US20060079546A1 - Aminopiperidine derivatives as antibacterials - Google Patents
Aminopiperidine derivatives as antibacterials Download PDFInfo
- Publication number
- US20060079546A1 US20060079546A1 US11/292,011 US29201105A US2006079546A1 US 20060079546 A1 US20060079546 A1 US 20060079546A1 US 29201105 A US29201105 A US 29201105A US 2006079546 A1 US2006079546 A1 US 2006079546A1
- Authority
- US
- United States
- Prior art keywords
- alkyl
- optionally substituted
- hydroxy
- alkenyl
- aminocarbonyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- LWMPFIOTEAXAGV-UHFFFAOYSA-N piperidin-1-amine Chemical class NN1CCCCC1 LWMPFIOTEAXAGV-UHFFFAOYSA-N 0.000 title abstract description 4
- 230000000844 anti-bacterial effect Effects 0.000 title description 7
- 229940088710 antibiotic agent Drugs 0.000 title description 4
- 238000000034 method Methods 0.000 claims abstract description 53
- 241000124008 Mammalia Species 0.000 claims abstract description 7
- 208000035143 Bacterial infection Diseases 0.000 claims abstract description 5
- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 5
- -1 amino, piperidyl Chemical group 0.000 claims description 118
- 150000001875 compounds Chemical class 0.000 claims description 99
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 76
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 38
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 34
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 33
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 27
- 125000005090 alkenylcarbonyl group Chemical group 0.000 claims description 27
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 25
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 claims description 25
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 125000003277 amino group Chemical group 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 22
- 125000003342 alkenyl group Chemical group 0.000 claims description 21
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 21
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 125000004414 alkyl thio group Chemical group 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000002252 acyl group Chemical group 0.000 claims description 10
- 125000004423 acyloxy group Chemical group 0.000 claims description 10
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 8
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 7
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000001414 1,2,4-triazol-5-yl group Chemical group [H]N1N=C([H])N=C1[*] 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 5
- 125000004642 (C1-C12) alkoxy group Chemical group 0.000 claims description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 125000005936 piperidyl group Chemical group 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 125000004442 acylamino group Chemical group 0.000 claims description 2
- 125000005035 acylthio group Chemical group 0.000 claims description 2
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 2
- 125000002947 alkylene 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
- 239000004305 biphenyl Substances 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 125000006267 biphenyl group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 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
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 99
- 238000006243 chemical reaction Methods 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 239000000203 mixture Substances 0.000 description 35
- 150000002500 ions Chemical class 0.000 description 33
- 230000008569 process Effects 0.000 description 30
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 29
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 29
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- 239000000741 silica gel Substances 0.000 description 22
- 229910002027 silica gel Inorganic materials 0.000 description 22
- 239000007787 solid Substances 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 150000001412 amines Chemical class 0.000 description 17
- 150000002148 esters Chemical class 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000002253 acid Substances 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 150000003839 salts Chemical class 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 229940093499 ethyl acetate Drugs 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000012458 free base Substances 0.000 description 12
- 125000000623 heterocyclic group Chemical group 0.000 description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- 238000004587 chromatography analysis Methods 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 7
- 0 [1*]C1=CC2=C(C=C1)N=CC=C2CN1CCC(C)CC1.[3*]C Chemical compound [1*]C1=CC2=C(C=C1)N=CC=C2CN1CCC(C)CC1.[3*]C 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- 239000003981 vehicle Substances 0.000 description 7
- TZRSKDVHKGYCON-LBPRGKRZSA-N 6-methoxy-4-[(2r)-oxiran-2-yl]quinoline Chemical compound C12=CC(OC)=CC=C2N=CC=C1[C@@H]1CO1 TZRSKDVHKGYCON-LBPRGKRZSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 150000002118 epoxides Chemical class 0.000 description 6
- 229910052744 lithium Inorganic materials 0.000 description 6
- 239000012280 lithium aluminium hydride Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 5
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 5
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 5
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000012948 isocyanate Substances 0.000 description 5
- 150000002513 isocyanates Chemical class 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- 125000004043 oxo group Chemical group O=* 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 150000003573 thiols Chemical class 0.000 description 5
- 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 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 238000006969 Curtius rearrangement reaction Methods 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- WJYIASZWHGOTOU-UHFFFAOYSA-N Heptylamine Chemical compound CCCCCCCN WJYIASZWHGOTOU-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 239000003638 chemical reducing agent Substances 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
- 239000003814 drug Substances 0.000 description 4
- 238000006735 epoxidation reaction Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 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 3
- TZRSKDVHKGYCON-GFCCVEGCSA-N 6-methoxy-4-[(2s)-oxiran-2-yl]quinoline Chemical compound C12=CC(OC)=CC=C2N=CC=C1[C@H]1CO1 TZRSKDVHKGYCON-GFCCVEGCSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- 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
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
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- 230000000694 effects Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 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 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- MHCFAGZWMAWTNR-UHFFFAOYSA-M lithium perchlorate Chemical compound [Li+].[O-]Cl(=O)(=O)=O MHCFAGZWMAWTNR-UHFFFAOYSA-M 0.000 description 3
- 229910001486 lithium perchlorate Inorganic materials 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000002524 organometallic group Chemical group 0.000 description 3
- 150000003891 oxalate salts Chemical class 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
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- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical group O=C1CSC(=O)N1 ZOBPZXTWZATXDG-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
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- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000005633 phthalidyl group Chemical group 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- PYNUOAIJIQGACY-UHFFFAOYSA-N propylazanium;chloride Chemical compound Cl.CCCN PYNUOAIJIQGACY-UHFFFAOYSA-N 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000004892 pyridazines Chemical class 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- VSGPVHSTVTXREH-UHFFFAOYSA-N quinolin-4-one Chemical compound C1=CC=C[C]2C(=O)C=CN=C21 VSGPVHSTVTXREH-UHFFFAOYSA-N 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 229910000080 stannane Inorganic materials 0.000 description 1
- 125000003638 stannyl group Chemical group [H][Sn]([H])([H])* 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000002278 tabletting lubricant Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- XJPANWOKBWZVHC-UHFFFAOYSA-N tetrazol-2-amine Chemical compound NN1N=CN=N1 XJPANWOKBWZVHC-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 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
- 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
- 238000001665 trituration Methods 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- This invention relates to novel aminopiperidine compounds, compositions containing them and their use as antibacterials.
- EP0579263, EP0742207, JP2169569, EP0296560, WO9103243, EP0449186 disclose piperidine compounds as acetylcholinesterase inhibitors and sigma receptor antagonists.
- WO9802438 and WO9703069 disclose certain bicyclic heteroaromatic compounds having protein tyrosine kinase and cell proliferation inhibitor activity.
- WO9217475, WO9802438, WO9703069 and WO9639145 disclose certain bicyclic heteroaromatic compounds having cholinesterase inhibitor, protein tyrosine kinase inhibitor, cell proliferation inhibitor and human epidermal growth factor receptor type 2 inhibitor activity.
- This invention provides a compound of formula (I) or a pharmaceutically acceptable derivative thereof: wherein:
- 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
- a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.
- Preferred groups of compounds include those where:
- R 1 or R 1a is substituted alkoxy it is preferably (C 2-6 )alkoxy substitituted by optionally N-substituted amino, guanidino or amidino, or (C 1-6 )alkoxy optionally substituted by piperidyl.
- Suitable examples of R 1 and R 1a alkoxy include methoxy, n-propyloxy, iso-butyloxy, aminoethyloxy, aminopropyloxy, aminobutyloxy, amiinopentyloxy, guanidinopropyloxy, piperidin-4-ylmethyloxy and phthalimido pentyloxy.
- R 1 and R 1a are independently methoxy, amino(C 3-5 )alkyloxy, guanidino(C 3-5 )alkyloxy, piperidyl(C 3-5 )alkyloxy, nitro or fluoro; more preferably methoxy, amino(C 3-5 )alkyloxy or guanidino(C 3-5 )alkyloxy.
- Z 2 and Z 4 are preferably CH.
- R 1a is preferably hydrogen, cyano, hydroxymethyl or carboxy.
- n 0.
- R 2 is preferably hydrogen; (C 1-4 )alkyl substituted with carboxy, optionally substituted hydroxy, optionally substituted aminocarbonyl, optionally substituted amino or (C 1-4 )alkoxycarbonyl; or (C 1-4 )alkenyl substituted with (C 1-4 )alkoxycarbonyl or carboxy. More preferred groups for R 2 are hydrogen, carboxymethyl, hydroxyethyl, aminocarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylallyl and carboxyallyl.
- R 3 include hydrogen; optionally substituted aminocarbonyl; optionally substituted (C 1-6 )alkyl; carboxy(C 1-4 )alkyl; optionally substituted aminocarbonyl(C 1-4 )alkyl; cyano(C 1-4 )alkyl; optionally substituted 2-oxo-oxazolidinyl and optionally substituted 2-oxo-oxazolidinyl(C 1-4 alkyl). More preferred R 3 groups are hydrogen; CONH 2 ; 1-hydroxyalkyl e.g. CH 2 OH, CH(OH)CH 2 CN; CH 2 CO 2 H; CH 2 CONH 2 ; 1,2-dihydroxyalkyl e.g. CH(OH)CH 2 OH; CH 2 CN; 2-oxo-oxazolidin-5-yl and 2-oxo-oxazolidin-5-yl(C 1-4 alkyl).
- R 3 is preferably in the 3- or 4-position.
- A is CHOH or NR 11 .
- B is CH 2 , SO 2 or CO.
- R 11 is hydrogen or (C 1-4 )alkyl e.g. methyl, more preferably hydrogen.
- R 4 is (C 5-12 )alkyl, unsubstituted phenyl(C 2-3 )alkyl or unsubstituted phenyl(C 3-4 )alkenyl.
- Suitable groups R 4 include n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-dodecyl, phenylethyl, phenylpropyl or 3-phenyl-prop-2-en-yl optionally substituted on the phenyl ring; more preferably R 4 is hexyl, heptyl, 5-methylhexyl, 6-methyl heptyl or 3-phenyl-prop-2-en-yl, especially heptyl or hexyl.
- 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.
- alkenyl should be interpreted accordingly.
- Preferred R 5 groups are unbranched at the ⁇ and, where appropriate, ⁇ positions.
- Halo or halogen includes fluoro, chloro, bromo and iodo.
- 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 substituted by, for example, up to three groups selected from optionally substituted amino, halogen, (C 1-6 )alkyl, (C 1-6 )alkoxy, halo(C 1-6 )alkyl, hydroxy, carboxy, carboxy salts, carboxy esters such as (C 1-6 )alkoxycarbonyl, (C 1-6 )alkoxycarbonyl(C 1-6 )alkyl, aryl, 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.
