WO2013072703A1

WO2013072703A1 - Antibacterial drug derivatives

Info

Publication number: WO2013072703A1
Application number: PCT/GB2012/052855
Authority: WO
Inventors: Neil Murray; Ronald Palin; Derek Lindsay; Mark Craighead
Original assignee: Redx Pharma Limited
Priority date: 2011-11-18
Filing date: 2012-11-16
Publication date: 2013-05-23
Also published as: GB2496972A; GB201220680D0

Abstract

This invention relates toderivatives of antibacterial drug compounds. It also relates to pharmaceutical formulations of derivatives of antibacterial drug compounds. It also relates to uses of the derivatives in treating bacterial infections and in methods of treating bacterial infections. The antibacterial compounds of this invention are all based on the fluoroquinolone antibacterial family. These are synthetic broad-spectrum antibiotics. They were originally introduced to treat Gram negative bacterial infections, but are also used for the treatment of Gram positive strains.

Description

Antibacterial Drug Derivatives

This invention relates to derivatives of antibacterial drug compounds. It also relates to pharmaceutical formulations of derivatives of antibacterial drug compounds. It also relates to uses of the derivatives in treating bacterial infections and in methods of treating bacterial infections.

The fluoroquinolone antibacterial family are synthetic broad-spectrum antibiotics. They were originally introduced to treat Gram negative bacterial infections, but are also used for the treatment of Gram positive strains. One problem with existing fluoroquinolones can be the negative side effects that may sometimes occur as a result of fluoroquinolone use. In general, the common side-effects are mild to moderate but, on occasion, more serious adverse effects occur. Some of the serious side effects that occur, and which occur more commonly with fluoroquinolones than with other antibiotic drug classes, include central nervous system (CNS) toxicity and cardiotoxicity. In cases of acute overdose there may be renal failure and seizure.

A particular problem, both with antibiotics in general and with fluoroquinolones in particular, is the increasing frequency of resistant strains of bacterial pathogens such as Staphylococcus aureus, Streptococcus pneumonia, Clostridium difficile and Pseudomonas aeruginosa. In fact, multidrug resistance has become the norm for some pathogens. Of these, Staphylococcus aureus, a Gram positive bacteria, is the most concerning due to its potency and its capacity to adapt to environmental conditions. MRSA (methicillin resistant Staphylococcus aureus) is probably the most well known and has reached pandemic proportions. Of particular concern is the increasing incidence of 'community acquired' infections, those occurring in subjects with no prior hospital exposure. Many strains of MRSA are also resistant to fluoroquinolones, in addition to β-lactam antibiotics such as methicillin. While less wide-spread, antibiotic resistant Gram negative strains, such as either E. Coli NDM-1 (New Delhi metallo^-lactamase) mutation or Klebsiella pneumoniae with the same mutation, are very difficult to treat, with only expensive antibiotics such as vancomycin and colistin being effective. The present invention seeks to overcome the disadvantages of known fluoroquinolones. In spite of the numerous different antibiotics known in the art for a variety of different infections, there continues to be a need to provide antibiotics that can provide an effective treatment in a reliable manner. In addition, there remains a need for antibiotic drugs which can avoid or reduce the side-effects associated with known antibiotics. A further aim is to provide treatment which is effective in a selective manner at a chosen site of interest. Another aim is to provide antibiotics having a convenient pharmacokinetic profile and a suitable duration of action following dosing. It is an aim of this invention to provide new antibiotics. In particular it is an aim to provide antibiotics which are active against resistant strains of Gram positive and/or Gram negative bacteria. It is also an aim to provide antibiotics which are active against strains of bacteria which may be associated with biowarfare. Such strains are typified by high mortality and/or rapid onset of disease.

A further aim of the present invention is to provide antibiotics in which the metabolised fragment or fragments of the drug after absorption are GRAS (Generally Regarded As Safe). A further aim of the invention is to provide prodrugs which are not species dependent and/or which reduce inter-patient variability due to differences in metabolism. Another aim of the invention is to provide prodrugs which are able to overcome the food effect in the sense that they can be administered to fed or fasted patients without the need to control carefully the dosing schedule relative to meal times.

The present invention satisfies some or all of the above aims.

According to a first aspect, there is provided a compound of formula (I):

R¹ is selected from the group consisting of: H, NR⁷R⁸, C C₄ alkyl, C C₄ alkyloxy and Ci-C₄ haloalkyl; wherein R⁷ and R⁸ are each independently selected from the group consisting of: H , C C₄ alkyl and Ac;

X is C or N;

Y is O or NR¹³; wherein R¹³ is selected from the group consisting of: H , C C₄ alkyl and Ac;

P is N or CR¹⁰;

Q is N or CR⁹;

R² is selected from the group consisting of: aryl and heteroaryl;

R³ and R⁴ are each independently selected from: C₄-C₂o alkyl, aryl and heteroaryl;

R⁵ is selected from the group consisting of: C C₄ alkyl, C C₄ haloalkyl, C₃-C₅ cycloalkyi,

C3-C5 halocycloalkyl; unsubstituted phenyl; phenyl substituted with from 1 to 3 independently selected halogen atoms; unsubstituted pyridyl; and pyridyl substituted with from 1 to 3 independently substituents selected from the group consisting of: halo and N HR_a; wherein R_a is H or Ac;

R⁶ is selected from the group consisting of: H , C C₄ alkyl and C C₄ haloalkyl;

or alternatively, R⁵ and R⁶, together with the atoms to which they are attached to form a 4-6-membered ring which optionally contains an O or S atom; wherein the 4-6- membered ring is optionally substituted with 1 or 2 groups independently selected from halo and C C₄ alkyl;

R⁹ is selected from the group consisting of: H , N H R_a and C C₄-alkyl; wherein R_a is H or Ac;

R¹⁰ is selected from the group consisting of: H and F;

R^{1 1} is selected from the group consisting of: an N-heterocycloalkyl group and a C₃-C₈ cycloalkyi group; wherein the N-heterocycloalkyl group comprises from 5 to 10 ring atoms and at least one nitrogen atom wherein the N-heterocycloalkyl group is optionally substituted with from 1-3 groups independently selected from halo, tri(C C₄ alkyl)silyloxy, hydroxyl, C C₄ alkyl, oxo or oxime and wherein any nitrogen which does not attach the N-heterocycloalkyl group to the rest of the compound of Formula (I) is an NR_a group; and the C₃-C₈ cycloalkyl group is optionally substituted with at least one NHR_a group and optionally further substituted with from 1-3 groups independently selected from halo, hydroxyl, tri(C C₄ alkyl)silyloxy, C C₄ alkyl, oxo or oxime; wherein R_a is H or Ac;

R¹² is absent or is selected from the group consisting of: H, OR¹⁶ and halo; wherein R¹⁶ is selected from the group consisting of: C C₄ alkyl and C C₄ haloalkyl;

or alternatively R¹² and R⁵, together with the atoms to which they are attached, form a 6-membered ring which optionally contains an O or S atom; wherein the 6-membered ring is optionally substituted with 1 or 2 groups independently selected from halo and Ci-C₄ alkyl; wherein if X is N, R¹² is absent; and

wherein each of the aforementioned alkyl, haloalkyl, cycloalkyl, halocycloalkyl, aryl (e.g. phenyl) and heteroaryl (e.g. pyridyl) groups are optionally substituted, where chemically possible, by 1 to 3 substituents which are each independently selected at each occurrence from the group consisting of: oxo, imino, oximo, halo, nitro, cyano, hydroxyl, amino, C0₂H, C0₂-(C C₄alkyl), C(0)H, C C₄-alkyl, C C₄ haloalkyl, C C₄ alkoxy, and Ci-C₄ haloalkoxy. When X is N, R¹² is absent and when X is C, the additional valency is occupied by the group R¹².

