TWI380819B - Quinoline derivatives as antibacterial agents - Google Patents

Description

Quinoline derivative used as an antibacterial agent

The present invention relates to the use of quinoline derivatives for the manufacture of a medicament for the treatment of bacterial infections.

The resistance of bacteria to first-line antibiotics has gradually become a problem. Some important examples include anti-penicillin Streptococcus pneumoniae , anti-vancomycin-resistant enterococci, anti-dimethoxy Methalillin Staphylococcus aureus , multiplex-resistant Salmonella.

The results of resistance to antibiotics are extremely severe and are infected by resistant microorganisms, causing no response to treatment, leading to long-term risk of disease and death. Treatment failure also leads to long-term contagiousness, which increases movement between communities. Infected people and thus expose the general population to the risk of contracting resistant strains. In all parts of the world, hospitals are an important place for antimicrobial resistance problems, a combination of highly susceptible patients, dense and long-term antibacterial agents. The use, as well as cross-infection, lead to highly resistant pathogens in infection.

Self-use of antimicrobial agents is another important factor contributing to drug resistance. Self-use of antimicrobial agents may not be necessary, and often inadequate or may not contain sufficient amounts of active drug.

Whether the patient follows the recommended treatment system is another major problem, the patient forgets Taking medication, interrupting treatment when they feel comfortable, or failing to achieve a complete treatment, has created an ideal environment for microbes to adapt rather than be killed.

Because of the emergence of resistance to a variety of antibiotics, doctors are faced with infections without effective therapies. The incidence of such infections, mortality, and money costs add a significant burden to health care systems around the world.

Thus, there is a high demand for new compounds for the treatment of bacterial infections, especially for infections caused by therapeutic drug resistant strains.

WO 2004/011436 discloses substituted quinoline derivatives which are active against Mycobacteria, in particular Mycobacterium tuberculosis , and one of these substituted quinoline derivatives is disclosed in Science (2005). ), 307, 223-227.

It has now been found that the quinoline derivatives disclosed in WO 2004/011436 also exhibit activity against other bacteria other than mycobacteria.

Thus, the present invention relates to the use of a compound for the preparation of a medicament for the treatment of a bacterial infection, the compound having the formula a pharmaceutically acceptable acid or base addition salt thereof, a stereochemical isomer thereof or an N -oxide thereof, wherein R ¹ is hydrogen, halo, polyhalo C _1-6 alkyl, C _1-6 alkane a group, Ar or Het; p is an integer equal to 1 or 2; R ² is a C _1-6 alkoxy group, a C _1-6 alkoxy C _1-6 alkoxy group or a C _1-6 alkylthio group; ³ is Ar, Het or Het ¹ ; R ⁴ and R ⁵ are each independently hydrogen, C _1-6 alkyl or benzyl; or R ⁴ together with R ⁵ and including their attached N may be selected from The following groups: pyrrolidinyl, 2-pyrrolyl, 3-pyrrolyl, pyrrolyl, imidazolidinyl, pyrazolyl, 2-imidazolinyl, 2-pyrazolyl, imidazolyl, pyridyl Azyl, triazolyl, hexahydropyridyl, pyridyl, hexahydropyridyl Base Base, pyrimidinyl, pyridyl Base, three a morpholino group and a thiomorpholinyl group, each of which may be optionally substituted with a C _1-6 alkyl group, a halogen group, a polyhalogenyl C _1-6 alkyl group, a hydroxyl group, a hydroxyl group C _{1- 6} alkyl, C _1-6 alkoxy, amine, mono- or di(C _1-6 alkyl)amino, C _1-6 alkylthio, C _1-6 alkoxy C _1-6 alkane , C _1-6 alkylthio C _1-6 alkyl or pyrimidinyl; R ⁶ is hydrogen, halo, polyhalo C _1-6 alkyl, C _1-6 alkyl, C _1-6 alkoxy a C _1-6 alkylthio group; or two adjacent R ⁶ groups may together form a divalent group of the formula -CH=CH-CH=CH-; r is an integer equal to 1 or 2; R ⁷ is Hydrogen, C _1-6 alkyl, Ar, Het or Het ¹ ; Ar is a homocyclic ring selected from the group consisting of phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, optionally ring Substituted 1, 2 or 3 independently selected from the following substituents: hydroxy, halo, cyano, nitro, amine, mono- or di(C _1-6 alkyl)amine, C _{1- 6} alkyl, polyhalo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, polyhalo C _1-6 alkoxy, C _1-6 alkoxy C _{1 -6} alkyl, carboxy, C _1-6 alkoxycarbonyl, aminocarbonyl, morpholinyl and mono- or di(C _1-6 alkyl) Aminocarbonyl; Het is a heterocyclic ring selected from the group consisting of N -phenoxyhexahydropyridyl, hexahydropyridyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, Oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridyl Base and 哒 Each monocyclic heterocyclic ring optionally has 1, 2 or 3 substituents independently selected from the group consisting of halo, hydroxy, C _1-6 alkyl, polyhalo C _1-6 alkyl, Hydroxy C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl or Ar-C(=O)-; Het ¹ is selected from the group consisting of bicyclic Heterocycle: quinolyl, quinolinolyl, fluorenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, Benzothiophenyl, 2,3-dihydrobenzo[1,4] dioxins Or benzo[1,3]dioxazolyl; each bicyclic heterocyclic ring may be optionally substituted 1, 2 or 3 independently selected from the following substituents: halo, hydroxy, C _1-6 alkane , polyhalo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl or Ar-C(=O)- The condition is that the infection of this bacterium is not a mycobacterial infection.

