CN101400350A - 用于治疗性功能障碍的血清素能活性剂 - Google Patents
用于治疗性功能障碍的血清素能活性剂 Download PDFInfo
- Publication number
- CN101400350A CN101400350A CNA2006800537941A CN200680053794A CN101400350A CN 101400350 A CN101400350 A CN 101400350A CN A2006800537941 A CNA2006800537941 A CN A2006800537941A CN 200680053794 A CN200680053794 A CN 200680053794A CN 101400350 A CN101400350 A CN 101400350A
- Authority
- CN
- China
- Prior art keywords
- chemical compound
- patient
- alkyl
- formula
- described method
- 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.)
- Pending
Links
- 201000001880 Sexual dysfunction Diseases 0.000 title claims abstract description 64
- 231100000872 sexual dysfunction Toxicity 0.000 title claims abstract description 64
- 239000003762 serotonin receptor affecting agent Substances 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 86
- 239000003814 drug Substances 0.000 claims abstract description 83
- 238000011282 treatment Methods 0.000 claims abstract description 59
- 229940079593 drug Drugs 0.000 claims abstract description 43
- 239000000203 mixture Substances 0.000 claims abstract description 15
- 239000002464 receptor antagonist Substances 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 175
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 104
- 125000000217 alkyl group Chemical group 0.000 claims description 80
- 150000003839 salts Chemical class 0.000 claims description 52
- 125000003118 aryl group Chemical group 0.000 claims description 45
- 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 claims description 38
- 239000002253 acid Substances 0.000 claims description 38
- 229960002464 fluoxetine Drugs 0.000 claims description 38
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 30
- 125000001072 heteroaryl group Chemical group 0.000 claims description 30
- 239000005557 antagonist Substances 0.000 claims description 26
- 230000001225 therapeutic effect Effects 0.000 claims description 26
- 239000000935 antidepressant agent Substances 0.000 claims description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 150000002367 halogens Chemical class 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 claims description 21
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 claims description 21
- -1 4Be hydrogen Chemical class 0.000 claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 230000000561 anti-psychotic effect Effects 0.000 claims description 17
- 229940125782 compound 2 Drugs 0.000 claims description 17
- 201000010099 disease Diseases 0.000 claims description 17
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 17
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
- 239000000556 agonist Substances 0.000 claims description 15
- 229940126214 compound 3 Drugs 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 238000002651 drug therapy Methods 0.000 claims description 14
- 239000001961 anticonvulsive agent Substances 0.000 claims description 13
- 150000002431 hydrogen Chemical class 0.000 claims description 13
- 238000010171 animal model Methods 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 229940125904 compound 1 Drugs 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 230000036299 sexual function Effects 0.000 claims description 10
- PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 claims description 8
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 7
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 7
- 229940123445 Tricyclic antidepressant Drugs 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 239000003029 tricyclic antidepressant agent Substances 0.000 claims description 7
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical group C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 230000001430 anti-depressive effect Effects 0.000 claims description 6
- 229940005513 antidepressants Drugs 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 208000010877 cognitive disease Diseases 0.000 claims description 6
- 229960003914 desipramine Drugs 0.000 claims description 6
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 claims description 6
- 229960001800 nefazodone Drugs 0.000 claims description 6
- VRBKIVRKKCLPHA-UHFFFAOYSA-N nefazodone Chemical compound O=C1N(CCOC=2C=CC=CC=2)C(CC)=NN1CCCN(CC1)CCN1C1=CC=CC(Cl)=C1 VRBKIVRKKCLPHA-UHFFFAOYSA-N 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 5
- 229940087098 Oxidase inhibitor Drugs 0.000 claims description 5
- 208000006011 Stroke Diseases 0.000 claims description 5
- 125000001118 alkylidene group Chemical group 0.000 claims description 5
- 125000002619 bicyclic group Chemical group 0.000 claims description 5
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 claims description 4
- GJJFMKBJSRMPLA-HIFRSBDPSA-N (1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenyl-1-cyclopropanecarboxamide Chemical compound C=1C=CC=CC=1[C@@]1(C(=O)N(CC)CC)C[C@@H]1CN GJJFMKBJSRMPLA-HIFRSBDPSA-N 0.000 claims description 4
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 claims description 4
- 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 claims description 4
- 206010003805 Autism Diseases 0.000 claims description 4
- 208000020706 Autistic disease Diseases 0.000 claims description 4
- GDLIGKIOYRNHDA-UHFFFAOYSA-N Clomipramine Chemical compound C1CC2=CC=C(Cl)C=C2N(CCCN(C)C)C2=CC=CC=C21 GDLIGKIOYRNHDA-UHFFFAOYSA-N 0.000 claims description 4
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 claims description 4
- 208000018737 Parkinson disease Diseases 0.000 claims description 4
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 claims description 4
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 claims description 4
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 4
- 229960001653 citalopram Drugs 0.000 claims description 4
- 229960004606 clomipramine Drugs 0.000 claims description 4
- 229960005426 doxepin Drugs 0.000 claims description 4
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 claims description 4
- 229960002866 duloxetine Drugs 0.000 claims description 4
- WSEQXVZVJXJVFP-FQEVSTJZSA-N escitalopram Chemical compound C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-FQEVSTJZSA-N 0.000 claims description 4
- 229960004341 escitalopram Drugs 0.000 claims description 4
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 claims description 4
- 229960004801 imipramine Drugs 0.000 claims description 4
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 claims description 4
- 230000001939 inductive effect Effects 0.000 claims description 4
- 238000002483 medication Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 229960000600 milnacipran Drugs 0.000 claims description 4
- 229960001158 nortriptyline Drugs 0.000 claims description 4
- 229960002296 paroxetine Drugs 0.000 claims description 4
- 229960003770 reboxetine Drugs 0.000 claims 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 claims description 4
- 229940076279 serotonin Drugs 0.000 claims description 4
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 claims description 4
- 229960002073 sertraline Drugs 0.000 claims description 4
- 229960004688 venlafaxine Drugs 0.000 claims description 4
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 claims description 4
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 3
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 claims description 3
- MPDHRNITJIUNDI-UHFFFAOYSA-N 10h-phenothiazine;piperazine Chemical compound C1CNCCN1.C1=CC=C2NC3=CC=CC=C3SC2=C1 MPDHRNITJIUNDI-UHFFFAOYSA-N 0.000 claims description 3
- NHFRGTVSKOPUBK-UHFFFAOYSA-N 4-phenylbutanal Chemical compound O=CCCCC1=CC=CC=C1 NHFRGTVSKOPUBK-UHFFFAOYSA-N 0.000 claims description 3
- PQJUJGAVDBINPI-UHFFFAOYSA-N 9H-thioxanthene Chemical compound C1=CC=C2CC3=CC=CC=C3SC2=C1 PQJUJGAVDBINPI-UHFFFAOYSA-N 0.000 claims description 3
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 claims description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 3
- 208000017701 Endocrine disease Diseases 0.000 claims description 3
- 201000004311 Gilles de la Tourette syndrome Diseases 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- RMUCZJUITONUFY-UHFFFAOYSA-N Phenelzine Chemical group NNCCC1=CC=CC=C1 RMUCZJUITONUFY-UHFFFAOYSA-N 0.000 claims description 3
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 claims description 3
- 206010041250 Social phobia Diseases 0.000 claims description 3
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 claims description 3
- 208000000323 Tourette Syndrome Diseases 0.000 claims description 3
- 208000016620 Tourette disease Diseases 0.000 claims description 3
- 206010046543 Urinary incontinence Diseases 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- 229960000836 amitriptyline Drugs 0.000 claims description 3