According to an embodiment, the compound of formula (I) is a compound of formula (II):

X is C or N;

R² is selected from the group consisting of: aryl and heteroaryl;

R⁵ is selected from the group consisting of: C C₄ alkyl, C C₄ haloalkyl, C₃-C₅ cycloalkyl, C3-C5 halocycloalkyl; unsubstituted phenyl; phenyl substituted with from 1 to 3 independently selected halogen atoms; unsubstituted pyridyl; and pyridyl substituted with from 1 to 3 independently substituents selected from the group consisting of: halo and N HR_a; wherein R_a is H or Ac;

R⁶ is selected from the group consisting of: H, C C₄ alkyl and C C₄ haloalkyl;

R⁹ is selected from the group consisting of: H , NH R_a and C C₄-alkyl; wherein R_a is H or Ac;

R¹⁰ is selected from the group consisting of: H and F;

R^{1 1} is selected from the group consisting of: an N-heterocycloalkyl group and a C₃-C₈ cycloalkyl group; wherein the N-heterocycloalkyl group comprises from 5 to 10 ring atoms and at least one nitrogen atom wherein the N-heterocycloalkyl group is optionally substituted with from 1 -3 groups independently selected from halo, tri(C C₄ alkyl)silyloxy, hydroxyl, C C₄ alkyl, oxo or oxime and wherein any nitrogen which does not attach the N-heterocycloalkyl group to the rest of the compound of Formula (I) is an NR_a group; and the C₃-C₈ cycloalkyl group is optionally substituted with at least one NHR_a group and optionally further substituted with from 1 -3 groups independently selected from halo, hydroxyl, tri(C C₄ alkyl)silyloxy, C C₄ alkyl, oxo or oxime; wherein R_a is H or Ac;

or alternatively R¹² and R⁵, together with the atoms to which they are attached, form a 6-membered ring which optionally contains an O or S atom; wherein the 6-membered ring is optionally substituted with 1 or 2 groups independently selected from halo and C1-C4 alkyl; wherein if X is N, R¹² is absent; and

wherein each of the aforementioned alkyl, haloalkyl, cycloalkyl, halocycloalkyl, aryl (e.g. phenyl) and heteroaryl (e.g. pyridyl) groups are optionally substituted, where chemically possible, by 1 to 3 substituents which are each independently selected at each occurrence from the group consisting of: oxo, imino, oximo, halo, nitro, cyano, hydroxyl, amino, C0₂H, C0₂-(CrC₄alkyl), C(0)H, C C₄-alkyl, C C₄ haloalkyl, C C₄ alkoxy, and Ci-C₄ haloalkoxy. According to an embodiment, the compound of formula (I) is a compound of formula (III):

According to an embodiment, the compound of formula (I) is a compound of formula (IV):

The embodiments described in this specification may apply to any of the aspects or other embodiments of the invention providing where chemically possible. Thus, features described in any one embodiment may be combined with the features described in any one or more other embodiments where chemically possible. In particular, the embodiments may apply to compounds of any of formulae (l)-(IV) and/or any compound with partial formulae (V) and (VI) and/or any of formulae 1-26. In an embodiment, Y is O. In an embodiment, R¹ is selected from H, C C₄ haloalkyl or C C₄ alkyl. In an embodiment, R¹ is selected from H, or C C₄ alkyl.

In an embodiment, R¹ is H.

In an alternative embodiment, R¹ is C C₄ alkyl, e.g. R¹ is Me or R¹ is Et. In an alternative embodiment Y is NH.

In a preferred embodiment, R¹ is H and Y is O. In another embodiment, R¹ is C C₄ alkyl and Y is O. In an embodiment, R₂ is a 6-membered aryl group, wherein the aryl group is optionally substituted with 1-4 groups selected from the group consisting of: halo, nitro, cyano, hydroxyl, NHR_a, C0₂H, C0₂-(C C₄alkyl), C(0)H, C C₄-alkyl, C C₄ haloalkyl, C C₄ alkoxy, and C C₄ haloalkoxy. In an embodiment, R³ and R⁴ are each independently selected from the group consisting of: C₄-C₂o alkyl, 6-membered aryl group and a 5- or 6-membered heteroaryl group.

In an embodiment, R³ and R⁴ are each independently selected from the group consisting of: an aryl group and a heteroaryl group.

In an embodiment, R³ and R⁴ are each independently selected from the group consisting of: 6-membered aryl group and a 5- or 6-membered heteroaryl group. In an embodiment, R³ and R⁴ are each a 6-membered aryl group, wherein the aryl groups are optionally substituted with 1-4 groups selected from: halo, nitro, cyano, hydroxyl, NHR_a, C0₂H, C0₂-(C C₄alkyl), C(0)H, C C₄-alkyl, C C₄ haloalkyl, C C₄ alkoxy, and C C₄ haloalkoxy. In a preferred embodiment, R₂, R₃ and R₄ are each independently selected from optionally substituted phenyl. In a further preferred embodiment, R₂, R₃ and R₄ are each unsubstituted phenyl. In an embodiment X is N. In an alternative embodiment, X is C.

In an embodiment, P is CR¹⁰. In an alternative embodiment, P is N.

In an embodiment, Q is CR⁹. In an alternative embodiment, Q is N .

In an embodiment R⁹ is H. Alternatively, R⁹ is NHR_a. In a further alternative embodiment, R⁹ is C C₄ alkyl, e.g. R⁹ may be methyl, ethyl, propyl, butyl, iso-propyl or tert-butyl. In a particular embodiment, R⁹ is methyl. In an embodiment, R¹⁰ is H. In an alternative embodiment R¹⁰ is F.

R¹¹ is selected from the group consisting of: an N-heterocycloalkyl group and a C₃-C₈ cycloalkyi group; wherein the N-heterocycloalkyl group comprises from 5 to 10 ring atoms and at least one nitrogen atom wherein the N-heterocycloalkyl group is optionally substituted with from 1-3 groups independently selected from halo, tri(C C₄ alkyl)silyloxy, hydroxyl, C C₄ alkyl, oxo or oxime and wherein any nitrogen which does not attach the N-heterocycloalkyl group to the rest of the compound of Formula (I) is an NR_a group; and the C₃-C₈ cycloalkyi group is optionally substituted with at least one NHR_a group and optionally further substituted with from 1-3 groups independently selected from halo, hydroxyl, tri(C C₄ alkyl)silyloxy, C C₄ alkyl, oxo or oxime; wherein R_a is H or Ac. The N-heterocycloalkyl group may be monocyclic or bicyclic.

In an embodiment, R¹¹ is a piperazine ring which is optionally substituted with from 1-3 groups independently selected from halo, hydroxyl, C C₄ alkyl, oxo or oxime. In a preferred embodiment, R¹¹ is a piperazine ring which is optionally substituted with from 1-3 independently selected C C₄ alkyl groups. In a further preferred embodiment, R¹¹ is a piperazine ring substituted with a methyl group, e.g. an N-methyl piperazine ring. In an alternative preferred embodiment, R¹¹ is a 3-methyl piperazine ring. In a further alternative, R¹¹ may be a 2-methyl piperazine ring. In another preferred embodiment, R¹¹ is a piperazine ring which is optionally substituted with a Ci_₄ alkanoyl group. In an embodiment, the R¹¹ group is an acetyl piperazine group. In an alternative embodiment, R¹¹ is a piperidine ring which is optionally substituted with from 1-3 groups independently selected from halo, hydroxyl, C C₄ alkyl, oxo, oxime.

alternative embodiment,

embodiment, the NH moiety in the structure depicted may alternatively be substituted with an acetyl group.

In an alternative embodiment, R¹¹ is C₃-C₈ cycloalkyl group substituted with at least one NHR_a group and optionally further substituted with from 1-3 groups independently selected from halo, hydroxyl, C C₄ alkyl, oxo or oxime. In a preferred embodiment, R¹¹ is a cyclopropyl group substituted with a NHR_a group.

In an embodiment, R¹² is H. In an alternative embodiment, R¹² is CI or F. In a further alternative, R¹² is OR¹⁶. In an embodiment, R¹⁶ is C C₄ alkyl, e.g. R¹⁶ may be methyl. In an alternative embodiment, R¹⁶ is C C₄ haloalkyl, e.g. C C₄ fluoroalkyl such as trifluoromethyl or difluoromethyl.

In an alternative embodiment, R¹² and R⁵, together with the atoms to which they are attached, form a 6-membered ring which optionally contains an O or S atom; wherein the 6-membered ring is optionally substituted with 1 or 2 groups independently selected from halo and C C₄ alkyl. In an embodiment, the ring contains an O atom. Alternatively, the ring contains a S atom. The ring may be substituted with a C C₄ alkyl group, e.g. a methyl group. In an embodiment, R⁵ is C C₄ alkyl, e.g. ethyl. In an embodiment, alternative embodiment R⁵ is C C₄ haloalkyl, e.g. a 2-fluoroethyl group. In a further alternative embodiment, R⁵ is C₃-C₅ cycloalkyl, e.g. cyclopropyl. In yet a further alternative embodiment, R⁵ is C₃-C₅ halocycloalkyl, e.g.fluoro cyclopropyl. In other embodiments R⁵ is phenyl which may be optionally substituted with from 1-3 halo groups, i.e. R⁵ may be a difluorophenyl group, such as 2,4-difluorophenyl.

