JP5086069B2 - 重硫酸アタザナビルおよび新規形態の製造方法 - Google Patents
重硫酸アタザナビルおよび新規形態の製造方法 Download PDFInfo
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- AXRYRYVKAWYZBR-GASGPIRDSA-N CC(C)(C)[C@@H](C(N[C@@H](Cc1ccccc1)[C@H](CN(Cc(cc1)ccc1-c1ncccc1)NC([C@H](C(C)(C)C)NC(OC)=O)=O)O)=O)NC(OC)=O Chemical compound CC(C)(C)[C@@H](C(N[C@@H](Cc1ccccc1)[C@H](CN(Cc(cc1)ccc1-c1ncccc1)NC([C@H](C(C)(C)C)NC(OC)=O)=O)O)=O)NC(OC)=O AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 description 1
- YTDMTTYOLYTDMS-LLVKDONJSA-N CC(C)(C)[C@@H](C(O[n]1nnc2ccccc12)=O)NC(OC)=O Chemical compound CC(C)(C)[C@@H](C(O[n]1nnc2ccccc12)=O)NC(OC)=O YTDMTTYOLYTDMS-LLVKDONJSA-N 0.000 description 1
- BBMPHERXUYPXDO-UNMCSNQZSA-N N[C@@H](Cc1ccccc1)[C@H](CN(Cc(cc1)ccc1-c1ccccn1)N)O Chemical compound N[C@@H](Cc1ccccc1)[C@H](CN(Cc(cc1)ccc1-c1ccccn1)N)O BBMPHERXUYPXDO-UNMCSNQZSA-N 0.000 description 1
- 0 [*+]N(C[C@@]([C@](Cc1ccccc1)N)O)Cc(cc1)ccc1-c1ccccn1 Chemical compound [*+]N(C[C@@]([C@](Cc1ccccc1)N)O)Cc(cc1)ccc1-c1ccccn1 0.000 description 1
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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
- C07D213/06—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/127—Preparation from compounds containing pyridine rings
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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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- C—CHEMISTRY; METALLURGY
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- 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
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
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- 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
- A61K31/33—Heterocyclic compounds
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- 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
- A61P31/12—Antivirals
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- 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
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- 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
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
Description
R1は、低級アルコキシカルボニルであり、
R2は、二級または三級低級アルキルまたは低級アルキルチオール−低級アルキルであり、
R3は、1またはそれ以上の低級アルコキシ基、またはC4−C8シクロアルキルによって非置換または置換されるフェニルであり、
R4は、フェニルまたはシクロヘキシルであり、それぞれが環の炭素原子を経由して結合し、5〜8個の環の原子を有し、窒素、酸素、硫黄、スルフィニル(−SO−)およびスルホニル(−SO2−)から選択される1〜4個のヘテロ原子を含み、低級アルキルまたはフェニル−低級アルキルによって非置換または置換される不飽和ヘテロシクリルによってその4位で置換され、
R5は、R2とは独立して、R2に記載される意味の一つを有し、および
R6は、R1とは独立して、低級アルコキシカルボニル、またはその塩であるが、但し、少なくとも一つの塩を形成する基が存在する]および種々のその医薬的に許容される酸付加塩を有するアザペプチドHIVプロテアーゼ阻害剤(アタザナビルを含む)のシリーズを開示する。
