CN114144179A - 含血清素的试剂和5-ht1a受体拮抗剂 - Google Patents
含血清素的试剂和5-ht1a受体拮抗剂 Download PDFInfo
- Publication number
- CN114144179A CN114144179A CN202080053794.1A CN202080053794A CN114144179A CN 114144179 A CN114144179 A CN 114144179A CN 202080053794 A CN202080053794 A CN 202080053794A CN 114144179 A CN114144179 A CN 114144179A
- Authority
- CN
- China
- Prior art keywords
- serotonin
- containing agent
- compound
- formula
- combination
- 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
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 title claims abstract description 216
- 229940076279 serotonin Drugs 0.000 title claims abstract description 98
- 239000003795 chemical substances by application Substances 0.000 title claims abstract description 87
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 title description 23
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 title description 22
- 239000002464 receptor antagonist Substances 0.000 title description 22
- 229940044551 receptor antagonist Drugs 0.000 title description 18
- 206010036596 premature ejaculation Diseases 0.000 claims abstract description 29
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 claims description 56
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 claims description 55
- 150000001875 compounds Chemical class 0.000 claims description 43
- 230000000694 effects Effects 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 15
- 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 13
- 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 13
- 229960002296 paroxetine Drugs 0.000 claims description 13
- 230000001568 sexual effect Effects 0.000 claims description 13
- -1 methoxy, hydroxyl Chemical group 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 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 5
- 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 5
- 229960001653 citalopram Drugs 0.000 claims description 5
- USRHYDPUVLEVMC-FQEVSTJZSA-N dapoxetine Chemical compound C1([C@H](CCOC=2C3=CC=CC=C3C=CC=2)N(C)C)=CC=CC=C1 USRHYDPUVLEVMC-FQEVSTJZSA-N 0.000 claims description 5
- 229960005217 dapoxetine Drugs 0.000 claims description 5
- 229960002464 fluoxetine Drugs 0.000 claims description 5
- 239000003772 serotonin uptake inhibitor Substances 0.000 claims description 5
- ZHFIAFNZGWCLHU-YPMHNXCESA-N ifoxetine Chemical compound CC1=CC=CC(O[C@@H]2[C@@H](CNCC2)O)=C1C ZHFIAFNZGWCLHU-YPMHNXCESA-N 0.000 claims description 4
- 229950006314 ifoxetine Drugs 0.000 claims description 4
- 229960002791 zimeldine Drugs 0.000 claims description 4
- 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 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229960004341 escitalopram Drugs 0.000 claims description 3
- 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 3
- 229960004038 fluvoxamine Drugs 0.000 claims description 3
- CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229960002073 sertraline Drugs 0.000 claims description 3
- 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 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 239000003420 antiserotonin agent Substances 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000000952 serotonin receptor agonist Substances 0.000 claims description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 2
- 229910052717 sulfur Chemical group 0.000 claims description 2
- 239000011593 sulfur Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- WIQRCHMSJFFONW-HNNXBMFYSA-N (3s)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine Chemical compound O([C@@H](CCN)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 WIQRCHMSJFFONW-HNNXBMFYSA-N 0.000 claims 1
- ZWLMLVIUWRUDBD-BTJKTKAUSA-N (z)-but-2-enedioate;3-(2-methoxy-10h-phenothiazin-10-ium-10-yl)propyl-dimethylazanium Chemical compound OC(=O)\C=C/C(O)=O.C1=CC=C2N(CCCN(C)C)C3=CC(OC)=CC=C3SC2=C1 ZWLMLVIUWRUDBD-BTJKTKAUSA-N 0.000 claims 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 claims 1
- 229960000590 celecoxib Drugs 0.000 claims 1
- YZBLFMPOMVTDJY-CBYMMZEQSA-N moxidectin Chemical compound O1[C@H](C(\C)=C\C(C)C)[C@@H](C)C(=N/OC)\C[C@@]11O[C@H](C\C=C(C)\C[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 YZBLFMPOMVTDJY-CBYMMZEQSA-N 0.000 claims 1