- 229960004372 aripiprazole Drugs 0.000 claims description 3
- 229960000623 carbamazepine Drugs 0.000 claims description 3
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 claims description 3
- 229960004170 clozapine Drugs 0.000 claims description 3
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 claims description 3
- 235000005911 diet Nutrition 0.000 claims description 3
- 230000037213 diet Effects 0.000 claims description 3
- 208000030172 endocrine system disease Diseases 0.000 claims description 3
- 229960003878 haloperidol Drugs 0.000 claims description 3
- 229960002715 nicotine Drugs 0.000 claims description 3
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims description 3
- 229960005017 olanzapine Drugs 0.000 claims description 3
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 claims description 3
- 229960000964 phenelzine Drugs 0.000 claims description 3
- 229960002695 phenobarbital Drugs 0.000 claims description 3
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 claims description 3
- 229950000688 phenothiazine Drugs 0.000 claims description 3
- 229960002036 phenytoin Drugs 0.000 claims description 3
- 229960003634 pimozide Drugs 0.000 claims description 3
- YVUQSNJEYSNKRX-UHFFFAOYSA-N pimozide Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCN1CCC(N2C(NC3=CC=CC=C32)=O)CC1 YVUQSNJEYSNKRX-UHFFFAOYSA-N 0.000 claims description 3
- 229960002393 primidone Drugs 0.000 claims description 3
- DQMZLTXERSFNPB-UHFFFAOYSA-N primidone Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NCNC1=O DQMZLTXERSFNPB-UHFFFAOYSA-N 0.000 claims description 3
- 229960002601 protriptyline Drugs 0.000 claims description 3
- BWPIARFWQZKAIA-UHFFFAOYSA-N protriptyline Chemical compound C1=CC2=CC=CC=C2C(CCCNC)C2=CC=CC=C21 BWPIARFWQZKAIA-UHFFFAOYSA-N 0.000 claims description 3
- 229960001534 risperidone Drugs 0.000 claims description 3
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 claims description 3
- 208000019116 sleep disease Diseases 0.000 claims description 3
- 208000020685 sleep-wake disease Diseases 0.000 claims description 3
- 230000028016 temperature homeostasis Effects 0.000 claims description 3
- 229960002431 trimipramine Drugs 0.000 claims description 3
- ZSCDBOWYZJWBIY-UHFFFAOYSA-N trimipramine Chemical compound C1CC2=CC=CC=C2N(CC(CN(C)C)C)C2=CC=CC=C21 ZSCDBOWYZJWBIY-UHFFFAOYSA-N 0.000 claims description 3
- 229960000607 ziprasidone Drugs 0.000 claims description 3
- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 claims description 3
- 206010013754 Drug withdrawal syndrome Diseases 0.000 claims description 2
- LFMYNZPAVPMEGP-PIDGMYBPSA-N Fluvoxamine maleate Chemical compound OC(=O)\C=C/C(O)=O.COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 LFMYNZPAVPMEGP-PIDGMYBPSA-N 0.000 claims description 2
- QWCRAEMEVRGPNT-UHFFFAOYSA-N buspirone Chemical compound C1C(=O)N(CCCCN2CCN(CC2)C=2N=CC=CN=2)C(=O)CC21CCCC2 QWCRAEMEVRGPNT-UHFFFAOYSA-N 0.000 claims description 2
- 229960002495 buspirone Drugs 0.000 claims description 2
- 230000009986 erectile function Effects 0.000 claims description 2
- 229960002107 fluvoxamine maleate Drugs 0.000 claims description 2
- 206010027175 memory impairment Diseases 0.000 claims description 2
- 229940044551 receptor antagonist Drugs 0.000 abstract description 5
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 abstract 1
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 abstract 1
- 241000700159 Rattus Species 0.000 description 27
- 238000012360 testing method Methods 0.000 description 20
- 241001465754 Metazoa Species 0.000 description 18
- 230000000694 effects Effects 0.000 description 18
- 238000007912 intraperitoneal administration Methods 0.000 description 11
- 239000000463 material Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 230000004064 dysfunction Effects 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- ASXGJMSKWNBENU-UHFFFAOYSA-N 8-OH-DPAT Chemical compound C1=CC(O)=C2CC(N(CCC)CCC)CCC2=C1 ASXGJMSKWNBENU-UHFFFAOYSA-N 0.000 description 7
- 230000007774 longterm Effects 0.000 description 7
- 230000003042 antagnostic effect Effects 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- IWFHOSULCAJGRM-UAKXSSHOSA-N 5-bromouridine 5'-triphosphate Chemical compound O1[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@@H](O)[C@@H]1N1C(=O)NC(=O)C(Br)=C1 IWFHOSULCAJGRM-UAKXSSHOSA-N 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 238000010586 diagram Methods 0.000 description 5
- 230000001568 sexual effect Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 102000012289 Corticotropin-Releasing Hormone Human genes 0.000 description 4
- 108010022152 Corticotropin-Releasing Hormone Proteins 0.000 description 4
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000006698 induction Effects 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 208000012201 sexual and gender identity disease Diseases 0.000 description 4
- 208000015891 sexual disease Diseases 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010012289 Dementia Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 102000009493 Neurokinin receptors Human genes 0.000 description 3
- 108050000302 Neurokinin receptors Proteins 0.000 description 3
- 230000006399 behavior Effects 0.000 description 3
- 230000008901 benefit Effects 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
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- QOIGKGMMAGJZNZ-UHFFFAOYSA-N gepirone Chemical compound O=C1CC(C)(C)CC(=O)N1CCCCN1CCN(C=2N=CC=CN=2)CC1 QOIGKGMMAGJZNZ-UHFFFAOYSA-N 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- YHXISWVBGDMDLQ-UHFFFAOYSA-N moclobemide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCCN1CCOCC1 YHXISWVBGDMDLQ-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 3
- 229960003946 selegiline Drugs 0.000 description 3
- 239000003772 serotonin uptake inhibitor Substances 0.000 description 3
- IGLYMJRIWWIQQE-QUOODJBBSA-N (1S,2R)-2-phenylcyclopropan-1-amine (1R,2S)-2-phenylcyclopropan-1-amine Chemical compound N[C@H]1C[C@@H]1C1=CC=CC=C1.N[C@@H]1C[C@H]1C1=CC=CC=C1 IGLYMJRIWWIQQE-QUOODJBBSA-N 0.000 description 2
- YWPHCCPCQOJSGZ-LLVKDONJSA-N (2r)-2-[(2-ethoxyphenoxy)methyl]morpholine Chemical compound CCOC1=CC=CC=C1OC[C@@H]1OCCNC1 YWPHCCPCQOJSGZ-LLVKDONJSA-N 0.000 description 2
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 description 2
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- BGRJTUBHPOOWDU-NSHDSACASA-N (S)-(-)-sulpiride Chemical compound CCN1CCC[C@H]1CNC(=O)C1=CC(S(N)(=O)=O)=CC=C1OC BGRJTUBHPOOWDU-NSHDSACASA-N 0.000 description 2
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 description 2
- DVNYTAVYBRSTGK-UHFFFAOYSA-N 5-aminoimidazole-4-carboxamide Chemical compound NC(=O)C=1N=CNC=1N DVNYTAVYBRSTGK-UHFFFAOYSA-N 0.000 description 2
- XKFPYPQQHFEXRZ-UHFFFAOYSA-N 5-methyl-N'-(phenylmethyl)-3-isoxazolecarbohydrazide Chemical compound O1C(C)=CC(C(=O)NNCC=2C=CC=CC=2)=N1 XKFPYPQQHFEXRZ-UHFFFAOYSA-N 0.000 description 2
- QYFHCFNBYQZGKW-BDQAORGHSA-N 8-[4-[[(3s)-5-methoxy-3,4-dihydro-2h-chromen-3-yl]-propylamino]butyl]-8-azaspiro[4.5]decane-7,9-dione;hydrochloride Chemical compound Cl.CCCN([C@H]1CC2=C(OC)C=CC=C2OC1)CCCCN(C(C1)=O)C(=O)CC21CCCC2 QYFHCFNBYQZGKW-BDQAORGHSA-N 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000019802 Sexually transmitted disease Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 2
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 229950000420 alnespirone Drugs 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229960002519 amoxapine Drugs 0.000 description 2
- QWGDMFLQWFTERH-UHFFFAOYSA-N amoxapine Chemical compound C12=CC(Cl)=CC=C2OC2=CC=CC=C2N=C1N1CCNCC1 QWGDMFLQWFTERH-UHFFFAOYSA-N 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 239000002249 anxiolytic agent Substances 0.000 description 2
- 230000000949 anxiolytic effect Effects 0.000 description 2
- 239000003693 atypical antipsychotic agent Substances 0.000 description 2
- 229940127236 atypical antipsychotics Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 208000015114 central nervous system disease Diseases 0.000 description 2
- 230000036461 convulsion Effects 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical group NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 description 2
- 229960004038 fluvoxamine Drugs 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 230000005714 functional activity Effects 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 229960000647 gepirone Drugs 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 229960002672 isocarboxazid Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229960004090 maprotiline Drugs 0.000 description 2