- suitable optional substituents in such substituted amino groups include (C 1-6 )alkyl optionally substituted by hydroxy, (C 1-6 )alkoxy, thiol, (C 1-6 )alkylthio, halo or trifluoromethyl, and amino-protecting groups such as acyl or (C 1-6 )alkylsulphonyl groups.
- heteroaryl includes the aromatic heterocyclic groups referred to above.
- heteroaryl groups include pyridyl, triazolyl, tetrazolyl, indolyl, thienyl, isoimidazolyl, thiazolyl, furanyl, quinolinyl, imidazolidinyl and benzothienyl.
- aryl includes phenyl and naphthyl.
- Aryl groups e.g. phenyl and benzoyl; heteroaryl and heteroaroyl groups may be optionally substituted with up to five, preferably up to three, groups selected from halogen, mercapto, (C 1-6 )alkyl, phenyl, (C 1-6 )alkoxy, hydroxy(C 1-6 )alkyl, mercapto (C 1-6 )alkyl, halo(C 1-6 )alkyl, hydroxy, optionally substituted amino, nitro, carboxy, (C 1-6 )alkylcarbonyloxy, (C 1-6 )alkoxycarbonyl, formyl, and (C 1-6 )alkylcarbonyl groups.
- acyl includes formyl and (C 1-6 )alkylcarbonyl group.
- acyloxy includes (C 1-6 )alkoxycarbonyl.
- 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 produced by processes such as lyophilisation.
- 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.
- compositions include salts and esters.
- esters will be apparent to those skilled in the art and include for example benzyl, p-methoxybenzyl, benzoylmethyl, p-nitrobenzyl, 4-pyridylmethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, tert-butyl, tert-amyl, allyl, diphenylmethyl, triphenylmethyl, adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl, tetrahydropyran-2-yl, pentachlorophenyl, acetonyl, p-toluenesulphonylethyl, methoxymethyl, a silyl, stannyl or phosphorus-containing group, an oxime radical of formula —N ⁇ CHR y where R y is aryl or heterocyclyl, or an in vivo hydro
- Suitable in vivo hydrolysable ester groups include, for example, acyloxy(C 1-6 )alkyl groups such as acetoxymethyl, pivaloyloxymethyl, ⁇ -acetoxyethyl, ⁇ -pivaloyloxyethyl, 1-(cyclohexylcarbonyloxy)prop-1-yl, and (1-aminoethyl)carbonyloxymethyl; (C 1-6 )alkoxycarbonyloxy(C 1-6 )alkyl groups, such as ethoxycarbonyloxymethyl, ⁇ -ethoxycarbonyloxyethyl and propoxycarbonyloxyethyl; di(C 1-6 )alkylamino(C 1-6 )alkyl especially di(C 1-4 )alkylamino(C 1-4 )alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl;
- Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include for example acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulphonic, methanesulphonic or naphthalenesulphonic acid.
- Other salts e.g. oxalates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention.
- 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.
- the invention includes compound in which an A-B group CH(OH)—CH 2 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.
- 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 CHR 6 —CR 8 R 9 .
- Process variant (iii) initially produces compounds of formula (I) wherein A-B is CR 6 (OH)—CR 8 R 9 .
- Process variant (vi) initially produces compounds of formula (I) wherein A-B is CO—CH 2 or CH 2 —CO.
- Process variant (vii) initially produces compounds of formula (I) wherein A-B is CR 6 R 7 —CR 8 OH.
- Process variant (x) initially produces compounds of formula (I) where A-B is CO—NR 11 ′ or NR 11 ′—CO.
- Process variant (xi) initially produces compounds of formula (I) wherein A-B is CHR 6 —NR 11 ′ or NR 11 ′—CHR 6 .
- Process variant (xii) initially produces compounds of formula (I) wherein A-B is NR 11 ′—CR 8 R 9 .
- Process variant (xiii) initially produces compounds of formula (I) wherein A-B is CR 6 R 7 —NR 11 ′ or CR 6 R 7 —O.
- Process variant (xiv) initially produces compounds of formula (I) where A-B is CR 6 R 7 —SO 2 .
- Process variant (xv) initially produces compounds of formula (I) where A-B is NR 11 ′—SO 2 .
- reaction is a standard amide formation reaction involving e.g.:
- 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.
- 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). In some cases an elevated temperature such as 40-70° C. may be beneficial.
- the piperazine 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.
- an inert solvent such as tetrahydrofuran
- 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
- 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 HCl in aqueous organic solvent at 0-100° C.
- a base preferably sodium hydride or alkoxide, sodamide, alkyl lithium or lithium dialkylamide, preferably in an aprotic solvent e.g. ether, THF or benzene
- hydrolysis using an inorganic acid preferably HCl in aqueous organic solvent at 0-100° C.
- 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) JACS 100, 576).
- a base preferably organometallic or metal hydride e.g. NaH, lithium diisopropylamide or NaOEt
- an aprotic solvent preferably THF, ether or benzene
- a base is preferably NaH, KH, an alkyl lithium e.g. BuLi, a metal alkoxide e.g. NaOEt, sodamide or lithium dialkylamide e.g. di-isopropylamide.
- an analogous method is described in U.S. Pat. No. 3,989,691 and M. Gates et. al. (1970) J. Amer. Chem. Soc., 92, 205, as well as Taylor et al. (1972) JACS 94, 6218.
- reaction is a standard reductive alkylation using, e.g., sodium triacetoxyborohydride (Gribble, G. W. in Encyclopedia of Reagents for Organic Synthesis (Ed. Paquette, L. A.) (John Wiley and Sons, 1995), p 4649).
- sodium triacetoxyborohydride Gribble, G. W. in Encyclopedia of Reagents for Organic Synthesis (Ed. Paquette, L. A.) (John Wiley and Sons, 1995), p 4649.
- 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.
- Reduction of a carbonyl group 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 aluminiun hydride in ethereal solution. This is analogous to methods described in EP53964, US384556 and J. Gutzwiller et al, J. Amer. Chem. Soc., 1978, 100, 576.
- the carbonyl group B may be reduced to CH 2 by treatment with a reducing agent such as hydrazine in ethylene glycol, at e.g. 130-160° C., in the presence of potassium hydroxide.
- 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 B with an organometallic reagent yields a group where R 8 is OH and R 9 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 6 CR 8 OH or CR 6 (OH)CHR 8 may be dehydrated to give the group CR 6 ⁇ CR 8 by treatment with an acid anhydride such as acetic anhydride.
- Methods for conversion of CR 6 ⁇ CR 8 by reduction to CHR 6 CHR 8 are well known to those skilled in the art, for example using hydrogenation over palladium on carbon as catalyst.
- Methods for conversion of CR 6 ⁇ CR 8 to give the A-B group CR 6 (OH)CHR 8 or CHR 6 CR 8 OH 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.
- R 1 ′, R 2 ′, R 3 and R 4 ′ are preferably R 1 , R 2 , R 3 and R 4 .
- R 1 is preferably methoxy.
- R 2 ′ is preferably hydrogen.
- R 3 ′ is preferably hydrogen, CONH 2 , CH 2 OH, CH 2 CO 2 H, CH 2 CONH 2 , CH(OH)CH 2 OH, CH(OH)CH 2 CN, CH 2 CN, 2-oxo-oxazolidin-5-yl and 2-oxo-oxazolidin-5-yl(C 1-4 alkyl).
- R 4 ′ is preferably heptyl.
- Conversions of R 1 ′, R 2 ′, R 3 and R 4 ′ and interconversions of R 1 , R 2 , R 3 and R 4 are conventional.
- suitable conventional hydroxy protecting groups which may be removed without disrupting the remainder of the molecule include acyl and alkylsilyl groups.
- R 1 ′ methoxy is convertible to R 1 ′ 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, R 1 alkoxy substituted by optionally N-substituted amino, piperidyl, guanidino or amidino.
- R 3 alkenyl is convertible to hydroxyalkyl by hydroboration using a suitable reagent such as 9-borabicyclo[3.3.1]nonane, epoxidation and reduction or oxymercuration.
- R 3 1,2-dihydroxyalkyl can be prepared from R 3 ′ 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 epoxidation followed by hydrolysis (see Advanced Organic Chemistry, Ed. March, J. John Wiley and Sons, 1985, p 332, 333 and refs. cited therein).
- R 3 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 R 3 ′ group with azide anion yields an azide derivative which can be reduced to the amine. Conversion of the amine to a carbamate is followed by ring closure with base to give the 2-oxo-oxazolidinyl containing R 3 group.
- Substituted 2-oxo-oxazolidinyl containing R 3 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 R 10 groups by standard procedures.
- Carboxy groups within R 3 may be prepared by Jones' oxidation of the corresponding alcohols CH 2 OH 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).
- R 3 groups containing a cyano 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.
- R 3 Other functional groups in R 3 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 et 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. Ornstein, J. Org. Chem., 1994, 59, 7682 and J. Med. Chem, 1996, 39 (11), 2219).
- 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 et al, J. Med Chem, 1996, 39(11), 2232).
- alkyl- and alkenyl-sulphonylcarboxamides are similarly prepared from the corresponding carboxylic acid and the alkyl- or alkenyl-sulphonamide by dehydration with standard peptide coupling agents such as 1,1′-carbonyldiimidazole (P. L. Omstein et al, J. Med. Chem., 1996, 39(11), 2232).
- 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.
- 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 R 10 -substituted activated carboxylic acid (see J. B. Polya in “Comprehensive Heterocyclic Chemistry” Edition 1, p762, Ed A. R. Katritzky and C. W. Rees, Pergamon Press, Oxford, 1984 and J. J. Ares et al, J. Heterocyclic Chem., 1991, 28(5), 1197).
- R 3 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.
- R 61 can be prepared by treatment of a compound of formula (I) where R 3 is alken-1-yl with a strong base in an aprotic solvent.
- Suitable bases include Ph 2 PLi/PhLi (as described in Ireland et al, J. Amer. Chem. Soc., 1973, 7829), t-BuLi, and suitable solvents include THF and ether.
- NH is converted to NR 4 by conventional means such as alkylation with an alkyl halide in the presence of base, acylation/reduction or reductive alkylation with an aldehyde.
- 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)].
- DPPA diphenyl phosphoryl azide
- the 4-amino derivatives are commercially available or may be prepared by conventional procedures from a corresponding 4-chloro 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 (POCl 3 ) or phosphorus pentachloride, PCl 5 .
- a 4-chloroquinazoline is prepared from the corresponding quinazolin-4-one by reaction with phosphorus oxychloride (POCl 3 ) or phosphorus pentachloride, PCl 5 .
- 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.
- 4-Carboxy derivatives of compounds of formula (IV) are commercially available or may be prepared by conventional procedures for preparation of carboxy heteroaromatics well known to those skilled in the art.
