JP6515035B2 - マイコバクテリアに対して活性な抗生物質の活性を増強する飽和窒素及びn−アシル化複素環 - Google Patents
マイコバクテリアに対して活性な抗生物質の活性を増強する飽和窒素及びn−アシル化複素環 Download PDFInfo
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- JP6515035B2 JP6515035B2 JP2015548640A JP2015548640A JP6515035B2 JP 6515035 B2 JP6515035 B2 JP 6515035B2 JP 2015548640 A JP2015548640 A JP 2015548640A JP 2015548640 A JP2015548640 A JP 2015548640A JP 6515035 B2 JP6515035 B2 JP 6515035B2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—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
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
-
- A—HUMAN NECESSITIES
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Description
本発明は、また、医薬として、特に例えば結核、ハンセン病及び非定型マイコバクテリア感染症のような細菌及びマイコバクテリア感染症の治療における医薬として、使用することができる新規化合物に関する。
本発明は、また、活性成分として上記化合物の少なくとも一つと、場合によっては細菌及び/又はマイコバクテリアに対して活性な少なくとも一つの抗生物質、特にEthA経路を介して活性化可能な抗生物質、より特定的にはチオアミドファミリー、例えば、エチオナミド又はプロチオナミドから選択される抗生物質を含有する薬学的組成物に関する。
ますます増加する結核菌(マイコバクテリウム・ツベルクローシス)株は、イソニアジド(INH)やリファンピシン(RIF)等の第一選択抗生物質に対して多耐性であることが今や特徴となっている。そこで、これらの抗生物質は、株が耐性ではないが、低い治療指数(活性成分の治療指数は、毒性用量に対する治療用量の比である)であるという欠点があるエチオナミド(ETH)等の第二選択抗生物質と置き換えられなければならない。
本発明の他の目的は、チオアミドファミリー、特にエチオナミド及び/又はプロチオナミドから選択される、結核に対して活性な抗生物質と組み合わせて、同一の抗生物質の投薬量で、より高い効力を達成することを可能にし、あるいは上述の抗生物質投薬量を低減させて所与の効力を達成することを可能にする、先に述べられたような化合物を提案することである。
本発明の他の目的は、製造が簡単で安価である先に述べられたような化合物を提案することである。
本発明の他の目的は、生体液に満足できる程度に可溶性である先に述べられたような化合物を提案することである。
本発明の他の目的は、特に経口的に、活性であり、及び/又は引き起こす副作用がより少ない、先に述べられたような化合物を提供することである。
(上式中、
n=0又は1;
R1は、
特に少なくとも一つのフッ素原子(F)で置換された直鎖状又は分枝状の置換されていてもよいC1−C5アルキル鎖;
少なくとも一つのフッ素原子(F)によって又はC3−C6飽和もしくは不飽和の環式基によって置換された直鎖状又は分枝状C1−C3アルキル鎖;及び
基CH2CF3、(CH2)2CF3、CF2CF3
から選択される基を表し;
Xは、N及びCHから選択され;
R2は、次の基:フェニル、ベンジル、少なくとも一つの直鎖状又は分枝状C1−C4アルキル鎖によって置換されたフェニル又はベンジル基、少なくとも一つの直鎖状又は分枝状の置換された(特に、少なくとも一つのフッ素原子(F)によって置換された)C1−C4アルキル鎖によって置換されたフェニル又はベンジル基、Cl、F、CF3、OCH3、OCF3、又はOHから選択される少なくとも一つの基で置換されたフェニル基、及び1個、2個又は3個の窒素原子を含む飽和又は不飽和で6の頂点を有する複素環から選択される)
の化合物をこのように提案する。
R1は、次の基から選択できる:−CH2−イソプロピル、シクロプロピル、シクロブチル、シクロペンチル、−CH2−シクロプロピル、−CH2−シクロブチル、及び−CH2−シクロペンチル。
有利には、R1は−CH2CF3基である。このような成分は、特に結核菌に対する、エチオナミドの良好な増強活性を示す。
有利には、X=CHである。このような成分は、特に結核菌に対して、エチオナミドとの併用でより効果的であることが証明された。
第一の実施態様によれば、R2はフェニル基である。
第二の実施態様によれば、R2はベンジル基である。
第三の実施態様によれば、R2は、少なくとも一つのF原子で置換されたフェニル基である。
