JP2014508173A - 三環式ジャイレース阻害薬 - Google Patents
三環式ジャイレース阻害薬 Download PDFInfo
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- JP2014508173A JP2014508173A JP2013558143A JP2013558143A JP2014508173A JP 2014508173 A JP2014508173 A JP 2014508173A JP 2013558143 A JP2013558143 A JP 2013558143A JP 2013558143 A JP2013558143 A JP 2013558143A JP 2014508173 A JP2014508173 A JP 2014508173A
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- 239000002271 gyrase inhibitor Substances 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 419
- 238000000034 method Methods 0.000 claims abstract description 84
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 239000000651 prodrug Substances 0.000 claims abstract description 15
- 229940002612 prodrug Drugs 0.000 claims abstract description 15
- 150000002148 esters Chemical class 0.000 claims abstract description 8
- 125000001424 substituent group Chemical group 0.000 claims description 136
- -1 aminocyclopropyl Chemical group 0.000 claims description 60
- 150000003335 secondary amines Chemical class 0.000 claims description 54
- 125000004429 atom Chemical group 0.000 claims description 51
- 150000003512 tertiary amines Chemical class 0.000 claims description 45
- 125000001072 heteroaryl group Chemical group 0.000 claims description 38
- 229910052799 carbon Inorganic materials 0.000 claims description 36
- 125000005842 heteroatom Chemical group 0.000 claims description 36
- 229910052760 oxygen Inorganic materials 0.000 claims description 36
- 125000003118 aryl group Chemical group 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 150000001412 amines Chemical class 0.000 claims description 31
- 229910052717 sulfur Inorganic materials 0.000 claims description 31
- 125000004122 cyclic group Chemical group 0.000 claims description 28
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 27
- 230000002452 interceptive effect Effects 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
- 125000006239 protecting group Chemical group 0.000 claims description 22
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- SEOZPKYDFRZJMV-UHFFFAOYSA-N 3-[(2-oxo-1,3-oxazolidin-3-yl)phosphanyl]-1,3-oxazolidin-2-one Chemical compound O=C1OCCN1PN1C(=O)OCC1 SEOZPKYDFRZJMV-UHFFFAOYSA-N 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 13
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 229920006395 saturated elastomer Polymers 0.000 claims description 11
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 10
- 238000012545 processing Methods 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 229910052727 yttrium Inorganic materials 0.000 claims description 9
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 7
- 108010054814 DNA Gyrase Proteins 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 125000004434 sulfur atom Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 4
- 239000012964 benzotriazole Substances 0.000 claims description 4
- 150000004820 halides Chemical class 0.000 claims description 4
- 125000002950 monocyclic group Chemical group 0.000 claims description 4
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 3
- 230000008878 coupling Effects 0.000 claims description 3
- 238000010168 coupling process Methods 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 claims description 2
- 125000000928 benzodioxinyl group Chemical group O1C(=COC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- WGNZRLMOMHJUSP-UHFFFAOYSA-N benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphanium Chemical compound C1CCCN1[P+](N1CCCC1)(N1CCCC1)ON1C2=CC=CC=C2N=N1 WGNZRLMOMHJUSP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000005433 dihydrobenzodioxinyl group Chemical group O1C(COC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004612 furopyridinyl group Chemical group O1C(=CC2=C1C=CC=N2)* 0.000 claims description 2
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 claims description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 2
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims 1
- 238000010276 construction Methods 0.000 claims 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 25
- 230000000845 anti-microbial effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 267
- 239000000203 mixture Substances 0.000 description 185
- 239000000243 solution Substances 0.000 description 150
- 239000007787 solid Substances 0.000 description 103
- 235000019439 ethyl acetate Nutrition 0.000 description 98
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 91
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- 238000002360 preparation method Methods 0.000 description 69
- 238000006243 chemical reaction Methods 0.000 description 66
- 238000005481 NMR spectroscopy Methods 0.000 description 60
- 239000011541 reaction mixture Substances 0.000 description 54
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 52
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
- 239000012044 organic layer Substances 0.000 description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000005457 ice water Substances 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
- 239000011734 sodium Substances 0.000 description 35
- 239000002904 solvent Substances 0.000 description 32
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
- 239000000725 suspension Substances 0.000 description 30
- 239000000047 product Substances 0.000 description 29
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 26
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 26
- 238000004587 chromatography analysis Methods 0.000 description 23
- 239000000543 intermediate Substances 0.000 description 23
- 239000003208 petroleum Substances 0.000 description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
- 238000004128 high performance liquid chromatography Methods 0.000 description 22
- 238000003756 stirring Methods 0.000 description 20
- 230000015572 biosynthetic process Effects 0.000 description 19
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 19
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 239000013058 crude material Substances 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 18
- 238000004440 column chromatography Methods 0.000 description 17
