JP2022003049A - アミノピリミジンssao阻害剤 - Google Patents
アミノピリミジンssao阻害剤 Download PDFInfo
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- JP2022003049A JP2022003049A JP2021149451A JP2021149451A JP2022003049A JP 2022003049 A JP2022003049 A JP 2022003049A JP 2021149451 A JP2021149451 A JP 2021149451A JP 2021149451 A JP2021149451 A JP 2021149451A JP 2022003049 A JP2022003049 A JP 2022003049A
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- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
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- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
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- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- NSNNIMABMDKABJ-UHFFFAOYSA-N piperidin-4-ol;dihydrochloride Chemical compound Cl.Cl.OC1CCNCC1 NSNNIMABMDKABJ-UHFFFAOYSA-N 0.000 description 1
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- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
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- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
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- 239000003826 tablet Substances 0.000 description 1
- APCBTRDHCDOPNY-ZETCQYMHSA-N tert-butyl (3s)-3-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@H](O)C1 APCBTRDHCDOPNY-ZETCQYMHSA-N 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
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- 125000005490 tosylate group Chemical group 0.000 description 1
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- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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Abstract
Description
の化合物またはその薬学的に許容される塩を提供する。
次の製造例および実施例は、本発明をさらに説明し、本発明の化合物の典型的合成を示す。
tert−ブチル(3S)−3−メトキシピロリジン−1−カルボキシレート
ヨードメタン(0.398g、2.80mmol)を、tert−ブチル(3S)−3−ヒドロキシピロリジン−1−カルボキシレート(0.500g、2.67mmol)および水素化ナトリウム(鉱油中60重量%)(0.160g、4.01mmol)のDMF(5mL)中の混合物に加える。得られた混合物を室温で2時間撹拌する。飽和NH4Cl水溶液(30mL)で反応停止させ、EtOAc(3×30mL)で抽出する。水層を廃棄する。有機抽出物を合わせ、塩水で洗浄し、Na2SO4で乾燥させ、濾過し、濾液を蒸発乾固して、表題化合物(475mg、0.475g、88.4%)を得る。粗製物質をさらに精製することなく次工程で使用できる。ES/MS (m/z): 224.2 (M+Na)
(3S)−3−メトキシピロリジン
