CN105452222B - 包含苯氧基哌啶核结构的h3拮抗剂 - Google Patents
包含苯氧基哌啶核结构的h3拮抗剂 Download PDFInfo
- Publication number
- CN105452222B CN105452222B CN201480011655.7A CN201480011655A CN105452222B CN 105452222 B CN105452222 B CN 105452222B CN 201480011655 A CN201480011655 A CN 201480011655A CN 105452222 B CN105452222 B CN 105452222B
- Authority
- CN
- China
- Prior art keywords
- group
- purposes
- disorder
- compound
- piperidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- BRUWSFUBFQYNPG-UHFFFAOYSA-N 1-phenoxypiperidine Chemical class C1CCCCN1OC1=CC=CC=C1 BRUWSFUBFQYNPG-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 95
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims abstract description 69
- 229960001340 histamine Drugs 0.000 claims abstract description 34
- 239000003814 drug Substances 0.000 claims abstract description 29
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 24
- 239000000544 cholinesterase inhibitor Substances 0.000 claims abstract description 20
- 229940079593 drug Drugs 0.000 claims abstract description 11
- 208000019901 Anxiety disease Diseases 0.000 claims description 15
- 230000000694 effects Effects 0.000 claims description 15
- 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 14
- 239000000470 constituent Substances 0.000 claims description 13
- 201000000980 schizophrenia Diseases 0.000 claims description 12
- -1 Amide hydrochloride Chemical class 0.000 claims description 11
- 230000019771 cognition Effects 0.000 claims description 11
- 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 10
- 229940125425 inverse agonist Drugs 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- 208000024827 Alzheimer disease Diseases 0.000 claims description 9
- 208000015114 central nervous system disease Diseases 0.000 claims description 9
- 208000007590 Disorders of Excessive Somnolence Diseases 0.000 claims description 8
- 230000006870 function Effects 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 206010020751 Hypersensitivity Diseases 0.000 claims description 7
- 208000019022 Mood disease Diseases 0.000 claims description 7
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 7
- 208000010877 cognitive disease Diseases 0.000 claims description 7
- 229960003530 donepezil Drugs 0.000 claims description 7
- 230000004064 dysfunction Effects 0.000 claims description 7
- 201000003631 narcolepsy Diseases 0.000 claims description 7
- 230000004770 neurodegeneration Effects 0.000 claims description 7
- 208000019116 sleep disease Diseases 0.000 claims description 7
- 208000022925 sleep disturbance Diseases 0.000 claims description 7
- 108010022752 Acetylcholinesterase Proteins 0.000 claims description 6
- 208000007848 Alcoholism Diseases 0.000 claims description 6
- 208000030814 Eating disease Diseases 0.000 claims description 6
- 208000019454 Feeding and Eating disease Diseases 0.000 claims description 6
- 201000011240 Frontotemporal dementia 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
- 206010028735 Nasal congestion Diseases 0.000 claims description 6
- 208000012902 Nervous system disease Diseases 0.000 claims description 6
- 208000008589 Obesity Diseases 0.000 claims description 6
- 208000000609 Pick Disease of the Brain Diseases 0.000 claims description 6
- 208000024571 Pick disease Diseases 0.000 claims description 6
- 208000028017 Psychotic disease Diseases 0.000 claims description 6
- 206010001584 alcohol abuse Diseases 0.000 claims description 6
- 208000025746 alcohol use disease Diseases 0.000 claims description 6
- 208000026935 allergic disease Diseases 0.000 claims description 6
- 230000007815 allergy Effects 0.000 claims description 6
- 230000036506 anxiety Effects 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 206010012601 diabetes mellitus Diseases 0.000 claims description 6
- 235000014632 disordered eating Nutrition 0.000 claims description 6
- 208000002173 dizziness Diseases 0.000 claims description 6
- 206010015037 epilepsy Diseases 0.000 claims description 6
- 208000029364 generalized anxiety disease Diseases 0.000 claims description 6
- 239000003395 histamine H3 receptor antagonist Substances 0.000 claims description 6
- 206010020765 hypersomnia Diseases 0.000 claims description 6
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 6
- 208000012866 low blood pressure Diseases 0.000 claims description 6
- 208000004296 neuralgia Diseases 0.000 claims description 6
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 6
- 208000021722 neuropathic pain Diseases 0.000 claims description 6
- 235000020824 obesity Nutrition 0.000 claims description 6
- 208000019906 panic disease Diseases 0.000 claims description 6
- HPOIPOPJGBKXIR-UHFFFAOYSA-N 3,6-dimethoxy-10-methyl-galantham-1-ene Natural products O1C(C(=CC=2)OC)=C3C=2CN(C)CCC23C1CC(OC)C=C2 HPOIPOPJGBKXIR-UHFFFAOYSA-N 0.000 claims description 5
- LPCKPBWOSNVCEL-UHFFFAOYSA-N Chlidanthine Natural products O1C(C(=CC=2)O)=C3C=2CN(C)CCC23C1CC(OC)C=C2 LPCKPBWOSNVCEL-UHFFFAOYSA-N 0.000 claims description 5
- 206010020565 Hyperaemia Diseases 0.000 claims description 5
- 206010065390 Inflammatory pain 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
- 206010041250 Social phobia Diseases 0.000 claims description 5
- 229940022698 acetylcholinesterase Drugs 0.000 claims description 5
- 230000006978 adaptation Effects 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 230000007547 defect Effects 0.000 claims description 5
- 229960003980 galantamine Drugs 0.000 claims description 5
- BGLNUNCBNALFOZ-WMLDXEAASA-N galanthamine Natural products COc1ccc2CCCC[C@@]34C=CCC[C@@H]3Oc1c24 BGLNUNCBNALFOZ-WMLDXEAASA-N 0.000 claims description 5
- 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 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- IYVSXSLYJLAZAT-NOLJZWGESA-N lycoramine Natural products CN1CC[C@@]23CC[C@H](O)C[C@@H]2Oc4cccc(C1)c34 IYVSXSLYJLAZAT-NOLJZWGESA-N 0.000 claims description 5
- 208000030159 metabolic disease Diseases 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 201000008482 osteoarthritis Diseases 0.000 claims description 5
- 229960004136 rivastigmine Drugs 0.000 claims description 5
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- 230000001713 cholinergic effect Effects 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 4
- 229960001685 tacrine Drugs 0.000 claims description 4
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- 230000001419 dependent effect Effects 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 201000001880 Sexual dysfunction Diseases 0.000 claims description 2
- 230000004888 barrier function Effects 0.000 claims description 2
- 208000013403 hyperactivity Diseases 0.000 claims description 2
- 230000002441 reversible effect Effects 0.000 claims description 2
- 231100000872 sexual dysfunction Toxicity 0.000 claims description 2
- 230000000472 traumatic effect Effects 0.000 claims description 2
- 208000024172 Cardiovascular disease Diseases 0.000 claims 2
- 206010041349 Somnolence Diseases 0.000 claims 2
- 230000002265 prevention Effects 0.000 claims 2
- TVCXVUHHCUYLGX-UHFFFAOYSA-N 2-Methylpyrrole Chemical compound CC1=CC=CN1 TVCXVUHHCUYLGX-UHFFFAOYSA-N 0.000 claims 1
- 102000012440 Acetylcholinesterase Human genes 0.000 claims 1
