JP5613562B2 - 有機化合物 - Google Patents
有機化合物 Download PDFInfo
- Publication number
- JP5613562B2 JP5613562B2 JP2010515316A JP2010515316A JP5613562B2 JP 5613562 B2 JP5613562 B2 JP 5613562B2 JP 2010515316 A JP2010515316 A JP 2010515316A JP 2010515316 A JP2010515316 A JP 2010515316A JP 5613562 B2 JP5613562 B2 JP 5613562B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- acetyl
- amino
- mutilin
- phenylsulfanyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229940037649 staphylococcus haemolyticus Drugs 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- 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
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C07C323/23—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 nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/31—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 nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/32—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 nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
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- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
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- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
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- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
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- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D233/44—Nitrogen atoms not forming part of a nitro radical
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- C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
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- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/76—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members
- C07C2603/80—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings
- C07C2603/82—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings having three condensed rings with in total fourteen carbon atoms and having a having a [5.4.3.0(1,8)] ring structure, e.g. pleuromutiline
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Description
Xは酸素またはイオウであり,
Yは,ピペコリン酸の残基またはアミノ酸の残基,好ましくは天然に生ずるアミノ酸の残基である]
の化合物が提供される。アミノ酸はD型で存在してもL型で存在してもよく,そのカルボン酸基のCO基を介して窒素に結合している。
14−O−[(3−{[((R)−ピペリジン−2−カルボニル)−アミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((R)−2−アミノ−3−メチル)−ブチリルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((2R,4R)−4−ヒドロキシ−ピロリジン−2−カルボニル)−アミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(S)−2−アミノ−3−(3H−イミダゾール−4−イル)−プロピルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(R)−2−アミノ−プロピオニルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[2−(2−アミノ−アセチルアミノ)−アセチルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((R)−ピロリジン−2−カルボニル)−アミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(R)−2−アミノ−3−(4−ヒドロキシ−フェニル)−プロピオニルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[2−アミノ−アセチルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(S)−2−((S)−2−アミノ−プロピオニルアミノ)−プロピオニルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((S)−2−アミノ−3−メチル)−ブチリルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{(2−[((R)−ピロリジン−2−カルボニル)−アミノ]−アセチルアミノ)−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((2R,3S)−2−アミノ−3−ヒドロキシ)−ブチリルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(R)−2,6−ジアミノ−ヘキサノイルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(R)−2−アミノ−3−(1H−インドール−3−イル)−プロピルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(R)−2−アミノ−3−フェニル−プロピオニルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(R)−2−アミノ−3−カルバモイル−プロピオニルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(S)−2,6−ジアミノ−ヘキサノイルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(S)−2((S)−2−アミノ−4−メチル−ペンタノイルアミノ)−4−メチル−ペンタノイルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((R)−2−アミノ−3−ヒドロキシ)−プロピオニルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(S)−2−アミノ−プロピルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(R)−2−アミノ−4−カルバモイル−ブチリルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((S)−1−(2−アミノ−アセチル)−ピロリジン−2−カルボニル)−アミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(R)−2−アミノ−3−(3H−イミダゾール−4−イル)−プロピオニルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((2S,4R)−4−ヒドロキシ−ピロリジン−2−カルボニル)−アミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((S)−ピペリジン−2−カルボニル)−アミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((S)−ピロリジン−2−カルボニル)−アミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(S)−2−アミノ−3−(4−ヒドロキシ−フェニル)−プロピオニルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(S)−2−アミノ−3−フェニル−プロピオニルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((S)−2−アミノ−3−ヒドロキシ)−プロピオニルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((2S,3R)−2−アミノ−3−ヒドロキシ)−ブチリルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((R)−2−アミノ−3−ヒドロキシ)−プロピオニルアミノ]−メチル}−フェノキシ)−アセチル]−ムチリン,
14−O−[(3−{[((R)−ピロリジン−2−カルボニル)−アミノ]−メチル}−フェノキシ)−アセチル]−ムチリン,
14−O−[(3−{[(S)−2−アミノ−3−(4−ヒドロキシ−フェニル)−プロピオニルアミノ]−メチル}−フェノキシ)−アセチル]−ムチリン,
14−O−[(3−{[(R)−2−アミノ−3−(4−ヒドロキシ−フェニル)−プロピオニルアミノ]−メチル}−フェノキシ)−アセチル]−ムチリン,
14−O−[(3−{[((R)−ピロリジン−2−カルボニル)−アミノ]−メチル}−フェノキシ)−アセチル]−19,20−ジヒドロムチリン,
14−O−[(3−{[((R)−2−アミノ−3−ヒドロキシ)−プロピオニルアミノ]−メチル}−フェノキシ)−アセチル]−19,20−ジヒドロムチリン,
14−O−[(3−{[(S)−2−アミノ−3−(4−ヒドロキシ−フェニル)−プロピオニルアミノ]−メチル}−フェノキシ)−アセチル]−19,20−ジヒドロムチリン,
からなる群より選択される化合物が提供される。
−細菌,例えば,ブドウ球菌,連鎖球菌,腸球菌から選択される細菌により媒介される疾病;
