CN1448393A - 抗内寄生物用的新型二氧代吗啉 - Google Patents
抗内寄生物用的新型二氧代吗啉 Download PDFInfo
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- CN1448393A CN1448393A CN02108270A CN02108270A CN1448393A CN 1448393 A CN1448393 A CN 1448393A CN 02108270 A CN02108270 A CN 02108270A CN 02108270 A CN02108270 A CN 02108270A CN 1448393 A CN1448393 A CN 1448393A
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- phenyl
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- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 51
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 19
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- 229910052794 bromium Inorganic materials 0.000 claims description 19
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
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- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
- C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
- C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
Abstract
本发明涉及新型的二氧代吗啉,以及它们用来抗内寄生物的用途和它们的制备方法。
Description
发明领域
本发明涉及新型二氧代吗啉,以及它们用于抗内寄生物的用途和它们的制备方法。
技术背景
某些二氧代吗啉以及它们的制备方法是已知的(参考文献,例如Liebigs Ann.Chem.1952(1982),Makromol.Chem.,Rapid Commun.,6(1985),607;Tetrahedron,37(1981),2797;WO9403441A1;),但是没有公开涉及利用这些化合物来抗内寄生物方面的内容。
WO96/15121公开了适用于抗内寄生物的二氧代吗啉。但是所描述的该化合物不含有磺酰胺侧链。
发明内容
式(I)的化合物其中R1代表氢、卤素、硝基、氰基、烷基、芳基、三烷基甲硅烷基、烷氧基或-S(O)rR,它们可任选地被取代,
R2代表氢、卤素、硝基、氰基、烷基、芳基、三烷基甲硅烷基、烷氧基或-S(O)rR,它们可任选地被取代,
R3代表任选地被取代的烷基,
R4代表任选地被取代的烷基或
R3和R4合起来代表一个螺环基团,它可任选地被取代,
R5代表氢、烷基、芳烷基或被取代的苯基,它可任选地被取代,
r代表0、1或2,
R代表任选被取代的烷基,
m代表0、1、2、3、4或5,
n代表0、1、2、3、4或5,
及其旋光异构体和外消旋物。
式(I)的化合物可以,取决于取代基的类型和数目,任选地以几何异构体和/或旋光异构体或区域异构体或各种组成的异构体的混合物形式存在。纯异构体和异构体混合物均按照本发明提出权利要求。
按照本发明的二氧代吗啉通常定义为式(I)。
R1优选代表氢、溴、氯、氟、氰基、硝基、三(C1-C6烷基)甲硅烷基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、-S(O)rR或苯基,其中苯基任选地含有一个或多个相同或不同的W1取代基,
R2优选代表氢、溴、氯、氟、氰基、硝基、三(C1-C6烷基)甲硅烷基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、-S(O)rR或苯基,其中苯基任选地含有一个或多个相同或不同的W1取代基,
R3优选代表C1-C6烷基,它可任选地被C1-C6卤代烷基或C1-C6烷氧基取代,
R4优选代表C1-C6烷基,它可任选地被C1-C6卤代烷基或C1-C6烷氧基取代,
R3和R4也可以优选合起来代表C3-C8亚烷基,-(CH2)-O-(CH2)-或-(CH2)2-O-(CH2)2-,在每种情况下它都可以任选地被氟、氯、溴、C1-C6烷基或C1-C6烷氧基单或多取代,由此形成一个螺环基团,
R5优选代表氢、C1-C6烷基或苄基或苯基,其中苄基和苯基任选地含有一个或多个相同或不同的W1取代基,
R优选代表C1-C6烷基或C1-C6卤代烷基,
m优选代表0、1、2、3或4,
n优选代表0、1、2、3或4,
r优选代表0、1或2,
W1优选代表氢、溴、氯、氟、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、-S(O)rR、氰基或硝基,
R1特别优选代表氢、溴、氯、氟、氰基、三(C1-C4烷基)甲硅烷基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、-S(O)rR或苯基,其中苯基任选地含有一个或多个相同或不同的W1取代基,
R2特别优选代表氢、溴、氯、氟、氰基、三(C1-C4烷基)甲硅烷基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、-S(O)rR或苯基,其中苯基任选地含有一个或多个相同或不同的W1取代基,