tert−ブチル(3S)−3−メトキシピロリジン−1−カルボキシレート(475mg、2.36mmol)およびトリフルオロ酢酸(1mL、13.23mmol)のDCM(3mL)溶液を、室温で1時間撹拌する。反応混合物を減圧下濃縮して、表題化合物(240mg、2.35mmol、99.5%)を得て、これをさらに精製することなく次工程で使用できる。
1−(5−ベンジルオキシピリミジン−2−イル)ピペリジン−4−オール
2−(4−ヒドロキシ−1−ピペリジル)ピリミジン−5−オール
tert−ブチルN−[(E)−2−[(2−クロロピリミジン−5−イル)オキシメチル]−3−フルオロ−アリル]カルバメート
tert−ブチルN−[(Z)−3−フルオロ−2−[[2−(4−ヒドロキシ−1−ピペリジル)ピリミジン−5−イル]オキシメチル]アリル]カルバメート
tert−ブチルN−[(E)−3−F−2−[[2−(4−ヒドロキシ−1−ピペリジル)ピリミジン−5−イル]オキシメチル]アリル]カルバメート
tert−ブチルN−[(E)−3−フルオロ−2−[[2−(4−メトキシ−1−ピペリジル)ピリミジン−5−イル]オキシメチル]アリル]カルバメート
tert−ブチルN−[(E)−3−フルオロ−2−[[2−[(3S)−3−メトキシピロリジン−1−イル]ピリミジン−5−イル]オキシメチル]アリル]カルバメート
tert−ブチルN−[(E)−3−フルオロ−2−[[2−[(3S)−3−ヒドロキシピロリジン−1−イル]ピリミジン−5−イル]オキシメチル]アリル]カルバメート
1−[5−[(Z)−2−(アミノメチル)−3−フルオロ−アリルオキシ]ピリミジン−2−イル]ピペリジン−4−オール塩酸塩
1−[5−[(E)−2−(アミノメチル)−3−フルオロ−アリルオキシ]ピリミジン−2−イル]ピペリジン−4−オール二塩酸塩
(E)−3−フルオロ−2−[[2−(4−メトキシ−1−ピペリジル)ピリミジン−5−イル]オキシメチル]プロプ−2−エン−1−アミン、二塩酸塩
(E)−3−フルオロ−2−[[2−(4−メトキシ−1−ピペリジル)ピリミジン−5−イル]オキシメチル]プロプ−2−エン−1−アミン
(2E)−3−フルオロ−2−({[2−(4−メトキシピペリジン−1−イル)ピリミジン−5−イル]オキシ}メチル)プロプ−2−エン−1−アミン4−メチルベンゼンスルホン酸塩(1:1)
結晶(2E)−3−フルオロ−2−({[2−(4−メトキシピペリジン−1−イル)ピリミジン−5−イル]オキシ}メチル)プロプ−2−エン−1−アミン4−メチルベンゼンスルホン酸塩のX線粉末回折(XRD)パターンを、CuKa源(λ=1.54060Å)およびVantec検出器を備え、35kVおよび50mAで操作するBruker D4 Endeavor X線粉末回折計で得る。サンプルを、2θで4〜40°の間走査し、ステップサイズは2θで0.009°であり、走査速度は0.5秒/ステップであり、0.6mm発散、5.28固定散乱線除去および9.5mm検出器スリットである。乾燥粉末を石英サンプルホルダーに詰め、スライドグラスを使用して、表面を滑らかにする。結晶形態回折パターンを環境温度および相対湿度で得る。ある結晶形態について、回折ピークの相対強度は結晶形態および晶癖などの因子によりもたらされる好ましい配向により、変わり得ることは結晶学分野では周知である。好ましい配向の影響が存在するとき、ピーク強度は変わるが、多形の特徴的ピーク位置は変わらない。例えば、The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995参照。さらに、ある結晶形態について、角度ピーク位置がわずかに変わり得ることも結晶学分野では周知である。例えば、ピーク位置はサンプルを分析する時点での温度または湿度の差、サンプル移動または内部標準の存在または非存在によりシフトし得る。本件の場合、2θで±0.2のピーク位置変動性を、当該結晶形態の明確な同定を妨げることなく、これらの可能性のある変動を考慮に入れる。結晶形態の確認は、識別可能なピーク(2θ°単位)で、一般により顕著なピークの何れかの特有の組み合わせに基づいてなし得る。結晶形態回折パターンを環境温度および相対湿度で取り、8.853°および26.774°2シータでのNIST 675標準ピークに基づき調節する。
(E)−3−フルオロ−2−[[2−[(3S)−3−メトキシピロリジン−1−イル]ピリミジン−5−イル]オキシメチル]プロプ−2−エン−1−アミン
(3S)−1−[5−[(E)−2−(アミノメチル)−3−フルオロ−アリルオキシ]ピリミジン−2−イル]ピロリジン−3−オール;二塩酸塩
tert−ブチルN−[(E)−3−フルオロ−2−[[2−[(3S)−3−ヒドロキシピロリジン−1−イル]ピリミジン−5−イル]オキシメチル]アリル]カルバメート(1.1601g、3.15mmol)をHClのEtOAc溶液(50mL、50mmol、1.0mol/L)(0.5mol/L HClとMeOH、5mLを予め混合)に溶解する。得られた溶液を一夜撹拌する。白色懸濁液を減圧下濃縮して、白色粉末を得る。白色粉末を水に溶解し、溶液を凍結乾燥して、表題化合物を淡黄色固体(860.7mg、2.42mmol、77%)として得る。
