JP2681648B2 - Novel 2-azolyl-1-cyclopropylethanol derivative and its salt - Google Patents
Novel 2-azolyl-1-cyclopropylethanol derivative and its saltInfo
- Publication number
- JP2681648B2 JP2681648B2 JP63075154A JP7515488A JP2681648B2 JP 2681648 B2 JP2681648 B2 JP 2681648B2 JP 63075154 A JP63075154 A JP 63075154A JP 7515488 A JP7515488 A JP 7515488A JP 2681648 B2 JP2681648 B2 JP 2681648B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- solvent
- general formula
- reaction
- added
- 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.)
- Expired - Lifetime
Links
- 150000003839 salts Chemical class 0.000 title claims description 17
- YVSIWCWUDYLGKU-UHFFFAOYSA-N 1-cyclopropyl-2-(1h-pyrrol-2-yl)ethanol Chemical class C1CC1C(O)CC1=CC=CN1 YVSIWCWUDYLGKU-UHFFFAOYSA-N 0.000 title description 4
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 59
- 239000002904 solvent Substances 0.000 description 48
- 238000006243 chemical reaction Methods 0.000 description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- -1 2-azolyl Chemical group 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 238000002844 melting Methods 0.000 description 15
- 230000008018 melting Effects 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- 238000001953 recrystallisation Methods 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 9
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
- 239000012312 sodium hydride Substances 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000012156 elution solvent Substances 0.000 description 5
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 229960004125 ketoconazole Drugs 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 125000004442 acylamino group Chemical group 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 3
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 3
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- IYNRAXYWQIBVBN-UHFFFAOYSA-N C1CC1(C(=O)C2=CC=C(C=C2)Cl)C(=O)N Chemical compound C1CC1(C(=O)C2=CC=C(C=C2)Cl)C(=O)N IYNRAXYWQIBVBN-UHFFFAOYSA-N 0.000 description 2
- 241000222122 Candida albicans Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000000843 anti-fungal effect Effects 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000001769 aryl amino group Chemical group 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 229940095731 candida albicans Drugs 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 125000004663 dialkyl amino group Chemical group 0.000 description 2
- DKWOHBPRFZIUQL-UHFFFAOYSA-N dimethyl-methylidene-oxo-$l^{6}-sulfane Chemical compound C[S+](C)([CH2-])=O DKWOHBPRFZIUQL-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- DPBLXKKOBLCELK-UHFFFAOYSA-N pentan-1-amine Chemical compound CCCCCN DPBLXKKOBLCELK-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 1
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 1
- JFXQPRVYOYNIBY-UHFFFAOYSA-N 1-[1-(2,4-difluorophenyl)-1-hydroxy-2-(1,2,4-triazol-1-yl)ethyl]cyclopropane-1-carboxylic acid Chemical compound C1CC1(C(=O)O)C(CN2C=NC=N2)(C3=C(C=C(C=C3)F)F)O JFXQPRVYOYNIBY-UHFFFAOYSA-N 0.000 description 1
- DKKVKJZXOBFLRY-UHFFFAOYSA-N 1-cyclopropylethanol Chemical class CC(O)C1CC1 DKKVKJZXOBFLRY-UHFFFAOYSA-N 0.000 description 1
- KIPSRYDSZQRPEA-UHFFFAOYSA-N 2,2,2-trifluoroethanamine Chemical compound NCC(F)(F)F KIPSRYDSZQRPEA-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- CLVALLQETQTQMV-UHFFFAOYSA-N 2-(1,2,4-triazol-1-yl)ethanol Chemical compound OCCN1C=NC=N1 CLVALLQETQTQMV-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 125000000094 2-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
- SABFKWMEKIPNLE-UHFFFAOYSA-N 3-(4-chlorophenyl)-3-oxopropanamide Chemical compound NC(=O)CC(=O)C1=CC=C(Cl)C=C1 SABFKWMEKIPNLE-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- MYTWAVYEZDXWGV-UHFFFAOYSA-N 4-oxaspiro[2.3]hexane Chemical compound C1CC11OCC1 MYTWAVYEZDXWGV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 1
- 208000031295 Animal disease Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- BEKCBAAPPJBXDQ-UHFFFAOYSA-N C1(CC1)C(=O)O.ClC(Cl)Cl Chemical compound C1(CC1)C(=O)O.ClC(Cl)Cl BEKCBAAPPJBXDQ-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- 229960003942 amphotericin b Drugs 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 125000003180 beta-lactone group Chemical group 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- LRUKOLJDGBIZGA-UHFFFAOYSA-N ethyl 1-(4-chlorobenzoyl)cyclopropane-1-carboxylate Chemical compound C=1C=C(Cl)C=CC=1C(=O)C1(C(=O)OCC)CC1 LRUKOLJDGBIZGA-UHFFFAOYSA-N 0.000 description 1
- HLXRSEDFMJREFO-UHFFFAOYSA-N ethyl 1-[1-(4-chlorophenyl)-1-hydroxy-2-(1,2,4-triazol-1-yl)ethyl]cyclopropane-1-carboxylate Chemical compound CCOC(=O)C1(CC1)C(CN2C=NC=N2)(C3=CC=C(C=C3)Cl)O HLXRSEDFMJREFO-UHFFFAOYSA-N 0.000 description 1
- CMNRRJIKQZQSKI-UHFFFAOYSA-N ethyl 1-[2-(4-chlorophenyl)oxiran-2-yl]cyclopropane-1-carboxylate Chemical compound ClC1=CC=C(C=C1)C1(OC1)C1(CC1)C(=O)OCC CMNRRJIKQZQSKI-UHFFFAOYSA-N 0.000 description 1
- DGCZHKABHPDNCC-UHFFFAOYSA-N ethyl 3-(4-chlorophenyl)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=C(Cl)C=C1 DGCZHKABHPDNCC-UHFFFAOYSA-N 0.000 description 1
- LDDOSDVZPSGLFZ-UHFFFAOYSA-N ethyl cyclopropanecarboxylate Chemical compound CCOC(=O)C1CC1 LDDOSDVZPSGLFZ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 description 1
- 229960004413 flucytosine Drugs 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 208000024386 fungal infectious disease Diseases 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([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
- 125000005447 octyloxy group Chemical group [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])O* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000005400 pyridylcarbonyl group Chemical group N1=C(C=CC=C1)C(=O)* 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 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
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Epoxy Compounds (AREA)
- Pyridine Compounds (AREA)
Description
【発明の詳細な説明】 ［産業上の利用分野］ 本発明は、一般式［Ｉ］ 「式中、ＡはCHまたはＮを;R1は置換されていてもよい
アリール基を;R2はヒドロキシル基または置換されてい
てもよいアミノ基を示す。」 で表わされる新規な２−アゾリル−１−シクロプロピル
エタノール誘導体およびその塩に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a compound represented by the general formula [I]: A novel 2-azolyl represented by the formula: "wherein A represents CH or N; R 1 represents an optionally substituted aryl group; R 2 represents a hydroxyl group or an optionally substituted amino group." The present invention relates to a 1-cyclopropylethanol derivative and its salt.
而して、本発明の目的は、優れた抗真菌活性を有し、
人および動物の疾病に対し、優れた治療効果を発揮する
新規な２−アゾリル−１−シクロプロピルエタノール誘
導体およびその塩を提供することにある。Thus, the object of the present invention is to have excellent antifungal activity,
It is an object of the present invention to provide a novel 2-azolyl-1-cyclopropylethanol derivative and a salt thereof that exhibit excellent therapeutic effects against human and animal diseases.
［従来の技術］ 深在性真菌症の治療薬としては、現在アムホテリシン
Ｂ（米国特許第2908611号）およびフルシトシン（米国
特許第2802005号）が主に使用されており、さらに、最
近、アゾール系抗真菌剤として、シス−１−アセチル−
４−［４−［２−（2,4−ジクロロフェニル）−２−（1
H−イミダゾール−１−イルメチル）−1,3−ジオキソラ
ン−４−イルメトキシ］フェニル］ピペラジン（一般
名；ケトコナゾール、米国特許第4358449号）が上市さ
れ、真菌症の治療薬として有用であると報告されてい
る。[Prior Art] Currently, amphotericin B (US Pat. No. 2,908,611) and flucytosine (US Pat. No. 2802005) are mainly used as therapeutic agents for deep-seated mycosis. As a fungal agent, cis-1-acetyl-
4- [4- [2- (2,4-dichlorophenyl) -2- (1
H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl] piperazine (generic name; ketoconazole, U.S. Pat. No. 4,358,449) was marketed and reported to be useful as a therapeutic agent for fungal diseases. ing.
［発明が解決しようとする課題］ しかしながら、上記治療薬の作用は、体内動態、毒性
などの点で十分なものとは言えず、さらに優れた化合物
の開発が望まれていた。[Problems to be Solved by the Invention] However, the action of the above-mentioned therapeutic agents cannot be said to be sufficient in terms of pharmacokinetics, toxicity and the like, and there has been a demand for the development of more excellent compounds.
［課題を解決するための手段］ かかる状況下において、本発明者らは鋭意研究を行っ
た結果、一般式［Ｉ］で表わされる新規な２−アゾリル
−１−シクロプロピルエタノール誘導体およびその塩
が、優れた抗真菌作用を有し、吸収に優れ、さらには優
れた体内動態を示すものであることを見出し、本発明を
完成するに至った。[Means for Solving the Problem] Under these circumstances, the present inventors have conducted diligent research and as a result, found that the novel 2-azolyl-1-cyclopropylethanol derivative represented by the general formula [I] and its salt were The inventors have found that they have an excellent antifungal activity, are excellent in absorption, and exhibit excellent pharmacokinetics, and have completed the present invention.
以下、本発明化合物について詳しく述べる。 Hereinafter, the compound of the present invention will be described in detail.