−ヘリコバクターにより媒介される疾病
−レジオネラ属,ナイセリア科,モラクセラ属,パスツレラ科,コリネバクテリウム属により媒介される疾病
−Mycobacterium tuberculosisにより媒介される疾病
−例えば,マイコプラスマ科,クラミジア科および絶対嫌気性菌により媒介される疾病
−にきびの治療,
および/または
−細菌のコロニーをもつ個体の脱コロニー化
が挙げられる。
BOC tert−ブトキシ−カルボニル
DCC N,N’−ジシクロヘキシルカルボジイミド
DMAP 4−ジメチルアミノピリジン
DMF N,N−ジメチルホルムアミド
EtOAc 酢酸エチル
h 時間
MeOH メタノール
rt 室温
THF テトラヒドロフラン
実施例1:14−O−[(3−{[((R)−ピペリジン−2−カルボニル)−アミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン
工程1:プレウロムチリントシレート
1400mLのメチルエチルケトン中の18.63g(49.2mmol)のプレウロムチリンおよび9.39g(49.2mmol)の塩化トルエンスルホン酸の溶液に,300mLのメチルエチルケトン中の4.98g(49.2mmol)のトリエチルアミンの溶液を周囲温度でゆっくり加えた。反応液を周囲温度で24時間撹拌し,形成した沈殿物を濾別し,2800mLの水を溶液に加えた。溶液を酢酸エチルで3回抽出し,有機相をNa2SO4で乾燥し,減圧下で蒸発乾固させた。粗生成物をさらに精製することなく次の工程で用いた。
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.49 (d, 3H, J = 7Hz, CH3 -16); 0.8 (d, 3H, J = 7Hz, CH3 - 17); 1.02 (s, 3H, CH3 - 18); 1.29 (s, 3H, CH3 - 15); 2.38 (bs, 1H, H - 4); AB-システム (υA = 4.75, υB = 4.62, J = 16Hz, CH2 - 22); 5,00 (m, 2H, H - 20); 5.52 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 および 18Hz, H - 19); 7.46 (d, 2H, J = 8Hz, H - 24); 7.79 (d, 2H, J = 8Hz, H - 23)
90mLの純粋エタノール中の1.96g(14mmol)の(3−メルカプト−フェニル)−メタノール[3−メルカプト安息香酸からChemistry Express,Vol7,No.11,pp.865−868(1992)にしたがって製造]に,322mg(14mmol)のナトリウムを加えた。反応液を周囲温度で30分間撹拌した後,130mLのメチルエチルケトン中の7.45g(14mmol)のプレウロムチリントシレートの溶液を加え,反応液を周囲温度で16時間撹拌した。反応混合物を減圧下で蒸発乾固させ,酢酸エチルに溶解し,水で3回抽出した。有機相をNa2SO4で乾燥し,減圧下で蒸発乾固させ,残渣をジクロロメタン/メタノール100:1.5を移動相として用いてシリカゲルでクロマトグラフィーを行った。得られた物質は結晶であった(Fp.139−141℃)。
1H-NMR (500 MHz, CDCl3, δ, ppm, 特徴的シグナル): 0.68 (d, 3H, J = 7Hz, CH3 -16); 0.88 (d, 3H, J = 7Hz, CH3 - 17); 1.12 (s, 3H, CH3 - 18); 1.42 (s, 3H, CH3 - 15); 2.06 (bs, 1H, H - 4); 3.32 (t, 1H, J = 6Hz, H - 11); 3.59 (s, 2H, CH2 - 22); 4.66 (s, 2H, CH2 - 27); 5.15 および 5.30 (2xm, 2H, H - 20); 5.72 (d, 1H, J = 8Hz, H - 14); 6.41 (dd, 1H, J = 11 および 17Hz, H - 19); 7.19 および 7.28 (2xm, 3H, H - 24,25 および 26); 7.38 (s, 1H, H - 23)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7 Hz, CH3-16); 0.79 (d, 3H, J = 7 Hz, CH3 - 17); 0.98 (s, 3H, CH3 - 18); 1.30 (s, 3H, CH3 - 15); 2.35 (bs, 1H, H - 4); 3.37 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.81, υB = 3.74, J = 16Hz, CH2 - 22); 4.44 (d, 2H, J = 6Hz, CH2 - 27); 4.95 (m, 2H, H - 20); 5.49 (d, 1H, J = 8Hz, H - 14); 6.04 (m, 1H, H - 19), 7.10 - 7.27 (4xm, 4H, H - 23, 24, 25 および 26)
250mLの乾燥THF中の6g(12mmol)の14−O−[(3−ヒドロキシメチル−フェニルスルファニル)−アセチル]−ムチリンに,2.17mL(20mmol)のN−メチルモルホリンおよび3.06g(18mmol)の無水メタンスルホン酸を,触媒量の4−ジメチルアミノピリジンとともに加えた。反応混合物を周囲温度で2時間保持した。水を加えた後,混合物を酢酸エチルで抽出し,有機相を水およびブラインで数回洗浄した。有機相を無水硫酸ナトリウムで乾燥し,減圧下で濃縮した。有機相を無水硫酸ナトリウムで乾燥し,減圧下で濃縮し,ジクロロメタン/メタノール100:1を移動相として用いてシリカゲルでクロマトグラフィーを行った。
1H-NMR (400 MHz, CDCl3, δ, ppm, 特徴的シグナル): 0.68 (d, 3H, J = 7Hz, CH3 - 16); 0.87 (d, 3H, J = 7Hz, CH3 - 17); 1.12 (s, 3H, CH3 - 18); 1.40 (s, 3H, CH3 - 15); 2.08 (bs, 1H, H - 4); 2.96 (s, 3H, CH3 - 28); 3.34 (d, 1H, J = 6Hz, H - 11); 3.59 (s, 2H, CH2 - 22); 5.15 および 5.30 (2xm, 2H, H - 20); 5.72 (d, 1H, J = 8Hz, H - 14); 6.40 (dd, 1H, J = 11 および 17Hz, H - 19); 7.23 - 7.43 (m, 4H, H - 23,24,25 および 26)
10mLのDMF中の1g(1.73mmol)の14−O−[(3−メタンスルホニルオキシメチル−フェニルスルファニル)−アセチル]−ムチリンに,449mg(6.9mmol)のNaN3を加えた。得られた懸濁液を50℃で4.5時間撹拌し,周囲温度で一晩保持した。水および酢酸エチルを加え,有機相を水およびブラインで数回洗浄した。減圧下で濃縮した後,残渣をシリカでCH2Cl2/MeOH100:1を移動相として用いてクロマトグラフィーを行った。
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 1.00 (s, 3H, CH3 - 18); 1.30 (s, 3H, CH3 - 15); 2.34 (bs, 1H, H - 4); 3.37 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.85, υB = 3.78, J = 16Hz, CH2 - 22); 4.39 (s, 2H, CH2 - 27); 4.95 (m, 2H, H - 20); 5.49 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 および 18 Hz, H - 19); 7.18 (m, 1H, H - 25); 7.32 (m, 2H, H - 24 および 26); 7.34 (bs, 1H, H - 23)
1g(1.9mmol)の14−O−[(3−アジドメチル)−フェニルスルファニル−アセチル]−ムチリンを30mLのTHFに溶解し,900mgのリンドラー触媒を加え,反応混合物を6時間水素化した。反応混合物をセライトを通して濾過し,減圧下で濃縮し,残渣をシリカでCH2Cl2/MeOH10:1を移動相として用いてクロマトグラフィーを行った。塩酸塩は,125mgの14−O−[(3−アミノメチル)−フェニルスルファニル−アセチル]−ムチリンを3mLのCH2Cl2に溶解し,2mLのHCl−飽和Et2Oを加えることにより製造した。45分後,反応液を減圧下で蒸発乾固させた。
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.57 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 1.00 (s, 3H, CH3 - 18), 1.31 (s, 3H, CH3 - 15); 2.38 (bs, 1H, H - 4); 3.38 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.89, υB = 3.82, J = 16Hz, CH2 - 22); 3.95 (s, 2H, CH2 - 27); 4.98 (m, 2H, H - 20); 5.51 (d, 1H, J = 8Hz, H - 14); 6.05 (dd, 1H, J = 11 および 18Hz, H - 19); 7,30 (m, 3H, H - 24,25 および 26); 7,48 (s, 1H, H - 23)
2.5mLのTHF中の200mg(0.4mmol)の14−O−[(3−アミノメチル)−フェニルスルファニル−アセチル]−ムチリンに,180mg(0.6mmol)のBOC−D−ホモプロリンを124mg(0.6mmol)のDCCおよび49mg(0.4mmol)のDMAPとともに加えた。反応液を周囲温度で3時間撹拌し,形成された沈殿物を濾別し,濾液を減圧下で蒸発乾固させた。残渣をシリカでジクロロメタン/メタノール100:2を移動相として用いてクロマトグラフィーを行った。
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18), 1.31 (s, 3H, CH3 - 15); 1.34 (bs, 9H, CH3 - 33); 2.36 (bs, 1H, H - 4); 3.03 および 4.56 (2xbm, 2H, CH2 - 32); 3.38 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.81, υB = 3.74, J = 16Hz, CH2 - 22); 3.81 (bm, 1H, H - 28); 4.23 (bm, 2H, CH2 - 27); 4.98 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (m, 1H, H - 19); 7,05 (d, 1H, J = 7Hz, H - 23); 7.20 (m, 3H, H - 24,25 および 26)
208mgの14−O−[(3−{[((R)−BOC−ピペリジン−2−カルボニル)−アミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリンを3mLのジクロロメタンに溶解し,4mLのHCl−飽和Et2Oを加えた。反応液を周囲温度で4時間保持し,減圧下で蒸発乾固させた。
