TWI784199B - Dp拮抗劑 - Google Patents
Dp拮抗劑 Download PDFInfo
- Publication number
- TWI784199B TWI784199B TW108133822A TW108133822A TWI784199B TW I784199 B TWI784199 B TW I784199B TW 108133822 A TW108133822 A TW 108133822A TW 108133822 A TW108133822 A TW 108133822A TW I784199 B TWI784199 B TW I784199B
- Authority
- TW
- Taiwan
- Prior art keywords
- compound
- general formula
- phenyl
- chloro
- compound represented
- Prior art date
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- 239000005557 antagonist Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 252
- 150000003839 salts Chemical class 0.000 claims abstract description 49
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 100
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 239000004480 active ingredient Substances 0.000 abstract description 45
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 31
- 102000005962 receptors Human genes 0.000 abstract description 31
- 108020003175 receptors Proteins 0.000 abstract description 31
- 239000003814 drug Substances 0.000 abstract description 26
- 201000010099 disease Diseases 0.000 abstract description 23
- 229940079593 drug Drugs 0.000 abstract description 13
- 208000020685 sleep-wake disease Diseases 0.000 abstract description 13
- 230000003042 antagnostic effect Effects 0.000 abstract description 12
- 230000003449 preventive effect Effects 0.000 abstract description 11
- 230000001404 mediated effect Effects 0.000 abstract description 10
- 229940124597 therapeutic agent Drugs 0.000 abstract description 8
- 230000005012 migration Effects 0.000 abstract description 7
- 238000013508 migration Methods 0.000 abstract description 7
- 210000003169 central nervous system Anatomy 0.000 abstract description 5
- 239000002464 receptor antagonist Substances 0.000 abstract description 2
- 229940044551 receptor antagonist Drugs 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 111
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 63
- -1 2,3-dihydro-1H-inden-2-yl Chemical group 0.000 description 61
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 47
- 238000000034 method Methods 0.000 description 47
- 238000002360 preparation method Methods 0.000 description 46
- VWVRASTUFJRTHW-UHFFFAOYSA-N 2-[3-(azetidin-3-yloxy)-4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound O=C(CN1C=C(C(OC2CNC2)=N1)C1=CN=C(NC2CC3=C(C2)C=CC=C3)N=C1)N1CCC2=C(C1)N=NN2 VWVRASTUFJRTHW-UHFFFAOYSA-N 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 42
- 239000000126 substance Substances 0.000 description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 35
- 239000000243 solution Substances 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 32
- 230000000704 physical effect Effects 0.000 description 31
- 239000003826 tablet Substances 0.000 description 30
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 29
- 230000014759 maintenance of location Effects 0.000 description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 238000004128 high performance liquid chromatography Methods 0.000 description 26
- 239000000654 additive Substances 0.000 description 24
- 239000007924 injection Substances 0.000 description 24
- 238000002347 injection Methods 0.000 description 24
- 239000008187 granular material Substances 0.000 description 23
- 238000010511 deprotection reaction Methods 0.000 description 21
- 239000000203 mixture Substances 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 125000005843 halogen group Chemical group 0.000 description 20
- 239000002585 base Substances 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000003960 organic solvent Substances 0.000 description 18
- 125000002496 methyl group Chemical class [H]C([H])([H])* 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 17
- 238000004809 thin layer chromatography Methods 0.000 description 16
- 239000007788 liquid Substances 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 14
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 14
- 239000002775 capsule Substances 0.000 description 14
- 125000002950 monocyclic group Chemical group 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- 239000003795 chemical substances by application Substances 0.000 description 13
- 239000000843 powder Substances 0.000 description 13
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 12
- 125000000623 heterocyclic group Chemical group 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 11
- 239000000546 pharmaceutical excipient Substances 0.000 description 11
- 125000006239 protecting group Chemical group 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- 150000003527 tetrahydropyrans Chemical group 0.000 description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 10
- 239000013078 crystal Substances 0.000 description 10
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 10
- 125000004430 oxygen atom Chemical group O* 0.000 description 10
- 239000006188 syrup Substances 0.000 description 10
- 235000020357 syrup Nutrition 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- 208000026935 allergic disease Diseases 0.000 description 9
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 238000005259 measurement Methods 0.000 description 9
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 8
- 150000001204 N-oxides Chemical class 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 230000032050 esterification Effects 0.000 description 8
- 238000005886 esterification reaction Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 125000004434 sulfur atom Chemical group 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- 206010041349 Somnolence Diseases 0.000 description 7
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 7
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 125000001620 monocyclic carbocycle group Chemical group 0.000 description 7
- BHMBVRSPMRCCGG-OUTUXVNYSA-N prostaglandin D2 Chemical compound CCCCC[C@H](O)\C=C\[C@@H]1[C@@H](C\C=C/CCCC(O)=O)[C@@H](O)CC1=O BHMBVRSPMRCCGG-OUTUXVNYSA-N 0.000 description 7
- BHMBVRSPMRCCGG-UHFFFAOYSA-N prostaglandine D2 Natural products CCCCCC(O)C=CC1C(CC=CCCCC(O)=O)C(O)CC1=O BHMBVRSPMRCCGG-UHFFFAOYSA-N 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- 239000012453 solvate Substances 0.000 description 7
- 235000000346 sugar Nutrition 0.000 description 7
- CZSRXHJVZUBEGW-UHFFFAOYSA-N 1,2-thiazolidine Chemical compound C1CNSC1 CZSRXHJVZUBEGW-UHFFFAOYSA-N 0.000 description 6
- XJBHWDKRZXYEDL-UHFFFAOYSA-N 2-(oxan-2-yl)ethanol Chemical compound OCCC1CCCCO1 XJBHWDKRZXYEDL-UHFFFAOYSA-N 0.000 description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 6
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 6
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 6
- 206010020751 Hypersensitivity Diseases 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 6
- 230000007815 allergy Effects 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 239000011248 coating agent Substances 0.000 description 6
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 229960003529 diazepam Drugs 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 238000011049 filling Methods 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 201000003631 narcolepsy Diseases 0.000 description 6
- OSDBJMYIUDLIRI-UHFFFAOYSA-N oxo-[[1-[[4-[[4-(oxoazaniumylmethylidene)pyridin-1-yl]methoxy]cyclohexyl]oxymethyl]pyridin-4-ylidene]methyl]azanium;dichloride Chemical compound [Cl-].[Cl-].C1=CC(=C[NH+]=O)C=CN1COC1CCC(OCN2C=CC(=C[NH+]=O)C=C2)CC1 OSDBJMYIUDLIRI-UHFFFAOYSA-N 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- 238000004808 supercritical fluid chromatography Methods 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- RLTPJVKHGBFGQA-UHFFFAOYSA-N thiadiazolidine Chemical compound C1CSNN1 RLTPJVKHGBFGQA-UHFFFAOYSA-N 0.000 description 6
