JP5525612B2 - Nitrogen-containing heterocyclic derivatives - Google Patents
Nitrogen-containing heterocyclic derivatives Download PDFInfo
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- JP5525612B2 JP5525612B2 JP2012525426A JP2012525426A JP5525612B2 JP 5525612 B2 JP5525612 B2 JP 5525612B2 JP 2012525426 A JP2012525426 A JP 2012525426A JP 2012525426 A JP2012525426 A JP 2012525426A JP 5525612 B2 JP5525612 B2 JP 5525612B2
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Description
本発明は、Apoptosis signal-regulating kinase 1(以下、ASK1と表す場合もある)阻害活性を有し、例えば、筋萎縮性側索硬化症(Amyotrophic lateral sclerosis、以下、ALSと表す場合もある)の予防及び/又は治療剤として有用な含窒素複素環誘導体又はその薬学的に許容される塩等に関する。 The present invention has an inhibitory activity on Apoptosis signal-regulating kinase 1 (hereinafter also referred to as ASK1), for example, amyotrophic lateral sclerosis (hereinafter also referred to as ALS). The present invention relates to a nitrogen-containing heterocyclic derivative useful as a preventive and / or therapeutic agent or a pharmaceutically acceptable salt thereof.
MAPキナーゼ(mitogen-activated protein kinase、以下、MAPKと表す)カスケードは、サイトカインレセプター刺激や物理化学ストレス等の多様な刺激により活性化したMAPKキナーゼキナーゼ(以下、MAPKKKと表す)が下流のMAPKキナーゼ(以下、MAPKKと表す)をリン酸化することによりMAPKKを活性化し、活性化したMAPKKが更に下流のMAPKをリン酸化するという、真核生物に共通かつ普遍的に存在するシグナル伝達系である。MAPKカスケードは、細胞においては増殖や生存、分化、アポトーシス等、種々の細胞応答を誘導すると共に、個体レベルでは、癌、炎症、虚血性疾患、神経変性疾患等の様々な病態において重要な役割を果たしている。 The MAP kinase (mitogen-activated protein kinase, hereinafter referred to as MAPK) cascade is a downstream MAPK kinase (hereinafter referred to as MAPKKK) activated by various stimuli such as cytokine receptor stimulation and physicochemical stress. This is a signal transduction system that is common and universal in eukaryotes, in which MAPKK is activated by phosphorylating (hereinafter referred to as MAPKK), and the activated MAPKK further phosphorylates downstream MAPK. The MAPK cascade induces various cellular responses such as proliferation, survival, differentiation, and apoptosis in cells, and at the individual level, it plays an important role in various pathologies such as cancer, inflammation, ischemic diseases, and neurodegenerative diseases. Plays.
ASK1はMAPKKKの一つであり、サイトカインレセプター刺激のほか、酸化ストレスや小胞体ストレス等の物理化学ストレスによっても強く活性化される。構成的活性化型ASK1を細胞に過剰発現させると、SEK1-JNK経路とMKK3/6-p38経路を選択的に活性化すると共にアポトーシスを惹起する。一方、上皮細胞や未分化な神経細胞においては、ASK1の活性化を介してp38を活性化する経路が分化や生存を誘導することも報告されている。従って、ASK1は細胞の生死を制御するだけでなく、分化においても重要な役割を果たしていると考えられる。 ASK1 is one of MAPKKK and is strongly activated by physicochemical stress such as oxidative stress and endoplasmic reticulum stress in addition to cytokine receptor stimulation. When constitutively activated ASK1 is overexpressed in cells, it selectively activates the SEK1-JNK pathway and the MKK3 / 6-p38 pathway and induces apoptosis. On the other hand, in epithelial cells and undifferentiated neurons, it has also been reported that a pathway that activates p38 through activation of ASK1 induces differentiation and survival. Therefore, ASK1 is thought to play an important role not only in controlling cell survival but also in differentiation.
ALSは、運動神経が特異的に障害される進行性疾患である。ALSは、主に壮年期に発症し、筋萎縮が徐々に全身に広がり、歩行困難、言語障害、嚥下障害、呼吸障害に及び、気管切開/人工呼吸器装着等を施さなければ発症後3〜5年で死に至るきわめて重篤な疾患である。ALSは、「難病性疾患克服研究事業対象疾患」に指定されているにもかかわらず、日本国内での患者数は約7000人と、他の神経変性疾患(アルツハイマー病、パーキンソン病等)に比べて患者数が少ないため、治療薬開発への取り組みが遅れている。現在の治療法は、適度なリハビリテーションによる筋力低下予防と、唯一の保険適応薬剤であるリルゾール(グルタミン酸の神経終末放出を抑制する薬物)による一時的な病態進行の遅延だけであり、ALSの病態分子メカニズムに基づく根本的な治療法は皆無である。 ALS is a progressive disease in which motor nerves are specifically impaired. ALS mainly develops in middle age, muscle atrophy gradually spreads throughout the body, gait difficulty, speech disorder, dysphagia, breathing disorder, 3 to 1 after onset unless tracheostomy / ventilator wearing etc. It is a very serious disease that will die in 5 years. Despite being designated as a “target disease for intractable disease overcoming research project”, ALS has approximately 7,000 patients in Japan, compared with other neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, etc.). Due to the small number of patients, efforts to develop therapeutic drugs are delayed. The current treatment is only prevention of muscle weakness by moderate rehabilitation and temporary delay in the progression of disease due to riluzole (a drug that suppresses the release of glutamate nerve endings), the only insurance indication drug. There is no fundamental cure based on the mechanism.
ALSの原因を解明する上でのブレイクスルーは、家族性ALSの原因遺伝子として1993年にRosenらによって同定されたCu/Zn superoxide dismutase 1(SOD1)の遺伝子変異の発見である。全ALS患者のうち約10%が家族性であり、そのうちの約20%がSOD1遺伝子変異による。原因遺伝子であるSOD1の発見は、家族性ALSのみならず孤発性ALSの病態解明にも飛躍的な進歩をもたらすものと期待されているが、ALSに共通する病態を説明しうる分子メカニズムは明らかにされていない。SOD1遺伝子上には、これまで100種類以上の点変異が報告されており、それらの多くが優性遺伝形式をとること、幾つかの変異型SOD1トランスジェニックマウスがALSと類似した症状を呈すること、ならびにSOD1タンパク質の機能喪失によっては病態を発症しないこと等から、変異型SOD1タンパク質が何らかの獲得性神経細胞毒性を発揮し、運動神経細胞死とそれに伴う個体の神経症状をもたらすものと考えられている。しかし、その際に変異型SOD1が細胞内でどのようなシグナルを発信し、どのようなメカニズムで細胞を傷害するかという点については不明である。 A breakthrough in elucidating the cause of ALS was the discovery of a Cu / Zn superoxide dismutase 1 (SOD1) gene mutation identified in 1993 by Rosen et al. As a causative gene for familial ALS. About 10% of all ALS patients are familial, of which about 20% are due to SOD1 gene mutations. The discovery of the causative gene, SOD1, is expected to bring about dramatic progress in elucidating the pathogenesis of sporadic ALS as well as familial ALS, but the molecular mechanism that can explain the pathophysiology common to ALS is It has not been revealed. More than 100 types of point mutations have been reported so far on the SOD1 gene, many of them adopt a dominant inheritance form, some mutant SOD1 transgenic mice exhibit symptoms similar to ALS, In addition, it is considered that mutant SOD1 protein exerts some acquired neurocytotoxicity and causes motor neuron death and accompanying neurological symptoms due to loss of function of SOD1 protein. . However, at this time, it is unclear what signal the mutant SOD1 emits in the cell and what mechanism damages the cell.
一條らは、ALSにおける変異型SOD1による神経細胞死分子メカニズムとして、小胞体ストレスが深く関与していることを明らかにしている(Genes Dev. 2008年, Jun 1;22(11):1451-64頁)。すなわち、変異型SOD1が特異的に結合する標的タンパク質の一つとして、小胞体の品質管理に重要な役割を担う小胞体膜タンパク質Derlin-1を同定し、その結合が神経細胞の小胞体品質管理機構の破綻をきたし、小胞体ストレスを惹起することを見出した。さらに、変異型SOD1依存的小胞体ストレス誘導による神経細胞死のメディエーターとして、ストレス応答性MAPキナーゼの一つであるASK1が関与することを明らかにしている。従って、ASK1の阻害剤は、ALSの予防及び/又は治療剤になり得る可能性がある。 Ichijo et al. Revealed that endoplasmic reticulum stress is deeply involved as a neuronal death molecular mechanism by mutant SOD1 in ALS (Genes Dev. 2008, Jun 1; 22 (11): 1451-64 page). That is, we identified the endoplasmic reticulum membrane protein Derlin-1, which plays an important role in the quality control of the endoplasmic reticulum, as one of the target proteins to which the mutant SOD1 specifically binds. It has been found that the failure of the mechanism causes endoplasmic reticulum stress. Furthermore, it has been clarified that ASK1, one of stress-responsive MAP kinases, is involved as a mediator of neuronal cell death induced by mutant SOD1-dependent endoplasmic reticulum stress. Therefore, an ASK1 inhibitor may be a preventive and / or therapeutic agent for ALS.
