KR20030017610A - 9-치환된 미노사이클린 화합물 - Google Patents
9-치환된 미노사이클린 화합물 Download PDFInfo
- Publication number
- KR20030017610A KR20030017610A KR10-2003-7000160A KR20037000160A KR20030017610A KR 20030017610 A KR20030017610 A KR 20030017610A KR 20037000160 A KR20037000160 A KR 20037000160A KR 20030017610 A KR20030017610 A KR 20030017610A
- Authority
- KR
- South Korea
- Prior art keywords
- minocycline
- group
- compound according
- alkyl
- substituted
- Prior art date
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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 96
- -1 tetracycline compounds Chemical class 0.000 claims abstract description 336
- 229960004023 minocycline Drugs 0.000 claims abstract description 230
- 239000004098 Tetracycline Substances 0.000 claims abstract description 82
- 235000019364 tetracycline Nutrition 0.000 claims abstract description 82
- 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
- 208000035143 Bacterial infection Diseases 0.000 claims abstract description 13
- 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 51
- 125000000217 alkyl group Chemical group 0.000 claims description 103
- 150000001875 compounds Chemical class 0.000 claims description 81
- 125000003118 aryl group Chemical group 0.000 claims description 76
- 125000000304 alkynyl group Chemical group 0.000 claims description 74
- 125000003342 alkenyl group Chemical group 0.000 claims description 67
- 125000001424 substituent group Chemical group 0.000 claims description 63
- 125000003545 alkoxy group Chemical group 0.000 claims description 54
- 238000000034 method Methods 0.000 claims description 43
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 41
- 125000004414 alkyl thio group Chemical group 0.000 claims description 41
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 41
- 239000001257 hydrogen Substances 0.000 claims description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- 125000001072 heteroaryl group Chemical group 0.000 claims description 37
- 229910052736 halogen Inorganic materials 0.000 claims description 36
- 150000002367 halogens Chemical class 0.000 claims description 35
- 125000003282 alkyl amino group Chemical group 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 32
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 31
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 30
- 125000000623 heterocyclic group Chemical group 0.000 claims description 30
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 24
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 24
- 150000002431 hydrogen Chemical group 0.000 claims description 22
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 21
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 20
- 150000007942 carboxylates Chemical class 0.000 claims description 20
- 229910019142 PO4 Inorganic materials 0.000 claims description 19
- 125000004442 acylamino group Chemical group 0.000 claims description 19
- 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 19
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 19
- 239000010452 phosphate Substances 0.000 claims description 19
- 239000000651 prodrug Substances 0.000 claims description 19
- 229940002612 prodrug Drugs 0.000 claims description 19
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 19
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 18
- 125000004457 alkyl amino carbonyl group Chemical group 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- 125000005110 aryl thio group Chemical group 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
- 125000005200 aryloxy carbonyloxy group Chemical group 0.000 claims description 16
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- 125000002252 acyl group Chemical group 0.000 claims description 13
- 125000005089 alkenylaminocarbonyl group Chemical group 0.000 claims description 13
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 13
- 125000005090 alkenylcarbonyl group Chemical group 0.000 claims description 12
- 125000003368 amide group 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 239000003937 drug carrier Substances 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 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
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 9
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 9
- 241000588724 Escherichia coli Species 0.000 claims description 8
- 125000005036 alkoxyphenyl group Chemical group 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
- 125000005059 halophenyl group Chemical group 0.000 claims description 8
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 7
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 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
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000006501 nitrophenyl group Chemical group 0.000 claims description 7
