JP2003512452A - New indole compounds - Google Patents
New indole compoundsInfo
- Publication number
- JP2003512452A JP2003512452A JP2001533107A JP2001533107A JP2003512452A JP 2003512452 A JP2003512452 A JP 2003512452A JP 2001533107 A JP2001533107 A JP 2001533107A JP 2001533107 A JP2001533107 A JP 2001533107A JP 2003512452 A JP2003512452 A JP 2003512452A
- Authority
- JP
- Japan
- Prior art keywords
- chloro
- compound
- methylenedioxybenzyl
- compounds
- scheme
- 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.)
- Withdrawn
Links
- 150000002475 indoles Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- -1 6-chloro-3,4-methylenedioxybenzyl Chemical group 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 6
- 208000035143 Bacterial infection Diseases 0.000 claims description 2
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 2
- 239000003112 inhibitor Substances 0.000 abstract description 7
- 108010039731 Fatty Acid Synthases Proteins 0.000 abstract description 6
- 102000015303 Fatty Acid Synthases Human genes 0.000 abstract description 5
- 239000000203 mixture Substances 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
- 239000007787 solid Substances 0.000 description 13
- 239000003242 anti bacterial agent Substances 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 229910000104 sodium hydride Inorganic materials 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 229940088710 antibiotic agent Drugs 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
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- 241000588724 Escherichia coli Species 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 230000003115 biocidal effect Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- IUVDZGZOHOXWKG-UHFFFAOYSA-N 6-chloro-7-methyl-1h-indole Chemical compound CC1=C(Cl)C=CC2=C1NC=C2 IUVDZGZOHOXWKG-UHFFFAOYSA-N 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- ICTIKJBSBGIXOY-UHFFFAOYSA-N 1-[(6-chloro-1,3-benzodioxol-5-yl)methyl]-5-[(2,6-dichlorophenyl)methoxy]indole-2-carboxylic acid Chemical compound C=1C=C2N(CC=3C(=CC=4OCOC=4C=3)Cl)C(C(=O)O)=CC2=CC=1OCC1=C(Cl)C=CC=C1Cl ICTIKJBSBGIXOY-UHFFFAOYSA-N 0.000 description 3
- PDFGFQUSSYSWNI-UHFFFAOYSA-N 2-(bromomethyl)-1,3-dichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1CBr PDFGFQUSSYSWNI-UHFFFAOYSA-N 0.000 description 3
- 101710146995 Acyl carrier protein Proteins 0.000 description 3
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
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- 241000193998 Streptococcus pneumoniae Species 0.000 description 3
- ZSLZBFCDCINBPY-ZSJPKINUSA-N acetyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZSLZBFCDCINBPY-ZSJPKINUSA-N 0.000 description 3
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- LBOBESSDSGODDD-UHFFFAOYSA-N 1,3-dichloro-2-(chloromethyl)benzene Chemical compound ClCC1=C(Cl)C=CC=C1Cl LBOBESSDSGODDD-UHFFFAOYSA-N 0.000 description 2
- HCUARRIEZVDMPT-UHFFFAOYSA-M 1h-indole-2-carboxylate Chemical compound C1=CC=C2NC(C(=O)[O-])=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-M 0.000 description 2
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- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
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- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 description 2
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- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 2
- 229940100228 acetyl coenzyme a Drugs 0.000 description 2
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- 239000012669 liquid formulation Substances 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
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- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- FLJGVRPOHAIQRK-UHFFFAOYSA-N 1-[(6-chloro-1,3-benzodioxol-5-yl)methyl]-5-[(2,6-dichlorophenyl)methylamino]indole-2-carboxylic acid Chemical compound C=1C=C2N(CC=3C(=CC=4OCOC=4C=3)Cl)C(C(=O)O)=CC2=CC=1NCC1=C(Cl)C=CC=C1Cl FLJGVRPOHAIQRK-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- GVEZIHKRYBHEFX-MNOVXSKESA-N 13C-Cerulenin Natural products CC=CCC=CCCC(=O)[C@H]1O[C@@H]1C(N)=O GVEZIHKRYBHEFX-MNOVXSKESA-N 0.000 description 1
- 125000004098 2,6-dichlorobenzoyl group Chemical group O=C([*])C1=C(Cl)C([H])=C([H])C([H])=C1Cl 0.000 description 1
- 108010093803 3-ketoacyl-acyl carrier protein synthase III Proteins 0.000 description 1
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- AKKHEGPCNXPPLZ-UHFFFAOYSA-N 4-chloro-5-(chloromethyl)-1,3-benzodioxole Chemical compound ClCC1=CC=C2OCOC2=C1Cl AKKHEGPCNXPPLZ-UHFFFAOYSA-N 0.000 description 1
- SYQNUQSGEWNWKV-XUIVZRPNSA-N 4-hydroxy-3,5-dimethyl-5-(2-methyl-buta-1,3-dienyl)-5h-thiophen-2-one Chemical compound C=CC(/C)=C/[C@@]1(C)SC(=O)C(C)=C1O SYQNUQSGEWNWKV-XUIVZRPNSA-N 0.000 description 1
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- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 235000013379 molasses Nutrition 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008261 resistance mechanism Effects 0.000 description 1
- ZSLZBFCDCINBPY-YHBLMJDYSA-N s-[2-[3-[[(2r)-4-[[[(2r,3s,4r,5r)-5-(6-aminopurin-9-yl)-4-hydroxy-3-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]oxy-2-hydroxy-3,3-dimethylbutanoyl]amino]propanoylamino]ethyl] ethanethioate Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS[14C](=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZSLZBFCDCINBPY-YHBLMJDYSA-N 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 235000003441 saturated fatty acids Nutrition 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
(57)【要約】 本発明は、脂肪酸シンターゼFabHの阻害剤としての化合物の使用に関する。 (57) [Summary] The present invention relates to the use of compounds as inhibitors of fatty acid synthase FabH.
Description
【0001】発明の分野
本発明は、脂肪酸シンターゼFabHの阻害剤としての化合物の使用に関する
。FIELD OF THE INVENTION The present invention relates to the use of compounds as inhibitors of the fatty acid synthase FabH.