In an alternative embodiment, R⁵ and R⁶, together with the atoms to which they are attached to form a 4-6-membered ring which optionally contains an O or S atom; wherein the 4-6-membered ring is optionally substituted with 1 or 2 groups independently selected from halo and C C₄ alkyl

In an embodiment, R⁶ is H.

In an embodiment, R¹ is H, R⁶ is H and Y is O.

Thus in an embodiment, there is provided an oxime or hydrazone derivative (i.e. a compound of formula (I) in which Y is O or NH) of an antibacterial compound selected from the group comprising: enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, rufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, besifloxacin, clinafloxacin, garenoxacin, gemifloxacin, gatifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, ciprofloxacin, pefloxacin, moxifloxacin, ofloxacin, levofloxacin, delafloxacin and jnj-q2. In these compounds the carboxylic acid of the antibacterial compound is replaced by an oxime group or a hydrazone group having the following partial formula (V):

wherein:

Y is O or NR¹³;

R¹ is selected from the group consisting of: H, NR⁷R⁸, C C₄ alkyl, C C₄ alkyloxy, and C1-C4 haloalkyi;

R² is selected from the group consisting of: an aryl group and a heteroaryl group;

R³ and R⁴ are each independently selected from: C₄-C₂o - alkyl, aryl group and heteroaryl group;

R¹³, R⁷ and R⁸ are each independently selected from the group consisting of: H, Ci_₄ alkyl and Ac;

wherein each of the aforementioned alkyl, haloalkyi, aryl and heteroaryl groups are optionally substituted, where chemically possible, by 1 to 3 substituents which are independently at each occurrence selected from: oxo, imino, oximo, halo, nitro, cyano, hydroxyl, amino, C0₂H, C0₂-(CrC₄alkyl), C(0)H, C C₄-alkyl, C C₄ haloalkyl, C C₄ alkoxy, and C C₄ haloalkoxy; and wherein any amine on the fluoroquinolone antibacterial structure may be acetylated.

In an embodiment, the carboxylic acid of the antibacterial compound is replaced by an oxime group having the following partial formula (VI):

In an embodiment, the parent compound upon which the derivatives of the invention are based is selected from the group comprising: Enoxacin, Fleroxacin, Lomefloxacin, Nadifloxacin, Norfloxacin, Rufloxacin, Balofloxacin, Grepafloxacin, Pazufloxacin, Sparfloxacin, Temafloxacin, Tosufloxacin, Besifloxacin, Clinafloxacin, Garenoxacin, Gemifloxacin, Gatifloxacin, Sitafloxacin, Trovafloxacin, Prulifloxacin, Ciprofloxacin, Moxifloxacin, Ofloxacin, jnj-q2, Levofloxacin, Delafloxacin,.

In an embodiment, the parent compound upon which the derivatives of the invention are based is selected from the group comprising: Enoxacin, Fleroxacin, Lomefloxacin, Nadifloxacin, Norfloxacin, Rufloxacin, Balofloxacin, Grepafloxacin, Pazufloxacin, Sparfloxacin, Temafloxacin, Tosufloxacin, Besifloxacin, Clinafloxacin, Garenoxacin, Gemifloxacin, Gatifloxacin, Sitafloxacin, Trovafloxacin, Prulifloxacin, Ciprofloxacin, Moxifloxacin, jnj-q2, Delafloxacin.

In an embodiment, the present invention provides a compound according to any one or any combination of more than one of the following formulae 1-26:









Y is O or NR¹³;

R¹ is selected from the group consisting of: H, NR⁷R⁸, C C₄ alkyl, and C C₄ haloalkyl; R² is independently selected from: aryl and heteroaryl;

R³ and R⁴ are independently selected at each occurrence from: C₄-C₂o alkyl, aryl and heteroaryl;

R¹³, R⁷ and R⁸ are independently at each occurrence H, Ci_-4 alkyl or Ac;

wherein each of the aforementioned alkyl, haloalkyl, phenyl and benzyl groups are optionally substituted, where chemically possible, by 1 to 3 substituents which are independently at each occurrence selected from: oxo, imino, oximo, halo, nitro, cyano, hydroxyl, amino, C0₂H, C0₂-(CrC₄alkyl), C(0)H, C C₄-alkyl, C C₄ haloalkyl, C C₄ alkoxy, and C C₄ haloalkoxy; and

R_a is independently at each occurrence H or Ac.

The compound may be selected from the group of compounds defined by all of the formulae 1-26, or it may be selected from a smaller group such as that defined by a single formula from within the formulae 1 to 26, or from a group of compounds defined by a combination of from two to twenty of any of the above formulae.

In an embodiment, the compound is according to any one or any combination of more than one of formulae 1-24.

In an embodiment, Y is O and the compound is not a compound according to formula 24 or 25. und is not

In an embodiment, R_a is H. In an embodiment, Y is O.

In an embodiment, R¹ is selected from H, C C₄ haloalkyl or C C₄ alkyl.

In an embodiment, R¹ is selected from H, or C C₄ alkyl. In an embodiment, R¹ is H. In an alternative embodiment, R¹ is C C₄ alkyl, e.g. R¹ is Me or R¹ is Et. In a preferred embodiment, R¹ is H and Y is O. In an alternative embodiment, R¹ is C C₄ alkyl and Y is O.

In an embodiment, R¹³ is H.

In an embodiment, Y is O. In an alternative embodiment Y is NH.

In a preferred embodiment, R¹ is H and Y is O. In an embodiment, R³ and R⁴ are independently selected at each occurrence from: C₄- C₂o - alkyl, aryl and heteroaryl;

In an embodiment, R₂ is aryl, wherein the aryl groups are optionally substituted with 1 -4 groups selected from: halo, nitro, cyano, hydroxyl, NHR_a, C0₂H, C0₂-(CrC₄alkyl), C(0)H, C C₄-alkyl, C C₄ haloalkyi, C C₄ alkoxy, and C C₄ haloalkoxy.

In an embodiment, R³ and R⁴ are each aryl, wherein the aryl groups are optionally substituted with 1-4 groups selected from: halo, nitro, cyano, hydroxyl, NHR_a, C0₂H, C0₂-(C C₄alkyl), C(0)H, C C₄-alkyl, C C₄ haloalkyi, C C₄ alkoxy, and C C₄ haloalkoxy.

In a preferred embodiment, R₂, R₃ and R₄ are each optionally substituted phenyl. In a further preferred embodiment, R₂, R₃ and R₄ are each unsubstituted phenyl. In one embodiment, R², R³ and R⁴ are independently selected at each occurrence from: aryl and heteroaryl; wherein aryl and heteroaryl groups are optionally substituted with from 1 to 4 groups independently selected at each occurrence from: halo; nitro; cyano; hydroxyl; NR⁶R⁷; C0₂H; C0₂-(C C₄alkyl); C(0)H; C C₄-alkyl; C C₄ haloalkyi; C C₄ alkoxy; and C C₄ haloalkoxy.

In an embodiment, there is provided an oxime or hydrazone derivative of an antibacterial compound selected from the group comprising: enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, rufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, besifloxacin, clinafloxacin, garenoxacin, gemifloxacin, gatifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, ciprofloxacin, pefloxacin, moxifloxacin, ofloxacin, levofloxacin, delafloxacin and jnj-q2, in which the carboxylic acid of the antibacterial compound is replaced by an oxime group or a hydrazone group having the following partial formula (V):

wherein:

Y is O or NR¹³;

wherein each of the aforementioned alkyl, haloalkyi, aryl and heteroaryl groups are optionally substituted, where chemically possible, by 1 to 3 substituents which are independently at each occurrence selected from: oxo, imino, oximo, halo, nitro, cyano, hydroxyl, amino, C0₂H, C0₂-(C C₄alkyl), C(0)H, C C₄-alkyl, C C₄ haloalkyi, C C₄ alkoxy, and C C₄ haloalkoxy;

and the compound is for use in treating resistant strains of bacteria (e.g. Gram positive resistant strains)

In an embodiment, the compound is selected from:

In an embodiment, the compound is selected from:

In an embodiment, the compound is selected from:

In compound is:

In another aspect the present invention provides a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable excipient. In another aspect of the present invention, there is provided a method of preparing a formulation of a derivative of an antibacterial compound as defined above, the method comprising:

(i) obtaining the derivative of an antibacterial drug molecule; and

(ii) mixing the derivative with one or more pharmaceutically acceptable excipients to produce the pharmaceutical formulation.

