CN1610542A - 用于治疗胃食管返流性疾病的新应用 - Google Patents
用于治疗胃食管返流性疾病的新应用 Download PDFInfo
- Publication number
- CN1610542A CN1610542A CNA028233514A CN02823351A CN1610542A CN 1610542 A CN1610542 A CN 1610542A CN A028233514 A CNA028233514 A CN A028233514A CN 02823351 A CN02823351 A CN 02823351A CN 1610542 A CN1610542 A CN 1610542A
- Authority
- CN
- China
- Prior art keywords
- receptor agonists
- cannabinoid receptor
- application
- treatment
- optical isomer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 208000021302 gastroesophageal reflux disease Diseases 0.000 title claims abstract description 26
- 229940121376 cannabinoid receptor agonist Drugs 0.000 claims abstract description 81
- 239000003537 cannabinoid receptor agonist Substances 0.000 claims abstract description 81
- 206010067171 Regurgitation Diseases 0.000 claims abstract description 20
- 210000000111 lower esophageal sphincter Anatomy 0.000 claims abstract description 20
- 208000019693 Lung disease Diseases 0.000 claims abstract description 14
- 201000008197 Laryngitis Diseases 0.000 claims abstract description 9
- 201000009243 chronic laryngitis Diseases 0.000 claims abstract description 7
- 230000005764 inhibitory process Effects 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 40
- 239000003814 drug Substances 0.000 claims description 34
- 229930003827 cannabinoid Natural products 0.000 claims description 29
- 239000003557 cannabinoid Substances 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 19
- 230000003287 optical effect Effects 0.000 claims description 17
- 208000006673 asthma Diseases 0.000 claims description 13
- 230000002265 prevention Effects 0.000 claims description 13
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 claims description 11
- 125000002252 acyl group Chemical group 0.000 claims description 9
- -1 aminoalkyl indole Chemical compound 0.000 claims description 8
- 235000013336 milk Nutrition 0.000 claims description 7
- 239000008267 milk Substances 0.000 claims description 7
- 210000004080 milk Anatomy 0.000 claims description 7
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 6
- 230000002496 gastric effect Effects 0.000 claims description 6
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 6
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 5
- 238000012545 processing Methods 0.000 claims description 5
- 102000009135 CB2 Cannabinoid Receptor Human genes 0.000 claims description 4
- 108010073376 CB2 Cannabinoid Receptor Proteins 0.000 claims description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- 239000013256 coordination polymer Substances 0.000 claims description 4
- 150000002066 eicosanoids Chemical class 0.000 claims description 4
- 102000009132 CB1 Cannabinoid Receptor Human genes 0.000 claims description 3
- 108010073366 CB1 Cannabinoid Receptor Proteins 0.000 claims description 3
- HQVHOQAKMCMIIM-HXUWFJFHSA-N WIN 55212-2 Chemical compound C([C@@H]1COC=2C=CC=C3C(C(=O)C=4C5=CC=CC=C5C=CC=4)=C(N1C3=2)C)N1CCOCC1 HQVHOQAKMCMIIM-HXUWFJFHSA-N 0.000 claims description 3
- HWDVTQAXQJQROO-UHFFFAOYSA-N cyclopropylazanide Chemical compound [NH-]C1CC1 HWDVTQAXQJQROO-UHFFFAOYSA-N 0.000 claims description 3
- 229960004242 dronabinol Drugs 0.000 claims description 3
- 239000002417 nutraceutical Substances 0.000 claims description 3
- 235000021436 nutraceutical agent Nutrition 0.000 claims description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 2
- 229950000251 nantradol Drugs 0.000 claims description 2
- 208000023819 chronic asthma Diseases 0.000 abstract description 3
