TWI402267B - 作為抗瘧疾劑之新穎哌 - Google Patents
作為抗瘧疾劑之新穎哌 Download PDFInfo
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- TWI402267B TWI402267B TW100100230A TW100100230A TWI402267B TW I402267 B TWI402267 B TW I402267B TW 100100230 A TW100100230 A TW 100100230A TW 100100230 A TW100100230 A TW 100100230A TW I402267 B TWI402267 B TW I402267B
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- Prior art keywords
- benzyl
- ethyl
- propenylamine
- ethenyl
- phenyl
- Prior art date
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- 239000003430 antimalarial agent Substances 0.000 title description 12
- 150000004885 piperazines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 121
- -1 methoxy, ethoxy, n-propoxy, isopropoxy Chemical group 0.000 claims description 64
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 33
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 31
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 30
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 28
- 241000009298 Trigla lyra Species 0.000 claims description 27
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 26
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 20
- 201000004792 malaria Diseases 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 13
- AMLFJZRZIOZGPW-UHFFFAOYSA-N prop-1-en-1-amine Chemical compound CC=CN AMLFJZRZIOZGPW-UHFFFAOYSA-N 0.000 claims description 12
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- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
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- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
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- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 2
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- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 7
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
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- 239000003937 drug carrier Substances 0.000 claims 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 claims 1
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- 208000028172 protozoa infectious disease Diseases 0.000 claims 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 claims 1
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- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 23
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- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 238000007429 general method Methods 0.000 description 12
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- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 8
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- 239000002904 solvent Substances 0.000 description 8
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- 239000012317 TBTU Substances 0.000 description 7
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 7
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- 239000007864 aqueous solution Substances 0.000 description 5
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Classifications
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
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- Hydrogenated Pyridines (AREA)
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Description
本發明係關於一種新穎的式I化合物。本發明亦關於相關態樣,其包括製備該等化合物之方法、含有一或多種式I化合物之醫藥組合物及尤其係其作為治療或預防瘧疾感染或治療或預防其他原蟲疾病(如昏睡病、南美錐蟲病(Chagas disease)、變形蟲病、梨形蟲病、滴蟲病、弓形蟲病、利什曼病(leishmaniasis))之藥物之用途。
許多影響人類及家養及家畜動物之嚴重疾病係由原蟲生物(例如,動基體目(kinetoplastida)、端複胞器門(apicomplexa)、厭氧原生動物(anaerobic protozoa)、微孢子目(microsporidia)及瘧原蟲屬(plasmodium))引起。臨床上最相關之此等疾病係瘧疾。
瘧疾係21世紀影響人類之最嚴重且最複雜的健康問題。該疾病影響全世界約3億人,每年致100至150萬人死亡。瘧疾係一種由四種瘧原蟲屬原生動物寄生蟲所引起之傳染性疾病,其中惡性瘧原蟲(P. falciparum)係四種中最嚴重的。迄今為止,研製抗惡性瘧原蟲疫苗之所有嘗試皆以失敗告終。因此,抗瘧疾之療法及預防措施係限於藥物。存在各種類型之抗瘧疾藥物。使用最廣泛的係喹啉抗瘧疾劑,例如氯喹(chloroquine),其係用於預防及治療之特別有效的藥物。然而,對許多目前可獲得之抗瘧疾藥物之抗性正迅速蔓延,並威脅瘧疾流行地區的人。瘧疾寄生蟲之多藥物抗性菌株之報告使得尋找新穎抗瘧疾劑變得尤為迫切。
惡性瘧原蟲藉由雌性按蚊之叮咬進入人體(其亦可藉由自漸進供體之輸血而傳播;幾乎所有受感染之血液組分(包括紅血球、血小板濃縮物、白細胞、冷沉澱物及新鮮血漿)皆可傳播瘧疾)。該瘧原蟲屬寄生蟲最初寄生於肝臟,且在感染週期之後期,於紅血球中繁殖。在此階段,該寄生蟲降解血紅蛋白並使用降解產物作為生長的營養物。
