CN1450989A - 7-取代的四环素化合物 - Google Patents
7-取代的四环素化合物 Download PDFInfo
- Publication number
- CN1450989A CN1450989A CN01815094A CN01815094A CN1450989A CN 1450989 A CN1450989 A CN 1450989A CN 01815094 A CN01815094 A CN 01815094A CN 01815094 A CN01815094 A CN 01815094A CN 1450989 A CN1450989 A CN 1450989A
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- CN
- China
- Prior art keywords
- alkyl
- carbonyl
- group
- sancycline
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 tetracycline compounds Chemical class 0.000 title claims abstract description 431
- 239000004098 Tetracycline Substances 0.000 title claims abstract description 177
- 229960002180 tetracycline Drugs 0.000 title claims abstract description 177
- 229930101283 tetracycline Natural products 0.000 title claims abstract description 176
- 235000019364 tetracycline Nutrition 0.000 title claims abstract description 176
- 150000003522 tetracyclines Chemical class 0.000 claims abstract description 19
- 208000035143 Bacterial infection Diseases 0.000 claims abstract description 4
- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 4
- 229950000614 sancycline Drugs 0.000 claims description 242
- MTCQOMXDZUULRV-ADOAZJKMSA-N (4s,4as,5ar,12ar)-4-(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=CC=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O MTCQOMXDZUULRV-ADOAZJKMSA-N 0.000 claims description 213
- 150000001875 compounds Chemical class 0.000 claims description 131
- 125000000217 alkyl group Chemical group 0.000 claims description 114
- 125000003118 aryl group Chemical group 0.000 claims description 97
- 125000000304 alkynyl group Chemical group 0.000 claims description 82
- 125000003342 alkenyl group Chemical group 0.000 claims description 80
- 125000003545 alkoxy group Chemical group 0.000 claims description 79
- 229910052760 oxygen Inorganic materials 0.000 claims description 54
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 52
- 125000001072 heteroaryl group Chemical group 0.000 claims description 51
- 239000001301 oxygen Substances 0.000 claims description 51
- 238000000034 method Methods 0.000 claims description 50
- 125000004414 alkyl thio group Chemical group 0.000 claims description 48
- 239000001257 hydrogen Substances 0.000 claims description 48
- 229910052739 hydrogen Inorganic materials 0.000 claims description 48
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 47
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 47
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 46
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 41
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 41
- 229910052736 halogen Inorganic materials 0.000 claims description 40
- 150000002367 halogens Chemical class 0.000 claims description 40
- 239000000203 mixture Substances 0.000 claims description 37
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 31
- 239000002253 acid Substances 0.000 claims description 30
- 125000003282 alkyl amino group Chemical group 0.000 claims description 30
- 125000003368 amide group Chemical group 0.000 claims description 29
- 150000002431 hydrogen Chemical group 0.000 claims description 29
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 27
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 26
- 125000004442 acylamino group Chemical group 0.000 claims description 25
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 24
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 23
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 22
- 201000010099 disease Diseases 0.000 claims description 22
- 229910019142 PO4 Inorganic materials 0.000 claims description 20
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 20
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 20
- 239000010452 phosphate Substances 0.000 claims description 20
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 claims description 19
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 19
- 125000004691 alkyl thio carbonyl group Chemical group 0.000 claims description 19
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 19
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 19
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 19
- 125000005110 aryl thio group Chemical group 0.000 claims description 19
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 19
- 125000003262 carboxylic acid ester group Chemical group [H]C([H])([*:2])OC(=O)C([H])([H])[*:1] 0.000 claims description 19
- 125000004185 ester group Chemical group 0.000 claims description 19
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 19
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims description 19
- 241000894006 Bacteria Species 0.000 claims description 17
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 16
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 16
- 239000000651 prodrug Chemical group 0.000 claims description 16
- 229940002612 prodrug Drugs 0.000 claims description 16
- 125000005089 alkenylaminocarbonyl group Chemical group 0.000 claims description 15
- 125000005090 alkenylcarbonyl group Chemical group 0.000 claims description 14
- 125000005125 aryl alkyl amino carbonyl group Chemical group 0.000 claims description 14
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 12
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 12
- 125000002971 oxazolyl group Chemical group 0.000 claims description 12
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 12
- 125000001544 thienyl group Chemical group 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 11
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- 125000000335 thiazolyl group Chemical group 0.000 claims description 10
- 229920002554 vinyl polymer Polymers 0.000 claims description 10