- 230000001052 transient effect Effects 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 description 23
- 102000005962 receptors Human genes 0.000 description 11
- 108020003175 receptors Proteins 0.000 description 11
- 241000282472 Canis lupus familiaris Species 0.000 description 9
- 210000003238 esophagus Anatomy 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- 210000002784 stomach Anatomy 0.000 description 6
- 239000000556 agonist Substances 0.000 description 5
- 239000002269 analeptic agent Substances 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 108010010803 Gelatin Proteins 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 241000792859 Enema Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 102100027297 Fatty acid 2-hydroxylase Human genes 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101000937693 Homo sapiens Fatty acid 2-hydroxylase Proteins 0.000 description 3
- 101000918494 Homo sapiens Fatty-acid amide hydrolase 1 Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000007920 enema Substances 0.000 description 3
- 229940095399 enema Drugs 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- GECBBEABIDMGGL-RTBURBONSA-N nabilone Chemical compound C1C(=O)CC[C@H]2C(C)(C)OC3=CC(C(C)(C)CCCCCC)=CC(O)=C3[C@@H]21 GECBBEABIDMGGL-RTBURBONSA-N 0.000 description 3
- 230000002085 persistent effect Effects 0.000 description 3
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 2
- 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 2
- 229920000945 Amylopectin Polymers 0.000 description 2
- 241000218236 Cannabis Species 0.000 description 2
- 244000025254 Cannabis sativa Species 0.000 description 2
- 206010011224 Cough Diseases 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 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 2
- 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 2
- CYQFCXCEBYINGO-DLBZAZTESA-N Dronabinol Natural products C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@H]21 CYQFCXCEBYINGO-DLBZAZTESA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 150000001200 N-acyl ethanolamides Chemical class 0.000 description 2
- 206010030216 Oesophagitis Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 239000003613 bile acid Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000002621 endocannabinoid Substances 0.000 description 2
- 208000006881 esophagitis Diseases 0.000 description 2
- 230000027119 gastric acid secretion Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 229960002967 nabilone Drugs 0.000 description 2
- 235000008935 nutritious Nutrition 0.000 description 2
- 239000004031 partial agonist Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 210000003800 pharynx Anatomy 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 150000003217 pyrazoles Chemical class 0.000 description 2
- JZCPYUJPEARBJL-UHFFFAOYSA-N rimonabant Chemical compound CC=1C(C(=O)NN2CCCCC2)=NN(C=2C(=CC(Cl)=CC=2)Cl)C=1C1=CC=C(Cl)C=C1 JZCPYUJPEARBJL-UHFFFAOYSA-N 0.000 description 2
- 229960003015 rimonabant Drugs 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- GYVJGLPVHBCECZ-RZLHGTIFSA-N (e)-2-octadecylbut-2-enedioic acid;sodium Chemical compound [Na].CCCCCCCCCCCCCCCCCC\C(C(O)=O)=C/C(O)=O GYVJGLPVHBCECZ-RZLHGTIFSA-N 0.000 description 1
- VKPPFDPXZWFDFA-UHFFFAOYSA-N 2-chloroethanamine Chemical compound NCCCl VKPPFDPXZWFDFA-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 229940124802 CB1 antagonist Drugs 0.000 description 1
- 102100033868 Cannabinoid receptor 1 Human genes 0.000 description 1
- 102100036214 Cannabinoid receptor 2 Human genes 0.000 description 1
