CN1690047A - 9-取代的二甲胺四环素化合物 - Google Patents
9-取代的二甲胺四环素化合物 Download PDFInfo
- Publication number
- CN1690047A CN1690047A CNA2005100530441A CN200510053044A CN1690047A CN 1690047 A CN1690047 A CN 1690047A CN A2005100530441 A CNA2005100530441 A CN A2005100530441A CN 200510053044 A CN200510053044 A CN 200510053044A CN 1690047 A CN1690047 A CN 1690047A
- Authority
- CN
- China
- Prior art keywords
- group
- alkyl
- minocycline
- carbonyl
- 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.)
- Granted
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- DYKFCLLONBREIL-KVUCHLLUSA-N minocycline Chemical class C([C@H]1C2)C3=C(N(C)C)C=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O DYKFCLLONBREIL-KVUCHLLUSA-N 0.000 title claims description 241
- -1 tetracycline compound Chemical class 0.000 claims abstract description 316
- 229960004023 minocycline Drugs 0.000 claims abstract description 138
- 239000004098 Tetracycline Substances 0.000 claims abstract description 91
- 229960002180 tetracycline Drugs 0.000 claims abstract description 91
- 229930101283 tetracycline Natural products 0.000 claims abstract description 91
- 235000019364 tetracycline Nutrition 0.000 claims abstract description 91
- 150000003522 tetracyclines Chemical class 0.000 claims abstract description 18
- 208000035143 Bacterial infection Diseases 0.000 claims abstract description 4
- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 111
- 125000003118 aryl group Chemical group 0.000 claims description 86
- 125000003545 alkoxy group Chemical group 0.000 claims description 74
- 125000003342 alkenyl group Chemical group 0.000 claims description 73
- 125000000304 alkynyl group Chemical group 0.000 claims description 73
- 150000001875 compounds Chemical class 0.000 claims description 73
- 238000000034 method Methods 0.000 claims description 50
- 229910052760 oxygen Inorganic materials 0.000 claims description 48
- 125000004414 alkyl thio group Chemical group 0.000 claims description 43
- 239000001301 oxygen Substances 0.000 claims description 43
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 41
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 41
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims description 40
- 239000001257 hydrogen Substances 0.000 claims description 40
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 40
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 39
- 125000001072 heteroaryl group Chemical group 0.000 claims description 37
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 36
- 239000000203 mixture Substances 0.000 claims description 32
- 125000003282 alkyl amino group Chemical group 0.000 claims description 31
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 30
- 239000002253 acid Substances 0.000 claims description 29
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 26
- 201000010099 disease Diseases 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 25
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 24
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 24
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 24
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 23
- 150000002431 hydrogen Chemical group 0.000 claims description 22
- 241000894006 Bacteria Species 0.000 claims description 21
- 125000003368 amide group Chemical group 0.000 claims description 21
- 125000003262 carboxylic acid ester group Chemical group [H]C([H])([*:2])OC(=O)C([H])([H])[*:1] 0.000 claims description 21
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 20
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 20
- 125000004442 acylamino group Chemical group 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 229910019142 PO4 Inorganic materials 0.000 claims description 18
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 18
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 18
- 239000011630 iodine Substances 0.000 claims description 18
