JP2010529124A - 新規方法 - Google Patents
新規方法 Download PDFInfo
- Publication number
- JP2010529124A JP2010529124A JP2010511179A JP2010511179A JP2010529124A JP 2010529124 A JP2010529124 A JP 2010529124A JP 2010511179 A JP2010511179 A JP 2010511179A JP 2010511179 A JP2010511179 A JP 2010511179A JP 2010529124 A JP2010529124 A JP 2010529124A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- disorder
- formula
- net
- sert
- 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.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims description 44
- 150000001875 compounds Chemical class 0.000 claims abstract description 239
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 54
- 150000003839 salts Chemical group 0.000 claims abstract description 51
- 102100028874 Sodium-dependent serotonin transporter Human genes 0.000 claims abstract description 41
- 101710114597 Sodium-dependent serotonin transporter Proteins 0.000 claims abstract description 41
- 208000024891 symptom Diseases 0.000 claims abstract description 41
- 208000033830 Hot Flashes Diseases 0.000 claims abstract description 38
- 206010060800 Hot flush Diseases 0.000 claims abstract description 38
- 230000001457 vasomotor Effects 0.000 claims abstract description 37
- 201000010099 disease Diseases 0.000 claims abstract description 30
- 238000011282 treatment Methods 0.000 claims abstract description 24
- 230000001404 mediated effect Effects 0.000 claims abstract description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 37
- 208000035475 disorder Diseases 0.000 claims description 24
- 208000019901 Anxiety disease Diseases 0.000 claims description 23
- 230000036506 anxiety Effects 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 20
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical class N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 19
- 208000020925 Bipolar disease Diseases 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 208000019116 sleep disease Diseases 0.000 claims description 11
- 208000007848 Alcoholism Diseases 0.000 claims description 10
- 208000000044 Amnesia Diseases 0.000 claims description 10
- 208000027559 Appetite disease Diseases 0.000 claims description 10
- 208000032841 Bulimia Diseases 0.000 claims description 10
- 206010006550 Bulimia nervosa Diseases 0.000 claims description 10
- 206010012335 Dependence Diseases 0.000 claims description 10
- 208000019454 Feeding and Eating disease Diseases 0.000 claims description 10
- 208000019695 Migraine disease Diseases 0.000 claims description 10
- 241000208125 Nicotiana Species 0.000 claims description 10
- 235000002637 Nicotiana tabacum Nutrition 0.000 claims description 10
- 208000008589 Obesity Diseases 0.000 claims description 10
- 206010036618 Premenstrual syndrome Diseases 0.000 claims description 10
- 201000001880 Sexual dysfunction Diseases 0.000 claims description 10
- 201000007930 alcohol dependence Diseases 0.000 claims description 10
- 230000030135 gastric motility Effects 0.000 claims description 10
- 206010027599 migraine Diseases 0.000 claims description 10
- 235000020824 obesity Nutrition 0.000 claims description 10
- 208000019906 panic disease Diseases 0.000 claims description 10
- 231100000872 sexual dysfunction Toxicity 0.000 claims description 10
- 201000009032 substance abuse Diseases 0.000 claims description 10
- 208000011117 substance-related disease Diseases 0.000 claims description 10
- 208000001640 Fibromyalgia Diseases 0.000 claims description 9
- 241001465754 Metazoa Species 0.000 claims description 9
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 9
- 231100000736 substance abuse Toxicity 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 208000026139 Memory disease Diseases 0.000 claims description 8
- 230000006984 memory degeneration Effects 0.000 claims description 8
- 208000023060 memory loss Diseases 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 208000029028 brain injury Diseases 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 208000020685 sleep-wake disease Diseases 0.000 claims description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 5
- 108010049586 Norepinephrine Plasma Membrane Transport Proteins Proteins 0.000 claims description 5
- 230000008482 dysregulation Effects 0.000 claims description 5
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- 206010029897 Obsessive thoughts Diseases 0.000 claims 1