- 235000008697 Cannabis sativa Nutrition 0.000 description 1
- 235000012766 Cannabis sativa ssp. sativa var. sativa Nutrition 0.000 description 1
- 235000012765 Cannabis sativa ssp. sativa var. spontanea Nutrition 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 101001090860 Homo sapiens Myeloblastin Proteins 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102100034681 Myeloblastin Human genes 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- LGEQQWMQCRIYKG-DOFZRALJSA-N anandamide Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)NCCO LGEQQWMQCRIYKG-DOFZRALJSA-N 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 229910052787 antimony Inorganic materials 0.000 description 1
- WATWJIUSRGPENY-UHFFFAOYSA-N antimony atom Chemical compound [Sb] WATWJIUSRGPENY-UHFFFAOYSA-N 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- LGEQQWMQCRIYKG-UHFFFAOYSA-N arachidonic acid ethanolamide Natural products CCCCCC=CCC=CCC=CCC=CCCCC(=O)NCCO LGEQQWMQCRIYKG-UHFFFAOYSA-N 0.000 description 1
- SCJNCDSAIRBRIA-DOFZRALJSA-N arachidonyl-2'-chloroethylamide Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)NCCCl SCJNCDSAIRBRIA-DOFZRALJSA-N 0.000 description 1
- GLGAUBPACOBAMV-DOFZRALJSA-N arachidonylcyclopropylamide Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)NC1CC1 GLGAUBPACOBAMV-DOFZRALJSA-N 0.000 description 1
- 125000004421 aryl sulphonamide group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229940041750 cesamet Drugs 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 208000018685 gastrointestinal system disease Diseases 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 208000024798 heartburn Diseases 0.000 description 1
- 210000003026 hypopharynx Anatomy 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229940028435 intralipid Drugs 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940099262 marinol Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 150000004880 oxines Chemical class 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 239000012925 reference material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000004206 stomach function Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 208000016752 upper digestive tract disease Diseases 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000001993 wax Substances 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- 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
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/04—Drugs for disorders of the respiratory system for throat disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- 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]
- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Rheumatology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Diabetes (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Otolaryngology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pyrane Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Indole Compounds (AREA)
Abstract
本发明涉及大麻素受体激动剂用于抑制暂时性下食管括约肌松弛的应用。本发明另一方面涉及大麻素受体激动剂用于治疗胃食管返流性疾病的应用、以及用于治疗反胃如婴儿吐奶、肺疾病、慢性喉炎和哮喘的应用。
Description
技术领域
本发明涉及大麻素(cannabinoid)受体激动剂用于抑制暂时性下食管括约肌松弛(transient lower esophageal sphincterrelaxations)的应用。本发明另一方面涉及大麻素受体激动剂用于治疗胃食管返流性疾病的应用、以及用于治疗反胃(regurgitation)如婴儿吐奶(regurgitation in infants)、肺疾病、慢性喉炎和哮喘的应用。
背景技术
下食管括约肌(LES)有间歇性松弛的倾向。因此,由于在该时候机械屏障暂时丧失,所以来自于胃的液体可进入食管,这种情况在下文中被称为“返流”。
胃食管返流性疾病(GERD)是最普遍的上胃肠道疾病。目前药物疗法的目标是降低胃酸分泌或中和食管中的酸。已经认定返流的主要机理是依赖于低张的下食管括约肌。但是,例如,Holloway&Dent(1990)Gastroenterol.Clin.N.Amer.19,517-535页,已经表明大多数返流发作发生于暂时性下食管括约肌松弛(TLESRs)即不是由吞咽所引发的松弛期间。还已经表明在GERD患者中胃酸分泌通常是正常的。