- 229910052740 iodine Inorganic materials 0.000 claims description 18
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 18
- 239000010452 phosphate Substances 0.000 claims description 18
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 17
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 17
- 125000004691 alkyl thio carbonyl group Chemical group 0.000 claims description 17
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 17
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 17
- 125000005110 aryl thio group Chemical group 0.000 claims description 17
- 125000004185 ester group Chemical group 0.000 claims description 17
- 239000000651 prodrug Substances 0.000 claims description 17
- 229940002612 prodrug Drugs 0.000 claims description 17
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 17
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 17
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims description 17
- 150000002148 esters Chemical class 0.000 claims description 15
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 14
- 125000005089 alkenylaminocarbonyl group Chemical group 0.000 claims description 13
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 13
- 125000005090 alkenylcarbonyl group Chemical group 0.000 claims description 12
- 125000005125 aryl alkyl amino carbonyl group Chemical group 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 11
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 10
- 125000002252 acyl group Chemical group 0.000 claims description 10
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 9
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 9
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 8
- 125000006323 alkenyl amino group Chemical group 0.000 claims description 8
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 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 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 7
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 239000004202 carbamide Substances 0.000 claims description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical group CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 claims description 6
- 125000002971 oxazolyl group Chemical group 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 241000194032 Enterococcus faecalis Species 0.000 claims description 5
- 125000003435 aroyl group Chemical group 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 208000015181 infectious disease Diseases 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 229940072172 tetracycline antibiotic Drugs 0.000 claims description 5
- IWTFOFMTUOBLHG-UHFFFAOYSA-N 2-methoxypyridine Chemical compound COC1=CC=CC=N1 IWTFOFMTUOBLHG-UHFFFAOYSA-N 0.000 claims description 4
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 4
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 4
- 125000006501 nitrophenyl group Chemical group 0.000 claims description 4
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical group CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 229940032049 enterococcus faecalis Drugs 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 230000000968 intestinal effect Effects 0.000 claims description 3
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 3
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 3
- 239000005077 polysulfide Substances 0.000 claims description 3
- 229920001021 polysulfide Polymers 0.000 claims description 3
- 150000008117 polysulfides Polymers 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000005493 quinolyl group Chemical group 0.000 claims description 3
- 125000005504 styryl group Chemical group 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 claims description 2
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- JRXXLCKWQFKACW-UHFFFAOYSA-N biphenylacetylene Chemical class C1=CC=CC=C1C#CC1=CC=CC=C1 JRXXLCKWQFKACW-UHFFFAOYSA-N 0.000 claims description 2
