JP2018511578A - 抗菌剤として使用されるスクアラミンの類似体である化合物 - Google Patents
抗菌剤として使用されるスクアラミンの類似体である化合物 Download PDFInfo
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- JP2018511578A JP2018511578A JP2017546099A JP2017546099A JP2018511578A JP 2018511578 A JP2018511578 A JP 2018511578A JP 2017546099 A JP2017546099 A JP 2017546099A JP 2017546099 A JP2017546099 A JP 2017546099A JP 2018511578 A JP2018511578 A JP 2018511578A
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- cholestane
- hydroxy
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- ASWVTGNCAZCNNR-UHFFFAOYSA-N sulfamethazine Chemical compound CC1=CC(C)=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 ASWVTGNCAZCNNR-UHFFFAOYSA-N 0.000 description 1
- 229960005158 sulfamethizole Drugs 0.000 description 1
- VACCAVUAMIDAGB-UHFFFAOYSA-N sulfamethizole Chemical compound S1C(C)=NN=C1NS(=O)(=O)C1=CC=C(N)C=C1 VACCAVUAMIDAGB-UHFFFAOYSA-N 0.000 description 1
- 229960005404 sulfamethoxazole Drugs 0.000 description 1
- 229960004936 sulfamethoxypyridazine Drugs 0.000 description 1
- VLYWMPOKSSWJAL-UHFFFAOYSA-N sulfamethoxypyridazine Chemical compound N1=NC(OC)=CC=C1NS(=O)(=O)C1=CC=C(N)C=C1 VLYWMPOKSSWJAL-UHFFFAOYSA-N 0.000 description 1
- 229960001544 sulfathiazole Drugs 0.000 description 1
- JNMRHUJNCSQMMB-UHFFFAOYSA-N sulfathiazole Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CS1 JNMRHUJNCSQMMB-UHFFFAOYSA-N 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940063650 terramycin Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960003053 thiamphenicol Drugs 0.000 description 1
- OTVAEFIXJLOWRX-NXEZZACHSA-N thiamphenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CO)NC(=O)C(Cl)Cl)C=C1 OTVAEFIXJLOWRX-NXEZZACHSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229960000223 tilmicosin Drugs 0.000 description 1
- JTSDBFGMPLKDCD-XVFHVFLVSA-N tilmicosin Chemical compound O([C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CCN1C[C@H](C)C[C@H](C)C1)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N(C)C)[C@H]1O JTSDBFGMPLKDCD-XVFHVFLVSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- 229960004059 tylosin Drugs 0.000 description 1
- WBPYTXDJUQJLPQ-VMXQISHHSA-N tylosin Chemical compound O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 WBPYTXDJUQJLPQ-VMXQISHHSA-N 0.000 description 1
- 235000019375 tylosin Nutrition 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
Classifications
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
-
- 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
-
- 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
- A61P31/10—Antimycotics
-
- 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
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Cephalosporin Compounds (AREA)
- Saccharide Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Quinoline Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Description
R1は、H、SO3H、C1〜C8アルキル基、C6〜C10アリール基又はC(=O)R11基から選択され、
R2は、−(CR3R4)m−(X)p−(CR5R6)n−[(Y)−(CR7R8)o]q−NR9R10であり、
R3、R4、R5、R6、R7及びR8は、それぞれ同一であるか又は異なっており、それぞれ独立してH、C1〜C8アルキル、C6〜C10アリール及びC(=O)OR12から選択され、
R9及びR10は、同一であるか又は異なっており、それぞれ独立してH、C1〜C8アルキル若しくは−(CH2)r−NH2基から選択されるか、又は一緒になって1個〜3個のR14基で任意に置換された5員〜7員のヘテロシクリル基を形成し、
X及びYは、同一であるか又は異なっており、それぞれ独立してNR13、O、又は5員〜6員の含窒素ヘテロシクリル基から選択され、
R11及びR12は、それぞれ独立してC1〜C8アルキル基又はC6〜C10アリール基から選択され、
R13は、H、C1〜C6アルキル基、又は−(CH2)s−NH2基であり、
R14は、=O又は=S基であり、
mは、1〜5の整数であり、
nは、1〜5の整数であり、
oは、1〜5の整数であり、
pは、0又は1であり、
qは、0、1又は2であり、
rは、1〜4の整数であり、
sは、1〜5の整数であり、
p=1及びq=1の場合、m+n+o≠7であると理解される)に関する。
R1は、H、SO3H、C1〜C8アルキル基、C6〜C10アリール基又はC(=O)R11基から選択され、
R2は、−(CR3R4)m−(X)p−(CR5R6)n−[(Y)−(CR7R8)o]q−NR9R10であり、
R3、R4、R5、R6、R7及びR8は、それぞれ同一であるか又は異なっており、それぞれ独立してH、C1〜C8アルキル、C6〜C10アリール及びC(=O)OR12から選択され、
R9及びR10は、同一であるか又は異なっており、それぞれ独立してH、C1〜C8アルキル若しくは−(CH2)r−NH2基から選択されるか、又は一緒になって1個〜3個のR14基で任意に置換された5員〜7員のヘテロシクリル基を形成し、
X及びYは、同一であるか又は異なっており、それぞれ独立してNR13、O、又は5員〜6員の含窒素ヘテロシクリル基から選択され、
R11及びR12は、それぞれ独立してC1〜C8アルキル基又はC6〜C10アリール基から選択され、
R13は、H、C1〜C6アルキル基、又は−(CH2)s−NH2基であり、
R14は、=O又は=S基であり、
mは、1〜5の整数であり、
nは、1〜5の整数であり、
oは、1〜5の整数であり、
pは、0又は1であり、
qは、0、1又は2であり、
rは、1〜4の整数であり、
sは、1〜5の整数である)に関する。
p=1及びq=0の場合、m+n≠6及び7であり、
p=0及びq=1の場合、m+n+o≠6及び7である、
と理解される。
3β−スペルミノ−7α−ヒドロキシ−5α−コレスタン(SA−1)
3β−スペルミノ−7β−ヒドロキシ−5α−コレスタン(SA−2)
3β−ノルスペルミジノ−7β−ヒドロキシ−5α−コレスタン(SA−3)
3β−(1,3−ジアミノプロパン)−7β−ヒドロキシ−5α−コレスタン(SA−4)
3β−(1,4−ジアミノブタン)−7β−ヒドロキシ−5α−コレスタン(SA−5)
3β−(トリス(2−アミノエチル)アミン)−7β−ヒドロキシ−5α−コレスタン(SA−6)
3β−(1,5−ジアミノペンタン)−7α−ヒドロキシ−5α−コレスタン(SA−7)
3β−(1,4−ビス(3−アミノプロピル)ピペラジン)−7β−ヒドロキシ−5α−コレスタン(SA−8)
3β−(1,4−ビス(3−アミノプロポキシ)ブタン)−7β−ヒドロキシ−5α−コレスタン(SA−9)
3β−(ノルスペルミノ)−7α−ヒドロキシ−5α−コレスタン(SA−10)
3β−(1−(3−アミノプロピル)イミダゾール)−7α−ヒドロキシ−5α−コレスタン(SA−11)
3β−(1−(3−アミノプロピル)モルホリン)−7α−ヒドロキシ−5α−コレスタン(SA−12)
から選択される。
3β−スペルミノ−7β−ヒドロキシ−5α−コレスタン(SA−2)
3β−(1,3−ジアミノプロパン)−7β−ヒドロキシ−5α−コレスタン(SA−4)
3β−(ノルスペルミノ)−7α−ヒドロキシ−5α−コレスタン(SA−10)