- 125000003396 thiol group Chemical group [H]S* 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 5
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 5
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 150000001266 acyl halides Chemical class 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 5
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 5
- 238000002567 electromyography Methods 0.000 description 5
- 230000001804 emulsifying effect Effects 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 4
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 4
- PZJFUNZDCRKXPZ-UHFFFAOYSA-N 2,5-dihydro-1h-tetrazole Chemical compound C1NNN=N1 PZJFUNZDCRKXPZ-UHFFFAOYSA-N 0.000 description 4
- GIQZBFXPNRTZRP-UHFFFAOYSA-N 4-acetyloxy-2,6-dimethylbenzoic acid Chemical compound CC(=O)OC1=CC(C)=C(C(O)=O)C(C)=C1 GIQZBFXPNRTZRP-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- 102100029100 Hematopoietic prostaglandin D synthase Human genes 0.000 description 4
- 101000988802 Homo sapiens Hematopoietic prostaglandin D synthase Proteins 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 208000008589 Obesity Diseases 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- 208000003251 Pruritus Diseases 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- 208000032140 Sleepiness Diseases 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000003125 aqueous solvent Substances 0.000 description 4
- 208000010668 atopic eczema Diseases 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 description 4
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 4
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 4
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 4
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 4
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000005187 foaming Methods 0.000 description 4
- 235000003599 food sweetener Nutrition 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 230000007803 itching Effects 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000007937 lozenge Substances 0.000 description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 4
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 4
- 235000020824 obesity Nutrition 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 230000007958 sleep Effects 0.000 description 4
- 150000008163 sugars Chemical class 0.000 description 4
- 239000003765 sweetening agent Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000009885 systemic effect Effects 0.000 description 4
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 4
- RWXZKKKYLRFREK-UHFFFAOYSA-N thiadiazepane Chemical compound C1CCSNNC1 RWXZKKKYLRFREK-UHFFFAOYSA-N 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
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- YVUQSNJEYSNKRX-UHFFFAOYSA-N pimozide Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCN1CCC(N2C(NC3=CC=CC=C32)=O)CC1 YVUQSNJEYSNKRX-UHFFFAOYSA-N 0.000 description 1
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- 150000003053 piperidines Chemical class 0.000 description 1
- LYKMMUBOEFYJQG-UHFFFAOYSA-N piperoxan Chemical compound C1OC2=CC=CC=C2OC1CN1CCCCC1 LYKMMUBOEFYJQG-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
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- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- ZUFQCVZBBNZMKD-UHFFFAOYSA-M potassium 2-ethylhexanoate Chemical compound [K+].CCCCC(CC)C([O-])=O ZUFQCVZBBNZMKD-UHFFFAOYSA-M 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229960003089 pramipexole Drugs 0.000 description 1
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- UARFKZSJGDQRLF-UHFFFAOYSA-N prop-2-ynylcyclohexane Chemical compound C#CCC1CCCCC1 UARFKZSJGDQRLF-UHFFFAOYSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 125000006410 propenylene group Chemical group 0.000 description 1
- 125000001436 propyl group Chemical class [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- NSETWVJZUWGCKE-UHFFFAOYSA-N propylphosphonic acid Chemical compound CCCP(O)(O)=O NSETWVJZUWGCKE-UHFFFAOYSA-N 0.000 description 1
- 210000004129 prosencephalon Anatomy 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229940127250 psychostimulant medication Drugs 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
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- 230000004044 response Effects 0.000 description 1
- QBERHIJABFXGRZ-UHFFFAOYSA-M rhodium;triphenylphosphane;chloride Chemical compound [Cl-].[Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QBERHIJABFXGRZ-UHFFFAOYSA-M 0.000 description 1
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- 239000004576 sand Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
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- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
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- 230000004622 sleep time Effects 0.000 description 1
- 230000008454 sleep-wake cycle Effects 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000019614 sour taste Nutrition 0.000 description 1
- DKGZKTPJOSAWFA-UHFFFAOYSA-N spiperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCC2(C(NCN2C=2C=CC=CC=2)=O)CC1 DKGZKTPJOSAWFA-UHFFFAOYSA-N 0.000 description 1
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- 230000000087 stabilizing effect Effects 0.000 description 1
- 210000002330 subarachnoid space Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
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- 230000009469 supplementation Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
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- 239000007939 sustained release tablet Substances 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- ZYXWYDDFNXBTFO-UHFFFAOYSA-N tetrazolidine Chemical compound C1NNNN1 ZYXWYDDFNXBTFO-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical class SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 1
- IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 description 1
- YDLQKLWVKKFPII-UHFFFAOYSA-N timiperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCC(N2C(NC3=CC=CC=C32)=S)CC1 YDLQKLWVKKFPII-UHFFFAOYSA-N 0.000 description 1
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- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- OHHDIOKRWWOXMT-UHFFFAOYSA-N trazodone hydrochloride Chemical compound [H+].[Cl-].ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 OHHDIOKRWWOXMT-UHFFFAOYSA-N 0.000 description 1
- 229960002301 trazodone hydrochloride Drugs 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- NFACJZMKEDPNKN-UHFFFAOYSA-N trichlorfon Chemical compound COP(=O)(OC)C(O)C(Cl)(Cl)Cl NFACJZMKEDPNKN-UHFFFAOYSA-N 0.000 description 1
- NLOUTGCXBXLQIA-UHFFFAOYSA-N trichloro phosphate Chemical compound ClOP(=O)(OCl)OCl NLOUTGCXBXLQIA-UHFFFAOYSA-N 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229960003986 tuaminoheptane Drugs 0.000 description 1
- VSRBKQFNFZQRBM-UHFFFAOYSA-N tuaminoheptane Chemical compound CCCCCC(C)N VSRBKQFNFZQRBM-UHFFFAOYSA-N 0.000 description 1
- 238000004724 ultra fast liquid chromatography Methods 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 239000000003 vaginal tablet Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- HDOZVRUNCMBHFH-UHFFFAOYSA-N zotepine Chemical compound CN(C)CCOC1=CC2=CC=CC=C2SC2=CC=C(Cl)C=C12 HDOZVRUNCMBHFH-UHFFFAOYSA-N 0.000 description 1
- 229960004496 zotepine Drugs 0.000 description 1
Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D309/06—Radicals substituted by oxygen atoms
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
- C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/38—Amides of thiocarboxylic acids
- C07C327/48—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to carbon atoms of six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