- 125000004799 bromophenyl group Chemical group 0.000 claims description 2
- 125000004494 ethyl ester group Chemical group 0.000 claims description 2
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 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
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 claims 1
- 125000005153 alkyl sulfamoyl group Chemical group 0.000 claims 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 4
- 230000014509 gene expression Effects 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 class 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 3
- 230000000903 blocking effect Effects 0.000 abstract 2
- 239000002585 base Substances 0.000 description 51
- 239000000243 solution Substances 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 19
- 229910052799 carbon Inorganic materials 0.000 description 18
- 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 description 17
- 230000008569 process Effects 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 14
- 150000001721 carbon Chemical group 0.000 description 13
- 239000003795 chemical substances by application Substances 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 12
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 9
- 125000005100 aryl amino carbonyl group Chemical group 0.000 description 9
- 150000002430 hydrocarbons Chemical group 0.000 description 9
- 125000004947 alkyl aryl amino group Chemical group 0.000 description 8
- 229910021529 ammonia Inorganic materials 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 125000001769 aryl amino group Chemical group 0.000 description 8
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 8
- 125000000753 cycloalkyl group Chemical group 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000004215 Carbon black (E152) Substances 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- 229930195733 hydrocarbon Natural products 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
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- 239000000126 substance Substances 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 150000001447 alkali salts Chemical class 0.000 description 5
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- 238000005516 engineering process Methods 0.000 description 4
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- 125000000623 heterocyclic group Chemical group 0.000 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 description 4
- 239000008101 lactose Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000463 material Substances 0.000 description 4
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
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- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 3
- 125000002723 alicyclic group Chemical group 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 150000001336 alkenes Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 3
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- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
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- 239000000706 filtrate Substances 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/65—Tetracyclines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
- C07C237/26—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
- C07C255/59—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
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Abstract
本发明至少部分涉及新的9-取代二甲胺四环素。这些二甲胺四环素化合物可用于治疗许多四环素化合物敏感性疾病,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,例如通常的阻断四环素化合物,例如阻断四环素流和调节基因表达。
Description
本申请是申请日为2001年6月29日,申请号为01815087.x,发明名称为“9-取代的二甲胺四环素化合物”的发明专利申请的分案申请。
相关申请
本申请要求以下申请的优先权:美国临时专利申请序号60/275,621,标题为“9-取代的二甲胺四环素化合物”,申请日为2001年3月13日;美国临时专利申请序号60/216,580,标题为“9-取代的二甲胺四环素化合物”,申请日为2000年7月7日;这两个申请均通过引用结合到本文中。本申请与以下申请有关:美国临时专利申请序号60/154,701,申请日为1999年9月14日;60/193,972,申请日为2000年3月31日;60/193,879,申请日为2000年3月31日;60/204,158,申请日为2000年5月15日;60/212,030,申请日为2000年6月16日;60/212,471,申请日为2000年6月16日,所述申请的全部内容通过引用结合到本文中。
