CN1068005C - 氧杂硼杂环戊烯及其盐,和它们作为生物杀伤剂的用途 - Google Patents
氧杂硼杂环戊烯及其盐,和它们作为生物杀伤剂的用途 Download PDFInfo
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- CN1068005C CN1068005C CN95194519A CN95194519A CN1068005C CN 1068005 C CN1068005 C CN 1068005C CN 95194519 A CN95194519 A CN 95194519A CN 95194519 A CN95194519 A CN 95194519A CN 1068005 C CN1068005 C CN 1068005C
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- Prior art keywords
- alkyl
- group
- heterocyclic pentene
- oxa
- phenyl
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- 150000003839 salts Chemical class 0.000 title claims abstract description 15
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- 150000001875 compounds Chemical class 0.000 claims abstract description 36
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- 229920003023 plastic Polymers 0.000 claims abstract description 11
- 239000000463 material Substances 0.000 claims abstract description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 95
- YWAKXRMUMFPDSH-UHFFFAOYSA-N pentene Chemical compound CCCC=C YWAKXRMUMFPDSH-UHFFFAOYSA-N 0.000 claims description 94
- 229910052796 boron Inorganic materials 0.000 claims description 69
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- 229910052799 carbon Inorganic materials 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 150000001721 carbon Chemical group 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
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- 125000003710 aryl alkyl group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 239000003973 paint Substances 0.000 claims description 7
- 125000004104 aryloxy group Chemical group 0.000 claims description 6
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
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- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 125000005647 linker group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 230000035945 sensitivity Effects 0.000 claims description 2
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 2
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- GCZKMLSMSHUQNO-UHFFFAOYSA-N 3-bromo-1-hydroxy-3h-2,1-benzoxaborole Chemical compound C1=CC=C2B(O)OC(Br)C2=C1 GCZKMLSMSHUQNO-UHFFFAOYSA-N 0.000 abstract 1
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- 238000012360 testing method Methods 0.000 description 11
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
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- 238000001035 drying Methods 0.000 description 7
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- MQIUGAXCHLFZKX-UHFFFAOYSA-N Di-n-octyl phthalate Natural products CCCCCCCCOC(=O)C1=CC=CC=C1C(=O)OCCCCCCCC MQIUGAXCHLFZKX-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
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- 239000002253 acid Substances 0.000 description 6
- 230000000845 anti-microbial effect Effects 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- BJQHLKABXJIVAM-UHFFFAOYSA-N bis(2-ethylhexyl) phthalate Chemical compound CCCCC(CC)COC(=O)C1=CC=CC=C1C(=O)OCC(CC)CCCC BJQHLKABXJIVAM-UHFFFAOYSA-N 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 235000015097 nutrients Nutrition 0.000 description 6
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- 241000223678 Aureobasidium pullulans Species 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 5
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 5
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 5
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- 241000228245 Aspergillus niger Species 0.000 description 4
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- 125000001246 bromo group Chemical group Br* 0.000 description 4
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- 125000001624 naphthyl group Chemical group 0.000 description 4
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- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical group NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 description 4
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- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
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- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
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Abstract
氧杂硼杂环戊烯和其盐作为工业生物杀伤剂,特别是作为杀真菌剂的应用,可用于保护塑性材料如增塑PVC。优选的化合物是5-和6-氟或溴代-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯,包括它们的O-酯。
Description
本发明涉及作为工业生物杀伤剂、特别是杀真菌剂的氧杂硼杂环戊烯(oxaborole)及其盐的应用,涉及含有包括它们的盐和某些氧杂硼杂环戊烯的氧杂硼杂环戊烯类化合物的生物杀伤剂组合物。
没有一种工业生物杀伤剂对所有的应用都是理想的,人们经常在探索对单一破坏性微生物有更好的活性,更宽的活性谱,与所应用的介质有改进的相容性和有改进的持久性的新生物杀伤剂,应用时的安全性是另一个要考虑的重要因素。
少量的含有氧杂硼杂环戊烯环的化合物(下文称为“氧杂硼杂环戊烯”)在文献中已有描述,它们是:N-(1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯-6-基)琥珀酰胺酸(CA 55 23423c);4-(1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯-6-基偶氮)-2-萘甲酸(CA 5523423c);1,3-二氢-1-羟基-6-硝基-2,1-苯并氧杂硼杂环戊烯(CA55 23423b);6-氨基-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯和其盐酸化物(CA 55 23423c);1,3-二氢-1-羟基-7-甲基-2,1-苯并氧杂硼杂环戊烯(CA 55 6473f);1-苄氧基-1,3-二氢-2,1-苯并氧杂硼杂环戊烯(CA 61 16084f);1,3-二氢-1-羟基-N,N-二甲基-2,1-苯并氧杂硼杂环戊烯-6-胺(CA 103(3)22633f);4-溴-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯(CA 103(3)22633f);1,1’-氧基双[4-溴-1,3-二氢-2,1-苯并氧杂硼杂环戊烯(CA 103(3)22633f);1-(环己基氧基)-1,3-二氢-2,1-苯并氧杂硼杂环戊烯(CA 61 16084f);1-乙氧基1,3-二氢-2,1-苯并氧杂硼杂环戊烯(CA 61 16084f);3,7-二氢-1,5-二羟基-1H,3H-苯并[1,2-c:4,5-c’]双[1,2]氧杂硼杂环戊烯(CA 6114698a);1,3-二氢-1-羟基-6-甲基-2,1-苯并氧杂硼杂环戊烯(CA61 14698b);5-溴-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯-6-甲醇(CA 5114698b);1,1’-氧基双[1,3-二氢-2,1-苯并氧杂硼杂环戊烯](CA103(3)22633f);和1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯(CA 116(13)129587q)。法国实用新型证书No.73,29370公开了1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯1-羟基-3H-1,2-苯并氧杂硼杂环戊烯,这在引用的文献中是唯一公开了氧杂硼杂环戊烯具有生物活性的,据披露它可用于抑制微生物在航空燃料中的生长。但是,为了保护燃料至少需要100ppm的1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯。
现在发现含有氧杂硼杂环戊烯环的化合物对微生物,例如细菌、藻类、酵母和特别是真菌尤其是能引起塑性材料降解的真菌是特别有效的。现在发现相对于上述实用新型证书公开的内容而言,微生物学活性的水平是意想不到的。
按照本发明,提供了保护对微生物的影响敏感的介质的方法,该方法是用有效量的下述通式(1)的化合物或其盐处理该介质:
其中
A和D各自独立地为氢,可被任选地取代的C1-18烷基,芳烷基,芳基,或杂环基,或者A和D和它们所连接的碳原子一起形成5,6或7元稠合环,该环本身是可被取代的;
X是-CR1R2,R1和R2各自独立地为氢,可被任选地取代的C1-6烷基,腈。硝基,芳基或芳烷基,或者R1和R2和它们所连接的碳原子一起形成脂族环;
R是氢,可被任选地取代的C1-18烷基,芳烷基,芳基,杂芳基,环烷基或下式(2)基团:其中A、D和X如上文定义,只是介质是航空燃料和仅有的氧杂硼杂环戊烯是1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯时除外。
当A和/或D是烷基时,它可以是直链的或支链的,优选C1-12烷基,更优选C1-8烷基,特别优选C1-4烷基。
当A和/或D是取代的烷基时,取代基可以是C1-6烷氧基、羟基、卤素、腈、氨基、取代的氨基、羧基、酰基、芳氧基或可任选地被C1-6烷基取代的羰基氨基。
当A和/或D是烷基时,该烷基(一个或多个)优选是未取代的。
当A和/或D是芳基时,优选其本身可以被取代的苯基。
当A和/或D是芳烷基时,优选苄基或2-乙基苯基,其中的苯环可以是取代的。
当苯环被取代时,取代基包括C1-6烷基、C1-6烷氧基、芳氧基、羟基、卤素、硝基、碳酰氨基、磺酰氨基、三氟甲基或可任选地被一个或多个C1-6烷基取代的氨基。
芳氧基优选苯氧基。
当A和D与它们所连接的二个碳原子一起形成稠合环时,该环可以是脂族的,如环戊烯、环己烯或环庚烯,或者可以是芳族的,如苯基、吡啶基、噻吩基或呋喃基。该稠合环也可以带有上文所述取代苯基和取代烷基的取代基。该稠合环也可以含有一个以上的环系,例如,萘基或喹啉基环系,或该稠合环也可以连接二个氧杂硼杂环戊烯环,如1H,3H-苯并[1.2-c:4,5-c’]双[1,2]氧杂硼杂环戊烯。
当R1和/或R2是芳基时,优选苯基。
当R1和/或R2是芳烷基时,优选苄基。
优选的是,R1和R2至少有一个是氢,特别优选两者都是氢。
当R是烷基时,它可以是直链的或支链的,优选C1-12烷基,特别优选C1-6烷基。
当R是取代的烷基时,取代基可以是包括C1-6烷氧基,C1-6烷硫基,羟基,氨基,取代的氨基,羧基,芳基,芳氧基,可任选地被C1-6烷基、芳基如苯基和芳烷基如苄基取代的碳酰氨基。
当R是芳烷基时,优选苄基或2-乙基苯基。
当R是芳基时,优选苯基。
当R是杂芳基时,优选喹啉基,特别优选喹啉-8-基。
当R是环烷基时,优选环己基。
当取代基是卤素时,优选溴、氯,特别优选氟。
优选的一类氧杂硼杂环戊烯是通式(1)的苯并氧杂硼杂环戊烯,其中A和D与它们所连接的碳原子一起形成稠合的苯基、萘基或噻吩基环。
当该稠合环是苯基时,氧杂硼杂环戊烯是苯并氧杂硼杂环戊烯,而一个或多个取代基可以在该苯并氧杂硼杂环戊烯的4,5,6或7位的任意位置上,优选有一个或多个取代基在5和/或6位上。优选的取代基为氨基、烷基、烷氧基、苯基、苯氧基、磺酰胺基、碳酰胺基,它们各自可以是被取代的,还有三氟甲基、氯、溴,和特别是氟。
当该稠合环是萘基时,另一稠合的苯环连接于该苯并氧杂硼杂环戊烯环系的4,5-或5,6-位。
在一类优选的氧杂硼杂环戊烯中,R是氢。
用于本发明的另一类优选的氧杂硼杂环戊烯是其中的R是取代的烷基,特别是其中的取代基是伯、仲或叔氨基的化合物,尤其是其中的亚烷基氨基同与R基团所连接的硼原子和氧原子一起形成5,6,或7元环的化合物。这些化合物是含有四面体硼原子的酯,例如下面的式(3):其中
A,D和X如上文定义;
R3和R4各自独立地为氢,可被任选地取代的C1-18烷基或可被任选地取代的苯基,或R3与Y和Y的一部分一起形成可被任选地取代的、含有氮原子的5,6或7元环;和
Y是可被任选地取代的最多有18个碳原子的二价亚烷基连接基团。
R3和R4优选可被任选地取代的C1-12烷基,更优选可被任选地取代的C1-8烷基,特别优选取代的C1-6烷基。
当R3和/或R4是烷基时,优选烷基是未取代的。
Y所表示的亚烷基可以是直链的或支链的。
当Y是取代的亚烷基时,取代基优选苯基,C1-6烷氧基,C1-6烷硫基,或如-COCH2-的羰基亚烷基。
当Y和Y的一部分形成可被任选地取代的5,6或7元环时,取代基可以是本身可被取代的稠合环。
优选的Y是未取代的亚烷基。
当R3和Y一起形成可被任选地取代的6元环时,该环优选为由例如8-羟基喹啉可得到的喹啉基环。
当R3和Y的一部分一起形成5元环时,该环优选为吡咯烷-2-基。
优选A和D与它们所连接的碳原子一起形成芳族环和环系,如稠合的苯基、噻吩基或萘基环,该环或环系可以如上文定义的取代的苯基和取代的烷基被取代。
当A和D与它们所连接的碳原子一起形成被取代的稠合苯基环时,氧杂硼杂环戊烯可以是在各硼原子上连接有酯基的1H,3H-苯并[1,2-c:4,5-c’]双[1,2]氧杂硼杂环戊烯。
A,D和X如上文定义;
n是1,2或3;
R3是氢,可被任选地取代的C1-18烷基或可被任选地取代的苯基,
R5和R6各自独立地为氢,最多含有总数为16个碳原子的可被任选地取代的烷基,或可被任选地取代的苯基。
优选R5和R6各自独立地为氢,可被任选地取代的C1-6烷基,特别优选可被任选地取代的C1-4烷基。
优选R3、R5和R6中的二个是氢。特别优选R5和R6二者都是氢。
优选n是1或2,特别是1。
当A和/或D和/或R是或者含有卤素的基团时,卤素可以是氟、氯、溴或碘。当A和/或D是卤素取代的烷基时,它可以含有一个以上的卤原子如三氟甲基。
当A和D与它们所连接的两个碳原子一起形成稠合环时,在稠合环上的任何取代基优选连接于不与氧杂硼杂环戊烯环相邻的碳原子上,因此在1,2-二氢-2,1-苯并氧杂硼杂环戊烯类的情况下,取代基(一个或多个)优选在5和/或6位上。
当式(1)的氧杂硼杂环戊烯是盐时,连接于硼原子上的-OR基团是阴离子,如-O-R+,其中R+是碱金属如锂、钾或钠,或R+是胺的盐或季铵阳离子。在后一情况下季铵阳离子本身可能是微生物学活性的。
当A和/或D是氨基或取代的氨基,或当A和/或D和/或R含有氨基或取代的氨基时,式(1)的氧杂硼杂环戊烯的盐可以是有机酸或无机酸的盐,这些酸的实例是乙酸和盐酸。
对塑性材料和涂料膜(paint film)得到了特别好的效果,其中的包含有氧杂硼杂环戊烯环的化合物是苯并氧杂硼杂环戊烯或其6-氯、5-氯、5-氟或5-溴衍生物,和通过与烷醇胺如乙醇胺、3-氨基丙醇和4-氨基丁醇反应而得到的氧杂硼杂环戊烯酯。
氧杂硼杂环戊烯可以未稀释的形式使用,但是优选与载体一起制成组合物使用。因此,本发明的另一方面提供了含有载体和通式(1)的氧杂硼杂环戊烯或其盐的组合物(下文称为“生物杀伤剂组合物”),条件是当1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯是仅有的氧杂硼环戊烯时载体不是航空燃料。
该载体,如果有的话,可以是没有什么抗微生物活性的物质,并且可以是或者可以包括介质,该介质对诸如细菌或真菌之类的微生物的生长是敏感的。载体可以是固体,但是优选是液体介质,而生物杀伤剂组合物最好是氧杂硼杂环戊烯在液体介质中的溶液、悬浮液或乳液。
该载体的选择一般应使该生物杀伤剂组合物与所保护的介质相容,因此,例如,如果要保护的介质是溶剂基的涂料、漆或清漆时,优选载体是溶剂,特别是非极性溶剂如石油溶剂。
如果要保护的介质是塑性材料,载体最好是一般用在塑料制品加工中增塑剂或稳定剂,如邻苯二甲酸二辛酯、己二酸二辛酯或环氧化的大豆油。如果要保护的介质是水性介质,优选载体是水或可与水混溶的有机溶剂或它们的混合物。适宜的可与水混溶的有机溶剂的实例是乙酸,N,N-二甲基甲酰胺,二甲亚砜,N-甲基-2-吡咯烷,醇类如乙醇或二醇类如乙二醇、丙二醇或二亚苯基二醇,和低级C1-4烷基卡必醇类如甲基卡必醇。如果载体是固体,组合物可以是如EP 407024中所描述的干燥固体。
