CN1886366A - 环戊基衍生物 - Google Patents
环戊基衍生物 Download PDFInfo
- Publication number
- CN1886366A CN1886366A CNA2004800346593A CN200480034659A CN1886366A CN 1886366 A CN1886366 A CN 1886366A CN A2004800346593 A CNA2004800346593 A CN A2004800346593A CN 200480034659 A CN200480034659 A CN 200480034659A CN 1886366 A CN1886366 A CN 1886366A
- Authority
- CN
- China
- Prior art keywords
- compound
- benzylamino
- fluoro
- carboxylic acid
- oxygen base
- 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.)
- Granted
Links
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 title abstract description 10
- 108010052164 Sodium Channels Proteins 0.000 claims abstract description 22
- 102000018674 Sodium Channels Human genes 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 108090000312 Calcium Channels Proteins 0.000 claims abstract description 16
- 102000003922 Calcium Channels Human genes 0.000 claims abstract description 16
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 16
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 11
- 150000002367 halogens Chemical group 0.000 claims abstract description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 9
- 239000011734 sodium Substances 0.000 claims abstract description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000003118 aryl group Chemical group 0.000 claims abstract description 8
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- 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 claims abstract description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 6
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 6
- 230000002503 metabolic effect Effects 0.000 claims abstract description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000005864 Sulphur Chemical group 0.000 claims abstract description 4
- 208000012931 Urologic disease Diseases 0.000 claims abstract description 4
- 125000004419 alkynylene group Chemical group 0.000 claims abstract description 4
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 4
- 208000014001 urinary system disease Diseases 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 108
- -1 methoxyl group Chemical group 0.000 claims description 49
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentane carboxylic acid Natural products OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 230000000694 effects Effects 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 15
- 239000001301 oxygen Chemical group 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 230000033228 biological regulation Effects 0.000 claims description 7
- 208000020016 psychiatric disease Diseases 0.000 claims description 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 5
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical group [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 5
- 230000002496 gastric effect Effects 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 230000002829 reductive effect Effects 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 208000012902 Nervous system disease Diseases 0.000 claims description 3
- 208000025966 Neurological disease Diseases 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 208000027866 inflammatory disease Diseases 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 2
- 208000037273 Pathologic Processes Diseases 0.000 claims 1
- 230000009054 pathological process Effects 0.000 claims 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical group O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 abstract description 9
- 230000002757 inflammatory effect Effects 0.000 abstract description 7
- 230000007170 pathology Effects 0.000 abstract description 5
- 230000007246 mechanism Effects 0.000 abstract description 4
- 230000000926 neurological effect Effects 0.000 abstract description 3
- 230000002526 effect on cardiovascular system Effects 0.000 abstract description 2
- 230000001575 pathological effect Effects 0.000 abstract description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 abstract 1
- 208000018522 Gastrointestinal disease Diseases 0.000 abstract 1
- 125000004450 alkenylene group Chemical group 0.000 abstract 1
- 208000030159 metabolic disease Diseases 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 20
- 208000002193 Pain Diseases 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 14
- 230000036407 pain Effects 0.000 description 14
- 238000011282 treatment Methods 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000011575 calcium Substances 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 210000000287 oocyte Anatomy 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 8
- 101000684820 Homo sapiens Sodium channel protein type 3 subunit alpha Proteins 0.000 description 8
- 229910052791 calcium Inorganic materials 0.000 description 8
- 239000012530 fluid Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 206010010904 Convulsion Diseases 0.000 description 7
- 206010019233 Headaches Diseases 0.000 description 7
- 102100023720 Sodium channel protein type 3 subunit alpha Human genes 0.000 description 7
- 238000013016 damping Methods 0.000 description 7
- 230000001419 dependent effect Effects 0.000 description 7
- 230000004054 inflammatory process Effects 0.000 description 7
- 239000012528 membrane Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000006073 displacement reaction Methods 0.000 description 6
- 231100000869 headache Toxicity 0.000 description 6
- 208000004296 neuralgia Diseases 0.000 description 6
- 208000020925 Bipolar disease Diseases 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- 208000028017 Psychotic disease Diseases 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000001961 anticonvulsive agent Substances 0.000 description 5
- 235000010418 carrageenan Nutrition 0.000 description 5
- 229920001525 carrageenan Polymers 0.000 description 5
- 230000001684 chronic effect Effects 0.000 description 5
- 201000006549 dyspepsia Diseases 0.000 description 5
- 206010015037 epilepsy Diseases 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 208000021722 neuropathic pain Diseases 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 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 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 208000000094 Chronic Pain Diseases 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 206010026749 Mania Diseases 0.000 description 4