- 229960004816 moxidectin Drugs 0.000 claims 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 claims 1
- 229940127221 norepinephrine reuptake inhibitor Drugs 0.000 claims 1
- AMJPIGOYWBNJLP-UHFFFAOYSA-N pirandamine Chemical compound C1C2=CC=CC=C2C2=C1C(CCN(C)C)(C)OCC2 AMJPIGOYWBNJLP-UHFFFAOYSA-N 0.000 claims 1
- 229950007239 pirandamine Drugs 0.000 claims 1
- 239000002207 metabolite Substances 0.000 abstract description 59
- 239000002243 precursor Substances 0.000 abstract description 59
- 239000003727 serotonin 1A antagonist Substances 0.000 abstract description 52
- 230000002265 prevention Effects 0.000 abstract description 9
- LYXKFNHUJJDTIA-UHFFFAOYSA-N 2-[4-[4-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]butyl]-1,1-dioxo-1,2-benzothiazol-3-one Chemical group O=C1C2=CC=CC=C2S(=O)(=O)N1CCCCN(CC1)CCN1C1=CC(Cl)=CC2=C1OCCO2 LYXKFNHUJJDTIA-UHFFFAOYSA-N 0.000 description 36
- 241000700159 Rattus Species 0.000 description 12
- 230000009329 sexual behaviour Effects 0.000 description 11
- 239000002552 dosage form Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 230000009471 action Effects 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 230000001154 acute effect Effects 0.000 description 5
- 230000000903 blocking effect Effects 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 230000000862 serotonergic effect Effects 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 230000001270 agonistic effect Effects 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 4
- 102000019208 Serotonin Plasma Membrane Transport Proteins Human genes 0.000 description 3
- 108010012996 Serotonin Plasma Membrane Transport Proteins Proteins 0.000 description 3
- 229940121991 Serotonin and norepinephrine reuptake inhibitor Drugs 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000003042 antagnostic effect Effects 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000002858 neurotransmitter agent Substances 0.000 description 3
- 239000003775 serotonin noradrenalin reuptake inhibitor Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000005062 synaptic transmission Effects 0.000 description 3
- CEMAWMOMDPGJMB-UHFFFAOYSA-N (+-)-Oxprenolol Chemical compound CC(C)NCC(O)COC1=CC=CC=C1OCC=C CEMAWMOMDPGJMB-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 2
- 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 description 2
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 description 2
- 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 2
- XIGAHNVCEFUYOV-BTJKTKAUSA-N (z)-but-2-enedioic acid;n-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-n-pyridin-2-ylcyclohexanecarboxamide Chemical compound OC(=O)\C=C/C(O)=O.COC1=CC=CC=C1N1CCN(CCN(C(=O)C2CCCCC2)C=2N=CC=CC=2)CC1 XIGAHNVCEFUYOV-BTJKTKAUSA-N 0.000 description 2
- FWYRGHMKHZXXQX-UHFFFAOYSA-N 3-(3,4-dichlorophenyl)-2-(dimethylamino)-2-methylpropan-1-ol Chemical compound CN(C)C(C)(CO)CC1=CC=C(Cl)C(Cl)=C1 FWYRGHMKHZXXQX-UHFFFAOYSA-N 0.000 description 2
- QXIUMMLTJVHILT-UHFFFAOYSA-N 4-[3-(tert-butylamino)-2-hydroxypropoxy]-1H-indole-2-carbonitrile Chemical compound CC(C)(C)NCC(O)COC1=CC=CC2=C1C=C(C#N)N2 QXIUMMLTJVHILT-UHFFFAOYSA-N 0.000 description 2
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 2
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 2
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229950000303 cericlamine Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 230000003291 dopaminomimetic effect Effects 0.000 description 2
- 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 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000008297 liquid dosage form Substances 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
- 230000004060 metabolic process Effects 0.000 description 2
- 229960000619 nebivolol Drugs 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- FAHGZANUNVVDFL-HYBUGGRVSA-N omiloxetine Chemical compound C1=CC(F)=CC=C1[C@@H]1[C@@H](COC=2C=C3OCOC3=CC=2)CN(CC(=O)C=2C=CC(F)=CC=2)CC1 FAHGZANUNVVDFL-HYBUGGRVSA-N 0.000 description 2
- 229950005637 omiloxetine Drugs 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 229960004570 oxprenolol Drugs 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 229960003712 propranolol Drugs 0.000 description 2
- 208000020016 psychiatric disease Diseases 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 2
