TW201522311A - 含有苯氧基哌啶核結構之ｈ拮抗劑 - Google Patents
含有苯氧基哌啶核結構之ｈ拮抗劑 Download PDFInfo
- Publication number
- TW201522311A TW201522311A TW103107713A TW103107713A TW201522311A TW 201522311 A TW201522311 A TW 201522311A TW 103107713 A TW103107713 A TW 103107713A TW 103107713 A TW103107713 A TW 103107713A TW 201522311 A TW201522311 A TW 201522311A
- Authority
- TW
- Taiwan
- Prior art keywords
- phenoxy
- compound
- piperidin
- formula
- methyl
- Prior art date
Links
- 239000005557 antagonist Substances 0.000 title description 7
- BRUWSFUBFQYNPG-UHFFFAOYSA-N 1-phenoxypiperidine Chemical group C1CCCCN1OC1=CC=CC=C1 BRUWSFUBFQYNPG-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 92
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims abstract description 79
- 229960001340 histamine Drugs 0.000 claims abstract description 40
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- 239000000544 cholinesterase inhibitor Substances 0.000 claims abstract description 29
- 238000011282 treatment Methods 0.000 claims abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 23
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 claims abstract description 18
- 239000012453 solvate Substances 0.000 claims abstract description 16
- 150000004677 hydrates Chemical class 0.000 claims abstract description 11
- 230000002265 prevention Effects 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims description 58
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 31
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical group O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 claims description 22
- 201000000980 schizophrenia Diseases 0.000 claims description 17
- 208000019901 Anxiety disease Diseases 0.000 claims description 13
- 239000004480 active ingredient Substances 0.000 claims description 13
- 208000010877 cognitive disease Diseases 0.000 claims description 13
- 208000008589 Obesity Diseases 0.000 claims description 12
- 206010041349 Somnolence Diseases 0.000 claims description 12
- 230000036506 anxiety Effects 0.000 claims description 12
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 claims description 12
- 239000003395 histamine H3 receptor antagonist Substances 0.000 claims description 12
- 235000020824 obesity Nutrition 0.000 claims description 12
- 208000020016 psychiatric disease Diseases 0.000 claims description 12
- -1 4-{4-[3-(piperidin-1-yl)-propoxy]-phenoxy}-piperidine 1-(3-[4-(piperidin-4-yl-oxy)-phenoxy]-propyl}-piperidine dihydrochloride Chemical compound 0.000 claims description 11
- 229960003530 donepezil Drugs 0.000 claims description 11
- 208000007590 Disorders of Excessive Somnolence Diseases 0.000 claims description 9
- 208000024827 Alzheimer disease Diseases 0.000 claims description 8
- 206010020751 Hypersensitivity Diseases 0.000 claims description 8
- 208000015114 central nervous system disease Diseases 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 208000002193 Pain Diseases 0.000 claims description 7
- 239000000556 agonist Substances 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 230000013016 learning Effects 0.000 claims description 7
- 201000003631 narcolepsy Diseases 0.000 claims description 7
- 208000007848 Alcoholism Diseases 0.000 claims description 6
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 6
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 6
- 208000028698 Cognitive impairment Diseases 0.000 claims description 6
- 208000011688 Generalised anxiety disease Diseases 0.000 claims description 6
- 208000023105 Huntington disease Diseases 0.000 claims description 6
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 6
- 208000001953 Hypotension Diseases 0.000 claims description 6
- 206010065390 Inflammatory pain Diseases 0.000 claims description 6
- 208000020358 Learning disease Diseases 0.000 claims description 6
- 206010024264 Lethargy Diseases 0.000 claims description 6
- 208000019022 Mood disease Diseases 0.000 claims description 6
- 206010028735 Nasal congestion Diseases 0.000 claims description 6
- 206010041250 Social phobia Diseases 0.000 claims description 6
- 238000013019 agitation Methods 0.000 claims description 6
- 201000007930 alcohol dependence Diseases 0.000 claims description 6
- 230000007815 allergy Effects 0.000 claims description 6
- 230000006735 deficit Effects 0.000 claims description 6
- 206010012601 diabetes mellitus Diseases 0.000 claims description 6
- 208000002173 dizziness Diseases 0.000 claims description 6
- 206010015037 epilepsy Diseases 0.000 claims description 6
- 229960003980 galantamine Drugs 0.000 claims description 6
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 claims description 6
- 208000029364 generalized anxiety disease Diseases 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 208000013403 hyperactivity Diseases 0.000 claims description 6
- 230000036543 hypotension Effects 0.000 claims description 6
- 201000003723 learning disability Diseases 0.000 claims description 6
- 230000003340 mental effect Effects 0.000 claims description 6
- 230000006371 metabolic abnormality Effects 0.000 claims description 6
- 208000004296 neuralgia Diseases 0.000 claims description 6
- 208000021722 neuropathic pain Diseases 0.000 claims description 6
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 6
- 208000019906 panic disease Diseases 0.000 claims description 6
- 201000011240 Frontotemporal dementia Diseases 0.000 claims description 5
- 208000000609 Pick Disease of the Brain Diseases 0.000 claims description 5
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 230000002996 emotional effect Effects 0.000 claims description 5
- 230000006870 function Effects 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 230000004770 neurodegeneration Effects 0.000 claims description 5
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 5
- 201000008482 osteoarthritis Diseases 0.000 claims description 5
- 229960004136 rivastigmine Drugs 0.000 claims description 5
- 229960001685 tacrine Drugs 0.000 claims description 5
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 206010017999 Gastrointestinal pain Diseases 0.000 claims description 4
- 208000024571 Pick disease Diseases 0.000 claims description 4
- 208000027744 congestion Diseases 0.000 claims description 4
- 230000004048 modification Effects 0.000 claims description 4
- 238000012986 modification Methods 0.000 claims description 4
- 208000028173 post-traumatic stress disease Diseases 0.000 claims description 4
- RGHPCLZJAFCTIK-UHFFFAOYSA-N 2-methylpyrrolidine Chemical group CC1CCCN1 RGHPCLZJAFCTIK-UHFFFAOYSA-N 0.000 claims description 3
- PSEIUCRNDYRZQE-GMUIIQOCSA-N ethyl 4-[4-[3-[(2r)-2-methylpyrrolidin-1-yl]propoxy]phenoxy]piperidine-1-carboxylate;hydrochloride Chemical compound Cl.C1CN(C(=O)OCC)CCC1OC(C=C1)=CC=C1OCCCN1[C@H](C)CCC1 PSEIUCRNDYRZQE-GMUIIQOCSA-N 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- RGHPCLZJAFCTIK-RXMQYKEDSA-N (R)-2-methylpyrrolidine Chemical group C[C@@H]1CCCN1 RGHPCLZJAFCTIK-RXMQYKEDSA-N 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 208000030814 Eating disease Diseases 0.000 claims 2