- 206010011224 Cough Diseases 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical group 0.000 claims 1
- 239000008280 blood Substances 0.000 claims 1
- 210000004369 blood Anatomy 0.000 claims 1
- 210000000988 bone and bone Anatomy 0.000 claims 1
- 230000006996 mental state Effects 0.000 claims 1
- 239000012453 solvate Substances 0.000 abstract description 13
- 239000003446 ligand Substances 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 99
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 40
- 239000002585 base Substances 0.000 description 40
- 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 34
- 239000000203 mixture Substances 0.000 description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
- 239000000243 solution Substances 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- 239000002178 crystalline material Substances 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 238000001816 cooling Methods 0.000 description 14
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 13
- 229960004373 acetylcholine Drugs 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 13
- 238000001556 precipitation Methods 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- 238000005406 washing Methods 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 239000007832 Na2SO4 Substances 0.000 description 12
- 239000012141 concentrate Substances 0.000 description 12
- 235000008504 concentrate Nutrition 0.000 description 12
- 108020003175 receptors Proteins 0.000 description 12
- 102000005962 receptors Human genes 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 10
- 238000002425 crystallisation Methods 0.000 description 10
- 230000008025 crystallization Effects 0.000 description 10
- 201000010099 disease Diseases 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 238000007792 addition Methods 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 239000002469 receptor inverse agonist Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 239000012043 crude product Substances 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000002464 receptor antagonist Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000003513 alkali Substances 0.000 description 7
- 239000005557 antagonist Substances 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- 210000001320 hippocampus Anatomy 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-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
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical class CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- 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 5
- 102100033639 Acetylcholinesterase Human genes 0.000 description 5
- 208000002193 Pain Diseases 0.000 description 5
- 239000003708 ampul Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 230000006698 induction Effects 0.000 description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000000829 suppository Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 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
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical class [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 239000008298 dragée Substances 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 235000019197 fats Nutrition 0.000 description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 210000002442 prefrontal cortex Anatomy 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000009097 single-agent therapy Methods 0.000 description 4
- 238000007864 suspending Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 229940122601 Esterase inhibitor Drugs 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
- 241000700159 Rattus Species 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000002329 esterase inhibitor Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 230000000742 histaminergic effect Effects 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000002858 neurotransmitter agent Substances 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 238000005457 optimization Methods 0.000 description 3
- 239000002287 radioligand Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- GSLTVFIVJMCNBH-UHFFFAOYSA-N 2-isocyanatopropane Chemical compound CC(C)N=C=O GSLTVFIVJMCNBH-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
- 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
- 102000007527 Autoreceptors Human genes 0.000 description 2
- 108010071131 Autoreceptors Proteins 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 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
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 235000011034 Rubus glaucus Nutrition 0.000 description 2
- 244000235659 Rubus idaeus Species 0.000 description 2
- 235000009122 Rubus idaeus Nutrition 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000007984 Tris EDTA buffer Substances 0.000 description 2
- 238000010521 absorption reaction Methods 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
- 230000027455 binding Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000001149 cognitive effect Effects 0.000 description 2
- 230000003920 cognitive function Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 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
- 239000012154 double-distilled water Substances 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000796 flavoring agent Substances 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
- 239000003349 gelling agent Substances 0.000 description 2
- 235000011187 glycerol Nutrition 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
- 238000002513 implantation Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- PTKHFRNHJULJKT-UHFFFAOYSA-N jnj-5207852 Chemical compound C1CCCCN1CCCOC(C=C1)=CC=C1CN1CCCCC1 PTKHFRNHJULJKT-UHFFFAOYSA-N 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 238000001690 micro-dialysis Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 210000000653 nervous system Anatomy 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 150000003053 piperidines Chemical class 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 208000028173 post-traumatic stress disease Diseases 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000000523 sample Substances 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
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 230000035882 stress Effects 0.000 description 2
- 238000006467 substitution reaction Methods 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
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-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
- AYUQICXJAMPXPF-UHFFFAOYSA-N 2-(1h-imidazol-5-yl)-n-methylethanamine;dihydrochloride Chemical compound Cl.Cl.CNCCC1=CN=CN1 AYUQICXJAMPXPF-UHFFFAOYSA-N 0.000 description 1
- BMGMINKVTPDDRZ-UHFFFAOYSA-N 2-acetamido-n-[1-[[5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-4-methylpentanamide;n-[1-[[5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-4-methyl-2-(propanoylamino)pentanamide Chemical compound CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N.CCC(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N BMGMINKVTPDDRZ-UHFFFAOYSA-N 0.000 description 1
