TW200301700A - Citric acid salt of a therapeutic compound and pharmaceutical compositions thereof - Google Patents
Citric acid salt of a therapeutic compound and pharmaceutical compositions thereof Download PDFInfo
- Publication number
- TW200301700A TW200301700A TW091135151A TW91135151A TW200301700A TW 200301700 A TW200301700 A TW 200301700A TW 091135151 A TW091135151 A TW 091135151A TW 91135151 A TW91135151 A TW 91135151A TW 200301700 A TW200301700 A TW 200301700A
- Authority
- TW
- Taiwan
- Prior art keywords
- depression
- citrate
- disorder
- patent application
- scope
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 title claims description 24
- 150000001875 compounds Chemical class 0.000 title claims description 9
- 230000001225 therapeutic effect Effects 0.000 title 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 46
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 18
- -1 4-methylhexahydropyridin-1-yl Chemical group 0.000 claims description 17
- 208000019901 Anxiety disease Diseases 0.000 claims description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 208000018737 Parkinson disease Diseases 0.000 claims description 14
- 208000035475 disorder Diseases 0.000 claims description 13
- 206010034912 Phobia Diseases 0.000 claims description 12
- 208000011580 syndromic disease Diseases 0.000 claims description 12
- 206010028980 Neoplasm Diseases 0.000 claims description 11
- 230000036506 anxiety Effects 0.000 claims description 11
- 201000011510 cancer Diseases 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 11
- 238000002441 X-ray diffraction Methods 0.000 claims description 10
- 238000005259 measurement Methods 0.000 claims description 10
- 208000019899 phobic disease Diseases 0.000 claims description 9
- 208000024891 symptom Diseases 0.000 claims description 9
- 206010012289 Dementia Diseases 0.000 claims description 8
- 206010019233 Headaches Diseases 0.000 claims description 8
- 230000001684 chronic effect Effects 0.000 claims description 8
- 208000019906 panic disease Diseases 0.000 claims description 8
- 208000020925 Bipolar disease Diseases 0.000 claims description 7
- 208000030814 Eating disease Diseases 0.000 claims description 7
- 208000027534 Emotional disease Diseases 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 208000019454 Feeding and Eating disease Diseases 0.000 claims description 7
- 235000014632 disordered eating Nutrition 0.000 claims description 7
- 230000036407 pain Effects 0.000 claims description 7
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 6
- 208000020401 Depressive disease Diseases 0.000 claims description 6
- 208000002193 Pain Diseases 0.000 claims description 6
- 206010047163 Vasospasm Diseases 0.000 claims description 6
- 229910052802 copper Inorganic materials 0.000 claims description 6
- 239000010949 copper Substances 0.000 claims description 6
- 208000011117 substance-related disease Diseases 0.000 claims description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 claims description 5
- 238000005481 NMR spectroscopy Methods 0.000 claims description 5
- 208000000810 Separation Anxiety Diseases 0.000 claims description 5
- 231100000869 headache Toxicity 0.000 claims description 5
- 238000012360 testing method Methods 0.000 claims description 5
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 4
- 208000031091 Amnestic disease Diseases 0.000 claims description 4
- 208000000103 Anorexia Nervosa Diseases 0.000 claims description 4
- 208000006561 Cluster Headache Diseases 0.000 claims description 4
- 208000012661 Dyskinesia Diseases 0.000 claims description 4
- 208000017701 Endocrine disease Diseases 0.000 claims description 4
- 240000006890 Erythroxylum coca Species 0.000 claims description 4
- 208000001613 Gambling Diseases 0.000 claims description 4
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 4
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 claims description 4
- 208000019695 Migraine disease Diseases 0.000 claims description 4
- 206010028403 Mutism Diseases 0.000 claims description 4
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 4
- 206010034158 Pathological gambling Diseases 0.000 claims description 4
- 206010036618 Premenstrual syndrome Diseases 0.000 claims description 4
- 206010039917 Selective mutism Diseases 0.000 claims description 4
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 claims description 4
- 206010041250 Social phobia Diseases 0.000 claims description 4
- 206010066218 Stress Urinary Incontinence Diseases 0.000 claims description 4
- 230000007000 age related cognitive decline Effects 0.000 claims description 4
- 230000002490 cerebral effect Effects 0.000 claims description 4
- 208000018912 cluster headache syndrome Diseases 0.000 claims description 4
- 235000008957 cocaer Nutrition 0.000 claims description 4
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 claims description 4
- 238000005388 cross polarization Methods 0.000 claims description 4
- 229960002069 diamorphine Drugs 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 208000029364 generalized anxiety disease Diseases 0.000 claims description 4
- 208000031424 hyperprolactinemia Diseases 0.000 claims description 4
- 208000021267 infertility disease Diseases 0.000 claims description 4
- 206010022437 insomnia Diseases 0.000 claims description 4
- 208000024714 major depressive disease Diseases 0.000 claims description 4
- 206010027599 migraine Diseases 0.000 claims description 4
- 208000010125 myocardial infarction Diseases 0.000 claims description 4
