Specification
FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
NITROGEN CONTAINING HETEROCYCLIC COMPOUNDS
2. APPLICANT
(a). NAME: WOCKHARDT LIMITED
(b). NATIONALITY: INDIAN
(c). ADDRESS: D-4, M.I.D.C INDUSTRIAL AREA,
CHIKALTHANA, AURANGABAD - 431 210 (M.S.) INDIA.
The following specification particularly describes the invention and the manner
in which it is to be performed
NITROGEN CONTAINING HETEROCYCLIC COMPOUNDS
RELATED PATENT APPLICATIONS
This application claims the benefit of Indian Provisional Patent Application No. 2424/MUM/2011 filed on August 30, 2011, the disclosures of which are incorporated herein by reference in its entirety as if fully rewritten herein. All references including patents, patent applications, and literature cited in the specification are expressly incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
The invention relates to nitrogen containing heterocyclic compounds, their preparation and their use in preventing and/or treating bacterial infections.
BACKGROUND OF THE INVENTION
Emergence of bacterial resistance to known antibacterial agents is becoming a major challenge in treating bacterial infections. One way forward to treat bacterial infections, and especially those caused by resistant bacteria, is to develop newer antibacterial agents that can overcome the bacterial resistance. Coates et al. (Br. J. Pharmacol. 2007; 152(8), 1147-1154.) have reviewed novel approaches to developing new antibiotics. However, the development of new antibacterial agents is a challenging task. For example, Gwynn et al. (Annals of the New York Academy of Sciences, 2010, 1213: 5-19) have reviewed the challenges in the discovery of antibacterial agents.
Several antibacterial agents have been described in the prior art (for example, see PCT International Application Nos. PCT/US2010/060923, PCT/EP2010/067647, PCT/US2010/052109, PCT/US2010/048109, PCT/GB2009/050609, PCT/EP2009/056178 and PCT/US2009/041200). However, there remains a need for potent antibacterial agents for preventing and/or treating bacterial infections, including those caused by bacteria that are resistant to known antibacterial agents.
The inventors have surprisingly discovered nitrogen containing heterocyclic compounds with antibacterial properties.
SUMMARY OF THE INVENTION
Accordingly there are provided nitrogen containing heterocyclic compounds, methods for preparation of these compounds, pharmaceutical compositions comprising these compounds, and method for preventing or treating bacterial infection in a subject using these compounds.
In one general aspect, there are provided compounds of Formula (I):
or a stereoisomer or a pharmaceutically acceptable salt thereof; wherein:
Q is heteroaryl;
Ri is:
(a) hydrogen,
(b) (CO)n-R3,or
(c) COOR4,
n is 0, 1 or 2; R2is:
(a) SO3M,
(b) S02NH2,
(c) PO3M,
[ 1,3,4]-oxadiazol-2-yl)-7-oxo-l ,6-diazabicyclo[3.2. l]-octane;
Sodium saltoftrans-6-(sulphooxy)-2-(5-(5,6-dihydro-8H-imidazo[2,l-c][l,4]-oxazin-2-yl)-[l,3,4]-oxadiazol-2-yI)-7-oxo-l,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-(morpholino-4-methyl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-sulfuric acid mono-[2-(5-(morpholin-4-yl-carbonyl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octan-6-yl] ester;
Sodium salt of trans-6-{sulphooxy)-2-(5-methyl-[l,3,4]-thiadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1 ]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-methyl-[l,2,4]-oxadiazol-3-yl)-7-oxo-1,6-diazabicyclo[3.2. l]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-ethoxycarbony 1-[1,2,4]-oxadiazol-3-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(2-methyl-2H-[l,2,3,4]-tetrazol-5-yl)-7-oxo-l,6-diazabicyclo[3.2.1 ]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(l-methyl-lH-[l,2,3,4]-tetrazol-5-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(3-ethoxycarbonyl-[l,2,41-oxadiazol-5-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-carboxamido-[ 1,2,4]-oxadiazol-3-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octane;
or a stereoisomer or a pharmaceutically acceptable salt thereof.
In general, the compounds of the invention can be prepared according to the following procedures. A person of skills in the art would appreciate that the described methods can be varied or optimized further to provide the desired and related compounds. In the following procedures, all variables are as defined above.
(A) Synthesis of compounds containing 1,3,4-Oxadiazole groups:
In general the compounds according to the invention containing 1,3,4-Oxadiazole groups were prepared using a procedure given in Scheme 1.
Typically, trans-6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1 ]octane-2-carboxylic acid (la, which is disclosed in WO 2009/091856 A2), was reacted with alkyl or aryl or suitably substituted aryl or alkyl acid hydrazides in the presence of a suitable coupling agent (for example, EDC hydrochloride, dicyclohexylcarbodiimide (DCC), or pivalyl chloride) in a suitable solvent (for example, N,N dimethyl formamide, N,N dimethyl acetamide, 1,4 dioxane or chloroform), and in the presence of a suitable base (for example, N-methyl morpholine, triethylamine or diisopropyl ethylamine), and N-hydroxybenzotriazole (HOBt) at a temperature ranging from about -15°C to 60°C, for about 1 to 24 hours to provide intermediate compound (lb).
The cyclization of intermediate compound (lb) was effected by treating intermediate compound (lb) with a suitable reagent such as p-toluene sulfonyl chloride, p-nitrobenzene sulfonyl chloride, or methane sulfonyl chloride, in a suitable solvent (for example, toluene, chloroform, dichloromethane, or N,N-dimethyl formamide), at a temperature ranging from 25°C to 110°C for about 1 to 24 hours to obtain 1,3,4-oxadiazole intermediate compound (lc). Alternatively, the intermediate compound (lc) may also be prepared by refluxing intermediate compound (lb) in toluene in presence of 4°A molecular sieves.
The 1,3,4-oxadiazole intermediate compound (lc) was subjected for hydrogenolysis by using a suitable catalyst (for example, 5% or 10% palladium on carbon or 20% palladium hydroxide on carbon), in presence of a suitable hydrogen source (for example, hydrogen gas, ammonium formate, or cyclohexene) in a suitable solvent (for example, methanol, ethanol, methanol-dichloromethane mixture, or N,N dimethyl formamide-dichloromethane mixture) at a temperature ranging from about 25°C to 60°C for about 1 to 24 hours to obtain intermediate compound (Id).
