JP2006513164A - 抗微生物剤としてのn−スルホニル−4−メチレンアミノ−3−ヒドロキシ−2−ピリドン - Google Patents
抗微生物剤としてのn−スルホニル−4−メチレンアミノ−3−ヒドロキシ−2−ピリドン Download PDFInfo
- Publication number
- JP2006513164A JP2006513164A JP2004551914A JP2004551914A JP2006513164A JP 2006513164 A JP2006513164 A JP 2006513164A JP 2004551914 A JP2004551914 A JP 2004551914A JP 2004551914 A JP2004551914 A JP 2004551914A JP 2006513164 A JP2006513164 A JP 2006513164A
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- Prior art keywords
- halo
- hydroxy
- heteroaryl
- aryl
- alkyl
- Prior art date
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- Granted
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- 239000004599 antimicrobial Substances 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 80
- 238000011282 treatment Methods 0.000 claims abstract description 15
- -1 cyano, hydroxy, carboxy Chemical group 0.000 claims description 54
- 125000003118 aryl group Chemical group 0.000 claims description 47
- 125000005843 halogen group Chemical group 0.000 claims description 44
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 38
- 125000001072 heteroaryl group Chemical group 0.000 claims description 38
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 34
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- 150000001408 amides Chemical group 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 26
- 125000004104 aryloxy group Chemical group 0.000 claims description 25
- 125000001188 haloalkyl group Chemical group 0.000 claims description 25
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- 125000004442 acylamino group Chemical group 0.000 claims description 23
- 125000003545 alkoxy group Chemical group 0.000 claims description 23
- 125000002252 acyl group Chemical group 0.000 claims description 22
- 229930194542 Keto Chemical group 0.000 claims description 21
- 125000003342 alkenyl group Chemical group 0.000 claims description 21
- 239000003795 chemical substances by application Substances 0.000 claims description 21
- 125000000468 ketone group Chemical group 0.000 claims description 21
- 125000000304 alkynyl group Chemical group 0.000 claims description 20
- 150000002431 hydrogen Chemical group 0.000 claims description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
- 125000005323 thioketone group Chemical group 0.000 claims description 20
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 6