GERD是由胃内容物返流到食管中所造成的,其导致烧心和其它典型症状。在许多情况中,在末梢食管中形成炎症(食管炎)。早就已知抑制胃酸产生可以改善症状和食管炎。但是,尽管充分控制了酸的分泌,一些患者仍然继续出现一些症状。据认为其它有害因素的返流是造成这些症状的原因。几乎全部焦点都集中于胆汁酸的重要性,并且严重GERD的形成与食管胆汁酸暴露的程度有关。
在过去,术语大麻素指的是大麻(Cannabis sativa)(大麻(marijuana))的主要成分,包括约六十种分子,但是该术语已扩展至还包括内源性大麻素和多种可以与两种已知的大麻素受体——CB1和CB2相互作用的化学实体。最近,已经提出存在以前未知的大麻素受体亚型(Mol.Pharmacol.(2001),60:155-163页,PNAS(1999),96:14136-14141页)。大麻素受体属于G-蛋白-偶联性超家族(superfamily),并且CB1受体主要在中枢神经系统中进行表达和在较小程度上在外周组织中进行表达(Nature(1990),346:561-564页),而CB2受体位于外周并且主要限于与免疫功能有关的细胞和组织(Nature(1993),365:61-65页)。
目前有四种已知的主要大麻素受体激动剂化学组:
1)类花生酸类物质及其类似物,其是得自动物的大麻素。花生四烯酰乙醇酰胺(Anandamide)是该组中的一个实例:
花生四烯酰乙醇酰胺
2)经典大麻素及其类似物,其是得自植物的大麻素,如Δ9-THC(Δ9-四氢大麻酚):
Δ9-THC
3)非经典的大麻素,如CP 55,940,是由Pfizer研制的:
和
CP 55,940
4)氨基烷基吲哚大麻素如WIN 55,212-2,是由Sterling-Winthrop研制的:
WIN 55,212-2
迄今为止唯一得到药物批准的大麻素类物质属于经典大麻素家族。通用名为屈大麻酚(Dronabinol)的Δ9-THC在美国以Marinol的商标进行了注册,用于对抗由于抗癌药而诱导的恶心并通过刺激食欲来对抗AIDS患者的体重减轻。大麻隆(Nabilone)是一种由EliLilly研制的合成衍生物(Cesamet),其在加拿大、UK和爱尔兰进行了注册,用于抑制由癌症化疗所诱导的恶心和呕吐。
Pertwee,R.G.在Curr.Med.Chem.(1999)6:635-664页中公开了对CB1和CB2受体配体的药理学综述。对于另外的综合性综述而言,可参见例如Barth F.Exp.Opin.Ther.Patents(1998)8(3):301-313页;Pertwee,R.G.Exp.Opin.Invest.Drugs(2000)9(7):1553-1571页;Goy,P.;Jagerovic,N.Exp.Opin.Ther.Patents(2000)10(10):1529-1538页,以及其中所引用的参考资料。
Yissum Research Development的WO 01/32169公开了一种特别是用于治疗或预防疼痛、胃肠病症、和自身免疫性疾病的药物组合物,其是将作用于CB2受体的特定化合物进行给药。炎性肠疾病(IBD)是一种已经用其中所公开的化合物进行了试验的疾病。
本发明的目的是找到一种抑制暂时性下食管括约肌松弛(TLESRs),从而预防返流的新方法。更特别地,本发明的目的是找到一种用于治疗胃食管返流性疾病(GERD)的改善的新方法以及一种用于治疗反胃如婴儿吐奶、肺疾病、慢性喉炎和哮喘的改善的新方法。
本发明的概述
现在令人吃惊地发现,可以用大麻素受体激动剂来抑制暂时性下食管括约肌松弛(TLESRs),从而可将其用来治疗胃食管返流性疾病(GERD)。
因此,本发明涉及大麻素受体激动剂用于制造抑制暂时性下食管括约肌松弛(TLESRs)的药物的应用。
本发明另一方面是大麻素受体激动剂用于制造预防返流的药物的应用。
本发明的另一方面还涉及大麻素受体激动剂用于制造治疗胃食管返流性疾病(GERD)的药物的应用。对反胃的有效控制是预防、以及医治由于吸入反胃的胃内容物而造成的肺疾病的重要方法。因此,本发明另一方面是大麻素受体激动剂用于制造治疗或预防反胃的药物的应用。
对婴儿吐奶进行有效控制是预防、以及医治由于吸入反胃的胃内容物而造成的肺疾病的重要方法、以及是用于处理不能茁壮成长,特别是由于所摄入营养物的过度损失而导致的不能茁壮成长的重要方法。因此,本发明另一方面是大麻素受体激动剂用于制造治疗婴儿吐奶的药物的应用。
本发明另一方面是大麻素受体激动剂用于制造处理不能茁壮成长的药物的应用。
本发明另一方面还涉及大麻素受体激动剂用于制造治疗或预防肺疾病的药物的应用。被治疗的肺疾病特别可以是由于吸入反胃的胃内含物而导致的。
本发明另一方面是大麻素受体激动剂用于制造治疗或预防哮喘,如与返流有关的哮喘的药物的应用。
本发明另一方面是大麻素受体激动剂用于制造治疗或预防慢性喉炎的药物的应用。
本发明另一方面是一种用于抑制暂时性下食管括约肌松弛(TLESRs)的方法,该方法是将药学和药理学有效量的大麻素受体激动剂给药于需要进行该类抑制的个体。
本发明另一方面是一种用于预防返流的方法,该方法是将药学和药理学有效量的大麻素受体激动剂给药于需要进行该类预防的个体。
本发明另一方面还是一种用于治疗胃食管返流性疾病(GERD)的方法,该方法是将药学和药理学有效量的大麻素受体激动剂给药于需要进行该类治疗的个体。
本发明另一方面是一种用于治疗或预防反胃的方法,该方法是将药学和药理学有效量的大麻素受体激动剂给药于需要进行该类治疗的个体。
本发明另一方面还是一种用于治疗或预防婴儿吐奶的方法,该方法是将药学和药理学有效量的大麻素受体激动剂给药于需要进行该类治疗的个体。
本发明另一方面还是一种用于治疗、预防或抑制肺疾病的方法,该方法是将药学和药理学有效量的大麻素受体激动剂给药于需要进行该类治疗的个体。被治疗的肺疾病特别可以是由于吸入反胃的胃内容物而导致的。
本发明另一方面还是一种用于处理不能茁壮成长的方法,该方法是将药学和药理学有效量的大麻素受体激动剂给药于需要进行该类治疗的个体。
本发明另一方面是一种用于治疗或预防哮喘,如与返流有关的哮喘的方法。
本发明另一方面是一种用于治疗或预防慢性喉炎的方法。
本发明另一方面是对CB1受体具有选择性的大麻素受体激动剂在上面所讨论的任何一种适应征中的应用。本发明另一方面还是对CB2受体具有选择性的大麻素受体激动剂在上面所讨论的任何一种适应征中的应用。
对于本发明的目的而言,术语“激动剂”应被理解为包括完全激动剂以及部分激动剂,而术语“部分激动剂”应被理解为能部分而不是完全活化大麻素受体的化合物。
这里所用的措词“大麻素受体激动剂”不仅包括完全大麻素受体激动剂或部分大麻素受体激动剂,而且还包括间接的大麻素受体激动剂。这里所用的措词“间接的大麻素受体激动剂”指的是酶-脂肪酸酰胺水解酶(FAAH)抑制剂以及酶-花生四烯酰乙醇酰胺转运蛋白(ANT)抑制剂。ANT或FAAH的抑制剂可通过增加大麻素受体处内大麻素(endocannabinoids)的浓度而被用作间接的大麻素受体激动剂,并从而可用于抑制TLESRs。
这里所定义的词语“TLESR”,暂时性下食管括约肌松弛,与Mittal,R.K.,Holloway,R.H.,Penagini,R.,Blackshaw,L.A.,Dent,J.,1995;暂时性下食管括约肌松弛。Gastroenterology 109,601-610页中的定义相一致。
词语“返流”被定义为因为在该时间机械屏障的暂时丧失,来自胃的流体能进入到食管中。
词语“GERD”,胃食管返流性疾病,的定义与van Heerwarden,M.A.,Smout A.J.P.M.,2000;返流性疾病的诊断。Baillière′sClin.Gastroenterol.14,759-774页中的定义相一致。
词语“反胃”被定义为未被消化的食物和胃液的排出。
词语“肺疾病”被定义为肺正常功能的任何偏差或任何中断。
词语“喉炎”被定义为喉的炎症,是一种具有咽喉干燥和疼痛、嘶哑、咳嗽和吞咽困难的状况。词语“慢性”定义的是长期持续。
哮喘是呼吸道的炎性病症,其特征为喘鸣、呼吸短促、胸闷和咳嗽的周期发作。措词“与返流有关的哮喘”的定义与Richter;J.E.2000;胃食管返流性疾病和哮喘:两种直接相关的疾病。Am.J.Med.108(4A),153S-158S中的定义相一致。