- quinazolines may be prepared by standard routes as described by T. A. Williamson in Heterocyclic Compounds, 6, 324 (1957) Ed. R. C. Elderfield.
- Pyridazines and napthyridines may be prepared by routes analogous to those described in Comprehensive Heterocyclic Chemistry , Volumes 2 & 3, Ed A. J. Boulton and A. McKillop.
- These 4-carboxy derivatives may be activated by conventional means, e.g. by conversion to an acyl halide or anhydride.
- 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 5M 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.
- 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 ethoxymethylenemalonic ester 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, Joe 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.
- a 4-amino 1,5-naphthyridine can be obtained from the 4-chloro derivative by reaction with n-propylamine in pyridine.
- 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).
- suitable amines may be prepared from the corresponding 4-substituted piperidine acid or alcohol.
- 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.
- an acid substituted N-protected piperidine can undergo a Curtius rearrangement e.g.
- 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.
- a Mitsunobu reaction for example as reviewed in Mitsunobu, Synthesis , (1981), 1
- succinimide in the presence of diethyl azodicarboxylate and triphenylphosphine to give the phthalimidoethylpiperidine.
- diethyl azodicarboxylate diethyl azodicarboxylate and triphenylphosphine
- 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.
- 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.
- 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.
- 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.
- compositions 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.
- 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.
- suitable 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.
- 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
- Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
- 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.
- the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
- agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
- 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.
- a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
- 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 and frequency of administration. Such a dosage corresponds to 1.5 to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg/kg per day.
- the compound of formula (I) may be the sole therapeutic agent in the compositions of the invention or a combination with other antibacterials. If the other antibacterial is a ⁇ -lactam then a ⁇ -lactamase inhibitor may also be employed.
- the absolute stereochemistry was defined to be (R) by an NMR study on the Mosher's esters derived from the product obtained by reaction with 1-t-butylpiperazine.
- the acetal (5a) was cleaved by treatment with 5M HCl (10 ml) in acetone (20 ml) at 60° C. overnight. The mixture was basified with sodium bicarbonate solution and concentrated. Extraction into dichloromethane, evaporation and chromatography on silica gel (dichloromethane then methanol-dichloromethane) gave a yellow gum (482 mg).
- the ketone (5b) (159 mg) was treated with hexylamine (0.12 ml) in methanol for 1 hour and sodium triacetoxyborohydride (170 mg) was added. The mixture was stirred for 4 hours, evaporated, and the residue partitioned between dichloromethane/water. The dichloromethane extract was evaporated and chromatographed on silica gel (dichloromethane then methanol-dichloromethane) to give a colourless oil as the free base (150 mg) which was converted to the dioxalate salt in the normal manner, affording a white solid.
- the title compound was prepared from the ketone (5b) as described in Example (5c), using heptylamine.
- the ester (8a) (0.642 g) in 10% aqueous sodium hydroxide (115 ml) was heated at reflux for 1.5 hours. The reaction mixture was cooled then acidified with glacial acetic acid. The precipitated solid was collected by filtration, washed with water and dried in vacuo to afford a beige solid (0.542 g).
- the acid (8b) (6.82 g) was heated in quinoline (20 ml) at reflux for 2 hours, the mixture was cooled and poured into ether (200 ml) and the orange solid was filtered and washed with ether (5 ⁇ 200 ml).
- a sample (3.87 g) of the dried solid was treated with phosphorus oxychloride (30 ml) at room temp for 3 hours, the solvent was removed in vacuo and the residue quenched with crushed ice (200 g).
- the mixture was basified with ammonia solution and filtered.
- the solid was washed with dichloromethane (10 ⁇ 100 ml), which was evaporated and chromatographed on silica gel (dichloromethane as eluent) to give a yellow solid (3.0 g).
- Example (8e) (0.46 g, 1.4 mmol) in acetone (25 ml) and water (5 ml) was treated with concentrated hydrochloric acid (0.2 ml) and the mixture heated to reflux for 4 hours. The cooled mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic extract was dried and evaporated to give a white solid (0.4 g). Chromatography gave the title compound (0.2 g, 46%).
- Example (8f) (0.17 g, 0.6 mmol) in methanol (5 ml) was treated with heptylamine (0.13 ml, 0.1 g, 0.85 mmol) and sodium triacetoxyborohydride (0.18 g, 0.85 mmol). After 3 hours the mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic extract was dried and evaporated to give a white solid (0.3 g). Chromatography gave the title compound (0.13 g, 60%).
- the ester Example (9) (60 mg) was hydrolysed in 2M hydrochloric acid at 1000C. After evaporation to dryness, the product was triturated with ether. The salt obtained was converted to the free base, and then to the oxalate salt in the normal manner.
- the ester Example (9) (60 mg) was dissolved in dry tetrahydrofuran (2 ml) and treated with lithium aluminium hydride (1M in ether, 0.14 ml) at 0° C. for 3 hours. The mixture was treated with sodium hydroxide, and magnesium sulfate, filtered and evaporated to give the free base (38 mg, 68%). This was converted to the dioxalate salt in the normal manner.
- the free base was converted to the dioxalate salt in the normal manner, giving a white solid.
- the MIC ( ⁇ g/ml) of test compounds against various organisms was determined: S. aureus Oxford, S. aureus WCUH29, S. pneumoniae 1629, S. pneumoniae N1387, S. pneumoniae ERY 2.
- Example 4 has an MIC of less than or equal to 1 ⁇ g/ml against one or more of the above range of gram positive and gram negative bacteria.
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Abstract
Description
- This is a divisional of U.S. application Ser. No. 10/031,844, filed Jul. 17, 2002, which is a 371 of International Application PCT/EP00/06938, filed Jul. 17, 2000, which claims benefit from GB priority application 9917408.8, filed Jul. 23, 1999.
- This invention relates to novel aminopiperidine compounds, compositions containing them and their use as antibacterials.
- DE2315148A, EP0030044, NL7908030, EP0053964, EP0031753, EP0042781 and BE706646 disclose quinoline compounds having cardiovascular, hypnotic, anticonvulsant, and antimalarial effects.
- EP0579263, EP0742207, JP2169569, EP0296560, WO9103243, EP0449186 disclose piperidine compounds as acetylcholinesterase inhibitors and sigma receptor antagonists.
- WO9802438 and WO9703069 disclose certain bicyclic heteroaromatic compounds having protein tyrosine kinase and cell proliferation inhibitor activity.
- WO9217475, WO9802438, WO9703069 and WO9639145 disclose certain bicyclic heteroaromatic compounds having cholinesterase inhibitor, protein tyrosine kinase inhibitor, cell proliferation inhibitor and human epidermal growth factor receptor type 2 inhibitor activity.
- We have now found a novel group of aminopiperidines which have antibacterial activity.
-
- one of Z1, Z2, Z3, Z4 and Z5 is N, and the remainder are CR1a;
- R1 and R1a are independently hydrogen; hydroxy; (C1-6)alkoxy optionally substituted by (C1-6)alkoxy, amino, piperidyl, guanidino or amidino optionally N-substituted by one or two (C1-6)alkyl, acyl or (C1-6)alkylsulphonyl groups, CONH2, hydroxy, thiol, (C1-6)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy or (C1-6)alkylsulphonyloxy; (C1-6)alkoxy-substituted (C1-6)alkyl; halogen; (C1-6)alkyl; (C1-6)alkylthio; nitro; azido; acyl; acyloxy; (C1-6)alkylsulphonyl; (C1-6)alkylsulphoxide; arylsulphonyl; arylsulphoxide or an amino, piperidyl, guanidino or amidino group optionally N-substituted by one or two (C1-6)alkyl, acyl or (C1-6)alkylsulphonyl groups; and
- additionally when Z5 is CR1a, R1a may be (C1-4)alkyl-CO2H or (C1-4)alkyl-CONH2 in which the C1-4 alkyl is substituted by R12; (C1-4)alkyl substituted by cyano, amino or guanidino; aminocarbonyl optionally substituted by hydroxy, (C1-6)alkyl, hydroxy(C1-6)alkyl, aminocarbonyl(C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkylsulphonyl, trifluoromethylsulphonyl, (C1-6)alkenylsulphonyl, (C1-6)alkoxycarbonyl, (C1-6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl, (C2-6)alkenylcarbonyl, or CH(R13)CO2H or CH(R13)CO2NH2 optionally further substituted by (C1-6)alkyl, hydroxy(C1-6)alkyl, aminocarbonyl(C1-6)alkyl or (C2-6)alkenyl; hydroxy(C1-6)alkyl; carboxy; cyano or (C1-6)alkoxycarbonyl;
- wherein R13 is a natural α-amino acid side chain or its enantiomer;
- provided that when Z1, Z2, Z3, Z4 and Z5 are CR1a, then R1 is not hydrogen;
- R2 is hydrogen, or (C1-4)alkyl or (C1-4)alkenyl optionally substituted with 1 to 3 groups selected from:
- amino optionally substituted by one or two (C1-4)alkyl groups; carboxy; (C1-4)alkoxycarbonyl; (C1-4)alkylcarbonyl; (C2-4)alkenyloxycarbonyl; (C2-4)alkenylcarbonyl; aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (C1-4)alkyl, hydroxy(C1-4)alkyl, aminocarbonyl(C1-4)alkyl, (C2-4)alkenyl, (C1-4)alkylsulphonyl, trifluoromethylsulphonyl, (C1-4)alkenylsulphonyl, (C1-4)alkoxycarbonyl, (C1-4)alkylcarbonyl, (C2-4)alkenyloxycarbonyl or (C2-4)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-oxo-1,2,4-oxadiazol-3-yl; thiol; halogen; (C1-4)alkylthio; trifluoromethyl; azido; hydroxy optionally substituted by (C1-4)alkyl, (C2-4)alkenyl, (C1-4)alkoxycarbonyl, (C1-4)alkylcarbonyl, (C2-4)alkenyloxycarbonyl, (C2-4)alkenylcarbonyl; oxo; (C1-4)alkylsulphonyl; (C2-4)alkenylsulphonyl; or (C1-4)arinosulphonyl wherein the amino group is optionally substituted by (C1-4)alkyl or (C2-4)alkenyl;
- R3 is hydrogen; or
- R3 is in the 2-, 3- or 4-position and is:
- carboxy; (C1-6)alkoxycarbonyl; aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (C1-16)alkyl, hydroxy(C1-6)alkyl, aminocarbonyl(C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkylsulphonyl, trifluoromethylsulphonyl, (C1-6)alkenylsulphonyl, (C1-6)alkoxycarbonyl, (C1-6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl or (C2-6)alkenylcarbonyl and optionally further substituted by (C1-6)alkyl, hydroxy(C1-6)alkyl, aminocarbonyl(C1-6)alkyl or (C2-6)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 R10; or 5-oxo-1,2,4-oxadiazol-3-yl; or
- (C1-4)alkyl or ethenyl substituted with any of the substituents listed above for R3 and up to 3 groups R12 independently selected from:
- thiol; halogen; (C1-6)alkylthio; trifluoromethyl; azido; (C1-6)alkoxycarbonyl; (C1-6)alkylcarbonyl; (C2-6)alkenyloxycarbonyl; (C2-6)alkenylcarbonyl; hydroxy optionally substituted by (C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkoxycarbonyl, (C1-6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl, (C2-6)alkenylcarbonyl or aminocarbonyl wherein the amino group is optionally substituted by (C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkylcarbonyl or (C2-6)alkenylcarbonyl; amino optionally mono- or disubstituted by (C1-6)alkoxycarbonyl, (C1-6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl, (C2-6)alkenylcarbonyl, (C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkylsulphonyl, (C2-6)alkenylsulphonyl or aminocarbonyl wherein the amino group is optionally substituted by (C1-6)alkyl or (C2-6)alkenyl; aminocarbonyl wherein the amino group is optionally substituted by (C1-6)alkyl, hydroxy(C1-6)alkyl, aminocarbonyl(C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkoxycarbonyl, (C1-6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl or (C2-6)alkenylcarbonyl and optionally further substituted by (C1-6)alkyl, hydroxy(C1-6)alkyl, aminocarbonyl(C1-6)alkyl or (C2-6)alkenyl; oxo; (C1-6)alkylsulphonyl; (C2-6)alkenylsulphonyl; or (C1-6)aminosulphonyl wherein the amino group is optionally substituted by (C1-6)alkyl or (C2-6)alkenyl;
- 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; or
- when R3 is in the 3- or 4-position it may with R2 or R4 form a C3-5 alkylene group optionally substituted by a group R5 selected from:
- (C1-12)alkyl; hydroxy(C1-12)alkyl; (C1-12)alkoxy(C1-12)alkyl; (C1-12)alkanoyloxy(C1-12)alkyl; (C3-6)cycloalkyl; hydroxy(C3-6)cycloalkyl; (C1-12)alkoxy(C3-6)cycloalkyl; (C1-12)alkanoyloxy(C3-6)cycloalkyl; (C3-6)cycloalkyl(C1-12)alkyl; hydroxy-, (C1-12)alkoxy- or (C1-12)alkanoyloxy-(C3-6)cycloalkyl(C1-12)alkyl; cyano; cyano(C1-12)alkyl; (C2-12)alkenyl; (C2-12)alkynyl; tetrahydrofuryl; mono- or di-(C1-12)alkylamino(C1-12)alkyl; acylamino(C1-12)alkyl; (C1-12)alkyl- or acyl-aminocarbonyl(C1-12)alkyl; mono- or di- (C1-2)alkylamino(hydroxy) (C1-2)alkyl; optionally substituted phenyl(C1-12)alkyl, phenoxy(C1-12)alkyl or phenyl(hydroxy)(C1-12)alkyl; optionally substituted diphenyl(C1-12)alkyl; optionally substituted phenyl(C2-12)alkenyl; optionally substituted benzoyl or benzoyl(C1-12)alkyl; optionally substituted heteroaryl or heteroaryl(C1-2)alkyl; and optionally substituted heteroaroyl or heteroaroyl(C1-12)alkyl;
- R4 forms a group with R3 as above defined, or is a group —CH2—R5 where R5 is as defined above:
- n is 0, 1 or 2;
- A is NR11 or CR6R7 and B is NR11, O, SO2 or CR8R9 and wherein:
- each of R6, R7, R8 and R9 is independently selected from: hydrogen; (C1-6)alkylthio; halo; trifluoromethyl; azido; (C1-6)alkyl; (C2-6)alkenyl; (C1-6)alkoxycarbonyl; (C1-6)alkylcarbonyl; (C2-6)alkenyloxycarbonyl; (C2-6)alkenylcarbonyl; hydroxy, amino or aminocarbonyl optionally substituted as for corresponding substituents in R3; (C1-6)alkylsulphonyl; (C2-6)alkenylsulphonyl; or (C1-6)aminosulphonyl wherein the amino group is optionally substituted by (C1-6)alkyl or (C1-6)alkenyl;
- or R6 and R8 together represent a bond and R7 and R9 are as above defined;
- or R6 and R7 or R8 and R9 together represent oxo;
- provided that:
- when A is NR11, B is not NR11, O or SO2;
- when A is CO, B is not CO, O or SO2;
- when n is 0 and A is NR11, CR8R9 can only be CO;
- when A is CR6R7 and B is SO2, n is 0;
- when n is 0, B is not NR11 or O; and
- when A-B is CR7═CR9, n is 1 or 2;
- R10 is selected from (C1-4)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, (C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkylsulphonyl, trifluoromethylsulphonyl, (C1-6)alkenylsulphonyl, (C1-6)alkoxycarbonyl, (C1-6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl or (C2-6)alkenylcarbonyl and optionally further substituted by (C1-6)alkyl or (C2-6)alkenyl; (C1-6)alkylsulphonyl; trifluoromethylsulphonyl; (C1-6)alkenylsulphonyl; (C1-6)alkoxycarbonyl; (C1-6)alkylcarbonyl; (C2-6)alkenyloxycarbonyl; and (C2-6)alkenylcarbonyl;
- R11 is hydrogen; trifluoromethyl, (C1-6)alkyl; (C1-6)alkenyl; (C1-6)alkoxycarbonyl; (C1-6)alkylcarbonyl; aminocarbonyl wherein the amino group is optionally substituted by (C1-6)alkoxycarbonyl, (C1-6)alkylcarbonyl, (C1-6)alkenyloxycarbonyl, (C2-6)alkenylcarbonyl, (C1-6)alkyl or (C1-6)alkenyl and optionally further substituted by (C1-6)alkyl or (C1-6)alkenyl;
- 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.
- Preferred groups of compounds include those where:
-
- (a) Z1 is N, and Z2-Z5 are CH,
- (b) Z1-Z5 are each CH, and
- (c) Z5 is N, and Z1-Z4 are CH.
- When R1 or R1a is substituted alkoxy it is preferably (C2-6)alkoxy substitituted by optionally N-substituted amino, guanidino or amidino, or (C1-6)alkoxy optionally substituted by piperidyl. Suitable examples of R1 and R1a alkoxy include methoxy, n-propyloxy, iso-butyloxy, aminoethyloxy, aminopropyloxy, aminobutyloxy, amiinopentyloxy, guanidinopropyloxy, piperidin-4-ylmethyloxy and phthalimido pentyloxy.
- Preferably R1 and R1a are independently methoxy, amino(C3-5)alkyloxy, guanidino(C3-5)alkyloxy, piperidyl(C3-5)alkyloxy, nitro or fluoro; more preferably methoxy, amino(C3-5)alkyloxy or guanidino(C3-5)alkyloxy.
- Z2 and Z4 are preferably CH.
- When Z5 is CR1a, R1a is preferably hydrogen, cyano, hydroxymethyl or carboxy.
- 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 (C1-4)alkenyl substituted with (C1-4)alkoxycarbonyl or carboxy. More preferred groups for R2 are hydrogen, carboxymethyl, hydroxyethyl, aminocarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylallyl and carboxyallyl.
- Preferred examples of R3 include hydrogen; optionally substituted aminocarbonyl; optionally substituted (C1-6)alkyl; carboxy(C1-4)alkyl; optionally substituted aminocarbonyl(C1-4)alkyl; cyano(C1-4)alkyl; optionally substituted 2-oxo-oxazolidinyl and optionally substituted 2-oxo-oxazolidinyl(C1-4alkyl). More preferred R3 groups are hydrogen; CONH2; 1-hydroxyalkyl e.g. CH2OH, CH(OH)CH2CN; CH2CO2H; CH2CONH2; 1,2-dihydroxyalkyl e.g. CH(OH)CH2OH; CH2CN; 2-oxo-oxazolidin-5-yl and 2-oxo-oxazolidin-5-yl(C1-4alkyl).
- R3 is preferably in the 3- or 4-position.
- In a preferred aspect, when R3 is in the 3-position the substitutents at the 3- and 4-position of the piperidine ring are cis.
- Preferably A is CHOH or NR11.
- Preferably B is CH2, SO2 or CO.
- Particularly preferred are those compounds where A is NH and B is CO, or A is CHOH and B is CH2, when more preferably A is the R-isomer of CHOH.
- Preferably R11 is hydrogen or (C1-4)alkyl e.g. methyl, more preferably hydrogen.
- Preferably R4 is (C5-12)alkyl, unsubstituted phenyl(C2-3)alkyl or unsubstituted phenyl(C3-4)alkenyl. Suitable groups R4 include n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-dodecyl, phenylethyl, phenylpropyl or 3-phenyl-prop-2-en-yl optionally substituted on the phenyl ring; more preferably R4 is hexyl, heptyl, 5-methylhexyl, 6-methyl heptyl or 3-phenyl-prop-2-en-yl, especially heptyl or hexyl.
- 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.
- Preferred R5 groups are unbranched at the α and, where appropriate, β positions.
- Halo or halogen includes fluoro, chloro, bromo and iodo.
- 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 substituted by, for example, up to three groups selected from optionally substituted amino, halogen, (C1-6)alkyl, (C1-6)alkoxy, halo(C1-6)alkyl, hydroxy, carboxy, carboxy salts, carboxy esters such as (C1-6)alkoxycarbonyl, (C1-6)alkoxycarbonyl(C1-6)alkyl, aryl, 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 (C1-6)alkyl optionally substituted by hydroxy, (C1-6)alkoxy, thiol, (C1-6)alkylthio, halo or trifluoromethyl, and amino-protecting groups such as acyl or (C1-6)alkylsulphonyl groups.
- The term “heteroaryl” includes the aromatic heterocyclic groups referred to above. Examples of heteroaryl groups include pyridyl, triazolyl, tetrazolyl, indolyl, thienyl, isoimidazolyl, thiazolyl, furanyl, quinolinyl, imidazolidinyl and benzothienyl.
- When used herein the term “aryl”, includes phenyl and naphthyl.
- Aryl groups, e.g. phenyl and benzoyl; heteroaryl and heteroaroyl groups may be optionally substituted with up to five, preferably up to three, groups selected from halogen, mercapto, (C1-6)alkyl, phenyl, (C1-6)alkoxy, hydroxy(C1-6)alkyl, mercapto (C1-6)alkyl, halo(C1-6)alkyl, hydroxy, optionally substituted amino, nitro, carboxy, (C1-6)alkylcarbonyloxy, (C1-6)alkoxycarbonyl, formyl, and (C1-6)alkylcarbonyl groups.
