JP5230448B2 - 選択的アンドローゲン受容体モジュレーターとして有用な新イミダゾロピラゾール誘導体 - Google Patents
選択的アンドローゲン受容体モジュレーターとして有用な新イミダゾロピラゾール誘導体 Download PDFInfo
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- JP5230448B2 JP5230448B2 JP2008554460A JP2008554460A JP5230448B2 JP 5230448 B2 JP5230448 B2 JP 5230448B2 JP 2008554460 A JP2008554460 A JP 2008554460A JP 2008554460 A JP2008554460 A JP 2008554460A JP 5230448 B2 JP5230448 B2 JP 5230448B2
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- Prior art keywords
- alkyl
- trifluoromethyl
- phenyl
- acid
- methyl
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- CYCBAKHQLAYYHQ-UHFFFAOYSA-N imidazo[4,5-c]pyrazole Chemical class N1=NC2=NC=NC2=C1 CYCBAKHQLAYYHQ-UHFFFAOYSA-N 0.000 title abstract description 4
- 239000000849 selective androgen receptor modulator Substances 0.000 title description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 160
- 150000001875 compounds Chemical class 0.000 claims description 140
- -1 cyano, nitro, amino Chemical group 0.000 claims description 79
- 239000001257 hydrogen Substances 0.000 claims description 37
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 150000002431 hydrogen Chemical class 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 125000003282 alkyl amino group Chemical group 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 150000004677 hydrates Chemical class 0.000 claims description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- QLOBYXWYPXNRDM-ZMMDDIOLSA-N 4-[[(3r)-6-amino-3-methyl-2-(trifluoromethyl)-3,3a-dihydroimidazo[1,5-b]pyrazol-4-ylidene]amino]-2-(trifluoromethyl)benzonitrile Chemical compound C1([C@H](C(=N2)C(F)(F)F)C)N2C(N)=NC1=NC1=CC=C(C#N)C(C(F)(F)F)=C1 QLOBYXWYPXNRDM-ZMMDDIOLSA-N 0.000 claims 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
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- PMDYLCUKSLBUHO-UHFFFAOYSA-N 4-amino-2-(trifluoromethyl)benzonitrile Chemical compound NC1=CC=C(C#N)C(C(F)(F)F)=C1 PMDYLCUKSLBUHO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 6
- 229920000609 methyl cellulose Polymers 0.000 description 6