- 208000019454 Feeding and Eating disease Diseases 0.000 claims 2
- 230000004888 barrier function Effects 0.000 claims 2
- 235000014632 disordered eating Nutrition 0.000 claims 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims 1
- 208000002551 irritable bowel syndrome Diseases 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 108020003175 receptors Proteins 0.000 abstract description 25
- 102000005962 receptors Human genes 0.000 abstract description 25
- 239000003814 drug Substances 0.000 abstract description 11
- 239000003446 ligand Substances 0.000 abstract description 6
- 102000004384 Histamine H3 receptors Human genes 0.000 abstract description 2
- 108090000981 Histamine H3 receptors Proteins 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 123
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- 235000019439 ethyl acetate Nutrition 0.000 description 43
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- 239000002253 acid Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 15
- 229960004373 acetylcholine Drugs 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000013078 crystal Substances 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- NRLUYESWNVICHE-GGMCWBHBSA-N 4-[4-[3-[(2r)-2-methylpyrrolidin-1-yl]propoxy]phenoxy]piperidine;dihydrochloride Chemical compound Cl.Cl.C[C@@H]1CCCN1CCCOC(C=C1)=CC=C1OC1CCNCC1 NRLUYESWNVICHE-GGMCWBHBSA-N 0.000 description 10
- 239000002178 crystalline material Substances 0.000 description 10
- 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 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 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
- 229940079593 drug Drugs 0.000 description 9
- 210000001320 hippocampus Anatomy 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000002469 receptor inverse agonist Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 238000007792 addition Methods 0.000 description 7
- 210000004556 brain Anatomy 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- IRTTXYWMHFLYFK-UHFFFAOYSA-N 1-[3-(4-piperidin-4-yloxyphenoxy)propyl]piperidine Chemical compound C1CCCCN1CCCOC(C=C1)=CC=C1OC1CCNCC1 IRTTXYWMHFLYFK-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 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 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 238000009739 binding Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 5
- 239000010408 film Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000002464 receptor antagonist Substances 0.000 description 5
- 238000009097 single-agent therapy Methods 0.000 description 5
- 239000000829 suppository Substances 0.000 description 5
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 230000027455 binding Effects 0.000 description 4
- 230000033228 biological regulation Effects 0.000 description 4
- 210000003169 central nervous system Anatomy 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 235000005911 diet Nutrition 0.000 description 4
- 230000037213 diet Effects 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 210000002442 prefrontal cortex Anatomy 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 208000019116 sleep disease Diseases 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000010159 Duncan test Methods 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 208000032140 Sleepiness Diseases 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 239000003708 ampul Substances 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 230000019771 cognition Effects 0.000 description 3
- 230000003920 cognitive function Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000007937 lozenge Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000002287 radioligand Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- OVOCBFDIARGWAI-UHFFFAOYSA-N (1-methylcyclopropyl)-[4-[4-(3-piperidin-1-ylpropoxy)phenoxy]piperidin-1-yl]methanone Chemical compound C1CC(OC=2C=CC(OCCCN3CCCCC3)=CC=2)CCN1C(=O)C1(C)CC1 OVOCBFDIARGWAI-UHFFFAOYSA-N 0.000 description 2
- OTYQNNWMGWVHCD-FSRHSHDFSA-N (1-methylcyclopropyl)-[4-[4-[3-[(2r)-2-methylpyrrolidin-1-yl]propoxy]phenoxy]piperidin-1-yl]methanone;hydrochloride Chemical compound Cl.C[C@@H]1CCCN1CCCOC(C=C1)=CC=C1OC1CCN(C(=O)C2(C)CC2)CC1 OTYQNNWMGWVHCD-FSRHSHDFSA-N 0.000 description 2
- HDDNBUNZJIQDBQ-UHFFFAOYSA-N 1-(3-chloropropyl)piperidine Chemical compound ClCCCN1CCCCC1 HDDNBUNZJIQDBQ-UHFFFAOYSA-N 0.000 description 2
- NJYPSROLMXCRRG-UHFFFAOYSA-N 1-[3-(4-piperidin-4-yloxyphenoxy)propyl]piperidine;dihydrochloride Chemical compound Cl.Cl.C1CCCCN1CCCOC(C=C1)=CC=C1OC1CCNCC1 NJYPSROLMXCRRG-UHFFFAOYSA-N 0.000 description 2
- BYOQMPYHQAEVNW-UHFFFAOYSA-N 1-[4-[4-(3-piperidin-1-ylpropoxy)phenoxy]piperidin-1-yl]ethanone hydrochloride Chemical compound Cl.CC(=O)N1CCC(CC1)Oc1ccc(OCCCN2CCCCC2)cc1 BYOQMPYHQAEVNW-UHFFFAOYSA-N 0.000 description 2
- BDDVHFUUXVOMBE-QGZVFWFLSA-N 1-[4-[4-[3-[(2r)-2-methylpyrrolidin-1-yl]propoxy]phenoxy]piperidin-1-yl]ethanone Chemical class C[C@@H]1CCCN1CCCOC(C=C1)=CC=C1OC1CCN(C(C)=O)CC1 BDDVHFUUXVOMBE-QGZVFWFLSA-N 0.000 description 2
- DIZKLZKLNKQFGB-UHFFFAOYSA-N 1-methylcyclopropane-1-carboxylic acid Chemical compound OC(=O)C1(C)CC1 DIZKLZKLNKQFGB-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 102100033639 Acetylcholinesterase Human genes 0.000 description 2
- 108010022752 Acetylcholinesterase Proteins 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 206010012289 Dementia Diseases 0.000 description 2
- 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 2
- 208000027534 Emotional disease Diseases 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229920002873 Polyethylenimine Polymers 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000007984 Tris EDTA buffer Substances 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- KFHYZKCRXNRKRC-MRXNPFEDSA-N abt-239 Chemical compound C[C@@H]1CCCN1CCC1=CC2=CC(C=3C=CC(=CC=3)C#N)=CC=C2O1 KFHYZKCRXNRKRC-MRXNPFEDSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 2
- 235000013877 carbamide Nutrition 0.000 description 2
- 229960001631 carbomer Drugs 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 229910000420 cerium oxide Inorganic materials 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000007278 cognition impairment Effects 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- SAIMNGONWHTXQQ-UHFFFAOYSA-N cyclobutyl-[4-[4-(3-piperidin-1-ylpropoxy)phenoxy]piperidin-1-yl]methanone;hydrochloride Chemical compound Cl.C1CC(OC=2C=CC(OCCCN3CCCCC3)=CC=2)CCN1C(=O)C1CCC1 SAIMNGONWHTXQQ-UHFFFAOYSA-N 0.000 description 2
- BZCUYJPRYANZFF-FSRHSHDFSA-N cyclobutyl-[4-[4-[3-[(2r)-2-methylpyrrolidin-1-yl]propoxy]phenoxy]piperidin-1-yl]methanone;hydrochloride Chemical compound Cl.C[C@@H]1CCCN1CCCOC(C=C1)=CC=C1OC1CCN(C(=O)C2CCC2)CC1 BZCUYJPRYANZFF-FSRHSHDFSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- IXFRYVXYOWVOMW-UHFFFAOYSA-N ethyl 4-[4-(3-piperidin-1-ylpropoxy)phenoxy]piperidine-1-carboxylate hydrochloride Chemical compound Cl.CCOC(=O)N1CCC(CC1)OC1=CC=C(OCCCN2CCCCC2)C=C1 IXFRYVXYOWVOMW-UHFFFAOYSA-N 0.000 description 2
