JP5173763B2 - 抗細菌活性を有するプレウロムチリン誘導体 - Google Patents
抗細菌活性を有するプレウロムチリン誘導体 Download PDFInfo
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- JP5173763B2 JP5173763B2 JP2008300463A JP2008300463A JP5173763B2 JP 5173763 B2 JP5173763 B2 JP 5173763B2 JP 2008300463 A JP2008300463 A JP 2008300463A JP 2008300463 A JP2008300463 A JP 2008300463A JP 5173763 B2 JP5173763 B2 JP 5173763B2
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- hydrogen
- acetyl
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- 0 C[C@]([C@@](C)[C@@](*)(C[C@]([C@]1(C)C(*)C2*C3C2)OC(C(*)(*)**)=O)C=C)C3(CC2(*)*)[C@]1(*)C2=O Chemical compound C[C@]([C@@](C)[C@@](*)(C[C@]([C@]1(C)C(*)C2*C3C2)OC(C(*)(*)**)=O)C=C)C3(CC2(*)*)[C@]1(*)C2=O 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/53—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
-
- 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
-
- 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
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/93—Spiro compounds
- C07C2603/95—Spiro compounds containing "not free" spiro atoms
- C07C2603/98—Spiro compounds containing "not free" spiro atoms containing at least one ring with more than six ring members
- C07C2603/99—Spiro compounds containing "not free" spiro atoms containing at least one ring with more than six ring members containing eight-membered rings
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Emergency Medicine (AREA)
- Epidemiology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
Xはイオウ、酸素またはNR10であり、ここでR10は水素またはアルキルであり;および、
R9はアミノ、アルキル、アリールまたはヘテロサイクリルであり;および、Xが酸素である場合は、R9は更に水素でもあり;
Yはイオウまたは酸素であり;
R2は水素または例えば有機化学、例えば(プレウロ)ムチリン化学において従来用いられている置換基を含む1つ以上の置換基であり、R4は水素またはアルキルであり;R5は水素またはアルキルであり;R3およびR3’は水素、重水素またはハロゲンであり;R6、R7およびR8は水素または重水素であり;mは0〜4から選択される数であり、nは0〜10から選択される数であり、および、pは0〜10から選択される数であり;ただし、n+pは少なくとも1であり;例えば好ましくは13未満である。]の化合物を提供する。
Rは水素であり;R1は水素または式−C(=X)R9の基であり、
ここでXは酸素であり;および、
R9はアルキル、例えば(C1−8)アルキル、例えば(C1−4)アルキル、例えば未置換または置換されたアルキル、例えば有機化学、例えばプレウロムチリン化学で従来使用されている基、例えばアミノ1個以上で置換されたものであり;例えばR9がアミノで置換されたアルキルである場合は、R9は好ましくは例えばバリン等のアミノ酸の残基であり、および例えば該残基にはカルボキシル基が脱離した後に残るアミノ酸の部分が包含され;
Yはイオウであり;
R2は水素であり;
R4、R5、R3、R3’、R6、R7およびR8は水素であり;
mは0であり;
nは3または4であり;および、
pは0または1であり;および例えばpプラスnは3または4である。
a.下記式:
b. 工程aで得られた式Iの化合物に重水素を導入してY、R1、R,R2、R3、R3’、R4、R5、m、nおよびpが前記したものであり、そしてR6、R7およびR8が重水素である式Iの化合物とすること、
を包含する式Iの化合物の製造方法を提供する。
DCCI ジシクロヘキシルカルボジイミド
BOC t−ブトキシカルボニル
DMF ジメチルホルムアミド
実施例において示したムチリン環のナンバリングは以下の式において示す。
14−O−[(3−(R)−アミノ−2−メチル−プロパンカルボニルアミノ)−シクロヘキサン−1−イル)−スルファニル)−アセチル]ムチリン(=14−O−[(N−(R)−バリル−(R)−アミノシクロヘキサン−3(R)−イル)スルファニル)−アセチル]ムチリン)
A.1,3−ビス−(4−トルエン−スルホニルオキシ)−シクロヘキサン
塩化メチレン200mL中の1,3−ジヒドロシクロヘキサン11.6g、無水4−トルエンスルホン酸6.52gおよびN−メチルモルホリン40.4gの溶液を室温で約24時間攪拌する。得られた混合物を1N塩酸に注ぎ込み、そして得られた混合物を塩化メチレンで抽出する。得られた有機層を乾燥し、溶媒を蒸発させる。1,3−ビス−(4−トルエン−スルホニルオキシ)−シクロヘキサン38.5gを得る。
