JP6501947B2 - 抗腫瘍化合物 - Google Patents
抗腫瘍化合物 Download PDFInfo
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- JP6501947B2 JP6501947B2 JP2018086737A JP2018086737A JP6501947B2 JP 6501947 B2 JP6501947 B2 JP 6501947B2 JP 2018086737 A JP2018086737 A JP 2018086737A JP 2018086737 A JP2018086737 A JP 2018086737A JP 6501947 B2 JP6501947 B2 JP 6501947B2
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- cancer
- compound
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- lung cancer
- pharmaceutically acceptable
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- C07D515/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Description
Xは-O-であり、
R2はアセチルであり、
R3は水素であり、
R4は水素又は-CH2OHから選択される]
を含む方法を提供する。
・ 本発明の化合物及び二糖を含む医薬組成物を含む。特に好ましい二糖は、ラクトース、トレハロース、スクロース、マルトース、イソマルトース、セロビオース、イソサッカロース、イソトレハロース、ツラノース、メリビオース、ゲンチオビオース、及び、それらの混合物から選択される。
・ 更に、前記の好ましい組成物は、本発明の化合物及び二糖を含む凍結乾燥医薬組成物を含む。特に好ましい二糖は、ラクトース、トレハロース、スクロース、マルトース、イソマルトース、セロビオース、イソサッカロース、イソトレハロース、ツラノース、メリビオース、ゲンチオビオース及び、それらの混合物から選択される。
Xは-O-であり、
R2はアセチルであり、
R3は水素であり、
R4は-CH2OHである]
を含む方法を提供する。
・ 式IIIの化合物が式IIIaの化合物である
Xは-O-であり、
R3は水素であり、
R4は-CH2OHである]
方法を含む。
Xは-O-であり、
R2はアセチルであり、
R3は水素であり、
R4は水素である]
を含む方法を提供する。
抗腫瘍活性検出のためのインビトロバイオアッセイ
このアッセイの目的は、被験サンプルのインビトロでの細胞分裂抑制(腫瘍細胞増殖の遅延又は停止能)又は細胞傷害活性(腫瘍細胞殺傷能)を評価することである。
スルホローダミンB(SRB)反応を使った比色アッセイを採用し、細胞の増殖及び生存率の定量を提供した(Skehan et al. J. Natl. Cancer Inst. 1990, 82, 1107-1112に記載の技術に従った)。3-(4,5-ジメチルチアゾール-2-イル)-2,5-ジフェニルテトラゾリウムブロミド(MTT)から紫色のホルマザンへの還元に基づく別の比色アッセイも使用して抗増殖活性を評価した(Mosmann et al. J. Immunol. Meth. 1983, 65, 55-63の説明の技術に従った)。
MTD及びMTMDの定量
全実験に雌CD-1又は胸腺欠損ヌード-Fox1 nu/nuマウス(Envigo社)を用いた。動物(N=10匹/ケージ)を21〜23℃及び湿度40〜60%、12時間明暗周期下で、個別換気ケージ内(Sealsafe Plus(登録商標) Techniplast S.P.A.社)に収容した。マウスには、放射線照射げっ歯類用標準食(Tecklad 2914C)と滅菌水を自由に摂取させた。動物を個別にタトゥーで識別する前に、5日間順化した。動物プロトコルは、the regional Institutional Animal Care and Use Committeesにより、再審査され、承認された。
インビボ異種移植
雌胸腺欠損nu/nuマウス(Harlan Laboratories Models, S.L社 バルセロナ、スペイン又はEnvigo社 スペイン)を全実験に用いた。動物を21〜23℃及び湿度40〜60%、12時間明暗周期下で、個別換気ケージ内(Sealsafe Plus(登録商標) Techniplast S.P.A.社)に1ケージ10匹を収容した。マウスには、放射線照射げっ歯類用標準食(Tecklad 2914C)と滅菌水を自由に摂取させた。腫瘍細胞懸濁液で腫瘍を移植する前に、少なくとも5日間動物を順化した。