如果生物杀伤剂组合物是悬浮剂或乳剂的形式,优选还含有表面活性剂使其形成稳定的分散液或保持非连续相均匀分配于连续相之中。对通式(1)化合物的生物杀伤活性没有不利作用的任何表面活性剂都可以使用,例如脂肪醇的烯化氧加合物,烷基酚,胺如乙二胺和阴离子表面活性剂如萘酚磺酸盐与甲醛的加合物。
氧杂硼杂环戊烯在生物杀伤剂组合物中的浓度优选最高达到的量是在此浓度时生物杀伤剂组合物在储存和运输的条件下是稳定的,优选相对于生物杀伤剂组合物的总重量的重量比为1-50%,更优选为5-30%以及特别优选10-20%。
如上文所述,很多氧杂硼杂环戊烯是新的。
按照本发明的另一方面,本发明还提供了式(1)化合物或其盐:其中A,D,X和R都如上文定义,只是除了下述化合物:N-(1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯-6-基)琥珀酰胺酸;6-硝基-、6-氨基-、7-甲基-、6-(N,N-二甲氨基)-、5-(N,N-二甲氨基)-、4-溴-、6-甲基-、5-溴-6-羟甲基-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯;1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯;1-苄氧基-、1-环己氧基-、1-乙氧基-1,3-二氢-2,1-苯并氧杂硼杂环戊烯;1,1’-氧双[1,3-二氢-2,1-苯并氧杂硼杂环戊烯];1,1’-氧双[4-溴-1,3-二氢-2,1-苯并氧杂硼杂环戊烯;和3,7-二氢-1,5-二羟基-1H,3H-苯并[1,2-c:4,5-c’]双[1,2]氧杂硼杂环戊烯。
优选A和D与它们所连接的碳原子一起形成稠合苯基环,其本身如上文所述可被取代,以及优选R是氢和氨基取代的烷基,还优选X是-CH2-。
优选稠合苯基环在苯并氧杂硼杂环戊烯环系的5-和/或6-位上含有卤原子,特别是在5-位上。优选的卤素是氟和氯。实例包括5-氯和特别是5-氟苯并氧杂硼杂环戊烯。
其它优选的氧杂硼杂环戊烯是由氧杂硼杂环戊烯与氨基脂肪族羧酸如甘氨酸或链烷醇胺如乙醇胺、3-氨基丙醇或4-氨基丁醇反应得到的O-酯。
按照本发明的另一方面,还提供了式(3)化合物:
其中
A,D和X如上文定义;
R3和R4各自独立地为氢,可被任选地取代的C1-18烷基或可被任选地取代的苯基,或R3与Y或Y的一部分一起形成含有氮原子的5,6或7元环;和
Y是可被任选地取代的最多有18个碳原子的二价亚烷基连接基团。
氧杂硼杂环戊烯可用本领域任何已知的方法制备。因此,1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯可通过在Sandmeyer条件下使邻甲苯胺反应得到邻位卤素取代的甲苯,然后在惰性溶剂中与镁或烷基锂如丁基锂反应,并使该如此得到的格利雅试剂或芳基锂与硼酸酯如三丁基硼酸酯反应得到甲苯硼酸。然后在惰性溶剂如四氯化碳中使此硼酸与溴化剂如N-溴代琥珀酰亚胺反应给出溴甲基苯硼酸,将其在碱中水解得到羟甲基类似物,最后使其在酸条件下环化得到苯并氧杂硼杂环戊烯,这是方法A.O-溴甲基苯硼酸的制备在JACS 1958 80 835中已述。
另外,在惰性溶剂如无水二氯甲烷中使适当的苯甲醛与对甲苯磺酰肼反应,接着在催化剂如氯化铁或氯化铝存在下使产物与三溴化硼反应然后环化成1。2-二氢-1-羟基-2-(4-甲基苯基-磺酰基)-2,3,1-苯并二氮杂硼杂苯(benzodiazaborine),接着在碱性条件下水解,然后在酸条件下转化成苯并氧杂硼杂环戊烯。通常,中间体二氮杂硼杂苯不必分离。这是方法B,在Liebigs Ann.Chem.,1985,683中已有描述。
含有稠合芳环的氧杂硼杂环戊烯可以通过在无水惰性有机液体溶剂中使含有-CH2OH基团的芳香族化合物与烷基锂或芳基锂和有机硼酸酯反应而制备。
本发明的另一方面还提供了含有稠合芳环的氧杂硼杂环戊烯的制备方法,该方法包括在无水惰性有机液体溶剂中使含有-CH2OH的芳香族化合物与烷基或芳基锂和有机硼酸酯反应。
优选的稠合芳环是稠合苯环,以及含有-CH2OH的芳香族化合物是可被任选地取代的苯甲醇。
优选的含有-CH2OH的芳香族化合物还含有一个或多个其它的取代基,这些取代基是邻位锂化(ortho-lithiation)的活化基团,由于这些基团的存在使反应可在更温和的条件下进行。这样的活性基团优选的位置是除在-CH2OH的邻位以外的位置。活性基团的实例是C1-6烷氧基,卤素如氯和氟,取代的烷基如-CH2OCH3、-CH2NT2、-CH2CH2NT2,取代的氨基如-NT2、-NHCOT、-NHCO2T和酰胺如-SO2NHT、-SO2NT2、-CONHT和-CONT2,其中T是芳基或烷基。当T是芳基时优选是苯基,当T是烷基时优选是C1-6烷基。
优选的烷基锂化合物可以是直链的或支链的,以及优选C1-6烷基,特别优选C1-4烷基如丁基锂。
有机液体溶剂优选是烷基醚如乙醚,或优选环醚如四氢呋喃。
反应可在高达有机溶剂沸点的温度下进行,但是,当含有-CH2OH的芳香族化合物还含有邻位锂化的活化基团时,优选反应在低于0℃,更优选在低于-50℃的温度下进行,特别优选在-70与-100℃之间进行。
含有-CH2OH的芳香族化合物还可含有不与该烷基或芳基锂化合物反应的其它取代基。
优选的有机硼酸酯可以是直链的或支链的,更优选C1-6烷基,特别优选C1-4烷基硼酸酯。
仲丁基锂和正丁基硼酸酯是优选的。
含有-CH2OH的芳香族化合物与烷基或芳基锂之间的反应优选在螯合剂存在下进行,优选的螯合剂是四亚甲基乙二胺。
含有稠合芳环的氧杂硼杂环戊烯还可以通过使含有-CH2OH基团和邻位碘或溴基团的芳香族化合物与烷基或芳基锂和有机硼酸酯反应来制备。
本发明的另一方面还提供了含有稠合芳环的氧杂硼杂环戊烯的制备方法,该方法包括在惰性有机液体溶剂中使含有-CH2OH基团和邻位碘或溴基团的芳香族化合物与烷基或芳基锂和有机硼酸酯反应。
优选的反应条件如在含有-CH2OH的芳香族化合物中所说明的。
典型地,氧杂硼杂环戊烯的硼酸酯通过在惰性溶剂中,于25-125℃由R是氢的通式(1)化合物与适当的氨基-脂肪族羧酸或优选的烷醇胺反应制备,几乎立刻生成硼酸酯。当烷醇胺与氧杂硼杂环戊烯反应时,优选惰性溶剂与水生成共沸以利于除去生成的水。特别优选的溶剂是甲苯。这是方法C。
氧杂硼杂环戊烯或含有氧杂硼杂环戊烯的组合物可用于处理各种介质以抑制微生物的生长,以及其抗真菌活性特别有效。
本发明的另一方面还提供了在介质之上或在其内抑制微生物生长的方法,该方法包括用氧杂硼杂环戊烯或含有氧杂硼杂环戊烯的生物杀伤剂组合物处理所述介质。
可以把氧杂硼杂环戊烯用于微生物生长和产生问题的条件下。微生物生长和产生问题的体系包括液体,特别是水性液体,如冷却水体系,造纸厂废液,金属加工液,地质钻探润滑剂,聚合物乳液,特别是表面涂覆组合物如涂料、清漆和油漆,尤其是固体材料如木材、塑性材料和皮革。
已经发现氧杂硼杂环戊烯在抑制塑性材料如增塑的PVC和聚氨酯的微生物降解中特别有效。因为这些产品的加工通常所采用的高温对,它们不会有明显的负面影响。在这方面已经发现苯并氧杂硼杂环戊烯特别有效,特别是在苯并氧杂硼杂环戊烯的稠和苯环上含有一个或多个卤素取代基的化合物。
在这些材料中可包含氧杂硼杂环戊烯以具有抗微生物作用。相对于所加入的体系而言,该化合物的量一般在0.00001-2.0%(重量)范围内,优选0.0001-1%,特别是0.0002-0.5%。在某些情况下,0.0005-0.01%(重量)的氧杂硼杂环戊烯可以实现微生物的抑制。因此,在塑性材料的情况下,发现氧杂硼杂环戊烯在小于0.05%,特别是小于0.01%,尤其是小于0.005%和更特别是小于0.001%的应用浓度时能抑制微生物的生长。
氧杂硼杂环戊烯可以是仅有的用于保护介质的抗微生物化合物,或者它可以与一种或多种不同的氧杂硼杂环戊烯一起使用,或与一种或多种其它有抗微生物活性的化合物一起使用。下文被称作“生物杀伤剂混合物”的抗微生物化合物的混合物通常有更宽的抗微生物谱,因此通常比混合物的各组分更有效。其它的抗微生物化合物(一种或多种)可以具有抗菌、抗真菌、抗藻类或其它抗微生物活性。在生物杀伤剂混合物中,相对于抗微生物活性化合物总重量而言生物杀伤剂混合物一般含有1-99%(重量)优选40-60%(重量)的氧杂硼杂环戊烯。
可以与氧杂硼杂环戊烯一起使用的其它抗微生物化合物的实例是季铵化合物,例如:
氯化N,N-二乙基-N-十二烷基-N-苄基铵;
氯化N,N-二甲基-N-十八烷基-N-(二甲基苄基)铵;
氯化N,N-二甲基-N,N-二癸基铵;
氯化N,N-二甲基-N,N-二(十二烷基)铵;
氯化N,N,N-三甲基-N-十四烷基铵;
氯化N-苄基-N,N-二甲基-N-(C12-18烷基)铵;
氯化N-(二氯苄基)-N,N-二甲基-N-十二烷基铵;
氯化N-十六烷基吡啶鎓;
溴化N-十六烷基吡啶鎓;
溴化N-十六烷基-N,N,N-三甲基铵;
氯化N-十二烷基吡啶鎓;
N-十二烷基吡啶硫酸氢盐;
氯化N-苄基-N-十二烷基-N,N-双(β-羟基乙基)铵;
氯化N-十二烷基-N-苄基-N,N-二甲基铵;
氯化N-苄基-N,N-二甲基-N-(C12-18烷基)铵;
乙基硫酸N-十二烷基-N,N-二甲基-N-乙基铵;
氯化N-十二烷基-N,N-二甲基-N-(1-萘基甲基)铵;
氯化N-十六烷基-N,N-二甲基-N-苄基铵;
氯化N-十二烷基-N,N-二甲基-N-苄基铵;和
1-(3-氯烯丙基)-3,5,7-三氮杂-1-氮鎓-金刚烷氯化物;
脲衍生物,如:
1,3-二(羟基甲基)-5,5-二甲基海因;
二(羟基甲基)脲;
3-(3,4-二氯苯基)-1,1-二甲基脲;
3-(4-异丙基苯基)-1,1-二甲基脲;
四(羟基甲基)双亚乙基二脲;
1-(羟基甲基)-5,5-二甲基海因;和
咪唑烷基脲;
氨基化合物,如:
1,3-二(2-乙基己基)-5-甲基-5-氨基-六氢嘧啶;
六亚甲基四胺;
1,3-二(4-氨基苯氧基)丙烷;和
2-[(羟基甲基)-氨基]乙醇;
咪唑衍生物,如:
1-[2-(2,4-二氯苯基)-2-(2-丙烯基氧基)乙基]-1H-咪唑;
2-(甲氧羰基-氨基)苯并咪唑;
溴化1-癸基-3-十二烷基-2-甲基咪唑鎓;
十二烷基双(1-癸基-2-甲基-咪唑鎓)二溴化物;
腈化合物,如:
2-溴-2-溴甲基戊二腈;
2-氯-2-氯甲基戊二腈;
2,4,5,6-四氯间苯二甲腈;
硫代氰酸酯衍生物,如:
亚甲基二硫代氰酸酯;
锡化合物或复合物,如:
三丁基锡氧化物、氯化物、萘甲酸盐、苯甲酸盐或2-羟基苯甲酸盐;
异噻唑啉-3-酮类,如:
4,5-三亚甲基-4-异噻唑啉-3-酮;
2-甲基-4,5-三亚甲基-4-异噻唑啉-3-酮;
2-甲基异噻唑啉-3-酮;
5-氯-2-甲基异噻唑啉-3-酮;
苯并异噻唑啉-3-酮;
2-甲基苯并异噻唑啉-3-酮;
2-辛基异噻唑啉-3-酮;
4,5-二氯-2-辛基异噻唑啉-3-酮;
N-(2-乙基丁基)苯并异噻唑啉-3-酮;
N-正己基苯并异噻唑啉-3-酮;
噻唑衍生物,如:
2-(氰硫基甲硫基)苯并噻唑;和
巯基苯并噻唑;
硝基化合物,如:
三(羟甲基)硝基甲烷;
5-溴5-硝基1,3-二噁烷;和
2-溴-2-硝基丙烷-1,3-二醇;
碘化合物,如:
碘代丙炔基丁基氨基甲酸酯;和
三碘代烯丙基醇;
醛和其衍生物,如:
戊二醛;
对氯苯基-3-碘代炔丙基半缩甲醛、甲醛和乙二醛;
酰胺,如:
氯代乙酰胺;
N,N-二(羟甲基)氯代乙酰胺;
N-羟甲基氯代乙酰胺;和
二硫代-2,2-双(苯甲基)酰胺;
胍衍生物,如:
聚(六亚甲基双胍);和
1,6-六亚甲基双[5-(4-氯苯基)双胍];
卤化咪唑鎓,如:
N,N’-二癸基-2-甲基咪唑鎓溴化物;和
1,12-双(N-癸基-2-甲基咪唑鎓)-十二烷基二溴化物;
硫酮,如:
3,5-二甲基四氢-1,3,5-2H-硫代二嗪-2-硫酮;
三嗪衍生物,如:
六氢三嗪;
1,3,5-三羟乙基-1,3,5-六氢三嗪;
6-氯-2,4-二乙氨基-s-三嗪;和
4-环丙基氨基-2-甲硫基-6-叔丁基氨基-s-三嗪;
噁唑烷和其衍生物,如:双-噁唑烷;
呋喃和其衍生物,如:
2,5-二氢-2,5-二烷氧基-2,5-二烷基呋喃;
羧酸及其盐和酯,如:
山梨酸和4-羟基苯甲酸和它们的盐和酯;
苯酚和其衍生物,如:
5-氯-2-(2-,4-二氯苯氧基)苯酚;
硫代-双(4-氯苯酚)和2-苯基苯酚;
砜衍生物如:
二碘甲基对甲苯基砜;
2,3,5,6-四氯-4-(甲基磺酰基)吡啶;和
六氯二甲基砜;
硫代酰胺,如:
二硫代氨基甲酸二甲酯和其金属配合物;
亚乙基双二硫代氨基甲酸酯和其金属配合物;和
2-巯基吡啶-N-氧化物和其金属配合物;和
酰亚胺,如:
三氯甲基巯基邻苯二甲酰亚胺,
氟二氯甲基巯基邻苯二甲酰亚胺,和
三氯甲基巯基四氢邻苯二甲酰亚胺。
本发明的另一方面在下面的说明实施例中描述,除非另有说明,其中所有制备的详细描述中以重量份数说明。对化合物抗微生物性质的评价是在无菌条件下用下文描述的实验方法进行的。
测定MIC的微量滴定筛选方法
对细菌的试验
对适当的微生物在营养肉汤中进行过夜培养(18小时,37℃),在1ml培养液中得到大约109个能存活的细胞。在无菌条件下把20μl此培养液转移到20ml营养肉汤中,然后把200μl此接种液加到微量滴定板的所有竖向的孔中,再把100μl此接种液加到竖向孔的每个相邻列的孔中。
在适当的溶剂中制成试验化合物的5000ppm溶液,取20μl加到竖向孔的第二列的第一孔作为对照。把每个孔内的内容物混匀,取出100μl并转移到该列中相邻的水平孔中,重复此过程经过每个垂直列的孔,在500ppm-0.25ppm的实验范围内对每个化合物进行一系列稀释。然后把微量滴定板封好并在25℃培养42-48小时。最小抑制浓度(MIC)是指没有可看到的细菌生长的最小浓度。
对Saccharomyces Cerevisiae的试验
如上述对细菌一样制备培养液,只是用Oxoid Malt肉汤代替营养肉汤,在30℃培养42-72小时。
对真菌的试验
在25℃使真菌在麦芽琼脂板上生长1周,注入2ml无菌盐水,用无菌环小心搅拌释放出孢子,将孢子悬浮液倾入一玻璃的25ml Universal烧瓶中(孢子计数大约为107ml-1)。
然后将20μl此孢子悬浮液加入到20ml麦芽肉汤中, 并用于接种微量滴定板。如对细菌的MIC所述进行稀释并在25℃培养42-72小时。
涂料膜的试验方法
与微量滴定筛选方法相同,只是把板培养4天,使用的微生物是真菌,该真菌是由变坏的涂料膜表面分离出来的,其名称为
瓦格链格孢(Alternaria alternata)(AA) PRA FS 4
出芽短梗霉菌(Aureobasidium pullulans)(AP) PRS FS 1
腊叶枝孢(Cladosporium herbarum) (CH) CMI 16203
Phoma Violacia (PV) PRA FS 13
Stemphylium dendriticum(SD) PRA FS 15
实施例1
制备5-氯-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯(方法B)
a)制备3-氯苯甲醛甲苯磺酰肼
在低于10℃,向搅拌着的对甲苯磺酰肼(20.7份;0.108M)于甲基化酒精(150ml)中的悬浮液之中缓慢地加入3-氯苯甲醛(15.56份;0.109M;Aldrich)的甲基化酒精(40ml)溶液,反应物料于20-25℃搅拌1小时,当反应物和产物溶解时在60-70℃加热1.5小时。然后用旋转蒸发器去除溶剂,得到固体产物,该产物用乙醚制浆和用正己烷洗涤。产率=27.2份(理论值的81.5%),mpt 122-3℃。
元素分析
理论值54.5%C;4.2% H;9.1% N
测定值54.5%C;4.3% H;9.1% N
质子NMR(CDCl3:ppm)
8.5,s,1H(-NH-);7.9,d,2H(芳香族,甲苯磺酰基);7.7,s,1H(CH=N);7.5,s,1H(芳香族);7.2-7.4,m,5H(芳香族,甲苯磺酰基);2.3,s,3H(-CH3)
b)制备标题化合物
在氮气层中,20-25℃,在搅拌着的上述步骤a)得到的酰肼(10.18份,0.033M)于无水二氯甲烷(160ml)中的悬浮液之中加入无水氯化铁催化剂(0.75份,Fisons)于无水二氯甲烷(20ml)中的悬浮液,同时,加入三溴化硼(25份,0.1M,Aldrich)的无水二氯甲烷(100ml)液。然后回流搅拌反应物,逸出的溴化氢用氢氧化钠水溶液收集。回流搅拌3小时后,使反应物在20-25℃静置48小时,再回流搅拌4小时。然后冷却反应物料,用旋转蒸发器取去除溶剂,得到的固体用2N氢氧化钠溶液(160ml)回流搅拌3小时。棕色的水性悬浮液用二氯甲烷(50ml)萃取,过筛,然后加入2N盐酸酸化至约pH2,固体经过滤、用二氯甲烷(400ml)制浆,和先用饱和的碳酸氢钠水溶液,再用水洗涤。产率=24份(理论值的43%)。把固体在热二氯甲烷中制浆,过滤后给出0.36份氧杂硼杂环戊烯,mp140-45℃。冷却该二氯甲烷溶液,过滤出固体,又得到0.35份氧杂硼杂环戊烯,mp146-8℃。合并固体并用甲基化酒精重结晶。
产率=0.51份(理论值的9.2%),mp 150-4℃。
元素分析
理论值49.8% C;3.5% H;21.06% Cl
测定值49.5% C;3.5% H;21.0% Cl
质子NMR (CDCl3)ppm
9.3,s,1H(-OH);7.5,d,s,d,3H(芳香族);5.0,s,2H(-CH2-O)
实施例2
制备1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯的乙醇胺酯(方法C)
在80℃把1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯(0.22份,0.0016M)溶于甲苯(40ml),缓慢加入乙醇胺(0.1份,0.00164M),立即形成酯,加入甲苯(50ml),加热回流反应物以溶解该酯,过筛后,冷却分离产物,为浅色固体0.15份(理论值的52%),mp214-216℃。
元素分析
理论值61% C;6.8% H;7.9% N
测定值60.3% C;6.7% H;7.6% N
实施例3
制备1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯的3-氨基丙醇酯
按实施例2所述制备,使用1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯(0.15份,0.00112M)和3-氨基丙醇(0.084份,0.00112M,Aldrich),由甲苯/100-120℃石油醚重结晶得到无色固体。产率=0.18份(理论值的84%),mp174-6℃。
元素分析
理论值62.8% C;7.3% H;7.3% N
测定值64.5% C;7.5% H;7.1% N
实施例4-14
用上文所述的微量滴定筛选方法测定下面的1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯衍生物的MIC。
在这些实施例中,使用了两种真菌和两种细菌,名称为酿酒酵母(Saccharomyces cerevisiae) NCYC 124 (SC),黑曲霉(Aspergillus niger) CMI 17454 (AN),绿脓杆菌(Pseudomonasaeruginosa)NCIB 1042l(PA)和金黄色葡萄球菌(Staphylococcusaureus)NCIB 9518 (SA).
结果列于下表1
表1
实施例 | 取代基 | MIC数据(ppm)微生物 | |||
SC | AN | PA | SA | ||
4 | - | 0.5 | 0.25 | >50 | 62 |
5 | 6 Cl- | 2 | 2 | N | 62 |
6 | 5 PhO- | 31 | 16 | N | 31 |
7 | 5 tert Bu- | 125 | 62 | N | 31 |
8 | 5 F- | <0.25 | <0.25 | 125 | 31 |
9 | 5.6稠合的Ph | 31 | 16 | N | 16 |
10 | 4.5稠合的Ph | 16 | 16 | N | 62 |
11 | 3 ph- | 16 | 31 | N | 125 |
12 | S Cl- | 0.5 | <0.25 | N | 62 |
13 | 5 CF1- | 8 | 0.25-0.5 | 125 | 62 |
14 | 5 Br- | 8 | 1 | N | 125 |
表1的附注
N=在100ppm没有活性
SC,AN,PA,SA 如在微量滴定筛选中所述
实施例5-18
在50/50邻苯二甲酸二辛酯和己二酸二辛酯中制备试验的杀真菌剂的0.1%(w/w)溶液。把每份为0.125、0.25、0.5、2.0和3.0ml的溶液(给出1.25、 2.5、5、20和30ppm杀真菌剂)通过加入邻苯二甲酸二辛酯/己二酸二辛酯混合物以调整体积到3ml,然后,用马铃薯葡萄糖胰蛋白冻大豆琼脂制备成100ml并均化。把板放入培养皿并使其静置。使用多点涂布器(applicator),用103 AP、FS、PF和SB的孢子悬浮液和105 SW菌落悬浮液给每个板接种,将板在20℃培养4天后测定MIC值,结果列于下表2.
表2
表2的附注SK=2-正辛基异噻唑啉-3-酮DS=2,3,5,6-四氯-(4-甲基砜)吡啶AP=出芽短梗霉茵(Aureobasjdium pullulans)FS=茄病镰孢(Fusarium solani)PP=Penicilljum pinophylumSB=短柄帚霉(Scopulariopsis brevicaulis)SW=Streptoverticillium waksmanii
实施例 | 取代基 | 真菌 | ||||
Ap | FS | PP | SB | SW | ||
15 | <1.25 | <1.25 | <1.25 | <1.25 | <1.25 | |
16 | 6 Cl- | 20 | 20 | 2.5 | 2.5 | 2.5 |
17 | S Cl- | <1.25 | <1.25 | <1.25 | <1.25 | j |
18 | 5 F- | <1.25 | <1.25 | <1.25 | <1.25 | <1.25 |
A | SK | 2.5 | 20 | <1.25 | <2.5 | 2.5 |
B | DS | 6D | 80 | 4.0 | 2.5 | 2.5 |
实施例19-22
用上述涂料膜的方法测定下面的苯并氧杂硼杂环戊烯衍生物的MIC,得到的值列于下表3。
表3
表3的附注SK=2-正辛基异噻唑啉-3-酮TP=碘代丙炔基丁基氨基甲酸酯
实施例 | 取代基 | 微生物 | ||||
PV | CH | AA | AP | SD | ||
19 | 1 | 4 | 2 | 2 | 1 | |
20 | 5 F- | <0.25 | 0.5 | <0.25 | <O.25 | <0.25 |
21 | 5 Cl- | <0.25 | 0.5 | <0.25 | <0.25 | <0.25 |
22 | 5 Br- | 2 | 4 | 2 | 1 | 2 |
C | SK | 1 | 8 | 0.5 | <0.25 | 8 |
D | TP | 0.8 | 0.8 | 0.4 | 0.4 | 0.8 |
制备实施例23-58
重复实施例1a)和(b),但用等当量的苯甲醛和3-氟苯甲醛代替实施例1a中所用的3-氯苯甲醛,得到类似的1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯衍生物。然后,以等当量的烷醇胺代替乙醇胺如实施例2所述使这些苯并氧杂硼杂环戊烯衍生物与烷醇胺反应。得到的苯并氧杂硼杂环戊烯酯有式2的结构:
所得到的化合物的元素分析和/或熔点列于下表4。
表4
实施例 | R7 | R3 | R4 | Y | mp℃ | 元素分析(1) | |||||
测定值 | 理论值 | ||||||||||
23 | N | N | N | -(CH2)2- | 214-216 | 60.3 C | 6.7 H | 7.6 N | 61.0 C | 6.8 H | 7.9 N |
24 | N | N | N | -(CH2)3- | 174-176 | 64.5 C | 7.5 H | 7.1 N | 62.0 C | 7.3 H | 7.3 N |
25 | N | N | N | -(CH2)4- | 161-163 | 64.9 C | 8.1 H | 7.0 N | 64.4 C | 7.8 H | 6.8 N |
26 | 5-Cl | N | N | -(CH2)3- | 196-199 | ||||||
27 | 5-Cl | N | N | -(CH2)4- | 169-171.5 | ||||||
28 | 5-Cl | Ne | N | -(CH2)2- | 143-148 | ||||||
29 | 5-Cl | N | N | -CH2-CH(CH3)- | 191-194 | ||||||
30 | 5-Cl | N | N | -CH(CH3)-CH2- | 206-210 | ||||||
31 | 5-Cl | N | N | -CH2-C(CH3)2- | 172-175 | ||||||
32 | N | Ne | N | -(CH2)2- | 167-169 | 62.4 C | 7.4 H | 7.2 N | 62.8 C | 7.3 H | 7.3 N |
33 | N | N | N | -CH2C(CH3)2- | 176-178 | 61.5 C | 7.4 H | 5.3 N | 64.4 C | 7.8 H | 6.8 N |
34 | 5-F | N | N | -(CH2)3- | 186-187 | 62.6 C | 6.1 H | 5.5 N | 62.6 C | 6.2 H | 6.7 N |
35 | N | Ne | Ne | -(CH2)2- | 61.5 C | 7.4 H | 5.3 N | 61.7 C | 7.9 H | 6.5 N | |
36 | 5-F | Ne | N | -(CH2)2- | 184-192 | 57.0 C | 6.0 H | 7.3 N | 57.4 C | 6.2 H | 6.7 N |
37 | 5-F | N | N | -(CH2)2- | 232-234 | 55.0 C | 5.5 H | 7.1 N | 55.4 C | 5.6 H | 7.2 N |
38 | 5-F | N | N | -CN2-C(CH3)2- | 132-134 | 57.9 C | 6.7 H | 6.1 N | 58.0 C | 6.8 H | 6.2 N |
39 | 5-F | N | N | -(CH2)4- | 163-165 | 58.6 C | 6.8 H | 6.5 N | 59.2 C | 6.7 H | 6.3 N |
40 | N | tBu | N | -(CH2)2- | 141-143 | 62.4 C | 8.3 H | 4.7 N | 62.2 C | 8.8 H | 5.6 N |
41 | N | Et | N | -(CH2)2- | 178-180 | 64.2 C | 7.2 H | 6.7 N | 64.4 C | 7.9 H | 6.8 N |
42 | N | npr | N | -(CH2)2- | 166-168 | 64.9 C | 7.1 H | 6.4 N | 64.8 C | 8.3 H | 6.3 N |
表4(续)
实施例 | R7 | R3 | R4 | Y | mp℃ | 元素分析(1) | |||||
测定值 | 理论值 | ||||||||||
43 | N | nBu | N | -(CH2)2- | 159-161 | 66.4 C | 7.6 H | 5.9 N | 67.0 C | 8.6 H | 6.0 N |
44 | N | nPe | N | -(CH2)2- | 135-131 | 67.0 C | 8.3 H | 5.7 N | 68.0 C | 9.0 H | 5.7 N |
45 | N | N | N | -CH(CH3)-CH2- | 213-216 | 62.6 C | 7.0 H | 7.2 N | 62.8 C | 7.3 H | 7.3 N |
46 | 5-Cl | N | N | -CH-(CH2CH3)CH2- | 213-214.5 | ||||||
47 | 5-Cl | N | N | -CH2-CH(CH2CH3)- | 187.5-189 | ||||||
48 | N | N | N | -CH2CH(CH3)- | 113-175 | 64.5 C | 7.5 H | 6.4 N | 62.8 C | 7.3 H | 7.3 N |
49 | N | N | N | -CH2CH(CH2CH3)- | 205-207 | 64.4 C | 7.5 H | 6.8 N | 64.4 C | 7.9 H | 6.8 N |
50 | N | N | N | -CH(CH2CH3)CH2- | 207-210 | 64.2 C | 7.9 H | 7.1 N | 64.4 C | 7.9 H | 6.8 N |
51 | N | N | N | -CH2CH((CH2)2CH3)- | 180-191 | 66.0 C | 8.7 H | 6.4 N | 67.0 C | 8.6 H | 6.8 N |
52 | N | N | N | -CH2H(CH2CH(CH3)2)- | 204-207 | 66.6 C | 7.6 H | 6.0 N | 67.0 C | 8.6 H | 6.0 N |
53 | N | N | N | -CH2CH((CH2)2CH3)- | 210-213 | 66.4 C | 8.4 H | 6.5 N | 65.8 C | 8.3 H | 6.4 N |
54 | N | N | N | -CH2CH((CH2)2SCH3)- | 174-175 | 57.4 C | 6.1 H | 5.0 N13.0 S | 57.4 C | 7.2 H | 5.6 N12.8 S |
55 | 5-F | EL | N | -(CH2)2- | 108-109 | 59.2 C | 6.0 H | 6.3 N | 59.2 C | 6.1 H | 6.1 N |
56 | 5-F | N | N | -CH2CH(CH2CH3)- | 212-214 | 59.0 C | 6.5 H | 6.2 N | 59.2 C | 6.8 H | 6.3 N |
57 | 5-F | N | N | -CH(CH2CH3)CH2- | 205-208 | 58.3 C | 6.6 H | 6.2 N | 59.2 C | 6.8 H | 6.3 N |
58 | 5-F | pr | N | -(CH2)2- | 182-184 | 60.B C | 7.4 H | 5.8 N | 60.8 C | 7.2 H | 5.9 N |
制备实施例59-78(65和71除外)
按与实施例1a)和b)类似的方法,用等当量的适当的醛代替3-氯苯甲醛,制备下述的氧杂硼杂环戊烯。
得到的苯并氧杂硼杂环戊烯衍生物有下面通式的结构:
这些化合物的元素分析和/或熔点列于下表5。
表5
实施例 | R8 | R9 | mp℃ | 元素分析 (1) | |||||
测定值 | 理论值 | ||||||||
59 | 6-Cl | N | 156-158 | 49.5 C | 3.5 H | 21.0 N | 49.0 C | 3.5 H | 21.0 N |
60 | 5-PhO | N | 101-105 | ||||||
61 | 5-C(CH3)3 | N | 119-123 | ||||||
62 | 4,5 fusedPh | N | 137-139.5 | ||||||
63 | 5,6 fusedPh | N | 161-163.5 | ||||||
64 | 5-F | N | 127-129 | 54.9 C | 4.2 H | 55.2 C | 3.9 H | ||
65 | N | Ph | 145-147 | ||||||
66 | 5-Cl | N | 150-155 | 49.9 C | 3.5 H | 20.8 N | 49.8 C | 3.5 H | 21.0 N |
67 | 5-CF3 | N | 47.6 C | 3.1 H | 47.5 C | 2.9 H | |||
68 | 5-Br | N | 39.4 C | 2.7 H | 39.0 | 39.4 C | 2.8 H | 37.6 Br | |
69 | 4-F | N | 54.8 C | 4.2 H | 6.9 B8.9 F | 55.2 C | 3.95 H | 7.2 B12.5 F | |
70 | 6-F | N | 54.5 C | 4.1 H | 7.1 B8.5 F | 55.2 C | 3.95 H | 7.2 B12.5 F | |
71 | N | -CH | 114-115 | 59.O C | 3.5 H | 8.6 N | 60.3 C | 3.8 H | 8.8 N |
72 | 4-CH3,5-F | N | 162-163 | 57.4 C | 4.4 H | 5.9 B | 57.8 C | 4.8 H | 6.6 B |
73 | 5,6 diF | N | 148-151 | 49.2 C | 3.0 H | 6.2 B | 49.4 C | 2.9 H | 6.4 B |
74 | 5-CH3O | N | 122-124 | 50.5 C | 5.4 H | 6.7 B | |||
75 | 7-F | N | 132-134 | 55.0 C | 4.0 H | 7.1 B | |||
76 | 4.7 diF | N | |||||||
77 | 6,7 diF | N | |||||||
78 | 5,7 diF | N |
制备实施例65
制备3-苯基-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯
a)制备二苯甲酮对甲苯磺酰腙
将二苯甲酮(15.0份,0.082M,购自Fluka)与对甲苯磺酰肼(15.33份,0.082M,购自Aldrich)在乙醇(125ml)中回流搅拌10小时,逐渐形成浅黄色溶液,由其中逐渐沉淀出腙,冷却至20℃后加入乙醚(20ml),过滤出该腙并用乙醚洗涤。得到的腙为白色粉末(24.0份,理论值的83%),mp184-6℃。
质子NMR分析
2.44(s,3H);7.0-7.18(m,2H);7.27-7.38(m,5H);2.42-2.48(m,2H);7.48-7.55(m,4H);7.56(s,H);7.86(d,2H).
b)制备二氮杂硼杂苯(Diazaborine)衍生物
把无水氯化铁(0.75份)悬浮于无水二氯乙烷(75ml)中,在氮气氛中,于20℃,用15分钟时间边搅拌边同时加入三溴化硼(131ml 的M二氯甲烷溶液,0.131M,购自Aldrich)和上述(a)中得到的腙(15.0份,0.043M无水二氟甲烷溶液,200ml)的溶液,温度升高大约2℃,回流搅拌暗红色反应混合物4.5小时以除去溴化氢。
然后冷却反应物,倒入冰(500份)和水(500份)中,分离出有机相并用氢氧化钠水溶液萃取,然后分离水层并加入浓盐酸调节pH至3.水层用二氯甲烷萃取,分离,用硫酸镁干燥,去除溶剂得到乳黄色固体。产率=3.83份(理论值的24%),mp239-42℃。
质子NMR分析
2.44(s,3H);7.33(d,2H);7.37-7.52(m,5H);7.44(s,H);7.55-7.71(m,3H);7.95(d,2H);8.25-8.35(m,H).
c)制备标题化合物
由(b)得到的二氮杂硼杂苯(2.6份)于含有乙醇(50ml)的10%氢氧化钾水溶液(100ml)中回流搅拌4.5小时。然后冷却溶液,用二氯甲烷洗涤,用浓盐酸调节pH至3。用二氯甲烷萃取如此得到的悬浮液,去除溶剂后得到的浅乳黄色固体,发现它是起始原料和产物的混合物。用制备柱色谱纯化,使用二氧化硅柱,用二氯甲烷展开。
蒸发去除溶剂后,得到白色固体产物(0.49份,理论值的24%),mp
质子NMR分析
6.14(s,H);7.15(d,H);7.21-7.46(m,7H);7.83(d,H);8.51(s,H).
制备实施例71
制备3-氰基-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯
a)制备2-甲酰基苯基硼酸
(参见JACS 86 1964 p435)
把邻甲苯基硼酸(10份;0.0714M,购自Aldrich)和N-溴代琥珀酰亚胺(30.13g;0.169M,购自Aldrich)在110℃干燥16小时。将这两种反应物加入四氯化碳(450ml)并蒸出50ml溶剂以去除任何残留的水。加入过氧化苯甲酰(1.5份),回流搅拌反应物6小时,冷却后加入环己烷(1.25份)以去除溴,和将溶液过筛以去除琥珀酰亚胺。然后产物用15%氢氧化钾水溶液萃取(4×35ml)。合并此水性萃取液并用浓盐酸酸化到大约pH4,再将产物萃取至乙醚(3×200ml)中。合并的醚萃取液用硫酸镁干燥,蒸发醚,最后,产物用水重结晶。产率=1.69份(理论值的15.3%),mp122-4℃。
元素分析
测定值 55.3% C, 4.7% H
理论值 56.0% C, 4.7% H
b)制备标题化合物
(参见JOC 29 1964 p2172)
于20℃,一边搅拌一边将2-甲酰基苯基硼酸(1.0份,0.007M)加入氰化钠(0.35份)的水(20ml)溶液中,15分钟后将反应物冷却至5℃,并小心地用浓盐酸中和至pH5。过滤得到的白色沉淀,用水(25ml)重结晶。产物用氯化钙干燥。产率=0.29份(理论值的26%), mp114-5℃。
元素分析
测定值 59.0% C, 3.5% H; 8.6% N
理论值 60.3% C, 2.8% H; 8.8% N
制备实施例79和80
重复实施例2,只是用等当量的8-羟基喹啉代替乙醇胺得到实施例79的苯并氧杂硼杂环戊烯。通过用等当量的5-氟类似物代替实施例79的1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯可得到实施例80。下式苯并氧杂硼杂环戊烯的分析数据和/或熔点列于表6,
表6
实施例 | R10 | mp℃ | 元素分析 (1) | |||||
测定值 | 理论值 | |||||||
79 | H | 189-190 | 73.4 C | 4.4 H | 5.4 N | 73.6 C | 4.6 H | 5.4 N |
8O | F | 118-119 | 68.8 C | 3.9 H | 5.0 N |
制备实施例81-90
这些化合物的熔点列于下表7。
表7
制备实施例91
制备5-甲氧基-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯
将2-溴-5-甲氧基苄醇(6.5份;0.03M)溶于无水THF(100ml)并冷却至-78℃。在氮气氛中用20分钟时间一边搅拌一边加入正丁基锂(26.4ml 2.5M的己烷溶液,购自Aldrich,0.066M),使温度保持低于-60℃。在-70℃再搅拌1小时后,HPLC表明反应是不完全的,留有20%的起始原料。再加入一份正丁基锂的己烷溶液(5ml;0.0125M),使反应物温热至-50℃。
然后,在氮气氛中于-70至-50℃之间加入三丁基硼酸酯(17.8ml,0.066M),使反应物温热至约20℃。加水(20ml),用盐酸调节pH至10。在用乙醚洗涤之后,用盐酸调节水相的pH至1-2,再用乙醚洗涤。乙醚萃取液用饱和盐水洗涤,用无水硫酸镁干燥,蒸出乙醚留下的产物为浅色油状物(3.7份)。用含有少量甲醇的水将其制备成浆液,通过过滤,用水洗涤和干燥,由此分离出粉白色固体(2.0份),在用含水甲醇重结晶后mp=110-115℃。
制备实施例92
制备7-氟-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯
将3-氟苄醇(3.5份;0.028M)在含有四亚甲基乙二胺(10.2ml,0.067M)的THF(100ml)中搅拌,冷却至-78℃后,在氮气氛中于-78至-65℃之间用45分钟时间一边搅拌一边缓慢加入仲丁基锂(77ml 0.8M的环己烷溶液,购自Aldrich,0.061M)。于-78℃1小时后,滴加三丁基硼酸酯(16.78ml,0.061M),反应物在氮气中搅拌16小时,使温度缓慢升至20℃。加入稀盐酸使pH至大约12,分离水相,用乙醚洗涤,用盐酸酸化调节水相的pH至约2,用乙醚萃取(3×100ml)。乙醚萃取液用饱和盐水洗涤,用无水硫酸镁干燥,蒸出乙醚分离出的产物为浅色固体(2.6份;理论值的62%),在由含水甲醇重结晶后mp=132-134℃。
制备实施例93
制备下式化合物:
a)制备3-溴2-甲酰基噻吩
参考Acta Chem Scand 22 (1968) 41354
将2,3-二溴噻吩(14份,0.058M,购自Lancaster Chemicals)称重后加入装备有橡胶隔膜的反应容器中,在氮气氛中通过注射器加入无水乙醚(112ml)并冷却至-70℃。用20分钟时间缓慢加入正丁基锂(26.8ml 2.5M的己烷溶液,购自Aldrich),在-70℃搅拌0.5小时后,用5分钟时间加入溶于乙醚中的二甲基甲酰胺(6.3份)。使反应物温热至20℃,一边搅拌一边加入100ml水。然后,乙醚溶液用 N盐酸、碳酸氢盐水溶液和水洗涤,用无水硫酸镁干燥,蒸出乙醚,留下橙色/棕色油状物(12.32份)。将此油状物在0.05mmHg和68℃下蒸馏得到淡黄色油状物(4.5份)。将此油溶于二氯甲烷,并蒸入二氧化硅,使此二氧化硅装柱,产品用快速色谱分离,二氧化硅柱用含有不断增加量的二氯甲烷的己烷洗涤展开,产物在含10-30%二氯甲烷的己烷的流分中洗脱出。
产率=4.05份。
元素分析
测定值 32.0% C, 1.8% H;16.7% S
理论值 31.4% C, 1.6% H;16.8% S
b)制备2-(3-溴-2-噻吩基)-1,3-二氧杂戊环
将3-溴-2-甲酰基噻吩(3.89份,0.02M)和无水乙二醇(1.6份)、甲苯(25份)和对甲苯磺酸(0.1份)在装备有迪安-斯达克分水器的容器中回流加热16小时,然后冷却反应物并蒸入二氧化硅,将此二氧化硅装柱,用含有不断增加量的二氯甲烷的己烷洗脱展开,在含10-60%二氯甲烷的己烷的流分中得到产物,为淡黄色油状物(4.42份)。
元素分析
测定值 35.6% C, 3.1% H;13.6% S
理论值 35.8% C, 3.0% H;13.7% S
c)制备2-甲酰基-3-噻吩硼酸
在氮气氛中和在-70℃下,于由(b)得到的二氧杂戊环(4.28份,0.018M)的无水乙醚溶液中一边搅拌一边缓慢加入丁基锂(7.9ml 2.5M的己烷溶液,购自Aldrich)。搅拌15分钟后,于-70℃缓慢加入溶于乙醚(20ml)的丁基硼酸酯(6ml,购自Aldrich),反应物于-70℃再搅拌4小时然后温热至20℃。加入25ml N盐酸,于20℃搅拌反应物1小时。然后分离出乙醚层并用N碳酸钠水溶液萃取(3×10ml),将此碳酸盐水溶液缓慢的酸化,经过滤和干燥分离出产物。产率=0.89份。
元素分析
测定值 36.6% C, 3.0% H;19.6% S
理论值 38.5% C, 3.2% H;20.5% S
d)制备标题化合物
把由(c)得到的硼酸化合物(0.5份,0.0032M)溶于乙醇,在20℃一边搅拌一边加入硼氢化钠(30mg,购自Aldrich)。30分钟后将反应物料蒸入二氧化硅,将此二氧化硅装柱,先用含有不断增加量的二氯甲烷的己烷,再用含有不断增加量的甲醇的二氯甲烷展开,在含3-4%甲醇的二氯甲烷的流分中得到产物。蒸出溶剂后,产物用甲苯重结晶,产率=0.13份,mp203-4℃。
元素分析
测定值 45.5% C, 3.2% H;23.3% S
理论值 45.8% C, 3.1% H;26.4% S
此化合物的微生物学试验数据是:
AN CA AP GR PP EC PA SA BS
N N N N N N N 100 25
符号的解释见表8的附注。
微生物学试验实施例23-58
R7表示苯环上的一个或多个取代基。
试验方法如下:
细菌接种物是生长在Oxoid营养肉汤中的微生物的24小时培养物,在37℃一昼夜传代培养。
按下面的方法制备每种试验真菌的孢子悬浮液。在250ml锥形瓶中装有真菌的良好的孢子形成培养物,该真菌生长于Oxoid麦芽提取物琼脂上,向其中加入一些无菌的3mm玻璃珠和大约50ml 0.01%(v/v)的聚乙二醇(20)脱水山梨糖醇单油酸酯(购自ICI,为Tween-80,Tween为注册商标)的水溶液,将每个烧瓶旋涡搅拌,使得玻璃珠迁移孢子,并将形成的悬浮液倾入无菌的100g平底药瓶中,其中含有大约50ml无菌的0.01%(v/v)tween 80溶液。在4℃下该悬浮液可储存达4周。
在微生物学试验中,氧杂硼杂环戊烯化合物以5,25和100ppm对表8的附注中所列出的细菌、酵母和真菌进行试验。
表8
实施例 | R7 | R3 | R4 | Y | 真菌 | 细菌 | |||||||
CA | CA | AP | GR | PP | EC | PA | SA | BS | |||||
23 | N | N | N | -(CH2)2- | 5 | 5 | 5 | 5 | 5 | 25 | 25 | 25 | 25 |
24 | N | N | N | -(CH2)3- | 5 | 5 | 5 | 5 | 5 | 25 | 25 | 25 | 25 |
25 | N | N | N | -(CH2)4- | 5 | 5 | 5 | 5 | 5 | 25 | 25 | 25 | 25 |
26 | 5-Cl | N | N | -(CH2)3- | 5 | 5 | 5 | 5 | 5 | 25 | 25 | 100 | 25 |
27 | 5-Cl | N | N | -(CH2)4- | 5 | 5 | 5 | 5 | 5 | 25 | 25 | N | 25 |
28 | 5-Cl | -CH3 | N | -(CH2)2- | 5 | 5 | 5 | 5 | 5 | 25 | 25 | N | 25 |
29 | 5-Cl | N | N | -CH2-CH(CH3)- | 5 | 5 | 5 | 5 | 5 | 25 | 25 | 100 | 25 |
30 | 5-Cl | N | N | -CH(CH3)-CH2- | 5 | 5 | 5 | 5 | 5 | 25 | 25 | N | 25 |
31 | 5-Cl | N | N | -CH2-C(CH3)2- | 5 | 5 | 5 | 5 | 5 | 25 | 25 | N | 25 |
32 | N | -CH3 | N | -(CH2)2- | 5 | 5 | 5 | 5 | 5 | 25 | 25 | 100 | 25 |
33 | N | N | N | -CH2C(CH3)2- | 5 | 5 | 5 | 5 | 5 | 25 | 25 | 100 | 25 |
34 | 5-F | N | N | -(CH2)3- | 5 | 5 | 5 | 5 | 5 | 25 | 25 | 100 | 25 |
35 | N | -CH3 | -CH3 | -(CH2)2- | 5 | 5 | 5 | 5 | 5 | 100 | 25 | N | 25 |
36 | 5-F | -CH3 | N | -(CH2)2- | 5 | 5 | 5 | 5 | 5 | 25 | 25 | 25 | 25 |
37 | 5-F | N | N | -(CH2)2- | 5 | 5 | 5 | 5 | 5 | 25 | 25 | 100 | 25 |
38 | 5-F | N | N | -CH2-C(CH3)2- | 5 | 5 | 5 | 5 | 5 | 25 | 25 | 100 | 25 |
39 | 5-F | N | N | -(CH2)4- | 5 | 5 | 5 | 5 | 5 | 100 | 100 | N | 25 |
40 | N | -C(CH3)3 | N | -(CH2)2- | 5 | 5 | 5 | 5 | 5 | 25 | 25 | 25 | 25 |
41 | N | -CH2CH3 | N | -(CH2)2- | 5 | 5 | 5 | 5 | 5 | 25 | 25 | 25 | 25 |
42 | N | -(CH2)2CH3 | N | -(CH2)2- | 5 | 5 | 5 | 5 | 5 | 25 | 25 | 25 | 25 |
表8(续)
表8的附注N=在100ppm水平时无活性对照=boronophthalideAN=黑曲霉(Aspergillus niger)AP=出芽短梗霉菌(Aureobasidium pullulans)CA=白色念珠菌(Candida albicans)GR=玫瑰色胶霉(Gliocladium roseum)PP=Pencillium pinophylumBS=枯草芽孢杆菌(Bacillus subtilis)EC=大肠杆菌(Escherichia coli)PA=绿脓杆菌(Pseudomonas aeruginosa)SA=金黄色葡萄球菌(Staphylococcus aureus)
实施例 | R7 | R3 | R4 | Y | 真菌 | 细菌 | |||||||
AH | CA | AP | GR | PP | EC | PA | SA | BS | |||||
43 | N | -(CH2)3CH3 | N | -(CH2)2- | 5 | 5 | 5 | 5 | 5 | 25 | 25 | 25 | 25 |
44 | N | -(CH2)4CH3 | N | -(CH2)2- | 5 | 25 | 5 | 5 | 5 | N | 100 | 25 | 100 |
45 | N | N | N | -CH-(CH3CH3)CH2- | 5 | 5 | 5 | 5 | 5 | 100 | N | 25 | 25 |
46 | 5-Cl | N | N | -CH2-CH(CH2CH3)- | 5 | 5 | 5 | 5 | 5 | 100 | N | 25 | N |
47 | 5-Cl | N | N | -CH2-CH(CH2CH3)- | 5 | 5 | 5 | 5 | 5 | 25 | N | 25 | N |
48 | N | N | N | -CH2CH(CH3)- | 5 | 5 | 5 | 5 | 5 | 25 | N | 25 | 100 |
49 | N | N | N | -CH2CH(CH2CH3)- | 5 | 5 | 5 | 5 | 5 | 25 | N | 25 | 25 |
50 | N | N | N | -CH(CH2CH3)CH2- | 5 | 5 | 5 | 5 | 5 | 100 | N | 25 | 100 |
51 | N | N | N | -CH2CH((CH2)3CH3)- | 5 | 5 | 5 | 5 | 5 | 100 | N | 25 | 100 |
52 | N | N | N | -CH2CH(CH2CH(CH3)2)- | 5 | 5 | 5 | 5 | 5 | 100 | N | 25 | 100 |
53 | N | N | N | -CH2CH((CH2)2CH3)3- | 5 | 5 | 5 | 5 | 5 | 25 | 100 | 25 | 25 |
54 | N | N | N | -CH2CH((CH2)2SCH3)- | 5 | 5 | 5 | 5 | 5 | 25 | 100 | 100 | 25 |
55 | 5-F | -CH2CH3 | N | -(CH2)2- | 5 | 5 | 5 | 5 | 5 | 25 | N | 100 | 25 |
56 | 5-F | N | N | -CH2CH(CH2CH3)- | 5 | 5 | 5 | 5 | 5 | 25 | N | 100 | 25 |
57 | 5-F | N | N | -CH(CH2CH3)CH2- | 5 | 5 | 5 | 5 | 5 | 25 | N | 100 | 25 |
58 | 5-F | -(CH2)2- | N | -(CH2)3 | 5 | 5 | 5 | 5 | 5 | 25 | N | 100 | 2S |
对照 | N | - | - | - | 25 | 25 | 5 | 5 | 5 | 100 | N | N | 25 |
微生物学试验实施例59-78重复实施例23-58,测定下式结构的苯并氧杂硼杂环戊烯的MIC值:
R8表示苯环上的一个或多个取代基。
结果列于下表9。
表2
表9的附注对照是1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯(R8=R9=H)
实施例 | R8 | R9 | 真菌 | 细菌 | |||||||
AH | CA | Al' | Gk | PP | EC | PA | SA | BS | |||
59 | 6-Cl | N | 100 | 100 | 100 | 5 | 5 | N | N | N | N |
60 | 5-phO | N | 5 | 5 | 5 | 5 | 5 | 25 | N | 25 | 25 |
61 | 5-C(CH1)3 | N | 100 | 100 | 100 | 100 | 100 | 100 | N | 100 | 100 |
62 | 4,5稠合的Ph | N | 25 | 25 | 25 | 25 | 25 | 100 | N | 25 | 25 |
63 | 5,6稠合的ph | N | 25 | 25 | 25 | 25 | 25 | 25 | N | 100 | 100 |
64 | 5-F | N | 5 | 5 | 5 | 5 | 5 | 100 | N | 100 | 25 |
65 | N | ph | N | N | 100 | 100 | 100 | N | N | N | 11 |
66 | 5-Cl | N | 5 | 5 | 5 | 5 | 5 | N | N | N | N |
67 | 5-CF3 | It | 25 | 25 | 25 | 25 | 25 | N | N | N | 25 |
68 | S-Br | N | 5 | 25 | 5 | 5 | 5 | 100 | 100 | 25 | 25 |
69 | 4-F | N | 100 | 100 | 25 | 25 | 100 | 100 | N | 100 | 25 |
70 | 6-F | N | 100 | 25 | 25 | 25 | 25 | 25 | N | 100 | 25 |
71 | N | -CH | N | N | N | N | N | N | N | N | N |
72 | 4-CH3,5-F | N | N | N | N | N | N | N | N | N | N |
73 | 5.6 dlF | N | 25 | 25 | 25 | 5 | 5 | 25 | N | N | 25 |
74 | 5-CH30 | N | 250 | 125 | 62.5 | 125 | 250 | 250 | 250 | 250 | 500 |