The invention also relates to a method of treating bacterial infections in mammals, particularly humans, of warm-blooded animals, including administering an effective amount of a compound of the invention to a mammal.

The C _1-6 alkyl group referred to in the context, by itself or as part of another group, refers to a straight or branched chain saturated hydrocarbon group having from 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, pentyl, hexyl, 2-methylbutyl, and the like.

In this context, when (=O) is attached to a carbon atom, a carbonyl moiety is formed.

Halo means an atom of the group of fluorine, chlorine, bromine and iodine. In this context, a polyhalo C _1-6 alkyl group, by itself or as part of another group, is substituted by a single- or multiple halo group. C _1-6 alkyl, for example, a methyl group having one or more fluorine atoms, for example, difluoromethyl or trifluoromethyl, 1,1-difluoro-ethyl, etc., when there is more than one When the fluorine atom is attached to the alkyl group of the polyhalogenyl C _1-6 alkyl group, they may be the same or different.

In the definition of Het or Het ¹ or when R ⁴ and R ⁵ together, it is meant to include all possible isomeric forms of the heterocyclic ring, for example, the pyrrolyl group includes 1 H -pyrrolyl and 2 H -pyrrolyl.

Ar, Het or Het ¹ (see, for example, R ³ ) in the definition of the substituents of the compound of the formula (I), as mentioned in the context, may be via a suitable ring carbon atom or hetero atom unless otherwise specified. The remainder of the molecule of formula (I) is attached, thus, for example, when Het is imidazolyl, it may be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, and the like.

A line drawn from a substituent into a ring system means that it can be attached to any suitable ring. On the atom.

When two adjacent R ⁶ groups are taken together to form a divalent group having the formula -CH=CH-CH=CH-, it is meant that two adjacent R ⁶ groups together form a naphthyl group with the phenyl group to which they are attached.

As a therapeutic agent, the counterion in the salt of the compound of formula (I) is pharmaceutically acceptable, however, the non-pharmaceutically acceptable acid or base salt also has its use, for example, for pharmaceutical use. The preparation or purification of the above acceptable compounds, all salts, whether pharmaceutically acceptable or not, are within the scope of the invention.

A pharmaceutically acceptable addition salt as used in the context is meant to include a therapeutically active non-toxic acid addition salt form which the compound of formula (I) is capable of forming, which readily facilitates the passage of a salt-based compound with a suitable acid. Treated, for example, using inorganic acids such as hydrohalic acids, for example, hydrochloric acid, hydrobromic acid, etc.; sulfuric acid; nitric acid; phosphoric acid, etc.; or organic acids such as acetic acid, propionic acid, glycolic acid, 2-hydroxypropionic acid, 2-ketopropionic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, 2-hydroxy-1,2,3-propane Tricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexane aminosulfonic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, etc. The acid is, in contrast, the salt form of the compound can be converted to the free form by alkali treatment.

Compounds of formula (I) containing an acidic proton may be converted to their therapeutically active non-toxic metal or amine addition salt forms by treatment with suitable organic and inorganic bases, including, for example, ammonium Salts, alkali metal and alkaline earth metal salts, for example, salts of lithium, sodium, potassium, magnesium, calcium, etc., salts with organic bases, for example, aliphatic, aromatic, primary, secondary and tertiary Group of amines, such as methylamine, ethylamine, propylamine, isopropylamine, four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, Diisopropylamine, di-n-butylamine, pyrrolidine, hexahydropyridine, morpholine, trimethylamine, triethylamine, tripropylamine, quinacridine, pyridine, quinoline and isoquine Porphyrin, benzathine, N -methyl-D-glucosamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, hydrabamine salts, and Salts formed from amino acids, for example, arginine, lysine, and the like. Conversely, the salt formed can be converted to the free acid form by acid treatment.

The term addition salt also encompasses hydrate and solvent adduct forms which may be formed by the compounds of formula (I), examples of which are, for example, hydrates, alcoholates, and the like.

The N -oxide form of the present compound is meant to comprise a compound of formula (I) wherein one or more tertiary nitrogen atoms are oxidized to the so-called N -oxide.

