CN1127294C - 杀内/外寄生虫组合物 - Google Patents
杀内/外寄生虫组合物 Download PDFInfo
- Publication number
- CN1127294C CN1127294C CN97180962A CN97180962A CN1127294C CN 1127294 C CN1127294 C CN 1127294C CN 97180962 A CN97180962 A CN 97180962A CN 97180962 A CN97180962 A CN 97180962A CN 1127294 C CN1127294 C CN 1127294C
- Authority
- CN
- China
- Prior art keywords
- group
- ivermectin
- spp
- imidacloprid
- avermectins
- 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
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Abstract
本发明涉及源自一类大环内酯的阿凡曼菌素、22，23-二氢阿凡曼菌素B1(异阿凡曼菌素)和米尔倍霉素与昆虫烟碱能乙酰胆碱受体激动剂或拮抗剂的混合物，如果适当的话，所述混合物中存在其它活性化合物和稀释剂或赋形剂。
Description
本发明涉及用来防治外和内寄生虫的源自一类大环内酯的阿凡曼菌素、22，23-二氢阿凡曼菌素B1(异阿凡曼菌素)和米尔倍霉素和昆虫的烟碱能(nicotinergic)乙酰胆碱受体激动剂或拮抗剂的混合物。
在大多数情况下，狗的胃肠线虫感染是由三种线虫科的种引起的，即蛔虫科(
Ascarididae)、钩虫科(
Ancylostomatidae)和鞭虫科(
Trichuridae)。在猫中，全世界主要存在两个线虫科，即蛔虫科和钩虫科。在各种宿主动物组织中经历许多发展阶段之后，胃肠道可发生明显的感染。在感染潜伏期和明显感染期间，特别是在处于青春期、生长期的狗、猫以及人中，蛔虫、钩虫和鞭虫的寄生虫病可能会导致相当大的问题。因此为了治愈已经感染的动物和保持未感染动物处于健康情况下，非常需要进行治疗或预防性治疗。
由此可见，正如预防人(特别是儿童)不受感染一样，保护狗和猫不受感染非常重要。
应当特别提及的是寄生虫犬恶丝虫(
Dirofilaria immitis)-一种在北美至南美、非洲、亚洲以及澳大利亚的部分地区的丝虫属地方性流行病。这种寄生虫是形成犬科和猫科动物心血管恶丝虫病的重要原因。发生在狗和猫的犬恶丝虫感染期间的心血管系统内的一些病理学变化可能是导致宿主动物疾病的重要原因。
来自大环内酯种类的驱虫药异阿凡曼菌素/米尔倍霉素在狗和猫中显示出了抗犬恶丝虫的活性。这些活性化合物通常经口或非经胃肠道给药。
宠物(如狗和猫)的跳蚤浸染不仅对感染动物是一件令人讨厌的事，而且它们可导致感染动物的剧痛(螫伤、瘙痒和过敏症)和损伤(失血)。跳蚤也可转变成各种种类的绦虫。因此，它们不但对感染动物而且对动物看守人都提出了医疗问题。动物看守人也会被跳蚤袭击；在一些人中可导致跳蚤螫伤过敏症。特别是随着大量宠物的增长，而且它们与人的接触更密切，所以需要且有必要有效地控制狗和猫中存在的跳蚤。
至今人们已经公知许多用于控制跳蚤的杀虫活性化合物。例如，这些活性化合物可源自一类氨基甲酸酯(残杀威、虫威、甲萘威)，源自一类磷酸酯(肟硫磷、二嗪农)和源自一类拟除虫菊酯(苄氯菊酯、氯氰菊酯、苄呋菊酯)。
这些活性化合物为经皮肤给药的接触杀虫剂，主要作用于成年跳蚤。
为了保护宠物免遭两方面的问题，进行两种独立地治疗(对内寄生虫采用非经胃肠道或口服给药治疗；对外寄生虫采用经皮肤治疗)至今已成为惯例。现在需要利用一种单个的治疗取代这两种治疗。
在治疗内寄生虫中常用来扩大活性范围的组合制品已为公知。
迄今为止，组合给用杀内寄生虫剂和杀外寄生虫剂的方法还没有在实践中成为惯例。
本发明提供了包含至少一种源自大环内酯的阿凡曼菌素、22，23-二氢阿凡曼菌素B1(异阿凡曼菌素)或米尔倍霉素与昆虫的烟碱能乙酰胆碱受体激动剂或拮抗剂的组合物。
令人惊奇地是，这些源自完全不同化学类型且具有完全不同生物化学的活性化合物彼此协同影响。
很长时间以来，人们已经公知源自一类大环内酯的阿凡曼菌素、22，23-二氢阿凡曼菌素B1(异阿凡曼菌素)或米尔倍霉素可用作杀内寄生虫剂，这也是许多专利申请和综述论文的目的所在(例如Biological effects in：Ivermectin and Abamectin，W.C.Campbell，Ed.，Springer Verlag，New York，N.Y.，1989；Avermectins andMilbemycins Part II，H.G.Davies et al.，Chem.Soc.Rev.20(1991)p.271-339；Chemical Modifications in：G.Lukacs et al.(Eds.)，Springer-Verlag，New York，(1990)，Chapter 3；CydectinTM[moxidectin and dervatives]；G.T.Carter et al.，J.Chem.Soc.Chem.Commun.(1987)，p.402-404；EP 423 445-A1)。将多拉美丁(doramectin)(Pfizer)用作杀内寄生虫剂也是已知的(参见“Doramectin-a potnet novel endectozide”A.C.Goudieet al.，Vet.Parasitol，49(1993)，p.5-15)。