本明細書において特にことわらない限り、ハロゲン原
子とは、たとえば、フッ素原子、塩素原子、臭素原子、
ヨウ素原子を；アルキル基とは、たとえば、メチル、エ
チル、ｎ−プロピル、イソプロピル、ｎ−ブチル、イソ
ブチル、sec−ブチル、tert−ブチル、ペンチル、ヘキ
シル、ヘプチル、オクチルなどのＣ１〜10アルキル基
を；アルコキシ基とは、たとえば、メトキシ、エトキ
シ、ｎ−プロポキシ、イソプロポキシ、ｎ−ブトキシ、
イソブトキシ、sec−ブトキシ、tert−ブトキシ、ペン
チルオキシ、ヘキシルオキシ、ヘプチルオキシ、オクチ
ルオキシなどのＣ１〜10アルコキシ基を；アルキルチオ
基とは、たとえば、メチルチオ、エチルチオ、ｎ−プロ
ピルチオ、イソプロピルチオ、ｎ−ブチルチオ、イソブ
チルチオ、sec−ブチルチオ、tert−ブチルチオ、ペン
チルチオ、ヘキシルチオ、ヘプチルチオ、オクチルチオ
などのＣ１〜10アリキルチオ基を；アリール基とは、た
とえば、フェニル、ナフチルなどの基を；シクロアルキ
ル基とは、たとえば、シクロプロピル、シクロブチル、
シクロペンチル、シクロヘプチルなどのＣ３〜８シクロ
アルキル基を；アルアルキル基とは、たとえば、ベンジ
ル、フェネチル、ナフチルメチルなどの基を；アルケニ
ル基とは、たとえば、ビニル、プロペニル、ブテニルな
どのＣ２〜６アルケニル基を；ハロ低級アルキル基とし
ては、たとえば、フルオロメチル、クロロメチル、トリ
フルオロメチル、トリクロロメチル、2,2,2−トリフル
オロエチルなどのフッ素原子または塩素原子で置換され
たＣ１〜４アルキル基を；アシル基とは、たとえば、ホ
ルミル、アセチル、プロピオニルなどのＣ１〜５アルカ
ノイル基、ベンゾイルなどのアロイル基およびピリジル
カルボニル、フリルカルボニル、チエニルカルボニルな
どの複素環−カルボニル基を；複素環式基とは、たとえ
ば、ピリジル、チエニル、フリルなどの複素環式基を；
アルキルアミノ、ジアルキルアミノ、アリールアミノ、
アシルアミノ、アルキルオキシカルボニルにおける“ア
ルキル”、“アリール”、“アシル”は、それぞれ上記
したと同様の基を；また“低級”とは、Ｃ１〜４の基を
それぞれ表わす。Unless otherwise specified in this specification, the halogen atom is, for example, a fluorine atom, a chlorine atom, a bromine atom,
An iodine atom is an alkyl group, and examples thereof include a C 1-10 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl. And an alkoxy group is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
Isobutoxy, sec- butoxy, tert- butoxy, pentyloxy, hexyloxy, heptyloxy, a C 1 to 10 alkoxy groups such as octyloxy, and alkylthio group such as methylthio, ethylthio, n- propylthio, isopropylthio, n -Butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, heptylthio, octylthio and other C 1-10 alkylalkyl groups; aryl groups include groups such as phenyl and naphthyl; cycloalkyl groups and Is, for example, cyclopropyl, cyclobutyl,
C 3-8 cycloalkyl groups such as cyclopentyl and cycloheptyl; aralkyl groups include groups such as benzyl, phenethyl and naphthylmethyl; alkenyl groups include C 2 such as vinyl, propenyl and butenyl. ~ 6 alkenyl group; as the halo lower alkyl group, for example, C 1 substituted with a fluorine atom or a chlorine atom such as fluoromethyl, chloromethyl, trifluoromethyl, trichloromethyl, and 2,2,2-trifluoroethyl. An acyl group is, for example, a C 1-5 alkanoyl group such as formyl, acetyl or propionyl, an aroyl group such as benzoyl or a heterocycle-carbonyl group such as pyridylcarbonyl, furylcarbonyl or thienylcarbonyl; Heterocyclic groups include, for example, pyridyl and thiyl. Cycloalkenyl, a heterocyclic group such as furyl;
Alkylamino, dialkylamino, arylamino,
“Alkyl”, “aryl” and “acyl” in acylamino and alkyloxycarbonyl are the same groups as described above; and “lower” is a C 1-4 group, respectively.
R1におけるアリール基は、たとえば、ハロゲン原子、
低級アルキル、低級アルコキシ、低級アルキルチオおよ
びハロ低級アルキル基から選ばれる１つ以上の置換基で
置換されていてもよい。The aryl group for R 1 is, for example, a halogen atom,
It may be substituted with one or more substituents selected from lower alkyl, lower alkoxy, lower alkylthio and halo lower alkyl groups.
R2の置換されていてもよいアミノ基は、式 で表わすことができ、この式において、R3およびR4は同
一もしくは異なって、たとえば、水素原子、アルキル、
シクロアルキル、アルアルキル、アリール、アルキルア
ミノ、ジアルキルアミノ、アリールアミノおよびアシル
アミノ基などが挙げられ、上記した基は、さらにヒドロ
キシル、カルバモイル、アシルアミノ、低級アルキル、
低級アルコキシ、低級アルキルチオ、ハロ低級アルキル
および複素環式基並びにハロゲン原子から選ばれる１つ
以上の置換基で置換されていてもよい。さらに、R3およ
びR4はそれらが結合している窒素原子と一緒になってア
ジリジニル、アゼチジニル、ピロリジニル、ピペリジニ
ル、モルホリニル、ピペラジニルなどの３〜６員含窒素
複素環式基を形成してもよく、これらは、低級アルキ
ル、オキソ、低級アルキルオキシカルボニル基などの１
つ以上の置換基で置換されていてもよい。The optionally substituted amino group of R 2 has the formula And R 3 and R 4 are the same or different in this formula, for example, a hydrogen atom, alkyl,
Examples thereof include cycloalkyl, aralkyl, aryl, alkylamino, dialkylamino, arylamino and acylamino groups, and the above-mentioned groups further include hydroxyl, carbamoyl, acylamino, lower alkyl,
It may be substituted with one or more substituents selected from lower alkoxy, lower alkylthio, halo lower alkyl and heterocyclic groups and halogen atoms. Further, R 3 and R 4 together with the nitrogen atom to which they are attached may form a 3-6 membered nitrogen-containing heterocyclic group such as aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl. , These are lower alkyl, oxo, lower alkyloxycarbonyl groups and the like 1
It may be substituted with one or more substituents.
一般式［Ｉ］の化合物の塩としては、医薬として許容
される塩、たとえば、塩酸、臭化水素酸、硫酸、リン
酸、硝酸などの鉱酸との塩；酢酸、フマル酸、マレイン
酸、リンゴ酸、酒石酸、クエン酸、アスパラギン酸など
の有機カルボン酸との塩；メタンスルホン酸、ベンゼン
スルホン酸、トルエンスルホン酸などのスルホン酸との
塩；ナトリウム、カリウムなどのアルカリ金属との塩な
どが挙げられる。The salt of the compound of the general formula [I] is a pharmaceutically acceptable salt, for example, a salt with a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid; acetic acid, fumaric acid, maleic acid, Salts with organic carboxylic acids such as malic acid, tartaric acid, citric acid, aspartic acid; salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid; salts with alkaline metals such as sodium and potassium Can be mentioned.
なお、一般式［Ｉ］で表わされる本発明化合物におい
ては、R2が置換されていてもよいアミノ基のものが好ま
しい。また、さらに好ましいものとしては、ヒドロキシ
ル基で置換されていてもよいアルキル基またはシクロア
ルキル基で置換されていてもよいアミノ基が挙げられ
る。In the compound of the present invention represented by the general formula [I], R 2 is preferably an amino group which may be substituted. Further, more preferable examples include an alkyl group optionally substituted with a hydroxyl group or an amino group optionally substituted with a cycloalkyl group.
本発明化合物は、さらにすべての異性体（幾何異性
体、光学異性体）、水和物およびすべての結晶形を包含
するものである。The compound of the present invention further includes all isomers (geometric isomers, optical isomers), hydrates and all crystal forms.
［製造法］ 一般式［Ｉ］の２−アゾリル−１−シクロプロピルエ
タノール誘導体およびその塩は一般に自体公知の方法を
組み合わせることにより製造されるが、たとえば、つぎ
に示す方法によって製造することができる。[Production Method] The 2-azolyl-1-cyclopropylethanol derivative of the general formula [I] and its salt are generally produced by combining methods known per se. For example, they can be produced by the following method. .
製法１ 「式中、Ａ、R1およびR2は前記したと同様の意味を有す
る。」 一般式［III］の化合物の塩としては、たとえば、カ
リウムまたはナトリウムなどのアルカリ金属との塩また
はトリエチルアミン、トリブチルアミン、ピリジンまた
は1,8−ジアザビシクロ［5,4,0］ウンデク−７−エン
（DBU）などの有機塩基との塩が挙げられる。また、こ
れらの塩は反応系内で作らせることもできる。Manufacturing method 1 "In the formula, A, R 1 and R 2 have the same meanings as described above." As the salt of the compound of the general formula [III], for example, a salt with an alkali metal such as potassium or sodium or triethylamine, triethylamine or triethylamine. Mention may be made of salts with organic bases such as butylamine, pyridine or 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU). Also, these salts can be prepared in the reaction system.
本反応は、不活性溶媒の存在下または不存在下に行う
ことができる。This reaction can be carried out in the presence or absence of an inert solvent.
使用される溶媒としては、反応に悪影響を及ぼさない
ものであれば特に限定されないが、たとえば、N,N−ジ
メチルホルムアミド、N,N−ジメチルアセトアミドなど
のアミド類；ジメチルスルホキシドなどのスルホキシド
類；スルホラン；アセトニトリルなどのニトリル類；ジ
オキサン、テトラヒドロフランなどのエーテル類；メタ
ノール、エタノール、ｎ−プロパノール、ｎ−ブタノー
ルなどのアルコール類；ベンゼンなどの芳香族炭化水素
類または水などが挙げられ、これらの溶媒は二種以上混
合して使用してもよい。The solvent used is not particularly limited as long as it does not adversely affect the reaction, and for example, amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; sulfolane Nitriles such as acetonitrile; ethers such as dioxane and tetrahydrofuran; alcohols such as methanol, ethanol, n-propanol and n-butanol; aromatic hydrocarbons such as benzene or water, and the like. You may use it in mixture of 2 or more types.
