TW201201802A - Substituted isoxazoline derivatives - Google Patents
Substituted isoxazoline derivatives Download PDFInfo
- Publication number
- TW201201802A TW201201802A TW100111814A TW100111814A TW201201802A TW 201201802 A TW201201802 A TW 201201802A TW 100111814 A TW100111814 A TW 100111814A TW 100111814 A TW100111814 A TW 100111814A TW 201201802 A TW201201802 A TW 201201802A
- Authority
- TW
- Taiwan
- Prior art keywords
- alkyl
- group
- trifluoromethyl
- compound
- dihydroisoxazol
- Prior art date
Links
- 0 *C(NCc1cc(C(C2)=NOC2(C(F)(F)F)c2cc(*)c(*)c(*)c2)ccc1)=O Chemical compound *C(NCc1cc(C(C2)=NOC2(C(F)(F)F)c2cc(*)c(*)c(*)c2)ccc1)=O 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
201201802 六、發明說明: 相關申請案之交互參照 本案主張審查中的2010年4月8日申請之美國臨時 申請案序號61/322,144及2011年1月10日申請之美國臨 時申請案序號61/4 31,107的優先權》 【發明所屬之技術領域】 本發明係有關具有殺寄生蟲活性之異鸣唑啉衍生物。 關注之化合物係爲經取代異噚唑啉3 -苄基乙醯胺、胺基甲 酸酯及脲。本發明亦有關獸醫組成物及其使用方法。 【先前技術】 需要動物及鳥類使用之改良抗寄生蟲劑,尤其需要改 良之殺昆蟲劑及殺蟎劑。再者,需要可簡便投藥之改良局 部及經口產品,其含有至少一種可用以有效的處置(treat) 體外寄生蟲諸如昆蟲(例如,蚤類、蝨類及蠅類)及蟎類(例 如,蟎類及壁蝨)之抗寄生蟲劑。該等產品特別可用於處 置陪伴動物、家畜及家禽。 目前用於陪伴動物、家畜及家禽之殺昆蟲及殺蟎處置 的化合物並非始終展現良好之活性、作用速度或作用歷時 。大部分之處置皆含有會有嚴重後果之危險性化學物質, 包括誤食致死。通常建議施加此等藥劑者限制藥劑之曝露 。已採用寵物項圏及標簽以克服某些問題,但此等方式無 法耐受咀嚼、攝食及對動物之後續毒理效應。因此,目前 -5- 201201802 之處置達成的程度不同,有一部分係取決於毒性、投藥方 法及效能。目前,有些藥劑實際上因爲寄生蟲抗藥性而變 成無效。 技術界已揭示異噚唑啉衍生物具有殺昆蟲及殺蟎活性 。例如,W02005/085216、W02007/1 058 1 4、W02007/026965、 WO2008/122375 及 JP2008239611 描述 4-(5-經取代-5-經取 代芳基-4,5-異噚唑-3-基)苯甲醯胺及胺衍生物。再者, W02005/051932列出特定之4,5-二氫異噚唑苯甲醯胺衍生 物,但未揭示本發明化合物。儘管可以取得有效之廣效型 抗寄生蟲劑,但仍需要可克服現在仍存在發展抗藥性之威 脅的較安全、便利且對環境友善之產品。 此等引文未舉出任何本發明經異噚唑啉取代之噚唑的 實例,亦未指出該等化合物可用於對抗與陪伴動物、家畜 、家禽有關之範圍的寄生物種,或對抗該範圍之寄生形態 生命週期階段。 本發明克服或改善現存化合物之性質的各種不同缺點 中之一或多項。尤其,本發明描述展現該等性質之新穎經 異噚唑啉取代之芳基及雜芳基噚唑。 【發明內容】 本發明提供式(1)化合物、或其獸醫上可接受之鹽, 其係作爲殺寄生蟲劑,尤其是殺體外寄生蟲劑,因此,可 用以預防、處置、驅除及防治動物及鳥類之蟎類及昆蟲感 染及侵襲》此外’本發明預期防治及預防蜱傳染疾病,例201201802 VI. INSTRUCTIONS: Cross-references to relevant applications. The US provisional application number 61/322,144 filed on April 8, 2010 and the US provisional application number 61/4 applied for on January 10, 2011 Priority of 31,107 [Technical Field to Be Invented by the Invention] The present invention relates to an isoxazoline derivative having parasiticidal activity. The compound of interest is the substituted isoxazoline 3-benzylacetamide, urethane and urea. The invention also relates to veterinary compositions and methods of use thereof. [Prior Art] There is a need for improved antiparasitic agents for use in animals and birds, and in particular, improved insecticides and acaricides are required. Furthermore, there is a need for improved topical and oral products that can be easily administered, which contain at least one species that can be used to effectively treat ectoparasites such as insects (eg, mites, mites and flies) and mites (eg, Anti-parasitic agents for mites and tick. These products are especially useful for the disposal of companion animals, livestock and poultry. Compounds currently used for the insecticidal and acaricidal treatment of companion animals, livestock and poultry do not always exhibit good activity, speed of action or duration of action. Most of the treatments contain dangerous chemicals that can have serious consequences, including eating and killing. It is generally recommended that the application of such agents limit the exposure of the agent. Pet items and labels have been used to overcome certain problems, but these methods are not resistant to chewing, feeding and subsequent toxicological effects on animals. Therefore, the current level of treatment of -5-201201802 is different, depending on toxicity, dosage method and efficacy. Currently, some agents are actually ineffective due to parasite resistance. The technical community has revealed that isoxazoline derivatives have insecticidal and acaricidal activity. For example, WO2005/085216, WO2007/1 058 1 4, WO2007/026965, WO2008/122375 and JP2008239611 describe 4-(5-substituted-5-substituted aryl-4,5-isoxazol-3-yl) Benzylamine and amine derivatives. Further, W02005/051932 lists specific 4,5-dihydroisoxazole benzamide derivatives, but does not disclose the compounds of the present invention. Although effective broad-spectrum anti-parasitic agents are available, there is still a need for safer, more convenient, and environmentally friendly products that overcome the threat of developing resistance. These references do not cite any examples of the isoxazoline-substituted oxazoles of the present invention, nor do they indicate that such compounds can be used against parasitic species in the range associated with companion animals, livestock, poultry, or against parasites in the range. Formal life cycle stage. The present invention overcomes or ameliorates one or more of the various disadvantages of the nature of the existing compounds. In particular, the present invention describes novel transoxazoline substituted aryl and heteroaryl carbazoles exhibiting such properties. SUMMARY OF THE INVENTION The present invention provides a compound of formula (1), or a veterinary acceptable salt thereof, as a parasiticidal agent, especially an ectoparasite, and thus, useful for preventing, treating, repelling and controlling animals. And avian mites and insect infections and invasions. In addition, the present invention contemplates the prevention and treatment of sputum infectious diseases,
S • 6- 201201802 如,萊姆病(Lyme disease)、犬及牛邊蟲(canine and bovine anaplasmosis)' 犬艾利希體症(canine ehrlichiosis)、犬立 克次體症(canine rickettsiosis)、犬及牛焦蟲病(canine and bovine babesiosis)、牛流行性流產(epizootic bovine abortion) 以及泰勒原蟲病(theileriosis)。因此,根據本發明,提供 一種式(1)化合物S • 6- 201201802 For example, Lyme disease, canine and bovine anaplasmosis' canine ehrlichiosis, canine rickettsiosis, canine And canine and bovine babesiosis, epizootic bovine abortion, and theileriosis. Therefore, according to the present invention, a compound of the formula (1) is provided
或其獸醫上可接受之鹽,其中Or a veterinary acceptable salt thereof, wherein
Rla、1111>及111<:係各自獨立的選自鹵素、氰基、Ci-Cs 烷基、Ci.Q鹵烷基及Ci.Ce鹵烷氧基,且各R1可彼此相 同或相異; R2係爲氫、鹵基、氰基、烷基、鹵烷基或 C^-Ce烷氧基、(:丨-(:6鹵烷氧基、C3-C6環烷基,其中η係 爲整數1、2或3,且當η係2或3時,各R2可彼此相同 或相異; R3係選自C丨-C8烷基、C〇-C3烷基C3-C6環烷基、Ci· 201201802 c6烷基-OR4或c!-C6烷基C(0)NRaRb,其中該C丨-C8烷基 及C^C3烷基(:3.(:6環烷基係任意地經至少一個選自以下 之基團所取代:鹵基 '氰基、羥基及S(0)pR4 ; R係Ci.Ce院基或C1.C6鹵院基;Rla, 1111> and 111<: are each independently selected from the group consisting of halogen, cyano, Ci-Cs alkyl, Ci. Q haloalkyl and Ci. Ce haloalkoxy, and each R1 may be the same or different from each other; R2 is hydrogen, halo, cyano, alkyl, haloalkyl or C^-Ce alkoxy, (: 丨-(: 6 haloalkoxy, C3-C6 cycloalkyl, wherein η is an integer 1, 2 or 3, and when η is 2 or 3, each R2 may be the same or different from each other; R3 is selected from C丨-C8 alkyl, C〇-C3 alkyl C3-C6 cycloalkyl, Ci· 201201802 c6 alkyl-OR4 or c!-C6 alkyl C(0)NRaRb, wherein the C丨-C8 alkyl group and the C^C3 alkyl group (:3.(6)cycloalkyl group are optionally at least one selected Substituted from the following groups: halo-cyano, hydroxy and S(0)pR4; R-based Ci.Ce or C1.C6 halogen;
Ra係爲氫或Ci.c6院基; 1^係爲氫、c丨-C6烷基、C丨.c6鹵烷基、c0.c4烷基c3-c6環烷基或ChG烷基Het,其中Het係爲含有至少一個 選自N、0或S之雜原子的5-或6-員單環性芳族環,且 Het可任意地經至少一個選自以下基團的取代基所取代: 鹵基 '氰基、<:丨—C6烷基及C丨.C6_烷基;且 P係爲整數〇、1或2。 本發明另一態樣中’當該整數η係3時,(R2)n係R2a 、R2b及R2e。當該整數η係2時’貝IJ (R2)n係R2a及R2b、 R2a及R2°或R2b及R2c。當該整數n爲1時,貝U (R2)n係 R2a、R2b 或 R2c。 本發明另一態樣中’式(1)化合物包括式(1 A)、( 1 B )、 (1C)及(ID)化合物Ra is hydrogen or Ci.c6; 1^ is hydrogen, c丨-C6 alkyl, C丨.c6 haloalkyl, c0.c4 alkyl c3-c6 cycloalkyl or ChG alkyl Het, wherein Het is a 5- or 6-membered monocyclic aromatic ring containing at least one hetero atom selected from N, 0 or S, and Het may be optionally substituted with at least one substituent selected from the group consisting of: a base 'cyano group, <: 丨-C6 alkyl group and C丨.C6_alkyl group; and P is an integer 〇, 1 or 2. In another aspect of the invention, when the integer η is 3, (R2)n is R2a, R2b and R2e. When the integer η is 2, the shell IJ (R2) n is R2a and R2b, R2a and R2° or R2b and R2c. When the integer n is 1, the shell U (R2)n is R2a, R2b or R2c. In another aspect of the invention, the compound of formula (1) comprises compounds of formula (1 A), (1 B), (1C) and (ID)
S -8- 201201802S -8- 201201802
或其獸醫上可接受之鹽。 本發明另一態樣中,式(1)化合物包括式(1A)化合物。 本發明再另一態樣中’式(1)化合物包括式(1B)化合物。本 發明再另一態樣中,式(1)化合物包括式(1 C)化合物。本發 明再另一態樣中,式(1)化合物包括式(i D)化合物。 本發明另一態樣中’ Rla、Rlb及R1。係各自獨立的選 自鹵素、氰基、C^Cs烷基或Ci—Ce鹵烷基》本發明又另一 態樣中,Rla、Rlb及Ric係各自獨立的選自氟、氯、溴、 氰基、Ci.Cs烷基及Ci_C6鹵烷基。本發明再另—態樣中, Rla、Rlb& Rle各獨立的選自氟、氯、溴、氰基、甲基、 乙基、-CF3及-CH2CF3。本發明再另—態樣中,Rla ' Rib -9- 201201802 及Rle各獨立的選自氟、氯、溴、及CF3。本發明再另一 態樣中’ Rla、Rlb及Ri。係各自獨立的選自氟或氯。本發 明再另一態樣中,Rla及Ri。係各爲氯且Rlb係爲氟。本發 明再另一態樣中,R 1 a、R 1 b及R 1。係各爲氯。 本發明另一態樣中,R2a、R2b及R2。係各獨立的爲氫 、鹵基、氰基、C丨.c6烷基、C丨-C6鹵烷基或C3-C6環烷基 。本發明又另一態樣中,R2a、R2b及R2c係各獨立的爲氫 、鹵基、氰基、甲基、乙基、-CF3、-CH2CF3、環丙基或 環丁基。本發明又另一態樣中,R2a、R2b及R2e係各獨立 的爲氫、氟、氯、溴、氰基、甲基或CF3。本發明又另一 態樣中,R2a、R2b及R2<=係各獨立的爲氟、氯、溴、甲基 或 CF3。 本發明又另一態樣中,R2a及R2b兩者皆爲氫,且R2c 係爲氫、鹵基、氰基、甲基、乙基、-CF3、-CH2CF3、環 丙基或環丁基。本發明又另一態樣中,R2a及R2b兩者皆 爲氫,且R2e係爲氫、氟、氯、溴、氰基、甲基或CF3。 本發明又另一態樣中,1123及R2b兩者皆爲氫,且R2e係爲 氟、氯、溴、甲基或CF3。本發明又另一態樣中,R2a及 R2b兩者皆爲氫,且R2e係爲氟、氯或溴。本發明又另一 態樣中’ 1123及R2b兩者皆爲氫,且R2c係爲氟。本發明又 另一態樣中’ R2a及R2b兩者皆爲氫,且R2e係爲氯。本發 明又另一態樣中,R2a及R2b兩者皆爲氫,且R2。係爲溴。 本發明又另一態樣中’ R3係選自Ci.C8烷基或CQ.C3 烷基C3_c6環烷基;其中該(^-(^烷基及該C〇-C3烷基c3.Or a veterinary acceptable salt thereof. In another aspect of the invention, the compound of formula (1) comprises a compound of formula (1A). In still another aspect of the invention, the compound of the formula (1) comprises a compound of the formula (1B). In still another aspect of the invention, the compound of formula (1) comprises a compound of formula (1 C). In still another aspect of the invention, the compound of formula (1) comprises a compound of formula (i D). In another aspect of the invention, 'Rla, Rlb and R1. In another aspect of the present invention, each of Rla, Rlb and Ric is independently selected from the group consisting of fluorine, chlorine, and bromine, and is independently selected from the group consisting of halogen, cyano, C^Cs alkyl or Ci-Ce haloalkyl. Cyano, Ci.Cs alkyl and Ci_C6 haloalkyl. In still another aspect of the invention, Rla, Rlb& Rle are each independently selected from the group consisting of fluorine, chlorine, bromine, cyano, methyl, ethyl, -CF3 and -CH2CF3. In still another aspect of the invention, Rla ' Rib -9- 201201802 and Rle are each independently selected from the group consisting of fluorine, chlorine, bromine, and CF3. In still another aspect of the invention, 'Rla, Rlb and Ri. They are each independently selected from fluorine or chlorine. In still another aspect of the invention, Rla and Ri. Each is chlorine and Rlb is fluorine. In still another aspect of the invention, R 1 a, R 1 b and R 1 are used. Each is chlorine. In another aspect of the invention, R2a, R2b and R2. Each is independently hydrogen, halo, cyano, C丨.c6 alkyl, C丨-C6 haloalkyl or C3-C6 cycloalkyl. In still another aspect of the invention, R2a, R2b and R2c are each independently hydrogen, halo, cyano, methyl, ethyl, -CF3, -CH2CF3, cyclopropyl or cyclobutyl. In still another aspect of the invention, each of R2a, R2b and R2e is independently hydrogen, fluorine, chlorine, bromine, cyano, methyl or CF3. In still another aspect of the invention, R2a, R2b and R2<= are each independently fluorine, chlorine, bromine, methyl or CF3. In still another aspect of the invention, both R2a and R2b are hydrogen, and R2c is hydrogen, halo, cyano, methyl, ethyl, -CF3, -CH2CF3, cyclopropyl or cyclobutyl. In still another aspect of the invention, both R2a and R2b are hydrogen, and R2e is hydrogen, fluorine, chlorine, bromine, cyano, methyl or CF3. In still another aspect of the invention, both 1123 and R2b are hydrogen and R2e is fluorine, chlorine, bromine, methyl or CF3. In still another aspect of the invention, both R2a and R2b are hydrogen, and R2e is fluorine, chlorine or bromine. In still another aspect of the invention, both '1232 and R2b are hydrogen and R2c is fluorine. In still another aspect of the invention, both ' R2a and R2b are hydrogen and R2e is chlorine. In still another aspect of the invention, both R2a and R2b are hydrogen and R2. It is bromine. In still another aspect of the invention, the 'R3 is selected from the group consisting of Ci.C8 alkyl or CQ.C3 alkyl C3_c6 cycloalkyl; wherein (^-(^ alkyl and the C〇-C3 alkyl c3.
S -10- 201201802 c6環烷基係任意地經至少一個選自以下之基團所取代:鹵 基、羥基及S(0)pR4,其中p係爲整數0、1或2且R4係 甲基、乙基或異丙基。 本發明又另一態樣中,R3係選自C^C8烷基、環丙基 、環丁基、環戊基、甲基環丙基、乙基環丙基、甲基環丁 基、乙基環丁基及甲基環戊基;其中該烷基、環烷基及烷 基環烷基係任意地經至少一個選自以下之基團所取代:鹵 基、羥基、-SCH3 及-S(0)2CH3。 本發明又再另一態樣中,R3係選自甲基、乙基、丙基 、丁基、異丙基、異丁基、正丁基、第三丁基、環丙基、 環丁基 '環戊基、甲基環丙基、乙基環丙基、甲基環丁基 、乙基環丁基及甲基環戊基;其中該烷基、環烷基及烷基 環烷基係任意地經至少一個選自以下之.基團所取代:鹵基 、羥基、-sch3 及-s(o)2ch3。 本發明又再另一態樣中,R3係選自甲基、乙基、丙基 、丁基、異丙基、異丁基、正丁基、第三丁基、環丙基、 環丁基、環戊基、甲基環丙基、乙基環丙基、甲基環丁基 、乙基環丁基及甲基環戊基;其中該烷基、環烷基及烷基 環烷基係任意地經至少一個選自以下之基團所取代:氟、 氯、-SCH3 及-S(0)2CH3。 本發明又再另一態樣中,R3係選自甲基、乙基、異丙 基、異丁基、環丙基、環丁基及甲基環丙基;其中該烷基 、環烷基及烷基環烷基係任意地經至少一個選自以下之基 團所取代:氟、氯、-SCH3及- S(0)2CH3。本發明又再另一 • 11- 201201802 態樣中,R3係選自甲基、乙基、異丙基、異丁基、環丙基 、環丁基及甲基環丙基。 本發明又另一態樣中,R3係Ct.Ce烷基-OR4,其中 Ci-Cfi烷基係甲基、乙基或丙基,且R4係甲基、乙基、異 丙基或三氟甲基。本發明又另一態樣中,R3係爲-CH2-0-CH3 、-ch2-o-ch2ch3 或-ch2-o-cf3。 本發明又另一態樣中,113係υ6烷基C(0)NRaRb, 其中Ci-Ce烷基係甲基或乙基,Ra係爲氫,且Rb係甲基 、乙基、三氟甲基、甲基環丙基、-CH2-吡唑、-CH2-噚唑 、-CH2-咪唑、-CH2-噻唑基、-CH2-異噻唑基、-CH2-三唑 、-CH2-四唑、-CH2·吡啶、-CH2-嗒畊及-CH2-嘧啶。本發 明再另一態樣中,Rb係爲甲基、乙基、甲基環丙基、_CH21& 唑、-ch2-咪唑、-ch2-三唑、-ch2-四唑、-ch2-吡啶、-ch2-嗒哄及- ch2-嘧啶。 本發明再另一態樣中,該整數P係爲〇。本發明再另 —態樣中,該整數p係爲1。本發明再另一態樣中,該整 數P係爲2。 本發明另一態樣中,式(1 )化合物包括: N-{5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二氫異噚 哩-3-基]-2-氟苄基}乙醯胺; 1^-{2-氟-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異噚唑_3_基]苄基卜2_甲基丙醯胺; N-{2-氟-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異噚唑-3-基]苄基}環丙烷甲醯胺;S -10- 201201802 c6 cycloalkyl is optionally substituted with at least one group selected from the group consisting of halo, hydroxy and S(0)pR4, wherein p is an integer of 0, 1 or 2 and R4 is methyl , ethyl or isopropyl. In still another aspect of the present invention, R3 is selected from the group consisting of C^C8 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopropyl, ethylcyclopropyl, methylcyclobutyl, and B. a cyclobutyl group and a methylcyclopentyl group; wherein the alkyl group, the cycloalkyl group and the alkylcycloalkyl group are optionally substituted with at least one group selected from the group consisting of halo, hydroxy, -SCH3 and -S (0) 2CH3. In still another aspect of the invention, R3 is selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl 'Cyclopentyl, methylcyclopropyl, ethylcyclopropyl, methylcyclobutyl, ethylcyclobutyl and methylcyclopentyl; wherein the alkyl, cycloalkyl and alkylcycloalkyl groups Optionally substituted with at least one group selected from the group consisting of halo, hydroxy, -sch3 and -s(o)2ch3. In still another aspect of the invention, R3 is selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl , cyclopentyl, methylcyclopropyl, ethylcyclopropyl, methylcyclobutyl, ethylcyclobutyl and methylcyclopentyl; wherein the alkyl, cycloalkyl and alkylcycloalkyl groups Optionally substituted with at least one group selected from the group consisting of fluorine, chlorine, -SCH3 and -S(0)2CH3. In still another aspect of the invention, R3 is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl and methylcyclopropyl; wherein the alkyl, cycloalkyl And the alkylcycloalkyl group is optionally substituted with at least one group selected from the group consisting of fluorine, chlorine, -SCH3 and -S(0)2CH3. In still another aspect of the invention, R3 is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl and methylcyclopropyl. In still another aspect of the invention, R3 is Ct.Ce alkyl-OR4, wherein Ci-Cfi alkyl is methyl, ethyl or propyl, and R4 is methyl, ethyl, isopropyl or trifluoro methyl. In still another aspect of the invention, R3 is -CH2-0-CH3, -ch2-o-ch2ch3 or -ch2-o-cf3. In still another aspect of the invention, 113 is υ6 alkyl C(0)NRaRb, wherein the Ci-Ce alkyl is methyl or ethyl, the Ra is hydrogen, and the Rb is methyl, ethyl, trifluoromethyl. , methylcyclopropyl, -CH2-pyrazole, -CH2-carbazole, -CH2-imidazole, -CH2-thiazolyl, -CH2-isothiazolyl, -CH2-triazole, -CH2-tetrazole, -CH2·pyridine, -CH2-indole, and -CH2-pyrimidine. In still another aspect of the present invention, Rb is methyl, ethyl, methylcyclopropyl, _CH21&azole, -ch2-imidazole, -ch2-triazole, -ch2-tetrazole, -ch2-pyridine, -ch2-嗒哄 and - ch2-pyrimidine. In still another aspect of the invention, the integer P is 〇. In still another aspect of the invention, the integer p is 1. In still another aspect of the invention, the integer P is two. In another aspect of the invention, the compound of formula (1) comprises: N-{5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-di Hydroisoiso-3-yl]-2-fluorobenzyl}acetamidamine; 1^-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(three Fluoromethyl)-4,5-dihydroisoxazole_3_yl]benzyl b-2-methylpropionamide; N-{2-fluoro-5-[5-(3,4,5-three Chlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}cyclopropanecarbamide;
S -12- 201201802 N-{2-氟-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異噚唑-3 _基]苄基}環丁烷甲醯胺; N-{2-氟-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異噚唑-3-基]苄基}丙醯胺; 2-環丙基- N-{2-氟- 5-[5-(3,4,5-三氯苯基)-5-(三氟甲基 )-4,5-二氫異卩f唑-3-基]苄基}乙醯胺; N-{2-氟-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異噚唑-3-基]苄基}-3-甲基丁烷醯胺; 2-環丙基-N-{5-[5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氫異噚唑-3-基]-2-氟苄基}乙醯胺; N-{5-[5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氫 異噚唑-3-基]-2-氟苄基}乙醯胺; N-{5-[5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氫 異噚唑-3-基]-2-氟苄基}環丙烷甲醯胺; N-{5-[5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氫 異噚唑-3-基]-2-氟苄基}-3,3-二氟環丁烷甲醯胺 N-{2-氯- 5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異鸣唑-3-基]苄基}乙醯胺; N-{2_氯-5_[5-(3,4,5·三氯苯基)-5-(三氟甲基)-4,5-二 氫異鸣唑-3-基]苄基}環丙烷甲醯胺; N-{2-氯-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異噚唑-3-基]苄基}-2-甲基丙醯胺; N-{2-氯- 5-[5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氫異噚唑-3-基]苄基}乙醯胺; -13- 201201802 N-(2-溴- 5-(5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異噚唑-3-基)苄基)乙醯胺, N-環丙基甲基-N’-{2-氟- 5-[5-(3,4,5-三氯-苯基)-5-三 氟甲基-4,5-二氫-異噚唑-3-基]-苄基}-丙二醯胺;及 N-乙基-N’-{2-氟- 5-[5-(3,4,5-三氯-苯基)-5-三氟甲基-4,5-二氫-異噚唑-3-基]-苄基}-丙二醯胺、或其獸醫上可接 受之鹽。 本發明再另一態樣中,式(1)化合物包括: N-{5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二氫異噚 唑-3-基]-2-氟苄基}乙醯胺; N-{2-氟-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異噚唑-3-基]苄基}-2-甲基丙醯胺; N-{2-氟-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異噚唑-3-基]苄基}環丙烷甲醯胺; N-{2-氟-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異噚唑-3-基]苄基}環丁烷甲醯胺; N-{2-氟- 5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異鸣唑-3-基]苄基}丙醯胺; 2-環丙基-N-{2-氟- 5-[5-(3,4,5-三氯苯基)-5-(三氟甲基 )-4,5-二氫異噚唑-3-基]苄基}乙醯胺; N-{2-氟- 5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異噚唑-3-基]苄基}-3-甲基丁烷醯胺; N-{5-[5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氫 異噚唑-3-基]-2-氟苄基}乙醯胺:S -12- 201201802 N-{2-Fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3 _yl]benzyl}cyclobutanecarbamamine; N-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5 -dihydroisoxazol-3-yl]benzyl}propanamine; 2-cyclopropyl-N-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5 -(trifluoromethyl)-4,5-dihydroisoindolefoxa-3-yl]benzyl}acetamidamine; N-{2-fluoro-5-[5-(3,4,5-three Chlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}-3-methylbutane decylamine; 2-cyclopropyl-N-{ 5-[5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-fluorobenzyl} Acetamine; N-{5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl] 2-fluorobenzyl}acetamide; N-{5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroiso Oxazol-3-yl]-2-fluorobenzyl}cyclopropanecarbamide; N-{5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl -4,5-dihydroisoxazol-3-yl]-2-fluorobenzyl}-3,3-difluorocyclobutanecarbamamine N-{2-chloro-5-[5-(3 ,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroiso N-oxazol-3-yl]benzyl}acetamidamine; N-{2_chloro-5_[5-(3,4,5·trichlorophenyl)-5-(trifluoromethyl)-4,5 -dihydroisoxazole-3-yl]benzyl}cyclopropanecarbamide; N-{2-chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoro Methyl)-4,5-dihydroisoxazol-3-yl]benzyl}-2-methylpropanoxime; N-{2-chloro-5-[5-(3,5-dichloro- 4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}acetamidamine; -13- 201201802 N-(2-bromo-5 (5-(3,4,5-Trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzyl)acetamide, N-cyclopropane Methyl-N'-{2-fluoro-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole-3 -yl]-benzyl}-propanediamine; and N-ethyl-N'-{2-fluoro-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoro Methyl-4,5-dihydro-isoxazol-3-yl]-benzyl}-propanediamine, or a veterinary acceptable salt thereof. In still another aspect of the invention, the compound of formula (1) comprises: N-{5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5- Dihydroisoxazol-3-yl]-2-fluorobenzyl}acetamidamine; N-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(three Fluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}-2-methylpropanamide; N-{2-fluoro-5-[5-(3,4,5- Trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}cyclopropanecarbamide; N-{2-fluoro-5-[5- (3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}cyclobutanecarbamamine; N-{2 -fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}propanamine 2-cyclopropyl-N-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole -3-yl]benzyl}acetamidamine; N-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5- Dihydroisoxazol-3-yl]benzyl}-3-methylbutane decylamine; N-{5-[5-(3,5-dichloro-4-fluorophenyl)-5-(three Fluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-fluorobenzyl}acetamide:
S -14- 201201802 N-{2-氯-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異噚唑-3_基]苄基}乙醯胺; N-{2-氯-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異鸣唑-3-基]苄基}環丙烷甲醯胺; N-{2-氯- 5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異噚唑-3-基]苄基}-2-甲基丙醯胺; N-{2-氯- 5-[5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氫異噚唑-3-基]苄基}乙醯胺;及 N-(2-溴-5-(5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異噚唑-3-基)苄基)乙醯胺、或其獸醫上可接受之鹽。 本發明再另一態樣中,式(1)化合物包括: N-{5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二氫異噚 唑-3-基]-2-氟苄基}乙醯胺; N-{2-氟-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異噚唑-3-基]苄基}-2-甲基丙醯胺; N-{2-氟-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異噚唑-3-基]苄基}環丙烷甲醯胺; N-{2-氟-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異喟唑-3-基]苄基}環丁烷甲醯胺; N-{2-氟- 5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異噚唑-3-基]苄基}丙醯胺; N-{5-[5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氫 異鸣唑-3-基]-2-氟苄基}乙醯胺; N-{2-氯- 5-[5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5- -15- 201201802 二氫異噚唑-3-基]苄基}乙醯胺;及 N-(2-溴- 5-(5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異Df唑-3-基)苄基)乙醯胺、或其獸醫上可接受之鹽。 本發明另一具體實施態樣係一種獸醫組成物,其包含 a)式(1)化合物、或其獸醫上可接受之鹽,及(b)獸醫上可 接受之賦形劑、稀釋劑或載劑。較佳係該組成物包含治療 有效量之式(1)化合物、或其獸醫上可接受之鹽及獸醫上可 接受之賦形劑、稀釋劑或載劑。 該組成物可包含至少一種附加之獸醫藥劑。較佳附加 獸醫藥劑包括殺體內寄生蟲劑、因得托菌素(endectocide) 、殺體外寄生蟲劑、殺昆蟲劑及驅蟲劑。 本發明再另一態樣係爲式(1)化合物用於製造醫藥之 用途。 本發明再另一態樣係爲該铒成物用以處置動物或鳥類 之寄生蟲感染或侵襲的用途,其包括在需要該處置之動物 或鳥類身上投予治療有效量之本發明化合物或其獸醫上可 接受之鹽的步驟。式(1)化合物、或其獸醫上可接受之鹽或 其組成物可經口、局部或皮下投藥。更佳係該等組成物可 經口或局部投藥。 本發明再另一態樣係爲該組成物用以處置動物或鳥類 之寄生蟲感染或侵襲的用途,其包括在需要該處置之動物 或鳥類身上投予治療有效量之本發明化合物或其獸醫上可 接受之鹽且結合至少一種附加之獸醫藥劑的步驟。式(1 )化 合物、或其獸醫上可接受之鹽可單獨或與附加獸醫藥劑一S -14- 201201802 N-{2-Chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3 _yl]benzyl}acetamide; N-{2-chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro Isoxazol-3-yl]benzyl}cyclopropanecarbamide; N-{2-chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl) -4,5-dihydroisoxazol-3-yl]benzyl}-2-methylpropanamine; N-{2-chloro-5-[5-(3,5-dichloro-4-fluoro Phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}acetamidamine; and N-(2-bromo-5-(5-(3, 4,5-Trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzyl)acetamide, or a veterinary acceptable salt thereof. In still another aspect of the invention, the compound of formula (1) comprises: N-{5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5- Dihydroisoxazol-3-yl]-2-fluorobenzyl}acetamidamine; N-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(three Fluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}-2-methylpropanamide; N-{2-fluoro-5-[5-(3,4,5- Trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}cyclopropanecarbamide; N-{2-fluoro-5-[5- (3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}cyclobutanecarbamamine; N-{2 -fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}propanamide ; N-{5-[5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2- Fluorobenzyl}acetamide; N-{2-chloro-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5--15 - 201201802 Dihydroisoxazol-3-yl]benzyl}acetamidamine; and N-(2-bromo-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoro) Methyl)-4,5-dihydroiso Dfoxazol-3-yl)benzyl)acetamide, or a veterinary acceptable salt thereof. Another embodiment of the invention is a veterinary composition comprising a) a compound of formula (1), or a veterinary acceptable salt thereof, and (b) a veterinary acceptable excipient, diluent or carrier Agent. Preferably, the composition comprises a therapeutically effective amount of a compound of formula (1), or a veterinary acceptable salt thereof, and a veterinary acceptable excipient, diluent or carrier. The composition can comprise at least one additional veterinary agent. Preferred additional veterinary agents include endoparasites, endectocides, ectoparasites, insecticides, and insect repellents. Still another aspect of the invention is the use of a compound of formula (1) for the manufacture of a medicament. Still another aspect of the present invention is the use of the composition for treating a parasitic infection or invasion of an animal or a bird, comprising administering a therapeutically effective amount of a compound of the present invention or an animal or a bird thereof, or a bird thereof, or a bird thereof The step of veterinary acceptable salt. The compound of formula (1), or a veterinary acceptable salt thereof, or a composition thereof can be administered orally, topically or subcutaneously. More preferably, the compositions can be administered orally or topically. Still another aspect of the invention is the use of the composition for the treatment of a parasitic infection or invasion of an animal or bird comprising administering a therapeutically effective amount of a compound of the invention or a veterinarian thereof to an animal or bird in need of such treatment The step of accepting a salt in combination with at least one additional veterinary agent. The compound of formula (1), or a veterinary acceptable salt thereof, may be used alone or in combination with an additional veterinary agent.
