JP2011515359A - 治療用トリアゾールアミド誘導体 - Google Patents
治療用トリアゾールアミド誘導体 Download PDFInfo
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- JP2011515359A JP2011515359A JP2011500176A JP2011500176A JP2011515359A JP 2011515359 A JP2011515359 A JP 2011515359A JP 2011500176 A JP2011500176 A JP 2011500176A JP 2011500176 A JP2011500176 A JP 2011500176A JP 2011515359 A JP2011515359 A JP 2011515359A
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- JP
- Japan
- Prior art keywords
- compound
- methyl
- triazole
- carboxamide
- pharmaceutically acceptable
- 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.)
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- -1 triazole amide Chemical class 0.000 title abstract description 40
- 230000001225 therapeutic effect Effects 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 18
- 208000011117 substance-related disease Diseases 0.000 claims abstract description 13
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 199
- 125000000217 alkyl group Chemical group 0.000 claims description 68
- 150000003839 salts Chemical class 0.000 claims description 57
- 125000005843 halogen group Chemical group 0.000 claims description 39
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 33
- 125000003545 alkoxy group Chemical group 0.000 claims description 30
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 24
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 125000004995 haloalkylthio group Chemical group 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000004741 (C1-C6) haloalkylsulfonyl group Chemical group 0.000 claims description 9
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 8
- UNAQKDVUSXFMHP-UHFFFAOYSA-N 1-(3,4-dimethylphenyl)-5-methyl-n-(2-methylpyrimidin-4-yl)triazole-4-carboxamide Chemical compound CC1=C(C(=O)NC=2N=C(C)N=CC=2)N=NN1C1=CC=C(C)C(C)=C1 UNAQKDVUSXFMHP-UHFFFAOYSA-N 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 125000004692 haloalkylcarbonyl group Chemical group 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 claims description 7
- CWVSBXKZRRZIRB-UHFFFAOYSA-N 1-(3,4-difluorophenyl)-5-methyl-n-(2-methylpyridin-4-yl)triazole-4-carboxamide Chemical compound CC1=C(C(=O)NC=2C=C(C)N=CC=2)N=NN1C1=CC=C(F)C(F)=C1 CWVSBXKZRRZIRB-UHFFFAOYSA-N 0.000 claims description 7
- YENHHVXIBSYOJI-UHFFFAOYSA-N 1-(3-chloro-4-fluorophenyl)-5-methyl-n-(2-methylpyridin-4-yl)triazole-4-carboxamide Chemical compound CC1=C(C(=O)NC=2C=C(C)N=CC=2)N=NN1C1=CC=C(F)C(Cl)=C1 YENHHVXIBSYOJI-UHFFFAOYSA-N 0.000 claims description 7
- HNGHMRKFNMUTKY-UHFFFAOYSA-N 1-(3-chloro-4-fluorophenyl)-5-methyl-n-(2-methylpyrimidin-4-yl)triazole-4-carboxamide Chemical compound CC1=C(C(=O)NC=2N=C(C)N=CC=2)N=NN1C1=CC=C(F)C(Cl)=C1 HNGHMRKFNMUTKY-UHFFFAOYSA-N 0.000 claims description 7
- OUESNQHVZULBRN-UHFFFAOYSA-N 1-(4-fluorophenyl)-5-methyl-n-(2-methylpyridin-4-yl)triazole-4-carboxamide Chemical compound CC1=C(C(=O)NC=2C=C(C)N=CC=2)N=NN1C1=CC=C(F)C=C1 OUESNQHVZULBRN-UHFFFAOYSA-N 0.000 claims description 7
- IZOZFVDZTRZSBM-UHFFFAOYSA-N 1-(4-fluorophenyl)-5-methyl-n-(2-methylpyrimidin-4-yl)triazole-4-carboxamide Chemical compound CC1=C(C(=O)NC=2N=C(C)N=CC=2)N=NN1C1=CC=C(F)C=C1 IZOZFVDZTRZSBM-UHFFFAOYSA-N 0.000 claims description 7
- IKEMBYLUJQUGPG-UHFFFAOYSA-N 1-(4-fluorophenyl)-5-methyl-n-(6-methylpyridin-2-yl)triazole-4-carboxamide Chemical compound CC1=C(C(=O)NC=2N=C(C)C=CC=2)N=NN1C1=CC=C(F)C=C1 IKEMBYLUJQUGPG-UHFFFAOYSA-N 0.000 claims description 7
- VNGHLYCXTIBZGU-UHFFFAOYSA-N 1-(4-fluorophenyl)-n-(6-fluoropyridin-2-yl)-5-methyltriazole-4-carboxamide Chemical compound CC1=C(C(=O)NC=2N=C(F)C=CC=2)N=NN1C1=CC=C(F)C=C1 VNGHLYCXTIBZGU-UHFFFAOYSA-N 0.000 claims description 7
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 claims description 7
