JP6445046B2 - 1,1’−(1,6−ジオキソ−1,6−ヘキサンジイル)ビス−d−プロリンのプロドラッグ - Google Patents
1,1’−(1,6−ジオキソ−1,6−ヘキサンジイル)ビス−d−プロリンのプロドラッグ Download PDFInfo
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- JP6445046B2 JP6445046B2 JP2016565212A JP2016565212A JP6445046B2 JP 6445046 B2 JP6445046 B2 JP 6445046B2 JP 2016565212 A JP2016565212 A JP 2016565212A JP 2016565212 A JP2016565212 A JP 2016565212A JP 6445046 B2 JP6445046 B2 JP 6445046B2
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- 239000001044 red dye Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 210000001258 synovial membrane Anatomy 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
- 238000012250 transgenic expression Methods 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- A—HUMAN NECESSITIES
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A61P25/00—Drugs for disorders of the nervous system
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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Description
定義
以下の用語は、以下に本明細書に提示される意味を有することが意図され、本発明の説明および範囲を理解する上で有用である。
療法において式(I)の化合物を使用するために、それは通常、標準的な製薬実務に従って医薬組成物に処方される。
2−MeTHF 2−メチルテトラヒドロフラン
aq. 水性
BnOH ベンジルアルコール
Bu4NI テトラブチルアンモニウムヨージド
DCM ジクロロメタン/塩化メチレン
DMAP ジメチルアミノピリジン
ESI エレクトロスプレーイオン化
EtOAc 酢酸エチル
Et2O ジエチルエーテル
h 時間
HCl 塩化水素/塩酸
HPLC 高速液体クロマトグラフィー
IPA イソプロピルアルコール
iPr2O イソプロピルエーテル
MeCN/CH3CN アセトニトリル
Min 分
MS 質量分析
Na2SO4 硫酸ナトリウム
NMR 核磁気共鳴
PhMe トルエン
py ピリジン
RT 室温
TBAI テトラブチルアンモニウムヨージド
TEA トリエチルアミン
TOF 飛行時間
THF テトラヒドロフラン
ジエチルエーテル(500mL)中のテトラヒドロ−2H−ピラン−4−オール(40g、392mmol)の溶液に、ピリジン(38.0mL、470mmol)を加え、溶液を0℃に冷却した。クロロメチルカルボノクロリデート(41.8mL、470mmol)を滴下し、白色固体を生成させた。反応混合物を室温で18時間撹拌した。反応混合物を水(200mL)、HCl 0.5N(200mL)、次に、NaHCO3飽和溶液(200mL)で洗浄した。有機相をNa2SO4で乾燥させ、減圧下で濃縮した。
1H NMR (400 MHz, CDCl3) δ ppm 5.75 (s, 2 H), 4.92 (m, 1 H), 3.95 (m, 2 H), 3.56 (m, 2 H), 2.02 (m, 2 H), 1.80 (m, 2 H)。
DCM(50mL)中のクロロメチルカルボノクロリデート(5g、38.8mmol)の溶液に、テトラヒドロ−2H−ピラン−4−オール(3.96g、38.8mmol)を加え、溶液を0℃に冷却した。DMAP(4.97g、40.7mmol)を加え、次いで、反応混合物を室温で18時間撹拌した。反応混合物を水で希釈し、DCM(3×100mL)で抽出した。有機相を合わせ、Na2SO4で乾燥させ、減圧下で濃縮した。淡黄色油状物を、シクロヘキサン中10%EtOAcで溶出するクロマトグラフィーにより精製した。適当な画分を合わせ、真空で濃縮し、必要な生成物を無色油状物として得た(2.2g、11.3mmol、収率29.2%)。
1H NMR (300 MHz, CDCl3) δ ppm 5.76 (s, 2 H), 4.92 (m, 1 H), 3.94 (m, 2 H), 3.57 (m, 2 H), 2.02 (m, 2 H), 1.80 (m, 2 H)。
1H NMR (400 MHz, CDCl3) δ ppm 5.88 (d, J = 5.5 Hz, 2 H), 5.73 (d, J = 5.5 Hz, 2 H), 4.87 (m, 2 H), 4.50 (m, 2 H), 3.93 (m, 4 H), 3.65 (m, 2 H), 3.55 (m, 6 H), 2.42 - 1.90 (m, 16 H), 1.84 - 1.60 (m, 8H)。
