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CN1649582A - 氨基－甲基取代的四环素类化合物 - Google Patents

氨基－甲基取代的四环素类化合物 Download PDF

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Publication number
CN1649582A
CN1649582A CNA038099799A CN03809979A CN1649582A CN 1649582 A CN1649582 A CN 1649582A CN A038099799 A CNA038099799 A CN A038099799A CN 03809979 A CN03809979 A CN 03809979A CN 1649582 A CN1649582 A CN 1649582A
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CN
China
Prior art keywords
alkyl
hydrogen
tetracycline compound
tetracycline
alkynyl
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CNA038099799A
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Inventor
M·L·内尔森
K·奥赫蒙
R·弗雷谢特
M·Y·伊斯迈尔
L·麦金太尔
T·鲍泽
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Paratek Pharmaceuticals Inc
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Paratek Pharmaceuticals Inc
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Publication of CN1649582A publication Critical patent/CN1649582A/zh
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
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Abstract

本发明涉及氨基甲基取代的四环素类化合物，其药物组合物，以及其应用。

Description

氨基-甲基取代的四环素类化合物
相关申请
本申请是以US专利系列申请，于2002，7，12提出的名为“氨基-甲基取代的四环素类化合物”的60/395,495，和2002，3，8提出的名为“9-氨基-甲基取代的米诺环素类化合物”的60/362,654为优选权。每个在先申请均全文引用于此作参考。
背景技术
四环素类抗生素的发展直接导致了在全世界许多地方收集的污物样本的系统筛选以证实微生物能够产生杀菌和/或抑菌的组合物。这些新化合物首先是在1948年引入，并取名为氯四环素。两年后，土霉素投入使用。这些化合物的化学结构证实了它们的相似性，并提供了分析的基础，以至在1952年得到了第三个成员，四环素。一类新的在初期四环素中不带有环连接的甲基基团的四环素类化合物家族在1 957年制备而成，并在1967年公开应用。
最近，研究主要集中于对于各种治疗状况有效的，并有各种给药途径的新的四环素类抗生素的发展。研究表明新的四环素类似物较之早期的四环素具有相同或更高的治疗效果。这样的实例包括在US专利3,957,980、3,674,859、2,980,584、2,990,331、3,062,717、3,557,280、4,018,889、4,024,272、4,126,680、3,454,697和3,165,531之中。这些化合物代表了具有药理活性的四环素及四环素类似物的组合物的范围。
从历史上看，随着四环素类早期的发展和引入，发现它们具有较高的对抗立克次体、部分革兰氏阳性菌和革兰氏阴性菌以及性病淋巴肉芽肿，包括结膜炎和鹦鹉热病的药理活性。由此，四环素成为“广谱”抗生素。随着后来的体外抗微生物活性的实验、抗实验性感染的效果以及药理学性质研究，四环素很快成为一类抗生素并广泛用于医学治疗中。然而，四环素对各种大病小病的广泛应用直接导致了这些抗生素耐药性的出现，甚至在高度敏感的共生菌和致病菌中(例如，肺炎双球菌和沙门氏菌)。四环素耐药生物体引起了四环素及四环素类似物的药物组合物作为抗生素应用的减退。
发明概述
在一个具体实施方式中，本发明是涉及一种如通式(I)的四环素类化合物：
Figure A0380997900111
其中，R1和R2形成环，或其药学上可接受的盐、前药及酯化物。
本发明还涉及，至少部分是以下通式的四环素类化合物：
Figure A0380997900112
或其药学上可接受的盐、酯化物或前药。
本发明还涉及，至少部分是通式(II)的四环素类化合物，其药学上可接受的盐、酯或前药：
Figure A0380997900113
其中，J1和J2各自独立为氢、芳基、磺酰基、酰基，或形成一个环，条件是至少J1或J2的一个不是氢；
J3和J4各自独立为烷基、卤素或氢；
X为CHC(R13Y’Y)、CR6’R6、C＝CR6’R6、S、NR6或O；
R2、R2’、R4’和R4”各自独立为氢、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基、芳烷基、芳基、杂环基、杂芳基或前药基团；
R4是NR4’R4”、烷基、链烯基、炔基、芳基、羟基、卤素或氢；
R2’、R3、R10、R11和R12分别为氢或前药基团；
R5是羟基、氢、巯基、烷酰基、芳酰基、烷芳酰基、芳基、杂芳基、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基、芳烷基、烷碳酰氧基或芳基碳酰氧基；
R6和R6’各自独立为氢、亚甲基、缺损、羟基、卤素、巯基、烷基、链烯基、炔基、芳基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基或芳烷基；
R9是氢、硝基、烷基、链烯基、炔基、芳基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、芳烷基、氨基、芳烯基、芳炔基、硫代亚硝基或(CH2)0-3NR9cC(＝Z’)ZR9a；
Z是CR9dR9e、S、NR9b或O；
Z’是O、S或NR9f；
R9a、R9b、R9c、R9d和R9e分别独立为氢、酰基、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基、芳烷基、芳基、杂环基、杂芳基或前药基团；
R8是氢、羟基、卤素、巯基、烷基、链烯基、炔基、芳基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基或芳烷基；
R13是氢、羟基、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基或芳烷基；和
Y’和Y各自独立为氢、卤素、羟基、氰基、巯基、氨基、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基或芳烷基。
本发明还涉及，至少部分是如通式(III)的四环素类化合物，其药学上可接受的盐：
其中：J5和J6各自独立为氢、烷基、链烯基、炔基、芳基、磺酰基、酰基、烷氧羰基、烷氨羰基、烷氨硫代羰基、取代的硫代羰基、取代的羰基、烷氧硫代羰基，或形成一个环；
J7和J8分别为烷基、卤素或氢；
X为CHC(R13Y’Y)、CR6’R6、C＝CR6’R6、S、NR6或O；
R2、R2’、R4’和R4”各自独立为氢、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基、芳烷基、芳基、杂环基、杂芳基或前药基团；
R4是NR4’R4”、烷基、链烯基、炔基、芳基、羟基、卤素或氢；R2’、R3、R10、R11和R12分别为氢或前药基团；
R5是羟基、氢、巯基、烷酰基、芳酰基、烷芳酰基、芳基、杂芳基、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基、芳烷基、烷碳酰氧基或芳基碳酰氧基；
R6和R6’各自独立为氢、亚甲基、缺损、羟基、卤素、巯基、烷基、链烯基、炔基、芳基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基或芳烷基；
R7是氢；
R8是氢、羟基、卤素、巯基、烷基、链烯基、炔基、芳基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基，或芳烷基；
R13是氢、羟基、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基，或芳烷基；和
Y’和Y各自独立为氢、卤素、羟基、氰基、巯基、氨基、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基或芳烷基。
本发明还涉及表1所示的化合物，其药学上可接受的酯、盐和前药。
本发明还涉及，至少部分是包含如通式(I)、(II)、(III)、表1或本发明中其它所述的氨基甲基四环素类化合物的药物组合物。药物组合物优选包含有效量的米诺环素化合物及药学上可接受的载体。
在另一个具体实施方式中，本发明还涉及，至少部分是应用本发明所述的氨基甲基四环素类化合物(例如，如通式(I)、(II)、(III)、表1或本发明中其它所述的化合物)的方法，治疗患者对四环素敏感的症状。
在另一个具体实施方式中，本发明还涉及，至少部分是合成氨基烷基四环素类化合物的方法。该方法包括在适当的条件下，将四环素类物质与氨基烷基试剂反应，得到氨基烷基四环素类化合物。
在另一个具体实施方式中，本发明还涉及含有本发明的氨基烷基四环素类化合物的药物组合物，和通过本发明的方法合成的氨基烷基四环素类化合物。
发明详述
在一个具体实施方式中，本发明涉及如通式(I)的四环素类化合物，或其药学上可接受的盐、前药和酯化物：
其中，R1和R2形成环。
在一个具体实施方式中，R1和R2形成一五员或六员环。在另一个具体实施方式中，R1和R2形成一六员环。R1和R2可以由一原子链连接，如-(CH2)5-6、-(CH2)1-5-CH＝CH-(CH2)1-5-、-(CH2)1-5-O-(CH2)1-5-、-(CH2)1-5-NR-(CH2)1-5-等。该环可以是饱和或不饱和的。例如，R1和R2可以形成一哌啶环、吗啉环、吡啶环或吡嗪环。
在另一个具体实施方式中，四环素类化合物是：
或其药学上可接受的盐、酯或前药。
在另一个具体实施方式中，本发明涉及如通式(II)的氨基甲基四环素类化合物，及其药学上可接受的盐、酯和前药：
Figure A0380997900151
其中：J1和J2各自独立为氢、芳基、磺酰基、酰基，或形成一个环，条件是至少J1或J2的一个不是氢；
J3和J4各自独立为烷基、卤素或氢；
X为CHC(R13Y’Y)、CR6’R6、C＝CR6’R6、S、NR6或O；R2、R2’、R4’和R4”各自独立为氢、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基、芳烷基、芳基、杂环基、杂芳基或前药基团；
R4是NR4’R4”、烷基、链烯基、炔基、芳基、羟基、卤素或氢；
R2’、R3、R10、R11和R12分别为氢或前药基团；
R5是羟基、氢、巯基、烷酰基、芳酰基、烷芳酰基、芳基、杂芳基、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基、芳烷基、烷碳酰氧基或芳基碳酰氧基；
R6和R6’各自独立为氢、亚甲基、缺损、羟基、卤素、巯基、烷基、链烯基、炔基、芳基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基或芳烷基；
R9是氢、硝基、烷基、链烯基、炔基、芳基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、芳烷基、氨基、芳烯基、芳炔基、硫代亚硝基或(CH2)0-3NR9cC(＝Z’)ZR9a；
Z是CR9dR9e、S、NR9b或O；
Z’是O、S或NR9f；
R9a、R9b、R9c、R9d和R9e分别独立为氢、酰基、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基、芳烷基、芳基、杂环基、杂芳基或前药基团；
R8是氢、羟基、卤素、巯基、烷基、链烯基、炔基、芳基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基或芳烷基；
R13是氢、羟基、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基或芳烷基；和
Y’和Y各自独立为氢、卤素、羟基、氰基、巯基、氨基、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基或芳烷基。
在一个具体实施方式中，四环素类化合物是土霉素类化合物(例如，其中的R4是NR4’R4”，R4’和R4”为甲基，R5是OH，X是CR6R6’，R6是OH，R6’是CH3)。在另一个具体实施方式中，氨基烷基四环素类化合物是脱甲氯四环素类化合物(例如，其中的R4是NR4’R4”，R4’和R4”为甲基，R5是氢，X是CR6R6’，R6是OH，R6’是氢，R7是氯)。在另一个具体实施方式中，氨基烷基四环素类化合物是甲烯土霉素类化合物(例如，其中的R4是NR4’R4”，R4’和R4”为甲基，R5是OH，X是CR6R6，R6和R6’一起为CH2)。在另一个具体实施方式中，氨基烷基四环素类化合物是脱氧土霉素类化合物(例如，其中的R4是NR4’R4”，R4’和R4”为甲基，R5是OH，X是CR6R6’，R6是OH，R6’是CH3)。在另一个具体实施方式中，氨基烷基四环素类化合物是金霉素类化合物(例如，其中的R4是NR4’R4”，R4’和R4”为甲基，R5是氢，X是CR6R6’，R6是OH，R6’是CH3，R7是氯)。在另一个具体实施方式中，氨基烷基四环素类化合物是四环素类化合物(例如，其中的R4是NR4’R4”，R4’和R4”为甲基，R5是氢，X是CR6R6’，R6和R6’是氢，R7是N(CH3)2)。在进一步的具体实施方式中，式I中的R5是保护的羟基基团，例如前药基团。前药基团的例子有酰基酯和酯基团。在一个特定的具体实施方式中，前药基团是芳酰基、烷酰基、或烷芳酰基，其在体外可以或不裂解为羟基基团。在一个特定的具体实施方式中，R4是氢。
在一个具体实施方式中，J3和J4为氢。在另一个具体实施方式中，J1是取代或非取代的烷基。J1还可以是磺酰基，或J1和J2形成一个环。在进一步的具体实施方式中，J1可以是杂芳基或取代的羰基。
氨基烷基四环素类化合物的合成是通过本发明描述的方法完成，包括但不限于，以下通式的化合物，或其药学上可接受的盐或前药：
Figure A0380997900171
Figure A0380997900181
其中R是取代或非取代的烷基、链烯基、炔基、卤素、烷氧基；Y是N、O或S。
在另一个具体实施方式中，本发明的氨基烷基四环素类化合物是如通式(II)的化合物，或其药学上可接受的盐：
Figure A0380997900191
其中，J5和J6各自独立为氢、烷基、链烯基、炔基、芳基、磺酰基、酰基、烷基羰基、烷氨羰基、烷氨硫代羰基、取代的硫代羰基、取代的羰基、烷氧硫代羰基，或形成一个环；
J7和J8分别为烷基、卤素或氢；
X为CHC(R13Y’Y)、CR6’R6、C＝CR6’R6、S、NR6或O；
R2、R2’、R4’和R4”各自独立为氢、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基、芳烷基、芳基、杂环基、杂芳基或前药基团；
R4是NR4’R4”、烷基、链烯基、炔基、芳基、羟基、卤素或氢；
R2’、R3、R10、R11和R12分别为氢或前药基团；
R5是羟基、氢、巯基、烷酰基、芳酰基、烷芳酰基、芳基、杂芳基、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基、芳烷基、烷碳酰氧基或芳基碳酰氧基；
R6和R6’各自独立为氢、亚甲基、缺损、羟基、卤素、巯基、烷基、链烯基、炔基、芳基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基或芳烷基；
R7是氢；
R8是氢、羟基、卤素、巯基、烷基、链烯基、炔基、芳基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基，或芳烷基；
R13是氢、羟基、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基，或芳烷基；和
Y’和Y各自独立为氢、卤素、羟基、氰基、巯基、氨基、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基或芳烷基。
在一个具体实施方式中，四环素类化合物是土霉素类化合物(例如，其中的R4是NR4’R4”，R4’和R4”为甲基，R5是OH，X是CR6R6’，R6是OH，R6’是CH3)。在另一个具体实施方式中，氨基烷基四环素类化合物是脱甲氯四环素类化合物(例如，其中的R4是NR4’R4”，R4’和R4”为甲基，R5是氢，X是CR6R6’，R6是OH，R6’是氢，R7是氯)。在另一个具体实施方式中，氨基烷基四环素类化合物是甲烯土霉素类化合物(例如，其中的R4是NR4’R4”，R4’和R4”为甲基，R5是OH，X是CR6R6’，R6和R6’一起为CH2)。在另一个具体实施方式中，氨基烷基四环素类化合物是脱氧土霉素类化合物(例如，其中的R4是NR4’R4”，R4’和R4”为甲基，R5是OH，X是CR6R6’，R6是OH，R6’是CH3)。在另一个具体实施方式中，氨基烷基四环素类化合物是金霉素类化合物(例如，其中的R4是NR4’R4”，R4’和R4”为甲基，R5是氢，X是CR6R6’，R6是OH，R6’是CH3，R7是氯)。在另一个具体实施方式中，氨基烷基四环素类化合物是四环素类化合物(例如，其中的R4是NR4’R4”，R4’和R4”为甲基，R5是氢，X是CR6R6’，R6和R6’是氢，R7是N(CH3)2)。在进一步的具体实施方式中，式I中的R5是保护的羟基基团，例如前药基团。前药基团的例子有酰基酯和酯基团。在一个特定的具体实施方式中，前药基团是芳酰基、烷酰基、或烷芳酰基，其在体外可以裂解或不裂解为羟基基团。在一个特定的具体实施方式中，R4是氢。
在一个具体实施方式中，J7和J8为氢。在另一个具体实施方式中，J5是取代或非取代的烷基。J5还可以是磺酰基，或J5和J6形成一个环。在进一步的具体实施方式中，J5可以是杂芳基或取代的羰基。
氨基烷基四环素类化合物的合成是通过本发明描述的方法完成，包括但不限于，以下通式的化合物，或其药学上可接受的盐或前药：
Figure A0380997900221
其中R是取代或非取代的烷基、链烯基、炔基、卤素、烷氧基；Y是N、O或S。
其它本发明的氨基烷基四环素类化合物参见表1所述。本发明包括表1所述化合物的药学上可接受的酯、盐和前药。
                              表1
Figure A0380997900241
本发明还涉及至少部分是氨基烷基四环素类化合物的合成的方法，如以上所描述的那样。该方法包括在适当的条件下，将四环素类化合物与氨基烷基化试剂反应，得到相应的氨基烷基四环素类化合物。
术语“四环素类化合物”包括许多具有与四环素类似的环状结构的物质。四环素类化合物的例子包括：四环素、氯四环素、土霉素、脱甲氯四环素、甲烯土霉素、去甲去氧四环素、脱氧土霉素、米诺环素、四环林、吡甲四环素、赖氨甲四环素、羟哌羧四环素、羟甲金霉素、胍甲四环素、甲葡四环素、mepylcycline、青哌四环素、羟哌四环素、乙胺双四环素、苄青四环素等等。其它的衍生物和类似物含有具有类似的四环结构的物质，也包括在其中(作为回顾，参见W.Rogalski，“Chemical Modifications of Tetracyclines，”，其全文引用于此作参考)。表2描述了四环素和一些已知的四环素衍生物。
                    表2
Figure A0380997900281
其它经本发明的方法修饰的四环素类化合物包括，但不限于，6-去甲基-6-去氧-4-去二甲基氨基四环素；四环素吡唑；7-氯-4-去二甲基氨基四环素；4-羟基-4-去二甲基氨基四环素；12α-去氧-4-去二甲基氨基四环素；5-羟基-6α-去氧-4-去二甲基氨基四环素；4-去二甲基氨基-12α-去氧无水四环素；7-去二甲基氨基-6-去甲基-6-去氧-4-去二甲基氨基四环素；四环素腈；4-氧代-4-去二甲基氨基四环素4，6-半缩酮；4-氧代-11a Cl-4-去二甲基氨基四环素-4，6-半缩酮；5a，6-脱水-4-肼叉-4-去二甲基氨基四环素；4-肟基-4-去二甲基氨基四环素；4-肟基-4-去二甲基氨基5a，6-无水四环素；4-氨基-4-去二甲基氨基5a，6无水四环素；4-甲基氨基-4-去二甲基氨基四环素；4-肼叉-11a-氯-6-去氧-6-去甲基-6-亚甲基-4-去二甲基氨基四环素；四环素季铵盐化合物；无水四环素甜菜碱；4-羟基-6-甲基-前四环酰胺；4-酮基-四环素；5-酮基四环素；5a，11a无水四环素；11a Cl-6，12半缩酮四环素；11a Cl-6-亚甲基四环素；6，13二醇四环素；6-苄基硫代亚甲基四环素；7，11a-二氯-6-氟-甲基-6-去氧四环素；6-氟(α)-6-去甲基-6-去氧四环素；6-氟(β)-6-去甲基-6-去氧四环素；6-α乙酰氧基-6-去甲基四环素；6-β乙酰氧基-6-去甲基四环素；7，13-环硫四环素；土霉素；吡唑四环素；11a卤代四环素；12a甲酸基其它四环素的酯；5，12a四环素的酯；10，12a-四环素二酯；异四环素；12-a-去氧无水四环素；6-去甲基-12a-去氧-7-氯代无水四环素；B-nor四环素；7-甲氧基-6-去甲基-6-去氧四环素；6-去甲基-6-去氧-5a-差向四环素；8-羟基-6-去甲基-6-去氧四环素；monardene；色四环素chromocycline；5a甲基-6-去甲基-6-去氧四环素；6-乙二酸四环素，和6硫代四环素。
术语“氨基烷基四环素类化合物”包括在7位和/或9位由氨基烷基(例如，-CH2NR’R”)取代的四环素类化合物。在一个具体实施方式中，在7位和/或9位的取代可以加强四环素类化合物的功能(例如，作为抗生素治疗对四环素类化合物敏感的症状，等等)。术语“氨基烷基化试剂”包括那些能够在适当的条件下与四环素类化合物反应，生成氨基烷基四环素类化合物的试剂。氨基烷基化试剂可以加入到反应混和物中，或在原地生成。氨基烷基化试剂的例子包括，但不限于，如下通式(IV)的化合物：
Figure A0380997900291
其中，Ra’和Ra”分别独立为氢或卤素；
R’是氢、烷基、链烯基、炔基、芳基、杂芳基或卤素；和
R”是氢或任选与R’形成一个4-8员环。该环可任选被例如卤素取代，并可包含碳和/或杂原子，例如氧、氮和硫。R’可以进一步被取代，只要不阻碍在适当的条件下与本发明的四环素类化合物反应即可。在另一个进一步的具体实施方式中，R’是非取代或取代(例如被卤素氯、氟、溴、碘等取代)的烷基。在另一个具体实施方式中，R’是芳基，例如非取代或取代(例如被卤素氯、溴、碘等取代)的苯基。在另一个具体实施方式中，Ra’和Ra”为氢。其它氨基烷基化试剂包括N-羟基甲基邻苯二甲酰亚胺。
氨基烷基化试剂的实例包括但不限于：
Figure A0380997900301
Y＝CH2，CH2CH2，N，O，S，等
术语“适当的条件”包括那些可以使氨基烷基化试剂与四环素类化合物反应，得到氨基烷基四环素类化合物的条件。在一个具体实施方式中，适当的条件包括先用酸处理四环素类化合物，或同时将氨基烷基化试剂加入反应混和物中。酸的实例包括那些已知的常规酸，如硫酸、氢氟酸(HF)、甲磺酸、三氟甲基硫酸、氢氯酸、氢氯酸乙醇溶液、乙酸、甲磺酸和三氟乙酸(TFA)。在进一步的具体实施方式中，适当的条件还可以包括用猝火剂(如水)处理四环素类化合物的产物。
以下所描述的每个反应都可以应用于其它以上所述的四环素类化合物。另外，虽然许多方案都描述了9位取代的四环素类化合物，但其它类似的取代物也可以通过用保护基团(例如叔丁基)保护9位后在7位加入。
方案1描述了用氨基烷基化试剂与去甲去氧四环素在适当的条件下生成氨基烷基四环素类化合物。
Figure A0380997900311
                           方案1
方案2描述了两个四环素类化合物与包含5员环的氨基烷基化试剂的氨基烷基化反应。类似的反应还可以使用例如6或7员环的试剂。
Figure A0380997900312
                           方案2
如以下方案3所示，7-单取代的氨基甲基四环素的合成可以在应用保护基团(即9-叔丁基保护基团)的情况下应用公知技术裂解得到，例如使用酸。所述酸的实例包括但不限于HF、三氟乙酸(TFA)、H2SO4和它们的混和物。通过这种方式，在7位选择性的氨基甲基化即可完成。
Figure A0380997900321
                    方案3
在进一步的具体实施方式中，适当的条件可以进一步包含用衍生物试剂在第二适当条件下处理反应混和物(可含有氨基烷基四环素类化合物的中间体)，得到需要的氨基烷基四环素类化合物的步骤。方案4的反应是在9位上，但也可以在四环素类化合物的其它位置上。附加的衍生试剂和第二适当条件可以获得，例如在化学文献中。参见R.C.LaRock，Comprehensive Organic Transformations，(New York：VCH Publishers，Inc.，1989)及在其中引用的文献。任何可以与伯胺反应形成新产物的试剂都是可能的。各种不同结构的试剂参见以下的方案4。
Figure A0380997900322
                            方案4
例如，在方案5中，酰基氯衍生试剂加入到反应混和物中得到需要的酰胺化的氨基烷基四环素类化合物(J.Am.Chem Soc.71，2215(1949)；J.Am.Chem.Soc.108，1039(1986)；
Org.Syn.Coll.Vol.4,339(1963)；Org.Syn.Coll.Vol.5,387(1973))。
Figure A0380997900331
                    方案5
方案6描述了中间体氨基烷基四环素化合物和适当的磺酰氯衍生化试剂的反应，得到氨苯磺酰胺氨基烷基化合物(Org.Syn.Coll.Vol.5,736,758(1973))。
Figure A0380997900332
                    方案6
方案7描述了衍生化试剂和氨基烷基四环素化合物中间体的反应，得到氨基烷基四环素类化合物的氨基甲酸酯。
Figure A0380997900333
                    方案7
术语“烷基”包括饱和的脂肪族基团，包含直链的烷基基团、支链的烷基基团，环烷基(脂环族)基团、烷基取代的环烷基基团和环烷基取代的烷基基团。术语烷基进一步包含还含有氧、氮、硫或磷原子取代烃链中的碳原子的烷基基团。在一个优选的具体实施方式中，直链或支链的烷基基团具有6个或更少的碳原子的主链(例如C1-C6的直链，C3-C6的去链)，更优选是具有4个或更少的碳原子主链。同样，优选的环烷基基团具有4-7个碳原子环结构，更优选是5或6个碳原子环结构。
而且，术语烷基包括“非取代的烷基”和“取代的烷基”，后者指的是烷基基团主链的一个或多个碳上的氢被取代。取代基包括卤素、羟基、烷基碳酰氧基、芳基碳酰氧基、烷氧基碳酰氧基、芳氧基碳酰氧基、羧基、烷基羰基、烷氧羰基、氨基羰基、烷基硫代羰基、烷氧基、芳氧基、磷酸基、碳磷酸盐、膦酸基、氰基、氨基(包括烷基氨基、双烷基氨基、芳氨基、双芳基氨基和烷芳基氨基)、酰氨基(包括烷基酰氨基、芳基酰氨基、氨甲酰基和脲基)、脒基、亚胺基、巯基、硫烷基、硫芳基、硫代羧基、硫酸基、磺酸基、氨磺酰基、氨苯磺胺基、硝基、三氟甲基、氰基、叠氮基、杂环基、烷基芳基，或芳基或杂芳基基团。环烷基可以进一步被取代，例如用以上所描述的取代基。“一个烷基芳基”基团是用芳基取代的烷基(例如苯甲基(苄基))。
术语“芳基”包括含有5-及6-员环的芳香基团，其可以含有0-4个杂原子，例如，苯、吡咯、呋喃、噻吩、咪唑、苯  唑、苯并噻唑、三唑、四唑、吡唑、吡啶、吡嗪、哒嗪和嘧啶等等。芳基基团还可以包括多环稠合的芳基基团，如萘基、喹啉基、吲哚基等等。那些环中带有杂原子的芳基基团可以称为“芳基杂环”、“杂芳基”或“杂芳香基”。芳香环可以在环的一个或多个位置上被以上所描述的基团所取代，例如被卤素、羟基、烷氧基、烷基碳酰氧基、芳基碳酰氧基、烷氧基碳酰氧基、芳氧基碳酰氧基、羧基、烷基羰基、烷氧羰基、氨基羰基、烷基硫代羰基、磷酸基、碳磷酸盐、膦酸基、氰基、氨基(包括烷基氨基、双烷基氨基、芳氨基、双芳基氨基和烷芳基氨基)、酰氨基(包括烷基酰氨基、芳基酰氨基、氨甲酰基和脲基)、脒基、亚胺基、巯基、硫烷基、硫芳基、硫代羧基、硫酸基、磺酸基、氨磺酰基、氨苯磺胺基、硝基、三氟甲基、氰基、叠氮基、杂环基、烷基芳基，或芳基或杂芳基基团。芳基可以与非芳得的脂环或杂环稠合或桥联，形成多环物质(例如四氢萘)。
术语“链烯基”和“炔基”包括不饱和的脂肪族基团类似物，其链长和取代同以上所述的烷基情况相同，分别至少含有一个双键或三键。
除非碳原子数另有规定，这里所述的“低级烷基”指的是如上所描述的烷基基团，主链具有1-5个碳原子。同样，“低级链烯基”和“低级炔基”亦指的是同样的链长。
术语“烷氧基烷基”、“聚氨基烷基”和“硫代烷氧基烷基”包括如上所述的烷基基团，其中进一步包含取代烃主链的一个或多个碳原子的氧、氮或硫原子。
术语“多环”或“多环基团”表示两个或多个环(例如环烷基、环烯基、环炔基、芳基和/或杂环基)，其中两个相邻环以两个或多个碳原子毗邻，如环为“稠合环”。以非相邻原子联结的环称为“桥联环”。每个多环可以被以上所描述的取代基取代，例如，卤素、羟基、烷基碳酰氧基、芳基碳酰氧基、烷氧基碳酰氧基、芳氧基碳酰氧基、羧基、烷基羰基、烷氧羰基、氨基羰基、烷基硫代羰基、烷氧基、芳氧基、磷酸基、碳磷酸盐、膦酸基、氰基、氨基(包括烷基氨基、双烷基氨基、芳氨基、双芳基氨基和烷芳基氨基)、酰氨基(包括烷基酰氨基、芳基酰氨基、氨甲酰基和脲基)、脒基、亚胺基、巯基、硫烷基、硫芳基、硫代羧基、硫酸基、磺酸基、氨磺酰基、氨苯磺胺基、硝基、三氟甲基、氰基、叠氮基、杂环基、烷基芳基，或芳基或杂芳基基团。
术语“杂环”指的是包含一个或多个杂原子组成的环。“杂环”的例子包括四氢呋喃、呋喃、环氧乙烷、吡咯烷、哌啶、噻吩和吡咯。
这里的术语“杂原子”指的是除碳和氢以外的任何原子。优选的杂原子是氮、氧、硫和磷。
术语“二环”包括两个原子被共享的环。实例包括双环丁烷、樟脑萜、十氢化萘和邻苯二甲酰亚胺。
术语“羰基”包括包含有碳氧双键的基团。术语“取代的羰基”包括那些羰基上的碳原子进一步键合另一个碳原子或杂原子的基团。取代基的例子包括，但不限于，烷基、链烯基、炔基、芳基、卤素、羟基、烷基碳酰氧基、芳基碳酰氧基、烷氧基碳酰氧基、芳氧基碳酰氧基、烷氧基、芳氧基、芳氧基碳酰氧基、羧基、烷基羰基、烷氧羰基、氨基羰基、烷基硫代羰基、磷酸基、碳磷酸盐、膦酸基、氰基、氨基(包括烷基氨基、双烷基氨基、芳氨基、双芳基氨基和烷芳基氨基)、酰氨基(包括烷基酰氨基、芳基酰氨基、氨甲酰基和脲基)、脒基、亚胺基、巯基、硫烷基、硫芳基、硫代羧基、硫酸基、磺酸基、氨磺酰基、氨苯磺胺基、硝基、三氟甲基、氰基、叠氮基、杂环基、烷基芳基，或芳基或杂芳基基团。
术语“硫代羰基”包括那些含有布碳硫双键的基团。术语“取代的硫代羰基”包括那些羰基上的碳原子进一步键合另一个碳原子或杂原子的基团。取代基的例子包括，但不限于，烷基、链烯基、炔基、芳基、卤素、羟基、烷基碳酰氧基、芳基碳酰氧基、烷氧基碳酰氧基、芳氧基碳酰氧基、烷氧基、芳氧基、芳氧基碳酰氧基、羧基、烷基羰基、烷氧羰基、氨基羰基、烷基硫代羰基、磷酸基、碳磷酸盐、膦酸基、氰基、氨基(包括烷基氨基、双烷基氨基、芳氨基、双芳基氨基和烷芳基氨基)、酰氨基(包括烷基酰氨基、芳基酰氨基、氨甲酰基和脲基)、脒基、亚胺基、巯基、硫烷基、硫芳基、硫代羧基、硫酸基、磺酸基、氨磺酰基、氨苯磺胺基、硝基、三氟甲基、氰基、叠氮基、杂环基、烷基芳基，或芳基或杂芳基基团。
适当的烷酰基基团包括含有1-约4或5个羰基基团的基团。适当的芳酰基基团包括带有一个或多个由芳基取代的羰基的基团，芳基的例子如苯基或其它芳香碳环基团。适当的烷酰基基团具有一个或多个由芳基取代的烷基羰基的基团，芳基的例子如苯乙酰基团等等。合适的碳环芳基具有6或更多的碳，如苯、萘等等。合适的芳酰基基团是碳环芳基基团，由一个或多个羰基基团取代，典型的是1或2个羰基基团。
前药是那些在体内转化为活性形式的化合物(参见：R.B.Silverman，1992，“The Organic Chemistry of Drug Action”，Academic Press，Chp.8)。前药可以改变特定药物的生物分布(例如使不易进入蛋白酶反应位点的化合物的性能改变)或药代动力学性能。例如，羟基，通过羧酸进行酯化产生酯。酯类给予患者后，通过酶或不通过酶裂解、降解或水解，转变为羟基基团。前药可以在体内通过酯酶或其它机现代谢，得到羟基或其它有益的基团。前药的例子及它们的用途均为现有技术已知的(参见：Berge et.al.(1977)“Pharmaceutical Salts”，J.Pharm.Sci.66：1-19)。前药可以在最后分离及纯化过程中就地制备，或使纯的自由酸形式或醇形式的物质与适当的酯化试剂反应得到。羟基基团可以通过用羧酸处理转化成酯。前药的例子包括取代和未取代的支链或非支链的低级烷基酯基团(比如丙酸酯)、低级烷烯基酯基团、二-低级烷基氨低级烷基酯(比如二甲基氨基乙酯)、酰氨基低级烷基酯(比如酰氧甲基酯)、酰氧基低级烷基酯(比如特戊酰氧基甲基酯)、芳基酯(苯基酯)、芳基低级烷基酯(比如苄基酯)、取代的(如被甲基、卤素或甲氧基取代)芳基和芳基低级烷基酯，酰胺、低级烷基酰胺、二-低级烷基酰胺，及羟基酰胺。
应该注意到本发明的部分化合物的结构中包含手性碳原子。因而可以理解因这些手性中心而产生的异构体(例如，所有的对映体和非对映体)也是包括在本发明的范围之内，除非另有说明。这样的异构体可以通过经典的纯化技术和可控立体化学合成得到。
本发明至少部分还涉及治疗患者，如哺乳动物，例如人的对四环素敏感的症状的方法，是给予有效量的本发明的氨基甲基四环素类化合物，如通式I、II、III、表1所表示的化合物，及其它以上所描述的化合物。
术语“对四环素类化合物敏感的症状”或“对四环素敏感的症状”包括那些能通过给予本发明的四环素类化合物，例如9-氨基甲基四环素化合物，而得到治疗、预防或其它改善的症状。对四环素类化合物敏感的症状包括细菌、病毒及真菌感染(包括那些对其它四环素类化合物耐药的)、癌症(比如前列腺癌、乳癌、结肠癌、肺癌、黑色素瘤和淋巴癌，以及其它以不正常细胞增殖为特征的疾病，包括，但不限于，那些在US6100248中描述的)、关节炎、骨质疏松症、糖尿病、囊性纤维化、神经障碍疾病和其它显示四环素类化合物活性的症状(参见：US专利5789395、5834450、6277061和5532227，这些文献均全文结合于此作参考)。本发明的化合物可以用于预防或控制重要哺乳动物和兽医学的疾病，如腹泻、尿路感染、皮肤感染、耳鼻喉感染、伤口感染、乳腺炎等等。另外，应用本发明的四环素类化合物治疗赘生物的方法还可以包括在其内(参见：van der Bozert et al.，Cnacer Res.，48：6686-6690(1988))。在进一步的具体实施方式中，对四环素敏感的症状不是细菌感染。其它对四环素类化合物敏感的症状包括例如在U.S.S.N.10/196010中描述的那些。
对四环素类化合物敏感的症状还包括和炎症相关的症状(IPAS)。术语“和炎症相关的症状”包括炎症或炎症因子(例如基质金属蛋白酶(MMPs)、一氧化氮(NO)、TNF、白细胞介素、血浆蛋白、细胞防御系统、细胞因子、脂类代谢物、蛋白酶、毒素基团、粘附分子等)相关的或局部非正常量(例如会使如有利于施用主体的量改变)引起的症状。炎症过程会导致组织损伤。炎症的起因是由于物理损伤、化学物质、微生物、组织坏死、癌症或其它因素。急性炎症持续时间短，一般只有几天。如果持续时间较长，便可能是慢性炎症。
IPAS包括炎症疾病。炎症疾病通常的症状为发烧、发红、发肿、疼痛和功能的丧失。炎症疾病起因的例子包括但不限于微生物感染(如细菌和真菌感染)、物理因素(如烧伤、辐射和创伤)、化学因素(如毒素和腐蚀性物质)、组织坏死和各种免疫反应。
炎症疾病的例子包括，但不限于，骨关节炎、类风湿性关节炎、急性及慢性感染(细菌和真菌引起的，包括白喉和百日咳)；急性及慢性支气管炎、鼻窦炎和上呼吸道感染，包括普通感冒；急性和慢性肠胃炎和大肠炎；急性和慢性膀胱炎和尿道炎；急性和慢性皮炎；急性和慢性结膜炎；急性和慢性浆膜炎(心包炎、腹膜炎、滑膜炎、胸膜炎和腱炎)；尿毒性心包炎；急性和慢性胆囊炎、急性和慢性阴道炎、急性和慢性葡萄膜炎；药物反应；昆虫咬伤；烧伤(热烧伤、化学烧务和电烧伤)；和晒伤。
对四环素类化合物敏感的症状还包括与NO相关的症状。术语“与NO相关的症状”包括涉及或相关于一氧化氮(NO)或诱导一氧化氮氧合酶(iNOS)的症状。与NO相关的症状表现为非正常量的NO和/或iNOS。优选的是，与NO相关的症状可以通过给予本发明的四环素类化合物治疗，例如式I、II、III、表1及上述其它的化合物。所述疾病及症状在US专利6231894、6015804、5919774和5789395中描述，其中包含了与NO相关的症状。以上专利文献全文引用于些作参考。
其它与NO相关的症状的例子包括，但不限于，疟疾、衰老、糖尿病、中风、神经变性疾病(阿尔海默茨病Alzheimer’s disease、亨廷顿病Huntington’s disease)心脏病(梗塞后的再灌注损伤)、青少年糖尿病、炎性疾病、骨关节炎、类风湿性关节炎、急性和慢性感染(细菌、病毒和真菌感染)；囊性纤维化、急性和慢性支气管炎、鼻窦炎和呼吸系统感染，包括普通感冒；急性和慢性肠胃炎和大肠炎；急性和慢性膀胱炎和尿道炎；急性和慢性皮炎；急性和慢性结膜炎；急性和慢性浆膜炎(心包炎、腹膜炎、滑膜炎、胸膜炎和腱炎)；尿毒性心包炎；急性和慢性胆囊炎、急性和慢性阴道炎、急性和慢性葡萄膜炎；药物反应；昆虫咬伤；烧伤(热烧伤、化学烧务和电烧伤)；和晒伤。
术语“与炎性过程相关的症状”在一个具体实施方式中，还包括基质金属蛋白酶相关的症状(MMPAS)。MMPAS表现为非正常量的MMPs或MMP活性。还包括如四环素类化合物相关的症状，其可以用本发明的化合物进行治疗，如9-氨基甲基四环素化合物，正如那些如通式I所描述的物质。
基质金属蛋白酶相关的症状(MMPAS)的实例包括，但不限于，动脉硬化、角膜溃疡、肺气肿、骨关节炎、多发性硬化症(Diedtke et al.，Ann.Neurol.1998，44：35-46；Chandler et al.，J.Neuroimmunol.1997，72：155-71)、骨肉瘤、骨髓炎、支气管扩张、慢性肺梗阻、皮肤和眼部疾病、牙周炎、骨质疏松症、类风湿性关节炎、溃疡性结肠炎、炎症疾病、肿瘤生长和侵袭(Stetler-Stevenson et al.，Annu.Rev.CellBiol.1993，9：541-73；tryggvason et al.，Biochim.Biophys.Acta 1987，907：191-217；Li et al.，Mol Carcinog.1998，22：84-89)、肿瘤转移、急性肺损伤、中风、局部缺血、糖尿病、主动脉瘤或动脉瘤、皮肤组织损伤、干眼、骨和软骨降解(Greenwald et al.，Bone 1998，22：33-38；Ryanet al.，Curr.Op.Rheumatol.1996，8；238-247)。其它MMPAS包括在US专利5459135、5321017、5308839、5258371、4935412、4704383、4666897和RE34656中，这些文献均全文引用于此作参考。
在另一个具体实施方式中，对四环素类化合物敏感的症状是癌症。可以用本发明的四环素类化合物治疗的癌症包括所有的实体瘤，如腺癌和肉瘤。腺癌是衍生自腺体组织的癌或肿瘤细胞形成可辨认的腺体结构。肉瘤广泛地包括细胞嵌入纤维状或类似的象胚胎样组织中的肿瘤。可以用本发明的方法治疗的肉瘤的例子包括，但不限于，前列腺癌、乳腺癌、卵巢癌、睾丸癌、肺癌、结肠癌、和乳癌。本发明的方法不限于治疗这些肿瘤的形式，其可延伸至衍生自任何器官系统的任何实体瘤。可以治疗的癌症的例子包括，但不限于，结肠癌、膀胱癌、乳腺癌、黑色素瘤、卵巢癌、前列腺癌、肺癌、和许多其它的癌。本发明的方法还可以抑制腺体肿瘤的生长，如前列腺癌、乳腺癌、肾癌、卵巢癌、睾丸癌和结肠癌。
在另一个具体实施方式中，对四环素敏感的症状是癌症。本发明涉及治疗方法，该方法是对于遭受癌症或有癌症危险的对象的，该方法是通过给予对象有效量的取代的四环素类化合物，可以抑制肿瘤细胞的生长，即抑制肿瘤细胞的增殖、侵袭、转移，或降低、延缓或阻止肿瘤的发生。该抑制作用是通过抑制炎症过程，减量调节炎症过程，一些其它机理，或这些机理的组合完成的。另外，四环素化合物可以用于预防癌症的复发，例如，在手术切除或放射治疗后治疗残余癌。本发明的四环素类化合物特别有利的是相对于其它癌症的治疗，它们几乎无毒。在进一步的具体实施方式中，本发明的化合物是在标准的癌症治疗，例如但不限于化疗中联合给予。
所述与其它治疗剂或治疗方法“联合”应用包括共同给予四环素类化合物，或先给予四环素类化合物，再给予其它治疗剂，或先给予其它治疗剂，再给予四环素类化合物。其它治疗剂可以是任何已知用于治疗、预防或减少对四环素敏感的症状的试剂。而且，其它治疗剂可以是任何在同四环素类化合物联合给予时有益于患者的试剂。在一个具体实施方式中，本发明方法治疗的癌症包括那些在US专利6100248、5843925、5837696或5668122中描述的，这些文献全文结合于此作参考。
在另一个具体实施方式中，对四环素类化合物敏感的症状是糖尿病，例如青少年糖尿病、I型糖尿病、II型糖尿病、糖尿病溃疡或其它糖尿病并发症。在进一步的具体实施方式中，蛋白质糖基化作用不受本发明的四环素类化合物的给予的影响。在另一个具体实施方式中，本发明的四环素类化合物是同标准的糖尿病治疗联合应用的，例如但不限于，胰岛素治疗。在进一步的具体实施方式中，IPAS包括在US专利5929055和5532227中描述的疾病，这些文献均全文结合于此作参考。
在另一个具体实施方式中，对四环素类化合物敏感的症状是骨量性疾病。骨量性疾病包括患者的骨患有疾病并其骨形成、修复和再造是有利的。骨量性疾病的例子包括骨质疏松症(例如，骨强度和骨密度减少)、骨折、外科手术过程中的骨形成(例如，面部改造)、成骨不全(脆骨症)、低磷酸酶症、佩吉特病Paget’s disease、纤维性结构不良、骨硬化症、骨髓瘤和骨钙缺失，例如与初级甲状旁腺功能亢进有关的症状。骨量性疾病包括所有的骨形成、修复和再造有利于患者的症状，如同其它的可以用本发明的四环素类化合物治疗的骨骼系统的相关疾病。在进一步的具体实施方式中，骨量性疾病包括那些在US专利5459135、5231017、5998390、5770588、RE34656、5308839、4925833、3304227和4666897中描述的，这些文献均全文结合于此作参考。
在另一个具体实施方式中，对四环素类化合物敏感的症状是急性肺损伤。急性肺损伤包括成人呼吸障碍综合征(ARDS)、后泵式综合征(PPS)和肺损伤。肺损伤包括外来试剂或事件引起的肺部活体组织的任何损伤。肺部损伤的例子包括，但不限于，挤压伤、硬表面擦伤、或割伤，或其它肺部的伤害。
本发明还涉及肺损伤的治疗方法，是通过给予本发明的四环素类化合物完成。
本发明的对四环素敏感的症状还包括慢性肺部疾病。本发明涉及治疗慢性肺部疾病的方法，通过给予如以上所述的那些四环素类化合物。该方法包括给予患者有效量的取代的四环素类化合物，得以治疗慢性肺部疾病。慢性肺部疾病例子包括，但不限于，哮喘、囊性纤维化和肺气肿。在进一步的具体实施方式中，本发明的四环素类化合物用于治疗急性和/或慢性肺部疾病，如那些在US专利5977091、6043231、5523297和5773430中描述的，这些文献均全文结合在此作参考。
在另一个具体实施方式中，对四环素类化合物敏感的症状是局部缺血、中风或缺血性发作。本发明还涉及治疗局部缺血、中风或缺血性发作的方法，是通过给予患者本发明有效量的取代的四环素类化合物。在进一步的具体实施方式中，本发明的四环素类化合物用于治疗如US专利6231894、5773430、5919775或5789395中描述的疾病，这些文献均全文结合于此作参考。
在另一具体实施方式中，对四环素类化合物敏感的症状是皮肤创伤。本发明至少部分还涉及在急性外伤中(例如割伤、灼伤、擦伤等)，促进上皮组织愈合(例如皮肤、粘膜)的方法。该方法可包括应用本发明的四环素类化合物(具有或不具有抗菌活性)以改善急性创伤上皮组织愈合的能力。该方法可以增加愈合组织中胶原的积累率。该方法还可以通过降低MMPs的溶胶原和/或裂解明胶的活性来降低上皮组织蛋白水解的活性。在进一步的具体实施方式中，本发明的四环素类化合物施予皮肤表面(比如局部)。在进一步的具体实施方式中，本发明的四环素类化合物用于治疗皮肤创伤，及其它在US专利5827840、4704383、4935412、5258371、53088391、5459135、5532227和6015804中描述的疾病，这些文献均全文引用于此作参考。
对四环素敏感的症状的实例还包括神经障碍性疾病，如精神病和神经变性性疾病，包括但不限于阿尔海默茨病Alzheimer’s disease、与阿尔海默茨病相关的痴呆(如Pick’s病)、帕金森病及其它Lewy弥漫性体病、老年性痴呆、亨廷顿病Huntington’s disease、Gilles de laTourette’s综合征、多发性硬化症、肌萎缩性侧索硬化(ALS)、进行性核上性麻痹、癫痫和痉挛性假性硬化；自律功能性疾病如高血压睡眠障碍，以及精神疾病，如抑郁症、精神分裂症、情感分裂性精神障碍、Korsakoff氏精神病、躁狂症、焦虑症、或恐怖症；学习和记忆性疾病，如健忘症或老年记忆丧失、注意力缺陷障碍、情绪恶劣性障碍、严重抑郁性障碍、躁狂、强制性障碍、精神活性物质使用障碍、焦虑症、恐怖症、惊恐性障碍，以及双相情感障碍，如严重的双相情感(情绪)障碍(BP-1)、双相情感神经障碍如偏头痛和肥胖症。更多的神经障碍性疾病包括，如那些在美国Psychiatric Association’s Diagnostic及Statistical manual of Mental Disorders(DSM)文献中所列举的，其最新版本全文结合于此作参考。
在另一个具体实施方式中，对四环素类化合物敏感的症状是患者血管组织的主动脉或动脉瘤，其中所述患者为患有主动脉或动脉瘤或具有主动脉或动脉瘤的潜在危险等的主体。四环素类化合物可以有效地缩小主动脉或动脉瘤，或可以预先给予主体以预防主动脉或动脉瘤的发生。在一个具体实施方式中，血管组织是动脉，比如主动脉、腹主动脉。在进一步的具体实施方式中，本发明的四环素类化合物用于治疗那些在US专利6043225和5834449中描述的疾病，这些文献均全文结合在此作参考。
细菌感染可由许多革兰氏阳性菌和革兰氏阴性菌引起。本发明的化合物可用于在对其它四环素类化合物耐受的有机体的抗菌作用。本发明的四环素类化合物的抗菌活性可以通过在实施例2所述的方法，或应用在Waita，J.A.，National Commission for Clinical LaboratoryStandards，Document M7-A2，vol.10，No8，pp13-20，第2版，Villanova，PA(1990)中所描述的体外标准培养基稀释方法测定。
本发明的四环素类化合物还可以用于治疗传统的可用四环素类化合物治疗的感染，例如，立克次体；部分革兰氏阳性菌和革兰氏阴性菌；以及有关性病性淋巴肉芽肿、包涵体性结膜炎、鹦鹉热的因素。四环素类化合物可以用于治疗如K.pneumoniae、沙门氏菌、E.hirae、A.鲍曼不动杆菌、B.catarrhalis、H.influenzae、P.aeruginosa、E.faecium、大肠杆菌、S.aureus或E.faecalis的感染。在一个具体实施方式中，四环素类化合物可用于治疗对其它四环素类化合物耐受的细菌的感染。本发明的四环素类化合物可以同药学上可接受的载体一起施用。
术语化合物的“有效量”是指所用四环素类化合物的量足够起治疗或预防对四环素类化合物敏感的症状的作用。有效量可以依据如患者身高体重、疾病类型、或特定的四环素类化合物的因素而变化。例如，对四环素类化合物的选择可影响“有效量”的构成。对于一个普通技术人员来说，能够研究上述这些因素，并可以在不进行实验验证的情况下确定相应的有效量。
在一个具体实施方式中，本发明涉及包含本发明的四环素类化合物的药物组合物，如通式I、II、III或其它以上所描述的那些。优选的是，四环素类化合物是以有效量，例如可有效治疗患者，如哺乳动物特别是人，的对四环素敏感的症状的量，提供的。在进一步的具体实施方式中，本发明的药物组合物还可包括适当的药学上可接受的载体。
术语“药学上可接受的载体”包括能够与四环素类化合物共同给予，并可发挥其功能例如，治疗或预防对四环素类化合物敏感的症状的物质。合适的药学上可接受的载体包括，但不限于，水、盐溶液、醇、植物油、聚乙二醇、明胶、乳糖、直链淀粉、硬脂酸镁、滑石粉、硅酸、粘性石蜡、香料油、脂肪酸单甘油酯和二甘油酯、凡士林安氟醚脂肪酸酯、羟甲基纤维素、聚乙烯吡咯烷酮等等。药物制剂可以灭菌处理，并且如果需要，可以与辅助剂混合，比如润滑剂、防腐剂、稳定剂、润湿剂、乳化剂、调节渗透压的盐类、缓冲剂、着色剂、调味剂和/或芳香物质等，这些物质不会与本发明的活性化合物起不利的反应。
本发明的天然为碱的四环素类化合物能够与各种无机酸或有机酸形成各种盐。该酸可以用于制备本发明的四环素类化合物的药学可接受的酸式盐，它们可形成无毒的酸式盐，即含有药学可接受的阴离子的盐，如盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、重硫酸盐、磷酸盐、酸式磷酸盐、异烟酸盐、乙酸盐、乳酸盐、水杨酸盐、柠檬酸盐、酒石酸盐、泛酸盐、酒石酸氢盐、抗坏血酸、琥珀酸盐、马来酸盐、gentisinate、延胡索酸盐、葡萄糖酸盐、glucaronate、蔗糖盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对-甲苯磺酸盐和棕榈酸盐[即1，1’-亚甲基-二-(2-羟基-3-萘甲酸盐)。虽然盐必须对于患者，如哺乳动物，是药学可接受的，但其通常是最初在从反应混和物中分离本发明的四环素类化合物时作为药学不可接受的盐得到的，并通过碱性试剂处理简单转变为化合物的自由碱形式，再转变为药学可接受的酸式盐形式。本发明的化合物原碱的酸式盐可以容易地通过将化合物原碱与大致等量的无机或有机酸在水性溶剂介质或合适的有机溶剂如甲醇或乙醇中制备而得。小心蒸去溶剂后，所需要的固体盐即可得到。
本发明的天然为酸的四环素类化合物能够形成各种碱式盐。化学碱可以用作制备本发明的天然为酸的四环素类化合物的药学可接受的碱式盐，其形式可以是无毒的碱式盐。这些盐包括，但不限于，那些衍生自诸如碱金属(如钾盐和钠盐)阳离子、碱土金属(如钙盐和镁盐)阳离子、铵盐或水溶性胺式盐(如N-甲基还原葡糖胺-(葡甲胺))、和低级烷基化铵盐以及其它药学可接受的有机胺的碱式盐的盐。本发明的天然为酸的四环素类化合物的药学可接受的碱式盐可以用药学可接受的阳离子按常规方法形成。因此，这些盐可以容易地通过用需要的药学可接受的阳离子的水性溶液处理本发明的四环素类化合物，并蒸干所得溶液，优选减压蒸干的方法制备。另外，本发明的四环素类化合物的低级烷基醇溶液可以通过混合所需的金属醇盐和溶液，随后蒸干而得到。
未特别地在前面的实验部分描述的本发明的其它的四环素类化合物的制备可以通过前述的反应的组合由本领域普通技术人员简单得到。
本发明的四环素类化合物及其药学上可接受的盐可以通过口服、非胃肠道给药或局部给药的方式给药。通常，这些化合物需要以有效剂量依据需特定给药的患者的体重及健康状况给药。根据所治疗的患者的情况及对药物的反应的个体差异情况，所选的药物制剂和给药时间及间隔也会不同。
本发明的药物组合物可以单独给药，也可以与已知的治疗患者如哺乳动物的对四环素敏感的症状的药物组合物联合应用。所述患者可能正患有对四环素敏感的症状，或有患病的潜在危险。患者的例子包括宠物(如猫、狗、雪貂等)、牲畜(牛、绵羊、猪、马、山羊等)、实验室动物(大鼠、小鼠、猴等)、及灵长目动物(黑猩猩、人、大猩猩)。
术语“与已知组合物的联合应用”是包括已知组合物与本发明的组合物同时给药，或先给予已知组合物，再给予本发明的组合物。任何已知的用于治疗对四环素敏感的症状的药用组合物均可用于本发明的方法中。
本发明的化合物可以单独应用，或与药用载体或稀释剂通过在先描述的任何途径联合给予，并给药亦可以以单剂量形式或多剂量形式进行。例如，本发明的新的治疗剂可以方便地以各种不同的剂型给药，即可以与多种药用惰性载体联合，以片剂、胶囊、锭剂、糖锭、硬糖、粉剂、喷雾剂、乳剂、膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水制混悬液、注射液、酏剂、糖浆剂等等。所述载体包括固体稀释剂、或填充剂、无菌水性介质和各种无毒的有机溶剂等等。而且，口服药物组合物可以适当地加入甜味和/或香味。通常，治疗有效的本发明的化合物以剂型总重量的5.0％-70％的浓度水平存在于制剂中。
对于口服给药来说，包含各种赋形剂，如微晶纤维素、柠檬酸钠、碳酸钙、磷酸二钙和甘氨酸片剂可以与各种崩解剂诸如淀粉(优选是玉米淀粉、土豆淀粉和木薯淀粉)、藻酸和一定的复合硅酸盐共同应用，其中还可包含制粒用粘合剂如聚乙烯吡咯烷酮、蔗糖、明胶和阿拉伯胶。另外，润滑剂如硬脂酸镁、月桂基硫酸钠和滑石粉是常用于片剂制备的。类似的固体组合物还可以作为填充剂用于胶囊；优选的材料包括乳糖，及高分子量的聚乙二醇。当需要应用水性悬浮剂和/或酏剂的口服给药时，活性组分可与各种甜味剂或香味剂、色素或染料及，如果需要的话，乳化和/或悬浮剂联用，还可以加入稀释剂如水、乙醇、丙二醇、丙三醇，及它们的混和物。
对于非胃肠道给药(包括腹膜内给药、皮下给药、静脉给药或肌内注射给药)来说，可应用含本发明的治疗物质的芝麻油或花生油溶液或在水性丙二醇溶液。水性溶液在需要的时候应适当的加入缓冲剂(优选pH大于8的)并首先用液体稀释剂进行等张。这些水性溶液适于静脉注射给药。油性溶液适于关节内注射给药、肌内注射给药和皮下注射给药。所有在灭菌条件下溶液的制备均很容易地在在已知的标准制药工艺技术下完成。对于非胃肠道给药的应用，适当的制剂包括溶液剂，优选油性或水性溶液，及悬浮剂、乳剂或植入物，包括栓剂。治疗用物质可以以无菌形式配制成单剂或多剂形式，如分散在液体载体中，所述液体载体如无菌生理盐水或5％的葡萄糖盐溶液，通常注射给药。
另外，在治疗皮肤炎症时也可以局部给予本发明的化合物。局部给药的方法的实例包括经皮给药、含服给药或舌下给药。对于局部给药，治疗用物质可以掺入药学上可接受的惰性局部用载体使用，如凝胶、软膏、洗剂或乳剂。所述的局部用载体包括水、甘油、乙醇、丙二醇、脂肪醇、甘油三酯、脂肪酸酯或矿物油。其它可能的局部载体是液体凡士林、棕榈酸异丙酯、聚乙二醇、95％乙醇、聚氧乙烯甘油月桂酯的5％水溶液、月桂基硫酸钠的5％水溶液等等。另外，象抗氧化剂、润湿剂、粘性稳定剂等的物质也可以在需要的时候加入。
对于肠内给药，特别适合的是含有滑石粉和/或糖类载体粘合剂等的片剂、锭剂或胶囊，载体优选是乳糖和/或玉米淀粉和/或土豆淀粉。糖浆剂、酏剂等可以加入甜味剂一起应用。持续释放组合物的制剂中包括活性化合物可以用不同的可降解的包衣保护，例如微囊、多层包衣等等。
除了对人进行治疗，本发明的治疗方法还可以有效地用于兽医，例如治疗家畜如牛、绵羊、山羊、奶牛、猪等等；家禽如鸡、鸭、鹅、火鸡等等；马类；及狗和猫。而且，本发明的化合物还可以用于治疗非动物的主体，如植物。
可以理解优选的用于治疗化合物的量应根据所用的特定的物质、特别的组合物剂型、给药方式、特定的给药位置等的不同而变化。最适的给药方案可以容易地由本领域普通技术人员通过传统的从前的方法测量确足。
通常，本发明的用于治疗的化合物可以以一定的具体实施方式以先前的四环素的治疗剂量给予患者。参见，例如，Physician’s DeskReference。例如，本发明的一种或多种化合物的适宜的有效量的范围在0.01-100毫克每公斤体重每天。优选的范围在0.1-50毫克每公斤体重每天，更优选是1-20毫克每公斤体重每天。适宜的给药是每天一次，或每天几次，如每生2-5次，每生的给药按适当的时间间隔，或其它适当的方案。
可以理解正常的、常规的、已知的预防方法可以按照在正常使用环境中确定疗效的四环素的给药确定。特别是在体内治疗人及动物时，医生会考虑避免已知的毒性作用和已知的抵触作用而进行有效的预防。因此，已知的胃肠道刺激及炎症的副作用、肾脏毒性、过敏反应、血变化和对铝、钙和镁离子的吸收的损伤会以常规方式进行考虑。
通过以下非限制性的实施例将进一步说明本发明。
本发明的实施例
实施例1：9-氨基甲基米诺环素及其衍生物的合成
三氟乙酸(1L)置于2L烧瓶中，加入氩气和米诺环素。HCl(200g，1当量)和N-羟甲基邻苯二甲酰亚胺(100g)加入烧瓶中，搅拌。固体溶解后，H2SO4(200mL)加入反应。反应在40-50℃下进行5-6小时。加入N-羟甲基胺(100g)。HPLC证实起始物完全转化成2，9-二-氨基甲基酞酰亚胺米诺环素，混和物置于4L丙酮中沉淀。观察到15-20℃的放热。搅拌1小时后，过滤，用丙酮(200ml)洗涤，用橡胶乳进行干燥。固体加入甲醇(1L)/t-BME(2L)混和溶剂，用三乙胺调pH值到3。过滤，并用50mL甲醇洗涤。2，9-二-氨基甲基酞酰亚胺米诺环素的产率为97％。
2，9-二-氨基甲基酞酰亚胺米诺环素(100g)悬浮于2M甲基胺的甲醇(10当量)溶液中。在室温下搅拌反应2-3小时，HPLC证实起始物完全转化成2，9-二-氨基甲基米诺环素。反应混和物倾入至t-BME(5体积)中，搅拌30分钟。接着，悬浮物过滤，用t-BME(200mL)洗涤，分离所需产物2，9-二-氨基甲基米诺环素。
2，9-二-氨基甲基米诺环素(40g)置于200ml水/甲醇(1/9)中成淤浆，滴加三氟乙酸调节pH值至3。混和物加热至40℃1-2小时。HPLC证实2，9-二-氨基甲基米诺环素转化成9-氨基甲基米诺环素，反应温度降回至室温，用三乙胺调节pH值至7。加入异丙醇(200mL)沉淀出固体。过滤，用50mL IPA洗涤，再用100mL乙醚洗涤，减压干燥，分离得到9-氨基甲基米诺环素。
9-[(苄氨基)-甲基]-米诺环素二盐酸盐
Figure A0380997900481
在室温下，向1.0mmol(600mg)9-(氨基甲基)-米诺环素二盐酸盐和5mL二甲基酰胺中加入0.2mmol(5mg)的三氯化铟和1.5mmol(160mg)苯甲醛。振摇30分钟后，加入2mmol(424mg)三乙酰硼氢化钠，反应由HPLC监测。1.5小时后，加入3等当量的三乙胺和1等当量的三乙酰硼氢化钠。3小时后反应完成。真空蒸去溶剂，粗品用制备用HPLC进行纯化，得到60mg 9-[(苄氨基)-甲基]米诺环素二盐酸盐。LCMS(MH+)＝577
9-[(2，2，二甲基-丙氨基)-甲基]-米诺环素二盐酸盐
9-二甲基氨基米诺环素(200mg，1当量)、DMF和三甲在三甲基乙醛(45μl，1当量)混和置于40mL烧瓶中搅拌。加入三乙胺(150μl，3当量)。在室温下搅拌数分钟后，加入NaBH(OAc)3(175mg，2当量)和InCl3(9mg，0.1当量)。1小时后，反应混和物澄清为红色。液相显示反应有单一的产物。反应用甲醇急冷，除去溶剂，产物用柱层析纯化。
9-[3，4-(亚甲二氧基)苯基-脲基]-甲基米诺环素二盐酸盐
在室温下，向0.25mmol(150mg)9-(氨基甲基)-米诺环素二盐酸盐和2等当量的三乙胺的3mL二甲基酰胺溶液中加入0.5mmol(81.5mg)的3，4-(亚甲二氧基)苯基异氰酸盐。振摇至反应完全(3小时)。真空除去溶剂，粗品用制备用HPLC进行纯化，得到66mg 9-[3，4-(亚甲二氧基)苯基-脲基]-甲基米诺环素二盐酸盐。产率41％。LCMS(MH+)＝650
9-[4-(三氟甲氧基)苯基-脲基]-甲基米诺环素二盐酸盐
Figure A0380997900492
在室温下，向0.25mmol(150mg)9-(氨基甲基)-米诺环素二盐酸盐和2等当量的三乙胺的3mL二甲基酰胺溶液中加入0.5mmol(101.5mg)的4-(三氟甲氧基)苯基异氰酸盐。振摇至反应完全(3小时)。真空除去溶剂，粗品用制备用HPLC进行纯化，得到68mg 9-[4-(三氟甲氧基)苯基-脲基]-甲基米诺环素二盐酸盐。产率39％。LCMS(MH+)＝690
7-[(二-二甲氧基甲基-氨基)-甲基]-去甲去氧四环素二盐酸盐
在室温下，向1.34mmol(1g)7-(氨基甲基)-去甲去氧四环素二盐酸盐和2等当量的三乙胺的5mL二甲基酰胺溶液中加入0.134mmol(29mg)的三氯化铟和2.68mmol(465mg)60％水性二甲氧基乙醛。振摇30分钟，加入2.68mmol(568mg)三乙酰硼氢化钠，反应用HPLC监测。反应在1小时后完全。真空除去溶剂，粗品用制备用HPLC进行纯化，得到100mg 7-[(二-二甲氧基甲基-氨基)-甲基]-去甲去氧四环素二盐酸盐。LCMS(MH+)＝620
9-[(2’-苯基-乙基-1’-氨基)-甲基]-脱氧土霉素
在通入氮气的条件下，9-氨基甲基脱氧土霉素二盐酸盐(1.21g，2.21mmol)的DMF(10mL)溶液振摇，并用InCl3(0.076g，0.34mmol)和苯乙醛(0.511mL，4.4mmol)处理。HPLC和LCMS监测反应显示在12小时内起始原料消耗完毕。产物是单-和双-取代的氨基脱氧土霉素，其中主要是单取代的。用甲醇(10mL)使反应骤冷。反应混和物通过硅藻土床过滤，硅藻土用甲醇(2×5mL)洗涤，合并有机相，浓缩至大约7-8mL，用醚稀释。过滤得到无定形固体，用醚(6×15mL)洗涤，真空干燥后，得到红色粉末，用制备用HPLC进行纯化。最终产品用HPLC、MS和1H NMR鉴定。MS(m/z)理论值577.24；测定值：578.17(M+1)
实施例2：体外最小抑制浓度(MIC)检测
以下检测是用于确定四环素衍生物对普通细菌的作用效果。2mg的每种化合物溶于100μl的DMSO中。溶液随即加入到阳离子调节Mueller Hinton培养基(CAMHB)中，最终化合物的浓度为每毫升200μg。溶液稀释到50μl体积，检测化合物的浓度为0.098ug/ml。从新鲜的检测菌落的培养基对数相对光密度(OD)值进行检测。稀释是为达到最终细胞密度为l×106CFU/ml。OD＝1时，各菌属的细胞密度值大约为：
大肠杆菌                     1×109CFU/ml
金黄色葡萄球菌               5×108CFU/ml
肠道球菌                     2.5×109CFU/ml
50μl的细胞悬浮物加入到微孔滴定板的孔中。最终细胞密度大约为5×105CFU/ml。这些板在35℃下在环境空气条件下培养大约18小时。这些板用微板读数器读取数据，并在需要的时候进行视觉检查。MIC值为抑制细菌生长的化合物的最低浓度。
那些本领域普通技术人员能够了解，或有能力通过不超过常规的试验确定许多的等价于这里所描述的物质或方法。这样的等价物应当看作在本发明的范围之内，并被以下的权利要求所覆盖。所有在本申请中引用的参考文献、专利文献和专利申请的内容均全文结合在这里作参考。这些专利文献、专利申请及其它文献中的适当的组成、步骤及方法均可以为本发明的具体实施方式所选择。
本申请是关于“9-取代的米诺环素化合物”，WO02/04406，2001.06.29公开，其全文结合在这里作参考。

Claims (41)

1.一种式I所示的四环素类化合物：
其中，R1和R2形成环，或其药学上可接受的盐、前药及酯化物。
2.如权利要求1所述的四环素类化合物，其中R1和R2形成一五员环。
3.如权利要求1所述的四环素类化合物，其中R1和R2形成一六员环。
4.如权利要求3所述的四环素类化合物，其中R1和R2形成一哌啶环、吗啉环、吡啶环或吡嗪环。
5.如权利要求4所述的四环素类化合物，其中所述化合物为：
Figure A038099790002C2
6.如下式所示的四环素类化合物，
Figure A038099790002C3
或其药学上可接受的盐、酯或前药。
7.一种式II所示的四环素类化合物，其药学上可接受的盐、酯或前药：
Figure A038099790003C1
其中：J1和J2各自独立为氢、芳基、磺酰基、酰基，或形成一个环，条件是至少J1或J2的一个不是氢；
J3和J4各自独立为烷基、卤素或氢；
X为CHC(R13Y’Y)、CR6’R6、C＝CR6’R6、S、NR6或O；
R2、R2’、R4’和R4”各自独立为氢、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基、芳烷基、芳基、杂环基、杂芳基或前药基团；
R4是NR4’R4”、烷基、链烯基、炔基、芳基、羟基、卤素或氢；
R2’、R3、R10、R11和R12分别为氢或前药基团；
R5是羟基、氢、巯基、烷酰基、芳酰基、烷芳酰基、芳基、杂芳基、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基、芳烷基、烷碳酰氧基或芳基碳酰氧基；
R6和R6’各自独立为氢、亚甲基、缺损、羟基、卤素、巯基、烷基、链烯基、炔基、芳基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基或芳烷基；
R9是氢、硝基、烷基、链烯基、炔基、芳基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、芳烷基、氨基、芳烯基、芳炔基、硫代亚硝基或(CH2)0-3NR9cC(＝Z’)ZR9a；
Z是CR9dR9e、S、NR9b或O；
Z’是O、S或NR9f；
R9a、R9b、R9c、R9d和R9e分别独立为氢、酰基、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基、芳烷基、芳基、杂环基、杂芳基或前药基团；
R8是氢、羟基、卤素、巯基、烷基、链烯基、炔基、芳基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基或芳烷基；
R13是氢、羟基、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基或芳烷基；和
Y’和Y各自独立为氢、卤素、羟基、氰基、巯基、氨基、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基或芳烷基。
8.如权利要求7所述的四环素类化合物，其中R4是NR4’R4”，X是CR6R6’；R2、R2’、R6、R6’、R8、R9、R10、R11和R12分别为氢；R4’和R4”为低级烷基；R5为羟基或氢。
9.如权利要求8所述的四环素类化合物，其中R4’和R4”分别是甲基，R5为氢。
10.如权利要求7所述的四环素类化合物，其中J3和J4为氢。
11.如权利要求7所述的四环素类化合物，其中J1是取代或非取代的烷基。
12.如权利要求7所述的四环素类化合物，其中J1是磺酰基。
13.如权利要求7所述的四环素类化合物，其中J1和J2形成一个环。
14.如权利要求7所述的四环素类化合物，其中J1是杂芳基。
15.一种四环素类化合物，所述化合物选自由下列物质及其药学上可接受的盐、酯或前药组成的组：
Figure A038099790004C1
Figure A038099790005C1
其中R是取代或非取代的烷基、链烯基、炔基、卤素、烷氧基；Y是N、O或S。
16.一种式III所示的四环素类化合物，及其药学上可接受的盐：
Figure A038099790006C1
其中：J5和J6各自独立为氢、烷基、链烯基、炔基、芳基、磺酰基、酰基、烷氧羰基、烷氨羰基、烷氨硫代羰基、取代的硫代羰基、取代的羰基、烷氧硫代羰基，或形成一个环；
J7和J8分别为烷基、卤素或氢；
X为CHC(R13Y’Y)、CR6’R6、C＝CR6’R6、S、NR6或O；
R2、R2’、R4’和R4”各自独立为氢、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基、芳烷基、芳基、杂环基、杂芳基或前药基团；
R4是NR4’R4”、烷基、链烯基、炔基、芳基、羟基、卤素或氢；
R2’、R3、R10、R11和R12分别为氢或前药基团；
R5是羟基、氢、巯基、烷酰基、芳酰基、烷芳酰基、芳基、杂芳基、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基、芳烷基、烷碳酰氧基或芳基碳酰氧基；
R6和R6’各自独立为氢、亚甲基、缺损、羟基、卤素、巯基、烷基、链烯基、炔基、芳基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基或芳烷基；
R7是氢；
R8是氢、羟基、卤素、巯基、烷基、链烯基、炔基、芳基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基，或芳烷基；
R13是氢、羟基、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基，或芳烷基；和
Y’和Y各自独立为氢、卤素、羟基、氰基、巯基、氨基、烷基、链烯基、炔基、烷氧基、硫代烷基、亚磺酰烷基、烷基磺酰基、烷基氨基或芳烷基。
17.如权利要求16所述的四环素类化合物，其中R4是NR4’R4”，X是CR6R6’；R2、R2’、R6、R6’、R8、R10、R11和R12分别为氢；R4’和R4”为低级烷基；R5为羟基或氢。
18.如权利要求17所述的四环素类化合物，其中R4’和R4”分别为甲基，R5为氢。
19.如权利要求16所述的四环素类化合物，其中J7和J8为氢。
20.如权利要求16所述的四环素类化合物，其中J5为取代或非取代的烷基。
21.如权利要求16所述的四环素类化合物，其中J5为磺酰基。
22.如权利要求16所述的四环素类化合物，其中J5和J6形成一个环。
23.如权利要求16所述的四环素类化合物，其中J5是杂芳基。
24.如权利要求16所述的四环素类化合物，其中J5是取代的羰基。
25.如权利要求16所述的四环素类化合物，其中所述化合物选自由下列物质或其药学上可接受的盐或前药组成的组：
其中R是取代或非取代的烷基、链烯基、炔基、卤素、烷氧基；Y是N、O或S。
26.表1所示的四环素类化合物，或其药学上可接受的盐。
27.包含有效量的权利要求1-26任一所述的四环素类化合物，及药学上可接受的载体的药物组合物。
28.如权利要求27所述的药物组合物，其中所述有效量是指治疗对四环素敏感的症状的有效量。
29.一种治疗患者对四环素敏感的症状的方法，包括给予所述患者权利要求1-26任一所述的四环素类化合物。
30.如权利要求29所述的方法，其中所述对四环素敏感的症状为与炎症有关的症状。
31.如权利要求29所述的方法，其中所述对四环素敏感的症状为癌症、肺损伤、眼疾、神经系统疾病或中风。
32.如权利要求29所述的方法，其中所述对四环素敏感的症状为细菌感染。
33.如权利要求32所述的方法，其中所述细菌感染为与大肠杆菌有关的感染。
34.如权利要求32所述的方法，其中所述细菌感染为与金葡菌有关的感染。
35.如权利要求32所述的方法，其中所述细菌感染为与E.faecalis.有关的感染。
36.如权利要求32所述的方法，其中所述细菌感染为对其它四环素类抗生素耐受的细菌感染。
37.如权利要求32所述的方法，其中所述细菌感染为与革兰氏阳性菌有关的感染。
38.如权利要求32所述的方法，其中所述细菌感染为与革兰氏阴性菌有关的感染。
39.如权利要求29所述的方法，其中所述对四环素敏感的症状为病毒或真菌感染。
40.如权利要求29-39中任一所述的方法，其中所述四环素类化合物是与药学上可接受的载体一起给药。
41.如权利要求29-39中任一所述的方法，其中所述患者为人。
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KR20100090310A (ko) 2010-08-13
EA200401169A1 (ru) 2005-04-28
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WO2003075857A2 (en) 2003-09-18
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