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 claims description 7
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 claims description 7
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 claims description 7
- 229940125904 compound 1 Drugs 0.000 claims description 7
- 229940125782 compound 2 Drugs 0.000 claims description 7
- 229940125810 compound 20 Drugs 0.000 claims description 7
- 229940126086 compound 21 Drugs 0.000 claims description 7
- 229940126208 compound 22 Drugs 0.000 claims description 7
- 229940125846 compound 25 Drugs 0.000 claims description 7
- 229940125851 compound 27 Drugs 0.000 claims description 7
- 229940127204 compound 29 Drugs 0.000 claims description 7
- YKANAHJYEVFARM-UHFFFAOYSA-N n-(6-chloropyridin-2-yl)-1-(4-fluorophenyl)-5-methyltriazole-4-carboxamide Chemical compound CC1=C(C(=O)NC=2N=C(Cl)C=CC=2)N=NN1C1=CC=C(F)C=C1 YKANAHJYEVFARM-UHFFFAOYSA-N 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 6
- 150000001408 amides Chemical group 0.000 claims description 6
- XDWBMMTYGGQYRY-UHFFFAOYSA-N n-(3-chlorophenyl)-5-methyl-1-(2-methylphenyl)triazole-4-carboxamide Chemical compound CC1=C(C(=O)NC=2C=C(Cl)C=CC=2)N=NN1C1=CC=CC=C1C XDWBMMTYGGQYRY-UHFFFAOYSA-N 0.000 claims description 6
- OVBIYEALZAROPF-UHFFFAOYSA-N n-(3-chlorophenyl)-5-methyl-1-phenyltriazole-4-carboxamide Chemical compound CC1=C(C(=O)NC=2C=C(Cl)C=CC=2)N=NN1C1=CC=CC=C1 OVBIYEALZAROPF-UHFFFAOYSA-N 0.000 claims description 6
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 claims description 5
- 229940125877 compound 31 Drugs 0.000 claims description 5
- YXVDIAOSTBVVQR-UHFFFAOYSA-N n-(3-chlorophenyl)-1-(4-fluorophenyl)-5-methyltriazole-4-carboxamide Chemical compound CC1=C(C(=O)NC=2C=C(Cl)C=CC=2)N=NN1C1=CC=C(F)C=C1 YXVDIAOSTBVVQR-UHFFFAOYSA-N 0.000 claims description 5
- SJLXRWDUNZIXQY-UHFFFAOYSA-N n-(3-chlorophenyl)-1-(5-fluoropyridin-2-yl)-5-methyltriazole-4-carboxamide Chemical compound CC1=C(C(=O)NC=2C=C(Cl)C=CC=2)N=NN1C1=CC=C(F)C=N1 SJLXRWDUNZIXQY-UHFFFAOYSA-N 0.000 claims description 5
- TUVIVDCYBDOOJB-UHFFFAOYSA-N n-(3-chlorophenyl)-5-methyl-1-(3-methylsulfanylphenyl)triazole-4-carboxamide Chemical compound CSC1=CC=CC(N2C(=C(C(=O)NC=3C=C(Cl)C=CC=3)N=N2)C)=C1 TUVIVDCYBDOOJB-UHFFFAOYSA-N 0.000 claims description 5
- ANYGFFVLRXMIKE-UHFFFAOYSA-N n-(3-fluorophenyl)-1-(4-fluorophenyl)-5-methyltriazole-4-carboxamide Chemical compound CC1=C(C(=O)NC=2C=C(F)C=CC=2)N=NN1C1=CC=C(F)C=C1 ANYGFFVLRXMIKE-UHFFFAOYSA-N 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- SPVSQGFBJVELLX-UHFFFAOYSA-N n-(3-cyanophenyl)-1-(4-fluorophenyl)-5-methyltriazole-4-carboxamide Chemical compound CC1=C(C(=O)NC=2C=C(C=CC=2)C#N)N=NN1C1=CC=C(F)C=C1 SPVSQGFBJVELLX-UHFFFAOYSA-N 0.000 claims description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 2
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- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 2
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- GMMAPXRGRVJYJY-UHFFFAOYSA-J tetrasodium 4-acetamido-5-hydroxy-6-[[7-sulfonato-4-[(4-sulfonatophenyl)diazenyl]naphthalen-1-yl]diazenyl]naphthalene-1,7-disulfonate Chemical compound [Na+].[Na+].[Na+].[Na+].OC1=C2C(NC(=O)C)=CC=C(S([O-])(=O)=O)C2=CC(S([O-])(=O)=O)=C1N=NC(C1=CC(=CC=C11)S([O-])(=O)=O)=CC=C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 GMMAPXRGRVJYJY-UHFFFAOYSA-J 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229960002784 thioridazine Drugs 0.000 description 1
- PBJUNZJWGZTSKL-MRXNPFEDSA-N tiagabine Chemical compound C1=CSC(C(=CCCN2C[C@@H](CCC2)C(O)=O)C2=C(C=CS2)C)=C1C PBJUNZJWGZTSKL-MRXNPFEDSA-N 0.000 description 1
- 229960001918 tiagabine Drugs 0.000 description 1
- 208000016686 tic disease Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 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
