CN1046278C - 吡咯胺衍生物 - Google Patents
吡咯胺衍生物 Download PDFInfo
- Publication number
- CN1046278C CN1046278C CN94192041A CN94192041A CN1046278C CN 1046278 C CN1046278 C CN 1046278C CN 94192041 A CN94192041 A CN 94192041A CN 94192041 A CN94192041 A CN 94192041A CN 1046278 C CN1046278 C CN 1046278C
- Authority
- CN
- China
- Prior art keywords
- compound
- difluorophenyl
- triazol
- butan
- acid addition
- 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
- QLSWIGRIBOSFMV-UHFFFAOYSA-N 1h-pyrrol-2-amine Chemical class NC1=CC=CN1 QLSWIGRIBOSFMV-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- 239000002253 acid Substances 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 229940121375 antifungal agent Drugs 0.000 claims abstract description 13
- 239000003429 antifungal agent Substances 0.000 claims abstract description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 12
- 239000004480 active ingredient Substances 0.000 claims abstract description 9
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 6
- -1 (2R, 3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butyl Chemical group 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 1
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 37
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 23
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- 238000006243 chemical reaction Methods 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
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- 239000000126 substance Substances 0.000 description 9
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- MPPIBJJDFLONMO-UHFFFAOYSA-N 1-benzylpiperidine;hydron;chloride Chemical compound Cl.C=1C=CC=CC=1CN1CCCCC1 MPPIBJJDFLONMO-UHFFFAOYSA-N 0.000 description 7
- 230000000843 anti-fungal effect Effects 0.000 description 7
- 229960004022 clotrimazole Drugs 0.000 description 7
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
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- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
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- 150000001412 amines Chemical group 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 4
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- NFEZZTICAUWDHU-RDTXWAMCSA-N efinaconazole Chemical compound N1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)CCC(=C)CC1 NFEZZTICAUWDHU-RDTXWAMCSA-N 0.000 description 4
- 229960004884 fluconazole Drugs 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical class N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 201000007336 Cryptococcosis Diseases 0.000 description 3
- 241000221204 Cryptococcus neoformans Species 0.000 description 3
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 3
- 206010017533 Fungal infection Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 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
- 241001045770 Trichophyton mentagrophytes Species 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 230000037396 body weight Effects 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
- 239000006071 cream Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- USWWVZJEOYCMQL-UHFFFAOYSA-N 1,4-dibenzylpiperidine Chemical compound C=1C=CC=CC=1CC(CC1)CCN1CC1=CC=CC=C1 USWWVZJEOYCMQL-UHFFFAOYSA-N 0.000 description 2
- QANJLSHZDUOBBP-QPUJVOFHSA-N 1-[[(2r,3s)-2-(2,4-difluorophenyl)-3-methyloxiran-2-yl]methyl]-1,2,4-triazole Chemical class C[C@@H]1O[C@]1(C=1C(=CC(F)=CC=1)F)CN1N=CN=C1 QANJLSHZDUOBBP-QPUJVOFHSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 2
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 2