- 総直径(腫瘍+脚部)の測定値をデジタルカリパー(Fowler Sylvac社, S235PAT)を使って決定した。この総直径と動物の体重を、治療初日(ゼロ日目)から週2〜3回測定した。
- 総直径が約7.0〜8.0mmの長さに達した時点で、NewLab Oncologyソフトウェア(バージョン2.25.06.00)を使って、体重及び腫瘍測定値に基づいて、マウスを治療群と対照群に無作為に割付けた(N=8〜10匹/群)。
- 抗腫瘍効果の評価に、対照群の総直径(腫瘍+脚部)中央値に対する治療群の総直径(腫瘍+脚部)中央値の比較を使用した。
- 総脚部直径が約18mmに達した時、動物を安楽死させた。
- 方程式(a・b2)/2を使って腫瘍体積を算出し、この場合、aの長さ(最長直径)、bの幅(最短直径)をデジタルカリパー(Fowler Sylvac社、S235PAT)を使ってmmで測定した。腫瘍の寸法と体重を、治療初日から週に2〜3回記録した。
- 腫瘍が約150〜250mm3に達した時点で、NewLab Oncologyソフトウェア(バージョン2.25.06.00)を使用し、体重と腫瘍測定値に基づいて、担腫瘍マウス(N=8〜10匹/群)を治療群に無作為に割付けた。
- 抗腫瘍効果の評価に、治療群と対照群の腫瘍体積中央値の比較を使用した。
- 腫瘍が約2000mm3に達した及び/又は重症壊死が見られた時、動物を安楽死させた。
数種の異種移植モデルにおける39-Sの作用を決定するインビボ試験
化合物39-S及びCは、凍結乾燥品のフリーズドライバイアルの形態で提供された。注射用に、各バイアルを滅菌水に溶解し、濃度0.5mg/mLとした。投与する配合物濃度まで注射用5%デキストロース溶液で更に希釈を行った。39-SとCの投与量は、それぞれ、1.25mg/Kgと3mg/Kgであった。
ヒト線維肉腫異種移植において39-Sの作用を決定するインビボ試験
この試験の目的は、ヒト肉腫の異種移植モデルを使った化合物Cの抗腫瘍活性との比較により化合物39-Sの抗腫瘍活性を評価することであった。
ヒト乳腺癌異種移植において39-Sの作用を決定するインビボ試験
この試験の目的は、ヒト乳がんの異種移植モデルを使った39-S及び化合物Cの抗腫瘍活性を比較することであった。
ヒト肺がん異種移植において39-Sの作用を決定するインビボ試験
この試験の目的は、ヒト肺がんの3種の異なる異種移植モデルを使って39-Sの抗腫瘍活性を化合物Cの抗腫瘍活性と比較することであった。これらのモデルは、非小細胞肺がん(H-460細胞系)と小細胞肺がん(H526及びH82細胞系)に対応する。
ヒト卵巣腫瘍異種移植において39-Sの作用を決定するインビボ試験
この試験の目的は、ヒト卵巣がんの異種移植モデルを使って39-Sの抗腫瘍活性を化合物Cの抗腫瘍活性と比較することであった。
ヒト胃腫瘍異種移植において39-Sの作用を決定するインビボ試験
この試験の目的は、ヒト胃がんの異種移植モデルを使って39-Sの抗腫瘍活性を化合物Cの抗腫瘍活性と比較することであった。
数種の異種移植モデルにおいて32の作用を決定するインビボ試験
化合物32及びET-736は、凍結乾燥品のフリーズドライバイアルの形態で提供された。0.5mg/mL濃度の注射用に、各バイアルを滅菌水に溶解した。投与配合物濃度まで注射用5%デキストロース溶液で更に希釈を行った。32及びET-736の投与量は、0.5mg/Kgであった。
ヒト線維肉腫異種移植において32の作用を決定するインビボ試験
この試験の目的は、ヒト肉腫の異種移植モデルを使ってET-736の抗腫瘍活性と比較して化合物32の抗腫瘍活性を評価することであった。
ヒト乳腺癌異種移植において32の作用を決定するインビボ試験
この試験の目的は、ヒト乳がんの異種移植モデルを使って32とET-736の抗腫瘍活性を比較することであった。
ヒト肺がん異種移植において32の作用を決定するインビボ試験
この試験の目的は、ヒト肺がんの3種の異なる異種移植モデルを使って32とET-736の抗腫瘍活性を比較することであった。これらのモデルは、非小細胞肺がん(H-460細胞系)と小細胞肺がん(H526及びH82細胞系)に対応する。
ヒト卵巣腫瘍異種移植において32の作用を決定するインビボ試験
この試験の目的は、ヒト卵巣がんの異種移植モデルを使って32とET-736の抗腫瘍活性を比較することであった。