- 229960002715 nicotine Drugs 0.000 claims description 4
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims description 4
- 208000022821 personality disease Diseases 0.000 claims description 4
- 230000005855 radiation Effects 0.000 claims description 4
- 201000000980 schizophrenia Diseases 0.000 claims description 4
- 230000028327 secretion Effects 0.000 claims description 4
- 201000001716 specific phobia Diseases 0.000 claims description 4
- 208000019553 vascular disease Diseases 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 208000000044 Amnesia Diseases 0.000 claims description 3
- 201000006062 Asperger syndrome Diseases 0.000 claims description 3
- 208000032841 Bulimia Diseases 0.000 claims description 3
- 206010006550 Bulimia nervosa Diseases 0.000 claims description 3
- 208000012239 Developmental disease Diseases 0.000 claims description 3
- 208000026331 Disruptive, Impulse Control, and Conduct disease Diseases 0.000 claims description 3
- 206010013654 Drug abuse Diseases 0.000 claims description 3
- 208000001640 Fibromyalgia Diseases 0.000 claims description 3
- 208000011688 Generalised anxiety disease Diseases 0.000 claims description 3
- 206010020772 Hypertension Diseases 0.000 claims description 3
- 208000030990 Impulse-control disease Diseases 0.000 claims description 3
- 208000026139 Memory disease Diseases 0.000 claims description 3
- 208000008589 Obesity Diseases 0.000 claims description 3
- 201000009916 Postpartum depression Diseases 0.000 claims description 3
- 208000028017 Psychotic disease Diseases 0.000 claims description 3
- 208000027520 Somatoform disease Diseases 0.000 claims description 3
- 230000006986 amnesia Effects 0.000 claims description 3
- 239000000164 antipsychotic agent Substances 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 230000036461 convulsion Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 206010013663 drug dependence Diseases 0.000 claims description 3
- 210000002919 epithelial cell Anatomy 0.000 claims description 3
- 208000013403 hyperactivity Diseases 0.000 claims description 3
- 238000002844 melting Methods 0.000 claims description 3
- 230000008018 melting Effects 0.000 claims description 3
- 235000020824 obesity Nutrition 0.000 claims description 3
- 230000001107 psychogenic effect Effects 0.000 claims description 3
- 230000000306 recurrent effect Effects 0.000 claims description 3
- 230000000472 traumatic effect Effects 0.000 claims description 3
- 201000009030 Carcinoma Diseases 0.000 claims description 2
- 238000013019 agitation Methods 0.000 claims description 2
- 229940005529 antipsychotics Drugs 0.000 claims description 2
- CIZVQWNPBGYCGK-UHFFFAOYSA-N benzenediazonium Chemical class N#[N+]C1=CC=CC=C1 CIZVQWNPBGYCGK-UHFFFAOYSA-N 0.000 claims description 2
- 208000028683 bipolar I disease Diseases 0.000 claims description 2
- 208000025307 bipolar depression Diseases 0.000 claims description 2
- 238000000354 decomposition reaction Methods 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 240000004308 marijuana Species 0.000 claims description 2
- 230000002969 morbid Effects 0.000 claims description 2
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 claims description 2
- 229960002695 phenobarbital Drugs 0.000 claims description 2
- 238000007689 inspection Methods 0.000 claims 3
- 206010006100 Bradykinesia Diseases 0.000 claims 1
- 206010010904 Convulsion Diseases 0.000 claims 1
- 208000006083 Hypokinesia Diseases 0.000 claims 1
- 230000006978 adaptation Effects 0.000 claims 1
- 238000005516 engineering process Methods 0.000 claims 1
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 1
- 239000011707 mineral Substances 0.000 claims 1
- 230000001314 paroxysmal effect Effects 0.000 claims 1
- 230000002028 premature Effects 0.000 claims 1
- 239000011593 sulfur Substances 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 210000001260 vocal cord Anatomy 0.000 claims 1
- 150000001860 citric acid derivatives Chemical class 0.000 abstract description 4
- LHYMPSWMHXUWSK-STZFKDTASA-N (2z)-4-(3,4-dichlorophenyl)-2-[[2-(4-methylpiperazin-1-yl)phenyl]methylidene]thiomorpholin-3-one Chemical compound C1CN(C)CCN1C1=CC=CC=C1\C=C/1C(=O)N(C=2C=C(Cl)C(Cl)=CC=2)CCS\1 LHYMPSWMHXUWSK-STZFKDTASA-N 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- 239000013078 crystal Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 9
- 238000000634 powder X-ray diffraction Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 238000006073 displacement reaction Methods 0.000 description 6
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- 238000004364 calculation method Methods 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 230000001629 suppression Effects 0.000 description 4
- 101710138068 5-hydroxytryptamine receptor 1D Proteins 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010012335 Dependence Diseases 0.000 description 3
- 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 3
- 125000005233 alkylalcohol group Chemical group 0.000 description 3
- 208000014679 binge eating disease Diseases 0.000 description 3
- 208000015114 central nervous system disease Diseases 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 206010036596 premature ejaculation Diseases 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- GAYHSOMQUZWPIU-UHFFFAOYSA-N ClC=1C=C(C=CC1Cl)N1C(C(SCC1)=CC1=C(C=CC=C1)N1CCC(CC1)C)=O Chemical compound ClC=1C=C(C=CC1Cl)N1C(C(SCC1)=CC1=C(C=CC=C1)N1CCC(CC1)C)=O GAYHSOMQUZWPIU-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000033039 Somatisation disease Diseases 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 206010047139 Vasoconstriction Diseases 0.000 description 2