在本发明的一个方面,本发明所用的大麻素受体激动剂(激动剂们)作用的持续时间为约4至24小时。词语“持续时间”被定义为从起效的时间到测量不到作用时的时间期间。
在本发明的范围内,大麻素受体激动剂特别是使用属于大麻素受体激动剂的四种主要化学类型的大麻素受体激动剂。因此,本发明特别是使用类花生酸类物质及其类似物;经典的大麻素类物质及其类似物;非经典的大麻素类物质及其类似物;和氨基烷基吲哚大麻素及其类似物。
具有激动、间接或部分激动活性的对大麻素(CB)受体有亲合力从而可用于本发明的特别化合物的实例是下面的化合物。
I)类花生酸CB受体激动剂:
●花生四烯酰乙醇酰胺(可以由例如Tocris Cookson,Bristol,U.K.通过商业途径获得),其是下式的化合物
●二十-5,8,11,14-四烯酸(2-氯-乙基)-酰胺,也被称为花生四烯酰基(Arachidonyl)-2′-氯乙基酰胺(ACEA,可以由例如TocrisCookson,Bristol,U.K.通过商业途径获得);和
·二十-5,8,11,14-四烯酸环丙基酰胺,也被称为花生四烯酰基环丙基酰胺(ACPA,可以由例如Tocris Cookson,Bristol,U.K.通过商业途径获得)。
II)经典的CB受体激动剂:
·Δ9-THC(Δ9-四氢大麻酚,可以由例如Sigma-Aldrich通过商业途径获得),其是一种具有下式的化合物
化学名为6,6,9-三甲基-3-戊基-6a,7,8,10a-四氢-6H-苯并[c]色烯-1-醇,以及对映异构体(-)-Δ9-四氢大麻酚[(-)-Δ9-THC)];和
·(-)-(R,R)-6,6-二甲基-(1,1-二甲基庚基)-1-羟基-9-(羟基甲基)-6a,7,10,10a-四氢-6H-二苯并[b,d]吡喃,[11-羟基-Δ8-THC-二甲基庚基],也被称为HU-210(可以由例如Tocris Cookson,Bristol,U.K.通过商业途径获得)
III)非经典的CB受体激动剂:
·CP 55,940,一种化学名为5-(1,1-二甲基-庚基)-2-[5-羟基-2-(3-羟基-丙基)-环己基]-苯酚的化合物(可以由例如TocrisCookson,Bristol,U.K.通过商业途径获得),并且具有如下的化学结构
·(-)-(6S,6aR,9R,10aR)-5,6,6a,7,8,9,10a-八氢-6-甲基-3-[(R)-1-甲基-4-苯基丁氧基]-1,9-菲啶二醇1-醋酸酯,也被称为L-南曲朵(CP 50,556)。
IV)氨基烷基吲哚CB受体激动剂:
·WIN 55,212-2(可以由例如Tocris Cookson,Bristol,U.K.通过商业途径获得),具有如下的化学结构
其化学名为(2-甲基-3-吗啉-4-基甲基-3,4-二氢-5-氧杂-2a-氮杂-苊-1-基)-萘-1-基-甲酮;和
·L-768,242,化学名为(2,3-二氯-苯基)-[5-甲氧基-2-甲基-3-(2-吗啉-4-基-乙基)-吲哚-1-基]-甲酮,并且具有如下的化学结构
本发明另外方面还涉及在下面的文献中所公开的有用的大麻素受体激动剂:WO 01/31169;WO 99/51560;EP 0860168;WO 97/00860;WO01/32169,如化合物HU-308;WO 01/28497,如化合物AM 1703;WO01/74763;WO 01/29007;WO 01/28557。可用于本发明的另外的大麻素受体激动剂是在WO 97/29079中所公开的化合物,如下式的芳基酰胺类物质
在WO 98/41519中所公开的化合物,如下式的吡唑类物质
如下结构的喹啉类物质
在WO 98/37061;和WO 00/10967中所公开的化合物,并且其中更特别地是芳基磺胺
可用于本发明的另外的化合物是被F.Barth在Exp.Opin.Ther.Patents(1998)8(3):301-313页中所公开的大麻素受体激动剂;和被P.Goya&N.Jagerovic在Exp.Opin.Ther.Patents(2000)10(10):1529-1538页中所公开的大麻素受体激动剂。上述特定的大麻素受体激动剂以及在上面所公开的专利申请的任何一种中所公开的大麻素受体激动剂在这里都被引入作为参考。这些列举的大麻素受体激动剂无论如何不应被认为是对限制本发明范围的穷举。
可用于本发明的间接的大麻素受体激动剂的实例是化合物AM374(可以由例如Calbiochem-Novabiochem Corporation通过商业途径获得)和AM 404(可以由例如Tocris Cookson,Bristol,U.K.通过商业途径获得)。
大麻素受体激动剂可药用盐的应用也在本发明的范围内。该类盐有例如与无机酸如盐酸形成的盐;碱金属盐如钠盐或钾盐;或碱土金属盐如钙盐或镁盐。
大麻素受体激动剂光学异构体的应用也在本发明的范围内。具有不对称碳原子的大麻素受体激动剂是手性化合物,并且取决于所存在的不对称原子,大麻素受体激动剂可以以异构体混合物,特别是外消旋体的形式存在,或者可以以纯异构体如特定的对映异构体的形式存在。
药物制剂
对于临床应用而言,本发明的大麻素受体激动剂适宜被制备成用于口服给药的药物制剂。制剂领域技术人员也可以考虑直肠、胃肠外或任何其它给药途径。因此,将大麻素受体激动剂与至少一种可药用的和药理学上可接受的载体或助剂一起进行配制。该载体可以是固态、半固态或液态稀释剂。
在制备本发明的口服药物制剂中,将被进行配制的大麻素受体激动剂(激动剂们)与固态粉状成分如乳糖、蔗糖、山梨醇、甘露醇、淀粉、支链淀粉、纤维素衍生物、明胶、或其它适宜成分以及崩解剂和润滑剂如硬脂酸镁、硬脂酸钙、硬脂酰基延胡索酸钠和聚乙二醇蜡类进行混合。然后将该混合物制成颗粒或压成片剂。
可以用包含本发明活性化合物或化合物们、植物油、脂肪、或用于软明胶胶囊的其它适宜赋形剂的胶囊来制备软明胶胶囊。硬明胶胶囊可包含活性化合物和固态粉状成分如乳糖、蔗糖、山梨醇、甘露醇、马铃薯淀粉、支链淀粉、纤维素衍生物或明胶。
用于直肠给药的剂量单位可以被制备成(i)包含与中性脂肪基质混合的活性物质(活性物质们)的栓剂形式;(ii)包含与植物油、石蜡油、或用于明胶直肠胶囊的其它适宜赋形剂混合的活性物质的明胶直肠胶囊形式;(iii)做好的小灌肠剂(micro enema)的形式;或(iv)就在使用前用适宜的溶剂进行重组的干的小灌肠剂的形式。
用于口服给药的液体制剂可以被制备成包含活性化合物和由糖或糖醇、以及乙醇、水、甘油、丙二醇和聚乙二醇的混合物所组成的制剂的其余部分的溶液、糖浆或混悬液的形式。如果需要,该类液体制剂可包含着色剂、矫味剂、糖精和羧甲基纤维素或其它增稠剂。用于口服的液体制剂还可以被制备成在使用前用适宜的溶剂进行重组的干粉形式。
用于胃肠外给药的溶液可以被制备成本发明的化合物在可药用溶剂中的溶液。这些溶液还可以包含稳定成分和/或缓冲成分并且可以被分配成安瓿或小瓶形式的单位剂量。用于胃肠外给药的溶液还可以被制备成在使用前用适宜的溶剂进行即时重组的干制剂。
在本发明的一个方面,该大麻素受体激动剂可以被一天给药一次或两次,其取决于患者病症的严重程度。大麻素受体激动剂典型的日剂量为0.1-500mg(包括0.1和500mg),如0.1-100mg,但是其将取决于诸如给药途径、患者的年龄和体重以及患者病症的严重程度之类的因素。
生物学评估
可有效对抗TLESR的化合物的筛选
使用被训练站在Pavlov吊具中的两种性别的成年拉布拉多拾物猎狗。形成粘膜-至-皮肤的食管造口术并且在进行任何试验之前要使这些狗完全恢复。
运动性测量
简单地说,在自由饮水但禁食约17小时后,通过手术作成的进入食管的孔口引入一种多腔套管/侧孔(sidehole)组件(Dentsleeve,Adelaide,South Australia)来对胃、下食管括约肌(LES)和食管的压力进行测量。用低-顺应性的压力计灌注泵(Dentsleeve,Adelaide,South Australia)用水对该组件进行灌注。将一根空气灌注的管插到口腔中来测量吞咽,和将一个监测pH的锑电极放置在LES上3cm处。所有的信号都是在10Hz下在一台个人计算机上被放大和获得的。