【0002】発明の背景
飽和脂肪酸の生合成経路は原核生物および真核生物において非常に類似してい
る。しかしながら、化学反応は異なっている可能性があり、生合成装置の構成は
非常に異なっている。脊椎動物および酵母はI型脂肪酸シンターゼ(FASs)
を有し、それらにおいてすべての酵素活性はそれぞれ1本または2本のポリペプ
チド鎖上にコードされている。アシルキャリヤ蛋白(ACP)はその複合体の必
須部分である。対照的に、大部分の細菌および植物のFASs(II型)におい
ては、各反応は別々の単機能酵素により触媒され、ACPは別個の蛋白である。
ミコバクテリア(Mycobacteria)は、それらがI型およびII型両方のFASs
を有することにおいてユニークであり、前者は基本的な脂肪酸の生合成に関与し
ているが、後者はミコリン酸のごとき複雑な細胞エンベロープ脂質の合成に関与
している。それゆえ、広スペクトル抗細菌剤による細菌系の選択的阻害に関して
かなりの有効性があると思われる(Jackowski, S. 1992. Emerging Targets in
Antibacterial and Antifungal Chemotherapy. Ed. J. Sutcliffe & N. Georgo
papadakou. Chapman & Hall, New York 中;および Jackowski, S. et al. (19
89). J. Biol. Chem. 264, 7624-7629.)。[0002] The biosynthetic pathway of background saturated fatty acids invention are very similar in prokaryotes and eukaryotes. However, the chemical reactions may be different and the biosynthetic device configurations are very different. Vertebrate and yeast are type I fatty acid synthases (FASs)
, In which all enzymatic activities are each encoded on one or two polypeptide chains. Acyl carrier protein (ACP) is an essential part of the complex. In contrast, in most bacterial and plant FASs (type II), each reaction is catalyzed by a separate monofunctional enzyme, and ACP is a distinct protein.
Mycobacteria contain FASs of both type I and type II
Are unique in that they are involved in the biosynthesis of basic fatty acids, while the latter are involved in the synthesis of complex cell envelope lipids such as mycolic acid. Therefore, it appears to have considerable efficacy in the selective inhibition of bacterial systems by broad spectrum antibacterial agents (Jackowski, S. 1992. Emerging Targets in
Antibacterial and Antifungal Chemotherapy. Ed. J. Sutcliffe & N. Georgo
papadakou. Chapman & Hall, New York; and Jackowski, S. et al. (19
89). J. Biol. Chem. 264, 7624-7629.).
【0003】
生合成サイクルの第1段階はFabHによるマロニル−ACPとアセチル−C
oAとの縮合である。その後のラウンドにおいて、マロニル−ACPは鎖伸長中
のアシル−ACPと縮合する(FabBおよびFabF、それぞれシンターゼI
およびII)。鎖伸長サイクルにおける第2段階はNADPH依存性β−ケトア
シル−ACPレダクターゼ(FabG)によるケトエステル還元である。β−ヒ
ドロキシアシル−ACPデヒドラーゼ(FabAまたはFabZ)によるその後
の脱水はトランス−2−エノイル−ACPを生じさせ、次いでそれがNADH−
依存性エノイル−ACPレダクターゼ(FabI)によりアシル−ACPに変換
される。このサイクルのさらなるラウンドは1サイクルあたり2個の炭素原子を
付加し、最終的にはパルミトイル−ACPを生じさせた後、大体においてパルミ
トイル−ACPによるFabHおよびIのフィードバック阻害によりサイクルが
停止する(Heath. et al. (1996). J. Biol. Chem. 271, 1833-1836)。それゆ
え、FabHは合成経路全体における重要な調節ポイントでもある主要生合成酵
素である(Heath, R. J. and Rock, C. O. 1996. J. Biol. Chem. 271, 1833-18
36; Heath, R. J. and Rock, C. O. 1996. J. Biol. Chem. 271, 10996-11000)
。The first step in the biosynthesis cycle is malonyl-ACP and acetyl-C by FabH.
Condensation with oA. In a subsequent round, malonyl-ACP condensed with acyl-ACP during chain extension (FabB and FabF, synthase I, respectively).
And II). The second step in the chain extension cycle is the ketoester reduction by NADPH-dependent β-ketoacyl-ACP reductase (FabG). Subsequent dehydration with β-hydroxyacyl-ACP dehydrase (FabA or FabZ) gives rise to trans-2-enoyl-ACP, which is then NADH-.
It is converted to acyl-ACP by the dependent enoyl-ACP reductase (FabI). A further round of this cycle adds two carbon atoms per cycle, ultimately giving rise to palmitoyl-ACP, followed mostly by feedback inhibition of FabH and I by palmitoyl-ACP to halt the cycle (Heath . et al. (1996). J. Biol. Chem. 271, 1833-1836). Therefore, FabH is a major biosynthetic enzyme that is also an important regulatory point in the overall synthetic pathway (Heath, RJ and Rock, CO 1996. J. Biol. Chem. 271, 1833-18.
36; Heath, RJ and Rock, CO 1996. J. Biol. Chem. 271, 10996-11000)
.
【0004】
抗生物質チオラクトマイシンはインビボおよびインビトロの両方において広ス
ペクトル抗細菌活性を有し、3つの縮合酵素すべてを特異的に阻害することが示
されている。それは無毒であり、哺乳動物のFASsを阻害しない(Hayashi, T
. et al.,1984. J. Antibiotics 37, 1456-1461; Miyakawa, S. et al., 1982.
J. Antibiotics 35, 411-419; Nawata, Y et al., 1989. Acta Cryst. C45,
978-979; Noto, T. et al., 1982. J. Antibiotics 35, 401-410; Oishi, H.
et al., 1982. J. Antibiotics 35, 391-396)。同様に、セルレニンはFab
BおよびFの強力な阻害剤であり、殺細菌性であるが、真核生物に対して毒性が
ある。なぜなら、それは両方のFASタイプに共通する脂肪酸−アシル結合部位
を求めて競争するからである(D'Agnolo, G. et al.,1973. Biochim. Biophys.
Acta. 326, 155-166)。これらの阻害剤に関するさらなる研究により、これら
の酵素が生存能力に必須であることが証明された。グラム陽性細菌における研究
はわずかである。The antibiotic thiolactomycin has broad spectrum antibacterial activity both in vivo and in vitro and has been shown to specifically inhibit all three condensing enzymes. It is non-toxic and does not inhibit FASs in mammals (Hayashi, T
. et al., 1984. J. Antibiotics 37, 1456-1461; Miyakawa, S. et al., 1982.
J. Antibiotics 35, 411-419; Nawata, Y et al., 1989. Acta Cryst. C45,
978-979; Noto, T. et al., 1982. J. Antibiotics 35, 401-410; Oishi, H.
et al., 1982. J. Antibiotics 35, 391-396). Similarly, cerulenin is Fab
It is a potent inhibitor of B and F, bactericidal but toxic to eukaryotes. Because it competes for a fatty acid-acyl binding site common to both FAS types (D'Agnolo, G. et al., 1973. Biochim. Biophys.
Acta. 326, 155-166). Further studies with these inhibitors have demonstrated that these enzymes are essential for viability. There are few studies on Gram-positive bacteria.
【0005】
現存する耐性機構には屈しない新たなクラスの抗生物質化合物の開発に対して
、かつてない必要性が存在している。市販抗生物質には脂肪酸生合成を標的とし
たものはなく、それゆえ、このタイプの新規抗生物質が既知の抗生物質耐性機構
により不活性化される可能性はない。そのうえ、これは潜在的に広いスペクトル
標的である。それゆえ、FabH阻害剤はこのようなかつてない必要性を満たす
であろう。There is an unprecedented need for the development of new classes of antibiotic compounds that do not succumb to existing resistance mechanisms. No commercial antibiotics target fatty acid biosynthesis and therefore no new antibiotics of this type can be inactivated by known antibiotic resistance mechanisms. Moreover, this is a potentially broad spectrum target. Therefore, FabH inhibitors will meet such an unprecedented need.