- 208000019695 Migraine disease Diseases 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 241000700157 Rattus norvegicus Species 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 241000269370 Xenopus <genus> Species 0.000 description 4
- HUCJFAOMUPXHDK-UHFFFAOYSA-N Xylometazoline Chemical compound CC1=CC(C(C)(C)C)=CC(C)=C1CC1=NCCN1 HUCJFAOMUPXHDK-UHFFFAOYSA-N 0.000 description 4
- 206010009887 colitis Diseases 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 206010027599 migraine Diseases 0.000 description 4
- 229960005425 nitrendipine Drugs 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 210000001519 tissue Anatomy 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 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 208000008035 Back Pain Diseases 0.000 description 3
- 206010012289 Dementia Diseases 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 102000004129 N-Type Calcium Channels Human genes 0.000 description 3
- 108090000699 N-Type Calcium Channels Proteins 0.000 description 3
- 101100522110 Oryza sativa subsp. japonica PHT1-10 gene Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 101100522109 Pinus taeda PT10 gene Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 206010052428 Wound Diseases 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 230000027455 binding Effects 0.000 description 3
- 230000000747 cardiac effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 208000002551 irritable bowel syndrome Diseases 0.000 description 3
- 239000003589 local anesthetic agent Substances 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- 201000008482 osteoarthritis Diseases 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- 239000003053 toxin Substances 0.000 description 3
- 231100000765 toxin Toxicity 0.000 description 3
- 108700012359 toxins Proteins 0.000 description 3
- JWYOAMOZLZXDER-UHFFFAOYSA-N (1RS,2RS)-2-Aminocyclopentanecarboxylic acid Natural products NC1CCCC1C(O)=O JWYOAMOZLZXDER-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 description 2
- 108091006146 Channels Proteins 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- 206010013935 Dysmenorrhoea Diseases 0.000 description 2
- 208000001640 Fibromyalgia Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 2
- 208000007882 Gastritis Diseases 0.000 description 2
- 206010061172 Gastrointestinal injury Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 208000010412 Glaucoma Diseases 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
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 206010065390 Inflammatory pain Diseases 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 208000008930 Low Back Pain Diseases 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 206010029333 Neurosis Diseases 0.000 description 2
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 2
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 206010036600 Premature labour Diseases 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 206010046543 Urinary incontinence Diseases 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 230000009692 acute damage Effects 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000003872 anastomosis Effects 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 239000003416 antiarrhythmic agent Substances 0.000 description 2
- 229960003965 antiepileptics Drugs 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 2
- 208000028683 bipolar I disease Diseases 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000000872 buffer Substances 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
- 239000002775 capsule Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- 230000002566 clonic effect Effects 0.000 description 2
- 230000001149 cognitive effect Effects 0.000 description 2
- 238000004590 computer program Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000005611 electricity Effects 0.000 description 2
- 230000007831 electrophysiology Effects 0.000 description 2
- 238000002001 electrophysiology Methods 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000003365 glass fiber Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 230000002779 inactivation Effects 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
- 238000001802 infusion Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 210000003141 lower extremity Anatomy 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 229960001252 methamphetamine Drugs 0.000 description 2
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 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
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 229960005016 naphazoline Drugs 0.000 description 2
- 208000015238 neurotic disease Diseases 0.000 description 2
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 2
- 229960001597 nifedipine Drugs 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 210000001672 ovary Anatomy 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
- 239000000825 pharmaceutical preparation Substances 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
- 239000002244 precipitate Substances 0.000 description 2
- JCRIVQIOJSSCQD-UHFFFAOYSA-N propylhexedrine Chemical compound CNC(C)CC1CCCCC1 JCRIVQIOJSSCQD-UHFFFAOYSA-N 0.000 description 2
- 229960000786 propylhexedrine Drugs 0.000 description 2
- 201000007094 prostatitis Diseases 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000003340 retarding agent Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000001148 spastic effect Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000006228 supernatant Substances 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
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000010936 titanium Substances 0.000 description 2
- REZQBEBOWJAQKS-UHFFFAOYSA-N triacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO REZQBEBOWJAQKS-UHFFFAOYSA-N 0.000 description 2
- ZISSAWUMDACLOM-UHFFFAOYSA-N triptane Chemical compound CC(C)C(C)(C)C ZISSAWUMDACLOM-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 229960000833 xylometazoline Drugs 0.000 description 2
- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 1
- NQBWNECTZUOWID-UHFFFAOYSA-N (E)-cinnamyl (E)-cinnamate Natural products C=1C=CC=CC=1C=CC(=O)OCC=CC1=CC=CC=C1 NQBWNECTZUOWID-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
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 229940124125 5 Lipoxygenase inhibitor Drugs 0.000 description 1
