Patent EA-004920-B1 (EA)
Title: Azabicyclic compounds, preparation thereof and use as medicines, in particular as antibacterial agents
Inventor: LAMPILAS MAXIME
IPC: A61P31/04
Filed: 2001-07-24
Abstract: 1. A compound of general formula (I), or one of its salts with a base or with an acid: in which: R1 is a hydrogen atom, COON radical, N, COOR, CONR6R7, (CH2)nR5 or a radical wherein R is selected from the group consisting of alkyl of 1 to 6 carbon atoms, optionally substituted with pyridyl or carbamoyl; -CH2- alkenyl comprising 3 to 9 carbon atoms; aryl of 6 to 10 carbon atoms or aralkyl of 7 to 11 carbon atoms, the aryl or aralkyl core may be substituted with a OH radical, NH2, NO2, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or one or a plurality of halogen atoms; R6 and R7, identical or different, are selected from the group consisting of hydrogen atoms, alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms and aralkyl of 7 to 11 carbon atoms optionally substituted with carbamoyl, ureido group or dimethylamino group, and alkyl of 1 to 6 carbon atoms substituted with pyridyl; n' is 1 or 2; R5 is selected from the group consisting of COOH radical, CN, OH, NH2, CO-NR6R7, COOR, OR, OCOH, OCOR, OCOOR, OCONHR, OCONH2, NHR, NHCOH, NHCOR, NHSO2R, NH-COOR, NH-CO-NHR or NHCONH2, R, R6 and R7 are as defined above; R3 is a hydrogen atom or a (CH2)n'1R5 group, n'1 is 0, 1 or 2 and R5 is as defined above; R3 is a hydrogen atom or alkyl of 1 to 6 carbon atoms; A is a bond between two carbon atoms, carrying R1 and R2 radicals, or a group wherein R4 is a hydrogen atom or a (CH2)n'1R5 group, n'1 and R5 are as defined above, a dotted line is an optional bond with one or the other of carbon atoms, carrying R1 and R2 substituents; n is 1 or 2; X is a divalent -C(O)-B- group, bonded with a nitrogen atom by a carbon atom; wherein B is a divalent -O-(CH2)n"- bonded with carbonyl by an oxygen atom; a -NR8-(CH2)n"- or -NR8-O- boned with carbonyl by a nitrogen atom; n" is 0 or 1; and R8 is selected from the group consisting of a hydrogen atom, OH radical, R, OR, Y, OY, Y1, OY1, Y2, OY2, Y3, OCH2CH2SOmR, OSiRaRbRc and SiRaRbRc wherein Ra, Rb and Rc are separately a linear or branched alkyl of 1 to 6 carbon atoms or aryl of 6 to 10 carbon atoms, R is as defined above and m is 0, 1 or 2; Y is selected from the group consisting of COH, COR, COOR, CONH2, CONHR, CONHOH, CONHSO2R, CH2COOH, CH2COOR, CH2CONHOH, CH2CONHCN, CH2-tetrazole, protected CH2-tetrazole, CH2SO3H, CH2SO2R, CH2PO (OR)2, CH2PO (OR) (OH), CH2PO(R)(OH) and CH2PO(OH)2; Y1 is selected from the group consisting of SO2R, SO2NHCOH, SO2NHCOR, SO2NHCOOR, SO2NHCONHR, SO2NHCONH2 and SO3H, Y2 selected from the group consisting of PO(OH)2, PO(OR)2, PO(OH)(OR) and PO (OH) (R); Y3 is selected from the group consisting of tetrazolyl, tetrazolyl substituted with a R radical, squarate, NH or NR- tetrazolyl, NH or NR-tetrazolyl substituted with a R radical, NHSO2R and NRSO2R, wherein R is as defined above; meaning that when n is 1 and A is in which R4 is a hydrogen atom, and either X is a -C (O)-O-(CH2)n" group, in which n" is 0 or 1, or X is -CO-NR8-(CH2)n", in which n" is 1 and R8 is isopropyl, or X is -CO-NR8-(CH2)n", in which n" is 0 and R8 is a hydrogen atom or phenyl, then R1, R2 and R3 all three can not be simultaneously a hydrogen atom. 2. Compound according to claim 1, characterized in that n is 1. 3. Compound according to claim 1 or 2, characterized in that A is a group as defined in claim 1. 4. Compound according to claim 3, characterized in that R4 is a hydrogen atom. 5. Compound according to any one of claims 1-4, characterized in that X is divalent -CO-B- group, in which B is a -NR8-(CH2)n"- group defined in claim 1. 6. Compound according to any one of claims 1-4, characterized in that R8 group is a Y1 or OY1, in which Y1 is selected from the group SO2R, SO2NHCOR, SO2NHCOOR, SO2NHCONHR and SO3H and R is as defined in claim 1. 7. Compounds of formula (I) according to claim 1 selected from the group, comprising: trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1] octane-2-carboxamide and salts thereof with bases, in particular, sodium salt; trans-7-oxo-N-(phenylmethyl)-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and salts thereof with bases, in particular, sodium salt; trans-7-oxo-N-(4-pyridinyl methyl)-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and salts thereof with bases, in particular, sodium salt; trans-7-oxo-N-(3-pyridinyl methyl)-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and salts thereof with bases, in particular, sodium salt; trans-7-oxo-N-(2-amino 2-oxo ethyl)-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and salts thereof with bases, in particular, sodium salt; trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1] octane-2-carboxylate de phenylmethyl. 8. A method for preparing a compound according to any one of claims 1-7, characterized in that comprises: a) a step in which a compound of formula (II): in which R'1 is a hydrogen atom or a CN radical, protected COOH, COOR', (CH2)n'R'5, CONR6R7 or a protected radical wherein n', R6 and R7 are as defined in claim 1 and R' and R'5 are as defined for R and R5 in claim 1, in which optionally reactive groups are protected; R'2 is a hydrogen atom or a (CH2)n'1R'5, wherein n'1 is as defined in claim 1, and R'5 is as defined above; R3 is as defined in claim 1; A' is a bond between two carbon atoms carrying R'1 and R'2 radicals or a group wherein R'4 is a hydrogen atom or a group (CH2)n'1R'5, wherein n'1 and R'5 are as defined above, dotted line is an optional bond with one or the other carbon atoms carrying R'1 and R'2 substituents; n is as defined in claim 1; HZ is a group HO-(CH2)n"-, HNR'8-(CH2)n"- or HNR'8-O-, wherein n" is as defined above and R'8 is a hydrogen atom, protected hydroxy, R', OR', a Y' or OY' radical, Y' is selected from the group of COH, COR', COOR', CONH2, CONHR', protected CONHOH, CONHSO2R', protected CH2COOH, CH2COOR', protected CH2CONHOH, CH2CONHCN, CH2- tetrazole substituted with a R' radical, CH2SO2R', CH2PO(OR')2, protected CH2SO3, protected CH2PO(OR')OH, protected CH2PO(R')OH, protected CH2PO(OH)2, a Y'1 or OY'1 radical, Y'1 is selected from the group of: SO2R', SO2NHCOH, SO2NHCOR', SO2NHCOOR', SO2NHCONH2, SO2NHCONHR' and protected SO3H, a Y'2 or OY'2 radical, Y'2 is a protected PO(OH)2 group, protected PO(OH)(OR'), protected PO(OH)R' or PO(OR')2, or a Y'3 radical, Y'3 is selected from the group of protected tetrazole, tetrazole substituted with R' radical, protected NH or NR' tetrazole substituted with a R' radical, NHSO2R' and NR'SO2R', wherein R' is as defined above; reacting with a carbonylation agent, if necessary, in the presence of a base to obtain an intermediate compound of formula (III): R'1, R'2, R'3, A' and n are as defined above and either X1 is a hydrogen atom and X2 is a -Z-CO-X3 group, wherein X3 is a moiety of the carbonylation agent, or X2 is a -ZH group and X1 is a CO-X3, wherein X is as defined above; b) a step in which the obtained intermediate compound is cyclized in the presence of a base; and c) if necessary, prior to the step a) and/or after the step b) one or a plurality of reactions are carried out in the following order:- protection of reactive functional groups, deprotection of the reactive functional groups, esterification, saponification, sulfatation, phosphatation, amidification, acylation, sulfonylation; alkylation; introduction of double bond; formation of carbamide group; introduction of tetrazole group; reduction of carboxylic acids; deshydratation of amide to nitrite; salification; ions exchange; splitting or separation of diastereoisomers; oxydation of sulfur to sulfoxyde and/or sulfone. 9. A method according to claim 8, characterized in that the carbonylation agent, is selected from the group of phosgene, diphosgene, triphosgene, aryl-, aralkyl-, alkyl- and alkenylchloroformiates, alkyldicarbonates, carbonyldiimidazole and mixtures thereof. 10. A method according to claim 8 or 9, characterized in that reaction of carbonylation is carried out in the presence of a base. 11. A method according to claim 10, characterized in that the base is amine. 12. A method according to claim 8, characterized in that the in the step b) the base is selected from group of amines, hydrides, alcoholates, amides or carbonates of alcali or alcali-earth metals. 13. A medicament, which is a product of formula (I) according to claim 1, and salts thereof with pharmaceutically acceptable salts and bases. 14. A medicament, which is a product according to any one of claims 2 to 7, and salts thereof with pharmaceutically acceptable salts and bases. 15. A pharmaceutical composition comprising at least one medicament as an active substance according to any one of claims 13 or 14. 16. A compound of general formula (III) or one of its salts with acid, in particular, hydrochloride: in which R'1, R'2, R'3, A', n, X1 and X2 are as defined in claim 8.