JP2009029785A - 9−置換ミノサイクリン化合物 - Google Patents
9−置換ミノサイクリン化合物 Download PDFInfo
- Publication number
- JP2009029785A JP2009029785A JP2008157219A JP2008157219A JP2009029785A JP 2009029785 A JP2009029785 A JP 2009029785A JP 2008157219 A JP2008157219 A JP 2008157219A JP 2008157219 A JP2008157219 A JP 2008157219A JP 2009029785 A JP2009029785 A JP 2009029785A
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- JP
- Japan
- Prior art keywords
- minocycline
- group
- compound according
- alkyl
- substituted
- 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
Links
- -1 minocycline compound Chemical class 0.000 title claims abstract description 332
- 229960004023 minocycline Drugs 0.000 title claims abstract description 210
- 239000004098 Tetracycline Substances 0.000 claims abstract description 84
- 235000019364 tetracycline Nutrition 0.000 claims abstract description 84
- 229960002180 tetracycline Drugs 0.000 claims abstract description 79
- 229930101283 tetracycline Natural products 0.000 claims abstract description 79
- 150000003522 tetracyclines Chemical class 0.000 claims abstract description 30
- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 13
- 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 claims abstract 48
- 125000000217 alkyl group Chemical group 0.000 claims description 106
- DYKFCLLONBREIL-KVUCHLLUSA-N minocycline Chemical compound 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 claims description 90
- 125000003118 aryl group Chemical group 0.000 claims description 77
- 150000001875 compounds Chemical class 0.000 claims description 77
- 125000003342 alkenyl group Chemical group 0.000 claims description 72
- 125000000304 alkynyl group Chemical group 0.000 claims description 69
- 125000001424 substituent group Chemical group 0.000 claims description 61
- 125000003545 alkoxy group Chemical group 0.000 claims description 54
- 125000004414 alkyl thio group Chemical group 0.000 claims description 41
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 41
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 37
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 229910052736 halogen Inorganic materials 0.000 claims description 36
- 125000001072 heteroaryl group Chemical group 0.000 claims description 36
- 150000002367 halogens Chemical class 0.000 claims description 35
- 125000003282 alkyl amino group Chemical group 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 33
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 31
- 125000000623 heterocyclic group Chemical group 0.000 claims description 31
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 30
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 24
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 24
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 23
- 150000002431 hydrogen Chemical class 0.000 claims description 22
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 22
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 20
- 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 20
- 150000007942 carboxylates Chemical group 0.000 claims description 20
- 229910019142 PO4 Inorganic materials 0.000 claims description 19
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical group [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 19
- 125000004442 acylamino group Chemical group 0.000 claims description 19
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical group [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 19
- 239000010452 phosphate Chemical group 0.000 claims description 19
- 239000000651 prodrug Substances 0.000 claims description 19
- 229940002612 prodrug Drugs 0.000 claims description 19