Abstract
本發明提供一種DP受體拮抗劑。
通式(I):
Description
前列腺素D2(簡稱為PGD2)作為花生四烯酸級聯反應之代謝產物而為人所知,已知參與過敏性疾病、睡眠、激素分泌、疼痛、血小板凝集、肝糖代謝、眼壓調整等(非專利文獻1~11)。已知於PGD2之受體中存在DP受體及CRTH2受體,其中存在於腦內、尤其是前腦基底部吻側腹側部之蛛網膜下腔之DP受體與PGD2之睡眠誘發作用相關(非專利文獻12)。即,為了抑制PGD2之睡眠誘發作用,製成睡眠覺醒障礙治療藥,必需一種不僅具有DP拮抗活性,亦具有向中樞之移行性之藥劑。
另一方面,於專利文獻1中,記載有以下之通式(A)所表示之化合物與DP受體特異性地結合而進行拮抗。
[化2]
(式中,R1A
表示(1)氫原子、(2)C1~4烷基等,EA
表示-C(=O)-等,R2A
表示(1)鹵素原子、(2)C1~6烷基等,R3A
表示(1)鹵素原子、(2)C1~6烷基等,WA
表示C5~12之單環或二環之碳環、或5~12員之單環或二環之雜環,R4A
表示(1)氫原子、(2)C1~6烷基等,R5A
表示C1~6烷基等,(1)GA
表示(1)包含選自氮原子、氧原子及硫原子中之0~2個雜原子之C1~6之伸烷基等,JA
表示C5~12之單環或二環之碳環、或5~12員之單環或二環之雜環,mA表示0或1~4之整數,nA表示0或1~4之整數,iA表示0或1~11之整數)
又,於專利文獻2中,記載有以下之通式(B)所表示之化合物係與DP受體特異性地結合而進行拮抗之化合物。
[化3]
(式中,R1B
表示(1)氫原子、(2)C1~4烷基等,EB
表示-CO-基等,R2B
表示(1)鹵素原子、(2)C1~6烷基等,R3B
表示(1)鹵素原子、(2)C1~6烷基等,R4B
表示(1)氫原子、(2)C1~6烷基等,R5B
表示C1~6烷基等,WB
表示C5~12之單環或二環之碳環、或5~12員之單環或二環之雜環,GB
表示(1)包含選自氮原子、氧原子及硫原子中之0~2個雜原子之C1~6之伸烷基等,JB
表示C5~12之單環或二環之碳環、或5~12員之單環或二環之雜環,mB表示0或1~4之整數,nB表示0或1~4之整數,iB表示0或1~11之整數,R12B
及R13B
分別獨立表示(1)可經氧化之C1~4烷基、(2)氫原子等)
然而,於該等先前技術文獻中,關於向中樞之移行性並無任何記載或提示。
[先前技術文獻]
[專利文獻]
[專利文獻1]國際公開第2003/078409號說明書
[專利文獻2]國際公開第2005/028455號說明書
[非專利文獻]
[非專利文獻1]The NEW ENGLAND JOURNAL of MEDICINENE、Vol.303, 1400-1404, 1980
[非專利文獻2]American Review of Respiratory Disease、Vol.128, 597-602, 1983
[非專利文獻3]The Journal of Allergy and Clinical Immunology、Vol.88, 33-42, 1991
[非專利文獻4]Archives of Otolaryngology-Head and Neck Surgery、Vol.113, 179-83, 1987
[非專利文獻5]The Journal of Allergy and Clinical Immunology、Vol.82, 869-77, 1988
[非專利文獻6]The Journal of Immunology、Vol.146, 671-676, 1991
[非專利文獻7]The Journal of Allergy and Clinical Immunology、Vol.83, 905-912, 1989
[非專利文獻8]The NEW ENGLAND JOURNAL of MEDICINENE、Vol.315, 800-804, 1986
[非專利文獻9]American Review of Respiratory Disease、Vol.142, 126-132, 1990
[非專利文獻10]The Journal of Allergy and Clinical Immunology、Vol.87, 540-548, 1991
[非專利文獻11]The Journal of Allergy and Clinical Immunology、Vol.78, 458-461, 1986
[非專利文獻12]Proceedings of the National Academy of Sciences of the United States of America、Vol.98, 11674-11679, 2001
[發明所欲解決之問題]
本發明之課題在於發現同時具有對DP受體之強力之拮抗活性及良好之中樞移行性之化合物,提供作為起因於DP受體之活化之疾病之預防及/或治療劑、尤其是睡眠覺醒障礙之治療劑而有用之化合物。
[解決問題之技術手段]
本發明者等人進行銳意研究,結果發現下述通式(I)所表示之化合物係解決上述課題者,藉由進而進行研究而完成本發明。
即,於一態樣中,本發明係關於如下等:
[1]一種化合物、或其藥學上所容許之鹽,該化合物係由通式(I)所表示:
[化4]
(式中,R1
表示氫原子、C1-4烷基、或苄基,
R2
、R3
、及R4
分別獨立表示(1)鹵素原子、(2)可經鹵素原子取代之C1-4烷基、或(3)可經鹵素原子取代之C1-4烷氧基,
於R2
或R4
分別存在複數個之情形時,分別可相同亦可不同,
J表示鍵結鍵、-O-、或-S-,
L表示鍵結鍵、C1-6伸烷基、C2-6伸烯基、或C2-6伸炔基,
R5
表示氫原子、C3-10碳環、或3-10員雜環,
R5
中之C3-10碳環及3-10員雜環可經1-6個R7
取代,
其中,於L為鍵結鍵之情形時,R5
不為氫原子,
R7
表示(1)鹵素原子、(2)可經鹵素原子取代之C1-4烷基、或(3)可經鹵素原子取代之C1-4烷氧基,
於R7
存在複數個之情形時,分別可相同亦可不同,
Q表示氧原子、或硫原子,
其中,於Q為氧原子之情形時,(1)L為C1-6伸烷基、C2-6伸烯基、或C2-6伸炔基,且R5
為C3-8單環碳環或3-8員單環雜環,或(2)L為鍵結鍵,且R5
為C3-10碳環或3-10員雜環,
R6
表示氫原子或C1-4烷基,
R11
表示氫原子、鹵素原子、或可經鹵素原子取代之C1-4烷基,
R12
表示氫原子、鹵素原子、或可經鹵素原子取代之C1-4烷基,
R11
與R12
可與其等所鍵結之碳原子一起形成C3-6飽和碳環,
n表示0-4之整數,
m表示0-3之整數);
[2]如上述[1]中記載之化合物、或其藥學上所容許之鹽,其中Q為硫原子;
[3]如上述[1]或[2]中記載之化合物、或其藥學上所容許之鹽,其中該化合物係由通式(I-1)所表示:
[化5]
(式中,R51
表示C3-10碳環、或3-10員雜環,J1
表示鍵結鍵、或-O-,其他記號表示與上述[1]中記載之記號相同之含義);
[4]如上述[3]中記載之化合物、或其藥學上所容許之鹽,其中R51
為C3-8單環碳環或3-8員單環雜環;
[5]如上述[3]中記載之化合物、或其藥學上所容許之鹽,其中R51
為3-8員飽和單環雜環;
[6]如上述[1]中記載之化合物、或其藥學上所容許之鹽,其中Q為氧原子,R5
為C3-8單環碳環或3-8員單環雜環;
[7]如上述[1]中記載之化合物、或其藥學上所容許之鹽,其中化合物為:
(1)(4-氯-3-{4-[2-(㗁烷-2-基)乙氧基]-2-(三氟甲基)苯甲醯胺}苯基)乙酸、
(2){4-氯-3-[4-(2-環己基乙氧基)-2-(三氟甲基)苯甲醯胺]苯基}乙酸、
(3){4-氯-3-[4-(2-苯基乙氧基)-2-(三氟甲基)苯甲醯胺]苯基}乙酸、
(4){4-氯-3-[4-(2-環丙基乙氧基)-2-(三氟甲基)苯甲醯胺]苯基}乙酸、
(5)(4-氯-3-{2,6-二甲基-4-[2-(㗁烷-2-基)乙氧基]苯甲醯胺}苯基)乙酸、
(6){4-氯-3-[4-(2-環己基乙氧基)-2,6-二甲基苯甲醯胺]苯基}乙酸、
(7){4-氯-3-[4-(2-環丙基乙氧基)-2,6-二甲基苯甲醯胺]苯基}乙酸、
(8)(3-{4-[(2,3-二氫-1H-茚-2-基)氧基]-2,6-二甲基苯甲醯胺}-4-氟苯基)乙酸、
(9){4-氯-3-[4-(3-環己基-1-丙炔-1-基)-2,6-二甲基苯甲醯胺]苯基}乙酸、
(10)(4-氯-3-{4-[(1E)-3-環己基-1-丙烯-1-基]-2,6-二甲基苯甲醯胺}苯基)乙酸、
(11)(4-氯-3-{[4-(2-環己基乙氧基)-2,6-二甲基苯-1-硫代羰基]胺基}苯基)乙酸、
(12)[4-氯-3-({4-[2-(㗁烷-2-基)乙氧基]-2-(三氟甲基)苯-1-硫代羰基}胺基)苯基]乙酸、
(13)(4-氯-3-{[4-(2-環己基乙氧基)-2-(三氟甲基)苯-1-硫代羰基]胺基}苯基)乙酸、
(14)(4-氯-3-{[4-(2-苯基乙氧基)-2-(三氟甲基)苯-1-硫代羰基]胺基}苯基)乙酸、
(15)(4-氯-3-{[4-(2-環丙基乙氧基)-2-(三氟甲基)苯-1-硫代羰基]胺基}苯基)乙酸、
(16)[4-氯-3-({2,6-二甲基-4-[2-(㗁烷-2-基)乙氧基]苯-1-硫代羰基}胺基)苯基]乙酸、
(17){4-氯-3-[(2,6-二甲基-4-{2-[(2R)-㗁烷-2-基]乙氧基}苯-1-硫代羰基)胺基]苯基}乙酸、
(18){4-氯-3-[(2,6-二甲基-4-{2-[(2S)-㗁烷-2-基]乙氧基}苯-1-硫代羰基)胺基]苯基}乙酸、
(19)2-{3-[({2,6-二甲基-4-[2-(四氫-2H-吡喃-2-基)乙氧基]苯基}硫代羰基)胺基]-4-氟苯基}丙酸、
(20)1-{3-[({2,6-二甲基-4-[2-(四氫-2H-吡喃-2-基)乙氧基]苯基}硫代羰基)胺基]-4-氟苯基}環丙烷羧酸、
(21)2-{4-氯-3-[({2,6-二甲基-4-[2-(四氫-2H-吡喃-2-基)乙氧基]苯基}硫代羰基)胺基]苯基}-2-甲基丙酸、
(22)2-{4-氯-3-[(2,6-二甲基-4-{2-[(2S)-㗁烷-2-基]乙氧基}苯-1-硫代羰基)胺基]苯基}-2-甲基丙酸、
(23)2-{4-氯-3-[(2,6-二甲基-4-{2-[(2R)-㗁烷-2-基]乙氧基}苯-1-硫代羰基)胺基]苯基}-2-甲基丙酸、
(24)2-{3-[({2,6-二甲基-4-[2-(四氫-2H-吡喃-2-基)乙氧基]苯基}硫代羰基)胺基]-4-氟苯基}-2-甲基丙酸、或
(25)2-(4-氯-3-{[(2,6-二甲基-4-{2-[(2R)-四氫-2H-吡喃-2-基]乙氧基}苯基)硫代羰基]胺基}苯基)丙酸;
[8]一種醫藥組合物,其係含有通式(I)所表示之化合物、或其藥學上所容許之鹽而成;
[9]如上述[8]中記載之醫藥組合物,其為DP受體拮抗劑;
[10]如上述[9]中記載之醫藥組合物,其為DP受體介導性疾病之預防及/或治療劑;
[11]如上述[10]中記載之醫藥組合物,其中DP受體介導性疾病為過敏性疾病、全身性肥胖細胞症、全身性肥胖細胞活化障礙、過敏性休克、呼吸道收縮、蕁麻疹、濕疹、痤瘡、過敏性支氣管肺麴菌病、鼻竇炎、偏頭痛、鼻瘜肉、過敏性血管炎、嗜酸性球增多症、接觸性皮膚炎、伴有瘙癢之疾病、因伴隨於瘙癢之行為而繼發產生之疾病、伴有潮紅之疾病、炎症、慢性阻塞性肺病、缺血再灌注障礙、腦血管障礙、自體免疫疾病、腦外傷、肝障礙、移植物排斥、類風濕性關節炎、胸膜炎、變形性關節病、克隆氏病、潰瘍性大腸炎、過敏性腸症候群、間質性膀胱炎、肌肉萎縮症、多發性肌炎、癌、白血病、病毒感染、多發性硬化症、睡眠覺醒障礙、或血小板凝集;
[12]如上述[11]中記載之醫藥組合物,其中DP受體介導性疾病為睡眠覺醒障礙;
[13]如上述[12]中記載之醫藥組合物,其中睡眠覺醒障礙為嗜眠症、失眠症、睡眠呼吸中止症候群之殘餘睡意、晝夜節律性睡眠-覺醒障礙、伴隨於神經退化性疾病之嗜眠症狀、伴隨於精神疾病之嗜眠症狀、以晝間之病態之睡意為基礎症狀之疾病;
[14]一種DP受體介導性疾病之預防及/或治療方法,其特徵在於:對哺乳動物投予如上述[1]中記載之通式(I)所表示之化合物、或其藥學上所容許之鹽之有效量;
[15]如上述[1]中記載之通式(I)所表示之化合物、或其藥學上所容許之鹽,其用於DP受體介導性疾病之預防及/或治療;
[16]一種如上述[1]中記載之通式(I)所表示之化合物、或其藥學上所容許之鹽之用途,其用以製造DP受體介導性疾病之預防及/或治療劑;
[17]一種DP受體介導性疾病之預防及/或治療劑,其含有如上述[1]中記載之通式(I)所表示之化合物、或其藥學上所容許之鹽。
[發明之效果]
本發明化合物具有對DP受體之強力之拮抗活性,且同時具有良好之中樞移行性,故而作為起因於DP受體之活化之疾病之預防及/或治療劑、尤其是睡眠覺醒障礙之治療劑而有用。又,本發明化合物選擇性地對DP受體進行拮抗,故而安全性亦優異。
以下,對本發明進行詳細說明。
於本說明書中,所謂C1-4烷基,係甲基、乙基、丙基、丁基、及其等之異構物。
於本說明書中,所謂C1-4烷氧基,係甲氧基、乙氧基、丙氧基、丁氧基、及其等之異構物。
於本說明書中,所謂C1-6伸烷基,例如為亞甲基、伸乙基、伸丙基、伸丁基、伸戊基、伸己基、及其等之異構物。
於本說明書中,所謂C2-6伸烯基,例如意指具有1~2個雙鍵之C2-6伸烯基,具體而言,係伸乙烯基、伸丙烯基、伸丁烯基、伸丁二烯基、伸戊烯基、伸戊二烯基、伸己烯基、伸己二烯基、及其等之異構物。
於本說明書中,所謂C2-6伸炔基,例如意指具有1~2個三鍵之C2-6伸炔基,具體而言,係伸乙炔基、伸丙炔基、伸丁炔基、伸丁二炔基、伸戊炔基、伸戊二炔基、伸己炔基、伸己二炔基、及其等之異構物。
於本說明書中,所謂鹵素原子,係氟、氯、溴、及碘原子。
於本說明書中,所謂C3-10碳環,係單環、或二環式之C3-10碳環,例如為環丙烷、環丁烷、環戊烷、環戊烯、環戊二烯、環己烷、環己烯、環己二烯、苯、環庚烷、環庚烯、環庚二烯、環辛烷、環辛烯、環辛二烯、環壬烷、環壬烯、環壬二烯、環癸烷、環癸烯、并環戊二烯、全氫并環戊二烯、薁、全氫薁、茚、全氫茚、茚滿、萘、二氫萘、四氫萘、及全氫萘環等。
於本說明書中,所謂3-10員雜環,意指包含選自氧原子、氮原子及硫原子中之1~5個雜原子之3-10員之單環或二環式雜環,例如為氮丙啶、環氧乙烷、環硫乙烷、吖丁啶、氧雜環丁烷、硫雜環丁烷、吡咯、咪唑、三唑、四唑、吡唑、呋喃、噻吩、㗁唑、異㗁唑、噻唑、異噻唑、呋呫、㗁二唑、噻二唑、吡咯啉、吡咯啶、咪唑啉、咪唑啶、三唑啉、三唑啶、四唑啉、四唑啶、吡唑啉、吡唑啶、二氫呋喃、四氫呋喃、二氫噻吩、四氫噻吩、二氫㗁唑、四氫㗁唑(㗁唑啶)、二氫異㗁唑、四氫異㗁唑(異㗁唑啶)、二氫噻唑、四氫噻唑(噻唑啶)、二氫異噻唑、四氫異噻唑(異噻唑啶)、二氫呋呫、四氫呋呫、二氫㗁二唑、四氫㗁二唑(㗁二唑啶)、二氫噻二唑、四氫噻二唑(噻二唑啶)、二氧戊環、二硫戊環、吡啶、吡𠯤、嘧啶、嗒𠯤、吡喃、噻喃、㗁 𠯤、㗁二𠯤、噻𠯤、噻二𠯤、二氫吡啶、四氫吡啶、哌啶、二氫吡𠯤、四氫吡𠯤、哌𠯤、二氫嘧啶、四氫嘧啶、全氫嘧啶、二氫嗒𠯤、四氫嗒𠯤、全氫嗒𠯤、二氫吡喃、四氫吡喃、二氫噻喃、四氫噻喃、二氫㗁 𠯤、四氫㗁 𠯤、二氫㗁二𠯤、四氫㗁二𠯤、二氫噻𠯤、四氫噻𠯤、二氫噻二𠯤、四氫噻二𠯤、𠰌啉、硫代𠰌啉、氧硫𠮿、二㗁烷、二噻烷、氮雜雙環[2.2.1]庚烷、氧雜雙環[2.2.1]庚烷、氮雜雙環[3.1.1]庚烷、氮雜雙環[2.2.2]辛烷、二氮雜雙環[2.2.2]辛烷、氮呯、二氮呯、㗁庚英、噻庚因、氧氮呯、氧二氮呯、噻氮呯、噻二氮呯、二氫氮呯、四氫氮呯、全氫氮呯、二氫二氮呯、四氫二氮呯、全氫二氮呯、二氫㗁庚英、四氫㗁庚英、全氫㗁庚英、二氫噻庚因、四氫噻庚因、全氫噻庚因、二氫氧氮呯、四氫氧氮呯、全氫氧氮呯、二氫氧二氮呯、四氫氧二氮呯、全氫氧二氮呯、二氫噻氮呯、四氫噻氮呯、全氫噻氮呯、二氫噻二氮呯、四氫噻二氮呯、全氫噻二氮呯、氮雜雙環[3.2.1]辛烷、氧雜雙環[3.2.1]辛烷、吲哚、異吲哚、吲哚𠯤、苯并呋喃、異苯并呋喃、苯并噻吩、異苯并噻吩、吲唑、嘌呤、苯并㗁唑、苯并噻唑、苯并咪唑、苯并呋呫、苯并噻二唑、苯并三唑、吲哚啉、異吲哚啉、二氫苯并呋喃、全氫苯并呋喃、二氫異苯并呋喃、全氫異苯并呋喃、二氫苯并噻吩、全氫苯并噻吩、二氫異苯并噻吩、全氫異苯并噻吩、二氫吲唑、全氫吲唑、二氫苯并㗁唑、全氫苯并㗁唑、二氫苯并噻唑、全氫苯并噻唑、二氫苯并咪唑、全氫苯并咪唑、二氧雜茚滿、苯并二硫戊環、氮螺[4.4]壬烷、氧氮螺[4.4]壬烷、二氧螺[4.4]壬烷、二硫雜萘、喹啉、異喹啉、喹𠯤、酞𠯤、喋啶、萘啶、喹㗁啉、喹唑啉、㖕啉、苯并吡喃、二氫喹啉、四氫喹啉、全氫喹啉、二氫異喹啉、四氫異喹啉、全氫異喹啉、二氫酞𠯤、四氫酞𠯤、全氫酞𠯤、二氫萘啶、四氫萘啶、全氫萘啶、二氫喹㗁啉、四氫喹㗁啉、全氫喹㗁啉、二氫喹唑啉、四氫喹唑啉、全氫喹唑啉、二氫㖕啉、四氫㖕啉、全氫㖕啉、苯并氧硫𠮿、二氫苯并㗁 𠯤、二氫苯并噻𠯤、吡𠯤并𠰌啉、苯并二㗁烷、苯并二氫哌喃、苯并二噻烷、氮螺[4.5]癸烷、硫螺[4.5]癸烷、二硫螺[4.5]癸烷、二氧螺[4.5]癸烷、及氧氮螺[4.5]癸烷環等。
於本說明書中,所謂C3-8單環碳環,係環丙烷、環丁烷、環戊烷、環戊烯、環戊二烯、環己烷、環己烯、環己二烯、苯、環庚烷、環庚烯、環庚二烯、環辛烷、環辛烯、及環辛二烯環等。
於本說明書中,所謂C3-6飽和碳環,係環丙烷、環丁烷、環戊烷、及環己烷。