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 229960002324 trifluoperazine Drugs 0.000 description 1
- ZEWQUBUPAILYHI-UHFFFAOYSA-N trifluoperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 ZEWQUBUPAILYHI-UHFFFAOYSA-N 0.000 description 1
- 229960002431 trimipramine Drugs 0.000 description 1
- 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 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229960000607 ziprasidone Drugs 0.000 description 1
- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
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- A—HUMAN NECESSITIES
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Abstract
Description
R1はフェニルまたは6員単環式ヘテロアリールであり、これらはそれぞれ、ハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシ、シアノ、C1−6アルキルチオ、C1−6ハロアルキルチオ、C1−6アルキルスルホニル、C1−6ハロアルキルスルホニル、C1−6アルキルカルボニルおよびC1−6ハロアルキルカルボニルから独立に選択される1、2または3個の基で置換されていてもよく;
R2はハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシまたはC1−4アルコキシC1−4アルキルであり;
YはOまたはSであり;
Aは6員複素芳香環またはベンゼン環のいずれかであり;ここで、XはCH、N、SまたはOであり;Aが6員複素芳香環である場合には、この環はN、OおよびSから独立に選択される全部で1〜4個のヘテロ原子を含んでもよく;
R3はハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシ、C1−4アルコキシC1−4アルキルまたはシアノであり;
R4はハロであり;かつ
nは0または1である]
の化合物またはその薬学上許容される塩を提供する。
を有するピリジン環である。
1−(4−フルオロフェニル)−5−メチル−N−(6−メチル−2−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物1);
1−(4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリミジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物2);
N−(3−クロロフェニル)−5−メチル−1−[3−(メチルチオ)フェニル]−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物4);
N−(3−クロロフェニル)−1−(2,5−ジフルオロフェニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物5);
N−(3−クロロフェニル)−5−メチル−1−フェニル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物6);
N−(3−クロロフェニル)−1−(4−フルオロフェニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物7);
N−(3−フルオロフェニル)−1−(4−フルオロフェニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物8);
N−(3−クロロフェニル)−5−メチル−1−(2−メチルフェニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物9);
N−(3−クロロフェニル)−1−(2−フルオロフェニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物10);
1−(3−クロロ−4−フルオロフェニル)−N−(3−フルオロフェニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物11);
N−(3−クロロフェニル)−1−(3−フルオロフェニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物13);
N−(3−クロロフェニル)−1−(3,4−ジメチルフェニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物14);
1−(4−フルオロフェニル)−N−(6−フルオロ−2−ピリジニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物20);
N−(6−クロロ−2−ピリジニル)−1−(4−フルオロフェニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物21);
1−(4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物22);
1−(3−クロロ−4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリミジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物25);
N−(3−シアノフェニル)−1−(4−フルオロフェニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物26);
1−(3,4−ジメチルフェニル)−5−メチル−N−(2−メチル−4−ピリミジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物27);
1−(3−クロロ−4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物28);
1−(3,4−ジフルオロフェニル)−5−メチル−N−(2−メチル−4−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物29);および
N−(3−クロロフェニル)−1−(5−フルオロ−2−ピリジニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物31);
またはこれらの化合物のいずれかの薬学上許容される塩から選択される。
1−(4−フルオロフェニル)−5−メチル−N−(6−メチル−2−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物1);
1−(4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリミジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物2);
1−(4−フルオロフェニル)−N−(6−フルオロ−2−ピリジニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物20);
N−(6−クロロ−2−ピリジニル)−1−(4−フルオロフェニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物21);
1−(4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物22);
1−(3−クロロ−4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリミジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物25);
