JP2010138182A - アミノアルキルテトラサイクリン化合物の合成方法および精製方法 - Google Patents
アミノアルキルテトラサイクリン化合物の合成方法および精製方法 Download PDFInfo
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- JP2010138182A JP2010138182A JP2010035276A JP2010035276A JP2010138182A JP 2010138182 A JP2010138182 A JP 2010138182A JP 2010035276 A JP2010035276 A JP 2010035276A JP 2010035276 A JP2010035276 A JP 2010035276A JP 2010138182 A JP2010138182 A JP 2010138182A
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- Prior art keywords
- compound
- tetracycline
- alkyl
- alkylaminomethylminocycline
- item
- Prior art date
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- -1 aminoalkyl tetracycline compound Chemical class 0.000 title claims abstract description 209
- 239000004098 Tetracycline Substances 0.000 title claims abstract description 168
- 235000019364 tetracycline Nutrition 0.000 title claims abstract description 168
- 229960002180 tetracycline Drugs 0.000 title claims abstract description 166
- 229930101283 tetracycline Natural products 0.000 title claims abstract description 166
- 238000000034 method Methods 0.000 title claims abstract description 162
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 144
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000002253 acid Substances 0.000 claims abstract description 21
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 15
- MNSGOOCAMMSKGI-UHFFFAOYSA-N N-(hydroxymethyl)phthalimide Chemical compound C1=CC=C2C(=O)N(CO)C(=O)C2=C1 MNSGOOCAMMSKGI-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000002516 radical scavenger Substances 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 59
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- 125000000304 alkynyl group Chemical group 0.000 claims description 39
- 125000003342 alkenyl group Chemical group 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 33
- 239000007864 aqueous solution Substances 0.000 claims description 31
- 239000001257 hydrogen Substances 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 229960004023 minocycline Drugs 0.000 claims description 29
- 239000000047 product Substances 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 239000012535 impurity Substances 0.000 claims description 20
- 239000006227 byproduct Substances 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 18
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 239000010410 layer Substances 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 15
- 238000010525 oxidative degradation reaction Methods 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- 239000007857 degradation product Substances 0.000 claims description 13
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- 239000003963 antioxidant agent Substances 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 125000002252 acyl group Chemical group 0.000 claims description 11
- 150000001299 aldehydes Chemical class 0.000 claims description 9
- 125000005233 alkylalcohol group Chemical group 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
- 239000012044 organic layer Substances 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
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- 229940098779 methanesulfonic acid Drugs 0.000 claims description 5
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 4
- 230000003078 antioxidant effect Effects 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical group CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 235000010265 sodium sulphite Nutrition 0.000 claims description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 4
- PQUCIEFHOVEZAU-UHFFFAOYSA-N Diammonium sulfite Chemical group [NH4+].[NH4+].[O-]S([O-])=O PQUCIEFHOVEZAU-UHFFFAOYSA-N 0.000 claims description 3
- 239000007983 Tris buffer Substances 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical group CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 150000003141 primary amines Chemical class 0.000 claims description 2
- 150000003335 secondary amines Chemical class 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
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Abstract
【解決手段】 上記方法は、第1の適切な条件下、水捕捉剤および酸の存在下でテトラサイクリン化合物をN−ヒドロキシメチル−フタルイミドと接触させ、第1のアミノメチルテトラサイクリン中間体を形成すること、第2の適切な条件下で該第1のアミノメチルテトラサイクリン中間体をメチルアミンで処理し、第2のアミノメチルテトラサイクリン中間体を形成すること、ならびに適切な水素化条件下で該第2のアミノメチルテトラサイクリン中間体を処理し、該アミノメチルテトラサイクリン化合物を形成することを含む。
【選択図】 なし
Description
本出願は、2007年4月27日に出願された米国仮特許出願第60/926,461号に対する優先権を主張し、この全内容は、本明細書中に参考として援用される。
テトラサイクリン抗生物質の開発は、殺菌性組成物および/または静菌性組成物を産生することができる微生物の証拠を求めて世界中の多数の地方から集められた土壌試料の組織的なスクリーニングの直接の成果であった。これらの新規な化合物の最初のものは1948年にクロルテトラサイクリンという名称で導入された。2年後、オキシテトラサイクリンが手に入るようになった。これらの化合物の化学構造の解明がそれらの類似性を確認し、1952年のこのグループの第3のメンバー(テトラサイクリン)の生産のための解析の基礎を提供した。1957年には初期のテトラサイクリン中に存在していた環に結合したメチル基のない新しい種類のテトラサイクリン化合物が調製され、1967年に一般に入手可能となった。1972年までにはミノサイクリンが使用に供された。
一実施態様では、本発明は、少なくとも部分的に、アミノアルキルテトラサイクリン化合物を合成する方法に関する。この方法は、アミノメチルテトラサイクリン中間体化合物が形成されるように、適切な条件下、水捕捉剤および酸の存在下でテトラサイクリン化合物をN−ヒドロキシメチル−フタルイミドと接触させることを含む。
したがって、本発明は、以下の項目を提供する:
(項目1)
アミノアルキルテトラサイクリン化合物を合成する方法であって、
アミノメチルテトラサイクリン中間体化合物が形成されるように、適切な条件下、水捕捉剤および酸の存在下でテトラサイクリン化合物をN−ヒドロキシメチル−フタルイミドと接触させること
を含む方法。
(項目2)
上記テトラサイクリン化合物は、ミノサイクリンである、項目1に記載の方法。
(項目3)
上記N−ヒドロキシメチルフタルイミドは、下式
R1およびR2は、それぞれ、水素、アルキル、ハロゲン、アルケニル、アルキニル、アリール、シアノ、アミノ、アミジノ、アルコキシおよびアシルである
のものである、項目1に記載の方法。
(項目4)
上記適切な条件は、約20〜25Cの反応温度である、項目1に記載の方法。
(項目5)
上記水捕捉剤は、酸塩化物または酸無水物である、項目1に記載の方法。
(項目6)
上記酸無水物は、メチルスルホン酸無水物である、項目5に記載の方法。
(項目7)
上記酸は、トリフルオロメタンスルホン酸またはメタンスルホン酸である、項目1に記載の方法。
(項目8)
上記アミノメチルテトラサイクリン中間体は、10%を超えてトリスアルキル化されていない、項目1に記載の方法。
(項目9)
上記アミノメチルテトラサイクリン中間体は、さらにアセトン中に溶解されている、項目1に記載の方法。
(項目10)
第2の適切な条件下で上記アミノメチルテトラサイクリン中間体をメチルアミンで処理することをさらに含む、項目1に記載の方法。
(項目11)
上記第2の適切な条件は、アルキルアルコールおよびアルキルエーテルを含む、項目9に記載の方法。
(項目12)
上記第2の適切な条件は、不活性雰囲気を含む、項目11に記載の方法。
(項目13)
第2の適切な条件下で上記アミノメチルテトラサイクリン中間体をメチルアミンで処理した後、第2のアミノメチルテトラサイクリン中間体が形成される、項目10に記載の方法。
(項目14)
上記第2のアミノメチルテトラサイクリン中間体は、上記第2のアミノメチルテトラサイクリン中間体の塩酸塩の形成によって精製される、項目13に記載の方法。
(項目15)
上記塩酸塩は、アルキルアルコール中で形成された後、アルキルエーテルによって沈殿させられる、項目14に記載の方法。
(項目16)
アミノアルキルテトラサイクリン化合物の合成のための方法であって、
適切な条件下、水捕捉剤および酸の存在下でテトラサイクリン化合物をN−ヒドロキシメチル−フタルイミドと接触させてアミノメチルテトラサイクリン中間化合物を形成させること、
第2の適切な条件下で上記アミノメチルテトラサイクリン中間化合物をメチルアミンで処理して第2のアミノメチルテトラサイクリン中間体を形成させること、
アミノメチルテトラサイクリン化合物が形成されるように、適切な水素化条件下で上記第2のアミノメチルテトラサイクリン中間体を処理すること
を含む方法。
(項目17)
上記テトラサイクリン化合物は、ミノサイクリンである、項目15に記載の方法。
(項目18)
置換アミノメチルテトラサイクリン化合物が形成されるように、適切な条件下で上記アミノメチルテトラサイクリン化合物をアルデヒドまたはケトンと接触させることをさらに含む、項目16または17に記載の方法。
(項目19)
上記水素化条件は、Pd/CまたはPd/C/S触媒を含む、項目16から18のいずれか1つに記載の方法。
(項目20)
上記水素化条件は、メタノールおよびアルデヒドを含む、項目16から19のいずれか1つに記載の方法。
(項目21)
上記適切な条件は、水素気体を含む、項目16から20のいずれか1つに記載の方法。
(項目22)
上記置換アミノメチルテトラサイクリン化合物は、過剰に水素化された不純物を実質的に含まないで形成される、項目16から21のいずれか1つに記載の方法。
(項目23)
上記置換アミノメチルテトラサイクリン化合物は、10%未満のβ異性体を含む、項目16から22のいずれか1つに記載の方法。
(項目24)
上記置換アミノメチルテトラサイクリン化合物は、約5%未満のβ異性体を含む、項目23に記載の方法。
(項目25)
上記アミノアルキルテトラサイクリン化合物は、
である、項目1から24のいずれか1つに記載の方法。
(項目26)
RBは水素である、項目25に記載の方法。
(項目27)
RAはアルキルである、項目25または26に記載の方法。
(項目28)
RAは(CH3)3CCH2−である、項目25から27のいずれか1つに記載の方法。
(項目29)
上記アミノアルキルテトラサイクリン化合物は、
(項目30)
アルキルアミノメチルミノサイクリン化合物を精製する方法であって、上記アルキルアミノメチルミノサイクリン化合物が精製されるように、上記化合物の低pH水溶液を極性有機溶媒グラジエントのHPLC中に注入し、上記生成物画分を一緒にすることを含む方法。
(項目31)
上記低pH溶液は、約2〜3のpHを有する、項目30に記載の方法。
(項目32)
上記低pH溶液は、メチルスルホン酸を含む、項目31に記載の方法。
(項目33)
上記極性有機溶媒は、アセトニトリルである、項目30に記載の方法。
(項目34)
上記アルキルアミノメチルミノサイクリン化合物は、エピマーおよび副生物から精製される、項目30に記載の方法。
(項目35)
上記一緒にされた生成物画分のpHを約4.0〜4.5に調節するステップをさらに含む、項目30に記載の方法。
(項目36)
上記生成物画分を非極性有機溶媒で洗浄すること、および有機層を廃棄し、水層を保持することをさらに含む、項目35に記載の方法。
(項目37)
上記非極性有機溶媒は、塩化メチレンである、項目36に記載の方法。
(項目38)
上記有機層は、上記ミノサイクリン化合物の疎水性不純物および酸化的分解物を含む、項目36に記載の方法。
(項目39)
上記pHが約7.5から8.5の間になって中性溶液を形成するように上記水層に塩基が加えられる、項目46に記載の方法。
(項目40)
上記中性溶液は非極性有機溶媒で洗浄され、上記ミノサイクリン化合物は上記有機溶媒中に溶解される、項目39に記載の方法。
(項目41)
上記非極性有機溶媒は、塩化メチレンである、項目40に記載の方法。
(項目42)
上記ミノサイクリン化合物のβエピマーおよび副生物は、上記中性水溶液中に保持される、項目40に記載の方法。
(項目43)
上記水溶液または画分に酸化防止剤が加えられる、項目30から42のいずれか1つに記載の方法。
(項目44)
上記酸化防止剤は、亜硫酸アンモニウムである、項目43に記載の方法。
(項目45)
アルキルアミノメチルミノサイクリン化合物から疎水性不純物および酸化的分解物を除去する方法であって、上記ミノサイクリン化合物を4.0〜4.5のpHの水溶液中に溶解すること、上記水溶液を非極性有機溶媒で洗浄すること、および上記アルキルアミノメチルミノサイクリン化合物から疎水性不純物および酸化分解物が除去されるように、上記非極性有機溶媒を廃棄し、上記水溶液を保持することを含む方法。
(項目46)
上記非極性有機溶媒は、塩化メチレンである、項目45に記載の方法。
(項目47)
アルキルアミノメチルミノサイクリン化合物からβエピマーおよび副生物を除去する方法であって、上記ミノサイクリン化合物を7.5〜8.5のpHの水溶液中に溶解すること、上記水溶液を非極性有機溶媒で洗浄すること、および上記アルキルアミノメチルミノサイクリン化合物からβエピマーおよび副生物が除去されるように、上記水溶液を廃棄し、上記無極性有機溶液を保持することを含む方法。
(項目48)
上記非極性有機溶媒は塩化メチレンである、項目47に記載の方法。
(項目49)
上記アルキルアミノメチルミノサイクリン化合物は、
である、項目30から48のいずれか1つに記載の方法。
(項目50)
RBは水素である、項目49に記載の方法。
(項目51)
RAはアルキルである、項目49または50に記載の方法。
(項目52)
RAは(CH3)3CCH2−である、項目49から51のいずれか1つに記載の方法。
(項目53)
上記アルキルアミノメチルミノサイクリン化合物は、
(項目54)
項目1から53のいずれか1つの方法によって合成されるかまたは精製されたテトラサイクリン化合物および薬学的に許容されるキャリアを含む医薬品組成物。
(項目55)
対象におけるテトラサイクリン応答性状態を治療するための方法であって、項目1から29のいずれか1つに記載の方法によって合成されるかまたは精製されたアミノアルキルテトラサイクリン化合物の有効な量を、上記テトラサイクリン応答性状態が治療されるように、上記対象に投与することを含む方法。
(項目56)
対象におけるテトラサイクリン応答性状態を治療するための方法であって、項目30から53のいずれか1つに記載の方法によって合成されるかまたは精製されたアルキルアミノメチルミノサイクリン化合物の有効な量を、上記テトラサイクリン応答性状態が治療されるように、上記対象に投与することを含む方法。
1. アミノ−メチルテトラサイクリン化合物を合成するための方法
実施態様において、本発明は、低い4−β−エピマー含有率を有する4−α−9−アミノメチルテトラサイクリンの改善された合成に関する。C−4位におけるテトラサイクリン化合物のエピマー化は、新しいテトラサイクリン誘導体を合成するように取り組んでいる化学者にとって難問であった。
Xは、CHC(R13Y’Y)、CR6’R6、S、NR6またはOであり、
R2、R2’、R4’およびR4”は、それぞれ独立に、水素、アルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノ、アリールアルキル、アリール、複素環、ヘテロ芳香族またはプロドラッグ部分であり、
R3、R11およびR12は、それぞれ、水素またはプロドラッグ部分であり、
R10は、水素、プロドラッグ部分であるかまたはR9と結合して環を形成し、
R5は、ヒドロキシル、水素、チオール、アルカノイル、アロイル、アルカロイル、アリール、ヘテロ芳香族、アルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノ、アリールアルキル、アルキルカルボニルオキシまたはアリールカルボニルオキシであり、
R6およびR6’は、それぞれ独立に、水素、メチレン、存在しない、ヒドロキシル、ハロゲン、チオール、アルキル、アルケニル、アルキニル、アリール、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノまたはアリールアルキルであり、
R7は、水素、ハロゲン、ニトロ、アルキル、アルケニル、複素環、アシル、アルキニル、アリール、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アリールアルキル、アミノ、アリールアルケニル、アリールアルキニルまたは−(CH2)0〜3(NR7c)0〜1C(=W’)WR7aであり、
R9は、水素であり、
Wは、CR7dR7e、S、NR7bまたはOであり、
W’は、O、NR7fSであり、
R7a、R7b、R7c、R7d、R7eおよびR7fは、それぞれ独立に、水素、アシル、アルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノ、アリールアルキル、アリール、複素環、ヘテロ芳香族またはプロドラッグ部分であり、
R8は、水素、ヒドロキシル、ハロゲン、チオール、アルキル、アルケニル、アルキニル、アリール、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノまたはアリールアルキルであり、
R13は、水素、ヒドロキシ、アルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノまたはアリールアルキルであり、
Y’およびYは、それぞれ独立に、水素、ハロゲン、ヒドロキシル、シアノ、スルフヒドリル、アミノ、アルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノまたはアリールアルキルである、の化合物およびその薬学的に許容される塩も含む。
R1およびR2は、それぞれ、水素、アルキル、ハロゲン、アルケニル、アルキニル、アリール、シアノ、アミノ、アミジノ、アルコキシおよびアシルである。さらに別の実施態様では、R1およびR2は、それぞれ、アルキルまたは水素である。
別の実施態様では、本発明は、9−アルキルアミノメチルテトラサイクリン(または本方法によって精製することができる任意のテトラサイクリン化合物)を不純物、β−エピマーおよび副生物から精製する方法に関する。
用語「エステル」は、カルボニル基の炭素に結合している酸素原子に結合している炭素またはヘテロ原子を含む化合物および部分を含む。用語「エステル」は、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、ブトキシカルボニル、ペントキシカルボニル等などのアルコキシカルボニル基を含む。アルキル、アルケニルまたはアルキニル基は、上記に定義されているとおりである。
さらに別の実施態様では、本発明は、本発明のテトラサイクリン化合物(例えば、本発明の方法によって合成されるかまたは精製された)またはその薬学的に許容される塩、プロドラッグまたはエステルを含む医薬品組成物に関する。医薬品組成物は、薬学的に許容されるキャリアを含んでよい。
本発明は、対象におけるテトラサイクリン応答性状態を、本発明の方法によって合成され、および/または精製されたテトラサイクリン化合物あるいは薬学的に許容されるその塩の有効な量を、該状態が治療されるように対象に投与することによって治療するための方法に関する。
本発明の実施例
9−アルキルアミノメチルミノサイクリンの合成
9−アルキルアミノメチルミノサイクリン化合物の単離および精製
粗製9−(2’,2’−ジメチルプロピルアミノメチル)ミノサイクリン遊離塩基(40g)が150mLの緩衝液A(メタンスルホン酸MSAの0.1%水溶液)に溶解され、pHはMSAで2〜3に調節された。
当業者は、本明細書に記載されている特定の実施態様および方法への多くの均等物を認識し、または日常的な程度の実験を用いて確認することができる。そのような均等物は、以下の請求項の範囲によって包含されるものとされる。
Claims (51)
- 式:
第1の適切な条件下、水捕捉剤および酸の存在下でテトラサイクリン化合物をN−ヒドロキシメチル−フタルイミドと接触させ、第1のアミノメチルテトラサイクリン中間体を形成すること
第2の適切な条件下で該第1のアミノメチルテトラサイクリン中間体をメチルアミンで処理し、第2のアミノメチルテトラサイクリン中間体を形成すること、ならびに
適切な水素化条件下で該第2のアミノメチルテトラサイクリン中間体を処理し、該アミノメチルテトラサイクリン化合物を形成すること
を含み、
ここで、該N−ヒドロキシメチルフタルイミドは、下式:
R1およびR2は、それぞれ独立して、水素、アルキル、ハロゲン、アルケニル、アルキニル、アリール、シアノ、アミノ、アミジノ、アルコキシまたはアシルであり、
RAは、アルキルであり、そしてRBは、水素またはアルキルである、
方法。 - R B が、水素である、請求項1に記載の方法。
- R A が、(CH 3 ) 3 CCH 2 −である、請求項1に記載の方法。
- 前記置換アミノメチルテトラサイクリン化合物が、
- 前記第1の適切な条件は、20〜35℃の反応温度を含む、請求項1に記載の方法。
- 前記水捕捉剤は、酸塩化物または酸無水物である、請求項1に記載の方法。
- 前記酸無水物は、メチルスルホン酸無水物である、請求項6に記載の方法。
- 前記酸は、トリフルオロメタンスルホン酸またはメタンスルホン酸である、請求項1に記載の方法。
- 前記第1のアミノメチルテトラサイクリン中間体は、10%を超えてトリスアルキル化されていない、請求項1に記載の方法。
- 前記第1のアミノメチルテトラサイクリン中間体は、アセトン中に溶解されている、請求項1に記載の方法。
- 前記第2の適切な条件は、アルキルアルコールおよびアルキルエーテルを含む、請求項1に記載の方法。
- 前記第2の適切な条件は、不活性雰囲気を含む、請求項1に記載の方法。
- 前記第2のアミノメチルテトラサイクリン中間体の塩酸塩を形成することによって、該第2のアミノメチルテトラサイクリン中間体を精製することをさらに含む、請求項1に記載の方法。
- 前記塩酸塩は、アルキルアルコール中で形成された後、アルキルエーテルによって沈殿させられる、請求項13に記載の方法。
- 前記適切な水素化条件は、Pd/CまたはPd/C/S触媒を含む、請求項1に記載の方法。
- 前記適切な水素化条件は、メタノールおよびアルデヒドを含む、請求項1に記載の方法。
- 前記適切な水素化条件は、水素気体を含む、請求項1に記載の方法。
- 第3の適切な条件下で前記アミノメチルテトラサイクリン化合物をアルデヒドまたはケトンと接触させて、置換アミノメチルテトラサイクリン化合物を形成することをさらに含む、請求項1に記載の方法。
- 前記第3の適切な条件は、Pd/CまたはPd/C/S触媒を含む、請求項18に記載の方法。
- 前記第3の適切な条件は、メタノールおよびアルデヒドを含む、請求項18に記載の方法。
- 前記第3の適切な条件は、水素気体を含む、請求項18に記載の方法。
- 前記置換アミノメチルテトラサイクリン化合物は、過剰に水素化された不純物を実質的に含まないで形成される、請求項18に記載の方法。
- 前記置換アミノメチルテトラサイクリン化合物は、10%未満のβ異性体を含む、請求項18に記載の方法。
- 前記置換アミノメチルテトラサイクリン化合物は、約5%未満のβ異性体を含む、請求項23に記載の方法。
- アルキルアミノメチルミノサイクリン化合物を精製する方法であって、該方法は:
a)該アルキルアミノメチルミノサイクリン化合物の低pH水溶液を極性有機溶媒グラジエントの液体クロマトグラフィー装置中に注入し、生成物画分を一緒にする工程、
b)該生成物画分のpHを4.0〜4.5に調節する工程、
c)該生成物画分を第1の非極性有機溶媒で洗浄し、第1の有機層および第1の水層を形成し、そして該第1の有機層を廃棄する工程、
d)該第1の水層のpHを7.5〜8.5に調節する工程、ならびに
e)該アルキルアミノメチルミノサイクリン化合物が精製されるように、該第1の水層を第2の非極性有機溶媒で洗浄し、第2の有機層および第2の水層を形成し、そして該第2の水層を廃棄する工程、
を含み、
ここで、該アルキルアミノメチルミノサイクリン化合物が、下式:
RAは、アルキルであり、そしてRBは、水素またはアルキルである、
方法。 - R B が、水素である、請求項25に記載の方法。
- R A が、(CH 3 ) 3 CCH 2 −である、請求項26に記載の方法。
- 前記アルキルアミノメチルミノサイクリン化合物が、
- 前記低pH水溶液は、2〜3のpHを有する、請求項25に記載の方法。
- 前記低pH水溶液は、メチルスルホン酸を含む、請求項25に記載の方法。
- 前記極性有機溶媒は、アセトニトリルである、請求項25に記載の方法。
- 工程b)または工程d)における前記phは、塩基で調節される、請求項25に記載の方法。
- 前記塩基が、金属の水酸化物、金属の炭酸塩、金属の炭酸水素塩、アンモニア、有機第一アミン、有機第二アミンおよび有機第三アミンからなる群より選択される、請求項32に記載の方法。
- 前記金属が、リチウム、ナトリウム、カリウム、カルシウム、マグネシウムおよびアルミニウムからなる群より選択される、請求項33に記載の方法。
- 前記塩基が、水酸化ナトリウムまたはアンモニアである、請求項33に記載の方法。
- 前記第1の非極性有機溶媒は、塩化メチレンである、請求項25に記載の方法。
- 前記第1の有機層は、前記アルキルアミノメチルミノサイクリン化合物の副生物、疎水性不純物および酸化的分解物を含む、請求項25に記載の方法。
- 前記第2の非極性有機溶媒は、塩化メチレンである、請求項25に記載の方法。
- 前記第2の水層は、前記アルキルアミノメチルミノサイクリン化合物の副生物およびβエピマーを含む、請求項25に記載の方法。
- 工程a)の前記水溶液に酸化防止剤が加えられる、請求項25に記載の方法。
- 前記酸化防止剤は、亜硫酸アンモニウム、亜硫酸ナトリウム、重亜硫酸塩またはメタ重亜硫酸塩である、請求項40に記載の方法。
- 疎水性不純物および酸化的分解物が、前記アルキルアミノメチルミノサイクリン化合物から除去される、請求項25に記載の方法。
- 副生物およびβ−C−4エピマーが、前記アルキルアミノメチルミノサイクリン化合物から除去される、請求項25に記載の方法。
- 前記アルキルアミノメチルミノサイクリン化合物が、本質的に疎水性不純物および酸化的分解物を含まない、請求項25に記載の方法。
- 前記アルキルアミノメチルミノサイクリン化合物が、本質的に副生物、β−C−4エピマー、疎水性不純物および酸化的分解物を含まない、請求項25に記載の方法。
- 前記アルキルアミノメチルミノサイクリン化合物が、少なくとも50%のα−C−4エピマーを含む、請求項25に記載の方法。
- 前記アルキルアミノメチルミノサイクリン化合物が、少なくとも95%のα−C−4エピマーを含む、請求項46に記載の方法。
- 前記アルキルアミノメチルミノサイクリン化合物が、少なくとも99.9%のα−C−4エピマーを含む、請求項47に記載の方法。
- 前記アルキルアミノメチルミノサイクリン化合物が、7%未満のβ−C−4エピマーを含む、請求項25に記載の方法。
- 前記アルキルアミノメチルミノサイクリン化合物が、3%未満のβ−C−4エピマーを含む、請求項49に記載の方法。
- 請求項1に記載の方法によって合成されたかまたは請求項25に記載の方法によって精製されたアルキルアミノメチルミノサイクリン化合物および薬学的に許容されるキャリアを含む医薬品組成物。
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2008
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- 2008-04-28 AU AU2008246119A patent/AU2008246119A1/en not_active Abandoned
- 2008-04-28 US US12/110,627 patent/US9434680B2/en active Active
- 2008-04-28 WO PCT/US2008/005452 patent/WO2008134048A2/en active Application Filing
- 2008-04-28 EP EP08754132A patent/EP2144870A2/en not_active Withdrawn
- 2008-04-28 EP EP10152022A patent/EP2216323A3/en not_active Withdrawn
- 2008-04-28 EP EP10152023A patent/EP2213655A1/en not_active Withdrawn
- 2008-04-28 CA CA2688662A patent/CA2688662A1/en not_active Abandoned
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2009
- 2009-10-29 US US12/608,227 patent/US20100113401A1/en not_active Abandoned
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2010
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- 2010-02-23 AU AU2010200643A patent/AU2010200643A1/en not_active Abandoned
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2013
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2016
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Publication number | Publication date |
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EP2144870A2 (en) | 2010-01-20 |
US20100113401A1 (en) | 2010-05-06 |
WO2008134048A2 (en) | 2008-11-06 |
AU2010200643A1 (en) | 2010-03-11 |
AU2008246119A1 (en) | 2008-11-06 |
US20170158616A1 (en) | 2017-06-08 |
US20080287401A1 (en) | 2008-11-20 |
US20140031319A1 (en) | 2014-01-30 |
EP2216323A3 (en) | 2010-12-29 |
EP2216323A2 (en) | 2010-08-11 |
US9434680B2 (en) | 2016-09-06 |
US8946196B2 (en) | 2015-02-03 |
CA2688662A1 (en) | 2008-11-06 |
EP2213655A1 (en) | 2010-08-04 |
JP2010525069A (ja) | 2010-07-22 |
WO2008134048A3 (en) | 2009-06-04 |
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