JP2023544643A - バクチオ-ル誘導体、その薬学的に許容される塩及びその調製方法並びに用途 - Google Patents
バクチオ-ル誘導体、その薬学的に許容される塩及びその調製方法並びに用途 Download PDFInfo
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- JP2023544643A JP2023544643A JP2023527021A JP2023527021A JP2023544643A JP 2023544643 A JP2023544643 A JP 2023544643A JP 2023527021 A JP2023527021 A JP 2023527021A JP 2023527021 A JP2023527021 A JP 2023527021A JP 2023544643 A JP2023544643 A JP 2023544643A
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- compound
- alkyl group
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- bakuchiol
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- 238000002360 preparation method Methods 0.000 title claims abstract description 78
- LFYJSSARVMHQJB-QIXNEVBVSA-N bakuchiol Chemical class CC(C)=CCC[C@@](C)(C=C)\C=C\C1=CC=C(O)C=C1 LFYJSSARVMHQJB-QIXNEVBVSA-N 0.000 title claims abstract description 63
- 150000003839 salts Chemical class 0.000 title claims abstract description 46
- 150000001875 compounds Chemical class 0.000 claims abstract description 108
- 238000000034 method Methods 0.000 claims description 57
- 125000000623 heterocyclic group Chemical group 0.000 claims description 34
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 14
- ZRALSGWEFCBTJO-UHFFFAOYSA-N guanidine group Chemical group NC(=N)N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 238000006482 condensation reaction Methods 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 3
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 3
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 3
- 150000001450 anions Chemical class 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 229940124350 antibacterial drug Drugs 0.000 claims 1
- 239000012634 fragment Substances 0.000 claims 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 20
- 206010059866 Drug resistance Diseases 0.000 abstract description 7
- 238000011161 development Methods 0.000 abstract description 6
- 206010034133 Pathogen resistance Diseases 0.000 abstract description 5
- 238000010586 diagram Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 98
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 80
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 57
- 239000007858 starting material Substances 0.000 description 49
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 46
- 230000002194 synthesizing effect Effects 0.000 description 46
- 238000005160 1H NMR spectroscopy Methods 0.000 description 34