第四の実施態様によれば、R2は、Xとの結合に対してメタ位がCl、F、CF3又はCH3によって置換されたフェニル基である。
有利には、R2はXへの結合に対してパラ位がフッ素原子Fによって置換されたフェニル基である。
本発明は、また、活性成分として、先に述べた一般式(I)の少なくとも一つの化合物と一種の薬学的に許容される賦形剤を含有する薬学的組成物に関する。
有利には、薬学的組成物は、活性成分として、細菌及び/又はマイコバクテリアに対して活性な少なくとも一つの抗生物質、特にEthA経路を介して活性化可能な抗生物質、より具体的には特にチオアミドファミリー、特にエチオナミド及びプロチオナミドから選択される抗生物質を更に含む。
しかし、本発明は、これらの抗生物質に限定されるものではない。
本出願の全体において、ある基が何であれ置換されることが示されていない場合、後者は置換されない。
本発明の意味において、置換されたフェニル基は、モノ−、ジ−又はトリ−置換フェニル基として定義される。置換基又は置換基群の位置は、それが示されていない場合、本発明においては限定されない。置換基又は置換基群が示される場合、フェニル基はまた記載されるものとは異なる一つ又は数個の他の置換基を含みうる。
好ましくは、Cl、CF3、及びCH3で置換されたフェニル基はモノ置換であり、置換基(Cl、CF3又はCH3)は、Xに結合しているベンゼン環の炭素に対してメタ位にあることが好ましい。好ましくは、XはCHである。
本発明によれば、「治療」という用語は、上述の感染症の治癒的処置及び/又は予防的処置を指す。「治療」という用語は、患者の状態のあらゆる改善、特に患者の少なくとも一つの感染部位に存在する細菌の数の何らかの削減を含む。
本発明の意味において、細菌及び/又はマイコバクテリアに対して活性な抗生物質とは、細菌及び/又はマイコバクテリウム、特に結核菌の増殖を少なくともインビトロで制限するか又は減少させることができる任意の薬剤として定義される。マイコバクテリウム、特に結核菌を少なくともインビトロ(in vitro)で破壊することができる薬剤はまた本発明の意味においてマイコバクテリアに対して活性な抗生物質である。マイコバクテリアに対して活性で、EthA酵素経路を介して活性化可能な抗生物質のなかで、エチオナミド、プロチオナミド、イソキシル、チアセタゾン及びこれらの抗生物質の少なくとも2種の混合物を挙げることができる。
本発明の意味における抗生物質はまた上記のもの以外の他の生理活性化経路を介して活性化可能な抗生物質であり得る。
合成法
核磁気共鳴スペクトル(NMR)1H及び13Cを300MHzでBrukerTMのDPX300分光計で、周囲温度で実施した。ケミカルシフトは百万分率(ppm)で表される。帰属は、1H及び13C一次元(1D)又は二次元(2D)HSQC−COSY実験を用いて実施された。質量スペクトルは、LCMS Waters Alliance Micromass ZQ2000システムで実施された。市販の試薬及び溶媒は、後で精製することなく使用された。
LDA(THF/ヘプタン/エチルベンゼン中2Mの溶液、3.3mmol、1.1当量)を、先にオーブン乾燥し、アルゴン下に置かれたフラスコに5mLの無水THFと共に加える。溶液を−78℃に冷却する。5mLのTHFに溶解させたN−Boc−4−ピペリドン(又はN−Boc−3−ピロリジノン)(3mmol、1当量)を滴下して加え、次いで、反応媒体を−78℃で20分間撹拌する。5mLのTHFに溶解させたN−フェニル−トリフルオロメタン−スルホンイミド(3.3mmol、1.1当量)を加える。溶液を0℃で2時間撹拌し、次いで蒸発させる。残留物を9:1のシクロヘキサン/AcOEt混合物に溶解し、次いでアルミナで濾過する。生成物(トリフレート)を精製することなく次の工程で使用する。
トリフレート(1当量)を含み、アルゴン下に置かれたフラスコに、ボロン酸(1.1当量)、LiCl(3当量)、Na2CO3(1.4当量)の2N溶液、DME(0.34M)及びテトラキス(トリフェニルホスフィン)パラジウム(0.05当量)を加える。溶液を還流下で1時間から16時間加熱した後、蒸発させる。残留物をAcOEtに取り、次いで水を使用して一回、NaClを飽和させた溶液を使用して一回洗浄する。有機相を乾燥させ、次いで蒸発させる。残留物をAcOEtに取り、次いで焼結ガラスで濾過する。溶媒を蒸発させ、次いで生成物をシリカゲルでのクロマトグラフィー(シクロヘキサン/AcOEt)を使用して精製する。
別法:不飽和誘導体(1当量)をギ酸アンモニウム(5当量)及びPd/C(10質量%)と共にメタノール(0.1M)に溶解する。反応混合物を、入れた生成物が消失するまで還流下で加熱する。溶液をセライトで濾過し、次いで蒸発させる。保護アミン(1当量)をジオキサン(1M)と共にフラスコに添加し、次いでジオキサン(5当量)中の4NのHCl溶液を添加する。溶液を周囲温度で1時間撹拌し、次いで蒸発させる。残留物を軽油に取り、その後、焼結ガラスで濾過する。