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 18
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 18
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 17
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 17
- 125000004691 alkyl thio carbonyl group Chemical group 0.000 claims description 17
- 125000005200 aryloxy carbonyloxy group Chemical group 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical group [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 claims description 16
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical group [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 16
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 15
- 125000005110 aryl thio group Chemical group 0.000 claims description 15
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical group [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 15
- 125000005089 alkenylaminocarbonyl group Chemical group 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 208000035143 Bacterial infection Diseases 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 12
- 125000005090 alkenylcarbonyl group Chemical group 0.000 claims description 12
- 150000001408 amides Chemical group 0.000 claims description 12
- 125000005125 aryl alkyl amino carbonyl group Chemical group 0.000 claims description 12
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims description 12
- KWEDUNSJJZVRKR-UHFFFAOYSA-N carbononitridic azide Chemical group [N-]=[N+]=NC#N KWEDUNSJJZVRKR-UHFFFAOYSA-N 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 239000003937 drug carrier Substances 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 10
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 10
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 9
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 8
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 7
- 125000005036 alkoxyphenyl group Chemical group 0.000 claims description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 239000004202 carbamide Substances 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 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
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 125000003277 amino group Chemical group 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
- 229910052801 chlorine Inorganic materials 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
- 239000011737 fluorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 6
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 5
- 125000003435 aroyl group Chemical group 0.000 claims description 5
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 5
- 239000011630 iodine Substances 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 229940072172 tetracycline antibiotic Drugs 0.000 claims description 5
- 241000588724 Escherichia coli Species 0.000 claims description 4
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 4
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 claims description 4
- 125000005179 haloacetyl group Chemical group 0.000 claims description 4
- 125000005059 halophenyl group Chemical group 0.000 claims description 4
- 125000006501 nitrophenyl group Chemical group 0.000 claims description 4
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
- 125000003011 styrenyl group Chemical group [H]\C(*)=C(/[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical group CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000005250 alkyl acrylate group Chemical group 0.000 claims description 3
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 3
- 125000005015 aryl alkynyl 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