目前的抗原蟲化療方法之侷限性強調在此治療領域中需要新穎藥物。本發明係關於一種新穎的低分子量非肽類非喹啉型式I化合物,其適用於治療及/或預防原蟲感染,尤其係用於治療及/或預防瘧疾,特定言之係惡性瘧原蟲瘧疾。
WO 2007/046075亦揭示哌衍生物作為抗瘧疾劑。與某些本發明化合物最接近之WO 2007/046075之化合物係實例54化合物,其對應於本文之參考實例1。然而,結構上最接近WO 2007/046075之實例54化合物之本發明化合物在50%血清之存在下顯示明顯高於WO 2007/046075之實例54化合物的抗紅血球內期惡性瘧原蟲菌株NF54之活體外活性(參見下表1)。
i)本發明係關於一種新穎的式I
化合物:
其中◆ X
係CH或N;R 1
表示-NO2
、-N(CH3
)2
、或-NCH3
(CH2
CH2
OH);且R 2
表示氫、甲基、乙基、正丙基、異丙基、第三丁基、氰基、鹵素、甲氧基、乙氧基、正丙氧基、異丙氧基、三氟甲基、二氟甲氧基、甲基磺醯基、乙醯基、或乙醯胺基;或◆ X
係CH,R 1
係氫,且R 2
係乙基、異丙基、第三丁基、乙氧基、正丙氧基、異丙氧基、甲基磺醯基、乙醯胺基、或甲氧羰基;或◆ X
係CH,R 1
係氰基,且R 2
係乙基、異丙基、第三丁基、乙氧基、正丙氧基、異丙氧基、三氟甲基、二氟甲氧基、三氟甲氧基、甲基磺醯基、或乙醯胺基;或◆ X
係CH,R 1
係氯,且R 2
係乙基、異丙基、第三丁基、乙氧基、正丙氧基、異丙氧基、二氟甲氧基、甲基磺醯基、或乙醯胺基;或◆ X
係CH,R 1
係甲氧基或異丙氧基,且R 2
係三氟甲基;或◆ X
係CH,R 1
係甲基磺醯基或乙基磺醯基,且R 2
係三氟甲基、乙基、異丙基、第三丁基、乙氧基、正丙氧基、異丙氧基、或二氟甲氧基,如尤其係三氟甲基、第三丁基、正丙氧基、或異丙氧基。
ii)本發明之另一實施例係關於如實施例i)之式I化合物,其中◆ X
係CH或N;R 1
表示-NO2
、-N(CH3
)2
、或-NCH3
(CH2
CH2
OH);且R 2
表示氫、甲基、乙基、正丙基、異丙基、第三丁基、氰基、鹵素、甲氧基、乙氧基、正丙氧基、異丙氧基、三氟甲基、二氟甲氧基、甲基磺醯基、乙醯基、或乙醯胺基;或◆ X
係CH,R 1
係氫,且R 2
係乙基、異丙基、第三丁基、乙氧基、正丙氧基、異丙氧基、甲基磺醯基、乙醯胺基、或甲氧羰基;或◆ X
係CH,R 1
係氰基,且R 2
係乙基、異丙基、第三丁基、乙氧基、正丙氧基、異丙氧基、三氟甲基、二氟甲氧基、三氟甲氧基、甲基磺醯基、或乙醯胺基;或◆ X
係CH,R 1
係氯,且R 2
係乙基、異丙基、第三丁基、乙氧基、正丙氧基、異丙氧基、二氟甲氧基、甲基磺醯基、或乙醯胺基;或◆ X
係CH,R 1
係甲氧基或異丙氧基,且R 2
係三氟甲基。
iii)本發明之另一實施例係關於如實施例i)之式I化合物,其中◆ X
係CH或N;R 1
表示-NO2
、-N(CH3
)2
、或-NCH3
(CH2
CH2
OH);且R 2
表示乙基、異丙基、第三丁基、甲氧基、乙氧基、正丙氧基、異丙氧基、三氟甲基、二氟甲氧基、甲基磺醯基、或乙醯胺基;或◆ X
係CH,R 1
係氫,且R 2
係乙基、異丙基、第三丁基、乙氧基、正丙氧基、異丙氧基、甲基磺醯基、乙醯胺基、或甲氧羰基;或◆ X
係CH,R 1
係氰基,且R 2
係乙基、異丙基、第三丁基、乙氧基、正丙氧基、異丙氧基、三氟甲基、二氟甲氧基、三氟甲氧基、甲基磺醯基、或乙醯胺基;或◆ X
係CH,R 1
係氯,且R 2
係乙基、異丙基、第三丁基、乙氧基、正丙氧基、異丙氧基、二氟甲氧基、甲基磺醯基、或乙醯胺基;或◆ X
係CH,R 1
係甲氧基或異丙氧基,且R 2
係三氟甲基。
iv)本發明之另一實施例係關於如實施例i)之式I化合物,其中R 1
表示-NO2
、-N(CH3
)2
、或-NCH3
(CH2
CH2
OH);且R 2
表示氫、甲基、乙基、正丙基、異丙基、第三丁基、氰基、鹵素、甲氧基、乙氧基、正丙氧基、異丙氧基、三氟甲基、二氟甲氧基、甲基磺醯基、乙醯基、或乙醯胺基。
v)本發明之另一實施例係關於如實施例i)之式I化合物,其中R 1
表示-NO2
、-N(CH3
)2
、或-NCH3
(CH2
CH2
OH);且R 2
表示乙基、異丙基、第三丁基、甲氧基、乙氧基、正丙氧基、異丙氧基、三氟甲基、二氟甲氧基、甲基磺醯基、或乙醯胺基。
vi)本發明之另一實施例係關於如實施例iv)或v)之式I化合物,其中X
係CH。
vii)本發明之另一實施例係關於如實施例iv)或v)之式I化合物,其中X
係N。
viii)本發明之另一實施例係關於如實施例iv)至vii)中任一項之式I化合物,其中R 1
表示-NO2
。
ix)本發明之另一實施例係關於如實施例iv)至vii)中任一項之式I化合物,其中R 1
表示-N(CH3
)2
。
x)本發明之另一實施例係關於如實施例iv)至vii)中任一項之式I化合物,其中R 1
表示-NCH3
(CH2
CH2
OH)。
xi)本發明之另一實施例係關於如實施例iv)至x)中任一項之式I化合物,其中R 2
係乙基、異丙基、第三丁基、乙氧基、正丙氧基、或異丙氧基。
xii)本發明之另一實施例係關於如實施例xi)之式I化合物,其中R 2
係異丙氧基。
xiii)本發明之另一實施例係關於如實施例iv)至x)中任一項之式I化合物,其中R 2
係三氟甲基、二氟甲氧基、甲基磺醯基、或乙醯胺基。
xiv)本發明之另一實施例係關於如實施例iv)至x)中任一項之式I化合物,其中R 2
係甲氧基。
xv)本發明之另一實施例係關於如實施例iv)至x)中任一項之式I化合物,其中R 2
係氫、甲基、正丙基、氰基、鹵素、或乙醯基。
本文使用之術語「鹵素」意指氟、氯、溴或碘,如尤其係氟或氯。
若化合物、鹽、醫藥組合物、疾病及類似名詞使用複數形式時,其亦希望意指單一化合物、鹽或類似物。
應瞭解任何上文或下文中所提及之式I化合物亦適當及有利於提及式I化合物之鹽,尤其係醫藥上可接受的鹽。
術語「醫藥上可接受的鹽」係指非毒性無機或有機之酸及/或鹼加成鹽。可參考「Salt selection for basic drugs」,Int. J. Pharm. 1986
,33
,201-17。
本發明亦包括同位素標記(尤其係2
H(氘)標記)之式I化合物,該等化合物除一或多個原子已各經具有相同原子數,但原子量不同於自然界常見原子量之原子置換以外,與式I化合物相同。同位素標記(尤其係2
H(氘)標記)之式I化合物及其鹽係在本發明範疇內。用較重的同位素2
H(氘)取代氫可產生更高的代謝安定性,從而(例如)增加活體內半衰期或減少劑量需求,或可降低細胞色素P450酶之抑制,從而(例如)提高安全特性。在本發明之一實施例中,該等式I化合物未經同位素標記,或其等僅經一或多個氘原子標記。在一子實施例中,該等式I化合物未經同位素標記。可類似下文所述之方法,但使用適宜反應物或起始物質之適當的同位素變體,製備同位素標記之式I化合物。
較佳的式I化合物之實例係選自由以下組成之群:(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-三氟甲基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(6-三氟甲基-吡啶-3-基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(6-甲氧基-吡啶-3-基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(6-乙氧基-吡啶-3-基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-乙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-甲磺醯基-苯基)-丙烯醯胺、(S)-3-(4-乙醯胺基-苯基)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-丙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-異丙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-乙基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-二氟甲氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-第三丁基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基)-3-(4-異丙基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基)-哌-1-基)-2-側氧基-乙基]-3-(4-三氟甲基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-3-(6-三氟甲基-吡啶-3-基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