- 239000003921 oil Substances 0.000 description 17
- 235000019198 oils Nutrition 0.000 description 17
- 239000000741 silica gel Substances 0.000 description 17
- 229910002027 silica gel Inorganic materials 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 16
- 239000012043 crude product Substances 0.000 description 16
- 239000001257 hydrogen Substances 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- 239000010410 layer Substances 0.000 description 15
- 239000002244 precipitate Substances 0.000 description 15
- 238000000746 purification Methods 0.000 description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
- 230000000694 effects Effects 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 13
- 239000012230 colorless oil Substances 0.000 description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 description 13
- 235000018102 proteins Nutrition 0.000 description 13
- 102000004169 proteins and genes Human genes 0.000 description 13
- 108090000623 proteins and genes Proteins 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000012267 brine Substances 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 239000003112 inhibitor Substances 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- 0 *C1C(N)=C=C*C1 Chemical compound *C1C(N)=C=C*C1 0.000 description 11
- 229910004298 SiO 2 Inorganic materials 0.000 description 11
- 238000009472 formulation Methods 0.000 description 11
- 238000002390 rotary evaporation Methods 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- 241000588724 Escherichia coli Species 0.000 description 10
- 239000012298 atmosphere Substances 0.000 description 10
- 239000013078 crystal Substances 0.000 description 10
- 150000004985 diamines Chemical class 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
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- 150000003141 primary amines Chemical group 0.000 description 10
- 231100000419 toxicity Toxicity 0.000 description 10
- 230000001988 toxicity Effects 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 239000003085 diluting agent Substances 0.000 description 9
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 9
- 239000000546 pharmaceutical excipient Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 208000035143 Bacterial infection Diseases 0.000 description 8
- 108010041052 DNA Topoisomerase IV Proteins 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 8
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- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
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- 238000001802 infusion Methods 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
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- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 6
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 6
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- 208000024891 symptom Diseases 0.000 description 6
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- OHFVPBGSKPYIED-UHFFFAOYSA-N 2-methylpyrimidin-5-ol Chemical compound CC1=NC=C(O)C=N1 OHFVPBGSKPYIED-UHFFFAOYSA-N 0.000 description 5
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 150000004703 alkoxides Chemical class 0.000 description 5
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
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- RPHOSVGTSZUHIK-UHFFFAOYSA-N 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-imidazole Chemical compound O1C(C)(C)C(C)(C)OB1C1=CNC=N1 RPHOSVGTSZUHIK-UHFFFAOYSA-N 0.000 description 4
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
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- 229910052786 argon Inorganic materials 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- QTYXZUKOJXGPRP-YVWKXTFCSA-N benzyl (1R,4R,5R)-5-(4-methoxyanilino)-2-azabicyclo[2.2.1]heptane-2-carboxylate Chemical compound COC1=CC=C(C=C1)N[C@H]1[C@H]2CN([C@@H](C1)C2)C(=O)OCC1=CC=CC=C1 QTYXZUKOJXGPRP-YVWKXTFCSA-N 0.000 description 4
- NDKQMNWQGHSZMJ-OLZOCXBDSA-N benzyl (1s,4r)-5-azabicyclo[2.2.1]hept-2-ene-5-carboxylate Chemical compound C([C@]1(C[C@]2([H])C=C1)[H])N2C(=O)OCC1=CC=CC=C1 NDKQMNWQGHSZMJ-OLZOCXBDSA-N 0.000 description 4
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
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- 229910000104 sodium hydride Inorganic materials 0.000 description 4
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
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Classifications
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
【選択図】図1
Description
本出願は、参照によって本明細書に組み込まれる2011年3月15日に出願された米国仮出願第61/453,011号の35U.S.C.§ 119(e)による優先権を主張する。
連邦の援助による研究開発に関する表明
共同研究協定の団体
関連技術の説明
H;
場合によって置換されたORa;
第二級または第三級アミンNを介してC環に結合している場合によって置換された第二級または第三級アミン;または
0〜3個のN、OもしくはSヘテロ原子を含有する、場合によって置換された五〜十員不飽和の環式または複素環の残基であってもよい。
チャート3
a)YのCまたはN原子と第一級もしくは第二級アミンNとの間の距離は、約7Å〜約10.5Åであり;
b)R8が結合しているC原子と第一級または第二級アミンNとの間の距離は約6Å〜約9Åであり;
c)R4が結合しているC原子と第一級または第二級アミンNとの間の距離は約3.5Å〜約6Åであり;
d)R2が結合しているC原子と第一級または第二級アミンNとの間の距離は、約5Å〜約7.5Åである。
第一級または第二級アミンに関して「C環に直接結合していない」は、C環に第一級または第二級アミンを結ぶ結合の欠如を指す。
チャート5
[式中、G1およびG2は、Cl、Br、F、I、SR、SOR、SO2R、OSO2R、およびO−ベンゾトリアゾール(OBt)からなる群から独立して選択される脱離基であり;ここで、Rは、メチル、ベンジルおよびp−メトキシベンジルなどのC1−4アルキル、C1−4アルキルオキシ、Cl、Br、F、I、またはNO2で場合によって置換された、0〜5個のO、SまたはN原子を含むC1−8アルキル、アリール、またはヘテロアリールであってもよい。]の化合物を塩基性条件下でR2LHと反応させ、構造
またはそのアミン保護された中間体の構造を有する;[式中、:G1およびG2は、SH、OH、Cl、Br、F、I、SR、SOR、SO2R、OSO2R、OArおよびOBtからなる群から独立して選択された脱離基であり;RはC1−8アルキル、アリール、またはヘテロアリールであり;Arは、Cl−4アルキル、Cl−4アルコキシ、ハロまたはNO2で場合によって置換された、0〜5個のO、SまたはN原子を含有するアリールまたはヘテロアリールであり;Btはベンゾトリアゾールであり;R8は、A環上の炭素結合点からR8中の末端原子まで約1Å〜約5Åの長さ、および約3.3Å以下の幅を有する相互作用する置換基であり;X、YおよびZは、X、YおよびZの2個以下がNであることを条件として、それぞれ、N、CRX、CRYおよびCRZからなる群から独立して選択され、ここで、Rxは、H、または、CRX中の炭素からRx中の末端原子まで約1Å〜約2Åの長さを有する相互作用する置換基であり;ここで、RYは、H、または、CRY中の炭素からRY中の末端原子まで約1Å〜約3Åの長さを有する相互作用する置換基であり;ここで、RZは、H、または、CRZ中の炭素からRZ中の末端原子まで約1Å〜約2Åの長さを有する相互作用する置換基であり;ただし、ここで、R8はCH3ではなく、かつ、R8がOCH3である場合は、RXおよびRYはOHではない。]。
1.三環式ピリミド[4,5−b]インドール核の調製のための一般手順
スキーム1:置換されたフェニル出発物質を調製するための一般手順:
スキーム1
スキーム2:置換されたピリミジンおよびピリジン出発物質を調製するための一般手順
スキーム3:インドール中間体の形成
スキーム4.重要な三環式中間体の調製
スキーム4.重要な三環式中間体の調製(続き)
スキーム5:
スキーム6:
スキーム7
スキーム8:
実験の部
セクションA
独特のR2部
実施例:
一般スキーム:
実験:
スキーム1:
1H NMR(400MHz, DMSO−d6):δ:7.42−7.39(m, 5H), 4.74(s, 2H), 3.32(s, 3H), 3.21(s, 3H).