R3特别优选代表C1-C4烷基,它可任选地被C1-C4卤代烷基或C1-C4烷氧基取代,
R4特别优选代表C1-C4烷基,它可任选地被C1-C4卤代烷基或C1-C4烷氧基取代,
R3和R4也可以特别优选合起来代表C3-C6亚烷基,-(CH2)-O-(CH2)-或-(CH2)2-O-(CH2)2-,在每种情况下它都可以任选地被氟、氯、溴、C1-C4烷基或C1-C4烷氧基单或多取代,由此形成一个螺环基团,
R5特别优选代表氢、C1-C4烷基或苄基或苯基,其中苄基和苯基任选地含有一个或多个相同或不同的W1取代基,
R特别优选代表C1-C4烷基或C1-C4卤代烷基,
m特别优选代表0、1、2或3,
n特别优选代表0、1、2或3,
r特别优选代表0、1和2,
W1特别优选代表氢、溴、氯、氟、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、-S(O)rR、氰基或硝基,
R1非常特别优选代表氢、溴、氯、氟、氰基、硝基、三甲基甲硅烷基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、三氟甲基、三氟乙基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、三氟甲氧基、三氟乙氧基、-SCH3、-SC2H5、-SOCH3、-SOC2H5、-SO2CH3、-SO2C2H5或苯基,其中苯基任选地含有一个或多个相同或不同的W1取代基,
R2非常特别优选代表氢、溴、氯、氟、氰基、硝基、三甲基甲硅烷基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、三氟甲基、三氟乙基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、三氟甲氧基、三氟乙氧基、-SCH3、-SC2H5、-SOCH3、-SOC2H5、-SO2CH3、-SO2C2H5或苯基,其中苯基任选地含有一个或多个相同或不同的W1取代基,
R3非常特别优选代表甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、三氟甲基、三氟乙基、-CH2CH2OCH3或-CH2CH2OCH2CH3,
R4非常特别优选代表甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、三氟甲基、三氟乙基、-CH2CH2OCH3或-CH2CH2OCH2CH3,
R3和R4也可以非常特别优选合起来代表环丙基、环丁基、环戊基、环己基、甲基环己基、甲氧基环己基、乙氧基环己基、-(CH2)2-O-(CH2)2-或-(CH2)2-O-CH(CH3)CH2一,由此形成一个螺环基团,
R5非常特别优选代表氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,或苄基或苯基,其中苄基和苯基任选地含有一个或多个相同或不同的W1取代基,
m非常特别优选代表0、1或2,
n非常特别优选代表0、1或2,
W1非常特别优选代表氢、溴、氯、氟、氰基、硝基、三甲基甲硅烷基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、三氟甲基、三氟乙基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、三氟甲氧基、三氟乙氧基、-SCH3、-SC2H5、-SOCH3、-SOC2H5、-SO2CH3、-SO2C2H5、氰基或硝基。
为制备式(I)的化合物,式(II)的化合物在一种脱水剂(或偶联剂)的作用下并任选地在一种溶剂和任选的一种碱存在下,按照下列方式进行分子内的内酯化反应:
优选的脱水剂是酸,例如4-甲苯磺酸、甲烷磺酸或三氟甲烷磺酸。它们可以催化量或过量使用。
烃类例如甲苯,或者含有卤素的溶剂,例如1,2-二氯乙烷,优选用作溶剂。反应温度优选20-200℃,且特别优选60-120℃(参考文献,G.Kardassis等人,Tetrahedron1998,54,3479)。
还可以使用所谓的肽偶联剂,例如氯代甲酸异丁酯。诸如CDI、DCC、EDCI、BOP、BOP-Cl和DEAD/Ph3P的试剂也是适合的。
叔胺,例如N-甲基吗啉优选用作辅助碱。优选的稀释剂是含有卤素的溶剂,例如二氯甲烷。也可以使用THF、DMF和CH3CN。反应温度优选-30℃~+60℃,特别优选-20℃~+40℃。
式(II)的化合物通过按照下列方式水解式(III)的酯来制备:
碱金属氢氧化物,例如氢氧化钠优选用来水解。优选的稀释剂是醇类,例如甲醇,或者二恶烷或水或它们的混合物。反应温度优选-10℃~+60℃,特别优选0℃~+30℃。
式(III)的化合物可以通过按照下列方式将式(IV)的β-内酰胺与式(V)的α-氨基酯反应来制备:
式(V)的α-氨基酯是已知的或者可以通过已知方法来制备(参见,例如Houben-Weyl,Methoden der organischen Chemie/Methodsof Organic Chemistry(有机化学方法))。它们可以作为游离碱或盐酸盐使用。该反应通常在一种碱和一种稀释剂存在下进行。合适的碱是碱金属碳酸盐或碱金属碳酸氢盐以及碱金属氢氧化物和叔胺,后者是优选的;可以提及的一个例子是N-甲基吗啉。合适的溶剂是烃类、THF、CH3CN、二噁烷或卤代烃,后者是优选的;二氯甲烷可以作为一个例子提及。优选的反应温度是0℃~+120℃,特别优选20℃~+60℃(参考文献,I.Ojima等人,J.Org.Chem.1994,59,1249;C.Palomo等人,J.Chem.Soc.Chem.Comm.1994,1957)。
式(IV)的β-内酰胺可以通过已知方法制备(参考文献,V.Srirajan等人,Tetrahedron Asymmetry1996,7,2733),即通过式(VI)的N-甲苯磺酰基亚胺和乙酰氧基乙烯酮的[2+2]-环加成反应。乙酰氧基乙烯酮按照下列方式通过乙酰氧基乙酰氯的碱诱导脱氢脱卤素反应来原位制备:
叔胺,例如三乙胺优选用作碱。含有卤素的溶剂,例如二氯甲烷优选使用。反应温度优选-40℃~+60℃,特别优选-20℃~+30℃。
乙酰氧基乙酰氯是已知的并且已商品化。
式(VI)的甲苯磺酰基亚胺是部分已知的,或者它们可以用已知方法按照下列方式通过式(VII)的芳基磺酰胺与式(VIII)的苯甲醛或苯甲醛缩乙醛的缩合反应来制备(参考文献,V.Srirajan等人,Tetrahedron Asymmetry1996,7,2733):
式(VII)和式(VIII)的化合物是部分商品化的,或者它们可以用已知方法来制备(例如参见Houben-Weyl,Methoden derorganischen Chemie/Methods of Organic Chemistry(有机化学方法))。
该活性化合物对温血动物具有适当程度的毒性,并且适用于攻击病原性内寄生物,该内寄生物产生在人体和在饲养与繁殖动物期间、在牲畜、动物园中的动物、实验室动物、实验用动物和动物宠物中。这些化合物具有抗病虫害的所有或个别发展阶段的活性,并且具有抗抵抗性和正常敏感种的活性。攻击病原性内寄生物的目的是为了减少疾病、死亡和产率的降低(例如在生产肉类、奶、羊毛、皮革、蛋、蜂蜜之类时),并且使用此活性化合物可以使动物饲养更加经济和简单。病原性内寄生物包括绦虫、吸虫、线虫和棘头虫,以及特别是:
由假叶目的次序,例如裂头绦虫属物种、叠宫绦虫属物种、裂首绦虫属物种、舌状绦虫属物种、突盘绦虫属物种以及Diphlogonoporus物种。
由圆叶目的次序,例如中植孔绦虫属物种、裸头绦虫属物种、副裸头绦虫属物种、蒙尼绦虫属物种、繸体绦虫属物种、繸体绦虫属物种、无卵黄腺绦虫属物种、斯泰绦虫属物种、锡带绦虫属物种、安氏绦虫属物种、伯特绦虫属物种、带绦虫属物种、棘球绦虫属物种、无颈绦虫属物种、戴维绦虫属物种、瑞立绦虫属物种、膜壳绦虫属物种、Echinolepis物种、Echinocotyle物种、双睾绦虫属物种、复孔绦虫属物种、Joyeuxiella物种和复孔绦虫属物种。
由单殖亚纲的亚类,例如三代虫属物种、指环虫属物种和多盘吸虫属物种。
由复殖亚纲的亚类,例如双穴吸虫属物种、茎双穴吸虫属物种、血吸虫属物种、毕吸虫属物种、鸟毕吸虫属物种、澳毕吸虫属物种、巨毕吸虫属物种、彩蚴吸虫属物种、短咽吸虫属物种、棘口吸虫属物种、棘缘吸虫属物种、棘隙吸虫属物种、低颈吸虫属物种、片吸虫属物种、拟片吸虫属物种、姜片吸虫属物种、环肠吸虫属物种、盲腔吸虫属物种、同吸盘吸虫属物种、杯殖吸虫属物种、殖盘吸虫属物种、巨盘吸虫属物种、菲策吸虫属物种、腹袋吸虫属物种、背孔吸虫属物种、下弯吸虫属物种、斜睾吸虫属物种、前殖吸虫属物种、双腔吸虫属物种、阔盘吸虫属物种、隐孔吸虫属物种、并殖吸虫属物种、肛瘤吸虫属物种、小叶吸虫属物种、后睾吸虫属物种、支睾吸虫属物种、次睾吸虫属物种、异形吸虫属物种以及后殖吸虫属物种。
由Enoplida的次序,例如鞭虫属物种、毛细线虫属物种、Trichomosoides物种、毛线虫属物种。
由小杆科的次序,例如Micronema物种和类圆线虫属物种。
由圆线虫科的次序,例如圆线虫属物种、三齿线虫属物种、食道齿线虫属物种、毛线线虫属物种、Gyalocephalus物种、筒咽线虫属物种、杯口线虫属物种、Cyclococercus物种、Cylicostephanus物种、结节线虫属物种、夏柏线虫属物种、肾线虫属物种、钩口线虫属物种、弯口线虫属物种、Bunostomum物种、球头线虫属物种、比翼线虫属物种、杯口线虫属物种、后圆线虫属物种、网尾线虫属物种、缪氏线虫属物种、原圆肺虫属物种、Neostrongylus物种、囊尾线虫属物种、肺圆线虫属物种、尖尾线虫属物种、Elaphostrongylus物种、Parelaphostrongylus物种、Crenosoma物种、Paracrenosoma物种、鼠肺线虫属物种、Aelurostrongylus物种、Filaroides物种、Parafilaroides物种、毛圆线虫属物种、血矛线虫属物种、奥斯特线虫属物种、马歇尔线虫属物种、古柏线虫属物种、细颈线虫属物种、舌圆线虫属物种、尖柱线虫属物种、裂口线虫属物种和盘头线虫属物种。
由尖尾科的次序,例如尖尾线虫属物种、蛲虫属物种、栓尾线虫属物种、管状线虫属物种、无刺线虫属物种和异刺线虫属物种。
由蛔科的次序,例如蛔虫属物种、弓蛔线虫属物种、弓蛔虫属物种、副蛔虫属物种、异尖线虫属物种和鸡蛔虫属物种。
由旋尾科的次序,例如颚口线虫属物种、泡翼线虫属物种、吸吮线虫属物种、筒线虫属物种、 胃线虫属物种、副柔线虫属物种、Draschia物种和龙线虫属物种。
由丝虫科的次序,例如冠丝虫属物种、副丝虫属物种、腹腔丝虫属物种、罗阿丝虫属物种、恶丝虫属物种、光丝虫属物种、布鲁丝虫属物种、吴策丝虫属物种和盘尾丝虫属物种。
由巨吻棘头虫属的次序,例如Filicollis物种、念珠棘头虫属物种、巨吻棘头虫属物种和前巨睾棘头虫属物种。
牲畜和育种动物包括哺乳动物,例如牛、马、绵羊、猪、山羊、骆驼、水牛、驴、兔、小鹿和驯鹿,利用毛皮的动物例如貂、栗鼠和浣熊,禽类例如鸡、鹅、火鸡和鸭,淡水鱼及海水鱼例如鳟鱼、鲤鱼和鳗鲡,爬行动物及昆虫例如蜜蜂和蚕。
实验室及实验动物包括大鼠、小鼠、豚鼠、金地鼠、狗和猫。
宠物动物包括狗和猫。
此化合物可以在预防和治疗两方面使用。
此活性化合物直接使用或者以适当配方的形式使用,通过环境的处理或在含有此活性化合物的成形制品协助下,例如条、盘、带、环、耳朵标签、四肢上的带子或标记设备,以肠道、不经肠的、皮肤、鼻等方式使用。
此活性化合物的经肠道给药以例如口服粉末、片剂、胶囊、饮剂、粒剂、适合于口服的溶液、悬浮液以及乳液、boli、含药的饲料或饮用水的形式进行。经皮肤给药以例如浸渍、喷雾或灌注或点斑的方式进行。不经肠给药以例如注射(肌肉、皮下、静脉或腹膜)或通过移植的方式进行。
合适的配方如下:
溶液例如注射溶液、口服溶液、稀释后的口服液浓缩物、用于皮肤上或体腔中的溶液、灌注配方或凝胶;
口服或经皮肤给药以及注射用的乳液和悬浮液;半固体配方;
此活性化合物加入到软膏基料中或加入到水包油或油包水乳液基料中的配方;