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 3
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- PPLCARITXNXUIS-UHFFFAOYSA-N 3-hydroxy-1-(4-methylphenyl)sulfonyl-4-(pyrrolidin-1-ylmethyl)pyridin-2-one Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C(=O)C(O)=C(CN2CCCC2)C=C1 PPLCARITXNXUIS-UHFFFAOYSA-N 0.000 claims description 2
- ZPXDJMZIOUFOQK-UHFFFAOYSA-N 3-hydroxy-1-(4-methylphenyl)sulfonyl-4-[(4-phenylpiperazin-1-yl)methyl]pyridin-2-one Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C(=O)C(O)=C(CN2CCN(CC2)C=2C=CC=CC=2)C=C1 ZPXDJMZIOUFOQK-UHFFFAOYSA-N 0.000 claims description 2
- BCEBDUJEQGOCKH-UHFFFAOYSA-N 3-hydroxy-4-[(2-methoxyethylamino)methyl]-1-(4-methylphenyl)sulfonylpyridin-2-one Chemical compound O=C1C(O)=C(CNCCOC)C=CN1S(=O)(=O)C1=CC=C(C)C=C1 BCEBDUJEQGOCKH-UHFFFAOYSA-N 0.000 claims description 2
- NYFFNBQMIOWAHV-UHFFFAOYSA-N 4-(azocan-1-ylmethyl)-3-hydroxy-1-(4-methylphenyl)sulfonylpyridin-2-one Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C(=O)C(O)=C(CN2CCCCCCC2)C=C1 NYFFNBQMIOWAHV-UHFFFAOYSA-N 0.000 claims description 2
- WKOHXGUFCXFRQQ-UHFFFAOYSA-N 4-[[4-(6-chloropyridazin-3-yl)piperazin-1-yl]methyl]-3-hydroxy-1-(4-methylphenyl)sulfonylpyridin-2-one Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C(=O)C(O)=C(CN2CCN(CC2)C=2N=NC(Cl)=CC=2)C=C1 WKOHXGUFCXFRQQ-UHFFFAOYSA-N 0.000 claims description 2
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- 230000000813 microbial effect Effects 0.000 abstract description 8
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 60
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- 125000002619 bicyclic group Chemical group 0.000 description 8
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 8
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- 150000001336 alkenes Chemical class 0.000 description 7
- 125000005553 heteroaryloxy group Chemical group 0.000 description 7
- 125000002950 monocyclic group Chemical group 0.000 description 7
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- 241000124008 Mammalia Species 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000003086 colorant Substances 0.000 description 6
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- 125000001183 hydrocarbyl group Chemical group 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 150000001345 alkine derivatives Chemical class 0.000 description 5