於本說明書中,所謂3-8員單環雜環,係包含選自氧原子、氮原子及硫原子中之1~3個雜原子之3-8員之單環雜環,例如為氮丙啶、環氧乙烷、環硫乙烷、吖丁啶、氧雜環丁烷、硫雜環丁烷、吡咯、咪唑、三唑、四唑、吡唑、呋喃、噻吩、㗁唑、異㗁唑、噻唑、異噻唑、呋呫、㗁二唑、噻二唑、吡咯啉、吡咯啶、咪唑啉、咪唑啶、三唑啉、三唑啶、四唑啉、四唑啶、吡唑啉、吡唑啶、二氫呋喃、四氫呋喃、二氫噻吩、四氫噻吩、二氫㗁唑、四氫㗁唑(㗁唑啶)、二氫異㗁唑、四氫異㗁唑(異㗁唑啶)、二氫噻唑、四氫噻唑(噻唑啶)、二氫異噻唑、四氫異噻唑(異噻唑啶)、二氫呋呫、四氫呋呫、二氫㗁二唑、四氫㗁二唑(㗁二唑啶)、二氫噻二唑、四氫噻二唑(噻二唑啶)、二氧戊環、二硫戊環、吡啶、吡𠯤、嘧啶、嗒𠯤、吡喃、噻喃、㗁 𠯤、㗁二𠯤、噻𠯤、噻二𠯤、二氫吡啶、四氫吡啶、哌啶、二氫吡𠯤、四氫吡𠯤、哌𠯤、二氫嘧啶、四氫嘧啶、全氫嘧啶、二氫嗒𠯤、四氫嗒𠯤、全氫嗒𠯤、二氫吡喃、四氫吡喃、二氫噻喃、四氫噻喃、二氫㗁 𠯤、四氫㗁 𠯤、二氫㗁二𠯤、四氫㗁二𠯤、二氫噻𠯤、四氫噻𠯤、二氫噻二𠯤、四氫噻二𠯤、𠰌啉、硫代𠰌啉、氧硫𠮿、二㗁烷、二噻烷、氮呯、二氮呯、㗁庚英、噻庚因、氧氮呯、氧二氮呯、噻氮呯、噻二氮呯、二氫氮呯、四氫氮呯、全氫氮呯、二氫二氮呯、四氫二氮呯、全氫二氮呯、二氫㗁庚英、四氫㗁庚英、全氫㗁庚英、二氫噻庚因、四氫噻庚因、全氫噻庚因、二氫氧氮呯、四氫氧氮呯、全氫氧氮呯、二氫氧二氮呯、四氫氧二氮呯、全氫氧二氮呯、二氫噻氮呯、四氫噻氮呯、全氫噻氮呯、二氫噻二氮呯、四氫噻二氮呯、及全氫噻二氮呯環等。
於本說明書中,所謂3-8員飽和單環雜環,係氮丙啶、環氧乙烷、環硫乙烷、吖丁啶、氧雜環丁烷、硫雜環丁烷、吡咯啶、咪唑啶、三唑啶、四唑啶、吡唑啶、四氫呋喃、四氫噻吩、四氫㗁唑(㗁唑啶)、四氫異㗁唑(異㗁唑啶)、四氫噻唑(噻唑啶)、四氫異噻唑(異噻唑啶)、四氫呋呫、四氫㗁二唑(㗁二唑啶)、四氫噻二唑(噻二唑啶)、二氧戊環、二硫戊環、哌啶、哌𠯤、全氫嘧啶、全氫嗒𠯤、四氫吡喃、四氫噻喃、四氫㗁 𠯤、四氫㗁二𠯤、四氫噻𠯤、四氫噻二𠯤、𠰌啉、硫代𠰌啉、氧硫𠮿、二㗁烷、二噻烷、全氫氮呯、全氫二氮呯、全氫㗁庚英、全氫噻庚因、全氫氧氮呯、全氫氧二氮呯、全氫噻氮呯、及全氫噻二氮呯環等。
於通式(I)所表示之化合物中,作為較佳之態樣,例如為
通式(I-a):
[化9]
(式中,L1
表示C1-6伸烷基、C2-6伸烯基、或C2-6伸炔基,R52
表示C3-8單環碳環或3-8員單環雜環,其他記號表示與上述相同之含義)所表示之化合物、及其藥學上所容許之鹽,作為較佳之另一態樣,為通式(I-b):
[化10]
(式中,全部之記號表示與上述相同之含義)所表示之化合物、及其藥學上所容許之鹽,作為尤佳之態樣,為通式(I-c-0)所表示之化合物、及其藥學上所容許之鹽:
[化11]
(式中,R1c
為氫原子或甲基,R2c
為氟原子或氯原子,R3c
為甲基、或三氟甲基,R4c
為氫原子、甲基、或三氟甲基,於-Lc
-Jc
-為-O-之情形時,R54
為
[化12],
或者於-Lc
-Jc
-為
[化13]
之情形時,R54
為
[化14],
其他記號表示與上述相同之含義)。
於通式(I)中,作為另一較佳之態樣,為通式(I-d)所表示之化合物、及其藥學上所容許之鹽:
[化16]
(式中,全部之記號表示與上述相同之含義)。作為更佳之態樣,為通式(I-1):
[化17]
(式中,全部之記號表示與上述相同之含義)所表示之化合物、及其藥學上所容許之鹽,作為進而較佳之態樣,為通式(I-2-0):
[化18]
(式中,全部之記號表示與上述相同之含義)所表示之化合物、及其藥學上所容許之鹽,作為進而較佳之另一態樣,為通式(I-2):
[化19]
(式中,全部之記號表示與上述相同之含義)所表示之化合物、及其藥學上所容許之鹽。作為最佳之態樣,為通式(I-3-0):
[化20]
(式中,R53
為3-8員飽和單環雜環,其他記號表示與上述相同之含義)所表示之化合物、及其藥學上所容許之鹽。作為最佳之另一態樣,為通式(I-3):
[化21]
(式中,全部之記號表示與上述相同之含義)所表示之化合物、及其藥學上所容許之鹽。
或者,最佳之態樣係通式(I-4):
[化22]
(式中,全部之記號表示與上述相同之含義)所表示之化合物、及其藥學上所容許之鹽。
於通式(I)、(I-a)、(I-b)、(I-d)、(I-1)、(I-2-0)、(I-2)、(I-3-0)、或(I-3)之任一者中,作為R1
,較佳為氫原子或C1-4烷基,更佳為氫原子或甲基,尤佳為氫原子。
於通式(I-c-0)、(I-c)、或(I-4)之任一者中,作為R1c
,較佳為氫原子。
於通式(I)、(I-a)、(I-b)、(I-d)、(I-1)、(I-2-0)、(I-2)、(I-3-0)、或(I-3)之任一者中,作為R2
,較佳為鹵素原子,更佳為氟原子或氯原子,尤佳為氯原子。
於通式(I-c-0)、(I-c)、或(I-4)之任一者中,作為R2c
,較佳為氯原子。
於通式(I)、(I-a)、(I-b)、(I-d)、(I-1)、(I-2-0)、(I-2)、(I-3-0)、或(I-3)之任一者中,作為R3
,較佳為可經鹵素原子取代之C1-4烷基,尤佳為甲基或三氟甲基。
於通式(I)、(I-a)、(I-b)、(I-d)、(I-1)、(I-2-0)、(I-2)、(I-3-0)、或(I-3)之任一者中,作為R4
,較佳為可經鹵素原子取代之C1-4烷基,更佳為甲基或三氟甲基,尤佳為甲基。
於通式(I-c-0)、(I-c)、或(I-4)中,作為R4c
,較佳為氫原子或甲基。
於通式(I)、(I-a)、(I-b)、或(I-d)之任一者中,作為J,較佳為鍵結鍵、或-O-,更佳為-O-。
於通式(I-1)、(I-2-0)、(I-2)、(I-3-0)、或(I-3)之任一者中,作為J1
,較佳為-O-。
於通式(I)或(I-d)中,作為R5
,較佳為C3-10碳環、或3-10員雜環,更佳為C3-8單環碳環或3-8員單環雜環,進而較佳為3-8員飽和單環雜環。或者,於通式(I)或(I-d)中,作為R5
,較佳為環丙烷、環丁烷、環戊烷、環己烷、苯、或四氫吡喃環,進而較佳為環己烷、苯、環丙烷、或四氫吡喃環,最佳為四氫吡喃環。又,上述較佳之R5
可經(較佳為1~3個)R7
取代。
於通式(I-b)或(I-1)中,作為R51
,較佳為C3-8單環碳環或3-8員單環雜環,更佳為3-8員飽和單環雜環。或者,於通式(I-b)或(I-1)中,作為R51
,較佳為環丙烷、環丁烷、環戊烷、環己烷、苯、或四氫吡喃環,進而較佳為環己烷、苯、環丙烷、或四氫吡喃環,最佳為四氫吡喃環。
於通式(I-a)、(I-2-0)、或(I-2)中,作為R52
,較佳為3-8員飽和單環雜環。或者,於通式(I-a)、(I-2-0)、或(I-2)中,作為R52
,較佳為環丙烷、環丁烷、環戊烷、環己烷、苯、或四氫吡喃環,更佳為環丙烷、環己烷、苯、或四氫吡喃環,最佳為四氫吡喃環。
於通式(I-3-0)或(I-3)中,作為R53
,較佳為四氫吡喃環。
於通式(I-c-0)、(I-c)或(1-4)中,作為R54
,較佳為四氫吡喃環。
於通式(I)中,作為Q,較佳為硫原子。
於通式(I)、(I-d)、(I-1)、(I-2-0)、(I-2)、(I-3-0)、或(I-3)之任一者中,作為L,較佳為C1-6伸烷基、C2-6伸烯基、或C2-6伸炔基,進而較佳為伸乙基、伸丙烯基、或伸丙炔基,更佳為伸乙基。
於通式(I-a)中,作為L1
,較佳為伸乙基、伸丙烯基、或伸丙炔基,更佳為伸乙基。
於通式(I)、(I-a)、(I-d)、(I-1)、(I-2-0)、(I-2)、(I-3-0)、或(I-3)中,作為-L-J-、-L1
-J-或-L-J1
-,較佳為-O-、
[化23],
更佳為
[化24]。
於通式(I)、(I-a)、(I-b)、(I-d)、(I-1)、(I-2-0)、(I-2)、(I-3-0)、或(I-3)之任一者中,作為R6
,較佳為氫原子。
於通式(I)、(I-a)、(I-b)、(I-c)、(I-d)、(I-1)、(I-2-0)、(I-3-0)、或(I-4)之任一者中,作為R11
,較佳為氫原子、甲基、或乙基,更佳為氫原子、或甲基,最佳為氫原子。
於通式(I)、(I-a)、(I-b)、(I-c)、(I-d)、(I-1)、(I-2-0)、(I-3-0)、或(I-4)之任一者中,作為R12
,較佳為氫原子、甲基、或乙基,更佳為氫原子、或甲基,最佳為氫原子。
於通式(I)、(I-a)、(I-b)、(I-c)、(I-d)、(I-1)、(I-2)、(I-3)、或(I-4)之任一者中,R11
及R12
可與所鍵結之碳原子一起形成C3-6員飽和碳環,作為該C3-6員飽和碳環,較佳為環丙烷環。
於通式(I)、(I-a)、(I-b)、(I-d)、或(I-1)之任一者中,作為n,較佳為1。
於通式(I)、(I-a)、(I-b)、(I-d)、(I-1)、(I-2-0)、(I-2)、(I-3-0)、或(I-3)之任一者中,作為m,較佳為0或1,更佳為1。
作為通式(I)所表示之化合物,較佳為將上述較佳之R1
、R2
、R3
、R4
、R5
、R6
、R11
、R12
、J、L、Q、n及m一部分或全部組合而成之化合物。
作為通式(I-a)所表示之化合物,較佳為將上述較佳之R1
、R2
、R3
、R4
、R52
、R6
、R11
、R12
、J、L1
、n及m一部分或全部組合而成之化合物。
作為通式(I-b)所表示之化合物,較佳為將上述較佳之R1
、R2
、R3
、R4
、R51
、R6
、R11
、R12
、J、n及m一部分或全部組合而成之化合物。
作為通式(I-c-0)所表示之化合物,較佳為將上述較佳之R1c
、R2c
、R3c
、R4c
、R11
、R12
、Jc
、Lc
、及R54
一部分或全部組合而成之化合物。
作為通式(I-c)所表示之化合物,較佳為將上述較佳之R1c
、R2c
、R3c
、R4c
、Jc
、Lc
、及R54
一部分或全部組合而成之化合物。
作為通式(I-d)所表示之化合物,較佳為將上述較佳之R1
、R2
、R3
、R4
、R5
、R6
、R11
、R12
、J、L、n及m一部分或全部組合而成之化合物。
作為通式(I-1)所表示之化合物,較佳為將上述較佳之R1
、R2
、R3
、R4
、R51
、R6
、R11
、R12
、J1
、L、n及m一部分或全部組合而成之化合物。
作為通式(I-2-0)所表示之化合物,較佳為將上述較佳之R1
、R2
、R3
、R4
、R52
、R6
、R11
、R12
、J1
、L、及m一部分或全部組合而成之化合物。
作為通式(I-2)所表示之化合物,較佳為將上述較佳之R1
、R2
、R3
、R4
、R52
、R6
、J1
、L、及m一部分或全部組合而成之化合物。
作為通式(I-3-0)所表示之化合物,較佳為將上述較佳之R1
、R2
、R3
、R4
、R53
、R6
、R11
、R12
、J1
、L、及m一部分或全部組合而成之化合物。
作為通式(I-3)所表示之化合物,較佳為將上述較佳之R1
、R2
、R3
、R4
、R53
、R6
、J1
、L、及m一部分或全部組合而成之化合物。
作為通式(I-4)所表示之化合物,較佳為將上述較佳之R1c
、R2c
、R3c
、R4c
、Jc
、Lc
、R11
、R12
、及R54
一部分或全部組合而成之化合物。
於本說明書中,作為通式(I)之另一態樣,最佳為下述實施例中記載之本發明化合物、或其藥學上所容許之鹽。
[異構物]
於本發明中,只要並無特別指示,則異構物包含其全部。例如,烷基、烷氧基、及伸烷基等中包含直鏈者及支鏈者。進而,雙鍵、環、縮合環中之異構物(E、Z、順式、反式體)、因不對稱碳之存在等產生之異構物(R、S體、α、β體、鏡像異構物、非鏡像異構物)、具有旋光性之光學活性體(D、L、d、l體)、藉由層析分離獲得之極性體(高極性體、低極性體)、平衡化合物、旋轉異構物、該等之任意之比率之混合物、外消旋混合物全部包含於本發明。又,於本發明中,因互變異構產生之異構物亦全部包含於本發明。
於本發明中,關於本發明化合物之言及全部包含通式(I)所表示之化合物、其藥學上所容許之鹽、其等之N-氧化物體、其等之溶劑合物、或其等之共結晶。
[鹽]
通式(I)所表示之化合物藉由公知之方法轉化為鹽。
作為鹽,係藥學上所容許之鹽。
鹽較佳為水溶性者。
作為藥學上所容許之鹽,例如可列舉:酸加成鹽、鹼金屬鹽、鹼土類金屬鹽、銨鹽、或胺鹽等。
作為酸加成鹽,例如可列舉:如鹽酸鹽、氫溴酸鹽、氫碘酸鹽、硫酸鹽、磷酸鹽、硝酸鹽之無機酸鹽、或如乙酸鹽、乳酸鹽、酒石酸鹽、苯甲酸鹽、檸檬酸鹽、甲磺酸鹽、乙磺酸鹽、三氟乙酸鹽、苯磺酸鹽、甲苯磺酸鹽、羥乙磺酸鹽、葡萄糖醛酸鹽、或葡萄糖酸鹽之有機酸鹽。
作為鹼金屬鹽,例如可列舉鉀鹽及鈉鹽等。
作為鹼土類金屬鹽,例如可列舉鈣鹽及鎂鹽等。
作為銨鹽,例如可列舉四甲基銨鹽等。
作為胺鹽,例如可列舉:三乙基胺鹽、甲基胺鹽、二甲基胺鹽、環戊基胺鹽、苄基胺鹽、苯乙基胺鹽、哌啶鹽、單乙醇胺鹽、二乙醇胺鹽、三(羥基甲基)胺基甲烷鹽、離胺酸鹽、精胺酸鹽、及N-甲基-D-還原葡糖胺鹽等。
[N-氧化物體]
通式(I)所表示之化合物可藉由任意之方法製成N-氧化物體。所謂N-氧化物體,表示通式(I)所表示之化合物之氮原子經氧化者。通式(I)所表示之化合物之N-氧化物體亦可為鹽。
[溶劑合物]
通式(I)所表示之化合物、其藥學上所容許之鹽、及其等之N-氧化物體可以未進行溶劑合之形態存在,亦可以與水、乙醇等藥學上可容許之溶劑進行溶劑合之形態存在。通式(I)所表示之化合物、其藥學上所容許之鹽、及其等之N-氧化物體可藉由公知之方法轉化為溶劑合物。
溶劑合物較佳為非毒性且水溶性。作為適當之溶劑合物,例如可列舉水合物、或如醇系之溶劑(例如乙醇等)之溶劑合物。
[共結晶]
通式(I)所表示之化合物、其藥學上所容許之鹽、其等之N-氧化物體可與適當之共結晶形成劑形成共結晶。作為共結晶形成劑,較佳為藥學上所容許者。所謂共結晶,典型而言,定義為2種以上之不同分子藉由與離子鍵不同之分子間相互作用所形成之結晶。又,共結晶亦可為中性分子與鹽之複合體。共結晶可藉由公知之方法、例如熔融結晶化、自溶劑之再結晶、或將成分一起物理粉碎而進行調整。作為適當之共結晶形成劑,包含國際公開2006/007448號說明書中記載者。
[前藥]
通式(I)所表示之化合物可以前藥之形式進行投予。所謂通式(I)所表示之化合物之前藥,係指於生物體內藉由利用酵素或胃酸等之反應而轉化為通式(I)所表示之化合物的化合物。作為通式(I)所表示之化合物之前藥,例如於通式(I)所表示之化合物具有羧基之情形時,可列舉:該羧基經酯化、醯胺化之化合物(例如,通式(I)所表示之化合物之羧基經乙酯化、苯酯化、羧基甲酯化、二甲基胺基甲酯化、特戊醯氧基甲酯化、1-{(乙氧基羰基)氧基}乙酯化、酞酯化、(5-甲基-2-氧代-1,3-二氧雜環戊烯-4-基)甲酯化、1-{[(環己氧基)羰基]氧基}乙酯化、甲基醯胺化之化合物等)等。該等化合物可藉由其自身公知之方法進行製造。又,通式(I)所表示之化合物之前藥亦可為如廣川書店1990年刊「醫藥品之開發」第7卷「分子設計」163~198頁中記載之於生理條件下變化為通式(I)所表示之化合物者。通式(I)所表示之化合物之前藥可為鹽或溶劑合物,或亦可與適當之共結晶形成劑形成共結晶。
[標記化合物]
本發明化合物亦包含構成其等之各原子之一部分或全部被取代為其同位元素而成之所謂標記化合物。該等標記化合物可藉由自身公知之方法進行製造。作為用於標記之同位元素,例如可適宜地使用2
H、3
H、11
C、13
C、14
C、13
N、15
N、17
O、18
O、18
F、35
S、36
Cl、77
Br、125
I等,但並不限定於此。
[本發明化合物之製造方法]
通式(I)所表示之本發明化合物可依照公知之方法、例如Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd
Edition (Richard C. Larock, John Wiley & Sons Inc, 2018)中所記載之方法、以下所示之方法、依據該等之方法或實施例所示之方法進行製造。再者,於以下之各製造方法中,原料化合物可以鹽之形式使用。作為此種鹽,較佳為作為通式(I)所表示之本發明化合物之藥學上所容許之鹽所記載者。
通式(I)所表示之化合物之中,R1
為氫原子、J為-O-或-S-、Q為氧原子之化合物,即通式(Ia):
[化25]
(式中,Ja
表示-O-或-S-,其他記號表示與上述相同之含義)
所表示之化合物可依據以下之反應步驟式A而製造。
[化26]
(式中,P表示羧基之保護基,其他記號表示與上述相同之含義)
即,藉由將通式(IIa)所表示之化合物與通式(IIIa)所表示之化合物供於光延反應而製造通式(IVa)所表示之化合物,其後進行羧基之脫保護反應,藉此可製造通式(Ia)所表示之化合物。
光延反應為公知,例如藉由使醇於有機溶劑(二氯甲烷、二乙醚、四氫呋喃、乙腈、苯、甲苯等)中,於光延試劑(重氮化合物(偶氮二羧酸二乙酯(DEAD)、偶氮二羧酸二異丙酯、1,1'-(偶氮二羰基)二哌啶、1,1'-偶氮雙(N,N-二甲基甲醯胺)等)與膦化合物(三苯基膦、三丁基膦、三甲基膦、聚合物載體三苯基膦等)之組合)、或偶極體試劑(氰基亞甲基三甲基磷烷(CMMP)、氰基亞甲基三丁基磷烷(CMBP)等)之存在下與苯酚衍生物或苯硫酚衍生物於0~60℃下進行反應而進行。
又,通式(IVa)所表示之化合物亦可藉由將通式(Va):
[化27]
(式中,X表示鹵素原子、甲苯磺醯氧基(TsO-)、甲磺醯氧基(MsO-)等脫離基,其他記號表示與上述相同之含義)所表示之化合物與通式(IIIa)所表示之化合物供於烷基化反應而製造。
該烷基化反應為公知,例如藉由在有機溶劑(二甲基甲醯胺、二甲基亞碸、氯仿、二氯甲烷、二乙醚、四氫呋喃、甲基第三丁醚等)中,於鹼金屬之氫氧化物(氫氧化鈉、氫氧化鉀、氫氧化鋰等)、鹼土類金屬之氫氧化物(氫氧化鋇、氫氧化鈣等)或碳酸鹽(碳酸鈉、碳酸鉀等)或其水溶液或該等之混合物之存在下於0~100℃下進行反應而進行。
於反應步驟式A中,羧基之脫保護反應為公知,可按照以下方式進行。
作為羧基之保護基,例如可列舉:甲基、乙基、烯丙基、第三丁基、三氯乙基、苄基(Bn)、苯甲醯甲基等。作為羧基之保護基,除了上述以外,只要為可容易地且選擇性地脫離之基則並無特別限定。例如可使用Peter G. M. Wuts, Green's Protective Groups in Organic Synthesis, Fifth Edition, Wiley, New York, 2014中記載者。
羧基之脫保護反應廣為人知,例如可列舉:
(1)鹼水解、
(2)酸性條件下之脫保護反應、
(3)藉由氫解進行之脫保護反應、
(4)矽烷基之脫保護反應、
(5)使用金屬之脫保護反應、
(6)使用金屬錯合物之脫保護反應等。
