CN1293664A - 环八缩肽类和其用于防治体内寄生虫的应用 - Google Patents
环八缩肽类和其用于防治体内寄生虫的应用 Download PDFInfo
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- CN1293664A CN1293664A CN99804115A CN99804115A CN1293664A CN 1293664 A CN1293664 A CN 1293664A CN 99804115 A CN99804115 A CN 99804115A CN 99804115 A CN99804115 A CN 99804115A CN 1293664 A CN1293664 A CN 1293664A
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- 125000005003 perfluorobutyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 description 1
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- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 229960005323 phenoxyethanol Drugs 0.000 description 1
- 229940067107 phenylethyl alcohol Drugs 0.000 description 1
- PMOIAJVKYNVHQE-UHFFFAOYSA-N phosphanium;bromide Chemical compound [PH4+].[Br-] PMOIAJVKYNVHQE-UHFFFAOYSA-N 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
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- 229920001223 polyethylene glycol Polymers 0.000 description 1
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- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
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- 125000005930 sec-butyloxycarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011697 sodium iodate Substances 0.000 description 1
- 235000015281 sodium iodate Nutrition 0.000 description 1
- 229940032753 sodium iodate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
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- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BPLUKJNHPBNVQL-UHFFFAOYSA-N triphenylarsine Chemical compound C1=CC=CC=C1[As](C=1C=CC=CC=1)C1=CC=CC=C1 BPLUKJNHPBNVQL-UHFFFAOYSA-N 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
-
- 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
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Tropical Medicine & Parasitology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
本发明涉及式(Ⅰ)的新的环八缩肽,其中R1代表氰基,C-C-连接的杂环基或者任选被取代的链烯基、炔烃基或芳基,和R2代表氢或者代表和R1一样的基团。本发明还涉及制备所述环八缩肽的方法,涉及制备它们的中间产物,涉及它们防治体内寄生虫的用途和涉及含有这些活性剂的药剂。
Description
本发明涉及新的环八缩肽类,它们制备的方法和它们防治寄生虫的用途,特别是在兽医和人体医学中防治蠕虫,以及涉及用于它们制备中的中间体。
文献中描述了各种各样的环缩肽具有抗寄生虫活性。EP382173A2公开了指定为PF1022的环八缩肽。EP626376A1,EP634408A1和EP718293A1公开了另外的24-元环缩肽。它们的抗蠕虫活性不是在所有的情况下都令人满意。
R1代表氰基,C-C-连接的杂环基或者任选被取代的链烯基,炔烃基或芳基和
R2代表氢或者代表和R1一样的基团。
X1代表溴,碘,-O-SO2-Rf,氨基或-N2 +(X3)-,其中
Rf代表氟化的C1-C4-烷基和
X3代表稳定重氮盐的阴离子例如四氟硼酸根阴离子,和
X2代表氢或者代表和X1相同的基团。
3.其中X1代表溴,碘,或代表其中Rf代表氟化的C1-C4-烷基的-OSO2Rf的式(Ⅱ)的环八缩肽是新的,并且构成本发明主题的一部分。
4.在下面的情况下得到了式(Ⅱ)的新的化合物
X2-1代表氢或溴,
对指定为PF1022的环八缩肽进行溴化或者
X2-2代表氢或碘,
对指定为PF1022的环八缩肽进行碘化
或者
c)在式(Ⅱ-c)的磺酰基环八缩肽的情况下其中
Rf代表氟化的C1-C4-烷基,和
X2-3代表氢或-O-SO2-Rf,
X3代表羟基或氢,
Rf-SO2-Y (Ⅳ)其中
Y代表-O-SO2-Rf,F或氯,或者
X4代表-N2 +(X3)-或氢,
X3代表稳定重氮盐的阴离子,
HO-SO2-Rf (Ⅵ)其中Rf如上定义。
5.此外,发现式(Ⅰ)的化合物出色地适合在人体医学和兽医中防治蠕虫。
式(Ⅰ)和(Ⅱ)提供了新的环八缩肽的一般定义。
取代基X1和X2以及R1和R2优选在对位或邻位。特别优选在对位。
优选给出式(Ⅰ)的化合物,其中:
R1代表氰基,C5-C8-环烯基,C-C-连接的5-至10-元的任选一-或多不饱和的具有一个或多个选自氧和氮的杂原子的任选被C1-C4-烷基,苄基,C1-C4-烷基羰基或者叔丁氧羰基取代的杂环基,代表选自-C(R3)=CH2,-CH=CR4R5,-CH=C(R6)CO2R7或-C≡C-R8的基团,或者代表任选被硝基,卤素,C1-C6-烷基,C2-C4-链烯基,C1-C4-卤代烷基,羟基,C1-C6-烷氧基,C1-C4-卤代烷氧基,四氢吡喃基氧基,氨基,吗啉代,哌啶子基,二-(C1-C4-烷基)氨基,C1-C3-烷基羰基氨基,C1-C4-烷氧羰基氨基,苄基氧基羰基氨基,羧基,C1-C4-烷氧羰基或苯基一或多独立取代的苯基或萘基,其中
R3代表C1-C4-烷氧基或C1-C4-烷基羰基氧基,
R4代表氰基或C1-C4-烷基,
R5和R6各自代表氢或甲基,
R7代表C1-C12-烷基,被卤素一或多取代的或者被氰基,羟基,C1-C4-烷氧基,C1-C4-二烷基氨基或者三-至八-元环氨基(=C2-C7-亚烷基氨基,其中一个亚甲基可以被一个氧,硫或者氮原子置换)一取代的C2-C12-烷基,代表(四氢)-糠基,C3-C6-2-链烯基,C3-C8-环烷基,任选被卤素-取代的苯基或苄基和
