CN109310689A - 用于治疗或预防血管舒缩症状的组合物 - Google Patents
用于治疗或预防血管舒缩症状的组合物 Download PDFInfo
- Publication number
- CN109310689A CN109310689A CN201780036529.0A CN201780036529A CN109310689A CN 109310689 A CN109310689 A CN 109310689A CN 201780036529 A CN201780036529 A CN 201780036529A CN 109310689 A CN109310689 A CN 109310689A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- alkoxy
- halogenated
- base
- halogen
- 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
- 208000024891 symptom Diseases 0.000 title claims abstract description 78
- 230000001457 vasomotor Effects 0.000 title claims abstract description 59
- 239000000203 mixture Substances 0.000 title claims abstract description 42
- 229940123537 TRPM8 antagonist Drugs 0.000 claims abstract description 58
- HHVOOJDLCVOLKI-VWLOTQADSA-N methyl (2S)-2-(dibenzylamino)-3-(1H-indol-3-yl)propanoate Chemical compound C=1C=CC=CC=1CN([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)OC)CC1=CC=CC=C1 HHVOOJDLCVOLKI-VWLOTQADSA-N 0.000 claims abstract description 58
- 238000000034 method Methods 0.000 claims abstract description 44
- 206010037660 Pyrexia Diseases 0.000 claims abstract description 37
- 230000001052 transient effect Effects 0.000 claims abstract description 7
- 239000005557 antagonist Substances 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 92
- 150000002367 halogens Chemical class 0.000 claims description 83
- 125000000217 alkyl group Chemical group 0.000 claims description 52
- 125000003545 alkoxy group Chemical group 0.000 claims description 49
- -1 amine compound Chemical class 0.000 claims description 39
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 35
- 238000011282 treatment Methods 0.000 claims description 33
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 32
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 31
- 239000003795 chemical substances by application Substances 0.000 claims description 30
- 229910052799 carbon Inorganic materials 0.000 claims description 27
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 25
- 230000003213 activating effect Effects 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 229960004365 benzoic acid Drugs 0.000 claims description 22
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 239000005711 Benzoic acid Substances 0.000 claims description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 19
- 235000010233 benzoic acid Nutrition 0.000 claims description 19
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 19
- 150000001721 carbon Chemical group 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 206010028980 Neoplasm Diseases 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 201000011510 cancer Diseases 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 claims description 12
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 12
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 11
- OZHGAIKBHMVOCV-UHFFFAOYSA-N 4-cyclopropylisoquinoline Chemical compound C1CC1C1=CN=CC2=CC=CC=C12 OZHGAIKBHMVOCV-UHFFFAOYSA-N 0.000 claims description 10
- 125000004429 atom Chemical group 0.000 claims description 10
- 206010029410 night sweats Diseases 0.000 claims description 10
- 230000036565 night sweats Effects 0.000 claims description 10
- 150000002825 nitriles Chemical class 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 229940124530 sulfonamide Drugs 0.000 claims description 8
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- NYGNCDFRMGYHBD-UHFFFAOYSA-N 1-cyclopropyl-4-methylisoquinoline Chemical compound C1(CC1)C1=NC=C(C2=CC=CC=C12)C NYGNCDFRMGYHBD-UHFFFAOYSA-N 0.000 claims description 6
- OCOLIBYZTNPPAB-UHFFFAOYSA-N 4-methylisoquinoline Chemical compound C1=CC=C2C(C)=CN=CC2=C1 OCOLIBYZTNPPAB-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 239000004215 Carbon black (E152) Substances 0.000 claims description 6
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical class C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 239000005864 Sulphur Substances 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 6
- 229930195733 hydrocarbon Natural products 0.000 claims description 6
- 150000002430 hydrocarbons Chemical class 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 150000004820 halides Chemical class 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- 150000003456 sulfonamides Chemical class 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 3
- SVDREOGWGOOYQQ-UHFFFAOYSA-N 4-methyl-1-propan-2-ylisoquinoline Chemical compound C1=CC=C2C(C(C)C)=NC=C(C)C2=C1 SVDREOGWGOOYQQ-UHFFFAOYSA-N 0.000 claims description 3
- XHJAOEKASUFHHN-UHFFFAOYSA-N 5-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=C=NC=C[CH]1 XHJAOEKASUFHHN-UHFFFAOYSA-N 0.000 claims description 3
- 125000002723 alicyclic group Chemical group 0.000 claims description 3
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 239000003163 gonadal steroid hormone Substances 0.000 claims description 3
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- 210000004907 gland Anatomy 0.000 claims description 2
- 238000009806 oophorectomy Methods 0.000 claims description 2
- 238000011474 orchiectomy Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 230000001568 sexual effect Effects 0.000 claims description 2
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims 2
- 125000000000 cycloalkoxy group Chemical group 0.000 claims 2
- 150000002390 heteroarenes Chemical class 0.000 claims 2
- 239000000470 constituent Substances 0.000 claims 1
- 229940126062 Compound A Drugs 0.000 description 20
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 20
- 230000000694 effects Effects 0.000 description 20
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 16
- 239000003814 drug Substances 0.000 description 12
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 11
- 108010000817 Leuprolide Proteins 0.000 description 10
- RGLRXNKKBLIBQS-XNHQSDQCSA-N leuprolide acetate Chemical compound CC(O)=O.CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 RGLRXNKKBLIBQS-XNHQSDQCSA-N 0.000 description 9
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 9
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 229960004338 leuprorelin Drugs 0.000 description 8
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 8
- 108010050144 Triptorelin Pamoate Proteins 0.000 description 7
- GZOSMCIZMLWJML-VJLLXTKPSA-N abiraterone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CC[C@H](O)CC3=CC2)C)CC[C@@]11C)C=C1C1=CC=CN=C1 GZOSMCIZMLWJML-VJLLXTKPSA-N 0.000 description 7
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 7
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 7
- HHXHVIJIIXKSOE-QILQGKCVSA-N histrelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC(N=C1)=CN1CC1=CC=CC=C1 HHXHVIJIIXKSOE-QILQGKCVSA-N 0.000 description 7
- 229940088597 hormone Drugs 0.000 description 7
- 239000005556 hormone Substances 0.000 description 7
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 7
- 239000000902 placebo Substances 0.000 description 7
- 229940068196 placebo Drugs 0.000 description 7
- 229960004622 raloxifene Drugs 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 229960001603 tamoxifen Drugs 0.000 description 7
- 229960005026 toremifene Drugs 0.000 description 7
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 7
- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 description 7
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 6
- 108010069236 Goserelin Proteins 0.000 description 6
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 6
- VIROVYVQCGLCII-UHFFFAOYSA-N amobarbital Chemical compound CC(C)CCC1(CC)C(=O)NC(=O)NC1=O VIROVYVQCGLCII-UHFFFAOYSA-N 0.000 description 6
- 239000000262 estrogen Substances 0.000 description 6
- 229960002258 fulvestrant Drugs 0.000 description 6
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- 108010037003 Buserelin Proteins 0.000 description 5
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 5
- 108010021717 Nafarelin Proteins 0.000 description 5
- 229960000853 abiraterone Drugs 0.000 description 5
- 229960002932 anastrozole Drugs 0.000 description 5
- 229960002719 buserelin Drugs 0.000 description 5
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 5
- 229940011871 estrogen Drugs 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 5
- 229960004421 formestane Drugs 0.000 description 5
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 5
- 108700020746 histrelin Proteins 0.000 description 5
- 229960002193 histrelin Drugs 0.000 description 5
- 229960002367 lasofoxifene Drugs 0.000 description 5
- 229940041616 menthol Drugs 0.000 description 5
- 229960002653 nilutamide Drugs 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 229960003387 progesterone Drugs 0.000 description 5
- 239000000186 progesterone Substances 0.000 description 5
- 230000007958 sleep Effects 0.000 description 5
- 229960004824 triptorelin Drugs 0.000 description 5
- 229960001771 vorozole Drugs 0.000 description 5
- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 5
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 4
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 4
- CLPFFLWZZBQMAO-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 description 4
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 4
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 4
- 108010037150 Transient Receptor Potential Channels Proteins 0.000 description 4
- 108010052004 acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide Proteins 0.000 description 4
- 238000009167 androgen deprivation therapy Methods 0.000 description 4
- 229960000997 bicalutamide Drugs 0.000 description 4
- 239000002981 blocking agent Substances 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- MEUCPCLKGZSHTA-XYAYPHGZSA-N degarelix Chemical compound C([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CC=1C=CC(NC(=O)[C@H]2NC(=O)NC(=O)C2)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(NC(N)=O)C=C1 MEUCPCLKGZSHTA-XYAYPHGZSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 235000015177 dried meat Nutrition 0.000 description 4
