JP2022518544A - TGF-βR1キナーゼ阻害剤としての5-(4-ピリジルオキシ)ピラゾール類化合物 - Google Patents
TGF-βR1キナーゼ阻害剤としての5-(4-ピリジルオキシ)ピラゾール類化合物 Download PDFInfo
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- JP2022518544A JP2022518544A JP2021543265A JP2021543265A JP2022518544A JP 2022518544 A JP2022518544 A JP 2022518544A JP 2021543265 A JP2021543265 A JP 2021543265A JP 2021543265 A JP2021543265 A JP 2021543265A JP 2022518544 A JP2022518544 A JP 2022518544A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
CN201910069936.2、出願日2019年01月24日。
C1-3アルコキシ、C1-3アルキル又はC3-6シクロアルキルであり、前記C1-3アルコキシ、C1-3アルキル及びC3-6シクロアルキルは1、2又は3個の独立的にF又はCから選ばれる置換基により任意に置換される。
本発明のある形態では、上記の各Rcは独立的にH、F、Cl、Br、I、-CN、-OH、-OCH3、-CH3又は-CH2CH3であり、他の変数は本発明に定義される通りである。
或いは、1、2又は3個の独立的にF、Cl、Br、I、-OH、-OCH3、-CN及びNH2から選ばれる置換基により任意に置換されたC1-4アルキルであり、他の変数は本発明に定義される通りである。
特に明記しない限り、本明細書で用いられる下記の用語と略語は以下の意味を有する。ある特定な用語又は略語は特に定義されていない場合、不確定又は不明白であると見なされるべきではなく、通常の意味で理解されるべきである。本明細書に商品名が現れるとき、対応する商品又はその活性成分を指すことを意味する。
で連結すれば、この化合物の(Z)型異性体、(E)型異性体又は2種の異性体の混合物を表す。例えば、次の式(A)は、化合物が式(A-1)又は式(A-2)の単一の異性体として、または式(A-1)及び式(A-2)の2つの異性体の混合物として存在することを表す。次の式(B)は、該化合物が式(B-1)又は式(B-2)の単一の異性体として、または式(B-1)及び式(B-2)の2つの異性体の混合物として存在することを表す。次の式(C)は、この化合物が式(C-1)又は式(C-2)の単一の異性体として、または式(C-1)及び式(C-2)の2つの異性体の混合物として存在することを表す。
前記連結基、置換基及び/又はその変体の組み合わせでは、このような組み合わせが安定な化合物をもたらす場合のみに許容される。
例えば、-OCH3における直線実線結合は、この基における酸素原子を介して他の基と連結していることを表す。
1H NMR(400MHz,DMSO-d6)δ=9.23(s,1H)、8.10(d,J=6.0Hz,1H)、8.02(t,J=1.6Hz,1H)、7.88-7.77(m,2H)、7.41(s,1H)、7.39-7.29(m,4H)、7.27(br d,J=4.0Hz,1H)、7.15-7.10(m,1H)、6.57(dd,J=2.4,6.0Hz,1H)、6.43(d,J=2.4Hz,1H)、6.13(s,1H)、2.32(s,3H)、2.28-2.24(m,3H)。
実験例1:Smadリン酸化阻害活性実験
実験の材料:
HEK-Blue-TGFβ細胞とQuanti-Blue試薬はInvivogen社から購入し、TGFβはPeproTechから購入した。
測定化合物をマイクロピペットで8回目の濃度まで5倍希釈し、つまり、1mmol/Lから12.8nmol/Lに希釈し、ジメチルスルホキシドの最終濃度を100%とし、ダブルマルチウェル実験を行った。マイクロプレートに2μL各濃度勾配の阻害剤、18μLTGFβ(20ng/mL)、180μLの細胞懸濁液(140000細胞/mL)を加え、この時点で、化合物の最終濃度勾配は10μmol/Lから0.13nmol/Lに希釈された。細胞プレートを37℃にし、5%のCO2インキュベーターに24時間続けて培養した。反応終了後、各ウェルから40μL細胞培養上清を新しい透明マイクロプレートに取り出し、各ウェルに160μLQuanti-Blue試薬を加え、37℃で60分間続けて反応し、反応終了後、PerkinElmer Envisionマルチラベルマイクロプレートアッセイシステムで630nmの吸収光を読み取った。
元のデータを阻害率に換算し、IC50の値は4パラメータによるカーブフィッティングによって取得できる。表1は、本発明の化合物のSmadリン酸化に対する阻害活性を示す。
実験の目的:
本実験の目的は、化合物の単回静脈注射と胃内投与後の薬物動態学的挙動を評価し、胃内投与後の生物学的利用率を考察することである。
7~10週齢のCD-1オスマウスを選び、静脈と経口投与の用量はそれぞれ1mg/kgと1.5mg/kgであった。マウスは投与前に少なくとも12時間断食し、投与後4時間に摂食を再開し、全試験期間中は自由に飲水できる。