R8代表C1-C12-烷基,C3-C8-环烷基,C1-C8-羟基烷基,C1-C4-烷氧基-C1-C8-烷基,四氢吡喃基氧基-C1-C4-烷基,1-羟基-C3-C8-环烷基,α-氨基-C1-C8-烷基,α-C1-C4-烷基氨基羰基-氨基-C1-C4-烷基,羧基-C1-C11-烷基,C1-C4-烷氧羰基-C1-C11-烷基,苯氧基羰基-C1-C11-烷基,三(C1-C4-烷基)甲硅烷基,C1-C11-烷基羰基,任选被卤素-取代的苯基-C1-C4-烷基或者α-羟基苄基。
R2代表氢或者代表对于R1所提到的基团之一。
特别优选给出式(Ⅰ)的化合物,其中
R1代表氰基,C5-C8-环烯基,C-C-连接的5-至6-元的任选一至三不饱和的具有一个或两个选自氧和氮的杂原子的任选被C1-C4-烷基,苄基,C1-C4-烷基羰基或叔丁氧羰基取代的杂环基,代表-C(R3)=CH2,-CH=CR4R5,-CH=C(R6)CO2R7或-C≡C-R8基团之一,或者代表任选被硝基,氟,氯,溴,C1-C4-烷基,C2-C4-链烯基,羟基,C1-C4-烷氧基,四氢吡喃基氧基,被氟-或氯-取代的C1-C4-烷基或C1-C4-烷氧基,氨基,吗啉代,哌啶子基,二-(C1-C4-烷基)氨基,C1-C3-烷基羰基氨基,C1-C4-烷氧羰基氨基,苄基氧基羰基氨基,羧基,C1-C4-烷氧羰基或苯基一至四独立地取代的苯基或萘基,其中
R3代表C1-C4-烷氧基或C1-C4-烷基羰基氧基,
R4代表氰基或C1-C4-烷基,
R5和R6各自代表氢或甲基,
R7代表C1-C8-烷基,正-C9-C12-烷基,被氟一或多取代的C2-C6-烷基或正-C7-C12-烷基,或在2位被氯,溴,氰基,羟基,C1-C4-烷氧基,C1-C4-二烷基氨基或者五-至六-元环氨基(=C4-C5-亚烷基氨基,其中一个亚甲基可以被一个氧,硫或者氮原子置换)取代的乙基,代表(四氢)-糠基,C3-C6-2-链烯基,C3-C8-环烷基,任选被氟-,氯-或溴-取代的苯基或苄基和
R8代表C1-C4-烷基,正-C5-C12-烷基,C5-C6-环烷基,α-羟基-C1-C8-烷基,ω-羟基-正-C2-C8-烷基,α-C1-C4-烷氧基-C1-C8-烷基,ω-四氢吡喃基氧基-正-C1-C4-烷基,1-羟基-C3-C6-环烷基,α-氨基-C1-C8-烷基,α-C1-C4-烷基氨基羰基氨基-C1-C3-烷基,ω-羧基-正-C1-C11-烷基,C1-C4-烷氧羰基-正-C1-C11-烷基,苯氧基羰基-C1-C11-烷基,三(C1-C4)烷基甲硅烷基,C1-C5-烷基羰基,正-C6-C11-烷基羰基,任选被氟-,氯-或溴-取代的苯基-C1-C2-烷基或者α-羟基苄基。
R2代表氢或者代表对于R1所提到的基团之一。
非常特别给出式(Ⅰ)的化合物,其中
R1代表氰基,1-环戊烯基,2-环戊烯基,1-环己烯基,2-环己烯基,呋喃基,二氢呋喃基,任选被甲基-,苄基-,乙酰基-,丙酰基-或叔丁氧羰基N-取代的2-或3-吡咯基,吡咯啉-2-基,代表二氢吡喃基,1,3-二噁英基,基团-C(R3)=CH2,-CH=CR4R5,-CH=C(R6)CO2R7或-C≡C-R8之一,或者代表任选地独立地被硝基,氟,氯,甲基,乙基,正丙基,异丙基,正丁基,异丁基,仲丁基,叔丁基,乙烯基,1-丙烯-1-基,1-丁烯-1-基,羟基,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,四氢吡喃基氧基,三氟甲基,三氟甲氧基,二氟甲氧基,氯代二氟甲氧基,氨基,吗啉代,哌啶子基,二甲基氨基,二乙基氨基,二丙基氨基,二异丙基氨基,乙酰基氨基,丙酰基氨基,甲氧基羰基氨基,乙氧基羰基氨基,苄基氧基羰基氨基,羧基,甲氧羰基,乙氧羰基,正丙氧基羰基,异丙氧基羰基,正丁氧基羰基,异丁氧基羰基,仲丁氧基羰基,叔丁氧基或苯基一-至三-取代的苯基,其中
R3代表甲氧基,乙氧基,正丙氧基,异丙氧基,乙酰基氧基或丙酰基氧基,
R4代表氰基或C1-C4-烷基,
R5和R6各自代表氢或甲基,
R7代表甲基,乙基,正丙基,异丙基,正丁基,异丁基,仲丁基,叔丁基,新戊基,正戊基,2-乙基丁基,正己基,正庚基,2-乙基己基,正辛基,正壬基,正癸基,2-氟乙基,2,2,2-三氟乙基,1,1,1,3,3,3-六氟异丙基,七氟异丙基,2,2,3,3,4,4-六氟丁基,2-氯乙基,2-溴乙基,2-氰基乙基,2-羟基乙基,2-甲氧基甲基,2-乙氧基甲基,2-N,N-二甲基氨基甲基,2-N,N-二乙基氨基甲基,2-吡咯烷子基乙基,2-哌啶子基乙基,2-吗啉代乙基,代表糠基,四氢糠基,烯丙基,2-丁烯基,环戊基,环己基,代表任选被氟,氯或溴独立地一-至三取代的苯基或苄基,和
R8代表甲基,乙基,正丙基,异丙基,正丁基,异丁基,仲丁基,叔丁基,正戊基,正己基,正庚基,正辛基,正壬基,正癸基,环戊基,环己基,羟基甲基,1-羟基乙基,1-羟基-1-甲基乙基,1-羟基丙基,1-羟基-1-甲基丙基,1-羟基-2-甲基丙基,1-羟基丁基,1-羟基-1,2-二甲基-丙基,1-羟基-3-甲基丁基,1-羟基戊基,2-乙基-1-羟基-丁基,1-羟基-1,3-二甲基丁基,1-羟基-1,2,2-三甲基丙基,1-羟基己基,1-羟基-1,4-二甲基戊基,1-羟基-1-异丙基-2-甲基丙基,2-乙基-1-羟基-己基,2-羟基乙基,3-羟基丙基,4-羟基丁基,5-羟基戊基,6-羟基己基,2-四氢吡喃基氧基乙基,1-羟基环丙基,1-羟基环戊基,1-羟基环己基,1-氨基甲基,1-氨基乙基,1-氨基-1-甲基乙基,1-氨基-1-乙基丙基,甲基氨基羰基二甲基甲基,叔丁基氨基羰基二甲基甲基,羧基甲基,羧基乙基,羧基丙基,羧基丁基,羧基戊基,羧基己基,羧基庚基,羧基辛基,苯氧羰基甲基,三甲基甲硅烷基,三乙基甲硅烷基,丁基二甲基甲硅烷基,三异丙基甲硅烷基,乙酰基,丙酰基,丁酰基,异丁酰基,异戊酰基,己酰基,或者任选被氟,氯或溴独立地一-至三取代的苄基,苯乙基或α-羟基苄基。
R2代表氢或者对于R1所提到的基团之一。
优选给出式(Ⅱ)的化合物,其中:
X1代表溴,碘,三氟甲基磺酰基氧基,九氟丁基磺酰基氧基,氨基或-N2 +(X3)-,其中X3代表四氟硼酸根;
X2代表对于X1提到的基团或者代表氢。
特别优选给出式(Ⅱ)的化合物,其中X1代表溴,碘或三氟甲基磺酰基氧基和X2代表氢或者对于X1提到的基团之一。
非常特别优选给出式(Ⅱ)的化合物,其中X1代表碘和X2代表氢或碘。
使用,例如,8-(2-溴苄基)-20-(4-溴苄基)-5,11,17,23-四异丁基-2,4,10,14,16,22-六甲基-1,7,13,19-四氧杂-4,10,16,22-四氮杂-环正二十四烷-3,6,9,12,15,18,21,24-八酮和4-三氟甲氧基苯基硼酸为起始物,则根据本发明方法(2)中的反应过程可以通过下面的反应式表示:
使用,例如,8,20-二苄基-5,11,17,23-四异丁基-2,4,10,14,16,22-六甲基-1,7,13,19-四氧杂-4,10,16,22-四氮杂-环正二十四烷-3,6,9,12,15,18,21,24-八酮(PF1022)为起始物,和溴/I,I-二(三氟乙酰氧基)-碘代苯为试剂,则根据本发明方法(4a)中的反应过程可以通过下面的反应式表示:
使用,例如,PF1022E和全氟丁基氟化物为起始物,则根据本发明方法(4c)中的反应过程可以通过下面的反应式表示:
使用,例如,4-(14-苄基-5,11,17,23-四异丁基-4,8,10,16,20,22-六甲基-1,7,13,19-四氧杂-4,10,16,22-四氮杂-环正二十四烷-3,6,9,12,15,18,21,24-八酮-2-基-甲基)苯基氯化重氮物和三氟甲磺酸为起始物,则根据本发明方法(4d)中的反应过程可以通过下面的反应式表示:
进行本发明方法(2)所需要的式(Ⅱ)的一些环八缩肽是新的化合物。这些新的化合物可以通过方法(4a),(4b),(4c)或(4d)制备。
EP-A634408描述了通过催化还原相应的硝基-取代的化合物制备其中R1和/或R2代表氨基的本发明式(Ⅰ)的化合物。EP-A634408的实施例14中描述了通过称之为重氮煮浓的方法将氨基转化为OH基团。如果在低温下(-50℃至+10℃),优选在-10℃至+5℃下进行这里所描述的该反应,则可以分离所研究的重氮盐。在该方法中,可以获得其中X1和/或X2代表重氮盐基团的式(Ⅱ)的化合物。
从EP382173A1得知进行根据本发明方法(4a)和(4b)所需要的环八缩肽PF1022,并且该化合物可以例如通过发酵制备。
从JP06184126(CA122:104043中引述)或者从WO97/11064(CA126:293615中引述)中得知进行根据本发明方法(4c)所需要的式(Ⅲ)的环八缩肽,例如作为PF1022E和PF1022H,或者它们可以类似于这里所描述的方法制备。
根据一般已知的方法,通过相应的氨基化合物的重氮化作用,可以制备进行根据本发明方法(4d)所需要的式(Ⅴ)的重氮化环八缩肽,其中所述相应的氨基化合物是已知的,例如从EP634408A1,WO97/11064(CA126:293615中引述)或者WO97/02256(CA126:171904中引述)中得知或者它们可以以这里所提到的方法获得。为了这个目的,可以使用无机亚硝酸盐,例如含水酸例如盐酸,三氟乙酸或四氟乙酸中的亚硝酸钠,或者亚硝酸烷基酯,例如无水介质例如含有氯化氢的乙酸中的亚硝酸异戊酯或亚硝酸丁酯。
进行根据本发明方法(2)所使用的试剂的例子是式(Ⅶ)的化合物
R1-1-H (Ⅶ)其中
R1-1代表对于R1所提到的杂环基之一,其是C-C-连接的,或者对于R1所提到的任选被取代的链烯基或炔烃基之一,
式(Ⅷ)的硼化合物其中
R1-2代表对于R1所提到的杂环基之一,其是C-C-连接的,任选被取代的烷基,链烯基或芳基,
R9和R10各自代表氢,异丙基或者一起代表1,2-亚丙基,环辛-1,5-二基或者邻-亚苯基,
式(Ⅸ)的锡化合物
R1-Sn(R11)3 (Ⅸ)其中
R1如上定义,和
R11代表甲基,丁基或苯基,或者
氰化锌。
式(Ⅶ)的化合物是一般已知的有机化学的化合物。式(Ⅷ)的硼化合物,特别是硼酸,是已知的,并且它们中的一些可以购得,或者它们可以通过已知方法制备[参见,例如,Chem.Rev.45,2457(1995);Pure Appl.Chem.66,213(1994);Synlett 1990,221]。式(Ⅸ)的锡化合物是已知的或者可以通过已知方法制备[参见,例如,M.Pereyre,J.-P.Quintard,A.Rahm:有机合成中的锡,Butterworths,伦敦,1987;有机化学(Org.Chem.)54,5064(1989)]。
适合进行根据本发明方法(2)的催化剂的例子是元素周期表Ⅷ副族金属的化合物,特别是配合物,所述金属是例如钯或镍,优选钯。例子包括:二-(1,5-环辛二烯)-镍(O),氯化镍(Ⅱ),二氯-二(三苯基膦)镍,乙酰基丙酮酸镍(Ⅱ),乙酸钯(Ⅱ),氯化钯(Ⅱ),二氯-二(三苯基膦)钯,二氯-二[三(2-甲基苯基)膦]-钯,二乙腈二氯钯,二[μ-(乙酸离子-κO:κO’)-二[[2-二(2-甲基苯基)膦基-κP]苯基]甲基-κC]二钯,三(二亚苄基丙酮)二钯,二(二亚苄基丙酮)钯,四(三苯基膦)钯或者上述化合物之一与生成配合物的自由配体结合,所述生成配合物的自由配体是例如三苯基膦,三-邻-甲苯基膦,三呋喃基膦,二(二苯基膦基)-乙烷,二(二苯基膦基)丙烷,二(二苯基膦基)丁烷,二苯基-膦基二茂铁或者三苯基胂。适合用作镍催化剂的是镍(O)或镍(Ⅱ)化合物。镍(Ⅱ)化合物可以在合适的配体存在下例如通过锌粉原位还原得到镍(O)化合物。在与炔烃的偶联中,可以使用也可以在与锡化合物反应中使用的碘化铜作为助催化剂。
如果适当,根据本发明方法(2)在反应助剂存在下进行,合适的反应助剂是:碱金属卤化物,例如氯化锂,溴化锂,氟化铯或酸结合剂。用于与式(Ⅷ)的硼化合物反应的优选的酸结合剂是碱土金属或碱金属的氢氧化物,乙酸盐,碳酸盐或碳酸氢盐,例如氢氧化钠,氢氧化钾,氢氧化钡或氢氧化铵,乙酸钠,乙酸钾,乙酸钙或乙酸铵,碳酸钠,碳酸钾,或碳酸铵,碳酸氢钠或碳酸氢钾,碳酸银,磷酸盐,例如磷酸三钠或者磷酸三钾,碱金属氟化物,例如氟化铯,还有叔胺类,例如三甲胺,三乙胺,三丁基胺,乙基二异丙基胺,N,N-二甲基苯胺,N,N-二甲基-苄基胺,吡啶,N-甲基哌啶,N-甲基吗啉,N,N-二甲基氨基吡啶,二氮杂双环辛烷(DABCO),二氮杂双环壬烯(DBN)或二氮杂双环十一烯(DBU),在与式(Ⅱ)的氨基-取代的化合物的反应中,对于重氮化作用使用碱金属亚硝酸盐,例如亚硝酸钠。
根据本发明方法(2)优选在稀释剂存在下进行。用于与式(Ⅷ)的硼化合物反应中的合适的稀释剂是水,有机溶剂和其任何混合物。例子包括脂肪族,脂环族或芳香族烃,例如石油醚,己烷,庚烷,环己烷,甲基环己烷,苯,甲苯,二甲苯或萘烷;卤化烃,例如氯苯,二氯苯,二氯甲烷,氯仿,四氯化碳,二氯乙烷,三氯乙烷或四氯乙烯;醚类,例如乙醚,二异丙基醚,甲基叔丁基醚,甲基叔戊基醚,二噁烷,四氢呋喃,1,2-二甲氧基乙烷,1,2-二乙氧基乙烷,二甘醇二甲基醚或茴香醚;醇类,例如甲醇,乙醇,正-或异-丙醇,正-,异-仲-或叔丁醇,乙二醇,丙烷-1,2-二醇,乙氧基乙醇,甲氧基乙醇,二甘醇一甲基醚,二甘醇一乙基醚;水。在(重氮化)胺类的式(Ⅱ)的化合物的反应中使用含水的酸,例如盐酸,三氟乙酸或四氟乙酸,如果适当,在加溶剂例如醇类,例如甲醇存在下使用。对于其它反应有利的稀释剂是偶极非质子溶剂。实施例包括:醚类,例如乙醚,二异丙基醚,甲基叔丁基醚,甲基叔戊基醚,二噁烷,四氢呋喃,1,2-二甲氧基乙烷,1,2-二乙氧基乙烷,二甘醇二甲基醚或茴香醚;酮类,例如丙酮,丁酮,甲基异丁基酮或环己酮;腈类,例如乙腈,丙腈,正-或异-丁腈或苄腈;酰胺类,例如甲酰胺,N,N-二甲基甲酰胺,N,N-二甲基乙酰胺,N-甲基-N-甲酰苯胺,N-甲基-吡咯烷酮或六甲基磷酸三酰胺;亚砜类,例如二甲亚砜。对于用作酸结合剂的上面提到的胺类当以相对大的过量使用时,同时也可以用作稀释剂。
根据本发明方法(2)也可以在两相体系中进行,例如二氯甲烷/水,优选使用合适的相转移催化剂。这样的催化剂的例子包括:四丁基铵碘化物,四丁基铵溴化物或者四丁基铵氯化物,三丁基甲基鏻溴化物,三甲基-C13/C15-烷基铵氯化物或者三甲基-C13/C15-烷基铵溴化物,二苄基二甲基铵甲基硫酸盐,二甲基-C12/C14-烷基苄基铵氯化物,15-冠醚-5,18-冠醚-6或三-[2-(2-甲氧基乙氧基)-乙基]-胺。
当进行根据本发明方法(2)时,反应温度可以在相当宽的范围内变化。一般情况下,反应在20℃和200℃之间的温度下进行,优选在50℃和150℃之间。在任选进行重氮化作用的情况下,反应最初在-20℃至+30℃下进行。
进行根据本发明方法(4a)时需要溴化剂。合适的溴化剂是例如在I,I-二(三氟乙酰氧基)-碘代苯存在下的溴。
