JP2021532107A - ジカチオン化合物及びその製造方法と使用 - Google Patents
ジカチオン化合物及びその製造方法と使用 Download PDFInfo
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- 0 CCC*(CC)Cc1ccc(C)cc1 Chemical compound CCC*(CC)Cc1ccc(C)cc1 0.000 description 8
- UBWRLJOYIXHFJQ-VZWFPFQJSA-N CC(C)OC(OCCN(C)C(CC/C=C\C=C(/C)\N=O)CC(C1)C=CC1(C)NC)=O Chemical compound CC(C)OC(OCCN(C)C(CC/C=C\C=C(/C)\N=O)CC(C1)C=CC1(C)NC)=O UBWRLJOYIXHFJQ-VZWFPFQJSA-N 0.000 description 1
- BFJRGJXDKPQYCP-GQCTYLIASA-N CC(C/C=C/[N+]([O-])=O)C=C Chemical compound CC(C/C=C/[N+]([O-])=O)C=C BFJRGJXDKPQYCP-GQCTYLIASA-N 0.000 description 1
- PNFUIZKVOJWUHW-UHFFFAOYSA-N CC(OCCC[N+](C)(Cc1ccccc1)Cc(cc1)ccc1N=O)=O Chemical compound CC(OCCC[N+](C)(Cc1ccccc1)Cc(cc1)ccc1N=O)=O PNFUIZKVOJWUHW-UHFFFAOYSA-N 0.000 description 1
- ZUPLJMRNZBJSFG-UHFFFAOYSA-O CCCCC[NH2+]Cc1c[o]cc1 Chemical compound CCCCC[NH2+]Cc1c[o]cc1 ZUPLJMRNZBJSFG-UHFFFAOYSA-O 0.000 description 1
- NJWCPKWJWFDHJT-UHFFFAOYSA-N CCNCCCC(NCOC(OCC[N](C)(Cc(cc1)ccc1N=O)Cc1ccc(C)c(C)c1)=O)=O Chemical compound CCNCCCC(NCOC(OCC[N](C)(Cc(cc1)ccc1N=O)Cc1ccc(C)c(C)c1)=O)=O NJWCPKWJWFDHJT-UHFFFAOYSA-N 0.000 description 1
- NFVXIOGQXDUNHP-CEARFRKXSA-O CC[N+](C)(CCOC(O)=O)CC([C@@H]1C2=C1)=CC(C)C2N=O Chemical compound CC[N+](C)(CCOC(O)=O)CC([C@@H]1C2=C1)=CC(C)C2N=O NFVXIOGQXDUNHP-CEARFRKXSA-O 0.000 description 1
- QDJOMFHPNVOMFM-YFKPBYRVSA-N C[C@@H](C=C1)C=C1[N+]([O-])=O Chemical compound C[C@@H](C=C1)C=C1[N+]([O-])=O QDJOMFHPNVOMFM-YFKPBYRVSA-N 0.000 description 1
- WGVLFWCFPYGVQM-UHFFFAOYSA-N C[N+](C)(CCOC(OCO)=O)Cc1ccccc1 Chemical compound C[N+](C)(CCOC(OCO)=O)Cc1ccccc1 WGVLFWCFPYGVQM-UHFFFAOYSA-N 0.000 description 1
- WMYAXCVVXQFXSJ-UHFFFAOYSA-N C[N]1(Cc(cc2)ccc2[N+]([O-])=O)CCCCC1 Chemical compound C[N]1(Cc(cc2)ccc2[N+]([O-])=O)CCCCC1 WMYAXCVVXQFXSJ-UHFFFAOYSA-N 0.000 description 1
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- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
Description
(I)
式中、n=1、2、3であり、a=0、1、2であり、
YはO、置換又は未置換のメチレン基であり、前記置換の基はハロゲン、C1〜C6のアルキル基であり、
L1、L2は、それぞれ独立して置換又は未置換のC1〜C8のアルキレン基から選択され、ここで、前記置換はアルキレン基におけるCがO又はSによって置換され及び/又はHがアルキル基又はハロゲンによって置換されることを指し、
R1、R2、R3、R4は、それぞれ独立してハロゲン、C1〜C20の置換又は無置換、飽和又は不飽和の炭化水素基から選択され、前記置換の基は、ハロゲン、アルコキシ基、ニトロ基、シアノ基、ヒドロキシ基、C1〜C6のアルキル基、トリフルオロメチル基、C3〜C6のヘテロシクリル基、エステル基、アルコキシカルボニル基から選択される1つ又は複数であり、R1、R2、R3、R4の骨格にヘテロ原子が含まれ又は含まれず、
R5はH、C1〜C6のアルキル基、C3〜C6のシクロアルキル基から選択され、
Mは薬学的に許容可能なアニオンである。
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から選択され、ここで、R6はH、ニトロ基、ハロゲン、メトキシ基、ヒドロキシ基、シアノ基、C1〜C3のアルキル基、フェニル基、トリフルオロメチル基から選択される1つ又は複数である。
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(1−i)化合物a−1と化合物a−2を反応させ、化合物a−3を得て、
(1−ii)化合物a−3と化合物R1−Brを反応させ、化合物a−4を得て、
(1−iii)化合物a−4と水酸化ナトリウムを反応させ、第四級アンモニウム中間体1を得て、
ステップ(2)第四級アンモニウム中間体2の調製、
(2−i)化合物b−1とR4−Brを反応させ、化合物b−2を得て、
(2−ii)化合物b−2とカップリング分子を反応させ、第四級アンモニウム中間体2を得て、
ステップ(3)第四級アンモニウム中間体1と第四級アンモニウム中間体2を反応させ、ジカチオン化合物を得て、
、化合物a−2は
、化合物a−3は
、化合物a−4は
、第四級アンモニウム中間体1は
、化合物b−1は
、化合物b−2は
、カップリング分子は
、第四級アンモニウム中間体2は
、ジカチオン化合物は
であり、N、Y、L1、L2、R1、R2、R3、R4、R5は前記のとおりである。
において、R6は、H、ニトロ基、ハロゲン、メトキシ基、ヒドロキシ基、シアノ基、C1〜C3のアルキル基、フェニル基、トリフロロメチル基から選択される1つ又は複数であり、
において、1つ又は複数の置換基(R6)を有し、且つ複数の場合、複数のR6は、それぞれ独立してH、ニトロ基、ハロゲン、メトキシ基、ヒドロキシ基、シアノ基、C1〜C3のアルキル基、フェニル基、トリフルオロメチル基から選択されることを意味する。
実施例1を参照し、第四級アンモニウム中間体1−1及び1−2それぞれにおいて使用した2−ブロモ酢酸メチル及びp−ニトロベンジルブロミドを、2−クロロ酢酸メチル及びp−ニトロベンジルクロリドに入れ替えることにより、最終的に製造される標的化合物(I)のアニオンを塩化物イオンとすることができる。すなわち化合物14である。
300mLの水に100mgの化合物14を溶解させ、撹拌下で、p−トルエンスルホン酸銀塩を40mg含む水溶液を滴下し、沈殿物をろ過によって除去し、濾過を凍結乾燥させて、アニオンがp−トルエンスルホン酸イオンである標的化合物(I)109mg、すなわち化合物15を得た。
本特許に開示されるその他の具体的な化合物やその合成方法については、実施例1に記載の製造方法を参照することができる。合成により第四級アンモニウム中間体1と第四級アンモニウム中間体2を得て、等モルの2種類の中間体をDMF又はアセトニトリルなどの非プロトン性極性溶媒の中で、室温〜80℃の範囲内で6〜24時間加熱撹拌し、分離精製して上記その他の具体的な化合物を得た。これらの好ましい化合物の構造及び質量スペクトルデータを表1に示す。
体重2〜3.5キログラムである雄のニュージーランドホワイト種のウサギを実験動物とし、筋弛緩実験を行った。具体的には、プロポフォール乳剤を用いて、静脈経由で動物の全身麻酔への導入、維持を行った(導入用量:10mg/kg、維持用量:105mg/hr/kg)。気管挿管し、呼吸補助を実施した。ED95の2倍の等価用量の陽性対照薬物及び本発明に記載の各化合物を静脈注射し、筋弛緩検出機(TOF)を用いて、薬物の作用発現(TOF=0)時間及び筋弛緩作用からの回復(TOF=90%)時間を観察した。結果を表1に示す。
Claims (12)
- 式(I)に示すジカチオン化合物であって、
(I)
式中、n=1、2、3であり、a=0、1、2であり、
YはO、置換又は未置換のメチレン基であり、前記置換の基はハロゲン、C1〜C6のアルキル基であり、
L1、L2は、それぞれ独立して置換又は未置換のC1〜C8のアルキレン基から選択され、ここで、前記置換はアルキレン基におけるCがO又はSによって置換され及び/又はHがアルキル基又はハロゲンによって置換されることを指し、
R1、R2、R3、R4は、それぞれ独立してハロゲン、C1〜C20の置換又は無置換、飽和又は不飽和の炭化水素基から選択され、前記置換の基は、ハロゲン、アルコキシ基、ニトロ基、シアノ基、ヒドロキシ基、C1〜C6のアルキル基、トリフルオロメチル基、C3〜C6のヘテロシクリル基、エステル基、アルコキシカルボニル基から選択される1つ又は複数であり、R1、R2、R3、R4の骨格にヘテロ原子が含まれ又は含まれず、
R5はH、C1〜C6のアルキル基、C3〜C6のシクロアルキル基から選択され、
Mは薬学的に許容可能なアニオンであることを特徴とする、ジカチオン化合物。 - YはO、CH2、CHCH3、CF2であり、前記ヘテロ原子はS又はOであることを特徴とする、請求項1に記載のジカチオン化合物。
- L1、L2は、それぞれ独立して置換又は未置換のC1〜C6のアルキレン基から選択され、ここで、前記置換とは、アルキレン基におけるCがO又はSによって置換され及び/又はHがC1〜C3のアルキル基によって置換されることを指すことを特徴とする、請求項1又は2に記載のジカチオン化合物。
- n=1、2であり、a=0、1であることを特徴とする、請求項1から4のいずれか1項に記載のジカチオン化合物。
- Mは臭化物イオン、塩化物イオン、R−SO3 −であり、前記Rは炭化水素基であり、好ましくは、前記R−SO3 −はp−トルエンスルホン酸イオン、メタンスルホン酸イオン、ベンゼンスルホン酸イオンから選択されることを特徴とする、請求項1から5のいずれか1項に記載のジカチオン化合物。
- 前記ハロゲンはF、Cl、Br、Iであることを特徴とする、請求項1から6のいずれか1項に記載のジカチオン化合物。
- 以下のステップ(1)〜ステップ(3)を含み、
ステップ(1)第四級アンモニウム中間体1の調製、
(1−i)化合物a−1と化合物a−2を反応させ、化合物a−3を得て、
(1−ii)化合物a−3と化合物R1−Brを反応させ、化合物a−4を得て、
(1−iii)化合物a−4と水酸化ナトリウムを反応させ、第四級アンモニウム中間体1を得て、
ステップ(2)第四級アンモニウム中間体2の調製、
(2−i)化合物b−1とR4−Brを反応させ、化合物b−2を得て、
(2−ii)化合物b−2とカップリング分子を反応させ、第四級アンモニウム中間体2を得て、
ステップ(3)第四級アンモニウム中間体1と第四級アンモニウム中間体2を反応させ、ジカチオン化合物を得て、
ここで、化合物a−1は
、化合物a−2は
、化合物a−3は
、化合物a−4は
、第四級アンモニウム中間体1は
、化合物b−1は
、化合物b−2は
、カップリング分子は
、第四級アンモニウム中間体2は
、ジカチオン化合物は
であり、N、Y、L1、L2、R1、R2、R3、R4、R5は請求項1から9のいずれか1項に記載のとおりであることを特徴とする、請求項1から9のいずれか1項に記載のジカチオン化合物の製造方法。 - 請求項1から9のいずれか1項に記載のジカチオン化合物、又はその立体異性体もしくは立体異性体の混合物、又はその薬学的に許容可能な塩、又はその溶媒和物、又はその結晶の、筋弛緩薬物の製造における使用。
- 請求項1から9又は11のいずれか1項に記載のジカチオン化合物、又はその立体異性体もしくは立体異性体混合物、又はその薬学的に許容可能な塩、又はその溶媒和物、又はその結晶を活性成分とし、薬学的に許容可能な補助材料を加えて製造した製剤である、筋弛緩薬物。
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