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;2,990,331;3,062,717;3,165,531;3,454,697;3,557,280;3,674,859;3,957,980;4,018,889;4,024,272;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的二甲胺四环素化合物及其药学上可接受盐、酯和前体药物:
其中:
X为CHC(R13Y’Y)、CR6’R6、S、NR6或O;
R2、R4’、R4”、R7’和R7”各自为氢、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’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;
R9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、芳基炔基、硫代亚硝基或-(CH2)0-3NR9cC(=Z’)ZR9a;
Z为CR9dR9e、S、NR9b或O;
Z’为NR9f、O或S;
R9a、R9b、R9c、R9d、R9e和R9f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。
本发明还至少部分涉及下式(II)的9-取代二甲胺四环素化合物及其药学上可接受盐、酯和前体药物:
其中:
R4’、R4”、R7′和R7″各自为烷基;
R9为吡啶基乙炔基;链烯基氨基甲酸酯基团;卤基;烷基丙烯酸酯基团;萘基;卤代乙酰基;烷基氨基甲酸酯基团;环戊基或环戊烯基;苯并呋喃基;苯基丙酰酮氨基;甲苯磺酰基氨基;甲氧基吡啶基;链烯基氨基;N-叔丁基;叔丁基酰胺基团;羟基丁基氨基;羟基丙基氨基;苯基;硝基苯基;硝基苯基炔基;氨基苯基;烷氧基苯基;卤代苯基脲基团;氰基苯基;羧基苯基;酰基苯基;烷基苯基;卤代苯基;烷氧基苯基;羧基烷基苯基;苯基炔基;链炔基;烷基甘氨酸乙酯基团;苯乙烯基;噻吩基;以及烷基氨基二氧磷基。
本发明还涉及用本发明二甲胺四环素化合物治疗患者的方法,所述患者患有可用本发明二甲胺四环素化合物治疗的疾病。
本发明还涉及药用组合物,该组合物包含本发明二甲胺四环素化合物和药学上可接受的载体。本发明还涉及本发明二甲胺四环素化合物用于制备药物(例如治疗四环素敏感性疾病的药物)的用途。
本发明的详细说明
本发明至少部分涉及新的9-取代二甲胺四环素化合物。这些二甲胺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。
本发明至少部分涉及下式I的二甲胺四环素化合物及其药学上可接受盐、酯和前体药物:
其中:
X为CHC(R13Y’Y)、CR6’R6、S、NR6或O;
R2、R4’、R4”、R7’和R7”各自为氢、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’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;
R9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、芳基炔基、硫代亚硝基或-(CH2)0-3NR9cC(=Z’)ZR9a;
Z为CR9dR9e、S、NR9b或O;
Z’为NR9f、O或S;
R9a、R9b、R9c、R9d、R9e和R9f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。
术语二甲胺四环素化合物是指上述式(I)化合物。在一个实施方案中,术语二甲胺四环素化合物包括的化合物中:X为CR6R6’;R2、R2’、R5、R6、R6’、R8、R9、R10、R11以及R12各自为氢;R4为NR4’R4”;R4’、R4”、R7’以及R7”各自为低级烷基,例如甲基。
R9的实例包括取代和未取代的芳基。芳基包括取代和未取代的杂芳基(例如呋喃基、咪唑基、苯并噻吩基、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、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、异噻唑基或去氮嘌呤基)、取代或未取代的苯基以及含有一个以上芳族环的基团,例如萘基。
R9的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、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、芳基烷基氨基羰基、链烯基氨基羰基、烷基羰基、芳基羰基、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、芳基以及杂芳基。
在进一步的实施方案中,芳基R9基团被一个或多个取代基取代,所述取代基例如羧酸酯基、烷基、链烯基、链炔基、芳基、杂环基、氰基、氨基、卤素、烷氧基、烷氧基羰基、酰氨基、烷基羰基或硝基。
在另一实施方案中,R9为取代或未取代的链炔基。炔基R9基团可以被取代或未取代的芳基取代,例如苯基。取代苯基的合适取代基包括例如以上所列的芳基R9基团的取代基。此外,取代炔基R9基团可以被以下基团取代:杂芳基(例如吡啶基)、烷基(例如甲基、乙基、丙基、丁基、戊基、己基、环丙基、环丁基、环戊基、环己基等)、链烯基(例如乙烯基、丙烯基、丁烯基、戊烯基、己烯基等)、羧酸酯基、甲硅烷基(例如三烷基甲硅烷基、例如三甲基甲硅烷基)、芳烷基或烷氧基羰基。
这些基团各自还可以进一步被取代,取代基包括例如烷基、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、芳基以及杂芳基。
在进一步的实施方案中,炔基R9基团被氨基烷基取代。氨基烷基还可以被取代,例如被烷基、链烯基、链炔基、酰基、羰基或烷基砜基取代。
在另一进一步的实施方案中,炔基R9基团被环烯基取代,例如环戊烯。
在另一实施方案中,R9为烷基。烷基可以为取代或未取代的基团。烷基的实例包括例如直链、支链以及环状烷基。例如,烷基包括甲基、乙基、异丙基、正丙基、异丁基、正丁基、叔丁基、戊基、己基、庚基、辛基、壬基、癸基等。环状烷基包括含一个或多个环的基团,例如环丙烷、环丁烷、环戊烷、环己烷、环庚烷等。在一个实施方案中,烷基R9基团为2-环戊基乙基。
烷基的取代基实例包括例如卤素(例如氟、氯、溴、碘等)、羟基、烷氧基(例如甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、全氟甲氧基、全氯甲氧基等)、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、芳基烷基氨基羰基、链烯基氨基羰基、羧基、烷基羰基、芳基羰基、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、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、芳硫基、硫代羧酸酯基、硫酸酯基、烷基亚磺酰基、链烯基、磺酸酯基、氨磺酰基、亚磺酰氨基、硝基、链烯基、氰基、叠氮基、杂环基、烷基芳基、芳基以及杂芳基。
在另一实施方案中,本发明二甲胺四环素化合物为这样的化合物: 其中R9为-NR9cC(=Z’)ZR9a、-CH2NR9cC(=Z’)ZR9a、-(CH2)2NR9cC(=Z’)ZR9a或-(CH2)3NR9cC(=Z’)ZR9a。在某些实施方案中,R9为-NR9cC(=Z′)ZR9a或-CH2NR9cC(=Z’)ZR9a。R9c的实例包括氢。Z’可以为例如S、NH或O。Z的实例包括NR9b(例如,当R9b为氢、烷基等)、O或S。
R9a基团的实例包括芳基,例如取代和未取代的苯基。芳基R9a基团的适当取代基实例包括但不限于烷基(例如甲基、乙基、丙基、丁基、戊基、己基、全氟甲基、全氯乙基等)、链烯基、卤素(例如氟、氯、溴、碘等)、羟基、烷氧基(例如甲氧基、乙氧基、丙氧基、全氟甲氧基、全氯甲氧基等)、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、芳基烷基氨基羰基、链烯基氨基羰基、烷基羰基、芳基羰基、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、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、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、乙酰基、烷基、氰基、叠氮基、杂环基、烷基芳基、芳基以及杂芳基。
