TW495508B - Amino acid ester containing azole antifungals - Google Patents

Amino acid ester containing azole antifungals Download PDF

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Publication number
TW495508B
TW495508B TW087101662A TW87101662A TW495508B TW 495508 B TW495508 B TW 495508B TW 087101662 A TW087101662 A TW 087101662A TW 87101662 A TW87101662 A TW 87101662A TW 495508 B TW495508 B TW 495508B
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Taiwan
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formula
phenyl
scope
amino acid
patent application
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TW087101662A
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English (en)
Inventor
Lieven Meerpoel
Jan Heeres
Robert J M Hendrickx
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Janssen Pharmaceutica Nv
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Description

495508 Α8 Β8 C8 D8 六、申請專利範圍 R1為i基； R2為氫或鹵基。 2. 根據申請專利範圍第1或2項之化合物，其中於1，3-二氧雜環戊烷環上之取代基具有膺式構形。 3. 根據申請專利範圍第1或2項之化合物，其中且R1 .與R2皆為氟基，X為N，且-A-B-係式(b)基團。 4. 根據申請專利範圍第1或2項之化合物，其中1-甲丙 基部分之二個不對稱碳皆具有*S組態，且D為式D1 基團，其中位於二氧雜環戊烷環上之取代基具有廣式 組態，且二氧雜環戊烷環上編號為2之碳原子具有絕 對S組態。 5. 根據申請專利範圍第1項之化合物，其中該化合物為 2-[4-[4-[4-[4-[|>(2,4-二氟苯基）-2-(1//-1,2,4-三唑-1-基曱基)-1，3-二氧雜環戊烷-4-基]曱氧基]苯基μι-六氫 吡畊基]苯基]-4,5-二氫-5-氧三唑-1-基]-1-曱 丙基二乙甘胺酸； 經濟部智慧財產局員工消費合作社印製 2-[4-[4-[4-[4-[[2-(2,4_ 二氟苯基）_2-(1//-1，2,4_ 三唑-1-基甲基)-1，3-二氧雜環戊烷-4-基]曱氧基]苯基]-1-六氫 吡畊基]苯基]-4,5-二氫-5-氧三唑-1-基]-1-甲 丙基L-苯丙胺酸； 2-[4-[4·[4-[4-[[2-(2,4-二氟苯基）-2-(1//-1,2,4-三唑-1-基曱基)-1，3-二氧雜環戊烷-4-基]甲氧基]苯基]-1-六氫 -55 - 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 495508 A8 B8 C8 D8 六、申請專利範圍 吡畊基]苯基]-4,5-二氳-5-氧-1//-1，2,4-三唑-1-基]-1-甲 丙基L-白胺酸， 2-[4-[4_[4-[4-[[2-(2,4-二氟苯基）-2-(1//-1，2,4-三唑-1-基曱基)-1，3-二氧雜環戊烷-4-基]曱氧基]苯基]-1-六氩 吡畊基]苯基]-4,5-二氫-5-氧-1//-1，2,4-三唑-1-基]-1-曱 -丙基L-纈胺酸； 2-[4-[4-[4-[4-[[2-(2,4-二氟苯基）-2-(1//-1，2,4-三唑-1-基曱基)-1，3-二氧雜環戊烷-4-基]甲氧基]苯基]-1-六氫 吡畊基]苯基]-4,5-二氫-5-氧-1//-1,2,4-三唑-1-基]-1-甲 丙基L-苯甘胺酸；其7V-氧化物形式，其醫藥上可接 受之加成鹽類以及其立體化學上異構形式。 6. —種式(II)中間物之鏡像異構上純的形式， I f 3 f
N^^N—CH—CH—CH3 (ID w 經濟部智慧財產局員工消費合作社印製