-3-(6-甲氧基-吡啶-3-基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-3-(6-乙氧基-吡啶-3-基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-3-(4-乙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-3-(4-甲磺醯基-苯基)-丙烯醯胺、(S)-3-(4-乙醯胺基-苯基)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-3-(4-丙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-3-(4-異丙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-3-(4-乙基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-3-(4-二氟甲氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-3-(4-異丙基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-3-(4-第三丁基-苯基)-丙烯醯胺、及(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-硝基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-三氟甲基-苯基)-丙烯醯胺。
較佳的式I化合物之其他實例係選自由以下組成之群:(S)-N-[4-(4-乙醯基-哌-1-基)苄基]-N-{1-(4-(4-(二甲胺基)苄基)哌-1-基)-1-側氧基-3-苯基丙-2-基}肉桂醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)苄基]-N-{1-[4-(4-(二甲胺基)苄基)哌-1-基]-1-側氧基-3-苯基丙-2-基}-3-(對甲苯基)丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)苄基]-N-{1-(4-(4-(二甲胺基)苄基)哌-1-基)-1-側氧基-3-苯基丙-2-基}-3-(4-丙基苯基)丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)苄基]-N-{1-(4-(4-(二甲胺基)苄基)哌-1-基)-1-側氧基-3-苯基丙-2-基}-3-(4-甲氧基苯基)丙烯醯胺、(S)-3-(4-乙醯基-苯基)-N-[4-(4-乙醯基-哌-1-基)苄基]-N-{1-(4-(4-(二甲胺基)苄基)哌-1-基)-1-側氧基-3-苯基丙-2-基}丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)苄基]-3-(4-氰基苯基)-N-{1-(4-(4-(二甲胺基)苄基)哌-1-基)-1-側氧基-3-苯基丙-2-基}丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)苄基]-N-{1-(4-(4-(二甲胺基)苄基)哌-1-基)-1-側氧基-3-苯基丙-2-基}-3-(4-氟苯基)丙烯醯胺、及(S)-N-[4-(4-乙醯基-哌-1-基)苄基]-3-(4-氯苯基)-N-{1-(4-(4-(二甲胺基)苄基)哌-1-基)-1-側氧基-3-苯基丙-2-基}丙烯醯胺。
較佳的式I化合物之其他實例係選自由以下組成之群:(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-苄基-哌-1-基)-2-側氧基-乙基]-3-(4-乙基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-苄基-哌-1-基)-2-側氧基-乙基]-3-(4-第三丁基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-苄基-哌-1-基)-2-側氧基-乙基]-3-(4-乙氧基-苯基)-丙烯醯胺、(S)-4-(2-{[4-(4-乙醯基-哌-1-基)-苄基]-[1-苄基-2-(4-苄基-哌-1-基)-2-側氧基-乙基]-胺甲醯基}-乙烯基)-苯甲酸甲酯、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-苄基-哌-1-基)-2-側氧基-乙基]-3-(4-甲磺醯基-苯基)-丙烯醯胺、(S)-3-(4-乙醯胺基-苯基)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-苄基-哌-1-基)-2-側氧基-乙基]-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-苄基-哌-1-基)-2-側氧基-乙基]-3-(4-丙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-苄基-哌-1-基)-2-側氧基-乙基]-3-(4-異丙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-苄基-哌-1-基)-2-側氧基-乙基]-3-(4-異丙基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氰基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-三氟甲基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氰基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-乙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氰基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-甲磺醯基-苯基)-丙烯醯胺、(S)-3-(4-乙醯胺基-苯基)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氰基-苄基)-哌-1-基]-2-側氧基-乙基}-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氰基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-丙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氰基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-異丙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氰基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-乙基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氰基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-二氟甲氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氰基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-異丙基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氰基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-三氟甲氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氰基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-第三丁基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氯-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-乙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氯-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-甲磺醯基-苯基)-丙烯醯胺、(S)-3-(4-乙醯胺基-苯基)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氯-苄基)-哌-1-基]-2-側氧基-乙基}-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氯-