S -16- 201201802 起或以其組成物經口、局部及皮下投藥。 詳言之,動物係包括陪伴動物及家畜。更具體的說, 陪伴動物包括貓、狗及馬。更具體的說,陪伴動物包括狗 及貓。最具體之陪伴動物係爲狗。明確之家畜包括牛、豬 、綿羊、山羊及野牛;更明確的說,家畜包括牛、豬及綿 羊。最明確的說,家畜係牛及綿羊。 明確言之,鳥類係家禽。更明確的說,家禽包括雞、 火雞、鴨及鵝,最明確之家禽係火雞及雞。 本發明化合物單獨或與附加之獸醫藥劑結合可於以下 形式投藥:(a)單一獸醫組成物,其包含本發明化合物或其 獸醫上可接受之鹽及任意地選用之至少一種如本文所述之 附加獸醫藥劑與獸醫上可接受之賦形劑、稀釋劑或載劑; 或(b)兩種個別之獸醫組成物,其包含(i)第一種組成物, 其包含本發明化合物或其獸醫上可接受之鹽及獸醫上可接 受之賦形劑、稀釋劑或載劑,及(Π)第二種組成物,其包 含至少一種如本文所述之附加獸醫藥劑及獸醫上可接受之 賦形劑、稀釋劑或載劑。該獸醫組成物可同時或依序且以 任一順序投藥。 本文中所列之WO專利公告及JP專利申請案皆以引 用方式併入本文。 爲避免質疑,應瞭解在整個申請案中,所有針對獸醫 可接受之化合物及其鹽的引言皆包括有關藥學上可接受之 化合物及其鹽或農業上可接受之化合物及其鹽。此外,應 瞭解在整件申請案中,所有對獸醫活性之指稱皆包括藥學 • 17- 201201802 活性或農藥活性之指稱。 定義 就本發明目的而言’如本發明所描述及申請,下列術 語及短語係定義如下: 如本發明所使用之“附加獸醫藥劑(等)”或“獸醫藥 劑(等)’除非另有指不’否則係指其他獸醫化合物或產 物’提供治療有效量之該(等)藥劑,如本文所述,可用於 處置動物及鳥類之寄生蟲感染或侵襲》 “烷氧基”使用於本發明時,除非另有陳述,否則係 意指另有其他烷基取代基的氧原子團。烷氧基之烷基部分 (即’烷基原子團)具有如下之相同定義。非限制烷氧基實 例包括:-〇ch3、-OCH2CH3及諸如此類者。烷氧基之鹵基 部分具有與下述相同之定義。鹵基烷氧基之非限制實例包 括: -OCH2F、-OCHF2、-OCF3、-0CF2C13 及諸如此類者。 "烷基"使用於本發明時,除非另有陳述,否則係包括 具有通式CnH2n + 1之飽和單價烴烷基。該烷基可爲直鏈或 分支鏈,且可爲未經取代或經取代。例如,術語“ CQ-C3 烷基”或"C^-Cs烷基”係意指個別含有0至3個或1至 8個碳原子之單價、直鏈或分支鏈脂族基團。C^-Cs烷基 之非排他性實例係包括但非限制於甲基、乙基、丙基、異 丙基、第二丁基、第三丁基、正丙基、正丁基、異丁基、 第二丁基、正戊基、1-甲基丁基、2-甲基丁基、3·甲基丁S -16- 201201802 or its composition is administered orally, topically and subcutaneously. In particular, animal departments include companion animals and livestock. More specifically, companion animals include cats, dogs, and horses. More specifically, companion animals include dogs and cats. The most specific companion animal is a dog. Clear livestock include cattle, pigs, sheep, goats and bison; more specifically, livestock include cattle, pigs and sheep. Most specifically, livestock are cattle and sheep. To be clear, birds are poultry. More specifically, poultry include chickens, turkeys, ducks and geese, and the most clear poultry is turkey and chicken. The compounds of the invention, alone or in combination with additional veterinary agents, can be administered in the form of: (a) a single veterinary composition comprising a compound of the invention or a veterinary acceptable salt thereof, and optionally at least one as described herein. An additional veterinary agent and a veterinary acceptable excipient, diluent or carrier; or (b) two individual veterinary compositions comprising (i) a first composition comprising a compound of the invention or a veterinarian thereof An acceptable salt and veterinary acceptable excipient, diluent or carrier, and (second) second composition comprising at least one additional veterinary agent as described herein and a veterinary acceptable Forming agent, diluent or carrier. The veterinary composition can be administered simultaneously or sequentially and in any order. The WO patent publications and JP patent applications listed herein are hereby incorporated by reference. For the avoidance of doubt, it should be understood that throughout the application, all references to veterinary acceptable compounds and salts thereof include pharmaceutically acceptable compounds and salts thereof or agriculturally acceptable compounds and salts thereof. In addition, it should be understood that all references to veterinary activity in the entire application include pharmacy • 17- 201201802 Activity or pesticide activity. DEFINITIONS For the purposes of the present invention 'As described and claimed herein, the following terms and phrases are defined as follows: "Additional Veterinary Agent (etc.)" or "Veterinary Agent (etc.)" as used in the present invention unless otherwise Does not mean 'otherwise refers to other veterinary compounds or products' that provide a therapeutically effective amount of the agent, as described herein, can be used to treat parasitic infections or invasions of animals and birds. "Alkoxy" is used in the present invention. Unless otherwise stated, it is intended to mean an oxygen radical of another alkyl substituent. The alkyl moiety of the alkoxy group (ie, the 'alkyl radical') has the same definition as follows. Examples of non-limiting alkoxy groups include: - 〇ch3, -OCH2CH3 and the like. The halo moiety of the alkoxy group has the same definition as the following. Non-limiting examples of haloalkoxy groups include: -OCH2F, -OCHF2, -OCF3, -0CF2C13 and the like "Alkyl" When used in the present invention, unless otherwise stated, includes a saturated monovalent hydrocarbon alkyl group having the formula CnH2n + 1. The alkyl group may be a straight or branched chain and may be Substituted or substituted. For example, the term "CQ-C3 alkyl" or "C^-Cs alkyl" means a monovalent, straight or branched chain ester containing from 0 to 3 or from 1 to 8 carbon atoms. Family group. Non-exclusive examples of C^-Cs alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, t-butyl, t-butyl, n-propyl, n-butyl, isobutyl , second butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3·methylbutyl
S -18- 201201802 基、新戊基、3,3_二甲基丙基、2 -甲基戊基、2,2-二甲基 戊基、己基、3-乙基己基、庚基、4-乙基庚基、辛基及諸 如此類者。與另一術語共同呈現之烷基(例如,烷基環烷 基(即,-ch2環戊基(甲基環戊基)’ -CH2環丁基、-(CH2)2 環丙基(乙基環丙基)及諸如此類者。該烷基、環烷基及烷 基環垸基可藉脂族鏈之任一碳原子附接於化學原子團。該 烷基及烷基環烷基原子團可任意地經取代。 "動物(等)"使用於本發明時,除非另有陳述,否則係 意指分類哺乳動物綱之成員的個別動物。動物之非排他性 實例係包括陪伴動物及家畜。 “本發明化合物"使用於本發明時,除非另有陳述, 否則係意指式(1)、(ΙΑ)、(IB)、(1C)及(1D)化合物或其獸 醫上可接受之鹽。 "環烷基"使用於本發明時,除非另有陳述,否則係包 括完全飽和或部分飽和碳環性烷基原子團,其中烷基係如 前文定義。部分飽和環烷基之非限制實例包括:環丙烯、 環丁烯、環庚烯、環辛烯、環庚-1,3 -二烯及諸如此類者。 較佳環烷基係3 -至6 -員飽和單環性環,包括環丙基、環丁 基、環戊基及環己基。環烷基可藉碳環性環內之任一碳原 子附接於化學原子團。環烷基係任意地經至少一個取代基 取代。 “家禽”使用於本發明時’除非另有陳述,否則係意 指雞、火雞、鴨及鵝’尤其是雞及火雞,更特別是雞。 “鹵素"或“鹵基”使用於本發明時,除非另有陳述 -19- 201201802 ,否則係意指氟、氯、溴或碘。再者,當使用於組合字諸 如"鹵烷基"或“鹵烷氧基”中時,該烷基及烷氧基可經鹵 原子部分或完全取代,烷基及烷氧基可部分或完全經鹵原 子取代,該等鹵原子可爲相同或相異,且該烷基及烷氧基 原子團具有如同前文之意義且可藉該脂族鏈之任一碳原子 附接於化學原子團。"鹵烷基"之實例包括F3c-、C1CH2-、 cf3ch2-及cf3cci2-及諸如此類者。術語"鹵烷氧基"係如 同術語"鹵烷基"般定義。"鹵烷氧基"之實例包括cf3o-、 CC13CH20-、hcf2ch2ch2o-及 CF3CH20-、CF2C1CH20-及 諸如此類者。 ” Het"或“雜芳基”使用於本發明時,除非另有陳述 ,否則係意指含有一或多個各獨立選自N、S或Ο之雜原 子的芳族單環性環,較佳係一至四個氮雜原子,及任意地 存在之一個氧或硫雜原子。單環性環之非排他性實例係包 括吡咯基、吡唑基、噚唑基、吡啶基、三唑基、四唑基、 嗒哄基、嘧啶基及諸如此類者》Het基可藉環內之任一碳 原子或雜原子附接於化學原子團。該Het係任意地經取代 〇 “昆蟲(等)”使用於本發明時,除非另有陳述,否則 係意指叮咬型、嚼食型或吸血型昆蟲。非排他性實例包括 叮咬型蠅類(例如,螫蠅、角蠅、黑蠅、牛蠅及馬蠅)、蝨 類、蠓、蚤類及諸如此類者。 "寄生蟲(等)”使用於本發明時,除非另有陳述,否 則係意指體內寄生蟲及體外寄生蟲。體內寄生蟲係爲生活S -18- 201201802 benzyl, neopentyl, 3,3-dimethylpropyl, 2-methylpentyl, 2,2-dimethylpentyl, hexyl, 3-ethylhexyl, heptyl, 4 - ethylheptyl, octyl and the like. An alkyl group co-presented with another term (eg, alkylcycloalkyl (ie, -ch 2 cyclopentyl (methylcyclopentyl)' -CH 2 cyclobutyl, -(CH 2 ) 2 cyclopropyl (ethyl) a cyclopropyl group and the like. The alkyl group, the cycloalkyl group and the alkylcycloalkyl group may be attached to a chemical atomic group by any carbon atom of the aliphatic chain. The alkyl group and the alkylcycloalkyl group may be optionally "Animal (etc.)" used in the present invention, unless otherwise stated, means an individual animal that is a member of a mammalian class. Non-exclusive examples of animals include companion animals and domestic animals. The invention of the invention " as used in the present invention, unless otherwise stated, means a compound of the formula (1), (ΙΑ), (IB), (1C) and (1D) or a veterinary acceptable salt thereof. "Cycloalkyl" as used in the present invention, unless otherwise stated, includes fully saturated or partially saturated carbocyclic alkyl groups, wherein the alkyl group is as defined above. Non-limiting examples of partially saturated cycloalkyl groups include : cyclopropene, cyclobutene, cycloheptene, cyclooctene, cycloheptane-1, 3-diene and the like. Preferred cycloalkyl is a 3- to 6-membered saturated monocyclic ring including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group can be carbocyclic. Any carbon atom in the ring is attached to a chemical atomic group. The cycloalkyl group is optionally substituted with at least one substituent. "Poultry" as used in the present invention ' unless otherwise stated, means chicken, turkey, duck And goose 'especially chickens and turkeys, more particularly chickens. "Halogen" or "halo" used in the present invention, unless otherwise stated -19-201201802, means fluorine, chlorine, bromine or iodine Furthermore, when used in a combination of words such as "haloalkyl" or "haloalkoxy", the alkyl and alkoxy groups may be partially or completely substituted by a halogen atom, and the alkyl group and the alkoxy group may be used. Partially or completely substituted by a halogen atom, the halogen atoms may be the same or different, and the alkyl and alkoxy radicals have the same meaning as defined above and may be attached to the chemical atomic group by any carbon atom of the aliphatic chain. Examples of "haloalkyl" include F3c-, C1CH2-, cf3ch2-, and cf3cci2- and such The term "haloalkoxy" is as defined in the term "haloalkyl". Examples of "haloalkoxy" include cf3o-, CC13CH20-, hcf2ch2ch2o-, and CF3CH20-, CF2C1CH20- and "Het" or "heteroaryl" as used in the present invention, unless otherwise stated, means an aromatic monocyclic ring containing one or more heteroatoms independently selected from N, S or fluorene. The ring, preferably one to four nitrogen heteroatoms, and optionally one oxygen or sulfur heteroatom. Non-exclusive examples of monocyclic rings include pyrrolyl, pyrazolyl, oxazolyl, pyridyl, triazolyl, tetrazolyl, indolyl, pyrimidinyl and the like. Hetyl can be used in the ring. A carbon atom or a hetero atom is attached to a chemical atomic group. The Het is optionally substituted 〇 "insect (etc.)" when used in the present invention, unless otherwise stated, means a bite type, a chewing type or a bloodsucking type insect. Non-exclusive examples include biting flies (e.g., flies, horn flies, black flies, bovine flies, and horse flies), ticks, ticks, ticks, and the like. "Parasites (etc.)" as used in the present invention, unless otherwise stated, means endoparasites and ectoparasites. Endoparasites are life.
S -20- 201201802 在其宿主體內之寄生蟲,包括蠕蟲(例如,吸蟲、條蟲及 線蟲)及原生動物。體外寄生蟲係節枝動物門之有機體(節 枝動物及昆蟲),饋送通過宿主皮膚或位於皮膚上。較佳 節枝動物係爲蟎蜱目,例如,壁蝨及蟎類。 "治療有效量”使用於本發明時,除非另有陳述,否則 係意指本發明化合物(i)處置或預防特定之寄生感染或侵襲 ,(Π)減弱、改善或消除特定寄生蟲感染或侵襲的一或多 個症狀,或(Hi)預防或延遲開始出現本文所述特定寄生蟲 感染或侵襲的一或多個症狀。 "處置(Treatment,treating”及諸如此類者)使用於本發 明時,除非另有陳述,否則係意指逆轉、減輕或抑制該寄 生蟲感染、侵襲或病況。使用於本發明時,此等術語亦涵 蓋(取決於動物之病況)預防或防治開始產生病症或病況或 與病症或病況有關之症狀,包括在受到該感染或侵襲之苦 痛之前先降低病症或病況或與其有關症狀的嚴重性。因此 ,處置可表示將本發明化合物投予非處於投藥時間且受到 感染或侵襲之苦的動物。處置亦涵蓋預防感染或侵襲或與 其有關之症候群復發,且"防治"之指稱亦然(例如,殺死、 擊退、驅除、喪失能力、阻止、消除、舒緩、減至最小及 根除)。 “獸醫上或藥學上可接受”使用於本發明時,除非另有 陳述,否則係表示該物質或組成物必需與調配物、組成物 之其他成份及/或待進行處置之動物在化學上且/或毒性上 可相容。 -21- 201201802 【實施方式】 本發明提供式(1)化合物、或其獸醫上可接受之鹽連 同獸醫組成物,其可用以作爲動物及鳥類之抗寄生蟲劑, 尤其是作爲殺體外寄生蟲劑的化合物。 本發明化合物亦可藉由包括類似化學技術界所熟知之 方法(尤其是本文所包含之描述)的合成路徑加以合成。起始物 質通常可自市售來源諸如 Aldrich Chemicals(Milwaukee, Wis.)取得或使用熟習此技術者所熟知之方法輕易的製備(例如 ,藉大致上描述於 Louis F.Fieser and Mary Fieser,“Reagents for Organic Synthesis” ,1; 19,Wiley, New York( 1967,1999 ed.)或 Beilsteins Handbuch der organischen Chemie,4, Aufl. ed. Springer-Verlag, B erlin,包括附刊(亦可經由 Beilstein 線上資料庫)中之方法)。 本發明化合物可以一或多種立體異構物之方式存在。 各種立體異構物係包括鏡像異構物、非鏡像異構物及阻轉 異構物。本發明範圍內包括所有立體異構物,諸如鏡像異 構物及非鏡像異構物,所有幾何異構物及式(I)化合物之互 變異構形式,包括展現多於一種類型之異構化的化合物, 及其中一或多種之混合物。本發明化合物可存在爲立體異 構物之混合物形式、個別立體異構物形式或光學活性形式 。例如’式1之兩種可能鏡像異構物係描述如式1 al及式 lbl ’包括以星號(*)標示之異噚唑啉對掌性中心。熟習此 技術者會明瞭其中一種立體異構物可能較具活性,且/或S -20- 201201802 Parasites in their hosts, including worms (eg, trematodes, barges, and nematodes) and protozoa. The ectoparasite is an organism of the phylum of the phylum of animals (nodules and insects) fed through the skin of the host or on the skin. Preferred branching animals are the order of the eye, such as ticks and mites. "Therapeutically effective amount" as used in the present invention, unless otherwise stated, means that the compound of the invention (i) treats or prevents a particular parasitic infection or invasion, (减弱) attenuates, ameliorates or eliminates a particular parasitic infection or One or more symptoms of invasion, or (Hi) prevention or delay in the onset of one or more symptoms of a particular parasitic infection or invasion described herein. "Treatment, treating, and the like when used in the present invention Unless otherwise stated, it is meant to reverse, alleviate or inhibit the parasitic infection, invasion or condition. When used in the present invention, these terms also encompass (depending on the condition of the animal) preventing or controlling the onset of a condition or condition or a condition associated with the condition or condition, including reducing the condition or condition prior to suffering from the infection or invasion. Or the severity of the symptoms associated with it. Thus, treatment can mean administration of a compound of the invention to an animal that is not at the time of administration and is suffering from infection or invasion. Disposal also covers the prevention of infection or invasion or recurrence of the syndrome associated with it, and the “control” is also the allegation (eg, killing, repelling, repelling, incapacity, stopping, eliminating, soothing, minimizing and eradicating) . "Veterinologically or pharmaceutically acceptable" as used in the present invention, unless otherwise stated, means that the substance or composition must be chemically and with the formulation, other components of the composition, and/or the animal to be treated. / or toxic compatible. -21-201201802 [Embodiment] The present invention provides a compound of formula (1), or a veterinary acceptable salt thereof, together with a veterinary composition, which can be used as an anti-parasitic agent for animals and birds, especially as an ectoparasite Compound of the agent. The compounds of the invention may also be synthesized by synthetic routes including methods well known in the chemical arts, especially as described herein. The starting materials are typically prepared from commercially available sources such as Aldrich Chemicals (Milwaukee, Wis.) or readily prepared by methods well known to those skilled in the art (e.g., as generally described in Louis F. Fieser and Mary Fieser, "Reagents For Organic Synthesis", 1; 19, Wiley, New York (1967, 1999 ed.) or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including the supplement (also via Beilstein online) Method in the library)). The compounds of the invention may exist as one or more stereoisomers. Various stereoisomers include mirror image isomers, non-image isomers, and atropisomers. Included within the scope of the invention are all stereoisomers, such as mirror image isomers and non-image isomers, all geometric isomers and tautomeric forms of the compounds of formula (I), including exhibiting more than one type of isomerization. a compound, and a mixture of one or more thereof. The compounds of the invention may exist in the form of a mixture of stereoisomers, individual stereoisomeric forms or optically active forms. For example, the two possible mirror image isomers of Formula 1 are described as Formula 1 al and Formula 1 bbl' includes the isoxazoline-to-palm center as indicated by an asterisk (*). Those skilled in the art will recognize that one of the stereoisomers may be more active and/or
S • 22- 201201802 在相對於另一種立體異構物增濃(enriched)時或當與另一 種立體異構物分離時,展現有利之效果。 習用於製備/單離個別鏡像異構物之技術包括自適當 之光學純前驅物開始之對掌性合成、自原對掌性前驅物開 始之立體選擇性合成或使用例如分步結晶或掌性高壓液相 層析(HPLC)將消旋物(或鹽或衍生物之消旋物)離析。參考 Wiley, NY,1981 出版之 “Enantiomers、Racemates and Resolutions” J.Jacques and A.Collet :及 “Handbook of Chiral Chemicals” chapter 8,Eds D.Ager and M. D ekker, ISBN: 0-8 247-1058-4。幾何異構物可藉熟習此技術者熟知之習用 技術分離,例如,層析及分步結晶。 或消旋物(或消旋物前驅物)可與適當之光學活性化合 物(例如醇’或若其中式(I)化合物含有酸性或鹼性原子團 ’則爲酸或鹼,諸如酒石酸或1-苯基乙基胺)反應。形成 之非鏡像異構混合物可藉層析及/或分步結晶分離,藉熟 習此技術者所熟知之方式,將非鏡像異構物中之一或兩者 轉化成對應之純鏡像異構物。S • 22- 201201802 exhibits an advantageous effect when enriched with respect to another stereoisomer or when separated from another stereoisomer. Techniques for the preparation/isolation of individual mirror image isomers include chiral synthesis starting from a suitable optically pure precursor, stereoselective synthesis starting from the original palm precursor, or using, for example, fractional crystallization or palm The racemate (or the racemate of the salt or derivative) is isolated by high pressure liquid chromatography (HPLC). See "Enantiomers, Racemates and Resolutions" by Wiley, NY, 1981 J. Jacques and A. Collet: and "Handbook of Chiral Chemicals" chapter 8, Eds D. Ager and M. D ekker, ISBN: 0-8 247- 1058-4. Geometric isomers can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. Or a racemate (or a racemate precursor) which may be an acid or a base such as tartaric acid or 1-benzene with a suitable optically active compound (for example, an alcohol ' or if the compound of formula (I) contains an acidic or basic atomic group' Glycolamine) reaction. The non-image-isomerized mixture formed can be separated by chromatography and/or fractional crystallization, and one or both of the non-image isomers can be converted to the corresponding pure mirror image isomers in a manner well known to those skilled in the art. .
