BR112020021104A2 - compostos moduladores alostéricos positivos gabaa, métodos de produção e usos dos mesmos - Google Patents
compostos moduladores alostéricos positivos gabaa, métodos de produção e usos dos mesmos Download PDFInfo
- Publication number
- BR112020021104A2 BR112020021104A2 BR112020021104-4A BR112020021104A BR112020021104A2 BR 112020021104 A2 BR112020021104 A2 BR 112020021104A2 BR 112020021104 A BR112020021104 A BR 112020021104A BR 112020021104 A2 BR112020021104 A2 BR 112020021104A2
- Authority
- BR
- Brazil
- Prior art keywords
- crystalline
- salt
- polymorphic
- phosphate
- cocrystalline
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 57
- 238000004519 manufacturing process Methods 0.000 title abstract description 7
- 229940126027 positive allosteric modulator Drugs 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 112
- 238000000034 method Methods 0.000 claims abstract description 67
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 57
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 27
- PCZLQMGFNUNVOM-UHFFFAOYSA-N 3-fluoro-2-[2-fluoro-5-[3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl]phenyl]benzonitrile Chemical compound C=1N=C2N=C(C(C)(O)C)C=NN2C=1C(C=1)=CC=C(F)C=1C1=C(F)C=CC=C1C#N PCZLQMGFNUNVOM-UHFFFAOYSA-N 0.000 claims description 182
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 144
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 77
- 239000000203 mixture Substances 0.000 claims description 75
- 208000002193 Pain Diseases 0.000 claims description 52
- 230000036407 pain Effects 0.000 claims description 46
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 45
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 44
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 42
- 208000003251 Pruritus Diseases 0.000 claims description 42
- 208000035475 disorder Diseases 0.000 claims description 39
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- 238000001757 thermogravimetry curve Methods 0.000 claims description 25
- 239000000843 powder Substances 0.000 claims description 24
- 229910001868 water Inorganic materials 0.000 claims description 24
- 206010015037 epilepsy Diseases 0.000 claims description 22
- 238000003860 storage Methods 0.000 claims description 18
- WLPATYNQCGVFFH-UHFFFAOYSA-N 2-phenylbenzonitrile Chemical compound N#CC1=CC=CC=C1C1=CC=CC=C1 WLPATYNQCGVFFH-UHFFFAOYSA-N 0.000 claims description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- 230000007803 itching Effects 0.000 claims description 16
- -1 2-methyl butanone Chemical compound 0.000 claims description 15
- 206010003805 Autism Diseases 0.000 claims description 15
- 208000020706 Autistic disease Diseases 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 206010061334 Partial seizures Diseases 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 239000012453 solvate Substances 0.000 claims description 13
- 208000011580 syndromic disease Diseases 0.000 claims description 13
- 206010010904 Convulsion Diseases 0.000 claims description 11
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 9
- 230000001037 epileptic effect Effects 0.000 claims description 9
- 201000007186 focal epilepsy Diseases 0.000 claims description 9
- 230000001225 therapeutic effect Effects 0.000 claims description 9
- 208000019901 Anxiety disease Diseases 0.000 claims description 8
- 201000009053 Neurodermatitis Diseases 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 208000007848 Alcoholism Diseases 0.000 claims description 6
- 206010071082 Juvenile myoclonic epilepsy Diseases 0.000 claims description 6
- 201000006792 Lennox-Gastaut syndrome Diseases 0.000 claims description 6
- 230000036506 anxiety Effects 0.000 claims description 6
- 230000001684 chronic effect Effects 0.000 claims description 6
- 208000034287 idiopathic generalized susceptibility to 7 epilepsy Diseases 0.000 claims description 6
- 230000001617 migratory effect Effects 0.000 claims description 6
- 208000004296 neuralgia Diseases 0.000 claims description 6
- 208000021722 neuropathic pain Diseases 0.000 claims description 6
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 6
- 230000000069 prophylactic effect Effects 0.000 claims description 6
- 201000000980 schizophrenia Diseases 0.000 claims description 6
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 5
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 5