酸(1.3当量)を、DIEA(4当量)の存在下、DMF(0.25M)中のEDCl(1.3当量)及びHOBt(0.4当量)を使用して活性化させ、その後、市販のピペラジン(1当量)を添加する。溶液を周囲温度で3時間撹拌し、次いで蒸発させる。残留物をAcOEtに溶解させた後、飽和NaHCO3を使用して2回、1NのHClを使用して2回、飽和NaClを使用して1回、洗浄する。有機相をMgSO4で乾燥させ、次いで蒸発させる。残留物を、分取HPLCを使用して精製する。
4−フェニルピペリジンは市販されている。カップリングのみが実施された。
1H NMR (CD2Cl2) δ 7.36-7.31 (m, 2H), 7.25-7.21 (m, 3H), 4.78-4.71 (m, 1H), 3.99-3.93 (m, 1H), 3.22-3.12 (m, 1H), 2.84-2.48 (m, 6H), 1.96-1.86 (m, 2H), 1.72-1.56 (m, 2H). MS [M + H]+ m/z 286。
4−フェニルピペリジンは市販されている。カップリングのみが実施された。
1H NMR (CD2Cl2) δ 7.36-7.31 (m, 2H), 7.25-7.20 (m, 3H), 4.78-4.72 (m, 1H), 3.99-3.92 (m, 1H), 3.19-3.09 (m, 1H), 2.81-2.60 (m, 2H), 2.45 (t, J = 7.0 Hz, 2H), 2.29-2.16 (m, 2H), 1.97-1.87 (m, 4H), 1.70-1.54 (m, 2H). MS [M + H]+ m/z 300。
1H NMR (CDCl3) δ 7.34-7.28 (m, 2H), 6.97-6.94 (m, 3H), 3.83-3.80 (m, 2H), 3.67-3.64 (m, 2H), 3.24-3.17 (m, 4H), 2.68-2.49 (m, 4H). MS [M + H]+ m/z 287。
1H NMR (CDCl3) δ 7.34-7.28 (m, 2H), 6.97-6.94 (m, 3H), 3.82-3.79 (m, 2H), 3.65-3.62 (m, 2H), 3.22-3.16 (m, 4H), 2.48 (t, J = 7.2 Hz, 2H), 2.31-2.15 (m, 2H), 2.03-1.92 (m, 2H).
MS [M + H]+ m/z 301.
1H NMR (CD2Cl2) δ 7.27-7.20 (m, 2H), 7.16-7.03 (m, 2H), 4.79-4.73 (m, 1H), 3.98-3.93 (m, 1H), 3.24-3.08 (m, 2H), 2.74-2.48 (m, 5H), 1.95-1.86 (m, 2H), 1.74-1.63 (m, 2H).
MS [M + H]+ m/z 304.
1H NMR (CD2Cl2) δ 7.27-7.20 (m, 2H), 7.16-7.02 (m, 2H), 4.79-4.74 (m, 1H), 3.99-3.94 (m, 1H), 3.24-3.09 (m, 2H), 2.75-2.49 (m, 5H), 1.95-1.86 (m, 2H), 1.75-1.59 (m, 2H).
MS [M + H]+ m/z 304.
1H NMR (CD2Cl2) δ 7.33-7.19 (m, 2H), 7.06-7.00 (m, 2H), 4.77-4.72 (m, 1H), 3.98-3.92 (m, 1H), 3.21-3.11 (m, 1H), 2.83-2.49 (m, 6H), 1.94-1.86 (m, 2H), 1.68-1.46 (m, 2H).
13C NMR (CD2Cl2) δ 167.64, 161.45 (d, J = 244 Hz), 141.20, 127.42 (q, J = 274 Hz), 128.16 (d, J = 8 Hz), 115.11 (d, J = 21 Hz), 45.83, 42.40, 41.91, 33.81, 32.96, 29.53 (q, J = 29 Hz), 25.79. MS [M + H]+ m/z 304.
1H NMR (CD2Cl2) δ 6.69 (t, J = 8.7 Hz, 2H), 4.78-4.72 (m, 1H), 3.98-3.92 (m, 1H), 3.27-3.10 (m, 2H), 2.68-2.48 (m, 5H), 2.07-1.90 (m, 2H), 1.82-1.74 (m, 2H). MS [M + H]+ m/z 340.
1H NMR (CD2Cl2) δ 7.04-6.98 (m, 2H), 6.95-6.90 (m, 2H), 3.79-3.75 (m, 2H), 3.64-3.61 (m, 2H), 3.14-3.07 (m, 4H), 2.61-2.46 (m, 4H). MS [M + H]+ m/z 305.
1H NMR (CD2Cl2) δ 7.04-6.98 (m, 2H), 6.94-6.89 (m, 2H), 3.77-3.74 (m, 2H), 3.62-3.59 (m, 2H), 3.12-3.06 (m, 4H), 2.45 (t, J = 7.2 Hz, 2H), 2.25-2.15 (m, 2H), 1.97-1.87 (m, 2H).