- The term “acyl” includes formyl and (C1-6)alkylcarbonyl group.
- The term “acyloxy” includes (C1-6)alkoxycarbonyl.
- 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 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 include salts and esters.
- Suitable pharmaceutically acceptable esters will be apparent to those skilled in the art and include for example benzyl, p-methoxybenzyl, benzoylmethyl, p-nitrobenzyl, 4-pyridylmethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, tert-butyl, tert-amyl, allyl, diphenylmethyl, triphenylmethyl, adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl, tetrahydropyran-2-yl, pentachlorophenyl, acetonyl, p-toluenesulphonylethyl, methoxymethyl, a silyl, stannyl or phosphorus-containing group, an oxime radical of formula —N═CHRy where Ry is aryl or heterocyclyl, or an in vivo hydrolysable ester radical such as defined below.
- Examples of suitable in vivo hydrolysable ester groups include, for example, acyloxy(C1-6)alkyl groups such as acetoxymethyl, pivaloyloxymethyl, α-acetoxyethyl, α-pivaloyloxyethyl, 1-(cyclohexylcarbonyloxy)prop-1-yl, and (1-aminoethyl)carbonyloxymethyl; (C1-6)alkoxycarbonyloxy(C1-6)alkyl groups, such as ethoxycarbonyloxymethyl, α-ethoxycarbonyloxyethyl and propoxycarbonyloxyethyl; di(C1-6)alkylamino(C1-6)alkyl especially di(C1-4)alkylamino(C1-4)alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; 2-((C1-6)alkoxycarbonyl)-2-(C2-6)alkenyl groups such as 2-(isobutoxycarbonyl)pent-2-enyl and 2-(ethoxycarbonyl)but-2-enyl; lactone groups such as phthalidyl and dimethoxyphthalidyl.
- Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include for example acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulphonic, methanesulphonic or naphthalenesulphonic acid. Other salts e.g. oxalates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention.
- 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)—CH2 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):
wherein Z1, Z2, Z3, Z4, Z5 and n are as defined in formula (I); R1, R2′, R3′ and R4′ are R1, R2, R3 and R4 as defined in formula (I) or groups convertible thereto; and X and Y may be the following combinations: - (i) X is A′-COW, Y is H and n is 0;
- (ii) X is CR6═CR8R9, Y is H and n is 0;
- (iii) X is oxirane, Y is H and n is 0;
- (iv) X is N═C═O and Y is H;
- (v) X is NH2 and Y is CO2W;
- (vi) one of X and Y is CO2Ry and the other is CH2CO2Rx;
- (vii) X is CHR6R7 and Y is CR80;
- (viii) X is CR6═PRz 3 and Y is CR8O;
- (ix) X is CR6O and Y is CR8═PRz 3;
- (x) one of X and Y is COW and the other is NHR11′ or NCO;
- (xi) X is CR6O and Y is NHR11 or X is NHR11′ and Y is C R8O;
- (xii) X is NHR11′ and Y is CR8R9W;
- (xiii) X is CR6R7W and Y is NR11′ or O; or
- (xiv) X is CR6R7SO2W and Y is H and n=0;
- (xv) X is NR11′ and Y is SO2W;
- in which W is a leaving group, e.g. halogen; Rx and Ry are (C1-6)alkyl; Rz is aryl or (C1-6)alkyl; A′ and NR11′ are A and NR11 as defined in formula (I), or groups convertible thereto; and oxirane is:
wherein R6, R8 and R9 are as defined in formula (I); - and thereafter optionally or as necessary converting A′, R1′, R2′, R3′, R4′ and NR11′; to A, R1, R2, 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.
- 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 CHR6—CR8R9.
- Process variant (iii) initially produces compounds of formula (I) wherein A-B is CR6(OH)—CR8R9.
- Process variants (iv) and (v) initially produce compounds of formula (I) where A-B is NH—CO.
- Process variant (vi) initially produces compounds of formula (I) wherein A-B is CO—CH2 or CH2—CO.
- Process variant (vii) initially produces compounds of formula (I) wherein A-B is CR6R7—CR8OH.
- Process variant (viii) and (ix) initially produce compounds of formula (I) wherein A-B is CR6═CR8.
- Process variant (x) initially produces compounds of formula (I) where A-B is CO—NR11′ or NR11′—CO.
- Process variant (xi) initially produces compounds of formula (I) wherein A-B is CHR6—NR11′ or NR11′—CHR6.
- Process variant (xii) initially produces compounds of formula (I) wherein A-B is NR11′—CR8R9.
- Process variant (xiii) initially produces compounds of formula (I) wherein A-B is CR6R7—NR11′ or CR6R7—O.
- Process variant (xiv) initially produces compounds of formula (I) where A-B is CR6R7—SO2.
- Process variant (xv) initially produces compounds of formula (I) where A-B is NR11′—SO2.
- In process variants (i), (v) and (x) the reaction is a standard amide 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 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
- 2. The specific methods of:
- 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).
- 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). In some cases an elevated temperature such as 40-70° C. may be beneficial. Alternatively, the piperazine 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 (vi) 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 HCl 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.
- In process variant (vii) 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) JACS 100, 576).
- In process variants (viii) and (ix) 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 e.g. di-isopropylamide. An analogous method is described in U.S. Pat. No. 3,989,691 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 (xi) where X or Y is CHO the reaction is a standard reductive alkylation using, e.g., 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 (xii) and (xiii). 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 (xiv) and (xv) 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.
- Reduction of a carbonyl group 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 aluminiun hydride in ethereal solution. This is analogous to methods described in EP53964, US384556 and J. Gutzwiller et al, J. Amer. Chem. Soc., 1978, 100, 576.
- The carbonyl group B may be reduced to CH2 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 B with an organometallic reagent yields a group where R8 is OH and R9 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 CHR6CR8OH or CR6(OH)CHR8 may be dehydrated to give the group CR6═CR8 by treatment with an acid anhydride such as acetic anhydride.
- Methods for conversion of CR6═CR8 by reduction to CHR6CHR8 are well known to those skilled in the art, for example using hydrogenation over palladium on carbon as catalyst. Methods for conversion of CR6═CR8 to give the A-B group CR6(OH)CHR8 or CHR6CR8OH 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.
- R1′, R2′, R3 and R4′ are preferably R1, R2, R3 and R4. R1 is preferably methoxy. R2′ is preferably hydrogen. R3′ is preferably hydrogen, CONH2, CH2OH, CH2CO2H, CH2CONH2, CH(OH)CH2OH, CH(OH)CH2CN, CH2CN, 2-oxo-oxazolidin-5-yl and 2-oxo-oxazolidin-5-yl(C1-4alkyl). R4′ is preferably heptyl.
- Conversions of R1′, R2′, 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.
- For example R1′ 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 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)—CH2CN group.
- Opening an epoxide-containing R3′ group with azide anion yields an azide derivative which can be reduced to the amine. Conversion of the amine to a carbamate is followed by ring closure with base to give the 2-oxo-oxazolidinyl containing R3 group.
- Substituted 2-oxo-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 CH2OH 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).
- Other routes to the synthesis of carboxy groups within R3 are well known to those skilled in the art.
- R3 groups containing a cyano 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.
- 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 et 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. Ornstein, 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. Soil, 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 (CH2)nCHO (n=0, 1, 2) is treated with triethylamine, carbontetrabromide-triphenylphosphine to give initially (CH2)nCH═CHBr; (2) dehydrobromination of this intermediate to give the corresponding bromoethyne derivative (CH2)nC≡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 —CH2CH2— 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 methylethoxyester 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 et al, J. Med Chem, 1996, 39(11), 2232).
- The alkyl- and alkenyl-sulphonylcarboxamides are similarly prepared from the corresponding carboxylic acid and the alkyl- or alkenyl-sulphonamide by dehydration with standard peptide coupling agents such as 1,1′-carbonyldiimidazole (P. L. Omstein 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 nitrites 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 A. R. Katritzky and C. W. Rees, Pergamon Press, Oxford, 1984 and J. 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.
- Compounds of formula (I) where R2 and R3 are a divalent residue ═CR5, R61 can be prepared by treatment of a compound of formula (I) where R3 is alken-1-yl with a strong base in an aprotic solvent. Suitable bases include Ph2PLi/PhLi (as described in Ireland et al, J. Amer. Chem. Soc., 1973, 7829), t-BuLi, and suitable solvents include THF and ether.
- NH is converted to NR4 by conventional means such as alkylation with an alkyl halide in the presence of base, acylation/reduction or reductive alkylation with an aldehyde.
- 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 NH will require protection e.g. as a carboxy- or silyl-ester group for hydroxy and as an acyl derivative for piperidine nitrogen, during conversion of R1′, R2′, R3′ or R4′.
- Compounds of formula (IV) where X is CR6R7SO2W 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 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 (POCl3) or phosphorus pentachloride, PCl5. A 4-chloroquinazoline is prepared from the corresponding quinazolin-4-one by reaction with phosphorus oxychloride (POCl3) or phosphorus pentachloride, PCl5. 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.
- 4-Carboxy derivatives of compounds of formula (IV) are commercially available 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. Pyridazines and napthyridines may be prepared by routes analogous to those described in Comprehensive Heterocyclic Chemistry, Volumes 2 & 3, Ed A. J. Boulton and A. McKillop. These 4-carboxy derivatives may be activated by conventional means, e.g. by conversion to an acyl halide or anhydride.
- 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 5M 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.
- If a chiral reducing agent such as (+) or (−)-B-chlorodiisopinocamphenylborane [‘DIP-chloride’ ] is substituted for sodium borohydride, the prochiral chloromethylketone 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 piperazine 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 ethoxymethylenemalonic ester 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, Joe 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. 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).
- 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 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).
- Conversions of R1′, 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 and frequency of administration. Such a dosage corresponds to 1.5 to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg/kg per day.
- No toxicological effects are indicated when a compound of formula (I) or a pharmaceutically acceptable derivative thereof is administered in the above-mentioned dosage range.
- The compound of formula (I) may be the sole therapeutic agent in the compositions of the invention or a combination with other antibacterials. If the other antibacterial is a β-lactam then a β-lactamase inhibitor may also be employed.
- Compounds of formula (I) are active against a wide range of organisms including both Gram-negative and Gram-positive organisms.
- All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
- The following examples illustrate the preparation of certain compounds of formula (I) and the activity of certain compounds of formula (I) against various bacterial organisms.