固体配方,例如粉末、预混物或浓缩物、颗粒、丸剂、片剂、boli、胶囊;气溶胶和气雾剂产品以及含有活性化合物的成形制品。
注射溶液以静脉、肌肉和皮下方式给药。注射溶液通过将此活性化合物溶解在适当溶剂中,并可能加入添加剂如增溶剂、酸、碱、缓冲盐、抗氧化剂和防腐剂来制备。该溶液经无菌过滤后置于容器中。
可以提及的溶剂有:生理上相容的溶剂如水、醇如乙醇、丁醇、苯甲醇、甘油、丙二醇、聚乙二醇、N-甲基吡咯烷酮和它们的混合物。
如果恰当,此活性化合物还可以溶解在生理上相容的、适于注射的蔬菜油或合成油。
可以提及的增溶剂是:促进此活性化合物在主要溶剂中的溶解或者防止其沉淀的溶剂。例子有聚乙烯基吡咯烷酮、聚氧乙基化蓖麻油和聚氧乙基化山梨醇酯。
防腐剂是:苯甲醇、三氯丁醇、对羟基苯甲酸酯和正丁醇。
口服溶液直接给药。浓缩物在稀释到使用浓度后再口服。口服溶液和浓缩物如上所述制备成注射用溶液,但是可以无须无菌条件。
皮肤用溶液以滴加、铺展、擦拭、喷雾或喷洒的方式使用。这些溶液如上所述制备成注射用溶液。
在制备期间加入增稠剂可能是有利的,增稠剂有:无机增稠剂如膨润土、胶态硅石、单硬脂酸铝,有机增稠剂如纤维素衍生物、聚乙烯醇和共聚物、丙烯酸酯及其甲基丙烯酸酯。
凝胶涂敷或铺展在皮肤上或加入到体腔中。凝胶通过加入如上所述已经制备成注射用溶液的溶液,一定量的增稠剂来制备,以形成软膏状稠度的清澈块状物,所使用的增稠剂是如上所述的增稠剂。
灌注配方被灌注或喷洒到皮肤指定区域,活性化合物穿透皮肤并系统地起作用。
灌注配方通过将此活性化合物溶解、悬浮或乳化到适当的皮肤相容性溶剂或溶剂混合物中来制备。如果需要,也可加入其它辅助剂如着色剂、促吸收物质、抗氧化剂、光保护剂和粘合剂。
可以提及的溶剂有:水、链烷醇、二醇、聚乙二醇、聚丙二醇、甘油、芳香族醇如苯甲醇、苯乙醇、苯氧乙醇、酯类如乙酸乙酯、乙酸丁酯、苯甲酸苯甲酯、醚类如烷撑二醇烷基醚如二丙二醇单甲基醚、二乙二醇单丁基醚、酮类如丙酮、甲基乙基酮、芳香族和/或脂肪族烃、蔬菜油或合成油、DMF、二甲基乙酰胺、N-甲基吡咯烷酮或2,2-二甲基-4-氧代-亚甲基-1,3-二氧戊环。
着色剂是可用于动物的所有着色剂,并且它们可以被溶解或悬浮。
促吸收物质是,例如DMSO、扩展性油如肉豆蔻酸异丙酯、壬酸二丙二醇酯、硅油、脂肪酸酯、三甘油酯和脂肪醇。
抗氧化剂是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、丁基羟基苯甲醚和生育酚。
光保护剂是,例如Novantisol酸。
粘合剂有,例如纤维素衍生物、淀粉衍生物、聚丙烯酸酯和天然聚合物如海藻酸盐和明胶。
乳液可以口服、经皮肤或以注射方式给药。
乳液或是油包水型或是水包油型。
它们通过将活性化合物溶解在疏水或亲水相中,然后将该相用其它相的溶剂均质化来制备,并在适当的时候辅以合适的乳化剂和其它辅助剂如着色剂、促吸收物质、防腐剂、抗氧化剂、光保护剂和增加粘度的物质。
以下物质可作为疏水相(油)提及:石蜡油、硅油、天然蔬菜油如芝麻油、杏仁油、蓖麻油、合成的三甘油酯如辛酸/癸酸二甘油酯、三甘油酯与链长C8-12的蔬菜脂肪酸或者其它特别选定的天然脂肪酸的混合物、饱和或不饱和脂肪酸(可能还含有羟基基团)的部分甘油酯混合物、以及C8/C10脂肪酸的单和二甘油酯。
脂肪酸酯如硬脂酸乙酯、己二酸二正丁酯、月桂酸己酯、壬酸二丙二醇酯、链长中等的支化脂肪酸与链长C16-C18的饱和脂肪醇的酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、链长C12-C18的饱和脂肪醇的辛酸/癸酸酯、硬脂酸异丙酯、油酸油基酯、油酸癸酯、油酸乙酯、乳酸乙酯、蜡状脂肪酸酯如合成的鸭尾臀腺脂肪、邻苯二甲酸二丁酯、己二酸二异丙酯以及涉及后者的酯混合物等。
脂肪醇,如异三癸基醇、2-辛基十二烷醇、十六烷基硬脂醇和油醇。
脂肪酸,如油酸及其混合物。
以下可以作为亲水相提及:
水、醇例如丙二醇、甘油、山梨醇和它们的混合物。
以下可以作为乳化剂提及:非离子型表面活性剂例如聚氧乙基化蓖麻油、聚氧乙基化山梨醇单油酸酯、山梨醇单硬脂酸酯、甘油单硬脂酸酯、聚氧乙基硬脂酸酯和烷基苯酚聚乙二醇醚。
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、脂肪醇醚硫酸盐和单/二烷基聚乙二醇醚正磷酸酯的单乙醇胺盐。
此外可以提及的辅助剂有:增加粘度和稳定乳化的物质,如羧甲基纤维素、甲基纤维素和其它纤维素以及淀粉衍生物、聚丙烯酸酯、海藻酸盐、明胶、阿拉伯树胶、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、胶态硅石或以上物质的混合物。
悬浮液可以口服、经皮肤或注射给药。它们通过将活性化合物悬浮在载体液中来制备,同时任选地另外加入辅助剂如湿润剂、着色剂、促吸收物质、防腐剂、抗氧化剂和光保护剂。
可以提及的载体液是所有均匀溶剂和溶剂混合物。
可以提及的湿润剂(分散剂)是以上提及的表面活性剂。
此外可以提及的辅助剂是以上提及的那些。
半固体制剂可以口服或经皮肤给药。它们与上述悬浮液和乳液的不同之处仅在于其粘度较高。
对于固体配方的制剂,活性化合物与适当的载体物质混合,任选地混以附加的辅助剂,然后制成所需形式。
可以提及的载体物质是所有生理相容的固体惰性物质。它们可以是无机和有机物。无机物例如是普通的盐、碳酸盐如碳酸钙、碳酸氢盐、氧化铝、硅酸、粘土、沉淀或胶态二氧化硅以及磷酸盐。
有机物例如是糖、纤维素、食品和饲料如奶粉、动物粉、精或粗的谷物粉以及淀粉。
辅助物质有防腐剂、抗氧化剂和着色剂,这些都已经在上面列出来了。
此外合适的辅助剂有润滑剂和滑爽剂例如硬脂酸镁、硬脂酸、滑石、膨润土、促崩解物质如淀粉或交联的聚乙烯基吡咯烷酮、粘结剂例如淀粉、明胶或线型聚乙烯基吡咯烷酮和干燥的粘结剂如微晶纤维素。
活性化合物也可以在配方中作为与增效剂或与其它具有抗病原性内寄生物作用的活性化合物的混合物存在,这些活性化合物例如是L-2,3,5,6-四羟基-6-苯基咪唑并噻唑、苯并咪唑氨基甲酸酯、吡喹酮、噻嘧啶和febantel.
