ZA200300589B - Aminopiperidine quinolines and their azaisosteric analogues with antibacterial activity. - Google Patents
Aminopiperidine quinolines and their azaisosteric analogues with antibacterial activity. Download PDFInfo
- Publication number
- ZA200300589B ZA200300589B ZA200300589A ZA200300589A ZA200300589B ZA 200300589 B ZA200300589 B ZA 200300589B ZA 200300589 A ZA200300589 A ZA 200300589A ZA 200300589 A ZA200300589 A ZA 200300589A ZA 200300589 B ZA200300589 B ZA 200300589B
- Authority
- ZA
- South Africa
- Prior art keywords
- alkyl
- optionally substituted
- hydroxy
- alkenyl
- amino
- Prior art date
Links
- 230000000844 anti-bacterial effect Effects 0.000 title description 7
- RUAZBTOBQDHQDX-UHFFFAOYSA-N piperidin-1-amine;quinoline Chemical class NN1CCCCC1.N1=CC=CC2=CC=CC=C21 RUAZBTOBQDHQDX-UHFFFAOYSA-N 0.000 title 1
- -1 amino, piperidyl Chemical group 0.000 claims description 159
- 125000000217 alkyl group Chemical group 0.000 claims description 139
- 150000001875 compounds Chemical class 0.000 claims description 90
- 238000000034 method Methods 0.000 claims description 70
- 125000003342 alkenyl group Chemical group 0.000 claims description 64
- 229910052739 hydrogen Inorganic materials 0.000 claims description 50
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 46
- 239000001257 hydrogen Substances 0.000 claims description 43
- 230000008569 process Effects 0.000 claims description 42
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 39
- 125000003118 aryl group Chemical group 0.000 claims description 38
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 37
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 36
- 125000003545 alkoxy group Chemical group 0.000 claims description 35
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 33
- 125000005090 alkenylcarbonyl group Chemical group 0.000 claims description 32
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 claims description 31
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 31
- 125000003277 amino group Chemical group 0.000 claims description 31
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 29
- 125000005843 halogen group Chemical group 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 23
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 125000004414 alkyl thio group Chemical group 0.000 claims description 18
- 125000000623 heterocyclic group Chemical group 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
- 125000002252 acyl group Chemical group 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000001408 amides Chemical class 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000004043 oxo group Chemical group O=* 0.000 claims description 12
- 101150020251 NR13 gene Proteins 0.000 claims description 11
- 101000585507 Solanum tuberosum Cytochrome b-c1 complex subunit 7 Proteins 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 10
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 10
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 9
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- 125000004429 atom Chemical group 0.000 claims description 8
- 229910052721 tungsten Inorganic materials 0.000 claims description 8
- 229910052727 yttrium Inorganic materials 0.000 claims description 8
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 7
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- 241000124008 Mammalia Species 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 5
- 208000035143 Bacterial infection Diseases 0.000 claims description 5
- 125000004423 acyloxy group Chemical group 0.000 claims description 5
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000001414 1,2,4-triazol-5-yl group Chemical group [H]N1N=C([H])N=C1[*] 0.000 claims description 4
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 4
- 125000005035 acylthio group Chemical group 0.000 claims description 4
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000005647 linker group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 101150009274 nhr-1 gene Proteins 0.000 claims description 4
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 4
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 3
- 101100240517 Caenorhabditis elegans nhr-11 gene Proteins 0.000 claims description 3
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- NUQXCJYVBQCDGF-FQEVSTJZSA-N (1r)-2-[4-[(4,6-difluoro-1h-benzimidazol-2-yl)methylamino]piperidin-1-yl]-1-(6-methoxy-1,5-naphthyridin-4-yl)ethanol Chemical compound C1=C(F)C=C2NC(CNC3CCN(CC3)C[C@H](O)C3=CC=NC4=CC=C(N=C43)OC)=NC2=C1F NUQXCJYVBQCDGF-FQEVSTJZSA-N 0.000 claims description 2
- 108020001305 NR1 subfamily Proteins 0.000 claims description 2
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- 125000005110 aryl thio group Chemical group 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 claims description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 2
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 2
- 125000004468 heterocyclylthio group Chemical group 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000004262 quinoxalin-2-yl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N=C1* 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 3
- ZRKPXJYWEZJHOR-SANMLTNESA-N (1r)-1-(6-methoxyquinolin-4-yl)-2-[4-(quinoxalin-2-ylmethylamino)piperidin-1-yl]ethanol Chemical compound C1=CC=CC2=NC(CNC3CCN(CC3)C[C@H](O)C3=CC=NC4=CC=C(C=C43)OC)=CN=C21 ZRKPXJYWEZJHOR-SANMLTNESA-N 0.000 claims 1
- CYZKEWUMLAXNFO-QHCPKHFHSA-N 2-[[[1-[(2r)-2-hydroxy-2-(6-methoxy-1,5-naphthyridin-4-yl)ethyl]piperidin-4-yl]amino]methyl]quinolin-8-ol Chemical compound C1=CC=C(O)C2=NC(CNC3CCN(CC3)C[C@H](O)C3=CC=NC4=CC=C(N=C43)OC)=CC=C21 CYZKEWUMLAXNFO-QHCPKHFHSA-N 0.000 claims 1
- BAWSQSHGTLVGQQ-UHFFFAOYSA-N 4-[(4,7-difluoro-1h-indol-2-yl)methylamino]-n-(6-methoxy-1,5-naphthyridin-4-yl)piperidine-1-carboxamide Chemical compound C1=CC(F)=C2NC(CNC3CCN(CC3)C(=O)NC3=CC=NC4=CC=C(N=C43)OC)=CC2=C1F BAWSQSHGTLVGQQ-UHFFFAOYSA-N 0.000 claims 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 55
- 239000002253 acid Substances 0.000 description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 150000001412 amines Chemical class 0.000 description 15
- 235000019441 ethanol Nutrition 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 150000001299 aldehydes Chemical class 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- 230000009467 reduction Effects 0.000 description 11
- 238000006722 reduction reaction Methods 0.000 description 11
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 230000003647 oxidation Effects 0.000 description 7
- 238000007254 oxidation reaction Methods 0.000 description 7
- 239000003981 vehicle Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000007796 conventional method Methods 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 150000002924 oxiranes Chemical class 0.000 description 6
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 6
- 238000005804 alkylation reaction Methods 0.000 description 5
- 239000003638 chemical reducing agent Substances 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 239000012948 isocyanate Substances 0.000 description 5
- 150000002513 isocyanates Chemical class 0.000 description 5
- 229910052744 lithium Inorganic materials 0.000 description 5
- 239000012280 lithium aluminium hydride Substances 0.000 description 5
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 4
- 241000283690 Bos taurus Species 0.000 description 4
- 238000006969 Curtius rearrangement reaction Methods 0.000 description 4
- 241000282414 Homo sapiens Species 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 4
- 238000006735 epoxidation reaction Methods 0.000 description 4
- 238000005755 formation reaction Methods 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- 125000005936 piperidyl group Chemical group 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
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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 3
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- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
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- 125000001072 heteroaryl group Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
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- 238000005932 reductive alkylation reaction Methods 0.000 description 3
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 229940124530 sulfonamide Drugs 0.000 description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 3
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- LQQKDSXCDXHLLF-UHFFFAOYSA-N 1,3-dibromopropan-2-one Chemical class BrCC(=O)CBr LQQKDSXCDXHLLF-UHFFFAOYSA-N 0.000 description 2
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical group O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 2
- 150000005055 1,5-naphthyridines Chemical class 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N 1-ethenoxybutane Chemical compound CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 1H-quinazolin-4-one Chemical compound C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 description 2
- NSPLFNGUPLZYHV-UHFFFAOYSA-N 1h-1,5-naphthyridin-4-one Chemical class C1=CN=C2C(O)=CC=NC2=C1 NSPLFNGUPLZYHV-UHFFFAOYSA-N 0.000 description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 2
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- FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo(3.3.1)nonane Chemical compound C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 description 2
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- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
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- 239000000654 additive Substances 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
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- DODZTSARNRLOKY-UHFFFAOYSA-N cinnolin-4-amine Chemical class C1=CC=C2C(N)=CN=NC2=C1 DODZTSARNRLOKY-UHFFFAOYSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- PBKSAWGZZXKEBJ-UHFFFAOYSA-N cyclopenta-1,3-diene;4-cyclopenta-2,4-dien-1-ylphenol;iron(2+) Chemical compound [Fe+2].C=1C=C[CH-]C=1.C1=CC(O)=CC=C1[C-]1C=CC=C1 PBKSAWGZZXKEBJ-UHFFFAOYSA-N 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000007269 dehydrobromination reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- XXTZHYXQVWRADW-UHFFFAOYSA-N diazomethanone Chemical class [N]N=C=O XXTZHYXQVWRADW-UHFFFAOYSA-N 0.000 description 1
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003221 ear drop Substances 0.000 description 1
- 229940047652 ear drops Drugs 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
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- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- ZRSDQBKGDNPFLT-UHFFFAOYSA-N ethanol;oxolane Chemical compound CCO.C1CCOC1 ZRSDQBKGDNPFLT-UHFFFAOYSA-N 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
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- 150000002170 ethers Chemical class 0.000 description 1
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
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- 239000000945 filler Substances 0.000 description 1
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- 238000006170 formylation reaction Methods 0.000 description 1
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- 238000004108 freeze drying Methods 0.000 description 1
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- 239000008103 glucose Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
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- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
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- 235000010299 hexamethylene tetramine Nutrition 0.000 description 1
- 239000004312 hexamethylene tetramine Substances 0.000 description 1
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- JUINSXZKUKVTMD-UHFFFAOYSA-N hydrogen azide Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 description 1
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- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical group O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- AQYSYJUIMQTRMV-UHFFFAOYSA-N hypofluorous acid Chemical group FO AQYSYJUIMQTRMV-UHFFFAOYSA-N 0.000 description 1
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- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 description 1
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- PYNUOAIJIQGACY-UHFFFAOYSA-N propylazanium;chloride Chemical compound Cl.CCCN PYNUOAIJIQGACY-UHFFFAOYSA-N 0.000 description 1
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- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000004526 pyridazin-2-yl group Chemical group N1N(C=CC=C1)* 0.000 description 1
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- GPPZVGNHXBJPRM-UHFFFAOYSA-N quinolin-4-one Chemical compound C1=CC=C2C(=O)C=C=NC2=C1 GPPZVGNHXBJPRM-UHFFFAOYSA-N 0.000 description 1
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- 239000000377 silicon dioxide Substances 0.000 description 1
- VFWRGKJLLYDFBY-UHFFFAOYSA-N silver;hydrate Chemical compound O.[Ag].[Ag] VFWRGKJLLYDFBY-UHFFFAOYSA-N 0.000 description 1
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- NZBUCABTIWJWAN-UHFFFAOYSA-N tetrabromomethane;triphenylphosphane Chemical compound BrC(Br)(Br)Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NZBUCABTIWJWAN-UHFFFAOYSA-N 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
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- 230000009466 transformation Effects 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
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical class OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- AHZJKOKFZJYCLG-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+) Chemical compound [Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F AHZJKOKFZJYCLG-UHFFFAOYSA-K 0.000 description 1
- PGAJYUDRKAPMPA-UHFFFAOYSA-N trimethylsilyl n-ethylcarbamate Chemical compound CCNC(=O)O[Si](C)(C)C PGAJYUDRKAPMPA-UHFFFAOYSA-N 0.000 description 1
- VFJYIHQDILEQNR-UHFFFAOYSA-M trimethylsulfanium;iodide Chemical compound [I-].C[S+](C)C VFJYIHQDILEQNR-UHFFFAOYSA-M 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
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- 230000029663 wound healing Effects 0.000 description 1
Description
AMINOPIPERIDINE QUINOLINES AND THEIR AZAISOSTERIC ANALOGUES WITH ANTIBACTERIAL
ACTIVITY
] This invention relates to novel compounds, compositions containing them and their use as antibacterials. , 5 W099/37635, WO00/21948, W0O00/21952, WO00/25227, WO00/43383,
WO00/78748, WO01/07432 and WO01/07433 disclose piperidine and piperazine derivatives having antibacterial activity.
WO9717957 discloses piperidyl compounds which are haemoregulatory and stimulate haematopoesis. JP07179407 discloses piperidyl compounds which are useful for preventing thrombotic diseases, inhibiting tumour metastasis and accelerating wound healing.