SSAO/VAP−1インビトロ活性
組み換えSSAO、MAOaおよびMAObアイソフォームのアミンオキシダーゼ活性を、PromegaのMAO-GloTMアッセイキット(V1402)を使用して測定する。試験化合物(SSAOについて媒体としてDMSO、0.5%v/v)および酵素を、10分、室温でインキュベートして、発光基質を加える。基質濃度はヒト組み換えSSAOについて10μMである。アッセイを、pH7.4緩衝液(50mM HEPES、120mM NaCl、5mM KCl、2mM CaCl2、1.4mM MgCl2、0.001%Tween−20)でウェルプレートで行う。基質酸化を2時間行い、製造業者のプロトコールに従い、検出試薬を加える。試験化合物のIC50値を、用量応答曲線を4パラメータ非線形回帰ルーティンに適合させることにより、計算する。実施例3、5および6の化合物のIC50値を表2に記載する。
データをアッセイ数(n)に対する平均±SEM(SEM=平均の標準誤差)で表す。
実施例化合物は、hSSAOに対して60nM未満のIC50を示す。実施例化合物は、それぞれ50μMおよび200μMを超えるhMAOaおよびhMAObに対するIC50を示し、実施例化合物がhMAOaまたはhMAObの何れよりもhSSAOに選択的であることが示される。
ラット血漿および肝臓組織でのSSAO活性を、PromegaからのMAO-GloTMアッセイキット(V1402)を使用して測定する。化合物処置後のラットにおける残存SSAO活性を、MAO阻害剤クロルギリンおよびパルギリン存在に非感受性である、血漿または肝臓ライセート中の総アミンオキシダーゼ活性の測定により概算する。ラットに、実施例化合物2を15mg/kg、3mg/kg、0.6mg/kg、0.12mg/kg、0.025mg/kg、0.005mg/kg用量で投与する。対照群に等量(2ml/kg)の投与媒体(ヒドロキシエチルセルロース1%w/v、0.25%Tween 80)を投与する。化合物処置2時間または24時間後の血漿および肝臓を採取し、分析まで−78℃で保存する。組織ライセートを、溶解緩衝液(20mM HEPES、pH7.4、150mM NaCl、1mM EDTA、1mM EGTA、1%Triton X−100および1×Roche Complete protease inhibitor錠)中で均質化することにより調製する。組織片を、12,000rpmで、4℃で30分の遠心分離により除く。40μlの血漿または肝臓ライセートをクロルギリン(10μM)およびパルギリン(10μM)と、20分、室温でインキュベートし、発光基質(50μM)を60分加える。生成物を、製造業者のプロトコールにより定量する。MAO阻害剤の存在に非感受性である活性画分を残存SSAO活性のサロゲートとして使用する。実施例化合物2を、本質的に上記プロトコールで、種々の用量で投与して評価した。結果を表3に記載する。
データを平均±SEM、n=6で表す
結果は、実施例化合物2がラット血漿および肝臓両者におけるSSAO活性を用量依存性に阻害することを示す。
雄C57BL/6NマウスにD09100301餌(Research Diets、40%脂肪、2%コレステロール、24%フルクトース(高脂肪、高コレステロールおよび高フルクトース、“3H餌”))を150日間与える。各マウスを、順応期間の5日間の後、一匹ずつで飼育する。血漿アラニンアミノトランスフェラーゼ(ALT)およびサイトケラチン18(CK18)を測定する。1週間の回復後、マウスをALT値、CK18値および体重に基づき5群に無作為化する。各群の動物に、媒体(蒸留水中0.5%メチルセルロース(MC)+0.25%Tween 80)または実施例6化合物(0.06mg/kg、2mg/kg、6mg/kgおよび20mg/kg用量)を、1日1回、5ml/kg容積で11週間与える。
実施例6化合物で76日処置マウスを、最終投与2時間後に採血する。血漿中の化合物レベルを質量分析で分析する。結果を下の表4に示す。処置マウスは、血漿化合物レベルの用量依存的増加を示す。実施例6で処置した全群のマウスは、ALTの有意な減少を示し、これらの動物における肝臓病変減少を示す。6mg/kgおよび20mg/kgの実施例6化合物で処置した動物も、血中トリグリセリドレベルの減少を示す。
実施例6化合物処置マウスからの肝臓の組織病理学的分析を表4に示す。結果は、20mg/kgの実施例化合物6で処置されたマウスにおいて、肝炎症、大滴性空胞化および類洞周囲線維症の有意な減少があることを示す。