1−(3,4−ジメチルフェニル)−5−メチル−N−(2−メチル−4−ピリミジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物27);
1−(3−クロロ−4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物28);および
1−(3,4−ジフルオロフェニル)−5−メチル−N−(2−メチル−4−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物29);
またはこれらの化合物のいずれかの薬学上許容される塩から選択される。
R1がフェニルまたは6員単環式ヘテロアリールであり、これらはそれぞれ、ハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシ、シアノ、C1−6アルキルチオ、C1−6ハロアルキルチオ、C1−6アルキルスルホニル、C1−6ハロアルキルスルホニル、C1−6アルキルカルボニルおよびC1−6ハロアルキルカルボニルから独立に選択される1または2個の基で置換されていてもよく;
R2がハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシまたはC1−4アルコキシC1−4アルキルであり;
YがOであり;
Aが6員複素芳香環であり;ここで、XはCH、N、SまたはOであり;Aが5または6員複素芳香環である場合には、この環はN、OおよびSから独立に選択される全部で1〜4個のヘテロ原子を含んでもよく;
R3がハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシ、C1−4アルコキシC1−4アルキルまたはシアノであり;
R4がハロであり;かつ
nが0または1である、
式(I)の化合物またはその塩を提供する。
を有するピリジン環である。
1−(4−フルオロフェニル)−5−メチル−N−(6−メチル−2−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物1);
1−(4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリミジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物2);
1−(4−フルオロフェニル)−N−(6−フルオロ−2−ピリジニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物20);
N−(6−クロロ−2−ピリジニル)−1−(4−フルオロフェニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物21);
1−(4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物22);
1−(3−クロロ−4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリミジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物25);
1−(3,4−ジメチルフェニル)−5−メチル−N−(2−メチル−4−ピリミジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物27);
1−(3−クロロ−4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物28);および
1−(3,4−ジフルオロフェニル)−5−メチル−N−(2−メチル−4−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物29);
またはこれらの化合物のいずれかの塩から選択される。
R1が、ハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシ、シアノ、C1−6アルキルチオ、C1−6ハロアルキルチオ、C1−6アルキルスルホニル、C1−6ハロアルキルスルホニル、C1−6アルキルカルボニルおよびC1−6ハロアルキルカルボニルから独立に選択される1または2個の基で置換されていてもよい6員単環式ヘテロアリールであり;
R2がハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシまたはC1−4アルコキシC1−4アルキルであり;
YがOであり;
Aが6員複素芳香環またはベンゼン環のいずれかであり;ここで、XはCH、N、SまたはOであり;Aが6員複素芳香環である場合には、この環はN、OおよびSから独立に選択される全部で1〜4個のヘテロ原子を含んでもよく;
R3がハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシ、C1−4アルコキシC1−4アルキルまたはシアノであり;
R4がハロであり;かつ
nが0または1である、
式(I)の化合物またはその塩を提供する。
を有するピリジン環である。
いくつかの本発明の化合物の製法を以下に記載する。
Cmp − 化合物
DCM − ジクロロメタン
DIPEA − ジイソプロピルエチルアミン
DMSO − ジメチルスルホキシド
EtOAc − 酢酸エチル
HATU − o−(7−アザベンゾトリアゾール−1−イル)−n,n,n’,n’−テトラメチルウロニウムヘキサフルオロホスフェート
HOAt − 1−ヒドロキシ−7−アザベンゾトリアゾール
HPLC − 高速液体クロマトグラフィー
MDAP − 質量スペクトル指示分取HPLC精製
NMP − N−メチル−2−ピロリドン
NMR − 核磁気共鳴
TEA − トリエチルアミン
1H NMRスペクトルは、a)5mm QNPプローブを備えたBruker Avance 400MHz装置、b)27℃、5mm QNPプローブを備えたBruker DPX−250 250MHz装置、またはc)Varian 300MHzのいずれかで行った。データは、内部参照としてテトラメチルシラン(TMS)を用い、ジュウテリオ−クロロホルム、D6−ジメチルスルホキシドまたはD4−ジュウテリオ−メタノールにて記録した。化学シフトはTMSに対するparts per million(ppm)で示した。多重度はs(一重線)、d(二重線)、t(三重線)、dd(二重線−二重線)、ddd(二重線−二重線−二重線)、dt(二重線 三重線)、m(多重線)として表す。
いくつかの化合物はHPLC技術およびWaters(登録商標)ZQ質量分析計などの適当な質量分析計を組み込んだ質量指示自動精製システム(MDAP)を用いて精製した。
6−フルオロ−3−ピリジンアミン(2g、17.84mmol)をアセトニトリル(40ml)に溶解させ、この混合物を0℃まで冷却した。亜硝酸1,1−ジメチルエチル(3.18ml、26.8mmol)を0℃で加えた後、トリメチルシリルアジド(2.82ml、21.41mmol)を加え、この混合物を室温で5時間攪拌した。溶媒を蒸発させ、残渣をシリカゲルクロマトグラフィー(EtOAc−ヘプタン)により精製し、標題化合物を得た(72.1%)。1HNMR (DMSO, 400 MHz): 7.26 (1H dd), 7.83 (1H, m), 8.06 (1H, m).
3−クロロ−4−フルオロフェニルアジド(中間体12)(618mg、3.60mmol)をトルエン(6ml)に溶解させた。2−ブチン酸エチル(0.420ml、3.60mmol)を加え、この混合物を120℃で2日間攪拌した。この混合物を冷却したところで、DCMで溶出するシリカゲルクロマトグラフィー(40M、Biotage SP1)により精製し、標題化合物(450mg、1.586mmol、収率44.0%)とその異性体1−(3−クロロ−4−フルオロフェニル)−4−メチル−1H−1,2,3−トリアゾール−5−カルボン酸エチル(373mg、1.315mmol、収率36.5%)の混合物を得た。1H NMR (500 MHz, アセトン) δppm 1.38 (t, J=7.12 Hz, 3 H) 2.61 (s, 3 H) 4.39 (q, J=7.09 Hz, 2 H) 7.64 (t, J=8.80 Hz, 1 H) 7.69 - 7.73 (m, 1 H) 7.90 (dd, J=6.45, 2.48 Hz, 1 H); ); UPLC-MS:0.82 mins; [MH+/-] =284.
室温にて、水(0.22ml)/DMSO(2ml)中、4−ヨード−1,2−ジメチルベンゼン(0.5g、2.155mmol)と2−ブチン酸エチル(0.250ml、2.155mmol)の混合物に、l−アスコルビン酸ナトリウム(0.043g、0.215mmol)、L−プロリン(0.050g、0.431mmol)、炭酸ナトリウム(0.046g、0.431mmol)、硫酸銅(II)五水和物(0.027g、0.108mmol)およびアジ化ナトリウム(0.168g、2.59mmol)を(同時に)加え、この混合物65℃で48時間加熱した。室温まで冷却したところで、この混合物をアンモニア水溶液(1ml)で急冷し、EtOAc(20ml)および水(20ml)を加えた。二層に分け、水相をEtOAc(3×30ml)で抽出した。総ての有機層を合わせ、水/ブライン(50ml)で繰り返し洗浄した。有機相を硫酸ナトリウムで乾燥させ、濾過し、溶媒を蒸発させて粗生成物を得、これをクロマトグラフィー(25Sシリカカラム、50/50酢酸エチル/イソヘキサン)により精製し、標題化合物を含有する7mgの不純な生成物を得た;MH+=260。
室温にて、水/DMSO(33μl/0.3ml)中、4−ヨード−1,2−ジメチルベンゼン(0.1g、0.431mmol)と2−ブチン酸エチル(0.050ml、0.431mmol)の混合物に、l−アスコルビン酸ナトリウム(8.54mg、0.043mmol)、L−プロリン(9.92mg、0.086mmol)、炭酸ナトリウム(9.13mg、0.086mmol)、硫酸銅(II)五水和物(5.38mg、0.022mmol)、アジ化ナトリウム(0.034g、0.517mmol)を同時に加え、この混合物をマイクロ波リアクターにて100℃で40分間、次いで120℃で1時間加熱した。この混合物をアンモニア水溶液(1ml)で急冷し、EtOAc(10ml)および水(10ml)を加えた。二層に分け、水相をEtOAc(3×15ml)で抽出した。総ての有機層を合わせ、水/ブライン(20ml)で繰り返し洗浄した。有機相をNa2SO4で乾燥させ、濾過し、溶媒を蒸発させて粗生成物を得、これをMDAPにより精製し、標題化合物を含有する6mgの不純な生成物を得た;MH+=260。
MH+=332.9;1HNMR (300MHz CDCl3): d 9.781 (s, 1H), 8.727-8.7309 (d, 1H), 8.391-8.394 (d, 1H), 7.468-7.479 (m, 2H), 7.264-7.335 (m, 2H), 2.674 (s, 3H).
%)。
細胞の調製
アッセイを行う24時間前に、遺伝子スイッチ発現制御技術(Invitrogenにより供給)で操作されたヒトmGluR5受容体を含むチャイニーズハムスター卵巣(CHO)細胞を調製した。これらの細胞を、発現を可能とするよう0.1nMミフェリプリストンで誘導し、増殖培地を加えた。この増殖培地はDMEM(ダルベッコの改変イーグル培地)500ml(Gibcoにより供給−カタログ番号31166)、50ml透析FCS(ウシ胎児血清)(Gibcoにより供給−カタログ番号26400−044)、0.02mg/mlプロリン、0.25mg/mlハイグロマイシンおよび0.5mg/mlゼオシンを含んでなった。次に、この増殖培地の細胞を、Multidrop(ThermoFisherにより供給)を用いて384ウェル黒透明底プレートに、容量50μl中、10K細胞/ウェルの密度で分注した。これらのプレートを37℃でインキュベートし、集密度80%の単層を得た。
DMSO中10mM濃度の試験化合物を、384ウェル化合物プレート(Greinerにより供給)にて、Biomek FX(Beckman Coulterにより供給)を用いてDMSOでさらに希釈した。次に、各希釈液の1μlアリコートをさらな化合物プレートに移し、アッセイバッファーを最終量50μlとなるように加え、最終アッセイ濃度を11.8μMとした。このアッセイバッファーはHBSSと2.5Mプロベニシドからなった。
水中0.38Mグルタミン酸溶液を、濃度204mMとなるようにDMSOでさらに希釈した。16×11点濃度応答曲線(CRC)を、上限濃度204mMとしてDMSOで作製し、最終アッセイ濃度を1mMとし、1:4に連続希釈した。これはBiomek FX液体ハンドリングデバイスを用いて行った。CRCの1μlスタンプを作製した。使用前に50μlの化合物バッファーを加えた。
グルタミン酸CRCプレートに50μlの化合物バッファーを加えた。このプレートを、FLIPRを用い、2時間のせた細胞のプレートに加えた。蛍光の読み取りを行った。グルタミン酸のEC80濃度は、作製した4×EC50濃度を用いて算出した。EC80濃度のグルタミン酸溶液を化合物バッファーで作製し、384ウェルプレートに分注した(化合物バッファー単独を加えたカラム18は除く)。
Cybiwell液体ハンドリングデバイス(Cybioにより供給)を用い、10μlの試験化合物を細胞プレートに加えた。これらの細胞プレートを37℃で15分間インキュベートし、EC80のFLIPRを添加し、蛍光の読み取りを行った。各ウェルに関して作成した時間に対するカルシウムのプロフィールから、用量依存的な試験化合物による受容体の遮断が明らかである。XC50ソフトウエアを用いてデータを分析してCRCを得、これから効力およびpIC50を求めることができる。
細胞の調製
Tet On発現制御技術(Clontechにより供給)を用いたヒトmGluR5受容体を含むCHO細胞を調製した。これらの細胞をセルファクトリーで増殖させ、発現が可能なように10ng/mlデオキシサイクリンで誘導し、採取した後、使用に備えて、1mlアリコートとして−140℃にて低温保存した。
試験化合物はDMSO中3mMの濃度で調製した。これらの溶液を、Biomek FX液体ハンドリングデバイス(Beckman Coulterにより供給)を用い、384ウェル化合物プレート(Greinerにより供給)にて、DMSOで1:4に連続希釈した。アッセイで使用するため、このマスタープレートから0.5μl/ウェルのドータープレートをスタンプした。
水で100mMグルタミン酸溶液を作製した。これを10mMの濃度となるようにDMSOでさらに希釈した。DMSOで16×11点濃度応答曲線(CRC)を作成し、最終アッセイ濃度を1.66×10−4Mとし、Biomek FXを用いて1:3の連続希釈を行った。アッセイで使用するため、このプレートの0.5μlスタンプを作製した。
グルタミン酸CRCプレートをLumiluxにのせ、20μl/ウェルの希釈バッファーを加えた後、10μl/ウェルの負荷済み細胞懸濁液を加え、蛍光の読み取りを行った。グルタミン酸のEC80濃度は、作製した4×EC50濃度を用いて算出した。EC80溶液は希釈バッファーで作製し、Lumilux内のリザーバーに加えた。
lumiluxを用い、20μl/ウェルのバッファーおよび10μl/ウェルの細胞懸濁液を試験化合物に加えた。これらのプレートを室温で15分間インキュベートし、10μl/ウェルのEC80溶液を加え、蛍光の読み取りを行った。各ウェルに関して作成した時間に対する蛍光のプロフィールから、用量依存的な試験化合物による受容体の遮断が明らかであった。XC50ソフトウエアを用いてデータを分析してCRCを得、これから効力およびpIC50を求めることができる。
Claims (39)
- 治療に用いるための、式(I)の化合物またはその薬学上許容される塩:
R1はフェニルまたは6員単環式ヘテロアリールであり、これらはそれぞれ、ハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシ、シアノ、C1−6アルキルチオ、C1−6ハロアルキルチオ、C1−6アルキルスルホニル、C1−6ハロアルキルスルホニル、C1−6アルキルカルボニルおよびC1−6ハロアルキルカルボニルから独立に選択される1、2または3個の基で置換されていてもよく;
R2はハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシまたはC1−4アルコキシC1−4アルキルであり;
YはOまたはSであり;
Aは6員複素芳香環またはベンゼン環のいずれかであり;ここで、XはCH、N、SまたはOであり;Aが6員複素芳香環である場合には、この環はN、OおよびSから独立に選択される全部で1〜4個のヘテロ原子を含んでもよく;
R3はハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシ、C1−4アルコキシC1−4アルキルまたはシアノであり;
R4はハロであり;かつ
nは0または1である]。 - R1が、ハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシ、シアノ、C1−6アルキルチオ、C1−6ハロアルキルチオ、C1−6アルキルスルホニル、C1−6ハロアルキルスルホニル、C1−6アルキルカルボニルおよびC1−6ハロアルキルカルボニルから独立に選択される1または2個の基で置換されている、請求項1に記載の化合物またはその薬学上許容される塩。
- R1がフェニルまたはピリジルであり、これらはそれぞれ、ハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシ、C1−6アルキルチオおよびC1−6ハロアルキルチオから独立に選択される1または2個の基で置換されていてもよい、請求項1に記載の化合物またはその薬学上許容される塩。
- R2がC1−6アルキルまたはC1−4アルコキシC1−4アルキルである、請求項1〜3のいずれか一項に記載の化合物またはその薬学上許容される塩。
- YがOである、請求項1〜4のいずれか一項に記載の化合物またはその薬学上許容される塩。
- Aが6員複素芳香環であり;ここで、XがCHまたはNであり;この環が全部で1〜4個の窒素原子を含んでもよい、請求項1〜5のいずれか一項に記載の化合物またはその薬学上許容される塩。
- Aが6員複素芳香環であり;ここで、XがCHまたはNであり;この環が全部で1または2個の窒素原子を含む、請求項1〜6のいずれか一項に記載の化合物またはその薬学上許容される塩。
- Aがピリジン環である、請求項1〜7のいずれか一項に記載の化合物またはその薬学上許容される塩。
- R3がハロ、C1−6アルキル、C1−6ハロアルキルまたはシアノである、請求項1〜9のいずれか一項に記載の化合物またはその薬学上許容される塩。
- nが0である、請求項1〜10のいずれか一項に記載の化合物またはその薬学上許容される塩。
- 1−(4−フルオロフェニル)−5−メチル−N−(6−メチル−2−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物1);
1−(4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリミジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物2);
N−(3−クロロフェニル)−5−メチル−1−[3−(メチルチオ)フェニル]−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物4);
N−(3−クロロフェニル)−1−(2,5−ジフルオロフェニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物5);
N−(3−クロロフェニル)−5−メチル−1−フェニル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物6);
N−(3−クロロフェニル)−1−(4−フルオロフェニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物7);
N−(3−フルオロフェニル)−1−(4−フルオロフェニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物8);
N−(3−クロロフェニル)−5−メチル−1−(2−メチルフェニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物9);
N−(3−クロロフェニル)−1−(2−フルオロフェニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物10);
1−(3−クロロ−4−フルオロフェニル)−N−(3−フルオロフェニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物11);
N−(3−クロロフェニル)−1−(3−フルオロフェニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物13);
N−(3−クロロフェニル)−1−(3,4−ジメチルフェニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物14);
1−(4−フルオロフェニル)−N−(6−フルオロ−2−ピリジニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物20);
N−(6−クロロ−2−ピリジニル)−1−(4−フルオロフェニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物21);
1−(4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物22);
1−(3−クロロ−4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリミジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物25);
N−(3−シアノフェニル)−1−(4−フルオロフェニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物26);
1−(3,4−ジメチルフェニル)−5−メチル−N−(2−メチル−4−ピリミジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物27);
1−(3−クロロ−4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物28);
1−(3,4−ジフルオロフェニル)−5−メチル−N−(2−メチル−4−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物29);および
N−(3−クロロフェニル)−1−(5−フルオロ−2−ピリジニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物31);
から選択される、請求項1に記載の化合物、またはこれらの化合物のいずれかの薬学上許容される塩。 - 1−(4−フルオロフェニル)−5−メチル−N−(6−メチル−2−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物1);
1−(4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリミジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物2);
1−(4−フルオロフェニル)−N−(6−フルオロ−2−ピリジニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物20);
N−(6−クロロ−2−ピリジニル)−1−(4−フルオロフェニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物21);
1−(4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物22);
1−(3−クロロ−4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリミジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物25);
1−(3,4−ジメチルフェニル)−5−メチル−N−(2−メチル−4−ピリミジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物27);
1−(3−クロロ−4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物28);および
1−(3,4−ジフルオロフェニル)−5−メチル−N−(2−メチル−4−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物29);
から選択される、請求項1に記載の化合物、またはこれらの化合物のいずれかの薬学上許容される塩。 - 式(I)の化合物またはその薬学上許容される塩:
R1はフェニルまたは6員単環式ヘテロアリールであり、これらはそれぞれ、ハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシ、シアノ、C1−6アルキルチオ、C1−6ハロアルキルチオ、C1−6アルキルスルホニル、C1−6ハロアルキルスルホニル、C1−6アルキルカルボニルおよびC1−6ハロアルキルカルボニルから独立に選択される1または2個の基で置換されていてもよく;
R2はハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシまたはC1−4アルコキシC1−4アルキルであり;
YはOであり;
Aは6員複素芳香環であり;ここで、XはCH、N、SまたはOであり;Aが5または6員複素芳香環である場合には、この環はN、OおよびSから独立に選択される全部で1〜4個のヘテロ原子を含んでもよく;
R3はハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシ、C1−4アルコキシC1−4アルキルまたはシアノであり;
R4はハロであり;かつ
nは0または1である]。 - R1がフェニルまたはピリジルであり、これらはそれぞれ、ハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシ、C1−6アルキルチオおよびC1−6ハロアルキルチオから独立に選択される1または2個の基で置換されていてもよい、請求項14に記載の化合物またはその薬学上許容される塩。
- R2がC1−6アルキルまたはC1−4アルコキシC1−4アルキルである、請求項14または15に記載の化合物またはその薬学上許容される塩。
- R2がC1−6アルキルである、請求項16に記載の化合物またはその薬学上許容される塩。
- Aが6員複素芳香環であり;ここで、XがCHまたはNであり;この環が全部で1〜4個の窒素原子を含んでもよい、請求項14〜17のいずれか一項に記載の化合物またはその薬学上許容される塩。
- Aが6員複素芳香環であり;ここで、XがCHまたはNであり;この環が全部で1または2個の窒素原子を含む、請求項14〜18のいずれか一項に記載の化合物またはその薬学上許容される塩。
- Aがピリジン環である、請求項14〜19のいずれか一項に記載の化合物またはその薬学上許容される塩。
- R3がハロ、C1−6アルキル、C1−6ハロアルキルまたはシアノである、請求項14〜21のいずれか一項に記載の化合物またはその薬学上許容される塩。
- nが0である、請求項14〜22のいずれか一項に記載の化合物またはその薬学上許容される塩。
- 1−(4−フルオロフェニル)−5−メチル−N−(6−メチル−2−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物1);
1−(4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリミジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物2);
1−(4−フルオロフェニル)−N−(6−フルオロ−2−ピリジニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物20);
N−(6−クロロ−2−ピリジニル)−1−(4−フルオロフェニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物21);
1−(4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物22);
1−(3−クロロ−4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリミジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物25);
1−(3,4−ジメチルフェニル)−5−メチル−N−(2−メチル−4−ピリミジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物27);