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.58 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18), 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 2.90 および 3.21 (2xm, 2H, CH2 - 32); 3.38 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.84, υB = 3.77, J = 16Hz, CH2 - 22); 3.78 (bm, 1H, H - 28); 4.29 (d, 2H, J = 6Hz, CH2- 27); 4.96 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 および 18Hz, H - 19); 7,07 (m, 1H, H - 23); 7.22 (m, 3H, H - 24,25 および 26)
実施例2:14−O−[(3−{[((R)−2−アミノ−3−メチル)−ブチリルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン塩酸塩
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.91 および 0.92 (2xd, 6H, J = 7Hz, CH3 - 30); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 3.38 (t, 1H, J = 6Hz, H - 11); 3.58 (bs, 1H, H - 28); AB-システム (υA = 3.84, υB = 3.77, J = 16Hz, CH2 - 22); ABX-システム (υA = 4.34, υB = 4.27, JAB = 15Hz, JAX = 6Hz, JBX = 6Hz, CH2- 27); 4.95 (m, 2H, H - 20); 5.51 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 および 18Hz, H - 19); 7.10 (d, 1H, J = 7Hz, H - 23); 7.24 (m, 3H, H - 24,25 および 26)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.57 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); ABX-システム (υA = 3.20, υB = 3.12, JAB = 12Hz, JAX = 5Hz, JBX= 2Hz, CH2 - 31); 3.38 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.85, υB = 3.77, J = 16Hz, CH2 - 22); 4.20 - 4.38 (3xm, 4H, CH2 - 27, H - 28 および 30); 4.96 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 および 18Hz, H - 19); 7.08 (m, 1H, H - 23); 7.22 (m, 3H, H - 24,25 および 26)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); ABX-システム (υA = 3.28, υB = 3.18, JAB = 16Hz, JAX = 7Hz, JBX= 7Hz, CH2 - 29); 3.37 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.85, υB = 3.78, J = 16Hz, CH2 - 22); 4.25 (m, 3H, CH2 - 27 および H - 28); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 および 18Hz, H - 19); 6.98 (m, 1H, H - 23); 7.21 (m, 3H, H - 24,25 および 26); 7.45 (s, 1H, H - 30); 9.02 (s, 1H, H - 31)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 1.37 (d, 3H, J = 7Hz, CH3 - 29); 2.36 (bs, 1H, H - 4); 3.38 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.84, υB = 3.77, J = 16Hz, CH2 - 22); 3.84 (bm, 1H, H - 28); 4.28 (d, 2H, J = 6Hz, CH2- 27); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 および 18Hz, H - 19); 7.07 (d, 1H, J = 7Hz, H - 23); 7.21 (m, 3H, H - 24,25 および 26)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 3.37 (t, 1H, J = 6Hz, H - 11); 3.58 (m, 2H, CH2 - 29); AB-システム (υA = 3.84, υB = 3.77, J = 16Hz, CH2 - 22); 3.84 (m, 2H, CH2 - 28); 4.23 (d, 2H, J = 6Hz, CH2 - 27); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.03 (m, 1H, H - 19); 7.07 (d, 1H, J = 7Hz, H - 23); 7.20 (m, 3H, H - 24,25 および 26)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 3.19 (bm, 2H, CH2 - 31); 3.37 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.84, υB = 3.77, J = 16Hz, CH2 - 22); 4.19 (bm, 1H, H - 28); 4.30 (m, 2H, CH2- 27); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (m, 1H, H - 19); 7.08 (m, 1H, H - 23); 7.23 (m, 3H, H - 24,25 および 26)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); ABX-システム (υA = 2.94, υB = 2.88, JAB = 15Hz, JAX = 7Hz, JBX= 7Hz, CH2 - 29); 3.37 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.84, υB = 3.77, J = 16Hz, CH2 - 22); 3.92 (t, 1H, J = 7Hz, H - 28); ABX-システム (υA = 4.27, υB = 4.20, JAB = 15Hz, JAX = 6Hz, JBX = 6Hz, CH2- 27); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 および 18Hz, H - 19); 6.68 (d, 2H, J = 8Hz, H - 31); 6.86 (m, 1H, H - 23); 6.99 (d, 2H, J = 8Hz, H - 30); 7.22 (m, 3H, H - 24,25 および 26)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.57 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 3.38 (t, 1H, J = 6Hz, H - 11); 3.59 (s, 2H, CH2 - 28); AB-システム (υA = 3.85, υB = 3.78, J = 16Hz, CH2 - 22); 4.29 (d, 2H, J = 6Hz, CH2 - 27); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 および 18Hz, H - 19); 7.11 (m, 1H, H - 23); 7.24 (m, 3H, H - 24,25 および 26)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.26 および 1.33 (2xd, 6H, J = 7Hz, CH3 - 29 および 31); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 3.37 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.83, υB = 3.76, J = 16Hz, CH2 - 22); 3.84 (m, 1H, H - 30); 4.22 (m, 2H, CH2- 27); 4.35 (m, 1H, H - 28); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.03 (m, 1H, H - 19); 7.04 (d, 1H, J = 7Hz, H - 23); 7.21 (m, 3H, H - 24,25 および 26)
1H-NMR (500 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.91 および 0.92 (2xd, 6H, J = 7Hz, CH3 - 30); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 3.37 (t, 1H, J = 6Hz, H - 11); 3.60 (m, 1H, H - 28); AB-システム (υA = 3.84, υB = 3.77, J = 16Hz, CH2 - 22); ABX-システム (υA = 4.34, υB = 4.25, JAB = 15Hz, JAX = 6Hz, JBX = 6Hz, CH2- 27); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 および 18Hz, H - 19); 7.12 (d, 1H, J = 7Hz, H - 23); 7.24 (m, 3H, H - 24,25 および 26)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.58 (d, 3H, J = 7Hz, CH3 - 16); 0.81 (d, 3H, J = 7Hz, CH3 - 17); 1.01 (s, 3H, CH3 - 18); 1.33 (s, 3H, CH3 - 15); 2.38 (bs, 1H, H - 4); 3.19 (m, 2H, CH2 - 32); 3.39 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.89, υB = 3.79, J = 16Hz, CH2 - 22); 3.85 (m, 2H, CH2 - 28); 4.24 (m, 3H, CH2 - 27 および H - 29); 4.97 (m, 2H, H - 20); 5.52 (d, 1H, J = 8Hz, H - 14); 6.05 (m, 1H, H - 19); 7.08 (m, 1H, H - 23); 7.23 (m, 3H, H - 24,25 および 