- A solution of 6-methoxyquinoline-4-carboxylic acid (10 g) in dichloromethane was heated under reflux with oxalyl chloride (5 ml) and dimethylformamide (2 drops) for 1 hour and evaporated to dryness. The residue, in dichloromethane (100 ml) was treated with a 2M solution of trimethylsilyldiazomethane in hexane (50 ml) and stirred at room temperature for 18 hours. 5M Hydrochloric acid (150 ml) was added and the solution was stirred at room temperature for 3 hours. It was basified with sodium carbonate solution, extracted with ethyl acetate and chromatographed on silica gel eluting with ethyl acetate-hexane to give the chloromethyl ketone (4.2 g). A batch of the chloromethyl ketone (20 g) was reduced with (+)-B-chlorodiisopinocamphenylborane (40 g) in dichloromethane (400 ml) at room temperature for 18 hours followed by treatment with diethanolamine (30 g) for 3 hours. The product was chromatographed on silica gel eluting with ethyl acetate-hexane to give the chloroalcohol (16.8 g), which was dissolved in tetrahydrofuran (100 ml) and reacted with sodium hydroxide (2.6 g) in water (13 ml) for 1.5 hours. The reaction mixture was evaporated to dryness and chromatographed on silica gel eluting with ethyl acetate-hexane to give the title compound as a solid (10.4 g) (84% ee by chiral HPLC). Recrystallisation from ether-pentane gave mother-liquor (7.0 g) (90% ee).
- MS (+ve ion electrospray) m/z 202 (MH+)
- The absolute stereochemistry was defined to be (R) by an NMR study on the Mosher's esters derived from the product obtained by reaction with 1-t-butylpiperazine.
- A solution of 1-tert-butoxycarbonyl-3-ethoxycarbonyl-piperidin-4-one (prepared from 3-ethoxycarbonyl-piperidin-4-one and di-tert-butyl-dicarbonate in dichloromethane and triethylamine) (8.5 g) and heptylamine (3.61 g) in toluene (100 ml) was heated under reflux in a Dean and Stark apparatus for 18 hours and then evaporated to dryness to give an oil.
- The enamine (1b) in ethanol (100 ml) was hydrogenated at 50 psi (Parr reaction vessel) over 10% palladium-carbon (2 g) for 48 hours, filtered and evaporated to dryness to give an oil. The product was chromatographed on silica gel (ethyl acetate-hexane) to afford the title compound (4.5 g), as an oil.
- MS (+ve ion electrospray) m/z 371 (MH+).
- The amine (1c) (1.2 g) was treated with dichloromethane (30 ml) and trifluoroacetic acid (30 ml) at room temperature for 3.5 hours and evaporated to dryness. It was basified with sodium carbonate solution, extracted with dichloromethane, dried over sodium sulfate and evaporated to afford an oil (0.9 g).
- A solution of [R]-2-(6-methoxyquinolin-4-yl)oxirane (1a) (0.626 g) and the piperidine (1d) (0.85 g) in acetonitrile (5 ml) containing lithium perchlorate (0.332 g) was stirred at room temperature for 15 hours and evaporated to dryness. The product was dissolved in dichloromethane, washed with sodium carbonate, dried over sodium sulfate, and chromatographed on silica gel (ethyl acetate-hexane) to afford the title compound (0.69 g) as the oily free base.
- MS (+ve ion electrospray) m/z 472 (MH+).
- The free base was treated with 2 molar equivalents of oxalic acid in ether and the resulting solid was collected, triturated with ether, to afford the dioxalate salt as a white solid.
-
- The ester Example (1) (0.105 g) in dry tetrahydrofuran (5 ml) at −10° C. was treated with lithium aluminium hydride (0.27 ml of a 1M solution in ether) for 3 hours and then quenched by the addition of 2M sodium hydroxide. Dichloromethane and sodium sulfate were added and the solution was filtered and evaporated to dryness. The product was chromatographed on silica gel (methanol-dichloromethane) to afford the title compound (0.057 g), as the oily free base.
- MS (+ve ion electrospray) m/z 430 (MH+).
- 1H NMR (CDCl3) δ: 0.88 (3H, t), 1.30 (9H, bs), 1.47 (2H, bs), 1.75 (1H, bt), 1.95-2.80 (˜8H, m), 2.98 (2H, m), 3.85 (1H, m), 3.95 (3H, s), 4.25 (1H, bt), 5.41 (1H, m) 7.17 (1H, bs), 7.39 (1H, dd), 7.65 (1H, d), 8.05 (1H, d), 8.78 (1H, d).
- The free base in dichloromethane-ether was converted to the dioxalate salt in the normal manner, affording a white solid.
- The ester Example (1) (0.07 g) was heated in 2M hydrochloric acid (7 ml) under reflux for 5 hours and then evaporated to dryness to give the title compound as a foam. MS (+ve ion electrospray) m/z 444 (MH+).
-
- The ester Example (1) (0.18 g) in methanol (3 ml) was heated with ammonia (3 ml) and sodium cyanide (5 mg) at 50° C. (sealed bomb) for 4 days and evaporated to dryness. Chromatography on silica gel (ethyl-acetate then methanol-dichloromethane) gave the title compound (0.046 g), as the free base.
- MS (+ve ion electrospray) m/z 443 (MH+).
- The free base in dichloromethane-ether was converted to the dioxalate salt in the normal manner, affording a white solid.
-
- [R]-2-(6-Methoxyquinolin-4-yl)oxirane (1a) (470 mg) and 1,4-dioxa-8-azaspiro-[4,5]-decane (0.33 ml) were dissolved in dry dichloromethane (5 ml) and ytterbium triflate (30 mol %) was added. The mixture was stirred for 6 hours, filtered through celite, evaporated and chromatographed on silica gel (dichloromethane then methanol-dichloromethane) to afford the title compound (690 mg).
- MS (+ve ion electrospray) m/z 345 (MH+).
- The acetal (5a) was cleaved by treatment with 5M HCl (10 ml) in acetone (20 ml) at 60° C. overnight. The mixture was basified with sodium bicarbonate solution and concentrated. Extraction into dichloromethane, evaporation and chromatography on silica gel (dichloromethane then methanol-dichloromethane) gave a yellow gum (482 mg).
- The ketone (5b) (159 mg) was treated with hexylamine (0.12 ml) in methanol for 1 hour and sodium triacetoxyborohydride (170 mg) was added. The mixture was stirred for 4 hours, evaporated, and the residue partitioned between dichloromethane/water. The dichloromethane extract was evaporated and chromatographed on silica gel (dichloromethane then methanol-dichloromethane) to give a colourless oil as the free base (150 mg) which was converted to the dioxalate salt in the normal manner, affording a white solid.
- MS (+ve ion electrospray) m/z 386 (MH+).
-
- The title compound was prepared from the ketone (5b) as described in Example (5c), using heptylamine.
- MS (+ve ion electrospray) m/z 400 (MH+).
- This was prepared by the method of Example (1a) except that the chloromethylketone was reduced with (−)-B-chlorodiisopinocamphenylborane. The product had 90% ee.
- MS (+ve ion electrospray) m/z 202 (MH+).
- The title compound was prepared from [S]-2-(6-methoxyquinolin-4-yl)oxirane (7a) as described in Example (5) using heptylamine.
- MS (+ve ion electrospray) m/z 400 (MH+).
-
- 3-Amino-6-methoxypyridine (12.41 g) and diethyl ethoxymethylene malonate (20.2 ml) in Dowtherm A (400 ml) were heated at reflux, under argon for 1 hour. The cooled reaction mixture was poured into pentane (1 litre). The precipitated solid was collected by filtration, washed with pentane and dried to afforded a solid (24.78 g, crude). MS (+ve ion electrospray) m/z 249 (MH+).
- The ester (8a) (0.642 g) in 10% aqueous sodium hydroxide (115 ml) was heated at reflux for 1.5 hours. The reaction mixture was cooled then acidified with glacial acetic acid. The precipitated solid was collected by filtration, washed with water and dried in vacuo to afford a beige solid (0.542 g).
- MS (+ve ion electrospray) m/z 221 (MH+).
- The acid (8b) (6.82 g) was heated in quinoline (20 ml) at reflux for 2 hours, the mixture was cooled and poured into ether (200 ml) and the orange solid was filtered and washed with ether (5×200 ml). A sample (3.87 g) of the dried solid was treated with phosphorus oxychloride (30 ml) at room temp for 3 hours, the solvent was removed in vacuo and the residue quenched with crushed ice (200 g). The mixture was basified with ammonia solution and filtered. The solid was washed with dichloromethane (10×100 ml), which was evaporated and chromatographed on silica gel (dichloromethane as eluent) to give a yellow solid (3.0 g).
- MS (+ve ion electrospray) m/z 195, 197 (MH+).
- A solution of the chloro compound (8c) (2.0 g) in pyridine (30 ml) was treated with n-propylamine hydrochloride (6.0 g) and the mixture heated at reflux for 16 hours. The reaction mixture was cooled and partitioned between water and ethyl acetate. The aqueous phase was washed with ethyl acetate, the combined organics dried (Na2SO4) and the solvent removed under reduced pressure. Purification by chromatography on silica gel (5-10% methanol in dichloromethane) afforded a yellow solid (1.0 g).
- 1H NMR (CDCl3) δ: 4.05 (3H, s), 5.36 (2H, bs), 6.71 (1H, d, J=5 Hz), 7.08 (1H, d, J=9 Hz), 8.10 (1H, d, J=9 Hz), 8.40 (1H, d, J=5 Hz).
- MS (+ve ion electrospray) m/z: 176 (MH+).
- A solution of the amine (8d) (0.32 g, 2 mmol) in chloroform (6 ml) was treated with N,N-dimethylaminopyridine (0.24 g, 2 mmol) then 1,1′-carbonyldiimidazole (0.42 g, 2.6 mmol). After 2 hours the chloroform was removed by evaporation and the residue treated with a solution of 4-oxopiperidine, ethylene ketal (0.31 g, 0.22 mmol) in N,N-dimethylformamide (5 ml). The mixture was heated at 100° C. for 1 hour, then partitioned between ethyl acetate and dilute brine. The organic extract was washed with water (3×), brine, dried and evaporated to give a yellow solid (0.8 g). Chromatography on silica gave the product as a white solid (0.47 g, 71%).
- MS (+ve ion electrospray) m/z 345 (MH+).
- A solution of Example (8e) (0.46 g, 1.4 mmol) in acetone (25 ml) and water (5 ml) was treated with concentrated hydrochloric acid (0.2 ml) and the mixture heated to reflux for 4 hours. The cooled mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic extract was dried and evaporated to give a white solid (0.4 g). Chromatography gave the title compound (0.2 g, 46%).
- MS (+ve ion electrospray) m/z 301 (MH+).
- A solution of Example (8f) (0.17 g, 0.6 mmol) in methanol (5 ml) was treated with heptylamine (0.13 ml, 0.1 g, 0.85 mmol) and sodium triacetoxyborohydride (0.18 g, 0.85 mmol). After 3 hours the mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic extract was dried and evaporated to give a white solid (0.3 g). Chromatography gave the title compound (0.13 g, 60%).
