JP6460789B2 - ポリエチレングリコールセグメントを有するヘテロ2官能性リンカー及び該リンカーから調製された免疫反応調節複合体 - Google Patents
ポリエチレングリコールセグメントを有するヘテロ2官能性リンカー及び該リンカーから調製された免疫反応調節複合体 Download PDFInfo
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- VLCMRTMCMQJSKM-UHFFFAOYSA-N phenyl-[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone Chemical compound C=1C=CC=CC=1C(=O)C1=CN=C2C(C(F)(F)F)=CC=CC2=C1C1=CC=CC=C1 VLCMRTMCMQJSKM-UHFFFAOYSA-N 0.000 description 1
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- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
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- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
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- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 1
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- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
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- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
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- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
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- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 239000003451 thiazide diuretic agent Substances 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
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- 229960002109 tuberculosis vaccine Drugs 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
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- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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
Description
本願は、いずれも2011年6月3日出願の米国仮特許出願第61/493,143号及び同第61/493,051号に基づく優先権を主張するものであり、当該出願の開示の全容を本明細書に援用するものである。
ヒドラジン又はヒドラジド置換された免疫反応調節物質と、
下式により表されるリンカー:
抗原と、の反応生成物を含む複合体を提供する。
免疫反応調節物質と、
下式により表されるリンカー:
抗原と、を含む複合体であって、