若具體地說明該等方法,則:
(1)藉由鹼水解進行之脫保護反應例如於有機溶劑(甲醇、四氫呋喃、二㗁烷等)中,使用鹼金屬之氫氧化物(氫氧化鈉、氫氧化鉀、氫氧化鋰等)、鹼土類金屬之氫氧化物(氫氧化鋇、氫氧化鈣等)或碳酸鹽(碳酸鈉、碳酸鉀等)或其水溶液或該等之混合物,於0~60℃之溫度下進行。
(2)酸條件下之脫保護反應例如於有機溶劑(二氯甲烷、氯仿、二㗁烷、乙酸乙酯、苯甲醚等)中,於有機酸(乙酸、三氟乙酸、甲磺酸、對甲苯磺酸等)、或無機酸(鹽酸、硫酸等)或該等之混合物(溴化氫/乙酸等)中,於0~100℃之溫度下進行。
(3)藉由氫解進行之脫保護反應例如於溶劑(醚系(四氫呋喃、二㗁烷、二甲氧基乙烷、二乙醚等)、醇系(甲醇、乙醇等)、苯系(苯、甲苯等)、酮系(丙酮、甲基乙基酮等)、腈系(乙腈等)、醯胺系(二甲基甲醯胺等)、水、乙酸乙酯、乙酸或其等之2種以上之混合溶劑等)中,於觸媒(鈀-碳、鈀黑、氫氧化鈀、氧化鉑、雷氏鎳等)之存在下,於常壓或加壓下之氫環境下或甲酸銨存在下,於0~200℃之溫度下進行。
(4)矽烷基之脫保護反應例如於可與水混合之有機溶劑(四氫呋喃、乙腈等)中,使用氟化四丁基銨,於0~40℃之溫度下進行。
(5)使用金屬之脫保護反應例如於酸性溶劑(乙酸、pH值4.2~7.2之緩衝液或其等之溶液與四氫呋喃等有機溶劑之混合液)中,於粉末鋅之存在下,視需要一面施加超音波,一面於0~40℃之溫度下進行。
(6)使用金屬錯合物之脫保護反應例如於有機溶劑(二氯甲烷、二甲基甲醯胺、四氫呋喃、乙酸乙酯、乙腈、二㗁烷、乙醇等)、水或其等之混合溶劑中,於捕捉試劑(氫化三丁基錫、三乙基矽烷、達米酮、𠰌啉、二乙基胺、吡咯啶等)、有機酸(乙酸、甲酸、2-乙基己酸等)及/或有機酸鹽(2-乙基己酸鈉、2-乙基己酸鉀等)之存在下,於膦系試劑(三苯基膦等)之存在下或非存在下,使用金屬錯合物(四(三苯基膦)鈀(0)、二氯化雙(三苯基膦)鈀(II)、乙酸鈀(II)、氯化三(三苯基膦)銠(I)等),於0~40℃之溫度下進行。
又,除了上述以外,亦可藉由例如Peter G. M. Wuts, Green's Protective Groups in Organic Synthesis, Fifth Edition, Wiley, New York, 2014中記載之方法進行脫保護反應。
對於業者可容易地理解,藉由適當地使用該等脫保護反應,可容易地製造目標之本發明化合物。
於通式(I)所表示之化合物之中,R1
為氫原子、Q為氧原子、J為鍵結鍵、L為伸炔基之化合物,即通式(Ib):
[化28]
(式中,nb表示0-4之整數,其他記號表示與上述相同之含義)
所表示之化合物可藉由將通式(IIIb):
[化29]
(式中,X表示鹵素原子、或三氟甲磺醯氧基(TfO-),其他記號表示與上述相同之含義)所表示之化合物、與通式(Vb)所表示之化合物:
[化30]
(式中,全部之記號表示與上述相同之含義)
供於偶合反應後進行羧基之脫保護反應而製造。該偶合化反應為公知,可藉由使通式(IIIb)所表示之化合物與通式(Vb)所表示之化合物例如於有機溶劑(例如,四氫呋喃、N,N-二甲基甲醯胺、乙腈等)中,於鈀觸媒(氯化雙(三苯基膦)鈀(II)等)之存在下、及銅觸媒(碘化銅(I)等)之存在下,於鹼(三乙基胺等)之存在下,於室溫~回流溫度下進行反應而製造。
於通式(I)所表示之化合物之中,R1
為氫原子,Q為氧原子,J為鍵結鍵,L為伸烯基或伸烷基之化合物可藉由將通式(Ib)所表示之化合物供於還原反應而製造。
還原反應為公知,例如於氫環境下,於有機溶劑(例如,甲醇、乙醇、乙酸乙酯、四氫呋喃、乙酸、1,2-二甲氧基乙烷、或適當混合該等有機溶劑而成之溶劑等)或該等有機溶劑與水之混合溶劑中,於鈀觸媒(例如,鈀-碳、氫氧化鈀、林德拉觸媒(Lindlar's catalyst)等)之存在下,於室溫~約80℃之溫度下進行。
於通式(I)所表示之化合物之中,R1
為氫原子、Q為硫原子之化合物,即通式(Ic):
[化31]
(式中,全部之記號表示與上述相同之含義)所表示之化合物可依據以下之反應步驟式C而製造。
[化32]
(式中,全部之記號表示與上述相同之含義)
即,藉由將通式(IVa)所表示之化合物供於硫化反應而製造通式(Vc)所表示之化合物,其後進行羧基之脫保護反應,藉此可製造通式(Ic)所表示之化合物。
於反應步驟式C中,硫化反應為公知,可藉由使醯胺體於有機溶劑(例如,四氫呋喃、甲苯、苯、乙腈、二氯甲烷、吡啶等)中,於鹼(碳酸氫鈉等)之存在下或非存在下,於硫化試劑(例如,勞森試劑(2,4-雙(4-甲氧基苯基)-1,3,2,4-二硫雜二磷雜環丁烷-2,4-二硫化物)、十硫化四磷、五硫化二磷、硫化氫、硫等)與膦試劑(例如三氯磷酸酯等)之存在下或非存在下,於室溫~回流溫度下進行反應而製造。
於上述各反應中,作為起始原料使用之化合物為公知,或可藉由公知之方法容易地製造。
例如,通式(IIIa)所表示之化合物:
[化33]
(式中,全部之記號表示與上述相同之含義)所表示之化合物可藉由依據以下之反應步驟式D,視需要進行保護・脫保護反應而製造。
[化34]
(式中,P2
表示羥基或硫醇基之保護基,其他記號表示與上述相同之含義)
即,藉由將通式(VId)所表示之化合物供於羥基或硫醇基之保護反應而製造通式(VIId)所表示之化合物,其後與通式(VIIId)所表示之化合物進行醯胺化反應,藉此可製造通式(IXd)所表示之化合物。其後,藉由將通式(IXd)所表示之化合物供於羥基或硫醇基之脫保護反應,可製造通式(IIIa)所表示之化合物。
作為羥基之保護基,例如可列舉:甲基、三苯甲基、甲氧基甲基(MOM)、1-乙氧基乙基(EE)、甲氧基乙氧基甲基(MEM)、2-四氫吡喃基(THP)、三甲基矽烷基(TMS)、三乙基矽烷基(TES)、第三丁基二甲基矽烷基(TBDMS)、第三丁基二苯基矽烷基(TBDPS)、乙醯基(Ac)、特戊醯基、苯甲醯基、苄基(Bn)、對甲氧基苄基、烯丙氧基羰基(Alloc)、2,2,2-三氯乙氧基羰基(Troc)等。
作為硫醇基之保護基,例如可列舉:苄基、甲氧基苄基、甲氧基甲基(MOM)、2-四氫吡喃基(THP)、二苯基甲基、乙醯基(Ac)。
作為羥基或硫醇基之保護基,除了上述以外,只要為可容易地且選擇性地脫離之基則並無特別限定。例如可使用Peter G. M. Wuts, Green's Protective Groups in Organic Synthesis, Fifth Edition, Wiley, New York, 2014中記載者。
於反應步驟式D中,醯胺化反應為公知,例如可列舉:
(1)使用醯鹵之方法、
(2)使用混合酸酐之方法、
(3)使用縮合劑之方法等。
若具體地說明該等方法,則:
(1)使用醯鹵之方法例如藉由使羧酸於有機溶劑(氯仿、二氯甲烷、二乙醚、四氫呋喃等)中或於無溶劑條件下與醯鹵化劑(草醯氯、亞硫醯氯等)於-20℃~回流溫度下進行反應,使所得之醯鹵於鹼(吡啶、三乙基胺、二甲基苯胺、二甲基胺基吡啶、二異丙基乙基胺等)之存在下,於有機溶劑(氯仿、二氯甲烷、二乙醚、四氫呋喃等)中,於0~80℃之溫度下與胺進行反應而進行。又,亦可藉由在有機溶劑(二㗁烷、四氫呋喃等)中,使用鹼水溶液(碳酸氫鈉溶液或氫氧化鈉溶液等),使所得之醯鹵與胺於0~40℃下進行反應而進行。
(2)使用混合酸酐之方法例如藉由使羧酸於有機溶劑(氯仿、二氯甲烷、二乙醚、四氫呋喃等)中或於無溶劑條件下,於鹼(吡啶、三乙基胺、二甲基苯胺、二甲基胺基吡啶、二異丙基乙基胺等)之存在下,與醯鹵(特戊醯氯、甲苯磺醯氯、甲磺醯氯等)、或酸衍生物(氯甲酸乙酯、氯甲酸異丁酯等)於0~40℃下進行反應,使所得之混合酸酐於有機溶劑(氯仿、二氯甲烷、二乙醚、四氫呋喃等)中,與胺於0~40℃下進行反應而進行。
(3)使用縮合劑之方法例如藉由在有機溶劑(氯仿、二氯甲烷、二甲基甲醯胺、二乙醚、四氫呋喃等)中或於無溶劑條件下,於鹼(吡啶、三乙基胺、二甲基苯胺、二甲基胺基吡啶等)之存在下或非存在下,使用縮合劑(1,3-二環己基碳二醯亞胺(DCC)、1-乙基-3-[3-(二甲基胺基)丙基]碳二醯亞胺(EDC)、1,1'-羰基二咪唑(CDI)、2-氯-1-甲基吡啶鎓碘、1-丙基膦酸環狀酐(1-propanephosphonic acid cyclic anhydride,T3
P)等),於1-羥基苯并三唑(HOBt)之存在下或非存在下,於0~80℃下使羧酸與胺進行反應而進行。
該等(1)、(2)及(3)之反應均較理想為於惰性氣體(氬、氮等)環境下,於無水條件下進行。
於反應步驟式D中,羥基或硫醇基之脫保護反應為公知,可與反應步驟式A中之羧基之脫保護反應同樣地進行。
對於業者可容易地理解,藉由適當地使用該等脫保護反應,可容易地製造目標之本發明化合物。
其他作為起始原料使用之化合物及作為試劑使用之化合物其自身公知,或可藉由組合使用公知之方法、例如Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018)中記載之方法等而容易地製造。
於本說明書中之各反應中,各基於必需保護之情形時可被保護,可適當將經保護基保護之化合物供於公知之脫保護反應。
於本說明書中之各反應中,伴有加熱之反應如業者所瞭解般,可使用水浴、油浴、砂浴或微波而進行。
於本說明書中之各反應中,亦可適當使用擔載於高分子聚合物(例如,聚苯乙烯、聚丙烯醯胺、聚丙烯、聚乙二醇等)之固相擔載試劑。
於本說明書中之各反應中,反應產物可藉由通常之純化方法、例如常壓下或減壓下之蒸餾、使用矽膠或矽酸鎂等之高效液相層析法、薄層層析法、離子交換樹脂、清除樹脂或管柱層析法、或洗淨、再結晶等方法而純化。純化可逐個反應地進行,亦可於若干個反應結束後進行。
[毒性]
本發明化合物之毒性非常低,對作為醫藥使用而言充分安全。
[對醫藥品之適應性]
本發明化合物由於具有優異之DP受體拮抗活性,故而對DP受體介導性疾病、例如過敏性疾病、全身性肥胖細胞症、全身性肥胖細胞活化障礙、過敏性休克、呼吸道收縮、蕁麻疹、濕疹、痤瘡、過敏性支氣管肺麴菌病、鼻竇炎、偏頭痛、鼻瘜肉、過敏性血管炎、嗜酸性球增多症、接觸性皮膚炎、伴有瘙癢之疾病、因伴隨於瘙癢之行為而繼發產生之疾病、伴有潮紅之疾病、炎症、慢性阻塞性肺病、缺血再灌注障礙、腦血管障礙、自體免疫疾病、腦外傷、肝障礙、移植物排斥、類風濕性關節炎、胸膜炎、變形性關節病、克隆氏病、潰瘍性大腸炎、過敏性腸症候群、間質性膀胱炎、肌肉萎縮症、多發性肌炎、癌、白血病、病毒感染、多發性硬化症、睡眠覺醒障礙、或血小板凝集有用。進而,本發明化合物由於向中樞之移行性優異,故而尤其是對睡眠覺醒障礙、例如嗜眠症(例如,麻醉樣昏睡、突發性嗜眠症、反覆性嗜眠症、及克萊恩-萊文症候群(Kleine Levin Syndrome)等)、失眠症、睡眠呼吸中止症候群之殘餘睡意、晝夜節律性睡眠-覺醒障礙(例如,倒班型晝夜節律障礙、不規則睡眠覺醒節律障礙等)、伴隨於神經退化性疾病(例如,帕金森氏症、路易體型癡呆症(Dementia with Lewy Bodies)、及阿茲海默型癡呆症等)之嗜眠症狀、伴隨於精神疾病(例如,抑鬱症、及躁鬱症等)之嗜眠症狀、以晝間之病態之睡意為基礎症狀之疾病)有用。
本發明化合物可為了
1)該化合物之預防及/或治療效果之補充及/或增強、
2)該化合物之動態・吸收改善、投予量之降低、及/或
3)該化合物之副作用之減輕而與其他藥劑組合,以併用劑之形式進行投予。
本發明化合物與其他藥劑之併用劑可以於1個製劑中調配有兩種成分之調配劑之形態進行投予,又,亦可採用製成各個製劑進行投予之形態。於該製成各個製劑進行投予之情形時,包含同時投予及利用時間差之投予。又,利用時間差之投予可先投予本發明化合物,後投予其他藥劑,亦可先投予其他藥劑,後投予本發明化合物。各自之投予方法可相同亦可不同。
藉由上述併用劑而起到預防及/或治療效果之疾病並無特別限定,只要為補充及/或增強本發明化合物之預防及/或治療效果之疾病即可。
作為用以補充及/或增強本發明化合物對睡眠覺醒障礙之預防及/或治療效果之其他藥劑,例如可列舉:精神刺激藥(例如,莫達非尼、(鹽酸)哌醋甲酯、(鹽酸)甲基安非他明、匹莫林(Pemoline)等)、麻醉樣昏睡治療藥(例如,γ-羥基丁酸、氯米帕明等)、乙醯膽鹼酯酶抑制藥(例如,(鹽酸)多奈哌齊、毒扁豆鹼、(酒石酸)利凡斯的明、(氫溴酸)加蘭他敏、(反丁烯二酸)紮那哌齊(Zanapezil);TAK-147、他克林、美曲膦酯(Metrifonate)等)、NMDA受體拮抗藥(例如,氯胺酮、美金剛(Memantine)、氫溴酸右美沙芬等)、多巴胺受體促效劑(例如,左旋多巴、溴麥角環肽、培高利特、他利克索、(鹽酸)普拉克索(水合物)、卡麥角林(Cabergoline)、(鹽酸)金剛烷胺等)、三環系抗抑鬱藥(例如,鹽酸阿密曲替林、鹽酸丙咪𠯤等)、選擇性血清素再吸收抑制藥(例如,帕羅西汀(Paroxetine)、依他普侖(Escitalopram)等)、狂躁症治療藥(例如,碳酸鋰等)、抗精神病藥(例如,Clofekton、螺哌隆(Spiperone)、舒必利(Sulpiride)、佐替平(Zotepine)、替米哌隆(timiperone)、癸酸氟哌啶醇、癸酸氟芬那辛、氟哌啶醇、匹莫齊特、哌氰𠯤、溴哌利多(Bromperidol)、奮乃靜(Perphenazine)、順丁烯二酸左美丙𠯤、鹽酸氯丙𠯤、鹽酸硫利達𠯤、鹽酸曲唑酮、鹽酸莫沙帕明、利培酮(Risperidone)、奧氮平(Olanzapine)等)、去甲腎上腺素再吸收抑制藥(例如,阿托莫西汀等)等。
本發明化合物與其他藥劑之質量比並無特別限定。
其他藥劑亦可組合任意之2種以上而投予。
又,於補充及/或增強本發明化合物之預防及/或治療效果之其他藥劑中,基於上述機制,不僅包含目前為止所發現者,而且亦包含今後所發現者。
為了將本發明化合物製成單劑或組合其他藥劑製成併用劑而用於上述疾病之預防及/或治療之目的,將作為有效成分之該物質通常與各種添加劑或溶劑等藥學上所容許之載體一起製劑化後,以經口或非經口之形式全身或局部地進行投予。此處,所謂藥學上所容許之載體,意指通常於醫藥品之製劑中使用之有效成分以外之物質。藥學上所容許之載體較佳為於其製劑之投予量下不顯示藥理作用,無害且不妨礙有效成分之治療效果者。又,藥學上所容許之載體亦可出於提高有效成分及製劑之有用性、使製劑化變得容易、謀求品質之穩定化、或提高使用性等目的而使用。具體而言,只要根據目的適當選擇藥事日報社2016年刊「醫藥品添加物事典」(日本醫藥品添加劑協會編輯)等中記載之物質即可。
作為用於投予之劑型,例如可列舉:經口投予用製劑(例:錠劑、膠囊劑、顆粒劑、散劑、經口液劑、糖漿劑、經口凍膠劑等)、口腔用製劑(例:口腔用錠劑、口腔用噴霧劑、口腔用半固形劑、含漱劑等)、注射用製劑(例:注射劑等)、透析用製劑(例:透析用劑等)、吸入用製劑(例:吸入劑等)、眼科用製劑(例:滴眼劑、眼軟膏劑等)、耳科用製劑(例:滴耳劑等)、鼻科用製劑(例:滴鼻劑等)、直腸用製劑(例:栓劑、直腸用半固形劑、灌腸劑等)、陰道用製劑(例:陰道錠、陰道用栓劑等)、及皮膚用製劑(例:外用固形劑、外用液劑、噴霧劑、軟膏劑、乳霜劑、凝膠劑、貼附劑等)等。
[經口投予用製劑]
於經口投予用製劑中,例如包含錠劑、膠囊劑、顆粒劑、散劑、經口液劑、糖漿劑、經口凍膠劑等。又,於經口投予用製劑中存在並未特別調節來自製劑之有效成分之釋出性之速崩性製劑、及根據目的藉由固有之製劑設計及製法調節釋出性之例如腸溶性製劑或緩釋性製劑等釋出調節製劑。腸溶性製劑係出於防止有效成分於胃內之分解、或降低有效成分對胃之刺激作用等目的,設計為使有效成分不於胃內釋出而主要於小腸內釋出之製劑,通常可藉由使用酸不溶性之腸溶性基劑施加皮膜而製造。緩釋性製劑係出於謀求投予次數之減少或副作用之降低等目的,調節了來自製劑之有效成分之釋出速度、釋出時間、釋出部位之製劑,通常可藉由使用適當之緩釋化劑而製造。於經口投予用製劑之中,膠囊劑、顆粒劑、錠劑等亦可出於使服用變得容易、或防止有效成分之分解等目的,利用糖類或糖醇類、高分子化合物等適當之包衣劑施加包衣。
(1)錠劑
錠劑係具有經口投予之一定之形狀之固形之製劑,除了包含素錠、膜衣錠、糖衣錠、多層錠、有核錠等通常被稱為錠劑者以外,亦包含口腔內速崩錠、咀嚼錠、發泡錠、分散錠、溶解錠等。於製造素錠時,通常使用下述之(a)、(b)、或(c)之方法:
(a)向有效成分中添加賦形劑、結合劑、崩解劑等添加劑進行混合使之均質,使用水或包含結合劑之溶液,藉由適當之方法製成粒狀後,添加潤滑劑等進行混合後進行壓縮成形;
(b)對向有效成分中添加賦形劑、結合劑、崩解劑等添加劑進行混合使之均質而成者直接進行壓縮成形,或者向預先利用添加劑製成之顆粒中添加有效成分及潤滑劑等進行混合使之均質後進行壓縮成形;
(c)使向有效成分中添加賦形劑、結合劑等添加劑進行混合使之均質且利用溶劑使之濕潤而成之混練物流入至固定之模具而成形後,藉由適當之方法進行乾燥。
膜衣錠通常可藉由利用高分子化合物等適當之包衣劑對素錠施加較薄之包衣而製造。糖衣錠通常可藉由利用包含糖類或糖醇之包衣劑對素錠施加包衣而製造。多層錠可藉由利用適當之方法將組成不同之粉粒體堆積成層狀且進行壓縮成形而製造。有核錠可藉由以組成不同之外層覆蓋內核錠而製造。又,錠劑亦可使用公知之適當之方法製成腸溶錠或緩釋錠。口腔內速崩錠、咀嚼錠、發泡錠、分散錠、及溶解錠係藉由添加劑之適當之選擇而對錠劑賦予獨特之功能者,可依據上述錠劑之製造方法而製造。再者,所謂口腔內速崩錠,係指可於口腔內迅速地溶解或崩解而服用之錠劑;所謂咀嚼錠,係指進行咀嚼而服用之錠劑;所謂發泡錠,係指一面於水中急速發泡一面溶解或分散之錠劑;所謂分散錠,係指分散於水中而服用之錠劑;所謂溶解錠,係指溶解於水中而服用之錠劑。發泡錠可藉由使用適當之酸性物質、碳酸鹽、碳酸氫鹽等作為添加劑而製造。
(2)膠囊劑
膠囊劑係填充於膠囊或利用膠囊基劑進行膠囊化成形而成之製劑,包含硬膠囊劑、軟膠囊劑等。硬膠囊劑可藉由將向有效成分中添加賦形劑等添加劑進行混合使之均質而成者、或利用適當之方法製成粒狀或成形物而成者直接填充於膠囊,或輕微成形後填充於膠囊而製造。軟膠囊劑可藉由利用添加甘油、D-山梨糖醇等而增加了塑性之明膠等適當之膠囊基劑,將向有效成分中加入添加劑而成者膠囊化成形為一定之形狀而製造。膠囊劑亦可使用公知之適當之方法製成腸溶性膠囊劑或緩釋性膠囊劑,又,亦可向膠囊基劑中添加著色劑或保存劑等。