在某些实施方案中,取代苯基的至少一个取代基为硝基、烷氧基(例如甲氧基、亚甲二氧基、全氟甲氧基)烷基(例如甲基、乙基、丙基、丁基或戊基)、乙酰基、卤素(例如氟、氯、溴或碘)或氨基(例如二烷基氨基)。在某些实施方案中,烷氧基为全卤代基团,例如全氟甲氧基。
芳基R9a基团的实例包括但不限于未取代的苯基、对硝基苯基、对甲氧基苯基、对全氟甲氧基苯基、对乙酰基苯基、3,5-亚甲二氧基苯基、3,5-二全氟甲基苯基、对溴苯基、对氯苯基以及对氟苯基。
芳基R9a基团的其它实例包括取代和未取代的杂环(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、嘧啶基、吡嗪基、嘌呤基、吡唑基、pyrolidinyl、噁唑基、异噁唑基、1,5-二氮杂萘基、噻唑基、异噻唑基或去氮嘌呤基(deazapurinyl))以及取代和未取代的联芳基,例如萘基和芴。
R9a还可以为取代或未取代的烷基,例如甲基、乙基、丙基、丁基、戊基等。取代基实例包括但不限于卤素(例如氟、溴、氯、碘等)、羟基、烷氧基(例如甲氧基、乙氧基、丙氧基、丁氧基等)、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、芳基烷基氨基羰基、链烯基氨基羰基、烷基羰基、芳基羰基、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、膦酸酯基、次膦酸酯基、氰基、氨基、酰基氨基、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、链烯基、杂环基、烷基芳基、芳基以及杂芳基。
R9a还可以为取代或未取代的链烯基。链烯基R9a基团的取代基实例包括烷基R9a基团的以上所列的取代基。链烯基R9a基团的实例包括戊-1-烯基。
在一个实施方案中,Z’为NH,Z为NH,并且R9a为烷基。
本发明还涉及这样的化合物:其中R9为氨基烷基(例如氨基甲基)。氨基烷基R9基团可以进一步被取代。取代基实例包括芳基例如取代或未取代的苯基(例如亚甲二氧基苯基或对全氟甲氧基苯基)或者允许本发明化合物发挥其预定作用的杂芳基。
本发明二甲胺四环素化合物的实例包括列于表1的化合物以及下列化合物:
这些化合物的药学上可接受的盐也包括在本发明。本发明的其它化合物列于表1中。
本发明还至少部分涉及下式的9-取代二甲胺四环素化合物及其药学上可接受盐:
其中:
R4’、R4”、R7’和R7”各自为烷基;
R9为吡啶基乙炔基;链烯基氨基甲酸酯基团;卤基;烷基丙烯酸酯基团;萘基脲基团;卤代乙酰基;烷基氨基甲酸酯基团;环戊基或环戊烯基;苯并呋喃基;苯基丙酰酮氨基;甲苯磺酰基氨基;甲氧基吡啶基;链烯基氨基;N-叔丁基;叔丁基酰胺基团;羟基丁基氨基;羟基丙基氨基;苯基;硝基苯基;硝基苯基炔基;氨基苯基;卤代苯基脲基团;烷氧基苯基;氰基苯基;羧基苯基;酰基苯基;烷基苯基;卤代苯基;烷氧基苯基;羧基烷基苯基;苯基炔基;链炔基;烷基甘氨酸乙酯基团;苯乙烯基;噻吩基;以及烷基氨基二氧磷基。
术语“9-取代二甲胺四环素化合物”包括9位含有取代基的二甲胺四环素化合物。在另一实施方案中,所述化合物为二甲胺四环素的衍生物。
在一个实施方案中,R9为链烯基氨基甲酸酯基团。合有该R9取代基的四环素化合物实例包括9-异丙烯基氨基甲酸酯二甲胺四环素。
在一个实施方案中,R9为吡啶基乙炔基。含有该R9取代基的四环素化合物的实例包括9-(2-吡啶基乙炔基)二甲胺四环素。
在一个实施方案中,R9为卤基。含有该R9取代基的四环素化合物实例包括9-碘二甲胺四环素。
在一个实施方案中,R9为烷基丙烯酸酯基团。含有该R9取代基的四环素化合物实例包括9-丁基丙烯酸酯二甲胺四环素。
在一个实施方案中,R9为萘基脲基团。含有该R9取代基的四环素化合物实例包括9-萘基二甲胺四环素脲。
在一个实施方案中,R9为卤代乙酰基。含有该R9取代基的四环素化合物实例包括9-氯乙酰基二甲胺四环素脲。
在一个实施方案中,R9为烷基氨基甲酸酯基团。含有该R9取代基的四环素化合物实例包括9-新戊基二甲胺四环素氨基甲酸酯。
在一个实施方案中,R9为环戊基或环戊烯基。含有该R9取代基的四环素化合物实例包括9-环戊烯二甲胺四环素。
在一个实施方案中,R9为苯并呋喃基。含有该R5取代基的四环素化合物实例包括9-苯并呋喃基二甲胺四环素。
在一个实施方案中,R9为苯基丙酰酮氨基。含有该R9取代基的四环素化合物实例包括9-(苯基丙酰酮氨基)二甲胺四环素。
在一个实施方案中,R9为甲苯磺酰基氨基。含有该R9取代基的四环素化合物实例包括9-甲苯磺酰基氨基二甲胺四环素。
在一个实施方案中,R9为甲氧基吡啶基。含有该R5取代基的四环素化合物实例包括9-(2-甲氧基-3-吡啶基)二甲胺四环素。
在一个实施方案中,R5为链烯基氨基。含有该R9取代基的四环素化合物实例包括9-(N-2’-羟基癸基-9’-烯-氨基)二甲胺四环素。
在一个实施方案中,R9为N-叔丁基。含有该R9取代基的四环素化合物实例包括N-叔丁基二甲胺四环素HCl。
在一个实施方案中,R9为叔丁基酰胺基团。含有该R9取代基的四环素化合物实例包括9-BOC-NH二甲胺四环素。
在一个实施方案中,R9为羟基丁基氨基。含有该R9取代基的四环素化合物实例包括9-(N-2’-羟基丁基氨基)二甲胺四环素。
在一个实施方案中,R9为羟基丙基氨基。含有该R9取代基的四环素化合物实例包括9-(N-3-氯,2-羟基丙基氨基)二甲胺四环素。
在一个实施方案中,R9为苯基。含有该R9取代基的四环素化合物实例包括9-苯基二甲胺四环素HCl以及9-对甲苯基二甲胺四环素。
在一个实施方案中,R9为硝基苯基。含有该R9取代基的四环素化合物实例包括9-(3’-硝基苯基)二甲胺四环素。
在一个实施方案中,R9为硝基苯基炔基。含有该R9取代基的四环素化合物实例包括9-(4’-硝基苯基乙炔基)二甲胺四环素。
在一个实施方案中,R9为氨基苯基。含有该R9取代基的四环素化合物实例包括9-(3-氨基苯基)二甲胺四环素。
在一个实施方案中,R9为卤代苯基脲基团。含有该R9取代基的四环素化合物实例包括9-(4-氯,2-三氟甲基苯基)二甲胺四环素脲。
在一个实施方案中,R9为烷氧基苯基。含有该R9取代基的四环素化合物实例包括9-(对甲氧基苯基)二甲胺四环素、9-(4’-甲氧基苯基)二甲胺四环素和9-(3,4-亚甲二氧基苯基)二甲胺四环素。
在一个实施方案中,R9为氰基苯基。含有该R9取代基的四环素化合物实例包括9-(4’-氰基苯基)二甲胺四环素。
在一个实施方案中,R9为羧基烷基苯基。含有该R9取代基的四环素化合物实例包括9-(4’-羧基苯基)二甲胺四环素。
在一个实施方案中,R9为酰基苯基。含有该R9取代基的四环素化合物实例包括9-(3-甲酰基苯基)二甲胺四环素。
在一个实施方案中,R9为烷基苯基。含有该R9取代基的四环素化合物实例包括9-(4’-叔丁基苯基)二甲胺四环素。
在一个实施方案中,R9为卤代苯基。含有该R9取代基的四环素化合物实例包括9-(3-氯苯基)二甲胺四环素、9-(2’,4′-二氟苯基)二甲胺四环素、9-(3,4-二氟苯基)二甲胺四环素、9-(4’-氯苯基)二甲胺四环素、9-(3,4-二氯苯基)二甲胺四环素和9-(4’-三氟甲基苯基)二甲胺四环素。
在一个实施方案中,R9为烷氧基苯基。含有该R9取代基的四环素化合物实例包括9-(3-乙氧基苯基)二甲胺四环素。
在一个实施方案中,R9为羧基烷基苯基。含有该R9取代基的四环素化合物实例包括9-(4-羧基甲基苯基)二甲胺四环素。
在一个实施方案中,R为苯基炔基。含有该R9取代基的四环素化合物实例包括9-(苯基乙炔基)二甲胺四环素、9-(3-羟基苯基乙炔基)二甲胺四环素、9-(对甲苯基乙炔基)二甲胺四环素和9-(对甲氧基苯基乙炔基)二甲胺四环素。
在一个实施方案中,R9为炔基。含有该R9取代基的四环素化合物实例包括9-乙炔基二甲胺四环素、9-(对氟乙炔基)二甲胺四环素、9-(三甲基甲硅烷基乙炔基)二甲胺四环素、9-(丙酰基)二甲胺四环素、9-(环己烯基乙炔基)二甲胺四环素和9-(1-环己基-1-羟基乙炔基)二甲胺四环素。
在一个实施方案中,R9为烷基甘氨酸乙酯基团。含有该R9取代基的四环素化合物实例包括9-丙基甘氨酸乙酯二甲胺四环素HCl和9-甲基甘氨酸乙酯二甲胺四环素。
在一个实施方案中,R9为苯乙烯基团。含有该R9取代基的四环素化合物实例包括9-(苯乙烯)二甲胺四环素、9-(4’-氟苯乙烯)二甲胺四环素。
在一个实施方案中,R9为噻吩基。含有该R9取代基的四环素化合物实例包括9-(2-噻吩基)二甲胺四环素和9-(5’-氯-2’-噻吩基)二甲胺四环素。
在一个实施方案中,R9为烷基氨基二氧磷基。含有该R9取代基的四环素化合物实例包括9-(对甲氧基苯基氨基二氧磷基)二甲胺四环素和9-(苯基氨基二氧磷基)二甲胺四环素。
本发明二甲胺四环素化合物可以用流程1-6介绍的方法合成。
9-取代二甲胺四环素可以用以下的常规方法合成,如流程1所示。
流程1
通常,9-取代二甲胺四环素化合物可以按照流程2所示用硫酸和硝酸钠处理二甲胺四环素(1A)而合成。所得产物为9-硝基(1B)二甲胺四环素。然后将硝基二甲胺四环素化合物用氢气和铂催化剂处理获得9-氨基二甲胺四环素化合物1C。为了合成9位衍生物,将9-氨基二甲胺四环素化合物用HONO处理,获得重氮盐(1D)。随后将所得盐用大量的具有链烯烃或π键官能团(例如链烯基、芳基以及炔基(例如R9Br))的化合物处理获得9-取代二甲胺四环素化合物(1E)。