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- 235000010981 methylcellulose Nutrition 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 210000001625 seminal vesicle Anatomy 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- 201000010653 vesiculitis Diseases 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 239000000654 additive Substances 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
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- 235000000346 sugar Nutrition 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 4
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- 206010020112 Hirsutism Diseases 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 206010060862 Prostate cancer Diseases 0.000 description 4
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 4
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
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- 125000003545 alkoxy group Chemical group 0.000 description 4
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
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- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
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- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 239000002745 poly(ortho ester) Substances 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 229920002721 polycyanoacrylate Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 102000005969 steroid hormone receptors Human genes 0.000 description 1
- 108020003113 steroid hormone receptors Proteins 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 229960002703 undecylenic acid Drugs 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/16—Masculine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/26—Androgens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Dermatology (AREA)
- Virology (AREA)
- Diabetes (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Urology & Nephrology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
Basaria,S.,Wahlstrom,J.T.,Dobs,A.S.,J.Clin Endocrinol Metab(2001),86,pp5108−5117 Shahidi,N.T.,Clin Therapeutics,(2001),23,pp1355−1390 Newling,D.W.,Br.J.Urol.,1996,77(6),pp.776−784
本発明は、式(I)
式中、
R1は水素、カルボキシ、アルキル、ハロゲン化C1−4アルキル、ヒドロキシ置換C1−4アルキル、シクロアルキル,アリール、アラルキル、ヘテロアリール、ヘテロアリール−アルキル−、ヘテロシクロアルキル、ヘテロシクロアルキル−アルキル−、−C(O)−アルキル、−C(O)−(ハロゲン化C1−4アルキル)、−C(O)O−C1−4アルキル、−C(O)O−アリール、−C1−4アルキル−S(O)0−2−C1−4アルキル、t−ブチル−ジメチル−シリル及びトリメチルシリルよりなる群から選択され、
ここでアリール、シクロアルキル、ヘテロアリール又はヘテロシクロアルキルは、単独でも又は置換基の一部としても、場合により、ハロゲン、ヒドロキシ、C1−4アルキル、C1−4アルコキシ、ハロゲン化C1−4アルキル、ハロゲン化C1−4アルコキシ、シアノ、ニトロ、アミノ、C1−4アルキルアミノ、ジ(C1−4アルキル)アミノ、−NRC−C(O)−C1−4アルキル、NRC−C(O)−(ハロゲン化C1−4アルキル)、−C(O)O−C1−4アルキル、−S(O)0−2−C1−4アルキル、−SO2−NRCRD、トリメチル−シリル及びt−ブチル−ジメチル−シリルオキシよりなる群から独立して選択される1個又は複数の置換基で置換されてもよく、ここでRC及びRDはそれぞれ、独立して水素又はC1−4アルキルから選択される、
R2はC1−4アルキル、ハロゲン化C1−4アルキルよりなる群から選択され、
XはO又はNHであり、
R3はC1−4アルキル、ハロゲン化C1−4アルキル、−C(O)−C1−4アルキル、−S(O)0−2−C1−4アルキル、−C(O)−NRA−C1−4アルキル、ベンジル、−C(O)−フェニル及び−S(O)0−2−フェニル及び−C(O)−NRA−フェニルよりなる群から選択され、ここでRAは水素又はC1−4アルキルである、
R4は不在であるか、又は、水素、ハロゲン、C1−4アルキル、ハロゲン化C1−4アルキル、シアノ、ニトロ、アミノ、C1−4アルキルアミノ、ジ(C1−4アルキル)アミノ,−O−C1−4アルキル、−S(O)0−2−C1−4アルキル、−NRB−C(O)−C1−4アルキル、ベンジル、−O−フェニル、−C(O)−フェニル及び−S(O)0−2−フェニルよりなる群から選択され、ここでRBは水素又はC1−4アルキルである、
R5は不在であるか、又は、水素、ハロゲン、C1−4アルキル、ハロゲン化C1−4アルキル、シアノ、ニトロ、アミノ、C1−4アルキルアミノ、ジ(C1−4アルキル)アミノ、−O−C1−4アルキル、−S(O)0−2−C1−4アルキル、−NRB−C(O)−C1−4アルキル、ベンジル、−O−フェニル、−C(O)−フェニル及び−S(O)0−2−フェニルよりなる群から選択され、ここでRBは水素又はC1−4アルキルである、
R6は不在であるか、又は、水素、ハロゲン、C1−4アルキル、ハロゲン化C1−4アルキル、シアノ、ニトロ、アミノ、−O−C1−4アルキル及び−S(O)0−2−C1−4アルキルよりなる群から選択される。
本発明は、前立腺癌、良性前立腺肥大(BPH)、多毛症、脱毛症、拒食症、乳癌、にきび、AIDS、悪液質の処置のため、男性避妊としてそして/又は男性行動促進剤としての選択的アンドローゲン受容体モジュレーターとして有用な、式(I)
ここで、アリール又はヘテロアリールは、単独でも又は置換基の一部としてでも、場合により、ハロゲン、ヒドロキシ、C1−4アルキル、C1−4アルコキシ、ハロゲン化C1−4アルキル、シアノ、ニトロ及び−C(O)O−C1−4アルキルよりなる群から独立して選択される1個又は複数の置換基で置換されてもよい。
本明細書で使用される「アルキル」は、単独で使用されようと、又は置換基の一部として使用されようと、直鎖及び分枝鎖を包含する。例えば、アルキル基はメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、t−ブチル、ペンチル等を包含する。別記されない限り、アルキルとともに使用される時の「低級」は、1〜4個の炭素原子の炭素鎖組成物を意味する。
Ac = アセチル(すなわち−C(O)CH3)
AcOH = 酢酸
CSA = カンファースルホン酸
DCM = ジクロロメタン
DIPEA又はDIEA = ジイソプロピルエチルアミン
DMA N,N−ジメチルアセトアミド
DMF = N,N−ジメチルホルムアミド
DMSO = ジメチルスルホキシド
Et3N = トリエチルアミン
Et2O = ジエチルエーテル
EtOAc = 酢酸エチル
MeOH = メタノール
Ms = メチルスルホン酸
PTSA又はpTSA = p−トルエンスルホン酸
TEA = トリエチルアミン
TFA = トリフルオロ酢酸
TFAA = トリフルオロ酢酸無水物
THF = テトラヒドロフラン
Ts = トシル(−SO2−(p−トルエン))