【0006】発明の概要
本発明は、インドール誘導体およびこれらの化合物を含む医薬組成物、ならび
にFabH阻害剤としてのそれらの使用を包含し、それらはグラム陽性およびグ
ラム陰性細菌感染を治療するための抗生物質として有用である。
さらに本発明は、ヒトを含む動物におけるグラム陰性またはグラム陽性細菌感
染の治療方法を包含し、該方法は、有効量の本発明の化合物を治療を要する動物
に投与することを特徴とする。SUMMARY OF THE INVENTION The present invention includes indole derivatives and pharmaceutical compositions containing these compounds, and their use as FabH inhibitors, which are antibiotics for treating Gram positive and Gram negative bacterial infections. It is useful as a substance. The invention further includes a method of treating Gram-negative or Gram-positive bacterial infections in animals, including humans, which method is characterized in that an effective amount of a compound of the invention is administered to the animal in need thereof.
【0007】発明の詳細な説明 本発明の化合物は式(I):[0007] Compounds of the Detailed Description of the Invention The present invention of formula (I):
【化2】
( I )
[式中、RはOHであり;
QはO、NHまたはCH2である]により示される化合物またはその医薬上許
容される塩である。[Chemical 2] (I) [wherein R is OH; Q is O, NH or CH 2 ], or a pharmaceutically acceptable salt thereof.
【0008】
また、医薬上許容される塩の複合体も本発明に包含される。
本発明の化合物は1個またはそれ以上の不斉炭素原子を含んでいてもよく、ラ
セミ体および光学活性形態として存在してもよい。これらの化合物およびジアス
テレオマーはすべて本発明の範囲内に包含される。
本発明の化合物のいくつかは有機溶媒のごとき溶媒から結晶化または再結晶化
されうる。そのような場合には溶媒和物が得られることがある。本発明は、水和
物をはじめとする化学量論的な溶媒和物ならびに凍結乾燥のごときプロセスによ
り得ることのできる種々の量の水を含有する化合物をその範囲内に包含する。Also included in the invention is a complex of pharmaceutically acceptable salts. The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds and diastereomers are included within the scope of the invention. Some of the compounds of this invention may be crystallized or recrystallised from solvents such as organic solvents. In such cases, solvates may be obtained. The present invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water obtainable by processes such as lyophilization.
【0009】
本発明の抗生物質化合物は医薬組成物中での使用が意図されるので、それらは
それぞれ実質的に純粋な形態で、例えば少なくとも純度60%で、より適当には
少なくとも純度75%で、好ましくは少なくとも純度85%で、特別には少なく
とも純度95%で、さらに特別には少なくとも純度98%で提供されることが容
易に理解されよう(%は重量基準)。医薬組成物中に使用されるより純粋な形態
を製造するために化合物の純粋でない調合物を使用してもよい。これらのあまり
純粋でない化合物の調合物は少なくとも1%、より適当には少なくとも5%、好
ましくは10ないし49%の式(I)の化合物またはその塩を含むべきである。Since the antibiotic compounds of the invention are intended for use in pharmaceutical compositions, they are each in a substantially pure form, eg at least 60% pure, more suitably at least 75% pure. It will be readily appreciated that, preferably at least 85% pure, especially at least 95% pure, and more particularly at least 98% pure (% by weight). Impure preparations of the compounds may be used to produce the purer forms used in pharmaceutical compositions. Formulations of these less pure compounds should contain at least 1%, more suitably at least 5%, preferably 10 to 49% of a compound of formula (I) or salt thereof.
【0010】 好ましい化合物はOまたはNHであるQを有する。[0010] Preferred compounds have Q which is O or NH.
【0011】
好ましい化合物は1−(6−クロロ−3,4−メチレンジオキシベンジル)−
5−(2,6−ジクロロベンジルオキシ)インドール−2−カルボン酸および1
−(6−クロロ−3,4−メチレンジオキシベンジル)−5−(2,6−ジクロ
ロベンジルアミノ)インドール−2−カルボン酸である。A preferred compound is 1- (6-chloro-3,4-methylenedioxybenzyl)-
5- (2,6-dichlorobenzyloxy) indole-2-carboxylic acid and 1
It is-(6-chloro-3,4-methylenedioxybenzyl) -5- (2,6-dichlorobenzylamino) indole-2-carboxylic acid.
【0012】 スキーム1に記載の方法により、QがOである式Iの化合物を製造する。[0012] The method of Scheme 1 produces compounds of formula I where Q is O.
【化3】スキーム1
a) 塩化6-クロロピペロニル, NaH, DMF; b) 10% Pd/C, H2, EtOAc; c) 臭
化2,6-ジクロロベンジル, NaH, DMF; d) KOH, EtOH/THF, 還流
インドールエステル1−スキーム−1(Aldrich)および塩基(水素化ナトリ
ウムのごとき)を溶媒(DMFのごとき)で処理し、次いで、塩化6−クロロピ
ペロニルを添加し、撹拌して(6時間ないし30時間、好ましくは20時間)、
2−スキーム−1を得る。2−スキーム−1を溶媒(酢酸エチルのごとき)に溶
解し、炭素上10%パラジウムで処理し、得られた混合物を振盪して(6時間な
いし30時間、好ましくは20時間)、3−スキーム−1を得る。溶媒(DMF
のごとき)中で塩基(水素化ナトリウムのごとき)を用いる、臭化2,6−ジク
ロロベンジルでの3−スキーム−1のアルキル化により、4−スキーム−1を得
る。溶媒(エタノールおよびテトラヒドロフランのごとき)中で塩基(水酸化カ
リウムのごとき)を用いる4−スキーム−1のケン化により5−スキーム−1を
得る。 Scheme 1 Scheme 1 a) 6-chloropiperonyl chloride, NaH, DMF; b) 10% Pd / C, H 2 , EtOAc; c) 2,6-dichlorobenzyl bromide, NaH, DMF; d) KOH, EtOH / THF, refluxing indole ester 1-Scheme-1 (Aldrich) and base (such as sodium hydride) are treated with solvent (such as DMF), then 6-chloropiperonyl chloride is added and stirred (6 hours to 30 hours, preferably 20 hours),
2-Scheme-1 is obtained. 2-Scheme-1 was dissolved in a solvent (such as ethyl acetate), treated with 10% palladium on carbon and the resulting mixture was shaken (6 to 30 hours, preferably 20 hours), 3-Scheme Get -1. Solvent (DMF
Alkylation of 3-Scheme-1 with 2,6-dichlorobenzyl bromide using a base (such as sodium hydride) to give 4-Scheme-1. Saponification of 4-Scheme-1 with a base (such as potassium hydroxide) in a solvent (such as ethanol and tetrahydrofuran) gives 5-Scheme-1.