- FXIPXWLVYIHFEP-OAQYLSRUSA-N 4-[4-[3-[(3r)-3-(dimethylamino)pyrrolidin-1-yl]propoxy]phenyl]benzonitrile Chemical compound C1[C@H](N(C)C)CCN1CCCOC1=CC=C(C=2C=CC(=CC=2)C#N)C=C1 FXIPXWLVYIHFEP-OAQYLSRUSA-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
- 108010039627 Aprotinin Proteins 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- CIWCLWZJTDFJPR-UHFFFAOYSA-N C(C(=O)O)(=O)O.C(CCCC)(=O)O Chemical compound C(C(=O)O)(=O)O.C(CCCC)(=O)O CIWCLWZJTDFJPR-UHFFFAOYSA-N 0.000 description 1
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 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
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102000004384 Histamine H3 receptors Human genes 0.000 description 1
- 108090000981 Histamine H3 receptors Proteins 0.000 description 1
- 102000000543 Histamine Receptors Human genes 0.000 description 1
- 108010002059 Histamine Receptors Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108010011078 Leupeptins Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229940099433 NMDA receptor antagonist Drugs 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 241001440143 Panula Species 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- 241000700157 Rattus norvegicus Species 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
- 239000005864 Sulphur Substances 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
- 206010047700 Vomiting Diseases 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000002411 adverse Effects 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
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 208000030961 allergic reaction Diseases 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
- 238000004458 analytical method Methods 0.000 description 1
- 230000008485 antagonism Effects 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
- 150000007514 bases Chemical class 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 150000003937 benzamidines Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000000035 biogenic effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation 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
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- PASOAYSIZAJOCT-UHFFFAOYSA-N butanoic acid Chemical compound CCCC(O)=O.CCCC(O)=O PASOAYSIZAJOCT-UHFFFAOYSA-N 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004568 cement Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 210000002932 cholinergic neuron Anatomy 0.000 description 1
- QZHPTGXQGDFGEN-UHFFFAOYSA-N chromene Chemical compound C1=CC=C2C=C[CH]OC2=C1 QZHPTGXQGDFGEN-UHFFFAOYSA-N 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- TXWOGHSRPAYOML-UHFFFAOYSA-N cyclobutanecarboxylic acid Chemical compound OC(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-N 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000013872 defecation Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000000938 histamine H1 antagonist Substances 0.000 description 1
- 230000003284 homeostatic effect Effects 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 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
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 238000009533 lab test 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
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- 235000021266 loss of appetite Nutrition 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
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 1
- 229960004640 memantine Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000029052 metamorphosis Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 210000005036 nerve Anatomy 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
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000009871 nonspecific binding Effects 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
- 238000010606 normalization Methods 0.000 description 1
- SYXUBXTYGFJFEH-UHFFFAOYSA-N oat triterpenoid saponin Chemical compound CNC1=CC=CC=C1C(=O)OC1C(C=O)(C)CC2C3(C(O3)CC3C4(CCC5C(C)(CO)C(OC6C(C(O)C(OC7C(C(O)C(O)C(CO)O7)O)CO6)OC6C(C(O)C(O)C(CO)O6)O)CCC53C)C)C4(C)CC(O)C2(C)C1 SYXUBXTYGFJFEH-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000008058 pain sensation Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 238000005498 polishing Methods 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
- 229920000036 polyvinylpyrrolidone Polymers 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
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 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
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000001397 quillaja saponaria molina bark Substances 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
- 230000005855 radiation Effects 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000003014 reinforcing effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 150000003335 secondary amines Chemical class 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
- 238000007873 sieving Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 230000001629 suppression Effects 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
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- BNBWOBMWJCGQCW-UHFFFAOYSA-N tert-butyl formate pyridine Chemical class C(C)(C)(C)OC=O.N1=CC=CC=C1 BNBWOBMWJCGQCW-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000012043 vestibular reflex Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000011534 wash buffer 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)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Diabetes (AREA)
- Psychiatry (AREA)
- Emergency Medicine (AREA)
- Cardiology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Heart & Thoracic Surgery (AREA)
- Dermatology (AREA)
- Pain & Pain Management (AREA)
- Addiction (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Endocrinology (AREA)
- Child & Adolescent Psychology (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
本发明涉及通式(I)的新的组胺H3(H3)受体亚型选择性配体和/或其几何异构体和/或立体异构体和/或非对映异构体和/或盐和/或水合物和/或溶剂化物。本发明还涉及包含所述化合物的药物组合物和这些化合物作为用于治疗和/或预防需要调节H3受体的病症的药物的用途。本发明还包括通式(I)的化合物和乙酰胆碱酯酶抑制剂的组合
Description
发明领域
本发明涉及通式(I)的新的组胺H3(H3)受体亚型选择性配体和/或其几何异构体和/或立体异构体和/或非对映异构体和/或盐和/或水合物和/或溶剂化物。本发明还涉及包含所述化合物的药物组合物和这些化合物作为用于治疗和/或预防需要调节H3受体的病症的药物的用途。本发明还包括通式(I)的化合物和乙酰胆碱酯酶抑制剂的组合。
发明背景
很早之前已经知道组胺在变态反应的介导中具有关键作用，且其调节胃酸分泌。在脑中组胺不仅调节基本自身稳定功能，而且还调节更高级的脑功能例如学习和认知功能、醒－睡周期、食物摄取。
组胺能神经元源于下丘脑的乳头结节核，并通过组胺能神经通路将投射送至脑的大多数部位。
组胺是与调节生理功能有关的重要的生物胺，其生物作用由命名为H1、H2、H3和H4的4种受体介导，它们的分类基于其序列差异、信号发放性质和药理学性质(Haas和Panula,Nat Rev Neurosci(2003) 4:121–130；Leurs等,Nat Rev Drug Discov(2005)4:107-120；Esbenshade等,Br J Pharmacol(2008)154(6):1166-1181)。
H1和H2受体是已知的药物靶点。H1受体在过敏反应中的重要作用众所周知，H1受体拮抗剂应用广泛。H2受体的主要功能是胃酸分泌的调节。H4受体的作用尚未完全研究清楚。根据临床前证据，它们可以涉及炎症性过程和痛觉。
组胺H3受体作为自身受体控制组胺合成和释放(Arrang等, Nature(1983)302:832-837)，且作为异身受体在乙酰胆碱和其他神经递质(去甲肾上腺素、5-羟色胺、多巴胺)的释放的调节中起关键作用 (Schlicker等,Naunyn Schmiedebergs Arch Pharmacol(1988) 337:588-590；Schlicker等,J Neural Transm Gen Sect(1993)93:1-10；Schlicker等,Naunyn Schmiedebergs Arch Pharmacol(1989) 340:633-638；Clapham和Kilpatrick,Br J Pharmacol(1992) 107:919-923；Blandina等,Br J Pharmacol(1996)119:1656-1664)。
组胺H3受体拮抗剂/反相激动剂作为自身受体和异身受体通过调节H3受体的功能在食物摄取的调节和体重控制中具有举足轻重的作用(Passani等,J Pharmacol Exp Ther(2011)336,24-29)。