The intermediate compound (Id) was sulfonated by reacting it with a suitable sulfonating reagent (for example, pyridine sulfur trioxide complex or N,N-dimethyl formide sulfur trioxide complex) in a suitable solvent (for example, pyridine, N,N-dimethyl formamide, dichlromethane or mixture thereof) at a temperature ranging from about 25°C to 80°C for about 1 to 24 hours to provide pyridine salt of sulfonic acid which was subsequently treated with tetrabutyl ammonium sulfate to provide terabutylammonium salt of sulfonic acid intermediate compound (le).
Some compounds of the invention were isolated as a sodium salt by passing intermediate compound (le) through sodium form of Aberlite 200C resin in aqueous tetrahydrofuran followed by evaporation of solvent fractions under vacuum.
Some other compounds, when R contains tert-butoxycarbonyl group or alkylsilyl group, were isolated as zwitterions by treating intermediate compound (le) with trifiuoroacetic acid in the absence of solvent or in the presence of the solvent {for example, dichloromethane, chloroform, or acetonitrile) at a temperature ranging from about -10°C to 40°C, for about 1 to 14 hours.
(B) Synthesis of compounds containing 1.3.4-Thiadiazole groups:
In general, the compounds according to the invention containing 1,3,4-Thiadiazole were prepared using a general procedure described in Scheme 2.
As per Scheme-2, trans-5-benzyloxyamino-piperidine-l,2-dicarboxylic acid-1-tert-butyl ester (2a), was reacted with alkyl or aryl or suitably substituted aryl or alkyl acid hydrazides in presence of a suitable coupling agent (for example, EDC hydrochloride, dicyclohexylcarbodiimide (DCC), or pivalyl chloride), in a suitable solvent (for example, N,N dimethyl formamide, N,N dimethyl acetamide, 1,4 dioxane or chloroform), in presence of a suitable base (for example, N-methyl morpholine, triethylamine or diisopropyl
ethylamine and N-hydroxybenzotriazole (HOBt)) at a temperature ranging from about -5°C to 60°C for about 1 to 24 hours to provide intermediate compound (2b).
The cyclization of intermediate compound (2b) was effected by treating intermediate compound (2b) with Lowesson's reagent, in a suitable solvent (for example, toluene, chloroform, tetrahydrofuran, or N,N-dimethyl formamide) at a temperature ranging from 25°C to 110°C, for about 1 to 24 hours to provide 1,3,4-thiadiazoIe intermediate compound (2c).
The intermediate compound (2c) was deprotected to provide intermediate compound (2d), using deprotecting agent such as trifluoro acetic acid or hydrochloric acid in a solvent such as dichloromethane, chloroform, acetonitrile, or water at a temperature ranging from about -5°C to 50°C for about 1 to 24 hours.
The cyclization of intermediate compound (2d) was achieved by treating intermediate compound (2d) using a suitable reagent (for example, phosgene solution, diphosgene or triphosgene) in a suitable solvent (for example, toluene, chloroform, acetonitrile and in presence of a suitable base (for example, triethyl amine, or diisopropyl ethyl amine, N,N-dimethylamino pyridine) at a temperature ranging from about -5°C to 50°C for about 1 to 24 hours to provide cyclized intermediate compound (2e).
The cyclized intermediate compound (2e) was subjected for hydrogenolysis by using a suitable catalyst (for example, 5% or 10% palladium on carbon, or 20% palladium hydroxide on carbon) in presence of a suitable hydrogen source (for example, hydrogen gas, ammonium formate, or cyclohexene) in a suitable solvent (for example, methanol, ethanol, methanol-dichloromethane mixture, or N,N dimethyl formamide dichloromethane mixture), at a temperature ranging from 25°C to 60°C for about 1 to 24 hours to provide N-hydroxy intermediate compound (2f).
The intermediate compound (2f) was sulfonated by reacting it with a suitable sulfonating reagent (for example, pyridine sulfur trioxide complex, or N,N-dimethyl formamide sulfur trioxide complex) in a suitable solvent (for example, pyridine, N,N-dimethyl formamide, dichloromethane or mixture thereof) at a temperature ranging from about 0°C to 50° C for about 1 to 24 hours to provide pyridine salt of sulfonic acid which was subsequently treated with tetrabutyl ammonium acetate to provide terabutylammonium salt of sulfonic acid intermediate compound (2g).
The compound of invention was isolated as a sodium salt by passing intermediate compound (2g) through sodium form of Aberlite SR-L resin in aqueous tetrahydrofuran followed by evaporation of solvent fractions under vacuum. Alternatively, when R contains tert-butoxycarbonyl group or alkylsilyl group, then compound of invention was isolated as zwitterions by treating intermediate compound (2g) with trifluoroacetic acid in absence of
solvent or in the presence of a suitable solvent (for example, dichloromethane, chloroform, or acetonitrile) at a temperature ranging from about -10°C to 40°C for about 1 to 14 hours.
(C) Synthesis of compounds containing l,2,4-Oxadiazol-3-yl groups:
In general, the compound according to the invention containing l,2,4-Oxadiazol-3-yl groups was prepared using a general procedure described in Scheme 3.
As per Scheme-3, trans-5-benzyIoxyamino-piperidine-l,2-dicarboxylic acid-1-tert-butyl ester compound (2a), was reacted with a suitable acid chloride (for example, pivolyl chloride) in presence of a suitable base (for example, N-methyl morpholine, triethylamine, diisopropyl ethylamine) in a suitable solvent (for example, dichloromethane, tetrahydrofuran, 1,4 dioxane or chloroform), at a temperature ranging from about -5°C to 35°C, for about 1 to 2 hours to provide anhydride which was subsequently treated with ammonia gas at a temperature ranging from about -50°C to 5°C for about 0.5 to 2 hours to provide amide intermediate compound (3b).
Dehydration of the intermediate compound (3b) was effected by treating intermediate (3b) with trifluoroacetic anhydride, in a suitable solvent (for example, toluene, chloroform, tetrahydrofuran, or dichloromethane), at a temperature ranging from about -5°C to 35°C, for about 1 to 24 hours to provide the nitrile intermediate compound (3c).
The intermediate compound (3c) was reacted with hydroxylamine hydrochloride in a suitable solvent (for example, methanol, water, ethanol, or mixture thereof), at a temperature ranging from about -5°C to 35°C, for about 1 to 24 hours to provide the amidoxime intermediate compound (3d).
The intermediate compound (3d) was reacted with suitably substituted alky] anhydride in a suitable solvent (for example, dichloromethane, chloroform, tetrahydrofuran, or mixture thereof), and in presence of a suitable base (for example, N-methyl morpholine, triethylamine, or diisopropyl ethylamine) at a temperature ranging from about -5°C to 35°C, for about 1 to 24 hours to provide the O-acylated amidoxime intermediate compound (3e).
Cyclization of the intermediate compound (3e) was affected by refluxing intermediate compound (3e) in pyridine for about 1 to 24 hours to provide the cyclized intermediate compound (3f).
The intermediate compound (3f) was deprotected to provide intermediate compound (3g), using a suitable deprotecting agent (for example, trifluoro acetic acid, or hydrochloric acid) in a suitable solvent (for example, dichloromethane, chloroform, acetonitrile or water), at a temperature ranging from about -25°C to 50°C for about 1 to 24 hours.
The cyclization of intermediate compound (3g) was achieved by treating intermediate compound (3g) with a suitable reagent (for example, phosgene solution, diphosgene or triphosgene) in a suitable solvent (for example, toluene, chloroform, or acetonitrile), and in presence of a suitable base (for example, triethyl amine or diisopropyl ethyl amine) at a temperature ranging from about -5°C to 50°C for about 1 to 24 hours to provide the cyclized intermediate compound (3h).
The cyclized intermediate compound (3h) was subjected for hydrogenolysis using a suitable catalyst (for example, 5% or 10% palladium on carbon, or 20% palladium hydroxide on carbon) in presence of a suitable hydrogen source (for example, hydrogen gas, ammonium formate, or cyclohexene) in a suitable solvent (for example, methanol, ethanol, methanol -dichloromethane mixture, or N,N dimethyl formamide dichloromethane mixture) at a temperature ranging from about 25°C to 60°C, for about 1 to 24 hours to provide N-hydroxy intermediate compound (3i).
The intermediate compound (3i) was sulfonated by reacting it with a suitable sulfonating reagent (for example, pyridine sulfur trioxide complex, or N,N-dimethyl formamide sulfur trioxide complex) in a suitable solvent (for example, pyridine, N,N-dimethyl formamide, dichloromethane or a mixture thereof), at a temperature ranging from about -5°C to 50°C, 0.5 to 24 hours to provide pyridine salt of sulfonic acid which subsequently was treated with tetrabutyl ammonium acetate to provide terabutylammonium salt of sulfonic acid intermediate compound (3j).
The compound of the invention was isolated as a sodium salt by passing intermediate compound (3j) through sodium form of Dowex 50WX8 200 resin in aqueous tetrahydrofuran followed by evaporation of solvent fractions under vacuum.
Alternatively, when R contains tert-butoxycarbonyl group or alkylsilyl group then compound of the invention was isolated as zwitterions by treating intermediate compound (3j) with trifluoroacetic acid in the absence of solvent or in the presence of the solvent (dor example, dichloromethane, chloroform, or acetonitrile) at a temperature ranging from -10°C to 40° C for about 1 to 14 hours.
(D) Synthesis of compounds containing 1.2.3,4-Tctrazol groups:
As per Scheme-4, trans-5-benzyloxyamino-2-cyano-piperidine-l-carboxylic acid-1-tert-butyl ester compound (3c), was reacted sodium azide in presence of triethylamine hydrochloride, in a suitable solvent (for example, toluene, or xylene) at a reflux temperature for about 1 to 12 hours to provide tetrazole intermediate compound (4b).
Alkylation of the intermediate compound (4b) was effected by treating intermediate compound (4b) with suitable alkyl halide in a suitable solvent (for example, N,N-dimethyl formamide, N,N-dimethyl acetamide, tetrahydrofuran) and in the presence of a suitable base (for example, cesium carbonate, potassium carbonate or sodium carbonate) at a temperature ranging from about -5°C to 35°C for about 1 to 24 hours to provide isomeric mixture of N-alkyl tetrazol intermediate compounds (4c) and (4c'), which was separated using column chromatography technique to provide isomerically pure compound (4c) and (4c') and hitherto the pure intermediate is referred as compound (4d).
The intermediate compound (4d) was deprotected to provide intermediate compound (4e), using a suitable deprotecting agent (trifluoro acetic acid or hydrochloric acid), in a suitable solvent (for example, dichloromethane, chloroform, acetonitrile or water), at a temperature ranging from about -25°C to 50°C, for about 1 to 24 hours.
The cyclization of intermediate compound (4e) was achieved by treating intermediate compound (4e) using a suitable reagent (for example, phosgene solution, diphosgene or triphosgene) in a suitable solvent (for example, toluene, chloroform, or acetonitrile) in the presence of a suitable base (for example, triethyl amine or diisopropyl ethyl amine) and N,N-dimethylamino pyridine at a temperature ranging from about -5°C to 50°C for about 1 to 24 hours to provide cyclized intermediate compound (4f).
The cyclized intermediate compound (4f) was subjected for hydrogenolysis by using a suitable catalyst (for example, 5% or 10% palladium on carbon or 20% palladium hydroxide on carbon) in presence of a suitable hydrogen source (for example, hydrogen gas, ammonium formate, or cyclohexene) in a suitable solvent (for example, methanol, ethanol, methanol-ethyl acetate mixture, or N,N dimethyl formamide-dichloromethane mixture) at a temperature ranging from about 25°C to 60°C, for 1 to 24 hours to provide N-hydroxy intermediate compound (4g).
The intermediate compound (4g) was sulfonated by reacting it with a suitable sulfonating reagent such (for example, pyridine sulfur trioxide complex, or N,N-dimethyl formamide sulfur trioxide complex) in a suitable solvent (for example, pyridine, N,N-dimethyl formamide, dichloromethane or mixture thereof) at a temperature ranging from about -5°C to 50°C for about 0.5 to 24 hours to provide pyridine salt of sulfonic acid which subsequently was treated with tetrabutyl ammonium acetate to provide terabutylammonium salt of sulfonic acid intermediate compound (4h).
The compound of invention was isolated as a sodium salt by passing intermediate 4h through sodium form of Dowex 50WX8 200 resin in aqueous tetrahydrofuran followed by evaporation of solvent fractions under vacuum. Alternatively, when R contains tert-butoxycarbonyl group or alkylsilyl group then compound of invention was isolated as zwitterions by treating intermediate 4h with trifluoroacetic acid in the absence of solvent or in the presence of a suitable solvent (for example, dichloromethane, chloroform, or acetonitrile) at a temperature ranging from about -10°C to 40°C for about 1 to 14 hours.
(E) Synthesis of compounds containing l,2,4-Oxadiazol-5-vl groups:
In general, the compounds according to the invention containing l,2,4-Oxadiazol-5-yl groups were prepared using a general procedure described in Scheme 5.
As per Scheme-5, trans-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid compound (la), was reacted with suitably substituted aryl or alkyl amidoxime in the presence of a suitable coupling agent (for example, EDC hydrochloride, dicyclohexylcarbodiimide (DCC), or pivalyl chloride) in a suitable solvent (for example N,N dimethyl formamide, N,N dimethyl acetamide, 1,4 dioxane or chloroform) and in presence of
a suitable base (for example, N-methyl morpholine, triethylamine or diisopropyl ethylamine) and N-hydroxybenzotriazole (HOBt) at a temperature ranging from about -5°C to 60°C, for about 1 to 24 hours to provide intermediate compound (5b).
The cyclization of intermediate compound (5b) was achieved by refluxing intermediate compound (5b) in pyridine for about 1 to 24 hours to provide cyclized intermediate compound (5c).
The cyclized intermediate compound (5c) was subjected for hydrogenolysis by using a suitable catalyst (for example, 5% or 10% palladium on carbon, or 20% palladium hydroxide on carbon) in presence of a suitable hydrogen source (for example, hydrogen gas, ammonium formate, or cyclohexene) in a suitable solvent (for example, methanol, ethanol, methanol-ethyl acetate mixture, N,N dimethyl formamide dichloromethane mixture) at a temperature ranging from about 25°C to 60°C for about 1 to 24 hours to provide N-hydroxy intermediate compound (5d).
The intermediate compound (5d) was sulfonated by reacting it with a suitable sulfonating reagent (for example, pyridine sulfur trioxide complex, or N,N-dimethyl formamide sulfur trioxide complex) in a suitable solvent (for example, pyridine, N,N-dimethyl formamide, dichloromethane or a mixture thereof) at a temperature ranging from about -5°C to 50°C for about 0.5 to 24 hours to provide pyridine salt of sulfonic acid which subsequently was treated with tetrabutyl ammonium acetate to provide terabutylammonium salt of sulfonic acid intermediate compound (5e).
The compound of invention was isolated as a sodium salt by passing intermediate 5e through sodium form of Amberlite 200C resin in aqueous tetrahydrofuran followed by evaporation of solvent fractions under vacuum. Alternatively, when R contains tert-butoxycarbonyl group or alkylsilyl group then compound of invention was isolated as zwitterions by treating intermediate (5e) with trifluoroacetic acid in the absence of solvent or in the presence of a suitable solvent (for example, dichloromethane, chloroform, or acetonitrile) at a temperature ranging from about -10°C to 40° C for about 1 to 14 hours.
In some embodiments, there are provided pharmaceutical compositions comprising a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof.
In some other embodiments, there is provided a method for preventing or treating bacterial infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.
In some embodiments, there is provided a method for preventing or treating a bacterial infection in a subject, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said subject a pharmaceutically effective amount of a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.
In some other embodiments, there is provided a method for preventing or treating bacterial infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.
In some other embodiments, there is provided a method for preventing or treating a bacterial infection in a subject, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.
In some embodiments, there are provided pharmaceutical compositions comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided pharmaceutical compositions comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there are provided pharmaceutical compositions comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutical ly acceptable derivative thereof, and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there is provided a method for preventing or treating bacterial infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there is provided a method for preventing or treating a bacterial infection in a subject, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there is provided a method for preventing or treating bacterial infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there is provided a method for preventing or treating a bacterial infection in a subject, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there is provided a method for preventing or treating bacterial infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there is provided a method for preventing or treating a bacterial infection in a subject, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said subject a pharmaceuticaliy effective amount of a pharmaceutical composition comprising: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there is provided a method for preventing or treating bacterial infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there is provided a method for preventing or treating a bacterial infection in a subject, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said subject a pharmaceutically effective amount of: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there is provided a method for preventing or treating bacterial infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there is provided a method for preventing or treating a bacterial infection in a subject, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said subject a pharmaceutically effective amount of: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there is provided a method for preventing or treating bacterial infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative
thereof, and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
In some other embodiments, there is provided a method for preventing or treating a bacterial infection in a subject, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said subject a pharmaceutically effective amount of: (a) a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
In some embodiments, there are provided methods for increasing antibacterial effectiveness of a antibacterial agent in a subject, said method comprising co-administering said antibacterial agent or a pharmaceutically acceptable derivative thereof with a pharmaceutically effective amount of a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.
In some embodiments, the compositions and methods according to the invention use compounds of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof in combination with at least one antibacterial agent or a pharmaceutically acceptable derivative thereof. A wide variety of antibacterial agents can be used. Typical, non-limiting examples of antibacterial agents include one or more of antibacterial compounds generally classified as aminoglycosides, Ansamycins, Carbacephems, Cephalosporins, Cephamycins, Lincosamides, Lipopeptides, Macrolides, Monobactams, Nitrofurans, Penicillins, Polypeptides, Quinolones, Sulfonamides, Tetracyclines, Oxazolidinone and the like.
Typical, non-limiting examples of Aminoglycoside antibacterial agents include Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Tobramycin, Paromomycin, Arbekacin, Streptomycin, Apramycin and the like.
Typical, non-limiting examples of Ansamycin antibacterial agents include Geldanamycin, Herbimycin and the like.
Typical, non-limiting examples of Carbacephem antibacterial agents include Loracarbef and the like.
Typical, non-limiting examples of Carbapenem antibacterial agents include Ertapenem, Doripenem, Imipenem, Meropenem and the like.
Typical, non-limiting examples of Cephalosporin and Cephamycin antibacterial agents include Cefazolin, Cefacetrile, Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium,
Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazedone, Cefazaflur, Cefradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole, Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cephamycin, Cefoxitin, Cefotetan, Cefmetazole, Carbacephem, Cefixime, Ceftazidime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime, Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime, Oxacephem, Cefepime, Cefozopran, Cefpirome, Cefquinome, Ceftobiprole, Ceftiofur, Cefquinome, Cefovecin, CXA-101, Ceftaroline, Ceftobiprole etc.
Typical, non-limiting examples of Lincosamide antibacterial agents include Clindamycin, Lincomycin and the like.
Typical, non-limiting examples of Macrolide antibacterial agents include Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin, Telithromycin, Spectinomycin, Solithromycin and the like.
Typical, non-limiting examples of Monobactam antibacterial agents include Aztreonam and the like.
Typical, non-limiting examples of Nitrofuran antibacterial agents include Furazolidone, Nitrofurantoin and the like.
Typical, non-limiting examples of Penicillin antibacterial agents include Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Mezlocillin, Methicillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Temocillin, Ticarcillin and the like.
Typical, non-limiting examples of Polypeptide antibacterial agents include Bacitracin, Colistin, Polymyxin B and the like.
Typical, non-limiting examples of Quinolone antibacterial agents include Ciprofloxacin, Enoxacin, Gatifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Levonadifloxacin, Norfloxacin, Ofloxacin, Trovafloxacin, Grepafloxacin, Sparfloxacin, Temafloxacin and the like.
Typical, non-limiting examples of Sulfonamide antibacterial agents include Mafenide, Sulfonamidochrysoidine, Sulfacetamide, Sulfadiazine, Sulfamethizole, Sulfamethoxazole, Sulfasalazine, Sulfisoxazole, Trimethoprim and the like.
Typical, non-limiting examples of Tetracycline antibacterial agents include Demeclocycline, Doxycycline, Minocycline, Oxytetracycline, Tetracycline, Tigecycline and the like.
Typical, non-limiting examples of Oxazolidinone antibacterial agents include Tedizolid, Linezolid, Ranbezolid, Torezolid, Radezolid etc.
The pharmaceutical compositions according to the invention may include one or more pharmaceutically acceptable carriers or excipients or the like, Typical, non-limiting examples of such carriers or excipient include mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, lubricants, stabilizing agents, binding agents etc.
The pharmaceutical compositions according to this invention can exist in various forms. In some embodiments, the pharmaceutical composition is in the form of a powder or a solution. In some other embodiments, the pharmaceutical compositions according to the invention are in the form of a powder that can be reconstituted by addition of a compatible reconstitution diluent prior to parenteral administration. Non-limiting example of such a compatible reconstitution diluent includes water.
In some other embodiments, the pharmaceutical compositions according to the invention are in the form of a frozen composition that can be diluted with a compatible diluent prior to parenteral administration.
In some other embodiments, the pharmaceutical compositions according to the invention are in the form ready to use for parenteral administration.
In the methods according to the invention, the pharmaceutical composition and/or other pharmaceutically active ingredients disclosed herein may be administered by any appropriate method, which serves to deliver the composition or its constituents or the active ingredients to the desired site. The method of administration can vary depending on various factors, such as for example, the components of the pharmaceutical composition and nature of the active ingredients, the site of the potential or actual infection, the microorganism (e.g. bacteria) involved, severity of infection, age and physical condition of the subject. Some non-limiting examples of administering the composition to a subject according to this invention include oral, intravenous, topical, intrarespiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, gene gun, dermal patch, eye drop, ear drop or mouthwash.
The compositions according to the invention can be formulated into various dosage forms wherein the active ingredients and/or excipients may be present either together (e.g. as an admixture) or as separate components. When the various ingredients in the composition are formulated as a mixture, such composition can be delivered by administering such a mixture. The composition or dosage form wherein the ingredients do not come as a mixture,
but come as separate components, such composition/dosage form may be administered in several ways. In one possible way, the ingredients may be mixed in the desired proportions and the mixture is then administered as required. Alternatively, the components or the ingredients (active or inert) may be separately administered (simultaneously or one after the other) in appropriate proportion so as to achieve the same or equivalent therapeutic level or effect as would have been achieved by administration of the equivalent mixture.
Similarly, in the methods according to the invention, the active ingredients disclosed herein may be administered to a subject in several ways depending on the requirements. In some embodiments, the active ingredients are admixed in appropriate amounts and then the admixture is administered to a subject. In some other embodiments, the active ingredients are administered separately. Since the invention contemplates that the active ingredients agents may be administered separately, the invention further provides for combining separate pharmaceutical compositions in kit form. The kit may comprise one or more separate pharmaceutical compositions, each comprising one or more active ingredients. Each of such separate compositions may be present in a separate container such as a bottle, vial, syringes, boxes, bags, and the like. Typically, the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral) ore are administered at different dosage intervals. When the active ingredients are administered separately, they may be administered simultaneously or sequentially.
The pharmaceutical composition or the active ingredients according to the present invention may be formulated into a variety of dosage forms. Typical, non-limiting examples of dosage forms include solid, semi-solid, liquid and aerosol dosage forms; such as tablets, capsules, powders, solutions, suspensions, suppositories, aerosols, granules, emulsions, syrups, elixirs and a like.
In general, the pharmaceutical compositions and method disclosed herein are useful in preventing or treating bacterial infections. Advantageously, the compositions and methods disclosed herein are also effective in preventing or treating infections caused by bacteria that are considered be less or not susceptible to one or more of known antibacterial agents or their known compositions. Some non-limiting examples of such bacteria known to have developed resistance to various antibacterial agents include Acinetobacter, E. coli, Pseudomonas aeruginosa, Staphylococcus aureus, Enterobacter, Klebsiella, Citrobacter and a like. Other non-limiting examples of infections that may be prevented or treated using the compositions and/or methods of the invention include: skin and soft tissue infections, febrile neutropenia, urinary tract infection, intraabdominal infections, respiratory tract infections, pneumonia (nosocomial), bacteremia meningitis, surgical, infections etc.
Surprisingly, the compounds, compositions and methods according to the invention are also effective in preventing or treating bacterial infections that are caused by bacteria
producing one or more beta-lactamase enzymes. The ability of compositions and methods according to the present invention to treat such resistant bacteria with typical beta-lactam antibiotics represents a significant improvement in the art.
In general, the compounds of Formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof according to invention are also useful in increasing antibacterial effectiveness of a antibacterial agent in a subject. The antibacterial effectiveness of one or more antibacterial agents may increased, for example, by co-administering said antibacterial agent or a pharmaceutically acceptable salt thereof with a pharmaceutically effective amount of a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to the invention.
It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. For example, those skilled in the art will recognize that the invention may be practiced using a variety of different compounds within the described generic descriptions.
EXAMPLES
The following examples illustrate the embodiments of the invention that are presently best known. However, it is to be understood that the* following are only exemplary or illustrative of the application of the principles of the present invention. Numerous modifications and alternative compositions, methods, and systems may be devised by those skilled in the art without departing from the spirit and scope of the present invention. The appended claims are intended to cover such modifications and arrangements. Thus, while the present invention has been described above with particularity, the following examples provide further detail in connection with what are presently deemed to be the most practical and preferred embodiments of the invention.
Example-1
Sodium salt of trans-6-fsulphooxv)-2-(5-methvl41.3.41-oxadiazol-2-vl)-7-oxo-1.6-
diazabicyclo[3.2.1]-octane.
Step-1: Preparation of trans-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid N'-acetyl hydrazide:
To a mixture of acetic acid hydrazide (1.47 gm, 19.9 mmol) and trans-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (5 gm, 18.1 mmol) in N,N-dimethyl formamide (50 ml), was added EDC hydrochloride (5.19 gm, 27.1 mmol), DIPEA (9.50 ml, 54.3 mmol) and HOBt ( 3.66 gm, 27.1 mmol). The reaction mixture was stirred at a temperature between 25°C to 35°C for 14 hours. It was diluted with water (250 ml) and extracted with ethyl acetate (75 ml x 3). The combined organic extract was washed with water, saturated aqueous sodium chloride solution (100 ml) and layers were separated. The organic layer was concentrated in vacuum to provide the crude compound, which was subjected for silica gel column chromatography using methanol chloroform to provide Step-1 product (2.2 gm) in 33% yield as powder.
Analysis:
MS (ES+) C16 H20N4O4 = 333.2 (M+l);
H'NMR (CDCI3) = 8.52 32 mcg/ml.
The antibacterial activity of representative compounds according to the invention was also investigated in combination with at least one antibacterial agent using the above study protocol and the results are given Table 3 and 4. As can be seen, the use of compounds according to the invention significantly lowered MIC values of the antibacterial agent (e.g. in this case Ceftazidime). The results also suggest the compounds according the invention increase antibacterial effectiveness of the antibacterial agent when said antibacterial agent is co-administered with a pharmaceutically effective amount of a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.
Table-3. Comparative activity of Ceftazidime (expressed as MIC representative compounds of the invention (each representative c concentration of 4 mcg/ml) in mcg/ml) in presence of ompound is present in a
Compound of Example No. E. colt NCTC 13351 E. coli M50 E. coli 7MP
1 0.5 1 4
2 16 16 32
3 16 16 32
4 0.5 1 2
5 4 4 16
6 32 16 32
7 16 16 32
8 16 16 32
9 2 8 >32
10 16 16 32
11 1 2 32
12 2 8 16
13 0.5 2 8
14 0.5 1 4
15 0.5 1 8
16 1 2 4
17 1 1 4
18 1 1 4
19 1 4 16
20 0.5 2 8
21 1 2 8
22 4 4 16
23 1 2 8
24 8 8 16
25 8 8 16
26 1 1 8
27 0.5 2 8
28 >32 >32 >32
Table 4.Comparative activity of Ceftazidime (expressed as MIC in mcg/ml) in representative compound is present in a concentration of 4 mcg/ml) presence of representative compounds of the invention (each
ESBL Type Strains Clavulanic acid Compound according to Example No.
20 21 23 1 15 13 14 16 4 17 26
Class A ESBL E.coli W 13353 0.25 0.25 0.25 0.5 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25
E. coli W 13351 0.5 0.5 1 1 0.5 0.5 0.5 0.5 1 0.5 1 1
E.coli W 13352 0.5 4 2 2 2 2 4 2 4 1 2 4
Class C ESBL E. coli M50 >32 2 2 2 1 1 2 1 2 1 1 1
E.coli 7MP >32 S 8 8 4 8 8 4 4 2 4 8
E.coli B89 >32 4 2 4 2 2 2 2 2 1 2 2
KPC ESBL K. pneumoniae H520 >32 16 8 8 8 2 8 4 4 1 2 4
K. pneumoniae H521 >32 16 8 8 8 2 8 4 4 1 2 4
K. pneumoniae H522 >32 16 4 8 4 1 4 1 1 1 1 1
Class D ESBL A. baumannii 13301 >32 >32 >32 >32 >32 >32 >32 >32 >32 >32 >32 >32
A. baumannii 13304 >32 >32 >32 >32 >32 16 >32 32 >32 8 16 16
CLAIMS
1. A compound of Formula (I)
or a stereoisomer or a pharmaceutically acceptable salt thereof; wherein:
Q is heteroaryl;
Ri is:
(a) hydrogen,
(b) (CO)n-R3,or
(c) COOR4,
n is 0, 1 or 2; R2is:
(a) S03M,
(b) SO2NH2,
(c) PO3M,
(d) CH2COOM,
(e) CF2COOM,
(f) CHFCOOM, or
(g) CF3;
M is hydrogen or a cation; R3IS:
(a) hydrogen,
(b) C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, OR5, CN, COOR5, CONR6R7, NR6R7, NRsCORg, NR5CONR6R7 heterocyclyl, heteroaryl, cycloalkyl or aryl,
(c) CN,
(d) NR6R7,
(e) CONR6R7,
(f) NHCONR6R7,
(g) aryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, OR5, NR6R7, halogen, CN, CONR6R7, S02-alkyl, S02-aryl, OS02-alkyl, OS02-aryl, orNHCONR6R7,
(h) heterocyclyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, OR5, NR6R7, halogen, CN, CONR6R7, S02-alkyl, S02-aryl, 0S02-alkyl, OS02-aryl, orNHCONR6R7,
(i) heteroaryl optionally substituted with one or more substituents
independently selected from C1-C6 alkyl, OR5, NR6R7, halogen, CN, CONR6R7, S02-alkyl, S02-aryl, 0S02-alkyl, OS02-aryl, orNHCONReR,,
(j) cycloalkyl optionally substituted with one or more substituents
independently selected from C1-C6 alkyl, OR5, NR6R7, halogen, CN, CONR6R7, S02-alkyl, S02-aryl, OS02-alkyl, OS02-aryl, or NHCONR6R7,
(k) cycloalkyl substituted with C1-C6 alkyl wherein C1-C6 alkyl is further
substituted with one or more substituents independently selected from O5, NR6R7, halogen, CN, or CONR6R7, or
(I) ORg;
R4 is:
(a) hydrogen,
(b) C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, OR5, CN, COOR5, CONR6R7, NRsR7, NRsCORg, heterocyclyl, heteroaryl, cycloalkyl or aryl,
(c) aryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, OR5, NR6R7, halogen, CN, CONR6R7, S02-alkyl, S02-aryl, OS02-alkyl, OS02-aryl, orNHCONR6R7,
(d) heterocyclyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, OR5, NR6R7, halogen, CN, CONR6R7, S02-alkyl, S02-aryl, OS02-alkyl, OS02-aryl, orNHCONR<;R7,
(e) heteroaryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, OR5, NR6R7, halogen, CN, CONR6R7, S02-alkyl, S02-aryl, OS02-alkyl, OS02-aryl, or NHCONR6R7, or
(f) cycloalkyl optionally substituted with one or more substituents
independently selected from C1-C6 alkyl, OR5, NR^Rj, halogen, CN, CONR6R7, S02-alkyl, S02-aryl, OS02-alkyl, OS02-aryl, orNHCONR^R?;
Rs and Rg are each independently:
(a) hydrogen, or
(b) C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, CN, CONR6R7, NR6R7, heterocyclyl, heteroaryl, cycloalkyl or aryl;
R6 and R7 are each independently:
(a) hydrogen,
(b) C1-C6-alkyl optionally substituted with one or more substituents independently selected from halogen, OR5, CN, COOR5, CONR6R7, NR5R8, NR5COR8, heterocyclyl, heteroaryl, cycloalkyl or aryl,
(c) aryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, OR5, NR5R8, halogen, CN, CONR5R«, S02-alkyl, S02-aryl, OS02-alkyl, OS02-aryl, orNHCONR5R«,
(d) heterocyclyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, OR5, NR6R7, halogen, CN, CONR5Rg8, S02-alkyl, S02-aryl, OS02-alkyl, OS02-aryl, or NHCONR5Rs,
(e) heteroaryl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, OR5, NR5Rg, halogen, CN, CONR5Rg, S02-alkyl, S02-aryl, OS02-alkyl, OS02-aryl, or NHCONR5Rg,
(f) cycloalkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, OR5, NR6R7, halogen, CN, CONRjRs, S02-alkyl, S02-aryl, OS02-alkyl, OS02-aryl, orNHCONR5Rs, or
(g) Rg and R7 are joined together to form a four to seven member ring.
2. A compound according Claim 1, selected from:
trans-sulfuricacidmono-[2-(5-aminomethyl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octan-6-yl] ester;
trans-sulfuric acid mono-[2-(5-((S)-l-amino-ethyl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1 ]-octan-6-yl] ester;
trans-sulfuric acid mono-[2-(5-((R)-1 -amino-ethyl)-[ 1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1]-octan-6-yl] ester;
trans-sulfuric acid mono-[2-(5-(piperidin-4-yl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octan-6-yl] ester;
trans-sulfuric acid mono-[2-(5-((S)-pyrrolidin-2-yl)-[l,3,4]-oxadiazol-2-yI)-7-oxo-l,6-diazabicyclo[3.2.1]-octan-6-yl] ester;
trans-sulfuric acid mono-[2-(5-(piperazin-1-yl-methyl)-[ 1,3,4]-oxadiazol-2-y])-7-oxo-l,6-diazabicyclo[3.2.1]-octan-6-yl] ester;
trans-sulfuric acidmono-[2-(5-((RS)-l-amino-l-phenyl-methyl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-l ,6-diazabicyclo[3.2. l]-octan-6-yl] ester;
trans-sulfuric acid mono-[2-(5-(piperidin-4-yl)-[l ,2,4]-oxadiazol-3-yl)-7-oxo-l ,6-diazabicyclo[3.2.1]-octane;
trans-sulfuric acid mono-[2-(5-((R)-piperidin-3-yl)-[ 1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1 ]-octane;
or a stereoisomer or a pharmaceutically acceptable salt thereof.
3. A compound according Claim 1, selected from:
Sodium saItoftrans-6-(sulphooxy)-2-(5-methyI-[l,3,4]-oxadiazol-2-yI)-7-oxo-l,6-diazabicyclo[3.2.1 ]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-ethyl-[ 1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1 ]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-trifluoromethyl-[l,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1 j-octane;
Sodium salt of trans-6-{sulphooxy)-2-(5-carboxamido-[l,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1 ]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-(isooxazol-3-yl)-[l,3J4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-(furan-2-yl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1 ]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5'phenyl-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1 ]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5~(pyridin-2-yl)-[ 1,3,4]-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1 ]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-(6-carboxamido-pyridin-2-yl)-[ 1,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-(5,6-dihydro-8H-imidazo[2,1 -c][ 1,4]-oxazin-2-yl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5~(morpholino-4-methyl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-l ,6-diazabicyclo[3.2. l]-octane;
Sodium salt of trans-sulfuric acid mono-[2-(5-(morpholin-4-yl-carbonyl)-[ 1,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octan-6-yl] ester;
Sodium salt of trans-6-(sulphooxy)-2-(5-methyl-[l,3,4]4hiadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2. l]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-methyl-[l,2,4]-oxadiazol-3-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-ethoxycarbonyl-[l,2,4]-oxadiazol-3-yl)-7-oxo-1,6-diazabicy clo[3.2.1 ]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(2^methyl-2H-[l,2,3,4]-tetrazol-5-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(l-methyl-lH-[l,2,3,4]-tetrazol-5-yl)-7-oxo-1,6-diazabicyclo[3.2.1 ]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(3-ethoxycarbonyl-[ 1,2,4]-oxadiazol-5-yl)-7-oxo-1,6-diazabicy clo[3.2.1 ]-octane;
Sodium salt of trans-6-(sulphooxy)-2-(5-carboxamido-[ 1,2,4]-oxadiazol-3-yl)-7-oxo-1,6-diazabicyclo[3.2.1 ]-octane;
or a stereoisomer thereof.
4. A pharmaceutical composition comprising a compound according to any of the Claims 1 to 3.
5. A method for preventing or treating bacterial infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of a compound according to any of the Claims 1 to 3.
6. A method for preventing or treating a bacterial infection in a subject, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said subject a pharmaceutically effective amount of a compound according to any of the Claims 1 to 3.
7. A pharmaceutical composition according to Claim 4, further comprising at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
8. A pharmaceutical composition according to Claim 4 or 7, further comprising at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
9. A method for preventing or treating bacterial infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of a pharmaceutical composition according to Claim 4, 7 or 8.
10. A method for preventing or treating a bacterial infection in a subject, said infection being caused by bacteria producing one or more beta-lactamase enzymes, wherein the method comprises administering to said subject a pharmaceutically effective amount of a pharmaceutical composition according to Claim 4, 7 or 8.
11. A method for preventing or treating a bacterial infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of: (a) a compound of Formula (I) according to Claim 1 or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
12. A method for preventing or treating a bacterial infection in a subject, said infection being caused by bacteria producing one or more beta-lactamase enzymes, said method comprising administering to said subject a pharmaceutically effective amount of: (a) a compound of Formula (I) according to Claim 1 or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof.
13. A method for preventing or treating a bacterial infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of: (a) a compound of Formula (I) according to Claim 1 or a stereoisomer or a pharmaceutically
acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutical ly acceptable derivative thereof.
14. A method for preventing or treating a bacterial infection in a subject, said infection being caused by bacteria producing one or more beta-lactamase enzymes, said method comprising administering to said subject a pharmaceutically effective amount of: (a) a compound of Formula (I) according to Claim 1 or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
15. A method for preventing or treating a bacterial infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of: (a) a compound of Formula (I) according to Claim 1 or a stereoisomer or a pharmaceutically acceptable salt thereof; (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
16. A method for preventing or treating a bacterial infection in a subject, said infection being caused by bacteria producing one or more beta-lactamase enzymes, said method comprising administering to said subject a pharmaceutically effective amount of: (a) a compound of Formula (I) according to Claim 1 or a stereoisomer or a pharmaceutically acceptable salt thereof, (b) at least one beta-lactamase inhibitor selected from sulbactam, tazobactam, clavulanic acid, or a pharmaceutically acceptable derivative thereof, and (c) at least one antibacterial agent or a pharmaceutically acceptable derivative thereof.
17. A method for increasing antibacterial effectiveness of a antibacterial agent in a subject, said method comprising co-administering said antibacterial agent or a pharmaceutically acceptable derivative thereof with a pharmaceutically effective amount of a compound of Formula (I) according to Claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition according to Claim 8 or a method according to any of the Claims 9, 10, 13, 14, 15, 16 or 17, wherein the antibacterial agent is selected from a group consisting of aminoglycosides, ansamycins, carbacephems, cephalosporins, cephamycins, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, penicillins, polypeptides, quinolones, sulfonamides, tetracyclines, or oxazolidinone antibacterial agents.
19. A pharmaceutical composition according to Claim 8 or a method according to any of the Claims 9, 10, 13, 14, 15, 16 or 17, wherein the antibacterial agent is a beta-lactam antibacterial agent.
20. A pharmaceutical composition according to Claim 8 or a method according to any of the Claims 9, 10, 13, 14, 15, 16 or 17, wherein said antibacterial agent is selected from a group consisting of penicillins, penems, carbapenems, cephalosporins, and monobactams.
21. A pharmaceutical composition according to Claim 8 or a method according to any of the Claims 9, 10, 13, 14, 15, 16 or 17, wherein the antibacterial agent is a cephalosporin antibiotic selected from a group consisting of cephalothin, cephaloridine, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin, cephacetrile, cefotiam, cefotaxime, cefsulodin, cefoperazone, ceftizoxime, cefmenoxime, cefmetazole, cephaloglycin, cefonicid, cefodizime, cefpirome, ceftazidime, ceifriaxone, cefpiramide, cefbuperazone, cefozopran, cefepime, cefoselis, cefluprenam, cefuzonam, cefpimizole, cefclidin, cefixime, ceftibuten, cefdinir, cefpodoxime axetil, cefpodoxime proxetil, cefteram pivoxil, cefetamet pivoxil, cefcapene pivoxil or cefditoren pivoxil, cefuroxime, cefuroxime axetil, loracarbacef, ceftaroline and latamoxef.
22. A pharmaceutical composition according to Claim 8 or a method according to any of the Claims 9, 10, 13, 14, 15, 16 or 17, wherein the antibacterial agent is selected from a group consisting of ceftazidime, cefepime, cefpirome, piperacillin doripenem, meropenem, imipenem, ceftaroline and ceftolozane.
23. A pharmaceutical composition according to Claim 8 or a method according to any of the Claims 9, 10, 13, 14, 15, 16 or 17, wherein the antibacterial agent is selected from a group consisting of aminoglycosides, ansamycins, carbacephems, cephalosporins, cephamycins, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, penicillins, polypeptides, quinolones, sulfonamides, tetracyclines, or oxazolidinone antibacterial agents.