CN1196681C - (+)诺西沙必利用于制备5－ht3和5ht4 介导的疾病的药物中的用途 - Google Patents
(+)诺西沙必利用于制备5－ht3和5ht4 介导的疾病的药物中的用途 Download PDFInfo
- Publication number
- CN1196681C CN1196681C CNB988069563A CN98806956A CN1196681C CN 1196681 C CN1196681 C CN 1196681C CN B988069563 A CNB988069563 A CN B988069563A CN 98806956 A CN98806956 A CN 98806956A CN 1196681 C CN1196681 C CN 1196681C
- Authority
- CN
- China
- Prior art keywords
- cisapride
- nuo
- purposes
- acid
- disease
- 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.)
- Expired - Fee Related
Links
- ZDLILMQNLSEPLK-UHFFFAOYSA-N 2-chloro-5-methoxy-n-piperidin-4-ylpyrimidin-4-amine Chemical compound COC1=CN=C(Cl)N=C1NC1CCNCC1 ZDLILMQNLSEPLK-UHFFFAOYSA-N 0.000 title abstract 2
- 230000001404 mediated effect Effects 0.000 title description 2
- 239000003814 drug Substances 0.000 claims abstract description 48
- DCSUBABJRXZOMT-IRLDBZIGSA-N cisapride Chemical compound C([C@@H]([C@@H](CC1)NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)OC)N1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-IRLDBZIGSA-N 0.000 claims description 95
- 229960005132 cisapride Drugs 0.000 claims description 95
- DCSUBABJRXZOMT-UHFFFAOYSA-N cisapride Natural products C1CC(NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)C(OC)CN1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-UHFFFAOYSA-N 0.000 claims description 94
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 60
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 30
- 201000010099 disease Diseases 0.000 claims description 29
- 238000011282 treatment Methods 0.000 claims description 28
- 238000002360 preparation method Methods 0.000 claims description 25
- 239000008141 laxative Substances 0.000 claims description 20
- 230000002475 laxative effect Effects 0.000 claims description 20
- -1 polyoxyethylene Polymers 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 210000002784 stomach Anatomy 0.000 claims description 13
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 8
- 206010012735 Diarrhoea Diseases 0.000 claims description 7
- 206010021518 Impaired gastric emptying Diseases 0.000 claims description 5
- 230000007812 deficiency Effects 0.000 claims description 5
- 201000006549 dyspepsia Diseases 0.000 claims description 5
- 208000001288 gastroparesis Diseases 0.000 claims description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 2
- 208000030814 Eating disease Diseases 0.000 claims 2
- 208000019454 Feeding and Eating disease Diseases 0.000 claims 2
- 235000014632 disordered eating Nutrition 0.000 claims 2
- 206010067171 Regurgitation Diseases 0.000 claims 1
- 239000008151 electrolyte solution Substances 0.000 claims 1
- 239000012466 permeate Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 27
- 239000002253 acid Substances 0.000 abstract description 26
- 150000001875 compounds Chemical class 0.000 abstract description 24
- 238000000034 method Methods 0.000 abstract description 22
- 150000003839 salts Chemical class 0.000 abstract description 13
- 238000007792 addition Methods 0.000 abstract description 10
- 210000003169 central nervous system Anatomy 0.000 abstract description 5
- 208000018522 Gastrointestinal disease Diseases 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract 2
- 239000000203 mixture Substances 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000000543 intermediate Substances 0.000 description 25
- 239000003826 tablet Substances 0.000 description 22
- 210000000936 intestine Anatomy 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 12
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 239000007788 liquid Substances 0.000 description 10
- 239000006210 lotion Substances 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 208000024891 symptom Diseases 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 206010047700 Vomiting Diseases 0.000 description 9
- 230000008673 vomiting Effects 0.000 description 9
- 230000005526 G1 to G0 transition Effects 0.000 description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 8
- 239000003513 alkali Substances 0.000 description 8
- 230000003042 antagnostic effect Effects 0.000 description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 8
- 239000008108 microcrystalline cellulose Substances 0.000 description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 7
- 229960004046 apomorphine Drugs 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 229960005139 epinephrine Drugs 0.000 description 7
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 7
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 239000000375 suspending agent Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 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 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 239000011248 coating agent Substances 0.000 description 6
- 238000000576 coating method Methods 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 235000013305 food Nutrition 0.000 description 6
- 230000002496 gastric effect Effects 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- 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 5
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical group O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 5
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 5
- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- 150000008064 anhydrides Chemical class 0.000 description 5
- 239000000084 colloidal system Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000000314 lubricant Substances 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 210000003205 muscle Anatomy 0.000 description 5
- 239000000377 silicon dioxide Substances 0.000 description 5
- 239000000600 sorbitol Substances 0.000 description 5
- 238000010254 subcutaneous injection Methods 0.000 description 5
- 239000007929 subcutaneous injection Substances 0.000 description 5
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 4
- 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 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 150000003851 azoles Chemical class 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 231100000673 dose–response relationship Toxicity 0.000 description 4
- 239000000945 filler Substances 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 231100000652 hormesis Toxicity 0.000 description 4