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-丙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氯-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-異丙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氯-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-乙基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氯-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-二氟甲氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氯-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-異丙基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氯-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-第三丁基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-甲氧基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-三氟甲基-苯基)-丙烯醯胺、及(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-異丙氧基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-三氟甲基-苯基)-丙烯醯胺。
較佳的式I化合物之其他實例係選自由以下組成之群:(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-(甲基磺醯基)-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-異丙氧基苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-(甲基磺醯基)-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-第三丁基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-(甲基磺醯基)-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-丙氧基苯基)-丙烯醯胺、(S)-N-(4-(4-乙醯基哌-1-基)苄基)-N-(1-(4-(4-(甲基磺醯基)苄基)哌-1-基)-1-側氧基-3-苯基丙-2-基)-3-(4-(三氟甲基)苯基)丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-(乙基磺醯基)-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-丙氧基苯基)-丙烯醯胺、及(S)-N-(4-(4-乙醯基哌-1-基)苄基)-N-(1-(4-(4-(乙基磺醯基)苄基)哌-1-基)-1-側氧基-3-苯基丙-2-基)-3-(4-(三氟甲基)苯基)丙烯醯胺。
該等式I化合物及其醫藥上可接受的鹽可(例如)以用於經腸或非經腸投藥之醫藥組合物形式用作藥物,且其係適於治療及/或預防本文所述及之疾病,如尤其係瘧疾。
可以任何熟習此項技術者熟悉之方式(參見(例如)Remington,The Scienceand Practice of Pharmacy
,第21版(2005),第5部份,「Pharmaceutical Manufacturing」[由Lippincott Williams & Wilkins出版]),製備該等醫藥組合物,其係藉由使所述之式I化合物或其醫藥上可接受的鹽視情況與其他治療上有價值之物質組合,並連同適宜的醫藥上可接受的非毒性惰性固體或液體載劑物質及(如果需要)常用醫藥佐劑製成草本投藥形式。
在一實施例中,本發明係關於一種治療或預防本文所述及之疾病(如尤其係瘧疾)之方法,該方法包括對個體投與醫藥上活性量之式I化合物。
該等式I化合物或上述醫藥組合物亦可與一或多種其他治療上有用之物質,例如,與其他抗瘧疾劑,如喹啉類(例如,喹寧(quinine)、氯喹(chloroquine)、阿莫地喹(amodiaquine)、甲氟喹(mefloquine)、伯胺喹啉(primaquine)、及他非諾喹(tafenoquine))、過氧化物抗瘧疾劑(例如,青蒿素、青蒿甲醚、及青蒿琥酯(artesunate))、乙嘧啶-周效磺胺抗瘧疾劑(例如,Fansidar)、羥基萘醌類(例如,阿托伐醌(atovaquone))、丙烯醛型抗瘧疾劑(例如,咯萘啶(pyronaridine)),及其他抗原蟲劑,如乙睇胺(ethylstibamine)、羥脒替(hydroxystilbamidine)、戊脘脒(pentamidine)、二脒替(stilbamidine)、喹匹拉明(quinapyramine)、普洛米新(puromycine)、丙脘脒(propamidine)、硝呋莫司(nifurtimox)、硫胂密胺(melarsoprol)、尼莫唑(nimorazole)、硝呋醛肟(nifuroxime)、醋胺硝唑(aminitrozole)及類似物組合使用。
本發明亦關於一種式I化合物於製備醫藥組合物之用途,其視情況與一或多種如彼等上段中所述及之其他治療上有用的物質組合使用,以用於預防及/或治療本文所述及之疾病,如尤其係瘧疾。
可根據本文所述,尤其係如實例部份所述之步驟,製備本發明式I化合物。
一般而言,可根據如文獻資料中所述之熟知標準方法或如以下步驟中所述,進行所有化學轉變。
除其中R1
係-NCH3
(CH2
CH2
OH)之化合物以外之式I
化合物之製法:
可在室溫及含於DCM(或DMF)中之鹼(如DIPEA(或NEM))之存在下,經由使用活化劑(如TBTU(或PyBOP/HOBt))之肽偶聯,使Boc-Phe-OH1
與苄基哌衍生物2
偶聯,以獲得中間體3
。或者,亦可將Cbz-Phe-OH用於最初之肽偶聯步驟中,以獲得3
。通常藉由使3
與HCl的4 N二噁烷溶液反應(使用DCM作為溶劑)來實現Boc-去保護,而Cbz-去保護係藉由於MeOH中用Pd/C觸媒氫化來實現,以獲得胺中間體4
。在回流下,游離胺4
與醛5
於MeOH中之還原性胺化作用獲得不安定的亞胺(該方案中未描述),其在室溫下經NaBH4
進一步還原,以獲得二級胺中間體6
。或者,可於溶劑(如CH3
CN)中,在還原劑(如NaBH(OAc)3
)之存在下,實現該還原性胺化,以獲得預期的二級胺中間體6
。隨後,可在室溫及鹼(如DIPEA(或NEM))之存在下,於溶劑(如DCM(或DMF))中,使用肽偶聯劑(如TBTU、PyBOP/HOBt)或Ghosez試劑使化合物6
與羧酸7
偶聯。或者,可使用含於DCM中之草醯氯將羧酸7
轉化為相應的醯基氯(該方案中未描述),以獲得最終的式I
化合物8
。
當R1
=-NCH3
(CH2
CH2
OH)時,根據方案2製備式I
化合物。
可在室溫及含於DCM(或DMF)中之鹼(如DIPEA(或NEM))之存在下,經由使用活化劑(如TBTU(或PyBOP/HOBt))之肽偶聯反應,使Boc-Phe-OH1
與苄基哌衍生物9
偶聯,以獲得中間體10
。或者,Cbz-Phe-OH亦可用於最初的肽偶聯步驟中,以獲得10
。通常藉由使10
與HCl的4 N二噁烷溶液反應(使用DCM作為溶劑)來實現Boc-去保護,而Cbz-去保護係藉由於MeOH中使用Pd/C觸媒氫化來實現,以獲得胺中間體11
。在室溫下,於還原劑(如NaBH(OAc)3
)之存在下,游離胺11
與醛5
於CH3
CN中之還原性胺化作用獲得二級胺中間體12
。使用(例如)TBDMSCl作為矽烷化劑,保護化合物12
之游離羥基,以獲得13
,隨後,在室溫及在鹼(如DIPEA)之存在下,於溶劑(如DCM(或DMF))中,使用肽偶聯劑(如TBTU(或PyBOP/HOBt))使13
與羧酸7
偶聯。或者,可藉由使用含於DCM中之草醯氯將羧酸7
轉化為相應的醯基氯(該方案中未描述),使該羧酸7
活化,以隨後獲得化合物14
。在微酸性條件(如含於MeOH中之1 M HCl水溶液或氟化試劑(如TBAF))下之進一步去保護產生最終的式I
化合物16
。
亦可根據方案3中所述之途徑製備該等式I
化合物。
在回流下,胺基酸H-Phe-OMe.HCl17
與醛5
於MeOH中之還原性胺化作用獲得相應的亞胺,其在室溫及還原劑(如NaBH4
)之存在下進一步還原成二級胺18
。亦可使用以上針對化合物6
及12
所述之條件獲得18
。隨後,使用含於DCM中之草醯氯或Ghosez試劑,使該酯18
與衍生自羧酸7
之醯基氯19
偶聯。或者,可在室溫及鹼(如DIPEA(或NEM))之存在下,於溶劑(如DCM(或DMF))中,經由使用TBTU(或PyBOP/HOBt)作為偶聯劑之肽偶聯反應,使18
