
- WSEQXVZVJXJVFP-FQEVSTJZSA-N escitalopram Chemical compound C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-FQEVSTJZSA-N 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229940043351 ethyl-p-hydroxybenzoate Drugs 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 229960005293 etodolac Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 229960003580 felodipine Drugs 0.000 description 1
- 229960001419 fenoprofen Drugs 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 1
- 229960004369 flufenamic acid Drugs 0.000 description 1
- SMANXXCATUTDDT-QPJJXVBHSA-N flunarizine Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)N1CCN(C\C=C\C=2C=CC=CC=2)CC1 SMANXXCATUTDDT-QPJJXVBHSA-N 0.000 description 1
- 229960000326 flunarizine Drugs 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- JKFAIQOWCVVSKC-UHFFFAOYSA-N furazan Chemical compound C=1C=NON=1 JKFAIQOWCVVSKC-UHFFFAOYSA-N 0.000 description 1
- 229960002870 gabapentin Drugs 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
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 229960002056 indoramin Drugs 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- HEBMCVBCEDMUOF-UHFFFAOYSA-N isochromane Chemical compound C1=CC=C2COCCC2=C1 HEBMCVBCEDMUOF-UHFFFAOYSA-N 0.000 description 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 229960004427 isradipine Drugs 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
- 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 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 229960004752 ketorolac Drugs 0.000 description 1
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000003199 leukotriene receptor blocking agent Substances 0.000 description 1
- XBMIVRRWGCYBTQ-AVRDEDQJSA-N levacetylmethadol Chemical compound C=1C=CC=CC=1C(C[C@H](C)N(C)C)([C@@H](OC(C)=O)CC)C1=CC=CC=C1 XBMIVRRWGCYBTQ-AVRDEDQJSA-N 0.000 description 1
- 229960004002 levetiracetam Drugs 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
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229960002394 lisinopril Drugs 0.000 description 1
- CZRQXSDBMCMPNJ-ZUIPZQNBSA-N lisinopril dihydrate Chemical compound O.O.C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 CZRQXSDBMCMPNJ-ZUIPZQNBSA-N 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 1
- 229950007692 lomerizine Drugs 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 229960003088 loratadine Drugs 0.000 description 1
- 229960002202 lornoxicam Drugs 0.000 description 1
- OXROWJKCGCOJDO-JLHYYAGUSA-N lornoxicam Chemical compound O=C1C=2SC(Cl)=CC=2S(=O)(=O)N(C)\C1=C(\O)NC1=CC=CC=N1 OXROWJKCGCOJDO-JLHYYAGUSA-N 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 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
- 241001515942 marmosets Species 0.000 description 1
- 229960003803 meclofenamic acid Drugs 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- 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 1
- 229960001929 meloxicam Drugs 0.000 description 1
- YECBIJXISLIIDS-UHFFFAOYSA-N mepyramine Chemical compound C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 YECBIJXISLIIDS-UHFFFAOYSA-N 0.000 description 1
- 229960000582 mepyramine Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- WZHJKEUHNJHDLS-QTGUNEKASA-N metergoline Chemical compound C([C@H]1CN([C@H]2[C@@H](C=3C=CC=C4N(C)C=C(C=34)C2)C1)C)NC(=O)OCC1=CC=CC=C1 WZHJKEUHNJHDLS-QTGUNEKASA-N 0.000 description 1
- 229960004650 metergoline Drugs 0.000 description 1
- 229960001797 methadone Drugs 0.000 description 1
- 229960001252 methamphetamine Drugs 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- VKQFCGNPDRICFG-UHFFFAOYSA-N methyl 2-methylpropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1C1=CC=CC=C1[N+]([O-])=O VKQFCGNPDRICFG-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 229960000328 methylergometrine Drugs 0.000 description 1
- 229960001186 methysergide Drugs 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical group CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 1
- 229960002237 metoprolol Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- 229960005127 montelukast Drugs 0.000 description 1
- 239000000472 muscarinic agonist Substances 0.000 description 1
- 239000003149 muscarinic antagonist Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- RCLXAPJEFHPYEG-ZWKOTPCHSA-N n-[(3r,4s)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-4-fluorobenzamide Chemical compound N([C@@H]1[C@@H](O)C(C)(C)OC2=CC=C(C=C21)C(=O)C)C(=O)C1=CC=C(F)C=C1 RCLXAPJEFHPYEG-ZWKOTPCHSA-N 0.000 description 1
- XLIIRNOPGJTBJD-ROUUACIJSA-N n-[(3s,4s)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide Chemical compound N([C@@H]1[C@H](O)C(C)(C)OC2=CC=C(C=C21)C(=O)C)C(=O)C1=CC=C(F)C(Cl)=C1 XLIIRNOPGJTBJD-ROUUACIJSA-N 0.000 description 1
- 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 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960004270 nabumetone Drugs 0.000 description 1
- VWPOSFSPZNDTMJ-UCWKZMIHSA-N nadolol Chemical compound C1[C@@H](O)[C@@H](O)CC2=C1C=CC=C2OCC(O)CNC(C)(C)C VWPOSFSPZNDTMJ-UCWKZMIHSA-N 0.000 description 1
- 229960004255 nadolol Drugs 0.000 description 1
- 229960005016 naphazoline Drugs 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 150000005054 naphthyridines Chemical class 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 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 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 229960000965 nimesulide Drugs 0.000 description 1
- HYWYRSMBCFDLJT-UHFFFAOYSA-N nimesulide Chemical compound CS(=O)(=O)NC1=CC=C([N+]([O-])=O)C=C1OC1=CC=CC=C1 HYWYRSMBCFDLJT-UHFFFAOYSA-N 0.000 description 1
- 229960000715 nimodipine Drugs 0.000 description 1
- 229960000227 nisoldipine Drugs 0.000 description 1
- 229960003753 nitric oxide Drugs 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 229960001158 nortriptyline Drugs 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- QIJKDGCMXZEJOH-UHFFFAOYSA-N o-carbamoyl benzenecarbothioate Chemical compound NC(=O)OC(=S)C1=CC=CC=C1 QIJKDGCMXZEJOH-UHFFFAOYSA-N 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- CKQVRZJOMJRTOY-UHFFFAOYSA-N octadecanoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCCCC(O)=O CKQVRZJOMJRTOY-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229960005017 olanzapine Drugs 0.000 description 1
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 1
- 229960005117 olmesartan Drugs 0.000 description 1
- 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 1
- 229960004110 olsalazine Drugs 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229960003684 oxedrine Drugs 0.000 description 1
- 125000005702 oxyalkylene group Chemical group 0.000 description 1
- 229960001528 oxymetazoline 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
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 229960002296 paroxetine Drugs 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229960003436 pentoxyverine Drugs 0.000 description 1
- IPVQLZZIHOAWMC-QXKUPLGCSA-N perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 description 1
- 229960002582 perindopril Drugs 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229960003893 phenacetin Drugs 0.000 description 1
- 229960000964 phenelzine Drugs 0.000 description 1
- 229960003534 phenindamine Drugs 0.000 description 1
- 229960001190 pheniramine Drugs 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- 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 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- IZRPKIZLIFYYKR-UHFFFAOYSA-N phenyltoloxamine Chemical compound CN(C)CCOC1=CC=CC=C1CC1=CC=CC=C1 IZRPKIZLIFYYKR-UHFFFAOYSA-N 0.000 description 1
- 229960001526 phenyltoloxamine Drugs 0.000 description 1
- 229960004838 phosphoric acid Drugs 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical class C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- 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 1
- PNTVCCRNJOGKGA-QFIPXVFZSA-N pnu-142633 Chemical group C([C@H]1C2=CC=C(C=C2CCO1)C(=O)NC)CN(CC1)CCN1C1=CC=C(C(N)=O)C=C1 PNTVCCRNJOGKGA-QFIPXVFZSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229960001233 pregabalin 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
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229960003910 promethazine Drugs 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 229960000786 propylhexedrine Drugs 0.000 description 1
- JCRIVQIOJSSCQD-UHFFFAOYSA-N propylhexedrine Chemical compound CNC(C)CC1CCCCC1 JCRIVQIOJSSCQD-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 229960002601 protriptyline Drugs 0.000 description 1
- BWPIARFWQZKAIA-UHFFFAOYSA-N protriptyline Chemical compound C1=CC2=CC=CC=C2C(CCCNC)C2=CC=CC=C21 BWPIARFWQZKAIA-UHFFFAOYSA-N 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- 229960003908 pseudoephedrine Drugs 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- ZZYXNRREDYWPLN-UHFFFAOYSA-N pyridine-2,3-diamine Chemical compound NC1=CC=CN=C1N ZZYXNRREDYWPLN-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 229960004431 quetiapine Drugs 0.000 description 1
- URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 description 1
- 229960001455 quinapril Drugs 0.000 description 1
- JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-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
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 229960003401 ramipril Drugs 0.000 description 1
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 108010074523 rimabotulinumtoxinB Proteins 0.000 description 1
- 229960000953 salsalate Drugs 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000003521 serotonin 5-HT1 receptor agonist Substances 0.000 description 1
- 239000003215 serotonin 5-HT2 receptor antagonist Substances 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- 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 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000003195 sodium channel blocking agent Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- UMZYVTHWQMCHRF-UHFFFAOYSA-N sodium dimethylsilylazanide Chemical compound [Na+].C[SiH](C)[NH-] UMZYVTHWQMCHRF-UHFFFAOYSA-N 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000006265 spirocyclization reaction Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Natural products 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 1
- 229960005322 streptomycin Drugs 0.000 description 1
- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.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](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.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](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 description 1
- 229960004739 sufentanil Drugs 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- 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 1
- 229940032330 sulfuric acid Drugs 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- 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 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000012622 synthetic inhibitor Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- 229960003676 tenidap Drugs 0.000 description 1
- LXIKEPCNDFVJKC-QXMHVHEDSA-N tenidap Chemical compound C12=CC(Cl)=CC=C2N(C(=O)N)C(=O)\C1=C(/O)C1=CC=CS1 LXIKEPCNDFVJKC-QXMHVHEDSA-N 0.000 description 1
- 229960002871 tenoxicam Drugs 0.000 description 1
- 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 1
- 229960000351 terfenadine Drugs 0.000 description 1
- XTDXZSGSIMLARD-UHFFFAOYSA-N tert-butyl 2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC=CC=C1 XTDXZSGSIMLARD-UHFFFAOYSA-N 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 150000004867 thiadiazoles Chemical class 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- PBJUNZJWGZTSKL-MRXNPFEDSA-N tiagabine Chemical compound C1=CSC(C(=CCCN2C[C@@H](CCC2)C(O)=O)C2=C(C=CS2)C)=C1C PBJUNZJWGZTSKL-MRXNPFEDSA-N 0.000 description 1
- 229960001918 tiagabine Drugs 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- YEZNLOUZAIOMLT-UHFFFAOYSA-N tolfenamic acid Chemical compound CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O YEZNLOUZAIOMLT-UHFFFAOYSA-N 0.000 description 1
- 229960002905 tolfenamic acid Drugs 0.000 description 1
- 229960001017 tolmetin Drugs 0.000 description 1
- 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 1
- 229950009080 tonabersat Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960002431 trimipramine Drugs 0.000 description 1
- ZSCDBOWYZJWBIY-UHFFFAOYSA-N trimipramine Chemical compound C1CC2=CC=CC=C2N(CC(CN(C)C)C)C2=CC=CC=C21 ZSCDBOWYZJWBIY-UHFFFAOYSA-N 0.000 description 1
- CBEQULMOCCWAQT-WOJGMQOQSA-N triprolidine Chemical compound C1=CC(C)=CC=C1C(\C=1N=CC=CC=1)=C/CN1CCCC1 CBEQULMOCCWAQT-WOJGMQOQSA-N 0.000 description 1
- 229960001128 triprolidine Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229960000833 xylometazoline Drugs 0.000 description 1
- 229960004764 zafirlukast Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229960002911 zonisamide Drugs 0.000 description 1
- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 description 1
- YKPUWZUDDOIDPM-VURMDHGXSA-N zucapsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C/C(C)C)=CC=C1O YKPUWZUDDOIDPM-VURMDHGXSA-N 0.000 description 1
- 229960002860 zucapsaicin Drugs 0.000 description 1
- YYWXOXLDOMRDHW-SDMXVIBFSA-N β-ergocryptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)[C@@H](C)CC)C(C)C)C2)=C3C2=CNC3=C1 YYWXOXLDOMRDHW-SDMXVIBFSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- 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
- 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
- A61P11/06—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
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- 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
-
- 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
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/06—Antimigraine agents
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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
- 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
Abstract
式(I)的化合物(其中变量R1、A、B、W、X、Y和Z如本文中所定义的)用作CGRP受体拮抗剂和用于治疗或预防其中涉及CGRP的疾病,例如头痛、偏头痛和丛集性头痛。本发明还涉及含有这些化合物的药用组合物和这些化合物与组合物在预防或治疗其中涉及CGRP的这样疾病中的用途。
Description
发明背景
CGRP(降钙素基因相关肽)是天然存在的37氨基酸肽,由降钙素信使RNA的组织特异性交替程序产生,广泛分布在中枢和外周神经系统内。CGRP主要集中在感觉传入和中枢神经元,介导包括血管舒张在内的几种生物作用。CGRP以α-和β-形式表达,在大鼠和人中各自通过1种和3种氨基酸变化。CGRP-α和CGRP-β表现类似的生物学性质。当从细胞释放时,CGRP通过与特异性细胞表面受体结合启动其生物反应,这些受体主要与活化的腺苷酸环化酶偶联。CGRP受体在几种组织和细胞(包括脑、心血管、内皮和平滑肌起始部)中已得到鉴定和药理学评估。
基于药理性质,将这些受体分成至少2种亚型,称为CGRP1和CGRP2。人α-CGRP-(8-37),缺乏7个N-末端氨基酸残基的CGRP片段是CGRP1的选择性拮抗剂,而CGRP的线性类似物二乙酰氨基甲基半胱氨酸CGRP([Cys(ACM)2,7]CGRP)是CGRP2的选择性激动剂。CGRP是牵涉脑血管疾病例如偏头痛和丛集性头痛发病机理的有效血管舒张剂。在临床研究中,发现偏头痛发作时颈静脉内CGRP水平提高(Goadsby等,Ann.Neurol.,1990,28,183-187)。CGRP激活颅内血管平滑肌上的受体,增强血管舒张,认为这是偏头痛发作时头痛的主要原因(Lance,Headache Pathogenesis:Monoamines,Neuropeptides,Purines and Nitric Oxide(头痛发病机理:单胺、神经肽、嘌呤和氧化氮),Lippincott-Raven Publishers,1997,3-9)。脑膜中动脉(硬脑膜的主要动脉)受来自三叉神经节的感觉神经纤维支配,三叉神经节包含包括CGRP在内的几种神经肽。刺激猫的三叉神经节使CGRP水平增加,激活人的三叉神经系统导致面部发红和颈外静脉中CGRP水平增加(Goadsby等,Ann.Neurol.,1988,23,193-196)。电刺激大鼠硬脑膜可增加脑膜中动脉的直径,预先给予CGRP(8-37)(肽CGRP拮抗剂)可阻断该作用(Williamson等,Cephalalgia,1997,17,525-531)。三叉神经节刺激增加大鼠面部血流,这种现象可由CGRP(8-37)抑制(Escott等,Brain Res.1995,669,93-99)。电刺激狨猴三叉神经节使面部血流增加,这可由非肽CGRP拮抗剂BIBN4096BS阻断(Doods等,Br.J.Pharmacol.,2000,129,420-423)。因此CGRP拮抗剂可减弱、预防或逆转CGRP的血管作用。
已显示大鼠脑膜中动脉的CGRP介导的血管舒张作用使三叉神经尾核的神经元致敏(Williamson等,The CGRP Family:CalcitoninGene-Related Peptide(CGRP),Amylin,and Adrenomedullin(CGRP家族:降钙素基因相关肽(CGRP)、糊精和肾上腺髓质素),LandesBioscience,2000,245-247)。类似地,偏头痛时硬脑膜血管的扩张可能使三叉神经元致敏。包括颅外疼痛和面部异常性疼痛在内的一些偏头痛相关症状可能是三叉神经元被致敏的结果(Burstein等,Ann.Neurol.2000,47,614-624)。CGRP拮抗剂可能有利于减弱、预防或逆转神经元致敏的效应。
本发明化合物充当CGRP拮抗剂的能力使它们可用作涉及人和动物(特别是人)中CGRP的疾病的药物。此类疾病包括偏头痛和丛集性头痛(Doods,Curr Opin Inves Drugs,2001,2(9),1261-1268;Edvinsson等,Cephalalgia,1994,14,320-327);慢性紧张性头痛(Ashina等,Neurology,2000,14,1335-1340);疼痛(Yu等,Eur.J.Pharm.,1998,347,275-282);慢性疼痛(Hulsebosch等,Pain,2000,86,163-175);神经源性炎症和炎性疼痛(Holzer,Neurosci.,1988,24,739-768;Delay-Goyet等,Acta Physiol.Scanda.1992,146,537-538;Salmon等,NatureNeurosci.,2001,4(4),357-358);眼痛(May等Cephalalgia,2002,22,195-196),牙痛(Awawdeh等,Int.Endocrin.J.,2002,35,30-36),非胰岛素依赖性糖尿病(Molina等,Diabetes,1990,39,260-265);血管疾病;炎症(Zhang等,Pain,2001,89,265),关节炎,支气管高反应性,哮喘,(Foster等,Ann.NY Acad.Sci,1992,657,397-404;Schini等,Am.J.Physiol.,1994,267,H2483-H2490;Zheng等,J.Virol,1993,67,5786-5791);休克,脓毒症(Beer等,Crit.Care Med.,2002,30(8),1794-1798);阿片样物质戒断综合征(Salmon等,Nature Neurosci.,2001,4(4),357-358),吗啡耐受(Menard等,J.Neurosci.,1996,16(7),2342-2351);男性和女性的热潮红(Chen等,Lancet,1993,342,49;Spetz等,J.Urology,2001,166,1720-1723);变应性皮炎(Wallengren,ContactDermatitis,2000,43(3),137-143);银屑病;脑炎,脑外伤,缺血,中风,癫痫和神经变性疾病(Rohrenbeck等,Neurobiol.ofDisease 1999,6,15-34);皮肤病(Geppetti和Holzer,Eds.,Neurogenic Inflammation,1996,CRC Press,Boca Raton,FL),神经源性皮肤发红,皮肤玫瑰疹和红斑;耳鸣(Herzog等,J.Membrane Biology,2002,189(3),225);炎性肠病,肠应激综合征,(Hoffman等Scandinavian Journal of Gastroenterology,2002,37(4)414-422)和膀胱炎。尤其重要的是头痛(包括偏头痛和丛集性头痛)的急性或预防性处理。用BIBN4096BS静脉内给药的临床研究已提供CGRP拮抗剂治疗偏头痛的有力证据。业已发现这种CGRP拮抗剂可安全且有效地急性处理偏头痛(Olesen等,N.Engl.J.Med.,2004,350(11),1104-1110)。
本发明涉及用作CGRP受体配体的化合物(特别是CGRP受体拮抗剂)、它们的制备方法、它们的治疗用途、含有它们的药用组合物和使用它们的治疗方法。
发明概述
本发明涉及以下式I的化合物
(其中变量R1、A、B、W、X、Y和Z如本文中所定义的),其用作CGRP受体拮抗剂和用于治疗或预防其中涉及CGRP的疾病,如头痛、偏头痛和丛集性头痛。本发明还涉及含有这些化合物的药用组合物和这些化合物与组合物在预防或治疗其中涉及CGRP的这样疾病中的用途。
发明详述
本发明涉及CGRP拮抗剂,其包括式I的化合物及其药学上可接受的盐和各非对映异构体:
其中:
Z选自:
和
A独立选自N和C(R2);
B为O或S;
R1独立选自:
1)H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-6环烷基和杂环,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)未取代或被1-5个各自独立选自R4的取代基取代的芳基,
d)未取代或被1-5个各自独立选自R4的取代基取代的杂芳基,
e)未取代或被1-5个各自独立选自R4的取代基取代的杂环,
f)(F)pC1-3烷基,
g)卤素,
h)OR4,
i)O(CH2)sOR4,
j)CO2R4,
k)(CO)NR10R11,
l)O(CO)NR10R11,
m)N(R4)(CO)NR10R11,
n)N(R10)(CO)R11,
o)N(R10)(CO)OR11,
p)SO2NR10R11,
q)N(R10)SO2R11,
r)S(O)mR10,
s)CN,
t)NR10R11,
u)N(R10)(CO)NR4R11,和
v)O(CO)R4;
2)芳基或杂芳基,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)未取代或被1-5个各自独立选自R4的取代基取代的芳基,
d)未取代或被1-5个各自独立选自R4的取代基取代的杂芳基,
e)未取代或被1-5个各自独立选自R4的取代基取代的杂环,
f)(F)pC1-3烷基,
g)卤素,
h)OR4,
i)O(CH2)sOR4,
j)CO2R4,
k)(CO)NR10R11,
l)O(CO)NR10R11,
m)N(R4)(CO)NR10R11,
n)N(R10)(CO)R11,
o)N(R10)(CO)OR11,
p)SO2NR10R11,
q)N(R10)SO2R11,
r)S(O)mR10,
s)CN,
t)NR10R11,
u)N(R10)(CO)NR4R11,和
v)O(CO)R4;
R2独立选自:
1)H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-6环烷基和杂环,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)未取代或被1-5个独立选自R4的取代基取代的芳基,
d)未取代或被1-5个各自独立选自R4的取代基取代的杂芳基,
e)未取代或被1-5个各自独立选自R4的取代基取代的杂环,
f)(F)pC1-3烷基,
g)卤素,
h)OR4,
i)O(CH2)sOR4,
j)CO2R4,
k)(CO)NR10R11,
l)O(CO)NR10R11,
m)N(R4)(CO)NR10R11,
n)N(R10)(CO)R11,
o)N(R10)(CO)OR11,
p)SO2NR10R11,
q)N(R10)SO2R11,
r)S(O)mR10,
s)CN,
t)NR10R11,
u)N(R10)(CO)NR4R11,和
v)O(CO)R4;
2)芳基或杂芳基,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)未取代或被1-5个独立选自R4的取代基取代的芳基,
d)未取代或被1-5个各自独立选自R4的取代基取代的杂芳基,
e)未取代或被1-5个各自独立选自R4的取代基取代的杂环,
f)(F)pC1-3烷基,
g)卤素,
h)OR4,
i)O(CH2)sOR4,
j)CO2R4,
k)(CO)NR10R11,
l)O(CO)NR10R11,
m)N(R4)(CO)NR10R11,
n)N(R10)(CO)R11,
o)N(R10)(CO)OR11,
p)SO2NR10R11,
q)N(R10)SO2R11,
r)S(O)mR10,
s)CN,
t)NR10R11,
u)N(R10)(CO)NR4R11,和
v)O(CO)R4,
其中在相邻原子上的R1和R2,或任何两个独立的R2任选连接形成选自C5-7环烷基、杂环、芳基和杂芳基的环,其中所述环为未取代或被1-10个各自独立选自R6的取代基取代;
R10和R11独立选自:H、C1-6烷基、(F)pC1-6烷基、C3-6环烷基、芳基、杂芳基和苄基,未取代或被卤素、羟基或者C1-C6烷氧基取代,其中R10和R11任选连接形成选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基或吗啉基的环,其为未取代或被1-5个各自独立选自R4的取代基取代的环;
R4独立选自:H、C1-6烷基、(F)pC1-6烷基、C3-6环烷基、芳基、杂芳基和苄基,未取代或被卤素、羟基或者C1-6烷氧基取代;
W为O、NR4或C(R4)2;
X为C或S;
Y为O、(R4)2、NCN、NSO2CH3或NCONH2,或者当X为S时Y为O2;
R6独立选自H和:
a)C1-6烷基,
b)C3-6环烷基,
c)未取代或被1-5个独立选自R4的取代基取代的芳基,
d)未取代或被1-5个各自独立选自R4的取代基取代的杂芳基,
e)未取代或被1-5个各自独立选自R4的取代基取代的杂环,
f)(F)pC1-3烷基,
g)卤素,
h)OR4,
i)O(CH2)sOR4,
j)CO2R4,
k)(CO)NR10R11,
l)O(CO)NR10R11,
m)N(R4)(CO)NR10R11,
n)N(R10)(CO)R11,
o)N(R10)(CO)OR11,
p)SO2NR10R11,
q)N(R10)SO2R11,
r)S(O)mR10,
s)CN,
t)NR10R11,
u)N(R10)(CO)NR4R11,和
v)O(CO)R4,
J为键、C(R6)2、O或NR6;
V选自键、C(R6)2、O、S(O)m、NR6、C(R6)2-C(R6)2、C(R6)=C(R6)、C(R6)2-N(R6)、C(R6)=N、N(R6)-C(R6)2、N=C(R6)和N(R6)-N(R6);
G-L选自:N、N-C(R6)2、C=C(R6)、C=N、C(R6)、C(R6)-C(R6)2、C(R6)-C(R6)2-C(R6)2、C=C(R6)-C(R6)2、C(R6)-C(R6)=C(R6)、C(R6)-C(R6)2-N(R6)、C=C(R6)-N(R6)、C(R6)-C(R6)=N、C(R6)-N(R6)-C(R6)2、C=N-C(R6)2、C(R6)-N=C(R6)、C(R6)-N(R6)-N(R6)、C=N-N(R6)、N-C(R6)2-C(R6)2、N-C(R6)=C(R6)、N-C(R6)2-N(R6)、N-C(R6)=N、N-N(R6)-C(R6)2和N-N=C(R6);
Q独立选自:
(1)=C(R7a)-,
(2)-C(R7a)2-,
(3)-C(=O)-,
(4)-S(O)m-,
(5)=N-,和
(6)-N(R7a)-;
T独立选自:
(1)=C(R7b)-,
(2)-C(R7b)2-,
(3)-C(=O)-,
(4)-S(O)m-,
(5)=N-,和
(6)-N(R7b)-;
R3独立选自H、取代或未取代的C1-C3烷基、F、CN和CO2R4;
R7a和R7b各自独立选自R2,其中R7a和R7b与它们连接的原子或多个原子任选连接形成选自C3-6环烷基、芳基、杂环和杂芳基的环,所述环为未取代或被1-10个各自独立选自R6的取代基取代;
对于具有q个碳的取代基而言p为0至2q+1;
m为0、1或2;
n为0或1;
s为1、2或3。
本发明另一个实施方案为式I的CGRP拮抗剂,其包括式Ia的化合物及其药学上可接受的盐和各立体异构体:
其中:
A独立选自N和C(R2);
R1、W和Z如在式I中所定义。
本发明另一个实施方案为式I的CGRP拮抗剂,其包括式Ib的化合物及其药学上可接受的盐和各立体异构体:
其中:
A独立选自N和C(R2);
R1、R2、W和Z如在式I中所定义。
本发明另一个实施方案为式I的CGRP拮抗剂,其包括式Ic的化合物及其药学上可接受的盐和各立体异构体:
其中:
R1、R2、W和Z如在式I中所定义。
本发明另外实施方案为式I的CGRP拮抗剂,其包括式Id的化合物及其药学上可接受的盐和各立体异构体:
其中:
R1、R2和Z如在式I中所定义。
本发明另外实施方案为式I的CGRP拮抗剂,其包括式Ie的化合物及其药学上可接受的盐和各立体异构体:
其中:
R1、R2和Z如在式I中所定义。
本发明另外的实施方案为式Ia-Ie的CGRP拮抗剂及其药学上可接受的盐和各立体异构体,
其中:
R1选自:
1)H、C1-6烷基、C3-6环烷基和杂环,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)未取代或被1-5个独立选自R4的取代基取代的芳基,
d)未取代或被1-5个各自独立选自R4的取代基取代的杂芳基,
e)未取代或被1-5个各自独立选自R4的取代基取代的杂环,
f)(F)pC1-3烷基,
g)卤素,
h)OR4,
i)O(CH2)sOR4,
j)CO2R4,
k)CN,
l)NR10R11,和
m)O(CO)R4;和
2)芳基或杂芳基,未取代或被一个或多个独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)(F)pC1-3烷基,
d)卤素,
e)OR4,
f)CO2R4,
g)(CO)NR10R11,
h)SO2NR10R11,
i)N(R10)SO2R11,
j)S(O)mR4,
k)CN,
l)NR10R11,和
m)O(CO)R4;
R2选自:
1)H、C1-C6烷基、C2-C6炔基、C3-6环烷基和杂环,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)未取代或被1-5个独立选自R4的取代基取代的芳基,
d)未取代或被1-5个各自独立选自R4的取代基取代的杂芳基,
e)未取代或被1-5个各自独立选自R4的取代基取代的杂环,
f)(F)pC1-3烷基,
g)卤素,
h)OR4,
i)O(CH2)sOR4,
j)CO2R4,
k)S(O)mR4,
l)CN,
m)NR10R11,和
n)O(CO)R4;和
2)芳基或杂芳基,未取代或被一个或多个独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)(F)pC1-3烷基,
d)卤素,
e)OR4,
f)CO2R4,
g)(CO)NR10R11,
h)SO2NR10R11,
i)N(R10)SO2R11,
j)S(O)mR4,
k)CN,
l)NR10R11,和
m)O(CO)R4,
其中在相邻原子上的R1和R2,或任何两个独立的R2任选连接形成选自C5-7环烷基、杂环、芳基和杂芳基的环,其中所述环为未取代或被1-10个各自独立选自R6的取代基取代;
R10和R11独立选自:H、C1-6烷基、(F)pC1-6烷基、C3-6环烷基、芳基、杂芳基和苄基,未取代或被卤素、羟基或者C1-C6烷氧基取代,其中R10和R11任选连接形成选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基和吗啉基的环,所述环为未取代或被1-5个各自独立选自R4的取代基取代;
R4独立选自:H、C1-6烷基、(F)pC1-6烷基、C3-6环烷基、芳基、杂芳基和苄基,未取代或被卤素、羟基或者C1-C6烷氧基取代;
W为O、NR4或C(R4)2;
R6独立选自H和:
a)C1-6烷基,
b)C3-6环烷基,
c)(F)pC1-3烷基,
d)卤素,
e)OR4,
f)CO2R4,
g)(CO)NR10R11,
h)SO2NR10R11,
i)N(R10)SO2R11,
j)S(O)mR4,
k)CN,
l)NR10R11,和
m)O(CO)R4;和
J为键、C(R5)2、O或NR5,V为键、C(R6)2、O、S(O)m、NR6、C(R6)2-C(R6)2、C(R6)=C(R6)、C(R6)2-N(R6)、C(R6)=N、N(R6)-C(R6)2、N=C(R6)或N(R6)-N(R6),从而当:
J为键,V为键,Z为Z1时,形成以下结构:
J为键,V为键,Z为Z1,T为-C(=O)-时,形成以下结构:
J为键,Z为Z1时,形成以下结构:
V为键,Z为Z1时,形成以下结构:
G-L为N,Z为Z2时,形成以下结构:
或
G-L为N-C(R6)2,Z为Z2时,形成以下结构:
G-L为C=C(R6),Z为Z2时,形成以下结构:
或
G-L为C=N,Z为Z2时,形成以下结构:
G-L为N-C(R6)2-C(R6)2,Z为Z2时,形成以下结构:
Q独立选自:
(1)=C(R7a)-,
(2)-C(R7a)2-,
(3)-C(=O)-,
(4)-S(O)m-,
(5)=N-,和
(6)-N(R7a)-;
T独立选自:
(1)=C(R7b)-,
(2)-C(R7b)2-,
(3)-C(=O)-,
(4)-S(O)m-,
(5)=N-,和
(6)-N(R7b)-;
R3独立选自H、取代或未取代的C1-C3烷基、F、CN和CO2R4;
R7a和R7b各自独立选自R2,其中R7a和R7b与它们连接的原子或多个原子任选连接形成选自C3-6环烷基、芳基、杂环和杂芳基的环,所述环为未取代或被1-10个各自独立选自R6的取代基取代;
对于具有q个碳的取代基而言p为0至2q+1;
m为0-2;
s为1-3。
本发明另外的实施方案为式Ia-Ib的CGRP拮抗剂及其药学上可接受的盐和各立体异构体:
其中:
R1选自:
1)H、C1-C6烷基、C3-6环烷基和杂环,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)未取代或被1-5个各自独立选自R4的取代基取代的苯基,
d)未取代或被1-5个各自独立选自R4的取代基取代的杂芳基,且其中杂芳基选自:咪唑、异唑、唑、吡嗪、吡唑、哒嗪、吡啶、嘧啶和噻唑;
e)未取代或被1-5个各自独立选自R4的取代基取代的杂环,所述杂环选自:氮杂环丁烷、二烷、二氧戊环、吗啉、氧杂环丁烷、哌嗪、哌啶、吡咯烷、四氢呋喃和四氢吡喃;
f)(F)pC1-3烷基,
g)卤素,
h)OR4,
i)O(CH2)sOR4,
j)CO2R4,
k)CN,
l)NR10R11,
m)O(CO)R4;
2)选自苯基、咪唑、异唑、唑、吡嗪、吡唑、哒嗪、吡啶、嘧啶和噻唑的芳基或杂芳基,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)(F)pC1-3烷基,
d)卤素,
e)OR4,
f)CO2R4,
g)(CO)NR10R11,
h)SO2NR10R11,
i)N(R10)SO2R11,
j)S(O)mR4,
k)CN,
l)NR10R11,和
m)O(CO)R4;
R2选自:
1)H、C1-C6烷基、C3-6环烷基和杂环,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)未取代或被1-5个各自独立选自R4的取代基取代的苯基,
d)未取代或被1-5个各自独立选自R4的取代基取代的杂芳基,且其中杂芳基选自:苯并咪唑、苯并噻吩、呋喃、咪唑、吲哚、异唑、唑、吡嗪、吡唑、哒嗪、吡啶、嘧啶、吡咯、噻唑、噻吩和三唑;
e)未取代或被1-5个独立选自R4的取代基取代的杂环,所述杂环选自氮杂环丁烷、咪唑烷、咪唑啉、异唑啉、异唑烷、吗啉、唑啉、唑烷、氧杂环丁烷、吡唑烷、吡唑啉、吡咯啉、四氢呋喃、四氢吡喃、噻唑啉和噻唑烷;
f)(F)pC1-3烷基,
g)卤素,
h)OR4,
i)O(CH2)sOR4,
j)CO2R4,
k)CN,
l)NR10R11,和
m)O(CO)R4;和
2)选自苯基、苯并咪唑、苯并噻吩、呋喃、咪唑、吲哚、异唑、唑、吡嗪、吡唑、哒嗪、吡啶、嘧啶、吡咯、噻唑、噻吩和三唑的芳基或杂芳基,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)(F)pC1-3烷基,
d)卤素,
e)OR4,
f)CO2R4,
g)(CO)NR10R11,
h)SO2NR10R11,
i)N(R10)SO2R11,
j)S(O)mR4,
k)CN,
l)NR10R11,和
m)O(CO)R4,
其中在相邻原子上的R1和R2,或任何两个独立的R2任选连接形成选自C5-7环烷基、杂环、芳基和杂芳基的环,其中所述环为未取代或被1-10个各自独立选自R6的取代基取代;
R10和R11独立选自:H、C1-6烷基、(F)pC1-6烷基、C3-6环烷基、芳基、杂芳基和苄基,未取代或被卤素、羟基或者C1-6烷氧基取代,其中R10和R11任选连接形成选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基和吗啉基的环,所述环为未取代或被1-5个各自独立选自R4的取代基取代;
R4独立选自:H、C1-6烷基、(F)pC1-6烷基、C3-6环烷基、芳基、杂芳基和苯基,未取代或被羟基或者C1-6烷氧基取代;
W为NR4或C(R4)2;
R6独立选自H和:
a)C1-6烷基,
b)C3-6环烷基,
c)(F)pC1-3烷基,
d)卤素,
e)OR4,
f)CO2R4,
g)(CO)NR10R11,
h)SO2NR10R11,
i)N(R10)SO2R11,
j)S(O)mR4,
k)CN,
l)NR10R11,和
m)O(CO)R4;
J为键,V为键,Z为Z1,Q为-N(R7a)-,T为-C(=O)-,从而形成以下结构:
J为键,V为键,Z为Z1,Q为-C(R7a)2-,T为-C(=O)-,从而形成以下结构:
J为键,V为键,Z为Z1,Q为-N=,T为=C(R7b)-,从而形成以下结构:
J为键,V为键,Z为Z1,Q为-C(R7a)2-,T为-C(R7b)2-,从而形成以下结构:
或
J为键,V为键,Z为Z1,Q为-C(R7a)=,T为=C(R7b)-,R7a和R7b连接的原子连接在一起形成苯、吡啶或者二嗪环从而形成以下结构之一:
J为键,V为C(R6)2,Z为Z1,Q为-C(R7a)=,T为=C(R7b)-,R7a和R7b连接的原子连接在一起形成苯或者吡啶环从而形成以下结构之
J为O,V为键,Z为Z1,Q为-C(R7a)=,T为=C(R7b)-,R7a和R7b连接的原子连接在一起形成苯或者吡啶环从而形成以下结构之一:
G-L为N,Z为Z2,Q为-C(R7a)2-,T为-C(R7b)2-,从而形成以下结构:
G-L为N,Z为Z2,Q为-C(R7a)=,T为=C(R7b)-,从而形成以下结构:
或
G-L为N,Z为Z2,Q为-N=,T为=C(R7b)-,从而形成以下结构:
G-L为N,Z为Z2,Q为-C(R7a)2-,T为-C(O)-,从而形成以下结构:
G-L为C=C(R6),Z为Z2,Q为-C(R7a)=,T为=C(R7b)-,从而形成以下结构:
G-L为C=C(R6),Z为Z2,Q为-C(R7a)=,T为=N-,从而形成以下结构:
G-L为C=C(R6),Z为Z2,Q为-N=,T为=C(R7b)-,从而形成以下结构:
或
G-L为C=N,Z为Z2,Q为-C(R7a)=,T为=C(R7b)-,从而形成以下结构:
G-L为N,Z为Z2,Q为-C(R7a)=,T为=C(R7b)-,R7a和R7b连接的原子连接在一起形成苯、吡啶或者二嗪环从而形成以下结构之一:
G-L为N-C(R6)2,Z为Z2,Q为-C(R7a)=,T为=C(R7b)-,R7a和R7b连接的原子连接在一起形成苯或者吡啶环从而形成以下结构之一:
G-J为C=N,Z为Z2,Q为-C(R7a)=,T为=C(R7b)-,R7a和R7b连接的原子连接在一起形成苯环从而形成以下结构:
G-L为C=C(R6),Z为Z2,Q为-C(R7a)=,T为=C(R7b)-,R7a和R7b连接的原子连接在一起形成苯环从而形成以下结构:
G-L为N-C(R6)2-C(R6)2,Z为Z2,Q为-C(R7a)=,T为=C(R7b)-,R7a和R7b连接的原子连接在一起形成苯环从而形成以下结构:
R3独立选自H、取代或未取代的C1-C3烷基、F、CN和CO2R4;
R7a和R7b独立选自R2,其中R7a和R7b与它们连接的原子或多个原子任选连接形成选自C3-6环烷基、芳基、杂环和杂芳基的环,所述环未取代或被1-10个各自独立选自R6的取代基取代;
对于具有q个碳的取代基而言p为0至2q+1;
m为0-2;
s为1-3。
应该理解当一个或更多个以上列举的结构或亚结构列举多个具有相同名称的取代基团时,每个这样的变量可以与每个相似命名的变量相同或不同。例如,在式I中R2列举4次,并且式I中的每一个R2可以独立地为R2定义下的任何亚结构。对于给定的结构,本发明不限于其中每一个R2必须相同的结构和亚结构。这点对于任何在结构或亚结构中多次出现的变量都适用。
本发明化合物可包含一个或更多个不对称中心并因此可作为外消旋体和外消旋混合物、单个对映异构体、非对映异构体混合物和各非对映异构体存在。可存在另外的不对称中心,这取决于分子上各取代基的性质。每一个这样的不对称中心会单独地产生2种光学异构体并且所有可能的混合物中的光学异构体和非对映异构体以及纯的或部分纯化的化合物都将包含在本发明的范围内。本发明意指包含这些化合物所有这样的异构体形式。
本文中描述的一些化合物中含有烯双键且除非另外指明意指包括E和Z两种几何异构体。
如本领域已知的那样,通过合适地修改本文中公开的方法可以实现这些非对映异构体的独立合成或它们的层析分离。通过结晶产物或结晶中间体的x-射线晶体学可测定它们的绝对立体化学,如果需要,结晶产物或结晶中间体可用含有已知绝对构型的不对称中心的试剂衍化。
如果需要,可以分离化合物的外消旋混合物,从而分离各对映异构体。分离可通过本领域已知的方法实施,例如将化合物的外消旋混合物偶联到对映异构体纯的化合物上以形成非对映异构体混合物,随后通过标准方法分离各非对映异构体,例如使用分级结晶或层析法。偶联反应通常是用对映异构体纯的酸或碱形成盐。然后通过裂解所加入的手性残余物可将非对映异构体衍生物转化为纯的对映异构体。化合物的外消旋混合物也可以通过使用手性固定相的层析法直接分离,这些方法是本领域熟知的。
或者,采用已知构型的光学纯原料或试剂,通过本领域已知的方法立体选择性合成可得到化合物的任何对映异构体。
如本领域技术人员应意识到的,并非所有R10和R11取代基能够形成环结构。此外,即使能成环的那些取代基也可形成或不形成环结构。
同样如本领域技术人员意识到的,本文中所用的卤基或卤素将包括氯、氟、溴和碘。
本文中所用的“烷基”将指不含双键或三键的直链、支链和环状结构。因此C1-6烷基定义为以直链或支链排列存在、具有1、2、3、4、5或6个碳的基团,从而C1-6烷基具体包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基和己基。“环烷基”为烷基,其部分或全部形成三个或更多个原子的环。C0或C0烷基定义为存在直接共价键。
术语“烯基”是指具有至少一个碳碳双键的指定数目碳的直链或支链结构及其组合。例如C2-6烯基包括乙烯基、丙烯基、1-甲基乙烯基、丁烯基等。
术语“炔基”是指具有至少一个碳碳三键的指定数目碳的直链或支链结构及其组合。因此C2-6炔基定义为以直链或支链排列存在、具有2、3、4、5或6个碳的基团,从而C2-6炔基具体包括2-己炔基和2-戊炔基。
本文中所用的“芳基”将指每个环上最多达7元的任何稳定的单环或双环碳环,其中至少一个环是芳环。这种芳基的实例包括苯基、萘基、四氢萘基、2,3-二氢化茚基或联苯基。
除非指明,本文中所用的术语“杂环”或“杂环的”表示稳定的5-7元单环或稳定的8-11元双环的杂环环系,其为饱和或不饱和的且由碳原子和1-4个选自N、O和S的杂原子组成,其中氮和硫杂原子可任选被氧化,氮杂原子可任选被季铵化,并且包括任何双环基团,其中任何以上定义的杂环稠合到苯环上。杂环可连接在任何杂原子或碳原子上从而产生稳定结构。这种杂环基团的实例包括,但不限于氮杂环丁烷、苯并二氢吡喃、二氢呋喃、二氢吡喃、二烷、1,3-二氧杂环戊烷、六氢氮杂、咪唑烷、咪唑烷酮、咪唑啉、咪唑啉酮、二氢吲哚、异苯并二氢吡喃、异二氢吲哚、异噻唑啉、异噻唑烷、异唑啉、异唑烷、吗啉、吗啉酮、唑啉、唑烷、唑烷酮、氧杂环丁烷、2-氧代六氢氮杂、2-氧代哌嗪、2-氧代哌啶、2-氧代吡咯烷、哌嗪、哌啶、吡喃、吡唑烷、吡唑啉、吡咯烷、吡咯啉、奎宁环、四氢呋喃、四氢吡喃、硫吗啉(thiamorpholine)、噻唑啉、噻唑烷、硫代吗啉及其N-氧化物。
除非指明,本文中所用的术语“杂芳基”表示稳定的5-7元单环或稳定的9-10元、含有芳环的稠合双环杂环环系,其任何环可为饱和的(如哌啶基)、部分饱和的或不饱和的(如吡啶基)且由碳原子和1-4个选自N、O、S的杂原子组成,其中氮和硫杂原子可任选被氧化,氮杂原子可任选被季铵化并且包括任何双环基团,其中任何以上定义的杂环稠合于苯环上。杂环可连接在任何杂原子或碳原子上从而产生稳定结构。这样杂芳基的实例包括(但不限于)苯并咪唑、苯并异噻唑、苯并异唑、苯并呋喃、苯并噻唑、苯并噻吩、苯并三唑、苯并唑、咔啉、噌啉、呋喃、呋咱、咪唑、吲唑、吲哚、吲嗪、异喹啉、异噻唑、异唑、萘啶、二唑、唑、酞嗪、蝶啶、嘌呤、吡喃、吡嗪、吡唑、哒嗪、吡啶、嘧啶、吡咯、喹唑啉、喹啉、喹喔啉、四唑、噻二唑、噻唑、噻吩、三嗪、三唑和它们的N-氧化物。
如在C1-C6烷氧基中的术语“烷氧基”将指包括1-6个碳原子的直链、支链和环状构型的烷氧基。实例包括甲氧基、乙氧基、丙氧基、异丙氧基、环丙氧基、环己氧基等。
短语“药学上可接受的”用于本文中指在可靠的医学判断范围内适合用于与人和动物组织接触而没有过度毒性、刺激、过敏反应或其它问题或并发症,与合理的收益/风险比相称的化合物、物质、组合物和/或剂型。
本文中所用的“药学上可接受的盐”指其中母体化合物通过制备其酸或碱盐而改变的衍生物。药学上可接受盐的实例包括但不限于碱性残基如胺的无机酸盐或有机酸盐;酸性残基如羧酸的碱盐或有机盐等。药学上可接受的盐包括母体化合物例如由非毒性无机或有机酸制备的常规非毒性盐或季铵盐。例如,这种常规非毒性盐包括衍生自无机酸如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐;以及由有机酸如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、双羟萘酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙二磺酸、草酸、羟乙磺酸等制备的盐。
某些情况中存在的某些变量数目根据存在的碳原子数目定义。例如,变量“p”有时定义为:“对于含有q个碳的取代基而言p为0至2q+1”。当取代基为“(F)pC1-3烷基”时,这是指当存在一个碳时,存在2(1)+1=3个氟。当存在两个碳时,存在2(2)+1=5个氟原子,并且当存在三个碳时,存在2(3)+1=7个氟。
当本发明化合物为碱性时,可由药学上可接受的非毒性酸包括无机酸和有机酸来制备盐。这种酸包括乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘液酸、硝酸、双羟萘酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、对-甲苯磺酸等。在本发明的一个方面,盐为柠檬酸、氢溴酸、盐酸、马来酸、磷酸、硫酸、富马酸和酒石酸盐。应该理解本文中所用的式I化合物还包括药学上可接受的盐。
以实施例和本文中公开的化合物用途为例例证性说明本发明。本发明范围内的具体化合物包括选自以下实施例中公开的化合物和它们药学上可接受的盐及各非对映异构体的化合物。
目标化合物可用于在需要这种拮抗的患者(例如哺乳动物)中拮抗CGRP受体的方法,该方法包括给予有效量的化合物。本发明涉及本文中公开的化合物用作CGRP受体拮抗剂的用途。除了灵长类、尤其是人之外,可按照本发明方法治疗各种其它哺乳动物。
本发明的另一个实施方案涉及治疗、控制、改善或减少患者中涉及CGRP受体的疾病或病症风险的方法,该方法包括给予患者治疗有效量的为CGRP受体拮抗剂的化合物。
本发明另外涉及用于制备拮抗人和动物中CGRP受体活性药物的方法,该方法包括将本发明化合物与药用载体或稀释剂组合。
本发明方法的治疗对象一般是其中需要拮抗CGRP受体活性的哺乳动物,例如人类,男性或女性。术语“治疗有效量”指引起为研究人员、兽医、医生或其他临床医师所探寻的组织、系统、动物或人的生物学或医学响应的目标化合物的量。本文中所用的术语“治疗”指针对上述病症的治疗和预防或预防性疗法,尤其是在易患有这种疾病或病症的患者中。
本文中所用的术语“组合物”将包括含有以具体量存在的具体组分的产物以及由以具体量存在的具体组分组合直接或间接形成的任何产物。与药用组合物有关的这种术语将包括含有活性组分和组成载体的惰性组分的产物以及由任何两种或更多种组分组合、复合或聚集直接或间接形成的任何产物;或者一种或多种组分分解直接或间接形成的产物;或者一种或多种组分的其它类型反应或相互作用直接或间接形成的产物。因此,本发明药用组合物包括通过混合本发明化合物和药学上可接受的载体制备的任何组合物。“药学上可接受的”是指载体、稀释剂或赋形剂必须与制剂的其它组分相容并且对它们的接受者无害。
术语“给药”和/或“给予”化合物应该理解为是指向需要治疗的个体提供本发明化合物或本发明化合物的前药。
通过本领域已知的方法可证实本发明化合物作为CGRP受体活性拮抗剂的用途。如下测定对125I-CGRP与受体结合的抑制作用和对CGRP受体的功能性拮抗:
天然受体结合试验:基本上如所描述的那样(Edvinsson等,(2001)Eur.J.Pharmacol.415,39-44)进行125I-CGRP与SK-N-MC细胞膜上受体的结合。简单地说,在1mL含有10pM125I-CGRP拮抗剂的结合缓冲液[10mM HEPES,pH7.4,5mM MgCl2和0.2%牛血清白蛋白(BSA)]中孵育细胞膜(25μg)。在室温下孵育3小时后,通过预先用0.5%聚乙烯亚胺阻断过3小时的GFB玻璃纤维过滤板(Millipore)过滤终止试验。用冰冷的试验缓冲液洗涤滤器三次,然后使板风干。加入闪烁液(50μl)并用Topcount(Packard Instrument)对放射性计数。使用Prism进行数据分析并用Cheng-Prusoff方程式(Cheng &Prusoff(1973)Biochem.Pharmacol.22,3099-3108)确定Ki。
天然受体功能试验:在37℃,95%湿度和5%CO2下,SK-N-MC细胞在用10%胎牛血清、2mM L-谷氨酰胺、0.1mM非必需氨基酸、1mM丙酮酸钠、100单位/mL青霉素和100μg/mL链霉素补充的最低必须培养基(MEM)中生长。对cAMP试验,将细胞以5×105个细胞/孔铺在聚D-赖氨酸包被的96孔板(Becton-Dickinson)上,在试验前培养~18小时。细胞用磷酸盐缓冲盐水(PBS,Sigma)洗涤然后在37℃下用无血清MEM中的300μM异丁基甲基黄嘌呤预孵育30分钟。加入拮抗剂并在加入CGRP前使细胞孵育10分钟。继续孵育另外15分钟,然后用PBS洗涤细胞并按照制造商的推荐方法进行cAMP测定。用100nM CGRP确定基础以上的最大刺激。用Prism生成剂量-响应曲线。计算剂量-比率(DR)并用于构建完整的Schild曲线图(Arunlakshana & Schild(1959)Br.J.Pharmacol.14,48-58)。
重组受体:将人CRLR(基因库登录号L76380)亚克隆入表达载体pIREShyg2(BD Biosciences Clontech)内成为5’NheI和3’PmeI片断。将人RAMPl(基因库登录号AJ001014)亚克隆入表达载体pIRESpuro2(BD Biosciences Clontech)内成为5’NheI和3’NotI片断。将293个细胞(人胚肾细胞;ATCC#CRL-1573)在含有4.5g/L葡萄糖、1mM丙酮酸钠和2mM谷氨酰胺用10%胎牛血清(FBS)、100单位/mL青霉素和100ug/mL链霉素补充并维持在37℃和95%湿度下的DMEM中培养。通过用含有在HBSS中的0.1%EDTA的0.25%胰蛋白酶处理将细胞传代培养。通过使10ug的DNA与30ug Lipofectamine2000(Invitrogen)在75cm2烧瓶中共转染实现生成稳定细胞系。CRLR和RAMPl表达构成以等量共转染。转染24小时后,在第二天稀释细胞并加入选择性培养基(生长培养基+300ug/ml潮霉素和1ug/ml嘌呤霉素)。通过采用FACS Vantage SE(Becton Dickinson)单细胞沉积产生克隆细胞系。生长培养基调节至150ug/ml潮霉素和0.5ug/ml嘌呤霉素用于细胞繁殖。
重组受体结合试验:用PBS洗涤表达重组人CRLR/RAMP1的细胞并用含有50mM HEPES、1mM EDTA和完全蛋白酶抑制剂(Roche)的收集缓冲液收集。用实验室匀浆器破裂细胞混悬液并在48000g下离心以分离膜。使沉淀再悬浮于收集缓冲液加250mM蔗糖中并在-70℃下储存。对于结合试验,在室温下,用1ml含有10 pM125I-hCGRP(Amersham Biosciences)和拮抗剂的结合缓冲液(10mM HEPES,pH7.4,5mM MgCl2和0.2%BSA)将10ug膜孵育3小时。经通过已经用0.05%聚乙烯亚胺阻断的96孔GFB玻璃纤维滤板(Millipore)过滤终止试验。滤器用冰冷的试验缓冲液(10mM HEPES,pH7.4)洗涤3次。加入闪烁液并用Topcount(Packard)对板计数。测定非特异性结合,并用表观解离常数(Ki)进行数据分析,通过将结合的CPM数据用非线性最小二乘法拟合至以下方程确定表观解离常数:
其中Y为所观察的CPM结合,Ymax为总结合数,Ymin为非特异性结合数,(Ymax-Ymin)为特异性结合数,%Imax为最大百分比抑制作用,%Imin为最小百分比抑制作用,放射性标记为探针,Kd为受体放射性配体的表观解离常数,如通过Hot饱和试验测定的那样。
重组受体功能试验:将细胞在完全生长培养基中以85000个细胞/孔铺在聚D-赖氨酸包被的96孔板(Corning)上并在试验前培养~19小时。用PBS洗涤细胞并然后在37℃和95%湿度下与抑制剂在含有L-谷氨酰胺和1g/L BSA的Cellgro Complete Serum-Free/Low-Protein培养基(Mediatech,Inc.)中孵育30分钟。以300μM的浓度向细胞中加入异丁基甲基黄嘌呤并在37℃下孵育30分钟。在0.3nM浓度下向细胞中加入人α-CGRP并在37℃下孵育5分钟。在α-CGRP刺激后,用PBS洗涤细胞并按照制造商的推荐方法(cAMP SPA直接筛选试验系统;RPA 559;Amersham Biosciences)采用两步试验方法进行cAMP测定。绘制剂量响应曲线,并如方程y=((a-d)/(1+(x/c)b)+d定义的那样自4参数逻辑拟合确定IC50值,其中y=响应,x=剂量,a=最大响应,d=最小响应,c=拐点,b=斜率。
具体地讲,以下实例的化合物在以上提及的试验中具有CGRP受体拮抗剂活性,一般它们的K1或IC50值小于约50μM。这样的结果表明这些化合物用作CGRP受体拮抗剂的内在活性。
本发明化合物用作CGRP拮抗剂的能力使它们成为可用于治疗涉及人和动物但尤其是人的CGRP的疾病的有用药物。
本发明的化合物具有治疗、预防、改善、控制或减少一种或多种以下症状或疾病风险的用途:头痛、偏头痛、丛集性头痛、慢性紧张型头痛、疼痛、慢性疼痛、神经源性炎症和炎性痛、神经病疼痛、眼痛、牙痛、糖尿病、非胰岛素依赖型糖尿病、血管紊乱、炎症、关节炎、支气管高反应性、哮喘、休克、脓毒症、阿片样物质戒断综合征、吗啡耐受、男性和女性的热潮红、变应性皮炎、银屑病、脑炎、脑损伤、癫痫、神经变性疾病、皮肤病、神经源性皮肤发红、皮肤玫瑰疹和红斑、炎性肠疾病、应激性肠道综合征、膀胱炎以及其它可通过CGRP受体拮抗治疗或预防的病症。其中特别重要的是急性或预防性治疗头痛,包括偏头痛和丛集性头痛。
目标化合物还可用于预防、治疗、控制、改善或减少本文中提到的疾病、病症和症状的风险的方法。
目标化合物还可与其它药物组合用于预防、治疗、控制、改善或减少上述疾病、病症和症状的风险的方法。
本发明化合物可与一种或多种其它药物组合用于治疗、预防、控制、改善或减少疾病或病症的风险,式I化合物或其它药物对所述疾病或病症可具有用途,其中多种药物组合在一起比单独使用任何一种药物更安全或更有效。这种其它药物可以通过常用的途径和量给药,与式I化合物同时或依次给药。当式I化合物与一种或多种其它药物同时使用时,优选含有这种其它药物和式I化合物、以单位剂型存在的药用组合物。然而,组合疗法也可包括其中式I化合物与一种或多种其它药物按不同重叠时间表给药的疗法。也期待当与一种或多种其它活性组分组合使用时,本发明化合物和其它活性组分可以比每一种单独使用时更低的剂量使用。因此,本发明药用组合物包括除式I化合物以外含有一种或多种其它活性组分的那些药用组合物。
例如,本发明化合物可与抗偏头痛药物例如麦角胺和二氢麦角胺或其它5-羟色胺激动剂尤其是5-HT1B/1D激动剂例如舒马曲坦、那拉曲坦、佐米曲坦、依来曲坦、阿莫曲坦、夫罗曲普坦、多尼普曲坦和利扎曲坦,与5-HT1D激动剂例如PNU-142633和5-HT1F激动剂例如LY334370,与环加氧酶抑制剂例如选择性环加氧酶-2抑制剂如罗非考昔、艾托考昔、塞来考昔、伐地考昔或帕瑞考昔,与非甾体抗炎药或细胞因子抑制抗炎药例如化合物如布洛芬、酮洛芬、非诺洛芬、萘普生、吲哚美辛、舒林酸、美洛昔康、吡罗昔康、替诺昔康、氯诺昔康、酮咯酸、依托度酸、甲芬那酸、甲氯芬那酸、氟芬那酸、托芬那酸、双氯芬酸、奥沙丙秦、阿扎丙宗、尼美舒利、萘丁美酮、替尼达普、依那西普、托美丁、保泰松、羟布宗、双氟尼柳、双水杨酯、奥沙拉秦或柳氮磺胺吡啶等或者糖皮质类固醇联合使用。同样,本发明化合物可与镇痛剂例如阿司匹林、对乙酰氨基酚、非那西汀、芬太尼、舒芬太尼、美沙酮、醋美沙朵、丁丙诺啡或吗啡一起给药。
此外,本发明化合物可与白介素抑制剂例如白介素-1抑制剂、NK-1受体拮抗剂例如阿瑞吡坦、NMDA拮抗剂、NR2B拮抗剂、缓激肽-1受体拮抗剂、腺苷Al受体激动剂、钠通道阻断剂例如拉莫三嗪、阿片样物质激动剂如左醋美沙朵或醋美沙朵、脂氧合酶抑制剂例如5-脂氧合酶抑制剂、α受体拮抗剂例如吲哚拉明、α受体激动剂、辣椒素(vanilloid)受体拮抗剂、肾素抑制剂、颗粒酶B抑制剂、P物质拮抗剂、内皮素拮抗剂、去甲肾上腺素前体,与抗焦虑药例如地西泮、阿普唑仑、氯氮和氯氮盐,与5-羟色胺5HT2受体拮抗剂,与阿片样物质激动剂例如可待因、氢考酮、曲马多、右丙氧芬和芬太尼,与mGluR5激动剂、拮抗剂或增效剂,与GABAA受体调节剂例如阿坎酸钙、包括烟碱在内的烟酸拮抗剂或激动剂、毒蕈碱激动剂或拮抗剂,与选择性5-羟色胺再摄取抑制剂例如氟西汀、帕罗西汀、舍曲林、度洛西汀、依他普仑或西酞普兰,与抗抑郁药例如阿米替林、去甲替林、氯米帕明、丙米嗪、文拉法辛、多塞平、普罗替林、地昔帕明、曲米帕明或丙米嗪,与白三烯拮抗剂例如孟鲁司特或扎鲁司特、氧化氮抑制剂或氧化氮合成抑制剂组合使用。
同样,本发明化合物可与间隙连接抑制剂、神经元钙通道阻断剂例如civamide、AMPA/KA拮抗剂例如LY293558、σ受体激动剂和维生素B2组合使用。
同样,本发明化合物可与除麦角胺和二氢麦角胺以外的麦角生物碱例如麦角新碱、麦角新碱、甲麦角新碱、甲麦角林、甲磺酸二氢麦角碱、二氢麦角科尔宁、双氢麦角汀、二氢麦角隐亭、二氢-α-麦角隐亭、二氢-β-麦角隐亭、麦角毒、麦角柯宁碱、麦角克碱、麦角隐亭碱、α-麦角隐亭碱、β-麦角隐亭碱、麦角生碱、麦角甾烷、溴隐亭或美西麦角组合使用。
此外,本发明化合物可与β-肾上腺素能拮抗剂例如噻吗洛尔、普萘洛尔、阿替洛尔、美托洛尔或纳多洛尔等,与MAO抑制剂例如苯乙肼,与钙通道阻断剂例如氟桂利嗪、地尔硫 、氨氯地平、非洛地平、尼索地平、伊拉地平、尼莫地平、洛美利嗪、维拉帕米、硝苯地平或丙氯拉嗪,与精神安定药如奥氮平、氟哌利多、丙氯拉嗪、氯丙嗪和喹硫平,与抗惊厥剂如托吡酯、唑尼沙胺、托那博沙、卡拉博沙、左乙拉西坦、拉莫三嗪、噻加宾、加巴喷丁、普加巴林或双丙戊酸钠,与抗高血压药例如血管紧张素II拮抗剂如氯沙坦、伊贝沙坦、缬沙坦、依普罗沙坦、替米沙坦、奥美沙坦、medoxomil、坎地沙坦和坎地沙坦西酯,与血管紧张素I拮抗剂,与血管紧张素转化酶抑制剂例如赖诺普利、依那普利、卡托普利、苯那普利、喹那普利、培哚普利、雷米普利和群多普利或与A型或B型肉毒毒素组合使用。
本发明化合物可与增效剂例如咖啡因、H2-拮抗剂、二甲基硅油、氢氧化铝或氢氧化镁,与减充血药例如羟甲唑啉、肾上腺素、萘甲唑啉、赛洛唑啉、丙己君或左旋去氧麻黄碱,与镇咳药例如卡拉美芬、喷托维林或右美沙芬,与利尿药、促动力药例如甲氧氯普胺或多潘立酮,与镇静或者非镇静型抗组胺药例如阿伐斯汀、阿扎他定、溴苯海拉明、溴苯那敏、卡比沙明、氯苯那敏、氯马斯汀、右溴苯那敏、右氯苯那敏、苯海拉明、多西拉敏、氯雷他定、苯茚胺、非尼拉敏、苯托沙敏、异丙嗪、美吡拉敏、特非那定、曲普利啶、去氧肾上腺素、苯丙醇胺或者伪麻黄碱组合使用。本发明化合物还可与止吐药组合使用。
在一个特别优选的实施方案中,本发明化合物与抗偏头痛药物例如麦角胺或者二氢麦角胺,与5-HT1激动剂尤其是5-HT1B/1D激动剂尤其是舒马曲坦、那拉曲坦、佐米曲坦、依来曲坦、阿莫曲坦、夫罗曲普坦、多尼普曲坦、阿维曲普坦和利扎曲坦及其它5-羟色胺激动剂,与环加氧酶抑制剂例如选择性环加氧酶-2抑制剂尤其是罗非考昔、艾托考昔、塞来考昔、伐地考昔或帕瑞考昔组合使用。
以上组合不仅包括本发明化合物与一种其它活性化合物的组合,而且包括本发明化合物与两种或多种其它活性化合物的组合。同样地,本发明化合物可与用于预防、治疗、控制、改善或减少疾病或病症的风险的其它药物组合使用,其中本发明化合物对所述疾病或病症是有用的。这种其它药物可以通过常用的途径和量与本发明化合物同时或依次给药。当本发明化合物与一种或多种其它药物同时使用时,优选除了本发明化合物以外包含这种其它药物的药用组合物。因此,本发明药用组合物包括除本发明化合物以外还含有一种或多种其它活性组分的那些药用组合物。
本发明化合物与其它活性组分的重量比可以变化,这取决于每一种组分的有效剂量。通常,将使用每一种的有效剂量。因此,例如当本发明化合物与另一种药物组合时,本发明化合物与另一种药物的重量比通常为约1000∶1-约1∶1000或者约200∶1-约1∶200。本发明化合物与其它活性组分的组合通常也在上述范围内,但是在每一种情况中,应该使用每一种活性组分的有效剂量。
在这种组合中,本发明化合物与其它活性药物可以单独或组合给药。另外,一种成分的给予可以先于、同时或后于其它药物的给予并且可采用相同或不同的给药途径。
本发明化合物可以通过口服、非肠道(如肌内、腹膜内、静脉内、ICV、脑池内注射或注入、皮下注射或植入)、吸入喷雾、鼻、阴道、直肠、舌下或局部给药途径给药,并且可以单独或共同配制成合适剂量的单位制剂,其含有适于每一种给药途径常规的非毒性药学上可接受的载体、佐剂和媒介物。除了治疗温血动物以外,本发明化合物有效用于人。
用于给予本发明化合物的药用组合物可以便利地以剂量单位形式呈现并可以药学领域任何熟知的方法制备。所有方法包括将活性成分与构成一种或多种辅助成分的载体组合的步骤。通常,通过将活性成分与液态载体或细碎的固体载体或两者均匀紧密地混合,然后如果必要,将产物成型为要求的制剂来制备药用组合物。药用组合物包含活性化合物的量足以对疾病的进程或情况产生所需作用。本文中所用的术语“组合物”将包括含有具体量的具体组分的产物以及由具体量的具体组分的组合直接或间接形成的任何产物。
含有活性成分的药用组合物可以适合于口服使用的形式存在,例如作为片剂、糖锭、锭剂、水或油混悬剂、可分散粉剂或颗粒剂、乳剂、溶液剂、硬或软胶囊剂、糖浆剂或酏剂。口服组合物可按照药用组合物制备领域任何已知的方法来制备并且这种组合物可含有一种或多种选自甜味剂、矫味剂、着色剂和防腐剂的试剂以提供药用精致和可口的制剂。片剂含有与适合于制备片剂的非毒性药学上可接受的赋形剂混合的活性成分。这些赋形剂可以是例如惰性稀释剂如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;造粒剂和崩解剂例如玉米淀粉或海藻酸;粘合剂例如淀粉、明胶或阿拉伯胶;和润滑剂例如硬脂酸镁、硬脂酸或滑石粉。片剂可以不包衣或者可以采用已知技术包衣以在胃肠道延迟崩解和吸收,因此在更长的时间内提供持久的作用。例如,可以使用延时材料如单硬脂酸甘油酯或甘油二硬脂酸酯。它们也可用在美国专利4256108、4166452和4265874中描述的技术包衣,形成渗透治疗片剂用于控释。口服片剂也可以配制成速释例如速融片或糯米纸囊剂、速溶片或速溶薄膜。
口服制剂也可以作为硬明胶胶囊呈现,其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合,或者作为软明胶胶囊呈现,其中活性成分与水或油媒介物例如花生油、液体石蜡或橄榄油混合。
水混悬剂含有与适合于制备水混悬剂的赋形剂混合的活性物质。这种赋形剂为悬浮剂例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯胶;分散剂或湿润剂可以是天然存在的磷脂例如卵磷脂或者是氧化烯与脂肪酸的缩合产物例如聚氧乙烯硬脂酸酯,或者是环氧乙烷与长链脂族醇的缩合产物例如十七碳亚乙基氧基鲸蜡醇(heptadecaethyleneoxycetanol),或者是环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物例如聚氧乙烯山梨醇单油酸酯,或是环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物例如聚氧乙烯脱水山梨醇单油酸酯。水混悬剂也可含有一种或多种防腐剂例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂例如蔗糖或糖精。
通过使活性组分悬浮于植物油例如花生油、橄榄油、芝麻油或椰子油或者矿物油例如液体石蜡中可配制油混悬剂。油混悬剂可包含增稠剂例如蜂蜡、硬石蜡或鲸蜡醇。可加入甜味剂(例如以上阐述的那些甜味剂)和矫味剂以提供可口的口服制剂。这些组合物可通过加入抗氧化剂例如抗坏血酸防腐。
适合于通过加入水制备水混悬剂的可分散粉末或颗粒剂提供与分散剂或润湿剂、悬浮剂和一种或多种防腐剂混合的活性组分。合适的分散剂或润湿剂和悬浮剂通过以上已经提及的那些举例说明。也可存在另外的赋形剂例如甜味剂、矫味剂和着色剂。
本发明药用组合物也可以水包油乳剂的形式存在。油相可以为植物油(例如橄榄油或花生油)或者矿物油(例如液体石蜡)或这些的混合物。合适的乳化剂可为天然存在的树胶例如阿拉伯胶或黄蓍胶、天然存在的磷脂例如大豆、卵磷脂和脂肪酸与己糖醇酐衍生的酯或偏酯例如脱水山梨醇单油酸酯和所述偏酯与环氧乙烷的缩合产物例如聚氧乙烯脱水山梨醇单油酸酯。乳剂也可含有甜味剂和矫味剂。
糖浆剂和酏剂可用甜味剂例如甘油、丙二醇、山梨糖醇或蔗糖配制。这种制剂也可包含缓和剂、防腐剂、矫味剂和着色剂。
药用组合物可以灭菌可注射水或油混悬剂的形式存在。该混悬剂可以按照已知技术采用以上已经提及的那些合适的分散剂或湿润剂和悬浮剂配制。灭菌可注射制剂也可为在非毒性非肠道可接受的稀释剂或溶剂中的灭菌可注射溶液剂或混悬剂例如在1,3-丁二醇中的溶液。可以使用的可接受媒介物和溶剂为水、林格氏溶液和等渗氯化钠溶液。另外,灭菌不挥发油常用作溶剂或悬浮介质。为此可使用任何温和的不挥发油包括合成的甘油单酯或甘油二酯。另外发现脂肪酸例如油酸可用于制备注射剂。
本发明化合物也可以栓剂的形式用于直肠给予药物。通过将药物与在常温下为固体但是在直肠温度下为液体并且因此将在直肠熔化以释放药物的合适的非刺激性赋形剂混合可制备这些组合物。这种材料为可可脂和聚乙二醇。
对于局部使用,可使用含有本发明化合物的霜剂、软膏剂、凝胶、溶液剂或混悬剂等。类似地,透皮贴剂也可用于局部给药。
本发明药用组合物和方法可另外包含本文中所提到的通常用于治疗以上提及的病理学病症的其它治疗活性化合物。
在治疗、预防、控制、改善或减少需要拮抗CGRP受体活性的病症的风险中,合适的剂量水平通常为每天约0.01-500mg/kg患者体重,可以单或多剂量给药。合适的剂量水平可为每天约0.01-250mg/kg、每天约0.05-100mg/kg或每天约0.1-50mg/kg。在该范围内,剂量可以是每天0.05-0.5、0.5-5或5-50mg/kg。对于口服给药,组合物可以片剂形式提供,其中含有1.0-1000毫克的活性成分,具体为1.0、5.0、10.0、15.0、20.0、25.0、50.0、75.0、100.0、150.0、200.0、250.0、300.0、400.0、500.0、600.0、750.0、800.0、900.0和1000.0毫克活性成分,针对所治疗的患者对症作出剂量调整。化合物可以每天1-4次的方案给药,或者可每天1次或2次给药。
在治疗、预防、控制、改善或降低头痛、偏头痛、丛集性头痛或其它适用本发明化合物的疾病的风险中,当本发明化合物以约0.1毫克-约100毫克/kg动物体重的每天剂量作为单日剂量或以每天2-6次的分剂量或以缓释形式给药时,通常可以得到满意的效果。对于大多数大型哺乳动物,总每天剂量为约1.0毫克-约1000毫克,或者为约1毫克-约50毫克。如果是70kg成年人,总每天剂量通常为约7毫克-约350毫克。可以调整该剂量方案以提供最佳治疗效果。
然而应该理解任何具体患者的具体剂量水平和给药频率可以不同,这取决于多种因素包括所使用具体化合物的活性、该化合物的代谢稳定性和作用时间长短、年龄、体重、一般健康、性别、饮食、给药方式和时间、排泄速率、药物组合、具体病症的严重性和经受治疗的宿主。
在以下方案和实施例中举例说明了用于制备本发明化合物的几种方法。原料按照本领域已知的方法或本文中所阐明的那样制备。
按照以下方案和具体实施例或其修改,使用容易得到的原料、试剂和常规合成方法,可容易地制备本发明化合物。在这些反应中,也可使用本身为本领域普通技术人员已知但没有更详细提到的变体。通过查看以下方案,本领域技术人员易于理解和领会本发明权利要求的化合物的制备通法。如在方案1-12中描述的那样进行中间体和最终化合物的合成。
反应方案
可用酮如2将二氨基杂环如2,3-二氨基吡啶1还原性烷基化得到单烷基化产物3(方案1)。用羰基二咪唑闭环得到咪唑酮4。最后在标准条件下脱保护得到中间体5。
方案1
方案2中以螺环氮杂吲哚酮为例显示了螺环内酰胺中间体的代表性合成。可用大量保护基如方案2中显示的(三甲基甲硅烷基)乙氧基甲基保护7-氮杂吲哚(6)。按照Marfat和Carter的方法(Tetrahedron Lett.,1987,28,4027-4030)用全溴化吡啶氢溴酸盐处理7得到二溴氮杂吲哚8,其可通过与锌反应还原成相应的氮杂吲哚9。采用碳酸铯/DMF,用顺-1,4-二氯-2-丁烯对9进行烷基化得到螺环氮杂吲哚酮10。在标准条件下除去SEM保护基,再经四氧化锇催化双羟基化得到二醇中间体12。将该二醇高锰酸盐氧化分离,再双还原胺化(Org.Lett.,2000,26,4205-4208)得到螺环哌啶13。方案2中的方法不局限于氮杂吲哚酮如9,但可用于大量合适被保护的杂环体系,得到相应螺环化合物。
方案2
可以按照方案3制备三唑啉酮。例如,可采用肼基甲酸酯还原胺化4-哌啶酮14,并将所得的腙15还原后得到单烷基化产物16。脱保护得到肼17并用硫代苯甲酰基氨基甲酸酯如18缩合/闭环得到三唑啉酮19。最后在标准条件下脱保护得到产物20。
方案3
可按照方案4中所示的Takai等,Chem.Pharm.Bull.1985,33,1116-1128中描述的通用方法制备中间体26。
方案4
可采用相似合成策略制备方案5中所示式34的相关苯并二氮杂酮。原料醇27通过购买得到,或按照本领域中技术人员已知的步骤制备。可采用标准条件将醇27转变成卤化物,如采用三苯基膦和溴制备溴化物28。用亲核叠氮化物置换该氯化物,且在标准条件将该叠氮化物29还原得到伯胺30。该胺可用合适受保护的4-哌啶酮还原性烷基化得到化合物31。采用许多条件容易进行硝基的还原,且随后可用羰基二咪唑进行环化得到环脲33。然后脱保护释放胺34。
方案5
可通过衍生自2-氯喹啉和二异丙基氨基锂的阴离子和哌啶酮36反应制备喹诺酮39(方案6)。用盐酸除去叔醇并使氯喹啉水解。通过催化加氢除去哌啶N-苄基保护基同时还原了上步骤中制备的烯烃并得到胺39。
方案6
可按照方案7合成螺环吡啶并苯并嗪酮。2-氨基-6-氯吡啶40可在六甲基二甲硅烷基氨基钠和二碳酸二叔丁酯作用下保护成其Boc衍生物。在Davies条件(Tetrahedron Lett,2004,45,1721-1724)下进行邻位金属化并将所得阴离子加入N-苄氧基羰基-4-哌啶酮,在原位环化后得到产物43。最后在标准氢解条件下脱保护并脱氯得到中间物44。
方案7
方案8中,4-哌啶烷酮42经Wittig反应得到α,β-不饱和酯45。在碱性条件下所得产物可异构化成β,γ-不饱和酯46(Tetrahedron Lett,2004,4401-4404)。以三甲基铝为介导,用2-氨基-3-溴吡啶进行胺化,再用2-(三甲基甲硅烷基)乙氧基甲基氯进行酰胺烷基化得到产物48。关键的钯介导的螺环化可按照Fu修改的Heck反应(J.Amer.Chem.Soc,2001,6989-7000)来进行。在标准条件下进行两级脱保护,同时双键还原得到所需螺环萘啶酮50。
方案8
如方案9中所示制备氨基吡啶酮。可采用各种亲电剂和碳酸铯对商业购得的羟基吡啶51进行选择性N-烷基化。用氯化锡(II)将硝基还原得到伯胺53。通过活化胺形成脲,在这种情况下用氯甲酸对硝基苯酯进行活化,并与所需取代的哌啶偶联得到54。与不同芳基、杂芳基和烷基进行钯介导的交叉偶联,得到取代的吡啶酮55。
方案9
如方案10中所示制备乙酰基连接的吡啶酮。可采用各种亲电剂和碳酸铯对商业购得的3-甲基-2-吡啶酮进行选择性N-烷基化。在无光的情况下用NBS处理得到一溴吡啶酮58。再于AIBN存在下用NBS处理得到二溴化产物59。在与氰化钠反应后,酸性水解,在标准条件下酸61与各种取代的哌啶偶联得到各种酰胺62。与不同芳基、杂芳基和烷基进行钯介导的交叉偶联,得到各种取代的吡啶酮63。
方案10
如方案11所示制备吡嗪酮。在连续将三氟乙胺和氨基醇66加入酰氯64后得到二酰胺67,用Dess-Martin Periodinane试剂进行氧化和环化。醇68经酸催化消除后,再用三溴氧化磷(III)处理得到溴吡嗪酮70。用苄胺置换溴,再脱保护得到胺72,其可在标准条件下与哌啶5偶联得到吡嗪酮73。
方案11
中间体和实施例
提供以下实施例以更充分地理解本发明。这些实施例只是例证性的并且不应以任何方式构成对本发明的限制。
中间体1
2-氧代-1-(4-哌啶基)-2,3-二氢-1H-咪唑并[4,5-b]吡啶二盐酸盐
步骤A.2-氨基-3-[(1-叔丁氧基羰基哌啶-4-基)氨基]吡啶
在室温下,将三乙酰氧基硼氢化钠(14.5g,68.7mmol)加入到2,3-二氨基吡啶(5.00g,45.8mmol)和N-(叔丁氧基羰基)-4-哌啶酮(9.58g,48.1mmol)在二氯乙烷(75mL)中的溶液中。5小时后,加入另外的三乙酰氧基硼氢化钠(1.8g)并在2.5小时后再加一次。将反应物搅拌整夜,用5%氢氧化钠水溶液猝灭。用二氯甲烷萃取并用5%氢氧化钠水溶液、水和饱和氯化钠溶液洗涤。在经硫酸钠干燥后,过滤溶液并蒸发,得到粗产物。该产物经层析法(硅胶,3-5%甲醇/二氯甲烷梯度洗脱)纯化,得到标题化合物(4.44g)。MS 293(M+1)
1HNMR(500 MHz,CD3OD)δ7.32(dd,J=5,1Hz,1H),6.85(dd,J=8,1Hz,1H),6.59(dd,J=8,5Hz,1H),4.04(d,J=13Hz,2H),3.46(m,1H),2.98(br s,2H),2.01(dd,J=12,2 Hz,2H),1.46(s,9H),1.37(qd,J=12,4Hz,2H).
步骤B.2-氧代-1-(1-叔丁氧基羰基哌啶-4-基)-2,3-二氢-1H-咪唑并[4,5-
b]吡啶
在室温下,将羰基二咪唑(0.70g,4.33mmol)加入到2-氨基-3-[(1-叔丁氧基羰基哌啶-4-基)氨基]吡啶(1.15g,3.93mmol)在乙腈(150mL)中的溶液中。几小时后,加入另外量的羰基二咪唑(0.81g)并搅拌反应物整夜。真空蒸发乙腈,在水和氯仿之间分配残留物并用饱和盐水洗涤有机相,经硫酸镁干燥。粗产物经层析法(硅胶,1.2-2.5%甲醇/二氯甲烷梯度洗脱)纯化,得到标题化合物(1.09g)。
1HNMR(500MHz,CDCl3)δ9.39(br s,1H),8.04(dd,J=5,1Hz,1H),7.33(dd,J=8,1Hz,1H),6.99(dd,J=8,5Hz,1H),4.50(m,1H),4.32(br s,2H),2.86(brs,2H),2.20(m,2H),1.86(d,J=12Hz,2H),1.50(s,9H).
步骤C.2-氧代-1-(4-哌啶基)-2,3-二氢-1H-咪唑并[4,5-b]吡啶二盐酸盐
在室温下,将2-氧代-1-(1-叔丁氧基羰基哌啶-4-基)-2,3-二氢-1H-咪唑并[4,5-b]吡啶(1.03g,3.23mmol)溶于甲醇(25mL)中,并加入2N盐酸在乙醚(8mL)中的溶液。2小时后,真空除去挥发物,得到标题化合物(0.92g)。MS 219(M+1)。
1H NMR(500MHz,CD3OD)δ8.01(dd,J=6,1Hz,1H),7.83(d,J=8Hz,1H),7.28(dd,J=8,6Hz,1H),4.60(m,1H),3.59(d,J=12Hz,2H),3.21(t,J=12Hz,2H),2.70(dq,J=13,4Hz,2H),2.12(d,J=13Hz,2H).
中间体2
4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-碳酰氯
在0℃下,将光气(20%重量在甲苯中,1.8mL,3.43mmol)加入到2-氧代-1-哌啶-4-基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-4-二氯化物(100mg,0.343mmol)和2,6-二甲基吡啶(0.50mL,4.293mmol)在二氯甲烷(5mL)中的悬浮液中。2小时后,将溶液加入到饱和碳酸氢钠水溶液中并用乙酸乙酯萃取。用水(2x)、饱和盐水洗涤有机层,经硫酸镁干燥,过滤并浓缩。加入二氯甲烷(10mL)并过滤混合物,得到固体状的标题化合物(48mg)。MS 281(M+1)。
1HNMR(500MHz,(CD3)2SO)δ11.58(s,1H),7.90(d,J=5.1Hz,1H),7.67(d,J=7.6Hz,1H),7.01-6.99(m,1H),4.52-4.46(m,1H),4.31-4.23(m,2H),3.38-3.33(m,1H),3.19-3.14(m,1H),2.32-2.24(m,2H),1.84-1.81(m,2H).
中间体3
7-哌啶-4-基-7,9-二氢-8H-嘌呤-8-酮盐酸盐
步骤A.4-氨基-5-[(1-叔丁氧基羰基哌啶-4-基)氨基]嘧啶
在室温下,将4,5-二氨基嘧啶(1.0g,9.1mmol)、N-(叔丁氧基羰基)-4-哌啶酮(3.0g,15mmol)和三乙酰氧基硼氢化钠(1.2g,5.6mmol)在二氯乙烷(60mL)中的混合物搅拌3天。在氯仿(200mL)和3N氢氧化钠(30mL)之间分配反应物。经硫酸镁干燥后,将有机相浓缩得到棕褐色胶状的标题化合物。MS 294(M+1)
步骤B.7-(1-苄基哌啶-4-基)-7,9-二氢-8H-嘌呤-8-西酮
将步骤A的粗产物4-氨基-5-[(1-叔丁氧基羰基哌啶-4-基)氨基]嘧啶与羰基二咪唑(3.0g,18mmol)在四氢呋喃(250mL)中回流2天,冷却并浓缩。将粗产物溶解于乙酸乙酯(25-50mL)中,分四次得到白色晶体的标题化合物(1.3g)。MS 320(M+1)
步骤C.7-哌啶-4-基-7,9-二氢-8H-嘌呤-8-酮盐酸盐
在室温下,将7-(1-苄基哌啶-4-基)-7,9-二氢-8H-嘌呤-8-酮(1.2g,3.7mmol)/4N盐酸/二烷(50mL)混合物剧烈搅拌3h。真空浓缩反应物得到白色固体的标题化合物。MS 220(M+1)
中间体4
4-氟-2-氧代-1-(4-哌啶基)-2,3-二氢--1H-咪唑并[4,5-b]吡啶
步骤A.N-(5-氟吡啶-2-基)-2,2-二甲基丙酰胺
向2-氨基-5-氟吡啶(1.00g,8.92mmol)和三乙胺(1.35g,13.4mmol)在二氯甲烷(30mL)中的0℃溶液中加入三甲基乙酰氯(1.29g,10.7mmol)和DMAP(0.11g,0.89mmol)。使所得溶液升到室温。4h后,加入饱和NaHCO3水溶液,分离这些层并用DCM反洗涤水相。合并的有机相经硫酸镁干燥、过滤并浓缩,经硅胶层析法(5%→40%EtOAc/己烷)纯化残余物,得到标题化合物(1.34g)。MS 197.3(M+1)。
步骤B.N-(3-叠氮-5-氟吡啶-2-基)-2,2-二甲基丙酰胺
向N-(5-氟吡啶-2-基)-2,2-二甲基丙酰胺(1.34g,6.83mmol)在四氢呋喃(25mL)中的-78℃溶液中逐滴加入叔丁基锂(1.31mL的1.7M溶液,20.5mmol)。在-78℃保持3小时后,在使反应物升到室温时加入4-十二烷基苯磺酰叠氮(3.60g,10.2mmol)。1小时后,加入饱和NH4Cl水溶液,通过旋转蒸发器将四氢呋喃除去。加入二氯甲烷,分离这些层并用DCM反洗涤水相。合并的有机相经硫酸镁干燥、过滤并浓缩,经连续两次硅胶层析法(10%→80%EtOAc/己烷,然后5%→42%EtOAc/己烷)纯化残余物,得到标题化合物(0.275g)。MS 234.0(M+1)。
步骤C.3-叠氮-5-氟吡啶-2-胺
将N-(3-叠氮-5-氟吡啶2-基)-2,2-二甲基丙酰胺(275mg,1.16mmol)/3N HCl(5mL)加热到100℃。2小时后,真空除去挥发物得到标题化合物的HCl盐(180mg)。MS 154.2(M+1)。
步骤D.5-氟吡啶-2,3-二胺
将3-叠氮-5-氟吡啶-2-胺的HCl盐(1.90g,10.0mmol)溶解于四氢呋喃(100mL)中并用MP-Carbonate(Argonaut,11.5g)处理。1小时后,将混合物过滤、用更多四氢呋喃清洗并浓缩。将残余物溶解于乙醇(50mL),用氩纯化,并加入10%披钯碳(0.15g)。引入氢(1atm)并搅拌反应物直到完成。过滤催化剂并将溶剂从滤液中蒸发出来得到标题化合物(1.18g)。MS 128.0(M+1)。
步骤E.4-[(2-氨基-5-氟吡啶-3-基)氨基]吡啶-1-甲酸叔丁基酯
在室温下,将三乙酰氧基硼氢化钠(2.95g,13.9mmol)加入5-氟吡啶-2,3-二胺(1.18g,9.28mmol)、乙酸(0.56g,9.28mmol)和1-(叔丁氧基羰基)-4-哌啶酮(1.85g,9.28mmol)在1,2-二氯乙烷(20mL)中的溶液中。1小时后,用水(20mL)将反应物猝灭并用二氯甲烷萃取。经硫酸钠干燥后,将溶液过滤并蒸发得到粗产物。经层析法(硅胶,5%→15%MeOH/DCM,然后C-18,95%水/乙腈→5%水/乙腈/0.1%三氟乙酸)纯化粗产物,得到标题化合物(0.73g)。MS 311.2(M+1)。
步骤F.4-(6-氟-2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲
酸叔丁酯
在室温下,将羰基二咪唑(1.53g,9.41mmol)加入4-[(2-氨基-5-氟吡啶-3-基)氨基]哌啶-1-甲酸叔丁酯(0.73g,2.35mmol)在乙腈(10mL)中的溶液中。搅拌反应物直到所有原料消耗掉(约2小时),然后真空蒸发溶剂。残余物用水稀释、用二氯甲烷萃取(3x),经硫酸镁干燥并然后浓缩。经层析法(硅胶,1%-10%甲醇/二氯甲烷梯度洗脱)纯化粗产物,得到标题化合物(0.309g)。MS 337.2(M+1)
步骤G.4-氟-2-氧代-1-(4-哌啶基)-2,3-二氢-1H-咪唑并[4,5-b]吡啶
将4-(6-氟-2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酸叔丁酯(340mg,1.01mmol)溶解于二氯甲烷(5mL)并加入三氟乙酸(5mL)。2小时后,将反应物浓缩、用二氯甲烷(5mL)稀释并在室温下加入1N盐酸在1,4-二烷(2mL)中的溶液。浓缩得到标题化合物(302mg)。
MS 237.2(M+1)1H NMR(500MHz,CD3OD)δ7.92(br s,1H),7.70(dd,1H),4.60(m,1H),3.60(s,2H),3.25(dd,2H),2.70(m,2H),2.10(d,2H).
中间体5
3-(4-哌啶基)-3,4-二氢喹唑啉-2(1H)-酮盐酸盐
按照H.Takai等在Chem.Pharm.Bulletin 1985,33(3)1116-1128中描述的步骤制备标题化合物。
1HNMR(500MHz,DMSO-d6)δ9.31(s,1H),8.79(br s,1H),8.58(br s,1H),7.13(t,J=8Hz,2H),6.88(t,J=8Hz,1H),6.77(d,J=8Hz,1H),4.37(tt,J=12,4Hz,1H),4.29(s,2H),3.00(q,J=11Hz,2H),2.06(dq,J=4,12Hz,2H),1.73(d,J=12Hz,2H).
中间体6
5-苯基-1-哌啶-4-基-2,4-二氢-3H-1,2,4-三唑-3-酮盐酸盐
步骤A:4-[(丁氧基羰基)亚肼]哌啶-1-甲酸9H-芴-9-基甲酯
将1-[(9H-芴-9-基)甲氧基羰基]-4-哌啶酮(16.0g,50.0mmol)和肼羧酸叔丁酯(7.25g,55.5mmol)在乙醇(250mL)中的溶液反洗涤1小时。将所得溶液冷却并浓缩。加入乙醚(100mL)得到白色沉淀物标题化合物(21.0g)。
1HNMR(500MHz,CDCl3)δ7.77(d,J=7Hz,2H,7.57(d,J=7Hz,2H),7.40(t,J=7Hz,2H),7.32(t,J=7Hz,2H),4.50(br s,2H),4.24(t,J=6Hz,1H),3.4-3.7(br m,4H),2.47(br s,2H),2.2-2.1(brm,2H),1.56(s,9H).
步骤B:4-[(叔丁氧基羰基)亚肼]哌啶-1-甲酸9H-芴-9-基甲酯
在Parr仪上将4-[(叔丁氧基羰基)亚肼]哌啶-1-甲酸9H-芴-9-基甲酯(10.0g,22.9mmol)在乙酸(150mL)中的溶液与氧化铂(1.0g)在45psi氢下振荡2小时。将溶液过滤并浓缩得到标题化合物。
步骤C:4-亚肼哌啶-1-甲酸9H-芴-9-基甲酯
在室温下,将4-[(叔丁氧基羰基)亚肼]哌啶-1-甲酸9H-芴-9-基甲酯溶液(20g,45.7mmol)溶解于三氟乙酸(100mL)中并搅拌1.5小时。将反应物浓缩并将残余物溶解于甲醇中,通过反相HPLC纯化。离析纯馏分并合并得到标题化合物的三氟乙酸盐(3.01g)。
1HNMR(500MHz,DMSO-d6)δ7.89(d,J=8Hz,2H),7.61(d,J=8Hz,2H),7.40(t,J=8Hz,2H),7.32(t,J=8Hz,2H),4.33(d,J=6Hz,2H),4.25(t,J=6Hz,1H),4.0-3.5(br s,6H),3.05(br s,1H),2.80(br s,2H),1.89(br s,2H),1.2(br s,2H).
步骤D:4-(5-氧代-3-苯基-4,5-二氢-1H-1,2,4-三唑-1-基)哌啶-1-甲酸
9H-芴-9-基甲酯
将4-亚肼哌啶-1-甲酸9H-芴-9-基甲酯三氟乙酸盐(2.95g,6.54mmol)溶液与N-硫代苯甲酰基氨基甲酸乙酯(1.50g,7.1mmol)(通过E.P.Papadopoulus,J.Org.Chem.,1976,41(6)962-965步骤制备)/四氢呋喃(30mL)/二异丙基乙胺(1.25ML,7.1mmol)一起回流2小时。将反应物冷却并浓缩,然后加热溶解于乙腈中。冷却后结晶出白色固体,得到标题化合物(2.06g)。
1H NMR(500MHz,CDCl3)δ7.80(d,J=7Hz,2H),7.77(d,J=7Hz,2H),7.61(d,J=7Hz,2H),7.48(m,3H),7.40(t,J=7Hz,2H,7.33(t,J=7Hz,2H),4.46(d,J=6Hz,2H),4.36(m,2H),4.27(t,J=6Hz,1H),4.26(br s,1H),3.02(br s,2H),2.04(br s,2H),1.94(br m,2H).
步骤E:5-苯基-1-哌啶-4-基-2,4-二氢-3H-1,2,4-三唑-3-酮盐酸盐
在室温下,将4-(5-氧代-3-苯基-4,5-二-1H-1,2,4-三唑-1-基)哌啶-1-甲酸9H-芴-9-基甲酯(2.06g,4.41mmol)和二乙胺(15mL)在四氢呋喃(15mL)中的溶液搅拌2小时。将反应物浓缩并通过柱层析法(硅胶,0-10%{5%氢氧化铵/甲醇}/二氯甲烷梯度洗脱)纯化粗产物,得到白色固体的标题化合物(0.95g)。
1H NMR(500MHz,CDCl3)δ7.84(d,J=7Hz,2H),7.47(m,3H),4.30(m,1H),3.25(d,J=13Hz,2H),2.79(t,J=13Hz,2H),2.04(d,J=4,12Hz,2H),1.93(br d,J=10Hz,2H).
中间体7
3-(-哌啶基)-1,3,4,5-四氢-2H-1,3-苯并二氮-2-酮盐酸盐
步骤A.2-(2-溴乙基)硝基苯
在0℃下,将三苯基膦(39.2g,0.150mol)和四溴化碳(49.5g,0.150mol)依次加入2-(2-羟乙基)硝基苯(25.0g,0.150mol)在二氯甲烷(400mL)中的溶液中。将反应物搅拌整夜并用饱和碳酸氢钠溶液猝灭。用饱和盐水洗涤二氯甲烷相并经硫酸镁干燥。用乙酸乙酯处理粗产物,通过过滤除去沉淀的三苯基氧化膦。通过快速层析法(硅胶,0-10%乙酸乙酯/己烷梯度洗脱)进一步纯化得到标题化合物(27.9g)。
步骤B.2-(2-叠氮乙基)硝基苯
将叠氮钠(22.8,0.351mol)/水(60mL)加入2-(2-溴乙基)-硝基苯(27.9g,0.121mol)在乙腈(120mL)中的溶液中。将反应物回流4小时,冷却并在二氯甲烷和水之间分配。用饱和盐水洗涤有机相,并经过硫酸镁干燥。得到油状标题化合物(22.8g)。
步骤C.2-(2-氨乙基)硝基苯
将三苯基膦(31.1g,0.118mol)和碳酸钙(50mg,0.5mmol)加入2-(2-叠氮乙基)硝基苯(22.8g,0.118mol)在苯(500mL)中的溶液中。室温下搅拌反应物直到完成。真空除去溶剂,并在100℃下用乙酸(100mL)和48%氢溴酸(100mL)处理残余物1小时。将反应物冷却并浓缩。加入水并用二氯甲烷萃取溶液。通过加入5%氢氧化钠溶液使得水层为碱性,然后用乙酸乙酯萃取。用饱和盐水洗涤有机相并经硫酸钠干燥。得到油状标题化合物(8.0g)。MS 167(M+1)。
步骤D.4-{[2-(2-硝基苯基)乙基]氨基}哌啶-1-甲酸叔丁酯
通过加入乙酸将2-(2-氨乙基)硝基苯(8.00g,48.1mmol)和1-叔丁氧基羰基-4-哌啶酮(9.59g,48.1mmol)在甲醇(100mL)中的溶液调整到pH为5。加入氰基硼氢化钠(4.53g,72.2mmol)并将反应物搅拌3小时。真空除去甲醇,且在乙酸乙酯和饱和碳酸氢钠溶液之间分配残余物。用饱和盐水洗涤有机相并经硫酸镁干燥。得到油状标题化合物(19.27g)。MS 350(M+1)。
步骤E.4-{[2-(2-氨基苯基)乙基]氨基}哌啶-1-甲酸叔丁酯
在一个大气压氢下将4-{[2-(2-硝基苯基)乙基]氨基}哌啶-1-甲酸叔丁酯和10%披钯碳(1.9g)在乙醇(250mL)中搅拌整夜。将催化剂从所得溶液中过滤掉并真空除去溶剂,得到标题化合物(17.2g)。MS 320(M+1)。
步骤F.3-(1-叔丁氧基羰基-4-哌啶基-1,3,4,5-四氢)-2H-1,3-苯并二氮-
2-酮
将羰基二咪唑(8.73g,53.8mmol)加入4-{[2-(2-氨基苯基)乙基]氨基}哌啶-1-甲酸叔丁酯(17.2g,53.8mmol)在二甲基甲酰胺(200mL)中的溶液中,并在室温下搅拌2小时。用乙酸乙酯稀释反应物并用水、然后饱和盐水萃取。经层析法(硅胶,0-30%乙酸乙酯/二氯甲烷梯度洗脱)纯化粗产物。得到深色固体标题化合物(4.8g)。
步骤G.3-(4-哌啶基)-1,3,4,5-四氢-2H-1,3-苯并二氮-2-酮盐酸盐
在0℃用氯化氢气体使3-(1-叔丁氧基羰基-4-哌啶基)-1,3,4,5-四氢-2H-1,3-苯并二氮-2-酮(4.80g,13.9mmol)在乙酸乙酯(300mL)中的溶液饱和。使反应物升到室温并搅拌整夜。过滤固体并用乙酸乙酯洗涤。将乙酸乙酯滤液浓缩以第二次获得固体。得到固体标题化合物(2.94g)。
MS 246(M+1).1H NMR(500MHz,CD3OD)δ7.10(m,2H),6.94(d,J=8Hz,1H),6.91(t,J=8Hz,1H),4.35(tt,J=10,1Hz,1H),3.52(m,4H),3.12(t,J =12Hz,2H),3.05(m,2H),2.07(qd,J=12,4Hz,2H),1.99(m,2H).
中间体8
3-(4-哌啶基)喹啉-2-(1H)-酮
步骤A.3-(1-苄基-4-羟基哌啶-4-基)-2-氯喹啉
在-78℃氩下,将正丁基锂在己烷中的溶液(1.6M,38.2Ml,61.1mmol)加入二异丙胺(8.6mL,61.1mmol)在四氢呋喃(140mL)中的溶液中。1小时后,通过注射器加入2-氯喹啉(10.00g,61.1mol)在四氢呋喃(30mL)中的溶液。1小时后加入1-苄基-3-哌啶酮的溶液(11.3mL,61.1mmol),并将反应物在-78℃另外搅拌40分钟,然后使之升到室温。将反应物冷却到-20℃并用水猝灭。用乙酸乙酯萃取反应溶液,并用饱和盐水洗涤有机相,经硫酸镁干燥。层析法纯化(硅胶,0-10%{5%氢氧化铵/甲醇}/二氯甲醇梯度洗脱)得到标题化合物11.3g。MS 353(M+1)。
1H NMR(500 MHz,CDCl3)δ8.33(s,1H),8.00(d,J=8Hz,1H),7.82(d,J=8Hz,1H),7.72(dt,J=1,1Hz,1H),7.57(dt,J=1,8Hz,1H),7.39-7.26(m,5H),3.61(s,2H),2.85(d,J=11Hz,2H),2.59(t,J=12Hz,2H),2.48(dt,J=4,13Hz,2H),2.13(d,J=12Hz,2H).
步骤B.3-(1-苄基-1,2,3,6-四氢吡啶-4-基)喹啉-2-(1H)-酮
将3-(1-苄基-4-羟基哌啶-4-基)-2-氯喹啉(11.0g,31.1mmol)在6N盐酸中回流8小时。将溶液冷却并加入水(100mL)。收集沉淀固体并干燥得到7.9g标题化合物。
MS 317(M+1).1HNMR(500MHz,CD3OD)δ7.97(s,1H),7.70(d,J=7 Hz,1H),7.60(m,2H),7.55(m,4H),7.35(d,J=9Hz,1H),7.27(t,J=8Hz,1H),6.50(m,1H),4.49(ABq,J=13Hz,Δv=16 Hz,2H),3.92(m,2H),3.76(dt,J=12,4Hz,1H),3.40(m,1H),2.96(m,2H).
步骤C.3-(4-哌啶基)喹啉-2-(1H)-酮
用氩气使3-(1-苄基-1,2,3,6-四氢吡啶-4-基)喹啉-2-(1H)-酮(4.00g,12.6mmol)在甲醇(500mL)中的溶液脱气,并加入10%披钯碳(1.2g)。将反应物放在1 atm氢气下并在5.5小时内加热到50℃。使反应物冷却并通过Celite硅藻土过滤。浓缩得到2.7g标题化合物。
MS 229 (M+1).1H NMR(500MHz,CD3OD)δ7.80(s,1H),7.67(d,J=8Hz,1H),7.51(t,J=8Hz,1H),7.33(d,J=8Hz,1H),7.25(t,J=8Hz,1H),3.52(t,J=12Hz,2H),3.17(dt,J=3,13Hz,2H),3.15(m,overlaps with δ3.17peak,1H),2.18(d,J=14Hz,2H),1.91(dq,J=3,12Hz,2H).
中间体9
1-哌啶-4-基咪唑烷基-2,4-二酮
步骤A:4-[(2-乙氧基-2-氧代乙基)氨基]哌啶-1-甲酸叔丁酯
将氰基硼氢化钠(189mg,3.01mmol)加入1-boc-4-哌啶酮(500mg,2.51mmol)和甘氨酸乙酯盐酸盐(350mg,2.51mmol)在甲醇(12.5mL)中的溶液中。16小时后,用饱和氯化铵溶液将混合物猝灭、浓缩,并在二氯甲烷和饱和碳酸氢钠溶液之间分配。用盐水洗涤有机层,经硫酸镁干燥,过滤并浓缩。通过硅胶层析法[100%二氯甲烷→95%二氯甲烷/5%(10%氢氧化铵/甲醇)]纯化得到标题化合物(600mg)。
步骤B:4-(2,4-二氧代咪唑烷-1-基)哌啶-1-甲酸叔丁酯
将氰酸钾(31mg,0.384mmol)加入4-[(2-乙氧基-2-氧代乙基)氨基]哌啶-1-甲酸叔丁酯(100mg,0.384mmol)在水(2mL)中的溶液中。然后加入乙酸来将反应物的pH调整到4-5并将混合物加热到40℃。16小时后,将反应物冷却到室温并通过反相HPLC(C-18,95%水/乙腈→5%水/乙腈/0.1%三氟乙酸)纯化得到标题化合物(33mg)。
步骤C:1-哌啶-4-基咪唑烷-2,4-二酮
将三氟乙酸(0.300mL)加入4-(2,4-二氧代咪唑烷-1-基)哌啶-1-甲酸叔丁酯(32mg,0.113mmol)在二氯甲烷(1mL)中的溶液中。4小时后,将反应物浓缩得到标题化合物。MS 184.04(M+1)。
中间体10
4-苯基-1-哌啶-4-基-1,3-二氢-2H-咪唑-2-酮盐酸盐
按照US 6,344,449 B1中描述的步骤制备4-苯基-1-哌啶-4-基-1,3-二氢-2H-咪唑-2-酮盐酸盐。
中间体11
螺环[哌啶-4,3′-吡咯并[2,3-b]吡啶]-2′(1′H)-酮二盐酸盐
步骤A.1-{[2-(三甲基甲硅烷基)乙氧基]甲基}-1H-吡咯并[2,3-b]吡啶
在0℃下,将氢化钠(在矿物油中的60%分散液;16.2g,0.404mol)在25分钟内分次加入7-氮杂吲哚(39.8g,0.337mol)在DMF(200mL)中的溶液中并搅拌所得混合物1小时。然后在15分钟内缓慢加入2-(三甲基甲硅烷基)乙氧基甲基氯(71.8mL,0.404mol),保持反应混合物的温度低于10℃。1小时后,用H2O(500mL)将反应物猝灭并用CH2Cl2(5x300mL)萃取混合物。合并的有机层用盐水洗涤,经MgSO4干燥,过滤,浓缩并高真空干燥得到标题化合物。MS:m/z=249(M+1)。
步骤B.3,3-二溴-1-{[2-(三甲基甲硅烷基)乙氧基]甲基}-1,3-二氢-2H-
吡咯并[2,3-b]吡啶-2-酮
在30分钟内将步骤A的1-{[2-(三甲基甲硅烷基)乙氧基]甲基}-1H-吡咯并[2,3-b]吡啶(43.1g,0.174mol)在二烷(300mL)中的溶液逐滴加入全溴化吡啶氢溴酸盐(277g,0.868mol)在二烷(300mL)中的悬浮液中。采用顶部机械搅拌器在室温下搅拌反应物。60分钟后,用H2O(300mL)将两相反应混合物猝灭并用EtOAc萃取。用EtOAc(2x300mL)洗涤含水层并用H2O(4x300mL;最后洗涤液的pH为5-6)洗涤合并的有机层,然后用盐水(300mL)洗涤,然后经MgSO4干燥,过滤并在减压下浓缩。将粗产物立即溶解于CH2Cl2并通过硅胶柱过滤溶液,用CH2Cl2洗脱直到深红色完全从管中流出。用饱和NaHCO3(400mL)水溶液、然后盐水(400mL)洗涤滤液,经MgSO4干燥并真空浓缩得到标题化合物。MS:m/z=423(M+1)。
步骤C.1-{[2-(三甲基甲硅烷基)乙氧基]甲基}-1,3-二氢-2H-吡咯并
[2,3-b]吡啶-2-酮
将锌(100g,1.54mol)加入步骤B的3,3-二溴-1-{[2-(三甲基甲硅烷基)乙氧基]甲基}-1,3-二氢-2H-吡咯并[2,3-b]吡啶-2-酮(65g,0.154mol)在THF(880mL)和饱和氯化铵水溶液(220mL)中的溶液中。3小时后,将反应物过滤并真空浓缩。在EtOAc和H2O之间分配残余物,这导致白色沉淀的形成。两层都通过Celite硅藻土垫过滤并将这些层分离。用EtOAc(2x)洗涤水层并用H2O洗涤合并的有机层,经MgSO4干燥,过滤并浓缩。粗产物通过硅胶柱(CH2Cl2∶EtOAc-90∶10)洗脱过滤且将洗脱液在减压下浓缩得到标题化合物。MS:m/z=265(M+1)。
步骤D.螺环[环戊-3-烯-1,3′-吡咯并[2,3-b]吡啶]-2′(1′H)-酮
向顺(式)-1,4-二氯-2-丁烯(1.98g,15.8mmol)和1-{[2-(三甲基甲硅烷基)乙氧基]甲基}-1,3-二氢-2H-吡咯并[2,3-b]吡啶-2-酮(3.49g,13.2mmol)在DMF(175mL)中的溶液中加入碳酸铯(10.7g,32.9mmol)。24小时后,在Et2O(200mL)和H2O(200mL)之间分配反应混合物。进一步用Et2O(2x200mL)萃取水相。用H2O(2x100mL),然后盐水(100mL)洗涤合并的有机相,经MgSO4干燥,过滤并减压浓缩。向所得物质在二氯甲烷(150mL)中的溶液中加入三氟乙酸(150mL)。1小时后,将反应物浓缩,溶解于EtOH(150mL)并加入2N HCl(150mL)。将混合物在45℃加热48小时。将所得混合物浓缩、用饱和NaHCO3水溶液稀释并用二氯甲烷(2x)萃取。干燥并浓缩合并的有机相。通过硅胶层析法(用0-50%甲醇∶二氯甲烷梯洗脱)纯化粗产物,得到标题化合物(0.62g)。MS:m/z=187.1(M+1)。
步骤E.3,4-二羟基螺环[环戊烷-1,3′-吡咯并[2,3-b]吡啶]-2′(1′H)-酮
向二水合氧化三甲胺(408mg,3.67mmol)和螺环[环戊-3-烯-1,3′-吡咯并[2,3-b]吡啶]-2′(1′H)-酮(622mg,3.34mmol)在二氯甲烷(115mL)中的混合物加入四氧化锇(25uL在2-甲基-2-丙醇中的2.5%溶液)。24小时后,浓缩反应混合物。将粗产物装到带有最少量甲醇的硅胶层析柱,并用5-20%甲醇∶二氯甲烷梯度洗脱,得到标题化合物(0.63g)。MS:m/z=221.0(M+1)。
步骤F.2′-氧代-1′,2′-二氢-1H-螺环[哌啶-4,3′-吡咯并[2,3-b]吡啶]-1-甲
酸叔丁酯
向3,4-二羟基螺环[环戊烷-1,3′-吡咯并[2,3-b]吡啶]-2′(1′H)-酮(640mg,2.91mmol)在3∶1乙醇∶水(160mL)中的混合物中加入高碘酸钠(622mg,2.91mmol)。原料消耗后,将氢氧化铵(50mL)缓慢加入反应混合物。加入氢氧化钯(200mg,20%)并将反应物在50psi氢化。24小时后,加入200mg氢氧化钯并继续氢化另外24小时。反应混合物通过Celite硅藻土过滤并浓缩。将所得物质溶解于DMF(10L)并加入二碳酸二叔丁酯(635mg,2.91mmol),然后加入三乙胺(0.811mL,5.82mmol)。24小时后,用饱和NaHCO3水溶液稀释反应物并用乙醚萃取(3x)。合并的有机层用水洗涤(3x),干燥并浓缩。通过硅胶层析法(用0-10%甲醇∶二氯甲烷梯洗脱)纯化粗产物,得到标题化合物(489mg)。MS:m/z=304.1(M+1)。
步骤G.螺环[哌啶-4,3′-吡咯并[2,3-b]吡啶]-2′(1′H)-酮盐酸盐
将2′-氧代-1′,2′-二氢-1H-螺环[哌啶-4,3′-吡咯并[2,3-b]吡啶]-1-甲酸叔丁酯(451mg,1.49mmol)溶解于乙酸乙酯(3mL)并在室温下加入4N盐酸在二烷(7.5mmol)中的溶液。24小时后,真空除去挥发物,得到标题化合物(404mg)。
MS 204.1(M+1).1HNMR(500MHz,CD3OD)δ8.31(d,J=7.1Hz,1H),8.20(d,J=6.1Hz,1H),7.45(dd,J=6.8,6.8Hz,1H),3.74(brdd,2H),3.47(brdd,2H),2.35(brddd,2H),2.21(brd,2H).
中间体12
螺环[哌啶-4,4′-吡啶并[2,3-d][1,3]嗪]-2′(1′H)-酮
步骤A.(6-氯吡啶-2-基)氯基甲酸叔丁酯
向2-氨基-6氯吡啶(5.24g,40.8mmol)和六甲基二甲硅烷基氨基钠(1.0M,89.8mL,89.8mmol)在THF(35mL)中的溶液中加入二碳酸二叔丁酯(9.80g,44.9mmol)在THF(35mL)中的溶液。24小时后,将反应物浓缩,在EtOAc(30mL)和1N HCl(100mL)之间分配残余物。进一步用EtOAc(2x)萃取水层。合并的有机层用NaHCO3洗涤,经MgSO4干燥,过滤并减压浓缩。通过硅胶层析法纯化粗产物,用20-100%二氯甲烷∶己烷梯度洗脱,得到标题化合物(7.73g)。MS:m/z=173.0(M-tBu)。
步骤B.7′-氯-2′-氧代-1′,2′-二氢-1H-螺环[哌啶-4,4′-吡啶并[2,3-d]1,3]
嗪]-1-甲酸苄酯
在10分钟内向N,N,N′,N′-四甲基乙二胺(0.335g,2.89mmol)在THF(1mL)中的-20℃溶液中加入正丁基锂(2.5M,1.15mL,2.89mmo1)。30分钟后,将混合物冷却到-78℃并在15分钟内加入(6-氯吡啶-2-基)氨基甲酸叔丁酯(0.300g,1.31mmol)在THF(0.8mL)中的溶液。1小时后,将反应物加热到-50℃,搅拌2小时并然后在10分钟内加入N-苄氧基羰基-4-哌啶酮(0.459g,1.97mmol)在THF(1mL)中的溶液。使反应物升到室温并然后搅拌24小时。加入饱和NaHCO3水溶液并用EtOAc(3x)萃取混合物。合并的有机层用H2O、盐水洗涤,经MgSO4干燥,过滤并减压浓缩。通过硅胶层析法纯化粗产物,用25-50%乙酸乙酯∶己烷梯度洗脱,得到标题化合物(0.160g)。MS:m/z=338.0(M+1)。
步骤C.螺环[哌啶-4,4′-吡啶并[2,3-d][1,3]嗪]-2′(1′H)-酮
将10%披钯碳(300mg)加入7′-氯-2′-氧代-1′,2′-二氢-1H-螺环[哌啶-4,4′-吡啶并[2,3-][1,3]嗪]-1-甲酸苄酯(1.85g,1.77mmol)在EtOH(250mL)中的溶液中。将反应容器抽空并反填充氮气(3x),然后反填充氢气(1 atm)。24小时后,混合物通过Celite硅藻土过滤并浓缩,得到标题化合物(1.07g)。
MS 220.1(M+1).1H NMR(500MHz,CD3OD)δ8.26(dd,J=1.7,5.0Hz,1H),7.69(dd,J=1.6,7.7Hz,1H),7.16(dd,J=5.0,7.7Hz,1H),3.49-3.42(m,4H),2.38-2.25(m,4H).
中间体13
1H-螺环[1,8-萘啶-4,4′-哌啶]-2(3H)-酮
步骤A.4-(2-甲氧基-2-氧代亚乙基)哌啶-1-甲酸苄酯
将N-苄氧基羰基-4-哌啶酮(5.0g,21.4mol)和(三苯基磷烷亚基)(triphenylphosporanylidene)乙酸甲酯(10.0g,30.0mmol)在苯(100mL)中的溶液在75℃加热48小时。将反应物浓缩、用乙醚稀释,过滤掉沉淀物,并将清洗液浓缩。通过硅胶层析法纯化粗产物,用20-60%乙酸乙酯∶己烷梯度洗脱,得到标题化合物(5.25g)。MS:m/z=290.1(M+1)。
步骤B.4-(2-甲氧基-2-氧代乙基)-3,6-二氢吡啶-1(2H)-甲酸苄酯
室温下,搅拌4-(2-甲氧基-2-氧代亚乙基)哌啶-1-甲酸苄酯(5.25g,18.1mol)和1,8-二氮杂双环[5,4,0]十一烯-7(2.71mL,18.1mol)在DMF(120mL)中的溶液。3天后,用水稀释反应物并用乙醚萃取(4x)。将有机洗涤液合并,经MgSO4干燥,过滤并在减压下浓缩。通过硅胶层析法纯化粗产物,用5-30%乙酸乙酯∶己烷梯度洗脱,得到标题化合物(2.44g)。
MS:m/z=290.1(M+1).1HNMR(500MHz,CDCl3)δ7.30-7.25(m,5H),5.5(brs,1H),5.2 (s,2H),4.0(brs,2H),3.7(s,3H),3.6(brs,2H),3.0(s,2H),2.2(brs,2H).
步骤C.4-{2-[(3-溴吡啶-2-基)氨基]-2-氧代乙基}-3,6-二氢吡啶-1(2H)-
甲酸苄酯
将三甲基铝(2.0M,2.05mL,4.10mol)缓慢加入4-(2-甲氧基-2-氧代乙基)-3,6-二氢哌啶-1(2H)-甲酸苄酯(0.79g,2.73mol)和2-氨基-3溴吡啶(0.520g,3.00mmol)在1,2-二氯乙烷(15mL)中的0℃溶液中。30分钟,将反应物加热到55℃48小时。通过小心加入饱和碳酸钠水溶液来将反应物猝灭并用二氯甲烷萃取混合物(4x)。用1N酒石酸钾钠、盐水洗涤合并的有机层,经MgSO4干燥,过滤并浓缩。通过硅胶层析法纯化粗产物,用50-100%乙酸乙酯∶己烷梯度洗脱,得到标题化合物(2.44g)。MS:m/z=430.0(M+1)。
步骤D.4-[ 2-((3-溴吡啶-2-基){[2-(三甲基甲硅烷基)乙氧基]甲基}氨基)-
2-氧代乙基]-3,6-二氢吡啶-1(2H)-甲酸苄酯
0℃下,在10分钟内将氢化钠(在矿物油中的60%分散液;117mg,4.88mol)分次加入4-{2-[(3-溴吡啶-2-基)氨基]-2-氧代乙基}-3,6-二氢吡啶-1(2H)-甲酸苄酯(1.91g,4.43mol)在THF(15mL)的中溶液中。0.5小时后,再缓慢加入2-(三甲基甲硅烷基)乙氧基甲基氯(0.861mL,4.88mol),保持反应混合物的温度低于10℃。4小时后,加入氢化钠(60mg)和2-(三甲基甲硅烷基)乙氧基甲基氯(0.45ml)并使反应物升到室温整夜。用饱和氯化铵水溶液将反应物猝灭并用CH2Cl2(3x)萃取混合物。合并的有机层经MgSO4干燥,过滤并浓缩。通过硅胶层析法纯化粗产物,用40-70%乙酸乙酯∶己烷梯度洗脱,得到标题化合物(1.51g)。MS:m/z=560.2(M+1)。
步骤E.2-氧代-1-{[2-(三甲基甲硅烷基)乙氧基]甲基}-2,2′,3,3′-四氢-
1H,1′H-螺环[1,8-萘啶-4,4′-吡啶]-1′-甲酸苄酯
向N-甲基二环己胺(0.042mg,0.20mmol)和4-[2-((3-溴吡啶-2-基){[2-(三甲基甲硅烷基)乙氧基]甲基}氨基)-2-氧代乙基]-3,6-二氢吡啶-1(2H)-甲酸苄酯(100mg,0.178mmol)在二烷(2mL)中的混合物中加入二(三叔丁基膦)合钯(0)(9mg,0.018mmol)。5分钟,将反应物加热到50℃。90分钟后,加入二(三叔丁基膦)合钯(0)(9mg)。在50℃另外30分钟后,用水稀释反应混合物并用乙醚(3x)萃取。合并的有机层经MgSO4干燥,过滤并浓缩。通过硅胶层析法纯化粗产物,用5-60%乙酸乙酯∶己烷梯度洗脱,得到标题化合物(68mg)。MS:m/z=480.2(M+1)。
步骤F.1H-螺环[1,8-萘啶-4,4′-哌啶]-2(3H)-酮
向2-氧代-1-{[2-(三甲基甲硅烷基)乙氧基]甲基}-2,2′,3,3′-四氢-1H,1′H-螺环[1,8-萘啶-4,4′-吡啶]-1′-甲酸苄酯(384mg,0.800mmol)在二氯甲烷(10mL)中的混合物中加入三氟乙酸(10mL)。3小时后,将反应物浓缩,用二氯甲烷(10mL)稀释并加入乙二胺(720mg,12.0mmol)。18小时后,将反应物浓缩,残余物在饱和NaHCO3水溶液和二氯甲烷之间分配,并将这些层分离。进一步分次用二氯甲烷(2x)萃取水相,将有机层合并、干燥和浓缩。将10%披钯碳加入所得物质在EtOH(10mL)中的溶液中。将反应容器抽空并用氮气(3x)反填充,然后用氢气(1atm)反填充。24小时后,通过Celite硅藻土过滤所得混合物并浓缩得到标题化合物(130mg)。
MS 218.1(M+1).1H NMR(500MHz,CD3OD)δ8.14(dd,J=1.6,5.0Hz,1H),7.80(dd,J=1.6,7.7Hz,1H),7.10(dd,J=5.0,7.7Hz,1H),2.98-2.95(m,4H),2.78(s,2H),1.96-1.90(m,2H),1.69(brd,J=11.5Hz,2H).
实施例1
N-(1-甲基-2-氧代-5-苯基-1,2-二氢吡啶-3-基)-4-(2-氧代-2,3-二氢-1H-咪
唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺
步骤A.5-溴-1-甲基-3-硝基吡啶-2(1H)-酮
将碳酸铯(44.6g,137mmol)加入5-溴-2-羟基-3-硝基吡啶(20.0g,91.3mmol)和碘代甲烷(19.4,137mmol)在N,N-二甲基甲酰胺(500mL)中的溶液中。18小时后,用水将反应混合物猝灭。用乙酸乙酯(3x)萃取混合物并用水、饱和盐水洗涤合并的有机萃取液,经硫酸钠干燥,过滤并浓缩。MS 233.1(M)。
步骤B.3-氨基-5-溴-1-甲基吡啶-2(1H)-酮
在80℃下,将氯化锡(II)二水合物(53.3g,236mmol)加入5-溴-1-甲基-3-硝基吡啶-2(1H)-酮(11.0g,47.2mmol)在乙酸乙酯(400mL)中的溶液中。1.5小时后,用饱和碳酸氢钠将反应混合物猝灭。用乙酸乙酯萃取混合物(3x),用水、饱和盐水洗涤合并的有机萃取液,经硫酸钠干燥,过滤并浓缩。MS 203.1(M)。
步骤C.N-(5-溴-1-甲基-2-氧代-1,2-二氢吡啶-3-基)-4-(2-氧代-2,3-二氢-
1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺
在0℃下,将三乙胺(21μL,0.15mmol)加入3-氨基-5-溴-1-甲基吡啶-2(1H)-酮(30.0mg,0.15mmol)和光气(20%重量/甲苯;16.0μL,0.15mmol)在四氢呋喃(1mL)中的溶液中。1小时后,依次加入1-哌啶-4-基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(32mg,0.15mmol)和三乙胺(62μL,0.44mmol)。使反应混合物升到室温。18小时后,将反应混合物过滤并浓缩。通过反相HPLC(C-18,95%水/乙腈→5%水/乙腈/0.1%三氟乙酸)纯化,得到标题化合物(26mg)。MS 447.1(M)。
步骤D.N-(1-甲基-2-氧代-5-苯基-1,2-二氢吡啶-3-基)-4-(2-氧代-2,3-二
氢-1H-咪唑并[4.5-b]吡啶-1-基)哌啶-1-甲酰胺
将二异丙胺(0.15mL,1.07mmol)加入N-(5-溴-1-甲基-2-氧代-1,2-二氢吡啶-3-基)-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺(120mg,0.27mmol)、乙酸钯(18mg,0.08mmol)、3,3′,3′-次膦基三(苯磺酸)三钠盐(137mg,0.24mmol)和苯基硼酸(65.0mg,0.54mmol)在N,N-二甲基甲酰胺(0.6mL)和水(0.2mL)中的溶液中。将反应混合物加热到80℃。18小时后,过滤反应混合物。通过反相HPLC(C-18,95%水/乙腈→5%水/乙腈/0.1%三氟乙酸)纯化,得到标题化合物的三氟乙酸盐(52mg)。MS 445.1(M+1)。
1H NMR(500MHz,CDCl3)δ8.55(d,J=2.4Hz,1H),8.06(s,1H),8.02(d,J=5.1Hz,1H),7.50(d,J=7.3Hz,2H),7.41(t,J=7.6Hz,2H),7.32(d,J=8.3Hz,2H),7.17(d,J=2,2Hz,1H),6.98(dd,J=7.8,5.1Hz,1H),4.60-4.57(m,1H),4.38(d,J=14.2Hz,2H),3.70(s,3H),3.09(t,J=12.2Hz,2H),2.31-2.36(m,2H),1.98(d,J=10.0Hz,2H).
基本上按照对实施例1的制备概述的方法制备表1中的实施例。
表1
实施例90
1-(1-{[2-氧代-5-苯基-1-(2,2,2-三氟乙基)-1,2-二氢吡啶-3-基]乙酰基}哌
啶-4-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮
步骤A.3-甲基-1-(2,2,2-三氟乙基)吡啶-2(1H)-酮
将碳酸铯(11.4g,34.9mmol)加入3-甲基吡啶-2(1H)-酮(3.81g,34.9mmol)和三氯甲烷磺酸2,2,2-三氟乙酯(9.81g,34.9mmol)在二氯甲烷(80mL)中的溶液中。2小时后,加入水。用乙醚(3x)萃取混合物,合并的有机萃取物经硫酸钠干燥,过滤并浓缩。通过硅胶层析法纯化粗产物(100%二氯甲烷→25%甲醇/二氯甲烷),得到标题化合物(3.73g)。MS 192.3(M+1)。
步骤B.5-溴-3-(溴甲基)-1-(2,2,2-三氟乙基)吡啶-2(1H)-酮
将N-溴代丁二酰亚胺(2.89g,16.2mmol)加入3-甲基-1-(2,2,2-三氟乙基)吡啶-2(1H)-酮(2.82g,14.8mmol)在1,2-二氯乙烷(60mL)中的溶液中并在黑暗中(用Al箔覆盖)将所得混合物加热到85℃。2小时后,将反应物从黑暗中取出并加入N-溴代丁二酰亚胺(2.89g,16.2mmol)和AIBN(24mg)。在85℃保持24小时后,用饱和NaHCO3水溶液稀释反应物,用二氯甲烷(3x)萃取,合并的有机萃取物经硫酸钠干燥,过滤并浓缩。通过硅胶层析法纯化粗产物(100%二氯甲烷→5%甲醇/二氯甲烷),得到标题化合物(2.89g)。MS 349.9(M+1)。
步骤C.[5-溴-2-氧代-1-(2,2,2-三氟乙基)-1,2-二氢吡啶-3-基]乙腈
在15分钟内将5-溴-3-(溴甲基)-1-(2,2,2-三氟乙基)吡啶-2(1H)-酮(1.40g,4.01mmol)分次加入氰化钠(1.48g,30.1mmol)在甲醇(15mL)中的溶液中。1小时后,将反应物浓缩至干,用水稀释,用二氯甲烷(3x)萃取,合并的有机萃取物经硫酸钠干燥,过滤并浓缩。通过硅胶层析法纯化(100%二氯甲烷→5%甲醇/二氯甲烷),得到标题化合物(0.740g)。MS 296.9(M+1)。
步骤D.[5-溴-2-氧代-1-(2,2,2-三氟乙基)-1,2-二氢吡啶-3-基]乙酸
用6N HCl(10mL)稀释[5-溴-2-氧代-1-(2,2,2-三氟乙基)-1,2-二氢吡啶-3-基]乙腈(223mg,0.756mmol)并加热到85℃。24小时后,用乙酸乙酯萃取反应物(5x),合并的有机萃取物经硫酸钠干燥,过滤并浓缩,得到标题化合物(0.231g)。MS 316.0(M+1)。
步骤E.1-(1-{[5-溴-2-氧代-1-(2,2,2-三氟乙基)-1,2-二氢吡啶-3-基]乙酰
基}哌啶-4-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮
将三乙胺(410μL,2.94mmol)加入[5-溴-2-氧代-1-(2,2,2-三氟乙基)-1,2-二氢吡啶-3-基]乙酸(231mg,0.736mmol)、2-氧代-1-(4-哌啶基)-2,3-二氢-1H-咪唑并[4,5-b]吡啶盐酸盐(236mg,0.809mmol)、EDC(212mg,1.10mmol)和HOAt(100mg,0.736mmol)在DMF(13mL)中的溶液中。24小时后,加入饱和碳酸钠水溶液并用乙酸乙酯(3x)萃取混合物。有机层经硫酸钠干燥,过滤并浓缩。通过硅胶层析法纯化(100%二氯甲烷→90%二氯甲烷/甲醇),得到标题化合物(0.192g)。MS 516.0(M+1)。
步骤F.1-(1-{[2-氧代-5-苯基-1-(2,2,2-三氟乙基)-1,2-二氢吡啶-3-基]乙
酰基}哌啶-4-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮
将1,1′-双(二苯基膦基)二茂铁二氯化钯(II)二氯甲烷络合物(5mg,0.006mmol)加入1-(1-{[5-溴-2-氧代-1-(2,2,2-三氟乙基)-1,2-二氢吡啶-3-基]乙酰基}哌啶-4-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(50mg,0.097mmol)、苯基硼酸(14mg,0.117mmol)和磷酸钾(45mg,0.214mmol)在DME(2mL)中的溶液中并加热到85℃。24小时后,加入水,用乙酸乙酯萃取混合物(3x),合并的有机萃取物经硫酸钠干燥,过滤并浓缩。通过硅胶层析法纯化(99%→85%二氯甲烷/甲醇),得到标题化合物(25mg)。MS 512.1861(M+1)。
基本上按照对实施例90的制备概述的方法制备表2中的各实施例化合物。
表2
实施例103
1-{[5-(2,3-二氟苯基)-2-氧代-1-(2,2,2-三氟乙基)-1,2-二氢吡啶-3-基]乙
酰基}螺[哌啶-4,3′-吡咯并[2,3-b]吡啶-2′(1′H)-酮
基本上按照对实施例90的制备概述的方法制备。MS 533.1586(M+1)。
实施例104
N-[6-(2-氯苯基)-1-(环丙基甲基)-2-氧代-1,2-二氢吡啶-3-基]-4-(2-氧代-
4-苯基-2,3-二氢-1H-咪唑-1-基)哌啶-1-甲酰胺
步骤A:6-(2-氯苯基)-1-(环丙基甲基)-2-氧代-1,2-二氢吡啶-3-基氨基
甲酸苄酯
将碳酸铯(1.07g,3.30mmol)加入6-(2-氯苯基)-2-氧代-1,2-二氢吡啶-3-基氨基甲酸苄酯(J.Med.Chem.1994,37,3303-3312)(585mg,1.65mmol)和环丙基甲基溴(0.19M1,1.98mmol)在N,N-二甲基甲酰胺(5mL)中的溶液中。4小时后,加入水并用乙酸乙酯萃取混合物。用水(2x)、饱和盐水洗涤有机层,经硫酸镁干燥,过滤并浓缩。通过硅胶层析法纯化(己烷→30%乙酸乙酯/乙烷),得到标题化合物(258mg)。MS 409.0(M+1)。
步骤B:3-氨基-6-(2-氯苯基)-1-(环丙基甲基)吡啶-2(1H)-酮
将10%披钯碳(80mg)加入6-(2-氯苯基)-1-(环丙基甲基)-2-氧代-1,2-二氢吡啶-3-基氨基甲酸苄酯(280mg,0.69mmol)在乙醇(40mL)中的溶液中。将反应容器抽空并用氮气(3x)反填充,然后用氢气(50psi)反填充。5小时后,将混合物过滤并浓缩,得到标题化合物(17mg)。MS 274.9(M+1)。
步骤C:N-[6-(2-氯苯基)-1-(环丙基甲基)-2-氧代-1,2-二氢吡啶-3-基]-
4-(2-氧代-4-苯基-2,3-二氢-1H-咪唑-1-基)哌啶-1-甲酰胺
在0℃下,将三乙胺(9μL,0.062mmol)加入氨基-6-(2-氯苯基)-1-(环丙基甲基)吡啶-2(1H)-酮(17mg,0.062mmol)和氯甲酸4-硝基苯酯(13mg,0.062mmol)在四氢呋喃(2mL)中的溶液中。0.5小时后,加入氯化4-(2-氧代-4-苯基-2,3-二氢-1H-咪唑-1-基)哌啶(20mg,0.071mmol)和三乙胺(0.030mL,0.215mmol)并使混合物升到室温。2小时后,真空浓缩混合物。通过硅胶层析法(100%二氯甲烷→95%二氯甲烷/甲醇),然后反相HPLC(C-18,95%水/乙腈→5%水/乙腈/0.1%三氟乙酸)纯化,得到标题化合物(5mg)。MS 544.2(M+1)。
实施例105
N-[1-(环丙基甲基)-2-氧代-6-苯基-1,2-二氢吡啶-3-基]-4-(2-氧代-4-苯
基-2,3-二氢-1H-咪唑-1-基)哌啶-1-甲酰胺
基本上按照对实施例104的制备概述的方法制备。MS 510.2(M+1)。
实施例106
4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)-N-[3-氧代-6-苯基-4-
(2,2,2-三氟乙基)-3,4-二氢吡嗪-2-基]哌啶-1-甲酰胺
按照方案12中概述的路线制备。MS574.1829(M+1)。
实施例107
N-[2-(2-甲氧基乙基)-3-氧代-6-苯基-2,3-二氢哒嗪-4-基]-4-(2-氧代-2,3-
二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺
按照方案12中概述的路线制备。MS 490(M+1)。
尽管本发明参照其某些具体实施方案得到描述和阐明,但是本领域技术人员应意识到可对方法和方案作各种修改、改变、修饰、代替、删除或添加而不脱离本发明的精神和范围。例如,作为受治疗的哺乳动物对采用本发明上述化合物的任何适应症的响应性的变化的结果,可以采用除本文中所阐述的具体剂量之外的有效剂量。
同样,所观察到的具体药理学响应可以根据和依所选择的具体活性化合物或是否存在药用载体以及所采用的制剂类型和给药方式而定变化,并且根据本发明的目的和实践期待这样预期的变化或结果差异。因此,将通过随后的权利要求范围定义本发明并且这样的权利要求应得到合理广泛的解释。
Claims (38)
1.一种式I的化合物及其药学上可接受的盐和各非对映异构体:
其中:
Z选自:
和
A独立选自N和C(R2);
B为O或S;
R1独立选自:
1)H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-6环烷基和杂环基,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)未取代或被1-5个各自独立选自R4的取代基取代的芳基,
d)未取代或被1-5个各自独立选自R4的取代基取代的杂芳基,
e)未取代或被1-5个各自独立选自R4的取代基取代的杂环,
f)(F)pC1-3烷基,
g)卤素,
h)OR4,
i)O(CH2)sOR4,
j)CO2R4,
k)(CO)NR10R11,
1)O(CO)NR10R11,
m)N(R4)(CO)NR10R11,
n)N(R10)(CO)R11,
o)N(R10)(CO)OR11,
p)SO2NR10R11,
q)N(R10)SO2R11,
r)S(O)mR10,
s)CN,
t)NR10R11,
u)N(R10)(CO)NR4R11,和
v)O(CO)R4;
2)芳基或杂芳基,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)未取代或被1-5个各自独立选自R4的取代基取代的芳基,
d)未取代或被1-5个各自独立选自R4的取代基取代的杂芳基,
e)未取代或被1-5个各自独立选自R4的取代基取代的杂环,
f)(F)pC1-3烷基,
g)卤素,
h)OR4,
i)O(CH2)sOR4,
j)CO2R4,
k)(CO)NR10R11,
l)O(CO)NR10R11,
m)N(R4)(CO)NR10R11,
n)N(R10)(CO)R11,
o)N(R10)(CO)OR11,
p)SO2NR10R11,
q)N(R10)SO2R11,
r)S(O)mR10,
s)CN,
t)NR10R11,
u)N(R10)(CO)NR4R11,和
v)O(CO)R4;
R2独立选自:
1)H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-6环烷基和杂环,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)未取代或被1-5个独立选自R4的取代基取代的芳基,
d)未取代或被1-5个各自独立选自R4的取代基取代的杂芳基,
e)未取代或被1-5个各自独立选自R4的取代基取代的杂环,
f)(F)pC1-3烷基,
g)卤素,
h)OR4,
i)O(CH2)sOR4,
j)CO2R4,
k)(CO)NR10R11,
l)O(CO)NR10R11,
m)N(R4)(CO)NR10R11,
n)N(R10)(CO)R11,
o)N(R10)(CO)OR11,
p)SO2NR10R11,
q)N(R10)SO2R11,
r)S(O)mR10,
s)CN,
t)NR10R11,
u)N(R10)(CO)NR4R11,和
v)O(CO)R4;
2)芳基或杂芳基,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)未取代或被1-5个独立选自R4的取代基取代的芳基,
d)未取代或被1-5个各自独立选自R4的取代基取代的杂芳基,
e)未取代或被1-5个各自独立选自R4的取代基取代的杂环,
F)(F)pC1-3烷基,
g)卤素,
h)OR4,
i)O(CH2)sOR4,
j)CO2R4,
k)(CO)NR10R11,
l)O(CO)NR10R11,
m)N(R4)(CO)NR10R11,
n)N(R10)(CO)R11,
o)N(R10)(CO)OR11,
p)SO2NR10R11,
q)N(R10)SO2R11,
r)S(O)mR10,
s)CN,
t)NR10R11,
u)N(R10)(CO)NR4R11,和
v)O(CO)R4,
其中在相邻原子上的R1和R2,或任何两个独立的R2任选连接形成选自C5-7环烷基、杂环、芳基和杂芳基的环,其中所述环为未取代或被1-10个各自独立选自R6的取代基取代;
R10和R11独立选自:H、C1-6烷基、(F)pC1-6烷基、C3-6环烷基、芳基、杂芳基和苄基,未取代或被卤素、羟基或者C1-6烷氧基取代,其中R10和R11任选连接形成选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基或吗啉基的环,所述环为未取代或被1-5个各自独立选自R4的取代基取代;
R4独立选自:H、C1-6烷基、(F)pC1-6烷基、C3-6环烷基、芳基、杂芳基和苄基,未取代或被卤素、羟基或者C1-6烷氧基取代;
W为O、NR4或C(R4)2;
X为C或S;
Y为O、(R4)2、NCN、NSO2CH3或NCONH2,或者当X为S时Y为O2;
R6独立选自H和:
a)C1-6烷基,
b)C3-6环烷基,
c)未取代或被1-5个独立选自R4的取代基取代的芳基,
d)未取代或被1-5个各自独立选自R4的取代基取代的杂芳基,
e)未取代或被1-5个各自独立选自R4的取代基取代的杂环,
f)(F)pC1-3烷基,
g)卤素,
h)OR4,
i)O(CH2)sOR4,
j)CO2R4,
k)(CO)NR10R11,
l)O(CO)NR10R11,
m)N(R4)(CO)NR10R11,
n)N(R10)(CO)R11,
o)N(R10)(CO)OR11,
p)SO2NR10R11,
q)N(R10)SO2R11,
r)S(O)mR10,
s)CN,
t)NR10R11,
u)N(R10)(CO)NR4R11,和
v)O(CO)R4,
J为键、C(R6)2、O或NR6;
V选自键、C(R6)2、O、S(O)m、NR6、C(R6)2-C(R6)2、C(R6)=C(R6)、C(R6)2-N(R6)、C(R6)=N、N(R6)-C(R6)2、N=C(R6)和N(R6)-N(R6);
G-L选自:N、N-C(R6)2、C=C(R6)、C=N、C(R6)、C(R6)-C(R6)2、C(R6)-C(R6)2-C(R6)2、C=C(R6)-C(R6)2、C(R6)-C(R6)=C(R6)、C(R6)-C(R6)2-N(R6)、C=C(R6)-N(R6)、C(R6)-C(R6)=N、C(R6)-N(R6)-C(R6)2、C=N-C(R6)2、C(R6)-N=C(R6)、C(R6)-N(R6)-N(R6)、C=N-N(R6)、N-C(R6)2-C(R6)2、N-C(R6)=C(R6)、N-C(R6)2-N(R6)、N-C(R6)=N、N-N(R6)-C(R6)2和N-N=C(R6);
Q独立选自:
(1)=C(R7a)-,
(2)-C(R7a)2-,
(3)-C(=O)-,
(4)-S(O)m-,
(5)=N-,和
(6)-N(R7a)-;
T独立选自:
(1)=C(R7b)-,
(2)-C(R7b)2-,
(3)-C(=O)-,
(4)-S(O)m-,
(5)=N-,和
(6)-N(R7b)-;
R3独立选自H、取代或未取代的C1-C3烷基、F、CN和CO2R4;
R7a和R7b各自独立选自R2,其中R7a和R7b与它们连接的原子或多个原子任选连接形成选自C3-6环烷基、芳基、杂环和杂芳基的环,所述环为未取代或被1-10个各自独立选自R6的取代基取代;
对于具有q个碳的取代基而言p为0至2q+1;
m为0、1或2;
n为0或1;
s为1、2或3。
2.权利要求1的化合物及其药学上可接受的盐和各立体异构体,所述化合物具有式Ia:
5.权利要求1的化合物及其药学上可接受的盐和各立体异构体,所述化合物具有式Id:
7.一种选自以下的化合物及其药学上可接受的盐和各立体异构体:
其中:
A独立选自N和C(R2);
R1独立选自:
1)H、C1-6烷基、C3-6环烷基和杂环,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)未取代或被1-5个独立选自R4的取代基取代的芳基,
d)未取代或被1-5个各自独立选自R4的取代基取代的杂芳基,
e)未取代或被1-5个各自独立选自R4的取代基取代的杂环,
f)(F)pC1-3烷基,
g)卤素,
h)OR4,
i)O(CH2)sOR4,
j)CO2R4,
k)CN,
l)NR10R11,和
m)O(CO)R4;和
2)芳基或杂芳基,未取代或被一个或多个独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)(F)pC1-3烷基,
d)卤素,
e)OR4,
f)CO2R4,
g)(CO)NR10R11,
h)SO2NR10R11,
i)N(R10)SO2R11,
j)S(O)mR4,
k)CN,
l)NR10R11,和
m)O(CO)R4;
R2选自:
1)H、C1-C6烷基、C2-C6炔基、C3-6环烷基和杂环,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)未取代或被1-5个独立选自R4的取代基取代的芳基,
d)未取代或被1-5个各自独立选自R4的取代基取代的杂芳基,
e)未取代或被1-5个各自独立选自R4的取代基取代的杂环,
f)(F)pC1-3烷基,
g)卤素,
h)OR4,
i)O(CH2)sOR4,
j)CO2R4,
k)S(O)mR4,
l)CN,
m)NR10R11,和
n)O(CO)R4;和
2)芳基或杂芳基,未取代或被一个或多个独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)(F)pC1-3烷基,
d)卤素,
e)OR4,
f)CO2R4,
g)(CO)NR10R11,
h)SO2NR10R11,
i)N(R10)SO2R11,
j)S(O)mR4,
k)CN,
l)NR10R11,和
m)O(CO)R4,
其中在相邻原子上的R1和R2,或任何两个独立的R2任选连接形成选自C5-7环烷基、杂环、芳基和杂芳基的环,其中所述环为未取代或被1-10个各自独立选自R6的取代基取代;
R10和R11独立选自:H、C1-6烷基、(F)pC1-6烷基、C3-6环烷基、芳基、杂芳基和苄基,未取代或被卤素、羟基或者C1-6烷氧基取代,其中R10和R11任选连接形成选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基和吗啉基的环,所述环为未取代或被1-5个各自独立选自R4的取代基取代;
R4独立选自:H、C1-6烷基、(F)pC1-6烷基、C3-6环烷基、芳基、杂芳基和苄基,未取代或被卤素、羟基或者C1-C6烷氧基取代;
W为O、NR4或C(R4)2;
R6独立选自H和:
a)C1-6烷基,
b)C3-6环烷基,
c)(F)pC1-3烷基,
d)卤素,
e)OR4,
f)CO2R4,
g)(CO)NR10R11,
h)SO2NR10R11,
i)N(R10)SO2R11,
j)S(O)mR4,
k)CN,
l)NR10R11,和
m)O(CO)R4;和
Z选自:
Q独立选自:
(1)=C(R7a)-,
(2)-C(R7a)2-,
(3)-C(=O)-,
(4)-S(O)m-,
(5)=N-,和
(6)-N(R7a)-;
T独立选自:
(1)=C(R7b)-,
(2)-C(R7b)2-,
(3)-C(=O)-,
(4)-S(O)m-,
(5)=N-,和
(6)-N(R7b)-;
J为键、C(R6)2、O或NR6;
V选自键、C(R6)2、O、S(O)m、NR6、C(R6)2-C(R6)2、C(R6)=C(R6)、C(R6)2-N(R6)、C(R6)=N、N(R6)-C(R6)2、N=C(R6)和N(R6)-N(R6);
R7a和R7b各自独立选自R2,其中R7a和R7b与它们连接的原子或多个原子任选连接形成选自C3-6环烷基、芳基、杂环和杂芳基的环,所述环为未取代或被1-10个各自独立选自R6的取代基取代;
对于具有q个碳的取代基而言p为0至2q+1;
m为0-2;
s为1-3。
13.一种选自以下的化合物及其药学上可接受的盐和各立体异构体:
其中:
A独立选自N和C(R2);
R1选自:
1)H、C1-6烷基、C3-6环烷基和杂环,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)未取代或被1-5个独立选自R4的取代基取代的苯基,
d)未取代或被1-5个各自独立选自R4的取代基取代的杂芳基,所述杂芳基选自:咪唑、异唑、唑、吡嗪、吡唑、哒嗪、吡啶、嘧啶和噻唑;
e)未取代或被1-5个各自独立选自R4的取代基取代的杂环,所述杂环选自:氮杂环丁烷、二烷、二氧戊环、吗啉、氧杂环丁烷、哌嗪、哌啶、吡咯烷、四氢呋喃和四氢吡喃;
f)(F)pC1-3烷基,
g)卤素,
h)OR4,
i)O(CH2)sOR4,
j)CO2R4,
k)CN,
l)NR10R11,和
m)O(CO)R4;
2)选自苯基、咪唑、异唑、唑、吡嗪、吡唑、哒嗪、吡啶、嘧啶和噻唑的芳基或杂芳基,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)(F)pC1-3烷基,
d)卤素,
e)OR4,
F)CO2R4,
g)(CO)NR10R11,
h)SO2NR10R11,
i)N(R10)SO2R11,
j)S(O)mR4,
k)CN,
l)NR10R11,和
m)O(CO)R4;
R2选自:
1)H、C1-C6烷基、C3-6环烷基和杂环,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)未取代或被1-5个各自独立选自R4的取代基取代的苯基,
d)未取代或被1-5个各自独立选自R4的取代基取代的杂芳基,所述杂芳基选自:苯并咪唑、苯并噻吩、呋喃、咪唑、吲哚、异唑、唑、吡嗪、吡唑、哒嗪、吡啶、嘧啶、吡咯、噻唑、噻吩和三唑;
e)未取代或被1-5个取代基取代的杂环,其中所述取代基独立选自R4的,且其中杂环选自氮杂环丁烷、咪唑烷、咪唑啉、异唑啉、异唑烷、吗啉、唑啉、唑烷、氧杂环丁烷、吡唑烷、吡唑啉、吡咯啉、四氢呋喃、四氢吡喃、噻唑啉和噻唑烷;
f)(F)pC1-3烷基,
g)卤素,
h)OR4,
i)O(CH2)sOR4,
j)CO2R4,
k)CN,
l)NR10R11,和
m)O(CO)R4;和
2)选自苯基、苯并咪唑、苯并噻吩、呋喃、咪唑、吲哚、异唑、唑、吡嗪、吡唑、哒嗪、吡啶、嘧啶、吡咯、噻唑、噻吩和三唑的芳基或杂芳基,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)(F)pC1-3烷基,
d)卤素,
e)OR4,
f)CO2R4,
g)(CO)NR10R11,
h)SO2NR10R11,
i)N(R10)SO2R11,
j)S(O)mR4,
K)CN,
l)NR10R11,和
m)O(CO)R4,
其中在相邻原子上的R1和R2,或任何两个独立的R2任选连接形成选自C5-7环烷基、杂环、芳基和杂芳基的环,其中所述环为未取代或被1-10个各自独立选自R6的取代基取代;
R10和R11独立选自:H、C1-6烷基、(F)pC1-6烷基、C3-6环烷基、芳基、杂芳基和苄基,未取代或被卤素、羟基或者C1-6烷氧基取代,其中R10和R11任选连接形成选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基和吗啉基的环,所述环为未取代或被1-5个各自独立选自R4的取代基取代;
R4独立选自:H、C1-6烷基、(F)pC1-6烷基、C3-6环烷基、芳基、杂芳基和苯基,未取代或被羟基或者C1-6烷氧基取代;
W为NR4或C(R4)2;
R6独立选自H和:
a)C1-6烷基,
b)C3-6环烷基,
c)(F)pC1-3烷基,
d)卤素,
e)OR4,
f)CO2R4,
g)(CO)NR10R11,
h)SO2NR10R11,
i)N(R10)SO2R11,
j)S(O)mR4,
k)CN,
l)NR10R11,和
m)O(CO)R4;
Z选自:
R7a和R7b独立选自R2,其中R7a和R7b与它们连接的原子或多个原子任选连接形成选自C3-6环烷基、芳基、杂环和杂芳基的环,所述环未取代或被1-10个各自独立选自R6的取代基取代;
对于具有q个碳的取代基而言p为0至2q+1;
m为0-2;
s为1-3。
19.一种下式的化合物及其药学上可接受的盐和各非对映异构体:
其中:
R1选自:
1)H、C1-C6烷基、C3-6环烷基和杂环,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)未取代或被1-5个各自独立选自R4的取代基取代的苯基,
d)未取代或被1-5个各自独立选自R4的取代基取代的杂芳基,所述杂芳基选自:咪唑、异唑、唑、吡嗪、吡唑、哒嗪、吡啶、嘧啶和噻唑;
e)未取代或被1-5个各自独立选自R4的取代基取代的杂环,所述杂环选自:氮杂环丁烷、二烷、二氧戊环、吗啉、氧杂环丁烷、哌嗪、哌啶、吡咯烷、四氢呋喃和四氢吡喃;
f)(F)pC1-3烷基,
g)卤素,
h)OR4,
i)O(CH2)sOR4,
j)CO2R4,
k)CN,
l)NR10R11,
m)O(CO)R4;
2)选自苯基、咪唑、异唑、唑、吡嗪、吡唑、哒嗪、吡啶、嘧啶和噻唑的芳基或杂芳基,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)(F)pC1-3烷基,
d)卤素,
e)OR4,
f)CO2R4,
g)(CO)NR10R11,
h)SO2NR10R11,
i)N(R10)SO2R11,
j)S(O)mR4,
k)CN,
l)NR10R11,和
m)O(CO)R4;
R2选自:
1)H、C1-C6烷基、C3-6环烷基和杂环,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)未取代或被1-5个各自独立选自R4的取代基取代的苯基,
d)未取代或被1-5个各自独立选自R4的取代基取代的杂芳基,所述杂芳基选自:苯并咪唑、苯并噻吩、呋喃、咪唑、吲哚、异唑、唑、吡嗪、吡唑、哒嗪、吡啶、嘧啶、吡咯、噻唑、噻吩和三唑;
e)未取代或被1-5个独立选自R4的取代基取代的杂环,所述杂环选自氮杂环丁烷、咪唑烷、咪唑啉、异唑啉、异唑烷、吗啉、唑啉、唑烷、氧杂环丁烷、吡唑烷、吡唑啉、吡咯啉、四氢呋喃、四氢吡喃、噻唑啉和噻唑烷;
f)(F)pC1-3烷基,
g)卤素,
h)OR4,
i)O(CH2)sOR4,
j)CO2R4,
k)CN,
l)NR10R11,和
m)O(CO)R4;和
2)选自苯基、苯并咪唑、苯并噻吩、呋喃、咪唑、吲哚、异唑、唑、吡嗪、吡唑、哒嗪、吡啶、嘧啶、吡咯、噻唑、噻吩和三唑的芳基或杂芳基,未取代或被一个或多个各自独立选自以下的取代基取代:
a)C1-6烷基,
b)C3-6环烷基,
c)(F)pC1-3烷基,
d)卤素,
e)OR4,
f)CO2R4,
g)(CO)NR10R11,
h)SO2NR10R11,
i)N(R10)SO2R11,
j)S(O)mR4,
k)CN,
l)NR10R11,和
m)O(CO)R4,
其中在相邻原子上的R1和R2,或任何两个独立的R2任选连接形成选自C5-7环烷基、杂环、芳基和杂芳基的环,其中所述环为未取代或被1-10个各自独立选自R6的取代基取代;
R10和R11独立选自:H、C1-6烷基、(F)pC1-6烷基、C3-6环烷基、芳基、杂芳基和苄基,未取代或被卤素、羟基或者C1-6烷氧基取代,其中R10和R11任选连接形成选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基和吗啉基的环,所述环为未取代或被1-5个各自独立选自R4的取代基取代;
R4独立选自:H、C1-6烷基、(F)pC1-6烷基、C3-6环烷基、芳基、杂芳基和苯基,未取代或被羟基或者C1-6烷氧基取代;
R6独立选自H和:
a)C1-6烷基,
b)C3-6环烷基,
c)(F)pC1-3烷基,
d)卤素,
e)OR4,
F)CO2R4,
g)(CO)NR10R11,
h)SO2NR10R11,
i)N(R10)SO2R11,
j)S(O)mR4,
k)CN,
l)NR10R11,和
m)O(CO)R4;
Z选自:
对于具有q个碳的取代基而言p为0至2q+1;
m为0-2。
21.一种药用组合物,所述组合物包含惰性载体和权利要求1的化合物。
22.一种用于在哺乳动物中拮抗CGRP受体活性的方法,所述方法包括给予有效量的权利要求1的化合物。
23.一种治疗、控制、改善或减少有需要的哺乳动物患者头痛、偏头痛或丛集性头痛风险的方法,所述方法包括给予患者治疗有效量的权利要求1的化合物。
24.一种治疗或预防偏头痛、丛集性头痛和头痛的方法,所述方法包括共给予需要这种治疗的患者:
治疗有效量的权利要求1的化合物或其药学上可接受的盐;和
治疗有效量的选自5-羟色胺激动剂、镇痛剂、抗炎药、降血压药和抗惊厥药的第二药物。
25.一种治疗或预防偏头痛、丛集性头痛和头痛的方法,所述方法包括共给予需要这种治疗的患者:
治疗有效量的权利要求1的化合物或其药学上可接受的盐;和
治疗有效量的选自抗焦虑药和神经安定剂的第二药物。
26.一种治疗或预防偏头痛、丛集性头痛和头痛的方法,所述方法包括共给予需要这种治疗的患者:
治疗有效量的权利要求1的化合物或其药学上可接受的盐;和
治疗有效量的选自β-阻断剂和钙通道阻断剂的第二药物。
27.一种治疗或预防偏头痛、丛集性头痛和头痛的方法,所述方法包括共给予需要这种治疗的患者:
治疗有效量的权利要求1的化合物或其药学上可接受的盐;和
治疗有效量的选自抗抑郁药、选择性5-羟色胺再摄取抑制剂和NE再摄取抑制剂的第二药物。
28.一种治疗或预防偏头痛、丛集性头痛和头痛的方法,所述方法包括共给予需要这种治疗的患者:
治疗有效量的权利要求1的化合物或其药学上可接受的盐;和
治疗有效量的选自肉毒杆菌毒素A或B的第二药物。
29.一种治疗或预防偏头痛、丛集性头痛和头痛的方法,所述方法包括共给予需要这种治疗的患者:
治疗有效量的权利要求1的化合物或其药学上可接受的盐;和
治疗有效量的选自以下的第二药物:辣椒素受体拮抗剂、腺苷1拮抗剂、NR2B拮抗剂、P物质拮抗剂、颗粒酶B抑制剂、内皮素拮抗剂、去甲肾上腺素前体、一氧化氮合成酶抑制剂、神经安定剂、血管舒缓激肽拮抗剂、间隙连接抑制剂、AMPA/KA拮抗剂、σ型受体激动剂、氯化物通道增强剂、单胺氧化酶抑制剂、阿片样物质激动剂和白三烯受体拮抗剂。
30.一种治疗或预防偏头痛、丛集性头痛和头痛的方法,所述方法包括共给予需要这种治疗的患者:
治疗有效量的权利要求1的化合物或其药学上可接受的盐;和
治疗有效量的选自止吐药、胃肠蠕动促进剂和组胺Hl拮抗剂的第二药物。
31.一种药用组合物,所述组合物包含:
治疗有效量的权利要求1的化合物或其药学上可接受的盐;和
治疗有效量的选自5-羟色胺激动剂、镇痛剂、抗炎药、降血压药和抗惊厥药的第二药物。
32.一种药用组合物,所述组合物包含:
治疗有效量的权利要求1的化合物或其药学上可接受的盐;和
治疗有效量的选自血管紧张素II拮抗剂、血管紧张素I拮抗剂、血管紧张素转换酶抑制剂和肾素抑制剂的第二药物。
33.一种药用组合物,所述组合物包含:
治疗有效量的权利要求1的化合物或其药学上可接受的盐;和
治疗有效量的选自抗焦虑药和神经安定剂的第二药物。
34.一种药用组合物,所述组合物包含:
治疗有效量的权利要求1的化合物或其药学上可接受的盐;和治疗有效量的选自β-阻断剂和钙通道阻断剂的第二药物。
35.一种药用组合物,所述组合物包含:
治疗有效量的权利要求1的化合物或其药学上可接受的盐;和治疗有效量的选自抗抑郁药、选择性5-羟色氨再摄取抑制剂和NE再摄取抑制剂的第二药物。
36.一种药用组合物,所述组合物包含:
治疗有效量的权利要求1的化合物或其药学上可接受的盐;和治疗有效量的选自肉毒杆菌毒素A或B的第二药物。
37.一种药用组合物,所述组合物包含:
治疗有效量的权利要求1的化合物或其药学上可接受的盐;和治疗有效量的选自以下的第二药物:辣椒素受体拮抗剂、腺苷1拮抗剂、NR2B拮抗剂、P物质拮抗剂、颗粒酶B抑制剂、内皮素拮抗剂、去甲肾上腺素前体、一氧化氮合成酶抑制剂、神经安定剂、血管舒缓激肽拮抗剂、间隙连接抑制剂、AMPA/KA拮抗剂、σ型受体激动剂、氯化物通道增强剂、单胺氧化酶抑制剂、阿片样物质激动剂和白三烯受体拮抗剂。
38.一种药用组合物,所述组合物包含:
治疗有效量的权利要求1的化合物或其药学上可接受的盐;和治疗有效量的选自止吐药、胃肠蠕动促进剂和组胺Hl拮抗剂的第二药物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US66156505P | 2005-03-14 | 2005-03-14 | |
US60/661,565 | 2005-03-14 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN101208303A true CN101208303A (zh) | 2008-06-25 |
Family
ID=36992322
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2006800080832A Pending CN101208303A (zh) | 2005-03-14 | 2006-03-14 | Cgrp受体拮抗剂 |
Country Status (8)
Country | Link |
---|---|
US (1) | US7994325B2 (zh) |
EP (1) | EP1861399B1 (zh) |
JP (1) | JP2008533147A (zh) |
CN (1) | CN101208303A (zh) |
AT (1) | ATE537170T1 (zh) |
AU (1) | AU2006223236A1 (zh) |
CA (1) | CA2599925A1 (zh) |
WO (1) | WO2006099268A2 (zh) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103328478A (zh) * | 2010-11-12 | 2013-09-25 | 默沙东公司 | 哌啶酮羧酰胺氮杂茚满cgrp受体拮抗剂 |
CN107207567A (zh) * | 2015-01-06 | 2017-09-26 | 辉凌公司 | Cgrp拮抗剂肽 |
CN107428744A (zh) * | 2014-12-23 | 2017-12-01 | 盖尔德马研究及发展公司 | 新型杂环化合物及其在医药和化妆品中的应用 |
US10640504B2 (en) | 2017-09-08 | 2020-05-05 | Amgen Inc. | Inhibitors of KRAS G12C and methods of using the same |
US11518808B2 (en) | 2018-01-12 | 2022-12-06 | Amgen Inc. | Anti-PD-1 antibodies and methods of treatment |
US11541103B2 (en) | 2017-08-03 | 2023-01-03 | Amgen Inc. | Interleukin-21 mutein/ anti-PD-1 antibody conjugates |
US11717515B2 (en) | 2020-12-22 | 2023-08-08 | Allergan Pharmaceuticals International Limited | Treatment of migraine |
US11925709B2 (en) | 2014-02-05 | 2024-03-12 | Merck Sharp & Dohme Corp. | Tablet formulation for CGRP active compounds |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7659264B2 (en) * | 2004-10-07 | 2010-02-09 | Merck Sharp & Dohme Corp. | CGRP receptor antagonists |
MX2007007330A (es) | 2004-12-16 | 2007-10-04 | Vertex Pharma | Piridonas de utilidad como inhibidores de quinasas . |
ES2368456T3 (es) | 2006-05-02 | 2011-11-17 | Bristol-Myers Squibb Company | Compuestos restringidos como antagonistas del receptor de cgrp. |
US7470680B2 (en) | 2006-05-03 | 2008-12-30 | Bristol-Myers Squibb Company | Constrained compounds as CGRP-receptor antagonists |
EA200870521A1 (ru) * | 2006-05-09 | 2009-04-28 | Мерк Энд Ко., Инк. | Замещенные спироциклические антагонисты cgrp-рецепторов |
GB0712392D0 (en) * | 2007-06-26 | 2007-08-01 | Glaxo Group Ltd | Novel compounds |
WO2009054544A1 (en) * | 2007-10-26 | 2009-04-30 | Eisai R & D Management Co., Ltd. | Ampa receptor antagonists for parkinson's disease and movement disorders |
WO2010016490A1 (ja) | 2008-08-05 | 2010-02-11 | 第一三共株式会社 | イミダゾピリジン-2-オン誘導体 |
EP2637656B1 (en) * | 2010-11-12 | 2016-12-14 | Merck Sharp & Dohme Corp. | N-Piperidinone-indane carboxamides as CGRP receptor antagonists |
WO2013097052A1 (en) | 2011-12-30 | 2013-07-04 | Abbott Laboratories | Bromodomain inhibitors |
KR20210022150A (ko) * | 2012-03-14 | 2021-03-02 | 머크 샤프 앤드 돔 코포레이션 | Cgrp 수용체 길항제의 제조 방법 |
US9487523B2 (en) | 2012-03-14 | 2016-11-08 | Merck Sharp & Dohme Corp. | Process for making CGRP receptor antagonists |
CN106660987B (zh) | 2014-06-27 | 2020-11-06 | 赛尔基因昆蒂赛尔研究公司 | 赖氨酸特异性脱甲基酶-1的抑制剂 |
DK3442972T3 (da) | 2016-04-15 | 2020-04-27 | Abbvie Inc | Bromdomænehæmmere |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5155115A (en) * | 1991-03-12 | 1992-10-13 | Kyowa Hakko Kogyo Co., Ltd. | Thienopyridine derivatives |
JO2355B1 (en) * | 2003-04-15 | 2006-12-12 | ميرك شارب اند دوم كوربوريشن | Hereditary calcitonin polypeptide receptor antagonists |
CN100572379C (zh) * | 2003-04-15 | 2009-12-23 | 麦克公司 | Cgrp受体拮抗剂 |
WO2005013894A2 (en) * | 2003-06-26 | 2005-02-17 | Merck & Co., Inc. | Benzodiazepine cgrp receptor antagonists |
EP1765805B1 (en) * | 2004-01-29 | 2013-11-20 | Merck Sharp & Dohme Corp. | Cgrp receptor antagonists |
DE602005027230D1 (de) * | 2004-10-22 | 2011-05-12 | Merck Sharp & Dohme | Cgrp-rezeptorantagonisten |
-
2006
- 2006-03-14 US US11/885,926 patent/US7994325B2/en active Active
- 2006-03-14 AU AU2006223236A patent/AU2006223236A1/en not_active Abandoned
- 2006-03-14 CN CNA2006800080832A patent/CN101208303A/zh active Pending
- 2006-03-14 JP JP2008501934A patent/JP2008533147A/ja active Pending
- 2006-03-14 CA CA002599925A patent/CA2599925A1/en not_active Abandoned
- 2006-03-14 AT AT06748359T patent/ATE537170T1/de active
- 2006-03-14 WO PCT/US2006/008859 patent/WO2006099268A2/en active Application Filing
- 2006-03-14 EP EP06748359A patent/EP1861399B1/en active Active
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103328478A (zh) * | 2010-11-12 | 2013-09-25 | 默沙东公司 | 哌啶酮羧酰胺氮杂茚满cgrp受体拮抗剂 |
CN103328478B (zh) * | 2010-11-12 | 2015-10-07 | 默沙东公司 | 哌啶酮羧酰胺氮杂茚满cgrp受体拮抗剂 |
US11925709B2 (en) | 2014-02-05 | 2024-03-12 | Merck Sharp & Dohme Corp. | Tablet formulation for CGRP active compounds |
CN107428744A (zh) * | 2014-12-23 | 2017-12-01 | 盖尔德马研究及发展公司 | 新型杂环化合物及其在医药和化妆品中的应用 |
CN107207567A (zh) * | 2015-01-06 | 2017-09-26 | 辉凌公司 | Cgrp拮抗剂肽 |
CN107207567B (zh) * | 2015-01-06 | 2021-11-23 | 辉凌公司 | Cgrp拮抗剂肽 |
US11541103B2 (en) | 2017-08-03 | 2023-01-03 | Amgen Inc. | Interleukin-21 mutein/ anti-PD-1 antibody conjugates |
US10640504B2 (en) | 2017-09-08 | 2020-05-05 | Amgen Inc. | Inhibitors of KRAS G12C and methods of using the same |
US11518808B2 (en) | 2018-01-12 | 2022-12-06 | Amgen Inc. | Anti-PD-1 antibodies and methods of treatment |
US11717515B2 (en) | 2020-12-22 | 2023-08-08 | Allergan Pharmaceuticals International Limited | Treatment of migraine |
US11857542B2 (en) | 2020-12-22 | 2024-01-02 | Allergan Pharmaceuticals International Limited | Treatment of migraine |
Also Published As
Publication number | Publication date |
---|---|
EP1861399A4 (en) | 2010-06-02 |
AU2006223236A1 (en) | 2006-09-21 |
JP2008533147A (ja) | 2008-08-21 |
WO2006099268A3 (en) | 2007-11-22 |
WO2006099268A2 (en) | 2006-09-21 |
ATE537170T1 (de) | 2011-12-15 |
US20080261972A1 (en) | 2008-10-23 |
CA2599925A1 (en) | 2006-09-21 |
EP1861399B1 (en) | 2011-12-14 |
EP1861399A2 (en) | 2007-12-05 |
US7994325B2 (en) | 2011-08-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101208303A (zh) | Cgrp受体拮抗剂 | |
CN1812982B (zh) | 苯并二氮杂*cgrp受体拮抗剂 | |
CN103328478B (zh) | 哌啶酮羧酰胺氮杂茚满cgrp受体拮抗剂 | |
CN101448821B (zh) | 羧酰胺螺内酰胺降钙素基因相关肽受体拮抗剂 | |
JP4705912B2 (ja) | ベンゾジアゼピンcgrp受容体拮抗物質 | |
CN101072771B (zh) | Cgrp受体拮抗剂 | |
CN101014602B (zh) | 单环酰苯胺螺环内酰胺cgrp受体拮抗剂 | |
CN101014576B (zh) | 芳基螺内酰胺cgrp受体拮抗剂 | |
CN101232887A (zh) | 杂环苯并二氮杂䓬cgrp受体拮抗剂 | |
CN100384843C (zh) | Cgrp受体拮抗剂 | |
CN100572379C (zh) | Cgrp受体拮抗剂 | |
CN101018781A (zh) | 双环n-酰苯胺螺内酰胺cgrp受体拮抗剂 | |
CN101124217A (zh) | Cgrp受体拮抗剂 | |
JP2008515991A (ja) | Cgrp受容体拮抗薬 | |
JP2008517916A (ja) | Cgrp受容体拮抗薬 | |
EP2685826B1 (en) | Piperidinone carboxamide spirohydantoin cgrp receptor antagonists | |
AU2006206718B2 (en) | CGRP receptor antagonists | |
EP2846799B1 (en) | Spirolactam cgrp receptor antagonists | |
CN101090902B (zh) | Cgrp受体拮抗剂 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20080625 |