アセテート、ベンゼンスルホネート、ベンゾエート、ビカルボネート、ビスルフェート、ビタルトレート、ボレート、ブロミド、カルシウムエデテート、カムシラート、カルボネート、クロリド、クラブラネート、シトレート、ジヒドロクロリド、エデテート、エジシレート、エストレート、エシラート、フマレート、グルセプテート、グルコネート、グルタメート、グリコリルアルサニレート、ヘキシルレソルシネート、ヒドラバミン、ヒドロブロミド、ヒドロクロリド、ヒドロキシナフトエート、ヨージド、イソチオネート、ラクテート、ラクトビオネート、ラウレート、マレート、マレエート、マンデレート、メシラート、メチルブロミド、メチルナイトレート、メチルスルフェート、ムケート、ナプシレート、ナイトレート、N−メチルグルカミンアンモニウム塩、オレエート、パモエート(エンボネート)、パルミテート、パントテネート、ホスフェート/ジホスフェート、ポリガラクツロネート、サリチレート、ステアレート、スルフェート、サブアセテート、スクシネート、タンネート、タルトレート、テオクレート、トシラート、トリエチオヂド及びバレレート。
酢酸、2,2−ジクロロ酢酸、アシル化アミノ酸、アジピン酸、アルギン酸、アスコルビン酸、L−アスパラギン酸、ベンゼンスルホン酸、安息香酸、4−アセトアミド安息香酸、(+)−カンファー酸、カンファースルホン酸、(+)−(1S)−カンファー−10−スルホン酸、カプリン酸、カプロン酸、カプリル酸、桂皮酸、クエン酸、シクラミン酸、ドデシル硫酸、エタン−1,2−ジスルホン酸、エタンスルホン酸、2−ヒドロキシ−エタンスルホン酸、ギ酸、フマル酸、ガラクタル酸、ゲンチシン酸、グルコヘプトン酸、D−グルコン酸、D−グルコロン酸、L−グルタミン酸、α−オキソ−グルタル酸、グリコール酸、馬尿酸、臭化水素酸、塩化水素酸、(+)−L−乳酸、(±)−DL−乳酸、ラクトビオニック酸、マレイン酸、(−)−L−リンゴ酸、マロン酸、(±)−DL−マンデル酸、メタンスルホン酸、ナフタレン−2−スルホン酸、ナフタレン−1,5−ジスルホン酸、1−ヒドロキシ−2−ナフトエ酸、ニコチン酸、硝酸、オレイン酸、オロチン酸、蓚酸、パルミトリン酸、パモエ酸、リン酸、L−ピログルタミン酸、サリチル酸、4−アミノ−サリチル酸、セバシン酸(sebaic acid)、ステアリン酸、コハク酸、硫酸、タンニン酸、(+)−L−酒石酸、チオシアン酸、p−トルエンスルホン酸及びウンデシレン酸を包含する酸;並びに、アンモニア、L−アルギニン、ベネサミン、ベンザチン、水酸化カルシウム、コリン、デアノール、ジエタノールアミン、ジエチルアミン、2−(ジエチルアミノ)−エタノール、エタノールアミン、エチレンジアミン、N−メチル−グルカミン、ヒドラバミン、1H−イミダゾール、L−リシン、水酸化マグネシウム、4−(2−ヒドロキシエチル)−モルホリン、ピペラジン、水酸化カリウム、1−(2−ヒドロキシエチル)−ピロリジン、第二級アミン、水酸化ナトリウム、トリエタノールアミン、トロメサミン及び水酸化亜鉛を包含する塩基。
4−(6−アミノ−3aR−メチル−2−トリフルオロメチル−3,3a−ジヒドロ−イミダゾ[1,5−b]ピラゾル−4−イリデンアミノ)−2−トリフルオロメチル−ベンゾニトリル(1.5ミリモル)(5mLのTHF及び5mLの1N、HCl中)を室温で24時間撹拌した。溶媒を除去し、残渣を酢酸エチルと飽和NaHCO3水溶液間に分配した。有機層を水及び生理食塩水で洗浄し、無水Na2SO4上で乾燥し、濾過し、濃縮すると粗物質を与えた。NMRは8:1:1の比率の水和物1:水和物2:水和物3を示した。粗物質を、溶離液としてヘキサン:酢酸エチル1:1〜純粋な酢酸エチル(0.5%のEt3Nを添加)を使用するフラッシュカラムクロマトグラフィーにより分離すると、白色固体としての主題化合物を与えた。
1H NMR(CDCl3)δ 8.02(s,1H),7.90(d,J=7.5Hz,1H),7.72(d,J=7.5Hz,1H),5.55(br,s,1H),5.22(br,s,1H),4.38(d,J=12.0Hz,1H),3.02(d,J=12.0Hz,1H),1.98(s,3H).MS(m/z):MH+ 407。
水和物2 JNJ:
1H NMR(CDCl3)δ 7.75(d,J=8.0Hz,1H),7.22(s,1H),7.10(d,J=7.5Hz,1H),6.10(br,s,2H),4.50(d,J=12.5Hz,1H),2.98(d,J=12.5Hz,1H),1.95(s,3H).MS(m/z):MH+ 407。
水和物3:
1H NMR(CDCl3)δ 8.00(s,1H),7.85(d,J=8.5Hz,1H),7.72(d,J=8.5Hz,1H),6.20(br,s,1H),5.15(br,s,1H),4.35(d,J=11.5Hz,1H),3.05(d,J=11.5Hz,1H),1.93(s,3H).MS(m/z):MH+ 407。
実施例37の方法に従い、出発物質として4−(6−アミノ−3aS−メチル−2−トリフルオロメチル−3,3a−ジヒドロ−イミダゾ[1,5−b]ピラゾル−4−イリデンアミノ)−2−トリフルオロメチル−ベンゾニトリルを使用すると、白色固体としての主題化合物を生成した。
水和物2:NMR及びMSデータは化合物17のものと同様である。
水和物3:NMR及びMSデータは化合物20のものと同様である。
未成熟(約50g)の去勢雄Sprague Dawleyラット(Charles River)を、試験化合物(通常0.3mLの容量を40mg/kgで経口投与、30%シクロデキストリン又は0.5%メチルセルロースベヒクル中)又はテストステロンプロピオネート(0.1mLの容量を5mg/kgで頸部首筋に皮下注射投与、ゴマ油中)又はベヒクル(1mLの30%シクロデキストリン又は0.5%のメチルセルロース、経口投与)で5日間1日1回処置した。6日目に、ラットを二酸化炭素中での窒息により安楽死させた。腹側前立腺及び肛門挙筋を切除し、それらの湿式重量を測定した。
未成熟(約50g)の去勢雄Sprague Dawleyラット(Charles River)を、試験化合物(通常、0.3mLの容量を40mg/kgで経口投与、30%シクロデキストリン又は0.5%メチルセルロースベヒクル中)及びテストステロンプロピオネート(0.1mLの容量を、2mg/kgで頸部首筋に皮下注射投与、ゴマ油中)で5日間毎日1回処置した。6日目に、ラットを二酸化炭素中での窒息により安楽死させた。腹側前立腺及び精嚢を切除し、それらの湿式重量を測定した。試験化合物の活性を、ベヒクル処置した対照群をゼロパーセントに設定し、そしてテストステロン単独処置した対照群を100%と設定して、テストステロン−刺激組織重量の抑制パーセントとして決定した。化合物が30mg/kgで腹側前立腺又は精嚢の30%以上の抑制をもたらした場合にレベル1のアンタゴニスト活性と表示した。化合物が30mg/kgで腹側前立腺又は精嚢の5%以上〜30%未満の抑制をもたらした場合に、レベル2のアンタゴニスト活性と表示した。
Claims (5)
- 式(I)
式中、
R1は水素、カルボキシ、アルキル、ハロゲン化C1-4アルキル、アリール、アラルキル、ヘテロアリール、−C(O)−アルキル、−C(O)−(ハロゲン化C1-4アルキル)及び−C(O)O−C1-4アルキルよりなる群から選択され、
R2はC1-4アルキル及びハロゲン化C1-4アルキルよりなる群から選択され、
XはO又はNHであり、
R4 は、水素、ハロゲン、C1-4アルキル、ハロゲン化C1-4アルキル、シアノ、ニトロ、アミノ、C1-4アルキルアミノ、ジ(C1-4アルキル)アミノ,−O−C1-4アルキル、−S(O)0-2−C1-4アルキル、−NRB−C(O)−C1-4アルキル、ベンジル、−O−フェニル、−C(O)−フェニル及び−S(O)0-2−フェニルよりなる群から選択され、ここでRBは水素又はC1-4アルキルである、
R5 は、水素、ハロゲン、C1-4アルキル、ハロゲン化C1-4アルキル、シアノ、ニトロ、アミノ、C1-4アルキルアミノ、ジ(C1-4アルキル)アミノ、−O−C1-4アルキル、−S(O)0-2−C1-4アルキル、−NRB−C(O)−C1-4アルキル、ベンジル、−O−フェニル、−C(O)−フェニル及び−S(O)0-2−フェニルよりなる群から選択され、ここでRBは水素又はC1-4 アルキルである、
R6 は、水素、ハロゲン、C1-4アルキル、ハロゲン化C1-4アルキル、シアノ、ニトロ、アミノ、−O−C1-4アルキル及び−S(O)0-2−C1-4アルキルよりなる群から選択される。 - 請求項1における化合物であって、
式中、
R1が水素、カルボキシ、アルキル、ハロゲン化C1-4アルキル、アリール、アラルキル、ヘテロアリール、−C(O)−アルキル、−C(O)−(ハロゲン化C1-4アルキル)及び−C(O)O−C1-4アルキルよりなる群から選択され、
R2がC1-4アルキル及びハロゲン化C1-4アルキルよりなる群から選択され、
XがO又はNHであり、
R3がC1-4アルキル、ハロゲン化C1-4アルキル、−C(O)−C1-4アルキル、−C(O)−NRA−C1-4アルキル、ベンジル、−C(O)−フェニル及び−C(O)−NRA−フェニルよりなる群から選択され、ここでRAは水素又はC1-4アルキルである、
R4 が、水素、ハロゲン、C1-4アルキル、ハロゲン化C1-4アルキル、シアノ、ニトロ、アミノ、C1-4アルキルアミノ、ジ(C1-4アルキル)アミノ、−O−C1-4アルキル、−S(O)0-2−C1-4アルキル、−NRB−C(O)−C1-4アルキル、ベンジル、−O−フェニル、−C(O)−フェニル及び−S(O)0-2−フェニルよりなる群から選択され、ここでRBは水素又はC1-4 アルキルである、
R5 が、水素、ハロゲン、C1-4アルキル、ハロゲン化C1-4アルキル、シアノ、ニトロ、アミノ、C1-4アルキルアミノ、ジ(C1-4アルキル)アミノ、−O−C1-4アルキル、−S(O)0-2−C1-4アルキル、−NRB−C(O)−C1-4アルキル、ベンジル、−O−フェニル、−C(O)−フェニル及び−S(O)0-2−フェニルよりなる群から選択され、ここでRBは水素又はC1-4 アルキルである、