- 150000005215 alkyl ethers Chemical class 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 2
- 208000022804 avoidant personality disease Diseases 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 201000001881 impotence Diseases 0.000 description 2
- 239000007788 liquid 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
- 238000002156 mixing Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 238000000371 solid-state nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 208000016994 somatization disease Diseases 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 208000002271 trichotillomania Diseases 0.000 description 2
- 230000025033 vasoconstriction Effects 0.000 description 2
- 230000001755 vocal effect Effects 0.000 description 2
- APEJJZWSMSARIL-UHFFFAOYSA-N 1,2,2,3,3,4,4-heptamethylpyridine Chemical compound CN1C=CC(C)(C)C(C)(C)C1(C)C APEJJZWSMSARIL-UHFFFAOYSA-N 0.000 description 1
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- FZIPCQLKPTZZIM-UHFFFAOYSA-N 2-oxidanylpropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O FZIPCQLKPTZZIM-UHFFFAOYSA-N 0.000 description 1
- YNKUJUOSWZNSJW-UHFFFAOYSA-N 3,4-dimethylpiperidine Chemical compound CC1CCNCC1C YNKUJUOSWZNSJW-UHFFFAOYSA-N 0.000 description 1
- UZOFELREXGAFOI-UHFFFAOYSA-N 4-methylpiperidine Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 description 1
- WKEFLFITHLGEHT-UHFFFAOYSA-N 6-hydroxy-4,8-dioxotrioxocane-6-carboxylic acid Chemical compound C1C(=O)OOOC(=O)CC1(C(=O)O)O WKEFLFITHLGEHT-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 208000008811 Agoraphobia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000036640 Asperger disease Diseases 0.000 description 1
- AOCUIRLSFONLMP-UHFFFAOYSA-N C1(=CC=CC=2C3=CC=CC=C3CC12)C1CCNCC1 Chemical compound C1(=CC=CC=2C3=CC=CC=C3CC12)C1CCNCC1 AOCUIRLSFONLMP-UHFFFAOYSA-N 0.000 description 1
- 244000025254 Cannabis sativa Species 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010008025 Cerebellar ataxia Diseases 0.000 description 1
- 206010068631 Childhood depression Diseases 0.000 description 1
- 206010009094 Chronic paroxysmal hemicrania Diseases 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 229910016523 CuKa Inorganic materials 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 208000001836 Firesetting Behavior Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 208000027030 Premenstrual dysphoric disease Diseases 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 1
- 206010043118 Tardive Dyskinesia Diseases 0.000 description 1
- 208000023655 Tic Diseases 0.000 description 1
- 241001648319 Toronia toru Species 0.000 description 1
- 208000000323 Tourette Syndrome Diseases 0.000 description 1
- 208000016620 Tourette disease Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229910001573 adamantine Inorganic materials 0.000 description 1
- 208000012826 adjustment disease Diseases 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 208000029560 autism spectrum disease Diseases 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229960003563 calcium carbonate Drugs 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000004568 cement Substances 0.000 description 1
- 230000035606 childbirth Effects 0.000 description 1
- 208000021703 chronic tic disease Diseases 0.000 description 1
- 239000000571 coke Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 125000004188 dichlorophenyl group Chemical group 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 238000009499 grossing Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 208000015046 intermittent explosive disease Diseases 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 206010023461 kleptomania Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000015122 lemonade Nutrition 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 201000003995 melancholia Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- VSEAAEQOQBMPQF-UHFFFAOYSA-N morpholin-3-one Chemical compound O=C1COCCN1 VSEAAEQOQBMPQF-UHFFFAOYSA-N 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 208000027753 pain disease Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 208000007777 paroxysmal Hemicrania Diseases 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 201000004645 pyromania Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 208000025874 separation anxiety disease Diseases 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 230000000697 serotonin reuptake Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 210000004927 skin cell Anatomy 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 208000022170 stress incontinence Diseases 0.000 description 1
- 238000000547 structure data Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 208000016686 tic disease Diseases 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000008733 trauma Effects 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
- A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic 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
- A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- 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
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/34—Tobacco-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Addiction (AREA)
- Psychiatry (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Reproductive Health (AREA)
- Cardiology (AREA)
- Pain & Pain Management (AREA)
- Psychology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Anesthesiology (AREA)