We have now found a novel group of aminopiperidines which have antibacterial activity. :
This invention provides a compound of formula (I) or a pharmaceutically acceptable derivative thereof:
AB(CH,), — {ovo } Re Zz! 6 ” R3 1
FAN 73 | nN” ra @ wherein: one of Z1,72,73, 74 and Z5 is N, one is CR12 and the remainder are CH , OT one or two of z1,22, 73, 74 and Z5 are independently CR12 and the remainder are CH;
R1 and R12 are independently hydro gen; hydroxy; (Cj _g)alkoxy optionally substituted by (Cj.p)alkoxy, amino, piperidyl, guanidino or amidino any of which is optionally N- substituted by one or two (C1.g)alkyl, acyl or (C1.g)alkylsulphonyl groups, CONHaj, hydroxy, (C1-g)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy or (C1-g)alkylsulphonyloxy; (Cj_g)alkoxy-substituted(C1.¢)alkyl; halogen; (C1. ‘ 6)alkyl; (C1.g)alkylthio; trifluoromethyl; trifluoromethoxy; nitro; azido; acyl; acyloxy; acylthio; (Cj_g)alkylsulphonyl; (C1._g)alkylsulphoxide; arylsulphonyl; arylsulphoxide or ’ an amino, piperidyl, guanidino or amidino group optionally N-substituted by one or two (C1-g)alkyl, acyl or (Cj _g)alkylsulphonyl groups; ° provided that when Z1, 72, 73, 74 and Z5 are CR12 or CH, then R1 is not hydrogen; i R2 is hydrogen, or (Cy.4)alkyl or (C_4)alkenyl optionally substituted with 1 to 3 groups selected from: , 5 amino optionally substituted by one or two (C1-4)alkyl groups; carboxy; (Cy. 4)alkoxycarbonyl; (Cj.g)alkylcarbonyl; (C2-4)alkenyloxycarbonyl; (Cs. 4)alkenylcarbonyl; aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (C1.4)alkyl, hydroxy(Cj_g)alkyl, aminocarbonyl(C1.4)alkyl, (Cr_g)alkenyl, (C1-4)alkylsulphonyl, trifluoromethylsulphonyl, (C2-4)alkenylsulphonyl, (Cj. galkoxycarbonyl, (Cy_4)alkylcarbonyl, (C2.4)alkenyloxycarbonyl or (Co_ 4)alkenylcarbonyl; cyano; tetrazolyl; 2-oxo-oxazolidinyl optionally substituted by R10; 3- hydroxy-3-cyclobutene-1,2-dione-4-yl; 2,4-thiazolidinedione-5-yl; tetrazol-5- ylaminocarbonyl; 1,2,4-triazol-5-yl optionally substituted by R10; 5-0x0-1,2,4-oxadiazol- 3-yl; halogen; (Cj._4)alkylthio; trifluoromethyl; hydroxy optionally substituted by (Cj. galkyl, (Ca-4)alkenyl, (C1_g)alkoxycarbonyl, (C1-4)alkylcarbonyl, (Co. g)alkenyloxycarbonyl, (C3_4)alkenylcarbonyl; oxo; (C1-g)alkylsulphonyl; (Cp. 4)alkenylsulphonyl; or (C1_4)aminosulphonyl wherein the amino group is optionally substituted by (C1 .4)alkyl or (Co_g)alkenyl; R3 is hydrogen; or
R3 is in the 2-, 3- or 4-position and is: carboxy; (C1-g)alkoxycarbonyl; aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (C1.g)alkyl, hydroxy(C1_g)alkyl, aminocarbonyl(Cy g)alkyl, (Co. 6)alkenyl, (C1_g)alkylsulphonyl, trifluoromethylsulphonyl, (C2-6)alkenylsulphonyl, (C1. g)alkoxycarbonyl, (C1_g)alkylcarbonyl, (C2-6)alkenyloxycarbonyl or (Co. 6)alkenylcarbonyl and optionally further substituted by (C1-g)alkyl, hydroxy(Cy_g)alkyl, aminocarbonyl(C1 _g)alkyl or (Co_g)alkenyl; cyano; tetrazolyl; 2-oxo0-oxazolidinyl optionally substituted by R1 0. 3-hydroxy-3-cyclobutene-1,2-dione-4-yl; 2,4- thiazolidinedione-5-yl; tetrazol-5-ylaminocarbonyl; 1,2,4-triazol-5-yl optionally substituted by R10; or 5-o0x0-1,2,4-oxadiazol-3-yl; or (C1-4)alkyl or ethenyl optionally substituted with any of the substituents listed above for
R3 and/or 0 to 2 groups R12 independently selected from: ’ halogen; (C1.g)alkylthio; trifluoromethyl; (Cj .g)alkoxycarbonyl; (C1. 6)alkylcarbonyl; (Co_g)alkenyloxycarbonyl; (Co _g)alkenylcarbonyl; hydroxy optionally - 35 substituted by (C1_g)alkyl, (C2-g)alkenyl, (C1_g)alkoxycarbonyl, (C1.g)alkylcarbonyl, (C2-g)alkenyloxycarbonyl, (Cy-g)alkenylcarbonyl or aminocarbonyl wherein the amino group is optionally substituted by (Cy.g)alkyl, (Cp.¢g)alkenyl, (C1-g)alkylcarbonyl or (Cs.
6)alkenylcarbonyl; amino optionally mono- or disubstituted by (C1-g)alkoxycarbonyl, (Cy.6)alkylcarbonyl, (Co.6)alkenyloxycarbonyl, (Co_g)alkenylcarbonyl, (C1-g)alkyl, ) (Ca.g)alkenyl, (C1.g)alkylsulphonyl, (Cp_g)alkenylsulphonyl or aminocarbonyl wherein the amino group is optionally substituted by (Cj.¢)alkyl or (Co_g)alkenyl; aminocarbony! , 5 wherein the amino group is optionally substituted by (C1-g)alkyl, hydroxy(Cj.g)alkyl, aminocarbonyl(C1_g)alkyl, (Co_g)alkenyl, (Cj-6)alkoxycarbonyl, (Cj.g)alkylcarbonyl, (C2-6)alkenyloxycarbonyl or (C;_g)alkenylcarbonyl and optionally further substituted by (C1-g)alkyl, hydroxy(C1.g)alkyl, aminocarbonyl(C 1-6)alkyl or (Co_g)alkenyl; oxo; (Cq- 6)alkylsulphonyl; (C2_g)alkenylsulphonyl; or (C1.g)aminosulphonyl wherein the amino group is optionally substituted by (C1_g)alkyl or (C9.g)alkenyl; or when R3 is in the 3- position, hydroxy optionally substituted as described above; in addition when R3 is disubstituted with a hydroxy or amino containing substituent and carboxy containing substituent these may together form a cyclic ester or amide linkage, respectively;
R4isa group -U-R3 where
U is selected from CO, SO and CH» and
R? is an optionally substituted bicyclic carbocyclic or heterocyclic ring system (A): ~N x Xo N
C @
REY @ containing up to four heteroatoms in each ring in which ring (a) is aromatic or non aromatic;
X1 is C when part of an aromatic ring or CR14 when part of a non aromatic ring;
X2isN, NR13, 0, S(O)y, CO or CR14 when part of an aromatic or non-aromatic ring or may in addition be CR14R15 when part of a non aromatic ring;
X4 is N, NR13, 0, S(O), CO or CR14;
X3 and X53 are independently N or C;
Ylisa1 to 3 atom linker group each atom of which is independently selected from N, NR13, 0, S(O)y, CO and CR14 when part of an aromatic or non-aromatic ring or may additionally be CR14R15 when part of a non aromatic ring,
Y2 is a 2 or 3 atom linker group completing an aromatic ring, each atom of Y2 being independently selected from N, NR13, O, S(O), CO and CR14; each of R14 and R15 is independently selected from: H; (Cj .4)alkylthio; halo; . carboxy(Cj_4)alkyl; halo(Cj_4)alkoxy; halo(C1.g)alkyl; (C1_g)alkyl; (C2-4)alkenyl; (Cj. g)alkoxycarbonyl; formyl; (C1_g)alkylcarbonyl; (C2-4)alkenyloxycarbonyl; (Co. g)alkenylcarbonyl; (Cy_4)alkylcarbonyloxy; (C1.4)alkoxycarbonyl(C 1-4)alkyl; hydroxy; hydroxy(Ci.4)alkyl; mercapto(Cy-g)alkyl; (C1-4)alkoxy; nitro; cyano; carboxy; amino or aminocarbonyl optionally substituted as for corresponding substituents in R3; (Cy. 4)alkylsulphonyl; (Cp-4)alkenylsulphonyl; or aminosulphonyl wherein the amino group is - optionally mono- or di-substituted by (C1-4)alkyl or (C2.4)alkenyl; aryl; aryl(Cy._4)alkyl; aryl(Cy.4)alkoxy or , 5 R14 and R15 may together represent oxo; each R13 is independently H; trifluoromethyl; (C1_g)alkyl optionally substituted by hydroxy, (C1.g)alkoxy, (C1.g)alkylthio, carboxy, halo or trifluoromethyl; (Co 4)alkenyl; aryl; aryl (C1-4)alkyl; arylcarbonyl; heteroarylcarbonyl; (C1.4)alkoxycarbonyl; (C1-g)alkylcarbonyl; formyl; (C1.g)alkylsulphonyl; or aminocarbonyl wherein the amino group is optionally substituted by (C1.4)alkoxycarbonyl, (C;_g)alkylcarbonyl, (Cp. 4)alkenyloxycarbonyl, (Cp_4)alkenylcarbonyl, (C1.4)alkyl or (Cp_4)alkenyl and optionally further substituted by (C1.4)alkyl or (Co_4)alkenyl; nisOorl; each x is independently 0, 1 or 2
A isNR!L, O or CROR7 and B is NR11, O, SO or CR8RY and wherein: each of RO, R7, R8 and RY is independently selected from: hydrogen; (Cy_g)alkoxy; (Ci. alkylthio; halo; trifluoromethyl; azido; (Cj_g)alkyl; (Ca.¢)alkenyl; (C1. 6)alkoxycarbonyl; (C1.g)alkylcarbonyl; (C3.g)alkenyloxycarbonyl; (Co. 6)alkenylcarbonyl; hydroxy, amino or aminocarbonyl optionally substituted as for corresponding substituents in R3; (C1-6)alkylsulphonyl; (Co_g)alkenylsulphonyl; or aminosulphonyl wherein the amino group is optionally substituted by (Cj_g)alkyl or (Co. g)alkenyl; : or when n=1 RO and R8 together represent a bond and R7 and RY are as above defined; or R6 and R7 or R8 and RY together represent oxo; provided that: when A is NR!1, Bis not NR!11 or O; when A is CO, B is not CO, O or SO; when n is 0 and A is NR11, CR8R? can only be CO; ) when A is CROR7 and B is SOy, n is 0; when n is 0, B is not NR11 or O or R8 and R9 are not optionally substituted hydroxy or ’ 35 amino; when A is O, B is not NR11, 0, SO; or CO and n=1; and when A-B is CR7=CRS, nis 1
R10 js selected from (C1-4)alkyl; (Co_g)alkenyl and aryl any of which may be optionally . substituted by a group R12 as defined above; carboxy; aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (C1.g)alkyl, (Cp.g)alkenyl, (Cj. ; 5 eakylsulphonyl, trifluoromethylsulphonyl, (Cy.g)alkenylsulphonyl, (C1. 6)alkoxycarbonyl, (C1_g)alkylcarbonyl, (Co_g)alkenyloxycarbonyl or (Co_ 6)alkenylcarbonyl and optionally further substituted by (C1.g)alkyl or (Co_g)alkenyl; (C1-g)alkylsulphonyl; trifluoromethylsulphonyl; (C2-g)alkenylsulphonyl; (Cj. 6)alkoxycarbonyl; (C1_g)alkylcarbonyl; (Cy_g)alkenyloxycarbonyl; and (Cs. g)alkenylcarbonyl; and
RIL js hydrogen; trifluoromethyl, (C1.g)alkyl; (Co.g)alkenyl; (C1.g)alkoxycarbonyl; (C1-g)alkylcarbonyl; or aminocarbonyl wherein the amino group is optionally substituted by (Cj-g)alkoxycarbonyl, (C1.g)alkylcarbonyl, (Co_g)alkenyloxycarbonyl, (Cp. g)alkenylcarbonyl, (Cj_g)alkyl or (C_g)alkenyl and optionally further substituted by (Cy. 6)alkyl or (Co_g)alkenyl; or where one of R3 and RS, R7, R8 or RI contains a carboxy group and the other contains a hydroxy or amino group they may together form a cyclic ester or amide linkage.
This invention also provides a method of treatment of bacterial infections in mammals, particularly in man, which method comprises the administration to a mammal : in need of such treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable derivative thereof.
The invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for use in the treatment of bacterial infections in mammals.
The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.
In one aspect, when U is CHp, R3 is not a heteroaryl group. In another aspect, : when U is CHp, RS is not indolyl, quinolinyl or benzothienyl.
Preferably one of Z1, 72, Z3, 74 and Z5 is N, one is CR12 and the remainder are ) 35 CH,oroneofZl,72, 73, z4 and Z5 is CR12 and the remainder are CH.