R6 が、水素、ハロゲン、C1-4アルキル、ハロゲン化C1-4アルキル、シアノ、ニトロ、アミノ、−O−C1-4アルキル及び−S(O)0-2−C1-4 アルキルよりなる群から選択される。 - 請求項2における化合物であって、
式中、
R1が水素、カルボキシ、アルキル、ハロゲン化C1-4アルキル、アリール、アラルキル、ヘテロアリール、−C(O)−アルキル、−C(O)−(ハロゲン化C1-4アルキル)及び−C(O)O−C1-4アルキルよりなる群から選択され、
R2がC1-4アルキル及びハロゲン化C1-4アルキルよりなる群から選択され、
XがO又はNHであり、
R3がC1-4アルキル、ハロゲン化C1-4アルキル、−C(O)−C1-4アルキル、−C(O)−NRA−C1-4アルキル、ベンジル、−C(O)−フェニル及び−C(O)−NRA−フェニルよりなる群から選択され、ここでRAは水素又はC1-4アルキルである、
R4 が、水素、ハロゲン、C1-4アルキル、ハロゲン化C1-4アルキル、シアノ、ニトロ、アミノ、C1-4アルキルアミノ、ジ(C1-4アルキル)アミノ、−O−C1-4アルキル、−S(O)0-2−C1-4アルキル、−NRB−C(O)−C1-4アルキル、ベンジル、−O−フェニル、−C(O)−フェニル及び−S(O)0-2−フェニルよりなる群から選択され、ここでRBは水素又はC1-4アルキルである、
R5 が、水素、ハロゲン、C1-4アルキル、ハロゲン化C1-4アルキル、シアノ、ニトロ、アミノ、C1-4アルキルアミノ、ジ(C1-4アルキル)アミノ、−O−C1-4アルキル、−S(O)0-2−C1-4アルキル、−NRB−C(O)−C1-4アルキル、ベンジル、−O−フェニル、−C(O)−フェニル及び−S(O)0-2−フェニルよりなる群から選択され、ここでRBは水素又はC1-4アルキルである、
R6 が、水素、ハロゲン、C1-4アルキル、ハロゲン化C1-4アルキル、シアノ、ニトロ、アミノ、−O−C1-4アルキル及び−S(O)0-2−C1-4アルキルよりなる群から選択される。 - 請求項3における化合物であって、
式中、
R1が水素、トリフルオロメチル、2,3,4,5,6−ペンタフルオロフェニル及びエトキシカルボニルよりなる群から選択され、
R2がメチルであり、
R3が水素又はトリフルオロメチルカルボニルであり、
XがO又はNであり、
R4がクロロ、シアノ及びニトロよりなる群から選択され、
R5がトリフルオロメチルであり、
R6がH又はエチルである。 - 4−(6−アミノ−3R−メチル−2−トリフルオロメチル−3,3a−ジヒドロ−イミダゾ[1,5−b]ピラゾル−4−イリデンアミノ)−2−トリフルオロメチル−ベンゾニトリル、
4−(6−アミノ−3aR−メチル−2−トリフルオロメチル−3,3a−ジヒドロ−イミダゾ[1,5−b]ピラゾル−4−イリデンアミノ)−2−トリフルオロメチル−ベンゾニトリル、
4−(6−アミノ−3aS−メチル−2−トリフルオロメチル−3,3a−ジヒドロ−イミダゾ[1,5−b]ピラゾル−4−イリデンアミノ)−2−トリフルオロメチル−ベンゾニトリル、
N−[4−(4−シアノ−3−トリフルオロメチル−フェニルイミノ)−3aR−メチル−2−トリフルオロメチル−3a,4−ジヒドロ−3H−イミダゾ[1,5−b]ピラゾル−6−イル]−2,2,2−トリフルオロ−アセトアミド、
4−(6−アミノ−3aR−メチル−2−トリフルオロメチル−3,3a−ジヒドロ−イミダゾ[1,5−b]ピラゾル−4−イリデンアミノ)−2−トリフルオロメチル−ベンゾニトリルの水和物、
4−(6−アミノ−3aS−メチル−2−トリフルオロメチル−3,3a−ジヒドロ−イミダゾ[1,5−b]ピラゾル−4−イリデンアミノ)−2−トリフルオロメチル−ベンゾニトリルの水和物
よりなる群から選択される請求項4における化合物。
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EP1991223A1 (en) | 2008-11-19 |
ATE473741T1 (de) | 2010-07-15 |
WO2007092727A1 (en) | 2007-08-16 |
AU2007212191A1 (en) | 2007-08-16 |
JP2009526077A (ja) | 2009-07-16 |
EP1991223B1 (en) | 2010-07-14 |
US20070197616A1 (en) | 2007-08-23 |
CN101415419B (zh) | 2012-06-13 |
AU2007212191B2 (en) | 2011-12-22 |
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