- QSLMDECMDJKHMQ-GSXCWMCISA-N maprotiline Chemical compound C12=CC=CC=C2[C@@]2(CCCNC)C3=CC=CC=C3[C@@H]1CC2 QSLMDECMDJKHMQ-GSXCWMCISA-N 0.000 description 2
- 229960001785 mirtazapine Drugs 0.000 description 2
- RONZAEMNMFQXRA-UHFFFAOYSA-N mirtazapine Chemical compound C1C2=CC=CN=C2N2CCN(C)CC2C2=CC=CC=C21 RONZAEMNMFQXRA-UHFFFAOYSA-N 0.000 description 2
- 229960004644 moclobemide Drugs 0.000 description 2
- 229950010911 orazamide Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000036632 reaction speed Effects 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 229960004425 sibutramine Drugs 0.000 description 2
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 2
- 238000003153 stable transfection Methods 0.000 description 2
- 239000008174 sterile solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229960004940 sulpiride Drugs 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 229960003741 tranylcypromine Drugs 0.000 description 2
- 229960003991 trazodone Drugs 0.000 description 2
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 2
- 229960001255 viloxazine Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- LHYMPSWMHXUWSK-STZFKDTASA-N (2z)-4-(3,4-dichlorophenyl)-2-[[2-(4-methylpiperazin-1-yl)phenyl]methylidene]thiomorpholin-3-one Chemical compound C1CN(C)CCN1C1=CC=CC=C1\C=C/1C(=O)N(C=2C=C(Cl)C(Cl)=CC=2)CCS\1 LHYMPSWMHXUWSK-STZFKDTASA-N 0.000 description 1
- JTVLYHXMPUSZIT-VKAVYKQESA-N (6z)-6-[butylamino-(2-chlorophenyl)methylidene]-4-chlorocyclohexa-2,4-dien-1-one Chemical compound C=1C=CC=C(Cl)C=1C(/NCCCC)=C1\C=C(Cl)C=CC1=O JTVLYHXMPUSZIT-VKAVYKQESA-N 0.000 description 1
- LDXQLWNPGRANTO-GOSISDBHSA-N (9r)-7-[[3,5-bis(trifluoromethyl)phenyl]methyl]-9-methyl-5-(4-methylphenyl)-8,9,10,11-tetrahydro-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-dione Chemical compound C([C@H](CN(CC=1C=C(C=C(C=1)C(F)(F)F)C(F)(F)F)C1=O)C)CN(C(C2=NC=CC=C22)=O)C1=C2C1=CC=C(C)C=C1 LDXQLWNPGRANTO-GOSISDBHSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- KOHIRBRYDXPAMZ-YHBROIRLSA-N (S,R,R,R)-nebivolol Chemical compound C1CC2=CC(F)=CC=C2O[C@H]1[C@H](O)CNC[C@@H](O)[C@H]1OC2=CC=C(F)C=C2CC1 KOHIRBRYDXPAMZ-YHBROIRLSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- KGSABFQIAANNPS-UHFFFAOYSA-N 1-(3-chlorophenyl)-3-(dimethylamino)-1-phenylpropan-2-ol Chemical compound C=1C=CC(Cl)=CC=1C(C(O)CN(C)C)C1=CC=CC=C1 KGSABFQIAANNPS-UHFFFAOYSA-N 0.000 description 1
- UXWBIYCPUVWKHP-KBPBESRZSA-N 1-[[(7s,9as)-2-pyrimidin-2-yl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-7-yl]methyl]pyrrolidine-2,5-dione Chemical compound O=C1CCC(=O)N1C[C@@H]1CN2CCN(C=3N=CC=CN=3)C[C@@H]2CC1 UXWBIYCPUVWKHP-KBPBESRZSA-N 0.000 description 1
- STDYWHYUOSSCBO-UHFFFAOYSA-N 2,3-dimethyl-4-phenyl-4,5-dihydro-1,3-benzodiazepine Chemical compound C1C2=CC=CC=C2N=C(C)N(C)C1C1=CC=CC=C1 STDYWHYUOSSCBO-UHFFFAOYSA-N 0.000 description 1
- GFGSZUNNBQXGMK-UHFFFAOYSA-N 2-chloro-4-nitrobenzamide Chemical compound NC(=O)C1=CC=C([N+]([O-])=O)C=C1Cl GFGSZUNNBQXGMK-UHFFFAOYSA-N 0.000 description 1
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 description 1
- IOWKRFFHXWDUIS-UHFFFAOYSA-N 2-phenylcyclopropane-1-carboxamide Chemical compound NC(=O)C1CC1C1=CC=CC=C1 IOWKRFFHXWDUIS-UHFFFAOYSA-N 0.000 description 1
- MVVJINIUPYKZHR-UHFFFAOYSA-N 3-[[4-[5-(methoxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenoxy]methyl]benzonitrile Chemical compound O=C1OC(COC)CN1C(C=C1)=CC=C1OCC1=CC=CC(C#N)=C1 MVVJINIUPYKZHR-UHFFFAOYSA-N 0.000 description 1
- NOIIUHRQUVNIDD-UHFFFAOYSA-N 3-[[oxo(pyridin-4-yl)methyl]hydrazo]-N-(phenylmethyl)propanamide Chemical compound C=1C=CC=CC=1CNC(=O)CCNNC(=O)C1=CC=NC=C1 NOIIUHRQUVNIDD-UHFFFAOYSA-N 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
- NDPOGPAZKKPOPV-UHFFFAOYSA-N 4-(4-ethylphenyl)piperidine Chemical compound C1=CC(CC)=CC=C1C1CCNCC1 NDPOGPAZKKPOPV-UHFFFAOYSA-N 0.000 description 1
- USEDMAWWQDFMFY-UHFFFAOYSA-N 4-cyanobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(C#N)C=C1 USEDMAWWQDFMFY-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- MXUNKHLAEDCYJL-UHFFFAOYSA-N 5-(hydroxymethyl)-3-(3-methylphenyl)-1,3-oxazolidin-2-one Chemical compound CC1=CC=CC(N2C(OC(CO)C2)=O)=C1 MXUNKHLAEDCYJL-UHFFFAOYSA-N 0.000 description 1
- QPGGEKPRGVJKQB-UHFFFAOYSA-N 5-[2-(dimethylamino)ethyl]-11-methyl-6-benzo[b][1,4]benzodiazepinone Chemical compound O=C1N(CCN(C)C)C2=CC=CC=C2N(C)C2=CC=CC=C21 QPGGEKPRGVJKQB-UHFFFAOYSA-N 0.000 description 1
- JICJBGPOMZQUBB-UHFFFAOYSA-N 7-[(3-chloro-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-yl)amino]heptanoic acid Chemical compound O=S1(=O)N(C)C2=CC=CC=C2C(NCCCCCCC(O)=O)C2=CC=C(Cl)C=C21 JICJBGPOMZQUBB-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 208000032841 Bulimia Diseases 0.000 description 1
- 206010006550 Bulimia nervosa Diseases 0.000 description 1
- SBPRIAGPYFYCRT-UHFFFAOYSA-N COc(cccc1)c1N1CCN(CCN(C(C2CCCCC2)=O)c2ncccc2)CC1 Chemical compound COc(cccc1)c1N1CCN(CCN(C(C2CCCCC2)=O)c2ncccc2)CC1 SBPRIAGPYFYCRT-UHFFFAOYSA-N 0.000 description 1
- OJRMFZGBJSJFPE-HSZRJFAPSA-N C[C@H](CN(C(C1CCCCC1)=O)c1ccccn1)N1CCC(CCc2cccc3c2cc[nH]3)CC1 Chemical compound C[C@H](CN(C(C1CCCCC1)=O)c1ccccn1)N1CCC(CCc2cccc3c2cc[nH]3)CC1 OJRMFZGBJSJFPE-HSZRJFAPSA-N 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 244000060011 Cocos nucifera Species 0.000 description 1
- 235000013162 Cocos nucifera Nutrition 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- SUZLHDUTVMZSEV-UHFFFAOYSA-N Deoxycoleonol Natural products C12C(=O)CC(C)(C=C)OC2(C)C(OC(=O)C)C(O)C2C1(C)C(O)CCC2(C)C SUZLHDUTVMZSEV-UHFFFAOYSA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- NMYAHEULKSYAPP-UHFFFAOYSA-N Eptapirone Chemical compound O=C1N(C)C(=O)C=NN1CCCCN1CCN(C=2N=CC=CN=2)CC1 NMYAHEULKSYAPP-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- PLDUPXSUYLZYBN-UHFFFAOYSA-N Fluphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 PLDUPXSUYLZYBN-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000011688 Generalised anxiety disease Diseases 0.000 description 1
- 235000017309 Hypericum perforatum Nutrition 0.000 description 1
- 244000141009 Hypericum perforatum Species 0.000 description 1
- MADRVGBADLFHMO-UHFFFAOYSA-N Indeloxazine Chemical compound C=1C=CC=2C=CCC=2C=1OCC1CNCCO1 MADRVGBADLFHMO-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010024419 Libido decreased Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 1
- UEQUQVLFIPOEMF-UHFFFAOYSA-N Mianserin Chemical compound C1C2=CC=CC=C2N2CCN(C)CC2C2=CC=CC=C21 UEQUQVLFIPOEMF-UHFFFAOYSA-N 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- KLPWJLBORRMFGK-UHFFFAOYSA-N Molindone Chemical compound O=C1C=2C(CC)=C(C)NC=2CCC1CN1CCOCC1 KLPWJLBORRMFGK-UHFFFAOYSA-N 0.000 description 1
- RSHMQGIMHQPMEB-IXOXFDKPSA-N Montirelin Chemical compound N1C(=O)[C@@H](C)SC[C@H]1C(=O)N[C@H](C(=O)N1[C@@H](CCC1)C(N)=O)CC1=CN=CN1 RSHMQGIMHQPMEB-IXOXFDKPSA-N 0.000 description 1
- JTAJFHGSVCEPKC-KUHUBIRLSA-N N,N-dimethyl-3-[(9S,10R)-10-methyl-2-(trifluoromethyl)-9,10-dihydroanthracen-9-yl]propan-1-amine Chemical compound FC(F)(F)C1=CC=C2[C@H](C)C3=CC=CC=C3[C@H](CCCN(C)C)C2=C1 JTAJFHGSVCEPKC-KUHUBIRLSA-N 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-UHFFFAOYSA-N N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine Chemical compound C=1C=CC=CC=1C(CCNC)OC1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-UHFFFAOYSA-N 0.000 description 1
- QSQQPMHPCBLLGX-UHFFFAOYSA-N N-methyl-4-[2-(phenylmethyl)phenoxy]-1-butanamine Chemical compound CNCCCCOC1=CC=CC=C1CC1=CC=CC=C1 QSQQPMHPCBLLGX-UHFFFAOYSA-N 0.000 description 1
- 241001229135 Nassa Species 0.000 description 1
- RGPDEAGGEXEMMM-UHFFFAOYSA-N Nefopam Chemical compound C12=CC=CC=C2CN(C)CCOC1C1=CC=CC=C1 RGPDEAGGEXEMMM-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 206010029897 Obsessive thoughts Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010033664 Panic attack Diseases 0.000 description 1
- RGCVKNLCSQQDEP-UHFFFAOYSA-N Perphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 RGCVKNLCSQQDEP-UHFFFAOYSA-N 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
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- KLBQZWRITKRQQV-UHFFFAOYSA-N Thioridazine Chemical compound C12=CC(SC)=CC=C2SC2=CC=CC=C2N1CCC1CCCCN1C KLBQZWRITKRQQV-UHFFFAOYSA-N 0.000 description 1
- GFBKORZTTCHDGY-UWVJOHFNSA-N Thiothixene Chemical compound C12=CC(S(=O)(=O)N(C)C)=CC=C2SC2=CC=CC=C2\C1=C\CCN1CCN(C)CC1 GFBKORZTTCHDGY-UWVJOHFNSA-N 0.000 description 1
- RUJBDQSFYCKFAA-UHFFFAOYSA-N Tofisopam Chemical compound N=1N=C(C)C(CC)C2=CC(OC)=C(OC)C=C2C=1C1=CC=C(OC)C(OC)=C1 RUJBDQSFYCKFAA-UHFFFAOYSA-N 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 206010047163 Vasospasm Diseases 0.000 description 1
- 206010048010 Withdrawal syndrome Diseases 0.000 description 1