DMF100mL中の1,3−ビス−(4−トルエン−スルホニルオキシ)−シクロヘキサン3.9gの溶液に、アジ化ナトリウム0.55gを1回で添加する。得られた反応混合物を約2時間約80℃に加熱し、溶媒を真空下に除去し、得られた残存物を塩化メチレン200mLに溶解し、クロマトグラフィーに付す。1トルエンスルホニルオキシ−3−アジドシクロヘキサン1.2gを得る。
H1−NMR(CDCl3):ジアステレオマー混合物:7.8, 7.3(2×d, 4H,芳香族H), 4.8, 4.4(2×m,1H,CHO),3.2,3.7(2×m,1H,CHN),2.4(s,3H,芳香族CH3),1.2−1.8(m,8H,シクロヘキシル)。
酢酸エチル50mL中の1−トルエンスルホニルオキシ−3−アジド−シクロヘキサン2.75gの溶液を触媒量のPd/C(10%)の存在下に水素化する。触媒を濾去し、得られた濾液にN−BOC−(D)−バリン2.2gおよびDCC2gを添加する。得られた反応混合物を約15時間室温で攪拌し、濾過し、溶媒を蒸発させる。得られた残存物をクロマトグラフィーに付す。
エタノール100mL中の14−メルカプトアセチル−ムチリン1.75gおよびナトリウム70mgの溶液に、1−トルエンスルホニルオキシ−3−(3(R)−t−ブトキシカルボニルアミノ−2−メチルプロパンカルボニルアミノ)−シクロヘキサン1.4gおよびN−メチルモルホリン0.7mLを添加する。得られた混合物を約90℃で約8時間加熱する。得られた混合物を食塩水に注ぎ込み、得られた混合物を酢酸エチルで抽出し、得られた有機層を蒸発させる。得られた残存物をトリフルオロ酢酸/塩化メチレンの1:1混合物で処理し、クロマトグラフィーに付す。
A.N−(R)−(N−BOC−(R)−バリル)−2(R)−ヒドロキシ−シクロヘキシルアミン
塩化メチレン40mL中のトランス−2−アミノシクロヘキサノール1.5g、BOC−(RR)−バリン2.17g、DCC2.06gおよびN−メチルモルホリン1.01gの混合物を25℃で約24時間保持する。沈殿(尿素)が形成し、これを濾去する。得られた濾液を水で抽出し、乾燥し、溶媒を蒸発させ、得られた蒸発残差をシリカゲル上のクロマトグラフィーに付す。
H1NMR(D6DMSO, ジアステレオマー混合物):6.1,6.25(3×d,1H,CONH),5.1,5.2(2×b,1H,BOC−HN),3.85(m,1H,α−H−Val), 3.3, 3.65(2×m,NCH,OCH)。
塩化メチレン15mL中のN−(R)−(N−BOC−(R)−バリル)−2(R)−ヒドロキシ−シクロヘキシルアミン710mg、無水メタンスルホン酸393mgおよびN−メチルモルホリン236mgの混合物を約12時間25℃で攪拌する。得られた混合物を1N塩酸で抽出し、乾燥し、溶媒を蒸発させ、N−(R)−(N−BOC−(R)−バリル)−2(R)−メタンスルホニルオキシ−シクロヘキシルアミン685gを得る。
乾燥エタノール10mL中のN−(R)−(N−BOC−(R)−バリル)−2(R)−メタンスルホニルオキシ−シクロヘキシルアミン588mg、22−デスオキシ−22−プレウロムチリン−チオール591mgおよびナトリウム35mgの混合物を25℃で約24時間攪拌し、90℃で約2時間加熱する。得られた混合物から溶媒を蒸発させる。蒸発残差に酢酸エチルと水を添加し、形成した層を分離し、そして有機層をシリカゲル上のクロマトグラフィーに付す。14−O−[(N−(R)−(N−BOC−(R)−バリル)−(R)−アミノシクロヘキサン−2(S)−イル)スルファニル)−アセチル]ムチリンが得られ、これをエーテル性塩酸で処理する。
適切な出発物質、即ち、N−(R)−(N−BOC−(R)−バリル)−2(R)−メタンスルホニルオキシ−シクロヘキシルアミンの代わりにN−(R)−(N−BOC−(R)−バリル)−2(S)−メタンスルホニルオキシ−シクロヘキシルアミンを用いた以外は実施例2の工程C)に記載の通り調製する。
Claims (3)
- 塩の形態、または塩の形態と溶媒和物の形態、または溶媒和物の形態の請求項1または2に記載の化合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0017031.6A GB0017031D0 (en) | 2000-07-11 | 2000-07-11 | Antimicrobials |
GB0017031.6 | 2000-07-11 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2002509081A Division JP4255282B2 (ja) | 2000-07-11 | 2001-07-09 | 抗細菌活性を有するプレウロムチリン誘導体 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2009108088A JP2009108088A (ja) | 2009-05-21 |
JP5173763B2 true JP5173763B2 (ja) | 2013-04-03 |
Family
ID=9895454
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2002509081A Expired - Lifetime JP4255282B2 (ja) | 2000-07-11 | 2001-07-09 | 抗細菌活性を有するプレウロムチリン誘導体 |
JP2008300463A Expired - Lifetime JP5173763B2 (ja) | 2000-07-11 | 2008-11-26 | 抗細菌活性を有するプレウロムチリン誘導体 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2002509081A Expired - Lifetime JP4255282B2 (ja) | 2000-07-11 | 2001-07-09 | 抗細菌活性を有するプレウロムチリン誘導体 |