の酸またはその活性な酸誘導体と縮合される化合物の製造を含む、アザペプチドを製造するためのいくつかの方法が提供される。
本発明によれば、Cパターン物質およびE3型を含む、重硫酸アタザナビルの新規形態が提供される。Cパターン物質が好ましい。
[格子サイズ:
a=9.86(5)Å
b=29.245(6)Å
c=8.327(2)Å
α=93.56(2)°
β=114.77(3)°
γ=80.49(3)°
空間群1
分子/非対称単位2]
と実質的に同等である単位格子パラメーターによって特徴付けられ、結晶形態が約+22℃で存在する。
[a=10.749Å
b=13.450(4)Å
c=9.250(2)Å
α=98.33(2)°
β=95.92(3)°
γ=102.82(3)°
空間群P1
分子/非対称単位1]
と実質的に同等である表5に示される結晶学的データによって特徴付けられ、結晶形が約−23℃で存在する。
本発明は、少なくとも一部分で重硫酸アタザナビルの形態、すなわち新規材料として、特に医薬的に許容される形態でE3型およびCパターンを提供する。本明細書で用いられる用語「医薬的に許容される」とは、合理的な利点/リスク比に相応して過剰毒性、刺激作用、アレルギー反応、または他の問題のある合併症がなく、正しい医療判断の範囲内で、ヒトおよび動物組織と接するのに適した、それらの化合物、物質、組成物および/または製剤を意味する。ある好ましい態様において、その遊離塩基Iおよびその塩の結晶形は、実質的に純粋な形態である。本明細書で用いられる用語「実質的に純粋」とは、例えば約91%、約92%、約93%、約94%、約95%、約96%、約97%、約98%、約99%、および約100%を含む、約90%以上の純度を有する化合物を意味する。
の保護されたトリアミン塩溶液を、塩化メチレン、テトラヒドロフラン、またはメタノールのような有機溶媒、好ましくは塩化メチレンの存在下、約25〜約50℃、好ましくは約30〜約40℃の温度範囲で、酸、好ましくは塩酸(Bocが用いられる場合)、または塩基(トリフルオロアセチルが用いられる)と処理し、トリアミン酸塩、好ましくは構造:
トリアミン酸塩を単離することなく、該トリアミン酸塩を構造:
をヒドラジンカーバメート体:
と、イソプロピルアルコールまたはエタノールまたはブタノールのような他のアルコールの存在下で反応することにより調製される。
1−[4−(ピリジン−2−イル)フェニル]−5(S)−2,5−ビス{[N−(メトキシカルボニル)−L−tert−ロイシニル]アミノ}−4−(S)−ヒドロキシ−6−フェニル−2−アザヘキサン・重硫酸塩(A型)(重硫酸アタザナビルA型)
メカニカルスターラー、窒素吸気口および温度プローブを取り付けた1000mLの3頸丸底フラスコに、保護トリアミン体、1−[4−(ピリジン−2−イル)フェニル]−5(S)−2,5−ビス[tert−ブチルオキシカルボニル)アミノ]−4(S)−ヒドロキシ−6−フェニル−2−アザヘキサン:
メカニカルスターラー、滴下ロート、窒素吸気口、および温度プローブを取り付けた3000mLの3頸丸底フラスコに、N−メトキシカルボニル−L−tert−ロイシン(77.2g,0.408mol,2.30当量)、1−ヒドロキシベンゾトリアゾール(HOBT)(60.8g,0.450mol,2.53当量)、およびN−エチル N’−ジメチルアミノプロピルカルボジイミド(EDAC)(82.0g,0.430mol,2.42当量)、続いて、CH2Cl2(880mL;8.8mL/gの保護したトリアミン体の投入量)を加え、該活性エステル体の形成がHPLCで完了したと判断するまで、該混合物を周囲温度(18〜25℃)で攪拌した。
無水第二リン酸カリウム(K2HPO4;226g,1.30mol,保護トリアミン体に対して7.30当量)を1130mLの水(11.3mL/gの保護アミン体;5mL/gのK2HPO4)に溶解した。
メカニカルスターラー、温度プローブ、および蒸留冷却管を取り付けた3000mLの3頸丸底フラスコ中のパートCの遊離塩基リッチな溶液に、N−メチルピロリドン(148mL;製造過程の定量アッセイに基づく1.25mL/gのパートCの遊離塩基)を加えた。該溶液を70℃またはそれ以下のジャケット温度を用いて、約360mL(2.5〜3.5mL/gのパートCの遊離塩基)まで濃縮し;500mLのアセトン(4〜5mL/gのパートCの遊離塩基)を濃縮液に加え、該混合液を約400mLまたはそれ以下の量まで蒸留した。
40〜50℃の温度を維持しながら、表面添加によって濃硫酸(19g,1.10当量)の総添加量の約10%(2g)をパートDの遊離塩基のアセトン/N−メチルピロリドン溶液に加えた。
重硫酸アタザナビル−Cパターン物質
方法A:
重硫酸アタザナビルのA型結晶(実施例1に記載されるように調製した)(25.33g)を200mLの水に懸濁し、該混合物を機械的に攪拌し、厚いゲルを生じ乾燥した。
重硫酸アタザナビルのA型結晶は、適当な混合造粒機において、充分な量の水(約40%w/w)を用いて湿式造粒した。湿塊をオーブンで乾燥した。該生成物を適当なふるいを用いて、等しい大きさにした。生じた生成物のX線回折パターンは、図6に示されるCパターン物質と一致する。
重硫酸アタザナビル−E3型(トリエタノール溶媒和物)
メカニカルスターラー、温度プローブ、および圧力を等しくする液体滴下ロートを取り付けた100mLの3頸丸底フラスコにおいて、アタザナビル遊離塩基(実施例1、パートCに記載されるように調製)(3.0g,4.26mmol)を無水の200プルーフ(proof)のエタノール(20.25mL,6.75mL/gの遊離塩基)中でスラリーにした。
Claims (25)
- 下記:
[格子サイズ:
a=9.86(5)Å
b=29.245(6)Å
c=8.327(2)Å
α=93.56(2)°
β=114.77(3)°
γ=80.49(3)°