现成的配方中此活性化合物的含量浓度为10ppm~20重量%,优选0.1~10重量%。
使用前稀释的配方中此活性化合物的含量浓度为0.5~90重量%,优选5-50重量%。
已经证实为了获得有效的结果,通常每日服用约1~约100mg此活性化合物/kg体重是有利的。
没有抗内寄生物作用或者只有轻微抗内寄生物作用的式(I)化合物适合用作制备高效活性化合物的有利中间体。
实施例:
制备实施例
实施例VI-1
苯甲醛二甲基乙缩醛(8.24g,0.12摩尔)和对甲苯磺酰胺(17.10g,0.10摩尔)加热到120-130℃,并连续蒸馏掉甲醇。反应经过4小时后,此混合物冷却到室温,然后残留物从甲苯/甲基叔丁基醚中重结晶。
产率=21.20g,理论值的82%,
熔点=85-87℃。
按类似方式制备以下式(VI)的化合物:
实施例编号 | R1 | R2 | 熔点/℃ |
VI-2 | 4-OMe | 4-OMe | 147-148 |
VI-3 | 4-Br | 4-OMe | 149-150 |
VI-4 | 4-F | 4-OMe | 97-98 |
VI-5 | 4-Me | H | 138-139 |
VI-6 | H | 4-Cl | 107-110 |
实施例编号 | R1 | R2 | 熔点/℃ |
VI-7 | 4-Me | 4-Cl | 134 |
VI-8 | H | 4-OMe | 108-109 |
VI-9 | 4-Me | 4-Me | 119-121 |
VI-10 | 4-C1 | H | 194-196 |
VI-11 | 4-Cl | 4-Me | 178-179 |
VI-12 | 4-Cl | 4-Cl | 169-170 |
VI-13 | 4-F | H | 122-124 |
VI-14 | 4-Br | H | 205-206 |
VI-15 | H | 4-F | 77-78 |
VI-16 | H | 4-Br | 120-122 |
VI-17 | 2,4-Cl2 | H | 142 |
VI-18 | 4-F | 4-Me | 117-118 |
实施例IV-1
N-对甲苯磺酰基-苄二亚胺(2.59g,10.00mmol)和三乙胺(1.31g,13.00mmol)最初加入到二氯甲烷(20ml)中,并冷却至-20℃。缓慢滴加乙酰氧基乙酰氯(1.64g,12.00mmol)在二氯甲烷(8ml)中的溶液,然后此混合物在室温下搅拌过夜。用0.1N盐酸(20ml)、饱和碳酸氢钠水溶液(20ml)和水(20ml)依次洗涤反应溶液。有机相用硫酸钠干燥,过滤并在旋转蒸发器中真空蒸发,粗产物用硅胶色谱术纯化(洗脱液:二氯甲烷/正己烷,1∶1,v/v),然后重结晶(二氯甲烷/正己烷)。
得到1.90g(理论值的53%)的顺-1-(对甲苯磺酰基)-3-乙酰氧基-4-苯基乙酸乙酯-2-酮。熔点:135℃。
类似地制备以下式(IV)的化合物:
实施例编号 | R1 | R2 | 熔点/℃ |
IV-2 | 4-OMe | 4-OMe | 148 |
IV-3 | H | H | 107-108 |
IV-4 | 4-Me | H | 113-115 |
IV-5 | H | 4-Cl | 1154-155 |
IV-6 | 4-Me | 4-Cl | —— |
IV-7 | H | 4-OMe | 94-95 |
IV-8 | 4-Me | 4-Me | 99-101 |
IV-9 | 4-Cl | H | 147-149 |
IV-10 | 4-Cl | 4-Me | 108-111 |
IV-11 | 4-Cl | 4-Cl | 159 |
IV-12 | 4-Br | H | 130-131 |
IV-13 | 4-F | H | 135 |
IV-14 | H | 4-F | 109-110 |
IV-15 | H | 4-Br | 114-115 |
IV-16 | 4-F | 4-Me | 166 |
实施例III-1
顺-1-(对甲苯磺酰基)-3-乙酰氧基-4-苯基乙酸乙酯-2-酮(1.80g,5.00mmol)、氨基异丁酸甲酯盐酸盐(0.92g,6.00mmol)和N-甲基吗啉(0.61g,6.00mmol)在二氯甲烷(25ml)中室温下搅拌过夜。反应溶液用水(20ml)洗涤,有机相用硫酸钠干燥,过滤并在旋转蒸发器中真空蒸发,粗产物用重结晶从乙酸乙酯中纯化。
得到1.69g(理论值的71%)的N-(甲苯磺酰基)-O-乙酰基-3-苯基异丝氨酰基-2,2-二甲基甘氨酸甲酯。熔点:175-176℃。
按类似方式制备以下式(III)的化合物:
实施例编号 | R1 | R2 | R3 | R4 | R5 | 熔点/℃ |
III-2 | H | H | Me | Me | H | 177-180 |
III-3 | H | H | 环己基 | H | 184-186 | |
III-4 | H | H | 2-甲基-四羟基吡喃基 | H | 180-184 | |
III-5 | H | H | 4-甲氧基环己基 | H | 204-207 | |
III-6 | H | H | 4-乙氧基环己基 | H | 199-204 | |
III-7 | H | 4-Me | 4-甲基环己基 | H | 172-173 | |
III-8 | H | 4-Me | 环己基 | H | 196-197 | |
III-9 | 4-Me | H | 2-甲基-四羟基吡喃基 | H | 186-189 | |
III-10 | 4-Me | H | 4-甲氧基环己基 | H | 16I-162 | |
III-11 | 4-Me | H | 4-甲基环己基 | H | 182-183 | |
III-12 | 4-Me | H | Me | Me | H | 155-157 |
III-13 | 4-Me | H | 环己基 | H | 191-194 | |
III-14 | 4-Me | H | 4-乙氧基环己基 | H | 162-164 | |
III-15 | H | 4-Cl | Me | Me | H | 180-183 |
III-16 | H | 4-Cl | 环己基 | H | 194-195 | |
III-17 | H | 4-Cl | 2-甲基-四羟基吡喃基 | H | —— | |
III-18 | H | 4-Cl | 4-甲氧基环己基 | H | 168-169 | |
III-19 | H | 4-Cl | 4-甲基环己基 | H | 189-190 | |
III-20 | H | 4-Cl | 4-乙氧基环己基 | H | 183-184 | |
III-21 | H | 4-Me | 2-甲基-四羟基吡喃基 | H | 195-196 |
实施例编号 | R1 | R2 | R3 | R4 | R5 | 熔点/℃ |
III-22 | H | 4-Me | 4-甲氧基环己基 | H | —— | |
III-23 | H | 4-Me | 4-乙氧基环己基 | H | 178-179 | |
III-24 | 4-Me | 4-Cl | Me | Me | H | 167-168 |
III-25 | 4-Me | 4-Cl | 环己基 | H | 177-178 | |
III-26 | 4-Me | 4-Cl | 4-甲基环己基 | H | 212-213 | |
III-27 | 4-Me | 4-Cl | 4-甲氧基环己基 | H | 193-194 | |
III-28 | 4-Me | 4-Cl | 4-乙氧基环己基 | H | 188-190 | |
III-29 | 4-Me | 4-Cl | 2-甲基-四羟基吡喃基 | H | 204-205 | |