- HLAFSNJRKZLMPT-UHFFFAOYSA-N [2-[2-(aminomethyl)phenyl]sulfanylphenyl]methanol Chemical compound NCC1=CC=CC=C1SC1=CC=CC=C1CO HLAFSNJRKZLMPT-UHFFFAOYSA-N 0.000 description 1
- WHDHEVMINMZADQ-UHFFFAOYSA-N [F].N1C=CC=C1 Chemical class [F].N1C=CC=C1 WHDHEVMINMZADQ-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- CGIHPACLZJDCBQ-UHFFFAOYSA-N acibenzolar Chemical compound SC(=O)C1=CC=CC2=C1SN=N2 CGIHPACLZJDCBQ-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- GJSLOMWRLALDCT-UHFFFAOYSA-N adinazolam Chemical compound C12=CC(Cl)=CC=C2N2C(CN(C)C)=NN=C2CN=C1C1=CC=CC=C1 GJSLOMWRLALDCT-UHFFFAOYSA-N 0.000 description 1
- 229960003148 adinazolam Drugs 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229960002629 agomelatine Drugs 0.000 description 1
- YJYPHIXNFHFHND-UHFFFAOYSA-N agomelatine Chemical compound C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 YJYPHIXNFHFHND-UHFFFAOYSA-N 0.000 description 1
- 229950009418 aklomide Drugs 0.000 description 1
- 108020004101 alpha-2 Adrenergic Receptor Proteins 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 102000015006 alpha2-adrenergic receptor activity proteins Human genes 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- NTJOBXMMWNYJFB-UHFFFAOYSA-N amisulpride Chemical compound CCN1CCCC1CNC(=O)C1=CC(S(=O)(=O)CC)=C(N)C=C1OC NTJOBXMMWNYJFB-UHFFFAOYSA-N 0.000 description 1
- 229940042749 amitriptyline / chlordiazepoxide Drugs 0.000 description 1
- 229960002980 amitriptyline oxide Drugs 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 description 1
- 230000037007 arousal Effects 0.000 description 1
- HSWPZIDYAHLZDD-UHFFFAOYSA-N atipamezole Chemical compound C1C2=CC=CC=C2CC1(CC)C1=CN=CN1 HSWPZIDYAHLZDD-UHFFFAOYSA-N 0.000 description 1
- 229960003002 atipamezole Drugs 0.000 description 1
- VHGCDTVCOLNTBX-QGZVFWFLSA-N atomoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=CC=C1C VHGCDTVCOLNTBX-QGZVFWFLSA-N 0.000 description 1
- 229960002430 atomoxetine Drugs 0.000 description 1
- KRNDIPHOJLIHRI-UHFFFAOYSA-N bazinaprine Chemical compound N#CC1=CC(C=2C=CC=CC=2)=NN=C1NCCN1CCOCC1 KRNDIPHOJLIHRI-UHFFFAOYSA-N 0.000 description 1
- 229950005683 bazinaprine Drugs 0.000 description 1
- SRIJFPBZWUFLFD-UHFFFAOYSA-N befuraline Chemical compound C=1C2=CC=CC=C2OC=1C(=O)N(CC1)CCN1CC1=CC=CC=C1 SRIJFPBZWUFLFD-UHFFFAOYSA-N 0.000 description 1
- 229950000159 befuraline Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004933 bifemelane Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- SXYFFMXPDDGOEK-UHFFFAOYSA-N binedaline Chemical compound C12=CC=CC=C2N(N(C)CCN(C)C)C=C1C1=CC=CC=C1 SXYFFMXPDDGOEK-UHFFFAOYSA-N 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229950009454 bipenamol Drugs 0.000 description 1
- 208000028683 bipolar I disease Diseases 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- WZXHSWVDAYOFPE-UHFFFAOYSA-N brofaromine Chemical compound C=1C2=CC(OC)=CC(Br)=C2OC=1C1CCNCC1 WZXHSWVDAYOFPE-UHFFFAOYSA-N 0.000 description 1
- 229950004068 brofaromine Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 150000001722 carbon compounds Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- KYCBWEZLKCTALM-UHFFFAOYSA-N caroxazone Chemical compound C1=CC=C2OC(=O)N(CC(=O)N)CC2=C1 KYCBWEZLKCTALM-UHFFFAOYSA-N 0.000 description 1
- 229950006044 caroxazone Drugs 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- LQXYCDLHSKICDY-UHFFFAOYSA-N cianopramine Chemical compound C1CC2=CC=C(C#N)C=C2N(CCCN(C)C)C2=CC=CC=C21 LQXYCDLHSKICDY-UHFFFAOYSA-N 0.000 description 1
- 229950001408 cianopramine Drugs 0.000 description 1
- 229950001660 cimoxatone Drugs 0.000 description 1
- 229950009328 clemeprol Drugs 0.000 description 1
- XXPVSQRPGBUFKM-SAPNQHFASA-N clovoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(Cl)C=C1 XXPVSQRPGBUFKM-SAPNQHFASA-N 0.000 description 1
- 229950002663 clovoxamine Drugs 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 230000001113 coital effect Effects 0.000 description 1
- OHCQJHSOBUTRHG-UHFFFAOYSA-N colforsin Natural products OC12C(=O)CC(C)(C=C)OC1(C)C(OC(=O)C)C(O)C1C2(C)C(O)CCC1(C)C OHCQJHSOBUTRHG-UHFFFAOYSA-N 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000002508 compound effect Effects 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000027326 copulation Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229950005551 dazepinil Drugs 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- 229950010189 demexiptiline Drugs 0.000 description 1
- SEDQWOMFMIJKCU-UHFFFAOYSA-N demexiptiline Chemical compound C1=CC2=CC=CC=C2C(=NOCCNC)C2=CC=CC=C21 SEDQWOMFMIJKCU-UHFFFAOYSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 229960003075 dibenzepin Drugs 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 229960001393 dosulepin Drugs 0.000 description 1
- 229960001104 droxidopa Drugs 0.000 description 1
- QXWYKJLNLSIPIN-SFYZADRCSA-N droxidopa Chemical compound OC(=O)[C@H](N)[C@@H](O)C1=CC=C(O)C(O)=C1 QXWYKJLNLSIPIN-SFYZADRCSA-N 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 229950007566 elzasonan Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 229950004233 enefexine Drugs 0.000 description 1
- 229950002850 eptapirone Drugs 0.000 description 1
- CDCHDCWJMGXXRH-UHFFFAOYSA-N estazolam Chemical compound C=1C(Cl)=CC=C(N2C=NN=C2CN=2)C=1C=2C1=CC=CC=C1 CDCHDCWJMGXXRH-UHFFFAOYSA-N 0.000 description 1
- 229960002336 estazolam Drugs 0.000 description 1
- 230000012173 estrus Effects 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- IZBNNCFOBMGTQX-UHFFFAOYSA-N etoperidone Chemical compound O=C1N(CC)C(CC)=NN1CCCN1CCN(C=2C=C(Cl)C=CC=2)CC1 IZBNNCFOBMGTQX-UHFFFAOYSA-N 0.000 description 1
- 229960005437 etoperidone Drugs 0.000 description 1
- OJSFTALXCYKKFQ-YLJYHZDGSA-N femoxetine Chemical compound C1=CC(OC)=CC=C1OC[C@@H]1[C@@H](C=2C=CC=CC=2)CCN(C)C1 OJSFTALXCYKKFQ-YLJYHZDGSA-N 0.000 description 1
- 229950003930 femoxetine Drugs 0.000 description 1
- 229950004395 fengabine Drugs 0.000 description 1
- NELSQLPTEWCHQW-UHFFFAOYSA-N fezolamine Chemical compound N=1N(CCCN(C)C)C=C(C=2C=CC=CC=2)C=1C1=CC=CC=C1 NELSQLPTEWCHQW-UHFFFAOYSA-N 0.000 description 1
- 229950000761 fezolamine Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229950006420 fluotracen Drugs 0.000 description 1
- 229940104076 fluoxetine / olanzapine Drugs 0.000 description 1
- 229960002690 fluphenazine Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 208000029364 generalized anxiety disease Diseases 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 235000015220 hamburgers Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000010376 human cloning Methods 0.000 description 1
- HPMRFMKYPGXPEP-UHFFFAOYSA-N idazoxan Chemical compound N1CCN=C1C1OC2=CC=CC=C2OC1 HPMRFMKYPGXPEP-UHFFFAOYSA-N 0.000 description 1
- 229950001476 idazoxan Drugs 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- SADQVAVFGNTEOD-UHFFFAOYSA-N indalpine Chemical compound C=1NC2=CC=CC=C2C=1CCC1CCNCC1 SADQVAVFGNTEOD-UHFFFAOYSA-N 0.000 description 1
- 229950002473 indalpine Drugs 0.000 description 1
- 229960004333 indeloxazine Drugs 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- PLIGPBGDXASWPX-UHFFFAOYSA-N iprindole Chemical compound C1CCCCCC2=C1N(CCCN(C)C)C1=CC=CC=C12 PLIGPBGDXASWPX-UHFFFAOYSA-N 0.000 description 1
- 229960002844 iprindole Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- FDXQKWSTUZCCTM-ZUIJCZDSSA-N levoprotiline Chemical compound C12=CC=CC=C2C2(C[C@@H](O)CNC)C3=CC=CC=C3C1CC2 FDXQKWSTUZCCTM-ZUIJCZDSSA-N 0.000 description 1
- 229950003041 levoprotiline Drugs 0.000 description 1
- 210000004558 lewy body Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229960001078 lithium Drugs 0.000 description 1
- MJJDYOLPMGIWND-UHFFFAOYSA-N litoxetine Chemical compound C=1C=C2C=CC=CC2=CC=1COC1CCNCC1 MJJDYOLPMGIWND-UHFFFAOYSA-N 0.000 description 1
- 229950004138 litoxetine Drugs 0.000 description 1
- SAPNXPWPAUFAJU-UHFFFAOYSA-N lofepramine Chemical compound C12=CC=CC=C2CCC2=CC=CC=C2N1CCCN(C)CC(=O)C1=CC=C(Cl)C=C1 SAPNXPWPAUFAJU-UHFFFAOYSA-N 0.000 description 1
- 229960002813 lofepramine Drugs 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- XJGVXQDUIWGIRW-UHFFFAOYSA-N loxapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2OC2=CC=C(Cl)C=C12 XJGVXQDUIWGIRW-UHFFFAOYSA-N 0.000 description 1
- 229960000423 loxapine Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000013011 mating Effects 0.000 description 1
- 229960003123 medifoxamine Drugs 0.000 description 1
- QNMGHBMGNRQPNL-UHFFFAOYSA-N medifoxamine Chemical compound C=1C=CC=CC=1OC(CN(C)C)OC1=CC=CC=C1 QNMGHBMGNRQPNL-UHFFFAOYSA-N 0.000 description 1
- 229960003987 melatonin Drugs 0.000 description 1
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 1
- SLVMESMUVMCQIY-UHFFFAOYSA-N mesoridazine Chemical compound CN1CCCCC1CCN1C2=CC(S(C)=O)=CC=C2SC2=CC=CC=C21 SLVMESMUVMCQIY-UHFFFAOYSA-N 0.000 description 1