前記免疫反応調節物質が前記リンカーと*においてヒドラゾン官能基を介して共有結合により結合し、前記抗原が前記リンカーと**において共有結合により結合されている複合体を提供する。
抗原を下式により表されるリンカー:
−アルキレン−O−であり、R’は場合により1以上のアミド又はエーテル基により分断されるか又はこれらで終端するアルキレンであり、Eはアミン又はチオール反応基である]と結合して修飾された抗原を与えることと、
前記修飾された抗原を、ヒドラジン又はヒドラジド置換された免疫反応調節物質と結合して複合体を与えることと、を含む方法を提供する。
RA及びRBは、
水素、
ハロゲン、
アルキル、
アルケニル、
アルコキシ、
アルキルチオ、及び
−N(R9)2からなる群からそれぞれ独立して選択されるか;
又は、RAとRBとは共に、N及びSからなる群から選択される1種類のヘテロ原子を含む縮合ヘテロアリール環、又はアリール若しくはヘテロアリール環が非置換であるか又は1以上のR基により置換されるか、若しくは1個のR3基により置換されるか、若しくは1個のR3基及び1個のR基により置換された縮合アリール環を形成するか;
又は、RAとRBとは共に、N及びSからなる群から選択されるヘテロ原子を場合により含み、非置換又は1以上のR基により置換された縮合5〜7員飽和環を形成し;
Rは、
ハロゲン、
ヒドロキシ、
アルキル、
アルケニル、
ハロアルキル、
アルコキシ、
アルキルチオ、及び
−N(R9)2からなる群からそれぞれ独立して選択されるか;
R2は、
アミノ、
−R4、
−X−R4、
−X−Y−R4、及び
−X−R5からなる群から選択され;
R3は、
−Z−R4、
−Z−X−R4、
−Z−X−Y−R4、
−Z−X−Y−X−Y−R4、及び
−Z−X−R5からなる群から選択され;
Xは、アルキレン、アルケニレン、アルキニレン、アリーレン、ヘテロアリーレン、及びヘテロシクリレンからなる群から選択され、ただし、前記アルキレン、アルケニレン、及びアルキニレン基は、1以上の−O−基により分断されるか又は−O−若しくは−N(H)−で終端するアリーレン、ヘテロアリーレン、又はヘテロシクリレンにより場合により分断されるか又はこれらで終端しうるものであり;
Yは、
−O−、
−S(O)0〜2−、
−S(O)2−N(R8)−、
−C(R6)−、
−C(R6)−O−、
−O−C(R6)−、
−O−C(O)−O−、
−N(R8)−Q−、
−C(R6)−N(R8)−、
−O−C(R6)−N(R8)−、
−C(R6)−N(OR9)−、
−O−N(R8)−Q−、
−O−N=C(R4)−、
−C(=N−O−R8)−、
−CH(−N(−O−R8)−Q−R4)−、
X’は、−X−、−X−C(O)−、−X−Y−X−、及び−X−Y−X−C(O)−からなる群から選択され;
Zは、結合であるか又は−O−であり;
R4は、水素、アルキル、アルケニル、アルキニル、アリール、アリールアルキレニル、アリールオキシアルキレニル、アルキルアリーレニル、ヘテロアリール、ヘテロアリールアルキレニル、ヘテロアリールオキシアルキレニル、アルキルヘテロアリーレニル、及びヘテロシクリルからなる群から選択され、ただし、前記アルキル、アルケニル、アルキニル、アリール、アリールアルキレニル、アリールオキシアルキレニル、アルキルアリーレニル、ヘテロアリール、ヘテロアリールアルキレニル、ヘテロアリールオキシアルキレニル、アルキルヘテロアリーレニル、及びヘテロシクリル基は、非置換であるか又はアルキル、アルコキシ、ヒドロキシアルキル、ハロアルキル、ハロアルコキシ、ハロゲン、ニトロ、ヒドロキシ、メルカプト、シアノ、アリール、アリールオキシ、アリールアルキレンオキシ、ヘテロアリール、ヘテロアリールオキシ、ヘテロアリールアルキレンオキシ、ヘテロシクリル、アミノ、アルキルアミノ、ジアルキルアミノ、(ジアルキルアミノ)アルキレンオキシ、並びにアルキル、アルケニル、アルキニル、及びヘテロシクリルである場合にはオキソからなる群から独立して選択される1以上の置換基により置換されてよく、
R5は、
R6は、=O及び=Sからなる群から選択され;
R7は、C2〜7アルキレンであり;
R8は、水素、アルキル、アルコキシアルキレニル、ヒドロキシアルキレニル、アリールアルキレニル、及びヘテロアリールアルキレニルからなる群から選択され;
R9は、水素及びアルキルからなる群から選択され;