- 229960001534 risperidone Drugs 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 229960004380 tramadol Drugs 0.000 description 2
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 2
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 description 1
- ZQPXSRTZFYHSFB-UHFFFAOYSA-N 1-[4-[2-hydroxy-3-(4-phenylpiperazin-1-yl)propoxy]phenyl]propan-1-one Chemical compound C1=CC(C(=O)CC)=CC=C1OCC(O)CN1CCN(C=2C=CC=CC=2)CC1 ZQPXSRTZFYHSFB-UHFFFAOYSA-N 0.000 description 1
- MOILFCKRQFQVFS-UHFFFAOYSA-N 4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1C2C(C)(C)C1CC(O)C2(O)C MOILFCKRQFQVFS-UHFFFAOYSA-N 0.000 description 1
- BQGLPDFQLBNUGU-UHFFFAOYSA-N 4-(fluoromethyl)-n-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-n-pyridin-2-ylcyclohexane-1-carboxamide Chemical compound COC1=CC=CC=C1N1CCN(CCN(C(=O)C2CCC(CF)CC2)C=2N=CC=CC=2)CC1 BQGLPDFQLBNUGU-UHFFFAOYSA-N 0.000 description 1
- NRPQELCNMADTOZ-OAQYLSRUSA-N 4-cyano-n-[(2r)-2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]propyl]-n-pyridin-2-ylbenzamide Chemical compound C([C@@H](C)N1CCN(CC1)C=1C=2OCCOC=2C=CC=1)N(C=1N=CC=CC=1)C(=O)C1=CC=C(C#N)C=C1 NRPQELCNMADTOZ-OAQYLSRUSA-N 0.000 description 1
- QZHXKQKKEBXYRG-UHFFFAOYSA-N 4-n-(4-aminophenyl)benzene-1,4-diamine Chemical compound C1=CC(N)=CC=C1NC1=CC=C(N)C=C1 QZHXKQKKEBXYRG-UHFFFAOYSA-N 0.000 description 1
- AYYCFGDXLUPJAQ-UHFFFAOYSA-N 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione Chemical compound COC1=CC=CC=C1N1CCN(CCN2C(CC3(CCCC3)CC2=O)=O)CC1 AYYCFGDXLUPJAQ-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
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- GDLIGKIOYRNHDA-UHFFFAOYSA-N Clomipramine Chemical compound C1CC2=CC=C(Cl)C=C2N(CCCN(C)C)C2=CC=CC=C21 GDLIGKIOYRNHDA-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 102000006441 Dopamine Plasma Membrane Transport Proteins Human genes 0.000 description 1
- 108010044266 Dopamine Plasma Membrane Transport Proteins Proteins 0.000 description 1
- PTHLEKANMPKYDB-UHFFFAOYSA-N Flopropione Chemical compound CCC(=O)C1=C(O)C=C(O)C=C1O PTHLEKANMPKYDB-UHFFFAOYSA-N 0.000 description 1
- 102000034354 Gi proteins Human genes 0.000 description 1
- 108091006101 Gi proteins Proteins 0.000 description 1
- 102000017911 HTR1A Human genes 0.000 description 1
- 101150015707 HTR1A gene Proteins 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
- 241001465754 Metazoa Species 0.000 description 1
- SJDOMIRMMUGQQK-UHFFFAOYSA-N NAN 190 Chemical compound COC1=CC=CC=C1N1CCN(CCCCN2C(C3=CC=CC=C3C2=O)=O)CC1 SJDOMIRMMUGQQK-UHFFFAOYSA-N 0.000 description 1
- 102000008092 Norepinephrine Plasma Membrane Transport Proteins Human genes 0.000 description 1
- 108010049586 Norepinephrine Plasma Membrane Transport Proteins Proteins 0.000 description 1
- KYYIDSXMWOZKMP-UHFFFAOYSA-N O-desmethylvenlafaxine Chemical compound C1CCCCC1(O)C(CN(C)C)C1=CC=C(O)C=C1 KYYIDSXMWOZKMP-UHFFFAOYSA-N 0.000 description 1
- 240000001987 Pyrus communis Species 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 101710164184 Synaptic vesicular amine transporter Proteins 0.000 description 1
- 102100034333 Synaptic vesicular amine transporter Human genes 0.000 description 1
- FZSPJBYOKQPKCD-VIFPVBQESA-N [1-(4-chlorophenyl)-2-methylpropan-2-yl] (2s)-2-aminopropanoate Chemical compound C[C@H](N)C(=O)OC(C)(C)CC1=CC=C(Cl)C=C1 FZSPJBYOKQPKCD-VIFPVBQESA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229960003225 alaproclate Drugs 0.000 description 1
- 229960002213 alprenolol Drugs 0.000 description 1
- PAZJSJFMUHDSTF-UHFFFAOYSA-N alprenolol Chemical compound CC(C)NCC(O)COC1=CC=CC=C1CC=C PAZJSJFMUHDSTF-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 229960002430 atomoxetine 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
- 230000003542 behavioural effect Effects 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229960004606 clomipramine Drugs 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- JJCFRYNCJDLXIK-UHFFFAOYSA-N cyproheptadine Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2C=CC2=CC=CC=C21 JJCFRYNCJDLXIK-UHFFFAOYSA-N 0.000 description 1