26)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.11 (d, 3H, J = 6Hz, CH3 - 30); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 3.38 (t, 1H, J = 6Hz, H - 11); 3.58 (d, 1H, J = 6Hz, H - 28); AB-システム (υA = 3.84, υB = 3.78, J = 16Hz, CH2 - 22); 3.91 (m, 1H, H - 29); 4.30 (m, 2H, CH2 - 27); 4.95 (m, 2H, H - 20); 5.51 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 および 18Hz, H - 19); 7.12 (d, 1H, J = 7Hz, H - 23); 7.25 (m, 3H, H - 24,25 および 26)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 2.72 (m, 2H, CH2 - 32); 3.38 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.86, υB = 3.78, J = 16Hz, CH2 - 22); 3.79 (m, 1H, H - 28); ABX-システム (υA = 4.33, υB = 4.25, JAB = 15Hz, JAX = 6Hz, JBX = 6Hz, CH2- 27); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.05 (dd, 1H, J = 11 および 18Hz, H - 19); 7.11 (d, 1H, J = 7Hz, H - 23); 7.25 (m, 3H, H - 24,25 および 26)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.55 (d, 3H, J = 7Hz, CH3 - 16); 0.78 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.35 (bs, 1H, H - 4); ABX-システム (υA = 3.23, υB = 3.12, JAB = 15Hz, JAX = 6Hz, JBX= 8Hz, CH2 - 29); 3.38 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.83, υB = 3.76, J = 16Hz, CH2 - 22); 4.00 (t, 1H, J = 7Hz, H - 28); 4.23 (m, 2H, CH2- 27); 4.94 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 および 18Hz, H - 19); 6.89 (m, 1H, H - 23); 6.99 および 7.08 (2xt, 2H, J = 7Hz, H - 32 および 33); 7.18 (m, 4H, H - 24,25,26 および 30); 7.36 および 7.65 (2xd, 2H, J = 8Hz, H - 31 および 34)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 3.03 (m, 2H, CH2 - 29); 3.37 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.83, υB = 3.76, J = 16Hz, CH2 - 22); 4.01 (m, 1H, H - 28); ABX-システム (υA = 4.26, υB = 4.17, JAB = 15Hz, JAX = 6Hz, JBX = 5Hz, CH2- 27); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 および 18Hz, H - 19); 6.86 (m, 1H, H - 23); 7.18 および 7.27 (2xm, 8H, H - 24,25,26,30,31 および 32)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.57 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); ABX-システム (υA = 2.71, υB = 2.63, JAB = 17Hz, JAX = 5Hz, JBX= 8Hz, CH2 - 29); 3.38 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.85, υB = 3.78, J = 16Hz, CH2 - 22); 4.07 (dd, 1H, J = 5 および 8Hz, H - 28); 4.28 (m, 2H, CH2- 27); 4.95 (m, 2H, H - 20); 5.51 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 および 18Hz, H - 19); 7.09 (d, 1H, J = 7Hz, H - 23); 7.22 (m, 3H, H - 24,25 および 26)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 2.73 (t, 2H, J = 8Hz, CH2 - 32); 3.38 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.85, υB = 3.78, J = 16Hz, CH2 - 22); 3.80 (m, 1H, H - 28); ABX-システム (υA = 4.33, υB = 4.25, JAB = 15Hz, JAX = 6Hz, JBX = 6Hz, CH2- 27); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.05 (dd, 1H, J = 11 および 18Hz, H - 19); 7.11 (d, 1H, J = 7Hz, H - 23); 7.23 (m, 3H, H - 24,25 および 26)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.82 - 0.88 (4xd, 12H, J = 7Hz, CH3 - 31 および 35); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 3.39 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.82, υB = 3.75, J = 15Hz, CH2 - 22); 3.77 (m, 1H, H - 32); 4.20 (m, 2H, CH2- 27); 4.38 (m, 1H, H - 28); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.05 (dd, 1H, J = 11 および 18Hz, H - 19); 7.00 (m, 1H, H - 23); 7.22 (m, 3H, H - 24,25 および 26)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 3.38 (t, 1H, J = 6Hz, H - 11); 3.75 (m, 2H, CH2 - 29); 3.84 (m, 1H, H - 28); AB-システム (υA = 3.84, υB = 3.78, J = 16Hz, CH2 - 22); 4.29 (m, 2H, CH2- 27); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (m, 1H, H - 19); 7.10 (d, 1H, J = 7Hz, H - 23); 7.22 (m, 3H, H - 24,25 および 26)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 1.37 (d, 3H, J = 7Hz, CH3 - 29); 2.36 (bs, 1H, H - 4); 3.38 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.84, υB = 3.77, J = 16Hz, CH2 - 22); 3.86 (m, 1H, H - 28); 4.28 (d, 2H, J = 6Hz, CH2- 27); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 および 18Hz, H - 19); 7.08 (d, 1H, J = 7Hz, H - 23); 7.22 (m, 3H, H - 24,25 および 26)
1H-NMR (500 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 3.38 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.84, υB = 3.78, J = 16Hz, CH2 - 22); 3.82 (m, 1H, H - 28); ABX-システム (υA = 4.35, υB = 4.23, JAB = 15Hz, JAX = 6Hz, JBX = 5Hz, CH2- 27); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 および 18Hz, H - 19); 7.11 (m, 1H, J = 7Hz, H - 23); 7.24 (m, 3H, H - 24,25 および 26)
1H-NMR (500 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 3.38 (t, 1H, J = 6Hz, H - 11); 3.45 および 3.56 (2xm, 2H, CH2 - 30); AB-システム (υA = 3.83, υB = 3.76, J = 16Hz, CH2 - 22); 3.78 (m, 2H, CH2 - 32); ABX-システム (υA = 4.26, υB = 4.16, JAB = 15Hz, JAX = 6Hz, JBX = 6Hz, CH2- 27); 4.36 (m, 1H, H - 28); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 および 17Hz, H - 19); 7.07 (d, 1H, J = 7Hz, H - 23); 7.21 (m, 3H, H - 24,25 および 26)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); ABX-システム (υA = 3.27, υB = 3.19, JAB = 17Hz, JAX = 6Hz, JBX= 7Hz, CH2 - 29); 3.37 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.85, υB = 3.78, J = 16Hz, CH2 - 22); 4.24 (m, 3H, CH2 - 27 および H - 28); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 および 18Hz, H - 19); 6.98 (m, 1H, H - 23); 7.22 (m, 3H, H - 24,25 および 26); 7.44 (s, 1H, H - 30); 9.00 (s, 1H, H - 