- 229960000300 mesoridazine Drugs 0.000 description 1
- YXVZOBVWVRFPTE-UHFFFAOYSA-N metapramine Chemical compound CNC1CC2=CC=CC=C2N(C)C2=CC=CC=C12 YXVZOBVWVRFPTE-UHFFFAOYSA-N 0.000 description 1
- 229950006180 metapramine Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- GVXBHSBKKJRBMS-UHFFFAOYSA-N metralindole Chemical compound C1CN(C)C2=NCCC3=C2N1C1=CC=C(OC)C=C13 GVXBHSBKKJRBMS-UHFFFAOYSA-N 0.000 description 1
- 229950006787 metralindole Drugs 0.000 description 1
- 229960003955 mianserin Drugs 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- LDMWSLGGVTVJPG-UHFFFAOYSA-N minaprine Chemical compound CC1=CC(C=2C=CC=CC=2)=NN=C1NCCN1CCOCC1 LDMWSLGGVTVJPG-UHFFFAOYSA-N 0.000 description 1
- 229960004758 minaprine Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960004938 molindone Drugs 0.000 description 1
- 229950004759 montirelin Drugs 0.000 description 1
- 108700023195 montirelin Proteins 0.000 description 1
- NXLUTEDAEFXMQR-BJKOFHAPSA-N n-[(2r,4s)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(4-chlorophenyl)methyl]piperidin-4-yl]quinoline-4-carboxamide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C(=O)N2[C@@H](C[C@H](CC2)NC(=O)C=2C3=CC=CC=C3N=CC=2)CC=2C=CC(Cl)=CC=2)=C1 NXLUTEDAEFXMQR-BJKOFHAPSA-N 0.000 description 1
- XZOCIZHAHWDUPU-QWRGUYRKSA-N n-[(2s)-1-[(2s)-2-carbamoylpyrrolidin-1-yl]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]-2,4-dioxo-1h-pyrimidine-6-carboxamide Chemical compound NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)C=1NC(=O)NC(=O)C=1)CC1=CN=CN1 XZOCIZHAHWDUPU-QWRGUYRKSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 229960000619 nebivolol Drugs 0.000 description 1
- 229960000751 nefopam Drugs 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229960003057 nialamide Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960001073 nomifensine Drugs 0.000 description 1
- XXPANQJNYNUNES-UHFFFAOYSA-N nomifensine Chemical compound C12=CC=CC(N)=C2CN(C)CC1C1=CC=CC=C1 XXPANQJNYNUNES-UHFFFAOYSA-N 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 230000000966 norepinephrine reuptake Effects 0.000 description 1
- WIQRCHMSJFFONW-UHFFFAOYSA-N norfluoxetine Chemical compound C=1C=CC=CC=1C(CCN)OC1=CC=C(C(F)(F)F)C=C1 WIQRCHMSJFFONW-UHFFFAOYSA-N 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 230000031868 operant conditioning Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- QZYYPQAYSFBKPW-UHFFFAOYSA-N org 12962 Chemical compound N1=C(Cl)C(C(F)(F)F)=CC=C1N1CCNCC1 QZYYPQAYSFBKPW-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229950005403 orotirelin Drugs 0.000 description 1
- 108700031265 orotirelin Proteins 0.000 description 1
- DZOJBGLFWINFBF-UMSFTDKQSA-N osanetant Chemical compound C([C@](C1)(CCCN2CCC(CC2)(N(C(C)=O)C)C=2C=CC=CC=2)C=2C=C(Cl)C(Cl)=CC=2)CCN1C(=O)C1=CC=CC=C1 DZOJBGLFWINFBF-UMSFTDKQSA-N 0.000 description 1
- 229950009875 osanetant Drugs 0.000 description 1
- MEEQBDCQPIZMLY-HNNXBMFYSA-N osemozotan Chemical compound C1=C2OCOC2=CC(OCCCNC[C@@H]2OC3=CC=CC=C3OC2)=C1 MEEQBDCQPIZMLY-HNNXBMFYSA-N 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 229960002019 oxaflozane Drugs 0.000 description 1
- FVYUQFQCEOZYHZ-UHFFFAOYSA-N oxaflozane Chemical compound C1N(C(C)C)CCOC1C1=CC=CC(C(F)(F)F)=C1 FVYUQFQCEOZYHZ-UHFFFAOYSA-N 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 239000012057 packaged powder Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 210000003899 penis Anatomy 0.000 description 1
- 229960000762 perphenazine Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 229960002034 pinazepam Drugs 0.000 description 1
- MFZOSKPPVCIFMT-UHFFFAOYSA-N pinazepam Chemical compound C12=CC(Cl)=CC=C2N(CC#C)C(=O)CN=C1C1=CC=CC=C1 MFZOSKPPVCIFMT-UHFFFAOYSA-N 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- FIADGNVRKBPQEU-UHFFFAOYSA-N pizotifen Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CCC2=C1C=CS2 FIADGNVRKBPQEU-UHFFFAOYSA-N 0.000 description 1
- 229960004572 pizotifen Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229940071643 prefilled syringe Drugs 0.000 description 1
- 206010036596 premature ejaculation Diseases 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- ZTHJULTYCAQOIJ-WXXKFALUSA-N quetiapine fumarate Chemical compound [H+].[H+].[O-]C(=O)\C=C\C([O-])=O.C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12.C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 ZTHJULTYCAQOIJ-WXXKFALUSA-N 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- JUQLTPCYUFPYKE-UHFFFAOYSA-N ritanserin Chemical compound CC=1N=C2SC=CN2C(=O)C=1CCN(CC1)CCC1=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 JUQLTPCYUFPYKE-UHFFFAOYSA-N 0.000 description 1
- 229950009626 ritanserin Drugs 0.000 description 1
- MQTUXRKNJYPMCG-CYBMUJFWSA-N robalzotan Chemical compound C1CCC1N([C@H]1COC=2C(F)=CC=C(C=2C1)C(=O)N)C1CCC1 MQTUXRKNJYPMCG-CYBMUJFWSA-N 0.000 description 1
- 229950003023 robalzotan Drugs 0.000 description 1
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 1
- 229950005741 rolipram Drugs 0.000 description 1
- PGKXDIMONUAMFR-AREMUKBSSA-N saredutant Chemical compound C([C@H](CN(C)C(=O)C=1C=CC=CC=1)C=1C=C(Cl)C(Cl)=CC=1)CN(CC1)CCC1(NC(C)=O)C1=CC=CC=C1 PGKXDIMONUAMFR-AREMUKBSSA-N 0.000 description 1
- 229950004387 saredutant Drugs 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- FTKTZRKAVSDSRA-UHFFFAOYSA-N sercloremine Chemical compound C1CN(C)CCC1C1=CC2=CC(Cl)=CC=C2O1 FTKTZRKAVSDSRA-UHFFFAOYSA-N 0.000 description 1
- 229940035004 seroquel Drugs 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229950002275 setiptiline Drugs 0.000 description 1
- GVPIXRLYKVFFMK-UHFFFAOYSA-N setiptiline Chemical compound C12=CC=CC=C2CC2=CC=CC=C2C2=C1CN(C)CC2 GVPIXRLYKVFFMK-UHFFFAOYSA-N 0.000 description 1
- 238000012154 short term therapy Methods 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 229960003211 sulbutiamine Drugs 0.000 description 1
- CKHJPWQVLKHBIH-ZDSKVHJSSA-N sulbutiamine Chemical compound C=1N=C(C)N=C(N)C=1CN(C=O)C(/C)=C(/CCOC(=O)C(C)C)SS\C(CCOC(=O)C(C)C)=C(\C)N(C=O)CC1=CN=C(C)N=C1N CKHJPWQVLKHBIH-ZDSKVHJSSA-N 0.000 description 1
- 229950011106 sunepitron Drugs 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- OILWWIVKIDXCIB-UHFFFAOYSA-N teniloxazine Chemical compound C1NCCOC1COC1=CC=CC=C1CC1=CC=CS1 OILWWIVKIDXCIB-UHFFFAOYSA-N 0.000 description 1
- 229950003014 teniloxazine Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229960002784 thioridazine Drugs 0.000 description 1
- JJSHYECKYLDYAR-UHFFFAOYSA-N thozalinone Chemical compound O1C(N(C)C)=NC(=O)C1C1=CC=CC=C1 JJSHYECKYLDYAR-UHFFFAOYSA-N 0.000 description 1
- 229960005138 tianeptine Drugs 0.000 description 1
- 229950008817 tiflucarbine Drugs 0.000 description 1
- BNKIWXODDDABSJ-UHFFFAOYSA-N tiflucarbine Chemical compound N1C2=CC(F)=C3SC=C(C)C3=C2C2=C1CCN(CC)C2 BNKIWXODDDABSJ-UHFFFAOYSA-N 0.000 description 1
- 229960005013 tiotixene Drugs 0.000 description 1
- 229950010076 tofenacin Drugs 0.000 description 1
- PNYKGCPSFKLFKA-UHFFFAOYSA-N tofenacin Chemical compound C=1C=CC=C(C)C=1C(OCCNC)C1=CC=CC=C1 PNYKGCPSFKLFKA-UHFFFAOYSA-N 0.000 description 1
- 229960002501 tofisopam Drugs 0.000 description 1
- 229960002309 toloxatone Drugs 0.000 description 1
- PHTUQLWOUWZIMZ-GZTJUZNOSA-N trans-dothiepin Chemical compound C1SC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 PHTUQLWOUWZIMZ-GZTJUZNOSA-N 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- ZEWQUBUPAILYHI-UHFFFAOYSA-N trifluoperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 ZEWQUBUPAILYHI-UHFFFAOYSA-N 0.000 description 1
- 229960002324 trifluoperazine Drugs 0.000 description 1
- 229960001968 veralipride Drugs 0.000 description 1
- RYJXBGGBZJGVQF-UHFFFAOYSA-N veralipride Chemical compound COC1=CC(S(N)(=O)=O)=CC(C(=O)NCC2N(CCC2)CC=C)=C1OC RYJXBGGBZJGVQF-UHFFFAOYSA-N 0.000 description 1
- 229960003740 vilazodone Drugs 0.000 description 1
- UXDQRXUZPXSLJK-UHFFFAOYSA-N vilazodone Chemical compound C1=CC(C#N)=C[C]2C(CCCCN3CCN(CC3)C=3C=C4C=C(OC4=CC=3)C(=O)N)=CN=C21 UXDQRXUZPXSLJK-UHFFFAOYSA-N 0.000 description 1
- XFXANHWIBFMEOY-JKSUJKDBSA-N viqualine Chemical compound C12=CC(OC)=CC=C2N=CC=C1CCC[C@@H]1CCNC[C@@H]1C=C XFXANHWIBFMEOY-JKSUJKDBSA-N 0.000 description 1
- 229950006360 viqualine Drugs 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- OYPPVKRFBIWMSX-SXGWCWSVSA-N zimeldine Chemical compound C=1C=CN=CC=1C(=C/CN(C)C)\C1=CC=C(Br)C=C1 OYPPVKRFBIWMSX-SXGWCWSVSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- 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
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/32—Alcohol-abuse
-
- 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
- A61P25/34—Tobacco-abuse
-
- 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
