JP4262982B2 - α−アミノ−N−ヒドロキシ−アセトアミド誘導体 - Google Patents
α−アミノ−N−ヒドロキシ−アセトアミド誘導体 Download PDFInfo
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- JP4262982B2 JP4262982B2 JP2002564485A JP2002564485A JP4262982B2 JP 4262982 B2 JP4262982 B2 JP 4262982B2 JP 2002564485 A JP2002564485 A JP 2002564485A JP 2002564485 A JP2002564485 A JP 2002564485A JP 4262982 B2 JP4262982 B2 JP 4262982B2
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- triazol
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- 150000003839 salts Chemical class 0.000 claims description 37
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- 125000001607 1,2,3-triazol-1-yl group Chemical group [*]N1N=NC([H])=C1[H] 0.000 claims description 9
- 125000001401 1,2,4-triazol-4-yl group Chemical group N=1N=C([H])N([*])C=1[H] 0.000 claims description 9
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Description
のα−アミノ−N−ヒドロキシ−アセトアミド誘導体またはその塩に関する。
nは好ましくは1〜4の整数であり、さらに好ましくはnは1である。
mは好ましくは1〜5の整数である。さらに好ましくはmは1、2もしくは3であり、そして最も好ましくはmは1である。
低級アルキル基は分枝しているか直鎖状であり、1〜7個の炭素原子、好ましくは1〜4個の炭素原子、さらに好ましくは1もしくは2個の炭素原子を含有し、そして例えばメチルまたはエチルを表す。
塩は主として、例えば塩酸、のような鉱酸の酸付加塩である。
有効な効果は当分野で一般的に公知の、および本明細書中で例示されるような薬理学的試験で評価される。
Q−Sepharoseカラムクロマトグラフィーにより精製した約2ngの組換え型トランケート化マウスマクロファージメタロエラスターゼ(FASEB Journal Vol. 8, A151, 1994)を所望濃度の被検化合物と共に、5nM CaCl2、400nM NaCl、[3H]−エラスチン(60,000cpm/チューブ)、および20mM Tris、pH8.0の存在下に37℃で一夜インキュベートする。サンプルをマイクロ遠心分離器中12,000rpmで15分間遠心する。上清のアリコートをシンチレーションカウンター中で計数して、分解した[3H]−エラスチンを定量する。被検化合物の濃度幅および得られた酵素活性の阻害パーセントからIC50を決定する。
基質(MCA−Pro−Leu−Gly−Leu−Dpa−Ala−Arg−NH2, C.G. Knight, et al., FEBS lett., 296, 263-266, (1992))のストック溶液を100%DMSO中で1.0mM濃度に調製する。阻害剤のストック溶液を100%DMSO中で調製する。阻害剤を100%DMSO溶液からアッセイ液の中に希釈し、そして対照は等量のDMSOで置換して阻害剤および基質の希釈による最終DMSO濃度が全てのアッセイにおいて6.0%になるようにする。アッセイは、一旦基質と阻害剤がその中に希釈されて6.0%のDMSOを含むアッセイ用緩衝液(150mM NaCl、10mM CaCl2、50mM Tris−Cl、pH7.5、0.05%Brij−35)中で行なわれる。アッセイに使用する基質濃度は10μMである。試験は37℃で実施される。