- NFEZZTICAUWDHU-UHFFFAOYSA-N 2-(2,4-difluorophenyl)-3-(4-methylidenepiperidin-1-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol Chemical compound C1=NC=NN1CC(O)(C=1C(=CC(F)=CC=1)F)C(C)N1CCC(=C)CC1 NFEZZTICAUWDHU-UHFFFAOYSA-N 0.000 description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 241001225321 Aspergillus fumigatus Species 0.000 description 2
- 241000222122 Candida albicans Species 0.000 description 2
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- 239000004593 Epoxy Substances 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
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
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- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
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Abstract
本发明涉及含有以通式(Ⅰ)
表示的化合物及其酸加成盐，特别是以它的不对称碳原子的绝对构型为(R，R)的化合物及其酸加成盐作为有效成分的抗真菌剂。
Description
本发明是关于对人及动物的真菌疾病有效，而且作为农业园艺及工业用的抗真菌剂有效的吡咯胺衍生物。
关于在分子中同时含有三唑基或咪唑基等唑胺基以及1-哌啶基、吡咯烷基或吗啉代基等胺基环的吡咯胺衍生物的报道，在特开昭57-140768号公报以及英国专利GB2159148A号公报中均有记载，但都没有从抗真菌作用等方面涉及它作为医药品的有效效果。另外也没有记载在胺基环上含有亚甲基或取代亚甲基的化合物。
本发明的特征是在胺环上含有亚甲基或者取代亚甲基，提供了具有强抗真菌活性的新型吡咯胺衍生物。
本发明提供了以通式(Ⅰ)表示的化合物及其酸加成盐，
(Ⅰ)(式中、Ar表示没有取代或以从卤素原子及三氟甲基中选择的1-3个取代基所取代的苯基、R1和R2可以相同也可以不同，表示氢原子、低级烷基、没有取代或从卤素原子及低级烷基中选择1-3个取代基所取代的芳基、链烯基、炔基或者芳烷基、m表示2或3、n表示1或2、X表示氮原子或者CH、*1、*2表示不对称碳原子)。
上述通式(Ⅰ)表示的化合物，特别是*1、*2表示的不对称碳原子的绝对构型为(R,R)的物质，优选含有*1,*2的不对称碳原子的绝对构型为(R,R)的，由通式(Ⅰ)表示的化合物及其酸加成盐，及它的光学异构体的混合物。
另外，本发明提供了含有以上述通式(Ⅰ)表示的化合物及其酸加成盐作为有效成分的抗真菌剂，及使用上述化合物作为治疗真菌感染症的方法。
在上述通式(Ⅰ)中，被取代的苯基可以是含有从卤素原子以及三氟甲基中选出的1-3个取代基的苯基，例如2,4-二氟苯基、2,4-二氯苯基、4-氟苯基、4-氯苯基、2-氯苯基、4-三氟甲基苯基、2-氯-4-氟苯基及4-溴苯基等、作为低级烷基可以如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基等碳原子数为1-6的直链、支链或环状烷基、作为无取代的芳香基，例如苯基、萘基或二苯基等，作为取代苯基，例如为2,4-二氟苯基、2,4-二氯苯基、4-氟苯基、4-氯苯基、2-氯苯基、4-三氟甲基苯基、2-氯-4-氟苯基、4-溴苯基、4-叔丁基苯基或4-硝基苯基等，作为链烯基，例如可以是乙烯基、1-丙烯基或苯乙烯基等，作为炔基，例如可以为乙炔基等，芳烷基例如可以为苄基、萘甲基或4-硝基苄基等。
用通式(Ⅰ)表示的本发明化合物包括分子内含有2个以上的不对称碳原子的光学异构体及非对映立体异构体。光学异构体通过一般的光学分割的方法，或者不对称合成的方法，可以得到两个对映体。另外，非对映立体异构体的分离可以使用重结晶或色谱法等通常的分离方法，分别得到异构体。通式(Ⅰ)包含这些异构体的一种或者它们的混合物。
其中，不对称碳原子的绝对构型为(R,R)的物质具有强力的抗真菌的作用，所以特别优选。
用通式(Ⅰ)表示的本发明化合物的代表例有，(2R,3R)-2-(2,4-二氟苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2S,3S)-2-(2,4-二氟苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2RS,3RS)-2-(2,4-二氟苯基)-3-(4-亚甲基哌啶-I-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2R,3R)-2-(2,4-二氟苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-咪唑-1-基)丁烷-2-醇)、(2S,3S)-2-(2,4-二氟苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-咪唑-1-基)丁烷-2-醇)、(2RS,3RS)-2-(2,4-二氟苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-咪唑-1-基)丁烷-2-醇)、(2R,3R)-2-(4-氯苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2S,3S)-2-(4-氯苯基)3-(4-亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2RS,3RS)-2-(4-氯苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2R,3R)-2-(4-氯苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-咪唑-1-基)丁烷-2-醇)、(2S,3S)-2-(4-氯苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-咪唑-1-基)丁烷-2-醇)、(2RS,3RS)-2-(4-氯苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-咪唑-1-基)丁烷-2-醇)、(2R,3R)-2-(4-三氟甲苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2S,3S)-2-(4-三氟甲苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2RS,3RS)-2-(4-三氟甲苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2R,3R)-2-(4-三氟甲苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-咪唑-1-基)丁烷-2-醇)、(2S,3S)-2-(4-三氟甲苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-咪唑-1-基)丁烷-2-醇)、(2RS,3RS)-2-(4-三氟甲苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-咪唑-1-基)丁烷-2-醇)、(2R,3R)-2-(2,4-二氯苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2S,3S