1H NMR(400MHz, CDCl3):δ:8.44(s, 2H), 7.46−7.28(m, 5H), 5.24(s, 2H), 2.18−2.12(m, 1H), 0.99−0.90(m, 2H), 0.89−0.86(m, 2H).
1H NMR(300MHz, DMSO−d6):δ:10.05(s, 1H), 8.17(s, 2H), 2.12−2.05(m, 1H), 0.93−0.91(m, 2H), 0.86−0.83(m, 2H).LCMS[移動相:6分で2〜60%アセトニトリル−0.05%TFA、最終的に0.5分間この条件下で]、純度は>95%、保持時間2.564分;MS理論値:136.1 ;MS実測値:137.1([M+1]+)
スキーム2:
1H NMR(300MHz, CDCl3):δ:8.84(s, 2H), 7.48(m, 3H), 7.37(m, 2H), 5.20(s, 2H), 4.68(m, 1H), 3.25(m, 1H), 1.48(d, 3H).
1H NMR(400MHz, CDCl3):δ:8.84(s, 2H), 5.40(brd, 1H), 4.66(m, 1H), 3.25(m, 1H), 1.46(d, 3H).LCMS実測値:141.1([M(+)1]+)
スキーム3:
1H NMR(400MHz, CDCl3):δ:8.54(s, 2H).
1H NMR(400MHz, CDCl3):δ:8.75(s, 2H), 5.26(s, 2H), 5.06(s, 1H), 1.28(s, 9H)。
1H NMR(400MHz, CDCl3):δ:8.97(s, 2H), 5.30(s, 2H), 1.35(s, 9H), 1.28(s, 9H).
1H NMR(400MHz, DMSO−d6):δ:10.48(s, 1H), 8.31(s, 2H), 5.11(s, 2H), 1.21(s, 9H).
1H NMR(300MHz, CDCl3):6:8.43(s, 2H), 7.35(d, J=8.8Hz, 2H), 6.93(d, J=8.8Hz, 2H), 5.09(s, 2H), 4.78(s, 2H).
スキーム4:
1H NMR(300MHz, CDCl3):δ:8.41(s, 2H), 7.34(d, J=8.8Hz, 2H), 6.93(d, J=8.8Hz, 2H), 5.24(s, 2H), 5.07(s, 2H), 3.82(s, 3H), 1.26(s, 9H).
1H NMR(400MHz, CDCl3):δ:8.45(s, 2H), 7.34(d, J=8.8Hz, 2H), 6.92(d, J=8.8Hz, 2H), 5.08(s, 2H), 4.64(s, 2H), 3.82(s, 3H), 3.52(s, 3H).
1H NMR(400MHz, DMSO−d6):δ:10.45(s, 1H), 8.33(s, 2H), 4.44(s, 2H), 3.31(s, 3H).LCMS[移動相:6分で95〜5%アセトニトリル−0.02%NH4Ac、最終的に0.5分間この条件下で]、純度は>95%、保持時間3.3分;MS理論値140.1.1;MS実測値:141.1([M+1]+).
スキーム5:
スキーム6:
スキーム7
1H NMR(400MHz, CDCl3):δ:8.43(d, J=2.4Hz, 1H), 7.99(d, J=1.6Hz, 1H), 4.41−4.35(q, J=3.2Hz, 3H), 2.83(s, 3H), 2.34(s, 3H), 1.42−4.39(t, J=3.2Hz, 3H).
1H NMR(400MHz, DMSO−d6):δ:10.0(s, 1H), 8.18(d, J=2.4Hz, 1H), 7.54(d, J=2.8Hz, 1H), 4.32−4.26(q, J=3.2Hz, 3H), 2.57(s, 3H), 1.33−1.29(t, J=3.2Hz, 3H).
1H NMR(400MHz, CDCl3):δ:8.12(d, J=2.8Hz, 1H), 7.54(d, J=2.8Hz, 1H), 4.30−4.26(q, J=3.2Hz, 3H), 2.64(s, 3H), 1.32−1.28(t, J=3.2Hz, 3H), 0.92(s, 9H), 0.12(s, 6H).
1H NMR(400MHz, CDCl3):δ:8.28(d, J=3.2Hz, 1H), 7.68(d, J=3.2Hz, 1H), 4.98(s, 3H), 4.45−4.40(q, J=3.2Hz, 3H), 1.45−1.42(t, J=2.8Hz, 3H), 1.00(s, 9H), 0.26(s, 6H).
1H NMR(400MHz, DMSO−d6):δ:8.34(d, J=2.8Hz, 1H), 7.43(d, J=2.8Hz, 1H), 4.42(s, 2H), 3.06(s, 3H), 0.95(s, 9H), 0.20(s, 6H).
1H NMR(400MHz, DMSO−d6):δ:10.27(s, 1H), 8.27(d, J=2.4Hz, 1H), 7.32(d, J=2.8Hz, 1H), 4.37(s, 2H), 3.0(s, 3H).LCMS移動相:6分で40%水(0.05%TFA)および60%CH3CNから10%水(0.05%TFA)および90%CH3CNに、最終的に0.5分間この条件下に]純度は>95%、保持時間3.7分;MS理論値:164.1 ;MS実測値:165.1([M(+)1]+).
1H NMR(300MHz, DMSO−d6):δ:10.42(s, 1H), 8.60(d, J=1.6Hz, 1H), 8.36(d, J=2.8Hz, 1H), 7.60−7.61(m, 1H), 3.87(s, 3H).
1H NMR(300MHz, CDCl3):δ:8.83(d, J=1.6Hz, 1H), 8.54(d, J=2.8Hz, 1H), 7.85−7.86(m, 1H), 7.27−7.46(m, 5H), 5.15(s, 2H), 3.95(s, 3H).