23- 201201802 爲說明起見,下述反應流程圖係例示用以合成關鍵中 間物及本發明化合物的可能路徑。個別反應步驟更詳細描 述請參看以下實施例部分。熟習此技術者會明瞭其他適當 之起始物質、試劑及合成路徑皆可使用以合成中間物及本 發明化合物及其各種衍生物。再者,下述方法所製備之許 多化合物可根據此揭示內容使用習用化學進一步修飾。流 程圖1至7勾勒出可用於製備本發明化合物的一般方法。 然而,應瞭解如本文所詳細描述且如申請專利範圍所列示 之本發明不限於以下流程圖或製備模式的細節。 以下流程圖及實施例中,下列觸媒/反應物係包括: N,N-二甲基甲醯胺(DMF); N-溴-琥珀醯亞胺(NBS); N-氯-琥 珀醯亞胺(NCS);乙腈(CAN)、乙酸乙酯(EtoAc)、四氫呋喃 (THF);三苯膦(PPh3);戴斯馬丁過碘烷(DMP);正丁基鋰 (n-BuLi);二甲基亞颯(DMSO);三乙胺(TEA或NEt3);乙酸 乙酯(EtOAc);氯化雙(三苯膦)鈀II(Pd(PPh3)2Cl2),得自 Strem;六氟磷酸N,N,N’,N’-四甲基-〇-(7-氮雜苯並三唑-1-基)脲鑰(HATU),得自Aldrich ;雙(1,5-環辛二烯)二-mu-甲 氧基銦(I)(Ir[C0D])2),得自 Aldrich; 4,4,4,,4,,5,5,5,,5,-八 甲基[2,2’-聯-1,3,2 -—氧雜環戊硼院](B2pin2),得自Aldrich ;4,4’-二-第三丁基-2,2’-聯卩比陡(dtbpy)得自 Aldrich; N-羥 基苯並三唑(H0BT),得自 Aldrich,二碳酸二-第三丁酯 (B0C20) ’得自Aldrich,1-乙基-3-(3-二甲基胺基丙基)碳化 二醯亞胺鹽酸鹽(EDC),得自Aldrich,二甲基乙醯胺(DMA) ’三氟乙酸(TFA)及疊氮磷酸二苯酯(DPPA)。23-201201802 For purposes of illustration, the following reaction schemes illustrate possible pathways for the synthesis of key intermediates and compounds of the invention. The individual reaction steps are described in more detail in the Examples section below. Those skilled in the art will recognize that other suitable starting materials, reagents, and synthetic routes can be used to synthesize the intermediates and the compounds of the present invention and their various derivatives. Further, many of the compounds prepared by the methods described below can be further modified according to the disclosure using conventional chemistry. Schemes 1 through 7 outline the general methods that can be used to prepare the compounds of the invention. However, it is to be understood that the invention as described in detail herein and as set forth in the appended claims In the following schemes and examples, the following catalyst/reactant systems include: N,N-dimethylformamide (DMF); N-bromo-succinimide (NBS); N-chloro-amber Amine (NCS); acetonitrile (CAN), ethyl acetate (EtoAc), tetrahydrofuran (THF); triphenylphosphine (PPh3); Des Martin Sodium Periodane (DMP); n-Butyllithium (n-BuLi); Methyl hydrazine (DMSO); triethylamine (TEA or NEt3); ethyl acetate (EtOAc); bis(triphenylphosphine)palladium chloride (Pd(PPh3)2Cl2), obtained from Strem; , N, N', N'-tetramethyl-hydrazine-(7-azabenzotriazol-1-yl)urea (HATU), available from Aldrich; bis(1,5-cyclooctadiene) Di-mu-methoxy indium (I) (Ir[C0D]) 2), available from Aldrich; 4,4,4,,4,,5,5,5,,5,-octamethyl [2, 2'-linked-1,3,2-oxo-boron] (B2pin2), available from Aldrich; 4,4'-di-t-butyl-2,2'-bi-pyrene ratio (dtbpy ) from Aldrich; N-hydroxybenzotriazole (H0BT) from Aldrich, di-t-butyl dicarbonate (B0C20) 'from Aldrich, 1-ethyl-3-(3-dimethylamine) Dipropyl) carbodiimide hydrochloride (EDC) from Aldrich, dimethyl acetamide DMA) 'trifluoroacetic acid (TFA) and diphenylphosphoryl azide (DPPA).
S -24- 201201802 流程圖1S -24- 201201802 Flowchart 1
Rla、Rlb、Rle、R2及η係如本文所定義。 流程圖1中,中間物(1 · 2 )化合物可藉由中間物(1 . 1 )化 合物與Ν-羥基胺於諸如乙酸鈉之鹼存在下於諸如乙醇之 溶劑中反應而製備。中間物(1.2)化合物之氯化可於諸如 DMF之溶劑中在介於約及50°C間之溫度下,以Ν-氯 琥珀醯亞胺(NCS)完成,提供中間物(1.3)。中間物(1.3)化 合物與中間物(1.4)化合物於鹼(諸如碳酸氫鈉)存在於諸如 乙酸乙酯、THF或DMF中進行反應,可產生中間物(I.5) 化合物。中間物(1.5)化合物之脫保護可使用標準條件(例 如於二氯甲烷中使用TFA)進行,產生中間物(1.6)化合物 -25- 201201802 。式(1)化合物可藉由中間物(1.6)化合物與醯基氯於諸如 三乙胺或吡啶之鹼存在下,於諸如二氯甲烷或DMF溶劑 中進行反應而製備。式(1)化合物亦可藉由中間物(1.6)化 合物與羧酸在適當之胜肽偶合劑諸如EDC、二環己基碳化 二醯亞胺(DCC)、HBTU、HATU或N,N’-二異丙基碳化二 醯亞胺(DIC)存在下進行反應,產生式(1)化合物而製備。 此外’式(1)化合物亦可藉由中間物(1.6)化合物與羧酸酐 於非質子溶劑諸如THF、二氯甲烷或DMF中進行反應而 製備。 流程圖 2A/B ΠΜ 2A V 二曙掠或·ΤΗΡRla, Rlb, Rle, R2 and η are as defined herein. In Scheme 1, the intermediate (1.2) compound can be prepared by reacting an intermediate (1.1) compound with a guanidine-hydroxyamine in the presence of a base such as sodium acetate in a solvent such as ethanol. The chlorination of the intermediate (1.2) compound can be carried out in a solvent such as DMF at a temperature between about and 50 ° C with hydrazine-chlorosuccinimide (NCS) to provide the intermediate (1.3). The intermediate (1.3) compound and the intermediate (1.4) compound are reacted in a base such as sodium hydrogencarbonate such as ethyl acetate, THF or DMF to give an intermediate (I.5) compound. Deprotection of the intermediate (1.5) compound can be carried out using standard conditions (e.g., using TFA in dichloromethane) to yield intermediate (1.6) compound -25 - 201201802. The compound of the formula (1) can be produced by reacting a compound of the intermediate (1.6) with mercapto chloride in the presence of a base such as triethylamine or pyridine in a solvent such as dichloromethane or DMF. The compound of formula (1) can also be obtained by the intermediate compound (1.6) with a carboxylic acid in a suitable peptide coupling agent such as EDC, dicyclohexylcarbodiimide (DCC), HBTU, HATU or N, N'- The reaction is carried out in the presence of isopropyl carbodiimide (DIC) to produce a compound of formula (1). Further, the compound of the formula (1) can also be produced by reacting a compound of the intermediate (1.6) with a carboxylic acid anhydride in an aprotic solvent such as THF, dichloromethane or DMF. Flowchart 2A/B ΠΜ 2A V 2 Sweeping or ΤΗΡ
Rla、Rlb及Rle係如本文定義。 流程圖2描述中間化合物1.4之合成。必要之有機硼 酸酯可自文獻方法(Org.Lett.2007,9,761 -764)製備成硼酸Rla, Rlb and Rle are as defined herein. Scheme 2 depicts the synthesis of intermediate compound 1.4. The necessary organic borate can be prepared as boric acid from the literature method (Org. Lett. 2007, 9, 761-764).
S 201201802 酯中間物(2B.2)形式或自Aldrich購得硼酸(2A.1)形式諸如 3,5-二氯硼酸自Aldrich。中間物2Α.1或2Β.2化合物可添 加至二噚烷或THF及水中,接著2_溴- 3,3,3 -三氟丙烯' 碳酸鉀及氯化雙(三苯膦)鈀Π,產生中間物(1.4)化合物。S 201201802 Ester intermediate (2B.2) form or a boronic acid (2A.1) form such as 3,5-dichloroboric acid from Aldrich is commercially available from Aldrich. The intermediate 2Α.1 or 2Β.2 compound can be added to dioxane or THF and water, followed by 2-bromo-3,3,3-trifluoropropene' potassium carbonate and bis(triphenylphosphine)palladium chloride. An intermediate (1.4) compound is produced.
R2及η係如前文定義。 式(1 .1)化合物可經由流程圖3所示方法製得。中間物 (3.1)化合物可購自市售來源。於諸如CC14溶劑中以NBS 及催化量之過氧化苯甲醯處理中間物(3.1)化合物,產生中 間物(3.2)化合物。於諸如DMSO溶劑中以疊氮化鈉處理中 間物(3 · 2)化合物產生中間物(3 . 3 )化合物。中間物(3.4)化 合物可藉由於諸如THF溶劑中以三苯膦及水處理中間物 (3.3)化合物而製備。或可在觸媒(諸如碳上鈀)存在下於適 當之溶劑(諸如乙醇)中,以氫將中間物0.3)化合物還原, -27- 201201802 而製得中間物(3.4)化合物。中間物(3.5)化合物可藉由中間 物(3.4)化合物與Boc-酐於一或更多當量之鹼(諸如三乙胺) 存在下於適當之溶劑(諸如二氯甲烷)中反應而製得。式 (1.1)化合物可藉由中間物(3.5)化合物與觸媒(諸如二氯雙( 三苯膦)鈀)於一氧化碳及甲酸鈉存在下於溶劑系統(諸如 DMF)中在80°C至100°C之昇高的溫度下進行反應而製得 ,如美國專利申請案US2004/0 1 3 827 1所述。中間物(3.5) 化合物亦可在以二或更高當量之烷基鋰處理中間物(3.4)化 合物之後以DMF淬火而製得。反應係於低溫(-78°C)在溶 劑(諸如THF)中進行。 流程圖4R2 and η are as defined above. The compound of formula (1.1) can be obtained by the method shown in Scheme 3. Intermediate (3.1) compounds are commercially available from commercial sources. The intermediate (3.1) compound is treated with NBS and a catalytic amount of benzamidine peroxide in a solvent such as CC14 to produce the intermediate (3.2) compound. Treatment of the intermediate (3.2) compound with sodium azide in a solvent such as DMSO produces an intermediate (3.3) compound. The intermediate (3.4) compound can be prepared by treating the intermediate (3.3) compound with triphenylphosphine and water in a solvent such as THF. Alternatively, the intermediate (3.4) compound can be prepared by reduction of the intermediate 0.3) compound with hydrogen in the presence of a catalyst such as palladium on carbon in a suitable solvent such as ethanol, -27-201201802. The intermediate (3.5) compound can be prepared by reacting a compound of the intermediate (3.4) with a Boc-anhydride in the presence of one or more equivalents of a base such as triethylamine in a suitable solvent such as dichloromethane. . The compound of the formula (1.1) can be used in the presence of carbon monoxide and sodium formate in a solvent system (such as DMF) at 80 ° C to 100 ° by using an intermediate (3.5) compound and a catalyst such as dichlorobis(triphenylphosphine)palladium in the presence of carbon monoxide and sodium formate. The reaction is carried out at an elevated temperature of C, as described in U.S. Patent Application Serial No. US 2004/0 1 3 827. The intermediate (3.5) compound can also be obtained by quenching with DMF after treating the intermediate (3.4) compound with two or more equivalents of alkyllithium. The reaction is carried out at a low temperature (-78 ° C) in a solvent such as THF. Flow chart 4
R2及η係如前文定義。 式(3.3)中間化合物亦可如流程圖4所示般製備。市售 苯甲酸酯可與氫化物還原劑(諸如硼氫化鋰)反應,產生式 (4.2)化合物。式(3-3)化合物可藉由式(4-2)化合物與疊氮 磷酸二苯酯反應或經由羥基轉化成脫離基(例如甲磺酸根 ' C1或Br)且以疊氮化鈉置換而製備。R2 and η are as defined above. The intermediate compound of formula (3.3) can also be prepared as shown in Scheme 4. Commercially available benzoates can be reacted with a hydride reducing agent such as lithium borohydride to produce a compound of formula (4.2). The compound of the formula (3-3) can be obtained by reacting a compound of the formula (4-2) with diphenyl azide or by a hydroxyl group to form a leaving group (for example, mesylate 'C1 or Br) and replacing it with sodium azide. preparation.
S -28- 201201802 流程圖5S -28- 201201802 Flowchart 5
R2及η係如前文定義。 具有式(1.1)之化合物亦可如流程圖5所示般的自市售 (5.1)化合物製備。式(5-2)化合物可藉(5.1)與Ν-溴琥珀醯 亞胺(NBS)於催化量之過氧化苯甲醢存在下於諸如氯仿或 四氯化碳之有機溶劑中進行反應而製備。式(5.3)化合物可 在不超過50 °C之溫度下,於溶劑諸如DM SO中,以一當 量疊氮化鈉處理(5.2)後製得。式(5.4)化合物可在諸如THF 之溶劑中以三苯膦及水處理(5.3)而製得。或式(5.4)化合物 可在溶劑(諸如乙醇)中,於觸媒諸如碳上鈀存在下,以氫 將式(5.3)化合物還原而製備。式(5 5)化合物可藉由於鹼( -29- 201201802 諸如三乙胺)存在下,於諸如二氯甲烷之溶劑中,藉以二 碳酸二-第三丁酯處理(5.4)而製備。式(5.6)化合物可藉由 (5.5)與氫化物還原劑(諸如硼氫化鋰)於THE與甲醇之雙溶 劑系統中進行反應而製備。式(1.1)化合物可藉由(5.6)以戴 斯馬丁過碘烷(1,1,1-三乙醯氧基-1,1-二氫-1,2 -苯碘醯 (benziodoxol)-3(lH)-酮)氧化而製備。 流程圖6R2 and η are as defined above. Compounds of formula (1.1) can also be prepared from commercially available (5.1) compounds as shown in Scheme 5. The compound of the formula (5-2) can be prepared by reacting (5.1) with hydrazine-bromosuccinimide (NBS) in the presence of a catalytic amount of benzamidine peroxide in an organic solvent such as chloroform or carbon tetrachloride. . The compound of the formula (5.3) can be obtained by treating (5.2) with a quantity of sodium azide in a solvent such as DM SO at a temperature not exceeding 50 °C. Compounds of formula (5.4) can be prepared by treatment with triphenylphosphine and water (5.3) in a solvent such as THF. Or a compound of the formula (5.4) can be produced by reducing a compound of the formula (5.3) with hydrogen in a solvent such as ethanol in the presence of a catalyst such as palladium on carbon. The compound of the formula (5 5) can be produced by treating (5.4) di-tert-butyl dicarbonate in the presence of a base (-29-201201802 such as triethylamine) in a solvent such as dichloromethane. The compound of the formula (5.6) can be produced by reacting (5.5) with a hydride reducing agent such as lithium borohydride in a double solvent system of THE and methanol. The compound of formula (1.1) can be obtained by (5.6) with Dess Martin Sauerane (1,1,1-triethoxymethoxy-1,1-dihydro-1,2-phenyliodonium (benziodoxol)-3 (lH)-ketone) is prepared by oxidation. Flow chart 6
R2及η係如本文定義。 式(3-5)化合物亦可自對應之市售腈類製備,如Tetrahedron 59,5417,(2003)及 Biorganic and Medicinal Chemistry Letters, 18, 2362,(2 008)所述,經由單鍋還原-保護策略而製備。 流程圖7R2 and η are as defined herein. Compounds of formula (3-5) can also be prepared from the corresponding commercially available nitriles, as described in Tetrahedron 59, 5417, (2003) and Biorganic and Medicinal Chemistry Letters, 18, 2362, (2 008), via single pot reduction - Prepared by a protection strategy. Flow chart 7
R2及η係如本文定義。 式6-1化合物可經由如流程圖7所示般的置換原子(諸如R2 and η are as defined herein. A compound of formula 6-1 can be substituted via an atom as shown in flow chart 7 (such as
S -30- 201201802 氟)而製備(Tetrahedron Letters, 50(12),1 286-1289,(2009))。 熟習此技術者應認知在某些情況下,在如流程圖所述 般的導入特定試劑後,可能必需執行未詳細描述之額外合 成步驟,以完成式(1)化合物之合成。 熟習此技術者亦認知式(1)化合物及本文所述中間物 可施以各種親電子、親核、自由基、有機金屬、氧化及還 原反應,以添加取代基或修飾現存之取代基。 式(1)、(ΙΑ)、(IB)、(1C)或(1D)化合物之獸醫可接受 之鹽係包括其酸加成鹽及鹼鹽。適當之酸加成鹽係自酸形成 ,其形成非毒性鹽類。實例包括乙酸鹽、天冬胺酸鹽、苯甲 酸鹽、苯磺酸鹽、碳酸氫鹽/碳酸鹽、硫酸氫鹽/硫酸鹽、硼 酸鹽、樟腦磺酸鹽、檸檬酸鹽、乙二磺酸鹽、乙磺酸鹽、甲 酸鹽、反丁烯二酸鹽、葡庚糖酸鹽、穀胺酸鹽、葡糖醛酸鹽 、六氟磷酸鹽、羥苯醯苯酸鹽、鹽酸鹽/氯化物 '氫溴酸鹽/ 溴化物、氫碘酸鹽/碘化物、羥乙基磺酸鹽、乳酸鹽、月桂 酸鹽、蘋果酸鹽、順丁烯二酸鹽、丙二酸鹽、甲磺酸鹽、甲 基硫酸鹽、萘甲酸鹽、2-萘磺酸鹽、菸鹼酸鹽、硝酸鹽、乳 清酸鹽、草酸鹽、棕櫚酸鹽、羥萘酸鹽、磷酸鹽/磷酸氫鹽/ 磷酸二氫鹽、糖酸鹽、硬脂酸鹽、琥珀酸鹽、酒石酸鹽、甲 苯磺酸鹽及三氟乙酸鹽。適當之鹼鹽係自形成無毒鹽之鹼形 成。實例包括鋁、精胺酸'苄乙二胺、鈣、膽鹼、二乙胺、 二醇胺、甘胺酸、離胺酸 '鎂' 葡甲胺(meglumine)、醇胺 、鉀、鈉、胺丁三醇(tromethamine)及鋅鹽。 特定式⑴、(1A)、(1B)、(1C)、(1D)化合物之獸醫可 -31- 201201802 接受之酸加成鹽亦可依習用方式製備。例如,游離鹼溶液 可使用適當之酸(純或於適當之溶劑中)處理,形成之鹽藉 過濾或藉於減壓下蒸發反應溶劑加以單離》針對適當之鹽 的評論參見 “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and W ermu th (Wi 1 ey-V C H, Weinheim, Germany, 2 002) 〇 本發明化合物可存在未溶合及溶合兩種形式。術語‘ 溶合物’在本發明係用以描述包含本發明化合物及一或多 個獸醫可接受之溶劑分子(例如乙醇)的分子錯合物。術語‘ 水合物’係用於該溶劑爲水之情況。本發明獸醫可接受溶 合物係包括其中該結晶溶劑可經同位素取代的溶劑,例如 D^O、d$-丙醒、de-DMSO。 下文及遍及整份申請案中,所有有關式(1)、(ΙΑ)、 (1Β)、(1C)、(ID)化合物之指稱皆包括其鹽、溶合物及錯 合物與其鹽之錯合物。 如前所述,本發明包括所有本發明定義之式(1)、(1A) 、(1 B )、( 1 C)、( 1 D)化合物的所有多晶形態。 本發明包括所有獸醫可接受之經同位素標記式(1 )化 合物,其中一或多個原子被具有相同原子序但原子量或質 量數異於一般在自然界所發現之原子量或質量數的原子所 置換。 適於包含在本發明化合物中之同位素的實例係包括氫 之同位素,諸如2H及3H’碳’諸如^C、13c及14c,氯 ,諸如36C1,氟,諸如18f,碘,諸如1231及|251 ’氮,Prepared by S-30-201201802 Fluoride (Tetrahedron Letters, 50(12), 1 286-1289, (2009)). Those skilled in the art will recognize that in certain instances, after introduction of a particular reagent as described in the schemes, it may be necessary to perform additional synthetic steps not described in detail to accomplish the synthesis of the compound of formula (1). Those skilled in the art will also recognize that the compounds of formula (1) and the intermediates described herein can be subjected to various electrophilic, nucleophilic, free radical, organometallic, oxidative, and reducing reactions to add substituents or to modify existing substituents. Veterinarily acceptable salts of the compounds of formula (1), (ΙΑ), (IB), (1C) or (1D) include the acid addition salts and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, hydrogen sulfate/sulfate, borate, camphorsulfonate, citrate, ethanedisulfonate Acid salt, ethanesulfonate, formate, fumarate, glucoheptonate, glutamate, glucuronate, hexafluorophosphate, hydroxybenzophenone, hydrochloric acid Salt/chloride 'hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, laurate, malate, maleate, malonate , mesylate, methyl sulfate, naphthoate, 2-naphthalene sulfonate, nicotinic acid salt, nitrate, orotate, oxalate, palmitate, hydroxynaphate, phosphoric acid Salt/hydrogen phosphate/dihydrogen phosphate, sugar acid salt, stearate, succinate, tartrate, tosylate and trifluoroacetate. Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine 'benzyl ethylenediamine, calcium, choline, diethylamine, glycolamine, glycine, lysine 'magnesium' meglumine, alcohol amine, potassium, sodium, Tromethamine and zinc salts. Veterinary addition compounds of the formula (1), (1A), (1B), (1C), (1D) can be prepared by conventional methods. For example, the free base solution can be treated with a suitable acid (either neat or in a suitable solvent), and the salt formed can be isolated by filtration or by evaporation of the solvent under reduced pressure. For comments on suitable salts, see "Handbook of Pharmaceutical" Salts: Properties, Selection, and Use" by Stahl and W ermu th (Wi 1 ey-V CH, Weinheim, Germany, 2 002) 化合物 The compounds of the invention may exist in both unfused and solvated forms. The term 'lysate' is used herein to describe a molecular complex comprising a compound of the invention and one or more veterinary acceptable solvent molecules (e.g., ethanol). The term 'hydrate' is used when the solvent is water. The veterinary acceptable solvent system of the present invention includes a solvent in which the crystallization solvent can be isotopically substituted, for example, D^O, d$- ing, de-DMSO. In the following and throughout the application, all references to compounds of formula (1), (ΙΑ), (1Β), (1C), (ID) include the faults of their salts, solvates and complexes and their salts. Compound. As stated previously, the invention encompasses all polymorphic forms of all of the compounds of formula (1), (1A), (1 B), (1 C), (1 D) as defined herein. The present invention encompasses all veterinary acceptable isotopically labeled compounds of formula (1) wherein one or more atoms are replaced by an atom having the same atomic order but an atomic mass or mass number different from the atomic mass or mass number generally found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as 2H and 3H' carbons such as ^C, 13c and 14c, chlorine, such as 36C1, fluorine, such as 18f, iodine, such as 1231 and |251 'nitrogen,
S -32- 201201802 諸如13n及I5N ’氧,諸如l5o、17〇及18〇及硫,諸如 35s。 熟習此技術者應理解本發明化合物可藉由調整本發明 所述方法及/或調整技術界已知方法,以除本發明所述以引用 方式倂入的方法以外的方法製得,例如本發明技術之業界, 或使用標準教科書諸如"Comprehensive Organic Transformations-A Guide to Functional Group Transformations" ' RC Larock, Wiley-VCH (1 999 或較新版本)。 式(i)化合物可用爲體外寄生蟲劑,因此,本發明另 一具體實施態樣係爲一種獸醫組成物,其包含治療有效量 之式(1)化合物、或其獸醫上可接受之鹽及獸醫上可接受之 賦形劑、稀釋劑或載劑。本發明化合物(包括其中所使用 之組成物及方法)亦可使用於製造供本發明所述治療應用 使用的醫藥。 典型調配物係藉由混合式(1)化合物與載劑、稀釋劑 或賦形劑而製備。適當之載劑、稀釋劑及賦形劑係熟習此 技術者所熟知,包括諸如醣類、蠟、水溶性及/或水潤脹 性聚合物、親水性或疏水性材料、明膠、油、溶劑、水及 諸如此類者。所使用之特定載劑、稀釋劑或賦形劑係取決 於本發明化合物所應用之方式及目的。溶劑通常係基於熟 習此技術者所公認對於待投藥之動物具安全性之溶劑而加 以選擇。調配物亦可包括一或多種緩衝劑、安定劑、界面 活性劑、潤濕劑、潤滑劑、乳化劑、懸浮劑、防腐劑、抗 氧化劑、不透光化劑、助流劑、加工助劑、著色劑、甜味 -33- 201201802 劑、香料、調味劑及其他已知添加劑,以提供優雅的外觀 (即,本發明化合物或其獸醫組成物)或幫助製造獸醫產品( 即,醫藥)。 調配物可使用習用溶解及混合方法製備。該等組成物 及其製備方法可參見例如‘Remington’s Veterinary Sciences,, 19th Edition(Mack Publishing Company, 1995;及 H.Lieberman 之 “ Veterinary Dosage Forms: Tablets,Vol. 1 ” 及 L.Lachman, Marcel Dekker,N.Y·,1980(ISBN 0-8247-69 1 8-X)。例如,整 體藥物物質(即,本發明化合物或該化合物經安定化形式( 例如,具有環糊精衍生物或其他已知錯合劑的錯合物))於 —或多種其他賦形劑存在下溶於適當之溶劑中。本發明化 合物一般係調配成獸醫劑量形式以提供用以投藥之可輕易 控制之劑型。 化合物可單獨或以適於所預想之特定用途、所處置之 宿主動物及鳥類的特定物種及相關之寄生物的調配物形式 投藥。通常,其係以與一或多種獸醫可接受之賦形劑、稀 釋劑或載劑結合而以調配物形式投藥。術語“賦形劑”、 “稀釋劑”或“載劑”於本文中係用以描述除式(1 )化合物 或附加之抗寄生蟲劑以外的任一成份。賦形劑、稀釋劑或 載劑之選擇相當大程度的取決於以下因素:諸如特定投藥 模式、賦形劑、載劑或稀釋劑對溶解度及安定性之影響及 該劑型之本質。 可藉以投予本發明化合物之方法係包括經口、局部及 皮下投藥。本發明預期每月投予所述組成物。S -32- 201201802 such as 13n and I5N ' oxygen, such as l5o, 17〇 and 18〇 and sulfur, such as 35s. It will be understood by those skilled in the art that the compounds of the present invention can be prepared by methods other than those described in the context of the present invention by adjusting the methods of the present invention and/or methods known in the art, such as the present invention. The industry of technology, or use standard textbooks such as "Comprehensive Organic Transformations-A Guide to Functional Group Transformations" ' RC Larock, Wiley-VCH (1 999 or newer). The compound of formula (i) may be used as an ectoparasite. Thus, another embodiment of the invention is a veterinary composition comprising a therapeutically effective amount of a compound of formula (1), or a veterinary acceptable salt thereof, and A veterinary acceptable excipient, diluent or carrier. The compounds of the invention, including the compositions and methods used therein, can also be used in the manufacture of a medicament for use in the therapeutic applications described herein. A typical formulation is prepared by mixing a compound of formula (1) with a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include, for example, sugars, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents , water and the like. The particular carrier, diluent or excipient used will depend on the mode and purpose of the compound of the invention. Solvents are generally selected based on solvents known to those skilled in the art to be safe for the animal to be administered. The formulation may also include one or more buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaque agents, glidants, processing aids. , Colorants, Sweeteners - 33 - 201201802 Agents, perfumes, flavorings, and other known additives to provide an elegant appearance (ie, a compound of the invention or a veterinary composition thereof) or to aid in the manufacture of a veterinary product (ie, a pharmaceutical). Formulations can be prepared using conventional dissolution and mixing methods. Such compositions and methods for their preparation can be found, for example, in 'Remington's Veterinary Sciences,, 19th Edition (Mack Publishing Company, 1995; and H. Lieberman, "Veterinary Dosage Forms: Tablets, Vol. 1" and L. Lachman, Marcel Dekker, NY, 1980 (ISBN 0-8247-69 1 8-X). For example, a monolithic drug substance (ie, a compound of the invention or a stabilized form of the compound (eg, having a cyclodextrin derivative or other known intermixing agent) The complex of the compound) is dissolved in a suitable solvent in the presence of one or more other excipients. The compounds of the invention are generally formulated in a veterinary dosage form to provide an easily controllable dosage form for administration. Formulated in a formulation suitable for the particular use envisioned, the host animal being treated, and the particular species of the bird and the associated parasite. Typically, it is administered with one or more veterinary acceptable excipients, diluents or carriers. The agent is administered in combination as a formulation. The terms "excipient", "diluent" or "carrier" are used herein to describe a compound or formula other than formula (1). In addition to any component other than the anti-parasitic agent, the choice of excipient, diluent or carrier depends to a considerable extent on factors such as the particular mode of administration, excipient, carrier or diluent to solubility and stability. The effects and the nature of the dosage form. The methods by which the compounds of the invention may be administered include oral, topical and subcutaneous administration. The present invention contemplates administration of the composition monthly.