R10は、C3〜8アルキレンであり;
Aは、−O−、−C(O)−、−S(O)0〜2−、及び−N(R4)−からなる群から選択され;
A’は、−O−、−S(O)0〜2−、−N(−Q−R4)−、及び−CH2−からなる群から選択され;Qは、結合、−C(R6)−、−C(R6)−C(R6)−、−S(O)2−、−C(R6)−N(R8)−W−、−S(O)2−N(R8)−、
−C(R6)−O−、−C(R6)−S−、及び−C(R6)−N(OR9)−からなる群から選択され;
Vは、−C(R6)−、−O−C(R6)−、−N(R8)−C(R6)−、及び−S(O)2−からなる群から選択され;
Wは、結合、−C(O)−、及び−S(O)2−からなる群から選択され;
a及びbは、a+b≦7であるものとして、独立して1〜6の整数である]のものである。
[式中、R2、X’、及びZは上記に定義したとおりであり、AはCH又はNであり、R1は、
−N(H)−R4、
−O−R4、
−R4、
−X−R4、
−X−Y−R4、
−N(H)−X−Y−R4、
−X−Y−X−Y−R4、及び
−X−R5からなる群から選択され;
式中、X、Y、R4、及びR5は上記に定義したとおり]のものである。
本発明を実施するうえで有用なIRM化合物及びリンカーは、特に本明細書に含まれる説明を考慮することで、化学の技術分野では周知のものと同様のプロセスを含む合成経路により合成することができる。開始物質は、アルドリッチ・ケミカルズ社(Aldrich Chemicals)(米国、ウィスコンシン州、ミルウォーキー)などの商業的供給元から一般的に入手されるか、又は当業者には周知の方法を用いて容易に調製される(例えば、Louis F.Fieser and Mary Fieser,Reagents for Organic Synthesis,v.1〜19,Wiley,New York,(1967〜1999 ed.);Alan R.Katritsky,Otto Meth−Cohn,Charles W.Rees,Comprehensive Organic Functional Group Transformations,v 1〜6,Pergamon Press,Oxford,England,(1995);Barry M.Trost and Ian Fleming,Comprehensive Organic Synthesis,v.1〜8,Pergamon Press,Oxford,England,(1991);又は、Beilsteins Handbuch der organischen Chemie,4,Aufl.Ed.Springer−Verlag,Berlin,Germany,(補遺を含む)(Beilsteinオンラインデータベースから入手することも可能)に一般的に述べられる方法により調整される。)。
本発明の複合体は、本明細書に開示される医薬組成物中で、任意の適当な方法(例えば経口又は非経口)で投与することができる。本明細書で用いるところの腸管内とは、経口摂取によるものを含む消化管を経由する投与のことを指す。腸管外とは、経鼻投与(例えば、吸入による経粘膜投与)、局所投与、眼内投与、及び頬側投与を含む、消化管を経由するもの以外の投与法のことを指すが、実際には、例えば従来の針注射、マイクロニードルアレイを使用した注射、又は他の任意の公知の注射法を用いた注射(例えば、静脈内、筋内、皮下、腫瘍内、又は経皮注射)のことを通常は指す。
(a)アデノウイルス、ヘルペスウイルス(例えば、HSV−I、HSV−II、CMV、又はVZV)、ポックスウイルス(例えば、天然痘若しくはワクシニアなどのオルソポックスウイルス、又は伝染性軟属腫)、ピコルナウイルス(例えば、ライノウイルス又はエンテロウイルス)、オルソミクソウイルス(例えばインフルエンザウイルス)、パラミクソウイルス(例えば、パラインフルエンザウイルス、ムンプスウイルス、麻疹ウイルス、及び呼吸器合胞体ウイルス(RSV))、コロナウイルス(例えばSARS)、パポバウイルス(例えば、性器疣贅、尋常性疣贅、又は足底疣贅を引き起こすものなどのパピローマウイルス)、ヘパドナウイルス(例えばB型肝炎ウイルス)、フラビウイルス(例えば、C型肝炎ウイルス又はデングウイルス)、又はレトロウイルス(例えば、HIVなどのレンチウイルス)による感染によって引き起こされる疾患などのウイルス性疾患;