本反応において、一般式［III］の化合物またはその
塩は、一般式［II］の化合物に対して１〜10倍モル使用
することができる。In this reaction, the compound of the general formula [III] or a salt thereof can be used in a 1- to 10-fold molar quantity versus the compound of the general formula [II].
本反応は、通常、０〜200℃、好ましくは20〜80℃
で、１〜24時間実施すればよい。This reaction is generally 0 to 200 ° C, preferably 20 to 80 ° C.
Then, it may be carried out for 1 to 24 hours.
なお、COR2がカルボキシル基である一般式［Ｉ］の化
合物は、COR2がカルボキシル基である一般式［II］の化
合物を、あらかじめ通常のカルボキシル保護基で保護
し、反応後、常法によりカルボキシル保護基を脱離する
ことによって得ることもできる。The compound of the general formula [I] COR 2 is a carboxyl group, a compound of general formula [II] COR 2 is a carboxyl group, protected with previously normal carboxyl protecting group, after the reaction, by conventional methods It can also be obtained by removing the carboxyl protecting group.
製法２ 「式中、Ａ、R1、R3およびR4は前記したと同様の意味を
示す。」 一般式［IV］の反応性誘導体としては、たとえば、酸
ハロゲン化物、酸無水物、混合酸無水物、活性酸アミ
ド、活性エステルおよびビルスマイヤー試薬との反応性
誘導体などが挙げられる。Manufacturing method 2 “In the formula, A, R 1 , R 3 and R 4 have the same meanings as described above.” Examples of the reactive derivative of the general formula [IV] include acid halides, acid anhydrides and mixed acid anhydrides. Compounds, active acid amides, active esters, and reactive derivatives with Vilsmeier reagent.
（ｉ） 一般式［I a］の化合物を常法により一般式［I
V］の反応性誘導体に誘導した後、一般式［VI］のアミ
ン類を反応させることにより、一般式［I b］の化合物
に誘導することができる。(I) A compound of the general formula [I a]
The compound of the general formula [I b] can be derived by reacting with a reactive derivative of the V] and then reacting with an amine of the general formula [VI].
本反応は溶媒中で行うことができ、その溶媒として
は、反応に悪影響を及ぼさないものであれば特に限定さ
れないが、たとえば、塩化メチレン、クロロホルム、四
塩化炭素などのハロゲン化炭化水素類；ベンゼン、トル
エン、キシレンなどの芳香族炭化水素類；テトラヒドロ
フラン、ジオキサンなどのエーテル類；酢酸エチル、酢
酸ブチルなどのエステル類;N,N−ジメチルホルムアミ
ド、N,N−ジメチルアセトアミドなどのアミド類；アセ
トン、メチレエチルケトンなどのケトン類およびアセト
ニトリルなどのニトリル類などが挙げられ、これらの溶
媒は二種以上混合して使用してもよい。This reaction can be carried out in a solvent, and the solvent is not particularly limited as long as it does not adversely influence the reaction, and examples thereof include halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; benzene. , Aromatic hydrocarbons such as toluene and xylene; ethers such as tetrahydrofuran and dioxane; esters such as ethyl acetate and butyl acetate; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; acetone, Examples thereof include ketones such as methylethylketone and nitriles such as acetonitrile. These solvents may be used as a mixture of two or more kinds.
（ii） また、別法としては、一般式［IV］の反応性誘
導体を一般式［Ｖ］のβ−ラクトン体に誘導した後、一
般式［VI］のアミン類と反応させることにより、一般式
［I b］の化合物に誘導することもできる。一般式
［Ｖ］のβ−ラクトン体は、一般式［IV］の化合物を上
記（ｉ）で述べたと同様の溶媒中、トリメチルアミン、
トリエチルアミンなどの有機塩基と０〜70℃で、５分〜
24時間反応させることによって得ることができる。(Ii) Alternatively, as an alternative method, a reactive derivative of the general formula [IV] is converted to a β-lactone of the general formula [V] and then reacted with an amine of the general formula [VI] to give a general derivative. It can also be derived to compounds of formula [Ib]. The β-lactone compound of the general formula [V] is obtained by reacting the compound of the general formula [IV] with trimethylamine in the same solvent as described in (i) above.
Organic base such as triethylamine at 0 ~ 70 ℃ for 5 minutes ~
It can be obtained by reacting for 24 hours.
本反応（［IV］→［I b］および［Ｖ］→［I b］）に
おいて、一般式［VI］の化合物の使用量は、一般式［I
V］または一般式［Ｖ］の化合物に対して１〜20倍モル
であり、また、脱酸剤を用いることもでき、その脱酸剤
としては、たとえば、トリエチルアミン、ピリジン、Ｎ
−メチルモルホリンなどの有機塩基が使用される。In this reaction ([IV] → [I b] and [V] → [I b]), the amount of the compound of the general formula [VI] used is
V] or the compound of the general formula [V] in an amount of 1 to 20 times mol, and a deoxidizing agent can also be used, and examples of the deoxidizing agent include triethylamine, pyridine, and N.
An organic base such as methylmorpholine is used.
本反応は、通常、−60〜200℃で、0.5〜24時間実施す
ればよい。This reaction may be carried out usually at -60 to 200 ° C for 0.5 to 24 hours.
上記の説明から明らかなように、R2がヒドロキシル基
である一般式［Ｉ］の化合物（すなわち、一般式［I
a］の化合物）は、中間体としても有用である。As is clear from the above description, the compound of the general formula [I] in which R 2 is a hydroxyl group (ie, the compound of the general formula [I
The compound (a)) is also useful as an intermediate.
つぎに、本発明化合物を製造するための原料である一
般式［II a］の化合物の製造法について説明する。一般
式［II a］の化合物は、たとえば、つぎに示す製造法に
したがって製造することができる。Next, a method for producing the compound of the general formula [IIa] which is a raw material for producing the compound of the present invention will be described. The compound of general formula [II a] can be produced, for example, according to the following production method.
「式中、R1、R2、R3およびR4は前記したと同様の意味を
有し、R2aはカルボキシル保護基および前記したR2と同
様の意味を有し、R5はカルボキシル保護基を示す。」 R2aおよびR5のカルボキシル保護基としては、通常の
カルボキシル基の保護基であり、具体的には、たとえ
ば、アルキル基が挙げられる。 `` In the formula, R 1 , R 2 , R 3 and R 4 have the same meanings as described above, R 2a has the same meaning as the carboxyl protecting group and R 2 described above, and R 5 is a carboxyl protecting group. The carboxyl protecting group for R 2a and R 5 is a usual protecting group for a carboxyl group, and specific examples thereof include an alkyl group.
また、一般式［VII］および一般式［VIII］の化合物
は公知方法またはそれに準じた方法によて製造すること
ができる。In addition, the compound of the general formula [VII] and the general formula [VIII] can be produced by a known method or a method analogous thereto.
ついで、各工程について説明する。 Next, each step will be described.
（１）一般式［IX］の化合物の製造 一般式［VII］の化合物に適切な溶媒中、塩基の存在
下に1,2−ジブロモエタンを反応させることによって一
般式［IX］の化合物を得ることができる。(1) Preparation of compound of general formula [IX] A compound of general formula [IX] is obtained by reacting compound of general formula [VII] with 1,2-dibromoethane in the presence of a base in a suitable solvent. be able to.
使用される溶媒としては、反応に悪影響を及ぼさない
ものであれば時に限定されないが、たとえば、水；メタ
ノール、エタノール、２−プロパノールなどのアルコー
ル類；ジエチルエーテル、テトラヒドロフラン、ジオキ
サンなどのエーテル類；ベンゼン、トルエン、キシレン
などの芳香族炭化水素類;N,N−ジメチルホルムアミド、
N,N−ジメチルアセトアミドなどのアミド類；ジメチル
スルホキシドなどのスルホキシド類などが挙げられ、こ
れらの溶媒は二種以上混合して使用してもよい。The solvent used is not particularly limited as long as it does not adversely influence the reaction, and examples thereof include water; alcohols such as methanol, ethanol and 2-propanol; ethers such as diethyl ether, tetrahydrofuran and dioxane; benzene. , Toluene, aromatic hydrocarbons such as xylene; N, N-dimethylformamide,
Examples thereof include amides such as N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide. These solvents may be used as a mixture of two or more kinds.
また、使用される塩基としては、たとえば、水酸化ア
ルカリ、炭酸水素アルカリ、炭酸アルカリなどの無機塩
基；水素化ナトリウム、水素化カリウムなどの金属水素
化物；ナトリウムエチラート、ナトリウムメチラートな
どの金属アルコラートが挙げられる。Examples of the base used include inorganic bases such as alkali hydroxide, alkali hydrogen carbonate and alkali carbonate; metal hydrides such as sodium hydride and potassium hydride; metal alcoholates such as sodium ethylate and sodium methylate. Is mentioned.
1,2−ジブロモエタンおよび塩基の使用量は、一般式
［VII］の化合物に対してそれぞれ等モル以上、好まし
くは１〜５倍モルである。The amounts of 1,2-dibromoethane and the base to be used are equimolar or more, preferably 1 to 5 times the molar amount of the compound of the general formula [VII].
本反応は、０℃から使用される溶媒の沸点まで、好ま
しくは20〜100℃で、通常、0.5〜50時間、好ましくは３
〜20時間実施すればよい。This reaction is carried out at 0 ° C to the boiling point of the solvent used, preferably at 20-100 ° C, usually for 0.5-50 hours, preferably 3
It may be carried out for up to 20 hours.
また、一般式［IX］の化合物は、一般式［VIII］の化
合物を上で述べたと同様に1,2−ジブロモエタンと反応
させて得られる一般式［XI］の化合物を通常のカルボキ
シル保護基を脱離する方法、たとえば、加水分解などに
よって一般式［Ｘ］の化合物へ誘導し、しかるのち一般
式［Ｘ］のカルボン酸をその反応性誘導体に導いた後、
一般式［VI］の化合物を反応させることによっても得る
ことができる。なお、一般式［Ｘ］の化合物と一般式
［VI］の化合物の反応は前記した製法２に準じて行うこ
とができる。The compound of the general formula [IX] is a compound of the general formula [XI] obtained by reacting the compound of the general formula [VIII] with 1,2-dibromoethane in the same manner as described above. By derivatizing the compound of the general formula [X] by, for example, hydrolysis and then leading the carboxylic acid of the general formula [X] to its reactive derivative.