31)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); AB-システム (υA = 3.38, υB = 3.07, J = 12Hz, CH2 - 31); 3.38 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.85, υB = 3.78, J = 16Hz, CH2 - 22); 4.27 - 4.46 (3xm, 4H, CH2 - 27, H - 28 および 30); 4.96 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (m, 1H, H - 19); 7.08 (d, 1H, J = 7Hz, H - 23); 7.23 (m, 3H, H - 24,25 および 26)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18), 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 2.89 および 3.19 (2xm, 2H, CH2 - 32); 3.38 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.85, υB = 3.78, J = 16Hz, CH2 - 22); 3.78 (bm, 1H, H - 28); 4.29 (d, 2H, J = 6Hz, CH2- 27); 4.96 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 および 18Hz, H - 19); 7,08 (m, 1H, H - 23); 7.23 (m, 3H, H - 24,25 および 26)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 3.29 (m, 2H, CH2 - 31); 3.37 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.84, υB = 3.76, J = 16Hz, CH2 - 22); 4.19 (m, 1H, H - 28); 4.30 (m, 2H, CH2- 27); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (m, 1H, H - 19); 7.09 (d, 1H, J = 7Hz, H - 23); 7.24 (m, 3H, H - 24,25 および 26)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.78 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); ABX-システム (υA = 2.95, υB = 2.88, JAB = 15Hz, JAX = 7Hz, JBX= 7Hz, CH2 - 29); 3.37 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.83, υB = 3.76, J = 16Hz, CH2 - 22); 3.92 (t, 1H, J = 7Hz, H - 28); ABX-システム (υA = 4.27, υB = 4.19, JAB = 15Hz, JAX = 6Hz, JBX = 6Hz, CH2- 27); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 および 18Hz, H - 19); 6.68 (d, 2H, J = 8Hz, H - 31); 6.85 (m, 1H, H - 23); 6.99 (d, 2H, J = 8Hz, H - 30); 7.22 (m, 3H, H - 24,25 および 26)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 3.03 (m, 2H, CH2 - 29); 3.37 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.83, υB = 3.77, J = 16Hz, CH2 - 22); 4.00 (t, 1H, J = 7Hz, H - 28); ABX-システム (υA = 4.27, υB = 4.17, JAB = 15Hz, JAX = 6Hz, JBX = 6Hz, CH2- 27); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (dd, 1H, J = 11 および 18Hz, H - 19); 6.86, (m, 1H, H - 23); 7.17 および 7.27 (2xm, 8H, H - 24,25,26,30,31 および 32)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 3.38 (t, 1H, J = 6Hz, H - 11); 3.73 (m, 3H, CH2 - 29); 3.84 (m, 1H, H - 28); AB-システム (υA = 3.84, υB = 3.77, J = 16Hz, CH2 - 22); 4.29 (m, 2H, CH2- 27); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (m, 1H, H - 19); 7.10 (d, 1H, J = 7Hz, H - 23); 7.22 (m, 3H, H - 24,25 および 26)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.99 (s, 3H, CH3 - 18); 1.13 (d, 3H, J = 6Hz, CH3 - 30); 1.31 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 3.38 (t, 1H, J = 6Hz, H - 11); 3.58 (d, 1H, J = 6Hz, H - 28); AB-システム (υA = 3.84, υB = 3.77, J = 16Hz, CH2 - 22); 3.89 (m, 1H, H - 29); 4.29 (m, 2H, CH2 - 27); 4.95 (m, 2H, H - 20); 5.50 (d, 1H, J = 8Hz, H - 14); 6.04 (m, 1H, H - 19); 7.12 (bd, 1H, J = 7Hz, H - 23); 7.25 (m, 3H, H - 24,25 および 26)
工程1:14−O−[3−ヒドロキシメチル−フェノキシアセチル]−ムチリン
150mLのDMF中の1.42g(56.4mmol)の水素化ナトリウムに,80mLのDMF中の7g(56.4mmol)の3−ヒドロキシメチル−フェノールを室温で加えた。反応液を30℃で30分間撹拌した後,130mLのアセトン中の30g(56.4mmol)のプレウロムチリントシレートの溶液を加え,反応液を周囲温度で2時間撹拌した。反応混合物を減圧下で蒸発乾固させ,酢酸エチルに溶解し,水で3回抽出した。有機相をNa2SO4で乾燥し,減圧下で蒸発乾固させ,残渣をジクロロメタン/メタノール100:2を移動相として用いてシリカゲルでクロマトグラフィーを行った。
400mLの乾燥THF中の23g(47.5mmol)の14−O−[3−ヒドロキシメチル−フェノキシアセチル]−ムチリンおよび8.88mL(80.8mmol)のN−メチルモルホリンおよび触媒量の4−ジメチルアミノピリジンに,80mLの乾燥THF中の14.42g(82.8mmol)の無水メタンスルホン酸を+4℃で加えた。反応混合物を周囲温度で1時間撹拌した。水を加えた後,混合物を酢酸エチルで抽出し,次に有機相を水およびブラインで数回洗浄した。有機相を無水硫酸ナトリウムで乾燥し,減圧下で濃縮し,シリカゲルでジクロロメタン/メタノール100:1を移動相としてクロマトグラフィーを行った。
1H-NMR (400 MHz, DMSO, δ, ppm, 特徴的シグナル): 0.64 (d, 3H, J = 7Hz, CH3- 16); 0.81 (d, 3H, J = 7Hz, CH3 - 17); 1.04 (s, 3H, CH3- 18); 1.34 (s, 3H, CH3 - 15); 2.40 (bs, 1H, H - 4); 3.20 (s, 3H, CH3- 28); 3.39 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 4.76, υB = 4.68, J = 16Hz, CH2 - 22); 5.01 および 5.07 (2xdd, 2H, J = 2 および 11Hz; J = 2 および 18Hz, H - 20); 5.60 (d, 1H, J = 8Hz, H - 14); 6.11 (dd, 1H, J = 11 および 17Hz, H - 19); 6.92 (dd, 1H, J = 2 および 8Hz, H - 26); 6.98 (d, 1H, J = 2Hz, H - 23);7.03 (d, 1H, J = 8Hz, H - 24); 7.31 (t, 1H, J = 8Hz, H - 25)
80mLのDMF中の8.14g(14.5mmol)の14−O−[(3−メタンスルホニルオキシメチル−フェノキシ)−アセチル]−ムチリンに,3.77g(58mmol)のNaN3を加えた。得られた懸濁液を50℃で4.5時間撹拌し,周囲温度で一晩保持した。水および酢酸エチルを加え,有機相を水およびブラインで数回洗浄した。減圧下で濃縮した後,残渣をシリカでCH2Cl2/MeOH100:1を移動相として用いてクロマトグラフィーを行った。
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.64 (d, 3H, J = 7Hz, CH3 - 16); 0.81 (d, 3H, J = 7Hz, CH3 - 17); 1.04 (s, 3H, CH3 - 18); 1.33 (s, 3H, CH3 - 15); 2.41 (bs, 1H, H - 4); 3.41 (t, 1H, J = 6Hz, H - 11); 4.38 (m, 2H, CH2 - 27); AB-システム (υA = 4.74, υB = 4.68, J = 17Hz, CH2 - 22); 5.03 (m, 2H, H - 20); 5.60 (d, 1H, J = 8Hz, H - 14); 6.11 (dd, 1H, J = 11 および 18 Hz, H - 19); 6.88 (dd, 1H, J = 2 および 8Hz, H - 26); 6.90 (bs, 1H, H - 23); 6.95 (d, 1H, J = 8Hz, H - 24); 7.29 (t, 1H, J = 8Hz, H - 25)
5.6g(11mmol)の14−O−[(3−アジドメチル−フェノキシ)−アセチル]−ムチリンを170mLのTHFに溶解し,5.1gのリンドラー触媒を加え,反応混合物を30分間水素化した。反応混合物をセライトを通して濾過し,減圧下で濃縮し,残渣をCH2Cl2/MeOH10:1を移動相として用いてシリカでクロマトグラフィーを行った。