The derivative may be formed by reacting a derivative of an antibacterial fluoroquinolone drug molecule in which the carboxylic acid of the fluoroquinolone drug molecule is replaced by aldehyde with a hydroxylamine or a hydrazine. Synthetic procedures for effecting such transformations are known in the art. Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of the invention contains a double bond such as a C=C or C=N group, geometric cis/trans (or Z/E) isomers are possible. Specifically, the oxime group present in the compounds of the invention may be present as the E-oxime, as the Z-oxime or as a mixture of both in any proprotion. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of the invention containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of the invention, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counter ion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.

Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.

Conventional techniques for the preparation/isolation of individual enantiomers when necessary include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.

When any racemate crystallises, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.

While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel and S. H. Wilen (Wiley, 1994).

Many of the compounds of the invention are based on a parent approved pharmaceutically active compounds as described in the appropriate sections of this specificaiton. The synthetic routes to each of the parent compounds are available in the literature and in the relevant EMA and FDA regulatory files and accordingly are not reproduced here. These disclosures insofar as the synthetic procedures are concerned form part of the disclosure of the present invention. In the interests of brevity, the details of these synthetic procedures are not reproduced here but it is intended that this subject matter is specifically incorporated into the disclosure of these documents by reference.

Throughout this specification, jnj-q2 refers to a fluoroquinolone with the following structure:

The skilled man will appreciate that adaptation of methods known in the art could be applied in the manufacture of the compounds of the present invention.

For example, the skilled person will be immediately familiar with standard textbooks such as "Comprehensive Organic Transformations - A Guide to Functional Group Transformations", RC Larock, Wiley-VCH (1999 or later editions), "March's Advanced Organic Chemistry - Reactions, Mechanisms and Structure", MB Smith, J. March, Wiley, (5th edition or later) "Advanced Organic Chemistry, Part B, Reactions and Synthesis", FA Carey, RJ Sundberg, Kluwer Academic/Plenum Publications, (2001 or later editions), "Organic Synthesis - The Disconnection Approach", S Warren (Wiley), (1982 or later editions), "Designing Organic Syntheses" S Warren (Wiley) (1983 or later editions), "Guidebook To Organic Synthesis" RK Mackie and DM Smith (Longman) (1982 or later editions), etc., and the references therein as a guide.

The skilled chemist will exercise his judgement and skill as to the most efficient sequence of reactions for synthesis of a given target compound and will employ protecting groups as necessary. This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the protection / deprotection steps. These and other reaction parameters will be evident to the skilled person by reference to standard textbooks and to the examples provided herein.

Sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional methods, for example as described in "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley & Sons Inc (1999), and references therein. Each of the compounds of the present invention may be used as a medicament. Thus, in another aspect of the invention, there is provided an oxime or hydrazone derivative of an antibacterial compound as defined above for the treatment of antibacterial infections.

The compounds and formulations of the present invention may be used in the treatment of a wide range of bacterial infections.

The compounds and formulations of the present invention can be used to treat both Gram positive and Gram negative bacterial infections such as infections of the urinary tract, the respiratory tract, the ear, the skin, the throat, soft tissue, bone and joints (including infections caused by Staph Aureus). The compounds can be used to treat pneumonia, sinusitis, acute bacterial sinusitis, bronchitis, acute bacterial exacerbation of chronic bronchitis, anthrax, chronic bacterial prostatitis, acute pyelonephritis, pharyngitis, tonsillitis, eColi, prophylaxis before dental surgery, cellulitis, acnes, cystitis, infectious diarrhoea, typhoid fever, infections caused by anaerobic bacteria, peritonitis, malaria, babesiosis bacterial vaginosis, pelvic inflammatory disease, pseudomembranous colitis, helicobacter pylori, amoebiasis, giardasis, acute gingivitis, Crohn's Disease, rosacea, fungating Tumours, MRSA, impetigo. In an embodiment, the compounds can be used to treat bacterial infections caused by Gram positive bacteria. In one embodiment, the compounds of the invention can be used to treat bacterial infections caused by resistant strains of bacteria. In a further embodiment, the compounds can be used to treat bacterial infections caused by resistant strains of Gram positive bacteria. In a further embodiment, the compounds can be used to treat bacterial infections caused by resistant strains of Gram negative bacteria.

In an embodiment, the compounds and formulations of the present invention can be used to treat or to prevent infections caused by bacterial strains associated with biowarfare. These may be strains which are category A pathogens as identified by the US government (e.g. those which cause anthrax, plague etc.) and/or they may be strains which are category B pathogens as identified by the US government (e.g. those which cause Glanders disease, mellioidosis etc). In a specific embodiment, the compounds and formulations of the present invention can be used to treat or to prevent infections caused by Gram positive bacterial strains associated with biowarfare (e.g. anthrax). More particularly, the compounds and formulations may be used to treat category A and/or category B pathogens as defined by the US government on 1^s Nov 2012.

The compounds of the present invention may also be used in treating other conditions treatable by eliminating or reducing a bacterial infection. In this case they will act in a secondary manner alongside for example a chemotherapeutic agent used in the treatment of cancer.

The compounds of the present invention can be used in the treatment of the human body. They may be used in the treatment of the animal body. In particular, the compounds of the present invention can be used to treat commercial animals such as livestock. Alternatively, the compounds of the present invention can be used to treat companion animals such as cats, dogs, etc. In an embodiment, R_a is H at each occurrence and the compound is for use in treating resistant strains of bacteria (e.g. Gram positive resistant strains).

In an embodiment, is H and the compound is for use in treating resistant strains of bacteria (e.g. Gram positive resistant strains).

In an embodiment, the compound is selected from:

and is for use in treating an infection associated with Gram positive bacterial strains. In an embodiment, the compound is selected from

and is for use in treating an infection associated with Gram positive bacterial strains. In an embodiment, the compound is selected from:

and is for use in treating an infection associated with resistant bacterial strains (e.g. Gram positive resistant bacterial strains). compound is:

and is for use in treating or preventing infections caused by bacterial strains associated with biowarfare (e.g. Gram positive bacterial strains associated with biowarfare, e.g. anthrax).

Aryl groups may be 6-membered aryl groups. Aryl groups may be optionally substituted phenyl groups, optionally substituted biphenyl groups, optionally substituted

naphthalenyl groups or optionally substituted anthracenyl groups. Heteroaryl groups may be selected from 5- or 6- membered heteroaryl groups.

Heteroaryl groups may be selected from: 5-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-3 heteroatoms selected from O, S and N; and 6-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-2 nitrogen atoms; 9-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 heteroatoms selected from O, S and N; 10-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 nitrogen atoms. Specifically, heteroaryl groups may be selected from: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiodiazole, pyridine, pyridazine, pyrimidine, pyrazine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, indazole, benzimidazole, benzoxazole, benzthiazole, benzisoxazole, purine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, pteridine, phthalazine, naphthyridine.

The aryl and heteroaryl groups are optionally substituted with from 1 to 4 groups independently selected at each occurrence from: halo, nitro, cyano, hydroxyl, NHR_a, C0₂H, C0₂-(CrC₄alkyl), C(0)H, C C₄-alkyl, C C₄ haloalkyl, C C₄ alkoxy, and C C₄ haloalkoxy.

The present invention also includes the synthesis of all pharmaceutically acceptable isotopically-labelled compounds of formulae (I) to (VI) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶CI, fluorine, such as ¹⁸F, iodine, such as ¹²³l and ¹²⁵l, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵0, ¹⁷0 and ¹⁸0, phosphorus, such as ³²P, and sulphur, such as ³⁵S.

Certain isotopically-labelled compounds, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵0 and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labelled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.

Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, for example "comprising" and "comprises", means "including but not limited to", and is not intended to (and does not) exclude other moieties, additives, components, integers or steps.

Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.

Examples

Supplementary Material (for NMR, couplings constants are quoted in Hz)

Formation of fluoroquinolone aldehyde derivatives have been undertaken by modifying a reduction/ decarboxylation/ Claisen addition/ oxidation protocol reported by Kondo et al. (Kondo, H.; Sakamoto, F.; Kawakami, K.; Tsukamoto, G. J. Med. Chem., 1988, 31, 221.)

General Procedure Fluoroquinolone Aldehyde Synthesis

30 min

Fluoroquinolone

To a 0 °C stirring solution of fluoroquinolone in anhydrous methanol under inert atmosphere was added solid sodium borohydride (4.5 eq.) slowly over 30 minutes. The mixture was allowed to warm to room temperature and p-toluene sulfonic acid (0.1 eq.) was added. After heating at reflux for 3.5 hours, the mixture was allowed to cool and the solvent removed in vacuo. The crude solid was washed with hot chloroform and water and then extracted with chloroform (* 3). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude mixture

wassubjected to flash column chromatography (20 % methanol/ chloroform) to afford the intermediate.

To a room temperature stirring solution of fluoroquinolone intermediate in anhydrous dichloromethane under inert atmosphere was added sodium methoxide (3.9 eq.) and ethyl formate (3.94 eq.). After eighteen hours, the mixture was quenched with ice-water. After separation, the organic layer was washed with 3 M sodium hydroxide (* 2). The aqueous washings were acidified to pH 6 with concentrated hydrochloric acid and then extracted with dichloromethane (* 3). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude mixture was dissolved in anhydrous methanol and manganese dioxide was added (excess). After stirring at room temperature for eighteen hours, the mixture washed filtered through Celite®. After flushing the filter cake with methanol and dichloromethane, the solvent was removed in vacuo and the crude solidsubjected to flash column chromatography (20 % methanol/ chloroform) to afford the desiredfluoroquinolonealdehyde.

General Procedure for Trityl Oxime Formation from a Fluoroquinolone Aldehyde

To a room temperature stirring solution of the aldehyde in anhydrous chloroform under inert atmosphere was added o-tritylhydroxylamine (1 eq.). After three hours, the mixture was partitioned between chloroform/ water and extracted with chloroform (* 2). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude mixture was subjected to flash column chromatography (5 % methanol/ chloroform) to afford the product.

Example 1 - Levofloxacin Aldehyde Trityl Oxime 1

Title compound was formed in 57 %.

¹ H NMR, 400MHz (CDCI₃) δ 8.59 (1 H, s), 7.47 (1 H, d, J = 12.4), 7.36 (1 H, s), 7.36-7.14 (15H, m, 3 Ph), 4.14 (2H, m), 3.82 (1 H, m), 3.26 (4H, t, J = 4.4), 2.47 (4H, t, J = 4.4), 2.29 (3H, s) and 1.27 (3H, d, J = 6.8).

Example 2 - N-Acetyl Clinafloxacin Aldehyde Trityl Oxime 2

Title compound was formed in 46 %.

¹H NMR, 400MHz (CDCI₃) δ 8.56 (1H, s), 7.93 (1H, d, J = 12.8), 7.88 (1H, s), 7.43-7.41 (6H, m), 7.35-7.24 (10H, m), 5.83 (1H, m), 4.61 (1H, m), 4.35 (1H, m),3.82 (1H, m), 3.71 (1H, m), 3.51 (1H, m), 3.32 (1H, m), 2.30 (1H, m),2.00 (3H, s), 1.95 (1H, m), 1.08 (2H, m)and 0.69 (2H, m).

Example 3 - Di-N-Acetyl Sparfloxacin Aldehyde Trityl Oxime 3

Ή NMR, 400MHz (CDCI₃) δ 11.49 (1H, s), 8.50 (1H, s), 7.78 (1H, s), 7.42-7.40 (6H, m), 7.33-7.25 (9H, m), 4.70 (1H, br s), 4.00 (1H, br s), 3.80 (1H, m), 3.43-3.39 (2H, m), 3.31- 3.28 (2H, m), 2.24 (3H, s), 2.16 (3H, s), 1.46 (6H, m),1.08 (2H, m) and 0.84 (2H, m).

Example 4 - fe/t-Butyldimethylsiloxy Nadifloxacin Aldehyde Trityl Oxime 4

Title compound was formed in 60 %.

¹ H NMR, 400MHz (CDCI₃) δ 8.70 (1 H, s), 7.94 (1 H, d, J = 12.8), 7.71 (1 H, s), 7.44-7.41 (6H, m), 7.34-7.22 (9H, m), 4.17 (1 H, m), 3.26-2.89 (5H, m), 2.77 (1 H, m), 2.04-2.00 (2H, m), 1.88 (2H, m), 1.73 (2H, m), 1.33 (3H, d,J = 6.8), 0.92 (9H, s), and 0.09 (6H, s).

Example 5 - N-Acetyl Ciprofloxacin Aldehyde Trityl Oxime 5

Ph

Ph . . Ph

Title compound was formed in 70 %.

¹ H NMR, 400MHz (CDCI₃) δ 8.63 (1 H, s), 8.02 (1 H, d, J = 13.2), 7.78 (1 H, s), 7.44-7.42 (6H, m), 7.33-7.24 (10H, m), 3.84 (2H, t, J = 5.0), 3.66 (2H, t, J = 5.0), 3.29-3.24 (3H, m), 3.19 (2H, t, J = 5.0), 2.15 (3H, s), 1.20 (2H, m) and 0.93 (2H, m).

Example 6 - Ciprofloxacin Aldehyde Trityl Oxime 6

Ή NMR, 400MHz (CDCI₃) δ 8.64 (1 H, s), 7.98 (1 H, d, J = 13.2), 7.77 (1 H, s), 7.44-7.42 (6H, m), 7.33-7.23 (10H, m), 3.22 (1 H, m), 3.28 (4H, t), 3.20 (4H, t), 1.20 (2H, m) and 0.93 (2H, m).

Example 7 - N-Acetyl Gatifloxacin Aldehyde Trityl Oxime 7

Title compound was formed in 70 %.

¹ H NMR, 400MHz (CDCI₃) δ 8.59 (1 H, s), 7.84 (1 H, d, J = 12.8), 7.82 (1 H, s), 7.44-7.42 (6H, m), 7.33-7.23 (9H, m), 4.05 (1 H, m), 3.73 (2H, m),3.64 (3H, s), 3.42-3.15 (6H, m),2.14 (3H, m), 1.44 and 1.34 (3H, 2 m), 1.01 (2H, m) and 0.70 (2H, m).

Example 8 - N-Acetyl Moxifloxacin Aldehyde Trityl Oxime 8

Title compound was formed in 70 %.

¹H NMR, 400MHz (CDCI₃) δ 8.60 (1H, s), 7.78 (1H, s), 7.77 (1H, d, J = 13.2), 7.44-7.42 (6H, m), 7.36-7.23 (9H, m), 4.65 and 4.45 (1H, 2 xm), 4.05 (1H, m), 3.73 (2H, m),3.51 (3H, s), 3.17 (2H, m),2.72 and 2.25 (1H, 2 m), 2.14 (3H, s), 1.83-1.78 (3H, m), 1.56 (2H, 2m), 1.04 (1H, m), 0.91 (1H, m),0.78 (1H, m) and 0.61 (1H, m).

Example 9 - Moxifloxacin Aldehyde Trityl Oxime 9

¹H NMR, 400MHz (CDCI₃) δ 8.59 (1H, s), 7.79 (1H, d, J = 12.8), 7.75 (1H, s), 7.44-7.42 (6H, m), 7.35-7.23 (9H, m), 3.75-3.69 (3H, m), 3.62 (3H, s), 3.45 (1H, m), 3.09 (2H, m), 2.79 (1H, m), 2.02 (1H, m), 1.71-1.63 (3H, m), 1.52 (1H, m), 0.98 (2H, m) and 0.72 (2H, m).