根据本发明方法(4a)优选在稀释剂存在下进行。合适的稀释剂是水,有机溶剂和其任何混合物。例子包括脂肪族,脂环族或芳香族烃,例如石油醚,己烷,庚烷,环己烷,甲基环己烷,苯,甲苯,二甲苯或萘烷;卤化烃,例如氯苯,二氯苯,二氯甲烷,氯仿,四氯化碳,二氯乙烷,三氯乙烷或四氯乙烯;醚类,例如乙醚,二异丙基醚,甲基叔丁基醚,甲基叔戊基醚,二噁烷,四氢呋喃,1,2-二甲氧基乙烷,1,2-二乙氧基乙烷,二甘醇二甲基醚或茴香醚;酮类,例如丙酮,丁酮,甲基异丁基酮或环己酮;腈类,例如乙腈,丙腈,正-或异-丁腈或苄腈;酰胺类,例如甲酰胺,N,N-二甲基甲酰胺,N,N-二甲基乙酰胺,N-甲基-N-甲酰苯胺,N-甲基-吡咯烷酮或六甲基磷酸三酰胺;N-氧化物,例如N-甲基吗啉N-氧化物;酯类,例如乙酸甲酯,乙酸乙酯或乙酸丁酯;亚砜类,例如二甲亚砜;砜类,环丁砜;醇类,例如甲醇,乙醇,正-或异-丙醇,正-、异-、仲-或叔丁醇,乙二醇,丙烷-1,2-二醇,乙氧基乙醇,甲氧基乙醇,二甘醇一甲基醚,二甘醇一乙基醚;水。
当进行根据本发明方法(4a)时,反应温度可以在相当宽的范围内变化。一般情况下,反应在-50℃和+50℃之间的温度下进行,优选在-20℃和+30℃之间。
进行根据本发明方法(4a)时,对于每摩尔PF1022一般使用0.5至5摩尔溴。如果一溴代化合物(X2-1=H)是需要的,则使用0.5至1.0摩尔的溴,如果二溴代化合物(X2-1=Br)是优选的,则使用3-5摩尔的溴。一般情况下对于每摩尔溴使用1.0-1.2摩尔的I,I-二(三氟乙酰氧基)-碘代苯。
进行根据本发明方法(4b)时,需要碘化试剂。合适的碘化试剂是例如I,I-二(三氟乙酰氧基)-碘代苯存在下的碘或者碱金属碘酸盐碘酸钠存在下的碘,和质子酸例如乙酸或硫酸存在下的碘,或者在质子酸例如三氟甲磺酸或者四氟硼酸氢盐存在下的二(吡啶)碘鎓(I)四氟硼酸盐(J.Org.Chem.58,2058(1993))。
根据本发明方法(4b)优选在稀释剂存在下进行。对于与I,I-二(三氟乙酰氧基)-碘代苯反应的合适的稀释剂是例如对于方法(4a)所列出的所有溶剂,而对于与碘酸盐反应的稀释剂是例如乙酸和硫酸。
当进行根据本发明方法(4b)时,反应温度可以在相当宽的范围内变化。一般情况下,当使用I,I-二(三氟乙酰氧基)-碘代苯时,反应在-50℃和+50℃之间的温度下进行,优选在-20℃和+30℃之间;当使用碘酸盐时,在0℃和+100℃之间的温度下进行,优选在20℃和+80℃之间。
进行根据本发明方法(4b)时,对于每摩尔PF1022一般使用1至5摩尔碘。如果一碘代化合物(X2-2=H)是需要的,则使用1至5摩尔的碘和2至10摩尔的I,I-二(三氟乙酰氧基)-碘代苯。如果二碘代化合物(X2-2=I)是优选的,则使用1.5至2摩尔的碘和0.5至1.5摩尔的碘酸盐。
用于进行根据本发明方法(4c)的合适的酸结合剂主要是有机碱。实施例包括:叔胺类,例如三甲胺,三乙胺,三丁基胺,N,N,-二甲基苯胺,N,N,-二甲基-苄基胺,吡啶,N-甲基哌啶,N-甲基吗啉,N,N-二甲基氨基吡啶,二氮杂双环辛烷(DABCO),二氮杂双环壬烯(DBN)或二氮杂双环十一烯(DBU)。
如果适当,方法(4c)在稀释剂存在下进行。合适的稀释剂是有机溶剂和其任何混合物。例子包括:脂肪族,脂环族或芳香族烃,例如石油醚,己烷,庚烷,环己烷,甲基环己烷,苯,甲苯,二甲苯或萘烷;卤化烃,例如氯苯,二氯苯,二氯甲烷,氯仿,四氯化碳,二氯乙烷,三氯乙烷或四氯乙烯;醚类,例如乙醚,二异丙基醚,甲基叔丁基醚,甲基叔戊基醚,二噁烷,四氢呋喃,1,2-二甲氧基乙烷,1,2-二乙氧基乙烷,二甘醇二甲基醚或茴香醚;以及过量的有机碱本身。
当进行根据本发明方法(4c)时,反应温度可以在相当宽的范围内变化。一般情况下,反应在-50℃和+50℃之间的温度下进行,优选在-20℃和+30℃之间。
进行根据本发明方法(4c)时,对于每当量羟基-取代的式(Ⅲ)的环八缩肽,一般使用1至10摩尔,优选1.2至5摩尔磺酸衍生物(Ⅳ),和1至10摩尔,优选1至5摩尔酸结合剂。
当进行根据本发明方法(4d)时,反应温度可以在相当宽的范围内变化。一般情况下,反应在50℃和180℃之间的温度下进行,优选在60℃和140℃之间。如果需要,另外用发射UV射线的光源照射反应。
一般以相对大的过量使用式(Ⅵ)的氟化磺酸。
根据本发明方法的反应可以在大气压或者在升高的压力下进行。优选在大气压下进行。使用一般常规已知的方法进行该反应和进行后处理和分离反应产物。终产物优选通过结晶,层析分离或者通过去除挥发成分,如果需要的话在减压下进行,来纯化(也参见制备实施例)。
本发明活性化合物适于防治人和畜牧业和家畜饲养,农业生产家禽,饲料,动物园动物,实验室动物,试验中使用的动物,和宠物所遇到的病原体体内寄生虫,并且对于温血动物有低毒性。它们有抗抗性和一般敏感性物种和抗害虫发育的所有或一些阶段的活性。通过防治病原体体内寄生虫,以减少疾病,避免家畜死亡并且避免产品量的减少(例如肉,奶,羊毛,皮革,蛋,蜂蜜等的生产中),因此通过使用本发明活性化合物可以实现更经济更简单的动物的喂养。病原体体内寄生虫包括绦虫属(Cestodes),Trematodes,线虫属(Nematodes),特别是:
来自假叶目(Pseudophyllidea)例如裂头绦虫属(Diphyllobothriumspp.),裂头绦虫属(Spirometra spp.),裂首绦虫属(Schistocephalusspp.),舌状绦虫属(Ligula spp.),沟槽绦虫属(Bothridium spp.),Diphlogonoorus spp.。
来自圆叶目(Cyclophyllidea),例如中殖孔绦虫属(Mesocestoidesspp.),拟裸头绦虫属(Anoplocephala spp.),副裸头绦虫属(Paranoplocephala spp.),蒙尼绦虫属(Moniezia spp.),燧体绦虫属(Thysanosmsa spp_Thysaniezia spp.),无卵黄线绦虫属(Avitellinaspp.),斯泰绦虫属(Stilesia spp.),锡带绦虫属(Cittotaenia spp.),Anhyra spp_伯特绦虫属(Bertiella spp.),带绦虫属(Taenia spp.),棘球绦虫属(Echinococcus spp.),Hydratigera spp.戴维绦虫属(Davainea spp.),瑞利绦虫属(Raillietina spp.),膜壳绦虫属(Hymenolepsis spp.),Echinolepsis spp_Echinocotyl spp_双睾绦虫属(Diorchis spp.),Dipylidium spp_Joyeuxiella spp_Diplopylidium spp.。
来自单殖亚纲(Monogenea),例如Cyrodactylus spp_指环虫属(Dactylogyrus spp.),多盘吸虫属(Polystoma spp.)。
来自复殖亚纲(Digenea),例如双穴吸虫属(Diplostomum spp.),茎双穴吸虫属(Posthodiplostomum spp.),血吸虫属(Schistosomaspp.),毛毕吸虫属(Trichobilharzia spp.),鸟毕吸虫属(Ornithobilharzia spp.),澳毕吸虫属(Austrobilharzia spp.),巨毕吸虫属(Gigantobilharzia spp.),彩蚴吸虫属(Leucochloridiumspp.),短咽吸虫属(Brachylaima spp.),棘口吸虫属(Echinostomaspp.),棘缘吸虫属(Echinoparyphium spp.),棘隙吸虫属(Echinochasmus spp.),寡肉吸虫属(Hypoderaeum spp.),肝片吸虫属(Fasciola spp.),Fasciolides spp_姜片吸虫属(Fasciolopsisspp.),环肠吸虫属(Cyclocoelum spp.),盲腔属(Typhloccelum spp.),同端盘吸虫属(Paramphistomum spp.),杯殖吸虫属(Calicophoronspp.),殖盘吸虫属(Cotylphoron spp.),巨盘吸虫属(Gigantocotylespp.),菲策吸虫属(Fischoederius spp.),腹袋吸虫属(Gastrothylacusspp.),背孔吸虫属(Notocotylus spp.),下弯吸虫属(Catatropisspp.),斜睾吸虫属(Plagiorchis spp.),前殖吸虫属(Prosthogonismusspp.),双腔吸虫属(Dicrocoelium spp.),肛瘤吸虫属(Collyriclumspp.),小叶吸虫属(Nanophyetus spp.),后睾吸虫属(Opisthorchisspp.),Clonorchis spp_次睾吸虫属(Metorchis spp.),Heterophyesspp_Metagonimus spp.。