The compounds of formula (I) may utilize known in the literature that N trivalent nitrogen into - Method oxides, are converted into the associated N - oxide, the N - oxidation reaction may generally orders of formula ( The compound of I) is obtained by reacting a suitable organic or inorganic peroxide, and for example, a peroxide such as hydrogen peroxide, an alkali metal or an alkaline earth metal, for example, sodium peroxide, Potassium peroxide; suitable organic peroxides may include peroxyacids such as phenylcarbon peroxyacid or halo substituted phenylcarbon peroxyacids, for example, 3-chlorophenylcarbon-peroxyacid, peroxygen Alkanoic acids, for example, peroxyacetic acid, alkyl hydrogen peroxides, for example, tert-butyl hydroperoxide, suitable solvents are, for example, water, lower alcohols such as ethanol, etc., hydrocarbons such as toluene Ketones, for example, 2-butanone, halogenated hydrocarbons, for example, dichloromethane, and mixtures of such solvents.

It will be apparent that some of the compounds of formula (I), as well as their N -oxides or addition salts, may contain one or more isomeric forms which are centered on the palm and are stereochemically present.

The term "stereochemical isomer type" in this context means a compound of formula (I), and a stereoisomer thereof which may be possessed by an N -oxide, addition salt or physiologically functional derivative, unless otherwise Illustrating or indicating that the chemical formula of the compound represents a mixture of all possible stereoisomeric forms containing all non-mirrored and mirror images of the basic molecular structure.

In particular, the stereoisomerization center may have an R- or S-configuration; the substituent on the bivalent, cyclically (partially) saturated base may have either a cis- or trans-configuration, The compound containing a double bond may have E (entgegen) or Z (Zusammen)-stereochemistry at the double bond position, and the stereochemically isomer of the compound of the formula (I) is obviously included in the scope of the present invention.

According to the CAS-naming rule, when two stereoisomerization centers of known absolute configuration appear in one molecule, the R or S designation symbols are assigned (according to the Cahn-Ingold-Prelog order rule) the lowest numbered palm Center, reference center, second stereoisomerization center is shown by the relative sign [ R ^* , R ^* ] or [ R ^* , S ^* ], where R ^{* is} always used as the reference center and [ R ^* , R ^* ] represents the same pair of palms, and [ R ^* , S ^* ] represents the center of different pairs of palms, for example, if the lowest numbered palm center has an S configuration in the numerator and the second center is R, The stereoscopic notation will be denoted as S -[ R ^* S ^* ] if " α " and " β " are used: and the position of the largest preferential substituent on the asymmetric carbon atom in the lowest numbered ring system, Will be arbitrarily labeled as the " α " position of the plane determined by the ring system, the highest priority substituent position on another asymmetric carbon atom of the ring system relative to the highest priority substituent position on the reference atom, if based upon the same side of the ring system determines the plane, are classified as the "α", When it is located in the plane of the ring system different sides of the decision, it is classified as "β".

The terms "erythro" and "threo" can also be used as descriptive symbols for relative stereochemistry. When a molecule carries two asymmetric carbons, there are four molecular stereoisomers that can exist. Divided into two pairs of mirror images, the difference between the two pairs of mirrors can be distinguished by erythro and threo annotations (originally used in sugars), two asymmetric carbon atoms on the side chain of the compound of the invention, in the structure below Indicated by ^* , is the determinant of the stereochemistry of the molecule. If the group is classified according to the rules of priority (rules of Cahn, Ingold, Prelog), the projection is observed in the same direction when Newman is projected. The relative configuration of the molecules is indicated as erythro, and if the group is classified according to the rules of preference (Rules of Cahn, Ingold, Prelog), when the Newman is projected, the coils are observed to be in the opposite direction. The relative configuration of the molecules is labeled as threo.

In addition to erythro and threo, "syn" and "anti" can also be used as relative stereoscopic symbols for two pairs of mirrors. To determine whether the molecule belongs to syn or anti, the main chain of the molecule is drawn into the usual zigzag. If the two major substituents (the substituents are sorted according to their priority (Cahn, Ingold, Prelog rules)) are located on the same side of the plane determined by the main chain, their stereochemistry is shown as syn, and if two When the main substituent is located on the opposite side of the plane defined by the main chain, its stereochemistry is shown as anti.

The stereoscopic symbols cis, trans, E, Z, R, S, erythro, threo, syn, and anti are well known to those skilled in the art, and can be referred to: J. Am. Chem. Soc., 1982, 104, 5521. 5523, which is incorporated herein by reference.

When a particular stereoisomeric form is indicated, this means that the form is substantially free, i.e., is present in combination with less than 50% of other isomers, preferably less than 20%, more preferably less. 10%, more preferably less than 5%, especially less than 2%, and most preferably less than 1%, thus, for example, when the compound of formula (1) is labeled as ( α S, β In the case of R), it is indicated that the compound does not substantially have an isomer of ( α S, β R).

The compound of formula (I) can be synthesized as a racemic mixture of mirror images which can be separated by known analytical methods. The compound of formula (I) can be reacted by reacting with an appropriate acid to the palm. After the non-mirrored salt form, it is separated, for example, by selective or split crystallization, and then using a base to release the mirror image; or, the separation of the mirror image of formula (I) can be achieved by using the stationary phase of the palm And performing the liquid chromatography; the stereochemically isoforms may also be derived from the pure stereochemical isomers of the relevant appropriate starting compounds, under stereospecific reaction conditions; Good place, if needed For particular stereoisomers, the compounds are suitable for synthesis in a stereospecific manner, which methods advantageously start with a mirror image of a pure starting material.