- Hospice & Palliative Care (AREA)
- Rheumatology (AREA)
- Nutrition Science (AREA)
- Obesity (AREA)
- Gynecology & Obstetrics (AREA)
- Child & Adolescent Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Description
(i) 200301700 终.„、發明說0月 (發明說明應敘明··發明所屬之技術領域、先前技術、内容、實施方式及圖式簡單說明) 本發明係關於4-(3,4-二氯基苯基）-2-[2-(4-甲基六氫吡呼_ 1-基）-亞苄基]-硫嗎P林基酮之擰檬酸鹽多形：
CIN
cl
及其.醫藥組成物。 化合物4-(3,4-二氯基苯基）_2·[2·(4_甲基六氤吡畊_丨·基） 亞下.基卜硫嗎啉基-3-酮為一種血清素]D(5-HT|〇)受器之扣 抗劑，其在許多中樞神經系統之失調、疾病及病況之治瘰 上是有用的，此化合物在哺乳類（特別是人類）治療高土 壓；所有抑鬱型式；癌症病患抑鬱；帕金森氏症病患抑鬱； 心肌梗塞後抑鬱；亞症候群表徵型抑鬱（subsyndr〇ma symptomatic depression);不孕婦女之抑鬱；兒童抑鬱症； 重鉍症（major depressive disorder);單次抑鬱發病；復發崔 抑營’兒里I虐導致之抑费；產後憂縈症；輕營症 (dys thy mi a);具有或不具有非典型特徵、病態憂鬱症 (melancholic depression) '精神病特徵、僵直性特徵之輕度、 中度及重度抑寶’季節影響型症候群（seas〇nalaffectiv disorder);老年抑鬱；慢性抑鬱；具有抑鬱情緒或具有旁 慮及抑#情緒之適應障礙（adjustment dis〇rder);混合型焦肩 及抑敦’藥物盡用導致之情緒失調（substance induced m〇〇 200301700 (2) 發明說明續頁 disorder);以及一般醫學症狀、躁鬱症（bipolar disorder)、躁 # 症抑# 期、廣泛性焦慮症（generalized anxiety disorder)、 恐懼症（phobias)、懼曠症（agoraphobia)、社會焦慮症（social anxiety)、社會恐懼症（social phobia)、單純型恐懼症（simple phobia)、分離焦慮症（separation anxiety disorder)、創傷壓力 症候群、畏避型人格障礙（avoidant personality disorder)、 早洩（premature ejaculation)、進食障礙、飲食疾患（binge eating disorder )、神經性厭食症（anorexia nervosa)、心因性暴食症 (bulimia)、肥胖引起之二次性情緒障礙；化學依賴及酒精、 古柯驗、海洛因、禾巴比妥、尼古丁、大麻及苯重氮基鹽 (benzodiazepine)成瘾；叢發性頭痛（cluster headache)、偏頭 痛（migraine)、疼痛、阿茲海默氏症、強迫症、恐慌症、具 懼瞻症之恐慌症、記憶障礙、痴呆、健忘症（amnestic disorder) 及年齡相關性知能減退（age related cognitive decline， ARCD)、帕金森氏症、在帕金森氏症中之痴呆、抗精神藥 物引起之巴金森症（neuroleptic-induced parkinsonism)及遲緩 性動作困難（tardive dyskinesia)、内分泌失調、高泌乳激素 血症、血管瘦攣、腦血管之血管瘦攣、小腦性運動失調 (cerebellar ataxia);與運動及分泌有關之腸胃道障礙；精神 分裂（schizophrenia)之負性症狀（negative symptom)、經前症 候群（premenstrual syndrome)、纖維肌痛症候群（fibromyalgia syndrom)、應力尿失禁（stress incontinence)、妥瑞症（Tourette’s syndrome)、拔毛癖（trichotillomania)、竊盜癖（kleptomania)、 男性陽萎（male impotence)、癌症、小細胞肺臟上皮細胞癌、 200301700 (3) 發明說明績頁 慢性發作性單側頭痛（chronic paroxysmal hemicrania)、與血 管疾病有關之頭痛、廣泛性發展障礙症（pervasive developmental disorder NOS)、亞斯伯格症（Asperger ’ s disorder)、選擇性緘默症（selective mutism)、慢性運動或聲 帶抽搐性失常（chronic motor or vocal tic disorder)、軀體化失 常（somatization disorder)、失眠（insomnia)、間歇性狂暴症 (intermittent explosive disorder)、縱火癖（pyromania)、病理性 賭博（pathological gambling)、衝動控制性障礙（impulse-control disorder)、經前焦躁症（premenstrual dysphoric disorder)及注 意力缺乏及過動障礙（attention deficit/hyper activity disorder(ADHD))上是特別有用的。本發明之擰檬酸鹽亦可 用於與血清素重新收抑制抗抑蕾劑（serotonin reuptake inhibiting antidepressant，SRI)合併之醫藥組成物中，以治療 多種此等病況。 血清素-1D受器拮抗劑之化合物包括4-(3，4-二氯基苯基）-2-[2-(4-甲基六氫吡畊-1-基）-亞苄基]-硫嗎啉基-3-酮，特別 包括其氫氯酸鹽，在於1998年4月9日公告之WO 98/ 1443 3中 被提及（依據1997年9月8日提出申請之U.S. Ser. No. 09/254,999 ; 2000年 12 月 8 日提出中請之 ν〇· 09/733,346及 2001 年11月12日才疋出申δ青之PCT/IB01/02139號）。前述申請案和 本發明為同一所有人，並在此以其完整性、在此所指化合 物所再次引用之醫藥上可接受的酸加成鹽類併入參考文獻 〇 本發明之檸檬酸鹽所展示之性質包括彼等與某些藥物產 200301700 (4) I發明說明喊頁 物調配賦形劑之固態穩定性及可配伍性，而優於先前已知 之4-(3,4-二氯基苯基）-2-[2-(4-甲基六氫吡畊-1-基）-亞苄基]-硫嗎17林基-3-酮之鹽類。 圖示簡要說明 圖1為4-(3,4-二氯基苯基）-2-[2-(4-甲基六氫吡畊-1-基）-亞 芊基]-硫嗎啉基-3-酮之檸檬酸鹽之示差掃描熱卡計 (Differential Scanning Calorimetric，DSC)之跡線。 圖2為所觀察之4-(3,4-二氯基苯基）-2-[2-(4-曱基六氫吡畊· 1-基）-亞芊基]-硫嗎啉基-3-酮之檸檬酸鹽之X光粉末繞射樣 式（y軸為每秒之線狀計數，X軸為2 0度）。 圖3為4-(3,4-二氯基苯基）-2-[2-(4-甲基六氫吡畊-1-基）··亞 苄基]-硫嗎啉基-3-酮之檸檬酸鹽之X光粉末繞射（y軸為每 秒之線狀計數，X軸為2 0度）計算。 圖4為4-(3,4->一 SL基+基）-2-[2-(4 -甲基氮卩比呼-1-基）-亞 苄基]-硫嗎啉基-3-酮之檸檬酸鹽之X射線結晶結構。
圖5為4-(3,4-二氯基苯基）-2-[2-(4-甲基六氫吡畊-1-基）_亞 苄基]-硫嗎啉基-3-酮之檸檬酸鹽在固相中，在295 K下以位 在固態核磁共振光譜儀（Bruker Avance DRX 500 MHz NMR
Spectrometer)下之Bruker 7mm廣π魔角自旋（WB MAS)探針之 交叉極化魔角自旋（CPMAS)收集13C NMR光譜。 發明摘要 本發明係關於4-(3,4·二氯基苯基）-2-[2-(4-甲基六氫吡畊-1-基）-亞芊基]-硫嗎啉基-3-酮之檸檬酸鹽’此發明之檸檬 酸鹽為無水的或接近無水的多形。 200301700 (5) 昼明說明:績頁 以銅放射測量本發明之檸檬酸鹽，其主要X射線繞射樣 式高峰表現在2 Θ度及d空隙期間（在指示錯誤之邊緣間）之 進一步特徵為： 20 角度(±0.2) d 值(A)(±0.2) 13.0 6.8 17.4 5.1 18.0 4.9 18.9 4.7 20.0 4.4 21.2 4.2 22.2 4.0 24.0 3.7 27.1 3.3 32.4 2.8
本發明之檸檬酸鹽具有一般薄片形式之特徵，此外，此 檸檬酸鹽亦具有形成屬於Pc空間群之單斜晶形晶體之特 徵。此檸檬酸鹽進一步以示差掃描熱卡計（DSC)測量後， 為具有開始約在198-199°C之熔點轉移/分解點之特性，此 外，本發明檸檬酸鹽亦具有1.3毫克/毫升之水溶性特徵， 且在水溶液中pH值為3.37，此外，本檸檬酸鹽在90%之相 對溼度下具有接近1.27%之吸濕性。 本發明之檸檬酸鹽亦具有當以固態i3C NMR交叉極化魔 角自旋技術檢測時顯示出下列主要下半部共振高峰之特 徵，由每百萬100份（±〇·1 ppm;相對於在29.5 ppm之金剛燒 -10- 200301700 發明說明績頁 (6) 標準）：（5 179.3、177.0、171.6、164.0、15 1.0及 144.1。 本發明之另一具體實施例係關於一種醫藥組成物，其含 有4-(3,4-二氯基苯基）-2-[2-(4-甲基六氫吡畊-1-基）-亞苄基]-硫嗎p林基-3 -酮之檸檬酸鹽及醫藥上可接受的載體或賦形 劑，特別是在治療高血壓；所有抑鬱型式；癌症病患抑鬱； 帕金森氏症病患抑鬱；心肌梗塞後抑鬱；亞症候群表徵型 抑鬱；不孕婦女之抑鬱；兒童抑鬱症；重鬱症；單次抑鬱 發病；復發型抑鬱；兒童受虐導致之抑鬱；產後憂鬱症； 輕鬱症；具有或不具有非典型特徵、病態憂鬱症、精神病 特徵、僵直性特徵之輕度、中度及重度抑鬱；季節影響型 症候群；老年抑鬱；慢性抑鬱；具有抑鬱情緒或具有焦慮 及抑鬱情緒之適應障礙；混合型焦慮及抑鬱；藥物濫用導 致之情緒失調；以及一般醫學症狀、躁鬱症、躁鬱症抑鬱 期、廣泛性焦慮症、恐懼症、懼曠症、社會焦慮症、社會 恐懼症、單純型恐懼症、分離焦慮症、創傷壓力症候群、 畏避型人格障礙、早洩、進食障礙、飲食疾患、神經性厭 食症、心因性暴食症、肥胖引起之二次性情緒障礙；化學 依賴及酒精、古柯驗、海洛因、苯巴比妥、尼古丁、大麻 及苯重氮基鹽成瘾；叢發性頭痛、偏頭痛、疼痛、阿茲海 默氏症、強迫症、恐慌症、具懼日廣症之恐慌症、記憶障礙、 痴呆、健忘症及年齡相關性知能減退、帕金森氏症、在帕 金森氏症中之痴呆、抗精神藥物引起之巴金森症及遲缓性 動作困難、内分泌失調、高泌乳激素血症、血管痙攣、腦 血管之血管痙攣、小腦性運動失調；與運動及分泌有關之 (7) 200301700 腸胃道障礙；精神分裂之負 痛症候群、應力尿失禁、妥 陽萎、癌症、小細胞肺臟上 痛、與血管疾病有關之頭痛 格症、選擇性緘默症、慢性 化失常、失眠、間歇性狂暴 動控制性障礙、經前焦躁症 使用。 #明說明讀;頁 性症狀、經前症候群、纖維肌 瑞症、拔毛癖、竊盜癖、男性 皮細胞癌、慢性發作性單側頭 、廣泛性發展障礙症、亞斯伯 運動或聲帶抽搐性失常、軀體 症、縱火癖、病理性賭博、衝 及 >王意力缺乏及過動障礙上之 茲海默氏症、強迫症、恐慌症、 本發明進-步係關於治療高血壓；戶斤有抑#型式；癌症 病患抑#;帕金森氏症病患抑# ;心肌梗塞後抑# ;亞症 候群表徵型抑鬱；不孕婦女之抑鬱；兒童抑鬱症；重鬱症； 單次抑蕾發病：復發型抑# ;兒童受虐導致之抑鬱；產後 憂鬱症；輕鬱症；具有或不具有非典型特徵、病態憂鬱症、 精神病特徵、僵直性特徵之輕度、中度及重度抑鬱；季節 影響型症候群；老年抑#;慢性抑鬱；具有抑鬱情緒或具 有焦慮及抑费情緒之適應障礙。昆合型焦慮及抑# ;藥物 濫用導致之情緒失調·』及一般醫學症狀、躁鬱症、躁鬱 症抑费期、廣泛性焦慮症、恐懼症、懼瞻症社會焦慮症、 社會恐隸、單純型恐懼症、分離焦慮症、創傷塵力症候 群κ避型人格障礙、早洩、進食障礙、飲食疾患、神經 性厭食症'心因性暴食症1畔引起之二次性情緒障礙； :學依賴及酒精、古柯驗、⑨洛因'笨巴比妥、尼古丁、 麻及苯重氣基鹽成癌；叢發性頭痛、偏頭痛、疼痛、阿 具懼曠症之恐慌症、記憶 -12- 200301700 發明說明續頁 (8) 障礙、痴呆、健忘症及年齡相關性知能減退、帕金森氏症、 在帕金森氏症中之痴呆、抗精神藥物引起之巴金森症及遲 缓性動作困難、内分泌失調、高泌乳激素血症、血管痙攣、 腦血管之血管痙攣、小腦性運動失調；與運動及分泌有關 之腸胃道障礙；精神分裂之負性症狀、經前症候群、纖維 肌痛症候群、應力尿失禁、妥瑞症、拔毛癖、竊盜癖、男 性陽萎、癌症、小細胞肺臟上皮細胞癌、慢性發作性單側 頭痛、與血管疾病有關之頭痛、廣泛性發展障礙症、亞斯 伯格症、選擇性緘默症、慢性運動或聲帶抽搐性失常、軀 體化失常、失眠、間歇性狂暴症、縱火癖、病理性賭博、 衝動控制性障礙、經前焦躁症及注意力缺乏及過動障礙之 方法，其包含給與需要之個體4-(3,4-二氯基苯基）-2-[2-(4-甲基六氫吡畊-1-基）·亞苄基]-硫嗎啉基-3-酮之檸檬酸鹽。 