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 235000012631 food intake Nutrition 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 230000027119 gastric acid secretion Effects 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000001738 genotoxic effect Effects 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000000742 histaminergic effect Effects 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 229940125425 inverse agonist Drugs 0.000 description 2
- PTKHFRNHJULJKT-UHFFFAOYSA-N jnj-5207852 Chemical compound C1CCCCN1CCCOC(C=C1)=CC=C1CN1CCCCC1 PTKHFRNHJULJKT-UHFFFAOYSA-N 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 2
- 229960004640 memantine Drugs 0.000 description 2
- 238000001690 micro-dialysis Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- LLCJDYPBWHVYNH-UHFFFAOYSA-N n-ethyl-4-[4-(3-piperidin-1-ylpropoxy)phenoxy]piperidine-1-carboxamide Chemical compound C1CN(C(=O)NCC)CCC1OC(C=C1)=CC=C1OCCCN1CCCCC1 LLCJDYPBWHVYNH-UHFFFAOYSA-N 0.000 description 2
- TYOVRHXFPNBDQG-GOSISDBHSA-N n-ethyl-4-[4-[3-[(2r)-2-methylpyrrolidin-1-yl]propoxy]phenoxy]piperidine-1-carboxamide Chemical compound C1CN(C(=O)NCC)CCC1OC(C=C1)=CC=C1OCCCN1[C@H](C)CCC1 TYOVRHXFPNBDQG-GOSISDBHSA-N 0.000 description 2
- ZHXPGCGQCQMOSB-UHFFFAOYSA-N n-ethyl-n-methyl-4-[4-(3-piperidin-1-ylpropoxy)phenoxy]piperidine-1-carboxamide;hydrochloride Chemical compound Cl.C1CN(C(=O)N(C)CC)CCC1OC(C=C1)=CC=C1OCCCN1CCCCC1 ZHXPGCGQCQMOSB-UHFFFAOYSA-N 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 238000001543 one-way ANOVA Methods 0.000 description 2
- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 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
- 230000037321 sleepiness Effects 0.000 description 2
- 239000011343 solid material Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000008174 sterile solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- WWUZIQQURGPMPG-UHFFFAOYSA-N (-)-D-erythro-Sphingosine Natural products CCCCCCCCCCCCCC=CC(O)C(N)CO WWUZIQQURGPMPG-UHFFFAOYSA-N 0.000 description 1
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- BAKHPYGIWRQPMS-MRVPVSSYSA-N (2r)-1-(3-chloropropyl)-2-methylpyrrolidine Chemical compound C[C@@H]1CCCN1CCCCl BAKHPYGIWRQPMS-MRVPVSSYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- GSLTVFIVJMCNBH-UHFFFAOYSA-N 2-isocyanatopropane Chemical compound CC(C)N=C=O GSLTVFIVJMCNBH-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229940124596 AChE inhibitor Drugs 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000019737 Animal fat Nutrition 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 102000007527 Autoreceptors Human genes 0.000 description 1
- 108010071131 Autoreceptors Proteins 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 230000010665 Enzyme Interactions Effects 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010017367 Frequent bowel movements Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 102000000543 Histamine Receptors Human genes 0.000 description 1
- 108010002059 Histamine Receptors Proteins 0.000 description 1
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- FHQDWPCFSJMNCT-UHFFFAOYSA-N N(tele)-methylhistamine Chemical compound CN1C=NC(CCN)=C1 FHQDWPCFSJMNCT-UHFFFAOYSA-N 0.000 description 1
- QKDDJDBFONZGBW-UHFFFAOYSA-N N-Cyclohexy-4-(imidazol-4-yl)-1-piperidinecarbothioamide Chemical compound C1CC(C=2NC=NC=2)CCN1C(=S)NC1CCCCC1 QKDDJDBFONZGBW-UHFFFAOYSA-N 0.000 description 1
- 229940127523 NMDA Receptor Antagonists Drugs 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 244000004005 Nypa fruticans Species 0.000 description 1
- 235000005305 Nypa fruticans Nutrition 0.000 description 1
- 241001440143 Panula Species 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 206010062519 Poor quality sleep Diseases 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 235000011034 Rubus glaucus Nutrition 0.000 description 1
- 244000235659 Rubus idaeus Species 0.000 description 1
- 235000009122 Rubus idaeus Nutrition 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 208000013200 Stress disease Diseases 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
- 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 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 230000004596 appetite loss Effects 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000037007 arousal Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical compound NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 1
- 239000012148 binding buffer Substances 0.000 description 1
- 230000000035 biogenic effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- PASOAYSIZAJOCT-UHFFFAOYSA-N butanoic acid Chemical compound CCCC(O)=O.CCCC(O)=O PASOAYSIZAJOCT-UHFFFAOYSA-N 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 210000002932 cholinergic neuron Anatomy 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 230000007370 cognitive improvement Effects 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- PUSKHXMZPOMNTQ-UHFFFAOYSA-N ethyl 2,1,3-benzoselenadiazole-5-carboxylate Chemical compound CCOC(=O)C1=CC=C2N=[Se]=NC2=C1 PUSKHXMZPOMNTQ-UHFFFAOYSA-N 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 150000003948 formamides Chemical class 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 210000005153 frontal cortex Anatomy 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000023266 generation of precursor metabolites and energy Effects 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229960004931 histamine dihydrochloride Drugs 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- QNJSWVQHWIFPGY-UHFFFAOYSA-N hydrazinecarboxylic acid;hydrochloride Chemical compound Cl.NNC(O)=O QNJSWVQHWIFPGY-UHFFFAOYSA-N 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 238000005470 impregnation Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- JBJOBYTVTLNTCL-FSRHSHDFSA-N n-ethyl-n-methyl-4-[4-[3-[(2r)-2-methylpyrrolidin-1-yl]propoxy]phenoxy]piperidine-1-carboxamide;hydrochloride Chemical compound Cl.C1CN(C(=O)N(C)CC)CCC1OC(C=C1)=CC=C1OCCCN1[C@H](C)CCC1 JBJOBYTVTLNTCL-FSRHSHDFSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 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
- 229960002748 norepinephrine Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229950000964 pepstatin Drugs 0.000 description 1
- 108010091212 pepstatin Proteins 0.000 description 1
- FAXGPCHRFPCXOO-LXTPJMTPSA-N pepstatin A Chemical compound OC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)CC(C)C FAXGPCHRFPCXOO-LXTPJMTPSA-N 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- NNACHAUCXXVJSP-UHFFFAOYSA-N pitolisant Chemical compound C1=CC(Cl)=CC=C1CCCOCCCN1CCCCC1 NNACHAUCXXVJSP-UHFFFAOYSA-N 0.000 description 1
- 229960003651 pitolisant Drugs 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000003414 procognitive effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000003014 reinforcing effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- JXOHGGNKMLTUBP-HSUXUTPPSA-N shikimic acid Chemical compound O[C@@H]1CC(C(O)=O)=C[C@@H](O)[C@H]1O JXOHGGNKMLTUBP-HSUXUTPPSA-N 0.000 description 1