実験当日に静脈組動物は尾静脈を通して対応する化合物を単回注射し、投与体積は5mL/kgであった。経口組は対応する化合物を単回胃内投与し、投与体積は5mL/kgであった。投与前に動物の体重を測り、体重に基づいて投与体積を計算した。サンプリング時間:注射組は0.083時間、0.25時間、0.5時間、1時間、2時間、4時間、8時間、24時間であり、胃内投与組は0.25時間、0.5時間、1時間、2時間、4時間、6時間、8時間、24時間であった。各時点で伏在静脈から約30μLの全血を採取し、濃度測定を行うための高速液体クロマトグラフィー-タンデム質量分析(LC-MS/MS)に用いられる血漿を調製した。最後の時点のPKサンプルを採取した後、すべての動物をCO2麻酔で安楽死させた。WinNonlin(商標) Version 6.3(Pharsight、Mountain View、CA)薬物動態ソフトウェアの非コンパートメントモデルで血漿濃度を処理し、線形対数台形法で薬物動態パラメータを計算した。
実験の目的:
本研究の主な目的は、CT26マウス同種移植腫瘍モデルに対して測定化合物の抗腫瘍効果を研究することである。
細胞培養:マウス結腸癌CT-26細胞を体外で単層培養し、培養条件は、RPMI-1640培地に10%牛胎児血清を加え、37℃で5%二酸化炭素のインキュベーターで培養した。週2回トリプシン-エチレンジアミン四酢酸(EDTA)で常例的な消化処理と継代を行った。細胞の飽和度が80%~90%で、数が要求に達すると、細胞を収集し、カウントし、接種した。
動物:BALB/cマウス、雌、6~8週齢。
腫瘍接種:3×105個のCT26細胞を含むDPBS細胞懸濁液0.1mLを各マウスの右側鼡径部に皮下接種し、接種当日に投与を開始した。
実験の指標:実験の指標は、腫瘍の成長が阻害、遅延、又は治癒したかどうかを考察することである。週2回ノギスで腫瘍の直径を測定した。腫瘍体積の計算式は、V=0.5L×W2であり、LとWはそれぞれ腫瘍の長径と短径を表す。
実験の目的:
本実験の目的は、化合物の単回静脈注射と胃内投与後の薬物動態学的挙動を評価し、胃内投与後の生物学的利用率を考察することである。
7~10週齢のCD-1オスマウスを選び、静脈と経口投与の用量はそれぞれ1mg/kgと2.5mg/kgであった。マウスは投与前に少なくとも12時間断食し、投与後4時間に摂食を再開し、全試験期間中は自由に飲水できる。
Claims (22)
- 式(I)で表される化合物、その薬学的に許容できる塩又はその異性体。
(ただし、R1及びR2はそれぞれ独立的に
C1-3アルコキシ、C1-3アルキル又はC3-6シクロアルキルであり、前記C1-3アルコキシ、C1-3アルキル及びC3-6シクロアルキルは1、2又は3個の独立的にF又はCから選ばれる置換基により任意に置換され、
又はR1及びR2はそれらに隣接している炭素原子と一緒に連結されて、
から選ばれることになり、
R3は、C1-6アルキル、5~6員ヘテロアリール、フェニル又は5~6員ヘテロシクロアルキルであり、前記C1-6アルキル、5~6員ヘテロアリール、フェニル及び5~6員ヘテロシクロアルキルは1、2又は3個のRcにより任意に置換され、
各Rcは独立的にH、F、Cl、Br、I、-CN、-OH、C1-3アルコキシ又はC1-3アルキルであり、
R4は5~6員ヘテロアリール又はフェニルであり、前記5~6員ヘテロアリール及びフェニルは1、2又は3個のRdにより任意に置換され、
各Rdは独立的に
或いは1、2又は3個の独立的にF、Cl、Br、I、-OH、-OCH3、-CN及びNH2から選ばれる置換基により任意に置換されたC1-6アルキルであり、
Ra、Rb、Re及びRfはそれぞれ独立的にH、-CH3、-CH2CH3、-CH2CH2CH3又は-CH(CH3)2であり、
前記5~6員ヘテロアリール及び5~6員ヘテロシクロアルキルはそれぞれ1、2、3又は4個の独立的にN、-O-及び-S-から選ばれるヘテロ原子を含む。) - 前記各Rcは独立的にH、F、Cl、Br、I、-CN、-OH、-OCH3、-CH3又は-CH2CH3である請求項1に記載の化合物、その薬学的に許容できる塩又はその異性体。
- 前記R3はC1-3アルキル、ピリジル、フェニル又はテトラヒドロ-2H-ピラニルであり、前記C1-3アルキル、ピリジル、フェニル及びテトラヒドロ-2H-ピラニルは1、2又は3個のRcにより任意に置換される請求項1~6のいずれか一項に記載の化合物、その薬学的に許容できる塩又はその異性体。
- 前記R4はピロリル、ピラゾリル、ピリジル、ピラジニル、ピリミジニル又はフェニルであり、前記ピロリル、ピラゾリル、ピリジル、ピラジニル、ピリミジニル及びフェニルは1、2又は3個のRdに置換されてもよい請求項1、4、5又は10~13のいずれか一項に記載の化合物、その薬学的に許容できる塩又はその異性体。
- 請求項1~19のいずれか一項に記載の化合物、その薬学的に許容できる塩又はその異性体のTGF-β R1阻害剤薬物の調製における使用。
- 請求項1~19のいずれか一項に記載の化合物、その薬学的に許容できる塩又はその異性体の固形腫瘍薬物の調製における使用。
- 治療有効量の請求項1~19のいずれか一項に記載の化合物、その薬学的に許容できる塩又はその異性体、及び薬学的に許容できるキャリアを含有する医薬組成物。
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