MT1−MMP:
プラスミド:完全長のヒトMT1−MMP遺伝子[H. Sato et al., Nature (London), 370: 61-65, 1994]をコードするcDNAフラグメントの触媒領域をポリメラーゼ連鎖反応(PCR)で増幅する。使用するプライマーは次の通りである:
ATG開始コドンとして5’末端にNdeI部位を含むセンスプライマーとしてCTCCATATGTACGCCATCCAGGGTCTCAA、および1個のTGA停止コドンを持つBamHI部位を所有するアンチセンスプライマーとしてCTCGGATCCTCACCCATAAAGTTGCTGGAT-GCC(1)。ここで得られた519−bpフラグメントのPCR生成物をpET11a(Stratagene)のNdeIおよびBamHIの特異的部位間でサブクローン化する。MT1−MMP(CD−MT1−MMP)の触媒領域の配列をABI PRISMTM377DNAシーケンサー(Perkin Elmer)を持つABI PRISMTMダイターミネーターサイクルシーケンシングキットにより検証する。
溶出したタンパク質を5mM CaCl2、0.5mM ZnSO4、20mM Tris−Cl、pH7.5の緩衝液5Lに対して2回透析して、次いでAmicon攪拌型セル中でYM2膜により濃縮する。このような条件下において、組換え型タンパク質は可溶性を保ちかつ正しくフォールディングされている。
プラスミド:ヒトコラゲナーゼのcDNAは、ヒトU937細胞(ATCC#CRL−2367)から単離されたRNA由来のcDNAのPCRにより作成される。このcDNAを作成するのに用いられるプライマーは、AAGAAGCTTAAGGCCAGTATGCACAGCTTTCCT、およびAAGGCGGCCGCACACCTTCTTTGGACTCACACCAであり、これらは報告されているcDNA配列、GenBank登録番号X05231、のヌクレオチドの58〜1526に相当する。ここで得られたcDNAフラグメントを哺乳動物発現ベクターのpBPV−MMT(Matthias, P. et al., J. Mol. Biol. 1986, 187(4):557-68)のNotI部位にサブクローン化する。
プラスミド:ヒトプロMMP2用のcDNAは東京大学医科学研究所清木元治教授(Prof. Motoharu Seiki)により供与された。ヒトプロMMP2をコードする完全長のcDNAをヒトHT1080細胞(ATCC#CCL121)から単離したRNA由来のcDNAのPCRにより生成させる。このcDNAを生成させるためのプライマーは、報告されているcDNA配列のヒトプロMMP2、GenBank登録番号J03210、の完全長に対応する、GAATTCGATGGAGGCGCTAATGGCCCGGおよびCTCGAGTCAGCAGCCTAGCCAGTCGGATTTGATである。ここで得られた2.0KbのPCRフラグメントをpFAST BAC1ベクターのEcoR1/Xhoの1部位 (pBAC−MMP2)(I. E. Collier et al., J. Biol. Chem., 263:6679-6587, 1988)にクローン化する。
MMP9はTPAで処理したTHP1ヒト単球性白血病細胞の培養液から製造される。THP1細胞を10%FCSを含有するDMEM/F−12培地で保持して、無血清培地中TPA(1nM)で48時間刺激して、プロ−MMP9を産生させる。全ての精製手順は4℃で行われる。1リットルの培養液をCentricon(Amicon)で濃縮して100mlにして、50mM Tris−Cl(pH=8.0)、300mM NaClで平衡化させたゼラチン−Sepharose(Pharmacia)のカラム(1×8cm)に加える。プロ−MMP−9を含有するフラクションを10%DMSOの50mM Tris−Cl(pH=8.0)、300mM NaCl溶液で溶出させ、次いで50mM Tris−Cl(pH=7.5)、150mM NaClに対して透析する。フラクションをCentriconで濃縮し、150mM NaClを含有する50mM Tris−Cl(pH=7.5)で平衡化させたSephadexG200(2×20cm)のカラムクロマトグラフィーに供する。精製したプロ−MMP9をストックとして−80℃で保存し、必要量のプロ体を用いて活性化する。プロ−MMP9を150mM NaCl、10mM CaCl2および0.05%Brij−35を含有する50mM Tris−Cl(pH7.5)(MMPアッセイ緩衝液)中、酢酸アミノフェニル水銀(APMA、ICN Pharmaceuticals)を用いて37℃で18時間活性化して、MMPアッセイ緩衝液に対して徹底的に透析することによりAPMAを除去する。活性化されたMMP9は使用するまで−80℃で凍結保存される。