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.64 (d, 3H, J = 7Hz, CH3 - 16); 0.81 (d, 3H, J = 7Hz, CH3 - 17); 1.04 (s, 3H, CH3 - 18), 1.34 (s, 3H, CH3 - 15); 2.40 (bs, 1H, H - 4); 3.42 (t, 1H, J = 6Hz, H - 11); 3.64 (s, 2H, CH2 - 27); AB-システム (υA = 4.69, υB = 4.62, J = 17Hz, CH2 - 22); 5.01 および 5.07 (2xdd, 2H, J = 2 および 11Hz; J = 2 および 18Hz, H - 20); 5.60 (d, 1H, J = 8Hz, H - 14); 6.11 (dd, 1H, J = 11 および 18Hz, H - 19); 6.70 (dd, 1H, J = 2 および 8Hz; H - 26); 6.86 (d, 1H, J = 2Hz, H - 23); 6.89 (d, 1H, J = 8Hz, H - 24); 7.16 (t, 1H, J = 8Hz, H - 25)
6mLのTHF中の300mg(0.62mmol)の14−O−[(3−アミノメチル−フェノキシ)−アセチル]−ムチリンに,207mg(0.96mmol)のBOC−D−プロリンを198mg(0.96mmol)のDCCおよび75mg(0.62mmol)のDMAPとともに加えた。反応液を周囲温度で3時間撹拌し,形成した沈殿物を濾別し,濾液を減圧下で蒸発乾固させた。残渣をジクロロメタン/メタノール100:4を移動相として用いてシリカでクロマトグラフィーを行った。
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.64 (d, 3H, J = 7Hz, CH3 - 16); 0.81 (d, 3H, J = 7Hz, CH3 - 17); 1.05 (s, 3H, CH3 - 18); 1.34 (s, 3H, CH3 - 15); 1.37 (s, 9H, CH3 - 30); 2.40 (bs, 1H, H - 4); 3.41 (t, 1H, J = 6Hz, H - 11); 3.56 (m, 2H, CH2 - 29); 3.98 (m, 1H, H - 28); ABX-システム (υA = 4.26, υB = 4.19, JAB = 16Hz, JAX = 6Hz, JBX = 6Hz, CH2- 27); (AB-システム (υA = 4.68, υB = 4.64, J = 17Hz, CH2 - 22); 5.01 および 5.07 (2xdd, 2H, J = 2 および 11Hz; J = 2 および 18Hz, H - 20); 5.61 (d, 1H, J = 8Hz, H - 14); 6.12 (dd, 1H, J = 11 および 18 Hz, H - 19); 6.72 (dd, 1H, J = 2 および 8Hz, H - 26); 6.79 (bs, 1H, H - 23); 6.83 (d, 1H, J = 8Hz, H - 24); 7.16 (t, 1H, J = 8Hz, H - 25)
173mg(0.28mmol)の14−O−[(3−{[((R)−2−tert−ブトキシカルボニルアミノ−3−ヒドロキシ)−プロピオニルアミノ]−メチル}−フェノキシ)−アセチル]−ムチリンを2mLのジクロロメタンに溶解し,5mLのHCl−飽和Et2Oを加えた。反応液を周囲温度で3時間保持し,減圧下で蒸発乾固させた。
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.64 (d, 3H, J = 7Hz, CH3 - 16); 0.81 (d, 3H, J = 7Hz, CH3 - 17); 1.05 (s, 3H, CH3 - 18), 1.35 (s, 3H, CH3 - 15); 2.40 (bs, 1H, H - 4); 3.41 (t, 1H, J = 6Hz, H - 11); 3.76 (m, 2H, CH2 - 29); 3.84 (dd, 1H, J = 4 および 6Hz, H - 28); ABX-システム (υA = 4.32, υB = 4.26, JAB = 16Hz, JAX = 6Hz, JBX= 6Hz, CH2 - 27); AB-システム (υA = 4.71, υB = 4.62, J = 17Hz, CH2 - 22); 5.01 および 5.07 (2xdd, 2H, J = 2 および 11Hz; J = 2 および 18Hz, H - 20); 5.60 (d, 1H, J = 8Hz, H - 14); 6.11 (dd, 1H, J = 11 および 18 Hz, H - 19); 6.76 (dd, 1H, J = 2 および 8Hz, H - 26); 6.84 (bs, 1H, H - 23); 6.87 (d, 1H, J = 8Hz, H - 24); 7.21 (t, 1H, J = 8Hz, H - 25)
実施例33:14−O−[(3−{[((R)−ピロリジン−2−カルボニル)−アミノ]−メチル}−フェノキシ)−アセチル]−ムチリン塩酸塩
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.63 (d, 3H, J = 7Hz, CH3 - 16); 0.81 (d, 3H, J = 7Hz, CH3 - 17); 1.05 (s, 3H, CH3 - 18), 1.34 (s, 3H, CH3 - 15); 2.40 (bs, 1H, H - 4); 3.18 (m, 2H, CH2 - 31); 3.41 (d, 1H, J = 6Hz, H - 11); 4.18 (m, 1H, H - 28); 4.28 (m, 2H, CH2 - 27); AB-システム (υA = 4.72, υB = 4.63, J = 17Hz, CH2 - 22); 5.01 および 5.07 (2xdd, 2H, J = 2 および 11Hz; J = 2 および 18Hz, H - 20); 5.60 (d, 1H, J = 8Hz, H - 14); 6.11 (dd, 1H, J = 11 および 18Hz, H - 19); 6.77 (dd, 1H, J = 2 および 8Hz; H - 26); 6.83 (bs, 1H, H - 23); 6.86 (d, 1H, J = 8Hz, H - 24); 7.22 (t, 1H, J = 8Hz, H - 25)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.63 (d, 3H, J = 7Hz, CH3 - 16); 0.81 (d, 3H, J = 7Hz, CH3 - 17); 1.03 (s, 3H, CH3 - 18); 1.34 (s, 3H, CH3 - 15); 2.39 (bs, 1H, H - 4); ABX-システム (υA = 2.97, υB = 2.89, JAB = 14Hz, JAX = 7Hz, JBX= 7Hz, CH2 - 29); 3.39 (t, 1H, J = 6Hz, H - 11); 3.92 (t, 1H, J = 7Hz, H - 28); ABX-システム (υA = 4.25, υB = 4.19, JAB = 15Hz, JAX = 6Hz, JBX = 6Hz, CH2- 27); AB-システム (υA = 4.70, υB = 4.62, J = 17Hz, CH2 - 22); 5.01 および 5.07 (2xdd, 2H, J = 2 および 11Hz; J = 2 および 18Hz, H - 20); 5.60 (d, 1H, J = 8Hz, H - 14); 6.11 (dd, 1H, J = 11 および 18Hz, H - 19); 6.65 (d, 2H, J = 8Hz, H - 24); 6.68 (d, 2H, J = 8Hz, H - 31); 6.76 (dd, 1H, J = 2 および 8Hz, H - 26); 6.79 (bs, 1H, H - 23); 7.00 (d, 2H, J = 8Hz, H - 30); 7.17 (t, 1H, J = 8Hz, H - 25)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.63 (d, 3H, J = 7Hz, CH3 - 16); 0.80 (d, 3H, J = 7Hz, CH3 - 17); 1.02 (s, 3H, CH3 - 18); 1.34 (s, 3H, CH3 - 15); 2.40 (bs, 1H, H - 4); ABX-システム (υA = 2.96, υB = 2.88, JAB = 14Hz, JAX = 7Hz, JBX= 7Hz, CH2 - 29); 3.41 (t, 1H, J = 6Hz, H - 11); 3.92 (t, 1H, J = 7Hz, H - 28); 4.23 (m, 2H, CH2 - 27); AB-システム (υA = 4.71, υB = 4.62, J = 17Hz, CH2 - 22); 5.01 および 5.07 (2xdd, 2H, J = 2 および 11Hz; J = 2 および 18Hz, H - 20); 5.60 (d, 1H, J = 8Hz, H - 14); 6.11 (dd, 1H, J = 11 および 18Hz, H - 19); 6.65 (d, 2H, J = 8Hz, H - 24); 6.68 (d, 2H, J = 8Hz, H - 31); 6.76 (dd, 1H, J = 2 および 8Hz, H - 26); 6.79 (bs, 1H, H - 23); 6.99 (d, 2H, J = 8Hz, H - 30); 7.17 (t, 1H, J = 8Hz, H - 25)
工程1:14−O−[(3−アミノメチル−フェノキシ)−アセチル]−19,20−ジヒドロムチリン
5.3g(10.4mmol)の14−O−[(3−アジドメチル−フェノキシ)−アセチル]−ムチリンを160mLのTHFに溶解し,4.8gのリンドラー触媒を加え,反応混合物を周囲温度で65時間水素化した。反応混合物をセライトを通して濾過し,減圧下で濃縮し,残渣をCH2Cl2/MeOH10:1を移動相として用いてシリカでクロマトグラフィーを行った。
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.61 (t, 3H, J = 7Hz, CH3 - 20); 0.64 (d, 3H, J = 7Hz, CH3 - 16); 0.80 (d, 3H, J = 7Hz, CH3 - 17); 0.84 (s, 3H, CH3 - 18), 1.33 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 3.34 (t, 1H, J = 6Hz, H - 11); 3.64 (s, 2H, CH2 - 27); AB-システム (υA = 4.71, υB = 4.62, J = 17Hz, CH2 - 22); 5.58 (d, 1H, J = 8Hz, H - 14); 6.70 (dd, 1H, J = 2 および 8Hz; H - 26); 6.87 (bs, 1H, H - 23); 6.90 (d, 1H, J = 8Hz, H - 24); 7.16 (t, 1H, J = 8Hz, H - 25)
6mLのTHF中の300mg(0.62mmol)の14−O−[(3−アミノメチル−フェノキシ)−アセチル]−ムチリンに,212mg(0.99mmol)のBOC−D−プロリンを204mg(0.99mmol)のDCCおよび75mg(0.62mmol)のDMAPとともに加えた。反応液を周囲温度で12時間撹拌し,形成した沈殿物を濾別し,濾液を減圧下で蒸発乾固させた。残渣をジクロロメタン/メタノール100:2を移動相として用いてシリカでクロマトグラフィーを行った。