It can also be obtained by reacting a compound of the general formula [VI]. The reaction between the compound of general formula [X] and the compound of general formula [VI] can be carried out according to the above-mentioned production method 2.
（２）一般式［II a］の化合物の製造 一般式［IX］の化合物に適切な溶媒中、ジメチルオキ
ソスルホニウムメチリドを反応させることによって一般
式［II a］の化合物を得ることができる。通常、ジメチ
ルオキソスルホニウムメチリドは、ジメチルスルホキシ
ド中、ヨウ化トリメチルオキソスルホニウムと水素化ナ
トリウムなどの強塩基を反応させることによって生成さ
せる。(2) Production of compound of general formula [IIa] The compound of general formula [IIa] can be obtained by reacting the compound of general formula [IX] with dimethyloxosulfonium methylide in a suitable solvent. Usually, dimethyloxosulfonium methylide is produced by reacting trimethyloxosulfonium iodide with a strong base such as sodium hydride in dimethyl sulfoxide.
本反応は、通常、０〜80℃、好ましくは10〜30℃で、
0.5〜24時間実施すればよい。This reaction is generally 0 to 80 ° C, preferably 10 to 30 ° C,
It may be carried out for 0.5 to 24 hours.
なお、本反応はケトン類からエポキシ誘導体を製造す
るための自体公知の方法［参照:JACS（ジャーナル・オ
ブ・アメリカン・ケミカル・ソサエティー）87,1353（1
965）］に準じて実施することができる。Incidentally, a method known per se for the reaction for producing the epoxy derivative from ketones [See: JACS (Journal of American Chemical Society) 87, 1353 (1
965)].
本発明化合物を医薬として用いる場合、医薬上許容さ
れ得る賦形剤、担体、希釈剤などの添加剤を適宜混合し
てもよく、これらは、常法により錠剤、カプセル剤、顆
粒剤、細粒剤、粉末剤または注射剤などの形態として経
口または非経口投与することができる。投与量は、経口
投与の場合、通常成人の体重1kg当り約0.05〜200mg/日
程度で、これを１回または数回に分けて投与されるが、
年齢、体重および症状に応じて適宜選択される。When the compound of the present invention is used as a medicine, additives such as pharmaceutically acceptable excipients, carriers and diluents may be appropriately mixed, and these can be used in the form of tablets, capsules, granules and fine granules by a conventional method. It can be administered orally or parenterally in the form of a drug, powder or injection. In the case of oral administration, the dose is usually about 0.05 to 200 mg / kg body weight of an adult, which is administered once or in several divided doses.
It is appropriately selected according to age, weight and symptoms.
［発明の効果］ つぎに、本発明の代表的化合物の薬理作用について述
べる。[Effect of the Invention] Next, the pharmacological action of the representative compound of the present invention will be described.
なお、以下の薬理試験に使用する被検化合物No.は、
実施例番号を引用した。Incidentally, the test compound No. used in the following pharmacological test,
Example numbers are quoted.
1.感染治療実験 実験的にカンジダ・アルビカンスON−28に感染させた
マウスを用い、本発明化合物の経口による治療効果を測
定した。1. Infection treatment experiment Using mice experimentally infected with Candida albicans ON-28, the therapeutic effect of the compound of the present invention by oral administration was measured.
１群10匹のICR系雄性マウス（体重17〜21g）にカンジ
ダ・アルビカンスON−28 3.2×106細胞／匹をマウス尾
静脈投与し、感染を惹起した。感染２時間後、マウス１
匹当たり被検化合物0.1mgを１回経口投与し、10日間生
死を観察し、平均生存日数より治療係数を求めた。対照
化合物として、ケトコナゾールを用いた。その結果を表
−１に示す。なお、表−１においては、ケトコナゾール
を100とした場合の被検化合物の相対治療係数を表わし
た。Candida albicans ON-28 3.2 × 10 6 cells / mouse was intravenously administered to 10 ICR male mice (body weight: 17 to 21 g) per group by tail vein injection to induce infection. 2 hours after infection, mouse 1
The test compound (0.1 mg) was orally administered once to each animal, and life and death were observed for 10 days, and the therapeutic index was calculated from the average number of days of survival. Ketoconazole was used as a control compound. Table 1 shows the results. In Table 1, the relative therapeutic index of the test compound when ketoconazole is set to 100 is shown.
2.急性毒性 １群３匹のICR系雄性マウス（体重:20±1g）に被検化
合物を静脈内投与し、急性毒性を検討した。 2. Acute toxicity A test compound was intravenously administered to 3 male ICR mice (body weight: 20 ± 1 g) per group to examine the acute toxicity.
なお、被検化合物は、プロピレングリコールに溶解さ
せて調製した。The test compound was prepared by dissolving in propylene glycol.
その結果、被検化合物No.1およびNo.16は、200mg/Kg
投与で死亡例は認められなかった。As a result, the test compounds No. 1 and No. 16 were 200 mg / Kg.
No deaths were observed after administration.
一方、ケトコナゾールは、200mg/Kg投与で全例死亡し
た。On the other hand, 200 mg / Kg of ketoconazole died in all patients.
以上のことから明らかなように、本発明化合物は、優
れた薬理効果を発揮し、安全性の高い化合物である。As is clear from the above, the compounds of the present invention exhibit excellent pharmacological effects and are highly safe compounds.
［実施例］ 本発明をさらに詳細に説明するために参考例および実
施例を挙げるが、本発明はこれらに限定されるものでは
ない。[Examples] Reference examples and examples are given to describe the present invention in more detail, but the present invention is not limited thereto.
なお、カラムクロマトグラフィーにおける担体は、メ
ルク社製のシリカゲル［キーゼルゲル60、アート.7734
（Kieselgel 60,Art.7734）］を用いた。また、溶離液
における混合比は容量比による。さらに、文中におい
て、つぎの略語は以下の意味を有する。The carrier in the column chromatography was silica gel manufactured by Merck [Kieselgel 60, Art.7734].
(Kieselgel 60, Art.7734)]. The mixing ratio in the eluent depends on the volume ratio. Further, in the text, the following abbreviations have the following meanings.
IPE;ジイソプロピルエーテル IPA;イソフロピルアルコール 参考例１ N,N−ジメチルホルムアミド198mlに水素化ナトリウム
（純度60％）4.0gを加え、５〜10℃で４−クロロベンゾ
イル酢酸アミド19.8gを分割添加した後、20〜40℃で水
素の発生が止むまで反応させる。ついで、同温度で1,2
−ジブロモエタン18.8gを加え、50〜60℃で２時間反応
させる。反応液を冷却し、５〜10℃で水素化ナトリウム
（純度60％）2.0gを加えた後、20〜40℃で水素の発生が
止むまで反応させる。ついで、同温度で1,2−ジブロモ
エタン9.4gを加え、50〜60℃で２時間反応させる。反応
終了後、減圧下に溶媒を留去し、水200mlおよび酢酸エ
チル200mlを加え、2N塩酸でpH6.0に調整する。有機層を
分取し、水および飽和食塩水で順次洗浄した後、無水硫
酸マグネシウムで乾燥し、減圧下に溶媒を留去する。得
られた残留物をカラムクロマトグラフィー（溶出溶媒；
クロロホルム）で精製すれば、１−カルバモイル−１−
（４−クロロベンゾイル）シクロプロパン13.0g（収率5
8.2％）を得る。IPE; diisopropyl ether IPA; isofluropyl alcohol Reference Example 1 To 198 ml of N, N-dimethylformamide, 4.0 g of sodium hydride (purity 60%) was added, and 19.8 g of 4-chlorobenzoyl acetic acid amide was added portionwise at 5-10 ° C. After that, react at 20 to 40 ° C until hydrogen generation stops. Then at the same temperature 1,2
-Add 18.8 g of dibromoethane and react at 50-60 ° C for 2 hours. The reaction solution is cooled, 2.0 g of sodium hydride (purity 60%) is added at 5 to 10 ° C, and then the reaction is allowed to proceed at 20 to 40 ° C until generation of hydrogen stops. Then, 9.4 g of 1,2-dibromoethane is added at the same temperature, and the mixture is reacted at 50-60 ° C for 2 hours. After completion of the reaction, the solvent is distilled off under reduced pressure, 200 ml of water and 200 ml of ethyl acetate are added, and the pH is adjusted to 6.0 with 2N hydrochloric acid. The organic layer is separated, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was subjected to column chromatography (elution solvent;
1-carbamoyl-1-
(4-chlorobenzoyl) cyclopropane 13.0 g (yield 5
8.2%).
融点 161〜162℃（再結晶溶媒；ベンゼン） IR（KBr）cm-1; 3390,3140,1680,1645,1620,1575 NMR（CDCl3）δ値； 1.10〜1.85（4H,m）,5.20〜6.25（2H,bs）， 7.42（2H,d,J＝9Hz）,7.90（2H,d,J＝9Hz） 同様にして、表−２の化合物を得た。Melting point 161 to 162 ° C (recrystallization solvent; benzene) IR (KBr) cm -1 ; 3390,3140,1680,1645,1620,1575 NMR (CDCl 3 ) δ value; 1.10 to 1.85 (4H, m), 5.20 to 6.25 (2H, bs), 7.42 (2H, d, J = 9Hz), 7.90 (2H, d, J = 9Hz) Similarly, the compounds of Table-2 were obtained.
