CA2978668A1 - Organic compounds - Google Patents
Organic compoundsInfo
- Publication number
- CA2978668A1 CA2978668A1 CA2978668A CA2978668A CA2978668A1 CA 2978668 A1 CA2978668 A1 CA 2978668A1 CA 2978668 A CA2978668 A CA 2978668A CA 2978668 A CA2978668 A CA 2978668A CA 2978668 A1 CA2978668 A1 CA 2978668A1
- Authority
- CA
- Canada
- Prior art keywords
- disease
- net
- sert
- disorder
- compound
- 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.)
- Abandoned
Links
- 150000002894 organic compounds Chemical class 0.000 title description 2
- 108010049586 Norepinephrine Plasma Membrane Transport Proteins Proteins 0.000 claims abstract description 75
- 238000000034 method Methods 0.000 claims abstract description 34
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 113
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 66
- 101710114597 Sodium-dependent serotonin transporter Proteins 0.000 claims description 59
- 102100028874 Sodium-dependent serotonin transporter Human genes 0.000 claims description 58
- 150000003839 salts Chemical group 0.000 claims description 49
- 208000024891 symptom Diseases 0.000 claims description 38
- 201000010099 disease Diseases 0.000 claims description 36
- 206010060800 Hot flush Diseases 0.000 claims description 35
- 238000011282 treatment Methods 0.000 claims description 35
- 208000033830 Hot Flashes Diseases 0.000 claims description 34
- 230000001457 vasomotor Effects 0.000 claims description 34
- 208000035475 disorder Diseases 0.000 claims description 30
- 208000024827 Alzheimer disease Diseases 0.000 claims description 26
- 208000019901 Anxiety disease Diseases 0.000 claims description 23
- 230000036506 anxiety Effects 0.000 claims description 23
- 230000001404 mediated effect Effects 0.000 claims description 22
- 208000020925 Bipolar disease Diseases 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 208000019116 sleep disease Diseases 0.000 claims description 12
- 201000009032 substance abuse Diseases 0.000 claims description 12
- 231100000736 substance abuse Toxicity 0.000 claims description 12
- 208000011117 substance-related disease Diseases 0.000 claims description 12
- 208000007848 Alcoholism Diseases 0.000 claims description 11
- 208000000044 Amnesia Diseases 0.000 claims description 11
- 208000027559 Appetite disease Diseases 0.000 claims description 11
- 208000032841 Bulimia Diseases 0.000 claims description 11
- 206010006550 Bulimia nervosa Diseases 0.000 claims description 11
- 208000000094 Chronic Pain Diseases 0.000 claims description 11
- 206010012335 Dependence Diseases 0.000 claims description 11
- 206010013954 Dysphoria Diseases 0.000 claims description 11
- 208000019454 Feeding and Eating disease Diseases 0.000 claims description 11
- 208000001640 Fibromyalgia Diseases 0.000 claims description 11
- 208000026139 Memory disease Diseases 0.000 claims description 11
- 208000019695 Migraine disease Diseases 0.000 claims description 11
- 241000208125 Nicotiana Species 0.000 claims description 11
- 235000002637 Nicotiana tabacum Nutrition 0.000 claims description 11
- 208000008589 Obesity Diseases 0.000 claims description 11
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 11
- 208000002193 Pain Diseases 0.000 claims description 11
- 206010036618 Premenstrual syndrome Diseases 0.000 claims description 11
- 201000001880 Sexual dysfunction Diseases 0.000 claims description 11
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 11
- 201000007930 alcohol dependence Diseases 0.000 claims description 11
- 230000006735 deficit Effects 0.000 claims description 11
- 230000030135 gastric motility Effects 0.000 claims description 11
- 230000006984 memory degeneration Effects 0.000 claims description 11
- 208000023060 memory loss Diseases 0.000 claims description 11
- 206010027599 migraine Diseases 0.000 claims description 11
- 208000004296 neuralgia Diseases 0.000 claims description 11
- 208000021722 neuropathic pain Diseases 0.000 claims description 11
- 235000020824 obesity Nutrition 0.000 claims description 11