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000004998 Abdominal Pain Diseases 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010000599 Acromegaly Diseases 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 229920001817 Agar Polymers 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
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 208000032467 Aplastic anaemia Diseases 0.000 description 1
- 206010003628 Atonic seizures Diseases 0.000 description 1
- 208000004300 Atrophic Gastritis Diseases 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- 208000000412 Avitaminosis Diseases 0.000 description 1
- 206010004142 Bartholinitis Diseases 0.000 description 1
- 208000027496 Behcet disease Diseases 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 208000021465 Brief psychotic disease Diseases 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 229910000882 Ca alloy Inorganic materials 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 241000375384 Cannaboides Species 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
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 206010008334 Cervicobrachial syndrome Diseases 0.000 description 1
- 206010008479 Chest Pain Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 208000006561 Cluster Headache Diseases 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 241000237942 Conidae Species 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 241000237971 Conus magus Species 0.000 description 1
- 208000011990 Corticobasal Degeneration Diseases 0.000 description 1
- 229940093444 Cyclooxygenase 2 inhibitor Drugs 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-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 208000024254 Delusional disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 206010051153 Diabetic gastroparesis Diseases 0.000 description 1
- 201000010374 Down Syndrome Diseases 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 208000017701 Endocrine disease Diseases 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 208000037767 Gallbladder pain Diseases 0.000 description 1
- 208000036495 Gastritis atrophic Diseases 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 229940127337 Glycine Antagonists Drugs 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 229940122957 Histamine H2 receptor antagonist Drugs 0.000 description 1
- 101000935123 Homo sapiens Voltage-dependent N-type calcium channel subunit alpha-1B Proteins 0.000 description 1
- 206010065952 Hyperpathia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010020853 Hypertonic bladder Diseases 0.000 description 1
- 206010021030 Hypomania Diseases 0.000 description 1
- 206010021135 Hypovitaminosis Diseases 0.000 description 1
- 206010021518 Impaired gastric emptying Diseases 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 208000005615 Interstitial Cystitis Diseases 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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 1
- 102000004016 L-Type Calcium Channels Human genes 0.000 description 1
- 108090000420 L-Type Calcium Channels Proteins 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 208000007914 Labor Pain Diseases 0.000 description 1
- 208000035945 Labour pain Diseases 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 239000000867 Lipoxygenase Inhibitor Substances 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010065673 Nephritic syndrome Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 102100022397 Nitric oxide synthase, brain Human genes 0.000 description 1
- 101710111444 Nitric oxide synthase, brain Proteins 0.000 description 1
- 102100029438 Nitric oxide synthase, inducible Human genes 0.000 description 1
- 101710089543 Nitric oxide synthase, inducible Proteins 0.000 description 1
- 206010062501 Non-cardiac chest pain Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 206010034759 Petit mal epilepsy Diseases 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 208000036757 Postencephalitic parkinsonism Diseases 0.000 description 1
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- 208000006399 Premature Obstetric Labor Diseases 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 229920003110 Primojel Polymers 0.000 description 1
- 206010036774 Proctitis Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 206010036968 Prostatic pain Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 206010037779 Radiculopathy Diseases 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038910 Retinitis Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 206010049677 Salpingo-oophoritis Diseases 0.000 description 1
- 208000020186 Schizophreniform disease Diseases 0.000 description 1
- 208000008765 Sciatica Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 241000239226 Scorpiones Species 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 208000019568 Shared Paranoid disease Diseases 0.000 description 1
- 208000028810 Shared psychotic disease Diseases 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 229940089973 Sodium channel antagonist Drugs 0.000 description 1
- 102000013275 Somatomedins Human genes 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 208000020307 Spinal disease Diseases 0.000 description 1
- 208000020339 Spinal injury Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 206010042496 Sunburn Diseases 0.000 description 1
- 206010043269 Tension headache Diseases 0.000 description 1
- 208000008548 Tension-Type Headache Diseases 0.000 description 1
- 240000006474 Theobroma bicolor Species 0.000 description 1
- 208000009205 Tinnitus Diseases 0.000 description 1
- 206010043994 Tonic convulsion Diseases 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- 206010044688 Trisomy 21 Diseases 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000009911 Urinary Calculi Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 206010046914 Vaginal infection Diseases 0.000 description 1
- 201000008100 Vaginitis Diseases 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 102100026383 Vasopressin-neurophysin 2-copeptin Human genes 0.000 description 1
- 108010053752 Voltage-Gated Sodium Channels Proteins 0.000 description 1
- 102000016913 Voltage-Gated Sodium Channels Human genes 0.000 description 1
- 102100025342 Voltage-dependent N-type calcium channel subunit alpha-1B Human genes 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 241000269368 Xenopus laevis Species 0.000 description 1