- 102100033929 Sodium-dependent noradrenaline transporter Human genes 0.000 claims 1
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 18
- 229960002748 norepinephrine Drugs 0.000 description 18
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 18
- 206010027304 Menopausal symptoms Diseases 0.000 description 12
- -1 (R)-(−)-N-methyl-3-substituted pyridineoxy-3-phenylpropanamines Chemical class 0.000 description 11
- 241000700159 Rattus Species 0.000 description 11
- 230000027455 binding Effects 0.000 description 11
- 210000004556 brain Anatomy 0.000 description 11
- 125000005843 halogen group Chemical group 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 10
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 206010012374 Depressed mood Diseases 0.000 description 7
- 208000024714 major depressive disease Diseases 0.000 description 7
- 230000009245 menopause Effects 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- 102000019208 Serotonin Plasma Membrane Transport Proteins Human genes 0.000 description 6
- 108010012996 Serotonin Plasma Membrane Transport Proteins Proteins 0.000 description 6
- 230000006978 adaptation Effects 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 208000024732 dysthymic disease Diseases 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- ITJNARMNRKSWTA-UHFFFAOYSA-N nisoxetine Chemical compound C=1C=CC=CC=1C(CCNC)OC1=CC=CC=C1OC ITJNARMNRKSWTA-UHFFFAOYSA-N 0.000 description 5
- 229950004211 nisoxetine Drugs 0.000 description 5
- 238000002603 single-photon emission computed tomography Methods 0.000 description 5
- 102000008092 Norepinephrine Plasma Membrane Transport Proteins Human genes 0.000 description 4
- 239000000935 antidepressant agent Substances 0.000 description 4
- 229940005513 antidepressants Drugs 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000001276 controlling effect Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000004064 dysfunction Effects 0.000 description 4
- 229960005181 morphine Drugs 0.000 description 4
- 238000012636 positron electron tomography Methods 0.000 description 4
- 229960003770 reboxetine Drugs 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 4
- UXABARREKCJULM-UHFFFAOYSA-N 2-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-1-ethylimidazole Chemical compound CCN1C=CN=C1CC1OC2=CC=CC=C2OC1 UXABARREKCJULM-UHFFFAOYSA-N 0.000 description 3
- SAJKHRHHDGSJEZ-UHFFFAOYSA-N 2-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-4,4-dimethylisoquinoline-1,3-dione;dihydrochloride Chemical compound Cl.Cl.COC1=CC=CC=C1N1CCN(CCN2C(C(C)(C)C3=CC=CC=C3C2=O)=O)CC1 SAJKHRHHDGSJEZ-UHFFFAOYSA-N 0.000 description 3
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 3
- 208000008454 Hyperhidrosis Diseases 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000008499 blood brain barrier function Effects 0.000 description 3
- 210000001218 blood-brain barrier Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229960003914 desipramine Drugs 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 3
- 229960004127 naloxone Drugs 0.000 description 3
- 210000004129 prosencephalon Anatomy 0.000 description 3
- 239000002287 radioligand Substances 0.000 description 3
- 238000011552 rat model Methods 0.000 description 3
- CBQGYUDMJHNJBX-RTBURBONSA-N reboxetine Chemical compound CCOC1=CC=CC=C1O[C@H](C=1C=CC=CC=1)[C@@H]1OCCNC1 CBQGYUDMJHNJBX-RTBURBONSA-N 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 3
- 229940076279 serotonin Drugs 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- MYUBYOVCLMEAOH-UHFFFAOYSA-N 2-(2,3-dihydro-1,4-benzodioxin-3-yl)-4,5-dihydro-1h-imidazole;hydrochloride Chemical compound Cl.N1CCN=C1C1OC2=CC=CC=C2OC1 MYUBYOVCLMEAOH-UHFFFAOYSA-N 0.000 description 2
- DWOIUCRHVWIHAH-UHFFFAOYSA-N 2-(2-ethyl-3h-1-benzofuran-2-yl)-4,5-dihydro-1h-imidazole;hydrochloride Chemical compound Cl.C1C2=CC=CC=C2OC1(CC)C1=NCCN1 DWOIUCRHVWIHAH-UHFFFAOYSA-N 0.000 description 2
- IMPOOMVZVWKSAP-UHFFFAOYSA-N 2-(3-methoxy-2h-1,4-benzodioxin-3-yl)-4,5-dihydro-1h-imidazole;hydrochloride Chemical compound Cl.C1OC2=CC=CC=C2OC1(OC)C1=NCCN1 IMPOOMVZVWKSAP-UHFFFAOYSA-N 0.000 description 2
- ITJNARMNRKSWTA-RLXJOQACSA-N 3-(2-methoxyphenoxy)-3-phenyl-n-(tritritiomethyl)propan-1-amine Chemical compound C=1C=CC=CC=1C(CCNC([3H])([3H])[3H])OC1=CC=CC=C1OC ITJNARMNRKSWTA-RLXJOQACSA-N 0.000 description 2