- 125000001181 organosilyl group Chemical group [SiH3]* 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
- 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
- 239000004202 carbamide Substances 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
- 125000003435 aroyl group Chemical group 0.000 claims description 5
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 5
- 229940072172 tetracycline antibiotic Drugs 0.000 claims description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 125000005250 alkyl acrylate group Chemical group 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
- 125000005179 haloacetyl group Chemical group 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 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
- 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 claims description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 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
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical group CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 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
- 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
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 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
- 150000003457 sulfones Chemical class 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
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 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
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 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
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- ZHCAAFJSYLFLPX-UHFFFAOYSA-N nitrocyclohexatriene Chemical group [O-][N+](=O)C1=CC=C=C[CH]1 ZHCAAFJSYLFLPX-UHFFFAOYSA-N 0.000 claims description 2
- RUVINXPYWBROJD-UHFFFAOYSA-N para-methoxyphenyl Natural products COC1=CC=C(C=CC)C=C1 RUVINXPYWBROJD-UHFFFAOYSA-N 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
- 125000003396 thiol group Chemical class [H]S* 0.000 claims 3
- 241000495778 Escherichia faecalis Species 0.000 claims 2
- 125000004422 alkyl sulphonamide group Chemical group 0.000 claims 1
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 5
- 230000000903 blocking effect Effects 0.000 abstract description 3
- 230000014509 gene expression Effects 0.000 abstract description 2
- 108090000623 proteins and genes Proteins 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 18
- 239000000203 mixture Substances 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 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 229910052757 nitrogen Inorganic materials 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
- 239000002585 base Substances 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
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- 239000002253 acid Substances 0.000 description 9
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 9
- 125000004658 aryl carbonyl amino group Chemical group 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 125000004947 alkyl aryl amino group Chemical group 0.000 description 8
- 125000001769 aryl amino group Chemical group 0.000 description 8
- 125000004986 diarylamino group Chemical group 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- 241000894006 Bacteria Species 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
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- 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
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
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- 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
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- A61P31/04—Antibacterial agents
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Abstract
Description
Claims (83)
- 하기 화학식 I의 미노사이클린 화합물, 또는 그의 제약학상 허용가능한 염, 에스테르 또는 프로드럭.<화학식 I>식 중,X는 CHC(R13Y'Y), CR6'R6, S, NR6또는 O이고;R2, R4', R4", R7'및 R7"은 각각 수소, 알킬, 알케닐, 알키닐, 알콕시, 알킬티오, 알킬술피닐, 알킬술포닐, 알킬아미노, 아릴알킬, 아릴, 헤테로시클릭, 헤테로방향족 또는 프로드럭 잔기이고;R4는 NR4'R4", 알킬, 알케닐, 알키닐, 아릴, 히드록실, 할로겐 또는 수소이고;R2', R3, R10, R11및 R12는 각각 수소 또는 프로드럭 잔기이고;R5는 히드록실, 수소, 티올, 알카노일, 아로일, 알카로일, 아릴, 헤테로방향족, 알킬, 알케닐, 알키닐, 알콕시, 알킬티오, 알킬술피닐, 알킬술포닐, 알킬아미노, 아릴알킬, 알킬카르보닐옥시 또는 아릴카르보닐옥시이고;R6및 R6'은 독립적으로 수소, 메틸렌, 히드록실, 할로겐, 티올, 알킬, 알케닐, 알키닐, 아릴, 알콕시, 알킬티오, 알킬술피닐, 알킬술포닐, 알킬아미노, 아릴알킬이거나 또는 존재하지 않고;R9는 니트로, 알킬, 알케닐, 알키닐, 아릴, 알콕시, 알킬티오, 알킬술피닐, 알킬술포닐, 아릴알킬, 아미노, 아릴알케닐, 아릴알키닐, 티오니트로소 또는 -(CH2)0-3NR9cC(=Z')ZR9a이고;Z는 CR9dR9e, S, NR9b또는 O이고;Z'는 NR9f, O 또는 S이고;R9a, R9b, R9c, R9d, R9e및 R9f는 각각 독립적으로 수소, 아실, 알킬, 알케닐, 알키닐, 알콕시, 알킬티오, 알킬술피닐, 알킬술포닐, 알킬아미노, 아릴알킬, 아릴, 헤테로시클릭, 헤테로방향족 또는 프로드럭 잔기이고;R8은 수소, 히드록실, 할로겐, 티올, 알킬, 알케닐, 알키닐, 아릴, 알콕시, 알킬티오, 알킬술피닐, 알킬술포닐, 알킬아미노 또는 아릴알킬이고;R13은 수소, 히드록시, 알킬, 알케닐, 알키닐, 알콕시, 알킬티오, 알킬술피닐, 알킬술포닐, 알킬아미노 또는 아릴알킬이며;Y' 및 Y는 각각 독립적으로 수소, 할로겐, 히드록실, 시아노, 술프히드릴, 아미노, 알킬, 알케닐, 알키닐, 알콕시, 알킬티오, 알킬술피닐, 알킬술포닐, 알킬아미노 또는 아릴알킬이다.
- 제1항에 있어서, R4는 NR4'R4"이고, X는 CR6R6'이고; R2, R2', R5, R6, R6', R8, R9, R10, R11및 R12는 각각 수소이며, R4', R4", R7'및 R7"는 각각 저급 알킬인 미노사이클린 화합물.
- 제2항에 있어서, R4', R4", R7'및 R7"이 각각 메틸인 미노사이클린 화합물.
- 제1항 내지 제3항 중 어느 한 항에 있어서, R9가 치환 또는 비치환 아릴인 미노사이클린 화합물.
- 제4항에 있어서, R9가 치환 또는 비치환 페닐인 미노사이클린 화합물.
- 제5항에 있어서, R9가 비치환 페닐인 미노사이클린 화합물.
- 제5항에 있어서, R9가 할로겐, 히드록실, 알콕시, 포르밀, 알킬카르보닐옥시, 아릴카르보닐옥시, 카르복실, 알콕시카르보닐옥시, 아릴옥시카르보닐옥시, 카르복실레이트, 알킬카르보닐, 알킬아미노카르보닐, 아릴알킬아미노카르보닐, 알케닐아미노카르보닐, 알킬카르보닐, 아릴카르보닐, 아릴알킬카르보닐, 알케닐카르보닐, 알콕시카르보닐, 아미노카르보닐, 알킬티오카르보닐, 포스페이트, 포스포네이토, 포스피네이토, 시아노, 아미노, 아실아미노, 아미도, 이미노, 술프히드릴, 알킬티오, 아릴티오, 티오카르복실레이트, 술페이트, 알킬술피닐, 술포네이토, 술파모일, 술폰아미도, 니트로, 트리플루오로메틸, 시아노, 아지도, 헤테로시클릴, 알킬아릴, 또는 방향족 또는 및 헤테로방향족 잔기로 구성된 군 중에서 선택된 1개 이상의 치환체로 치환되는 미노사이클린 화합물.
- 제7항에 있어서, R9가 카르복실레이트, 알킬, 알케닐, 알키닐, 아릴, 헤테로시클릭, 시아노, 아미노, 할로겐, 알콕시, 알콕시카르보닐, 아미도, 알킬카르보닐 및 니트로로 구성된 군 중에서 선택된 1개 이상의 치환체로 치환되는 미노사이클린 화합물.
- 제4항에 있어서, R9가 치환 또는 비치환 헤테로아릴인 미노사이클린 화합물.
- 제9항에 있어서, 상기 헤테로아릴이 푸라닐, 이미다졸릴, 벤조티오페닐, 벤조푸라닐, 퀴놀리닐, 이소퀴놀리닐, 벤조디옥사졸릴, 벤족사졸릴, 벤조티아졸릴, 벤조이미다졸릴, 메틸렌디옥시페닐, 인돌릴, 티에닐, 피리미딜, 피라지닐, 푸리닐, 피라졸릴, 옥사졸릴, 이소옥사졸릴, 나프트리디닐, 티아졸릴, 이소티아졸릴 또는 데아자푸리닐로 구성된 군 중에서 선택되는 미노사이클린 화합물.
- 제10항에 있어서, 상기 헤테로아릴이 티에닐 또는 벤조푸라닐인 미노사이클린 화합물.
- 제1항 내지 제3항 중 어느 한 항에 있어서, R9가 치환 또는 비치환 알키닐인 미노사이클린 화합물.
- 제12항에 있어서, 상기 치환된 알키닐기가 치환 또는 비치환 아릴기로 치환되는 미노사이클린 화합물.
- 제13항에 있어서, 상기 아릴기가 치환 또는 비치환 페닐인 미노사이클린 화합물.
- 제14항에 있어서, 상기 페닐기가 알킬, 알케닐, 할로겐, 히드록실, 알콕시, 알킬카르보닐옥시, 알킬옥시카르보닐, 아릴카르보닐옥시, 알콕시카르보닐옥시, 아릴옥시카르보닐옥시, 카르복실레이트, 알킬카르보닐, 알킬아미노카르보닐, 아릴알킬아미노카르보닐, 알케닐아미노카르보닐, 알킬카르보닐, 아릴카르보닐, 아릴알킬카르보닐, 알케닐카르보닐, 알콕시카르보닐, 실릴, 아미노카르보닐, 알킬티오카르보닐, 포스페이트, 아르알킬, 포스포네이토, 포스피네이토, 시아노, 아미노, 아실아미노, 아미도, 이미노, 술프히드릴, 알킬티오, 술페이트, 아릴티오, 티오카르복실레이트, 알킬술피닐, 술포네이토, 술파모일, 술폰아미도, 니트로, 시아노, 아지도, 헤테로시클릴, 알킬아릴, 아릴 및 헤테로아릴 중에서 선택된 기로 치환되는 미노사이클린 화합물.
- 제13항에 있어서, 상기 아릴기가 헤테로아릴인 미노사이클린 화합물.
- 제12항에 있어서, 상기 알키닐기가 알킬, 알케닐, 카르복실레이트, 실릴, 아르알킬 또는 알킬옥시카르보닐기로 치환되는 미노사이클린 화합물.
- 제15항에 있어서, 상기 알킬 치환체가 아미노알킬인 미노사이클린 화합물.
- 제18항에 있어서, 상기 아미노알킬이 알킬술폰아미드기로 치환되는 미노사이클린 화합물.
- 제17항에 있어서, 상기 알키닐기가 시클로알케닐기로 치환되는 미노사이클린 화합물.
- 제20항에 있어서, 상기 시클로알케닐기가 시클로펜테닐인 미노사이클린 화합물.
- 제1항 내지 제3항 중 어느 한 항에 있어서, R9가 알킬인 미노사이클린 화합물.
- 제22항에 있어서, 상기 알킬기가 할로겐, 히드록실, 알콕시, 알킬카르보닐옥시, 아릴카르보닐옥시, 알콕시카르보닐옥시, 아릴옥시카르보닐옥시, 카르복실레이트, 알킬카르보닐, 알킬아미노카르보닐, 아릴알킬아미노카르보닐, 알케닐아미노카르보닐, 알킬카르보닐, 아릴카르보닐, 아릴알킬카르보닐, 알케닐카르보닐, 알콕시카르보닐, 실릴, 아미노카르보닐, 알킬티오카르보닐, 포스페이트, 포스포네이토, 포스피네이토, 시아노, 아미노, 아실아미노, 아미디노, 이미노, 술프히드릴, 알킬티오, 아릴티오, 티오카르복실레이트, 술페이트, 알킬술피닐, 술포네이토, 술파모일, 술폰아미도, 니트로, 알케닐, 시아노, 아지도, 헤테로시클릴, 알킬아릴, 아릴 및 헤테로아릴로 구성된 군 중에서 선택된 1개 이상의 치환체로 치환되는 미노사이클린 화합물.
- 제22항에 있어서, 상기 알킬기가 고리를 포함하는 미노사이클린 화합물.
- 제24항에 있어서, 상기 알킬기가 2-시클로펜틸에틸인 미노사이클린 화합물.
- 제1항 내지 제3항 중 어느 한 항에 있어서, R9가 -(CH2)0-3NR9cC(=Z')ZR9a인 미노사이클린 화합물.
- 제26항에 있어서, R9가 -NR9cC(=Z')ZR9a인 미노사이클린 화합물.
- 제26항에 있어서, R9가 -CH2NR9cC(=Z')ZR9a인 미노사이클린 화합물.
- 제27항 또는 제28항에 있어서, R9c가 수소인 미노사이클린 화합물.
- 제27항 내지 제29항 중 어느 한 항에 있어서, Z'가 S인 미노사이클린 화합물.
- 제27항 내지 제29항 중 어느 한 항에 있어서, Z'가 O인 미노사이클린 화합물.
- 제27항 내지 제31항 중 어느 한 항에 있어서, Z가 NR9b인 미노사이클린 화합물.
- 제27항 내지 제31항 중 어느 한 항에 있어서, Z가 O인 미노사이클린 화합물.
- 제27항 내지 제31항 중 어느 한 항에 있어서, Z가 S인 미노사이클린 화합물.
- 제32항에 있어서, R9b가 수소인 미노사이클린 화합물.
- 제26항 내지 제35항 중 어느 한 항에 있어서, R9a가 아릴인 미노사이클린 화합물.
- 제36항에 있어서, R9a가 치환 또는 비치환 페닐인 미노사이클린 화합물.
