WO2018203194A1 - Diazabicyclooctane derivatives comprising a quaternery ammonium group for use as antibacterial agents - Google Patents

Abstract

Compounds of Formula (I), pharmaceutical compositions comprising these compounds and their use in treating bacterial infection is disclosed.

Description

DIAZABICYCLOOCTANE DERIVATIVES COMPRISING A QUATERNERY AMMONIUM GROUP FOR USE AS

ANTIBACTERIAL AGENTS

RELATED PATENT APPLICATIONS

This application claims the priority to and benefit of Indian Provisional Patent Application No. 201721015502 filed on May 02, 2017; the disclosures of which are incorporated herein by reference in its entirety as if fully rewritten herein.

FIELD OF THE INVENTION

The invention relates to quaternary ammonium compounds, their preparation and their treating and/or preventing bacterial infections.

BACKGROUND OF THE INVENTION

The 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 new antibacterial agents that can overcome the bacterial resistance. Coates et al. (Br. J. Pharmacol. 2007; 152(8), 1147-1154) have reviewed 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. However, there remains a need for potent antibacterial agents for use in treatment and/or prevention of bacterial infections, including those caused by bacteria that have acquired resistance to one or more of the known antibacterial agents. The inventors have surprisingly discovered certain quaternary ammonium compounds having antibacterial properties.

SUMMARY OF THE INVENTION

Accordingly, there are provided compounds of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof;

Formula (I)

wherein:

Y is Ci-C₆ alkyl;

Ri R₂ and R₃ are:

(a) each of Ri, R₂ and R₃ are independently selected from: (i) Ci-C₆ alkyl, optionally substituted with one or more substituents independently selected from OR₄, NR₄R₅, SOR₄, SR₄, halogen, CN, COOR₄, CONR₄R₅, NHCOR₄, aryl, heteroaryl, heterocycloalkyl, cycloalkyl , NHCONR₄R₅, NHCSNR₄R₅, and (=N-OR₆); (ii) aryl; (iii) heteroaryl; (iv) cycloalkyl; (v) COOR₄;(vi) CONR₄R5;(vii) OR4; or (viii) heterocycloalkyl;

(b) Ri and R₂ are combined to form a hetrocycloalkyl ring which is optionally substituted with one or more substituents selected from: (i) Ci-C₆ alkyl, optionally substituted with one or more substituents independently selected from OR₄, NR₄R₅, SOR₄, SR₄, halogen, CN, COOR₄, CON jRs, NHCOR₄, aryl, heteroaryl, heterocycloalkyl, cycloalkyl , NHCONR₄Rs, NHCSNR₄R₅, and (=N-OR₄); (ii) NR₄R₅; (iii) NHCOOR₄; (iv) aryl; (v)CN; (vi)NHCONR₄R₅; (vii)heteroaryl; (viii) cycloalkyl; (ix) halogen; (x) COOR*; (xi) CONR₄R₅; (xii) NHCOR^ (xiii) OR₄; (n) heterocycloalkyl; (o) (=0); or (p) (=N-OR4); or

(c) Ri, R₂, R3 are combined to form a heteroaryl ring which is optionally substituted with one or more substituents selected from: (i) Ci-C₆ alkyl, optionally substituted with one or more substituents independently selected from OR₄, NR4R5, SOR₄, SR₄, halogen, CN, COOR₄, CONR^, NHCOR , aryl, heteroaryl, heterocycloalkyl, cycloalkyl , NHCONR₄R₅, NHCSNR₄R₅, and (=N-OR₄); (ii) NR₄R₅; (iii) NHCOOR₄; (iv) aryl; (v) CN; (vi) NHCONR₄R₅;(vii) heteroaryl; (viii)cycloalkyl; (ix) halogen; (x) COOR₄; (xi) CONR R₅; (xii) NHCOR₄; (xiii) OR ; (xiv) heterocycloalkyl; or (xv) trifluoromethyl;

R t_, R5 and R6 are each independently:

(a) hydrogen;

(b) Ci-C₆ alkyl, optionally substituted with one or more substituents independently selected from OR₇, NR₇R_S, COOR7, CONR₇R₈, SOR₇, aryl, aryl optionally substituted with one or more substituents independently selected from halogen, OR₇ or NR₇Rs , heteroaryl, heterocycloalkyl, cycloalkyl , NHCONR₇R₈, NHCSNR₇R₈, and (=N-OR₇);

(c) trifluoromethyl;

(d) aryl, optionally substituted with one or more substituents

independently selected from halogen, OR₇ and NR₇R₈;

(e) heteroaryl; or

(f) heterocycloalkyl;

R₇ and R₈ are each independently:

(a) hydrogen; or

(b) Ci-Cg alkyl

In another general aspect, there are provided pharmaceutical compositions comprising a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof. In another general aspect, there is provided a method for treating or preventing a bacterial infection in a subject, said method comprising administering to said subject a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.