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 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
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 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
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 2
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 241000191967 Staphylococcus aureus Species 0.000 claims description 2
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 125000005841 biaryl group Chemical group 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 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
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims 4
- 125000004494 ethyl ester group Chemical group 0.000 claims 2
- GVOUFPWUYJWQSK-UHFFFAOYSA-N Cyclofenil Chemical group C1=CC(OC(=O)C)=CC=C1C(C=1C=CC(OC(C)=O)=CC=1)=C1CCCCC1 GVOUFPWUYJWQSK-UHFFFAOYSA-N 0.000 claims 1
- 241000283984 Rodentia Species 0.000 claims 1
- 241000194017 Streptococcus Species 0.000 claims 1
- 125000005422 alkyl sulfonamido group Chemical group 0.000 claims 1
- 125000004799 bromophenyl group Chemical group 0.000 claims 1
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- 230000000112 colonic effect Effects 0.000 claims 1
- 229960002944 cyclofenil Drugs 0.000 claims 1
- HKIOYBQGHSTUDB-UHFFFAOYSA-N folpet Chemical group C1=CC=C2C(=O)N(SC(Cl)(Cl)Cl)C(=O)C2=C1 HKIOYBQGHSTUDB-UHFFFAOYSA-N 0.000 claims 1
- 125000001841 imino group Chemical group [H]N=* 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 229910021653 sulphate ion Inorganic materials 0.000 claims 1
- 201000010099 disease Diseases 0.000 abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 8
- 206010028980 Neoplasm Diseases 0.000 abstract description 3
- 230000014509 gene expression Effects 0.000 abstract description 2
- 238000012986 modification Methods 0.000 abstract description 2
- 230000004048 modification Effects 0.000 abstract description 2
- LUBJCRLGQSPQNN-UHFFFAOYSA-N 1-Phenylurea Chemical compound NC(=O)NC1=CC=CC=C1 LUBJCRLGQSPQNN-UHFFFAOYSA-N 0.000 abstract 2
- PIVQQUNOTICCSA-UHFFFAOYSA-N ANTU Chemical group C1=CC=C2C(NC(=S)N)=CC=CC2=C1 PIVQQUNOTICCSA-UHFFFAOYSA-N 0.000 abstract 1
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 abstract 1
- 208000035269 cancer or benign tumor Diseases 0.000 abstract 1
- 230000005764 inhibitory process Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 239000000203 mixture Substances 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 11
- 239000000126 substance Substances 0.000 description 10
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 9
- 125000004658 aryl carbonyl amino group Chemical group 0.000 description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 8
- 125000004947 alkyl aryl amino group Chemical group 0.000 description 8
- 125000001769 aryl amino group Chemical group 0.000 description 8
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 8
- 125000004986 diarylamino group Chemical group 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- 229940124530 sulfonamide Drugs 0.000 description 8
- 150000003456 sulfonamides Chemical class 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 230000002378 acidificating effect Effects 0.000 description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- 150000002430 hydrocarbons Chemical group 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 125000004434 sulfur atom Chemical group 0.000 description 6
- IQIPCMYBFDOLBO-IRDJJEOVSA-N (4s,4as,5ar,12ar)-9-amino-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=C(N)C(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 IQIPCMYBFDOLBO-IRDJJEOVSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- 150000001447 alkali salts Chemical class 0.000 description 5