Preferably Z is CH or N, Z3 is CH or CF and zl, Z2 and Z4 are each CH, or 71 is N, Z3 is CH or CF and Z2, Z4 and ZS are each CH.
When RI or R12 is substituted alkoxy it is preferably (Co._g)alkoxy substitituted by optionally N-substituted amino, guanidino or amidino, or (C1.g)alkoxy substituted by . piperidyl. Suitable examples of Rl and R12 alkoxy include methoxy, trifluoromethoxy, n-propyloxy, iso-butyloxy, aminoethyloxy, aminopropyloxy, aminobutyloxy, ; 5 aminopentyloxy, guanidinopropyloxy, piperidin-4-ylmethyloxy, phthalimido pentyloxy or 2-aminocarbonylprop-2-oxy.
Preferably R1 and R12 are independently methoxy, amino(C3_s)alkyloxy, guanidino(C3_s)alkyloxy, piperidyl(C3.s)alkyloxy, nitro or fluoro; R1 is more preferably methoxy, amino(C3_5)alkyloxy or guanidino(C3_5)alkyloxy. R12 is more preferably H or F. Most preferably R1 is methoxy. and R12 is H or when Z3 is CR12 it may be C-F.
When Z° is CR12, R12 js preferably hydrogen, cyano, hydroxymethyl or carboxy, most preferably hydrogen.
Preferably n is 0. :
R2 is preferably hydrogen; (C1-4)alkyl substituted with carboxy, optionally substituted hydroxy, optionally substituted aminocarbonyl, optionally substituted amino or (C1.4)alkoxycarbonyl; or (C2-gjalkenyl substituted with (C1 _.4)alkoxycarbonyl or carboxy. More preferred groups for R2 are hydrogen, carboxymethyl, hydroxyethyl, aminocarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylallyl and carboxyallyl, most preferab ly hydrogen.
Preferred examples of R3 include hydrogen; optionally substituted hydroxy; (C1. 4) alkyl; ethenyl; optionally substituted 1-hydroxy-(C1.4) alkyl; optionally substituted aminocarbonyl; carboxy(Cj_4)alkyl; optionally substituted aminocarbonyl(Cj.4)alkyl; cyano(Cj_4)alkyl; optionally substituted 2-oxo-oxazolidinyl and optionally substituted 2- oxo-oxazolidinyl(Cy_galkyl). More preferred R3 groups are hydro gen; CONHp; 1- hydroxyalkyl e.g. CHpOH, CH(OH)CH,CN; CHCOoH; CH9CONHy; -
CONHCH2CONHjy; 1,2-dihydroxyalkyl e.g. CH(OH)CH,OH; CH, CN; 2-o0xo0- oxazolidin-5-yl and 2-oxo0-oxazolidin-5-yl(Cj_4alkyl). Most preferably R3 is hydrogen.
R3 is preferably in the 3- or 4-position.
When R3 and RS, R7, R8 or RY together form a cyclic ester or amide linkage, it is preferred that the resulting ring is 5-7 membered. It is further preferred that the group A or B which does not form the ester or amide linkage is CH».
When A is CH(OH) the R-stereochemistry is preferred. ’ Preferably A is NH, NCH3, CHp, CHOH, CH(NH2), C(Me)(OH) or CH(Me).
Preferably B is CH7 or CO.
Preferably A-B is CHOH-CHj, NR11-CH, or NR11-CO.
Particularly preferred are those compounds where n=0, A is NH and B is CO, or A is CHOH and B is CHp, when more preferably A is the R-isomer of CHOH.
Preferably R11 is hydrogen or (C1-4)alkyl e.g. methyl, more preferably hydrogen.
U is most preferably CH». . Preferably R? is an aromatic heterocyclic ring (A) having 1-4 heteroatoms of which one is N or NR13, . 5 Examples of rings (A) include optionally substituted: (a) and (b) aromatic - 1H-pyrrolo[2,3-b]-pyridin-2-yl, 1H-pyrrolo[3,2-b]-pyridin-2-yl, 3H-imidazo[4,5-b}-pyrid- 2-yl, 3H-quinazolin-4-one-2-yl, benzimidazol-2-yl, benzo[1,2,3]-thiadiazol-5-yl, benzo[1,2,5]-oxadiazol-5-yl, benzofur-2-yl, benzothiazol-2-yl, benzo[b]thiophen-2-yl, benzoxazol-2-yl, chromen-4-one-3-yl, imidazo[1,2-a]pyridin-2-yl, imidazo-[1,2-a}- pyrimidin-2-yl, indol-2-yl, indol-6-yl, isoquinolin-3-yl, [1,8]}-naphthyridine-3-yl, oxazolo[4,5-b]-pyridin-2-yl, quinolin-2-yl, quinolin-3-yl, quinoxalin-2-yl, indan-2-yl, naphthalen-2-yl, 1,3-dioxo-isoindol-2yl, benzimidazol-2-yl, benzothiophen-2-yl, 1H- benzotriazol-5-yl, 1H-indol-5-yl, 3H-benzooxazol-2-one-6-yl, 3H-benzooxazol-2-thione- 6-yl, 3H-benzothiazol-2-one-5-yl, 3H-quinazolin-4-one-2-yl, 3H-quinazolin-4-one-6-yl, 4-ox0-4H-pyrido[1,2-a]pyrimidin-3-yl, benzo[1,2,3Jthiadiazol-6-yl, benzo[1,2,5]thiadiazol-5-yl, benzo[ 1,4]oxazin-2-one-3-yl, benzothiazol-5-yl, benzothiazol-6-yl, cinnolin-3-yl, imidazo[1,2-a]pyridazin-2-yl, imidazo[1,2-b]pyridazin- 2-yl, pyrazolo[1,5-a]pyrazin-2-yl, pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a}pyrimidin- 6-yl, pyrazolo[5,1-c}[1,2,4]triazin-3-yl, pyrido[1,2-a]pyrimdin-4-one-2-yl, pyrido[1,2- a]pyrimidin-4-one-3-yl, quinazolin-2-yl, quinoxalin-6-yl, thiazolo[3,2-a]pyrimidin-5-one- 7-yl, thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-b]pyridin-6-yl, thieno[3,2-b]pyridin-6-yl, 2H-isoquinolin-1-one-3-yl. (a) is non aromatic (25)-2,3-dihydro-1H-indol-2-yl, (2S)-2,3-dihydro-benzo[1,4]dioxine-2-yl, 3-(R,S)-3,4- dihydro-2H-benzo[ 1,4]thiazin-3-yl, 3-(R)-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl, and 3-substituted-3H-quinazolin-4-one-2-yl.
In one aspect, when R13 is optionally substituted (C1 _4)alkyl, the optional substituent is other than carboxy.
R13 is preferably H if in ring (a) or in addition (C1_4)alkyl such as methyl or isopropyl when in ring (b). More preferably, in ring (b) R13 is hydrogen when NR!3 is bonded to X3 and (Cj_4)alkyl when NR13 is bonded to X5.
R14 and R13 are preferably independently selected from hydrogen, halo, hydroxy, (C1-4)alkyl, (C1-4)alkoxy, trifluoromethoxy, nitro, cyano, aryl(C1.4)alkoxy and (C1. 4)alkylsulphonyl. More preferably R13 is hydrogen.
More preferably each R14 is selected from hydrogen, chloro, fluoro, hydroxy, methyl, methoxy, trifluoromethoxy, benzyloxy, nitro, cyano and methylsulphonyl. Most . preferably R14 is selected from hydrogen, hydroxy, fluorine or nitro. Preferably 0-3 groups R14 are substituents other than hydrogen. Preferably when R14 is not hydrogen, , 5 X4is CR14 and/or CR14isa component of YZ.
Most preferred groups R include 4,6-difluoro-indol-2-yl, 1H-pyrrolo[2,3-b]- pyridin-2-yl, 1H-pyrrolo[3,2-b]-pyridin-2-yl,, 8-hydroxy-quinolin-2-yl, quinoxalin-2-yI, benzimidazol-2-yl, benzo[1,2,3]-thiadiazol-5-yl, benzothiophen-2-yl, 4,6-difluoro-1H- benzimidazol-2-yl, benzothiazole-5-yl and 3-(R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin- 3-yl
When used herein, the term "alkyl" includes groups having straight and branched chains, for instance, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t- butyl, pentyl and hexyl. The term 'alkenyl’ should be interpreted accordingly.
Halo or halogen includes fluoro, chloro, bromo and iodo.
Haloalkyl moieties include 1-3 halogen atoms.
Unless otherwise defined, the term "heterocyclic" as used herein includes optionally substituted aromatic and non-aromatic, single and fused, rings suitably containing up to four hetero-atoms in each ring selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or C-substituted by, for example, up to three groups selected from (C1_4)alkylthio; halo; carboxy(Cj _4)alkyl; halo(C1_g)alkoxy; halo(C1.4)alkyl; (C1.g)alkyl; (Cp-g)alkenyl; (C1.4)alkoxycarbonyl; formyl; (Cj. 4)alkylcarbonyl; (Cy.4)alkenyloxycarbonyl; (Co_g)alkenylcarbonyl; (C1. 4)alkylcarbonyloxy; (C1-4)alkoxycarbonyl(Cy_g)alkyl; hydroxy; hydroxy(Cq.4)alkyl; mercapto(C1-4)alkyl; (C1-g)alkoxy; nitro; cyano, carboxy; amino or aminocarbonyl optionally substituted as for corresponding substituents in R3; (C}_4)alkylsulphonyl; (Co. 4)alkenylsulphonyl; or aminosulphonyl wherein the amino group is optionally substituted by (C1-4)alkyl or (Cy_g)alkenyl; optionally substituted aryl, aryl(C1_4)alkyl or aryl(Cy. 4)alkoxy and oxo groups. * Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms. A fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring. Compounds within the invention containing a heterocyclyl group may occur in two or more tautometric forms depending on the nature of the heterocyclyl group; all such tautomeric forms are included within the scope of the invention.
Where an amino group forms part of a single or fused non-aromatic heterocyclic ring as defined above suitable optional substituents in such substituted amino groups include H; trifluoromethyl; (C1.4)alkyl optionally substituted by hydroxy, (C.g)alkoxy, (C1-g)alkylthio, halo or trifluoromethyl; (Co_g)alkenyl; aryl; aryl (C1_4)alkyl; (Cy.
g)alkoxycarbonyl; (Cj.4)alkylcarbonyl; formyl; (C1-g)alkylsulphonyl; or aminocarbonyl wherein the amino group is optionally substituted by (C1-4)alkoxycarbonyl, (C1. . 4)alkylcarbonyl, (Cy_4)alkenyloxycarbonyl, (C2-g)alkenylcarbonyl, (Cj.4)alkyl or (Cy. 4)alkenyl and optionally further substituted by (C1-g)alkyl or (Cy_g)alkenyl. } 5 When used herein the term "aryl", includes optionally substituted phenyl and naphthyl.
Aryl groups may be optionally substituted with up to five, preferably up to three, groups selected from (Cj_4)alkylthio; halo; carboxy(Cq_g)alkyl; halo(C1.4)alkoxy; " halo(C}.g)alkyl; (C1-g)alkyl; (Cp-g)alkenyl: (C1-4)alkoxycarbonyl; formyl; (Cy. glalkylcarbonyl; (Cp_g)alkenyloxycarbonyl; (Ca-galkenylcarbonyl; (Cj. 4)alkylcarbonyloxy; (C1-4)alkoxycarbonyl(C1_4)alkyl; hydroxy; hydroxy(Cy.4)alkyl; mercapto(Cy.4)alkyl; (Cy-4)alkoxy; nitro; cyano; carboxy; amino or aminocarbonyl optionally substituted as for corresponding substituents in R3; (C1-4)alkylsulphonyl; (Co. 4)alkenylsulphonyl; or aminosulphonyl wherein the amino group is optionally substituted by (Cy-g)alkyl or (Cy_4)alkenyl; phenyl, phenyl(Cj_4)alkyl or phenyl(C1_4)alkoxy
The term "acyl" includes formyl and (Cj.g)alkylcarbonyl group.