Example 10 - Nadifloxacin Aldehyde Trityl Oxime 10

1 H NMR (CDCI3, 400 MHz) δ 8.699 (s, 1 H), 7.919-7.951 (d, 1 H), 7.715 (s, 1 H), 7.413-7.437 (m, 4H), 7.224-7.407 (m, 7H), 4.093-4.173 (m, 1 H), 3.8-3.9 (s, 1 H), 3.214-3.258 (m, 4H), 2.760-2.782 (m, 1 H), 2.01 1 (s,4H), 1.702-1.771 (m, 3H), 1.315-1.332 (m, 2H), 1.200-1.275 (m, 2H)

Mass Spec: m/z [M + Na] ⁺ calcd for CssHseFNsNaOs: 624.70. Found 624.30.

Example 11 - Gatifloxacin Aldehyde Trityl Oxime 11

¹ H NMR, 400MHz (CDCI₃) δ 8.59 (1 H, s), 7.83 (1 H, d, J = 12.0), 7.82 (1 H, s), 7.44-7.42 (6H, m), 7.37-7.24 (9H, m), 3.75 (3H, s), 3.44-3.42 (3H, m), 3.32-3.17 (5H, m), 1.35 (3H, d, J = 6.0), 1.00 (2H, m) and 0.72 (2H, m).

Levofloxacin Ketooximes

Example 12 - Procedure for Levofloxacin Ethyl Ketone Trityl Oxime 12 Formation Ph

Ph . . Ph

To a room temperature stirring solution of levofloxacin ethyl ketone in anhydrous ethanol (2 mL) under inert atmosphere was added o-tritylhydroxylamine (3 eq.). After stirring overnight, the mixture was fully solubilised by adding 1 ,4-dioxane (1 mL) and then stirred for a further two days. The reaction mixture was evaporated onto silica gel and thensubjected to flash column chromatography (0-10 % methanol/ dichloromethane containing 1-3 % ammonia solution) to afford the product in 40 %.

¹ H NMR, 400MHz (CDCI₃) δ 7.63 (1 H, d, J = 12.4), 7.44-7.42 (6H, m), 7.32-7.23 (9H, m), 6.77 (1 H, s), 4.23 (1 H, m), 4.17 (1 H, m), 3.90 (1 H, m), 3.32 (4H, m), 2.55 (4H, m), 2.36 (3H, s), 1.57 (2H, m), 1.36 (3H, d, J = 6.8) and1.23 (3H, t, J = 7.6).

Example 13 - Procedure for Levofloxacin Methyl Ketone Trityl Oxime 13 Formation

Ph

Ph . I . Ph

To a room temperature stirring solution of levofloxacin methyl ketone in anhydrous ethanol (2 mL) under inert atmosphere was added o-tritylhydroxylamine (3 eq.). After stirring overnight, the mixture was fully solubilised by adding 1 ,4-dioxane (1 mL) and then stirred for a further two days. The reaction mixture was evaporated onto silica gel and thensubjected to flash column chromatography (4-10 % methanol/ dichloromethane containing 1 % ammonia solution) to afford the product in 40 %. ¹ H NMR, 400MHz (CDCI₃) δ 7.63 (1 H, d, J = 12.4), 7.43-7.41 (6H, m), 7.32-7.23 (9H, m), 6.90 (1 H, s), 4.24 (1 H, m), 4.16 (1 H, m), 3.94 (1 H, m), 3.32 (4H, m), 2.52 (4H, m), 2.50 (3H, s),2.36 (3H, s) and 1.36 (3H, d, J = 6.8).

Example 14

The in vitro efficacy of a series of compounds was assessed for activity against a range of bacterial strains. All test articles were stored in the dark at 4 °C following delivery. Immediately prior to use, approximately 1 mg of each compound was accurately weighed and dissolved in the appropriate volume of DMSO to give a stock concentration of 1.28g/L.

Strains

Susceptibility tests were performed against a range of anaerobic bacterial strains as indicated in Tables 1-4 below. Revival and Growth of the Strains

All strains were recovered from long-term storage at -80 °C by sub-culturing onto fresh blood agar plates and incubating at 35-37 °C in air, except for Streptococcus pneumoniae which was incubated in the presence of 5% C0₂, for 24 hours. Following visual checks to ensure purity and appropriate colony characteristics, isolates were deemed suitable for use.

Preparation of the Inoculum

The inocula for each bacterial strain were prepared by picking 5-10 distinct colonies from the culture plates and suspending them in 3ml of sterile saline. The inoculum was resuspended by vigorous shaking on a vortex mixer for 15s. The turbidity was then adjusted to McFarland standard 0.5 (1-5 x 106 CFU/ml). The inoculum was further diluted in Mueller Hinton Broth for MIC tests to give a final inoculum in each well of 2-8 x 105 CFU/ml. For Streptococcus pneumoniae the Mueller Hinton broth was supplemented with 5% lysed horse blood (MHLB).

MIC Assay Conditions

MICs were tested in Mueller Hinton broth (MHLB for S. pneumoniae) in accordance with the appropriate CLSI guidelines. STEP 1: Addition of Test Article

a. A stock solution was prepared at a concentration of 1.28 g/L in DMSO. The stock was further diluted in Mueller Hinton broth (or MHLB) to give a top starting concentration of 128 mg/L in the assay. In addition, for each strain, a comparator control was included. The final concentration range for the comparator control (ciprofloxacin) was 0.03 -16 ΓΤ^/Ι_.100μΙ_ of Mueller Hinton broth was dispensed into each well in columns 2-12. 200μΙ_ of the appropriate test compound solution (at 256mg/L) was dispensed into each well in column 1. b. 100μΙ_ aliquots were pipetted from column 1 wells and dispensed into column 2 with a multichannel pipette (± 2% coefficient of variation) thus diluting two-fold. 100 μΙ_ samples were then pipetted from column 2 wells and dispensed into column 3. The process was repeated through to column 10. The final 100 μΙ_ of diluted drug from column 10 was then discarded. Row 1 1 acted as a positive control (no drug or test article, organisms added), Row 12 acted as a negative control (no drug or test article, and no organisms added).

STEP 2: Addition of Bacterial Strains

100μΙ_ of the appropriate inoculum suspension in Mueller Hinton broth (or MHLB) was added to the appropriate wells. This resulted in a well containing 200μΙ_ final volume (made up of 100μΙ_ diluted compound or diluents and 100μΙ_ of inoculum or broth alone).

STEP 3: Incubation of Assay Plates

All plates were incubated in the dark at 35-37 °C in air for 18-24 hours. STEP 4: Reading of Plates

Plates were read visually and spectrophotometrically (450nm) where possible, 24 hours post inoculation. Endpoints of 50%, 80% and 100% inhibition were determined (or CLSI interpretation endpoints following visual examination).

Compounds

In addition to the compounds of the invention described in Examples 1-13, the following compounds were tested: Levofloxacin A Levofloxacin oxime B

Levofloxacin ethyl oxime C Levofloxacin benzyl oxime D

Levofloxacin diphenylmethyl oxime E

Compounds A-E are included as comparative examples only and fall outside the scope of this invention. The activities of the compounds of the invention are compared to those of compounds A-E in Tables 1 and 2. Table 1 - Results

Table 2 - Results against resistant strains

Further data showing the activity of the compounds of the invention against both resistant and non-resistant strains of Gram negative and Gram positive bacteria are shown in Table 3.

Table 3

Compound Strain Resistance Gram MIC 100

14 Klebsiella pneumoniae - ATCC 700603 - negative >128

Streptococcus pneumoniae - ATCC 49619 - positive 64

Escherichia coli - ATCC 25922 - negative 128 Acinetobacter baumannii - ATCC BAA 747 - negative >128 Pseudomonas aeruginosa - ATCC 27853 - negative >128

Enterococcus faecalis - ATCC 29212 - positive >128 Staphylococcus epidermidis - ATCC 35984 - positive >128 Staphylococcus aureus - ATCC 29213 - positive >128 10 Acinetobacter baumannii - ATCC BAA 747 - negative 16

Klebsiella pneumoniae - ATCC 700603 - negative >128 Staphylococcus aureus - ATCC 25923 - positive 2 Staphylococcus epidermidis - ATCC 35984 - positive 1 Staphylococcus aureus - ATCC 29213 - positive 2 Streptococcus pneumoniae - 3297 03 Resistant positive >128 Staphylococcus aureus - NRS 382 Resistant positive >128 Pseudomonas aeruginosa - ATCC 27853 - negative >128 Staphylococcus aureus - NRS 383 Resistant positive >128 Enterococcus faecalis - ATCC 29212 - positive 16