其N-氧化物型式，或其加成鹽類，其中D與-A-B-係 如申請專利範圍第1項中所定義。 7. 根據申請專利範圍第6項之式(II)中間物，其中該中 間物為[2S-[2a，4cx[CR*，i?*)]]]-4-[4-[4-[4-[[2-(2,4-二氟 苯基)-2_(1/Μ，2,4-三唑-1-基曱基)-1，3-二噚戊烷-4-基] 曱氧基]-苯基]-1 -六氮17比17井基]苯基]-2,4-二氮-2-(2-罗坐 -56 - 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 495508 Α8 Β8 C8 D8 六、申請專利範圍 基-1-曱基丙基）-3//-1，2,4-三唑-3-酮或[28-[2〇6,4叫(及*，7?*)]]]-4-[4-[4-[4-[[2-(2,4-二氣苯基)-2-(1//-1，2,4-三唑-1-基曱基)-1，3-二畤戊烷_4_基]甲氧基]-苯 基]-1-六氩吡畊基]苯基]-2,4-二氫-2·(2•羥基-1-甲基丙 基)-3//-1，2,4-三唑-3-酮。 8. 一種式(II)中間物之鏡像異構混合物，
經濟部智慧財產局員工消費合作社印製 其Ν-氧化物型式，或其加成鹽類，其中D與-Α-Β-係 如申請專利範圍第1項中所定義。 9. 根據申請專利範圍第8項之鏡像異構混合物，其中該 鏡像異構混合物為[2a，4oc[(7?*，*)]]-4-[4-[4-[4-[[2-(2,4_ 二氟苯基)-2-(1//-1，2,4-三唑-1-基甲基)-1，3-二口号戊烷-4-基]甲氧基]-苯基]-1-六氫吼畊基]苯基]-2,4-二氫-2-(2-羥基-1-曱基丙基)-3/Μ，2,4-三唑-3-酮。 10. 根據申請專利範圍第1或2項之化合物，其係用作為 供治療或預防真菌感染之醫藥品。 11. 一種供治療或預防真菌感染之醫藥組合物，其包含治 療上有效量做為活性成份之根據申請專利範圍第1項 化合物，以及醫藥上可接受之載體。 -57 - 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 495508 六、申請專利範圍12 ·根據申請專利蘇 脈内投藥。第項之醫藥組合物，其適合靜 13· -種製備根據中請專利範圍第〗項之化合物 其特徵在於 方法， a)將一 種具式(II)之醇類中間物與式(ΠΙ)醯化 醯化作用， ” 進行 D- 經濟部智慧財產局員工消費合作社印製
又 A~E 、~Qr — 〇1) (ΠΙ) 其中W1為連接至L之醯基部分之具反應性脫離 基丄且L、D與-A_B_係如申請專利範圍第i項中 所定義，其係藉由於如二氣甲烷之反應惰性之溶 劑中，且較佳於室溫下，擾拌該反應物，視需要 払入如N，N-二甲基吡啶胺之鹼，以吸收反應期 間所形成之酸； b)將式(IV)之紛與式(v)烧化劑進行〜烧化作用， -Ν Ν Η 一〇
Ν Η—
ch3 oh Ν—CH—CH—CH3 + w1- η w2-d 〇) ψ 計 線
A—B
(D 〇V) (V) 其中W2為具反應性之脫離基，且L、D與-A-B-係如申請專利範圍第1項中所定義；其係藉由於 反應惰性之溶劑中攪拌該反應物，視需要摻入 58 - 本纸張尺度適用中國國家標準(CNS)A4規格（210 Χ 297公釐） 495508 A8 B8 C8 D8 六、申請專利範圍 鹼，以吸收反應期間所形成之酸； c) 較佳於N，N-二甲基曱醯胺中且於室溫下，將一 種具式（II)之中間物與式（VI)之試劑進行Ο-醯化 作用，並接著將由此所獲得之式（VII)中間物與 具式（VIII)之胺類反應， D 一〇
^~J A—B CH3 oh I I N—CH——CH—CH3
+ WI-L*-—W3 一 (VI) nh〜(vm) (I) 經濟部智慧財產局員工消費合作社印製 其中W3為具反應性之脫離基，D與-A-B_係如申 請專利範圍第1項中所定義，NRxRy係如申請專 利範圍第1項中L所定義之胺基酸的視需要經單-或二取代胺基酸部分，L’與如申請專利範圍第1 項中所定義之L相同，惟除了該視需要經單-或二 取代之胺基酸部分以外； 且，若希望，根據技藝所知之轉變作用，而將式 (I)化合物互相轉換；並進一步，若希望，藉由以 酸處理，而將式(I)化合物轉化成治療上具活性之 無毒酸加成鹽，或相反地，藉由以驗酸處理，而 將酸加成鹽形式轉化成自由態驗；以及，若希 望，製備其立體化學上異構型式或其N-氧化物型 式。 -59 - 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐）
TW087101662A 1997-02-11 1998-02-09 Amino acid ester containing azole antifungals TW495508B (en)