與羧酸7
直接偶聯。在0℃下,用含於THF中之0.5 N LiOH水溶液使酯20
小心皂化,獲得酸21
。與苄基哌 2
之最終肽偶聯獲得最終的式I
化合物8
。
苄基哌 2
及9
可購得及/或可根據以下合成方案4合成:
肉桂酸7
可購得或/及可根據以下途徑合成:途徑A:
克諾維納蓋爾(Knoevenagel)反應
藉由於哌啶/吡啶之混合物中,使醛25
與丙二酸回流,獲得肉桂酸7
(WO 00/66566)。
途徑B:
霍納-埃蒙斯(Horner-Emmons)反應
藉由在鹼(如NaH)之存在下,於非質子溶劑(如THF)中,使醛25
與磷酸乙酸三乙酯26
反應,接著用含於EtOH中之4 NKOH皂化所得之乙酯,分兩步驟獲得肉桂酸7
。
以下實例說明本發明。所有溫度係以攝氏度計及壓力係以mbar計。除非另外述及,否則該等反應係在室溫下進行。溶劑對另一溶劑之數量比通常係以體積份計。已基於化學結構式,在ChemDrawPro Automatic Nomenclature程式之輔助下,生成最終產物及中間體之化學名稱。
分析型HPLC條件:
(I)具有UV/Vis及MS檢測(MS:Thermo Finnigan單四極)之Agilent 1100系列。管柱(4.6x50 mm,5 μm):Waters X-Bridge C18或Waters Atlantis T3。鹼性條件:洗脫劑:A:MeCN,B:濃NH3
水溶液(1.0 mL/L)。梯度5至95%A,歷時1.5 min。流速:4.5 mL/min。
酸性條件:洗脫劑A:水+0.04%TFA,B:MeCN。梯度5至95%,歷時1.5 min。流速4.5 mL/min。
製備型HPLC條件:
具有UV/Vis+MS或UV/Vis+ELSD檢測之Gilson。鹼性條件:洗脫劑:A:MeCN,B:H2
O+0.5%NH3
(25%水溶液)。
(II) Waters X-Bridge管柱,19×50 mm,5 μm。梯度:20至90%A,歷時5 min。流速:40 mL/min。
(III) Waters X-Bridge管柱,30×75 mm,10 μm。梯度:20至90%A,歷時6 min。流速:75 mL/min。
本文使用以下縮寫:
AcOH 乙酸
Boc 第三丁氧羰基
Boc-Phe-OH Boc-L-苯丙胺酸
Cbz 苄氧羰基
Cbz-Phe-OH Cbz-L-苯丙胺酸
DCM 二氯甲烷
DIPEA N,N-二異丙基乙胺
DMF N,N-二甲基甲醯胺
Et 乙基
EtOH 乙醇
EtOAc 乙酸乙酯
Et2
O 乙醚
ELSD 蒸發光散射檢測
h 小時
HOBt 羥基苯并三唑
H-Phe-OMe.HCl L-苯丙胺酸甲酯鹽酸鹽
HPLC 高效液相層析
LC-MS 液相層析-質譜分析
Me 甲基
MeOH 甲醇
min 分鐘
MS 質譜分析
NaBH(OAc)3
三乙醯氧基硼氫化鈉
NEM N-乙基嗎啉
PBS 磷酸鹽緩衝鹽水
Pd/C 碳載鈀
PG 保護基
PyBOP 六氟磷酸苯并三唑-1-基-氧基-叁-吡咯啶鏻
quant. 定量
RT 室溫
Rt 物質於HPLC中之滯留時間(以分鐘計)
TBAF 氟化四正丁銨
TBDMSCl 第三丁基二甲基氯矽烷
TBTU 四氟硼酸O
-苯并三唑-1-基-N
,N
,N’
,N’
-四甲基脲鎓
TFA 三氟乙酸
THF 四氫呋喃
UV 紫外線
Vis 可見光
# 號
經由方案1中所述之途徑之式I化合物之製法-一般步驟及實例:
一般方法A-步驟1
在氮氣下,依次將1 mmol TBTU及2 mmol NEM添加至含於0.6 mL無水DCM(或DMF)中之1 mmol Boc-Phe-OH或Cbz-Phe-OH之攪拌懸浮液中。在室溫下,攪拌所得之淡黃色懸浮液1 h,然後添加含於0.25 mL無水DCM(或DMF)中之1 mmol苄基哌之溶液。在室溫下,另外攪拌所獲得之反應混合物過夜。在完成後,用DCM稀釋該反應,並用NaHCO3
之飽和溶液中止。用DCM(X3)萃取該水相,依次用H2
O及鹽水清洗合併的有機相,在Na2
SO4
上乾燥,過濾,並在減壓下濃縮。藉由急驟層析(SiO2
60F)純化該殘留物,以獲得標題化合物。
中間體1
*分析型I,X-Bridge管柱,鹼性條件
**分析型Waters Atlantis T3管柱,酸性條件
一般方法B-步驟2
其中PG=Boc:在0℃下,將4.5 mL HCl的4 N二噁烷溶液滴加至含於9 mL無水DCM中之1 mmol經Boc保護之胺之溶液中。在室溫下,於氮氣氛下,攪拌所得反應混合物4 h,冷卻至0℃,並用1 N NaOH水溶液小心中和至pH=7。隨後,用DCM(X3)萃取水相。依次用H2
O及鹽水清洗合併的有機相,在Na2
SO4
上乾燥,過濾並在減壓下濃縮,以獲得游離一級胺,其無需進一步純化而用於下一步驟中。
其中PG=Cbz:在氫氣氛及室溫下,攪拌含於無水EtOH(25 mL)中之2 mmol經Cbz-保護之胺及10% Pd-C(100 mg)之混合物3 h。在矽藻土上過濾該反應混合物,並在減壓下濃縮,以獲得游離一級胺,其無需進一步純化而用於下一步驟中。
中間體2
*分析型I,X-Bridge管柱,鹼性條件
**分析型Waters Atlantis T3管柱,酸性條件
一般方法C1及C2-步驟3
一般方法C1:
在氮氣下,使含於5 mL無水MeOH中之1 mmol胺及1 mmol醛之溶液回流24 h。隨後,將所得混合物冷卻至室溫,然後再分批添加1.5 mmol NaBH4
。在室溫下,另外攪拌所得之非均勻混合物2 h,用NaHCO3
之飽和水溶液中止,並用EtOAc(X3)萃取。用鹽水清洗合併之有機相,在Na2
SO4
上乾燥,過濾並在減壓下濃縮。藉由急驟層析(SiO2
60F)純化該殘留物,以獲得標題化合物。
一般方法C2:
將1.5 mmol NaBH(OAc)3
分批添加至含於5 mL無水CH3
CN中之1 mmol胺及1 mmol醛之溶液中。在室溫下,另外攪拌所得之非均勻混合物4 h,用NaHCO3
之飽和水溶液中止,並用EtOAc(X3)萃取。用鹽水清洗合併之有機相,在Na2
SO4
上乾燥,過濾並在減壓下濃縮。藉由急驟層析(SiO2
60F)純化該殘留物,以獲得標題化合物。
中間體3
*分析型I,X-Bridge管柱,鹼性條件
**分析型Waters Atlantis T3管柱,酸性條件
一般方法D1及D2-步驟4
一般方法D1:
在氮氣下,將1.4 mmol 1-氯-N,N-2-三甲基丙烯胺(Ghosez試劑)添加至含於5 mL無水DCM中之1 mmol肉桂酸之溶液中。在室溫下攪拌所得混合物1 h,然後添加含於4 mL無水DCM中之1 mmol胺及3 mmol DIPEA之溶液。在室溫下,另外攪拌該反應混合物過夜。在完成後,添加NaHCO3
之飽和水溶液,並用DCM(X3)萃取該混合物。用鹽水清洗合併之有機相,在Na2
SO4
上乾燥,過濾並在減壓下濃縮。藉由急驟層析(SiO2
60F)或製備型HPLC純化該殘留物,以獲得最終化合物。
一般方法D2:
在0℃及氮氣下,將1.1 mmol草醯氯及3滴DMF添加至含於3.5 mL無水DCM中之1.05 mmol肉桂酸之溶液(或懸浮液)中。在室溫下,攪拌所得混合物1 h,冷卻至0℃,然後添加含於3 mL無水DCM中之1 mmol胺及2 mmol DIPEA之溶液。在室溫下,另外攪拌該反應混合物過夜。在完成後,添加NaHCO3
之飽和水溶液,並用DCM(X3)萃取該混合物。用鹽水清洗合併之有機相,在Na2
SO4
上乾燥,過濾並在減壓下濃縮。藉由急驟層析(SiO2
60F)或製備型HPLC純化該殘留物,以獲得最終化合物。
*分析型I,X-Bridge管柱,鹼性條件
**參考實例
***分析型,Waters Atlantis T3管柱,酸性條件
經由方案2中所述之途徑之式I化合物之製法-一般步驟及實例:
步驟1:(S)-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-胺基甲酸第三丁酯。
根據一般方法A,使用60 mmol Boc-Phe-OH,以獲得50%產率之標題化合物。Rt=0.87;[M+H]+
=497.42(分析型I,X-Bridge管柱,鹼性條件)。
步驟2:(S)-2-胺基-1-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-3-苯基-丙-1-酮。
根據一般方法B,使用12 mmol經Boc保護之胺10
,以獲得定量產率之標題化合物。Rt=0.69;[M+H]+
=397.18(分析型I,X-Bridge管柱,鹼性條件)。
步驟3:(S)-2-[4-(4-乙醯基-哌-1-基)-苄基胺基]-1-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-3-苯基-丙-1-酮。
根據一般方法C2,使用11.4 mmol游離胺11
,以獲得定量產率之標題化合物。Rt=0.74;[M+H]+
=613.24(分析型I,X-Bridge管柱,鹼性條件)。
一般方法E-步驟4:(S)-2-[4-(4-乙醯基-哌-1-基)-苄基胺基]-1-[4-(4-{[2-(第三丁基-二甲基-矽烷氧基)-乙基]-甲基-胺基}-苄基)-哌-1-基]-3-苯基-丙-1-酮。