次いで、活性化したMMP−9(82kDa)を化合物のスクリーニングに使用する。蛍光発生源となるペプチドの2−N−メチルアミノ安息香酸(Nma)−Gly−Pro−Gln−Gly−Leu−Ala−Gly−Gln−Lys−Nl−(2,4−ジニトロフェニル)(Dnp)−NH2(ペプチド研究所、大阪、日本)をこの試験における全てのMMPアッセイで唯一の基質として25μMで使用する。基質のストック溶液を100%DMSO中で1.0mMの濃度で調製する。アッセイはMMPアッセイ緩衝液中で実施される。反応混合物を96ウェル微蛍光測定プレートの適切なウェルに2組ずつ加えて、37℃で30分間プレインキュベートする。0.5nMの活性化MMP9の添加により反応を開始する。それぞれの阻害剤のストック溶液は100%DMSOに溶解して調製する。ストック溶液より100%DMSOで調製した希釈液から阻害剤をアッセイ混合物の中に添加する。対照には等量のDMSOを添加する。阻害剤および基質溶液からのDMSOの最終濃度は5.0%である。蛍光の増加を励起波長355nmを用いて460nmでモニターする。曲線の直線部分の時点を選んで活性を測定する。阻害結果は、対照反応における活性を50%阻害する阻害剤の濃度(IC50)で表わされる。
2−[(シクロプロピルメトキシ−ベンゼンスルホニル)−(4−[1,2,3]トリアゾール−2−イル−ベンジル)−アミノ]−N−ヒドロキシ−アセトアミド、
2−[(シクロプロピルメトキシ−ベンゼンスルホニル)−(4−[1,2,3]トリアゾール−2−イル−ベンジル)−アミノ]−N−ヒドロキシ−アセトアミド塩酸塩、
2−[(シクロプロピルメトキシ−ベンゼンスルホニル)−(4−ジメチルアミノベンジル)−アミノ]−N−ヒドロキシ−アセトアミド、
2−[(シクロプロピルメトキシ−ベンゼンスルホニル)−(4−ジメチルアミノベンジル)−アミノ]−N−ヒドロキシ−アセトアミド塩酸塩、
2−[(シクロプロピルメトキシ−ベンゼンスルホニル)−(4−[1,2,3]トリアゾール−1−イル−ベンジル)−アミノ]−N−ヒドロキシ−アセトアミド、
2−[(シクロプロピルメトキシ−ベンゼンスルホニル)−(4−[1,2,4]トリアゾール−4−イル−ベンジル)−アミノ]−N−ヒドロキシ−アセトアミド、
2−[(シクロプロピルメトキシ−ベンゼンスルホニル)−(4−ジエチルアミノベンジル)−アミノ]−N−ヒドロキシ−アセトアミド、および
2−[(シクロプロピルメトキシ−ベンゼンスルホニル)−(4−ジエチルアミノベンジル)−アミノ]−N−ヒドロキシ−アセトアミド塩酸塩。
式IIのカルボン酸とカルボン酸を対応する酸塩化物へ転換する能力のある試薬との間の反応は、クロロホルムもしくは好ましくは、ジクロロメタンのような適当な溶媒中で行われることができる。カルボン酸を対応する酸塩化物へ転換する能力のある適当な試薬は、例えば(COCl)2であるが、またCOCl2、SOCl2、POCl3もしくはPOBr3である。適当な触媒は、例えばジメチルホルムアミドである。反応は振とうもしくは攪拌下に行われる。特定の反応物の性質に依存して、反応は、−10℃〜+50℃、好ましくは0℃〜+30℃の温度で、30分〜10時間、好ましくは1〜3時間の期間で行われる。好ましくは新たに製造された酸塩化物とNH2OHとの水およびさらなる成分と均一な溶液を生成する第二溶媒、例えばテトラヒドロフラン、の混液の中でのさらなる反応は、好ましくは、−35℃〜−5℃、例えば−20℃〜−10℃の温度で、約1もしくは2時間行われる。次いで好ましくは、氷水の中に反応混合液を注入することにより、反応が停止される。
式III
のα−アミノ酸誘導体を式IV