来自嘴刺目(Enoplida),例如鞭虫属(Trichuris spp.),毛细线虫属(Capillaria spp.),Trichlomosoides spp_毛线虫(Trichinellaspp.)。
来自小杆亚纲(Rhabditia),例如Micronema spp_类圆线虫属(Strongyloides spp.)。
来自圆线目(Strongylida),例如圆线虫(Stronylus spp.),三齿线虫(Triodontophorus spp.),食道齿线虫属(Oesophagodontusspp.),毛线线虫属(Trichonema spp.),Gyalocephalus spp_Cylindropharynx spp_杯口线虫属(Poteriostomum spp.),Cyclococercus spp_Cylicostephanus spp_结节线虫属(Oesophagostomum spp.),夏柏线虫属(Chabertia spp.),肾线虫属(Stephanurus spp.),Ancylostoma spp_弯口线虫属(Uncinariaspp.),Bunostomum spp_球头线虫属(Globocephalus spp.),比翼线虫属(Syngamus spp.),杯口线虫属(Cyathostoma spp.),后圆线虫属(Metastrongylus spp.),网尾线虫属(Dictyocaulus spp.),缪氏线虫属(Muellerius spp.),原圆肺虫(Protostrongylus spp.),Neostrongylus spp_囊尾线虫属(Cystocaulus spp.),肺圆线虫属(Pneumostrongylus spp.),尖尾线虫属(spicocaulus spp.),Elaphostrongylus spp_Parelaphostrongylus spp_环棘属(Crenosoma spp.),Paracrenosoma spp_鼠肺线虫属(Angiostrongylus spp.),Aelurostrongylus spp_Filaroides spp_Parafilaroides spp_毛圆属(Trichostrongylus spp.),血矛属(Haemonchus spp.),奥斯特属(Ostertagia spp.),马歇尔属(Marshallagia spp.),古伯属(Cooperia spp.),细颈属(Nematodirusspp.),猪圆属(Hyostrongylus spp.),若剑属(Obeliscoides spp.),Amidostomum spp_壶肛属(Ollulanus spp.)。
来自尖尾目(Oxyurida),例如尖尾属(Oxyuris spp.),住肠属(Enterobius spp.),钉尾属(Passalurus spp.),管线属(Syphaciaspp.),无剌属(Aspiculuris spp.),异刺属(Heterakis spp.)。
来自蛔虫目(Ascaridia),例如蛔属(Ascaris spp.),弓蛔属(Toxascaris spp.),弓首属(Toxoscara spp.),副蛔属(Parascarisspp.),无饰属(Anisakis spp.),蛔型属(Ascaridia spp.)。
来自旋尾属(Spirurida),例如颚口属(Gnathostoma spp.),泡翼属(Physaloptera spp.),雄突属(Thelazia spp.),筒线属(Gongylonemaspp.),柔线属(Habronema spp.),副柔线属(Parabronema spp.),德拉西属(Draschia spp.),龙线属(Dracunculus spp.)。
来自线虫目(Filariida),例如Stephanofilaria spp_副丝虫属(Parafilaria spp.),丝状属(Setaria spp.),罗阿属(Loa spp.),噁丝虫属(Dirofilaria spp.),Litomosoides spp_Brugia spp_吴策属(Wuchereria spp.),盘尾属(Onchocerca spp.)。
来自巨吻棘头虫族(Gigantohynchida),例如Filicollis spp_捻珠棘虫属(Moniliformis spp.),Macracanthorhynchus spp_前巨睾棘头虫属(Prosthenorchis spp.)。
本发明活性化合物具有例如出色的抗线虫例如捻转血矛线虫(Haemonchus contortus),长刺蛇形毛圆线虫(Trichostrongyluscolubriformis),Nematospiroides dubius和多泡异刺线虫(Heterkisspumosa)的活性。
家畜和家禽包括哺乳动物,例如牛,马,绵羊,猪,山羊,骆驼,水牛,驴,兔子,驯鹿,黄占鹿,毛皮动物,例如水貂,灰鼠,或浣熊,鸟类,例如鸡,火鸡,鸭,或鹅。
实验室和试验用动物包括小鼠,大鼠,豚鼠,金色仓鼠,狗和猫。
宠物包括狗和猫。
给药可以起预防性作用以及治疗性作用。
活性物质可以直接给药或者以合适的制剂形式,通过肠内,肠胃外,皮肤,鼻给药,处理寄生处或者借助于含有活性化合物的有形物品,例如条子,片,带子。
本发明活性化合物的经肠胃给药是有效的,例如以粉剂,栓剂,片剂,胶囊,糊剂,饮用剂,颗粒剂,顿服药,巨丸剂,含药饲料或饮用水来口服。皮肤施用是有效的,例如以浸浴,喷洒,洗浴,冲洗,涂敷和点施和撒粉。肠胃外给药是有效的,例如以注射液形式(肌内,皮下,静脉内或腹膜内)或者通过埋入。
合适的制剂包括:
溶液,例如注射液,口服液,用于稀释后口服给药的浓缩液,用于皮肤或在体腔中使用的溶液,涂敷制剂,凝胶;
用于口服或皮肤给药和用于注射的乳剂和混悬剂;半固体制剂;
其中活性化合物掺入到乳膏基质或者水包油或油包水乳化物基质中的制剂;
固体制剂,例如粉剂,预混剂或浓缩液,颗粒剂,丸剂,片剂,巨丸剂,胶囊;气雾剂和吸入剂,含有活性化合物的有形物品。
注射液是静脉内,肌内和皮下给药。
通过将活性化合物溶解于合适的溶剂中,并且如果需要,加入添加剂,例如加溶剂,酸,碱,缓冲盐,抗氧化剂,或防腐剂来制备注射液。将溶液灭菌过滤并装入容器中。
合适的溶剂包括:生理可接受溶剂,例如水,醇,例如乙醇,丁醇,苯甲醇,甘油,烃类,丙二醇,聚乙二醇和N-甲基吡咯烷酮,及其混合物。
如果合适,活性化合物也可以溶解于生理可接受的适于注射的植物油或合成油中。
合适的加溶剂包括:有利于活性化合物溶解于主要溶剂或者防止活性化合物沉淀的溶剂。加溶剂的例子是聚乙烯吡咯烷酮,多乙氧化蓖麻油和多乙氧基化脱水山梨糖醇酯。
防腐剂是苯甲醇,三氯丁醇,对羟基苯甲酸酯或正丁醇。
口服液直接给药。浓缩液首先稀释到给药浓度后再口服。根据上述注射液情况下的说明制备口服液和浓缩液。不需要灭菌过程。