- 208000007101 Muscle Cramp Diseases 0.000 claims description 5
- 208000036572 Myoclonic epilepsy Diseases 0.000 claims description 5
- 206010036376 Postherpetic Neuralgia Diseases 0.000 claims description 5
- 208000004550 Postoperative Pain Diseases 0.000 claims description 5
- 201000004681 Psoriasis Diseases 0.000 claims description 5
- 208000005392 Spasm Diseases 0.000 claims description 5
- 201000008937 atopic dermatitis Diseases 0.000 claims description 5
- 238000002512 chemotherapy Methods 0.000 claims description 5
- 230000003211 malignant effect Effects 0.000 claims description 5
- 201000001119 neuropathy Diseases 0.000 claims description 5
- 230000007823 neuropathy Effects 0.000 claims description 5
- 230000001107 psychogenic effect Effects 0.000 claims description 5
- 208000014644 Brain disease Diseases 0.000 claims description 4
- 208000028698 Cognitive impairment Diseases 0.000 claims description 4
- 208000032274 Encephalopathy Diseases 0.000 claims description 4
- 208000002091 Febrile Seizures Diseases 0.000 claims description 4
- 208000001640 Fibromyalgia Diseases 0.000 claims description 4
- 208000003078 Generalized Epilepsy Diseases 0.000 claims description 4
- 208000037004 Myoclonic-astatic epilepsy Diseases 0.000 claims description 4
- 208000037158 Partial Epilepsies Diseases 0.000 claims description 4
- 208000004983 Phantom Limb Diseases 0.000 claims description 4
- 206010056238 Phantom pain Diseases 0.000 claims description 4
- 206010071141 Rasmussen encephalitis Diseases 0.000 claims description 4
- 208000004160 Rasmussen subacute encephalitis Diseases 0.000 claims description 4
- 206010060875 Uraemic pruritus Diseases 0.000 claims description 4
- 238000002441 X-ray diffraction Methods 0.000 claims description 4
- 201000007930 alcohol dependence Diseases 0.000 claims description 4
- 208000010877 cognitive disease Diseases 0.000 claims description 4
- 206010013663 drug dependence Diseases 0.000 claims description 4
- 206010014599 encephalitis Diseases 0.000 claims description 4
- 201000001993 idiopathic generalized epilepsy Diseases 0.000 claims description 4
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 4
- 229940011051 isopropyl acetate Drugs 0.000 claims description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 4
- 230000000366 juvenile effect Effects 0.000 claims description 4
- 208000016313 myoclonic-astastic epilepsy Diseases 0.000 claims description 4
- 230000001272 neurogenic effect Effects 0.000 claims description 4
- 230000002093 peripheral effect Effects 0.000 claims description 4
- 208000017940 prurigo nodularis Diseases 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 208000011117 substance-related disease Diseases 0.000 claims description 4
- 206010052075 Acquired epileptic aphasia Diseases 0.000 claims description 3
- 208000008882 Benign Neonatal Epilepsy Diseases 0.000 claims description 3
- 208000020749 Benign familial neonatal-infantile seizures Diseases 0.000 claims description 3
- 206010070666 Cortical dysplasia Diseases 0.000 claims description 3
- 201000007547 Dravet syndrome Diseases 0.000 claims description 3
- 201000008009 Early infantile epileptic encephalopathy Diseases 0.000 claims description 3
- 206010071545 Early infantile epileptic encephalopathy with burst-suppression Diseases 0.000 claims description 3
- 208000001914 Fragile X syndrome Diseases 0.000 claims description 3
- 208000011688 Generalised anxiety disease Diseases 0.000 claims description 3
- 241000208818 Helianthus Species 0.000 claims description 3
- 235000003222 Helianthus annuus Nutrition 0.000 claims description 3
- 206010065390 Inflammatory pain Diseases 0.000 claims description 3
- 102000004310 Ion Channels Human genes 0.000 claims description 3
- 201000005802 Landau-Kleffner Syndrome Diseases 0.000 claims description 3
- 208000000676 Malformations of Cortical Development Diseases 0.000 claims description 3
- 206010028391 Musculoskeletal Pain Diseases 0.000 claims description 3
- 206010073677 Severe myoclonic epilepsy of infancy Diseases 0.000 claims description 3
- 206010042496 Sunburn Diseases 0.000 claims description 3
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 3
- 206010044565 Tremor Diseases 0.000 claims description 3
- 208000026911 Tuberous sclerosis complex Diseases 0.000 claims description 3
- 208000029650 alcohol withdrawal Diseases 0.000 claims description 3