MS [M + H]+ m/z 319.
1H NMR (CD2Cl2) δ 6.99-6.82 (m, 3H), 3.79-3.76 (m, 2H), 3.64-3.61 (m, 2H), 3.05-2.99 (m, 4H), 2.67-2.48 (m, 4H). MS [M + H]+ m/z 323.
1H NMR (CD2Cl2) δ 7.41-7.39 (m, 1H), 7.32-7.17 (m, 3H), 4.80-4.75 (m, 1H), 3.99-3.94 (m, 1H), 3.35-3.17 (m, 2H), 2.76-2.49 (m, 5H), 1.99-1.89 (m, 2H), 1.66-1.53 (m, 2H).
MS [M + H]+ m/z 320.
1H NMR (CD2Cl2) δ 7.32-7.21 (m, 3H), 7.15-7.13 (m, 1H), 4.78-4.72 (m, 1H), 3.98-3.93 (m, 1H), 3.21-3.11 (m, 1H), 2.83-2.48 (m, 6H), 1.95-1.87 (m, 2H), 1.69-1.52 (m, 2H).
MS [M + H]+ m/z 320.
1H NMR (CD2Cl2) δ 7.33-7.30 (m, 2H), 7.20-7.17 (m, 2H), 4.78-4.71 (m, 1H), 3.99-3.92 (m, 1H), 3.21-3.11 (m, 1H), 2.82-2.48 (m, 6H), 1.94-1.86 (m, 2H), 1.67-1.51 (m, 2H).
MS [M + H]+ m/z 320.
1H NMR (CD2Cl2) δ 7.28-7.23 (m, 2H), 6.91-6.86 (m, 2H), 3.78-3.75 (m, 2H), 3.64-3.61 (m, 2H), 3.20-3.13 (m, 4H), 2.67-2.46 (m, 4H). MS [M + H]+ m/z 321.
1H NMR (CD2Cl2) δ 7.27-7.22 (m, 2H), 6.91-6.86 (m, 2H), 3.77-3.74 (m, 2H), 3.62-3.59 (m, 2H), 3.18-3.12 (m, 4H), 2.45 (t, J = 7.2 Hz, 2H), 2.31-2.15 (m, 2H), 1.97-1.87 (m, 2H).
MS [M + H]+ m/z 335.
1H NMR (CDCl3) δ 7.39 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.04 (dd, J = 8.3 Hz, J = 2.0 Hz, 1H), 4.82-4.77 (m, 1H), 4.00-3.94 (m, 1H), 3.21-3.12 (m, 1H), 2.79-2.48 (m, 6H), 1.96-1.88 (m, 2H), 1.67-1.51 (m, 2H).
13C NMR (CDCl3) δ 167.99, 145.10, 132.60, 130.58, 128.84, 127.11 (q, J = 275 Hz), 126.11, 45.74, 42.40, 41.90, 33.48, 32.53, 29.69 (q, J = 29 Hz), 25.95. MS [M + H]+ m/z 354.
1H NMR (CD2Cl2) δ 7.68 (d, J = 4.5 Hz, 1H), 7.58 (t, J = 4.5 Hz, 1H), 7.46 (d, J = 4.5 Hz, 1H), 7.37 (t, J = 4.5 Hz, 1H), 4.81-4.77 (m, 1H), 4.00-3.97 (m, 1H), 3.23-3.17 (m, 2H), 2.73-2.52 (m, 5H), 1.92-1.85 (m, 2H), 1.75-1.68 (m, 2H). MS [M + H]+ m/z 354.
1H NMR (CD2Cl2) δ 7.51-7.46 (m, 4H), 4.80-4.75 (m, 1H), 4.01-3.95 (m, 1H), 3.23-3.14 (m, 1H), 2.93-2.82 (m, 1H), 2.74-2.50 (m, 5H), 1.99-1.90 (m, 2H), 1.74-1.57 (m, 2H).
13C NMR (CD2Cl2) δ 167.72, 146.30, 130.56 (q, J = 32 Hz), 130.37, 129.09, 127.44 (q, J = 275 Hz), 124.35 (q, J = 275 Hz), 123.51 (q, J = 4 Hz), 123.25 (q, J = 4 Hz), 45.73, 42.48, 42.29, 33.46, 32.63, 29.52 (q, J = 28 Hz), 25.83. MS [M + H]+ m/z 354.
1H NMR (CD2Cl2) δ 7.61 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 4.80-4.74 (m, 1H), 4.01-3.95 (m, 1H), 3.23-3.13 (m, 1H), 2.92-2.82 (m, 1H), 2.73-2.48 (m, 5H), 1.98-1.89 (m, 2H), 1.73-1.61 (m, 2H). MS [M + H]+ m/z 354.