此外，将阿凡曼菌素、22，23-二氢阿凡曼菌素B1(异阿凡曼菌素)或米尔倍霉素与一些种类的驱虫剂如苯并咪唑类、水杨酰胺类、左旋咪唑、噻吩嘧啶或吡喹酮组合也是大量专利申请的目的(如GB 2 252730；GB 2 224 933；GB 2 213 722；EP-A 59 074)。
阿凡曼菌素及其衍生物的实例包括通式(I)大环内酯的混合物：其中R1至R4各自如下表1定义，X表示C22和C23位置之间(-C22R1X-C23R2-)的单键或双键。
当为双键时，C22和C23位置之间没有取代基(R1、R2)。表1
22，23-二氢阿凡曼菌素B1表示异阿凡曼菌素B1；-Me＝甲基
| 大环内酯 | -C22R1-X-C23R2- | R3 | R4 |
| 阿凡曼菌素A1a | -CH＝CH- | 仲丁基 | -Me |
| 阿凡曼菌素A1b | -CH＝CH- | 异丙基 | -Me |
| 阿凡曼菌素A2a | -CH2-CHOH- | 仲丁基 | -Me |
| 阿凡曼菌素A2b | -CH2-CHOH- | 异丙基 | -Me |
| 阿凡曼菌素B1a | -CH＝CH- | 仲丁基 | -H |
| 阿凡曼菌素B1b | -CH＝CH- | 异丙基 | -H |
| 阿凡曼菌素B2a | -CH2-CHOH- | 仲丁基 | -H |
| 阿凡曼菌素B2b | -CH2-CHOH- | 异丙基 | -H |
| 22，23-二氢阿凡曼菌B1a | -CH2-CH2- | 仲丁基 | -H |
| 22，23-二氢阿凡曼菌素B1b | -CH2-CH2- | 异丙基 | -H |
| 多拉美丁 | -CH＝CH- | 环己基 | -H |
通式(I)的阿凡曼菌素和22，23-二氢阿凡曼菌素B1(异阿凡曼菌素B1)一般是以其混合物形式使用。这里特别有意义的产物是阿巴美丁(abamectin)，它主要包括阿凡曼菌素B1及其氢化产物22，23-二氢阿凡曼菌素B1(异阿凡曼菌素)。
大环内酯中标记“b”的化合物在C25位置上含有异丙基基团，该化合物不必要从标记“a”的化合物中分离出来，所述标记“a”化合物在C25位置上含有仲丁基基团。一般地，由＞80％仲丁基衍生物(B1a)和＜20％异丙基衍生物(B1b)组成的两种物质的混合物被分离并可用于本发明。再者，在立体异构体情况下，环系中C13和C23位置上的取代基可以是α和β两种构型，也就是说，它们可位于分子平面之上或之下。
米尔倍霉素具有与阿凡曼菌素或22，23-二氢阿凡曼菌素B1(异阿凡曼菌素)相同的大环内酯环结构，但在位置13不带取代基(R5＝氢)(即不存在齐墩果糖双糖片段)。
源自一类大环内酯的米尔倍霉素实例包括通式(II)化合物：其中R1至R5各自如下表2定义：表2 
对于本发明的混合物特别适合的共组分为阿凡曼菌素B1a/B1b；22，23-二氢阿凡曼菌素B1a/B1b(或异阿凡曼菌素B1a/B1b)；多拉美丁；摩西德素(Moxidectin)；
昆虫烟碱能乙酰胆碱受体激动剂或拮抗剂可从下列文献中得知，如欧洲公开申请464 830、428 941、425 978、386 565、383 091、375 907、364 844、315 826、259 738、254 859、235 725、212 600、192 060、163 855、154 178、136 636、303 570、302 833、306 696、189 972、455 000、135 956、471 372、302 389；德国公开申请3 639877、3 712 307；日本公开申请03 220 176、02 207 083、63 307 857、63 287 764、03 246 283、04 9371、03 297 359、03 255 072；美国专利5 034 524、4 948 798、4 918 086、5 039 686、5 034 404；PCT申请WO 91/17 659、91/4965；法国申请2 611 114；巴西申请88 03 621。
这些出版物中描述的通式和定义以及其中描述的各制备方法和化合物在此引作参考。
这些化合物可由通式(I)表示：
其中R 表示氢或表示任选取代的下述基团：酰基、烷基、芳基、芳烷基、杂芳基和杂芳烷基；A 表示选自下述的单官能基团：氢、酰基、烷基或芳基；或表示与基团Z相连的双官能基团；E 表示吸电子基团；X 表示基团-CH＝或＝N-，其中，代替氢原子，基团-CH＝可与基团Z相连；Z 表示选自下列的单官能基团：烷基、-O-R、-S-R和
或表示与基团A或与基团X相连的双官能基团。
特别优选的式(I)化合物是基团如下述定义的化合物：R 表示氢或表示任选取代的下述基团：酰基、烷基、芳基、芳烷基、杂芳基和杂芳烷基。