)-2-(2,4-二氯苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2RS,3RS)-2-(2,4-二氟苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2R,3R)-2-(2,4-二氯苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-咪唑-1-基)丁烷-2-醇)、(2S,3S)-2-(2,4-二氟苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-咪唑-1-基)丁烷-2-醇)、(2RS,3RS)-2-(2,4-二氯苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-咪唑-1-基)丁烷-2-醇)、(2R,3R)-2-(2,4-二氟苯基)-3-(4-亚乙基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2S,3S)-2-(2,4-二氟苯基)-3-(4-亚乙基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2RS,3RS)-2-(2,4-二氟苯基)-3-(4-亚乙基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2R,3R)-2-(2,4-二氟苯基)-3-(4-亚丙基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2S,3S)-2-(2,4-二氟苯基)-3-(4-亚丙基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2RS,3RS)-2-(2,4-二氟苯基)-3-(4-亚丙基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2R,3R)-2-(2,4-二氟苯基)-3-(4-正亚丁基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2S,3S)-2-(2,4-二氟苯基)-3-(4-正亚丁基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2RS,3RS)-2-(2,4-二氟苯基)-3-(4-正亚丁基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2R,3R)-2-(2,4-二氟苯基)-3-(4-正亚戊基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2S,3S)-2-(2,4-二氟苯基)-3-(4-正亚戊基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2RS,3RS)-2-(2,4-二氟苯基)-3-(4-正亚戊基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2R,3R)-2-(2,4-二氟苯基)-3-(4-正亚己基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2S,3S)-2-(2,4-二氟苯基)-3-(4-正亚己基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2RS,3RS)-2-(2,4-二氟苯基)-3-(4-正亚己基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2R,3R)-2-(2,4-二氟苯基)-3-(4-环丙基亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2S,3S)-2-(2,4-二氟苯基)-3-(4-环丙基亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2RS,3RS)-2-(2,4-二氟苯基)-3-(4-环丙基亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2R,3R)-2-(2,4-二氟苯基)-3-(4-环己基亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2S,3S)-2-(2,4-二氟苯基)-3-(4-环己基亚甲基哌啶-1-基)1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2RS,3RS)-2-(2,4-二氟苯基)-3-(4-环己基亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2R,3R)-2-(2,4-二氟苯基)-3-(4-亚苄基哌啶-1-基)-1-(1H-1,2,4三唑-1-基)丁烷-2-醇)、(2S,3S)-2-(2,4-二氟苯基)-3-(4-亚苄基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2RS,3RS)-2-(2,4-二氟苯基)-3-(4-亚苄基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2R,3R)-2-(2,4-二氟苯基)-3-(4-异丙叉哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2S,3S)-2-(2,4-二氟苯基)-3-(4-亚异丙基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2RS,3RS)-2-(2,4-二氟苯基)-3-(4-异丙叉哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2R,3R)-2-(2,4-二氟苯基)-3-(4-二苯基亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2S,3S)-2-(2,4-二氟苯基)-3-(4-二苯基亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2RS,3RS)-2-(2,4-二氟苯基)-3-(4-二苯基亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2R,3R)-2-(2,4-二氟苯基)-3-(4-亚丙烯基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2S,3S)-2-(2,4-二氟苯基)-3-(4-亚丙烯基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2RS,3RS)-2-(2,4-二氟苯基)-3-(4-亚丙烯基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2R,3R)-2-(2,4-二氟苯基)-3-(4-亚丙炔基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2S,3S)-2-(2,4-二氟苯基)-3-(4-亚丙炔基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2RS,3RS)-2-(2,4-二氟苯基)-3-(4-亚丙炔基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2R,3R)-2-(2,4-二氟苯基)-3-(3-亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2S,3S)-2-(2,4-二氟苯基)-3-(3-亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2RS,3RS)-2-(2,4-二氟苯基)-3-(3-亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2R,3R)-2-(2,4-二氟苯基)-3-(3-亚甲基吡咯烷-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2S,3S)-2-(2,4-二氟苯基)-3-(3-亚甲基吡咯烷-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)、(2RS,3RS)-2-(2,4-二氟苯基)-3-(3-亚甲基吡咯烷-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)等。