- 208000019906 panic disease Diseases 0.000 claims description 11
- 231100000872 sexual dysfunction Toxicity 0.000 claims description 11
- 230000033228 biological regulation Effects 0.000 claims description 10
- 241001465754 Metazoa Species 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 8
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 239000003112 inhibitor Substances 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 102100033929 Sodium-dependent noradrenaline transporter Human genes 0.000 claims 1
- 102000008092 Norepinephrine Plasma Membrane Transport Proteins Human genes 0.000 abstract description 73
- 229960002748 norepinephrine Drugs 0.000 abstract description 34
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 abstract description 33
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 abstract description 33
- 102000019208 Serotonin Plasma Membrane Transport Proteins Human genes 0.000 abstract description 6
- 108010012996 Serotonin Plasma Membrane Transport Proteins Proteins 0.000 abstract description 6
- 230000008499 blood brain barrier function Effects 0.000 abstract description 4
- 210000001218 blood-brain barrier Anatomy 0.000 abstract description 4
- 238000002560 therapeutic procedure Methods 0.000 abstract description 4
- YERLRZHCJQXVGS-UHFFFAOYSA-N 1-phenyl-1-pyridin-2-yloxypropan-1-amine Chemical class C=1C=CC=CC=1C(N)(CC)OC1=CC=CC=N1 YERLRZHCJQXVGS-UHFFFAOYSA-N 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 230000027455 binding Effects 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 12
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 12
- 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 12
- 210000004556 brain Anatomy 0.000 description 11
- 241000700159 Rattus Species 0.000 description 10
- -1 hydroxy ethoxy Chemical group 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-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 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 206010072742 Late onset hypogonadism syndrome Diseases 0.000 description 9
- 206010027304 Menopausal symptoms Diseases 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 206010001297 Adjustment disorder with depressed mood Diseases 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 208000024732 dysthymic disease Diseases 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000003446 ligand Substances 0.000 description 8
- 208000024714 major depressive disease Diseases 0.000 description 8
- 239000000700 radioactive tracer Substances 0.000 description 8
- 238000002603 single-photon emission computed tomography Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000012636 positron electron tomography Methods 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- VVFOTZVAOGBWDZ-GFCCVEGCSA-N 3-[(1R)-3-chloro-1-phenylpropoxy]-2-iodopyridine Chemical compound ClCC[C@@H](OC=1C(=NC=CC=1)I)C1=CC=CC=C1 VVFOTZVAOGBWDZ-GFCCVEGCSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 238000003384 imaging method Methods 0.000 description 6
- 210000000627 locus coeruleus Anatomy 0.000 description 6
- 230000009245 menopause Effects 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 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 5
- 238000003556 assay Methods 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- APFVFJFRJDLVQX-AHCXROLUSA-N indium-111 Chemical compound [111In] APFVFJFRJDLVQX-AHCXROLUSA-N 0.000 description 5
- 229960005181 morphine Drugs 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 230000005855 radiation Effects 0.000 description 5
- 229960003770 reboxetine Drugs 0.000 description 5
- 238000011894 semi-preparative HPLC Methods 0.000 description 5
- 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 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- CRPIHINVYOGTOM-CQSZACIVSA-N 3-[(1R)-3-chloro-1-phenylpropoxy]-2-ethoxypyridine Chemical compound ClCC[C@@H](OC=1C(=NC=CC=1)OCC)C1=CC=CC=C1 CRPIHINVYOGTOM-CQSZACIVSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 230000004064 dysfunction Effects 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- ITJNARMNRKSWTA-UHFFFAOYSA-N nisoxetine Chemical compound C=1C=CC=CC=1C(CCNC)OC1=CC=CC=C1OC ITJNARMNRKSWTA-UHFFFAOYSA-N 0.000 description 4