- 229960001375 lactose Drugs 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 229960001021 lactose monohydrate Drugs 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 125000003386 piperidinyl group Chemical group 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000012266 salt solution Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000002689 soil Substances 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 239000004408 titanium dioxide Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 3
- 241000700199 Cavia porcellus Species 0.000 description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000003420 antiserotonin agent Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 210000000941 bile Anatomy 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 235000011089 carbon dioxide Nutrition 0.000 description 3
- 230000007541 cellular toxicity 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
- 210000001072 colon Anatomy 0.000 description 3
- 229960001681 croscarmellose sodium Drugs 0.000 description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 3
- 108010037444 diisopropylglutathione ester Proteins 0.000 description 3
- 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 3
- 230000005611 electricity Effects 0.000 description 3
- 239000007920 enema Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 230000007794 irritation Effects 0.000 description 3
- 238000012417 linear regression Methods 0.000 description 3
- 230000037353 metabolic pathway Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 230000002980 postoperative effect Effects 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000000452 restraining effect Effects 0.000 description 3
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000000935 solvent evaporation Methods 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 229940095064 tartrate Drugs 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 2
- NUFKRGBSZPCGQB-FLBSXDLDSA-N (3s)-3-amino-4-oxo-4-[[(2r)-1-oxo-1-[(2,2,4,4-tetramethylthietan-3-yl)amino]propan-2-yl]amino]butanoic acid;pentahydrate Chemical compound O.O.O.O.O.OC(=O)C[C@H](N)C(=O)N[C@H](C)C(=O)NC1C(C)(C)SC1(C)C.OC(=O)C[C@H](N)C(=O)N[C@H](C)C(=O)NC1C(C)(C)SC1(C)C NUFKRGBSZPCGQB-FLBSXDLDSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- 239000004377 Alitame Substances 0.000 description 2
- 108010011485 Aspartame Proteins 0.000 description 2
- 206010003830 Automatism Diseases 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010010774 Constipation Diseases 0.000 description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 241000792859 Enema Species 0.000 description 2
- 206010016948 Food interaction 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
- 108010010803 Gelatin Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 208000002720 Malnutrition Diseases 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 208000005392 Spasm Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 235000019409 alitame Nutrition 0.000 description 2
- 108010009985 alitame Proteins 0.000 description 2
- 230000003474 anti-emetic effect Effects 0.000 description 2
- 239000002111 antiemetic agent Substances 0.000 description 2
- 239000008365 aqueous carrier Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000000605 aspartame Substances 0.000 description 2
- 235000010357 aspartame Nutrition 0.000 description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 2
- 229960003438 aspartame Drugs 0.000 description 2
- 235000019658 bitter taste Nutrition 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 229960001380 cimetidine Drugs 0.000 description 2
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 229940095399 enema Drugs 0.000 description 2
- 210000003238 esophagus Anatomy 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 125000000524 functional group Chemical group 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
- 229920000591 gum Polymers 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 229940102223 injectable solution Drugs 0.000 description 2
- 208000003243 intestinal obstruction Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 230000001071 malnutrition Effects 0.000 description 2
- 235000000824 malnutrition Nutrition 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 208000015380 nutritional deficiency disease Diseases 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 238000003307 slaughter Methods 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 150000003892 tartrate salts Chemical class 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 238000009736 wetting Methods 0.000 description 2
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 1
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- YXTDAZMTQFUZHK-ZVGUSBNCSA-L (2r,3r)-2,3-dihydroxybutanedioate;tin(2+) Chemical compound [Sn+2].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O YXTDAZMTQFUZHK-ZVGUSBNCSA-L 0.000 description 1
- VLSDXINSOMDCBK-BQYQJAHWSA-N (E)-1,1'-azobis(N,N-dimethylformamide) Chemical compound CN(C)C(=O)\N=N\C(=O)N(C)C VLSDXINSOMDCBK-BQYQJAHWSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- YOYAIZYFCNQIRF-UHFFFAOYSA-N 2,6-dichlorobenzonitrile Chemical compound ClC1=CC=CC(Cl)=C1C#N YOYAIZYFCNQIRF-UHFFFAOYSA-N 0.000 description 1
- YTFVRYKNXDADBI-UHFFFAOYSA-N 3,4,5-trimethoxycinnamic acid Chemical compound COC1=CC(C=CC(O)=O)=CC(OC)=C1OC YTFVRYKNXDADBI-UHFFFAOYSA-N 0.000 description 1
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 1
- RVEATKYEARPWRE-UHFFFAOYSA-N 4-amino-5-chloro-2-methoxybenzoic acid Chemical compound COC1=CC(N)=C(Cl)C=C1C(O)=O RVEATKYEARPWRE-UHFFFAOYSA-N 0.000 description 1
- QFMZVCBZQAEZSJ-OIKXSMCUSA-N 4-amino-5-chloro-n-[(3s,4r)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-yl]-2-methoxybenzamide;(2r,3r)-2,3-dihydroxybutanedioic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C([C@@H]([C@@H](CC1)NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)OC)N1CCCOC1=CC=C(F)C=C1 QFMZVCBZQAEZSJ-OIKXSMCUSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 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
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 244000144725 Amygdalus communis Species 0.000 description 1