- 239000000499 gel Substances 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 238000005481 NMR spectroscopy Methods 0.000 description 24
- 239000003921 oil Substances 0.000 description 24
- 235000019198 oils Nutrition 0.000 description 24
- -1 1-ethyl- 2-methylpropyl group Chemical group 0.000 description 22
- 239000007821 HATU Substances 0.000 description 22
- 229940125782 compound 2 Drugs 0.000 description 20
- 229940125898 compound 5 Drugs 0.000 description 19
- 230000001580 bacterial effect Effects 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 229940127573 compound 38 Drugs 0.000 description 14
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 14
- 241000699666 Mus <mouse, genus> Species 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- 230000002829 reductive effect Effects 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 11
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 10
- 241000191967 Staphylococcus aureus Species 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- LFYJSSARVMHQJB-UHFFFAOYSA-N Backuchiol Natural products CC(C)=CCCC(C)(C=C)C=CC1=CC=C(O)C=C1 LFYJSSARVMHQJB-UHFFFAOYSA-N 0.000 description 9
- LFYJSSARVMHQJB-GOSISDBHSA-N bakuchinol Natural products CC(C)=CCC[C@@](C)(C=C)C=CC1=CC=C(O)C=C1 LFYJSSARVMHQJB-GOSISDBHSA-N 0.000 description 9
- 229940117895 bakuchiol Drugs 0.000 description 9
- KXXXNMZPAJTCQY-UHFFFAOYSA-N bakuchiol Natural products CC(C)CCCC(C)(C=C)C=Cc1ccc(O)cc1 KXXXNMZPAJTCQY-UHFFFAOYSA-N 0.000 description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 239000003242 anti bacterial agent Substances 0.000 description 8
- 229940125904 compound 1 Drugs 0.000 description 8
- 230000002949 hemolytic effect Effects 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 230000003013 cytotoxicity Effects 0.000 description 7
- 231100000135 cytotoxicity Toxicity 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 6
- 208000035143 Bacterial infection Diseases 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- 238000002835 absorbance Methods 0.000 description 6
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 6
- 208000022362 bacterial infectious disease Diseases 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229940125961 compound 24 Drugs 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- 125000006413 ring segment Chemical group 0.000 description 6
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 5