- JXOHGGNKMLTUBP-JKUQZMGJSA-N shikimic acid Natural products O[C@@H]1CC(C(O)=O)=C[C@H](O)[C@@H]1O JXOHGGNKMLTUBP-JKUQZMGJSA-N 0.000 description 1
- 230000008454 sleep-wake cycle Effects 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- PESXGULMKCKJCC-UHFFFAOYSA-M sodium;4-methoxycarbonylphenolate Chemical compound [Na+].COC(=O)C1=CC=C([O-])C=C1 PESXGULMKCKJCC-UHFFFAOYSA-M 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- WWUZIQQURGPMPG-KRWOKUGFSA-N sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 description 1
- KQOCMRACUONAJY-UHFFFAOYSA-N spiro[chromene-2,4'-piperidine] Chemical class C1CNCCC21C=CC1=CC=CC=C1O2 KQOCMRACUONAJY-UHFFFAOYSA-N 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000010972 statistical evaluation Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- XTDXZSGSIMLARD-UHFFFAOYSA-N tert-butyl 2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC=CC=C1 XTDXZSGSIMLARD-UHFFFAOYSA-N 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000012043 vestibular reflex Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000004260 weight control Methods 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- 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
- 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
- A61P25/14—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
- A61P25/18—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
- A61P25/22—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
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- 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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- 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
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Diabetes (AREA)
- Psychiatry (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Obesity (AREA)
- Dermatology (AREA)
- Pain & Pain Management (AREA)
- Addiction (AREA)
- Psychology (AREA)
- Child & Adolescent Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本發明係關於通式(I)之新組織胺H3(H3)受體亞型選擇性配位體及/或其幾何異構物及/或立體異構物及/或非鏡像異構物及/或鹽及/或水合物及/或溶劑合物。本發明另外係關於含有該等化合物之醫藥組成物，及此等化合物作為用於治療及/或預防需要調節H3受體之病況的藥物之用途。本發明也涵蓋通式(I)化合物及乙醯膽鹼酯酶抑制劑的組合物。
Description
本發明係關於通式(I)之新組織胺H3(H3)受體亞型選擇性配位體及/或其幾何異構物及/或立體異構物及/或非鏡像異構物及/或鹽及/或水合物及/或溶劑合物。本發明另外係關於含有此等化合物之醫藥組成物，及此等化合物作為用於治療及/或預防需要調節H3受體之病況的藥物之用途。本發明也涵蓋通式(I)化合物及乙醯膽鹼酯酶抑制劑的組合物。
早就知道：組織胺在過敏反應的媒介中具有核心作用且其調節胃酸分泌。在大腦中組織胺不僅調節基本體內平衡功能且也調節高級腦功能例如學習及認知功能、睡眠-覺醒週期，食物攝取。
組織胺能神經元(Histaminergic neurons)源自下丘腦的乳頭結節核，並經由組織胺能路徑將投射作用送到大部分的大腦。
組織胺是參與調節生理功能的重要生物胺，其生物學
作用是經由四種受體(命名為H1、H2、H3和H4)媒介，彼等的分類係根據其序列的差異、傳訊性質和藥理學特性(Haas和Panula，Nat Rev Neurosci(2003)4：121-130；Leurs等人，Nat Rev Drug Discov(2005)4：107-120；Esbenshade等人，Br J Pharmacol(2008)154(6)：1166-1181)。
H1及H2受體為已知的藥物標靶。H1受體在過敏性反應中的重要作用是眾所周知的，H1受體拮抗劑被廣泛使用。H2受體的主要功能是調節胃酸分泌。H4受體的作用還沒有充分研究。根據臨床前的證據，彼等會涉及發炎過程和疼痛感。
組織胺H3受體控制組織胺合成並釋放作為自身受體(Arrang等人，Nature(1983)302：832-837)，和作為異身受體，在乙醯膽鹼及其他神經傳遞物(去甲腎上腺素、血清素、多巴胺)之釋放的調節中具有基本作用(Schlicker等人，Naunyn Schmiedebergs Arch Pharmacol(1988)337：588-590；Schlicker等人，J Neural Transm Gen Sect(1993)93：1-10；Schlicker等人，Naunyn Schmiedebergs Arch Pharmacol(1989)340：633-638；Clapham和Kilpatrick,Br J Pharmacol(1992)107：919-923；Blandina等人，Br J Pharmacol(1996)119：1656-1664)。
組織胺H3受體拮抗劑/反向促效劑經由調節H3受體充當自體及異體受體在食物攝取的調節和體重控制具有顯著的作用(Passani等人，J Pharmacol Exp Ther(2011)
336，24-29)。
組織胺H3受體拮抗劑在大腦中引起組織胺和其他單胺類的合成和釋放。根據此機制，彼等加強覺醒、改善認知功能、正常化前庭反射。組織胺H3受體反向促效劑增加組織胺之突觸釋放，其經由突觸後H1受體的活化加強覺醒。促認知(procognitive)作用可能不只經由H3自身受體媒介，且經由H3異身受體調節之其他發射器系統(如膽鹼能神經元，其在認知方面發揮重要作用)也受到影響(Khateb等人，Neuroscience(1995)69(2)：495-506；Lin等人，J Neurosci(1996)16(4)：1523-1537；Passani等人，Trends Pharmacol Sci(2004)25：618-625；Jones,Trends Pharmacol Sci(2005)26：578-586；Bonaventure等人，Biochem Pharmacol(2007)73：1084-1096；Ligneau等人，Biochem Pharmacol(2007)73：1215-1224；Parmentier等人，Biochem Pharmacol(2007)73：1157-1171；Haas等人，Physiol Rev(2008)88：1183-1241)。
已描述許多H3反向促效劑或拮抗劑(Berlin等人，J Med Chem(2011)54：26-53；Lazewska等人，Expert Opin.Ther.Patents(2010)20：1147-1169；Raddatz等人，Cur Top Med Chem(2010)10：153-169)，因為發現組織胺H3受體(Arrang等人，Nature(1983)302：832-837)。雖然有幾種化合物已經前進到臨床階段，但彼等沒有獲得治療性應用，只有一種化合物匹托立生(pitolisant)(1-{3[3(4-氯苯基)丙氧基]丙基}哌啶)已經開始第3期臨床試驗使用在
猝睡症適應症中(Kuhne等人，Expert Opin Investig(2011)20：1629-1648)。組織胺H3受體反向促效劑或拮抗劑化合物使藥物推向市場的主要缺點為下列：(Lazewska等人，Expert Opin.Ther.Patents(2010)20：1147-1169)
磷脂質病：在組織胺H3受體反向促效劑或拮抗劑之結構中有一或二個鹼性氮。磷脂質病最可能是由二元性質引起，但單元化合物的情況下也可發生磷脂質病(Ratcliffe Curr Med Chem(2009)16：2816-2823)。二元JNJ-5207852被捨棄，因為其造成磷脂質病(Bonaventure等人，Biochem Pharmacol(2007)73：1084-1096)。
心血管副作用，與hERG鉀離子通道的相互作用：ABT-239(Hancock,Biochem Pharmacol(2006)71：1103-1113)
高血漿蛋白結合：ABT-239(Hancock,Biochem Pharmacol(2006)71：1103-1113)
遺傳毒性：A-331440(Hancock等人，Basic Clin Pharmacol Toxicol(2004)95：144-152)
不良藥物動力學性質：JNJ-5207852(Bonaventure等人，Biochem Pharmacol(2007)73：1084-1096)。螺[苯並吡喃-2,4’-哌啶]衍生物，其與我們的發明化合物在結構上最密切相關，但彼等具有較不靈活的結構，遭受不良口服生體可用率，因此它們應該被進一步最佳化。(Dandu等人，Bioorg Med Chem Lett(2012)22：2151-2153)
CYP酵素交互作用：NNC 38-1202(Peschke等人，
Bioorg Med Chem(2004)12：2603-2616)。
從潛在組織胺H3受體反向促效劑或拮抗劑消除不需要的性質不是簡單的任務，考慮到雖然幾種組織胺H3受體反向促效劑或拮抗劑已在不同的適應症中進行臨床研究，但彼等沒有被推出。(Kuhne等人，Expert Opin Investig(2011)20：1629-1648)
組織胺H3反向促效劑及拮抗劑的潛在治療應用包括多種適應症例如神經變性疾病和認知缺陷的治療選項。
主要有兩種類型之用於症狀治療阿滋海默症(其屬於神經變性疾病)的藥物治療，其中之一是利用乙醯膽鹼酯酶酵素抑制劑藥物(諸如多奈派齊(donepezil)、利斯的明(rivastigmine)、加蘭他敏(galantamine)、塔克林(tacrine))，而另一種是利用NMDA受體拮抗劑(美金剛(memantine))。臨床試驗顯示：乙醯膽鹼酯酶抑制劑和美金剛的組合物給藥並沒有優於單一療法。迄今已批准的使用於單一療法之藥物的功效是有限的，彼等在改善認知功能方面只有微弱作用，且此作用限制於治療的前6-12個月，而且乙醯膽鹼酯酶抑制劑僅在30-40%的療患者中是有效的。常見的副作用是噁心、嘔吐、食慾不振和排便更頻繁。
由阿滋海默症引起的認知功能障礙之改善表示重要的未滿足之醫療需求，非常需要新的藥物(Gerald及Ockert,Nat Rev Drug Discov(2013)12(1)：19-20.；Molino等人，(2013)ScientificWorldJournal 2013：925702；McGleenon
等人，(1999)Br J Clin Pharmacol 48(4)：471-480)。
已嘗試經由共同給藥具有不同作用機制的藥物來改善乙醯膽鹼酯酶抑制劑的功效。
在最近的臨床試驗中已嘗試組織胺H3反向促效劑或拮抗劑化合物與乙醯膽鹼酯酶抑制劑的共同給藥。在三種候選藥物的情況下，對主要療效指標(endpoint)沒有改善，因此停止彼等的進一步開發(NCT01181310；Cho等人，Psychopharmacology(2011)218(3)：513-524；NCT 00420420；Egan等人，Curr Alzheimer Res(2012)9(4)：481-490；NCT01266525；Kirkesseli等人，J Nutr Health Aging(2013)17(9)：804)。
事實上，沒有用於治療阿滋海默症之令人滿意的單一療法或組合療法。
我們的目標是合成結構上是新的、化學上可變的、選擇性及藥物類似之H3拮抗劑及反向促效劑。
令人驚奇地發現，所合成的含有苯氧基-哌啶核心結構之化合物以高親和性及選擇性結合至H3受體，藥物類似分子，即彼等具有可接受的藥物動力學性質，例如彼等的吸收良好、彼等能夠穿越血腦障壁、彼等沒有心血管副作用、彼等不會導致磷脂質病、彼等不具有遺傳毒性及沒有與CYP酶的相互作用。
許多疾病可用組織胺H3受體配位體治療，其中H3配
位體可為拮抗劑或反向促效劑。
本發明之組織胺H3受體拮抗劑和反向促效劑及此等化合物與乙醯膽鹼酯酶抑制劑之組合物可用於治療與神經退行性疾病相關的認知功能障礙(例如阿滋海默症、匹克症)或與年齡相關的學習及精神障礙、或其他由於一般醫療病況之認知障礙(例如注意力不足過動(ADHD)或亨汀頓氏舞蹈症)、精神障礙(例如精神分裂感情型障礙或精神分裂症)、睡眠障礙(例如猝睡症、嗜睡、白天過度嗜睡(EDS))、飲食異常、肥胖、肥胖相關的代謝異常(例如高脂血症、糖尿病)、暈眩及癲癇。
此外本發明之組織胺H3受體拮抗劑和反向促效劑及此等化合物與乙醯膽鹼酯酶抑制劑之組合物可用於治療焦慮症(例如廣泛性焦慮症、恐慌症、創傷後精神壓力障礙、或社交焦慮症)、情感疾病(例如憂鬱情緒、併發憂鬱情緒和焦慮之適應障礙症)、中樞神經系統的障礙(例如精神激動或抑鬱)、及其他中樞神經系統障礙(例如精神分裂症)。
此外本發明之組織胺H3受體拮抗劑和反向促效劑及此等化合物與乙醯膽鹼酯酶抑制劑之組合物可用於治療例如過敏、充血(例如鼻充血)、低血壓、心血管疾病、炎症性疼痛、其他疼痛引起的病症(例如神經性疼痛)、酗酒、腸躁症及骨關節炎。
本發明化合物以高親和性及選擇性(如與其他組織胺受體H1、H2及H4比較)結合至H3受體。
發明係關於通式(I)化合物
其中R1、R2彼此獨立地表示氫原子、或C1-C6烷基、或C3-C7環烷基，或R1和R2與相鄰鹼性氮原子一起形成4-10員的一或二個環狀飽和雜環基，其隨意含有一或二個氧原子及/或硫原子，且此等雜環基係隨意地經一或二個鹵素原子、側氧基、C1-C6烷基及其組合取代；R3表示：氫原子、-C(=O)R4、-C(=O)-OR4、-C(=O)-NR4R5基，其中R4和R5彼此獨立地表示氫原子、C1-C6直鏈或支鏈烷基、或隨意地經C1-C4烷基取代之C3-C7環烷基，及/或其鹽及/或立體異構物及/或非鏡像異構物及/或水合物及/或溶劑合物及/或多形體修飾物。
術語“C1-C6烷基”如使用於本文中係指包含一至六個
碳原子之支鏈或直鏈烷基。
術語“C3-C7環烷基”如使用於本文中係指包含三至七個碳原子之碳環基。