- 125000005907 alkyl ester group Chemical group 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 229940040944 tetracyclines Drugs 0.000 description 5
- 230000000699 topical effect Effects 0.000 description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 150000001336 alkenes Chemical class 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 150000001768 cations Chemical class 0.000 description 4
- 239000007789 gas Substances 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
- 238000001727 in vivo Methods 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
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 125000004430 oxygen atom Chemical group O* 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000011593 sulfur Chemical group 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
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- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
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- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
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- 238000010791 quenching Methods 0.000 description 1
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- 238000011160 research Methods 0.000 description 1
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- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
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- 229950000614 sancycline Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
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- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- 238000000967 suction filtration Methods 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
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- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
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- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 125000006248 tosyl amino group Chemical group [H]N(*)S(=O)(=O)C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Classifications
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- A61K31/65—Tetracyclines
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- 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
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- 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
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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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- C07C275/48—Y being a hydrogen or a carbon atom
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- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C311/06—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C07C333/02—Monothiocarbamic acids; Derivatives thereof
- C07C333/08—Monothiocarbamic acids; Derivatives thereof having nitrogen atoms of thiocarbamic groups bound to carbon atoms of six-membered aromatic rings
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- C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C335/22—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
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- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
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Abstract
Description
本明細書は、2001年3月13日に出願された米国特許仮出願第60/275,621号、名称「9-置換ミノサイクリン化合物」、および2000年7月7日に出願された米国特許仮出願第60/216,580号、名称「9-置換ミノサイクリン化合物」に優先して主張するものであり;これらの両明細書は、本明細書に参照として組入れられている。本明細書は、1999年9月14日に出願された米国特許仮出願60/154,701号;2000年3月31日に出願された第60/193,972号;2000年3月31日に出願された第60/193,879号;2000年5月15日に出願された第60/204,158号;2000年6月16日に出願された第60/212,030号;および、2000年6月16日に出願された第60/212,471号に関連しており、これら各々の全内容は本明細書に参照として組入れられる。