Preferred compounds of formula (I) include: (R)-2-{4-[(4-fluoro-1H-benzimidazol-2-ylmethyl)-amino] -piperidin-1-y1}-1-(6- methoxyquinolin-4-yl)-ethanol; (R)-1-(6-methoxy-quinolin-4-yl) -2- {4-[(1H-pyrrolo[2,3-b]pyridine-2-ylmethyl)-amino]- piperidin-1-yl}-ethanol; 2-({1-[(R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]- piperidin-4-ylamino}-methyl)- quinolin-8-ol; (R)-2-{4-[(benzo[1,2,3]thiadiazol-5-ylmethyl)-amino] -piperidin-1-yl}-1-(6-methoxy- quinolin-4-yl)-ethanol; (R)-1-(6-methoxy-quinolin-4-yl) -2- {4- [(quinoxalin-2-ylmethyl)-amino]-piperidin-1-y1}- ethanol; 2-({1-{(R)-2-hydroxy-2-(6-methoxy-[1,5Inaphthyridin-4-y1)-ethyl]- piperidin-4-ylamino}- methyl)-quinolin-8-ol; 4-[(4,7-difluoro-1H-indol-2-ylmethyl)-amino]-piperidine-1-carboxylic acid (6-methoxy- [1,5]naphthyridin-4-y1)-amide; oo (R)-2-(4-{[(R)-1-(2,3-Dihydro-[1,4] dioxino[2,3-]pyridin-3-yl)methyl]-amino}-piperidin- 1-yD)-1-(8-fluoro-6-methoxy-quinolin-4-yl)-ethanol; (R)-2-{4-[(Benzothiazol-5-ylmethyl)-amino}-piperidin-1-y1}-1 -(6-methoxy-quinolin-4- : 35 yD-ethanol; and (R)-2-{4-[(4,6-Difluoro-1H-benzimidazol-2-ylmethyl)-amino]-piperidin-1-yl}-1 -(6- methoxy[ 1,5]naphthyridin-4-yl)-ethanol; and pharmaceutically acceptable derivatives thereof,
Some of the compounds of this invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed. This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be ) 5 produced by processes such as lyophilisation.
Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably from 10 to 59% of a compound of the formula (I) or pharmaceutically acceptable derivative thereof.
Particular compounds according to the invention include those mentioned in the examples and their pharmaceutically acceptable derivatives.
Pharmaceutically acceptable derivatives of the above-mentioned compounds of formula (I) include the free base form or their acid addition or quaternary ammonium salts, for example their salts with mineral acids e.g. hydrochloric, hydrobromic, sulphuric nitric or phosphoric acids, or organic acids, e.g. acetic, fumaric, succinic, maleic, citric, benzoic, p-toluenesulphonic, methanesulphonic, naphthalenesulphonic acid or tartaric acids. Compounds of formula (I) may also be prepared as the N-oxide. Compounds of formula (I) having a free carboxy group may also be prepared as an in vivo hydrolysable ester. The invention extends to all such derivatives.
Examples of suitable pharmaceutically acceptable in vivo hydrolysable ester- forming groups include those forming esters which break down readily in the human body to leave the parent acid or its salt. Suitable groups of this type include those of part formulae (i), (ii), (iii), (iv) and (v):
Rr? i 0 — CH-0.CO.R
RY
: —R=N< (i) —CH,—OR' (iil)
R®
Q—CO—CH—R® (iv) —- CHOCO —
RoC R 0 - < v)
R" R wherein R2 is hydrogen, (C1.¢) alkyl, (C3.7) cycloalkyl, methyl, or phenyl, Rb is (C1-6) alkyl, (Cy.6) alkoxy, phenyl, benzyl, (C3.7) cycloalkyl, (C3.7) cycloalkyloxy, (C1-6) alkyl (C37) cycloalkyl, 1-amino (Cj_g) alkyl, or 1-(C1.6 alkyl)amino (C1.g) alkyl; or R2 and Rb together form a 1,2-phenylene group optionally substituted by one or two methoxy groups; RC represents (Cg) alkylene optionally substituted with a methyl or ethyl group and Rd and R® independently represent (C1.¢) alkyl; Rf represents (Cq.6) alkyl; R8 represents hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (C1.¢) alkyl, or (C1.g) alkoxy; Q is oxygen or NH; Rb is hydrogen or (C1_g) alkyl; Ri is hydrogen, (C1-6) alkyl optionally substituted by halogen, (Cy-6) alkenyl, (C1.¢g) alkoxycarbonyl, aryl or heteroaryl; or Rh and Ri together form (C1-¢) alkylene; Ri represents hydrogen, (Cj .¢) alkyl or (C1_g) alkoxycarbonyl; and RK represents (C1.g) alkyl, (Cj_g) alkoxy, (Cj.¢) alkoxy(C1_g)alkoxy or aryl.
Examples cf suitable in vivo hydrolysable ester groups include, for example, acyloxy(C1.6)alkyl groups such as acetoxymethyl, pivaloyloxymethyl, o-acetoxyethyl, - o-pivaloyloxyethyl, 1-(cyclohexylcarbonyloxy)prop-1-yl, and (1-aminoethyl)carbonyloxymethyl; (C1_g)alkoxycarbonyloxy(C1-g)alkyl groups, such as ethoxycarbonyloxymethyl, o-ethoxycarbonyloxyethyl and propoxycarbonyloxyethyl; di(C1.g)alkylamino(C1_g)alkyl especially di(C1_4)alkylamino(Cj_4)alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethy! or diethylaminoethyl; 2-((Cq-g)alkoxycarbonyl)-2-(Cs.g)alkenyl groups such as . 2-(isobutoxycarbonyl)pent-2-enyl and 2-(ethoxycarbonyl)but-2-enyl; lactone groups such as phthalidyl and dimethoxyphthalidyl. . 5 A further suitable pharmaceutically acceptable in vivo hydrolysable ester-forming group is that of the formula:
CH, R" hd
O wherein RK is hydrogen, C1.¢ alkyl or phenyl.
R is preferably hydrogen.
Compounds of formula (I) may also be prepared as the corresponding N-oxides.
Certain of the compounds of formula (I) may exist in the form of optical isomers, e.g. diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures. The invention includes all such forms, in particular the pure isomeric forms. For example the invention includes compound in which an A-B group CH(OH)-CHj, is in either isomeric configuration, the R-isomer is preferred. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
In a further aspect of the invention there is provided a process for preparing compounds of formula (I), and pharmaceutically acceptable derivatives thereof, which process comprises: reacting a compound of formula (IV) with a compound of formula (V):
X rR z" 1 ~~ 7 oF | Z | y —{(CH,);—N a
FAN " a 2 Q?
Z N : rR : Iv) WV) : wherein n is as defined in formula (I); Z1', 72', z3', z4', Z5', Rl" and R3' are 71, 72, 73,
Z4,75, R1 and R3 as defined in formula (I) or groups convertible thereto;
QlisNR2R4 or a group convertible thereto wherein R2' and R4' are R2 and R4 as defined in formula (I) or groups convertible thereto and Q2 is H or R3' or Q1 and Q2 . together form an optionally protected oxo group; and X and Y may be the following combinations: . 5 (4) Xis A-COW,Y isHand nis 0; (ii) XisCRO6=CR8RY, YisHandnisO; (iii) Xs oxirane, YisH and nis 0; (ivy XisN=C=OandYisHandnisO; (v) oneofXandY is CORY and the other is CHyCO9RX; (vi) Xis CHROR7 and Y is C(=O)RY; (vii) Xis CR7=PRZ3 and Y is C(=O)R9 and n=1; (viii) Xis C(=O)R7 and Y is CR9=PRZ3 and n=l; (ix) Yis COW and X is NHR11', NCO or NR11'COW and n=0 or 1 or when n=1 X is COW and Y is NHR1!' NCO or NR11'COW; (x) XisC(O=)RS and Yis NHR1! or X is NHR!!' and Y is C(=O)RS and n=1; (xi) XisNHRI!'and Y is CR8ROW and n=1; (xii) Xis CROR7W and Y is NHR!!' or OH and n=1; (xiii) X is CROSR7SO,W and Y is H and n=0; (xiv) Xis Wor OH and Y is CH2OH and n=1; (xv) XisNHRI!!' andY is SOoW or X is NR11'SO,W and Y is H, and n=0; (xvi) Xis NR11'COCH,W or NR11'SO,CHoW and Y is H and n=0; (xvii) Xis W and Y is CONHR11', in which W is a leaving group, e.g. halo or imidazolyl; RX and RY are (C1-g)alkyl; RZ is arylor (Cy.g)alkyl; A' and NR11' are A and NR!! as defined in formula (, or groups convertible thereto; and oxirane is:
RS [®) R®
SAL wherein RO, R8 and R? are as defined in formula D; and thereafter optionally or as necessary converting Ql and Q2 to NR2'R4, converting A’, 21,72, 73,74, 25, RV, R?, R3, R¥ and NR11' 10 A, 71, 72, 73, 74, 75, R1, R2, R3,
R4 and NR11 converting A-B to other A-B, interconverting Rl, R2, R3 and/or R4, \ and/or forming a pharmaceutically acceptable derivative thereof.
Process variant (i) initially produces compounds of formula (I) wherein A-B is A*-
CO.
Process variant (ii) initially produces compounds of formula (I) wherein A-B is
CHRO-CRER. . Process variant (iii) initially produces compounds of formula (I) wherein A-B is
CRO(OH)-CRERS. . 5 Process variant (iv) initially produces compounds of formula (I) where A-B is
NH-CO. :
Process variant (v) initially produces compounds of formula (I) wherein A-B is
CO-CHj or CH2-CO.
Process variant (vi) initially produces compounds of formula (I) wherein A-B is
CROR7-CROOH.
Process variant (vii) and (viii) initially produce compounds of formula (I) wherein
A-Bis CR7=CRS.
Process variant (ix) initially produces compounds of formula (I) where A-B is CO-
NR!1 or NR11-CO.
Process variant (x) initially produces compounds of formula (I) wherein A-B is
CHRO- NR!1 or NR11.CHRS.
Process variant (xi) initially produces compounds of formula (I) wherein A-B is
NRII'.CRERY.
Process variant (xii) initially produces compounds of formula (I) wherein A-B is
CROR7-NRI!' or CROR7-O.
Process variant (xiii) initially produces compounds of formula (I) where A-B is
CROR7-S0;.
Process variant (xiv) initially produces compounds of formula (I) wherein A-B is
O-CHj.
Process variant (xv) initially produces compounds where AB is NR1 150,.
Process variant (xvi) initially produces compounds of formula (I) where A-B is
NRI1.CO or NR11'-S0O and n=1.
Process variant (xvii) initially produces compounds of formula (I) where A-B is
NR!1-co.
In process variants (i) and (ix) the reaction is a standard amide or urea formation reaction involving e.g.: 1. Activation of a carboxylic acid (e.g. to an acid chloride, mixed anhydride, active ester,
O-acyl-isourea or other species), and treatment with an amine (Ogliaruso, M.A.; Wolfe,
J.F. in The Chemistry of Functional Groups (Ed. Patai, S.) Suppl. B: The Chemistry of ) 35 Acid Derivatives, Pt. 1 (John Wiley and Sons, 1979), pp 442-8; Beckwith, A.L.J. in The
Chemistry of Functional Groups (Ed. Patai, S.) Suppl. B: The Chemistry of Amides (Ed.
Zabricky, J.) John Wiley and Sons, 1970), p 73 ff. The acid and amide are preferably reacted in the presence of an activating agent such as 1-(dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDC) or 1-hydroxybenzotriazole (HOBT) or O-(7- . azabenzotriazol-1-yl)-N, N,N’, N'-tetramethyluronium hexafluorophosphate (HATU); or 2. The specific methods of: . 5 a. in situ conversion of an acid into the amine component by a modified Curtius reaction procedure (Shioiri, T., Murata, M., Hamada, Y., Chem. Pharm. Bull. 1987, 35, 2698) b. in situ conversion of the acid component into the acid chloride under neutral conditions (Villeneuve, G. B.; Chan, T. H., Tetrahedron. Lett. 1997, 38, 6489).
A' may be, for example. protected hydroxymethylene.
The process variant (ii) is a standard addition reaction using methods well known to those skilled in the art. The process is preferably carried out in a polar organic solvent e.g. acetonitrile in the presence of an organic base e.g. triethylamine.
In process variant (iii) the coupling may be effected in acetonitrile at room temperature in the presence of one equivalent of lithium perchlorate as catalyst (general method of J.E. Chateauneuf et al, J. Org. Chem., 56, 5939-5942, 1991) or more preferably with ytterbium triflate in dichloromethane. In some cases an elevated - temperature such as 40 — 70 °C may be beneficial. Alternatively, the piperidine may be treated with a base, such as one equivalent of butyl lithium, and the resulting salt reacted with the oxirane in an inert solvent such as tetrahydrofuran, preferably at an elevated temperature such as 80°C. Use of a chiral epoxide will afford single diastereomers.
Alternatively, mixtures of diastereomers may be separated by preparative HPLC or by conventional resolution through crystallisation of salts formed from chiral acids.