当已经获得没有禁食的基础测量的胃/LES第III相运动活性时,在前腿静脉通过静脉内(i.v.0.5ml/kg)给药来给予安慰剂(0.9%NaCl)或试验化合物。在静脉内给药后10分钟,通过该组件中间的腔以100ml/分钟的速度将营养餐(10%蛋白胨、5%D-葡萄糖、5%Intralipid,pH 3.0)灌注到胃中至30ml/kg的最终体积。在营养餐后立即以40ml/分钟的速度吹入空气。从开始营养灌注到吹气结束的实验时间为45分钟。已经证明该操作是触发TLESRs的可靠手段。
TLESRs被定义为下食管括约肌压力(参考胃内压力)以>1mmHg/秒的速度降低。在其开始前松弛不应以咽信号≤2秒为先导,在该情况中松弛被归为咽诱导的。LES和胃之间的压力差应小于2mmHg,并且完全松弛的持续时间高于1秒。
实施例
实施例1
根据上述试验模型用两种性别的成年拉布拉多拾物猎狗对购自Tocris Cookson(Bristol,U.K.)的氨基烷基吲哚大麻素WIN55,212-2进行试验。
相对五次之前的对照试验来计算各狗TLESRs的抑制数,得到下面表1中所述的结果。
表1
化合物 | 剂量[mg/kg] | 抑制%±SEM(N) |
WIN 55,212-2 | 0.003 | 20±18(4) |
WIN 55,212-2 | 0.01 | 70±10(4) |
WIN 55,212-2 | 0.03 | 82±1(4) |
N=进行试验的狗的数目;SEM=平均值的标准误差
实施例2
氨基烷基吲哚大麻素L-768,242是根据Bioorg.&Med.Chem.Lett.(1996);第6卷,第19期,2263-2268页所描述的方法,在AstraZeneca R&D Mlndal,Sweden,合成的,并如上面实施例1那样来对其进行试验。
相对五次之前的对照试验来计算各狗TLESRs的抑制数,得到下面表2中所述的结果。
表2
化合物 | 剂量[μmol/kg] | 抑制%±SEM(N) |
L-768,242 | 0.3 | 8±21(4) |
L-768,242 | 1 | 44±6(5) |
L-768,242 | 5 | 63±5(4) |
L-768,242 | 7 | 76±12(3) |
N=进行试验的狗的数目;SEM=平均值的标准误差
实施例3
吡唑SR141716A(CB1拮抗剂)是根据J.Chem.Soc.,Chem.Commun.(1995);第15期,1549-1560页所描述的方法,在AstraZeneca R&D Mlndal,Sweden,合成的,并如上面实施例1所述的那样来对其进行试验。
相对五次之前的对照试验来计算各狗TLESRs的兴奋数,得到下面表3中所述的结果。
表3
化合物 | 剂量[μmol/kg] | 抑制%±SEM(N) |
SR141716A | 0.22 | 43±16(6) |
N=进行试验的狗的数目;SEM=平均值的标准误差
上面实施例3中的结果表明了调解TLESRs的抑制的内大麻素的紧张活性,这又表明间接的大麻素激动剂(FAAH和ANT的抑制剂)可用于抑制TLESRs,从而可以用于治疗GERD。
上面实施例1-3中所示的结果表明大麻素受体激动剂可用于抑制TLESRs,从而可用于治疗GERD。
Claims (36)
1.大麻素受体激动剂、或其可药用的盐或其光学异构体用于制造抑制暂时性下食管括约肌松弛(TLESRs)的药物的应用。
2.大麻素受体激动剂、或其可药用的盐或其光学异构体用于制造治疗胃食管返流性疾病(GERD)的药物的应用。
3.大麻素受体激动剂、或其可药用的盐或其光学异构体用于制造预防返流的药物的应用。
4.大麻素受体激动剂、或其可药用的盐或其光学异构体用于制造治疗或预防反胃的药物的应用。
5.如权利要求4所述的应用,其中被治疗或预防的反胃是婴儿吐奶。
6.大麻素受体激动剂、或其可药用的盐或其光学异构体用于制造治疗或预防肺疾病的药物的应用。
7.如权利要求6所述的应用,其中所说的肺疾病是由于吸入了反胃的胃内容物而导致的。
8.大麻素受体激动剂、或其可药用的盐或其光学异构体用于制造处理不能茁壮成长的药物的应用。
9.如权利要求8所述的应用,其中所说的不能茁壮成长是由于所摄入营养物的过度损失所导致的。
10.大麻素受体激动剂、或其可药用的盐或其光学异构体用于制造治疗或预防哮喘的药物的应用。
11.如权利要求10所述的应用,其中所说的哮喘是与返流有关的哮喘。
12.大麻素受体激动剂、或其可药用的盐或其光学异构体用于制造治疗或预防慢性喉炎的药物的应用。
13.如权利要求1-12中任意一项所述的应用,其中所说的大麻素受体激动剂是CB1受体选择性大麻素受体激动剂。
14.如权利要求1-12中任意一项所述的应用,其中所说的大麻素受体激动剂是CB2受体选择性大麻素受体激动剂。
15.如前面权利要求中任意一项所述的应用,其中所说的大麻素受体激动剂是类花生酸。
16.如权利要求1-14中任意一项所述的应用,其中所说的大麻素受体激动剂是经典的大麻素。
17.如权利要求1-14中任意一项所述的应用,其中所说的大麻素受体激动剂是非经典的大麻素。
18.如权利要求1-14中任意一项所述的应用,其中所说的大麻素受体激动剂是氨基烷基吲哚大麻素。
19.如权利要求15所述的应用,其中所说的大麻素受体激动剂选自花生四烯酰乙醇酰胺;花生四烯酰基-2′-氯乙基酰胺(ACEA);和花生四烯酰基环丙基酰胺(ACPA)。
20.如权利要求16所述的应用,其中所说的大麻素受体激动剂是Δ9-四氢大麻酚(AQ-THC);或11-羟基-Δ8-THC-二甲基庚基(HU-210)。
23.如权利要求1-22中任意一项所述的应用,其中所说大麻素受体激动剂的日剂量为0.1-500mg。
24.一种抑制暂时性下食管括约肌松弛(TLESRs)的方法,其是将药学和药理学有效量的大麻素受体激动剂、或其可药用的盐或其光学异构体给药于需要进行该类抑制的个体。
25.一种治疗胃食管返流性疾病(GERD)的方法,其是将药学和药理学有效量的大麻素受体激动剂、或其可药用的盐或其光学异构体给药于需要进行该类治疗的个体。
26.一种用于预防返流的方法,其是将药学和药理学有效量的大麻素受体激动剂、或其可药用的盐或其光学异构体给药于需要进行该类治疗的个体。
27.一种用于治疗或预防反胃的方法,其是将药学和药理学有效量的大麻素受体激动剂、或其可药用的盐或其光学异构体给药于需要进行该类治疗或预防的个体。
28.如权利要求27所述的方法,其中被治疗或预防的反胃是婴儿吐奶。
29.一种用于预防或治疗肺疾病的方法,其是将药学和药理学有效量的大麻素受体激动剂、或其可药用的盐或其光学异构体给药于需要进行该类治疗或预防的个体。
30.如权利要求29所述的方法,其中所说的肺疾病是由于吸入反胃的胃内容物而导致的。
31.一种处理不能茁壮成长的方法,其是将药学和药理学有效量的大麻素受体激动剂、或其可药用的盐或其光学异构体给药于需要进行该类处理的个体。
32.如权利要求31所述的方法,其中所说的不能茁壮成长是由于被摄入的营养物的过度损失所导致的。
33.一种治疗或预防哮喘的方法,其是将药学和药理学有效量的大麻素受体激动剂、或其可药用的盐或其光学异构体给药于需要进行该类治疗或预防的个体。
34.如权利要求33所述的方法,其中所说的哮喘是与返流有关的哮喘。
35.一种用于治疗或预防慢性喉炎的方法,其是将药学和药理学有效量的大麻素受体激动剂、或其可药用的盐或其光学异构体给药于需要进行该类治疗或预防的个体。
36.如权利要求24-35中任意一项所述的方法,其中所说大麻素受体激动剂的日剂量为0.1-500mg。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE0103936 | 2001-11-23 | ||
SE01039361 | 2001-11-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1610542A true CN1610542A (zh) | 2005-04-27 |
Family
ID=20286096
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA028233514A Pending CN1610542A (zh) | 2001-11-23 | 2002-11-20 | 用于治疗胃食管返流性疾病的新应用 |
Country Status (20)
Country | Link |
---|---|