テトラサイクリン系抗生物質の開発は、殺菌性および/または静菌性組成物の製造が可能な微生物の証拠のために世界中の多くの地域から収集された土壌標本の系統的スクリーニングの直接の結果であった。これらの新規化合物の最初のものは、1948年にクロルテトラサイクリンという名称で紹介された。2年後、オキシテトラサイクリンが利用可能になった。これらの化合物の化学構造の解明は、それらの類似性を確認し、かつ1952年にはこの群の第三の要員であるテトラサイクリンの製造のための解析的基礎を提供した。初期のテトラサイクリン類に存在する環に結合したメチル基を伴わない、テトラサイクリン化合物の新規ファミリーが、1957年に調製され、かつ1967年には公に利用可能となり;および、ミノサイクリンは1972年までに使用されていた。
本発明は、少なくとも一部が、式Iのミノサイクリン化合物:
R2、R4'、R4"、R7'およびR7"は各々、水素、アルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、アルキルスルフィル、アルキルスルホニル、アルキルアミノ、アリールアルキル、アリール、ヘテロ環式、ヘテロ芳香族またはプロドラッグ部分であり;
R4は、NR4'R4"、アルキル、アルケニル、アルキニル、アリール、ヒドロキシル、ハロゲン、または水素であり;
R2'、R3、R10、R11およびR12は、各々水素またはプロドラッグ部分であり;
R5は、ヒドロキシル、水素、チオール、アルカノイル、アロイル、アルカロイル、アリール、ヘテロ芳香族、アルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノ、アリールアルキル、アルキルカルボニルオキシ、またはアリールカルボニルオキシであり;
R6およびR6'は、独立して、水素、メチレン、非存在、ヒドロキシル、ハロゲン、チオール、アルキル、アルケニル、アルキニル、アリール、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノ、またはアリールアルキルであり;
R9は、ニトロ、アルキル、アルケニル、アルキニル、アリール、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アリールアルキル、アミノ、アリールアルケニル、アリールアルキニル、チオニトロソ、または-(CH2)0-3NR9cC(=Z')ZR9aであり;
Zは、CR9dR9e、S、NR9bまたはOであり;
Z'は、NR9f、OまたはSであり;
R9a、R9b、R9c、R9d、R9eおよびR9fは、各々独立して、水素、アシル、アルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノ、アリールアルキル、アリール、ヘテロ環式、ヘテロ芳香族またはプロドラッグ部分であり;
R8は、水素、ヒドロキシル、ハロゲン、チオール、アルキル、アルケニル、アルキニル、アリール、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノ、またはアリールアルキルであり;
R13は、水素、ヒドロキシ、アルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノ、またはアリールアルキルであり;
Y'およびYは、各々独立して、水素、ハロゲン、ヒドロキシル、シアノ、スルフヒドリル、アミノ、アルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノ、またはアリールアルキルである。)、ならびにそれらの薬学的に許容できる塩、エステルおよびプロドラッグに関する。
R9は、ピリジルエチニル基;アルケニルカルバメート基;ハロ基;アルキルアクリレート基;ナフチル基;ハロアセチル基;アルキルカルバメート基;シクロペンチルまたはシクロペンテニル基;ベンゾフラニル基;フェニルプロピオノンアミノ基;トシルアミノ基;メトキシピリジル基;アルケンアミノ基;N-t-ブチル基;t-ブチルアミド基;ヒドロキシブチルアミノ基;ヒドロキシプロピルアミノ基;フェニル基;ニトロフェニル基;ニトロフェニルアルキニル基;アミノフェニル基;アルコキシフェニル基;ハロフェニル尿素基;シアノフェニル基;カルボキシフェニル基;アシルフェニル基;アルキルフェニル基;ハロフェニル基;アルコキシフェニル基;カルボキシアルキルフェニル基;フェニルアルキニル基;アルキニル基;アルキルグリシンエチルエステル基;スチレン基;チオフェン基;および、アルキルアミノホスホ基である。);ならびに、それらの薬学的に許容できる塩、エステル、およびプロドラッグに関する。
本発明は、少なくとも一部において、新規9-置換ミノサイクリン化合物に関する。これらのミノサイクリン化合物は、多くのテトラサイクリン化合物-反応状態、例えば細菌感染症および新生物形成性疾患を治療するため、更には一般的ミノサイクリンおよびテトラサイクリン化合物のその他の公知の適用、例えばテトラサイクリン排出の防止および遺伝子発現の変調などに使用することができる。
R2、R4'、R4"、R7'およびR7"は各々、水素、アルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、アルキルスルフィル、アルキルスルホニル、アルキルアミノ、アリールアルキル、アリール、ヘテロ環式、ヘテロ芳香族またはプロドラッグ部分であり;
R4は、NR4'R4"、アルキル、アルケニル、アルキニル、アリール、ヒドロキシル、ハロゲン、または水素であり;
R2'、R3、R10、R11およびR12は、各々水素またはプロドラッグ部分であり;
R5は、ヒドロキシル、水素、チオール、アルカノイル、アロイル、アルカロイル、アリール、ヘテロ芳香族、アルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノ、アリールアルキル、アルキルカルボニルオキシ、またはアリールカルボニルオキシであり;
R6およびR6'は、独立して、水素、メチレン、非存在、ヒドロキシル、ハロゲン、チオール、アルキル、アルケニル、アルキニル、アリール、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノ、またはアリールアルキルであり;
R9は、ニトロ、アルキル、アルケニル、アルキニル、アリール、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アリールアルキル、アミノ、アリールアルケニル、アリールアルキニル、チオニトロソ、または-(CH2)0-3NR9cC(=Z')ZR9aであり;
Zは、CR9dR9e、S、NR9bまたはOであり;
Z'は、NR9f、OまたはSであり;
R9a、R9b、R9c、R9d、R9eおよびR9fは、各々独立して、水素、アシル、アルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノ、アリールアルキル、アリール、ヘテロ環式、ヘテロ芳香族またはプロドラッグ部分であり;
R8は、水素、ヒドロキシル、ハロゲン、チオール、アルキル、アルケニル、アルキニル、アリール、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノ、またはアリールアルキルであり;
R13は、水素、ヒドロキシ、アルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノ、またはアリールアルキルであり;
Y'およびYは、各々独立して、水素、ハロゲン、ヒドロキシル、シアノ、スルフヒドリル、アミノ、アルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノ、またはアリールアルキルである。)、ならびにそれらの薬学的に許容できる塩、エステルおよびプロドラッグに関する。
R9は、ピリジルエチニル基;アルケニルカルバメート基;ハロ基;アルキルアクリレート基;ナフチル尿素基;ハロアセチル基;アルキルカルバメート基;シクロペンチルまたはシクロペンテニル基;ベンゾフラニル基;フェニルプロピオノンアミノ基;トシルアミノ基;メトキシピリジル基;アルケンアミノ基;N-t-ブチル基;t-ブチルアミド基;ヒドロキシブチルアミノ基;ヒドロキシプロピルアミノ基;フェニル基;ニトロフェニル基;ニトロフェニルアルキニル基;アミノフェニル基;ハロフェニル尿素基;アルコキシフェニル基;シアノフェニル基;カルボキシフェニル基;アシルフェニル基;アルキルフェニル基;ハロフェニル基;アルコキシフェニル基;カルボキシアルキルフェニル基;フェニルアルキニル基;アルキニル基;アルキルグリシンエチルエステル基;スチレン基;チオフェン基;および、アルキルアミノホスホ基である。);ならびに、それらの薬学的に許容できる塩に関する。