- 239000000328 estrogen antagonist Substances 0.000 description 4
- 229960000255 exemestane Drugs 0.000 description 4
- 229950011548 fadrozole Drugs 0.000 description 4
- 229960002913 goserelin Drugs 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- GXESHMAMLJKROZ-IAPPQJPRSA-N lasofoxifene Chemical compound C1([C@@H]2[C@@H](C3=CC=C(C=C3CC2)O)C=2C=CC(OCCN3CCCC3)=CC=2)=CC=CC=C1 GXESHMAMLJKROZ-IAPPQJPRSA-N 0.000 description 4
- 229960003881 letrozole Drugs 0.000 description 4
- RWHUEXWOYVBUCI-ITQXDASVSA-N nafarelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 RWHUEXWOYVBUCI-ITQXDASVSA-N 0.000 description 4
- 229960002333 nafarelin Drugs 0.000 description 4
- 238000012216 screening Methods 0.000 description 4
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 4
- 229960002256 spironolactone Drugs 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical group NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 4
- 229960004688 venlafaxine Drugs 0.000 description 4
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 4
- 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 description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 3
- 229940122815 Aromatase inhibitor Drugs 0.000 description 3
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 3
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 3
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 3
- 102000011753 Transient Receptor Potential Channels Human genes 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 230000003042 antagnostic effect Effects 0.000 description 3
- 229940046836 anti-estrogen Drugs 0.000 description 3
- 230000001833 anti-estrogenic effect Effects 0.000 description 3
- 239000003886 aromatase inhibitor Substances 0.000 description 3
- 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 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 description 3
- 229960004170 clozapine Drugs 0.000 description 3
- 238000011284 combination treatment Methods 0.000 description 3
- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 description 3
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 229960002296 paroxetine Drugs 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- DIWRORZWFLOCLC-HNNXBMFYSA-N (3s)-7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound N([C@H](C(NC1=CC=C(Cl)C=C11)=O)O)=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-HNNXBMFYSA-N 0.000 description 2
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- ZEHYJZXQEQOSON-AATRIKPKSA-N (e)-1-chloro-3-ethylpent-1-en-4-yn-3-ol Chemical compound CCC(O)(C#C)\C=C\Cl ZEHYJZXQEQOSON-AATRIKPKSA-N 0.000 description 2
- DWPQODZAOSWNHB-UHFFFAOYSA-N 1-(3-chlorophenyl)-3-(3-methyl-5-oxo-4H-imidazol-2-yl)urea Chemical compound CN1CC(=O)N=C1NC(=O)NC1=CC=CC(Cl)=C1 DWPQODZAOSWNHB-UHFFFAOYSA-N 0.000 description 2
- MFKMXUFMHOCZHP-RQZHXJHFSA-N 1-[2-[4-[(z)-1-(4-methoxyphenyl)-2-nitro-2-phenylethenyl]phenoxy]ethyl]pyrrolidine Chemical compound C1=CC(OC)=CC=C1C(\C=1C=CC(OCCN2CCCC2)=CC=1)=C([N+]([O-])=O)/C1=CC=CC=C1 MFKMXUFMHOCZHP-RQZHXJHFSA-N 0.000 description 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 2
- KYWMWUUMCDZISK-UHFFFAOYSA-N 2,2,5,5-tetrakis(trifluoromethyl)-1h-imidazol-4-amine Chemical compound NC1=NC(C(F)(F)F)(C(F)(F)F)NC1(C(F)(F)F)C(F)(F)F KYWMWUUMCDZISK-UHFFFAOYSA-N 0.000 description 2
- FXZJKVODWNYPKK-UHFFFAOYSA-N 3-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-1h-quinazoline-2,4-dione Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(C4=CC=CC=C4NC3=O)=O)CC2)=C1 FXZJKVODWNYPKK-UHFFFAOYSA-N 0.000 description 2
- PCTRYMLLRKWXGF-UHFFFAOYSA-N 4-(butylamino)-1-ethyl-6-methyl-5-pyrazolo[3,4-b]pyridinecarboxylic acid ethyl ester Chemical compound CCCCNC1=C(C(=O)OCC)C(C)=NC2=C1C=NN2CC PCTRYMLLRKWXGF-UHFFFAOYSA-N 0.000 description 2
- XWVOEFLBOSSYGM-UHFFFAOYSA-N 4-morpholinyl-(3,4,5-trimethoxyphenyl)methanone Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CCOCC2)=C1 XWVOEFLBOSSYGM-UHFFFAOYSA-N 0.000 description 2
- FTOAOBMCPZCFFF-UHFFFAOYSA-N 5,5-diethylbarbituric acid Chemical compound CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- UMSGKTJDUHERQW-UHFFFAOYSA-N Brotizolam Chemical compound C1=2C=C(Br)SC=2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl UMSGKTJDUHERQW-UHFFFAOYSA-N 0.000 description 2
- 108091006146 Channels Proteins 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 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 2
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 2
- GJKXGJCSJWBJEZ-XRSSZCMZSA-N Deslorelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CNC2=CC=CC=C12 GJKXGJCSJWBJEZ-XRSSZCMZSA-N 0.000 description 2
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 2
- 229940102550 Estrogen receptor antagonist Drugs 0.000 description 2
- 108700012941 GNRH1 Proteins 0.000 description 2
- JMBQKKAJIKAWKF-UHFFFAOYSA-N Glutethimide Chemical compound C=1C=CC=CC=1C1(CC)CCC(=O)NC1=O JMBQKKAJIKAWKF-UHFFFAOYSA-N 0.000 description 2
- NMJREATYWWNIKX-UHFFFAOYSA-N GnRH Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CC(C)C)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 NMJREATYWWNIKX-UHFFFAOYSA-N 0.000 description 2
- WYCLKVQLVUQKNZ-UHFFFAOYSA-N Halazepam Chemical compound N=1CC(=O)N(CC(F)(F)F)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 WYCLKVQLVUQKNZ-UHFFFAOYSA-N 0.000 description 2
- 206010019233 Headaches Diseases 0.000 description 2
- 208000033830 Hot Flashes Diseases 0.000 description 2
- 206010060800 Hot flush Diseases 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- JJKOTMDDZAJTGQ-DQSJHHFOSA-N Idoxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN2CCCC2)=CC=1)/C1=CC=C(I)C=C1 JJKOTMDDZAJTGQ-DQSJHHFOSA-N 0.000 description 2
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 2
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 2
- JEYCTXHKTXCGPB-UHFFFAOYSA-N Methaqualone Chemical compound CC1=CC=CC=C1N1C(=O)C2=CC=CC=C2N=C1C JEYCTXHKTXCGPB-UHFFFAOYSA-N 0.000 description 2
- LKJPYSCBVHEWIU-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CS(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-UHFFFAOYSA-N 0.000 description 2
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 2
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 2
- 102000048266 Nociceptin Human genes 0.000 description 2
- 108090000622 Nociceptin Proteins 0.000 description 2
- PWRPUAKXMQAFCJ-UHFFFAOYSA-N Perlapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2CC2=CC=CC=C12 PWRPUAKXMQAFCJ-UHFFFAOYSA-N 0.000 description 2
- RMUCZJUITONUFY-UHFFFAOYSA-N Phenelzine Chemical compound NNCCC1=CC=CC=C1 RMUCZJUITONUFY-UHFFFAOYSA-N 0.000 description 2
- MWQCHHACWWAQLJ-UHFFFAOYSA-N Prazepam Chemical compound O=C1CN=C(C=2C=CC=CC=2)C2=CC(Cl)=CC=C2N1CC1CC1 MWQCHHACWWAQLJ-UHFFFAOYSA-N 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 102000003923 Protein Kinase C Human genes 0.000 description 2
- 108090000315 Protein Kinase C Proteins 0.000 description 2
- IKMPWMZBZSAONZ-UHFFFAOYSA-N Quazepam Chemical compound FC1=CC=CC=C1C1=NCC(=S)N(CC(F)(F)F)C2=CC=C(Cl)C=C12 IKMPWMZBZSAONZ-UHFFFAOYSA-N 0.000 description 2
- PPTYJKAXVCCBDU-UHFFFAOYSA-N Rohypnol Chemical compound N=1CC(=O)N(C)C2=CC=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1F PPTYJKAXVCCBDU-UHFFFAOYSA-N 0.000 description 2
- 208000010340 Sleep Deprivation Diseases 0.000 description 2
- SEQDDYPDSLOBDC-UHFFFAOYSA-N Temazepam Chemical compound N=1C(O)C(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 SEQDDYPDSLOBDC-UHFFFAOYSA-N 0.000 description 2
- KLBQZWRITKRQQV-UHFFFAOYSA-N Thioridazine Chemical compound C12=CC(SC)=CC=C2SC2=CC=CC=C2N1CCC1CCCCN1C KLBQZWRITKRQQV-UHFFFAOYSA-N 0.000 description 2
- IWEQQRMGNVVKQW-OQKDUQJOSA-N Toremifene citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 IWEQQRMGNVVKQW-OQKDUQJOSA-N 0.000 description 2
- YYQRGCZGSFRBAM-UHFFFAOYSA-N Triclofos Chemical compound OP(O)(=O)OCC(Cl)(Cl)Cl YYQRGCZGSFRBAM-UHFFFAOYSA-N 0.000 description 2
- GDSCFOSHSOWNDL-UHFFFAOYSA-N Zolasepam Chemical compound N=1CC(=O)N(C)C(N(N=C2C)C)=C2C=1C1=CC=CC=C1F GDSCFOSHSOWNDL-UHFFFAOYSA-N 0.000 description 2
- IHGLINDYFMDHJG-UHFFFAOYSA-N [2-(4-methoxyphenyl)-3,4-dihydronaphthalen-1-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]methanone Chemical compound C1=CC(OC)=CC=C1C(CCC1=CC=CC=C11)=C1C(=O)C(C=C1)=CC=C1OCCN1CCCC1 IHGLINDYFMDHJG-UHFFFAOYSA-N 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 229960003148 adinazolam Drugs 0.000 description 2
- 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 2
- 229960004538 alprazolam Drugs 0.000 description 2
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- 229960000711 alprostadil Drugs 0.000 description 2
- 229960000836 amitriptyline Drugs 0.000 description 2
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 2
- 229960001301 amobarbital Drugs 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
- 230000002280 anti-androgenic effect Effects 0.000 description 2
- 239000000051 antiandrogen Substances 0.000 description 2
- 229940078010 arimidex Drugs 0.000 description 2
- 229940087620 aromasin Drugs 0.000 description 2
- 229940125717 barbiturate Drugs 0.000 description 2
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 2
- AIZFEOPQVZBNGH-UHFFFAOYSA-N bentazepam Chemical compound C1=2C=3CCCCC=3SC=2NC(=O)CN=C1C1=CC=CC=C1 AIZFEOPQVZBNGH-UHFFFAOYSA-N 0.000 description 2
- 229950001957 bentazepam Drugs 0.000 description 2
- GNRXCIONJWKSEA-UHFFFAOYSA-N benzoctamine Chemical compound C12=CC=CC=C2C2(CNC)C3=CC=CC=C3C1CC2 GNRXCIONJWKSEA-UHFFFAOYSA-N 0.000 description 2
- 229960001303 benzoctamine Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- IEPBPSSCIZTJIF-UHFFFAOYSA-N bis(2,2,2-trichloroethyl) carbonate Chemical compound ClC(Cl)(Cl)COC(=O)OCC(Cl)(Cl)Cl IEPBPSSCIZTJIF-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
- 229960003051 brotizolam Drugs 0.000 description 2
- 229960001058 bupropion Drugs 0.000 description 2
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 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 description 2
- 229960002495 buspirone Drugs 0.000 description 2