- 235000011437 Amygdalus communis Nutrition 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 208000031295 Animal disease Diseases 0.000 description 1
- 208000000103 Anorexia Nervosa Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- MCRNHLQVPJEMSQ-UHFFFAOYSA-N C(C=CC(=O)O)(=O)O.C(CCCCCCCCCCCCCCCCC)[Na] Chemical compound C(C=CC(=O)O)(=O)O.C(CCCCCCCCCCCCCCCCC)[Na] MCRNHLQVPJEMSQ-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 229920000742 Cotton Polymers 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
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 201000003066 Diffuse Scleroderma Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 235000016623 Fragaria vesca Nutrition 0.000 description 1
- 240000009088 Fragaria x ananassa Species 0.000 description 1
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 240000004859 Gamochaeta purpurea Species 0.000 description 1
- 208000012895 Gastric disease Diseases 0.000 description 1
- 206010019909 Hernia Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- AYRXSINWFIIFAE-SCLMCMATSA-N Isomaltose Natural products OC[C@H]1O[C@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)[C@@H](O)[C@@H](O)[C@@H]1O AYRXSINWFIIFAE-SCLMCMATSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 108050004114 Monellin Proteins 0.000 description 1
- 206010028347 Muscle twitching Diseases 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- KBGUMYCIYYYBDY-UHFFFAOYSA-N O.C(CCC)(C(=O)O)C(=O)O Chemical compound O.C(CCC)(C(=O)O)C(=O)O KBGUMYCIYYYBDY-UHFFFAOYSA-N 0.000 description 1
- 206010030216 Oesophagitis Diseases 0.000 description 1
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 description 1
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241001290151 Prunus avium subsp. avium Species 0.000 description 1
- 235000001466 Ribes nigrum Nutrition 0.000 description 1
- 241001312569 Ribes nigrum Species 0.000 description 1
- 244000178231 Rosmarinus officinalis Species 0.000 description 1
- SMTZFNFIKUPEJC-UHFFFAOYSA-N Roxane Chemical compound CC(=O)OCC(=O)NCCCOC1=CC=CC(CN2CCCCC2)=C1 SMTZFNFIKUPEJC-UHFFFAOYSA-N 0.000 description 1
- 235000011034 Rubus glaucus Nutrition 0.000 description 1
- 244000235659 Rubus idaeus Species 0.000 description 1
- 235000009122 Rubus idaeus Nutrition 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 description 1
- 239000004376 Sucralose Substances 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 240000006474 Theobroma bicolor Species 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 235000010358 acesulfame potassium Nutrition 0.000 description 1
- 229960004998 acesulfame potassium Drugs 0.000 description 1
- 239000000619 acesulfame-K Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- WQZGKKKJIJFFOK-PQMKYFCFSA-N alpha-D-mannose Chemical compound OC[C@H]1O[C@H](O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-PQMKYFCFSA-N 0.000 description 1
- SRBFZHDQGSBBOR-LECHCGJUSA-N alpha-D-xylose Chemical compound O[C@@H]1CO[C@H](O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-LECHCGJUSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 229960004977 anhydrous lactose Drugs 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000001458 anti-acid effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 210000001815 ascending colon Anatomy 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 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
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- YYRMJZQKEFZXMX-UHFFFAOYSA-L calcium bis(dihydrogenphosphate) Chemical compound [Ca+2].OP(O)([O-])=O.OP(O)([O-])=O YYRMJZQKEFZXMX-UHFFFAOYSA-L 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 235000013736 caramel Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000035568 catharsis Effects 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 230000000112 colonic effect Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000001595 contractor effect Effects 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 description 1
- IDAGXRIGDWCIET-SDFKWCIISA-L disodium;(2s,3s,4s,5r)-2,3,4,5-tetrahydroxyhexanedioate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O IDAGXRIGDWCIET-SDFKWCIISA-L 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
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000001839 endoscopy Methods 0.000 description 1
- 208000006881 esophagitis Diseases 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 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
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960001596 famotidine Drugs 0.000 description 1
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 206010016766 flatulence Diseases 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 229960004038 fluvoxamine Drugs 0.000 description 1
- CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 description 1
- 230000009246 food effect Effects 0.000 description 1
- 235000021471 food effect Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000030135 gastric motility Effects 0.000 description 1
- 230000007661 gastrointestinal function Effects 0.000 description 1
- 208000018685 gastrointestinal system disease Diseases 0.000 description 1
- 239000007897 gelcap Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 229940056944 golytely Drugs 0.000 description 1
- 238000011597 hartley guinea pig Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000014617 hemorrhoid Diseases 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 235000012907 honey Nutrition 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000000077 insect repellent Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- DLRVVLDZNNYCBX-RTPHMHGBSA-N isomaltose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)C(O)O1 DLRVVLDZNNYCBX-RTPHMHGBSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- JCQLYHFGKNRPGE-FCVZTGTOSA-N lactulose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 JCQLYHFGKNRPGE-FCVZTGTOSA-N 0.000 description 1
- 229960000511 lactulose Drugs 0.000 description 1
- PFCRQPBOOFTZGQ-UHFFFAOYSA-N lactulose keto form Natural products OCC(=O)C(O)C(C(O)CO)OC1OC(CO)C(O)C(O)C1O PFCRQPBOOFTZGQ-UHFFFAOYSA-N 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
- 229940125722 laxative agent Drugs 0.000 description 1