In yet another general aspect, there is provided a method for treating or preventing a bacterial infection in a subject, said method comprising administering to said subject a pharmaceutical composition comprising a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the following description including claims.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made to the exemplary embodiments, and specific language will be used herein to describe the same. It should nevertheless be understood that no limitation of the scope of the invention is thereby intended. Alterations and further modifications of the inventive features illustrated herein, and additional applications of the principles of the invention as illustrated herein, which would occur to one of ordinary skills in the relevant art and having possession of this disclosure, are to be considered within the scope of the invention. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. All references including patents, patent applications, and literature cited in the specification are expressly incorporated herein by reference in their entirety.

The inventors have surprisingly discovered certain quaternary ammonium compounds having antibacterial properties.

The term "Ci-C₆ alkyl" as used herein refers to branched or unbranched acyclic hydrocarbon radical with 1 to 6 carbon atoms. Typical, non-limiting examples of "Ci-C₆ alkyl" include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and the like. The "Ci-C₆ alkyl" may be unsubstituted, or substituted with one or more substituents. Typical, non- limiting examples of such substituents include halogen, alkoxy, CN, COOH, CONH₂, OH, -NH₂, - NHCOCH₃, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, urea, thiourea, keto, oxime, O-alkyl, O- aryl, N-alkyl, N-aryl, SO-alkyl, SO-aryl, S-alkyl, S-aryl S0₂-alkyl, S0₂-aryl, OS0₂-alkyl, OS0₂- aryl COO-alkyl, COO-aryl, CON-alkyl, CON-aryl, NHCO-alkyl, NHCO-aryl, NHCON-alkyl ,NHCON-aryl, NHCSN-alkyl, NHCSN-aryl, (=N-0-alkyl) and the like.

The term "cycloalkyl" as used herein refers to three to seven member cyclic hydrocarbon radicals. The cycloalkyl group optionally incorporates one or more double or triple bonds, or a combination of double bonds and triple bonds, but which is not aromatic. Typical, non-limiting examples of cycloalkyl groups include cyclopropane, cyclobutane,cyclopentane, cyclohexane, and cycloheptane. The cycloalkyl may be unsubstituted, or substituted with one or more substituents. Typical, non- limiting examples of such substituents include Ci-C₆ alkyl, halogen, alkoxy, CN, COOH, CONH₂, OH, -NH₂, -NHCOCH₃, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, urea, thiourea, keto, oxime, O-alkyl, O-aryl, N-alkyl, N-aryl, SO-alkyl, SO-aryl, S-alkyl, S-aryl SO₂- alkyl, S0₂-aryl, OS0₂-alkyl, OS0₂-aryl COO-alkyl, COO-aryl, CON-alkyl, CON-aryl, NHCO- alkyl, NHCO-aryl, NHCON-alkyl ,NHCON-aryl, NHCSN-alkyl, NHCSN-aryl, (=N-0-alkyl) and the like.

The term "heterocycloalkyl" as used herein refers to four to seven member cycloalkyl group containing one or more heteroatoms selected from nitrogen, oxygen or sulfur. The heterocycloalkyl group optionally incorporates one or more double or triple bonds, or a combination of double bonds and triple bonds, but which is not aromatic. Typical, non-limiting examples of heterocycloalkyl groups include azetidine, pyrrolidine, 2-oxopyrrolidine, imidazolidin-2-one, piperidine, oxazine, thiazine, piperazine, morpholine, thiomorpholine, azapane, piperazin-2,3-dione and the like. The heterocycloalkyl may be unsubstituted, or substituted with one or more substituents. Typical, non-limiting examples of such substituents include Ci-C₆ alkyl, halogen, alkoxy, CN, COOH, CONH₂, OH, -NH₂, -NHCOCH₃, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, urea, thiourea, keto, oxime, O-alkyl, O-aryl, N-alkyl, N-aryl, SO-alkyl, SO-aryl, S-alkyl, S- aryl S0₂-alkyl, S0₂-aryl, OS0₂-alkyl, OS0₂-aryl COO-alkyl, COO-aryl, CON-alkyl, CON-aryl, NHCO-alkyl, NHCO-aryl, NHCON-alkyl ,NHCON-aryl, NHCSN-alkyl, NHCSN-aryl, (=N-0- alkyl) and the like.

The term "aryl" as used herein refers to a monocyclic or polycyclic aromatic hydrocarbon. Typical, non-limiting examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, phenanthrenyl, and the like. The aryl group may be unsubstituted, or substituted with one or more substituents. Typical, non-limiting examples of such substituents include Ci-C₆ alkyl, halogen, alkoxy, CN, COOH, CONH₂, OH, -NH₂, -NHCOCH₃, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, urea, thiourea, keto, oxime, O-alkyl, O-aryl, N-alkyl, N-aryl, SO-alkyl, SO-aryl, S-alkyl, S- aryl S0₂-alkyl, S0₂-aryl, OS0₂-alkyl, OS0₂-aryl COO-alkyl, COO-aryl, CON-alkyl, CON-aryl, NHCO-alkyl, NHCO-aryl, NHCON-alkyl ,NHCON-aryl, NHCSN-alkyl, NHCSN-aryl, (=N-0- alkyl) and the like.