75 | 7-F | N | 16 | 16 | 16 | 31 | 16 | 125 | 250 | 125 | N |
76 | 4,7 dlF | N | |||||||||
77 | 6,7 dlF | N | |||||||||
78 | 5,7 dlF | N | |||||||||
对照 | N | N | 25 | 25 | 5 | 5 | 5 | 100 | N | N | 25 |
实施例79-80重复实施例23-58,测定下式结构的苯并氧杂硼杂环戊烯的MIC值:
结果列于下表10。
表10
实施例 | R10 | 真菌 | 细菌 | |||||||
AH | CA | AP | GR | PP | EC | PA | SA | BS | ||
79 | H | 25 | 25 | 25 | 25 | 25 | 100 | 100 | 25 | 25 |
80 | F | 5 | 5 | 5 | 5 | 5 | 25 | 25 | 25 | 25 |
实施例23-24,36-58,68和80的塑料破坏作用(deteriogen)
对塑料破坏(deteriogen)活性的测定
用列于实施例23-78的一些实施例样品重复进行实施例15-18,各种苯并氧杂硼杂环戊烯的活性列于下表11。表8和9中使用的实施例编号仍然保留。
表11
实施例 | AP | FS | PF | SB | SW |
23 | 1.25 | 1.25 | 1.25 | 1.25 | 2.5 |
24 | 1.25 | 1.25 | 2.5 | 2.5 | 5.0 |
25 | 1.25 | 2.5 | 2.5 | 2.5 | 20 |
25 | 1.25 | 1.25 | 1.25 | 1.25 | 2.5 |
27 | 1.25 | 1.25 | 1.25 | 1.25 | 2.5 |
28 | 1.25 | 1.25 | 1.25 | 1.25 | 1.25 |
29 | 1.25 | 1.25 | 1.25 | 1.25 | 1.25 |
30 | 1.25 | 1.25 | 1.25 | 1.25 | 1.25 |
31 | 1.25 | 1.25 | 1.25 | 1.25 | 1.25 |
32 | 1.25 | 1.25 | 1.25 | 1.25 | 1.25 |
33 | 1.25 | 1.25 | 1.25 | 1.25 | 1.25 |
34 | 1.25 | 1.25 | 1.25 | 1.25 | 1.25 |
36 | 1.25 | 1.25 | 1.25 | 1.25 | 5.0 |
37 | 1.25 | 1.25 | 1.25 | 1.25 | 5.0 |
38 | 1.25 | 1.25 | 1.25 | 2.25 | 5.0 |
39 | 1.25 | 1.25 | 1.25 | 1.25 | 2.25 |
4O | 2.5 | 1.25 | 1.25 | 1.25 | 1.25 |
表11(续)
表11的附注对照1是1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯对照2是2-正辛基异噻唑啉-3-酮。
实施例 | AP | FS | PF | SB | SW |
41 | 1.25 | 1.25 | 1.25 | 1.25 | 1.25 |
42 | 2.5 | 2.5 | 1.25 | 1.25 | 1.25 |
43 | 2.5 | 2.5 | 1.25 | 1.25 | 1.25 |
44 | 1.25 | 2.5 | 1.25 | 1.25 | 1.25 |
45 | 1.25 | 2.5 | 1.25 | 1.25 | 1.25 |
46 | 1.25 | 2.5 | 1.25 | 1.25 | 1.25 |
47 | 1.25 | 2.5 | 1.25 | 1.25 | 1.25 |
48 | 1.25 | 1.25 | 1.25 | 1.25 | 1.25 |
49 | 1.25 | 1.25 | 1.25 | 1.25 | 1.25 |
50 | 1.25 | 1.25 | 1.25 | 1.25 | 1.25 |
51 | 1.25 | 1.25 | 1.25 | 1.25 | 1.25 |
52 | 1.25 | 1.25 | 1.25 | 1.25 | 1.25 |
53 | 1.25 | 1.25 | 1.25 | 1.25 | 1.25 |
54 | 5.0 | 1.25 | 5.0 | 1.25 | 5.0 |
55 | 2.5 | 1.25 | 1.25 | 1.25 | 2.25 |
56 | 1.25 | 1.25 | 1.25 | 1.25 | 2.25 |
57 | 1.25 | 1.25 | 1.25 | 1.25 | 1.25 |
58 | 1.25 | 1.25 | 1.25 | 1.25 | 1.25 |
68 | 5.0 | 5.0 | 1.25 | 1.25 | 1.25 |
80 | 1.25 | 1.25 | 1.25 | 1.25 | 1.25 |
对照1 | 2.5 | 2.5 | 2.5 | 2.5 | 20.0 |
对照2 | 2.5 | 20 | 2.5 | 1.25 | 1.2 |
Claims (8)
1.保护对微生物作用敏感的介质的方法,该方法是用有效量的下式(1)的化合物或其盐处理该介质:其中
A和D和它们所连接的碳原子一起形成5、6或7元稠合环,该环本身可以被C1-6烷基、C1-6烷氧基、羟基、卤素、硝基、氰基、可被一个或两个C1-6烷基任选地取代的氨基、羧基、酰基、芳氧基、可被C1-6烷基任选地取代的碳酰氨基、磺酰氨基或三氟甲基任选地取代,或稠和环可与两个氧杂硼杂环戊烯环相连;
X是-CR1R2基团,其中R1和R2各自独立地为氢,C1-6烷基,氰基,硝基,芳基或芳烷基,或者R1和R2和它们所连接的碳原子一起形成脂族环;和
2.按照权利要求1的方法,其中A和D与它们所连接的碳原子一起形成稠合的苯基环。
3.按照权利要求1的方法,其中稠合环的取代基是卤素。
4.按照权利要求1的方法,其中R是氢。
5.按照权利要求1的方法,其中的R是喹啉基。
8.按照权利要求1-7中任意一项的方法,其中的介质是涂料膜和塑性材料。
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GB9411587A GB9411587D0 (en) | 1994-06-09 | 1994-06-09 | Compound, composition and use |
GB9411587.0 | 1994-06-09 |
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CN1068005C true CN1068005C (zh) | 2001-07-04 |
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US (1) | US5880188A (zh) |
EP (1) | EP0765331B1 (zh) |
JP (1) | JPH10500983A (zh) |
KR (1) | KR970703349A (zh) |
CN (1) | CN1068005C (zh) |
AT (1) | ATE195316T1 (zh) |
AU (1) | AU681291B2 (zh) |
BR (1) | BR9507966A (zh) |
CA (1) | CA2190155A1 (zh) |
DE (1) | DE69518323T2 (zh) |
GB (1) | GB9411587D0 (zh) |
NO (1) | NO965235L (zh) |
TW (1) | TW368397B (zh) |
WO (1) | WO1995033754A1 (zh) |
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- 1995-05-26 BR BR9507966A patent/BR9507966A/pt not_active Application Discontinuation
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- 1995-05-30 TW TW084105427A patent/TW368397B/zh active
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CN107404873A (zh) * | 2015-02-12 | 2017-11-28 | 阿格洛法士公司 | 杀真菌化合物和组合物 |
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KR970703349A (ko) | 1997-07-03 |
JPH10500983A (ja) | 1998-01-27 |
AU2534895A (en) | 1996-01-04 |
WO1995033754A1 (en) | 1995-12-14 |
TW368397B (en) | 1999-09-01 |
CN1155286A (zh) | 1997-07-23 |
DE69518323T2 (de) | 2001-02-01 |
NO965235D0 (no) | 1996-12-06 |
GB9411587D0 (en) | 1994-08-03 |
ATE195316T1 (de) | 2000-08-15 |
CA2190155A1 (en) | 1995-12-14 |
EP0765331B1 (en) | 2000-08-09 |
EP0765331A1 (en) | 1997-04-02 |
AU681291B2 (en) | 1997-08-21 |
BR9507966A (pt) | 1997-09-02 |
US5880188A (en) | 1999-03-09 |
DE69518323D1 (de) | 2000-09-14 |
NO965235L (no) | 1997-01-21 |
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