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.61 (t, 3H, J = 7Hz, CH3 - 20); 0.64 (d, 3H, J = 7Hz, CH3 - 16); 0.80 (d, 3H, J = 7Hz, CH3 - 17); 0.84 (s, 3H, CH3 - 18), 1.27 (bs, 9H, CH3 - 32); 1.39 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 3.35 (2xm, 3H, CH2 - 31 および H - 11); 4.10 および 4.26 (2xm, 3H, CH2 -27 および H - 28); AB-システム (υA = 4.70, υB = 4.60, J = 17Hz, CH2 - 22); 5.58 (d, 1H, J = 8Hz, H - 14); 6.72 (m, 1H, H - 26); 6.80 (bs, 1H, H - 23); 6.72 (bd, 1H, J = 8Hz, H - 24); 7.17 (m, 1H, H - 25)
337mgの14−O−[(3−{[((R)−BOC−ピペリジン−2−カルボニル)−アミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリンを2mLのジクロロメタンに溶解し,5mLのHCl−飽和Et2Oを加えた。反応液を周囲温度で4時間保持し,減圧下で蒸発乾固させた。
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.61 (t, 3H, J = 7Hz, CH3 - 20); 0.63 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.84 (s, 3H, CH3 - 18), 1.33 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 3.18 (m, 2H, CH2- 31); 3.32 (t, 1H, J = 6Hz, H - 11); 4.18 (t, 1H, J = 7Hz, H - 28); 4.29 (d, 2H, J = 6Hz, CH2 -27); AB-システム (υA = 4.74, υB = 4.63, J = 17Hz, CH2 - 22); 5.58 (d, 1H, J = 8Hz, H - 14); 6.78 (dd, 1H, J = 2 および 8Hz; H - 26); 6.83 (d, 1H, J = 2Hz, H - 23); 6.85 (d, 1H, J = 8Hz, H - 24); 7.22 (t, 1H, J = 8Hz, H - 25)
実施例37:14−O−[(3−{[((R)−2−アミノ−3−ヒドロキシ)−プロピオニルアミノ]−メチル}−フェノキシ)−アセチル]−19,20−ジヒドロムチリン塩酸塩
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.61 (t, 3H, J = 7Hz, CH3 - 20); 0.63 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.84 (s, 3H, CH3 - 18); 1.34 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); 3.38 (t, 1H, J = 6Hz, H - 11); 3.77 (m, 2H, CH2 - 29); 3.86 (m, 1H, H - 28); 4.29 (t, 2H, J = 6Hz, CH2 - 27); AB-システム (υA = 4.73, υB = 4.62, J = 17Hz, CH2 - 22); 5.59 (d, 1H, J = 8Hz, H - 14); 6.77 (dd, 1H, J = 2 および 8Hz, H - 26); 6.84 (bs, 1H, H - 23); 6.87 (d, 1H, J = 8Hz, H - 24); 7.20 (t, 1H, J = 8Hz, H - 25)
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.61 (t, 3H, J = 7Hz, CH3 - 20); 0.64 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.84 (s, 3H, CH3 - 18); 1.33 (s, 3H, CH3 - 15); 2.36 (bs, 1H, H - 4); ABX-システム (υA = 2.96, υB = 2.88, JAB = 15Hz, JAX = 7Hz, JBX = 7Hz, CH2- 29); 3.34 (t, 1H, J = 6Hz, H - 11); 3.92 (t, 1H, J = 7Hz, H - 28); 4.22 (m, 2H, CH2 - 27); AB-システム (υA = 4.72, υB = 4.62, J = 17Hz, CH2 - 22); 5.58 (d, 1H, J = 8Hz, H - 14); 6.65 (d, 1H, J = 8Hz, H - 24); 6.68 (d, 2H, J = 8Hz, H - 31); 6.77 (dd, 1H, J = 2 および 8Hz, H - 26); 6.80 (bs, 1H, H - 23); 7.00 (d, 2H, J = 8Hz, H - 30); 7.16 (t, 1H, J = 8Hz, H - 25)
実施例39は,実施例1,工程2と同様にして製造した。
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.56 (d, 3H, J = 7Hz, CH3 - 16); 0.79 (d, 3H, J = 7Hz, CH3 - 17); 0.97 (s, 3H, CH3 - 18); 1.30 (s, 3H, CH3- 15); 2.24 (s, 3H, CH3 - 27); 2.35 (bs, 1H, H - 4); 3.37 (t, 1H, J = 6Hz, H - 11); AB-システム (υA = 3.80, υB = 3.73, J = 16Hz, CH2 - 22); 4.94 (m, 2H, H - 20); 5.48 (d, 1H, J = 8Hz, H - 14); 6.03 (dd, 1H, J = 11, および 18Hz, H - 19); 6.98 および 7.23 (2xm, 4H, arom-H)
実施例40は,実施例32,工程1と同様にして製造した。
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.64 (d, 3H, J = 7Hz, CH3 - 16); 0.81 (d, 3H, J = 7Hz, CH3 - 17); 1.04 (s, 3H, CH3 - 18); 1.33 (s, 3H, CH3- 15); 2.23 (s, 3H, CH3 - 27); 2.40 (bs, 1H, H - 4); 3.41 (bs, 1H, H - 11); AB-システム (υA = 4.68, υB = 4.62, J = 17Hz, CH2 - 22); 5.01 および 5.06 (2xd, 2H, J = 11Hz および 18Hz, H - 20); 5.60 (d, 1H, J = 8Hz, H - 14); 6.11 (dd, 1H, J = 11, および 18Hz, H - 19); 6.67 および 6.77 (2xd, 2H, J = 7Hz, H - 24 および 26); 6.68 (s, 1H, H - 23); 7.12 (t, 1H, J = 8Hz, H - 25)
実施例41は,実施例40の生成物をPd/Cで水素化することにより製造した。
1H-NMR (400 MHz, DMSO-d6, δ, ppm, 特徴的シグナル): 0.64 (d, 3H, J = 7Hz, CH3 - 16); 0.81 (d, 3H, J = 7Hz, CH3 - 17); 1.04 (s, 3H, CH3 - 18); 1.33 (s, 3H, CH3 - 15); 2.23 (s, 3H, CH3 - 27); 2.40 (bs, 1H, H - 4); 3.41 (bs, 1H, H - 11); AB-システム (υA = 4.68, υB = 4.62, J = 17Hz, CH2 - 22); 5.01 および 5.06 (2xd, 2H, J = 11Hz および 18Hz, H - 20); 5.60 (d, 1H, J = 8Hz, H - 14); 6.11 (dd, 1H, J = 11, および 18Hz, H - 19); 6.67 および 6.77 (2xd, 2H, J = 7Hz, H - 24 および 26); 6.68 (s, 1H, H - 23); 7.12 (t, 1H, J = 8Hz, H - 25)
最少阻害濃度(MIC)として表される抗微生物活性は,認められているCLSI(元NCCLS)の標準的な参考推奨法にしたがって測定した。
Claims (10)
- 式(I):
Xは酸素またはイオウであり,および
Yはピペコリン酸の残基またはカルボン酸基のCO基を介して窒素に結合しているアミノ酸の残基である]
の化合物。 - Yにおけるアミノ酸がD型またはL型の天然に生ずるアミノ酸である,請求項1記載の化合物。
- 請求項1記載の式(I)または(II)の化合物であって、
Xが請求項1に定義される通りであり、Yがピペコリン酸の残基、またはD型またはL型の天然に生ずるアミノ酸の残基であるか、
14−O−[(3−{[((2R,4R)−4−ヒドロキシ−ピロリジン−2−カルボニル)−アミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[2−(2−アミノ−アセチルアミノ)−アセチルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(S)−2−((S)−2−アミノ−プロピオニルアミノ)−プロピオニルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{(2−[((R)−ピロリジン−2−カルボニル)−アミノ]−アセチルアミノ)−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(S)−2((S)−2−アミノ−4−メチル−ペンタノイルアミノ)−4−メチル−ペンタノイルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((S)−1−(2−アミノ−アセチル)−ピロリジン−2−カルボニル)−アミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,または