(3)顆粒劑
顆粒劑係造粒成粒狀之製劑,除了通常被稱為顆粒劑者以外,亦包含發泡性顆粒劑等。於製造顆粒劑時,通常使用下述之(a)、(b)、或(c)之方法:
(a)向粉末狀之有效成分中添加賦形劑、結合劑、崩解劑、或其他添加劑進行混合使之均質後,藉由適當之方法製成粒狀;
(b)向預先製成粒狀之有效成分中添加賦形劑等添加劑進行混合使之均質;
(c)向預先製成粒狀之有效成分中添加賦形劑等添加劑進行混合,藉由適當之方法製成粒狀。
對於顆粒劑,視需要亦可施加包衣,又,亦可使用公知之適當之方法製成腸溶性顆粒劑或緩釋性顆粒劑。發泡顆粒劑可藉由使用適當之酸性物質、碳酸鹽、碳酸氫鹽等作為添加劑而製造。再者,所謂發泡顆粒劑,係指一面於水中急速發泡一面溶解或分散之顆粒劑。顆粒劑亦可藉由調節粒子之大小而製成細粒劑。
(4)散劑
散劑係粉末狀之製劑,通常可藉由向有效成分中添加賦形劑或其他添加劑進行混合使之均質而製造。
(5)經口液劑
經口液劑係液狀或具有流動性之黏稠之凝膠狀之製劑,除了通常被稱為經口液劑者以外,亦包含酏劑、懸浮劑、乳劑、檸檬水(lemonade)劑等。經口液劑通常可藉由向有效成分中加入添加劑及純化水進行混合使之均質地溶解、或者乳化或懸浮,視需要進行過濾而製造。所謂酏劑,係指包含具有甜味及芳香之乙醇之澄清之液狀之經口液劑,通常可藉由向固形之有效成分或其浸出液中添加乙醇、純化水、著香劑、及白糖、其他糖類、或甜味劑使之溶解,利用過濾或其他方法製成澄清之溶液而製造。所謂懸浮劑,係指使有效成分微細均質地懸浮而成之經口液劑,通常可藉由向固形之有效成分中添加懸浮化劑或其他添加劑與純化水或油,利用適當之方法進行懸浮,且使整體變得均質而製造。所謂乳劑,係指使有效成分微細均質地乳化而成之經口液劑,通常可藉由向液狀之有效成分中添加乳化劑與純化水,利用適當之方法進行乳化,且使整體變得均質而製造。再者,所謂檸檬水劑,係指具有甜味及酸味之澄清之液狀之經口液劑。
(6)糖漿劑
糖漿劑係包含糖類或甜味劑之具有黏稠性之液狀或固形之製劑,包含糖漿用劑等。糖漿劑通常可藉由向白糖、其他糖類、或甜味劑之溶液、或單糖漿中添加有效成分進行溶解、混合、懸浮、或乳化,視需要將混合溶液煮沸後進行熱過濾而製造。所謂糖漿用劑,係指添加水時成為糖漿劑之顆粒狀或粉末狀之製劑,有時亦稱為乾糖漿劑。糖漿用劑通常使用糖類或甜味劑作為添加劑,依據上述顆粒劑或散劑之製造方法而製造。
(7)經口凍膠劑
經口凍膠劑係不具流動性之經成形之凝膠狀之製劑,通常可藉由向有效成分中加入添加劑及高分子凝膠基劑進行混合,利用適當之方法使之凝膠化且成形為一定之形狀而製造。
[注射用製劑]
(1)注射劑
注射劑係向皮下、肌肉內、或血管等體內組織或器官直接投予之溶液、懸浮液、或乳濁液、或者用時溶解或用時懸浮而使用之固形之無菌製劑,除了通常被稱為注射劑者以外,亦包含冷凍乾燥注射劑、粉末注射劑、預填充注射器劑、筒劑、輸液劑、埋入式注射劑、及持續性注射劑等。於製造注射劑時,通常使用下述之(a)或(b)之方法:
(a)將使有效成分直接或使向有效成分中加入添加劑而成者於注射用水、其他水性溶劑、或非水性溶劑等中溶解、懸浮、或乳化且使之均質而成者,填充於注射劑用之容器中進行密封且滅菌;
(b)對使有效成分直接或使向有效成分中加入添加劑而成者於注射用水、其他水性溶劑、或非水性溶劑等中溶解、懸浮、或乳化且使之均質而成者進行無菌過濾,或者將進行無菌製備且使之均質而成者,填充於注射劑用之容器進行密封。
冷凍乾燥注射劑通常可藉由將有效成分直接或將有效成分及賦形劑等添加劑溶解於注射用水,進行無菌過濾,填充至注射劑用之容器後進行冷凍乾燥,或者於專用容器中進行冷凍乾燥後填充至直接之容器而製造。粉末注射劑通常可藉由利用無菌過濾進行處理後,將利用晶析所得之粉末或對該粉末加入經滅菌處理之添加劑後再予填充至注射劑用之容器而製造。預填充注射器劑通常可藉由直接使用有效成分或使用有效成分及添加劑製備溶液、懸浮液、或乳濁液且填充至注射筒而製造。所謂筒劑,係指將填充有藥液之筒放入至專用之注射器而使用之注射劑,填充有藥液之筒通常可藉由直接使用有效成分或使用有效成分及添加劑製備溶液、懸浮液、或乳濁液且填充至筒而製造。所謂輸液劑,係指向靜脈內投予之通常100 mL以上之注射劑。所謂埋入式注射劑,係指以長期之有效成分之釋出為目的,使用向皮下、肌肉內等埋入用之器具,或藉由手術而應用之固形或凝膠狀之注射。埋入式注射劑通常可藉由使用生物降解性高分子化合物製成顆粒(pellet)、微球體、或凝膠狀而製造。所謂持續性注射劑,係指以長期之有效成分之釋出為目的,應用於肌肉內等之注射劑,通常可藉由使有效成分於植物油等中溶解或懸浮,或者製成使用生物降解性高分子化合物之微球體之懸浮液而製造。
本發明化合物、或本發明化合物與其他藥劑之併用劑之投予量因年齡、體重、症狀、治療效果、投予方法、處理時間等而異,通常於成人每人每次1 ng至1000 mg之範圍內一日一次至數次進行經口投予,或者於成人每人每次0.1 ng至100 mg之範圍內一日一次至數次進行非經口投予,或者於一日1小時至24小時之範圍內向靜脈內持續投予。當然,如上所述,投予量根據各種條件而變動,故而存在少於上述投予量之量即充分之情形,又,亦存在需要超出範圍進行投予之情形。
只要未作其他定義,則本說明書中所使用之全部技術性、科學性用語、及縮寫具有與屬於本發明之領域之業者普通所理解者同樣之含義。
又,於本說明書中,明示引用之全部之專利文獻及非專利文獻或參考文獻之內容全部可作為本說明書之一部分引用於本文中。
[實施例]
以下,藉由實施例對本發明進行詳述,但本發明並不限定於該等。
[合成實施例]
利用層析法之分離之位置及TLC所示之括號內之溶劑表示所使用之溶出溶劑或展開溶劑,比率表示體積比。
NMR之位置所示之括號內之溶劑表示用於測定之溶劑。
本說明書中所使用之化合物名係使用通常依據IUPAC之規則進行命名之計算機程式、ACD/Name(註冊商標),或者使用Chemdraw Ultra(版本12.0,Cambridge Soft公司製造),或者為依據IUPAC命名法所命名者。
LC-MS/ELSD係於下述條件下進行。
管柱:Waters Triart C18
(粒徑:1.9×10-6
m;管柱長:30×2.0 mm I.D.);流速:1.0 mL/min;管柱溫度:30℃;流動相(A):0.1%三氟乙酸水溶液;流動相(B):0.1%三氟乙酸-乙腈溶液;梯度(記載流動相(A):流動相(B)之比率):[0分鐘]95:5;[0.1分鐘]95:5;[1.2分鐘]5:95;[1.4分鐘]5:95;[1.41分鐘]95:5;[1.5分鐘]95:5;檢測器:UV(PDA)、ELSD、MS。
HPLC保持時間若無另外記載,則表示上述LC-MS/ELSD中記載之條件下之保持時間。
超臨界流體層析法(SFC)係於下述條件下進行。
管柱:CHIRAL PAK IC/SFC(Daicel)、內徑20 mm×長度250 mm、粒徑5 μm;流速:100 mL/min;共溶劑/CO2
=12/88;ISOCRATIC 21min(共溶劑:MeCN/MeOH=9/1);背壓:120 bar。
參考例 1 : 4-( 乙醯氧基 )-2-( 三氟甲基 ) 苯甲酸
向4-羥基-2-(三氟甲基)苯甲酸(CAS. No.320-32-1,500 mg)之乙酸乙酯(7.5 mL)溶液中添加吡啶(0.392 mL)、乙酸酐(0.573 mL),攪拌一晩。向反應混合物中添加水、稀鹽酸後,利用乙酸乙酯進行萃取。將有機層利用水、飽和食鹽水洗淨,利用硫酸鈉乾燥後進行減壓濃縮,藉此獲得具有以下之物性值之標題化合物(528 mg)。1
H-NMR (DMSO-d6
) : δ 2.34, 7.56, 7.70, 7.91, 13.66。
參考例 2 :乙酸 4-( 氯羰基 )-3-( 三氟甲基 ) 苯酯
向參考例1中製造之化合物(1.0 g)之甲苯(1.6 mL)-乙腈(0.26 mL)溶液中添加亞硫醯氯(0.17 mL),於60℃下攪拌4小時。將藉由對反應液進行減壓濃縮所得之化合物不進行純化而用於下一反應。
參考例 3 : {3-[4-( 乙醯氧基 )-2-( 三氟甲基 ) 苯甲醯胺 ]-4- 氯苯基 } 乙酸甲酯
向參考例2中製造之化合物之甲苯(1.6 mL)-乙腈(1.6 mL)溶液中添加吡啶(0.342 mL)及2-(3-胺基-4-氯苯基)乙酸甲酯(CAS. No.59833-69-1,422 mg),於室溫下攪拌一晩。向反應混合物中添加水,利用乙酸乙酯進行萃取。將有機層利用1 mol/L鹽酸、水、飽和食鹽水依序洗淨,利用硫酸鈉乾燥後進行減壓濃縮。將所得之殘渣利用矽膠管柱層析法(己烷:乙酸乙酯=70:30)進行純化,藉此獲得具有以下之物性值之標題化合物(715 mg)。1
H-NMR (CDCl3
) : δ 2.37, 3.68, 3.72, 7.07, 7.37, 7.43, 7.53, 7.71, 7.93, 8.45。
參考例 4 : {4- 氯 -3-[4- 羥基 -2-( 三氟甲基 ) 苯甲醯胺 ] 苯基 } 乙酸甲酯
向參考例3中製造之化合物(1.75 g)之甲醇(8.8 mL)-四氫呋喃(8.8 mL)溶液中添加碳酸鉀(404 mg),於室溫下攪拌2小時。向反應混合物中添加水、1 mol/L鹽酸後,利用乙酸乙酯進行萃取。將有機層利用水、飽和食鹽水洗淨,利用硫酸鈉乾燥後進行減壓濃縮,藉此獲得具有以下之物性值之標題化合物(1.36 g)。
TLC:Rf 0.55 (己烷:乙酸乙酯=1:1);1
H-NMR (CDCl3
) : δ 3.63, 3.75, 7.12 - 7.16, 7.19, 7.49, 7.52, 7.59, 10.07, 10.52。
實施例 1 : (4- 氯 -3-{4-[2-( 㗁烷 -2- 基 ) 乙氧基 ]-2-( 三氟甲基 ) 苯甲醯胺 } 苯基 ) 乙酸甲酯
[化35]
向參考例4中製造之化合物(500 mg)、2-(四氫吡喃-2-基)乙醇(CAS. No.38786-79-7,218 mg)之甲苯(5 mL)溶液中添加氰基亞甲基三苯基膦(0.507 mL),於60℃下攪拌一晩。對反應液進行減壓濃縮後,將所得之殘渣利用矽膠管柱層析法(己烷:乙酸乙酯=3:1)進行純化,藉此獲得具有以下之物性值之標題化合物(564 mg)。
HPLC保持時間(分鐘):1.15;1
H-NMR (CDCl3
) : δ 1.37, 1.47 - 1.68, 1.86, 1.94, 3.40 - 3.53, 3.67, 3.72, 3.98, 4.13, 4.20, 7.04, 7.13, 7.29, 7.36, 7.62, 7.93, 8.47。
實施例 2 : (4- 氯 -3-{4-[2-( 㗁烷 -2- 基 ) 乙氧基 ]-2-( 三氟甲基 ) 苯甲醯胺 } 苯基 ) 乙酸
[化36]
向實施例1中製造之化合物(40.0 mg)之二甲氧基乙烷(0.4 mL)溶液中添加2 mol/L氫氧化鋰水溶液(0.12 mL),於室溫下攪拌1小時。向反應混合物中添加1 mol/L鹽酸後,利用乙酸乙酯進行萃取。將有機層利用水、飽和食鹽水洗淨,利用硫酸鈉乾燥後進行減壓濃縮,藉此獲得具有以下之物性值之標題化合物(29 mg)。
HPLC保持時間(分鐘):1.03;1
H-NMR (DMSO-d6
) : δ 1.25, 1.41 - 1.53, 1.63, 1.77, 1.83 - 1.89, 3.45, 3.63, 3.88, 4.14 - 4.23, 7.19, 7.32, 7.35, 7.48, 7.51, 7.68, 10.14, 12.46。
實施例2-1~2-3
使用相當於2-(四氫-2H-吡喃-2-基)乙醇之替代品之醇體,進行與實施例1→實施例2同樣之操作,藉此獲得具有以下之物性值之標題化合物。實施例 2-1 : {4- 氯 -3-[4-(2- 環己基乙氧基 )-2-( 三氟甲基 ) 苯甲醯胺 ] 苯基 } 乙酸
[化37]
TLC:Rf 0.60(乙酸乙酯:甲醇=9:1);1
H-NMR (CDCl3
) : δ 0.85 - 1.10, 1.13 - 1.35, 1.52, 1.63 - 1.83, 3.71, 4.08, 7.05, 7.10, 7.38, 7.62, 7.94, 8.49。實施例 2-2 : {4- 氯 -3-[4-(2- 苯基乙氧基 )-2-( 三氟甲基 ) 苯甲醯胺 ] 苯基 } 乙酸
[化38]
HPLC保持時間(分鐘):1.07;1
H-NMR (DMSO-d6
) : δ 3.09, 3.63, 4.36, 7.18, 7.24, 7.31 - 7.37, 7.48, 7.51, 7.68, 10.14, 12.45。實施例 2-3 : {4- 氯 -3-[4-(2- 環丙基乙氧基 )-2-( 三氟甲基 ) 苯甲醯胺 ] 苯基 } 乙酸
[化39]
HPLC保持時間(分鐘):1.05;1
H-NMR (DMSO-d6
) : δ -0.02 - 0.01, 0.28 - 0.32, 0.70, 1.51, 3.48, 4.02, 7.03, 7.16, 7.20, 7.33, 7.36, 7.53, 9.99, 12.29。
實施例 3 : (4- 氯 -3-{2,6- 二甲基 -4-[2-( 㗁烷 -2- 基 ) 乙氧基 ] 苯甲醯胺 } 苯基 ) 乙酸甲酯
[化40]
使用{4-氯-3-[(4-羥基-2,6-二甲基苯甲醯基)胺基]苯基}乙酸甲酯(CAS No.1351163-96-6,Bioorganic & Medicinal Chemistry 19 (2011) 6935-6948, Compound 44)替代參考例4中製造之化合物,進行與實施例1同樣之反應,藉此獲得具有以下之物性之標題化合物。
TLC:Rf 0.75(己烷:乙酸乙酯=1:1);1
H-NMR (CDCl3
) : δ 1.33, 1.51, 1.63, 1.85, 1.91, 2.38, 3.43, 3.50, 3.68, 3.73, 3.97, 4.08, 6.63, 7.03, 7.35, 7.74, 8.49。
實施例 3-1 : {4- 氯 -3-[4-(2- 環己基乙氧基 )-2,6- 二甲基苯甲醯胺 ] 苯基 } 乙酸甲酯
[化41]
使用{4-氯-3-[(4-羥基-2,6-二甲基苯甲醯基)胺基]苯基}乙酸甲酯替代參考例4中製造之化合物,使用2-環己基乙醇(CAS No.28438-52-0)替代2-(四氫-2H-吡喃-2-基)乙醇,進行與實施例1同樣之操作,藉此獲得具有以下之物性值之標題化合物。
TLC:Rf 0.68(乙酸乙酯:己烷=2:1);1
H-NMR (CDCl3
) : δ 0.80 - 1.05, 1.10 - 1.35, 1.40 - 1.55, 1.65 - 1.80, 2.35, 3.53, 3.68, 3.73, 4.00, 4.19, 6.61, 7.04, 7.36, 7.74, 8.50。
實施例 4 : (4- 氯 -3-{2,6- 二甲基 -4-[2-( 㗁烷 -2- 基 ) 乙氧基 ] 苯甲醯胺 } 苯基 ) 乙酸
[化42]
使用實施例3中製造之化合物替代實施例1中製造之化合物,進行與實施例2同樣之反應,藉此獲得具有以下之物性值之標題化合物。
HPLC保持時間(分鐘):1.02;1
H-NMR (DMSO-d6
) : δ 1.16 - 1.83, 2.32, 3.39, 3.61, 3.86, 4.02, 6.66, 7.15, 7.45, 7.49, 9.95, 12.44。
實施例 4-1 ~ 4-2 :
使用相當於2-(四氫-2H-吡喃-2-基)乙醇之替代品之醇體,且使用{4-氯-3-[(4-羥基-2,6-二甲基苯甲醯基)胺基]苯基}乙酸甲酯替代參考例4中製造之化合物,進行與實施例1→實施例2同樣之操作,藉此獲得具有以下之物性值之標題化合物。實施例 4-1 : {4- 氯 -3-[4-(2- 環己基乙氧基 )-2,6- 二甲基苯甲醯胺 ] 苯基 } 乙酸
[化43]
TLC:Rf 0.27(己烷:乙酸乙酯=1:2);1
H-NMR (CD3
OD) : δ 0.83 - 1.08, 1.13 - 1.38, 1.42 - 1.59, 1.60 - 1.91, 2.41, 3.64, 4.01, 6.65, 7.19, 7.43, 7.72。實施例 4-2 : {4- 氯 -3-[4-(2- 環丙基乙氧基 )-2,6- 二甲基苯甲醯胺 ] 苯基 } 乙酸
[化44]
HPLC保持時間(分鐘):1.05;
MS (ESI, Pos.) : 402 (M+H)+
;
實施例 5 : (3-{4-[(2,3- 二氫 -1H- 茚 -2- 基 ) 氧基 ]-2,6- 二甲基苯甲醯胺 }-4- 氟苯基 ) 乙酸
[化45]
使用2-(3-胺基-4-氟苯基)乙酸甲酯(CAS No.257632-77-2)替代2-(3-胺基-4-氯苯基)乙酸甲酯,使用4-羥基-2,6-二甲基苯甲酸(CAS No.75056-97-2)替代4-羥基-2-(三氟甲基)苯甲酸,使用2-茚醇(CAS No.4254-29-9)替代2-(四氫-2H-吡喃-2-基)乙醇,進行與參考例1→參考例2→參考例3→參考例4→實施例1→實施例2同樣之操作,藉此獲得具有以下之物性值之標題化合物。
HPLC保持時間(分鐘):1.02;1
H-NMR (DMSO-d6
) : δ 2.29, 3.02, 3.39, 3.60, 5.27, 6.70, 7.13 - 7.28, 7.57, 10.07, 12.38。
參考例 5 : (4- 氯 -3-{2,6- 二甲基 -4-[( 三氟甲磺醯基 ) 氧基 ] 苯甲醯胺 } 苯基 ) 乙酸甲酯
向[4-氯-3-(4-羥基-2,6-二甲基苯甲醯胺)苯基]乙酸甲酯(1.00 g)之二氯甲烷(15 mL)溶液中添加三乙基胺(0.52 mL)及N,N-雙(三氟甲基磺醯基)苯胺(1.23 g),於室溫下攪拌4小時。向反應混合物中添加水,利用乙酸乙酯進行萃取。將有機層利用水、飽和食鹽水洗淨,利用硫酸鈉乾燥後進行減壓濃縮。將所得之殘渣利用矽膠管柱層析法(己烷:乙酸乙酯=10:0→7:3)進行純化,藉此獲得具有以下之物性值之標題化合物(1.38 g)。