- JVGBTTIJPBFLTE-UHFFFAOYSA-N 8-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one Chemical compound C1CN(CC2OC3=CC=CC=C3OC2)CCC11C(=O)NCN1C1=CC=CC=C1 JVGBTTIJPBFLTE-UHFFFAOYSA-N 0.000 description 2
- 206010003439 Artificial menopause Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 0 ClCC*c1ccccc1 Chemical compound ClCC*c1ccccc1 0.000 description 2
- 208000020401 Depressive disease Diseases 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 2
- 238000006751 Mitsunobu reaction Methods 0.000 description 2
- 229940123685 Monoamine oxidase inhibitor Drugs 0.000 description 2
- 208000019022 Mood disease Diseases 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000001800 adrenalinergic effect Effects 0.000 description 2
- 239000000670 adrenergic alpha-2 receptor antagonist Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- SGOFAUSEYBZKDQ-UHFFFAOYSA-N brl-44408 Chemical compound C1C2=CC=CC=C2C(C)N1CC1=NCCN1 SGOFAUSEYBZKDQ-UHFFFAOYSA-N 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000000451 chemical ionisation Methods 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000011284 combination treatment Methods 0.000 description 2
- 230000036757 core body temperature Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 206010016256 fatigue Diseases 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 206010022437 insomnia Diseases 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229960003299 ketamine Drugs 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 231100000863 loss of memory Toxicity 0.000 description 2
- 229940049920 malate Drugs 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 2
- 208000008013 morphine dependence Diseases 0.000 description 2
- 229940024844 naloxone injection Drugs 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 238000009206 nuclear medicine Methods 0.000 description 2
- 238000009806 oophorectomy Methods 0.000 description 2
- 238000012831 peritoneal equilibrium test Methods 0.000 description 2
- 238000002600 positron emission tomography Methods 0.000 description 2
- 238000012877 positron emission topography Methods 0.000 description 2
- 206010036601 premature menopause Diseases 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000003772 serotonin uptake inhibitor Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000035900 sweating Effects 0.000 description 2
- 210000000225 synapse Anatomy 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- BDOYEKHHQGJGIK-UHFFFAOYSA-N (1-ethyl-3h-indazol-2-yl)-(3-methyl-2h-1,4-benzodioxin-3-yl)methanone;hydrochloride Chemical compound Cl.C1OC2=CC=CC=C2OC1(C)C(=O)N1N(CC)C2=CC=CC=C2C1 BDOYEKHHQGJGIK-UHFFFAOYSA-N 0.000 description 1
- JZFUHAGLMZWKTF-SECBINFHSA-N (1r)-3-chloro-1-phenylpropan-1-ol Chemical compound ClCC[C@@H](O)C1=CC=CC=C1 JZFUHAGLMZWKTF-SECBINFHSA-N 0.000 description 1
- JZFUHAGLMZWKTF-VIFPVBQESA-N (1s)-3-chloro-1-phenylpropan-1-ol Chemical compound ClCC[C@H](O)C1=CC=CC=C1 JZFUHAGLMZWKTF-VIFPVBQESA-N 0.000 description 1
- ALYCEQJIRFYVGE-VASSOYJASA-N (2s,12bs)-1',3'-dimethylspiro[1,3,4,6,7,12b-hexahydro-[1]benzofuro[2,3-a]quinolizine-2,4'-1,3-diazinane]-2'-one;hydrochloride Chemical compound Cl.CN1C(=O)N(C)CC[C@@]11C[C@H]2C(OC=3C4=CC=CC=3)=C4CCN2CC1 ALYCEQJIRFYVGE-VASSOYJASA-N 0.000 description 1
- DZTZUOBWDBPPJQ-BQBHMPFISA-N (8ar,12as,13as)-12-ethylsulfonyl-3-methoxy-5,6,8,8a,9,10,11,12a,13,13a-decahydroisoquinolino[2,1-g][1,6]naphthyridine;hydrochloride Chemical compound Cl.C1CC2=CC(OC)=CC=C2[C@H]2N1C[C@H]1CCCN(S(=O)(=O)CC)[C@H]1C2 DZTZUOBWDBPPJQ-BQBHMPFISA-N 0.000 description 1
- GOZNZGWCQSNZFX-UHFFFAOYSA-N 1,6-naphthyridine;hydrochloride Chemical compound Cl.C1=CN=CC2=CC=CN=C21 GOZNZGWCQSNZFX-UHFFFAOYSA-N 0.000 description 1
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 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 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- SFLSHLFXELFNJZ-CMIMLBRMSA-N 4-[(1r)-2-amino-1-hydroxy-1-tritioethyl]benzene-1,2-diol Chemical compound NC[C@@](O)([3H])C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-CMIMLBRMSA-N 0.000 description 1
- QGNQEODJYRGEJX-UHFFFAOYSA-N 4h-isoquinoline-1,3-dione Chemical compound C1=CC=C2C(=O)NC(=O)CC2=C1 QGNQEODJYRGEJX-UHFFFAOYSA-N 0.000 description 1
- MBYSTKNEMJZSIK-UHFFFAOYSA-N 6-chloro-3-methyl-9-(3-methylbut-2-enoxy)-1,2,4,5-tetrahydro-3-benzazepine Chemical compound C1CN(C)CCC2=C(Cl)C=CC(OCC=C(C)C)=C21 MBYSTKNEMJZSIK-UHFFFAOYSA-N 0.000 description 1
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 1