1H NMR(300MHz, CDCl3):δ:8.50(d, J=1.6Hz, 1H), 8.48(d, J=2.8Hz, 1H), 7.73−7.74(m, 1H), 7.73−7.74(m, 5H), 6.16(s, 1H), 3.15(s, 2H), 3.04(d, J=4.4Hz, 3H).
1H NMR(300MHz, CDCl3):δ:8.59(d, J=2.8Hz, 1H), 8.56(d, J=1.6Hz, 1H), 7.68−7.69(m, 1H), 7.3−7.46(m, 5H), 5.21(s, 2H), 4.17(s, 3H).
1H NMR(300MHz, DMSO−d6):δ:10.56(s, 1H), 8.49(d, J=1.6Hz, 1H), 8.36(d, J=2.8Hz, 1H), 7.61−7.62(m, 1H), 4.19(s, 3H).
セクションB
独特のR4部の合成
(1R,4R,5R)tert−ブチル−5−アミノ−2−アザビシクロ[2.2.1]ヘプタン−2−カルボキシラートの不斉合成一般スキーム:
1H NMR(300MHz, CDCl3):6 7.35−7.27(m, 5H), 4.21(s, 0.5H), 4.08(s, 0.5H), 3.80−3.68(m, 2H), 3.58(d, J=10.0Hz, 1H), 3.28−3.22(m, 1H), 3.20−3.11(m, 1H), 2.62(m, 1H), 2.05−1.97(m, 1H), 1.76−1.69(m, 1H), 1.55−1.51(m, 1H), 1.48(s, 9H), 1.30−1.14(m, 1H).
オクタヒドロシクロペンタ[c]ピロール−4−アミンの合成:
1H NMR(300MHz,MeOD):δ 3.89(d, J=11.2Hz, 1H), 3.42(s, 1H), 3.01(d, J=10.4Hz, 1H), 2.74−2.69(m, 1H), 2.58(bs, 1H), 2.12−2.02(m, 1H), 1.64(s, 2H), 1.46(s, 9H), 1.19−1.13(m, lH).
セクションC
L=Sの化合物のセクション
一般スキーム1:
1H NMR(CDCl3、300MHz):δ=6.97−6.88(m、2H)、3.27(s、3H)。
1H NMR(CDCl3, 300 MHz): δ=6.93−6.85(m, 2H), 3.20(s, 3H), 1.32(s, 9H).
1H NMR(CDCl3 .300 MHz): δ=6.93−6.85(m, 2H), 4.88(m, 1H), 4.33(m, 2H), 3.20(s, 3H), 1.32(s, 9H), 1.28(t, 3H).
1H NMR(300MHz, DMSO−d6)δ(ppm):11.75(s, 1H), 8.09(d, 1H), 8.95(s, 1H), 8.52(m, 1H), 8.35(s, 1H), 7.75(m, 1H), 7.01(d, J=11.2, 1H), 5.96(d, 1H), 4.10(s, 1H), 2.98(s, 3H), 2.85(m, 2H), 2.67(m, 2H), 1.38(m, 1H), 0.75(br m, 2H).
実験:
1H NMR(300MHz, DMSO−d6)δ(ppm):11.75(s, 1H), 8.09(d, 1H), 8.95(s, 1H), 8.52(m, 1H), 8.35(s, 1H), 7.75(m, 1H), 7.01(d, J=11.2, 1H), 5.96(d, 1H), 4.10(s, 1H), 2.85(m, 2H), 2.67(m, 2H), 1.38(m, 1H), 0.75(br m, 2H).
R8がNHアルキルではないL=Oの三環式核の合成
1H NMR(400MHz, CDCl3):5:6.93(s, 1H), 6.91(s, 1H), 4.33−4.27(m, 2H), 2.73−2.68(m, 2H), 1.29−1.25(t, J=7.6Hz, 2H).
1H NMR(400MHz, CDCl3):δ:7.33−7.04(dd, J=4.4, 2.4Hz, 1H), 7.16−7.13(dd, J=4.4, 2.4Hz, IE), 5.06(s, 1H), 4.32−4.27(m, 2H), 2.74−2.68(m, 2H), 1.35−1.26(m, 6H).
1H NMR(400MHz, DMSO−d6):6:10.75(s, 1H), 7.08(dd, J=9.6, 2.4Hz, 1H), 6.55(dd, J=10.8, 2.4Hz, 1H), 6.44(s, 2H), 4.21(q, J=7.2Hz, 2H), 2.71(q, J=7.6Hz, 2H), 1.31(t, J=6.8Hz, 3H), 1.20(t, J=7.6Hz, 3H).LCMS[移動相:6分で30%〜95%アセトニトリル−0.02%NH4Ac、最終的に0.5分間この条件下に]、純度は>95%、保持時間=2.953分];MS理論値:250;MS実測値:251([M+1]+).
1H NMR(400MHz, DMSO−d6):δ:11.44(s, 1H), 10.75(s, 1H), 7.22(s, 1H), 7.08(dd, J=9.6, 2.4Hz, 1H), 6.55(dd, J=10.8, 2.4Hz, 1H),2.70(q, J=7.6Hz, 2H),1.22(t, J=7.6Hz, 3H).
1H NMR(300 MHz, DMSO−d6): 6: 11.44(s, 1H), 10.75(s, 1H), 7.22(s, 1H), 7.08(dd, J=9.6, 2.4 Hz, 1H), 6.55(dd, J=10.8, 2.4 Hz, 1H),2.70(q, J=7.6 Hz, 2H), 2.64(m,−2.41(m, 4H), 1.22(t, J=7.6 Hz, 3H).
1H NMR(300MHz, DMSO−d6)δ(ppm):11.75(s, 1H), 8.72(s, 2H), 8.09(br s, 3H), 7.01(d, J=11.2, 1H), 6.31(d, J=9.7, 1H), 4.40(d, J=9.9, 1H), 4.32(dd, J=7.6,4.5, 1H), 4.03(d, J=12.3, 1H), 3.50(d, J=9.8, 2H), 2.67(s, 3H), 2.05(s, 3H),1.09(m, 1H), 0.81(br m, 3H).
ビススルホン経路の一般スキーム:
スキーム
1H NMR(DMSO−d6, 300MHz):δ=10.77(s, 1H), 6.84−6.80(m, 1H), 6.69(s, 2H), 6.69−6.66(m, 1H), 3.14(s, 3H), 1.33(s, 9H).
1H NMR(CDCl3, 300MHz):δ=8.72(s, 1H), 7.66−7.62(dd, J=8.37, 2.28Hz, 1H), 7.48−7.27(m, 10H), 7.05−7.01(dd, J=10.14, 2.28Hz, 1H), 4.69(s, 2H), 4.55(s, 2H), 3.37(s, 3H), 1.48(s, 9H).
1H NMR(CDCl3, 300MHz):δ=10.07(s, 1H), 8.49−8.46(dd, J=8.64, 2.22Hz, 1H), 7.54−7.51(m, 1H), 7.38−7.27(m, 10H), 4.95(s, 2H), 4.84(s, 2H), 3.40(s, 3H), 1.52(s, 9H).
スキーム
1H NMR(300MHz, DMSO−d6)δ(ppm):11.75(s, 1H), 8.72(s, 2H), 8.09(br s, 3H), 7.01(d, J=11.2, 1H), 6.31(d, J=9.7, 1H), 4.40(d, J=9.9, 1H), 4.32(dd, J=7.6,4.5, 1H), 4.03=12.3, 1H), 3.50(d, J=9.8, 2H), 2.85(s, 3H), 2.67(s, 3H), 1.09(m, 1H), 0.81(br m, 3H).
1H NMR(500MHz, DMSO−d6)δ(ppm):11.75(brm, 1H), 8.92(brm, 1H), 8.66(brs, 1H), 7.44(d, J=9.7, 1H), 7.04(d, J=5.2), 6.31(d, J=12.2, 1H), 5.56(s, 1H), 4.38(m, 1H), 4.04(s, 1H), 3.37(m, 1H), 3.01(m, 1H), 2.87(m, 1H), 2.85(m, 3H), 2.66(s, 3H), 2.16(m, 1H), 1.86(m,1H),1.79(m,1H),1.75(m,1H)
1H NMR(300MHz, DMSO−d6)δ(ppm):11.75(s, 1H), 8.72(s, 2H), 7.01(d, J=11.2, 1H), 6.31(d, J=9.7, 1H), 4.82(brm, 1H), 4.02(m, 1H), 3.81(m, 1H), 3.49(m, 1H), 2.85(s, 3H), 2.63 −182(m, 2H), 1.47(d, 3H), 1.38(m, 1H).
1H NMR(500MHz, DMSO)δ(ppm):11.35(brm, 1H), 8.82(s, 2H), 7.07(d, J=9.7, 1H), 6.31(d, J=12.2, 1H), 5.63(m, 2H), 5.11(brs, 1H), 4.67(m, 1H), 3.96(m, 1H), 3.33−3.53(m,6H),301(m, 1H),2.85(s,3H),2.70(m, 1H),2.51(m, 1H),1.55(s,6H)
1H NMR(300MHz, DMSO)δ(ppm):8.71(s, 2H), 6.96(d, J=11.2, 1H), 6.28(d, J=11.9, 1H), 5.56(m, 1H), 3.85(m, 1H), 3.73(m, 1H),’ 3.68(d, J=11.2, 1H), 3.60(d, J=11.3, 1H), 2.92(m, 1H), 2.83(m, 4H), 2.77(m, 1H), 2.67(s, 3H), 1.85(m, 1H), 1.62(m, 1H).
1H NMR(300MHz, DMSO−d6)δ(ppm):11.05(s, 1H), 8.72(s, 2H), 7.21(s, 2H), 7.01(d, J=11.2, 1H), 6.11(d, 3=9.7, 1H), 5.01(s, 2H), 4.03(d, J=12.3, 1H), 2.95(s, 3H), 2.81(m,2H), 2.75(m, 2H), 2.67(s, 3H), 0.85(br m, 2H).
ジクロロ経路
一般スキーム
最初R4、次いでR2の添加によって作製する化合物の実施例
1H−NMR(400MHz, CDCl3)δ(ppm):=7.37(5H,m), 6.43(2H,m), 4.40(2H,s),2.84(3H,s).
1H−NMR(400MHz, CDCl3)δ(ppm):7.33(5H,m), 6.92(1H, d, J=8Hz), 6.84(1H, d, J=8Hz), 5.13(1H, s), 4.37(2H,s). 4.30(2H. dd , J=14.4Hz), 2.78(3H. s), 1.35(3H. t, J=7.2Hz).
1H NMR(400MHz, CDCl3)6(ppm):8.02(1H,S), 7.33(5H,m), 6.52(1H, d, J=2.4Hz), 6.49(1H, d, J=2.4Hz), 5.73(2H, s), 4.35(2H,dd, J=15.2Hz). 4.19(2H. s), 2.73(3H. s), 1.44(3H. t, J=7.2Hz).
1H−NMR(400MHz, DMSO− 6)δ(ppm):12.01(1H,S), 11.12(1H,S), 11.06(1H,S), 10.41(1H,S), 7.33(5H,m), 6.63(1H, d, J=2.0Hz), 6.60(1H, d, J=2.4Hz), 4.34(2H,dd, J=7.2Hz), 4.28(2H, s), 4.24(2H,dd, J=7.2Hz), 4.14(2H,dd, J=7.2Hz), 2.75(3H. s), 1.37(3H. t,=7.2Hz)1.27(3H. t, J=7.2Hz), 1.22(3H, t, J=6.8Hz).
1H−NMR(400MHz, DMSO−d6)δ(ppm):7.25(5H,m), 7.01(1H, dd, J=8.8Hz), 6.35(1H, d, J=12.0Hz), 4.45(2H,s), 2.76(3H. s).
R4が窒素と結合していない類似体の合成
1H NMR(300MHz, DMSO−d6)δ(ppm):14.01(S, 1H), 11.71(s, 1H), 7.98(s, 2H), 7.51(d, J=11.2, 1H), 6.30(d, J=9.7, 1H), 4.12(s, 1H), 3.15(s, 3H).