The term "heteroaryl" as used herein refers to a monocyclic or polycyclic aromatic hydrocarbon group wherein one or more carbon atoms have been replaced with heteroatoms selected from nitrogen, oxygen, and sulfur. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different. Typical, non-limiting example of heteroaryl groups include 1,2,4-oxadiazol, 1,3,4-oxadiazol, 1,3,4-thiadiazol, 1,2,3-triazol, 1,2,3,4- tetrazol, 1,3-oxazol, 1,3-thiazole, pyridine, pyrimidine, pyrazine, pyridazine, furan, pyrrol, thiophene, imidazole, pyrazole, benzofuran, benzothiophene, benzimidazole, benzoxazole, benzothiazole, thiazole, and the like. The heteroaryl group may be unsubstituted, or substituted with one or more substituents. Typical, non-limiting examples of such substituents include Ci-C₆ alkyl, halogen, alkoxy, CN, COOH, CONH₂, OH, -NH₂, -NHCOCH₃, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, urea, thiourea, keto, oxime, O-alkyl, O-aryl, N-alkyl, N-aryl, SO-alkyl, SO-aryl, S- alkyl, S-aryl S0₂-alkyl, S0₂-aryl, OS0₂-alkyl, OS0₂-aryl COO-alkyl, COO-aryl, CON-alkyl, CON- aryl, NHCO-alkyl, NHCO-aryl, NHCON-alkyl ,NHCON-aryl, NHCSN-alkyl, NHCSN-aryl, (=N- O-alkyl) and the like.

The term "stereoisomers" as used herein refers to and includes compounds that have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space. It is intended, unless specified otherwise, that all stereoisomers forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, all geometric and positional isomers (including cis/trans forms or E/Z forms) as well as mixtures thereof, are also embraced within the scope of the invention. In general, a reference to a compound is intended to cover its stereoisomers and a mixture of various stereoisomers.

The term "optionally substituted" as used herein means that substitution is optional and therefore includes both unsubstituted and substituted atoms and moieties. A "substituted" atom or moiety indicates that any hydrogen on the designated atom or moiety can be replaced with a selection from the indicated substituent group, provided that the normal valence of the designated atom or moiety is not exceeded, and that the substitution results in a stable compound.

The term "pharmaceutically acceptable salt" as used herein refers to one or more salts of a given compound which possesses the desired pharmacological activity of the free compound and which are neither biologically nor otherwise undesirable. In general, the "pharmaceutically acceptable salts" refer to and include those salts that are suitable for use in contact with the tissues of human and animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. (J. Pharmaceutical Sciences, 66: 1-19 (1977)), incorporated herein by reference in its entirety, describes various pharmaceutically acceptable salts in details.

In general, the compounds according to the invention contain basic (e.g. nitrogen atoms) as well as acid moieties (e.g S0₃H group). A person of skills in the art would appreciate that such compounds, therefore, can form acidic salts (formed with inorganic and/or organic acids), as well as basic salts (formed with inorganic and/or organic bases). Such salts can be prepared using procedures described in the art. For example, the basic moiety can be converted to its salt by treating a compound with a suitable amount of acid. Typical, non-limiting examples of such suitable acids include hydrochloric acid, trifluoroacetic acid, methanesulphonic acid, or the like. Alternatively, the acid moiety may be converted into its salt by treating with a suitable base. Typical non-limiting examples of such bases include sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate or the like. In case of compounds containing more than one functional group capable of being converted into salt, each such functional group may be converted to a salt independently. For example, in case of compounds containing two basic nitrogen atoms, one of the basic nitrogen can form salt with one acid while the other basic nitrogen can form salt with another acid. The compounds according to the invention contain both, acidic as well as basic moieties, and thus can form inner salts or corresponding zwitterions. In general, all pharmaceutically acceptable salt forms of compounds of Formula (I) according to invention including acid addition salts, base addition salts, zwitterions or the like are contemplated to be within the scope of the present invention and are generically referred to as pharmaceutically acceptable salts.

The term "infection" or "bacterial infection" as used herein refers to and includes presence of bacteria, in or on a subject, which, if its growth were inhibited, would result in a benefit to the subject. As such, the term "infection" in addition to referring to the presence of bacteria also refers to normal flora, which is not desirable. The term "infection" includes infection caused by bacteria.

The term "treat", "treating" or "treatment" as used herein refers to administering a medicament, including a pharmaceutical composition, or one or more pharmaceutically active ingredients, for prophylactic and/or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who is not yet infected, but who is susceptible to, or otherwise at a risk of infection (preventing the bacterial infection). The term "therapeutic treatment" refers to administering treatment to a subject already suffering from infection. The terms "treat", "treating" or "treatment" as used herein also refer to administering compositions or one or more of pharmaceutically active ingredients discussed herein, with or without additional pharmaceutically active or inert ingredients, in order to: (i) reduce or eliminate either a bacterial infection or one or more symptoms of the bacterial infection, or (ii) retard the progression of a bacterial infection or of one or more symptoms of the bacterial infection, or (iii) reduce the severity of a bacterial infection or of one or more symptoms of the bacterial infection, or (iv) suppress the clinical manifestation of a bacterial infection, or (v) suppress the manifestation of adverse symptoms of the bacterial infection.