- 239000000796 flavoring agent Substances 0.000 description 5
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- 239000003826 tablet Substances 0.000 description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 125000006580 bicyclic heterocycloalkyl group Chemical group 0.000 description 4
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- 108010010803 Gelatin Proteins 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
Description
以下に、本明細書で使用する用語に関する定義を列記する。
1.エノール(二重結合を担う炭素に付いたOH)。
2.二重結合を担う炭素に付いたアミノ基(ビニル系アミドを除く)。
3.単一炭素に付いた1個より多いヒドロキシ、アミノ、又はアミド(2個の窒素原子が単一炭素原子に付いて、3個の原子すべてがヘテロシクロアルキル環内の構成原子である場合を除く)。
4.炭素に付いた、ヒドロキシ、アミノ、又はアミドであって、その炭素にヘテロ原子も付いているもの。
5.炭素に付いた、ヒドロキシ、アミノ、又はアミドであって、その炭素にハロゲンも付いているもの。
本発明対象は式(I)の化合物に関係する:
本発明の化合物は多様な方法を使用して調製できる。特に好ましい合成については、以下の一般反応スキーム中で述べる。(反応スキームを説明するために用いるR基は、式(I)の化合物の様々な態様を述べるために使用されるそれぞれのR基と、必ずしも相関があるわけではない。つまり、例えば式(I)のR1はここでのR1と同じ部分には相当しない。)本発明の化合物を製造するための具体的な例が以下の段落VIIに明示される。
最後にS3は、ホルミル化剤及びアミノ化剤により、それぞれホルミル化及びアミノ化される。本明細書で使用する時、「ホルミル化剤」は、メチレン単位、「CH2」又は
本発明の化合物は、抗微生物剤として有用である。理論に束縛されることを望まないが、これらの化合物は、bMap活性部位のコバルトイオンのキレート剤として作用できる。キレート剤として、これらの化合物は、金属酵素の阻害剤として作用できる。
本発明の組成物は、次を含む。
(a)安全及び有効な量の本発明の化合物;及び
(b)製薬上許容できる担体
本発明の化合物は、したがって微生物感染の治療に用いる医薬組成物中に配合できる。レミントンの製薬科学(Remington's Pharmaceutical Sciences)(ペンシルバニア州、イーストンのマック出版社(Mack Publishing Company))最新版に開示されているもの等の、標準的な医薬品製剤技術を使用する。
もし主題化合物を注射するなら、好ましい製薬上許容できる担体は、血液適合性懸濁剤を伴う、滅菌、生理学的塩水で、そのpHを約7.4に調整する。
主題発明の組成物は、任意選択的に他の薬品活性物質を包含してもよい。
本発明はまた、ヒト又は他の動物被験体に安全で有効な量の式(I)の化合物を投与することによって、前記被験体の微生物感染を治療する方法を提供する。
本発明の組成物は、局所に又は全身に投与され得る。全身投与には、式(I)の化合物を体組織に導入するいずれかの方法、例えば、経皮的、静脈内、腹腔内、皮下、舌下、直腸、及び経口投与が挙げられる。本発明の式(I)の化合物は、経口投与されることが好ましい。
全身投与の好ましい方法は、経口投与である。個体投与量は、約10mg〜約1000mg、好ましくは約10mg〜約300mgであることが好ましい。
前述のすべてにおいて、言うまでもなく、本発明の化合物は単体又は混合物として投与することができ、その組成物は適応症にふさわしいその他の薬剤又は賦形剤を更に包含してもよい。
以下の部分構造及び表は、本明細書の以下に記載される手順に従って製造される実施例1〜8の化合物の構造を示す。化合物の実施例を示すために用いられるR基又はX基は、請求項の中の式(I)の様々な部分を記載するために用いられる、それぞれのR基及びX基に必ずしも相関しているわけではない。
工程Aのピリドン中間体(1当量)、HCHO又はアルデヒド(2.2当量)を水性EtOH(10mL)中で共に混合し、30分間攪拌する。アミン(2.2当量)を添加し、12時間攪拌し、濃縮する。残留物をEtOH(10mL)中に溶解し、及びHPLC(水/アセトニトリル/0.1%TFA)により精製する。特に指定しない限り、生成物をTFA塩として単離する。収率は75〜95%である。
3−ヒドロキシ−4−ピロリジン−1−イルメチル−1−(トルエン−4−スルホニル)−1H−ピリジン−2−オン
1H NMR(300MHz,DMSO)δ1.87(m,2H),1.99(m,2H),2.44(s,3H),3.09(m,2H),3.40(m,2H),4.19(s,2H),6.51(d,J=7.5Hz,1H),7.51(d,J=8.4Hz,1H),7.76(d,J=7.5Hz,1H),7.98(d,J=8.1Hz,1H),9.93(broad s,1H);19F NMR(252MHz,DMSO)δ88.4;13C NMR(75MHz,DMSO)δ21.5,22.7,50.5,53.7,108.7,118.6,119.4,128.4,129.7,130.1,133.1,146.8,147.7,156.2;ES MS(M+1)349.25;C17H20N2O4SについてのHRMS計算値348.42。実測値(M+1)349.42。