Staphylococcus aureus - NRS 384 Resistant positive >128 Streptococcus pneumoniae - 4066 01 Resistant positive >128 Streptococcus pneumoniae - 4478 07 Resistant positive 32 Streptococcus pneumoniae - ATCC 49619 - positive >128 Escherichia coli - ATCC 25922 - negative 8 Staphylococcus aureus - NRS 1 Resistant positive >128 Staphylococcus aureus - NRS 74 Resistant positive >128

12 Escherichia coli - ATCC 25922 - negative >128

Klebsiella pneumoniae - ATCC 700603 - negative >128 Enterococcus faecalis - ATCC 29212 - positive 4 Streptococcus pneumoniae - ATCC 49619 - positive 32 Acinetobacter baumannii - ATCC BAA 747 - negative >128

Staphylococcus aureus - ATCC 29213 - positive 4 Staphylococcus epidermidis - ATCC 35984 - positive 4 Pseudomonas aeruginosa - ATCC 27853 - negative >128

Klebsiella pneumoniae - ATCC 700603 negative >128 Escherichia coli - ATCC 25922 negative 128 Streptococcus pneumoniae - ATCC 49619 positive 16

Enterococcus faecalis - ATCC 29212 positive 8 Staphylococcus epidermidis - ATCC 35984 positive 4 Pseudomonas aeruginosa - ATCC 27853 negative >128 Acinetobacter baumannii - ATCC BAA 747 negative 128 Staphylococcus aureus - ATCC 29213 positive 8

Escherichia coli - ATCC 25922 negative >128 Klebsiella pneumoniae - ATCC 700603 negative >128 Acinetobacter baumannii - ATCC BAA 747 negative >128 Streptococcus pneumoniae - ATCC 49619 positive

Pseudomonas aeruginosa - ATCC 27853 negative >128

Enterococcus faecalis - ATCC 29212 positive >128 Staphylococcus epidermidis - ATCC 35984 positive >128

Staphylococcus aureus - ATCC 29213 positive >128 Pseudomonas aeruginosa - ATCC 27853 negative 32 Klebsiella pneumoniae - ATCC 700603 negative 32 Streptococcus pneumoniae - ATCC 49619 positive 16 Staphylococcus epidermidis - ATCC 35984 positive 4 Acinetobacter baumannii - ATCC BAA 747 negative 4 Enterococcus faecalis - ATCC 29212 positive 16

Escherichia coli - ATCC 25922 negative 1 Staphylococcus aureus - ATCC 29213 positive 8

Escherichia coli - ATCC 25922 negative >128 Klebsiella pneumoniae - ATCC 700603 negative >128 Acinetobacter baumannii - ATCC BAA 747 negative >128 Pseudomonas aeruginosa - ATCC 27853 negative >128 Streptococcus pneumoniae - ATCC 49619 positive 128

Enterococcus faecalis - ATCC 29212 positive >128 Staphylococcus epidermidis - ATCC 35984 positive >128 Staphylococcus aureus - ATCC 29213 positive >128

Escherichia coli - ATCC 25922 - negative >128 Klebsiella pneumoniae - ATCC 700603 - negative >128 Streptococcus pneumoniae - 4478 07 Resistant positive 16 Pseudomonas aeruginosa - ATCC 27853 - negative 128 Staphylococcus aureus - ATCC 25923 - positive 2 Streptococcus pneumoniae - 4066 01 Resistant positive 16 Enterococcus faecalis - ATCC 29212 - positive 4 Staphylococcus aureus - ATCC 29213 - positive 2 Staphylococcus aureus - NRS 74 Resistant positive 2 Staphylococcus epidermidis - ATCC 35984 - positive 2 Streptococcus pneumoniae - ATCC 49619 - positive 16 Acinetobacter baumannii - ATCC BAA 747 - negative >128 Staphylococcus aureus - NRS 382 Resistant positive 1 Staphylococcus aureus - NRS 383 Resistant positive 2

Staphylococcus aureus - NRS 1 Resistant positive 4 Staphylococcus aureus - NRS 384 Resistant positive 0.5000 Streptococcus pneumoniae - 3297 03 Resistant positive 32

Escherichia coli - ATCC 25922 - negative >128 Klebsiella pneumoniae - ATCC 700603 - negative >128 Streptococcus pneumoniae - ATCC 49619 - positive 16 Acinetobacter baumannii - ATCC BAA 747 - negative >128

Staphylococcus aureus - ATCC 29213 - positive 4 Staphylococcus epidermidis - ATCC 35984 - positive 4 Pseudomonas aeruginosa - ATCC 27853 - negative >128 Enterococcus faecalis - ATCC 29212 - positive >128

Escherichia coli - ATCC 25922 - negative >128 Klebsiella pneumoniae - ATCC 700603 - negative >128 Streptococcus pneumoniae - 4478 07 Resistant positive 16 Staphylococcus aureus - ATCC 25923 - positive 2 Staphylococcus aureus - NRS 74 Resistant positive 2 Staphylococcus epidermidis - ATCC 35984 - positive 32 Streptococcus pneumoniae - ATCC 49619 - positive 32 Acinetobacter baumannii - ATCC BAA 747 - negative >128 Staphylococcus aureus - NRS 382 Resistant positive 1 Staphylococcus aureus - NRS 384 Resistant positive 1 Enterococcus faecalis - ATCC 29212 - positive 8 Pseudomonas aeruginosa - ATCC 27853 - negative >128 Staphylococcus aureus - NRS 383 Resistant positive 2

Staphylococcus aureus - ATCC 29213 - positive 8

Staphylococcus aureus - NRS 1 Resistant positive 4 Streptococcus pneumoniae - 3297 03 Resistant positive 32 Streptococcus pneumoniae - 4066 01 Resistant positive 32

Escherichia coli - ATCC 25922 - negative >128 Acinetobacter baumannii - ATCC BAA 747 - negative >128 Pseudomonas aeruginosa - ATCC 27853 - negative >128 Enterococcus faecalis - ATCC 29212 - positive >128 Klebsiella pneumoniae - ATCC 700603 - negative 128 Staphylococcus epidermidis - ATCC 35984 - positive >128 Streptococcus pneumoniae - ATCC 49619 - positive >128 Staphylococcus aureus - ATCC 29213 - positive >128

Staphylococcus aureus - NRS 74 Resistant positive 1 Pseudomonas aeruginosa - ATCC 27853 - negative 128 Staphylococcus aureus - NRS 382 Resistant positive 0.5000 Escherichia coli - ATCC 25922 - negative 128 Streptococcus pneumoniae - ATCC 49619 - positive 16 Acinetobacter baumannii - ATCC BAA 747 - negative 64

Staphylococcus aureus - NRS 384 Resistant positive 1 Staphylococcus epidermidis - ATCC 35984 - positive 0.5000 Staphylococcus aureus - ATCC 29213 - positive 4 Enterococcus faecalis - ATCC 29212 - positive 16 Klebsiella pneumoniae - ATCC 700603 - negative 128

Staphylococcus aureus - NRS 383 Resistant positive 2 Streptococcus pneumoniae - 4478 07 Resistant positive 32

Staphylococcus aureus - ATCC 25923 - positive 1

Pseudomonas aeruginosa - ATCC 27853 - negative 128

Escherichia coli - ATCC 25922 - negative 128 Acinetobacter baumannii - ATCC BAA 747 - negative 64 Enterococcus faecalis - ATCC 29212 - positive 128 Staphylococcus aureus - ATCC 29213 - positive 128 Streptococcus pneumoniae - ATCC 49619 - positive 128

Klebsiella pneumoniae - ATCC 700603 - negative 128 Staphylococcus epidermidis - ATCC 35984 - positive 64

Escherichia coli - ATCC 25922 negative >128 Klebsiella pneumoniae - ATCC 700603 negative >128

Staphylococcus aureus - NRS 74 Resistant positive 1 Streptococcus pneumoniae - 4478 07 Resistant positive 16

Staphylococcus aureus - NRS 382 Resistant positive 0.5000 Streptococcus pneumoniae - 4066 01 Resistant positive 16 Enterococcus faecalis - ATCC 29212 positive 4 Streptococcus pneumoniae - 3297 03 Resistant positive 16 Streptococcus pneumoniae - ATCC 49619 positive 16 Acinetobacter baumannii - ATCC BAA 747 negative 64 Staphylococcus aureus - NRS 384 Resistant positive 1 Staphylococcus aureus - ATCC 29213 positive 4 Staphylococcus epidermidis - ATCC 35984 positive 4 Pseudomonas aeruginosa - ATCC 27853 negative >128 SStaphylococcus aureus - ATCC 29213 8

Staphylococcus aureus - NRS 383 Resistant positive 2 Staphylococcus aureus - ATCC 25923 positive 1 Staphylococcus aureus - NRS 1 Resistant positive 4

Example 15 - Biodefense

Compound 1 was further tested for activity against strains which are known surrogates for bacterial strains associated with biowarfare. The activity is shown in Table 4 and the surrogate relationship is shown in Table 5.