- MS (+ve ion electrospray) m/z 400 (MH+).
- 4-Heptylamino-1-[2-(R)-hydroxy-2-(6-methoxyquinolin-4-yl)]ethylpiperidine (Example 6) (100 mg) was alkylated with ethyl bromoacetate (0.026 ml) in the presence of potassium carbonate (105 mg) in dimethylformamide (3 ml). After removal of solvent, the crude product was dissolved in dichloromethane and washed with water. Chromatography on silica gel (10% methanol/dichloromethane) gave the title compound (85 mg, 70%). This was converted to the oxalate salt in the normal manner.
- MS (+ve ion electrospray) m/z 486 (MH+).
- The ester Example (9) (60 mg) was hydrolysed in 2M hydrochloric acid at 1000C. After evaporation to dryness, the product was triturated with ether. The salt obtained was converted to the free base, and then to the oxalate salt in the normal manner.
- MS (+ve ion electrospray) m/z 458 (MH+).
- The ester Example (9) (60 mg) was dissolved in dry tetrahydrofuran (2 ml) and treated with lithium aluminium hydride (1M in ether, 0.14 ml) at 0° C. for 3 hours. The mixture was treated with sodium hydroxide, and magnesium sulfate, filtered and evaporated to give the free base (38 mg, 68%). This was converted to the dioxalate salt in the normal manner.
- MS (+ve ion electrospray) m/z 444 (MH+).
- 4-Heptylamino-1-[2-(R)-hydroxy-2-(6-methoxyquinolin-4-yl)]ethylpiperidine (Example 6) (100 mg) was alkylated with 2-bromoacetamide (38 mg) in the presence of potassium carbonate (105 mg) in dimethylformamide (5 ml). After removal of solvent, the crude product was dissolved in dichloromethane and washed with water. Chromatography on silica gel (dichloromethane) gave the title compound (43 mg, 38%). This was converted to the dioxalate salt in the normal manner. MS (+ve ion electrospray) m/z 457 (MH+).
- 4-Heptylamino-1-[2-(R)-hydroxy-2-(6-methoxyquinolin-4-yl)]ethylpiperidine (Example 6) (190 mg) was acylated with a mixture of N-tert-butoxycarbonylglycine (87 mg), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (230 mg) and N-methyl morpholine (0.11 ml) in dry dichloromethane (10 ml). The mixture was poured into water and extracted with dichloromethane. The extract was washed with water and brine, dried and evaporated. The crude product was chromatographed on silica gel (2-10% methanov/dichloromethane) to give a mixture of N-acylated and N,O-diacylated products (86 mg).
- The above acylated mixture (43 mg) was reduced with lithium aluminium hydride as in Example (11). Chromatography on silica gel (dichloromethane) gave an N-(2-tert-butoxycarbonylaminoethyl) product (15 mg) which was heated in 5M hydrochloric acid at 100° C. Evaporation to dryness gave the title compound (12 mg).
- MS (+ve ion electrospray) m/z 443 (MH+).
- 4-Heptylamino-1-[2-(R)-hydroxy-2-(6-methoxyquinolin-4-yl)]ethylpiperidine (Example 6) (200 mg) was alkylated with ethyl 4-bromocrotonate (96 mg) in the presence of potassium carbonate (210 mg) in dimethylformamide (10 ml). After removal of solvent, the crude product was dissolved in dichloromethane and washed with water. Chromatography on silica gel (dichloromethane) gave the title compound (43 mg, 17%). MS (+ve ion electrospray) m/z 512 (MH+).
- The ester Example (14) (35 mg) was hydrolysed in 5M hydrochloric acid at 100° C. Evaporation to dryness gave the title compound (60 mg).
- MS (+ve ion electrospray) mnz 484 (MH+).
- 4-Amino-1-tert-butoxycarbonylpiperidine-4-carboxylate (5 g) in acetonitrile (22 ml) and methanol (2 ml) was treated with di-isopropylethylamine (3.65 ml) and trimethylsilyldiazomethane (2M in hexane, 13.9 ml). After overnight stirring and evaporation of solvent, the crude product was chromatographed on silica gel (0-50% ethyl acetate/petrol) to give a yellow oil (4 g, 76%).
- MS (+ve ion electrospray) m/z 259 (MH+).
- A solution of the aminoester (16a) (3.77 g) in methanol (40 ml) was treated with heptaldehyde (2.03 ml) and stirred for 2 hours. Sodium triacetoxyborohydride (3.43 g) was added and the mixture was stirred for 16 hours. Solvent was evaporated and the residue was dissolved in dichloromethane, washed with water, dried and evaporated, to give a yellow oil (4.34 g, 83%).
- MS (+ve ion electrospray) m/z 357 (MH+).
- To a solution of the tert-butoxycarbonylpiperidine (16b) (0.2 g) in dichloromethane (1 ml) was added trifluoroacetic acid (1 ml). When hydrolysis was complete the mixture was extracted with water. The aqueous extract was washed with ether, basified with sodium hydrogen carbonate and saturated with sodium chloride, then extracted with 5% methanol/dichloromethane. The extract was dried and evaporated to give a yellow oil (90 mg, 63%).
- MS (+ve ion electrospray) m/z 257 (MH+).
- A mixture of the piperidine (16c) (0.5 g), oxirane Example 1(a) (0.43 g) and lithium perchlorate (0.28 g) in acetonitrile (2 ml) was stirred for 3 days at room temperature, then heated at 50° C. for 16 hours. Solvent was evaporated and the residue was dissolved in dichloromethane, washed with water, dried and evaporated. The crude product was chromatographed on silica gel (ethyl acetate) to give the free base (0.35 g, 39%), which was converted to the dioxalate salt in the normal manner.
- MS (+ve ion electrospray) m/z 458 (MH+).
- The ester Example (16) (50 mg) was heated under reflux in 2M hydrochloric acid for 18 hours. Evaporation to dryness and trituration with ethyl acetate and ether gave the title compound (51 mg).
- MS (+ve ion electrospray) m/z 444 (MH+).
-
- The ester Example (16) (60 mg) was reduced with lithium aluminium hydride as in Example (11). Chromatography on silica gel (0-20% methanol/dichloromethane) gave the title compound (31 mg).
- MS (+ve ion electrospray) m/z 430 (MH+).
- 1H NMR (CDCl3): δ0.88 (3H, t, J=7), 1.28 (8H, m), 1.46 (2H, m), 1.68 (4H, m), 2.41-2.58 (5H, m), 2.73 (1H, quintet, J=5), 2.85 (2H, dd, J=12,3), 3.38 (2H, s), 3.93 (3H, s), 5.43 (1H, dd, J=13,3), 7.18 (1H.d, J=3), 7.37 (1H, dd, J=9,3), 7.63 (1H, d, J=4.5), 8.03 (1H, d, J=9), 8.77 (1H, d,J=4.5)
- The free base was converted to the dioxalate salt in the normal manner, giving a white solid.
- A solution of amine (8d) (0.26 g) in chloroform (7 ml) was treated with 4-dimethylaminopyridine (0.2 g) and 1,1′-carbonyldiimidazole (0.44 g) and stirred for 18 hours. The solvent was evaporated and replaced with dimethyl formamide (5 ml). The piperidine ester Example (16c) (0.46 g) was added and the mixture was stirred for 2 hours at 100° C. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried and evaporated The crude product was chromatographed on silica gel (1:1 hexane/ethyl acetate) to give the free base (0.25 g, 34%).
- MS (+ve ion electrospray) m/z 458 (MH+).
-
- The ester Example (19) (0.1 g)) was reduced with lithium aluminium hydride as in Example 11. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and brine, dried and evaporated. The crude product was chromatographed on silica gel (0-1% methanol/dichloromethane) to give the title compound (50 mg, 53%) as a white solid.
- MS (+ve ion electrospray) m/z 430 (MH+).
- 1H-NMR (CDCl3): δ 0.88(3H,t,J=7 Hz), 1.28(8H,m), 1.47(2H,m), 1.70(4H,m), 2.51(2H,t,J=7 Hz), 3.452H,s), 3.59(2H,dm,J=13 Hz), 3.73(2H,dm,J=13 Hz), 4.05(3H,s), 7.13(1H,d,J=9 Hz), 8.20(1H,d,J=9 Hz), 8.31(1H,d,J=5 Hz), 8.64(1H,d,J=5 Hz), 9.08(1H,s).
- Biological Activity
- The MIC (μg/ml) of test compounds against various organisms was determined: S. aureus Oxford, S. aureus WCUH29, S. pneumoniae 1629, S. pneumoniae N1387, S. pneumoniae ERY 2.
- Example 4 has an MIC of less than or equal to 1 μg/ml against one or more of the above range of gram positive and gram negative bacteria.