用通式(Ⅰ)表示的本发明化合物可以用以下所示的方法制得。(上式中，Ar、R1、R2、X、m及n与上述意义相同)。
即，通式(Ⅱ)表示的环氧化合物与通式(Ⅲ)所表示的氨衍生物反应，可以得到通式(Ⅰ)所表示的化合物。通式(Ⅱ)所表示的环氧化合物在特开平2-191262号公报等中有记载，例如通式(Ⅳ)：
(Ⅳ)(式中，Ar及X与上述意义相同)所表示的化合物在碱性条件下，通过与含有式R3SO2-O-SO2R3或R3SO2-Z(式中，R3表示低级烷基、卤化低级烷基或取代苯基、Z表示卤原子等脱离基)的化合物反应，得到化合物(Ⅴ)：(Ⅴ)然后通过使其与碱反应等方法得到。
由通式(Ⅲ)表示的氨衍生物，可以通过公知的合成法(例如hem.Pharm.Bull.1(11)1971-1986(1993))、或者通过本发明的参考例中记载的方法可以制得。
另外，氨衍生物是碱等与酸的盐时，预先使用氢氧化钠等无机碱或者三乙基氨等有机碱、或者在反应液中中和，作为游离胺使用。
反应通常使用水或有机溶剂或水和有机溶剂的混合液、或无溶剂进行。有机溶剂最好使用不与反应起始化合物反应的物质，如甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇、乙烯醇、丙烯醇、甘油或甲基溶纤素等醇类、四氢呋喃、二噁烷或二甲氧乙烷等醚类、N,N-二甲酰胺或N,N-二甲基乙酰胺等胺类、二甲亚砜等单独使用或者作为混合液使用。
在上述反应中，与仅使用有机溶剂相比，如在反应系统中加入1-80v/v％的水则反应更容易进行。
反应液中各原料的使用量，相对于化合物(Ⅱ)来说，应使用1-20倍摩尔的化合物(Ⅲ)。
反应结束后，馏去溶剂，通过重结晶或色谱分离法等方法精制，可以分离得到通式(Ⅰ)表示的本发明化合物。
通式(Ⅰ)所表示的本发明的化合物在必要时，可以为医药上允许的盐，例如与盐酸、硫酸、硝酸、磷酸或氢溴酸等形成的无机酸盐，与富马酸、马来酸、醋酸、苹果酸、酒石酸、枸橼酸、甲磺酸或甲苯磺酸等形成的有机酸盐。
下而介绍一下上述通式(Ⅰ)所表示的本发明化合物的抗真菌活性。再有，以下的试验中使用的被检验化合物的序号是引用后而记载的实施例中的序号。1、最小抑菌浓度(MIC)的测定
对白色念珠菌(Candida albicaus ATCC-10259)来说，使用合成氨基酸培养基(SAAMF培养基)通过液体培养基稀释法来测定被检验化合物的MIC。即，在2倍阶段稀释系列的药液3μl中，加入接种过的最终菌浓度为1×103cells/ml的SAAMF培养基300μl，在35℃下培养2天后，阻止菌发育的被检验化合物的最小浓度即为MIC。对于白色念珠菌以外的菌，使用萨氏琼脂培养基，通过琼脂平板稀释法来测定MIC。即，将溶解在二甲基亚砜中的调制成浓度为10mg/ml的被检药剂溶液，及用二甲基亚砜进行2倍阶段稀释得到的溶液0.1ml置于灭菌培养皿中，加入萨氏琼脂培养基9.9ml充分混合，制成添加药剂的平板，用微型种植机(佐久间制作所株式会社制)接种浓度调制成106cells/ml的菌浮游液体5μl。将烟曲霉(Aspergillus fumigatus NI-5561)和新型隐球菌(Cryptococcus neoformans NI-7496)在30℃下培养48小时，将毛藓菌·须苍菌(Trichophyton mentagrophytes KD-01)在30℃下培养7天后，可以得到抑制菌发育的被检验化合物的最小抑菌浓度MIC。其结果如表1所示。使用克霉唑和氟克那唑(F/uconazole)作为对照化合物进行比较。
各供试菌名的简称如下所示。
菌名 简称Candida albicans ATCC 10259 C.a.Cryptococcus neoformans NI-T496 Cr.n.Aspergillus fumigatus NI-5561 A.f.Trichophyton mentagrophytes KD-01 T.m.表1所示为本发明实施例的化合物对各种真菌的抗真菌活性(最小抑菌浓度MIC)。
表1
| 被检化合物(实施例序号) | 最小抑菌浓发(MIC(μg/ml) |
| 试验菌C.a Cr.n. A.f. T.m. | |
| 1234567810121314克霉唑Fluconazole | ＜0.025 0.05 0.05 0.39＜0.025 0.1 0.1 0.390.39 0.78 ＞100 50＜0.025 ＜0.025 0.05 ＜0.025＜0.025 0.025 0.05 0.1＜0.0125 0.2 6.25 3.130.025 0.05 0.39 0.39＜0.025 0.1 0.2 0.78＜0.025 0.025 0.1 0.39＜0.025 0.1 0.2 0.780.1 0.39 0.78 1.56＜0.025 0.39 0.39 0.780.025 0.2 0.78 0.390.39 12.5 ＞100 ＞100 |
克霉唑： 氟克那唑(Fluconazole)
从以上结果可知，通式(Ⅰ)所表示的本发明化合物，特别是绝对构型为(R,R)的物质，与以往的抗真菌剂相比，具有非常高的活性。
另外，通过与克霉唑及氟克那唑(フルコナゾ-ル)的比较，发现与本发明化合物一样，在与含有亚甲基的胺基环结合的化合物具有惊人的高活性。2、治疗感染的试验(1)对感染白癣的豚鼠模型的治疗效果
将Hartley系雄性豚鼠(体重400-500g)的背部皮肤的毛拔去，轻轻用金刚砂纸摩擦皮肤。将毛藓菌·须苍菌(Trichophytonmentagrophytes KD-04)的小分裂子浮游液(107cells/ml)0.1ml滴在皮肤表面，用玻璃棒摩擦使其感染。将被验化合物溶解在聚乙二醇400-乙醇(75∶25)中配制成1％的溶液，从感染第3日起每日一次涂布治疗，每次0.2ml，共10天。最后一次治疗的2天后，将动物用乙醚麻醉后处死，从感染部位取出10个皮肤组织切片，在琼脂培养基上培养7天。用下式计算抑制率。抑制率(％)=(1-阳性菌的组织切片数/全组织切片数)×100其结果如表2所示。使用克霉唑作为时照化合物。表2
(2)对皮肤感染念珠菌的豚鼠模型的治疗效果
| 组 | 抑制率(％) |
| 感染无处置对照组基剂对照组实施例1的化合物克霉唑 | 009820 |
将Hartley系雄性豚鼠(体重400-500g)的背部皮肤的毛拔去。将白色念珠菌(Candida albicans KC-36)的孢子浮游液(5×107cells/ml)0.1ml滴在皮肤表面，用玻璃棒摩擦使其感染。为使感染容易，应在感染的1日前、感染当日及感染的4日后皮下注射泼尼松30mg/kg。将被检验化合物溶解在聚乙二醇400-乙醇(75∶25)中配制成1％的溶液，从感染第2日起每日一次涂布治疗，每次0.2ml，共3天。最后一次治疗的2天后，将动物用乙醚麻醉后处死，从感染部位取出10个皮肤组织切片，在念珠菌GS培养基(荣研化学株式会社制)上培养7天。抑制率用与上述相同的公式计算。其结果如表3所示。使用克霉唑作为对照化合物。
通过以上1、2的试验，可以确认本发明的化合物具有广谱及强力的抗真菌的作用。
表3
3、小鼠的急性毒性试验
| 组 | 抑制率(％) |
| 感染无处置对照组基剂对照组实施例1的化合物克霉唑 | 489896 |
使用5周的ICR雄性小鼠，将实施例1的化合物溶解在聚乙烯醇200中，皮下及经口给药。结果如表4所示。
表4
如上表所示，可知本发明化合物具有极低的毒性。
| 给药量 | 死亡数/使用只数 | |
| 皮下 | 经口 | |
| 1000mg/kg500mg/kg250mg/kg125mg/kg | 0/30/30/30/3 | 0/30/3-- |