の化合物と、ジクロロメタンのような適当な溶媒の中で、塩基、特に第三級アミン、ならびに任意に、触媒、好ましくはジメチルアミノピリジン、の存在下で、0℃〜50℃の温度、例えば室温で、約30分〜24時間、例えば10、12もしくは15時間、の間反応させて、式V
のカルボン酸エステルを得る。次いで、得られたカルボン酸エステルを加水分解して、それ自体公知の方法により遊離カルボン酸を得ることができる。適当な反応条件は、例えば、式Vのカルボン酸エステルをテトラヒドロフラン中に溶解して、水酸化リチウム一水和物および水を−10℃〜+10℃、好ましくは0〜+5℃の温度で、順次加えることである。次いで、反応混合液を室温にまで温めて、約2〜12時間、例えば4、6もしくは8時間、攪拌する。
のα−アミノ酸誘導体を、例えば、式VIII
のアルデヒドを第一の工程で式IX
のα−アミノ酸エステルの塩酸塩と、好ましくは、式IXのエステルを第三級アミン、例えばトリエチルアミン、およびMgSO4と一緒に適当な溶媒、例えばジクロロメタン、の中に溶解した式VIIIのアルデヒドに加えることにより反応させて、対応するイミンを製造する。次いで、イミンを0℃以下、好ましくは−30℃〜−5℃、さらに好ましくは−20℃〜−10℃の温度で、好ましくはテトラヒドロフランおよびメタノールもしくはエタノールの混液の中に溶解して、約30分〜240分、例えば60もしくは90分、の間でNaBH4とさらに反応させる。
この方法で取得可能であり塩を形成する性質を有する、式Iの遊離化合物は、それ自身公知の様式で、例えば酸もしくはそれらの誘導体との処理により、例えば、適当な溶媒、例えば、環状エーテル、特にジオキサン、および特にテトラヒドロフランのようなエーテル中に溶解した式Iの化合物への問題の酸の添加により、それらの塩に変換されることができる。
本発明にしたがって取得し得る異性体の混合物は、それ自身公知の様式で、例えば分別再結晶により個々の異性体に分離されることができる。
それぞれの場合で具体的に述べられる反応条件が好ましい。
出発原料および中間体は、例えば、最後に記述したような、後処理の後の純粋な形で、部分的に精製された形で、さもなければ、例えば、粗生成物として直接に使用され得る。
それらの塩を含む化合物をまた、水和物の形で得ることできて、またはそれらの結晶は、例えば、結晶化に用いた溶媒を含むことができる。
式Iの化合物のようなヒドロキサム酸化合物のプロドラッグ誘導体の製造は当業者に公知である。
CH2Cl2500ml中の[(4−シクロプロピルメトキシ−ベンゼンスルホニル)−(4−ジメチルアミノ−ベンジル)−アミノ]酢酸36g(85.2mmol)の溶液に、塩化オキサリル14.8ml(169.7mmol)に引き続きDMF1ml(12.9mol)を滴下して(注意:激しいガスの発生)、0〜5℃で1時間攪拌する。さらに1時間室温で攪拌後、得られた酸塩化物の溶液をTHF400ml中の50%NH2OH水溶液157ml(2379mmol)の中に−20〜−10℃でN2圧下にテフロン(登録商標)チューブを用いてゆっくりと加える。−10℃で1.5時間攪拌後、反応混合液を氷水で反応停止させて、沈澱した粉末をろ去する。ろ液をCH2Cl2で抽出し、MgSO4上で乾燥して、減圧下に濃縮すると、ジエチルエーテルで洗浄後に表題化合物を無色の固体として得る;1H−NMR(400MHz、DMSO−d6):0.30〜0.40(m、2H)、0.55〜0.65(m、2H)、1.20〜1.30(m、1H)、2.85(s、6H)、3.54(s、2H)、3.91(d、2H、J=6.56Hz)、4.23(s、2H)、6.64(d、2H、J=8.04Hz)、7.00(d、2H、J=7.56Hz)、7.06(d、2H、J=8.04Hz)、7.76(d、2H、J=7.56Hz)、8.82(brs、1H)、10.42(brs、1H)。
CH2Cl21000ml中の4−アミノベンズアルデヒド50g(335mmol)の溶液に、グリシンメチルエステル塩酸塩67.3g(536mmol)、トリエチルアミン182ml(1305mmol)およびMgSO470gを順次0〜5℃で加える。混合液を室温で18時間攪拌して、セライトを通してろ過する。ろ液を減圧下に濃縮して、残渣をAcOEtで希釈する。Et3N−塩酸塩をろ去して、ろ液をトルエンを用いる共沸蒸留様式で減圧下に濃縮すると、粗イミンを得る。THF500mlおよびMeOH500ml中の粗イミンの溶液に、NaBH418g(475mmol)を−20〜−10℃で少しずつ加えて、混合液を1時間攪拌する。反応混合液を飽和NH4Cl水溶液でゆっくりと反応停止させて、次いでCH2Cl2で抽出する。合併した抽出液を水、ブラインで洗浄し、MgSO4上で乾燥して、減圧下に濃縮する。残渣をシリカゲル上のCC(n−ヘキサン:AcOEt=5:1〜1:1)で精製すると、表題化合物を微黄色の油として得る。
DMF1350ml中の4−ヒドロキシベンゼンスルホン酸ナトリウム塩75g(323mmol)の懸濁液に、油に懸濁した60%NaH20.67g(517mmol)を室温で小分けして注意深く加える。この混合液に、ヨウ化テトラブチルアンモニウム11.93g(32.2mmol)および(ブロモメチル)−シクロプロパン50.13ml(517mmol)を順次加える。60℃で25時間攪拌後、反応混合液を室温へ冷却する。沈澱を収集し、CH2Cl2で数回洗浄して、次いで混合溶媒(EtOH:H2O=2:1)で再結晶すると、表題化合物を無色の固体として得る。
4−シクロプロピルメトキシ−ベンゼンスルホン酸ナトリウム塩100g(399.6mmol)の懸濁液に、塩化チオニル186.55ml(2557.5mmol)およびDMF6.19ml(80mmol)を室温で滴下する。15時間攪拌後、混合液を氷水の中に注入して、CH2Cl2で抽出する。合併した抽出液を水で洗浄し、MgSO4上で乾燥して、減圧下に濃縮すると、表題化合物を無色の固体として得る;1H−NMR(400MHz、CDCl3):0.35〜0.45(m、2H)、0.65〜0.75(m、2H)、1.25〜1.35(m、1H)、3.91(d、2H、J=7.04Hz)、7.02(d、2H、J=9.04Hz)、7.96(d、2H、J=9.04Hz)。
CH2Cl2600ml中の[(4−ジメチルアミノ−ベンジルアミノ)酢酸メチルエステル]49.4g(222mmol)、ジイソプロピルエチルアミン41.4ml(244mmol)およびDMAP0.271g(2.2mmol)の溶液に、CH2Cl2100ml中の塩化4−シクロプロピルメトキシ−ベンゼンスルホニル54.8g(222mmol)を0〜5℃で加える。室温で15時間攪拌後、反応混合液を氷水および飽和NH4CO3水溶液で反応停止させる。混合液をAcOEtで抽出して、合併した抽出液を飽和NH4CO3水溶液およびブラインで洗浄し、MgSO4上で乾燥して、減圧下に濃縮する。残渣をシリカゲル上のCC(n−ヘキサン:AcOEt=4:1)で精製すると、表題化合物を無色の固体として得る。
THF800ml中の1.4段階の化合物74.6g(172.4mmol)の溶液に、水酸化リチウム一水和物14.5g(345.6mmol)および水400mlを0〜5℃で順次加える。室温で4時間攪拌後、混合液を0〜5℃で2M HClを用いて中和して、CH2Cl2で数回抽出する。合併した抽出液をMgSO4上で乾燥して、減圧下に濃縮すると、表題化合物を得る
90%CH3CN水溶液500ml中の実施例1の化合物50g(114.3mmol)の溶液に、1M HCl水溶液137ml(137mmol)およびさらに500mlの水を室温で順次加える。混合液を凍結乾燥して、表題化合物を無色の固体として得る;1H−NMR(400MHz、DMSO−d6):0.30〜0.40(m、2H)、0.55〜0.65(m、2H)、1.20〜1.30(m、1H)、3.02(s、6H)、3.91(d、2H、J=7.08Hz)、4.0(brs、1H)、4.33(s、2H)、7.07(d、2H、J=8.56Hz)、7.30(brs、4H)、7.76(d、2H、J=9.08Hz)、10.53(brs、1H)。
[(4−シクロプロピルメトキシ−ベンゼンスルホニル)−(4−[1,2,3]トリアゾール−2−イル−ベンジル)アミノ]酢酸から出発し実施例1と同様にして、表題化合物を製造する;1H−NMR(400MHz、CDCl3):0.32〜0.45(m、2H)、0.55〜0.65(m、2H)、1.15〜1.30(m、1H)、3.66(s、3H)、3.90(d、2H、J=7.04Hz)、4.41(s、2H)、7.07(d、2H、J=8.56Hz)、7.45(d、2H、J=8.56Hz)、7.79(d、2H、J=8.04Hz)、7.96(d、2H、J=8.04Hz)、8.12(s、2H)、8.84(brs、1H)、10.49(brs、1H)。
DMF400ml中のp−フルオロベンズアルデヒド100g(803mmol)の溶液に、1−H−1,2,3−トリアゾール95g(1377mmol)およびK2CO3200g(1449mmol)を順次加えて、混合液を100℃で4時間攪拌する。混合液を室温へ冷却して、セライトを通してろ過する。ろ液を減圧下に濃縮して、粗結晶を得て、それをAcOEtで数回洗浄する。AcOEt中に良く溶けない固体を水で洗浄して、真空で乾燥すると、4−[1,2,3]−トリアゾール−1−イル−ベンズアルデヒド(B)を得る。ろ液を減圧下に濃縮して、得られた固体をCH2Cl2中に溶解し、次いでシリカゲル上に吸着させてドライCC(n−ヘキサン:AcOEt=2:1〜1:2)を行って、4−[1,2,3]−トリアゾール−2−イル−ベンズアルデヒド(A)およびさらなる化合物(B)を微黄色の固体として得る;1H−NMR(400MHz、CDCl3):化合物A、7.88(s、2H)、8.01(d、2H、J=8.56Hz)、8.29(d、2H、J=8.56Hz)、10.06(s、1H);化合物B、7.90(s、1H)、7.98(d、2H、J=8.56Hz)、8.07(d、2H、J=8.56Hz)、8.13(s、1H)、10.09(s、1H)。
CH2Cl21000ml中の4−[1,2,3]−トリアゾール−2−イル−ベンズアルデヒド60g(347mmol)の溶液に、グリシンメチルエステル塩酸塩78.9g(629mmol)、トリエチルアミン104.2ml(749mmol)およびMgSO4150gを順次0〜5℃で加える。混合液を室温で18時間攪拌して、セライトを通してろ過する。ろ液を減圧下に濃縮して、残渣をAcOEtで希釈する。Et3N−塩酸塩をろ去して、ろ液をトルエンを用いる共沸蒸留様式で減圧下に濃縮すると、粗イミンを得る。THF600mlおよびMeOH600ml中の粗イミンの溶液に、NaBH420g(526mmol)を−20〜−10℃で少しずつ加えて、混合液を1時間攪拌する。反応混合液を飽和NH4Cl水溶液でゆっくりと反応停止させて、次いでCH2Cl2で抽出する。合併した抽出液を水、ブラインで洗浄し、MgSO4上で乾燥して、減圧下に濃縮する。残渣をシリカゲル上のCC(n−ヘキサン:AcOEt=2:1〜1:1)で精製すると、表題化合物を得る。
CH2Cl21000ml中の3.2段階の化合物79.5g(323.2mmol)、Et3N80.9ml(581.6mmol)およびDMAP1.97g(16.1mmol)の溶液に、CH2Cl2150ml中の塩化4−シクロプロピルメトキシ−ベンゼンスルホニル99.6g(404mmol)を加えて、0〜5℃で60分間攪拌する。室温でさらに18時間攪拌後、反応混合液を氷水で反応停止させて、CH2Cl2で抽出する。合併した抽出液を水、ブラインで洗浄し、MgSO4上で乾燥して、減圧下に濃縮する。残渣をシリカゲル上のCC(n−ヘキサン:AcOEt=4:1〜2:1)で精製すると、表題化合物を無色の固体として得る;1H−NMR(400MHz、CDCl3):0.35〜0.45(m、2H)、0.65〜0.75(m、2H)、1.25〜1.35(m、1H)、3.58(s、3H)、3.87(d、2H、J=7.04Hz)、3.94(s、2H)、4.52(s、2H)、6.99(d、2H、J=7.04Hz)、7.37(d、2H、J=8.56Hz)、7.81(s、2H)、7.82(d、2H、J=7.04Hz)、8.02(d、2H、J=8.56Hz)。
1.5段階と同様にして、表題化合物を得る;1H−NMR(400MHz、CDCl3):0.35〜0.45(m、2H)、0.65〜0.75(m、2H)、1.25〜1.35(m、1H)、3.86(d、2H、J=7.04Hz)、3.95(s、2H)、4.51(s、2H)、6.97(d、2H、J=8.56Hz)、7.34(d、2H、J=8.56Hz)、7.80(s、2H)、7.83(d、2H、J=8.56Hz)、7.80(s、2H)、7.83(d、2H、J=8.56Hz) 、8.01(d、2H、J=8.56Hz)。
3.5段階:(4−[1,2,3]−トリアゾール−2−イル−フェニル)−メタノール
THF140mlおよびMeOH420ml中の4−[1,2,3]−トリアゾール−2−イル−ベンズアルデヒド42.26g(244mmol)の溶液に、NaBH49.23g(244mmol)を0〜5℃で少しずつ加えて、混合液を30分間同じ温度で攪拌する。反応を飽和NH4Clにより0〜5℃で停止させて、混合液をAcOEtで抽出する。合併した抽出液をブラインで洗浄し、MgSO4上で乾燥して、減圧下に濃縮して、表題化合物を無色の固体として得る。
CH2Cl22000ml中の(4−[1,2,3]トリアゾール−2−イル−フェニル)−メタノール50.58g(289.6mmol)の溶液に、塩化チオニル31.59ml(433mmol)を0〜5℃で滴下して、反応混合液を室温へ暖める。16時間攪拌後、反応混合液を0〜5℃で飽和NaHCO3により塩基性にして、CH2Cl2で抽出する。合併した抽出液をブラインで洗浄し、MgSO4上で乾燥して、減圧下に濃縮すると、表題化合物を得る。
ジオキサン60mlおよびH20 24ml中のグリシンメチルエステル塩酸塩7.125g(56.75mmol)の溶液に、Et3N15ml(107.8mmol)および次いでジオキサン10ml中の塩化4−シクロプロピルメトキシ−ベンゼンスルホニル10g(40.53mmol)を0〜5℃で滴下する。室温でさらに3時間攪拌後、反応を氷水で停止させて、混合液をAcOEtで抽出する。合併した抽出液を水、ブラインで洗浄し、MgSO4上で乾燥して、減圧下に濃縮すると、表題化合物を無色の固体として得る;1H−NMR(400MHz、CDCl3):0.3〜0.40(m、2H)、0.65〜0.72(m、2H)、1.20〜1.35(m、1H)、3.65(m、3H)、3.77(d、2H、J=5.04Hz)、3.86(d、2H、J=7.08Hz)、4.98(brs、1H)、6.96(d、2H、J=8.52Hz)、7.77(d、2H、J=8.52Hz)。
DMF10ml中の3.7段階の化合物1g(3.3mmol)の溶液に、2−(4−クロロメチル−フェニル)−2H−[1,2,3]トリアゾール0.8086g(4.175mmol)、KI0.0555g(0.33mmol)およびK2CO30.646g(4.68mmol)を室温で順次加える。18時間攪拌後、反応を氷水で停止させて、混合液をAcOEtで抽出する。合併した抽出液を水、ブラインで洗浄し、MgSO4上で乾燥して、減圧下に濃縮すると固体を得て、それをジエチルエーテルおよびメタノールで洗浄すると、表題化合物を得る。
それぞれが、先行する実施例で記述された式Iの化合物の一つの0.25gを有効成分として含有する、3000個のカプセルを以下のように作成する:
組成
有効成分 75.00g
乳糖 750.00g
アビセルPH102 300.00g
(微結晶セルロース)
ポリプラスドンXL 30.00g
(ポリビニルピロリドン)
ステアリン酸マグネシウム 9.00g
本出願で説明されたインビトロ試験で測定されたような、実施例2の化合物の阻害活性を表2(Table 2)に提示する。
Claims (6)
- Rがジメチルアミノまたは1,2,3−トリアゾール−2−イルである、請求項1に記載の化合物またはその塩。
- mが1であり、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塩。
- 2−[(シクロプロピルメトキシ−ベンゼンスルホニル)−(4−[1,2,3]トリアゾール−2−イル−ベンジル)−アミノ]−N−ヒドロキシ−アセトアミド、
2−[(シクロプロピルメトキシ−ベンゼンスルホニル)−(4−[1,2,3]トリアゾール−2−イル−ベンジル)−アミノ]−N−ヒドロキシ−アセトアミド、
2−[(シクロプロピルメトキシ−ベンゼンスルホニル)−(4−ジメチルアミノベンジル)−アミノ]−N−ヒドロキシ−アセトアミド、
2−[(シクロプロピルメトキシ−ベンゼンスルホニル)−(4−ジメチルアミノベンジル)−アミノ]−N−ヒドロキシ−アセトアミド、
2−[(シクロプロピルメトキシ−ベンゼンスルホニル)−(4−[1,2,3]トリアゾール−1−イル−ベンジル)−アミノ]−N−ヒドロキシ−アセトアミド、