The term "administration" or "administering" refers to and includes delivery of a composition or one or more pharmaceutically active ingredients to a subject, including for example, by any appropriate methods, which serves to deliver the composition or its active ingredients or other pharmaceutically active ingredients to the site of the infection. The method of administration may vary depending on various factors, such as for example, the components of the pharmaceutical composition or the nature of the pharmaceutically active or inert ingredients, the site of the potential or actual infection, the microorganism involved, severity of the infection, age and physical condition of the subject and a like. Some non-limiting examples of ways to administer a composition or a pharmaceutically active ingredient to a subject according to this invention includes oral, intravenous, topical, intra-respiratory, intra-peritoneal, intra-muscular, parenteral, sublingual, transdermal, intranasal, aerosol, intra-ocular, intra-tracheal, intra-rectal, vaginal, gene gun, dermal patch, eye drop, ear drop or mouthwash. In case of a pharmaceutical composition comprising more than one ingredient (active or inert), one of way of administering such composition is by admixing the ingredients (e.g. in the form of a suitable unit dosage form such as tablet, capsule, solution, powder and a like) and then administering the dosage form. Alternatively, the ingredients may also be administered separately (simultaneously or one after the other) as long as these ingredients reach beneficial therapeutic levels such that the composition as a whole provides a synergistic and/or the desired effect.

The term "subject" as used herein refers to a vertebrate or invertebrate, including a mammal. The term "subject" includes human, animal, a bird, a fish, or an amphibian. Typical, non-limiting examples of a "subject" includes humans, cats, dogs, horses, sheep, bovine cows, pigs, lambs, rats, mice and guinea pigs.

In one general aspect, there is provided a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof;

Formula (I)

wherein:

Y is Ci-C₆ alkyl;

Ri b and R₃ are:

(a) each of Ri, R₂ and R₃ are independently selected from: (i) Ci-C₆ alkyl, optionally substituted with one or more substituents independently selected from OR₄, NR4R5, SOR₄, SR4, halogen, CN, COOR₄, CONR4R5, NHCOR₄, aryl, heteroaryl, heterocycloalkyl, cycloalkyl , NHCONR₄Rs, NHCSNR₄R₅, and (=N-OR₆); (ii) aryl; (iii) heteroaryl; (iv) cycloalkyl; (v) COOR₄;(vi) CONR₄R₅;(vii) OR₄; or (viii) heterocycloalkyl;

(b) Ri and R₂ are combined to form a hetrocycloalkyl ring which is optionally substituted with one or more substituents selected from: (i) Ci-C₆ alkyl, optionally substituted with one or more substituents independently selected from OR₄, NR₄R₅, SOR₄, SR4, halogen, CN, COOR₄, CONR^s, NHCOR , aryl, heteroaryl, heterocycloalkyl, cycloalkyl , NHCONR R₅, NHCSNR4R5, and (=N-OR₄); (ii) NR₄Rs; (iii) NHCOOR₄; (iv) aryl; (v)CN; (vi)NHCONR₄R₅; (vii)heteroaryl; (viii) cycloalkyl; (ix) halogen; (x) COOR₄; (xi) CONR4R5; (xii) NHCOR₄; (xiii) OR₄; (n) heterocycloalkyl; (o) (=0); or (p) (=N-OR4); or

(c) Ri, R₂, R₃ are combined to form a heteroaryl ring which is optionally substituted with one or more substituents selected from: (i) Ci-C₆ alkyl, optionally substituted with one or more substituents independently selected from OR4, NR4R₅, SOR4, SR₄, halogen, CN, COOR₄, CONR^s, NHCOR₄, aryl, heteroaryl, heterocycloalkyl, cycloalkyl , NHCONR₄R₅, NHCSNR₄R₅, and

(ii) NR₄R₅; (iii) NHCOORt; (iv) aryl; (v) CN; (vi) NHCONR₄R₅;(vii) heteroaryl; (viii)cycloalkyl; (ix) halogen; (x) COOR₄; (xi) CONR₄R₅; (xii) NHCOR₄; (xiii) OR₄; (xiv) heterocycloalkyl; or (xv) trifluoromethyl;

R^ R5 and R6 are each independently:

(a) hydrogen;

(b) Ci-Ce alkyl, optionally substituted with one or more substituents independently selected from OR₇, NR₇R₈, COOR₇, CONR₇R₈, SOR₇, aryl, aryl optionally substituted with one or more substituents independently selected from halogen, OR₇ or NR₇R₈ , heteroaryl, heterocycloalkyl, cycloalkyl , NHCONR₇R₈, NHCSNR₇R₈, and (=N-OR₇);

(c) trifluoromethyl;

(d) aryl, optionally substituted with one or more substituents independently selected from halogen, OR₇ and NR₇R₈; (e) heteroaryl; or

(f) heterocycloalkyl;

R₇ and Rg are each independently:

(a) hydrogen; or

(b) Ci-C₆ alkyl

Typical, non-limiting examples of compounds according to the invention include:

The compounds of the invention can be prepared according to the general procedure given in Scheme 1. Individual stereoisomers can be prepared using appropriate starting materials and reagents. A person of skills in the art would appreciate that the described methods can be varied and/or optimized further to provide the desired and related compounds.