对皮肤施用的溶液是逐滴施用,平敷,涂揉,泼涂或喷施,或者通过浸浴,洗浴或冲洗施用。这些溶液根据上文有关注射液情况下的说明来制备。
在制备过程中加入增稠剂是有好处的。增稠剂是无机增稠剂,例如膨润土,胶体二氧化硅,一硬脂酸铝,或有机增稠剂,例如纤维素衍生物,聚乙烯醇及其共聚物,丙烯酸酯和甲基丙烯酸酯。
凝胶被施用到皮肤或平敷到皮肤上或者施用到体腔内。通过向根据对于注射液说明的形成澄清的组合物的溶液中加入一定量的增稠剂,使具有类软膏剂稠度来制备凝胶。使用的增稠剂是上文指出的增稠剂。
涂敷和点施制剂是将制剂涂敷或泼涂到有限面积的皮肤上。活性化合物渗透皮肤而在全身起作用,或者将其分布于身体表面。
通过将活性化合物溶解,悬浮在合适的为皮肤所耐受的溶剂或溶剂混合物中或者在合适的为皮肤所耐受的溶剂或溶剂混合物中乳化,来制备涂敷和点施制剂。如果合适,加入其它助剂,例如着色剂,生物吸收促进剂,抗氧化剂,光稳定剂或增粘剂。
合适的溶剂包括:水,醇类,二醇类,聚乙二醇,聚丙二醇,甘油,芳香醇,例如苯甲醇,苯基乙醇或苯氧基乙醇,酯类,例如乙酸乙酯,乙酸丁酯或苯甲酸苯甲酯,醚类,例如亚烷基二醇烷基醚,例如二亚丙基二醇一甲基醚或二甘醇一丁基醚,酮类,例如丙酮或甲基乙基酮,芳烃和/或脂肪烃,植物油或合成油,DMF,二甲基乙酰胺,N-甲基吡咯烷酮或2,2-二甲基-4-氧基-亚甲基-1,3-二氧戊环。
着色剂是能溶解或悬浮的并且证明适用于动物的所有着色剂。
生物吸收促进剂的例子是DMSO,涂敷油,例如十四烷酸异丙酯,壬酸二亚丙基二醇酯,硅油,脂肪酸酯,甘油三酯或脂肪醇。
下面是抗氧化剂:亚硫酸盐或偏亚硫酸氢盐,例如偏硫酸氢钾,抗坏血酸,丁基羟基甲苯,丁基羟基苯甲醚或生育酚。
光稳定剂的例子是选自二苯酮或novantisolic acid类的物质。
增粘剂是例如纤维素衍生物,淀粉衍生物,聚丙烯酸酯或天然聚合物例如藻酸盐或明胶。
乳剂可以口服,皮肤给药或作为注射剂给药。
乳剂可以是油包水型或水包油型。
通过将活性化合物溶解于疏水或亲水相,并且通过借助于合适的乳化剂,用另一相的溶剂将该相匀化,并且如果合适,借助于其它助剂,例如着色剂,生物吸收促进剂,防腐剂,抗氧化剂,光稳定剂,和增粘物质,来制备乳剂。
合适的疏水相(油)包括:石蜡油,硅油,天然植物油,例如芝麻油,杏仁油或蓖麻油,合成的三甘油酯,例如正辛酸/正癸酸甘油二酯,与C8-12链长植物脂肪酸或其它具体选择的天然脂肪酸的甘油三酯混合物,也可以包含羟基的饱和的或不饱和的脂肪酸的部分甘油酯的混合物,和C8/C10-脂肪酸甘油一-和二酯。
脂肪酸酯是例如硬脂酸乙酯,己二酸二正丁酰基酯,月桂酸己酯,壬酸二亚丙基二醇酯,具有中等链长支链脂肪酸与C16-C18-链长饱和脂肪醇的酯,十四烷酸异丙酯,十六烷酸异丙酯,C12-C18-链长饱和脂肪醇的正辛酸/正癸酸的酯,硬脂酸异丙酯,油酸油酯,油酸癸酯,油酸乙酯,乳酸乙酯,蜡脂肪酸酯,例如人工的鸭尾脂腺脂肪,苯二甲酸二丁酯,己二酸二异丙酯,与后者相关的酯混合物等。
脂肪醇是例如异十三烷基醇,2-辛基十二烷醇,十六烷基十八烷基醇或油醇。
脂肪酸是例如油酸及其混合物。
合适的亲水相包括:水,醇,例如丙二醇,甘油,山梨糖醇及其混合物。
合适的乳化剂包括:非离子表面活性剂,例如多乙氧基化蓖麻油,多乙氧基化脱水山梨糖醇一油酸酯,脱水山梨糖醇一硬脂酸酯,甘油一硬脂酸酯,聚氧乙基硬脂酸酯或烷基苯酚聚乙二醇醚;
两性表面活性剂是例如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,例如月桂基硫酸钠,脂肪醇醚硫酸盐,及单/二烷基聚乙二醇醚正磷酸酯的一乙醇胺盐。
阳离子表面活性剂是例如十六烷基三甲基氯化铵。
其它合适的助剂包括:提高乳剂粘度和稳定性的物质,例如羧甲基纤维素,甲基纤维素和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,聚乙烯吡咯烷酮,聚乙烯醇,甲基乙烯基醚/马来酸酐共聚物,聚乙二醇,蜡,胶体二氧化硅,或者所列物质的混合物。
混悬剂可以口服给药,皮肤给药或作为注射剂给药。其通过将活性化合物悬浮于液体赋形剂来制备,如果需要,加入其它助剂,例如湿润剂,着色剂,生物吸收促进剂,防腐剂,抗氧化剂和光稳定剂。
合适的液体赋形剂包括所有均匀溶剂和溶剂混合物。
合适的湿润剂(分散剂)包括上文指出的表面活性剂。
合适的其它助剂包括上文指出的那些助剂。
半固体制剂可以口服给药或皮肤给药。其只是根据其较高的粘度区别于上述混悬剂和乳化剂。
为了制备固体制剂,将活性化合物与合适的赋形剂混合,如果合适,加入助剂,并且根据需要配制混合物。
合适的赋形剂包括所有的生理可接受固体惰性物质。适于该目的的是无机和有机物质。无机物质是例如食盐,碳酸盐例如碳酸钙,碳酸氢盐,氧化铝,二氧化硅,粘土,沉积的或胶体二氧化硅,和磷酸盐。
有机物质是例如糖,纤维素,食料和动物饲料,例如奶粉,动物粉,谷粉,粗谷粉和淀粉。
助剂是上文已经提到的防腐剂,抗氧化剂和着色剂。
其它合适的助剂是润滑剂和滑动剂,例如硬脂酸镁,硬脂酸,滑石,膨润土,崩解剂,例如淀粉或交联的聚乙烯吡咯烷酮,粘合剂,例如淀粉,明胶或线性聚乙烯吡咯烷酮,和干粘合剂,例如微晶纤维素。
在制剂中,活性化合物也可以与协同剂或对抗病原性内寄生虫有活性的其它活性化合物的混合物存在。这样的活性化合物的例子是L-2,3,5,6-四氢-6-苯基-咪唑并噻唑,苯并咪唑氨基甲酸酯,吡喹酮,噻嘧啶或苯硫氨酯。
即用型制剂含有10ppm至20%重量,优选0.1-10%重量浓度的活性化合物。
使用前稀释的制剂含有0.5-90%重量,优选5-50%重量浓度的活性化合物。
一般情况下,发现每天每千克体重给药量大约是1-100mg活性化合物以获得有效结果是有利的。
下面的实施例说明本发明中间体或活性化合物的制备和应用。
制备实施例
实施例1
氩气下,将PF1022(0.95g,1mmol)悬浮于冰醋酸(4ml)中。加入硫酸(浓硫酸;0.44ml)后,计量加入碘酸钠(166mg;0.84mmol)和碘(406mg;1.60mmol)。剧烈搅拌该混合物并且在油浴中加热到70℃。7小时后,使该混合物冷却并且加入一些氯仿稀释。用亚硫酸钠溶液(30%浓度水溶液)洗涤反应混合物。相分离后,用碳酸钠中和含水相并且再次用氯仿萃取。用碳酸氢钠溶液(饱和的水溶液)洗涤合并的有机相并且接着用氯化钠溶液(饱和的水溶液)洗涤。干燥有机相(硫酸镁)然后蒸馏出溶剂。残留的油状物通过柱色谱纯化(硅胶;φ×1=5cm×50cm;环己烷/乙酸乙酯=4+1)。得到0.9g(理论量的75%)无色固体。半制备HPLC(乙腈/H2O=75+25)得到0.6g异构体二碘代苄基化合物。
FAB-MS:m/z(标称质量):1223(M+Na+);1201(M+H+)
m.p.:84℃。
实施例2
制备PF1022的一碘代衍生物
氩气下,将PF1022(0.96g,1mmol)溶解于氯仿(25ml)中.0℃下加入I,I-二(三氟乙酰氧基)-碘代苯(=PhIL2)(2.76g,6.44mmol)后计量加入碘(1.10g;4mmol)。使混合物温热至室温。室温下反应7天后,将反应溶液倒入亚硫酸钠溶液(30%浓度,水溶液)中。分离各相。相分离后,用碳酸钠中和含水相并且再次用氯仿萃取。用碳酸氢钠溶液(饱和的水溶液)洗涤合并的有机相并且接着用氯化钠溶液(饱和的水溶液)洗涤。干燥有机相(硫酸镁)然后蒸馏出溶剂。残留的油状物通过柱色谱纯化(硅胶;φ×1=5cm×50cm;环己烷/乙酸乙酯=4+1)。得到0.44g无色固体。利用半制备HPLC(乙腈/H2O=75+25)分离得到0.2g异构体一碘代苄基化合物。
FAB-MS:m/z:1097(M+Na+);1075(M+H+)
m.p.:95℃。
实施例3