- 208000032212 benign familial infantile 3 seizures Diseases 0.000 claims description 3
- 208000023397 cerebral cortical dysplasia Diseases 0.000 claims description 3
- 208000013257 developmental and epileptic encephalopathy Diseases 0.000 claims description 3
- 230000004064 dysfunction Effects 0.000 claims description 3
- 206010016284 febrile convulsion Diseases 0.000 claims description 3
- 208000029364 generalized anxiety disease Diseases 0.000 claims description 3
- 230000035772 mutation Effects 0.000 claims description 3
- 208000017127 myoclonic-atonic epilepsy Diseases 0.000 claims description 3
- 210000000653 nervous system Anatomy 0.000 claims description 3
- 201000008482 osteoarthritis Diseases 0.000 claims description 3
- 208000035824 paresthesia Diseases 0.000 claims description 3
- 230000037322 slow-wave sleep Effects 0.000 claims description 3
- 230000009529 traumatic brain injury Effects 0.000 claims description 3
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 229940113088 dimethylacetamide Drugs 0.000 claims description 2
- 208000005809 status epilepticus Diseases 0.000 claims description 2
- 208000024658 Epilepsy syndrome Diseases 0.000 claims 1
- 208000002877 Epileptic Syndromes Diseases 0.000 claims 1
- 230000001747 exhibiting effect Effects 0.000 claims 1
- 230000002151 myoclonic effect Effects 0.000 claims 1
- 230000003281 allosteric effect Effects 0.000 abstract description 6
- SIJDJNWCIGLIAB-UHFFFAOYSA-N C=1N=C2N=C(C(C)(O)C)C=NN2C=1C(C=1F)=CCC(F)(C#N)C=1C1=CC=CC=C1 Chemical compound C=1N=C2N=C(C(C)(O)C)C=NN2C=1C(C=1F)=CCC(F)(C#N)C=1C1=CC=CC=C1 SIJDJNWCIGLIAB-UHFFFAOYSA-N 0.000 abstract 1
- 239000012458 free base Substances 0.000 description 159
- 229910019142 PO4 Inorganic materials 0.000 description 133
- 239000010452 phosphate Substances 0.000 description 133
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 132
- 239000002904 solvent Substances 0.000 description 61
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 41
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 38
- 239000002253 acid Substances 0.000 description 34
- 239000007787 solid Substances 0.000 description 32
- 239000000243 solution Substances 0.000 description 32
- 235000011007 phosphoric acid Nutrition 0.000 description 27
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 23
- 238000012216 screening Methods 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 19
- 239000012296 anti-solvent Substances 0.000 description 19
- 238000004128 high performance liquid chromatography Methods 0.000 description 18
- KQROHCSYOGBQGJ-UHFFFAOYSA-N 5-Hydroxytryptophol Chemical compound C1=C(O)C=C2C(CCO)=CNC2=C1 KQROHCSYOGBQGJ-UHFFFAOYSA-N 0.000 description 17
- 239000013078 crystal Substances 0.000 description 17
- 238000002844 melting Methods 0.000 description 17
- 230000008018 melting Effects 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 16
- 238000010438 heat treatment Methods 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 238000002411 thermogravimetry Methods 0.000 description 14
- 239000012535 impurity Substances 0.000 description 13
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 12
- 239000008194 pharmaceutical composition Substances 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- 238000005119 centrifugation Methods 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 9
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000012530 fluid Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 7
- 239000008186 active pharmaceutical agent Substances 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 125000005490 tosylate group Chemical group 0.000 description 7
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 230000000968 intestinal effect Effects 0.000 description 6
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 6
- 229940098779 methanesulfonic acid Drugs 0.000 description 6
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 230000008901 benefit Effects 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 5
- 230000002981 neuropathic effect Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- 208000008035 Back Pain Diseases 0.000 description 4
- 206010058019 Cancer Pain Diseases 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- 208000000094 Chronic Pain Diseases 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 230000003542 behavioural effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 239000001103 potassium chloride Substances 0.000 description 4