组胺H3受体拮抗剂在脑中引起组胺和其它单胺的合成和释放。根据该机制它们增强醒觉状态、改善认知功能、使前庭反射正常化。组胺H3受体反相激动剂增加组胺的突触释放(synaptic release)，其通过激活突触后H1受体增强醒觉状态。不仅促认知作用可能通过H3自身受体介导，而且通过H3异身受体调节的其他递质系统(诸如胆碱能神经元，其在认知中起重要作用)也受到影响(Khateb等,Neuroscience (1995)69(2):495-506；Lin等,JNeurosci(1996)16(4):1523-1537；Passani等,Trends Pharmacol Sci(2004)25:618-625；Jones,Trends Pharmacol Sci(2005)26:578-586；Bonaventure等,Biochem Pharmacol(2007)73:1084-1096；Ligneau等,Biochem Pharmacol (2007)73:1215-1224；Parmentier等,Biochem Pharmacol(2007) 73:1157-1171；Haas等,Physiol Rev(2008)88:1183-1241)。
自从发现组胺H3受体后(Arrang等,Nature(1983)302:832-837)，已经记载众多H3反相激动剂或拮抗剂(Berlin等,J Med Chem(2011) 54:26-53；等,ExpertOpin.Ther.Patents(2010) 20:1147-1169；Raddatz等,Cur Top Med Chem(2010)10:153-169)。尽管一些化合物已经进展到临床阶段，但没有一种获得治疗性的应用，仅有一种化合物，替洛利生(1-{3-[3-(4-氯苯基)丙氧基]丙基}哌啶)，已经开始在发作性睡病适应症中进行3期临床试验,(Kuhne等,Expert Opin Investig(2011)20:1629-1648)。将组胺H3受体反相激动剂或拮抗剂化合物作为药物推向市场主要缺陷如下:(等,ExpertOpin.Ther.Patents(2010)20:1147-1169)
磷脂质病:在组胺H3受体反相激动剂或拮抗剂的结构中有一个或二个碱性氮。磷脂质病最可能由二碱基的性质引起，但在一碱基化合物的情况中，也可以发生磷脂质病(Ratcliffe Curr Med Chem(2009) 16:2816-2823)。二碱基的JNJ-5207852由于其引起磷脂质病被驳回 (Bonaventure等,Biochem Pharmacol(2007)73:1084-1096)。
心血管副作用，其与hERG钾通道相互作用:ABT-239(Hancock, BiochemPharmacol(2006)71:1103-1113)
高血浆蛋白结合:ABT-239(Hancock,Biochem Pharmacol(2006) 71:1103-1113)
基因毒性:A-331440(Hancock等,Basic Clin Pharmacol Toxicol (2004)95:144-152)
药物动力学性质不佳:JNJ-5207852(Bonaventure等,Biochem Pharmacol(2007)73:1084-1096)。螺[苯并吡喃-2,4’-哌啶]衍生物，其在结构上与本发明的化合物最相近，但它们的结构柔性少得多，其口服生物利用度差，因此它们应当进一步优化。(Dandu等,Bioorg Med Chem Lett(2012)22:2151-2153)
CYP酶相互作用:NNC 38-1202(Peschke等,Bioorg Med Chem (2004)12:2603-2616)
从潜在的组胺H3受体反相激动剂或拮抗剂除去不期望的性质不是容易的任务，鉴于尽管若干组胺H3受体反相激动剂或拮抗剂已经在不同适应症中进行了临床研究，但没有一种获批。(Kuhne等,Expert Opin Investig(2011)20:1629-1648)
组胺H3反相激动剂和拮抗剂的潜在的治疗应用包括多种适应症，例如神经变性疾病和认知缺陷的治疗选项。
用于阿尔茨海默病(属于神经变性疾病)的对症治疗的药物疗法主要有两种类型，其中之一是使用乙酰胆碱酯酶酶抑制剂药物(例如多奈哌齐、雷司替明、加兰他敏、他克林)，而另一种是使用NMDA受体拮抗剂(美金刚)。临床试验显示乙酰胆碱酯酶抑制剂与美金刚组合施用并不优于单一疗法。迄今为止批准的用于单一疗法的药物的功效是有限的，它们在改善认知功能方面仅具有微弱功效，且该功效局限于治疗法的前6-12个月，此外乙酰胆碱酯酶抑制剂仅在30-40％的治疗患者中有效。常见的副作用为恶心、呕吐、食欲不振和更频繁的排便。
由阿尔茨海默病引起的认知功能障碍的改善代表重要的未满足的医学需求；对新的药物有高度需求(Gerald和Ockert,Nat Rev Drug Discov(2013)12(1):19-20.；Molino等,(2013)ScientificWorldJournal 2013:925702；McGleenon等,(1999)Br J ClinPharmacol 48(4):471-480)。
已经试验了通过与具有不同作用机制的药物共施用改善了乙酰胆碱酯酶抑制剂的功效。
在最近的临床试验中已经试验了组胺H3反相激动剂或拮抗剂化合物与乙酰胆碱酯酶抑制剂的共施用。在三种候选药物的情况中，在主要终点没有改善，因此停止了它们的进一步开发(NCT01181310； Cho等,Psychopharmacology(2011)218(3):513-524；NCT00420420； Egan等,Curr Alzheimer Res(2012)9(4):481-490；NCT01266525； Kirkesseli等,J Nutr Health Aging(2013)17(9):804)。
事实仍然是对于阿尔茨海默病的治疗没有满意的单一疗法或组合疗法。
发明概述
本发明的目标为合成新结构的、化学可变的、选择性的和类药的 H3拮抗剂和反相激动剂。
令人惊讶地发现含苯氧基-哌啶核结构的合成的化合物以高亲和性和选择性结合于H3受体，其是类药分子，即它们具有可接受的药物动力学性质，例如它们的吸收良好，它们可以穿越血脑屏障，它们没有心血管副作用，它们不引起磷脂质病，它们没有遗传毒性和不与 CYP酶相互作用。
使用组胺H3受体配体可以治疗多种疾病，其中H3配体可以为拮抗剂或反相激动剂。
本发明的组胺H3受体拮抗剂和反相激动剂以及这些化合物与乙酰胆碱酯酶抑制剂的组合用于治疗与神经变性疾病(例如阿尔茨海默病、皮克病)或年龄相关的学习和精神障碍有关的认知功能障碍、或由于一般医学病症导致的其它的认知障碍(例如注意缺陷多动症(ADHD) 或亨廷顿病)、精神障碍(例如例如情感性分裂症或精神分裂症)、睡眠障碍(例如例如发作性睡病、睡眠过度、白天睡眠过多(EDS))、进食障碍、肥胖、与肥胖相关的代谢紊乱(例如例如高脂血症、糖尿病)、头晕和癫痫。
此外，本发明的组胺H3受体拮抗剂和反相激动剂以及这些化合物与乙酰胆碱酯酶抑制剂的组合用于治疗焦虑症(例如例如泛焦虑症、惊恐障碍、创伤后精神紧张性障碍或社交焦虑障碍)、心境障碍(例如例如情感低落、带有情感低落和焦虑的适应障碍)、中枢神经系统失调(例如例如激动或抑郁)和其它中枢神经系统障碍(例如精神分裂症)。
此外，本发明的组胺H3受体拮抗剂和反相激动剂以及这些化合物与乙酰胆碱酯酶抑制剂的组合用于治疗例如变态反应、充血(例如鼻充血)、低血压、心血管疾病、炎性痛、其它疼痛诱导的障碍(例如神经病性疼痛)、酒精滥用、肠易激综合征和骨关节炎。
本发明的化合物以高亲和性和选择性结合于H3受体(与其他组胺受体H1、H2和H4相比)。
发明详述
本发明涉及通式(I)的化合物
其中
R1、R2彼此独立地表示氢原子，或
C1-C6烷基基团，或
C3-C7环烷基基团，或
R1和R2与相邻的碱性氮原子一起形成4-10元的一或二环的饱和的杂环基团，其任选地包含一个或两个氧原子和/或硫原子，且这些杂环基团任选地被一个或两个卤素原子、氧代基团、C1-C6烷基基团及其组合取代；
R3表示:
氢原子、-C(＝O)R4、-C(＝O)-OR4、-C(＝O)-NR4R5基团，
其中R4和R5彼此独立地表示氢原子、C1-C6直链或支链的烷基基团或C3-C7环烷基基团，其任选地被C1-C4烷基基团取代，
和/或其盐和/或立体异构体和/或非对映异构体和/或水合物和/或溶剂化物和/或多晶型物变型。
如本文使用的术语“C1-C6烷基”是指包含1-6个碳原子的支链或直链的烷基基团。
如本文使用的术语“C3-C7环烷基”是指包含3至7个碳原子的碳环基团。
如本文使用的术语“卤素”单独或作为另一个基团的部分是指氟、氯、溴和碘原子。
有机酸和无机酸均可用于形成酸加成盐。适合的无机酸包括但不限于氢氯酸、硫酸、硝酸和磷酸。一价有机酸的代表包括但不限于甲酸、乙酸、丙酸和不同的丁酸(酪酸)、缬草酸(戊酸)和羊油酸(己酸)。二价有机酸的代表包括但不限于草酸、丙二酸、马来酸、富马酸和琥珀酸。还可以使用其他有机酸，例如羟基羧酸，例如柠檬酸、酒石酸或芳族羧酸类，例如苯甲酸或水杨酸、以及脂肪族和芳族的磺酸，例如甲磺酸、萘磺酸和对甲苯磺酸。
优选的酸加成盐为这样的酸加成盐，这些酸加成盐的酸成分自身是药学上可接受的和在施用剂量上不具有治疗效果，以及其对活性成分的效果没有不利影响。这些酸加成盐为药学上可接受的酸加成盐。药学上不可接受的酸加成盐在所期望的式(I)化合物的纯化和/或分离中可以是有益的，并因此也将其包括在本发明的范围内。
一些通式(I)的化合物
-其中R1、R2和R3的含义如上文所述–可以具有几何异构体、立体异构体和/或非对映异构体形式。这些化合物及其混合物也包括在本发明的范围内。
本发明的优选的化合物为那些式(I)的化合物：其中R1和R2与相邻的氮原子一起形成5-元的任选地被取代的杂环。
本发明的进一步优选的化合物为那些式(I)的化合物，其中R1和 R2与相邻的氮原子一起形成2-甲基-吡咯烷环。
本发明的进一步优选的化合物为那些式(I)的化合物，其中R1和 R2与相邻的氮原子一起形成2-(R)-甲基-吡咯烷环。
本发明的进一步优选的化合物为那些式(I)的化合物，其中R3的含义为–C(＝O)R4，其中R4的含义为C1-C6直链或支链的烷基基团或 C3-C7环烷基基团，其任选地被C1-C4烷基基团取代。
本发明的优选的通式(I)的化合物为以下化合物:
4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酸叔丁酯
1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二盐酸盐
1-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-基)-乙酮盐酸盐
环丁基-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-基)-甲酮盐酸盐
(1-甲基-环丙基)-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1- 基)-甲酮盐酸盐
4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酸乙酯盐酸盐
N-乙基-4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酰胺
N-乙基-N-甲基-4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酰胺盐酸盐
4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酸叔丁酯
4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶二盐酸盐
1-[4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1- 基]-乙酮盐酸盐
环丁基-[4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶 -1-基]-甲酮盐酸盐
(1-甲基-环丙基)-[4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-基]-甲酮盐酸盐
4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酸乙酯盐酸盐
N-乙基-4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶 -1-甲酰胺
N-乙基-N-甲基-4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酰胺盐酸盐
本发明还包括通式(I)的化合物和乙酰胆碱酯酶抑制剂的组合。本发明的组合优选地包含作为乙酰胆碱酯酶抑制剂的多奈哌齐、加兰他敏、他克林或雷司替明。
本发明的通式(I)的化合物可以根据下文的反应方案合成(基团的含义如上文对式(I)所述，PG表示用于仲胺的保护的保护基团)
步骤A:
将式(II)的中间体、优选含叔丁氧基羰基保护基团的化合物 (Waterson等,WO2006064218A1(2006)；实施例1和7；Ishii等, EP1849773A1(2007)实施例29)，与式(III)的中间体、优选1-氯-3-(1- 哌啶基)-丙烷(Buchanan等,Bioorg.Med.Chem.Let.(2011)21:2394-2399；Sann等,Tetrahedron(2007)63:12903-12911)或 (2R)-1-(3-氯丙基)-2-甲基吡咯烷(Nakamura等,WO2010090347A1 (2010))在惰性溶剂、优选在乙腈或N,N-二甲基甲酰胺中在有机或无机碱(优选K2CO3)的存在下进行反应。
步骤B
将式(IA)的中间体的保护基团裂解。将优选使用的叔丁氧羰基保护基团用酸、优选用吸附在有机溶剂中的氯化氢裂解。盐形成:将得到的式(IB)的化合物溶于极性溶剂中，加入等摩尔量的酸，并通过蒸发除去溶剂。
步骤C
可以根据以下方法将式(IB)的中间体转化为式(I)的烷基胺、羧酰胺(carboxamides)、脲或氨基甲酸酯，且在给定情况下形成盐:
步骤C1，羧酰胺:
将式(IB)的中间体与适合的羧酸在偶联剂的存在下反应，或与适合的羧酰氯(carboxylic acid chloride)在碱的存在下、在惰性溶剂中反应。
步骤C2，脲:
将式(IB)的中间体与适合的氨基甲酰氯在碱的存在下、在惰性溶剂中反应。
步骤C3，氨基甲酸酯:
将式(IB)的中间体与适合的碳酰氯在碱的存在下、在惰性溶剂中反应。
步骤C4，盐的形成:
将在步骤C1、C2、C3中任一项中得到的式(I)的化合物溶于极性溶剂中，加入等摩尔量的酸，并通过蒸发除去溶剂，或将沉淀的结晶滤出。
本发明涉及药物组合物，其包含治疗有效量的式(I)的化合物和/ 或其几何异构体和/或立体异构体和/或非对映异构体和/或盐和/或水合物和/或溶剂化物，和/或这些化合物与乙酰胆碱酯酶抑制剂及一种或多种药学上可接受的载体的组合。
本发明优选地涉及药物组合物，其包含治疗有效量的式(I)的化合物和/或其几何异构体和/或立体异构体和/或非对映异构体和/或盐和/ 或水合物和/或溶剂化物，和/或这些化合物与乙酰胆碱酯酶抑制剂和一种或多种药学上可接受的载体的组合，其用于治疗和/或预防需要调节组胺H3受体的和/或强化调节胆碱能系统的病症。
本发明的药物组合物最优选地包含具有H3受体拮抗剂或反相激动剂效应的式(I)的化合物和/或其几何异构体和/或立体异构体和/或非对映异构体和/或盐和/或水合物和/或溶剂化物和/或这些化合物与乙酰胆碱酯酶抑制剂的组合。
本发明还涉及药物组合物，其包含式(I)的化合物和/或其几何异构体和/或立体异构体和/或非对映异构体和/或盐和/或水合物和/或溶剂化物和/或这些化合物与乙酰胆碱酯酶抑制剂的组合，其将有效治疗和 /或预防与年龄相关的认知功能障碍、学习和精神障碍(例如阿尔茨海默病、皮克病)或由于一般医学病症导致的其它的认知障碍(例如注意缺陷多动症(ADHD)或亨廷顿病)、精神障碍(例如情感性分裂症或精神分裂症)、睡眠障碍(例如发作性睡病、睡眠过度、白天睡眠过多(EDS))、进食障碍、肥胖、与肥胖相关的代谢紊乱(例如高脂血症、糖尿病)、头晕、癫痫、焦虑症(例如泛焦虑症、惊恐障碍、创伤后精神紧张性障碍或社交焦虑障碍)、心境障碍(例如情感低落、带有情感低落和焦虑的适应障碍)、中枢神经系统失调(例如激动或抑郁)、其它中枢神经系统障碍(例如精神分裂症)、变态反应、充血(例如鼻充血)、低血压、心血管疾病、炎性痛、其它疼痛诱导的障碍(例如神经病性疼痛)、酒精滥用、肠易激综合征和骨关节炎。
本发明还涉及式(I)的化合物和/或其几何异构体和/或立体异构体和/或非对映异构体和/或盐和/或水合物和/或溶剂化物和/或这些化合物与乙酰胆碱酯酶抑制剂的组合在制备药物中的用途。