- 125000002252 acyl group Chemical group 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
- 125000005907 alkyl ester group Chemical group 0.000 claims description 8
- 125000002541 furyl group Chemical group 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 7
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 claims description 6
- 125000005015 aryl alkynyl group Chemical group 0.000 claims description 6
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 6
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 6
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 6
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 6
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 6
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 125000005493 quinolyl group Chemical group 0.000 claims description 6
- 125000003435 aroyl group Chemical group 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 208000015181 infectious disease Diseases 0.000 claims description 5
- 241000194032 Enterococcus faecalis Species 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 125000005014 aminoalkynyl group Chemical group 0.000 claims description 4
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 229940072172 tetracycline antibiotic Drugs 0.000 claims description 4
- 150000003577 thiophenes Chemical class 0.000 claims description 4
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 229940032049 enterococcus faecalis Drugs 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- UEXCJVNBTNXOEH-UHFFFAOYSA-N phenyl acethylene Natural products C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- 125000002071 phenylalkoxy group Chemical group 0.000 claims 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 125000002431 aminoalkoxy group Chemical group 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 5
- 230000014509 gene expression Effects 0.000 abstract description 5
- 229960004023 minocycline Drugs 0.000 abstract description 4
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 abstract 1
- 230000000903 blocking effect Effects 0.000 abstract 1
- 239000002585 base Substances 0.000 description 72
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract
本发明至少部分涉及新的7-取代四环素化合物。这些四环素化合物能够用于治疗很多四环素敏感性疾病,例如细菌感染和肿瘤以及其它已知的通常应用二甲胺山环素和四环素化合物的疾病,例如阻止四环素流和调节基因表达。
Description
相关申请
本申请要求以下申请的优先权:美国临时申请序列号为60/275,576,名称为“7-取代四环素化合物”,申请日为2001年3月13日和美国临时申请序号为60/216,760,名称为“7-取代山环素化合物”,申请日为2000年7月7日;上述各申请的全部内容通过引用结合到本发明。
发明背景
***筛选从世界各地收集的土壤样品以寻找微生物能够产生杀菌和/或抗菌组合物的证据而直接导致了四环素类抗生素的发展。这些新化合物中的第1个化合物是1948年的金霉素化合物。两年后出现了土霉素。在1952年对这些化合物化学结构的阐明,证实了它们的相似性并且提供了生产此类化合物的第三种四环素化合物的分析基础。四环素化合物新系列没有早期四环素连接环的甲基,它在1957年制备,1967年开始公开使用;二甲胺四环素在1972投入使用。
最近,研究工作关注于开发在各种治疗条件和给药途径下有效的新四环素抗生素组合物。还研究了新四环素类似物,证实其效果可能等于或大于最初的四环素化合物。实例包括美国专利号2,980,584、3,990,331、3,062,717、3,165,531、3,454,697、3,557,280、3,674,859、3,957,980、4,018,889、4,024,272和4,126,680。这些专利代表一系列药物活性四环素和四环素类似物组合物。
过去,在其最初开发和采用后不久,发现四环素对立克次氏体、许多革兰氏阳性和革兰氏阴性细菌、以及性病性淋巴肉芽肿、包涵体结膜炎和鹦鹉热病病原体有很好的药理效应。因此,四环素成为众所周知的“广谱”抗生素。随着对其体外抗菌活性、对试验性感染的疗效及药学性质的确定,四环素作为一类抗生素迅速广泛用于治疗目的。但是,对主要和次要病症及疾病广泛使用四环素直接导致出现对这些抗生素的耐药性,甚至出现在高度敏感的共生菌及致病菌(例如肺炎双球菌和沙门氏菌)中。四环素耐药性微生物的增加导致四环素和四环素类似物组合物作为抗生素在使用中全面减少。
发明概述:
本发明至少部分涉及下式I的7-取代四环素化合物及其药学上可接受盐:其中:
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、链炔基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基氨基、芳基烷基、芳基、杂环基、杂芳基或前体药物部分;
R4为NR4’R4”、烷基、链烯基、链炔基、羟基、卤素或氢;
R2’、R3、R10、R11和R12各自为氢或前体药物部分;
R5为羟基、氢、巯基、烷酰基、芳酰基、烷芳酰基、芳基、杂芳基、烷基、链烯基、链炔基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基氨基、芳基烷基、烷基羰氧基或芳基羰氧基;
R6和R6’各自独立为氢、亚甲基、不存在、羟基、卤素、巯基、烷基、链烯基、链炔基、芳基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基氨基或芳基烷基;
R7为氢、硝基、烷基、链烯基、链炔基、芳基、杂环基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、芳基烷基、氨基、酰氨基、芳基链烯基、芳基链炔基或-(CH2)0-3NR7cC(=W’)WR7a;
R9为氢、硝基、烷基、链烯基、链炔基、芳基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、芳基烷基、氨基、酰氨基、芳基链烯基、芳基链炔基、硫代亚硝基(例如-N=S)或-(CH2)0-3NR9cC(=Z’)ZR9a;
Z为CR9dR9e、S、NR9b或O;
Z’为O、S或NR9f;
W为CR7dR7e、S、NR7b或O;
W’为O或NR7fS;
R7a、R7b、R7c、R7d、R7e、R9a、R9b、R9c、R9d和R9e各自独立为氢、酰基、烷基、链烯基、链炔基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基氨基、芳基烷基、芳基、杂环基、杂芳基或前体药物部分;
R8为氢、羟基、卤素、巯基、烷基、链烯基、链炔基、芳基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基氨基或芳基烷基;
R13为氢、羟基、烷基、链烯基、链炔基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基氨基或芳基烷基;
Y’和Y各自独立为氢、卤素、羟基、氰基、巯基、氨基、酰氨基、烷基、链烯基、链炔基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基氨基、或芳基烷基。
本发明还涉及下式的7-取代山环素化合物及其药学上可接受盐:其中:
R4’和R4”各自为烷基;
R7为式
的稠环部分,其中Q为C或杂原子;酰基呋喃基;三、四或五卤代苯基;氨基甲基苯基;酰基氨基甲基;烷基酯苯基;酰基苯基;酰基炔基;酰基烷氧基苯基;甲基苯基;二甲基苯基;羧基苯基;羧基炔基;噻吩基;卤代噻吩基;烷氧基羰基苯基;烷氧基苯基;烷氧基苯基炔基;烷氧基吡啶基;亚烷基吡啶基;环戊基或环戊烯基;环己基炔基;环己烯基炔基;环己烯基卤代链烯基;羟基环己基炔基;苯基炔基;苯基链烯基;氨基炔基;环丁基链烯基;吡啶基炔基;吡啶基链烯基;硝基苯基炔基;硝基苯基链烯基;氰基炔基;链炔基;氰基链烯基;氰基苯基;二烷基酰氨基链烯基;二烷基酰氨基苯基;氨基苯基乙基;氨基苯基乙炔基;卤代乙烯基;卤代苯基炔基;或烷基酯取代的戊烯基。
本发明还涉及治疗患者四环素敏感性疾病的方法,该方法给予所述患者本发明7-取代四环素化合物(例如式I或II),由此治疗四环素敏感性疾病。
本发明还包括药用组合物,该组合物包含有效量的本发明7-取代四环素化合物和任选的药学上可接受的载体。本发明的详细说明
本发明至少部分涉及新的7-取代四环素化合物。这些四环素化合物可用于治疗许多四环素敏感性疾病,例如细菌感染和肿瘤,也可用于治疗其它已知通常应用二甲胺四环素和四环素化合物的疾病,例如阻断四环素流和调节基因表达。
术语“四环素化合物”包括许多具有类似四环素环结构的化合物。四环素化合物的实例包括:四环素、金霉素、土霉素、脱甲金霉素、甲烯土霉素、山环素、脱氧土霉素以及二甲胺四环素。其它衍生物以及包含类似四环结构的类似物也包括在内。表1中图示了四环素和几个已知的四环素衍生物。表1
术语“7-取代四环素化合物”包括在7位有取代基的四环素化合物。在一个实施方案中,在7位的取代增强四环素化合物发挥其预定作用的能力,例如治疗四环素敏感性疾病。在一个实施方案中,7-取代四环素化合物为7-取代四环素(例如其中R4为NR4’R4”,R4’和R4”为甲基,R5为氢,X为CR6R6’,其中R6为甲基而R6’为羟基);7-取代脱氧土霉素(例如其中R4为NR4’R4”,R4’和R4”为甲基,R5为羟基,X为CR6R6’,其中R6为甲基,R6’为氢);7-取代四环素化合物,其中X为CR6R6’、R4、R5、R6’,R6为氢;或者7-取代山环素(其中R4为NR4’R4”,R4’和R4”为甲基;R5为氢,X为CR6R6’,其中R6和R6’为氢原子。
本发明至少部分涉及下式I的7-取代四环素化合物及其药学上可接受盐:
其中:
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、链炔基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基氨基、芳基烷基、芳基、杂环基、杂芳基或前体药物部分;
R4为NR4’R4”、烷基、链烯基、链炔基、羟基、卤素或氢;
R2’、R3、R10、R11和R12各自为氢或前体药物部分;
R5为羟基、氢、巯基、烷酰基、芳酰基、烷芳酰基、芳基、杂芳基、烷基、链烯基、链炔基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基氨基、芳基烷基、烷基羰氧基或芳基羰氧基;
R6和R6’各自独立为氢、亚甲基、不存在、羟基、卤素、巯基、烷基、链烯基、链炔基、芳基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基氨基、芳基烷基或连接在一起;
R7为硝基、烷基、链烯基、链炔基、芳基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、芳基烷基、氨基、酰氨基、芳基链烯基、芳基链炔基或-(CH2)0-3NR7cC(=W’)WR7a;
R9为氢、硝基、烷基、链烯基、链炔基、芳基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、芳基烷基、氨基、酰氨基、芳基链烯基、芳基链炔基、硫代亚硝基(例如-N=S)或-(CH2)0-3NR9cC(=Z’)ZR9a;
Z为CR9dR9e、S、NR9b或O;
Z’为O、S或NR9f;
W为CR7dR7e、S、NR7b或O;
W’为O或NR7fS;
R7a、R7b、R7c、R7d、R7e、R9a、R9b、R9c、R9d和R9e各自独立为氢、酰基、烷基、链烯基、链炔基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基氨基、芳基烷基、芳基、杂环基、杂芳基或前体药物部分;
R8为氢、羟基、卤素、巯基、烷基、链烯基、链炔基、芳基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基氨基或芳基烷基;
R13为氢、羟基、烷基、链烯基、链炔基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基氨基或芳基烷基;
Y’和Y各自独立为氢、卤素、羟基、氰基、巯基、氨基、酰氨基、烷基、链烯基、链炔基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基氨基、或芳基烷基。在某些实施方案中,R7不为硝基或氨基。
在一个实施方案中,X为CR6R6’;R2、R2’、R6、R6’、R8、R9、R10、R11和R12各自为氢;R4为NR4’R4”;R4’和R4”为低级烷基(例如甲基);R5为羟基或氢。
在一个实施方案中,R7为芳基。芳基R7基团的实例包括取代或未取代的苯基。所述苯基R7基团可以被任何允许四环素化合物发挥其预定作用的取代基取代。取代基的实例包括但不限于烷基、链烯基、卤素、羟基、烷氧基、烷基羰氧基、烷氧基羰基、芳基羰氧基、烷氧基羰基氨基、烷氧基羰氧基、芳氧基羰氧基、羧酸酯基、烷基羰基、烷基氨基羰基、芳基烷基氨基羰基、链烯基氨基羰基、烷基羰基、芳基羰基、氨基烷基、芳基烷基羰基、链烯基羰基、烷氧基羰基、甲硅烷基、氨基羰基、烷硫基羰基、磷酸酯基、芳烷基、膦酸酯基、次膦酸酯基、氰基、氨基、酰基氨基、酰氨基、亚氨基、巯基、烷硫基、硫酸酯基、芳硫基、硫代羧酸酯基、烷基亚磺酰基、磺酸酯基、氨磺酰基、亚磺酰氨基、硝基、氰基、叠氮基、杂环基、烷基芳基、芳基和杂芳基。
在进一步的实施方案中,苯基R7基团被取代或未取代的烷基取代。烷基的取代基实例包括杂环,例如吗啉、哌啶(piperdine)和吡咯烷。在另一进一步的实施方案中,苯基R7基团被氨基取代。氨基还可被进一步取代,例如被烷基、链烯基、链炔基、羰基、烷氧基或芳基(例如取代或未取代的杂芳基、苯基等)基团取代。苯基氨基取代基可以被任何允许实现其预定功能的取代基或取代基组合取代。这样的取代基实例包括卤素(例如氟、氯、溴、碘等)、氨基(例如它可再被烷基、羰基、链烯基、链炔基或芳基部分取代)和芳基氨基(例如苯基氨基)。
R7苯基还可以被烷氧基取代。烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、全氟甲氧基、全氯甲氧基、亚甲二氧基等。苯基还可以被酰胺基团取代,例如氨基甲酸酯部分(例如烷氧基羰基氨基)。
芳基R7基团还可以为取代或未取代的联芳基,例如萘基、芴基等。联芳基R7基团可以被任何允许实现其预定功能的取代基取代。取代基实例包括但不限于烷基、链烯基、卤素、羟基、烷氧基、烷基羰氧基、烷氧基羰基、羧基、芳基羰氧基、烷氧基羰基氨基、烷氧基羰氧基、芳氧基羰氧基、羧酸酯基、烷基羰基、烷基氨基羰基、芳基烷基氨基羰基、链烯基氨基羰基、烷基羰基、芳基羰基、氨基烷基、芳基烷基羰基、链烯基羰基、烷氧基羰基、甲硅烷基、氨基羰基、烷硫基羰基、磷酸酯基、芳烷基、膦酸酯基、次膦酸酯基、氰基、氨基、酰基氨基、酰氨基、亚氨基、巯基、烷硫基、硫酸酯基、芳硫基、硫代羧酸酯基、烷基亚磺酰基、磺酸酯基、氨磺酰基、亚磺酰氨基、硝基、氰基、叠氮基、杂环基、烷基芳基、芳基和杂芳基。
在一个实施方案中,所述取代基为氨基或甲酰基。
芳基R7基团还可以为杂芳基。杂芳基R7部分的实例包括但不限于呋喃基、咪唑基、苯并硫代苯基、苯并呋喃基、喹啉基、异喹啉基、吡啶基、吡唑基、苯并二噁唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、亚甲二氧基苯基、吲哚基、噻吩基、嘧啶基、吡嗪基、嘌呤基、吡唑基、噁唑基、异噁唑基、1,5-二氮杂萘基(naphthridinyl)、噻唑基、异噻唑基和去氮嘌呤基。在某些实施方案中,杂芳基R7基团为噻唑基、硫代苯基或呋喃基。
R7还可以为取代或未取代的烷基。烷基可以为直链或支链基团,例如甲基、乙基、异丙基、正丙基、正丁基、异丁基、叔丁基、戊基、己基等。烷基还可以包含环,例如环烷基(例如环戊基、环己基、环丙基或环丁基)。烷基R7基团可以被任何允许实现其预定功能的取代基或取代基组合取代。所述取代基的实例包括但不限于链烯基、卤素、羟基、烷氧基、烷基羰氧基、烷氧基羰基、羧基、芳基羰氧基、烷氧基羰基氨基、烷氧基羰氧基、芳氧基羰氧基、羧酸酯基、烷基羰基、烷基氨基羰基、芳基烷基氨基羰基、链烯基氨基羰基、烷基羰基、芳基羰基、氨基烷基、芳基烷基羰基、链烯基羰基、烷氧基羰基、甲硅烷基、氨基羰基、烷硫基羰基、磷酸酯基、芳烷基、膦酸酯基、次膦酸酯基、氰基、氨基、酰基氨基、酰氨基、亚氨基、巯基、烷硫基、硫酸酯基、芳硫基、硫代羧酸酯基、烷基亚磺酰基、磺酸酯基、氨磺酰基、亚磺酰氨基、硝基、氰基、叠氮基、杂环基、烷基芳基、芳基和杂芳基。
在某些实施方案中,烷基被氨基、羟基、羧基、羰基(例如取代羰基,例如吗啉基羰基)、杂环或芳基取代。杂环基团的实例包括例如呋喃基、咪唑基、苯并硫代苯基、苯并呋喃基、喹啉基、异喹啉基、苯并二噁唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、亚甲二氧基苯基、吲哚基、噻吩基、吡啶基、吡唑基、嘧啶基、吡嗪基、嘌呤基、吡唑基、噁唑基、异噁唑基、1,5-二氮杂萘基、噻唑基、异噻唑基和去氮嘌呤基。在进一步的实施方案中,芳基为吡啶基。
在进一步的实施方案中,芳烷基R7基团包含取代或未取代苯基。该苯基还可以被任何允许实现其预定功能的取代基取代。取代基的实例包括但不限于亚磺酰氨基、烷基以及其它上述烷基R7基团的取代基。
R7还可以为取代或未取代链烯基。取代基实例包括允许化合物实现其预定功能的基团。所述取代基实例包括但不限于烷基、卤素、羟基、烷氧基、烷基羰氧基、烷氧基羰基、羧基、芳基羰氧基、烷氧基羰基氨基、烷氧基羰氧基、芳氧基羰氧基、羧酸酯基、烷基羰基、烷基氨基羰基、芳基烷基氨基羰基、链烯基氨基羰基、烷基羰基、芳基羰基、氨基烷基、芳基烷基羰基、链烯基羰基、烷氧基羰基、甲硅烷基、氨基羰基、烷硫基羰基、磷酸酯基、芳烷基、膦酸酯基、次膦酸酯基、氰基、氨基、酰基氨基、酰氨基、亚氨基、巯基、烷硫基、硫酸酯基、芳硫基、硫代羧酸酯基、烷基亚磺酰基、磺酸酯基、氨磺酰基、亚磺酰氨基、硝基、氰基、叠氮基、杂环基、烷基芳基、芳基和杂芳基部分。
在进一步的实施方案中,链烯基R7基团被氨基羰基(例如烷基氨基羰基、二烷基氨基羰基、二甲基氨基羰基)或烷氧基羰基取代。链烯基R7基团还可以被一个或多个以下基团取代:卤素(例如氟、氯、溴、碘等)、羟基、杂芳基(例如呋喃基、咪唑基、苯并硫代苯基、苯并呋喃基、喹啉基、异喹啉基、苯并二噁唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、亚甲二氧基苯基、吲哚基、噻吩基、吡啶基、吡唑基、嘧啶基、吡嗪基、嘌呤基、吡唑基、噁唑基、异噁唑基、1,5-二氮杂萘基、噻唑基、异噻唑基、去氮嘌呤基等)。在一个实施方案中,杂芳基取代基为噻唑基。
在进一步的实施方案中,链烯基R7基团被取代或未取代的苯基取代。苯基可以被任何允许其实现预定功能的取代基取代。取代基实例包括上述其它苯基部分的基团。其它取代基实例包括但不限于卤素(例如氟、氯、溴、碘等)、烷氧基(例如甲氧基、乙氧基、丙氧基、全氟甲基、全氯甲基等)、羟基或烷基(例如甲基、乙基、丙基、丁基、戊基、己基等)基团。
R7的另一实例包括取代和未取代链炔基。链炔基部分可以被任何允许本发明四环素化合物实现其预定功能的取代基或取代基组合取代。取代基的实例包括但不限于烷基、卤素、羟基、烷氧基、烷基羰氧基、烷氧基羰基、羧基、芳基羰氧基、烷氧基羰基氨基、烷氧基羰氧基、芳氧基羰氧基、羧酸酯基、烷基羰基、烷基氨基羰基、芳基烷基氨基羰基、链烯基氨基羰基、烷基羰基、芳基羰基、氨基烷基、芳基烷基羰基、链烯基羰基、烷氧基羰基、甲硅烷基、氨基羰基、烷硫基羰基、磷酸酯基、芳烷基、膦酸酯基、次膦酸酯基、氰基、氨基、酰基氨基、酰氨基、亚氨基、巯基、烷硫基、硫酸酯基、芳硫基、硫代羧酸酯基、烷基亚磺酰基、磺酸酯基、氨磺酰基、亚磺酰氨基、硝基、氰基、叠氮基、杂环基、烷基芳基、芳基和杂芳基部分。
在一个实施方案中,链炔基R7部分被芳基取代,例如取代或未取代的杂芳基、苯基等。该芳基部分可以被任何上述链炔基R7部分的取代基或取代基组合取代。有利的取代基实例包括但不限于羰基氨基(例如烷基羰基氨基、二烷基羰基氨基、芳基羰基氨基等)和亚磺酰氨基。
在另一实施方案中,链炔基R7基团被四环素部分取代。术语“四环素部分”包括上述四个环的四环素环系。该环系可以通过1-20原子的连接基连接到链炔基R7基团。所述连接基可以连接于有利于或允许化合物实现其预定功能的四环素部分环系的任何位置。在某一实施方案中,四环素部分的7位连接所述连接基。
R7部分的其它实例包括取代和未取代的烷基羰基氨基、亚磺酰氨基、亚氨基和羰基部分。羰基部分可以被取代或未取代的烷基取代。烷基的合适取代基实例包括但不限于芳基部分,例如苯基和杂芳基(例如吡啶基等)。亚氨基的取代基实例包括但不限于羟基和烷氧基。
在另一实施方案中,R7为NR7c(C=W’)WR7a。本发明四环素化合物的实例包括其中R7c为氢,W’为氧,W为氧的化合物。在某些实施方案中,R7a为取代或未取代的苯基。取代基的实例包括但不限于烷基、卤素、羟基、烷氧基、烷基羰氧基、烷氧基羰基、羧基、烷基羰基氨基、芳基羰氧基、烷氧基羰基氨基、烷氧基羰氧基、芳氧基羰氧基、羧酸酯基、烷基羰基、烷基氨基羰基、芳基烷基氨基羰基、链烯基氨基羰基、烷基羰基、芳基羰基、氨基烷基、芳基烷基羰基、链烯基羰基、烷氧基羰基、甲硅烷基、氨基羰基、烷硫基羰基、磷酸酯基、芳烷基、膦酸酯基、次膦酸酯基、氰基、氨基、酰基氨基、酰氨基、亚氨基、巯基、烷硫基、硫酸酯基、芳硫基、硫代羧酸酯基、烷基亚磺酰基、磺酸酯基、氨磺酰基、亚磺酰氨基、硝基、氰基、叠氮基、杂环基、烷基芳基、芳基和杂芳基。在进一步的实施方案中,R7a为取代或未取代的烷基。
其中:
R4’和R4”各自为烷基;
R7为式
的稠环部分,其中Q为C或杂原子;酰基呋喃基;三、四或五卤代苯基;氨基甲基苯基;酰基氨基甲基;烷基酯苯基;酰基苯基;酰基炔基;酰基烷氧基苯基;甲基苯基;二甲基苯基;羧基苯基;羧基炔基;噻吩基;卤代噻吩基;烷氧基羰基苯基;烷氧基苯基;烷氧基苯基炔基;烷氧基吡啶基;亚烷基吡啶基;环戊基或环戊烯基;环己基炔基;环己烯基炔基;环己烯基卤代链烯基;羟基环己基炔基;苯基炔基;苯基链烯基;氨基炔基;环丁基链烯基;吡啶基炔基;吡啶基链烯基;硝基苯基炔基;硝基苯基链烯基;氰基炔基;链炔基;氰基链烯基;氰基苯基;二烷基酰氨基链烯基;二烷基酰氨基苯基;氨基苯基乙基;氨基苯基乙炔基;卤代乙烯基;卤代苯基炔基;或烷基酯取代的戊烯基。
术语“7-取代山环素化合物”包括如式I所述的在7位有取代基的山环素化合物。在进一步的实施方案中,R4’和R4”各自均为甲基。
在进一步的实施方案中,R7为式
的稠环部分,其中Q为C或杂原子。含所述R7取代基的山环素化合物实例包括7-(2-苯并呋喃)山环素。
在再一实施方案中,R7为酰基呋喃基。含有该R7取代基的山环素化合物实例包括7-(3-甲酰基呋喃基)山环素。
在再一实施方案中,R7为三、四或五卤代苯基。含有该R7取代基的山环素化合物实例包括7-(2,3,4,5,6-五氟苯基)山环素。
在再一实施方案中,R7为氨基甲基苯基。含有该R7取代基的山环素化合物实例包括7-(4-氨基甲基苯基)山环素。
在再一实施方案中,R7为酰基氨基甲基。含有该R7取代基的山环素化合物实例包括7-(4-甲酰基氨基甲基苯基)山环素。
在再一实施方案中,R7为烷基酯苯基。含有该R7取代基的山环素化合物实例包括7-(4-羧基苯基甲酯)山环素和7-(2-羧基苯基乙酯)山环素。
在再一实施方案中,R7为烷基苯基。含有该R7取代基的山环素化合物实例包括7-(4-甲苯基)山环素。
在再一实施方案中,R7为酰基苯基。含有该R7取代基的山环素化合物实例包括7-(3-甲酰基苯基)山环素、7-(4-甲酰基苯基)山环素、7-(3-乙酰基苯基)山环素、7-(2-乙酰基苯基)山环素、7-(3-乙酰基苯基)山环素和7-(4-乙酰基苯基)山环素。
在再一实施方案中,R7为酰基烷氧基苯基。含有该R7取代基的山环素化合物实例包括7-(3-甲酰基-6-甲氧基苯基)山环素。
在再一实施方案中,R7为甲基苯基。含有该R7取代基的山环素化合物实例包括7-(4-甲基苯基)山环素。
在再一实施方案中,R7为二甲基苯基。含有该R7取代基的山环素化合物实例包括7-(3,5-二甲基苯基)山环素。
在再一实施方案中,R7为羧基苯基。含有该R7取代基的山环素化合物实例包括7-(3-羧基苯基)山环素。
在再一实施方案中,R7为羧基炔基。含有该R7取代基的山环素化合物实例包括7-(羧基乙炔基)山环素。
在再一实施方案中,R7为噻吩基。含有该R7取代基的山环素化合物实例包括7-(3-噻吩基)山环素、7-(3-甲基-2-噻吩基)山环素和7-(3-甲基-5-噻吩基)山环素。
在再一实施方案中,R7为卤代噻吩基。含有该R7取代基的山环素化合物实例包括7-(3-氯-2-噻吩基)山环素和7-(4-氯-2-噻吩基)山环素。
在再一实施方案中,R7为烷氧基羰基苯基。含有该R7取代基的山环素化合物实例包括7-(2-乙氧基羰基苯基)山环素。
在再一实施方案中,R7为烷氧基苯基。含有该R7取代基的山环素化合物实例包括7-(2-乙氧基苯基)山环素、7-(3-乙氧基苯基)山环素、7-(4-甲氧基苯基)山环素和7-(2,5-二甲氧基苯基)山环素。
在再一实施方案中,R7为烷氧基苯基炔基。含有该R7取代基的山环素化合物实例包括7-(4-甲氧基苯基乙炔基)山环素。
在再一实施方案中,R7为烷氧基吡啶基。含有该R7取代基的山环素化合物实例包括7-(4-甲氧基-5-吡啶基)山环素。
在再一实施方案中,R7为环戊基或环戊烯基。含有该R7取代基的山环素化合物实例包括7-(环戊烯基)山环素。
在再一实施方案中,R7为环己基炔基。含有该R7取代基的山环素化合物实例包括7-(环己基乙炔基)山环素。
在再一实施方案中,R7为环己烯基炔基。含有该R7取代基的山环素化合物实例包括7-(1-乙炔基-1-环己基)山环素。
在再一实施方案中,R7为环己烯基卤代链烯基。含有该R7取代基的山环素化合物实例包括7-(1-氯乙烯基-1-环己基)山环素。
在再一实施方案中,R7为羟基环己基炔基。含有该R7取代基的山环素化合物实例包括7-(1-乙炔基-1-羟基环己基)山环素。
在再一实施方案中,R7为苯基炔基。含有该R7取代基的山环素化合物实例包括7-(苯基乙炔基)山环素、7-(甲苯基乙炔基)山环素和7-(4-甲氧基苯基乙炔基)山环素。
在再一实施方案中,R7为苯基链烯基。含有该R7取代基的山环素化合物实例包括7-(2-乙烯基吡啶基)山环素和7-(乙烯基苯基)山环素。
在再一实施方案中,R7为氨基炔基。含有该R7取代基的山环素化合物实例包括7-(二甲基氨基乙炔基)山环素。
在再一实施方案中,R7为环丁基链烯基。含有该R7取代基的山环素化合物实例包括7-(环丁基甲烯基)山环素。
在再一实施方案中,R7为吡啶基炔基。含有该R7取代基的山环素化合物实例包括7-(2-吡啶基乙炔基)山环素和7-(3-吡啶基乙炔基)山环素。
在再一实施方案中,R7为吡啶基链烯基。含有该R7取代基的山环素化合物实例包括7-(4-吡啶基乙烯基)山环素。
在再一实施方案中,R7为硝基苯基炔基。含有该R7取代基的山环素化合物实例包括7-(4-硝基苯基乙炔基)山环素。
在再一实施方案中,R7为硝基苯基链烯基。含有该R7取代基的山环素化合物实例包括7-(4-硝基苯乙烯基)山环素。
在再一实施方案中,R7为炔基。含有该R7取代基的山环素化合物实例包括7-(乙炔基)山环素。
在再一实施方案中,R7为氰基炔基。含有该R7取代基的山环素化合物实例包括7-(氰基-1-戊炔基)山环素。
在再一实施方案中,R7为氰基链烯基。含有该R7取代基的山环素化合物实例包括7-(氰基己烯基)山环素。
在再一实施方案中,R7为氰基苯基。含有该R7取代基的山环素化合物实例包括7-(3-氰基苯基)山环素和7-(4-氰基苯基)山环素。
在再一实施方案中,R7为羟基苯基乙炔基。含有该R7取代基的山环素化合物实例包括7-(3-羟基苯基乙炔基)山环素。
在再一实施方案中,R7为二烷基酰氨基链烯基。含有该R7取代基的山环素化合物实例包括7-(N,N-二甲基丙烯酰胺)山环素和7-(二甲基酰氨基乙烯基)山环素。
在再一实施方案中,R7为二烷基酰氨基苯基。含有该R7取代基的山环素化合物实例包括7-(3-二甲基酰氨基苯基)山环素。
在再一实施方案中,R7为氨基苯基乙基。含有该R7取代基的山环素化合物实例包括7-(4-氨基苯基乙基)山环素。
在再一实施方案中,R7为氨基苯基乙炔基。含有该R7取代基的山环素化合物实例包括7-(4-氨基苯基乙炔基)山环素。
在再一实施方案中,R7为卤代乙烯基。含有该R7取代基的山环素化合物实例包括7-(2-氯乙烯基)山环素。
在再一实施方案中,R7为卤代苯基炔基。含有该R7取代基的山环素化合物实例包括7-(2-氟苯基乙烯基)山环素。
在再一实施方案中,R7为烷基酯取代的戊烯基。含有该R7取代基的山环素化合物实例包括7-(1-碘-1,3-二乙酯基-1,3-丁二烯)山环素。
在再一实施方案中,R7为氨基苯基炔基。含有该R7取代基的山环素化合物实例包括7-(4-氨基苯基乙烯基)山环素。
本发明还涉及以下的四环素化合物:
还包括以上所示化合物的盐、酯以及前体药物。
在进一步的实施方案中,本发明涉及下式的7-取代四环素化合物:
本发明还涉及表2所示的各7-取代四环素化合物及其药学上可接受的盐、酯和前体药物。
本发明四环素化合物可以用流程1-8的方法合成。
流程1
通常,7-取代四环素化合物可以按照用于山环素的流程1所示合成。将山环素(1A)用硫酸和硝酸钠处理。所得产物为7-硝基(1B)山环素(与9-位异构体的混合物)。然后将硝基山环素化合物用氢气和铂催化剂处理获得7-氨基山环素化合物1C。为了合成7位衍生物,将7-氨基山环素化合物用HONO处理,获得重氮盐(1D)。随后将所得盐用大量具有链烯烃或π键官能团(例如链烯基、芳基以及炔基(例如R7Br))的化合物处理获得7-取代山环素化合物(1E)。
流程2
如流程2所示,R7为氨基甲酸酯或脲衍生物的本发明四环素化合物可以用以下方案合成。山环素(2A)用NaNO2在酸性条件下处理生成7-硝基山环素(2B)的位置异构体混合物。然后将7-硝基山环素(2B)用氢气和铂催化剂处理生成7-氨基山环素衍生物(2C)。为了生成脲衍生物(2E),使异氰酸酯(2D)与7-氨基山环素衍生物(2C)反应。为了生成氨基甲酸酯(2G),使合适的氯化酰基酯(2F)与2C反应。
流程3
如流程3所示,R7为杂环(即噻唑)取代的氨基的本发明四环素化合物可以按照上述方案合成。使7-氨基山环素(3A)与Fmoc-异硫代氰酸酯(3B)反应生成被保护的硫脲(3C)。然后将被保护的硫脲(3C)去保护获得活性山环素硫脲(3D)化合物。使山环素硫脲(3D)与α-卤代酮(3E)反应生成噻唑取代的7-氨基山环素(3F)。
流程4
7-链烯基山环素化合物(例如7-炔基山环素(4A)和7-链烯基山环素化合物(4B))可以氢化生成烷基7-取代四环素化合物(例如7-烷基山环素4C)。流程4图示在饱和甲醇和盐酸溶液中,在压力下用钯/碳催化剂选择性氢化7-位的双键或三键获得产物。
流程5
在流程5中,显示合成7-位芳基衍生物的通常合成流程。显示芳基硼酸与碘代山环素化合物的Suzuki偶合。碘代山环素化合物(5B)的合成可以通过在酸性条件下用至少1当量的N-碘琥珀酰亚胺(NIS)处理山环素(5A)。将所述反应猝灭,然后将所得7-碘山环素(5B)用已知的标准技术提纯。为了生成芳基衍生物,将7-碘山环素(5B)用碱的水溶液(例如碳酸钠)和适当的硼酸(5C)在惰性气体中处理。该反应用钯催剂(例如Pd(OAc)2)催化。产物(5D)可以用本领域已知方法提纯(例如HPLC)。其它7-芳基和炔基四环素化合物可以用类似的方案合成。
本发明的7-取代四环素化合物也可以用Stille交联偶合法合成。Stille交联偶合可以用合适的锡试剂(例如R-SnBu3)和卤代四环素化合物(例如7-碘山环素)完成。锡试剂和碘代山环素化合物可以用钯催化剂(例如Pd(PPh3)2Cl2或Pd(AsPh3)2Cl2)以及任选另外的铜盐例如CuI处理。然后可以将所得化合物用本领域已知技术提纯。
流程6
由Suzuki或Stille偶合生成的芳基衍生物可以进一步衍化。例如在流程6中,将甲酰基芳基山环素(6A)、胺和溶剂(例如1,2-二氯乙烷)加入反应瓶中。然后加入还原剂(例如NaBH(OAc)3),然后让反应继续进行直至完成获得产物(6B)。将产物用标准技术提纯和表征。
流程7
本发明化合物还可以用Heck-型交联偶合反应合成。如流程7所示,Heck-型交联偶合可以用卤代四环素化合物(例如7-碘山环素,7A)和合适的钯或其它过渡金属催化剂(例如Pd(OAc)2和CuI)在合适的溶剂(例如脱气乙腈)中完成。然后加入反应物:活性链烯烃(7B)或炔烃(7D)和三乙胺,将混合物加热几个小时,然后冷却至室温。然后可以将所得7-取代链烯基(7C)或7-取代炔基(7E)四环素化合物用本领域已知技术提纯。
流程8
为了制备7-(2’-氯-链烯基)-四环素化合物,可以使用以下的方法。将7-(炔基)-山环素(8A)溶于饱和甲醇和盐酸并搅拌。然后将溶剂除去获得产物(8B)。
术语“烷基”包括饱和脂肪族基团,包括直链烷基(例如甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基等)、支链烷基(异丙基、叔丁基、异丁基等)、环烷基(脂环烃)基团(环丙基、环戊基、环己基、环庚基、环辛基)、烷基取代的环烷基以及环烷基取代的烷基。术语烷基还包括这样的烷基:它还包含氧、氮、硫或磷原子,替代所述烃主链的一个或多个碳原子。在某些实施方案中,直链或支链烷基主链具有6个或6个以下碳原子(例如C1-C6直链,C3-C6支链),更优选4个或更少。同样,优选环烷基的环结构具有3-8个碳原子,更优选具有5个或6个碳原子的环结构。术语C1-C6包括含1-6个碳原子的烷基。
此外,术语烷基包括“未取代的烷基”和“取代的烷基”,后者是指烃主链一个或多个碳原子上的氢被取代基取代的烷基部分。这样的取代基包括例如链烯基、链炔基、卤素、羟基、烷基羰氧基、芳基羰氧基、烷氧基羰氧基、芳氧基羰氧基、羧酸酯基、烷基羰基、芳基羰基、烷氧基羰基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、烷硫基羰基、烷氧基、磷酸酯基、膦酸酯基、次膦酸酯基、氰基、氨基(包括烷基氨基、二烷基氨基、芳基氨基、二芳基氨基和烷基芳基氨基)、酰基氨基(包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基)、脒基、亚氨基、巯基、烷硫基、芳硫基、硫代羧酸酯基、硫酸酯基、烷基亚磺酰基、磺酸酯基、氨磺酰基、亚磺酰氨基、硝基、三氟甲基、氰基、叠氮基、杂环基、烷基芳基、或者芳族或杂芳族部分。环烷基可进一步被取代,例如被上述取代基取代。“烷基芳基”或“芳烷基”部分为芳基取代的烷基(例如苯基甲基(苄基))。术语“烷基”还包括天然氨基酸和非天然氨基酸的侧链。
术语“芳基”包括可含0-4个杂原子的5-元和6-元单环芳族基团以及含,例如苯、苯基、吡咯、呋喃、噻吩、噻唑、异噻唑、咪唑、***、四唑、吡唑、噁唑、异噁唑、吡啶、吡嗪、哒嗪以及嘧啶等。此外,术语“芳基”包括多环芳基,例如三环、双环,例如萘、苯并噁唑、苯并二噁唑、苯并噻唑、苯并咪唑、苯并噻吩、亚甲二氧基苯基、喹啉、异喹啉、萘啶(napthridine)、吲哚、苯并呋喃、嘌呤、苯并呋喃、去氮嘌呤(deazapurine)或吲嗪。环结构中含有杂原子的芳基还可以称为“芳基杂环”、“杂环”、“杂芳基”或“杂芳族”。所述芳环可以在一个或多个环位上被上述取代基取代,这样的取代基例如卤素、羟基、烷氧基、烷基羰氧基、芳基羰氧基、烷氧基羰氧基、芳氧基羰氧基、羧酸酯基、烷基羰基、烷基氨基羰基、芳烷基氨基羰基、链烯基氨基羰基、烷基羰基、芳基羰基、芳烷基羰基、链烯基羰基、烷氧基羰基、氨基羰基、烷硫基羰基、磷酸酯基、膦酸酯基、次膦酸酯基、氰基、氨基(包括烷基氨基、二烷基氨基、芳基氨基、二芳基氨基和烷基芳基氨基)、酰基氨基(包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基)、脒基、亚氨基、巯基、烷硫基、芳硫基、硫代羧酸酯基、硫酸酯基、烷基亚磺酰基、磺酸酯基、氨磺酰基、亚磺酰氨基、硝基、三氟甲基、氰基、叠氮基、杂环基、烷基芳基、或者芳族或杂芳族部分。芳基还可以与非芳族脂环或杂环稠合或桥接形成多环(例如四氢萘)。
术语“链烯基”包括长度和可能的取代与上述烷基类似、但是至少包含一个双键的不饱和脂肪族基团。
例如,术语“链烯基”包括直链链烯基(例如乙烯基、丙烯基、丁烯基、戊烯基、己烯基、庚烯基、辛烯基、壬烯基、癸烯基等)、支链链烯基、环烯基(脂环烃)基团(环丙烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基)、烷基或链烯基取代的环烯基以及环烷基或环烯基取代的链烯基。术语链烯基还包括烃主链的一个或多个碳被氧、氮、硫或磷原子替代的链烯基。在某些实施方案中,直链或支链链烯基的主链具有6个或6个以下碳原子(例如C2-C6直链、C3-C6支链)。同样,环烯基的环结构中可以具有3-8个碳原子,更优选环结构中具有5个或6个碳原子。术语C2-C6包括含2-6个碳原子的链烯基。
此外,术语链烯基包括“未取代的链烯基”和“取代的链烯基”,后者是指烃主链一个或多个碳原子上的氢被取代基取代的链烯基部分。这样的取代基可包括例如烷基、链炔基、卤素、羟基、烷基羰氧基、芳基羰氧基、烷氧基羰氧基、芳氧基羰氧基、羧酸酯基、烷基羰基、芳基羰基、烷氧基羰基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、烷硫基羰基、烷氧基、磷酸酯基、膦酸酯基、次膦酸酯基、氰基、氨基(包括烷基氨基、二烷基氨基、芳基氨基、二芳基氨基和烷基芳基氨基)、酰基氨基(包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基)、脒基、亚氨基、巯基、烷硫基、芳硫基、硫代羧酸酯基、硫酸酯基、烷基亚磺酰基、磺酸酯基、氨磺酰基、亚磺酰氨基、硝基、三氟甲基、氰基、叠氮基、杂环基、烷基芳基、或者芳族或杂芳族部分。
术语“链炔基”包括长度和可能的取代与上述烷基类似、但是至少包含一个三键的不饱和脂肪族基团。
例如,术语“链炔基”包括直链链炔基(例如乙炔基、丙炔基、丁炔基、戊炔基、己炔基、庚炔基、辛炔基、壬炔基、癸炔基等)、支链链炔基以及环烷基或环烯基取代的链炔基。术语链炔基还包括烃主链的一个或多个碳被氧、氮、硫或磷原子替代的链炔基。在某些实施方案中,直链或支链链炔基主链具有6个或6个以下碳原子(例如C2-C6直链、C3-C6支链基团)。术语C2-C6包括含2-6个碳原子的链炔基。
此外,术语链炔基包括“未取代的链炔基”和“取代的链炔基”,后者是指烃主链一个或多个碳原子上的氢被取代基取代的链炔基部分。这样的取代基可以包括例如烷基、链炔基、卤素、羟基、烷基羰氧基、芳基羰氧基、烷氧基羰氧基、芳氧基羰氧基、羧酸酯基、烷基羰基、芳基羰基、烷氧基羰基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、烷硫基羰基、烷氧基、磷酸酯基、膦酸酯基、次膦酸酯基、氰基、氨基(包括烷基氨基、二烷基氨基、芳基氨基、二芳基氨基和烷基芳基氨基)、酰基氨基(包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基)、脒基、亚氨基、巯基、烷硫基、芳硫基、硫代羧酸酯基、硫酸酯基、烷基亚磺酰基、磺酸酯基、氨磺酰基、亚磺酰氨基、硝基、三氟甲基、氰基、叠氮基、杂环基、烷基芳基、或者芳族或杂芳族部分。
除非对碳原子的数量有其它具体说明,否则本文使用的“低级烷基”是指上文定义的烷基,但是其主链结构具有1-5个碳原子。“低级链烯基”和“低级链炔基”具有例如2-5个碳原子的链长。
术语“酰基”包括含酰基(CH3CO-)或羰基的化合物和部分。它包括取代的酰基部分。术语“取代的酰基”包括一个或多个氢原子被例如以下基团取代的酰基:烷基、链炔基、卤素、羟基、烷基羰氧基、芳基羰氧基、烷氧基羰氧基、芳氧基羰氧基、羧酸酯基、烷基羰基、芳基羰基、烷氧基羰基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、烷硫基羰基、烷氧基、磷酸酯基、膦酸酯基、次膦酸酯基、氰基、氨基(包括烷基氨基、二烷基氨基、芳基氨基、二芳基氨基和烷基芳基氨基)、酰基氨基(包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基)、脒基、亚氨基、巯基、烷硫基、芳硫基、硫代羧酸酯基、硫酸酯基、烷基亚磺酰基、磺酸酯基、氨磺酰基、亚磺酰氨基、硝基、三氟甲基、氰基、叠氮基、杂环基、烷基芳基、或者芳族或杂芳族部分。
术语“酰基氨基″包括其中酰基部分连接到氨基的部分。例如,所述术语包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基。
术语“芳酰基”包括芳基或杂芳族部分连接到羰基的化合物和部分。芳酰基的实例包括苯基羧基、萘基羧基等。
术语“烷氧基烷基”、“烷基氨基烷基”和“硫代烷氧基烷基”包括烃主链的一个或多个碳原子进一步被氧、氮或硫原子替代的上述烷基。
术语“烷氧基”包括取代和未取代的烷基、链烯基和链炔基以共价键连接到氧原子。烷氧基的实例包括甲氧基、乙氧基、异丙氧基、丙氧基、丁氧基以及戊氧基。取代的烷氧基的实例包括卤代烷氧基。烷氧基可以被例如以下基团取代:链烯基、链炔基、卤素、羟基、烷基羰氧基、芳基羰氧基、烷氧基羰氧基、芳氧基羰氧基、羧酸酯基、烷基羰基、芳基羰基、烷氧基羰基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、烷硫基羰基、烷氧基、磷酸酯基、膦酸酯基、次膦酸酯基、氰基、氨基(包括烷基氨基、二烷基氨基、芳基氨基、二芳基氨基和烷基芳基氨基)、酰基氨基(包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基)、脒基、亚氨基、巯基、烷硫基、芳硫基、硫代羧酸酯基、硫酸酯基、烷基亚磺酰基、磺酸酯基、氨磺酰基、亚磺酰氨基、硝基、三氟甲基、氰基、叠氮基、杂环基、烷基芳基、或者芳族或杂芳族部分。卤素取代的烷氧基实例包括但不限于氟甲氧基、二氟甲氧基、三氟甲氧基、氯甲氧基、二氯甲氧基、三氯甲氧基等。
术语“胺”或“氨基”包括氮原子以共价键连接至少一个碳或杂原子上的化合物。该术语包括“烷基氨基”,而“烷基氨基”包括其中的氮连接至少一个额外烷基的基团和化合物。术语“二烷基氨基”包括其中的氮原子连接至少两个额外烷基的基团。术语“芳基氨基”和“二芳基氨基”包括其中的氮分别连接至少一个或两个芳基的基团。术语“烷基芳基氨基”、“烷基氨基芳基”或“芳基氨基烷基”是指连接至少一个烷基和至少一个芳基的氨基。术语“链烷氨基烷基”是指烷基、链烯基或链炔基连接到氮原子,而氮原子再连接到烷基。
术语“酰胺”、“酰氨基”或“氨基羰基”包括所含氮原子连接到羰基或硫代羰基的碳原子的化合物或部分。该术语包括“链烷氨基羰基”或“烷基氨基羰基”,其为烷基、链烯基、芳基或炔基连接到氨基,而氨基再连接到羰基的基团。上述术语包括芳基氨基羰基和芳基羰基氨基,其为芳基或杂芳基部分连接到氨基,而氨基连接到羰基或硫代羰基的碳原子的基团。术语“烷基氨基羰基”、“链烯基氨基羰基”、“炔基氨基羰基”、“芳基氨基羰基”、“烷基羰基氨基”、“链烯基羰基氨基”、“炔基羰基氨基”以及“芳基羰基氨基”包括在术语“酰胺”中。酰胺也包括脲基(氨基羰基氨基)以及氨基甲酸酯(氧基羰基氨基)。
术语“羰基”或“羧基”包括含双键连接的碳原子和氧原子的化合物和部分。羰基可以进一步被任何允许本发明化合物发挥其预定作用的部分取代。例如,羰基部分可以被烷基、链烯基、链炔基、芳基、烷氧基、氨基等取代。含羰基的实例包括醛、酮、羧酸、酰胺、酯、酸酐等。
术语“硫代羰基”或“硫代羧基”包括含双键连接的碳原子和硫原子的化合物和部分。
术语“醚”包括含氧原子连接两个不同碳原子或杂原子的化合物或部分。例如,上述术语包括“烷氧基烷基”,它是指烷基、链烯基或链炔基以共价键连接到氧原子,氧原子再以共价键连接到另一烷基。
术语“酯”包括含碳原子或杂原子连接氧原子,而氧原子又连接到羰基碳原子上的化合物和部分。术语“酯”包括烷氧基羧基,例如甲氧基羰基、乙氧基羰基、丙氧基羰基、丁氧基羰基、戊氧基羰基等。烷基、链烯基或链炔基定义同上。
术语“硫醚”包括含硫原子连接两不同碳原子或杂原子的化合物和部分。硫醚的实例包括但不限于烷硫基烷基、烷硫基链烯基和烷硫基链炔基。术语“链烷硫基烷基”包括含烷基、链烯基或链炔基连接到硫原子,而硫原子又连接到烷基的化合物。同样地,术语“链烷硫基链烯基”和“链烷硫基链炔基”是其中烷基、链烯基或链炔基连接到硫原子,而硫原子又以共价键连接到链炔基的化合物或部分。
术语“氢氧基”或“羟基”包括-OH或-O-基团;
术语“卤素”包括氟、溴、氯、碘等。术语“全卤代”一般是指其中所有的氢原子被卤素原子取代的部分。
术语“多环基”或“多环基团”是指2个或2个以上环的基团(例如环烷基、环烯基、环炔基、芳基和/或杂环基),其中两个相邻环共有两个或多个碳原子,例如所述环为“稠合环”。环间连接不是通过相邻原子连接的环称为“桥连”环。多环中的各环可以被上述取代基取代,例如卤素、羟基、烷基羰氧基、芳基羰氧基、烷氧基羰氧基、芳氧基羰氧基、羧酸酯基、烷基羰基、烷氧基羰基、烷基氨基羰基、芳烷基氨基羰基、链烯基氨基羰基、烷基羰基、芳基羰基、芳烷基羰基、链烯基羰基、氨基羰基、烷硫基羰基、烷氧基、磷酸酯基、膦酸酯基、次膦酸酯基、氰基、酰氨基、氨基(包括烷基氨基、二烷基氨基、芳基氨基、二芳基氨基和烷基芳基氨基)、酰基氨基(包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基)、脒基、亚氨基、巯基、烷硫基、芳硫基、硫代羧酸酯基、硫酸酯基、烷基亚磺酰基、磺酸酯基、氨磺酰基、亚磺酰氨基、硝基、三氟甲基、氰基、叠氮基、杂环基、烷基、烷基芳基、或者芳族或杂芳族部分。
术语“杂原子”包括碳和氢以外的任何元素原子。杂原子优选氮、氧、硫和磷。
术语“前体药物部分”包括在体内可以代谢为羟基的部分和有利地在体内保持酯化的部分。优选前体药物部分通过酯酶或其它机制体内代谢为羟基或其它有益基团。药物前体实例及其用途为本领域众所周知(参见例如Berge等(1977)“Pharmaceutical Salts”,J.Pharm.Sci.66:1-19)。前体药物可以在最终分离或提纯化合物时在原位制备,或通过使纯化合物以其游离酸形式或羟基形式分别与合适的酯化剂反应制备。羟基可以通过用羧酸处理转化成酯。药物前体部分的实例包括取代和未取代、直链或支链低级烷基酯部分(例如丙酸酯)、低级链烯酯、二低级烷基-氨基低级-烷基酯(例如二甲基氨基乙酯)、酰基氨基低级烷基酯(例如乙酰氧基甲酯)、酰氧基低级烷基酯(例如新戊酰氧基甲酯)、芳基酯(苯基酯)、芳基-低级烷基酯(例如苯甲酯)、取代的(例如甲基、卤基或甲氧基取代基)芳基和芳基低级烷基酯、酰胺、低级烷基酰胺、二低级烷基酰胺以及羟基酰胺。优选前体药物部分为丙酸酯和酰基酯。
应当注意的是本发明部分四环素化合物的结构包括非对称碳原子。因此,应当理解除非另有说明,否则由于所述不对称引起的异构体(例如所有对映异构体和非对映异构体)都包括在本发明范围内。所述异构体可以通过标准分离技术和立体化学控制合成获得充分纯度异构体。此外,本申请讨论的结构和其它化合物及部分也包含其所有互变异构体。
本发明还涉及治疗患者四环素敏感性疾病的方法,该方法通过给予患者有效量的本发明7-取代四环素化合物(例如式(I)化合物或表1所示化合物),由此治疗四环素敏感性疾病。
术语“四环素化合物敏感性疾病”包括给予本发明四环素化合物能够治疗、预防或改善的疾病。四环素化合物敏感性疾病包括细菌感染(包括其它四环素化合物耐药性细菌感染)、癌症、糖尿病和已经发现四环素化合物对其有效的其它疾病(参见例如美国专利号5,789,395;5,834,450和5,532,227)。本发明化合物能够用于防止或控制重要哺乳动物和牲畜疾病,例如腹泻、泌尿道感染、皮肤和皮肤结构感染、耳鼻喉感染、伤口感染、乳腺炎等。此外,还包括用本发明四环素化合物***的方法(van der Bozert等,Cancer Res.,48:6686-6690(1988))。
细菌感染可能由各种不同革兰氏阳性和革兰氏阴性细菌引起。本发明化合物有效用作其它四环素化合物耐药性微生物的抗生素。本发明四环素化合物的抗生素活性可以用实施例2所述方法测定,或用Waitz,J.A.,National Commission for Clinical LaboratoryStandards,Document M7-A2,vol.10,no.8,pp.13-20,第二版,Villanova,PA(1990)中介绍的体外标准肉汤稀释法测定。
本发明四环素化合物还可以用来治疗传统用四环素化合物治疗的感染,例如立克次氏体;大量革兰阳性和革兰阴性细菌;以及性病性淋巴肉芽肿、包涵体结膜炎和鹦鹉热病原体。本发明四环素化合物可以用来治疗例如K.peneumoniae、沙门氏菌(Salmonella)、E.hirae、A.baumanii、B.catarrhalis、流感嗜血杆菌(H.influenzae)、P.aeruginosa、屎肠球菌(E.faecium)、大肠杆菌(E.coli)、S.aureus或粪肠球菌(E.faecalis)。在一个实施方案中,本发明四环素化合物用来治疗其它四环素抗生素化合物耐药性细菌感染。本发明四环素化合物可以与药学上可接受载体一起给药。
术语本发明化合物的“有效量”是治疗或预防四环素化合物敏感性疾病的必需量或合适量。有效量可以根据各种因素变化,这样的因素包括患者体型和体重、疾病类型或具体的四环素化合物。例如,对本发明四环素化合物的选择能够影响“有效量”。本领域普通技术人员应该能够考虑上述因素,无需过度试验就能确定本发明四环素化合物的有效量。
本发明还涉及微生物感染和相关性疾病的治疗方法。该方法包括给予患者有效量的一种或多种四环素化合物。所述患者可以是植物或动物,优选动物,例如哺乳动物,例如人类。
本发明治疗方法中,一种或多种本发明四环素化合物可以单独给予患者,更常见的是本发明化合物作为药用组合物组成部分与常规赋型剂混合给予,赋型剂即适用于肠胃外、口服或其它需要给药方式的药学上可接受的有机或无机载体物质,它不与活性化合物产生有害反应并且对其接患者无害。
本发明还涉及药用组合物,该组合物包含治疗有效量的四环素化合物(例如式I化合物、表2化合物以及本文介绍的其它化合物)以及任选药学上可接受的载体。
术语“药学上可接受的载体”包括能够与一种或多种本发明四环素化合物一起给予的物质,并且它允许两者都发挥其预定作用,例如治疗或预防四环素化合物敏感性疾病。适当的药学上可接受的载体包括(但不仅限于)水、盐溶液、醇、植物油、聚乙二醇、明胶、乳糖、直链淀粉、硬酯酸镁、滑石粉、硅酸、粘性石蜡、芳香油、甘油单脂肪酸酯和甘油二脂肪酸酯、petroethral脂肪酸酯、羟甲基纤维素、聚乙烯吡咯烷酮等。可以将药用制剂灭菌,如果需要可以与辅助剂混合,例如润滑剂、防腐剂、稳定剂、湿润剂、乳化剂、影响渗透压的盐、缓冲剂、着色剂、调味剂和/或芳香物质等,它们不与本发明活性化合物产生有害反应。
本身为碱性的本发明四环素化合物能够与不同无机或有机酸形成各种盐。可以用来制备本发明碱性四环素化合物的药学上可接受的酸加成盐的酸为形成非毒性酸加成盐的酸,所述盐即包含药学上可接受阴离子的盐,例如盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟碱酸盐、醋酸盐、乳酸盐、水杨酸盐、柠檬酸盐、酸式柠檬酸盐、酒石酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、延胡索酸盐、葡萄糖酸盐、葡萄糖二酸盐、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、棕榈酸盐[即1,1′-亚甲基-二-(2-羟基-3-萘甲酸盐)]。尽管所述盐给予患者例如哺乳动物时必须是药学上可接受的,但是实践中常常需要首先从反应混合物中分离出本发明四环素化合物的药学上不可接受的盐,然后用碱性试剂处理后者简单地将其转化为游离碱化合物,接着将后一游离碱转化为药学上可接受的酸加成盐。本发明碱性化合物的酸加成盐容易制备:在水性溶剂介质中或在合适的有机溶剂中,例如甲醇或乙醇,用足够当量的所选无机或有机酸处理所述碱性化合物。在小心地蒸去溶剂后,容易地获得所需要的固体盐。本领域熟练技术人员显而易见的是:在前述试验部分没有具体说明的本发明其它四环素化合物的制备,可以用不同组合的上述反应完成。
本领域熟练技术人员显而易见的是:在前述试验部分没有具体说明的本发明其它四环素化合物的制备,可以用不同组合的上述反应完成。
本身为酸性的本发明四环素化合物能够形成各种不同碱盐。可以用作制备本发明酸性四环素化合物的药学上可接受的碱盐的化学碱为与所述化合物形成非毒性碱盐的碱。这样的非毒性碱盐包括但不限于所述药学上可接受的阳离子产生的盐例如碱金属阳离子(例如钾和钠)和碱土金属阳离子(例如钙和镁)、铵或水溶性胺加成盐(例如N-甲基葡糖胺-(葡甲胺)和低级烷醇铵)以及药学上可接受的有机胺的其它碱盐。本身为酸性的本发明四环素化合物的药学上可接受的碱加成盐可以用常规方法与药学上可接受的阳离子形成。因此,这些盐很容易制备:用所需要的药学上可接受的阳离子水溶液处理本发明四环素化合物,蒸发所得溶液至干,优选减压蒸发。或者,可以将本发明四环素化合物的低级烷醇溶液与要求的金属醇化物混合,然后将溶液蒸发至干。
本领域熟练技术人员显而易见的是:在前述试验部分没有具体说明的本发明其它四环素化合物的制备,可以通过组合上述反应完成。
本发明四环素化物及其药学上可接受的盐可以通过口服、肠胃外或局部途径给药。通常,这些化合物的最理想给药是根据所治疗的患者的体重和病症以及所选择的给予其有效剂量的具体给药途径,给予有效剂量。给药变化的依据是所治疗的患者类型、对所述药物的个体反应以及所选择药物制剂的类型和进行所述给药的周期和间隔。
本发明药用组合物可以单独给予或者联合其它已知组合物用于治疗例如哺乳动物四环素敏感性疾病。优选哺乳动物包括宠物(例如猫、狗、雪貂等)、家畜(牛、绵羊、猪、马、山羊等)、试验动物(大鼠、小鼠、猴子等)以及灵长目(黑猩猩、人类、大猩猩)。术语“联合”已知组合物意味着包括同时给予本发明组合物和已知组合物、给予本发明组合物后给予已知组合物以及给予已知组合物后给予本发明组合物。本领域已知的用于治疗四环素敏感性疾病的任何治疗组合物可以用于本发明所述方法。
本发明化合物可以通过上述任何途径单独给予或联合药学上可接受的载体或稀释剂给予,并且可以单剂或多剂给予。例如,本发明的新的治疗药物可以以各种不同剂型给予,即它们可以为联合不同的药学上可接受的惰性载体的以下制剂形式:片剂、胶囊剂、锭剂、糖锭、硬糖、粉剂、喷雾剂、乳膏、油膏、栓剂、凝胶剂、凝胶体、糊剂、洗剂、软膏、水性混悬剂、注射溶液剂、酏剂、糖浆剂等。所述载体包括固体稀释剂或填充剂、无菌水介质和各种非毒性有机溶剂等。此外,口服药用组合物可以适当地增甜和/或调味。通常,本发明治疗有效化合物为所述剂型,浓度范围约为5.0%-70%重量百分比。
对于口服给药,包含不同赋型剂例如微晶纤维素、柠檬酸钠、碳酸钙、磷酸二钙和甘氨酸的片剂中可以使用不同的崩解剂例如淀粉(优选玉米、马玲薯或木薯淀粉)、藻酸和某些硅酸盐复合物,以及造粒粘合剂例如聚乙烯吡咯烷酮、蔗糖、明胶和***胶。此外,润滑剂例如硬酯酸镁、硫酸月桂酯钠和滑石粉经常用于压片。类似类型的固体组合物还可以用作明胶胶囊剂的填充剂;该方面的优选物质还包括乳糖或乳糖以及高分子量聚乙二醇。当需要口服给药的水性混悬剂和/或酏剂时,活性成分可以与不同甜味剂或调味剂、着色物质或颜料组合,并且如果需要也可加入乳化剂和/或混悬剂以及例如水、乙醇、丙二醇、甘油等稀释剂以及其不同的类似组合。
对于肠胃外给药(包括腹膜内、皮下、静脉、皮内或肌内注射),可以使用本发明治疗化合物在芝麻油或花生油或丙二醇水溶液中的溶液。如果需要,水溶液可适当缓冲(优选pH大于8),液体稀释剂首先使其等渗。这些水溶液适合静脉注射用。油性溶液适合关节、肌内以及皮下注射。用本领域熟练技术人员熟知的标准药学技术很容易在无菌条件下制备所有上述溶液剂。对于肠胃外应用,合适制剂的实例包括溶液剂,优选油性或水性溶液以及混悬剂、乳化剂或植入剂,包括栓剂。治疗化合物可以配制成无菌多剂或单剂形式,例如将其分散于液体载体例如常规注射用无菌生理盐水或5%盐的葡萄糖溶液。
此外,当治疗皮肤炎症时,也可以局部给予本发明化合物。局部给药方法实例包括透皮、口腔或舌下应用。对于局部应用,治疗化合物可以与药用惰性局部载体适当混合,例如凝胶、软膏、洗液或乳膏。所述局部载体包括水、甘油、乙醇、丙二醇、脂肪醇、甘油三酸酯、脂肪酸酯或矿物油。其它可能的局部载体为液体凡士林、棕榈酸异丙酯、聚乙二醇、95%乙醇、5%聚环氧乙烷单月桂酸酯水溶液、5%硫酸月桂酯钠水溶液等。另外,如果需要也可加入例如抗氧剂、湿润剂、粘度稳定剂等物质。
对于肠内应用,特别适合的是含有滑石粉和/或糖类载体粘合剂等的片剂、糖锭剂或胶囊剂,所述载体优选乳糖和/或玉米淀粉和/或马铃薯淀粉。可以使用其中应用增甜型溶媒的糖浆剂、酏剂等。可以配制持续释放组合物,包括例如通过微囊包封、复合包衣等用差别降解包衣保护活性成分的组合物。
除了治疗人类患者外,本发明治疗方法还具有有效兽医用途,例如治疗家畜,例如牛、绵羊、山羊、母牛、猪等;家禽例如鸡、鸭、鹅、火鸡等;马;以及宠物例如狗和猫。本发明化合物还可用于治疗非动物对象,例如植物。
应当知道,特定治疗中活性化合物的实际优选用量将根据使用的具体化合物、所配制的具体组合物、使用方式、具体给药位置等变化。特定给药方案的最佳给药速率可由本领域熟练技术人员按照上述原则用常规剂量测试试验就可容易地确定。
通常,用于治疗的本发明化合物可以按照以前四环素治疗使用的剂量给予患者。参见例如Physicians′Desk Reference。例如,本发明的一种或多种化合物的合适的有效剂量范围从0.01到100毫克/公斤患者体重/天,优选0.1到50毫克/公斤患者体重/天,更优选1到20毫克/公斤患者体重/天。要求的剂量可适当按每天一次或几次分剂量给予,例如2到5次分剂量,每天以适当间隔或其它适当进度给药。
应当理解,应该考虑通常给予四环素的常规已知注意事项以确保其在正常条件下的功效。尤其是当用于人和动物体内治疗性治疗时,医师应当考虑所有常识性注意事项以避免常规已知禁忌症或毒性作用。因此,通常公认的副作用:胃肠道不适和炎症、肾毒性、过敏反应、血象变化、以及铝、钙和镁离子吸收障碍应该常规适当考虑。
此外,本发明还涉及应用式I四环素化合物用于制备药物。所述药物可包括药学上可接受载体和有效量的四环素化合物,例如治疗四环素敏感性疾病的有效量。
举例说明本发明
本发明化合物可以如下所述制备,并可在本领域普通技术人员知识范围内进行改进。实施例1:合成7-取代山环素7-碘山环素
将1克山环素溶于用冰冷却至0℃的25mL TFA(三氟醋酸)。将1.2当量N-碘琥珀酰亚胺(NIS)加入反应混合物,反应40分钟。将反应除去冰浴,在室温下再反应5小时。然后将混合物用HPLC和TLC分析,逐步加入NIS使反应完成。反应完成后,真空除去TFA,加入3mL MeOH溶解残余物。将该甲醇溶液缓慢地加入快速搅拌的***溶液中以形成绿褐色的沉淀。山环素的7-碘异构体的提纯通过用活性炭处理,用硅藻土过滤,然后真空除去溶剂获得黄色固体的7-异构体化合物,收率75%。
MS(M+H)(甲酸溶剂)541.3。
\Rt:Hypersil C18BDS柱,11.73
1H NMR(甲醇d4-300MHz)δ7.87-7.90(d,1H),6.66-6.69(d,1H),4.06(s,1H),2.98(s,6H),2.42(M,1H),2.19(M,1H),1.62(M,4H),0.99(M,2H)化合物B(7-苯基山环素)
将7-碘山环素150mg(0.28mM)、Pd(OAc)2和10mL MeOH加入带搅拌棒的烧瓶,该体系用氩脱气三次。将溶解于水中并用氩脱气的Na2CO3(87mg,0.8mM)与苯基硼酸(68mg,0.55mM)的MeOH溶液(也经过脱气)一起用注射器加入。反应用HPLC监测2小时,冷却至室温。将溶液过滤,干燥获得粗制混合物。将固体溶解于二甲基甲酰胺,注入用C18反相二氧化硅的制备型HPLC体系。分离36-38分钟的部分,真空除去溶剂获得产物及盐。将盐萃取入50∶25∶25水∶丁醇∶醋酸乙酯中除去,再真空干燥。将该固体溶于MeOH,通入HCl气体制得HCl盐。除去溶剂获得产率为42%的黄色固体产物。
Rt21.6分钟:MS(M+H,甲酸溶剂):491.3
1H NMR(甲醇d4-300MHz)δ7.87(d,J=8.86Hz,1H),7.38(M,5H),6.64(d,8.87Hz,1H),4.00(s,1H),3.84(s,2H),3.01(s,6H),2.46(m,2H),1.63(M,4H),0.95(M,2H)化合物E(7-(4’-氯苯基)山环素)
将7-碘山环素500mg(0.91mM)、Pd(OAc)221mg和20mL MeOH加入带搅拌棒的烧瓶中,该体系用氩脱气3次。将溶解于水并且用氩脱气的Na2CO3(293mg,2.8mM)和4-Cl-苯基硼酸(289mg,1.85mM)的MeOH溶液(也经过脱气)一起用注射器加入。反应用HPLC监测45分钟,冷却至室温。将溶液过滤,干燥获得粗制混合物。将固体溶解于二甲基甲酰胺,注入用C18反相二氧化硅的制备型HPLC体系。分离39分钟的部分,真空除去溶剂获得产物及盐。将盐萃取入50∶25∶25水∶丁醇∶醋酸乙酯中除去,再真空干燥。将该固体溶于MeOH,通入HCl气体制得HCl盐。除去溶剂获得产率为57%的黄色固体产物。
Rt20.3分钟:MS(M+H,甲酸溶剂):525.7
1H NMR(甲醇D4-300MHz)δ7.47-7.52(d,J=8.54Hz,1H),6.97-7.01(d,8.61Hz,1H),4.12(s,1H),3.67(M,1H),3.06(s,6H),2.58(M,2H),1.62(m,4H),1.01(m,2H)化合物A(7-(4’-氟苯基)山环素)
将7-碘山环素200mg(0.3mM)、Pd(OAc)28.3mg和10mL MeOH加入带搅拌棒的烧瓶中,该体系用氩脱气3次。将溶解于水并且用氩脱气的Na2CO3(104mg,1.1mM)和4-F-苯基硼酸(104mg,0.7mM)的MeOH溶液(也经过脱气)一起用注射器加入。反应用HPLC监测20分钟,冷却至室温。将溶液过滤,干燥获得粗制混合物。将固体溶解于二甲基甲酰胺,注入用C18反相二氧化硅的制备型HPLC体系。分离19-20分钟的部分,真空除去溶剂获得产物及盐。将盐萃取入50∶25∶25水∶丁醇∶醋酸乙酯中除去,再真空干燥。将该固体溶于MeOH,通入HCl气体制得HCl盐。除去溶剂获得产率为47%的黄色固体产物。
Rt19.5分钟:MS(M+H,甲酸溶剂):509.4
1H NMR(甲醇d4-300MHz)δ6.92-6.95(d,1H),7.45-7.48(d,1H),7.15-7.35(M,4H),4.05(s,1H),3.62(m,1H),3.08(s,6H),2.55(M,2H),1.65(m,4H),1.00(m,2H)化合物AT(7-(4’-碘-1’,3’-乙酯基-1’,3’-丁二烯)山环素)
将7-I-山环素(1gm,1.86mmol)溶于25mL乙腈并脱气,通入氮气(三次)。在该悬浮液中加入Pd(OAc)2(20mg,.089mmol)、CuI(10mg,.053mmol)、(间甲苯基)3P(56mg,.183mmol),通入氮气。将丙炔酸乙酯(1mL)和三乙胺(1mL)加入悬浮液。悬浮液在加入Et3N后马上变为褐色溶液。然后将反应混合物加热至70℃2小时。反应进度用HPLC监测。然后将其冷却至室温,用硅藻土过滤。蒸去溶剂获得褐色固体,然后将其用制备型HPLC提纯获得黄色固体。化合物AI(7-(2’-氯乙烯基)-山环素)
0.65g(1mmol)7-碘山环素、0.05g四三苯基亚膦酸钯、0.012g醋酸钯、0.05g碘化亚铜(I)的10ml乙腈溶液/悬浮液在室温下加入2mL三乙胺和0.5g三甲基甲硅烷基乙炔。反应进行2小时,然后用硅藻土垫过滤,浓缩。粗产物用制备型HPLC提纯。浓缩收集的部分,将残余物溶解于约1mL甲醇和2mL HCl饱和的甲醇。用醚沉淀出产物。滤出固体,减压干燥。NMR光谱和LC-MS证实所得化合物为7-(2-氯乙烯基)山环素。化合物D(7-(4’-氨基苯基)山环素)
200mg7-(4-硝基苯基)山环素的50mL甲醇溶液中加入10mg10%碳载钯催化剂。将反应混合物在40psi氢气压下振摇2小时,然后过滤,再浓缩。残余物进一步用制备型HPLC提纯。分离出35mg的HCl盐,其结构通过MNR和LC-MS证实为7-(4-氨基苯基)山环素。化合物EF(1,8-二-7-山环素基-1,8-庚炔)
流程9
烧瓶中装入7-碘山环素(3.0g,4.57mmol,9A)、Pd(OAC)2(0.102g,0.46mmol)、CuI(0.044g,0.23mmol)和P(o-Tol)3(0.278g,0.91mmol),所有原料悬浮于无水乙腈。在60℃(浴温)通入氮后,加入1,7-辛二炔(0.305mL,2.29mmol,9B),接着加入三乙胺。将黑色溶液在60℃搅拌3小时,用硅藻土垫过滤,干燥。将产物(9C)的甲醇∶DMF∶TFA(90∶8∶2)溶液用制备型HPLC柱提纯。最终产品(9C)用HPLC、MS和1H NMR光谱表征。化合物U(7-(NN-二甲基丙炔基)-山环素)
将溶解于25mL乙腈的7-1-山环素(1gm,1.86mmol)脱气,通入氮(三次)。在该悬浮液中加入Pd(OAc)2(20mg,.089mmol)、CuI(10mg,.053mmol)、(间甲苯基)3P(56mg,0.183mmol),通入氮气几分钟。将N,N-二甲基丙炔(308mg,3.72mmol)和三乙胺(1mL)加入悬浮液。悬浮液在加入Et3N后马上变为褐色溶液。然后将反应混合物加热至70℃3小时。反应进度用HPLC监测。然后将其冷却至室温,用硅藻土过滤。蒸去溶剂获得褐色固体,然后将其用制备型HPLC提纯获得黄色固体。该化合物的结构已经用1H NMR、HPLC和MS表征。化合物BA(7-(2’-氯-3-羟基丙烯基)-山环素)
将7-(炔基)-山环素(100mg)溶解于20ml饱和MeOH/HCl,搅拌20分钟。然后将溶剂蒸去获得黄色粉末。该化合物的结构已经用1HNMR、HPLC和MS表征。化合物CC(7-(3’-甲氧基苯基乙基)-山环素)
将7-(3’-甲氧基苯基乙炔基)-山环素(1mmol)溶于MeOH/HCl饱和溶液。在该溶液中加入10%Pd/C,在50psi氢化12小时。然后用硅藻土过滤。将溶剂蒸去获得黄色粉末。最后,用MeOH/***沉淀出产物。所得化合物的结构已经用1H NMR、HPLC和MS表征。化合物CW((2-二甲基氨基-乙酰基氨基)-山环素)
流程10
将N,N-二甲基甘氨酸(1.2mmol)溶解于DMF(5mL),加入间苯并***-1-基-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(HBTU,1.2mmol)。然后将溶液在室温下搅拌5分钟。在该溶液中加入7-氨基山环素(1mmol,10A),接着加入二异丙基乙胺(DIEA,1.2mmol)。将反应物在室温下搅拌2小时。真空除去溶剂DMF。将粗制产物溶解于5mLMeOH,用autovials过滤,用制备型HPLC提纯。产物的结构(10B)已经用1H NMR、HPLC和MS表征。化合物DJ(7-(N-甲基亚磺酰氨基炔丙基胺)山环素)
流程11
在干净无水2颈圆底烧瓶中,7-碘山环素单三氟醋酸盐(1g;1.53mmoles,11A)、醋酸钯II(17.2mg;0.076mmoles)、四三苯基膦钯(176.8mg;0.153mmoles)和碘化亚铜(I)(49mg;0,228mmoles)的混合物中加入装有15ml试剂级乙腈。反应物在搅拌下通入缓慢的氩气流5分钟,然后加入(一次性加入固体)N-甲基亚磺酰氨基炔丙基胺(11B)。磺胺按照本领域已知的方法制备(J.Med.Chem31(3)1988;577-82)。然后加入1ml三乙胺(1ml;0.726mg;7.175mmoles),在亚气氛下于室温搅拌反应物约1.0小时。将反应混合物用硅藻土垫抽滤,用乙腈洗涤。滤液在真空下除去至干,残余物用三氟醋酸的乙腈溶液处理以调节pH至约2。残余物再用稀三氟醋酸乙腈溶液处理,导致沉淀形成,将其抽滤移出。将粗制的滤液用反相HPLC(DVB作为固体相;梯度1∶1甲醇/乙腈的1%三氟醋酸和1%三氟醋酸水溶液)提纯。将适当的部分减压下除去至干,收集固体。产物(11C)用1H NMR、质谱和LC反相表征。化合物BK(7-(2’-甲氧基-5’-甲酰基苯基)山环素)
流程12
将7-碘-山环素(12A,1g,1.53mmol)、Pd(OAc)2(34mg,0.153mmol)和MeOH(50mL)加入配有冷凝器和氩气管的250mL2颈圆底烧瓶中。然后在溶液中通入氩气(15分钟),同时在油浴中加热至约70℃。将碳酸钠(482mg,4.58mmol)溶于水(3-5mL),加入反应烧瓶。然后在烧瓶中再通入氩气5分钟。将2-甲氧基-5-甲酰基苯基硼酸(12B,333mg,1.83mmol)溶于MeOH(5ml),加入反应烧瓶。然后向烧瓶中再次通入氩气10分钟。监测到反应在3小时内完成。烧瓶内的所有反应物用滤纸过滤,排空残留溶剂。为了制备盐酸盐,将残余物溶于MeOH(饱和HCl)制备HCl盐。然后过滤溶液,排空溶剂。然后将产物(12C)用1H NMR、LC-MS表征。化合物FD(7-(2’-甲氧基-5'-N,N’-二甲基氨基甲基苯基)山环素)
流程13
将醛(12A,1g,1.82mmol)、二甲胺HCl(13B,297mg,3.64mmol)、三乙胺(506μL,3.64mmol)和1,2-DCE(7mL)合并加入40ml小瓶中。将反应物经过几分钟振摇或搅拌溶解。然后加入固体三乙氧基硼氢化钠(772mg,3.64mmol)。反应用HPLC和LC-MS监测,在3小时内完成。将反应用MeOH(20mL)猝灭,随后排空溶剂。将残余物再次溶解于3mL DMF,用C-18柱分离。制备柱部分在真空下干燥,HCl盐通过将反应物溶解于甲醇(饱和HCl)制备。除去溶剂,生成黄色粉末(13C)。用1H NMR、LC-MS、HPLC表征。实施例2:体外最小抑制浓度(MIC)测定
下述实验用于测定四环素化合物对普通细菌的作用。将2mg各化合物溶解于100μl DMSO。然后将该溶液加入已调节阳离子的Mueller Hinton肉汤培养基(CAMHB)中,最终化合物浓度200μg/ml。把四环素化合物溶液稀释为50μL体积,受试化合物的浓度为0.098μg/ml。用受试菌株的新鲜对数期肉汤培养基测定光密度(OD)。进行稀释使得细胞最终密度为1×106CFU/ml。OD=1时,不同属细菌细胞密度大约为:
大肠杆菌 1×109CFU/ml
S.aureus 5×108CFU/ml
肠球菌(Enterococcus sp.) 2.5×109CFU/ml
在微量滴定板每孔中加入50μl细菌细胞悬浮液。最终细胞密度大约为5×105CFU/ml。将板在35℃环境大气的孵箱中培养约18小时。用微量板读数仪读板,必要时肉眼检测。MIC定义为抑制生长的最小四环素化合物浓度。本发明化合物显示良好的生长抑制作用。
在表1中,*表示化合物为特定细菌的良好生长抑制剂,**表示化合物为特定细菌的非常好的生长抑制剂,***表示化合物为特定细菌的特别良好的生长抑制剂。等同实施方案
Claims (88)
1.一种下式I的取代四环素化合物及其药学上可接受盐:
其中:
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、链炔基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基氨基、芳基烷基、芳基、杂环基、杂芳基或前体药物部分;
R4为NR4’R4”、烷基、链烯基、链炔基、芳基、羟基、卤素或氢;
R2’、R3、R10、R11和R12各自为氢或前体药物部分;
R5为羟基、氢、巯基、烷酰基、芳酰基、烷芳酰基、芳基、杂芳基、烷基、链烯基、链炔基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基氨基、芳基烷基、烷基羰氧基或芳基羰氧基;
R6和R6’各自独立为氢、亚甲基、不存在、羟基、卤素、巯基、烷基、链烯基、链炔基、芳基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基氨基或芳基烷基;
R7为硝基、烷基、链烯基、链炔基、芳基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、芳基烷基、氨基、芳基链烯基、芳基链炔基或-(CH2)0-3NR7cC(=W’)WR7a;
R9为氢、硝基、烷基、链烯基、链炔基、芳基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、芳基烷基、氨基、芳基链烯基、芳基链炔基、硫代亚硝基(例如-N=S)或-(CH2)0-3NR9cC(=Z’)ZR9a;
Z为CR9dR9e、S、NR9b或O;
Z’为O、S或NR9f;
W为CR7dR7e、S、NR7b或O;
W’为O、NR7fS;
R7a、R7b、R7c、R7d、R7e、R9a、R9b、R9c、R9d和R9e各自独立为氢、酰基、烷基、链烯基、链炔基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基氨基、芳基烷基、芳基、杂环基、杂芳基或前体药物部分;
R8为氢、羟基、卤素、巯基、烷基、链烯基、链炔基、芳基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基氨基或芳基烷基;
R13为氢、羟基、烷基、链烯基、链炔基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基氨基或芳基烷基;
Y’和Y各自独立为氢、卤素、羟基、氰基、巯基、氨基、烷基、链烯基、链炔基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基氨基、或芳基烷基。
2.权利要求1的四环素化合物,其中R4为NR4’R4”,X为CR6R6’;R2、R2’、R6、R6’、R8、R9、R10、R11和R12各自为氢;R4’和R4”为低级烷基;R5为羟基或氢。
3.权利要求2的四环素化合物,其中R4’和R4”各自为甲基,R5为氢。
4.权利要求1-3任一项的四环素化合物,其中R7为芳基。
5.权利要求4的四环素化合物,其中R7为取代或未取代的苯基。
6.权利要求5的四环素化合物,其中所述苯基被选自以下的取代基取代:烷基、链烯基、卤素、羟基、烷氧基、烷基羰氧基、烷氧基羰基、芳基羰氧基、烷氧基羰基氨基、烷氧基羰氧基、芳氧基羰氧基、羧酸酯基、烷基羰基、烷基氨基羰基、芳基烷基氨基羰基、链烯基氨基羰基、烷基羰基、芳基羰基、氨基烷基、芳基烷基羰基、链烯基羰基、烷氧基羰基、甲硅烷基、氨基羰基、烷硫基羰基、磷酸酯基、芳烷基、膦酸酯基、次膦酸酯基、氰基、氨基、酰基氨基、酰氨基、亚氨基、巯基、烷硫基、硫酸酯基、芳硫基、硫代羧酸酯基、烷基亚磺酰基、磺酸酯基、氨磺酰基、亚磺酰氨基、硝基、氰基、叠氮基、杂环基、烷基芳基、芳基和杂芳基。
7.权利要求6的四环素化合物,其中所述取代基为取代或未取代的烷基。
8.权利要求5的四环素化合物,其中所述烷基被杂环取代。
9.权利要求8的四环素化合物,其中所述杂环为吗啉、哌啶或吡咯烷。
10.权利要求5的四环素化合物,其中所述苯基被氨基取代。
11.权利要求10的四环素化合物,其中所述氨基被一个或多个选自烷基、链烯基、链炔基、羰基、烷氧基和芳基的取代基取代。
12.权利要求11的四环素化合物,其中所述氨基被烷氧基取代。
13.权利要求11的四环素化合物,其中所述氨基被取代或未取代的苯基取代。
14.权利要求13的四环素化合物,其中所述取代的苯基被卤素取代。
1 5.权利要求13的四环素化合物,其中所述取代的苯基氨基被第二个取代的氨基取代。
16.权利要求15的四环素化合物,其中所述第二个取代的氨基为取代或未取代的芳基。
17.权利要求16的四环素化合物,其中所述第二个取代的氨基为第二个取代的苯基。
18.权利要求5的四环素化合物,其中所述苯基被烷氧基取代。
19.权利要求5的四环素化合物,其中所述苯基被烷氧基羰基氨基取代。
20.权利要求4的四环素化合物,其中所述芳基为取代或未取代的萘基。
21.权利要求20的四环素化合物,其中所述萘基被一个或多个选自以下的取代基取代:烷基、链烯基、卤素、羟基、烷氧基、烷基羰氧基、烷氧基羰基、羧基、芳基羰氧基、烷氧基羰基氨基、烷氧基羰氧基、芳氧基羰氧基、羧酸酯基、烷基羰基、烷基氨基羰基、芳基烷基氨基羰基、链烯基氨基羰基、烷基羰基、芳基羰基、氨基烷基、芳基烷基羰基、链烯基羰基、烷氧基羰基、甲硅烷基、氨基羰基、烷硫基羰基、磷酸酯基、芳烷基、膦酸酯基、次膦酸酯基、氰基、氨基、酰基氨基、酰氨基、亚氨基、巯基、烷硫基、硫酸酯基、芳硫基、硫代羧酸酯基、烷基亚磺酰基、磺酸酯基、氨磺酰基、亚磺酰氨基、硝基、氰基、叠氮基、杂环基、烷基芳基、芳基和杂芳基。
22.权利要求21的四环素化合物,其中所述取代基为氨基或甲酰基。
23.权利要求4的四环素化合物,其中R7为杂芳基。
24.权利要求23的四环素化合物,其中所述杂芳基选自:呋喃基、咪唑基、苯并硫代苯基、苯并呋喃基、喹啉基、异喹啉基、吡啶基、吡唑基、苯并二噁唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、亚甲二氧基苯基、吲哚基、噻吩基、嘧啶基、吡嗪基、嘌呤基、吡唑基、噁唑基、异噁唑基、1,5-二氮杂萘基、噻唑基、异噻唑基和去氮嘌呤基。
25.权利要求24的四环素化合物,其中所述杂芳基为噻唑基、硫代苯基或呋喃基。
26.权利要求1-3任一项的四环素化合物,其中R7为取代或未取代的烷基。
27.权利要求26的四环素化合物,其中所述烷基为直链或支链烷基。
28.权利要求27的四环素化合物,其中所述烷基为甲基、乙基、异丙基、正丙基、正丁基、异丁基、叔丁基、戊基或己基。
29.权利要求26的四环素化合物,其中所述烷基包括环烷基。
30.权利要求29的四环素化合物,其中所述环烷基为环戊基、环己基、环丙基或环丁基。
31.权利要求26的四环素化合物,其中所述烷基被一个或多个选自以下的取代基取代:链烯基、卤素、羟基、烷氧基、烷基羰氧基、烷氧基羰基、羧基、芳基羰氧基、烷氧基羰基氨基、烷氧基羰氧基、芳氧基羰氧基、羧酸酯基、烷基羰基、烷基氨基羰基、芳基烷基氨基羰基、链烯基氨基羰基、烷基羰基、芳基羰基、氨基烷基、芳基烷基羰基、链烯基羰基、烷氧基羰基、甲硅烷基、氨基羰基、烷硫基羰基、磷酸酯基、芳烷基、膦酸酯基、次膦酸酯基、氰基、氨基、酰基氨基、酰氨基、亚氨基、巯基、烷硫基、硫酸酯基、芳硫基、硫代羧酸酯基、烷基亚磺酰基、磺酸酯基、氨磺酰基、亚磺酰氨基、硝基、氰基、叠氮基、杂环基、烷基芳基、芳基和杂芳基。
32.权利要求31的四环素化合物,其中所述烷基被氨基、羟基、羧基、羰基或芳基取代。
33.权利要求32的四环素化合物,其中所述芳基为杂芳基。
34.权利要求33的四环素化合物,其中所述杂芳基为呋喃基、咪唑基、苯并硫代苯基、苯并呋喃基、喹啉基、异喹啉基、苯并二噁唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、亚甲二氧基苯基、吲哚基、噻吩基、吡啶基、吡唑基、嘧啶基、吡嗪基、嘌呤基、吡唑基、噁唑基、异噁唑基、1,5-二氮杂萘基、噻唑基、异噻唑基和去氮嘌呤基。
35.权利要求34的四环素化合物,其中所述杂芳基为吡啶基。
36.权利要求32的四环素化合物,其中所述芳基为取代或未取代的苯基。
37.权利要求36的四环素化合物,其中所述苯基被亚磺酰氨基或烷基取代。
38.权利要求32的四环素化合物,其中所述羰基为吗啉基羰基。
39.权利要求1-3任一项的四环素化合物,其中R7为取代或未取代的链烯基。
40.权利要求39的四环素化合物,其中所述链烯基被一个或多个选自以下的取代基取代:烷基、卤素、羟基、烷氧基、烷基羰氧基、烷氧基羰基、羧基、芳基羰氧基、烷氧基羰基氨基、烷氧基羰氧基、芳氧基羰氧基、羧酸酯基、烷基羰基、烷基氨基羰基、芳基烷基氨基羰基、链烯基氨基羰基、烷基羰基、芳基羰基、氨基烷基、芳基烷基羰基、链烯基羰基、烷氧基羰基、甲硅烷基、氨基羰基、烷硫基羰基、磷酸酯基、芳烷基、膦酸酯基、次膦酸酯基、氰基、氨基、酰基氨基、酰氨基、亚氨基、巯基、烷硫基、硫酸酯基、芳硫基、硫代羧酸酯基、烷基亚磺酰基、磺酸酯基、氨磺酰基、亚磺酰氨基、硝基、氰基、叠氮基、杂环基、烷基芳基、芳基和杂芳基。
41.权利要求40的四环素化合物,其中所述链烯基被氨基羰基或烷氧基羰基取代。
42.权利要求41的四环素化合物,其中所述氨基羰基为二烷基氨基羰基。
43.权利要求40的四环素化合物,其中所述链烯基被一个或多个卤素取代。
44.权利要求40的四环素化合物,其中所述链烯基被一个或多个羟基取代。
45.权利要求40的四环素化合物,其中所述链烯基被杂芳基取代。
46.权利要求45的四环素化合物,其中所述杂芳基选自:呋喃基、咪唑基、苯并硫代苯基、苯并呋喃基、喹啉基、异喹啉基、苯并二噁唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、亚甲二氧基苯基、吲哚基、噻吩基、吡啶基、吡唑基、嘧啶基、吡嗪基、嘌呤基、吡唑基、噁唑基、异噁唑基、1,5-二氮杂萘基、噻唑基、异噻唑基和去氮嘌呤基。
47.权利要求46的四环素化合物,其中所述杂芳基为噻唑基。
48.权利要求40的四环素化合物,其中所述芳基取代基为取代或未取代的苯基。
49.权利要求48的四环素化合物,其中所述取代的苯基被一个或多个卤素、烷氧基、羟基或烷基取代。
50.权利要求49的四环素化合物,其中所述取代的苯基被一个或多个氟取代。
51.权利要求1-3任一项的四环素化合物,其中R7为取代或未取代的链炔基。
52.权利要求51的四环素化合物,其中所述取代的链炔基被芳基取代。
53.权利要求52的四环素化合物,其中所述取代的链炔基被取代或未取代的苯基取代。
54.权利要求53的四环素化合物,其中所述取代的苯基被一个或多个选自以下的取代基取代:烷基、卤素、羟基、烷氧基、烷基羰氧基、烷氧基羰基、羧基、烷基羰基氨基、芳基羰氧基、烷氧基羰基氨基、烷氧基羰氧基、芳氧基羰氧基、羧酸酯基、烷基羰基、烷基氨基羰基、芳基烷基氨基羰基、链烯基氨基羰基、烷基羰基、芳基羰基、氨基烷基、芳基烷基羰基、链烯基羰基、烷氧基羰基、甲硅烷基、氨基羰基、烷硫基羰基、磷酸酯基、芳烷基、膦酸酯基、次膦酸酯基、氰基、氨基、酰基氨基、酰氨基、亚氨基、巯基、烷硫基、硫酸酯基、芳硫基、硫代羧酸酯基、烷基亚磺酰基、磺酸酯基、氨磺酰基、亚磺酰氨基、硝基、氰基、叠氮基、杂环基、烷基芳基、芳基和杂芳基。
55.权利要求54的四环素化合物,其中所述苯基被烷基羰基氨基或亚磺酰氨基取代。
56.权利要求51的四环素化合物,其中所述取代的链炔基被四环素部分取代。
57.权利要求1-3任一项的四环素化合物,其中R7为烷基羰基氨基。
58.权利要求1-3任一项的四环素化合物,其中R7为羰基。
59.权利要求58的四环素化合物,其中R7为取代或未取代的烷基羰基。
60.权利要求59的四环素化合物,其中所述烷基羰基被芳基取代。
61.权利要求60的四环素化合物,其中所述芳基取代基为杂芳基。
62.权利要求61的四环素化合物,其中所述杂芳基取代基为吡啶基。
63.权利要求1-3任一项的四环素化合物,其中R7为取代或未取代的亚氨基。
64.权利要求1-3任一项的四环素化合物,其中所述取代的亚氨基被羟基或烷基取代。
65.权利要求1-3任一项的四环素化合物,其中R7为NR7c(C=W’)WR7a。
66.权利要求55的四环素化合物,其中R7c为氢,W’为氧,W为氧。
67.权利要求65或66的四环素化合物,其中R7a为取代或未取代的苯基。
68.权利要求67的四环素化合物,其中所述取代的苯基被一个或多个选自以下的取代基取代:烷基、卤素、羟基、烷氧基、烷基羰氧基、烷氧基羰基、羧基、烷基羰基氨基、芳基羰氧基、烷氧基羰基氨基、烷氧基羰氧基、芳氧基羰氧基、羧酸酯基、烷基羰基、烷基氨基羰基、芳基烷基氨基羰基、链烯基氨基羰基、烷基羰基、芳基羰基、氨基烷基、芳基烷基羰基、链烯基羰基、烷氧基羰基、甲硅烷基、氨基羰基、烷硫基羰基、磷酸酯基、芳烷基、膦酸酯基、次膦酸酯基、氰基、氨基、酰基氨基、酰氨基、亚氨基、巯基、烷硫基、硫酸酯基、芳硫基、硫代羧酸酯基、烷基亚磺酰基、磺酸酯基、氨磺酰基、亚磺酰氨基、硝基、氰基、叠氮基、杂环基、烷基芳基、芳基和杂芳基。
69.权利要求65或66的四环素化合物,其中R7a为烷基。
70.权利要求1-3任一项的四环素化合物,其中R7为亚磺酰氨基。
其中:
R4’和R4”各自为烷基;
R7为式
的稠环部分,其中Q为C或杂原子;酰基呋喃基;三、四或五卤代苯基;氨基甲基苯基;酰基氨基甲基;烷基酯苯基;酰基苯基;酰基炔基;酰基烷氧基苯基;甲基苯基;二甲基苯基;羧基苯基;羧基炔基;噻吩基;卤代噻吩基;烷氧基羰基苯基;烷氧基苯基;烷氧基苯基炔基;烷氧基吡啶基;亚烷基吡啶基;环戊基或环戊烯基;环己基炔基;环己烯基炔基;环己烯基卤代链烯基;羟基环己基炔基;苯基炔基;苯基链烯基;氨基炔基;环丁基链烯基;吡啶基炔基;吡啶基链烯基;硝基苯基炔基;硝基苯基链烯基;氰基炔基;链炔基;氰基链烯基;氰基苯基;二烷基酰氨基链烯基;二烷基酰氨基苯基;氨基苯基乙基;氨基苯基乙炔基;卤代乙烯基;卤代苯基炔基;或烷基酯取代的戊烯基。
73.权利要求72的化合物,其中所述化合物为7-(2-苯并呋喃)山环素、7-(3-甲酰基呋喃基)山环素、7-(2,3,4,5,6-五氟苯基)山环素、7-(4-氨基甲基苯基)山环素、7-(4-甲酰基氨基甲基苯基)山环素、7-(4-羧基苯基甲酯)山环素、7-(2-羧基苯基乙酯)山环素、7-(4-甲苯基)山环素、7-(3-甲酰基苯基)山环素、7-(4-甲酰基苯基)山环素、7-(3-乙酰基苯基)山环素、7-(2-乙酰基苯基)山环素、7-(3-乙酰基苯基)山环素、7-(4-乙酰基苯基)山环素、7-(3-甲酰基-6-甲氧基苯基)山环素、7-(4-甲基苯基)山环素、7-(3,5-二甲基苯基)山环素、7-(3-羧基苯基)山环素、7-(羧基乙炔基)山环素、7-(3-噻吩)山环素、7-(3-甲基-2-噻吩)山环素、7-(3-甲基-5-噻吩)山环素、7-(3-氯-2-噻吩)山环素和7-(4-氯-2-噻吩)山环素、7-(2-乙氧基羰基苯基)山环素、7-(2-乙氧基苯基)山环素、7-(3-乙氧基苯基)山环素、7-(4-甲氧基苯基)山环素、7-(2,5-二甲氧基苯基)山环素、7-(4-甲氧基苯基乙炔基)山环素、7-(4-甲氧基-5-吡啶基)山环素、7-(环戊烯基)山环素、7-(环己基乙炔基)山环素、7-(1-乙炔基-1-环己基)山环素、7-(1-氯乙烯基-1-环己基)山环素、7-(1-乙炔基-1-羟基环己基)山环素、7-(苯基乙炔基)山环素、7-(甲苯基乙炔基)山环素、7-(4-甲氧基苯基乙炔基)山环素、7-(2-乙烯基吡啶基)山环素、7-(乙烯基苯基)山环素、7-(二甲基氨基乙炔基)山环素、7-(环丁基甲烯基)山环素、7-(2-吡啶基乙炔基)山环素、7-(3-吡啶基乙炔基)山环素、7-(4-吡啶基乙烯基)山环素、7-(氰基-1-戊炔基)山环素、7-(氰基己烯基)山环素、7-(3-氰基苯基)山环素、7-(4-氰基苯基)山环素、7-(3-羟基苯基乙炔基)山环素、7-(N,N-二甲基丙烯酰胺)山环素、7-(二甲基酰氨基乙烯基)山环素、7-(4-硝基苯基乙炔基)山环素、7-(4-硝基苯乙烯基)山环素、7-(乙炔基)山环素、7-(N,N-二甲基丙烯酰胺)山环素、7-(3-二甲基酰氨基苯基)山环素、7-(4-甲氧基苯基)山环素、7-(4-氨基苯基乙基)山环素、7-(2-氯乙烯基)山环素、7-(2-氟苯基乙烯基)山环素、7-(1-碘-1,3-二乙酯基-1,3-丁二烯)山环素或7-(4-氨基苯基乙烯基)山环素。
74.权利要求1或71的化合物,其中所述化合物至少为75%,其不包括位置异构体。
75.权利要求74的化合物,其中所述化合物至少为80%,其不包括位置异构体。
76.权利要求75的化合物,其中所述化合物至少为85%,其不括位置异构体。
77.权利要求76的化合物,其中所述化合物至少为90%,其不括位置异构体。
78.权利要求77的化合物,其中所述化合物至少至95%,其不括位置异构体。
79.一种治疗患者四环素敏感性疾病的方法,该方法包括给予所述患者权利要求1、71或72的四环素化合物,由此治疗所述患者。
80.权利要求79的方法,其中所述四环素敏感性疾病为细菌感染。
81.权利要求80的方法,其中所述细菌感染为大肠杆菌感染。
82.权利要求80的方法,其中所述细菌感染为S.aureus感染。
83.权利要求80的方法,其中所述细菌感染为粪肠球菌(E.faecalis)感染。
84.权利要求80的方法,其中所述细菌感染为其它四环素抗生素耐药性细菌感染。
85.权利要求79的方法,其中所述患者为人。
86.权利要求79的方法,其中所述四环素化合物用药学上可接受的载体给药。
87.一种取代的四环素化合物,该化合物选自表2所列的化合物。
88.一种药用组合物,该组合物包含治疗有效量的权利要求1、71、72或87的四环素化合物和药学上可接受的载体。
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103214409A (zh) * | 2004-05-21 | 2013-07-24 | 哈佛大学校长及研究员协会 | 四环素及其类似物的合成 |
CN103214409B (zh) * | 2004-05-21 | 2015-10-21 | 哈佛大学校长及研究员协会 | 四环素及其类似物的合成 |
CN113717073A (zh) * | 2021-08-26 | 2021-11-30 | 河北圣雪大成制药有限责任公司 | 一种合成盐酸米诺环素的新方法 |
CN113717073B (zh) * | 2021-08-26 | 2023-11-14 | 河北圣雪大成制药有限责任公司 | 一种合成盐酸米诺环素的新方法 |
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