- A61P25/36—Opioid-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Addiction (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Psychology (AREA)
- Endocrinology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cardiology (AREA)
- Hospice & Palliative Care (AREA)
- Anesthesiology (AREA)
- Hematology (AREA)
- Child & Adolescent Psychology (AREA)
- Reproductive Health (AREA)
- Nutrition Science (AREA)
- Urology & Nephrology (AREA)
- Obesity (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明提供了使用5-HT1A受体拮抗剂治疗性功能障碍例如与药物治疗有关的性功能障碍的方法和组合物。
Description
本专利申请是2006年1月11日提交的序列号为11/330907的共同待批专利申请的部分延续申请,而专利申请11/330907是2003年5月20日提交的序列号为10/441,536的专利申请的延续申请,而专利申请10/441,536是2002年8月14日提交的序列号为10/218,251的专利申请的延续申请,而专利申请10/218,251是2001年11月13日提交的序列号为10/010,575的专利申请的延续申请,而专利申请10/010,575要求2000年11月28日提交的序列号为60/253,301和2001年6月13日提交的序列号为60/297,814的临时专利申请的优先权,以上专利申请均全文引入本文作为参考。
发明领域
本发明涉及新的哌嗪衍生物用于治疗例如性功能障碍的用途以及含有它们的药物组合物。所述的新化合物可用作5-HT1A结合活性剂,特别是作为5-HT1A受体拮抗剂。
发明背景
性功能障碍与各种药物治疗有关,包括使用抗抑郁药物、抗精神病药物、抗惊厥药物进行的治疗。药物治疗表现出的该种作用是患者对药物治疗顺应性差的重要原因。因此,需要寻找可有效改善或预防与药物治疗有关的性功能障碍的化合物。
美国专利6,127,357公开了通式(I)的化合物及其可药用酸加成盐,其中:
A是具有2-4个碳原子的亚烷基链,其任选被一个或多个低级烷基基团取代,
Z是氧或硫,
R是H或低级烷基,
R1是单环或二环芳基或杂芳基基团,
R2是单环或二环杂芳基基团,且
R3是氢、低级烷基、环烷基、环烯基、环烷基(低级)烷基、芳基、芳基(低级)烷基、杂芳基、杂芳基(低级)烷基、式-NR4R5的基团[其中R4是氢、低级烷基、芳基或芳基(低级)烷基,且R5是氢、低级烷基、-CO(低级)烷基、芳基、-CO芳基、芳基(低级)烷基、环烷基或环烷基(低级)烷基,或R4和R5与其共同连接的氮原子一起形成饱和杂环,所述杂环可进一步含有其它杂原子],或者式OR6的基团[其中R6是低级烷基、环烷基、环烷基(低级)烷基、芳基、芳基(低级)烷基、杂芳基或杂芳基(低级)烷基]。
WO 97/03982公开了通式(II)的化合物,包括其对映体和可药用酸加成盐。
式(II)化合物包含在美国专利6,127,357所公开的范围内但却未在其中具体公开。其中教导式II化合物在口服施用时在体内具有很强的5-HT1A拮抗剂活性。
发明内容
已发现具有5-HT1A受体拮抗活性的化合物可用于治疗性功能障碍,例如与药物治疗例如使用抗抑郁药物、抗精神病药物或抗惊厥药物进行的治疗有关的性功能障碍。因此,本发明涉及一种在有需要的患者中治疗与药物治疗有关的性功能障碍的方法。所述方法包括向所述患者施用有效量的具有5-HT1A拮抗活性的化合物。在一些实施方案中,所述药物治疗是抗抑郁药物治疗、抗精神病药物治疗或抗惊厥药物治疗。所述化合物可以是式(I)化合物或其可药用酸加成盐,
其中
A是具有2-4个碳原子的亚烷基链,其任选被一个或多个低级烷基基团取代,
Z是氧或硫,
R是H或低级烷基,
R1是单环或二环芳基或杂芳基基团,
R2是单环或二环杂芳基基团,且
R3是氢、低级烷基、环烷基、环烯基、环烷基(低级)烷基、芳基、芳基(低级)烷基、杂芳基、杂芳基(低级)烷基、式-NR4R5的基团[其中R4是氢、低级烷基、芳基或芳基(低级)烷基,且R5是氢、低级烷基、-CO(低级)烷基、芳基、-CO芳基、芳基(低级)烷基、环烷基或环烷基(低级)烷基,或R4和R5与其共同连接的氮原子一起形成饱和杂环,所述杂环可进一步含有其它杂原子],或者式OR6的基团[其中R6是低级烷基、环烷基、环烷基(低级)烷基、芳基、芳基(低级)烷基、杂芳基或杂芳基(低级)烷基]。
在其它实施方案中,所述化合物是如本文所述的式(III)化合物或其可药用盐。在其它实施方案中,所述化合物是如本文所述的式(IV)化合物。
所述化合物可以是(R)-4-氰基-N-{2-[4-(2,3-二氢-苯并[1,4]二噁英-5-基)-哌嗪-1-基]丙基}-N-吡啶-2-基-苯甲酰胺或其可药用酸加成盐(实施例化合物1)、N-[2-[4-(2-甲氧基苯基)-1-哌嗪基]乙基]-N-(2-吡啶基)环己烷甲酰胺(实施例化合物2)或其可药用酸加成盐或(R)-N-(2-甲基-(4-吲哚基-1-哌嗪基)乙基)-N-(2-吡啶基)环己烷甲酰胺(实施例化合物3)或其可药用酸加成盐。
在某些实施方案中,所述的与性功能障碍有关的药物是选择性血清素再摄取抑制剂(SSRI)(例如氟西汀、西酞普兰、草酸依地普仑、马来酸氟伏沙明、帕罗西汀或舍曲林)、三环类抗抑郁药物(例如去甲丙米嗪、阿米替林、阿莫西平、氯米帕明、多塞平、丙米嗪、去甲替林、普罗替林或曲米帕明)、氨基酮类化合物(例如丁氨苯丙酮)。在一些实施方案中,所述药物是单胺氧化酶抑制剂(MAOI)(例如苯乙肼)、血清素和去甲肾上腺素再摄取抑制剂(SNRI)(例如文拉法辛、奈法唑酮、米那普仑、度洛西汀)、去甲肾上腺素再摄取抑制剂(NRI)(例如瑞波西汀)、部分5-HT1A激动剂(例如丁螺环酮)、5-HT2A受体拮抗剂(例如奈法唑酮)、典型抗精神病药物或非典型抗精神病药物。这种抗精神病药物的实例包括脂肪族吩噻嗪、哌嗪吩噻嗪、苯丁酮、取代的苯甲酰胺和硫代黄嘌呤。这种药物的其它实例包括氟哌啶醇、奥氮平、氯氮平、利培酮、匹莫齐特、阿立哌唑和齐拉西酮。在一些情况下,所述药物是抗惊厥药物,例如苯巴比妥、苯妥英、扑米酮或卡马西平。在一些情况下,需要治疗性功能障碍的患者正在接受抗抑郁药物、抗精神病药物或抗惊厥药物或其组合中至少两种药物的治疗。
在某些实施方案中,本发明包括口服递送用于治疗性功能障碍的化合物。所述化合物在一些情况下可以作为持续释放化合物的形式递送。在其它实施方案中,所述的性功能障碍包括阴茎勃起功能障碍。
本发明还涉及在有需要的患者中改善性功能的方法。所述方法包括向所述患者施用药学有效量的具有5-HT1A拮抗活性的化合物。在一些实施方案中,所述化合物是式(I)化合物或其可药用酸加成盐,
其中
A是具有2-4个碳原子的亚烷基链,其任选被一个或多个低级烷基基团取代,
Z是氧或硫,
R是H或低级烷基,
R1是单环或二环芳基或杂芳基基团,
R2是单环或二环杂芳基基团,且
R3是氢、低级烷基、环烷基、环烯基、环烷基(低级)烷基、芳基、芳基(低级)烷基、杂芳基、杂芳基(低级)烷基、式-NR4R5的基团[其中R4是氢、低级烷基、芳基或芳基(低级)烷基,且R5是氢、低级烷基、-CO(低级)烷基、芳基、-CO芳基、芳基(低级)烷基、环烷基或环烷基(低级)烷基,或R4和R5与其共同连接的氮原子一起形成饱和杂环,所述杂环可进一步含有其它杂原子],或者式OR6的基团[其中R6是低级烷基、环烷基、环烷基(低级)烷基、芳基、芳基(低级)烷基、杂芳基或杂芳基(低级)烷基];
或式(III)化合物或其可药用酸加成盐,
其中R1是氰基、硝基、三氟甲基或卤素;
或式(IV)化合物或其可药用酸加成盐,
其中Ra和Rb都是氢或甲基,且Rc是氢、卤素或C1-4烷基。在该方法的一些实施方案中,所述化合物是实施例化合物1、实施例化合物2或实施例化合物3。
本发明的另一方面涉及用于治疗与药物治疗有关的性功能障碍的药物组合物,所述组合物包含式(I)、式(III)或式(IV)的化合物。在一些实施方案中,所述药物是抗抑郁药物、抗精神病药物或抗惊厥药物。在其它实施方案中,所述化合物可在与药物治疗有关的性功能障碍动物模型例如抗抑郁药物诱导的性功能障碍模型中有效改善性功能障碍。
本发明的另一方面涉及药物包装,其中包含5-HT1A拮抗剂和说明书,其中说明书内容包括治疗性功能障碍的说明,例如说明书内容包括治疗与药物治疗有关的性功能障碍的说明。
本发明的另一方面涉及在有需要的患者中治疗记忆缺陷或认知障碍的方法;治疗酒精、尼古丁或药物停药症状的方法;治疗帕金森病或运动病症的方法;治疗偏头痛的方法;治疗饮食病症的方法;治疗性功能障碍的方法;治疗尿失禁的方法;治疗中风的方法;治疗内分泌病症的方法;治疗睡眠障碍的方法;治疗注意力缺陷障碍的方法;治疗儿童秽语综合征、自闭症、社交恐惧症、多动症或温度调节病症的方法;其包括向所述患者施用治疗有效量的式(III)化合物或其可药用酸加成盐:
其中R1是氰基、硝基、三氟甲基或卤素。
若非另外定义,本文使用的全部科技术语具有本发明所属技术领域技术人员通常理解的含义。虽然描述了适当的材料和方法,但也可以使用与本文所述材料方法相似或相当的材料和方法测试本发明。本文通过参考本文提及的全部出版物、专利申请、专利和其它参考文献的全文而引入这些参考文献。此外,所述材料、方法和实例仅仅是为了举例说明的目的,而无意限制本发明。
从发明详述、附图说明和权利要求书中可以看出本发明的其它特征和优点。
附图说明
图1描述在30分钟的试验期内,非接触性阴茎勃起次数的实验结果的柱状图,实验中使用性成熟的大鼠,大鼠接受14天的腹膜内(i.p.)注射载体(0.9%盐水)、丁氨苯丙酮(20mg/kg)、去甲丙米嗪(10mg/kg)或氟西汀(10mg/kg)。
图2描述在30分钟的试验期内,非接触性阴茎勃起次数的实验结果的柱状图,实验中使用性成熟的大鼠,大鼠接受6天的载体给药,在第七天接受氟西汀注射,共给药7天(中长期);或接受14天氟西汀给药(长期)。最后一次施用载体或含有药物的载体之后立即对动物进行测试。
图3描述在30分钟的试验期内,非接触性阴茎勃起次数的实验结果的柱状图,实验中使用性成熟的大鼠,大鼠接受载体本身(0.9%盐水)、N-[2-[4-(2-甲氧基苯基)-1-哌嗪基]乙基-N-(2-吡啶基)环己烷甲酰胺)(实施例化合物2)(短期或中长期)、氟西汀或实施例化合物2和氟西汀。给药组如下(图中从左至右):第一组=第1-6天载体,第7天单剂量的实施例化合物2;第二组=第1-7天实施例化合物2;第三组=第1-7天只接受载体;第四组=第1-7天氟西汀;第五组=第1-6天氟西汀,第7天实施例化合物2+氟西汀;第六组=第1-7天实施例化合物2+氟西汀。最后一次施用后立即对动物进行测试。药物和化合物在载体中递送。
图4描述在30分钟的试验期内,非接触性阴茎勃起次数的实验结果的柱状图,实验中使用性成熟的大鼠,大鼠接受如下处理(图中从左至右):第一组=第1-13天载体+第14天单次施用0.1mg/kg(R)-N-(2-甲基-(4-吲哚基-1-哌嗪基)乙基)-N-(2-吡啶基)环己烷甲酰胺(实施例化合物3);第二组=第1-13天载体+第14天单次急性施用1.0mg/kg实施例化合物3;第三组=第1-14天载体;第四组=第1-14天氟西汀;第五组=第1-13天只接受氟西汀+第14天单次施用0.1mg/kg实施例化合物3+氟西汀;第六组=第1-13天氟西汀+第14天单次施用1.0mg/kg实施例化合物3+氟西汀。在第14天最后一次施用后立即对动物进行测试。药物和化合物在载体中递送。
图5描述在30分钟的试验期内,非接触性阴茎勃起次数的实验结果的柱状图,实验中使用性成熟的大鼠,大鼠接受如下处理(图中从左至右):第一组=实施例化合物2共14天;第二组=实施例化合物3共14天;第三组=载体共14天;第四组=氟西汀共14天;第五组=实施例化合物2+氟西汀共14天;第六组=实施例化合物3+氟西汀共14天。最后一次施用后立即对动物进行测试。药物和化合物在载体中递送。
图6是实施例化合物1、实施例化合物2和实施例化合物3的化学结构。
发明详述
本发明的新化合物具有式(III)的结构:
其中R1是氰基、硝基、三氟甲基或卤素,或其可药用酸加成盐。
本文使用的卤素是指氯、氟、溴和碘。
式(III)化合物含有不对称碳原子。因此,它们可以以不同的立体异构体形式存在。在一些实施方案中,使用具有式(IIIa)结构的(R)异构体。
根据本发明的一些实施方案,(R)立体异构体基本不含(S)异构体。本文使用的“基本不含”是指所述化合物的组成中(R)异构体的比例显著高于(S)异构体。在一些实施方案中,所述化合物含有至少约90重量%的(R)异构体和约10重量%或更低的(S)异构体。在本发明的其它实施方案中,所述化合物含有至少约99重量%的(S)异构体和约1重量%或更低的(R)异构体。在一些情况下,立体异构体可以根据本领域技术人员已知的任何方法,包括高效液相色谱法(HPLC)、形成手性盐并结晶的方法从外消旋混合物中分离出来。参见例如Jacques等,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981);Wilen,S.H.等,Tetrahedron 33:2725(1977);Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962);Wilen,S.H.Tables of Resolving Agents and Optical Resolutionsp.268(E.L.Eliel,编,Univ.of Notre Dame Press,Notre Dame,IN1972)。
可用于治疗性功能障碍例如与药物使用例如抗抑郁药物、抗精神病药物或抗惊厥药物有关的性功能障碍的化合物的实例包括美国专利6,127,357中公开的化合物(式(I)化合物);WO 95/33725中公开的化合物;WO 95/33743中公开的化合物例如式(IV)的化合物或其可药用酸加成盐,
其中Ra和Rb都是氢或甲基,且Rc是氢、卤素或C1-4烷基,以及本文公开的化合物。
有用的化合物是具有5-HT1A拮抗活性并可抑制或预防性功能障碍(例如使用药物诱导的性功能障碍动物模型可以证明)的化合物。可用于本发明的化合物的非限制性实例有(R)-4-氰基-N-{2-[4-(2,3-二氢-苯并[1,4]二噁英-5-基)-哌嗪-1-基]丙基}-N-吡啶-2-基-苯甲酰胺及其可药用酸加成盐(实施例化合物1)、N-[2-[4-(2-甲氧基苯基)-1-哌嗪基]乙基]-N-(2-吡啶基)环己烷甲酰胺(实施例化合物2)及其可药用酸加成盐和(R)-N-(2-甲基-(4-吲哚基-1-哌嗪基)乙基)-N-(2-吡啶基)环己烷甲酰胺(实施例化合物3)及其可药用酸加成盐(图6)。
可药用盐通常是酸加成盐,本文所述通式的化合物与可药用酸例如苯甲酸、磷酸、硫酸、盐酸、氢溴酸、柠檬酸、马来酸、苹果酸、扁桃酸、粘酸、硝酸、富马酸、琥珀酸、酒石酸、乙酸、乳酸、巴莫酸、泛酸、苯磺酸或甲磺酸形成所述酸加成盐。在本发明的一些实施方案中,所述酸加成盐是盐酸盐。可以使用本领域技术人员已知的其它可药用盐。
本发明的化合物可以根据已知的方法从可以根据常规方法获得的已知原料来制备。例如所述化合物可以通过EP-A-0512755和WO 97/03982中公开的一般方法制备。
该公开的方法包括,将式(IV)的胺用已知的苯甲酰氯(V)或它的其它酰化衍生物进行酰化。酰化衍生物的实例包括酸酐、咪唑酰胺(例如从羰基二咪唑获得的咪唑酰胺)或活化酯。
其中R1是氰基、卤素、三氟甲基或硝基。
本发明的新化合物是与5-HT1A受体选择性结合的5-HT1A结合活性剂。此外,根据标准药理学方法测试时,本发明的新化合物是5-HT1A拮抗剂。
此外,式(III)的新化合物与之前公开的5-HT1A受体拮抗剂的不同之处在于它们体内施用时作为5-HT1A受体拮抗剂的作用格外持久。
实施例
通过参考以下的实施例和其它信息举例说明本发明。实验实施例仅仅为了举例说明的目的,而不应理解为其以任何方式限制本发明的范围或内容。有机合成领域的技术人员可能知道其它可用于合成本发明化合物的路线。本文使用的试剂和中间体或者可商购获得或者可以根据标准文献方法制备。
以下描述用于测试本发明化合物对于性功能障碍的作用的方法。这种方法可用于鉴别可有效治疗性功能障碍的5-HT1A拮抗剂(5-HT1A受体拮抗剂)。用于测试化合物对性功能障碍的作用的其它方法是本领域已知的,包括例如配对交配观察(例如驾乘、尝试驾乘、性交、驾乘频率、射精、驾乘并性交、射精潜伏期、性交频率、交尾效率、嗅外阴或射精后间隔)或阴茎勃起分析(例如测定阴茎海绵体血压或观察无性经验的雄性大鼠中非接触性阴茎勃起次数)。
实施例1
(R)-4-氰基-N-{2-[4-(2,3-二氢-苯并[1,4]二噁英-5-基)-哌嗪-1-基]-丙基}-N-吡啶-2-基-苯甲酰胺(实施例化合物1)
在0℃下向{(R)-2-[4-(2,3-二氢苯并[1,4]二噁英-5-基)哌嗪-1-基]丙基}-吡啶-2-基胺(0.846g,2.38mmol)在二氯甲烷(20mL)中的溶液中滴入4-氰基苯甲酰氯在二氯甲烷中的溶液(1.1当量,2.63mmol在5mL中)。搅拌16小时后,将混合物倾入己烷(100mL)中使标题化合物沉淀,为其一盐酸盐(白色固体,1.2g,97%收率),将其从二氯甲烷/己烷中重结晶。
MS(+)484(M+H)+
m.p.239-240℃
[α]25/D=+56(c=0.6,MeOH)
元素分析:C28H29N5O3·1.0HCl
计算值:C,64.67;H,5.81;N,13.47:
实测值:C,64.69;H,5.93;N,13.52:
为证明式(III)化合物作用时间长的优点,将实施例1与美国专利6,127,357和WO 97/03892中的代表性化合物比较。
美国专利6,127,357中的代表性化合物具有环己基酰胺基团和2-甲氧基苯基哌嗪基团。该通式结构中最有效的实例(也是美国专利6,127,357中教导的最有效的化合物)是化合物A,在美国专利6,127,357中被描述为“实施例3”。美国专利6,127,357中给出数据的唯一其它类别的化合物是具有环己基酰胺和苯并二噁英基哌嗪基团的化合物(美国专利6,127,357中的“实施例17”)。WO97/03892中特别要求保护该类化合物的一个小的子集,优选的化合物为化合物B(WO97/03892中的“实施例A1”)。因此,EP-A-0512755和WO 97/03892中两个优选的实施例被选作与式(III)化合物进行比较的代表性化合物。
化合物A 化合物B
(US6,127,357中的“实施例3”)(WO97/03892中的“实施例A1”)实施例2结合特征
测试化合物与稳定转染于CHO细胞的克隆人5-HT1A受体的结合情况,使用[3H]8-OH-DPAT作为5-HT1A放射性配体(根据J.Dunlop等,J.Pharmacol.Tox.Methods,40,47-55(1998)中所述的一般方法)。如表1所示,本发明的化合物与5-HT1A具有高亲和力。
实施例3体外功能活性
将用人5-HT1A受体稳定转染的克隆细胞系用于测定化合物的内在活性(根据J.Dunlop等,J.Pharmacol.Tox.Methods,40,47-55(1998)中所述的一般方法)。数据见表1。如表1所示,本发明的化合物以浓度相关的方式拮抗10nM8-OH-DPAT对毛喉素刺激cAMP生成的抑制作用。
表1
化合物 | 5-HT1A亲和力Ki(nM) | 5-HT1A拮抗活性cAMP分析IC50(nM) |
实施例1 | 1.6 | 25 |
化合物A | 0.96 | 7 |
化合物B | 0.97 | 20 |
实施例4体内功能活性