(b)例えば、エシェリキア属、エンテロバクター属、サルモネラ属、スタフィロコッカス属、シゲラ属、リステリア属、エアロバクター属、ヘリコバクター属、クレブシラ属、プロテウス属、シュードモナス属、ストレプ卜コッカス属、クラミジア属、マイコプラズマ属、ニューモコッカス属、ナイセリア属、クロストリジウム属、バチルス属、コリネバクテリウム属、マイコバクテリウム属、カンピロバクター属、ビブリオ属、セラチア属、プロビデンシア属、クロモバクテリウム属、ブルセラ属、エルシニア属、ヘモフィルス属、又はボルデテラ属の細菌による感染によって引き起こされる疾患などの細菌性疾患;
(c)クラミジア、真菌性疾患(例えば、カンジダ症、アスペルギルス症、ヒストプラスマ症、又はクリプトコッカス髄膜炎)、又は寄生虫疾患(例えば、マラリア、ニューモシスチスカリニ肺炎、リーシュマニア症、クリプトスポリジウム症、トキソプラズマ症、及びトリパノソーマ感染)などの他の感染症;
(d)上皮内腫瘍、子宮頚部異形成、日光角化症、基底細胞癌、扁平上皮細胞癌、腎細胞癌、カポジ肉腫、メラノーマ、白血病(例えば、骨髄性白血病、慢性リンパ性白血病、多発性骨髄腫、非ホジキンリンパ腫、皮膚T細胞リンパ腫、B細胞リンパ腫、及びヘアリーセル白血病)、乳癌、肺癌、前立腺癌、結腸癌、及び他の癌などの腫瘍性疾患;
(e)アトピー性皮膚炎又は湿疹、好酸球増加、喘息、アレルギー、アレルギー性鼻炎、オメン症候群などのTH2媒介性アトピー性疾患;
(f)全身性エリテマトーデス、原発性血小板血症、多発性硬化症,円板状エリテマトーデス、及び円形脱毛症などの特定の自己免疫疾患;並びに、
(g)ケロイド形成及び他の種類の瘢痕化の阻害などの創傷修復に関連する疾患(例えば、慢性創傷を含む創傷治癒の促進)が挙げられる。
第1の実施形態では、本発明は、
ヒドラジン又はヒドラジド置換された免疫反応調節物質と、
下式により表されるリンカー:
抗原と、の反応生成物を含む複合体を提供する。
免疫反応調節物質と、
下式により表されるリンカー:
抗原と、を含む複合体であって、
前記免疫反応調節物質が前記リンカーと*においてヒドラゾン官能基を介して共有結合により結合し、前記抗原が前記リンカーと**においてアミド、ジスルフィド、尿素、チオ尿素、カルバメート、又はアミド若しくはスルホンに対してα位の炭素−硫黄若しくは炭素−窒素結合を介して共有結合により結合されるか又はスクシンイミド環に直接結合されている複合体を提供する。これらの実施形態では、抗原は、リンカーと**においてアミド官能基を介して共有結合により結合される。
抗原を下式により表されるリンカー:
前記修飾された抗原を、ヒドラジン又はヒドラジド置換された免疫反応調節物質と結合して複合体を与えることと、を含む方法を提供する。
抗原を下式により表されるリンカー:
前記修飾された抗原を、ヒドラジン又はヒドラジド置換された免疫反応調節物質と結合して複合体を与えることと、を含む方法を提供する。
CA(PEG)12((式H2N−CH2CH2−(OCH2CH2)12−CO2H);MW=617.7、サーモ・サイエンティフィック社(Thermo Scientific)(イリノイ州ロックフォード)より入手したもの、115mg)、N−スクシンイミジル−4−ホルミルベンゾエート(イー・エム・ディー・ケミカルズ社(EMD Chemicals)(ニュージャージー州ギブスタウン)より入手した乾燥ジクロロメタン(0.5mL)に52mgを溶解したもの)、乾燥トリエチルアミン(52μL)、及び触媒量のDMAPを窒素雰囲気下で加え合わせた。反応液を3時間撹拌した後、ジクロロメタン(25mL)で希釈した。有機画分を0.1Mリン酸ナトリウム(2×10mL)、次いで食塩水で洗浄した。有機画分を硫酸ナトリウム上で乾燥し、濾過してから減圧下で濃縮した。水性洗浄画分を加え合わせ、ジクロロメタンで数回に分けて抽出した。次いで、水性画分を希塩酸により約pH 2まで酸性化し、ジクロロメタンで更に2回抽出した。有機抽出液を加え合わせ、硫酸ナトリウム上で乾燥し、減圧下で濃縮した。得られた物質を、最初の抽出から得られた物質と加え合わせ、シリカゲルの細いカラムを使用して精製した。水で飽和させた10〜25%メタノール/クロロホルムで溶出し、58mgのアミド生成物を無色の固体として得た。1H NMR(クロロホルム−d,500MHz)δ 10.08(s,1H),8.00(d,J=8.2Hz,2H),7.95(d,J=8.4Hz,2H),7.19(m,1H),3.77(t,J=6.1Hz,2H),3.70−3.60(m,48H),2.60(t,J=6.1Hz,2H)。