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EP97200374 1997-02-11
EP97203228 1997-10-15

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TW495508B true TW495508B (en) 2002-07-21

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US (3) US6262052B1 (zh)
EP (1) EP0958289B1 (zh)
JP (1) JP4347911B2 (zh)
KR (1) KR100509171B1 (zh)
CN (1) CN1238353C (zh)
AT (1) ATE270290T1 (zh)
AU (1) AU725302C (zh)
BG (1) BG63872B1 (zh)
BR (1) BR9809744A (zh)
CA (1) CA2262791C (zh)
CZ (1) CZ297197B6 (zh)
DE (1) DE69824834T2 (zh)
DK (1) DK0958289T3 (zh)
EE (1) EE03876B1 (zh)
ES (1) ES2224364T3 (zh)
HU (1) HU227744B1 (zh)
ID (1) ID21755A (zh)
IL (2) IL128513A (zh)
MY (1) MY129537A (zh)
NO (1) NO316668B1 (zh)
NZ (1) NZ334477A (zh)
PL (1) PL191152B1 (zh)
PT (1) PT958289E (zh)
RU (1) RU2197489C2 (zh)
SI (1) SI0958289T1 (zh)
SK (1) SK284910B6 (zh)
TR (1) TR199900584T2 (zh)
TW (1) TW495508B (zh)
UA (1) UA61919C2 (zh)
WO (1) WO1998034934A1 (zh)
ZA (1) ZA981079B (zh)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0957101A1 (en) * 1998-05-14 1999-11-17 Janssen Pharmaceutica N.V. Water soluble azoles as broad-spectrum antifungals
WO2000030655A1 (en) 1998-11-20 2000-06-02 Bristol-Myers Squibb Company Water soluble prodrugs of azole compounds
BR0010279A (pt) * 1999-05-04 2002-05-14 Janssen Phamaceutica N V éteres antifúngicos
WO2003052117A2 (en) * 2001-09-19 2003-06-26 Massachusetts Institute Of Technology Methods and products related to non-viral transfection
ITMI20032020A1 (it) * 2003-10-17 2005-04-18 Italfarmaco Spa Nuovi agenti antifungini azolici con diminuita interazione con i citocromi metabolici
MX342850B (es) * 2010-05-19 2016-10-14 Sandoz Ag Proceso para la preparacion de triazolonas quirales.
BR102019004480B1 (pt) * 2018-03-08 2023-03-28 Dow Agrosciences Llc Picolinamidas como fungicidas
CN111138421A (zh) * 2019-12-26 2020-05-12 上海英诺富成生物科技有限公司 抗真菌水溶性化合物及其制备方法与应用