1−アルキル置換キノリン−4−オン誘導体(特許文献1、2)、ATP-binding cassettes transporterの調節作用を有するキノリン−4−オン誘導体(特許文献3)、PGD2産生抑制作用、PGD2合成酵素阻害活性を有する複素環誘導体(特許文献4)、及び1−フェニル置換キノリン−4−オン誘導体(特許文献5)が知られている。 1-alkyl-substituted quinolin-4-one derivatives (Patent Documents 1 and 2), quinolin-4-one derivatives having a regulatory action of ATP-binding cassettes transporter (Patent Document 3), PGD2 production inhibitory activity, PGD2 synthase inhibitory activity A heterocyclic derivative (Patent Document 4) having 1 and a 1-phenyl-substituted quinolin-4-one derivative (Patent Document 5) are known.
更に、以下の化合物A(CAS Registry 番号:1091987-46-0)、化合物B(CAS Registry 番号:1115424-11-7)、化合物C(CAS Registry 番号:929844-56-4)、化合物D(CAS Registry 番号:743441-24-9)、化合物E(CAS Registry 番号:440656-72-4)、及び化合物F(非特許文献1)が知られている。 Furthermore, the following compound A (CAS Registry Number: 1091987-46-0), Compound B (CAS Registry Number: 1115424-11-7), Compound C (CAS Registry Number: 929844-56-4), Compound D (CAS Registry Number: 743441-24-9), Compound E (CAS Registry Number: 440656-72-4), and Compound F (Non-Patent Document 1) are known.
本発明の目的は、ASK1阻害活性を有し、例えば、ALSの予防及び/又は治療剤として有用な含窒素複素環誘導体又はその薬学的に許容される塩等を提供することにある。 An object of the present invention is to provide a nitrogen-containing heterocyclic derivative or a pharmaceutically acceptable salt thereof which has ASK1 inhibitory activity and is useful, for example, as a preventive and / or therapeutic agent for ALS.
本発明は、以下の(1)〜(5)に関する。
(1)以下の化合物1、化合物2、化合物3、化合物4、化合物6、化合物7及び化合物8から選ばれる化合物又はその薬学的に許容される塩。The present invention relates to the following (1) to (5).
(1) A compound selected from the following Compound 1, Compound 2, Compound 3, Compound 4, Compound 6, Compound 7, and Compound 8, or a pharmaceutically acceptable salt thereof.
(2)前記(1)記載のいずれかの化合物又はその薬学的に許容される塩を含有する医薬。
(3)前記(1)記載のいずれかの化合物又はその薬学的に許容される塩を含有するASK1阻害剤。
(4)前記(1)記載のいずれかの化合物又はその薬学的に許容される塩を含有する筋萎縮性側索硬化症(Amyotrophic lateral sclerosis)の予防及び/又は治療剤。
(5)前記(1)記載のいずれかの化合物又はその薬学的に許容される塩を含有する肝炎の予防及び/又は治療剤。(2) A medicament comprising any of the compounds described in (1) above or a pharmaceutically acceptable salt thereof.
(3) An ASK1 inhibitor comprising any of the compounds described in (1) above or a pharmaceutically acceptable salt thereof.
(4) A preventive and / or therapeutic agent for amyotrophic lateral sclerosis comprising any of the compounds described in (1) above or a pharmaceutically acceptable salt thereof.
(5) A prophylactic and / or therapeutic agent for hepatitis comprising any one of the compounds described in (1) above or a pharmaceutically acceptable salt thereof.
本発明により、ASK1阻害活性を有し、例えば、ALSの予防及び/又は治療剤として有用な含窒素複素環誘導体又はその薬学的に許容される塩等が提供される。 The present invention provides a nitrogen-containing heterocyclic derivative or a pharmaceutically acceptable salt thereof, which has ASK1 inhibitory activity and is useful, for example, as an agent for preventing and / or treating ALS.
化合物の薬学的に許容される塩は、例えば薬学的に許容される酸付加塩、金属塩、アンモニウム塩、有機アミン付加塩、アミノ酸付加塩等を包含する。化合物の薬学的に許容される酸付加塩としては、例えば塩酸塩、臭化水素酸塩、硝酸塩、硫酸塩、リン酸塩等の無機酸塩、酢酸塩、シュウ酸塩、マレイン酸塩、フマル酸塩、クエン酸塩、安息香酸塩、メタンスルホン酸塩等の有機酸塩等が挙げられ、薬学的に許容される金属塩としては、例えばナトリウム塩、カリウム塩、マグネシウム塩、カルシウム塩、アルミニウム塩、亜鉛塩等が挙げられ、薬学的に許容されるアンモニウム塩としては、例えばアンモニウム塩、テトラメチルアンモニウム塩等の塩が挙げられ、薬学的に許容される有機アミン付加塩としては、例えばモルホリン、ピペリジン等の付加塩が挙げられ、薬学的に許容されるアミノ酸付加塩としては、例えばリジン、グリシン、フェニルアラニン、アスパラギン酸、グルタミン酸等の付加塩が挙げられるがこれらに限定されるものではない。 Pharmaceutically acceptable salts of the compound include, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. Examples of pharmaceutically acceptable acid addition salts of the compound include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, and phosphate, acetate, oxalate, maleate, and fumarate. Organic acid salts such as acid salts, citrate salts, benzoate salts, methanesulfonate salts, etc., and pharmaceutically acceptable metal salts include, for example, sodium salts, potassium salts, magnesium salts, calcium salts, aluminum Examples of the pharmaceutically acceptable ammonium salt include salts such as ammonium salt and tetramethylammonium salt. Examples of the pharmaceutically acceptable organic amine addition salt include morpholine. And pharmaceutically acceptable amino acid addition salts include, for example, lysine, glycine, phenylalanine, aspartic acid, glutamic acid, and the like. Although addition salts such as acid but not limited thereto.
次に代表的な化合物の薬理作用について、試験例により具体的に説明する。なお、以下の試験例における%は体積%を表す。 Next, the pharmacological action of typical compounds will be specifically described with reference to test examples. In addition,% in the following test examples represents volume%.
試験例1:ASK1阻害活性
GenBankにアクセッション番号NM_005923で登録されているASK1のアミノ酸配列649から946までをコードする遺伝子をpGEX-6P1(GEヘルスケア)に導入し、BL21(GEヘルスケア)にトランスフォームした。28℃で培養、IPTG(イソプロピル-β-チオガラクトピラノシド)で発現誘導して菌体回収後、超音波破砕した上清から、GSH-sepharose (GEヘルスケア)によりGST-ASK1(GST(glutathione S-transferase)融合ASK1(アミノ酸配列649から946)蛋白質)を精製した。Test Example 1: ASK1 inhibitory activity
A gene encoding the amino acid sequence 649 to 946 of ASK1 registered in GenBank with accession number NM_005923 was introduced into pGEX-6P1 (GE Healthcare) and transformed into BL21 (GE Healthcare). After culturing at 28 ° C., expression induction with IPTG (isopropyl-β-thiogalactopyranoside), cell recovery, and sonication of the supernatant, GST-ASK1 (GST (GST ( glutathione S-transferase) fusion ASK1 (amino acid sequence 649 to 946) protein) was purified.
96穴の黒色プレート(住友ベークライト)にGST-ASK1(50-100 ng)と3 μM ATPを含む45μLの反応溶液(40 mM MOPS (3-Morpholinopropanesulfonic acid)/NaOH pH 7.9, 0.1 mM EDTA(ethylenediaminetetraacetic acid))に試験化合物のDMSO溶液(10%)5 μLを添加し、室温で60分間保温した。反応後、50 μLのKinase-Glo (プロメガ)を加え、室温で10分間保温してトップカウント(パーキンエルマー)で化学発光を測定した。Kinase-Gloのプロトコールに従って、化合物のASK1活性の阻害値を計算した。
なお、化合物5は化合物3の塩酸塩である。A 96-well black plate (Sumitomo Bakelite) containing 45 μL of GST-ASK1 (50-100 ng) and 3 μM ATP (40 mM MOPS (3-Morpholinopropanesulfonic acid) / NaOH pH 7.9, 0.1 mM EDTA (ethylenediaminetetraacetic acid) )) Was added to the test compound in DMSO (10%) (5 μL) and incubated at room temperature for 60 minutes. After the reaction, 50 μL of Kinase-Glo (Promega) was added, and incubated at room temperature for 10 minutes, and chemiluminescence was measured by top count (Perkin Elmer). The inhibition value of the ASK1 activity of the compound was calculated according to the Kinase-Glo protocol.
Compound 5 is the hydrochloride of compound 3.
以上の結果より、本発明の化合物はASK1阻害活性を有することが分かった。 From the above results, it was found that the compound of the present invention has ASK1 inhibitory activity.