2−[(シクロプロピルメトキシ−ベンゼンスルホニル)−(4−[1,2,4]トリアゾール−4−イル−ベンジル)−アミノ]−N−ヒドロキシ−アセトアミド、
2−[(シクロプロピルメトキシ−ベンゼンスルホニル)−(4−ジエチルアミノベンジル)−アミノ]−N−ヒドロキシ−アセトアミド、および
2−[(シクロプロピルメトキシ−ベンゼンスルホニル)−(4−ジエチルアミノベンジル)−アミノ]−N−ヒドロキシ−アセトアミド
からなる群から選択される化合物またはその塩。
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CN101410370B (zh) * | 2006-03-29 | 2013-06-12 | 诺瓦提斯公司 | 基于异羟肟酸酯的选择性mmp抑制剂 |
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US11058804B2 (en) | 2017-06-13 | 2021-07-13 | Ethicon Llc | Surgical fastener device for the prevention of ECM degradation |
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-
2001
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2002
- 2002-02-07 AR ARP020100398A patent/AR032553A1/es unknown
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- 2002-02-08 EP EP02718115A patent/EP1360175A1/en not_active Withdrawn
- 2002-02-08 CA CA2435611A patent/CA2435611C/en not_active Expired - Fee Related
- 2002-02-08 WO PCT/EP2002/001345 patent/WO2002064552A1/en active Application Filing
- 2002-02-08 JP JP2002564485A patent/JP4262982B2/ja not_active Expired - Fee Related
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Also Published As
Publication number | Publication date |
---|---|
JP2004523545A (ja) | 2004-08-05 |
CN1525956A (zh) | 2004-09-01 |
US7112611B2 (en) | 2006-09-26 |
US20080176916A1 (en) | 2008-07-24 |
CA2435611C (en) | 2011-07-12 |
WO2002064552A8 (en) | 2002-12-12 |
US7291634B2 (en) | 2007-11-06 |
EP1360175A1 (en) | 2003-11-12 |
US20040082630A1 (en) | 2004-04-29 |
US20060270719A1 (en) | 2006-11-30 |
GB0103303D0 (en) | 2001-03-28 |
CA2435611A1 (en) | 2002-08-22 |
US7659293B2 (en) | 2010-02-09 |
PE20020845A1 (es) | 2002-10-30 |
AU2002249197A1 (en) | 2002-08-28 |
CN100509773C (zh) | 2009-07-08 |
WO2002064552A1 (en) | 2002-08-22 |
AR032553A1 (es) | 2003-11-12 |
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