- 235000011164 potassium chloride Nutrition 0.000 description 4
- 239000013557 residual solvent Substances 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- QKIWQBLNTSQOLY-UHFFFAOYSA-N tpa-023 Chemical group CCN1N=CN=C1COC(C(=C1)C(C)(C)C)=NN2C1=NN=C2C1=CC=CC=C1F QKIWQBLNTSQOLY-UHFFFAOYSA-N 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- 230000004580 weight loss Effects 0.000 description 4
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 3
- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical compound CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 description 3
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 3
- 208000008238 Muscle Spasticity Diseases 0.000 description 3
- 208000001294 Nociceptive Pain Diseases 0.000 description 3
- 239000005642 Oleic acid Substances 0.000 description 3
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000006184 cosolvent Substances 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000001530 fumaric acid Substances 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 239000000174 gluconic acid Substances 0.000 description 3
- 235000012208 gluconic acid Nutrition 0.000 description 3
- 229940097043 glucuronic acid Drugs 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
- 229940071870 hydroiodic acid Drugs 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 229940045996 isethionic acid Drugs 0.000 description 3
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 3
- 239000004310 lactic acid Substances 0.000 description 3
- 235000014655 lactic acid Nutrition 0.000 description 3
- 229960000448 lactic acid Drugs 0.000 description 3
- 239000011976 maleic acid Substances 0.000 description 3
- 239000001630 malic acid Substances 0.000 description 3
- 235000011090 malic acid Nutrition 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 3
- 235000006408 oxalic acid Nutrition 0.000 description 3
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 3
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 3
- 238000001907 polarising light microscopy Methods 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 208000018198 spasticity Diseases 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- SVYOXGBINYWSDQ-UHFFFAOYSA-N 1,4-dioxane;ethanol Chemical compound CCO.C1COCCO1 SVYOXGBINYWSDQ-UHFFFAOYSA-N 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- 241000282465 Canis Species 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 2
- 208000002162 Delusional Parasitosis Diseases 0.000 description 2
- 206010019233 Headaches Diseases 0.000 description 2
- 206010021750 Infantile Spasms Diseases 0.000 description 2
- 208000035899 Infantile spasms syndrome Diseases 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 241000233805 Phoenix Species 0.000 description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 208000013200 Stress disease Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 208000024780 Urticaria Diseases 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 201000006791 West syndrome Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 208000005298 acute pain Diseases 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 208000008233 autosomal dominant nocturnal frontal lobe epilepsy Diseases 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 229940050410 gluconate Drugs 0.000 description 2
- 231100000869 headache Toxicity 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000003305 oral gavage Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 2
- 244000045947 parasite Species 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000012430 stability testing Methods 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 201000008914 temporal lobe epilepsy Diseases 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 208000009935 visceral pain Diseases 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- BHPFESMHJFSRJR-UHFFFAOYSA-N (4-fluorophenyl)-[5-[(4-fluorophenyl)methylamino]-3-pyridin-3-yl-1,2,4-triazol-1-yl]methanone Chemical compound C1=CC(F)=CC=C1CNC1=NC(C=2C=NC=CC=2)=NN1C(=O)C1=CC=C(F)C=C1 BHPFESMHJFSRJR-UHFFFAOYSA-N 0.000 description 1
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N 1-Heptene Chemical compound CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 241000238876 Acari Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000008811 Agoraphobia Diseases 0.000 description 1
- 208000000412 Avitaminosis Diseases 0.000 description 1
- 208000037157 Azotemia Diseases 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- 206010006002 Bone pain Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010064190 Cholestatic pruritus Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 208000014094 Dystonic disease Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 206010016059 Facial pain Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010021135 Hypovitaminosis Diseases 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 206010061217 Infestation Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000006877 Insect Bites and Stings Diseases 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 206010033647 Pancreatitis acute Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 206010034912 Phobia Diseases 0.000 description 1
- 206010065016 Post-traumatic pain Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 208000033063 Progressive myoclonic epilepsy Diseases 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- 208000017794 Reading seizures Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 208000036755 Schizophrenia simple Diseases 0.000 description 1
- 208000036752 Schizophrenia, paranoid type Diseases 0.000 description 1
- 208000000810 Separation Anxiety Diseases 0.000 description 1
- 206010041250 Social phobia Diseases 0.000 description 1
- 208000020339 Spinal injury Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 208000031674 Traumatic Acute Stress disease Diseases 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 201000003229 acute pancreatitis Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 201000002426 animal phobia Diseases 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 229940125683 antiemetic agent Drugs 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000003416 augmentation Effects 0.000 description 1
- 208000017210 benign occipital epilepsy Diseases 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 208000003295 carpal tunnel syndrome Diseases 0.000 description 1
- 206010007776 catatonia Diseases 0.000 description 1
- 208000013116 chronic cough Diseases 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 230000037411 cognitive enhancing Effects 0.000 description 1
- 239000002361 compost Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 208000026725 cyclothymic disease Diseases 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000037336 dry skin Effects 0.000 description 1
- 208000010118 dystonia Diseases 0.000 description 1
- 201000009028 early myoclonic encephalopathy Diseases 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 201000006517 essential tremor Diseases 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 208000037870 generalized anxiety Diseases 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- YEMWINDXAKRPBK-UHFFFAOYSA-N heptane;2-methoxy-2-methylpropane Chemical compound COC(C)(C)C.CCCCCCC YEMWINDXAKRPBK-UHFFFAOYSA-N 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 208000003532 hypothyroidism Diseases 0.000 description 1
- 230000002989 hypothyroidism Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 201000003152 motion sickness Diseases 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- QAXZWHGWYSJAEI-UHFFFAOYSA-N n,n-dimethylformamide;ethanol Chemical compound CCO.CN(C)C=O QAXZWHGWYSJAEI-UHFFFAOYSA-N 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000003040 nociceptive effect Effects 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 231100000862 numbness Toxicity 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 208000002851 paranoid schizophrenia Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 208000019899 phobic disease Diseases 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 208000028173 post-traumatic stress disease Diseases 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 206010036596 premature ejaculation Diseases 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 201000001204 progressive myoclonus epilepsy Diseases 0.000 description 1
- 229940043274 prophylactic drug Drugs 0.000 description 1