- ZRIHAIZYIMGOAB-UHFFFAOYSA-N butabarbital Chemical compound CCC(C)C1(CC)C(=O)NC(=O)NC1=O ZRIHAIZYIMGOAB-UHFFFAOYSA-N 0.000 description 2
- UZVHFVZFNXBMQJ-UHFFFAOYSA-N butalbital Chemical compound CC(C)CC1(CC=C)C(=O)NC(=O)NC1=O UZVHFVZFNXBMQJ-UHFFFAOYSA-N 0.000 description 2
- 229960002546 butalbital Drugs 0.000 description 2
- HLSLSXBFTXUKCY-UHFFFAOYSA-N capuride Chemical compound CCC(C)C(CC)C(=O)NC(N)=O HLSLSXBFTXUKCY-UHFFFAOYSA-N 0.000 description 2
- 229950003152 capuride Drugs 0.000 description 2
- ITMSAWKLJVGBIT-UHFFFAOYSA-N carbocloral Chemical compound CCOC(=O)NC(O)C(Cl)(Cl)Cl ITMSAWKLJVGBIT-UHFFFAOYSA-N 0.000 description 2
- 229950003854 carbocloral Drugs 0.000 description 2
- 229960000590 celecoxib Drugs 0.000 description 2
- UKFDTMNJMKWWNK-UHFFFAOYSA-N chembl2104165 Chemical compound C12=CC(Cl)=CC=C2N\C(=N\CC2CC2)C[N+]([O-])=C1C1=CC=CC=C1 UKFDTMNJMKWWNK-UHFFFAOYSA-N 0.000 description 2
- ONAOIDNSINNZOA-UHFFFAOYSA-N chloral betaine Chemical compound OC(O)C(Cl)(Cl)Cl.C[N+](C)(C)CC([O-])=O ONAOIDNSINNZOA-UHFFFAOYSA-N 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 229960004606 clomipramine Drugs 0.000 description 2
- 229960002896 clonidine Drugs 0.000 description 2
- 229950000551 cloperidone Drugs 0.000 description 2
- 230000036757 core body temperature Effects 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 229950010040 cyprazepam Drugs 0.000 description 2
- 229960002272 degarelix Drugs 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 229960003914 desipramine Drugs 0.000 description 2
- 108700025485 deslorelin Proteins 0.000 description 2
- 229960005408 deslorelin Drugs 0.000 description 2
- UPMOVJBGNREKJV-CQOQZXRMSA-N dexclamol Chemical compound C12=CC=CC=C2CCC2=CC=CC3=C2[C@@H]1CN1CC[C@@](C(C)C)(O)C[C@@H]13 UPMOVJBGNREKJV-CQOQZXRMSA-N 0.000 description 2
- 229950005215 dexclamol Drugs 0.000 description 2
- 229960003529 diazepam Drugs 0.000 description 2
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 2
- 229960000520 diphenhydramine Drugs 0.000 description 2
- 229960005426 doxepin Drugs 0.000 description 2
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 2
- 229950004203 droloxifene Drugs 0.000 description 2
- 229960002336 estazolam Drugs 0.000 description 2
- 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 2
- 229960005309 estradiol Drugs 0.000 description 2
- 229930182833 estradiol Natural products 0.000 description 2
- 229960004447 ethchlorvynol Drugs 0.000 description 2
- 229960005293 etodolac Drugs 0.000 description 2
- NNYBQONXHNTVIJ-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=C1C(C=CC=C1CC)=C1N2 NNYBQONXHNTVIJ-UHFFFAOYSA-N 0.000 description 2
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 2
- 229960001690 etomidate Drugs 0.000 description 2
- 229960004945 etoricoxib Drugs 0.000 description 2
- 229940085363 evista Drugs 0.000 description 2
- 229940043168 fareston Drugs 0.000 description 2
- 229940087861 faslodex Drugs 0.000 description 2
- 229940087476 femara Drugs 0.000 description 2
- 229950002489 fenobam Drugs 0.000 description 2
- 229940002006 firmagon Drugs 0.000 description 2
- 229950005722 flosulide Drugs 0.000 description 2
- 229960002200 flunitrazepam Drugs 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 229960003528 flurazepam Drugs 0.000 description 2
- SAADBVWGJQAEFS-UHFFFAOYSA-N flurazepam Chemical compound N=1CC(=O)N(CCN(CC)CC)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1F SAADBVWGJQAEFS-UHFFFAOYSA-N 0.000 description 2
- 229960002074 flutamide Drugs 0.000 description 2
- 229960004038 fluvoxamine Drugs 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
- 238000009472 formulation Methods 0.000 description 2
- JMYCGCXYZZHWMO-UHFFFAOYSA-N fosazepam Chemical compound N=1CC(=O)N(CP(C)(=O)C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 JMYCGCXYZZHWMO-UHFFFAOYSA-N 0.000 description 2
- 229950006306 fosazepam Drugs 0.000 description 2
- 229960002870 gabapentin Drugs 0.000 description 2
- 229960002972 glutethimide Drugs 0.000 description 2
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 2
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 2
- 229960002158 halazepam Drugs 0.000 description 2
- 231100000869 headache Toxicity 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 230000003054 hormonal effect Effects 0.000 description 2
- ZQDWXGKKHFNSQK-UHFFFAOYSA-N hydroxyzine Chemical compound C1CN(CCOCCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZQDWXGKKHFNSQK-UHFFFAOYSA-N 0.000 description 2
- 229960000930 hydroxyzine Drugs 0.000 description 2
- 229950002248 idoxifene Drugs 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229940126602 investigational medicinal product Drugs 0.000 description 2
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 2
- 229960000991 ketoprofen Drugs 0.000 description 2
- BWHLPLXXIDYSNW-UHFFFAOYSA-N ketorolac tromethamine Chemical compound OCC(N)(CO)CO.OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 BWHLPLXXIDYSNW-UHFFFAOYSA-N 0.000 description 2
- 229960004384 ketorolac tromethamine Drugs 0.000 description 2
- XZEUAXYWNKYKPL-WDYNHAJCSA-N levormeloxifene Chemical compound C1([C@H]2[C@@H](C3=CC=C(C=C3OC2(C)C)OC)C=2C=CC(OCCN3CCCC3)=CC=2)=CC=CC=C1 XZEUAXYWNKYKPL-WDYNHAJCSA-N 0.000 description 2
- 229960004391 lorazepam Drugs 0.000 description 2
- 229940087857 lupron Drugs 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
- SFITWQDBYUMAPS-UHFFFAOYSA-N mecloqualone Chemical compound CC1=NC2=CC=CC=C2C(=O)N1C1=CC=CC=C1Cl SFITWQDBYUMAPS-UHFFFAOYSA-N 0.000 description 2
- 229950007403 mecloqualone Drugs 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 229960004296 megestrol acetate Drugs 0.000 description 2
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 2
- 229960003987 melatonin Drugs 0.000 description 2
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 2
- ALARQZQTBTVLJV-UHFFFAOYSA-N mephobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)N(C)C1=O ALARQZQTBTVLJV-UHFFFAOYSA-N 0.000 description 2
- 229960002803 methaqualone Drugs 0.000 description 2
- OJLOPKGSLYJEMD-URPKTTJQSA-N methyl 7-[(1r,2r,3r)-3-hydroxy-2-[(1e)-4-hydroxy-4-methyloct-1-en-1-yl]-5-oxocyclopentyl]heptanoate Chemical compound CCCCC(C)(O)C\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC OJLOPKGSLYJEMD-URPKTTJQSA-N 0.000 description 2
- 229960001703 methylphenobarbital Drugs 0.000 description 2
- 229950010642 midaflur Drugs 0.000 description 2
- 229960003793 midazolam Drugs 0.000 description 2
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-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
- 229960005249 misoprostol Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- NLRFFZRHTICQBO-UHFFFAOYSA-N n-[2-(diethylamino)-2-oxoethyl]-3,4,5-trimethoxybenzamide Chemical compound CCN(CC)C(=O)CNC(=O)C1=CC(OC)=C(OC)C(OC)=C1 NLRFFZRHTICQBO-UHFFFAOYSA-N 0.000 description 2
- CXJONBHNIJFARE-UHFFFAOYSA-N n-[6-(2,4-difluorophenoxy)-1-oxo-2,3-dihydroinden-5-yl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2CCC(=O)C=2C=C1OC1=CC=C(F)C=C1F CXJONBHNIJFARE-UHFFFAOYSA-N 0.000 description 2
- 229960004270 nabumetone Drugs 0.000 description 2
- 229960002009 naproxen Drugs 0.000 description 2
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 2
- 229960003940 naproxen sodium Drugs 0.000 description 2
- CDBRNDSHEYLDJV-FVGYRXGTSA-M naproxen sodium Chemical compound [Na+].C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CDBRNDSHEYLDJV-FVGYRXGTSA-M 0.000 description 2
- 229960001800 nefazodone Drugs 0.000 description 2
- 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 description 2
- HYWYRSMBCFDLJT-UHFFFAOYSA-N nimesulide Chemical compound CS(=O)(=O)NC1=CC=C([N+]([O-])=O)C=C1OC1=CC=CC=C1 HYWYRSMBCFDLJT-UHFFFAOYSA-N 0.000 description 2
- CBDPCXYQNVDTMW-UHFFFAOYSA-N nisobamate Chemical compound NC(=O)OCC(C)(C(C)CC)COC(=O)NC(C)C CBDPCXYQNVDTMW-UHFFFAOYSA-N 0.000 description 2
- 229950008643 nisobamate Drugs 0.000 description 2
- 229960001454 nitrazepam Drugs 0.000 description 2
- KJONHKAYOJNZEC-UHFFFAOYSA-N nitrazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1 KJONHKAYOJNZEC-UHFFFAOYSA-N 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 229950004982 nitromifene Drugs 0.000 description 2
- PULGYDLMFSFVBL-SMFNREODSA-N nociceptin Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)[C@@H](C)O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 PULGYDLMFSFVBL-SMFNREODSA-N 0.000 description 2
- 229940085033 nolvadex Drugs 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- 229960003327 ormeloxifene Drugs 0.000 description 2
- 229960004535 oxazepam Drugs 0.000 description 2
- ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 description 2
- 229960005489 paracetamol Drugs 0.000 description 2
- 229960003868 paraldehyde Drugs 0.000 description 2
- SQYNKIJPMDEDEG-UHFFFAOYSA-N paraldehyde Chemical compound CC1OC(C)OC(C)O1 SQYNKIJPMDEDEG-UHFFFAOYSA-N 0.000 description 2
- 229960004662 parecoxib Drugs 0.000 description 2
- TZRHLKRLEZJVIJ-UHFFFAOYSA-N parecoxib Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 TZRHLKRLEZJVIJ-UHFFFAOYSA-N 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 229950009253 perlapine Drugs 0.000 description 2
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 2
- 229960002695 phenobarbital Drugs 0.000 description 2
- 229960002702 piroxicam Drugs 0.000 description 2
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 2
- 229960004856 prazepam Drugs 0.000 description 2
- 229960004134 propofol Drugs 0.000 description 2
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 2
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 229960002601 protriptyline Drugs 0.000 description 2
- BWPIARFWQZKAIA-UHFFFAOYSA-N protriptyline Chemical compound C1=CC2=CC=CC=C2C(CCCNC)C2=CC=CC=C21 BWPIARFWQZKAIA-UHFFFAOYSA-N 0.000 description 2
- 229960001964 quazepam Drugs 0.000 description 2
- MQGIGGJUPITZSE-UHFFFAOYSA-N reclazepam Chemical compound C12=CC(Cl)=CC=C2N(C=2OCC(=O)N=2)CCN=C1C1=CC=CC=C1Cl MQGIGGJUPITZSE-UHFFFAOYSA-N 0.000 description 2
- 229950004797 reclazepam Drugs 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000002040 relaxant effect Effects 0.000 description 2