(2R,2’R)−ビス(((((テトラヒドロ−2H−ピラン−4−イル)オキシ)カルボニル)オキシ)メチル)1,1’−アジポイルビス(ピロリジン−2−カルボキシレート)(170g、259mmol)を2−MeTHF中に懸濁し、完全に溶解するまで90℃に加熱した。まだ熱いうちに溶液を濾過し、室温に冷却した。沈殿物を濾過し、2−MeTHF/iPr2O 70/30の混合物で洗浄し、(2R,2’R)−ビス(((((テトラヒドロ−2H−ピラン−4−イル)オキシ)カルボニル)オキシ)メチル)1,1’−アジポイルビス(ピロリジン−2−カルボキシレート)(130g、198mmol、収率76%)を灰白色結晶性固体として得た。生成物を減圧下(5ミリバール)および35℃で12時間乾燥させた。
LC/MS: m/z 657 [M+H]+, Rt 1.98分。
1H NMR (400 MHz, CDCl3) δ ppm 5.87 (d, J = 5.5 Hz, 2 H), 5.71 (d, J = 5.5 Hz, 2 H), 4.86 (m, 2 H), 4.49 (m, 2 H), 3.91 (m, 4 H), 3.63 (m, 2 H), 3.54 (m, 6 H), 2.43 - 1.85 (m, 16 H), 1.84 - 1.59 (m, 8H)。
13C NMR (100 MHz, CDCl3) 171.69, 170.85, 153.12, 82.26, 77.36, 77.05, 76.72, 73.94, 65.02, 58.41, 46.95, 34.11, 31.47, 29.02, 24.80, 24.17。
HRMS:C30H45N2O14 [M+H]+のm/z計算値657.2870、実測値657.2883。
[図1]
以下に報告するデータは、式(I)の化合物を(2R,2’R)−ビス(1−(ピバロイルオキシ)エチル)1,1’−アジポイルビス(ピロリジン−2−カルボキシレート)(比較化合物)と比較している。
物理的形態
式(I)の化合物は、結晶性固体として得ることができる。対照的に、比較化合物は油状物として得られる(国際公開第2003/051836号参照)。
溶解度を決定するためのプロトコール
式(I)の化合物の既知量を好適な容器(例えば、スクリューキャップ付き透明ガラスバイアル)に秤量し、必要な媒体の既知容量を加えた(例えば、人工胃液(Simulated Gastric Fluid)pH1.6[SGF]、摂食時における人工腸液(Simulated Fed State Intestinal Fluid)pH6.5[FeSSIF]、空腹時における人工腸液(Simulated Fasted State Intestinal Fluid)pH6.5[FaSSIF]、水[精製水]、またはブリトン・ロビンソン緩衝液(Britton-Robinson buffer))。化合物を30秒〜1分間ボルテックス混合することにより媒体で湿潤させた。次いで、サンプルを目視観察して、溶解していない固体が残っていることを確認した。サンプルを穏やかなミキサー(例えば、ローラーミキサーなど)に移し、所望の時点に達するまで撹拌した。適当な時間に、サンプルを視覚的に再評価した。総ての固体が溶解していた場合、溶解度は>x mg/mlとして記録した。ここで、xは、使用した既知の重量を加えた容量で割ったものである。溶解していない固体が残っていた場合、サンプルの一部を採取し、遠心分離して、固体を除去し、透明な上清を残した。上清を好適な希釈液で容量測定希釈して、分析に適した濃度の分析サンプルを得た。次いで、この希釈サンプルを、既知の濃度の標準と比較してHPLCなどの好適な方法により分析した。次いで、化合物の溶解度を、標準の濃度、標準の相対応答(例えば、ピーク面積)および記載した分析サンプル、ならびに分析サンプルの希釈の知識を用いて計算することができる。
式(I)の化合物および比較化合物を、以下のシトクロムp450(CYP 450)アッセイにより評価した。結果を以下の表3に示す。
・7−メトキシ−4−トリフルオロメチルクマリン−3−酢酸エチルエステル(FCA):アセトニトリル中12.5mM
・エトキシレゾルフィン(ER):アセトニトリル中0.05mM
・4−メチルアミノメチル−7−メトキシクマリン(MMC):メタノール中2.5mM
・3−ブチリル−7メトキシクマリン(BMC):DMSO中2.5mM
・7−ベンジルオキシキノリン(7BQ):アセトニトリル中2.5mM
・ジエトキシフルオレセイン(DEF):アセトニトリル中0.1mM
・bactosomes CYP2C9 0.33mlと、バッファー23.8mlおよびFCA 0.11ml
・bactosomes CYP1A2 0.33mlと、バッファー23.6mlおよびER 0.275ml
・bactosomes CYP2D6 0.33mlと、バッファー23.8mlおよびMMC 0.11ml
・bactosomes CYP2C19 0.33mlと、バッファー23.8mlおよびBMC 0.11ml
・bactosomes CYP3A4H 0.33mlと、バッファー23.6mlおよび7BQ 0.275ml
・bactosomes CYP3A4L 0.33mlと、バッファー23.6mlおよびDEF 0.275ml
・FCA(2C9):410nmでの励起および510nmでの発光
・ER(1A2):530nmでの励起および590nmでの発光
・MMC(2D6):410nmでの励起および485nmでの発光
・BMC(2C19):410nmでの励起および465nmでの発光
・7BQ(3A4H):410nmでの励起および530nmでの発光
・DEF(3A4L):485nmでの励起および530nmでの発光
物理的安定性を決定するためのプロトコール:
様々なpHのバッファー中での化合物の物理的安定性を決定するために、アッセイを設計した。式(I)の化合物をDMSOに1mg/mlで溶解した。リン酸バッファー(PBS)は、pH6.0、7.0、7.5、8.0の4種のバッファーを得るために、K2HPO4 50mM溶液およびKH2PO4 50mM溶液を混合することにより調製した。
・式(I)の化合物:657〜384
・CPHPCのモノエステル:499〜226
・CPHPC:341〜226
[図2]
腸および肝臓ミクロソームアッセイプロトコール