US (1) | US7358245B2 (zh) |
EP (1) | EP1453497A1 (zh) |
JP (1) | JP2005511632A (zh) |
KR (1) | KR20050044582A (zh) |
CN (1) | CN1610542A (zh) |
AR (1) | AR037299A1 (zh) |
AU (1) | AU2002353700A1 (zh) |
BR (1) | BR0214319A (zh) |
CA (1) | CA2466916A1 (zh) |
HU (1) | HUP0402080A3 (zh) |
IL (1) | IL161748A0 (zh) |
IS (1) | IS7272A (zh) |
MX (1) | MXPA04004774A (zh) |
NO (1) | NO20042613L (zh) |
NZ (1) | NZ532844A (zh) |
PL (1) | PL369402A1 (zh) |
RU (1) | RU2280443C2 (zh) |
TW (1) | TW200407110A (zh) |
WO (1) | WO2003043619A1 (zh) |
ZA (1) | ZA200403785B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103588672A (zh) * | 2013-10-28 | 2014-02-19 | 史克勇 | 一种治疗癌性疼痛的药物 |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1753413A2 (en) * | 2003-10-24 | 2007-02-21 | Solvay Pharmaceuticals GmbH | Novel medical uses of compounds showing cb sb 1/sb -antagonistic activity and combination treatment involving said compounds |
WO2005060971A1 (en) * | 2003-12-18 | 2005-07-07 | Astrazeneca Ab | Treatment of reflux-related diseases |
SE0303490D0 (sv) * | 2003-12-19 | 2003-12-19 | Astrazeneca Ab | New use V |
WO2006045799A2 (en) | 2004-10-25 | 2006-05-04 | Solvay Pharmaceuticals Gmbh | Pharmaceutical compositions comprising cb1 cannabinoid receptor antagonists and potassium channel openers for the treatment of diabetes mellitus type i, obesity and related conditions |
AU2005314021B2 (en) * | 2004-12-09 | 2010-02-11 | Insys Therapeutics, Inc. | Room-temperature stable dronabinol formulations |
US20080112895A1 (en) * | 2006-08-04 | 2008-05-15 | Insys Therapeutics Inc. | Aqueous dronabinol formulations |
CA2698752A1 (en) * | 2007-08-06 | 2009-02-12 | Insys Therapeutics Inc. | Oral cannabinoid liquid formulations and methods of treatment |
WO2009044402A1 (en) | 2007-10-02 | 2009-04-09 | Ariel - University Research And Development Company Ltd. | Endocannabinoids for enhancing growth and development in infants |
US20090208588A1 (en) * | 2008-02-19 | 2009-08-20 | Roger Wayne Brown | GERD carbohydrate compositions |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2735774B1 (fr) * | 1995-06-21 | 1997-09-12 | Sanofi Sa | Utilisation de composes agonistes du recepteur cb2 humain pour la preparation de medicaments immunomodulateurs, nouveaux composes agonistes du recepteur cb2 et les compositions pharmaceutiques les contenant |
DE69910373T2 (de) * | 1998-05-04 | 2004-04-01 | The University Of Connecticut, Farmington | Analgetische und immunomodulierende cannabinoiden |
AU776414B2 (en) | 1998-05-29 | 2004-09-09 | Neurosciences Research Foundation, Inc. | Control of pain with endogenous cannabinoids |
GB9923738D0 (en) | 1999-10-07 | 1999-12-08 | Nestle Sa | Nutritional composition |
IL132661A (en) * | 1999-10-31 | 2008-11-26 | Raphael Mechoulam | Agonists specific for peripheral cannabinoid receptors |
SE9904507D0 (sv) | 1999-12-09 | 1999-12-09 | Astra Ab | New compounds |
CA2410177C (en) * | 2000-06-15 | 2010-05-11 | Schering Corporation | Thrombin receptor antagonists |
AUPR118000A0 (en) * | 2000-11-02 | 2000-11-23 | Amrad Operations Pty. Limited | Therapeutic molecules and methods |
FR2816938B1 (fr) * | 2000-11-22 | 2003-01-03 | Sanofi Synthelabo | Derives de 3-aroylindole, leur procede de preparation et les compositions pharmaceutiques en contenant |
US20020077322A1 (en) * | 2000-12-15 | 2002-06-20 | Ayoub George S. | Protection of neurons against glutamate-induced damage in glaucoma and other conditions |
-
2002
- 2002-11-07 TW TW091132760A patent/TW200407110A/zh unknown
- 2002-11-11 AR ARP020104319A patent/AR037299A1/es not_active Application Discontinuation