本发明化合物不仅具有强力的抗真菌活性，而且毒性低。以通式(Ⅰ)表示的本发明化合物作为有效成分的抗真菌剂，对包括人在内的哺乳动物，特别是由念珠菌属、毛癣菌属、小孢子菌属、表皮癣菌属、马拉色代菌属、新型隐球菌属、曲霉菌属、球孢子菌属、类球孢子菌属、组织胞浆菌属及芽生菌属等属的菌种产生的局部或全身的真菌感染症具有治疗作用。以本发明化合物作为有效成分的抗真菌剂，不仅对于人及动物的真菌感染症有用，而且可以作为农业园艺用抗真菌剂和工业用的抗真菌剂等使用。
含有用通式(Ⅰ)表示的本发明化合物作为有效成分的抗真菌剂，其化合物可以单独或与液体或固体制剂辅料，例如赋形剂、粘合剂、稀释剂等混合，可外用涂抹、经口或非经口给药。另外，必要时可以与其他药剂组和使用。
作为外用药时，可以调制成霜剂、液剂、软膏剂、眼用软膏剂、栓剂、阴道剂、粉剂、乳剂等剂型。调制时可以使用油性基质或乳剂性基质，有效成分的含量最好为0.1-10重量％。给药量可以根据患部的大小以及症状的程度进行调节。
经口给药时，可作为粉剂、片剂、颗粒剂、胶囊剂或糖浆剂使用，另外，在皮下、肌肉内或静脉内注射时可以作为注射剂使用。
给药量根据患者的年龄、体重及个体条件不同而不同，成人的有效成分为10mg-10g。优选50mg-5g，给药方法是将上述的给药量一次或分几次给药。
以下，通过实施例以及参考例来更详细的说明本发明，但本发明不只局限于这些实施例。
另外，1H-NMR光谱是通过在重氯仿(CDCl3)溶液中，使用四甲基硅烷作为内标物质，用JNM-EX270型光谱仪(日本电子株式会社制)测定，用化学位移(δ)PPM来表示。另外，高速液相色谱法(以下简称HPLC)，使用光学活性柱(CHIRALCEL)OJ(4.6mm*25cm，大赛路化学工业(株)制)、用LC6A(HPLC装置，(株)岛津制作所制)来测定。实施例1(2R,3R)-2-(2,4-二氟苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇)
在4-亚甲基哌啶盐酸盐1.336g中加入50％的氢氧化钠水溶液11.2ml，搅拌溶解后用20ml乙醚萃取，再用10ml乙醚萃取水层，合并有机层，馏去乙醚，在残留物中依次加入3ml乙醇、(2R,3S)-2-(2,4-二氟苯基)-3-甲基-2-[(1H-1,2,4-三唑-1-基)甲基]环氧乙烷251mg、蒸馏水3ml，在85℃油浴上加热回流24小时。反应后将反应液冷却至室温，加入乙酸乙酯20ml和蒸馏水20ml，分离有机层。再用乙酸乙酯10ml萃取水层，与上述的有机层合并，用饱和食盐水洗净，再用无水硫酸镁干燥后，馏去溶剂。将残留物加在8g硅胶的HPLC上，用醋酸乙酯/环己烷(4∶1-3∶1)的混合溶液洗脱得到188g的标题化合物。收率为54.0％。再用乙醚/环己烷的混合溶剂进行重结晶，可以得到熔点86-87℃的纯品。HPLC：流动相使用环己烷/异丙醇=9/1，在流速1.0ml/分、室温、UV(254nm)的检测条件下进行分析，得到保持时间为6.6分钟的单一的峰。比施光度：[α]D 28-93°(C=1.00、
CHCl3)元素分析：C18H22F2N4O
計算值：C、62.15；H、6.36；
N、16.02
実测值：C、62.05；H、6.37；
N、16.081H-NMR光谱(CDCl3)δppm:
0.96(3H,dd)、2.1-2.5(6H,m)、
2.6-2.8(2H,m)、2.91(1H,q)、4.64(2H,s)、
4.80(1H,d)、4.89(1H,d)、5.48(1H,brs)、
6.7-6.8(2H,m)、7.47-7.63(1H,m)、
7.79(1H,s)、8.03(1H,s)。实施例2(2RS,3RS)-2-(2,4-二氟苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇
用(2R,3S)-2-(2,4-二氟苯基)-3-甲基-2-〔(1H-1,2,4-三唑-1-基)甲基〕环氧乙烷的外消旋体(2RS,3SR)-2-(2,4-二氟苯基)-3-甲基-2〔(1H-1,2,4-三唑-1-基)甲基〕环氧乙烷来代特使用，与实施例1相同可以得到标题化合物。HPLC：流动相使用环己烷/异丙醇=9/1，流速1.0ml/分、室温、UV(254nm)作为检出条件进行分析，得到保持时间为6.6分钟和5.8分钟面积比为1∶1的两个峰。1H-NMR光谱(CDCl3)δppm:
0.96(3H,dd,J=3Hz,7Hz)、2.1-2.5(6H,m)、
2.6-2.8(2H,m)、2.91(1H,q,J=7Hz)、
4.64(2H,s)、4.80(1H,d,J=15Hz)、
4.89(1H,d,J=15Hz)、5.47(1H,brs)、
6.7-6.8(2H,m)、7.5-7.6(1H,m)、
7.79(1H,s)、8.02(1H,s)实施例3(2S,3S)-2-(2,4-二氟苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷2-醇用(2R,3S)-2-(2,4-二氟苯基)3-甲基-2-((1H-1,2,4-三唑-1-基)甲基〕环氧乙烷的对映体(2S,3R)-2-(2,4-二氟苯基)-3-甲基-2-〔(1H-1,2,4-三唑-1-基)甲基〕环氧乙烷来代替使用，与实施例1相同可以得到标题化合物。HPLC：流动相使用环己烷/异丙醇=9/1，流速1.0ml/分、室温、UV(254nm)作为检出条件进行分析，得到保持时间为5.8分钟的单一的峰。1H-NMR光谱(CDCl3)δppm:
0.96(3H,dd,J=3Hz,7Hz)、2.1-2.5(6H,m)、
2.6-2,8(2H,m)、2.91(1H,q,J=7Hz)、
4.64(2H,s)、4.80(1H,d,J=15Hz)、
4.89(1H,d,J=15Hz)、5.48(1H,brs)、
6.7-6.8(2H,m)、7.5-7.6(1H,m)、
7.78(1H,s)、8.03(1H,s)实施例4-14
与实施例1相同，使用表5中所示的原料，合成表6中所示的实施例4到实施例14中的化合物。
表5
*Ph表示苯基
表6 
实施例15(实施例1的化合物的其他途径的合成法)
将(2R,3S)-2-(2,4-二氟苯基)-3-甲基-2-〔(1H-1,2,4-三唑-1-基)甲基〕环氧乙烷11.59g(70mmol)溶解到113g4-亚甲基哌啶水溶液中(含量为61％)，在90C下加热回流21个小时。反应后，将过剩的4-亚甲基吡啶在减压下馏去，将残留物溶解在140ml异丙醇中，加入溶解在50ml异丙醇中的对甲苯磺酸一水合物13.32g(70mmol)。在室温下放置1小时，冰箱放置一夜后，过滤析出的晶体后，用50ml异丙醇洗净，干燥，得到(2R,3R)-2-(2,4-二氟苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇的对甲苯磺酸盐的结晶32.20g。
将上述得到的对甲苯磺酸盐18.3g，加入到40ml乙醚和35ml1N的氢氧化钠水溶液中，分离有机层，用无水硫酸镁5g干燥后馏去溶剂。在残留液中加入正己烷40ml，过滤析出的晶体，干燥后得到目的产物(2R,3R)-2-(2,4-二氟苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇9.34g。得到的物质与实施例1的化合物的1H-NMR光谱一致。参考例14-苄基哌啶盐酸盐的合成(1)在通入氢气条件下，将氯化苄基三苯磷49.0g(126mmol)悬浊在100ml无水四氢呋喃中，在冰浴下，滴加86ml丁基锂。在室温下搅拌1小时后，在冰浴下滴加1-苄基-4-哌啶酮的无水四氢呋喃溶液，加热回流15小时。过滤反应溶液后，在滤液中加入二乙醚及水，萃取有机层。将有机层用水、饱和食盐水洗净，用无水硫酸镁干燥。在减压下馏去溶剂，得到的油状物质添加到使用1kg的硅胶的色谱柱上，用乙酸己酯-己烷(1∶100-3∶100)洗脱，得到22.6g 1-苄基-4-苄基哌啶。
1H-NMR光谱(CDCl3)δppm:
2.4-2.5(4H,m)、2.5-2.6(4H,m)、
3.52(2H,s)、6.27(1H,s)、7.1-7.4(10H,m)(2)将1-苄基-4-苄基哌啶24.6g(96mmol)溶解在200ml的二氯乙烷中，在冰浴下，滴加11.1ml(102mmol)的氯甲酸1-氯乙酯。反应液加热回流30分钟，然后在室温下搅拌1.5小时。减压馏去溶剂，将反应液浓缩至80ml，加入20ml甲醇，加热回流12小时。减压下馏去溶剂，在得到的残留物加入100ml异丙醚，过滤沉淀物，得到8.6g标题化合物。