(I)

Scheme 1

Typically, a compound of Formula (II) is reacted with a compound of Formula (III) to obtain a compound of Formula (IV) in presence of suitable reagents. Typical, non-limiting example of suitable reagents includes diisopropylethyl amine, tetrabutylammonium hydrogen sulphate in presence dichloromethane as a solvent.

The compound of Formula (IV) is reacted with a compound of Formula (V) to obtain a compound of Formula (I) in presence of suitable solvents using appropriate conditions varying from stirring at ambient temperature to reflux conditions. Typical, non-limiting examples of suitable solvents include dichloromethane, toluene, N-methyl pyrrolidinone, methanol, acetonitrile or a mixture thereof. A wide variety of other reagents which can bring about these functional group transformations can be used.

In another general aspect, there are provided pharmaceutical compositions comprising a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions according to the invention may include one or more pharmaceutically acceptable carriers or excipients or a like. Typical, non-limiting examples of such carriers or excipients 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 and a like.

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 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, intra- respiratory, intra-peritoneal, intra-muscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intra-tracheal, intra-rectal, vaginal, gene gun, dermal patch, eye drop, ear drop or mouthwash.

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.

In some other embodiments, there are provided methods for treating or preventing bacterial infection in a subject, said method comprising administering to said subject a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof.

In some embodiments, there are provided methods for treating or preventing bacterial infection in a subject, said method comprising administering to said subject a pharmaceutical composition comprising a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof.

In general, the compounds, pharmaceutical compositions and method disclosed herein are useful in treating and/or preventing bacterial infections. Advantageously, the compounds, compositions and methods disclosed herein are also effective in treating or preventing 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 treated or prevented using the compounds, compositions and/or methods according to 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.

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.

Preparations

Preparation 1 ;- Synthesis of l-(pyridin-3-yl)urea.

Step 1: Synthesis of phenyl pyridin-3-ylcarbamate.

To a stirred solution of 3-amino pyridine (20g, 0.212 mol) in dichloromethane (200 ml) was added pyridine (21.8 ml, 0.276 mol) at 0°C and to this solution was added a solution of phenyl chloroformate (33.8 g, 0.276 mol) in dichloromethane (50 ml) dropwise under stirring. The reaction mixture was stirred at 0°C to 25°C for 2 hours. After completion of the reaction, the reaction mixture was added water (500 ml) and layers were separated. Organic layer was dried over anhydrous sodium sulphate and the solvent was evaporated under reduced pressure to provide 22 g of phenyl pyridin-3-ylcarbamate as a white solid (48% yield).

Analysis:

Mass: 215.2 (M+l): for Molecular Weight of 214 and Molecular Formula of C12H10N2O2; 1H NMR (CDCI₃): δ 8.67-8.68 (m, 1H), 8.37-8.38 (m, 1H), 8.07 (s, 1H), 8.85-8.87 (d, 1H, / = 8.4Hz), 7.13-7.26 (m, 5H), 7.19-7.23 (dd, 1H, = 4.4 Hz).

Step 2: Synthesis of l-(pyridin-3-yl)urea. To a stirred solution of phenyl pyridine-3-ylcarbamate (5g, 0.023 mol) in ethanol (50 ml), was added ammonium hydroxide (1.63g, 0.0046mol) at 25°C and the stirring was continued at 80°C for 4 hours. After completion of the reaction, solvent was evaporated under reduced pressure to provide 2.9 g of l-(pyridin-3-yl)urea as a white solid (90% yield).

Analysis:

Mass: 136.1(M-1): for Molecular Weight of 137 and Molecular Formula of C₆H₇N₃0;

1H NMR (DMSO-d₆): δ 8.67 (s, 1H), 8.49 (s, 1H), 8.08-8.09 (d, 1H, J = 4Hz), 7.85-7.87

(d, 1H, J = 8.4Hz), 7.19-7.23 (dd, 1H, J = 4.4Hz), 5.96 (s, 2H).

The following preparations 2 and 3 were prepared according to the procedure described for preparation 1 using the appropriate reactant (listed in Table 1) in place of ammonium hydroxide in step 2. The preparations 4-7 were prepared as per the step 1 of preparation 1 using 4-amino pyridine in place of 3-amino pyridine and using the appropriate reactant (listed in Table 1) in place of ammonium hydroxide in step 2. The list of preparations with data was mentioned in Table 1.

1H NMR (DMSO-d₆): δ 8.38-8.39 (d, 2H, / = 6Hz),

7.29-7.31 (m, 2H), 5.82(s, 1H), 3.30-3.33 (q, 2H, J = 5.2Hz ), 2.52 (s, 1H), 2.31(s, 6H), 1.98 (s, 1H)

Mass: 209.3(M+1); Molecular Formula: Ci₀H₁₆N₄O.

Preparation 8 :- Synthesis of l-(pyridin-3-ylmethyl) urea.

Step 1: Synthesis of phenyl (pyridin-3-ylmethyl)carbamate.