- 229960000371 rofecoxib Drugs 0.000 description 2
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 2
- 229960002060 secobarbital Drugs 0.000 description 2
- KQPKPCNLIDLUMF-UHFFFAOYSA-N secobarbital Chemical compound CCCC(C)C1(CC=C)C(=O)NC(=O)NC1=O KQPKPCNLIDLUMF-UHFFFAOYSA-N 0.000 description 2
- 239000000932 sedative agent Substances 0.000 description 2
- 230000001624 sedative effect Effects 0.000 description 2
- 230000035807 sensation Effects 0.000 description 2
- 230000000697 serotonin reuptake Effects 0.000 description 2
- 229960002073 sertraline Drugs 0.000 description 2
- 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 description 2
- 230000003860 sleep quality Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- WZAIVXXKOAWTGQ-UHFFFAOYSA-N spiro[2,3-dihydronaphthalene-4,3'-piperidine]-1,2',6'-trione Chemical compound O=C1NC(=O)CCC11C2=CC=CC=C2C(=O)CC1 WZAIVXXKOAWTGQ-UHFFFAOYSA-N 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- IBAUKGNDWVSETP-UHFFFAOYSA-N suproclone Chemical compound C1CN(C(=O)CC)CCN1C(=O)OC1C(SCCS2)=C2C(=O)N1C1=CC=C(C=CC(Cl)=N2)C2=N1 IBAUKGNDWVSETP-UHFFFAOYSA-N 0.000 description 2
- 229950003877 suproclone Drugs 0.000 description 2
- 229960003188 temazepam Drugs 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229960002784 thioridazine Drugs 0.000 description 2
- 108010050939 thrombocytin Proteins 0.000 description 2
- 229950002859 tracazolate Drugs 0.000 description 2
- 229960003386 triazolam Drugs 0.000 description 2
- JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 0.000 description 2
- 229960001147 triclofos Drugs 0.000 description 2
- 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 2
- 229960002324 trifluoperazine Drugs 0.000 description 2
- 229950001577 trimetozine Drugs 0.000 description 2
- 229960002431 trimipramine Drugs 0.000 description 2
- ZSCDBOWYZJWBIY-UHFFFAOYSA-N trimipramine Chemical compound C1CC2=CC=CC=C2N(CC(CN(C)C)C)C2=CC=CC=C21 ZSCDBOWYZJWBIY-UHFFFAOYSA-N 0.000 description 2
- 229950000212 trioxifene Drugs 0.000 description 2
- WVPSKSLAZQPAKQ-CDMJZVDBSA-N trovafloxacin Chemical compound C([C@H]1[C@@H]([C@H]1C1)N)N1C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=NC=1N2C1=CC=C(F)C=C1F WVPSKSLAZQPAKQ-CDMJZVDBSA-N 0.000 description 2
- 229960000497 trovafloxacin Drugs 0.000 description 2
- DTMPGSXFUXZBDK-UHFFFAOYSA-N uldazepam Chemical compound C12=CC(Cl)=CC=C2N=C(NOCC=C)CN=C1C1=CC=CC=C1Cl DTMPGSXFUXZBDK-UHFFFAOYSA-N 0.000 description 2
- 229950004526 uldazepam Drugs 0.000 description 2
- 229960002004 valdecoxib Drugs 0.000 description 2
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 2
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 2
- 229960000604 valproic acid Drugs 0.000 description 2
- 229940097704 vantas Drugs 0.000 description 2
- HUNXMJYCHXQEGX-UHFFFAOYSA-N zaleplon Chemical compound CCN(C(C)=O)C1=CC=CC(C=2N3N=CC(=C3N=CC=2)C#N)=C1 HUNXMJYCHXQEGX-UHFFFAOYSA-N 0.000 description 2
- 229960004010 zaleplon Drugs 0.000 description 2
- 229940033942 zoladex Drugs 0.000 description 2
- 229960001366 zolazepam Drugs 0.000 description 2
- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 description 2
- 229960001475 zolpidem Drugs 0.000 description 2
- 229940051084 zytiga Drugs 0.000 description 2
- AELCINSCMGFISI-DTWKUNHWSA-N (1R,2S)-tranylcypromine Chemical compound N[C@@H]1C[C@H]1C1=CC=CC=C1 AELCINSCMGFISI-DTWKUNHWSA-N 0.000 description 1
- INEHJXCWEVNEDZ-LUDNRVPPSA-N (2s,3s)-2,3-dihydroxybutanedioic acid;(5r,6s)-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O.C1([C@@H]2[C@@H](C3=CC=C(C=C3CC2)O)C=2C=CC(OCCN3CCCC3)=CC=2)=CC=CC=C1 INEHJXCWEVNEDZ-LUDNRVPPSA-N 0.000 description 1
- FJIKWRGCXUCUIG-HNNXBMFYSA-N (3s)-7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-3h-1,4-benzodiazepin-2-one Chemical compound O=C([C@H](O)N=1)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1Cl FJIKWRGCXUCUIG-HNNXBMFYSA-N 0.000 description 1
- ICPHJSKVAZMKIV-QGZVFWFLSA-N (5r)-7,8-dimethoxy-3-methyl-5-phenyl-1,2,4,5-tetrahydro-3-benzazepine Chemical compound C1([C@H]2CN(C)CCC=3C=C(C(=CC=32)OC)OC)=CC=CC=C1 ICPHJSKVAZMKIV-QGZVFWFLSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 1
- QECAKYKTTYQVKX-RMKNXTFCSA-N (e)-3-(2,5-dihydropyrrol-1-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one Chemical compound COC1=C(OC)C(OC)=CC(C(=O)\C=C\N2CC=CC2)=C1 QECAKYKTTYQVKX-RMKNXTFCSA-N 0.000 description 1
- RCEFMOGVOYEGJN-UHFFFAOYSA-N 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-1,4-dihydropyrimidin-2-one Chemical compound OC1=CC=CC=C1N1C(=O)NC(C=2C=C(C=CC=2)[N+]([O-])=O)=CC1 RCEFMOGVOYEGJN-UHFFFAOYSA-N 0.000 description 1
- QQKZKKGJLBAVDV-UHFFFAOYSA-N 4,5,6,7-tetrahydro-3h-diazepine Chemical compound C1CCN=NCC1 QQKZKKGJLBAVDV-UHFFFAOYSA-N 0.000 description 1
- FDQGNLOWMMVRQL-UHFFFAOYSA-N Allobarbital Chemical compound C=CCC1(CC=C)C(=O)NC(=O)NC1=O FDQGNLOWMMVRQL-UHFFFAOYSA-N 0.000 description 1
- 201000000736 Amenorrhea Diseases 0.000 description 1
- 206010001928 Amenorrhoea Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 108091005462 Cation channels Proteins 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- UMRURYMAPMZKQO-NDKKBYRMSA-N Clometherone Chemical compound C1([C@@H](Cl)C2)=CC(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(C)=O)[C@@]2(C)CC1 UMRURYMAPMZKQO-NDKKBYRMSA-N 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 206010009866 Cold sweat Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 229940093444 Cyclooxygenase 2 inhibitor Drugs 0.000 description 1
- AJFTZWGGHJXZOB-UHFFFAOYSA-N DuP 697 Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC(F)=CC=2)SC(Br)=C1 AJFTZWGGHJXZOB-UHFFFAOYSA-N 0.000 description 1
- UKCVAQGKEOJTSR-UHFFFAOYSA-N Fadrozole hydrochloride Chemical compound Cl.C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 UKCVAQGKEOJTSR-UHFFFAOYSA-N 0.000 description 1
- 206010016275 Fear Diseases 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-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
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-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
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 102000009151 Luteinizing Hormone Human genes 0.000 description 1
- 108010073521 Luteinizing Hormone Proteins 0.000 description 1
- 229940082819 Luteinizing hormone releasing hormone (LHRH) agonist Drugs 0.000 description 1
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 1
- NPPQSCRMBWNHMW-UHFFFAOYSA-N Meprobamate Chemical compound NC(=O)OCC(C)(CCC)COC(N)=O NPPQSCRMBWNHMW-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229940123685 Monoamine oxidase inhibitor Drugs 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
- KTDZCOWXCWUPEO-UHFFFAOYSA-N NS-398 Chemical compound CS(=O)(=O)NC1=CC=C([N+]([O-])=O)C=C1OC1CCCCC1 KTDZCOWXCWUPEO-UHFFFAOYSA-N 0.000 description 1
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 description 1
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 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
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- JHBIMJKLBUMNAU-UHFFFAOYSA-N SC-58125 Chemical compound C1=CC(S(=O)(=O)C)=CC=C1N1C(C=2C=CC(F)=CC=2)=CC(C(F)(F)F)=N1 JHBIMJKLBUMNAU-UHFFFAOYSA-N 0.000 description 1
- 229940121991 Serotonin and norepinephrine reuptake inhibitor Drugs 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 1
- WWSKHPDYSWDMNC-YRNSVOBJSA-N [(8r,9s,10r,13s,14s,16r,17r)-17-acetyl-6-chloro-10,13,16-trimethyl-3-oxo-2,8,9,11,12,14,15,16-octahydro-1h-cyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1=C(Cl)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(C)=O)(OC(C)=O)[C@@]1(C)CC2 WWSKHPDYSWDMNC-YRNSVOBJSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229960000880 allobarbital Drugs 0.000 description 1
- 229950003674 alonimid Drugs 0.000 description 1
- 231100000540 amenorrhea Toxicity 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940098184 amytal Drugs 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229960002319 barbital Drugs 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- AXMWZLVAETYZDP-UHFFFAOYSA-N benzene;1h-benzimidazole Chemical class C1=CC=CC=C1.C1=CC=C2NC=NC2=C1 AXMWZLVAETYZDP-UHFFFAOYSA-N 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 208000015294 blood coagulation disease Diseases 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229940015694 butabarbital Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229940097647 casodex Drugs 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 229940118803 chloral betaine Drugs 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 229960004782 chlordiazepoxide Drugs 0.000 description 1
- ANTSCNMPPGJYLG-UHFFFAOYSA-N chlordiazepoxide Chemical compound O=N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 ANTSCNMPPGJYLG-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000027288 circadian rhythm Effects 0.000 description 1
- 229950008630 clomegestone Drugs 0.000 description 1
- 229950004984 cloral betaine Drugs 0.000 description 1
- 229960004362 clorazepate Drugs 0.000 description 1
- XDDJGVMJFWAHJX-UHFFFAOYSA-M clorazepic acid anion Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(C(=O)[O-])N=C1C1=CC=CC=C1 XDDJGVMJFWAHJX-UHFFFAOYSA-M 0.000 description 1
- 229950001542 cloretate Drugs 0.000 description 1
- 230000009852 coagulant defect Effects 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 210000004246 corpus luteum Anatomy 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- ZSAMZEYLGUEVJW-TTYLFXKOSA-N delmadinone Chemical compound C1=C(Cl)C2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 ZSAMZEYLGUEVJW-TTYLFXKOSA-N 0.000 description 1
- 229950006309 delmadinone Drugs 0.000 description 1
- 230000030609 dephosphorylation Effects 0.000 description 1
- 238000006209 dephosphorylation reaction Methods 0.000 description 1
- 238000000586 desensitisation Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 229960005422 dichloralphenazone Drugs 0.000 description 1