- 229960001140 cyproheptadine Drugs 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229960001623 desvenlafaxine Drugs 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- LRMJAFKKJLRDLE-UHFFFAOYSA-N dotarizine Chemical compound O1CCOC1(C=1C=CC=CC=1)CCCN(CC1)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 LRMJAFKKJLRDLE-UHFFFAOYSA-N 0.000 description 1
- 229950005624 dotarizine Drugs 0.000 description 1
- 229960002866 duloxetine Drugs 0.000 description 1
- 230000003028 elevating effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229950003930 femoxetine Drugs 0.000 description 1
- 229960000430 flopropione Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000009539 inhibitory neurotransmission Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- WGSPBWSPJOBKNT-UHFFFAOYSA-N iodocyanopindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=C1C(I)=C(C#N)N2 WGSPBWSPJOBKNT-UHFFFAOYSA-N 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 229950007396 lecozotan Drugs 0.000 description 1
- 229960000685 levomilnacipran Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 229960000600 milnacipran Drugs 0.000 description 1
- YJZYDPRMWYWYCG-UHFFFAOYSA-N mppf Chemical compound COC1=CC=CC=C1N1CCN(CCN(C(=O)C=2C=CC(F)=CC=2)C=2N=CC=CC=2)CC1 YJZYDPRMWYWYCG-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- AQFFJGJVFJCQQL-UHFFFAOYSA-N panuramine Chemical compound C1CN(CC=2C=C3C=CC=CC3=CC=2)CCC1NC(=O)NC(=O)C1=CC=CC=C1 AQFFJGJVFJCQQL-UHFFFAOYSA-N 0.000 description 1
- 229950010577 panuramine Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960002508 pindolol Drugs 0.000 description 1
- PHUTUTUABXHXLW-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=NC=C[C]12 PHUTUTUABXHXLW-UHFFFAOYSA-N 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- 238000011552 rat model Methods 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
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 239000003762 serotonin receptor affecting agent Substances 0.000 description 1
- 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 1
- 229960004425 sibutramine Drugs 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 230000003442 weekly effect Effects 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- 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
- 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
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Endocrinology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Reproductive Health (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及用于5‑HT1A受体拮抗剂或其衍生物、前体或代谢产物与至少一种含血清素的试剂或其衍生物、前体或代谢产物的组合用于预防和/或治疗早泄的用途,其中5‑HT1A受体拮抗剂或其衍生物、前体或代谢产物与至少一种含血清素的试剂或其衍生物、前体或代谢产物分别、依次或同时施用。
Description
技术领域
本公开涉及早泄(PE)的治疗。
背景技术
选择性血清素再摄取抑制剂(SSRI)之前已经被建议用于治疗早泄(PE)。在对PE起效之前,需要几周的慢性治疗。理想地,应使用能够在性交前不久服用并且可按需(即立即或在数小时内)起作用的药物。
尽管已引入达泊西汀(SSRI)用于PE的“按需”使用,但是现有数据不支持达泊西汀的“按需”性质。该产品的高停药率似乎支持了这一点,这可能是由达泊西汀的不良副作用引起的。
本公开的目的是提供新的用于PE的药物,尤其是用于PE的“按需”药物。
发明内容
本公开提供了至少一种含血清素的试剂或其衍生物、前体或代谢产物与至少一种5-HT1A受体拮抗剂或其衍生物、前体或代谢产物组合用于预防和/或治疗早泄(PE)的用途,其中至少一种含血清素的试剂或其前体或代谢产物与至少一种5-HT1A受体拮抗剂分别、依次或同时施用。优选地,至少一种含血清素的试剂或其前体或代谢产物为至少一种SSRI,并且至少一种5-HT1A受体拮抗剂为DU125530。
本发明人发现,含血清素的试剂和5-HT1A受体拮抗剂的组合施用出人意料地增加了(首次)射精的延迟,并且起效快,从而为早泄提供了“按需”药物。
在本文和其权利要求中,动词“包括”和其变形以其非限制性意义使用,表示包括该词后面的项目,但不排除未特别提及的项目。另外,通过不定冠词“一个(a)”或“一个(an)”提及某一要素并不排除存在多于一个要素的可能性,除非上下文明确要求存在且仅存在一个要素。因此,不定冠词“一个”或“一种”通常意味着“至少一个/至少一种”。
具体实施方式
本公开涉及至少一种含血清素的试剂或其衍生物、前体或代谢产物,与至少一种5-HT1A拮抗剂或其衍生物、前体或代谢产物组合,用于延长射精延迟,尤其用于预防和/或治疗早泄(PE)的方法中的用途,其中至少一种含血清素的试剂或其前体或代谢产物与至少一种5-HT1A拮抗剂分别、依次或同时施用至有需要的受试者。优选地,至少一种含血清素的试剂为至少一种SSRI,并且至少一种5-HT1A受体拮抗剂为DU125530。
早泄(PE),也称为提早射精或早泄,发生在男性受试者在刺激相对较少的情况下在开始性行为后不久就经历性高潮并且排出精液。在本公开的上下文中,“早”的定义是:插入后最多一分钟(根据i.a.Serefoglu等;Sexual medicine.2(2):41-59)或性交开始后15秒内(根据国际疾病分类(ICD-10))。
可选地和/或另外,根据2014年国际性医学学会(International Society forSexual Medicine)制定的循证标准,早泄可被定义为不是无性精神疾病的结果,而是特定关系中的问题或药物造成的结果,患者在插入后一分钟内在想要射精之前射精,持续时间超过6个月并且(几乎)每次性交时(或90%的情况下)都会发生,给该患者造成极大痛苦。这些因素能够通过与男性受试者交谈而不需通过任何诊断测试来确定。早泄(PE)也可以定义为不受控的射精,和/或在最初插入后最多15秒或最多1分钟、2分钟或3分钟内射精(根据2007ICD-10)。
在优选的实施方式中,本公开旨在增加(人类)男性射精的(延迟)时间。
在本公开的上下文中,含血清素的试剂是改变体内血清素作用的化合物和/或通过与血清素能系统的相互作用(例如通过刺激或阻断血清素神经传递)产生其作用的化合物。可使用不同类型的含血清素的试剂,包括下述:
血清素再摄取抑制剂;
血清素去甲肾上腺素再摄取抑制剂(SNRI);
血清素受体激动剂或拮抗剂;
血清素释放剂;和/或
在其工作机制中含有SSRI组分的任何药剂(例如,曲马多)。
在本发明的上下文中,SSRI是修饰体内血清素作用的化合物和/或通过刺激血清素神经传递,通过与血清素能系统的相互作用产生血清素作用的化合物。
在本公开中,优选血清素再摄取抑制剂(SRI)。SRI是通过例如阻断血清素转运体(SERT)的作用而作为神经递质血清素(5-羟色胺(5-HT))的再摄取抑制剂的化合物。而这又导致细胞外血清素浓度增加,从而增加血清素能神经传递。