本發明亦係關於4-(3,4-二氯基苯基）-2-[2-(4-甲基六氫吡 畊-1-基）-亞苄基]-硫嗎啉基-3-酮之檸檬酸鹽之製法，其包 含下列步驟： (i) 溶解於適當溶劑之4-(3,4-二氯基苯基）-2-[2-(心甲基六 氫巧b _ -1 -基）-亞芊基]-硫嗎琳基-3 -酮與檸檬酸接觸；且 (ii) 收集所形成之晶體。 在較佳之具體實施例中，適當之溶劑係自（CrC6)烷基 醇、（CrC6)烷基酮或（CrC6)烷基醚所組成之群中選擇，更 較佳之適當溶劑為2-丙醇。在本發明之製程中，以檸檬酸 溶液與溶液相之4-(3,4-二氯基苯基）-2-[2-(4-甲基六氫吡畊-1-基）-亞苄基]-硫嗎啉基-3-酮接觸實行步驟（i)之接觸為較 (9)200301700 佳，更佳之執行步 氯基苯基 3- 酮之溶液中。 較佳之接觸步驟 至20小時間，並包 之較佳具體實施例 之回流溫度間；更 (即約80°C )間；本. 旦檸檬酸加入後， 佳，且在反應期間 本發明亦係關於 苯基）-2-[2-(4-甲基 之檸檬酸鹽。 化合物4-(3,4-二 亞芊基]-硫嗎p林基, 之拮抗劑，且在許 用的。此化合物之 1998年4月9曰公開: 來製備，其在此完 檸檬酸鹽可在多 4- (；3,4-二氯基苯基: 嗎啉基-3-酮之自由 溶解，隨後將檸檬 s母肩明續:頁 __二 w、、 驟⑴接觸為加入固體檸檬酸至4-(3,4-二 甲基六氫吡畊+基）-亞苄基]-硫嗎啉基- 為處理超過1至24小時的時間，更佳為⑺ 含攪拌或混合產生之混合物，在此製程 中’其中步騾（i)運轉在周遭溫度及溶劑 佳為介於周遭溫度及2-丙醇之回流溫度 發明最佳之製成運轉在3〇至6〇。〇間，一 使反應混合物冷卻至室溫而完成者為較 可允許攪摔殘餘物。 依據本發明製程所製備之4-(3,4-二氯基 ^氣叫：_ -1-基）_亞苄基]•硫嗎啉基-3-酮 I基苯基）-2-[2-(4-甲基六氫吡畊-1-基）-_3、鋼為一種血清素-1D受器（5-HT1D受器） 夕CNS疾病、失調及症狀之治療上是有 自由驗基及其氯化氫鹽類可依據陳述於 、國際專利公告No·WO 98/H433中之方法 整併入參考文獻中。 種不同情況下製備，然而，依據本發明， -2-[2-(4·甲基六氫吡畊-丨·基卜亞芊基]-硫 驗基較佳為溶解於適當溶劑直到完全地 §又加入落液中從而製備出本發明之檸棟 ，14- 200301700 發明說明續頁 (ίο) 酸加成鹽。適當溶劑較佳選自（crc6)烷基醇、（crc6)烷基 酮或（crc6)烷基醚所組成之群；更較佳之適當溶劑為（crc6) 烷基醇；最佳者為2-丙醇。在本發明之製程中，其中以檸 檬酸溶液或檸檬酸之固體形式與溶液相之4-(3,4-二氯基苯 基）-2-[2-(4-甲基六氫吡畊-1-基）-亞苄基]-硫嗎啉基-3-酮作 接觸之實行步驟（i)之接觸為較佳。 較佳之接觸步驟為處理超過1至24小時的時間，更佳為1 0 至20小時間，並包含攪拌或混合所產生之混合物，在此製 程之較佳具體實施例中，其中步驟（i)運轉在周遭溫度及溶 劑之回流溫度間；更佳為介於周遭溫度及2-丙醇之回流溫 度（即約80°C )間；最佳之製程運轉在30至60°C間。一旦檸 檬酸加入後使反應混合物冷卻至室溫而完成者為較佳，且 在反應期間可允許攪拌殘餘物。 4-(3,4-二氯基苯基）-2-[2-(4-甲基六氫吡畊-1-基）-亞芊基]-硫嗎啉基-3-酮之擰檬酸鹽只具有些微的吸濕性並具有高的 水溶性，此等併有對於醫藥調配物所使用之一般賦形劑為 相對惰性之特徵，使其為高度適合於醫藥調配物之使用。 儘管一般之4-(3,4-二氯基苯基）-2-[2-(4-甲基六氫吡畊-1-基）-亞苄基]-硫嗎啉基-3-酮之已知酸加成鹽類皆為晶體， 但是彼等大部分鹽類皆具吸濕性，成為在醫藥調配物之使 用上不好的候選物。本發明之檸檬酸鹽在暴露於90%之相 對溼度之潮濕箱中，展現了約1.27% wt/wt之吸濕性。此檸 檬酸鹽之水溶性為1.3毫克/毫升，pH值為3.37，此外，4-(3,4-二氯基苯基）2-[2-(4-甲基六氫吡畊-1-基）-亞芊基卜硫嗎啉基 200301700 (11) 明績頁 -3-§同之彳宁樣鹽在光知、及^疋南溫度兩者以及高澄度之挑戰 下展現了絕佳之固態穩定性。 示差掃描熱卡計 以示差掃描熱卡計（DSC)調查本發明檸檬酸鹽之固態熱 行為’此鹽之跡線顯示於圖1中，DSC溫度自記圖 (thermograms)在 Mettler Toledo DSC 831e(STARe System)上獲 得。一般在有小孔之摺皺的鋁盤中製備1至1〇毫克間之樣 品，在每分鐘5°c之加熱速率下，30至300 °C的範圍内， 進行測量。 如在圖1中所見，檸檬酸鹽在約198-199°C時展現溶態轉 變的開始，然而熟習本項技藝者將注意到DSC測量在實際 測量開始及溫度高峰上具有某些程度上的變化性，其發生 係依據加熱速率、晶體形狀及純度，及其他測量參數而變 化。 X光粉末繞射樣式 使用裝配銅射線CuKa、固定長條（1.〇、1·〇、0.6毫米）及 Kevex固態偵測器之 Bruker D5000繞射儀（Bruker AXS，Madison， Wisconsing)收集本發明檸檬酸鹽之χ光粉末繞射樣式，使 用每階段大小為〇·〇4度及每階段時間為1 ·0秒，在2 0中之3.0 至40.0度收集資料。 以銅陽極在1.54056之波長1及1.54439之波長2(相對強度： 0.500)下表現檸檬酸鹽之χ光粉末繞射樣式，在2 0中之3.0 至40·0度間使用每階段大小為〇 〇4度、每階段時間為1·〇〇 秒、平滑寬度為0·300及閾值為i.O之值。 •16· 200301700 發明說明續頁 (12) 此鹽類所測量的X光粉末繞射之繞射角（2 Θ )之繞射高峰 分析顯示在表I中，然而相對強度可依據晶體大小及形態 而改變，實際測量的粉末繞射圖顯示在圖2中。 表I擰檬酸鹽X光粉末繞射樣式之強度及繞射線高峰位 Angle d-value Angle d-value 1 Angle d-value 1 2Θ (A) (rel·) \2Θ (A) (rel.) 2Θ (A) (rel.) 8.2 10.7 3.7 23.1 3.9 13.6 32.4 2.8 18.6 11.5 7.7 4.9 24.0 3.7 33.5 32.8 2.7 7.4 13.0 6.8 14.5 24.7 3.6 5.3 33.6 2.7 3.3 13.7 6.5 5.6 25.1 3.5 9.9 34.5 2.6 6.3 14.9 5.9 9.8 26.2 3.4 6.9 34.9 2.6 4.7 16.3 5.4 7.0 26.6 3.4 11.2 35.8 2.5 4.1 16.6 5.3 13.1 27.1 3.3 20.4 36.3 2.5 7.5 17.4 5.1 100.0 27.7 3.2 6.2 36.8 2.4 4.3 18.0 4.9 40.2 28.3 3.2 6.3 37.3 2.4 5.7 18.9 4.7 17.3 29.6 3.0 10.7 38.3 2.4 6.3 20.0 4.4 71.6 30.4 2.9 8.3 38.9 2.3 4.3 21.2 4.2 23.4 31.0 2.9 3.4 22.2 4.0 20.0 31.6 2.8 2.8 | 表II陳述了 2 0 、d-間隔及相對強度，以及代表擰檬酸鹽
之X光粉末繞射樣式高峰位，所列數目由電腦產生。 -17- (13) 200301700 犛明說明續頁 表11 rM^末繞檬酸鹽之高辛位
Angle ϋ 13.0 d-value(Al 6.8 17.4 5.1 1 100.0 18.0 4.9 18.9 4.7 40^ 17.3 20.0 4.4 71.6 21.2 4.2 23..4 22.2 4.0 20.0 24.0 3.7 33.5 27.1 3.3 20.4
EH 2.8 18.6 單一晶體X射線分折 獲得本發明檸檬酸鹽之單一晶體並以χ射線繞射調查， 測量代表晶體並在Siemens R4RA/V繞射儀上收集1Α資料組 (最大 sin 0 / λ =θ·5) 〇 以 International Tables for X-Ray Crystajlpgraphy, Vol. IV, pp. 55, 99，149 (Birmingham: Kynoch Press, 1974)去除原子散射因子。自單一晶體上收集的資料， 計算X光粉末繞射樣式以提供相對於實際測量的繞射樣 式0 使用直接方法解釋結構，由Bruker AXS，Inc提供 SHELXTL™電腦資料庫幫助所有必要的晶體學計算及分子 陳列（SHELXTLTM Reference Manual，Version 5.1，Bruker AXS， -18- (14) 200301700 資料收集及精製摘要在
Madison，WI 1997)，適當的晶體 表III中。 以直接方法獲得試驗处错Y、，1 、 又仟飞馱〜構並以常規方式精鍊，在任何可 能處計异氫的位置，以不同傅上一 J 乂某（Fourier)技術定位甲燒 及氮和氧上面的氫’將氫參數加至結構因子計算中但未被 精鍊，在最後方格精鍊之最終循環平移計算皆符合標準差 之少於0.1。最後的R指數為4·72%，最後區別所顯示之傅立 茱無遺失或錯置電子密度。精鍊之結構使用SHELXTL繪圖 套組製圖並顯示在圖4中。 _ 表IV陳列該鹽之原子配位結合（X丨〇4)及等量等向性位移 參數（A2x 103)。表V列出觀察到此擰檬酸鹽之鍵長[A]及角 [° ]’在表VI中陳列檸檬酸鹽之非等向性的位移參數（A2X 1 03)而能夠作非等向性位移因子指數之計算，其具有下式： -2 7Γ 2[h2a*2Uu+... + 2hka*b*U12]。最後，在下表 VII 中列出該 鹽之氫配位結合（X 1〇4)及等向性位移參數（A2X 1〇3)。
•19- 200301700(15) 奈明說明續頁 表III檸檬酸鹽之晶體結構資料及測量參數 參數 檸檬酸鹽 實驗式 C22H24N30SC12+C6H707 分子量 640.52 溫度 293(2) k 波長 1.54178A 晶體系 單斜晶 間群 Pc 單間隔尺度 a=6.5940(10) A a =90° b二 15.257(2) A β= 101.440( 10)° c=15.099(2) A γ=90° 體積 1488.9(4)A3 Z 2 密度(經計算的） 1.429 Mg/m3 吸收係數 3.081 mnr1 F(OOO) 668 晶體大小 0.24X0.04X0.04 mm3 收集到之反射 1707 獨立反射 1707[R(int)=0.0000] 完整之0=49.980 100.0% 吸收修正數 血 精標方法 Full-matrix least-squares on F2 資料/管制/數 1707/0/391 F2上符合優點值 1.065 最後R指數[1>2 sigma(I)] Rl=0.0472， wR2=0.1028 絕對結構參數 -0.01(3) 諧減係數 0.0038(6) 最大區別高峰及低減 0.223 及-0.268 e. A·3
-20- 200301700 (16) 「發明說明續頁 移 表iv檸檬酸鹽 參數（A2 X ίο3)。 之原子配位結合（X 1 〇4)及等量等向性位 (U(eq)被定義為正交Uij張量之1/3軌跡） X y X U(eq) S(1X) 1600 3502(2) 8401 53⑴ CI(1X) 7950(8) 4063(2) 13244(3) 83⑴ CI(2X) 11404(8) 2613(2) 13403(3) 73⑴ N(1) 8720(15) 1936(5) 6037(6) 42(2) C(2) 9164(19) 2836(7) 5723(7) 50(3) C(3) 7216(19) 3358(7) 5475(7) 48(3) N(4) 6189(14) 3417(5) 6246(5) 37(2) C(5) 5665(19) 2527(6) 6513(7) 44(3) C(6) 7568(18) 1994(7) 6786(6) 41(3) C(7) 4480(17) 4015(6) 6160(6) 34(3) C(8) 3464(19) 4335(7) 5318(7) 45(3) C(9) 1780(20) 4884(8) 5270(8) 57⑷ C(10) 1145(19) 5140(7) 6041(9) 55(3) C(11) 2141(19) 4849(7) 6862(7) 47(3) C(12) 3874(17) 4282(6) 6954(6) 36(3) C(13) 5020(16) 4044(6) 7850(6) 35(3) C(14) 4255(15) 3731(6) 8528(6) 32(3) C(15) 5686(18) 3625(7) 9400(7) 41(3) N(16) 5221(14) 3032(5) 10007(5) 38(2) C(17) 3520(20) 2409(8) 9721(10) 77(4) C(18) 1591(19) 2834(8) .9378(8) 58(3) C(19). 6643(17) 2904(7) 10837(6) 33(3) C(20) 8123(17) 2257(7) 10928(7) 40(3) C(21) 9521(19) 2151(7) 11710(7) 51(3) C(22) 9542(18) 2713(7) 12428(7) 45(3) C(23) 8029(19) 3353(7) 12367(6) 43(3) C(24) 6611(19) 3453(7) 11563(7) 45(3) 0(25) 7262(14) 4069(6) 9602(5) 70(3) C(26) 10622(18) 1388(7) 6296(8) 57(3) C(1X) 10057(19) -243(7) 3822(8) 53(3) 0(2X) 11060(17} -820(6) 3541(6) 100(4) 0(3X) 10378(16) -38(6) 4658(6) 84(3) C(4X) 8610(18) 320(6) 3209(6) 40(3)