- ATKXDQOHNICLQW-UHFFFAOYSA-N dichloralphenazone Chemical compound OC(O)C(Cl)(Cl)Cl.OC(O)C(Cl)(Cl)Cl.CN1C(C)=CC(=O)N1C1=CC=CC=C1 ATKXDQOHNICLQW-UHFFFAOYSA-N 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 210000000613 ear canal Anatomy 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 229960002690 fluphenazine Drugs 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
- 239000008103 glucose Substances 0.000 description 1
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 230000001709 ictal effect Effects 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000021267 infertility disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229960004033 lormetazepam Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229940040129 luteinizing hormone Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229960001929 meloxicam Drugs 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- 229960004815 meprobamate Drugs 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- FSBTYDWUUWLHBD-UDXTWCDOSA-N nafarelin acetate hydrate Chemical compound O.CC(O)=O.C([C@@H](C(=O)N[C@H](CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 FSBTYDWUUWLHBD-UDXTWCDOSA-N 0.000 description 1
- 229950002366 nafoxidine Drugs 0.000 description 1
- 229940087524 nardil Drugs 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229940099637 nilandron Drugs 0.000 description 1
- 229960000965 nimesulide Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000000422 nocturnal effect Effects 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 230000000966 norepinephrine reuptake Effects 0.000 description 1
- 229960001158 nortriptyline Drugs 0.000 description 1
- 229940127234 oral contraceptive Drugs 0.000 description 1
- 239000003539 oral contraceptive agent Substances 0.000 description 1
- 210000004798 organs belonging to the digestive system Anatomy 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000016087 ovulation Effects 0.000 description 1
- 229960002739 oxaprozin Drugs 0.000 description 1
- OFPXSFXSNFPTHF-UHFFFAOYSA-N oxaprozin Chemical compound O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229960000762 perphenazine Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229960000964 phenelzine Drugs 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001072 progestational effect Effects 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 229960003910 promethazine Drugs 0.000 description 1
- 229940035613 prozac Drugs 0.000 description 1
- 210000001147 pulmonary artery Anatomy 0.000 description 1
- OENLEHTYJXMVBG-UHFFFAOYSA-N pyridine;hydrate Chemical compound [OH-].C1=CC=[NH+]C=C1 OENLEHTYJXMVBG-UHFFFAOYSA-N 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229940075993 receptor modulator Drugs 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 239000003488 releasing hormone Substances 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229950004692 roletamide Drugs 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 210000001044 sensory neuron Anatomy 0.000 description 1
- 230000020341 sensory perception of pain Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000003215 serotonin 5-HT2 receptor antagonist Substances 0.000 description 1
- 239000003775 serotonin noradrenalin reuptake inhibitor Substances 0.000 description 1
- 230000004622 sleep time Effects 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 210000003594 spinal ganglia Anatomy 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical class NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 229940072345 suprelorin Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 229940086546 synarel Drugs 0.000 description 1
- 208000011580 syndromic disease Diseases 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
- 210000001994 temporal artery Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 102000042565 transient receptor (TC 1.A.4) family Human genes 0.000 description 1
- 108091053409 transient receptor (TC 1.A.4) family Proteins 0.000 description 1
- 229960003991 trazodone Drugs 0.000 description 1
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 1
- 229950002464 trepipam Drugs 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Vascular Medicine (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本公开内容涉及用于治疗或预防血管舒缩症状(诸如潮热)的组合物及方法,所述组合物包含瞬时受体电位Melastatin 8(TRPM8)拮抗剂,所述方法包括施用TRPM8拮抗剂。
Description
技术领域
本公开内容涉及用于治疗或预防受试者的血管舒缩症状的组合物及方法,所述组合物包含瞬时受体电位Melastatin 8(TRPM8)拮抗剂,和所述方法包括施用TRPM8拮抗剂。
背景技术
血管舒缩症状经常被报道,例如更年期的症状。血管舒缩症状包括盗汗、潮热和潮红。主要且最常见的血管舒缩症状为潮热。一般而言,潮热(或热潮红或盗汗)为热感的间歇性发作。潮热为近更年期或更年期后的女性经历的最常见症状,且正接受或曾接受癌症治疗的男性及女性(例如正接受抑制性激素的产生或活性的乳癌或前列腺癌治疗的患者)亦经常经历。参见非专利文献1及2。研究提出在潮热之前可能会先发生核心体温(core bodytemperature)的上升。参见非专利文献3。
血管舒缩症状的发作可能亦与发汗、潮红、发冷、焦虑和心悸相关。例如,潮热的症状包括突然感到发热(时常伴随着出汗、皮肤发红或潮红中的一种或多种)以及感到湿冷及发冷。潮热可以短暂轻微的发热至热浪及大量出汗为特征。典型的潮热发生于在胸部突然开始感到发热,其接着向上扩展至涵盖颈部及面部且亦可能扩展遍及全身。其他则可能整个身体上部感觉到突然开始发热。潮热亦可能伴随着头晕、恶心、头痛和心悸。在夜晚亦可能发生伴随出汗的潮热。这些被称为盗汗且与慢性失眠及较差的主观睡眠质量相关。参见非专利文献4。最近的多道睡眠描记术(polysomnography)研究已断定在夜晚发生的潮热与睡眠片段化增加相关,其可能导致例如睡眠剥夺、疲劳和急躁易怒。因此,潮热可能中断睡眠及工作且干扰生活质量。
血管舒缩症状的严重性因人而异且在相同的人中因时而异。例如,潮热可由数种因素诱发,诸如炎热的天气、压力、饮食、饮酒、激素变化、医学状况或医学治疗。发作可持续数秒至数分钟或在极少数情况下会长达一小时或更久。血管舒缩症状可一年发生数次至一周发生数次至频繁到每小时发生一次或多次。
潮热已在近更年期及更年期后的女性中被广泛地研究。研究已显示出约60%至80%的女性在近更年期及更年期后期间经历潮热。在此群体中,40%至60%报道有中度至重度潮热,且10%至20%感到几乎无法忍受。因此,为了维持众多女性的生活质量,需要有效地治疗或预防血管舒缩症状(例如潮热)。
男性和女性皆亦可能经历血管舒缩症状作为医学状况的症状或治疗的症状。例如,许多癌症患者经历血管舒缩症状作为癌症的症状或癌症治疗的症状。
例如,经历雄激素剥夺治疗(androgen deprivation therapy,ADT)的患有前列腺癌的男性可能具有潮热。这对于显著比例的接受ADT的男性而言为重大的生活质量问题。已报道约40%至80%的这种男性罹患潮热且30%至40%报道在这种发作期间有重大不适。参见非专利文献5。
有数种已知的针对血管舒缩症状的治疗;然而,现有的治疗并非完全有效且可能致使严重的并发症的风险增加。尽管雌激素替代疗法可在女性中有效地最小化或预防血管舒缩症状,但许多女性担心激素替代疗法的潜在风险。这对于罹患乳癌或具有乳癌家族病史和/或凝血疾病病史的女性而言尤其如此。选择性血清素再吸收抑制剂(selectiveserotonin reuptake inhibitor, SSRI)、血清素及去甲基肾上腺素再吸收抑制剂(serotonin and norepinephrine reuptake inhibitor, SNRI)、加巴喷丁(gabapentin)及可尼丁(clonidine)亦可用于治疗血管舒缩症状,但在治疗症状时并非总是有效且多数与不良的副作用相关。
现有技术文献
非专利文献
[NPL1] R. E. Williams等人, "Frequency and severity of vasomotor symptomsamong peri- and postmenopausal women in the United States," Climacteric, 11:32-43 (2008)
[NPL2] Laura J. Hanisch等人, "Increases in core body temperature precedehot flashes in a prostate cancer patient, "Psycho-Oncology, 18:564-567 (2009)
[NPL3] Karen Elkind-Hirsch, "Cooling off hot flashes: uncoupling of thecircadian pattern of core body temperature and hot flash frequency in breastcancer survivors, "Menopause: The Journal of The North American MenopauseSociety, Vol. 11, No. 4, pp. 369-371 (2004)
[NPL4] Hadine Joffe等人, "A Gonadotropin-Releasing Hormone Agonist ModelDemonstrates That Nocturnal Hot Flashes Interrupt Objective Sleep,"Sleep,Vol. 36, No. 12, pp. 1977-1985 (2013)
[NPL5] Naseem A. Aziz, "Evaluation of Core and Surface Body Temperatures,Prevalence, Onset, Duration and Severity of Hot Flashes in Men afterBilateral Orchidectomy for Prostate Cancer, "Int. Braz. J. Urol., 34:15-22(2008)。
发明内容
技术问题
因此,需要全新的安全且有效的针对血管舒缩症状的治疗。本公开内容的发明人发现了新的针对血管舒缩症状的治疗,其是通过施用作为瞬时受体电位melastatin-8(TRPM8)拮抗剂的活性剂。
瞬时受体电位(TRP)通道为通过各种物理性(例如温度、渗透性、机械性)及化学性刺激而活化的非选择性阳离子通道。一部分的TRP通道超家族为热应答性的,各通道在离散的温度范围内被活化,所述范围累积跨越有害的冷至有害的热。TRPM8属于TRP通道超家族的melastatin亚组。TRPM8对寒冷的温度及薄荷醇敏感,因此亦被称为冷及薄荷醇受体-1(cold and menthol receptor-1, CMR-1)。McKemy等人,"Identification of a coldreceptor reveals a general role for TRP channels in thermosensation,"Nature,Vol.416,No.6876,pp.52-58(2002)。已知TRPM8受到凉至冷的温度(8至28℃)以及受到诸如薄荷醇及icilin的化学物质刺激。
TRPM8位于初级伤害感受性神经元(A-δ及C-纤维)且亦受到炎症介导的次级信使信号调控。Abe等人,"Ca2±-dependent PKC activation mediates menthol-induceddesensitization of transient receptor potential M8,"Neuroscience Letters,Vol.397,No.1-2,p.140-144(2006);Premkumar等人,"Downregulation of TransientReceptor Potential Melastatin 8 by Protein Kinase C-MediatedDephosphorylation,"The Journal of Neuroscience,Vol.25,No.49,p.11322-11329(2005)。TRPM8在三叉及背根神经节的感觉神经元中高表达。亦已知TRPM8在脑、肺、膀胱、胃肠道、血管、前列腺和免疫细胞中表达。
TRPM8拮抗剂及其治疗中的用途已公开于先前的专利文献(参见例如美国专利第8,987,445号;美国专利第9,096,527号;国际专利公开案第WO2014/042238号)中。这些公开内容报道诸如用于治疗慢性疼痛(例如神经性疼痛)、泌尿道疾病、胃肠道疾病和头痛的用途。然而,这些公开内容皆未阐述利用TRPM8拮抗剂治疗或预防血管舒缩症状。
技术问题
本公开内容涉及一种用于治疗或预防有需要的受试者的血管舒缩症状的方法,其包括对所述受试者施用有效量的TRPM8拮抗剂。
本公开内容亦涉及一种组合物,其包括用于治疗或预防受试者的血管舒缩症状的有效量的TRPM8拮抗剂及药学上可接受的载体。
附图被并入本说明书中且构成本说明书的一部分。
附图说明
图1示出施用TRPM8拮抗剂(特别是本文所述的化合物A)对大鼠中的直肠温度的效果。
图2示出用于评估多剂量的本文所述的化合物A在经历血管舒缩症状的雌性受试者中的安全性、耐受性及药物动力学的计划性I期随机双盲安慰剂对照研究的研究设计。
图3示出在14天的治疗期期间在第一次投药后24小时内的随时间变化的血管舒缩症状(VMS)频率的平均观测值的变化。在图3中,三角形或正方形符号各分别表示50mg的化合物A或安慰剂的结果。
图4示出于诊视日第1、7、10或14天在投药后24小时内的随时间变化的核心体温自基线的变化。在图4中,正方形、三角形、空心圆形或实心圆形符号各分别表示于诊视日第1、7、10或14天的结果。
具体实施方式
描述
应了解以上一般性说明及以下详细说明皆仅为例示性及说明性的,而并不限制所要求保护的发明。亦应了解本公开内容并不限于特定的活性剂、制剂、投药方案等,因为这些可有所差异。
以下更详细地说明本公开内容的特定方面。本申请中所使用及本文中所阐明的术语及定义旨在表示在本公开内容中的意义。
在本文中使用时,除非上下文另行表明,否则单数形“一个”、“一种”及“所述”包括复数的指涉物。
术语“大约”及“约”意指与所提及的数目或数值几乎相同,包括考虑到测量的性质或精确度的所测得量的可接受程度的误差。在本文中使用时,术语“大约”及“约”一般应理解为涵盖特定的量、频率或数值的±20%。除非另行指明,否则本文中所给定的数量是大约的,意指当未明确地指明时可推论出术语“约”或“大约”。在本文中使用时,“血管舒缩症状”为本领域中已知的,且包括所有潮热,无论是轻度、中度或重度。血管舒缩症状亦可包括但不限于盗汗及潮红。
在本文中使用时,“潮热”是指发作性热感,任选地伴随潮红及出汗,亦任选地伴随心跳过速及发冷。在本文中使用时,“潮热”可指与更年期、医学状况的症状或效果、针对医学状况的治疗的副作用(例如癌症治疗的副作用)或任何其他潮热的诱因或成因相关的潮热。所述术语亦包括“热潮红”。“盗汗”为在睡眠期间发生的潮热。
术语“活性剂”是指诱发期望的效果的化合物。本公开内容涉及TRPM8拮抗剂,但是将TRPM8拮抗剂与一种或多种另外的活性剂一起施用的组合疗法亦在本公开内容的范围内。这种组合疗法可通过以单一组合物的形式施用不同的活性剂、以不同的组合物的形式同时施用不同的活性剂或依序施用不同的活性剂而施行。诱发期望的效果的本文中所公开的活性剂及活性剂类别的衍生物及类似物在本公开内容的范围内。
在本文中使用时,“瞬时受体电位melastatin 8 (TRPM8)拮抗剂”为在施用至个体后,具有TRPM8拮抗活性或转化为具有TRPM8拮抗活性的代谢物的任何化合物,无论是选择性或非选择性的。
在本文中使用时,“治疗”或“预防”血管舒缩症状或血管舒缩症状的“治疗”或“预防”包括以下的一种或多种:(1)减少、最小化或消除血管舒缩症状的发生或频率;(2)在发生时缓和血管舒缩症状;(3)减少或最小化血管舒缩症状的一种或多种症状的严重性(或减轻)或消除血管舒缩症状的一种或多种症状;以及(4)延迟血管舒缩症状的进展或发展。本文中所述的组合物及方法可治疗或预防在夜晚发生的血管舒缩症状(例如潮热)(即盗汗)。在这些实施方案中,本文中所述的治疗或预防亦可包括减少入睡的起始时间、增加总睡眠时间、减少睡眠干扰或觉醒的次数及增加更深度的睡眠。
在本文中使用时,“受试者”可为人或动物。
在本文中使用时,“核心体温”是指受试者的内部体温。核心体温可使用本领域中已知的技术测量。在某些实施方案中,使用侵入性工具,诸如将温度探针置入食道、肺动脉或膀胱。在某些实施方案中,核心体温是在消化器官进行测量。在某些实施方案中,核心体温是在非侵入性位置进行测量,诸如直肠、口腔、腋窝、颞动脉或外耳道。在某些实施方案中,核心体温是固定地在相同的位置进行测量,例如在评价受试者的核心体温降低的发生和/或程度时。
术语“施用(administer)”、“施用(administration)”或“施用(administering)”意指对个体提供、给予、投予和/或开处方根据本公开内容的药物的步骤或个体接收、应用、摄取和/或服用根据本公开内容的药物的步骤。根据本公开内容的活性剂或组合物的施用途径可经由任何施用途径,例如经口、非经口、经粘膜、鼻内、吸入或经皮。
在本文中使用时,“有效量”是指足以提供期望的效果(即,在该情况下,治疗或预防本文中所述的血管舒缩症状)的化合物的量。此外,“有效量”亦可指在未增添或未增加不期望的效果(即不需要的副作用)的情形下提供期望的效果的化合物的量。在某些实施方案中,以治疗或预防本文中所述的在夜晚发生的血管舒缩症状(例如潮热)(即盗汗)为目标选择有效量的TRPM8拮抗剂。如在临床背景中所了解的,药物、化合物或组合物的施用可与另一药物、化合物或组合物的施用结合。因此,“有效量”可在施用一种或多种活性剂的状况下进行考虑,如果联合一种或多种其他制剂便可达成或达成期望的结果,则单一制剂可被视为以有效量进行给予。