适当的酰基基团包括：甲酰基、烷基羰基、芳基羰基、烷基磺酰基、芳基磺酰基、(烷基-)-(芳基-)-磷酰基，它们各又可以被取代。
适当的烷基包括C1-10烷基，特别是C1-4烷基，尤其是甲基、乙基、异丙基、仲-或叔-丁基，它们各又可以被取代。
适当的芳基包括苯基和萘基，特别是苯基。
适当的芳烷基包括苯甲基和苯乙基。
适当的杂芳基包括含有最多10个环原子和N、O和S(特别是N)作为杂原子的杂芳基。特别实例包括噻吩基、呋喃基、噻唑基、咪唑基、吡啶基和苯并噻唑基。
适当的杂芳烷基包括具有最多6个环原子和N、O和S(特别是N)作为杂原子的杂芳基甲基、杂芳基乙基。
优选取代基的实例为：优选具有1至4、特别是1或2个碳原子的烷基，如甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基；优选具有1至4、特别是1或2个碳原子的烷氧基，如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基和叔丁氧基；优选具有1至4、特别是1或2个碳原子的烷硫基，如甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、异丁硫基和叔丁硫基；优选具有1至4、特别是1或2个碳原子和优选1至5、特别是1至3个卤原子的卤代烷基，其中卤原子相同或不同，优选氟、氯或溴，特别是氟，如三氟甲基；羟基；卤素，优选氟、氯、溴和碘，特别是氟、氯和溴；氰基；硝基；氨基；每个烷基优选具有1至4、特别是1或2个碳原子的一烷基氨基和二烷基氨基，如甲氨基、甲基-乙基-氨基、正丙氨基、异丙氨基和甲基-正丁基-氨基；羧基；优选具有2至4、特别是2或3个碳原子的烷氧基羰基，如甲氧基羰基和乙氧基羰基；磺基(-SO3H)；优选具有1至4、特别是1或2个碳原子的烷基磺酰基，如甲磺酰基和乙磺酰基；优选具有6或10个芳基碳原子的芳基磺酰基，如苯磺酰基；以及杂芳基氨基和杂芳基烷氨基，如氯吡啶氨基和氯吡啶甲氨基。A 特别优选地表示氢和表示任选取代的下述基团：酰基、烷基和芳基，各自优选如R下的定义。此外，A表示双官能基团。适当的双官能团包括具有1-4、特别是1-2个碳原子的任选取代的亚烷基，适当的取代基如上文进一步所列的取代基，所述亚烷基可被选自N、O和S的杂原子间断。A和Z一起和与它们相连的原子可形成饱和或不饱和的杂环。该杂环可含有一个或两个相同或不同的杂原子和/或杂原子基团。优选的杂原子为氧、硫或氮，优选的杂原子基团为N-烷基，所述N-烷基的烷基部分优选地包含1至4、特别是1或2个碳原子。适当的烷基包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基。杂环含有5至7、优选5或6个环原子。
杂环实例包括：吡咯烷、哌啶、哌嗪、六亚甲基亚胺、六氢-1，3，5-三嗪和吗啉，它们各自可任选被取代，优选被甲基取代。E 表示吸电子基团；特别优选NO2、CN和卤代烷基羰基，如1，5-卤代-C1-4-羰基，特别是COCF3。X 表示基团-CH＝或-N＝。Z 表示任选取代的下列基团：烷基、-OR、-SR和-NRR，其中R和取代基优选如上文定义。Z 除了上述环之外，还可和与其相连的原子及X位置上的下列基团一起形成饱和或不饱和杂环。该杂环可含一个或两个相同或不同的杂原子或杂原子基团。优选的杂原子为氧、硫或氮，优选的杂原子基团为N-烷基，其中烷基或N-烷基优选包含1至4、特别是1或2个碳原子。适当的烷基包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基。杂环含有5至7、优选5或6个环原子。
杂环实例包括：吡咯烷、哌啶、哌嗪、六亚甲基亚胺、吗啉和N-甲基哌嗪。
可用于本发明的非常特别优选化合物为通式(II)和(III)化合物：其中n 表示1或2，subst.表示上述取代基之一，特别是卤素，尤其是氯，A、Z、X和E如上文定义。
特别优选的化合物实例为：
吡虫啉 
非常特别优选的化合物为吡虫啉、Ti 435和AKD 1022。
例如，将源自一类大环内酯的通式(Ia)的22，23-二氢阿凡曼菌素B1a/B1b(异阿凡曼菌素B1a/B1b)：
其中R5 表示甲基或乙基，作为本发明的共组分与吡虫啉以协同比例混合，如果适当的话，可以存在其它活性化合物和载体。
例如，将源自一类大环内酯的通式(Ia)的22，23-二氢阿凡曼菌素B1a/B1b(异阿凡曼菌素B1a/B1b)：其中R5 表示甲基或乙基，作为本发明共组分与Ti 435以协同比例混合，如果适当的话，可以存在其它活性化合物和载体。
本发明活性化合物结合物的杀内寄生虫活性显著地高于各单个组成分所预期的活性。因此，通过利用这些结合物，可降低施用率和施用次数。
由于对温血种类的低毒性，本发明组合物适于防治存在于人和动物喂养和动物繁殖中，存在于生产性动物、繁殖性动物、动物园动物、实验室动物、实验动物和宠物中的致病的内寄生虫和外寄生虫。它们对害虫发育的所有阶段或各阶段具有活性，对具有抗性和一般敏感性害虫具有活性。通过防治致病内寄生虫，可降低疾病、死亡率和减产，因此使用所述的活性化合物可使得喂养动物变得更经济、更简单。致病内寄生虫包括线虫和刺头虫，特别是：
单殖亚纲，如三代虫属、指环虫属、多盘吸虫属；
嘴刺目，如鞭虫属、毛细线虫属、Trichomosides spp.、毛线虫属；