パートAで得られた物質を、乾燥N,N−ジメチルホルムアミド(0.5mL)及び乾燥ピリジン(0.5mL)に溶解した。O−(N−スクシンイミジル)−1,1,3,3−テトラメチルウロニウムテトラフルオロボレート(TSTU;46mg;シグマ・アルドリッチ社(Sigma-Aldrich)(ミズーリ州セントルイス)より販売されるもの)を加え、反応液を窒素雰囲気下で3時間撹拌した。溶媒の大部分を減圧下で除去した。得られた物質をクロロホルム(25mL)及びメタノール(5mL)に溶解し、分液漏斗に入れた。緩衝溶液(水酸化ナトリウムによりpH 7.5に調整した0.10M塩化ナトリウム、0.05Mリン酸ナトリウム、1.0mM EDTAの溶液10mL)を加え、混合物を2時間振盪した。有機画分を回収し、更なる量の緩衝溶液(10mL)、水(3×10mL)、及び食塩水で順次洗浄した。有機画分を硫酸ナトリウム上で乾燥し、濾過してから、減圧下で濃縮して55mgの化合物Aを無色のシロップ状物として得た。1H NMR(クロロホルム−d,500MHz)δ 10.08(s,1H),7.99(d,J=8.2Hz,2H),7.95(d,J=8.1Hz,2H),7.10(m,1H),3.85(t,J=6.5Hz,2H),3.70−3.60(m,48H),2.90(t,J=6.9Hz,2H)2.84(brs,4H)。
H1N1 PR8由来の組換えヘマグルチニン1(HA)をクローニングし、大腸菌で発現させ、標準的な方法により精製した。分子量が32083.11ダルトンであり、C末端に6個のヒスチジンを有するこのHAを、0.15MのNaClを含むpH 7.5、0.1Mのリン酸緩衝溶液に入れた。HAの分子量及びタンパク質の質量に基づいて、HA溶液のモル濃度を確立した。ジメチルスルホキシド(DMSO)に溶解した化合物Aを、HAに10倍のモル過剰量で加えた。次いでこの溶液を室温で2時間インキュベートした。化合物Aで修飾されたHA(HA−化合物として表される)を、0.15MのNaClを含むpH 6.0、0.1Mのリン酸緩衝溶液で予め平衡化したZEBAスピンカラム(サーモ・サイエンティフィック社(Thermo Scientific)、イリノイ州ロックフォード)を使用して遊離化合物Aから分離した。この工程により、複合化反応に備えてHA−化合物A溶液をpH 6.0に変化させた。
N−(4−{[4−アミノ−2−ブチル−1H−イミダゾ[4,5−c]キノリン−1−イル]オキシ}ブチル)−6−(N’−イソプロピリデンヒドラジノ)ニコチンアミド(下記に述べるようにして調製したもの)をDMSOに溶解し、緩衝したHA−化合物Aの溶液に10倍のモル過剰量で加えた。反応媒質の酸性条件のため、N−(4−{[4−アミノ−2−ブチル−1H−イミダゾ[4,5−c]キノリン−1−イル]オキシ}ブチル)−6−(N’−イソプロピリデンヒドラジノ)ニコチンアミドのアセトイミン保護基が脱保護され、N−(4−{[4−アミノ−2−ブチル−1H−イミダゾ[4,5−c]キノリン−1−イル]オキシ}ブチル)−6−ヒドラジノニコチンアミドがその場で生成した。試料を、室温で2時間インキュベートした。N−(4−{[4−アミノ−2−ブチル−1H−イミダゾ[4,5−c]キノリン−1−イル]オキシ}ブチル)−6−ヒドラジノニコチンアミドと共有結合により複合体化したHA−化合物A(HA−化合物A−化合物2として表される)を、ダルベッコリン酸緩衝溶液(PBS)(シグマ・アルドリッチ社(Sigma-Aldrich)ミズーリ州セントルイス)で予め平衡化したZEBAスピンカラムを使用して複合化していない成分から分離した。
N−(4−{[4−アミノ−2−ブチル−1H−イミダゾ[4,5−c]キノリン−1−イル]オキシ}ブチル)−6−ヒドラジノニコチンアミド(化合物2)