1MIXEDモデルを適用して、化合物処置群と媒体群間のベースラインにより調節したベースラインからの変化倍率を比較する(“Generalized, Linear, and Mixed Models,” McCulloch, C.E., and Searle, S.R., Eds. John Wiley and Sons, 2000 and “Mixed-Effects Models in S and S-PLUS”, Pinheiro J.C., and Bates, D. M., Eds. Springer, 2000.参照)データを平均±SEMで示す。* p<0.05;**p<0.01;*** p<0.001
Claims (17)
- nが1である、請求項1または2に記載の化合物またはその薬学的に許容される塩。
- nが2である、請求項1または2に記載の化合物またはその薬学的に許容される塩。
- R1がHである、請求項1〜4の何れかに記載の化合物またはその薬学的に許容される塩。
- R1が−CH3である、請求項1〜4の何れかに記載の化合物またはその薬学的に許容される塩。
- 一または二塩酸付加塩、メチルスルホン酸付加塩または4−メチルベンゼンスルホン酸付加塩として提供される、請求項1〜8の何れかに記載の化合物。
- (2E)−3−フルオロ−2−({[2−(4−メトキシピペリジン−1−イル)ピリミジン−5−イル]オキシ}メチル)プロプ−2−エン−1−アミン4−メチルベンゼンスルホン酸塩である、化合物。
- CuKα源(λ=1.54056Å)から得た
a)2シータで18.6、19.1、21.0、21.9および22.4±0.2°または
b)2シータで17.6、11.0、16.8、18.6、19.1、21.0、21.9、22.4および26.1±0.2°
のピークを含むX線粉末回折パターンにより特徴付けられる結晶形態の(2E)−3−フルオロ−2−({[2−(4−メトキシピペリジン−1−イル)ピリミジン−5−イル]オキシ}メチル)プロプ−2−エン−1−アミン4−メチルベンゼンスルホン酸塩である、化合物。 - 請求項1〜11の何れかに記載の化合物および薬学的に許容される担体、希釈剤または添加物を含む、医薬組成物。
- 非アルコール性脂肪性肝炎の処置を必要とする患者を処置する方法であって、患者に有効量の請求項12に記載の医薬組成物を投与することを含む、方法。
- 非アルコール性脂肪性肝炎の処置を必要とする患者を処置する方法であって、患者に有効量の請求項1〜11の何れかに記載の化合物を投与することを含む、方法。
- 治療に使用するための、請求項1〜11の何れかに記載の化合物。
- 非アルコール性脂肪性肝炎の処置に使用するための、請求項1〜11の何れかに記載の化合物。
- 非アルコール性脂肪性肝炎を処置するための医薬の製造における、請求項1〜11の何れかに記載の化合物の使用。
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WO2018148856A1 (en) | 2017-02-14 | 2018-08-23 | Eli Lilly And Company | Diazaspirodecanyl-pyrimidine compounds useful as ssao inhibitors |
CN109810041B (zh) * | 2017-11-21 | 2023-08-15 | 药捷安康(南京)科技股份有限公司 | 卤代烯丙基胺类ssao/vap-1抑制剂及其应用 |
KR20190110740A (ko) | 2018-03-21 | 2019-10-01 | 주식회사유한양행 | 신규의 아릴 또는 헤테로아릴 트라이아졸론 유도체 또는 이의 염 및 이를 포함하는 약학 조성물 |
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WO2020063854A1 (zh) * | 2018-09-27 | 2020-04-02 | 南京明德新药研发有限公司 | 作为vap-1抑制剂的喹啉类衍生物 |
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UA126997C2 (uk) * | 2019-01-11 | 2023-03-01 | Транстера Саєнсиз (Наньцзин), Інк. | Галоаліламінові сполуки та їх застосування |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007120528A2 (en) * | 2006-03-31 | 2007-10-25 | La Jolla Pharmaceutical Company | Inhibitors of semicarbazide-sensitive amine oxidase (ssao) and vap-1 mediated adhesion useful for treatment and prevention of diseases |