流程2
如流程3所示,R9为氨基甲酸酯或脲衍生物的本发明二甲胺四环素化合物可以用以下方案合成。二甲胺四环素(2A)用NaNO2在酸性条件下处理生成9-硝基二甲胺四环素(2B)。然后将9-硝基二甲胺四环素(2B)用氢气和铂催化剂处理生成9-氨基二甲胺四环素衍生物(2C)。为了生成脲衍生物(2E),使异氰酸酯(2D)与9-氨基二甲胺四环素衍生物(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,R9为杂环(即噻唑)取代的氨基的本发明二甲胺四环素化合物可以按照上述方案合成。使9-氨基二甲胺四环素(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)去保护获得活性四环素脲或四环素硫脲(3D)化合物。使四环素硫脲(3D)与α-卤代酮(3E)反应生成噻唑取代的9-氨基二甲胺四环素(3F)。
流程4
如流程4所示,9-链烯基二甲胺四环素化合物(4A)可以氢化生成烷基9-取代二甲胺四环素化合物(4B)。流程4图示用氢气和钯/碳催化剂选择性氢化9-位的双键。同样,9-炔基二甲胺四环素也可氢化生成9-烷基二甲胺四环素化合物。
流程5
在流程5中,显示合成二甲胺四环素化合物的9-位芳基衍生物的通用合成流程。在流程5中,显示了芳基硼酸与碘代二甲胺四环素化合物的Suzuki偶合。碘代二甲胺四环素化合物(5B)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)处理二甲胺四环素(5A),由山环素合成。将所述反应猝灭,然后将所得9-碘二甲胺四环素(5B)用本领域已知的标准技术提纯。为了生成芳基衍生物,将9-碘二甲胺四环素(5B)用硼酸(5C)加上碳酸钠水溶液处理,并且用钯催化。产物(5D)可以用本领域已知方法提纯(例如HPLC)。其它9-芳基二甲胺四环素化合物可以用类似的方案合成。
本发明9-取代的二甲胺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9-碘二甲胺四环素)完成。锡试剂和碘代二甲胺四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
本发明化合物还可以用Heck-型交联偶合反应合成。如流程6所示,Heck-型交联偶合可以用卤代四环素化合物(例如9-碘二甲胺四环素,6A)、活性链烯烃(6B)或炔烃(6D)以及合适的钯或其它过渡金属催化剂完成。然后可以将所得9-取代链烯基(6C)或9-取代炔基(6E)二甲胺四环素化合物用本领域已知技术提纯。
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,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。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。术语“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”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,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。含碳基的实例包括醛、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碳原子连接的环称为“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、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”包括碳或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二甲胺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所有其互变异构体。
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二甲胺四环素化合物(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”包括给予本发明二甲胺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,CancerRes.,48:6686-6690(1988))。对某些四环素敏感性疾病,可能需要微小或没有抗菌活性的本发明二甲胺四环素化合物。
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。
本发明二甲胺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,本发明二甲胺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。本发明二甲胺四环素化合物可以用药学上可接受载体给药。
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,对本发明二甲胺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二甲胺化合物的有效量。
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二甲胺四环素化合物。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,一种或多种本发明二甲胺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二甲胺四环素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二甲胺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二甲胺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二甲胺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二甲胺四环素化合物的制备,可以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二甲胺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二甲胺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二甲胺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二甲胺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二甲胺四环素化合物,蒸发所得溶液至干,优选减压蒸发。或者,可以将本发明二甲胺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二甲胺四环素化合物的制备,可以通过组合上述反应完成。
本发明二甲胺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种类、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二甲胺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。
在一个实施方案中,本发明二甲胺四环素不包括那些在美国专利申请序号第09/823,884中介绍的化合物,所述专利通过引用结合到本发明。
此外,本发明还涉及应用式I或II二甲胺四环素化合物用于制备药物。所述药物可包含药学上可接受载体和有效量的二甲胺四环素化合物,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:制备本发明二甲胺四环素化合物
制备9-碘二甲胺四环素
在室温下向200ml 97%甲磺酸中缓慢地逐量加入二甲胺四环素-二盐酸盐[30g;56.56mM]。然后将深黄褐色溶液在室温下搅拌,同时在3.0小时内分6等分加入N-碘琥珀酰亚胺[38g;169.7mM]。反应通过分析型LC监测,指示原料的消失。
在快速搅拌下将反应物缓慢的加入2L包含硫代硫酸钠[17.88g;1134.1mM]的冰冷水溶液中猝灭。所述猝灭在室温下搅拌大约30分钟。然后将水层用6×200ml醋酸乙酯萃取,然后将水相倾入包含300ml正丁醇的碳酸氢钠[259.8g;3.08M]。分出各相,水相用4×250ml正丁醇萃取。合并有机部分,用3×250ml水洗涤并用250ml饱和盐水洗涤一次。将所得有机相减压蒸发至干。残余物悬浮于甲醇(~600ml),此混合物中通入无水HCl气体直至呈溶液。将此溶液减压蒸发至干。滤液减压蒸发至干。所得产物用300ml甲基叔丁醚研磨,过滤分离。将此物质溶解于300ml甲醇,用0.5g木炭处理,过滤,减压蒸发滤液至干。所得产物用甲基叔丁醚再次粉化,抽滤分离,再用醚洗涤,最后用己烷洗涤。真空干燥所得产物获得22.6g淡黄褐色粉末。