ミクロソームマトリックス中での化合物の安定性を決定するために、アッセイを設計した。化合物(式(I)の化合物)をDMSOに1mg/mlで溶解した。娘溶液は、メタノール/水(50/50)で30.3ng/mlで調製した。ミクロソーム(Xenotech製)は、リン酸バッファー(50mM pH7.4)で1ml当たりタンパク質0.625mgに希釈した。
・式(I)の化合物:657〜384
・CPHPCのモノエステル:499〜226
・CPHPC:341〜226
[図3]
新鮮な血液中での化合物の安定性を決定するために、アッセイを設計した。化合物(式(I)の化合物)をDMSOに1mg/mlで溶解した。娘溶液は、DMSOで100μg/mlで調製した。新鮮な血液は、等張バッファー(pH7.4)で1/2希釈した。
・式(I)の化合物:657〜384
・CPHPCのモノエステル:499〜226
・CPHPC:341〜226
[図4]
[図5]
Claims (13)
- 式(I):
- 結晶形態の、請求項1に記載の化合物。
- 治療上有効な量の請求項1または請求項2に記載の化合物と、場合により、1種類以上の薬学上許容可能な担体および/または賦形剤とを含んでなる、医薬組成物。
- 経口投与のための、請求項3に記載の医薬組成物。
- 1以上の投与形態の抗SAP抗体と、1以上の投与形態の請求項1〜4のいずれか一項に記載の化合物または医薬組成物とを含んでなる、キット。
- 療法における使用のための、請求項3または4に記載の医薬組成物。
- SAPの枯渇における使用のための、請求項3または4に記載の医薬組成物。
- SAP枯渇が有益である疾患または障害の治療における使用のための、請求項3または4に記載の医薬組成物。
- 前記疾患または障害が、アミロイドーシス、アルツハイマー病、2型真性糖尿病および変形性関節症からなる群から選択される、請求項8に記載の医薬組成物。
- 前記疾患または障害がアミロイドーシスである、請求項8または9に記載の医薬組成物。
- 前記疾患または障害が全身性アミロイドーシスである、請求項8〜10のいずれか一項に記載の医薬組成物。
- アミロイドーシスの治療における使用のための、抗SAP抗体と共投与される、請求項3または4に記載の医薬組成物。
- 請求項1〜4のいずれか一項に記載の化合物または医薬組成物と、抗SAP抗体とを含んでなる、アミロイドーシスの治療における使用のための、組み合わせ医薬。
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GBGB1407506.3A GB201407506D0 (en) | 2014-04-29 | 2014-04-29 | Novel compound |
PCT/EP2015/058998 WO2015165833A1 (en) | 2014-04-29 | 2015-04-27 | A prodrug of 1,1'-(1,6-dioxo-1,6-hexanediyl)bis-d-proline |
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US9737505B2 (en) | 2014-04-29 | 2017-08-22 | Glaxosmithkline Intellectual Property Development Limited | Prodrug of 1,1′-(1,6-dioxo-1,6-hexanediyl)bis-D-proline |
GB201518950D0 (en) * | 2015-10-27 | 2015-12-09 | Glaxosmithkline Ip Dev Ltd | Compound |
GB202213162D0 (en) | 2022-09-08 | 2022-10-26 | Cambridge Entpr Ltd | Prodrugs |
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SI0915088T1 (en) | 1997-10-31 | 2002-12-31 | F. Hoffmann-La Roche Ag | D-proline derivatives |
US6903129B2 (en) * | 2001-12-14 | 2005-06-07 | Hoffman-La Roche Inc. | D-proline prodrugs |
EP1636240A1 (en) | 2003-06-05 | 2006-03-22 | Pfizer Products Inc. | Beta-lactamase inhibitor prodrug |
GB0313386D0 (en) | 2003-06-10 | 2003-07-16 | Univ London | Treatment of disease |
EP1870412A4 (en) | 2005-04-12 | 2009-12-30 | Meiji Seika Kaisha | 2-THIOETHENYLCARBAPENEM DERIVATIVE |
GB0712503D0 (en) | 2007-06-27 | 2007-08-08 | Therapeutics Pentraxin Ltd | Use |
UA108227C2 (xx) | 2010-03-03 | 2015-04-10 | Антигензв'язуючий білок | |
US9737505B2 (en) | 2014-04-29 | 2017-08-22 | Glaxosmithkline Intellectual Property Development Limited | Prodrug of 1,1′-(1,6-dioxo-1,6-hexanediyl)bis-D-proline |
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