To a stirred solution of l-(pyridin-3-yl)methanamine (30g, 0.277mol) in dichloromethane (300 ml), was added triethyl amine (79.3 ml, 0.55 mol) at 0°C and to this solution was added a solution of phenyl chloroformate (33.8 g, 0.277 mol) in dichloromethane (50 ml) dropwise under stirring. The reaction mixture was stirred at 0°C to 25°C for 2 hours. After completion of the reaction, the reaction mixture was added water (500 ml) and layers were separated. Organic layer was dried over anhydrous sodium sulphate and the solvent was evaporated under reduced pressure to provide 38 g of the phenyl (pyridin-3-ylmethyl)carbamate as a white solid (60% yield).

Analysis:

Mass: 229.2 (M+l): for Molecular Weight of 228.1 and Molecular Formula of C13H12N2O2; 1H NMR (CDCI3): 8.59 (s, 1H), 8.55-8.56 (d, 1H, J = 4.2Hz), 7.69-7.71 (d, lH, i =

7.6Hz), 7.30-7.38 (t, 2H, / = 8Hz), 7.26-7.30 (m, 1H), 7.19-7.22 (t,lH, / = 7.6 Hz), 7.13- 7.15 (d, 2H, J = 8 Hz), 5.66 (s, 1H), 4.45-4.46 (d,2H, 7 = 6 Hz).

Step 2: Synthesis of l-(pyridin-3-ylmethyl) urea.

To a stirred solution of phenyl (pyridin-3-ylmethyl) carbamate (5g, 0.021mol) in ethanol (50 ml) was added ammonium hydroxide (1.5g, 0.043mol) at 25°C and the stirring was continued at 80°C for 4 hours. After completion of the reaction, solvent was evaporated under reduced pressure to provide 3g of the l-(pyridin-3-ylmethyl) urea as a white solid (92% yield).

Analysis:

Mass: 152.3(M+1): for Molecular Weight of 151.17 and Molecular Formula of C₇H₉N₃O; 1H NMR (DMSO-d₆): 8.47 (s, 1H), 8.43-8.44 (d, 1H, / = 4.8Hz), 7.63-7.65(d, 1H, J = 8Hz), 7.31-7.35 (m, 1H), 6.48-6.51 (t, 1H, J = 5.6Hz), 5.58 (s, 2H), 4.18-4.20 (d, 2H, J = 6Hz).

The following preparations 9 - 12 were prepared according to the procedure described for preparation 8 using appropriate starting reactant in place of ammonium hydroxide in step 2. The list of preparation with the data was mentioned in Table 2.

Example- 1

(i r(2S, 5R)-7-oxo-2-i r2-(pyridinium-l-ylacetyl) hydrazinyll carbonyll- 1, 6-diazabicyclo Γ3.2.11 oct-6-yll oxy) sulfonyl) oxidanide.

Step 1: Synthesis of tetrabutylammonium salt of (2S,5i?)-N-(bromoacetyl)-7-oxo-6-(sulfooxy)- 1 ,6-diazabicyclo [3.2.1 ]octane-2-carbohydrazide( 1 a) .

To a solution of (2S, 5R)-7-oxo-6-(sulfooxy)-l, 6-diazabicyclo [3.2.1] octane-2- carbohydrazide (II) (20 g, 0.071 mol, prepared according procedure described in PCT International Patent Application No. PCT/IB2016/053965) in dichloromethane (100 ml) was added diisopropylethyl amine (26.39 ml, 0.142 mol) and tetrabutylammonium hydrogen sulphate (24.2 g, 0.071 mol) at -10°C under stirring. To the resulted reaction mixture was added a solution of bromoacetyl bromide (6.37 ml, 0.071 mol) in dichloromethane (100 ml) drop wise at -10°C and the temperature of the reaction mixture was allowed to come at 25°C. After completion of the reaction, the reaction mixture diluted with water (500 ml) and dichloromethane (200 ml). Layers were separated, organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum to provide 14g of tetrabutylammonium salt of (25,5R)-N-(bromoacetyl)-7-oxo-6-(sulfooxy)-l,6- diazabicyclo[3.2.1]octane-2-carbohydrazide (la) as oily mass.

Step 2: Synthesis of ({ [(25, 5R)-7-oxo-2-{ [2-(pyridinium-l-ylacetyl) hydrazinyl] carbonyl}-l, 6- diazabicyclo [3.2.1] oct-6-yl] oxy} sulfonyl) oxidanide (1).

To a solution of tetrabutylammonium salt of (25,5 ?)-N-(bromoacetyl)-7-oxo-6-(sulfooxy)- l,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (la, 3 g, 0.004 mol) in dichloromethane (30 ml) was added pyridine (3 ml) and the reaction mixture was stirred at room temperature for 6 hours. The solid obtained was filtered on Buchner funnel and washed with dichloromethane (2 x 10 ml). The solid obtained was dried at 45°C to obtain 0.500g of compound (1). The crude compound (1) was dissolved in water (5 ml) and to this solution was added Isopropanol (25 ml) at 25°C drop wise under continuous stirring. The compounds precipitated out slowly during stirring and after completion of 6 hrs stirring. The precipitates were filtered and dried under vacuum, to provide 0.320 g of compound (1), (17%Yield).