1H-NMR光谱(CDCl3)δppm:
2.74(2H,t,J=6Hz)、2.84(2H,t,J=6Hz)、
3.18(2H,brs)、3.31(2H,brs)、6.47(1H,s)、
7.1-7.4(5H,m)、9.8(2H,brs)参考例24-二苯基亚甲基哌啶的合成(1)将102g(650mmol)六氢异於酸乙酯悬浊在100ml二恶烷中，冰浴下加入叔丁氧基二氨甲酸酯213g(974mmol)，搅拌15小时，减压馏去溶剂，得到叔丁氧羰基-4-己氧羰基吡啶234g。
1H-NMR光谱(CDCl3)δppm:
1.27(3H,t,J=7Hz)、1.46(9H,s)、
1.6-1.7(2H,m)、1.8-1.9(2H,m)、
2.3-2.5(1H,m)、2 8-2.9(2H,m)、
3.7-4.0(2H,m)、4.14(2H,q,J=7Hz)(2)在通入氢气条件下，将1-叔丁氧羰基-4-乙氧羰基吡啶26.4g(72mmol)溶解在100ml无水四氢呋喃中，在冰浴下，滴加2mol/ml的苯溴化镁108ml。搅拌2天。在反应液中加入200ml饱和氯化铵溶液、200ml乙酸乙酯溶液，萃取有机层。将有机层用水、饱和食盐水洗净，用无水硫酸镁干燥。减压馏去溶剂，得到34.7g 1-叔丁氧羰基-4-(羟基二苯)甲基哌啶。
1H-NMR光谱(CDCl3)δppm:
1.2(4H,m)、1.42(9H,s)、2.5-2.7(3H,m)、
4.1-4.2(2H,m)、7.2-7.5(10H,m)(3)将20g(54mmol)1-叔丁氧羰基-4-(羟基二苯)甲基哌啶溶解在12.8g苯酚及210ml 48％的氢溴酸水溶液中，在140℃下搅拌5小时，室温下搅拌15小时。萃取有机层，加入二乙醚，过滤析出的沉淀。在沉淀中加入二乙醚、氧氧化钾溶液，萃取有机层，用氢氧化钾干燥。减压馏去溶剂，得到6.1g标题化合物。
1H-NMR光谱(CDCl3)δppm:
2.0(1H,brs)、2.32(4H,t,J=6Hz)、
2.91(4H,t,J=6Hz)、7.1-7.3(10H,m)参考例34-亚丙烯基哌啶盐酸盐的合成(1)在通入氢气条件下，将溴化烯丙基三苯磺酸2.9g(7.5mmol)悬浊在10ml无水四氢呋喃中，在冰浴下，滴加4.3ml丁基锂。在室温下搅拌30分钟后，在冰浴下滴加1-苄基-4-吡啶酮1g(5.3mmol)的无水四氧呋喃溶液，室温下搅拌15小时。过滤反应溶液后，在滤液中加入乙酸乙酯和水，萃取有机层。将有机层用水、饱和食盐水洗净，用无水硫酸镁干燥。在减压下馏去溶剂，得到的油状物质加入到使用40g的硅胶的色谱柱上，用乙酸乙酯-己烷(1∶1-1∶3)洗脱，得到200mg 1-苄基-4-亚丙烯基哌啶。
1H-NMR光谱(CDCl3)δppm:
2.2-2.3(2H,m)、2.4-2.5(6H,m)、
3.50(2H,s)、4.98(1H,d,J=10Hz)、
5.11(1H,d,J=17Hz)、5.82(1H,d,J=11Hz)、
6.5-6.6(1H,m)、7.2-7.3(5H,m)(2)将1-苄基-4-亚丙烯基哌啶4.5g(21mmol)溶解在20ml的二氯乙烷中，在冰浴下，滴加2.8ml(25mmol)的氯甲酸1-氯乙酯。反应液在室温搅拌30分钟后，加热回流30分钟。减压馏去溶剂，将反应液浓缩至10ml，加入60ml甲醇，加热回流12小时。减压下馏去溶剂，得到3.7g标题化合物。
1H-NMR光谱(CDCl3)δppm:
2.3-3.0(4H,m)、3.0-3.6(4H,m)、
4.7-6.3(4H,m)制剂例1 液体制剂
将200ml聚乙二醇400溶解在750ml乙醇中，在其中加入5g实施例1的化合物(2R,3R)-2-(2,4-二氟苯基)-3-( 4-亚甲基哌啶-1-基)1-(1H-1,2,4-二唑-1-基)丁烷-2-醇)，溶解。再加入乙醇至总量为100ml，作为供使用的液体药剂。制剂例2 软膏剂将白色凡士林400g、鲸蜡醇180g、对羟基苯甲酸丙酯1g以及倍半油酸山梨聚糖50g在水浴上保持在80℃溶解，然后加入5g实施例1的化合物(2R,3R)-2-(2,4-二氟苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-1,2,4三唑-1-基)丁烷-2-醇)溶解。将1g对羟基苯甲香酸甲酯加入到水中，加热至80℃溶解，并缓慢的加入到上述液体中。冷却后作为软膏剂使用。制剂例3 霜剂
将15g白色凡士林、200g液体石蜡、50g硬脂醇、40g单硬脂酸甘油酯、145g丙二醇以及1g对羟基苯甲酸丙酯的混合物在80℃的水浴上溶解，然后加入10g实施例1的化合物(2R,3R)-2(2,4-二氟苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇溶解，另外将40g聚环氧乙烷硬酯酸酯40以及1g对羟基苯甲酸甲酯加入到4982精制水中，加热至80℃溶解，加入至上述溶液中，充分搅拌。搅拌后，一边用冷却水冷却，一边充分搅拌至凝固，作为霜剂使用。
本发明化合物具有很强的抗真菌活性。所以，以用通式(Ⅰ)表示的本发明化合物作为有效成分的抗真菌剂，对人及动物的真菌疾病的预防以及治疗有效。另外，作为农业园艺用防真菌剂及工业用防真菌剂非常有用。
Claims (7)
1．由通式(Ⅰ)表示的化合物及其酸加成盐，(Ⅰ)式中Ar表示未取代或被1～3个选自卤素原子和三氟甲基的取代基所取代的苯基，R1和R2相同或不同地表示氢原子、C1-6烷基、C2-6链烯基、苯基或被1～3个选自卤素原子和C1-6烷基的取代基所取代的苯基，m表示2或3,n表示1或2,X表示氮原子或CH,*1和*2表示不对称碳原子。
2．权利要求1中记载的化合物及其酸加成盐，其中*1和*2的不对称碳原子的绝对构型为(R,R)。
3．权利要求1中记载的化合物及其酸加成盐，是含有*1和*2的不对称碳原子的绝对构型为(R,R)的通式(Ⅰ)表示的化合物及其酸加成盐以及选自*1和*2的不对称碳原子的绝对构型为(R,S)、(S,R)和(S,S)的通式(Ⅰ)表示的化合物中的1个或1个以上化合物的混合物。
4．权利要求1、2或3中记载的化合物及其酸加成盐，其中X是氮原子。
5．权利要求1、2或3中记载的化合物及其酸加成盐，其中X是CH。
6．权利要求2或3中记载的化合物及其酸加成盐，其中*1和*2的不对称碳原子的绝对构型为(R,R)的通式(Ⅰ)表示的化合物是(2R,3R)-2-(2,4-二氟苯基)-3-(4-亚甲基哌啶-1基)-1-(1H-1,2,4-三唑-1-基)丁烷-2-醇。
7．含有权利要求1-6的化合物及其酸加成盐作为有效成分的抗真菌剂。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP132931/93 | 1993-05-10 | ||
| JP13293193 | 1993-05-10 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1122598A CN1122598A (zh) | 1996-05-15 |
| CN1046278C true CN1046278C (zh) | 1999-11-10 |
Family
ID=15092851
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94192041A Expired - Lifetime CN1046278C (zh) | 1993-05-10 | 1994-05-02 | 吡咯胺衍生物 |
Country Status (15)
| Country | Link |
|---|---|
| US (3) | US5620994A (zh) |
| EP (1) | EP0698606B1 (zh) |
| KR (1) | KR100339166B1 (zh) |
| CN (1) | CN1046278C (zh) |
| AT (1) | ATE161257T1 (zh) |
| AU (1) | AU685116B2 (zh) |
| CA (1) | CA2162463C (zh) |