参考例２ N,N−ジメチルホルムアミド100mlに水素化ナトリウム
（純度60％）3.53gを加え、５〜10℃で４−クロロベン
ゾイル酢酸エチルエステル20.0gを滴下した後、15〜20
℃で水素の発生が止むまで反応させる。ついで、同温度
で1,2−ジブロモエタン16.6gを加え、50〜60℃で３時間
反応させる。反応液を冷却し、５〜10℃で水素化ナトリ
ウム（純度60％）3.53gを加えた後、15〜20℃で水素の
発生が止むまで反応させる。ついで、同温度で1,2−ジ
ブロモエタン16.6gを加え、50〜60℃で４時間反応させ
る。反応液を冷却し、５〜10℃で水素化ナトリウム（純
度60％）2.47gを加えた後、15〜20℃で水素の発生が止
むまで反応させる。ついで、同温度で1,2−ジブロモエ
タン11.6gを加え、50〜60℃で４時間反応させる。反応
終了後、水400mlおよび酢酸エチル400mlを加え、2N塩酸
でpH6.0に調整する。有機層を分取し、水および飽和食
塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥
し、減圧下に溶媒を留去する。得られた残留物をカラム
クロマトグラフィー（溶出溶媒；トルエン）で精製すれ
ば、１−（４−クロロベンゾイル）−１−エトキシカル
ボニルシクロプロパン14.6g（収率65.5％）を得る。 Reference Example 2 To 100 ml of N, N-dimethylformamide, 3.53 g of sodium hydride (purity 60%) was added, and 20.0 g of 4-chlorobenzoylacetic acid ethyl ester was added dropwise at 5 to 10 ° C, and then 15 to 20
React at ℃ until hydrogen generation stops. Then, 16.6 g of 1,2-dibromoethane is added at the same temperature, and the mixture is reacted at 50-60 ° C for 3 hours. The reaction solution is cooled, 3.53 g of sodium hydride (purity 60%) is added at 5 to 10 ° C, and then the reaction is allowed to proceed at 15 to 20 ° C until generation of hydrogen stops. Then, 16.6 g of 1,2-dibromoethane is added at the same temperature, and the mixture is reacted at 50-60 ° C for 4 hours. The reaction solution is cooled, 2.47 g of sodium hydride (purity 60%) is added at 5 to 10 ° C., and then reacted at 15 to 20 ° C. until the generation of hydrogen stops. Then, 11.6 g of 1,2-dibromoethane is added at the same temperature, and the mixture is reacted at 50-60 ° C for 4 hours. After the reaction is completed, 400 ml of water and 400 ml of ethyl acetate are added, and the pH is adjusted to 6.0 with 2N hydrochloric acid. The organic layer is separated, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography (eluting solvent: toluene) to obtain 14.6 g (yield 65.5%) of 1- (4-chlorobenzoyl) -1-ethoxycarbonylcyclopropane.
油状物 IR（ニート）cm-1; 2960,1725,1675,1580 NMR（CDCl3）δ値； 1.00（3H,t,J＝7HZ）,1.40〜1.65（4H,m）， 4.06（2H,q,J＝7Hz）,7.10〜8.00（4H,m） 同様にして、つぎの化合物を得た。Oily substance IR (neat) cm -1 ; 2960,1725,1675,1580 NMR (CDCl 3 ) δ value; 1.00 (3H, t, J = 7HZ), 1.40 to 1.65 (4H, m), 4.06 (2H, q , J = 7 Hz), 7.10 to 8.00 (4H, m) Similarly, the following compound was obtained.
１−エトキシカルボニル−１−（2,4−ジフレオロベ
ンゾイル）シクロプロパン 油状物 IR（ニート）cm-1; 1710,1655,1590,1405,1125 NMR（CDCl3）δ値； 1.05（3H,t,J＝7Hz）,1.63（4H,s）， 4.09（2H,q,J＝7Hz）,6.45〜8.20（3H,m） 参考例３ エタノール100mlに１−（４−クロロベンゾイル）−
１−エトキシカルボニルシクロプロパン10.0gを加え、1
5〜20℃で1N水酸化ナトリウム水溶液100mlを滴下した
後、同温度で５時間反応させる。反応終了後、水200ml
を加え、6N塩酸でpH1.0に調整する。析出する結晶を
取し、水洗すれば、１−カルボキシ−１−（４−クロロ
ベンゾイル）シクロプロパン7.8g（収率87.6％）を得
る。1-Ethoxycarbonyl-1- (2,4-difluorobenzoyl) cyclopropane oil IR (neat) cm −1 ; 1710,1655,1590,1405,1125 NMR (CDCl 3 ) δ value; 1.05 (3H, t, J = 7Hz), 1.63 (4H, s), 4.09 (2H, q, J = 7Hz), 6.45 to 8.20 (3H, m) Reference Example 3 1- (4-chlorobenzoyl) -in 100 ml of ethanol
Add 1-ethoxycarbonylcyclopropane 10.0g,
After adding 100 ml of a 1N aqueous sodium hydroxide solution at 5 to 20 ° C, the mixture is reacted at the same temperature for 5 hours. After the reaction, 200 ml of water
And adjust to pH 1.0 with 6N hydrochloric acid. The precipitated crystals are collected and washed with water to obtain 7.8 g of 1-carboxy-1- (4-chlorobenzoyl) cyclopropane (yield 87.6%).
融点 152〜163℃ IR（KBr）cm-1; 1670,1580 NMR（d6−DMSO）δ値； 1.10〜1.65（4H,m）,7.59（2H,d,J＝9Hz）， 7.91（2H,d,J＝9Hz）,11.50〜13.50（1H,bs） 参考例４ クロロホルム20mlに１−（４−クロロベンゾイル）−
１−ヒドロキシカルボニルシクロプロパン2.0gおよびN,
N−ジメチルホルムアミド0.05mlを加え、５〜10℃でオ
キサリルクロリド2.3gを滴下した後、５〜15℃で３時間
反応させる。ついで、減圧下に溶媒を留去し、得られた
残留物をクロロホルム10mlに溶解させた後、５〜10℃で
2,2,2−トリフルオロエチルアミン・塩酸塩2.4gおよび
トリエチルアミン5mlを含むクロロホルム溶液20mlに滴
下し、15〜20℃で１時間反応させる。反応終了後、反応
液を水、1N塩酸、水および飽和食塩水で順次洗浄した
後、無水硫酸マグネシウムで乾燥し、減圧下に溶媒を留
去する。得られた残留物をカラムクロマトグラフィー
（溶出溶媒；トルエン：酢酸エチル＝20:1）で精製すれ
ば、１−（４−クロロベンゾイル）−１−［Ｎ−（2,2,
2−トリフルオロエチル）カルバモイル］シクロプロパ
ン1.3g（収率47.8％）を得る。Melting point 152-163 ° C IR (KBr) cm -1 ; 1670,1580 NMR (d 6 -DMSO) δ value; 1.10-1.65 (4H, m), 7.59 (2H, d, J = 9Hz), 7.91 (2H, d, J = 9 Hz), 11.50 to 13.50 (1H, bs) Reference Example 4 1- (4-chlorobenzoyl)-in 20 ml of chloroform
1-hydroxycarbonylcyclopropane 2.0 g and N,
0.05 ml of N-dimethylformamide was added, 2.3 g of oxalyl chloride was added dropwise at 5 to 10 ° C., and then the mixture was reacted at 5 to 15 ° C. for 3 hours. Then, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in 10 ml of chloroform, and then at 5-10 ° C.
It is added dropwise to 20 ml of a chloroform solution containing 2.4 g of 2,2,2-trifluoroethylamine.hydrochloride and 5 ml of triethylamine, and reacted at 15 to 20 ° C for 1 hour. After completion of the reaction, the reaction solution is washed successively with water, 1N hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (elution solvent; toluene: ethyl acetate = 20: 1) to give 1- (4-chlorobenzoyl) -1- [N- (2,2,2,
1.3 g (yield 47.8%) of 2-trifluoroethyl) carbamoyl] cyclopropane are obtained.
融点 115.5〜116.5℃ （再結晶溶媒；ベンゼン−ｎ−ヘキサン） IR（KBr）cm-1; 3330,1680,1650,1580,1540 NMR（CDCl3）δ値； 1.10〜1.90（4H,m）， 3.85（2H,dq,J＝6Hz,J＝9Hz）， 6.00〜6.70（1H,m）,7.42（2H,d,J＝9Hz）， 7.80（2H,d,J＝9Hz） 同様にして、表−３の化合物を得た。Melting point 115.5 to 116.5 ° C (recrystallization solvent; benzene-n-hexane) IR (KBr) cm -1 ; 3330,1680,1650,1580,1540 NMR (CDCl 3 ) δ value; 1.10 to 1.90 (4H, m), 3.85 (2H, dq, J = 6Hz, J = 9Hz), 6.00 to 6.70 (1H, m), 7.42 (2H, d, J = 9Hz), 7.80 (2H, d, J = 9Hz) -3 compound was obtained.
参考例５ 乾燥ジメチルスルホキシド180mlに水素化ナトリウム
（純度60％）4.2gを加え、撹拌下、20℃でヨウ化トリメ
チルオキソスルホニウム26.4gを分割添加し、20〜25℃
で水素の発生が止むまで反応させる。ついで、同温度で
１−カルバモイル−１−（４−クロロベンゾイル）シク
ロプロパン22.4gを加え、２時間反応させる。反応終了
後、反応液を水450mlおよび酢酸エチル540mlの混合溶媒
の中へ導入し、2N塩酸でpH6.0に調整した後、有機層を
分取する。ついで、有機層を水洗し、無水硫酸マグネシ
ウムで乾燥した後、減圧下に溶媒を留去する。得られた
残留物にジエチルエーテルを加え、結晶を取すれば、
２−［１−（カルバモイル）シクロプロパン−１−イ
ル］−２−（４−クロロフェニル）オキシラン21.2g
（収率89.1％）を得る。 Reference Example 5 To 180 ml of dry dimethylsulfoxide, 4.2 g of sodium hydride (purity 60%) was added, and 26.4 g of trimethyloxosulfonium iodide was added in portions at 20 ° C. under stirring to 20 to 25 ° C.
Then react until hydrogen generation stops. Then, 22.4 g of 1-carbamoyl-1- (4-chlorobenzoyl) cyclopropane was added at the same temperature and the reaction was carried out for 2 hours. After completion of the reaction, the reaction solution is introduced into a mixed solvent of 450 ml of water and 540 ml of ethyl acetate, adjusted to pH 6.0 with 2N hydrochloric acid, and the organic layer is separated. Then, the organic layer is washed with water and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Diethyl ether was added to the obtained residue and crystals were taken,
2- [1- (carbamoyl) cyclopropan-1-yl] -2- (4-chlorophenyl) oxirane 21.2 g
(Yield 89.1%) is obtained.