JP2010533658A (ja) * | 2007-07-20 | 2010-10-28 | メルク フロスト カナダ リミテツド | ステアロイル補酵素aデルタ−9デサチュラーゼ阻害剤としての二環性へテロ芳香族化合物 |
WO2012124696A1 (ja) * | 2011-03-15 | 2012-09-20 | アステラス製薬株式会社 | グアニジン化合物 |
JP2015521167A (ja) * | 2012-05-02 | 2015-07-27 | ファームアクシス・リミテッドPharmaxis Ltd | Ssaoの置換3−ハロアリルアミン阻害剤およびその使用 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008123469A1 (ja) * | 2007-03-30 | 2008-10-16 | Japan Tobacco Inc. | 6員環アミド化合物およびその用途 |
WO2009066152A2 (en) | 2007-11-21 | 2009-05-28 | Pharmaxis Ltd. | Haloallylamine inhibitors of ssao/vap-1 and uses therefor |
JP2011136942A (ja) * | 2009-12-28 | 2011-07-14 | Kowa Co | 新規な置換ピリミジン誘導体およびこれを含有する医薬 |
ES2606197T3 (es) * | 2012-11-16 | 2017-03-23 | Bristol-Myers Squibb Company | Moduladores pirrolidina de GPR40 |
US8962641B2 (en) * | 2013-04-17 | 2015-02-24 | Boehringer Ingelheim International Gmbh | Pyrimidine-substituted pyrrolidine derivatives, pharmaceutical compositions and uses thereof |
EP2997024B1 (en) * | 2013-05-17 | 2018-03-28 | Boehringer Ingelheim International GmbH | Pyrrolidine derivatives, pharmaceutical compositions and uses thereof |
GB201416444D0 (en) | 2014-09-17 | 2014-10-29 | Proximagen Ltd | New compounds |
WO2018027892A1 (en) * | 2016-08-12 | 2018-02-15 | Eli Lilly And Company | Amino pyrimidine ssao inhibitors |
WO2018148856A1 (en) | 2017-02-14 | 2018-08-23 | Eli Lilly And Company | Diazaspirodecanyl-pyrimidine compounds useful as ssao inhibitors |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007120528A2 (en) * | 2006-03-31 | 2007-10-25 | La Jolla Pharmaceutical Company | Inhibitors of semicarbazide-sensitive amine oxidase (ssao) and vap-1 mediated adhesion useful for treatment and prevention of diseases |
JP2010533658A (ja) * | 2007-07-20 | 2010-10-28 | メルク フロスト カナダ リミテツド | ステアロイル補酵素aデルタ−9デサチュラーゼ阻害剤としての二環性へテロ芳香族化合物 |
WO2012124696A1 (ja) * | 2011-03-15 | 2012-09-20 | アステラス製薬株式会社 | グアニジン化合物 |
JP2015521167A (ja) * | 2012-05-02 | 2015-07-27 | ファームアクシス・リミテッドPharmaxis Ltd | Ssaoの置換3−ハロアリルアミン阻害剤およびその使用 |
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