III-30 | 4-Me | 4-Me | 4-甲基环己基 | H | 181-182 | |
III-31 | 4-Me | 4-Me | 环己基 | H | —— | |
III-32 | 4-Me | 4-Me | 2-甲基-四羟基吡喃基 | H | 181-182 | |
III-33 | 4-Me | 4-Me | 4-甲氧基环己基 | H | 142-143 | |
III-34 | H | 4-OMe | Me | Me | H | 163-164 |
III-35 | H | 4-OMe | 环己基 | H | 185-186 | |
III-36 | H | 4-OMe | 4-甲基环己基 | H | 207-208 | |
III-37 | H | 4-OMe | 4-甲氧基环己基 | H | 199-202 | |
III-38 | H | 4-OMe | 2-甲基-四羟基吡喃基 | H | 194-195 | |
III-39 | 4-Me | 4-Me | Me | Me | H | 153-155 |
III-40 | 4-Cl | H | 4-甲氧基环己基 | H | 126-129 | |
III-41 | 4-Cl | H | 4-甲基环己基 | H | 184-185 | |
III-42 | 4-Cl | H | Me | Me | H | 112-115 |
III-43 | 4-Cl | H | 环己基 | H | 159-161 | |
III-44 | 4-Cl | 4-Me | 4-甲氧基环己基 | H | 168-170 | |
III-45 | 4-Cl | 4-Me | 4-甲基环己基 | H | 204-207 | |
III-46 | 4-Cl | 4-Me | Me | Me | H | 146-148 |
III-47 | 4-Cl | 4-Me | 环己基 | H | 155-156 | |
III-48 | 4-Cl | 4-Cl | 4-甲氧基环己基 | H | 207-210 | |
III-49 | 4-Cl | 4-Cl | 4-甲基环己基 | H | 238-239 | |
III-50 | 4-Cl | 4-Cl | Me | Me | H | 184-185 |
实施例编号 | R1 | R2 | R3 | R4 | R5 | 熔点/℃ |
III-51 | 4-Br | H | Me | Me | H | 168 |
III-52 | 4-Br | H | 环己基 | H | 182-185 | |
III-53 | 4-F | H | 4-甲基环己基 | H | 189-192 | |
III-54 | 4-F | H | Me | Me | H | 162 |
III-55 | 4-F | H | 环己基 | H | 158-159 | |
III-56 | H | 4-F | Me | Me | H | 168 |
III-57 | H | 4-Br | 4-甲基环己基 | H | 192-194 | |
III-58 | H | 4-F | 环己基 | H | 178-179 | |
III-59 | H | 4-Br | Me | Me | H | 179-180 |
III-60 | H | 4-Br | 环己基 | H | 199-200 | |
III-61 | 4-Br | H | 4-甲基环己基 | H | 215-216 | |
III-62 | 4-F | 4-Me | 4-甲基环己基 | H | —— | |
III-63 | 4-F | 4-Me | Me | Me | H | 155-158 |
III-64 | 4-F | 4-Me | 环己基 | H | 91-94 |
实施例II-1
N-(甲苯磺酰基)-3-苯基异丝氨酰基-2,2-二甲基甘氨酸
N-(甲苯磺酰基)-0-乙酰基-3-苯基异丝氨酰基-2,2-二甲基甘氨酸甲酯(1.60g,3.36mmol)在室温下加入到氢氧化钠(0.50g,12.6mmol)在水(30ml)的溶液中,然后在此温度下搅拌4小时。pH值用2N盐酸调节到pH为2-3,然后反应溶液用乙酸乙酯(3×50ml)萃取。有机相用硫酸钠干燥,过滤并在旋转蒸发器中真空蒸发。
得到1.30g(理论值的92%)的N-(甲苯磺酰基)-3-苯基异丝氨酰基-2,2-二甲基甘氨酸。
该粗产物进一步反应而不纯化。
类似地制备以下式(II)的化合物:
实施例编号 | R1 | R2 | R3 | R4 | R5 | 熔点/℃ |
II-2 | H | H | Me | Me | H | 176-178 |
II-3 | H | H | 4-甲氧基环己基 | H | 194-196 | |
II-4 | H | H | 2-甲基-四羟基吡喃基 | H | 184-186 | |
II-5 | H | H | 环己基 | H | 206-207 | |
II-6 | H | H | 4-甲基环己基 | H | 208-210 | |
II-7 | H | H | 4-乙氧基环己基 | H | 146-149 | |
II-8 | H | 4-Me | 4-甲基环己基 | H | 214-216 | |
II-9 | H | 4-Me | 环己基 | H | 194-195 | |
II-10 | 4-Me | H | 2-甲基-四羟基吡喃基 | H | 26-131 | |
II-11 | 4-Me | H | 4-甲氧基环己基 | H | 153-156 | |
II-12 | 4-Me | H | 4-甲基环己基 | H | 190-191 | |
II-13 | 4-Me | H | Me | Me | H | 197-198 |
II-14 | 4-Me | H | 环己基 | H | 177-179 | |
II-15 | 4-Me | H | 4-乙氧基环己基 | H | 156-157 | |
II-16 | H | 4-Cl | Me | Me | H | 195-196 |
II-17 | H | 4-Cl | 4-乙氧基环己基 | H | 189-190 | |
II-18 | H | 4-Cl | 环己基 | H | 208-209 | |
II-19 | H | 4-Cl | 2-甲基-四羟基吡喃基 | H | 147-149 | |
II-20 | H | 4-Cl | 4-甲氧基环己基 | H | 216-217 | |
II-21 | H | 4-Cl | 4-甲基环己基 | H | 217-220 | |
II-22 | H | 4-Me | 4-甲氧基环己基 | H | 213-214 | |
II-23 | H | 4-Me | 4-乙氧基环己基 | H | 186-187 | |
II-24 | H | 4-Me | 2-甲基-四羟基吡喃基 | H | 159-161 | |
II-25 | 4-Me | 4-Cl | Me | Me | H | 179-180 |
II-26 | 4-Me | 4-Me | 4-甲氧基环己基 | H | 163-164 | |
II-27 | 4-Me | 4-Me | 2-甲基-四羟基吡喃基 | H | 148-53 | |
II-28 | 4-Me | 4-Cl | 环己基 | H | 150-151 | |
II-29 | 4-Me | 4-Cl | 4-甲基环己基 | H | 209-210 |
实施例编号 | R1 | R2 | R3 | R4 | R5 | 熔点/℃ |
II-30 | 4-Me | 4-Cl | 4-甲氧基环己基 | H | 178-179 | |
II-31 | 4-Me | 4-Cl | 4-乙氧基环己基 | H | 180-182 | |