- 230000000845 anti-microbial effect Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 4
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 4
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 4
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
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- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 4
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- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 4
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- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 3
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- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 125000005259 triarylamine group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000005580 triphenylene group Chemical group 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
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- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/16—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring not being further substituted
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- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
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- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/62—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
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- 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
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- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/08—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by singly-bound oxygen atoms
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- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
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- C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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Abstract
Description
Rは、ハロゲン基、-CONR1R2、-COOR3、-NR4R5、
から選択され、
R1とR2は、それぞれ独立して-H、
から選択され、
R12とR13は、それぞれ独立して-H、
から選択され、
R22とR23は、それぞれ独立して-H、
から選択され、
R32とR33は、それぞれ独立して-H、
から選択され、
R42とR43は、それぞれ独立して-H、
から選択され、
R52とR53は、それぞれ独立して-H、
から選択され、
R62とR63は、それぞれ独立して-H又は
から選択され、
から選択され、
R18、R28、R38、R48、R58、R68は、それぞれ独立して-H、C1-6アルキル基又はハロゲンから選択され、
R77は、-H又はC1-6アルキル基から選択され、
R3は、-H又はC1-4アルキル基から選択され、
Rbは、C1-10アルキル基、-(CH2)pNRb1Rb2又は-SRb3から選択され、pは0、1、2、3、4、5、6、7、8、9又は10であり、
Ra3とRb3は、それぞれ独立してC1-10アルキル基であり、