在本文中使用时,“药学上可接受的”意指不是在生物学上或在其他方面不期望的物质。换言之,所述物质可掺入施用至个体的组合物中而不会引起不期望的生物学效果或以有害的方式与内含所述物质的组合物的其他成分进行相互作用。
“近更年期的女性”是指处在下列间隔时间的女性:所述女性的身体由或多或少较规律周期的排卵及月经转变成永久不孕或更年期。所述间隔时间可为在更年期前数月、至数年、至15年或更久的时间段。“近更年期”亦被称为更年期过渡期。“更年期后的女性”是指已经历更年期,即经历连续十二个月无月经的女性。在本文中使用时,“更年期的女性”包括本文中所定义的近更年期的女性及更年期后的女性两者。在这些女性中更年期可为自然发生(诸如随着年龄增长)、由外科手术所引起(诸如经移除两个卵巢)或由化学治疗所诱发(诸如经利用雌激素拮抗剂(例如氟维司群(fulvestrant)、雷洛昔芬(raloxifene)、他莫昔芬(tamoxifen)或托瑞米芬(toremifene))的治疗)。
本公开内容的发明人发现了全新的针对血管舒缩症状的治疗,其是通过施用作为TRPM8拮抗剂的活性剂。不期望受任何特定理论的限制,本公开内容的发明人认为TRPM8拮抗剂利用身体的被动散热方法来预期性地降低核心体温。在使用时,本公开内容的发明人认为TRPM8拮抗剂将重新平衡感觉输入(sensory input),容许新的平衡至略低且新稳定但仍正常的核心体温。身体对于过度的热调节转移的需求将被预防,而本将以潮热另行转移至皮肤表面的热将趋于不必要。
本公开内容涉及一种用于治疗或预防有需要的受试者的血管舒缩症状的方法,其包括对所述受试者施用有效量的TRPM8拮抗剂。在某些实施方案中,血管舒缩症状为潮热。在某些实施方案中,受试者为人。受试者可为雄姓或雌性。预想将所述方法用于易患有、正患有或被预期患有血管舒缩症状(诸如潮热)的受试者。有需要的受试者可能罹患或预期罹患与更年期、医学状况的症状或效果、针对医学状况的治疗的副作用或任何其他血管舒缩症状的诱因或成因相关的血管舒缩症状。
受试者包括但不限于更年期的女性、正摄取或预期摄取抗雌激素药物(诸如他莫昔芬或芳香酶抑制剂)的受试者、预期或曾经历外科手术的受试者或正患有或预期患有任何其他病症或正接受或预期接受会导致激素水平变化的任何其他治疗的受试者。
受试者进一步包括但不限于肿瘤患者。例如,受试者可包括预期接受、正接受或曾接受癌症治疗(诸如经由外科手术或放射疗法)的那些。例如,受试者可包括预期接受、正接受或曾接受性腺切除疗法或性激素抑制疗法的那些。在受试者正接受或曾接受癌症治疗时,癌症治疗可为影响受试者的激素水平的治疗,例如针对乳癌、卵巢癌及前列腺癌的激素疗法治疗。针对癌症的激素疗法的实例包括:选择性雌激素受体拮抗剂,包括他莫昔芬(tamoxifen)(Nolvadex®)、雷洛昔芬(raloxifene)(Evista®)、拉索昔芬(lasofoxifene)(Fablyn)及托瑞米芬(toremifene)(Fareston®);抗雌激素药物,包括氟维司群(fulvestrant)(Faslodex®);芳香酶抑制剂,包括阿那曲唑(anastrozole)(Arimidex®)、来曲唑(letrozole)(Femara®)、伏氯唑(vorozole)(Rivizor)、福美司坦(formestane)(Lentaron)、法倔唑(fadrozole)(Afema)及依西美坦(exemestane)(Aromasin®);促黄体生成激素释放激素(luteinizing-hormone-releasing hormone,LHRH)激动剂,包括戈舍瑞林(goserelin)(Zoladex®)、亮脯利特(leuprolide)(Lupron®);促黄体生成激素(luteinizing hormone,LH)阻断剂,包括布舍瑞林(buserelin)、亮丙瑞林(leuprorelin)(Prostap®)、组氨瑞林(histrelin)(Vantas®)、德舍瑞林(deslorelin)(Suprelorin®)、那法瑞林(nafarelin)(Synarel®)及曲普瑞林(triptorelin)(Decapeptyl®);抗雄激素,包括氟他米特(flutamide)(Drogenil®)、尼鲁米特(nilutamide)(Nilandron(USA)/Anandron(Canada))及比卡鲁胺(bicalutamide)(Casodex®);促性腺激素释放激素(gonadotrophin releasing hormone,GnRH)阻断剂,包括地加瑞克(degarelix)(Firmagon®);以及阿比特龙(abiraterone)(Zytiga®)。
受试者亦包括但不限于预期或曾经历外科手术诱发的激素变化(诸如子宫切除术、卵巢切除术和睾丸切除术)的受试者。
有效量的TRPM8拮抗剂可以包含TRPM8拮抗剂及药学上可接受的载体的组合物的形式施用。在某些实施方案中,组合物为药用组合物。
有效量的TRPM8拮抗剂或其组合物的施用可根据需要或可按照计划(诸如依进行中的投药方案)。例如,有效量可在需要时,诸如在感受到血管舒缩症状(诸如潮热)发作后立即施用。计划性施用可按照一致性计划或按照非一致性计划(其中,施用频率与有症状群体中或所治疗的个体的血管舒缩症状的昼夜节律相关)。即便使用计划性施用,若仍持续经历血管舒缩症状,亦可根据需要施用所述化合物。在某些实施方案中,有效量的TRPM8拮抗剂或其组合物是每日施用,诸如每日施用一次或每日施用两次。在某些实施方案中,以治疗或预防本文中所述的在夜晚发生的血管舒缩症状(例如潮热)(即盗汗)为目标,选择施用的时机及频率。在某些实施方案中,有效量的TRPM8拮抗剂或其组合物是在夜间施用,诸如包括每日在夜间施用一次的投药方案。在某些实施方案中,有效量的TRPM8拮抗剂或其组合物是在就寝时间前施用,诸如包括每日在就寝时间前施用一次的投药方案。
TRPM8拮抗剂或其组合物的施用并不限于任何特定施用途径,诸如经口施用。
本公开内容的TRPM8拮抗剂并不限于任何特定化合物或化合物类别。未具体提及但表现出TRPM8拮抗活性的化合物及化合物类别在本公开内容的范围内。TRPM8拮抗剂的实例包括但不限于磺胺类(sulfonamides) (US 8,987,445)、磺酰胺类(sulfamides)(WO2010/080397)、酰胺类(US 9,096,527)、2-芳基噁唑类(US2014/0371276)、2-芳基噻唑类(US2014/0371276)、螺环哌啶类(WO2010/103381)、萘基衍生物类(US 8,906,946)、及苯并咪唑衍生物类(WO2010/144680),其全部公开内容在此以参考的方式并入本文中。例如,TRPM8拮抗剂可选自磺胺化合物。在某些实施方案中,磺胺化合物由下式(I)表示:
[化1]
其中:
环A为双环状芳香族杂环,包括(a)与苯稠合的吡啶;或(b)与含有碳原子及选自氧原子、硫原子及氮原子的1至4个杂原子的5至6员单环状芳香族杂环稠合的吡啶,且环A在构成环A的吡啶环的氮原子所邻接的碳原子上结合磺酰基氨基部分,
环B为(a)具有6至11个碳作为环原子的单环状或双环状芳香族烃;(b)具有3至12个碳作为环原子的单环状或双环状脂环族烃;(c)含有碳原子及选自氧原子、硫原子及氮原子的1至4个杂原子的5至11员单环状或双环状芳香族杂环;或(d)含有碳原子及选自氧原子、硫原子及氮原子的1至4个杂原子的4至12员单环状或双环状非芳香族杂环,
环C为(a)苯;或(b)含有碳原子及选自氧原子、硫原子及氮原子的1至4个杂原子的5至6员单环状芳香族杂环,
R1为(a)氢;(b)C1-C6烷基,其可任选经选自C3-C7环烷基、C1-C6烷氧基、卤素、氧代基及羟基的1至7个基团取代;(c)C3-C7环烷基,其可任选经选自C1-C6烷基、C1-C6烷氧基及卤素的1至7个基团取代;(d)C1-C6烷氧基,其可任选经选自C3-C7环烷基、C1-C6烷氧基、卤素及羟基的1至7个基团取代;(e)苯基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(f)卤素;或(g)腈,
R2a、R2b、R2c及R2d各自独立地为(a)氢;(b)C1-C6烷基,其可任选经选自C1-C6烷氧基、C3-C7环烷基、卤素、氧代基及羟基的1至7个基团取代;(c)C3-C7环烷基,其可任选经选自C1-C6烷基、C1-C6烷氧基及卤素的1至7个基团取代;(d)C1-C6烷氧基,其可任选经选自C1-C6烷氧基、C3-C7环烷基及卤素的1至7个基团取代;(e)苯基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(f)5至6员单环状芳香族杂环基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(g)4至7员单环状非芳香族杂环基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(h)卤素;或(i)腈,
R3a、R3b、R3c及R3d各自独立地为(a)氢;(b)C1-C6烷基,其可任选经选自C3-C7环烷基、C3-C7卤代环烷基(其中,所述环烷基及卤代环烷基可各自独立地任选经选自C1-C6烷基及C1-C6卤代烷基的1至3个基团取代)、C1-C6烷氧基、C1-C6卤代烷氧基、苯基、5至6员单环状芳香族杂环基、4至7员单环状非芳香族杂环基(其中,所述苯基、芳香族杂环基及非芳香族杂环基可各自独立地任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代)、卤素、氧代基及羟基的1至7个基团取代;(c)C3-C7环烷基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、卤素及羟基的1至7个基团取代;(d)C1-C6烷氧基,其可任选经选自C3-C7环烷基、C3-C7卤代环烷基(其中,所述环烷基及卤代环烷基可各自独立地任选经选自C1-C6烷基及C1-C6卤代烷基的1至3个基团取代)、C1-C6烷氧基、C1-C6卤代烷氧基、苯基、5至6员单环状芳香族杂环基、4至7员单环状非芳香族杂环基(其中,所述苯基、芳香族杂环基及非芳香族杂环基可各自独立地任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代)、卤素及羟基的1至7个基团取代;(e)C3-C7环烷氧基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、卤素及羟基的1至7个基团取代;(f)苯基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(g)5至6员单环状芳香族杂环基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(h)4至7员单环状非芳香族杂环基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(i)苯氧基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(j)卤素;或(k)羟基,或
两个选自R3a、R3b、R3c及R3d的取代基彼此组合形成氧代基,
R5及R6各自独立地为(a)氢;(b)C1-C6烷基;(c)C1-C6卤代烷基;(d)C3-C7环烷基;或(e)C3-C7卤代环烷基,或R5及R6在其末端连同邻接的碳原子彼此组合形成3至7员单环状脂环族烃,
n为0、1或2;
X为(a)羧基;(b)C1-C6烷氧基羰基;(c)羟基-C1-C6烷基;(d)氨基羰基,其中,氮原子可任选经选自C1-C6烷基、C1-C6烷氧基及腈的一个基团取代;或(e)C2-C7烷酰基,其可任选经1至3个卤素取代;
或其药学上可接受的盐。
在磺胺化合物的一个实施方案中,下式的部分结构:
[化2]
为下式的基团:
[化3]
环B为苯或吡啶,且下式的部分结构:
[化4]
为下式的基团:
[化5]
其中,R1为(a)C1-C6烷基,其可任选经1至7个卤素取代;(b)C3-C7环烷基;(c)C1-C6烷氧基;或(d)卤素,
R2d为(a)氢;(b)C1-C6烷基,其可任选经1至7个卤素取代;(c)C3-C7环烷基;或(d)C1-C6烷氧基,
R3a及R3b各自独立地为(a)氢;(b)C1-C6烷基,其可任选经选自C3-C7环烷基(其中,所述环烷基可任选经选自C1-C6烷基及C1-C6卤代烷基的1至3个基团取代)、C1-C6烷氧基、C1-C6卤代烷氧基、及卤素的1至7个基团取代;(c)C3-C7环烷基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、及卤素的1至7个基团取代;(d)C1-C6烷氧基,其可任选经选自C3-C7环烷基、C1-C6烷氧基、C1-C6卤代烷氧基、及卤素的1至7个基团取代;或(e)卤素,
R3c及R3d为氢,
R5及R6为氢,
n为1;
或其药学上可接受的盐。
在某些实施方案中,磺胺化合物选自:
4-({(1-环丙基-4-甲基异喹啉-3-基)[4-(三氟甲氧基)苯甲基]氨基}磺酰基)苯甲酸、
4-({(1-异丙基-4-甲基异喹啉-3-基)[4-(三氟甲氧基)苯甲基]氨基}磺酰基)苯甲酸、
4-{[{3-氯-4-[环丙基(二氟)甲基]苯甲基}(4-甲基异喹啉-3-基)氨基]磺酰基}苯甲酸、
4-({(4-环丙基异喹啉-3-基)[4-(三氟甲氧基)苯甲基]氨基}磺酰基)苯甲酸、
4-{[{3-氯-4-[环丙基(二氟)甲基]苯甲基}(1-环丙基-4-甲基异喹啉-3-基)氨基]磺酰基}苯甲酸、
4-{[{4-[环丙基(二氟)甲基]-3-氟苯甲基}(4-甲基异喹啉-3-基)氨基]磺酰基}苯甲酸、
4-({[4-(三氟甲氧基)苯甲基][4-(三氟甲基)异喹啉-3-基]氨基}磺酰基)苯甲酸、
4-[((4-环丙基异喹啉-3-基){[5-(三氟甲基)吡啶-2-基]甲基}氨基)磺酰基]苯甲酸、
4-{[{4-[环丙基(二氟)甲基]-3-氟苯甲基}(4-环丙基异喹啉-3-基)氨基]磺酰基}苯甲酸、及
其药学上可接受的盐。
在某些实施方案中,磺胺化合物为具有下式的化合物:
[化6]
(即4-({(4-环丙基异喹啉-3-基)[4-(三氟甲氧基)苯甲基]氨基}磺酰基)苯甲酸)(下文中称为“化合物A”);
或其药学上可接受的盐。
式(I)的磺胺化合物可通过本领域技术人员已知的方法合成。这些方法中的一些见述于例如美国专利第8,987,445及9,096,527号以及国际专利公开第WO2014/042238号中。
尽管尚未完全了解精确的作用机制,但是已知这些磺胺化合物并非经由与大部分其他已知的针对血管舒缩症状的治疗相同的机制发生作用。因此,磺胺化合物适合用作用于治疗或预防血管舒缩症状的单独或附加治疗,或与已知产生血管舒缩症状作为副作用的其他活性剂组合使用,以便最小化或消除此副作用。在某些实施方案中,TRPM8拮抗剂选自式(I)所示的磺胺化合物,诸如化合物A或其药学上可接受的盐,且治疗或预防本文中所述的血管舒缩症状包括降低受试者的核心体温,诸如降低约0.5℃至约1℃、约0.5℃至约1.5℃或约0.5℃至约2℃,诸如多达0.5℃、多达1℃、多达1.5℃或多达2℃或之间的任何数目。
另外,例如,TRPM8拮抗剂可选自酰胺化合物。在某些实施方案中,酰胺化合物由下式表示:
[化7]
其药学上可接受的盐、其互变异构体、所述互变异构体的药学上可接受的盐、其立体异构体或其混合物,
其中:
m为0、1、2或3;
n为0或1;
X1为C(R4);
X2为N;
R1为C1-6烷基或经直接键合、经C1-2烷基连接、经C1-2烷基O连接的含有选自N、O及S的0、1、2、3或4个杂原子但不含超过一个O或S原子的饱和、部分饱和或不饱和3、4、5、6或7员单环状或7、8、9、10或11员双环状环,所述C1-6烷基及环经独立地选自卤基、氧代基、C1-6烷基、C1-6烷基OH、C1-6烷基-C(=O)Ra、C1-6烷基-C(=O)ORa、C1-4卤代烷基、氰基、硝基、-C(=O)Ra、-C(=O)ORa、-C(=O)NRaRa、-C(=NRa)NRaRa、-ORa、-OC(=O)Ra、-OC(=O)NRaRa、-OC(=O)N(Ra)S(=O)2Ra、-OC2-6烷基NRaRa、-OC2-6烷基ORa、-SRa、=S、-S(=O)Ra、-S(=O)2Ra、-S(=O)2NRaRa、-S(=O)2N(Ra)C(=O)Ra、-S(=O)2N(Ra)C(=O)ORa、-S(=O)2N(Ra)C(=O)NRaRa、-NRaRa、-N(Ra)C(=O)Ra、-N(Ra)C(=O)ORa、-N(Ra)C(=O)NRaRa、-N(Ra)C(=NRa)NRaRa、-N(Ra)S(=O)2Ra、-N(Ra)S(=O)2NRaRa、-NRaC2-6烷基NRaRa及-NRaC2-6烷基ORa的0、1、2或3个取代基取代,其中,所述环另外经0或1个直接键合、经SO2连接、经C(=O)连接或经CH2连接的含有选自N、O及S的0、1、2、3或4个杂原子但不含超过一个O或S原子且经选自卤基、氧代基、C1-6烷基、C1-4卤代烷基、氰基、硝基、-C(=O)Ra、-C(=O)ORa、-C(=O)NRaRa、-C(=NRa)NRaRa、-ORa、-OC(=O)Ra、-SRa、-S(=O)Ra、-S(=O)2Ra、-S(=O)2NRaRa、-NRaRa、及-N(Ra)C(=O)Ra的0、1、2或3个基团取代的饱和、部分饱和或不饱和3、4、5、6或7员单环状环取代;
R2为-F或-CF3;
R3为-OCF3或-CF3;
R4在各情况下独立地为H、C1-6烷基、-C1-3卤代烷基、-OC1-6烷基、-OC1-3卤代烷基、-N(C1-6烷基)C1-6烷基、-NHC1-6烷基、-NC(=O)C1-6烷基、-N(C1-6烷基)C1-6烷基、F、Cl、Br、CN、OH或NH2;或R3及R4共同形成含有0或1个N原子的四原子不饱和桥,其中,所述桥经0、1或2个R5取代基取代;
R5在各情况下独立地为卤基、ORa、CH3或CF3;
R6为F、C1-6烷基或ORa;
Ra在各情况下独立地为H或Rb;以及
Rb在各情况下独立地为苯基、苯甲基或C1-6烷基,所述苯基、苯甲基及C1-6烷基经选自卤基、氧代基、C1-4烷基、C1-3卤代烷基、-OC1-4烷基、-OH、-NH2、-OC1-4烷基、-OC1-4卤代烷基、-NHC1-4烷基、及-N(C1-4烷基)C1-4烷基的0、1、2或3个取代基取代。
在某些实施方案中,酰胺化合物选自:
(S)-N-((3-氟-4-(三氟甲氧基)苯基)(3-氟吡啶-2-基)甲基)-6-氧代基-1,6-二氢吡啶-3-甲酰胺;
(S)-N-((3-氟-4-(三氟甲氧基)苯基)(3-(三氟甲基)吡啶-2-基)甲基)-6-氧代基-1,6-二氢吡啶-3-甲酰胺;
(S)-N-((2-氟-4-(三氟甲氧基)苯基)(3-氟吡啶-2-基)甲基)-6-氧代基-1,6-二氢吡啶-3-甲酰胺;
(S)-5-氟-N-((3-氟-4-(三氟甲氧基)苯基)(3-氟吡啶-2-基)甲基)-6-氧代基-1,6-二氢吡啶-3-甲酰胺;
(S)-N-((3-氟-4-(三氟甲基)苯基)(3-氟吡啶-2-基)甲基)-6-氧代基-1,6-二氢吡啶-3-甲酰胺;
(S)-6-(((3-氟-4-(三氟甲氧基)苯基)(3-氟吡啶-2-基)甲基)胺甲酰基)烟酸;
其药学上可接受的盐、其互变异构体、所述互变异构体的药学上可接受的盐、及其混合物。
在某些实施方案中,TRPM8拮抗剂选自磺胺化合物,诸如式(I)的磺胺化合物,诸如化合物A或其药学上可接受的盐,且用于经口施用的有效量选自每日约0.01至约100mg/kg,诸如每日约0.1至约10mg/kg或之间的任何量。在某些实施方案中,TRPM8拮抗剂选自磺胺化合物,诸如式(I)的磺胺化合物,诸如化合物A,且用于经口施用的有效量为约10mg至约400mg,例如每日约10mg至约400mg。TRPM8拮抗剂的有效量可有所差异且可能取决于数种因素,诸如特定的活性剂、组合物或剂型的类型、所选择的施用途径、及治疗中的受试者(包括诸如受试者的年龄、体重、性别和医学状况的因素)。
在某些实施方案中,TRPM8拮抗剂选自磺胺化合物,诸如式(I)的磺胺化合物,诸如化合物A或其药学上可接受的盐,且有效量的TRPM8拮抗剂或其组合物是根据需要,诸如在感受到血管舒缩症状(诸如潮热)发作后立即施用,或依进行中的投药方案施用。在某些实施方案中,TRPM8拮抗剂选自磺胺化合物,诸如式(I)的磺胺化合物,诸如化合物A或其药学上可接受的盐,且有效量的TRPM8拮抗剂或其组合物是每日施用,例如每日施用一次,诸如每日在夜间施用一次。在某些实施方案中,有效量的TRPM8拮抗剂或其组合物是每日施用,诸如每日施用一次。在某些实施方案中,TRPM8拮抗剂选自磺胺化合物,诸如式(I)的磺胺化合物,诸如化合物A或其药学上可接受的盐,且以治疗或预防本文中所述的在夜间发生的血管舒缩症状(例如潮热)(即盗汗)为目标选择施用的时机及频率。
可将一种或多种另外的活性剂与TRPM8拮抗剂一起施用,诸如以组合疗法的形式。不同的活性剂的施用可以单一组合物的形式、通过以不同的组合物的形式同时施用不同的活性剂或通过依序施用不同的活性剂而施行。