- 239000012658 prophylactic medication Substances 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 201000005070 reflex epilepsy Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 230000037380 skin damage Effects 0.000 description 1
- 238000007613 slurry method Methods 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 208000030401 vitamin deficiency disease Diseases 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Dermatology (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Psychiatry (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201862659226P | 2018-04-18 | 2018-04-18 | |
| US62/659,226 | 2018-04-18 | ||
| PCT/US2019/027880 WO2019204446A1 (en) | 2018-04-18 | 2019-04-17 | Gabaa positive allosteric modulator compounds, methods of making, and uses thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BR112020021104A2 true BR112020021104A2 (pt) | 2021-02-23 |
Family
ID=68239798
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BR112020021104-4A BR112020021104A2 (pt) | 2018-04-18 | 2019-04-17 | compostos moduladores alostéricos positivos gabaa, métodos de produção e usos dos mesmos |
Country Status (14)
| Country | Link |
|---|---|
| US (3) | US11542263B2 (https=) |
| EP (1) | EP3781566A4 (https=) |
| JP (3) | JP7449272B2 (https=) |
| KR (2) | KR102799156B1 (https=) |
| CN (2) | CN112384513A (https=) |
| AU (2) | AU2019255282B2 (https=) |
| BR (1) | BR112020021104A2 (https=) |
| CA (1) | CA3096890A1 (https=) |
| CL (1) | CL2020002663A1 (https=) |
| IL (1) | IL278067A (https=) |
| MX (2) | MX2020010878A (https=) |
| SG (1) | SG11202010220QA (https=) |
| TW (1) | TW202012402A (https=) |
| WO (1) | WO2019204446A1 (https=) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP7449272B2 (ja) * | 2018-04-18 | 2024-03-13 | ニューロサイクル・セラピューティクス・インコーポレイテッド | Ｇａｂａａ陽性アロステリックモジュレーター化合物、その作製の方法および使用 |
| SG11202109526PA (en) * | 2019-03-18 | 2021-10-28 | Neurocycle Therapeutics Inc | Use of gabaa receptor modulators for treatment of pain |
| JP2022553718A (ja) * | 2019-10-22 | 2022-12-26 | ニューロサイクル・セラピューティクス・インコーポレイテッド | Ｇａｂａａ陽性アロステリック調節因子化合物、作成方法、およびその使用 |
| KR20220087507A (ko) * | 2019-10-23 | 2022-06-24 | 뉴로사이클 테라퓨틱스, 인크. | Gabaa 수용체 조절제를 사용한 간질 병태의 치료 |
| US12233070B2 (en) * | 2020-06-30 | 2025-02-25 | University Of Mississippi Medical Center | Methods for treating benzodiazepine misuse/use disorder |
| AU2023356939A1 (en) * | 2022-10-04 | 2025-04-10 | Engrail Therapeutics, Inc. | Gaba a receptor modulators and uses thereof |
| WO2025175214A1 (en) * | 2024-02-16 | 2025-08-21 | Engrail Therapeutics, Inc. | Methods of treating generalized anxiety disorder |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2802343C2 (de) | 1978-01-20 | 1982-04-22 | Peter Prof. Dr.-Ing. Friderichs | Latentwärmespeicher-Behälter |
| GB9813576D0 (en) * | 1998-06-24 | 1998-08-19 | Merck Sharp & Dohme | Therapeutic agents |
| CA2427779A1 (en) * | 2000-11-10 | 2002-05-16 | Merck Sharp & Dohme Limited | Imidazo-triazine derivatives as ligands for gaba receptors |
| GB0117277D0 (en) | 2001-07-16 | 2001-09-05 | Merck Sharp & Dohme | Therapeutic agents |
| TWI248936B (en) | 2001-03-21 | 2006-02-11 | Merck Sharp & Dohme | Imidazo-pyrimidine derivatives as ligands for GABA receptors |
| JP2004170323A (ja) | 2002-11-22 | 2004-06-17 | Sumitomo Pharmaceut Co Ltd | 皮膚疾患治療剤のスクリーニング方法 |
| WO2009021957A2 (en) | 2007-08-14 | 2009-02-19 | Novartis Ag | Tricyclic heterocyclic compounds as gaba a modulators |
| WO2009143211A2 (en) | 2008-05-21 | 2009-11-26 | Incyte Corporation | Salts of 2-fluoro-n-methyl-4-[7-(quinolin-6-yl-methyl)- imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same |
| US20110082147A1 (en) | 2009-07-24 | 2011-04-07 | Concert Pharmaceuticals, Inc. | Substituted imidazotriazines |
| MX362181B (es) | 2013-02-19 | 2019-01-08 | Ono Pharmaceutical Co | Compuesto inhibidor de cinasa del receptor de tropomiosina (trk). |
| WO2015072853A1 (en) | 2013-11-13 | 2015-05-21 | Rjg Developments B.V. | Treatment of herpes virus infection outbreaks |
| SG11201806393QA (en) * | 2016-01-27 | 2018-08-30 | Univ Zuerich | Use of gabaa receptor modulators for treatment of itch |
| JP7449272B2 (ja) * | 2018-04-18 | 2024-03-13 | ニューロサイクル・セラピューティクス・インコーポレイテッド | Ｇａｂａａ陽性アロステリックモジュレーター化合物、その作製の方法および使用 |
-
2019
- 2019-04-17 JP JP2021506619A patent/JP7449272B2/ja active Active
- 2019-04-17 TW TW108113441A patent/TW202012402A/zh unknown
- 2019-04-17 CN CN201980041321.7A patent/CN112384513A/zh active Pending
- 2019-04-17 KR KR1020207033073A patent/KR102799156B1/ko active Active
- 2019-04-17 BR BR112020021104-4A patent/BR112020021104A2/pt unknown
- 2019-04-17 WO PCT/US2019/027880 patent/WO2019204446A1/en not_active Ceased
- 2019-04-17 MX MX2020010878A patent/MX2020010878A/es unknown
- 2019-04-17 CA CA3096890A patent/CA3096890A1/en active Pending
- 2019-04-17 KR KR1020257012376A patent/KR20250057112A/ko active Pending
- 2019-04-17 EP EP19788410.9A patent/EP3781566A4/en active Pending
- 2019-04-17 SG SG11202010220QA patent/SG11202010220QA/en unknown
- 2019-04-17 AU AU2019255282A patent/AU2019255282B2/en active Active
- 2019-04-17 CN CN202511219750.2A patent/CN121135719A/zh active Pending
-
2020
- 2020-10-14 MX MX2024004400A patent/MX2024004400A/es unknown
- 2020-10-15 IL IL278067A patent/IL278067A/en unknown
- 2020-10-15 CL CL2020002663A patent/CL2020002663A1/es unknown
- 2020-10-16 US US17/072,282 patent/US11542263B2/en active Active
-
2022
- 2022-12-28 US US18/089,661 patent/US12134619B2/en active Active
-
2024
- 2024-02-29 JP JP2024030150A patent/JP7721712B2/ja active Active
- 2024-10-02 US US18/904,228 patent/US20250034155A1/en active Pending
- 2024-11-07 AU AU2024259803A patent/AU2024259803A1/en active Pending
-
2025
- 2025-07-30 JP JP2025127411A patent/JP2025166011A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JP7721712B2 (ja) | 2025-08-12 |
| AU2019255282B2 (en) | 2024-08-08 |
| WO2019204446A1 (en) | 2019-10-24 |
| SG11202010220QA (en) | 2020-11-27 |
| AU2019255282A1 (en) | 2020-11-05 |
| AU2024259803A1 (en) | 2024-11-28 |
| CN112384513A (zh) | 2021-02-19 |
| US20230139418A1 (en) | 2023-05-04 |
| EP3781566A4 (en) | 2022-06-22 |
| JP2025166011A (ja) | 2025-11-05 |
| JP2024063136A (ja) | 2024-05-10 |
| CN121135719A (zh) | 2025-12-16 |
| MX2024004400A (es) | 2024-04-29 |
| KR20210011921A (ko) | 2021-02-02 |
| KR20250057112A (ko) | 2025-04-28 |
| US20210040103A1 (en) | 2021-02-11 |
| JP7449272B2 (ja) | 2024-03-13 |
| US20250034155A1 (en) | 2025-01-30 |
| JP2021522330A (ja) | 2021-08-30 |
| MX2020010878A (es) | 2021-01-29 |
| US12134619B2 (en) | 2024-11-05 |
| IL278067A (en) | 2020-11-30 |
| CA3096890A1 (en) | 2019-10-24 |
| KR102799156B1 (ko) | 2025-04-21 |
| TW202012402A (zh) | 2020-04-01 |
| CL2020002663A1 (es) | 2021-06-11 |
| EP3781566A1 (en) | 2021-02-24 |
| US11542263B2 (en) | 2023-01-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| BR112020021104A2 (pt) | compostos moduladores alostéricos positivos gabaa, métodos de produção e usos dos mesmos | |
| PT2414356E (pt) | Composições de {3-[5-(4-cloro-fenil)-1h-pirrol[2,3-b]piridin-3-carbonil]-2,4-difluoro-fenil}-amida do ácido propano-1-sulfónico e utilizações das mesmas | |
| BR112020011625A2 (pt) | formas sólidas de canabidiol e usos das mesmas | |
| KR102442536B1 (ko) | 리나글립틴 결정형 및 이의 제조방법 | |
| US12319652B2 (en) | Salts and solid forms of (R)-1-(5-methoxy-1H-indol-1-yl)-N,N-dimethylpropan-2-amine | |
| JP2026021408A (ja) | Ｇａｂａａ陽性アロステリック調節因子化合物、作成方法、およびその使用 | |
| EP1163241A1 (en) | Zolpidem salts | |
| CN121039114A (zh) | 1,5-二氢-2,4-苯二氮䓬-3-酮衍生物枸橼酸盐的晶型、制备方法及其应用 | |
| HK40100619A (zh) | 一种p2x3抑制剂化合物及其盐、多晶型和用途 | |
| CN107586293A (zh) | 含硫二苯并噻嗪生物碱类化合物及其用途 | |
| HK40116672A (zh) | 治疗实体瘤的泛素特异性处理蛋白酶1(usp1)抑制剂 | |
| KR20230026458A (ko) | Shp2 억제제의 결정형 및 이의 조성물, 제조 방법과 용도 | |
| HK40063558A (en) | Pharmaceutical salts of benzothiazol compounds, polymorphs and methods for preparation thereof | |
| CN113631554A (zh) | 苯并噻唑化合物的药用盐、多晶型物及其制备方法 | |
| BR112020007538B1 (pt) | Forma sólida, processo para preparar a forma sólida, composição farmacêutica, processo para preparar a composição farmacêutica e uso da forma sólida | |
| BR122025019554A2 (pt) | Forma sólida de 3-(5-flúor-benzofuran-3-il)-4-(5-metil-5h-[1,3]dioxolo[4,5- f]indol-7-il)pirrol-2,5-diona, seus usos, composição farmacêutica e processo para preparar a mesma | |
| BR112019005450B1 (pt) | Polimorfos cristalinos de um agonista do receptor de acetilcolina muscarínico, processos para preparar tais polimorfos, processo para manter estável um Forma II do polimorfo, composição farmacêutica, processo para preparar medicamento e uso de tais polimorfos |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B350 | Update of information on the portal [chapter 15.35 patent gazette] | ||
| B06W | Patent application suspended after preliminary examination (for patents with searches from other patent authorities) chapter 6.23 patent gazette] |