Analysis:

Mass: 398.2 (M-H) for Molecular weight 399 and Molecular Formula of C14H17N5O7S ; 1H NMR (400MHz, DMSO-d₆): δ 10.61 (s, 1H), 10.25 (s, 1H), 9.00-9.01 (d, 2H), 8.66- 8.70 (t, 1H), 8.19-8.22 (t, 2H), 5.57 (s, 2H), 3.99 (s, 1H), 3.87-3.89 (d, 1H),3.11-3.13 (d, 1H), 2.96-2.99 (d, 1H), 1.59-2.00 (m, 4H).

The compounds of Examples 2 to 29 (Table 3) were prepared by following the procedure described in Example 1 and following the Scheme 1, wherein appropriately substituted and protected tertiary nitrogen containing heteroaryls or heterocycles or trialkyl amines are used in place of pyridine in Step 2 of Example 1 using appropriate conditions varying from stirring at ambient temperature to reflux conditions in a suitable solvent like dichloromethane, toluene, N- methyl pyrrolidinone, methanol, acetonitrile or a mixture thereof etc.

BIOLOGICAL ACTIVITY

The biological activity of representative compounds according to the invention against various bacterial strains was investigated. In a typical study, overnight grown bacterial cultures were diluted appropriately and inoculated on the agar media containing doubling dilutions of the test compounds. Observations for growth or no growth was performed after 16-20 hours of incubation at 35 ± 2°C in the ambient air. The overall procedure was performed as per Clinical and Laboratory Standards Institute (CLSI) recommendations, (Clinical and Laboratory Standards Institute (CLSI), Performance Standards for Antimicrobial Susceptibility Testing, 20th Informational Supplement, M07-A9, Volume 32, No. 2, 2012). Molten Mueller Hinton Agar (BD, USA) containing serial dilutions of each antibacterial agent were poured on to the plates and allowed to solidify. Appropriate suspensions from the freshly grown cultures were prepared in normal saline so that about 10 CFU/spot of the organism was delivered on to the drug containing agar plates using automated multipoint inoculator (Mast, UK). The plates were incubated in Biochemical oxygen demand (BOD) incubator at 37°C for 18 hours and then examined for growth.

The Minimum Inhibitory Concentration (MIC) determination for the combinations was carried out in Muller Hinton Agar (MHA) (BD, USA) according to Clinical and Laboratory Standards Institute (CLSI) recommendations, (Clinical and Laboratory Standards Institute (CLSI), Performance Standards for Antimicrobial Susceptibility Testing, 20^th Informational Supplement, M 100-S20, Volume 30, No. 1, 2010). In short, the test strains were adjusted to deliver about 10⁴ CFU per spot with a multipoint inoculator (Applied Quality Services, UK). The plates were poured with MHA containing doubling concentration range of representative compounds according to present invention. The plates were inoculated and were incubated at 35°C for 18 hour. MICs were read as the lowest concentration of drug that completely inhibited bacterial growth. The Table 4 depicts the antibacterial activity profile of compounds according to present invention against various multidrug resistant bacterial strains. These compounds when tested alone exhibited lower MIC values in most of the strains in comparison to standard.

Table 4. Antibacterial activity of representative compounds according to invention (expressed as MICs (mcg ml).

Strains

Claims

1. A compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof:

Formula (I)

wherein

Y is Ci-C₆ alkyl;

Ri_, R₂ and R3 are:

(a) each of R_1; R₂ and R3 are independently selected from: (i) C_\-C alkyl, optionally substituted with one or more substituents independently selected from OR , NR4R5, SOR , SR₄, halogen, CN, COOR4, CONR4R5, NHCOR4, aryl, heteroaryl, heterocycloalkyl, cycloalkyl , NHCONR4R5, NHCSNR4R5, and (=N-OR₆); (ii) aryl; (iii) heteroaryl; (iv) cycloalkyl; (v) COOR₄;(vi) CONR₄R₅;(vii) OR₄; or (viii) heterocycloalkyl;

(b) Ri and R₂ are combined to form a hetrocycloalkyl ring which is optionally substituted with one or more substituents selected from: (i) d- C₆ alkyl, optionally substituted with one or more substituents independently selected from OR4, NR4R5, SOR4, SR4, halogen, CN, COOR4, CONR4R5, NHCOR4, aryl, heteroaryl, heterocycloalkyl, cycloalkyl , NHCONR4R5, NHCSNR4R5, and (=N-OR₄); (ii) NR4R5; (iii) NHCOOR4; (iv) aryl; (v)CN; (vi)NHCONR₄R₅; (vii)heteroaryl; (viii) cycloalkyl; (ix) halogen; (x) COOR₄; (xi) CONR4R5; (xii) NHCOR4; (xiii) OR₄; (n) heterocycloalkyl; (o) (=0); or (p) (=N-OR₄); or

(c) Ri, R2, R3 are combined to form a heteroaryl ring which is optionally substituted with one or more substituents selected from: (i) Ci- C₆ alkyl, optionally substituted with one or more substituents independently selected from OR4, NR4R5, SOR4, SR4, halogen, CN, COOR4, CONR4R5, NHCOR4, aryl, heteroaryl, heterocycloalkyl, cycloalkyl , NHCONR4R5, NHCSNR4R5, and (=N-OR₄); (ii) NR4R5; (iii) NHCOOR4; (iv) aryl; (v) CN; (vi) NHCONR₄R₅;(vii) heteroaryl; (viii)cycloalkyl; (ix) halogen; (x) COOR₄; (xi) CONR₄R₅; (xii) NHCOR4; (xiii) OR4; (xiv) heterocycloalkyl; or (xv) trifluoromethyl;