試験例2:SOD1(G93A)の過剰発現による運動神経細胞死に対する抑制作用
<初代運動神経細胞培養>
C57BL/6マウスの妊娠12.5日後の胎仔より脊髄を摘出し、0.05%トリプシン溶液中で37℃、15分間静置した。トリプシン処理した細胞を0.1% ポリエチレンイミンでコートしたカバーガラス(直径13 mm)に6×105cells/cm2の密度で播種し、DMEM/F12Ham (Sigma) (10% Fetal bovine serum (FBS), 1% G5-supplement(Gibco))中で培養した。1時間後、7倍量のDMEM/F12Ham (2% Horse Serum, 10 mg/ml Bovine serum albumin (BSA), 10 mg/ml Insulin, 26 ng/ml sodium selenite, 20 ng/ml Triiodothyronine (T3), 100 mg/ml conalbumin, 20 mg/ml hydrocortisone, 13 ng/ml progesterone, 100 pg/ml Brain-derived neurotrophic factor (BDNF), 10 ng/ml Ciliary neurotrophic factor (CNTF), 100 pg/ml neurotrophin-3 (NT-3), 100 U/ml penicillin/streptomycin)をさらに加えて一晩培養した。1日後と3日後に全量、6日後に半量をDMEM/F12Ham培地(2% Horse Serum, 10 mg/ml BSA, 10 mg/ml Insulin, 26 ng/ml sodium selenite, 20 ng/ml T3, 100 mg/ml conalbumin, 20 mg/ml hydrocortisone, 13 ng/ml progesterone, 100 pg/ml BDNF, 10 ng/ml CNTF, 100 pg/ml NT-3, 100 U/ml penicillin/streptomycin)で培地交換を行い培養した。Test Example 2: SOD1 (G93A) overexpression suppresses motor neuron death <Primary motor neuron culture>
The spinal cord was removed from the fetus 12.5 days after gestation of C57BL / 6 mice and allowed to stand in a 0.05% trypsin solution at 37 ° C. for 15 minutes. Trypsinized cells were seeded at a density of 6 × 10 5 cells / cm 2 on a cover glass (diameter 13 mm) coated with 0.1% polyethyleneimine, and DMEM / F12Ham (Sigma) (10% Fetal bovine serum (FBS), The cells were cultured in 1% G5-supplement (Gibco)). After 1 hour, 7 volumes of DMEM / F12Ham (2% Horse Serum, 10 mg / ml Bovine serum albumin (BSA), 10 mg / ml Insulin, 26 ng / ml sodium selenite, 20 ng / ml Triiodothyronine (T3), 100 mg / ml conalbumin, 20 mg / ml hydrocortisone, 13 ng / ml progesterone, 100 pg / ml Brain-derived neurotrophic factor (BDNF), 10 ng / ml Ciliary neurotrophic factor (CNTF), 100 pg / ml neurotrophin-3 ( NT-3), 100 U / ml penicillin / streptomycin) was further added and cultured overnight. DMEM / F12Ham medium (2% Horse Serum, 10 mg / ml BSA, 10 mg / ml Insulin, 26 ng / ml sodium selenite, 20 ng / ml T3, 100 mg) / ml conalbumin, 20 mg / ml hydrocortisone, 13 ng / ml progesterone, 100 pg / ml BDNF, 10 ng / ml CNTF, 100 pg / ml NT-3, 100 U / ml penicillin / streptomycin) did.
<SOD1レンチウィルス感染およびASK1阻害剤(化合物6)投与>
上記の初代運動神経細胞培養の開始から7日後に、野生型SOD1レンチウイルス又は変異型SOD1(G93A)レンチウィルスを感染させ、12時間後に化合物6(DMSO溶液)を各濃度にて投与した。溶媒投与群(DMSO投与群)をコントロール群とした。レンチウィルス投与72時間後に、細胞免疫染色を行った。<SOD1 lentivirus infection and ASK1 inhibitor (compound 6) administration>
Seven days after the start of the primary motor neuron cell culture, wild type SOD1 lentivirus or mutant SOD1 (G93A) lentivirus was infected, and 12 hours later, compound 6 (DMSO solution) was administered at each concentration. A solvent administration group (DMSO administration group) was used as a control group. Cell immunostaining was performed 72 hours after lentivirus administration.
<細胞免疫染色>
運動神経細胞をリン酸緩衝生理食塩水(PBS)で洗い、3.7% ホルムアルデヒド(in PBS)で処置して細胞を固定した。再びPBSで洗った後、0.2% Triton X 100 (in PBS) で処置し、PBSで洗浄した。1% FBS (in PBS) によりブロッキングを60分間行った後、一次抗体として抗非リン酸化Neurofilament H(SMI-32抗体:COVANCE社)と抗glial fibrillary acidic protein (GFAP)抗体(DAKO社)を、二次抗体としてmouse IgG-FITC抗体と抗rabbit IgG-Texas Red抗体を用いて染色した。PBSで洗浄後、Prolong Gold antifade reagent with 4',6-diamino-2-phenylindole (DAPI)(invitrogen)を核染色剤および抗退色剤として加え封入した後、蛍光顕微鏡で観察した。<Cellular immunostaining>
Motor neurons were washed with phosphate buffered saline (PBS) and treated with 3.7% formaldehyde (in PBS) to fix the cells. After washing again with PBS, it was treated with 0.2% Triton X 100 (in PBS) and washed with PBS. After blocking with 1% FBS (in PBS) for 60 minutes, anti-non-phosphorylated Neurofilament H (SMI-32 antibody: COVANCE) and anti-glial fibrillary acidic protein (GFAP) antibody (DAKO) were used as primary antibodies. Staining was performed using mouse IgG-FITC antibody and anti-rabbit IgG-Texas Red antibody as secondary antibodies. After washing with PBS, Prolong Gold antifade reagent with 4 ′, 6-diamino-2-phenylindole (DAPI) (invitrogen) was added as a nuclear stain and an anti-bleaching agent, sealed, and then observed with a fluorescence microscope.
<生細胞測定>
SMI-32抗体陽性かつDAPI陽性細胞を生運動神経細胞として、抗GFAP抗体陽性かつDAPI陽性細胞を生グリア細胞として数えた。
結果を図1、図2に示す。<Live cell measurement>
SMI-32 antibody positive and DAPI positive cells were counted as live motor neurons, and anti-GFAP antibody positive and DAPI positive cells were counted as live glial cells.
The results are shown in FIGS.
レンチウィルスを用いたSOD1(G93A)の過剰発現によって約80%の運動神経細胞死が起こることが示されている(Genes Dev. 2008年, Jun 1;22(11):1451-64頁)。一方、支持細胞であるGFAP陽性のグリア細胞は、SOD1(G93A)によって影響を受けない。これらの結果とほぼ同様の結果が、図1及び図2のコントロール群(溶媒DMSO投与群)において観察された。この運動神経細胞死実験系にASK1活性阻害剤(化合物6)を作用させたところ、0.1μM、0.3μM、1μMと濃度依存的に運動神経細胞死の抑制が観察された(図1)。しかしながら、3μMにおいては野生型SOD1を発現させた細胞においても、約70%の運動神経細胞死が観察され、化合物6による運動神経細胞毒性が認められた(図1)。また、グリア細胞においても、3μMでは約40%の細胞死が観察された(図2)。 Overexpression of SOD1 (G93A) using lentivirus has been shown to cause about 80% motor neuron death (Genes Dev. 2008, Jun 1; 22 (11): 1451-64). On the other hand, GFAP-positive glial cells that are support cells are not affected by SOD1 (G93A). Results similar to these results were observed in the control group (solvent DMSO administration group) of FIGS. When an ASK1 activity inhibitor (compound 6) was allowed to act on this motor neuron death experimental system, suppression of motor neuron death was observed in a concentration-dependent manner of 0.1 μM, 0.3 μM, and 1 μM (FIG. 1). However, at 3 μM, about 70% of motor neuron death was observed even in cells expressing wild-type SOD1, and motor neurotoxicity due to compound 6 was observed (FIG. 1). In addition, about 40% cell death was observed in glial cells at 3 μM (FIG. 2).
従って、in vitro初代運動神経細胞培養の実験系においては、1μMまでの濃度において化合物6は変異型SOD1(G93A)依存的運動神経細胞死抑制効果があることが明らかとなった。 Therefore, in an experimental system for primary motor neuron culture in vitro, it was revealed that Compound 6 has a mutant SOD1 (G93A) -dependent motor neuron death inhibitory effect at concentrations up to 1 μM.
以上の結果より、本発明の化合物は、変異型SOD1(G93A)依存的運動神経細胞死抑制効果を介し、ALSの予防及び/又は治療剤として有望であることが示唆された。 From the above results, it was suggested that the compound of the present invention is promising as a preventive and / or therapeutic agent for ALS via the mutant SOD1 (G93A) -dependent motor neuron death inhibitory effect.
試験例3:肝炎への治療作用
<化合物6のFasによる肝障害に対する影響>
マウス(C57BL/6、オス)17匹を2群に分け、一方の群(9匹)に化合物6を100 mg/kgで経口投与し(薬物投与群)、他方の群(8匹)には溶媒(10% DMSO, 10% Cremophore EL)を投与した(薬物非投与群)。薬物投与群及び薬物非投与群に90分後に0.4 μg/gの抗Fas抗体(Jo2, BD PharMingen社)を腹腔内投与した。各群の抗Fas抗体投与の0時間後および5時間後の血清中のALT値を測定した。薬物投与群は、0時間後は3匹、5時間後は6匹の、薬物非投与群は、0時間後は3匹、5時間後は5匹の平均を取り、データは平均+/- SEMで示した。Test Example 3: Therapeutic effect on hepatitis <Influence of compound 6 on liver damage caused by Fas>
17 mice (C57BL / 6, male) were divided into 2 groups. One group (9 mice) was orally administered Compound 6 at 100 mg / kg (drug administration group), and the other group (8 mice) A solvent (10% DMSO, 10% Cremophore EL) was administered (drug non-administration group). After 90 minutes, 0.4 μg / g anti-Fas antibody (Jo2, BD PharMingen) was intraperitoneally administered to the drug administration group and the drug non-administration group. Serum ALT levels were measured at 0 and 5 hours after administration of anti-Fas antibody in each group. The drug administration group averaged 3 animals at 0 hours, 6 animals at 5 hours, the non-drug administration group averaged 3 animals at 0 hours, and 5 animals after 5 hours, and the data is the average +/- Shown by SEM.
<化合物7のFasによる肝障害に対する影響>
マウス(C57BL/6、オス)20匹を2群に分け、一方の群(10匹)に化合物7を100 mg/kgで経口投与し(薬物投与群)、他方の群(10匹)には溶媒(10% DMSO, 10% Cremophore EL)を投与した(薬物非投与群)。薬物投与群及び薬物非投与群に90分後に0.4 μg/gの抗Fas抗体(Jo2, BD PharMingen社)を腹腔内投与した。各群の抗Fas抗体投与の0時間後、3.5時間後及び5時間後の血清中のALT値を測定した。薬物投与群は、0時間後は3匹、3.5時間後は3匹、5時間後は4匹の、薬物非投与群は、0時間後は3匹、3.5時間後は4匹、5時間後は3匹の平均を取り、データは平均+/- SEMで示した。
結果を図3A(化合物6)、図3B(化合物7)に示す。<Influence of Compound 7 on Fas Caused by Fas>
20 mice (C57BL / 6, male) were divided into 2 groups, and one group (10 mice) was orally administered Compound 7 at 100 mg / kg (drug administration group), the other group (10 mice) A solvent (10% DMSO, 10% Cremophore EL) was administered (drug non-administration group). After 90 minutes, 0.4 μg / g anti-Fas antibody (Jo2, BD PharMingen) was intraperitoneally administered to the drug administration group and the drug non-administration group. Serum ALT levels were measured at 0, 3.5, and 5 hours after administration of anti-Fas antibody in each group. The drug-administered group was 3 animals after 0 hours, 3 animals after 3.5 hours, 4 animals after 5 hours, and the non-drug-administered group was 3 animals after 0 hours, 4 animals after 3.5 hours, and 5 hours later Took the average of 3 animals and the data are shown as mean +/- SEM.
The results are shown in FIG. 3A (Compound 6) and FIG. 3B (Compound 7).
C57BL/6マウスにJo2を投与するとALTが上昇し、肝障害が惹起された。しかしながら、Jo2投与の90分前に100 mg/kgの化合物6あるいは化合物7を投与すると、ALTが低下していることから肝障害が軽減されたことが分かった。従って、抗Fas抗体誘発肝障害実験系においては、化合物6および化合物7に肝障害軽減効果があることが明らかとなった。
以上の結果より、本発明の化合物は、肝炎の予防及び/又は治療剤として有望であることが示唆された。When Jo2 was administered to C57BL / 6 mice, ALT increased and liver damage was induced. However, when 100 mg / kg of Compound 6 or Compound 7 was administered 90 minutes before Jo2 administration, it was found that liver damage was alleviated because ALT decreased. Therefore, in the anti-Fas antibody-induced liver injury experimental system, it was revealed that Compound 6 and Compound 7 have a liver injury reducing effect.
From the above results, it was suggested that the compound of the present invention is promising as an agent for preventing and / or treating hepatitis.
本発明の化合物又はその薬学的に許容される塩は、そのまま単独で投与することも可能であるが、通常各種の医薬製剤として提供するのが望ましい。また、それら医薬製剤は、動物(人又は人以外の動物、特に哺乳動物)に使用されるものである。 The compound of the present invention or a pharmaceutically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide it as various pharmaceutical preparations. These pharmaceutical preparations are used for animals (human or non-human animals, particularly mammals).
本発明に係わる医薬製剤は、活性成分として本発明の化合物又はその薬学的に許容される塩を単独で、又は任意の他の治療のための有効成分との混合物として含有することができる。また、それら医薬製剤は、活性成分を薬学的に許容される一種又はそれ以上の担体(例えば、希釈剤、溶剤、賦形剤等)と一緒に混合し、製剤学の技術分野においてよく知られている任意の方法により製造される。 The pharmaceutical preparation according to the present invention may contain the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient alone or as a mixture with any other active ingredient for treatment. These pharmaceutical preparations are well known in the technical field of pharmaceutics by mixing the active ingredient together with one or more pharmaceutically acceptable carriers (eg, diluents, solvents, excipients, etc.). Manufactured by any method.
投与経路としては、治療に際し最も効果的なものを使用するのが望ましく、経口又は、例えば静脈内等の非経口を挙げることができる。
投与形態としては、例えば錠剤、注射剤等が挙げられる。
錠剤は、乳糖等の賦形剤、澱粉等の崩壊剤、ステアリン酸マグネシウム等の滑沢剤、ヒドロキシプロピルセルロース等の結合剤等を用いて製造でき、経口投与に適当である。
注射剤等は、塩溶液、ブドウ糖溶液又は塩水とブドウ糖溶液の混合液等の希釈剤又は溶剤等を用いて製造できる。As an administration route, it is desirable to use the most effective one in the treatment, and examples thereof include oral or parenteral such as intravenous.
Examples of the dosage form include tablets and injections.
Tablets can be produced using excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and the like, and are suitable for oral administration.
An injection or the like can be produced using a diluent or a solvent such as a salt solution, a glucose solution, or a mixed solution of salt water and a glucose solution.
本発明の化合物及びその薬学的に許容される塩の投与量及び投与回数は、投与形態、患者の年齢、体重、治療すべき症状の性質もしくは重篤度等により異なるが、通常経口投与の場合、成人一人あたり、0.01〜1000 mg、好ましくは0.05〜100 mgの範囲で、1日1回ないし数回投与する。静脈内投与等の場合、成人一人あたり0.001〜1000 mg、好ましくは0.01〜100 mgを1日1回ないし数回投与する。しかしながら、これら投与量及び投与回数に関しては、前述の種々の条件により変動する。 The dose and frequency of administration of the compound of the present invention and pharmaceutically acceptable salt thereof vary depending on the administration form, patient age, body weight, nature or severity of symptoms to be treated, etc. In the range of 0.01 to 1000 mg, preferably 0.05 to 100 mg per adult, it is administered once to several times a day. In the case of intravenous administration, etc., 0.001 to 1000 mg, preferably 0.01 to 100 mg is administered once a day to several times per adult. However, the dose and the number of doses vary depending on the various conditions described above.
以下、本発明を実施例によりさらに具体的に説明するが、本発明の範囲はこれらの実施例に限定されることはない。
なお、実施例で用いられるプロトン核磁気共鳴スペクトル(1H-NMR)においては、化合物及び測定条件によって交換性プロトンが明瞭には観測されないことがある。なお、シグナルの多重度の表記としては通常用いられるものを用いるが、bsとは見かけ上幅広いシグナルであることを表す。EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the scope of the present invention is not limited to these examples.
In the proton nuclear magnetic resonance spectrum ( 1 H-NMR) used in the examples, exchangeable protons may not be clearly observed depending on the compound and measurement conditions. In addition, although what is used normally is used as description of the multiplicity of a signal, bs represents that it is an apparent wide signal.
N−[4−(6,7−ジメトキシキノリン−4−イルオキシ)フェニル]−4−オキソ−1,4−ジヒドロキノリン−3−カルボキサミド(化合物1)
文献[ジャーナル・オブ・メディシナル・ケミストリー(J.Med.Chem.),2006年,49巻,70−79頁]に従って合成した4−オキソ−1,4−ジヒドロキノリン−3−カルボン酸エチル(4.36g、20.2mmol)にエタノール(100mL)、水(5mL)、水酸化カリウム(12g、182mmol)を順に加え、加熱還流下、2時間攪拌した。反応液を室温に冷却し、1mol/L塩酸を加えpH3にした。析出した沈殿を濾取し、真空下で乾燥することにより4−ヒドロキシキノリン−3−カルボン酸(3.66g、収率96%)を得た。 N- [4- (6,7-dimethoxyquinolin-4-yloxy) phenyl] -4-oxo-1,4-dihydroquinoline-3-carboxamide (Compound 1)
Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate synthesized according to the literature [Journal of Medicinal Chemistry (J. Med. Chem.), 2006, 49, 70-79] (4 Ethanol (100 mL), water (5 mL), and potassium hydroxide (12 g, 182 mmol) were sequentially added to .36 g, 20.2 mmol), and the mixture was stirred for 2 hours while heating under reflux. The reaction solution was cooled to room temperature and adjusted to pH 3 by adding 1 mol / L hydrochloric acid. The deposited precipitate was collected by filtration and dried under vacuum to obtain 4-hydroxyquinoline-3-carboxylic acid (3.66 g, yield 96%).
4−ヒドロキシキノリン−3−カルボン酸(1.5g、7.98mmol)、文献[バイオオーガニック・メディシナル・ケミストリー(Bioorg.Med.Chem.),2003年,11(23)巻,5117−5134頁]に従って合成した4−(6,7−ジメトキシキノリン−4−イルオキシ)アニリン(2.15g、7.25mmol)、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩(2.78g、14.5mmol)及び1−ヒドロキシベンゾトリアゾール一水和物(2.22g、14.5mmol)にクロロホルム(73mL)、トリエチルアミン(3.64g、36.3mmol)を順に加え、加熱還流下、3時間攪拌した。反応液を冷却後、水を加えて分液した。水層をクロロホルムで2回抽出した後、有機層を合わせて水、食塩水で順に洗浄した。硫酸ナトリウムで乾燥後、減圧下で溶媒を留去して得られた残渣をクロロホルム/メタノール系のカラムクロマトグラフィーで精製し、得られた粗結晶をクロロホルム/メタノール/ジエチルエーテルで再結晶することにより標題の化合物(1.77g、収率52%)を得た。 4-hydroxyquinoline-3-carboxylic acid (1.5 g, 7.98 mmol), literature [Bioorgan. Med. Chem., 2003, 11 (23), 5117-5134] 4- (6,7-dimethoxyquinolin-4-yloxy) aniline (2.15 g, 7.25 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.78 g, 14 0.5 mmol) and 1-hydroxybenzotriazole monohydrate (2.22 g, 14.5 mmol) were added chloroform (73 mL) and triethylamine (3.64 g, 36.3 mmol) in this order, and the mixture was stirred for 3 hours with heating under reflux. . After cooling the reaction solution, water was added for liquid separation. The aqueous layer was extracted twice with chloroform, and then the organic layers were combined and washed sequentially with water and brine. After drying with sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography using chloroform / methanol, and the resulting crude crystals were recrystallized from chloroform / methanol / diethyl ether. The title compound (1.77 g, 52% yield) was obtained.
1H-NMR (CDCl3, 270 MHz): δ 12.60 (s, 1H), 11.72 (bs, 1H), 8.99 (s, 1H), 8.55 - 8.46 (m, 2H), 7.93 - 7.85 (m, 2H), 7.73 - 7.64 (m, 1H), 7.60 (s, 1H), 7.55 - 7.46 (m, 2H), 7.38 (s, 1H), 7.24 - 7.17 (m, 2H), 6.51 (d, J = 5.3 Hz, 1H), 4.06 (s, 3H), 4.01 (s, 3H)
質量分析値(ESI-MS, m/z): 468(M+1)+, 466(M-1)- 1 H-NMR (CDCl 3 , 270 MHz): δ 12.60 (s, 1H), 11.72 (bs, 1H), 8.99 (s, 1H), 8.55-8.46 (m, 2H), 7.93-7.85 (m, 2H ), 7.73-7.64 (m, 1H), 7.60 (s, 1H), 7.55-7.46 (m, 2H), 7.38 (s, 1H), 7.24-7.17 (m, 2H), 6.51 (d, J = 5.3 Hz, 1H), 4.06 (s, 3H), 4.01 (s, 3H)
Mass Spec (ESI-MS, m / z): 468 (M + 1) + , 466 (M-1) -
N−[4−(6,7−ジメトキシキノリン−4−イルオキシ)フェニル]−2−オキソ−1,2−ジヒドロキノリン−3−カルボキサミド(化合物2)
文献[バイオオーガニック・メディシナル・ケミストリー・レターズ(Bioorg.Med.Chem.Lett.),2003年,13巻,1187−1189頁]に従って合成した2−オキソ−1,2−ジヒドロキノリン−3−カルボン酸(97mg、0.513mmol)を実施例1と同様の方法でアミド化反応に付した。加熱還流下で終夜攪拌した後、室温に冷却し、析出した結晶を濾取することにより標題の化合物(95mg、収率65%)を得た。 N- [4- (6,7-dimethoxyquinolin-4-yloxy) phenyl] -2-oxo-1,2-dihydroquinoline-3-carboxamide (Compound 2)
2-oxo-1,2-dihydroquinoline-3-carboxylic acid synthesized according to the literature [Bioorgan. Med. Chem. Lett., 2003, 13, pp. 1187-1189] (97 mg, 0.513 mmol) was subjected to an amidation reaction in the same manner as in Example 1. The mixture was stirred overnight with heating under reflux, then cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (95 mg, yield 65%).
1H-NMR (DMSO-d6, 300 MHz): δ 12.69 (bs, 1H), 12.27 (s, 1H), 9.01 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.03 (d, J = 7.3 Hz, 1H), 7.93 - 7.86 (m, 2H), 7.76 - 7.67 (m, 1H), 7.53 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.41 (s, 1H), 7.39 - 7.28 (m, 3H), 6.51 (d, J = 5.1 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H)
質量分析値(ESI-MS, m/z): 468(M+1)+, 466(M-1)- 1 H-NMR (DMSO-d 6 , 300 MHz): δ 12.69 (bs, 1H), 12.27 (s, 1H), 9.01 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.03 ( d, J = 7.3 Hz, 1H), 7.93-7.86 (m, 2H), 7.76-7.67 (m, 1H), 7.53 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.41 (s , 1H), 7.39-7.28 (m, 3H), 6.51 (d, J = 5.1 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H)
Mass Spec (ESI-MS, m / z): 468 (M + 1) + , 466 (M-1) -
N−{3−フルオロ−4−[6−メトキシ−7−(2−モルホリノエトキシ)キノリン−4−イルオキシ]フェニル}−4−オキソ−1,4−ジヒドロキノリン−3−カルボキサミド(化合物3)
特許文献(国際公開第03/000660号パンフレット)に従って合成した4−(7−ベンジルオキシ−6−メトキシキノリン−4−イルオキシ)−3−フルオロアニリン(10g、25.6mmol)にトリフルオロ酢酸(150mL)及びメタンスルホン酸(1mL)を加え、加熱還流下で2時間攪拌した。室温に冷却後、減圧下で溶媒を留去し、得られた残渣に水酸化ナトリウム水溶液を加えてアルカリ性にした。不溶物を濾取し、水で洗浄後に真空下で乾燥することにより4−(4−アミノ−2−フルオロフェノキシ)−6−メトキシキノリン−7−オール(7.20g、収率94%)を得た。 N- {3-Fluoro-4- [6-methoxy-7- (2-morpholinoethoxy) quinolin-4-yloxy] phenyl} -4-oxo-1,4-dihydroquinoline-3-carboxamide (Compound 3)
4- (7-Benzyloxy-6-methoxyquinolin-4-yloxy) -3-fluoroaniline (10 g, 25.6 mmol) synthesized according to the patent document (WO 03/000660 pamphlet) was added to trifluoroacetic acid (150 mL). ) And methanesulfonic acid (1 mL) were added, and the mixture was stirred for 2 hours under heating to reflux. After cooling to room temperature, the solvent was distilled off under reduced pressure, and an aqueous sodium hydroxide solution was added to the resulting residue to make it alkaline. Insoluble matter was collected by filtration, washed with water, and dried under vacuum to give 4- (4-amino-2-fluorophenoxy) -6-methoxyquinolin-7-ol (7.20 g, yield 94%). Obtained.
4−(4−アミノ−2−フルオロフェノキシ)−6−メトキシキノリン−7−オール(4.5g、15.0mmol)にN,N−ジメチルホルムアミド(100mL)、炭酸カリウム(10.4g、75.0mmol)及び1−ブロモ−2−クロロエタン(6.23mL、75.0mmol)を加え、室温で終夜攪拌した後、炭酸カリウム(2g、14.5mmol)を追加して室温でさらに1日攪拌した。反応液に水を加え酢酸エチルで3回抽出し、有機層を合わせて飽和食塩水で3回洗浄した後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた残渣を酢酸エチルに懸濁させ、濾取することにより、4−[7−(2−クロロエトキシ)−6−メトキシキノリン−4−イルオキシ]−3−フルオロアニリン(2.61g、収率48%)を得た。 4- (4-Amino-2-fluorophenoxy) -6-methoxyquinolin-7-ol (4.5 g, 15.0 mmol) to N, N-dimethylformamide (100 mL), potassium carbonate (10.4 g, 75.75). 0 mmol) and 1-bromo-2-chloroethane (6.23 mL, 75.0 mmol) were added and stirred overnight at room temperature, then potassium carbonate (2 g, 14.5 mmol) was added, and the mixture was further stirred at room temperature for 1 day. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed 3 times with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was suspended in ethyl acetate and collected by filtration to give 4- [7- (2-chloroethoxy) -6-methoxyquinolin-4-yloxy] -3- Fluoroaniline (2.61 g, yield 48%) was obtained.
4−[7−(2−クロロエトキシ)−6−メトキシキノリン−4−イルオキシ]−3−フルオロアニリン(2.61g、7.19mmol)にN,N−ジメチルホルムアミド(100mL)、炭酸カリウム(5.0g、36.0mmol)、ヨウ化ナトリウム(2.16g、14.4mmol)及びモルホリン(3.14mL、36.0mmol)を加え、70℃で2日間攪拌した。更に炭酸カリウム(1g、7.23mmol)及びモルホリン(0.6mL、6.88mmol)を追加して70℃で終夜攪拌した。室温に冷却し、水を加えて酢酸エチルで2回抽出した。有機層を合わせて、飽和食塩水で2回洗浄し、硫酸ナトリウムで乾燥後に減圧下で溶媒を留去した。得られた残渣を酢酸エチルに懸濁させ、濾取することにより3−フルオロ−4−[6−メトキシ−7−(2−モルホリノエトキシ)キノリン−4−イルオキシ]アニリン(1.74g、58%)を得た。 4- [7- (2-Chloroethoxy) -6-methoxyquinolin-4-yloxy] -3-fluoroaniline (2.61 g, 7.19 mmol) was added to N, N-dimethylformamide (100 mL), potassium carbonate (5 0.0 g, 36.0 mmol), sodium iodide (2.16 g, 14.4 mmol) and morpholine (3.14 mL, 36.0 mmol) were added and stirred at 70 ° C. for 2 days. Further, potassium carbonate (1 g, 7.23 mmol) and morpholine (0.6 mL, 6.88 mmol) were added, and the mixture was stirred at 70 ° C. overnight. After cooling to room temperature, water was added and extracted twice with ethyl acetate. The organic layers were combined, washed twice with saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was suspended in ethyl acetate and collected by filtration to give 3-fluoro-4- [6-methoxy-7- (2-morpholinoethoxy) quinolin-4-yloxy] aniline (1.74 g, 58%). )
3−フルオロ−4−[6−メトキシ−7−(2−モルホリノエトキシ)キノリン−4−イルオキシ]アニリン(50.0mg、0.121mmol)、4−ヒドロキシキノリン−3−カルボン酸(25mg、0.132mmol)、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩(47.0g、0.245mmol)及び1−ヒドロキシベンゾトリアゾール一水和物(37.5mg、0.245mmol)にクロロホルム(8mL)、トリエチルアミン(84μL、0.606mmol)を順に加え、加熱還流下、終夜攪拌した。反応液を冷却後、食塩水で洗浄した。硫酸ナトリウムで乾燥後、減圧下で溶媒を留去して得られた残渣を酢酸エチルに懸濁させて濾取することにより標題の化合物(52.0mg、収率74%)を得た。 3-Fluoro-4- [6-methoxy-7- (2-morpholinoethoxy) quinolin-4-yloxy] aniline (50.0 mg, 0.121 mmol), 4-hydroxyquinoline-3-carboxylic acid (25 mg, 0. 132 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (47.0 g, 0.245 mmol) and 1-hydroxybenzotriazole monohydrate (37.5 mg, 0.245 mmol) in chloroform ( 8 mL) and triethylamine (84 μL, 0.606 mmol) were added in this order, and the mixture was stirred overnight with heating under reflux. The reaction solution was cooled and washed with brine. After drying over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was suspended in ethyl acetate and collected by filtration to give the title compound (52.0 mg, yield 74%).
1H-NMR (CDCl3/CD3OD, 300 MHz): δ12.72 (s, 1H), 8.77 (s, 1H), 8.48 - 8.39 (m, 2H), 8.00 (dd, J = 2.2, 12.5 Hz, 1H), 7.73 - 7.65 (m, 1H), 7.57 (s, 1H), 7.53 - 7.40 (m, 3H), 7.36 (s, 1H), 7.27 - 7.16 (m, 1H), 6.44 (d, J = 5.1 Hz, 1H), 4.31 (t, J = 5.9 Hz, 2H), 4.01 (s, 3H), 3.77 - 3.69 (m, 4H), 2.93 (t, J = 5.9 Hz, 2H), 2.67 - 2.57 (m, 4H)
質量分析値(ESI-MS, m/z): 585(M+1)+, 583(M-1)- 1 H-NMR (CDCl 3 / CD 3 OD, 300 MHz): δ12.72 (s, 1H), 8.77 (s, 1H), 8.48-8.39 (m, 2H), 8.00 (dd, J = 2.2, 12.5 Hz, 1H), 7.73-7.65 (m, 1H), 7.57 (s, 1H), 7.53-7.40 (m, 3H), 7.36 (s, 1H), 7.27-7.16 (m, 1H), 6.44 (d, J = 5.1 Hz, 1H), 4.31 (t, J = 5.9 Hz, 2H), 4.01 (s, 3H), 3.77-3.69 (m, 4H), 2.93 (t, J = 5.9 Hz, 2H), 2.67- 2.57 (m, 4H)
Mass Spec (ESI-MS, m / z): 585 (M + 1) + , 583 (M-1) -
N−[4−(6,7−ジメトキシキノリン−4−イルオキシ)フェニル]−1−エチル−6−フルオロ−4−オキソ−1,4−ジヒドロキノリン−3−カルボキサミド(化合物4)
文献[テトラへドロンレターズ(Tetrahedron Lett.),2007年,48(15)巻,2765−2768頁]に従って合成したN−エチル−4−フルオロアニリン(2.37g、17.0mmol)に2−プロパノール(5mL)及び5−(メトキシメチレン)−2,2−ジメチル−1,3−ジオキサン−4,6−ジオン(3.80g、20.4mmol)を加えて100℃で40分間攪拌した。室温に冷却後、減圧下で溶媒を留去した。残渣をジエチルエーテルに懸濁させ濾取した残渣をさらに精製することなく次の反応に用いた。 N- [4- (6,7-dimethoxyquinolin-4-yloxy) phenyl] -1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxamide (Compound 4)
N-ethyl-4-fluoroaniline (2.37 g, 17.0 mmol) synthesized according to the document [Tetrahedron Lett., 2007, 48 (15), 2765-2768] was prepared with 2-propanol. (5 mL) and 5- (methoxymethylene) -2,2-dimethyl-1,3-dioxane-4,6-dione (3.80 g, 20.4 mmol) were added and stirred at 100 ° C. for 40 minutes. After cooling to room temperature, the solvent was distilled off under reduced pressure. The residue was suspended in diethyl ether and the residue collected by filtration was used in the next reaction without further purification.
上記反応で得られた残渣にトルエン(40mL)及びポリリン酸(7.56g)を加え100℃で40分間攪拌した。室温に冷却後、トルエンをデカントで除いた。残渣を水に懸濁させ濾取し、水、ジエチルエーテルで順に洗浄し、減圧下で乾燥することにより1−エチル−6−フルオロ−4−オキソ−1,4−ジヒドロキノリン−3−カルボン酸(0.94g、2段階収率15%)を得た。 Toluene (40 mL) and polyphosphoric acid (7.56 g) were added to the residue obtained by the above reaction, and the mixture was stirred at 100 ° C. for 40 minutes. After cooling to room temperature, toluene was removed by decantation. The residue is suspended in water, collected by filtration, washed successively with water and diethyl ether, and dried under reduced pressure to give 1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. (0.94 g, 2 stage yield 15%).
1−エチル−6−フルオロ−4−オキソ−1,4−ジヒドロキノリン−3−カルボン酸(0.94g、4.00mmol)を実施例1と同様の方法でアミド化することにより標題の化合物(1.35g、収率66%)を得た。 1-Ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.94 g, 4.00 mmol) was amidated in the same manner as in Example 1 to give the title compound ( 1.35 g, 66% yield).
1H-NMR (CDCl3, 400 MHz): δ 12.30 (s, 1H), 8.91 (s, 1H), 8.50 (d, J = 5.4 Hz, 1H), 8.25 (dd, J = 2.9, 8.8 Hz, 1H), 7.94 - 7.82 (m, 2H), 7.65 - 7.50 (m, 3H), 7.43 (s, 1H), 7.24 - 7.18 (m, 2H), 6.51 (d, J = 5.4 Hz, 1H), 4.41 (q, J = 7.3 Hz, 2H), 4.06 (s, 3H), 4.06 (s, 3H), 1.62 (t, J = 7.3 Hz, 3H)
質量分析値(ESI-MS, m/z): 536(M+23)+, 512(M-1)- 1 H-NMR (CDCl 3 , 400 MHz): δ 12.30 (s, 1H), 8.91 (s, 1H), 8.50 (d, J = 5.4 Hz, 1H), 8.25 (dd, J = 2.9, 8.8 Hz, 1H), 7.94-7.82 (m, 2H), 7.65-7.50 (m, 3H), 7.43 (s, 1H), 7.24-7.18 (m, 2H), 6.51 (d, J = 5.4 Hz, 1H), 4.41 (q, J = 7.3 Hz, 2H), 4.06 (s, 3H), 4.06 (s, 3H), 1.62 (t, J = 7.3 Hz, 3H)
Mass Spec (ESI-MS, m / z): 536 (M + 23) + , 512 (M-1) -
N−{3−フルオロ−4−[6−メトキシ−7−(2−モルホリノエトキシ)キノリン−4−イルオキシ]フェニル}−4−オキソ−1,4−ジヒドロキノリン−3−カルボキサミド塩酸塩(化合物5)
実施例3で得られた化合物3[N−{3−フルオロ−4−[6−メトキシ−7−(2−モルホリノエトキシ)キノリン−4−イルオキシ]フェニル}−4−オキソ−1,4−ジヒドロキノリン−3−カルボキサミド](20mg)に塩酸−メタノール溶液(1mL)を室温で加え、30分間攪拌した。減圧下で溶媒を留去し、アセトンに懸濁させて濾取することにより標題の化合物(22.4mg、収率100%)を得た。 N- {3-Fluoro-4- [6-methoxy-7- (2-morpholinoethoxy) quinolin-4-yloxy] phenyl} -4-oxo-1,4-dihydroquinoline-3-carboxamide hydrochloride (Compound 5 )
Compound 3 [N- {3-Fluoro-4- [6-methoxy-7- (2-morpholinoethoxy) quinolin-4-yloxy] phenyl} -4-oxo-1,4-dihydro obtained in Example 3 To a quinoline-3-carboxamide] (20 mg) was added a hydrochloric acid-methanol solution (1 mL) at room temperature, and the mixture was stirred for 30 minutes. The solvent was distilled off under reduced pressure, suspended in acetone and collected by filtration to give the title compound (22.4 mg, yield 100%).
1H-NMR (DMSO-d6, 300 MHz): δ 13.55 - 13.28 (m, 1H), 12.86 (s, 1H), 12.00 - 11.50 (m, 1H), 8.94 - 8.85 (m, 2H), 8.34 (d, J = 8.1 Hz, 1H), 8.24 - 8.16 (m, 1H), 7.89 - 7.78 (m, 4H), 7.70 - 7.53 (m, 3H), 7.06 (d, J = 6.6 Hz, 1H), 4.82 - 4.70 (m, 2H), 4.40 - 3.10 (m, 13 H) 1 H-NMR (DMSO-d 6 , 300 MHz): δ 13.55-13.28 (m, 1H), 12.86 (s, 1H), 12.00-11.50 (m, 1H), 8.94-8.85 (m, 2H), 8.34 (d, J = 8.1 Hz, 1H), 8.24-8.16 (m, 1H), 7.89-7.78 (m, 4H), 7.70-7.53 (m, 3H), 7.06 (d, J = 6.6 Hz, 1H), 4.82-4.70 (m, 2H), 4.40-3.10 (m, 13 H)
N−[4−(6,7−ジメトキシシンノリン−4−イルオキシ)フェニル]−1−イソプロピル−4−オキソ−1,4−ジヒドロキノリン−3−カルボキサミド(化合物6)
2−フルオロ安息香酸(10.0g、71.4mmol)にトルエン(70mL)を加え、塩化チオニル(17.0g、142mmol)を室温で滴下し、N,N−ジメチルホルムアミド(3滴)を加えて加熱還流下2.5時間攪拌した。減圧下で濃縮し、トルエンを加えて減圧下で留去する操作を2回繰り返すことにより2−フルオロ安息香酸クロリド(11.5g)を得た。 N- [4- (6,7-dimethoxycinnolin-4-yloxy) phenyl] -1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (Compound 6)
Toluene (70 mL) was added to 2-fluorobenzoic acid (10.0 g, 71.4 mmol), thionyl chloride (17.0 g, 142 mmol) was added dropwise at room temperature, and N, N-dimethylformamide (3 drops) was added. The mixture was stirred for 2.5 hours with heating under reflux. The operation of concentration under reduced pressure, addition of toluene and distillation under reduced pressure were repeated twice to obtain 2-fluorobenzoic acid chloride (11.5 g).
別フラスコで3−(ジメチルアミノ)アクリル酸エチル(71.4mmol)をアセトニトリル(70mL)に溶解し、トリエチルアミン(14.4g、142mmol)を加えた後、2−フルオロ安息香酸クロリド(11.5g)のアセトニトリル(20mL)溶液を室温で滴下し、加熱還流下3時間攪拌した。反応液を室温に冷却後、減圧下で溶媒を留去して得られた残渣にジクロロメタンを加えて濾過した。濾液から減圧下で溶媒を留去し、得られた残渣をカラムクロマトグラフィー(n−ヘプタン/酢酸エチル系の溶媒で展開後、n−ヘプタン/アセトン系の溶媒で展開)で精製することにより3−(ジメチルアミノ)−2−(2−フルオロベンゾイル)アクリル酸エチル(12.5g、収率66%)を得た。 In another flask, ethyl 3- (dimethylamino) acrylate (71.4 mmol) was dissolved in acetonitrile (70 mL), triethylamine (14.4 g, 142 mmol) was added, and 2-fluorobenzoic acid chloride (11.5 g) was then added. Of acetonitrile (20 mL) was added dropwise at room temperature, and the mixture was stirred for 3 hours with heating under reflux. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure, and dichloromethane was added to the resulting residue and filtered. The solvent was distilled off from the filtrate under reduced pressure, and the resulting residue was purified by column chromatography (developed with an n-heptane / ethyl acetate solvent and then developed with an n-heptane / acetone solvent). -(Dimethylamino) -2- (2-fluorobenzoyl) ethyl acrylate (12.5 g, yield 66%) was obtained.
3−(ジメチルアミノ)−2−(2−フルオロベンゾイル)アクリル酸エチル(12.5g、47.1mmol)をテトラヒドロフラン(40mL)に溶解し、室温でイソプロピルアミン(8.13mL、94.2mmol)を加えて2.5時間攪拌した。減圧下、溶媒を留去し、得られた残渣に炭酸カリウム(13.0g、94.2mmol)及びN,N−ジメチルホルムアミド(80mL)を加え、100℃で17時間攪拌した。減圧下、溶媒を留去して得られた残渣を水に加え、クロロホルムで3回抽出した。有機層を合わせて飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥した。減圧下で溶媒を留去することにより得られた残渣にメタノール(140mL)、水(4.7mL)及び水酸化リチウム一水和物(5.93g、141mmol)を加え、室温で3時間攪拌した。反応液を減圧濃縮後、氷冷下で1mol/L塩酸を加えてpH1にし、析出した沈殿を濾取した。濾液はクロロホルムで2回抽出し、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。先の濾取物を加え、減圧下で溶媒を留去することにより1−(2−プロピル)−4−オキソ−1,4−ジヒドロキノリン−3−カルボン酸(10.2g、収率94%)を得た。 Ethyl 3- (dimethylamino) -2- (2-fluorobenzoyl) acrylate (12.5 g, 47.1 mmol) is dissolved in tetrahydrofuran (40 mL), and isopropylamine (8.13 mL, 94.2 mmol) is added at room temperature. The mixture was further stirred for 2.5 hours. The solvent was distilled off under reduced pressure, and potassium carbonate (13.0 g, 94.2 mmol) and N, N-dimethylformamide (80 mL) were added to the resulting residue, followed by stirring at 100 ° C. for 17 hours. The residue obtained by distilling off the solvent under reduced pressure was added to water and extracted three times with chloroform. The organic layers were combined, washed with saturated brine, and dried over sodium sulfate. Methanol (140 mL), water (4.7 mL) and lithium hydroxide monohydrate (5.93 g, 141 mmol) were added to the residue obtained by distilling off the solvent under reduced pressure, and the mixture was stirred at room temperature for 3 hours. . The reaction solution was concentrated under reduced pressure, 1 mol / L hydrochloric acid was added under ice-cooling to pH 1, and the deposited precipitate was collected by filtration. The filtrate was extracted twice with chloroform, washed with saturated brine, and dried over sodium sulfate. The previous filtered product was added and the solvent was distilled off under reduced pressure to give 1- (2-propyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (10.2 g, yield 94%). )
文献[ジャーナル・オブ・オーガニック・ケミストリー(J.Org.Chem.),1952年,17巻,1571−1574頁]に従い合成した4−クロロ−6,7−ジメトキシシンノリン(2.0g、9.0mmol)とp−ニトロフェノール(2.5g、18.0mmol)にクロロベンゼン(4.5mL)を加え、115℃で9時間攪拌した。反応液を1mol/L水酸化カリウム水溶液に加え、クロロホルムで5回抽出した。有機層を合わせて、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後に減圧下で溶媒を留去した。残渣にメタノールを加えて濾過後、濾取物を減圧下で乾燥することにより6,7−ジメトキシ−4−(4−ニトロフェノキシ)シンノリン(1.72g、収率58%)を得た。 4-chloro-6,7-dimethoxycinnoline (2.0 g, 9.15) synthesized according to the literature [Journal of Organic Chemistry (J. Org. Chem.), 1952, Vol. 17, pp. 1571-1574]. 0 mmol) and p-nitrophenol (2.5 g, 18.0 mmol) were added with chlorobenzene (4.5 mL), and the mixture was stirred at 115 ° C. for 9 hours. The reaction solution was added to a 1 mol / L aqueous potassium hydroxide solution and extracted five times with chloroform. The organic layers were combined, washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Methanol was added to the residue and filtered, and then the filtered product was dried under reduced pressure to obtain 6,7-dimethoxy-4- (4-nitrophenoxy) cinnoline (1.72 g, yield 58%).
水酸化パラジウム(0.17g、20%、wet)をN,N−ジメチルホルムアミド(60mL)に加え、6,7−ジメトキシ−4−(4−ニトロフェノキシ)シンノリン(1.72g、5.26mmol)のN,N−ジメチルホルムアミド(30mL)溶液を室温で加えた。水素気流下、室温で21時間攪拌した後、水酸化パラジウム(0.17g、20%、wet)を追加し、室温で40時間攪拌した。さらに水酸化パラジウム(0.85g、20%、wet)を追加し、室温で4時間攪拌した。反応液を濾過し、減圧下で溶媒を留去して得られた残渣にクロロホルムを加え、飽和重曹水、飽和食塩水で順に洗浄した後、硫酸ナトリウムで乾燥した。減圧下で溶媒を留去し、得られた残渣にメタノールを加えて濾過し、濾取物を減圧下で乾燥することにより4−(6,7−ジメトキシシンノリン−4−イルオキシ)アニリン(1.19g、収率76%)を得た。 Palladium hydroxide (0.17 g, 20%, wet) was added to N, N-dimethylformamide (60 mL) and 6,7-dimethoxy-4- (4-nitrophenoxy) cinnoline (1.72 g, 5.26 mmol). Of N, N-dimethylformamide (30 mL) was added at room temperature. After stirring for 21 hours at room temperature under a hydrogen stream, palladium hydroxide (0.17 g, 20%, wet) was added, and the mixture was stirred for 40 hours at room temperature. Further, palladium hydroxide (0.85 g, 20%, wet) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was filtered, the solvent was distilled off under reduced pressure, chloroform was added to the resulting residue, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine in that order, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, methanol was added to the resulting residue and filtered, and the filtrated product was dried under reduced pressure to give 4- (6,7-dimethoxycinnolin-4-yloxy) aniline (1 .19 g, yield 76%).