【0013】 スキーム2に記載の方法により、QがNHである式Iの化合物を製造する。[0013] The method described in Scheme 2 produces compounds of formula I where Q is NH.
【化4】スキーム2
a) 6-chloropiperonyl chloride, NaH, DMF; b) SnCl2, EtOH, 70℃; c) 2,6-di
chlorobenzyl chloride, NaH, DMF; d) 1) NaOH, THF, MeOH. 2) 10% HCl
DMFのごとき極性非プロトン性溶媒中においてNaHのごとき塩基を用いて
市販5−ニトロインドール6−スキーム−2を塩化6−クロロピペロニルでアル
キル化した。このアルキル化法によりイントロインドール7−スキーム−2を得
た。塩化すず(II)を還元剤として使用して、ニトロ基を還元して対応アミン
8−スキーム−2を得たが、他の適当な試薬を使用することができた。塩基とし
てNaH、アルキル化剤として塩化2,6−ジクロロベンジルを用いてN−アル
キル化により9−スキーム−2を得た。9−スキーム−2のエチルエステルの標
準的な加水分解により10−スキーム−2の合成を行った。 Scheme 2 Scheme 2 a) 6-chloropiperonyl chloride, NaH, DMF; b) SnCl 2 , EtOH, 70 ° C; c) 2,6-di
chlorobenzyl chloride, NaH, DMF; d) 1) NaOH, THF, MeOH. 2) 10% HCl Commercially available 5-nitroindole 6-Scheme-2 using a base such as NaH in a polar aprotic solvent such as DMF. Alkylated with 6-chloropiperonyl chloride. This alkylation method provided Introindole 7-Scheme-2. Tin (II) chloride was used as a reducing agent to reduce the nitro group to give the corresponding amine 8-Scheme-2, although other suitable reagents could be used. N-Alkylation gave 9-Scheme-2 using NaH as base and 2,6-dichlorobenzyl chloride as alkylating agent. The synthesis of 10-Scheme-2 was performed by standard hydrolysis of the ethyl ester of 9-Scheme-2.
【0014】
生物学的アッセイ:
FabH阻害
Streptococcus pneumoniaeのβ−ケトアシル−ACPシンターゼIII(Fa
bH)に対するIC50を測定するようにアッセイを設計する。基質マロニル−
ACP、[14C]−アセチル−CoAをFabHと混合して[14C]−アセ
トアセチル−ACPを生成させる。アッセイ条件:
リン酸ナトリウムpH7.0 100mM
β−メルカプトエタノール 1mM
マロニルアシルキャリヤ蛋白 20μM
アセチルコエンザイムA 70μM
[14C]アセチルコエンザイムA 5μM
FabH 1〜16nM
合計反応体積は50μl
1)酵素を除くすべての試薬を混合し、あらかじめ阻害剤を入れた96ウェルプ
レートに分注する。
2)1mM β−メルカプトエタノールを含むアッセイバッファーでFabHを
希釈し、プレートに添加して反応を開始させ、37℃で40分インキュベーショ
ンする。
3)150μlの10% TCAで反応を停止させる。
4)あらかじめ10% TCAでGF/Cフィルターマットを湿らせ、反応停止
した反応物を濾過し、ウェルを150μlの10% TCAで2回すすぎ、次い
で、濾過する。
5)フィルターマットを60℃でオーブン乾燥させ、フィルターマットを透明プ
ラスチック袋中に密封し、Betaplateシンチレーションカクテルを添加し、Walla
c Microbeta液体シンチレーションカウンターでカウントする。Biological assay: FabH inhibition Streptococcus pneumoniae β-ketoacyl-ACP synthase III (Fa
The assay is designed to measure the IC50 for bH). Substrate malonyl-
ACP, [14C] -acetyl-CoA, is mixed with FabH to produce [14C] -acetoacetyl-ACP. Assay conditions: sodium phosphate pH 7.0 100 mM β-mercaptoethanol 1 mM malonyl acyl carrier protein 20 μM acetyl coenzyme A 70 μM [14 C] acetyl coenzyme A 5 μM FabH 1-16 nM Total reaction volume 50 μl 1) Mix all reagents except enzyme Then, dispense into a 96-well plate containing an inhibitor in advance. 2) FabH is diluted with an assay buffer containing 1 mM β-mercaptoethanol, added to the plate to start the reaction, and incubated at 37 ° C. for 40 minutes. 3) Stop the reaction with 150 μl of 10% TCA. 4) Pre-wet GF / C filter mat with 10% TCA, filter the quenched reaction, rinse wells twice with 150 μl 10% TCA, then filter. 5) Oven dry the filter mat at 60 ° C, seal the filter mat in a clear plastic bag, add Betaplate scintillation cocktail, and add Walla
c Count with a Microbeta liquid scintillation counter.
【0015】
抗微生物活性のアッセイ
National Committee for Clinical Laboratory Standards(NCCLS)によ
り推奨された手順であるDocument M7-A4, "Methods for Dilution Susceptibili
ty Tests for Bacteria that Grow Aerobically"(参照により本明細書に組み込
む)を用いてブロスマイクロダイリューションにより全−細胞抗微生物活性を調
べた。0.06ないし64mcg/mlの範囲で2倍系列希釈した化合物を試験
した。アッセイにおいて12株のパネルを評価した。このパネルは下記の研究室
株からなっていた:Staphylococcus aureus Oxford, Streptococcus pneumoniae
R6, Streptococcus pyogenes CN10, Enterococcus faecalis I, Haemophilus i
nfluenzae Q1, Escherichia coli DC0, E. coli ESS, E. coli 7623 (AcrAB+) E
. coli 120 (AcrAB-) Klebsiella pneumoniae E70, Pseudomonas aeruginosa K7
99wt および Candida albicans GRI 681。最小阻害濃度(MIC)を、目に見え
る増殖を阻害した化合物の最小濃度として決定した。Assay for Antimicrobial Activity Document M7-A4, "Methods for Dilution Susceptibili, which is a procedure recommended by the National Committee for Clinical Laboratory Standards (NCCLS).
ty Tests for Bacteria that Grow Aerobically "(incorporated herein by reference) was used to examine whole-cell antimicrobial activity by broth microdilution. 2-fold serial dilutions ranging from 0.06 to 64 mcg / ml. A panel of 12 strains was evaluated in the assay, which panel consisted of the following laboratory strains: Staphylococcus aureus Oxford, Streptococcus pneumoniae.
R6, Streptococcus pyogenes CN10, Enterococcus faecalis I, Haemophilus i
nfluenzae Q1, Escherichia coli DC0, E. coli ESS, E. coli 7623 (AcrAB +) E
.coli 120 (AcrAB-) Klebsiella pneumoniae E70, Pseudomonas aeruginosa K7
99 wt and Candida albicans GRI 681. The minimum inhibitory concentration (MIC) was determined as the lowest concentration of compound that inhibited visible growth.