1H NMR (CD2Cl2) δ 7.19-7.09 (m, 4H), 4.80-4.74 (m, 1H), 4.00-3.94 (m, 1H), 3.23-3.14 (m, 1H), 3.06-2.95 (m, 1H), 2.74-2.47 (m, 5H), 2.38 (s, 3H), 1.88-1.80 (m, 2H), 1.71-1.54 (m, 2H). MS [M + H]+ m/z 300.
1H NMR (CD2Cl2) δ 7.23-7.20 (m, 1H), 7.06-7.01 (m, 3H), 4.77-4.71 (m, 1H), 3.98-3.92 (m, 1H), 3.20-3.11 (m, 1H), 2.79-2.46 (m, 6H), 2.33 (s, 3H), 1.94-1.85 (m, 2H), 1.71-1.53 (m, 2H). MS [M + H]+ m/z 300.
1H NMR (CD2Cl2) δ 7.16-7.10 (m, 4H), 4.77-4.70 (m, 1H), 3.97-3.91 (m, 1H), 3.20-3.10 (m, 1H), 3.06-2.95 (m, 1H), 2.77-2.47 (m, 5H), 2.33 (s, 3H), 1.93-1.85 (m, 2H), 1.69-1.51 (m, 2H). MS [M + H]+ m/z 300.
1H NMR (CD2Cl2) δ 7.25-7.15 (m, 2H), 6.98-6.91 (m, 2H), 4.78-4.72 (m, 1H), 3.97-3.92 (m, 1H), 3.86 (s, 3H), 3.28-3.14 (m, 2H), 2.75-2.47 (m, 5H), 1.94-1.84 (m, 2H), 1.69-1.54 (m, 2H).
13C NMR (CD2Cl2) δ 167.59, 156.89, 133.37, 127.49 (q, J = 275 Hz), 127.18, 126.35, 120.56, 110.44, 55.23, 46.16, 42.73, 35.54, 32.31, 31.48, 29.59 (q, J = 29 Hz), 25.81.
MS [M + H]+ m/z 316.
1H NMR (CD2Cl2) δ 7.27-7.22 (m, 1H), 6.83-6.76 (m, 3H), 4.78-4.71 (m, 1H), 3.99-3.92 (m, 1H), 3.80 (s, 3H), 3.20-3.11 (m, 1H), 2.81-2.47 (m, 6H), 1.95-1.87 (m, 2H), 1.71-1.54 (m, 2H). MS [M + H]+ m/z 316
1H NMR (CD2Cl2) δ 7.17-7.14 (m, 2H), 6.89-6.86 (m, 2H), 4.76-4.71 (m, 1H), 3.97-3.92 (m, 1H), 3.79 (s, 3H), 3.20-3.11 (m, 1H), 2.74-2.50 (m, 6H), 1.93-1.86 (m, 2H), 1.63-1.55 (m, 2H).
13C NMR (CD2Cl2) δ 168.38, 158.58, 138.06, 127.49 (q, J = 275 Hz), 127.56, 113.81, 55.16, 45.97, 42.53, 41.76, 34.06, 33.12, 29.56 (q, J = 29 Hz), 25.80. MS [M + H]+ m/z 316.
1H NMR (MeOD) δ 7.08 (dd, J = 7.6 Hz, J = 1.5 Hz, 1H), 7.00 (td, J = 7.6 Hz, J = 1.7 Hz, 1H), 6.80-6.74 (m, 2H), 4.71-4.64 (m, 1H), 4.09-4.02 (m, 1H), 3.27-3.15 (m, 2H), 2.80-2.70 (m, 3H), 2.58-2.47 (m, 2H), 1.96-1.83 (m, 2H), 1.74-1.53 (m, 2H). MS [M + H]+ m/z 302.
1H NMR (MeOD) δ 7.04 (d, J = 8.7 Hz, 2H), 6.72 (d, J = 8.7 Hz, 2H), 4.67-4.61 (m, 1H), 4.04-3.98 (m, 1H), 3.21-3.12 (m, 1H), 2.75-2.66 (m, 4H), 2.58-2.46 (m, 2H), 1.89-1.79 (m, 2H), 1.67-1.44 (m, 2H). MS [M + H]+ m/z 302.
1H NMR (CD2Cl2) δ 8.52 (d, J = 6.1 Hz, 2H), 7.16 (d, J = 6.1 Hz, 2H), 4.80-4.73 (m, 1H), 4.01-3.93 (m, 1H), 3.22-3.13 (m, 1H), 2.84-2.48 (m, 6H), 1.98-1.89 (m, 2H), 1.71-1.54 (m, 2H). MS [M + H]+ m/z 287.
4−ベンジルピペリジンは市販されている。カップリングのみが実施された。
1H NMR (CD2Cl2) δ 7.33-7.28 (m, 2H), 7.24-7.16 (m, 3H), 4.59-4.51 (m, 1H), 3.82-3.77 (m, 1H), 3.02-2.92 (m, 1H), 2.59-2.47 (m, 7H), 1.85-1.67 (m, 3H), 1.24-1.07 (m, 2H).
MS [M + H]+ m/z 300.
1H NMR (CD2Cl2) δ 7.35-7.26 (m, 5H), 3.61 (t, J = 5.1 Hz, 2H), 3.54 (s, 2H), 3.45 (t, J = 5.1 Hz, 2H), 2.61-2.41 (m, 8H). MS [M + H]+ m/z 301.
1H NMR (CDCl3) δ 7.24-7.18 (m, 2H), 7.07-7.00 (m, 2H), 4-09-3.99 (m, 0.5H), 3.91-3.81 (m, 1H), 3.72-3.64 (m, 0.5H), 3.60-3.31 (m, 3H), 2.61-2.50 (m, 4H), 2.46-2.27 (m, 1H), 2.16-1.95 (m, 1H). MS [M + H]+ m/z 290.
1H NMR (CDCl3) δ 7.34-7.28 (m, 2H), 6.97-6.90 (m, 3H), 3.80 (t, J = 5.1 Hz, 2H), 3.66 (t, J = 5.1 Hz, 2H), 3.22-3.15 (m, 4H), 2.42-2.37 (m, 2H), 1.70-1.53 (m, 3H), 0.95 (d, J = 6.3 Hz, 6H). MS [M + H]+ m/z 261.
1H NMR (CDCl3) δ 7.26-7.22 (m, 2H), 6.91-6.86 (m, 2H), 3.74 (t, J = 5.1 Hz, 2H), 3.63 (t, J = 5.1 Hz, 2H), 3.18-3.11 (m, 4H), 2.39-2.34 (m, 2H), 1.67-1.49 (m, 3H), 0.95 (d, J = 6.3 Hz, 6H). MS [M + H]+ m/z 295.
1H NMR (CDCl3) δ 7.04-6.98 (m, 2H), 6.94-6.90 (m, 2H), 3.74 (t, J = 5.1 Hz, 2H), 3.63 (t, J = 5.1 Hz, 2H), 3.12-3.05 (m, 4H), 2.39-2.34 (m, 2H), 1.64-1.49 (m, 3H), 0.95 (d, J = 6.6 Hz, 6H). MS [M + H]+ m/z 279.
4−フェニルピペリジンは市販されている。カップリングのみが実施された。
1H NMR (CD2Cl2) δ 7.36-7.31 (m, 2H), 7.25-7.20 (m, 3H), 4.77-4.73 (m, 1H), 4.02-3.98 (m, 1H), 3.18-3.09 (m, 1H), 2.81-2.71 (m, 1H), 2.66-2.57 (m, 1H), 2.39-2.34 (m, 2H), 1.94-1.85 (m, 2H), 1.69-1.51 (m, 5H), 0.95 (d, J = 6.4 Hz, 6H). MS [M + H]+ m/z 260.
エチオナミド増強の細胞試験
使用される試験は、これらの化合物が結核菌に対するエチオナミドの殺菌活性を増強することができることを確認することを可能にする。この試験は「ハイコンテントスクリーニング」(HCS)又は高密度コンテントスクリーニング試験である。HCS試験は、与えられた環境において微生物(例えば細菌)の所定の表現型の特徴を研究することを可能にする細胞培養上で実施される。観察される表現型の変化は、所定の標識タンパク質の産生の増加(又は減少)から検討中の微生物の形態の変形までの範囲でありうる。該方法は次の刊行物に記載されている:“Ethionamide Boosters: Synthesis, Biological Activity, and Structure-Activity Relationships of a Series of 1,2,4-Oxadiazole EthR Inhibitors”, M. Flipoら, Journal of Medicinal Chemistry, 2011, 54(8), 2994-3010。
ETHの活性を10倍増強するために必要なリガンド濃度を測定するために、一定濃度のエチオナミド(そのCMI99の1/10に相当する0.1μg/mL)が選択される。リガンド濃度を変化させることにより、細菌増殖を50%阻害するのに必要な濃度、すなわち、エチオナミドの活性を10倍増強するために必要な濃度を決定することができる。この濃度はEC50で示される。
サンプルのDMSO中の10mMの溶液40μLをpH7.4の1.96mLのMeOH又はPBSに添加する。次いで、サンプルを室温で24時間攪拌し、5分間遠心分離し、その後、0.45μmサイズのフィルターで濾過する。次いで20μLの各溶液を180μLのMeOHに添加し、次いでLC−MSにより分析する。溶解度は、質量シグナルPBS/MeOHの表面の比として決定される。
以下の表IからIIIは、試験された本発明の化合物の化学式と上述のプロトコルに従って実験的に測定されたEC50の値をまとめたものである。
表Iの結果では、CH2CF3基が、化合物の溶解度にマイナスの影響を与えることなく、エチオナミドの活性を大きく増強できていることが観察される。
結果は、同じ基R1と同じ基R2に対しては、本発明の化合物の増強活性はn=1の場合に改善されることを示している。
Claims (20)
- 式(I):
(上式中、
nは、0又は1であり;
R1は、−CH2CF3及び−CH2CH2CF3からなる群から選択され、
Xは、N又はCHであり、
R2は、フェニル、ベンジル、直鎖状又は分枝状C1−C4アルキルによって置換されたフェニル、直鎖状又は分枝状C1−C4アルキルによって置換されたベンジル、フッ素によって置換されている直鎖状又は分枝状C1−C4アルキルによって置換されているフェニル、フッ素によって置換されている直鎖状又は分枝状C1−C4アルキルによって置換されているベンジル、Cl、F、CF3、OCH3及びOHから選択される1以上の基で置換されているフェニル、並びに1個、2個又は3個の窒素原子を含む6員複素環からなる群から選択される)
の化合物。 - nが1である、請求項1に記載の化合物。
- R1が−CH2CF3である、請求項1又は2に記載の化合物。
- XがCHである、請求項1、2又は3に記載の化合物。
- R2がフェニル又はベンジルである、請求項1から4の何れか一項に記載の化合物。
- R2が、Xとの結合に対してメタ位でCl、F、CF3及びOCH3から選択される置換基で置換されているフェニルである、請求項1から4の何れか一項に記載の化合物。
- R2が、フッ素で置換されているフェニルである、請求項1から4の何れか一項に記載の化合物。
- R2が、Xとの結合に対してパラ位でフッ素で置換されているフェニルである、請求項1から4の何れか一項に記載の化合物。
- 医薬として使用するための、請求項1から10の何れか一項に記載の化合物。
- 細菌及びマイコバクテリア感染症の治療に使用するための、請求項1から10の何れか一項に記載の化合物。
- 結核、ハンセン病及び非定型マイコバクテリア感染症の治療に使用するための、請求項1から10の何れか一項に記載の化合物。
- 活性成分として請求項1から10の何れか一項に記載の化合物と薬学的に許容される賦形剤を含む、EthA酵素経路を介して活性化可能な抗生物質の活性を増強するための薬学的組成物。
- 活性成分として請求項1から10の何れか一項に記載の化合物と薬学的に許容される賦形剤を含む、エチオナミド、プロピオンアミド、イソキシルおよびチアセタゾンから選択される抗生物質の活性を増強するための薬学的組成物。
- 活性成分として、請求項1から10の何れか一項に記載の化合物、薬学的に許容される賦形剤、及びEthA酵素経路を介して活性化可能な抗生物質を含む薬学的組成物。
- 活性成分として、請求項1から10の何れか一項に記載の化合物、薬学的に許容される賦形剤、及びチオアミドファミリーから選択される抗生物質を含む薬学的組成物であって、前記抗生物質がEthA酵素経路を介して活性化可能である、薬学的組成物。
- 活性成分として、請求項1から10の何れか一項に記載の化合物、薬学的に許容される賦形剤、及びエチオナミド又はプロチオナミドを含む薬学的組成物。
- EthA経路を介して活性化可能な抗生物質を含む、請求項1から10の何れか一項に記載の化合物と組み合わせて結核、ハンセン病又は非定型マイコバクテリア感染症を治療するための医薬。
- 請求項1から10の何れか一項に記載の化合物を含む、EthA経路を介して活性化可能な抗生物質と組み合わせて結核、ハンセン病又は非定型マイコバクテリア感染症を治療するための医薬。
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EP1118612A1 (en) * | 2000-01-21 | 2001-07-25 | Universita Degli Studi di Firenze | Piperazine derivatives possesing nootropic activity |
TW593556B (en) * | 2002-12-27 | 2004-06-21 | Ind Tech Res Inst | Dichroic dye, composition thereof, and liquid crystal composition and liquid-crystal display element containing the same |
US7601844B2 (en) * | 2006-01-27 | 2009-10-13 | Bristol-Myers Squibb Company | Piperidinyl derivatives as modulators of chemokine receptor activity |
FR2903405B1 (fr) | 2006-07-04 | 2011-09-09 | Pasteur Institut | Composes a effet potentialisateur de l'activite de l'ethionamide et leurs applications |
TW200938203A (en) * | 2007-12-17 | 2009-09-16 | Intervet Int Bv | Anthelmintic agents and their use |
WO2009080432A2 (en) | 2007-12-21 | 2009-07-02 | Eth Zurich | Composition for treatment of tuberculosis |
CA2730116A1 (en) * | 2008-07-08 | 2010-01-14 | Boehringer Ingelheim International Gmbh | Pyrrolidinyl and piperidinyl compounds useful as nhe-1 inhibitors |
EP2350053B1 (en) * | 2008-10-17 | 2013-12-11 | Whitehead Institute For Biomedical Research | Modulators of MTOR Complexes |
FR2939135B1 (fr) * | 2008-12-02 | 2010-12-03 | Galderma Res & Dev | Nouveaux composes 4-(azacycloalkyl)-benzene-1,3-diol comme inhibiteurs de la tyrosinase, leur procede de preparation et leur utilisation en medecine humaine ainsi qu'en cosmetique |
US8912329B2 (en) | 2009-06-25 | 2014-12-16 | BioVersys AG | Composition for treatment of tuberculosis |
KR101179508B1 (ko) * | 2010-06-24 | 2012-09-07 | 한국과학기술연구원 | 1,6-이치환-3-아미노-4,5,6,7-테트라하이드로-1H-피라졸로[3,4-c]피리딘-7-온 화합물 및 이 화합물의 제조방법 |
US8962658B2 (en) | 2011-10-25 | 2015-02-24 | Universite De Droit Et De La Sante De Lille 2 | Fluoralkylcarbonyl-oxadiazoles |
WO2013170113A1 (en) * | 2012-05-11 | 2013-11-14 | Abbvie Inc. | Nampt inhibitors |