4−(6,7−ジメトキシシンノリン−4−イルオキシ)アニリン(0.41g、1.38mmol)、1−(2−プロピル)−4−オキソ−1,4−ジヒドロキノリン−3−カルボン酸(0.47g、2.07mmol)、O−(7−アザベンゾトリアゾール−1−イル)−N,N,N’,N’,−テトラメチルウロニウムヘキサフルオロリン酸(0.96g、2.07mmol)、4−ジメチルアミノピリジン(0.006g、0.053mmol)及びトリエチルアミン(0.7mL、5.05mmol)をN,N−ジメチルホルムアミド(15mL)に加え、室温で72時間攪拌した後、反応液から減圧下で溶媒を留去した。得られた残渣に水を加えて、クロロホルムで3回抽出し、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。得られた残渣をクロロホルム/メタノール系のカラムクロマトグラフィーで精製し、さらにクロロホルム/アセトン系のカラムクロマトグラフィーで精製することにより、標題の化合物(0.55g、収率78%)を得た。 4- (6,7-dimethoxycinnolin-4-yloxy) aniline (0.41 g, 1.38 mmol), 1- (2-propyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( 0.47 g, 2.07 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ′, N ′,-tetramethyluronium hexafluorophosphate (0.96 g, 2.07 mmol) ), 4-dimethylaminopyridine (0.006 g, 0.053 mmol) and triethylamine (0.7 mL, 5.05 mmol) were added to N, N-dimethylformamide (15 mL), and the mixture was stirred at room temperature for 72 hours. The solvent was distilled off under reduced pressure. Water was added to the resulting residue, extracted three times with chloroform, washed with saturated brine, and dried over sodium sulfate. The obtained residue was purified by chloroform / methanol column chromatography and further purified by chloroform / acetone column chromatography to give the title compound (0.55 g, yield 78%).
1H-NMR (CDCl3, 270 MHz): δ 12.53 (s, 1H), 9.10 (s, 1H), 8.67 - 8.61 (m, 2H), 7.99 - 7.89 (m, 2H), 7.88 - 7.66 (m, 3H), 7.61 - 7.52 (m, 1H), 7.46 (s, 1H), 7.25 - 7.17 (m, 2H), 5.05 (heptet, J = 6.6 Hz, 1H), 4.12 (s, 3H), 4.10 (s, 3H), 1.70 (d, J = 6.6 Hz, 6H)
質量分析値(ESI-MS, m/z): 533(M+23)+, 509(M-1)- 1 H-NMR (CDCl 3 , 270 MHz): δ 12.53 (s, 1H), 9.10 (s, 1H), 8.67-8.61 (m, 2H), 7.99-7.89 (m, 2H), 7.88-7.66 (m , 3H), 7.61-7.52 (m, 1H), 7.46 (s, 1H), 7.25-7.17 (m, 2H), 5.05 (heptet, J = 6.6 Hz, 1H), 4.12 (s, 3H), 4.10 ( s, 3H), 1.70 (d, J = 6.6 Hz, 6H)
Mass Spec (ESI-MS, m / z): 533 (M + 23) + , 509 (M-1) -
N−[4−(6,7−ジメトキシキノリン−4−イルオキシ)フェニル]−1−イソプロピル−4−オキソ−1,4−ジヒドロキノリン−3−カルボキサミド(化合物7)
1−(2−プロピル)−4−オキソ−1,4−ジヒドロキノリン−3−カルボン酸(262mg、0.804mmol)を実施例1と同様にしてアミド化することにより標題の化合物を得た。 N- [4- (6,7-dimethoxyquinolin-4-yloxy) phenyl] -1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (Compound 7)
1- (2-Propyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (262 mg, 0.804 mmol) was amidated as in Example 1 to give the title compound.
1H-NMR (CDCl3, 400 MHz): δ 12.48 (s, 1H), 9.10 (s, 1H), 8.64 (d, J = 8.1 Hz, 1H), 8.50 (d, J = 5.2 Hz, 1H), 7.94 - 7.87 (m, 2H), 7.85 - 7.77 (m, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.59 (s, 1H), 7.56 (dd, J = 7.8, 7.8 Hz, 1H), 7.43 (s, 1H), 7.23 - 7.17 (m, 2H), 6.52 (d, J = 5.4 Hz, 1H), 5.04 (heptet, J = 6.8 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 1.70 (d, J = 6.8 Hz, 6H)
質量分析値(ESI-MS, m/z): 532 (M+23)+, 508(M-1)- 1 H-NMR (CDCl 3 , 400 MHz): δ 12.48 (s, 1H), 9.10 (s, 1H), 8.64 (d, J = 8.1 Hz, 1H), 8.50 (d, J = 5.2 Hz, 1H) , 7.94-7.87 (m, 2H), 7.85-7.77 (m, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.59 (s, 1H), 7.56 (dd, J = 7.8, 7.8 Hz, 1H ), 7.43 (s, 1H), 7.23-7.17 (m, 2H), 6.52 (d, J = 5.4 Hz, 1H), 5.04 (heptet, J = 6.8 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 1.70 (d, J = 6.8 Hz, 6H)
Mass Spec (ESI-MS, m / z): 532 (M + 23) + , 508 (M-1) -
N−[4−(6,7−ジメトキシシンノリン−4−イルオキシ)フェニル]−1−イソプロピル−4−オキソ−1,4−ジヒドロ−1,7−ナフチリジン−3−カルボキサミド(化合物8)
実施例6と同様にして、2−フルオロ安息香酸の代わりに3−フルオロイソニコチン酸を原料として用い合成した1−(2−プロピル)−4−オキソ−1,4−ジヒドロ−1,7−ナフチリジン−3−カルボン酸(24mg、0.103mmol)と、4−(6,7−ジメトキシシンノリン−4−イルオキシ)アニリン(30.6mg、0.103mmol)を用いて、実施例6と同様にしてアミド化することにより標題の化合物(34.2mg、収率65%)を得た。 N- [4- (6,7-dimethoxycinnolin-4-yloxy) phenyl] -1-isopropyl-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxamide (Compound 8)
1- (2-propyl) -4-oxo-1,4-dihydro-1,7- synthesized in the same manner as in Example 6 using 3-fluoroisonicotinic acid as a raw material instead of 2-fluorobenzoic acid As in Example 6, using naphthyridine-3-carboxylic acid (24 mg, 0.103 mmol) and 4- (6,7-dimethoxycinnolin-4-yloxy) aniline (30.6 mg, 0.103 mmol). The title compound (34.2 mg, yield 65%) was obtained by amidation.
1H-NMR (CDCl3, 400 MHz): δ 12.17 (s, 1H), 9.30 (s, 1H), 9.14 (s, 1H), 8.77 (d, J = 5.2 Hz, 1H), 8.62 (s, 1H), 8.39 (d, J = 5.1 Hz, 1H), 7.95 - 7.88 (m, 2H), 7.74 (s, 1H), 7.46 (s, 1H), 7.26 - 7.19 (m, 2H), 5.19 (heptet, J = 6.8 Hz, 1H), 4.12 (s, 3H), 4.10 (s, 3H), 1.75 (d, J = 6.6 Hz, 6H)
質量分析値(ESI-MS, m/z): 534(M+23)+, 510(M-1)- 1 H-NMR (CDCl 3 , 400 MHz): δ 12.17 (s, 1H), 9.30 (s, 1H), 9.14 (s, 1H), 8.77 (d, J = 5.2 Hz, 1H), 8.62 (s, 1H), 8.39 (d, J = 5.1 Hz, 1H), 7.95-7.88 (m, 2H), 7.74 (s, 1H), 7.46 (s, 1H), 7.26-7.19 (m, 2H), 5.19 (heptet , J = 6.8 Hz, 1H), 4.12 (s, 3H), 4.10 (s, 3H), 1.75 (d, J = 6.6 Hz, 6H)
Mass Spec (ESI-MS, m / z): 534 (M + 23) + , 510 (M-1) -
本発明により、ASK1阻害活性を有し、例えば、ALSの予防及び/又は治療剤として有用な含窒素複素環誘導体又はその薬学的に許容される塩等が提供される。 The present invention provides a nitrogen-containing heterocyclic derivative or a pharmaceutically acceptable salt thereof, which has ASK1 inhibitory activity and is useful, for example, as an agent for preventing and / or treating ALS.
本出願は、日本で出願された特願2010−165514を基礎としており、その内容は本明細書にすべて包含される。 This application is based on patent application No. 2010-165514 filed in Japan, the contents of which are incorporated in full herein.
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