本发明还提供式(I)的化合物和/或其几何异构体和/或立体异构体和/或非对映异构体和/或盐和/或水合物和/或溶剂化物和/或这些化合物与乙酰胆碱酯酶抑制剂的组合在制备药物中的用途，所述药物用于治疗和/或预防与年龄相关的认知功能障碍、学习和精神障碍(例如阿尔茨海默病、皮克病)或由于一般医学病症导致的其它的认知障碍(例如注意缺陷多动症(ADHD)或亨廷顿病)、精神障碍(例如情感性分裂症或精神分裂症)、睡眠障碍(例如发作性睡病、睡眠过度、白天睡眠过多(EDS))、进食障碍、肥胖、与肥胖相关的代谢紊乱(例如高脂血症、糖尿病)、头晕、癫痫、焦虑症(例如泛焦虑症、惊恐障碍、创伤后精神紧张性障碍或社交焦虑障碍)、心境障碍(例如情感低落、带有情感低落和焦虑的适应障碍)、中枢神经系统失调(例如激动或抑郁)、其它中枢神经系统障碍(例如精神分裂症)、变态反应、充血(例如鼻充血)、低血压、心血管疾病、炎性痛、其它疼痛诱导的障碍(例如神经病性疼痛)、酒精滥用、肠易激综合征和骨关节炎。
本发明还提供治疗和/或预防需要调节组胺H3受体功能的病症的方法，其包括向待治疗的哺乳动物–包括人–施用有效量的式(I)的化合物和/或其几何异构体和/或立体异构体和/或非对映异构体和/或盐和/或水合物和/或溶剂化物本身或其药物组合物。
本发明还提供了治疗和/或预防需要调节组胺H3受体功能的病症的方法，所述病症例如与年龄相关的认知功能障碍、学习和精神障碍 (例如阿尔茨海默病、皮克病)或由于一般医学病症导致的其它的认知障碍(例如注意缺陷多动症(ADHD)或亨廷顿病)、精神障碍(例如情感性分裂症或精神分裂症)、睡眠障碍(例如发作性睡病、睡眠过度、白天睡眠过多(EDS))、进食障碍、肥胖、与肥胖相关的代谢紊乱(例如高脂血症、糖尿病)、头晕、癫痫、焦虑症(例如泛焦虑症、惊恐障碍、创伤后精神紧张性障碍或社交焦虑障碍)、心境障碍(例如情感低落、带有情感低落和焦虑的适应障碍)、中枢神经系统失调(例如激动或抑郁)、其它中枢神经系统障碍(例如精神分裂症)、变态反应、充血(例如鼻充血)、低血压、心血管疾病、炎性痛、其它疼痛诱导的病症(例如神经病性疼痛)、酒精滥用、肠易激综合征和骨关节炎，所述方法包括向待治疗受试者施用有效量的式(I)的化合物和/或其几何异构体和/或立体异构体和/或非对映异构体和/或盐和/或水合物和/或溶剂化物本身或其药物组合物。
本发明的式(I)的化合物和/或其几何异构体和/或立体异构体和/或非对映异构体和/或盐和/或水合物和/或溶剂化物可以通过任何适宜的方法施用，例如口服、胃肠外、口腔、舌下、鼻、直肠或经皮施用。
通式(I)的化合物与乙酰胆碱酯酶抑制剂的组合还可以通过多种途径和剂型施用。所述组合的活性成分可以组合地或单独地配制为药物组合物，且所述组合物可以以单次剂量或多倍剂量施用。通式(I)的化合物与乙酰胆碱酯酶抑制剂的组合同时或相继被施用。
本发明的组合优选地包含作为乙酰胆碱酯酶抑制剂的多奈哌齐、加兰他敏、他克林或雷司替明。
用于口服施用的本发明的药物组合物可以是液体或固体形式，例如糖浆剂、混悬剂或乳剂、片剂、膜片剂、糖锭剂和胶囊剂。
混悬液或液体组合物可以在适合的液体载体，例如水性溶剂例如水、乙醇或甘油中或在非水溶剂例如聚乙二醇或油中包含活性成分。所述制剂还可包含一种或多种助悬剂、防腐剂、矫味剂和着色剂或其组合。
以片剂的固体形式存在的组合物可以使用常规用于制备固体制剂的任何适合的药物载体制备。所述载体的实例包括硬脂酸镁、淀粉、乳糖、蔗糖、纤维素等。
以胶囊的固体形式存在的组合物可以使用常规的胶囊化方法制备。例如使用标准载体制备包含活性成分的球粒，然后将其填充至硬的明胶胶囊；或者使用任何适合的药物载体、例如水性胶、纤维素、硅酸盐或油类制备分散体系或混悬体系，并将得到的分散体系或混悬体系随后填充至软的明胶胶囊中。
用于肠胃外施用的组合物可以以液体或混悬剂形式配制，其除了包含本发明的式(I)的化合物之外，还包含无菌水性载体或胃肠外可接受的油、例如聚乙二醇、聚乙烯吡咯烷、卵磷脂、花生油或芝麻油。或者，可以将得到的溶液冻干，并将冻干物在即将施用前再溶于适合的溶剂中。
用于鼻施用的组合物可以以气雾剂、滴剂、凝胶剂和粉剂的形式配制。用于口腔或舌下施用的本发明的化合物可以以片剂、糖锭剂和软锭剂的形式制备，其中将活性成分与载体、例如糖和阿拉伯胶、黄蓍胶或明胶和甘油等一起配制。
用于直肠施用的组合物可以方便地以包含常用的栓剂成分，例如可可酯的栓剂的形式配制。
用于经皮施用的组合物包括软膏剂、凝胶剂和贴剂。
上述成分和不同的施用途径仅仅是代表性的。本领域熟知的其他材料以及处理技术也可以使用。
在所有类型的组合物的情况中，药学上可接受的本发明的式(I)的化合物–其中R1和R2的含义如上文所述–和/或其几何异构体和/或立体异构体和/或非对映异构体和/或药学上可接受的盐和/或水合物和/ 或溶剂化物可以正常地以每日剂量方案(用于成人患者)每日1至4次地施用，其中每个剂量单位可包含0.05(或优选0.005)至2000mg式(I) 的化合物(以游离碱计算)。本发明的化合物可以适合地在一段连续治疗的时间施用，例如一周或更多。
实施例
通过以下非限制性实施例说明本发明。
通过NMR和质谱测定所有中间体和最终产物的结构。
实施例1
4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酸叔丁酯
在氮气下将4.2g(14.3mmol)4-(4-羟基苯氧基)哌啶-1-甲酸叔丁酯、3.7g(18.7mmol)N-(3-氯丙基)-哌啶和5.9g(42.9mmol)K2CO3于50ml N,N-二甲基甲酰胺中的混合物在50℃搅拌16小时。在冷却至室温后将沉淀的固体物质滤出，用乙腈洗涤，并将滤液在真空下浓缩。将残余物经柱色谱法(使用100g硅胶和作为洗脱剂的乙酸乙酯: 乙醇＝9:1的混合物)纯化，得到3.15g(53％)为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):1.40s(9H,H3-18,H3-18’,H3-18”)； 2.31br(4H,H2-2,H2-2’)；3.15t br(2H,Hax-14,Hax-14’)；3.91t(2H, H2-7)4.38tt(1H,H-12)；6.82m(2H,H-9,H-9’)；6.89m(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
实施例2
1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二盐酸盐
向2.5g(6mmol)4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1甲酸叔丁酯(实施例1)于20ml乙酸乙酯中的搅拌的溶液中加入25ml含 21w/w％氯化氢的乙酸乙酯，保持温度低于10℃。使该混合物放置回温至室温，并在该温度搅拌16小时。将沉淀的结晶滤出，并接连用乙酸乙酯和乙醚洗涤，得到2.16g(92％)为结晶物质的标题化合物。
1HNMR(500MHz,DMSO-d6):2.80br(2H,Hx-2,Hx-2’)；3.03 ddd(2H,Hx-14,Hx-14’)；3.99t(2H,H2-7)；4.51tt(1H,H-12)；6.88 m(2H,H-9,H-9’)；6.95m(2H,H-10,H-10’)；9.14br(2H,NH2 +-15)； 10.50br(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
实施例3
1-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-基)-乙酮盐酸盐
向0.39g(1mmol)1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二盐酸盐(实施例2)在20ml二氯甲烷中的冰冷却的溶液中加入0.56 ml(4mmol)三乙胺，将该混合物搅拌20分钟，并滴加0.11ml(1.5 mmol)乙酰氯。将该反应混合物在室温搅拌16小时，然后用20ml8 w/w％NaHCO3水溶液洗涤，将水相用20ml二氯甲烷萃取，并将合并的有机相用20ml水洗涤，经Na2SO4干燥，过滤，并浓缩。将粗制的产物溶于10ml乙酸乙酯中，并加入10ml含21w/w％氯化氢的乙酸乙酯，将沉淀的结晶滤出，接连用乙酸乙酯和乙醚洗涤，得到0.33g (83％)为结晶物质的标题化合物。
1HNMR(500MHz,DMSO-d6):2.01s(3H,H3-17)；3.43d(2H, Heq-2,Heq-2’)；3.98t(2H,H2-7)；4.46tt(1H,H-12)；6.87m(2H,H-9, H-9’)；10.47br(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
实施例4
环丁基-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-基)-甲酮盐酸盐
向0.39g(1mmol)1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二盐酸盐(实施例2)于20ml二氯甲烷中的冰冷却的溶液中加入0.56 ml(4mmol)三乙胺，将该混合物搅拌20min，并逐滴加入0.17ml(1.5 mmol)环丁基甲酰氯(cyclobutyl carboxylic acidchloride)。将该反应混合物在室温搅拌16小时，然后用20ml 8w/w％NaHCO3水溶液洗涤，将水相用20ml二氯甲烷萃取，并将合并的有机相用20ml水洗涤，经Na2SO4干燥，过滤，并浓缩。将粗制的产物溶于10ml乙酸乙酯中，并加入10ml含21w/w％氯化氢的乙酸乙酯，将沉淀的结晶滤出，接连用乙酸乙酯和乙醚洗涤，得到0.28g(64％)为结晶物质的标题化合物。
1HNMR(500MHz,DMSO-d6):1.71m(2H,Hx-4,Hx-19)；3.34m (1H,H-17)；3.43d(2H,Heq-2,Heq-2’)；3.98t(2H,H2-7)；4.45tt(1H, H-12)；6.86m(2H,H-9,H-9’)；10.32br(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
实施例5
(1-甲基-环丙基)-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1- 基)-甲酮盐酸盐
向0.39g(1mmol)1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二盐酸盐(实施例2)于10ml N,N-二甲基甲酰胺中的冰冷却的溶液中加入0.46ml(3.25mmol)三乙胺，将该混合物搅拌10min，然后加入0.48 g(1.25mmol)HBTU和0.13g(1.25mmol)1-甲基-环丙烷-甲酸。将该反应混合物在室温搅拌16小时，然后加入15ml 8w/w％NaHCO3水溶液，将该混合物用3x8ml二氯甲烷萃取，并将合并的有机相用10ml 水洗涤，经Na2SO4干燥，过滤，并浓缩。经柱色谱法使用15g硅胶并使用乙酸乙酯:乙醇＝1:1的混合物作为洗脱剂纯化残余物。将纯化的碱形式的标题化合物溶于10ml乙酸乙酯中，并加入5ml含21w/w％氯化氢的乙酸乙酯，将沉淀的结晶滤出，接连用乙酸乙酯和乙醚洗涤，得到0.23g(53％)为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):0.53m(2H,Hx-18,Hx-18’)；0.78 m(2H,Hy-18,Hy-18’)；1.22s(3H,H3-19)；1.40m(1H,Hx-4)；2.86br (4H,Heq-2,Heq-2’)；3.98t(2H,H2-7)；4.47tt(1H,H-12)；6.86m(2H, H-9,H-9’)；10.06br(1H,NH+-1)
MS:m/z:[M+H]+＝401
实施例6
4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酸乙酯盐酸盐
向0.39g(1mmol)1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二盐酸盐(实施例2)在20ml二氯甲烷中的冰冷却的溶液中加入0.56 ml(4mmol)三乙胺，将该混合物搅拌10分钟，并逐滴加入0.14ml(1.5 mmol)氯甲酸乙酯。将该反应混合物在室温搅拌16小时，然后用3x20 ml水洗涤，将有机相经Na2SO4干燥，过滤，并浓缩。将粗制的产物溶于10ml乙酸乙酯中，并加入4ml含21w/w％氯化氢的乙酸乙酯，将沉淀的结晶滤出，接连用乙酸乙酯和乙醚洗涤，得到0.34g(80％) 为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):1.18t(3H,H3-18)；1.40m(1H, Hax-4)；2.88q br(2H,Hax-2,Hax-2’)；3.99t(2H,H2-7)；4.04q(2H, H2-17)；4.43tt(1H,H-12)；6.87m(2H,H-9,H-9’)；10.04br(1H, NH+-1)
MS:m/z:M·+＝390
实施例7
N-乙基-4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酰胺
向0.39g(1mmol)1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二盐酸盐(实施例2)于20ml二氯甲烷中的冰冷却的溶液中加入0.35 ml(2.5mmol)三乙胺，将该混合物搅拌10分钟，并逐滴加入0.12ml (1.5mmol)异氰酸乙酯。将该反应混合物在室温搅拌16小时，然后用 3x20ml水洗涤，将有机相经Na2SO4干燥，过滤，并浓缩，得到0.28 g(72％)为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):1.00t(3H,H3-19)；1.37m(2H, H2-4)；2.31br(4H,H2-2,H2-2’)；3.91t(2H,H2-7)；4.36tt(1H,H-12)；6.47t(1H,NH-17)；6.82m(2H,H-9,H-9’)
MS:m/z:M·+＝389
实施例8
N-乙基-N-甲基-4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酰胺盐酸盐
向0.39g(1mmol)1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二盐酸盐(实施例2)于20ml二氯甲烷中的冰冷却的溶液中加入0.35 ml(2.5mmol)三乙胺，将该混合物搅拌10分钟，并逐滴加入0.18g (1.5mmol)甲基乙基异氰酸酯(methyl ethyl isocyanate)。将该反应混合物在室温搅拌16小时，然后用3x20ml水洗涤，将有机相经Na2SO4干燥，过滤，并浓缩。将粗制的产物溶于15ml乙酸乙酯中，并加入 8ml含21w/w％氯化氢的乙酸乙酯，将该混合物浓缩，并将残余物用乙醚研磨，得到0.34g(77％)为结晶物质的标题化合物。
1HNMR(800MHz,DMSO-d6):1.05t(3H,H3-19)；1.37m(2H, H2-4)；2.72s(3H,H3-17)；2.87q br(2H,Hax-2,Hax-2’)；3.10q(2H, H2-18)；3.98t(2H,H2-7)；4.39tt(1H,H-12)；6.86m(2H,H-9,H-9’)
MS:m/z:M·+＝403
实施例9
4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酸叔丁基酯
将4.3g(14.7mmol)4-(4-羟基苯氧基)哌啶-1-甲酸叔丁酯、3.1g (19.1mmol)(2R)-1-(3-氯丙基)-2-甲基吡咯烷、5.3g(38.2mmol) K2CO3和50ml N,N-二甲基甲酰胺的混合物在氮气下在50℃搅拌16h。将该反应混合物冷却至室温，将沉淀的固体物质过滤，用乙腈洗涤，并将滤液在真空下浓缩。将残余物经柱色谱法使用100g硅胶并使用乙酸乙酯:乙醇＝4:1的混合物作为洗脱剂纯化，得到2.4g(39％)为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):0.99d(3H,H3-6)；1.40s(9H, H3-20,H3-20’,H3-20”)；2.24sex(1H,H-5)；3.93t(2H,H2-9)；4.38tt (1H,H-14)；6.83m(2H,H-11,H-11’)
MS:m/z:M·+＝418
实施例10
4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶二盐酸盐
向2.3g(5.5mmol)4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酸叔丁酯(实施例9)于20ml乙酸乙酯中的搅拌的溶液中加入25ml含21w/w％氯化氢的乙酸乙酯，保持温度低于10℃。将该混合物放置回温至室温，并在该温度搅拌16小时。将沉淀的结晶滤出，并接连用乙酸乙酯和乙醚洗涤，得到1.76g(82％)为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):1.36br(3H,H3-6)；1.92m(2H, H2-3)；4.01t(2H,H2-9)；4.51tt(1H,H-14)；6.89m(2H,H-11,H-11’)； 9.12br(2H,NH2 +-17)；10.52br(1H,NH+-1)
MS:m/z:M·+＝318
实施例11
1-[4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1- 基]-乙酮盐酸盐
向0.39g(1mmol)4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶二盐酸盐(实施例10)在20ml二氯甲烷中的冰冷却的溶液中加入0.56ml(4mmol)三乙胺，将该混合物搅拌20分钟，并滴加0.11 ml(1.5mmol)乙酰氯。将该反应混合物在室温搅拌16小时，然后用 20ml 8w/w％NaHCO3水溶液洗涤，将水相用3x10ml二氯甲烷萃取，并将合并的有机相用20ml水洗涤，经Na2SO4干燥，过滤，并浓缩。将粗制的产物溶于10ml乙酸乙酯中，并加入5ml含21w/w％氯化氢的乙酸乙酯，将沉淀的结晶滤出，用乙酸乙酯和乙醚连续洗涤，得到0.37g(82％)为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):1.39d(3H,H3-6)；2.01s(3H, H3-19)；4.01t(2H,H2-9)；4.46tt(1H,H-14)；6.87m(2H,H-11,H-11’)； 10.37br(1H,NH+-1)
MS:m/z:[M+H]+＝361
实施例12
环丁基-[4-(4-{3-[(2R)-2-甲基吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶 -1-基]-甲酮盐酸盐
向0.39g(1mmol)4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶二盐酸盐(实施例10)在20ml二氯甲烷中的冰冷却的溶液中加入0.56ml(4mmol)三乙胺，将该混合物搅拌20分钟，并逐滴加入0.17ml(1.5mmol)环丁基甲酰氯。将该反应混合物在室温搅拌16h，然后用20ml 8w/w％NaHCO3水溶液洗涤，将水相用3x10ml二氯甲烷萃取，并将合并的有机相用20ml水洗涤，经Na2SO4干燥，过滤，并浓缩。将粗制的产物溶于10ml乙酸乙酯中，并加入5ml含21w/w％氯化氢的乙酸乙酯，将沉淀的结晶滤出，接连用乙酸乙酯和乙醚洗涤，得到0.17g(39％)为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):1.36br(3H,H3-6)；1.73m(1H, Hx-21)；2.09m(2H,Hx-20,Hx-20’)；4.00t(2H,H2-9)；4.45tt(1H,H-14)； 6.87m(2H,H-11,H-11’)；10.06br(1H,NH+-1)
MS:m/z:M·+＝400
实施例13
(1-甲基-环丙基)-[4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-基]-甲酮盐酸盐
向0.39g(1mmol)4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶二盐酸盐(实施例10)在10ml N,N-二甲基甲酰胺中的冰冷却的溶液中加入0.46ml(3.25mmol)三乙胺，将该混合物搅拌10分钟，然后加入0.48g(1.25mmol)HBTU和0.13g(1.25mmol)1-甲基-环丙烷-甲酸。将该反应混合物在室温搅拌16小时，然后加入20ml 8w/w％ NaHCO3水溶液，将该混合物用3x10ml二氯甲烷萃取，并将合并的有机相用10ml水洗涤，经Na2SO4干燥，过滤，并浓缩。将残余物经柱色谱法(使用15g硅胶并用乙酸乙酯:乙醇＝1:1的混合物作为洗脱剂)纯化。将纯化的碱形式的标题化合物溶于10ml乙酸乙酯中，
并加入5ml含21w/w％氯化氢的乙酸乙酯，将沉淀的结晶滤出，接连用乙酸乙酯和乙醚洗涤，得到0.15g(34％)为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):0.53m(2H,Hx-20,Hx-20’)；0.79 m(2H,Hy-20,Hy-20’)；1.22s(3H,H3-21)；1.37br(3H,H3-6)；4.00t(2H, H2-9)；4.47tt(1H,H-14)；6.88m(2H,H-11,H-11’)；10.43br(1H, NH+-1)
MS:m/z:M·+＝400
实施例14
4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酸乙酯盐酸盐
向0.39g(1mmol)4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶二盐酸盐(实施例10)在20ml二氯甲烷中的冰冷却的溶液中加入0.56ml(4mmol)三乙胺，将该混合物搅拌10分钟，并逐滴加入0.14ml(1.5mmol)氯甲酸乙酯。将该反应混合物在室温搅拌16小时，然后用3x20ml水洗涤，将有机相经Na2SO4干燥，过滤，并浓缩。将粗制的产物溶于10ml乙酸乙酯中，并加入4ml含21w/w％氯化氢的乙酸乙酯，将沉淀的结晶滤出，接连用乙酸乙酯和乙醚洗涤，得到0.32g(75％)为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):1.18t(3H,H3-20)；1.38d(3H, H3-6)；4.01m(2H,H2-9)；4.04q(2H,H2-19)；4.43tt(1H,H-14)；6.88 m(2H,H-11,H-11’)；9.98br/10.43br(1H,NH+-1)
MS:m/z:M·+＝390
实施例15
N-乙基-4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶 -1-甲酰胺
向0.39g(1mmol)4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶二盐酸盐(实施例10)于20ml二氯甲烷中的冰冷却的溶液中加入0.35ml(2.5mmol)三乙胺，将该混合物搅拌10分钟，并逐滴加入0.12ml(1.5mmol)异氰酸乙酯。将该反应混合物在室温搅拌16 小时，然后用3x20ml水洗涤，将有机相经Na2SO4干燥，过滤，并浓缩。将残余物用乙醚研磨，得到0.27g(69％)为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):0.99d(3H,H3-6)；1.00t(3H, H3-21)；2.23sex(1H,H-5)；3.03m(2H,H2-20)；3.93t(2H,H2-9)；4.36 tt(1H,H-14)；6.46t(1H,NH-19)；6.83m(2H,H-11,H-11’)
MS:m/z:M·+＝389
实施例16
N-乙基-N-甲基-4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酰胺盐酸盐
向0.39g(1mmol)4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶二盐酸盐(实施例10)于20ml二氯甲烷中的冰冷却的溶液中加入0.35ml(2.5mmol)三乙胺，将该混合物搅拌10分钟，并逐滴加入0.18ml(1.5mmol)甲基乙基异氰酸酯。将该反应混合物在室温搅拌16小时，然后用3x20ml水洗涤，将有机相经Na2SO4干燥，过滤，并浓缩。将粗制的产物溶于10ml乙酸乙酯中，加入4ml含21w/w％氯化氢的乙酸乙酯，将该混合物浓缩，并将残余物用乙醚研磨，得到 0.28g(64％)为结晶物质的标题化合物。
1HNMR(400MHz,DMSO-d6):1.06t(3H,H3-21)；1.37d(3H, H3-6)；2.73s(3H,H3-22)；4.01t(2H,H2-9)；3.11q(2H,H2-20)；4.39 tt(1H,H-14)；6.88m(2H,H-11,H-11’)；9.60br(1H,NH+-1)
MS:m/z:M·+＝403
实施例17
组胺H3拮抗剂的评估
可以根据以下程序测定本发明的化合物对大鼠组胺H3受体的体外亲和力。
膜制备
如Witte等人(British Journal of Pharmacol.1-14,2006)之前的记载来制备大鼠组胺H3受体膜。将雄性Sprague-Dawley大鼠断头，将它们的脑取出，并分离皮层。通过搅拌匀浆器(Ultra-Turrax)将得到的组织在Tris-EDTA缓冲液(50mM Tris-HCl，pH 7.4，5mMEDTA， 2μg/ml抑酶肽，1mM苄脒,2μg/ml亮抑蛋白酶肽,1μg/ml胃蛋白酶抑制剂)中匀化。将该匀浆在4℃以40000g离心20min。通过重复上述匀化和离心步骤将膜球粒进一步纯化。通过将该球粒以1:10的比例在Tris-EDTA缓冲液(50mM Tris-HCl，pH 7.4，5mM EDTA)中再次匀化得到最终的膜制剂。将由此得到的膜制剂分成等分试样，速冻，并在-80℃存储直至使用。通过罗氏蛋白质定量法使用牛血清白蛋白 (BSA)做为标准品测定蛋白质含量。
体外结合测定
在至少两个独立的实验中，使用结合缓冲液(50mM Tris-HCl、pH 7.4、5mMMgCl2)、大鼠H3膜(140μg蛋白质/管)和作为放射性配体的N-α-[甲基-3H]甲基组胺二盐酸盐(1nM)在至少5种浓度进行受体结合测定，每种浓度两个平行的样品。在10μM噻普酰胺的存在下测定非特异性结合。在25℃将样品以0.50ml的最终体积温育30分钟。通过在0.5％聚乙烯亚胺(PEI)中预浸渍至少2小时的 GF/BTM玻璃纤维过滤器快速过滤来终止结合反应。将滤板用0.5ml 冰冷的洗涤缓冲液(50mM Tris-HCl，pH 7.4，5mM MgCl2，10μg/ml 皂苷(saponine))洗涤9次。将滤板在50℃干燥45分钟，并将40μl Microscint20(Packard)闪烁混合物加入各孔中。通过TopCount (Packard)闪烁计数器测定过滤器放射性。
数据分析
在至少两个平行实验中测定本发明的化合物的配体替代。将特异性放射性配体结合定义为总的结合与非特异性的结合之间的差异，所述结合在过量的未标记配体或用于特异性替代放射性配体的测试化合物的存在下测定。结果表示为在测试化合物的存在下得到的特异性结合的抑制百分比。从浓度-替代曲线通过S型曲线拟合(使用GraphPad Prism软件4.0)计算IC50值。使用Cheng-Prusoff等式(Cheng YC和 Prusoff WH(1973)BiochemPharmacol 22:3099-3108)计算抑制常数 (Ki值)。
Ki值
通过下表说明本发明的化合物在大鼠H3受体的亲和力。
其中符号的含义为
++Ki<10nM
+Ki<10-50nM
实施例18a-f
药物组合物的制备
a)片剂
将0.01-50w/w％式(I)的活性成分、15-50w/w％乳糖、15-50w/w％土豆淀粉、5-15w/w％聚乙烯吡咯烷酮、1-5w/w％滑石粉、0.01-3w/w％硬脂酸镁、1-3w/w％胶态二氧化硅和2-7w/w％超支链淀粉 (ultraamylopectin)混合，然后通过湿制粒法造粒，并压缩为片剂。
b)糖锭剂、膜包衣片剂
将根据上述方法制备的片剂通过由肠-或胃溶解膜(entero-or gastrosolventfilm)组成的层或由糖和滑石粉组成的层进行包衣。将糖锭剂通过蜂蜡和巴西棕榈蜡的混合物抛光。
c)胶囊
将0.01-50w/w％式(I)的活性成分、1-5w/w％十二烷基硫酸钠、 15-50w/w％淀粉、15-50w/w％乳糖、1-3w/w％胶态二氧化硅和0.01-3 w/w％硬脂酸镁彻底混合，将该混合物过筛，并填充至硬明胶胶囊中。
d)混悬剂
成分:0.01-15w/w％式(I)的活性成分、0.1-2w/w％氢氧化钠、0.1-3 w/w％柠檬酸、0.05-0.2w/w％尼泊金(4-羟基苯甲酸甲酯钠)、0.005-0.02 w/w％对羟苯甲酸丙酯、0.01-0.5w/w％聚羧乙烯(聚丙烯酸)、0.1-5w/w％的96％乙醇、0.1-1w/w％矫味剂、20-70w/w％山梨醇(70％水溶液)和 30-50w/w％蒸馏水。
在剧烈搅拌下向尼泊金和柠檬酸在20ml蒸馏水中的溶液少量多次地加入聚羧乙烯，并将该溶液放置10-12小时。然后在搅拌下加入于1ml蒸馏水中的氢氧化钠和山梨醇的水溶液，最后加入乙醇覆盆子香料(ethanolic raspberry flavor)。向该载体中少量多次地加入活性成分，并用沉浸式匀浆器混悬。最后用蒸馏水将该混悬液填充至所需的最后体积，将该混悬糖浆剂通过胶体磨设备。
e)栓剂
对各栓剂将0.01-15w/w％式(I)的活性成分和1-20w/w％乳糖彻底混合，然后将50-95w/w％豚脂前栓剂(pro suppository)(例如 Witepsol 4)熔化，冷却至35℃，并用匀浆器将活性成分和乳糖的混合物混合在其中。将得到混合物以冷却形式成型。
f)冻干粉末安瓿瓶组合物
用注射用重蒸馏水制备5％甘露醇或乳糖溶液，并将该溶液过滤以得到灭菌溶液。还用注射用重蒸馏水制备0.01-5％式(I)的活性成分的溶液，并将该溶液过滤以得到灭菌溶液。将这两个溶液在无菌状态下混合，以每份1ml将其填充入安瓿瓶中，将安瓿瓶内的物质冻干，并将安瓿瓶在氮气下密封。在施用前将安瓿瓶内的物质溶于无菌水或 0.9％(生理学)无菌氯化钠水溶液中。
本发明不限于本文公开的特定实施方案的范围，因为这些实施方式旨在说明本发明的若干方面。任何等同的实施方式旨在包括在本发明的范围内。事实上，除本文所示和所述的那些之外，本发明的各种修饰对于本领域技术人员将是显而易见的。所述修饰也旨在落入本发明的范围内。
实施例19
同时施用的组胺H3拮抗剂和乙酰胆碱酯酶抑制剂的评估
额叶前皮质和海马这两个脑区域在认知过程中起重要作用。组胺 (HA)和乙酰胆碱(ACh)均是在认知中起重要作用的递质。中枢胆碱能系统和组胺能系统的功能减退被认为是以痴呆为特征的认知缺陷的致病原因之一。通过大脑微透析技术在有意识的、自由移动的雄性 Wistar大鼠(4-6只动物/组)的额叶前皮质和海马中使用组胺H3拮抗剂和乙酰胆碱酯酶抑制剂(AChEIs)单独和同时治疗后研究HA和ACh 的细胞外水平的变化。
将微透析探针植入中间的额叶前皮质(MPFC)和海马(HC)，并用人工的无AChEI的脑脊髓液(aCSF)灌注。
通过手术植入的导管将本研究中检验的化合物在1％羟基丙基-甲基纤维素(HPMC)和5％聚氧乙烯(8)-脱水山梨醇-单油酸酯(Tween 80) 中施用于胃中。
收集30-分钟的样品，并通过高灵敏度和选择性的与质谱/质谱联用的液相色谱(LC-MS/MS)分析方法追踪细胞外ACh和组胺HA的暂时变化。
以相对于基态水平(药物治疗前得到的)的百分比变化表达神经递质水平，且效果以基线曲线上面积(AOBC)给出。
通过ANOVA/post hoc邓肯检验进行结果的统计评估。
结果
使用H3拮抗剂的治疗在MPFC和HC中均导致细胞外HA水平明确增加，然而它们仅产生中等增强的ACh释放。另一方面，AChE 抑制剂治疗后证实两个区域中的细胞外ACh水平均明确增加。该结果与公布的使用AChEI的数据吻合良好(Cerbai等,Eur.J.Pharmacol.(2007)572:142-150；Scali等,J Neural Transm.(2002) 109(7-8):1067-80；Kosasa等,Jpn.J.Pharmacol.(1999)81:216-222)。
0.5和1mg/kg的剂量的化合物11的单独治疗在两个区域中均产生细胞外HA水迅速和明确的增加(图1.)。无论哪种剂量施用后均没有观测到ACh水平的显著变化。(图2.)