- 239000012633 leachable Substances 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 239000002932 luster Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000009115 maintenance therapy Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 229910000150 monocalcium phosphate Inorganic materials 0.000 description 1
- 235000019691 monocalcium phosphate Nutrition 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003249 myenteric plexus Anatomy 0.000 description 1
- 230000003274 myotonic effect Effects 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 1
- 229960004127 naloxone Drugs 0.000 description 1
- 235000019462 natural additive Nutrition 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- SGXXNSQHWDMGGP-IZZDOVSWSA-N nizatidine Chemical compound [O-][N+](=O)\C=C(/NC)NCCSCC1=CSC(CN(C)C)=N1 SGXXNSQHWDMGGP-IZZDOVSWSA-N 0.000 description 1
- 229960004872 nizatidine Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- OMLDMGPCWMBPAN-YPMHNXCESA-N norcisapride Chemical compound CO[C@H]1CNCC[C@H]1NC(=O)C1=CC(Cl)=C(N)C=C1OC OMLDMGPCWMBPAN-YPMHNXCESA-N 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 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
- 239000002674 ointment Substances 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 229940127240 opiate Drugs 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229960005019 pantoprazole Drugs 0.000 description 1
- 229960002296 paroxetine Drugs 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000000247 postprecipitation Methods 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940107700 pyruvic acid Drugs 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
- 229960004157 rabeprazole Drugs 0.000 description 1
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 1
- 229960000620 ranitidine Drugs 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 235000015639 rosmarinus officinalis Nutrition 0.000 description 1
- 229960003320 roxatidine Drugs 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000000387 serotonin 5-HT4 receptor agonist Substances 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229940083037 simethicone Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229940013618 stevioside Drugs 0.000 description 1
- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 description 1
- 235000019202 steviosides Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 235000019640 taste Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 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
- 238000001291 vacuum drying Methods 0.000 description 1
- 210000001186 vagus nerve Anatomy 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 235000019220 whole milk chocolate Nutrition 0.000 description 1
- 229960003487 xylose Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/10—Laxatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Child & Adolescent Psychology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Rheumatology (AREA)
- Nutrition Science (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Electrochromic Elements, Electrophoresis, Or Variable Reflection Or Absorption Elements (AREA)
- Preparing Plates And Mask In Photomechanical Process (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明相关于(+)-诺西沙必利(norcisapride)，及其药学上可接受的酸加成盐类、其制法、及其用于制备供治疗胃肠疾病但避免中枢神经系统影响的医药品的用途。本发明也提供一种治疗胃肠疾病的方法。
Description
本发明相关于(+)-诺西沙必利(norcisapride)，及其药学上可接受的酸加成盐类、其制法、及其用于制备供治疗胃肠疾病但不影响中枢神经系统的医药品的用途。
西沙必利是已广泛被使用于调整胃动力学上的商品，其商品名为“PrepulsidTM”，目前其主要用途为供治疗胃-食道的反流疾病，此疾病的特点是胃中的内容物会回流至食道。其他发病因子则是因延迟的胃排空、食道蠕动不全而无法净空，也由于回流物质使食道粘膜受伤所致。
由于其活性而被做为前动力学的(prokinctic)试剂，西沙必利(cisapride)也有用于供治疗消化不良、胃轻瘫、便秘、手术后肠隔、及假性肠阻塞。
西沙必利的代谢主要是通过P 450 3A4酶细胞色素，经口服的西沙必利于全面代谢后，尿液及粪便中回收得的未经改变的西沙必利，其回收率少于10％，而在胞浆、粪便与尿液中发现的主要代谢物，依Meuldermans W.等人发表于Drug Metab.Dispos.16(3)：410-419，1988中的报告，称之为“诺西沙必利”，是其两种镜相物的消旋混合物。
1983年4月13日发表的EP-A-0,076,530中揭示过消旋性诺西沙必利，其经编为化合物211，据称其对胃肠有刺激特性。
“(+)-诺西沙必利”是光学立体异构体。其化学全名是(+)-4-氨基-5-氯-N-(3-甲氧基-4-哌啶基)-2-甲氧基苯甲酰胺，以后称为(+)-诺西沙必利。(+)-诺西沙必利一词，特别是“光学上纯态(+)-诺西沙必利”，意指实质上不含其(-)-立体异构物的(+)-立体异构物。
WO 96/40133中教示，可使用(-)-诺西沙必利以治疗消化道疾病，特别是用于治疗胃-食道的反流疾病，同时能实质减少因施用消旋性西沙必利伴随的不利反应。此文件尚提及，光学纯态的(-)-诺西沙必利将是种有效的止吐剂，在癌症治疗上，可有效减轻因化学疗法或放射线疗法所引起的恶心及呕吐。
已发现，(+)-诺西沙必利，特别是“光学纯态(+)-诺西沙必利”，亦即实质不含其(-)-立体异构物者，同时具有5-HT3拮抗性与5-HT4催动性，且进一步实质上避免了对中枢神经系统的影响。
本发明相关于(+)-诺西沙必利，特别是不带有其(-)-立体异构物的(+)-诺西沙必利，其药学上可接受的酸加成盐，及其用于治疗5-HT3和/或5-HT4媒介的疾病，能避免中枢神经系统影响的用途。
(+)-诺西沙必利的化学结构式可以下式代表：
(+)-顺
上述(+)-诺西沙必利的结构式中，连结NH-CO与OCH基至哌啶环的键是以粗线表示，代表此两基团是呈顺式结构。
(+)-诺西沙必利，特别是所称“光学纯态(+)-诺西沙必利”，是包括实质不含其(-)-立体异构物的(+)立体异构物。而“实质不含其(-)-立体异构物”一词是指此诺西沙必利的立体异构物混合物中含有至少90％重量计的(+)-诺西沙必利与10％或更少的(-)-诺西沙必利。在更优选的实施方案中，此“实质不含(-)-立体异构物”意指此诺西沙必利的立体异构物混合物含有至少98％重量计的(+)-诺西沙必利，与2％或更少的(-)-诺西沙必利。在最优选的实施方案中，“实质不含(-)-立体异构物”意指混合物中含有超过99％重量计的(+)-诺西沙必利。这些百分比是以总立体混合物的量为计算依据。
能将平面偏光旋转的化合物，称之为具有光学活性。在描述具有光学活性的化合物时，字头D与L，或R与S是用以表示其分子相对于不对称中心的绝对结构，字头d与l，或(+)与(-)是用以代表此化合物对平面偏光的旋转性，(-)及l代表此化合物是左旋性的，(+)与d则是代表其为右旋性的。就所给化学结构，这些化合物，称之为立体异构物，除了互为镜相对称外，彼此完全相同。对特定的立体异构物也可归之为对映体，这类异构体的混合物常被称之为消旋异构物混合物。
就所给对映体，其旋光度α并非一个常数，要视样品被装载的管长、温度、溶剂及溶液浓度与光的波长而定。故，比旋光度〔α〕被定义，以便能有一个独立于管长和溶液浓度的参数。比旋光度〔α〕＝α/lc，其中的α为观测得的旋光度，l为管长(单位为分米)，c为浓度(单位为克/毫升)。比旋光度通常与温度及波长一起记录成[α]D 20，其中的20代表摄氏温度，D代表利用钠D光照射(波长为589nm)测得的旋光度。
(+)-诺西沙必利的L-酒石酸盐，即(+)-(3S，4R)-顺式-4-氨基-5-氯-2-甲氧基-N-(3-甲氧基-4-哌啶基)苯甲酰胺〔R-(R*，R*)〕-2，3-二羟基丁烷二羧酸盐单水合物，利用X-射线分析结果显示，其绝对结构为(3S，4R)的(+)-诺西沙必利。故，(+)-诺西沙必利具有如下的绝对立体化学结构式：
(3S，4R)-顺式-4-氨基-5-氯-2-甲氧基-N-(3-甲氧基-4-哌啶基)苯甲酰胺
上述的药学上可接受的酸加成盐类系指包括(+)-诺西沙必利碱能形成的，具有治疗活性的无毒酸加成盐类。使用适当的酸可将(+)-诺西沙必利碱转变成其药学上可接受的酸加成盐类，适当的酸有，例如有机酸类，例如氢卤酸类，例如盐酸或氢溴酸；硫酸；硝酸；磷酸等酸类；或有机酸类，例如，醋酸、丙酸、羟基乙酸、乳酸、丙酮酸、草酸、丙二酸、琥珀酸(即丁二酸)、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、环己烷胺磺酸、水杨酸、对氨基水杨酸、棕榈酸等酸类。
反之，所述的酸加成盐类可经适当的碱处理转变成游离态(+)-诺西沙必利碱。
此处所指酸加成盐类也包括(+)-诺西沙必利及其盐类所能形成的溶剂化物。这类溶剂化物有如水合物、醇化物等。
此后，凡提到(+)-诺西沙必利，意指也包括其药学上可接受的酸加成盐类及其溶剂化物。
(+)-诺西沙必利碱的制法如下面式1所示
式1
顺-(II) 顺-(IV)
→(+)-诺西沙必利(I)
顺式-(II)的中间物，与顺式-(IV)的反应产品，其哌啶环上的氨基与甲氧基取代基具有顺式-构型，即，其甲氧基与氨基是位于由哌啶环为主平面的同一边，且为含二种对映体的消旋混合物。为显示此种结构，式1中是以粗线示出连接这些官能基的键。依式1，是将顺式-(II)的中间物，其PG是适当的保护基，例如甲氧羰基、乙氧羰基、叔丁氧羰基、苯甲基等，与式(III)的羧酸或其具有反应性的官能基衍生物反应，生成酰胺，制得具有顺式-(IV)化学式的中间物。顺式-(II)与(III)的中间物在脱水剂(例如二环己基碳化二亚胺)存在下反应，或顺式-(II)的中间物与具有反应性的羧酸(III)衍生物(例如其酸氯化物或混合的酸酐类)反应。此反应可在惰性溶剂(例如二氯甲烷或氯仿)中，且选择地含适当的碱，例如碳酸钠、碳酸钾或三乙基胺存在下进行。予以搅拌可加速反应速率，可方便地于介于室温及反应混合物的回流温度下反应，接着，分出顺式-(IV)的中间物的对映体，并将分离出的各顺式-(IV)中间物对映体经除去保护基PG而转变成其相关的诺西沙必利对映体，视PG的性质而进行酸性或碱性溶剂分解反应，或通过催化氢化反应，例如，使用如氢氧化钾的无机碱，于水溶液中进行。或是，将顺式-(IV)中间物的保护基PG移除，形成消旋性诺西沙必利的混合物，接着再进行分出其对映体的步骤。