【0016】
また本発明は、式(I)の化合物またはその医薬上許容される塩またはそのイ
ンビボにおいて加水分解されうるエステルおよび医薬上許容される担体を含む医
薬組成物を提供する。本発明の組成物は、経口、局所または非経口用途に適した
形態のものを包含し、ヒトを含む哺乳動物における細菌感染の治療に使用できる
。
他の抗生物質から類推して、本発明の抗生物質化合物をヒトまたは家畜の医療
に使用するためのいずれかの慣用的方法で投与するように処方してもよい。
経口、局所または非経口、特に経口のごとき、いずれの経路による投与のため
に組成物を処方してもよい。組成物は錠剤、カプセル、粉末、顆粒、ロゼンジ、
クリームまたは滅菌非経口溶液もしくは懸濁液のごとき液体調合物の形態であっ
てもよい。
本発明の局所処方を、例えば、軟膏、クリームまたはローション、目の軟膏お
よび目もしくは耳用の滴剤、含浸包帯およびエアロゾルとして提供してもよく、
保存料、薬剤の浸透を促進する溶媒および軟膏やクリーム中のエモリエントのご
とき適切で慣用的な添加物を含んでいてもよい。The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester thereof and a pharmaceutically acceptable carrier. The compositions of the present invention, including those in a form suitable for oral, topical or parenteral use, can be used to treat bacterial infections in mammals, including humans. By analogy with other antibiotics, the antibiotic compounds of the invention may be formulated for administration in any conventional manner for use in human or veterinary medicine. The composition may be formulated for administration by any route, such as oral, topical or parenteral, especially oral. The composition can be tablets, capsules, powders, granules, lozenges,
It may be in the form of liquid preparations such as creams or sterile parenteral solutions or suspensions. The topical formulations of the present invention may be provided as, for example, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated bandages and aerosols,
Preservatives, solvents that enhance drug penetration and suitable and conventional additives such as emollients in ointments or creams may be included.
【0017】
処方は、クリームまたは軟膏基材あるいはローション用のエタノールまたはオ
レイルアルコールのごとき適合する慣用的な担体を含んでいてもよい。かかる担
体は処方中約1%ないし約98%を占めてもよい。より通常には、それらは処方
の約80%までを占めるであろう。
経口投与用の錠剤およびカプセルは単位投与提供形態(unit dose presentati
on form)であってもよく、結合剤、例えば糖蜜、アラビアゴム、ゼラチン、ソ
ルビトール、トラガカント、またはポリビニルピロリドン;充填剤、例えばラク
トース、砂糖、トウモロコシデンプン、リン酸カルシウム、ソルビトールまたは
グリシン;成形滑沢剤、例えばステアリン酸マグネシウム、タルク、ポリエチレ
ングリコールまたはシリカ;崩壊剤、例えばバレイショデンプン;あるいはラウ
リル硫酸ナトリウムのごとき許容される湿潤剤のような慣用的な賦形剤を含んで
いてもよい。通常の製薬慣習においてよく知られた方法により錠剤をコーティン
グしてもよい。経口液体調合物は、例えば、水性または油性懸濁液、溶液、エマ
ルジョン、シロップまたはエリキシルの形態であってもよく、あるいは使用前に
水または他の適当な担体で復元される乾燥製品として提供されてもよい。かかる
液体調合物は、懸濁化剤、例えばソルビトール、メチルセルロース、グルコース
シロップ、ゼラチン、ヒドロキシエチルセルロース、カルボキシメチルセルロー
ス、ステアリン酸アルミニウムゲルまたは水素添加された食用油;乳化剤、例え
ばレシチン、ソルビタンモノオレエートまたはアラビアゴム;非水性担体(食用
油を包含しうる)、例えばアーモンド油、グリセリンのごとき油性エステル、プ
ロピレングリコールまたはエチルアルコール;保存料、例えばp−ヒドロキシ安
息香酸メチルもしくはプロピルまたはソルビン酸;ならびに所望ならば慣用的な
香料または着色料のような慣用的な添加物を含んでいてもよい。The formulations may contain compatible conventional carriers, such as ethanol or oleyl alcohol for cream or ointment bases or lotions. Such carriers may make up from about 1% to about 98% of the formulation. More usually they will comprise up to about 80% of the formulation. Tablets and capsules for oral administration include unit dose presentati
on form) and binders such as molasses, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; molding lubricants, Conventional excipients such as, for example, magnesium stearate, talc, polyethylene glycol or silica; disintegrants such as potato starch; or acceptable wetting agents such as sodium lauryl sulfate may be included. The tablets may be coated by methods well known in normal pharmaceutical practice. Oral liquid formulations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or provided as a dry product for constitution with water or other suitable carrier before use. May be. Such liquid formulations include suspending agents such as sorbitol, methylcellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible oils; emulsifiers such as lecithin, sorbitan monooleate or arabic. Gums; non-aqueous carriers (which may include edible oils) such as almond oil, oily esters such as glycerin, propylene glycol or ethyl alcohol; preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired It may contain conventional additives such as conventional flavors or colors.
【0018】
坐薬は慣用的な坐薬基材、例えば、カカオ脂または他のグリセリドを含むであ
ろう。
非経口投与には、化合物および滅菌担体(水が好ましい)を用いて液体単位投
与形態(fluid unit dosage form)を調製する。担体および使用濃度にもよるが
、化合物を担体に懸濁または溶解することができる。溶液の調製において、化合
物を注射用水に溶解し、フィルター滅菌し、次いで、バイアルまたはアンプル中
に充填し、密封することができる。好ましくは、溶液はpHを約3.5ないし7
の範囲に保つためにバッファー(ホスフェートのごとき)を含有する。式(I)
の化合物の溶解度および浸透を促進するためにDMSOまたはアルコール性溶媒
が存在していてもよい(0.01ないし10mL/リットルのごとき濃度)。有
利には、局所麻酔剤、保存料およびバッファー剤のごとき薬剤を担体に溶解する
ことができる。安定性を高めるために、組成物をバイアル中に充填した後凍結し
て、水分を減圧除去することができる。次いで、乾燥した凍結乾燥粉末をバイア
ル中に密封し、使用前に液体を復元させるために注射用水をバイアルに添付して
提供してもよい。化合物を担体に溶解せずに懸濁し、濾過によっては滅菌を行わ
ないこと以外は実質的に同じ方法で非経口懸濁液を調製する。化合物をエチレン
オキサイドに曝露することにより滅菌し、次いで、滅菌担体に懸濁することがで
きる。有利には、界面活性剤または湿潤剤を組成物中に含有させて化合物の均一
な分散を容易ならしめる。Suppositories will contain conventional suppository bases, eg cocoa-butter or other glyceride. For parenteral administration, a fluid unit dosage form is prepared using the compound and a sterile carrier, water being preferred. The compound, depending on the carrier and concentration used, can be either suspended or dissolved in the carrier. In preparing solutions, the compound can be dissolved in water for injection, filter sterilized, then filled into vials or ampoules and sealed. Preferably, the solution has a pH of about 3.5 to 7
Buffer (such as phosphate) to maintain the range. Formula (I)
DMSO or an alcoholic solvent may be present (concentrations such as 0.01 to 10 mL / liter) to enhance the solubility and penetration of the compounds of. Advantageously, agents such as local anesthetics, preservatives and buffers can be dissolved in the carrier. To increase stability, the composition can be filled into vials and then frozen to remove water under reduced pressure. The dried lyophilized powder may then be sealed in a vial and water for injection may be provided with the vial to reconstitute the liquid before use. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the carrier, undissolved, and sterilized by filtration. The compound can be sterilized by exposure to ethylene oxide and then suspended in a sterile carrier. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
【0019】
投与方法にもよるが、組成物は0.1重量%、好ましくは10〜60重量%の
活性物質を含んでいてもよい。組成物が投与単位(dosage unit)を含む場合、
好ましくは、各単位は50〜500mgの活性成分を含有するであろう。成人の
治療に使用される用量は、投与経路および頻度にもよるが、好ましくは、1ない
し140mg/体重1kgであろう。
式(I)の化合物またはその医薬上許容される塩またはそのインビボにおいて
加水分解されうるエステルを上記用量範囲で投与する場合、許容されない毒物学
的効果は考えられない。The composition may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. When the composition comprises a dosage unit,
Preferably, each unit will contain 50-500 mg of active ingredient. The dose used for adult treatment will depend on the route and frequency of administration, but will preferably be between 1 and 140 mg / kg body weight. No unacceptable toxicological effects are expected when the compounds of formula (I) or their pharmaceutically acceptable salts or their in vivo hydrolysable esters are administered in the above dosage range.