1H NMR(300MHz, DMSO−d6)δ(ppm):14.01(S, 1H), 11.71(s, 1H), 7.98(s, 2H), 7.69(s, 2H), 7.51(d, J=11.2, 1H), 5.98(d, J=9.7, 1H), 4.02(s, 1H), 3.10(s, 3H), 2.65(s, 3H).
1H NMR(300MHz, DMSO−d6)δ(ppm):11.71(s, 1H), 9.10(s, 1H), 8.52(d, 1H), 7.63−7.80(m,=9.7, 1H), 4.10(s, 1H), 2.98(s, 3H), 2.66(s, 3H).
R4でのプロドラッグの合成
(S)−2−アミノ−N−((R)−5−(6−フルオロ−8−(メチルアミノ)−2−(2−メチルピリミジン−5−イルオキシ)−9H−ピリミド[4.5−b]インドール−4−イル)−5−アザスピロ[2.4]ヘプタノ−7−イル)プロパンアミドD76(4.424)
R8でプロドラッグの合成
(S)−2−アミノ−N−(4−((R)−7−アミノ−5−アザスピロ[2.4]ヘプタノ−5−イル)−6−フルオロ−2−(2−メチルピリミジン−5−イルオキシ)−9H−ピリミド[4.5−b]インドール−8−イル)−N−メチルプロパンアミド
R4およびR8でのプロドラッグ:
(R)−2−アミノ−N−(4−(7−(2−アミノアセトアミド)−5−アザスピロ[2.4]ヘプタノ−5−イル)−6−フルオロ−2−(2−メチルピリミジン−5−イルオキシ)−9H−ピリミド[4.5−b]オンドル−8−イル)−N−メチルアセトアミド
実験:
1H NMR(300MHz, DMSO−d6)δ(ppm):11.75(s, 1H), 8.72(s, 2H), 6.45(dd, J=2.7, J=5.2, 1H), 5.37(brm, 1H), 4.46(s, 1H), 3.78(m, 1H), 3.67(m, 1H), 3.33(brs, 1H), 2.83(brs, 3H), 2.67(s, 3H), 2.37(brs, 1H), 2.01(brt, 1H), 1.20(brt, 1H).
1H NMR(300MHz, DMSO−d6)δ(ppm):11.75(s, 1H), 8.72(s, 2H), 6.37(dd, J=2.7, J=5.2, 1H), 5.45(brs, 1H), 4.63(d, J=3, 1H), 4.12(s, 3H), 3.20(t, 1H), 2.83(d, J=2, 3H), 2.67(s, 3H), 1.75−2.01(m, 7H), 1.39(m, 1H).
ピリミジン類
化合物D105の調製:化合物D104(200g、1.27mol)をPOCl3(1300ml)およびDMA(255ml)の混合物に室温で添加し、全体は2−3時間加熱還流し、反応をTLCによってモニターする。反応混合物を氷水へ注ぎ、EtOAc(1L*3)で抽出した。飽和塩水で洗浄し、乾燥し(Na2SO4)、真空内で濃縮した。黒色の固体として粗生成化合物D105(170g)が得られた。これをさらなる精製をせず次のステップに直接使用した。LC−MS :M+1 :194
化合物D109の調製:化合物D108(10.00g、30.73mmol)および尿素(50.0g)の混合物を180℃に終夜加熱した、TLCおよびLCMSは、反応が完了したことを示した。これをDMSOで希釈し、180℃に10分間加熱した。室温に冷却した後、不溶性物質を濾別し、濾液はH2Oへ注いだ。沈殿した固体を濾過によって収集した。固体をH2Oで処理し、懸濁液は加熱還流し、それが熱いうちに濾過した。収集した固体は、さらに4回熱水で洗浄した。次いで、これを高温のMeOHおよびEtOAcで洗浄し、真空内で乾燥した。白色の固体*soldとして、十分に純粋な生成化合物D109(6.20g、62%の収率)が得られた。LC−MS :M+1 :323.
1H−NMR(300MHz, DMSO−d6)δ(ppm):8.23(lH,s), 7.25−7.36(5H, m), 3.37(2H. s), 2.51(3H.s)
ピリジン類
1H NMR(300MHz, DMSO−d6)δ(ppm):14.01(S, 1H), 11.71(s, 1H), 8.98(s, 2H), 8.78(s, 2H), 7.84(d, J=7.5, 1H), 7.47(m, 1H), 6.90(d, J=9.7, 1H), 4.18(s, 1H), 3.10(s, 3H), 2.65(s, 3H), 2.64(s, 3H).