式1中制得的顺式-(IV)中间物是对映体的混合物，其可依文献已知的解析法将其彼此分开。顺式-(IV)中间物的对映体混合物可借与适当的不对称酸作用而将其转变成其相关的非对映立体异构物盐，接着分开此非对映立体异构物盐，例如进行选择性或分级结晶法分出，并利用碱类将对映体释出。另种分开顺式-(IV)对映体的方法为，使用适当的不对称固定相，进行液相层析，适当的不对称固定相为，例如，多糖类，特别是纤维素或直链淀粉衍生物。市售属于多糖类的不对称固定相有ChiralCelTM CA，OA，OB，OC，OD，OF，OG，OJ与OK，以及ChiralpakTM AD，AS，OP(+)与OT(+)。配合此多糖类不对称固定相使用的适当的冲洗剂或移动相为己烷等，可加入醇类，例如乙醇，异丙醇等进行改性。
顺式-(IV)中间物的纯态对映体亦可由相当的对映体纯态起始材料衍生，只要其间的反应具有立体专一性，如想特制某种立体异构物，此化合物优选依立体专一性的方法合成。这些方法宜使用对映体纯态起始材料进行。
本发明也提供具有式(V)的新颖中间物。式(V)的中间物是顺式-(IV)的中间物，其哌啶环具有绝对的(3S，4R)构型且PG是一种适当的保护基，例如甲氧羰基、乙氧羰基、叔丁氧羰基、苯甲基等等。
起始化合物及部分的中间物是已知化合物，通常可自市面购得或可借文献已知的反应方法制得，例如：顺式-(II)的中间物(即，顺式-4-氨基-3-甲氧基-1-哌啶羧酸乙基酯，在EP-0,076,530中记作为中间物54)，及顺式-(IV)的中间物(即，顺式-4-(4-氨基-5-氨-2-甲氧基苯甲酰基氨基)-3-甲氧基-1-哌啶羧酸乙酯，在EP-0,076,530中记作化合物168)。此外，中间物(III)(即，4-氨基-5-氯-2-甲氧基苯甲酸)，均可购得。
由于(+)-诺西沙必利具有5-HT3-拮抗活性，故在治疗与过度刺激5-HT3-受体活性有关的疾病上相当有用，受5-HT3-介导的疾病为，例如呕吐，例如细胞毒药物及辐射引起的呕吐(Drugs 42(4)，551-568(1991))，肠应激综合征，尤其是腹泻性肠应激综合征与相关症状。因此，本发明提供一种治疗温血动物因过度刺激5-HT3-受体活性所引发或通常是由5-HT3-介导的疾病(例如呕吐)的方法，例如细胞毒药物及辐射引起的呕吐、肠应激综合征，特别是腹泻性肠应激综合征与相关症状。此方法包括对温血动物投用具有疗效量的(+)-诺西沙必利，或其药学上可接受的酸加成盐。
或者，(+)-诺西沙必利，及其药学上可接受的酸加成盐类用于制作医药品，用于治疗因过度刺激5-HT3-受体活性所引发或通常是由5-HT3-介导的疾病或症状，例如呕吐，例如细胞毒药物及辐射引起的呕吐、肠应激综合征，特别是腹泻性肠应激综合征与相关症状。
明确地说，(+)-诺西沙必利是一种有效的止吐剂，可用于辅助治疗，缓解在癌症治疗上因使用化学疗法或照射所引起的噁心及呕吐现象。
(+)-诺西沙必利也具有5-HT4-兴奋剂的特性，因此，本发明也提供一种方法用于治疗温血动物，包括人类，因5-HT4-受体活性刺激不足所引起的疾病，更通常的说法为，提供一种治疗5-HT4-介导的疾病或症状的方法，这种症状的例子为，有如胃排空发生紊乱或不全，或更常见的例子为胃肠道的移转发生紊乱或不全。因此，提供了此种方法用于缓和温血动物的这类病况，例如胃-食道的反流(包括食道炎的治疗及维持性疗法)、消化不良、及胃轻瘫。此方法包括对温血动物投用有疗效量的(+)-诺西沙必利，或其药学上可接受的酸加成盐。
胃轻瘫的发生可能因胃的不正常或因某些疾病所导致的并发症，例如糖尿病、进行性全身硬化症、神经性厌食症、迷走神经或部分胃切除术之后、及肌强直性的营养不良。消化不良是消化功能不全所致，可因胃肠功能不正常所起，特别是因肌肉紧张度或因其他疾病(例如阑尾炎，膀胱炎，或营养不良)所造成，因此(+)-诺西沙必利可被用于消除实际发病的原因或缓和其所引起的征状。消化不良的病征也可能是因摄入化学物质所起，例如选择性血清素再利用抑制剂(SSRI’s)，例如富克辛(fluoxetine)、巴洛克心(paroxetine)、富沃胺(fluvoxamine)、色特林(sertraline)等。其他可被治疗的症状包括术后肠隔(其是因手术后肠道的肌肉紧张度被打断而造成阻碍或自动力不足所致)、上消化道的X-射线或内视镜检查后的病征、婴儿方面疾病、慢性及过度的反胃或呕吐、因自动性官能障碍而使胃肠蠕动性不全及内容物停滞的假性肠阻塞、因肠的紧张度不足或肠痉挛产生的便秘，特别是于长期治疗慢性秘结后结肠自动能力的复元。
因此，提供的用途包括使用(+)-诺西沙必利做为一种医药品，用于治疗因5-HT4-受体活性的刺激不足所引起的疾病或状态；也提供使用(+)-诺西沙必利制备一种医药品的用途，是用于治疗由5-HT4-介导的疾病，例如胃-食道的反流、消化不良或胃轻瘫，对预防及治疗均涉及。
从另一观点，也可使用(+)-诺西沙必利制备一种医药品，供治疗饮食上疾病，例如厌食症。因此，本发明也提供一种治疗温血动物在饮食上疾病(例如厌食症)的方法，包括对所述温血动物投用具有疗效量的(+)-诺西沙必利。
因此，本发明也提供一种方法供治疗温血动物的胃肠疾病，其是因5-HT4-受体活性的刺激不足以及因5-HT3-受体活性的过度刺激所引起，包括对所述温血动物投用具有疗效量的(+)-诺西沙必利。因此，本发明包括使用(+)-诺西沙必利制备医药品供治疗同时有5-HT4-受体活性的刺激不足以及5-HT3-受体活性的过度刺激所引起的胃肠道疾病。
此外，(+)-诺西沙必利对渗透压试剂有种协同效果以达到灌肠效果，即，引发腹泻。因此，本发明也相关于使用(+)-诺西沙必利供制备一种医药品，其能改善原是借轻泻剂，特别是渗透性试剂进行的肠道清净工作。因此，本发明提供一种将具有疗效的(+)-诺西沙必利配合轻泻剂的治疗法。另外，也提供一种加速和/或加强轻泻剂(尤其是渗透性试剂)的作用的方法。
需接受此种处置的病人是于进行诊断或外科手术之前需将肠道清净的。另种有需要的病人则是为预防发生便时用力，包括发生患疝或心血管疾病者。此外，配合本发明的混合使用，包括手术前后，对患有痔疮及其他肛门与直肠疾病者，均能维持软便状态。
导泻剂量的渗透性试剂常在欲做胃肠道、肾脏，或其他腹部或腹膜内结构的照射检视以及选择性肠外科手术之前使用。故对这类应用，(中)-诺西沙必利与轻泻剂的混合使用法颇为有用。
另外，混合(+)-诺西沙必利与轻泻剂的用法，也可应用在供治疗药物的过量使用与中毒上，利用其将肠道内的试剂除掉。这样的混合物尚可与某些驱虫药混合使用。
轻泻剂是一种可帮助通便的药物。许多轻泻剂的正确作用机制仍未明，乃因有复杂的因素影响结肠的功能，在此领域，实验的种类与制剂，及某种研究的秘结性间，水与电解质的移动为主要变因。轻泻剂作用的三种一般机制可予描述成：(1)借其亲水特性或渗透特性，轻泻剂可让液体停留在结肠内容物内，因而增加体积与软度及使移动容易。(2)轻泻剂可直接或间接作用于结肠粘膜以减少水与氯化钠的净吸收。(3)轻泻剂可增加肠子的自动性，造成盐与水的减少吸收以减少移转时间。大致上，轻泻剂可被区分成三大类，即，1)食用纤维与形成大体积的物质的轻泻剂，2)盐水及渗透性轻泻剂类，与3)刺激物质轻泻剂。(参考Goodman and Gilman，第七版，994-1003页)。
本发明中使用的主要轻泻剂是盐水与渗透性轻泻剂。盐水与渗透性轻泻剂包括各种镁盐；钠与钾的硫酸盐，磷酸盐与酒石酸盐类；乳果糖；甘油；与山梨糖醇。它们被少量缓慢地吸收，借其渗透特性在内腔流体中作用。属于这类渗透性试剂，可购自市面供清理肠道的两例为：KleanPrep与GoLytely。KleanPrep溶液含有聚乙二醇3350(59克/升)、硫酸钠(5.685克/升)、碳酸氢钠(1.685克/升)、氯化钠(1.465克/升)、氯化钾(0.7425克/升)，阿斯巴甜(0.0494克/升)与香草精(0.3291克/升)。
另外，(+)-诺西沙必利及其药学上可接受的盐类实质上不影响中枢神经系统，特别是不存在中枢的多巴胺拮抗剂与中枢的血清素拮抗剂活性。
已发现，(+)-诺西沙必利的代谢路径与西沙必利的代谢路径不同。后者显然主要是通过细胞色素p450系统。某些用于抑制西沙必利的主要代谢途径的治疗试剂可能会使血液中的西沙必利值升至过高而引起副作用。因此不可将这类治疗剂与西沙必利混合制药，但(+)-诺西沙必利则无此情况。
本发明也相关于含有(+)-诺西沙必利的(L)-酒石酸盐或(D)-酒石酸盐的口服剂量型药剂，此盐类型态宜为其溶解性较不受pH影响，但药物的吸收及生化可利用性则受pH影响而有不同溶解度，当通过口服时，会受存在于胃肠道(GI)，特别是胃中食物的影响。药物在胃中的残留时间显然会因有食物存在而呆得更久，即，食物的存在会延长药物在相对为酸性状态的胃中停留时间。如果药物的生物可利用性会因存在于胃肠道的食物影响达某一量时，此药物被认为具有“食勿效果”或具有药物-食物交互作用影响，为使药物达足够的生物可利用性，常需于特定的状态下服食(例如饭前)，服用西沙必利即为一例。含前述酒石酸盐类的口服制剂，其(+)-诺西沙必利的生物可利用性有不受食物影响的好处。这类药剂因此极具吸引力，乃因患者无需严格要求服药的最适当时刻，以免有不同的结果，有时则效果不足，特别是小儿科用药的情况，这样的剂量型可有随时(指视病况)投药的额外好处。此外，因其不受pH影响，这类口服药剂可与会改变胃的酸碱度(例如增加胃的pH)的药剂一同服用。这类可并用的药剂包括，例如抗酸剂类，例如含铝的抗酸剂类，如Al(OH)3；含钙的抗酸剂类，如CaCO3；或含镁的抗酸剂类，如Mg(OH)2；H2-拮抗剂类，如甲腈咪胺(cimetidine)、雷尼丁(ranitidine)、费莫提丁(famotidine)’尼查丁(nizatidine)、螺塞丁(roxatidine)等；质子诱出抑制剂类，例如欧莫比唑(omeprazole)、兰索普唑(lansoprazole)、蜡比普唑(rabeprazole)、贝多普唑(pantoprazole)等。因此提供的剂量型，宜为供口服用的固态剂型，含有(+)-诺西沙必利酒石酸盐与任何这类抗酸剂者，可被做成供同时使用的混合制剂、分别使用或接续使用的剂型。
因此，另一方面，本发明相关于一种医药制剂，特别是固态型式，宜为口服用，适于迅速溶出，含(+)-诺西沙必利的L-或D-酒石酸盐为活性成分与适当的载体。“适于迅速溶出”一词，意指此活性成分在pH为1-7的范围间，一小时内自药剂型式可溶出超过60％的剂量。溶出作用可依欧洲药典或USP-2溶出装置中的USP试验法<711>(美国药典XXII，pp 1578-1579中所载)所述标准方法测定。为达到迅速溶出，应选用能让片剂足够迅速分散的赋形剂，这类赋形剂宜能在少于约30分钟、甚或少于20分钟、15分钟，更佳地在少于约3或1.5分钟即能崩散。另一方面，本发明相关于一种不必考虑到药物-食物间的交互作用而治疗患胃肠道疾病者的方法，包括施用含(+)-诺西沙必利(D)-或(L)-酒石酸盐，或者对已服用他种会增加胃的酸碱度的药剂的患者治疗胃肠疾病，或在制备不受药物-食品交互作用影响的医药品供治疗这类胃肠病中的用途。
本发明的配制剂可选择地含有防胃肠胀气剂，例如喜美斯康(simethicone)，α-D-半乳糖甙等。
为制备本发明的医药品组合物，将有效量的此种化合物，呈碱态或酸加成盐态者，做为活性成分，与药学上可接受的载体充分混合，后者可视欲投药的剂型而选用多种适当的载体，这些药学上制剂宜被做成单一的剂量型，供口服、经直肠或非经胃肠注射施用，例如，制备口服用制剂时，可使用任何常用的药学介质，例如可采用水、甘醇类、油质类、醇类等，制备悬浮剂、浓浆剂、酏剂与溶液类的口服制剂；使用淀粉类、糖类、高岭土、润滑剂、粘结剂、崩散剂等制备粉剂、丸剂、胶囊剂与片剂等。以使用方便性而言，片剂与胶囊剂为最适当的口服剂型，显然，此时可配合使用药学上的固态载体制备。欲制备胃肠外使用的组合物时，可使用的载体为灭菌水(至少占大部分)，也可包括其他成分，例如助溶剂。制备可注射溶液可以使用的载体为，例如盐水、葡萄糖溶液或盐与葡萄糖的混合溶液。可注射的悬浮剂可使用适当的液体载体、悬浮剂等制备。制备适于经皮下注射施用的组合物时，可选择地在载体中包括使用助穿透试剂和/或适当的润湿剂，也可选择地配合少量适当的，不会对皮肤造成伤害的任何天然添加剂。这类添加剂可帮助对皮肤施用和/或帮助所要组合物的制备。这类组合物的施用途径有各种方式，例如经皮贴片、涂抹上去、做成油膏。由于式(I)化合物的酸加成盐类较其相对的碱态物更能溶解在水中，因此显然在制备含水的组合物时较适合。
尤其适宜的方式是将上述医药组合物做成易于供施用及均匀剂量的药剂单位型式。说明书及权利要求中所称的药剂单位型式意指适于单独服用的分立态单位，各单位中含有预计能达疗效的活性成分量及所要的药学上载体。这种剂量型式为片剂(包括药心或包衣片)、胶囊剂、丸剂、粉剂包、扁片、可注射的溶液或悬浮剂、茶匙量、汤匙量等，以及其分隔的多重包装。
供口服投药时，此医药品组合物可被做成固态剂量型式，例如片剂(仅供吞服及可咀嚼的剂型)、胶囊剂、利用传统方法配合药学上可接受的赋形剂(例如粘结剂、填料或稀释剂、润滑剂、崩散剂、可湿剂(如十二烷基硫酸钠))及其他赋形剂(例如着色剂与色料)制备的gelcaps。这些片剂可依文献所载方法将之包层。
粘结剂可能为阿拉伯胶、藻酸、羧甲基纤维素(钠)、纤维素(微晶纤维素)、糊精、乙基纤维素、动物胶、葡萄糖(液态)、古阿胶、羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素、聚氧化乙烯、聚乙烯吡咯烷酮(povidorne)、或淀粉(预糊化过)、羟丙基甲基纤维素类，特别是低粘性的羟丙基甲基纤维素类。
填料或稀释剂的例子为经喷雾干燥的或无水的乳糖、蔗糖、葡萄糖、甘露糖、山梨糖醇、淀粉、纤维素(例如微晶纤维素；AvicelTM)、经水合的或无水的磷酸二氢钙、及其他文献已知者，或它们的混合物，例如可使用乳糖与微晶纤维素的混合物，乳糖可被当作纯稀释剂使用，而微晶纤维素是一种填料；可令片剂产生适当的硬度，且因纤维素与水接触后会膨胀而具有崩散剂的特性。较佳的乳糖是乳糖单水合物DC，特别是经喷雾干燥的乳糖单水合物(Pharmatose DCL 11TM)。填料及稀释剂的量可介于约50％至约95％，或介于约65％至约90％，或介于约66％至约86％，以含约75％(w/w)重量最好(以整个药片或药心量为计算标准)。此75％的混合物可购得，商品名为MICROCELAC，其用量宜占约80％(w/w)至95％(w/w)，相对片芯或整颗药片而计(经涂装薄膜的药片时)。
润滑剂的例子为硬脂酸镁、滑石粉、二氧化硅、硬脂酸、富马酸硬脂基钠、十二烷基硫酸镁、氢化植物油及其他文献所述者。润滑剂的量通常约占片剂总重量或片剂心(以薄膜涂装的片而言)的0.2％(w/w)至7.0％(w/w)。较佳的润滑剂量为使用约0.5％(w/w)至约3.0％(w/w)，更佳的用量为使用约0.9％(w/w)至约1.25％(w/w)的润滑剂。
崩散剂包括淀粉，例如玉米淀粉、预糊化淀粉、淀粉糖酸钠(Explotab)、交联的聚乙烯吡咯烷酮、交联的羧甲基纤维素钠、粘土、微晶纤维素(Avicel)、藻酸盐、胶质物、羟甲基纤维素钠、以及其他文献中已知者。崩散剂的存在量为约2％(w/w)至约15％(w/w)，或为约3％(w/w)至约10％(w/w)。
在此，百分比是依重量对重量表示，代表相对于整个片剂(或仅是包衣的锭剂心)的总重量的成分或赋形剂的百分比。
通常，在制成片之前，片剂混合物是呈干态团粒或润湿态团粒，某些情况下，特别是当使用(D)-或(L)-酒石酸盐类时，或可直接进行压制，可制得具有更好溶解性能。
供口服的制剂可予做成，例如，溶液，浓浆液或悬浮剂，或可被做成干态产品，于服用前再加水或其他适当载体使用。这类液态制剂可用常用方法制备，选择地配合使用药学上可接受的添加剂，例如悬浮剂(例如山梨糖醇浓浆液、甲基纤维素、羟基-丙基甲基纤维素或经氢化的食用油脂)；乳化剂(例如卵磷脂或阿拉伯胶)；非含水的载体(例如杏仁油，油质酯类或乙酸乙酯)；以及防腐剂类(例如甲基或丙基对羟基苯甲酸类或山梨酸)。
药学上可接受的甜味剂包括，宜含有至少一种强甜味剂，例如糖精、糖精钠或钙、阿斯巴甜、艾西斯费钾(acesulfame potassium)、环己胺磺酸钠、阿力甜(alitame)、双氢抑素甜味剂、莫内林(monellin)、司特维塞糖(stevioside)或菜可洛糖(sucralose)(4，1′，6′-三氯-4，1′，6′-三去氧半乳糖蔗糖)，其中又以糖精、糖精钠或钙较佳，选择地配合使用大体积的甜味剂，例如山梨糖醇、甘露糖醇、果糖、蔗糖、麦芽糖、异麦芽糖、葡萄糖、经氢化的葡萄糖浓浆、木糖、焦糖或峰蜜。
具强甜味的甜味剂通常以低浓度使用。例如使用糖精钠时，其用量可能介于0.04％至0.1％(w/v)，相对最后配制剂的总体积而计。在低剂量的配方中使用约0.06％，高剂量的配方中使用约0.08％(w/v)，更佳。增大体积的甜味剂其使用量介于约10％至约35％，优选介于约10％至15％(w/v)。
选择地，组合物中亦可添加入矫味用香料，例如，用于矫饰苦味而使用者。低剂量的配方中可用来矫饰苦味的成分，宜使用水果香味，例如樱桃、覆盆子、黑醋栗或草莓香味。使用两种香味混合物也可产生极好的结果。高剂量的配方中可能需使用较强烈的矫味剂，例如牛奶巧克力香味、薄荷、迷迭香等药学上可接受的强烈香味。各种香味剂在最后组合物中的浓度可介于0.05％至1％(w/v)。混合使用这类强烈香味剂也甚有利。使用的香味剂优选在制剂的酸性状态下也不会发生任何改变或减少味道及色泽者。
本发明的化合物也可被配制成贮存制剂。这类长时间作用的配方可经植入法施用(例如经皮或经肌肉)或通过肌肉注射。故，例如，使用适当的聚合性或疏水性材料(例如在可接受的油质中的乳剂)或离子交换树脂配制本化合物，或予做成微溶的衍生物，例如制成微溶性盐。
本发明的化合物可予配成供非经胃肠施用的配制剂，通过注射、经静脉、经肌肉或经皮下注射而施用，例如经大丸药(bolus)注射或连续式经静脉灌注。供注射用配方可呈单位剂量型，例如，制成安瓿剂或置于多重容器内，配合添加防腐剂。组合物的型式可为悬浮剂、溶液或分配于油质或含水载体中的乳化液、且另可含有配方试剂，例如调节渗透压的、悬浮用的、稳定用的和/或分散用的试剂。或者，此活性成分可被做成粉状，使用前再配合适当载体，例如灭过菌无热原的水。
本发明的化合物也可予以配成供直肠使用的组合物，例如栓药或灌肠剂，例如含传统栓药基质(例如可可脂或其他甘油脂)的制品。
经鼻使用的本发明化合物配方可以是液态喷剂，粉剂或滴剂。
通常，为达到治疗效果，相对每千克体重，建议使用约0.001至约2毫克，更佳为自约0.02至约0.5毫克的量。适当的固态口服制剂，其单位剂量相当于包含约0.1至100毫克的活性成分，特别是约1至约50毫克至约20毫克。治疗的方法也可能包括在一天当中，分多次，例如2-4次，对患者施用活性成分。
下述实例是用于对本发明再做详细说明，非指本发明仅限于此。
实验部分
后面提到的“ACN”意指乙腈，“CH3OH”意指甲醇，而“DIPE”是指二异丙基醚。
本发明的部分化合物，未进行其绝对立体结构测定。是将先行分离得的立体异构物标示成“B”，再次分离得的标示成“A”，不代表其真正的立体构型。
其旋光度(OR)，或其比旋光度[α]D 20，是使用Perkin Elmer 241型的观测仪测得的。在20℃，钠光线(波长为589nm)下，装在长度为100毫米的观测管中测其〔α〕。化合物是溶解于甲醇里，浓度为1％(w/v)。Chiralpak AD(直链淀粉3，5-二甲基苯基氨基甲酸酯)是一种不对称固定相柱层材料，购自日本的Daicel ChemicalIndustries，Ltd。
A.(+)-诺西沙必利的合成
实例A.1
利用不对称柱层层析法，使用Chiralpak AD(2千克；柱层内径(ID)为110毫米，洗脱剂为正己烷/乙醇70/30；注入量：5克/升，流速：400毫升/分，检测：UV 254nm波长)，将顺式-4-(4-氨基-5-氯-2-甲氧基苯甲酰基氨基)-3-甲氧基-1-哌啶羧酸乙基酯(0.12摩尔，46克)(EP-0,076,303编号为168的化合物)分离成其对映异构物。收集所要的两组分，蒸发除去其溶剂。将首次流出的对映体溶解在甲醇中，经dicalite过滤，将溶剂蒸发。残存物悬浮至DIPE内，再冷却至0℃，滤下所得沉淀，干燥(40℃，真空)，制得18克的(-)-顺式-4-(4-氨基-5-氯-2-甲氧基苯甲酰基氨基)-3-甲氧基-1-哌啶羧酸乙基酯(对映体1；OR(-)；熔点：164℃)；[α]D 20＝-55.88°(c＝1％w/v，甲醇中)(中间物1)。此中间物的光学纯度超过99％。
将其次流洗出的对映体的残存物溶于甲醇，经dicalite过滤后，蒸发除去溶剂。将残存物分散至DIPE内，再冷却至0℃，滤下所得沉淀，干燥之(40℃，真空)，制得17.6克的(+)-顺式-4-(4-氨基-5-氯-2-甲氧基苯甲酰基氨基)-3-甲氧基-1-哌啶羧酸乙基酯(对映体2；OR(+)；熔点：164℃)；[α]D 20＝+55.10°(c＝1％w/v，甲醇中)(中间物2)。此中间物的光学纯度超过98％。
实例A.2
将中间物(2)(0.042摩尔，16克)与氢氧化钾(23克)的混合物共置于2-丙醇(230毫升)中，搅拌并予廻流6小时。将反应混合物冷却后，蒸发除去溶剂。加水。溶剂蒸发除去后将残存物悬浮于水中，过滤，将固体溶解于二氯甲烷。有机层经水洗，干燥，过滤，浓缩。令残存物自ACN结晶。将沉淀过滤出，经真空干燥后，得到组分1(57％；熔点：188℃)。此组分再放入ACN进行再结晶，滤出沉淀并予干燥，得到组分2(5.3克)。收集全部结晶后滤液，蒸发除去溶剂。残存物与组分2，经硅胶柱层纯化(洗脱剂为：CH2Cl2/(CH3OH/NH3)90/10)。收集纯态组分，除去溶剂，将固态残存物干燥，得5.6克的(+)-顺式-4-氨基-5-氯-2-甲氧基-N-(3-甲氧基-4-哌啶基)苯甲酰胺(此即为(+)-诺西沙必利)；[α]D 20＝+5.60°(c＝1％w/v，甲醇中)(化合物1)
实例A.3
将中间物(1)(0.044摩尔，17克)与氢氧化钾(24克)的混合物共置于2-丙醇(250毫升)中，搅拌并予廻流6小时。将反应混合物冷却后，蒸发除去溶剂。加水。将溶剂蒸发除去后，残存物搅拌入水中，过滤，将固体置于ACN中结晶。滤出沉淀后，使溶解于DCM内。将有机溶液经水洗，干燥，过滤，浓缩除去溶剂。自ACN中进行结晶。滤下沉淀并予干燥后，收得7克(54％)的(-)-顺式-4-氨基-5-氯-2-甲氧基-N-(3-甲氧基-4-哌啶基)苯甲酰胺(此即为(-)-诺西沙必利)；[α]D 20＝-6.09°(c＝50.90毫克/5毫升甲醇)(化合物2)
实例A.4
往搅拌的、溶解于水及甲醇中的(+)-顺式-4-氨基-5-氯-2-甲氧基-N-(3-甲氧基-4-哌啶基)苯甲酰胺(化合物1)中，加入溶解于水及乙醇的〔R(R*，R*)〕-2，3-二羟基丁二酸(L-酒石酸)溶液，然后令产品产生结晶。滤下结晶，干燥后可得(+)-(3S，4R)-顺式-4-氨基-5-氯-2-甲氧基-N-(3-甲氧基-4-哌啶基)苯甲酰胺〔R(R*，R*)〕-2，3-二羟基丁二酸盐单水合物。X-射线衍射测定是使用Siemens P4 four-circle衍射机进行。
B.药学上实例
实例B.1硫酸镁引起的肠灌洗法
以一种小猎犬(Beagle dogs)进行试验，性别不拘，各种体重均有，先经16小时禁食，预先使其服用(+)诺西沙必利或溶剂，一小时后令其于服用硫酸镁(MgSO4·7H2O，64克/升，0.26M；200毫升)，评估因硫酸镁而发作的肠灌洗四小时，以蒸馏水处理的对照组在四小时期间几乎无液态粪便发生(2.5％伪正值；n＝200)，被当做能反映受硫酸镁引起的肠灌洗的有意义加速作用，每种试验的活性物质剂量各施用于五只动物。依Finney的重复试验法(Finney，1962)，全有-或-全无的标准，为大量经溶剂处理的动物所得结果的分布，用来计算ED50-值(有效剂量)及95％置信限度。
如表B.1中的说明，剂量只要由0.032毫克/千克略增加至0.15毫克/千克，即足以在经硫酸镁挑起肠灌洗后一小时达到泻肚子的作用。
表B.1：给狗口服硫酸镁一小时后，(+)诺西沙必利可促进其肠灌洗效果的ED50值(95％置信限度，毫克/千克，经口)，以硫酸镁进行肠灌洗，欲在1-4小时内得到液态粪便的ED50值
| 效果 | ED50值(毫克/千克，经口) |
| 发作于四小时 | 0.032 |
| 发作于三小时 | 0.049 |
| 发作于二小时 | 0.064 |
| 发作于一小时 | 0.15 |
实例B.2以老鼠进行“阿补吗啡、色胺、正肾上腺素(ATN)试验”
本发明化合物不具有中枢的多巴胺拮抗剂及血清素拮抗剂活性这一事实可借对老鼠进行混合的阿朴吗啡(APO)、色胺(TRY)与原肾上腺素(NOR)试验数据证明。此种混合的阿朴吗啡、色胺与原肾上腺素试验法描述于Arch.Int.Pharmacodyn.，227，238-253(1977)，能提供一种经验评估，解释那种药物特别会影响中枢的与周围的神经介质系统，此试验里，观察老鼠受周围的或中枢的活性的影响或反应，中枢的多巴胺拮抗作用借受试老鼠经皮下注入不同剂量的受试化合物及阿朴吗啡(其为一种多巴胺兴奋剂)进行评估。其次，血清素的拮抗作用借同样受试老鼠经皮下注入不同剂量的受试化合物及色胺(其为一种血清素5HT2-受体兴奋剂)进行评估。中枢的与周围的血清素拮抗作用均可在此试验中评估。中枢作用的血清素拮抗剂是具潜力的抗精神病药物，特别是同时显现多巴胺拮抗作用于本试验的第一部分时。最后，本发明化合物的α-肾上腺素激导性的拮抗活性是用相同老鼠，经皮下注入不同剂量的受试化合物及原肾上腺素(其为α-肾上腺素激导性的兴奋剂)进行评估。
实验数据被摘记于表B.2示出其ED50值，毫克/千克体重，代表各受试化合物保护50％的受试动物免于受上述物质唤起的有关联反应的剂量。APO一栏列出阿朴吗啡的影响，代表中枢的多巴胺拮抗活性。TRY痉挛与TRY充血栏列出色胺的影响，分别代表中枢的与周围的血清素拮抗活性。NOR栏列出原肾上腺素的影响，代表α-肾上腺素激导性的兴奋剂活性。(+)-诺西沙必利的受欢迎的药学上特性是其显示不存在中枢的多巴胺(APO栏)与中枢的血清素(TRY痉挛栏)拮抗活性。
表B.2：
| 化合物 | 以老鼠进行混合试验，ED50值(毫克/千克) | |||
| APO | TRY痉挛 | TRY充血 | NOR | |
| (+)-诺西沙必利 | ＞40 | ＞40 | 4.7 | ＞40 |
实例B.3：以天竺鼠廻肠进行的5-羟基犬尿胺拮抗作用
已知5-HT3受体在呕吐上扮演一相当重要的角色。由于5-OH-K(5-羟基犬尿胺，5-hydroxykynuramine)对5-HT3受体有专性兴奋性，乃用其评估5-HT3拮抗效果的潜力。
选用体重为450克左右，公母不拘的天竺鼠，以斩首方式宰杀，取其非末端(除去10cm)，完整的廻肠段，清洗后，4.5cm长，预先加载0.75克一起垂直悬吊置于100毫升浴液里供等渗记录〔(Displacement Transducer Control Unit；Jassen ScientificInstrument Division)，HP7 DGDT-1000(Hewlett-PackardCY)〕。此器官浴是以Tyrode溶液(37.5℃)充填，混有由95％氧气与9％二氧化碳所成混合气体，经20分钟的稳定期间后，加甲基胆汁碱(3.10-6M，接触30秒)至浴液中以评估潜在的最大收缩，其后更新浴液，接着，加入血清素兴奋素5-OH-K(接触30秒)(最后浓度为3.10-6M)，间隔十分钟，每次加入后经30秒即将浴液更新，待达到具有再现性的收缩效果时，于加入5-OH-K之后五分钟，加入一剂量的受试化合物，待建立了受试化合物之对数浓度反应曲线后，利用线性回归分析，计算减少50％受5-OH-K诱发的影响的IC50值。
化合物1〔即：(+)-诺西沙必利〕具有的IC50值为93nM；化合物2〔即：(-)-诺西沙必利〕具有的IC50值为450nM。
实例B.4：“天竺鼠廻肠的同轴刺激作用”
取体重介于600-900克，公母不拘的Dunkin-Hartley天竺鼠，以斩首方式宰杀，取出其廻肠，以温热并加有氧气的Krebs-Henseleit溶液清洗，将廻肠部分(15cm)披在玻璃吸管上，以经Krebs溶液润湿的棉线将肠肌丛的纵向肌肉层除去，将长8cm的长条片折叠并将这些长条片(4cm)架在两白金电极间(8cm长，分开0.5cm)，此长条片与预先加载1.5克共悬吊于100毫升Krebs-Henseleit液中(37.5℃)，打入由95％氧气与5％二氧化碳所成气体，使用单长方形刺激物激发此处理物〔1ms；0.1Hz；次高反应(电流指向最高反应的80％)，自可预定程序的刺激器发出(Jassen Scientific InstrumentDivision)〕。测量其等长收缩(Statham UC2，Jassen ScientificInstruments amplifer，Kipp BD-9 pen-recoder)，于30分钟稳定期间，此长条片被反复拉伸以得到1.5克的稳定状态张力。于开始进行电刺激作用之前，给予乙酰基胆素的累加的浓度反应曲线(3.10-9，10-8，3.10-8与10-7M)，以Krebs溶液将浴液更新并让其再经30分钟的稳定化，接着以0.1Hz频率将长条片做电刺激1ms。测试电压是逐步调升2V(最高为15V)至观察到发展至最大力量，抽搐反应渐减(借减弱电压)至约以最大电压操作下的80％。小心调整电压有可能得到至少两小时期间不会改变的次抽搐反应，当抽搐反应稳定至少15分钟时，将受试化合物加至浴液经30分钟，如果受试化合物引起少于50％的抑制作用时，加入3.10-7M的西沙必利至浴液里，看看受试化合物是否能拮抗西沙必利的刺激效果，如果受试化合物引起多于50％的抑制作用时，则加入10-7M那诺松(naloxone)，看看是否抑制作用是通过鸦片剂受体介导的。于加入西沙必利或那诺松后，会再得到超大的刺激作用，其后，中断电流刺激，得到第二条乙酰基胆素累加浓度-反应曲线，此两种乙酰基胆素累加浓度-反应曲线是为了用来区分效果是来自减少乙酰基胆素的释出还是直接的抗胆素激发的影响，或是区分来自提高的乙酰基胆素释出影响还是通过蕈毒素受体的敏感化作用所致。化合物的EC50(即，其刺激得的反应能达电刺激50％的浓度)是以当受试化合物能引起刺激作用时利用线性回归分析计算得的。