The invention also encompasses a compound derived from a pharmacologically active compound according to the invention (generally referred to as a "prodrug") which is degraded in vivo to produce a compound according to the invention, the prodrug usually (not often) It has lower potency at the target receptor than its decomposed compound, and the prodrug is particularly useful when the desired compound has chemical or physical properties such that it is difficult or insufficient to be administered, for example, The compound is extremely difficult to dissolve, it may not be easily transported through the endothelial layer of the mucosa, or it may have an undesirable half-life of the plasma. For a discussion of the prodrug, refer to: Stella, VJ et Al. , "Prodrugs", Drug Delivery Systems , 1985, pp. 112-176, and Drugs , 1985, 29 , pp. 455-473.

The pharmacologically active compound of the present invention is in the form of a pre-formulation, usually a compound of the formula (I) according to the invention, a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, The isomer form and its N -oxide, having an acid group which can be esterified or decylated, are included in such an esterified acid group as a group of the formula -COOR ^x wherein R ^x is C _1-6 An alkyl group, a phenyl group, a benzyl group or one of the following groups:

The amide group includes a group of the formula -CONR ^y R ^z wherein R ^y is H, C _1-6 alkyl, phenyl or benzyl and R ^z is -OH, H, C _1-6 alkyl, Phenyl or benzyl.

The compounds of the invention having an amine group, possibly with a ketone or an aldehyde, such as formaldehyde, are derivatized into a Mannich base which is hydrolyzed in a first order kinetic reaction in aqueous solution.

The term "compound of the formula (I)" means an isomeric form which also includes its N -oxide, its addition salt or its stereochemistry, and is of particular interest in the form of a stereochemically pure state ( I) Compound.

A first interesting embodiment of the invention relates to a compound of formula (Ia) A pharmaceutically acceptable acid or base addition salt thereof, a stereochemical isomer thereof or an N -oxide thereof.

A second interesting embodiment of the invention relates to a compound of formula (Ib) A pharmaceutically acceptable acid or base addition salt thereof, a stereochemical isomer thereof or an N -oxide thereof.

A third embodiment of interest is a compound of formula (I) or any subgroup thereof as mentioned above as a particular embodiment of interest, wherein R ¹ represents hydrogen, halo, C _{1- 6} alkyl, Ar or Het; preferably hydrogen, halo, optionally substituted phenyl or Het; more preferably hydrogen, halo, optionally substituted phenyl, optionally substituted furanyl, Or pyridyl; even more preferably hydrogen, halo, or alternatively substituted phenyl; most preferably halo, for example bromine or chlorine, especially bromine.

A fourth specific embodiment of interest relates to a compound of formula (I) or any subgroup thereof as mentioned above as a particular embodiment of interest, wherein R ¹ is halo, polyhalo C _{1 -6} alkyl, At or Het; preferably, halo, Ar or Het; more preferably halo, optionally substituted phenyl, or Het; more preferably halo, phenyl, Optionally substituted furanyl, or pyridyl; most preferably halo or phenyl.

A fifth specific embodiment of interest relates to a compound of formula (I) or any subgroup thereof as mentioned above as a particular embodiment of interest, wherein R ² is C _1-6 alkoxy or C _1-6 alkylthio, especially methoxy or methylthio; preferably C _1-6 alkoxy; most preferably methoxy.

A sixth embodiment of interest is a compound of formula (I) or any subgroup thereof as mentioned above as a particular embodiment of interest, wherein R ³ is Ar or Het or wherein R ³ is Ar or Het ¹ ; preferably, R ³ is Ar; more preferably a selectively substituted phenyl or a selectively substituted naphthyl group; still more preferably a halo group or a C _1-6 alkoxy group a substituted phenyl group, or a naphthyl group optionally substituted by a halo group or a C _1-6 alkoxy group; most preferably a phenyl group or a naphthalene which is optionally substituted with 1 or 2 halo groups (especially fluorine) Base, especially 1-naphthyl or 2-naphthyl.