尤其优选的是选择性血清素再摄取抑制剂(SSRI)。SSRI是在治疗(重度)抑郁症和焦虑症时也用作抗抑郁药的一类化合物。SSRI在抑郁、焦虑和射精中的确切作用机制尚不清楚。SSRI被认为通过限制其再吸收(再摄取)至突触前细胞中,增加可与突触后受体结合的突触间隙中的血清素水平,从而增加神经递质血清素的细胞外水平。它们可能对其他单胺转运体有不同程度的选择性,纯SSRI对去甲肾上腺素和多巴胺转运体仅有微弱的亲和力。SSRI的适合示例包括西酞普兰(Citalopram)、艾司西酞普兰(Escitalopram)、氟西汀(Fluoxetine)、氟伏沙明(Fluvoxamine)、帕罗西汀(Paroxetine)、舍曲林(Sertraline)、达泊西汀(Dapoxetine)、吲达品(Indalpine)、齐美利定(Zimelidine)、阿拉丙酯(Alaproclate)、桑普罗帕嗪(Centpropazine)、西文氯胺(Cericlamine)(JO-1017)、非莫西汀(Femoxetine)(马来西汀(Malexil);FG-4963)、伊福西汀(Ifoxetine)(CGP-15210)、奥米西汀(Omiloxetine)、帕努拉明(Panuramine)(WY-26002)、吡喃达明(Pirandamine)(AY-23713)、塞罗西汀(Seproxetine)((S)-诺氟西汀)。
SNRI抑制血清素和去甲肾上腺素的再摄取。适合的示例包括阿托莫西汀、去甲文拉法辛、度洛西汀、左旋米那普仑、米那普仑、西布曲明、曲马多和/或文拉法辛。
根据本公开的含血清素的试剂也可为氯丙咪嗪。
含血清素的试剂或其衍生物、前体或代谢产物优选以在血液循环中存在含血清素的试剂的短时高峰的剂型施用,例如以口服或舌下剂型的形式,例如以环糊精为载体的片剂或舌下剂型。优选地,含血清素的试剂是SSRI。含血清素的试剂的另一种适合的施用途径是经鼻、粘膜或鼻内施用。配方中含血清素的试剂或其衍生物、前体或代谢产物的剂量可为0.1mg至10mg,优选2mg至8mg。本公开的目的在于使受试者的含血清素的试剂血浆水平暂时升高(短时峰值)。术语“短时”指施加含血清素的试剂使得血浆中的含血清素的试剂水平在施用后2至4小时或3至5小时内恢复到基线水平。
如上述,本公开将至少一种含血清素的试剂或其衍生物、前体或代谢产物与至少一种5-HT1A受体拮抗剂或其衍生物、前体或代谢产物组合。优选地,至少一种含血清素的试剂为至少一种SSRI,并且至少一种5-HT1A受体拮抗剂为DU125530。
5-HT1A受体(或血清素1A受体)是结合神经递质血清素(5-羟色胺,5-HT)的血清素受体(5-HT受体)的一种亚型。其为G蛋白偶联受体(GPCR),与介导抑制性神经传递的Gi蛋白偶联。5-HT1A受体蛋白由HTR1A基因编码。5-HT1A受体拮抗剂为一类受体配体或化合物,其通过结合和/或阻断5-HT1A受体而不是像激动剂一样激活它来阻断或抑制生物反应。5-HT1A受体拮抗剂的适合示例包括阿普雷诺醇(Alprenolol)、AV-965、BMY-7378、氰基吲哚洛尔(Cyanopindolol)、赛庚啶(Cyproheptadine)、多他利嗪(Dotarizine)、夫洛丙酮(Flopropione)、GR-46611、碘代氰基吲哚洛尔(Iodocyanopindolol)、艾沙莫坦(Isamoltane)、乐可佐坦(Lecozotan)、美法韦(Mefway)、甲氧肝素(Methiothepin)、MPPF、NAD-299、NAN-190、奈比洛尔(Nebivolol)、氧烯洛尔(Oxprenolol)、品多芬(Pindobind)、吲哚洛尔(Pindolol)、普萘洛尔(Propranolol)、利司培酮(Risperidone)、罗巴佐坦(Robalzotan)、SB-649915、Z-216525、螺哌酮(Spiperone)、螺酰胺(Spiramide)、螺沙坦(Spiroxatrine)、UH-301、WAY 100635和WAY-100135。
上述大多数5-HT1A受体拮抗剂具有仅次于5-HT1A受体拮抗剂的其他药理机制,通常表现出令人不安的副作用。5-HT1A受体拮抗剂可刺激或阻断血清素能非5-HT1A受体和/或非血清素能受体,可在5-HT1A受体上具有偏向性激动效应,或可在位于突触前或突触后的5-HT1A受体上具有差异性拮抗/激动作用。另外,一些5-HT1A受体拮抗剂具有部分5-HT1A受体激动作用,是拮抗/激动对映体的外消旋混合物,可导致不必要的副作用。
由于5-HT1A拮抗作用以外的另一种机制,许多5-HT1A受体拮抗剂主要用于其他目的,例如用于心脏病。例如,这种5-HT1A受体拮抗剂可为β受体阻滞剂,有可能导致心率降低或不规则和/或血压降低。一些5-HT1A受体拮抗剂用于某些精神疾病(如精神分裂症)并且具有导致不必要的多巴胺能副作用的多巴胺能机制。5-HT1A受体拮抗剂可降低血脑屏障的渗透性,从而降低其有效性。
根据本公开的5-HT1A受体拮抗剂优选由式I表征:
其中
R1为卤素、甲基、甲氧基、羟基、三氟甲基或氰基,优选氯;
m为1或2,优选1;
R2为氢或氯,优选氢;
A表示含有2至6个C原子,优选含有3个C原子的亚烷基链,其可被苯基取代,并且;
B为亚甲基、亚乙基、羰基、亚磺酰基、磺酰基或硫,优选磺酰基。
根据本公开的式I的化合物或其盐与至少一种含血清素的试剂(例如SSRI)或其盐组合可用于预防和/或治疗早泄,其中优选地分别、依次或同时施用式I的化合物与至少一种含血清素的试剂。
出人意料的是,根据本公开的式I的化合物和至少一种含血清素的试剂(优选SSRI)的组合显著增加射精延迟时间。
尤其优选的5-HT1A受体拮抗剂是DU125530。DU125530与至少一种SSRI组合进一步增加射精延迟。另外,使用DU125530和至少一种SSRI的组合进一步增加射精延迟的技术效果可以通过降低SSRI剂量获得,与治疗抑郁症所需的SSRI剂量相当。SSRI剂量降低与副作用发生率降低以及副作用症状减轻有关。
DU125530可表征为具有式II的化合物
(式II)(2-[4-[4-(7-氯-2,3-二氢-1,4-苯并二氧杂苯-5-基)-1-哌嗪基]丁基]-1,2-苯并异噻唑-3(2H)-酮-1,1-二氧化物)
和/或CAS[161611-99-0],其分子式为C23H26ClN3O5S和/或分子量为491.99。
提及含血清素的试剂和/或5-HT1A受体拮抗剂,尤其是关于治疗用途,将理解为也包括其药学上可接受的盐。优选地,含血清素的试剂为SSRI,并且5-HT1A受体拮抗剂为DU125530。术语“药学上可接受的盐”是指由药学上可接受的无毒碱或无毒酸(包括无机碱或无机酸以及有机碱或有机酸)制备的盐或酯,如本领域技术人员公知的。许多合适的无机碱和有机碱是本领域已知的。
本公开的范围还扩展到保留期望活性的含血清素的试剂和/或5-HT1A受体拮抗剂的衍生物。可根据本领域公知的药物化学标准原理来制备保留与起始材料基本相同活性或更优选地表现出改进活性的衍生物。这种衍生物的活性可低于起始材料,只要它们保持足够的活性以达到治疗效果即可。衍生物可表现出药学活性剂所需的其他性质的改善,例如,改善的溶解度、降低的毒性、增强的吸收等。优选地,将与至少一种5-HT1A受体拮抗剂组合的至少一种含血清素的试剂配制成进一步包含一种或多种药学上可接受的载体、赋形剂或稀释剂的药物组合物。优选地,至少一种含血清素的试剂为至少一种SSRI,并且至少一种5-HT1A受体拮抗剂为DU125530。
至少一种含血清素的试剂或其衍生物、前体或代谢产物以及至少一种5-HT1A受体拮抗剂或其衍生物、前体或代谢产物的施用途径优选为非侵入性(例如口服)施用。优选地,至少一种含血清素的试剂为至少一种SSRI,并且至少一种5-HT1A受体拮抗剂为DU125530。通常,施用为口服施用、舌下施用或吸入施用,或以乳膏方式施用。
每单位剂量的至少一种含血清素的试剂和/或至少一种5-HT1A受体拮抗剂的量可根据活性化合物的性质和预期剂量方案而变化。优选地,至少一种含血清素的试剂为至少一种SSRI,并且至少一种5-HT1A受体拮抗剂为DU125530。通常应使用有效剂量,其范围可为每单位剂量0.01mg至5000mg,优选0.01至4000mg、0.1至3000mg、1至2500mg、1至1000mg、10至100mg、1至10mg、1至5mg。
优选地,本公开中施用的不同化合物按照以下时间表在血流中释放:
至少一种含血清素的试剂或其衍生物、前体或代谢产物基本上在性行为前0.5至1.5小时释放;和/或
5-HT1A拮抗剂或其衍生物、前体或代谢产物基本上在性行为前0.5至1.5小时释放。
优选地,至少一种含血清素的试剂为至少一种SSRI,并且至少一种5-HT1A受体拮抗剂为DU125530。
同时或可选地,剂量为使得至少一种含血清素的试剂(或其衍生物、前体或代谢产物)和/或5-HT1A拮抗剂或其衍生物、前体或代谢产物的峰值效应部分重叠的剂量。优选地,至少一种含血清素的试剂为至少一种SSRI,并且至少一种5-HT1A受体拮抗剂为DU125530。
优选地,在性行为前24小时至1分钟,比如20小时至1分钟、15小时至1分钟、10小时至1分钟、8小时至1分钟、6小时1分钟、4小时1分钟、120至1分钟,比如60分钟至1分钟、40分钟至1分钟、30分钟至1分钟、20分钟至1分钟、15分钟至1分钟、10分钟至1分钟、5分钟至1分钟、3分钟至1分钟向男性受试者施用根据本发明的用于预防和/或治疗早泄的至少一种含血清素的试剂或其衍生物、前体或代谢产物,和/或至少一种5-HT1A受体拮抗剂或衍生物、前体或其代谢产物,其中含血清素的试剂或其衍生物、前体或代谢产物优选为SSRI,例如帕罗西汀(paroxetine),并且其中5-HT1A受体拮抗剂或其衍生物、前体或代谢产物优选为DU125530。
优选地,在向受试者施用至少一种含血清素的试剂或其衍生物、前体或代谢产物和/或至少一种5-HT1A受体拮抗剂或其衍生物、前体或代谢产物的至少一种5-HT1A受体拮抗剂或其衍生物、前体或代谢产物之前10小时到1分钟,例如在施用至少一种5-HT1A受体拮抗剂或其衍生物、前体或代谢产物之前8小时至10分钟、6小时至30分钟、5小时至1小时或4小时至2小时向男性受试者施用根据本发明的用于预防和/或治疗早泄的至少一种含血清素的试剂或其衍生物、前体或代谢产物。至少一种含血清素的试剂或其衍生物、前体或代谢产物可在性行为之前4小时至10分钟施用,其中5-HT1A受体拮抗剂或其衍生物、前体或代谢产物可在性行为前10分钟至1分钟施用,其中含血清素的试剂或其衍生物、前体或代谢产物优选为SSRI,例如帕罗西汀,并且其中5-HT1A受体拮抗剂或其衍生物、前体或代谢产物优选为DU125530。
优选地,在向受试者施用至少一种5-HT1A受体拮抗剂或其衍生物、前体或代谢产物,和/或至少一种5-HT1A受体拮抗剂或其衍生物、前体或代谢产物的至少一种含血清素的试剂或其衍生物、前体或代谢产物之前10小时到1分钟,例如在施用至少一种含血清素的试剂或其衍生物、前体或代谢产物之前8小时至10分钟、6小时至30分钟、5小时至1小时或4小时至2小时向男性受试者施用根据本发明的用于预防和/或治疗早泄的至少一种5-HT1A受体拮抗剂或其衍生物、前体或代谢产物。可在性行为之前4小时至10分钟之间施用至少一种5-HT1A受体拮抗剂或其衍生物、前体或代谢产物,并且可在性行为之前10分钟至1分钟施用含血清素的试剂或其衍生物、前体或代谢产物,其中所述含血清素的试剂或其衍生物、前体或代谢产物优选为SSRI,例如帕罗西汀,并且其中所述5-HT1A受体拮抗剂优选为DU125530。
优选地,用于预防和/或治疗早泄的至少一种含血清素的试剂或其衍生物、前体或代谢产物和/或至少一种5-HT1A受体拮抗剂或其衍生物、前体或代谢产物不用于预防和/或治疗除早泄以外的任何其他病症、紊乱或疾病。
优选地,不是定期施用根据本发明用于预防和/或治疗早泄的至少一种含血清素的试剂或其衍生物、前体或代谢产物和/或至少一种5-HT1A受体拮抗剂或其衍生物、前体或代谢产物,例如每天、每周、每两周、每月、每12小时、每8小时、每天两次、每天三次或每天四次。优选地,其中含血清素的试剂或其衍生物、前体或代谢产物优选为SSRI,例如帕罗西汀,并且其中5-HT1A受体拮抗剂或其衍生物、前体或代谢产物优选为DU125530。
在优选的实施方式中,根据本公开使用的至少一种含血清素的试剂(或衍生物、前体或代谢产物)和/或至少一种5-HT1A拮抗剂或衍生物、前体或代谢产物作为包含叙述的化合物的单一组合物提供,例如片剂。优选地,至少一种含血清素的试剂为至少一种SSRI,并且至少一种5-HT1A受体拮抗剂为DU125530。
该组合物可进一步包括一种或多种药学上可接受的载体、赋形剂或稀释剂。
在可选的实施方式中,根据本公开使用的至少一种含血清素的试剂(或其衍生物、前体或代谢产物)和/或至少一种5-HT1A拮抗剂或衍生物、前体或代谢产物作为包含单独组合物的组合或套装提供,例如,包含至少一种含血清素的试剂(或其衍生物、前体或代谢产物)的组合物和/或包含至少一种5-HT1A拮抗剂或衍生物、前体或代谢产物的组合物。优选地,至少一种含血清素的试剂为至少一种SSRI,并且至少一种5-HT1A受体拮抗剂为DU125530。这些单独的组合物可进一步包含一种或多种药学上可接受的载体、赋形剂或稀释剂。
在本公开的上下文中,用于至少一种含血清素的试剂(或其衍生物、前体或代谢产物)和/或至少一种5-HT1A拮抗剂或衍生物、前体或代谢产物,优选其中至少一种含血清素的试剂为至少一种SSRI,并且至少一种5-HT1A受体拮抗剂为DU125530的适合剂型,包括但不限于固体剂型,例如片剂、胶囊剂、粉剂、分散粒剂、扁囊剂和栓剂,包括缓释制剂和延迟释放制剂。粉剂和片剂通常包含约5%至约70%的活性成分。固体载体和赋形剂在本领域中是众所公知的,并且包括例如碳酸镁、硬脂酸镁、滑石、糖、乳糖等。片剂、粉剂、扁囊剂和胶囊剂都是适于口服的剂型。
用于至少一种含血清素的试剂(或其衍生物、前体或代谢产物)和/或至少一种5-HT1A拮抗剂或衍生物、前体或代谢产物,优选其中至少一种含血清素的试剂为至少一种SSRI,并且至少一种5-HT1A受体拮抗剂为DU125530的适合液体剂型,包括溶液剂、混悬剂和乳剂。液体形式制剂可通过静脉、脑内、腹膜内、肠胃外或肌肉内注射或输注施用。无菌注射制剂可包括无毒、药学上可接受的稀释剂或溶剂中的活性剂的无菌溶液或混悬剂。液体剂型还包括用于鼻内、含服或舌下施用的溶液剂或喷雾剂。适于吸入的气溶胶制剂可包括粉末形式的溶液和固体,其可与药学上可接受的载体(例如惰性压缩气体)组合。
还包括用于经皮施用的至少一种含血清素的试剂(或其衍生物、前体或代谢产物)和/或至少一种5-HT1A拮抗剂或衍生物、前体或代谢产物的剂型,例如乳剂、洗液、油剂、气溶胶和/或乳液。优选地,至少一种含血清素的试剂为至少一种SSRI,并且至少一种5-HT1A受体拮抗剂为DU125530。这些剂型可包括在本领域中通常已知的基质型或储库型透皮贴剂中。
根据药物配制的标准程序,可方便地以单位剂型制备药物制剂剂量。
在本公开中,“衍生物”可被视为至少一个原子(和/或化学键)和/或至少一个官能团与参考化合物不同的化合物。差异还可在于至少两个、三个或四个原子(和/或化学键)和/或至少两个、三个或四个官能团。在本发明中,术语“前体”指比如通过宿主的新陈代谢转化为参考化合物的化合物。在本发明中,术语“代谢产物”指在作用于宿主的代谢时由参考化合物产生的化合物。
实验部分
实施例1
本发明人开发了一种雄性大鼠性行为模型,可预测SSRI对人类男性性行为的影响(Bijlsma等,2014年;Olivier等,2006年;2017年)。在该雄性大鼠性行为模型中,SSRI抑制性行为,但仅在长期施用后,从而模仿和模拟人类男性中的SSRI效应。
本发明人发现,在急性SSRI剂量中急性添加5-HT1A受体拮抗剂,可立即抑制男性性行为。最初,使用了原型5-HT1A受体拮抗剂WAY100635,但是该化合物优选不用于人。
本发明人认为,向SSRI中添加5-HT1A受体拮抗剂可加速抗抑郁活性行为的出现。选择了一种化合物DU125530,该化合物在体外和体内具有选择性5-HT1A受体拮抗活性(Mos等,1997年)。在几种动物模型中对该化合物进行测试,显示出良好且可靠的5-HT1A受体拮抗活性,但其本身没有生物活性(所谓的沉默拮抗剂)(Joordens等,1997年)。在对健康人类志愿者进行的正电子发射断层扫描研究(Rabiner等,2002年)中,10mg至40mg每日剂量范围具有良好的耐受性,副作用较小,并且在最后一次施用后2小时表现出剂量依赖性5-HT1A受体占有率(occupancy)为0%至72%。占有率与血浆DU125530水平高度相关。
在上述大鼠模型中,急性施用DU125530(20mg/kg)与急性施用帕罗西汀(SSRI,5mg/kg)的组合强烈抑制雄性大鼠的性行为。由于原型5-HT1A受体拮抗剂WA100635表现出相当的抑制作用(自身的数据),本发明人认为,阻断5-HT1A受体与阻断血清素转运体的组合,具有急性男性性行为抑制作用,特别是在射精过程中(见图1)。
发现:将阻断5-HT1A受体的药物(如DU125530)与含血清素的化合物(如SSRI)组合,可快速抑制雄性大鼠的性行为,包括射精。该发现有力地支持了这种组合在“按需”治疗人类早泄中的应用。
材料和方法
1克DU125530是从RUG(格罗宁根大学,University of Groningen)泽尼克校区(Zernike Campus)的一家(医药)化学公司SYNCOM订购的。合成路线描绘在图2中,并且本领域技术人员能够复制。发现该化合物与帕罗西汀组合时是安全的、药理活性高,并且单独使用时无任何作用(所谓的“沉默”拮抗剂)。
对雄性大鼠进行性训练,直到它们获得稳定的性行为(平均每30分钟射精2次,标准测试持续时间)。在试验前30分钟,对动物实施腹膜内注射,之后,雄性动物有30分钟的时间接触行为上接受性的雌性动物。由一位训练有素的研究人员根据已发表和公认的方法对雄性的性行为进行评分(Chan等,2010年)。
结果
图1显示了用媒介(Vh+Vh)、SSRI帕罗西汀(5-mg/kg:Px+Vh)、5-HT1A受体拮抗剂WAY100635(0.3-mg/kg)和帕罗西汀(5-mg/kg)(WAY+Px)的组合以及DU125530(20-mg/kg)和帕罗西汀(5-mg/kg)(Du+Px)的组合处理的效果。在分开的实验中,两种5-HT1A受体拮抗剂WAY100625(剂量高达1mg/kg,IP)和DU125530(剂量高达20mg/kg)对性行为没有行为影响(这里未显示),说明这两种化合物都是沉默拮抗剂。
实施例2
本发明人预期将DU125530与SSRI组合施用至雄性大鼠可增加雄性大鼠的射精延迟。另外,与无DU125530的SSRI施用相比,射精延迟时间的增加仅需要较低剂量的SSRI。因此,添加DU125530将射精延迟的剂量-反应曲线向左移动。图3显示了5-HT1A受体拮抗剂DU125530和SSRI组合对与发情期雌性大鼠进行30分钟的接触的经过性训练大鼠射精延迟(秒)的预期剂量-反应曲线。在图3中,横轴上的字母A至D表示SSRI浓度增加,纵轴上示出了射精延迟。浓度A、B、C和D分别对应于约1mg/kg、10mg/kg、20mg/kg和30mg/kg。图3图例中的缩写P.O.是per os,意思是口服施用。这些数据表明,将DU125530添加到SSRI中,使得增加射精延迟所需的SSRI的剂量更低。这是有利的,因为在较低的SSRI剂量下,SSRI的副作用也会降低。
实施例3