S -34- 201201802 式(1)化合物可藉由膠囊、藥九、錠劑、粉末、口含 片、嚼錠、多重奈米粒子、凝膠、固體溶液、薄膜、噴劑 或液體形式而經口投藥。此係較佳投藥方法,且期望發展 特別適合該等調配物之活性式(1)化合物。該等調配物可在 軟質或硬質膠囊中作爲塡料,且調配物一般包含載劑,例 如水、乙醇、聚乙二醇、N-甲基吡咯啶酮、丙二醇、甲基 纖維素或適當之油及一或多種乳化劑及/或懸浮劑。液體 形式包括懸浮液、溶液、糖漿、灌食及酊劑。液體調配物 亦可藉著如同固體復原(例如自囊室)而製備。經口灌食一 般係藉由將活性成份溶解或懸浮於適當之介質中而製備。 此係較佳投藥方法,且期望發展特別適合該等調配物之活 性式(1)化合物。經口調配物可包含約 0.5 mg/kg至 50 mg/kg之式(1)化合物,較佳係約1 mg/kg至30 mg/kg之 式(1)化合物。 化合物可局部投藥至皮膚或黏膜,即投予皮膚或經皮 投予。此係較佳投藥方法,且期望發展特別適合該等調配 物(例如液體形式)之活性式(1)化合物。用於此目的之典型 調配物係包括倒上、點上、多重點上、條黏於表面(stripe-on) 、 梳上 (C〇mb-〇n) 、 滾壓 於表面 、浸漬 、噴灑 、慕 思、 洗髮精、粉末調配物 '凝膠、水凝膠、洗劑、溶液、乳霜 、軟膏、撒粉、敷料、發泡物、薄膜、皮膚敷料、薄片、 植入物、海棉’、纖維、繃帶及微乳液。亦可使用脂質體。 一般載劑係包括醇、水、礦’油、液體石油、白蠟油、甘胺 酸、N-甲基甲醯胺、甘醇單甲基醚、聚乙二醇、丙二醇及 -35- 201201802 諸如此類者。可倂入滲透促進劑,參見例如,J Pharm Sci,8 8 (10),955-958 by Finnin and Morgan (October 1999)。倒上 或點上調配物可藉由將活性成份溶於可接受液體載劑,諸 如二乙二醇丁醚、液體石蠟或非揮發性酯' 任意地添加揮 發性組份諸如丙-2-醇或二醇醚而製備。或者,倒上、點上 或噴灑調配物可藉由封包製備,在動物表面上留下活性劑 之殘留物,此效果可確認式(1)化合物具有較長的持續性且 更耐用,例如,其可能具較高之耐水牢度(water fast)。本發 明預期之局部調配物可包含約0.5 mg/kg至50 mg/kg之式(1) 化合物,較佳約1 mg/kg至10mg/kg之式(1)化合物。 本發明化合物亦可經由支撐基質例如合成或天然樹脂 、塑料、布、皮革或其他該種爲軸環或耳標形狀之聚合物 系統。該軸環或耳標可藉任何方式加以塗覆、浸漬、分層 ,以提供獸翳上可接受之量的本發明化合物本身,或同時 提供獸醫上可接受之賦形劑、稀釋劑或載劑及任意地存在 之附加獸醫藥劑或其獸醫上可接受之鹽。 適於本發明點上應用之組成物可藉習用混合方式製備 。所施加組成物的體積係約0.5 mL/kg至5 mL/kg且較佳 係約 1 mL/kg 至 3mL/kg。 可在本發明調配物中添加藥劑,以改善該調配物於施 加該調配物之動物的表面耐久性,例如,改善其於動物覆 層上之耐久性。特佳係於待倒上或點上調配物之方式包括 該等藥劑。該等藥劑之實例係包括丙烯酸系共聚物,尤其 是氟化之丙烯酸系共聚物。特別適當之試劑爲經註冊商標S -34- 201201802 The compound of the formula (1) can be used in the form of a capsule, a drug, a lozenge, a powder, a buccal tablet, a chewable tablet, a multiple nanoparticle, a gel, a solid solution, a film, a spray or a liquid. Oral administration. This is a preferred method of administration and it is desirable to develop active compounds of formula (1) which are particularly suitable for such formulations. The formulations may be used as a dip in soft or hard capsules, and the formulation will generally comprise a carrier such as water, ethanol, polyethylene glycol, N-methylpyrrolidone, propylene glycol, methylcellulose or suitable Oil and one or more emulsifiers and/or suspending agents. Liquid forms include suspensions, solutions, syrups, feedings and elixirs. Liquid formulations can also be prepared by reconstitution as a solid (e.g., from a pocket). Oral feeding is generally prepared by dissolving or suspending the active ingredient in a suitable medium. This is a preferred method of administration and it is desirable to develop an active compound of formula (1) which is particularly suitable for such formulations. The oral formulation may comprise from about 0.5 mg/kg to about 50 mg/kg of the compound of formula (1), preferably from about 1 mg/kg to about 30 mg/kg of the compound of formula (1). The compound can be administered topically to the skin or mucosa, i.e., administered to the skin or transdermally. This is a preferred method of administration and it is desirable to develop a compound of formula (1) which is particularly suitable for such formulations (e.g., in liquid form). Typical formulations used for this purpose include topping, spotting, multi-focusing, stripe-on, combing (C〇mb-〇n), rolling on the surface, dipping, spraying, Mousse, shampoo, powder formulation 'gel, hydrogel, lotion, solution, cream, ointment, dusting, dressing, foam, film, skin dressing, sheet, implant, sponge ', fiber, bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petroleum, ash oil, glycine, N-methylformamide, glycol monomethyl ether, polyethylene glycol, propylene glycol, and -35-201201802. By. Penetration enhancers can be incorporated, see, for example, J Pharm Sci, 8 8 (10), 955-958 by Finnin and Morgan (October 1999). Pour or pour the formulation by arbitrarily adding a volatile component such as propan-2-ol by dissolving the active ingredient in an acceptable liquid carrier such as diethylene glycol butyl ether, liquid paraffin or a non-volatile ester. Or prepared by glycol ether. Alternatively, the topping, spotting or spraying of the formulation can be prepared by encapsulation, leaving a residue of the active agent on the surface of the animal, which effect confirms that the compound of formula (1) has a longer persistence and is more durable, for example, It may have a higher water fastness. The topical formulations contemplated by the present invention may comprise from about 0.5 mg/kg to about 50 mg/kg of the compound of formula (1), preferably from about 1 mg/kg to about 10 mg/kg of the compound of formula (1). The compounds of the invention may also be via a support matrix such as a synthetic or natural resin, plastic, cloth, leather or other such polymer system in the shape of a collar or ear tag. The collar or ear tag can be coated, impregnated, layered in any manner to provide an acceptable amount of the compound of the invention itself, or a veterinary acceptable excipient, diluent or carrier. And optionally additional veterinary agents or veterinary acceptable salts thereof. The composition suitable for the application of the present invention can be prepared by a conventional mixing method. The volume of the applied composition is from about 0.5 mL/kg to 5 mL/kg and preferably from about 1 mL/kg to 3 mL/kg. An agent may be added to the formulation of the invention to improve the surface durability of the formulation to the animal to which the formulation is applied, e.g., to improve its durability on animal coatings. The means for attaching or arranging the formulation include the agents. Examples of such agents include acrylic copolymers, especially fluorinated acrylic copolymers. Particularly suitable reagents are registered trademarks
S -36- 201201802 之試劑 “Foraperle”(Redline Products Inc,Texas, USA) 特定之局部調配物可包括不適口之添加劑,以將經口 暴露減至最少" 皮下可注射調配物可製備成無菌溶液形式,其可含有 其他物質,例如足以使溶液與血液等張之鹽或葡萄糖。可 接受之液體載劑包括植物油,諸如芝麻油、甘油酯類諸如 三乙酸甘油酯,酯類諸如苯甲酸酯、肉豆蔻酸異丙酯及丙 二醇之脂肪酸衍生物,連同有機溶劑諸如吡咯啶-2-酮及甘 油縮甲醛,該等調配物係藉由將本發明化合物單獨或與附 加獸醫藥劑一起溶解或懸浮於液體載劑中,使得最終調配 物含有約0.01至10重量%之活性成份。 適於皮下投藥之裝置包括針頭(包括微針)注射器、無 針注射器及輸液技術。皮下調配物一般爲水溶液,可含賦 形劑,諸如鹽、醣及緩衝劑(較佳係達3至9之pH),但就 某些應用而言’可能更適合調配成無菌非水性溶液或待與 適當之佐藥’諸如無菌、無熱源之水,連同使用的乾燥粉 末形式。皮下調配物於無菌條件下藉由例如冷凍乾燥之製 備’可使用熟習此技術者熟知之標準獸醫技術達成。用以 製備皮下溶液之式(1)化合物可利用適當之調配技術而增加 ’諸如併入增進溶解度用劑。 該等調配物係根據標準醫藥或獸醫實務而以習用方式 製備。再者’此等調配物會視其中所含之活性化合物的重 量變化’取決於待處置之宿主動物的種類、感染或侵襲的 -37- 201201802 嚴重性及類型,及動物之體重。 如本文所述,本發明化合物可單獨投藥或結合至少一 種附加獸醫藥劑(包括殺昆蟲劑、殺蟎劑、驅蟲劑、殺真 菌劑、殺線蟲劑、抗原生動物、殺細菌劑及生長調節劑) ,以形成產生更廣效之獸醫設施。因此,本發明亦有關一 種組成物,其包含有效量之式(1)化合物或其獸醫可接受之 鹽,至少一種附加獸醫藥劑且可進一步包含一或多種獸醫 上可接受之賦形劑、稀釋劑或載劑。 下列附加之獸醫藥劑連同本發明化合物一起可用以說 明可能之組合,但不構成任何限制。附加獸醫藥劑之非限制 實例包括:雙甲脒、公開之W01998/24767及W02005/060749 所列之芳基卩比哩、胺基乙腈、驅蟲劑(例如,albendazole、 cambendazole、 fenbendazole 、 flubendazole、 mebendazole 、 octadepsipeptides、oxfendazole、oxibendazole、paraherquamide 、 parbendazole 、 piperazines 、 praziquantel 、 thiabendazole 、 tetramisole 、 triclabendazole 、 levamisole 、 pyrantel pamoate 、 oxantel、morantel及諸如此類者)、阿維菌素(avermectin)(例如 ,abamectin, doramectin, emamectin, eprinomectin, ivermectin, moxidectin,selamectin及諸如此類者)、DEET、得米地曲 (demiditraz)、二乙基乙胺香豆素、芬普尼(fipronil)、昆 蟲生長調節劑(例如,hydroprene, kinoprene, methoprene 及諸如此類者)、metaflumizone,niclosamide, permethrin, pyrethrins,pyriproxyfen,spinosad 及諸如此類者。特定情 況中,式(1)化合物與附加獸醫藥劑之組合可產生大於加成S-36-201201802 Reagent "Foraperle" (Redline Products Inc, Texas, USA) Specific topical formulations may include unsuitable additives to minimize oral exposure " Subcutaneous injectable formulations may be prepared as sterile In the form of a solution, it may contain other substances, such as a salt or glucose sufficient to make the solution isotonic with blood. Acceptable liquid carriers include vegetable oils such as sesame oil, glycerides such as triacetin, esters such as benzoates, isopropyl myristate and fatty acid derivatives of propylene glycol, together with organic solvents such as pyrrolidine-2 Ketones and glycerol formals, which are prepared by dissolving or suspending the compound of the invention, alone or in combination with an additional veterinary agent, in a liquid carrier such that the final formulation contains from about 0.01% to about 10% by weight of active ingredient. Devices suitable for subcutaneous administration include needle (including microneedle) syringes, needleless syringes, and infusion techniques. The subcutaneous formulation is typically an aqueous solution, which may contain excipients such as salts, sugars, and buffers (preferably at a pH of from 3 to 9), but may be more suitable for formulation into a sterile non-aqueous solution or for some applications. Wait with the appropriate adjuvant 'such as sterile, non-pyrogenic water, together with the dry powder form used. Subcutaneous formulations can be prepared under sterile conditions, for example by lyophilization, using standard veterinary techniques well known to those skilled in the art. The compound of formula (1) used to prepare the subcutaneous solution can be increased by appropriate formulation techniques such as incorporation of a solubility enhancing agent. Such formulations are prepared in a conventional manner in accordance with standard pharmaceutical or veterinary practice. Further, 'these formulations will vary depending on the weight of the active compound contained therein' depending on the species of host animal to be treated, the severity and type of infection or invasion, and the weight of the animal. As described herein, the compounds of the invention may be administered alone or in combination with at least one additional veterinary agent (including insecticides, acaricides, insect repellents, fungicides, nematicides, antiprotozoa, bactericides, and growth regulators). To form a more versatile veterinary facility. Accordingly, the invention also relates to a composition comprising an effective amount of a compound of formula (1) or a veterinary acceptable salt thereof, at least one additional veterinary agent, and further comprising one or more veterinary acceptable excipients, diluted Agent or carrier. The following additional veterinary agents can be used in conjunction with the compounds of the invention to illustrate possible combinations without any limitation. Non-limiting examples of additional veterinary agents include: amitraz, published W01998/24767 and WO2005/060749 listed as arylpyridinium, aminoacetonitrile, insect repellent (eg, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole) , octadepsipeptides, oxfendazole, oxibendazole, paraherquamide, parbendazole, piperazines, praziquantel, thiabendazole, tetramisole, triclabendazole, levamisole, pyrantel pamoate, oxantel, morantel, and the like), avermectin (eg, abamectin, doramectin, emamectin, Eprinomectin, ivermectin, moxidectin, selamectin and the like), DEET, demiditraz, diethylethylamine coumarin, fipronil, insect growth regulators (eg hydroprene, kinoprene, methoprene) And the like), metaflumizone, niclosamide, permethrin, pyrethrins, pyriproxyfen, spinosad and the like. In certain cases, the combination of a compound of formula (1) with an additional veterinary agent can produce greater than additive
S -38- 201201802 之效果。降低釋入環境中之活性成份的量’同時確定有效 防治害蟲,始終是期望値。 可能期望單獨投予本發明化合物或其獸醫上可接受之 鹽,或使用包含獸醫上可接受之賦形劑、稀釋劑或載劑的 組成物,例如,目的係處置特定寄生蟲感染或侵襲,或與 其相關之狀況。本發明範圍內包括二或更多種獸醫組成物 、至少一種含有本發明式(1)化合物及另一種附加獸醫藥劑 ,可簡易的以適於共同投予組成物之組套形式結合。 本發明化合物(包括其中所使用之組成物及方法)亦可 使用於製造供文中所述治療應用使用的醫藥。 本發明化合物、或其獸醫上可接受之鹽及包含治療有 效量之式(1)化合物及獸醫上可接受之賦形劑、稀釋劑或載 劑的組成物可用爲殺體外寄生蟲劑,用以防治及處置該體 外寄生蟲在動物或鳥類體內展現之感染或侵襲。本發明化 合物具有作爲殺體外寄生蟲劑之用途,尤其是作爲殺蟎劑 及殺昆蟲劑。其尤其可使用於獸醫學、家畜畜養及維持公 共衛生之領域中:對抗寄生於脊椎動物之蟎類及昆蟲,尤 其是溫血脊椎動物,包括陪伴動物、家畜及鳥類。蟎及昆 蟲寄生物包括:壁蝨(例如,真壁蝨(Ixodes spp.)、扇頭壁 蝨(Rhipicephalus spp.) ’ 牛尾壁蝨(Boophilus spp.),大壁蝨 (Amblyomma spp·),長鬚壁蝨(Hyalomma spp·),(Haemaphysalis spp·,矩頭壁蝨(Dermacentor spp.),〇rnithodorus spp.及 諸如此類者),鍋類(例如,剌皮蝴(Dermanyssus spp·),穿 孔济癖蟲(Sarcoptes spp.)’ 痴恙蟲(psor〇ptes spp.),食皮 -39- 201201802 疥蟲(Chorioptes spp.),毛囊蟲(Demodex spp.)及諸如此類 者);嚼食型及吸血型蟲類(例如,Damalinia spp·, Linognathus spp.及諸如此類者);蚤類(例如,Siphonaptera spp.,樹頭 蚤(Ctenocephalides spp.)及諸如此類者);及叮咬型蠅類及 蠓(例如,Tabanidae spp.,Haematobia spp·,刺蠅(Stomoxys spp.),Dermatobia spp ., S imul iidae spp., Ceratopogonidae spp_,Psychodidae spp·及諸如此類者)。 本發明化合物及包含本發明化合物連同至少一種其他 獸醫藥劑的組成物在防治體外寄生蟲、體內寄生蟲及昆蟲 (傷害陪伴動物、家畜及鳥類或擴張或作爲疾病載體者特 別有價値。可使用式(1)化合物與附加獸醫藥劑之組合物處 置的體外寄生蟲、昆蟲及體內寄生蟲包括前文所述者,且 包括扇形動物門之蠕蟲(例如,吸蟲、條蟲亞綱及條蟲)及 線蟲類(例如,線蟲)。 任一種本發明化合物或本發明化合物與任意地使用之 至少一種附加獸醫藥劑的適當組合物可直接投藥至該動物 或鳥類,且/或藉由施加至該動物或鳥類居住之局部環境( 諸如墊料、防護物及諸如此類者)而間接投藥。直接投藥 包括使受藥動物或鳥類之皮膚、毛皮或羽毛與該(等)化合 物接觸或藉由將該等化合物飼餵或注射至該動物或鳥類體 內。 式(1)化合物、或其獸醫上可接受之鹽及其與至少一 種附加獸醫藥劑之組合物(如本發明所述)具有用以處置及 防治各種生命週期階段之昆蟲及寄生物的價値,該等階段The effect of S -38- 201201802. It is always desirable to reduce the amount of active ingredient released into the environment while also determining the effective control of pests. It may be desirable to administer the compound of the present invention alone or a veterinary acceptable salt thereof, or to use a composition comprising a veterinary acceptable excipient, diluent or carrier, for example, for the treatment of a particular parasitic infection or invasion, Or the status associated with it. Included within the scope of the invention are two or more veterinary compositions, at least one compound of formula (1) of the invention, and another additional veterinary agent, which can be readily combined in a kit suitable for co-administering the composition. The compounds of the invention, including the compositions and methods used therein, can also be used in the manufacture of a medicament for use in the therapeutic applications described herein. A compound of the present invention, or a veterinary acceptable salt thereof, and a composition comprising a therapeutically effective amount of a compound of formula (1) and a veterinary acceptable excipient, diluent or carrier can be used as an ectoparasite. To prevent and treat the infection or invasion exhibited by the ectoparasite in an animal or bird. The compounds of the invention have utility as ectoparasites, especially as acaricides and insecticides. It can be used, inter alia, in the fields of veterinary medicine, livestock breeding and maintaining public health: against mites and insects that are parasitic on vertebrates, especially warm-blooded vertebrates, including companion animals, livestock and birds. Insects and insect parasites include: niches (eg, Ixodes spp., Rhipicephalus spp. 'Boophilus spp.'), Ambryomma spp., Hyaloma spp ·), (Haemaphysalis spp., Dermacentor spp., 〇rnithodorus spp. and the like), pots (eg, Dermanyssus spp., Sarcoptes spp.) Insect worm (psor〇ptes spp.), food skin-39- 201201802 locust (Chorioptes spp.), hairy worm (Demodex spp.) and the like); chewing type and blood-sucking worms (eg, Damalinia spp) ·, Linognathus spp. and the like; 蚤 (eg, Siphonaptera spp., Ctenocephalides spp., and the like); and biting flies and ticks (eg, Tabanidae spp., Haematobia spp., Stomoxys spp., Dermatobia spp., S imul iidae spp., Ceratopogonidae spp_, Psychodidae spp. and the like. Compounds of the invention and compounds comprising the invention together with at least one other The composition of veterinary medicaments is particularly valuable in the control of ectoparasites, endoparasites and insects (injury companion animals, livestock and birds or expansion or as a carrier of disease. Treatment with a combination of a compound of formula (1) and an additional veterinary agent can be used. The ectoparasites, insects, and endoparasites include those described above, and include worms of the scallops (eg, trematodes, worms, and worms) and nematodes (eg, nematodes). A suitable composition of the compound of the invention or a compound of the invention and at least one additional veterinary agent optionally used may be administered directly to the animal or bird and/or by application to the local environment in which the animal or bird resides (such as litter, protection) Indirect administration of a substance and the like. Direct administration includes contacting a skin, fur or feather of a medicated animal or bird with the compound or feeding or injecting the compound into the animal or bird. (1) a compound, or a veterinary acceptable salt thereof, and a composition thereof with at least one additional veterinary agent (such as the present invention) ) Has to dispose of and controlling insects and parasites of various life cycle stages of price Zhi, such stage