Table 4

Compound Strain Gram MIC 100

1 Bacillus cereus - QBR1 14769-06 positive 16

Bacillus subtilis - QBR1 14769-04 positive 8

Bacillus subtilis - QBR1 14769-05 positive 8

Yersinia enterocolitica - QBR1 14769-02 negative >64

Yersinia enterocolitica - QBR1 14769-01 negative >64

Burkholderia cepacia - QBR1 14769-08 negative >64

Burkholderia cepacia - QBR1 14769-09 negative >64

Burkholderia cepacia - QBR1 14769-07 negative >64

Yersinia enterocolitica - QBR1 14769-03 negative >64

Table 5

These preliminary studies show that, against many bacterial strains, the compounds of the invention have comparable antibacterial activity to the corresponding approved parent compounds.

This preliminary data indicates that the compounds have antibacterial activity and can be used as a medicament against one of the above bacterial strains.

In particular, the compounds of the invention are active against resistant strains of bacteria, particularly resistant strains of Gram positive bacteria.

In addition, the compounds are active against bacterial strains associated with biowarfare, particularly Gram positive strains.

Thus the compounds of the invention are active in the treatment of one or more of the above strains. In some cases the activity is broad spectrum. In other cases the activity is selective over one or more strains.

Claims

1. A compound of formula (I):

R¹ is selected from the group consisting of: H, NR⁷R⁸, C C₄ alkyl, C C₄ alkyloxy and C C₄ haloalkyl; wherein R⁷ and R⁸ are each independently selected from the group consisting of: H, C1-C4 alkyl and Ac;

X is C or N;

Y is O or NR¹³; wherein R¹³ is selected from the group consisting of: H, C C₄ alkyl and Ac; P is N or CR¹⁰;

Q is N or CR⁹;

R² is selected from the group consisting of: aryl and heteroaryl;

R⁵ is selected from the group consisting of: C C₄ alkyl, C C₄ haloalkyl, C₃-C₅ cycloalkyl,

C3-C5 halocycloalkyl; unsubstituted phenyl; phenyl substituted with from 1 to 3 independently selected halogen atoms; unsubstituted pyridyl; and pyridyl substituted with from 1 to 3 independently substituents selected from the group consisting of: halo and

NHR_a; wherein R_a is H or Ac;

or alternatively, R⁵ and R⁶, together with the atoms to which they are attached to form a 4-

6-membered ring which optionally contains an O or S atom; wherein the 4-6-membered ring is optionally substituted with 1 or 2 groups independently selected from halo and C C₄ alkyl;

R⁹ is selected from the group consisting of: H, NHR_a and C C₄-alkyl; wherein R_a is H or Ac; R¹⁰ is selected from the group consisting of: H and F; R¹¹ is selected from the group consisting of: an N-heterocycloalkyl group and a C₃-C₈ cycloalkyi group; wherein the N-heterocycloalkyl group comprises from 5 to 10 ring atoms and at least one nitrogen atom wherein the N-heterocycloalkyl group is optionally substituted with from 1-3 groups independently selected from halo, tri(C C₄ alkyl)silyloxy, hydroxyl, C C₄ alkyl, oxo or oxime and wherein any nitrogen which does not attach the N- heterocycloalkyl group to the rest of the compound of Formula (I) is an NR_a group; and the C₃-C₈ cycloalkyi group is optionally substituted with at least one NHR_a group and optionally further substituted with from 1-3 groups independently selected from halo, hydroxyl, tri(C C₄ alkyl)silyloxy, C C₄ alkyl, oxo or oxime; wherein R_a is H or Ac;

or alternatively R¹² and R⁵, together with the atoms to which they are attached, form a 6- membered ring which optionally contains an O or S atom; wherein the 6-membered ring is optionally substituted with 1 or 2 groups independently selected from halo and C C₄ alkyl; wherein if X is N, R¹² is absent; and

wherein each of the aforementioned alkyl, haloalkyl, cycloalkyi, halocycloalkyl, aryl (e.g. phenyl) and heteroaryl (e.g. pyridyl) groups are optionally substituted, where chemically possible, by 1 to 3 substituents which are each independently selected at each occurrence from the group consisting of: oxo, imino, oximo, halo, nitro, cyano, hydroxyl, amino, C0₂H, C0₂-(C C₄alkyl), C(0)H, C C₄-alkyl, C C₄ haloalkyl, C C₄ alkoxy, and C C₄ haloalkoxy.

2. A compound according to claim 1 , wherein P is CR¹⁰ and Q is CR⁹.

3. A compound according to claim 1 or claim 2, wherein Y is O.

4. A compound according to claim 1 or claim 2, wherein Y is NH.

5. A compound according to any preceding claim, wherein R¹ is selected from H, C C₄ haloalkyl or C C₄ alkyl.

6. A compound according to any preceding claim, wherein R₂ is a 6-membered aryl group, wherein the aryl group is optionally substituted with 1-4 groups selected from the group consisting of: halo, nitro, cyano, hydroxyl, NHR_a, C0₂H, C0₂-(C C₄alkyl), C(0)H, C C₄-alkyl, C C₄ haloalkyl, C C₄ alkoxy, and C C₄ haloalkoxy.

7. A compound according to any preceding claim, wherein R³ and R⁴ are each independently selected from the group consisting of: C₄-C₂o alkyl, 6-membered aryl group and a 5- or 6-membered heteroaryl group.

8. A compound according to claim 7, wherein R³ and R⁴ are each independently selected from the group consisting of: 6-membered aryl group and a 5- or 6-membered heteroaryl group.

9. A compound according to claim 8, wherein R³ and R⁴ are each a 6-membered aryl group, wherein the aryl groups are optionally substituted with 1-4 groups selected from: halo, nitro, cyano, hydroxyl, NHR_a, C0₂H, C0₂-(C C₄alkyl), C(0)H, C C₄-alkyl, C C₄ haloalkyl, C C₄ alkoxy, and C C₄ haloalkoxy.

10. A compound according to any preceding claim, wherein R₂, R3 and R₄ are each independently selected from optionally substituted phenyl.

1 1. A compound according to any preceding claim, wherein X is N.

12. A compound according to any preceding claim, wherein X is C.

13. A compound according to any preceding claim, wherein R¹⁰ is F and R⁹ is H.

14. A compound according to any preceding claim, wherein R¹¹ is a piperazine ring or a piperidine ring each of which is optionally substituted with from 1-3 groups independently selected from halo, hydroxyl, C C₄ alkyl, oxo or oxime.

15. A compound according to any preceding claim, wherein R¹² is selected from the group comprising: H, halo or OR¹⁶; wherein R¹⁶ is selected from: C C₄ alkyl, C C₄ haloalkyl; or wherein R¹² and R⁵, together with the atoms to which they are attached, form a 6-membered ring which optionally contains an O or S atom; wherein the 6-membered ring is optionally substituted with 1 or 2 groups independently selected from halo and C C₄ alkyl.

16. A compound according to any preceding claim, wherein R⁵ is C C₄ alkyl.

17. A compound according to any preceding claim, wherein R⁶ is H.

wherein R¹ , R², R³, R⁴, R^a and Y are as defined in any of claims 1 to 17.

19. A compound according to claim 1 , wherein the compound is selected from the group

20. A use of a compound according to any one of claims 1 to 19 in medicine.

21. A use of a compound according to any one of claims 1 to 19 in treating a bacterial infection.

22. A use according to claim 21 wherein the bacterial infection is caused by a resistant strain.

23. A use of a compound according to any one of claims 1 to 19 in treating a disease caused by a category A or category B pathogen.

24. A pharmaceutical formulation comprising a compound according to any of claims 1 to 19 and a pharmaceutically acceptable excipient.