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 1
- FDZUJJJSDXJJMX-UHFFFAOYSA-N C(C)N1C(=NC=C1)C1(COC2=C(O1)C=CC=C2)C Chemical group C(C)N1C(=NC=C1)C1(COC2=C(O1)C=CC=C2)C FDZUJJJSDXJJMX-UHFFFAOYSA-N 0.000 description 1
- WJBZMBSSYCVTOQ-CYBMUJFWSA-N CNCC[C@H](C1=CC=CC=C1)OC=1C(=NC=CC1)Br Chemical compound CNCC[C@H](C1=CC=CC=C1)OC=1C(=NC=CC1)Br WJBZMBSSYCVTOQ-CYBMUJFWSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OZEVKPZNNNQIJB-UHFFFAOYSA-N ClCCC1(CC1)c1ccccc1 Chemical compound ClCCC1(CC1)c1ccccc1 OZEVKPZNNNQIJB-UHFFFAOYSA-N 0.000 description 1
- 208000014311 Cushing syndrome Diseases 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- 206010013954 Dysphoria Diseases 0.000 description 1
- 206010016334 Feeling hot Diseases 0.000 description 1
- MTCJZZBQNCXKAP-UHFFFAOYSA-N Formycin B Natural products OC1C(O)C(CO)OC1C1=C(NC=NC2=O)C2=NN1 MTCJZZBQNCXKAP-UHFFFAOYSA-N 0.000 description 1
- 101000639975 Homo sapiens Sodium-dependent noradrenaline transporter Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- 206010022998 Irritability Diseases 0.000 description 1
- 206010025421 Macule Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- XCPRMIKNNFEPKJ-UHFFFAOYSA-N N-methyl-1-phenyl-1-pyridin-2-yloxypropan-1-amine Chemical class C=1C=CC=CC=1C(NC)(CC)OC1=CC=CC=N1 XCPRMIKNNFEPKJ-UHFFFAOYSA-N 0.000 description 1
- 206010033165 Ovarian failure Diseases 0.000 description 1
- 238000012879 PET imaging Methods 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 241001504519 Papio ursinus Species 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- 208000002500 Primary Ovarian Insufficiency Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- VHGCDTVCOLNTBX-QGZVFWFLSA-N atomoxetine Chemical class O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=CC=C1C VHGCDTVCOLNTBX-QGZVFWFLSA-N 0.000 description 1
- 125000005604 azodicarboxylate group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001743 benzylic group Chemical group 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- UXCGGTCHSALBPY-UGSOOPFHSA-N brl 41992 Chemical compound C1C2=CC=CC=C2[C@@H]2[C@H](C)N(C)CN2C2=CC=CC=C21 UXCGGTCHSALBPY-UGSOOPFHSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000013066 combination product Substances 0.000 description 1
- 229940127555 combination product Drugs 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 210000001723 extracellular space Anatomy 0.000 description 1
- 238000010265 fast atom bombardment Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- MTCJZZBQNCXKAP-KSYZLYKTSA-N formycin B Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1C1=NNC2=C1NC=NC2=O MTCJZZBQNCXKAP-KSYZLYKTSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 230000002710 gonadal effect Effects 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 102000055827 human SLC6A2 Human genes 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- PIPZGJSEDRMUAW-VJDCAHTMSA-N hydron;methyl (1s,15r,18s,19r,20s)-18-hydroxy-1,3,11,12,14,15,16,17,18,19,20,21-dodecahydroyohimban-19-carboxylate;chloride Chemical compound Cl.C1=CC=C2C(CCN3C[C@@H]4CC[C@H](O)[C@@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 PIPZGJSEDRMUAW-VJDCAHTMSA-N 0.000 description 1
- 230000037315 hyperhidrosis Effects 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 238000009802 hysterectomy Methods 0.000 description 1
- 229950008608 imiloxan Drugs 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940090044 injection Drugs 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000002332 leydig cell Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 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
- 238000013507 mapping Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 210000001640 nerve ending Anatomy 0.000 description 1
- 206010029410 night sweats Diseases 0.000 description 1
- 230000036565 night sweats Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 1
- 230000002474 noradrenergic effect Effects 0.000 description 1
- 229940127221 norepinephrine reuptake inhibitor Drugs 0.000 description 1
- 150000002871 norepinephrines Chemical class 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003401 opiate antagonist Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 201000004535 ovarian dysfunction Diseases 0.000 description 1
- 231100000539 ovarian failure Toxicity 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 235000003784 poor nutrition Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 1