抗菌の有効性の測定
Claims (36)
- 式I
[式中、
LはOまたはSであり;
R8は、H、またはA環上の炭素結合点からR8の末端原子まで約1Å〜約5Åの長さおよび約3.3Å以下の幅を有する相互作用する置換基であり;
X、YおよびZは、X、YおよびZの2個以下がNであることを条件として、N、CRX、CRY、およびCRZからなる群から独立して選択され、ここで、Rは、H、またはCRXの炭素からRxの末端原子まで約1Å〜約2Åの長さを有する相互作用する置換基であり;
ここで、RYは、H、またはCRYの炭素からRYの末端原子まで約1Å〜約3Åの長さを有する相互作用する置換基であり;
ここで、Rzは、H、またはCRZの炭素からRzの末端原子まで約1Å〜約2Åの長さを有する相互作用する置換基であり;
R2は、R2は、0〜3個の非干渉置換基で場合によって置換された、0〜3個のO、SまたはNヘテロ原子を含有する、六員アリールまたはヘテロアリール環であり、ここで、R2上の2個の隣接する非干渉置換基は、六員アリールまたはヘテロアリール環と1個または複数の縮合環を形成することができ;
ここで、R2の六員アリールまたはヘテロアリール環は、R2がLに結合している位置のすぐ隣の位置にCHを有し;
R4は:H;場合によって置換されたORa;第二級または第三級アミンNを介してC環に結合している、場合によって置換された第二級または第三級アミン;
または0〜3個のN、OまたはSヘテロ原子を含有する、場合によって置換された五〜十員不飽和の環式または複素環の残基であり;
ここで、任意選択の置換基は0〜3個の非干渉置換基であり;
Raは、0〜3個の非干渉置換基で場合によって置換された、0〜3個のO、SまたはNヘテロ原子を含有する五〜六員アリールまたはヘテロアリールであり;
ここで、R4置換基は、A、BおよびC環の面より下に結合配座のGyrB/ParE結合窪み床に向かって約3Åを超えて突き出さず;
ここで、該化合物が結合配座にある場合、R4は立体的にR2またはZと干渉しない。]。 - LがOである、請求項1に記載の化合物。
- LがSである、請求項1に記載の化合物。
- R8が、H、Cl、F、Br、OH、NH2、1−3Cアルキル、アミノ−1−3Cアルキル、アミノシクロプロピル、OCH3、OCH2CH3、シクロプロピル、CH2シクロプロピル、CH2Cl、CHCl2、CCl3、CH2CH2Cl、CH2Br、CHBr2、CH2F、CHF2、CF3、CH2CH2F、CH2CHF2、CH2CF3、NHNH2、NHOH、NHNHCH3、NHOCH3、NHCD3、SCH3、またはNHCOHである、請求項1から3のいずれか一項に記載の化合物。
- R8が、H、CH3、CH2CH3、Cl、OCH3、NHCD3、NHCH3、NHCH2CH3、またはNH2である、請求項1から4のいずれか一項に記載の化合物。
- R8がNHCH3である、請求項1から5のいずれか一項に記載の化合物。
- X、YおよびZが、それぞれCRX、CRY、およびCRZであり;
Rxが、H、CH3、Cl、BrまたはFであり;
RYが、H、CH3、CHF2、CF3、CN、CH2CH3、Cl、Br、またはFであり;
Rzが、H、CH3、Cl、Br、またはFである、請求項1から6のいずれか一項に記載の化合物。 - R2の場合によって置換された六員のアリールまたはヘテロアリール環が、場合によって置換されたヘテロアリール環である、請求項1から7のいずれか一項に記載の化合物。
- R2の六員アリールまたはヘテロアリール環上の0〜3個の非干渉置換基が、OH、CO2H、CN、NH2、Br、Cl、F、SO3H、S02NH2、SO2CH3、SOCH3、NHOH、NHOCH3およびNO2からなる群から選択される置換基;または、
OH、CN、=O、NH2、NHOH、=NOH、=NNH2、=NOCH3、Br、F、Cl、SO3H、またはNO2で場合によって置換された、0〜5個のO、SまたはNヘテロ原子を含有する場合によって置換されたCl−15ヒドロカルビル残渣である、請求項1から9のいずれか一項に記載の化合物。 - R2上の2個の隣接する非干渉置換基が1個または複数の縮合環を形成し、ここで、1個または複数の縮合環と、R2の六員アリールまたはヘテロアリール環との組み合わせが、OH、=O、CN、NH2、Br、FまたはClで場合によって置換された、五〜十五員、および0〜5個のO、SまたはNヘテロ原子を含む、請求項1から9のいずれか一項に記載の化合物。
- R2が、場合によって置換されたピリミジニル、フェニルおよびピリジルからなる群から選択され;または、
ここで、1個または複数の縮合環と組み合わせたR2の場合によって置換された六員アリールまたはヘテロアリール環が存在し、場合によって置換されたインドリル、アザインドリル、ピリミドピリジル、キナゾリニル、キノキサリニル、ナフチリジニル、プリニル、イミダゾ*imidizoピリジニル、フロピリジニル、イソインドリリニル、ベンゾジオキシニル、ジヒドロベンゾジオキシニル、ベンゾチアゾリル、ピロロピリジニル、ジヒドロピロロピリジニル、ベンゾイミダゾリル、イミダゾピリジニル、ジヒドロイミダゾピリジニル、テトラヒドロイソインドリル、クロメニル、ベンズチオフェン、ベンズトリアゾリル、ベンズフラニル、ベンゾオキサジアゾリル、インダゾリル、キノリニル、イソキノリニル、インドリン、アザインドリニル、および
- R2が、CH(OH)CH3、C(OH)(CH3)2、OCH3、CN、CH3、CH2CH3、O−シクロプロピル、SCH3、Br、Cl、FまたはNH2で場合によって置換されたピリミジニルまたはピリジニルである、請求項1から11のいずれか一項に記載の化合物。
- R2が、チャート1中の置換基の群から選択される、請求項1から12のいずれか一項に記載の化合物。
- R4が、場合によって置換されたORaであり、Raが場合によって置換されたピリミジニルまたはピリジニルである、請求項1から13のいずれか一項に記載の化合物。
- Raが、非置換のピリミジニル、またはCH3もしくはNH2で置換されたピリミジニルである、請求項14に記載の化合物。
- R4が、第二級または第三級アミンNを介してC環に結合した、場合によって置換された第二級または第三級アミンであり、第一級または第二級アミンをさらに含み、ここで、第一級または第二級アミンはC環に直接結合していず;
ここで、C環に直接結合していない第一級または第二級アミンは、結合配座の化合物中に位置し、ここで、YのCまたはN原子と第一級もしくは第二級アミンNとの間の距離は、約7Å〜約10.5Åであり;
R8が結合しているC原子と第一級または第二級アミンNの間の距離は約6Å〜約9Åであり;
R4が結合しているC原子と第一級または第二級アミンNの間の距離は約3.5Å〜約6Åであり;
R2が結合しているC原子と第一級または第二級アミンNの間の距離は、約5Å〜約7.5Åである、
請求項1から15のいずれか一項に記載の化合物。 - R4が、1〜3個のN原子、0〜3個のO原子および0〜1個のS原子を含有する、場合によって置換された四〜十四員飽和シクロヘテロ脂肪族の第三級アミン環系であり、ここで、四〜十四員飽和シクロヘテロ脂肪族の環系は、場合によって置換された単環、縮合環系、架橋環系またはスピロ環系である、請求項1から16のいずれか一項に記載の化合物。
- R4が、第三級アミンNを介してC環と結合した場合によって置換された第三級アミンであり、ここで、場合によって置換された第三級アミンは第三級アミンNから2〜3個の原子を隔てて少なくとも1個の追加のNを含んでいる、請求項1から17のいずれか一項に記載の化合物。
- R4が、1〜2個の非干渉置換基で置換された非環式の第二級または第三級アミンである、請求項1から18のいずれか一項に記載の化合物。
- R4が、場合によって置換されたピラゾリル、フェニル、ピペラジニル、ピリジニル、およびテトラヒドロピリジニルからなる群から選択される、上記請求項のいずれか一項に記載の化合物。
- R4が、0〜3個のN、OまたはSヘテロ原子を含有する、場合によって置換された五〜十員不飽和の環式または複素環の残基であり、任意選択の置換基は、CH3、NH2、F、ClおよびCH2NH2からなる群から選択される0〜2個の任意選択の置換基を含む、請求項1から20のいずれか一項に記載の化合物。
- R4上の非干渉置換基が、OH、NO、CO2H、CN、NH2、Br、Cl、F、SO3H、およびNO2からなる群から選択される置換基である、または、OH、CN、=O、NH2、=NOH、=NNH2、=NOCH3、Br、F、Cl、SO3H、またはNO2で場合によって置換された、0〜5個のO、SまたはNヘテロ原子を含有するC1−15ヒドロカルビル残渣である、請求項1から21のいずれか一項に記載の化合物。
- R4が、H、またはチャート3、4および5中の置換基の群から選択される置換基である、請求項1から22のいずれか一項に記載の化合物。
- LがOであり;
R8がNHCH3であり;
X、YおよびZがそれぞれCRX、CRYまたはCRZであり、ここで、RxはHまたはFであり;
RYはH、F、ClまたはCF3であり;
Rzは、H、CH3またはFであり;
R2がチャート2中の置換基から選択され;
R4がチャート6中の置換基から選択される、
請求項1から23のいずれか一項に記載の化合物。 - 実施例における請求項1から24のいずれか一項に記載の化合物。
- チャート7中の請求項1から25のいずれか一項に記載の化合物。
- R4が、第二級または第三級アミンNを介してC環に結合した、場合によって置換された第二級または第三級アミンであり、
処理するステップの前に、R8を保護基で保護するステップ、または存在する場合、第二級または第三級アミンNでないR4中のアミンを保護基で保護するステップ;および、処理するステップの後、R8およびR4を脱保護するステップを場合によってさらに含む、
請求項1に記載の化合物を作製する方法。 - 構造
[式中、G1およびG2は、SH、OH、Cl、Br、F、I、SR、SOR、SO2R、OSO2R、OArおよびOBtからなる群から独立して選択される脱離基であり;
Rは、C1−8アルキル、アリール、またはヘテロアリールであり;
Arは、Cl−4アルキル、Cl−4アルコキシ、ハロまたはNO2で場合によって置換された、0〜5個のO、SまたはN原子を含有するアリールまたはヘテロアリールであり;
Btはベンゾトリアゾールであり;
R8は、A環上の炭素結合点からR8中の末端原子まで約1Å〜約5Åの長さ、および約3.3Å以下の幅を有する相互作用する置換基であり;
X、YおよびZは、X、YおよびZの2個以下がNであることを条件として、それぞれ、N、CRX、CRYおよびCRZからなる群から独立して選択され、ここで、Rxは、H、または、CRX中の炭素からRx中の末端原子まで約1Å〜約2Åの長さを有する相互作用する置換基であり;
ここで、RYは、H、または、CRY中の炭素からRY中の末端原子まで約1Å〜約3Åの長さを有する相互作用する置換基であり;
ここで、RZは、H、または、CRZ中の炭素からRZ中の末端原子まで約1Å〜約2Åの長さを有する相互作用する置換基であり;ただし、ここで、R8はCH3ではなく、かつ、R8がOCH3である場合は、RXおよびRYはOHではない。]。 - 中間化合物がアミン保護された中間体であり、化合物中の1個または複数の窒素がカルボベンジルオキシ(Cbz)またはBOCで保護された、請求項34に記載の中間化合物。
- G1およびG2が、トシラート、メシラート、トリフラート*trifilate、O−ピリミジン、O−フェニルおよびO−ピリジンからなる群から独立して選択される脱離基である、請求項34または35に記載の中間化合物。
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US10336747B2 (en) | 2012-01-27 | 2019-07-02 | Université de Montréal | Pyrimido[4,5-B]indole derivatives and use thereof in the expansion of hematopoietic stem cells |
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Cited By (7)
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US10336747B2 (en) | 2012-01-27 | 2019-07-02 | Université de Montréal | Pyrimido[4,5-B]indole derivatives and use thereof in the expansion of hematopoietic stem cells |
JP2021525745A (ja) * | 2018-05-28 | 2021-09-27 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | 細菌感染症の処置および予防のための新規オキソキノリジン化合物 |
JP7296992B2 (ja) | 2018-05-28 | 2023-06-23 | エフ. ホフマン-ラ ロシュ アーゲー | 細菌感染症の処置および予防のための新規オキソキノリジン化合物 |
JP2022501391A (ja) * | 2018-09-26 | 2022-01-06 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | 細菌感染症の治療及び予防のための、置換ピリドインドール |
JP7443351B2 (ja) | 2018-09-26 | 2024-03-05 | エフ. ホフマン-ラ ロシュ アーゲー | 細菌感染症の治療及び予防のための、置換ピリドインドール |
JP7463369B2 (ja) | 2018-11-27 | 2024-04-08 | エフ. ホフマン-ラ ロシュ アーゲー | 細菌性感染症の処置および予防のためのアリール化合物 |
JP7465266B2 (ja) | 2018-11-27 | 2024-04-10 | エフ. ホフマン-ラ ロシュ アーゲー | 細菌感染症の治療と予防のための三環式化合物 |
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