Country Status (29)
Country | Link |
---|---|
US (1) | US6753445B2 (ja) |
EP (1) | EP1305282B1 (ja) |
JP (2) | JP4255282B2 (ja) |
KR (1) | KR100893426B1 (ja) |
CN (1) | CN1308301C (ja) |
AR (1) | AR029590A1 (ja) |
AT (1) | ATE408596T1 (ja) |
AU (2) | AU7638901A (ja) |
BR (1) | BRPI0112452B8 (ja) |
CA (1) | CA2412932C (ja) |
CZ (1) | CZ200342A3 (ja) |
DE (1) | DE60135848D1 (ja) |
EC (1) | ECSP024400A (ja) |
ES (1) | ES2313969T3 (ja) |
GB (1) | GB0017031D0 (ja) |
HK (1) | HK1052683B (ja) |
HU (1) | HU229510B1 (ja) |
IL (2) | IL153839A0 (ja) |
MX (1) | MXPA02012828A (ja) |
NO (1) | NO329091B1 (ja) |
NZ (1) | NZ523415A (ja) |
PE (1) | PE20020144A1 (ja) |
PL (1) | PL209305B1 (ja) |
RU (1) | RU2003103101A (ja) |
SI (1) | SI1305282T1 (ja) |
SK (1) | SK292003A3 (ja) |
TW (1) | TWI311552B (ja) |
WO (1) | WO2002004414A1 (ja) |
ZA (1) | ZA200300280B (ja) |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0017031D0 (en) | 2000-07-11 | 2000-08-30 | Biochemie Gmbh | Antimicrobials |
GB0207495D0 (en) * | 2002-03-28 | 2002-05-08 | Biochemie Gmbh | Organic compounds |
GB0209262D0 (en) | 2002-04-23 | 2002-06-05 | Biochemie Gmbh | Organic compounds |
GB0513058D0 (en) * | 2005-06-27 | 2005-08-03 | Sandoz Ag | Organic compounds |
EP2298733B1 (en) * | 2005-06-27 | 2016-05-25 | Nabriva Therapeutics AG | Pleuromutilin derivatives containing a hydroxyamino- or acyloxyaminocycloalkyl group |
GB0515995D0 (en) | 2005-08-03 | 2005-09-07 | Sandoz Ag | Organic compounds |
EP1808431A1 (en) * | 2006-01-16 | 2007-07-18 | Nabriva Therapeutics Forschungs GmbH | Mutilin derivatives and their use as pharmaceutical |
EP1972618A1 (en) * | 2007-03-20 | 2008-09-24 | Nabriva Therapeutics AG | Pleuromutilin derivatives for the treatment of diseases mediated by microbes |
US8222407B2 (en) | 2007-05-24 | 2012-07-17 | Kyorin Pharmaceutical Co., Ltd. | Mutilin derivative having heterocyclic aromatic ring carboxylic acid structure in substituent at 14-position |
EP2159220A1 (en) * | 2008-09-02 | 2010-03-03 | Nabriva Therapeutics AG | Organic compounds |
CN101671367B (zh) * | 2008-09-12 | 2012-09-05 | 中国科学院上海药物研究所 | 截短侧耳素磷酸酯类化合物、其药物组合物及其制备方法和用途 |
WO2010056855A1 (en) * | 2008-11-13 | 2010-05-20 | Teva Pharmaceutical Industries Ltd. | Preparation of retapamulin via its pleuromutilin-thiol precursor |
EP2399904A1 (en) * | 2010-05-26 | 2011-12-28 | Nabriva Therapeutics AG | Process for the preparation of pleuromutilins |
CN103204787B (zh) * | 2012-01-17 | 2014-10-01 | 北京艾百诺科技有限公司 | 含有取代方酸的乙酸妙林酯及其应用 |
CN102924350B (zh) * | 2012-10-31 | 2014-04-09 | 中国农业科学院兰州畜牧与兽药研究所 | 截短侧耳素衍生物及其制备方法和应用 |
TWI762573B (zh) | 2017-02-10 | 2022-05-01 | 奧地利商納畢瓦治療有限責任公司 | 截短側耳素之純化 |