| DE (1) | DE69407409T2 (zh) |
| DK (1) | DK0698606T3 (zh) |
| ES (1) | ES2110749T3 (zh) |
| GR (1) | GR3025715T3 (zh) |
| HU (1) | HU225416B1 (zh) |
| TW (1) | TW325473B (zh) |
| UA (1) | UA41365C2 (zh) |
| WO (1) | WO1994026734A1 (zh) |
Families Citing this family (34)
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|---|---|---|---|---|
| DK0698606T3 (da) * | 1993-05-10 | 1998-08-24 | Kaken Pharma Co Ltd | Azolylaminderivat |
| CN1125814C (zh) * | 1995-09-28 | 2003-10-29 | 科研制药株式会社 | 4－亚甲基哌啶的制备方法 |
| EP2112228A1 (en) * | 1999-07-28 | 2009-10-28 | Kaken Pharmaceutical Co., Ltd. | Method for detecting pathogenic microorganism and antimicrobial agent, method for evaluating effect of antimicrobial agent, and antimicrobial agent |
| US20090162481A1 (en) * | 2004-05-25 | 2009-06-25 | Watson James B | Live bacteria product |
| US20100080869A1 (en) * | 2004-05-25 | 2010-04-01 | Watson James B | Live Bacteria product |
| US20090162419A1 (en) * | 2004-05-25 | 2009-06-25 | Watson James B | Live bacteria product |
| US7625927B2 (en) * | 2006-02-27 | 2009-12-01 | Alcon Research, Ltd. | Method of treating glaucoma |
| ES2350806T3 (es) * | 2006-12-28 | 2011-01-27 | Kaken Pharmaceutical Co., Ltd. | Composición de gel para el tratamiento de micosis. |
| US20090175810A1 (en) | 2008-01-03 | 2009-07-09 | Gareth Winckle | Compositions and methods for treating diseases of the nail |
| US8039494B1 (en) | 2010-07-08 | 2011-10-18 | Dow Pharmaceutical Sciences, Inc. | Compositions and methods for treating diseases of the nail |
| DK2612859T3 (en) * | 2010-08-31 | 2015-10-19 | Kaken Pharma Co Ltd | PROCEDURE FOR PREPARING 1-TRIAZOL-2-BUTANOL DERIVATE. |
| MX363386B (es) | 2013-10-03 | 2019-03-20 | Dow Pharmaceutical Sciences | Formulaciones de efinaconazol estabilizadas. |
| CN105848719A (zh) | 2013-11-22 | 2016-08-10 | 道尔医药科学公司 | 抗感染的方法、组合物和装置 |
| CN104292214B (zh) * | 2014-09-24 | 2017-04-05 | 南京华威医药科技开发有限公司 | 艾氟康唑及其中间体的合成方法 |
| CN104327047B (zh) * | 2014-10-17 | 2016-04-06 | 苏州明锐医药科技有限公司 | 艾菲康唑的制备方法 |
| CA2910990C (en) | 2014-11-23 | 2022-03-22 | Mapi Pharma Ltd. | Intermediate compounds and process for the preparation of efinaconazole |
| JP2018502165A (ja) * | 2015-01-20 | 2018-01-25 | ペリゴ・エーピーアイ・リミテッド | エフィナコナゾールの結晶形態 |
| ITUB20150417A1 (it) | 2015-05-08 | 2016-11-08 | Dipharma Francis Srl | Procedimento per la preparazione di composti piperidinici |
| WO2016181306A1 (en) * | 2015-05-12 | 2016-11-17 | Lupin Limited | Process for the preparation of efinaconazole |
| EP3112360A1 (en) * | 2015-06-29 | 2017-01-04 | Dipharma Francis S.r.l. | Process for the preparation of efinaconazole |
| CN106565672A (zh) * | 2015-10-08 | 2017-04-19 | 中美华世通生物医药科技（武汉）有限公司 | 制备艾氟康唑的方法 |
| US20170129874A1 (en) * | 2015-11-10 | 2017-05-11 | Virupaksha Organics Limited | Novel improved process for preparing a triazole antifungal agent |
| CN106810534A (zh) * | 2015-11-30 | 2017-06-09 | 中美华世通生物医药科技（武汉）有限公司 | 艾氟康唑晶型及其制备方法 |
| CN106928186A (zh) * | 2015-12-29 | 2017-07-07 | 中美华世通生物医药科技（武汉）有限公司 | 化合物及其制备方法和用途 |
| ITUB20159795A1 (it) | 2015-12-30 | 2017-06-30 | Procos Spa | Processo per la sintesi di efinaconazolo |
| ITUA20162545A1 (it) | 2016-04-13 | 2017-10-13 | Laboratorio Chimico Int S P A | Procedimento per la preparazione di intermedi utili nella sintesi di farmaci |
| EP3558304A2 (en) | 2016-12-23 | 2019-10-30 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) | Inhibitors of cytochrome p450 family 7 subfamily b member 1 (cyp7b1) for use in treating diseases |
| IT201700048270A1 (it) | 2017-05-04 | 2018-11-04 | Seegpharm Sa | Procedimento per la preparazione di un derivato azolico. |