TLC:Rf 0.39(己烷:乙酸乙酯=2:1);1
H-NMR (CDCl3
) : δ 1.55, 2.45, 3.69, 3.73, 7.02, 7.08, 7.37, 7.40, 7.73, 8.43。
實施例 6 : {4- 氯 -3-[4-(3- 環己基 -1- 丙炔 -1- 基 )-2,6- 二甲基苯甲醯胺 ] 苯基 } 乙酸甲酯
[化46]
向參考例5中製造之化合物(1.38 g)之N,N-二甲基甲醯胺(12 mL)溶液中添加3-環己基-1-丙炔(1.26 mL)、三乙基胺(8.1 mL),設為氬環境下。添加碘化銅(55 mg)及二氯化雙(三苯基膦)鈀(II)(204 mg),於50℃下攪拌整夜。向反應混合物中添加水,利用乙酸乙酯/己烷混合溶劑進行萃取。將有機層利用水、飽和食鹽水洗淨,利用硫酸鈉乾燥後進行減壓濃縮。將所得之殘渣利用矽膠管柱層析法(己烷:乙酸乙酯=10:0→7:3)進行純化,藉此獲得具有以下之物性值之標題化合物(1.46 g)。
TLC:Rf 0.45(己烷:乙酸乙酯=4:1);1
H-NMR (CDCl3
) : δ 0.95 - 1.40, 1.45 - 1.78, 1.85 - 1.90, 2.30, 2.37, 3.68, 3.73, 7.05, 7.14, 7.35, 7.38, 7.71, 8.47。
實施例 7 : {4- 氯 -3-[4-(3- 環己基 -1- 丙炔 -1- 基 )-2,6- 二甲基苯甲醯胺 ] 苯基 } 乙酸
[化47]
使用實施例6中製造之化合物替代實施例1中製造之化合物,進行與實施例2同樣之操作,藉此獲得具有以下之物性值之標題化合物。
TLC:Rf 0.61(乙酸乙酯:甲醇=9:1);1
H-NMR (CDCl3
) : δ 0.98 - 1.35, 1.56, 1.65 - 1.80, 1.82 - 1.90, 2.30, 2.38, 3.72, 7.06, 7.14, 7.36, 7.39, 7.71, 8.48。
實施例 8 : (4- 氯 -3-{4-[(1E)-3- 環己基 -1- 丙烯 -1- 基 ]-2,6- 二甲基苯甲醯胺 } 苯基 ) 乙酸
[化48]
向參考例5中製造之化合物(1000 mg)之二㗁烷(12 mL)溶液中添加2-[(E)-3-環己基丙烯-3-基]-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(626 mg)、磷酸鉀(884 mg)、二氯化[1,1'-雙(二苯基膦基)二茂鐵]鈀(II)二氯甲烷加成物,於50℃下攪拌18小時。向反應混合物中添加水、乙酸乙酯後,利用Celite(商品名)進行過濾。將濾液利用乙酸乙酯進行萃取後,將有機層利用水、飽和食鹽水洗淨,利用硫酸鈉乾燥後進行減壓濃縮。將所得之殘渣利用矽膠管柱層析法進行純化,藉此獲得標題化合物之甲酯體(533 mg)。使用所得之甲酯體,進行與實施例2同樣之操作,藉此獲得具有以下之物性值之標題化合物。
TLC:Rf 0.38(己烷:乙酸乙酯:乙酸=14:5:1);
HPLC保持時間(分鐘):1.31;
MS (ESI, Pos.) : 440 (M+H)+
。
實施例 9 : [4- 氯 -3-({2,6- 二甲基 -4-[2-( 㗁烷 -2- 基 ) 乙氧基 ] 苯 -1- 硫代羰基 } 胺基 ) 苯基 ] 乙酸甲酯
[化49]
向實施例3中製造之化合物(40 mg)之甲苯(0.4 mL)溶液中添加勞森試劑(CAS No.19172-47-5,21 mg),於100℃下攪拌24小時。對反應混合物進行減壓濃縮,將所得之殘渣利用矽膠管柱層析法(己烷:乙酸乙酯=20:1→4:1)進行純化,藉此獲得具有以下之物性值之標題化合物(40 mg)。
TLC:Rf 0.50(己烷:乙酸乙酯=2:1);1
H-NMR (DMSO-d6
) : δ 1.25, 1.46, 1.62, 1.81, 2.37, 3.44, 3.64, 3.80, 3.87, 4.02, 6.68, 7.30, 7.42, 7.55, 11.74。
實施例 10 : [4- 氯 -3-({2,6- 二甲基 -4-[2-( 㗁烷 -2- 基 ) 乙氧基 ] 苯 -1- 硫代羰基 } 胺基 ) 苯基 ] 乙酸
[化50]
使用實施例9中製造之化合物替代實施例1中製造之化合物,進行與實施例2同樣之操作,藉此獲得具有以下之物性值之標題化合物。
TLC:Rf 0.28(二氯甲烷:甲醇=9:1);1
H-NMR (DMSO-d6
) : δ 1.25, 1.47, 1.62, 1.80, 2.37, 3.42, 3.67, 3.87, 4.04, 6.68, 7.29, 7.39, 7.54, 11.74, 12.46。
實施例 10-1 ~ 10-5 :
使用實施例1、實施例3-1中製造之化合物、實施例2-1~2-3中製造之化合物之甲酯體替代實施例3中製造之化合物,進行與實施例9→實施例2同樣之操作,藉此獲得具有以下之物性值之標題化合物。實施例 10-1 : (4- 氯 -3-{[4-(2- 環己基乙氧基 )-2,6- 二甲基苯 -1- 硫代羰基 ] 胺基 } 苯基 ) 乙酸
[化51]
TLC:Rf 0.46(乙酸乙酯:甲醇=9:1);1
H-NMR (DMSO-d6
) : δ 0.85 - 1.02, 1.10 - 1.30, 1.43, 1.55 - 1.75, 2.35, 3.65, 3.99, 6.67, 7.28, 7.36, 7.51, 7.54, 11.71, 12.44。實施例 10-2 : [4- 氯 -3-({4-[2-( 㗁烷 -2- 基 ) 乙氧基 ]-2-( 三氟甲基 ) 苯 -1- 硫代羰基 } 胺基 ) 苯基 ] 乙酸
[化52]
HPLC保持時間(分鐘):1.05;1
H-NMR (DMSO-d6
) : δ 1.25, 1.42 - 1.51, 1.63, 1.77, 1.83 - 1.89, 3.45, 3.67, 3.88, 4.12 - 4.21, 7.25, 7.29 - 7.32, 7.35, 7.47, 7.55, 11.90, 12.46。實施例 10-3 : (4- 氯 -3-{[4-(2- 環己基乙氧基 )-2-( 三氟甲基 ) 苯 -1- 硫代羰基 ] 胺基 } 苯基 ) 乙酸
[化53]
HPLC保持時間(分鐘):1.21;1
H-NMR (DMSO-d6
) : δ 0.92 - 1.02, 1.13 - 1.29, 1.49, 1.63 - 1.77, 3.66, 4.14, 7.24, 7.29 - 7.32, 7.34, 7.46, 7.54, 11.89, 12.46。實施例 10-4 : (4- 氯 -3-{[4-(2- 苯基乙氧基 )-2-( 三氟甲基 ) 苯 -1- 硫代羰基 ] 胺基 } 苯基 ) 乙酸
[化54]
HPLC保持時間(分鐘):1.09;1
H-NMR (DMSO-d6
) : δ 3.08, 3.66, 4.34, 7.23 - 7.27, 7.29 - 7.37, 7.46, 7.55, 11.90, 12.50。實施例 10-5 : (4- 氯 -3-{[4-(2- 環丙基乙氧基 )-2-( 三氟甲基 ) 苯 -1- 硫代羰基 ] 胺基 } 苯基 ) 乙酸
[化55]
HPLC保持時間(分鐘):1.06;1
H-NMR (DMSO-d6
) : δ -0.02 - 0.01, 0.28 - 0.32, 0.70, 1.51, 3.50, 4.00, 7.08, 7.13 - 7.18, 7.31, 7.38, 11.74, 12.30。
實施例11:
使用實施例9中製造之化合物,藉由超臨界流體層析法(SFC)進行化學拆分,藉此獲得具有以下之物性值之標題化合物。實施例 11-1 : {4- 氯 -3-[(2,6- 二甲基 -4-{2-[(2R)- 㗁烷 -2- 基 ] 乙氧基 } 苯 -1- 硫代羰基 ) 胺基 ] 苯基 } 乙酸甲酯
[化56]
HPLC保持時間(分鐘):13.2(CHIRAL PAK IC,己烷:異丙醇=70:30);實施例 11-2 : {4- 氯 -3-[(2,6- 二甲基 -4-{2-[(2S)- 㗁烷 -2- 基 ] 乙氧基 } 苯 -1- 硫代羰基 ) 胺基 ] 苯基 } 乙酸甲酯
[化57]
HPLC保持時間(分鐘):11.8(CHIRAL PAK IC,己烷:異丙醇=70:30);
實施例 12 : {4- 氯 -3-[(2,6- 二甲基 -4-{2-[(2R)- 㗁烷 -2- 基 ] 乙氧基 } 苯 -1- 硫代羰基 ) 胺基 ] 苯基 } 乙酸
[化58]
使用實施例11-1中製造之化合物替代實施例1中製造之化合物,進行與實施例2同樣之操作,藉此獲得具有以下之物性值之標題化合物。
TLC:Rf 0.28(二氯甲烷:甲醇=9:1);
HPLC保持時間(分鐘):1.05;
MS (ESI, Pos.) : 462 (M+H)+
;1
H-NMR (DMSO-d6
) : δ 1.25, 1.47, 1.62, 1.80, 2.37, 3.42, 3.67, 3.87, 4.04, 6.68, 7.29, 7.39, 7.54, 11.74, 12.46。
實施例 13 : {4- 氯 -3-[(2,6- 二甲基 -4-{2-[(2S)- 㗁烷 -2- 基 ] 乙氧基 } 苯 -1- 硫代羰基 ) 胺基 ] 苯基 } 乙酸
[化59]
使用實施例11-2中製造之化合物替代實施例1中製造之化合物,進行與實施例2同樣之操作,藉此獲得具有以下之物性值之標題化合物。
TLC:Rf 0.28(二氯甲烷:甲醇=9:1);
HPLC保持時間(分鐘):1.05;
MS (ESI, Pos.) : 462 (M+H)+
;1
H-NMR (DMSO-d6
) : δ 1.25, 1.47, 1.62, 1.80, 2.37, 3.42, 3.67, 3.87, 4.04, 6.68, 7.29, 7.39, 7.54, 11.74, 12.46。
參考例 6 : 2-(3- 胺基 -4- 氟苯基 ) 丙酸甲酯
向乙酸(34 mL)、水(4.0 mL)中添加鐵粉(4.8 g),加熱至65℃,向所得之混合物中添加利用國際公開第2013/045451號說明書中記載之方法所製造之2-(4-氟-3-硝基苯基)丙酸甲酯(CAS No.1428790-43-5,3.9 g)之乙酸(5 mL)溶液,將反應混合物於65℃下攪拌30分鐘。將反應混合物冷卻至室溫後,利用Celite(商品名)進行過濾,將濾液冷卻至0℃後,注入2 N氫氧化鈉水溶液(345 mL),再次利用Celite(商品名)進行過濾。將濾液利用第三丁基甲醚萃取2次,將有機層利用飽和食鹽水洗淨,利用無水硫酸鎂乾燥後進行減壓濃縮。將所得之殘渣利用矽膠管柱層析法(己烷:乙酸乙酯=99:1→65:35)進行純化,藉此獲得具有以下之物性值之標題化合物(3.4 g)。1
H-NMR (CDCl3
) : δ 1.45, 3.60, 3.63, 3.71, 6.60, 6.73, 6.91。
實施例 14 : 2-{3-[({2,6- 二甲基 -4-[2-( 四氫 -2H- 吡喃 -2- 基 ) 乙氧基 ] 苯基 } 硫代羰基 ) 胺基 ]-4- 氟苯基 } 丙酸
[化60]
使用參考例6中製造之化合物替代2-(3-胺基-4-氯苯基)乙酸甲酯,使用藉由Bioorganic & Medicinal Chemistry, vol. 19, 6935-6948, 2011中記載之方法而製造之4-乙醯氧基-2,6-二甲基苯甲酸(CAS No.1351163-93-3)替代參考例1中製造之化合物,進行與參考例2→參考例3→參考例4→實施例1→實施例9→實施例2同樣之操作,藉此獲得具有以下之物性值之標題化合物。
HPLC保持時間(分鐘):1.07;
MS (ESI, Pos., 20V) : 460 (M+H)+
;1
H-NMR (DMSO-d6
) : δ 1.18, 1.19 - 1.29, 1.38, 1.39 - 1.55, 1.62, 1.71 - 1.87, 2.32, 3.26 - 3.52, 3.77, 3.87, 4.04, 6.69, 7.26 - 7.43, 11.64, 12.44。
實施例 15 : 1-{3-[({2,6- 二甲基 -4-[2-( 四氫 -2H- 吡喃 -2- 基 ) 乙氧基 ] 苯基 } 硫代羰基 ) 胺基 ]-4- 氟苯基 } 環丙烷羧酸
[化61]
使用4-乙醯氧基-2,6-二甲基苯甲酸替代藉由國際公開第2019/003143號說明書中記載之方法而製造之1-(4-氟-3-硝基苯基)環丙烷-1-羧酸甲酯(CAS No.2260554-65-0)、參考例1中製造之化合物,進行與參考例6→參考例2→參考例3→參考例4→實施例1→實施例9→實施例2同樣之操作,藉此獲得具有以下之物性值之標題化合物。
HPLC保持時間(分鐘):1.09;
MS (ESI, Pos., 20V) : 472 (M+H)+
;1
H-NMR (DMSO-d6
) : δ 1.12 - 1.31, 1.38 - 1.54, 1.61, 1.71 - 1.86, 2.32, 3.27 - 3.47, 3.87, 4.03, 6.68, 7.26, 7.36, 7.43, 11.64, 12.42。
實施例 16 : 2-[4- 氯 -3-({2,6- 二甲基 -4-[2-( 㗁烷 -2- 基 ) 乙氧基 ] 苯 -1- 硫代羰基 } 胺基 ) 苯基 ]-2- 甲基丙酸甲酯
[化62]
使用4-乙醯氧基-2,6-二甲基苯甲酸替代藉由Bioorganic Medicinal Chemistry, 2011, vol. 19, 6935-6948中記載之方法而製造之2-(3-胺基-4-氯苯基)-2-甲基丙酸甲酯(CAS No.343326-75-0)與參考例1中製造之化合物,進行與參考例2→參考例3→參考例4→實施例1→實施例9同樣之操作,藉此獲得具有以下之物性值之標題化合物。1
H-NMR (DMSO-d6
) : δ 1.20 - 1.28, 1.42 - 1.50, 1.53, 1.58 - 1.65, 1.72 - 1.85, 2.36, 3.28 - 3.48, 3.61, 3.85 - 3.90, 4.00 - 4.08, 6.68, 7.35, 7.43, 7.58, 11.75。
實施例 17 : 2-{4- 氯 -3-[({2,6- 二甲基 -4-[2-( 四氫 -2H- 吡喃 -2- 基 ) 乙氧基 ] 苯基 } 硫代羰基 ) 胺基 ] 苯基 }-2- 甲基丙酸
[化63]
使用實施例16中製造之化合物,進行與實施例2同樣之操作,藉此獲得具有以下之物性值之標題化合物。
HPLC保持時間(分鐘):1.14;
MS (ESI, Pos., 20V) : 490 (M+H)+
;1
H-NMR (DMSO-d6
) : δ 1.20 - 1.25, 1.43 - 1.49, 1.49, 1.58 - 1.65, 2.36, 3.26 - 3.48, 3.77, 4.00 - 4.08, 6.68, 7.38, 7.46, 7.58, 11.74, 12.57。
實施例 18 : 2-{4- 氯 -3-[(2,6- 二甲基 -4-{2-[(2S)- 㗁烷 -2- 基 ] 乙氧基 } 苯 -1- 硫代羰基 ) 胺基 ] 苯基 }-2- 甲基丙酸甲酯、及 2-{4- 氯 -3-[(2,6- 二甲基 -4-{2-[(2R)- 㗁烷 -2- 基 ] 乙氧基 } 苯 -1- 硫代羰基 ) 胺基 ] 苯基 }-2- 甲基丙酸甲酯
使用實施例16中製造之化合物,藉由超臨界流體層析法(SFC)進行化學拆分,藉此獲得具有以下之物性值之標題化合物。
分離條件 管柱:CHIRAL PAK IC 5 μm 20 mm×250(Daicel公司製造);CO2
:(乙酸乙酯/甲醇=9/1)=78/22實施例 18-1 : ( 第一波峰 )
SFC保持時間(分鐘):3.69(CHIRAL PAK IC 5 μm 20 mm×250(Daicel公司製造);CO2
:(乙酸乙酯/甲醇=9:1)=78:22)實施例 18-2 : ( 第二波峰 )
SFC保持時間(分鐘):5.32(CHIRAL PAK IC 5 μm 20 mm×250(Daicel公司製造);CO2
:(乙酸乙酯/甲醇=9:1)=78:22)
實施例 19 : 2-{4- 氯 -3-[(2,6- 二甲基 -4-{2-[(2S)- 㗁烷 -2- 基 ] 乙氧基 } 苯 -1- 硫代羰基 ) 胺基 ] 苯基 }-2- 甲基丙酸、及 2-{4- 氯 -3-[(2,6- 二甲基 -4-{2-[(2R)- 㗁烷 -2- 基 ] 乙氧基 } 苯 -1- 硫代羰基 ) 胺基 ] 苯基 }-2- 甲基丙酸
使用實施例18-1或實施例18-2中所得之化合物,進行與實施例2同樣之操作,藉此獲得具有以下之物性值之標題化合物。實施例 19-1 : ( 使用實施例 18-1 中製造之化合物所製造之化合物 )
HPLC保持時間(分鐘):1.14;
MS (ESI, Pos., 20V) : 490 (M+H)+
;1
H-NMR (DMSO-d6
) : δ 1.20 - 1.25, 1.43 - 1.49, 1.49, 1.58 - 1.65, 2.36, 3.26 - 3.48, 3.77, 4.00 - 4.08, 6.68, 7.38, 7.46, 7.58, 11.74, 12.57。實施例 19-2 : ( 使用實施例 18-2 中製造之化合物所製造之化合物 )
HPLC保持時間(分鐘):1.14;
MS (ESI, Pos., 20V) : 490 (M+H)+
;1
H-NMR (DMSO-d6
) : δ 1.20 - 1.25, 1.43 - 1.49, 1.49, 1.58 - 1.65, 2.36, 3.26 - 3.48, 3.77, 4.00 - 4.08, 6.68, 7.38, 7.46, 7.58, 11.74, 12.57。