另外的活性剂的实例包括但不限于用于治疗或预防血管舒缩症状或可用于治疗激素变化的其他病征及症状的活性剂,诸如雌激素、雌激素受体调节剂、雌激素激动剂、雄激素受体调节剂、肽激素、镇静剂、安眠药、消惧剂、抗精神病药、抗焦虑剂、轻镇静剂、苯并二氮杂环庚烯、巴比妥酸盐(barbiturate)、血清素(5-HT)激动剂、选择性血清素再吸收抑制剂(SSRI)、5HT-2拮抗剂、非类固醇消炎药、经口避孕药、孕酮(progesterone)、孕激素(progestin)、单胺氧化酶抑制剂、碳水化合物混合物等,或物理方法,诸如冷却剂。另外的活性剂的其他实例包括但不限于雌激素、孕酮、可尼丁(clonidine)、文拉法辛(venlafaxine)、醋酸甲地孕酮(megestrol acetate)、米氮平(mirtazapine)、非类固醇消炎药,诸如乙酰胺酚(acetaminophen)、前列地尔(alprostadil)、阿司匹林(aspirin)、双氯芬酸(diclofenac)、依托度酸(etodolac)、布洛芬(ibuprofen)、吲哚美辛(indomethacin)、酮洛芬(ketoprofen)、酮洛酸氨丁三醇(ketorolac tromethamine)、米索前列醇(misoprostol)、萘丁美酮(nabumetone)、萘普生(naproxen)、萘普生钠(naproxensodium)、奥沙普秦(oxaprozin)、吡罗昔康(piroxicam)、螺内酯(spironolactone)、螺内酯与氢氯噻嗪(spironolactone with hydrochlorothiazide)或曲伐沙星(trovafloxacin);皮质类固醇;选择性环加氧酶-2抑制剂,诸如塞来考昔(celecoxib)、依托考昔(etoricoxib)、帕瑞考昔(parecoxib)、罗非考昔(rofecoxib)、伐地考昔(valdecoxib)、美洛昔康(meloxicam)、氟舒胺(flosulide)、尼美舒利(nimesulide)、MK-663、NS 398、DuP697、SC-58125、SC-58635或RS 57067、阿地唑仑(adinazolam)、阿比特龙(abiraterone)、阿洛巴比妥(allobarbital)、阿洛米酮(alonimid)、阿普唑仑(alprazolam)、阿米替林(amitriptyline)、异戊巴比妥(amobarbital)、阿莫沙平(amoxapine)、阿那曲唑(anastrozole)、苯他西泮(bentazepam)、苯佐他明(benzoctamine)、比卡鲁胺(bicalutamide)、溴替唑仑(brotizolam)、安非他酮(bupropion)、布舍瑞林(buserelin)、丁螺环酮(buspirone)、仲丁巴比妥(butabarbital)、布他比妥(butalbital)、卡普脲(capuride)、卡波氯醛(carbocloral)、氯醛甜菜碱(chloral betaine)、水合氯醛(chloralhydrate)、氯二氮平(chlordiazepoxide)、氯甲孕酮(clometherone)、氯米帕明(clomipramine)、氯哌喹酮(cloperidone)、氯氮平酸盐(clorazepate)、氯乙双酯(clorethate)、氯氮平(clozapine)、环丙西泮(cyprazepam)、地加瑞克(degarelix)、地马孕酮(delmadinone)、地昔帕明(desipramine)、德舍瑞林(deslorelin)、代克拉莫(dexclamol)、地西泮(diazepam)、二氯醛安替比林(dichloralphenazone)、双丙戊酸(divalproex)、苯海拉明(diphenhydramine)、多塞平(doxepin)、屈洛昔芬(droloxifene)、艾司唑仑(estazolam)、雌二醇(estradiol)、雌激素、乙氯维诺(ethchlorvynol)、依托咪酯(etomidate)、依西美坦(exemestane)、法倔唑(fadrozole)、非诺班(fenobam)、氟硝西泮(flunitrazepam)、氟西泮(flurazepam)、氟他米特(flutamide)、氟伏沙明(fluvoxamine)、氟西汀(fluoxetine)、福美司坦(formestane)、膦西泮(fosazepam)、氟维司群(fulvestrant)、格鲁米特(glutethimide)、戈舍瑞林(goserelin)、哈拉西泮(halazepam)、组氨瑞林(histrelin)、羟嗪(hydroxyzine)、艾多昔芬(idoxifene)、伊米帕明(imipramine)、拉索昔芬(lasofoxifene)、亮脯利特(leuprolide)、锂、来曲唑(letrozol)、亮氨酸、亮脯利特(leuprolide)、亮丙瑞林(leuprorelin)、劳拉西泮(lorazepam)、氯甲西泮(lormetazepam)、马普替林(maprotiline)、甲氯喹酮(mecloqualone)、褪黑激素(melatonin)、甲苯巴比妥(mephobarbital)、甲氨丙酯(meprobamate)、甲喹酮(methaqualone)、咪达氟(midaflur)、咪达唑仑(midazolam)、那法瑞林(nafarelin)、萘福昔定(nafoxidine)、奈法唑酮(nefazodone)、硝米芬(nitromifene)、尼鲁米特(nilutamide)、尼索氨酯(nisobamate)、硝西泮(nitrazepam)、痛敏肽(nociceptin)、去甲替林(nortriptyline)、奥美昔芬(ormeloxifene)、奥沙西泮(oxazepam)、三聚乙醛(paraldehyde)、帕罗西汀(paroxetine)、戊巴比妥(pentobarbital)、哌拉平(perlapine)、羟哌氯丙嗪(perphenazine)、苯乙肼(phenelzine)、苯巴比妥(phenobarbital)、普拉西泮(prazepam)、孕酮、普鲁米嗪(promethazine)、丙泊酚(propofol)、普罗替林(protriptyline)、夸西泮(quazepam)、雷洛昔芬(raloxifene)、瑞氯西泮(reclazepam)、咯来米特(roletamide)、司可巴比妥(secobarbital)、舍曲林(sertraline)、舒普罗酮(suproclone)、他莫昔芬(tamoxifen)、替马西泮(temazepam)、硫利达嗪(thioridazine)、托瑞米芬(toremifene)、曲卡唑酯(tracazolate)、反苯环丙胺(tranylcypromaine)、曲唑酮(trazodone)、曲沃昔芬(trioxifene)、三唑仑(triazolam)、曲普瑞林(triptorelin)、曲匹泮(trepipam)、三甲氧苯醋酰胺(tricetamide)、三氯福司(triclofos)、三氟拉嗪(trifluoperazine)、曲美托嗪(trimetozine)、曲米帕明(trimipramine)、乌达西泮(uldazepam)、丙戊酸(valproate)、文拉法辛(venlafaxine)、伏氯唑(vorozole)、扎来普隆(zaleplon)、唑拉西泮(zolazepam)、唑吡坦(zolpidem)、及其盐、及其组合等、以及其掺合物及组合。另外的活性剂的其他实例包括但不限于选择性雌激素受体拮抗剂,包括他莫昔芬(Nolvadex®)、雷洛昔芬(Evista®)、及托瑞米芬(Fareston®);抗雌激素药物,包括氟维司群(Faslodex®);芳香酶抑制剂,包括阿那曲唑(Arimidex®)、来曲唑(Femara®)及依西美坦(Aromasin®);促黄体生成激素释放激素(LHRH)激动剂,包括戈舍瑞林(Zoladex®)、亮脯利特(Lupron®);促黄体生成激素(LH)阻断剂,包括布舍瑞林、亮丙瑞林(Prostap®)、组氨瑞林(Vantas®)及曲普瑞林(Decapeptyl®);抗雄激素,包括氟他米特(Drogenil®)及比卡鲁胺(Casodex®);促性腺激素释放激素(GnRH)阻断剂,包括地加瑞克(Firmagon®);以及阿比特龙(Zytiga®)。
在某些实施方案中,本公开内容包括一种组合物,其包括有效量的用于治疗或预防血管舒缩症状的TRPM8拮抗剂及药学上可接受的载体。在某些实施方案中,组合物为药用组合物。组合物可与适合各施用方法的惰性载体一起使用,且可配制成惯用制剂(例如片剂、颗粒、胶囊、粉末、溶液、悬浮液、乳液、注射剂、输注剂等)。作为这种载体,可提及例如粘合剂(例如阿拉伯胶、明胶、山梨糖醇、聚乙烯吡咯烷酮等)、赋形剂(例如乳糖、糖(sugar)、玉米淀粉、山梨糖醇等)、润滑剂(硬脂酸镁、滑石、聚乙二醇等)、崩解剂(例如马铃薯淀粉等)等,其皆为药学上可接受的。当组合物用作注射液或输注液时,其可通过使用例如注射用蒸馏水、生理盐水、葡萄糖水溶液等进行配制。
在某些实施方案中,本公开内容包括TRPM8拮抗剂或包含TRPM8拮抗剂作为活性成分的组合物用于治疗或预防有需要的受试者的血管舒缩症状的用途。另外,在某些实施方案中,本公开内容包括TRPM8拮抗剂用于制备用于治疗或预防血管舒缩症状的药物的用途。
应了解以上说明及以下实施例旨在举例说明而并不限制本公开内容的范围。在本公开内容的范围内的其他方面、优点及改良对本公开内容所属领域的技术人员而言是明显的。
实施例
实施例1:TRPM8拮抗剂针对大鼠中的核心体温的评价
方法:将化合物A(0.3及3mg/kg)或溶媒经口施用至首经实验的SD大鼠(n=6)。在施用前、施用后1、2、3及6小时测量直肠温度。计算并在统计学上分析0至6小时的AUC。
结果:如图1所示,相较于溶媒而言,化合物A显著地减低直肠温度(P<0.01)。在施用3mg/kg后2小时观察到直肠温度的最大降低且其幅度为0.82℃。经口施用前的直肠温度是在37.0℃至37.8℃之间。
实施例2:用于评估多剂量的化合物A在经历血管舒缩症状的雌性受试者中的安全性、耐受性及药物动力学的I期随机双盲安慰剂对照研究
研究设计:此为Ib期随机双盲安慰剂对照研究。研究设计示于图2。在最初的筛选诊视后,将活动记录检查事件监测器(actigraphy event monitor)(手表)给予合适的受试者以在筛选期间2周的时间段内记录潮热的发作作为血管舒缩症状(VMS)事件,以便确认VMS合格标准(在2周期间平均≥7次VMS/天)。在筛选期期间受试者可能需要回到场所读取或更换活动记录检查事件监测器。征求检视VMS数据后被认为合适的受试者参与临床研究单位(clinical research unit,CRU)持续一段16天的住宿期,包括14天的调查药品(Investigational Medicinal Product,IMP)施用。在投药前1天(第-1天)准许受试者进入CRU。于第-1天未施用药品。于第1天,以双盲的方式使符合研究合格标准的受试者随机接受一个剂量水平的化合物A(6位受试者)或相称的安慰剂(2位受试者)。随机治疗是每晚施用一次,开始于第1天,总共持续14天。
所施用的化合物A的预期剂量水平为第1组50mg、第2组200mg及第3组400mg。在第2组及第3组中朝向下一剂量水平的进展及所施用的剂量的选择是基于来自前一投药组的新出现的安全性及耐受性数据以及可得的核心体温数据。若符合剂量增量停止标准,便减少随后的组的剂量。所评估的最低潜在剂量为10mg且用于研究的最大剂量不超过400mg。必要时,为了调查其他剂量水平,这三个组相继地进行投药且伴随第四个额外的组进行投药。
于第15天夜间或于第16天早晨(若受试者认为较方便)在所有投药后24小时程序结束后准许受试者离开CRU,并于第21天回来进行随访诊视。各受试者参与的总持续时间是最大63天(于第-42天的最初的筛选诊视至于第21天的随访)。
终点:
初级评估
‧安全性及耐受性:生命体征、ECG参数、临床实验室评估、体格检查、不利事件及总耐受性的评估
次级评估
‧药物动力学评估
核心体温评估
‧核心体温自基线的变化
探索性评估
‧VMS的频率及睡眠评估
‧心情及主观睡眠品质
将五十(50)mg的化合物A施用至经历血管舒缩症状(VMS)的雌性受试者,作为上述的评估,检查VMS的频率及核心体温评估。
关于VMS的频率,在14天的治疗期期间在第一次投药后24小时内的时间内观察血管舒缩症状(VMS)频率的平均观测值的变化。在此,中度VMS及重度VMS皆以VMS频率计数。于各诊视日的VMS频率的平均观测值概述于表1。
如图3所示,针对安慰剂及化合物A标绘出各VMS频率的平均观测值。在图3中,三角形或正方形符号各分别表示50mg的化合物A或安慰剂的结果。如图3所示,相较于雌激素或选择性血清素再吸收抑制剂(诸如帕罗西汀)而言,化合物A显著地减少VMS的频率,且由于VMS频率的减少效果是在第2天或之后(即在施用数日内)显现,故化合物A具有立即的效果。
关于核心体温评估,于诊视日第1、7、10或14天在投药后24小时内的时间内观察受试者的核心体温自基线的变化。将测试结果示于图4。正方形、三角形、空心圆形或实心圆形符号各分别表示于诊视日第1、7、10或14天的结果。如图4所示,化合物A显示显著地降低核心体温。
考虑本文中所公开的发明的说明书及实施,本公开内容的其他实施方案对本领域技术人员而言是显然的。说明书及实施例仅旨在被视为例示性的,本发明的真正的范围及精神由以下权利要求书表明。
Claims (36)
1.一种用于治疗或预防有需要的受试者的血管舒缩症状的方法,包括:
对所述受试者施用有效量的瞬时受体电位Melastatin 8(TRPM8)拮抗剂。
2.权利要求1的方法,其中,所述受试者为人受试者。
3.权利要求2的方法,其中,所述TRPM8拮抗剂是以包含所述TRPM8拮抗剂及药学上可接受的载体的组合物的形式施用。
4.权利要求2的方法,其中,所述人受试者为更年期的女性。
5.权利要求4的方法,其中,所述人受试者为近更年期的女性。
6.权利要求4的方法,其中,所述人受试者为更年期后的女性。
7.权利要求2的方法,其中,所述人受试者为癌症患者。
8.权利要求2的方法,其中,所述人受试者正接受或曾接受癌症治疗。
9.权利要求8的方法,其中,所述癌症治疗为性腺切除疗法或性激素抑制疗法。
10.权利要求2的方法,其中,所述人受试者曾接受外科手术。
11.权利要求10的方法,其中,所述外科手术为子宫切除术、卵巢切除术或睾丸切除术。
12.权利要求2的方法,其中,所述血管舒缩症状为潮热。
13.权利要求2的方法,其中,所述血管舒缩症状为盗汗。
14.权利要求2的方法,其中,所述TRPM8拮抗剂是在感受到血管舒缩症状发作后立即施用。
15.权利要求2的方法,其中,所述TRPM8拮抗剂是每日施用。
16.权利要求15的方法,其中,所述TRPM8拮抗剂是每日施用一次。
17.权利要求15的方法,其中,所述TRPM8拮抗剂是每日施用两次。
18.权利要求2和3中任一项的方法,其中,所述TRPM8拮抗剂包含选自磺胺类、磺酰胺类、酰胺类、2-芳基噁唑类、2-芳基噻唑类、螺环哌啶类、萘基衍生物类及苯并咪唑衍生物类的化合物。
19.权利要求18的方法,其中,所述TRPM8拮抗剂为选自磺胺类的化合物。
20. 权利要求19的方法,其中,所述磺胺化合物由下式(I)表示:
[化1]
其中:
环A为双环状芳香族杂环,包括(a)与苯稠合的吡啶;或(b)与含有碳原子及选自氧原子、硫原子及氮原子的1至4个杂原子的5至6员单环状芳香族杂环稠合的吡啶,且环A在构成环A的吡啶环的氮原子所邻接的碳原子上结合磺酰基氨基部分,
环B为(a)具有6至11个碳作为环原子的单环状或双环状芳香族烃;(b)具有3至12个碳作为环原子的单环状或双环状脂环族烃;(c)含有碳原子及选自氧原子、硫原子及氮原子的1至4个杂原子的5至11员单环状或双环状芳香族杂环;或(d)含有碳原子及选自氧原子、硫原子及氮原子的1至4个杂原子的4至12员单环状或双环状非芳香族杂环,
环C为(a)苯;或(b)含有碳原子及选自氧原子、硫原子及氮原子的1至4个杂原子的5至6员单环状芳香族杂环,
R1为(a)氢;(b)C1-C6烷基,其可任选经选自C3-C7环烷基、C1-C6烷氧基、卤素、氧代基及羟基的1至7个基团取代;(c)C3-C7环烷基,其可任选经选自C1-C6烷基、C1-C6烷氧基及卤素的1至7个基团取代;(d)C1-C6烷氧基,其可任选经选自C3-C7环烷基、C1-C6烷氧基、卤素及羟基的1至7个基团取代;(e)苯基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(f)卤素;或(g)腈,
R2a、R2b、R2c及R2d各自独立地为(a)氢;(b)C1-C6烷基,其可任选经选自C1-C6烷氧基、C3-C7环烷基、卤素、氧代基及羟基的1至7个基团取代;(c)C3-C7环烷基,其可任选经选自C1-C6烷基、C1-C6烷氧基及卤素的1至7个基团取代;(d)C1-C6烷氧基,其可任选经选自C1-C6烷氧基、C3-C7环烷基及卤素的1至7个基团取代;(e)苯基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(f)5至6员单环状芳香族杂环基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(g)4至7员单环状非芳香族杂环基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(h)卤素;或(i)腈,
R3a、R3b、R3c及R3d各自独立地为(a)氢;(b)C1-C6烷基,其可任选经选自C3-C7环烷基、C3-C7卤代环烷基(其中,所述环烷基及卤代环烷基可各自独立地任选经选自C1-C6烷基及C1-C6卤代烷基的1至3个基团取代)、C1-C6烷氧基、C1-C6卤代烷氧基、苯基、5至6员单环状芳香族杂环基、4至7员单环状非芳香族杂环基(其中,所述苯基、芳香族杂环基及非芳香族杂环基可各自独立地任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代)、卤素、氧代基及羟基的1至7个基团取代;(c)C3-C7环烷基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、卤素及羟基的1至7个基团取代;(d)C1-C6烷氧基,其可任选经选自C3-C7环烷基、C3-C7卤代环烷基(其中,所述环烷基及卤代环烷基可各自独立地任选经选自C1-C6烷基及C1-C6卤代烷基的1至3个基团取代)、C1-C6烷氧基、C1-C6卤代烷氧基、苯基、5至6员单环状芳香族杂环基、4至7员单环状非芳香族杂环基(其中,所述苯基、芳香族杂环基及非芳香族杂环基可各自独立地任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代)、卤素及羟基的1至7个基团取代;(e)C3-C7环烷氧基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、卤素及羟基的1至7个基团取代;(f)苯基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(g)5至6员单环状芳香族杂环基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(h)4至7员单环状非芳香族杂环基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(i)苯氧基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(j)卤素;或(k)羟基,
或
两个选自R3a、R3b、R3c及R3d的取代基彼此组合形成氧代基,
R5及R6各自独立地为(a)氢;(b)C1-C6烷基;(c)C1-C6卤代烷基;(d)C3-C7环烷基;或(e)C3-C7卤代环烷基,或R5及R6在其末端连同邻接的碳原子彼此组合形成3至7员单环状脂环族烃,
n为0、1或2;
X为(a)羧基;(b)C1-C6烷氧基羰基;(c)羟基-C1-C6烷基;(d)氨基羰基,其中,氮原子可任选经选自C1-C6烷基、C1-C6烷氧基及腈的一个基团取代;或(e)C2-C7烷酰基,其可任选经1至3个卤素取代;
或其药学上可接受的盐。
21.权利要求20的方法,其中,对所述人受试者施用有效量的所述TRPM8拮抗剂降低所述人受试者的核心体温约0.5℃至约2℃。
22. 权利要求20的方法,其中,所述磺胺化合物选自:
4-({(1-环丙基-4-甲基异喹啉-3-基)[4-(三氟甲氧基)苯甲基]氨基}磺酰基)苯甲酸、
4-({(1-异丙基-4-甲基异喹啉-3-基)[4-(三氟甲氧基)苯甲基]氨基}磺酰基)苯甲酸、
4-{[{3-氯-4-[环丙基(二氟)甲基]苯甲基}(4-甲基异喹啉-3-基)氨基]磺酰基}苯甲酸、
4-({(4-环丙基异喹啉-3-基)[4-(三氟甲氧基)苯甲基]氨基}磺酰基)苯甲酸、
4-{[{3-氯-4-[环丙基(二氟)甲基]苯甲基}(1-环丙基-4-甲基异喹啉-3-基)氨基]磺酰基}苯甲酸、
4-{[{4-[环丙基(二氟)甲基]-3-氟苯甲基}(4-甲基异喹啉-3-基)氨基]磺酰基}苯甲酸、
4-({[4-(三氟甲氧基)苯甲基][4-(三氟甲基)异喹啉-3-基]氨基}磺酰基)苯甲酸、
4-[((4-环丙基异喹啉-3-基){[5-(三氟甲基)吡啶-2-基]甲基}氨基)磺酰基]苯甲酸、
4-{[{4-[环丙基(二氟)甲基]-3-氟苯甲基}(4-环丙基异喹啉-3-基)氨基]磺酰基}苯甲酸、及
其药学上可接受的盐。
23.权利要求18的方法,其中,所述TRPM8拮抗剂为选自酰胺类的化合物。
24.权利要求18的方法,其中,所述TRPM8拮抗剂是每日施用。
25.权利要求24的方法,其中,所述TRPM8拮抗剂是每日施用一次。
26.权利要求24的方法,其中,所述TRPM8拮抗剂是每日施用两次。
27.权利要求2或3的方法,其中,所述TRPM8拮抗剂是与另外的活性剂一起施用。
28. 权利要求3的方法,其中,所述组合物为药用组合物。
29.一种组合物,包含
有效量的用于治疗或预防血管舒缩症状的TRPM8拮抗剂及药学上可接受的载体。
30.权利要求29的组合物,其中,所述TRPM8拮抗剂包含选自磺胺类、磺酰胺类、酰胺类、2-芳基噁唑类、2-芳基噻唑类、螺环哌啶类、萘基衍生物类、及苯并咪唑衍生物类的化合物。
31.权利要求29的组合物,其中,所述TRPM8拮抗剂为选自磺胺类的化合物。
32. 权利要求31的组合物,其中,所述磺胺化合物由下式(I)表示:
[化1]
其中:
环A为双环状芳香族杂环,包括(a)与苯稠合的吡啶;或(b)与含有碳原子及选自氧原子、硫原子及氮原子的1至4个杂原子的5至6员单环状芳香族杂环稠合的吡啶,且环A在构成环A的吡啶环的氮原子所邻接的碳原子上结合磺酰基氨基部分,
环B为(a)具有6至11个碳作为环原子的单环状或双环状芳香族烃;(b)具有3至12个碳作为环原子的单环状或双环状脂环族烃;(c)含有碳原子及选自氧原子、硫原子及氮原子的1至4个杂原子的5至11员单环状或双环状芳香族杂环;或(d)含有碳原子及选自氧原子、硫原子及氮原子的1至4个杂原子的4至12员单环状或双环状非芳香族杂环,
环C为(a)苯;或(b)含有碳原子及选自氧原子、硫原子及氮原子的1至4个杂原子的5至6员单环状芳香族杂环,
R1为(a)氢;(b)C1-C6烷基,其可任选经选自C3-C7环烷基、C1-C6烷氧基、卤素、氧代基及羟基的1至7个基团取代;(c)C3-C7环烷基,其可任选经选自C1-C6烷基、C1-C6烷氧基及卤素的1至7个基团取代;(d)C1-C6烷氧基,其可任选经选自C3-C7环烷基、C1-C6烷氧基、卤素及羟基的1至7个基团取代;(e)苯基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(f)卤素;或(g)腈,
R2a、R2b、R2c及R2d各自独立地为(a)氢;(b)C1-C6烷基,其可任选经选自C1-C6烷氧基、C3-C7环烷基、卤素、氧代基及羟基的1至7个基团取代;(c)C3-C7环烷基,其可任选经选自C1-C6烷基、C1-C6烷氧基及卤素的1至7个基团取代;(d)C1-C6烷氧基,其可任选经选自C1-C6烷氧基、C3-C7环烷基及卤素的1至7个基团取代;(e)苯基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(f)5至6员单环状芳香族杂环基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(g)4至7员单环状非芳香族杂环基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(h)卤素;或(i)腈,