在大鼠中使用固定反应模型(D.Blackman,“Operant Conditioning:An Experimental Analysis of Behavior”,J.Butcher编,Methuen and Co.,Ltd.,London)评价本发明化合物作为5-HT1A拮抗剂在体内的功能。在该模型中,训练大鼠使之对固定比例30个时程内出现的食物作出反应以获得一块食物的奖励。施用5-HT1A激动剂8-OH-DPAT降低对照反应速率(通过施用载体安慰剂来评价)。通过测定受试化合物对激动剂诱导的反应速率下降的拮抗能力来测定受试化合物的拮抗活性。若受试化合物使激动剂诱导的反应速率完全逆转,使其回到对照水平,则其具有完全拮抗作用。表2数据表明剂量为1mg/kg的实施例1的化合物使施用0.3mg/kg剂量的8-OH-DPAT诱导的反应速率的下降完全逆转。因此,本发明的化合物在体内作为5-HT1A拮抗剂发挥作用。
表2
实施例5体内作用时间
在固定反应模型中,通过预先向动物施用受试化合物然后在施用后不同时间间隔给予0.3mg/kg剂量的5-HT1A激动剂8-OH-DPAT来评估作用持续时间。所有药物和载体均通过皮下途径施用。被选出进行比较的受试化合物剂量为在施用激动剂30分钟之前施用时,使8-OH-DPAT的剂量反应曲线发生10倍平移的剂量。被选出用于比较作用时间的剂量见表3。
表3
给出在施用0.3mg/kg剂量的8-OH-DPAT之前半小时、2小时和4小时预先给予动物受试化合物的数据。将结果以对照值标准化,其中100%是施用载体而不施用激动剂8-OH-DPAT时观察到的对照反应速率。
表4
如表4所示,施用30分钟后,全部三种受试化合物(化合物A、B和实施例化合物1)对激动剂诱导的反应速率下降均有完全的拮抗效果,使反应速率降至对照水平。但是,当施用受试化合物后2小时再施用激动剂时(第三列),化合物A和B的5-HT1A拮抗效果不能再使反应速率降至对照水平,而实施例化合物1仍然显示出完全的5-HT1A拮抗效果。在施用4小时后(第四列),化合物A和B完全丧失了5-HT1A拮抗作用,而实施例化合物1对激动剂诱导的反应速率下降仍保持着完全的拮抗作用。因此,实施例化合物1的作用时间长于4小时,而化合物A和B的作用时间在30分钟与2小时之间。
与美国专利6,127,357和WO 97/03892中公开的这些类别的化合物相比,本发明的新化合物作用时间延长这一点的特别优势在于可以施用较少剂量的本发明化合物来产生相似的治疗效果。
本发明的化合物可用于治疗罹患CNS病症的个体,所述CNS病症例如精神分裂症(以及其它精神病症例如偏执症和躁狂抑郁症)、帕金森病和其它运动病症、焦虑症(例如广泛性焦虑症、惊恐发作、强迫症)、抑郁症(例如通过增强血清素再摄取抑制剂和血清素去甲肾上腺素再摄取抑制剂的作用)、儿童秽语综合征、偏头痛、自闭症、注意力缺陷障碍和多动症。本发明的化合物还可用于治疗睡眠障碍、社交恐惧症、疼痛、温度调节病症、内分泌病症、尿失禁、血管痉挛、中风、饮食病症例如肥胖症、厌食症、易饿症、性功能障碍和治疗酒精、药物和尼古丁停药综合征。
本发明化合物、包括本文公开的化合物和美国专利6,127,357和WO95/33743中公开的化合物可用于治疗性功能障碍,例如与药物治疗有关的性功能障碍。性功能障碍可以发生在雄性或雌性个体中。该病症可包括勃起功能障碍以及性唤起障碍、性需求障碍、性欲低下、性欲下降、性高潮缺失病症、延迟射精、早泄、性焦虑病症、性疼痛病症、性反感病症。原因可能不明,或者可以由已知的原因引起,例如与毒品有关的性功能障碍。
如本文所述的与本文可以治疗的性功能障碍有关的药物包括抗抑郁药物。这种抗抑郁药物包括例如血清素再摄取抑制剂(SRI)、去甲肾上腺素再摄取抑制剂(NRI)、血清素去甲肾上腺素再摄取联合抑制剂(SNRI)、单胺氧化酶抑制剂(MAOI)、可逆性单胺氧化酶抑制剂(RIMA)、磷酸二酯酶-4(PDE4)抑制剂、促肾上腺皮质激素释放因子(CRF)拮抗剂(例如国际专利说明书WO 94/13643、WO 94/13644、WO 94/13661、WO 94/13676和WO94/13677中所述化合物)、α-肾上腺素受体拮抗剂、非典型抗抑郁药物(例如丁氨苯丙酮、锂、奈法唑酮、曲唑酮、维洛沙秦及其可药用盐,以及西布曲明)。这种抗抑郁药物的其它实例包括三重摄取抑制剂例如DOV 216303和DOV 2194;褪黑激素激动剂例如阿戈美拉汀、超级神经递质摄取阻断剂(SNUB;例如格兰素史克和Neurosearch的NS-2389;Sepracor的(R)-DDMA)、P物质/神经激肽受体拮抗剂(例如默克的阿瑞匹坦/MK-869;诺华的NKP-608;辉瑞的CPI-122721;罗氏的R673;Takeda的TAK637和格兰素史克的GW-97599)。
如本文所述的与本文可以治疗的性功能障碍有关的另一类抗抑郁药物是去甲肾上腺素能和特异性血清素能抗抑郁药物(NaSSA)。NRI的实例包括三环类叔胺和三环类仲胺。三环类叔胺的具体实例包括但不限于阿米替林、氯米帕明、多塞平、丙米嗪和曲米帕明及其可药用盐。三环类仲胺的适当实例包括但不限于阿莫沙平、去甲丙米嗪、马普替林、去甲替林和普罗替林及其可药用盐。可能与性功能障碍有关的另一类NRI是瑞波西汀(2-[α-(2-乙氧基)苯氧基-苄基]吗啉),其通常以外消旋形式施用。
如本文所述的与本文可以治疗的性功能障碍有关的SSRI可能包括但不限于西酞普兰(1-[3-(二甲基氨基)丙基]-(4-氟苯基)-1,3-二氢-5-异苯并呋喃甲腈;以盐酸盐形式和两种异构体的外消旋体形式上市的氟西汀(N-甲基-3-(对三氟甲基苯氧基)-3-苯基丙胺;氟西汀/奥氮平组合;氟伏沙明(5-甲氧基-1-[4-(三氟甲基)苯基]-1-戊酮O-(2-氨基乙基)肟;帕罗西汀(反式-(-)-3-[(1,3-苯并二氧杂戊烷-5-基氧基)甲基]-4-(4-氟苯基)哌啶);舍曲林(1S-顺式)-4-(3,4-二氯苯基)-1,2,3,4-四氢-N-甲基-1-萘基胺盐酸盐;依他普仑;新的5HT1A激动剂瓦利扎(variza)、阿奈螺酮、吉哌隆、苏尼匹酮(sunepitron)、MKC242、维拉唑酮(vilazodone)、依他匹酮(eptapirone)和Organon的ORG12962及其可药用盐。
与可以通过本文所述方法和化合物治疗的性功能障碍有关的MAOI包括但不限于异卡波肼、苯乙肼、司来吉兰和反苯环丙胺及其可药用盐。与性功能障碍有关的可逆性MAOI可能包括但不限于吗氯贝胺(4-氯-N-[2-(4-吗啉基)-乙基]苯甲酰胺;司来吉兰及其可药用盐。
与可以如本文所述治疗的性功能障碍有关的SNRI包括但不限于文拉法辛及其可药用盐和类似物,包括O-去甲基文拉法辛琥珀酸盐;米那普仑(N,N-二乙基-2-氨基甲基-1-苯基环丙烷甲酰胺;米氮平;奈法唑酮;度洛西汀及其可药用盐。
与可以通过本文所述方法和化合物治疗的性功能障碍有关的具体抗抑郁药物包括但不限于阿地唑仑、阿克洛胺、阿奈螺酮、安咪奈丁、阿米替林、阿米替林/氯氮卓组合、阿莫沙平、阿瑞匹坦、阿替美唑、米塔扎平、巴嗪普令、苯呋拉林、二苯美伦、宾诺达林(binodaline)、比培那醇、溴法罗明、丁氨苯丙酮、卡罗沙酮、西文氯胺、氰帕明、西莫沙酮、西酞普兰、氯美醇、氯米帕明、氯伏胺、氮卓尼尔、地阿诺、地美替林、去甲丙米嗪、O-去甲基文拉法辛、二苯西平、二苯噻庚英、多塞平、屈昔多巴、度洛西汀、依拉松喃(elzasonan)、乙非辛、依他匹酮、依他普仑、艾司唑仑、依托哌酮、非莫西汀、酚加宾、非唑拉明、氟曲辛、氟西汀、氟伏沙明、吉哌隆、咪唑克生、丙米嗪、吲达品、茚洛秦、伊普吲哚、异卡波肼、左丙替林、利托西汀、洛非帕明、马普替林、美地沙明、美他帕明、美曲吲哚、米安色林、米那普仑、米那普令、米氮平、吗氯贝胺、孟替瑞林、奈必洛尔、奈福泮、尼氟唑丁(nefozodine)、尼米替太(nemititide)、尼亚拉胺、诺米芬辛、去甲氟西汀、去甲替林、奥替瑞林、奥沙氟生、帕罗西汀、Pheneizine、匹那西泮、匹尔啉酮(pirlindone)、苯噻啶、Protryptiline、瑞波西汀、利坦色林、罗巴唑坦(robalzotan)、咯利普兰、司来吉兰、Sercloremine、舍曲林、司普替林、西布曲明、舒布硫胺、舒必利、苏尼匹酮、替尼沙秦、托扎啉酮、Thymoliberin、噻奈普汀、替氟卡宾、托芬那辛、托非索泮、托洛沙酮、托莫西汀、反苯环丙胺、曲唑酮、Trimiprimine、文拉法辛、维拉必利、维拉唑酮、维洛沙秦、维喹啉、齐美利定和Zometrapine及其可药用盐,以及贯叶连翘(St.John′s wort herb)或Hypencuin perforatum或其提取物。
在一些情况下,抗焦虑药物与可以通过本文所述方法和化合物治疗的性功能障碍有关。这种抗焦虑药物可包括但不限于神经激肽受体(NK)拮抗剂(例如沙瑞度坦和奥沙奈坦)和促肾上腺皮质激素释放因子(CRF)拮抗剂。
抗精神病药物也与可以用本文所述的5-HT1A拮抗剂治疗的性功能障碍有关。这种药物包括但不限于典型抗精神病药物或非典型抗精神病药物例如脂肪族吩噻嗪、哌嗪吩噻嗪、苯丁酮、取代的苯甲酰胺或硫代黄嘌呤。这种药物的其它实例包括阿米舒必利(amisulpiride)、阿立哌唑、氯丙嗪、氯氮平、氟奋乃静、氟哌啶醇、洛沙平、美索达嗪、吗茚酮、奥氮平、奋乃静、匹莫齐特、奎硫平、利培酮、思瑞康、舒必利、硫利达嗪、替沃噻吨、三氟拉嗪、齐拉西酮和(S)-2-(苄基氨基-甲基)-2,3,8,9-四氢-7H-1,4-二噁英并[2,3-e]吲哚-8-酮、美国专利5,756,532中公开的D2部分激动剂;或其可药用盐。
5-HT1A受体拮抗剂也可在进行多个药物组合例如一种或多种抗抑郁药物和抗精神病药物组合治疗的患者中用于治疗性功能障碍。抗惊厥治疗也与本文公开的化合物可以治疗的性功能障碍有关。与性功能障碍有关的抗惊厥药物的实例包括苯巴比妥、苯妥英、扑米酮和卡马西平。
本发明化合物也可用于治疗认知功能障碍。因此,本发明化合物可用于治疗与轻度认知损伤(MCI)有关的认知功能障碍、阿尔茨海默病和其它痴呆包括路易体痴呆、血管性痴呆和中风后痴呆。与手术过程、创伤性脑损伤或中风有关的认知功能障碍也可以根据本发明进行治疗。此外,本发明的化合物可用于治疗其中认知功能障碍属于共发性病症的疾病例如帕金森病、自闭症和注意力缺陷障碍。
本文在提及提供本发明范围内的化合物或物质时,“提供”是指直接施用这种化合物或物质或者施用在体内可以形成等量所述化合物或物质的前药、衍生物或类似物。前药的制备请参见Design of Prodrugs,Bundgaard,H.编,(Elsevier,New York 1985);Prodrugs as Novel Drug Delivery Systems,Higuchi,T和Stella,V.编,(American Chemical Society,Washington,D.C.1975);Design of Biopharmaceutical Properties through Prodrugs andAnalogs,Roche,E.编,(American Pharmaceutical Association Academy ofPharmaceutical Sciences,Washington,D.C,1977);和MetabolicConsiderations in Prodrug Design,Balant,L.P.和Doelker,E.,Burger′sMedicinal Chemistry amd Drug Discovery。第5版,Wolff,M.编,第1卷,949-982页,(John Wiley & Sons,Inc.1995)。
本文所述的化合物可用于制备用于治疗性障碍的药物,例如所述性障碍为与使用药物例如抗抑郁药物、抗精神病药物、抗惊厥药物或一种或多种这种药物的组合有关的性障碍。
本发明化合物可以口服施用或经胃肠外途径施用,直接施用或与常规药物载体一起施用。可以应用的固体载体可包括一种或多种也可充当矫味剂、润滑剂、助溶剂、助混剂、填充剂、助流剂、压缩助剂、粘合剂、片剂崩解剂或包囊物质的物质。在散剂中,载体是与细研的活性成分一起混合的细研的固体。在片剂中,活性成分与具有必要压制性质的载体以适当的比例混合并压制为期望的形状和大小。散剂和片剂可以含有最多99%的活性成分。合适的固体载体包括例如但不限于磷酸钙、硬脂酸镁、滑石、糖、乳糖、糊精、淀粉、明胶、纤维素、甲基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮、低熔点蜡和离子交换树脂。液体载体可用于制备溶液剂、混悬剂、乳剂、糖浆剂和酏剂。本发明的活性成分可以溶于或混悬于可药用液体载体例如水、有机溶剂、两者的混合物或可药用油或脂肪中。所述液体载体可以含有其它合适的药学添加剂例如助溶剂、乳化剂、缓冲剂、防腐剂、甜味剂、矫味剂、助悬剂、增稠剂、着色剂、粘度调节剂、稳定剂或渗透压调节剂。用于口服或非胃肠途径施用的液体载体的适当实例包括水(特别是含有以上添加剂例如纤维素衍生物、优选羧甲基纤维素钠的溶液)、醇(包括一元醇和多元醇例如甘醇类)及其衍生物和油类(例如分馏的椰油和花生油)。对于非胃肠途径施用,所述载体还可以是油酯例如油酸乙酯和肉豆蔻酸异丙酯。无菌液体载体用于经非胃肠道途径施用的无菌液体组合物中。无菌溶液剂或混悬剂形式的液体药物组合物可用于例如肌内、腹膜内或皮下注射。无菌溶液剂还可用于静脉内施用。口服施用的可以是液体组合物或固体组合物的形式。优选所述含有本发明化合物的药物组合物为单位剂型形式,例如片剂或胶囊剂形式。这种形式中,所述组合物被细分为含有适当量活性成分的单位剂型。单位剂型可以是包装的组合物,例如包装的散剂、小瓶、安瓿、预填充注射器或包含液体的小药袋。或者,所述单位剂型可以是例如片剂或胶囊剂本身,或者可以是适当数目的这种组合物在一个包装中的形式。医师可改变或调节待使用的治疗有效剂量,根据待治疗的具体病症、患者的体重、年龄和反应模式,通常该量为0.5mg-750mg。包装的组合物还可以包括使用说明书,例如用于治疗已出现的性功能障碍病症或预防或改善预期的性功能障碍病症例如与药物治疗(例如使用抗抑郁药物例如SSRI、抗精神病药物或抗惊厥药物进行治疗)有关的性功能障碍。
实施例6治疗性功能障碍
使用动物模型证明可作为5-HT1A拮抗剂的化合物治疗或预防性功能障碍例如与SSRI治疗有关的性功能障碍的用途。所述动物模型基于有过性经历的大鼠接受用于治疗某些病症例如抑郁症的药物SSRI后非接触性阴茎勃起次数下降的实验结果。SSRI治疗与人类个体的性功能障碍有关。一般而言,所述动物模型中,使有过性经历的雄性大鼠(Sprague-Dawley大鼠)在新的测试区域内而不是常规的饲养环境中接触发情期的雌性大鼠。在特定的测试期内例如30分钟内分析非接触性阴茎勃起次数(SukoffRizzo等,2006,Society for Neuroscience Abst.#559.4;美国临时专利申请60/682,3379,于2005年5月19日提交)。在本文所述实验中,通常给予动物0.9%盐水(载体)或药物在载体中的混合物。
使用三种不同的药物测试与人类性功能障碍有关的各种药物在动物模型中引发性功能障碍的能力,这三种药物是丁氨苯丙酮(20mg/kg)、去甲丙米嗪(10mg/kg)和氟西汀(10mg/kg)或单独使用载体(0.9%盐水),每种药物均经腹膜内(i.p.)施用,每日一次共14天。给药期过后,在30分钟的测试期内计数非接触性阴茎勃起的频率。
与单独施用载体相比,全部三种化合物在实验条件下都使性功能下降(图1)。这些数据表明,使用与人类性功能障碍有关的药物在动物模型中可诱发性功能障碍,从而为使用该动物模型的有效性提供了证据支持。
为研究引起性功能障碍的药物的作用时程,对如上所述处理和测试的大鼠进行短期给药:向大鼠给予载体6天,在第七个试验日,动物接受单个剂量的氟西汀在载体中的溶液(i.p.)。在中长期(7天)研究中,连续7天每日向动物施用氟西汀并在第7天对动物进行评估。对于长期的14天研究,连续14天每日向动物施用氟西汀并在第14天对动物进行测试。每个氟西汀剂量为10mg/kg在载体中的溶液,在每个试验日如上所述向动物腹膜内施用。每个研究阶段的试验期在施用化合物后立即开始算起,在施用药物后观察30分钟动物行为。
发现中长期和长期施用氟西汀与性功能障碍增加有关(图2),这进一步证明了使用该动物模型进行性功能障碍试验的合理性。
为测试5-HT1A拮抗剂改善性功能障碍的效果,利用短期或中长期(7天)给药方案,向有过性经历的大鼠施用SSRI,然后如上所述进行性功能测试。
在已发生一定水平的药物诱导的性功能障碍一段时间后,施用单个短期剂量的化合物(实施例化合物2)改善了性功能障碍的情况。因此,短期治疗性功能障碍可使性功能水平升高(例如正常)。图3、图4、图5中给药组的数据支持这一结论,其中在7天或14天的氟西汀治疗后短期施用实施例化合物2或实施例化合物3使氟西汀诱导的性功能障碍完全、显著地逆转。这些数据表明与诱导性功能障碍的药物一起短期施用5-HT1A拮抗剂可用于改善与性功能障碍有关的药物的这一作用。这些数据还表明单独短期施用5-HT1A拮抗剂可改善性功能(图3)。
在另一试验中,测试5-HT1A拮抗剂改善性功能障碍的能力,将实施例化合物3以短期给药的方式施用于有性经历的雄性大鼠。在这些实验中,在第1-13天向大鼠单独施用载体,然后在第14天施用单个短期剂量的0.1mg/kg化合物(第1组),在第1-13天向大鼠单独施用载体,然后在第14天施用单个剂量的1.0mg/kg的化合物(第2组),在第1-14天向大鼠单独施用载体(第3组),在第1-14天施用氟西汀(第4组),在第1-13天向大鼠单独施用氟西汀,然后在第14天施用单个剂量的0.1mg/kg的化合物和氟西汀(第5组);在第1-13天向大鼠施用氟西汀,然后在第14天施用单个剂量的1.0mg/kg的化合物和氟西汀(第6组)。对于每组而言,只在第14天施用药物后立即观察30分钟的动物行为。在这些实验中,施用化合物的两种不同剂量:0.1mg/kg或1.0mg/kg,两种剂量均使长期SSRI氟西汀(10mg/kg/天,i.p.)治疗引起的非接触性阴茎勃起次数下降的情况发生完全逆转。这些数据进一步表明使用本发明化合物治疗性功能障碍的效果,同时也提供了有效剂量的实例和剂量范围的实例(图4、图5)。
为评价5-HT1A拮抗剂预防SSRI治疗副作用的能力而进行实验。如上所述,向大鼠同时施用5-HT1A拮抗剂和SSRI。5-HT1A拮抗剂为实施例化合物3(1mg/kg)或实施例化合物2(0.3mg/kg)。施用的SSRI为氟西汀(10mg/kg)。5-HT1A拮抗剂与SSRI共同施用7天或14天。在这些条件下,5-HT1A拮抗剂预防了由长期单独使用氟西汀进行治疗所引起的非接触性阴茎勃起次数的下降。这些数据证明,当与SSRI共同施用时,长期用5-HT1A进行治疗可预防或改善与SSRI治疗有关的性功能障碍(图5、图6)。
不论5-HT1A拮抗剂治疗与抗抑郁治疗(例如SSRI治疗)同时启动还是5-HT1A拮抗剂治疗在抗抑郁治疗之后启动,这些数据综合表明了5-HT1A拮抗剂在治疗性功能障碍例如与抗抑郁治疗有关的性功能障碍方面的效果。
给动物口服(p.o.)或腹膜内(i.p.)注射5-HT1A拮抗剂或氟西汀(i.p.)以测试14天长期治疗在动物模型中的效果。测试两种治疗在有过性经历的雄性大鼠中对阴茎勃起次数的影响。确定与接受载体的动物相比所述化合物影响非接触性阴茎勃起次数的能力,比较两种治疗方案的结果。与SSRI治疗的动物相比,预计可用于治疗SSRI相关性性功能障碍的化合物对于性功能的影响将很小或没有影响。
以上实施例举例说明了可用于测试本文所述化合物改善与药物治疗有关的性功能障碍的能力的方法。也可以使用本领域已知的其它用于测试与抗抑郁治疗、抗精神病治疗或抗惊厥治疗有关的性功能障碍的模型。
其它实施方案
本发明可以以其它具体形式实施而不偏离本发明的精神和基本属性,因此,本发明的范围应该参考所附的权利要求书而不是上述说明书。
Claims (50)
1.一种在有需要的患者中治疗与药物治疗有关的性功能障碍的方法,所述方法包括向所述患者施用有效量的5-HT1A拮抗剂化合物。
2.权利要求1所述的方法,其中所述药物治疗是抗抑郁药物治疗、抗精神病药物治疗或抗惊厥药物治疗。
3.权利要求1所述的方法,其中所述化合物是式(I)化合物或其可药用酸加成盐,
其中
A是具有2-4个碳原子的亚烷基链,其任选被一个或多个低级烷基基团取代,
Z是氧或硫,
R是H或低级烷基,