S -40- 201201802 包括卵、若蟲、幼蟲、幼年期及成年階段。 本發明亦有關一種方法,將本發明化合物單獨或與至 少一種附加獸醫藥劑、任意地投予之獸醫上可接受的賦形 劑、稀釋劑或載劑組合投予至健康良好之動物及鳥類,其 包含施加至該動物或鳥類,以降低或消除人類因動物或鳥 類帶原之寄生蟲而發生寄生蟲感染或侵襲之可能,且改善 該動物、鳥類及人類棲息的環境。 下文所列之反應通常係於氬或氮正壓下或使用乾燥管 於環境溫度(除非另有陳述)於無水溶劑中完成,反應燒瓶 設置橡膠隔板以經由注射器導入基材及試劑。玻璃儀器係 烘乾且/或加熱乾燥。分析型薄層層析(TLC)係使用玻璃背 襯矽膠60 F 254預先塗覆之分析板執行,且以適當之溶劑 比例(v/v)洗提。反應係藉TLC或LCMS檢測,且由起始 物質之消耗判斷反應終止。TLC板之顯影係以UV光(254 nm波長)完成或以適當之TLC顯影溶劑加以顯影且以熱活 化而完成。快速管柱層析(Still等人,J. Org. Chem. 43, 2923,(1 978)係使用矽膠(RediSep Rf)或各種MPLC系統, 諸如Biotage或ISCO純化系統來執行。 可使用一般技術者已知之習用方法及/或分離及純化 技術皆,以單離本發明化合物連同各種與其相關之中間物 。該等技術係一般技術者所熟知且可包括例如所有類型之 層析(高壓液相層析(HPLC)、使用一般吸附劑諸如矽膠之 管柱層析及薄層層析(TLC)、再結晶及差示(即液體-液體) 萃取技術。 -41- 201201802 以下實施例中之化合物結構係藉以下一或多項之方法確 定:質磁共振光譜及質譜。質磁共振CH NMR)光譜係使用 Bruker光譜儀於400百萬赫茲(MHz)場強度下操作決定。化 學位移以距離內部四甲基甲矽烷標準物下場(downfieid)之每 百萬分之份數(PPM ’ δ)記錄。質譜(MS)數據係使用Agilent 質譜儀以大氣壓化學游離化得到。方法:Acquity UPLC, 層析係於 Waters BEH C18 管柱(2·1χ50 mm,1.7 μπι)於 50 °〇執行。移動相係乙腈(含有〇.1%三氟乙酸)及水(5_100%) 之二元梯度。 以下實施例係說明本發明具體實施態樣。然而,應瞭 解本發明具體實施態樣不限於此等實施例之特定細節,因 爲一般技術者可由本發明揭示內容而得知或明瞭其他變化 實施例 以下實施例係提供製程條件的更詳細描述。然而’應 瞭解如本文所完全描述且如申請專利範圍所列示之本發明 不限於以下流程圖或製備模式的細節。 製備例1 1,2,3-三氯-5-(1,1,1-三氟丙-2-烯-2-基)苯:S -40- 201201802 Includes eggs, nymphs, larvae, infancy and adulthood. The invention also relates to a method of administering a compound of the invention, alone or in combination with at least one additional veterinary agent, arbitrarily administered veterinary acceptable excipient, diluent or carrier, to healthy animals and birds. It includes application to the animal or bird to reduce or eliminate the possibility of parasitic infection or invasion by humans due to parasites of the animal or bird, and to improve the environment in which the animal, bird and human inhabit. The reactions listed below are typically carried out under argon or nitrogen positive pressure or using a drying tube at ambient temperature (unless otherwise stated) in an anhydrous solvent. The reaction flask is provided with a rubber separator to introduce the substrate and reagents via a syringe. The glassware is dried and/or dried by heating. Analytical thin layer chromatography (TLC) was performed using a glass backed silica gel 60 F 254 pre-coated analytical plate and eluted in a suitable solvent ratio (v/v). The reaction was detected by TLC or LCMS and the reaction was terminated by the consumption of the starting material. The development of the TLC plate was carried out by UV light (254 nm wavelength) or developed with a suitable TLC developing solvent and completed by heat activation. Rapid column chromatography (Still et al, J. Org. Chem. 43, 2923, (1 978) is performed using tannin (RediSep Rf) or various MPLC systems, such as Biotage or ISCO purification systems. Known methods of use and/or separation and purification techniques are employed to isolate the compounds of the invention, together with various intermediates associated therewith. Such techniques are well known to those of ordinary skill and may include, for example, all types of chromatography (high pressure liquid layer Analytical (HPLC), column chromatography using conventional adsorbents such as silica gel and thin layer chromatography (TLC), recrystallization and differential (ie liquid-liquid) extraction techniques. -41- 201201802 Compound structure in the following examples It is determined by one or more of the following methods: mass spectrometry and mass spectrometry. The mass spectrometry (CH NMR) spectroscopy is determined using a Bruker spectrometer operating at a field intensity of 400 megahertz (MHz). The chemical shift is determined by the distance from the internal tetramethyl group. The fraction of parts per million (PPM ' δ) of the downfieid of the methotrex standard. Mass spectrometry (MS) data was obtained by chemical free radicalization using an Agilent mass spectrometer. Method: Acquity UPLC, chromatography was performed on a Waters BEH C18 column (2·1χ50 mm, 1.7 μm) at 50 ° 。. Binary gradient of mobile phase acetonitrile (containing 1% trifluoroacetic acid) and water (5_100%) The following examples are intended to illustrate the specific embodiments of the present invention. However, it is understood that the specific embodiments of the invention are not limited to the specific details of the embodiments, EXAMPLES The following examples are provided to provide a more detailed description of the process conditions. However, it is to be understood that the invention as fully described herein and as set forth in the appended claims , 3-trichloro-5-(1,1,1-trifluoroprop-2-en-2-yl)benzene:
SS
-42· 201201802 對 25.0 g(131 mmol)之 3,4,5-三氯苯硼酸(2A.1)於 200 mL之THF及100 mL之水中的混合物添加2·溴-3,3,3-三 氟丙烯、碳酸鉀及氯化雙(三苯膦)鈀11 ’且於回流下攪拌 隔夜。反應混合物分溶於水及乙酸乙酯之間’有機物以鹽 水洗滌,以MgS04乾燥,過濾’產生.濃縮物橘色固體(7g) 。粗製物質吸附於矽膠上且藉管柱層析純化’ 〇_10%丙酮/ 庚烷,120 g二氧化矽。結合相關之部分且濃縮產生標題 化合物之無色油(5.35 g)» 4 NMR(CDC13)5 5·85(1Η),6·07 (1Η),7.48(2Η)。 製備例2 1,3-二氯-2-氣- 5- (1,1,1-二氧丙_2 -嫌-2-基)本--42· 201201802 Add 2·bromo-3,3,3- to a mixture of 25.0 g (131 mmol) of 3,4,5-trichlorobenzeneboronic acid (2A.1) in 200 mL of THF and 100 mL of water Trifluoropropene, potassium carbonate and bis(triphenylphosphine)palladium 11 ' were stirred and stirred overnight under reflux. The reaction mixture was partitioned between water and ethyl acetate. <RTI ID=0.0>>>> The crude material was adsorbed onto silica gel and purified by column chromatography < 〇 10% acetone / heptane, 120 g cerium oxide. A colorless oil (5.35 g) of 4 4 NMR (CDC13) 5 5·85 (1 Η), 6·07 (1 Η), 7.48 (2 Η). Preparation 2 1,3-Dichloro-2- gas-5-(1,1,1-dioxoprop-2-yes-2-yl)-
對 2-溴-3,3,3-三氟丙烯(2.65 g,15.1 mmol)及 2-(3,5-二氯-4-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷 (2A.1)(4.4 g,15.1 mmol)於 1,4-二噚烷(60 mL)中之攪拌 溶液添加 Na2CO3(4.02 g,38 mmol)及水(20 mL)。接著, 添加氯化雙(三苯膦)鈀(220 mg,0·3 mmol),反應混合物 加熱至80°C歷經1 8小時。將反應混合物冷卻,過濾且於 減壓下濃縮以移除二鸣烷。殘留物以水(100 mL)稀釋,以 EtOAc(2xl25 mL)萃取,乾燥(Na2S04)且於減壓下濃縮。 粗製物於矽膠上以1 〇〇%庚烷純化,產生中間物之澄清油 -43- £ 201201802 (1.8 g,47%)。4 NMR(CDC13) : δ 7.43(2H),6.07(1H),5.82 (1H)。 製備例3(5-溴-2-氟苄基)胺基甲酸第三丁酯:2-Bromo-3,3,3-trifluoropropene (2.65 g, 15.1 mmol) and 2-(3,5-dichloro-4-fluorophenyl)-4,4,5,5-tetramethyl Add a solution of -1,3,2-dioxaborolane (2A.1) (4.4 g, 15.1 mmol) in 1,4-dioxane (60 mL), Na2CO3 (4.02 g, 38 mmol ) and water (20 mL). Next, bis(triphenylphosphine)palladium chloride (220 mg, 0.3 mmol) was added and the reaction mixture was heated to 80 ° C for 18 hours. The reaction mixture was cooled, filtered and concentrated under reduced pressure to remove diane. The residue was diluted with EtOAc (EtOAc m. The crude material was purified on silica gel eluting with 1% heptane to give the crude oil of the intermediate - 43- £ 201201802 (1.8 g, 47%). 4 NMR (CDC13): δ 7.43 (2H), 6.07 (1H), 5.82 (1H). Preparation 3 (5-Bromo-2-fluorobenzyl)carbamic acid tert-butyl ester:
對1-(5-溴-2-氟苯基)鹽酸鹽(10g,41_6 mmol)於二氯 甲烷(100 mL)之冷(0°C)溶液添加二碳酸二-第三丁酯(9.07g ,41.6 mmol)接著添加三乙胺(8.4 g,83.2 mmol)。溶液於 0°C攪拌30分鐘,之後於室溫攪拌兩小時。反應以水(2x 2 5 mL)洗滌,使用旋轉蒸發濃縮產生黏稠油狀粗製產物。 產物於矽膠上使用乙酸乙酯於己烷中之梯度純化,產生標 題化合物之黏稠無色油。(12.51 g,41.6 mmol,99%)(4 NMR (CDC13)5 ppm : 7.46(1H), 7.40(1H), 6.92(1H), 4.90 (1H), 4.30(1 Η), 1 ·48(9Η)。 製備例4(2_氟-5-甲醯基苄基)胺基甲酸第三丁醋Add a di-t-butyl dicarbonate solution to a solution of 1-(5-bromo-2-fluorophenyl) hydrochloride (10 g, 41_6 mmol) in dichloromethane (100 mL). g, 41.6 mmol) followed by the addition of triethylamine (8.4 g, 83.2 mmol). The solution was stirred at 0 ° C for 30 minutes and then at room temperature for 2 hours. The reaction was washed with water (2×2 5 mL) and concentrated using rotary evaporation to yield crude crude oil. The product was purified on silica gel eluting with EtOAc EtOAc (12.51 g, 41.6 mmol, 99%) (4 NMR (CDC13) 5 ppm: 7.46 (1H), 7.40 (1H), 6.92 (1H), 4.90 (1H), 4.30 (1 Η), 1 · 48 (9 Η) Preparation Example 4 (2-Fluoro-5-methylbenzylidenebenzyl)carbamic acid terpene vinegar
SS
-44- 201201802 將(5-溴-2-氟苄基)胺基甲酸酯(丨〇·2 g,33·5 mmol)溶 於無水THF(80 mL)中,溶液於乾冰丙酮浴中冷卻至-78°C 。在反應保持於氮惰性氛圍下之同時在溫度保持-78 t下 於30分鐘期間經由添液漏斗逐滴添加正丁基鋰(n_BuLi )(44 mL,1.6M之己烷溶液,70.3 mmol)。溶液多攪拌10 分鐘,之後添加DMF(4.9 g,68 mmol),一次全部添加。 移除冷浴,反應以兩小時平衡至室溫。將反應冷卻至0°C 且藉添加飽和氯化銨水溶液(50 mL)驟冷。該等層一起攪 拌30分鐘,之後使其分離。收集有機相,以硫酸鈉乾燥 ,使用旋轉蒸發於低壓下濃縮以產生黏性油。該油使用乙 酸乙酯於己烷中之梯度施以快速管柱層析’產生標題化合 物之黏性油。(6.78 g,80%)lH NMR(400 MHz’ CDC13)5 ppm 1.48(s, 9 H)4.45(d, J = 5.56 Hz, 2 H) 4.9 9 - 5.0 6 (b r, 1 H)7.1 7-7.25(m, 1 H) 7.8 2 - 7.8 6 (m, 1 H)7.92(d, J = 5.05 Hz, 1 H)9.97(s, 1 H)。 製備例5 {2-氟-5-[(E/Z)_(羥基亞胺)甲基]-苄基}-胺基甲酸 第三丁酯:-44- 201201802 (5-Bromo-2-fluorobenzyl)carbamate (丨〇·2 g, 33·5 mmol) was dissolved in anhydrous THF (80 mL), and the solution was cooled in a dry ice acetone bath To -78 ° C. n-Butyllithium (n-BuLi) (44 mL, 1.6 M in hexanes, 70.3 mmol) was added dropwise via a funnel over 30 min while maintaining the reaction under nitrogen atmosphere. The solution was stirred for a further 10 minutes, then DMF (4.9 g, 68 mmol) was added and all added at once. The cold bath was removed and the reaction was allowed to equilibrate to room temperature over two hours. The reaction was cooled to 0.degree. C. and quenched with saturated aqueous ammonium chloride (50 mL). The layers were stirred together for 30 minutes and then allowed to separate. The organic phase was collected, dried over sodium sulfate and concentrated using EtOAc (EtOAc) EtOAc. The oil was subjected to flash column chromatography using a gradient of ethyl acetate in hexane to give the title compound as a viscous oil. (6.78 g, 80%) lH NMR (400 MHz 'CDC13) 5 ppm 1.48 (s, 9 H) 4.45 (d, J = 5.56 Hz, 2 H) 4.9 9 - 5.0 6 (br, 1 H) 7.1 7- 7.25(m, 1 H) 7.8 2 - 7.8 6 (m, 1 H) 7.92 (d, J = 5.05 Hz, 1 H) 9.97 (s, 1 H). Preparation 5 {2-Fluoro-5-[(E/Z)-(hydroxyimino)methyl]-benzyl}-carbamic acid tert-butyl ester:
-45- 201201802 對(2-氟-5-甲醯基苄基)胺基甲酸第三丁酯(1.0 g,3·9 mmol)之乙醇(2〇 mL)混合物添加羥基胺鹽酸鹽(1.37g,19.7 mmol)且乙酸鈉(1.62 g,19.7 mmol)。混合物於室溫攪拌 四小時。於低壓下藉旋轉蒸發移除揮發物。將水(40 mL) 添加至燒瓶’以懸浮產物。混合物攪拌30分鐘後,抽氣 過濾收集白色固體,水洗(2x20 mL),風乾產生中間物,在 不額外純化下使用於後續步驟。1H NMR(400 MHz,CDC13)3 ppm 1.48(s, 9 H)4.40(d, J = 5.05 Hz, 2 H) 4.9 3 - 5.0 2 (b r s, 1 H)7.04-7.09(m, 1 H)7.49(br m, 1 H)7.57(dd, J = 7.20, 2.15 Hz, 1 H)8.1 〇(s,1 H)。 製備例6{5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二氫異 噚唑-3-基]-2-氟苄基}胺基甲酸第三丁酯:-45- 201201802 Add a hydroxylamine hydrochloride (1.37) to a mixture of (2-fluoro-5-methylbenzylidenebenzyl)carbamic acid tert-butyl ester (1.0 g, 3·9 mmol) in ethanol (2 mL). g, 19.7 mmol) and sodium acetate (1.62 g, 19.7 mmol). The mixture was stirred at room temperature for four hours. The volatiles were removed by rotary evaporation at low pressure. Water (40 mL) was added to the flask to suspend the product. After the mixture was stirred for 30 minutes, a white solid was collected by suction, washed with water (2×20 mL), and dried to give the intermediate. 1H NMR (400 MHz, CDC13) 3 ppm 1.48 (s, 9 H) 4.40 (d, J = 5.05 Hz, 2 H) 4.9 3 - 5.0 2 (brs, 1 H) 7.04-7.09 (m, 1 H) 7.49 (br m, 1 H) 7.57 (dd, J = 7.20, 2.15 Hz, 1 H) 8.1 〇(s, 1 H). Preparation 6 {5-[5-(3,4,5-Trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-fluorobenzyl Tert-butyl carbamic acid:
對{2-氟-5-[(Ε/Ζ)-(羥基亞胺)甲基]苄基}胺基甲酸第 三丁醋(製備例 5,250 mg,0.826 mmols)之 DMF(5 mL)溶 液添加N-氯琥珀醯亞胺(115 mg,0.858),分三等份以30 分鐘添加,各次添加之間約十分鐘》反應混合物於氮氛圍 中攪拌十二小時。在粗製反應混合物中添加1,2,3-三氯-5-三氟丙-2-烯-2-基)苯(製備例 1,228 mg,0.826To a solution of {2-fluoro-5-[(Ε/Ζ)-(hydroxyimino)methyl]benzyl}aminocarbamic acid terpene vinegar (Preparation 5, 250 mg, 0.826 mmols) in DMF (5 mL) N-chlorosuccinimide (115 mg, 0.858) was added to the solution and added in three equal portions over 30 minutes with about ten minutes between each addition. The reaction mixture was stirred for 12 hours under nitrogen. Add 1,2,3-trichloro-5-trifluoroprop-2-en-2-yl)benzene to the crude reaction mixture (Preparation Example 1,228 mg, 0.826)
S -46- 201201802 mmol)及固體碳酸氫鈉(300 mg)。混合物於室溫攪拌24小 時。反應混合物分溶於水(10 mL)及EtOAc(40 mL)之間。 有機相連續的以水(3xl5mL)洗滌,乾燥(硫酸鈉),於低壓 下餾除溶劑,產生粗產物之黏稠無色油。產物於矽膠上純 化(EtOAc於己烷中之梯度)產生標題化合物之非晶形玻璃 狀物(221 mg,49%)。m/z(CI)443 [M + H]+(在游離化時失去 Boc基團)》 製備例7 1-{2-氟-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)- 4,5-二氫異噚唑-3-基]苯基}甲胺鹽酸鹽:S-46- 201201802 mmol) and solid sodium bicarbonate (300 mg). The mixture was stirred at room temperature for 24 hours. The reaction mixture was partitioned between water (10 mL) and EtOAc (40 mL). The organic phase was washed successively with water (3.times.5 mL), dried (Na.sub.2), and evaporated. The product was purified on EtOAc (EtOAc:EtOAc) m/z (CI) 443 [M + H] + (lost Boc group upon liberation). Preparation 7 1-{2-Fluoro-5-[5-(3,4,5-trichlorophenyl) -5-(Trifluoromethyl)- 4,5-dihydroisoxazol-3-yl]phenyl}methylamine hydrochloride:
對{5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二氫異噚 唑-3-基]-2-氟苄基}-胺基甲酸第三丁酯(製備例6)添加TF A (3 mL)。反應於室溫攪拌隔夜。於低壓下餾除揮發物。使 用乙腈(3x20 mL)執行數個蒸發週期以移除過多的TFA。 粗製殘留物溶於EtOAc(40 mL)中,且於攪拌混合物時添 加4N HC1之二D辱烷溶液(5mL)。形成白色沉澱物(HC1鹽) 。混合物於密閉容器中進行耐衝性歷經九十分鐘。使用抽吸過 濾揷集白色固體,以產生標題化合物。m/z(CI)443[M + H]+。 ( -47- 201201802 製備例8: 3·(2-氟-5-(5-(3,4,5-三氯苯基)-5-(三氟甲基)· 4,5-二氫異噚唑-3-基)苄基胺基)_3_合氧基丙酸乙酯。For {5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-fluorobenzyl} -T-butyl carbamic acid (Preparation Example 6) TF A (3 mL) was added. The reaction was stirred overnight at room temperature. The volatiles were distilled off under reduced pressure. Several evaporation cycles were performed using acetonitrile (3 x 20 mL) to remove excess TFA. The crude residue was dissolved in EtOAc (40 mL)EtOAc. A white precipitate (HC1 salt) is formed. The mixture was subjected to impact resistance in a closed container for ninety minutes. The white solid was collected using suction filtration to give the title compound. m/z (CI) 443 [M + H]+. ( -47- 201201802 Preparation 8: 3·(2-Fluoro-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)·4,5-dihydroiso Ethyl oxazol-3-yl)benzylamino)_3-oxypropionic acid ethyl ester.
1-{2-氟-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二氫 異噚唑-3-基]苯基}甲胺鹽酸鹽(6 g,13.6 mm〇1)溶於(6〇 mL),置於惰性氛圍(N2)下且冷卻至〇。(:。反應混合物逐滴 以三乙胺(0.69 mL,4.9 mmol)及乙基丙二醯氯(0.63 mL, 4.9 m m ο 1)處理。使反應增溫至室溫並攪拌1小時。反應混 合物藉管柱層析、矽膠(200 g)0-50%乙酸乙酯/庚烷純化, 產生所需產物之乳白色粉末(4 g,7.2 mmol)。4 NMR( CDC13) 1 ·3 1 3Ht, 3.3 8 2hs, 3.71 1 Hd, 4.10 1 Hd, 4.23 2Hq, 4.55 2Hd, 7.10-7.15 lHm, 7.45-7.52 lHm, 7.65-7.70 4Hm 。MH + 5 5 5。 製備例9: 3-(2-氟-5-(5-(3,4,5-三氯苯基)-5·(三氟甲基)- 4,5-二氫異噚唑-3-基)苄基胺基)-3-合氧基丙酸。 F39n1-{2-Fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]phenyl }Methylamine hydrochloride (6 g, 13.6 mm 〇1) was dissolved in (6 〇 mL), placed under an inert atmosphere (N2) and cooled to hydrazine. (: The reaction mixture was treated with triethylamine (0.69 mL, 4.9 mmol) and ethylpropanedichloride (0.63 mL, 4.9 mm ο 1) dropwise. The reaction was warmed to room temperature and stirred for 1 hour. Purification by column chromatography, EtOAc (EtOAc)EtOAc (EtOAc (EtOAc) 8 2hs, 3.71 1 Hd, 4.10 1 Hd, 4.23 2Hq, 4.55 2Hd, 7.10-7.15 lHm, 7.45-7.52 lHm, 7.65-7.70 4Hm MH + 5 5 5. Preparation 9: 3-(2-Fluoro-5 -(5-(3,4,5-trichlorophenyl)-5.(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzylamino)-3-oxo Propionic acid. F39n
S -48- 201201802 l-{2-氟-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二氫 異卩号哩-3-基]苯基}甲胺鹽酸鹽(4 g,7.2 mmol)於乙醇40 mL中之漿液係以iNNaOH水溶液(40 mL)處理,於室溫攪 拌2小時。反應混合物於減壓下濃縮至乾燥,分溶於乙酸 乙酯與IN HC1水溶液之間。將有機萃取液乾燥並濃縮成 白色發泡物(3.7 g,7.0 mmol,97%)4 NMR(CDC13)3.39 2Hs, 3.70 1 Hd, 4.08 lHd, 4.54 2Hd 7.09-7.14 lHm, 7.38-7.41 lHm, 7.5 8-7.63 3Hm, 7.66-7.68 lHm。MH+ 527。 實施例1 N-乙基-N’-{2-氟-5-[5-(3,4,5-三氯-苯基)-5-三氟 甲基-4,5-二氫-異噚唑-3-基]-苄基}-丙二醯胺S-48- 201201802 l-{2-Fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoindole 哩- A slurry of 3-yl]phenyl}methanamine hydrochloride (4 g, 7.2 mmol) in EtOAc (EtOAc) The reaction mixture was concentrated to dryness <RTI ID=0.0> The organic extract was dried and concentrated to a white foam (3.7 g, 7.0 mmol, 97%) 4 NMR (CDC13) 3.39 2Hs, 3.70 1 Hd, 4.08 lHd, 4.54 2Hd 7.09-7.14 lHm, 7.38-7.41 lHm, 7.5 8-7.63 3Hm, 7.66-7.68 lHm. MH+ 527. Example 1 N-Ethyl-N'-{2-fluoro-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-iso Oxazol-3-yl]-benzyl}-propanediamine
將乙基胺(2.44mm〇l)稱重置入8 mL管瓶中。添加3-(2-氟- 5-(5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二氫異噚 唑-3-基)苄基胺基)-3-合氧基丙酸(〇·〇82 mmol,40 mg)於 DMF 1 mL中之溶液。添加六氟磷酸〇-(7-氮雜苯並三唑-卜基)-N,N,N’,N’-四甲基脲鑰(0.09 mmol ’ 34.2 mg)於 DMF(1 mL)中之溶液,接著添加三乙胺(0.82 mmol’ 83 mg )。反應混合物於室溫搖動72小時。反應混合物以MP-異 氰酸酯樹脂(0.82 mmol,560 mg,〜1.47 mmol/g)及 MP-碳酸醋樹脂(0.82 mmol,260 mg,〜3.14 mmol/g)處理, -49- 201201802 且於室溫搖動16小時。將反應過濾,濃縮至產生粗製產 物。粗製產物藉製備型 HPLC純化(Waters,Gemini NX C 1 8 2 1 x 1 00mm 5μιη、移動相A =於H2O中0.1%三氟乙酸 ,移動相B =乙腈,於8分鐘中線性梯度3 0%B至100%,保 持1分鐘,20毫升/分鐘,藉質量收集之尖峰)產生所需產物 16.3 mg。29% 產率 Μ H +[ 5 5 4]。滯留時間 2 · 8 4 分鐘(A gi 1 en t 1 200,管柱=Gemini NX C1 8 4.6x50 mm 3 μιη,移動相 A = 於H20中0.1 %三氟乙酸,移動相B =乙腈,於5分鐘線性 梯度30%B至100%,保持1分鐘,1.5毫升/分鐘)。 實施例2 N-環丙基甲基-N’-{2-氟-5-[5-(3,4,5-三氯-苯基)- 5-三氟甲基-4,5-二氫-異噚唑-3-基]-苄基}-丙二醯胺Ethylamine (2.44 mm 〇l) was weighed into an 8 mL vial. Add 3-(2-fluoro-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzyl A solution of the aminoamino)-3-oxypropionic acid (〇·〇 82 mmol, 40 mg) in DMF 1 mL. Add ruthenium hexafluorophosphate-(7-azabenzotriazol-bu)-N,N,N',N'-tetramethylurea (0.09 mmol '34.2 mg) in DMF (1 mL) The solution was then added triethylamine (0.82 mmol '83 mg). The reaction mixture was shaken at room temperature for 72 hours. The reaction mixture was treated with MP-isocyanate resin (0.82 mmol, 560 mg, ~ 1.47 mmol/g) and MP-carbonic acid resin (0.82 mmol, 260 mg, ~3.14 mmol/g), -49-201201802 and shaken at room temperature 16 hours. The reaction was filtered and concentrated to give a crude material. The crude product was purified by preparative HPLC (Waters, Gemini NX C 1 8 2 1 x 1 00 mm 5 μιη, mobile phase A = 0.1% trifluoroacetic acid in H2O, mobile phase B = acetonitrile, linear gradient 30% in 8 minutes) B to 100%, held for 1 minute, 20 ml/min, spiked by mass collection) yielded the desired product 16.3 mg. 29% yield Μ H + [ 5 5 4]. Retention time 2 · 8 4 minutes (A gi 1 en t 1 200, column = Gemini NX C1 8 4.6x50 mm 3 μιη, mobile phase A = 0.1% trifluoroacetic acid in H20, mobile phase B = acetonitrile, at 5 Minute linear gradient 30% B to 100% for 1 minute, 1.5 ml/min). Example 2 N-cyclopropylmethyl-N'-{2-fluoro-5-[5-(3,4,5-trichloro-phenyl)- 5-trifluoromethyl-4,5-di Hydrogen-isoxazol-3-yl]-benzyl}-propanediamine
環丙烷甲基胺(2.44 mmol)稱重置入8 mL管瓶^ 3-(2-氟-5-(5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二氫異噚唑-3-基)苄基胺基)-3-合氧基丙酸(0.082 mmol’ 40 mg)於DMF (1 mL)中之溶液係添加至該管瓶。添加六氟磷酸0-(7-氮 雜苯並三唑-1-基)-N,N,N’,N’-四甲基脲鑰(0_09 mmol, 34.2 mg)於DMF(1 mL)中之溶液,接著添加三乙胺(0.82 mmol,83 mg)。反應混合物於室溫搖動72小時。反應混 合物以 MP -異氰酸酯樹脂(0.82 mmol,560 mg’〜1.47Cyclopropane methylamine (2.44 mmol) was weighed into an 8 mL vial ^ 3-(2-fluoro-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl) a solution of -4,5-dihydroisoxazol-3-yl)benzylamino)-3-oxypropanoic acid (0.082 mmol '40 mg) in DMF (1 mL) was added to the tube bottle. Add 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (0-09 mmol, 34.2 mg) in DMF (1 mL) The solution was then added triethylamine (0.82 mmol, 83 mg). The reaction mixture was shaken at room temperature for 72 hours. The reaction mixture was MP-isocyanate resin (0.82 mmol, 560 mg'~1.47)