Claims (9)
1. A compound of formula (I) or a pharmaceutically acceptable derivative thereof:
wherein:
Z1, Z2, Z3, Z4 and Z5 are each CH;
R1 is hydroxy; (C1-6)alkoxy optionally substituted by (C1-6)alkoxy, amino, piperidyl, guanidino or amidino optionally N-substituted by one or two (C1-6)alkyl, acyl or (C1-6)alkylsulphonyl groups, CONH2, hydroxy, thiol, (C1-6)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy or (C1-6)alkylsulphonyloxy; (C1-6)alkoxy-substituted (C1-6)alkyl; halogen; (C1-6)alkyl; (C1-6)alkylthio; nitro; azido; acyl; acyloxy; (C1-6)alkylsulphonyl; (C1-6)alkylsulphoxide; arylsulphonyl; arylsulphoxide or an amino, piperidyl, guanidino or amidino group optionally N-substituted by one or two (C1-6)alkyl, acyl or (C1-6)alkylsulphonyl groups;
R2 is hydrogen, or (C1-4)alkyl or (C1-4)alkenyl optionally substituted with 1 to 3 groups selected from:
amino optionally substituted by one or two (C1-4)alkyl groups; carboxy; (C1-4)alkoxycarbonyl; (C1-4)alkylcarbonyl; (C2-4)alkenyloxycarbonyl; (C2-4)alkenylcarbonyl; aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (C1-4)alkyl, hydroxy(C1-4)alkyl, aminocarbonyl(C1-4)alkyl, (C2-4)alkenyl, (C1-4)alkylsulphonyl, trifluoromethylsulphonyl, (C1-4)alkenylsulphonyl, (C1-4)alkoxycarbonyl, (C1-4)alkylcarbonyl, (C2-4)alkenyloxycarbonyl or (C2-4)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-oxo-1,2,4-oxadiazol-3-yl; thiol; halogen; (C1-4)alkylthio; trifluoromethyl; azido; hydroxy optionally substituted by (C1-4)alkyl, (C2-4)alkenyl, (C1-4)alkoxycarbonyl, (C1-4)alkylcarbonyl, (C2-4)alkenyloxycarbonyl, (C2-4)alkenylcarbonyl; oxo; (C1-4)alkylsulphonyl; (C2-4)alkenylsulphonyl; or (C1-4)aminosulphonyl wherein the amino group is optionally substituted by (C1-4)alkyl or (C2-4)alkenyl;
R3 is hydrogen; or
R3 is in the 2-, 3- or 4-position and is:
carboxy; (C1-6)alkoxycarbonyl; aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (C1-6)alkyl, hydroxy(C1-6)alkyl, aminocarbonyl(C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkylsulphonyl, trifluoromethylsulphonyl, (C1-6)alkenylsulphonyl, (C1-6)alkoxycarbonyl, (C1-6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl or (C2-6)alkenylcarbonyl and optionally further substituted by (C1-6)alkyl, hydroxy(C1-6)alkyl, aminocarbonyl(C1-6)alkyl or (C2-6)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 R10; or 5-oxo-1,2,4-oxadiazol-3-yl; or
(C1-4)alkyl or ethenyl substituted with any of the substituents listed above for R3 and up to 3 groups R12 independently selected from:
thiol; halogen; (C1-6)alkylthio; trifluoromethyl; azido; (C1-6)alkoxycarbonyl; (C1-6)alkylcarbonyl; (C2-6)alkenyloxycarbonyl; (C2-6)alkenylcarbonyl; hydroxy optionally substituted by (C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkoxycarbonyl, (C1-6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl, (C2-6)alkenylcarbonyl or aminocarbonyl wherein the amino group is optionally substituted by (C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkylcarbonyl or (C2-6)alkenylcarbonyl; amino optionally mono- or disubstituted by (C1-16)alkoxycarbonyl, (C1-6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl, (C2-6)alkenylcarbonyl, (C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkylsulphonyl, (C2-6)alkenylsulphonyl or aminocarbonyl wherein the amino group is optionally substituted by (C1-6)alkyl or (C2-6)alkenyl; aminocarbonyl wherein the amino group is optionally substituted by (C1-6)alkyl, hydroxy(C1-6)alkyl, aminocarbonyl(C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkoxycarbonyl, (C1-6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl or (C2-6)alkenylcarbonyl and optionally further substituted by (C1-6)alkyl, hydroxy(C1-6)alkyl, aminocarbonyl(C1-6)alkyl or (C2-6)alkenyl; oxo; (C1-6)alkylsulphonyl; (C2-6)alkenylsulphonyl; or (C1-6)aminosulphonyl wherein the amino group is optionally substituted by (C1-6)alkyl or (C2-6)alkenyl;
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; or
when R3 is in the 3- or 4-position it may with R2 or R4 form a C3-5 alkylene group optionally substituted by a group R5 selected from:
(C1-12)alkyl; hydroxy(C1-12)alkyl; (C1-12)alkoxy(C1-12)alkyl; (C1-12)alkanoyloxy(C1-12)alkyl; (C3-6)cycloalkyl; hydroxy(C3-6)cycloalkyl; (C1-12)alkoxy(C3-6)cycloalkyl; (C1-12)alkanoyloxy(C3-6)cycloalkyl; (C3-6)cycloalkyl(C1-12)alkyl; hydroxy-, (C1-12)alkoxy- or (C1-12)alkanoyloxy-(C3-6)cycloalkyl(C1-12)alkyl; cyano; cyano(C1-12)alkyl; (C2-12)alkenyl; (C2-12)aynyl; tetrahydrofuryl; mono- or di-(C1-12)alkylamino(C1-12)alkyl; acylamino(C1-12)alkyl; (C1-12)alkyl- or acyl-aminocarbonyl(C1-12)alkyl; mono- or di- (C1-12)alkylamino(hydroxy) (C1-12)alkyl; optionally substituted phenyl(C1-12)alkyl, phenoxy(C1-12)alkyl or phenyl(hydroxy)(C1-12)alkyl; optionally substituted diphenyl(C1-12)alkyl; optionally substituted phenyl(C2-12)alkenyl; optionally substituted benzoyl or benzoyl(C1-12)alkyl; optionally substituted heteroaryl or heteroaryl(C1-12)alkyl; and optionally substituted heteroaroyl or heteroaroyl(C1-12)alkyl;
R4 forms a group with R3 as above defined, or is a group —CH2—R5 where R5 is as defined above:
n is 0, 1 or 2;
A is NR11 or CR6R7 and B is NR11, O, SO2 or CR8R9 and wherein:
each of R6, R7, R8 and R9 is independently selected from: hydrogen; (C1-6)alkylthio; halo; trifluoromethyl; azido; (C1-6)alkyl; (C2-6)alkenyl; (C1-6)alkoxycarbonyl; (C1-6)alkylcarbonyl; (C2-6)alkenyloxycarbonyl; (C2-6)alkenylcarbonyl; hydroxy, amino or aminocarbonyl optionally substituted as for corresponding substituents in R3; (C1-6)alkylsulphonyl; (C2-6)alkenylsulphonyl; or (C1-6)aminosulphonyl wherein the amino group is optionally substituted by (C1-6)alkyl or (C1-6)alkenyl;
or R6 and R8 together represent a bond and R7 and R9 are as above defined;
or R6 and R7 or R8 and R9 together represent oxo;
provided that:
when A is NR11, B is not NR11, O or SO2;
when A is CO, B is not CO, O or SO2;
when n is 0 and A is NR11, CR8R9 can only be CO;
when A is CR6R7 and B is SO2, n is 0;
when n is 0, B is not NR11 or O; and
when A-B is CR7═CR9, n is 1 or 2;
R10 is selected from (C1-4)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, (C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkylsulphonyl, trifluoromethylsulphonyl, (C1-6)alkenylsulphonyl, (C1-6)alkoxycarbonyl, (C1-6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl or (C2-6)alkenylcarbonyl and optionally further substituted by (C1-6)alkyl or (C2-6)alkenyl; (C1-6)alkylsulphonyl; trifluoromethylsulphonyl; (C1-6)alkenylsulphonyl; (C1-6)alkoxycarbonyl; (C1-6)alkylcarbonyl; (C2-6)alkenyloxycarbonyl; and (C2-6)alkenylcarbonyl;
R11 is hydrogen; trifluoromethyl, (C1-6)alkyl; (C1-6)alkenyl; (C1-6)alkoxycarbonyl; (C1-6)alkylcarbonyl; aminocarbonyl wherein the amino group is optionally substituted by (C1-6)alkoxycarbonyl, (C1-6)alkylcarbonyl, (C1-6)alkenyloxycarbonyl, (C2-6)alkenylcarbonyl, (C1-6)alkyl or (C1-6)alkenyl and optionally further substituted by (C1-6)alkyl or (C1-6)alkenyl.
2. A compound according to claim 1 wherein R1 is methoxy, amino(C3-5)alkyloxy, guanidino(C3-5)alkyloxy, piperidyl(C3-5)alkyloxy, nitro or fluoro.
3. A compound according to claim 1 wherein R3 is hydrogen; optionally substituted aminocarbonyl; optionally substituted (C1-6)alkyl; carboxy(C1-4)alkyl; optionally substituted aminocarbonyl(C1-4)alkyl; cyano(C1-4)alkyl; optionally substituted 2-oxo-oxazolidinyl or optionally substituted 2-oxo-oxazolidinyl(C1-4alkyl).
4. A compound according to claim 1 wherein R3 is in the 3-position and the substitutents at the 3- and 4-position of the piperidine ring are cis.
5. A compound according to claim 1 wherein A is NH and B is CO, or A is CHOH and B is CH2.
6. A compound according to claim 1 wherein R11 is hydrogen.
7. A compound according to claim 1 wherein R4 is (C5-12)alkyl, optionally substituted phenyl(C2-3)alkyl or optionally substituted phenyl(C3-4)alkenyl.
8. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.
9. A method of treatment of bacterial infections in mammals which method comprises the administration to a mammal in need of such treatment an effective amount of a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable derivative thereof.
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US11/292,011 US20060079546A1 (en) | 1999-07-23 | 2005-12-01 | Aminopiperidine derivatives as antibacterials |
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GB9917408.8 | 1999-07-23 | ||
PCT/EP2000/006938 WO2001007432A2 (en) | 1999-07-23 | 2000-07-17 | Aminopiperidine derivatives as antibacterials |
US10/031,844 US7001913B1 (en) | 1999-07-23 | 2000-07-17 | Aminopiperidine derivatives as antibacterials |
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US20040053928A1 (en) * | 2000-09-21 | 2004-03-18 | Davies David Thomas | Quinoline derivatives as antibacterials |
US20040077655A1 (en) * | 2000-12-20 | 2004-04-22 | Dartois Catherine Genevieve Yvette | Piperazine derivatives for treatment of bacterial infections |
US20040077656A1 (en) * | 2000-12-20 | 2004-04-22 | Markwell Roger Edward | Quinolines and nitrogenated derivatives thereof substituted in 4-position by a piperazine-containing moiety and their use as antibacterial agents |
US20040198755A1 (en) * | 2001-05-25 | 2004-10-07 | Dartois Catherine Genevieve Yvette | Bicyclic nitrogen-containing heterocyclic derivatives for use as antibacterials |
US7186730B2 (en) | 2001-05-25 | 2007-03-06 | Smithkline Beecham P.L.C. | Bicyclic nitrogen-containing heterocyclic derivatives for use as antibacterials |
US20040198756A1 (en) * | 2001-07-26 | 2004-10-07 | Davies David Thomas | Medicaments |
US7232832B2 (en) | 2002-11-05 | 2007-06-19 | Smithkline Beecham Corporation | Antibacterial agents |
US7618959B2 (en) | 2002-11-05 | 2009-11-17 | Smithklinebeecham Corp | Antibacterial agents |
Also Published As
Publication number | Publication date |
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GB9917408D0 (en) | 1999-09-22 |
EP1214314B1 (en) | 2005-09-07 |
DE60022523T2 (en) | 2006-06-29 |
DE60022523D1 (en) | 2005-10-13 |
WO2001007432A3 (en) | 2001-05-25 |
US7001913B1 (en) | 2006-02-21 |
WO2001007432A2 (en) | 2001-02-01 |
ATE304006T1 (en) | 2005-09-15 |
EP1214314A2 (en) | 2002-06-19 |
AU5986200A (en) | 2001-02-13 |
ES2246244T3 (en) | 2006-02-16 |
JP2003505455A (en) | 2003-02-12 |
WO2001007432A8 (en) | 2001-09-07 |
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