空間群1
分子/非対称単位2]
と同等である単位格子パラメーターによって特徴付けられ、結晶形態が+22℃で存在する重硫酸アタザナビルのA型結晶の製造方法であって、アセトン、またはアセトンおよびN−メチルピロリドンの混合物である有機溶媒中で、アタザナビル遊離塩基の溶液を該アタザナビル遊離塩基の15重量%未満が反応する量の濃硫酸の一部と最初に反応させ、上記と同義のA型結晶の種晶を該反応混合物に加え、重硫酸アタザナビルの結晶が形成するように、追加の濃硫酸を段階的に増加する速度で加えて重硫酸アタザナビルの結晶形成を行い、該重硫酸アタザナビルを乾燥して、上記と同義のA型結晶を形成することを特徴とする方法。 - 該アタザナビル遊離塩基の溶液を、用いられる硫酸の全重量の5〜15%と最初に反応させる、請求項1の方法。
- 該アタザナビル遊離塩基の溶液を、用いられる硫酸の全重量の8〜12%と最初に反応させる、請求項1の方法。
- 該アタザナビル遊離塩基を35〜55℃の温度範囲で硫酸の一部と最初に反応させる、請求項1の方法。
- 該アタザナビル遊離塩基の溶液を35〜55℃の温度範囲に加熱した後、硫酸と反応させる、請求項1の方法。
- アタザナビル遊離塩基および硫酸の反応混合物に、アタザナビル遊離塩基の重量に基づいて0.1〜80重量%の、請求項1と同義のA型結晶の種晶を加える、請求項1の方法。
- 種晶を加えた反応混合物を35〜55℃の温度範囲で加熱する、請求項1の方法。
- 該アタザナビル遊離塩基のための有機溶媒がアセトンおよびN−メチルピロリドンの混合物である、請求項1の方法。
- (a)アセトン、またはアセトンおよびN−メチルピロリドンの混合物である有機溶媒中で、アタザナビル遊離塩基の溶液を該アタザナビル遊離塩基の15重量%未満が反応する量の濃硫酸の一部と最初に反応させ、下記:
[格子サイズ:
a=9.86(5)Å
b=29.245(6)Å
c=8.327(2)Å
α=93.56(2)°
β=114.77(3)°
γ=80.49(3)°
空間群1
分子/非対称単位2]
と同等である単位格子パラメーターによって特徴付けられ、結晶形態が+22℃で存在する重硫酸アタザナビルのA型結晶の種晶を該反応混合物に加え、重硫酸アタザナビルの結晶が形成するように、追加の濃硫酸を段階的に増加する速度で加えて重硫酸アタザナビルの結晶形成を行い、該重硫酸アタザナビルを乾燥して、上記と同義のA型結晶を形成し;
(b)水中で、段階(a)からの重硫酸アタザナビルのA型結晶を懸濁し、該懸濁液を乾燥して、下記:
に示されるパターンに一致する粉末X線回折パターンによって特徴付けられるCパターン物質を形成すること
を特徴とする、重硫酸アタザナビルのCパターン物質の製造方法。 - 下記:
[格子サイズ:
a=9.86(5)Å
b=29.245(6)Å
c=8.327(2)Å
α=93.56(2)°
β=114.77(3)°
γ=80.49(3)°
空間群1
分子/非対称単位2]
と同等である単位格子パラメーターによって特徴付けられ、結晶形態が+22℃で存在する重硫酸アタザナビルのA型結晶:
の製造方法であって、構造:
のトリアミン塩を有機溶媒の存在下で、構造:
の酸の活性エステル体および塩基と反応させて、構造:
のアタザナビル遊離塩基の溶液を形成し、遊離塩基の塩化メチレン溶液にN−メチルピロリドンおよびアセトンを加え、上記の混合物を加熱して、塩化メチレンを除去し、上記の混合物に硫酸を加え、該遊離塩基の重硫酸塩を形成することによって、該遊離塩基を対応の重硫酸塩に変換し、その中で、該硫酸を、下式:
[式中、
Vtime=経過時間内に加えられた硫酸の量
Vtotal=90%添加を表す酸の全量
time=結晶化における経過時間
timetotal=結晶化の全時間または酸を添加するための全時間]
に従う、段階的に増加する速度で加えることを特徴とする方法。 - 該塩基が、アルカリ金属水酸化物、アルカリ土類金属水酸化物、アルカリ金属炭酸塩、アルカリ土類金属炭酸塩、アルカリ金属リン酸塩、アルカリ土類金属リン酸塩または有機塩基である、請求項10の方法。
- 該塩基が、NaOH、KOH、Mg(OH)2、K2HPO4、MgCO3、Na2CO3、K2CO3、トリエチルアミン、ジイソプロピルエチルアミンまたはN−メチルモルホリンであり、該有機溶媒が、塩化メチレン、酢酸エチル、ジクロロエタン、テトラヒドロフラン、アセトニトリルまたはN,N−ジメチルホルムアミドである、請求項13の方法。
- 該トリアミン塩および該活性エステル体を、30〜40℃の温度範囲で反応させる、請求項10の方法。
- 該トリアミン塩および該活性エステル体を、該塩基としてK2HPO4の存在下で、該溶媒として塩化メチレン中で反応させる、請求項15の方法。
- 遊離塩基、アセトンおよびN−メチルピロリドンの混合物に重硫酸アタザナビルの結晶の種晶を加える段階を含むことを特徴とする、請求項10の方法。
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US60753304P | 2004-09-07 | 2004-09-07 | |
US60/607,533 | 2004-09-07 | ||
US11/119,558 US7829720B2 (en) | 2004-05-04 | 2005-05-02 | Process for preparing atazanavir bisulfate and novel forms |
US11/119,558 | 2005-05-02 | ||
PCT/US2005/015333 WO2005108349A2 (en) | 2004-05-04 | 2005-05-03 | Process for preparing atazanavir bisulfate and novel forms |
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