化合物1〔即：(+)-诺西沙必利〕具有的EC50为0.6μM；化合物2〔即：(-)-诺西沙必利〕具有的EC50为5μM。
实例B.5：“天竺鼠结肠的同轴刺激作用”
取体重在450克左右，两种性别的天竺鼠，以斩首方式宰杀，取出其上升结肠，予以淋洗，其后准备约3cm长的段落，将这些条片悬吊于100毫升器官浴中，连结至预先加载2克的等渗功率转换器；〔Displacement Transducer Control Unit(Jassen ScientificInstrument Division)；HP 7 DGDT 1000(Hewlett-Packard)〕。此器官浴使用DeJalon溶液(37.5℃)浸泡，打入由95％氧气与5％二氧化碳所成气体，经20分钟的稳定期间后，加入甲基胆汁碱(3.10-6M)至浴液中以评估潜在的最大影响(接触30秒)；其后，更新浴液，每间隔十分钟重复做一次，待达到具有再现性的效果，其后，加入受试化合物经十分钟。其后，不再更新浴液，加入3.10-7M的西沙必利以评估5HT4的影响。当西沙必利的影响达到稳定的最高值后，加入甲基胆汁碱(3.10-6M)至达到最高的收缩值，用于评估潜在的抗胆素激导性的影响。化合物的EC50(即，其刺激得的反应能达最高强度50％的浓度)是利用线性回归分析计算得到。
化合物1〔即：(+)-诺西沙必利〕具有的EC50为1.9μM；化合物2〔即：(-)-诺西沙必利〕具有的EC50为11μM。
C.药学组合物实例
C.1加薄膜涂层的片剂
在流动床制法中，将活性成分，乳糖，及未经改性的淀粉予以充分混合，使用溶解在水中的HPMC溶液喷射所得粉剂，制成被均匀润湿的团粒，将其干燥，与微晶纤维素、croscarmellose sodium、胶体无水二氧化硅及硬脂酸镁一同过筛。将筛过的粉末混合后，予以压制成片剂。涂层用的悬浮液是先将HPMC与丙二醇一起溶解于水中，再将其加入至含水、滑石粉、二氧化钛及染料的经均质化混合物中。在加热的涂层装备中，将涂层液喷射至片剂上。
片剂的片心成分为：
成分 量 ％(w/w)
相对药心计量
(+)-诺西沙必利-(L)-酒石酸盐 13.23毫克 7.35％(w/w)
乳糖单水合物200筛目(*1) 107.73毫克 59.85％(w/w)
未改性玉米淀粉 36.00毫克 20.00％(w/w)
HPMC 2910 15mPa.s(*2) 3.60毫克 2.00％(w/w)
微晶纤维素 12.60毫克 7.00％(w/w)
交联羟甲基纤维素钠(croscarmellose sodium) 5.40毫克 3.00％(w/w)
胶体无水二氧化硅 0.54毫克 0.30％(w/w)
硬脂酸镁 0.90毫克 0.50％(w/w)
药心总重量： 180.00毫克
片剂涂层组成：
成分 量 ％(w/w)
相对涂层物计量
HPMC 2910 15mPa.s 4.00毫克 55.95％(w/w)
丙二醇 1.00毫克 13.99％(w/w)
二氧化钛(E171) 1.20毫克 16.78％(w/w)
滑石粉 0.80毫克 11.19％(w/w)
黄色氧化铁(E171/C177492) 0.15毫克 2.10％(w/w)
总涂层物量： 7.15毫克
(*1)200筛目，指所用乳糖单水合物的类型。
(*2)HPMC是羟基丙基甲基纤维素，数字“2910”，指所用羟丙基甲基纤维素的类型，前两个数字“29”，代表甲氧基所占的大约比例，第三及第四个数字，“10”，代表羟丙基所占的大约比例。也示出其粘度(15mPa.s)，是2％的水溶液于20℃下测得的。为所用HPMC的分子量的表示法。
C.2不加涂层的片剂
将各成分置于齿轮带动混合机中混合，并在制片装置中予以压制成片剂。
成分 量 ％(w/w)
片剂C.2.1
(+)-诺西沙必利 10.387毫克 5.8
乳糖单水合物200筛目 110.393毫克 61.3
未改性玉米淀粉 36.毫克 20.0
微晶纤维素 18.毫克 10.0
polyvidone K90 3.6毫克 2.0
硬脂酸镁 0.9毫克 0.5
胶体无水二氧化硅 0.54毫克 0.3
聚山梨糖醇酯20 0.18毫克 0.1
药片总重量： 180.00毫克
片剂C.2.2
(+)-诺西沙必利-(L)-酒石酸盐 13.23毫克 7.35
MICROCELAC 157.23毫克 87.35
交联羟甲基纤维素钠(croscarmellose sodium) 7.2毫克 4.00
胶体无水二氧化硅 0.54毫克 0.3
硬脂酸镁 1.8毫克 1.00
Claims (12)
1.(+)-诺西沙必利在制备用于治疗5-HT4介导的疾病的药物中的用途。
2.根据权利要求1的用途，其中所述疾病是胃肠道穿过滞碍或不足。
3.根据权利要求1的用途，其中所述疾病是胃排空滞碍或不足。
4.根据权利要求1的用途，其中所述疾病是胃-食道反流。
5.根据权利要求1的用途，其中所述疾病是消化不良或胃轻瘫。
6.(+)-诺西沙必利在制备用于治疗饮食疾病的药物中的用途。
7.根据权利要求6的用途，其中的饮食疾病是厌食症。
8.(+)-诺西沙必利在制备供加速轻泻剂清除肠道的药物中的用途。
9.根据权利要求8的用途，其中的轻泻剂是一种渗透剂。
10.根据权利要求8的用途，其中的轻泻剂是聚乙二醇(PEG)-电解质溶液。
11.(+)-诺西沙必利在制备用于治疗5-HT3介导的疾病的药物中的用途。
12.根据权利要求11的用途，其中所述疾病是肠应激综合征或腹泻性肠应激综合征。
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP97202161 | 1997-07-11 | ||
| EP97202161.2 | 1997-07-11 | ||
| EP98200661.1 | 1998-03-04 | ||
| EP98200661 | 1998-03-04 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1262675A CN1262675A (zh) | 2000-08-09 |
| CN1196681C true CN1196681C (zh) | 2005-04-13 |
Family
ID=26146686
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB988069563A Expired - Fee Related CN1196681C (zh) | 1997-07-11 | 1998-07-07 | (+)诺西沙必利用于制备5－ht3和5ht4 介导的疾病的药物中的用途 |
Country Status (31)
| Country | Link |
|---|---|
| US (2) | US20030060485A1 (zh) |
| EP (1) | EP1000029B1 (zh) |
| JP (1) | JP3529102B2 (zh) |
| KR (1) | KR100358374B1 (zh) |
| CN (1) | CN1196681C (zh) |
| AT (1) | ATE251139T1 (zh) |
| AU (1) | AU757077B2 (zh) |
| BG (1) | BG64824B1 (zh) |
| BR (1) | BR9811676A (zh) |
| CA (1) | CA2292480A1 (zh) |
| CO (1) | CO4940432A1 (zh) |
| CZ (1) | CZ296212B6 (zh) |
| DE (1) | DE69818678T2 (zh) |
| DK (1) | DK1000029T3 (zh) |
| EA (1) | EA002362B1 (zh) |
| EE (1) | EE04491B1 (zh) |
| ES (1) | ES2209190T3 (zh) |
| HK (1) | HK1025092A1 (zh) |
| HR (1) | HRP20000004A2 (zh) |
| HU (1) | HUP0003078A3 (zh) |
| ID (1) | ID24228A (zh) |
| IL (1) | IL133225A (zh) |
| MY (1) | MY129130A (zh) |
| NO (1) | NO315183B1 (zh) |
| NZ (1) | NZ502207A (zh) |
| PL (1) | PL190296B1 (zh) |
| PT (1) | PT1000029E (zh) |
| SK (1) | SK284941B6 (zh) |
| TR (1) | TR200000020T2 (zh) |
| TW (1) | TW553934B (zh) |
| WO (1) | WO1999002496A1 (zh) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6147093A (en) | 1996-07-19 | 2000-11-14 | Sepracor Inc. | Methods for treating gastroesophageal reflux disease |
| TR200103757T2 (tr) * | 1998-06-15 | 2002-06-21 | Sepracor Inc. | Apne, bulimi ve başka bozuklukların tedavi edilmesi için optik açıdan saf (-) norsisapridin kullanımı |
| IL140118A0 (en) * | 1998-06-15 | 2002-02-10 | Sepracor Inc | Use of optically pure (+) norcisapride for treating apnea, bulimia and other disorders |
| EP1468685A3 (en) * | 1998-06-15 | 2004-12-15 | Sepracor Inc. | Use of optically pure (+)-norcisapride for treating apnea, bulimia and other disorders |
| EP1464333A3 (en) * | 1998-06-15 | 2004-12-15 | Sepracor Inc. | Use of optically pure (-) norcisapride in the treatment of apnea, bulimia, and other disorders |
| US6362202B1 (en) * | 1999-03-02 | 2002-03-26 | Sepracor Inc. | Methods and compositions using (−) norcisapride in combination with proton pump inhibitors or H2 receptor antagonists |
| US6353005B1 (en) | 1999-03-02 | 2002-03-05 | Sepracor, Inc. | Method and compositions using (+) norcisapride in combination with proton pump inhibitors or H2 receptor antagonist |
| AU4491200A (en) * | 1999-08-03 | 2001-02-19 | Lilly Icos Llc | Beta-carboline pharmaceutical compositions |
| AU2001275326C1 (en) * | 2000-06-07 | 2006-09-21 | Aryx Therapeutics | Treatment of gastroesophageal reflux disease using piperidine derivatives |
| WO2002041918A2 (en) * | 2000-11-24 | 2002-05-30 | Janssen Pharmaceutica N.V. | Use of a triple combination comprising a 5ht3 antagonist, a 5ht4 agonist and a laxative for promoting intestinal lavage |
| MXPA04003002A (es) * | 2001-10-08 | 2004-07-15 | Sun Pharmaceutical Ind Ltd | Un sistema de administracion espacial de farmacos para agentes antiespasmodicos. |
| JP2003342186A (ja) * | 2002-05-24 | 2003-12-03 | Taisho Pharmaceut Co Ltd | 鼻炎用内服液剤組成物 |
| US8138204B2 (en) | 2004-01-07 | 2012-03-20 | Aryx Therapeutics, Inc. | Stereoisomeric compounds and methods for the treatment of gastrointestinal and central nervous system disorders |