本発明の化合物は、当業者の技術の範囲内で下記の手法の変更を伴い、下記に説明したように作成することができる。
9-ヨードミノサイクリンの調製
97%メタンスルホン酸200mlに、周囲温度で、ミノサイクリン-ビス-塩酸塩[30g;56.56mM]を滴下により添加した。暗黄褐色溶液をその後周囲温度で攪拌しながら、N-ヨードスクシンイミド[38g;169.7mM]を、6回等量に分け、3時間かけて添加した。反応は、分析的LCによりモニタリングし、出発物質が消滅したことを調べた。
9-ヨードミノサイクリン1mmol、テトラキストリペニル(penyl)ホスフィン酸パラジウム50mg、酢酸パラジウム12mg、ヨウ化銅(I)32mgを、アセトアニリド10mlに溶解/懸濁した。トリエチルアミン2〜5mlおよびアルキニル誘導体3〜5mmolを添加した。反応混合液を、周囲温度から70℃の間で激しく攪拌した。反応時間は、2〜24時間であった。反応が完了した時点で、暗色懸濁液を、セライト床を通して濾過し、濃縮した。粗生成物を、分取HPLCにより精製した。一緒にした画分を濃縮し、かつ最大〜1mlメタノール中に仕上げた。HCl飽和メタノール〜3mlを添加し、かつ生成物をエーテルにより沈殿した。
9-ヨードミノサイクリン0.15mmol、PdOAc(3.2mg)、2M Na2CO3 229μlおよびフェニルボロン酸2当量を、メタノール10ml中に溶解/懸濁した。反応フラスコを、アルゴンで一掃し、反応を最低4時間またはHPLCモニタリングが出発物質の消費および/または生成物の出現を示すまで進行させた。懸濁液をセライトで濾過し、ジビニルベンゼンカラム上での分取HPLCによる精製にかけた。
下記のアッセイを用い、共通の細菌に対するミノサイクリン化合物の効能を決定した。各化合物2mgを、DMSO 100μlに溶解した。次にこの溶液を、カチオン調節したMueller Hintonブロス(CAMHB)に添加し、これは最終化合物濃度200μg/mlを得た。ミノサイクリン化合物溶液を、容量50μLに希釈し、被験化合物濃度0.098μg/mlとした。試験菌株の新鮮な対数相ブロス培養物から光学濃度(OD)測定を行った。希釈を行い、最終細胞濃度1x106 CFU/mlとした。OD=1で、異なる属の細胞濃度をおよそ以下のようにした:
大腸菌 1x109 CFU/ml
黄色ブドウ球菌 5x108 CFU/ml
エンテロコッカス種 2.5x109 CFU/ml
細胞懸濁液50μlを、マイクロタイタープレートの各ウェルに添加した。最終細胞濃度は、およそ5x105 CFU/mlとした。これらのプレートを、大気中のインキュベーターで35℃でおよそ18時間インキュベーションした。これらのプレートを、マイクロプレートリーダーで読み取り、必要ならば肉眼で検査した。MICは、増殖を阻害するミノサイクリン化合物の最低濃度と定義した。本発明の化合物は、良好な増殖阻害を示した。
当業者は、日常的な範囲内の実験を用いて、本明細書において説明された特定の手段に対して同等物を多く認めるだろう、もしくは確認することができるであろう。このような同等物は、本発明の範囲内であると考えられ、かつ添付の特許請求の範囲に含まれる。本明細書を通じて引用された参考文献、特許および特許明細書の全ての内容は、本明細書に参照として組入れられる。これらの特許、明細書および他の文書の適当な成分、手法および方法を、本発明およびその態様のために選択してもよい。
Claims (83)
- 式Iのミノサイクリン化合物:ならびにそれらの薬学的に許容できる塩、エステルおよびプロドラッグ:
R2、R4'、R4"、R7'およびR7"は、各々、水素、アルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノ、アリールアルキル、アリール、ヘテロ環式、ヘテロ芳香族またはプロドラッグ部分であり;
R4は、NR4'R4"、アルキル、アルケニル、アルキニル、アリール、ヒドロキシル、ハロゲン、または水素であり;
R2'、R3、R10、R11およびR12は、各々水素またはプロドラッグ部分であり;
R5は、ヒドロキシル、水素、チオール、アルカノイル、アロイル、アルカロイル、アリール、ヘテロ芳香族、アルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノ、アリールアルキル、アルキルカルボニルオキシ、またはアリールカルボニルオキシであり;
R6およびR6'は、独立して、水素、メチレン、非存在、ヒドロキシル、ハロゲン、チオール、アルキル、アルケニル、アルキニル、アリール、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノ、またはアリールアルキルであり;
R9は、ニトロ、アルキル、アルケニル、アルキニル、アリール、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アリールアルキル、アミノ、アリールアルケニル、アリールアルキニル、チオニトロソ、または-(CH2)0-3NR9cC(=Z')ZR9aであり;
Zは、CR9dR9e、S、NR9bまたはOであり;
Z'は、NR9f、OまたはSであり;
R9a、R9b、R9c、R9d、R9eおよびR9fは、各々独立して、水素、アシル、アルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノ、アリールアルキル、アリール、ヘテロ環式、ヘテロ芳香族またはプロドラッグ部分であり;
R8は、水素、ヒドロキシル、ハロゲン、チオール、アルキル、アルケニル、アルキニル、アリール、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノ、またはアリールアルキルであり;
R13は、水素、ヒドロキシ、アルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノ、またはアリールアルキルであり;
Y'およびYは、各々独立して、水素、ハロゲン、ヒドロキシル、シアノ、スルフヒドリル、アミノ、アルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、アルキルスルフィニル、アルキルスルホニル、アルキルアミノ、またはアリールアルキルである)。 - R4は、NR4'R4"であり;Xは、CR6CR6'であり;R2、R2'、R5、R6、R6'、R8、R9、R10、R11およびR12は、各々水素であり;かつ、R4'、R4"、R7'およびR7"は、各々低級アルキルである、請求項1記載のミノサイクリン化合物。
- R4'、R4"、R7'およびR7"は、各々メチルである、請求項2記載のミノサイクリン化合物。
- R9が、置換または未置換のアリールである、請求項1〜3のいずれか一項記載のミノサイクリン化合物。
- R9が、置換または未置換のフェニルである、請求項4記載のミノサイクリン化合物。
- R9が、未置換のフェニルである、請求項5記載のミノサイクリン化合物。
- R9が、以下の群より選択される1個または複数の置換基により置換されている、請求項5記載のミノサイクリン化合物であり、その群がハロゲン、ヒドロキシル、アルコキシ、ホルミル、アルキルカルボニルオキシ、アリールカルボニルオキシ、カルボキシ、アルコキシカルボニルオキシ、アリールオキシカルボニルオキシ、カルボキシラート、アルキルカルボニル、アルキルアミノアカルボニル、アリールアルキルアミノカルボニル、アルケニルアミノカルボニル、アルキルカルボニル、アリールカルボニル、アリールアルキルカルボニル、アルケニルカルボニル、アルコキシカルボニル、アミノカルボニル、アルキルチオカルボニル、リン酸塩、ホスホン酸塩、ホスフィン酸塩、シアノ、アミノ、アシルアミノ、アミド、イミノ、スルフヒドリル、アルキルチオ、アリールチオ、チオカルボキシラート、硫酸塩、アルキルスルフィニル、スルホナト、スルファモイル、スルホンアミド、ニトロ、トリフルオロメチル、シアノ、アジド、ヘテロ環式、アルキルアリール、または芳香族もしくはヘテロ芳香族残基を含む、化合物。