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 208000003554 absence epilepsy Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000036982 action potential Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000002582 adenosine A1 receptor agonist Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- 229910045601 alloy Inorganic materials 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
- 229910000147 aluminium phosphate Inorganic materials 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
- 238000002266 amputation Methods 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- 230000001458 anti-acid effect Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 238000009175 antibody therapy Methods 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 238000013528 artificial neural network Methods 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-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
- 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 1
- 230000005540 biological transmission Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 201000008247 brain infarction Diseases 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 206010006451 bronchitis Diseases 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
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 230000008061 calcium-channel-blocking effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 208000003295 carpal tunnel syndrome Diseases 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- MVQBFZXBLLMXGS-UHFFFAOYSA-N chembl331220 Chemical compound C1=CC=C2C(N=NC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C=C(S(O)(=O)=O)C2=C1 MVQBFZXBLLMXGS-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 208000016644 chronic atrophic gastritis Diseases 0.000 description 1
- 208000019069 chronic childhood arthritis Diseases 0.000 description 1
- NQBWNECTZUOWID-QSYVVUFSSA-N cinnamyl cinnamate Chemical compound C=1C=CC=CC=1\C=C/C(=O)OC\C=C\C1=CC=CC=C1 NQBWNECTZUOWID-QSYVVUFSSA-N 0.000 description 1
- 208000018912 cluster headache syndrome Diseases 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
- 208000010877 cognitive disease Diseases 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 208000008609 collagenous colitis Diseases 0.000 description 1
- 201000005108 complex partial epilepsy Diseases 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 208000026725 cyclothymic disease Diseases 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
- 239000000850 decongestant Substances 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 230000002999 depolarising effect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 201000010064 diabetes insipidus Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 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
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000000750 endocrine system Anatomy 0.000 description 1
- 208000030172 endocrine system disease Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 208000037902 enteropathy Diseases 0.000 description 1
- 201000001564 eosinophilic gastroenteritis Diseases 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002870 gabapentin Drugs 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 208000001288 gastroparesis Diseases 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000024798 heartburn Diseases 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 description 1
- 229960000240 hydrocodone Drugs 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 208000009326 ileitis Diseases 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 208000018937 joint inflammation Diseases 0.000 description 1
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- 229960001848 lamotrigine Drugs 0.000 description 1
- PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 description 1
- 239000008141 laxative Substances 0.000 description 1
- 230000002475 laxative effect Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- MKXZASYAUGDDCJ-CGTJXYLNSA-N levomethorphan Chemical compound C([C@H]12)CCC[C@@]11CCN(C)[C@@H]2CC2=CC=C(OC)C=C21 MKXZASYAUGDDCJ-CGTJXYLNSA-N 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 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
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 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
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003771 matrix metalloproteinase inhibitor Substances 0.000 description 1
- 229940121386 matrix metalloproteinase inhibitor Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000028161 membrane depolarization Effects 0.000 description 1
- 230000006386 memory function Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 238000002625 monoclonal antibody therapy Methods 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 230000004118 muscle contraction Effects 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 210000002346 musculoskeletal system Anatomy 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- UNHGSHHVDNGCFN-UHFFFAOYSA-N naratriptan Chemical compound C=12[CH]C(CCS(=O)(=O)NC)=CC=C2N=CC=1C1CCN(C)CC1 UNHGSHHVDNGCFN-UHFFFAOYSA-N 0.000 description 1
- 229960005254 naratriptan Drugs 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 239000002742 neurokinin 1 receptor antagonist Substances 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000008587 neuronal excitability Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 230000003957 neurotransmitter release Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 238000011369 optimal treatment Methods 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 208000020629 overactive bladder Diseases 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229960003684 oxedrine Drugs 0.000 description 1
- 229960001528 oxymetazoline Drugs 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 208000002851 paranoid schizophrenia Diseases 0.000 description 1
- 208000007777 paroxysmal Hemicrania Diseases 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 229960003436 pentoxyverine Drugs 0.000 description 1
- 238000003359 percent control normalization Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 229960003893 phenacetin Drugs 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
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 201000006292 polyarteritis nodosa Diseases 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 208000000170 postencephalitic Parkinson disease Diseases 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 208000026440 premature labor Diseases 0.000 description 1
- 238000010880 proctocolectomy Methods 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 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
- 230000001185 psoriatic effect Effects 0.000 description 1
- 206010037628 pylorospasm Diseases 0.000 description 1
- 208000024981 pyrosis Diseases 0.000 description 1
- 150000004728 pyruvic acid derivatives Chemical class 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
- BHJIBOFHEFDSAU-LBPRGKRZSA-N ralfinamide Chemical compound C1=CC(CN[C@@H](C)C(N)=O)=CC=C1OCC1=CC=CC=C1F BHJIBOFHEFDSAU-LBPRGKRZSA-N 0.000 description 1
- GGWBHVILAJZWKJ-KJEVSKRMSA-N ranitidine hydrochloride Chemical compound [H+].[Cl-].[O-][N+](=O)\C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 GGWBHVILAJZWKJ-KJEVSKRMSA-N 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 208000022610 schizoaffective disease Diseases 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000020341 sensory perception of pain Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000003195 sodium channel blocking agent Substances 0.000 description 1
- 229940126121 sodium channel inhibitor Drugs 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- FJPYVLNWWICYDW-UHFFFAOYSA-M sodium;5,5-diphenylimidazolidin-1-ide-2,4-dione Chemical class [Na+].O=C1[N-]C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 FJPYVLNWWICYDW-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 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 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 1
- 229960003708 sumatriptan Drugs 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 206010048627 thoracic outlet syndrome Diseases 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- ISNYUQWBWALXEY-OMIQOYQYSA-N tsg6xhx09r Chemical compound O([C@@H](C)C=1[C@@]23CN(C)CCO[C@]3(C3=CC[C@H]4[C@]5(C)CC[C@@](C4)(O)O[C@@]53[C@H](O)C2)CC=1)C(=O)C=1C(C)=CNC=1C ISNYUQWBWALXEY-OMIQOYQYSA-N 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 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
- 239000002435 venom Substances 0.000 description 1
- 231100000611 venom Toxicity 0.000 description 1
- 210000001048 venom Anatomy 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 208000030401 vitamin deficiency disease Diseases 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- KNJNGVKTAFTUFL-OCMUWRIYSA-N ω-conotoxin Chemical compound N([C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H]1C(N[C@@H](CSSC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H]1C(N[C@@H](CCCN=C(N)N)C(=O)N[C@H](CO)C(=O)NCC(=O)N[C@H](CCCCN)C(=O)N[C@H](CSSC1)C(N)=O)=O)=O)C(=O)[C@@H]1CSSC[C@@H](N)C(=O)N[C@H](CCCCN)C(=O)NCC(=O)N[C@H](CCCCN)C(=O)NCC(=O)N[C@H](C)C(=O)N[C@@H](CCCCN)C(=O)N1 KNJNGVKTAFTUFL-OCMUWRIYSA-N 0.000 description 1
- 108091058550 ω-conotoxin Proteins 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
-
- 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
- A61P13/00—Drugs for disorders of the urinary 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
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Ophthalmology & Optometry (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Heart & Thoracic Surgery (AREA)
- Obesity (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
- Photoreceptors In Electrophotography (AREA)
- Lubricants (AREA)
Abstract
本发明涉及以下通式(I)的新的环戊基衍生物,其中X是亚甲基、氧、硫或NR7基团;R1是直链或支链的C1-C8烷基或C3-C8亚链烯基或C3-C8亚炔基链,其任选地被CF3、苯基、苯氧基或萘基取代,芳族环任选地被一个或多个C1-C4烷基、卤素、三氟甲基、羟基或C1-C4烷氧基取代;R2、R3独立地是氢、C1-C3烷基链、卤素、三氟甲基、羟基或C1-C4烷氧基;R4、R5、R6、R7独立地是氢或C1-C6烷基;和其药学上可接受的盐,它们具有作为钠和/或钾通道调控剂的活性,因此可用于预防、减轻和治愈各种病变,包括但不限于神经病学疾病、精神病学疾病、心血管疾病、炎性疾病、眼科疾病、泌尿系疾病、代谢疾病和胃肠疾病,其中上述机理已被描述为发挥病理学作用。
Description
本发明涉及以下通式(I)的新的环戊基衍生物:
其中
X是亚甲基、氧、硫或NR7基团;
R1是直链或支链的C1-C8烷基或C3-C8亚链烯基或C3-C8亚炔基链,其任选地被CF3、苯基、苯氧基或萘基取代,芳族环任选地被一个或多个C1-C4烷基、卤素、三氟甲基、羟基或C1-C4烷氧基取代;
R2,R3独立地是氢、C1-C3烷基链、卤素、三氟甲基、羟基或C1-C4烷氧基;
R4,R5,R6,R7独立地是氢或C1-C6烷基;
和其药学上可接受的盐,它们具有作为钠和/或钾通道调控剂的活性,因此可用于预防、减轻和治愈各种病变,包括但不限于神经病学疾病、精神病学疾病、心血管疾病、炎性疾病、眼科疾病、泌尿系疾病、代谢疾病和胃肠疾病,其中上述机理已被描述为发挥病理学作用。
发明背景
化学背景
DE 2624290描述了具有以下通式的2-氨基环烷烃羧酸和其衍生物以及它们作为镇痛剂、退热剂和麻醉剂的用途:
其中R1是羟基或NR4R5基团,R2和R3是氢、烷基、芳烷基、芳基或酰基,R4和R5是氢、C1-C8烷基、芳烷基、芳基或杂芳基。
生物学背景
众所周知,钠通道在神经元网络中发挥重要作用,它们在细胞和细胞网络各处迅速传递电脉冲,从而协调从运动到认知的高级过程。这些通道是大的跨膜蛋白质,它们能够在不同状态之间切换,使钠离子能够选择性地渗透。对于该过程而言,需要动作电位使膜去极化,因此这些通道是电压-门控的。在过去几年中,已经对钠通道有了更深入的了解,并且开发了与它们作用相互的药物。
已经清楚的是,许多作用机理未知的药物实际上通过调控钠通道电导来发挥作用,包括局部麻醉剂、I类抗心律失常剂和抗惊厥剂。已经发现神经元钠通道阻滞剂可用于治疗癫痫(苯妥英和卡马西平)、双相性精神障碍(拉莫三嗪)、预防神经变性和减轻神经性疼痛。各种使神经元兴奋性稳定的抗癫痫药对神经性疼痛是有效的(加巴喷丁)。
另外,在多种炎性疼痛模型中也已经观察到钠通道表达或活性的增加,提示了钠通道在炎性疼痛中的作用。
钙通道是跨膜多亚基蛋白质,其控制钙离子从细胞外液进入细胞。一般,钙通道是电压依赖性的,被称为电压敏感性钙通道(VSCC)。VSCC见于哺乳动物神经系统各处,它们调节诸如细胞兴奋性、递质释放、细胞内代谢、神经分泌活动和基因表达等各种活动。动物中所有“可兴奋的”细胞例如中枢神经系统(CNS)的神经元、外周神经细胞和包括骨骼肌、心肌和静脉与动脉平滑肌的细胞在内的肌肉细胞均具有电压依赖性钙通道。钙通道在调节细胞内钙离子水平上具有核心作用,而细胞内钙离子水平对细胞活力和功能而言是很重要的。细胞内钙离子浓度与动物的许多生命过程有关,例如神经递质释放、肌肉收缩、起博点活性和激素分泌。据信,钙通道与某些疾病状态有关。许多可用于治疗包括人在内的哺乳动物的各种心血管疾病的化合物被认为通过调控存在于心脏和/或血管平滑肌中的电压依赖性钙通道的功能来发挥它们的有益作用。对钙通道具有活性的化合物也已用于治疗疼痛。具体而言,负责神经递质调节的N-型钙通道(Cav2.2)被认为在伤害感受传递中发挥重要作用,这不仅是由于它们的组织分布,而且来自多种药理学研究的结果。这种假设已经在临床上被Zinocotide证实,Zinocotide是一种从海洋蜗牛—僧袍芋螺(Conus Magus)的毒液中得到的肽。这种肽的治疗用途的局限在于它在人中必须进行鞘内施用(BowersoxS.S.和Luther R.Toxicon,1998,36,11,1651-1658)。
所有这些发现共同表明,具有钠和/或钙通道阻滞作用的化合物在预防、减轻和治愈各种病变中具有高的治疗潜能,包括神经病学疾病、精神病学疾病、心血管疾病、泌尿系疾病、代谢疾病和胃肠疾病,其中上述机理已被描述为发挥病理学作用。
有很多文章和专利描述了治疗或调控多种障碍的钠通道和/或钙通道调控剂或拮抗剂,例如它们用作局部麻醉剂、抗心律失常剂、止吐剂、抗躁狂抑郁剂、治疗单相性抑郁、心血管疾病、尿失禁、腹泻、炎症、癫痫、神经变性病症、神经细胞死亡的药物、抗惊厥剂、治疗神经性疼痛、偏头痛、急性痛觉过敏与炎症、肾病、变态反应、哮喘、支气管痉挛、痛经、食道痉挛、青光眼、泌尿道障碍、胃肠蠕动障碍、早产(premature labour)、肥胖的药物。以下给出了非常不完全的列表。
在WO 03/057219(和其中的参考文献)中报道了广泛和充分的现有技术综述;在以下参考文献中报道了现有技术的其它选择:Alzheimer,C.Adv.Exp.Med.Biol.2002,513,161-181;Vanegas,H.;Schaible,H.Pain2000,85,9-18;美国专利5,051,403;美国专利5,587,454;美国专利5,863,952;美国专利6,011,035;美国专利6,117,841;美国专利6,362,174;美国专利6,380,198;美国专利6,420,383;美国专利6,458,781;美国专利6,472,530;美国专利6,518,288;美国专利6,521,647;WO 97/10210;WO03/018561。
发明内容
本发明涉及式(I)的新化合物
其中
X是亚甲基、氧、硫或NR7基团;
R1是直链或支链的C1-C8烷基或C3-C8亚链烯基或C3-C8亚炔基链,其任选地被CF3、苯基、苯氧基或萘基取代,芳族环任选地被一个或多个C1-C4烷基、卤素、三氟甲基、羟基或C1-C4烷氧基取代;
R2,R3独立地是氢、C1-C3烷基链、卤素、三氟甲基、羟基或C1-C4烷氧基;
R4,R5,R6,R7独立地是氢或C1-C6烷基;和其药学上可接受的盐。
本发明的化合物可用作钠和/或钙通道调控剂。
苯环中的取代基R1-X、R2和R3可以位于任何位置。式I化合物的药学上可接受的盐包括与无机酸或有机酸的酸加成盐,无机酸例如盐酸、氢溴酸、硫酸和磷酸,有机酸例如乙酸、丙酸、苯甲酸、肉桂酸、扁桃酸、水杨酸、乙醇酸、乳酸、草酸、苹果酸、马来酸、丙二酸、富马酸、酒石酸、柠檬酸等。
本发明优选的化合物是这样的式I化合物,其中X是氧、亚甲基、NH或NCH3,R1是C1-C8烷基链,其任选地被CF3、苯基或苯氧基取代,其中R1中的芳族环任选地被一个或两个卤素或甲氧基或三氟甲基取代,R2和R3是氢、甲基、甲氧基、氟、氯或溴,R4、R5和R6是氢或甲基。
本发明的具体化合物的实例有:
2-(2-苄基氧基-苄基氨基)-环戊烷羧酸酰胺;
2-(3-苄基氧基-苄基氨基)-环戊烷羧酸酰胺;
2-(4-苄基氧基-苄基氨基)-环戊烷羧酸酰胺;
2-[2-(2-氟-苄基氧基)-苄基氨基]-环戊烷羧酸酰胺;
2-[3-(2-氟-苄基氧基)-苄基氨基]-环戊烷羧酸酰胺;
顺式-2-[3-(2-氟-苄基氧基)-苄基氨基]-环戊烷羧酸酰胺;
2-[4-(2-氟-苄基氧基)-苄基氨基]-环戊烷羧酸酰胺;
2-[4-(2-氟-苄基硫基)-苄基氨基]-环戊烷羧酸酰胺;
2-[4-(2-氟-苄基氨基)-苄基氨基]-环戊烷羧酸酰胺;
2-[2-(2-氟-苄基氧基)-3-氟-苄基氨基]-环戊烷羧酸酰胺;
2-[4-(2-氟-苄基氧基)-3-氟-苄基氨基]-环戊烷羧酸酰胺;
2-[2-(2-氟-苄基氧基)-3-氯-苄基氨基]-环戊烷羧酸酰胺;
(2-[4-(2-氟-苄基氧基)-3-氯-苄基氨基]-环戊烷羧酸酰胺;
(2-[4-(2-氟-苄基氧基)-3-溴-苄基氨基]-环戊烷羧酸酰胺;
(2-[4-(2-氟-苄基氧基)-2-甲氧基-苄基氨基]-环戊烷羧酸酰胺;
(2-[4-(2-氟-苄基氧基)-3-甲氧基-苄基氨基]-环戊烷羧酸酰胺;
2-[4-(2-氟-苄基氧基)-3,5-二甲基-苄基氨基]-环戊烷羧酸酰胺;
顺式-2-[4-(2-氟-苄基氧基)-3,5-二甲基-苄基氨基]-环戊烷羧酸酰胺;和其所有立体异构体和/或药学上可接受的盐。
本发明的化合物和其盐可以通过包括以下步骤的方法得到:
a)在还原剂的存在下,使式II化合物与式III化合物反应,
所述的式II化合物是
其中R1、R2、R3和X如上文所定义,
所述的式III化合物是
其中R4、R5和R6如上文所定义,
由此得到式I化合物;或者
b)使式IV化合物与式III化合物反应,
所述的式IV化合物是
其中R1、R2、R3和X如上文所定义,Y是卤素原子或O-EWG基团,其中EWG表示能够将它们所连接的氧转化为良好离去基团的吸电子基团,
例如甲磺酰基、甲苯磺酰基或三氟乙酰基,
由此得到式I化合物;或者
c)使式Ia化合物与式V或VI化合物反应,
所述的式Ia化合物是
其中R1、R2、R3、R5、R6和X如上文所定义,
所述的式V或VI化合物是
R4Y R8CHO
V VI
其中Y和R4如上文所定义,R8是氢或C1-C5烷基,
由此得到其中R4是C1-C6烷基的本发明化合物;
和如果需要的话,将一种本发明的化合物转化为另一种本发明的化合物,和/或如果需要的话,将本发明的化合物转化为药学上可接受的盐,和/或如果需要的话,将盐转化为游离化合物,和/或如果需要的话,将本发明的化合物的异构体混合物分离为单个的异构体。
化合物II、III、IV、V和VI是可商购获得的化合物或者是利用已知方法以可商购获得的化合物为原料制备的。
生成式I化合物的式II化合物与式III化合物的反应和式Ia化合物与式VI化合物的反应是还原性氨基化反应,其可以按照已知方法进行。根据本发明的一个优选实施方案,它可以如下进行:在氮气氛下,在适合的有机溶剂中,例如醇,例如低级链烷醇,特别是甲醇,或者乙腈,或者四氢呋喃,在约0℃至约80℃的温度下,在还原剂的存在下,最适当的是硼氢化钠或氰基硼氢化钠。有时可以向反应混合物中加入异丙醇钛IV和分子筛以促进反应。
在式IV和V化合物中,卤素优选地是溴或碘。式IV化合物与式III化合物的烷基化反应和式Ia化合物与式V化合物的烷基化反应可以如下进行:在适合的有机溶剂中,例如醇,例如甲醇、乙醇或异丙醇,特别是乙醇,在约0℃至约50℃的温度下。
当本发明的化合物和其中间产物中存在需要在进行上述反应之前加以保护的基团时,可以按照已知的方法在反应之前对它们进行保护、然后去保护。
药理学
在体外结合研究中使用选择性放射性配体证明了本发明的化合物对钙和/或钠通道结合位点显示出亲和性。
本发明的化合物是电压依赖性钠通道和/或钙通道的阻滞剂。因此这些化合物以高亲和性从钠通道的结合位点上置换3H-箭毒蛙碱(BTX),IC50在低μM或亚μM范围内。类似地,这些化合物从钙通道的结合位点上置换3H-尼群地平,IC50在低μM或最通常在亚μM范围内,以及抑制经由细胞去极化通过钙通道所诱导的钙内流。
当钠通道被阻滞时这类物质表现出“使用-依赖性”,即,仅在反复刺激钠通道之后才达到钠通道的最大阻滞。所以,这些物质优选地与被多次活化的钠通道结合。结果,这些物质能够优先在被病理性过度刺激的那些机体区域中发挥活性,正如膜片钳实验所示的那样(W.A.Catteral,TrendsPharmacol.Sci.,8,57-65;1987),该实验表明本发明的化合物以“使用-依赖性”方式阻滞电刺激的钠通道。
作为这些机理的结果,当在各种动物模型中以0.1至100mg/kg口服施用时,本发明的化合物具有体内活性,特别是MES电惊厥试验、持续性疼痛福尔马林模型和角叉菜胶炎症模型。
荧光钙内流测定法和电生理学研究已经证明了本发明化合物的钙和/或钠通道的电压依赖性阻滞作用。
通过基于荧光的钙内流测定法测定了通式I的环戊基衍生物的N-型钙通道调控活性。
在表达Na通道Nav1.3的离体非洲爪蟾卵母细胞(xenopus oocyte)中,利用双电极电压钳(TEVC)技术通过电生理学测定法测定了通式I的环戊基衍生物的钠通道调控活性。
鉴于上述作用机理,本发明的化合物可用于治疗或预防神经性疼痛。神经性疼痛综合征包括但不限于:糖尿病性神经病;坐骨神经痛;非特异性下背部疼痛;多发性硬化疼痛;纤维肌痛;HIV-相关性神经病;神经痛,例如带状疱疹后神经痛和三叉神经痛;和由身体创伤、切断术、癌症、毒素或慢性炎性病症导致的疼痛。
本发明的化合物也可用于治疗慢性疼痛。慢性疼痛包括但不限于由炎症或炎性相关性病症、骨关节炎、类风湿性关节炎所导致的慢性疼痛或者作为疾病、急性损伤或创伤的后遗症的慢性疼痛,包括上背部疼痛或下背部疼痛(由全身、局部或原发性脊柱疾病(例如神经根病)所引起)、骨痛(由骨关节炎、骨质疏松、骨转移或未知原因引起)、骨盆痛、与脊髓损伤有关的疼痛、心脏性胸痛、非心脏性胸痛、中风后中枢性痛、肌筋膜痛、癌症疼痛、AIDS疼痛、镰状细胞性疼痛、老年病性疼痛或者由头痛、颞下颌关节综合征、痛风、纤维化或胸腔出口综合征所导致的疼痛。
本发明的化合物也可用于治疗急性疼痛(由急性损伤、疾患、运动医学损伤、腕管综合征、灼伤、肌肉骨骼扭伤与拉伤、肌腱拉伤、颈臂痛综合征、消化不良(dyspepsis)、胃溃疡、十二指肠溃疡、痛经、子宫内膜异位症或手术(例如心脏直视手术或旁路手术)所导致)、术后疼痛、肾结石疼痛、胆囊疼痛、胆结石疼痛、分娩疼痛或牙痛。
本发明的化合物也可用于治疗偏头痛例如紧张性头痛、变形偏头痛(transformed migraine)或进行性头痛(evolutive headache)、丛集性头痛,以及继发性头痛障碍例如由感染、代谢障碍或其它全身性疾患衍生的头痛障碍,和由上述原发性和继发性头痛的恶化所导致的其它急性头痛、发作性偏头痛等。
本发明的化合物也可用于治疗神经病学病症和认知障碍。神经病学病症包括但不限于诸如以下病症:癫痫(包括单纯性部分癫痫发作、复杂性部分癫痫发作、继发性泛化性癫痫发作,进一步包括癫痫小发作、肌阵挛性癫痫发作、阵挛性癫痫发作、强直性癫痫发作、强直性阵挛性癫痫发作和无张力性癫痫发作),退行性痴呆(包括老年性痴呆、阿尔茨海默病、皮-尼病、帕金森病)和血管性痴呆(包括多发性脑梗塞痴呆、中风和脑缺血),以及与颅内占位性病变、创伤、感染及相关病症(包括HIV感染)、代谢、毒素、缺氧和维生素缺乏有关的痴呆;和与衰老有关的轻微认知功能减退,特别是与年龄有关的记忆功能减退,运动障碍(脑炎后帕金森综合征、进行性核上麻痹、皮质基底节变性),发作性睡眠,注意缺陷多动症(ADHD),肌萎缩性侧索硬化,唐氏综合征。
本发明的化合物也可用于治疗精神病学障碍。精神病学障碍包括但不限于又称为双相性精神障碍的躁狂抑郁(例如I型双相性精神障碍、II型双相性精神障碍)、循环性情感障碍、快速循环、极快速循环(ultradiancycling)、双相性抑郁、急性躁狂、躁狂、混合躁狂、轻躁狂或单相性抑郁、精神分裂症、精神分裂样障碍、分裂情感性障碍、妄想性障碍、短时精神障碍、分享性精神障碍、由一般医学病症引起的精神病性精神障碍、精神作用物质-诱发的精神病性精神障碍或未另外指定的精神病性精神障碍、焦虑症以及吸烟和药物成瘾。
本发明的化合物也可用于治疗外周疾病,例如耳鸣、肌肉痉挛、肌肉硬化和其它障碍,包括但不限于心血管疾病(例如心律失常、心肌梗塞或心绞痛、高血压、缺氧、心肌缺血)、内分泌障碍(例如肢端肥大症或尿崩症)、其中其病理生理学涉及内源性物质(例如儿茶酚胺、激素或生长因子)的过量或过多分泌或其它不适当的细胞分泌的疾病。
本发明的化合物也可用于治疗肝病,例如炎性肝病,例如慢性病毒性乙型肝炎、慢性病毒性丙型肝炎、酒精性肝损伤、原发性胆汁性肝硬化、自身免疫性肝炎、非酒精性脂肪性肝炎和肝移植物排斥。
本发明的化合物抑制影响所有机体系统的炎性过程。因此可用于治疗肌肉骨骼系统的炎性过程,下面是实例列表,但不是所有目标障碍的全部:关节炎性病症,例如强直性脊柱炎、颈椎关节炎、纤维肌痛、痛风、幼年型类风湿关节炎、腰骶关节炎、骨关节炎、骨质疏松、银屑病性关节炎、风湿性疾病;影响皮肤和相关组织的障碍:湿疹、银屑病、皮炎和炎性病症如晒伤;呼吸系统障碍:哮喘、变应性鼻炎和呼吸窘迫综合征、其中涉及炎症的肺障碍如哮喘和支气管炎;慢性阻塞性肺病;免疫与内分泌系统障碍:结节性动脉外膜炎、甲状腺炎、再生障碍性贫血、硬皮病、重症肌无力、多发性硬化、结节病、肾炎综合征、贝赫切特综合征、多肌炎、龈炎。
本发明的化合物也可用于治疗胃肠(GI)道障碍,例如炎性肠病,包括但不限于溃疡性结肠炎、克隆病、回肠炎、直肠炎、乳糜泻、肠病、显微镜性结肠炎或胶原性结肠炎、嗜酸细胞性胃肠炎或者直肠结肠切除术后和回肠肛门吻合术(ileonatal anastomosis)后导致的隐窝炎,和肠易激惹综合征,包括任何与腹部疼痛和/或腹部不适有关的障碍,例如幽门痉挛、神经性消化不良、痉挛性结肠、痉挛性结肠炎、痉挛性肠、肠神经官能症(intestinal neurosis)、功能性结肠炎、粘液性结肠炎、轻泻性结肠炎和功能性消化不良;也用于治疗萎缩性胃炎、变形性胃炎(gastritis varialoforme)、溃疡性结肠炎、消化性溃疡、胃灼热(pyresis)和其它胃肠道损伤,例如幽门螺旋杆菌(Helicobacter pylori)引起的胃肠道损伤、胃食管反流病、胃轻瘫,例如糖尿病胃轻瘫;和其它功能性肠病,例如非溃疡性消化不良(NUD);呕吐、腹泻和内脏炎症。
本发明的化合物也可用于治疗泌尿-生殖道障碍,例如膀胱过度活动症、前列腺炎(慢性细菌性和慢性非细菌性前列腺炎)、前列腺痛、间质性膀胱炎、尿失禁和良性前列腺增生、子宫附件炎、盆腔炎、前庭大腺炎和阴道炎。
本发明的化合物也可用于治疗眼科疾病,例如视网膜炎、视网膜病变、眼色素层炎和急性眼组织损伤、黄斑变性或青光眼、结膜炎。
本发明的化合物也可用于治疗肥胖。
本发明的化合物也可用于治疗所有其它由对电压门控钠通道和/或电压门控钙通道的抑制作用所介导的病症。
应当领会的是,本发明的化合物可以有利地与一种或多种其它治疗剂联合使用。适合用于辅助治疗的药物的实例包括5HT1B/1D激动剂,例如曲坦类(例如舒马普坦或那拉曲坦);腺苷A1激动剂;EP配体;NMDA调控剂,例如甘氨酸拮抗剂;P物质拮抗剂(例如NK1拮抗剂);大麻素;对乙酰氨基酚或非那西丁;5-脂氧化酶抑制剂;白三烯受体拮抗剂;DMARD(例如甲氨蝶呤);加巴喷丁和相关化合物;三环抗抑郁剂(例如阿米替林);神经元稳定性抗癫痫药;单胺能摄取抑制剂(例如文拉法辛);基质金属蛋白酶抑制剂;氧化氮合酶(NOS)抑制剂,例如iNOS或nNOS抑制剂;肿瘤坏死因子α释放或作用的抑制剂;抗体疗法,例如单克隆抗体疗法;抗病毒剂,例如核苷抑制剂(例如拉米夫定)或免疫系统调控剂(例如干扰素);镇痛剂,例如环加氧酶-2抑制剂;局部麻醉剂;兴奋剂,包括咖啡因;H2-拮抗剂(例如雷尼替丁);质子泵抑制剂(例如奥美拉唑);抗酸剂(例如氢氧化铝或氢氧化镁);抗胃肠气胀药(例如semethicone);减充血剂(例如去氧肾上腺素、苯丙醇胺、伪麻黄碱、羟甲唑啉、肾上腺素、萘甲唑林、赛洛唑啉、丙己君或左旋去氧麻黄碱、萘甲唑林、赛洛唑啉、丙己君或左旋去氧麻黄碱);镇咳剂(例如可待因、氢可酮、carmiphen、喷托维林或右旋甲吗喃);利尿剂;或者镇静性或非镇静性抗组胺剂。应当理解的是,本发明包括式(I)化合物或其药学上可接受的盐与一种或多种治疗剂组合的用途。
本发明的化合物可用于人和兽医学。应当理解的是,对治疗的称谓包括已有症状的治疗和预防性治疗,另有明确规定除外。
上文所定义的通式I的环戊基衍生物可以作为药学上可接受的组合物的“活性成分”被施用,所述组合物可以通过常规工艺制备,例如通过将活性成分与药学上可接受的、治疗上惰性的有机和/或无机载体物质相混合来制备。
包含上文所定义的环戊基衍生物的组合物可以以多种形式施用,例如以片剂、锭剂(troch)、胶囊剂、糖衣片或薄膜衣片、液体溶液剂、乳剂或混悬剂的形式口服施用;以栓剂形式直肠施用;胃肠外施用,例如通过肌内或静脉内注射或输注进行胃肠外施用;和透皮施用。
可用于制备这类组合物的适合的药学上可接受的、治疗上惰性的有机和/或无机载体物质包括例如水、明胶、阿拉伯胶、乳糖、淀粉、纤维素、硬脂酸镁、滑石粉、植物油、聚亚烷基二醇等。包含上文所定义的式I的环戊基衍生物的组合物可以被灭菌,并且可以含有其它已知的组分,例如防腐剂、稳定剂、湿润剂或乳化剂,例如石蜡油、二缩甘露醇单油酸酯、调节渗透压的盐、缓冲剂等。
例如,除了活性成分以外,固体口服剂型还可以含有稀释剂,例如乳糖、葡萄糖、蔗糖、纤维素、玉米淀粉或马铃薯淀粉;润滑剂,例如二氧化硅、滑石粉、硬脂酸、硬脂酸镁或硬脂酸钙,和/或聚乙二醇;粘合剂,例如淀粉、阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素或聚乙烯吡咯烷酮;崩解剂,例如淀粉、海藻酸、藻酸盐或淀粉羟乙酸钠;泡腾混合物;染料;甜味剂;湿润剂,例如卵磷脂、聚山梨醇酯、十二烷基硫酸盐;和一般而言,用在药物制剂中的无毒的与无药理活性的物质。所述药物制剂可以用已知方法制备,例如通过混合、造粒、压片、包糖衣或包薄膜衣方法制备。
口服制剂包含缓释制剂,其可以按常规方式制备,例如通过给片剂和颗粒涂敷肠溶衣来制备。
口服施用的液体分散物可以是例如糖浆剂、乳剂和混悬剂。
糖浆剂可以含有作为载体的例如蔗糖或蔗糖与甘油和/或甘露醇和/或山梨醇。
混悬剂和乳剂可以含有作为载体的例如天然树胶、琼脂、藻酸钠、果胶、甲基纤维素、羧甲基纤维素或聚乙烯醇。除了活性化合物以外,肌内注射的混悬剂或溶液剂还可以含有药学上可接受的载体,例如无菌水、橄榄油、油酸乙酯、二醇类,例如丙二醇,和如果需要的话,适量盐酸利多卡因。静脉内注射或输注的溶液剂可以含有作为载体的例如无菌水,或者优选地它们可以是无菌、水性、等张盐水溶液的形式。
除了活性成分以外,栓剂还可以含有药学上可接受的载体,例如可可脂、聚乙二醇、聚氧乙烯脱水山梨醇脂肪酸酯表面活性剂或卵磷脂。
适合的治疗每天给予1、2或3次,这取决于清除率。因此,所需剂量可以以单剂量形式或者作为以适当时间间隔施用的多剂量形式给予,例如每天二至四个或更多个分剂量。
包含上文所定义的式I的环戊基衍生物的药物组合物每个剂量单元中将含有约0.1至约500mg活性成分,最优选含有1至10mg活性成分,所述的剂量单元例如胶囊剂、片剂、粉针剂、茶匙(teaspoonful)、栓剂等。
待施用的最佳治疗有效剂量可以由本领域技术人员容易地确定,并且基本上将因制剂的强度、施用方式和所治疗的病症或障碍的进展程度而异。另外,包括个体的年龄、体重、饮食和施用时间在内的与所治疗的特定个体有关的因素也将导致需要调整剂量至适当的治疗有效水平。
以下实施例进一步阐述了发明。
实施例1
顺式-2-[3-(2-氟-苄基氧基)-苄基氨基]-环戊烷羧酸酰胺
将2M的2-氨基-环戊烷羧酸酰胺(0.75g,6.5mmol)在干燥THF中的溶液加入到1M的如实施例3所述制备的3-(2-氟-苄基氧基)-苯甲醛(1.64g,7.15mmol)在干燥THF中的溶液中。向该混合物中滴加2M的Ti(O-iPr)4(2.77g,9.75mmol)在干燥THF中的溶液,将反应混合物在室温、氮气下搅拌12小时。
加入0.75M的硼氢化钠(0.69g,18.2mmol)在无水乙醇中的溶液,将所得混合物在70℃下加热6小时。冷却后,加入8ml水猝灭反应,滤出所得白色沉淀。用SCX柱(强阳离子交换树脂)纯化粗化合物。用3%氨的甲醇溶液洗脱回收纯产物。在真空下蒸发溶剂后,得到标题化合物(2.08g),最后收率94%。
MS(ESI Pos Spray 3.5 kV;Skimmer 20 V;Probe 250℃):343[MH+]
1H-NMR(DMSO-d6)δ:7.55(m,1H),7.45(m,2H),7.25(m,3H),7.0(s,1H),6.88(m,2H),6.78(s,1H),5.1(s,2H),3.7(dd,2H),3.10(m,1H),2.65(m,1H),1.90-1.4(m,6H).
实施例2
顺式-2-[4-(2-氟-苄基氧基)-3,5-二甲基-苄基氨基]-环戊烷羧酸酰胺
将2M的2-氨基-环戊烷羧酸酰胺(0.75g,6.5mmol)在干燥THF中的溶液加入到1M的如实施例4所述制备的4-(2-氟-苄基氧基)-3,5-二甲基-苯甲醛(1.84g,7.15mmol)在干燥THF中的溶液中。向该混合物中滴加2M的Ti(O-iPr)4(2.77g,9.75mmol)在干燥THF中的溶液,将反应混合物在室温、氮气下搅拌12小时。
加入0.75M的硼氢化钠(0.69g,18.2mmol)在无水乙醇中的溶液,将所得混合物在70℃下加热6小时。冷却后,加入8ml水猝灭反应,滤出所得白色沉淀。用SCX柱(强阳离子交换树脂)纯化粗化合物。用3%氨的甲醇溶液洗脱回收纯产物。在真空下蒸发溶剂后,得到标题化合物(2.14g),最后收率89%。
MS(ESI Pos Spray 3.5 kV;Skimmer 20 V;Probe 250℃):371[MH+]
1H-NMR(DMSO-d6)δ:7.60(m,1H),7.48(m,2H),7.28(m,2H),6.95(s,2H),6.78(s,1H),4.80(s,2H),3.6(dd,2H),3.15(m,1H),2.68(m,1H),2.2(s,6H),1.85-1.51(m,6H).
实施例3
3-(2-氟-苄基氧基)-苯甲醛
将0.5M的1-溴甲基-2-氟-苯(1.50g,8.0mmol)在DMF中的溶液滴加到3-羟基-苯甲醛(0.89g,7.3mmol)、K2CO3(1.51g,11mmol)与KI(0.12g,0.73mmol)在100ml DMF中的混悬液中。将反应混合物在90℃下搅拌过夜。冷却至室温后,滤出固体残余物,在真空下蒸发溶剂。将残余物溶于乙酸乙酯,将有机层用1M NaOH洗涤两次,用Na2SO4干燥,蒸发至干。将残余物在硅胶上纯化,得到167mg标题化合物(定量收率)。
实施例4
4-(2-氟-苄基氧基)-3,5-二甲基-苯甲醛
将0.5M的1-溴甲基-2-氟-苯(1.50g,8.0mmol)在DMF中的溶液滴加到1.09g 4-羟基-3,5-二甲基-苯甲醛(7.3mmol)、1.51g K2CO3(11mmol)与120mg KI(0.73mmol)在100ml DMF中的混悬液中。反应按照与实施例3所述的相同方法进行。将残余物在硅胶上纯化,得到定量收率的标题化合物(1.88g)。
实施例5
大鼠脑膜中3H-箭毒蛙碱的体外结合
膜制备物(P2级分):在轻微麻醉下处死雄性Wistar大鼠(Harlan,意大利,175-200g),迅速取出脑,切下皮质,在10体积冰冷的0.25M蔗糖缓冲液(50mM Tris-HCl,pH 7.4)中匀化。将粗匀浆在3250rpm下离心10分钟,回收上清液。将沉淀再次匀化和离心,合并两份上清液,在+4℃、14750rpm下离心10分钟。将所得沉淀贮存在-20℃下备用。
结合测定:利用Polytron PT10将沉淀重新混悬在50mM pH 7.4的Hepes缓冲液中,其含有0.8mM MgSO4、5.4mM KCl、5.5mM葡萄糖和130mM胆碱。结合测定是在0.25ml终体积中进行的,其中含有50μl膜制备物(约200μg蛋白质)、50μl 3H-箭毒蛙碱配体(10nM)、50μl TTX(1μM)、50μl蝎毒素(37.5μg/ml)和50μl供试化合物或缓冲液或300μM藜芦定,以测定非特异性结合。在37℃下进行结合测定达30分钟,在真空下迅速通过Whatman GF/B玻璃纤维滤器过滤来终止测定。将滤器(预先用聚乙烯亚胺0.1%浸泡)用3×5ml冰冷的缓冲液洗涤,置于含有闪烁合剂(FilterCount,Packard)的微型瓶中。以45%的效率用液体闪烁谱测量法测量所结合的放射性。
数据分析:通过计算机程序LIGAND由置换曲线计算IC50(McPherson,J.Pharmacol.Methods,14,213.1985)。使用至少9种浓度得到置换曲线,各浓度均一式两份,覆盖100000倍范围。
实施例6
大鼠脑膜中3H-尼群地平的体外结合
膜制备物:在轻微麻醉下处死雄性Wistar大鼠(Harlan,意大利,175-200g),迅速取出脑,切下皮质,利用Polytron PT10在10体积冰冷的50mM pH 7.7的Tris·HCl中匀化。将粗匀浆在50000×g下离心10分钟。将沉淀在+4℃、50000×g下在新鲜缓冲液中匀化并离心10分钟,该操作进行两次。将所得沉淀贮存在-20℃下备用。
结合测定:利用Polytron PT10将沉淀重新混悬在50mM pH 7.7的Tris·HCl中。结合测定是在1ml终体积中进行的,其中含有900μl膜制备物(约700μg蛋白质)、50μl 3H-尼群地平(0.15nM)和50μl供试化合物或缓冲液或1μM尼群地平,以测定非特异性结合。在25℃下进行结合测定达45分钟,在真空下迅速通过Whatman GF/B玻璃纤维滤器过滤来终止测定。将滤器用3×5ml冰冷的缓冲液洗涤,置于含有闪烁合剂(Filter Count,Packard)的微型瓶中。以45%的效率用液体闪烁谱测量法测量所结合的放射性。
数据分析:通过计算机程序LIGAND由置换曲线计算IC50(McPherson,J.Pharmacol.Methods,14,213.1985)。使用至少9种浓度得到置换曲线,各浓度均一式两份,覆盖100000倍范围。
实施例7
钙内流测定
IMR32人神经母细胞瘤细胞在组成上具有L和N型通道。在分化条件下,IMR32优先在膜表面上表达N-型通道。利用选择性L型阻滞剂硝苯地平阻滞其余L-型钙通道。在这些实验条件下,仅能检测N-型通道。
在225cm2烧瓶中,使用1mM dibutyrril-cAMP和2.5μM溴脱氧尿苷使IMR32细胞分化8天(4次),然后分离,以200,00个细胞/孔接种在聚赖氨酸包被的96孔板上,在分化缓冲液的存在下进一步温育18-24小时,备用。
基于荧光钙指示剂485-535nm波长,使用Ca2+Kit Assay(MolecularDevices)。
将分化的细胞与染剂加载物一起在37℃下温育30分钟,然后单独加入硝苯地平(1μM)或者在存在ω-芋螺毒素或供试化合物的情况下加入,进一步温育15分钟。
在自动注入100mM KCl去极化溶液之前和之后(30-40秒),利用Victor读板器(Perkin Elmer)测量荧光(485-535nm)。
由5种浓度计算抑制曲线,各浓度均一式三份,利用线性回归分析确定IC50。
通式I的优选化合物抑制N-型钙通道,IC50值小于10μM。
实施例8
电生理学测定
用表达Na通道Nav1.3的离体非洲爪蟾卵母细胞进行测定强直性阻滞的实验。利用双电极电压钳(TEVC)技术记录电流。
卵母细胞制备:
将青蛙(非洲爪蟾(Xenopus laevis))用含3-氨基苯甲酸乙酯的溶液(1g/l)麻醉,25分钟后将其背朝下置于“冰床”上。切开皮肤和其它组织,拉出卵巢叶(ovarian lobe),保持在ND96Ca2+(NaCl 96mM,KCl 2mM,MgCl21mM,Hepes 10mM,用NaOH调至pH 7.85)中。
取出卵母细胞后,分别缝合肌肉和皮肤。
将卵巢叶缩减至10/20卵母细胞群,置于含胶原酶溶液(1mg/ml)的试管中,在温育器中保持运动约1小时。
此步骤结束时,卵母细胞彼此完全分开,用ND96Ca2+冲洗三次,用NDE(ND96Ca2++CaCl 0.9mM,MgCl2 0.9mM,丙酮酸盐2.5mM,庆大霉素50mg/l)冲洗三次。
所得卵母细胞处于不同的发育阶段。仅选择处于V或VI阶段的细胞用于RNA注入后的实验。
制备后的那天,用20ng Nav1.3 cRNA注入卵母细胞(DrummondNanoject),供养在NDE中。
从mRNA注入后48小时开始,利用双微电极电压钳自动化工作站记录全细胞电流。
典型的微电极具有0.5至1MΩ电阻,填充有KCl 3M。
对照浴溶液含有(mM):NaCl 98,MgCl2 1,CaCl2,1.8,HEPES 5(pH7.6)。
制备化合物贮备液(20mM),溶于外部浴液至终浓度。
电流记录:
首先研究卵母细胞中表现的Nav1.3电流的电流/电压(I/V)关系,目的是测定激发最大活化的膜电位。在0mV下Nav1.3显示最大活化,我们将其用作强直性阻滞研究的测试电位(Vtest)。
然后研究Nav1.3电流的稳态失活性质,目的是分别测定通道可用性为最大(Imax)的静息态膜电位(Vrest)和产生半数最大电流可用性(I)的半数最大失活膜电位(V)。然后利用这两种电压条件评价强直性阻滞的电压依赖性。
最后利用一个两步方案测定Nav1.3阻滞的电压依赖性:使卵母细胞在-80mV下与膜片接触,通过100ms步进脉冲将电流分别从在-80mV(静息,Imax条件)和-40mV(去极化,I条件)下的3000ms的预调节电位(preconditioning potential)活化至0mV(Vtest)。
在不存在和存在不同浓度化合物的情况下记录两种条件下的电流振幅(在两次之间进行洗脱),目的是测定浓度-抑制作用曲线和去极化(半数最大电流可用性)条件下强直性阻滞的IC50值。
优选的通式I化合物抑制Nav1.3钠通道,IC50值低于参比钠通道阻滞剂ralfinamide。
实施例9
大鼠和小鼠最大电击试验
通过耳内夹电极使Wistar大鼠接受电击(160mA 0.2s,脉冲列60Hz,脉冲持续时间0.4ms;ECT单元模式7801,Ugo Basile,Comerio,意大利),在至少97%对照动物中足以产生后肢强直性伸肌反应。
小鼠接受28mA电击0.7s,脉冲列80Hz,脉冲持续时间0.4ms。在MES诱导之前对小鼠或大鼠施用多个剂量的供试化合物和标准AED,每个剂量组10至20只,施用体积5ml/kg,对于口服施用而言在MES诱导之前60分钟进行或者对于腹膜内施用而言在MES诱导之前30分钟进行,计算ED50值。癫痫发作的后肢强直性伸肌组分的完全抑制被视为抗惊厥活性的证据。
实施例10
小鼠福尔马林试验
按照Rosland等,(1990)的改进方案,向小鼠皮下(s.c.)注射20μl 2.7%福尔马林溶液至左后足足底表面内,立即置于透明的PVC观察室(23×12×13cm)内。通过对注射足的累积舔舐时间(秒)进行计数来量化疼痛行为。在福尔马林注射后早期(0-5min)和后期(30-40min)进行测量(Tjolsen等1992)。
在福尔马林注射前15分钟口服施用供试化合物,施用体积为10ml/kg体重,每个剂量组10只小鼠。对照组用载体处理。
实施例11
角叉菜胶炎症模型
使用175-200克的雄性Wistar大鼠。
向左后足注射100μl角叉菜胶(2%w/v在盐水中)。在角叉菜胶注射前1小时口服施用本发明化合物(30mg/kg)、吲哚美辛(5mg/kg)或对照载体(例如蒸馏水)。在角叉菜胶注射前即刻(基础值)和之后1、2、3、4和5小时,利用器官充满度测量器(Ugo Basile)测量足体积。
Claims (6)
1.式I化合物
其中
X是亚甲基、氧、硫或NR7基团;
R1是直链或支链的C1-C8烷基或C3-C8亚链烯基或C3-C8亚炔基链,其任选地被CF3、苯基、苯氧基或萘基取代,芳族环任选地被一个或多个C1-C4烷基、卤素、三氟甲基、羟基或C1-C4烷氧基取代;
R2,R3独立地是氢、C1-C3烷基链、卤素、三氟甲基、羟基或C1-C4烷氧基;
R4,R5,R6,R7独立地是氢或C1-C6烷基;
和其药学上可接受的盐。
2.根据权利要求1所述的式I化合物,其中X是氧、亚甲基、NH或NCH3,R1是C1-C8烷基链,其任选地被CF3、苯基或苯氧基取代,其中R1中的芳族环任选地被一个或两个卤素或甲氧基或三氟甲基取代,R2和R3是氢、甲基、甲氧基、氟、氯或溴,R4、R5和R6是氢或甲基。
3.选自下组的化合物:
2-(2-苄基氧基-苄基氨基)-环戊烷羧酸酰胺;
2-(3-苄基氧基-苄基氨基)-环戊烷羧酸酰胺;
2-(4-苄基氧基-苄基氨基)-环戊烷羧酸酰胺;
2-[2-(2-氟-苄基氧基)-苄基氨基]-环戊烷羧酸酰胺;
2-[3-(2-氟-苄基氧基)-苄基氨基]-环戊烷羧酸酰胺;
顺式-2-[3-(2-氟-苄基氧基)-苄基氨基]-环戊烷羧酸酰胺;
2-[4-(2-氟-苄基氧基)-苄基氨基]-环戊烷羧酸酰胺;
2-[4-(2-氟-苄基硫基)-苄基氨基]-环戊烷羧酸酰胺;
2-[4-(2-氟-苄基氨基)-苄基氨基]-环戊烷羧酸酰胺;
2-[2-(2-氟-苄基氧基)-3-氟-苄基氨基]-环戊烷羧酸酰胺;
2-[4-(2-氟-苄基氧基)-3-氟-苄基氨基]-环戊烷羧酸酰胺;
2-[2-(2-氟-苄基氧基)-3-氯-苄基氨基]-环戊烷羧酸酰胺;
(2-[4-(2-氟-苄基氧基)-3-氯-苄基氨基]-环戊烷羧酸酰胺;
(2-[4-(2-氟-苄基氧基)-3-溴-苄基氨基]-环戊烷羧酸酰胺;
(2-[4-(2-氟-苄基氧基)-2-甲氧基-苄基氨基]-环戊烷羧酸酰胺;