-21 _ 200301700 發明說明續頁(17) 卜' 〇…一 X y X U(eq) C(5X) 6358(19) 214(6) 3317(7) 35(3) 0(6X) 5754(14) -675(5) 3152(5) 52(2) C(7X) 6105(16) 491(8) 4257(6) 39(3) 〇(8X) 5421(15) -95(6) 4709(5) 75(3) 0(9Χ) 6600(14) 1254(5) 4507(5) 55(2) C(10X) 4897(18) 794(7) 2640(6) 46(3) C(11X) 4463(19) 533(6) 1651(6) 32(2) 0(12Χ) 2826(13) 708(5) 1170(5) 50(2) 0(13Χ) 5938(13) 140(6) 1372(5) 64(3)
-22- 200301700 (18) 表V檸檬酸鹽 觀祭到的鍵長[A ]及角[° ] 發明說明續頁 S(1X)-C(14) S(1X)-C(18) CI(1X)-C(23) CI(2X)-C(22) N(1)-C(6) N(1 )-0(2) N(1)-C(26) C(2)-C(3) C(3)-N(4) N(4)-C(7) N(4)-C(5) C(5)-C(6) C(7)-C(8) C(7)-C(12) C(8)-C(9) C(9)-C(10) C(10)-C(11) C(11)-C(12) C(12)-C(13) C(13)-C(14) C(14)-C(15) C(15)-0(25) C(i4)-S(1X)-C(18) C(6)-N(1)-C(2) C(6)-N(1)-C(26) C(2)-N(1)-C(26) N(1)-C(2)-C(3) N(4)-C(3)-C(2) C(7)-N(4)-C(3) C(7)-N(4)-C(5) C(3)-N(4)-C(5) N(4)-C(5)-C(6) C(5)-C(6)-N(1) C(8)-C(7)-C(12) 1.758(10) C(15)-N(16) 1.365(12) 1.794(11) N(16)-C(19) 1.422(12) 1.719(10) N(16)-C(17) 1.470(13) 1.727(10) C(17)-C(18) 1.429(17) 1.486(12) C(19)-C(20) 1.375(13) 1.500(12) C(19)-C(24) 1.385(14) 1.493(13) C(20)-C(21) 1.356(14) 1.495(16) C(21)-C(22) 1.380(14) 1.461(12) C(22)-C(23) 1.386(14) 1.435(13) C(23)-C(24) 1.386(14) 1.478(12) C(1X)-0(2X) 1.227(13) 1.483(14) C(1X)-〇(3X) 1.278(13) 1.402(13) C(1X)-C(4X) 1.468(14) 1.398(13) C(4X)-C(5X) 1.534(15) 1.384(16) C(5X)-〇(6X) 1.423(11) 1.369(15) C(5X)-C(7X) 1.522(14) 1.357(14) C(5X)-C(10X) 1.537(14) 1.418(15) C(7X)-〇(9X) 1.247(12) 1.458(13) C(7X)-0(8X) 1.261(12) 1.317(12) C(10X)-C(11X) 1.517(13) 1.470(14) C(11X)-0(12X) 1.205(11) 1.227(12) C(11X)«0(13X) 1.283(11) 100.9(5) C(18)-C(17)-N(16) 112.7(10) 110.3(8) C(17)-C(18)-S(1X) 114.1(9) 111.3(8) C(20)-C(19)-0(24) 118.5(9) 112.9(9) C(20)-C(19)-N(16) 121.2(9) 110.8(9) C(24)-C(19)-N(16) 120.3(9) 110.2(8) C(21)-C(20)-C(19) 121.3(10) 116.6(8) C(20)-C(21)-C(22) 120.6(10) 112.8(8) C(21)-C(22)-C(23) 119.4(10) 109.3(8) C(21)-C(22)-CI(2X) 120.6(9) 110.4(9) C(23)-C(22)-CI(2X) 119.9(8) 110.7(8) C(24)-C(23)-C(22) 119.2(9) 120.7(10) C(24)-C(23)-CI(1X) 119.1(9) -23- 200301700 (19) 發明說明續頁 C{8)-C(7)-N(4) C(12)-C(7)-N(4) C(9)-C(8)-C(7) C(10)-C(9)-C(8) C(11)-C(10)-C(9) C(10)-C(11)-0(12) C(7)-C(12)-C(11) C(7)-C(12)-C(13) C(11)-C(12)-C(13) C(14)-C(13)-C(12) C(13)-C(14)-C(15) C(13)-C(14)-S(1X) C(15)-C(14)-S(1X) 0(25)-C(15)-N(16) 0(25)-C(15)-C(14) N(16)-C(15)-C(14) C(15)-N(16)-C(19) C(15)-N(16)-C(17) C(19)-N(16)-C(17) 121.9(9) C(22)-C(23)-CI(1X) 121.6(8) 117.4(8) C(23)-C(24)-C(19) 120.9(10) 119.6(10) 0(2X)-C(1X)-0(3X) 121.5(11) 120.3(10) 0(2X)-C(1X)-C(4X) 122.0(11) 120.6(11) 0(3X)-C(1X)-C(4X) 116.1(10) 121.6(11) C(1X)-C(4X)-C(5X) 113.2(9) 117.1(9) 0(6X)-C(5X)-C(7X) 110.4(9) 122.6(10) 0(6X)-C(5X)-C(4X) 109.0(8) 120.2(9) C(7X)-C(5X)-C(4X) 110.9(8) 127.1(9) O(6X)-C(5X)-C(10X) 108.4(8) 117.4(9) C(7X)-C(5X)-C(10X) 106.9(8) 120.9(7) C(4X)-C(5X)-C(10X) 111.1(8) 121.6(8) 0(9X)-C(7X)-0(8X) 126.8(9) 119.5(9) 0(9X)-C(7X)-C(5X) 118.0(10) 121.5(10) 0(8X)-C(7X)-C(5X) 115.2(10) 119.0(10) C(11X)-C(10X)-C(5X) 118.4(8) 119.1(9) 〇(12X)-C(11X)-〇(13X) 123.6(9) 119.5(9) O(12X)-C(11X)-C(10X) 120.4(9) 120.1(9) O(13X)-C(11X)-C(10X) 116.0(9)
-24- 200301700 (20) 發明說明續頁 表VI檸檬酸鹽之非等向性 向性位移因子指數成為下式： 的位移參數（A2 X 103)，非等 -2 7Γ 2[h2a*2Uu+...-f-2hka*b*U12]
Un U22 U33 u23 u13 U12 S(1X) 40(2) 76(2) 39(2) 6(2) 2(1) -14(2) CI(1X) 128(3) 69(2) 46(2) -17(2) 1(2) 24(2) CI(2X) 81(2) 82(2) 47(2) 7(2) -13(2) 13(2) N⑴ 53(6) 44(6) 30(5) -11(4) 10(5) -16(5) C(2) 53(8) 57(8) 46(7) -9(6) 28(6) -22⑺ C(3) 56(8) 56(7) 35(6) 1(5) 16(6) •14(6) N(4) 45(6) 45(6) 23(5) -1(4) 12(4) -2(5) C(5) 61(8) 39(6) 36(6) 15(5) 24(6) -7(6) C(6) 63(8) 41(6) 22(6) 2(5) 17(6) -2(6) C(7) 43(7) 37(6) 21(6) 3(5) 4(5) -23(6) C(8) 51(8) 49(7) 33(7) 6(5) 6(6) -15(7) C(9) 64(10) 52(7) 45(8) 22(6) -15(7) -17(8) C(1〇) 49(9) 43(7) 66(9) 11(7) -5(7) -1(6) C(11) 55(8) 46(7) 36(7) 1〇(5) -1(6) 4(6) C(12) 47(7) 27(6) 33(7) 6(5) 5(5) -9(6) C(13) 38(7) 43(6) 24(6) 0(5) 6(5) -4(5) C(14) 35(6) 39(6) 19(5) -6(5) 2(5) -12(5) C(15) 35(7) 51(7) 38(7) -5(6) 5(6) -8(6) N(16) 53(6) 28(5) 30(5) 6⑷ -1(5) -8(5) C(17) 77(10) 58(8) 78(9) 22(7) -26(8) -39(8) C(18) 46(8) 56(8) 71(8) 18(7) 7(7) -22(7) C(19) 39(7) 35(6) 22(6) 5(5) -2(5) -1(6) C(20) 51(8) 41(7) 29(6) -1(5) 9(6) 7(6) C(21) 61(8) 50(7) 45(7) 1〇(6) 22(7) 19(6) C(22) 49(8) 45(7) 39(7) 18(6) 3(6) 19(6) C(23) 70(8) 47(7) 14(6) -2(5) 12(6) 1(7) C(24) 60(9) 35(7) 41(7) -2(6) 13(7) 1(6) 0(25) 60(6) 104(7) 39⑷ 29(4) -6(4) -35(6) C(26) 57(9) 55(7) 60(8) -12(6) 14(7) 2(7) C(1X) 54(8) 41(7) 61(9) -9(6) 2(7) 4(7) 0(2X) 106(9) 93(7) 87(7) -21(6) -13(6) 43(7) 0(3X) 99(8) 107(7) 33(5) -7(5) -21(5) 52(6) C(4X) 53(8) 30(6) 34(6) -1(5) 4(6) 14(6) -25 - 200301700 (21) 發明說明績頁
Un U22 U33 U23 u13 Ui2 C(5X) 49(8) 31(6) 24(5) 1(5) 7(5) 3(6) 0(6X) 71(6) 43(5) 40(5) -4(3) 8(4) -5⑷ C(7X) 38(7) 62(8) 15(6) -7(6) -2(5) 9(6) 〇(8X) 106(8) 108(7) 18(4) •7(4) 29(5) -51(6) 0(9X) 75(6) 51(5) 34(4) -18(4) 0⑷ 10(5) C(10X) 54(8) 60(7) 23(6) -4(5) 9(5) 18(6) C(11X) 40(7) 33(6) 27(6) 1〇(5) 13(6) 6(6) 0(12X) 43(5) 75(5) 28(4) -12(4) -7(4) 15(4) 0(13X) 68(6) 104(7) 19(4) 9(4) 5(4) 44(5)
-26- 200301700 (22) 發明說明續頁 表VII檸檬酸鹽之氫配位結合（X 1〇。及等向性位移參數 (A2 X 1〇3) X y z U(eq) H(1X) 7880(190) 1710(70) 5570(80) 80 Η (2 A) 9814 2789 5202 80 H(2B) 10118 3134 6199 80 H(3A) 7538 3942 5290 80 H(3B) 6298 3082 4971 80 H(5A) 4753 2246 6011 80, H(5B) 4944 2564 7013 80 H(6A) 7199 1410 6952 80 H(6B) 8445 2258 7310 80 H(8) 3923 4179 4796 80 H(9) 1065 5080 4711 80 H(1〇) 23 5518 6002 80 H(11) 1675 5026 7377 80 H(13) 6447 4120 7953 80 H(17A) 3859 2028 9257 80 H(17B) 3373 2045 10232 80 H(18A) 1235 3198 9851 80 H(18B) 524 2391 9226 80 H(20) 8167 1886 10444 80 H(21) 10473 1695 11764 80 H(24) 5623 3895 11512 80 H(2GA) 11422 1595 6859 80 H(26B) 11432 1429 5835 80 H(26C) 10234 789 6361 80 H(3XX) 11700(300) -220(100) 5150(100) 140(60) H(4XA) 8699 184 2591 80 H(4XB) 9020 927 3321 80 H(6XX) 6600(200) -1000(80) 3490(80) 80 H(10A) 3582 822 2834 80 H(10B) 5465 1382 2683 80 H(13X) 5480(180) 190(70) 610(80) 80 -27- 200301700 (23) ¥明說明續頁 經由SHELXTLTM電腦資料庫之配件所提供之XFOG及 XPOW電腦程式之使用，自所收集之檸檬酸鹽之單一晶體 資料計算X光粉末繞射樣式，所計算之粉末樣式顯示在第3 圖中。
固態NMR 以固態NMR技術描繪檸檬酸鹽之特性。將約300毫克之 樣品緊密裝入7毫米Zr〇旋轉器中，在295 K下使用交叉極化 魔角自旋（CPMAS)，以裝置在廣口 Bruker Avance DRX 500 MHz NMR光譜儀之7 mm WB MAS探針收集13C NMR光譜，樣品 在15 kHz下自轉，交叉極化接觸時間被設定為1分鐘，大部 分樣品在約30分鐘之探測次數内總共獲得5 12次掃描，使 用金剛烷（5 29.5 ppm)與大部分在前部的甲基訊號設定在 29.5 ppm之外部樣品作為參考光譜。 檸檬酸鹽之13C NMR CPMAS光譜顯示在圖5中，由固態光 譜品質之觀點來看，檸檬酸鹽樣品是適度反應的，此解析 度是良好的且敏感性是可接受的。 自100 ppm下半部之4-(3,4-二氯基苯基）-2-[2-(4-甲基六氫 吡畊-1-基）-亞苄基]-硫嗎啉基-3-酮之檸檬酸鹽固態碳光譜 之解析度高峰列在表VIII中。 表VIII擰檬酸鹽之主要固態13C NMR解析度高峰（金剛烷 標準 29.5 ppm) -28- 200301700 (24) 發明說明績頁
本發明之檸檬酸鹽（之後稱為“活性鹽”）可經由口服、經 皮（例如透過貼布的使用）、鼻内、舌下、直腸、腸胃外或 局部之途徑給藥，以經皮及口服給藥為較佳。最希望之活 性鹽給藥劑量範圍每日約由0.01至約1 500毫克，較佳為每 日約0.1至約300毫克之以單一劑或分劑方式給藥，雖然依 據重量及欲治療病患之病況以及所選擇之特定給藥途徑， 劑量的變動將必定發生，然而，劑量在約每公斤體重每曰 0.001毫克至約10毫克為最妥當應用的。不過依據體重及欲 治療病患及其個體對該藥劑之反應，以及所選擇之醫藥配 方形式及執行給藥之期間及間期，劑量可能發生變動。在 一些情況中，劑量低於前述範圍之限制可能是較適當的， 在其他情況中則可能使用較大劑量而不會引起任何有害的 副作用，此被提供之較大劑量首先會被分成數小份劑量而 於一日之給藥使用。 活性鹽可單獨或與醫藥上可接受的載體或稀釋劑合併， 以先前所提之數種途徑中之任一方式給藥，具體而言，活 -29- 200301700 (25) 發明說明續頁 性鹽可以多樣化之不同劑量形式而被給予，例如可與各種 醫藥上可接受的惰性載體合併形成片劑、膠囊、經皮貼布、 鍵劑、糖錠、硬糖、粉末、噴劑、乳霜、軟膏、栓劑、膠 凍、膠體、糊狀物、乳液、油膏、水性懸浮液、可注射溶 液、酏劑、糖漿等形式，此等載體包括固體稀釋劑或填充 劑、無菌水溶液介質及各種無毒性有機溶劑。此外，口服 醫藥組成物可適當地增甜及/或增味。一般而言，活性鹽 以濃度範圍由約5.0重量％至約70重量％之劑量形式存在。 於口服給藥時，含有各種賦形劑如微晶體纖維素、檸檬 酸鈉、碳酸鈣、磷酸二鈣及甘胺酸之片劑可與各種藥片分 解素如澱粉（較佳為玉米、馬鈴薯或木薯澱粉）、褐藻酸及 某些複合矽酸鹽與顆粒化膠合劑如聚乙烯四氫吡咯酮、蔗 糖、明膠及阿拉伯膠一起使用，。此外，於壓片目的上， 潤滑劑如硬脂酸鎂、十二基硫酸鈉及滑石可被使用。相似 形式之固體組合物亦可被使用作為明膠膠囊中之填充劑； 就此而論，較佳材料亦包括乳糖或牛奶糖，以及高分子量 之聚乙二醇。當希望水性懸浮液及/或酏劑於口服給藥時， 活性成分可與各種增甜或增味劑、色素合併，若更希望時， 乳化劑及/或懸浮劑，可與稀釋劑如水一起、乙醇、丙二 醇、甘油及其各種合劑一起合併。 於腸胃外給藥時，活性鹽之溶液以在芝麻或花生油，或 在水性丙二醇中可被使用，若需要時水溶液應為適當緩衝 的（較佳之pH大於8)，首先被提供之液體稀釋劑為等張性 的，此等水性溶液是適合於靜脈注射目的。油性溶液適合 -30- 200301700 發明說明續頁 (26) 於關節内、肌肉内及皮下注射目的。所有此等溶液之製備 對於此項技藝中彼等熟習此藝者在無菌狀態下以標準醫藥 技術是客易達成的。 局部給予活性鹽亦為可能的，且其可依據標準醫藥習慣 以乳霜、貼布、膠康、膠體、糊狀物、油膏等方式作成。 實例 下列實例說明本發明之方法及化合物，其應可被了解， 然而，本發明並不被限於此具體實例中。 4-(3,4-二氯基苯基甲基六氫吡畊-1-基）-亞芊基1-硫嗎啉基-3-酮之檸檬酸鹽 在裝配沒頂之機械攪拌器之1公升圓底燒瓶中，將4-(3，4-二氯基苯基）-2-[2-(4-甲基六氫吡畊-1-基）-亞芊基]-硫嗎啉 基-3-酮（3 0.14克；0.067莫耳；依據陳述於國際專利公告案No. WO 98/14433號之步驟製備）之自由鹼基溶解於525毫升之2-丙醇中，將溶液攪拌並加熱至50°C，分次加入檸檬酸（16.2 克；0.084莫耳）以獲得清澈溶液，反應混合物能夠冷卻並 在室溫下18小時而被顆粒化；在收集白色結晶固體產物 前，將沉澱的固體樣品以DSC檢驗，確定是否有任何未反 應的自由基存在；過濾後，以2-丙醇（1 00毫升）清洗固體產 物並在45 °C之灌注氮氣之真空箱中乾燥。以94%之產率生 產標題檸檬酸鹽（40·6克；0.063莫耳）。
Claims (1)
- 200301700 拾、申請專利範圍 1. 一種4-(3,4-二氯基苯基）-2-[2-(4-甲基六氫吡畊-1-基）-亞 芊基]-硫嗎啉基-3-酮之擰檬酸鹽。 2. —種下式化合物之擰檬酸鹽：3. 如申請專利範圍第1項之檸檬酸鹽，其具有2 0銅放射測 量之X光繞射樣式實質特徵為約17.4之X光繞射樣式高 (1^· 〇 4. 如申請專利範圍第1項之檸檬酸鹽，其具有2 0銅放射測 量之X光繞射樣式實質特徵為約20.0之X光繞射樣式高 〇 5. 如申請專利範圍第1項之擰檬酸鹽，其具有2 0銅放射測 量之X光繞射樣式實質特徵為約17.4及20.0之X光繞射樣 式高峰。 6. 如申請專利範圍第1項之檸檬酸鹽，其具有X光繞射樣 式實質特徵為下列在2 0間期及d間隔表現之銅放射測量 之主要X光繞射樣式高峰： 200301700 申請專利範圍續頁 2 0 角度(±0.2) d 值(Α)(±0·2) 13.0 6.8 17.4 5.1 18.0 4.9 18.9 4.7 20.0 4.4 21.2 4.2 22.2 4.0 24.0 3.7 27.1 3.3 32.4 2.8 7. 如申請專利範圍第1項之擰檬酸鹽，其係以在198- 1 99°C 之熔化/分解轉換的開始為特徵。 8. 如申請專利範圍第1項之檸檬酸鹽，其特徵為當以固態 13C NMR交叉極化魔角自旋技術檢查時，其展現下列主 要共振高峰：5 179.3。 9. 如申請專利範圍第1項之檸檬酸鹽，其特徵為當以固態 13C NMR交叉極化魔角自旋技術檢查時，其展現下列主 要共振高峰：（5 177.0。 10. 如申請專利範圍第1項之檸檬酸鹽，其特徵為當以固態 13C NMR交叉極化魔角自旋技術檢查時，其展現下列主 要共振南學· 5 171.6。 11. 如申請專利範圍第1項之檸檬酸鹽，其特徵為當以固態 200301700 申請專利範圍績頁 i3C NMR交叉極化魔角自旋技術檢查時，其展現下列主 要共振高峰：5 179.3、177.0、171.6、164.0、15 1.0及 144」。 12. —種含有如申請專利範圍第1項之檸檬酸鹽及醫藥上可 接受載體之醫藥組合物。 13. —種如申請專利範圍第1項之檸檬酸鹽之於製造藥劑之 用途，該藥劑可用來治療哺乳類之高血壓；所有抑鬱型 式；癌症病患抑鬱；帕金森氏症病患抑鬱；心肌梗塞後 抑鬱；亞症候群表徵型抑鬱；不孕婦女之抑鬱；兒童抑 鬱症；重鬱症；單次抑鬱發病；復發型抑鬱；兒童受虐 導致之抑鬱；產後憂鬱症；輕鬱症；具有或不具有非典 型特徵、病態憂鬱症、精神病特徵、僵直性特徵之輕度、 中度及重度抑鬱；季節影響型症候群；老年抑鬱；慢性 抑鬱；具有抑鬱情緒或具有焦慮及抑鬱情緒之適應障 礙；混合型焦慮及抑鬱；藥物濫用導致之情緒失調；以 及一般醫學症狀、躁鬱症、躁鬱症抑鬱期、廣泛性焦慮 症、恐懼症、懼曠症、社會焦慮症、社會恐懼症、單純 型恐懼症、分離焦慮症、創傷壓力症候群、畏避型人格 障礙、早淺、進食障礙、飲食疾患、神經性厭食症、心 因性暴食症、肥胖引起之二次性情緒障礙；化學依賴及 酒精、古柯驗、海洛因、苯巴比妥、尼古丁、大麻及苯 重氮基鹽成癮；叢發性頭痛、偏頭痛、疼痛、阿茲海默 氏症、強迫症、恐慌症、具懼礦症之恐慌症、記憶障礙、 疾^呆、健忘症及年齡相關性知能減退、帕金森氏症、在 帕金森氏症中之痴呆、抗精神藥物引起之巴金森症及遲 200301700 申請專利範圍續頁 缓性動作困難、内分泌失調、高泌乳激素血症、血管痙 攣、腦血管之血管痙攣、小腦性運動失調；與運動及分 泌有關之腸胃道障礙；精神分裂之負性症狀、經前症候 群、纖維肌痛症候群、應力尿失禁、妥瑞症、拔毛癖、 竊盜癖、男性陽萎、癌症、小細胞肺臟上皮細胞癌、慢 性發作性單側頭痛、與血管疾病有關之頭痛、廣泛性發 展障礙症、亞斯伯格症、選擇性緘默症、慢性運動或聲 帶抽搐性失常、軀體化失常、失眠、間歇性狂暴症、縱 火癖、病理性賭博、衝動控制性障礙、經前焦躁症及注 意力缺乏及過動障礙。
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US33834301P | 2001-12-07 | 2001-12-07 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW200301700A true TW200301700A (en) | 2003-07-16 |
| TWI233356B TWI233356B (en) | 2005-06-01 |
Family
ID=23324428
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW091135151A TWI233356B (en) | 2001-12-07 | 2002-12-04 | Citric acid salt of a therapeutic compound and pharmaceutical compositions thereof |
Country Status (28)
| Country | Link |
|---|---|
| US (1) | US6825193B2 (zh) |
| EP (1) | EP1451166B1 (zh) |
| JP (1) | JP4165882B2 (zh) |
| KR (1) | KR100572430B1 (zh) |
| CN (1) | CN100358878C (zh) |
| AR (1) | AR037711A1 (zh) |
| AT (1) | ATE301647T1 (zh) |
| AU (1) | AU2002347504B2 (zh) |
| BR (1) | BR0214780A (zh) |
| CA (1) | CA2469225C (zh) |
| DE (1) | DE60205504T2 (zh) |
| DK (1) | DK1451166T3 (zh) |
| ES (1) | ES2243774T3 (zh) |
| GT (1) | GT200200260A (zh) |
| HN (1) | HN2002000354A (zh) |
| IL (1) | IL162096A0 (zh) |
| MX (1) | MXPA04005418A (zh) |
| NO (1) | NO327100B1 (zh) |
| NZ (1) | NZ532993A (zh) |
| PA (1) | PA8560101A1 (zh) |
| PE (1) | PE20030663A1 (zh) |
| PL (1) | PL370307A1 (zh) |
| PT (1) | PT1451166E (zh) |
| RU (1) | RU2270834C2 (zh) |
| TW (1) | TWI233356B (zh) |
| UY (1) | UY27570A1 (zh) |
| WO (1) | WO2003048141A1 (zh) |
| ZA (1) | ZA200404226B (zh) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1746091A1 (en) * | 2001-08-30 | 2007-01-24 | Pfizer Products Inc. | Process for the preparation of 2-substituted 2-[-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one citrate |
| US20050171095A1 (en) * | 2004-01-06 | 2005-08-04 | Pfizer Inc | Combination of CRF antagonists and 5-HT1B receptor antagonists |
| CA2565996A1 (en) * | 2004-05-11 | 2005-11-17 | Pfizer Products Inc. | Combination of atypical antipsychotics and 5-ht1b receptor antagonists |
| WO2005113526A2 (en) * | 2004-05-21 | 2005-12-01 | Pfizer Products Inc. | Metabolites of 4-(3,4-dichloro-phenyl)-2-[2-(4-methyl-piperazin-1-yl)-benzylidene]-thiomorpholin-3-one |
| CA2580034A1 (en) * | 2004-09-10 | 2006-03-16 | Pfizer Products Inc. | Methods of treating mood disorders using benzisoxazole containing diazabicyclic compounds |
| US8080584B2 (en) | 2009-01-23 | 2011-12-20 | Teva Pharmaceuticals Industries, Ltd. | Delayed release rasagiline citrate formulation |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL111960A (en) * | 1993-12-17 | 1999-12-22 | Merck & Co Inc | Morpholines and thiomorpholines their preparation and pharmaceutical compositions containing them |
| US6423708B1 (en) * | 1996-09-30 | 2002-07-23 | Pfizer Inc | Aralkyl and aralkylidene heterocyclic lactams and imides |
| UA56185C2 (uk) * | 1996-09-30 | 2003-05-15 | Пфайзер Інк. | Аралкіл- та аралкіліденгетероциклічні лактами та іміди, фармацевтична композиція та спосіб лікування |
-
2002
- 2002-11-25 IL IL16209602A patent/IL162096A0/xx unknown
- 2002-11-25 NZ NZ532993A patent/NZ532993A/en unknown
- 2002-11-25 CA CA2469225A patent/CA2469225C/en not_active Expired - Fee Related
- 2002-11-25 AU AU2002347504A patent/AU2002347504B2/en not_active Ceased
- 2002-11-25 RU RU2004117091/04A patent/RU2270834C2/ru not_active IP Right Cessation
- 2002-11-25 JP JP2003549332A patent/JP4165882B2/ja not_active Expired - Fee Related
- 2002-11-25 PT PT02783438T patent/PT1451166E/pt unknown
- 2002-11-25 ES ES02783438T patent/ES2243774T3/es not_active Expired - Lifetime
- 2002-11-25 DE DE60205504T patent/DE60205504T2/de not_active Expired - Lifetime
- 2002-11-25 WO PCT/IB2002/004972 patent/WO2003048141A1/en not_active Ceased
- 2002-11-25 EP EP02783438A patent/EP1451166B1/en not_active Expired - Lifetime
- 2002-11-25 BR BR0214780-7A patent/BR0214780A/pt not_active IP Right Cessation
- 2002-11-25 KR KR1020047008647A patent/KR100572430B1/ko not_active Expired - Fee Related
- 2002-11-25 AT AT02783438T patent/ATE301647T1/de not_active IP Right Cessation
- 2002-11-25 PL PL02370307A patent/PL370307A1/xx not_active Application Discontinuation
- 2002-11-25 DK DK02783438T patent/DK1451166T3/da active
- 2002-11-25 MX MXPA04005418A patent/MXPA04005418A/es active IP Right Grant
- 2002-11-25 CN CNB028243129A patent/CN100358878C/zh not_active Expired - Fee Related
- 2002-12-03 PE PE2002001163A patent/PE20030663A1/es not_active Application Discontinuation
- 2002-12-04 TW TW091135151A patent/TWI233356B/zh not_active IP Right Cessation
- 2002-12-05 HN HN2002000354A patent/HN2002000354A/es unknown
- 2002-12-05 AR ARP020104718A patent/AR037711A1/es unknown
- 2002-12-06 GT GT200200260A patent/GT200200260A/es unknown
- 2002-12-06 UY UY27570A patent/UY27570A1/es not_active Application Discontinuation
- 2002-12-06 US US10/313,467 patent/US6825193B2/en not_active Expired - Fee Related
- 2002-12-06 PA PA20028560101A patent/PA8560101A1/es unknown
-
2004
- 2004-05-28 ZA ZA200404226A patent/ZA200404226B/en unknown
- 2004-07-06 NO NO20042871A patent/NO327100B1/no not_active IP Right Cessation
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3740206B1 (en) | Inhibitors of cyclin-dependent kinase 7 (cdk7) | |
| KR20150107872A (ko) | 고체 형태의 선택적인 cdk4/6 억제제 | |
| JP6929857B2 (ja) | ６，７，８，９−テトラヒドロ−５Ｈ−ピリド［２，３−ｄ］アゼピンドーパミンＤ３リガンド | |
| TW201024301A (en) | Amino pyrazole compound | |
| JP2018527363A (ja) | リナグリプチン結晶形及びこの製造方法 | |
| CN104725380B (zh) | 卢索替尼的氘代衍生物 | |
| JP2020534331A (ja) | （（１ｓ，２ｓ，４ｒ）−４−｛４−［（１ｓ）−２，３−ジヒドロ−１ｈ−インデン−１−イルアミノ］−７ｈ−ピロロ［２，３−ｄ］ピリミジン−７−イル｝−２−ヒドロキシシクロペンチル）メチルスルファメートの共結晶形態、その製剤及び使用 | |
| TW200301700A (en) | Citric acid salt of a therapeutic compound and pharmaceutical compositions thereof | |
| CN104364255A (zh) | 取代的黄嘌呤衍生物 | |
| JP7712994B2 (ja) | 疾患の治療用のホスホイノシチド３－キナーゼ（ｐｉ３ｋ）のアロステリッククロメノン阻害剤 | |
| JP6526060B2 (ja) | 置換トリアゾロベンゾジアゼピン | |
| CN112759546B (zh) | 3-(二甲氨基甲基)哌啶-4-醇衍生物及其制备方法和药物用途 | |
| JP3902751B2 (ja) | ２−（４−アルキル−１−ピペラジニル）−ベンズアルデヒドおよびベンジリデニル化合物の製造方法 | |
| TWI909104B (zh) | 抑制ｎｌｒｐ３的化合物及其用途 | |
| CN110139855B (zh) | 新型的氘代脲类化合物 | |
| JP2007517855A (ja) | セロトニン及びノルアドレナリン再取込み阻害剤としての活性を示すピペラジン誘導体 | |
| WO2025133307A1 (en) | Heterocyclic modulators of the nlrp3 inflammasome pathway | |
| CN118702697A (zh) | 苯甲酰基吡咯并嘧啶类衍生物及其用途和制备方法 | |
| HK1071133B (zh) | 治疗化合物的柠檬酸盐及其药物组合物 | |
| CN119823022A (zh) | 一种nlrp3小分子蛋白质降解剂及其制备方法和应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Annulment or lapse of patent due to non-payment of fees |