- 제36항에 있어서, 상기 페닐기가 할로겐, 히드록실, 알콕시, 알킬카르보닐옥시, 아릴카르보닐옥시, 알콕시카르보닐옥시, 아릴옥시카르보닐옥시, 카르복실레이트, 알킬카르보닐, 알킬아미노카르보닐, 아릴알킬아미노카르보닐, 알케닐아미노카르보닐, 알킬카르보닐, 아릴카르보닐, 아릴알킬카르보닐, 알케닐카르보닐, 알콕시카르보닐, 실릴, 아미노카르보닐, 알킬티오카르보닐, 포스페이트, 포스포네이토, 포스피네이토, 시아노, 아미노, 아실아미노, 아미디노, 이미노, 술프히드릴, 알킬티오, 아릴티오, 티오카르복실레이트, 술페이트, 알킬술피닐, 술포네이토, 술파모일, 술폰아미도, 니트로, 아세틸, 알킬, 시아노, 아지도, 헤테로시클릴, 알킬아릴, 아릴 및 헤테로아릴로 구성된 군 중에서 선택된 1개 이상의 치환체로 치환되는 미노사이클린 화합물.
- 제38항에 있어서, 상기 치환체가 니트로, 알콕시, 알킬, 아실, 할로겐 또는 아미노 중에서 선택되는 미노사이클린 화합물.
- 제39항에 있어서, 상기 아미노기가 디알킬아미노인 미노사이클린 화합물.
- 제39항에 있어서, 상기 알콕시기가 메톡시인 미노사이클린 화합물.
- 제39항에 있어서, 상기 알콕시기가 메틸렌디옥시인 미노사이클린 화합물.
- 제41항에 있어서, 상기 알콕시기가 과할로겐화되는 것인 미노사이클린 화합물.
- 제43항에 있어서, 상기 알콕시기가 퍼플루오로메톡시인 미노사이클린 화합물.
- 제39항에 있어서, 상기 알킬기가 메틸, 에틸, 프로필, 부틸 또는 펜틸인 미노사이클린 화합물.
- 제39항에 있어서, 상기 할로겐이 불소, 염소, 브롬 또는 요오드인 미노사이클린 화합물.
- 제36항에 있어서, 상기 페닐기가 비치환 페닐, 파라-니트로페닐, 파라-메톡시페닐, 파라-퍼플루오로메톡시페닐, 파라-아세틸 페닐, 3,5-메틸렌디옥시페닐, 3,5-디퍼플루오로메틸페닐, 파라-브로모 페닐, 파라-클로로 페닐 또는 파라-플루오로 페닐인 미노사이클린 화합물.
- 제38항에 있어서, R9a가 아릴카르보닐인 미노사이클린 화합물.
- 제36항에 있어서, R9a가 비아릴인 미노사이클린 화합물.
- 제49항에 있어서, R9a가 나프틸인 미노사이클린 화합물.
- 제26항 내지 제35항에 있어서, R9a가 치환 또는 비치환 알킬인 미노사이클린 화합물.
- 제51항에 있어서, R9a가 비치환 알킬인 미노사이클린 화합물.
- 제52항에 있어서, R9a가 메틸, 에틸, 프로필, 부틸 또는 펜틸인 미노사이클린 화합물.
- 제51항에 있어서, 상기 알킬이 할로겐, 히드록실, 알콕시, 알킬카르보닐옥시, 아릴카르보닐옥시, 알콕시카르보닐옥시, 아릴옥시카르보닐옥시, 카르복실레이트, 알킬카르보닐, 알킬아미노카르보닐, 아릴알킬아미노카르보닐, 알케닐아미노카르보닐, 알킬카르보닐, 아릴카르보닐, 아릴알킬카르보닐, 알케닐카르보닐, 알콕시카르보닐, 실릴, 아미노카르보닐, 알킬티오카르보닐, 포스페이트, 포스포네이토, 포스피네이토, 시아노, 아미노, 아실아미노, 아미디노, 이미노, 술프히드릴, 알킬티오, 아릴티오, 티오카르복실레이트, 술페이트, 알킬술피닐, 술포네이토, 술파모일, 술폰아미도, 니트로, 트리플루오로메틸, 시아노, 아지도, 알케닐, 헤테로시클릴, 알킬아릴, 아릴 및 헤테로아릴로 구성된 군 중에서 선택된 1개 이상의 치환체로 치환되는 미노사이클린 화합물.
- 제26항 내지 제35항 중 어느 한 항에 있어서, R9a가 치환 또는 비치환 알케닐인 미노사이클린 화합물.
- 제55항에 있어서, R9a가 펜트-1-에닐인 미노사이클린 화합물.
- 제26항에 있어서, Z'가 NH이고, Z가 NH이며, R9a가 알킬인 미노사이클린 화합물.
- 제1항 내지 제3항 중 어느 한 항에 있어서, R9가 -N=S인 미노사이클린 화합물.
- 제1항 내지 제3항 중 어느 한 항에 있어서, R9가 아미노알킬인 미노사이클린 화합물.
- 제59항에 있어서, 상기 아미노알킬이 알킬아미노알킬인 미노사이클린 화합물.
- 제1항 내지 제3항 중 어느 한 항에 있어서, R9가 치환 또는 비치환 알킬아미노인 미노사이클린 화합물.
- 제61항에 있어서, 상기 알킬아미노가 아릴기로 치환되는 미노사이클린 화합물.
- 제62항에 있어서, 상기 아릴기가 치환 또는 비치환 페닐인 미노사이클린 화합물.
- 제63항에 있어서, 상기 치환 페닐이 메틸렌디옥시페닐 또는 파라-퍼플루오로메톡시페닐인 미노사이클린 화합물.
- 하기 화합물들로 구성된 군 중에서 선택되는 미노사이클린 화합물 또는 그의 제약학상 허용가능한 염.
- 제1항 또는 제65항의 미노사이클린 화합물을 포유류에게 투여하여 상기 대상자를 치료하는 것을 포함하는, 상기 대상자의 테트라사이클린 반응성 상태의 치료방법.
- 제66항에 있어서, 상기 테트라시아클린 반응성 상태가 세균 감염인 방법.
- 제67항에 있어서, 상기 세균 감염이 이. 콜리(E. coli)와 관련이 있는 것인 방법.
- 제68항에 있어서, 상기 세균 감염이 에스. 아우레우스(S. aureus)와 관련이 있는 것인 방법.
- 제68항에 있어서, 상기 세균 감염이 이. 파에칼리스(E. faecalis)와 관련이 있는 것인 방법.
- 제67항에 있어서, 상기 세균 감염이 다른 테트라아시클린 항생제에는 내성이 있는 것인 방법.
- 제66항에 있어서, 상기 미노사이클린 화합물을 제약학상 허용가능한 담체와 함께 투여하는 것인 방법.
- 제66항에 있어서, 상기 대상자가 인간인 방법.
- 치료 유효량의 제1항 또는 제65항의 미노사이클린 화합물 및 제약학상 허용가능한 담체를 포함하는 제약 조성물.
- 하기 화학식 I의 9-치환된 미노사이클린 화합물 또는 그의 제약학상 허용가능한 염.<화학식 II>식 중,R4'R4"R7'및 R7"은 각각 알킬이고;R9는 피리딜에티닐기; 알케닐카르바메이트기; 할로기; 알킬아크릴레이트기; 나프틸기; 할로아세틸기; 알킬카르바메이트기; 시클로펜틸 또는 시클로펜테닐기; 벤조푸라닐기; 페닐프로피오논아미노기; 토실아미노기; 메톡시피리딜기; 알켄아미노기; N-t-부틸기; t-부틸아미드기; 히드록시부틸아미노기; 히드록시프로필아미노기; 페닐기; 니트로페닐기; 니트로페닐알키닐기; 아미노페닐기; 알콕시페닐기; 할로페닐 우레아기; 시아노페닐기; 카르복시페닐기; 아실페닐기; 알킬페닐기; 할로페닐기; 알콕시페닐기; 카르복시알킬페닐기; 페닐알키닐기; 알키닐기; 알킬글리신에틸에스테르기; 스티렌기; 티오펜기; 및 알킬아미노포스포기이다.
- 제74항에 있어서, 상기 화합물이 9-이소프로페닐 카르바메이트 미노사이클린, 9-(2-피리딜에티닐) 미노사이클린, 9-요오도 미노사이클린, 9-부틸아크릴레이트 미노사이클린, 9-나프틸 미노사이클린 우레아, 9-클로로아세틸 미노사이클린, 9-네오펜틸 미노사이클린 카르바메이트, 9-시클로펜텐 미노사이클린, 벤조푸라닐 미노사이클린, 9-(페닐프로피오논아미노) 미노사이클린, 9-토실아미노 미노사이클린, 9-(2-메톡시-3-피리딜) 미노사이클린, 9-(N-2'-히드록시데실-9'-엔-아미노) 미노사이클린, N-t-부틸-미노사이클린, 9-BOC-NH 미노사이클린, 9-(N-2'-히드록시부틸아미노) 미노사이클린, 9-(N-3-클로로,2-히드록실프로필아미노) 미노사이클린, 9-페닐 미노사이클린, 9-p-톨릴 미노사이클린, 9-3'-니트로페닐 미노사이클린, 9-(4-니트로페닐에티닐) 미노사이클린, 9-(3-아미노페닐) 미노사이클린, 9-(4-클로로,2-트리플루오로메틸페닐) 미노사이클린 우레아, 9-(p-메톡시페닐) 미노사이클린, 9-(4'-메톡시페닐) 미노사이클린, 9-(3,4-메틸렌디옥시페닐) 미노사이클린, 9-(4'-시아노페닐) 미노사이클린, 9-(4'-카르복시페닐) 미노사이클린, 9-(3-포르밀페닐) 미노사이클린, 9-(4'-t-부틸페닐) 미노사이클린, 9-(3-클로로페닐) 미노사이클린, 9-(2',4'-디플루오로페닐) 미노사이클린, 9-(3,4-디플루오로페닐) 미노사이클린, 9-(4'-클로로페닐) 미노사이클린, 9-(3,4-디클로로페닐) 미노사이클린, 9-(4'-트리플루오로메틸페닐) 미노사이클린, 9-(3-에톡시페닐) 미노사이클린, 9-(4-카르복시메틸페닐) 미노사이클린, 9-(페닐에티닐) 미노사이클린, 9-(3-히드록시페닐에티닐) 미노사이클린, 9-(p-톨릴에티닐) 미노사이클린, 9-(p-메톡시페닐에티닐) 미노사이클린, 9-에티닐 미노사이클린, 9-(p-플루오로에티닐) 미노사이클린, 9-(트리메틸실릴에티닐) 미노사이클린, 9-(프로피오닐) 미노사이클린, 9-(시클로헥세닐에티닐) 미노사이클린, 9-(1-시클로헥실-1-히드록시에티닐) 미노사이클린, 9-프로필글리신에틸에스테르 미노사이클린 HCl, 9-메틸글리신에틸에스테르 미노사이클린, 9-스티렌 미노사이클린, 9-4'-플루오로스티렌 미노사이클린, 9-2-티오펜 미노사이클린, 9-(5'-클로로-2'-티오펜) 미노사이클린, 9-(p-메톡시페닐아미노포스포) 미노사이클린, 9-(페닐아미노포스포) 미노사이클린, 9-(p-메톡시페닐아미노포스포) 미노사이클린 또는 9-(페닐아미노포스포) 미노사이클린인 9-치환된 미노사이클린 화합물.
- 제75항 또는 제76항의 9-치환된 미노사이클린 화합물을 대상자에게 투여하여 테트라사이클린 반응성 상태를 치료하는 것을 포함하는, 상기 대상자의 테트라사이클린 반응성 상태의 치료 방법.
- 제77항에 있어서, 상기 테트라사이클린 반응성 상태가 세균 감염인 것인 방법.
- 제78항에 있어서, 상기 세균 감염이 이. 콜리(E. coli), 에스. 아우레우스(S. aureus) 또는 이. 파에칼리스(E. faecalis)와 관련이 있는 것인 방법.
- 제78항에 있어서, 상기 세균 감염이 다른 테트라아시클린 항생제에는 내성이 있는 것인 방법.
- 제77항에 있어서, 상기 화합물을 제약학상 허용가능한 담체와 함께 투여하는 것인 방법.
- 표 1에 열거한 군 중에서 선택되는 미노사이클린 화합물.
- 치료 유효량의 제75항, 제76항 또는 제82항의 화합물 및 제약학상 허용가능한 담체를 포함하는 제약 조성물.
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