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4218458A (en) 1978-06-23 1980-08-19 Janssen Pharmaceutica, N.V. Heterocyclic derivatives of (4-aryloxy-methyl-1,3-dioxolan-2-yl)methyl-1H-imidazoles and 1H-1,2,4-triazoles
US4791111A (en) * 1985-12-23 1988-12-13 Janssen Pharmaceutica, N.V. [[4-[4-(4-phenyl-1-piperazinyl)phenoxymethyl]-1,3-dioxolan-2-yl]methyl]-1H-imidazoles and 1H-1,2,4-triazoles having anti-microbial properties
US4916134A (en) 1987-03-25 1990-04-10 Janssen Pharmacuetica N.V. 4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-azolylmethyl)-1,3-dioxolan-4-yl]me]phenyl]-1-piperazinyl]phenyl]triazolones
CA1331757C (en) 1988-02-29 1994-08-30 Janssen Pharmaceutica Naamloze Vennootschap 5-lipoxygenase inhibiting 4-(4-phenyl-1-piperazinyl)phenols
NZ249494A (en) 1992-03-18 1996-04-26 Janssen Pharmaceutica Nv Itraconazole and saperconazole stereoisomers; pharmaceutical compositions
CZ294823B6 (cs) * 1993-12-21 2005-03-16 Schering Corporation Fungicidní tetrahydrofurany
SI0741737T1 (en) * 1994-01-24 2000-02-29 Janssen Pharmaceutica N.V. Watersoluble azole antifungals
AR002751A1 (es) 1995-06-02 1998-04-29 Schering Corp Antifungicos de tetrahidrofurano, composiciones farmaceuticas que los contienen y el uso de los compuestos para preparar composiciones farmaceuticas utiles para el tratamiento de infecciones fungicas
WO1997000255A1 (en) * 1995-06-19 1997-01-03 Schering Corporation Tetrahydrofuran antifungals

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IL128513A0 (en) 2000-01-31
CZ297197B6 (cs) 2006-09-13
HUP0001050A3 (en) 2001-07-30
AU725302B2 (en) 2000-10-12
EP0958289B1 (en) 2004-06-30
ID21755A (id) 1999-07-22
KR20000068526A (ko) 2000-11-25
BG63872B1 (bg) 2003-04-30
US6703506B2 (en) 2004-03-09
NO990484L (no) 1999-10-11
EE03876B1 (et) 2002-10-15
CA2262791C (en) 2008-10-28
BG103171A (en) 1999-09-30
MY129537A (en) 2007-04-30
WO1998034934A1 (en) 1998-08-13
DE69824834T2 (de) 2005-07-21
US6512116B2 (en) 2003-01-28
PL191152B1 (pl) 2006-03-31
IL149285A0 (en) 2002-11-10
US6262052B1 (en) 2001-07-17
DK0958289T3 (da) 2004-11-01
US20010039281A1 (en) 2001-11-08
HUP0001050A2 (hu) 2001-04-28
JP2001508080A (ja) 2001-06-19
AU6620798A (en) 1998-08-26
RU2197489C2 (ru) 2003-01-27
NO316668B1 (no) 2004-03-29
PT958289E (pt) 2004-11-30
AU725302C (en) 2001-08-23
EP0958289A1 (en) 1999-11-24
IL128513A (en) 2002-11-10
SK105999A3 (en) 2000-06-12
JP4347911B2 (ja) 2009-10-21
NO990484D0 (no) 1999-02-02
SK284910B6 (sk) 2006-02-02
CN1236366A (zh) 1999-11-24
ZA981079B (en) 1999-08-10
DE69824834D1 (de) 2004-08-05
ATE270290T1 (de) 2004-07-15
CZ283599A3 (cs) 2000-02-16
BR9809744A (pt) 2000-06-20
CN1238353C (zh) 2006-01-25
CA2262791A1 (en) 1998-08-13
ES2224364T3 (es) 2005-03-01
SI0958289T1 (en) 2004-12-31
US20030158210A1 (en) 2003-08-21
PL332008A1 (en) 1999-08-16
NZ334477A (en) 2001-05-25
UA61919C2 (uk) 2003-12-15
EE9900100A (et) 1999-10-15
TR199900584T2 (xx) 1999-10-21
KR100509171B1 (ko) 2005-08-22
HU227744B1 (en) 2012-02-28
IL149285A (en) 2007-08-19

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