- 2002-11-20 RU RU2004114843/15A patent/RU2280443C2/ru not_active IP Right Cessation
- 2002-11-20 US US10/496,431 patent/US7358245B2/en not_active Expired - Fee Related
- 2002-11-20 JP JP2003545300A patent/JP2005511632A/ja active Pending
- 2002-11-20 CN CNA028233514A patent/CN1610542A/zh active Pending
- 2002-11-20 EP EP02789069A patent/EP1453497A1/en not_active Withdrawn
- 2002-11-20 NZ NZ532844A patent/NZ532844A/en unknown
- 2002-11-20 BR BR0214319-4A patent/BR0214319A/pt not_active IP Right Cessation
- 2002-11-20 HU HU0402080A patent/HUP0402080A3/hu unknown
- 2002-11-20 AU AU2002353700A patent/AU2002353700A1/en not_active Abandoned
- 2002-11-20 CA CA002466916A patent/CA2466916A1/en not_active Abandoned
- 2002-11-20 WO PCT/SE2002/002108 patent/WO2003043619A1/en active IP Right Grant
- 2002-11-20 MX MXPA04004774A patent/MXPA04004774A/es not_active Application Discontinuation
- 2002-11-20 KR KR1020047007819A patent/KR20050044582A/ko not_active Application Discontinuation
- 2002-11-20 IL IL16174802A patent/IL161748A0/xx unknown
- 2002-11-20 PL PL02369402A patent/PL369402A1/xx unknown
-
2004
- 2004-05-17 ZA ZA200403785A patent/ZA200403785B/en unknown
- 2004-05-19 IS IS7272A patent/IS7272A/is unknown
- 2004-06-22 NO NO20042613A patent/NO20042613L/no not_active Application Discontinuation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103588672A (zh) * | 2013-10-28 | 2014-02-19 | 史克勇 | 一种治疗癌性疼痛的药物 |
Also Published As
Publication number | Publication date |
---|---|
WO2003043619A8 (en) | 2005-03-17 |
MXPA04004774A (es) | 2004-07-30 |
PL369402A1 (en) | 2005-04-18 |
AR037299A1 (es) | 2004-11-03 |
CA2466916A1 (en) | 2003-05-30 |
RU2004114843A (ru) | 2005-05-27 |
HUP0402080A3 (en) | 2008-03-28 |
RU2280443C2 (ru) | 2006-07-27 |
WO2003043619A1 (en) | 2003-05-30 |
NO20042613L (no) | 2004-08-13 |
NZ532844A (en) | 2005-12-23 |
US7358245B2 (en) | 2008-04-15 |
AU2002353700A1 (en) | 2003-06-10 |
KR20050044582A (ko) | 2005-05-12 |
IS7272A (is) | 2004-05-19 |
HUP0402080A2 (hu) | 2005-02-28 |
IL161748A0 (en) | 2005-11-20 |
ZA200403785B (en) | 2005-05-19 |
JP2005511632A (ja) | 2005-04-28 |
BR0214319A (pt) | 2004-11-03 |
US20040266861A1 (en) | 2004-12-30 |
EP1453497A1 (en) | 2004-09-08 |
TW200407110A (en) | 2004-05-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1501797A (zh) | 抗增殖药物 | |
CN1610542A (zh) | 用于治疗胃食管返流性疾病的新应用 | |
CN1420768A (zh) | 含有非甾类抗雄激素和egfr酪氨酸激酶抑制剂的联合产品 | |
CN1968696A (zh) | 用于治疗和控制肺高血压的包含沙利度胺的组合物以及其使用方法 | |
KR20120053008A (ko) | 암 및 다른 질환 또는 장애의 치료용 약제학적 조성물 | |
CA2990835A1 (en) | Compositions and methods for treating cancer | |
CN101801187B (zh) | 大麻素受体的杂环调节剂 | |
CN1820743A (zh) | 尿苷二磷酸-葡萄糖醛酸基转化酵素2b(ugt2b)的抑制剂及促进剂 | |
CN1197568C (zh) | 用于控制广谱疟疾的双氢青蒿素制剂及其制备方法 | |
CN1680390A (zh) | 卤代二氢青蒿素及其制备方法以及用途 | |
CN106474132B (zh) | 聚普瑞锌在制备治疗或减轻放化疗所致消化道并发症及肠易激综合征药物中的应用 | |
EP1010425B1 (en) | Remedies for irritable bowel syndrome | |
CN1889948A (zh) | 他汀用于治疗代谢综合征的用途 | |
CN1424312A (zh) | 一种特异性吲哚类化合物及制备方法与其在治疗和预防癌症等疾病中的应用 | |
CN1907314A (zh) | 蒲公英中酚酸类有效部位抑制妇科乳腺炎症的用途 | |
CN1680389A (zh) | 溴代二氢青蒿素 | |
CN1772022A (zh) | 阿魏及阿魏挥发油在制备抗癌药剂中的应用 | |
CN1736400A (zh) | 阿魏挥发油在制备肠易激综合症药剂中的应用 | |
KR101232425B1 (ko) | 요관결석증 치료용 의약 | |
Mierzwa et al. | Laryngological symptoms of gastroesophageal reflux disease | |
CN1600330A (zh) | 五味子及其提取物治疗肿瘤多药耐药的用途 | |
Joshi | Endocannabinoid system-A novel target for cardiometabolic risk | |
CN1872050A (zh) | 一种水飞蓟素滴丸及其制备方法 | |
CN1872046A (zh) | 一种黄豆苷元滴丸及其制备方法 | |
CN1579374A (zh) | 阿魏提取物的制药用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |