JP2012524060A - リファマイシン誘導体 - Google Patents
リファマイシン誘導体 Download PDFInfo
- Publication number
- JP2012524060A JP2012524060A JP2012505257A JP2012505257A JP2012524060A JP 2012524060 A JP2012524060 A JP 2012524060A JP 2012505257 A JP2012505257 A JP 2012505257A JP 2012505257 A JP2012505257 A JP 2012505257A JP 2012524060 A JP2012524060 A JP 2012524060A
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- Prior art keywords
- formula
- compound
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- compounds
- methyl
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- HJYYPODYNSCCOU-ODRIEIDWSA-N rifamycin SV Chemical class OC1=C(C(O)=C2C)C3=C(O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O HJYYPODYNSCCOU-ODRIEIDWSA-N 0.000 title claims abstract description 50
- 150000001875 compounds Chemical class 0.000 claims abstract description 131
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 49
- 238000000034 method Methods 0.000 claims abstract description 48
- 239000001257 hydrogen Substances 0.000 claims abstract description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 35
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 21
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims abstract description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 94
- 239000008194 pharmaceutical composition Substances 0.000 claims description 34
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 33
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 31
- -1 di-substituted benzene ring Chemical group 0.000 claims description 29
- 230000001580 bacterial effect Effects 0.000 claims description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 24
- 208000012868 Overgrowth Diseases 0.000 claims description 23
- NZCRJKRKKOLAOJ-XRCRFVBUSA-N rifaximin Chemical group OC1=C(C(O)=C2C)C3=C4N=C5C=C(C)C=CN5C4=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O NZCRJKRKKOLAOJ-XRCRFVBUSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 18
- 206010012735 Diarrhoea Diseases 0.000 claims description 17
- 229960003040 rifaximin Drugs 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 239000002552 dosage form Substances 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000003242 anti bacterial agent Substances 0.000 claims description 13
- 229910052740 iodine Inorganic materials 0.000 claims description 13
- 239000011630 iodine Substances 0.000 claims description 12
- 239000007800 oxidant agent Substances 0.000 claims description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 12
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 11
- 229930189077 Rifamycin Natural products 0.000 claims description 10
- 125000003282 alkyl amino group Chemical group 0.000 claims description 10
- 229960003292 rifamycin Drugs 0.000 claims description 10
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 10
- 208000011231 Crohn disease Diseases 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 125000001931 aliphatic group Chemical group 0.000 claims description 8
- 230000001590 oxidative effect Effects 0.000 claims description 8
- 229940088710 antibiotic agent Drugs 0.000 claims description 7
- 150000001555 benzenes Chemical group 0.000 claims description 7
- 235000015097 nutrients Nutrition 0.000 claims description 7
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 claims description 6
- 208000007386 hepatic encephalopathy Diseases 0.000 claims description 6
- 230000000968 intestinal effect Effects 0.000 claims description 6
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 claims description 6
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 6
- 229930193140 Neomycin Natural products 0.000 claims description 5
- 206010071061 Small intestinal bacterial overgrowth Diseases 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 150000002334 glycols Chemical class 0.000 claims description 5
- 239000004615 ingredient Substances 0.000 claims description 5
- 229960004927 neomycin Drugs 0.000 claims description 5
- 230000007142 small intestinal bacterial overgrowth Effects 0.000 claims description 5
- 235000010288 sodium nitrite Nutrition 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- ORLGLBZRQYOWNA-UHFFFAOYSA-N 4-methylpyridin-2-amine Chemical compound CC1=CC=NC(N)=C1 ORLGLBZRQYOWNA-UHFFFAOYSA-N 0.000 claims description 4
- 208000000668 Chronic Pancreatitis Diseases 0.000 claims description 4
- 206010033649 Pancreatitis chronic Diseases 0.000 claims description 4
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 4
- 229950011175 aminopicoline Drugs 0.000 claims description 4
- 206010009887 colitis Diseases 0.000 claims description 4
- 208000007784 diverticulitis Diseases 0.000 claims description 4
- 150000008282 halocarbons Chemical class 0.000 claims description 4
- 244000005700 microbiome Species 0.000 claims description 4
- SQTCRTQCPJICLD-KTQDUKAHSA-N rifamycin B Chemical class OC1=C(C(O)=C2C)C3=C(OCC(O)=O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O SQTCRTQCPJICLD-KTQDUKAHSA-N 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 125000005907 alkyl ester group Chemical group 0.000 claims description 3
- 229910001870 ammonium persulfate Inorganic materials 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 150000003930 2-aminopyridines Chemical class 0.000 claims description 2
- 208000004232 Enteritis Diseases 0.000 claims description 2
- 230000000813 microbial effect Effects 0.000 claims description 2
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 10
- 125000003545 alkoxy group Chemical group 0.000 abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 5
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract 1
- 238000011282 treatment Methods 0.000 description 39
- 239000004480 active ingredient Substances 0.000 description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000003814 drug Substances 0.000 description 21
- 208000035475 disorder Diseases 0.000 description 20
- 238000009472 formulation Methods 0.000 description 16
- 239000002904 solvent Substances 0.000 description 15
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 13
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
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Abstract
(式中、Rは水素又はアセチルであり;R1及びR2は、独立して、水素、(C1−4)アルキル、ベンジルオキシ、モノ−及びジ−(C1−3)アルキルアミノ−(C1−4)アルキル、(C1−3)アルコキシ、(C1−4)アルキル、ヒドロキシ−メチル、ヒドロキシ−(C2−4)−アルキル、及びニトロからなる群より選択されるか;あるいはR1及びR2は、ピリジン核の連続する2つの炭素原子とともに、任意に1つ又は2つのメチル又はエチル基によって置換されたベンゼン環を形成し;かつR3はヒドロキシアルキル(C1−4)である)を有する。さらに、これらの化合物を得るための方法が記載される。これらの化合物は抗菌性を有する。
【選択図】なし
Description
本発明は、医薬組成物の分野、特に炎症性腸疾患の治療のための経口処方物の分野にある。
リファキシミン(INN;メルクインデックス第13版(The Merck Index、XIII Ed.)、8304(非特許文献1)参照)はリファマイシン系に属する抗生物質であり、イタリア国特許IT 1154655(特許文献1)に記載され、特許請求されたピリド−イミダゾリファマイシンである。欧州特許EP 0161534(特許文献2)には、リファマイシンO(メルクインデックス第13版(The Merck Index、XIII Ed.)、8301(非特許文献2))を出発物質としてリファキシミンを製造する方法が記載されている。リファキシミンの多形体(polymorphic forms)を作製するための方法は、ヴィスコミ(Viscomi)らによる米国特許出願公開第2008−0262232号公報(特許文献3)に記載されており、この文献の全内容は、言及することにより本明細書に組み入れられる。
本明細書は、式Iの化合物を開示する。
R1及びR2は、各々独立して、水素、(C1−4)アルキル、ベンジルオキシ、モノ−又はジ−(C1−3)アルキルアミノ(C1−4)アルキル、(C1−3)アルコキシ−(C1−4)アルキル、ヒドロキシ−メチル、ヒドロキシ−(C2−4)−アルキル及びニトロからなる群より選択されるか;あるいはR1及びR2は、ピリジン環の連続する(又は隣り合う)2つの炭素原子とともに、無置換のベンゼン環又は1つもしくは2つのメチルもしくはエチル基によって置換された一もしくは二置換のベンゼン環を形成し;かつ
R3はヒドロキシアルキル(C1−4)である。
リファマイシンB誘導体の産生に適した微生物水溶液と栄養剤とを含む生物学的培養菌(biological culture)を得る工程;並びに
得られた培養菌を酸化剤で酸化する工程
を含む。
と、式IIIの化合物:
とを、有機溶媒、1より多い有機溶媒の混合物又は有機溶媒と水との混合物の存在下、雰囲気温度(又は室温)(ambient temperature)〜60℃の温度で1〜100時間反応させる工程を含む。
一態様において、本明細書は、式I:
R1及びR2は、各々独立して、水素、(C1−4)アルキル、ベンジルオキシ、モノ−及びジ−(C1−3)アルキルアミノ−(C1−4)アルキル、(C1−3)アルコキシ、(C1−4)アルキル、ヒドロキシ−メチル、ヒドロキシ−(C2−4)アルキル及びニトロからなる群より選択されるか;あるいはR1及びR2は、ピリジン環の連続する2つの炭素原子とともにベンゼン環を形成し、ここで、ベンゼン環は無置換であるか、メチルもしくはエチルによって一置換もしくは二置換され;かつ
R3は(C1−4)ヒドロキシアルキルである)
のリファマイシン誘導体を開示する。
式IIの化合物は、酸化剤(亜硝酸ナトリウム、重クロム酸カリウム、過硫酸アンモニウム、過ヨウ素酸ナトリウムなど)の存在下、ストレプトマイセス・メディテラネイ(Streptomyces mediterranei)又はノカルディア・メディテラネア(Nocardia mediterranea)などの微生物の適切な生物学的培養菌から得てもよい。一般に、式IIの化合物(特に、R1がHであり、R2がメチルであり、Rがアセチルであり、かつR3がヒドロキシメチルである場合)は、上記生物学的培養菌から得られた混合物の精製方法によって得ることができる。精製技術は、例えば、クロマトグラフィ、結晶化及び有機溶媒抽出であってもよい。得られた化合物を同定するため及び特徴付けるために有用な分析技術は、1H−NMR、IR分光法、EIMS分光分析法及びクロマトグラフィ(HPLC)である。得られた式IIの化合物は、適切な溶媒系中で過剰モル量の式IIIの選択されたアミノ−ピリジン誘導体と反応させることができ、当業者に公知の技術を用いて、式Iの所望の最終生成化合物を回収する。過剰モル量は、約2〜約8又はそれ以上の当量まで様々であり、当量は、式IIの化合物に基づいて計算される。
(12’Z,14’E,24’E)−5’,17’,19’−トリヒドロキシ−12’−(ヒドロキシ−メチル)−23’−メトキシ−2’,4’,16’,18’,20’,22’−ヘキサメチル−1’,4,6’11’テトラ−オキソ−1’,2’−ジヒドロ−6’H−スピロ[1,3−ジオキソラン−2,9’−[2,7]エポキシペンタデカ[1,11,13]トリエノイミノ)ナフト[2,1−b]フラン]−21’−イル=アセテート(アセタート(acetate))の合成
この実施例は、Rがアセチルであり、R1が水素であり、R2がp−メチルであり、かつR3がヒドロキシメチルである式IIの化合物を作製するための一つの方法を提供する。
(16Z,18E,28E)−25−(アセチルオキシ)−5,21,23−トリヒドロキシ−16−(ヒドロキシメチル)−27−メトキシ−2,4,11,20,22,24,26−ヘプタメチル−1,15−ジオキソ−1,13−ジヒドロ−2H−2,7−(エポキシペンタデカ[1,11,13]トリエノイミノ)フロ[2’’,3’’:7’,8’]ナフト[1’,2’:4,5]イミダゾ[1,2−a]ピリジン−8−イウム−6−オラート(olate)の合成
この化合物は、Rがアセチルであり、R1が水素であり、R2がp−メチルであり、かつR3がヒドロキシメチルである式Iの化合物である。
病原菌のインビトロ(in vitro)増殖を阻害できる活性物質の最小濃度(MIC)
病原菌のインビトロ(in vitro)増殖を阻害できる活性物質の最小濃度(MIC)を、National Committee for Clinical Laboratory Standards NCCLS, 2003に記載される微量希釈法によって測定し、E.coli(ATCC 25922)、P.aeruginosa(ATCC 27853)、S.aureus (ATCC 29213)、E.faecalis(ATCC 29212)を、対照基準(control standard)として挿入した。
細菌感染における(16Z,18E,28E)−25−(アセチルオキシ)−5,21,23−トリヒドロキシ−16−(ヒドロキシメチル)−27−メトキシ−2,4,11,20,22,24,26−ヘプタメチル−1,15−ジオキソ−1,13−ジヒドロ−2H−2,7−(エポキシペンタデカ[1,11,13]トリエノイミノ)フロ[2’’,3’’:7’,8’]の使用
細菌感染している患者を同定する。(16Z,18E,28E)−25−(アセチルオキシ)−5,21,23−トリヒドロキシ−16−(ヒドロキシメチル)−27−メトキシ−2,4,11,20,22,24,26−ヘプタメチル−1,15−ジオキソ−1,13−ジヒドロ−2H−2,7−(エポキシペンタデカ[1,11,13]トリエノイミノ)フロ[2’’,3’’:7’,8’]ナフト[1’,2’:4,5]イミダゾ[1,2−a]ピリジン−8−イウム−6−オラート(Rがアセチルであり、R1が水素であり、R2がメチルであり、かつR3がヒドロキシメチルである化合物I)を含む医薬処方物をこの患者に投与する。上記の処方物を用いる10日の治療クールの後、患者の細菌感染レベルは低減する。
式Iの誘導体の合成
式Iの別の化合物を、以下の方法に従って合成する。特に、この方法を使用して、Rがアセチルであり、R1が(C1−4)アルキル、ベンジルオキシ、モノ−及びジ−(C1−3)アルキルアミノ(C1−4)アルキル、(C1−3)アルコキシ−(C1−4)アルキル、ヒドロキシ−メチル、ヒドロキシ−(C2−4)−アルキル、及びニトロのうちの一つであり、R2が(C1−4)アルキル、ベンジルオキシ、モノ−及びジ−(C1−3)アルキルアミノ(C1−4)アルキル、(C1−3)アルコキシ−(C1−4)アルキル、ヒドロキシ−メチル、ヒドロキシ−(C2−4)−アルキル、及びニトロのうちの一つであるか、あるいはR1及びR2が、ピリジン核の連続する2つの炭素原子とともに、無置換のベンゼン環又はメチルもしくはエチルによって置換された一もしくは二置換のベンゼン環を形成し、かつR3がヒドロキシエチル、ヒドロキシプロピル又はヒドロキシブチルのうちの一つである式Iの化合物を調製する。
式Iの誘導体の合成
式Iの別の化合物を、以下の方法に従って製造する。特に、この方法を使用して、Rがアセチルであり、R1が(C1−4)アルキル、ベンジルオキシ、モノ−及びジ−(C1−3)アルキルアミノ(C1−4)アルキル、(C1−3)アルコキシ−(C1−4)アルキル、ヒドロキシ−メチル、ヒドロキシ−(C2−4)−アルキル及びニトロのうちの一つであり、R2が(C1−4)アルキル、ベンジルオキシ、モノ−及びジ−(C1−3)アルキルアミノ(C1−4)アルキル、(C1−3)アルコキシ−(C1−4)アルキル、ヒドロキシ−メチル、ヒドロキシ−(C2−4)−アルキル及びニトロのうちの一つであるか、あるいはR1及びR2が、ピリジン核の連続する2つの炭素原子とともに、無置換のベンゼン環又はメチルもしくはエチルによって置換された一もしくは二置換のベンゼン環を形成し、かつR3がヒドロキシエチル、ヒドロキシプロピル又はヒドロキシブチルのうちの一つである式Iの化合物を調製する。
Claims (22)
- Rがアセチル基であり、R1及びR2が独立して水素又はメチルであり、かつR3がヒドロキシアルキル(C1−4)である請求項1記載の化合物。
- Rがアセチル基であり、R1が水素であり、R2がp−メチルであり、かつR3がヒドロキシメチルであり、(16Z,18E,28E)−25−(アセチルオキシ)−5,21,23−トリヒドロキシ−16−(ヒドロキシメチル)−27−メトキシ−2,4,11,20,22,24,26−ヘプタメチル−1,15−ジオキソ−1,13−ジヒドロ−2H−2,7−(エポキシペンタデカ[1,11,13]トリエノイミノ)フロ[2’’,3’’:7’,8’]ナフト[1’,2’:4,5]イミダゾ[1,2−a]ピリジン−8−イウム−6−オラートと命名される請求項2記載の化合物。
- 酸化剤が、亜硝酸ナトリウム、重クロム酸カリウム水溶液、過硫酸アンモニウム又は過ヨウ素酸ナトリウムの1又は複数から選択される請求項4記載の方法。
- Rが水素又はアセチルであり、かつR3がヒドロキシアルキル(C1−4)である請求項4記載の方法。
- Rがアセチルであり、かつR3がヒドロキシメチルである請求項6記載の方法。
- 請求項1記載の化合物を合成するための方法であって、式IIの化合物:
と式IIIの化合物:
とを、有機溶媒、1より多い有機溶媒の混合物又は有機溶媒と水との混合物の存在下、雰囲気温度〜60℃の温度で1〜100時間反応させる工程を含む方法。 - 有機溶媒が、芳香族炭化水素類、脂肪族アルカノール、ハロゲン化炭化水素類、低級脂肪族酸の低級アルキルエステル、グリコール類、アセトニトリル、ジオキサン、テトラヒドロフラン及びこれらの組み合わせからなる群より選択されるか、又は種々の体積比での水との混合物である請求項8記載の方法。
- 約0.1〜約1モル当量のヨウ素又はヨウ素/酸化剤の組み合わせが、それぞれモル当量の式IIの化合物に対して用いられる請求項8記載の方法。
- 式IIIの化合物が2−アミノ−4−メチル−ピリジンである請求項8記載の方法。
- 請求項1記載の化合物を合成するための方法であって、
水溶液中でリファマイシンB誘導体の産生に適した微生物及び栄養剤を含む生物学的培養菌を得る工程;
得られた培養菌を酸化剤で酸化して酸化生成物を得る工程;並びに
前記酸化生成物と2−アミノ−ピリジン誘導体とを反応させる工程
を含む方法。 - 治療的に効果のある量の式Iの化合物と1又は複数の薬学的に許容可能な成分とを組み合わせて含む医薬組成物。
- 抗菌剤としての使用のための請求項13記載の医薬組成物。
- 1もしくは複数の式Iの化合物又は1もしくは複数の式Iの化合物と1もしくは複数の式IIの化合物との組み合わせ、及び
薬学的に許容可能な賦形剤
を含む医薬組成物。 - 組成物が、単回投与形態であるか、又は分離投与形態(separate dosage form)である請求項15記載の医薬組成物。
- さらに、リファマイシン誘導体又はネオマイシンを含む請求項15記載の医薬組成物。
- リファマイシン誘導体がリファキシミンである請求項17記載の医薬組成物。
- 式Iの化合物が、リファキシミンに対して約0.01〜100%(w/w)の比である請求項18記載の医薬組成物。
- 腸関連障害の患者における細菌過剰増殖(bacterial overgrowth)を治療、予防又は緩和する方法において、任意に1又は複数のさらなる抗生物質とともに使用する請求項15記載の医薬組成物。
- 1又は複数のさらなる抗生物質が、リファマイシン、リファキシミン又はネオマイシンの1又は複数を含む請求項20記載の使用のための医薬組成物。
- 腸関連障害が、過敏性腸症候群、旅行者下痢症、小腸細菌過剰増殖、クローン病、慢性膵炎、膵不全、肝性脳症、憩室炎、腸炎又は大腸炎の1又は複数である請求項20記載の使用のための医薬組成物。
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JP2017515821A (ja) * | 2014-05-12 | 2017-06-15 | アルファ ワッセルマン ソシエタ ペル アチオニAlfa Wassermann S.P.A. | リファキシミンの新規溶媒和物結晶形、生成物、組成物及びそれらの使用 |
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SI1698630T1 (sl) | 2005-03-03 | 2015-01-30 | Alfa Wassermann S.P.A. | Nove polimorfne oblike rifaksimina, postopki za njihovo pripravo in njihova uporaba v medicinskih pripravkih |
ITBO20050123A1 (it) | 2005-03-07 | 2005-06-06 | Alfa Wassermann Spa | Formulazioni farmaceutiche gastroresistenti contenenti rifaximina |
IT1398550B1 (it) | 2010-03-05 | 2013-03-01 | Alfa Wassermann Spa | Formulazioni comprendenti rifaximina utili per ottenere un effetto prolungato nel tempo |
ITBO20110461A1 (it) | 2011-07-29 | 2013-01-30 | Alfa Wassermann Spa | Composizioni farmaceutiche comprendenti rifaximina, processi per la loro preparazione e loro uso nel trattamento di infezioni vaginali. |
ITBO20120368A1 (it) | 2012-07-06 | 2014-01-07 | Alfa Wassermann Spa | Composizioni comprendenti rifaximina e amminoacidi, cristalli di rifaximina derivanti da tali composizioni e loro uso. |
CA2886264A1 (en) * | 2012-09-12 | 2014-03-20 | Salix Pharmaceuticals, Inc. | Methods of administering rifaximin without producing antibiotic resistance |
CN103709177B (zh) * | 2013-12-20 | 2016-02-24 | 武汉工程大学 | 利福霉素类沃尼妙林杂合抗生素及其制备方法 |
HUE054832T2 (hu) | 2017-06-26 | 2021-10-28 | Biofer Spa | Pirido-imidazo rifamicinszármazékok baktériumellenes szerként |
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IT1154655B (it) | 1980-05-22 | 1987-01-21 | Alfa Farmaceutici Spa | Derivati imidazo-rifamicinici metodi per la loro preparazione e loro uso come sostanza ad azione antibatterica |
US7923553B2 (en) | 2003-11-07 | 2011-04-12 | Alfa Wassermann, S.P.A. | Processes for the production of polymorphic forms of rifaximin |
ITMI20032144A1 (it) | 2003-11-07 | 2005-05-08 | Alfa Wassermann Spa | Forme polimorfe di rifaximina, processi per ottenerle e |
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JP2017515821A (ja) * | 2014-05-12 | 2017-06-15 | アルファ ワッセルマン ソシエタ ペル アチオニAlfa Wassermann S.P.A. | リファキシミンの新規溶媒和物結晶形、生成物、組成物及びそれらの使用 |
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