小杆亚纲，如Micronema spp.、类圆线虫属；
类圆线虫科，如类圆线虫属、Triodontophorus spp.、Oesophagondontus spp.、Trichonema spp.、Gyalocephalus spp.、Cylindropharynx spp.、Poteriostomun spp.、Cyclococercus spp.、Cylicostephanus spp.、结节线虫属、夏氏线虫属、冠线虫属、钩虫属、钩虫属(旧名)、Bunostomum spp.；
Globocephalus spp.、比翼线虫属、Cyathostoma spp.、后圆线虫属、网尾线虫属、苗氏线虫属、原圆线虫属、Neostrongylus spp.、Cystocaulus spp.、Pneumostrongylus spp.、Spicocaulus spp.、Elaphostrongylus spp.、Parelaphostrongylus spp.、Crenosomaspp.、Paracrenosoma spp.、Angiostrongylus spp.、Aelurostrongylus spp.、丝虫属、Parafilaroides spp、毛圆线虫属、血茅线虫属、胃线虫属、Marshallagia spp.、库柏线虫属、细颈属、猪圆线虫属、Obeliscoides spp.、裂口线虫属、Ollulanusspp.、
尖尾科，如尖尾线虫属、蛲虫属、Passalurus spp.、管状线虫属、Aspiculuris spp.、异刺线虫属。
蛔虫科，如蛔虫属、弓蛔线虫属、弓蛔虫属、Parascaris spp.、Anisakis spp.、Ascaridia spp.。
旋尾科，如鄂口线虫属、高加索泡翼线虫属、吸吮线虫属、筒线虫属、丽线虫属、Parabronema spp.、Draschia spp.、龙线虫属。
丝虫科，如冠丝虫属、Parafilaria spp.、腹腔丝虫属、罗阿丝虫属、Dirofilaria spp.、棉鼠丝虫属、Brugia spp.、吴策丝虫属、盘尾属。
巨吻棘头虫属，如Filicollis spp.、念珠棘虫属、巨吻棘头虫属、Prosthenorchis spp.。
外寄生虫包括：
虱目，如血虱属、长鄂虱属、水牛盲虱、虱属、Pthirus spp.；
食毛目，如Trimenopon spp.、Menopon spp.、Ecomenacanthusspp.、Menacanthus spp.、啮毛虱属、Felicola spp.、Damalineaspp.、Bovicola spp.；
双翅目，如斑虻属、虻属、蝇属、Hydrotaea spp.、腐蝇属、Haematobosca spp.、扰血蝇属、螫蝇属、厕蝇属、舌蝇属、绿蝇属、丽蝇属、燥蝇属、瘤蝇属、锥蝇属、金蝇属、麻蝇属、污蝇属、胃蝇属、Oesteromyia spp.、皮下蝇属、狂蝇属、鼻狂蝇属、蜱蝇属、虱蝇属。
蚤目，如栉头蚤属、冠蚤属、角叶蚤属。
特别重要的是对蚤目具有活性，尤其是对跳蚤。
生产性和繁殖性动物包括哺乳动物，如牛、马、绵羊、猪、山羊、骆驼、水牛、猴子、兔、黇鹿和驯鹿；毛皮动物，如貂、真灰鼠和浣熊；鸟类，如母鸡、鹅、火鸡和鸭；淡水鱼和咸水鱼，如鲑鱼、鲤鱼和鳗鱼。
实验室和实验动物包括小鼠、大鼠、天竺鼠、金仓鼠、狗和猫。
宠物包括狗和猫。
给药可通过预防和治疗两种方式进行。
活性化合物的给药可直接或以适当制剂形式经口或皮肤进行，特别优选经皮给药。
活性化合物的肠内给药可通过如下述剂型经口进行：粉剂，片剂，胶囊，糊剂，饮剂，颗粒剂，可口服的溶液、悬浮液和乳液，大丸剂，含药的饲料或饮水。经皮给药可通过如喷洒或浇泼和点涂等形式进行。
适当的制剂为：
溶液，如口服溶液；用于稀释后经口给药的浓缩物；用于皮肤上或体腔内的溶液；浇泼剂型；凝胶；
用于经口或经皮给药的乳液和悬浮液；半固体制剂；
活性化合物包含在油基或水包油或油包水乳液基中的剂型；
固体制剂，如粉剂、预混剂或浓缩物、颗粒剂、小药丸、片剂、大药丸、胶囊；气溶胶和吸入剂，含活性物质的成型制品。
可提及的溶剂为：生理上可接受的溶剂，如水，醇类如乙醇、丁醇、苯甲醇、甘油、丙二醇、聚乙二醇、N-甲基-吡咯烷酮、2-吡咯烷酮，以及它们的混合物。
活性化合物也可任选地溶解在适于注射的生理上可接受的植物油或合成油中。
可提及的增溶剂为：能够促进活性化合物溶解在主要溶剂或防止其沉淀的溶剂。实例包括聚乙烯基吡咯烷酮、聚乙烯醇、多氧乙基化的蓖麻油、多氧乙基化的脱水山梨醇酯。
防腐剂为：苯甲醇、三氯丁醇、对羟基苯甲酸酯、正丁醇。
口服溶液可直接给药。浓缩物可在稀释至使用浓度后经口给药。口服溶液和浓缩物可根据现有技术制备，灭菌步骤是不需要的。
用于皮肤的溶液可以通过滴流、涂敷、搓擦、散洒或喷雾使用。
在制备制剂过程中加入增稠剂是有利的。增稠剂为：无机增稠剂，如膨润土、胶状硅酸、单硬脂酸铝；有机增稠剂，如纤维素共聚物、聚乙烯醇及其共聚物、丙烯酸酯和异丁烯酸酯。
凝胶可应用或涂敷至皮肤上或引入到体腔中。凝胶可通过利用足够的增稠剂处理在注射液的情况下所述那样已经制备的从而得到具有软膏状粘度的清亮物质来制备。所使用的增稠剂如上文给出的增稠剂。
浇泼制剂浇泼或喷洒在皮肤的有限区域内，活性化合物渗透到皮肤中并系统地产生作用。
浇泼制剂可通过将活性化合物溶解、悬浮或乳化在适当皮肤相容溶剂或溶剂混合物中而制备。如果适当的话，可加入其它助剂，如着色剂、促进生物吸收物质、抗氧化剂、光稳定剂、粘合剂。
可提及的溶剂为：水，链烷醇，二醇类，聚乙二醇类，聚丙二醇类，甘油，芳族醇(如苯甲醇、苯乙醇、苯氧基乙醇)，酯类(如乙酸乙酯、乙酸丁酯、苯甲酸苯甲酯)，醚类(如亚烷基二醇烷基醚，如一缩二丙二醇一甲基醚、二甘二醇一丁基醚)，酮类(如丙酮、甲乙酮)，环碳酸酯(如碳酸亚丙基酯、碳酸亚乙基酯)，芳烃和/或脂烃，植物油或合成油，DMF，二甲基乙酰胺，正烷基吡咯烷酮(如甲基吡咯烷酮、正丁基吡咯烷酮或正辛基吡咯烷酮)，N-甲基吡咯烷酮，2-吡咯烷酮，2，2-二甲基-4-氧基-亚甲基-1，3-二氧戊环和甘油甲缩醛。
着色剂为可用于动物上且可被溶解或悬浮的所有着色剂。
促进吸收物质为：如DMSO、涂敷油(如肉豆蔻酸异丙基酯)、壬酸一缩二丙二醇酯、硅油及其与聚醚的共聚物、脂肪酸酯、甘油三酯、脂肪醇。
抗氧化剂为亚硫酸盐或偏亚硫酸氢盐，如偏亚硫酸氢钾，抗坏血酸，丁基羟基甲苯，丁基羟基苯甲醚，生育酚。
光稳定剂为；如novantisolic acid。
粘合剂为：如纤维素衍生物、淀粉衍生物、聚丙烯酸酯、天然聚合物(如藻酸盐)、明胶。
乳液可经口、经皮或以注射剂给药。
乳液既可以是油包水型，也可以是水包油型。
它们可通过下述方法制备：将活性化合物溶解在疏水或亲水相中，借助于适当的乳化剂及如果需要的话其它助剂(如着色剂、促进吸收物质、防腐剂、抗氧化剂、光稳定剂、粘度增强物质)，利用另一相溶剂进行均化。
可提及的疏水相(油)为：液体石蜡，硅油，天然植物油(如芝麻油、杏仁油、蓖麻油)，合成甘油三酯如辛酸/癸酸甘油二酯，具有链长为C8-12的植物脂肪酸或其它具体选定的天然脂肪酸的甘油三酯混合物，也可含有羟基的饱和或不饱和脂肪酸的部分甘油酯混合物，以及C8/C10脂肪酸的甘油单酯和二酯)。
尤其是脂肪酸酯，如硬脂酸乙酯、己二酸二正丁基酯、月桂酸己基酯、一缩二丙二醇perlargonate；中链支化脂肪酸与链长为C16-C18的饱和脂肪醇形成的酯；肉豆蔻酸异丙基酯；棕榈酸异丙基酯；链长为C12-C18的饱和脂肪醇与辛酸/癸酸形成的酯；硬脂酸异丙基酯；油酸油酯；油酸癸酯；油酸乙酯；乳酸乙酯；蜡状脂肪酸酯，如合成鸭尾骨腺脂；邻苯二甲酸二丁酯；己二酸二异丙基酯；与后者有关的酯混合物。
脂肪醇包括异十三烷醇、2-辛基十二烷醇、琼蜡基硬脂醇、油醇。
脂肪酸包括油酸及其混合物。
可提及的亲水相为：
水；醇类如丙二醇、甘油、山梨醇及其混合物。
可提及的乳化剂为：非离子表面活性剂，如多乙氧化蓖麻油、多乙氧化一油酸脱水山梨糖醇酯、一硬脂酸脱水山梨醇酯、一硬脂酸甘油酯、聚氧乙基硬脂酸酯、烷基酚聚二醇醚；
两性表面活性剂，如N-月桂基-β-亚氨基二丙酸二钠或卵磷脂；
阴离子表面活性剂，如月桂基硫酸钠、脂肪醇醚硫酸盐、一/二烷基聚二醇醚正磷酸酯单乙醇胺盐；
阳离子活性表面活性剂，如琼蜡基三甲基氯化铵。
可提及的进一步助剂为：增强粘度和稳定乳液的物质，如羧甲基纤维素、甲基纤维素及其它纤维素和淀粉衍生物、聚丙烯酸酯、藻酸盐、明胶、阿拉伯胶、聚乙烯基吡咯烷酮、聚乙烯醇、甲基乙烯基醚和马来酸酐的共聚物、聚乙二醇、石蜡、胶态硅酸及上述物质的混合物。
悬浮液可经口或经皮给药。它们可通过下述方法制备：将活性化合物悬浮在悬浮剂中，如果适当的话，可加入其它助剂，如湿润剂、着色剂、生物吸收促进物质、防腐剂、抗氧化剂、光稳定剂。
可提及的液体赋形剂为所有均质溶剂和溶剂混合物。
可提及的湿润剂(分散剂)为上述表面活性剂。
可提及的其它助剂如上文所述。
半固体制剂可经口或经皮给药。它们与上述悬浮液和乳液的不同点仅在于其粘度更高。
为了制备固体制剂，可将活性化合物与适当的赋形剂混合，如果适当的话可加入助剂，并使其具有所需的形式。
可提及的赋形剂为所有生理可接受固态惰性物质，可使用无机和有机物质。无机物质为：如氯化钠；碳酸盐，如碳酸钙；碳酸氢盐；氧化铝；氧化钛；硅酸；泥质土；沉淀或胶态硅石；磷酸盐。
有机物质为：如糖；纤维素；食品和饲料，如奶粉、动物饲料、谷物粗粉和碎片；淀粉。
助剂为上述防腐剂、抗氧化剂、着色剂。
其它适当的助剂为润滑剂，如硬脂酸镁、硬脂酸、滑石、膨润土；崩解促进物质，如淀粉或交联聚乙烯基吡咯烷酮；粘合剂，如淀粉、明胶或线性聚乙烯基吡咯烷酮；以及干性粘合剂，如微晶纤维素。
活性化合物也可存在于作为含有增效剂或其它用作抗病源内寄生虫的活性化合物的混合物的制剂中。这类活性化合物为：如L-2，3，5，6-四氢-6-苯基咪唑并噻唑、苯并咪唑氨基甲酸酯、噻吩嘧啶、吡喹酮、epsiprantel。
即用型制剂含有浓度为10ppm-20％(重量)的用作抗外寄生虫的化合物，优选含0.1-12.5％(重量)。
在使用前稀释的制剂包含浓度为0.5-90％(重量)、优选5-50％(重量)的用作抗外寄生虫的化合物。
此外，制剂包含浓度为10ppm-2％(重量)、优选0.05-0.9％(重量)、特别优选0.005-0.25％(重量)的用作抗内寄生虫的上述化合物。
当用于宠物狗时，本发明组合物中的大环内酯与昆虫烟碱能乙酰胆碱受体激动剂或拮抗剂的重量比例一般为1∶500至1000，优选1∶500至850，特别优选1∶500。
最后，当用于实用动物时，本发明组合物中的大环内酯与昆虫烟碱能乙酰胆碱受体激动剂或拮抗剂的重量比例一般为1∶20至400，优选1∶20至250，特别优选1∶20至50。
在下列实施例中，昆虫烟碱能乙酰胆碱受体激动剂或拮抗剂为1-[(6-氯-3-吡啶基)甲基]-N-硝基-2-咪唑烷鎓(通用名为吡虫啉)，大环内酯为异阿凡曼菌素。
实施例
实施例1
SL制剂(水溶性浓缩物)18.3g 吡虫啉0.2g 异阿凡曼菌素2.5g 以烷芳基聚二醇醚为基的天然乳化剂3.5g 磺基琥珀酸二异辛基酯，钠盐38.4g 二甲亚砜，和37.5g 2-丙醇实施例2
浇泼制剂20.3g 吡虫啉0.2g 异阿凡曼菌素1.8g 聚乙烯醇1.8g 以环氧乙烷和环氧丙烷为基的嵌段共聚物0.26g 黄蓍胶9.0g 甘油59.2g 蒸馏水实施例3
点涂制剂10.000g 吡虫啉0.006g 异阿凡曼菌素83.394g 苯甲醇16.300g 碳酸亚丙基酯0.100g BHT(丁基化羟基甲苯)实施例4
点涂制剂10.000g 吡虫啉0.050g 异阿凡曼菌素83.350g 苯甲醇16.300g 碳酸亚丙基酯0.100g BHT实施例5
点涂制剂10.000g 吡虫啉0.200g 异阿凡曼菌素83.200g 苯甲醇16.300g 碳酸亚丙基酯0.100g BHT应用实施例A
通过浇泼，将1ml作为溶液的实施例1的SL制剂应用到感染有200跳蚤的狗背上。试验动物立即没有成年跳蚤。本发明的处理能够使跳蚤的死亡率达到100％。应用实施例B
将1ml实施例1的制剂稀释在1l水中，再将该溶液浇到感染有跳蚤的大约20kg狗身上，直至狗被滴湿，得到下列结果：表B
应用实施例C体内线虫试验小鼠中的
Nematospiroides dubius
| 时间 天 | 每只狗中的跳蚤数量 | 活性％ | |
| 未处理 | 处理后 | ||
| -1 感染100只跳蚤 | |||
| 0 处理并计数 | 30 | 0 | 100 |
| 5，8 感染100只跳蚤 | |||
| 9 计数 | 56 | 0 | 100 |
| 15 感染100只跳蚤 | |||
| 16 计数 | 76 | 0 | 100 |
| 19 感染100只跳蚤(未处理动物)250只跳蚤(处理的动物) | |||
| 20 计数 | 39 | 0 | 100 |
| 26 感染100只跳蚤 | |||
| 27 计数 | 43 | 0 | 100 |
将小鼠实验性地用
Nematospiroides dubius类线虫感染。特别地，小鼠经口给用60只
Nematospiroides dubius丝状幼虫。
在潜伏期过期之后，在感染后第12天口服给用悬浮的实施例2活性化合物。活性测定：
在感染后20天选择小鼠。通过压迫装置对十二指肠中的成年寄生虫计数。将剂量组中的成功处理与未处理对照组进行比较。
下列表A和B表明了结合物对抗小鼠中
Nematospiroides dubius的作用。表C 口服给药后吡虫啉和异阿凡曼菌素B1a/B1b的结合物对抗小鼠中Nematospiroides dubius的作用
实施例D体内线虫试验小鼠中的
Heterakis spumosa
| 活性化合物和剂量(mg/kg) | 减少速率(％) | |
| 吡虫啉 | 50.0 | 0 |
| 异阿凡曼菌素B1a/B1b | 0.1 | 0 |
| 异阿凡曼菌素B1a/B1b+吡虫啉 | 50.00.1 | 100 |
| 吡虫啉 | 25.0 | 0 |
| 吡虫啉+异阿凡曼菌素B1a/B1b | 25.00.1 | ＞80 |
用
Heterakis spumosa类线虫对小鼠进行实验性感染。具体地，小鼠经口给用作为90只含胚卵的
Heterakis spumosa。
在潜伏期过期之后，在感染后46天给用悬浮的实施例2的活性化合物。活性测定：
在感染后54天选择小鼠。用显微镜对结肠和盲肠中的成年寄生虫计数。将剂量组中的成功处理与未处理对照组进行比较。
下表表明对结合物小鼠中
Heterakis spumosa的作用。表D 口服给药后吡虫啉和异阿凡曼菌素B1a/B1b的结合物对抗小鼠中Heterakis spumosa的作用
应用实施例E
| 活性化合物和剂量(mg/kg) | 减少速率(％) | |
| 吡虫啉 | 50.0 | 0 |
| 异阿凡曼菌素B1a/B1b | 0.1 | ＜50 |
| 吡虫啉+异阿凡曼菌素B1a/B1b | 50.00.1 | 100 |
| 吡虫啉 | 25.0 | 0 |
| 吡虫啉+异阿凡曼菌素B1a/B1b | 25.00.1 | 100 |
| 吡虫啉 | 10.0 | 0 |
| 吡虫啉+异阿凡曼菌素B1a/B1b | 10.00.1 | ＞80 |
| 吡虫啉 | 5.0 | 0 |
| 吡虫啉+异阿凡曼菌素B1a/B1b | 5.00.1 | ＞80 |
利用0.1ml/kg的恒定应用体积，在四组试验狗中进行三种吡虫啉/异阿凡曼菌素制剂的杀昆虫和杀线虫的活性比较。通过点涂应用试验物质。制剂中异阿凡曼菌素的百分比为0.006％、0.05％和0.2％。每种试验物质中含有恒定的10％吡虫啉。在处理之前或之后的给定间隔内，对分别处理组和对照组的动物分别就跳蚤和线虫进行临床测定。试验时间：4周试验物质：I.吡虫啉活性成分含量：10％w/vII.异阿凡曼菌素活性成分含量：0.006％w/v(实施例E1)
0.05％w/v(实施例E2)
0.2％w/v(实施例E3)试验动物：种类：狗(家犬)品种：长耳短腿小猎犬数量：8性别：4只雌性和4只雄性年龄：小动物：2-3月龄用跳蚤实验性感染
在治疗前3天，每只狗在其大腿内侧褶痕区域内用大约100只跳蚤感染，它们最多四周大。每周都再感染一次。利用线虫进行实验性感染
在治疗20天之前，每只狗均感染250只Acylostoma caninum幼虫(1，3)。给药
利用点涂对动物进行一次处理。每种情况下的处理组均由两只动物组成。对于所有的动物，给药体积为0.1ml/kg。活性的临床测定
为了测定处理后的杀虫作用，先在处理之前进行跳蚤感染定量测定，然后每种情况下在处理后24小时或在每次再感染后进行测定。通过在处理之前或之后(处理后1-3天)对排泄粪便中的蠕虫进行计数，测定杀内寄生虫的活性。结果
在所有的试验组中，经28天时间检测百分杀虫活性。杀内寄生虫活性取决于剂量，参见下表。
| 制剂(吡虫啉％/异阿凡曼菌素％) | 活性 |
| 10/0.006 | 60％ |
| 10/0.05 | 95％ |
| 10/0.2 | 99％ |
Claims (4)
1.下述组分(a)结合(b)并如果适当的话在(c)存在下用于制备同时控制内寄生虫和外寄生虫的药物的应用，
(a)选自大环内酯类的阿凡曼菌素、22，23-二氢阿凡曼菌素B1(异阿凡曼菌素)或米尔倍霉素；
(b)式(I)的昆虫的烟碱能乙酰胆碱受体的激动剂或拮抗剂，其中R 表示氢，或表示任选取代的选自下述的基团：酰基、烷基、芳基、芳烷基、杂芳基和杂芳烷基；A 表示选自下述的单官能基团：氢、酰基、烷基或芳基；或表示与基团Z相连的双官能基团；E 表示吸电子基团；X 表示基团-CH＝或＝N-，其中，代替氢原子，基团-CH＝可与基团Z相连；Z 表示选自下列的单官能基团：烷基、-O-R、-S-R和
或表示与基团A或与基团X相连的双官能基团；
(c)如果适当的话，其它活性化合物和稀释剂或赋形剂。
2.根据权利要求1的应用，其中昆虫烟碱能乙酰胆碱受体的激动剂或拮抗剂是选自下列的化合物：
吡虫啉
3.根据权利要求1的、22，23-二氢阿凡曼菌素B1(异阿凡曼菌素)结合吡虫啉的应用。
4.根据权利要求1的摩西德素结合吡虫啉的应用。
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| US4199569A (en) * | 1977-10-03 | 1980-04-22 | Merck & Co., Inc. | Selective hydrogenation products of C-076 compounds and derivatives thereof |
| JPS57139012A (en) | 1981-02-23 | 1982-08-27 | Sankyo Co Ltd | Anthelmintic composition |
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| GB2224933A (en) | 1988-11-21 | 1990-05-23 | Merck & Co Inc | Synergistic antiparasitic combinations |
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| ATE130006T1 (de) | 1989-09-11 | 1995-11-15 | American Cyanamid Co | 13-alkyl-23-imino und 13-halo-23-imino-derivate von ll-f28249-verbindungen und ihre verwendung als endo- und ectoparasitizide, insektizide, akarizide und nematozide mittel. |
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| DE4443888A1 (de) | 1994-12-09 | 1996-06-13 | Bayer Ag | Dermal applizierbare Formulierungen von Parasitiziden |
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1996
- 1996-12-23 DE DE19654079A patent/DE19654079A1/de not_active Withdrawn
-
1997
- 1997-12-11 PL PL334181A patent/PL201763B1/pl unknown
- 1997-12-11 CN CN97180962A patent/CN1127294C/zh not_active Expired - Lifetime
- 1997-12-11 DK DK97953783.4T patent/DK0946099T3/en active