A seventh embodiment of interest is a compound of formula (I) or any subgroup thereof as mentioned above as a particular embodiment of interest, wherein R ⁴ and R ⁵ are each independently hydrogen or C _1-6 alkyl; or R ⁴ together with R ⁵ and comprising the N appended thereto may form a group selected from the group consisting of pyrrolidinyl, 2-pyrroline, 3-pyrroline, pyrrolyl , imidazolidinyl, pyrazolyl, 2-imidazolinyl, 2-pyrazolyl, imidazolyl, pyrazolyl, triazolyl, hexahydropyridyl, pyridyl, hexahydropyridyl Base Base, pyrimidinyl, pyridyl Base, three a morpholino group and a thiomorpholinyl group, each of which may be optionally substituted with a C _1-6 alkyl group, a halogen group, a polyhalogenyl C _1-6 alkyl group, a hydroxyl group, a hydroxyl group C _{1- 6} alkyl, C _1-6 alkoxy, amine, mono- or di(C _1-6 alkyl)amino, C _1-6 alkylthio, C _1-6 alkoxy C _1-6 alkane a C _1-6 alkylthio C _1-6 alkyl or pyrimidinyl group; more preferably, R ⁴ is C _1-6 alkyl and R ⁵ is hydrogen or C _1-6 alkyl; or R ⁴ and R ⁵ together with N which may be attached thereto may form a group selected from the group consisting of pyrrolidinyl, 2-pyrroline, 3-pyrrolidino, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2- Imidazolinyl, 2-pyrazolyl, imidazolyl, pyrazolyl, triazolyl, hexahydropyridyl, pyridyl, hexahydropyridyl Base Base, pyrimidinyl, pyridyl Base, three a morpholino group and a thiomorpholinyl group, each of which may be optionally substituted with a C _1-6 alkyl group, a halogen group, a polyhalogenyl C _1-6 alkyl group, a hydroxyl group, a hydroxyl group C _{1- 6} alkyl, C _1-6 alkoxy, amine, mono- or di(C _1-6 alkyl)amino, C _1-6 alkylthio, C _1-6 alkoxy C _1-6 alkane a C _1-6 alkylthio C _1-6 alkyl or pyrimidinyl group; more preferably, R ⁴ is C _1-6 alkyl and R ⁵ is hydrogen or C _1-6 alkyl; or R ⁴ is R ⁵ together and comprising the N appended thereto may form a group selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, hexahydropyridyl, pyridyl, hexahydropyridyl Base Base, pyrimidinyl, pyridyl Base, three a morpholino group and a thiomorpholinyl group, each of which may be optionally substituted with a C _1-6 alkyl group, a halogen group, a polyhalogenyl C _1-6 alkyl group, a hydroxyl group, a hydroxyl group C _{1- 6} alkyl, C _1-6 alkoxy, amine, mono- or di(C _1-6 alkyl)amino, C _1-6 alkylthio, C _1-6 alkoxy C _1-6 alkane a C _1-6 alkylthio C _1-6 alkyl or pyrimidinyl; most preferably, R ⁴ is C _1-6 alkyl, especially methyl or ethyl, more preferably methyl, and R ⁵ It is hydrogen or C _1-6 alkyl, especially methyl or ethyl, more particularly methyl.

An eighth embodiment of interest is a compound of formula (I) or any subgroup thereof as mentioned above as a particular embodiment of interest, wherein R ⁴ and R ⁵ are each independently hydrogen, C _1-6 alkyl or benzyl; preferably, R ⁴ and R ⁵ are each independently hydrogen or C _1-6 alkyl; more preferably, R ⁴ is C _1-6 alkyl and R ⁵ is Hydrogen or C _1-6 alkyl; more preferably, R ⁴ and R ⁵ are C _1-6 alkyl, especially methyl or ethyl, especially methyl.

A ninth interesting embodiment is a compound of formula (I) or any subgroup of the specific embodiments referred to above as being of interest, wherein R ⁴ together with R ⁵ and comprising The N may be formed from a group including a pyrrolidinyl group, a 2-pyrroline group, a 3-pyrroline group, a pyrrolyl group, an imidazolidinyl group, a pyrazolidine group, a 2-imidazolidinyl group, and a 2-pyridyl group. Oxazolinyl, imidazolyl, pyrazolyl, triazolyl, hexahydropyridyl, pyridyl, hexahydropyridyl Base Base, pyrimidinyl, pyridyl Base, three a morpholino group and a thiomorpholinyl group, each of which may be optionally substituted with a C _1-6 alkyl group, a halogen group, a polyhalogenyl C _1-6 alkyl group, a hydroxyl group, a hydroxyl group C _{1- 6} alkyl, C _1-6 alkoxy, amine, mono- or di(C _1-6 alkyl)amino, C _1-6 alkylthio, C _1-6 alkoxy C _1-6 alkane a C _1-6 alkylthio C _1-6 alkyl or pyrimidinyl group; preferably, R ⁴ together with R ⁵ and comprising the N appended thereto may form a group selected from the group consisting of pyrrolyl, Imidazolyl, pyrazolyl, triazolyl, hexahydropyridyl, pyridyl, hexahydropyridyl Base Base, pyrimidinyl, pyridyl Base, three a morpholino group and a thiomorpholinyl group, each of which may be optionally substituted with a C _1-6 alkyl group, a halogen group, a polyhalogenyl C _1-6 alkyl group, a hydroxyl group, a hydroxyl group C _{1- 6} alkyl, C _1-6 alkoxy, amine, mono- or di(C _1-6 alkyl)amino, C _1-6 alkylthio, C _1-6 alkoxy C _1-6 alkane a C _1-6 alkylthio C _1-6 alkyl or pyrimidinyl group; more preferably, R ⁴ together with R ⁵ and comprising the N appended thereto may form a group selected from the group consisting of pyrrolyl groups, Imidazolyl, pyrazolyl, triazolyl, hexahydropyridyl, hexahydropyridyl a morpholino group and a thiomorpholinyl group, each of which may be optionally substituted with a C _1-6 alkyl group, a halogen group, a polyhalogenyl C _1-6 alkyl group, a hydroxyl group, a hydroxyl group C _{1- 6} alkyl, C _1-6 alkoxy, amine, mono- or di(C _1-6 alkyl)amino, C _1-6 alkylthio, C _1-6 alkoxy C _1-6 alkane a C _1-6 alkylthio C _1-6 alkyl or pyrimidinyl group; more preferably, R ⁴ together with R ⁵ and comprising the N appended thereto may form a group selected from the group consisting of imidazolyl , triazolyl, hexahydropyridyl, hexahydropyridyl a morpholino group and a thiomorpholinyl group, each of which may be optionally substituted with a C _1-6 alkyl group, a halogen group, a polyhalogenyl C _1-6 alkyl group, a hydroxyl group, a hydroxyl group C _{1- 6} alkyl, C _1-6 alkoxy, amine, mono- or di(C _1-6 alkyl)amino, C _1-6 alkylthio, C _1-6 alkoxy C _1-6 alkane A, C _1-6 alkylthio C _1-6 alkyl or pyrimidinyl; most preferably, R ⁴ together with R ⁵ and including the N attached thereto forms an imidazolyl group.

Preferably, the substituent on the ring system, when R ⁴ and R ⁵ are taken together, is selected from the group consisting of C _1-6 alkyl, halo, polyhalo C _1-6 alkyl, hydroxy, C _{1 -6} alkoxy, C _1-6 alkylthio and pyrimidinyl; more preferably, the substituent is selected from C _1-6 alkyl or pyrimidinyl.

A tenth specific embodiment of interest relates to a compound of formula (I) or any subgroup thereof as mentioned above as a specific embodiment of interest, wherein R ⁶ is hydrogen, halo, polyhalo C _1-6 alkyl or C _1-6 alkyl; or two adjacent R ⁶ groups may together form a divalent group of the formula -CH=CH-CH=CH-; preferably, R ⁶ is hydrogen , halo, polyhalo C _1-6 alkyl or C _1-6 alkyl; more preferably, R ⁶ is hydrogen, halo or C _1-6 alkyl; more preferably, R ⁶ is hydrogen or Halogen; optimally, R ⁶ is hydrogen.

Any particular embodiment of the compounds of the first subgroup 11 of concern based on the specific embodiments of formula (I) or of concern mentioned hereinbefore, wherein R ⁷ is hydrogen.

A twelfth specific embodiment of interest relates to a compound of formula (I) or any subgroup thereof as mentioned above as a particular embodiment of interest, wherein r is an integer of one.

A 13th specific embodiment of interest relates to a compound of formula (I) or any subgroup of the specific embodiments thereof mentioned above, wherein p is an integer of one.

A specific example of the 14th aspect concerns a compound of formula (I) or any subgroup thereof as mentioned above as a particular embodiment of interest, provided that one R ¹ is C _1-6 In the case of an alkyl group, p is an integer equal to 2 and the other R ¹ substituent is selected from the group consisting of halo, polyhalo C _1-6 alkyl, C _1-6 alkyl, Ar or Het.

A specific embodiment of the fifteenth interest relates to a compound of formula (I) or any subgroup thereof as mentioned above as a particular embodiment of interest, wherein the compound is different from (αS, βR)-6 -Bromo- α- [2-(dimethylamino)ethyl]-2-methoxy- α- 1-naphthyl- β -phenyl-3-quinolineethanol, its pharmaceutically acceptable acid Or a base addition salt or an N -oxide thereof.

A specific embodiment of the sixteenth aspect of interest is the use of a compound of formula (I) or any subgroup thereof as mentioned above for the particular embodiment of interest for the preparation of a Gram-positive bacterium and/or Or the use of drugs for Gram-negative infections.

A specific embodiment of the 17th interest is the use of a compound of formula (I) or any subgroup thereof as mentioned above for the particular embodiment of interest for the preparation of a Gram-positive infection. The use of the drug.

A specific embodiment of the 18th aspect of interest is the use of a compound of formula (1) or any subgroup thereof as mentioned above for the specific embodiment of interest for the preparation of a Gram-negative infection. The use of the drug.

A specific embodiment of the 19th interest is the use of a compound of formula (I) or any subgroup thereof as mentioned above for the specific embodiment of interest for the preparation of a medicament for the treatment of a bacterial infection, Wherein the compound of formula (I) has an IC ₉₀ < 15 μl/ml against at least one of the bacteria, particularly Gram-positive bacteria, preferably having an IC ₉₀ <10 μL/ml, more preferably IC ₉₀ < The ability of 5 μl/ml; the determination of the IC ₉₀ value is described later.

Also of interest in the present invention are compounds of formula (I) wherein one or more, preferably all, are as defined for use in the following: a) R ¹ is hydrogen; C _1-6 alkyl; a halogen group, especially bromine or chlorine; a phenyl group; a furyl group optionally substituted by a hydroxy C _1-6 alkyl group; or a pyridyl group; b) R ² is a C _1-6 alkoxy group, especially a methoxy group or Ethoxy; C _1-6 alkylthio, especially methylthio; or C _1-6 alkoxy C _1-6 alkoxy; c) R ³ is optionally substituted by 1 or 2 halo, Particularly a phenyl group of fluorine or chlorine; a naphthyl group optionally substituted with 1 or 2 halo or C _1-6 alkoxy groups; a thienyl group; a hexahydropyridyl group substituted with Ar-C(=O); , 3-dihydrobenzo[1,4] dioxins a benzo[1,3]dioxazolyl group; or a fluorenyl group; d) R ⁴ and R ⁵ are each independently hydrogen; C _1-6 alkyl; benzyl; or R ⁴ together with R ⁵ ; Including its attached N, can form a group selected from the group consisting of imidazolyl; substituted by C _1-6 alkyl a hexahydropyridyl substituted by a C _1-6 alkyl group; Pyrimidine-substituted hexahydropyridyl a hexahydropyridyl group; a thiomorpholinyl group; a morpholinyl group; a pyrrolidinyl group; or a triazolyl group; e) R ⁶ is hydrogen; a halogen group, particularly chlorine, fluorine or bromine; a C _1-6 alkyl group; Or two adjacent R ⁶ groups may together form a divalent group of the formula -CH=CH-CH=CH-; f) R ⁷ is hydrogen.

Preferred compounds of the invention are compounds 50, 206, 31, 26, 27, 32, 33, 109, 39, 44, 41, compounds A, E and F, pharmaceutically acceptable acid or base addition salts thereof , or its N -oxide.

Another group of preferred compounds are the compounds defined in claim 24 of the patent application, namely, compounds 36, 46, 206, 31, 26, 33, 13, 39, 44, compounds A, E and F, and their pharmaceuticals An acceptable acid or base addition salt, or an N -oxide thereof.

The invention also relates to compounds which are defined in claim 29, ie, compounds A, B, C, D, E, F, G, H, I, pharmaceutically acceptable acid or base addition salts thereof , or its N -oxide.

Compounds of formula (I) can be prepared according to the method disclosed in WO 2004/011436, which is incorporated herein by reference.

In general, the compounds according to the present invention can be prepared by a series of steps, each of which is well known to those skilled in the art.

Specifically, the preparation of the compound of the formula (I) allows the intermediate compound of the formula (II) and the intermediate compound of the formula (III) to be carried out according to the following reaction chart (1):

BuLi is used in a mixture of diisopropylamine and tetrahydrofuran, and each of the variables is defined in formula (I), stirring or increasing the reaction rate, which is conveniently between -20 and -70 ° C The temperature is carried out between.

The starting material and the intermediate of formula (II) and (III) are commercially available or can be prepared according to methods known in the literature. For example, the compound of formula (II-a) can be used according to the following reaction chart ( 2) Preparation of the method:

Wherein all the variables are as defined in formula (I), and reaction scheme (2) comprises step (a) wherein the appropriate substituted aniline is combined with a suitable mercapto chloride, such as 3-phenylpropionyl chloride, 3-fluorophenylpropionyl chloride or p -chlorophenylpropionyl chloride in a suitable base (for example, triethylamine) and a suitable reaction-inert solvent (for example, dichloromethane or dichloroethylene) The reaction can be conveniently carried out at a temperature between room temperature and reflux temperature; in the next step (b), the adduct obtained in (a) is reacted with phosphonium chloride (POCl ₃ ). Reacting in the presence of N,N -dimethylformamide (Vilsmeier-Haack hydroformylation reaction, followed by cyclization), the reaction is conveniently carried out at a temperature between room temperature and reflux temperature; In the next step (c), a particular R ² - group, wherein R ² is, for example, a C _1-6 alkoxy group or a C _1-6 alkylthio group, is obtained by carrying out the step (b) The intermediate is introduced by reaction with a compound of the formula HXC _1-6 alkyl, wherein X is S or O.

Obviously, in the above reaction with the following, the reaction product can be self-reactive The medium is isolated and, if desired, purified by methods known in the literature, for example, by extraction, crystallization and chromatography; furthermore, it is apparent that more than one product is present. The mirror image can be isolated from its mixture by known techniques, particularly preparative chromatography, such as preparative HPLC. Typically, the compound of formula (I) can be isolated as its isomer. type.