| US8524736B2 (en) | 2004-01-07 | 2013-09-03 | Armetheon, Inc. | Stereoisomeric compounds and methods for the treatment of gastrointestinal and central nervous system disorders |
| PT1704146E (pt) | 2004-01-07 | 2010-06-30 | Aryx Therapeutics Inc | Compostos estereoisoméricos e processos para o tratamento de distúrbios gastrointestinais e do sistema nervoso central |
| US20060247180A1 (en) * | 2005-04-29 | 2006-11-02 | Bergey James L | Purgative composition and uses thereof |
| AU2006284601B2 (en) | 2005-08-31 | 2012-12-20 | Renexxion, Llc | Synthetic methods and intermediates for stereoisomeric compounds useful for the treatment of gastrointestinal and central nervous system disorders |
| KR20100026641A (ko) * | 2008-09-01 | 2010-03-10 | 동아제약주식회사 | 신규한 벤즈아미드 유도체 화합물 및 그의 제조방법 |
| AU2018302170B2 (en) * | 2017-07-19 | 2024-02-29 | Ignyta, Inc. | Pharmaceutical compositions comprising entrectinib |
| WO2020014334A1 (en) * | 2018-07-11 | 2020-01-16 | Duke University | Use of sustained-release 5-hydroxytryptophan in treating gastrointestinal disorders |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1183847A (en) * | 1981-10-01 | 1985-03-12 | Georges Van Daele | N-(3-hydroxy-4-piperidinyl)benzamide derivatives |
| US4820715A (en) * | 1984-06-28 | 1989-04-11 | Bristol-Myers Company | Anti-emetic quinuclidinyl benzamides |
| NZ225152A (en) * | 1987-07-17 | 1990-04-26 | Janssen Pharmaceutica Nv | Heterocyclically substituted piperidinyl benzamides as pharmaceuticals |
| US4975439A (en) * | 1987-09-25 | 1990-12-04 | Janssen Pharmaceutical N.V. | Novel substituted N-(1-alkyl-3-hydroxy-4-piperidinyl)benzamides |
| IL89848A (en) * | 1988-04-07 | 1997-08-14 | Sepracor | Chiral ester derivatives |
| TW213460B (zh) * | 1991-02-15 | 1993-09-21 | Hokuriku Pharmaceutical | |
| TW294595B (zh) * | 1992-11-20 | 1997-01-01 | Janssen Pharmaceutica Nv | |
| FR2717174B1 (fr) * | 1994-03-14 | 1996-05-31 | Sanofi Sa | Utilisation de pipéridinoéthyl esters de l'acide 4-amino-5-chloro-2-méthoxybenzoïque comme 5-HT4 agonistes. |
| US5712293A (en) * | 1995-06-07 | 1998-01-27 | Sepracor, Inc. | Methods for treating gastro-esophageal reflux disease and other disorders associated with the digestive tract using optically pure (-) norcisapride |
| US5739151A (en) * | 1996-07-19 | 1998-04-14 | Sepracor Inc. | Method for treating emesis and central nervous system disorders using optically pure (+) norcisapride |
| US6147093A (en) * | 1996-07-19 | 2000-11-14 | Sepracor Inc. | Methods for treating gastroesophageal reflux disease |
-
1998
- 1998-07-07 DK DK98940159T patent/DK1000029T3/da active
- 1998-07-07 CN CNB988069563A patent/CN1196681C/zh not_active Expired - Fee Related
- 1998-07-07 AT AT98940159T patent/ATE251139T1/de not_active IP Right Cessation
- 1998-07-07 WO PCT/EP1998/004193 patent/WO1999002496A1/en active IP Right Grant
- 1998-07-07 CA CA002292480A patent/CA2292480A1/en not_active Abandoned
- 1998-07-07 AU AU88575/98A patent/AU757077B2/en not_active Ceased
- 1998-07-07 IL IL13322598A patent/IL133225A/xx not_active IP Right Cessation
- 1998-07-07 EA EA200000057A patent/EA002362B1/ru not_active IP Right Cessation
- 1998-07-07 DE DE69818678T patent/DE69818678T2/de not_active Expired - Fee Related
- 1998-07-07 JP JP50812899A patent/JP3529102B2/ja not_active Expired - Fee Related
- 1998-07-07 HU HU0003078A patent/HUP0003078A3/hu unknown
- 1998-07-07 TR TR2000/00020T patent/TR200000020T2/xx unknown
- 1998-07-07 PL PL98337648A patent/PL190296B1/pl unknown
- 1998-07-07 SK SK1829-99A patent/SK284941B6/sk unknown
- 1998-07-07 EP EP98940159A patent/EP1000029B1/en not_active Expired - Lifetime
- 1998-07-07 BR BR9811676-2A patent/BR9811676A/pt not_active Application Discontinuation
- 1998-07-07 CZ CZ0461799A patent/CZ296212B6/cs not_active IP Right Cessation
- 1998-07-07 EE EEP200000014A patent/EE04491B1/xx not_active IP Right Cessation
- 1998-07-07 KR KR1019997012056A patent/KR100358374B1/ko not_active IP Right Cessation
- 1998-07-07 PT PT98940159T patent/PT1000029E/pt unknown
- 1998-07-07 ID IDW20000033A patent/ID24228A/id unknown
- 1998-07-07 NZ NZ502207A patent/NZ502207A/en unknown
- 1998-07-07 ES ES98940159T patent/ES2209190T3/es not_active Expired - Lifetime
- 1998-07-08 TW TW087111013A patent/TW553934B/zh not_active IP Right Cessation
- 1998-07-08 MY MYPI98003108A patent/MY129130A/en unknown
- 1998-07-09 CO CO98038980A patent/CO4940432A1/es unknown
-
1999
- 1999-11-30 BG BG103934A patent/BG64824B1/bg unknown
-
2000
- 2000-01-05 HR HR20000004A patent/HRP20000004A2/xx not_active Application Discontinuation
- 2000-01-07 NO NO20000093A patent/NO315183B1/no unknown
- 2000-07-08 HK HK00104200A patent/HK1025092A1/xx not_active IP Right Cessation
-
2002
- 2002-09-16 US US10/244,365 patent/US20030060485A1/en not_active Abandoned
-
2004
- 2004-03-23 US US10/807,035 patent/US20040176414A1/en not_active Abandoned
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1196681C (zh) | (+)诺西沙必利用于制备5－ht3和5ht4 介导的疾病的药物中的用途 | |
| CN1022566C (zh) | 制备新的取代的1-哌啶亚烷基-吡啶并嘧啶酮或噻唑并嘧啶酮的方法 | |
| JP4584534B2 (ja) | 胃食道逆流性疾患の治療のための材料 | |
| WO2005037792A1 (fr) | Derives de n-``phenyl(piperidin-2-yl)methyl !benzamide, leur preparation et leur application en therapeutique | |
| CN1409634A (zh) | 药物组合产品及其在治疗胃肠疾病中的应用 | |
| CN1058014C (zh) | 新的杂环螺环化合物,它们的制备方法以及含有它们的药物组合物 | |
| US11498896B2 (en) | Dopamine D2 receptor ligands | |
| JP2022535744A (ja) | てんかんを治療するための方法および組成物 | |
| CN1149996C (zh) | 抗精神病药哌啶并[4,3-b]吲哚衍生物 | |
| CN1033451C (zh) | α-取代的苯甲胺衍生物 | |
| CN1320036A (zh) | 治疗胃－食管返流性疾病的方法和组合物 | |
| CN1033454C (zh) | 4-[(2-苯并噻唑基)甲氨基]-α-[(3，4-二氟苯氧基)甲基]-1-哌啶乙醇的制备方法 | |
| US7005524B2 (en) | Methods for the stereoselective synthesis of substituted piperidines | |
| CN1073942A (zh) | 杂环取代的苯甲胺衍生物 | |
| CN1067888A (zh) | 2-哌啶基嘧啶-4-甲酰胺衍生物及其制法和医疗应用 | |
| Heykants et al. | Norcisapride | |
| FR2763950A1 (fr) | 2- {4- [4-(4,5-dichloro-2-methylimidazol-1-yl)butyl] -1- piperazinyl }-5-fluoropyrimidine, sa preparation et son utilisation therapeutique | |
| CN1188410A (zh) | N-环己基苯甲酰胺类化合物治疗肠疾病的用途 | |
| UA63954C2 (en) | (+/-) norcisapride, a process for the preparation thereof, intermediate compounds, composition based thereon for use in the manufacture of medicaments for treating gastro-intestinal disorders |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |