TW200808791A - CGRP antagonists - Google Patents
CGRP antagonists Download PDFInfo
- Publication number
- TW200808791A TW200808791A TW096120440A TW96120440A TW200808791A TW 200808791 A TW200808791 A TW 200808791A TW 096120440 A TW096120440 A TW 096120440A TW 96120440 A TW96120440 A TW 96120440A TW 200808791 A TW200808791 A TW 200808791A
- Authority
- TW
- Taiwan
- Prior art keywords
- doc
- group
- acid
- disease
- bowel
- Prior art date
Links
- 229940127597 CGRP antagonist Drugs 0.000 title claims abstract description 15
- 239000003735 calcitonin gene related peptide receptor antagonist Substances 0.000 claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- 208000009935 visceral pain Diseases 0.000 claims abstract description 10
- 208000018522 Gastrointestinal disease Diseases 0.000 claims abstract description 8
- 208000035475 disorder Diseases 0.000 claims abstract description 7
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims description 35
- 239000013543 active substance Substances 0.000 claims description 21
- 239000000126 substance Substances 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 9
- 208000004998 Abdominal Pain Diseases 0.000 claims description 6
- 208000011231 Crohn disease Diseases 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 5
- 210000001072 colon Anatomy 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 208000011580 syndromic disease Diseases 0.000 claims description 5
- 208000023373 Crohn ileitis Diseases 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- 208000009326 ileitis Diseases 0.000 claims description 3
- 208000028774 intestinal disease Diseases 0.000 claims description 3
- 238000009097 single-agent therapy Methods 0.000 claims description 3
- 208000014540 Functional gastrointestinal disease Diseases 0.000 claims description 2
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 208000025865 Ulcer Diseases 0.000 claims description 2
- 201000007637 bowel dysfunction Diseases 0.000 claims description 2
- 230000000112 colonic effect Effects 0.000 claims description 2
- 208000010643 digestive system disease Diseases 0.000 claims description 2
- 201000006549 dyspepsia Diseases 0.000 claims description 2
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 2
- 208000018685 gastrointestinal system disease Diseases 0.000 claims description 2
- 230000004054 inflammatory process Effects 0.000 claims description 2
- 230000000968 intestinal effect Effects 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 3
- 206010009900 Colitis ulcerative Diseases 0.000 claims 1
- 201000006704 Ulcerative Colitis Diseases 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 22
- 238000000034 method Methods 0.000 abstract description 5
- 239000002253 acid Substances 0.000 description 12
- 208000002551 irritable bowel syndrome Diseases 0.000 description 11
- -1 hydrazine compound Chemical class 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- 239000000556 agonist Substances 0.000 description 7
- 229910052751 metal Inorganic materials 0.000 description 7
- 239000002184 metal Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 5
- 150000007524 organic acids Chemical class 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 239000000454 talc Substances 0.000 description 5
- 229910052623 talc Inorganic materials 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000009278 visceral effect Effects 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 4
- 239000000443 aerosol Substances 0.000 description 4
- 239000002585 base Chemical class 0.000 description 4
- 239000000812 cholinergic antagonist Substances 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 239000007937 lozenge Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 230000035945 sensitivity Effects 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 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
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 206010036790 Productive cough Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 235000021355 Stearic acid Nutrition 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 239000000835 fiber Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 229960005150 glycerol Drugs 0.000 description 3
- 150000004678 hydrides Chemical class 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 description 3
- 239000000387 serotonin 5-HT4 receptor agonist Substances 0.000 description 3
- 210000003802 sputum Anatomy 0.000 description 3
- 208000024794 sputum Diseases 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008117 stearic acid Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- 239000011975 tartaric acid Substances 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
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 241001674044 Blattodea Species 0.000 description 2
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 2
- 206010010774 Constipation Diseases 0.000 description 2
- 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 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 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 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- 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 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 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
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 230000003187 abdominal effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 230000001078 anti-cholinergic effect Effects 0.000 description 2
- 230000002921 anti-spasmodic effect Effects 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 239000003557 cannabinoid Substances 0.000 description 2
- 229930003827 cannabinoid Natural products 0.000 description 2
- 229940065144 cannabinoids Drugs 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 229960002896 clonidine Drugs 0.000 description 2
- 206010009887 colitis Diseases 0.000 description 2
- 229940111134 coxibs Drugs 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 2
- 229960003957 dexamethasone Drugs 0.000 description 2
- 230000001079 digestive effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 235000019264 food flavour enhancer Nutrition 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000007149 gut brain axis pathway Effects 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 230000009610 hypersensitivity Effects 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008141 laxative Substances 0.000 description 2
- 230000002475 laxative effect Effects 0.000 description 2
- 239000003589 local anesthetic agent Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 229960002009 naproxen Drugs 0.000 description 2
- 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 2
- 210000000653 nervous system Anatomy 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
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 2
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 2
- 210000001044 sensory neuron Anatomy 0.000 description 2
- 229940076279 serotonin Drugs 0.000 description 2
- 239000002689 soil Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 229960003708 sumatriptan Drugs 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
- 239000000829 suppository Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 210000001835 viscera Anatomy 0.000 description 2
- 229960001360 zolmitriptan Drugs 0.000 description 2
- ULSDMUVEXKOYBU-ZDUSSCGKSA-N zolmitriptan Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1C[C@H]1COC(=O)N1 ULSDMUVEXKOYBU-ZDUSSCGKSA-N 0.000 description 2
- GJJFMKBJSRMPLA-HIFRSBDPSA-N (1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenyl-1-cyclopropanecarboxamide Chemical compound C=1C=CC=CC=1[C@@]1(C(=O)N(CC)CC)C[C@@H]1CN GJJFMKBJSRMPLA-HIFRSBDPSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-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
- BDNFQGRSKSQXRI-XMMPIXPASA-N (3R)-1-[2-(1,3-benzodioxol-5-yl)ethyl]-3-(diphenylmethyl)oxypiperidine Chemical compound O([C@@H]1CCCN(C1)CCC=1C=C2OCOC2=CC=1)C(C=1C=CC=CC=1)C1=CC=CC=C1 BDNFQGRSKSQXRI-XMMPIXPASA-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
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- NHJVRSWLHSJWIN-UHFFFAOYSA-N 2,4,6-trinitrobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O NHJVRSWLHSJWIN-UHFFFAOYSA-N 0.000 description 1
- ASUZQXBECRATCB-UHFFFAOYSA-N 2-methylsulfonylsulfanylacetic acid Chemical compound CS(=O)(=O)SCC(O)=O ASUZQXBECRATCB-UHFFFAOYSA-N 0.000 description 1
- LORDFXWUHHSAQU-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid [2-(dimethylamino)-2-phenylbutyl] ester Chemical compound C=1C=CC=CC=1C(CC)(N(C)C)COC(=O)C1=CC(OC)=C(OC)C(OC)=C1 LORDFXWUHHSAQU-UHFFFAOYSA-N 0.000 description 1
- VYVKHNNGDFVQGA-UHFFFAOYSA-N 3,4-dimethoxybenzoic acid 4-[ethyl-[1-(4-methoxyphenyl)propan-2-yl]amino]butyl ester Chemical compound C=1C=C(OC)C=CC=1CC(C)N(CC)CCCCOC(=O)C1=CC=C(OC)C(OC)=C1 VYVKHNNGDFVQGA-UHFFFAOYSA-N 0.000 description 1
- ASNHGEVAWNWCRQ-UHFFFAOYSA-N 4-(hydroxymethyl)oxolane-2,3,4-triol Chemical compound OCC1(O)COC(O)C1O ASNHGEVAWNWCRQ-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- PJJGZPJJTHBVMX-UHFFFAOYSA-N 5,7-Dihydroxyisoflavone Chemical compound C=1C(O)=CC(O)=C(C2=O)C=1OC=C2C1=CC=CC=C1 PJJGZPJJTHBVMX-UHFFFAOYSA-N 0.000 description 1
- 102000035037 5-HT3 receptors Human genes 0.000 description 1
- 108091005477 5-HT3 receptors Proteins 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 240000002900 Arthrospira platensis Species 0.000 description 1
- 235000016425 Arthrospira platensis Nutrition 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
- 241000186000 Bifidobacterium Species 0.000 description 1
- 241000282817 Bovidae Species 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920001268 Cholestyramine Polymers 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 208000002881 Colic Diseases 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
- 206010012735 Diarrhoea Diseases 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- QEVGZEDELICMKH-UHFFFAOYSA-N Diglycolic acid Chemical compound OC(=O)COCC(O)=O QEVGZEDELICMKH-UHFFFAOYSA-N 0.000 description 1
- 239000004097 EU approved flavor enhancer Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- 108010086677 Gonadotropins Proteins 0.000 description 1
- 102000006771 Gonadotropins Human genes 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- SNIXRMIHFOIVBB-UHFFFAOYSA-N N-Hydroxyl-tryptamine Chemical compound C1=CC=C2C(CCNO)=CNC2=C1 SNIXRMIHFOIVBB-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000008896 Opium Substances 0.000 description 1
- 102100040479 P2X purinoceptor 2 Human genes 0.000 description 1
- 101710189968 P2X purinoceptor 2 Proteins 0.000 description 1
- 102100040460 P2X purinoceptor 3 Human genes 0.000 description 1
- 101710189970 P2X purinoceptor 3 Proteins 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 229940121991 Serotonin and norepinephrine reuptake inhibitor Drugs 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 102000003566 TRPV1 Human genes 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 101150016206 Trpv1 gene Proteins 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 229940126157 adrenergic receptor agonist Drugs 0.000 description 1
- 238000011256 aggressive treatment Methods 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- FLZQKRKHLSUHOR-UHFFFAOYSA-N alosetron Chemical compound CC1=NC=N[C]1CN1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FLZQKRKHLSUHOR-UHFFFAOYSA-N 0.000 description 1
- 229960003550 alosetron Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- ZPFXAOWNKLFJDN-UHFFFAOYSA-N alverine Chemical compound C=1C=CC=CC=1CCCN(CC)CCCC1=CC=CC=C1 ZPFXAOWNKLFJDN-UHFFFAOYSA-N 0.000 description 1
- 229960000845 alverine Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000001142 anti-diarrhea Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940125714 antidiarrheal agent Drugs 0.000 description 1
- 239000003793 antidiarrheal agent Substances 0.000 description 1
- 239000003420 antiserotonin agent Substances 0.000 description 1
- 229940124575 antispasmodic agent Drugs 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 229950002360 avitriptan 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
- 229960002170 azathioprine Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 230000006399 behavior 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
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 239000007767 bonding agent Substances 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
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 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 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003754 cholecystokinin receptor blocking agent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- IAQRGUVFOMOMEM-ARJAWSKDSA-N cis-but-2-ene Chemical group C\C=C/C IAQRGUVFOMOMEM-ARJAWSKDSA-N 0.000 description 1
- DCSUBABJRXZOMT-IRLDBZIGSA-N cisapride Chemical compound C([C@@H]([C@@H](CC1)NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)OC)N1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-IRLDBZIGSA-N 0.000 description 1
- 229960005132 cisapride Drugs 0.000 description 1
- DCSUBABJRXZOMT-UHFFFAOYSA-N cisapride Natural products C1CC(NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)C(OC)CN1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-UHFFFAOYSA-N 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 229940109275 cyclamate Drugs 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 230000013872 defecation Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 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
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229960000616 diflunisal Drugs 0.000 description 1
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 229960002866 duloxetine Drugs 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 229960002472 eletriptan Drugs 0.000 description 1
- OTLDLQZJRFYOJR-LJQANCHMSA-N eletriptan Chemical compound CN1CCC[C@@H]1CC1=CN=C2[C]1C=C(CCS(=O)(=O)C=1C=CC=CC=1)C=C2 OTLDLQZJRFYOJR-LJQANCHMSA-N 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 229960001395 fenbufen Drugs 0.000 description 1
- ZPAKPRAICRBAOD-UHFFFAOYSA-N fenbufen Chemical compound C1=CC(C(=O)CCC(=O)O)=CC=C1C1=CC=CC=C1 ZPAKPRAICRBAOD-UHFFFAOYSA-N 0.000 description 1
- 229960001419 fenoprofen Drugs 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229940050521 gelatin agent Drugs 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 239000002622 gonadotropin Substances 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 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 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 238000007130 inorganic reaction Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- YWXYYJSYQOXTPL-SLPGGIOYSA-N isosorbide mononitrate Chemical compound [O-][N+](=O)O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-SLPGGIOYSA-N 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
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 229920005610 lignin Polymers 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- RDOIQAHITMMDAJ-UHFFFAOYSA-N loperamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N(C)C)CCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 RDOIQAHITMMDAJ-UHFFFAOYSA-N 0.000 description 1
- 229960001571 loperamide 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
- 229960002202 lornoxicam Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 229960003577 mebeverine Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 229960000600 milnacipran Drugs 0.000 description 1
- 229960005254 naratriptan Drugs 0.000 description 1
- AMKVXSZCKVJAGH-UHFFFAOYSA-N naratriptan Chemical compound C12=CC(CCS(=O)(=O)NC)=CC=C2NC=C1C1CCN(C)CC1 AMKVXSZCKVJAGH-UHFFFAOYSA-N 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 1
- 229940127221 norepinephrine reuptake inhibitor Drugs 0.000 description 1
- 239000003402 opiate agonist Substances 0.000 description 1
- 229960001027 opium Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000001354 painful effect Effects 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229960004662 parecoxib Drugs 0.000 description 1
- 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 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-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
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- CHWRSCGUEQEHOH-UHFFFAOYSA-N potassium oxide Chemical compound [O-2].[K+].[K+] CHWRSCGUEQEHOH-UHFFFAOYSA-N 0.000 description 1
- 229910001950 potassium oxide Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000002400 pro-nociceptive effect Effects 0.000 description 1
- 239000006041 probiotic Substances 0.000 description 1
- 235000018291 probiotics Nutrition 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- GZSKEXSLDPEFPT-IINYFYTJSA-N renzapride Chemical compound COC1=CC(N)=C(Cl)C=C1C(=O)N[C@H]1[C@H](C2)CCC[N@]2CC1 GZSKEXSLDPEFPT-IINYFYTJSA-N 0.000 description 1
- 229950003039 renzapride Drugs 0.000 description 1
- 229960000425 rizatriptan Drugs 0.000 description 1
- TXHZXHICDBAVJW-UHFFFAOYSA-N rizatriptan Chemical compound C=1[C]2C(CCN(C)C)=CN=C2C=CC=1CN1C=NC=N1 TXHZXHICDBAVJW-UHFFFAOYSA-N 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- 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 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 239000004003 serotonin 1D agonist Substances 0.000 description 1
- 239000003775 serotonin noradrenalin reuptake inhibitor Substances 0.000 description 1
- 239000000952 serotonin receptor agonist Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- LLDXOPKUNJTIRF-QFIPXVFZSA-N solabegron Chemical compound C([C@H](O)C=1C=C(Cl)C=CC=1)NCCNC(C=1)=CC=CC=1C1=CC=CC(C(O)=O)=C1 LLDXOPKUNJTIRF-QFIPXVFZSA-N 0.000 description 1
- 229950009659 solabegron Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940082787 spirulina Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- IKBKZGMPCYNSLU-RGVLZGJSSA-N tegaserod Chemical compound C1=C(OC)C=C2C(/C=N/NC(=N)NCCCCC)=CNC2=C1 IKBKZGMPCYNSLU-RGVLZGJSSA-N 0.000 description 1
- 229960002876 tegaserod Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 210000001170 unmyelinated nerve fiber Anatomy 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- 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 1
- 235000012141 vanillin Nutrition 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229960004688 venlafaxine Drugs 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
- 210000004760 visceral afferent Anatomy 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229950010749 zamifenacin Drugs 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
- 229960003414 zomepirac Drugs 0.000 description 1
- ZXVNMYWKKDOREA-UHFFFAOYSA-N zomepirac Chemical compound C1=C(CC(O)=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C ZXVNMYWKKDOREA-UHFFFAOYSA-N 0.000 description 1
- 229940126158 β3 adrenergic receptor agonist Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
-
- 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
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- 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
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Nutrition Science (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
200808791 九、發明說明： 【發明所屬之技術領域】 本發明係關於一種藉由使用.有效量之充當CGRp拮抗劑 之化合物來預防及治療内臟痛及腸胃障礙（諸如功能性腸 障礙及發炎性腸疾病）之方法。 【先前技術】 内臟涵蓋腹腔之器官。與内臟相關之疼痛可分為消化性 内臟痛及非消化性内臟痛。通常遇到之腸胃障礙包括功能 性腸障礙及發炎性腸疾病。該等腸胃障礙包括多種當前僅 適度控制之病狀，包括胃食道逆流、消化不良、大腸急躁 症及功能性腹痛症候群、克羅恩氏症（Cr〇hn,s disease)、回 腸炎及潰瘍性結腸炎，以及所有規律性發生之内臟痛。 亦％為’’結腸激躁”、”結腸痙攣"或”黏液性結腸炎，，之大 腸急躁症（IBS)之特徵在於與排便紊亂相關之下腹不適或 疼痛。症狀之性質可隨患者而變化，由顯著便秘或腹瀉變 1匕主頌著疼痛。 最為常見之慢性腸胃障礙侵襲著約2〇%之全世界人口。 该生物-心理-社會性病症涉及神經系統之調節異常、腸道 運動之改變及内臟敏感性之增加。 所有该等病症均由受多種社會心理及環境因素調控之腸 及八腸神經系統與腦（腦_腸軸）之間的雙向通信之調節異常 (例如’感染、發炎）所引起。腦及腸中可見大量調節〇1活 ^生之神經傳遞素，包括羥基色胺（5_ΗΤ，血清素）及其 5-ΗΤ3及5-ΗΤ4受體。針對患者之當前方法係基於症狀 121019.doc 200808791 綜合體之陽性診斷、潛在器 .。疾病之排除及治療試驗之执 立。傳統症狀治療包括止涫 縻飞汾之叹 /爲条、輕為藥及膨化劑/纖維、 低片彳里二ί衣抗憂鬱華、用 ,α ；疼痛之鎮痙劑及，替代，療法（例 如，知神療法、催眠療法）。 支持該療法之科學證摅古服 ^ ^ 、。新穎方法包括内臟止痛劑 以及血清素促效劑及拮抗劑。在具有嚴重腹填之患者中， 經指示用5-HT3受體拮抗劑(例如，阿洛司璦―_ 選擇性M3型抗膽鹼能藥；在便秘患者中，經指示用％町4 促效劑（例如，替加色羅（tegaserGd));且在疼痛患者中， I扣不用（X2·腎上腺素（例如，可樂定（ci〇nidineu、膽囊收 縮素払抗劑、K-類鴉片促效劑（例如，非多托秦 (fedotozine))及神經激肽拮抗劑；一些該等藥劑仍在研究 之中。應瞭解，腦-腸軸在開發用於IBS之有效療法中至關 緊要（Med· Science Monit· 2004，10(6)，RA125-131)。 已提出内臟高敏感性為IBS三個潛在機制中之一個且此 由如下事實所支持：患IBS之患者對内臟事件的感知力增 強。此内臟高敏感性似乎為極有可能為肽能c-纖維之内臟 傳入機構敏化之結果。彼等傳入C -纖維含有降妈素基因相 關肽（CGRP)且已展示該肽為傷害性前遞質 (pronociceptive) ° 【發明内容】 現在已發現，可藉由能拮抗CGRP效應之物質（CGRP拮 抗劑）或能抑制或減少CGRP自感覺神經末梢釋放之物質 (CGRP釋放抑制劑）而有效預防IBS之症狀且大體上減輕其 121019.doc 200808791 痛苦效應。 因此，本發明係關於CGRP拮抗劑（A)及/或釋放抑制劑 用於對抗IBS(包括預防與積極治療）之用途。本發明之用 途較佳不僅包含用單一物質之單一療法，而且包括用多種 來自指定活性物質群之物質（B)的組合療法。 本發明亦係關於CGRP拮抗劑及/或釋放抑制劑用於製備 供治療IBS用之醫藥組合物之用途以及含有作為活性物質 之一或多種CGRP拮抗劑及/或釋放抑制劑之相應醫藥組合 物。 出於本發明之目的，可使用任何能拮抗CGRP之已知效 應或抑制CGRP自感覺神經末梢釋放之醫藥學上可接受之 活性物質。 【實施方式】 CGRP拮抗劑之實例包括國際專利申請案 PCT7EP97/04802中所述之胺基酸衍生物以及如下國際專利 申請案中所述之非肽類活性物質：PCT7EP03/1 1762、 PCT/EP03/11763、PCT/EP2004/000087、PCT/EP2005/003094、 PCT/US03/16576、PCT/US2004/040721、PCT/US2003/038799、 PCT/US2005/010330、PCT/GB99/03154、PCT/US2004/007226、 PCT/US2004/007289、PCT/US2004/007686、PCT/US2004/007678、 PCT/US2004/007715、PCT/US2004/011254、PCT/US2004/010851、 PCT/US2004/011280、PCT/US2004/020206、PCT/US2004/021888、 PCT/US2004/020209、PCT/US2005/002199、PCT/US2005/031713、 PCT/US2005/031617、PCT/US2005/031712、PCT/US2005/032036、 121019.doc 200808791 PCT/US2005/032041 > PCT/US2005/032288 > PCT/US2005/035654 及US 2006/0094707。 CGRP釋放抑制劑之實例包括諸如阿韋曲坦 (avitriptan)、依來曲普坦（eletriptan)、那拉曲坦 (naratriptan)、利紮曲普坦（rizatriptan)、舒馬普坦 (sumatriptan)或佐米曲普坦（zolmitriptan)之血清素 5-HT1D-促效劑以及5 -HT1 f-促效劑或NP Y-促效劑。
在上述CGRP拮抗劑中，下列化合物（A)(例如）可用於治 療IBS，用於製備相應醫藥組合物且用作相應醫藥組合物 之成分。 因此，本發明之第一目標為選自由以下各物組成之群之 CGRP拮抗劑（A): 編號 結構
(3)
121019.doc 200808791 結構 編號
121019.doc -10- 200808791 (10) (11) (12) (13) (14) (15) (16) 121019.doc
-11 - 200808791 編號 結構 (17) (18)
(19)
〇\^v^CH3 (20)
(21) (22)
(23)
121019.doc •12- 200808791 編號
結構
(28)
其對映異構體、非對映異構體、混合物及鹽， 有機或無機酸或鹼形成之醫藥學上可接受之鹽， 藥調配物之一之形式用於製備供治療IBS用之 途： 含有1 mg活性物質（A)之粉末吸入劑之膠囊； 尤其為與 以下列醫 醫藥的用 121019.doc -13 - 200808791 含有1 mg活性物質（A)之喷霧劑之可吸入溶液； 含有1 mg活性物質（A)之氣體推進劑操作之計量氣霧劑； 含有1 mg活性物質（A)之鼻用喷霧； 含有20 mg活性物質（A)之錠劑； 含有20 mg活性物質（A)之膠囊； 含有10 mg活性物質（A)之鼻用水溶液； 含有5 mg活性物質（A)之鼻用水溶液； 含有20 mg活性物質（A)之鼻用懸浮液。 本發明之特定提及之化合物（A)描述於國際專利申請案 PCT/EP97/04862及 PCT/EP2005/003094 中且可根據該等申 請案中所述之方法製備。 该專化合物係經口應用且在〇·〇1 mg/kg至1〇〇 mg/kg劑量 範圍内具有活性。 所使用之術語及定義 本發明之標的亦包括一或多個氫原子（例如1、2、3、4 或5個氫原子）經氛置換之本發明之化合物（包括其鹽）。 本發明之化合物可具有酸基（主要為羧基）及/或諸如胺基 官能基之鹼基。因此，本發明之化合物可以内鹽形式、與 醫藥學上可用之無機酸或有機酸形成之鹽形式存在，其中 該等無機酸係諸如氫溴酸、磷酸、硝酸、鹽酸、硫酸、甲 烷磺酸、乙烷磺酸、苯磺酸、對甲苯磺酸，該等有機酸係 諸如蘋果酸、丁二酸、乙酸、反丁烯二酸、順丁烯二酸、 扁桃酸、乳酸、酒石酸、檸檬酸；或以與醫藥學上可用之 驗形成之鹽形式存在，其中該等驗係諸如鹼金屬氫氧化物 121019.doc -14- 200808791 或鹼土金屬之氫氧化物（例如，氫氧化鈉或氫氧化鉀）或碳 酸鹽、氨、氫氧化鋅或氫氧化銨或尤其諸如二乙胺、三乙 胺、乙醇胺、二乙醇胺、三乙醇胺、環己胺、二環己胺之 有機胺類。 如上文所提及，本發明之化合物可轉化為其鹽，尤其就 醫藥用途而言可轉化為其生理學上及藥理學上可接受之 鹽。一方面，該等鹽可呈式丨化合物與無機酸或有機酸形 成之生理學上及藥理學上可接受之酸加成鹽形式。另一方 面，右其含有酚系0H基團，則本發明之化合物亦可藉由 與無機驗反應而轉化為與作&抗衡離子之驗金屬或驗土金 屬陽離子形成之生理學上及藥理學上可接受之i該等酸 加成鹽可（例如）使用以下各酸製備：鹽酸、氫溴酸、硫 甲烷磺酸、乙酸、反丁烯二酸、丁二酸、乳 、酒石酸或順丁烯二酸。亦有可能使用上述酸 酸、填酸、 酸、檸檬酸 之混合*。式I化合物之驗金屬鹽及驗土金屬帛較 :金屬及驗土金屬之氫氧化物及氫化物，丨中較佳為驗1 金屬之氫氧化物及氫化物，尤其為鈉及鉀之氫氧化物及氫 化物’且尤其較佳為氫氧化鈉及氫氧化鉀。 消 即 消 若本發明之化合物僅具有_個對掌性元素，則其可以 旋體之形式存在，但其亦可以純對映異構體之形式， 罐)型或⑻型之形式獲得。較佳化合物為彼等以 旋體或（R)型之形式存在之化合物 素 然而，若本發明之化合物中存在 ’本申請案亦包括其中所存在的對 一個以上之對掌性元 映體之個別非對映異 121019.doc 200808791 構體對或其混合物，以及構成上述外消旋體之個別光學活 性對映異構體。
本备明係關於所討論之化合物，其視情況呈個別光學異 2體'_對映異構體之混合物或外消旋體之形式，呈互 又異構體之形式以及呈游離鹼或與藥理學上可接受之酸形 成之相應酸加成鹽的形式，其中該等酸加成鹽係諸如與氫 鹵酸（例如，鹽酸或氫溴酸）或有機酸（諸如，草酸、反丁烯 一酸、二甘醇酸或甲烷磺酸）形成之酸加成鹽。 組合 如以上所提及，本發明之CGRP拮抗劑（A)可以單一療法 之形式使甩，但其亦可與其他活性化合物（B)組合使用以 治療IBS。 基於此目的，化合物（B)可選自由以下各物組成之群： 5·ΗΤΜ效劑、5-HT3拮抗劑、5_HT4促效劑、混合5_吨拮 抗劑/5-HT4促效劑、血清素去甲腎上腺素再攝取抑制劑、 鎮痙劑、抗膽鹼能藥、輕瀉藥、鎮定劑（ballast)、止瀉 藥、二裱抗憂鬱藥及SSRI、類鴉片、局部麻醉劑、u促效 劑、大麻素、P2X3/P2X2/3拮抗劑、CCK-拮抗劑、 VR-1/TRPV1拮抗劑、神經激肽拮抗劑、p3_腎上腺素受體 促效劑、NSAID、COX 2抑制劑及益生菌，其可與一或多 種惰性習知載劑及/或稀釋劑一起調配成習知蓋倫製^ (galenic preparation)，其中該等载劑及/或稀釋劑係例如1 米澱粉、乳糖、葡萄糖、微晶纖維素、硬脂酸鎂、聚乙烯 吡咯啶酮、檸檬酸、酒石酸、水、水/乙醇、水/甘油、水/ 121019.doc -16- 200808791 山梨糖醇、水/聚乙二醇、丙二醇、十六基十八醇、羚甲 基纖維素或諸如硬脂之脂肪物質或其合適混合物，該^ 倫製劑係諸如普通錠劑或包衣錠劑、膠囊、散劑、懸； 液、溶液、計量氣霧劑或栓劑。 争 %ΗΤι促效劑可選自由阿韋曲坦、依 h 心札 日坦、那拉曲 利糸曲普坦、舒馬普坦或佐米曲普坦或其醫藥學上可 接受之鹽組成之群。 子
5-HT3拮抗劑可選自由阿洛司瓊、西蘭司瓊 (cdansetron)、格拉司瓊（granisetr〇n)或其醫藥卜 之鹽組成之群。 ’、上可接受 5-ΗΤ4促效劑可選自由替加色羅、並 曰卡比利 (pmCal〇pride)或其醫藥學上可接受之鹽組成之群。 此合5-HT3拮抗劑/5-HT4促效劑可選自由倫紮必利 (renzapride)、西沙必利（cisapride)或其醫藥學， /、卞工卩j接堂之 鹽組成之群。 血清素去甲腎上腺素再攝取抑制劑可選自由文拉法辛 (venlafaxine)、度洛西汀（duloxetine)及米那並人 (milnacipran)或其醫藥學上可接受之鹽組成之群。 鎮痙劑可選自由匹維溴銨（pinave:rium)、美貝維林 (mebeverine)、阿爾維林（alverine)或其醫藥學上可接a之 鹽組成之群。 抗膽驗能藥可選自由紮非那新（zamifenacin)、達非那新 (danfenacin)或其醫藥學上可接受之鹽組成之群。 輕瀉藥可選自由乳膠糖及聚乙二醇組成之群。 121019.doc -17- 200808791 •ά ^可4自由甲基纖維素及車前轩㈣Ui_)組成之 群。 止瀉藥可選自由洛哌丁胺（l〇peramide)、消膽胺 (㈤二yramine)或其醫藥學上可接受之鹽組成之群。° 衣抗抑鬱藥及SSRI可選自由阿米替林 (armtnptylme)、丙口米嗓（㈣贿㈣或其|藥學上可接受 之鹽組成之群。 類鴉片可選自由非多托秦、曲美布汀（tHmeb加h幻或其 醫藥學上可接受之鹽組成之群。 〃 局部麻醉劑可選自由曲美布、;丁或其醫藥學上可接受之鹽 組成之群。 α2促效劑可選自由可樂定或其醫藥學上可接受之鹽組成 之群。 大麻素可選自由瑞莫那班（rem〇nabant)或其醫藥學上可 接受之鹽組成之群。 神經激肽#抗劑可選自由艾羅皮坦（ez：l〇pitant)、那帕都 蘭（nepadulant)或其醫藥學上可接受之鹽組成之群。 β3-腎上腺素受體促效劑可選自由索拉比格隆 (solabegron)或ΥΜ178或其醫藥學上可接受之鹽組成之群。 NSAID可選自由以下各物組成之群：阿羅芬那 (acclofenac)、阿西美辛（acenietacin)、阿司匹林 (acetylsalicylic acid)、硫唑嘌呤（azathioprin)、塞來昔布 (celecoixb)、雙氯芬酸（diclofenac)、二敗尼柳 (diflunisal)、芬布芬（fenbufen)、非諾洛芬（fenopr〇fen)、 121019.doc -18- 200808791 氟比洛芬（flurbiprofen)、布洛芬（ibuprofen)、吲哚美辛 (indometacin)、酮基布洛芬（ket〇pr〇fen)、來氟米特 (leflunomid) 氣諾昔康（lornoxicam)、甲芬那酸 (mefenamic acid)、美儂西康（mei〇xicam)、萘普生 (naProxen)、保泰松（phenylbutazon) 、σ比羅昔康 (piroxicam)、柳氮績胺。比 σ定（suifasaiazin)、佐美酸 (zomepirac)或其醫藥學上可接受之鹽。
COX 2抑制劑可選自由美儂西康、羅非昔布 (rofecoxib) 伐地昔布（valdecoxib)、帕瑞昔布 (parecoxib)、依託昔布（et〇ric〇xib)、塞來昔布或其醫藥學 上可接受之鹽組成之群。 盈生&可為雙歧桿菌屬（bifidobacterium)。 調配物 根據本發明所製備之化合物可經靜脈内、皮下、肌肉 内、關節内、直腸内或鼻内路徑，藉由吸入、局部、經皮 或經口獨立投與或視情況與其他活性物質組合投與以用於 治療偏頭痛，而氣霧劑調配物尤其適合於吸入。該等組合 可同時或相繼投與。 投與之合適形式包括（例如）錠劑、膠囊、溶液 礼液或可吸人散劑或氣霧劑。—或多種醫藥活性化合物之 比例應在總組合物之O.i重量％至9〇重量％、較佳U重量％ 至50重量％之範圍内，亦即，為足以 範圍之量。 $成下文k及之劑量 該等製劑可以鍵劑 散劑、於膠囊中之散劑（例如 硬 121019.doc -19- 200808791 之形式經口給予。當 散劑、水溶液或水性 調配物投與。 明膠膠囊）之形式或以溶液或懸浮液 藉由吸入服用時，活性物質組合可以 乙醇溶液之形式或借助於氣體推進劑 上 因此’醫藥調配物之特徵較佳在於其含有—或多種根據 述較佳實施例之式I化合物。 若式I之化合物係經口投與，則為尤其較佳，且若其— 天投與-或兩次’則為最佳。合適錠劑可(例如)藉由將活
性物質與已知賦形劑混合來獲得，其中該等賦形劑例如為 諸如碳_、輕料乳糖之惰性稀_ ;諸如n殿粉 或褐藻酸之崩解劑；諸如澱粉或明膠之黏合劑；諸如硬脂 酸鎂或滑石之潤滑劑；及/或諸如竣甲基纖維素、酜心 酸纖維素或聚乙酸乙❹旨之心延遲釋放之試劑。鍵劑亦 可包含數層。 相應地，包衣錠劑可藉由用常用於錠劑包衣之物質（例 如可力酮（collidone)或蟲膠、阿拉伯膠（gum訂此⑷、滑 石、二氧化鈦或糖）包覆類似於錠劑所產生之核心來製 備。為達成延遲釋放或防止不相容性，該核心亦可由若干 層組成。類似地，錠劑包衣可由若干層組成，以便可能使 用以上提及用於錠劑之賦形劑來達成延遲釋放。 3有本明之活性物質或其組合之糖漿可另外含有諸如 糖精、賽克拉美（cyclamate)、甘油或糖之甜味劍及例如芳 香背i (諸如香蘭素或柑橘提取物）之香味增強劑。其亦可含 有諸如羧甲基纖維素鈉之懸浮佐劑或增稠劑、諸如脂肪醇 與％氧乙烷之縮合產物之潤濕劑或諸如對羥基苯甲酸鹽之 121019.doc -20- 200808791 防腐劑。 含有—或多種活性物質或活性物質之組合的膠囊可(例 將该等活性物質與諸如乳糖或山梨糖醇之惰性載 劑混合且將其填充至明膠膠囊中來製備。 =適栓劑可（例如）藉由與為此目的提供之諸如中性脂肪 攻隶乙二醇或其衍生物之載劑混合來製備。 一可使用之賦形劑包括（例如）水；醫藥學上可接受之有 溶劑二諸如石蠟(石油餾分)、植物油(例如花生油或芝麻 油）、早官能醇或多官能醇（例如乙醇或甘油）；冑劑，諸如 天然礦物粉末（例如高嶺土、黏土、滑石、白堊）、合成礦 物粉末（例如高度分散之㈣及㈣鹽）；糖（例如斧糖、乳 糖及葡萄糖)；乳化劑(例如木質素、亞硫酸廢液、甲基纖 、准素、澱粉及聚乙烯吡咯啶酮）；及潤滑劑(例如硬脂酸 鎮、滑石、硬脂酸及月桂基硫酸鈉）。 就口服使用而言’除所說明之載劑外，錠劑可顯然含有 冑如檸檬酸鈉、碳_及魏二狀添加劑以及各種諸如 歲粉（較佳為馬鈴薯澱粉）、明膠及其類似物之其他物質。 諸如硬脂酸鎮、月桂基硫酸鈉及滑石之潤滑劑亦可用於製 仏叙劑。在水性懸浮液之情況下，除上述賦形劑以外，活 生物貝可與各種香味增強劑或著色劑組合。 治療方法 本發明之CGRP拮抗劑（A)在齧齒動物之内臟痛模型中具 有/舌丨生在5亥模型中，由結腸激躁（例如，藉由丁酸鹽、 三硝基苯磺酸或乙酸滴注）誘導高敏感性。將結腸直腸氣 121019.doc 200808791 囊擴張用於誘導例如腹部收縮之疼痛行為（見Bourdu等 人，Gastroenterology 2005，128，1996-2008 ; Diop等人，J· Phamacol. Exp. Ther. 2002，302，1013-1022 ； Plourde 等 人，Am. J. Physiol. 1997, 273, G191-G196)。 因為該等化合物在以上所提及之模型中使結腸高敏感性 逆轉，所以主張本發明之CGRP拮抗劑（A)可用於治療内臟 痛/高敏感性，尤其具有IBS之患者之腹痛，以及絞痛及痛 121019.doc -22-
Claims (1)
- 200808791 十、申請專利範圍： 1. 一種選自以下 編號 (1) (2) (3) (4) / ： v (5) I (6) 各物之CGRP拮抗劑（A) 結構121019.doc 200808791121019.doc -2- 200808791 編"5^ (13) 結構 (14)(15)(16) (17) (18) (19)121019.doc 200808791 編號 (20) (21) 結構(22) Br(23)(24)(25) (26)121019.doc 200808791 編號 結構(27) (28) 其對映異構體、非對映異構體、混合物及其生理學上 可接受之鹽之用途，其用於製備適用於預防或治療内臟 痛之藥劑。 2. —種選自以下各物之CGRP拮抗劑（A) ·· 編號 結構 (1)121019.doc 200808791 編號 結構121019.doc 200808791 編號 結構1210I9.doc 200808791 編號 (16) (17) ， (18) (19) (20) . (21) (22) 結構121019.doc 200808791 編號 (23) (24)(25) 結構其對映異構體、非對映異構體、混合物及其生理學上 可接受之鹽之用途，其用於製備適用於預防或治療腸胃 障礙之藥劑。 121019.doc 200808791 3·如請求項丨或2之用途，其特徵在於該内臟痛係選自由功 能性腸障礙及發炎性腸疾病組成之群。 4·如請求項3之用途，其特徵在於該功能性腸障礙係選自 由月食道逆流、消化不良、大腸急躁症及功能性腹痛症 候群組成之群。 5·如请求項3之用途，其特徵在於該發炎性腸疾病係選自 由克羅恩氏症（Cr〇hn，s disease)、回腸炎及潰瘍性結腸炎 組成之群。 6·如明求項3之用途，其特徵在於該功能性腸障礙為該大 腸急躁症。 7·如明求項丨或2之用途，其特徵在於其係以用單一活性物 質之單一療法形式實現。 月求項7之用途，其特徵在於該藥劑僅含有一種活 物質。 月长項7之用途，其特徵在於該藥劑為用於經口投與 之调配物。 1〇.=用於治療或預防内臟痛及腸胃障礙之醫藥組合物， 其3有作為活性物質之一或多種選自如請求項1之群之 :拮抗劑⑷，視情況連同一或多種惰性載劑及/或稀 释劑。 、、項1 〇之商藥組合物，其用於治療或預防選自由以 '且成之群之病症··功能性腸障礙，諸如胃食道逆 、消4匕不_ $,日 大腸急躁症及功能性腹痛症候群；或發 腸疾病，諸如克羅恩氏症、回腸炎及潰瘍性結腸 121D19.doc •10- 200808791 炎。 12·如請求項11之醫藥組合物，其用於治療或預防該大腸急 躁症。 13.如請求項10至12中任一項之醫藥組合物，其呈適合用於 經口投與之形式。121019.doc 200808791 七、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： 八、本案若有化學式時，請揭示最能顯示發明特徵的化學式: (無） 121019.doc
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP06011787 | 2006-06-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TW200808791A true TW200808791A (en) | 2008-02-16 |
Family
ID=37101671
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW096120440A TW200808791A (en) | 2006-06-08 | 2007-06-07 | CGRP antagonists |
| TW096120441A TW200815010A (en) | 2006-06-08 | 2007-06-07 | CGRP antagonists |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW096120441A TW200815010A (en) | 2006-06-08 | 2007-06-07 | CGRP antagonists |
Country Status (19)
| Country | Link |
|---|---|
| US (2) | US7807666B2 (zh) |
| EP (2) | EP2029234A1 (zh) |
| JP (2) | JP2009539800A (zh) |
| KR (1) | KR20090021214A (zh) |
| CN (1) | CN101500653A (zh) |
| AR (2) | AR061272A1 (zh) |
| AU (1) | AU2007255395A1 (zh) |
| BR (1) | BRPI0712492A2 (zh) |
| CA (2) | CA2654048A1 (zh) |
| CL (2) | CL2007001663A1 (zh) |
| EA (1) | EA200802381A1 (zh) |
| EC (1) | ECSP089025A (zh) |
| IL (1) | IL195712A0 (zh) |
| MX (1) | MX2008015562A (zh) |
| NO (1) | NO20085051L (zh) |
| PE (2) | PE20080153A1 (zh) |
| TW (2) | TW200808791A (zh) |
| UY (2) | UY30399A1 (zh) |
| WO (2) | WO2007141285A1 (zh) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2008015562A (es) * | 2006-06-08 | 2008-12-17 | Boehringer Ingelheim Int | Tratamiento de trastornos gastrointestinales con antagonistas de cgrp. |
| WO2010070023A2 (en) * | 2008-12-19 | 2010-06-24 | Boehringer Ingelheim International Gmbh | Formulations |
| FR2963738B1 (fr) * | 2010-08-10 | 2012-09-28 | Assist Publ Hopitaux De Paris | Compose destine au traitement des douleurs abdominales fonctionnelles |
| BR112013029951B1 (pt) | 2011-05-20 | 2020-10-20 | Alderbio Holdings Llc | composição farmacêutica e uso de anticorpos ou fragmentos de anticorpos anti-cgrp para tratar ou prevenir formas de diarreia crônicas e agudas |
| AU2012258980B8 (en) | 2011-05-20 | 2017-06-15 | H. Lundbeck A/S | Use of anti-CGRP antibodies and antibody fragments to prevent or inhibit photophobia or light aversion in subjects in need thereof, especially migraine sufferers |
| TR201904088T4 (tr) | 2011-05-20 | 2019-05-21 | Alderbio Holdings Llc | Anti-CGRP bileşimleri ve bunların kullanımları. |
| US20170114122A1 (en) | 2015-10-23 | 2017-04-27 | Alderbio Holdings Llc | Regulation of glucose metabolism using anti-cgrp antibodies |
| TWI636041B (zh) * | 2015-08-12 | 2018-09-21 | 美國禮來大藥廠 | Ｃｇｒｐ受體拮抗劑 |
| GB201519195D0 (en) | 2015-10-30 | 2015-12-16 | Heptares Therapeutics Ltd | CGRP Receptor Antagonists |
| GB201519194D0 (en) | 2015-10-30 | 2015-12-16 | Heptares Therapeutics Ltd | CGRP receptor antagonists |
| GB201519196D0 (en) | 2015-10-30 | 2015-12-16 | Heptares Therapeutics Ltd | CGRP Receptor Antagonists |
| EP3366286A1 (en) | 2017-02-22 | 2018-08-29 | Johannes Keller | Compounds for treating sepsis |
| MA54704A (fr) | 2019-01-08 | 2022-04-13 | H Lundbeck As | Traitement aigu et traitement rapide de maux de tête à l'aide d'anticorps anti-cgrp |
| SG10202003296VA (en) | 2020-04-06 | 2021-11-29 | H Lundbeck As | Treatment of most bothersome symptom (mbs) associated with migraine using anti-cgrp antibodies |
Family Cites Families (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5291960A (en) * | 1992-11-30 | 1994-03-08 | Ford Motor Company | Hybrid electric vehicle regenerative braking energy recovery system |
| DE10250080A1 (de) | 2002-10-25 | 2004-05-13 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
| DE10250082A1 (de) | 2002-10-25 | 2004-05-13 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
| US7595312B2 (en) | 2002-10-25 | 2009-09-29 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Selected CGRP antagonists, processes for preparing them and their use as pharmaceutical compositions |
| US20080070239A1 (en) * | 2003-10-29 | 2008-03-20 | University Of Rochester | Detection of neureopeptides associated with pelvic pain disorders and uses thereof |
| DE102004015723A1 (de) * | 2004-03-29 | 2005-10-20 | Boehringer Ingelheim Pharma | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
| DE102004019492A1 (de) * | 2004-04-22 | 2005-11-10 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
| DE102004063755A1 (de) * | 2004-12-29 | 2006-07-20 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung von CGRP-Antagonisten zur Behandlung und Vorbeugung von Hitzewallungen bei Patienten mit Prostatakrebs |
| DE102004063753A1 (de) * | 2004-12-29 | 2006-07-13 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung ausgewählter CGRP-Antagonisten in Kombination mit anderen Arzneistoffen gegen Migräne für die Behandlung von Migräne |
| DE102004063752A1 (de) * | 2004-12-29 | 2006-07-13 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung ausgewählter CGRP-Antagonisten zur Bekämpfung menopausaler Hitzewallungen |
| CN101146799A (zh) | 2005-03-23 | 2008-03-19 | 贝林格尔·英格海姆国际有限公司 | Cgrp拮抗剂、其制备方法以及其作为药物的用途 |
| EP1770091A1 (de) | 2005-09-29 | 2007-04-04 | Boehringer Ingelheim Pharma GmbH & Co. KG | CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
| US7491717B2 (en) | 2005-03-23 | 2009-02-17 | Boehringer Ingelheim International Gmbh | Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions |
| DE102005038831A1 (de) | 2005-08-17 | 2007-02-22 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
| EP1770087A1 (de) * | 2005-09-29 | 2007-04-04 | Boehringer Ingelheim Pharma GmbH & Co. KG | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
| EP1770086A1 (de) | 2005-09-29 | 2007-04-04 | Boehringer Ingelheim Pharma GmbH & Co. KG | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
| DE102006017827A1 (de) * | 2006-04-13 | 2007-10-18 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue kristalline Verbindungen |
| MX2008015562A (es) * | 2006-06-08 | 2008-12-17 | Boehringer Ingelheim Int | Tratamiento de trastornos gastrointestinales con antagonistas de cgrp. |
-
2007
- 2007-06-06 MX MX2008015562A patent/MX2008015562A/es not_active Application Discontinuation
- 2007-06-06 BR BRPI0712492-9A patent/BRPI0712492A2/pt not_active IP Right Cessation
- 2007-06-06 WO PCT/EP2007/055543 patent/WO2007141285A1/en not_active Ceased
- 2007-06-06 CA CA002654048A patent/CA2654048A1/en not_active Abandoned
- 2007-06-06 EA EA200802381A patent/EA200802381A1/ru unknown
- 2007-06-06 EP EP07729918A patent/EP2029234A1/en not_active Withdrawn
- 2007-06-06 WO PCT/EP2007/055542 patent/WO2007141284A2/en not_active Ceased
- 2007-06-06 AU AU2007255395A patent/AU2007255395A1/en not_active Abandoned
- 2007-06-06 EP EP07729917A patent/EP2029233A2/en not_active Withdrawn
- 2007-06-06 CN CNA2007800289541A patent/CN101500653A/zh active Pending
- 2007-06-06 CA CA002654047A patent/CA2654047A1/en not_active Abandoned
- 2007-06-06 PE PE2007000698A patent/PE20080153A1/es not_active Application Discontinuation
- 2007-06-06 KR KR1020097000327A patent/KR20090021214A/ko not_active Withdrawn
- 2007-06-06 PE PE2007000697A patent/PE20080370A1/es not_active Application Discontinuation
- 2007-06-06 JP JP2009513686A patent/JP2009539800A/ja active Pending
- 2007-06-06 JP JP2009513685A patent/JP2009539799A/ja active Pending
- 2007-06-07 UY UY30399A patent/UY30399A1/es not_active Application Discontinuation
- 2007-06-07 UY UY30398A patent/UY30398A1/es not_active Application Discontinuation
- 2007-06-07 TW TW096120440A patent/TW200808791A/zh unknown
- 2007-06-07 CL CL2007001663A patent/CL2007001663A1/es unknown
- 2007-06-07 TW TW096120441A patent/TW200815010A/zh unknown
- 2007-06-07 CL CL2007001662A patent/CL2007001662A1/es unknown
- 2007-06-08 US US11/760,057 patent/US7807666B2/en active Active
- 2007-06-08 AR ARP070102481A patent/AR061272A1/es unknown
- 2007-06-08 AR ARP070102480A patent/AR061271A1/es not_active Application Discontinuation
- 2007-06-08 US US11/760,054 patent/US20080139591A1/en not_active Abandoned
-
2008
- 2008-12-04 NO NO20085051A patent/NO20085051L/no not_active Application Discontinuation
- 2008-12-04 IL IL195712A patent/IL195712A0/en unknown
- 2008-12-31 EC EC2008009025A patent/ECSP089025A/es unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JP2009539800A (ja) | 2009-11-19 |
| AR061272A1 (es) | 2008-08-13 |
| ECSP089025A (es) | 2009-01-30 |
| UY30399A1 (es) | 2008-01-31 |
| UY30398A1 (es) | 2008-01-31 |
| WO2007141284A3 (en) | 2008-03-06 |
| US7807666B2 (en) | 2010-10-05 |
| PE20080370A1 (es) | 2008-06-13 |
| WO2007141285A1 (en) | 2007-12-13 |
| CN101500653A (zh) | 2009-08-05 |
| KR20090021214A (ko) | 2009-02-27 |
| NO20085051L (no) | 2008-12-19 |
| US20080139591A1 (en) | 2008-06-12 |
| CL2007001663A1 (es) | 2008-01-25 |
| WO2007141284A2 (en) | 2007-12-13 |
| CA2654048A1 (en) | 2007-12-13 |
| IL195712A0 (en) | 2009-09-01 |
| PE20080153A1 (es) | 2008-04-14 |
| CL2007001662A1 (es) | 2008-01-25 |
| CA2654047A1 (en) | 2007-12-13 |
| EA200802381A1 (ru) | 2009-06-30 |
| AR061271A1 (es) | 2008-08-13 |
| AU2007255395A1 (en) | 2007-12-13 |
| TW200815010A (en) | 2008-04-01 |
| MX2008015562A (es) | 2008-12-17 |
| BRPI0712492A2 (pt) | 2012-08-21 |
| EP2029234A1 (en) | 2009-03-04 |
| JP2009539799A (ja) | 2009-11-19 |
| US20080139537A1 (en) | 2008-06-12 |
| EP2029233A2 (en) | 2009-03-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TW200808791A (en) | CGRP antagonists | |
| ES2144980T3 (es) | Composiciones para tratar la rinitis alergica y otros trastornos descarboetoxiloratadina. | |
| US20030133951A1 (en) | Pharmaceutical composition for treatment of acute, chronic pain and/or neuropathic pain and migraines | |
| JP2002516864A (ja) | 両極性疾患の処置のための組合せ治療 | |
| JP2011157372A (ja) | 機能性腸障害を処置する方法 | |
| UA61081C2 (uk) | Активний компонент для придушення тимчасових релаксацій нижнього сфінктера, спосіб такого придушення та спосіб скринінгу сполук | |
| JP5208473B2 (ja) | アゼラスチンと抗コリン薬を含有する医薬組成物 | |
| AU748993B2 (en) | Pharmaceutical combinations containing tramadol | |
| BR112019022902A2 (pt) | composição, composição farmacêutica, uso da composição terapeuticamente eficaz, método e uso de uma composição terapeuticamente eficaz em um método de tratamento | |
| JP2005530779A (ja) | ベンラファキシンとその誘導体を用いた胃腸または尿生殖器痛障害の治療方法 | |
| JP2013536859A (ja) | ５−ｈｔ２ｃアゴニストの非吸湿性塩 | |
| US20230181572A1 (en) | Carbamoyl cyclohexane derivatives for treating autism spectrum disorder | |
| JPH05509293A (ja) | 不整脈および発作の治療における５―ｈｔ４受容体拮抗剤の使用 | |
| JP4648193B2 (ja) | 医薬組成物 | |
| AU2020271363A1 (en) | Carbamoyl cyclohexane derivatives for treating autism spectrum disorder | |
| RU2605283C2 (ru) | Фармацевтическая композиция для лечения зависимости у людей | |
| HK1134053A (zh) | 使用cgrp拮抗剂对胃肠道病症的治疗 | |
| EA048505B1 (ru) | Производные карбамоилциклогексана для лечения расстройства аутистического спектра | |
| CN101171011B (zh) | 用于治疗食欲紊乱的含有1-(3-氯苯基)-3-烷基哌嗪的药物组合物 | |
| CN113905736A (zh) | 用于治疗孤独症谱系障碍的选择性组胺h3受体拮抗剂 | |
| TW200425914A (en) | Pharmaceutical tablet composition comprising n-[(1-nbutyl-4-piperidinyl)methyl]-3,4-dihydro-2h-[1,3]oxazino[3,2-a]indole-10-carboxamide (sb 207266) or a salt thereof |