3−ヒドロキシ−4−チアゾリジン−3−イルメチル−1−(トルエン−4−スルホニル)−1H−ピリジン−2−オン
1H NMR(300MHz,DMSO)δ2.43(s,3H),2.94(t,J=6.6MHz,2H),3.18(t,J=6.0Hz,2H),3.66(s,2H),4.12(s,2H),6.51(d,J=7.5Hz,1H),7.51(d,J=8.4Hz,1H),7.76(d,J=7.5Hz,1H),7.98(d,J=8.1Hz,1H),19F NMR(252MHz,DMSO)δ87.9;13C NMR(75MHz,DMSO)δ21.5,21.9,24.6,25.8,50.3,51.6,108.7,118.6,120.8,129.7,130.1,133.1,146.9,148.1,156.1,158.4,158.8;ES MS(M+1)367.18;C16H18N2O4S2についてのHRMS計算値366.46。実測値(M+1)367.43。
4−アゾカン−1イルメチル−3−ヒドロキシ−1−(トルエン−4−スルホニル)−1H−ピリジン−2−オン
1H NMR(300MHz,DMSO)δ1.59(m,10H),2.44(s,3H),3.17(m,2H),3.32(m,2H),4.15(s,2H),6.51(d,J=7.5Hz,1H),7.51(d,J=8.4Hz,1H),7.76(d,J=7.5Hz,1H),7.98(d,J=8.1Hz);19F NMR(252MHz,DMSO)δ88.7;13C NMR(75MHz,DMSO)δ21.5,21.9,23.7,24.6,25.8,50.3,51.6,108.7,118.9,120.8,129.8,130.1,133.1,146.9,148.2,156.1;ES MS(M+1)391.18;C20H26N2O4SについてのHRMS計算値390.18。実測値(M+1)391.23。
3−ヒドロキシ−4−[(2−メトキシエチルアミノ)メチル]−1−(トルエン−4−スルホニル)−1H−ピリジン−2−オン
1H NMR(300MHz,DMSO)δ2.43(s,3H),3.12(m,2H),3.29(s,3H),3.56(t,J=5.1Hz,2H),3.99(s,2H),6.51(d,J=7.5Hz,1H),7.51(d,J=8.4Hz,1H),7.76(d,J=7.5Hz,1H),7.98(d,J=8.1Hz);19F NMR(252MHz,DMSO)δ88.6;13C NMR(75MHz,DMSO)δ21.5,43.8,46.2,46.5,58.5,67.2,106.7,119.2,120.2,123.9,128.4,129.7,130.1,133.1,146.8,147.0,156.0;ES MS(M+1)353.12,C16H20N2O5SについてのHRMS計算値352.41。実測値(M+1)353.11。
3−ヒドロキシ−4−(4−フェニルピペラジン−1−イルメチル)−1−(トルエン−4−スルホニル)−1H−ピリジン−2−オン
1H NMR(300MHz,DMSO)δ2.43(s,3H),3.13(m、8H),3.43(s,2H),6.47(d,J=7.5Hz,1H),6.78(t,J=7.2Hz,1H),7.21 9m,2H),7.50(d,J=8.1Hz,2H),7.67(d,J=7.8Hz,1H),7.97(d,J=8.4Hz,2H);13C NMR(75MHz,DMSO)δ21.5,42.6,45.6,46.2,50.8,51.9,109.6,116.4,116.8,117.7,120.6,121,1.129.5,129.6,129.8,130.1,133.2,146.8,149.5,156.1;ES MS(M+1)440.15;C23H25N3O5SについてのHRMS計算値439.53。実測値(M+1)440.16。
4−[1,4’]ビピペリジニル−1’−イルメチル−3−ヒドロキシ−1−(トルエン−4−スルホニル)−1H−ピリジン−2−オン
1H NMR(300MHz,DMSO)δ1.43(m,1h),1.67(m,2H),1.82(m,4H),2.19(m,2H),2.44(s,3H),2.94(m,4H),3.39(m,2H),3.54(m,3H),4.06(s,2H),6.47(d,J=8.1Hz,1H),7.51(d,J=8.1Hz,2H),7.73(d,7.8Hz,1H),7.99(d,J=8.4Hz,2H);19F NMR(252MHz,DMSO)δ88.7;13C NMR(75MHz,DMSO)δ21.4,22.9,23.6,48.4,49.5,59.4,109.3,114.8,117.6,120.5,122.7,129.7,130.1,133.1,146.9,148.6,156.2;ES MS(M+1)446.19;C23H31N3O4SについてのHRMS計算値445.58。実測値(M+1)446.21。
4−[4−(6−クロロピリダジン−3−イル)ピペラジン−1−イルメチル]−3−ヒドロキシ−1−(トルエン−4−スルホニル)−1H−ピリジン−2−オン