然而，令人惊讶地，H3拮抗剂显著增强AChEIs诱导的ACh上升，而同时保留它们对HA水平的正面作用。在额叶前皮质和海马中均发现该现象。
例如，在同时施用多奈哌齐、原型AChEI和化合物11后在两个区域中均观测到明确的和超相加的应答。0.5mg/kg多奈哌齐和0.5 mg/kg化合物11或1mg/kg化合物11的同时施用在MPFC和HC中均产生细胞外ACh的超相加的增加。该加强作用在0.5mg/kg的化合物11剂量更明确(图2)，然而由化合物11引起的HA释放不会由于多奈哌齐而改变(数据未显示)。
因为两种化合物之间不存在药物动力学相互作用(即在单独或同时施用后多奈哌齐和化合物11的血浆和脑水平不变化)，所以观测到的ACh水平的增强是意料之外的，且属于AChE抑制和H3受体拮抗的有益的药效重合。
这些结果显示具有组胺H3拮抗作用的化合物可具有有益的和有效的认知改善作用，且其单独(显著的HA增加和微小的ACh增加)或与AChEIs组合作为“添加”疗法(超相加的ACh增加和显著的HA 应答)，代表对于不同起因的痴呆的一种治疗选择。
Claims (48)
1.通式(I)的化合物
和/或其盐
其中
R1和R2与相邻的碱性氮原子一起形成被取代的5-元的杂环基团，且所述杂环基团任选地被一个或两个C1-C6烷基基团取代；
R3表示:
-C(＝O)R4、-C(＝O)-OR4、-C(＝O)-NR4R5基团，
其中R4和R5彼此独立地表示氢原子、C1-C6直链或支链的烷基基团或C3-C7环烷基基团，其任选地被C1-C4烷基基团取代。
2.根据权利要求1的通式(I)的化合物，其中R1和R2与相邻的氮原子一起形成2-甲基-吡咯烷环。
3.根据权利要求1的通式(I)的化合物，其中R1和R2与相邻的氮原子一起形成2-(R)-甲基-吡咯烷环。
4.根据权利要求1-3中任意一项的通式(I)的化合物，其中R3的含义是–C(＝O)R4，其中R4的含义为C1-C6直链或支链的烷基基团，或C3-C7环烷基基团，其任选地被C1-C4烷基基团取代。
5.化合物，其选自：
4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酸叔丁酯
1-{3-[4-(哌啶-4-基-氧基)-苯氧基]-丙基}-哌啶二盐酸盐
1-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-基)-乙酮盐酸盐
环丁基-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-基)-甲酮盐酸盐
(1-甲基-环丙基)-(4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-基)-甲酮盐酸盐
4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酸乙酯盐酸盐
N-乙基-4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酰胺
N-乙基-N-甲基-4-{4-[3-(哌啶-1-基)-丙氧基]-苯氧基}-哌啶-1-甲酰胺盐酸盐
4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酸叔丁酯
4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶二盐酸盐
1-[4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-基]-乙酮盐酸盐
环丁基-[4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-基]-甲酮盐酸盐
(1-甲基-环丙基)-[4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-基]-甲酮盐酸盐
4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酸乙酯盐酸盐
N-乙基-4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酰胺
N-乙基-N-甲基-4-(4-{3-[(2R)-2-甲基-吡咯烷-1-基]-丙氧基}-苯氧基)-哌啶-1-甲酰胺盐酸盐。
6.药物组合物，其包含治疗有效量的作为活性成分的权利要求1-5中任意一项所要求保护的化合物和/或盐及一种或多种药学上可接受的辅料。
7.根据权利要求6的药物组合物在制备用于治疗和/或预防需要调节组胺H3功能的病症的药物中的用途。
8.根据权利要求7的用途，其特征在于包含化合物，其具有组胺H3受体拮抗剂或反相激动剂效应。
9.根据权利要求7-8中任意一项的用途，其用于治疗和/或预防与神经变性疾病有关的认知功能障碍、或年龄相关的学习和精神障碍、或由于一般医学病症导致的其它的认知障碍、精神障碍、睡眠障碍、进食障碍、肥胖、与肥胖相关的代谢紊乱、头晕、癫痫、焦虑症、心境障碍、中枢神经系统失调、变态反应、充血、低血压、炎性痛、酒精滥用、肠易激综合征和骨关节炎。
10.根据权利要求7-8中任意一项的用途，其用于治疗和/或预防心血管疾病。
11.根据权利要求9的用途，其特征在于神经变性疾病为阿尔茨海默病或皮克病。
12.根据权利要求9的用途，其特征在于由于一般医学病症导致的其它的认知障碍为注意缺陷多动症或亨廷顿病。
13.根据权利要求9的用途，其特征在于精神障碍为情感性分裂症或精神分裂症。
14.根据权利要求9的用途，其特征在于睡眠障碍为发作性睡病、睡眠过度或白天睡眠过多。
15.根据权利要求9的用途，其特征在于与肥胖相关的代谢紊乱为高脂血症或糖尿病。
16.根据权利要求9的用途，其特征在于焦虑症为泛焦虑症、惊恐障碍、创伤后精神紧张性障碍或社交焦虑障碍。
17.根据权利要求9的用途，其特征在于心境障碍为情感低落或带有情感低落和焦虑的适应障碍。
18.根据权利要求9的用途，其特征在于中枢神经系统失调为激动或抑郁。
19.根据权利要求7-8中任意一项的用途，其用于治疗和/或预防精神分裂症。
20.根据权利要求9的用途，其特征在于充血为鼻充血。
21.根据权利要求7-8中任意一项的用途，其用于治疗和/或预防神经病性疼痛。
22.权利要求1-5中任意一项所要求保护的化合物和/或其盐在制备用于治疗和/或预防需要调节组胺H3功能的病症的药物组合物中的用途。
23.根据权利要求22的用途，其特征在于制备的药物组合物包含具有组胺H3受体拮抗剂或反相激动剂效应的化合物。
24.根据权利要求22-23中任意一项的用途，其特征在于制备药物组合物，所述药物组合物用于治疗和/或预防与神经变性疾病有关的认知功能障碍、或年龄相关的学习和精神障碍、或由于一般医学病症导致的其它的认知障碍、精神障碍、睡眠障碍、进食障碍、肥胖、与肥胖相关的代谢紊乱、头晕、癫痫、焦虑症、心境障碍、中枢神经系统失调、变态反应、充血、低血压、炎性痛、酒精滥用、肠易激综合征和骨关节炎。
25.根据权利要求22-23中任意一项的用途，其特征在于制备药物组合物，所述药物组合物用于治疗和/或预防心血管疾病。
26.根据权利要求24的用途，其特征在于神经变性疾病为阿尔茨海默病或皮克病。
27.根据权利要求24的用途，其特征在于由于一般医学病症导致的其它的认知障碍为注意缺陷多动症或亨廷顿病。
28.根据权利要求24的用途，其特征在于精神障碍为情感性分裂症或精神分裂症。
29.根据权利要求24的用途，其特征在于睡眠障碍为发作性睡病、睡眠过度或白天睡眠过多。
30.根据权利要求24的用途，其特征在于与肥胖相关的代谢紊乱为高脂血症或糖尿病。
31.根据权利要求24的用途，其特征在于焦虑症为泛焦虑症、惊恐障碍、创伤后精神紧张性障碍或社交焦虑障碍。
32.根据权利要求24的用途，其特征在于心境障碍为情感低落或带有情感低落和焦虑的适应障碍。
33.根据权利要求24的用途，其特征在于中枢神经系统失调为激动或抑郁。
34.根据权利要求22-23中任意一项的用途，其特征在于制备药物组合物，所述药物组合物用于治疗和/或预防精神分裂症。
35.根据权利要求24的用途，其特征在于充血为鼻充血。
36.根据权利要求22-23中任意一项的用途，其特征在于制备药物组合物，所述药物组合物用于治疗和/或预防神经病性疼痛。
37.根据权利要求1的通式(I)的化合物与乙酰胆碱酯酶抑制剂的组合。
38.根据权利要求37的组合，其中通式(I)的化合物为权利要求2中所定义。
39.根据权利要求37的组合，其中通式(I)的化合物为权利要求3中所定义。
40.根据权利要求37-39中任意一项的组合，其中通式(I)的化合物为权利要求4中所定义。
41.根据权利要求37-39中任意一项的组合，其中乙酰胆碱酯酶抑制剂为多奈哌齐、雷司替明、加兰他敏或他克林。
42.根据权利要求40的组合，其中乙酰胆碱酯酶抑制剂为多奈哌齐、雷司替明、加兰他敏或他克林。
43.根据权利要求37-42中任意一项的组合用于制备药物组合物的用途。
44.药物组合物，其包含权利要求1中所要求保护的通式(I)的化合物和乙酰胆碱酯酶抑制剂及一种或多种药学上可接受的辅料。
45.根据权利要求44的药物组合物，其特征在于包含权利要求2-4中任意一项中所定义的通式(I)的化合物。
46.根据权利要求44-45中任意一项的药物组合物，其中乙酰胆碱酯酶抑制剂为多奈哌齐、雷司替明、加兰他敏或他克林。
47.权利要求37-42中任意一项所要求保护的组合在制备用于治疗和/或预防需要调节组胺H3受体和胆碱能系统的病症的药物中的用途。
48.权利要求44-46中任意一项的药物组合物在制备用于治疗和/或预防需要调节组胺H3受体和胆碱能系统的病症的药物中的用途。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU1300139A HUP1300139A2 (en) | 2013-03-06 | 2013-03-06 | Phenoxypiperidine h3 antagonists |
| HUP1300139 | 2013-03-06 | ||
| PCT/IB2014/059489 WO2014136075A1 (en) | 2013-03-06 | 2014-03-06 | H3 antagonists containing phenoxypiperidine core structure |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105452222A CN105452222A (zh) | 2016-03-30 |
| CN105452222B true CN105452222B (zh) | 2018-10-02 |
Family
ID=89991058
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201480011655.7A Active CN105452222B (zh) | 2013-03-06 | 2014-03-06 | 包含苯氧基哌啶核结构的h3拮抗剂 |
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 |
| ME03812B (me) * | 2016-08-18 | 2021-04-20 | Suven Life Sciences Ltd | Kombinacija inverznih agonista histamin-3 receptora sa inhibitorima acetilholinesteraze |
| JP6734469B2 (ja) * | 2016-08-18 | 2020-08-05 | スヴェン・ライフ・サイエンシーズ・リミテッドＳｕｖｅｎ Ｌｉｆｅ Ｓｃｉｅｎｃｅｓ Ｌｉｍｉｔｅｄ | ヒスタミン−３受容体インバースアゴニスト、アセチルコリンエステラーゼ阻害剤及びｎｍｄａ受容体アンタゴニストの３種組合せ |
| HUP1900190A1 (hu) * | 2019-05-31 | 2020-12-28 | Richter Gedeon Nyrt | Szelektív hisztamin H3 receptor antagonisták autizmus spektrum betegség kezelésére |
| HU231335B1 (hu) * | 2019-05-31 | 2023-01-28 | Richter Gedeon Nyrt. | Szelektív hisztamin H3 receptor antagonista savaddíciós sók és eljárás előállításukra |
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002012190A2 (en) * | 2000-08-08 | 2002-02-14 | Ortho Mcneil Pharmaceutical, Inc. | Non-imidazole aryloxypiperidines as h3 receptor ligands |
| CN1468227A (zh) * | 2000-08-08 | 2004-01-14 | ����-������ҩƷ��˾ | 非咪唑芳氧基烷基胺 |
| CN1972914A (zh) * | 2004-03-31 | 2007-05-30 | 詹森药业有限公司 | 作为组胺h3受体配合体的非咪唑杂环化合物 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0308333D0 (en) * | 2003-04-10 | 2003-05-14 | Glaxo Group Ltd | Novel compounds |
| GB0427403D0 (en) | 2004-12-15 | 2005-01-19 | Astrazeneca Ab | Novel compounds I |
| RU2408580C2 (ru) | 2005-02-17 | 2011-01-10 | Астеллас Фарма Инк. | Пиридильное неароматическое азотсодержащее гетероцикло-1-карбоксилатное производное |
| US20080139564A1 (en) | 2006-11-16 | 2008-06-12 | Keith John M | Substituted phenyl propyl amines as histamine h3 receptor and serotonin transporter modulators |
| CA2705414C (en) * | 2007-10-19 | 2016-05-24 | Boehringer Ingelheim International Gmbh | Substituted piperidino-dihydrothienopyrimidines |
| AU2008339572B2 (en) * | 2007-12-21 | 2012-05-10 | 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 |
| CN103443093B (zh) | 2011-02-23 | 2015-02-25 | 苏文生命科学有限公司 | 作为组胺h3受体配体的化合物 |
-
2013
- 2013-03-06 HU HU1300139A patent/HUP1300139A2/hu not_active Application Discontinuation
-
2014
- 2014-03-06 US US14/770,111 patent/US9994525B2/en active Active
- 2014-03-06 AR ARP140100738A patent/AR095040A1/es unknown
- 2014-03-06 CN CN201480011655.7A patent/CN105452222B/zh active Active
- 2014-03-06 WO PCT/IB2014/059489 patent/WO2014136075A1/en active Application Filing
- 2014-03-06 HU HUE14712780A patent/HUE039801T2/hu unknown
- 2014-03-06 PT PT14712780T patent/PT2964613T/pt unknown
- 2014-03-06 ES ES14712780.7T patent/ES2688055T3/es active Active
- 2014-03-06 EA EA201591645A patent/EA029311B1/ru unknown
- 2014-03-06 LT LTEP14712780.7T patent/LT2964613T/lt unknown
- 2014-03-06 RS RS20181022A patent/RS57627B1/sr unknown
- 2014-03-06 EP EP14712780.7A patent/EP2964613B1/en active Active
- 2014-03-06 SI SI201430889T patent/SI2964613T1/sl unknown
- 2014-03-06 TW TW103107713A patent/TW201522311A/zh unknown
- 2014-03-06 JP JP2015560835A patent/JP6584960B2/ja active Active
- 2014-03-06 DK DK14712780.7T patent/DK2964613T3/en active
- 2014-03-06 PL PL14712780T patent/PL2964613T3/pl unknown
-
2018
- 2018-09-12 CY CY181100943T patent/CY1120680T1/el unknown
- 2018-10-02 HR HRP20181560TT patent/HRP20181560T1/hr unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002012190A2 (en) * | 2000-08-08 | 2002-02-14 | Ortho Mcneil Pharmaceutical, Inc. | Non-imidazole aryloxypiperidines as h3 receptor ligands |
| CN1468227A (zh) * | 2000-08-08 | 2004-01-14 | ����-������ҩƷ��˾ | 非咪唑芳氧基烷基胺 |
| CN1972914A (zh) * | 2004-03-31 | 2007-05-30 | 詹森药业有限公司 | 作为组胺h3受体配合体的非咪唑杂环化合物 |
Non-Patent Citations (2)
| Title |
|---|
| 4-Phenoxypiperidines: Potent, Conformationally Restricted, Non-Imidazole Histamine H3 Antagonists;Curt A. Dvorak，等;《J. Med. Chem》;20050205;第48卷;第2230页Scheme1 * |
| A New Class of Diamine-Based Human Histamine H3 Receptor Antagonists: 4-(Aminoalkoxy)benzylamines;Richard Apodaca，等;《J. Med. Chem》;20030723;第46卷;第3939页Scheme2-3 * |
Also Published As
| Publication number | Publication date |
|---|---|
| HUE039801T2 (hu) | 2019-02-28 |
| HRP20181560T1 (hr) | 2018-12-28 |
| LT2964613T (lt) | 2018-10-25 |
| JP6584960B2 (ja) | 2019-10-02 |
| ES2688055T3 (es) | 2018-10-30 |
| HUP1300139A2 (en) | 2014-09-29 |
| PT2964613T (pt) | 2018-11-08 |
| SI2964613T1 (sl) | 2018-10-30 |
| CY1120680T1 (el) | 2019-12-11 |
| PL2964613T3 (pl) | 2018-12-31 |
| US9994525B2 (en) | 2018-06-12 |
| EA029311B1 (ru) | 2018-03-30 |
| DK2964613T3 (en) | 2018-11-12 |
| EP2964613B1 (en) | 2018-07-18 |
| AR095040A1 (es) | 2015-09-16 |
| US20160009645A1 (en) | 2016-01-14 |
| JP2016510067A (ja) | 2016-04-04 |
| RS57627B1 (sr) | 2018-11-30 |
| EA201591645A1 (ru) | 2015-12-30 |
| EP2964613A1 (en) | 2016-01-13 |
| CN105452222A (zh) | 2016-03-30 |
| TW201522311A (zh) | 2015-06-16 |
| WO2014136075A1 (en) | 2014-09-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105452222B (zh) | 包含苯氧基哌啶核结构的h3拮抗剂 | |
| JP4225779B2 (ja) | Ｎｍｄａ受容体拮抗剤としてのアミド誘導体 | |
| DE60203917T2 (de) | Phenylsulfonyl-1,3-dihydro-2h-indol-2-on derivate, deren herstellung und deren therapeutische verwendung | |
| EP1773770B1 (en) | Indole-2-carboxamidine derivatives as nmda receptor antagonists | |
| WO2006072458A2 (de) | Substituierte oxindol-derivate, diese enthaltende arzneimittel und deren verwendung | |
| JP6339241B2 (ja) | Ａｌｋキナーゼ阻害剤並びにその調製方法及び使用 | |
| BR112019025836A2 (pt) | composto de aminopirimidina, método de preparação do mesmo e uso do mesmo | |
| BR112013021549B1 (pt) | Processos para preparação de forma cristalina anidra, para preparação de composição farmacêutica e para preparação de forma de dosagem, forma cristalina não solvatada anidra, composição farmacêutica, forma de dosagem, uso da referida forma cristalina e solvato | |
| BRPI0617654A2 (pt) | composto ou um sal farmaceuticamente aceitável do mesmo, composição farmacêutica, uso de um composto ou um sal farmaceuticamente aceitável do mesmo, métodos para produzir um efeito inibitório de hdac e do ciclo celular (anti-proliferação celular) e para tratar o cáncer em um animal de sangue quente, e, processo para preparar um composto ou um sal farmaceuticamente aceitável do mesmo | |
| PT2041093E (pt) | Derivados de piperazinilo úteis no tratamento de doenças mediadas pelo receptor gpr38 | |
| EA011635B1 (ru) | Новые производные амида гетероциклической карбоновой кислоты | |
| JP2008526895A (ja) | ヒスタミンｈ３アンタゴニストとして有用なイミダゾールおよびベンゾイミダゾール誘導体 | |
| TW200831077A (en) | N-substituted-azacyclylamines as histamine-3 antagonists | |
| EP4072548A1 (en) | Compositions and methods for substituted 7-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine analogs as inhibitors of kras | |
| EA011636B1 (ru) | Производные амида кинуреновой кислоты как антагонисты nr2b подтипа рецептора nmda | |
| EP1651638A1 (en) | Pyridyl piperazinyl ureas | |
| EA010893B1 (ru) | Новые производные бензоилмочевины | |
| WO2009071691A2 (de) | Oxindol-derivate und ihre verwendung als medikament | |
| JP2022537330A (ja) | インダゾール誘導体、その製造方法及び医薬上のその使用 | |
| DE60130691T2 (de) | Indolderivate zur Behandlung von Erkrankungen des Zentralnervensystems | |
| BRPI0620526A2 (pt) | sal de acetato e método para alcançar um efeito em um paciente | |
| TW202204343A (zh) | 經取代之３－苯氧基氮雜環丁烷－１－基－吡 | |
| BR112016028017B1 (pt) | Compostos inibidores de quinase alk, composições farmacêuticas compreendendo os mesmos, seus métodos de preparação e seus usos |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |