JP2021073278A - 抗生物質として有用なコロルマイシン誘導体 - Google Patents
抗生物質として有用なコロルマイシン誘導体 Download PDFInfo
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- JP2021073278A JP2021073278A JP2021015712A JP2021015712A JP2021073278A JP 2021073278 A JP2021073278 A JP 2021073278A JP 2021015712 A JP2021015712 A JP 2021015712A JP 2021015712 A JP2021015712 A JP 2021015712A JP 2021073278 A JP2021073278 A JP 2021073278A
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Abstract
Description
細菌感染症の処置および制圧に関する世界的危機についてはよく認識されている。医学上の懸念には、世界中で新しく出現する感染症に対処する十分な種類の抗生物質の不足および適応細菌で観察されている従来の抗生物質処置に対する耐性が含まれる。この状況に対処する新しい抗生物質は作り出されていない。1980年代の半ばに、16種の新しい抗生物質がFDAにより承認された。2008/2009年には、この数がただの1種に減少した(米国感染症学会)。ほぼ同じ期間中に、抗生物質に対する耐性の発生率は約5%から30〜60%に上昇した。これに突き動かされて世界保健機関は、「抗菌剤耐性の急速な発生は、ヒトの健康に対する3大脅威の1つである」という2009年の声明に至った。
したがって、代替抗生物質化合物に対する必要性が引き続き存在する。
式中、
R1〜R3およびR5〜R10は、H、アルキル基、置換アルキル基、ハロゲン、OH、NH2、またはSHから独立に選択され、
R4は、アルキル基または置換アルキル基であり、
X1〜X2は、O、S、NH、H、アルキル、ハロゲン、OH、SH、またはNH2から独立に選択され、
Wは、1〜15個の炭素原子を有し、水素および炭素原子から本質的になる飽和非環式炭化水素鎖であり、
Zは、CH3または任意の中性もしくは正電荷基である。
R1〜R3およびR5〜R10は、H、アルキル基、置換アルキル基、ハロゲン、OH、NH2、またはSHから独立に選択され、
R4は、H、アルキル基または置換アルキル基であり、
X1〜X2は、O、S、NH、H、アルキル、ハロゲン、OH、SH、またはNH2から独立に選択され、
Yは、2〜20個の炭素原子を有する非環式炭化水素鎖または2〜20個の炭素原子を有する置換非環式炭化水素鎖であり、
Wは、1〜15個の炭素原子を有する非環式炭化水素鎖または1〜15個の炭素原子を有する置換非環式炭化水素鎖であり、
Zは、CH3または任意の中性もしくは正電荷基である。
Claims (19)
- 2個のみのキラル中心5Sおよび3’Rを有する、請求項1に記載の化合物。
- R4がHであり、X1が=Oであり、X2がOHである、請求項1または2に記載の化合物。
- R1〜R3は、HまたはC1〜C3アルキル基から独立に選択され、
R5〜R10は、HまたはCH3から独立に選択され、
R4は、Hであり、
Wは、水素および炭素原子のみからなる、1〜8個の炭素原子の飽和非環式炭化水素鎖である、
請求項1〜3のいずれか1項に記載の化合物。 - R1〜R3は、HまたはC1〜C2アルキル基から独立に選択され、
R5〜R10は、HまたはC1〜C3アルキル基から独立に選択され、
R4は、Hである、
請求項1〜3のいずれか1項に記載の化合物。 - R1〜R2は、C1〜C2アルキル基から独立に選択され、
R3〜R10は、それぞれ独立にHである、
請求項1〜3のいずれか1項に記載の化合物。 - グラム陰性細菌のNa+−NQR活性を調節する、請求項1〜7のいずれか1項に記載の化合物。
- 抗菌有効量の請求項1〜8のいずれか1項に記載の化合物と薬学的に許容可能なキャリアとを含む、医薬組成物。
- グラム陰性細菌によって引き起こされる細菌性疾患の処置のための請求項1〜8のいずれか1項に記載の化合物を含む医薬組成物。
- 前記細菌性疾患が、コレラ、急性胃腸炎、潰瘍、胃腸感染症、創傷感染、敗血症、食物媒介性下痢、下痢、胃腸炎、在郷軍人病、壊死性歯肉炎、成人性歯周炎、歯周炎、若年性歯周炎、髄膜炎、淋病、肺炎、心内膜炎、耳炎、軟性下疳、肺感染症、皮膜感染症、腹膜炎、外傷、パラチフス熱、腸チフス熱、ペスト、極東猩紅様熱、気管支炎、トラコーマ、腟炎、若年性肺炎、急性細気管支炎、ヒト胎児死亡、腹膜感染症、呼吸器感染症、中耳炎、眼感染症および中枢神経系感染症からなる群より選択される、請求項10に記載の医薬組成物。
- 前記細菌性疾患は、コレラ菌(Vibrio cholerae)、腸炎ビブリオ菌(Vibrio parahaemolyticus)、ビブリオ・バルニフィカス(Vibrio vulnificus)、ビブリオ・ガストロエンテリティス(Vibrio gastroenteritis)、ビブリオ・ダムセラ(Vibrio damsela)、ビブリオ・フラビアリス(Vibrio fluvialis)、ビブリオ・ファーニッシイ(Vibrio furnissii)、ビブリオ・ハーベイ(Vibrio harveyi)、ビブリオ・ホリセ(Vibrio hollisae)、ビブリオ・コスティコラ(Vibrio costicola)、ビブリオ・ミミカス(Vibrio mimicus)、ビブリオ・シンシンナティエンシス(Vibrio cincinnatiensis)、アエロモナス・ベロニイ(Aeromonas veronii)、アエロモナス・カビアエ(Aeromonas caviae)、在郷軍人病菌(Legionella pneumophila)、トレポネーマ・デンティコーラ(Treponema denticola)、ジンジバリス菌(Porphyromonas gingivalis)、タネレラ・フォーサイシア(Tannerella forsythia)、ヘモフィラス・アクチノミセテムコミタンス(Actinobacillus actinomycetemcomitans)、髄膜炎菌(Neisseria meningitides)、淋菌(Neisseria gonorrhoeae)、ナイセリア・シッカ(Neisseria sicca)、インフルエンザ菌(Haemophilus influenzae)、軟性下疳菌(Haemophilus ducreyi)、緑膿菌(Pseudomonas aeruginosa)、シュードモナス・シュードアルカリゲネス(Pseudomonas pseudoalcaligenes)、フォトラブダス・アシンビオティカ(Photorhabdus asymbiotica)、サルモネラ菌(パラチフス菌)(Salmonella enterica(s.Paratyphi))、サルモネラ菌(チフス菌)(Salmonella enterica(s.Typhi))、クレブシェラ肺炎杆菌(Klebsiella pneumonia)、ペスト菌(Yersinia pestis)、仮性結核菌(Yersinia pseudotuberculosis)、肺炎クラミジア(Chlamydophila pneumoniae)、トラコーマ病原体(Chlamydia trachomatis)、シムカニア・ネゲベンシスZ(Simkania negevensis Z)、ワドリア・コンドロフィラ(Waddlia chondrophila)、動物パスツレラ症病原(Pasteurella multocida)、セラチア・プロテアマキュランス(Serratia proteamaculans)、バクテロイデス・フラギリス(Bacteroides fragilis)およびカタル球菌(Moraxella catarrhalis)からなる群より選択される細菌の感染により引き起こされる、請求項10に記載の医薬組成物。
- 前記グラム陰性細菌が、エンテロバクター目、ビブリオ目、パスツレラ目、エアロモナス目、シュードモナス目、およびナイセリア目からなる群より選択されるプロテオバクテリア門の菌種である、請求項10に記載の医薬組成物。
- 前記化合物は、哺乳動物細胞に対して非毒性の量で治療効果のある抗生物質である、請求項10〜13のいずれか1項に記載の医薬組成物。
- グラム陰性細菌によって引き起こされる細菌性疾患の処置のための医薬の製造のための、請求項1〜8のいずれか1項に記載の化合物の使用。
- 前記細菌性疾患が、コレラ、急性胃腸炎、潰瘍、胃腸感染症、創傷感染、敗血症、食物媒介性下痢、下痢、胃腸炎、在郷軍人病、壊死性歯肉炎、成人性歯周炎、歯周炎、若年性歯周炎、髄膜炎、淋病、肺炎、心内膜炎、耳炎、軟性下疳、肺感染症、皮膜感染症、腹膜炎、外傷、パラチフス熱、腸チフス熱、ペスト、極東猩紅様熱、気管支炎、トラコーマ、腟炎、若年性肺炎、急性細気管支炎、ヒト胎児死亡、腹膜感染症、呼吸器感染症、中耳炎、眼感染症および中枢神経系感染症からなる群より選択される、請求項15に記載の使用。
- 前記細菌性疾患が、コレラ菌(Vibrio cholerae)、腸炎ビブリオ菌(Vibrio parahaemolyticus)、ビブリオ・バルニフィカス(Vibrio vulnificus)、ビブリオ・ガストロエンテリティス(Vibrio gastroenteritis)、ビブリオ・ダムセラ(Vibrio damsela)、ビブリオ・フラビアリス(Vibrio fluvialis)、ビブリオ・ファーニッシイ(Vibrio furnissii)、ビブリオ・ハーベイ(Vibrio harveyi)、ビブリオ・ホリセ(Vibrio hollisae)、ビブリオ・コスティコラ(Vibrio costicola)、ビブリオ・ミミカス(Vibrio mimicus)、ビブリオ・シンシンナティエンシス(Vibrio cincinnatiensis)、アエロモナス・ベロニイ(Aeromonas veronii)、アエロモナス・カビアエ(Aeromonas caviae)、在郷軍人病菌(Legionella pneumophila)、トレポネーマ・デンティコーラ(Treponema denticola)、ジンジバリス菌(Porphyromonas gingivalis)、タネレラ・フォーサイシア(Tannerella forsythia)、ヘモフィラス・アクチノミセテムコミタンス(Actinobacillus actinomycetemcomitans)、髄膜炎菌(Neisseria meningitides)、淋菌(Neisseria gonorrhoeae)、ナイセリア・シッカ(Neisseria sicca)、インフルエンザ菌(Haemophilus influenzae)、軟性下疳菌(Haemophilus ducreyi)、緑膿菌(Pseudomonas aeruginosa)、シュードモナス・シュードアルカリゲネス(Pseudomonas pseudoalcaligenes)、フォトラブダス・アシンビオティカ(Photorhabdus asymbiotica)、サルモネラ菌(パラチフス菌)(Salmonella enterica(s.Paratyphi))、サルモネラ菌(チフス菌)(Salmonella enterica(s.Typhi))、クレブシェラ肺炎杆菌(Klebsiella pneumonia)、ペスト菌(Yersinia pestis)、仮性結核菌(Yersinia pseudotuberculosis)、肺炎クラミジア(Chlamydophila pneumoniae)、トラコーマ病原体(Chlamydia trachomatis)、シムカニア・ネゲベンシスZ(Simkania negevensis Z)、ワドリア・コンドロフィラ(Waddlia chondrophila)、動物パスツレラ症病原(Pasteurella multocida)、セラチア・プロテアマキュランス(Serratia proteamaculans)、バクテロイデス・フラギリス(Bacteroides fragilis)およびカタル球菌(Moraxella catarrhalis)からなる群より選択される細菌の感染により引き起こされる、請求項15に記載の使用。
- 前記グラム陰性細菌が、エンテロバクター目、ビブリオ目、パスツレラ目、エアロモナス目、シュードモナス目、およびナイセリア目からなる群より選択されるプロテオバクテリア門の菌種である、請求項15に記載の使用。
- 前記化合物は、哺乳動物細胞に対して非毒性の量で治療効果のある抗生物質である、請求項15〜18のいずれか1項に記載の使用。
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