- R9は、カルボキシラート、アルキル、アルケニル、アルキニル、アリール、ヘテロ環式、シアノ、アミノ、ハロゲン、アルコキシ、アルコキシカルボニル、アミド、アルキルカルボニルおよびニトロからなる群より選択される1個または複数の置換基により置換されている、請求項7記載のミノサイクリン化合物。
- R9が、置換または未置換のヘテロアリールである、請求項4記載のミノサイクリン化合物。
- ヘテロアリールが、フラニル、イミダゾリル、ベンゾチオフェニル、ベンゾフラニル、キノリニル、イソキノリニル、ベンゾジオキサゾリル、ベンゾオキサゾリル、ベンゾチアゾリル、ベンゾイミダゾリル、メチレンジオキシフェニル、インドリル、チエニル、ピリミジル、ピラジニル、プリニル、ピラゾリル、オキサゾリル、イソオキサゾリル、ナフトリジニル、チアゾリル、イソチアゾリル、またはデアザプリニルからなる群より選択される、請求項9記載のミノサイクリン化合物。
- ヘテロアリールが、チエニルまたはベンゾフラニルである、請求項10記載のミノサイクリン化合物。
- R9が、置換または未置換のアルキニルである、請求項1〜3のいずれか一項記載のミノサイクリン化合物。
- 置換されたアルキニル基が、置換または未置換のアリール基で置換されている、請求項12記載のミノサイクリン化合物。
- アリール基が、置換または未置換のフェニルである、請求項13記載のミノサイクリン化合物。
- フェニル基が、アルキル、アルケニル、ハロゲン、ヒドロキシル、アルコキシ、アルキルカルボニルオキシ、アルキルオキシカルボニル、アリールカルボニルオキシ、アルコキシカルボニルオキシ、アリールオキシカルボニルオキシ、カルボキシラート、アルキルカルボニル、アルキルアミノアカルボニル、アリールアルキルアミノカルボニル、アルケニルアミノカルボニル、アルキルカルボニル、アリールカルボニル、アリールアルキルカルボニル、アルケニルカルボニル、アルコキシカルボニル、シリル、アミノカルボニル、アルキルチオカルボニル、リン酸塩、アラルキル、ホスホン酸塩、ホスフィン酸塩、シアノ、アミノ、アシルアミノ、アミド、イミノ、スルフヒドリル、アルキルチオ、硫酸塩、アリールチオ、チオカルボキシラート、アルキルスルフィニル、スルホン酸塩、スルファモイル、スルホンアミド、ニトロ、シアノ、アジド、ヘテロ環式、アルキルアリール、アリールおよびヘテロアリールから選択された基で置換されている、請求項14記載のミノサイクリン化合物。
- アリール基がヘテロアリールである、請求項13記載のミノサイクリン化合物。
- アルキニル基が、アルキル、アルケニル、カルボキシラート、シリル、アラルキル、またはアルキルオキシカルボニル基で置換されている、請求項12記載のミノサイクリン化合物。
- アルキル置換基がアミノアルキルである、請求項15記載のミノサイクリン化合物。
- アミノアルキルが、アルキルスルホンアミド基で置換されている、請求項18記載のミノサイクリン化合物。
- アルキニル基が、シクロアルケニル基で置換されている、請求項17記載のミノサイクリン化合物。
- シクロアルケニル基が、シクロフェニルである、請求項20記載のミノサイクリン化合物。
- R9が、アルキルである、請求項1〜3のいずれか一項記載のミノサイクリン化合物。
- アルキル基が、ハロゲン、ヒドロキシル、アルコキシ、アルキルカルボニルオキシ、アリールカルボニルオキシ、アルコキシカルボニルオキシ、アリールオキシカルボニルオキシ、カルボキシラート、アルキルカルボニル、アルキルアミノアカルボニル、アリールアルキルアミノカルボニル、アルケニルアミノカルボニル、アルキルカルボニル、アリールカルボニル、アリールアルキルカルボニル、アルケニルカルボニル、アルコキシカルボニル、シリル、アミノカルボニル、アルキルチオカルボニル、リン酸塩、ホスホン酸塩、ホスフィン酸塩、シアノ、アミノ、アシルアミノ、アミジノ、イミノ、スルフヒドリル、アルキルチオ、アリールチオ、チオカルボキシラート、硫酸塩、アルキルスルフィニル、スルホン酸塩、スルファモイル、スルホンアミド、ニトロ、アルケニル、シアノ、アジド、ヘテロ環式、アルキルアリール、アリールおよびヘテロアリールからなる群より選択される1個または複数の置換基で置換されている、請求項22記載のミノサイクリン化合物方法。
- アルキル基が環を含む、請求項22記載のミノサイクリン化合物。
- アルキル基が、2-シクロペンチルエチルである、請求項24記載のミノサイクリン化合物。
- R9が、-(CH2)0-3NR9cC(=Z')ZR9aである、請求項1〜3のいずれか一項記載のミノサイクリン化合物。
- R9が、-NR9cC(=Z')ZR9aである、請求項26記載のミノサイクリン化合物。
- R9が、-CH2NR9cC(=Z')ZR9aである、請求項26項記載のミノサイクリン化合物。
- R9が、水素である、請求項27または28記載のミノサイクリン化合物。
- Z'がSである、請求項27〜29のいずれか一項記載のミノサイクリン化合物。
- Z'がOである、請求項27〜29のいずれか一項記載のミノサイクリン化合物。
- ZがNR9bである、請求項27〜31のいずれか1記載のミノサイクリン化合物。
- ZがOである、請求項27〜31のいずれか一項記載のミノサイクリン化合物。
- ZがSである、請求項27〜31のいずれか一項記載のミノサイクリン化合物。
- R9bが、水素である、請求項32記載のミノサイクリン化合物。
- R9aが、アリールである、請求項26〜35のいずれか一項記載のミノサイクリン化合物。
- R9aが、置換または未置換のフェニルである、請求項36記載のミノサイクリン化合物。
- フェニル基が、ハロゲン、ヒドロキシル、アルコキシ、アルキルカルボニルオキシ、アリールカルボニルオキシ、アルコキシカルボニルオキシ、アリールオキシカルボニルオキシ、カルボキシラート、アルキルカルボニル、アルキルアミノアカルボニル、アリールアルキルアミノカルボニル、アルケニルアミノカルボニル、アルキルカルボニル、アリールカルボニル、アリールアルキルカルボニル、アルケニルカルボニル、アルコキシカルボニル、シリル、アミノカルボニル、アルキルチオカルボニル、リン酸塩、ホスホン酸塩、ホスフィン酸塩、シアノ、アミノ、アシルアミノ、アミジノ、イミノ、スルフヒドリル、アルキルチオ、アリールチオ、チオカルボキシラート、硫酸塩、アルキルスルフィニル、スルホン酸塩、スルファモイル、スルホンアミド、ニトロ、アセチル、アルキル、シアノ、アジド、ヘテロ環式、アルキルアリール、アリールおよびヘテロアリールからなる群より選択される1個または複数の置換基で置換されている、請求項36記載のミノサイクリン化合物。
- 置換基が、 ニトロ、アルコキシ、アルキル、アシル、ハロゲンまたはアミノから選択される、請求項38記載のミノサイクリン化合物。
- アミノ基が、ジアルキルアミノである、請求項39記載のミノサイクリン化合物。
- アルコキシ基が、メトキシである、請求項39記載のミノサイクリン化合物。
- アルコキシ基が、メチレンジオキシである、請求項39記載のミノサイクリン化合物。
- アルコキシ基が、過ハロゲン化されている、請求項41記載のミノサイクリン化合物。
- アルコキシ基が、ペルフルオロメトキシである、請求項43記載のミノサイクリン化合物。
- アルキル基が、メチル、エチル、プロピル、ブチル、またはペンチルである、請求項39記載のミノサイクリン化合物。
- ハロゲンが、フッ素、塩素、臭素またはヨウ素である、請求項39記載のミノサイクリン化合物。
- フェニル基が、未置換のフェニル、p-ニトロフェニル、p-メトキシフェニル、p-ペルフルオロメトキシフェニル、p-アセチルフェニル、3,5-メチレンジオキシフェニル、3,5-ジペルフルオロメチルフェニル、p-ブロモフェニル、p-クロロフェニル、またはp-フルオロフェニルである、請求項36記載のミノサイクリン化合物。
- R9aが、アリールカルボニルである、請求項38記載のミノサイクリン化合物。
- R9aが、ビアリールである、請求項36記載のミノサイクリン化合物。
- R9aが、ナフチルである、請求項49記載のミノサイクリン化合物。
- R9aが、置換または未置換のアルキルである、請求項26〜35のいずれか一項記載のミノサイクリン化合物。
- R9aが、未置換のアルキルである、請求項51記載のミノサイクリン化合物。
- R9aが、メチル、エチル、プロピル、ブチル、またはペンチルである、請求項52記載のミノサイクリン化合物。