R1是单环或二环芳基或杂芳基基团,
R2是单环或二环杂芳基基团,且
R3是氢、低级烷基、环烷基、环烯基、环烷基(低级)烷基、芳基、芳基(低级)烷基、杂芳基、杂芳基(低级)烷基、式-NR4R5的基团[其中R4是氢、低级烷基、芳基或芳基(低级)烷基,且R5是氢、低级烷基、-CO(低级)烷基、芳基、-CO芳基、芳基(低级)烷基、环烷基或环烷基(低级)烷基,或R4和R5与其共同连接的氮原子一起形成饱和杂环,所述杂环可进一步含有其它杂原子],或者式OR6的基团[其中R6是低级烷基、环烷基、环烷基(低级)烷基、芳基、芳基(低级)烷基、杂芳基或杂芳基(低级)烷基]。
4.权利要求3所述的方法,其中所述化合物是式(III)化合物或其可药用盐。
5.权利要求1所述的方法,其中所述化合物是(R)-4-氰基-N-{2-[4-(2,3-二氢-苯并[1,4]二噁英-5-基)-哌嗪-1-基]丙基}-N-吡啶-2-基-苯甲酰胺或其可药用酸加成盐(实施例化合物1)、N-[2-[4-(2-甲氧基苯基)-1-哌嗪基]乙基]-N-(2-吡啶基)环己烷甲酰胺(实施例化合物2)或其可药用酸加成盐或(R)-N-(2-甲基-(4-吲哚基-1-哌嗪基)乙基)-N-(2-吡啶基)环己烷甲酰胺(实施例化合物3)或其可药用酸加成盐。
6.权利要求1所述的方法,其中所述药物是选择性血清素再摄取抑制剂(SSRI)。
7.权利要求6所述的方法,所述SSRI是氟西汀、西酞普兰、草酸依地普仑、马来酸氟伏沙明、帕罗西汀或舍曲林。
8.权利要求1所述的方法,其中所述药物是三环类抗抑郁药。
9.权利要求8所述的方法,其中所述三环类抗抑郁药是去甲丙米嗪、阿米替林、阿莫西平、氯米帕明、多塞平、丙米嗪、去甲替林、普罗替林、曲米帕明。
10.权利要求1所述的方法,其中所述药物是氨基酮类化合物。
11.权利要求10所述的方法,其中所述的氨基酮类化合物是丁氨苯丙酮。
12.权利要求1所述的方法,其中所述药物是单胺氧化酶抑制剂(MAOI)。
13.权利要求12所述的方法,其中所述单胺氧化酶抑制剂是苯乙肼。
14.权利要求1所述的方法,其中所述药物是血清素和去甲肾上腺素再摄取抑制剂(SNRI)。
15.权利要求14所述的方法,其中所述SNRI是文拉法辛、奈法唑酮、米那普仑或度洛西汀。
16.权利要求1所述的方法,其中所述的药物是去甲肾上腺素再摄取抑制剂(NRI)。
17.权利要求16所述的方法,其中所述药物是瑞波西汀。
18.权利要求1所述的方法,其中所述药物是部分5-HT1A激动剂。
19.权利要求18所述的方法,其中所述药物是丁螺环酮。
20.权利要求1所述的方法,其中所述药物是5-HT2A受体拮抗剂。
21.权利要求20所述的方法,其中所述药物是奈法唑酮。
22.权利要求1所述的方法,其中所述药物是典型抗精神病药物。
23.权利要求1所述的方法,其中所述药物是非典型抗精神病药物。
24.权利要求1所述的方法,其中所述药物是脂肪族吩噻嗪、哌嗪吩噻嗪、苯丁酮、取代的苯甲酰胺和硫代黄嘌呤。这种药物的其它实例包括氟哌啶醇、奥氮平、氯氮平、利培酮、匹莫齐特、阿立哌唑和齐拉西酮。
25.权利要求1所述的方法,其中所述药物是苯巴比妥、苯妥英、扑米酮和卡马西平。
26.权利要求2所述的方法,其中所述患者正在接受抗抑郁药物、抗精神病药物或抗惊厥药物或其组合中至少两种药物的治疗。
27.权利要求1所述的方法,其中所述方法包括口服递送所述化合物。
28.权利要求1所述的方法,其中所述方法包括递送持续释放化合物的形式。
29.权利要求1所述的方法,其中所述的性功能障碍包括阴茎勃起功能障碍。
30.在有需要的患者中改善性功能的方法,所述方法包括向所述患者施用药学有效量的5-HT1A拮抗剂化合物。
31.权利要求30所述的方法,其中所述化合物是式(I)化合物或其可药用酸加成盐,
其中
A是具有2-4个碳原子的亚烷基链,其任选被一个或多个低级烷基基团取代,
Z是氧或硫,
R是H或低级烷基,
R1是单环或二环芳基或杂芳基基团,
R2是单环或二环杂芳基基团,且
R3是氢、低级烷基、环烷基、环烯基、环烷基(低级)烷基、芳基、芳基(低级)烷基、杂芳基、杂芳基(低级)烷基、式-NR4R5的基团[其中R4是氢、低级烷基、芳基或芳基(低级)烷基,且R5是氢、低级烷基、-CO(低级)烷基、芳基、-CO芳基、芳基(低级)烷基、环烷基或环烷基(低级)烷基,或R4和R5与其共同连接的氮原子一起形成饱和杂环,所述杂环可进一步含有其它杂原子],或者式OR6的基团[其中R6是低级烷基、环烷基、环烷基(低级)烷基、芳基、芳基(低级)烷基、杂芳基或杂芳基(低级)烷基];
或式(III)化合物或其可药用酸加成盐,
其中R1是氰基、硝基、三氟甲基或卤素;
或式(IV)化合物或其可药用酸加成盐,
其中Ra和Rb都是氢或甲基,且Rc是氢、卤素或C1-4烷基。
32.权利要求30所述的方法,其中所述化合物是实施例化合物1、实施例化合物2或实施例化合物3。
33.一种用于治疗与药物治疗有关的性功能障碍的药物组合物,所述组合物包含式(I)、式(III)或式(IV)的化合物。
34.权利要求33所述的药物组合物,其中所述药物是抗抑郁药物、抗精神病药物或抗惊厥药物。
35.权利要求33所述的药物组合物,其中所述化合物可在与药物治疗有关的性功能障碍动物模型中有效改善性功能障碍。
36.权利要求35所述的药物组合物,其中所述性功能障碍动物模型是抗抑郁药物诱导的性功能障碍模型。
37.药物包装,其中包含5-HT1A拮抗剂和说明书,其中说明书的内容包括治疗性功能障碍的说明。
38.权利要求37所述的药物包装,其中所述的说明书内容包括治疗与药物治疗有关的性功能障碍的说明。
42.一种在有需要的患者中治疗偏头痛的方法,其包括向所述患者施用治疗有效量的式(III)化合物或其可药用酸加成盐:
其中R1是氰基、硝基、三氟甲基或卤素。
46.一种在有需要的患者中治疗中风的方法,其包括向所述患者施用治疗有效量的式(III)化合物或其可药用酸加成盐:
其中R1是氰基、硝基、三氟甲基或卤素。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/330,907 US20060223824A1 (en) | 2000-11-28 | 2006-01-11 | Serotonergic agents |
US11/330,907 | 2006-01-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN101400350A true CN101400350A (zh) | 2009-04-01 |
Family
ID=37251867
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2006800537941A Pending CN101400350A (zh) | 2006-01-11 | 2006-03-30 | 用于治疗性功能障碍的血清素能活性剂 |
Country Status (8)
Country | Link |
---|---|
US (2) | US20060223824A1 (zh) |
EP (1) | EP1971337A1 (zh) |
JP (1) | JP2009523169A (zh) |
CN (1) | CN101400350A (zh) |
AU (1) | AU2006335279A1 (zh) |
BR (1) | BRPI0620987A2 (zh) |
CA (1) | CA2637418A1 (zh) |
WO (1) | WO2007081374A1 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2022538955A (ja) * | 2019-03-19 | 2022-09-07 | ケンブリッジ コグニション リミテッド | 精神障害のための治療の診断および推奨の方法および利用 |
Family Cites Families (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MX9201991A (es) * | 1991-05-02 | 1992-11-01 | Jonh Wyeth & Brother Limited | Derivados de piperazina y procedimiento para su preparacion. |
GB9125900D0 (en) * | 1991-12-05 | 1992-02-05 | Wyeth John & Brother Ltd | Piperazine derivatives |
US6765008B1 (en) | 1992-12-17 | 2004-07-20 | Pfizer Inc | Pyrrolopyrimidines as CRF antagonists |
KR0170567B1 (ko) | 1992-12-17 | 1999-02-18 | 알렌 제이. 스피겔 | 부신피질자극호르몬-유리 인자 길항물질 활성을 갖는 피라졸 및 피라졸로피리미딘 |
DK0674631T3 (da) | 1992-12-17 | 2000-04-10 | Pfizer | Substituerede pyrazoler som CRF-antogonister |
TW336932B (en) | 1992-12-17 | 1998-07-21 | Pfizer | Amino-substituted pyrazoles |
TW370529B (en) | 1992-12-17 | 1999-09-21 | Pfizer | Pyrazolopyrimidines |
GB9411099D0 (en) * | 1994-06-03 | 1994-07-27 | Wyeth John & Brother Ltd | Piperazine derivatives |
DK0763024T3 (da) | 1994-06-03 | 2002-12-02 | Wyeth John & Brother Ltd | Fremgangmåde og mellemprodukter til fremstilling af piperazinderivater |
CA2134038C (en) * | 1994-06-16 | 1997-06-03 | David Taiwai Wong | Potentiation of drug response |
EP0714663A3 (en) * | 1994-11-28 | 1997-01-15 | Lilly Co Eli | Potentiation of drug responses by serotonin 1A receptor antagonists |
GB9514901D0 (en) | 1995-07-20 | 1995-09-20 | American Home Prod | Piperazine derivatives |
US5756532A (en) * | 1995-11-06 | 1998-05-26 | American Home Products Corporation | Aminomethyl-2 3 8 9-tetrahydro-7H-1 4-dioxino 2 3-E!-indol-8-ones and derivatives |
EP0792649A1 (en) | 1996-02-29 | 1997-09-03 | Eli Lilly And Company | Treatment of sleep disorders |
US5776969A (en) * | 1997-02-27 | 1998-07-07 | Eli Lilly And Company | Treatment of sleep disorders |
US6287839B1 (en) * | 1997-11-19 | 2001-09-11 | Genencor International, Inc. | Cellulase producing actinomycetes, cellulase produced therefrom and method of producing same |
CA2340952C (en) * | 1998-09-10 | 2009-12-08 | F. Hoffmann-La Roche Ag | Dihydrobenzodioxine carboxamide and ketone derivatives as 5-ht4 receptor antagonists |
IT1318394B1 (it) * | 2000-03-17 | 2003-08-25 | Enichem Spa | Processo per la preparazione di 1-esene. |
US20060287335A1 (en) * | 2000-11-28 | 2006-12-21 | Wyeth | Serotonergic agents for treating sexual dysfunction |
US6469007B2 (en) * | 2000-11-28 | 2002-10-22 | Wyeth | Serotonergic agents |
CA2477892C (en) * | 2002-03-12 | 2010-11-23 | Gregg Brian Feigelson | Process for synthesizing chiral n-aryl piperazines |
US7091349B2 (en) * | 2002-03-12 | 2006-08-15 | Wyeth | Process for synthesizing N-aryl piperazines with chiral N′-1-[benzoyl(2-pyridyl)amino]-2-propane substitution |
ATE449073T1 (de) | 2002-03-12 | 2009-12-15 | Wyeth Corp | Verfahren zur herstellung von n1-(2-pyridyl)-1,2- propandiaminsulfamidsäure und ihre verwendung zur herstellung von biologisch aktiven piperazinen |
WO2004082686A2 (en) | 2003-03-13 | 2004-09-30 | Dynogen Pharmaceuticals, Inc. | Use of compounds with combined 5-ht1a and ssri activities to treat sexual dysfunction |
US20050215561A1 (en) * | 2004-03-19 | 2005-09-29 | Krishnendu Ghosh | Pharmaceutical dosage forms and compositions |
PA8626301A1 (es) * | 2004-03-19 | 2006-12-07 | Wyeth Wyeth | Proceso para preparar derivados de n-aril-piperazina |
-
2006
- 2006-01-11 US US11/330,907 patent/US20060223824A1/en not_active Abandoned
- 2006-03-30 BR BRPI0620987-4A patent/BRPI0620987A2/pt not_active IP Right Cessation
- 2006-03-30 WO PCT/US2006/011760 patent/WO2007081374A1/en active Application Filing
- 2006-03-30 CN CNA2006800537941A patent/CN101400350A/zh active Pending
- 2006-03-30 EP EP06740111A patent/EP1971337A1/en not_active Withdrawn
- 2006-03-30 CA CA002637418A patent/CA2637418A1/en not_active Abandoned
- 2006-03-30 JP JP2008550289A patent/JP2009523169A/ja not_active Withdrawn
- 2006-03-30 AU AU2006335279A patent/AU2006335279A1/en not_active Abandoned
-
2009
- 2009-05-05 US US12/435,862 patent/US7816362B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
BRPI0620987A2 (pt) | 2011-11-29 |
US20060223824A1 (en) | 2006-10-05 |
WO2007081374A1 (en) | 2007-07-19 |
JP2009523169A (ja) | 2009-06-18 |
CA2637418A1 (en) | 2007-07-19 |
EP1971337A1 (en) | 2008-09-24 |
US20090215794A1 (en) | 2009-08-27 |
US7816362B2 (en) | 2010-10-19 |
AU2006335279A1 (en) | 2007-07-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101198322A (zh) | 用于治疗或预防抑郁症的新治疗组合 | |
CN101410112A (zh) | 治疗抑郁症的新治疗组合 | |
US20060258739A1 (en) | Dihydrobenzofuran derivatives and uses therof | |
CA2615271C (en) | Novel use of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine and its physiologically acceptable salts | |
CN100352437C (zh) | 哌嗪衍生物、它们的制备方法及其在制备治疗中枢神经系统(cns)疾病的药物中的应用 | |
JP2008531714A (ja) | 不安障害の治療用及び/又は予防用の医薬組成物 | |
EP1871755A1 (en) | Dihydrobenzofuran derivatives and uses thereof | |
JP2009520030A (ja) | 躁病および双極性障害を治療するためのベンゾ縮合複素環スルファミド誘導体の使用 | |
US7425558B2 (en) | Serotonergic agents for treating sexual dysfunction | |
CN101400350A (zh) | 用于治疗性功能障碍的血清素能活性剂 | |
MX2008008835A (en) | Serotonergic agents for treating sexual dysfunction | |
TW200808322A (en) | Serotonergic agents for treating sexual dysfunction | |
US20120077825A1 (en) | Novel use of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine and its physiologically acceptable salts |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20090401 |