CA2879369C (en) * | 2012-07-20 | 2020-09-22 | Bayer Pharma Aktiengesellschaft | Novel 5-aminotetrahydroquinoline-2-carboxylic acids and use thereof |
FR3000064A1 (fr) | 2012-12-21 | 2014-06-27 | Univ Lille Ii Droit & Sante | Composes de type spiroisoxazoline ayant une activite potentialisatrice de l'activite d'un antibiotique-composition et produit pharmaceutiques comprenant de tels composes |
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2012
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2013
- 2013-12-20 CN CN201380067137.2A patent/CN104955804B/zh active Active
- 2013-12-20 AU AU2013366503A patent/AU2013366503B2/en not_active Ceased
- 2013-12-20 PE PE2015001024A patent/PE20151327A1/es unknown
- 2013-12-20 US US14/653,669 patent/US9957249B2/en active Active
- 2013-12-20 KR KR1020157019623A patent/KR20150138152A/ko not_active Application Discontinuation
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- 2013-12-20 JP JP2015548640A patent/JP6515035B2/ja active Active
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- 2013-12-20 WO PCT/EP2013/077732 patent/WO2014096378A1/fr active Application Filing
- 2013-12-20 CA CA2895606A patent/CA2895606A1/fr not_active Abandoned
- 2013-12-20 EP EP13814948.9A patent/EP2935212B1/fr active Active
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2015
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- 2015-05-25 TN TNP2015000202A patent/TN2015000202A1/fr unknown
- 2015-06-12 CL CL2015001640A patent/CL2015001640A1/es unknown
- 2015-06-17 CR CR20150319A patent/CR20150319A/es unknown
- 2015-06-18 IL IL239504A patent/IL239504B/en not_active IP Right Cessation
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Also Published As
Publication number | Publication date |
---|---|
EP2935212B1 (fr) | 2019-02-27 |
US20150307471A1 (en) | 2015-10-29 |
EA028076B1 (ru) | 2017-10-31 |
US9957249B2 (en) | 2018-05-01 |
MX2015008029A (es) | 2015-10-30 |
PE20151327A1 (es) | 2015-10-12 |
SG11201504492UA (en) | 2015-07-30 |
JP2016503778A (ja) | 2016-02-08 |
UA117922C2 (uk) | 2018-10-25 |
WO2014096378A1 (fr) | 2014-06-26 |
GEP20186857B (en) | 2018-06-11 |
BR112015014279A2 (pt) | 2017-07-11 |
CN104955804B (zh) | 2018-02-09 |
TN2015000202A1 (en) | 2016-10-03 |
KR20150138152A (ko) | 2015-12-09 |
MA38275A1 (fr) | 2017-11-30 |
IL239504A0 (en) | 2015-08-31 |
AU2013366503A1 (en) | 2015-07-09 |
HK1215254A1 (zh) | 2016-08-19 |
MA38275B1 (fr) | 2018-09-28 |
EP2935212A1 (fr) | 2015-10-28 |
CN104955804A (zh) | 2015-09-30 |
EA201590828A1 (ru) | 2015-11-30 |
PH12015501427A1 (en) | 2015-09-14 |
AU2013366503B2 (en) | 2018-02-01 |
FR3000065A1 (fr) | 2014-06-27 |
CA2895606A1 (fr) | 2014-06-26 |
IL239504B (en) | 2018-10-31 |
CR20150319A (es) | 2015-09-14 |
CL2015001640A1 (es) | 2016-01-29 |
PH12015501427B1 (en) | 2015-09-14 |
ZA201503719B (en) | 2016-11-30 |
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