在用雄性大鼠的研究中,在性行为前不久,将10种不同的5-HT1A受体拮抗剂与5种不同的血清素能药物组合使用。在每组内,给每只雄性大鼠施用不同的含血清素的试剂与5-HT1A受体拮抗剂组合,该拮抗剂选自西酞普兰(Citalopram)、氟西汀(Fluoxetine)、伊福西汀(Ifoxetine)(CGP-15210)、帕罗西汀(Paroxetine)和齐美利定(Zimelidine),测量第一次射精前的时间,并除以未施用5-HT1A受体拮抗剂和含血清素的试剂的特定雄性大鼠第一次射精前的平均时间。下表给出了第一次射精的平均时间增长。
参考文献
Bijlsma EY,Chan JSW,Olivier B,Veening JG,Millan MJ,Waldinger MD,Oosting RS.Sexual side effects ofserotonergic antidepressants:Mediated byinhibition of serotonin on central dopamine release?PharmacolBiochem Behav121:88-101,2014
Chan JSW,Waldinger MD,Olivier B,Oosting RS.Drug-induced sexualdysfunction in rats.Current protocols in Neuroscience Suppl 53:9.34.1-9.34.11,2010
Chan JSW,Snoeren EMS,Cuppen E,Waldinger MD,Olivier B,Oosting RS.Theserotonin transporter plays animportant role in male sexual behavior:a studyin serotonin transporter knockout rats.J Sex Medicine 8:97-108,2011
Joordens RJE,Hijzen TH,Olivier B.The effects of 5-HT1A receptoragonists,5-HT1A receptor antagonists and their interaction in the fear-potentiated startle response paradigm.Psychopharmacology 1998;139:383-390.
Mos J,Van Hest A,Herremans AHJ,Van Drimmelen M,Olivier B.The putative5-HT1A receptor antagonistDU125530 blocks the discriminative stimulus effectsof the 5-HT1A agonist flesinoxan in the pigeon.Eur.J.Pharmacol.1997;325:145-153.
Olivier B,Chan JSW,Pattij T,de Jong TR,Oosting RS,Veening JG,Waldinger MD.Psychopharmacology of male rat sexual behavior:modeling humansexual dysfunctions?International Journal of Impotence Research18:S14-S23,2006
Olivier JDA,Esquivel Franco DC,Waldinger MD,Olivier B.Sexualdysfunction,depression and antidepressants:a translational approach.In:SexualDysfunction,Intech open,Ed.B.Olivier,pp 59-76,2017
RABINER EA,WILKINS MR,TURKHEIMER F,GUNN RN,UDO DE HAES J,DE VRIES M,GRASBY PM.5-Hydroxytryptamine1AReceptor Occupancy by Novel Full Antagonist 2-[4-[4-(7-Chloro-2,3-dihydro-1,4benzdioxyn-5-yl)-1-piperazinyl]butyl]-1,2-benzisothiazol-3-(2H)one-1,1-dioxide:A[11C][O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cy clohexanecarboxamideTrihydrochloride(WAY-100635)Positron Emission Tomography Study in Humans.JPharmacol Exp Ther 301:1144-1150,2002.
Claims (8)
3.根据权利要求1或2所述的式I的化合物与至少一种含血清素的试剂组合的用途,其中所述式I的化合物与所述至少一种含血清素的试剂组合用于增加射精的延迟。
4.根据前述权利要求中任一项所述的式I的化合物与至少一种含血清素的试剂组合的用途,其中
所述至少一种式I的化合物基本上在性行为前0.5至1.5小时释放;和/或
所述至少一种含血清素的试剂基本上在性行为前0.5至1.5小时释放;
其中优选地所述至少一种式I的化合物和/或所述至少一种含血清素的试剂的峰值效应部分重叠。
5.根据前述权利要求中任一项所述的式I的化合物与至少一种含血清素的试剂组合的用途,其中所述式I的化合物和/或至少一种含血清素的试剂作为包括式I的化合物和/或至少一种含血清素的试剂的组合物提供,优选地进一步包括一种或多种药学上可接受的载体、赋形剂或稀释剂。
6.根据前述权利要求中任一项所述的式I的化合物与至少一种含血清素的试剂组合的用途,其中式I的化合物和/或至少一种含血清素的试剂作为包括包含式I的化合物的组合物和/或包含至少一种含血清素的试剂的组合物的部分的套装提供,优选地其中一种或多种所述组合物进一步包括一种或多种药学上可接受的载体、赋形剂或稀释剂。
7.根据前述权利要求中任一项所述的式I的化合物与至少一种含血清素的试剂组合的用途,其中所述至少一种式I的化合物和/或至少一种含血清素的试剂口服施用和/或舌下施用。
8.根据前述权利要求中任一项所述的式I的化合物与至少一种含血清素的试剂组合的用途,其中所述至少一种含血清素的试剂为选自由血清素受体激动剂或拮抗剂、血清素再摄取抑制剂、选择性血清素和去甲肾上腺素再摄取抑制剂,以及血清素释放剂组成的组中的至少一种、两种或三种,其中优选地所述含血清素的试剂为选择性血清素再摄取抑制剂,更优选地选自由西酞普兰、艾司西酞普兰、氟西汀、氟伏沙明、帕罗西汀、舍曲林、达泊西汀、吲达品、齐美利定、阿拉丙酯、桑普罗帕嗪、西文氯胺(JO-1017)、非莫西汀(马来西利;FG-4963)、伊福西汀(CGP-15210)、奥米西汀、帕努拉明(WY-26002)、吡喃达明(AY-23713)和塞罗西汀((S)-诺氟西汀)组成的组中。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NL2023581 | 2019-07-29 | ||
NL2023581A NL2023581B1 (en) | 2019-07-29 | 2019-07-29 | Serotonergic agent and 5-HT1A-receptor antagonist |
PCT/EP2020/071410 WO2021018967A1 (en) | 2019-07-29 | 2020-07-29 | Serotonergic agent and 5-ht1a-receptor antagonist |
Publications (1)
Publication Number | Publication Date |
---|---|
CN114144179A true CN114144179A (zh) | 2022-03-04 |
Family
ID=67742920
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202080053794.1A Pending CN114144179A (zh) | 2019-07-29 | 2020-07-29 | 含血清素的试剂和5-ht1a受体拮抗剂 |
Country Status (11)
Country | Link |
---|---|
US (1) | US20220265641A1 (zh) |
EP (1) | EP4003347A1 (zh) |
JP (1) | JP2022542698A (zh) |
KR (1) | KR20220041134A (zh) |
CN (1) | CN114144179A (zh) |
AU (1) | AU2020320022A1 (zh) |
BR (1) | BR112022001504A2 (zh) |
CA (1) | CA3146098A1 (zh) |
MX (1) | MX2022001274A (zh) |
NL (1) | NL2023581B1 (zh) |
WO (1) | WO2021018967A1 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11977085B1 (en) | 2023-09-05 | 2024-05-07 | Elan Ehrlich | Date rape drug detection device and method of using same |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6169105B1 (en) * | 1994-11-28 | 2001-01-02 | Eli Lilly And Company | Potentiation of drug response |