融点 176〜178℃（再結晶溶媒；ベンゼン） IR（KBr）cm-1; 3480,3160,1690,1610,1490 NMR（CDCl3）δ値； 0.60〜1.95（4H,m）,2.91（1H,d,J＝5Hz）， 3.10（1H,d,J＝5Hz）,5.40〜6.30（2H,bs）， 7.20〜7.75（4H,m） 同様にして、表−４の化合物を得た。Melting point 176 to 178 ° C (recrystallization solvent; benzene) IR (KBr) cm -1 ; 3480,3160,1690,1610,1490 NMR (CDCl 3 ) δ value; 0.60 to 1.95 (4H, m), 2.91 (1H, d, J = 5Hz), 3.10 (1H, d, J = 5Hz), 5.40 to 6.30 (2H, bs), 7.20 to 7.75 (4H, m) In the same manner, the compounds of Table-4 were obtained.
実施例１ ２−［１−（カルバモイル）シクロプロパン−１−イ
ル］−２−（４−クロロフェニル）オキシラン23.8gを
N,N−ジメチルホルムアミド238mlに溶解させた後、1,2,
4−トリアゾールのナトリウム塩13.7gを加え、50〜60℃
で５時間反応させる。反応終了後、減圧下に溶媒を留去
し、得られた残留物に水200mlおよび酢酸エチル200mlを
加えて溶解させた後、2N塩酸でpH6.0に調整する。有機
層を分取し、水洗した後、無水硫酸マグネシウムで乾燥
し、減圧下に溶媒を留去する。得られた残留物をカラム
クロマトグラフィー（溶出溶媒；クロロホルム：メタノ
ール＝100:1）で精製すれば、１−［１−（カルバモイ
ル）シクロプロパン−１−イル］−１−（４−クロロフ
ェニル）−２−（1,2,4−トリアゾール−１−イル）エ
タノール16.2g（収率52.8％）を得る。 Example 1 23.8 g of 2- [1- (carbamoyl) cyclopropan-1-yl] -2- (4-chlorophenyl) oxirane
After dissolving in 238 ml of N, N-dimethylformamide, 1,2,
13.7 g of sodium salt of 4-triazole was added, and the temperature was 50 to 60 ° C.
React for 5 hours. After completion of the reaction, the solvent is distilled off under reduced pressure, 200 ml of water and 200 ml of ethyl acetate are added to the obtained residue to dissolve it, and the pH is adjusted to 6.0 with 2N hydrochloric acid. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluting solvent: chloroform: methanol = 100: 1) to give 1- [1- (carbamoyl) cyclopropan-1-yl] -1- (4-chlorophenyl)- 16.2 g (yield 52.8%) of 2- (1,2,4-triazol-1-yl) ethanol are obtained.
融点 181〜182℃ （再結晶溶媒；ベンゼン−酢酸エチル） IR（KBr）cm-1; 3400,3330,3160,1655,1485 NMR（d6−DMSO）δ値； 0.50〜1.40（4H,m）,4.77（2H,s）， 6.11（1H,bs）,6.86（2H,bs）， 7.10〜7.60（4H,m）,7.76（1H,s）， 8.20（1H,s） 実施例２ ２−（４−クロロフェニル）−２−［１−（Ｎ−シク
ロプロピルカルバモイル）シクロプロパン−１−イル］
オキシラン27.8gをN,N−ジメチルホルムアミド250mlに
溶解させ、イミダゾール13.6gおよび炭酸カリウム13.8g
を加えた後、60〜70℃で10時間反応させる。反応終了
後、減圧下に溶媒を留去し、得られた残留物に水250ml
および酢酸エチル250mlを加えて溶解させた後、2N塩酸
でpH6.0に調整する。有機層を分取し、水洗した後、無
水硫酸マグネシウムで乾燥し、減圧下に溶媒を留去す
る。得られた残留物をカラムクロマトグラフィー（溶出
溶媒；クロロホルム：メタノール＝25:1）で精製すれ
ば、１−（４−クロロフェニル）−１−［１−（Ｎ−シ
クロプロピルカルバモイル）シクロプロパン−１−イ
ル］−２−（イミダゾール−１−イル）エタノール16.7
g（収率48.3％）を得る。Melting point 181 to 182 ° C (recrystallization solvent; benzene-ethyl acetate) IR (KBr) cm -1 ; 3400,3330,3160,1655,1485 NMR (d 6 -DMSO) δ value; 0.50 to 1.40 (4H, m) , 4.77 (2H, s), 6.11 (1H, bs), 6.86 (2H, bs), 7.10 to 7.60 (4H, m), 7.76 (1H, s), 8.20 (1H, s) Example 2 2- ( 4-chlorophenyl) -2- [1- (N-cyclopropylcarbamoyl) cyclopropan-1-yl]
27.8 g of oxirane was dissolved in 250 ml of N, N-dimethylformamide, and 13.6 g of imidazole and 13.8 g of potassium carbonate.
Then, the mixture is reacted at 60 to 70 ° C for 10 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the resulting residue was mixed with 250 ml of water.
Then, 250 ml of ethyl acetate is added and dissolved, and the pH is adjusted to 6.0 with 2N hydrochloric acid. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (elution solvent; chloroform: methanol = 25: 1) to give 1- (4-chlorophenyl) -1- [1- (N-cyclopropylcarbamoyl) cyclopropane-1. -Yl] -2- (imidazol-1-yl) ethanol 16.7
g (yield 48.3%) is obtained.
融点 187〜188℃ （再結晶溶媒；ベンゼン−酢酸エチル） IR（KBr）cm-1; 3320,1630,1530,1505（sh） NMR（CDCl3）δ値； 0.35〜1.50（8H,m）,2.20〜2.70（1H,m）， 4.08（1H,d,J＝14Hz）,4.39（1H,d,J＝14Hz）， 4.80〜5.60（1H,m）,6.40〜7.55（7H,m） 実施例３〜17 実施例１と同様にして、表−５の化合物を得た。Melting point 187 to 188 ° C (recrystallization solvent; benzene-ethyl acetate) IR (KBr) cm -1 ; 3320,1630,1530,1505 (sh) NMR (CDCl 3 ) δ value; 0.35 to 1.50 (8H, m), 2.20 to 2.70 (1H, m), 4.08 (1H, d, J = 14Hz), 4.39 (1H, d, J = 14Hz), 4.80 to 5.60 (1H, m), 6.40 to 7.55 (7H, m) Example 3-17 It carried out similarly to Example 1, and obtained the compound of Table-5.
実施例18 （１） ２−（４−クロロフェニル）−２−［１−（エ
トキシカルボニル）シクロプロパン−１−イル］オキシ
ラン26.7gをN,N−ジメチルホルムアミド260mlに溶解さ
せた後、1,2,4−トリアゾールのナトウム塩18gを加え、
60〜70℃で５時間反応させる。反応終了後、減圧下に溶
媒を留去し、得られた残留物に水200mlおよび酢酸エチ
ル200mlを加えて溶解させた後、2N塩酸でpH6.0に調整す
る。有機層を分取し、水洗した後、無水硫酸マグネシウ
ムで乾燥し、減圧下に溶媒を留去する。得られた残留物
をカラムクロマトグラフィー（溶出溶媒；クロロホル
ム）で精製すれば、１−（４−クロロフェニル）−１−
［１−（エトキシカルボニル）シクロプロパン−１−イ
ル］−２−（1,2,4−トリアゾール−１−イル）エタノ
ール10.8g（収率32.1％）を得る。 Example 18 (1) 2-6.7 g of 2- (4-chlorophenyl) -2- [1- (ethoxycarbonyl) cyclopropan-1-yl] oxirane was dissolved in 260 ml of N, N-dimethylformamide, and then 1,2 18 g of 4,4-triazole sodium salt was added,
React at 60-70 ° C for 5 hours. After completion of the reaction, the solvent is distilled off under reduced pressure, 200 ml of water and 200 ml of ethyl acetate are added to the obtained residue to dissolve it, and the pH is adjusted to 6.0 with 2N hydrochloric acid. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluting solvent: chloroform) to give 1- (4-chlorophenyl) -1-
10.8 g (yield 32.1%) of [1- (ethoxycarbonyl) cyclopropan-1-yl] -2- (1,2,4-triazol-1-yl) ethanol are obtained.
融点 73〜76℃（再結晶溶媒:IPE） IR（KBr）cm-1; 3280,2950,1710,1505,1485 NMR（CDCl3）δ値； 0.50〜1.55（7H,m）,4.04（2H,q,J＝7Hz）， 4.74（1H,d,J＝14Hz）,4.95（1H,bs）， 5.36（1H,d,J＝14Hz）,7.27（2H,d,J＝9Hz）， 7.54（2H,d,J＝9Hz）,7.87（1H,s）,8.13（1H,s） （２） １−（４クロロフェニル）−１−［１−（エト
キシカルボニル）シクロプロパン−１−イル］−２−
（1,2,4−トリアゾール−１−イル）エタノール33.6gを
1N水酸化ナトリウム水溶液336mlおよびエタノール336ml
の混合溶媒に撹拌下添加し、25℃で３時間反応させる。
反応終了後、水350mlおよび酢酸エチル800mlを加え、2N
塩酸でpH3.5に調整する。ついで、有機層を分取し、水
および飽和食塩水で順次洗浄した後、無水硫酸マグネシ
ウムで乾燥する。減圧下に溶媒を留去し、得られた残留
物にジエチルエーテルを加えた後、結晶を取し、ジエ
チルエーテルで洗浄すれば、１−［１−（カルボキシ）
シクロプロパン−１−イル］−１−（４−クロロフェニ
ル）−２−（1,2,4−トリアゾール−１−イル）エタノ
ール28.3g（収率91.9％）を得る。Melting point 73 to 76 ° C (recrystallization solvent: IPE) IR (KBr) cm -1 ; 3280,2950,1710,1505,1485 NMR (CDCl 3 ) δ value; 0.50 to 1.55 (7H, m), 4.04 (2H, q, J = 7Hz), 4.74 (1H, d, J = 14Hz), 4.95 (1H, bs), 5.36 (1H, d, J = 14Hz), 7.27 (2H, d, J = 9Hz), 7.54 (2H) , d, J = 9Hz), 7.87 (1H, s), 8.13 (1H, s) (2) 1- (4chlorophenyl) -1- [1- (ethoxycarbonyl) cyclopropan-1-yl] -2-
(1,2,4-triazol-1-yl) ethanol 33.6 g
336 ml of 1N sodium hydroxide solution and 336 ml of ethanol
It is added to the mixed solvent of 1 under stirring and reacted at 25 ° C. for 3 hours.