ヒト胃腫瘍異種移植において32の作用を決定するインビボ試験
この試験の目的は、ヒト胃がんの異種移植モデルを使って32とET-736の抗腫瘍活性を比較することであった。
ヒト前立腺異種移植において39-Sの作用を決定するインビボ試験
この試験の目的は、ヒト前立腺がんの3種の異なる異種移植モデルを使って39-Sの抗腫瘍活性を比較することであった。これらのモデルは、PC-3、DU-145及び22Rv1細胞系に対応する。
Claims (20)
- 式Vの化合物、又はその薬学的に許容可能な塩。
- 前記塩が、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、硝酸塩、リン酸塩、酢酸塩、トリフルオロ酢酸塩、マレイン酸塩、フマル酸塩、クエン酸塩、シュウ酸塩、コハク酸塩、酒石酸塩、リンゴ酸塩、マンデル酸塩、メタンスルホン酸塩、p-トルエンスルホン酸塩、ナトリウム、カリウム、カルシウム、アンモニウム、エチレンジアミン、エタノールアミン、N,N-ジアルキレンエタノールアミン、トリエタノールアミン及び塩基性アミノ酸から選択される、請求項1に記載の化合物。
- 式VIの化合物、又はその薬学的に許容可能な塩。
- 前記塩が、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、硝酸塩、リン酸塩、酢酸塩、トリフルオロ酢酸塩、マレイン酸塩、フマル酸塩、クエン酸塩、シュウ酸塩、コハク酸塩、酒石酸塩、リンゴ酸塩、マンデル酸塩、メタンスルホン酸塩、p-トルエンスルホン酸塩、ナトリウム、カリウム、カルシウム、アンモニウム、エチレンジアミン、エタノールアミン、N,N-ジアルキレンエタノールアミン、トリエタノールアミン及び塩基性アミノ酸から選択される、請求項3に記載の化合物。
- 請求項1から4のいずれか一項に記載の化合物又はその薬学的に許容可能な塩、及び薬学的に許容可能な担体を含む、医薬組成物。
- 請求項5に記載の医薬組成物を含む剤形。
- 請求項1から4のいずれか一項に記載の化合物又はその薬学的に許容可能な塩、請求項5に記載の組成物、又は請求項6に記載の剤形を含む医薬。
- がんの治療用の、請求項7に記載の医薬。
- 前記がんが、非小細胞肺がん及び小細胞肺がんを含む肺がん、結腸がん、乳がん、膵臓がん、肉腫、卵巣がん、前立腺がん、胃がん並びに大腸がんから選択される、請求項8に記載の医薬。
- 前記がんが、非小細胞肺がん及び小細胞肺がんを含む肺がん、乳がん、膵臓がん並びに大腸がんから選択される、請求項9に記載の医薬。
- がんの治療用の医薬の製造における、請求項1から4のいずれか一項に記載の化合物又はその薬学的に許容可能な塩、請求項5に記載の組成物、又は請求項6に記載の剤形の使用。
- 前記がんが、非小細胞肺がん及び小細胞肺がんを含む肺がん、結腸がん、乳がん、膵臓がん、肉腫、卵巣がん、前立腺がん、胃がん並びに大腸がんから選択される、請求項11に記載の使用。
- 前記がんが、非小細胞肺がん及び小細胞肺がんを含む肺がん、乳がん、膵臓がん、並びに大腸がんから選択される、請求項12に記載の使用。
- 請求項1に記載の式Vの化合物又はその薬学的に許容可能な塩を得る方法であって、
式IIの化合物を式IIIの化合物と反応させて、式IVの化合物を生成する工程
Xは-O-であり、
R2はアセチルであり、
R3は水素であり、
R4は-CH2OHである]
を含む方法。 - 式IVの化合物中のシアノ基をヒドロキシ基で置き換えて式Vの化合物を生成する更なる工程を含む、請求項14に記載の方法。
- 請求項3に記載の式VIの化合物又はその薬学的に許容可能な塩を得る方法であって、
式IIの化合物を式IIIの化合物と反応させて、式IVの化合物を生成する工程
Xは-O-であり、
R2はアセチルであり、
R3は水素であり、
R4は水素である]
を含む方法。 - 式IVの化合物中のシアノ基をヒドロキシ基で置き換えて式VIの化合物を生成する更なる工程を含む、請求項16に記載の方法。
- 治療有効量の請求項1から4のいずれか一項に記載の化合物及び薬学的に許容可能な担体を含む、キット。
- がんの治療における前記化合物の使用説明書を更に含む、請求項18に記載のキット。
- 前記がんが、非小細胞肺がん及び小細胞肺がんを含む肺がん、結腸がん、乳がん、膵臓がん、肉腫、卵巣がん、前立腺がん、胃がん並びに大腸がんから選択される、請求項19に記載のキット。
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