WO2008122561A1 (en) * | 2007-04-05 | 2008-10-16 | Glaxo Group Limited | Pyridinone derivative for the treatment of premature ejaculation |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0318706D0 (en) * | 2003-08-08 | 2003-09-10 | Pfizer Ltd | Selective serotonin reuptake inhibitors in the treatment of disease |
WO2018102233A1 (en) * | 2016-11-30 | 2018-06-07 | Wang tian xin | Therapeutical methods, formulations and nutraceutical formulations |
-
2019
- 2019-07-29 NL NL2023581A patent/NL2023581B1/en active
-
2020
- 2020-07-29 EP EP20746976.8A patent/EP4003347A1/en not_active Withdrawn
- 2020-07-29 CN CN202080053794.1A patent/CN114144179A/zh active Pending
- 2020-07-29 CA CA3146098A patent/CA3146098A1/en active Pending
- 2020-07-29 KR KR1020227005808A patent/KR20220041134A/ko unknown
- 2020-07-29 AU AU2020320022A patent/AU2020320022A1/en active Pending
- 2020-07-29 US US17/627,602 patent/US20220265641A1/en active Pending
- 2020-07-29 JP JP2022506390A patent/JP2022542698A/ja active Pending
- 2020-07-29 WO PCT/EP2020/071410 patent/WO2021018967A1/en active Application Filing
- 2020-07-29 BR BR112022001504A patent/BR112022001504A2/pt unknown
- 2020-07-29 MX MX2022001274A patent/MX2022001274A/es unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6169105B1 (en) * | 1994-11-28 | 2001-01-02 | Eli Lilly And Company | Potentiation of drug response |
WO2008122561A1 (en) * | 2007-04-05 | 2008-10-16 | Glaxo Group Limited | Pyridinone derivative for the treatment of premature ejaculation |
Non-Patent Citations (2)
Title |
---|
MARCEL D. WALDINGER等: "On-Demand SSRI Treatment of Premature Ejaculation:Pharmacodynamic Limitations for Relevant Ejaculation Delay and Consequent Solutions", 《J SEX MED》, vol. 2, no. 1, pages 121 - 131, XP008063787, DOI: 10.1111/j.1743-6109.2005.20112.x * |
MC SCORZA等: "Preclinical and clinical characterization of the selective 5-HT1A receptor antagonist DU-125530 for antidepressant treatment", 《BRITISH JOURNAL OF PHARMACOLOGY》, vol. 167, no. 5, pages 1021 - 1034 * |
Also Published As
Publication number | Publication date |
---|---|
JP2022542698A (ja) | 2022-10-06 |
EP4003347A1 (en) | 2022-06-01 |
CA3146098A1 (en) | 2021-02-04 |
KR20220041134A (ko) | 2022-03-31 |
US20220265641A1 (en) | 2022-08-25 |
AU2020320022A1 (en) | 2022-03-03 |
NL2023581B1 (en) | 2021-02-22 |
BR112022001504A2 (pt) | 2022-03-22 |
WO2021018967A1 (en) | 2021-02-04 |
MX2022001274A (es) | 2022-02-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6169105B1 (en) | Potentiation of drug response | |
JP4886700B2 (ja) | 5ht2cレセプターモジュレーターの組成物およびその使用方法 | |
AU685510B2 (en) | Potentiation of drug response | |
JP2007533725A (ja) | Crth2受容体アンタゴニストを用いたニューロパシー性疼痛処置方法 | |
EP1988898A2 (en) | Pharmaceutical compositions for the treatment of attention deficit hyperactivity disorder comprising flibanserin | |
EP3094327A1 (en) | USE OF sGC STIMULATORS FOR THE TREATMENT OF NEUROMUSCULAR DISORDERS | |
TW200412240A (en) | Use for norepinephrine reuptake modulators for preventing and treating vasomotor symptoms | |
EP0759299B1 (en) | Potentiation of serotonin response | |
TW200413001A (en) | Use for norepinephrine reuptake modulators for preventing and treating vasomotor symptoms | |
JP2006516023A (ja) | ノルエピネフリン再取り込み阻害活性及び5−ht2aアンタゴニスト活性を示す化合物を有する、血管運動症状を治療する方法。 | |
AU2019200512B2 (en) | Use of phenoxypropylamine compounds to treat depression | |
US20220265641A1 (en) | Serotonergic agent and 5-ht1a-receptor antagonist | |
US6562858B2 (en) | Method for treating depression | |
EA015483B1 (ru) | ПРИМЕНЕНИЕ ИНГИБИТОРА p38 КИНАЗЫ ДЛЯ ЛЕЧЕНИЯ ПСИХИАТРИЧЕСКИХ РАССТРОЙСТВ | |
WO2017041112A1 (en) | Ketamine and cytochrome p 450 inhibitor combinations | |
KR20070034129A (ko) | 신경계 질환 및 장애의 치료 방법 | |
US20050130987A1 (en) | Methods of treating vasomotor symptoms | |
JP2011513319A (ja) | 活性化リンパ球に関連する疾患の処置のための組成物 | |
CA2453445C (fr) | Derives de pyridin-2-yl-methylamine pour le traitement de la dependance aux opioides | |
CN101495109A (zh) | 包含沙瑞度坦与5-羟色胺再摄取的选择性抑制剂或5-羟色胺/去甲肾上腺素的再摄取的抑制剂的联用的药物组合物 | |
AU2004281750A1 (en) | Use of adrenergic alphaze antagonists for the treatment of vasomotor symptoms | |
JP2005289886A (ja) | 自傷行動抑制薬 | |
JP2007515395A (ja) | 血管運動症状の治療方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40065810 Country of ref document: HK |