- 1997-12-11 JP JP52831098A patent/JP4445593B2/ja not_active Expired - Lifetime
- 1997-12-11 NZ NZ336344A patent/NZ336344A/xx not_active IP Right Cessation
- 1997-12-11 AU AU57561/98A patent/AU736083B2/en not_active Expired
- 1997-12-11 CA CA2275657A patent/CA2275657C/en not_active Expired - Lifetime
- 1997-12-11 ES ES97953783.4T patent/ES2536970T3/es not_active Expired - Lifetime
- 1997-12-11 EP EP97953783.4A patent/EP0946099B1/de not_active Expired - Lifetime
- 1997-12-11 RU RU99115825/13A patent/RU2222193C2/ru active
- 1997-12-11 WO PCT/EP1997/006926 patent/WO1998027817A1/de active IP Right Grant
- 1997-12-11 HU HU0000600A patent/HU230153B1/hu active Protection Beyond IP Right Term
- 1997-12-11 US US09/331,040 patent/US20030055089A1/en not_active Abandoned
- 1997-12-11 BR BRPI9714236-0A patent/BR9714236B1/pt not_active IP Right Cessation
- 1997-12-11 IL IL13033097A patent/IL130330A0/xx active IP Right Grant
- 1997-12-11 PT PT97953783T patent/PT946099E/pt unknown
- 1997-12-11 KR KR1019997005264A patent/KR100549093B1/ko not_active IP Right Cessation
- 1997-12-17 TW TW086119026A patent/TW448047B/zh not_active IP Right Cessation
- 1997-12-19 AR ARP970106069A patent/AR010375A1/es not_active Application Discontinuation
- 1997-12-22 ZA ZA9711496A patent/ZA9711496B/xx unknown
-
1999
- 1999-06-07 IL IL130330A patent/IL130330A/en not_active IP Right Cessation
-
2000
- 2000-07-14 HK HK00104344A patent/HK1025014A1/xx not_active IP Right Cessation
-
2003
- 2003-07-03 US US10/613,819 patent/US20040014689A1/en not_active Abandoned
-
2009
- 2009-07-01 JP JP2009157038A patent/JP2009263388A/ja active Pending
-
2015
- 2015-09-30 NL NL300761C patent/NL300761I2/nl unknown
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2016
- 2016-01-07 HU HUS1600003C patent/HUS1600003I1/hu unknown
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| GB2221621A (en) * | 1988-08-12 | 1990-02-14 | Merck & Co Inc | Synergistic antiparasitic combinations of avermectin and pyrantel |
| WO1995033453A1 (de) * | 1994-06-07 | 1995-12-14 | Bayer Aktiengesellschaft | Agonisten und antagonisten der nicotinergen acetylcholinrezeptoren von insekten als endoparasitizide |
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