- 238000011165 process development Methods 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 229960002601 protriptyline Drugs 0.000 description 1
- BWPIARFWQZKAIA-UHFFFAOYSA-N protriptyline Chemical compound C1=CC2=CC=CC=C2C(CCCNC)C2=CC=CC=C21 BWPIARFWQZKAIA-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 229940126570 serotonin reuptake inhibitor Drugs 0.000 description 1
- 208000012201 sexual and gender identity disease Diseases 0.000 description 1
- 208000015891 sexual disease Diseases 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- WKXSXFYQPCWZOS-UHFFFAOYSA-N skf 104856 Chemical compound C1N(C)CCC2=C(Cl)C=CC3=C2C1=C(C=C)S3 WKXSXFYQPCWZOS-UHFFFAOYSA-N 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229950001330 spiroxatrine Drugs 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 210000003568 synaptosome Anatomy 0.000 description 1
- 230000028016 temperature homeostasis Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001331 thermoregulatory effect Effects 0.000 description 1
- 238000011200 topical administration Methods 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
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229960000949 yohimbine hydrochloride Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Diabetes (AREA)
- Psychiatry (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Addiction (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pain & Pain Management (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Anesthesiology (AREA)
- Hospice & Palliative Care (AREA)
- Child & Adolescent Psychology (AREA)
- Emergency Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Gynecology & Obstetrics (AREA)
- Nutrition Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
Description
本発明は、新規のN−メチルピリジンオキシフェニルプロパンアミン類、その医薬組成物およびその使用方法に関する。特に、本発明は、(R)−(−)−N−メチル−3−置換ピリジンオキシ−3−フェニルプロパンアミン類およびその使用に関する。さらに、本発明は、血液脳関門を通過し、ノルエピネフリンおよびセロトニン・トランスポーター(“NET/SERT”)を制御する治療方法に関する。従って、本発明の化合物および組成物は、鬱病、血管運動性症状、例えばのぼせ、および、ノルエピネフリン・トランスポーター(“NET”)および/またはセロトニン・トランスポーター(“SERT”)が介在する他の疾患または状態を処置するのに有用である。
理論に束縛されることなく、NET、すなわちノルアドレナリン作動性神経終末にシナプス前性に位置する12種の膜貫通蛋白質は、NE再取り込みによって、シナプス性ノルエピネフリン(“NE”)の濃度制御に不可欠な役割を果たすと考えられている(R.D. Blakely et al., J. Exp. Biol., 196:263-281(1994); T. Pacholczyk et al., Nature, 350:350-354(1994); および S.G. Amara et al., Annu. Rev. Neurosci., 16:73-93(1993))。NETは、細胞外スペースからのNEの除去に不可欠であり(J. Axelrod et al., Porg. Brain Res., 31:21-32(1969); H. Bonisch at al., Ann. N.Y. Acad. Sci., 733:193-202(1994))、抗鬱剤作用の標的である(J.C. Nelso, Psychiatry, 46:1301-1308(1999) および H.J. Moller, J. Clin. Psychiatry, 61(Supp.6):24-27(2000))。
本発明は、例えば、鬱病(大鬱病性障害、気分変調症、抑鬱気分を伴う適応障害、および双極性障害に関連する鬱病を含む)、不快、不安症、睡眠障害、胃運動性障害、性機能障害、脳外傷、記憶喪失、食欲障害、過食症、肥満、物質乱用、アルコール依存症、タバコ中毒、強迫症、パニック障害、月経前症候群、偏頭痛、双極性障害、線維筋痛症、および、自然に、外科的にまたは医学的に誘発された閉経期または男性更年期症状、例えば血管運動性症状、例えばのぼせを処置するための、遊離形または塩形の式(I):
本発明の化合物は、遊離形または塩形の、式(I):
X、YおよびZの1つがNであり;他の2つがCHまたはC(R)であり;
Rは、H、ハロ、NO2、C1−6アルキル、C1−6アルコキシまたは−N(C0−6アルキル)(C0−6アルキル)であり;
nは、0、1または2である。]
によって表される。
1.1 XがNである、式(I)の化合物;
1.2 YがNである、式(I)の化合物または1.1の化合物;
1.3 ZがNである、式(I)の化合物あるいは1.1または1.2の化合物;
1.4 X、YおよびZの1つがNであり、他の2つがC(R)である、式(I)の化合物または1.1〜1.3の何れかの化合物;
1.5 nが0である、式(I)の化合物または1.1〜1.4の何れかの化合物;
1.6 nが1である、式(I)の化合物または1.1〜1.4の何れかの化合物;
1.7 nが2である、式(I)の化合物または1.1〜1.4の何れかの化合物;
1.8 Rが、H、ハロ、NO2、C1−6アルキル、C1−6アルコキシまたは−N(C0−6アルキル)(C0−6アルキル)である、式(I)の化合物または1.1〜1.7の何れかの化合物;
1.9 RがC1−6アルキル(例えばメチル)である、式(I)の化合物または1.1〜1.8の何れかの化合物;
1.10 Rがメチルである、式(I)の化合物または1.1〜1.9の何れかの化合物;
1.12 Rが−N(C0−6アルキル)(C0−6アルキル)である、式(I)の化合物または1.1〜1.11の何れかの化合物;
1.13 Rが−NH(CH3)である、式(I)の化合物または1.1〜1.12の何れかの化合物;
1.14 Rがハロである、式(I)の化合物または1.1〜1.13の何れかの化合物;
1.15 Rがブロモである、式(I)の化合物または1.1〜1.14の何れかの化合物;
1.16 Rがクロロである、式(I)の化合物または1.1〜1.14の何れかの化合物;
1.17 Rがフルオロである、式(I)の化合物または1.1〜1.14の何れかの化合物;
1.18 Rがヨードである、式(I)の化合物または1.1〜1.14の何れかの化合物;
1.19 Rが、独立して、メチルおよび/またはハロ(例えば4−メチルおよび2−ヨード置換)である、式(I)の化合物または1.1〜1.10または1.14〜1.18の何れかの化合物;
1.20 RがC1−6アルコキシである、式(I)の化合物または1.1〜1.19の何れかの化合物;
1.21 Rがメトキシである、式(I)の化合物または1.1〜1.19の何れかの化合物;
1.22 RがNO2である、式(I)の化合物または1.1〜1.19の何れかの化合物;
1.23 オキシ(−O−)基を有するキラル炭素が(R)絶対配置を有する、式(I)の化合物または1.1〜1.22の何れかの化合物;
1.24 オキシ(−O−)基を有するキラル炭素が(S)絶対配置を有する、式(I)の化合物または1.1〜1.22の何れかの化合物;
1.25 一方のエナンチオマーでエナンチオマー的に富化された(例えばオキシ(−O−)基を有するキラル炭素の絶対配置が優先的に(R)であるか、または優先的に(S)である)化合物、例えば、一方のエナンチオマーについて60%eeより高い、好ましくは75%eeより高い、より好ましくは85%eeより高い、さらにより好ましくは95%eeより高い、最も好ましくは98%eeより高いエナンチオマー過剰率(ee)を有する、式(I)の化合物または1.1〜1.24の何れかの化合物;