在室溫下,將3 mmol TBDMSCl分批添加至含於5 mL無水DMF中之1 mmol羥基12
及3 mmol咪唑之溶液中。在室溫下,攪拌該黃色溶液16 h,用H2
O中止,並用EtOAc(X3)萃取。用鹽水清洗合併之有機相,在Na2
SO4
上乾燥,過濾並在減壓下濃縮。藉由急驟層析(SiO2
60F;DCM/MeOH 92:8至95:5)純化該殘留物,以獲得81%產率之呈黃色泡沫之標題化合物。Rt=1.12 min;[M+H]+
=727.31。(分析型I,X-Bridge管柱,鹼性條件)。
步驟5
根據一般方法D1或D2,獲得式28
化合物。
*分析型I,X-Bridge管柱,鹼性條件。
一般方法F-步驟6
在0℃及氮氣下,將3.5 mmol TBAF(1 M THF溶液)添加至含於3.5 mL無水THF中之1 mmol經保護之醇28
之溶液中。在室溫下,攪拌所得混合物4 h,並冷卻至0℃。在完成後,添加H2
O,並用DCM(X3)萃取該混合物。用鹽水清洗合併之有機相,在Na2
SO4
上乾燥,過濾並在減壓下濃縮。藉由急驟層析(SiO2
60F)或製備型HPLC純化該殘留物,以獲得最終化合物。
*分析型I,X-Bridge管柱,鹼性條件。
經由方案3中所述之途徑之式I化合物之製法-一般步驟及實例:
步驟1:(S)-2-[4-(4-乙醯基-哌-1-基)-苄基胺基]-3-苯基-丙酸甲酯。
根據一般方法C1或C2,獲得二級胺18
,且其無需進一步純化而用於下一步驟中。Rt=0.82;[M+H]+
=396.20(分析型I,X-Bridge管柱,鹼性條件)。
步驟2
根據一般方法D1或D2,獲得式20
化合物。
一般方法G-步驟3
在0℃下,將10 mmol 2 M NaOH水溶液滴加至含於8 mL Et2
O及2 mL H2
O中之1 mmol甲酯20
之溶液中。在室溫下,另外攪拌該反應混合物2至3 h。在完成後,用1 N HCl將水相酸化至pH=2至3,且隨後用EtOAc(X3)萃取。用鹽水清洗合併之有機相,在Na2
SO4
上乾燥,過濾並在減壓下濃縮。該殘留物係無需進一步純化而用於下一步驟中。
步驟4
根據一般方法A,獲得式8
化合物。藉由急驟層析法(SiO2
60F)或製備型HPLC純化該殘留物,以獲得最終化合物。
*分析型I,X-Bridge管柱,鹼性條件。
根據一般方法D2獲得實例66至73之化合物。
*分析型I,X-Bridge管柱,鹼性條件。
活體外抗瘧疾活性:惡性瘧原蟲(
Plasmodium falciparum
)活體外試驗
利用[3
H]次黃嘌呤吸收試驗,測定人類紅血球中對抗紅血球內期惡性瘧原蟲之活體外活性。在此試驗中,使用一種對所有已知藥物敏感之菌株(惡性瘧原蟲NF54),且比較所有測試化合物與標準藥物氯喹(sigma C6628)及青蒿琥酯(sigma 36,159-3)之活性。在適當濃度範圍內,於96孔微量滴定盤中,用篩選培養基[RPMI 1640培養基,補充有HEPES(5.94 g/L)、NaHCO3
(2.1 g/L)、新黴素(100 U/mL)、及Albumax(5 g/L)或人類血清(50%最終濃度)]連續稀釋化合物,進行二重覆試驗。隨後,取在含有經洗滌之人類紅血球之篩選培養基中培養之寄生蟲培養物,依2.5%血球溶積比(瘧原蟲血症百分比為0.3%)添加至經過連續稀釋之化合物中,並於37℃、4%CO2
、3%O2
、及93%N2
之加濕氛圍中培養。48 h之後,將[3
H]次黃嘌呤(0.5 μCi)添加至盤之各孔中。在相同條件下,再培養該等盤24 h,隨後,用Betaplate細胞收集器(Wallac)收集,並用蒸餾水清洗。將乾燥過濾器插入含有10 mL閃爍液之塑料箔中,並在Betaplate液體閃爍計數器中計數。使用Microsoft Excel,自S形抑制曲線計算IC50
值。
表1:式I化合物之
IC50
值(nM):
活體內抗瘧疾效力研究
針對三組在第0天經伯氏瘧原蟲(P. berghei
)菌株GFP-ANKA(0.2 mL含有2×107
個被寄生紅血球之含肝素生理食鹽水懸浮液)靜脈注射感染之雌性NMRI小鼠(20至22 g),評估活體內抗瘧疾活性。在對照小鼠中,在感染後第3天,瘧原蟲血症百分比通常上升至約40%。於Tween 80/乙醇(7%/3%)中調配化合物,通常呈10 mg/mL之濃度。以體積為10 mL/kg的單劑量經口投與化合物(1×100 mg/kg,感染24 h後)。藥物處理48 h後(感染後第3天),取1 μl尾部血液,再懸浮於1 mL PBS緩衝液中,並利用FACScan(Becton Dickinson)計算100,000個紅血球,測定瘧原蟲血症百分比。以對照組與處理組之平均值之間的差異計算活性,並以相對於該對照組之百分比表示。
表2:
100 mg/kg之單次口服劑量之後,式I化合物之活性(瘧原蟲血症百分比之抑制)(以相對於該對照組之百分比表示)
*參考實例
Claims (25)
- 一種式I 化合物或該化合物之鹽,
- 如請求項1之化合物或該化合物之鹽,其中X 係CH或N;R 1 表示-NO2 、-N(CH3 )2 、或-NCH3 (CH2 CH2 OH);且R 2 表示氫、甲基、乙基、正丙基、異丙基、第三丁基、氰基、鹵素、甲氧基、乙氧基、正丙氧基、異丙氧基、三氟甲基、二氟甲氧基、甲基磺醯基、乙醯基、或乙醯胺基;或X 係CH,R 1 係氫,且R 2 係乙基、異丙基、第三丁基、乙氧基、正丙氧基、異丙氧基、甲基磺醯基、乙醯胺基、或甲氧羰基;或X 係CH,R 1 係氰基,且R 2 係乙基、異丙基、第三丁基、乙氧基、正丙氧基、異丙氧基、三氟甲基、二氟甲氧基、三氟甲氧基、甲基磺醯基、或乙醯胺基;或X 係CH,R 1 係氯,且R 2 係乙基、異丙基、第三丁基、乙氧基、正丙氧基、異丙氧基、二氟甲氧基、甲基磺醯基、或乙醯胺基;或X 係CH,R 1 係甲氧基或異丙氧基,且R 2 係三氟甲基。
- 如請求項1之化合物或該化合物之鹽,其中X 係CH或N;R 1 表示-NO2 、-N(CH3 )2 、或-NCH3 (CH2 CH2 OH);且R 2 表示乙基、異丙基、第三丁基、甲氧基、乙氧基、正丙氧基、異丙氧基、三氟甲基、二氟甲氧基、甲基磺醯基、或乙醯胺基;或X 係CH,R 1 係氫,且R 2 係乙基、異丙基、第三丁基、乙氧基、正丙氧基、異丙氧基、甲基磺醯基、乙醯胺基、或甲氧羰基;或X 係CH,R 1 係氰基,且R 2 係乙基、異丙基、第三丁基、乙氧基、正丙氧基、異丙氧基、三氟甲基、二氟甲氧基、三氟甲氧基、甲基磺醯基、或乙醯胺基;或X 係CH,R 1 係氯,且R 2 係乙基、異丙基、第三丁基、乙氧基、正丙氧基、異丙氧基、二氟甲氧基、甲基磺醯基、或乙醯胺基;或X 係CH,R 1 係甲氧基或異丙氧基,且R 2 係三氟甲基。
- 如請求項1之化合物或該化合物之鹽,其中R 1 表示-NO2 、-N(CH3 )2 、或-NCH3 (CH2 CH2 OH);且R 2 表示氫、甲基、乙基、正丙基、異丙基、第三丁基、氰基、鹵素、甲氧基、乙氧基、正丙氧基、異丙氧基、三氟甲基、二氟甲氧基、甲基磺醯基、乙醯基、或乙醯胺基。
- 如請求項1之化合物或該化合物之鹽,其中R 1 表示-NO2 、-N(CH3 )2 、或-NCH3 (CH2 CH2 OH);且R 2 表示乙基、異丙基、第三丁基、甲氧基、乙氧基、正丙氧基、異丙氧基、三氟甲基、二氟甲氧基、甲基磺 醯基、或乙醯胺基。
- 如請求項4或5之化合物或該化合物之鹽,其中X 係CH。
- 如請求項4或5之化合物或該化合物之鹽,其中X 係N。
- 如請求項4或5中任一項之化合物或該化合物之鹽,其中R 1 表示-NO2 。
- 如請求項4或5中任一項之化合物或該化合物之鹽,其中R 1 表示-N(CH3 )2 。
- 如請求項4或5中任一項之化合物或該化合物之鹽,其中R 1 表示-NCH3 (CH2 CH2 OH)。
- 如請求項4或5中任一項之化合物或該化合物之鹽,其中R 2 係乙基、異丙基、第三丁基、乙氧基、正丙氧基、或異丙氧基。
- 如請求項11之化合物或該化合物之鹽,其中R 2 係異丙氧基。
- 如請求項4或5中任一項之化合物或該化合物之鹽,其中R 2 係三氟甲基、二氟甲氧基、甲基磺醯基、或乙醯胺基。
- 如請求項4或5中任一項之化合物或該化合物之鹽,其中R 2 係甲氧基。
- 如請求項4或5中任一項之化合物或該化合物之鹽,其中R 2 係氫、甲基、正丙基、氰基、鹵素、或乙醯基。