制备9-炔基二甲胺四环素化合物的通用方法
将1mmol 9-碘二甲胺四环素、50mg四三苯基次膦酸钯、12mg醋酸钯、32mg碘化亚铜(I)溶于/悬浮于10ml乙腈。加入2-5ml三乙胺和3-5mmol炔基衍生物。在室温至70℃剧烈搅拌反应混合物。反应时间为2-24小时。反应完成后,将黑色悬浮液用硅藻土垫过滤并浓缩。粗产物用制备型HPLC提纯。浓缩合并部分,溶解于~1ml甲醇。加入~3ml HCl的饱和甲醇溶液,用醚沉淀出产品。
制备9-芳基二甲胺四环素化合物的通用方法
将15mmol 9-碘二甲胺四环素、PdOAc(3.2mg)、229μl 2M Na2CO3和2当量苯基硼酸溶解/悬浮于10ml甲醇。反应瓶内通入氩,反应进行至少4小时,或直到HPLC监测显示原料耗净和/或出现产物。悬浮液通过硅藻土过滤,并用制备型HPLC在二乙烯基苯柱上提纯。
化合物OU(9-(4-三氟甲氧基苯基脲基)-甲基二甲胺四环素)
流程7
在25℃向3mL二甲基甲酰胺中加入150mg(0.25mmol)9-甲基氨基二甲胺四环素三盐酸盐和67ml(0.50mmol)三乙胺。在搅拌下加入75mL(0.50mmol)4-三氟甲氧基苯基异氰酸酯,所得反应混合物在25℃搅拌2小时。反应用分析型HPLC(4.6×50MM反相Luna C18柱,5分钟线性梯度1-100%B缓冲液,A缓冲液为含0.1%三氟醋酸的水溶液,B缓冲液为合0.1%三氟醋酸的乙腈溶液)监测。反应完成后,反应用1mL水猝灭,用浓盐酸调节其pH至约2.0。将溶液过滤,用制备型HPLC提纯化合物。获得化合物OU 64mg(37%收率)。化合物OU的纯度用LCMS(M+1=690)测定为95%。
化合物LA(9-(4’羧基苯基)二甲胺四环素)
流程8
在一个干净干燥的反应容器中加入9-碘二甲胺四环素[500mg;0.762mmoles]二HCl盐、醋酸钯(II)[17.2mg;0.076mmoles]以及10ml试剂级甲醇。溶液在搅拌下立即通入氩气流约5分钟。将反应容器进行回流,接着用注射器向容器内加入2M碳酸钾溶液[1.91ml;3.81mmoles],然后加入对羧基苯基硼酸[238.3mg;1.53mmoles]的5ml试剂DMF溶液。上述两溶液都预先用氩气脱气约5分钟。将反应加热45分钟,其进度用反相HPLC监测。将反应物用硅藻土垫抽滤,用DMF洗涤硅藻土垫。滤液在真空下浓缩为油状物,残余物用叔丁基甲醚处理。粗产物用反相HPLC(DVB,包含1.0%三氟醋酸的梯度水和甲醇/乙腈)提纯。产物用质谱确证:实测值M+1 578.58;其结构用1H NMR确证。
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。把二甲胺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。最终细胞密度应该大约为5×105CFU/ml。将板在35℃环境大气的孵箱中培养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
本领域熟练技术人员知道或者仅仅使用常规实验就能够确定本文所述的具体方法的许多等同实施方案。这样的等同实施方案考虑在本发明范围内,而且包括在后面的权利要求书范围内。整个申请中引用的所有参考文献、专利和专利申请均通过引用结合到本文中。这些专利、申请和其它文献中的合适部分、工艺和方法可选用于本发明及其实施方案。
表1
Claims (83)
1.一种下式I的二甲胺四环素化合物及其药学上可接受盐、酯和前体药物:
其中:
X为CHC(R13Y’Y)、CR6’R6、S、NR6或O;
R2、R4’、R4”、R7’和R7”各自为氢、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’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;
R9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、芳基炔基、硫代亚硝基或-(CH2)0-3NR9cC(=Z’)ZR9a;
Z为CR9dR9e、S、NR9b或O;
Z’为NR9f、O或S;
R9a、R9b、R9c、R9d、R9e和R9f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的二甲胺四环素化合物,其中R4为NR4’R4”;X为CR6R6’;R2、R2’、R5、R6、R6’、R8、R9、R10、R11以及R12各自为氢;R4’、R4”、R7’以及R7”各自为低级烷基。
3.权利要求2的二甲胺四环素化合物,其中R4’、R4”、R7’以及R7”各自为甲基。
4.权利要求1-3任一项的二甲胺四环素化合物,其中R9为取代或未取代的芳基。
5.权利要求4的二甲胺四环素化合物,其中R9为取代或未取代的苯基。
6.权利要求5的二甲胺四环素化合物,其中R9为未取代的苯基。
7.权利要求5的二甲胺四环素化合物,其中R9被一个或多个选自以下的取代基取代:卤素、羟基、烷氧基、甲酰基、烷基羰氧基、芳基羰氧基、羧基、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、芳基烷基羰基、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、酰基氨基、酰氨基、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。
8.权利要求7的二甲胺四环素化合物,其中R9被一个或多个选自以下的取代基取代:羧酸酯基、烷基、链烯基、链炔基、芳基、杂环基、氰基、氨基、卤素、烷氧基、烷氧基羰基、酰氨基、烷基羰基以及硝基。
9.权利要求4的二甲胺四环素化合物,其中R9为取代或未取代的杂芳基。
10.权利要求9的二甲胺四环素化合物,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、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、异噻唑基或去氮嘌呤基。
11.权利要求10的二甲胺四环素化合物,其中所述杂芳基为噻吩基或苯并呋喃基。
12.权利要求1-3任一项的二甲胺四环素化合物,其中R9为取代或未取代的链炔基。
13.权利要求12的二甲胺四环素化合物,其中所述取代链炔基被取代或未取代的芳基取代。
14.权利要求13的二甲胺四环素化合物,其中所述芳基为取代或未取代的苯基。
15.权利要求14的二甲胺四环素化合物,其中所述苯基被选自以下的基团取代: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、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、芳基以及杂芳基。
16.权利要求13的二甲胺四环素化合物,其中所述芳基为杂芳基。
17.权利要求12的二甲胺四环素化合物,其中所述链炔基被烷基、链烯基、羧酸酯基、甲硅烷基、芳烷基或烷氧基羰基取代。
18.权利要求15的二甲胺四环素化合物,其中所述烷基取代基为氨基烷基。
19.权利要求18的二甲胺四环素化合物,其中所述氨基烷基被烷基氨磺酰基取代。
20.权利要求17的二甲胺四环素化合物,其中所述链炔基被环烯基取代。
21.权利要求20的二甲胺四环素化合物,其中所述环烯基为环戊烯基。
22.权利要求1-3任一项的二甲胺四环素化合物,其中R9为烷基。
23.权利要求22的二甲胺四环素化合物,其中所述烷基被一个或多个选自以下的基团取代: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、芳基烷基氨基羰基、链烯基氨基羰基、烷基羰基、芳基羰基、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、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、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、链烯基、氰基、叠氮基、杂环基、烷基芳基、芳基以及杂芳基。
24.权利要求22的二甲胺四环素化合物,其中所述烷基包含环。
25.权利要求24的二甲胺四环素化合物,其中所述烷基为2-环戊基乙基。
26.权利要求1-3任一项的二甲胺四环素化合物,其中R9为-(CH2)0-3NR9cC(=Z’)ZR9a。
27.权利要求26的二甲胺四环素化合物,其中R9为-NR9cC(=Z’)ZR9a。
28.权利要求26的二甲胺四环素化合物,其中R9为-CH2NR9cC(=Z’)ZR9a。