氩气下,将PF1022(1.9 g,2mmol)溶解于氯仿(30ml)中。0℃下计量加入PhIL2(3.6 g,8.4mmol)后滴加溴(1.28 g;8mmol)。使混合物温热至室温。室温下反应5天后,将反应混合物倒入亚硫酸钠溶液(30%浓度,水溶液)中。分离各相。用氯仿萃取含水相,含水相与用于中和的碳酸钠混合并且再次用氯仿萃取。用碳酸氢钠溶液(饱和的水溶液)洗涤合并的有机相并且接着用氯化钠溶液(饱和的水溶液)洗涤。干燥各相(硫酸镁)然后蒸馏出溶剂。残留的油状物通过柱色谱纯化(硅胶;φ×1=5cm×50cm;乙酸乙酯/环己烷=1+4)。得到1.24g(理论量的62%)异构体二溴代苄基化合物。
FAB-MS:m/z:1127(M+Na+);1105(M+H+)
m.p.:99℃。
实施例4
制备PF1022的一溴代衍生物
通过实施例3的方法进行反应和后处理,但是是在1.5当量溴和1.6当量PhIL2存在下(见上文)。通过半制备HPLC(乙腈/H2O=70+30)去除仍然存在的PF1022得到0.3g异构体一溴代苄基化合物。
FAB-MS:m/z:1049(M+Na+)
m.p.:136℃。
实施例5
-20℃下,向一羟基化合物PF1022E(386mg;0.40mmol)的无水吡啶(2ml)的溶液滴加三氟甲磺酸酐(79.1μl;135.4mg;0.22mmol)。使混合物温热至0℃,并且在该温度下又搅拌24小时。TLC后,将混合物倒入水中并且用乙酸乙酯萃取。合并的有机相用10%浓度的盐酸,水和饱和的氯化钠溶液洗涤,硫酸镁干燥并且接着浓缩。残留物通过柱色谱纯化(硅胶;φ×1=5cm×50cm;环己烷/乙酸乙酯=4+1;调节:+1%的三乙酸)。得到304.4mg(理论量的73%)20-苄基-5,11,17,23-四异丁基-2,4,10,14,16,22-六甲基-8-(4-三氟甲基磺酰基氧基苄基)-1,7,13,19-四氧杂-4,10,16,22-四氮杂正二十四烷-3,6,9,12,15,18,21,24-八酮。
ESI-MS:m/z(标称质量):1097(M+H+);1119(M+Na+)。
实施例6
制备PF1022的二(1-乙氧羰基乙烯-2-基)衍生物
氩气下,首先加入得自实施例1的异构体二碘代苄基化合物(0.87g,0.72mmol)和丙烯酸乙酯(0.36g,3.6mmol)的混合物。室温搅拌下加入三丁基胺(0.4g,2.20mmol)和乙酸钯(Ⅱ)(41mg,25mol%)。反应在100℃下进行27小时。后处理时,混合物溶解于10ml氯仿。有机相用水洗涤并且接着干燥(硫酸镁)。通过柱色谱进一步纯化(1.环己烷;2.环己烷/乙酸乙酯=3+1;3.环己烷/乙酸乙酯=1+1)得到0.5g粗产物。利用半制备HPLC(乙腈/H2O=80+20)分离得到0.14g二1-乙氧羰基乙烯-2-基取代的产物。
FAB-MS:m/z:1167(M+Na+)
实施例7
氩气下,首先加入得自实施例1的异构体二碘代苄基化合物(0.80g,0.67mmol)和2-甲基丁-3-炔-2-醇(0.22g,2.6mmol)的混合物。室温搅拌下加入三乙胺(1ml)和二(三苯基膦)-钯二氯化物(94mg,20mol%)和碘化铜(19mg;15mol%)。反应在80℃下进行15小时。后处理时,混合物溶解于10ml氯仿。有机相用水洗涤并且接着干燥(硫酸镁)。通过柱色谱进一步纯化(环己烷/乙酸乙酯=1+1)得到0.5g粗产物。利用半制备HPLC(乙腈/H2O=70+30)将一-和二-取代的产物相互分离。
二(3-羟基-3-甲基-1-丁炔-1-基)衍生物(7-1):
FAB-MS:m/z:1135(M+Na+)m.p.:179℃
一(3-羟基-3-甲基-1-丁炔-1-基)衍生物(7-2):
FAB-MS:m/z:1053(M+Na+) m.p.:85℃
实施例8
制备PF1022的二(4-甲氧基苯基)-衍生物
氩气下,将得自实施例1的异构体二碘代苄基化合物(0.50g,0.42mmol)和对-甲氧基苯基硼酸(0.14g,0.92mmol)的混合物溶解于甲苯(4ml)。室温搅拌下加入2M碳酸氢钠溶液(0.6ml)和四(三苯基膦)-钯(100mg,20mol%)。反应在80℃下进行18小时后,通过定量HPLC检测没有起始物。后处理时,混合物溶解于10ml氯仿。有机相用水洗涤并且接着干燥(硫酸镁)。通过柱色谱进一步纯化(环己烷/乙酸乙酯=1+1)得到0.42g(理论量的85%)二甲氧基二苯基化合物。
FAB-MS:m/z:1183(M+Na+)
实施例9
氩气下,将得自实施例3的异构体二溴代苄基化合物(0.87g,0.79mmol)和氰化锌(0.11g,0.9mmol)的混合物溶解于二甲基甲酰胺(5ml)。室温搅拌下加入四(三苯基膦)-钯(0.137g,15mol%)。反应在80℃下进行6小时后,后处理混合物。后处理时,混合物用甲苯稀释。有机相用氨水洗涤并且接着干燥(硫酸镁)。通过柱色谱进一步纯化(环己烷/乙酸乙酯=2+1)得到0.5g二氰基苄基化合物。
FAB-MS:m/z:1021(M+Na+)
实施例10
制备PF1022的二(氰基乙烯基)衍生物
氩气下,首先在四氟乙酸(653μl;5.0mmol)中加入8,20-二-(4-氨基苄基)-5,11,17,23-四异丁基-2,4,10,14,16,22-六甲基-1,7,13,19-四氧杂-4,10,16,22-四氮杂环正二十四烷-3,6,9,12,15,18,21,24-八酮(979.2mg;1.0mmol),加入水(1.5ml)并且在0℃下通过滴加亚硝酸钠溶液(141.5mg;2.05mmol,在0.5ml脱气水中)进行重氮化作用。0℃下搅拌30分钟后,加入甲醇(4ml),丙腈(163.3μl;212.2mg;4.0mmol)和乙酸钯(Ⅱ)(9mg),接着混合物在回流下沸腾1-2小时。
TLC后,混合物通过助滤剂Celite_过滤,用二氯甲烷洗涤滤饼并且减压蒸发滤液。柱色谱纯化(硅胶;φ×1=2.5cm×32cm;环己烷/乙酸乙酯=1+1)得到370mg(理论量的35%)8,20-二-[4-(2-氰基乙烯基)苄基]-5,11,17,23-四异丁基-2,4,10,14,16,22-六甲基-1,7,13,19-四氧杂-4,10,16,22-四氮杂环正二十四烷-3,6,9,12,15,18,21,24-八酮。
ESI-MS:m/z(标称质量):1053(M+H+)
应用实施例
实施例A
小鼠体内抗蠕虫活性
所有实验使用体重16-18g,SPF/CFW1品系的雄性小鼠。5只动物一起豢养在Makrolon_笼(聚碳酸酯)中并且随意进食水和“Sniff”鼠食。用线虫Nematospiroides dubius(=多旋类卷体线虫(Heligmosomoides polygyrus))和有泡异刺线虫(Heterakisspumosa)的混合物感染小鼠。感染后35-42天从小鼠结肠分离N.dubius线虫L3幼虫的感染物质并且在27℃下孵育3星期。将试验物质(1g)溶解于或悬浮于乳化剂Cremophor EL中。连续4天每天对小鼠服用溶液或悬浮液,每20g小鼠服用0.5ml。一只小鼠接受100mg/kg的剂量。分步进行小鼠的混合感染。首先用90个有泡异刺线虫的受孕卵口服感染小鼠,27天后,服用60-70个N.dubius的丝虫状幼虫。感染后第46天开始用所述物质治疗并且在第49天终止。又8天后,用CO2杀死小鼠并解剖。从盲肠和结肠分离有泡异刺线虫并且用显微镜计数。在十二指肠的压片标本中计数N.dubius线虫。如果标本中没有看到寄生虫,则得到3分。
在该项试验中,例如,下面的化合物表现出所述活性:
活性化合物制备实施例序号 | 剂量[mg/kg] | N.dubius | 有泡异刺线虫 |
1 | 100p.o. | 2 | |