After completion of the reaction, add 350 ml of water and 800 ml of ethyl acetate, and add 2N.
Adjust to pH 3.5 with hydrochloric acid. Then, the organic layer is separated, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the obtained residue, crystals were taken, and washed with diethyl ether to give 1- [1- (carboxy)
28.3 g (yield 91.9%) of cyclopropan-1-yl] -1- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl) ethanol are obtained.
融点 175〜179℃（再結晶溶媒;IPA） IR（KBr）cm-1; 3100,1710,1505,1480 NMR（d6−DMSO）δ値； 0.20〜1.40（4H,m）,4.88（1H,d,J＝14Hz）， 5.30（1H,d,J＝14Hz）,7.36（2H,d,J＝9Hz）， 5.32（2H,d,J＝9Hz）,7.89（1H,s）,8.29（1H,s） 実施例19 実施例18（１）、（２）と同様にして、それぞれつぎ
の化合物を得た。Melting point 175 to 179 ° C (recrystallization solvent; IPA) IR (KBr) cm -1 ; 3100,1710,1505,1480 NMR (d 6 -DMSO) δ value; 0.20 to 1.40 (4H, m), 4.88 (1H, d, J = 14Hz), 5.30 (1H, d, J = 14Hz), 7.36 (2H, d, J = 9Hz), 5.32 (2H, d, J = 9Hz), 7.89 (1H, s), 8.29 (1H) , s) Example 19 The following compounds were obtained in the same manner as in Example 18 (1) and (2).
１−［１−（エトキシカルボニル）シクロプロパン−
１−イル］−１−（2,4−ジフルオロフェニル）−２−
（1,2,4−トリアゾール−１−イル）エタノール 融点 114〜115℃（再結晶溶媒;IPE） IR（KBr）cm-1; 3120,1720,1610,1500,1310,1205 NMR（CDCl3）δ値； 0.60〜1.50（7H,m）,4.08（2H,q,J＝7Hz）， 4.86（1H,d,J＝14Hz）,5.13（1H,d,J＝14Hz）， 5.16（1H,bs）,6.30〜7.75（3H,m）， 7.80（1H,s）,8.13（1H,s） １−［１−（カルボキシ）シクロプロパン−１−イ
ル］−１−（2,4−ジフルオロフェニル）−２−（1,2,4
−トリアゾール−１−イル）エタノール 融点 180〜181℃（再結晶溶媒；酢酸エチル） IR（KBr）cm-1; 3320,1650,1605,1580,1490,1320,1180 NMR（d6−DMSO＋CDCl3）δ値； 0.25〜1.50（4H,m）,4.95（1H,d,J＝14Hz）， 5.25（1H,d,J＝14Hz）,5.75（2H,bs）， 6.45〜7.80（4H,m）,8.22（1H,s） 実施例20 １−（４−クロロフェニル）−１−［１−（エトキシ
カルボニル）シクロプロパン−１−イル］−２−（1,2,
4−トリアゾール−１−イル）エタノール3.4gを２−ア
ミノエタノール17mlに加え、150〜160℃で３時間反応さ
せる。反応終了後、反応液を水150mlおよび酢酸エチル1
50mlの混合溶媒の中へ導入し、2N塩酸でpH6.0に調整す
る。ついで、有機層を分取し、水および飽和食塩水で順
次洗浄した後、無水硫酸マグネシウムで乾燥する。減圧
下に溶媒を留去し、得られた残留物をカラムクロマトグ
ラフィー（溶出溶媒；クロロホルム：メタノール＝20:
1）で精製すれば、１−（４−クロロフェニル）−１−
｛１−［Ｎ−（２−ヒドロキシエチル）カルバモイル］
シクロプロパン−１−イル｝−２−（1,2,4−トリアゾ
ール−１−イル）エタノール2.17g（収率61.1％）を得
る。1- [1- (ethoxycarbonyl) cyclopropane-
1-yl] -1- (2,4-difluorophenyl) -2-
(1,2,4-triazol-1-yl) ethanol Melting point 114-115 ° C (recrystallization solvent; IPE) IR (KBr) cm -1 ; 3120,1720,1610,1500,1310,1205 NMR (CDCl 3 ). δ value: 0.60 to 1.50 (7H, m), 4.08 (2H, q, J = 7Hz), 4.86 (1H, d, J = 14Hz), 5.13 (1H, d, J = 14Hz), 5.16 (1H, bs ), 6.30 to 7.75 (3H, m), 7.80 (1H, s), 8.13 (1H, s) 1- [1- (carboxy) cyclopropan-1-yl] -1- (2,4-difluorophenyl) -2- (1,2,4
-Triazol-1-yl) ethanol Melting point 180-181 ° C (recrystallization solvent; ethyl acetate) IR (KBr) cm -1 ; 3320,1650,1605,1580,1490,1320,1180 NMR (d 6 -DMSO + CDCl 3 ). δ value: 0.25 to 1.50 (4H, m), 4.95 (1H, d, J = 14Hz), 5.25 (1H, d, J = 14Hz), 5.75 (2H, bs), 6.45 to 7.80 (4H, m), 8.22 (1H, s) Example 20 1- (4-chlorophenyl) -1- [1- (ethoxycarbonyl) cyclopropan-1-yl] -2- (1,2,
3.4 g of 4-triazol-1-yl) ethanol is added to 17 ml of 2-aminoethanol, and the mixture is reacted at 150 to 160 ° C. for 3 hours. After the reaction was completed, the reaction solution was mixed with 150 ml of water and ethyl acetate
It is introduced into 50 ml of a mixed solvent and adjusted to pH 6.0 with 2N hydrochloric acid. Then, the organic layer is separated, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (eluting solvent; chloroform: methanol = 20:
If purified in 1), 1- (4-chlorophenyl) -1-
{1- [N- (2-hydroxyethyl) carbamoyl]
2.17 g (yield 61.1%) of cyclopropan-1-yl} -2- (1,2,4-triazol-1-yl) ethanol are obtained.
融点 115.5〜116.5℃ （再結晶溶媒；ベンゼン−ｎ−ヘキサン） IR（KBr）cm-1; 3320,1625,1535,1085,820 NMR（CDCl3）δ値； 0.50〜1.40（4H,m）,2.50〜3.00（1H,m）， 3.00〜3.70（4H,m）,4.65（1H,d,J＝14Hz）， 4.96（1H,d,J＝14Hz）,5.61（1H,bs）， 6.40〜6.90（1H,m）,7.00〜7.50（4H,m）， 7.80（1H,s）,8.11（1H,s） 実施例21 実施例20と同様にして、つぎの化合物を得た。Melting point 115.5 to 116.5 ° C (recrystallization solvent; benzene-n-hexane) IR (KBr) cm -1 ; 3320,1625,1535,1085,820 NMR (CDCl 3 ) δ value; 0.50 to 1.40 (4H, m), 2.50 to 3.00 (1H, m), 3.00 to 3.70 (4H, m), 4.65 (1H, d, J = 14Hz), 4.96 (1H, d, J = 14Hz), 5.61 (1H, bs), 6.40 to 6.90 (1H, m), 7.00 to 7.50 (4H, m), 7.80 (1H, s), 8.11 (1H, s) Example 21 In the same manner as in Example 20, the following compound was obtained.
１−（４−クロロフェニル）−１−｛１−［Ｎ−（３
−ヒドロキシプロピル）カルバモイル］シクロプロパン
−１−イル｝−２−（1,2,4−トリアゾール−１−イ
ル）エタノール 融点 107〜109℃ （再結晶溶媒；ベンゼン−酢酸エチル） IR（KBr）cm-1; 3370,3270,1620,1540 NMR（d6−DMSO）δ値； 0.35〜1.60（6H,m）,2.60〜3.40（4H,m）， 3.95〜4.40（1H,m）， 4.64（1H,d,J＝15Hz）,4.94（1H,d,J＝15Hz）， 6.07（1H,bs）,6.95〜7.60（4H,m）， 7.77（1H,s）,8.25（1H,s） 実施例22 １−［１−（カルボキシ）シクロプロパン−１−イ
ル］−１−（４−クロロフェニル）−２−（1,2,4−ト
リアゾール−１−イル）エタノール3.1gおよびＮ−ヒド
ロキシスクシンイミド1.2gを無水ジオキサン150mlに溶
解させ、N,N′−ジシクロヘキシルカルボジイミド2.1g
を加えた後、室温で３時間反応させる。不溶物を去
し、５〜10℃でモルホリン6.1gを加えた後、室温で20時
間反応させる。反応終了後、減圧下に溶媒を留去し、得
られた残留物に水200mlおよび酢酸エチル200mlを加えて
溶解させる。有機層を分取し、飽和食塩水で２回洗浄し
た後、無水硫酸マグネシウムで乾燥し、減圧下に溶媒を
留去する。得られた残留物をカラムクロマトグラフィー
（溶出溶媒；クロロホルム：メタノール＝20:1）で精製
すれば、１−（４−クロロフェニル）−１−［１−（モ
ルホリノカルボニル）シクロプロパン−１−イル］−２
−（1,2,4−トリアゾール−１−イル）エタノール950mg
（収率25.0％）を得る。1- (4-chlorophenyl) -1- {1- [N- (3
-Hydroxypropyl) carbamoyl] cyclopropan-1-yl} -2- (1,2,4-triazol-1-yl) ethanol Melting point 107-109 ° C (recrystallization solvent; benzene-ethyl acetate) IR (KBr) cm -1 ; 3370,3270,1620,1540 NMR (d 6 -DMSO) δ value: 0.35 to 1.60 (6H, m), 2.60 to 3.40 (4H, m), 3.95 to 4.40 (1H, m), 4.64 (1H , d, J = 15Hz), 4.94 (1H, d, J = 15Hz), 6.07 (1H, bs), 6.95 to 7.60 (4H, m), 7.77 (1H, s), 8.25 (1H, s) 22 1- [1- (carboxy) cyclopropan-1-yl] -1- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl) ethanol 3.1 g and N-hydroxysuccinimide 1.2 g Was dissolved in 150 ml of anhydrous dioxane, and 2.1 g of N, N′-dicyclohexylcarbodiimide was dissolved.