29.权利要求27或28的二甲胺四环素化合物,其中R9c为氢。
30.权利要求27-29任一项的二甲胺四环素化合物,其中Z’为S。
31.权利要求27-29任一项的二甲胺四环素化合物,其中Z’为O。
32.权利要求27-31任一项的二甲胺四环素化合物,其中Z为NR9b。
33.权利要求27-31任一项的二甲胺四环素化合物,其中Z为O。
34.权利要求27-31任一项的二甲胺四环素化合物,其中Z为S。
35.权利要求32的二甲胺四环素化合物,其中R9b为氢。
36.权利要求26-35任一项的二甲胺四环素化合物,其中R9a为芳基。
37.权利要求36的二甲胺四环素化合物,其中R9a为取代或未取代的苯基。
38.权利要求36的二甲胺四环素化合物,其中所述苯基被一个或多个选自以下的取代基取代: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、芳基烷基氨基羰基、链烯基氨基羰基、烷基羰基、芳基羰基、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、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、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、乙酰基、烷基、氰基、叠氮基、杂环基、烷基芳基、芳基以及杂芳基。
39.权利要求38的二甲胺四环素化合物,其中所述取代基选自硝基、烷氧基、烷基、酰基、卤素或氨基。
40.权利要求39的二甲胺四环素化合物,其中所述氨基为二烷基氨基。
41.权利要求39的二甲胺四环素化合物,其中所述烷氧基为甲氧基。
42.权利要求39的二甲胺四环素化合物,其中所述烷氧基为亚甲二氧基。
43.权利要求41的二甲胺四环素化合物,其中所述烷氧基为全卤代烷氧基。
44.权利要求43的二甲胺四环素化合物,其中所述烷氧基为全氟甲氧基。
45.权利要求39的二甲胺四环素化合物,其中所述烷基为甲基、乙基、丙基、丁基或戊基。
46.权利要求39的二甲胺四环素化合物,其中所述卤素为氟、氯、溴或碘。
47.权利要求36的二甲胺四环素化合物,其中所述苯基为未取代的苯基、对硝基苯基、对甲氧基苯基、对全氟甲氧基苯基、对乙酰基苯基、3,5-亚甲二氧基苯基、3,5-二全氟甲基苯基、对溴苯基、对氯苯基或对氟苯基。
48.权利要求38的二甲胺四环素化合物,其中R9a为芳基羰基。
49.权利要求36的二甲胺四环素化合物,其中R9a为联芳基。
50.权利要求49的二甲胺四环素化合物,其中R9a为萘基。
51.权利要求26-35任一项的二甲胺四环素化合物,其中R9a为取代或未取代的烷基。
52.权利要求51的二甲胺四环素化合物,其中R9a为未取代的烷基。
53.权利要求52的二甲胺四环素化合物,其中R9a为甲基、乙基、丙基、丁基或戊基。
54.权利要求51的二甲胺四环素化合物,其中所述烷基被一个或多个选自以下的取代基取代: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、芳基烷基氨基羰基、链烯基氨基羰基、烷基羰基、芳基羰基、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、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、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、链烯基、杂环基、烷基芳基、芳基以及杂芳基。
55.权利要求26-35任一项的二甲胺四环素化合物,其中R9a为取代或未取代的链烯基。
56.权利要求55的二甲胺四环素化合物,其中R9a为戊-1-烯基。
57.权利要求26的二甲胺四环素化合物,其中Z’为NH,Z为NH,并且R9a为烷基。
58.权利要求1-3任一项的二甲胺四环素化合物,其中R9a为-N=S。
59.权利要求1-3任一项的二甲胺四环素化合物,其中R9a为氨基烷基。
60.权利要求59的二甲胺四环素化合物,其中所述氨基烷基为烷基氨基烷基。
61.权利要求1-3任一项的二甲胺四环素化合物,其中R9为取代或未取代的烷基氨基。
62.权利要求61的二甲胺四环素化合物,其中所述烷基氨基被芳基取代。
63.权利要求62的二甲胺四环素化合物,其中所述芳基为取代或未取代的苯基。
64.权利要求63的二甲胺四环素化合物,其中所述取代苯基为亚甲二氧基苯基或对全氟甲氧基苯基。
65.一种选自以下的二甲胺四环素化合物或其药学上可接受的盐:
66.一种治疗哺乳动物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或65的二甲胺四环素化合物,由此治疗所述患者。
67.权利要求66的方法,其中所述四环素敏感性疾病为细菌感染。
68.权利要求67的方法,其中所述细菌感染为大肠杆菌感染。
69.权利要求68的方法,其中所述细菌感染为S.aureus感染。
70.权利要求68的方法,其中所述细菌感染为粪肠球菌(E.faecalis)感染。
71.权利要求67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。
72.权利要求66的方法,其中所述二甲胺四环素化合物用药学上可接受的载体给药。
73.权利要求66的方法,其中所述患者为人。
74.一种药用组合物,该组合物包含治疗有效量的权利要求1或65的二甲胺四环素化合物和药学上可接受的载体。
76.权利要求74的9-取代二甲胺四环素化合物,其中所述化合物为:9-异丙烯基氨基甲酸酯二甲胺四环素、9-(2-吡啶基乙炔基)二甲胺四环素、9-碘二甲胺四环素、9-丁基丙烯酸酯二甲胺四环素、9-萘基二甲胺四环素脲、9-氯乙酰基二甲胺四环素、9-新戊基二甲胺四环素氨基甲酸酯、9-环戊烯二甲胺四环素、苯并呋喃基二甲胺四环素、9-(苯基丙酰酮氨基)二甲胺四环素、9-甲苯磺酰基氨基二甲胺四环素、9-(2-甲氧基-3-吡啶基)二甲胺四环素、9-(N-2’-羟基癸基-9’-烯-氨基)二甲胺四环素、N-叔丁基二甲胺四环素、9-BOC-NH二甲胺四环素、9-(N-2’-羟基丁基氨基)二甲胺四环素、9-(N-3-氯,2-羟基丙基氨基)二甲胺四环素、9-苯基二甲胺四环素、9-对甲苯基二甲胺四环素、9-3’-硝基苯基二甲胺四环素、9-(4-硝基苯基乙炔基)二甲胺四环素、9-(3-氨基苯基)二甲胺四环素、9-(4-氯,2-三氟甲基苯基)二甲胺四环素脲、9-(对甲氧基苯基)二甲胺四环素、9-(4’-甲氧基苯基)二甲胺四环素、9-(3,4-亚甲二氧基苯基)二甲胺四环素、9-(4’-氰基苯基)二甲胺四环素、9-(4’-羧基苯基)二甲胺四环素、9-(3-甲酰基苯基)二甲胺四环素、9-(4’-叔丁基苯基)二甲胺四环素、9-(3-氯苯基)二甲胺四环素、9-(2’,4′-二氟苯基)二甲胺四环素、9-(3,4-二氟苯基)二甲胺四环素、9-(4’-氯苯基)二甲胺四环素、9-(3,4-二氯苯基)二甲胺四环素和9-(4’-三氟甲基苯基)二甲胺四环素、9-(3-乙氧基苯基)二甲胺四环素、9-(4-羧基甲基苯基)二甲胺四环素、9-(苯基乙炔基)二甲胺四环素、9-(3-羟基苯基乙炔基)二甲胺四环素、9-(对甲苯基乙炔基)二甲胺四环素、9-(对甲氧基苯基乙炔基)二甲胺四环素、9-乙炔基二甲胺四环素、9-(对氟乙炔基)二甲胺四环素、9-(三甲基甲硅烷基乙炔基)二甲胺四环素、9-(丙酰基)二甲胺四环素、9-(环己烯基乙炔基)二甲胺四环素、9-(1-环己基-1-羟基乙炔基)二甲胺四环素、9-丙基甘氨酸乙酯二甲胺四环素HCl或9-甲基甘氨酸乙酯二甲胺四环素、9-苯乙烯二甲胺四环素、9-4’-氟苯乙烯二甲胺四环素、9-2-噻吩基二甲胺四环素、9-(5’-氯-2’-噻吩基)二甲胺四环素、9-(对甲氧基苯基氨基二氧磷基)二甲胺四环素、9-(苯基氨基二氧磷基)二甲胺四环素、9-(对甲氧基苯基氨基二氧磷基)二甲胺四环素或9-(苯基氨基二氧磷基)二甲胺四环素。
77.一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75或76的9-取代二甲胺四环素化合物,由此治疗所述患者的所述四环素敏感性疾病。
78.权利要求77的方法,其中所述四环素敏感性疾病为细菌感染。
79.权利要求78的方法,其中所述细菌感染为大肠杆菌、S.aureus或粪肠球菌感染。
80.权利要求78的方法,其中所述细菌感染为其它四环素抗生素耐药性感染。
81.权利要求77的方法,其中所述化合物用药学上可接受的载体给药。
82.一种二甲胺四环素化合物,该化合物选自表1所列的化合物。
83.一种药用组合物,该组合物包含治疗有效量的权利要求75、76或82的化合物和药学上可接受的载体。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN105348138A (zh) * | 2008-05-23 | 2016-02-24 | 帕拉特克药品公司 | 四环素化合物的盐和多晶型物 |
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