から選択される。
第2の主題によると、本発明は、式(I)の化合物、並びに更に式(I)の化合物の立体異性体、立体異性体の混合物及び/又は薬学的に許容可能な塩と、薬学的に許容可能な賦形剤とを含む医薬組成物又は獣医薬組成物に関する:
p=1及びq=0の場合、m+n≠6及び7であり、
p=0及びq=1の場合、m+n+o≠6及び7である、
と理解される。
第3の主題によると、本発明は、式(I)の化合物、並びに更に式(I)の化合物の立体異性体、立体異性体の混合物及び/又は薬学的に許容可能な塩に関する
p=1及びq=0の場合、m+n≠6及び7であり、
p=0及びq=1の場合、m+n+o≠6及び7である、
と理解される。
一般式(I)の化合物は、それ自体が既知の及び/又は当業者の範囲内にある任意の方法、特にComprehensive Organic Transformations, VCH Pub., 1989においてLarockにより記載されるものの適用若しくは適合、又は下記の実施例に記載の方法の適用若しくは適合により製造することができる。
本発明によると、「アルキル」基は、炭素数1〜8、特に炭素数1〜6、好ましくは炭素数1〜4である飽和の直鎖又は分岐鎖炭化水素基を指す。直鎖の場合、特にメチル基、エチル基、プロピル基、ブチル基、ペンチル基又はヘキシル基が挙げられ得る。分岐鎖の場合、特にイソプロピル基、tert−ブチル基、2−メチルブチル基、2−メチルペンチル基及び1−メチルペンチル基が挙げられ得る。
全ての合成は、通常の方法により精製された溶媒を用いて行った。市販の反応物を、予め精製することなく直接使用する。
1H NMR:300MHz、Si(CH3)4
13C NMR:75MHz、Si(CH3)4
s=シングレット
d=ダブレット
t=トリプレット
q=カルテット
m=広く分離されていないピーク
1H NMR:δ=5.45〜5.75(m,1H)、3.475〜3.75(m,1H)、2.125〜2.75(m,4H)、1.75〜2.075(m,6H)、0.8〜1.7(m,37H)、0.45〜0.75(m,4H);13C NMR:δ=202.81、165.59、126.49、70.89、55.17、50.34、45.80、43.49、39.87、38.67、36.57、36.11、28.40、26.72、24.22、23.22、22.96、21.61、19.26、17.71、12.37。
1H NMR:δ=5.65〜5.7(d、1H)、4.6〜4.75(m,1H)、0.6〜2.6(m,44H);13C NMR:δ=201.90、170.24、163.81、126.68、72.19、54.75、49.93、49.78、45.38、43.08、39.44、38.64、38.28、37.72、36.15、35.98、35.69、31.90、28.50、27.96、27.32、26.28、23.80、22.77、22.52、21.24、21.14、18.84、17.22、11.93。
1H NMR:δ=4.62〜4.70(m,1H)、0.64〜2.39(m,47H);13C NMR:δ=211.44、170.38、72.71、54.95、49.90、48.82、46.43、45.34、42.45、39.42、38.65、36.09、35.89、35.60、33.79、28.35、27.93、26.34、24.93、23.72、22.74、22.51、22.15、21.27、18.73、12.01、11.65。
1H NMR:δ=0.6〜3.82(m,48H);13C NMR:δ=75.11、71.08、70.99、67.96、62.57、56.45、56.08、55.68、55.19、51.85、50.51、45.83、43.95、43.35、42.60、42.00、39.46、37.62、37.11、36.54、36.24、35.73、35.51、34.88、31.30、29.82、28.05、27.95、26.86、23.79、23.71、22.76、22.51、21.56、20.96、18.60、12.40、12.11、11.79、11.20。
5a 1H NMR:δ=3.05〜3.55(m,1H)、2.2〜2.6(m,3H)、0.4〜1.92(m,42H);13C NMR:δ=211.55、74.66、55.61、55.24、51.83、44.18、43.94、43.66、39.90、39.54、38.12、35.72、35.16、28.75、28.06、23.89、22.87、22.62、21.80、18.84、12.22、11.63。
5b 1H NMR:δ=3.3〜3.85(m,1H)、0.60〜2.65(m,45H);13C NMR:δ=211.36、71.08、57.18、56.53、54.33、47.13、39.86、38.32、37.07、36.49、36.08、31.10、30.44、28.43、28.39、24.38、24.20、23.20、22.93、21.92、19.03、13.53、12.40。
アミノステロイド系誘導体は全て同じ手法に従って生成した。分子SA−1の例を考える。
A.式(I)の化合物の固有の抗菌活性
1)前培養物の調製
2つのチューブを準備した:
陰性対照(2mlの無菌培養培地)
解凍した生物菌株(生物菌株の保存はグリセロール中にて−80℃で行う)の陽性対照(1940μlの培養培地+40μlのDMSO+20μlの細菌懸濁液)。使用する菌株は、S.アウレウスATCC 25923、E.コリATCC 25922、P.エルギノーサATCC 27853、C.アルビカンスCIP 1180−79及びE.フェカリスCIP 103015である。
24時間インキュベートした後、900μlの無菌培養培地で希釈した100μlの細菌懸濁液を取り、600nmで分光光度計を使用して光学密度を測定した。この試験には96ウェルプレートを使用する必要があり、各ウェルにおける0.01に等しい値に相当するODに合わせて微生物懸濁液の必要接種量を計算した。このプレートにおいて、第1のラインが陰性対照に対応しており(各ウェル中、195μlの無菌培養培地)、第2のラインが陽性対照に対応しており(2%のDMSOを添加した接種済み培養培地)、第3のラインでは細菌懸濁液を2回投入し、8μlの試験生成物を各ウェルに入れた。その後、このラインから2倍段階希釈(cascade half dilution)を行った。
インキュベートした後、フィルターを透明なフィルムに交換した後、ODの読み取りをIEMSプレート分光光度計にて620nmで行った。最小阻害濃度(MIC)の計算を行った。
WST−1試験を用いて、生成物の細胞毒性の活性を測定した。この試験は、生存率及び細胞増殖の程度の測定を可能にする比色分析試験である。比色分析試験は、黄色のホルマザン誘導体をもたらすミトコンドリアのデヒドロゲナーゼによる無色のテトラゾリウム塩WST−1(4−[3−(4−ヨードフェニル)−2−(4−ニトロフェニル)−2H−5−テトラゾリオ(tetrazolio)]−1,3−ベンゼンジスルホネート)の切断に基づくものであり、420nm〜480nmでの分光光度法により定量可能である。
アミノステロイド系誘導体の存在下におけるドキシサイクリンの最小阻害濃度(MIC)の決定用のマイクロプレートの調製例
この方法には、96ウェルプレートを使用する必要があり、100μlの液体培養培地を各ウェルに置いた後、上記で調製した微生物懸濁液を接種させた。必要接種量は、各ウェルにおいておよそ5×106個の細菌に相当する0.01のODに合わせて計算する。このプレートにおいて、第1のラインが陰性対照に対応しており(各ウェル中、200μlの無菌培養培地)、第2のラインが陽性対照に対応しており(100μlの無菌培養培地+100μlの細菌懸濁液)、第3のラインが192μlの培養培地を含有し、試験する8μlのアミノステロイド系生成物を各ウェルに入れる。次いで、このラインから段階希釈を行う。続いて、最終濃度2μg/mlの抗生物質を得るために、8μlのドキシサイクリン溶液(1mgを20mlに溶解している)をライン3〜8の各ウェルに加える。その後、92μlの細菌懸濁液をライン3〜8に加える。湿潤雰囲気にて37℃で24時間インキュベートした後、結果(Xμg/mlのアミノステロイド系誘導体の存在下におけるMIC(2μg/mlのドキシサイクリン)の決定)を読み取る。37℃で24時間インキュベートした後、40μlのヨウ化ニトロテトラゾリウムを各ウェルに加え、ミディアムピンクの着色により生細菌の存在を明らかにすることが可能になる。
(1)Alhanout K, Brunel JM, Raoult D and Rolain JM, In vitro antibacterial activity of aminosterols against multidrug-resistant bacteria from patients with cystic fibrosis, J. Antimicrob. Chemother., 2009, Oct, 64(4), 810-4.
(2)Loncle et al., Tetrahedron, 2007, 63, 12968-12974.
(3)Salmi et al., European Journal of Medicinal Chemistry, 2008, 43, 540-547.
(4)Salmi et al., Letters in Drug Design & Discovery, 2008, 5, 169-172.
(5)Salmi et al., Journal of Enzyme Inhibition and Medicinal Chemistry, 2008, 23, 860-865.
(6)Loncle et al., Letters in Drug Design & Discovery, 2008, 5, 388-393.
(7)Salmi et al., Tetrahedron, 2008, 64, 4453-4459.
(8)Williams JI et al., Squalamine treatment of human tumors in nu/nu mice enhances platinum-based chemotherapies, Clin. Cancer Res., 2001 Mar, 7(3), 724-733.
(9)Daniel Amsterdam, “Susceptibility testing of antimicrobials in liquid media” in Antibiotics in Laboratory Medicine. 5th Edition. Editor Victor Lorian. Lippincott Williams and Wilkins, 2005, Philadelphia, USA.
Claims (19)
- ヒト又は動物における細菌感染症、真菌感染症、ウイルス感染症若しくは寄生虫感染症の治療、又は癌の治療への使用のための式(I)の化合物、並びに更にその立体異性体、立体異性体の混合物及び/又は薬学的に許容可能な塩:
R1は、H、SO3H、C1〜C8アルキル基、C6〜C10アリール基又はC(=O)R13基から選択され、
R2は、−(CR3R4)m−(X)p−(CR5R6)n−[(Y)−(CR7R8)o]q−NR9R10であり、
R3、R4、R5、R6、R7及びR8は、それぞれ同一であるか又は異なっており、それぞれ独立してH、C1〜C8アルキル、C6〜C10アリール及びC(=O)OR14から選択され、
R9及びR10は、同一であるか又は異なっており、それぞれ独立してH、C1〜C8アルキル若しくは−(CH2)r−NH2基から選択されるか、又は一緒になって1個〜3個のR14基で任意に置換された5員〜7員のヘテロシクリル基を形成し、
X及びYは、同一であるか又は異なっており、それぞれ独立してNR13、O、又は5員〜6員の含窒素ヘテロシクリル基から選択され、
R11及びR12は、それぞれ独立してC1〜C8アルキル基又はC6〜C10アリール基から選択され、
R13は、H、C1〜C6アルキル基、又は−(CH2)s−NH2基であり、
R14は、=O又は=S基であり、
mは、1〜5の整数であり、
nは、1〜5の整数であり、
oは、1〜5の整数であり、
pは、0又は1であり、
qは、0、1、2又は3であり、
rは、1〜4の整数であり、
sは、1〜5の整数である)。 - 3β−(ノルスペルミノ)−7α−ヒドロキシ−5α−コレスタン及び下記式を有する化合物を除く、
- p=1、q=0、m=3、n=3又は4、かつX=NHである化合物を除く、請求項1に記載の使用のための式(I)の化合物。
- p=1及びq=0の場合、m+n≠6及び7であり、
p=0及びq=1の場合、m+n+o≠6及び7である、
と理解される、請求項1に記載の使用のための式(I)の化合物。 - R1がHである、請求項1〜4のいずれか一項に記載の使用のための式(I)の化合物。
- XがNR13、好ましくはNHである、請求項1〜5のいずれか一項に記載の使用のための式(I)の化合物。
- R9及び/又はR10がHである、請求項1〜6のいずれか一項に記載の使用のための式(I)の化合物。
- mが2、3、4、又は5、好ましくは3である、請求項1〜7のいずれか一項に記載の使用のための式(I)の化合物。
- −NHR2基が下記から選択される、
- 3β−スペルミノ−7α−ヒドロキシ−5α−コレスタン(SA−1)
3β−スペルミノ−7β−ヒドロキシ−5α−コレスタン(SA−2)
3β−ノルスペルミジノ−7β−ヒドロキシ−5α−コレスタン(SA−3)
3β−(1,3−ジアミノプロパン)−7β−ヒドロキシ−5α−コレスタン(SA−4)
3β−(1,4−ジアミノブタン)−7β−ヒドロキシ−5α−コレスタン(SA−5)
3β−(トリス(2−アミノエチル)アミン)−7β−ヒドロキシ−5α−コレスタン(SA−6)
3β−(1,5−ジアミノペンタン)−7α−ヒドロキシ−5α−コレスタン(SA−7)
3β−(1,4−ビス(3−アミノプロピル)ピペラジン)−7β−ヒドロキシ−5α−コレスタン(SA−8)
3β−(1,4−ビス(3−アミノプロポキシ)ブタン)−7β−ヒドロキシ−5α−コレスタン(SA−9)
3β−(1−(3−アミノプロピル)イミダゾール)−7α−ヒドロキシ−5α−コレスタン(SA−11)
3β−(1−(3−アミノプロピル)モルホリン)−7α−ヒドロキシ−5α−コレスタン(SA−12)
から選択される、請求項1に記載の使用のための式(I)の化合物。 - 前記感染症が細菌感染症、特にグラム陽性菌感染症又はグラム陰性菌感染症である、請求項1〜10のいずれか一項に記載の使用のための式(I)の化合物。
- 動物、特にイヌ、ネコ又は反芻動物における請求項1〜11のいずれか一項に記載の使用のための式(I)の化合物。
- 動物の乳腺炎、子宮炎、歯感染症、膿皮炎又は耳炎の治療における請求項1〜12のいずれか一項に記載の使用のための式(I)の化合物。
- 式(I)の化合物を別の抗生化合物と併せて投与する、請求項1〜13のいずれか一項に記載の使用のための式(I)の化合物。
- 請求項1で定義された式(I)の化合物、又は式(I)の化合物の立体異性体、立体異性体の混合物及び/又は薬学的に許容可能な塩と、薬学的に許容可能な賦形剤とを含む医薬組成物又は獣医薬組成物。
- 3β−(ノルスペルミノ)−7α−ヒドロキシ−5α−コレスタン及び下記式を有する化合物を除く、
- 第2の抗生化合物を更に含む、請求項15又は16に記載の医薬組成物又は獣医薬組成物。
- 請求項1で定義された記載の式(I)の化合物。
- 請求項1で定義された記載の式(I)の化合物を製造する方法であって、アミンR2NH2の存在下における式(II)の化合物の還元的アミノ化により、式(I)の化合物を得る段階を含む、方法:
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