After adding, the mixture is reacted at room temperature for 3 hours. The insoluble matter was removed, 6.1 g of morpholine was added at 5 to 10 ° C, and the mixture was reacted at room temperature for 20 hours. After completion of the reaction, the solvent is distilled off under reduced pressure, and 200 ml of water and 200 ml of ethyl acetate are added to the obtained residue to dissolve it. The organic layer is separated, washed twice with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (elution solvent; chloroform: methanol = 20: 1) to give 1- (4-chlorophenyl) -1- [1- (morpholinocarbonyl) cyclopropan-1-yl]. -2
-(1,2,4-triazol-1-yl) ethanol 950mg
(Yield 25.0%) is obtained.
融点 160.5〜161.0℃ （再結晶溶媒；ベンゼン−ｎ−ヘキサン） IR（KBr）cm-1; 3400,3250,1605,1430,1120 NMR（CDCl3）δ値； 0.35〜1.50（4H,m）,2.50〜3.90（8H,m）， 4.84（1H,d,J＝14Hz）,5.11（1H,d,J＝14Hz）， 5.13（1H,bs）,6.80〜7.50（4H,m）， 7.80（1H,s）,8.20（1H,s） 実施例23〜29 実施例22と同様にして、表−６の化合物を得た。Melting point 160.5 to 161.0 ° C. (recrystallization solvent; benzene-n-hexane) IR (KBr) cm −1 ; 3400,3250,1605,1430,1120 NMR (CDCl 3 ) δ value; 0.35 to 1.50 (4H, m), 2.50 ~ 3.90 (8H, m), 4.84 (1H, d, J = 14Hz), 5.11 (1H, d, J = 14Hz), 5.13 (1H, bs), 6.80 ~ 7.50 (4H, m), 7.80 (1H) , s), 8.20 (1H, s) Examples 23 to 29 In the same manner as in Example 22, the compounds in Table 6 were obtained.
実施例30 （１） １−［１−（カルボキシ）シクロプロパン−１
−イル］−１−（４−クロロフェニル）−２−（1,2,4
−トリアゾール−１−イル）エタノール1.0gおよびＮ−
ヒドロキシスクシンイミド410mlを無水ジオキサン20ml
に溶解させ、N,N′−ジシクロヘキシルカルボジイミド7
40mgを加えた後、室温で３時間反応させる。ついで、５
〜10℃でトリエチルアミン1.0gを加えた後、室温で20時
間反応させる。反応終了後、不溶物を去し、減圧下に
溶媒を留去する。得られた残留物に水およびクロロホル
ム50mlを加えて溶解させる。有機層を分取し、水および
飽和食塩水で順次洗浄した後、無水硫酸マグネシウムで
乾燥し、減圧下に溶媒を留去する。得られた残留物をカ
ラムクロマトグラフィー（溶出溶媒；クロロホルム：メ
タノール＝50:1）で精製すれば、６−（４−クロロフェ
ニル）−２−オキソ−６−［（1,2,4−トリアゾール−
１−イル）メチル］−１−オキサスピロ［3.2］ヘキサ
ン650mg（収率69％）を得る。 Example 30 (1) 1- [1- (carboxy) cyclopropane-1
-Yl] -1- (4-chlorophenyl) -2- (1,2,4
-Triazol-1-yl) ethanol 1.0 g and N-
Hydroxysuccinimide 410ml anhydrous dioxane 20ml
Dissolved in N, N'-dicyclohexylcarbodiimide 7
After adding 40 mg, the mixture is reacted at room temperature for 3 hours. Then 5
After adding 1.0 g of triethylamine at ~ 10 ° C, the mixture is reacted at room temperature for 20 hours. After completion of the reaction, the insoluble matter is removed and the solvent is distilled off under reduced pressure. Water and 50 ml of chloroform are added to the obtained residue to dissolve it. The organic layer is separated, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluting solvent: chloroform: methanol = 50: 1) to give 6- (4-chlorophenyl) -2-oxo-6-[(1,2,4-triazole-
650 mg (69% yield) of 1-yl) methyl] -1-oxaspiro [3.2] hexane are obtained.
融点 108.0〜110.0℃ （再結晶溶媒；ベンゼン−ｎ−ヘキサン−IPE） IR（KBr）cm-1; 1820,1505,1265,1130,830 NMR（CDCl3）δ値； 0.60〜2.00（4H,m）,4.83（2H,s）， 7.10（2H,d,J＝9Hz）,7.39（2H,d,J＝9Hz）， 7.85（1H,s）,8.10（1H,s） （２） ６−（４−クロロフェニル）−２−オキソ−６
−［（1,2,4−トリアゾール−１−イル）メチル］−１
−オキサスピロ［3.2］ヘキサン200mgおよびｎ−ペンチ
ルアミン600mgをクロロホルム5mlに溶解させ、３時間還
流する。反応終了後、水および飽和食塩水で順次洗浄し
た後、無水硫酸マグネシウムで乾燥する。減圧下に溶媒
を留去し、得られた残留物をカラムクロマトグラフィー
（溶出溶媒；クロロホルム：メタノール＝50:1）で精製
すれば、１−（４−クロロフェニル）−１−［１−（Ｎ
−ｎ−ペンチルカルバモイル）シクロプロパン−１−イ
ル］−２−（1,2,4−トリアゾール−１−イル）エタノ
ール130mg（収率50％）を得る。Melting point 108.0-110.0 ° C (recrystallization solvent; benzene-n-hexane-IPE) IR (KBr) cm -1 ; 1820,1505,1265,1130,830 NMR (CDCl 3 ) δ value; 0.60-2.00 (4H, m ), 4.83 (2H, s), 7.10 (2H, d, J = 9Hz), 7.39 (2H, d, J = 9Hz), 7.85 (1H, s), 8.10 (1H, s) (2) 6- ( 4-chlorophenyl) -2-oxo-6
-[(1,2,4-triazol-1-yl) methyl] -1
200 mg of oxaspiro [3.2] hexane and 600 mg of n-pentylamine are dissolved in 5 ml of chloroform and refluxed for 3 hours. After completion of the reaction, the organic layer is washed with water and saturated saline solution in that order and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (elution solvent; chloroform: methanol = 50: 1) to give 1- (4-chlorophenyl) -1- [1- (N
130 mg (yield 50%) of -n-pentylcarbamoyl) cyclopropan-1-yl] -2- (1,2,4-triazol-1-yl) ethanol are obtained.
融点 96.0〜97.5℃ （再結晶溶媒；ベンゼン−ｎ−ヘキサン−IPE） IR（KBr）cm-1; 3320,1625,1530,1260,1080 NMR（CDCl3）δ値； 0.20〜1.80（13H,m）,2.70〜3.40（2H,m）， 4.30〜5.50（3H,m）,5.80〜6.50（1H,m）， 7.00〜7.50（4H,m）,7.82（1H,s）,8.15（1H,s）Melting point 96.0-97.5 ° C (recrystallization solvent; benzene-n-hexane-IPE) IR (KBr) cm -1 ; 3320,1625,1530,1260,1080 NMR (CDCl 3 ) δ value; 0.20-1.80 (13H, m ), 2.70 to 3.40 (2H, m), 4.30 to 5.50 (3H, m), 5.80 to 6.50 (1H, m), 7.00 to 7.50 (4H, m), 7.82 (1H, s), 8.15 (1H, s) )
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ａ６１Ｋ 31/44 Ａ６１Ｋ 31/44 Ｃ０７Ｃ 62/38 2115−4Ｈ Ｃ０７Ｃ 62/38 235/82 9547−4Ｈ 235/82 Ｃ０７Ｄ 213/40 Ｃ０７Ｄ 213/40 303/40 303/40 303/46 303/46 405/12 ２１３ 405/12 ２１３ ２４９ ２４９ (72)発明者 酒井 広志 富山県高岡市下牧野1575 審査官 冨士 美香─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. 6 Identification code Internal reference number FI Technical indication location A61K 31/44 A61K 31/44 C07C 62/38 2115-4H C07C 62/38 235/82 9547-4H 235/82 C07D 213/40 C07D 213/40 303/40 303/40 303/46 303/46 405/12 213 405/12 213 249 249 (72) Inventor Hiroshi Sakai 1575 Shimomakino, Takaoka, Toyama Prefecture Examiner Fuji Mika
Claims (1)
アリール基を;R2はヒドロキシル基または置換されてい
てもよいアミノ基を示す。」 で表わされる２−アゾリル−１−シクロプロピルエタノ
ール誘導体およびその塩。(1) General formula 2-azolyl-1 represented by the formula: "wherein A represents CH or N; R 1 represents an optionally substituted aryl group; R 2 represents a hydroxyl group or an optionally substituted amino group." -Cyclopropyl ethanol derivatives and their salts.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63075154A JP2681648B2 (en) | 1988-03-29 | 1988-03-29 | Novel 2-azolyl-1-cyclopropylethanol derivative and its salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63075154A JP2681648B2 (en) | 1988-03-29 | 1988-03-29 | Novel 2-azolyl-1-cyclopropylethanol derivative and its salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01249755A JPH01249755A (en) | 1989-10-05 |
| JP2681648B2 true JP2681648B2 (en) | 1997-11-26 |
Family
ID=13568003
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63075154A Expired - Lifetime JP2681648B2 (en) | 1988-03-29 | 1988-03-29 | Novel 2-azolyl-1-cyclopropylethanol derivative and its salt |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2681648B2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3839170A1 (en) * | 1988-11-19 | 1990-05-31 | Bayer Ag | CYCLOPROPYL-SUBSTITUTED AZOLYLMETHYL CARBINOLES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICAMENTS |
| GB9107055D0 (en) * | 1991-04-04 | 1991-05-22 | Pfizer Ltd | Triazole antifungal agents |
| DE4206529A1 (en) * | 1992-03-02 | 1993-09-09 | Bayer Ag | AZOLYL METHYL CYCLOPROPYL DERIVATIVES |
-
1988
- 1988-03-29 JP JP63075154A patent/JP2681648B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01249755A (en) | 1989-10-05 |
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