1.26 (R)エナンチオマーでエナンチオマー的に富化された、例えば(R)エナンチオマーについて60%eeより高い、より好ましくは75%eeより高い、さらにより好ましくは85%eeより高い、さらにより好ましくは95%eeより高い、最も好ましくは98%eeより高いeeを有する、式(I)の化合物または1.1〜1.25の何れかの化合物;
1.27 (S)エナンチオマーでエナンチオマー的に富化された、例えば(S)エナンチオマーについて60%eeより高い、より好ましくは75%eeより高い、さらにより好ましくは85%eeより高い、さらにより好ましくは95%eeより高い、最も好ましくは98%eeより高いeeを有する、式(I)の化合物または1.1〜1.25の何れかの化合物;
1.28 塩酸塩である、式(I)の化合物または1.1〜1.27の何れかの化合物;
1.29 下記のノルエピネフリン結合アッセイにおいて、10,000nM未満、好ましくは2,000nM未満、さらにより好ましくは100nM未満、最も好ましくは15nM未満のKiを有する、先に記載した何れかの化合物。
“NE”はノルエピネフリンを言う。
“NET”は、ノルエピネフリン・トランスポーターを言う。
“SERT”は、セロトニン・トランスポーターを言う。
“NET/SERT”は、ノルエピネフリンおよび/またはセロトニン・トランスポーターを言う。
“NRI/SRI”は、ノルエピネフリン/セロトニン再取り込み阻害剤を言う。
“TCA”は、三環系抗鬱剤を言う。
“MAOI”は、モノアミンオキシダーゼ阻害剤を言う。
“SSRI”は、選択的セロトニン再取り込み阻害剤を言う。
“5−HT”は、セロトニンを言う。
“VMS”は、血管運動性症状を言う。
“PET”は、陽電子放射型断層撮影を言う。
“SPECT”は、光子放射型コンピュータ断層撮影を言う。
“ee”はエナンチオマー過剰率を言う。
(i) 温度は、摂氏(℃)で示される;操作は、18〜25℃の範囲の温度である室温または環境温度(“rt”)で行った;
(ii) 有機溶液は、無水硫酸ナトリウムで乾燥させた;溶媒の蒸発は、ロータリーエバポレーターを用いて、減圧下(600〜4000Pascals;4.5〜30mmHg)で、60℃までの浴の温度で行う;
(iii) 一般的に反応の推移はTLCによって追跡し、反応時間は例示のためにのみ示す;
(iv) 最終生成物は、満足のいくプロトン核磁気共鳴(NMR)スペクトルおよび/または質量スペクトルデータを有した;
(v) 収率は例示のためのみに示し、必ずしも入念なプロセス開発によって得られたものではない;より多くの物質が必要ならば、製造を繰り返した;
(vii) 示されたときは、NMRデータは、主要な示性プロトンについてのδ値の形態であり、内部標準としてのテトラメチルシラン(TMS)に対する百万分率で示し、400MHzで、特記しない限り重水素化ジメチルスルホキシド(DMSO-d6)を溶媒として用いて測定した;
(vii) 化学記号は、その通常の意味を有する;国際単位系および記号を用いる;
(viii) 溶媒比は、容積:容積(v/v)で示される;
(ix) 質量スペクトルは、70eVの電子エネルギーで、化学イオン化(CI)モードで、直接曝露プローブを用いて測定した;示されるとき、イオン化は、電子衝撃(EI)、高速原子衝撃(FAB)またはエレクトロスプレー(ESP)によって行われる;m/zの値が示される;一般的に、親マスを示すイオンのみが報告される;特記しない限り、記載されたマス・イオンは[MH]+である;
(xi) 下記の略号を用いた:
ラットの前脳において、本化合物がNETに特異的に結合するかどうかを測定するために、NET結合がアッセイされた。前脳組織は、中程度の密度のNETを有し、他の脳構造から正確に分離され得る。ラットの前脳は、スプラーグドーリーラット(Taconic Farm, NY, U.S.A.)の脳から新しく得た。組織を30容積の緩衝液(120mM NaClおよび5mM KClを含む50mM Tris−HCl(pH 7.4))中でホモジナイズした。ホモジネートを、10,000rpmで15分間遠心分離した。得られたペレットを再度懸濁し、そして再度遠心分離し、その手順を1回以上繰り返した。結合試験は、7mLのガラス管中、1.0mL/管の最終容積で行った。阻害定数の測定において、膜懸濁液のアリコート(管当たり3mg wtに相当)を、緩衝液および1nM [3H]ニソキセチンと混合した。さらに、標識されていない試験NETリガンドを10−3〜10−12(μMからpM)の範囲の濃度で加えた。インキュベーションを室温で60分間行い、次いで、予め1%ポリエチレンイミンに浸したガラス繊維フィルターによる濾過によって、遊離の放射性リガンドから結合したものを分離することによって、試験を終了させた。フィルターを処理し、シンチレーション計数機を用いて、放射活性についてアッセイした。試験リガンド濃度に対する1分当たりの平均カウント数(CMP, n=3)をプロットし、Prism (3.0cx, GraphPad)を用いて、化合物の阻害定数(IC50)および結合親和性(Ki)を決定した。
LC-MS, EI (m/z): 321 (100%, M+), 323 (98%, (M+2)+).
1H-NMR(CD3OD), 400Mhz, δ(ppm): 7.95 (dd, J=4.2, 1.8Hz, 1H), 7.49 (m, 5H), 7.25 (m, 2H), 5.66 (dd, J=4.0, 8.5Hz, 1H), 3.32 (m, 2H), 2.82 (s, 3H), 2.49 (m, 1H), 2.38 (m, 1H).
13C-NMR (CDCl3, 100MHz), δ(ppm): 151.18, 145.85, 139.88, 133.08, 131.34, 131.06, 128.86, 126.41, 126.14, 83.01, 51.01, 39.13, 33.82.
卵巣摘出ラットモデル:Maswood et. al., Neuroendocrinology 84:330-338 (2006)で提供される手順に従って、のぼせの軽減に対する本発明の化合物の有効性を評価し得る。卵巣摘出したメスのラットを、12時間明/暗サイクルに置く。ラットの背中側の肩甲部に遠隔測定発信器を埋め込み、尾の皮膚の温度(TST)を測定するために、尾の基部から2.5cm離してトンネル・プローブのチップを挿入する。中核体温(CBT)を測定するために、3〜4cmの長さで、ラットの腹部の正中を、腹部の筋系を貫いて切開し、発信器を腹腔に置く。暗期の開始0.5時間前に、ビークルをラットに皮下投与し、TSTを12時間連続してモニターしてベースラインとする。24時間後、ビークルまたは本発明の試験化合物の何れかを皮下投与する。TSTを12時間モニターする。30分時点毎に平均温度を計算する。化合物投与日の各30分時点の平均温度からビークル投与日の総平均ベースライン温度(12時間に亘る平均温度)を引くことによって、温度変化を計算する。
Claims (28)
- 60%より高いエナンチオマー過剰率で(R)エナンチオマーで富化された、請求項1または2に記載された化合物。
- 60%より高いエナンチオマー過剰率で(S)エナンチオマーで富化された、請求項1または2に記載された化合物。
- 式(I)の化合物の塩が塩酸塩である、請求項1−4の何れか1項に記載された化合物。
- NET/SERTモジュレーターとして使用するための、請求項1−5の何れか1項に記載された化合物。
- NET/SERT阻害剤として使用するための、請求項1−6の何れか1項に記載された化合物。
- 該化合物が、60%より高いエナンチオマー過剰率で(S)エナンチオマーで富化された、請求項8または9に記載された方法。
- 該化合物が、60%より高いエナンチオマー過剰率で(R)エナンチオマーで富化された、請求項8または9に記載された方法。
- 該NETおよび/またはSERTが介在する疾患または状態が、不快、鬱病、不安症、睡眠障害、胃運動性障害、性機能障害、脳外傷、記憶喪失、食欲障害、過食症、肥満、物質乱用、アルコール依存症、タバコ中毒、強迫症、パニック障害、月経前症候群、偏頭痛、双極性障害、線維筋痛症、および血管運動性症状またはのぼせからなる群から選択される、請求項8−11の何れか1項に記載された方法。
- 該疾患または状態が鬱病である、請求項8−12の何れか1項に記載された方法。
- 該疾患または状態が不安症である、請求項8−12の何れか1項に記載された方法。
- 該疾患または状態が、血管運動性症状またはのぼせである、請求項8−12の何れか1項に記載された方法。
- 式(I)の化合物が塩酸塩の形態である、請求項8−15の何れか1項に記載された方法。
- 温血動物において、NET/SERTの制御に使用する医薬の製造における、遊離形または薬学的に許容される塩形の、請求項1−7の何れか1項に記載された化合物の使用。
- NETおよび/またはSERTが介在する疾患または障害の何れかを処置する医薬の製造における、遊離形または薬学的に許容される塩形の、請求項1−7の何れか1項に記載された化合物の使用。
- 該疾患または障害が、不快、鬱病、不安症、睡眠障害、胃運動性障害、性機能障害、脳外傷、記憶喪失、食欲障害、過食症、肥満、物質乱用、アルコール依存症、タバコ中毒、強迫症、パニック障害、月経前症候群、偏頭痛、双極性障害、線維筋痛症、および血管運動性症状またはのぼせからなる群から選択される、請求項18に記載された使用。
- 該疾患または障害が鬱病である、請求項18または19に記載された使用。
- 該疾患または障害が不安症である、請求項18または19に記載された使用。
- 該疾患または障害が血管運動性症状またはのぼせである、請求項18または19に記載された使用。
- 薬学的に許容される希釈剤または担体と組み合わせた、遊離形または薬学的に許容される塩形の請求項1−7の何れか1項に記載された化合物を含む医薬組成物。
- ノルエピネフリン・トランスポーターの制御不全によって特徴付けられる疾患の処置、制御および管理に使用するための、請求項23に記載された医薬組成物。
- 請求項8−16の何れか1項に記載された方法に使用するための、または、請求項17−22の何れか1項に記載された使用のための、請求項23に記載された医薬組成物。
- 鬱病の処置、制御および管理に使用するための、請求項23、24または25に記載された医薬組成物。
- 不安症の処置、制御および管理に使用するための、請求項23、24または25に記載された医薬組成物。
- 血管運動性症状またはのぼせの処置、制御および管理に使用するための、請求項23、24または25に記載された医薬組成物。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US93303707P | 2007-06-04 | 2007-06-04 | |
US60/933,037 | 2007-06-04 | ||
US3372008P | 2008-03-04 | 2008-03-04 | |
US61/033,720 | 2008-03-04 | ||
PCT/US2008/007011 WO2008150528A1 (en) | 2007-06-04 | 2008-06-04 | Novel methods |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2010529124A true JP2010529124A (ja) | 2010-08-26 |
JP5384487B2 JP5384487B2 (ja) | 2014-01-08 |
Family
ID=40094033
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2010511179A Expired - Fee Related JP5384487B2 (ja) | 2007-06-04 | 2008-06-04 | 新規方法 |
Country Status (5)
Country | Link |
---|---|
US (1) | US8183266B2 (ja) |
EP (1) | EP2161998B1 (ja) |
JP (1) | JP5384487B2 (ja) |
ES (1) | ES2553891T3 (ja) |
WO (1) | WO2008150528A1 (ja) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2016235483A1 (en) * | 2015-03-20 | 2017-10-12 | Intra-Cellular Therapies, Inc. | Organic compounds |
EP3339304A1 (en) * | 2016-12-20 | 2018-06-27 | Laboratorios del Dr. Esteve, S.A. | Quinoline and isoquinoline derivatives for treating pain and pain related conditions |
EP3339307A1 (en) * | 2016-12-20 | 2018-06-27 | Laboratorios del Dr. Esteve, S.A. | Nitrogen containing bicyclic derivatives for treating pain and pain related conditions |
Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2060622A (en) * | 1979-09-14 | 1981-05-07 | Wyeth John & Brother Ltd | 3-Aryl-3-aryloxyalkylamines |
WO2004043931A1 (en) * | 2002-11-05 | 2004-05-27 | Eli Lilly And Company | Propanamine derivatives as serotonin and norepinephrine reuptake inhibitors |
JP2004538313A (ja) * | 2001-07-31 | 2004-12-24 | アストラゼネカ・アクチエボラーグ | ヘテロアリールへテロアルキルアミン誘導体および一酸化窒素シンターゼの阻害剤としてのそれらの使用 |
JP2005501834A (ja) * | 2001-07-31 | 2005-01-20 | アストラゼネカ・アクチエボラーグ | ヘテロアリールヘテロアルキルアミン誘導体、および一酸化窒素合成酵素阻害剤としてのその使用 |
JP2005506308A (ja) * | 2001-05-08 | 2005-03-03 | アストラゼネカ・アクチエボラーグ | 新規アリールヘテロアルキルアミン誘導体 |
WO2005020976A2 (en) * | 2003-08-27 | 2005-03-10 | Eli Lilly And Company | Treatment of pervasive developmental disorders with norepinephrine reuptake inhibitors |
WO2005020975A2 (en) * | 2003-08-27 | 2005-03-10 | Eli Lilly And Company | Treatment of learning disabilities and motor skills disorder with norepinephrine reuptake inhibitors |
WO2005021095A2 (en) * | 2003-08-27 | 2005-03-10 | Eli Lilly And Company | Treatment of stuttering and other communication disorders with norepinephrine reuptake inhibitors |
WO2005023802A1 (en) * | 2003-08-22 | 2005-03-17 | Eli Lilly And Company | Pyridinylmorpholine derivatives |
WO2005060949A2 (en) * | 2003-12-12 | 2005-07-07 | Eli Lilly And Company | Selective norepinephrine reuptake inhibitors for the treatment of hot flashes, impulse control disorders and personality change due to a general medical condition |
WO2005105763A1 (en) * | 2004-04-30 | 2005-11-10 | Warner-Lambert Company Llc | Substituted morpholine compounds for the treatment of central nervous system disorders |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2432500A1 (fr) | 1978-02-24 | 1980-02-29 | Roussel Uclaf | Nouveaux derives de la benzene propanamine et leurs sels, procede de preparation et application a titre de medicaments |
US5166437A (en) | 1989-03-03 | 1992-11-24 | Orion-Yhtyma Oy | Process for the preparation of fluoxetine |
US6465467B1 (en) | 1999-05-21 | 2002-10-15 | Biovitrum Ab | Certain aryl-aliphatic and heteroaryl-aliphatic piperazinyl pyrazines and their use in the treatment of serotonin-related diseases |
ES2200699B1 (es) * | 2002-07-12 | 2005-10-01 | Ragactives, S.L | Procedimiento para la separacion de r(-) y s(+)-5-(2-((2-(etoxifenoxi)etil)amino)propil-2-metoxibenceno-sulfonamida. |
-
2008
- 2008-06-04 US US12/663,114 patent/US8183266B2/en not_active Expired - Fee Related
- 2008-06-04 EP EP08768098.9A patent/EP2161998B1/en not_active Not-in-force
- 2008-06-04 JP JP2010511179A patent/JP5384487B2/ja not_active Expired - Fee Related
- 2008-06-04 WO PCT/US2008/007011 patent/WO2008150528A1/en active Application Filing
- 2008-06-04 ES ES08768098.9T patent/ES2553891T3/es active Active
Patent Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2060622A (en) * | 1979-09-14 | 1981-05-07 | Wyeth John & Brother Ltd | 3-Aryl-3-aryloxyalkylamines |
JP2005506308A (ja) * | 2001-05-08 | 2005-03-03 | アストラゼネカ・アクチエボラーグ | 新規アリールヘテロアルキルアミン誘導体 |
JP2004538313A (ja) * | 2001-07-31 | 2004-12-24 | アストラゼネカ・アクチエボラーグ | ヘテロアリールへテロアルキルアミン誘導体および一酸化窒素シンターゼの阻害剤としてのそれらの使用 |
JP2005501834A (ja) * | 2001-07-31 | 2005-01-20 | アストラゼネカ・アクチエボラーグ | ヘテロアリールヘテロアルキルアミン誘導体、および一酸化窒素合成酵素阻害剤としてのその使用 |
WO2004043931A1 (en) * | 2002-11-05 | 2004-05-27 | Eli Lilly And Company | Propanamine derivatives as serotonin and norepinephrine reuptake inhibitors |
WO2005023802A1 (en) * | 2003-08-22 | 2005-03-17 | Eli Lilly And Company | Pyridinylmorpholine derivatives |
WO2005020976A2 (en) * | 2003-08-27 | 2005-03-10 | Eli Lilly And Company | Treatment of pervasive developmental disorders with norepinephrine reuptake inhibitors |
WO2005020975A2 (en) * | 2003-08-27 | 2005-03-10 | Eli Lilly And Company | Treatment of learning disabilities and motor skills disorder with norepinephrine reuptake inhibitors |
WO2005021095A2 (en) * | 2003-08-27 | 2005-03-10 | Eli Lilly And Company | Treatment of stuttering and other communication disorders with norepinephrine reuptake inhibitors |
WO2005060949A2 (en) * | 2003-12-12 | 2005-07-07 | Eli Lilly And Company | Selective norepinephrine reuptake inhibitors for the treatment of hot flashes, impulse control disorders and personality change due to a general medical condition |
WO2005105763A1 (en) * | 2004-04-30 | 2005-11-10 | Warner-Lambert Company Llc | Substituted morpholine compounds for the treatment of central nervous system disorders |
Also Published As
Publication number | Publication date |
---|---|
ES2553891T3 (es) | 2015-12-14 |
EP2161998B1 (en) | 2015-09-02 |
WO2008150528A1 (en) | 2008-12-11 |
US8183266B2 (en) | 2012-05-22 |
EP2161998A1 (en) | 2010-03-17 |
EP2161998A4 (en) | 2011-01-05 |
JP5384487B2 (ja) | 2014-01-08 |
US20100173951A1 (en) | 2010-07-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6964450B2 (ja) | 造影剤の合成および使用のための組成物、方法およびシステム | |
JP5738775B2 (ja) | ジスキネジア関連障害の治療 | |
AU2021200164B2 (en) | Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment | |
CZ290115B6 (cs) | Farmaceutický prostředek | |
Krause et al. | Synthesis, X-Ray Crystallography, and Pharmacokinetics of Novel Azomethine Prodrugs of (R)-. Alpha.-Methylhistamine: Highly Potent and Selective Histamine H3 Receptor Agonists | |
JP2001524954A (ja) | コカインの類似化合物 | |
JP6726200B2 (ja) | 有機化合物 | |
BR112019010127A2 (pt) | agentes psicotrópicos e usos dos mesmos | |
JP2009526776A (ja) | 新規なジアザビシクロアルカン誘導体及びその医療上の使用 | |
JP5384487B2 (ja) | 新規方法 | |
US20170166531A1 (en) | 2-alkoxy-11-hydroxyaporphine derivatives and uses thereof | |
JP2016522786A (ja) | [11c]及び[18f]標識化1,3−ジフェニルー5−(ピリミジン−2−イル)−ピリジン−2(1h)−オン誘導体並びにampa受容体のpetイメージングのためのそれらの使用 | |
WO1999012893A1 (en) | Diagnostic and therapeutic alkylenediamine compounds and process | |
MXPA04006142A (es) | Tratamiento de incontinencia fecal y otras condiciones con 1r, 2s-metoxamina. | |
JP2008528677A (ja) | Cnsの疾患および障害の処置のための四環系モノアミン再取り込み阻害薬 | |
EP3720445A1 (en) | Beta-2 selective adrenergic receptor agonists | |
EP3013339B1 (en) | Labeled pkg-1-alpha-binding compounds and their use in imaging and quantifying pain | |
US20110152288A1 (en) | Methods of treating vasomotor symptoms | |
MX2008015434A (es) | Combinanciones de inhibidores de recaptacion de monoamina y activadores de canales de potasio. | |
JP6591431B2 (ja) | 侵害受容処理並びに記憶障害及び認知異常の病態生理学的研究におけるプローブとして高度に選択的なシグマ受容体リガンド及び放射性リガンド | |
WO2024168098A2 (en) | 5-methoxy-n,n-dimethyltryptamine analogs, their synthesis, and methods for treatment of neurological, psychiatric, and substance use disorders | |
Goyal | Synthesis And Characterization Of Novel Valerophenone Oximes And Ethers Applicable In Psychiatric Disorders | |
MXPA00011353A (es) | Uso de olanzapida en combinación con fluoxetina para terapia de la depresión refractaria |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20110603 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20130423 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20130723 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20130730 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130807 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20130903 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20131002 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5384487 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
LAPS | Cancellation because of no payment of annual fees |