R6は、C1-4アルキル基であり、R7は、-H又はC1-4アルキル基から選択され、R8は、-H、C1-6アルキル基又は
であり、
Y-は、陰イオンである。
式(I-1)に示す化合物を
と反応させ、Rがハロゲンである式(I-1)に示す化合物を調製し取得するステップを含み、
であるときに、前記調製方法は、
式(I-1)に示す化合物を
と反応させ、RがBrである中間体を調製し取得するステップと、
である式(I)に示す化合物を調製し取得するステップと、
と反応させ、Rが
である式(I)に示す化合物を調製し取得するステップと、を含み、
式(I-1)に示す化合物とブロモアルキルアルキル酸エステルとを縮合反応させ、Rが-COOR3である式(I)に示す化合物を調製し取得するステップと、
式(I-2)に示す化合物と
とを縮合反応させ、RがCONR1R2である式(I)に示す化合物を調製し取得するステップと、を含む。
用語の解釈
定義と汎用用語
を指し、
本発明で、キラルな炭素原子の立体配置が示されていない場合に、当分野で許容される任意の構成を含むと理解されるべきであり、
本発明の化合物は、非溶媒和型及び薬学的に許容される溶媒(例えば水、エタノ-ルなど)を含む溶媒和型で存在し、即ち、溶媒和型及び非溶媒和型を含む。
本発明で、ある置換可能部分は、1つ又は複数の置換基で置換され、且つこの置換可能部分に複数の置換基がある場合に、複数の置換基は、互いに同じ又は異なっても良い。
詳細な説明
更に、式(I‘)に示す構造を有し、
ここで、nは1~16の整数であり、一実施例において、nは1、2、3、4、5、6、7、8、9、10、11又は12であり、
Rはハロゲン、CONR1R2、-COOR3、NR4R5、
から選択され、
R1とR2は、それぞれ独立して-H、
から選択され、
R12とR13は、それぞれ独立して-H、
から選択され、
R22とR23は、それぞれ独立して-H、
から選択され、
R32とR33は、それぞれ独立して-H、
から選択され、
R42とR43は、それぞれ独立して-H、
から選択され、
R52とR53は、それぞれ独立して-H、
から選択され、
R62とR63は、それぞれ独立して-H又は
から選択され、
ここで、R14、R24、R34、R44、R54、R64及びR74は、それぞれ独立して-H、グアニジン基、-NR4R5、-SR4、5~20員含窒素ヘテロアリ-ル、
から選択され、
R15~R17、R25~R27、R35~R37、R45~R47、R55~R57、R65~R67は、それぞれ独立して-H又はC1-6アルキル基から選択され、
R18、R28、R38、R48、R58、R68は、それぞれ独立して-H、C1-6アルキル基又はハロゲンから選択され、
n1、n2、n3、n4、n5、n6及びn7は、それぞれ独立して0、1、2、3、4、5、6、7、8、9又は10であり、
R77は、-H又はC1-6アルキル基から選択され、
R3は、-H又はC1-4アルキル基から選択され、
R4とR5は、それぞれ独立して-H、C1-16アルキル基、COOR8、-Fmoc、Ra置換C1-16アルキル基から選択され、或いは、R4、R5は、R4、R5に繋がるNとともに5~20員ヘテロサイクル、5~20員ヘテロ芳香族環、Rb置換5~20員ヘテロサイクル、又はRb置換5~20員ヘテロ芳香族環を形成してもよく、
Raは、5~10員アリ-ル基、5~10員ヘテロアリ-ル基、-NRa1Ra2又は-SRa3から選択され、
Rbは、C1-10アルキル基、-(CH2)pNRb1Rb2又は-SRb3から選択され、pは0、1、2、3、4、5、6、7、8、9又は10であり、
Ra1、Ra2、Rb1及びRb2は、それぞれ独立して-H、C1-10アルキル基、又はRc置換C1-10アルキル基であり、或いは、Ra1及びRa2は、Ra1及びRa2に繋がるN原子とともに5~10員ヘテロサイクル又は5~10員ヘテロ芳香族環を形成してもよく、或いは、Rb1及びRb2は、Rb1及びRb2に繋がるN原子とともに5~10員ヘテロサイクル又は5~10員ヘテロ芳香族環を形成してもよく、
Ra3とRb3は、それぞれ独立してC1-10アルキル基であり、
Rcは、-NRc1Rc2、グアニジン基又は5~6員含窒素ヘテロアリ-ルから選択され、Rc1とRc2は、それぞれ独立して-H、C1-4アルキル基であり、或いは、Rc1及びRc2は、Rc1及びRc2に繋がるN原子とともに5~10員ヘテロサイクル又は5~10員ヘテロ芳香族環を形成してもよく、
R6は、C1-4アルキル基であり、R7は、-H又はC1-4アルキル基から選択され、R8は、-H、C1-6アルキル基又は
であり、
Y-は陰イオンであり、更に、Y-はハロゲン陰イオンであり、より更に、Y-はヨウ素イオンであるバクチオ-ル誘導体及びその薬学的に許容される塩を提供する。
更に、R4とR5は、それぞれ独立してH、C1-12アルキル基、COOR8、-Fmoc、Ra置換C1-12アルキル基から選択され、且つR4、R5は、R4、R5に繋がるNとともに5~15員ヘテロサイクル、5~10員ヘテロ芳香族環、Rb置換5~15員ヘテロサイクル、Rb置換5~15員ヘテロ芳香族環を形成してもよく、更に、R4とR5は、それぞれ独立してH、C1-10アルキル基、COOR8、-Fmoc、Ra置換C1-10アルキル基から選択され、且つR4、R5は、R4、R5に繋がるNとともに5~15員ヘテロサイクル、5~10員ヘテロ芳香族環、Rb置換5~15員ヘテロサイクル、Rb置換5~15員ヘテロ芳香族環を形成してもよく、
更に、前記ヘテロサイクル基は、下記の構造基から選択され、
q1、q2、q3及びq4は、それぞれ独立して1、2、3又は4から選択され、
より更に、前記ヘテロサイクル基は、
から選択される。
更に、Ra1、Ra2は、それぞれ独立してH、C1-4アルキル基、NRc1Rc2置換C1-4アルキル基であり、更に、Ra3はC1-4アルキル基であり、更に、Rc1とRc2は、それぞれ独立してH又はC1-4アルキル基であり、更に、RbはH、C1-6アルキル基、-(CH2)pNRb1Rb2から選択され、pは0、1、2、3、4、5又は6であり、より更に、Rb1とRb2は、それぞれ独立してH又はC1-4アルキル基である。
ここで、m1とm2は、それぞれ独立して1、2、3、4、5、6、7又は8である。
であり、
一実施形態において、R12及びR13はいずれもHであり、一実施例において、R12及びR13のうち、一方がHであり、
他方が
から選択され、
一実施例において、R22及びR23はいずれもHであり、一実施例において、R22及びR23のうち、一方がHであり、
他方が
から選択され、
一実施例において、R32及びR33はいずれもHであり、一実施例において、R32及びR33のうち、一方がHであり、
他方が
から選択され、
一実施例において、R42及びR43はいずれもHであり、一実施例において、R42及びR43のうち、一方がHであり、
他方が
から選択され、
一実施例において、R52及びR53はいずれもHであり、一実施例において、R52及びR53のうち、一方がHであり、
他方が
から選択され、
更に、R14、R24、R34、R44、R54、R64及びR74は、それぞれ独立してH、グアニジン基、-NR4R5、-SR4、5~10員含窒素ヘテロアリ-ル、
から選択され、
更に、R14、R24、R34、R44、R54、R64及びR74は、それぞれ独立してH、グアニジン基、-NR4R5、-SR4、5員含窒素ヘテロアリ-ル、
から選択され、
更に、R14、R24、R34、R44、R54、R64及びR74は、それぞれ独立してH、グアニジン基、-NR4R5、-N(CH3)2、-SCH3、
から選択され、
更に、R4及びR5は、それぞれ独立してH又はC1-4アルキル基から選択され、より更に、R4とR5はそれぞれ独立してH、メチル基、エチル基、丙基、イソプロピル基又は丁基から選択され、
更に、上記バクチオ-ル誘導体は、下記の一般式の化合物から選択され、
Xは、NR12R13、OR15又は
である。
から選択される。更に、上記一般式(II)又は式(II‘)において、XはNR12R13であり、R14、R24、R34、R44、R54、R64及びR74のうち、少なくとも1つはグアニジン基である。
他方が
から選択され、
R22及びR23のうち、一方がHであり、
他方が
から選択され、
R32及びR33のうち、一方がHであり、
他方が
から選択され、
R42及びR43のうち、一方がHであり、
他方が
から選択され、
R62及びR63のうち、一方がHであり、
他方が
から選択される。
である。
他方が
から選択される。
他方が
から選択され、
R22及びR23のうち、一方がHであり、
他方が
から選択される。
他方が
から選択され、
R22及びR23のうち、一方がHであり、
他方が
から選択され、
R32及びR23のうち、一方がHであり、
他方が
から選択される。
ここで、X2は、NR22R23、OR25又は
X3は、NR32R33、OR35又は
X4は、NR42R43、OR45又は
X5はNR52R53、OR55又は
X6はNR62R63、OR65又は
更に、上記バクチオ-ル誘導体は、下記の一般式の化合物から選択される。
(1)Rはハロゲンであり、上記調製方法は、下記のステップを含み、
S101:式(I-1)に示す化合物を
Rがハロゲンである式(I-1)に示す化合物を調製し取得し、
前記調製方法は下記のステップを含み、
S201:式(I-1)に示す化合物を
RがBrである式(I)に示す化合物を調製し取得し、
S202:RがBrである式(I)に示す化合物をHNR4R5と反応させ、RがNR4R5である式(I)に示す化合物を調製し取得し、
S203:RがNR4R5である式(I)に示す化合物をハロアルキル基と反応させ、
である式(I)に示す化合物を調製し取得し、
S204:RがNH2である式(I)に示す化合物を
である式(I)に示す化合物を調製し取得し、
S301:式(I-1)に示す化合物とブロモアルキルアルキル酸エステルとを縮合反応させ、Rが-COOR3である式(I)に示す化合物を調製し取得し、
更に、ブロモアルキルアルキル酸エステルは、ブロモエチルC1-6アルキルエステルであり、
S302:将式(I-2)に示す化合物と
を縮合反応させ、式(II)に示す化合物を調製し取得し、
S303:式(II-1)に示す化合物に対して加水分解反応を行って、式(II-2)に示す化合物を調製し取得し、
S304:式(II-2)に示す化合物と
を縮合反応させ、式(III)に示す化合物を調製し取得し、
S305:任意的に、このように循環すると、エステル基を含む化合物を加水分解し、その後、対応するアミンと縮合反応させ、式(IV)、(V)、(VI)、(VII)に示す化合物を調製し取得し、各一般式の構造及び定義は上記した通りであり、ここで重複に説明しない。
化合物1の調製
化合物2の調製
化合物3の調製
化合物4の調製
化合物5の調製
化合物6の調製
化合物7の調製
化合物8の調製
化合物9の調製
化合物10の調製
化合物11の調製
化合物12の調製
化合物13の調製
化合物14の調製
化合物15の調製
化合物16の調製
化合物17の調製
化合物18の調製
化合物19の調製
化合物20の調製
化合物21の調製
化合物22の調製
化合物23の調製
化合物24の調製
化合物25の調製
化合物26の調製
化合物27の調製
化合物28の調製
化合物29の調製
化合物30の調製
化合物31の調製
化合物32の調製
化合物33の調製
化合物34の調製
化合物35の調製
化合物36の調製
化合物38の調製
化合物39の調製
化合物40の調製
化合物41の調製
化合物42の調製
化合物43の調製
化合物44の調製
化合物45の調製
化合物46の調製
化合物47の調製
化合物49の調製
化合物50の調製
化合物65及び51の調製
化合物52の調製
化合物53の調製
化合物55の調製
化合物66及び56の調製
化合物58の調製
化合物59の調製
化合物60の調製
化合物61の調製
化合物63の調製
化合物64の調製
生物実験評価方法
Aサンプル添加:細胞、CCK8溶液及び試験対象サンプル溶液を有する孔の吸光度、
Aブランク:培地及びCCK8溶液を有し、細胞を有しない孔の吸光度、
Aサンプル未添加:細胞、CCK8溶液を有し、試験対象サンプル溶液を有しない孔の吸光度。
実験結果
活性化合物44および60は、100μg/mLの濃度でマウス角膜細胞に対して明らかな細胞毒性を示せず、依然として90%超の細胞生存率を維持する。活性化合物58および60は、100μg/mLの濃度でマウス線維芽細胞NCTC clone929に対して明らかな細胞毒性を示せず、依然として89.3±0.6%および93.7±0.7%の細胞生存率を維持する。
薬剤耐性研究結果
インビボ抗菌活性の評価結果
Claims (15)
- バクチオ-ル誘導体及びその薬学的に許容される塩であって、前記バクチオ-ル誘導体は、式(I)に示す構造を有し、
ここで、nは1~16の整数であり、
Rは、ハロゲン基、-CONR1R2、-COOR3、-NR4R5、
から選択され、
R1とR2は、それぞれ独立して-H、
から選択され、
R12とR13は、それぞれ独立して-H、
から選択され、
R22とR23は、それぞれ独立して-H、
から選択され、
R32とR33は、それぞれ独立して-H、
から選択され、
R42とR43は、それぞれ独立して-H、
から選択され、
R52とR53は、それぞれ独立して-H、
から選択され、
R62とR63は、それぞれ独立して-H又は
から選択され、
ここで、R14、R24、R34、R44、R54、R64及びR74は、それぞれ独立して-H、グアニジン基、-NR4R5、-SR4、5~20員含窒素ヘテロアリ-ル、
から選択され、
R15~R17、R25~R27、R35~R37、R45~R47、R55~R57、R65~R67は、それぞれ独立して-H又はC1-6アルキル基から選択され、
R18、R28、R38、R48、R58、R68は、それぞれ独立して-H、C1-6アルキル基又はハロゲンから選択され、
n1、n2、n3、n4、n5、n6及びn7は、それぞれ独立して0、1、2、3、4、5、6、7、8、9又は10であり、
R77は、-H又はC1-6アルキル基から選択され、
R3は、-H又はC1-4アルキル基から選択され、
R4とR5は、それぞれ独立して-H、C1-16アルキル基、COOR8、-Fmoc、又はRa置換C1-16アルキル基から選択され、或いは、R4、R5は、R4、R5に繋がるNとともに5~20員ヘテロサイクル、5~20員ヘテロ芳香族環、Rb置換5~20員ヘテロサイクル、又はRb置換5~20員ヘテロ芳香族環を形成してもよく、
Raは、5~10員アリ-ル基、5~10員ヘテロアリ-ル基、-NRa1Ra2又は-SRa3から選択され、
Rbは、C1-10アルキル基、-(CH2)pNRb1Rb2又は-SRb3から選択され、pは0、1、2、3、4、5、6、7、8、9又は10であり、
Ra1、Ra2、Rb1及びRb2は、それぞれ独立して-H、C1-10アルキル基、又はRc置換C1-10アルキル基であり、或いは、Ra1及びRa2は、Ra1及びRa2に繋がるN原子とともに5~10員ヘテロサイクル又は5~10員ヘテロ芳香族環を形成してもよく、或いは、Rb1及びRb2は、Rb1及びRb2に繋がるN原子とともに5~10員ヘテロサイクル又は5~10員ヘテロ芳香族環を形成してもよく、
Ra3とRb3は、それぞれ独立してC1-10アルキル基であり、
Rcは、-NRc1Rc2、グアニジン基又は5~6員含窒素ヘテロアリ-ルから選択され、Rc1とRc2は、それぞれ独立して-H、C1-4アルキル基であり、或いは、Rc1及びRc2は、Rc1及びRc2に繋がるN原子とともに5~10員ヘテロサイクル又は5~10員ヘテロ芳香族環を形成してもよく、
R6は、C1-4アルキル基であり、R7は、-H又はC1-4アルキル基から選択され、R8は、-H、C1-6アルキル基又は
であり、
Y-は、陰イオンである
ことを特徴とするバクチオ-ル誘導体及びその薬学的に許容される塩。 - (I‘)に示す構造を有することを特徴とする請求項1に記載のバクチオ-ル誘導体及びその薬学的に許容される塩。
- R4とR5は、それぞれ独立してH、C1-12アルキル基、COOR8、-Fmoc、又はRa置換C1-10アルキル基から選択され、或いは、R4、R5は、R4、R5に繋がるNとともに下記のヘテロサイクルを形成してもよく、
Raは、ピリジン、ピリミジン、トリアジン、-NRa1Ra2又は-SRa3から選択され、
Ra1、Ra2は、それぞれ独立してH、C1-4アルキル基、又はNRc1Rc2置換C1-4アルキル基であり、Ra3は、C1-4アルキル基であり、
Rc1とRc2は、それぞれ独立してH又はC1-4アルキル基であり、
Rbは、H、C1-6アルキル基又は-(CH2)pNRb1Rb2から選択され、pは0、1、2、3、4、5又は6であり、
Rb1とRb2は、それぞれ独立してH又はC1-4アルキル基である
ことを特徴とする請求項1に記載のバクチオ-ル誘導体及びその薬学的に許容される塩。 - Rは、下記の基から選択され、
ここで、m1とm2は、それぞれ独立して1、2、3、4、5、6、7又は8である
ことを特徴とする請求項1に記載のバクチオ-ル誘導体及びその薬学的に許容される塩。 - R14、R24、R34、R44、R54、R64及びR74は、それぞれ独立して-H、グアニジン基、-NR4R5、-SR4、5員含窒素ヘテロアリ-ル、
から選択され、
R8は、C1-4アルキル基である
ことを特徴とする請求項1に記載のバクチオ-ル誘導体及びその薬学的に許容される塩。 - 下記の一般式に記載の化合物から選択され、
Xは、NR12R13、OR15又は
である
ことを特徴とする請求項1に記載のバクチオ-ル誘導体及びその薬学的に許容される塩。 - Xは、OR15であり、且つR14は、H、グアニジン基、-NH2、-SCH3、
から選択される
ことを特徴とする請求項6に記載のバクチオ-ル誘導体及びその薬学的に許容される塩。 - Xは、NR12R13であり、R12及びR13のうち、一方がHであり、他方が
から選択され、
R22及びR23のうち、一方がHであり、他方が
から選択され、
R32及びR33のうち、一方がHであり、他方が
から選択され、
R42及びR43のうち、一方がHであり、他方が
から選択され、
R62及びR63のうち、一方がHであり、他方が
から選択される
ことを特徴とする請求項6に記載のバクチオ-ル誘導体及びその薬学的に許容される塩。 - Xは、
であり、或いは、
Xは、NR12R13であり、
R12及びR13のうち、一方がHであり、他方が
から選択され、或いは、
Xは、NR12R13であり、
R12及びR13のうち、一方がHであり、他方が
から選択され、R22及びR23のうち、一方がHであり、他方が
から選択され、或いは、
Xは、NR12R13であり、
R12及びR13のうち、一方がHであり、他方が
から選択され、
R22及びR23のうち、一方がHであり、他方が
から選択され、
R32及びR23のうち、一方がHであり、他方が
から選択される
ことを特徴とする請求項6に記載のバクチオ-ル誘導体及びその薬学的に許容される塩。 - 下記のいずれか1つの一般式に示す化合物から選択され、
X2は、NR22R23、OR25又は
であり、
X3は、NR32R33、OR35又は
であり、
X4は、NR42R43、OR45又は
であり、
X5は、NR52R53、OR55又は
であり、
X6は、NR62R63、OR65又は
である
ことを特徴とする請求項1に記載のバクチオ-ル誘導体及びその薬学的に許容される塩。 - 下記の化合物から選択されることを特徴とする請求項1に記載のバクチオ-ル誘導体及びその薬学的に許容される塩。
- Rがハロゲンであるときに、前記調製方法は、
式(I-1)に示す化合物を
と反応させ、Rがハロゲンである式(I-1)に示す化合物を調製し取得するステップを含み、
RがNR4R5、
であるときに、
前記調製方法は、
式(I-1)に示す化合物を
と反応させ、RがBrである中間体を調製し取得するステップと、
RがBrである中間体をHNR4R5と反応させ、RがNR4R5である式(I)に示す化合物を調製し取得するステップと、
RがNR4R5である式(I)に示す化合物をハロアルキル基と反応させ、
Rが
である式(I)に示す化合物を調製し取得するステップと、
RがNH2である式(I)に示す化合物を
と反応させ、Rが
である式(I)に示す化合物を調製し取得するステップと、を含み、
RがCONR1R2、-COOR3から選択されるときに、前記調製方法は、
式(I-1)に示す化合物とブロモアルキルアルキル酸エステルとを縮合反応させ、Rが-COOR3である式(I)に示す化合物を調製し取得するステップと、
加水分解を行って、式(I-2)に示す化合物を調製し取得するステップと、
式(I-2)に示す化合物と
とを縮合反応させ、RがCONR1R2である式(I)に示す化合物を調製し取得するステップと、を含む
ことを特徴とする請求項1~11に記載のバクチオ-ル誘導体及びその薬学的に許容される塩の調製方法。 - RがCONR1R2から選択されるときに、さらに、
式(II-1)に示す化合物に対して加水分解反応を行って、式(II-2)に示す化合物を調製し取得するステップと、
式(II-2)に示す化合物と
とを縮合反応させ、式(III)に示す化合物を調製し取得するステップと、
必要に応じて、このように循環すると、エステル基含有化合物に対して加水分解を行って、その後、対応するアミンと縮合反応し、対象断片を含む式(I)に示す化合物を調製し取得するステップと、を含み、
X2は請求項10に定義される通りである
ことを特徴とする請求項12に記載の調製方法。 - 請求項1から11のいずれか一項に記載のバクチオ-ル誘導体及びその薬学的に許容される塩のうちの少なくとも1種類と、薬学的に許容される賦形剤と、を含むことを特徴とする医薬組成物。
- 抗菌薬の調製における請求項1から11のいずれか一項に記載のバクチオ-ル誘導体及びその薬学的に許容される塩、又は請求項14に記載の医薬組成物の用途。
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