S 201201802 mmol/g)及 ΜΡ·碳酸酯樹脂(0.82 mmol, 260 mg,〜3.14 mmol/g)處理,且於室溫搖動16小時。將反應過濾且於減 壓下濃縮至產生粗製產物。粗製產物藉製備型HPLC純化 (Waters,Gemini NX C18 21x100mm 5μιη、移動相 A =於 H20中0.1 %三氟乙酸,移動相B =乙腈,於8分鐘中線性 梯度30%B至100%,保持1分鐘,20毫升/分鐘,藉質量 收集之尖峰)產生所需產物23.4 mg。40%產率,MH + [5 80] 。滯留時間 3·09 分鐘(Agilent 1200,管柱=Gemini NX (:18 4.6><5〇1111113卩111,移動相八=於1120中0.1%三氟乙酸 ,移動相B =乙腈,於5分鐘線性梯度30%B至100%,保 持1分鐘,1.5毫升/分鐘)。 實施例3:^{5-[5-(3,4,5-三氯苯基)-5-(三氟甲基.)-4,5-二 氫異噚唑-3-基]-2-氟苄基}乙醯胺:Treatment with S 201201802 mmol/g) and hydrazine carbonate resin (0.82 mmol, 260 mg, ~3.14 mmol/g) and shaking at room temperature for 16 hours. The reaction was filtered and concentrated under reduced pressure to give a crude material. The crude product was purified by preparative HPLC (Waters, Gemini NX C18 21x100mm 5μιη, mobile phase A = 0.1% trifluoroacetic acid in H20, mobile phase B = acetonitrile, linear gradient 30% B to 100% in 8 minutes, keeping 1 Minutes, 20 ml/min, by spike of mass collection) yielded the desired product 23.4 mg. 40% yield, MH + [5 80]. The residence time is 3.09 minutes (Agilent 1200, column = Gemini NX (: 18 4.6 >< 5〇1111113卩111, mobile phase VIII = 0.1% trifluoroacetic acid in 1120, mobile phase B = acetonitrile, at 5 Minute linear gradient 30% B to 100% for 1 minute, 1.5 ml/min. Example 3: ^{5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl) ..-4,5-Dihydroisoxazol-3-yl]-2-fluorobenzyl}acetamidamine:
用於製備醯胺之方法A 對2_氟- 5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二氫 異噚唑-3-基]苯基}甲胺鹽酸鹽(100 mg,0.21 mmols)(製備 例7)之DMA(2 mL)混合物添力口吡陡(72 mg,0.9 mmol), 接著乙醢基氯(24 mg ’ 0.3 1 mmol)。使反應於室溫攪拌十 -51- 201201802 分鐘,之後添加水(25 mL) ◊混合物於室溫攪拌一小時。 抽氣過濾收集白色沉澱物形式之最終產物(95毫克,94%) 。NMR(400 MHz,氯仿-d)d ppm 2.05(s,3 H)3.69(d, J=17.18 Hz, 1 H)4.09(d, J=17.18 Hz, 1 H)4.50(d, J = 6.06 Hz, 2 H)5.90-6.00(m, 1 H) 7.0 8 - 7 . 1 7 (m, 1 H) 7.6 2 - 7.7 0 (m , 4 H)m/z(CI)483 [M + H]+。 實施例4: N-{2-氟-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二氫異卩弯唑-3·基]苄基}-2-甲基丙醯胺:Method for the preparation of guanamine A to 2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole- A mixture of DMA (2 mL) of 3-yl]phenyl}methylamine hydrochloride (100 mg, 0.21 mmol) (Preparation 7) was added to a mixture of EtOAc (. 24 mg '0.3 1 mmol). The reaction was allowed to stir at room temperature for ten - 51 - 201201802 minutes, then water (25 mL) was added and the mixture was stirred at room temperature for one hour. The final product in the form of a white precipitate (95 mg, 94%) was collected by suction filtration. NMR (400 MHz, chloroform-d) d ppm 2.05 (s, 3 H) 3.69 (d, J = 17.18 Hz, 1 H) 4.09 (d, J = 17.18 Hz, 1 H) 4.50 (d, J = 6.06 Hz , 2 H) 5.90-6.00 (m, 1 H) 7.0 8 - 7 . 1 7 (m, 1 H) 7.6 2 - 7.7 0 (m , 4 H)m/z (CI) 483 [M + H]+ . Example 4: N-{2-Fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoindolizole-3 · benzyl]-2-methylpropanamide:
用於製備醯胺之方法B 對1-{2-氟-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)_4,5· 二氫異噚唑-3-基]苯基}甲胺鹽酸鹽(45 mg,0.094 mmol )( 製備例7)之DMA(2 mL)溶液添加二異丙基乙基胺(36.4 mg ,0.28 mmol)、甲基丙酸(12.5 mg,0.14 mmol)、EDC( 23.4 mg,0.12 mmol)及 H0BT(1.2 mg,0.009 mmol)。反 應於室溫攪拌12小時。反應混合物分溶於乙酸乙酯(50 mL)及水(20mL)之間。有機相以水洗滌(3x20 mL)。蒸餾溶 劑產生標題化合物(42 mg ’ 87%)之白色固體》NMR( 4 0 0 MHz,CDCl3)8 ppm 1.19(dd, J = 6.82, 2.0 2 Hz, 6 s -52- 201201802 H)2.41(dt, J= 1 3.83, 6.85 Hz, 1 H)3.68(d, J=17.18 Hz, 1 H) 4.08(d, J=17.18 Hz, 1 H)4.51(d, J = 6.06 Hz, 2 H) 5.89 (br.s·, 1 H)7.06-7.20(m, 1 H) 7.5 9 - 7.7 1 (m, 4 H) ; m/z (CI)5 1 1 [M + H]+。 實施例5:N-{2-氟- 5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二氫異卩萼嗖_3_基]苄基}環丙烷甲醯胺:Method B for the preparation of decylamine for 1-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoindole Add isopropyl (36.4 mg, 0.28 mmol) to a solution of oxazol-3-yl]phenyl}methylamine hydrochloride (45 mg, 0.094 mmol) (Preparation 7) in DMA (2 mL) Propionic acid (12.5 mg, 0.14 mmol), EDC (23.4 mg, 0.12 mmol) and H0BT (1.2 mg, 0.009 mmol). The reaction was stirred at room temperature for 12 hours. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (20 mL). The organic phase was washed with water (3 x 20 mL). The solvent was distilled to give the title compound (42 mg <<>><>>>>><>>> , J = 1 3.83, 6.85 Hz, 1 H) 3.68 (d, J = 17.18 Hz, 1 H) 4.08 (d, J = 17.18 Hz, 1 H) 4.51 (d, J = 6.06 Hz, 2 H) 5.89 ( Br.s·, 1 H)7.06-7.20(m, 1 H) 7.5 9 - 7.7 1 (m, 4 H) ; m/z (CI)5 1 1 [M + H]+. Example 5: N-{2-Fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoindole_3 _yl]benzyl}cyclopropanecarbamide:
係自1-(2-氟-5_(5-(3,4,5-三氯苯基)-5-(三氟甲基)-From 1-(2-fluoro-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-
4.5- 二氫異噚唑-3-基)苯基)甲胺(製備例7)經由根據方法A 與環丙羰基氯反應而製備。4 NMR(400 MHz,CDC13)5 ppm 0.78-0.83(m, 2 H)1.00-1.04(m, 2 H)1.35-1.42(m, 1 H)3.69(d, J=17.43 Hz, 1 H)4.08(d, J=17.18 Hz, 1 H)4.53(d, J = 6.32 Hz, 1 H)6.05(br.s., 1 H)7.14(t, J = 8.97 Hz, 1 H)7.60-7.72(m,4 H) ; m/z(CI)509[M + H]+。 實施例6:Ν·{2-氟-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)- 4.5- 二氫異鸣唑-3-基]苄基}環丁烷甲醯胺: -53- 2012018024.5-Dihydroisoxazol-3-yl)phenyl)methanamine (Preparation Example 7) was prepared by reaction with cyclopropylcarbonyl chloride according to Method A. 4 NMR (400 MHz, CDC13) 5 ppm 0.78-0.83 (m, 2 H) 1.00-1.04 (m, 2 H) 1.35-1.42 (m, 1 H) 3.69 (d, J = 17.43 Hz, 1 H) 4.08 (d, J = 17.18 Hz, 1 H) 4.53 (d, J = 6.32 Hz, 1 H) 6.05 (br.s., 1 H) 7.14 (t, J = 8.97 Hz, 1 H) 7.60-7.72 (m , 4 H) ; m/z (CI) 509 [M + H]+. Example 6: Ν·{2-Fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4.5-dihydroisoxazol-3-yl] Benzyl}cyclobutanecarbamide: -53- 201201802
係自1-(2-氟- 5·(5-(3,4,5-三氯苯基)-5-(三氟甲基)- 4.5- 二氫異噚唑-3-基)苯基)甲胺鹽酸鹽(製備例7)經由與環 丁烷羰基氯根據方法Α反應而製備。4 NMR(400 MHz, CDC13)5 ppm 1.86-2.05 (m, 2 H ) 2.1 3 - 2.2 4 (m, 2 H)2.24- 2.37(m, 2 H)2.97-3.09(m, 1 H)3.69(d, J=16.93 Hz, 1 H)4.09(d, J=17.18 Hz, 1 H)4.51(d, J = 6.32 Hz, 2 H)5.76(br.s., 1 H)7.09-7.17(m,1 H)7.62-7.70(m,4 H) ; ) ; m/z(CI)525[M + H]+。 實施例7:N-{2-氟- 5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)- 4.5- 二氫異噚唑-3-基]苄基}丙醯胺:From 1-(2-fluoro-5(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4.5-dihydroisoxazol-3-yl)phenyl Methylamine hydrochloride (Preparation Example 7) was prepared by reaction with cyclobutanecarbonyl chloride according to the method. 4 NMR (400 MHz, CDC13) 5 ppm 1.86-2.05 (m, 2 H) 2.1 3 - 2.2 4 (m, 2 H) 2.24 - 2.37 (m, 2 H) 2.97-3.09 (m, 1 H) 3.69 ( d, J=16.93 Hz, 1 H)4.09 (d, J=17.18 Hz, 1 H) 4.51 (d, J = 6.32 Hz, 2 H) 5.76 (br.s., 1 H) 7.9-7.17 (m, 1 H) 7.62-7.70 (m, 4 H) ; ) ; m/z (CI) 525 [M + H]+. Example 7: N-{2-Fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4.5-dihydroisoxazol-3-yl] Benzyl}propanamine:
係自1-(2_氟- 5-(5-(3,4,5-三氯苯基)-5-(三氟甲基)- s 4,5-二氫異噚唑-3-基)苯基)甲胺鹽酸鹽經由根據方法A與 丙醯氯反應而製備。4 NMR(400 MHz,CDC13)5 ppm 1.19 (t, J = 7.58 Hz, 3 H)2.27(q, J = 7.58 Hz, 2 H)3.69(d, J=17.18 -54- 201201802From 1-(2-fluoro-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-s 4,5-dihydroisoxazol-3-yl Phenyl)methylamine hydrochloride was prepared by reaction with propional chloride according to Method A. 4 NMR (400 MHz, CDC13) 5 ppm 1.19 (t, J = 7.58 Hz, 3 H) 2.27 (q, J = 7.58 Hz, 2 H) 3.69 (d, J = 17.18 -54 - 201201802
Hz, 1 H)4.09(d, J=17.18 Hz, 1 H)4.51(d, J = 6.32 Hz, 2 H)5.87(br.s., 1 H) 7.0 8 - 7.1 8 (m, 1 H) 7.6 1 - 7.7 2 (m, 4 H); m/z(CI)497[M + H]+。 實施例8: 2-環丙基-N-{2-氟-5-[5-(3,4,5-三氯苯基)-5-(三 氟甲基)-4,5_二氫異噚唑-3-基]苄基}乙醯胺:Hz, 1 H)4.09 (d, J=17.18 Hz, 1 H) 4.51 (d, J = 6.32 Hz, 2 H) 5.87 (br.s., 1 H) 7.0 8 - 7.1 8 (m, 1 H) 7.6 1 - 7.7 2 (m, 4 H); m/z (CI) 497 [M + H]+. Example 8: 2-Cyclopropyl-N-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydrogen Isoxazol-3-yl]benzyl}acetamide:
係自1-(2-氟- 5-(5-(3,4,5-三氯苯基)-5-(三氟甲基)- 4.5- 二氫異噚唑-3-基)苯基)甲胺鹽酸鹽經由與2-環丙基乙 酸根據方法B反應而製得。4 NMR(400 MHz,CDC13)5 ppm-0.07-0.07(m, 2 Η) 0.3 6 - 0.4 8 (m, 2 H)0.76(t, J = 7.71 Hz, 1 H)1.98(d, J = 7.33 Hz, 2 H)3.45(d, J=17.18 Hz, 1 H) 3.85(d, J=17.1 8 Hz, 1 H)4.3 1 (d, J = 6.06 Hz, 2 H) 6.11(br.s., 1 H)6.91(t, J = 9.47 Hz, 1 H) 7.3 7 - 7.5 1 (m, 5 H) ;m/z(CI)525 [M + H]+ 〇 實施例9: N-{2-氟-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)- 4.5- 二氫異卩弯唑-3-基]苄基}-3-甲基丁烷醯胺: -55- 201201802From 1-(2-fluoro-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4.5-dihydroisoxazol-3-yl)phenyl Methylamine hydrochloride is prepared by reaction with 2-cyclopropylacetic acid according to Method B. 4 NMR (400 MHz, CDC13) 5 ppm-0.07-0.07 (m, 2 Η) 0.3 6 - 0.4 8 (m, 2 H) 0.76 (t, J = 7.71 Hz, 1 H) 1.98 (d, J = 7.33) Hz, 2 H) 3.45 (d, J = 17.18 Hz, 1 H) 3.85 (d, J = 17.1 Hz, 1 H) 4.3 1 (d, J = 6.06 Hz, 2 H) 6.11 (br.s., 1 H) 6.91 (t, J = 9.47 Hz, 1 H) 7.3 7 - 7.5 1 (m, 5 H) ; m/z (CI) 525 [M + H] + 〇 Example 9: N-{2- Fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4.5-dihydroisoindolizine-3-yl]benzyl}-3-methyl Butane amide: -55- 201201802
係自(2 -氟- 5- (5-(3,4,5 -三氯苯基)_5-(三氟甲基)-4,5 -二 氫異噚唑-3-基)苯基)甲胺經由與3-甲基丁酸根據方法B 進行反應而製備。4\1^11(4〇〇]\^2,€〇〇:130卩0111〇.83-0.91(m, 8 Η)1.01 -1.1 4(m, 1 Η)1.95 - 2.1 3(m, 4 H)3.59(d, J=17.43 Hz, 1 H)3.99(d, J=17.18 Hz, 1 H)4.42(d, J = 6.32 Hz, 2 H)5.79(br.s., 1 H) 6.9 7 - 7 . 1 1 (m, 1 H) 7.4 8 - 7.6 5 (m s 4 H) ; m/z(CI)527 [M + H]+。 製備例10: 5-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5- 二氫異噚唑-3-基)-2-氟苄基胺基甲酸第三丁酯:From (2-fluoro-5-(5-(3,4,5-trichlorophenyl)_5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl) Methylamine was prepared by reaction with 3-methylbutyric acid according to Method B. 4\1^11(4〇〇]\^2,€〇〇:130卩0111〇.83-0.91(m, 8 Η)1.01 -1.1 4(m, 1 Η)1.95 - 2.1 3(m, 4 H) 3.59 (d, J = 17.43 Hz, 1 H) 3.99 (d, J = 17.18 Hz, 1 H) 4.42 (d, J = 6.32 Hz, 2 H) 5.79 (br.s., 1 H) 6.9 7 - 7 . 1 1 (m, 1 H) 7.4 8 - 7.6 5 (ms 4 H) ; m/z (CI) 527 [M + H]+. Preparation 10: 5-(5-(3,5- Dibutyl 4-fluoro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-fluorobenzylaminocarboxylic acid tert-butyl ester:
對{2-氟-5-[(E/Z)-(羥基亞胺)甲基]苄基}胺基甲酸第 三丁酯(製備例 5,250 mg’ 0.826 mmols)之 DMF(5 mL)溶 液添加N -氯號拍醯亞胺(ll5 mg,0.858),分三等份以30 分鐘添加,各次添加之間約十分鐘。反應混合物於氮氛圍T-butyl {2-fluoro-5-[(E/Z)-(hydroxyimino)methyl]benzyl}carbamic acid (Preparation Example 5, 250 mg '0.826 mmols) in DMF (5 mL) The solution was added with N-chloro-sodium iodide (ll5 mg, 0.858) and added in three equal portions over 30 minutes with approximately ten minutes between each addition. Reaction mixture in nitrogen atmosphere
S -56- 201201802 中攪拌十二小時。在粗製反應混合物中添加1,3-二氯-2-氟-5-(1,1,1-三氟丙-2-烯-2-基)苯(製備例 2, 214 mg,0.826 mmol)及固體碳酸氫鈉(300 mg)。反應混合物於室溫攪拌 24小時》反應混合物分溶於水(10 mL)及EtOAc(40 mL)之 間。有機相係連續的以水(3x1 5mL)洗滌,乾燥(硫酸鈉), 於低壓下餾除溶劑,產生粗產物之黏稠無色油。產物於矽 膠上純化(EtOAc於己烷中之梯度)產生標題化合物之非晶 形玻璃狀物(28 6 mg,66%)。m/z(CI)425 [M + H]+(在游離化 時失去 Boc 基團)4 NMR(400 MHz,氯仿- d)d ppm 1.48(s, 9 H)3.69(d, J=17.43 Hz, 1 H)4.〇8(d, J=17.18 Hz, 1 H) 4.39(d, J = 6.06 Hz, 2 H)4.99(br.s., 1 H)7.12(t, J = 9.09 Hz, 1 H)7.55 -7.69(m, 4 H) 〇 製備例11(5-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二 氫異噚唑-3-基)-2-氟苯基)甲胺:Stir for 12 hours in S -56- 201201802. Add 1,3-dichloro-2-fluoro-5-(1,1,1-trifluoroprop-2-en-2-yl)benzene to the crude reaction mixture (Preparation Example 2, 214 mg, 0.826 mmol) And solid sodium bicarbonate (300 mg). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was partitioned between water (10 mL) andEtOAc. The organic phase was washed successively with water (3.times.5 mL), dried (sodium sulfate), and evaporated to dryness. The product was purified on EtOAc (EtOAc:EtOAc) m/z (CI) 425 [M + H] + (lost Boc group upon liberation) 4 NMR (400 MHz, chloroform - d) d ppm 1.48 (s, 9 H) 3.69 (d, J = 17.43 Hz , 1 H) 4. 〇 8 (d, J = 17.18 Hz, 1 H) 4.39 (d, J = 6.06 Hz, 2 H) 4.99 (br.s., 1 H) 7.12 (t, J = 9.09 Hz, 1 H) 7.55 - 7.69 (m, 4 H) 〇 Preparation 11 (5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5- Dihydroisoxazol-3-yl)-2-fluorophenyl)methylamine:
對5-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氫 異噚唑-3-基)-2_氟苄基胺基甲酸第三丁酯(製備例1〇,910 mg,1.73 mmols))之二氯甲院(10 mL)溶液添加 TFA(2 mL) 。反應於室溫攪拌隔夜。於低壓下餾除揮發物。殘留物質 -57- 201201802 攝入乙酸乙醋(60 ml)中。有機相係以飽和碳酸氫鈉水溶液 (2x2 5 ml)洗滌。結合之水性洗液以乙酸乙酯(2χ2〇 ml)逆萃 取。結合所有的有機萃取液且以硫酸鈉乾燥。於低壓下蒸 餾溶劑產生固體玻璃形式之產物,於真空下乾燥。(736 mg ’ 99%)m/z(CI)425 [M + H]+。 實施例10: 2 -環丙基-N-{5-[5-(3,5 -二氯-4-氟苯基)-5-(三 氟甲基)-4,5-二氫異噚唑-3-基]-2-氟苄基}乙醯胺:5-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-fluorobenzyl TCA (2 mL) was added to a solution of the third butyl carbamate (Preparation Example 1 〇, 910 mg, 1.73 mmols) in dichloromethane (10 mL). The reaction was stirred overnight at room temperature. The volatiles were distilled off under reduced pressure. Residual substances -57- 201201802 Ingested in ethyl acetate (60 ml). The organic phase was washed with saturated aqueous sodium bicarbonate (2×2 5 mL). The combined aqueous wash was back extracted with ethyl acetate (2 χ 2 〇 ml). All organic extracts were combined and dried over sodium sulfate. The solvent is distilled off under reduced pressure to give the product as a solid glass which is dried in vacuo. (736 mg '99%) m/z (CI) 425 [M + H]+. Example 10: 2 -Cyclopropyl-N-{5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoindole Zyrid-3-yl]-2-fluorobenzyl}acetamidamine:
用以製備醯胺之方法C 對(5-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氫 異噚唑-3-基)-2 -氟苯基)甲胺(48 mg,0.118 mmol,製備 例11)之DMF(2 mL)溶液添加2·環丙基乙酸(15mg,0.15 mmol)、三乙胺(55mg,0.542mmol)、H0BT(1.2mg ’ 0.009 mmol)及 HBTU(41.1 m g,0 · 1 1 〇 mm ο 1) ° 反應於室溫攪拌 1 2小時。反應經注射濾器過濾。對濾液施以逆相HPLC純 化,產生最終產物(12mg ’ 20%)呈非晶形玻璃°滯留時間 = 3.33 分鐘;且 m/z(CI)5 08.2 [M + H]+。 實施例11 : N-{5-[5-(3,5-二氯-4-氟苯基)-5-(二氟甲基)-Method C for the preparation of decylamine (5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3 a solution of 2-difluorophenyl)methylamine (48 mg, 0.118 mmol, Preparation 11) in DMF (2 mL). 0.542 mmol), H0BT (1.2 mg ' 0.009 mmol) and HBTU (41.1 mg, 0 · 1 1 〇mm ο 1) ° The reaction was stirred at room temperature for 12 hours. The reaction was filtered through a syringe filter. The filtrate was subjected to reverse phase HPLC to give the final product (12 mg ' 20%) as amorphous glass. Retention time = 3.33 min; and m/z (CI) 5 08.2 [M + H]+. Example 11: N-{5-[5-(3,5-Dichloro-4-fluorophenyl)-5-(difluoromethyl)-
S -58- 201201802 4,5-二氫異卩号唑-3-基]-2-氟苄基}乙醯胺:S -58- 201201802 4,5-Dihydroisoxazole-3-yl]-2-fluorobenzyl}acetamide:
係自(5-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二 氫異鸣唑-3-基)-2-氟苯基)甲胺根據方法A使其與乙醯氯 反鹰。NMR(400 MHz,CDC13)5 ppm 2.05(s,3 H)3.69(d, J = 17.43 Hz, 1 H)4.09(d, J = 17.18 Hz, 1 H)4.51(d, J = 6.06 Hz, 2 H)5.92(br.s., 1 H)7.14(t, J = 8.97 Hz, 1 H)7.60(d, J = 6.06 Hz,2 H)7.63-7.72(m,2 H) ; ) ; m/z(CI)467[M + H]+。 實施例12 N-{5-[5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氫異噚唑-3-基]-2_氟苄基}環丙烷甲醯胺:From (5-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-fluoro Phenyl)methylamine was reacted with ethyl chloroacetate according to Method A. NMR (400 MHz, CDC13) 5 ppm 2.05 (s, 3 H) 3.69 (d, J = 17.43 Hz, 1 H) 4.09 (d, J = 17.18 Hz, 1 H) 4.51 (d, J = 6.06 Hz, 2 H) 5.92 (br.s., 1 H) 7.14 (t, J = 8.97 Hz, 1 H) 7.60 (d, J = 6.06 Hz, 2 H) 7.63 - 7.72 (m, 2 H) ; ) ; m/ z(CI) 467 [M + H]+. Example 12 N-{5-[5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]- 2_fluorobenzyl}cyclopropanecarbamide:
係自(5-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二 氫異噚唑-3-基)-2-氟苯基)甲胺根據方法C於HBTU、HOBT 及Hunig鹼存在下經由與環丙烷羧酸反應而製備。分析型 -59- 201201802 HPLC 管柱=Waters X-Terra 3.5 μηι 4.6 x 50mm,移動相 Α = 0·1%三氟乙酸於H20中,移動相B =乙腈,5分鐘內50%B 至100%B,保持1分鐘,2毫升/分鐘。滯留時間:3.94分 鐘,m/z(CI)493 ·9[Μ + Η]+ » 實施例13::^-{5-[5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氫異噚唑-3-基]-2-氟苄基}-3,3-二氟環丁烷甲醯胺 CI尸From (5-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-fluoro Phenyl)methylamine was prepared by reaction with cyclopropanecarboxylic acid in the presence of HBTU, HOBT and Hunig base according to Method C. Analytical -59- 201201802 HPLC Column = Waters X-Terra 3.5 μηι 4.6 x 50mm, mobile phase Α = 0·1% trifluoroacetic acid in H20, mobile phase B = acetonitrile, 50% B to 100% in 5 minutes B, keep 1 minute, 2 ml / min. Residence time: 3.94 minutes, m/z (CI) 493 · 9 [Μ + Η] + » Example 13::^-{5-[5-(3,5-dichloro-4-fluorophenyl)- 5-(Trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-fluorobenzyl}-3,3-difluorocyclobutanecarbamide CI corpse
係自(5-(5-(3,5-二氯-4-氟苯基)·5-(三氟甲基)-4,5-二 氫異噚唑-3-基)-2-氟苯基)甲胺經由與3,3-二氟環丁院-甲 酸於HBTU、ΗΟΒΤ及Hunig鹼存在下,根據方法C進行 反應。分析型 HPLC 管柱=Waters X-Terra 3.5μπι 4.6x50mm, 移動相Α = 0·1%三氟乙酸於HzO中,移動相B =乙腈,5分鐘 內5 0%B至100%B,保持1分鐘,2毫升/分鐘。滯留時間: 4.16 分鐘,m/z(CI)543.9[M + H]+。 製備例12 : 5-溴-2-氯苯甲酸甲酯:From (5-(5-(3,5-Dichloro-4-fluorophenyl)·5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-fluoro Phenyl)methylamine was reacted according to Method C in the presence of 3,3-difluorocyclobutylene-formic acid in the presence of HBTU, hydrazine and Hunig base. Analytical HPLC column = Waters X-Terra 3.5μπι 4.6x50mm, mobile phase Α = 0·1% trifluoroacetic acid in HzO, mobile phase B = acetonitrile, 5 0% B to 100% B in 5 minutes, keep 1 Minutes, 2 ml / min. Residence time: 4.16 minutes, m/z (CI) 543.9 [M + H]+. Preparation 12: Methyl 5-bromo-2-chlorobenzoate:
S -60- 201201802S -60- 201201802
對2-氯-5-溴苯甲酸(10 g,42 mmol)之二氯甲烷(50 ml)懸浮液添加過量草醯氯及一滴DMF。反應混合物於室 溫在氮氛圍中攪拌十二小時。藉於低壓下蒸餾,移除所有 揮發物。產物(黏稠性油)溶於二氯甲烷(50 mL)中,於冷卻 溶液(〇°C)中添加甲醇(5 mL)。溶液於0°C攪拌十分鐘且於 室溫攪拌一小時。藉著於低壓蒸餾,移除揮發物,產生5-溴-2 -氯苯甲酸甲醋(10.5 g,99%)。4 NMR(400 MHz, CDC13)6 ppm 3.96(s, 3 H)7.35(d, J = 8.59 Hz, 1 H)7.56(dd, J = 8.59, 2.27 Hz, 1 H ) 7.9 9 (d,J = 2.5 3 H z,1 H)。 製備例13(5-溴-2-氯苯基)甲醇:To a suspension of 2-chloro-5-bromobenzoic acid (10 g, 42 mmol) in dichloromethane (50 ml) was added EtOAc < The reaction mixture was stirred at room temperature for 12 hours under a nitrogen atmosphere. All volatiles were removed by distillation at low pressure. The product (viscous oil) was dissolved in dichloromethane (50 mL) and MeOH (5 mL) was then evaporated. The solution was stirred at 0 ° C for ten minutes and at room temperature for one hour. The volatiles were removed by low pressure distillation to yield 5-bromo-2-chlorobenzoic acid methyl acetate (10.5 g, 99%). 4 NMR (400 MHz, CDC13) 6 ppm 3.96 (s, 3 H) 7.35 (d, J = 8.59 Hz, 1 H) 7.56 (dd, J = 8.59, 2.27 Hz, 1 H ) 7.9 9 (d, J = 2.5 3 H z,1 H). Preparation 13 (5-bromo-2-chlorophenyl)methanol:
對5-溴-2-氯苯甲酸甲醋(製備例12,10.5 g,42 mmol) 之THF(50 mL)溶液添加硼氬化鈉(3.18 g,84 mmol),之 後謹慎的以30分鐘逐滴添加MeOH(7 mL)。反應於室溫攪 拌一小時。添加額外量之硼氫化鈉(0.5 g),混合物於室溫 另外再攪拌一小時。反應混合物倒入乙酸乙酯(125 mL)內 且攪拌二十分鐘。添加水(50 mL),開始時緩緩添加,之 201201802 後則一次全部添加。該等層一起劇烈攪拌十五分鐘。收集 有機相,以硫酸鈉乾燥,於低壓下濃縮,產生(5-溴-2-氯 苯基)甲醇之白色固體(7.85 g,84%)。4 NMR(400 MHz, CDC13)5 ppm 4.77(s, 2 H)7.23(d, J = 8.34 Hz, 1 H)7.37(dd, J = 8.34,2.53 Hz, 1 H)7.68(d, J = 2.53 Hz, 1 H)。 製備例14甲磺酸5-溴-2-氯苄酯:Sodium borohydride (3.18 g, 84 mmol) was added to a solution of 5-bromo-2-chlorobenzoic acid in acetonitrile (Preparation 12, 10.5 g, 42 mmol) in THF (50 mL). MeOH (7 mL) was added dropwise. The reaction was stirred at room temperature for one hour. An additional amount of sodium borohydride (0.5 g) was added and the mixture was stirred at room temperature for an additional hour. The reaction mixture was poured into ethyl acetate (125 mL) and stirred for 20 min. Add water (50 mL) and add it slowly at the beginning. After 201201802, add it all at once. The layers were stirred vigorously for fifteen minutes. The organic phase was collected, dried over sodium sulfate and evaporated 4 NMR (400 MHz, CDC13) 5 ppm 4.77 (s, 2 H) 7.23 (d, J = 8.34 Hz, 1 H) 7.37 (dd, J = 8.34, 2.53 Hz, 1 H) 7.68 (d, J = 2.53) Hz, 1 H). Preparation 14 5-bromo-2-chlorobenzyl methanesulfonate:
5-溴-2-氯苯基)甲醇(製備例13,7.85 g,35.4 mmol) 之二氯甲烷(50 mL)溶液冷卻至0°C且添加甲磺醯氯(4.06 g ’ 35_4 mmol),接著添加三乙胺(3.64 g,36 mmol)。溶液 於〇°C攪拌兩小時,之後於室溫攪拌三小時。添加二氯甲 烷(50 mL),反應混合物以水洗滌。有機相以硫酸鈉乾燥 ,於低壓下濃縮,產生無色液體,於矽膠上純化,提供產 物甲磺酸 5-溴-2-氯苄酯(7.62 g,72%)4 NMR(400 MHz, CDC13)5 ppm 3.09(s, 3 H)5.32(s, 2 H)7.32(d, J = 8.59 Hz, 0 H)7.48(d, J = 2.27 Hz,0 H)7_66(d, J = 2.27 Hz, 1 H) » 製備例I5 2-(疊氮基甲基)-4_溴-1-氯苯: s -62- 201201802A solution of 5-bromo-2-chlorophenyl)methanol (Preparation 13, 7.85 g, 35.4 mmol) in dichloromethane (50 mL) was cooled to 0 <0> Then triethylamine (3.64 g, 36 mmol) was added. The solution was stirred at 〇 ° C for two hours and then at room temperature for three hours. Dichloromethane (50 mL) was added and the reaction mixture was washed with water. The organic phase was dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; 5 ppm 3.09(s, 3 H)5.32(s, 2 H)7.32(d, J = 8.59 Hz, 0 H) 7.48(d, J = 2.27 Hz, 0 H)7_66(d, J = 2.27 Hz, 1 H) » Preparation Example I5 2-(Azidomethyl)-4_bromo-1-chlorobenzene: s -62- 201201802
對甲石貝酸5 -漠-2-氣节醋(製備例14,7.68 g,25.6 mmol) 之DMS 0(3 0 mL)溶液中添加疊氮化鈉(1.75 g,25.6 mmol) 。反應於室溫攪拌隔夜。將水(120 mL)添加至反應混合物 。使用EtOAc(2xl〇〇 mL)萃取產物。結合之萃取液隨後以 水洗滌(6x50 mL)。有機相以硫酸鈉乾燥,於低壓及低於 40°C之溫度(浴溫)下蒸餾溶劑以提供產物2-(疊氮基甲基)-4-溴-1-氯苯之玻璃狀固體(5.78 g,25.6 mmol)。4 NMR (400 MHz > CDC13)6 ppm 4.48-4.53 (m, 1 H) 7.2 5 - 7.3 4 (m, 1 H)7.43(dd, J = 8.59, 2.27 Hz, 1 H)7.58(d, J = 2.27 Hz, 2 H) o 製備例16 1-(5-溴-2-氯苯基)甲胺鹽酸鹽:Sodium azide (1.75 g, 25.6 mmol) was added to a DMS 0 (30 mL) solution of methicillin 5-dihydro-2-glycolic acid (Preparation 14, 7.68 g, 25.6 mmol). The reaction was stirred overnight at room temperature. Water (120 mL) was added to the reaction mixture. The product was extracted with EtOAc (2×1 mL). The combined extracts were then washed with water (6 x 50 mL). The organic phase is dried over sodium sulfate, and the solvent is distilled at low pressure and below 40 ° C (bath temperature) to afford the product as a glassy solid of 2-(azidomethyl)-4-bromo-1-chlorobenzene ( 5.78 g, 25.6 mmol). 4 NMR (400 MHz > CDC13) 6 ppm 4.48-4.53 (m, 1 H) 7.2 5 - 7.3 4 (m, 1 H) 7.43 (dd, J = 8.59, 2.27 Hz, 1 H) 7.58 (d, J = 2.27 Hz, 2 H) o Preparation 16 1-(5-Bromo-2-chlorophenyl)methanamine hydrochloride:
Cl NH3+C|· 對2-(疊氮基甲基)-4-溴-1-氯苯(製備例15)之已先冷 卻至〇°C的THF(70 mL)溶液添加三苯膦及水(6 mL)。反應 於〇°C攪拌一小時,之後於室溫攪拌三十六小時。於低壓 下藉旋轉蒸發移除揮發物。白色殘留物溶於EtOAc(70 mL) -63- 201201802 中。添加4NHC1(6 mL)之二鸣烷溶液’混合物於〇°C攪拌 兩小時,而產物以鹽酸鹽形式沉澱析出。抽氣過濾收集白 色沉澱物,以冷乙酸乙酯(2x30 mL)洗滌’乾燥產生1-(5-溴-2-氯苯基)甲胺鹽酸鹽(4.38 g,73%)» 4 NMR(400 MHz’ D M S Ο - d 6) δ p p m 4.1 2 (s, 2 Η) 7 · 5 1 ( d,J = 8 · 5 9 Η z,1 Η) 7.63(dd, J = 8.59, 2.53 Hz, 1 H)7.89(d, 1 = 2.21 Hz, 1 H)8.61(br.s.,3 H)。 製備例17(5-溴-2-氯苄基)胺基甲酸第三丁酯:Cl NH3+C|· Addition of triphenylphosphine to a solution of 2-(azidomethyl)-4-bromo-1-chlorobenzene (Preparation 15) which has been cooled to 〇 ° C in THF (70 mL) Water (6 mL). The reaction was stirred at 〇 ° C for one hour and then at room temperature for thirty-six hours. The volatiles were removed by rotary evaporation at low pressure. The white residue was dissolved in EtOAc (EtOAc) (EtOAc) A mixture of 4NHC1 (6 mL) of dioxane solution was added and stirred at 〇 ° C for two hours, and the product was precipitated as hydrochloride. The white precipitate was collected by suction <RTI ID=0.0></RTI></RTI> to <RTI ID=0.0></RTI> <RTI ID=0.0> 400 MHz ' DMS Ο - d 6) δ ppm 4.1 2 (s, 2 Η) 7 · 5 1 ( d, J = 8 · 5 9 Η z, 1 Η) 7.63 (dd, J = 8.59, 2.53 Hz, 1 H) 7.89 (d, 1 = 2.21 Hz, 1 H) 8.61 (br.s., 3 H). Preparation 17 (5-Bromo-2-chlorobenzyl)carbamic acid tert-butyl ester:
對1-(5-溴-2-氯苯基)甲胺鹽酸鹽(製備例16,4.78 g ,18.6 mmol)之已冷卻至〇°C的二氯甲烷溶液(70 mL)添加 Boc 酐(4.06 g,18.6 mmol)及三乙胺(4.14 g,41 mmol)。 反應於室溫攪拌二十四小時。混合物以二氯甲烷(40 mL) 稀釋且以水洗滌(3x25 mL)。有機相以硫酸鈉乾燥,且溶 劑係於低壓下餾除。粗製液體於矽膠上純化提供(5-溴-2-氯苄基)胺基甲酸第三丁酯(5.9 g,17.5 mmol)。NMR (400 MHz > CDC13)6 ppm 1.49(s, 9 H) 4.3 4 - 4.4 5 (m, 2 H) 5.00(br.s., 1 H)7.24(d, J = 8.34 Hz, 1 H)7.35(dd, 1 H) 7.53(d, J = 2.53 Hz, 1 H)。 s -64- 201201802 製備例18(2-氯-5-甲醯基苄基)胺基甲酸第三丁酯:Add Boc anhydride to 1-(5-bromo-2-chlorophenyl)methanamine hydrochloride (Preparation 16, 4.78 g, 18.6 mmol) in dichloromethane (70 mL) cooled to EtOAc. 4.06 g, 18.6 mmol) and triethylamine (4.14 g, 41 mmol). The reaction was stirred at room temperature for twenty-four hours. The mixture was diluted with dichloromethane (40 mL) and washed with water (3×25 mL). The organic phase was dried over sodium sulfate and the solvent was distilled off at low pressure. The crude liquid was purified on silica gel afforded (5-bromo-2-chlorobenzyl) carbamic acid tributyl ester (5.9 g, 17.5 mmol). NMR (400 MHz > CDC13) 6 ppm 1.49 (s, 9 H) 4.3 4 - 4.4 5 (m, 2 H) 5.00 (br.s., 1 H) 7.24 (d, J = 8.34 Hz, 1 H) 7.35 (dd, 1 H) 7.53 (d, J = 2.53 Hz, 1 H). s -64- 201201802 Preparation Example 18 (2-Chloro-5-methylbenzylidenebenzyl) carbamic acid tert-butyl ester:
(5-溴-2-氯苄基)胺基甲酸第三丁酯(製備例17,3.5 g ,1 0.9 mmol)溶於無水THF(5 OmL)。溶液於氮氛圍中冷卻 至-78°C。隨後以十五分鐘時間經由添液漏斗逐滴添加n-BuLi(1.6. N己烷溶液15 mL,2.2當量)》反應於- 78t於氮 氛圍中攪拌另外十分鐘,之後以單一份量(aliquot)添加DMF (2.41 g,33 mmols)。移除冷浴,反應以兩小時增溫至室 溫。將反應冷卻至〇°C,之後藉添加飽和氯化銨水溶液(50 mL>驟冷。之後添加水(1〇〇 mL)及EtOAc(200 mL),將該 等層混合。收集有機相,以硫酸鈉乾燥,並濃縮成黏稠油 。粗製油溶於CH2C12(30 mL)且施加至80 g矽膠柱匣。柱 匣以EtOAc於己烷中之梯度(6管柱體積自5%變成60%)洗 提,產生純產物(2 -氯-5 -甲醯基辛基)胺基甲酸第三丁醋 (1.25 g,42%)之濃稠號珀色油。1H NMR(400 MHz’ CDC13)S ppm 1.49(s, 9 H)4.50(d, J = 6.06 Hz, 2 H) 5.10(br.s., 1 H)7.55(d, J = 8.08 Hz, 1 H)7.76(dd, J = 8.08, 2.02 Hz, 1 H)7.91(d,J = 2.02 Hz, 1 H)10.〇l(s,1 H)。 -65- 201201802 製備例19 {2-氯-5-[(E/Z)-(羥基亞胺)甲基]苄基胺基甲 酸第三丁酯:(5-Bromo-2-chlorobenzyl)carbamic acid tert-butyl ester (Preparation Example 17, 3.5 g, 1 0.9 mmol) was dissolved in anhydrous THF (5OmL). The solution was cooled to -78 ° C under a nitrogen atmosphere. Then, n-BuLi (1.6. N hexane solution 15 mL, 2.2 eq.) was added dropwise via a funnel over 15 minutes. The reaction was stirred at -78 Torr for a further ten minutes in a nitrogen atmosphere, followed by a single serving (aliquot). DMF (2.41 g, 33 mmols) was added. The cold bath was removed and the reaction was allowed to warm to room temperature over two hours. The reaction was cooled to 〇 ° C then EtOAc (EtOAc) (EtOAc) Dry over sodium sulfate and concentrate to a viscous oil. The crude oil was dissolved in CH2C12 (30 mL) and applied to <RTI ID=0.0>> Leaching gave the pure product (2-chloro-5-methylpyridyl octyl) amino carboxylic acid terpene vinegar (1.25 g, 42%) as a thick oil. 1H NMR (400 MHz ' CDC 13 ) Ppm 1.49 (s, 9 H) 4.50 (d, J = 6.06 Hz, 2 H) 5.10 (br.s., 1 H) 7.55 (d, J = 8.08 Hz, 1 H) 7.76 (dd, J = 8.08, 2.02 Hz, 1 H) 7.91 (d, J = 2.02 Hz, 1 H) 10. 〇l(s, 1 H) -65- 201201802 Preparation 19 {2-Chloro-5-[(E/Z)- (hydroxyimine) methyl]benzylaminocarboxylic acid tert-butyl ester:
對(2-氯-5-甲醯基苄基)_胺基甲酸第三丁酯(製備例18 ,1.25 g,4.6 mmol)之乙醇(20mL)溶液添加羥基胺鹽酸鹽 (0.95 g,13.8 mmol)及乙酸鈉(1·8 g,23 mmol)。混合物 於室溫攪拌4小時。藉於低壓下蒸餾,移除揮發物。殘留 物質分溶於水(50 mL)及EtOAc(70 mL)之間。將有機相乾 燥(硫酸鈉)且濃縮產生產物{2-氯-5-[(E,Z)-(羥基亞胺)甲基 ]苄基}胺基甲酸第三丁酯(1.12 g,85%)。 製備例20 {2-氯-5-[(E/Z)-氯(羥基亞胺)甲基]苄基}-胺基 甲酸第三丁酯:Hydroxylamine hydrochloride (0.95 g, 13.8) was added to a solution of (2-chloro-5-methylindenyl)-carbamic acid tert-butyl ester (Preparation 18, 1.25 g, 4.6 mmol) in EtOAc (20 mL) Methyl) and sodium acetate (1·8 g, 23 mmol). The mixture was stirred at room temperature for 4 hours. The volatiles were removed by distillation at low pressure. The residue was partitioned between water (50 mL) and EtOAc (EtOAc) The organic phase was dried (sodium sulphate) and concentrated to give <"""""""""""""" ). Preparation 20 {2-Chloro-5-[(E/Z)-chloro(hydroxyimino)methyl]benzyl}-aminocarboxylic acid tert-butyl ester:
SS
201201802 對{2-氯-5-[(E/Z)-(羥基亞胺)甲基]苄基}-胺基甲酸 第三丁酯(製備例 19,1.12 g,3.9 mmol)於 DMF(40 mL)中 之溶液添加N-氯琥珀醯亞胺(0.525 g,3.93 mmol)。溶液 於室溫攪拌12小時。含(2_氯-5-[(E/Z)-(羥基亞胺)甲基] 苄基}胺基甲酸第三丁酯之粗製反應混合物直接使用於下 一步驟。 製備例21 : 2-氯-5-(5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5- 二氫異噚唑-3-基)苄基胺基甲酸第三丁酯201201802 Pair of {2-chloro-5-[(E/Z)-(hydroxyimino)methyl]benzyl}-carbamic acid tert-butyl ester (Preparation Example 19, 1.12 g, 3.9 mmol) in DMF (40) The solution in mL) was added N-chlorosuccinimide (0.525 g, 3.93 mmol). The solution was stirred at room temperature for 12 hours. The crude reaction mixture containing (3-chloro-5-[(E/Z)-(hydroxyimino)methyl]benzyl}aminocarbamic acid tert-butyl ester was used directly in the next step. Preparation 21: 2- Chloro-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzylaminocarboxylic acid Butyl ester
對{2-氯-5-[(E/Z)-氯(羥基亞胺)-甲基苄基]-胺基甲酸 第三丁酯(製備例 20,692 mg,2.1 mmols)之 DMF(20 mL) 溶液添加1,2,3-三氯-5-(1,1,1-三氟丙-2-烯-2-基)苯(製備 例1,580 mg,2.1 mmols)及固體碳酸氫鈉(1000 mg)。反 應混合物於室溫攪拌24小時。反應混合物分溶於水(1 0 mL)及EtOAc(40 mL)之間。有機相係連續的以水(3xl5mL) 洗滌,乾燥(硫酸鈉),於低壓下餾除溶劑,產生粗產物之 黏稠無色油。產物於矽膠上純化(EtO Ac於己烷中之梯度) ,產生標題化合物之非晶形玻璃狀物(890 mg,76%)。 m/z(CI)459[M + H] + (在游離化時失去 Boc基團)。4 NMR -67- 201201802 (400 MHz,氯仿-d)d ppm 1.48(s,9 H)3.69(d, J=17.18 Hz, 1 H)4.08(d, J=17.18 Hz, 1 H)4.44(d, J=6.06 Hz, 2 H)5.02-5.12(m, 1 H)7.44(d,J = 8.34 Hz, 1 H)7.5 3 -7.68 (m,4 H)。 製備例22 l-{2-氯- 5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)- 4,5-二氫異卩号唑-3-基]苯基}甲胺:TMF of {2-chloro-5-[(E/Z)-chloro(hydroxyimino)-methylbenzyl]-carbamic acid tert-butyl ester (Preparation 20, 692 mg, 2.1 mmols). mL) 1,2,3-trichloro-5-(1,1,1-trifluoroprop-2-en-2-yl)benzene (Preparation 1, 580 mg, 2.1 mmols) and solid hydrogen carbonate Sodium (1000 mg). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was partitioned between water (10 mL) and EtOAc (40 mL). The organic phase was washed successively with water (3.times.5 mL), dried (sodium sulfate), and evaporated to dryness. The product was purified on EtOAc (EtOAc:EtOAc) m/z (CI) 459 [M + H] + (the Boc group is lost upon liberation). 4 NMR -67- 201201802 (400 MHz, chloroform-d) d ppm 1.48 (s, 9 H) 3.69 (d, J = 17.18 Hz, 1 H) 4.08 (d, J = 17.18 Hz, 1 H) 4.44 (d , J = 6.06 Hz, 2 H) 5.02-5.12 (m, 1 H) 7.44 (d, J = 8.34 Hz, 1 H) 7.5 3 - 7.68 (m, 4 H). Preparation 22 l-{2-Chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoindole-3- Phenyl]phenyl}methylamine:
對{2-氯- 5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異噚唑-3-基]苄基}胺基甲酸第三丁酯(製備例21,920 mg,1.65 mmol)於二氯甲烷(10 mL)中之溶液添加TFA(2 mL)。溶液於室溫攪拌隔夜。藉於低壓下蒸餾,移除揮發 物。殘留物質攝入乙酸乙酯(6 0 ml)中。有機相以飽和碳酸 氫鈉水溶液(2x25 ml)洗滌》結合之水性洗液以乙酸乙酯(2 x20 ml)萃取。結合所有的有機萃取液且以硫酸鈉乾燥。藉 於低壓下蒸餾移除溶劑,產生產物(595 mg,79%)。4 NMR (400 MHz » CDC13)6 ppm 3.68 -3.74(m, 1 H)4.02(s, 2 H)4.11(d, J=1 7.1 8 Hz, 1 H)7.45(d, J = 8.34 Hz, 1 H)7.55(dd, J —8.34, 2.02 Hz, 1 H) 7 · 6 6 (s,2 H) 7 · 7 5 (d, J = 2.02 Hz,1 H) ; m/z(CI)45 9 [M + H]+。 s -68- 201201802 實施例14: N-{2 -氛- 5- [5-(3,4,5-二氯苯基)-5-(二氣甲基)-4,5-二氫異噚唑-3-基]苄基}乙醯胺:For {2-chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl} TCA (2 mL) was added as a solution of EtOAc (EtOAc m. The solution was stirred overnight at room temperature. The volatiles are removed by distillation at low pressure. The residual material was taken up in ethyl acetate (60 ml). The organic phase was washed with saturated aqueous sodium bicarbonate (2×25 mL). All organic extracts were combined and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure to give the product (595 mg, 79%). 4 NMR (400 MHz » CDC13) 6 ppm 3.68 -3.74 (m, 1 H) 4.02 (s, 2 H) 4.11 (d, J = 1 7.1 8 Hz, 1 H) 7.45 (d, J = 8.34 Hz, 1 H) 7.55 (dd, J — 8.34, 2.02 Hz, 1 H) 7 · 6 6 (s, 2 H) 7 · 7 5 (d, J = 2.02 Hz, 1 H) ; m/z (CI) 45 9 [M + H]+. S -68- 201201802 Example 14: N-{2-Aromatic 5-[5-(3,4,5-dichlorophenyl)-5-(dimethylmethyl)-4,5-dihydroiso Oxazol-3-yl]benzyl}acetamide:
對1-{2-氯-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二氫異噚唑-3-基]苯基}甲胺(製備例 22,50 mg,0.11 mmol)及吡啶(0.1 mL)於DMF(3 mL)中之攪拌混合物添加 乙醯基氯(10 mg,0.12 mmol)。反應於室溫攪拌十分鐘。 添加水(12 mL)以使產物沉澱。使用抽氣過濾收集白色沉 澱物。以水洗滌(6x10 mL),之後風乾隔夜。得到白色固 體形式之N-{2-氯-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基ΙΑ, 5-二氫異 卩号唑 -3-基]苄基 } 乙醯胺 (40 mg, 73%)。 4 NMR (400 MHz > CDC13)5 ppm 2.06(s, 3 H)3.69(d, J=17.18 Hz, 1 H)4.09(d, J=17.1 8 Hz, 1 H)4.55(d, J = 6.32 Hz, 2 H)5.99(br.s., 1 H)7.46(d, J = 8.34 Hz, 1 H)7.62(dd, J = 8.34, 2.02 Hz, 1 H)7.66(s, 3 H) ; m/z (CI) 5 0 1 [ M + H ] + » 實施例15: N-{2-氯-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二氫異鸣唑-3-基]苄基}環丙烷甲醯胺: -69- 2012018021-{2-Chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzene To a stirred mixture of pyridine (Preparation 22, 50 mg, 0.11 mmol) The reaction was stirred at room temperature for ten minutes. Water (12 mL) was added to precipitate the product. The white precipitate was collected using suction filtration. Wash with water (6 x 10 mL) and air dry overnight. Obtained N-{2-chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethylhydrazine, 5-dihydroisoindole-3- Benzyl acetamide (40 mg, 73%) 4 NMR (400 MHz > CDC13) 5 ppm 2.06 (s, 3 H) 3.69 (d, J = 17.18 Hz, 1 H) 4.09 (d, J=17.1 8 Hz, 1 H)4.55 (d, J = 6.32 Hz, 2 H) 5.99 (br.s., 1 H) 7.46 (d, J = 8.34 Hz, 1 H) 7.62 (dd, J = 8.34 , 2.02 Hz, 1 H) 7.66 (s, 3 H) ; m/z (CI) 5 0 1 [ M + H ] + » Example 15: N-{2-chloro-5-[5-(3, 4,5-Trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}cyclopropanecarbamide: -69- 201201802
係自l-{2 -氯-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)- 4.5- 二氫異噚唑-3-基]苯基}甲胺(製備例22)根據方法A與 環丙烷羰基氯反應製得。1H NMR(400 MHz’ CDC13)S ppm 0.78 -0.8 3 (m, 2 H)0.99 - 1.03 (m, 2 H) 1 . 3 7 - 1.45(m , 1 H)3.69 (d, 17.43 Hz, 1 H)4.08(d, J=17.43 Hz, 1 H)4.57(d, J = 6.32 Hz, 2 H)6.12-6.1 8(m, 1 H)7.46(ds J = 8.34 Hz, 1 H)7.60- 7.67(m, 4 H) ; m/z ( CI) 5 2 7 [ M + H ] +。 實施例16: N-{2-氯-5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)- 4.5- 二氫異噚唑-3-基]苄基}-2-甲基丙醯胺:From 1-{2-chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4.5-dihydroisoxazol-3-yl]phenyl Methylamine (Preparation Example 22) was obtained by reacting Method A with cyclopropanecarbonyl chloride. 1H NMR (400 MHz ' CDC13) S ppm 0.78 -0.8 3 (m, 2 H) 0.99 - 1.03 (m, 2 H) 1 . 3 7 - 1.45 (m , 1 H) 3.69 (d, 17.43 Hz, 1 H ) 4.08 (d, J = 17.43 Hz, 1 H) 4.57 (d, J = 6.32 Hz, 2 H) 6.12 - 6.1 8 (m, 1 H) 7.46 (ds J = 8.34 Hz, 1 H) 7.60 - 7.67 ( m, 4 H) ; m/z ( CI) 5 2 7 [ M + H ] +. Example 16: N-{2-Chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4.5-dihydroisoxazol-3-yl] Benzyl}-2-methylpropanamide:
係自1-{2-氯- 5-[5-(3,4,5-三氯苯基)-5-(三氟甲基)- 4,5-二氫異噚唑-3-基]苯基}甲胺(製備例22)根據方法A與 異丁醯氯反應製得。4 NMR(4 00 MHz,CDC13)5 ppm 1.20 (dd, J = 6.82, 2.27 Hz, 6 H)2.43(s, 1 H)3.71(s, 1 H)4.08(d, -70- 201201802 J=17.18 Hz, 1 H)4.54(d, J = 6.06 Hz, 2 H) 5.9 6 - 6.02 (m, 1 H)7.45(d, J = 8.34 Hz, 1 H)7.59-7.67(m, 4 H) ; m/z(CI)529[M + H] + o 實施例17: N-{2 -氯- 5- [5-(3,5 -二氯-4-氟苯基)-5-(三氟甲 基)-4,5-二氫異鸣唑基]苄基}乙醯胺:From 1-{2-chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl] Phenyl}methylamine (Preparation Example 22) was obtained by reacting Method A with isobutylphosphonium chloride. 4 NMR (4 00 MHz, CDC13) 5 ppm 1.20 (dd, J = 6.82, 2.27 Hz, 6 H) 2.43 (s, 1 H) 3.71 (s, 1 H) 4.08 (d, -70- 201201802 J=17.18 Hz, 1 H) 4.54 (d, J = 6.06 Hz, 2 H) 5.9 6 - 6.02 (m, 1 H) 7.45 (d, J = 8.34 Hz, 1 H) 7.59-7.67 (m, 4 H) ; m /z(CI) 529 [M + H] + o Example 17: N-{2-chloro-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl) Base)-4,5-dihydroisozozolyl]benzyl}acetamide:
係自(2-氯_5-(5_(3,5-二氯_4·氟苯基)-5-(三氟甲基)-4,5-二氫異Df唑-3-基)苯基)甲胺根據方法Α與乙醯基氯以 類似反應製得。1H NMR(400 MHz,CDC13)5 ppm 2.06(s, 3 H)3.66-3.72(m, 1 H)4.09(d, J = 17.18 Hz, 1 H)4.55(d, J-6.32 Hz, 2 H)5.95-6.02(m, 1 H)7.46(d, J = 8.34 Hz, 1 H) 7.58-7.64(m,3 H)7.65-7.67(m,1 H) ; m/z(CI)48 5 [M + H]+。 製備例23 : 4-溴-3-(溴甲基)苯甲酸甲酯:From (2-chloro-5-(5-(3,5-dichloro_4.fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroiso Dfoxazol-3-yl)benzene Methylamine is prepared by a similar reaction with ethyl hydrazine chloride according to the method. 1H NMR (400 MHz, CDC13) 5 ppm 2.06 (s, 3 H) 3.66-3.72 (m, 1 H) 4.09 (d, J = 17.18 Hz, 1 H) 4.55 (d, J-6.32 Hz, 2 H) 5.95-6.02(m, 1 H)7.46(d, J = 8.34 Hz, 1 H) 7.58-7.64(m,3 H)7.65-7.67(m,1 H) ; m/z(CI)48 5 [M + H]+. Preparation 23: Methyl 4-bromo-3-(bromomethyl)benzoate:
Br Br -71- 201201802 對4-溴-3-甲基苯甲酸甲酯(10 g,43.6 mmol)之CC14 (30 mL)溶液添加NBS(4.8 g,44 mmol)及催化量之過氧化 苯醯。反應於回流下加熱18小時。混合物冷卻至室溫且 以CH2C12(5 0 mL)稀釋。有機相以水洗滌(3x20 mL),於低 壓下使用旋轉蒸發器濃縮。殘留物質溶於己烷且施加至 120 g矽膠柱匣。產物以乙酸乙酯於己烷中之梯度洗提, 產生4-溴-3-(溴甲基)苯甲酸甲酯(7·73 g,57%)。4 NMR (400 MHz > CDC13)5 ppm 3.95(s, 3 H)4.64(s, 2 H)7.68(d, J = 8.34 Hz, 1 H)7.83(dd, J = 8.34, 2.02 Hz, 1 H)8.14(d, J = 2.02 Hz, 1 H)。 製備例24 3-(疊氮基甲基)-4-溴苯甲酸甲酯:Br Br -71- 201201802 Add NBS (4.8 g, 44 mmol) and a catalytic amount of benzoquinone to a solution of methyl 4-bromo-3-methylbenzoate (10 g, 43.6 mmol) in CC14 (30 mL) . The reaction was heated under reflux for 18 hours. The mixture was cooled to room temperature and diluted with CH2C12 (50 mL). The organic phase was washed with water (3 x 20 mL) and concentrated using a rotary evaporator under low pressure. The residual material was dissolved in hexane and applied to a 120 g silica gel column. The product was eluted with a gradient of ethyl acetate in hexane to yield ethyl 4-bromo-3-(bromomethyl)benzoate (7·73 g, 57%). 4 NMR (400 MHz > CDC13) 5 ppm 3.95 (s, 3 H) 4.64 (s, 2 H) 7.68 (d, J = 8.34 Hz, 1 H) 7.83 (dd, J = 8.34, 2.02 Hz, 1 H ) 8.14 (d, J = 2.02 Hz, 1 H). Preparation 24 Methyl 3-(azidomethyl)-4-bromobenzoate:
對4-溴-3-(溴甲基)苯甲酸甲酯(製備例23,7.73 g, 25 mmol)之DMSO(40 mL)溶液添加疊氮化鈉(1.63 g,25 mmol)。混合物於室溫攪拌四小時。混合物於冰浴中冷卻 ,將水(250 mL)添加至反應。在0°C攪拌混合物一小時後 ,出現白色沉澱物。抽氣過濾所收集之白色固體,且以水 洗滌以產生3·(疊氮基甲基)-4-溴苯甲酸甲酯(6.78 g, 100%)。To a solution of methyl 4-bromo-3-(bromomethyl)benzoate (Preparation 23, 7.73 g, 25 mmol) in EtOAc (40 mL) The mixture was stirred at room temperature for four hours. The mixture was cooled in an ice bath and water (250 mL) was added to the mixture. After the mixture was stirred at 0 ° C for one hour, a white precipitate appeared. The collected white solid was filtered with suction and washed with water to give <RTI ID=0.0>>
S -72- 201201802 製備例25 3 -(胺基甲基)-4-溴苯甲酸甲酯:S-72- 201201802 Preparation 25 3-(Aminomethyl)-4-bromobenzoic acid methyl ester:
對3-(疊氮基甲基)-4-溴苯甲酸甲酯(製備例24,6.77 g,25 mmol)之THF(70 mL)溶液添加水(6 mL)及三苯膦 (6.57 g,25.1 mmol)。混合物於室溫攪拌隔夜。混合物藉 由添加 1 N HCl(aq)(40 mL)調酸。添加 EtOAc(100 mL)及 水(60 mL)。該等層一起劇烈攪拌。收集水相,再次以EtOAc (2x40 mL)洗滌。水相隨後以飽和碳酸氫鈉水溶液(40 mL) 中和。產物胺以二氯甲烷(3x40 mL)萃取。結合之萃取液 以硫酸鈉乾燥,於低壓下餾除溶劑,產生3-(胺基甲基)-4-溴苯甲酸甲酯(4_38 g,72%)。NMR(400 MHz,CDC13)5 ppm 3.94(s, 3 H)3.99(s, 2 H)7.65(d, J = 8.34 Hz, 1 H)7.79(d, J = 2.27 Hz, 1 H)8.09(d,J = 2.02 Hz, 1 H)。 製備例26 4-溴-3-((第三丁氧羰基)甲基)苯甲酸甲酯:To a solution of methyl 3-(azidomethyl)-4-bromobenzoate (Preparation 24, 6.77 g, 25 mmol) in EtOAc (EtOAc) 25.1 mmol). The mixture was stirred overnight at room temperature. The mixture was acidified by the addition of 1 N HCl (aq) (40 mL). Add EtOAc (100 mL) and water (60 mL). The layers are stirred vigorously together. The aqueous phase was taken and washed again EtOAc (2×40 mL). The aqueous phase was then neutralized with saturated aqueous sodium bicarbonate (40 mL). The product amine was extracted with dichloromethane (3 x 40 mL). The combined extracts were dried over sodium sulfate and evaporated to dryness crystals eluted NMR (400 MHz, CDC13) 5 ppm 3.94 (s, 3 H) 3.99 (s, 2 H) 7.65 (d, J = 8.34 Hz, 1 H) 7.79 (d, J = 2.27 Hz, 1 H) 8.09 (d , J = 2.02 Hz, 1 H). Preparation 26 Methyl 4-bromo-3-((t-butoxycarbonyl)methyl)benzoate:
對3-(胺基甲基)-4-溴苯甲酸酯(製備例25,4.38 g, 201201802 18 mmol)之已冷卻至0°C之 CH2C12(25 mL)溶液添加Boc 酐(3.92 g,18 mmol),之後添加 Hunig 驗(2.58 g,20 mmol)。反應於0°C攪拌一小時’之後於室溫攪拌五小時 。藉著於低壓下蒸餾將體積縮減到約10 mL。殘留液體施 加至矽膠卡匣(80 g),且卡匣以25% EtOAc之己烷溶液洗 提,產生4-溴-3-((第三丁氧羰基)甲基)苯甲酸甲酯(5.28 g » 85%)^ NMR(400 MHz> CDC13)6 ppm 1.49(s, 9 H)3.93 (s, 3 H)4.43(d, 2 H)5.01-5.15(m, 1 H)7.64(d, J = 8.34 Hz, 1 H)7.80(d, J = 2.02 Hz, 1 H)8.03(s,1 H)。 製備例27 2-溴- 5-(羥基甲基)苄基胺基甲酸第三丁酯:Boc anhydride (3.92 g, added to a solution of 3-(aminomethyl)-4-bromobenzoate (Preparation 25, 4.38 g, 201201802 18 mmol) in CH2C12 (25 mL) cooled to 0 °C 18 mmol) followed by a Hunig test (2.58 g, 20 mmol). The reaction was stirred at 0 ° C for one hour' and then stirred at room temperature for five hours. The volume was reduced to approximately 10 mL by distillation at low pressure. The residual liquid was applied to a silica gel (80 g) and the oxime was eluted with 25% EtOAc in hexanes to yield methyl 4-bromo-3-((t-butoxycarbonyl)methyl)benzoate (5.28) g » 85%) ^ NMR (400 MHz > CDC13) 6 ppm 1.49 (s, 9 H) 3.93 (s, 3 H) 4.43 (d, 2 H) 5.01-5.15 (m, 1 H) 7.64 (d, J = 8.34 Hz, 1 H) 7.80 (d, J = 2.02 Hz, 1 H) 8.03 (s, 1 H). Preparation 27 T-butyl 2-bromo-5-(hydroxymethyl)benzylcarbamic acid:
於氮氛圍中’對4-溴-3-((第三丁氧羰基)甲基)-苯甲 酸第三丁酯(製備例 26,5.28 g,15.3 mmol)之 THF(50mL) 溶液添加硼氫化鈉(579 mg,15.3 mmol)。於攪拌混合物中 ’以二十分鐘經添液漏斗逐滴添加Me〇H(l 0 mL)。反應增 溫至4 5 °C ’攪拌一小時。添加第二當量之硼氫化鈉(5 7 9 mg ’ 1 5.3 mmol)且持續於4〇〇c攪拌連續兩小時。反應冷卻 至〇 C ’以飽和氯化銨水溶液進行緩驟冷。添加Et〇Ac(60 mL)及水(5〇 mL)。該等層—起劇烈攪拌十五分鐘。收集有 機相’以硫酸鈉乾燥’蒸餾溶劑,產生(4 74 g,98%)2-Adding hydroboration to a solution of 4-bromo-3-((t-butoxycarbonyl)methyl)-benzoic acid tert-butyl ester (Preparation 26, 5.28 g, 15.3 mmol) in THF (50 mL) Sodium (579 mg, 15.3 mmol). Me 〇H (10 mL) was added dropwise to the mixture by stirring the funnel over twenty minutes. The reaction was warmed to 45 ° C and stirred for one hour. A second equivalent of sodium borohydride (5 7 9 mg '1 5.3 mmol) was added and stirring was continued for 4 hours for 4 hours. The reaction was cooled until 〇 C ' was slowly quenched with a saturated aqueous solution of ammonium chloride. Add Et〇Ac (60 mL) and water (5 〇 mL). The layers - stirred vigorously for fifteen minutes. The organic phase was collected and dried under sodium sulfate to produce a solvent (4 74 g, 98%) 2-
S -74- 201201802 溴-5-(羥基甲基)苄基胺棊甲酸第三丁酯。A NMR(400 MHz « CDC13)6 ppm 1.48(s, 9 H) 4.3 7 - 4.4 3 (m, 2H)4.66- 4.69(m, 2 H)5.01-5.09(m, 1 H) 7 . 1 6 - 7 2 0 (m, 1H)7.38- 7.40(m,1H) 7.55 (d,J = 8.〇8 Hz,1H)。 製備例28 2 -溴-5-甲醯基苄基胺基甲酸第三丁酯:S-74- 201201802 Tert-butyl bromide-5-(hydroxymethyl)benzylamine hydrazide. A NMR (400 MHz « CDC13) 6 ppm 1.48 (s, 9 H) 4.3 7 - 4.4 3 (m, 2H) 4.66 - 4.69 (m, 2 H) 5.01-5.09 (m, 1 H) 7. 16 - 7 2 0 (m, 1H) 7.38- 7.40 (m, 1H) 7.55 (d, J = 8.〇8 Hz, 1H). Preparation 28 2 -Bromo-5-methylindenylbenzylcarbamic acid tert-butyl ester:
以二十分鐘分成三個部分對2-溴-5-羥基甲基)苄基-胺 基甲酸第三丁酯(製備例27,4.73 g,15 mmol)之已冷卻至 0°C之CH2C12(50 mL)溶液添加戴斯馬丁過碘烷(6.7 g,1 5 mmol)。反應混合物以兩小時增溫至室溫。於低壓下餾除 溶劑。殘留物溶於CH2C12(100 mL),以飽和碳酸氫鈉水溶 液洗滌(3x40 mL)。將有機相乾燥(硫酸鈉)且於低壓下蒸餾 縮減體積。粗製物於矽膠上純化,產生2-溴-5-甲醯基苄 基胺基甲酸第三丁酯(1.2 g,25%)。4 NMR(400 MHz, CDCl3)3ppml.49(s,9H)4.48(d,J = 6.32Hz,2H)5.05-5.16(m, 1 H)7.65-7.70(m, 1 H) 7.7 3 - 7.7 8 (m, 1 H)7.88(d, J = 2.02 Hz, 1 H)10.01(s,1 H)。 製備例29 2-溴-5-((.經基亞胺)甲基)苄基胺基甲酸第三丁酯 -75- 201201802Distillation of three portions of 2-bromo-5-hydroxymethyl)benzyl-carbamic acid tert-butyl ester (Preparation 27, 4.73 g, 15 mmol) in CH.sub.2 C. 50 mL) solution was added to Dess Martin Sodium Periodane (6.7 g, 15 mmol). The reaction mixture was warmed to room temperature over two hours. The solvent was distilled off at a low pressure. The residue was dissolved in CH.sub.2Cl.sub.sub.sub.sub.sub. The organic phase was dried (sodium sulfate) and distilled under reduced pressure to reduce volume. The crude material was purified on EtOAc (EtOAc:EtOAc) 4 NMR (400 MHz, CDCl3) 3 ppm 1.49 (s, 9H) 4.48 (d, J = 6.32 Hz, 2H) 5.05-5.16 (m, 1 H) 7.65-7.70 (m, 1 H) 7.7 3 - 7.7 8 (m, 1 H) 7.88 (d, J = 2.02 Hz, 1 H) 10.01 (s, 1 H). Preparation 29 2-Bromo-5-((transmethylimido)methyl)benzylaminocarbamic acid tert-butyl ester -75- 201201802
對2-溴-5-甲醯基苄基胺基甲酸第三丁酯(製備例28, 1.15 g,3.7 mmol)之乙醇(20 mL)溶液添加羥基胺鹽酸鹽 (260 mg,3.8 mmol)及乙酸鈉(5當量)。混合物於室溫攪伴 4小時。於低壓下餾除揮發物。殘留物質分溶於水(50 mL) 及EtOAc(70 mL)之間。有機相經乾燥(硫酸鈉)且濃縮產生 2-溴-5-((羥基亞胺)甲基)苄基胺基甲酸酯(1.18 g,98%)。 製備例3 0 2·溴-5-(氯(羥基亞胺)甲基)苄基-胺基甲酸第三 丁酯:Hydroxylamine hydrochloride (260 mg, 3.8 mmol) was added to a solution of 2-bromo-5-carbamidobenzylaminocarbamic acid tert-butyl ester (Preparation 28, 1.15 g, 3.7 mmol) in EtOAc (20 mL) And sodium acetate (5 equivalents). The mixture was stirred at room temperature for 4 hours. The volatiles were distilled off under reduced pressure. The residue was partitioned between water (50 mL) and EtOAc (EtOAc) The organic phase was dried (Na2SO4) and concentrated to give 2-bromo-5 <RTI ID=0.0>((</RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Preparation 3 0 2 ·Bromo-5-(chloro(hydroxyimino)methyl)benzyl-carbamic acid tert-butyl ester:
Br 對5-((羥基亞胺)甲基)苄基胺基甲酸酯(製備例29, 1.18 g,3.6 mmol)之DMF(40mL)溶液添力卩N-氯琥珀醯亞 胺(0.48 g,3.6 mmol)。溶液於室溫攪拌12小時。含2-溴-5-(氯(羥基亞胺)甲基)苄基-胺基甲酸第三丁酯之粗製反 應混合物係直接使用於下一步驟。Br Add a solution of 5-((hydroxyimino)methyl)benzylcarbamate (Preparation 29, 1.18 g, 3.6 mmol) in DMF (40 mL) EtOAc (EtOAc) , 3.6 mmol). The solution was stirred at room temperature for 12 hours. The crude reaction mixture containing 2-bromo-5-(chloro(hydroxyimino)methyl)benzyl-carbamic acid tert-butyl ester was used directly in the next step.
S -76- 201201802 製備例31 2_溴-5-(5_(3,4,5-三氯苯基)-5-(三氟甲基)·4,5· 二氫異噚唑-3-基)苄基胺基甲酸第三丁酯:S-76- 201201802 Preparation 31 2_Bromo-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)·4,5·dihydroisoxazole-3- Tert-butyl benzylaminocarbamate:
對2-溴-5-(氯(羥基亞胺)-甲基)苄基胺基甲酸酯(製備 例 26’ 700 mg’ 1.9 mmol)之溶液(20 mL)添力 d 1,2,3 -三氯-二氣丙-2-稀-2 -基)苯(製備例 1,530 mg,1,92 mmol)及碳酸氫鈉(1 g)。混合物於室溫攪拌12小時。反應 混合物分溶於水(1〇〇 mL)及乙酸乙酯(120 mL)之間。有機 相以硫酸鈉乾燥,餾除溶劑。殘留油於矽膠上使用EtOAc/ 己烷作爲移動相而純化,產生2 -溴- 5- (5-(3,4,5 -三氯苯基 )-5-(三氟甲基)-4,5-二氫異卩琴唑-3-基)苄基-胺基甲酸第三 丁醋(854 mg,60%)。 製備例32(2-溴- 5-(5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二氫異鸣唑-3-基)苯基)甲胺:Add a solution of 2-bromo-5-(chloro(hydroxyimino)-methyl)benzylcarbamate (Preparation 26' 700 mg' 1.9 mmol) (20 mL) to d 1,2,3 -Trichloro-dipropion-2-ylidene-2-yl)benzene (Preparation Example 1, 530 mg, 1,92 mmol) and sodium hydrogencarbonate (1 g). The mixture was stirred at room temperature for 12 hours. The reaction mixture was partitioned between water (1 mL) and ethyl acetate (120 mL). The organic phase was dried over sodium sulfate and the solvent was evaporated. The residual oil was purified on silica gel using EtOAc / hexanes as mobile phase to yield 2-bromo-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4. 5-Dihydroisoindolin-3-yl)benzyl-aminocarbamic acid terpene vinegar (854 mg, 60%). Preparation 32 (2-bromo-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzene Methylamine:
Br C: • 77- 201201802 對2-溴- 5-(5-(3,4,5·三氯苯基)-5-(三氟甲基)-4,5-二氫 異噚唑-3-基)苄基胺基甲酸第三丁酯(製備例31,844 mg ,1.4 mmol)於 CH2C12(10 mL)中之溶液添加 TFA(2 mL)。 溶液於室溫攪拌隔夜。藉於低壓下蒸餾,移除揮發物。殘 留物質攝入乙酸乙酯(60 ml)中。有機相以飽和碳酸氫鈉水 溶液(2x25 ml)洗滌。結合之水性洗液以乙酸乙酯(2x20 mL)萃取。結合所有的有機萃取液且以硫酸鈉乾燥。藉著 於低壓下蒸餾移除溶劑,提供產物(2-溴·5-(5-(3,4,5-三氯 苯基)-5-(三氟甲基)-4,5-二氫異卩琴唑-3-基)苯基)甲胺(6 77 m g,1.4 m m ο 1)。m / z (C I) 5 0 3 [ M + Η ] +。 實施例18 : Ν-(2-溴-5-(5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二氫異噚唑-3-基)苄基)乙醯胺:Br C: • 77- 201201802 p- 2-Bromo-5-(5-(3,4,5·trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3 TPA (2 mL) was added as a solution of benzyl benzyl carbamic acid in the title compound (m.p. The solution was stirred overnight at room temperature. The volatiles were removed by distillation at low pressure. The residual material was taken up in ethyl acetate (60 ml). The organic phase was washed with a saturated aqueous solution of sodium bicarbonate (2×25 ml). The combined aqueous wash was extracted with ethyl acetate (2 x 20 mL). All organic extracts were combined and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure to provide the product (2-bromo-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro Isoxazol-3-yl)phenyl)methanamine (6 77 mg, 1.4 mm ο 1). m / z (C I) 5 0 3 [ M + Η ] +. Example 18: Ν-(2-bromo-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3- Base) benzyl) acetamamine:
對(2-溴-5-(5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二 氫異D辱唑-3-基)苯基)甲胺(製備例32,70 mg,0.14 mmol) 及吡哮(0.1 mL)於DMF(3 mL)中之攪拌混合物添加乙醯氯 (11 mg,0.14 mmol)。反應於室溫攪拌十分鐘。添加水(12 mL)以使產物沉澱。使用抽氣過濾收集白色沉澱物。以水(2-Bromo-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisooxazol-3-yl)phenyl To a stirred mixture of methylamine (Preparation 32, 70 mg, 0.14 mmol) and EtOAc (EtOAc) The reaction was stirred at room temperature for ten minutes. Water (12 mL) was added to precipitate the product. The white precipitate was collected using suction filtration. With water
S -78- 201201802 洗滌(6x10 mL),之後風乾隔夜。得到產物N-(2 -溴- 5- (5-(3,4,5 -三氯苯基)-5-(三氟甲基)-4,5 -二氫異噚唑-3-基)苄基 )乙醯胺(55 mg,73%)之白色固體。4 NMR(400 MHz,CDC13 )δ ppm 2.06(s, 3 H)3.66-3.74(m, J = 17.18 Hz, 1 H)4.09(d, J=17.18 Hz, 1 H)4.54(d, J = 6.32 Hz, 2 H)5.98-6.05(m, 1 H)7.51-7.56(m,1 H)7.62-7.67(m, 4 H); )。m/z(CI)545[M + H] + 生物分析 本發明化合物之生物活性係針對硬蜱幼蟲、軟蜱、角 蠅及蚤類使用下述試驗方法測試。 硬蜱幼蟲(Rhipicephalus sanguineus)全有機體接觸分析 式(1)化合物溶於異丙醇(IP A)中,分次將等分份量添 加至置於滾筒上之管瓶歷經至少2小時,使IPA蒸發。 IPA單獨使用作爲陰性對照組,而芬普尼(fipronU)則用作 陽性對照組。使用拭子將50至200隻壁蝨幼蟲添加至管 瓶,關上管瓶。在約24及48小時,管瓶加以檢測且倒地 記錄爲活性。約4 8小時時檢查顯示壁蝨癱瘓及/或死亡之 倒地情況之管瓶。終點數據可記錄爲有效劑量l〇〇%(ED1()())且 /或致死劑量l〇〇%(LD1QQ),單位pg/cm2。實施例1及2論 證 EDl°G 爲 1〇.〇 Hg/cm2。實施例 3-9、11 及 14-18 論證 ED1()()S1.0 pg/cm2,且其中實施例 5-7 及 11 論證 ED1()(^0.1 pg/cm2 ° -79- 201201802 軟蜱(Ornithidorus turicata)飼血分析 式(1)化合物溶於二甲基亞颯(DMS Ο),分次將等分份 量添加至位於覆有薄膜之培養皿中的經檸檬酸化之牛血。 隨後將培養皿放置於加溫托架上。將約5隻若蛛期壁蝨置 於膜上,加蓋且留置飼養。取出所飼養之壁蝨並置入含有 砂之培養皿中。在約24、48及72小時觀際所飼養之壁蝨 之癱瘓及/或死亡狀況。終點數據可記錄爲ED1()()及/或 LD1()(),單位pg/mL。陽性對照組爲芬普尼(fipronil)且 DMSO係用爲陰性對照組。此分析中,實施例3及1 1展 現 ED 10051 Mg/cm2。 東方臂蠅(Haematobia irritans)飼養分析 式(1)化合物溶於DMSO,分次將等分份量添加至置 於覆膜培養皿中經檸檬酸化牛血液中。每個培養皿各置入 約十隻角蠅並加蓋。在經處理血液細胞上飼養角蠅。角蠅 在最少約50%相對濕度下保持約80°F。在約2及24小時 檢視角蠅倒地情況及死亡率。終點數據記錄爲致死劑量 90%(LD9Q),單位pg/mL。此分析中,實施例3展現LD9G 爲10 pg/mL。此分析中,實施例6、8、9及1 1展現LD9Q 爲3 pg/mL。再者,此分析中,實施例4、5、7、17及18 展現 LD9()爲 1 pg/mL。 猫蛋(Ctenocephalides felis)膜飼養分析-成蟲S-78- 201201802 Wash (6x10 mL), then air dry overnight. The product N-(2-bromo-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl) was obtained. Benzyl)acetamide (55 mg, 73%) as a white solid. 4 NMR (400 MHz, CDC13) δ ppm 2.06 (s, 3 H) 3.66-3.74 (m, J = 17.18 Hz, 1 H) 4.09 (d, J = 17.18 Hz, 1 H) 4.54 (d, J = 6.32 Hz, 2 H) 5.98-6.05 (m, 1 H) 7.51-7.56 (m, 1 H) 7.62-7.67 (m, 4 H); m/z (CI) 545 [M + H] + Biological analysis The biological activity of the compounds of the present invention was tested against the hard larvae, soft mites, horn flies and mites using the following test methods. Rhipicephalus sanguineus whole organism contact analysis The compound of formula (1) is dissolved in isopropanol (IP A), and an aliquot is added to the vial placed on the drum for at least 2 hours to evaporate the IPA. . IPA was used alone as a negative control group, and fipronU was used as a positive control group. Use a swab to add 50 to 200 aphid larvae to the vial and close the vial. At about 24 and 48 hours, the vial was tested and recorded as active on the ground. Check the bottle showing the condition of the tick and/or the fall of the ground at about 48 hours. The endpoint data can be recorded as an effective dose of 〇〇% (ED1()()) and/or a lethal dose of 〇〇1% (LD1QQ) in pg/cm2. Examples 1 and 2 demonstrate that EDl °G is 1 〇.〇 Hg/cm2. Examples 3-9, 11 and 14-18 demonstrate ED1()()S1.0 pg/cm2, and wherein Examples 5-7 and 11 demonstrate ED1() (^0.1 pg/cm2 ° -79- 201201802 soft 蜱(Ornithidorus turicata) blood feeding analysis The compound of formula (1) is dissolved in dimethyl hydrazine (DMS hydrazine), and aliquots are added in divided portions to citrated bovine blood in a membrane-coated petri dish. The culture dish is placed on the heating bracket. About 5 spiders are placed on the membrane, capped and kept for feeding. The rear hatch is taken out and placed in a petri dish containing sand. At about 24, 48 and End-point data can be recorded as ED1()() and/or LD1()() in units of pg/mL for 72 hours of observation. The positive control group is fipronil. And DMSO was used as a negative control group. In this analysis, Examples 3 and 11 exhibited ED 10051 Mg/cm2. Haematobia irritans feeding analysis formula (1) compound dissolved in DMSO, divided into equal parts Add to the citrated bovine blood in a culture dish. Place about ten horn flies in each dish and cover. Treated blood The hornfly is maintained on the cell. The hornfly maintains about 80 °F at a minimum relative humidity of about 50%. The flies fall and the mortality rate are observed at about 2 and 24 hours. The endpoint data is recorded as a lethal dose of 90% (LD9Q). Unit pg/mL. In this analysis, Example 3 exhibited an LD9G of 10 pg/mL. In this analysis, Examples 6, 8, 9 and 1 1 showed an LD9Q of 3 pg/mL. Furthermore, in this analysis, implementation Examples 4, 5, 7, 17, and 18 show LD9() at 1 pg/mL. Cats (Ctenocephalides felis) membrane feeding analysis - adult
S -80- 201201802S -80- 201201802
式(1)化合物溶於DMS Ο,分次將等分份量添加至置於 覆膜之預先溫熱至3 7 °C的培養皿中經檸檬酸化牛血液中。 將含約30至35隻成蚤的飼餵管置於培養皿上。貓蚤飼餵 約2小時。於約2及24小時,觀察貓蚤倒地及/或死亡。 終點數據係記錄爲有效劑量80%(ED8Q),單位fig/mL。此 分析中,實施例6、7及18展現ED8()爲10 pg/mL。再者 ,此分析中’實施例3、5、12及13展現ED8Q爲3 pg/mL -81-The compound of the formula (1) was dissolved in DMS hydrazine, and an aliquot was added in portions to the citrated bovine blood in a petri dish which was pre-warmed to a temperature of 37 °C. A feeding tube containing about 30 to 35 sputum was placed on the culture dish. Cats are fed for about 2 hours. At about 2 and 24 hours, the cat was observed to fall to the ground and/or died. The endpoint data was recorded as an effective dose of 80% (ED8Q) in units of fig/mL. In this analysis, Examples 6, 7 and 18 exhibited an ED8() of 10 pg/mL. Furthermore, in this analysis, 'Examples 3, 5, 12 and 13 show ED8Q of 3 pg/mL -81-
Claims (1)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US32214410P | 2010-04-08 | 2010-04-08 | |
US43110711P | 2011-01-10 | 2011-01-10 |
Publications (1)
Publication Number | Publication Date |
---|---|
TW201201802A true TW201201802A (en) | 2012-01-16 |
Family
ID=46755948
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW100111814A TW201201802A (en) | 2010-04-08 | 2011-04-06 | Substituted isoxazoline derivatives |
Country Status (1)
Country | Link |
---|---|
TW (1) | TW201201802A (en) |
-
2011
- 2011-04-06 TW TW100111814A patent/TW201201802A/en unknown
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20110251247A1 (en) | Substituted isoxazoline derivatives | |
US8404649B2 (en) | Isoxazoline oximes as antiparasitic agents | |
KR101508862B1 (en) | Isoxazoline derivatives as antiparasitic agents | |
JP5806743B2 (en) | Spirocyclic isoxazoline derivatives as antiparasitic agents | |
TW201130417A (en) | Insecticidal compounds based on isoxazoline derivatives | |
JP5824573B2 (en) | Isoxazoline derivatives as antiparasitic agents | |
US9073912B2 (en) | Azetidine derivatives as antiparasitic agents | |
CA2863625C (en) | Dihydrofuran azetidine derivatives as antiparasitic agents | |
TW201201802A (en) | Substituted isoxazoline derivatives | |
JP2019006686A (en) | Pest control composition and use therefor | |
TW201249838A (en) | Organic compounds |