吉草酸無水物(6.03g)及び塩酸ピリジン(0.198g)をピリジン(8.28g)に加えた溶液を、3−アミノ−4−クロロキノリン(2.94g)をピリジン(5.0g)に加えた溶液に加え、反応液を室温で16時間攪拌した後、60℃で3時間加熱した。反応液を減圧下濃縮し、炭酸ナトリウム(15mLの10%水溶液)を加えた。反応液を30分間攪拌してから濾過した。得られた固体を水(60mL)で洗浄し、真空下で4時間乾燥して4.59gのN−(4−クロロキノリン−3−イル)バレルアミドの粗生成物を褐色のフレークとして得た。この粗生成物をヘプタン(10mL)から再結晶化し、回収された生成物をソックスレー抽出によりヘプタンを16時間還流して更に精製した。ソックスレー抽出装置からの回収フラスコをフリーザー内で2時間冷却した。得られた固体を濾過により回収し、真空下で乾燥して2.00gのN−(4−クロロキノリン−3−イル)バレルアミドを白色の固体として得た。
4−アミノ−1−ブタノール(7.68g)及びピリジン(7.00g)をジクロロメタン(100mL)に加えた溶液を氷浴中で冷やし、クロロギ酸ベンジル(14.37g)をジクロロメタン(100mL)に加えた溶液を攪拌しながら30分間かけて徐々に加えた。氷浴を外し、反応液を更に16時間攪拌した。塩酸(1.2M、200mL)を加え、各相を分離した。有機相を乾燥(MgSO4)、濾過し、減圧下で濃縮した。得られた残渣をトルエンから再結晶化し、真空下で乾燥して5.15gのベンジル(4−ヒドロキシブチル)カルバメートを得た。
N−(4−クロロキノリン−3−イル)バレルアミド(1.97g)、ベンジル(4−アミノオキシブチル)カルバメート(2.99g)、トリエチルアミン(0.89g)、及び2−プロパノール(40.69g)を加え合わせて、80℃で3.5時間加熱した。反応液を室温にまで冷却し、濾過してから、濾液を減圧下で濃縮した。得られた固体にジクロロメタン(20mL)を加え、混合物を20分間攪拌した。溶解しなかった固体を濾去し、20滴の塩酸(1.2M)を加えることによって弱酸性とした水を10mLずつ2回使用して濾液を洗浄した。有機画分を乾燥し、減圧下で濃縮した。この固体粗生成物をテトラヒドロフランから再結晶化して、2.56gのベンジル4−{[2−ブチル−1H−イミダゾ[4,5−c]キノリン−1−イル]オキシ}ブチルカルバメートを得た。
ベンジル4−{[2−ブチル−1H−イミダゾ[4,5−c]キノリン−1−イル]オキシ}ブチルカーバメート塩酸塩(10.05g)をジクロロメタン(80mL)に溶解し、炭酸ナトリウム(2.02g)を30mLのH2Oに加えた溶液で抽出した。有機層を氷浴中で冷却し、m−クロロ過安息香酸(5.93g,1.24当量)をジクロロメタン(30mL)に溶解した溶液を徐々に加えた。6時間後、水酸化アンモニウム(10mLの28〜30%水溶液)を反応液に加えた。ベンゼンスルホニルクロリド(6.96g)を10mLのジクロロメタンに加えた溶液を、激しく攪拌しながら徐々に加えた。冷却浴を外し、反応液を更に12時間攪拌した。反応液を水(100mL)で希釈し、有機画分と水性画分とを分離した。水性画分をジクロロメタン(30mL)で抽出した。合わせた有機画分を、5%炭酸ナトリウムを90mLずつ2回使用して洗浄した。
1−(4−アミノブトキシ)−2−ブチル−1H−イミダゾ[4,5−c]キノリン−4−アミンビスマレエート塩(0.2g)を1−ブタノール(5mL)に懸濁し、2×5mL量の5%炭酸ナトリウム溶液で順次洗浄した後、5mLの飽和塩化ナトリウム溶液で洗浄した。イリノイ州ロックフォード所在のサーモ・サイエンティフィック社(Thermo Scientific)より販売されるスクシンイミジル4−ヒドラジノニコチネートアセトンヒドラゾン(SANH,0.0216g)を加え、この溶液を室温で17.5時間撹拌した。薄層クロマトグラフィー(シリカゲル,メチル−tert−ブチルエーテル:エタノール=1:1の溶離液)により反応液を分析したところ、1−(4−アミノブトキシ)−2−ブチル−1H−イミダゾ[4,5−c]キノリン−4−アミン(Rf<0.05)及び所望の生成物であるN−(4−{[4−アミノ−2−ブチル−1H−イミダゾ[4,5−c]キノリン−1−イル]オキシ}ブチル)−6−(N’−イソプロピリデンヒドラジノ)ニコチンアミド(Rf0.30)の存在のみが示された。反応液を減圧下で濃縮し、5mLのジクロロメタンを残渣に加えた。少量の不溶性物質を濾去し、試料をカラムクロマトグラフィー(シリカゲル、メチル−tert−ブチルエーテル:エタノール=1:1の溶離液)により精製した。生成物を含む各画分を加え合わせ、減圧下で溶媒を除去してN−(4−{[4−アミノ−2−ブチル−1H−イミダゾ[4,5−c]キノリン−1−イル]オキシ}ブチル)−6−(N’−イソプロピリデンヒドラジノ)ニコチンアミドを淡黄色固体として得た(化合物1)。