(2-[4-(2-氟-苄基氧基)-3-甲氧基-苄基氨基]-环戊烷羧酸酰胺;
2-[4-(2-氟-苄基氧基)-3,5-二甲基-苄基氨基]-环戊烷羧酸酰胺;
顺式-2-[4-(2-氟-苄基氧基)-3,5-二甲基-苄基氨基]-环戊烷羧酸酰胺;
和其所有立体异构体和/或药学上可接受的盐。
4.制备权利要求1中所定义的式I化合物或其药学上可接受的盐的方法,该方法包括:
a)在还原剂的存在下,使式II化合物与式III化合物反应,
所述的式II化合物是
其中R1、R2、R3和X如上文所定义,
所述的式III化合物是
其中R4、R5和R6如上文所定义,
由此得到式I化合物;或者
b)使式IV化合物与式III化合物反应,
所述的式IV化合物是
其中X、R1、R2和R3如上文所定义,Y是卤素原子或O-EWG基团,其中EWG表示能够将它们所连接的氧转化为良好离去基团的吸电子基团,
例如甲磺酰基、甲苯磺酰基或三氟乙酰基,
由此得到式I化合物;或者
c)使式Ia化合物与式V或VI化合物反应,
所述的式Ia化合物是
其中R1、R2、R3、R5、R6和X如上文所定义,
所述的式V或VI化合物是
R4Y R8CHO
V VI
其中Y和R4如上文所定义,R8是氢或C1-C5烷基,
由此得到其中R4是C1-C6烷基的本发明的化合物;
和如果需要的话,将一种本发明的化合物转化为另一种本发明的化合物,和/或如果需要的话,将本发明的化合物转化为药学上可接受的盐,和/或如果需要的话,将盐转化为游离化合物,和/或如果需要的话,将本发明的化合物的异构体混合物分离为单个的异构体。
5.药物组合物,其含有权利要求1中所定义的式I化合物或其药学上可接受的盐以及与之混合的适合的载体和/或稀释剂,还任选地含有其它治疗剂。
6.权利要求1中所定义的式I化合物或其药学上可接受的盐在制备药物中的用途,所述药物具有钠和/或钙通道调控活性,用于预防、减轻和治愈神经病学疾病、精神病学疾病、心血管疾病、炎性疾病、眼科疾病、泌尿系疾病、代谢疾病和胃肠疾病,其中在病理学过程中涉及钠和/或钙通道。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP03027050A EP1533295A1 (en) | 2003-11-24 | 2003-11-24 | Cyclopentyl Derivatives |
EP03027050.8 | 2003-11-24 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1886366A true CN1886366A (zh) | 2006-12-27 |
CN100391935C CN100391935C (zh) | 2008-06-04 |
Family
ID=34429431
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB2004800346593A Expired - Fee Related CN100391935C (zh) | 2003-11-24 | 2004-11-12 | 环戊基衍生物 |
Country Status (22)
Country | Link |
---|---|
US (1) | US7265244B2 (zh) |
EP (2) | EP1533295A1 (zh) |
JP (1) | JP4769194B2 (zh) |
KR (1) | KR101142074B1 (zh) |
CN (1) | CN100391935C (zh) |
AT (1) | ATE369331T1 (zh) |
AU (1) | AU2004295043B2 (zh) |
BR (1) | BRPI0416842B8 (zh) |
CA (1) | CA2546962C (zh) |
CY (1) | CY1106930T1 (zh) |
DE (1) | DE602004008103T2 (zh) |
DK (1) | DK1687259T3 (zh) |
ES (1) | ES2291982T3 (zh) |
HK (1) | HK1097512A1 (zh) |
IL (1) | IL175847A (zh) |
NO (1) | NO335826B1 (zh) |
NZ (1) | NZ547393A (zh) |
PL (1) | PL1687259T3 (zh) |
PT (1) | PT1687259E (zh) |
RU (1) | RU2372325C2 (zh) |
SI (1) | SI1687259T1 (zh) |
WO (1) | WO2005054178A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5301431B2 (ja) * | 2006-05-18 | 2013-09-25 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | キラルな環状β−アミノカルボキサミドの製造方法 |
KR101500962B1 (ko) * | 2007-12-19 | 2015-03-10 | 뉴론 파마슈티칼즈 에스. 피. 에이. | 정신 장애의 치료에 유용한 알파아미노아미드 유도체 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HU177576B (en) * | 1975-06-02 | 1981-11-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing 2-amino-cyclohexane carboxylic acid,its amides and similar compounds |
US5532254A (en) * | 1995-06-07 | 1996-07-02 | Eli Lilly And Company | Modulation of calcium channels using benzothiophenes |
JP4160136B2 (ja) * | 1996-08-29 | 2008-10-01 | 武田薬品工業株式会社 | 縮合環状エーテル類、その製造法および剤 |
GB9727523D0 (en) * | 1997-12-31 | 1998-02-25 | Pharmacia & Upjohn Spa | Alpha-aminoamide derivatives useful as analgesic agents |
TWI283577B (en) * | 1999-10-11 | 2007-07-11 | Sod Conseils Rech Applic | Pharmaceutical composition of imidazole derivatives acting as modulators of sodium channels and the use thereof |
SI1458386T1 (sl) * | 2001-12-27 | 2007-08-31 | Ortho Mcneil Pharm Inc | Aroil pirol heteroeril in metanoli, uporabni za zdravljenje motnje centralnega živčnega sistema |
-
2003
- 2003-11-24 EP EP03027050A patent/EP1533295A1/en not_active Withdrawn
-
2004
- 2004-11-12 ES ES04819587T patent/ES2291982T3/es active Active
- 2004-11-12 RU RU2006117774/04A patent/RU2372325C2/ru active
- 2004-11-12 SI SI200430429T patent/SI1687259T1/sl unknown
- 2004-11-12 CN CNB2004800346593A patent/CN100391935C/zh not_active Expired - Fee Related
- 2004-11-12 KR KR1020067010038A patent/KR101142074B1/ko active IP Right Grant
- 2004-11-12 BR BRPI0416842A patent/BRPI0416842B8/pt not_active IP Right Cessation
- 2004-11-12 JP JP2006540265A patent/JP4769194B2/ja not_active Expired - Fee Related
- 2004-11-12 CA CA2546962A patent/CA2546962C/en active Active
- 2004-11-12 DK DK04819587T patent/DK1687259T3/da active
- 2004-11-12 EP EP04819587A patent/EP1687259B1/en active Active
- 2004-11-12 PL PL04819587T patent/PL1687259T3/pl unknown
- 2004-11-12 AT AT04819587T patent/ATE369331T1/de active
- 2004-11-12 WO PCT/EP2004/012835 patent/WO2005054178A1/en active IP Right Grant
- 2004-11-12 NZ NZ547393A patent/NZ547393A/en not_active IP Right Cessation
- 2004-11-12 AU AU2004295043A patent/AU2004295043B2/en not_active Ceased
- 2004-11-12 DE DE602004008103T patent/DE602004008103T2/de active Active
- 2004-11-12 US US10/580,366 patent/US7265244B2/en active Active
- 2004-11-12 PT PT04819587T patent/PT1687259E/pt unknown
-
2006
- 2006-05-23 NO NO20062352A patent/NO335826B1/no not_active IP Right Cessation
- 2006-05-23 IL IL175847A patent/IL175847A/en active IP Right Grant
-
2007
- 2007-03-09 HK HK07102611A patent/HK1097512A1/xx not_active IP Right Cessation
- 2007-10-11 CY CY20071101314T patent/CY1106930T1/el unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110382503A (zh) | 制备acc抑制剂及其固体形式的方法 | |
CN1141043A (zh) | 非肽类速激肽受体拮抗剂 | |
CN1909897A (zh) | 用于治疗阿尔茨海默病的苯基羧化物β-分泌酶抑制剂 | |
JP2008512405A (ja) | ナトリウムおよび/またはカルシウムチャンネル選択的調節因子として活性のある医薬の製造のための(ハロベンジルオキシ)ベンジルアミノ−プロパンアミドの使用 | |
CN1926136A (zh) | 作为缓激肽拮抗剂的氨基环丙烷羧酰胺衍生物 | |
CN1305465A (zh) | 芳基链烷酰基哒嗪化合物 | |
CN103781759B (zh) | 氟化的芳基烷基氨基甲酰胺衍生物 | |
CN1871242A (zh) | 作为mch r1拮抗剂用于治疗肥胖症、糖尿病、抑郁症和焦虑的3-(4-(氨基苯基)噻吩并嘧啶-4-酮衍生物 | |
CN1399633A (zh) | 嘧啶衍生物 | |
CN1966506A (zh) | 吡唑并嘧啶酮衍生物及其制备方法和用途 | |
JP2013526489A (ja) | 1−[(4−ヒドロキシピペリジン−4−イル)メチル]ピリジン−2(1h)−オン誘導体、その調製方法およびその使用 | |
CN1798744A (zh) | 作为nmda/nr2b拮抗剂的3-氟-哌啶化合物 | |
CN1050835C (zh) | 1,5-苯并二氮杂衍生物、其制备方法及其药物用途 | |
KR20000005505A (ko) | 피페리딘 및 피롤리딘 | |
CN1105360A (zh) | 1-[2h-1-苯并吡喃-2-酮-8-基]-哌嗪衍生物 | |
CN1104017A (zh) | 取代的(芳烷氧基苄基)氨基丙酰胺衍生物及其制备方法 | |
CN1564686A (zh) | 8-氨基-[1,2,4]三唑并[1,5-a]吡啶-6-甲酰胺 | |
CN1134149A (zh) | 苯基吲哚化合物 | |
CN1261414C (zh) | 作为单胺氧化酶(mao-b)抑制剂的吡啶酰氨基衍生物 | |
CN1255387C (zh) | 可用作选择性cox-2抑制剂的嘧啶衍生物 | |
WO2006095822A1 (ja) | スルホンアミド化合物およびその医薬 | |
CN1886366A (zh) | 环戊基衍生物 | |
CN1886370A (zh) | N-酰基-n′-苄基-亚烷基二氨基衍生物 | |
CN1726208A (zh) | E-2-甲氧基-n-( 3-{4-[3-甲基-4-( 6-甲基-吡啶-3-基氧基)-苯基氨基]-喹唑啉-6-基}-烯丙基)-乙酰胺的配合物、其制备方法和用途 | |
JP2012211086A (ja) | 関節リウマチの治療剤又は予防剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1097512 Country of ref document: HK |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1097512 Country of ref document: HK |
|
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20080604 |
|
CF01 | Termination of patent right due to non-payment of annual fee |