The process variant (iv) is a standard urea formation reaction from the reaction of an isocyanate with an amine and is conducted by methods well known to those skilled in the art (for example see March, J; Advanced Organic Chemistry, Edition 3 (John Wiley and Sons, 1985), p802-3). The process is preferably carried out in a polar solvent such as
N,N-dimethylformamide. )
In process variant (v) the process is two step: firstly a condensation using a base, preferably sodium hydride or alkoxide, sodamide, alkyl lithium or lithium dialkylamide, preferably in an aprotic solvent e.g. ether, THF or benzene; secondly, hydrolysis using an inorganic acid, preferably HCI in aqueous organic solvent at 0-100°C. Analogous routes are described in DE330945, EP31753, EP53964 and H. Sargent, J. Am. Chem. Soc. 68, 2688-2692 (1946). Similar Claisen methodology is described in Soszko et. al.,
Pr.Kom.Mat. Przyr.Poznan.Tow.Przyj.Nauk., (1962), 10, 15. ’ 35 In process variant (vi) the reaction is carried out in the presence of a base, preferably organometallic or metal hydride e.g. NaH, lithium diisopropylamide or NaOEt,
preferably in an aprotic solvent, preferably THF, ether or benzene at -78 to 25°C (analogous process in Gutswiller et al. (1978) J. Am. Chem. Soc. 100, 576). . In process variants (vii) and (viii) if a base is used it is preferably NaH, KH, an alkyl lithium e.g. BuLi, a metal alkoxide e.g. NaOEt, sodamide or lithium dialkylamide . 5 e.g.di- isopropylamide. An analogous method is described in US 3989691 and M.Gates et. al. (1970) J. Amer.Chem.Soc., 92, 205, as well as Taylor et al. (1972) JACS 94, 6218.
In process variant (x) where X or Y is CHO the reaction is a standard reductive alkylation using, e.g., sodium borohydride or sodium triacetoxyborohydride (Gribble, G.
W. in Encyclopedia of Reagents for Organic Synthesis (Ed. Paquette, L. A.) (John Wiley and Sons, 1995), p 4649).
The process variants (xi) and (xii) are standard alkylation reactions well known to those skilled in the art, for example where an alcohol or amine is treated with an alkyl halide in the presence of a base (for example see March, J; Advanced Organic Chemistry,
Edition 3 (John Wiley and Sons, 1985), p364-366 and p342-343). The process is preferably carried out in a polar solvent such as N,N-dimethylformamide
In process variant (xiii) the reaction is a standard sulphonamide formation reaction well known to those skilled in the art. This may be e.g. the reaction of a sulphonyl halide with an amine.
In process variant (xiv) where X is W such as halogen, methanesulphonyloxy or trifluoromethanesulphonyloxy, the hydroxy group in Y is preferably converted to an OM group where M is an alkali metal by treatment of an alcohol with a base. The base is preferably inorganic such as NaH, lithium diisopropylamide or sodium. Where X is OH, the hydroxy group in Y is activated under Mitsunobu conditions (Fletcher et.al. J Chem
Soc. (1995), 623). Alternatively the X=0 and Y=CH7OH groups can be reacted directly by activation with dichlorocarbodiimide (DCC) (Chem. Berichte 1962, 95, 2997 or
Angewante Chemie 1963 75, 377).
In process variant (xv) the reaction is conducted in the presence of an organic base such as triethylamine or pyridine such as described by Fuhrman et.al., J. Amer.
Chem. Soc.; 67, 1245, 1945. The X=NR11'SO,W or Y=SO,W intermediates can be formed from the requisite amine e.g. by reaction with SO,Cl, analogously to the procedure described by the same authors Fuhrman et.al., J. Amer. Chem. Soc.; 67, 1245, 1945.
In process variant (xvi) the reaction is an alkylation, examples of which are described in J. Med. chem. (1979) 22(10) 1171-6. The compound of formula (IV) may be prepared from the corresponding compound where X is NHR11' by acylation with an appropriate derivative of the acid WCH)COOH such as the acid chloride or sulphonation with an appropriate derivative of the sulphonic acid WCH»SO3H such as the sulphonyl chloride. . In process variant (xvii) the leaving group W is preferably chloro or trifluoromethylsulphonyl and the reaction is the palladium catalysed process known as the ) 5 "Buchwald" reaction (J. Yin and S. L. Buchwald, Org.Lett., 2000, 2, 1101).
Reduction of a carbonyl group A or B to CHOH can be readily accomplished using reducing agents well known to those skilled in the art, e.g. sodium borohydride in aqueous ethanol or lithium aluminium hydride in ethereal solution. This is analogous to methods described in EP53964, US384556 and J. Gutzwiller ef al, J. Amer. Chem. Soc., 1978, 100, 576.
The carbonyl group A or B may be reduced to CH» by treatment with a reducing agent such as hydrazine in ethylene glycol, at e.g. 130-160°C, in the presence of potassium hydroxide.
Reaction of a carbonyl group A or B with an organometallic reagent yields a group where R8 is OH and RY is alkyl.
A hydroxy group on A or B may be oxidised to a carbonyl group by oxidants well known to those skilled in the art, for example, manganese dioxide, pyridinium chlorochromate or pyridinium dichromate.
A hydroxyalkyl A-B group CHR’CR90H or CR7(OH)CHR? may be dehydrated to give the group CR7=CR? by treatment with an acid anhydride such as acetic anhydride.
Methods for conversion of CR7=CR? by reduction to CHR7CHRS are well known to those skilled in the art, for example using hydrogenation over palladium on carbon as catalyst. Methods for conversion of CR7=CRY to give the A-B group
CR7(OH)CHR? or CHR7CRIOH are well known to those skilled in the art for example by epoxidation and subsequent reduction by metal hydrides, hydration, hydroboration or oxymercuration.
An amide carbonyl group may be reduced to the corresponding amine using a reducing agent such as lithium aluminium hydride.
A hydroxy group in A or B may be converted to azido by activation and displacement e.g. under Mitsunobu conditions using hydrazoic acid or by treatment with diphenylphosphorylazide and base, and the azido group in turn may be reduced to amino by hydrogenation.
An example of a group Q! convertible to NR2 R4 is NR2'R4' or halogen. Halogen may be displaced by an amine HNR2'R4' by a conventional alkylation. ) 35 When Ql Q2 together form a protected oxo group this may be an acetal such as ethylenedioxy which can subsequently be removed by acid treatment to give a compound of formula (VI):
AB(CH,), — y= 2] 3 . R} Z' XS 8 3 ry
VAS 73 N* WD) wherein the variables are as described for formula (I)
Intermediates of formula (VI) are novel and as such form part of the invention.
The ketone of formula (VI) is reacted with an amine HNRZ'R4' by conventional reductive alkylation as described above for process variant (x).
Examples of groups Z1', 72', 23’, 74, Z5' convertible to Z1, 72, 73, 74 and Z5 include CR12 where R12' is a group convertible to Rla, zl 72 73 74 and Z5' are preferably Z1, 72, 73, 74 and Z5.
R12 R1' and R2 are preferably R13 R1 and R2. R1'is preferably methoxy. R2' is preferably hydrogen. R3'is R3 or more preferably hydrogen, vinyl, alkoxycarbonyl or carboxy. R# is R4 or more preferably H or an N-protecting group such as t- butoxycarbonyl, benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl.
Conversions of Rl, RZ R3' and R4' and interconversions of R1 ,R2,R3 and R4 are conventional. In compounds which contain an optionally protected hydroxy group, suitable conventional hydroxy protecting groups which may be removed without disrupting the remainder of the molecule include acyl and alkylsilyl groups. N-protecting groups are removed by conventional methods.
For example RY’ methoxy is convertible to R1' hydroxy by treatment with lithium and diphenylphosphine (general method described in Ireland et al, J. Amer. Chem. Soc., 1973, 7829) or HBr. Alkylation of the hydroxy group with a suitable alkyl derivative bearing a leaving group such as halide and a protected amino, piperidyl, amidino or guanidino group or group convertible thereto, yields, after conversion/deprotection, R1 alkoxy substituted by optionally N-substituted amino, piperidyl, guanidino or amidino.
R3 alkenyl is convertible to hydroxyalkyl by hydroboration using a suitable reagent such as 9-borabicyclo[3.3.1]nonane, epoxidation and reduction or oXymercuration.
R3 1,2-dihydroxyalkyl can be prepared from R3' alkenyl using osmium tetroxide or other reagents well known to those skilled in the art (see Advanced Organic Chemistry,
Ed. March, J., John Wiley and Sons, 1985, p 732-737 and refs. cited therein) or . 30 epoxidation followed by hydrolysis (see Advanced Organic Chemistry, Ed. March, J.
John Wiley and Sons, 1985, p 332,333 and refs. cited therein).
R3 vinyl can be chain extended by standard homologation, e.g. by conversion to hydroxyethyl followed by oxidation to the aldehyde, which is then subjected to a Wittig - reaction.
Opening an epoxide-containing R3' group with cyanide anion yields a CH(OH)- : 5 CH)CN group.
Opening an epoxide-containing R3' group with azide anion yields an a-hydroxy azide derivative which can be reduced to the a-hydroxy amine. Conversion of the o- hydroxy amine toa carbamate is followed by ring closure with base to give the 2-oxo- oxazolidinyl containing R3 group.
Substituted 2-oxo0-oxazolidinyl containing R3 groups may be prepared from the corresponding aldehyde by conventional reaction with a glycine anion equivalent, followed by cyclisation of the resulting amino alcohol (M. Grauert et al, Ann. Chem., 1985, 1817; Rozenberg et al, Angew. Chem. Int. Ed. Engl., 1994, 33(1), 91). The resulting 2-oxo-oxazolidinyl group contains a carboxy group which can be converted to other R10 groups by standard procedures.
Carboxy groups within R3 may be prepared by Jones' oxidation of the corresponding alcohols CH7OH using chromium acid and sulphuric acid in water/methanol (E.R.H. Jones et al, J. Chem. Soc., 1946, 39). Other oxidising agents may be used for this transformation such as sodium periodate catalysed by ruthenium trichloride (G.F. Tutwiler et al, J. Med. Chem., 1987, 30(6), 1094), chromium trioxide- pyridine (G. Just et al, Synth. Commun., 1979, 9(7), 613), potassium permanganate (D.E.
Reedich et al, J. Org. Chem.,1985, 50(19), 3535), and pyridinium chlorochromate (D.
Askin et al, Tetrahedron Lett., 1988, 29(3), 277).
The carboxy group may alternatively be formed in a two stage process, with an initial oxidation of the alcohol to the corresponding aldehyde using for instance dimethyl sulphoxide activated with oxalyl chloride (N.Cohen ef al, J. Am. Chem. Soc., 1983, 105, 3661) or dicyclohexylcarbodiimide (R.M.Wengler, Angew. Chim. Int. Ed. Eng., 1985, 24(2), 77), or oxidation with tetrapropylammonium perruthenate (Ley et al, J. Chem.Soc.
Chem Commun.,1987, 1625). The aldehyde may then be separately oxidised to the corresponding acid using oxidising agents such as silver (I) oxide (R.Grigg et al, J.
Chem. Soc. Perkin1,1983, 1929), potassium permanganate (A.Zurcher, Helv. Chim. } Acta., 1987, 70 (7), 1937), sodium periodate catalysed by ruthenium trichloride (T.Sakata et al, Bull. Chem. Soc. Jpn., 1988, 61(6), 2025), pyridinium chlorochromate (R.S.Reddy et al, Synth. Commun., 1988, 18(51), 545) or chromium trioxide (R.M.Coates et al, J.
Am. Chem. Soc.,1982, 104, 2198).
An R3 CO9H group may also be prepared from oxidative cleavage of the corresponding diol, CH(OH)CH,OH, using sodium periodate catalysed by ruthenium trichloride with an acetontrile-carbontetrachloride-water solvent system (V.S.Martin et al,
Tetrahedron Letters, 1988, 29(22), 2701).
Other routes to the synthesis of carboxy groups within R3 are well known to those skilled in the art.
R3 groups containing a cyano or carboxy group may be prepared by conversion of an alcohol to a suitable leaving group such as the corresponding tosylate by reaction with para-toluenesulphonyl chloride (M.R. Bell, J. Med. Chem.,1970, 13, 389), or the iodide using triphenylphosphine, iodine, and imidazole (G. Lange, Synth. Commun., 1990, 20, 1473). The second stage is the displacement of the leaving group with cyanide anion (L.A. Paquette et al, J. Org. Chem.,1979, 44(25), 4603; P.A. Grieco et al, J. Org. Chem., 1988, 53(16), 3658. Finally acidic hydrolysis of the nitrile group gives the desired acids (H.Rosemeyer et al, Heterocycles, 1985, 23 (10), 2669). The hydrolysis may also be carried out with base e.g. potassium hydroxide (H.Rapoport; J. Org. Chem.,1958, 23, 248) or enzymatically (T. Beard et al, Tetrahedron Asymmetry, 1993, 4 (6), 1085).
Other functional groups in R3 may be obtained by conventional conversions of carboxy or cyano groups.
Tetrazoles are conveniently prepared by reaction of sodium azide with the cyano group (e.g. F. Thomas ef al, Bioorg. Med. Chem. Lett., 1996, 6(6), 631; K. Kubo et al, J.