パートEで得たN−(4−{[4−アミノ−2−ブチル−1H−イミダゾ[4,5−c]キノリン−1−イル]オキシ}ブチル)−6−(N’−イソプロピリデンヒドラジノ)ニコチンアミドを、1mLの塩酸(0.6M)に懸濁し、60℃に90分間加熱した。得られた均質な溶液を室温にまで冷却し、反応液を減圧下で濃縮した。得られた残渣を水に溶解してから凍結乾燥して43.6mgのN−(4−{[4−アミノ−2−ブチル−1H−イミダゾ[4,5−c]キノリン−1−イル]オキシ}ブチル)−6−ヒドラジノニコチンアミド塩酸塩を黄色の固体として得た(化合物2)。MS(ESI)m/z 463.25661(C24H31N8O2に対する計算値463.25645,M+H+)。
実施例2の工程において、化合物Aの代わりにジメシルスルホキシド(DMSO)に溶解したスクシンイミジル4−ホルミルベンゾエート(SFB)(サーモ・サイエンティフィック社(Thermo Scientific)、イリノイ州ロックフォード)を10倍のモル過剰量でHAに加える改変を行い、実施例2及び3の方法にしたがって比較例Aを調製した。
共有結合により複合体化した生成物における化合物Aの使用が最終的なタンパク質の溶解度及び回収率(%)に与える影響をSFBと比較して表Iに示す。可溶性タンパク質の測定値は、100K×gで遠心分離した試料の上清中に回収された比較例A又は実施例3の量として測定した。全タンパク質の測定値を、遠心分離を行う前の試料中の比較例A又は実施例3の量として求めた。可溶性タンパク質及び全タンパク質の測定は、ビシンコニン酸(BCA)タンパク質アッセイ(サーモ・サイエンティフィック社(Thermo Scientific)(イリノイ州ロックフォード)より入手したもの)を使用して行った。
実施例3の複合体化生成物によるヒト末梢血単核球(PBMC)におけるインターフェロンα(IFN)及び腫瘍壊死因子(TNF)産生のインビトロでの誘導は、以下の手順を用いて測定することができる。ヒト提供者より調製したPBMCを、96穴マイクロタイタープレートに培養物として播種することができる。HA、実施例2の修飾されたHA、及び実施例3の複合体を、1μMタンパク質の最終濃度で各ウェルに加えることができる。細胞を37℃で一晩インキュベートすることができる。培地を除去し、IFN濃度(pg/mL)及びTNF濃度(ng/mL)をELISAアッセイにより測定することができる。
実施例3の複合体のワクチンアジュバント活性を、Balb/C雄性マウス(チャールズ・リバー・ラボラトリーズ・インターナショナル社(Charles River Laboratories,International)マサチューセッツ州ウィルミントン)において評価することができる。各群5匹のマウスを、10μgのPBSに加えたHA抗原(コントロール)、10μgの実施例2(コントロール)、又は実施例3の複合体を皮下注射することにより免疫化することができる。最初の免疫化の2週間後及び4週間後に、同じ組み合わせによってマウスを追加免疫することができる。最後の追加免疫の3週間後及び12週間後に再び、マウスから採血してHA特異的抗体の抗体価を測定することができる。この測定は、HAをコーティングしたマイクロタイタープレート中で標準的な血清ELISAにより、血清試料を連続希釈することにより行うことができる。抗体のデータは、エンドポイント(ベースラインの2倍)が得られた血清の希釈度として示すことができ、1群当たり5匹のマウスについての幾何平均である。免疫反応のTH1への偏りの指数として、HA特異的な全IgG以外に、HA特異的なIgG1及びIgG2aのサブタイプを測定することができる。
Claims (5)
- 免疫反応調節物質と、