實施例 20 : 2-{3-[({2,6- 二甲基 -4-[2-( 四氫 -2H- 吡喃 -2- 基 ) 乙氧基 ] 苯基 } 硫代羰基 ) 胺基 ]-4- 氟苯基 }-2- 甲基丙酸
[化64]
使用4-乙醯氧基-2,6-二甲基苯甲酸替代利用國際公開第2018/116107號說明書中記載之方法而製造之2-(4-氟-3-硝基苯基)-2-甲基丙酸甲酯與參考例1中製造之化合物,進行與參考例6→參考例2→參考例3→參考例4→實施例1→實施例9→實施例2同樣之操作,藉此獲得具有以下之物性值之標題化合物。
HPLC保持時間(分鐘):1.09;
MS (ESI, Pos., 20V) : 474 (M+H)+
;1
H-NMR (DMSO-d6
) : δ 1.25, 1.41 - 1.48, 1.49, 1.62, 1.71 - 1.85, 2.31, 3.32, 3.43, 3.87, 3.99 - 4.08, 6.68, 7.31, 7.38, 7.44, 11.65, 12.51。
實施例 21 : 2-(4- 氯 -3-{[(2,6- 二甲基 -4-{2-[(2R)- 四氫 -2H- 吡喃 -2- 基 ] 乙氧基 } 苯基 ) 硫代羰基 ] 胺基 } 苯基 ) 丙酸
[化65]
於0℃下向實施例11-1中製造之化合物(1200 mg)之二氯甲烷(25 mL)溶液中添加DIPEA(2.2 mL)及氯化甲氧基甲烷(0.57 mL),將反應混合物於室溫下攪拌1小時。將反應液利用矽膠管柱層析法(己烷:乙酸乙酯=95:5→35:65)進行純化,藉此獲得粗純化物(1300 mg)。向該粗純化物之二甲基乙醯胺(10 mL)溶液中添加碳酸銫(4.1 g)及碘化甲烷(0.78 mL),將反應混合物於35℃下攪拌16小時。將反應混合物冷卻至室溫後,注入氯化銨水溶液,利用第三丁基甲醚萃取2次,將有機層利用飽和食鹽水洗淨,利用無水硫酸鈉乾燥後進行減壓濃縮。將所得之殘渣利用矽膠管柱層析法(己烷:乙酸乙酯=90:10→0:100)進行純化,藉此獲得粗純化物(410 mg)。向該粗純化物之二㗁烷(10 mL)溶液中添加5 mol/L鹽酸水溶液(5 mL),將反應混合物於室溫下攪拌1小時。將反應混合物利用第三丁基甲醚萃取2次,將有機層利用飽和食鹽水洗淨,利用無水硫酸鈉乾燥後進行減壓濃縮。將所得之殘渣利用矽膠管柱層析法(己烷:乙酸乙酯=90:10→0:100)進行純化,藉此獲得粗純化物(320 mg)。向該粗純化物之四氫呋喃(4 mL)溶液中添加甲醇(4 mL)與2 mol/L氫氧化鈉水溶液(4 mL),將反應混合物於室溫下攪拌3小時。向反應混合物中添加2 mol/L鹽酸水溶液,利用第三丁基甲醚萃取2次,將有機層利用飽和食鹽水洗淨,利用無水硫酸鈉乾燥後進行減壓濃縮。將所得之殘渣利用矽膠管柱層析法(己烷:乙酸乙酯=90:10→0:100)進行純化,藉此獲得具有以下之物性值之標題化合物(275 mg)。
HPLC保持時間(分鐘):1.10;
MS (ESI, Pos., 20V) : 476 (M+H)+
;1
H-NMR (CDCl3
) : δ 0.78 - 0.84, 1.30 - 1.90, 2.17 - 2.25, 2.39, 3.39 - 3.60, 3.90 - 4.12, 4.54, 6.37, 6.52 - 6.65, 7.01 - 7.04, 7.25 - 7.30, 7.42 - 7.45, 8.71, 8.88, 9.70。
實施例 22 : [4- 氯 -3-({[4-(2- 環己基乙氧基 )-2,6- 二甲基苯基 ] 硫代羰基 } 胺基 ) 苯基 ] 乙酸鈉
[化66]
向實施例10-1中製造之化合物(60 mg)之二㗁烷(2 mL)溶液中添加1 mol/L氫氧化鈉水溶液(0.13 mL)後進行冷凍乾燥,藉此獲得具有以下之物性值之標題化合物(49 mg)。
HPLC保持時間(分鐘):1.38;
MS (ESI, Pos., 20V) : 460 (M+H-Na)+
;1
H-NMR (DMSO-d6
) : δ 0.87 - 1.02, 1.10 - 1.28, 1.47, 1.67 - 1.79, 2.36, 3.26, 3.99, 6.65, 7.12 - 7.28, 7.38, 11.70。
[藥理實施例]生物學實施例 1 :使用人 DP 受體表現細胞之 DP 受體拮抗活性之測定
於DP受體拮抗活性之測定中,使用cAMP-HTRF kit(Sceti Medical Lab,62AM6PEJ)。以10 μL/孔向384孔板中添加製備成各種濃度之本發明化合物及前列腺素D2(最終濃度10 nmol/L)。使人DP受體表現細胞於含有2 μmoL/L之雙氯芬酸及1 mmol/L之IBMX(3-異丁基-1-甲基黃嘌呤)之磷酸緩衝液中懸浮,以成為5000細胞/10 μL/孔之方式進行播種。細胞播種後於室溫下培養1小時。其後,依據測定套組之方法,添加anti-cAMP Cryptate conjugate及cAMP-d2溶液,於室溫下培養1小時後,對樣品中之cAMP濃度進行定量。
本發明化合物之DP受體拮抗作用之強度係表示為由對因10 nmol/L前列腺素D2刺激而增加之cAMP產生量之抑制率算出之IC50
值(將本發明化合物非存在下之cAMP產生量抑制50%所需之本發明化合物之濃度)。於表1中表示本發明化合物之DP受體拮抗活性。
[表1]
本發明化合物對DP受體顯示強力之拮抗活性。
實施例編號 | DP拮抗活性 IC50 (μM) |
2-1 | 0.034 |
4 | 0.058 |
4-1 | 0.011 |
5 | 0.010 |
7 | 0.016 |
8 | 0.0037 |
10 | 0.0096 |
10-1 | 0.0017 |
10-4 | 0.0051 |
12 | 0.0048 |
20 | 0.035 |
21 | 0.0078 |
藥物動態試驗 1 :腦脊髓液 ( 以下稱為 CSF) 中之本發明化合物濃度測定
(1)CSF採取
混合5個受驗物質,以各受驗物質之投予量成為3 mg/5 mL/kg之方式製備受驗物質溶液。介質使用5%DMSO 20%Kolliphor HS15/丙二醇(7:3)。對自Charles River Laboratories Japan購入之雄性之8~10週齡之Wistar大鼠經口投予受驗物質溶液。投予3小時後,對大鼠施加麻醉,藉由小腦延髓池穿刺(cisternal puncture)採取CSF。藉由用於採取之注射器採取與CSF等量之乙醇(wako)進行內部清洗,藉此回收吸附於注射器之化合物。
(2)測定
使用Candesartan(TRC)作為內部標準物質,向所得之CSF樣品10 μL中添加乙腈40 μL、含有Candesartan之乙腈/乙醇(7:3)160 μL進行攪拌。為了製作校準曲線,向血漿10 μL中添加化合物溶液40 μL、含有Candesartan之乙腈/乙醇(7:3)160 μL進行攪拌。將各溶液之全量移至除蛋白用濾板進行抽吸過濾。將所得之濾液利用乙腈/水(1:1)適當稀釋,用於測定。於測定中,分別以同一基質製備校準曲線用標準試樣,同樣地進行分析。測定係於以下之條件下進行。
液相層析系統:Prominence UFLCXR
(島津製作所)、
管柱:Shim-pack XR-ODSII 2.0 mm ID×75 mm(島津製作所)、
管柱溫度:40℃、
流動相:A:0.2%甲酸5 mmol/L乙酸銨水溶液、B:乙腈、
梯度程式:
時間(流動相B(%)):0分鐘(10)→1.5分鐘(90)→3.0分鐘(90)→3.1分鐘(10)→4分鐘(10)、
流量:0.5 mL/min
質量分析系統:API4000、API5000(AB SCIEX)
(3)分析
使用分析軟體Analyst ver. 1.5.2(AB SCIEX),由校準曲線用標準試樣之測定中所得之波峰面積比(受驗物質之波峰面積/內部標準物質之波峰面積)算出回歸方程式。亦對測定試樣求出波峰面積比,代入至回歸方程式算出定量值。於平均值及標準偏差之算出中,未達定量下限之點數計算為0。
將結果示於表2。
[表2]
作為比較化合物,使用先前技術文獻之專利文獻2中之實施例13-24中記載之化合物,測定CSF中化合物濃度,結果為4.8 ng/mL。本發明化合物之CSF中化合物濃度高於比較化合物,顯示良好之中樞移行性。
實施例編號 | CSF中化合物濃度(ng/mL) |
4-1 | 29 |
7 | 45 |
8 | 28 |
10 | 43 |
10-1 | 36 |
10-2 | 55 |
10-4 | 34 |
12 | 48 |
20 | 52 |
21 | 66 |
生物學實施例 2 :正常大鼠覺醒時間延長作用
將慢性電極置放於大鼠之腦及頸部肌肉內,製作能夠測定腦波及肌電圖之大鼠。於一週以上之恢復期間後,於遮斷了聲音及電氣雜訊之屏蔽箱內將大鼠與生物體信號放大裝置連接。於測定籠內使之適應1小時以上後,對大鼠單次經口投予各種用量之本發明化合物,記錄經口投予後6小時之腦波及肌電圖。測定結束後之大鼠每次均放回至飼養籠,介質及各化合物之評價係設置一週以上之停藥期間而實施。
所記錄之腦波及肌電圖係使用SleepSign Ver. 3進行分析,並分割成每個10秒之時期(epoch),以腦波及肌電圖之特徵、以及腦波之各頻率成分之圖譜分析結果為參考,階段判定為覺醒・非快速動眼睡眠・快速動眼睡眠之任一者。階段判定於確認到高振幅之肌電圖之情形時判定為「覺醒」,於確認到高振幅慢波及低振幅之肌電圖之情形時判定為「非快速動眼睡眠」,於確認到包含θ波成分之低振幅之腦波及低振幅之肌電圖之情形時判定為「快速動眼睡眠」。因雜訊等而難以階段判定之時期(epoch)係依據前一時期(epoch)之判定結果。
判定睡眠・覺醒狀態後,將本發明化合物投予群之投予後6小時之總覺醒時間與介質投予群之投予後6小時之總覺醒時間的差作為覺醒時間延長作用之指標來表示。
對本發明化合物之覺醒時間延長作用進行評價,結果例如實施例化合物8及實施例化合物12係以3 mg/kg之用量分別顯示48分鐘及60分鐘之覺醒時間延長作用,顯示出本發明化合物作為睡眠覺醒障礙治療劑有用。
[製劑例]
將本發明中使用之代表性之製劑例示於以下。
將{4-氯-3-[(2,6-二甲基-4-{2-[(2R)-㗁烷-2-基]乙氧基}苯-1-硫代羰基)胺基]苯基}乙酸(100 g)、羧甲基纖維素鈣(20 g)、硬脂酸鎂(10 g)及微結晶纖維素(870 g)藉由常法混合後進行打錠,藉此獲得一錠中含有10 mg之活性成分之錠劑約1萬錠。
[產業上之可利用性]
本發明化合物具有強力之DP受體拮抗活性,且具有優異之中樞移行性,故而作為DP受體介導性疾病、尤其是睡眠覺醒障礙之預防及/或治療劑有用。
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JP2020502189A (ja) | 2016-12-20 | 2020-01-23 | グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドGlaxosmithkline Intellectual Property Development Limited | インドールアミン2,3−ジオキシゲナーゼのモジュレーター |
JP6533249B2 (ja) | 2017-04-21 | 2019-06-19 | 山佐株式会社 | 遊技機用基板ケースの取り付け構造及び遊技機 |
US20210139467A1 (en) | 2017-06-28 | 2021-05-13 | Glaxosmithkline Intellectual Property Development Limited | Modulators of indoleamine 2,3-dioxygenase |
BR112021005260A2 (pt) | 2018-09-20 | 2021-06-15 | Ono Pharmaceutical Co., Ltd. | antagonista de dp |
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2019
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- 2019-09-19 WO PCT/JP2019/036725 patent/WO2020059790A1/ja active Application Filing
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- 2019-09-19 CA CA3113210A patent/CA3113210A1/en active Pending
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- 2019-09-19 US US17/276,284 patent/US11319296B2/en active Active
- 2019-09-19 TW TW111143026A patent/TWI822457B/zh active
- 2019-09-19 JP JP2020548589A patent/JP7021709B2/ja active Active
- 2019-09-19 IL IL310383A patent/IL310383A/en unknown
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- 2019-09-19 CN CN201980061636.8A patent/CN112739680A/zh active Pending
- 2019-09-19 TW TW108133822A patent/TWI784199B/zh active
- 2019-09-19 MX MX2021003131A patent/MX2021003131A/es unknown
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- 2021-03-12 PH PH12021550549A patent/PH12021550549A1/en unknown
- 2021-03-19 ZA ZA2021/01887A patent/ZA202101887B/en unknown
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2022
- 2022-01-13 JP JP2022003838A patent/JP7338711B2/ja active Active
- 2022-03-15 US US17/695,796 patent/US20220204468A1/en active Pending
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CN100378083C (zh) * | 2002-03-19 | 2008-04-02 | 小野药品工业株式会社 | 羧酸化合物和含有所述化合物作为活性成分的药物制剂 |
TW200524886A (en) * | 2003-09-17 | 2005-08-01 | Ono Pharmaceutical Co | Carboxylic acid compound and pharmaceutical composition containg same as active ingredient |
WO2005080367A1 (en) * | 2004-02-12 | 2005-09-01 | Pharmagene Laboratories Limited | Ep2 receptor agonists |
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US20220204468A1 (en) | 2022-06-30 |
MX2021003131A (es) | 2021-05-14 |
KR102425709B1 (ko) | 2022-07-28 |
CA3113210A1 (en) | 2020-03-26 |
KR20220107330A (ko) | 2022-08-02 |
JP2022058610A (ja) | 2022-04-12 |
IL310383A (en) | 2024-03-01 |
EP3854781A4 (en) | 2022-02-23 |
IL281433A (en) | 2021-04-29 |
US11319296B2 (en) | 2022-05-03 |
BR112021005260A2 (pt) | 2021-06-15 |
TW202308986A (zh) | 2023-03-01 |
WO2020059790A1 (ja) | 2020-03-26 |
KR20210065944A (ko) | 2021-06-04 |
CN112739680A (zh) | 2021-04-30 |
JPWO2020059790A1 (ja) | 2021-09-02 |
AU2019341082A1 (en) | 2021-04-15 |
JP7338711B2 (ja) | 2023-09-05 |
TW202023535A (zh) | 2020-07-01 |
PH12021550549A1 (en) | 2022-02-14 |
US20220033371A1 (en) | 2022-02-03 |
EP3854781A1 (en) | 2021-07-28 |
JP7021709B2 (ja) | 2022-02-17 |
ZA202101887B (en) | 2022-10-26 |
TWI822457B (zh) | 2023-11-11 |
SG11202102566YA (en) | 2021-04-29 |
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