【0020】
式(I)の化合物は本発明の組成物中の単一の治療薬剤であってもよく、ある
いは式(I)の化合物の抗細菌活性を向上させる他の抗生物質または化合物との
組み合わせを用いてもよい。
本発明の抗生物質化合物は、現存する抗生物質に対して耐性のある単離体を含
め、Escherichia coli および Klebsiella pneumoniae のごときグラム陰性生物
ならびにStaphylococcus aureus, Streptococcus pneumoniae, Enterococcus fa
ecalis および Enterococcus faecium のごときグラム陽性生物の両方を包含す
る広範な生物に対して活性がある。
下記実施例は本発明の化合物およびその中間体の製造を説明する。The compound of formula (I) may be the sole therapeutic agent in the composition of the invention, or may be combined with other antibiotics or compounds which enhance the antibacterial activity of the compound of formula (I). A combination may be used. The antibiotic compounds of the present invention include Gram-negative organisms such as Escherichia coli and Klebsiella pneumoniae, as well as Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus fa, including isolates resistant to existing antibiotics.
It is active against a wide range of organisms, including both Gram-positive organisms such as ecalis and Enterococcus faecium. The following examples illustrate the preparation of compounds of this invention and intermediates thereof.
【0021】実施例1
1−(6−クロロ−3,4−メチレンジオキシベンジル)−5−(2,6−ジク
ロロベンジルオキシ)インドール−2−カルボン酸の製造
a)1−(6−クロロ−3,4−メチレンジオキシベンジル)−5−(ベンジル
オキシ)インドールカルボン酸エチル
DMF(500mL)中の、ヘキサンですすいだNaH(6.1g,0.15
mol;ヘキサン中60%分散物)の溶液に、5−ベンジルオキシ−2−インド
ールカルボン酸エチルエステル(30g,0.1mol)を添加した。得られた
混合物を室温で1時間撹拌した。塩化クロロピペロニル(20.85g,0.1
mol)を添加した。得られた混合物を室温で24時間撹拌した。得られた混合
物を水中に注ぎ、EtOAcで抽出した(2回)。一緒にした有機層をH2O、
ブラインで洗浄し、乾燥させ(MgSO4)、濾過し、次いで、減圧濃縮して固
体を得た。エタノールから固体を再結晶させて標記化合物を白色固体として得た
(30.68g,66%)。MS (ES+) m/e 464.5[M+H]+
b)1−(6−クロロ−3,4−メチレンジオキシベンジル)−5−(ヒドロキ
シ)インドールカルボン酸エチル
EtOAc(800mL)中の1−(6−クロロ−3,4−メチレンジオキシ
ベンジル)−5−(ベンジルオキシ)インドールカルボン酸エチル(22.67
g,0.046mol)の溶液に炭素上10%Pd(11.34g,50% w
/w)を添加した。得られた混合物を、Parrシェーカー中60psiで18時間
水素添加した。得られた混合物を珪藻土で濾過し、減圧濃縮して標記化合物を白
色固体として得た(14.54%,80%)。MS (ES+) m/e 374.4[M+H]+
c)1−(6−クロロ−3,4−メチレンジオキシベンジル)−5−(2,6−
ジクロロベンジルオキシ)インドールカルボン酸エチル
DMF(390mL)中の、ヘキサンですすいだNaH(2.34g,0.0
6mol;ヘキサン中60%分散物)の溶液に、1−(6−クロロ−3,4−メ
チレンジオキシベンジル)−5−(ヒドロキシ)インドールカルボン酸エチル(
14.54g,0.04mol)を添加した。得られた混合物を室温で1時間撹
拌した。臭化2,6−ジクロロベンジル(9.36g,0.045mol)を添
加した。得られた混合物を室温で1時間撹拌した。得られた混合物を水中に注ぎ
、EtOAcで抽出した(2回)。一緒にした有機層をH2O、ブラインで洗浄
し、乾燥させ(MgSO4)、濾過し、次いで、減圧濃縮して固体を得た。Et
OAcから固体を再結晶させて標記化合物を白色固体として得た(17.07g
,82%)。MS (ES+) m/e 515.2[M+H]+
d)1−(6−クロロ−3,4−メチレンジオキシベンジル)−5−(2,6−
ジクロロベンジルオキシ)インドール−2−カルボン酸
THF(210mL)およびEtOH(210mL)中の1−(6−クロロ−
3,4−メチレンジオキシベンジル)−5−(2,6−ジクロロベンジルオキシ
)インドールカルボン酸エチル(5g,9.7mmol)の溶液にKOH(21
0mL,H2O中3N溶液)を添加した。得られた混合物を2時間還流させた。
得られた混合物をEtOAcおよび3N HCl間に分配させた。一緒にした有
機層をH2O、ブラインで洗浄し、乾燥させ(MgSO4)、濾過し、次いで、
減圧濃縮して固体を得た。EtOAcから固体を再結晶させて標記化合物を白色
固体として得た(4.7g,97%)。MS (ES+) m/e 505.2[M+H]+ Example 1 Preparation of 1- (6-chloro-3,4-methylenedioxybenzyl) -5- (2,6-dichlorobenzyloxy) indole-2-carboxylic acid a) 1- (6-chloro Ethyl -3,4-methylenedioxybenzyl) -5- (benzyloxy) indolecarboxylate NaH (6.1 g, 0.15) rinsed with hexane in DMF (500 mL).
mol; 60% dispersion in hexane) was added 5-benzyloxy-2-indolecarboxylic acid ethyl ester (30 g, 0.1 mol). The resulting mixture was stirred at room temperature for 1 hour. Chloropiperonyl chloride (20.85 g, 0.1
mol) was added. The resulting mixture was stirred at room temperature for 24 hours. The resulting mixture was poured into water and extracted with EtOAc (2x). The combined organic layers are H 2 O,
Wash with brine, dry (MgSO 4 ), filter, then concentrate under reduced pressure to give a solid. Recrystallization of the solid from ethanol gave the title compound as a white solid (30.68g, 66%). MS (ES +) m / e 464.5 [M + H] + b) 1- (6-Chloro-3,4-methylenedioxybenzyl) -5- (hydroxy) indolecarboxylate Ethyl 1- in EtOAc (800 mL). Ethyl (6-chloro-3,4-methylenedioxybenzyl) -5- (benzyloxy) indolecarboxylate (22.67
g, 0.046 mol) in a solution of 10% Pd on carbon (11.34 g, 50% w)
/ W) was added. The resulting mixture was hydrogenated in a Parr shaker at 60 psi for 18 hours. The resulting mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give the title compound as a white solid (14.54%, 80%). MS (ES +) m / e 374.4 [M + H] + c) 1- (6-chloro-3,4-methylenedioxybenzyl) -5- (2,6-
Ethyl dichlorobenzyloxy) indolecarboxylate NaH (2.34 g, 0.0) rinsed with hexane in DMF (390 mL).
6 mol; 60% dispersion in hexane), to a solution of ethyl 1- (6-chloro-3,4-methylenedioxybenzyl) -5- (hydroxy) indolecarboxylate (
14.54 g, 0.04 mol) was added. The resulting mixture was stirred at room temperature for 1 hour. 2,6-Dichlorobenzyl bromide (9.36 g, 0.045 mol) was added. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was poured into water and extracted with EtOAc (2x). The combined organic layers were washed with H 2 O, brine, dried (MgSO 4), filtered, and then to obtain a solid and concentrated under reduced pressure. Et
Recrystallization of the solid from OAc gave the title compound as a white solid (17.07g).
, 82%). MS (ES +) m / e 515.2 [M + H] + d) 1- (6-chloro-3,4-methylenedioxybenzyl) -5- (2,6-
Dichlorobenzyloxy) indole-2-carboxylic acid 1- (6-chloro-in THF (210 mL) and EtOH (210 mL).
A solution of ethyl 3,4-methylenedioxybenzyl) -5- (2,6-dichlorobenzyloxy) indolecarboxylate (5 g, 9.7 mmol) in KOH (21
0 mL, was added in H 2 O 3N solution). The resulting mixture was refluxed for 2 hours.
The resulting mixture was partitioned between EtOAc and 3N HCl. The combined organic layers were washed with H 2 O, brine, dried (MgSO 4 ), filtered and then
Concentration under reduced pressure gave a solid. Recrystallisation of the solid from EtOAc gave the title compound as a white solid (4.7g, 97%). MS (ES +) m / e 505.2 [M + H] +
【0022】実施例2 1−(6−クロロ−3,4−メチレンジオキシベンジル)−5−(2,6−ジク ロロベンジルアミノ)インドール−2−カルボン酸の製造
a)1−(6−クロロ−3,4−メチレンジオキシベンジル)−5−ニトロイン
ドール−2−カルボン酸エチル
無水DMF(4mL)中の5−ニトロインドール−2−カルボン酸エチル(0
.5g,2.1mmol)の溶液をNaH(鉱油中60%分散物)(93mg,
2.3mmol)で処理し、5分間撹拌し、その間に塩化6−クロロ−3,4−
メチレンジオキシベンジル(0.47g,2.3mmol)を添加した。得られ
た混合物を室温で20時間撹拌した。反応混合物をEtOAcで希釈し、水、次
いで、ブラインで洗浄した。有機抽出物をNa2SO4で乾燥させ、濾過し、次
いで、減圧濃縮した。得られた残さを、5%、10%、15%、次いで20%
EtOAc/ヘキサンで溶出するシリカゲルクロマトグラフィーに供して標記化
合物をわずかに灰色がかった白色の固体として得た(1.32g,82%)。ES
(MS) m/e 403.2 [M+H]+
b)1−(6−クロロ−3,4−メチレンジオキシベンジル)−5−アミノイン
ドール−2−カルボン酸エチル
エタノール(5mL)中の実施例2aの化合物(0.31g,0.77mmo
l)の溶液を塩化すず(II)(0.73g,4mmol)で処理し、70℃で
6時間加熱した。反応物を氷に注ぎ、50%NaOH水溶液で塩基性にし、次い
で、EtOAcで徹底的に洗浄した。一緒にした有機抽出物をNa2SO4で乾
燥させ、濾過し、次いで、減圧濃縮した。得られた残さを、25%、30%、3
5%、次いで40% EtOAc/ヘキサンで溶出するシリカゲルクロマトグラ
フィーに供して標記化合物をレンガ色固体として得た(172mg,60%)。
ES (MS) m/e 372.9 [M+H]+
c)1−(6−クロロ−3,4−メチレンジオキシベンジル)−5−(2,6−
ジクロロベンジルアミノ)インドール−2−カルボン酸エチル
5−ニトロインドール−2−カルボン酸エチルのかわりに実施例2bの化合物
を用い、塩化6−クロロ−3,4−メチレンジオキシベンジルのかわりに塩化2
,6−ジクロロベンジルを用いること以外は実施例2aの方法に従って、標記化
合物をうす黄色ガラス状泡状物質として得た。ES (MS) m/e 530.78 [M]+
d)1−(6−クロロ−3,4−メチレンジオキシベンジル)−5−(2,6−
ジクロロベンジルアミノ)インドール−2−カルボン酸
無水THF(0.4mL)およびメタノール(0.2mL)中の実施例2cの
化合物(46mg,0.086mmol)の溶液を1N NaOH(0.22m
L,0.22mmol)で処理し、20時間撹拌した。溶媒混合物を減圧除去し
た後、得られたナトリウム塩を水に懸濁し、10% HClで酸性(pH=6.
5まで)にして標記化合物をくすんだ黄色の固体として得た(35mg,80%
)。ES (MS) m/e 504.65 [M+2H]+ The preparation a of Example 2 1- (6-chloro-3,4-methylenedioxy-benzyl) -5- (2,6-dichlorobenzoyl lolo benzylamino) indole-2-carboxylic acid) 1- (6- Ethyl chloro-3,4-methylenedioxybenzyl) -5-nitroindole-2-carboxylate Ethyl 5-nitroindole-2-carboxylate (0 in anhydrous DMF (4 mL).
. A solution of 5 g, 2.1 mmol) was added to NaH (60% dispersion in mineral oil) (93 mg,
2.3 mmol) and stirred for 5 min, during which time 6-chloro-3,4-chloride
Methylenedioxybenzyl (0.47 g, 2.3 mmol) was added. The resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with EtOAc and washed with water then brine. The organic extract was dried over Na 2 SO 4 , filtered and then concentrated under reduced pressure. The resulting residue is 5%, 10%, 15%, then 20%
Chromatography on silica gel eluting with EtOAc / hexanes gave the title compound as a slightly off-white solid (1.32g, 82%). ES
(MS) m / e 403.2 [M + H] + b) Example 1 in ethyl 1- (6-chloro-3,4-methylenedioxybenzyl) -5-aminoindole-2-carboxylate ethanol (5 mL). Compound of 2a (0.31 g, 0.77 mmo
The solution of l) was treated with tin (II) chloride (0.73 g, 4 mmol) and heated at 70 ° C. for 6 hours. The reaction was poured onto ice, basified with 50% aqueous NaOH, then washed thoroughly with EtOAc. The combined organic extracts were dried over Na 2 SO 4 , filtered and then concentrated under reduced pressure. 25%, 30%, 3
Chromatography on silica gel eluting with 5% then 40% EtOAc / hexanes gave the title compound as a brick solid (172 mg, 60%).
ES (MS) m / e 372.9 [M + H] + c) 1- (6-chloro-3,4-methylenedioxybenzyl) -5- (2,6-
Ethyl dichlorobenzylamino) indole-2-carboxylate The compound of Example 2b was used in place of ethyl 5-nitroindole-2-carboxylate and 2 chloride of 2-chloro-3,4-methylenedioxybenzyl chloride was used instead of 6-chloro-3,4-methylenedioxybenzyl chloride.
The title compound was obtained as a pale yellow glassy foam according to the method of Example 2a, except that 6-dichlorobenzyl was used. ES (MS) m / e 530.78 [M] + d) 1- (6-chloro-3,4-methylenedioxybenzyl) -5- (2,6-
Dichlorobenzylamino) indole-2-carboxylic acid A solution of the compound of Example 2c (46 mg, 0.086 mmol) in anhydrous THF (0.4 mL) and methanol (0.2 mL) was treated with 1N NaOH (0.22 m).
L, 0.22 mmol) and stirred for 20 hours. After removing the solvent mixture under reduced pressure, the obtained sodium salt was suspended in water and acidified with 10% HCl (pH = 6.
Up to 5) to give the title compound as a dull yellow solid (35 mg, 80%
). ES (MS) m / e 504.65 [M + 2H] +
───────────────────────────────────────────────────── フロントページの続き (72)発明者 ジョージ・ワイ−キン・チャン アメリカ合衆国19096ペンシルベニア州ウ ィンウッド、ウィルトシャー・ロード249 番 (72)発明者 ケルビン・キン・チョン・シャム アメリカ合衆国91362カリフォルニア州サ ウザンド・オークス、ラ・カサ・コート 3111番 Fターム(参考) 4C063 AA01 BB03 CC81 DD06 EE01 4C086 AA01 AA02 BC13 GA02 GA07 MA01 MA04 NA14 ZB32 ZC20─────────────────────────────────────────────────── ─── Continued front page (72) Inventor George Wye-Kin Chan United States 19096 U, Pennsylvania Innwood, Wiltshire Road 249 Turn (72) Inventor Kelvin Kin Chong Sham United States 91362 Sa, California Thousand Oaks, La Casa Court No. 3111 F-term (reference) 4C063 AA01 BB03 CC81 DD06 EE01 4C086 AA01 AA02 BC13 GA02 GA07 MA01 MA04 NA14 ZB32 ZC20
Claims (3)
容される塩を、治療を要する患者に投与することにより細菌感染を治療する方法
。1. An effective amount of formula (I): A bacterial infection by administering a compound represented by I [wherein R is OH; Q is O, NH or CH 2 ] or a pharmaceutically acceptable salt thereof to a patient in need thereof. How to treat.
オキシベンジル)−5−(2,6−ジクロロベンジルオキシ)インドール−2−
カルボン酸である請求項1記載の治療方法。2. The compound of formula (I) is 1- (6-chloro-3,4-methylenedioxybenzyl) -5- (2,6-dichlorobenzyloxy) indole-2-.
The treatment method according to claim 1, which is a carboxylic acid.
オキシベンジル)−5−(2,6−ジクロロベンジルアミノ)インドール−2−
カルボン酸である請求項1記載の治療方法。3. The compound of formula (I) is 1- (6-chloro-3,4-methylenedioxybenzyl) -5- (2,6-dichlorobenzylamino) indole-2-.
The treatment method according to claim 1, which is a carboxylic acid.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US16112299P | 1999-10-22 | 1999-10-22 | |
US60/161,122 | 1999-10-22 | ||
PCT/US2000/029082 WO2001030752A2 (en) | 1999-10-22 | 2000-10-20 | Indole compounds for treating bacterial infections |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2003512452A true JP2003512452A (en) | 2003-04-02 |
Family
ID=22579913
Family Applications (1)
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---|---|---|---|
JP2001533107A Withdrawn JP2003512452A (en) | 1999-10-22 | 2000-10-20 | New indole compounds |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1242075A4 (en) |
JP (1) | JP2003512452A (en) |
AU (1) | AU3634001A (en) |
WO (1) | WO2001030752A2 (en) |
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AU2014249003A1 (en) | 2013-03-13 | 2015-10-15 | Forma Therapeutics, Inc. | Novel compounds and compositions for inhibition of FASN |
US10793554B2 (en) | 2018-10-29 | 2020-10-06 | Forma Therapeutics, Inc. | Solid forms of 4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone |
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AU4514496A (en) * | 1994-12-13 | 1996-07-03 | Smithkline Beecham Corporation | Novel compounds |
EP1021181A4 (en) * | 1996-03-28 | 2002-06-26 | Smithkline Beecham Corp | Carboxylic acid indole inhibitors of chemokines |
US6486211B1 (en) * | 1999-10-22 | 2002-11-26 | Smithkline Beecham Corporation | Indole compounds |
WO2002000620A1 (en) * | 2000-06-27 | 2002-01-03 | Smithkline Beecham Corporation | Fatty acid synthase inhibitors |
-
2000
- 2000-10-20 EP EP00991850A patent/EP1242075A4/en not_active Withdrawn
- 2000-10-20 JP JP2001533107A patent/JP2003512452A/en not_active Withdrawn
- 2000-10-20 WO PCT/US2000/029082 patent/WO2001030752A2/en not_active Application Discontinuation
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EP1242075A2 (en) | 2002-09-25 |
WO2001030752A2 (en) | 2001-05-03 |
WO2001030752A3 (en) | 2001-11-22 |
EP1242075A4 (en) | 2002-12-04 |
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