1H NMR(300MHz,DMSO)δ2.44(s,3H),3.17(m,2H),3.46(m,4H),4.17(s,2H),4.45(m,2H),6.77(d,J=7.8Hz,1H),7.04(m,1H),7.53(m,2H),7.68(m,2H),7.98(m,2H),11.3(broad s,1H),ES MS(M+1)476.92,C21H25ClN5O4SについてのHRMS計算値475.95。実測値(M+1)476.11。
4−(ベンジルアミノメチル)−3−ヒドロキシ−1−(トルエン−4−スルホニル)−1H−ピリジン−2−オン
1H NMR(300MHz,DMSO)d2.44(s,3H),3.96(s,2H),4.16(s,2H),6.69(d,J=8.1Hz),7.40(m,7H),7.52(m,1H),7.73(d,J=8.1Hz,1H),7.97(d,J=8.1Hz,1H),9.71(broad s,2H),10.44(broad s,1H);ES MS(M+1)396.67;C20H20N2O4SについてのHRMS計算値384.45。実測値(M+1)385.12。
特に指定される場合を除き、冠詞「a」、「an」及び「the」は「1以上」を意味する。
発明を実施するための最良の形態において引用したすべての文書は、関連する部分において、参考として本明細書に組み込まれるが、いかなる文書の引用も、本発明に関する先行技術であることの容認と考えられるべきではない。
本発明の特定の実施形態を例示し記載したが、本発明の精神及び範囲から逸脱することなく他の様々な変更及び修正を実施できることが、当業者には自明であろう。したがって、本発明の範囲内にあるそのようなすべての変更及び修正を、添付の特許請求の範囲で扱うものとする。
Claims (10)
- 式(I)の化合物であって、
a)R1は、アリール又はヘテロアリールから選択され、任意選択的に、これらは少なくとも水素、ハロ、シアノ、ヒドロキシ、カルボキシ、ケト、チオケト、アミノ、アシルアミノ、アシル、アミド、フェニル、アリールオキシ、アルキル、アルケニル、アルキニル、ヘテロアルキル、ハロ、ハロアルキル、アルコキシ、アリール、ヘテロアリール、シクロアルキル、及びヘテロシクロアルキルにより置換され;
b)各R2は、水素、ハロ、シアノ、ヒドロキシ、カルボキシ、ケト、チオケト、アミノ、アシルアミノ、アシル、アミド、フェニル、アリールオキシ、アルキル、アルケニル、アルキニル、ヘテロアルキル、ハロ、ハロアルキル、アルコキシ、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、スピロシクロアルキル、及びこれらの組合せから独立して選択され;及び
c)R3、及びR4は、各々水素、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アルキルヘテロアルキル、アルキルアリール、アルキルヘテロアリール、アルキルシクロアルキル、及びアルキルヘテロシクロアルキルから独立して選択されるか;又はR3、及びR4は、それらが結合する窒素原子と共に結合してヘテロアリール、又はヘテロシクロアルキル部分を形成し、任意選択的に、これらは少なくとも水素、ハロ、シアノ、ヒドロキシ、カルボキシ、ケト、チオケト、アミノ、アシルアミノ、アシル、アミド、フェニル、アリールオキシ、アルキル、アルケニル、アルキニル、ヘテロアルキル、ハロ、ハロアルキル、アルコキシ、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、スピロシクロアルキル、及びこれらの組合せにより置換されるか;又は
d)R5、及びR6は、各々水素、ハロ、シアノ、ヒドロキシ、カルボキシ、ケト、チオケト、アミノ、アシルアミノ、アシル、アミド、フェニル、アリールオキシ、アルキル、アルケニル、アルキニル、ヘテロアルキル、ハロ、ハロアルキル、アルコキシ、アリール、ヘテロアリール、シクロアルキル、及びヘテロシクロアルキルから独立して選択され;並びに
e)上記の式の光学異性体、ジアステレオマー及びエナンチオマー、並びにそれらの製薬上許容できる塩、生物学的加水分解の可能なアミド、エステル、及びイミドであることを特徴とする化合物。 - R1が、置換された又は置換されていないフェニルであることを特徴とする、請求項1に記載の化合物。
- R2が水素であることを特徴とする、請求項2に記載の化合物。
- R4、及びR5が水素であることを特徴とする、請求項3に記載の化合物。
- 次のものから選択されることを特徴とする、請求項1に記載の化合物:
3−ヒドロキシ−4−ピロリジン−1−イルメチル−1−(トルエン−4−スルホニル)−1H−ピリジン−2−オン;
3−ヒドロキシ−4−チアゾリジン−3−イルメチル−1−(トルエン−4−スルホニル)−1H−ピリジン−2−オン;
4−アゾカン−1イルメチル−3−ヒドロキシ−1−(トルエン−4−スルホニル)−1H−ピリジン−2−オン;
3−ヒドロキシ−4−[(2−メトキシエチルアミノ)メチル]−1−(トルエン−4−スルホニル)−1H−ピリジン−2−オン;
3−ヒドロキシ−4−(4−フェニルピペラジン−1−イルメチル)−1−(トルエン−4−スルホニル)−1H−ピリジン−2−オン;
4−[1,4’]ビピペリジニル−1’−イルメチル−3−ヒドロキシ−1−(トルエン−4−スルホニル)−1H−ピリジン−2−オン;