1−(3−クロロ−4−フルオロフェニル)−5−メチル−N−(2−メチル−4−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物28);および
1−(3,4−ジフルオロフェニル)−5−メチル−N−(2−メチル−4−ピリジニル)−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物29);
から選択される、請求項14に記載の化合物、またはこれらの化合物のいずれかの薬学上許容される塩。 - 式(I)の化合物またはその薬学上許容される塩:
R1は、ハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシ、シアノ、C1−6アルキルチオ、C1−6ハロアルキルチオ、C1−6アルキルスルホニル、C1−6ハロアルキルスルホニル、C1−6アルキルカルボニルおよびC1−6ハロアルキルカルボニルから独立に選択される1または2個の基で置換されていてもよい6員単環式ヘテロアリールであり;
R2はハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシまたはC1−4アルコキシC1−4アルキルであり;
YはOであり;
Aは6員複素芳香環またはベンゼン環のいずれかであり;ここで、XはCH、N、SまたはOであり;Aが6員複素芳香環である場合には、この環はN、OおよびSから独立に選択される全部で1〜4個のヘテロ原子を含んでもよく;
R3はハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシ、C1−4アルコキシC1−4アルキルまたはシアノであり;
R4はハロであり;かつ
nは0または1である]。 - R1が、ハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシ、C1−6アルキルチオおよびC1−6ハロアルキルチオから独立に選択される1または2個の基で置換されていてもよいピリジルである、請求項25に記載の化合物またはその薬学上許容される塩。
- R2がC1−6アルキルまたはC1−4アルコキシC1−4アルキルである、請求項25または26に記載の化合物またはその薬学上許容される塩。
- R2がC1−6アルキルである、請求項27に記載の化合物またはその薬学上許容される塩。
- Aが6員複素芳香環であり;ここで、XがCHまたはNであり;この環が全部で1〜4個の窒素原子を含んでもよい、請求項25〜28のいずれか一項に記載の化合物またはその薬学上許容される塩。
- Aが6員複素芳香環であり;ここで、XがCHまたはNであり;この環が全部で1または2個の窒素原子を含む、請求項29に記載の化合物またはその薬学上許容される塩。
- Aがピリジン環である、請求項30に記載の化合物またはその薬学上許容される塩。
- R3がハロ、C1−6アルキル、C1−6ハロアルキルまたはシアノである、請求項25〜32のいずれか一項に記載の化合物またはその薬学上許容される塩。
- nが0である、請求項25〜33のいずれか一項に記載の化合物またはその薬学上許容される塩。
- N−(3−クロロフェニル)−1−(5−フルオロ−2−ピリジニル)−5−メチル−1H−1,2,3−トリアゾール−4−カルボキサミド(化合物31)である、請求項25に記載の化合物、またはその薬学上許容される塩。
- 物質関連障害を処置するための薬剤の製造における、請求項1〜13のいずれか一項で定義される化合物またはその薬学上許容される塩の使用。
- 物質関連障害を処置するための、請求項1〜13のいずれか一項で定義される化合物またはその薬学上許容される塩。
- ヒトにおいて物質関連障害を処置する方法であって、有効量の請求項1〜13のいずれか一項で定義される化合物またはその薬学上許容される塩を投与することを含んでなる、方法、
- a)請求項1〜13のいずれか一項で定義される化合物またはその薬学上許容される塩と、b)1以上の薬学上許容される賦形剤とを含んでなる、医薬組成物。
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GB0807162.3 | 2008-04-18 | ||
GB0821274A GB0821274D0 (en) | 2008-11-20 | 2008-11-20 | Compounds for use in therapy |
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US20130203821A1 (en) * | 2010-09-13 | 2013-08-08 | Basf Se | Pyridine Compounds for Controlling Invertebrate Pests II |
US8742097B2 (en) * | 2010-11-09 | 2014-06-03 | Hoffmann-La Roche Inc. | Triazole compounds I |
ES2536980T3 (es) | 2010-12-20 | 2015-06-01 | Sigma-Tau Research Switzerland S.A. | Compuestos aril triazol con actividad antitumoral |
EP3423452A4 (en) | 2016-03-01 | 2019-10-30 | University of Maryland, Baltimore | INHIBITORS OF THE WNT SIGNALING PATHWAY FOR THE TREATMENT OF DISEASES |
US10961261B2 (en) | 2017-03-01 | 2021-03-30 | Anacor Pharmaceuticals, Inc. | Oxaborole analogs and uses thereof |
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WO2006109846A1 (ja) * | 2005-04-06 | 2006-10-19 | Takeda Pharmaceutical Company Limited | トリアゾール誘導体およびその用途 |
WO2007021573A1 (en) * | 2005-08-15 | 2007-02-22 | Astrazeneca Ab | Substituted piperazines as metabotropic glutamate receptor antagonists |
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WO2006109846A1 (ja) * | 2005-04-06 | 2006-10-19 | Takeda Pharmaceutical Company Limited | トリアゾール誘導体およびその用途 |
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