- アルキルが、ハロゲン、ヒドロキシル、アルコキシ、アルキルカルボニルオキシ、アリールカルボニルオキシ、アルコキシカルボニルオキシ、アリールオキシカルボニルオキシ、カルボキシラート、アルキルカルボニル、アルキルアミノアカルボニル、アリールアルキルアミノカルボニル、アルケニルアミノカルボニル、アルキルカルボニル、アリールカルボニル、アリールアルキルカルボニル、アルケニルカルボニル、アルコキシカルボニル、シリル、アミノカルボニル、アルキルチオカルボニル、リン酸塩、ホスホン酸塩、ホスフィン酸塩、シアノ、アミノ、アシルアミノ、アミジノ、イミノ、スルフヒドリル、アルキルチオ、アリールチオ、チオカルボキシラート、硫酸塩、アルキルスルフィニル、スルホン酸塩、スルファモイル、スルホンアミド、ニトロ、トリフルオロメチル、シアノ、アジド、アルケニル、ヘテロ環式基、アルキルアリール、アリールおよびヘテロアリールからなる群より選択される1個または複数の置換基で置換されている、請求項51記載のミノサイクリン化合物。
- R9aが、置換または未置換のアルケニルである、請求項26〜35のいずれか一項記載のミノサイクリン化合物。
- R9aが、ペント-1-エニルである、請求項55記載のミノサイクリン化合物。
- Z'がNHであり、ZがNHであり、およびR9aがアルキルである、請求項26記載のミノサイクリン化合物。
- R9が、-N=Sである、請求項1〜3のいずれか一項記載のミノイクリン化合物。
- R9が、アミノアルキルである、請求項1〜3のいずれか一項記載のミノイクリン化合物。
- アミノアルキルが、アルキルアミノアルキルである、請求項59記載のミノサイクリン化合物。
- R9が、置換または未置換のアルキルアミノである、請求項1〜3のいずれか一項記載のミノイクリン化合物。
- アルキルアミノが、アリール基で置換されている、請求項61記載のミノサイクリン化合物。
- アリール基が、置換または未置換のフェニルである、請求項62記載のミノサイクリン化合物。
- 置換されたフェニルが、メチレンジオキシフェニルまたはp-ペルフルオロメトキシフェニルである、請求項63記載のミノサイクリン化合物。
- 対象に、請求項1または65記載のミノサイクリン化合物を投与し、その結果該対象が治療されることを含む、哺乳類においてテトラサイクリン反応状態を治療する方法。
- テトラサイクリン反応状態が細菌感染症である、請求項66記載の方法。
- 細菌感染症が大腸菌に関連している、請求項67記載の方法。
- 細菌感染症が黄色ブドウ球菌に関連している、請求項68記載の方法。
- 細菌感染症が大腸レンサ球菌に関連している、請求項68記載の方法。
- 細菌感染症が、その他のテトラサイクリン抗生物質に対し耐性である、請求項67記載の方法。
- ミノサイクリン化合物が、薬学的に許容できる担体と共に投与される、請求項66記載の方法。
- 対象がヒトである、請求項66記載の方法。
- 請求項1または65記載のミノサイクリン化合物の治療有効量および薬学的に許容できる担体を含有する、薬学的組成物。
- 下記式の9-置換ミノサイクリン化合物;ならびに、それらの薬学的に許容できる塩:
R9は、ピリジルエチニル基;アルケニルカルバメート基;ハロ基;アルキルアクリレート基;ナフチル基;ハロアセチル基;アルキルカルバメート基;シクロペンチルまたはシクロペンテニル基;ベンゾフラニル基;フェニルプロピオノンアミノ基;トシルアミノ基;メトキシピリジル基;アルケンアミノ基;N-t-ブチル基;t-ブチルアミド基;ヒドロキシブチルアミノ基;ヒドロキシプロピルアミノ基;フェニル基;ニトロフェニル基;ニトロフェニルアルキニル基;アミノフェニル基;アルコキシフェニル基;ハロフェニル尿素基;シアノフェニル基;カルボキシフェニル基;アシルフェニル基;アルキルフェニル基;ハロフェニル基;アルコキシフェニル基;カルボキシアルキルフェニル基;フェニルアルキニル基;アルキニル基;アルキルグリシンエチルエステル基;スチレン基;チオフェン基;および、アルキルアミノホスホ基である)。 - 請求項74記載の9-置換ミノサイクリン化合物であって、それが9-イソプロペニルカルバメートミノサイクリン、9-(2-ピリジルエチニル)ミノサイクリン、9-ヨードミノサイクリン、9-ブチルアクリラートミノサイクリン、9-ナフチルミノサイクリン尿素、9-クロロアセチルミノサイクリン、9-ネオペンチルミノサイクリンカルバメート、9-シクロペンテンミノサイクリン、ベンゾフラニルミノサイクリン、9-(フェニルプロピオンアミノ)ミノサイクリン、9-トシルアミノミノサイクリン、9-(2-メトキシ-3-ピリジル)ミノサイクリン、9-(N-2'-ヒドロキシデシル-9'-エン-アミノ)ミノサイクリン、N-t-ブチル-ミノサイクリン、9-BOC-NHミノサイクリン、9-(N-2'-ヒドロキシブチルアミノ)ミノサイクリン、9-(N-3-クロロ,2-ヒドロキシルプロピルアミノ)ミノサイクリン、9-フェニルミノサイクリン、9-p-トリルミノサイクリン、9-3'-ニトロフェニルミノサイクリン、9-(4-ニトロフェニルエチニル)ミノサイクリン、9-(3-アミノフェニル)ミノサイクリン、9-(4-クロロ,2-トリフルオロメチルフェニル)ミノサイクリン尿素、9-(p-メトキシフェニル)ミノサイクリン、9-(4'-メトキシフェニル)ミノサイクリン、9-(3,4-メチレンジオキシフェニル)ミノサイクリン、9-(4'-シアノフェニル)ミノサイクリン、9-(4'-カルボキシフェニル)ミノサイクリン、9-(3-ホルミルフェニル)ミノサイクリン、9-(4'-t-ブチルフェニル)ミノサイクリン、9-(3-クロロフェニル)ミノサイクリン、9-(2',4'-ジフルオロフェニル)ミノサイクリン、9-(3,4-ジフルオロフェニル)ミノサイクリン、9-(4'-クロロフェニル)ミノサイクリン、9-(3,4-ジクロロフェニル)ミノサイクリン、9-(4'-トリフルオロメチルフェニル)ミノサイクリン、9-(3-エトキシフェニル)ミノサイクリン、9-(4-カルボキシメチルフェニル)ミノサイクリン、9-(フェニルエチニル)ミノサイクリン、9-(3-ヒドロキシフェニルエチニル)ミノサイクリン、9-(p-トリルエチニル)ミノサイクリン、9-(p-メトキシフェニルエチニル)ミノサイクリン、9-エチニルミノサイクリン、9-(p-フルオロエチニル)ミノサイクリン、9-(トリメチルシリルエチニル)ミノサイクリン、9-(プロピオニル)ミノサイクリン、9-(シクロヘキセニルエチニル)ミノサイクリン、9-(1-シクロヘキシル-1-ヒドロキシエチニル)ミノサイクリン、9-プロピルグリシンエチルエステルミノサイクリンHCl、または9-メチルグリシンエチルエステルミノサイクリン、9-スチレンミノサイクリン、9-4'-フルオロスチレンミノサイクリン、9-2-チオフェンミノサイクリン、9-(5'-クロロ-2'-チオフェン)ミノサイクリン、9-(p-メトキシフェニルアミノホスホ)ミノサイクリン、9-(フェニルアミノホスホ)ミノサイクリン、9-(p-メトキシフェニルアミノホスホ)ミノサイクリン、または9-(フェニルアミノホスホ)ミノサイクリンである、化合物。
- 対象に、請求項75または76記載の9-置換ミノサイクリン化合物を投与し、その結果該対象のテトラサイクリン反応状態が治療されることを含む、対象においてテトラサイクリン反応状態を治療する方法。
- テトラサイクリン反応状態が細菌感染症である、請求項77記載の方法。
- 細菌感染症が、大腸菌、黄色ブドウ球菌、または大腸レンサ球菌に関連している、請求項78記載の方法。
- 細菌感染症が、その他のテトラサイクリン抗生物質に対し耐性である、請求項78記載の方法。
- 前記化合物が、薬学的に許容できる担体と共に投与される、請求項77記載の方法。
- 表1に列記された群から選択されるミノサイクリン化合物。
- 請求項75、76または82記載の化合物の治療有効量および薬学的に許容できる担体を含有する、薬学的組成物。
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JP2004502752A (ja) * | 2000-07-07 | 2004-01-29 | トラスティーズ・オブ・タフツ・カレッジ | 9−置換ミノサイクリン化合物 |
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