Med. Chem., 1993, 36, 2182) or by reaction of azidotri-n-butyl stannane with the cyano group followed by acidic hydrolysis (P.L. Omstein, J. Org. Chem., 1994, 59, 7682 and J.
Med. Chem, 1996, 39 (11), 2219).
The 3-hydroxy-3-cyclobutene-1,2-dion-4-yl group (e.g. R.M. Soll, Bioorg. Med.
Chem. Lett., 1993, 3(4), 757 and W.A. Kinney, J. Med. Chem., 1992, 35(25), 4720) can be prepared by the following sequence:- (1) a compound where R3 is (CH7),CHO (n= 0,1,2) is treated with triethylamine, carbon tetrabromide-triphenylphosphine to give initially (CH2),CH=CHBr; (2) dehydrobromination of this intermediate to give the corresponding bromoethyne derivative (CH), C=CBr (for this 2 stage sequence see D.
Grandjean et al, Tetrahedron Lett., 1994, 35(21), 3529); (3) palladium-catalysed coupling of the bromoethyne with 4-(1-methylethoxy)-3-(tri-n-butylstannyl)cyclobut-3-ene-1,2- dione (Liebeskind et al, J. Org. Chem., 1990, 55, 5359); (4) reduction of the ethyne moiety to -CHpCH»- under standard conditions of hydrogen and palladium on charcoal catalysis(see Howard et al, Tetrahedron, 1980, 36, 171); and finally (4) acidic hydrolysis of the methyl ethoxyester to generate the corresponding 3-hydroxy-3-cyclobutene-1,2- dione group (R-M. Soll, Bioorg. Med. Chem. Lett., 1993, 3(4), 757).
The tetrazol-5-ylaminocarbonyl group may be prepared from the corresponding carboxylic acid and 2-aminotetrazole by dehydration with standard peptide coupling agents such as 1,1'-carbonyldiimidazole (P.L. Ornstein ef al, J. Med Chem, 1996, 39(11),
The alkyl- and alkenyl-sulphonylcarboxamides are similarly prepared from the corresponding carboxylic acid and the alkyl- or alkenyl-sulphonamide by dehydration : 5 with standard peptide coupling agents such as 1,1'-carbonyldiimidazole (P.L. Ornstein et al, J. Med. Chem., 1996, 39(11), 2232).
The hydroxamic acid groups are prepared from the corresponding acids by standard amide coupling reactions e.g. N.R. Patel et al, Tetrahedron, 1987, 43(22), 5375. 2,4-Thiazolidinedione groups may prepared from the aldehydes by condensation with 2,4-thiazolidinedione and subsequent removal of the olefinic double bond by hydrogenation.
The preparation of 5-oxo-1,2,4-oxadiazoles from nitriles is decribed by Y. Kohara et al, Bioorg. Med. Chem. Lett., 1995, 5(17), 1903. : 1,2,4-Triazol-5-yl groups may be prepared from the corresponding nitrile by reaction with an alcohol under acid conditions followed by reaction with hydrazine and then an R10-substituted activated carboxylic acid (see J.B. Polya in "Comprehensive
Heterocyclic Chemistry" Edition 1, p762, Ed AR. Katritzky and C.W. Rees, Pergamon
Press, Oxford, 1984 and 1.J. Ares et al, J. Heterocyclic Chem., 1991, 28(5), 1197).
Other substituents on R3 alkyl! or alkenyl may be interconverted by conventional methods, for example hydroxy may be derivatised by esterification, acylation or etherification. Hydroxy groups may be converted to halogen, thiol, alkylthio, azido, alkylcarbonyl, amino, aminocarbonyl, oxo, alkylsulphonyl, alkenylsulphonyl or aminosulphonyl by conversion to a leaving group and substitution by the required group or oxidation as appropriate or reaction with an activated acid, isocyanate or alkoxyisocyanate. Primary and secondary hydroxy groups can be oxidised to an aldehyde or ketone respectively and alkylated with a suitable agent such as an organometallic reagent to give a secondary or tertiary alcohol as appropriate. A carboxylate group may be converted to a hydroxymethyl group by reduction of an ester of this acid with a suitable reducing agent such as LiAlH4.
An NH) substituent on piperidine is converted to NR2R#4 by conventional means such as amide or sulphonamide formation with an acyl derivative RSCOW or R7SO,W, for compounds where U is CO or SO3 or, where U is CHp, alkylation with an alkyl halide
RICHj-halide in the presence of base, acylation/reduction with an acyl derivative
RICOW or reductive alkylation with an aldehyde RSCHO.
Where one of R3 and RS, R7, R8 or RY contains 2 carboxy group and the other contains a hydroxy or amino group they may together form a cyclic ester or amide linkage. This linkage may form spontaneously during coupling of the compound of formula (IV) and the piperidine moiety or in the presence of standard peptide coupling agents. . It will be appreciated that under certain circumstances interconvertions may interfere, for example, A or B hydroxy groups in A or B and the piperidine substituent
NH will require protection e.g. as a carboxy- or silyl-ester group for hydroxy and as an acyl derivative for piperidine NHj, during conversion of Rl’, RZ’, R3' or R#, or during the coupling of the compounds of formulae (IV) and (V).
Compounds of formulae (IV) and (V) are known compounds, (see for example
Smith et al, J. Amer. Chem. Soc., 1946, 68, 1301) or prepared analogously.
Compounds of formula (IV) where X is CROR7S0,W may be prepared by a route analogous to that of Ahmed El Hadri et al, J. Heterocyclic Chem., 1993, 30(3), 631. Thus compounds of formula (IV) where X is CH2SO2OH may be prepared by reacting the corresponding 4-methyl compound with N-bromosuccinimide, followed by treatment with sodium sulfite. The leaving group W may be converted to another leaving group W, e.g. a halogen group, by conventional methods.
The isocyanate of formula (IV) may be prepared conventionally from a 4-amino derivative such as 4-amino-quinoline, and phosgene, or phosgene equivalent (eg triphosgene) or it may be prepared more conveniently from a 4-carboxylic acid by a "one- pot" Curtius Reaction with diphenyl phosphoryl azide (DPPA) [see T. Shiori et al. Chem.
Pharm. Bull. 35, 2698-2704 (1987)].
The 4-amino derivatives are commercially available or may be prepared by conventional procedures from a corresponding 4-chloro or 4-trifluoromethanesulphonate derivative by treatment with ammonia (O.G. Backeberg et. al., J. Chem Soc., 381, 1942) or propylamine hydrochloride (R. Radinov et. al., Synthesis, 886, 1986). 4-Alkenyl compounds of formula (IV) may be prepared by conventional procedures from a corresponding 4-halogeno-derivative by e.g. a Heck synthesis as described in e.g. Organic Reactions, 1982, 27, 345. 4-Halogeno derivatives of compounds of formula (IV) are commercially available, or may be prepared by methods known to those skilled in the art. A 4-chloroquinoline is prepared from the corresponding quinolin-4-one by reaction with phosphorus oxychloride (POCIs) or phosphorus pentachloride, PCls. A 4-chloroquinazoline is prepared from the corresponding quinazolin-4-one by reaction with phosphorus oxychloride (POCl3) or phosphorus pentachloride, PCls. A quinazolinone and quinazolines may be prepared by standard routes as described by T.A. Williamson in Heterocyclic Compounds, 6, 324 (1957) Ed. R.C. Elderfield.
Activated carboxy derivatives X=A'COW of formula (IV) may be prepared from
X=A'CO9H derivatives in turn prepared from CO2H derivatives by conventional methods . such as homologation. 4-Carboxy derivatives of compounds of formula (IV) are commercially available . 5 or may be prepared by conventional procedures for preparation of carboxy heteroaromatics well known to those skilled in the art. For example, quinazolines may be prepared by standard routes as described by T.A. Williamson in Heterocyclic
Compounds, 6, 324 (1957) Ed. R.C. Elderfield. These 4-carboxy derivatives may be activated by conventional means, e.g. by conversion to an acyl halide or anhydride.
Pyridazines may be prepared by routes analogous to those described in
Comprehensive Heterocyclic Chemistry, Volume 3, Ed A.J. Boulton and A. McKillop and napthyridines may be prepared by routes analogous to those described in
Comprehensive Heterocyclic Chemistry, Volume 2, Ed A.J. Boulton and A. McKillop.
A 4-oxirane derivative of compounds of formula (IV) is conveniently prepared from the 4-carboxylic acid by first conversion to the acid chloride with oxalyl chloride and then reaction with trimethylsilyldiazomethane to give the diazoketone derivative.
Subsequent reaction with SM hydrochloric acid gives the chloromethylketone. Reduction with sodium borohydride in aqueous methanol gives the chlorohydrin which undergoes ring closure to afford the epoxide on treatment with base, e.g. potassium hydroxide in ethanol-tetrahydrofuran.
Alternatively and preferably, 4-oxirane derivatives can be prepared from bromomethyl ketones which can be obtained from 4-hydroxy compounds by other routes well known to those skilled in the art. For example, hydroxy compounds can be converted to the corresponding 4-trifluoromethanesulphonates by reaction with trifluoromethanesulphonic anhydride under standard conditions (see K. Ritter, Synthesis, 1993, 735). Conversion into the corresponding butyloxyvinyl ethers can be achieved by a
Heck reaction with butyl vinyl ether under palladium catalysis according to the procedure of W. Cabri et al, J. Org. Chem, 1992, 57 (5), 1481. (Alternatively, the same intermediates can be attained by Stille coupling of the trifluoromethanesulphonates or the analaogous chloro derivatives with (1-ethoxyvinyl)tributyl tin, T. R. Kelly, J. Org. Chem., 1996, 61, 4623.) The alkyloxyvinyl ethers are then converted into the corresponding bromomethylketones by treatment with N-bromosuccinimide in aqueous tetrahydrofuran in a similar manner to the procedures of J. F. W. Keana, J. Org. Chem., 1983, 48, 3621 and T. R. Kelly, J. Org. Chem., 1996, 61, 4623.
The 4-hydroxyderivatives can be prepared from an aminoaromatic by reaction with methylpropiolate and subsequent cyclisation, analogous to the method described in
N. E. Heindel et al, J. Het. Chem., 1969, 6, 77. For example, 5-amino-2-methoxy pyridine can be converted to 4-hydroxy-6-methoxy-[1,5]naphthyridine using this method. : If a chiral reducing agent such as (+) or (-)-B-chlorodiisopinocamphenylborane [DIP-chloride"] is substituted for sodium borohydride, the prochiral chloromethylketone . 5 is converted into the chiral chlorohydrin with ee values generally 85-95% [see C. Bolm et al, Chem. Ber. 125, 1169-1190, (1992)]. Recrystallisation of the chiral epoxide gives material in the mother liquor with enhanced optical purity (typically ee 95%).
The (R)-epoxide, when reacted with a piperidine derivative gives ethanolamine compounds as single diastereomers with (R)-stereochemistry at the benzylic position.
Alternatively, the epoxide may be prepared from the 4-carboxaldehyde by a Wittig approach using trimethylsulfonium iodide [see G.A. Epling and K-Y Lin, J. Het. Chem., 1987, 24, 853-857], or by epoxidation of a 4-vinyl derivative. 4-Hydroxy-1,5-naphthyridines can be prepared from 3-aminopyridine derivatives by reaction with diethyl ethoxymethylene malonate to produce the 4-hydroxy-3- carboxylic acid ester derivative with subsequent hydrolysis to the acid, followed by thermal decarboxylation in quinoline (as for example described for 4-Hydroxy- [1,5]naphthyridine-3-carboxylic acid, J. T. Adams et al., J. Amer.Chem.Soc., 1946, 68, 1317). A 4-hydroxy-[1,5]naphthyridine can be converted to the 4-chloro derivative by heating in phosphorus oxychloride, or to the 4-methanesulphonyloxy or 4- trifluoromethanesulphonyloxy derivative by reaction with methanesulphonyl chloride or. trifluoromethanesulphonic anhydride, respectively, in the presence of an organic base. A 4-amino 1,5-naphthyridine can be obtained from the 4-chloro derivative by reaction with n-propylamine in pyridine.
Similarly, 6-methoxy-1,5-naphthyridine derivatives can be prepared from 3- amino-6-methoxypyridine. 1,5-Naphthyridines may be prepared by other methods well known to those skilled in the art (for examples see P.A. Lowe in "Comprehensive Heterocyclic Chemistry"
Volume 2, p581-627, Ed A.R. Katritzky and C.W. Rees, Pergamon Press, Oxford, 1984).
The 4-hydroxy and 4-amino-cinnolines may be prepared following methods well known to those skilled in the art [see A.R. Osborn and K. Schofield, J. Chem. Soc. 2100 (1955)]. For example, a 2-aminoacetopheneone is diazotised with sodium nitrite and acid to produce the 4-hydroxycinnoline with conversion to chloro and amino derivatives as described for 1,5-naphthyridines.
For compounds of formula (V), suitable amines may be prepared from the corresponding 4-substituted piperidine acid or alcohol. In a first instance, an N-protected piperidine containing an acid bearing substituent, can undergo a Curtius rearrangement and the intermediate isocyanate can be converted to a carbamate by reaction with an alcohol. Conversion to the amine may be achieved by standard methods well known to those skilled in the art used for amine protecting group removal. For example, an acid substituted N-protected piperidine can undergo a Curtius rearrangement e.g. on treatment with diphenylphosphoryl azide and heating, and the intermediate isocyanate reacts in the : 5 presence of 2-trimethylsilylethanol to give the trimethylsilylethylcarbamate (T.L. Capson & C.D. Poulter, Tetrahedron Lett., 1984, 25, 3515). This undergoes cleavage on treatment with tetrabutylammonium fluoride to give the 4-amine substituted N-protected piperidine.
In a second instance, an N-protected piperidine containing an alcohol bearing substituent undergoes a Mitsunobu reaction (for example as reviewed in Mitsunobu,
Synthesis, (1981), 1), for example with succinimide in the presence of diethyl azodicarboxylate and triphenylphosphine to give the phthalimidoethylpiperidine.
Removal of the phthaloyl group, for example by treatment with methylhydrazine, gives the amine of formula (V).
R3CH)-halides, acyl derivative RICOW and R3SO,W or aldehydes RSCHO are commercially available or are prepared conventionally. The aldehydes may be prepared by partial reduction of the R3-ester with lithium aluminium hydride or di- isobutylaluminium hydride or more preferably by reduction to the alcohol, with lithium aluminium hydride or sodium borohydride, followed by oxidation to the aldehyde with manganese (I) dioxide. The aldehydes may also be prepared from carboxylic acids in two stages by conversion to a mixed anhydride for example by reaction with isobutyl chloroformate followed by reduction with sodium borohydride (R. J. Alabaster et al.,
Synthesis, 598, 1989) to give the hydroxymethyl substituted heteroaromatic or aromatic. and then oxidation with a standard oxidising agent such as pyridinium dichromate or manganese (I) dioxide. Acyl derivative RSCOW may be prepared by activation of the
R5-acid. R7CH»-halides such as bromides may be prepared from the alcohol R3 CH,O0H by reaction with phosphorus tribromide in DCM/triethylamine. Alternatively the aldehyde
RICHO and sulphonic acid derivative RISO,W may be generated by treatment of the
RH heterocycle with suitable reagents. For example by formylation with hexamine in either trifluoroacetic acid or methanesulfonic acid, in a modified Duff procedure [O. IL.
Petrov et al. Collect. Czech. Chem. Commun. 62, 494-497 (1997)]. Reaction of a RSH } heterocycle with chlorosulphonic acid gives the sulphonic acid derivative (by methods analogous to Techer et. al., C.R.Hebd. Seances Acad. Sci. Ser.C; 270, 1601, 1970)..
RS heterocycles are commercially available or may be prepared by conventional methods.
The amines RZR4'NH are available commercially or prepared conventionally. For example amines RS CHaNH) may be prepared from a bromomethyl derivative by reaction with sodium azide in dimethylformamide (DMF), followed by hydrogenation of the azidomethyl derivative over palladium-carbon. An alternative method is to use potassium . phthalimide/DMF to give the phthalimidomethyl derivative, followed by reaction with hydrazine in DCM to liberate the primary amine.
Conversions of R12, RI", R2', R3' and R4' may be carried out on the intermediates of formulae (IV), and (V) prior to their reaction to produce compounds of formula (I) in the same way as described above for conversions after their reaction.
Further details for the preparation of compounds of formula (I) are found in the examples.
The compounds of formula (I) may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, and more preferably 10 to 100 compounds of formula (I). Libraries of compounds of formula (I) may be prepared by a combinatorial "split and mix" approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.
Thus according to a further aspect of the invention there is provided a compound library comprising at least 2 compounds of formula (I) or pharmaceutically acceptable derivatives thereof.
Novel intermediates of formulae (IV) and (V) are also part of this invention.
The antibacterial compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibacterials.
The pharmaceutical compositions of the invention include those in a form adapted for oral, topical or parenteral use and may be used for the treatment of bacterial infection in mammals including humans.
The composition may be formulated for administration by any route. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
The topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams,
The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup,
acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for . example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient. The dosage as employed for adult human treatment will preferably range from 100 to 3000 mg per day, for instance 1500 mg per day depending on the route
Claims (18)
1. a compound of formula (I) or a pharmaceutically acceptable derivative thereof: AB(CH,), — {yr RN “I 55 Rr? A Las AN » y . z* @ wherein: one of Z1, 72, 73, 74 and Z3 is N, one is CR12 and the remainder are CH , or one or two of zl, 72, 73,74 and Z3 are independently CR 12 and the remainder are CH; R1 and R12 are independently hydrogen; hydroxy; (C1.g)alkoxy optionally substituted by (C1-g)alkoxy, amino, piperidyl, guanidino or amidino any of which is optionally N- substituted by one or two (Cj_g)alkyl, acyl or (C1.g)alkylsulphonyl groups, CONH>, hydroxy, (C1 _g)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy or (C1_g)alkylsulphonyloxy; (Cj_g)alkoxy-substituted(C1_g)alkyl; halogen; (Ci. 6)alkyl; (C1-g)alkylthio; trifluoromethyl; trifluoromethoxy; nitro; azido; acyl; acyloxy; acylthio; (C1 .¢g)alkylsulphonyl; (C1_g)alkylsulphoxide; arylsulphonyl; arylsulphoxide or an amino, piperidyl, guanidino or amidino group optionally N-substituted by one or two (C1-6)alkyl, acyl or (Cj_g)alkylsulphonyl groups; : provided that when zl 72, 73, Z4 and 75 are CR12 or CH, then R! is not hydrogen; R2 is hydrogen, or (C1-4)alkyl or (C5_g)alkenyl optionally substituted with 1 to 3 groups selected from: amino optionally substituted by one or two (C1 .4)alkyl groups; carboxy; (Cj. g)alkoxycarbonyl; (C1-g)alkylcarbonyl; (C9.4)alkenyloxycarbonyl; (Co. : 4)alkenylcarbonyl; aminocarbonyl wherein the amino group is optionally substituted by
. hydroxy, (C1-4)alkyl, hydroxy(C1.4)alkyl, aminocarbonyl(C1.4)alkyl, (Cy_4)alkenyl, : (C1-4)alkylsulphonyl, triflucromethylsulphonyl, (C7.4)alkenylsulphonyl, (Cy. R 30 g)alkoxycarbonyl, (C1-4)alkylcarbonyl, (Cy.4)alkenyloxycarbonyl or (Co. 4)alkenylcarbonyl; cyano; tetrazolyl; 2-oxo-oxazolidinyl optionally substituted by R10; 3. hydroxy-3-cyclobutene-1,2-dione-4-yl; 2,4-thiazolidinedione-5-yl; tetrazol-5- ylaminocarbonyl; 1,2,4-triazol-5-y1 optionally substituted by R10; 5-oxo0-1,2,4-oxadiazol-
3-yl; halogen; (C1.4)alkylthio; trifluoromethyl; hydroxy optionally substituted by (C1. a)alkyl, (Co_4)alkenyl, (C1.4)alkoxycarbonyl, (C1_4)alkylcarbonyl, (C5. : 4)alkenyloxycarbonyl, (C2-4)alkenylcarbonyl; oxo; (C1.4)alkylsulphonyl; (Co. 4)alkenylsulphonyl; or (Cj .4)aminosulphony! wherein the amino group is optionally
. 5 substituted by (C1.4)alky! or (Cy_4)alkenyl; R31is hydrogen; or R3 is in the 2-, 3- or 4-position and is: carboxy; (Cj.g)alkoxycarbonyl; aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (Cj-g)alkyl, hydroxy(Cj.g)alkyl, aminocarbonyl(Cy.g)alkyl, (Co. alkenyl, (Cy_g)alkylsulphonyl, triflucromethylsulphonyl, (Co_g)alkenylsulphonyl, (Cy. 6)alkoxycarbonyl, (C1.g)alkylcarbonyl, (Co-g)alkenyloxycarbonyl or (Co. ¢)alkenylcarbonyl and optionally further substituted by (C1_¢)alkyl, hydroxy(Cy.g)alkyl, aminocarbonyl(Cj_g)alkyl or (Cy_g)alkenyl; cyano; tetrazolyl; 2-oxo-oxazolidinyl optionally substituted by R10; 3-hydroxy-3-cyclobutene-1 ,2-dione-4-yl; 2,4- thiazolidinedione-5-yl; tetrazol-5-ylaminocarbonyl; 1,2,4-triazol-5-yl optionally substituted by Rl 0. or 5-0x0-1,2,4-oxadiazol-3-yl; or (C1-4)alkyl or ethenyl optionally substituted with any of the substituents listed above for R3 and/or 0 to 2 groups R12 independently selected from: halogen; (C1.g)alkylthio; trifluoromethyl; (C1 .g)alkoxycarbonyl; (C1. e)alkylcarbonyl; (Cy_g)alkenyloxycarbonyl; (Co.g)alkenylcarbonyl; hydroxy optionally substituted by (Cj1-g)alkyl, (C2.g)alkenyl, (C1.g)alkoxycarbonyl, (C_g)alkylcarbonyl,
(C1.¢)alkenyloxycarbonyl, (C5.g)alkenylcarbonyl or aminocarbonyl wherein the amino group is optionally substituted by (C1.g)alkyl, (Co.g)alkenyl, (C1_g)alkylcarbonyl or (Cy_ - g)alkenylcarbonyl; amino optionally mono- or disubstituted by (C1_g)alkoxycarbonyl, (C1-g)alkylcarbonyl, (C_g)alkenyloxycarbonyl, (Co_g)alkenylcarbonyl, (C1.g)alkyl, (Cy-g)alkenyl, (C1-g)alkylsulphonyl, (C;.g)alkenylsulphonyl or aminocarbonyl wherein the amino group is optionally substituted by (C1.g)alkyl or (Cy.g)alkenyl; aminocarbonyl wherein the amino group is optionally substituted by (C1-g)alkyl, hydroxy(Cj_g)alkyl, aminocarbonyl(Cj-g)alkyl, (Co_g)alkenyl, (C1.g)alkoxycarbonyl, (C_g)alkylcarbonyl, : (Cq_g)alkenyloxycarbonyl or (C3_g)alkenylcarbonyl and optionally further substituted by 3 (C1-g)alkyl, hydroxy(Cj_g)alkyl, aminocarbonyl(C1 .¢g)alkyl or (Co_g)alkenyl; oxo; (C1. 6)alkylsulphonyl; (C2.¢)alkenylsulphonyl; or (C1.g)aminosulphonyl wherein the amino group is optionally substituted by (Cj.g)alkyl or (Co_g)alkenyl; or when R3 is in the 3- position, hydroxy optionally substituted as described above;
in addition when R3 is disubstituted with a hydroxy or amino containing substituent and carboxy containing substituent these may together form a cyclic ester or amide linkage, respectively; R# is a group -U-R3 where
. 5 Ulis selected from CO, SO and CHy and R3 is an optionally substituted bicyclic carbocyclic or heterocyclic ring system (A): ~N x7 Xs \ L (a) y'— RK Y* (A) containing up to four heteroatoms in each ring in which ring (a) is aromatic or non aromatic; X1 is C when part of an aromatic ring or CR14 when part of a non aromatic ring; X2isN, NR13, 0, S(O), CO or CR14 when part of an aromatic or non-aromatic ring or may in addition be CR14R15 when part of a non aromatic ring; X4 is N, NR13, 0, S(O), CO or CR14; X3 and X3 are independently N or C; Ylis a1 to 3 atom linker group each atom of which is independently selected from N, NR13, O, S(O)x, CO and CR14 when part of an aromatic or non-aromatic ring or may additionally be CR14R15 when part of a non aromatic ring, Y2 is a 2 or 3 atom linker group completing an aromatic ring, each atom of Y2 being independently selected from N, NR13, O, S(Q)y, CO and CR14, each of R14 and R15 is independently selected from: H; (C1_4)alkylthio; halo; carboxy(C1-4)alkyl; halo(Cj_g)alkoxy; halo(C1._4)alkyl; (C1-4)alkyl; (Co.4)alkenyl; (Cy. 4)alkoxycarbonyl; formyl; (Cj_4)alkylcarbonyl; (C;.4)alkenyloxycarbonyl; (Co. g)alkenylcarbonyl; (C1.4)alkylcarbonyloxy; (C1-g)alkoxycarbonyl(C1.4)alkyl; hydroxy; hydroxy(C1-4)alkyl; mercapto(Cj.4)alkyl; (C1.4)alkoxy; nitro; cyano; carboxy; amino or aminocarbonyl optionally substituted as for corresponding substituents in R3; (C1. g)alkylsulphonyl; (C2_g)alkenylsulphonyl; or aminosulphonyl wherein the amino group is optionally mono- or di-substituted by (C1_4)alkyl or (Co_4)alkenyl; aryl; aryl(C1.4)alkyl; aryl(C1-4)alkoxy or : R14 and R15 may together represent oxo;
. 30 each R13 is independently H; trifluoromethyl; (C1.4)alkyl optionally substituted by hydroxy, (Cj .¢)alkoxy, (Cj.g)alkylthio, carboxy, halo or trifluoromethyl; (C».