II-32 | 4-Me | 4-Cl | 2-甲基-四羟基吡喃基 | H | 148-152 | |
II-33 | H | 4-OMe | Me | Me | H | 209-211 |
II-34 | H | 4-OMe | 环己基 | H | 182-184 | |
II-35 | H | 4-OMe | 4-甲基环己基 | H | 205-207 | |
II-36 | H | 4-OMe | 4-甲氧基环己基 | H | 211-213 | |
II-37 | H | 4-OMe | 2-甲基-四羟基吡喃基 | H | 127-128 | |
II-38 | 4-Me | 4-Me | 4-甲基环己基 | H | 211-213 | |
II-39 | 4-Me | 4-Me | 环己基 | H | 113-115 | |
II-40 | 4-Me | 4-Me | Me | Me | H | 204 |
II-41 | 4-Cl | H | 4-甲基环己基 | H | 207 | |
II-42 | 4-Cl | H | Me | Me | H | 212-214 |
II-43 | 4-Cl | H | 环己基 | H | 135 | |
II-44 | 4-Cl | H | 4-甲氧基环己基 | H | 102 | |
II-45 | 4-Cl | 4-Me | 4-甲氧基环己基 | H | 109 | |
II-46 | 4-Cl | 4-Me | 4-甲基环己基 | H | 218-220 | |
II-47 | 4-Cl | 4-Me | 环己基 | H | 151-152 | |
II-48 | 4-Cl | 4-Me | Me | Me | H | 187-189 |
II-49 | 4-Cl | 4-Cl | 4-甲氧基环己基 | H | 185-186 | |
II-50 | 4-Cl | 4-Cl | 4-甲基环己基 | H | 230-231 | |
II-51 | 4-Cl | 4-Cl | Me | Me | H | 191-192 |
II-52 | 4-Br | H | Me | Me | H | 232 |
II-53 | 4-Br | H | 环己基 | H | 143-144 | |
II-54 | 4-F | H | 4-甲基环己基 | H | 214-215 | |
II-55 | 4-F | H | Me | Me | H | 200-202 |
II-56 | 4-F | H | 环己基 | H | 197 | |
II-57 | H | 4-F | Me | Me | H | 220-221 |
实施例编号 | R1 | R2 | R3 | R4 | R5 | 熔点/℃ |
II-58 | H | 4-Br | Me | Me | H | 124-125 |
II-59 | H | 4-F | 环己基 | H | 206-207 | |
II-60 | H | 4-Br | 环己基 | H | 205-207 | |
II-61 | H | 4-Br | 4-甲基环己基 | H | 235 | |
II-62 | 4-Br | H | 4-甲基环己基 | H | 195-199 | |
II-63 | 4-F | 4-Me | 4-甲基环己基 | H | 229 | |
II-64 | 4-F | 4-Me | Me | Me | H | 196 |
实施例1
6-(对甲苯磺酰基氨基甲基)-(α-苯基)-吗啉-3,3-二甲基-2,5-二酮
N-(甲苯磺酰基)-3-苯基异丝氨酰基-2,2-二甲基甘氨酸(1.20g,2.86mmol)、甲烷磺酸(0.20g,2.0mmol)和1,2-二氯甲烷(200ml)于索格利特抽提器中(含有一个3埃的分子筛)在回流下加热约16小时(或直至起始材料完全反应)。滤除脱水剂,溶剂在旋转蒸发器中真空蒸发掉。粗产物用重结晶从乙酸乙酯中纯化。
得到0.63g(理论值的55%)的6-(对甲苯磺酰基氨基甲基)-(α-苯基)-吗啉-3,3-二甲基-2,5-二酮。
类似地制备以下式(I)的化合物:
实施例编号 | R1 | R2 | R3 | R4 | R5 | 熔点/℃ |
2 | H | H | Me | Me | H | 214-216 |
3 | H | H | 4-乙氧基环己基 | H | 113-116 | |
4 | H | H | 4-甲基环己基 | H | 241-242 | |
5 | H | H | 环己基 | H | 206-207 | |
6 | H | 4-Me | 4-甲基环己基 | H | 217-219 | |
7 | H | H | 2-甲基-四羟基吡喃基-4-基 | H | 255-257 | |
8 | H | H | 4-甲氧基环己基 | H | 175-177 | |
9 | H | 4-Me | 环己基 | H | 223-225 | |
10 | H | 4-Cl | Me | Me | H | 223-224 |
11 | H | 4-Cl | 环己基 | H | 224-25 | |
12 | H | 4-Cl | 4-甲氧基环己基 | H | 201-203 | |
13 | H | 4-Cl | 2-甲基-四羟基吡喃基-4-基 | H | 115-116 | |
14 | H | 4-Cl | 4-甲基环己基 | H | 236-237 | |
15 | H | 4-Cl | 4-乙氧基环己基 | H | 185 | |
16 | H | 4-Me | 4-甲氧基环己基 | H | 213-214 | |
17 | H | 4-Me | 4-乙氧基环己基 | H | 177-180 | |
18 | H | 4-Cl | 2-甲基-四羟基吡喃基-4-基 | H | 187-190 | |
19 | 4-Me | H | 4-甲氧基环己基 | H | 146-147 | |
20 | 4-Me | H | 4-甲基环己基 | H | 224-226 | |
21 | 4-Me | H | Me | Me | H | 232-234 |
22 | 4-Me | H | 环己基 | H | 228 | |
23 | 4-Me | H | 4-乙氧基环己基 | H | 193-195 | |
24 | 4-Me | 4-Cl | 环己基 | H | 215-216 | |
25 | 4-Me | 4-Cl | 4-甲基环己基 | H | 248-249 | |
26 | 4-Me | 4-Cl | Me | Me | H | 231-232 |
27 | 4-Me | 4-Cl | 4-甲氧基环己基 | H | 232 | |
28 | 4-Me | 4-Cl | 4-乙氧基环己基 | H | 200-203 | |
29 | 4-Me | 4-Cl | 2-甲基-四羟基吡喃基-4-基 | H | 189-193 | |
30 | H | 4-OMe | Me | Me | H | 214-216 |
31 | H | 4-OMe | 环己基 | H | 241 | |
32 | H | 4-OMe | 4-甲基环己基 | H | 189-192 | |
33 | H | 4-OMe | 4-甲氧基环己基 | H | 155-157 | |
34 | H | 4-OMe | 2-甲基-四羟基吡喃基-4-基 | H | 194-196 | |
35 | 4-Me | 4-Me | 2-甲基-四羟基吡喃基-4-基 | H | 215 | |
36 | 4-Me | 4-Me | 4-甲氧基环己基 | H | 204-205 | |