14−O−[(3−{[((2S,4R)−4−ヒドロキシ−ピロリジン−2−カルボニル)−アミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリンである化合物。 - 14−O−[(3−{[((R)−ピペリジン−2−カルボニル)−アミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((R)−2−アミノ−3−メチル)−ブチリルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((2R,4R)−4−ヒドロキシ−ピロリジン−2−カルボニル)−アミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(S)−2−アミノ−3−(3H−イミダゾール−4−イル)−プロピオニルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(R)−2−アミノ−プロピオニルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[2−(2−アミノ−アセチルアミノ)−アセチルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((R)−ピロリジン−2−カルボニル)−アミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(R)−2−アミノ−3−(4−ヒドロキシ−フェニル)−プロピオニルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[2−アミノ−アセチルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(S)−2−((S)−2−アミノ−プロピオニルアミノ)−プロピオニルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((S)−2−アミノ−3−メチル)−ブチリルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{(2−[((R)−ピロリジン−2−カルボニル)−アミノ]−アセチルアミノ)−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((2R,3S)−2−アミノ−3−ヒドロキシ)−ブチリルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(R)−2,6−ジアミノ−ヘキサノイルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(R)−2−アミノ−3−(1H−インドール−3−イル)−プロピルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(R)−2−アミノ−3−フェニル−プロピオニルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(R)−2−アミノ−3−カルバモイル−プロピオニルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(S)−2,6−ジアミノ−ヘキサノイルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(S)−2((S)−2−アミノ−4−メチル−ペンタノイルアミノ)−4−メチル−ペンタノイルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((R)−2−アミノ−3−ヒドロキシ)−プロピオニルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(S)−2−アミノ−プロピルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(R)−2−アミノ−4−カルバモイル−ブチリルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((S)−1−(2−アミノ−アセチル)−ピロリジン−2−カルボニル)−アミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(R)−2−アミノ−3−(3H−イミダゾール−4−イル)−プロピオニルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((2S,4R)−4−ヒドロキシ−ピロリジン−2−カルボニル)−アミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((S)−ピペリジン−2−カルボニル)−アミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((S)−ピロリジン−2−カルボニル)−アミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(S)−2−アミノ−3−(4−ヒドロキシ−フェニル)−プロピオニルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[(S)−2−アミノ−3−フェニル−プロピオニルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((S)−2−アミノ−3−ヒドロキシ)−プロピオニルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((2S,3R)−2−アミノ−3−ヒドロキシ)−ブチリルアミノ]−メチル}−フェニルスルファニル)−アセチル]−ムチリン,
14−O−[(3−{[((R)−2−アミノ−3−ヒドロキシ)−プロピオニルアミノ]−メチル}−フェノキシ)−アセチル]−ムチリン,
14−O−[(3−{[((R)−ピロリジン−2−カルボニル)−アミノ]−メチル}−フェノキシ)−アセチル]−ムチリン,
14−O−[(3−{[(S)−2−アミノ−3−(4−ヒドロキシ−フェニル)−プロピオニルアミノ]−メチル}−フェノキシ)−アセチル]−ムチリン,
14−O−[(3−{[(R)−2−アミノ−3−(4−ヒドロキシ−フェニル)−プロピオニルアミノ]−メチル}−フェノキシ)−アセチル]−ムチリン,
14−O−[(3−{[((R)−ピロリジン−2−カルボニル)−アミノ]−メチル}−フェノキシ)−アセチル]−19,20−ジヒドロムチリン,
14−O−[(3−{[((R)−2−アミノ−3−ヒドロキシ)−プロピオニルアミノ]−メチル}−フェノキシ)−アセチル]−19,20−ジヒドロムチリン,
14−O−[(3−{[(S)−2−アミノ−3−(4−ヒドロキシ−フェニル)−プロピオニルアミノ]−メチル}−フェノキシ)−アセチル]−19,20−ジヒドロムチリン,
からなる群より選択される、請求項1−3のいずれか一項に記載の化合物。 - 塩の形である,請求項1−4のいずれか一項に記載の化合物。
- 請求項1−5のいずれか一項に記載の化合物を含む抗微生物剤。
- 微生物により媒介される疾病の治療用の医薬品を製造するための,請求項1−5のいずれか一項に記載の化合物の使用。
- 微生物感染は皮膚または軟組織感染である,請求項7記載の使用。
- 請求項1−5のいずれか一項に記載の化合物を少なくとも1つの薬学的賦形剤とともに含む医薬組成物。
- さらに別の薬学的に活性な薬剤を含む,請求項9記載の医薬組成物。
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EP07450124A EP2014645A1 (en) | 2007-07-13 | 2007-07-13 | Pleuromutilin derivatives and their use as antimicrobials |
EP07450124.8 | 2007-07-13 | ||
PCT/AT2008/000254 WO2009009812A1 (en) | 2007-07-13 | 2008-07-11 | Pleuromutilin derivatives and their use as antimicrobials |
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EP2399904A1 (en) * | 2010-05-26 | 2011-12-28 | Nabriva Therapeutics AG | Process for the preparation of pleuromutilins |
CN102180809B (zh) * | 2011-03-08 | 2013-12-11 | 武汉工程大学 | 截短侧耳素的水杨酰胺醚化合物及其制备方法 |
CN103450057A (zh) * | 2012-05-29 | 2013-12-18 | 大英九合生物化工股份有限公司 | 一种合成对甲苯磺酸截短侧耳素酯的方法 |
CN104803911B (zh) * | 2014-01-23 | 2018-01-05 | 中国科学院上海药物研究所 | 一类截短侧耳素化合物、其药物组合物、合成方法与用途 |
CN103910664B (zh) * | 2014-03-31 | 2016-07-13 | 广东温氏大华农生物科技有限公司 | 一种抗菌活性截短侧耳素-磺胺衍生物及其制备方法和应用 |
CN103910663B (zh) * | 2014-03-31 | 2016-06-29 | 华南农业大学 | 一种具有抗菌活性的截短侧耳素衍生物及其制备和应用 |
EP3423065B1 (en) * | 2016-03-02 | 2021-07-21 | Anacor Pharmaceuticals, Inc. | Boron-containing small molecules |
US20190352262A1 (en) * | 2017-02-01 | 2019-11-21 | Yale University | New Pleuromutilin Antibiotic Compounds, Compositions and Methods of Use and Synthesis |
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 |
CN107417586A (zh) * | 2017-06-21 | 2017-12-01 | 华南农业大学 | 一种截短侧耳素类抗生素及其制备方法和应用 |
WO2021209173A1 (en) * | 2020-04-17 | 2021-10-21 | Nabriva Therapeutics GmbH | Novel therapeutic use of pleuromutilins |
US11117859B1 (en) * | 2021-02-12 | 2021-09-14 | Shaanxi University Of Science And Technology | Pleuromutilin hippuric acid ester with antibacterial activity and a method of preparing the same |
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AT301753B (de) * | 1969-07-25 | 1972-09-25 | Biochemie Gmbh | Verfahren zur Herstellung neuer Pleuromutilin-Derivate |
US4060542A (en) * | 1969-07-25 | 1977-11-29 | Biochemie Gesellschaft M.B.H. | 14-Desoxy-14 thiocyanato-acetoxy-mutilin |
GB9614017D0 (en) * | 1996-07-04 | 1996-09-04 | Biochemie Gmbh | Organic compounds |
WO2000027790A1 (en) * | 1998-11-11 | 2000-05-18 | Smithkline Beecham P.L.C. | Mutilin compounds |
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EP2173707B1 (en) | 2013-12-25 |
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EA201070138A1 (ru) | 2010-08-30 |
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EA019806B1 (ru) | 2014-06-30 |
CA2693015C (en) | 2016-10-18 |
US8173685B2 (en) | 2012-05-08 |
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