術語“鹵素”如使用於本文中單獨或作為其他基之一部分係指氟、氯、溴及碘原子。
有機及無機酸皆可用於形成酸加成鹽。適當無機酸包括(但不限於)鹽酸、硫酸、硝酸及磷酸。單價有機酸的代表包括(但不限於)甲酸、乙酸、丙酸、及不同丁酸(酪酸)、纈草酸(戊酸)及羊油酸(己酸)。二價有機酸的代表包括(但不限於)草酸、丙二酸、馬來酸、富馬酸及琥珀酸。也可使用其他有機酸，例如羥基羧酸(例如檸檬酸、酒石酸)、或芳族羧酸(例如苯甲酸或水楊酸)、以及脂族及芳族磺酸(例如甲磺酸、萘磺酸及對甲苯磺酸)。
酸加成的較佳群組為其中酸成分本身是藥學上可接受的並在施用劑量不具有治療效果且其對活性成分的效果沒有不利的影響。此等酸加成鹽為藥學上可接受的酸加成鹽。不是藥學上可接受的酸加成鹽之酸加成鹽在所要的式(I)化合物的純化及/或單離是有利的且因此也包括本發明的範圍內。
一些通式(I)化合物
- 其中R1、R2和R3之意義如上所述-可具有幾何異構物、立體異構物及/或非鏡像異構物形式。此等及其混合物也可包括在本發明之範圍內。
本發明較佳化合物為彼等式(I)化合物，其中R1和R2與相鄰氮原子一起形成5-員隨意經取代之雜環。
本發明之進一步較佳化合物為彼等式(I)化合物，其中R1和R2與相鄰氮原子一起形成2-甲基-吡咯啶環。
本發明之進一步較佳化合物為彼等式(I)化合物，其中R1和R2與相鄰氮原子一起形成2-(R)-甲基-吡咯啶環。
本發明之進一步較佳化合物為彼等式(I)化合物，其中R3之意義為-C(=O)R4，其中R4之意義為C1-C6直鏈或支鏈烷基、或隨意地經C1-C4烷基取代之C3-C7環烷基。
本發明之較佳通式(I)化合物為下列化合物：4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酸三級丁酯
1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二鹽酸鹽
1-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-基)-乙酮鹽酸鹽
環丁基-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-基)-甲酮鹽酸鹽
(1-甲基-環丙基)-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-基)-甲酮鹽酸鹽
4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酸乙酯鹽酸鹽
N-乙基-4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲醯胺
N-乙基-N-甲基-4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲醯胺鹽酸鹽
4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酸三級丁酯
4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶二鹽酸鹽
1-[4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶-1-基]-乙酮鹽酸鹽
環丁基-[4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶-1-基]-甲酮鹽酸鹽
(1-甲基-環丙基)-[4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶-1-基]-甲酮鹽酸鹽
4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酸乙酯鹽酸鹽
N-乙基-4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶-1-甲醯胺
N-乙基-N-甲基-4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶-1-甲醯胺鹽酸鹽。
本發明也還涵蓋通式(I)化合物及乙醯膽鹼酯酶抑制劑之組合物。本發明之組合物較佳地含有多奈派齊
(donepezil)、加蘭他敏(galantamine)、塔克林(tacrine)或利斯的明(rivastigmine)作為乙醯膽鹼酯酶抑制劑。
本發明之通式(I)化合物的可根據下列反應流程合成(基之意義係如上述關於式(I)所述，PG表示用於保護二級胺的保護基)
使式(II)之中間物，較佳含有三級丁氧羰基保護基之
化合物(Waterson等人，WO2006064218A1(2006)；實例1及7；Ishii等人，EP1849773A1(2007)實例29)、及式(III)之中間物，較佳1-氯-3-(1-哌啶基)-丙烷(Buchanan等人，Bioorg.Med.Chem.Let.(2011)21：2394-2399；Sann等人，Tetrahedron(2007)63：12903-12911)或(2R)-1-(3-氯丙基)-2-甲基吡咯啶(Nakamura等人，WO2010090347A1(2010))在惰性溶劑中(較佳地在乙腈或N,N-二甲基甲醯胺中)在有機或無機鹼(較佳地K2CO3)存在下反應。
裂解式(IA)中間物之保護基。用酸(較佳地用吸收在有機溶劑中之鹽酸)裂解較佳所使用之三級丁氧羰基保護基。鹽形成：將所得式(IB)化合物溶解在極性溶劑中，添加等莫耳量的酸及藉由蒸發移除溶劑。
式(IB)之中間物可根據下列方法轉換成式(I)之烷胺類、甲醯胺類、脲類或胺甲酸酯，及在給定的情況下，形成鹽：
使式(IB)之中間物與適當甲酸在偶合劑存在下反應，或與適當羧醯氯在鹼存在下、在惰性溶劑中反應。
使式(IB)之中間物與適當胺甲醯氯在鹼存在下、在惰性溶劑中反應。
使式(IB)之中間物與適當氯化羰基在鹼存在下、在惰性溶劑中反應。
將步驟C1、C2、C3任一者中所得之式(I)化合物溶解在極性溶劑中，添加等莫耳量之酸及藉由蒸發移除溶劑或濾出沉澱的晶體。
本發明係關於醫藥組成物，其包含治療有效量的式(I)化合物及/或其幾何異構物及/或立體異構物及/或非鏡像異構物及/或鹽及/或水合物及/或溶劑合物及/或此等化合物與乙醯膽鹼酯酶抑制劑之組合物及一或多種醫藥上可接受的載體。
本發明較佳地也關於用於治療及/或預防需要調節組織胺H3受體之病況的醫藥組成物，其包含治療有效量的式(I)化合物及/或其幾何異構物及/或立體異構物及/或非鏡像異構物及/或鹽及/或水合物及/或溶劑合物及/或此等化合物與乙醯膽鹼酯酶抑制劑之組合物及一或多種醫藥上可接受的載體。
本發明之醫藥組成物最佳含有具有H3受體拮抗劑或
反向促效劑作用之式(I)化合物及/或其幾何異構物及/或立體異構物及/或非鏡像異構物及/或鹽及/或水合物及/或溶劑合物及/或此等化合物與乙醯膽鹼酯酶抑制劑之組合物。
本發明也關於醫藥組成物，其含有式(I)化合物及/或其幾何異構物及/或立體異構物及/或非鏡像異構物及/或鹽及/或水合物及/或溶劑合物及/或此等化合物與乙醯膽鹼酯酶抑制劑之組合物，其在與年齡相關的認知功能障礙、學習及精神障礙(諸如阿滋海默症、匹克症)或其他由於一般醫療病況之認知障礙(諸如注意力不足過動(ADHD)或亨汀頓氏舞蹈症)、精神障礙(諸如精神分裂感情型障礙或精神分裂症)、睡眠障礙(諸如猝睡症、嗜睡、白天過度嗜睡(EDS))、飲食異常、肥胖、肥胖相關的代謝異常(諸如高脂血症、糖尿病)、暈眩、癲癇、焦慮症(諸如廣泛性焦慮症、恐慌症、創傷後精神壓力障礙或社交焦慮症)、情感疾病(諸如憂鬱情緒、併發憂鬱情緒和焦慮之適應障礙症)、中樞神經系統的障礙(諸如精神激動或抑鬱)、其他中樞神經系統障礙(諸如精神分裂症)、過敏、充血(諸如鼻充血)、低血壓、心血管疾病、炎症性疼痛、其他疼痛引起的病症(諸如神經性疼痛)、酗酒、腸躁症及骨關節炎之治療及/或預防中將是有效的。
本發明也關於式(I)化合物及/或其幾何異構物及/或立體異構物及/或非鏡像異構物及/或鹽及/或水合物及/或溶劑合物及/或此等化合物與乙醯膽鹼酯酶抑制劑之組合物
用於製造藥物之用途。
本發明也提供式(I)化合物及/或其幾何異構物及/或立體異構物及/或非鏡像異構物及/或鹽及/或水合物及/或溶劑合物及/或此等化合物與乙醯膽鹼酯酶抑制劑之組合物用於製造供治療及/或預防與年齡相關的認知功能障礙、學習及精神障礙(諸如阿滋海默症、匹克症)或其他由於一般醫療病況之認知障礙(諸如注意力不足過動(ADHD)或亨汀頓氏舞蹈症)、精神障礙(諸如精神分裂感情型障礙或精神分裂症)、睡眠障礙(諸如猝睡症、嗜睡、白天過度嗜睡(EDS))、飲食異常、肥胖、肥胖相關的代謝異常(諸如高脂血症、糖尿病)、暈眩、癲癇、焦慮症(諸如廣泛性焦慮症、恐慌症、創傷後精神壓力障礙或社交焦慮症)、情感疾病(諸如憂鬱情緒、併發憂鬱情緒和焦慮之適應障礙症)、中樞神經系統的障礙(諸如精神激動或抑鬱)、其他中樞神經系統障礙(諸如精神分裂症)、過敏、充血(諸如鼻充血)、低血壓、心血管疾病、炎症性疼痛、其他疼痛引起的病症(諸如神經性疼痛)、酗酒、腸躁症及骨關節炎的藥物之用途。
本發明也提供一種用於治療及/或預防需要調節組織胺H3受體功能的病況之方法，其包含將有效量之式(I)化合物及/或其幾何異構物及/或立體異構物及/或非鏡像異構物及/或鹽及/或水合物及/或溶劑合物以本身或以醫藥組成物給藥至待治療之哺乳動物-包括人類。
本發明也提供一種用於治療及/或預防需要調節組織
胺H3受體功能的病況(諸如與年齡相關的認知功能障礙、學習及精神障礙(諸如阿滋海默症、匹克症)或其他由於一般醫療病況之認知障礙(諸如注意力不足過動(ADHD)或亨汀頓氏舞蹈症)、精神障礙(諸如精神分裂感情型障礙或精神分裂症)、睡眠障礙(諸如猝睡症、嗜睡、白天過度嗜睡(EDS))、飲食異常、肥胖、肥胖相關的代謝異常(諸如高脂血症、糖尿病)、暈眩、癲癇、焦慮症(諸如廣泛性焦慮症、恐慌症、創傷後精神壓力障礙或社交焦慮症)、情感疾病(諸如憂鬱情緒、併發憂鬱情緒和焦慮之適應障礙症)、中樞神經系統的障礙(諸如精神激動或抑鬱)、其他中樞神經系統障礙(諸如精神分裂症)、過敏、充血(諸如鼻充血)、低血壓、心血管疾病、炎症性疼痛、其他疼痛引起的病症(諸如神經性疼痛)、酗酒、腸躁症及骨關節炎)之方法，其包含將有效量之式(I)化合物及/或其幾何異構物及/或立體異構物及/或非鏡像異構物及/或鹽及/或水合物及/或溶劑合物以本身或以醫藥組成物給藥至待治療之個體。
本發明式(I)化合物及/或其幾何異構物及/或立體異構物及/或非鏡像異構物及/或鹽及/或水合物及/或溶劑合物可藉由任何方便的方法例如藉由口服、腸胃外、經頰、舌下、鼻、直腸或經皮給藥來給藥。
通式(I)化合物及乙醯膽鹼酯酶抑制劑之組合物也可藉由多種及路徑及劑型給藥。組合物中的活性成分可組合或單獨地調配成醫藥組成物及組成物可以單一或多劑量給藥。通式(I)化合物及乙醯膽鹼酯酶抑制劑的組合物係同時
或順序給藥。
本發明之組合物較佳地含有多奈派齊(donepezil)、加蘭他敏(galantamine)、塔克林(tacrine)或利斯的明(rivastigmine)作為乙醯膽鹼酯酶抑制劑。
用於口服給藥之本發明醫藥組成物可於液體或固體形式，例如糖漿、懸浮液或乳劑、錠劑、膜衣錠、糖衣錠及膠囊。
懸浮液或液體組成物可含有在適當液體載體中(例如在水性溶劑(諸如水、乙醇或甘油)或在非水性溶劑(諸如聚乙二醇或油)中)之活性成分。該調配物也可含有一或多種懸浮劑、防腐劑、矯味及著色劑或其組合物。
錠劑的固體形式之組成物可使用任何例行用於製備固體製劑的適當藥物載體製造。該等載體的實例包括硬脂酸鎂、澱粉、乳糖、蔗糖、纖維素、等等。
於膠囊的固體形式之組成物可使用例行包囊步驟來製造。例如含有活性成分之小粒可使用標準載體製備且然後裝入硬明膠膠囊中；或者分散液或懸浮液可使用任何適當醫藥載體(例如水性膠、纖維素、矽酸鹽或油類)製備及然後將所得分散液或懸浮液裝入軟明膠膠囊中。
用於腸胃外給藥之組成物可調配成液體或懸浮液的形式，其除了本發明式(I)化合物之外，含有無菌水性載體或腸胃外可接受的油，例如聚乙二醇、聚乙烯基吡咯啶、卵磷脂、花生油或芝麻油。或者可將所得溶液冷凍乾燥並在給藥之前將該冷凍乾燥物再溶解於適當溶劑中。
用於鼻內給藥之組成物可調配成氣霧劑、滴劑、凝膠及粉末的形式。用於經頰或舌下給藥之本發明化合物可製造成錠劑、菱形錠及軟錠劑(pastille)的形式，其中活性成分與載體(諸如糖及阿拉伯膠、黃蓍膠或明膠及甘油等等)調配。
用於直腸給藥之組成物可方便地調配成含有常用栓劑成分(諸如可可脂)之栓劑的形式。
用於經皮給藥之組成物包括軟膏、凝膠及貼片。
上述的成分及不同的給藥路徑僅僅是代表性的。也可使用該技藝已知的其他材料以及加工技術。
本發明醫藥上可接受的式(I)化合物-其中R1和R2之意義如上所述-及/或其幾何異構物及/或立體異構物及/或非鏡像異構物及/或醫藥上可接受的鹽及/或水合物及/或溶劑合物通常在所有類型的組合物的情況下可以每天1至4次之每日劑量方案給藥(對成年患者)，其中各劑量單位可含有0.05(或較佳地0.005)至2000mg的式(I)化合物，以游離鹼計算。本發明化合物可適當地施用一段連續治療之時段，例如一週或更久。
圖1表示化合物11對內側前額葉皮質及海馬體之細胞外組織胺濃度的作用(AOBC-面積比基準曲線)。使用單向ANOVA接著/事後鄧肯測試(*P<0.05，對媒液)計算治療組之間的顯著差異。0.5及1mg/kg之劑量的化合物11
之單一治療在這二個區域中細胞外HA含量產生快速且表現增加。
圖2表示同時給藥之多奈派齊(donepezil)和化合物11對細胞外乙醯膽鹼濃度之超相加作用(AOBC-面積比基準曲線)。使用單向ANOVA接著/事後鄧肯測試(***：P<0.001對對應化合物11單一治療；##：P<0.01；###：P<0.001對多奈派齊(donepezil)單一治療)計算治療組之間的顯著差異。0.5mg/kg多奈派齊(donepezil)及0.5mg/kg化合物11或1mg/kg化合物11之同時給藥導致在MPFC及HC中細胞外ACh之超相加增加。此增強作用更表現於0.5mg/kg劑量的化合物1。
本發明以下列非限制性的實例說明。
所有中間物及最終產物的結構以NMR及質譜測定。
將4.2g(14.3mmol)的4-(4-羥苯氧基)哌啶-1-甲酸三級丁酯、3.7g(18.7mmol)的N-(3-氯丙基)-哌啶及5.9g(42.9mmol)的K2CO3在50ml的N,N-二甲基甲醯胺中之混合物在氮氣下於50℃攪拌16h。冷卻至室溫之後，濾
出沉澱的固體物質，用乙腈洗滌及在真空中濃縮濾液。藉由使用100g之矽凝膠及乙酸乙酯：乙醇=9：1之混合物作為溶析液的管柱層析法純化殘餘物以產生3.15g(53%)的呈晶體物質之標題化合物。
1HNMR(400MHz,DMSO-d6)：1.40 s(9H,H3-18,H3-18’,H3-18”)；2.31 br(4H,H2-2,H2-2’)；3.15 t br(2H,Hax-14,Hax-14’)；3.91 t(2H,H2-7)4.38 tt(1H,H-12)；6.82 m(2H,H-9,H-9’)；6.89 m(2H,H-10,H-10’)
13CNMR(100MHz,DMSO-d6)：28.0(C-18,C-18’,C-18”)；40.9(C-14,C-14’)；54.3(C-2,C2’)；66.4(C-7)；72.8(C-12)；115.3(C-9,C-9’)；117.4(C-10,C-10’)
MS：m/z：[M+H]+=419
將25ml的含有21w/w%之鹽酸的乙酸乙酯加至2.5g(6mmol)的4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1甲酸三級丁酯(實例1)在20ml的乙酸乙酯中的攪拌溶液，保持溫度低於10℃。使混合物加熱至室溫並在此溫度下攪拌16h。將沉澱的晶體濾出及用乙酸乙酯及乙醚連續洗滌以產生2.16g(92%)的呈晶體物質之標題化合物。
1HNMR(500MHz,DMSO-d6)：2.80 br(2H,Hx-2,Hx-2’)；3.03 ddd(2H,Hx-14,Hx-14’)；3.99 t(2H,H2-7)；4.51 tt(1H,H-12)；6.88 m(2H,H-9,H-9’)；6.95 m(2H,H-
10,H-10’)；9.14 br(2H,NH2 +-15)；10.50 br(1H,NH+-1)
13CNMR(125MHz,DMSO-d6)：40.3(C-14,C-14’)；52.0(C-2,C-2’)；65.5(C-7)；69.8(C-12)；115.5(C-9,C-9’)；117.4(C-10,C-10’)