- 如請求項1之化合物,其係選自由以下組成之群:(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-三氟 甲基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(6-三氟甲基-吡啶-3-基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(6-甲氧基-吡啶-3-基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(6-乙氧基-吡啶-3-基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-乙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-甲磺醯基-苯基)-丙烯醯胺、(S)-3-(4-乙醯胺基-苯基)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-丙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-異丙 氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-乙基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-二氟甲氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]2-側氧基-乙基}-3-(4-第三丁基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-二甲胺基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-異丙基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-3-(4-三氟甲基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-3-(6-三氟甲基-吡啶-3-基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-3-(6-甲氧基-吡啶-3-基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧 基-乙基]-3-(6-乙氧基-吡啶-3-基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-3-(4-乙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-3-(4-甲磺醯基-苯基)-丙烯醯胺、(S)-3-(4-乙醯胺基-苯基)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-3-(4-丙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-3-(4-異丙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-3-(4-乙基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-3-(4-二氟甲氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧 基-乙基]-3-(4-異丙基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-{4-[(2-羥基-乙基)-甲基-胺基]-苄基}-哌-1-基)-2-側氧基-乙基]-3-(4-第三丁基-苯基)-丙烯醯胺、及(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-硝基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-三氟甲基-苯基)-丙烯醯胺,或此等化合物之鹽。
- 如請求項1之化合物,其係選自由以下組成之群:(S)-N-[4-(4-乙醯基-哌-1-基)苄基]-N-{1-(4-(4-(二甲胺基)苄基)哌-1-基)-1-側氧基-3-苯基丙-2-基}肉桂醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)苄基]-N-{1-[4-(4-(二甲胺基)苄基)哌-1-基]-1-側氧基-3-苯基丙-2-基}-3-(對甲苯基)丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)苄基]-N-{1-(4-(4-(二甲胺基)苄基)哌-1-基)-1-側氧基-3-苯基丙-2-基}-3-(4-丙基苯基)丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)苄基]-N-{1-(4-(4-(二甲胺基)苄基)哌-1-基)-1-側氧基-3-苯基丙-2-基}-3-(4-甲氧基苯基)丙烯醯胺、(S)-3-(4-乙醯基-苯基)-N-[4-(4-乙醯基-哌-1-基)苄基]-N-{1-(4-(4-(二甲胺基)苄基)哌-1-基)-1-側氧基-3-苯基丙-2-基}丙烯醯胺、 (S)-N-[4-(4-乙醯基-哌-1-基)苄基]-3-(4-氰基苯基)-N-{1-(4-(4-(二甲胺基)苄基)哌-1-基)-1-側氧基-3-苯基丙-2-基}丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)苄基]-N-{1-(4-(4-(二甲胺基)苄基)哌-1-基)-1-側氧基-3-苯基丙-2-基}-3-(4-氟苯基)丙烯醯胺、及(S)-N-[4-(4-乙醯基-哌-1-基)苄基]-3-(4-氯苯基)-N-{1-(4-(4-(二甲胺基)苄基)哌-1-基)-1-側氧基-3-苯基丙-2-基}丙烯醯胺,或此等化合物之鹽。
- 如請求項1之化合物,其係選自由以下組成之群:(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-苄基-哌-1-基)-2-側氧基-乙基]-3-(4-乙基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-苄基-哌-1-基)-2-側氧基-乙基]-3-(4-第三丁基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-苄基-哌-1-基)-2-側氧基-乙基]-3-(4-乙氧基-苯基)-丙烯醯胺、(S)-4-(2-{[4-(4-乙醯基-哌-1-基)-苄基]-[1-苄基-2-(4-苄基-哌-1-基)-2-側氧基-乙基]-胺甲醯基}-乙烯基)-苯甲酸甲酯、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4- 苄基-哌-1-基)-2-側氧基-乙基]-3-(4-甲磺醯基-苯基)-丙烯醯胺、(S)-3-(4-乙醯胺基-苯基)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-苄基-哌-1-基)-2-側氧基-乙基]-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-苄基-哌-1-基)-2-側氧基-乙基]-3-(4-丙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-苄基-哌-1-基)-2-側氧基-乙基]-3-(4-異丙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-[1-苄基-2-(4-苄基-哌-1-基)-2-側氧基-乙基]-3-(4-異丙基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氰基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-三氟甲基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氰基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-乙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氰基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-甲磺醯基-苯基)-丙烯醯胺、(S)-3-(4-乙醯胺基-苯基)-N-[4-(4-乙醯基-哌-1-基)- 