US11518740B2 (en) * | 2021-04-24 | 2022-12-06 | Shaanxi University Of Science And Technology | Pleuromutilin (phenylthio)acetic acid ester with anti-drug resistant bacteria activity and a method of preparing the same |
CN115850137B (zh) * | 2022-11-12 | 2024-04-12 | 中国农业科学院兰州畜牧与兽药研究所 | 一种截短侧耳素衍生化合物及其制备方法与应用 |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AT301753B (de) * | 1969-07-25 | 1972-09-25 | Biochemie Gmbh | Verfahren zur Herstellung neuer Pleuromutilin-Derivate |
BE789629A (fr) * | 1971-10-05 | 1973-04-03 | Sandoz Sa | Nouveaux derives de la pleuromutiline, leur preparation et leurapplication en therapeutique |
BE896512A (fr) * | 1982-04-28 | 1983-10-20 | Sandoz Ag | Nouveaux derives de la pleuromutiline, leur preparation et leur utilisation comme medicaments |
FR2526019A1 (fr) * | 1982-04-28 | 1983-11-04 | Sandoz Sa | Nouveaux derives de la pleuromutiline, leur preparation et leur utilisation comme medicaments |
DE3560511D1 (en) * | 1984-02-17 | 1987-10-01 | Sandoz Ag | Pleuromutilin derivatives, process for their preparation and their use |
HU208115B (en) * | 1989-10-03 | 1993-08-30 | Biochemie Gmbh | New process for producting pleuromutilin derivatives |
JP3054875B2 (ja) * | 1995-02-13 | 2000-06-19 | 株式会社小松製作所 | プラズマトーチ |
GB9614017D0 (en) * | 1996-07-04 | 1996-09-04 | Biochemie Gmbh | Organic compounds |
UY25225A1 (es) | 1997-10-29 | 2000-12-29 | Smithkline Beecham Plc | Derivados de pleuromutilina utiles como agentes antimicrobianos |
WO2000027790A1 (en) | 1998-11-11 | 2000-05-18 | Smithkline Beecham P.L.C. | Mutilin compounds |
GB0017031D0 (en) | 2000-07-11 | 2000-08-30 | Biochemie Gmbh | Antimicrobials |
-
2000
- 2000-07-11 GB GBGB0017031.6A patent/GB0017031D0/en not_active Ceased
-
2001
- 2001-07-09 AT AT01954024T patent/ATE408596T1/de active
- 2001-07-09 BR BRPI0112452A patent/BRPI0112452B8/pt not_active IP Right Cessation
- 2001-07-09 AU AU7638901A patent/AU7638901A/xx active Pending
- 2001-07-09 RU RU2003103101/04A patent/RU2003103101A/ru not_active Application Discontinuation
- 2001-07-09 CZ CZ200342A patent/CZ200342A3/cs unknown
- 2001-07-09 NZ NZ523415A patent/NZ523415A/en unknown
- 2001-07-09 SI SI200130883T patent/SI1305282T1/sl unknown
- 2001-07-09 SK SK29-2003A patent/SK292003A3/sk unknown
- 2001-07-09 AU AU2001276389A patent/AU2001276389B2/en not_active Ceased
- 2001-07-09 DE DE60135848T patent/DE60135848D1/de not_active Expired - Lifetime
- 2001-07-09 WO PCT/EP2001/007875 patent/WO2002004414A1/en active IP Right Grant
- 2001-07-09 CN CNB018125417A patent/CN1308301C/zh not_active Expired - Lifetime
- 2001-07-09 MX MXPA02012828A patent/MXPA02012828A/es unknown
- 2001-07-09 TW TW090116687A patent/TWI311552B/zh not_active IP Right Cessation
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