. 4)alkenyl; aryl; aryl (Cy.4)alkyl; arylcarbonyl; heteroarylcarbonyl; (C1.4)alkoxycarbonyl; (C1-4)alkylcarbonyl; formyl; (Cj_g)alkylsulphonyl; or aminocarbonyl wherein the amino group is optionally substituted by (C1.4)alkoxycarbonyl, (C1_g)alkylcarbonyl, (Co.
4)alkenyloxycarbonyl, (Cy.4)alkenylcarbonyl, (C1.4)alkyl or (Cp_4)alkenyl and optionally further substituted by (Cy_g)alkyl or (Ca-4)alkenyl; nisQorl; : 5 each x is independently 0, 1 or 2 AisNR11 0 or CROR7 and Bis NR11, O, SO or CR8RY and wherein: each of RO, R7, R8 and RY is independently selected from: hydrogen; (C1.-6)alkoxy; (Cq- g)alkylthio; halo; trifluoromethyl; azido; (Cq_g)alkyl; (Co.g)alkenyl; (Cy. g)alkoxycarbonyl; (C1.g)alkylcarbonyl; (C,_g)alkenyloxycarbonyl; (Cy. ¢)alkenylcarbonyl; hydroxy, amino or aminocarbony! optionally substituted as for corresponding substituents in R3; (C1-6)alkylsulphonyl; (Cy_g)alkenylsulphonyl; or aminosulphonyl wherein the amino group is optionally substituted by (C1.¢)alkyl or (C2. g)alkenyl; or when n=1 R6 and R8 together represent a bond and R7 and R? are as above defined; or RO and R7 or R8 and RY together represent 0xo; provided that: when A is NR11, Bis not NR1! or O; when A is CO, B is not CO, O or SO9; when nis 0 and A is NR11, CR8RY can only be CO; : when A is CR6R7 and Bis SOg, nis 0; when n is 0, B is not NR11 or O or R8 and R9 are not optionally substituted hydroxy or amino; when A is O, B is not NR11, 0, SO; or CO and n=1; and when A-B is CR7=CR, nis 1 R10 is selected from (C1-g)alkyl; (C2.4)alkenyl and aryl any of which may be optionally substituted by a group R12 as defined above; carboxy; aminocarbonyl wherein the amino : group is optionally substituted by hydroxy, (C1.¢)alkyl, (C3.g)alkenyl, (C1. ] g)alkylsulphonyl, trifluoromethylsulphonyl, (Co_g)alkenylsulphonyl, (Cy. alkoxycarbonyl, (C1.g)alkylcarbonyl, (Cy_g)alkenyloxycarbonyl or (Co. ] g)alkenylcarbonyl and optionally further substituted by (Cj_g)alkyl or (Co_g)alkenyl; (Cj-g)alkylsulphonyl; trifluoromethylsulphonyl; (C.g)alkenylsulphonyl; (Cy. 6 alkoxycarbonyl; (C1.g)alkylcarbonyl; (C3.g)alkenyloxycarbonyl; and (C;. )alkenylcarbonyl; and
R11 js hydrogen; trifluoromethyl, (C1.g)alkyl; (Co.g)alkenyl; (C1 .g)alkoxycarbonyl; (C1-g)alkylcarbonyl; or aminocarbonyl wherein the amino group is optionally substituted by (Cy.6)alkoxycarbonyl, (C;_g)alkylcarbonyl, (Cy.g)alkenyloxycarbonyl, (C2- . 5 e)alkenylcarbonyl, (Cy_g)alkyl or (Co.g)alkenyl and optionally further substituted by (Cj. 6)alkyl or (Co_g)alkenyl; or where one of R3 and RS, R7, R8 or R9 contains a carboxy group and the other contains a hydroxy or amino group they may together form a cyclic ester or amide linkage.
2. A compound according to claim 1 wherein Z3 is CH or N, Z3 is CH or CF and Z1, Z2 and Z4 are each CH, or Z! is N, Z3 is CH or CF and Z2, Z*4 and Z5 are each CH.
3. A compound according to any preceding claim wherein R1 is methoxy, amino(C3. g)alkyloxy or guanidino(C3.5)alkyloxy.
4. A compound according to any preceding claim wherein R2 is hydrogen, carboxymethyl, hydroxyethyl, aminocarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylallyl or carboxyallyl.
5. A compound according to any preceding claim wherein R3 is hydrogen; optionally substituted hydroxy; (C1.4) alkyl; ethenyl; optionally substituted 1-hydroxy-(C1-4) alkyl; optionally substituted aminocarbonyl; carboxy(Cj._4)alkyl; optionally substituted aminocarbonyl(Cj_g)alkyl; cyano(Cj.4)alkyl; optionally substituted 2-oxo-oxazolidinyl or optionally substituted 2-0x0-oxazolidinyl(Cy_galkyl) in the 3-or 4-position.
6. A compound according to any preceding claim wherein n is 0, A-B is CHOH- CHp, NR11-CHy or NR11-CO and R11 is hydrogen or (Cy_g)alkyl.
7. A compound according to any preceding claim wherein U is CHy and RS is an : aromatic heterocyclic ring (A) having 1-4 heteroatoms of which one is N or NR13, R13 is H if in ring (a) or in addition (C14)alkyl, R14 and R15 are independently selected from hydrogen, hale, hydroxy, (C1-4)alkyl, (C.4)alkoxy, trifluoromethoxy, nitro, cyano, } aryl(C1-4)alkoxy and (Cj.4)alkylsulphonyl.
8. A compound according to any of claims 1 to 6 wherein R? is 4,6-difluoro-indol-2- yl, 1H-pyrrolo[2,3-b]-pyridin-2-yl, 1H-pyrrolo[3,2-b]-pyridin-2-yl,, 8-hydroxy-quinolin-
2-yl, quinoxalin-2-yl, benzimidazol-2-yl, benzo[1,2,3]-thiadiazol-5-yl, benzothiophen-2- yl, 4,6-difluoro-1H-benzimidazol-2-yl, benzothiazole-5-y! or 3-(R)-2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-3-yl. , 0 A compound according to claim 1 selected from: : (R)-2-{4-[(4-fluoro-1H-benzimidazol-2-ylmethyl)-amino]-piperidin-1-yl}-1-(6- : methoxyquinolin-4-yl)-ethanol; - (R)-1-(6-methoxy-quinolin-4-yl) -2- {4-[(1H-pyrrolo[2,3-b]pyridine-2-ylmethyl)-amino]- piperidin-1-yl}-ethanol; 2-({1-[(R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl}- piperidin-4-ylamino}-methyl)- quinolin-8-ol; (R)-2-{4-[(benzo[1,2,3]thiadiazol-5-ylmethyl)-amino]-piperidin-1-y1}-1-(6-methoxy- quinolin-4-yl)-ethanol; (R)-1-(6-methoxy-quinolin-4-yl) -2- {4-[(quinoxalin-2-ylmethyl)-amino]-piperidin-1-yl}- ethanol; 2-({1-[(R)-2-hydroxy-2-(6-methoxy-[ 1,5]naphthyridin-4-yl)-ethyl]- piperidin-4-ylamino}- methyl)-quinolin-8-ol; 4-[(4,7-difluoro-1H-indol-2-ylmethyl)-amino]-piperidine-1-carboxylic acid (6-methoxy- [1,5]naphthyridin-4-yl)-amide; (R)-2-(4-{I(R)-1-(2,3-Dihydro-{1,4]dioxino[2,3-]pyridin-3-yl)methyl]-amino}-piperidin- 1-y1)-1-(8-fluoro-6-methoxy-quinolin-4-yl)-ethanol; (R)-2-{4-[(Benzothiazol-5-ylmethyl)-amino]-piperidin-1-y1} -1-(6-methoxy-quinolin-4- yl)-ethanol; (R)-2-{4-[(4,6-Difluoro-1H-benzimidazol-2-ylmethyl)-amino]-piperidin-1-yl}-1-(6- methoxy[1,5]naphthyridin-4-yl)-ethanol; and pharmaceutically acceptable derivatives thereof.
10. A compound according to claim 1 for use in the treatment of bacterial infections in mammals.
11. The use of a compound according to claim 1, in the manufacture of a medicament for use in the treatment of bacterial infections in mammals. ’
12. A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier. :
13. A process for preparing compounds according to claim 1, which process comprises: reacting a compound of formula (IV) with a compound of formula (V):
. =T72- AMENDED SHEET
X : R" zt 1 hg or onl, XC Xs NS 15 Q av) ) wherein n is as defined in formula (I); Z!', z2, 23, 24, z5',R1' and R3' are 71, 72, 73, z4,75,R1 and R3 as defined in formula (I) or groups convertible thereto; Ql is NR2'R# or a group convertible thereto wherein R2' and R#' are R2 and R4 as defined in formula (I) or groups convertible thereto and Q2 is Hor R3' or Q! and Q2 together form an optionally protected oxo group; and X and Y may be the following combinations: () Xis A-COW,YisH and nis 0; (ii) Xis CR6=CRERY, YisH and nis 0; (iti) Xisoxirane, YisHandn is 0; (iv) XisN=C=OandYisHandnisO; (v) oneofXandY is COoRY and the other is CHyCO2RX; (vi) Xis CHROR7 and Y is C(=O)RY; (vii) Xis CR7=PRZ3 and Y is C(=O)R? and n=1; (viii) Xis C(=O)R7 and Y is CR9=PRZ3 and n=1; . (ix) Yis COW and Xis NHR1!' NCO or NR11'COW and n=0 or 1 or when n=1 X is COW and Y is NHR!" , NCO or NR11'COW; (x) Xis C(O=)R6 and Y is NHR11' or X is NHR!1' and Y is C(=0)R8 and n=1; (xi) Xis NHRI! and Y is CR8ROW and n=1; (xii) Xis CROR7W and Y is NHR1!' or OH and n=1; (xiii) X is CROR7SO,W and Y is H and n=0; (xiv) Xis Wor OH and Y is CHpOH and n=1; (xv) XisNHR!!' and Y is SOoW or X is NR11'SO,W and Y is H, and n=0; (xvi) Xis NR11'COCHoW or NR11'SO,CH,W and Y is H and n=0; (xvii) Xis W and Y is CONHR11', in which W is a leaving group, e.g. halo or imidazolyl; RX and RY are (C1.g)alkyl; RZ is . aryl or (C1.g)alkyl; A' and NR! are A and NR11 as defined in formula (I), or groups convertible thereto; and oxirane is:
+ WO 02/08224 PCT/EP01/08604 RS 0 Re Pm wherein RO, R8 and R9 are as defined in formula (I); and thereafter optionally or as necessary converting Ql and Q2 to NR2'R#4'; converting A’, zl' 72 73 74, 75 Rl, RZ, R3, R¥ and NR11't0 A, 71, 72, 73, 74, 75, R1, RZ, R3, R4 and NR11'; converting A-B to other A-B, interconverting R1, R2, R3 and/or R4, "and/or forming a pharmaceutically acceptable derivative thereof.
14, A compound of formula (1) as claimed in claim 1, substantially as herein described and exemplified and/or described with reference to the accompanying figures.
A compound as claimed in claim 10, substantially as herein described and exemplified and/or described with reference to the accompanying figures.
16. The use as claimed in claim 11, substantially as herein described and exemplified and/or described with reference to the accompanying figures.
17. A pharmaceutical composition as claimed in claims 12, substantially as herein described and exemplified and/or described with reference to the accompanying figures.
18. A process as claimed in claim 13, substantially as herein described and exemplified and/or described with reference to the accompanying figures. . =-T4- AMENDED SHEET
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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GB0018351A GB0018351D0 (en) | 2000-07-26 | 2000-07-26 | Compounds |
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ZA200300589B true ZA200300589B (en) | 2004-04-22 |
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ZA200300589A ZA200300589B (en) | 2000-07-26 | 2003-01-22 | Aminopiperidine quinolines and their azaisosteric analogues with antibacterial activity. |
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GB (1) | GB0018351D0 (en) |
ZA (1) | ZA200300589B (en) |
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2000
- 2000-07-26 GB GB0018351A patent/GB0018351D0/en not_active Ceased
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2003
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