苄基]-N-{1-苄基-2-[4-(4-氰基-苄基)-哌-1-基]-2-側氧基-乙基}-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氰基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-丙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氰基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-異丙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氰基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-乙基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氰基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-二氟甲氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氰基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-異丙基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氰基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-三氟甲氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氰基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-第三丁基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4- (4-氯-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-乙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氯-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-甲磺醯基-苯基)-丙烯醯胺、(S)-3-(4-乙醯胺基-苯基)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氯-苄基)-哌-1-基]-2-側氧基-乙基}-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氯-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-丙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氯-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-異丙氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氯-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-乙基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氯-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-二氟甲氧基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-氯-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-異丙基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4- (4-氯-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-第三丁基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-甲氧基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-三氟甲基-苯基)-丙烯醯胺、及(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-異丙氧基-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-三氟甲基-苯基)-丙烯醯胺,或此等化合物之鹽。
- 如請求項1之化合物,其係選自由以下組成之群:(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-(甲基磺醯基)-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-異丙氧基苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-(甲基磺醯基)-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-第三丁基-苯基)-丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-(甲基磺醯基)-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4-丙氧基苯基)-丙烯醯胺、(S)-N-(4-(4-乙醯基哌-1-基)苄基)-N-(1-(4-(4-(甲基磺醯基)苄基)哌-1-基)-1-側氧基-3-苯基丙-2-基)-3-(4-(三氟甲基)苯基)丙烯醯胺、(S)-N-[4-(4-乙醯基-哌-1-基)-苄基]-N-{1-苄基-2-[4-(4-(乙基磺醯基)-苄基)-哌-1-基]-2-側氧基-乙基}-3-(4- 丙氧基苯基)-丙烯醯胺、及(S)-N-(4-(4-乙醯基哌-1-基)苄基)-N-(1-(4-(4-(乙基磺醯基)苄基)哌-1-基)-1-側氧基-3-苯基丙-2-基)-3-(4-(三氟甲基)苯基)丙烯醯胺,或此等化合物之鹽。
- 一種醫藥組合物,其包含如請求項1至19中任一項之化合物或其醫藥上可接受的鹽、及醫藥上可接受的載劑物質。
- 如請求項1至5及16至19中任一項之化合物或其醫藥上可接受的鹽或如請求項20之組合物,其係用作藥物。
- 如請求項1至5及16至19中任一項之化合物或其醫藥上可接受的鹽,其係用於治療及/或預防原蟲感染。
- 如請求項1至5及16至19中任一項之化合物或其醫藥上可接受的鹽,其係用於治療及/或預防瘧疾。
- 一種如請求項1至19中任一項之化合物或其醫藥上可接受的鹽之用途,其係用於製備用於治療及/或預防原蟲感染之醫藥組合物。
- 如請求項24之用途,其係用於治療及/或預防瘧疾。
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WO2013018069A1 (en) | 2011-08-04 | 2013-02-07 | Actelion Pharmaceuticals Ltd | Combination of antimalarial agents |
WO2014072903A1 (en) * | 2012-11-06 | 2014-05-15 | Actelion Pharmaceuticals Ltd | Novel aminomethyl-phenol derivatives as antimalarial agents |
KR20150132437A (ko) * | 2013-03-15 | 2015-11-25 | 액테리온 파마슈티칼 리미티드 | 항말라리아제로서의 신규의 아크릴아미드 유도체 |
CA3164056A1 (en) * | 2020-01-21 | 2021-07-29 | Eisai R&D Management Co., Ltd. | Novel antimalarial agent containing heterocyclic compound |
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TW200800931A (en) * | 2005-10-21 | 2008-01-01 | Actelion Pharmaceuticals Ltd | Novel piperazines as antimalarial agents |
CN101544630A (zh) * | 2009-05-13 | 2009-09-30 | 中国科学院广州生物医药与健康研究院 | 羟基化茚地那韦及其制备方法和在制备抗疟药中的应用 |
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DE10008522A1 (de) * | 2000-02-24 | 2001-09-06 | Hassan Jomaa | Verwendung von 2-PHenylendiaminderivaten zur Behandlung von Infektionen |
IL151923A0 (en) * | 2000-03-31 | 2003-04-10 | Pfizer Prod Inc | Novel piperazine derivatives |
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TW200800931A (en) * | 2005-10-21 | 2008-01-01 | Actelion Pharmaceuticals Ltd | Novel piperazines as antimalarial agents |
CN101544630A (zh) * | 2009-05-13 | 2009-09-30 | 中国科学院广州生物医药与健康研究院 | 羟基化茚地那韦及其制备方法和在制备抗疟药中的应用 |
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