4 | 100p.o. | 3 | 3 |
7-1 | 100p.o. | 2 |
p.o.口服
2=好的活性(减少75-95%);3=完全活性(减少95%以上)
实施例B
绵羊体内抗蠕虫活性
用5000个捻转血矛线虫(Haemonchus contortus)L3幼虫实验性感染体重25-35kg的Merino或Blackhead绵羊,并且在寄生虫显露前期期满(3-4星期)后,用试验物质治疗。使用凝胶胶囊口服试验物质。在长刺蛇形毛圆线虫(Trichostrongylus colubriformis)情况下,使用12000L3幼虫进行感染。通过减少粪便排泄的卵数来测定抗蠕虫活性。最后,根据常规的McMaster方法制备新获得的粪便,并且测定每克粪便中的卵数。在治疗前后经6-8星期以有规律的间隔(3-4天)测定卵数。该试验中卵数的减少大于95%时指定为3。在该项试验中,例如,下面的化合物表现出所述活性:
活性化合物制备实施例序号 | 捻转血矛线虫0.05mg/kg P.O. | 长刺蛇形毛圆线虫0.25mg/kg |
2 | 3 | 3 |
4 | 3 | |
7-2 | 3 |
p.o.口服
3=完全活性(减少95%以上)
Claims (7)
1.式(Ⅰ)的环八缩肽其中
R1代表氰基,C-C-连接的杂环基或者任选被取代的链烯基,炔烃基或芳基,和
R2代表氢或者代表和R1一样的基团。
3.式(Ⅱ)的环八缩肽其中
X1代表溴,碘,-OSO2Rf,其中Rf代表氟化的C1-C4-烷基,和X2代表氢或者和X1相同的基团。
4.制备权利要求3的式(Ⅱ)的化合物的方法其中
X1代表溴,碘,-OSO2Rf,其中
Rf代表氟化的C1-C4-烷基,和
X2代表氢或者和X1相同的基团,
特征在于
b)在式(Ⅱ-b)的碘代环八缩肽的情况下其中
X2-2代表氢或碘,
对指定为PF1022的环八缩肽进行碘化,
或者
c)在式(Ⅱ-c)的磺酸环八缩肽酯的情况下其中
Rf代表氟化的C1-C4-烷基,
X2-3代表氢或代表-O-SO2-Rf,
X3代表羟基或氢,
Rf-SO2-Y (Ⅳ)其中
Y代表-O-SO2-Rf,F或氯,其中Rf代表氟化的C1-C4-烷基,或者
X4代表-N2 +(X3)-或氢,
X3代表稳定重氮盐的阴离子,
HO-SO2-Rf (Ⅵ)其中Rf如上定义。
5.权利要求1的式(Ⅰ)的环八缩肽在人医学和兽医中防治蠕虫的用途。
6.权利要求1的式(Ⅰ)的环八缩肽制备在人医学和兽医中防治体内寄生虫的组合物的用途。
7.防治体内寄生虫的组合物,特征在于它们含有权利要求1的式(Ⅰ)的环八缩肽和扩充剂和稀释剂和,如果需要,常规的添加剂。
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DE19811559A DE19811559A1 (de) | 1998-03-17 | 1998-03-17 | Cyclooctadepsipeptide |
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DE102009012423A1 (de) | 2009-03-10 | 2010-09-16 | Bayer Animal Health Gmbh | Zubereitung auf Ölbasis |
DE102010064245A1 (de) | 2010-12-28 | 2012-06-28 | Bayer Animal Health Gmbh | Makrocylischen Lactone und deren Verwendung und deren Kombinationen mit anderen Wirkstoffen |
WO2012028556A1 (en) | 2010-08-31 | 2012-03-08 | Bayer Animal Health Gmbh | Macrocyclic lactones and their use and their combinations with other active substances |
RU2020107484A (ru) | 2015-12-28 | 2020-03-19 | Мериал, Инк. | Противогельминтные депсипептидные соединения |
CA3044038A1 (en) | 2016-11-16 | 2018-05-24 | Boehringer Ingelheim Animal Health USA Inc. | Anthelmintic depsipeptide compounds |
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WO1994019334A1 (en) * | 1993-02-19 | 1994-09-01 | Meiji Seika Kaisha, Ltd. | Pf1022 derivative, cyclic depsipeptide |
DE4317457A1 (de) * | 1993-05-26 | 1994-12-01 | Bayer Ag | Octacyclodepsipeptide mit endoparasitizider Wirkung |
CZ295705B6 (cs) * | 1995-09-22 | 2005-10-12 | Bayer Aktiengesellschaft | Cyklodepsipeptidové deriváty sloučeniny PF1022 a farmaceutický prostředek s jejich obsahem |
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- 1999-03-04 JP JP2000536703A patent/JP2002506857A/ja active Pending
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---|---|---|---|---|
CN107835818A (zh) * | 2015-05-20 | 2018-03-23 | 梅里亚股份有限公司 | 驱虫缩酚酸肽化合物 |
CN107835818B (zh) * | 2015-05-20 | 2022-04-29 | 勃林格殷格翰动物保健美国公司 | 驱虫缩酚酸肽化合物 |
CN114891070A (zh) * | 2015-05-20 | 2022-08-12 | 勃林格殷格翰动物保健美国公司 | 驱虫缩酚酸肽化合物 |
Also Published As
Publication number | Publication date |
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KR20010041450A (ko) | 2001-05-25 |
CA2323628A1 (en) | 1999-09-23 |
WO1999047506A1 (de) | 1999-09-23 |
BR9908861A (pt) | 2000-11-21 |
JP2002506857A (ja) | 2002-03-05 |
AU3143899A (en) | 1999-10-11 |
EP1064272A1 (de) | 2001-01-03 |
PL342948A1 (en) | 2001-07-16 |
DE19811559A1 (de) | 1999-09-23 |
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