| PL3628668T3 (pl) | 2017-05-19 | 2023-04-24 | Kaken Pharmaceutical Co., Ltd. | Sposoby wytwarzania i oczyszczania efinakonazolu |
| US10730861B2 (en) | 2017-08-10 | 2020-08-04 | Sumitomo Chemical Company, Limited | Process for producing epoxy alcohol compound |
| JP2022515696A (ja) * | 2018-12-29 | 2022-02-22 | 威智医薬有限公司 | エフィナコナゾールの調製方法 |
| JP2021054781A (ja) | 2019-09-26 | 2021-04-08 | デボン エルエス，リミテッド | 共結晶形エフィナコナゾール、及びその製造方法 |
| KR102181155B1 (ko) | 2019-09-26 | 2020-11-20 | 대봉엘에스 주식회사 | 이온성 액체를 매개로 한 에피나코나졸의 신규 제조방법 |
| KR102301743B1 (ko) | 2020-12-29 | 2021-09-13 | 대봉엘에스 주식회사 | 에피나코나졸 경구용 조성물 |
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| US4507484A (en) * | 1982-07-24 | 1985-03-26 | Pfizer Inc. | Triazole antifungal agents |
| GB2159148A (en) * | 1984-05-18 | 1985-11-27 | Ici Plc | Fungicidal imidazole and 1,2,4-triazole derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1162540A (en) * | 1980-12-24 | 1984-02-21 | Ikutaro Saji | Imidazolylpropanol compounds and their acid addition salts, and production and use thereof |
| DK0698606T3 (da) * | 1993-05-10 | 1998-08-24 | Kaken Pharma Co Ltd | Azolylaminderivat |
-
1994
- 1994-05-02 DK DK94914585T patent/DK0698606T3/da active
- 1994-05-02 WO PCT/JP1994/000737 patent/WO1994026734A1/ja active IP Right Grant
- 1994-05-02 HU HU9503217A patent/HU225416B1/hu unknown
- 1994-05-02 KR KR1019950704971A patent/KR100339166B1/ko not_active IP Right Cessation
- 1994-05-02 EP EP94914585A patent/EP0698606B1/en not_active Expired - Lifetime
- 1994-05-02 DE DE69407409T patent/DE69407409T2/de not_active Expired - Lifetime
- 1994-05-02 CN CN94192041A patent/CN1046278C/zh not_active Expired - Lifetime
- 1994-05-02 AT AT94914585T patent/ATE161257T1/de active
- 1994-05-02 UA UA95125159A patent/UA41365C2/uk unknown
- 1994-05-02 ES ES94914585T patent/ES2110749T3/es not_active Expired - Lifetime
- 1994-05-02 CA CA002162463A patent/CA2162463C/en not_active Expired - Lifetime
- 1994-05-02 AU AU66896/94A patent/AU685116B2/en not_active Expired
- 1994-05-11 TW TW083104253A patent/TW325473B/zh not_active IP Right Cessation
-
1995
- 1995-11-07 US US08/532,800 patent/US5620994A/en not_active Expired - Lifetime
-
1997
- 1997-01-09 US US08/781,204 patent/US5716969A/en not_active Expired - Lifetime
- 1997-11-10 US US08/966,527 patent/US5962476A/en not_active Expired - Lifetime
- 1997-12-18 GR GR970403105T patent/GR3025715T3/el unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4507484A (en) * | 1982-07-24 | 1985-03-26 | Pfizer Inc. | Triazole antifungal agents |
| GB2159148A (en) * | 1984-05-18 | 1985-11-27 | Ici Plc | Fungicidal imidazole and 1,2,4-triazole derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| DE69407409T2 (de) | 1998-04-09 |
| US5962476A (en) | 1999-10-05 |
| HUT75031A (en) | 1997-03-28 |
| EP0698606A1 (en) | 1996-02-28 |
| CA2162463A1 (en) | 1994-11-24 |
| WO1994026734A1 (en) | 1994-11-24 |
| CN1122598A (zh) | 1996-05-15 |
| ES2110749T3 (es) | 1998-02-16 |
| UA41365C2 (uk) | 2001-09-17 |
| US5716969A (en) | 1998-02-10 |
| DE69407409D1 (de) | 1998-01-29 |
| AU6689694A (en) | 1994-12-12 |
| CA2162463C (en) | 2006-01-03 |
| EP0698606A4 (zh) | 1996-04-10 |
| KR100339166B1 (ko) | 2004-04-30 |
| AU685116B2 (en) | 1998-01-15 |
| ATE161257T1 (de) | 1998-01-15 |
| US5620994A (en) | 1997-04-15 |
| GR3025715T3 (en) | 1998-03-31 |
| HU225416B1 (en) | 2006-11-28 |
| TW325473B (en) | 1998-01-21 |
| HU9503217D0 (en) | 1996-01-29 |
| EP0698606B1 (en) | 1997-12-17 |
| DK0698606T3 (da) | 1998-08-24 |
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