CN1278722A - 用作兽用抗微生物剂的8a－azalides - Google Patents
用作兽用抗微生物剂的8a－azalides Download PDFInfo
- Publication number
- CN1278722A CN1278722A CN98810963A CN98810963A CN1278722A CN 1278722 A CN1278722 A CN 1278722A CN 98810963 A CN98810963 A CN 98810963A CN 98810963 A CN98810963 A CN 98810963A CN 1278722 A CN1278722 A CN 1278722A
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- Prior art keywords
- alkyl
- amino
- carbonyl
- aryl
- hydrogen
- Prior art date
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- -1 heterocyclic radical Chemical class 0.000 claims description 51
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 47
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- 238000000034 method Methods 0.000 claims description 29
- 125000003118 aryl group Chemical group 0.000 claims description 27
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Abstract
8a－azalides可用于治疗或预防牲畜、尤其是牛和猪的呼吸系统和肠细菌感染。
Description
发明简述
本发明提供了治疗或预防牲畜呼吸系统或肠细菌感染的方法。
本发明的背景技术
由牲畜呼吸系统或肠细菌感染导致的发病或死亡给动物饲养企业带来了严重的经济损失。在牛当中，尤其是年轻的牛当中，由断奶、运输、脱水、变更或剥夺食物导致的压力可使牛非常易患呼吸系统细菌感染，尤其当牛是群体饲养或饲养环境通风性不好时更是如此。导致牛呼吸系统细菌感染的主要细菌病原体是溶血巴斯德氏菌(Pasteurella haemolytica)、多杀巴斯德氏菌(Pasteurellamultocida)、睡眠嗜血菌(Haemophilus somnus)和枝原体属亚种(Mycoplasma spp．)。猪呼吸系统细菌感染是由多杀巴斯德氏菌或大叶性肺炎放线杆菌(Actinobacillus pleuropneumoniae)引起的，在一些牲畜群中，枝原体属亚种会带来严重损失。引起牛和猪肠病的最常见生物体是大肠杆菌(Escherichia coli)、猪痢疾小蛇菌(Treponema hyodysenteriae)和沙门氏菌属亚种(Salmonellaspp．)。
治疗牲畜呼吸系统或肠细菌感染的常用抗微生物产品包括，各种能有效地抗广谱细菌感染的老产品，其中最有名的是四环素；和一些最近使用的主要用于治疗牛呼吸系统疾病的产品，例如喹诺酮类抗菌剂(达氟沙星、恩氟杀星)、头孢菌素(头孢喹诺、头孢噻呋)、大环内酯类抗菌剂(替米考星)、和氟苯尼考。在本领域中，老的抗微生物剂已经产生了抗药性问题。虽然对于较新的产品抗药性不是问题，可是我们知道，长时间过多使用细菌容易对其产生抗药性，但是在应用中增加药物种类和作用机制可降低细菌对任意个别药物产生抗药性的可能性。因此，本领域仍不断需要开发出适用于兽医应用的抗微生物化合物；这类化合物优选与目前正在动物和人医药中使用的抗微生物剂属于不同化学类型。新的兽药用抗微生物产品的其它所需特征包括，抗靶微生物体的高度有效性、高组织浓度、和长的组织和血浆半衰期。
8a-Azalides的抗菌特征是，包含环氮原子的15元内酯环。欧洲专利申请508699中公开了一组8a-azalides，其抗菌谱类似于红霉素，并且在体外有抗包括大肠杆菌和流感嗜血杆菌(H．influenzae)在内的革兰氏阳性和革兰氏阴性细菌的活性。然而，EP 508699没有公开8a-Azalides在治疗和预防牲畜呼吸系统和肠细菌感染中的应用。此外，其没有提出8a-azalides具有抗引起牛和猪呼吸系统和肠细菌感染的常见微生物体的抗菌活性。
发明详述
本发明提供了治疗或预防牲畜呼吸系统或肠细菌感染的方法，包括将治疗或预防有效量的8a-azalide对需要所述治疗或预防的牲畜给药。
在优选的实施方案中，8a-azalide是式I化合物、或其可药用盐、或其可药用金属配合物，并且所述金属配合物中的金属选自铜、锌、钴、镍和镉：
其中R1是氢；
羟基；
C1-4烷氧基；
甲酰基；
C1-10烷基羰基、C1-10烷氧基羰基、芳氧基羰基、C1-10芳烷氧基羰基、C1-10烷基磺酰基或芳基磺酰基，其中所述C1-10烷基被1-3个卤素(F、Cl、Br)、羟基、氨基、C1-5酰氨基或C1-4烷基取代；或
未取代或取代的C1-10烷基、C2-10链烯基或C2-10炔基，其中所述烷基链如果长度超过2个碳原子，则可以具有1-2个插入其中的氧、硫或式-NR-所示的氮，其中R是氢或C1-3烷基，并且其中所述取代基独立地为1-3个
(a)芳基或杂芳基，其中所述芳基或杂芳基任选地被1-3个卤素(F、Cl、Br、I)、C1-4烷基、C1-3烷氧基、氨基、C1-4烷基氨基、二(C1-4烷基)氨基或羟基取代，
(b)未取代或被羟基、氨基、C1-4烷基氨基、二(C1-4烷基)氨基、C1-4烷基羰基氧基或C1-4烷基羰基氨基取代的杂环基，
(c)卤素(F、Cl、Br、I)，
(d)未酰化羟基，或被RaC(=0)或RbS(O)2酰化的羟基，其中Ra是氢、C1-6烷基、芳基、杂芳基、芳烷基或杂芳烷基，且Rb是C1-6烷基或芳基，
(e)C1-10烷氧基，
(f)未取代或被1-3个卤素、羟基、氨基或C1-4烷基取代的芳氧基或杂芳氧基，
(g)未酰化或被RaC(=O)、RaOC(=0)或RbSO2酰化的氨基或C1-10烷基氨基，其中Ra和Rb的定义同上，
(h)二(C1-10烷基)氨基，
(i)芳基氨基、杂芳基氨基、芳烷基氨基或杂芳烷基氨基，其中所述芳基或杂芳基未被取代或被1-3个卤素、羟基、氨基或C1-C4烷基取代，
(j)巯基，
(k)C1-10烷硫基、烷基亚磺酰基或烷基磺酰基、芳硫基、芳基亚磺酰基或芳基磺酰基，其中所述芳基未被取代或被1-3个卤素、羟基、氨基或C1-4烷基取代，
(l)甲酰基；
(m)C1-10烷基羰基；
(n)芳基羰基、杂芳基羰基、芳烷基羰基或杂芳烷基羰基，其中所述芳基或杂芳基未被取代或被1-3个卤素、羟基、氨基或C1-4烷基取代，
(o)羧基，
(p)C1-10烷氧基羰基，
(q)芳氧基羰基、杂芳氧基羰基、芳烷氧基羰基或杂芳烷氧基羰基，其中所述芳基或杂芳基未被取代或被1-3个卤素、羟基、氨基或C1-4烷基取代，
(r)氨基甲酰基或氨磺酰基，其中氮原子未被取代或被1-2个C1 -6烷基或C4-6亚烷基链取代，
(s)氰基，
(t)异腈基，
(u)硝基，
(v)叠氮基，
(w)未取代或在氮或碳上被C1-10烷基取代的亚氨基甲基，
(x)氧代基或
(y)硫代基；R2和R3独立地为氢、C1-10烷基、芳基；或者R2和R3一起为氧代基或硫代基；R4和R5独立地为氢或烷基羰基；或者R4和R5一起为羰基；或者R4和R1一起为未被取代或被氧代基取代的C1-C3亚烷基；R6和R7都是氢，或者R6和R7中一个是氢，另一个是羟基，选自甲酰氧基、C1-10烷基羰基氧基、芳基羰基氧基和芳烷基羰基氧基的酰氧基衍生物，或-NHR12，其中R12是氢，未被取代或被1-3个卤素或C1-3烷基取代的芳基磺酰基或杂芳基磺酰基，烷基磺酰基或-C(=O)-X-A-R13，其中X是连接键、O或NH，A是连接键或C1-C3亚烷基，R13是氢、C1-C10烷基、芳基、芳烷基、杂芳基、杂环基或C3-C7环烷基，任一不是氢的R13可被一个或多个下述基团取代：卤素、羟基、C1-C3烷氧基、氰基、异腈基、硝基、氨基、一(C1-C3烷基)氨基、二(C1-C3烷基)氨基、巯基、C1-C3烷硫基、C1-C3烷基亚磺酰基、C1-C3烷基磺酰基、芳硫基、芳基亚磺酰基、氨磺酰基、芳基磺酰基、羧基、氨基甲酰基、C1-C3烷基羰基、或C1-C3烷氧基羰基；或者R6和R7一起为氧代基、羟基亚氨基、烷氧基亚氨基、芳烷氧基亚氨基或氨基亚氨基；R8是甲基、芳烷氧基羰基或芳基磺酰基；R9是氢、甲酰基、C1-10烷基羰基、C1-10烷氧基羰基或芳基烷氧基羰基；R10是氢；或者R10与R1一起为未被取代或被氧代基取代的C1-C3亚烷基；m和n独立地为0或1。
8a-azalide更优选具有下述定义的式I，其中n和m是0；R1是氢、C1-10烷基、C2-10链烯基、C2-10炔基或芳基磺酰基，其中所述烷基和链烯基任选地被卤素、羟基、氰基、C1-10烷氧基羰基、氨基、C1-10烷基氨基、二(C1-10烷基)氨基、芳基或芳烷氧基羰基取代；R2、R3、R4、R5、R9和R10分别为氢；R6和R7中的一个是氢，另一个选自羟基、C1-10烷基羰基氧基、芳烷基羰基氧基、氨基，被下述基团取代的氨基：C1-10烷基羰基、芳基羰基、芳基C1-10烷基羰基、C1-10烷氧基羰基、芳基C1-10烷氧基羰基、杂芳基羰基、杂芳基烷基羰基或芳基磺酰基；R8是甲基。
8a-azalide还更优选具有下述定义的式I，其中n和m是0；R1是甲基、乙基、丙基、烯丙基、炔丙基、2-氰基乙基、2-羟基乙基、3-羟基丙基、2-甲氧基羰基乙基、2-苄氧基羰基乙基、氰基甲基、2-氨基乙基、2-(二甲基氨基)乙基、2-氟乙基、2-氟烯丙基、苄基或环氧乙烷基甲基；R2、R3、R4、R5、R9和R10分别为氢；R6和R7中的一个是氢，另一个是羟基或氨基；R8是甲基。R1最优选为甲基、乙基、丙基、烯丙基、2-甲氧基羰基乙基或2-(二甲基氨基)乙基。
在另一优选的实施方案中，本发明提供了治疗或预防其中致病微生物体选自巴斯德氏菌属亚种(Pasteurella spp．)、放线杆菌属亚种(Actinobacillus spp．)、睡眠嗜血菌(Haemoplhilus somnus)和枝原体属亚种(Mycoplasma spp．)的牛或猪呼吸系统细菌感染的方法，包括将预防或治疗有效量的8a-azalide对需要所述治疗和预防的牛或猪给药。8a-azalide更优选为式I化合物；特别优选为具有下述定义的式I的8a-azalides：其中R1是甲基、乙基、丙基、烯丙基、炔丙基、2-氰基乙基、2-羟基乙基、3-羟基丙基、2-甲氧基羰基乙基、2-苄氧基羰基乙基、氰基甲基、2-氨基乙基、2-(二甲基氨基)乙基、2-氟乙基、2-氟烯丙基、苄基或环氧乙烷基甲基；R2、R3、R4、R5、R9和R10分别为氢；R6和R7中的一个是氢，另一个是羟基或氨基；R8是甲基。R1最优选为甲基、乙基、丙基、烯丙基、2-甲氧基羰基乙基或2-(二甲基氨基)乙基。
在另一优选的实施方案中，本发明提供了治疗或预防其中致微生物体选自大肠杆菌、猪痢疾小蛇菌和沙门氏菌属亚种的牛或猪肠细菌感染的方法，包括将预防或治疗有效量的8a-azalide对需要所述治疗和预防的牛或猪给药。8a-azalide更优选为式I化合物；特别优选为具有下述定义的式I的8a-azalides：其中R1是甲基、乙基、丙基、烯丙基、炔丙基、2-氰基乙基、2-羟基乙基、3-羟基丙基、2-甲氧基羰基乙基、2-苄氧基羰基乙基、氰基甲基、2-氨基乙基、2-(二甲基氨基)乙基、2-氟乙基、2-氟烯丙基、苄基或环氧乙烷基甲基；R2、R3、R4、R5、R9和R10分别为氢；R6和R7中的一个是氢，另一个是羟基或氨基；R8是甲基。R1最优选为甲基、乙基、丙基、烯丙基、2-甲氧基羰基乙基或2-(二甲基氨基)乙基。
本说明书所用“8a-azalide”表示具有下述母核结构的化合物，其中星号是表示取代位点：
8a-azalides在下文中称为红霉素A衍生物，即9-去氧-8a-氮杂-8a-高红霉素A的衍生物。
术语“治疗或预防有效量”是指，该量的8a-azalide能在感染靶位点提供足以以下述方式抑制细菌的一定水平的抗菌活性：能使宿主动物克服或免受感染。
“治疗或预防”是指在表现出提示有细菌感染的征候或症状之后或之前使用8a-azalide来使宿主动物克服或免受感染。
“呼吸道或肠细菌感染”是指，致病微生物体或可能的致病微生物体对8α-azalide敏感的呼吸系统或消化道感染。这些微生物体包括但不限于巴斯德氏菌属细菌(Pasteurella species)(例如溶血巴斯德氏菌、多杀巴斯德氏菌)、睡眠嗜血菌、大叶性肺炎放线杆菌、枝原体属亚种、大肠杆菌、猪痢疾小蛇菌和沙门氏菌属亚种(例如鼠伤寒沙门氏菌(Salmonella typhimurium)、都柏林沙门氏菌(S．dublin))。
用于定义式I上各基团的术语(例如烷基、芳基、杂环基、取代的等)与在EP 508699中提供的这些术语含义相同。
术语“可药用盐”是表示，用包括无机酸和有机酸在内的可药用无毒酸制得的盐。这种酸包括乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、苦杏仁酸、甲磺酸、粘酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、对甲苯磺酸等。特别优选柠檬酸、氢溴酸、盐酸、马来酸、磷酸、硫酸和酒石酸。
8α-azalides是已知化合物，例如在欧洲专利申请508699中公开的化合物，或者可用已知方法由易得原料制得。
代表性8a-azalides如下：9-去氧-8a-氮杂-8a-高红霉素A；9-去氧-8a-氮杂-8a-甲基-8a-高红霉素A；9-去氧-8a-氮杂-8a-乙基-8a-高红霉素A；8a-(3-苯基丙基)-8a-氮杂-9-去氧-8a-高红霉素A；9-去氧-8a-氮杂-8a-烯丙基-8a-高红霉素A；9-去氧-8a-氮杂-8a-(丙-1-基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-(丙-1-氧基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-(2-氧代乙-1-基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-(2-羟基乙-1-基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-((2，3-环氧)丙-1-基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-((1-氮杂环丁基)-2-乙-1-基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-((1-吡咯烷基)-2-乙-1-基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-((N-哌啶基)-2-乙-1-基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-((4-吗啉基)-2-乙-1-基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-((2-氟乙-1-基)-2-氨基乙-1-基)-8a-高红霉素A；8a-(2-氯烯丙基)-8a-氮杂-9-去氧-8a-高红霉素A；8a-(2-氟烯丙基)-8a-氮杂-9-去氧-8a-高红霉素A；9-去氧-8a-氮杂-8a-((2-氰基)乙-1-基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-((3-氨基)丙-1-基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-(((N，N-二甲基)-3-氨基)丙-1-基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-((2-氰基乙基)-3-氨基丙-1-基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-((3，4-二羟基苄基)-3-氨基丙-1-基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-(3-乙酰氧基丙-1-基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-(3-羟基丙-1-基)-8a-高红霉素A；(3-甲氧基-3-氧代丙基)-8a-高红霉素A；8a-(3-辛氧基-3-氧代丙基)-9-去氧-8a-氮杂-8a-高红霉素A；8a-(3-(2-甲氧基乙氧基)-3-氧代丙基)-9-去氧-8a-氮杂-8a-高红霉素A；8a-(3-异丙氧基-3-氧代丙基)-9-去氧-8a-氮杂-8a-高红霉素A；8a-(3-苄氧基-3-氧代丙基)-9-去氧-8a-氮杂-8a-高红霉素A；8a-(2-羧基乙基)-9-去氧-8a-氮杂-8a-高红霉素A；9-去氧-8a-氮杂-8a-氰基甲基-8a-高红霉素A；9-去氧-8a-氮杂-8a-(2-氨基乙基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-(2-二甲基氨基乙基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-(N-L-亮氨酰基-2-氨基乙基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-羧基甲基-8a-高红霉素A；9-去氧-8a-氮杂-8a-甲氧基羰基甲基-8a-高红霉素A；9-去氧-8a-氮杂-3’-N-去甲基-8a-高红霉素A；9-去氧-8a-氮杂-3’-N-去甲基-3’-N-苯基磺酰基-8a-高红霉素A；9-去氧-8a-氮杂-8a-(2-氟乙-1-基)-3’-N-去甲基-3’-N-苯基磺酰基-8a-高红霉素A；9-去氧-8a-氮杂-8a-(2-氟乙-1-基)-3’-N-去甲基-8a-高红霉素A；9-去氧-8a-氮杂-8a-(2-氟乙-1-基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-(3-氟丙-1-基)-3’-N-去甲基-3’-N-苯基磺酰基-8a-高红霉素A；9-去氧-8a-氮杂-8a-(3-氟丙-1-基)-3’-N-去甲基-8a-高红霉素A；9-去氧-8a-氮杂-8a-(3-氟丙-1-基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-((4，4，4-三氟)丁-1-基)-3’-N-去甲基-3’-N-苯基磺酰基-8a-高红霉素A；9-去氧-8a-氮杂-8a-((4，4，4-三氟)丁-1-基)-3’-N-去甲基-8a-高红霉素A；9-去氧-8a-氮杂-8a-((4，4，4-三氟)丁-1-基)-8a-高红霉素A；9--去-氧-8a-氮杂-8a-(苄基)-3’-N-去甲基-3’-N-苯基磺酰基-8a-高红霉素A；9-去氧-8a-氮杂-8a-(苄基)-3’-N-去甲基-8a-高红霉素A；9-去氧-8a-氮杂-8a-(苄基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-(4-甲氧基苄基)-3’-N-去甲基-3’-N-苯基磺酰基-8a-高红霉素A；9-去氧-8a-氮杂-8a-(4-甲氧基苄基)-3’-N-去甲基-8a-高红霉素A；9-去氧-8a-氮杂-8a-(4-甲氧基苄基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-(2-(2-乙氧基乙氧基)乙-1-基)-3’-N-去甲基-3’-N-苯基磺酰基-8a-高红霉素A；9-去氧-8a-氮杂-8a-(2-(2-乙氧基乙氧基)乙-1-基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-(2，2-二氟乙-1-基)-3’-N-去甲基-3’-N-苯基磺酰基-8a-高红霉素A；9-去氧-8a-氮杂-8a-(2，2-二氟乙-1-基)-3’-N-去甲基-8a-高红霉素A；9-去氧-8a-氮杂-8a-(2，2-二氟乙-1-基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-羟基-8a-高红霉素A和9-去氧-8a-氮杂-8a-(丙-1-基)-8a-(丙-1-基)-8a-高红霉素A；9-去氧-8a-氮杂-8a-乙酰基-8a-高红霉素A；9-去氧-8a-氮杂-8a-甘氨酰基-8a-高红霉素A；9-去氧-8a-氮杂-8a-(Leu-Gly)-8a-高红霉素A；9-去氧-8a-氮杂-8a-苯基磺酰基-8a-高红霉素A；2’-0-乙酰基-9-去氧-8a-甲基-8a-氮杂-8a-高红霉素A；(11-0，12-0-氧亚甲基)-9-去氧-8a-甲基-8a-氮杂-8a-高红霉素A；4”-0-苯基乙酰基-8a-氮杂-8a-甲基-9-去氧-8a-高红霉素A；4”-0-(4-甲氧基苯基)乙酰基-8a-氮杂-8a-甲基-9-去氧-8a-高红霉素A；2’-0-乙酰基-9-去氧-8a-氮杂-8a-甲基-8a-高红霉素A；4”-表-9-去氧-8a-氮杂-8a-甲基-8a-高红霉素A；4”-去氧-4”-氨基-9-去氧-8a-氮杂-8a-甲基-8a-高红霉素A；4”-去氧-4”-(S)-氨基-9-去氧-8a-氮杂-8a-甲基-8a-高红霉素A；4”-去氧-4”-(R)-氨基-9-去氧-8a-氮杂-8a-甲基-8a-高红霉素A；4”-去氧-4”-(S)-乙酰基氨基-9-去氧-8a-氮杂-8a-甲基-8a-高红霉素A；4”-去氧-4”-(R)-乙酰基氨基-9-去氧-8a-氮杂-8a-甲基-8a-高红霉素A；4”-(4-甲氧基苯基乙酰基)氨基-4”-去氧-8a-氮杂-8a-甲基-8a-高红霉素A；4”-去氧-4”-(L-丙氨酰基)氨基-9-去氧-8a-氮杂-8a-甲基-8a-甲基-8a-高红霉素A；4”-去氧-4”-(L-缬氨酰基)氨基-9-去氧-8a-氮杂-8a-甲基-8a-高红霉素A；4”-去氧-4”-(L-亮氨酰基)氨基-9-去氧-8a-氮杂-8a-甲基-8a-高红霉素A；4”-去氧-4”-(L-苯丙氨酰基)氨基-9-去氧-8a-氮杂-8a-甲基-8a-高红霉素A；4”-去氧-4”-(O-叔丁基-L-酪氨酰基)氨基-9-去氧-8a-氮杂-8a-甲基-8a-高红霉素A；4”-去氧-4”-(L-丙基)氨基-9-去氧-8a-氮杂-8a-甲基-8a-高红霉素A；4”-去氧-4”-(L-天冬氨酰基-b-苄基酯)氨基-9-去氧-8a-氮杂-8a-甲基-8a-高红霉素A；4”-去氧-4'”-(L-天冬氨酰基)氨基-9-去氧-8a-氮杂-8a-甲基-8a-高红霉素A；4”-去氧-4”-(L-焦谷氨酰基)氨基-9-去氧-8a-氮杂-8a-甲基-8a-高红霉素A；4”-去氧-4”-(L-谷氨酰基)氨基-9-去氧-8a-氮杂-8a-甲基-8a-高红霉素A；2”-0-乙酰基-9-去氧-8a-氮杂-8a-烯丙基-8a-高红霉素A；4”-去氧-4-氨基-9-去氧-8a-氮杂-8a-烯丙基-8a-高红霉素A；4”-去氧-4”-氨基-9-去氧-8a-氮杂-8a-丙基-8a-高红霉素A；2”-0-乙酰基-9-去氧-8a-氮杂-8a-甲氧基羰基乙基-8a-高红霉素A；4”-去氧-4”-氨基-9-去氧-8a-氮杂-8a-(3-甲氧基-3-氧代丙基)-8a-高红霉素A；2’-0-乙酰基-8a-氮杂-8a-高红霉素；和4”-去氧-4”-氨基-8a-氮杂-8a-高红霉素A。
可将8a-azalides以类似于其它抗菌剂的方式给药到宿主中来治疗或预防呼吸系统或肠细菌感染；例如可将8a-azalides非胃肠道给药、口服给药、局部给药或直肠给药。给药剂量将根据所用具体化合物、致病感染性微生物体、具体宿主、疾病严重程度、宿主身体状况、以及所选给药途径的不同而不同；本领域技术人员可容易地确定出适当剂量。为了治疗细菌性疾病，口服剂量可以为1mg／kg-1000mg／kg；非胃肠道给药剂量可以为0．01mg／kg-500mg／kg。对于在动物中的预防应用，口服剂量可以为1mg／kg-1000mg／kg；非胃肠道给药剂量可以为0．01mg／kg-500mg／kg。优选以约0．1mg／kg-约10mg／kg的剂量将本发明8a-azalides非胃肠道给药。
8a-azalides优选在包含该活性组分和惰性可药用载体的药物组合物中使用。本发明药物组合物包含8a-azalide作为活性组分，还可以含有可药用载体，以及任选地含有其它治疗组分。制剂包括适于口服给药、直肠给药、局部给药和非胃肠道给药(包括皮下给药、肌内给药和静脉内给药)的组合物，但是在任一情况下最合适的给药途径将取决于具体宿主、将活性组分给药来进行治疗的病症的性质和严重程度。可以将药物组合物制成使用方便的单位剂型，并且可通过制药领域的任一众所周知的方法制得。
在具体应用中，可依据常规药物混合技术将8a-azalide作为活性组分与药物载体充分混合。根据给药例如口服给药或非胃肠道给药(包括静脉内给药、肌内给药和皮下给药)所需的剂型，载体可呈多种形式；通常优选非胃肠道给药。
为了制备口服剂型组合物，可使用任一常规药物载体。例如，对于口服液体制剂如悬浮剂、酏剂和溶液剂，可使用水、二醇、油、醇、调味剂、防腐剂、着色剂等；对于口服固体制剂如粉剂、胶囊和片剂，可使用载体例如淀粉、糖、微晶纤维素、稀释剂、造粒剂、润滑剂、粘合剂、崩解剂等。因为片剂和胶囊便于给药，所以它们代表着显然使用固体药物载体的最佳口服单位剂型。如果需要的话，可通过利用水或非水的标准技术将片剂包衣。除了上述常规剂型以外，还可以通过缓释手段和／或释放装置将8a-azalide给药。
适于口服给药的本发明药物组合物可以呈不连续单位，例如分别含有预定量活性组分的胶囊、扁囊剂或片剂，粉剂或粒剂，在水或非水液体中的溶液或悬浮液，水包油乳剂或油包水乳剂。这些组合物可通过任一制药方法制得，但是所有方法都包括将活性组分与构成一种或多种必需组分的载体混合的步骤。组合物一般是这样制得的：将活性组分与液体载体或精细分散的固体载体或二者均匀且充分混合，然后如果需要的话，将该混合产物定形成所需剂型。例如，片剂可通过任选地与一种或多种辅助组分压制或模制而制得。压制片可通过将任选地与粘合剂、润滑剂、惰性稀释剂、表面活性剂或分散剂混合的呈自由流动形式如粉末或颗粒的活性组分在适当机器中压片制得。通过将用惰性液体稀释剂湿润的粉末状化合物的混合物在适当机器中模制可制得模制片。每一片剂中含有约1mg-约500mg活性组分、每一扁囊剂或胶囊中含有约1mg-约500mg活性组分是可取的。
可将适于非胃肠道给药的本发明药物组合物制成在水中适当地与表面活性剂例如羟丙基纤维素混合的活性化合物的溶液或悬浮液。还可以在甘油、液体聚乙二醇、和它们在油中的混合物中制备分散体。在常规储存和使用条件下，这些制剂含有防腐剂来防止滋生微生物体。
适用于注射的药物剂型包括无菌水溶液或分散液以及用于临时配制成无菌注射溶液或分散液的无菌粉末。在所有情况下，所述剂型必须是无菌的，并且其流动性必须达到易于注射的程度。其在生产和储存条件下必须是稳定的，并且在保存时必须能抗微生物体如细菌和真菌的污染作用。载体可以是含有例如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇)、它们的适当混合物、和植物油的溶剂或分散介质。
合适的局部给药制剂包括透皮给药装置、气雾剂、霜剂、软膏剂、洗剂、扑粉剂等。
可通过常规方法制得含有活性组分的这些制剂。例如，通过将足量的亲水性材料和含有约5-10％重量的化合物、其量足以制成具有所需稠度的霜剂或软膏剂的水混合可制得霜剂或软膏剂。
其中载体是固体的适于直肠给药的药物组合物最优选呈单位剂量栓剂。合适的载体包括可可脂和其它本领域常用材料，通过将活性组分与软或熔化的载体混合，然后急冷并模制可方便地形成栓剂。
应当理解，除了上述载体组分以外，上述药物制剂适当时可含有一种或多种其它载体组分，例如稀释剂、缓冲剂、调味剂、粘合剂、表面活性剂、增稠剂、润滑剂、防腐剂(包括抗氧化剂)等、以及用于使制剂与受药者的血液等渗的物质。
还可以将含有8a-azalide的组合物制成粉末或液体浓缩形式。依据标准兽药制剂配制方法，可将常规水溶性赋形剂例如乳糖或蔗糖加到粉剂中以改善其物理性质。因此，本发明特别适当的粉剂包含50-100％重量、优选60-80％重量的结合物，和0-50％重量、优选20-40％重量的常规兽药用赋形剂。这些粉剂既可以加到动物饲料中，例如通过在中间预混合来加入，也可以稀释在动物饮用水中。
本发明液体浓缩物适当地含有水溶性化合物结合物，并可任选地含有可兽药用水可混性溶剂，例如聚乙二醇、丙二醇、甘油、甲醛缩甘油、或混合有高达30％体积的乙醇的这类溶剂。可将液体浓缩物加到动物饮用水中。
含有8a-azalide的药物组合物可任选地含有其它活性组分、生物组分如抗原、或食品强化剂例如矿物质或维生素。活性组分可包括免疫调节剂例如干扰素、白介素和其它化学促活剂，非甾体抗炎剂例如丙酸衍生物(例如布洛芬、酮基布洛芬、萘普生、苯噁洛芬、卡洛芬)、乙酸衍生物(例如醋炎痛、阿氯芬酸、环氯茚酸、双氯芬酸钠、二氯苯氧苯乙酸、氯苯噻唑乙酸、双苯噻酸、乙氧茚乙酸、异丁苯乙酸、氧卓乙酸、oxpinac、舒林酸、噻庚乙酸、托耳米丁、叠氮吲酸、和苯酰吡酸钠)、灭酸衍生物(例如氟灭酸、甲氯灭酸、甲灭酸、尼氟灭酸、和邻甲氯灭酸)、联苯羧酸(例如二氟苯乙酰水杨酸和氟苯乙酰水杨酸)、和环氧合酶-2(COX-2)抑制剂，和抗寄生物剂例如阿凡曼菌素、伊维菌素、米尔倍霉素、左旋咪唑、苯并咪唑类、噻嘧啶／甲噻嘧啶。生物制品可以是在牲畜业中通常用来抗牛细菌性鼻气管炎、牛病毒性腹泻、呼吸道合胞体病毒、副流感、传染性肠胃炎、猪生殖和呼吸症状、轮状病毒和冠状病毒的疫苗。食品强化剂可以是维生素、铁、硒等。
下述实施例是为了更详细地阐述本发明，而不应理解为以任何方式对本发明所要求保护的范围的限制。8a-azalides的体外活性
通过本领域众所周知的最小抑制浓度(MIC)法来测定代表性8a-azalides抗一组兽医领域病原体的抗菌活性。测定是这样进行的：制备一系列培养管，每一培养管中含有具有不同浓度抗菌剂的培养基，用相同微生物体给所有培养管接种。记录完全阻止了浑浊出现的抗菌剂的最小浓度，该浓度称为MIC。
4”-去氧-4”-氨基-9-去氧-8a-氮杂-8a-甲基-8a-高红霉素A、4”-去氧-4”(R)-氨基-9-去氧-8a-氮杂-8a-甲基-8a-高红霉素A、4”-去氧-4”(S)-氨基-9-去氧-8a-氮杂-8a-甲基-8a-高红霉素A和4”-去氧-4”-氨基-9-去氧-8a-氮杂-8a-烯丙基-8a-高红霉素A抗兽医领域要害微生物体的抗菌活性总结如下：微生物体 MIC(μg／ml)溶血巴斯德氏菌 0．125-0．5多杀巴斯德氏菌 0．125-0．5睡眠嗜血菌 0．125-0．250大叶性肺炎放线杆菌 0．062-0．125大肠杆菌 0．5-2沙门氏菌属亚种 0．5-4
Claims (19)
1．治疗或预防牲畜呼吸系统或肠细菌感染的方法，包括将治疗或预防有效量的8a-azalide对需要所述治疗或预防的牲畜给药。
2．权利要求1的方法，其中所述8a-azalide是式I化合物、或其可药用盐、或其可药用金属配合物，并且所述金属配合物中的金属选自铜、锌、钴、镍和镉：
其中R1是氢；
羟基；
C1-4烷氧基；
甲酰基；
C1-10烷基羰基、C1-10烷氧基羰基、芳氧基羰基、C1-10芳烷氧基羰基、C1-10烷基磺酰基或芳基磺酰基，其中所述C1-10烷基被1-3个卤素(F、Cl、Br)、羟基、氨基、C1-5酰氨基或C1-4烷基取代；或
未取代或取代的C1-10烷基、C2-10链烯基或C2-10炔基，其中所述烷基链如果长度超过2个碳原子，则可以具有1-2个插入其中的氧、硫或式-NR-所示的氮，其中R是氢或C1-3烷基，并且其中所述取代基独立地为1-3个
(a)芳基或杂芳基，其中所述芳基或杂芳基任选地被1-3个卤素(F、Cl、Br、I)、C1-4烷基、C1-3烷氧基、氨基、C1-4烷基氨基、二(C1-4烷基)氨基或羟基取代，
(b)未取代或被羟基、氨基、C1-4烷基氨基、二(C1-4烷基)氨基、C1-4烷基羰基氧基或C1-4烷基羰基氨基取代的杂环基，
(c)卤素(F、Cl、Br或I)，
(d)未酰化羟基，或被RaC(=0)或RbS(O)2酰化的羟基，其中Ra是氢、C1-6烷基、芳基、杂芳基、芳烷基或杂芳烷基，且Rb是C1-6烷基或芳基，
(e)C1-10烷氧基，
(f)未取代或被1-3个卤素、羟基、氨基或C1-4烷基取代的芳氧基或杂芳氧基，
(g)未酰化或被RaC(=0)、RaOC(=O)或RbSO2酰化的氨基或C1-10烷基氨基，其中Ra和Rb的定义同上，
(h)二(C1-10烷基)氨基，
(i)芳基氨基、杂芳基氨基、芳烷基氨基或杂芳烷基氨基，其中所述芳基或杂芳基未被取代或被1-3个卤素、羟基、氨基或C1-C4烷基取代，
(j)巯基，
(k)C1-10烷硫基、烷基亚磺酰基或烷基磺酰基、芳硫基、芳基亚磺酰基或芳基磺酰基，其中所述芳基未被取代或被1-3个卤素、羟基、氨基或C1-4烷基取代，
(l)甲酰基；
(m)C1-10烷基羰基；
(n)芳基羰基、杂芳基羰基、芳烷基羰基或杂芳烷基羰基，其中所述芳基或杂芳基未被取代或被1-3个卤素、羟基、氨基或C1-4烷基取代，
(o)羧基，
(p)C1-10烷氧基羰基，
(q)芳氧基羰基、杂芳氧基羰基、芳烷氧基羰基或杂芳烷氧基羰基，其中所述芳基或杂芳基未被取代或被1-3个卤素、羟基、氨基或C1-4烷基取代，
(r)氨基甲酰基或氨磺酰基，其中氮原子未被取代或被1-2个C1 -6烷基或C4-6亚烷基链取代，
(s)氰基，
(t)异腈基，
(u)硝基，
(v)叠氮基，
(w)未被取代或在氮或碳上被C1-10烷基取代的亚氨基甲基，
(x)氧代基，或
(y)硫羰基；
R2和R3独立地为氢、C1-10烷基、芳基；或者
R2和R3一起为氧代基或硫代基；
R4和R5独立地为氢或烷基羰基；或者
R4和R5一起为羰基；或者
R4和R1一起为未被取代或被氧代基取代的C1-C3亚烷基；
R6和R7都是氢，或者
R6和R7中一个是氢，另一个是羟基，选自甲酰氧基、C1-10烷基羰基氧基、芳基羰基氧基和芳烷基羰基氧基的酰氧基衍生物，或-NHR12，其中R12是氢，未被取代或被1-3个卤素或C1-3烷基取代的芳基磺酰基或杂芳基磺酰基，烷基磺酰基或-C(=O)-X-A-R13，其中X是连接键、O或NH，A是连接键或C1-C3亚烷基，R13是氢、C1-C10烷基、芳基、芳烷基、杂芳基、杂环基或C3-C7环烷基，任一不是氢的R13可被一个或多个下述基团取代：卤素、羟基、C1-C3烷氧基、氰基、异腈基、硝基、氨基、一(C1-C3烷基)氨基、二(C1-C3烷基)氨基、巯基、C1-C3烷硫基、C1-C3烷基亚磺酰基、C1-C3烷基磺酰基、芳硫基、芳基亚磺酰基、氨磺酰基、芳基磺酰基、羧基、氨基甲酰基、C1-C3烷基羰基或C1-C3烷氧基羰基；或者
R6和R7一起为氧代基、羟基亚氨基、烷氧基亚氨基、芳烷氧基亚氨基或氨基亚氨基；
R8是甲基、芳烷氧基羰基或芳基磺酰基；
R9是氢、甲酰基、C1-10烷基羰基、C1-10烷氧基羰基或芳基烷氧基羰基；
R10是氢；或者
R10与R1一起为未被取代或被氧代基取代的C1-C3亚烷基；
m和n独立地为0或1。
3．权利要求2的方法，其中所述8a-azalide具有式I，其中
n和m是0；
R1是氢、C1-10烷基、C2-10链烯基、C2-10炔基或芳基磺酰基，其中所述烷基和链烯基任选地被卤素、羟基、氰基、C1-10烷氧基羰基、氨基、C1-10烷基氨基、二(C1-10烷基)氨基、芳基或芳烷氧基羰基取代；
R2、R3、R4、R5、R9和R10分别为氢；
R6和R7中的一个是氢，另一个选自羟基、C1-10烷基羰基氧基、芳烷基羰基氧基、氨基，被下述基团取代的氨基：C1-10烷基羰基、芳基羰基、芳基C1-10烷基羰基、C1-10烷氧基羰基、芳基C1-10烷氧基羰基、杂芳基羰基、杂芳基烷基羰基或芳基磺酰基；
R8是甲基．
4．权利要求2的方法，其中所述8a-azalide具有式I，其中
n和m是0；
R1是甲基、乙基、丙基、烯丙基、炔丙基、2-氰基乙基、2-羟基乙基、3-羟基丙基、2-甲氧基羰基乙基、2-苄氧基羰基乙基、氰基甲基、2-氨基乙基、2-(二甲基氨基)乙基、2-氟乙基、2-氟烯丙基、苄基或环氧乙烷基甲基；
R2、R3、R4、R5、R9和R10分别为氢；
R6和R7中的一个是氢，另一个是羟基或氨基；
R8是甲基。
5．权利要求4的方法，其中R1是甲基、乙基、丙基、烯丙基、2-甲氧基羰基乙基或2-(二甲基氨基)乙基。
6．权利要求1的方法，其中所述细菌感染是牛或猪呼吸系统感染。
7．权利要求6的方法，其中所述呼吸系统感染是由巴斯德氏菌属亚种、放线杆菌属亚种、睡眠嗜血菌或枝原体属亚种引起的。
8．权利要求2的方法，其中所述细菌感染是牛或猪呼吸系统感染。
9．权利要求8的方法，其中所述呼吸系统感染是由巴斯德氏菌属亚种、放线杆菌属亚种、睡眠嗜血菌或枝原体属亚种引起的。
10．权利要求3的方法，其中所述细菌感染是牛或猪呼吸系统感染。
11．权利要求10的方法，其中所述呼吸系统感染是由巴斯德氏菌属亚种、放线杆菌属亚种、睡眠嗜血菌或枝原体属亚种引起的。
12．权利要求4的方法，其中所述细菌感染是牛或猪呼吸系统感染。
13．权利要求12的方法，其中所述呼吸系统感染是由巴斯德氏菌属亚种、放线杆菌属亚种、睡眠嗜血菌或枝原体属亚种引起的。
14．权利要求5的方法，其中所述细菌感染是牛或猪呼吸系统感染。
15．权利要求14的方法，其中所述呼吸系统感染是由巴斯德氏菌属亚种、放线杆菌属亚种、睡眠嗜血菌或枝原体属亚种引起的。
16．权利要求1的方法，其中所述细菌感染是牛或猪肠感染。
17．权利要求16的方法，其中所述肠感染是由大肠杆菌、猪痢疾小蛇菌或沙门氏菌属亚种引起的。
18．权利要求2的方法，其中所述细菌感染是牛或猪肠感染。
19．权利要求18的方法，其中所述肠感染是由大肠杆菌、猪痢疾小蛇菌或沙门氏菌属亚种引起的。
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| US5832997P | 1997-09-10 | 1997-09-10 | |
| US60/583,329 | 1997-09-10 | ||
| GBGB9806029.6A GB9806029D0 (en) | 1998-03-20 | 1998-03-20 | 8a-Azalides as veterinary antimicrobial agents |
| GB9806029.6 | 1998-03-20 |
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| FR2788524B1 (fr) * | 1999-01-18 | 2002-04-26 | Merial Sas | Procede utile pour transformer la fonction 4"(s)-oh du motif cladinose d'un aza macrolide en 4"(r)-nh2 |
| GB0025688D0 (en) * | 2000-10-19 | 2000-12-06 | Glaxo Group Ltd | Macrolides |
| US8779175B2 (en) | 2004-10-25 | 2014-07-15 | Synthonics, Inc. | Coordination complexes, pharmaceutical solutions comprising coordination complexes, and methods of treating patients |
| US20060141054A1 (en) | 2004-10-25 | 2006-06-29 | Thomas Piccariello | Metal coordinated compositions |
| US7799937B2 (en) | 2004-10-25 | 2010-09-21 | Synthonics, Inc. | Metal coordinated compositions |
| WO2006120545A1 (en) * | 2005-05-10 | 2006-11-16 | Glaxosmithkline Istrazivacki Centar Zagreb D.O.O. | 4' amino linked macrolides useful for the treatment of microbial infections |
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| US5281518A (en) * | 1986-05-01 | 1994-01-25 | Washington Research Foundation | Detection of a unique chlamydia strain associated with acute respiratory disease |
| GB8726384D0 (en) * | 1987-11-11 | 1987-12-16 | Coopers Animal Health | Veterinary treatment |
| US4956294A (en) * | 1988-03-07 | 1990-09-11 | Merck & Co., Inc. | Culture of Streptoverticillium synroense for producing an antibacterial |
| CA2064634C (en) * | 1991-04-04 | 1998-08-04 | James V. Heck | 9-deoxo-8a-aza-8a-homoerythromycin a derivatives modified at the 4"- and8a-positions |
| US5202434A (en) * | 1991-04-05 | 1993-04-13 | Merck & Co., Inc. | 8a-aza-8a-homoerythromycin lactams |
| US5189159A (en) * | 1992-04-02 | 1993-02-23 | Merck & Co., Inc. | 8a-AZA-8a-homoerythromycin cyclic iminoethers |
| EP0549040A1 (en) * | 1991-12-20 | 1993-06-30 | Merck & Co. Inc. | Methods of making 4" derivatives of 9-deoxo-8a-aza-8a-alkyl-8a-homoerythromycin A |
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