37 | 4-Me | 4-Me | 4-甲基环己基 | H | 210-211 | |
38 | 4-Me | 4-Me | 环己基 | H | 210-211 | |
39 | 4-Me | 4-Me | Me | Me | H | 230-231 |
40 | 4-Me | H | 2-甲基-四羟基吡喃基-4-基 | H | 209 | |
41 | 4-Cl | H | 4-甲氧基环己基 | H | 228-231 | |
42 | 4-Cl | H | 环己基 | H | 228 | |
43 | 4-Cl | H | Me | Me | H | 224-225 |
44 | 4-Cl | 4-Me | 4-甲氧基环己基 | H | 226-229 | |
45 | 4-Cl | 4-Me | Me | Me | H | 200-204 |
46 | 4-Cl | 4-Me | 4-甲基环己基 | H | 245 | |
47 | 4-Cl | 4-Me | 环己基 | H | 226-227 | |
48 | 4-Cl | 4-Cl | 4-甲氧基环己基 | H | 218-221 | |
49 | 4-Cl | 4-Cl | 4-甲基环己基 | H | 260 | |
50 | 4-Cl | 4-Cl | Me | Me | H | 237-239 |
51 | 4-Br | H | Me | Me | H | 220-221 |
52 | H | 4-F | Me | Me | H | 219-220 |
53 | H | 4-Br | Me | Me | H | 229-230 |
54 | H | 4-Br | 环己基 | H | 215-218 | |
55 | H | 4-F | 环己基 | H | 252-254 | |
56 | 4-Br | H | 4-甲基环己基 | H | 252-253 | |
57 | 4-F | H | 4-甲基环己基 | H | 254 | |
58 | 4-F | H | 环己基 | H | 240-242 | |
59 | 4-F | H | Me | Me | H | 207-209 |
生物学实施例:
绵羊的线虫纲感染
检测该化合物对绵羊的捻转血矛线虫的抗蠕虫活性。卵减少测试被用作测试方法,其中确定被感染绵羊每克粪便中卵的数目,绵羊分为处理或未处理(对照)两组。
卵减少测试:绵羊(美利奴绵羊或黑头绵羊,体重23-35kg)用5000H.contortus(捻转血矛线虫)三级蚴蠕虫实验性地感染,然后在寄生虫的潜伏期结束时用测试化合物处理。测试化合物以明胶胶囊形式口服,测试物的抗蠕虫活性确定为绵羊排泄粪便中卵数目减少的函数。为了计算卵的数目,测试动物的粪便在新鲜状态下使用,并且按照由Wetzel改进的McMaster方法处理,测定每克粪便中卵的数目。卵的数目在处理前和处理后按规定的间隔测定。抗蠕虫活性表示为卵数目减少的函数,即卵数目的减少表示为相对于处理前排泄的卵数目的百分数。
化合物/实施例编号 | 活性[%] |
7 | 98.2 |
17 | 99.5 |
53 | 44.2 |
55 | 36.8 |
27 | 98.7 |
30 | 99.1 |
31 | 97.3 |
35 | 96.7 |
57 | 89.7 |
Claims (7)
1.式(I)的化合物其中R1代表氢、卤素、硝基、氰基、烷基、芳基、三烷基甲硅烷基、烷氧基或-S(O)rR,它们可任选地被取代,
R2代表氢、卤素、硝基、氰基、烷基、芳基、三烷基甲硅烷基、烷氧基或-S(O)rR,它们可任选地被取代,
R3代表任选地被取代的烷基,
R4代表任选地被取代的烷基或
R3和R4合起来代表一个螺环基团,它可任选地被取代,
R5代表氢、烷基、芳烷基或被取代的苯基,它可任选地被取代,
r代表0、1或2,
R代表任选被取代的烷基,
m代表0、1、2、3、4或5,
n代表0、1、2、3、4或5,
及其旋光异构体和外消旋物。
2.按照权利要求1的化合物,其中
R1代表氢、溴、氯、氟、氰基、硝基、三(C1-C6烷基)甲硅烷基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、-S(O)rR或苯基,其中苯基任选地含有一个或多个相同或不同的W1取代基,
R2代表氢、溴、氯、氟、氰基、硝基、三(C1-C6烷基)甲硅烷基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、-S(O)rR或苯基,其中苯基任选地含有一个或多个相同或不同的W1取代基,
R3代表C1-C6烷基,它可任选地被C1-C6卤代烷基或C1-C6烷氧基取代,
R4代表C1-C6烷基,它可任选地被C1-C6卤代烷基或C1-C6烷氧基取代,
R3和R4合起来代表C3-C8亚烷基,-(CH2)-O-(CH2)-或-(CH2)2-O-(CH2)2-,在每种情况下它都可以任选地被氟、氯、溴、C1-C6烷基或C1-C6烷氧基单或多取代,由此形成一个螺环基团,
R5代表氢、C1-C6烷基或苄基或苯基,其中苄基和苯基任选地含有一个或多个相同或不同的W1取代基,
R代表C1-C6烷基或C1-C6卤代烷基,
m代表0、1、2、3或4,
n代表0、1、2、3或4,
r代表0、1或2,
W1代表氢、溴、氯、氟、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、-S(O)rR、氰基或硝基。
3.按照权利要求1的式(I)化合物,其中
R1代表氢、溴、氯、氟、氰基、三(C1-C4烷基)甲硅烷基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、-S(O)rR或苯基,其中苯基任选地含有一个或多个相同或不同的W1取代基,
R2代表氢、溴、氯、氟、氰基、三(C1-C4烷基)甲硅烷基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、-S(O)rR或苯基,其中苯基任选地含有一个或多个相同或不同的W1取代基,
R3代表C1-C4烷基,它可任选地被C1-C4卤代烷基或C1-C4烷氧基取代,
R4代表C1-C4烷基,它可任选地被C1-C4卤代烷基或C1-C4烷氧基取代,
R3和R4合起来代表C3-C6亚烷基,-(CH2)-O-(CH2)-或-(CH2)2-O-(CH2)2-,在每种情况下它都可以任选地被氟、氯、溴、C1-C4烷基或C1-C4烷氧基单或多取代,由此形成一个螺环基团,
R5代表氢、C1-C4烷基或苄基或苯基,其中苄基和苯基任选地含有一个或多个相同或不同的W1取代基,
R代表C1-C4烷基或C1-C4卤代烷基,
m代表0、1、2或3,
n代表0、1、2或3,
r代表0、1和2,以及
W1代表氢、溴、氯、氟、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、-S(O)rR、氰基或硝基。
4.按照权利要求1的式(I)化合物的制备方法,其特征在于用一种脱水剂或一种偶联剂作用于式(II)的化合物其中R1、R2、R3、R4和R5具有权利要求1中给出的含义。
5.按照权利要求1的式(I)化合物用来制备抗内寄生物用药物的用途。
6.含有按照权利要求1的式(I)化合物以及适当载体和/或辅助剂的组合物。
7.一种生产按照权利要求6的组合物的方法,其特征在于按照权利要求1的式(I)化合物与适当的赋形剂和/或辅助剂混合。
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AU2003212367A1 (en) | 2003-10-13 |
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