4−[4−(6−クロロピリダジン−3−イル)ピペラジン−1−イルメチル]−3−ヒドロキシ−1−(トルエン−4−スルホニル)−1H−ピリジン−2−オン;及び4−(ベンジルアミノメチル)−3−ヒドロキシ−1−(トルエン−4−スルホニル)−1H−ピリジン−2−オン。 - 治療を必要とする患者の細菌感染を治療するための医薬組成物の製造に、請求項1に記載の化合物を使用する方法。
- a.安全で有効な量の請求項1に記載の化合物と、
b.製薬上許容できる賦形剤と、を含むことを特徴とする医薬組成物。 - 式IIIの化合物を製造する方法であって:
a)R1は、アリール又はヘテロアリールから選択され、任意選択的に、これらは少なくとも水素、ハロ、シアノ、ヒドロキシ、カルボキシ、ケト、チオケト、アミノ、アシルアミノ、アシル、アミド、フェニル、アリールオキシ、アルキル、アルケニル、アルキニル、ヘテロアルキル、ハロ、ハロアルキル、アルコキシ、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、スピロシクロアルキル、及びこれらの組合せにより置換され;
b)各R2は、水素、ハロ、シアノ、ヒドロキシ、カルボキシ、ケト、チオケト、アミノ、アシルアミノ、アシル、アミド、フェニル、アリールオキシ、アルキル、アルケニル、アルキニル、ヘテロアルキル、ハロ、ハロアルキル、アルコキシ、アリール、ヘテロアリール、シクロアルキル、及びヘテロシクロアルキルから独立して選択され;及び
c)P1は、保護基である;
(a)式IIの化合物を提供する工程と:
(b)前記式IIの化合物を、塩基の存在下でスルホニルクロライド剤を用いてスルホン化する工程と、を含む方法であって:
(i)各R2は、水素、ハロ、シアノ、ヒドロキシ、カルボキシ、ケト、チオケト、アミノ、アシルアミノ、アシル、アミド、フェニル、アリールオキシ、アルキル、アルケニル、アルキニル、ヘテロアルキル、ハロ、ハロアルキル、アルコキシ、アリール、ヘテロアリール、シクロアルキル、及びヘテロシクロアルキルから独立して選択され;及び
(ii)P1は、保護基であることを特徴とする方法。 - アルコール溶媒中の濃縮酸を用いて前記式IIIの化合物の保護を外し、式IVの化合物を製造する工程を更に含む請求項8に記載の方法であって:
a)R1は、アリール又はヘテロアリールから選択され、任意選択的に、これらは少なくとも水素、ハロ、シアノ、ヒドロキシ、カルボキシ、ケト、チオケト、アミノ、アシルアミノ、アシル、アミド、フェニル、アリールオキシ、アルキル、アルケニル、アルキニル、ヘテロアルキル、ハロ、ハロアルキル、アルコキシ、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、スピロシクロアルキル、及びこれらの組合せにより置換され;並びに
b)各R2は、水素、ハロ、シアノ、ヒドロキシ、カルボキシ、ケト、チオケト、アミノ、アシルアミノ、アシル、アミド、フェニル、アリールオキシ、アルキル、アルケニル、アルキニル、ヘテロアルキル、ハロ、ハロアルキル、アルコキシ、アリール、ヘテロアリール、シクロアルキル、及びヘテロシクロアルキルから独立して選択されることを特徴とする方法。 - 式(IV)の前記化合物をホルミル化剤によりホルミル化し、そして、アミノ化剤によりアミノ化して、式(I)の化合物を製造する工程を更に含む請求項9に記載の方法であって:
a)R1は、アリール又はヘテロアリールから選択され、前記アリール又はヘテロアリールは、任意選択的に、少なくとも水素、ハロ、シアノ、ヒドロキシ、カルボキシ、ケト、チオケト、アミノ、アシルアミノ、アシル、アミド、フェニル、アリールオキシ、アルキル、アルケニル、アルキニル、ヘテロアルキル、ハロ、ハロアルキル、アルコキシ、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、スピロシクロアルキル、及びこれらの組合せにより置換され;
b)各R2は、水素、ハロ、シアノ、ヒドロキシ、カルボキシ、ケト、チオケト、アミノ、アシルアミノ、アシル、アミド、フェニル、アリールオキシ、アルキル、アルケニル、アルキニル、ヘテロアルキル、ハロ、ハロアルキル、アルコキシ、アリール、ヘテロアリール、シクロアルキル、及びヘテロシクロアルキルから選択され;及び
c)R3、及びR4は、各々水素、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アルキルヘテロアルキル、アルキルアリール、アルキルヘテロアリール、アルキルシクロアルキル、及びアルキルヘテロシクロアルキルから独立して選択されるか;又はR3、及びR4は、それらが結合する窒素原子と共に結合してヘテロアリール、又はヘテロシクロアルキル部分を形成し、任意選択的に、少なくとも水素、ハロ、シアノ、ヒドロキシ、カルボキシ、ケト、チオケト、アミノ、アシルアミノ、アシル、アミド、フェニル、アリールオキシ、アルキル、アルケニル、アルキニル、ヘテロアルキル、ハロ、ハロアルキル、アルコキシ、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、スピロシクロアルキル、及びこれらの組合せにより置換され;並びに
d)R5、及びR6は、各々水素、ハロ、シアノ、ヒドロキシ、カルボキシ、ケト、チオケト、アミノ、アシルアミノ、アシル、アミド、フェニル、アリールオキシ、アルキル、アルケニル、アルキニル、ヘテロアルキル、ハロ、ハロアルキル、アルコキシ、アリール、ヘテロアリール、シクロアルキル、及びヘテロシクロアルキルから独立して選択されることを特徴とする方法。