R3a、R3b、R3c及R3d各自独立地为(a)氢;(b)C1-C6烷基,其可任选经选自C3-C7环烷基、C3-C7卤代环烷基(其中,所述环烷基及卤代环烷基可各自独立地任选经选自C1-C6烷基及C1-C6卤代烷基的1至3个基团取代)、C1-C6烷氧基、C1-C6卤代烷氧基、苯基、5至6员单环状芳香族杂环基、4至7员单环状非芳香族杂环基(其中,所述苯基、芳香族杂环基及非芳香族杂环基可各自独立地任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代)、卤素、氧代基及羟基的1至7个基团取代;(c)C3-C7环烷基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、卤素及羟基的1至7个基团取代;(d)C1-C6烷氧基,其可任选经选自C3-C7环烷基、C3-C7卤代环烷基(其中,所述环烷基及卤代环烷基可各自独立地任选经选自C1-C6烷基及C1-C6卤代烷基的1至3个基团取代)、C1-C6烷氧基、C1-C6卤代烷氧基、苯基、5至6员单环状芳香族杂环基、4至7员单环状非芳香族杂环基(其中,所述苯基、芳香族杂环基及非芳香族杂环基可各自独立地任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代)、卤素及羟基的1至7个基团取代;(e)C3-C7环烷氧基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、卤素及羟基的1至7个基团取代;(f)苯基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(g)5至6员单环状芳香族杂环基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(h)4至7员单环状非芳香族杂环基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(i)苯氧基,其可任选经选自C1-C6烷基、C1-C6卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基及卤素的1至3个基团取代;(j)卤素;或(k)羟基,
或
两个选自R3a、R3b、R3c及R3d的取代基彼此组合形成氧代基,
R5及R6各自独立地为(a)氢;(b)C1-C6烷基;(c)C1-C6卤代烷基;(d)C3-C7环烷基;或(e)C3-C7卤代环烷基,或R5及R6在其末端连同邻接的碳原子彼此组合形成3至7员单环状脂环族烃,
n为0、1或2;
X为(a)羧基;(b)C1-C6烷氧基羰基;(c)羟基-C1-C6烷基;(d)氨基羰基,其中,氮原子可任选经选自C1-C6烷基、C1-C6烷氧基及腈的一个基团取代;或(e)C2-C7烷酰基,其可任选经1至3个卤素取代;
或其药学上可接受的盐。
33. 权利要求32的组合物,其中,所述磺胺化合物选自:
4-({(1-环丙基-4-甲基异喹啉-3-基)[4-(三氟甲氧基)苯甲基]氨基}磺酰基)苯甲酸、
4-({(1-异丙基-4-甲基异喹啉-3-基)[4-(三氟甲氧基)苯甲基]氨基}磺酰基)苯甲酸、
4-{[{3-氯-4-[环丙基(二氟)甲基]苯甲基}(4-甲基异喹啉-3-基)氨基]磺酰基}苯甲酸、
4-({(4-环丙基异喹啉-3-基)[4-(三氟甲氧基)苯甲基]氨基}磺酰基)苯甲酸、
4-{[{3-氯-4-[环丙基(二氟)甲基]苯甲基}(1-环丙基-4-甲基异喹啉-3-基)氨基]磺酰基}苯甲酸、
4-{[{4-[环丙基(二氟)甲基]-3-氟苯甲基}(4-甲基异喹啉-3-基)氨基]磺酰基}苯甲酸、
4-({[4-(三氟甲氧基)苯甲基][4-(三氟甲基)异喹啉-3-基]氨基}磺酰基)苯甲酸、
4-[((4-环丙基异喹啉-3-基){[5-(三氟甲基)吡啶-2-基]甲基}氨基)磺酰基]苯甲酸、
4-{[{4-[环丙基(二氟)甲基]-3-氟苯甲基}(4-环丙基异喹啉-3-基)氨基]磺酰基}苯甲酸、及
其药学上可接受的盐。
34.权利要求30的组合物,其中,所述TRPM8拮抗剂为选自酰胺类的化合物。
35.权利要求29的组合物,其进一步包含另外的活性剂。
36. TRPM8拮抗剂或包含所述TRPM8拮抗剂作为活性成分的组合物用于治疗或预防有需要的受试者的血管舒缩症状的用途。
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210390477.XA CN114748624A (zh) | 2016-06-13 | 2017-06-12 | 用于治疗或预防血管舒缩症状的组合物 |
CN202110496162.9A CN113398124A (zh) | 2016-06-13 | 2017-06-12 | 用于治疗或预防血管舒缩症状的组合物 |
CN202110496161.4A CN113384577A (zh) | 2016-06-13 | 2017-06-12 | 用于治疗或预防血管舒缩症状的组合物 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662349179P | 2016-06-13 | 2016-06-13 | |
US62/349179 | 2016-06-13 | ||
PCT/JP2017/021569 WO2017217351A1 (en) | 2016-06-13 | 2017-06-12 | Compositions for treating or preventing vasomotor symptoms |
Related Child Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110496162.9A Division CN113398124A (zh) | 2016-06-13 | 2017-06-12 | 用于治疗或预防血管舒缩症状的组合物 |
CN202210390477.XA Division CN114748624A (zh) | 2016-06-13 | 2017-06-12 | 用于治疗或预防血管舒缩症状的组合物 |
CN202110496161.4A Division CN113384577A (zh) | 2016-06-13 | 2017-06-12 | 用于治疗或预防血管舒缩症状的组合物 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN109310689A true CN109310689A (zh) | 2019-02-05 |
Family
ID=59101629
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210390477.XA Pending CN114748624A (zh) | 2016-06-13 | 2017-06-12 | 用于治疗或预防血管舒缩症状的组合物 |
CN202110496161.4A Pending CN113384577A (zh) | 2016-06-13 | 2017-06-12 | 用于治疗或预防血管舒缩症状的组合物 |
CN202110496162.9A Pending CN113398124A (zh) | 2016-06-13 | 2017-06-12 | 用于治疗或预防血管舒缩症状的组合物 |
CN201780036529.0A Pending CN109310689A (zh) | 2016-06-13 | 2017-06-12 | 用于治疗或预防血管舒缩症状的组合物 |
Family Applications Before (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210390477.XA Pending CN114748624A (zh) | 2016-06-13 | 2017-06-12 | 用于治疗或预防血管舒缩症状的组合物 |
CN202110496161.4A Pending CN113384577A (zh) | 2016-06-13 | 2017-06-12 | 用于治疗或预防血管舒缩症状的组合物 |
CN202110496162.9A Pending CN113398124A (zh) | 2016-06-13 | 2017-06-12 | 用于治疗或预防血管舒缩症状的组合物 |
Country Status (17)
Country | Link |
---|---|
US (2) | US10993939B2 (zh) |
EP (2) | EP4140484A1 (zh) |
JP (1) | JP6943887B2 (zh) |
KR (2) | KR20230005413A (zh) |
CN (4) | CN114748624A (zh) |
AU (2) | AU2017285609B2 (zh) |
BR (1) | BR112018075403A2 (zh) |
CA (1) | CA3022808A1 (zh) |
CO (1) | CO2018013692A2 (zh) |
ES (1) | ES2957232T3 (zh) |
IL (1) | IL262664B (zh) |
MX (1) | MX2018015399A (zh) |
PH (1) | PH12018502618A1 (zh) |
RU (1) | RU2768875C2 (zh) |
SG (1) | SG11201809802PA (zh) |
TW (1) | TWI739850B (zh) |
WO (1) | WO2017217351A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113677334A (zh) * | 2019-02-01 | 2021-11-19 | 马歇尔大学科研协会 | 瞬时受体电位melastatin 8(trpm8)拮抗剂和相关方法 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3727383A1 (en) | 2017-12-19 | 2020-10-28 | Mitsubishi Tanabe Pharma Corporation | Compositions and methods for treating or preventing vasomotor symptoms |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103443080A (zh) * | 2011-03-16 | 2013-12-11 | 田边三菱制药株式会社 | 具有trpm8拮抗活性的磺酰胺化合物 |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006122156A2 (en) * | 2005-05-09 | 2006-11-16 | Hydra Biosciences, Inc. | Compounds for modulating trpv3 function |
WO2009073788A1 (en) | 2007-12-07 | 2009-06-11 | Firestone Leigh H | Compositions and methods for treating menopausal females |
CA2747637A1 (en) | 2008-12-18 | 2010-07-15 | Janssen Pharmaceutica Nv | Sulfamides as trpm8 modulators |
WO2010103381A1 (en) | 2009-03-13 | 2010-09-16 | Glenmark Pharmaceuticals S.A. | Spirocyclic piperidine derivatives as trpm 8 modulators |
EP2424517A4 (en) | 2009-05-01 | 2013-01-23 | Raqualia Pharma Inc | SULFAMOYLBENZOIC ACID DERIVATIVES AS TRPM8 ANTAGONISTS |
TW201103941A (en) | 2009-06-10 | 2011-02-01 | Janssen Pharmaceutica Nv | Benzimidazole derivatives useful as TRPM8 channel modulators |
EP2481727A1 (en) | 2011-01-28 | 2012-08-01 | Dompe S.p.A. | TRPM8 receptor antagonists |
JP2014527511A (ja) | 2011-06-24 | 2014-10-16 | アムジエン・インコーポレーテツド | Trpm8拮抗剤及び治療におけるそれらの使用 |
DK2793883T3 (en) | 2011-12-19 | 2018-07-30 | Dompe Farm Spa | TRPM8 antagonists |
WO2014042238A1 (ja) * | 2012-09-14 | 2014-03-20 | 田辺三菱製薬株式会社 | スルホンアミド化合物 |
JP5985453B2 (ja) * | 2012-09-14 | 2016-09-06 | 田辺三菱製薬株式会社 | 医薬組成物 |
JP6352413B2 (ja) * | 2013-10-22 | 2018-07-04 | エドワード タク ウェイWEI, Edward Tak | 感覚的不快感の治療向け局所薬としてのジ−イソプロピル−アルカン(dapa)化合物 |
-
2017
- 2017-06-12 US US16/308,932 patent/US10993939B2/en active Active
- 2017-06-12 AU AU2017285609A patent/AU2017285609B2/en active Active
- 2017-06-12 TW TW106119449A patent/TWI739850B/zh active
- 2017-06-12 RU RU2019100424A patent/RU2768875C2/ru active
- 2017-06-12 EP EP22194364.0A patent/EP4140484A1/en not_active Withdrawn
- 2017-06-12 ES ES17732243T patent/ES2957232T3/es active Active
- 2017-06-12 SG SG11201809802PA patent/SG11201809802PA/en unknown
- 2017-06-12 WO PCT/JP2017/021569 patent/WO2017217351A1/en active Application Filing
- 2017-06-12 EP EP17732243.5A patent/EP3468557B1/en active Active
- 2017-06-12 CN CN202210390477.XA patent/CN114748624A/zh active Pending
- 2017-06-12 JP JP2018564985A patent/JP6943887B2/ja active Active
- 2017-06-12 KR KR1020227044605A patent/KR20230005413A/ko not_active Application Discontinuation
- 2017-06-12 MX MX2018015399A patent/MX2018015399A/es unknown
- 2017-06-12 CN CN202110496161.4A patent/CN113384577A/zh active Pending
- 2017-06-12 CN CN202110496162.9A patent/CN113398124A/zh active Pending
- 2017-06-12 BR BR112018075403-0A patent/BR112018075403A2/pt not_active Application Discontinuation
- 2017-06-12 CA CA3022808A patent/CA3022808A1/en active Pending
- 2017-06-12 KR KR1020187036433A patent/KR20190017800A/ko not_active IP Right Cessation
- 2017-06-12 CN CN201780036529.0A patent/CN109310689A/zh active Pending
-
2018
- 2018-10-29 IL IL262664A patent/IL262664B/en unknown
- 2018-12-12 PH PH12018502618A patent/PH12018502618A1/en unknown
- 2018-12-18 CO CONC2018/0013692A patent/CO2018013692A2/es unknown
-
2021
- 2021-02-27 US US17/187,769 patent/US20210177830A1/en active Pending
-
2022
- 2022-08-04 AU AU2022211877A patent/AU2022211877A1/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103443080A (zh) * | 2011-03-16 | 2013-12-11 | 田边三菱制药株式会社 | 具有trpm8拮抗活性的磺酰胺化合物 |
Non-Patent Citations (2)
Title |
---|
(美)古德曼等: "《西氏内科学》", 31 May 2015, 世界图书出版西安有限公司 * |
孙靖: "激活温度敏感性瞬时受体电位通道调控血管功能和血压的机制研究", 《中国博士学位论文全文数据库 医药卫生科技辑》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113677334A (zh) * | 2019-02-01 | 2021-11-19 | 马歇尔大学科研协会 | 瞬时受体电位melastatin 8(trpm8)拮抗剂和相关方法 |
CN113677334B (zh) * | 2019-02-01 | 2024-04-09 | 马歇尔大学科研协会 | 瞬时受体电位melastatin 8(trpm8)拮抗剂和相关方法 |
Also Published As
Publication number | Publication date |
---|---|
EP3468557A1 (en) | 2019-04-17 |
WO2017217351A1 (en) | 2017-12-21 |
AU2017285609B2 (en) | 2022-08-18 |
IL262664B (en) | 2021-10-31 |
CA3022808A1 (en) | 2017-12-21 |
ES2957232T3 (es) | 2024-01-15 |
PH12018502618A1 (en) | 2019-10-07 |
CN113384577A (zh) | 2021-09-14 |
CN113398124A (zh) | 2021-09-17 |
MX2018015399A (es) | 2019-04-29 |
CO2018013692A2 (es) | 2019-01-18 |
JP6943887B2 (ja) | 2021-10-06 |
IL262664A (en) | 2018-12-31 |
SG11201809802PA (en) | 2018-12-28 |
TWI739850B (zh) | 2021-09-21 |
EP3468557B1 (en) | 2023-07-26 |
US20210177830A1 (en) | 2021-06-17 |
BR112018075403A2 (pt) | 2019-03-19 |
KR20190017800A (ko) | 2019-02-20 |
US10993939B2 (en) | 2021-05-04 |
AU2022211877A1 (en) | 2022-09-01 |
RU2019100424A (ru) | 2020-07-15 |
US20190142821A1 (en) | 2019-05-16 |
JP2019517573A (ja) | 2019-06-24 |
RU2768875C2 (ru) | 2022-03-25 |
EP4140484A1 (en) | 2023-03-01 |
RU2019100424A3 (zh) | 2020-09-24 |
KR20230005413A (ko) | 2023-01-09 |
AU2017285609A1 (en) | 2019-01-03 |
TW201803595A (zh) | 2018-02-01 |
CN114748624A (zh) | 2022-07-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2212737B1 (es) | Ciclobenzaprina para tratar trastornos de ansiedad generalizada y composiciones de la misma. | |
TW201720439A (zh) | 用於預防及治療與神經退化性疾病相關的幻覺之作為5-ht2a血清素受體的二芳基及芳基雜芳基脲衍生物 | |
AU2022211877A1 (en) | Compositions for treating or preventing vasomotor symptoms | |
AU2024202139A1 (en) | Novel treatment for hot flushes | |
US11471452B2 (en) | Compositions and methods for treating or preventing vasomotor symptoms | |
RU2815402C2 (ru) | Композиции и способы для лечения или предотвращения вазомоторных симптомов | |
NZ747772A (en) | Compositions for treating or preventing vasomotor symptoms | |
NZ785802A (en) | Compositions for treating or preventing vasomotor symptoms | |
JP2020517670A (ja) | うつ病を治療するための組成物および方法 | |
TW202243675A (zh) | 焦慮症處置用組成物及處置方法 | |
CN113329747A (zh) | 用于治疗抑郁症的多潘立酮组合物和方法 | |
TAMIL et al. | A COMPARATIVE STUDY OF THE EFFECT OF CLONIDINE TRAMADOL AND NALBUPHINE ON POSTSPINAL ANAESTHESIA SHIVERING |
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 | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190205 |