- 229950004211 nisoxetine Drugs 0.000 description 4
- 230000007170 pathology Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 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 4
- 239000002464 receptor antagonist Substances 0.000 description 4
- 229940044551 receptor antagonist Drugs 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- 229940076279 serotonin Drugs 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- 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 3
- IXEMQJVCRXRZKP-OAHLLOKOSA-N 2-[3-[(1R)-3-(methylamino)-1-phenylpropoxy]pyridin-2-yl]oxyethanol Chemical compound CNCC[C@@H](OC1=CC=CN=C1OCCO)C1=CC=CC=C1 IXEMQJVCRXRZKP-OAHLLOKOSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 208000020401 Depressive disease Diseases 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- WHONHNFFZHUHNV-MRXNPFEDSA-N IC1=NC=CC=C1O[C@H](CCN(C(OC(C)(C)C)=O)C)C1=CC=CC=C1 Chemical compound IC1=NC=CC=C1O[C@H](CCN(C(OC(C)(C)C)=O)C)C1=CC=CC=C1 WHONHNFFZHUHNV-MRXNPFEDSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-AHCXROLUSA-N Iodine-123 Chemical compound [123I] ZCYVEMRRCGMTRW-AHCXROLUSA-N 0.000 description 3
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- KRHYYFGTRYWZRS-BJUDXGSMSA-N ac1l2y5h Chemical compound [18FH] KRHYYFGTRYWZRS-BJUDXGSMSA-N 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 239000000935 antidepressant agent Substances 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- OKTJSMMVPCPJKN-BJUDXGSMSA-N carbon-11 Chemical compound [11C] OKTJSMMVPCPJKN-BJUDXGSMSA-N 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 229940055742 indium-111 Drugs 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 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
- 238000012831 peritoneal equilibrium test Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000002600 positron emission tomography Methods 0.000 description 3
- 238000012877 positron emission topography Methods 0.000 description 3
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 3
- 238000011552 rat model Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 3
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 229940056501 technetium 99m Drugs 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- QZMPNVMLPVFOLS-CQSZACIVSA-N (3R)-3-(2-ethoxypyridin-3-yl)oxy-3-phenylpropan-1-amine Chemical compound C(C)OC1=NC=CC=C1O[C@H](CCN)C1=CC=CC=C1 QZMPNVMLPVFOLS-CQSZACIVSA-N 0.000 description 2
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 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 2
- HJBGMPCMSWJZNH-UHFFFAOYSA-N 2-iodopyridin-3-ol Chemical compound OC1=CC=CN=C1I HJBGMPCMSWJZNH-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
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 206010003439 Artificial menopause Diseases 0.000 description 2
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
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- 208000036110 Neuroinflammatory disease Diseases 0.000 description 2
- SWYXZAMGOFKQRC-GOSISDBHSA-N OCCOC1=NC=CC=C1O[C@H](CCN(C(OC(C)(C)C)=O)C)C1=CC=CC=C1 Chemical compound OCCOC1=NC=CC=C1O[C@H](CCN(C(OC(C)(C)C)=O)C)C1=CC=CC=C1 SWYXZAMGOFKQRC-GOSISDBHSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000002500 Primary Ovarian Insufficiency Diseases 0.000 description 2
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 2
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
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- 230000015556 catabolic process Effects 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Natural products OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 2
- 230000019771 cognition Effects 0.000 description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 2
- 230000036757 core body temperature Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 229960003914 desipramine Drugs 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229960002866 duloxetine Drugs 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 206010016256 fatigue Diseases 0.000 description 2
- 229960002464 fluoxetine Drugs 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 206010022437 insomnia Diseases 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
- 230000003902 lesion Effects 0.000 description 2
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 2
- 229940024844 naloxone injection Drugs 0.000 description 2
- 230000031990 negative regulation of inflammatory response Effects 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 230000003959 neuroinflammation Effects 0.000 description 2
- 231100000189 neurotoxic Toxicity 0.000 description 2
- 230000002887 neurotoxic effect Effects 0.000 description 2
- 238000009206 nuclear medicine Methods 0.000 description 2
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- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
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- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Physics & Mathematics (AREA)
- Optics & Photonics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Applications Claiming Priority (3)
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| US201562135915P | 2015-03-20 | 2015-03-20 | |
| US62/135,915 | 2015-03-20 | ||
| PCT/US2016/023198 WO2016154027A1 (en) | 2015-03-20 | 2016-03-18 | Organic compounds |
Publications (1)
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| CA2978668A1 true CA2978668A1 (en) | 2016-09-29 |
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| CA2978668A Abandoned CA2978668A1 (en) | 2015-03-20 | 2016-03-18 | Organic compounds |
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| 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 |
| CN113195489A (zh) * | 2018-11-02 | 2021-07-30 | 埃斯特韦制药股份公司 | 用于治疗疼痛和疼痛相关病症的新的烷氧基氨基吡啶衍生物 |
| EP3873902A1 (en) * | 2018-11-02 | 2021-09-08 | Esteve Pharmaceuticals, S.A. | New tetrahydropyrimidodiazepin and tetrahydropyridodiazepin compounds for treating pain and pain related conditions |
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| EA200601798A1 (ru) * | 2004-04-30 | 2007-04-27 | Уорнер-Ламберт Компани Ллс | Замещенные соединения морфолина для лечения расстройств центральной нервной системы |
| WO2007010082A1 (en) * | 2005-07-15 | 2007-01-25 | Fermion Oy | Process for preparing a 3-aryloxy-3-arylpropylamine |
| CA2661187A1 (en) * | 2006-08-23 | 2008-02-28 | Pfizer Products Inc. | Piperidine derivatives |
| EP2161998B1 (en) * | 2007-06-04 | 2015-09-02 | Intra-Cellular Therapies, Inc. | Pyridine derivatives as NET/SERT modulators |
| WO2010120910A1 (en) * | 2009-04-15 | 2010-10-21 | Theravance, Inc. | 3-(phenoxypyrrolidin-3-yl-methyl)heteroaryl, 3-(phenylpyrrolidin-3-ylmethoxy)heteroaryl, and 3-(heteroarylpyrrolidin-3-ylmethoxy)heteroaryl compounds |
| US9352218B2 (en) | 2009-04-21 | 2016-05-31 | Nintendo Co., Ltd. | Game apparatus and computer-readable storage medium |
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2016
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- 2016-03-18 WO PCT/US2016/023198 patent/WO2016154027A1/en not_active Ceased
- 2016-03-18 CA CA2978668A patent/CA2978668A1/en not_active Abandoned
- 2016-03-18 BR BR112017020135A patent/BR112017020135A2/pt not_active Application Discontinuation
- 2016-03-18 KR KR1020177030305A patent/KR20170129906A/ko not_active Withdrawn
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| EP3270920B1 (en) | 2020-06-17 |
| BR112017020135A2 (pt) | 2018-05-29 |
| EP3270920A4 (en) | 2018-10-24 |
| RU2017134796A (ru) | 2019-04-04 |
| KR20170129906A (ko) | 2017-11-27 |
| ES2819833T3 (es) | 2021-04-19 |
| US20180099060A1 (en) | 2018-04-12 |
| WO2016154027A1 (en) | 2016-09-29 |
| MX2017012022A (es) | 2018-01-30 |
| JP2018508556A (ja) | 2018-03-29 |
| US10188758B2 (en) | 2019-01-29 |
| CN107405339A (zh) | 2017-11-28 |
| AU2016235483A1 (en) | 2017-10-12 |
| EP3270920A1 (en) | 2018-01-24 |
| JP6726200B2 (ja) | 2020-07-22 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |
Effective date: 20190319 |