MS：m/z：M‧+=318
將0.56ml(4mmol)的三乙胺加至0.39g(1mmol)的1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二鹽酸鹽(實例2)在20ml的二氯甲烷中之冰冷卻溶液，將混合物攪拌20min及滴加0.11ml(1.5mmol)的乙醯氯。將反應混合物在室溫下攪拌16h，然後用20ml的8w/w% NaHCO3水溶液洗滌，用20ml的二氯甲烷萃取水相並將合併之有機相用20ml的水洗滌，經過Na2SO4乾燥，過濾及濃縮。將粗製產物溶解在10ml的乙酸乙酯中及添加10ml的含有21w/w%之鹽酸的乙酸乙酯，將沉澱的晶體濾出，用乙酸乙酯及乙醚連續洗滌以產生0.33g(83%)的呈晶體物質之標題化合物。
1HNMR(500MHz,DMSO-d6)：2.01 s(3H,H3-17)；3.43 d(2H,Heq-2,Heq-2’)；3.98 t(2H,H2-7)；4.46 tt(1H,H-12)；6.87 m(2H,H-9,H-9’)；10.47 br(1H,NH+-1)
13CNMR(125MHz,DMSO-d6)：21.2(C-17)；52.1(C-2,
C-2’)；65.4(C-7)；72.6(C-12)；115.5(C-9,C-9’)
MS：m/z：M‧+=360
將0.56ml(4mmol)的三乙胺加至0.39g(1mmol)的1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二鹽酸鹽(實例2)在20ml的二氯甲烷中之冰冷卻溶液，將混合物攪拌20min及滴加0.17ml(1.5mmol)的氯化環丁基甲酸。將反應混合物在室溫下攪拌16h，然後用20ml的8w/w% NaHCO3水溶液洗滌，用20ml的二氯甲烷萃取水相並將合併之有機相用20ml的水洗滌，經過Na2SO4乾燥，過濾及濃縮。將粗製產物溶解在10ml的乙酸乙酯中及添加10ml的含有21w/w%之鹽酸的乙酸乙酯，將沉澱的晶體濾出，用乙酸乙酯及乙醚連續洗滌以產生0.28g(64%)的呈晶體物質之標題化合物。
1HNMR(500MHz,DMSO-d6)：1.71 m(2H,Hx-4,Hx-19)；3.34 m(1H,H-17)；3.43 d(2H,Heq-2,Heq-2’)；3.98 t(2H,H2-7)；4.45 tt(1H,H-12)；6.86 m(2H,H-9,H-9’)；10.32 br(1H,NH+-1)
13CNMR(125MHz,DMSO-d6)：36.4(C-17)；52.0(C-2,C-2’)；65.4(C-7)；72.6(C-12)；115.4(C-9,C-9’)；171.8(C-16)
MS：m/z：[M+H]+=401
將0.46ml(3.25mmol)的三乙胺加至0.39g(1mmol)的1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二鹽酸鹽(實例2)在10ml的N,N-二甲基甲醯胺中之冰冷卻溶液，將混合物攪拌10min，然後添加0.48g(1.25mmol)的HBTU及0.13g(1.25mmol)的1-甲基-環丙烷-甲酸。將反應混合物在室溫下攪拌16h，然後添加15ml的8w/w% NaHCO3水溶液，用3×8ml的二氯甲烷萃取混合物並將合併之有機相用10ml的水洗滌，經過Na2SO4乾燥，過濾及濃縮。殘餘物藉由使用15g之矽凝膠及乙酸乙酯：乙醇=1：1之混合物作為溶析液的管柱層析法純化。將標題化合物的經純化之鹼形式溶解在10ml的乙酸乙酯中及添加5ml含有21w/w%之鹽酸的乙酸乙酯，將沉澱的晶體濾出，用乙酸乙酯及乙醚連續洗滌以產生0.23g(53%)的呈晶體物質之標題化合物。
1HNMR(400MHz,DMSO-d6)：0.53 m(2H,Hx-18,Hx-18’)；0.78 m(2H,Hy-18,Hy-18’)；1.22 s(3H,H3-19)；1.40 m(1H,Hx-4)；2.86 br(4H,Heq-2,Heq-2’)；3.98 t(2H,H2-7)；4.47 tt(1H,H-12)；6.86 m(2H,H-9,H-9’)；10.06 br(1H,NH+-1)
MS：m/z：[M+H]+=401
將0.56ml(4mmol)的三乙胺加至0.39g(1mmol)的1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二鹽酸鹽(實例2)在20ml的二氯甲烷中之冰冷卻溶液，將混合物攪拌10min及滴加0.14ml(1.5mmol)的氯甲酸乙酯。將反應混合物在室溫下攪拌16h，然後用3x20ml的水洗滌，將有機相經過Na2SO4乾燥，過濾及濃縮。將粗製產物溶解在10ml的乙酸乙酯中及添加4ml的含有21w/w%之鹽酸的乙酸乙酯，將沉澱的晶體濾出，用乙酸乙酯及乙醚連續洗滌以產生0.34g(80%)的呈晶體物質之標題化合物。
1HNMR(400MHz,DMSO-d6)：1.18 t(3H,H3-18)；1.40 m(1H,Hax-4)；2.88 q br(2H,Hax-2,Hax-2’)；3.99 t(2H,H2-7)；4.04 q(2H,H2-17)；4.43 tt(1H,H-12)；6.87 m(2H,H-9,H-9’)；10.04 br(1H,NH+-1)
MS：m/z：M‧+=390
將0.35ml(2.5mmol)的三乙胺加至0.39g(1mmol)的
1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二鹽酸鹽(實例2)在20ml的二氯甲烷中之冰冷卻溶液，將混合物攪拌10min及滴加0.12ml(1.5mmol)的異氰酸乙酯。將反應混合物在室溫下攪拌16h，然後用3×20ml的水洗滌，將有機相經過Na2SO4乾燥，過濾及濃縮以產生0.28g(72%)的呈晶體物質之標題化合物。
1HNMR(400MHz,DMSO-d6)：1.00 t(3H,H3-19)；1.37 m(2H,H2-4)；2.31 br(4H,H2-2,H2-2’)；3.91 t(2H,H2-7)；4.36 tt(1H,H-12)；6.47 t(1H,NH-17)；6.82 m(2H,H-9,H-9’)
MS：m/z：M‧+=389
將0.35ml(2.5mmol)的三乙胺加至0.39g(1mmol)的1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二鹽酸鹽(實例2)在20ml的二氯甲烷中之冰冷卻溶液，將混合物攪拌10min及滴加0.18g(1.5mmol)的異氰酸甲乙酯。將反應混合物在室溫下攪拌16h，然後用3×20ml的水洗滌，將有機相經過Na2SO4乾燥，過濾及濃縮。將粗製產物溶解在15ml的乙酸乙酯中及添加8ml的含有21w/w%之鹽酸的乙酸乙酯，濃縮混合物及將殘餘物與乙醚一起研磨以產生0.34g(77%)的呈晶體物質之標題化合物。
1HNMR(800MHz,DMSO-d6)：1.05 t(3H,H3-19)；1.37 m(2H,H2-4)；2.72 s(3H,H3-17)；2.87 q br(2H,Hax-2,Hax-2’)；3.10 q(2H,H2-18)；3.98 t(2H,H2-7)；4.39 tt(1H,H-12)；6.86 m(2H,H-9,H-9’)
MS：m/z：M‧+=403
將4.3g(14.7mmol)的4-(4-羥苯氧基)哌啶-1-甲酸三級丁酯、3.1g(19.1mmol)的(2R)-1-(3-氯丙基)-2-甲基吡咯啶、5.3g(38.2mmol)的K2CO3及50ml的N,N-二甲基甲醯胺之混合物在氮氣下於50℃攪拌16h。將反應混合物冷卻至室溫，將沉澱的固體物質過濾，用乙腈洗滌及在真空中濃縮濾液。藉由使用100g之矽凝膠及乙酸乙酯：乙醇=4：1之混合物作為溶析液的管柱層析法純化殘餘物以產生2.4g(39%)的呈晶體物質之標題化合物。
1HNMR(400MHz,DMSO-d6)：0.99 d(3H,H3-6)；1.40 s(9H,H3-20,H3-20’,H3-20”)；2.24 sex(1H,H-5)；3.93 t(2H,H2-9)；4.38 tt(1H,H-14)；6.83 m(2H,H-11,H-11’)
MS：m/z：M‧+=418
將25ml的含有21w/w%之鹽酸的乙酸乙酯加至2.3g(5.5mmol)的4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酸三級丁酯(實例9)在20ml的乙酸乙酯中的攪拌溶液，保持溫度低於10℃。使混合物加熱至室溫並在此溫度下攪拌16h。將沉澱的晶體濾出及用乙酸乙酯及乙醚連續洗滌以產生1.76g(82%)的呈晶體物質之標題化合物。
1HNMR(400MHz,DMSO-d6)：1.36 br(3H,H3-6)；1.92 m(2H,H2-3)；4.01 t(2H,H2-9)；4.51 tt(1H,H-14)；6.89 m(2H,H-11,H-11’)；9.12 br(2H,NH2 +-17)；10.52 br(1H,NH+-1)
MS：m/z：M‧+=318
將0.56ml(4mmol)的三乙胺加至0.39g(1mmol)的4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶二鹽酸鹽(實例10)在20ml的二氯甲烷中之冰冷卻溶液，將混合物攪拌20min及滴加0.11ml(1.5mmol)的乙醯氯。將反應混合物在室溫下攪拌16h，然後用20ml的8w/w% NaHCO3水溶液洗滌，用3×10ml的二氯甲烷萃取水相並將合併之有機相用20ml的水洗滌，經過Na2SO4
乾燥，過濾及濃縮。將粗製產物溶解在10ml的乙酸乙酯中及添加5ml的含有21w/w%之鹽酸的乙酸乙酯，將沉澱的晶體濾出，用乙酸乙酯及乙醚連續洗滌以產生0.37g(82%)的呈晶體物質之標題化合物。
1HNMR(400MHz,DMSO-d6)：1.39 d(3H,H3-6)；2.01 s(3H,H3-19)；4.01 t(2H,H2-9)；4.46 tt(1H,H-14)；6.87 m(2H,H-11,H-11’)；10.37 br(1H,NH+-1)
MS：m/z：[M+H]+=361
將0.56ml(4mmol)的三乙胺加至0.39g(1mmol)的4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶二鹽酸鹽(實例10)在20ml的二氯甲烷中之冰冷卻溶液，將混合物攪拌20min及滴加0.17ml(1.5mmol)的氯化環丁基甲酸。將反應混合物在室溫下攪拌16h，然後用20ml的8w/w% NaHCO3水溶液洗滌，用3×10ml的二氯甲烷萃取水相並將合併之有機相用20ml的水洗滌，經過Na2SO4乾燥，過濾及濃縮。將粗製產物溶解在10ml的乙酸乙酯中及添加5ml的含有21w/w%之鹽酸的乙酸乙酯，將沉澱的晶體濾出，用乙酸乙酯及乙醚連續洗滌以產生0.17g(39%)的呈晶體物質之標題化合物。
1HNMR(400MHz,DMSO-d6)：1.36 br(3H,H3-6)；
1.73 m(1H,Hx-21)；2.09 m(2H,Hx-20,Hx-20’)；4.00 t(2H,H2-9)；4.45 tt(1H,H-14)；6.87 m(2H,H-11,H-11’)；10.06 br(1H,NH+-1)
MS：m/z：M‧+=400
將0.46ml(3.25mmol)的三乙胺加至0.39g(1mmol)的4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶二鹽酸鹽(實例10)在10ml的N,N-二甲基甲醯胺中之冰冷卻溶液，將混合物攪拌10min，然後添加0.48g(1.25mmol)的HBTU及0.13g(1.25mmol)的1-甲基-環丙烷-甲酸。將反應混合物在室溫下攪拌16h，然後添加20ml的8w/w% NaHCO3水溶液，用3×10ml的二氯甲烷萃取混合物並將合併之有機相用10ml的水洗滌，經過Na2SO4乾燥，過濾及濃縮。藉由使用15g之矽凝膠及乙酸乙酯：乙醇=1：1之混合物作為溶析液的管柱層析法純化殘餘物。將標題化合物的經純化之鹼形式溶解在10ml的乙酸乙酯中及添加5ml的含有21w/w%之鹽酸的乙酸乙酯，將沉澱的晶體濾出，用乙酸乙酯及乙醚連續洗滌以產生0.15g(34%)的呈晶體物質之標題化合物。
1HNMR(400MHz,DMSO-d6)：0.53 m(2H,Hx-20,Hx-20’)；0.79 m(2H,Hy-20,Hy-20’)；1.22 s(3H,H3-21)；1.37
br(3H,H3-6)；4.00 t(2H,H2-9)；4.47 tt(1H,H-14)；6.88 m(2H,H-11,H-11’)；10.43 br(1H,NH+-1)
MS：m/z：M‧+=400
將0.56ml(4mmol)的三乙胺加至0.39g(1mmol)的4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶二鹽酸鹽(實例10)在20ml的二氯甲烷中之冰冷卻溶液，將混合物攪拌10min及滴加0.14ml(1.5mmol)的氯甲乙酯。將反應混合物在室溫下攪拌16h，然後用3×20ml的水洗滌，將有機相經過Na2SO4乾燥，過濾及濃縮。將粗製產物溶解在10ml的乙酸乙酯中及添加4ml的含有21w/w%之鹽酸的乙酸乙酯，將沉澱的晶體濾出，用乙酸乙酯及乙醚連續洗滌以產生0.32g(75%)的呈晶體物質之標題化合物。
1HNMR(400MHz,DMSO-d6)：1.18 t(3H,H3-20)；1.38 d(3H,H3-6)；4.01 m(2H,H2-9)；4.04 q(2H,H2-19)；4.43 tt(1H,H-14)；6.88 m(2H,H-11,H-11’)；9.98 br/10.43 br(1H,NH+-1)
MS：m/z：M‧+=390
將0.35ml(2.5mmol)的三乙胺加至0.39g(1mmol)的4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶二鹽酸鹽(實例10)在20ml的二氯甲烷中之冰冷卻溶液，將混合物攪拌10min及滴加0.12ml(1.5mmol)的異氰酸乙酯。將反應混合物在室溫下攪拌16h，然後用3×20ml的水洗滌，將有機相經過Na2SO4乾燥，過濾及濃縮。將殘餘物與乙醚一起研磨以產生0.27g(69%)的呈晶體物質之標題化合物。
1HNMR(400MHz,DMSO-d6)：0.99 d(3H,H3-6)；1.00 t(3H,H3-21)；2.23 sex(1H,H-5)；3.03 m(2H,H2-20)；3.93 t(2H,H2-9)；4.36 tt(1H,H-14)；6.46 t(1H,NH-19)；6.83 m(2H,H-11,H-11’)
MS：m/z：M‧+=389
將0.35ml(2.5mmol)的三乙胺加至0.39g(1mmol)的4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶二鹽酸鹽(實例10)在20ml的二氯甲烷中之冰冷卻溶液，將混合物攪拌10min及滴加0.18ml(1.5mmol)的異氰酸甲乙酯。將反應混合物在室溫下攪拌16h，然後用3×20
ml的水洗滌，將有機相經過Na2SO4乾燥，過濾及濃縮。將粗製產物溶解在10ml的乙酸乙酯中及添加4ml的含有21w/w%之鹽酸的乙酸乙酯，將混合物濃縮並將殘餘物與乙醚一起研磨以產生0.28g(64%)的呈晶體物質之標題化合物。
1HNMR(400MHz,DMSO-d6)：1.06 t(3H,H3-21)；1.37 d(3H,H3-6)；2.73 s(3H,H3-22)；4.01 t(2H,H2-9)；3.11 q(2H,H2-20)；4.39 tt(1H,H-14)；6.88 m(2H,H-11,H-11’)；9.60 br(1H,NH+-1)
MS：m/z：M‧+=403
根據下列步驟可測定本發明化合物對於大鼠組織胺H3受體之體外親和性。