下式:
により表されるリンカーと、
抗原と、
の複合体であって、
前記免疫反応調節物質が前記リンカーと、イミダゾキノリン4−アミン、イミダゾナフチリジン4−アミン、ピラゾロキノリン4−アミン若しくはピラゾロナフチリジン4−アミンの1位若しくは7位、又はチアゾロキノリン4−アミンの7位に位置したヒドラゾン官能基を介して*において共有結合により結合したイミダゾキノリン4−アミン、イミダゾナフチリジン4−アミン、ピラゾロキノリン4−アミン、ピラゾロナフチリジン4−アミン、又はチアゾロキノリン4−アミンであり、
前記抗原が前記リンカーと**においてアミド、ジスルフィド、尿素、チオ尿素、カルバメート、アミド若しくはスルホンに対してα位の炭素−硫黄若しくは炭素−窒素結合、又はスクシンイミド環に直接結合しているチオエーテル基若しくはアミノ基を介して共有結合により結合されている複合体。 - 前記イミダゾキノリン4−アミン、イミダゾナフチリジン4−アミン、ピラゾロキノリン4−アミン、若しくはピラゾロナフチリジン4−アミンの1位が、−X1−Y−X2−N(H)−N=C(H)−、若しくは−X1−Y−X2−C(O)−N(H)−N=C(H)−(式中、X1は、場合により1以上の−O−基により分断され、場合により−O−で終端するアルキレンであり、Yは−NH−C(O)−であり、X2はアルキレン、アリーレン、又はヘテロアリーレンである)により置換されているか、又は
前記イミダゾキノリン4−アミン、イミダゾナフチリジン4−アミン、ピラゾロキノリン4−アミン、ピラゾロナフチリジン4−アミン、若しくはチアゾロキノリン4−アミンの7位が、−Z−X1−Y−X2−N(H)−N=C(H)−、若しくは−Z−X1−Y−X2−C(O)−N(H)−N=C(H)−(式中、Zは、結合であるか、又は−O−であり、X1は、場合により1以上の−O−基により分断され、場合により−O−で終端するアルキレンであり、Yは−NH−C(O)−であり、X2はアルキレン、アリーレン、又はヘテロアリーレンである)により置換されている、請求項1に記載の複合体。 - 薬学的に許容される担体、及び有効量の請求項1又は2に記載の複合体を含む医薬組成物。
- 動物に有効量の複合体又は医薬組成物を投与することによって動物へのワクチン接種に使用するための、請求項1又は2に記載の複合体、又は請求項3に記載の医薬組成物。
- 動物に有効量の複合体又は医薬組成物を投与することによって動物におけるサイトカイン生合成の誘導に使用するための、請求項1又は2に記載の複合体、又は請求項3に記載の医薬組成物。
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AU2012261966A1 (en) | 2013-12-19 |
MX2013014146A (es) | 2014-01-31 |
US9902724B2 (en) | 2018-02-27 |
ZA201309686B (en) | 2015-04-29 |
US20140227317A1 (en) | 2014-08-14 |
CA2838158C (en) | 2019-07-16 |
BR112013031028A2 (pt) | 2016-11-29 |
US9475804B2 (en) | 2016-10-25 |
CN103582496B (zh) | 2016-05-11 |
EP2717919A4 (en) | 2014-10-15 |
WO2012167088A1 (en) | 2012-12-06 |
MX347240B (es) | 2017-04-20 |
CA2838158A1 (en) | 2012-12-06 |
EP2717919B1 (en) | 2016-08-03 |
US20180186792A1 (en) | 2018-07-05 |
JP2014516991A (ja) | 2014-07-17 |
US10723731B2 (en) | 2020-07-28 |
EP2717919A1 (en) | 2014-04-16 |
CN103582496A (zh) | 2014-02-12 |
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