R t_, R5 and R₆ are each independently:

(a) hydrogen;

(b) i-C alkyl, optionally substituted with one or more substituents independently selected from OR₇, NR₇R₈, COOR7, CONR₇R₈, SOR₇, aryl, aryl optionally substituted with one or more substituents independently selected from halogen, OR₇ or NR₇R₈ , heteroaryl, heterocycloalkyl, cycloalkyl , NHCONR₇R₈, NHCSNR₇R₈, and (=N-OR₇);

(c) trifluoromethyl;

(d) aryl, optionally substituted with one or more substituents independently selected from halogen, OR₇ and NR₇R₈;

(e) heteroaryl; or

(f) heterocycloalkyl;

R₇ and R₈ are each independently:

(a) hydrogen; or

(b) Ci-Ce alkyl.

2. The compound according to Claim 1 , selected from:

30

32

or a stereoisomer or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising a compound according to Claim 1 or 2.

4. Use of a compound according to Claim 1 or 2, in treating or preventing a bacterial infection.

5. Use of a pharmaceutical composition according to Claim 3, in treating or preventing a bacterial infection.

6. A method for treating or preventing bacterial infection in a subject, said method comprising administering to said subject a compound according to Claim 1 or 2.

7. A method for treating or preventing bacterial infection in a subject, said method comprising administering to said subject a composition according to Claim 3.

8. A process for preparation of a compound of Formula (I),

Formula (I)

wherein:

Y is Ci-C₆ alkyl;

Ri_, R₂ and R₃ are:

(a) each of R_1; R₂ and R3 are independently selected from: (i) Ci-C₆ alkyl, optionally substituted with one or more substituents independently selected from OR₄, NR4R5, SOR₄, SR₄, halogen, CN, COOR₄, CONR4R5, NHCOR₄, aryl, heteroaryl, heterocycloalkyl, cycloalkyl , NHCONR₄R₅, NHCSNR4R5, and (=N-OR₆); (ii) aryl; (iii) heteroaryl; (iv) cycloalkyl; (v) COOR₄;(vi) CONR₄R₅;(vii) OR₄; or (viii) heterocycloalkyl;

(b) Ri and R₂ are combined to form a hetrocycloalkyl ring which is optionally substituted with one or more substituents selected from: (i) Ci- C₆ alkyl, optionally substituted with one or more substituents independently selected from OR4, NR4R5, SOR4, SR4, halogen, CN, COOR4, CONR4R5, NHCOR4, aryl, heteroaryl, heterocycloalkyl, cycloalkyl , NHCONR4R5, NHCSNR4R5, and (=N-OR₄); (ii) NR4R5; (iii) NHCOOR4; (iv) aryl; (v)CN; (vi)NHCONR₄R₅; (vii)heteroaryl; (viii) cycloalkyl; (ix) halogen; (x) COOR₄; (xi) CONR4R5; (xii) NHCOR4; (xiii) OR₄; (n) heterocycloalkyl; (o) (=0); or (p) (=N-OR₄); or

(c) Ri, R2, R3 are combined to form a heteroaryl ring which is optionally substituted with one or more substituents selected from: (i) Ci- C alkyl, optionally substituted with one or more substituents independently selected from OR4, NR4R5, SOR4, SR4, halogen, CN, COOR4, CONR4R5, NHCOR4, aryl, heteroaryl, heterocycloalkyl, cycloalkyl , NHCONR4R5, NHCSNR4R5, and (=N-OR₄); (ii) NR₄R₅; (iii) NHCOOR4; (iv) aryl; (v) CN; (vi) NHCONR₄R₅;(vii) heteroaryl; (viii)cycloalkyl; (ix) halogen; (x) COOR₄; (xi) CONR4R5; (xii) NHCOR4; (xiii) OR4; (xiv) heterocycloalkyl; or (xv) trifluoromethyl;

R4_, R5 and R₆ are each independently:

(a) hydrogen;

(b) Ci-C₆ alkyl, optionally substituted with one or more substituents independently selected from OR₇, NR₇R₈, COOR7, CONR₇R₈, SOR₇, aryl, aryl optionally substituted with one or more substituents independently selected from halogen, OR₇ or NR₇R , heteroaryl, heterocycloalkyl, cycloalkyl , NHCONR₇R₈, NHCSNR₇R₈, and (=N-OR₇);

(c) trifluoromethyl;

(d) aryl, optionally substituted with one or more substituents independently selected from halogen, OR₇ and NR₇R₈;

(e) heteroaryl; or

(f) heterocycloalkyl;

R₇ and R₈ are each independently:

(a) hydrogen; or

(b) d-C₆ alkyl.

Comprising:

(a) reacting a compound of Formula (II) with a compound of Formula (III) to obtain a compound of Formula (IV); and

(b) reacting a compound of Formula (IV) with a compound of Formula (V) to obtain a compound of Formula (I).

(V)