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US6930117B2 (en) * | 2002-11-09 | 2005-08-16 | The Procter & Gamble Company | N-alkyl-4-methyleneamino-3-hydroxy-2-pyridones |
US6946479B2 (en) * | 2002-11-09 | 2005-09-20 | The Procter & Gamble Company | N-sulfonyl-4-methyleneamino-3-hydroxy-2-pyridones |
US20070275944A1 (en) * | 2006-04-05 | 2007-11-29 | The Board Of Trustees Operating Michigan State University | Antioxidants and methods of their use |
US7622593B2 (en) | 2006-06-27 | 2009-11-24 | The Procter & Gamble Company | Human protein tyrosine phosphatase inhibitors and methods of use |
MY160399A (en) | 2009-07-06 | 2017-03-15 | Aerpio Therapeutics Inc | Compounds, compositions, and methods for preventing metastasis of cancer cells |
AU2012376221A1 (en) | 2011-10-31 | 2014-06-19 | David S. Baskin | Compound comprising a MAO targeting/ seeker moiety for treating human gliomas |
CN103360308A (zh) * | 2012-03-28 | 2013-10-23 | 孙伟新 | 1,4-二羟基-6-甲基-2-吡啶酮类化合物及其制备方法和用途 |
CA2903871A1 (en) | 2013-03-15 | 2014-09-18 | Aerpio Therapeutics Inc. | Formulations with increased solubility of compounds that activate tie-2 |
US20150050277A1 (en) | 2013-03-15 | 2015-02-19 | Aerpio Therapeutics Inc. | Compositions and methods for treating ocular diseases |
SG11201606862VA (en) | 2014-02-19 | 2016-09-29 | Aerpio Therapeutics Inc | Process for preparing n-benzyl-3-hydroxy-4-substituted-pyridin-2-(1h)-ones |
JP6483148B2 (ja) | 2014-03-14 | 2019-03-13 | エアーピオ セラピューティクス インコーポレイテッド | HPTP−β阻害剤 |
WO2016022813A1 (en) | 2014-08-07 | 2016-02-11 | Aerpio Therapeutics, Inc. | Combination of immunotherapies with activators of tie-2 |
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DE4316077A1 (de) | 1993-05-13 | 1994-11-17 | Bayer Ag | Substituierte Mono- und Bihydridylmethylpyridone |
US5789426A (en) | 1995-01-20 | 1998-08-04 | Cornell Research Foundation, Inc. | Method for the treatment of fibroproliferative disorders by application of inhibitors of protein hydroxylation |
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JP2014139206A (ja) * | 2009-11-06 | 2014-07-31 | Aerpio Therapeutics Inc | プロリルヒドロキシラーゼ阻害剤 |
JP2014159427A (ja) * | 2009-11-06 | 2014-09-04 | Aerpio Therapeutics Inc | 低酸素誘導因子−1αの安定化を増大させるための方法 |
JP2014221826A (ja) * | 2009-11-06 | 2014-11-27 | エアーピオ セラピューティクス インコーポレイテッド | 大腸炎を治療するための組成物および方法 |
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