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Aminopiperidine derivatives as antibacterialsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbon Atoms, Polycyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos, Bicyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos, Plural Hetero Atoms In The Bicyclo Ring SystemAminopiperidine derivatives as antibacterials description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060079546, Aminopiperidine derivatives as antibacterials. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] 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. FIELD OF THE INVENTION [0002] This invention relates to novel aminopiperidine compounds, compositions containing them and their use as antibacterials. BACKGROUND OF THE INVENTION [0003] DE2315148A, EP0030044, NL7908030, EP0053964, EP0031753, EP0042781 and BE706646 disclose quinoline compounds having cardiovascular, hypnotic, anticonvulsant, and antimalarial effects. [0004] EP0579263, EP0742207, JP2169569, EP0296560, WO9103243, EP0449186 disclose piperidine compounds as acetylcholinesterase inhibitors and sigma receptor antagonists. [0005] WO9802438 and WO9703069 disclose certain bicyclic heteroaromatic compounds having protein tyrosine kinase and cell proliferation inhibitor activity. [0006] 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. SUMMARY OF THE INVENTION [0007] We have now found a novel group of aminopiperidines which have antibacterial activity. [0008] This invention provides a compound of formula (I) or a pharmaceutically acceptable derivative thereof: wherein: [0009] one of Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4 and Z.sup.5 is N, and the remainder are CR.sup.1a; [0010] R.sup.1 and R.sup.1a are independently hydrogen; hydroxy; (C.sub.1-6)alkoxy optionally substituted by (C.sub.1-6)alkoxy, amino, piperidyl, guanidino or amidino optionally N-substituted by one or two (C.sub.1-6)alkyl, acyl or (C.sub.1-6)alkylsulphonyl groups, CONH.sub.2, hydroxy, thiol, (C.sub.1-6)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy or (C.sub.1-6)alkylsulphonyloxy; (C.sub.1-6)alkoxy-substituted (C.sub.1-6)alkyl; halogen; (C.sub.1-6)alkyl; (C.sub.1-6)alkylthio; nitro; azido; acyl; acyloxy; (C.sub.1-6)alkylsulphonyl; (C.sub.1-6)alkylsulphoxide; arylsulphonyl; arylsulphoxide or an amino, piperidyl, guanidino or amidino group optionally N-substituted by one or two (C.sub.1-6)alkyl, acyl or (C.sub.1-6)alkylsulphonyl groups; and [0011] additionally when Z.sup.5 is CR.sup.1a, R.sup.1a may be (C.sub.1-4)alkyl-CO.sub.2H or (C.sub.1-4)alkyl-CONH.sub.2 in which the C.sub.1-4 alkyl is substituted by R.sup.12; (C.sub.1-4)alkyl substituted by cyano, amino or guanidino; aminocarbonyl optionally substituted by hydroxy, (C.sub.1-6)alkyl, hydroxy(C.sub.1-6)alkyl, aminocarbonyl(C.sub.1-6)alkyl, (C.sub.2-6)alkenyl, (C.sub.1-6)alkylsulphonyl, trifluoromethylsulphonyl, (C.sub.1-6)alkenylsulphonyl, (C.sub.1-6)alkoxycarbonyl, (C.sub.1-6)alkylcarbonyl, (C.sub.2-6)alkenyloxycarbonyl, (C.sub.2-6)alkenylcarbonyl, or CH(R.sup.13)CO.sub.2H or CH(R.sup.13)CO.sub.2NH.sub.2 optionally further substituted by (C.sub.1-6)alkyl, hydroxy(C.sub.1-6)alkyl, aminocarbonyl(C.sub.1-6)alkyl or (C.sub.2-6)alkenyl; hydroxy(C.sub.1-6)alkyl; carboxy; cyano or (C.sub.1-6)alkoxycarbonyl; [0012] wherein R.sup.13 is a natural .alpha.-amino acid side chain or its enantiomer; [0013] provided that when Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4 and Z.sup.5 are CR.sup.1a, then R.sup.1 is not hydrogen; [0014] R.sup.2 is hydrogen, or (C.sub.1-4)alkyl or (C.sub.1-4)alkenyl optionally substituted with 1 to 3 groups selected from: [0015] amino optionally substituted by one or two (C.sub.1-4)alkyl groups; carboxy; (C.sub.1-4)alkoxycarbonyl; (C.sub.1-4)alkylcarbonyl; (C.sub.2-4)alkenyloxycarbonyl; (C.sub.2-4)alkenylcarbonyl; aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (C.sub.1-4)alkyl, hydroxy(C.sub.1-4)alkyl, aminocarbonyl(C.sub.1-4)alkyl, (C.sub.2-4)alkenyl, (C.sub.1-4)alkylsulphonyl, trifluoromethylsulphonyl, (C.sub.1-4)alkenylsulphonyl, (C.sub.1-4)alkoxycarbonyl, (C.sub.1-4)alkylcarbonyl, (C.sub.2-4)alkenyloxycarbonyl or (C.sub.2-4)alkenylcarbonyl; cyano; tetrazolyl; 2-oxo-oxazolidinyl optionally substituted by R.sup.10; 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 R.sup.10; 5-oxo-1,2,4-oxadiazol-3-yl; thiol; halogen; (C.sub.1-4)alkylthio; trifluoromethyl; azido; hydroxy optionally substituted by (C.sub.1-4)alkyl, (C.sub.2-4)alkenyl, (C.sub.1-4)alkoxycarbonyl, (C.sub.1-4)alkylcarbonyl, (C.sub.2-4)alkenyloxycarbonyl, (C.sub.2-4)alkenylcarbonyl; oxo; (C.sub.1-4)alkylsulphonyl; (C.sub.2-4)alkenylsulphonyl; or (C.sub.1-4)arinosulphonyl wherein the amino group is optionally substituted by (C.sub.1-4)alkyl or (C.sub.2-4)alkenyl; [0016] R.sup.3 is hydrogen; or [0017] R.sup.3 is in the 2-, 3- or 4-position and is: [0018] carboxy; (C.sub.1-6)alkoxycarbonyl; aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (C.sub.1-16)alkyl, hydroxy(C.sub.1-6)alkyl, aminocarbonyl(C.sub.1-6)alkyl, (C.sub.2-6)alkenyl, (C.sub.1-6)alkylsulphonyl, trifluoromethylsulphonyl, (C.sub.1-6)alkenylsulphonyl, (C.sub.1-6)alkoxycarbonyl, (C.sub.1-6)alkylcarbonyl, (C.sub.2-6)alkenyloxycarbonyl or (C.sub.2-6)alkenylcarbonyl and optionally further substituted by (C.sub.1-6)alkyl, hydroxy(C.sub.1-6)alkyl, aminocarbonyl(C.sub.1-6)alkyl or (C.sub.2-6)alkenyl; cyano; tetrazolyl; 2-oxo-oxazolidinyl optionally substituted by R.sup.10; 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 R.sup.10; or 5-oxo-1,2,4-oxadiazol-3-yl; or [0019] (C.sub.1-4)alkyl or ethenyl substituted with any of the substituents listed above for R.sup.3 and up to 3 groups R.sup.12 independently selected from: [0020] thiol; halogen; (C.sub.1-6)alkylthio; trifluoromethyl; azido; (C.sub.1-6)alkoxycarbonyl; (C.sub.1-6)alkylcarbonyl; (C.sub.2-6)alkenyloxycarbonyl; (C.sub.2-6)alkenylcarbonyl; hydroxy optionally substituted by (C.sub.1-6)alkyl, (C.sub.2-6)alkenyl, (C.sub.1-6)alkoxycarbonyl, (C.sub.1-6)alkylcarbonyl, (C.sub.2-6)alkenyloxycarbonyl, (C.sub.2-6)alkenylcarbonyl or aminocarbonyl wherein the amino group is optionally substituted by (C.sub.1-6)alkyl, (C.sub.2-6)alkenyl, (C.sub.1-6)alkylcarbonyl or (C.sub.2-6)alkenylcarbonyl; amino optionally mono- or disubstituted by (C.sub.1-6)alkoxycarbonyl, (C.sub.1-6)alkylcarbonyl, (C.sub.2-6)alkenyloxycarbonyl, (C.sub.2-6)alkenylcarbonyl, (C.sub.1-6)alkyl, (C.sub.2-6)alkenyl, (C.sub.1-6)alkylsulphonyl, (C.sub.2-6)alkenylsulphonyl or aminocarbonyl wherein the amino group is optionally substituted by (C.sub.1-6)alkyl or (C.sub.2-6)alkenyl; aminocarbonyl wherein the amino group is optionally substituted by (C.sub.1-6)alkyl, hydroxy(C.sub.1-6)alkyl, aminocarbonyl(C.sub.1-6)alkyl, (C.sub.2-6)alkenyl, (C.sub.1-6)alkoxycarbonyl, (C.sub.1-6)alkylcarbonyl, (C.sub.2-6)alkenyloxycarbonyl or (C.sub.2-6)alkenylcarbonyl and optionally further substituted by (C.sub.1-6)alkyl, hydroxy(C.sub.1-6)alkyl, aminocarbonyl(C.sub.1-6)alkyl or (C.sub.2-6)alkenyl; oxo; (C.sub.1-6)alkylsulphonyl; (C.sub.2-6)alkenylsulphonyl; or (C.sub.1-6)aminosulphonyl wherein the amino group is optionally substituted by (C.sub.1-6)alkyl or (C.sub.2-6)alkenyl; [0021] in addition when R.sup.3 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 [0022] when R.sup.3 is in the 3- or 4-position it may with R.sup.2 or R.sup.4 form a C.sub.3-5 alkylene group optionally substituted by a group R.sup.5 selected from: [0023] (C.sub.1-12)alkyl; hydroxy(C.sub.1-12)alkyl; (C.sub.1-12)alkoxy(C.sub.1-12)alkyl; (C.sub.1-12)alkanoyloxy(C.sub.1-12)alkyl; (C.sub.3-6)cycloalkyl; hydroxy(C.sub.3-6)cycloalkyl; (C.sub.1-12)alkoxy(C.sub.3-6)cycloalkyl; (C.sub.1-12)alkanoyloxy(C.sub.3-6)cycloalkyl; (C.sub.3-6)cycloalkyl(C.sub.1-12)alkyl; hydroxy-, (C.sub.1-12)alkoxy- or (C.sub.1-12)alkanoyloxy-(C.sub.3-6)cycloalkyl(C.sub.1-12)alkyl; cyano; cyano(C.sub.1-12)alkyl; (C.sub.2-12)alkenyl; (C.sub.2-12)alkynyl; tetrahydrofuryl; mono- or di-(C.sub.1-12)alkylamino(C.sub.1-12)alkyl; acylamino(C.sub.1-12)alkyl; (C.sub.1-12)alkyl- or acyl-aminocarbonyl(C.sub.1-12)alkyl; mono- or di- (C.sub.1-2)alkylamino(hydroxy) (C.sub.1-2)alkyl; optionally substituted phenyl(C.sub.1-12)alkyl, phenoxy(C.sub.1-12)alkyl or phenyl(hydroxy)(C.sub.1-12)alkyl; optionally substituted diphenyl(C.sub.1-12)alkyl; optionally substituted phenyl(C.sub.2-12)alkenyl; optionally substituted benzoyl or benzoyl(C.sub.1-12)alkyl; optionally substituted heteroaryl or heteroaryl(C.sub.1-2)alkyl; and optionally substituted heteroaroyl or heteroaroyl(C.sub.1-12)alkyl; [0024] R.sup.4 forms a group with R.sup.3 as above defined, or is a group --CH.sub.2--R.sup.5 where R.sup.5 is as defined above: [0025] n is 0, 1 or 2; [0026] A is NR.sup.11 or CR.sup.6R.sup.7 and B is NR.sup.11, O, SO.sub.2 or CR.sup.8R.sup.9 and wherein: [0027] each of R.sup.6, R.sup.7, R.sup.8 and R.sup.9 is independently selected from: hydrogen; (C.sub.1-6)alkylthio; halo; trifluoromethyl; azido; (C.sub.1-6)alkyl; (C.sub.2-6)alkenyl; (C.sub.1-6)alkoxycarbonyl; (C.sub.1-6)alkylcarbonyl; (C.sub.2-6)alkenyloxycarbonyl; (C.sub.2-6)alkenylcarbonyl; hydroxy, amino or aminocarbonyl optionally substituted as for corresponding substituents in R.sup.3; (C.sub.1-6)alkylsulphonyl; (C.sub.2-6)alkenylsulphonyl; or (C.sub.1-6)aminosulphonyl wherein the amino group is optionally substituted by (C.sub.1-6)alkyl or (C.sub.1-6)alkenyl; [0028] or R.sup.6 and R.sup.8 together represent a bond and R.sup.7 and R.sup.9 are as above defined; [0029] or R.sup.6 and R.sup.7 or R.sup.8 and R.sup.9 together represent oxo; [0030] provided that: [0031] when A is NR.sup.11, B is not NR.sup.11, O or SO.sub.2; [0032] when A is CO, B is not CO, O or SO.sub.2; [0033] when n is 0 and A is NR.sup.11, CR.sup.8R.sup.9 can only be CO; [0034] when A is CR.sup.6R.sup.7 and B is SO.sub.2, n is 0; [0035] when n is 0, B is not NR.sup.11 or O; and [0036] when A-B is CR.sup.7.dbd.CR.sup.9, n is 1 or 2; [0037] R.sup.10 is selected from (C.sub.1-4)alkyl; (C.sub.2-4)alkenyl and aryl any of which may be optionally substituted by a group R.sup.12 as defined above; carboxy; aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (C.sub.1-6)alkyl, (C.sub.2-6)alkenyl, (C.sub.1-6)alkylsulphonyl, trifluoromethylsulphonyl, (C.sub.1-6)alkenylsulphonyl, (C.sub.1-6)alkoxycarbonyl, (C.sub.1-6)alkylcarbonyl, (C.sub.2-6)alkenyloxycarbonyl or (C.sub.2-6)alkenylcarbonyl and optionally further substituted by (C.sub.1-6)alkyl or (C.sub.2-6)alkenyl; (C.sub.1-6)alkylsulphonyl; trifluoromethylsulphonyl; (C.sub.1-6)alkenylsulphonyl; (C.sub.1-6)alkoxycarbonyl; (C.sub.1-6)alkylcarbonyl; (C.sub.2-6)alkenyloxycarbonyl; and (C.sub.2-6)alkenylcarbonyl; [0038] R.sup.11 is hydrogen; trifluoromethyl, (C.sub.1-6)alkyl; (C.sub.1-6)alkenyl; (C.sub.1-6)alkoxycarbonyl; (C.sub.1-6)alkylcarbonyl; aminocarbonyl wherein the amino group is optionally substituted by (C.sub.1-6)alkoxycarbonyl, (C.sub.1-6)alkylcarbonyl, (C.sub.1-6)alkenyloxycarbonyl, (C.sub.2-6)alkenylcarbonyl, (C.sub.1-6)alkyl or (C.sub.1-6)alkenyl and optionally further substituted by (C.sub.1-6)alkyl or (C.sub.1-6)alkenyl; [0039] 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. [0040] 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. [0041] The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier. DETAILED DESCRIPTION OF THE INVENTION [0042] Preferred groups of compounds include those where: [0043] (a) Z.sup.1 is N, and Z.sup.2-Z.sup.5 are CH, [0044] (b) Z.sup.1-Z.sup.5 are each CH, and [0045] (c) Z.sup.5 is N, and Z.sup.1-Z.sup.4 are CH. [0046] When R.sup.1 or R.sup.1a is substituted alkoxy it is preferably (C.sub.2-6)alkoxy substitituted by optionally N-substituted amino, guanidino or amidino, or (C.sub.1-6)alkoxy optionally substituted by piperidyl. Suitable examples of R.sup.1 and R.sup.1a alkoxy include methoxy, n-propyloxy, iso-butyloxy, aminoethyloxy, aminopropyloxy, aminobutyloxy, amiinopentyloxy, guanidinopropyloxy, piperidin-4-ylmethyloxy and phthalimido pentyloxy. [0047] Preferably R.sup.1 and R.sup.1a are independently methoxy, amino(C.sub.3-5)alkyloxy, guanidino(C.sub.3-5)alkyloxy, piperidyl(C.sub.3-5)alkyloxy, nitro or fluoro; more preferably methoxy, amino(C.sub.3-5)alkyloxy or guanidino(C.sub.3-5)alkyloxy. [0048] Z.sup.2 and Z.sup.4 are preferably CH. [0049] When Z.sup.5 is CR.sup.1a, R.sup.1a is preferably hydrogen, cyano, hydroxymethyl or carboxy. [0050] Preferably n is 0. [0051] R.sup.2 is preferably hydrogen; (C.sub.1-4)alkyl substituted with carboxy, optionally substituted hydroxy, optionally substituted aminocarbonyl, optionally substituted amino or (C.sub.1-4)alkoxycarbonyl; or (C.sub.1-4)alkenyl substituted with (C.sub.1-4)alkoxycarbonyl or carboxy. More preferred groups for R.sup.2 are hydrogen, carboxymethyl, hydroxyethyl, aminocarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylallyl and carboxyallyl. [0052] Preferred examples of R.sup.3 include hydrogen; optionally substituted aminocarbonyl; optionally substituted (C.sub.1-6)alkyl; carboxy(C.sub.1-4)alkyl; optionally substituted aminocarbonyl(C.sub.1-4)alkyl; cyano(C.sub.1-4)alkyl; optionally substituted 2-oxo-oxazolidinyl and optionally substituted 2-oxo-oxazolidinyl(C.sub.1-4alkyl). More preferred R.sup.3 groups are hydrogen; CONH.sub.2; 1-hydroxyalkyl e.g. CH.sub.2OH, CH(OH)CH.sub.2CN; CH.sub.2CO.sub.2H; CH.sub.2CONH.sub.2; 1,2-dihydroxyalkyl e.g. CH(OH)CH.sub.2OH; CH.sub.2CN; 2-oxo-oxazolidin-5-yl and 2-oxo-oxazolidin-5-yl(C.sub.1-4alkyl). Continue reading about Aminopiperidine derivatives as antibacterials... 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