如先前由Witte等人所述的方法製備大鼠組織胺H3受體膜(British Journal of Pharmacol.1-14,2006)。將雄性史-道二氏(Sprague-Dawley)大鼠斬首，將彼等之腦移除及分離皮層。藉由攪拌均質機(Ultra-Turrax)將所得組織在Tris-EDTA緩衝液(50mM Tris-HCl，pH值7.4，5mM EDTA，2μg/ml抑肽酶(aprotinin)，1mM苯甲脒，2μg/ml亮肽素(leupeptin)，1μg/ml抑胃肽(pepstatin))均質化。將
均質物在4℃下以40000g離心20分鐘。藉由重複上述均質化及離心步驟進一步純化該等膜顆粒。藉由將顆粒以1：10比再均質化於Tris-EDTA緩衝液(50mM Tris-HCl，pH值7.4，5mM EDTA)中獲得最終膜製劑。將如此獲得之膜製劑分成數等份，快速冷凍並儲存於-80℃直到使用。藉由使用牛血清血蛋白(BSA)作為標準之Lowry法測定蛋白質含量。
受體結合分析以至少5種濃度進行，在各濃度使用兩個平行樣品，在至少兩個獨立實驗中使用結合緩衝液(50mM Tris-HCl，pH值7.4，5mM MgCl2)、大鼠H3膜(140μg蛋白質/管)、及N-α-[甲基-3H]甲基組織胺二鹽酸鹽(1 nM)作為放射配位體。在10μM的噻普醯胺(thioperamide)存在下測定非特異性結合。將樣品在25℃下以0.50ml的最終體積培養30min。藉由在0.5%聚乙烯亞胺(PEI)預浸泡至少2小時的UniFilter® GF/BTM玻璃纖維過濾器快速過濾來終止結合反應。該等濾板用0.5ml的冰冷卻洗滌緩衝液(50mM Tris-HCl，pH 7.4，5mM MgCl2，10μg/ml石鹼素)洗滌9次。該等濾板在50℃下乾燥45分鐘並將40μl的Microscint20(Packard)閃爍混合液添加到各孔中。用TopCount(Packard)閃爍計數器測定過濾器放射活性。
該配位體被本發明化合物置換係以至少兩個平行實驗來測定。特異性放射配位體結合定義為在過量之用於特異性置換放射性配位體的未標記配位體或試驗化合物存在下所測定之總結合及非特異性結合之間的差異。結果表示為在試驗化合物存在下得到之特異性結合的百分比抑制。從藉由使用GraphPad Prism軟體4.0之S形擬合的濃度-置換曲線計算IC50值。使用Cheng-Prusoff方程式(Cheng YC及Prusoff WH(1973)Biochem Pharmacol 22：3099-3108)計算抑制常數(Ki值)。
本發明化合物於大鼠H3受體的親和性以下表說明。
+Ki<10-50nM
混合0.01-50w/w%之式(I)活性成分、15-50w/w%之乳糖、15-50w/w%之馬鈴薯澱粉、5-15w/w%之聚乙烯吡咯啶酮、1-5w/w%之滑石、0.01-3w/w%之硬脂酸鎂、1-3w/w%之膠體二氧化矽及2-7w/w%之超分枝澱粉，然後藉由濕法製粒來製粒及壓製成錠劑。
以由小腸或胃溶劑膜組成，或由糖及滑石組成的層塗布根據上述方法製造的錠劑。以蜂蠟及巴西棕櫚蠟之混合物拋光糖衣錠。
將0.01-50w/w%之式(I)活性成分、1-5w/w%之月桂硫酸鈉、15-50w/w%之澱粉、15-50w/w%之乳糖、1-3w/w%之膠體二氧化矽及0.01-3w/w%之硬脂酸鎂徹底混合，將混合物通過篩子並填充於硬明膠膠囊中。
組分：0.01-15w/w%之式(I)活性成分、0.1-2w/w%之氫氧化鈉、0.1-3w/w%之檸檬酸、0.05-0.2w/w%之尼泊金(nipagin)(4-羥基苯甲酸甲酯鈉)、0.005-0.02w/w%之尼泊
醇(nipasol)0.01-0.5w/w%之卡波姆(聚丙烯酸)、0.1-5w/w%之96%乙醇、0.1-1w/w%之矯味劑、20-70w/w%之山梨醇(70%水溶液)及30-50w/w%之蒸餾水。
在劇烈攪拌下以小部分將卡波姆加至尼泊金(nipagin)及檸檬酸在20ml的蒸餾水中之溶液，及使溶液靜置10-12h。然後添加在1ml蒸餾水中之氫氧化鈉、山梨糖醇的水溶液和最後乙醇覆盆子香料，並攪拌。將活性成分以小部分加至此載體中，並用浸漬均質機懸浮。最後，將懸浮液用蒸餾水填充到所要的最終體積，並將懸浮液糖漿通過膠體研磨設備。
對於各栓劑，將0.01-15w/w%之式(I)活性成分及1-20w/w%之乳糖徹底混合，然後將50-95w/w%之栓劑前動物脂肪(adeps pro suppository)(例如Witepsol 4)熔化，冷卻至35℃及用均質機將活性成分及乳糖混合於其中。所得混合物以冷卻形式模製。
以注射用重蒸餾水製造甘露醇或乳糖之5%溶液，及將溶液過濾以便具有無菌溶液。也以注射用重蒸餾水製造式(I)活性成分之0.01-5%溶液，及將此溶液過濾以便具有無菌溶液。在無菌條件下將此二溶液混合，將1ml部分充入安瓿，將安瓶之內容物冷凍乾燥，並在氮氣下將安瓿
密封。給藥之前，將安瓶之內容物溶解在無菌水或0.9%(生理)無菌氯化鈉水溶液中。
本發明不受本文中所揭示之特定具體實例限制，因為此等具體實例意欲作為本發明的幾個方面之說明。任何等效具體實例意欲在本發明的範圍內。實際上，除了彼等本文中所示及所述者之外，從前面的描述中，本發明的各種修改對於熟習該項技術者將變得顯而易知。該等修改也意欲落入本發明的範圍內。
前額葉皮質及海馬體，這兩個腦區在認知過程中發揮著重要作用。組織胺(HA)及乙醯膽鹼(ACh)二者皆為在認知中發揮著重要作用的發射器。中樞膽鹼能及組織胺能系統的機能減退被被認為是特性化癡呆症之認知缺陷的致病原因之一。用組織胺H3拮抗劑及乙醯膽鹼酯酶抑制劑(AChEIs)單一或及同時治療之後，藉由腦微透析技術研究有意識的自由活動雄性Wistar大鼠(4-6隻動物/組)之前額葉皮質及海馬體中的HA和ACh之細胞外含量改變。
將微透析探針植入內側前額葉皮質(MPFC)及海馬體(HC)中，和灌注人造無AChEI腦脊髓液(aCSF)。
將本研究中所檢查的化合物以在1%羥丙基-甲基纖維素(HPMC)及5%聚氧乙烯(polyoxiethelen)(8)-山梨醇酐單
油酸酯(Tween 80)中經由外科手術植入導管給藥至胃中。
收集三十分鐘的樣品及以高靈敏度及選擇性液體層析法配上質譜/質譜法(LC-MS/MS)分析方法追蹤細胞外ACh及組織胺HA之隨時間的變化。
神經傳遞物含量以相對於藥物治療前獲得的基本含量之百分比改變表示，且效果以面積比基線曲線給予(AOBC)。
藉由ANOVA/事後鄧肯測試進行結果的統計評估。
用H3拮抗劑治療在MPFC及HC二者中導致細胞外HA含量的明確增加，而彼等在ACh釋放方面只有適度提高。另一方面，證明AChE抑制劑之後，Ach在二區中細胞外含量明確增加。此結果顯示與AChEIs公佈的數據吻合(Cerbai等人，Eur.J.Pharmacol.(2007)572：142-150；Scali等人，J Neural Transm.(2002)109(7-8)：1067-80；Kosasa等人，Jpn.J.Pharmacol.(1999)81：216-222)
0.5及1mg/kg之劑量的化合物11之單一治療在這二個區域中細胞外HA含量產生快速且表現增加。(圖1)。注意到：任一劑量後ACh含量沒有顯著改變。(圖2)。
然而令人驚訝地，AchEIs透發之ACh上升被H3拮抗劑顯著增強，而維持彼等對HA含量的正作用。此現象在前額葉皮質及海馬體二者中皆發現。
例如，多奈派齊(donepezil)、原型AChEI和化合物
11之同時給藥後，注意到在二區域中明確且超相加反應。0.5mg/kg多奈派齊(donepezil)及0.5mg/kg化合物11或1mg/kg化合物11之同時給藥導致在MPFC及HC二區域中細胞外ACh超相加增加。此增強作用更表現於0.5mg/kg劑量的化合物11(圖2)，而由化合物11引起之HA釋放不被多奈派齊(donepezil)改變(數據未顯示)。
因為單一或同時給藥之後二種化合物之間不存在藥物動力學交互作用(即多奈派齊(donepezil)和化合物11之血漿及腦含量不改變)，所以所觀察到的ACh含量增強是意想不到且歸因於AChE抑制作用及H3受體拮抗作用的有利藥效重合。
此等結果指示：具有組織胺H3拮抗作用之化合物可具有有用且有效的認知改善作用，並表示單獨(顯著HA和輕微ACh增加)或與AChEIs組合為“附加(add-on)”治療(超相加ACh增加及顯著HA反應)在不同起源的癡呆之治療選項。
Claims (24)
- 一種通式(I)化合物，
- 如申請專利範圍第1項之通式(I)化合物，其中R1和R2與相鄰氮原子一起形成隨意地經取代之5-員雜環基。
- 如申請專利範圍第1項之通式(I)化合物，其中R1 和R2與相鄰氮原子一起形成2-甲基-吡咯啶環。
- 如申請專利範圍第1項之通式(I)化合物，其中R1和R2與相鄰氮原子一起形成2-(R)-甲基-吡咯啶環。
- 如申請專利範圍第1-4項中任一項之通式(I)化合物，其中R3之意義為-C(=O)R4，其中R4之意義為C1-C6直鏈或支鏈烷基、或隨意地經C1-C4烷基取代之C3-C7環烷基。
- 如申請專利範圍第1項之化合物，其係選自由下列所組成之群組：4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酸三級丁酯1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二鹽酸鹽1-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-基)-乙酮鹽酸鹽環丁基-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-基)-甲酮鹽酸鹽(1-甲基-環丙基)-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-基)-甲酮鹽酸鹽4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酸乙酯鹽酸鹽N-乙基-4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲醯胺N-乙基-N-甲基-4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧 基}-哌啶-1-甲醯胺鹽酸鹽4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酸三級丁酯4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶二鹽酸鹽1-[4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶-1-基]-乙酮鹽酸鹽環丁基-[4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶-1-基]-甲酮鹽酸鹽(1-甲基-環丙基)-[4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶-1-基]-甲酮鹽酸鹽4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酸乙酯鹽酸鹽N-乙基-4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶-1-甲醯胺N-乙基-N-甲基-4-(4-{3-[(2R)-2-甲基-吡咯啶-1-基]-丙氧基}-苯氧基)-哌啶-1-甲醯胺鹽酸鹽。
- 一種醫藥組成物，其包含治療有效量的如申請專利範圍第1至6項中任一項之通式(I)化合物及/或其幾何異構物及/或立體異構物及/或非鏡像異構物及/或鹽及/或水合物及/或溶劑合物作為活性成分及一或多種醫藥上可接受的輔助材料。
- 如申請專利範圍第7項之醫藥組成物，其用於治療及/或預防需要調節組織胺H3功能之病況。
- 如申請專利範圍第8項之醫藥組成物，其含有具有組織胺H3受體拮抗劑或反向促效劑作用之通式(I)化合物。
- 如申請專利範圍第7-9項中任一項之醫藥組成物，其用於治療及/或預防與神經退化性疾病相關之認知功能障礙(諸如阿滋海默症、匹克症)或與年齡相關的學習及精神障礙或其他由於一般醫療病況之認知障礙(諸如注意力不足過動(ADHD)或亨汀頓氏舞蹈症)、精神障礙(諸如精神分裂感情型障礙或精神分裂症)、睡眠障礙(諸如猝睡症、嗜睡、白天過度嗜睡(EDS))、飲食異常、肥胖、肥胖相關的代謝異常(諸如高脂血症、糖尿病)、暈眩、癲癇、焦慮症(諸如廣泛性焦慮症、恐慌症、創傷後精神壓力障礙或社交焦慮症)、情感疾病(諸如憂鬱情緒、併發憂鬱情緒和焦慮之適應障礙症)、中樞神經系統的障礙(諸如精神激動或抑鬱)、其他中樞神經系統障礙(諸如精神分裂症)、過敏、充血(諸如鼻充血)、低血壓、心血管疾病、炎症性疼痛、其他疼痛引起的病症(諸如神經性疼痛)、酗酒、腸躁症及骨關節炎。
- 一種如申請專利範圍第1-6項中任一項之式(I)化合物及/或其幾何異構物及/或立體異構物及/或非鏡像異構物及/或鹽及/或水合物及/或溶劑合物用於製造醫藥組成物之用途。
- 如申請專利範圍第11項之用途，其以製造用於治療及/或預防需要調節組織胺H3功能之病況的醫藥組成 物為特徵。
- 如申請專利範圍第12項之用途，其以所製造之醫藥組成物含有具有組織胺H3受體拮抗劑或反向促效劑作用之通式(I)化合物為特徵。
- 如申請專利範圍第11-13項中任一項之用途，其以製造用於治療及/或預防與神經退化性疾病相關之認知功能障礙(諸如阿滋海默症、匹克症)或與年齡相關的學習及精神障礙或其他由於一般醫療病況之認知障礙(諸如注意力不足過動(ADHD)或亨汀頓氏舞蹈症)、精神障礙(諸如精神分裂感情型障礙或精神分裂症)、睡眠障礙(諸如猝睡症、嗜睡、白天過度嗜睡(EDS))、飲食異常、肥胖、肥胖相關的代謝異常(諸如高脂血症、糖尿病)、暈眩、癲癇、焦慮症(諸如廣泛性焦慮症、恐慌症、創傷後精神壓力障礙或社交焦慮症)、情感疾病(諸如憂鬱情緒、併發憂鬱情緒和焦慮之適應障礙症)、中樞神經系統的障礙(諸如精神激動或抑鬱)、其他中樞神經系統障礙(諸如精神分裂症)、過敏、充血(諸如鼻充血)、低血壓、心血管疾病、炎症性疼痛、其他疼痛引起的病症(諸如神經性疼痛)、酗酒、腸躁症及骨關節炎的醫藥組成物為特徵。
- 一種如申請專利範圍第1項之通式(I)化合物及乙醯膽鹼酯酶抑制劑之組合物。
- 如申請專利範圍第15項之組合物，其中該通式(I)化合物為如申請專利範圍第2項中所定義者。
- 如申請專利範圍第15項之組合物，其中該通式 (I)化合物為如申請專利範圍第3項中所定義者。
- 如申請專利範圍第15項之組合物，其中該通式(I)化合物為如申請專利範圍第4項中所定義者。
- 如申請專利範圍第15-18項中任一項之組合物，其中該通式(I)化合物為如申請專利範圍第5項中所定義者。
- 如申請專利範圍第19項之組合物，其中該乙醯膽鹼酯酶抑制劑為多奈派齊(donepezil)、利斯的明(rivastigmine)、加蘭他敏(galantamine)或塔克林(tacrine)。
- 如申請專利範圍第15-20項中任一項之組合物用於製造醫藥組成物之用途。
- 一種醫藥組成物，其包含如申請專利範圍第1項之通式(I)化合物和乙醯膽鹼酯酶抑制劑及一或多種醫藥上可接受的輔助材料。
- 如申請專利範圍第22項之醫藥組成物，其含有如申請專利範圍第2-5項中任一項之通式(I)化合物。
- 如申請專利範圍第22-23項中任一項之醫藥組成物，其中該乙醯膽鹼酯酶抑制劑為多奈派齊(donepezil)、利斯的明(rivastigmine)、加蘭他敏(galantamine)或塔克林(tacrine)。
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU1300139A HUP1300139A2 (en) | 2013-03-06 | 2013-03-06 | Phenoxypiperidine h3 antagonists |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TW201522311A true TW201522311A (zh) | 2015-06-16 |
Family
ID=89991058
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW103107713A TW201522311A (zh) | 2013-03-06 | 2014-03-06 | 含有苯氧基哌啶核結構之ｈ拮抗劑 |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US9994525B2 (zh) |
| EP (1) | EP2964613B1 (zh) |
| JP (1) | JP6584960B2 (zh) |
| CN (1) | CN105452222B (zh) |
| AR (1) | AR095040A1 (zh) |
| CY (1) | CY1120680T1 (zh) |
| DK (1) | DK2964613T3 (zh) |
| EA (1) | EA029311B1 (zh) |
| ES (1) | ES2688055T3 (zh) |
| HR (1) | HRP20181560T1 (zh) |
| HU (2) | HUP1300139A2 (zh) |
| LT (1) | LT2964613T (zh) |
| PL (1) | PL2964613T3 (zh) |
| PT (1) | PT2964613T (zh) |
| RS (1) | RS57627B1 (zh) |
| SI (1) | SI2964613T1 (zh) |
| TW (1) | TW201522311A (zh) |
| WO (1) | WO2014136075A1 (zh) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104887658B (zh) * | 2015-05-18 | 2017-12-08 | 苏州大学附属第一医院 | 乙酰胆碱或乙酰胆碱酯酶抑制剂在制备治疗胎儿低血压药物中的用途 |
| US10603323B2 (en) * | 2016-08-18 | 2020-03-31 | Suven Life Sciences Limited | Combination of histamine-3 receptor inverse agonists with acetylcholinesterase inhibitors |
| MD3500306T2 (ro) * | 2016-08-18 | 2020-10-31 | Suven Life Sciences Ltd | Combinație triplă de agonist invers al receptorului histaminic 3, inhibitor al acetilcolinesterazei și antagonist al receptorului NMDA |
| HU231335B1 (hu) | 2019-05-31 | 2023-01-28 | Richter Gedeon Nyrt. | Szelektív hisztamin H3 receptor antagonista savaddíciós sók és eljárás előállításukra |
| HUP1900190A1 (hu) | 2019-05-31 | 2020-12-28 | Richter Gedeon Nyrt | Szelektív hisztamin H3 receptor antagonisták autizmus spektrum betegség kezelésére |
| TW202202495A (zh) | 2020-03-26 | 2022-01-16 | 匈牙利商羅特格登公司 | 作為ｇａｍｍａ－胺基丁酸Ａ受體次單元ａｌｐｈａ ５受體調節劑之㖠啶及吡啶并〔３，４－ｃ〕嗒𠯤衍生物 |
| WO2022113008A1 (en) | 2020-11-27 | 2022-06-02 | Richter Gedeon Nyrt. | Histamine h3 receptor antagonists/inverse agonists for the treatment of autism spectrum disorder |
| HUP2100338A1 (hu) | 2021-09-29 | 2023-04-28 | Richter Gedeon Nyrt | GABAA ALFA5 receptor modulátor hatású biciklusos aminszármazékok |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE60117814T2 (de) * | 2000-08-08 | 2006-11-02 | Ortho-Mcneil Pharmaceutical, Inc. | Nicht-imidazol aryloxyalkylamine als h3 rezeptor liganden |
| MXPA03001268A (es) * | 2000-08-08 | 2004-09-06 | Johnson & Johnson | Ariloxipiperidinas sin imidazol. |
| GB0308333D0 (en) * | 2003-04-10 | 2003-05-14 | Glaxo Group Ltd | Novel compounds |
| MXPA06011414A (es) * | 2004-03-31 | 2007-04-20 | Johnson & Johnson | Compuestos heterociclicos sin imidazol como ligandos del receptor de h3 histamina. |
| GB0427403D0 (en) | 2004-12-15 | 2005-01-19 | Astrazeneca Ab | Novel compounds I |
| PL1849773T3 (pl) | 2005-02-17 | 2014-03-31 | Astellas Pharma Inc | Pochodne piperazyny do leczenia nietrzymania moczu i bólu |
| WO2008064036A1 (en) * | 2006-11-16 | 2008-05-29 | Janssen Pharmaceutica N.V. | Substituted phenyl propyl amines as histamine h3 receptor and serotonin transporter modulators |
| EP2215092B1 (de) * | 2007-10-19 | 2012-01-25 | Boehringer Ingelheim International GmbH | Substituierte piperidino-dihydrothienopyrimidine |
| NZ586913A (en) * | 2007-12-21 | 2012-06-29 | Astrazeneca Ab | Bicyclic derivatives for use in the treatment of androgen receptor associated conditions |
| TW201039822A (en) | 2009-02-06 | 2010-11-16 | Taisho Pharmaceutical Co Ltd | Dihydroquinolinone derivatives |
| DK2694492T3 (en) * | 2011-02-23 | 2015-11-09 | Suven Life Sciences Ltd | NOVEL COMPOUNDS AS HISTAMINE H3 receptor ligands |
-
2013
- 2013-03-06 HU HU1300139A patent/HUP1300139A2/hu not_active Application Discontinuation
-
2014
- 2014-03-06 HU HUE14712780A patent/HUE039801T2/hu unknown
- 2014-03-06 ES ES14712780.7T patent/ES2688055T3/es active Active
- 2014-03-06 RS RS20181022A patent/RS57627B1/sr unknown
- 2014-03-06 DK DK14712780.7T patent/DK2964613T3/en active
- 2014-03-06 TW TW103107713A patent/TW201522311A/zh unknown
- 2014-03-06 PT PT14712780T patent/PT2964613T/pt unknown
- 2014-03-06 EP EP14712780.7A patent/EP2964613B1/en active Active
- 2014-03-06 LT LTEP14712780.7T patent/LT2964613T/lt unknown
- 2014-03-06 WO PCT/IB2014/059489 patent/WO2014136075A1/en active Application Filing
- 2014-03-06 SI SI201430889T patent/SI2964613T1/sl unknown
- 2014-03-06 EA EA201591645A patent/EA029311B1/ru unknown
- 2014-03-06 AR ARP140100738A patent/AR095040A1/es unknown
- 2014-03-06 JP JP2015560835A patent/JP6584960B2/ja active Active
- 2014-03-06 US US14/770,111 patent/US9994525B2/en active Active
- 2014-03-06 PL PL14712780T patent/PL2964613T3/pl unknown
- 2014-03-06 CN CN201480011655.7A patent/CN105452222B/zh active Active
-
2018
- 2018-09-12 CY CY181100943T patent/CY1120680T1/el unknown
- 2018-10-02 HR HRP20181560TT patent/HRP20181560T1/hr unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HUP1300139A2 (en) | 2014-09-29 |
| DK2964613T3 (en) | 2018-11-12 |
| CN105452222B (zh) | 2018-10-02 |
| US20160009645A1 (en) | 2016-01-14 |
| LT2964613T (lt) | 2018-10-25 |
| AR095040A1 (es) | 2015-09-16 |
| RS57627B1 (sr) | 2018-11-30 |
| JP2016510067A (ja) | 2016-04-04 |
| CN105452222A (zh) | 2016-03-30 |
| EA029311B1 (ru) | 2018-03-30 |
| EP2964613B1 (en) | 2018-07-18 |
| JP6584960B2 (ja) | 2019-10-02 |
| WO2014136075A1 (en) | 2014-09-12 |
| EA201591645A1 (ru) | 2015-12-30 |
| SI2964613T1 (sl) | 2018-10-30 |
| PL2964613T3 (pl) | 2018-12-31 |
| PT2964613T (pt) | 2018-11-08 |
| HUE039801T2 (hu) | 2019-02-28 |
| US9994525B2 (en) | 2018-06-12 |
| EP2964613A1 (en) | 2016-01-13 |
| CY1120680T1 (el) | 2019-12-11 |
| HRP20181560T1 (hr) | 2018-12-28 |
| ES2688055T3 (es) | 2018-10-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TW201522311A (zh) | 含有苯氧基哌啶核結構之ｈ拮抗劑 | |
| JP6391076B2 (ja) | アンドロゲン受容体モジュレーターおよびその使用 | |
| DE60203917T2 (de) | Phenylsulfonyl-1,3-dihydro-2h-indol-2-on derivate, deren herstellung und deren therapeutische verwendung | |
| JP4225779B2 (ja) | Ｎｍｄａ受容体拮抗剤としてのアミド誘導体 | |
| KR100936854B1 (ko) | 옥시토신 길항제로서의 치환된 트리아졸 유도체 | |
| TW201945357A (zh) | 化合物 | |
| BRPI0612599A2 (pt) | composto, composição farmacêutica compreendendo o mesmo, método de tratamento e uso do mesmo | |
| HRP20020626A2 (en) | Novel 1,3-dihydro-2h-indol-2-one derivatives and their use as ligands for v<sub>1b</sub> and v<sub>1a</sub> arginine-vasopressin receptors | |
| BR112019012906A2 (pt) | derivados de pirano como inibidores de cyp11a1 (citocromo p450 mono-oxigenase 11a1) | |
| JP2008531679A (ja) | オキシトシンアンタゴニストとしての１，２，４−トリアゾール誘導体とその使用 | |
| TW200922588A (en) | Pyrimidyl indoline compounds | |
| CN111491933A (zh) | 具有e3泛素连接酶部分的egfr双功能抑制剂 | |
| EA011635B1 (ru) | Новые производные амида гетероциклической карбоновой кислоты | |
| EP4345097A1 (en) | Substituted triazine compound | |
| KR101383538B1 (ko) | Ｎｋ3 수용체 길항제로서 피페리딘 유도체 | |
| EP1456200A1 (en) | Lactams as tachykinin antagonists | |
| KR20090078367A (ko) | 인돌 | |
| BR112013000253B1 (pt) | Derivados de (3-metilpirrolidin-3-il) metil piridinil éter, seu uso e processo de preparação e composição farmacêutica que os compreende | |
| CN112313220A (zh) | Pd-l1拮抗剂化合物 | |
| TW201406749A (zh) | 磺醯胺衍生物及彼等用於改良藥物之藥物動力學之用途 | |
| KR101372743B1 (ko) | Ｎｋ3 수용체 길항제로서 피페리딘 유도체 | |
| JP6783793B2 (ja) | インドール誘導体 | |
| KR20240017785A (ko) | 시그마 리간드로서 신규 (호모)피페리디닐 헤테로사이클 | |
| CN117242080A (zh) | 含硼吡唑化合物、包括其的组合物、其方法和用途 | |
| US5066651A (en) | Pyrrolidone compounds for treating cerebral disorders |