The intermediate of formula (III) is commercially available or can be prepared according to customary reaction procedures known in the literature, for example, an intermediate compound of formula (III-a) wherein R ³ is substituted with an R ¹⁰ substituent Ar, wherein each R ¹⁰ is independently selected from the group consisting of: hydroxy, halo, cyano, nitro, amine, mono- or di(C _1-6 alkyl)amine, C _1-6 alkane , polyhalo C _1-6 alkyl, C _1-6 alkoxy, polyhalo C _1-6 alkoxy, carboxy, C _1-6 alkoxycarbonyl, aminocarbonyl, morpholinyl Mono- or di(C _1-6 alkyl)aminocarbonyl, and s is an integer equal to 0, 1, 2 or 3, which can be prepared according to the reaction chart (3) below:

Reaction Scheme (3) comprises step (a) wherein the appropriate substituted Ar, especially a suitable substituted phenyl group, is reacted with a suitable mercapto chloride (eg, 3-chloropropene) using a Friedel-Craft reaction. Mercapto chloride), reacted with a suitable Lewis acid (eg, AlCl ₃ , FeCl ₃ , SnCl ₄ , TiCl ₄ or ZnCl ₂ ) with a suitable reaction-inert solvent (eg dichloromethane or dichloroethylene) The reaction can be conveniently carried out at a temperature between room temperature and reflux temperature. In the next step (b), the amine group (-NR ⁴ R ⁵ ) is obtained in the middle of the step (a). The compound is introduced in the reaction with HNR ⁴ R ⁵ .

In general, bacterial pathogens can be classified as Gram-positive or Gram-negative pathogens, and activity against Gram-positive and Gram-negative pathogens is generally considered to have broad-spectrum activity. The compounds of the invention are believed to be active against Gram-positive and/or Gram-negative bacterial pathogens, in particular, the compounds of the invention are active against at least one Gram-positive bacterium, Preferably, it is resistant to many species of Gram-positive bacteria, and more preferably to one or more Gram-positive bacteria and/or one or more Gram-negative bacteria.

The compounds of the invention have bactericidal or bacteriostatic activity.

Examples of Gram-positive and Gram-negative aerobic and anaerobic bacteria include, for example, Staphylococcus, for example, S. aureus ; Enterococcus, for example, Enterococcus faecalis ( E.faecalis), Streptococcus, e.g., Streptococcus pneumoniae (S. pneumoniae), Streptococcus mutans (of S. mutans), Streptococcus pyogenes (S.pyogens); Bacillus, e.g., Bacillus subtilis (Bacillus subtilis); Lees special bacteria, for example, monocytogenes Listeria (Listeria monocytogene) s; Haemophilus bacteria (Haemophilus), for example, Haemophilus influenzae bacteria (H.influenza), Mora (Moraxella) bacteria, for example, tamoxifen card M. catarrhalis ; Pseudomonas, for example, Pseudomonas aeruginosa ; and Escherichia coli, for example, E. coli. , Gram-positive pathogens, for example, Staphylococcus Enterococcus and Streptococcus are particularly important because of the development of resistant strains, both in terms of treatment and eradication. For example, once the established hospital environment, an example of such a strain is methicillin ( Methicillin) resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulatory ester-negative staphylococci (MRCNS), penicillin-resistant Streptococcus pneumoniae and multi-drug resistant Enterococcus faecalis.

The compounds of the invention also appear to be active against resistant strains.

The compounds of the invention are particularly active against S. aureus, including drug resistant Staphylococcus aureus, for example, methicillin-resistant Staphylococcus aureus (MRSA), and Streptococcus pneumoniae.

Specifically, the compounds of the present invention are those having an active effect, and their viability depends on the proper function of the F1F0 ATP synthase. Without any theory, the activity of the compound of the present invention is considered to be the inhibition of F1F0 ATP synthase. In particular, the inhibition of the F0 complex of the F1F0 ATP synthase, more specifically the inhibition of the subunit c of the F0 complex of the F1F0 ATP synthase, results in killing by attenuating the intracellular ATP value of the bacteria bacterial.

As used in this context, a compound that treats an infection of a bacterium means that the compound can be used to treat an infection caused by one or more bacteria; and as mentioned in the context, the bacterial infection is different from the infection of mycobacteria and refers to the bacterium. The infection is not an infection caused by one or more strains of mycobacteria.

The correct dosage and frequency of administration of a compound of the invention will depend on the particular compound of formula (I) employed, the particular condition being treated, and the condition being treated Severe, age, weight, sex, diet, time of administration, general physiological condition, mode of administration, and individual medications, etc., are all well-known situations. In addition, it is clear that the daily effective dose, It may decrease or increase depending on the response of the patient being treated and/or the evaluation of the medication prescribed by the doctor.

The compounds of the invention may be administered in a pharmaceutically acceptable form, optionally in a pharmaceutically acceptable carrier; the compound and the composition comprising the compound may be, for example, locally, regionally or systemically Sexually administered, systemic administration includes any method of introducing a compound into body tissues, for example, intracapsular, dura, intramuscular, percutaneous, intravenous, intraperitoneal , subcutaneous, sublingual, rectal, and oral, the specific dose of antibacterial administered, and the duration of treatment, may be adjusted as appropriate.

Infections of bacteria which can be treated using the compounds of the invention include, for example, central nervous system infections, external ear infections, middle ear infections, for example, acute otitis media, cranial sinuses infections, eye infections, oral infections, such as teeth, Gum and mucosal infections, upper respiratory tract infections, lower respiratory tract infections, urinary tract infections, gastrointestinal infections, gynecological infections, sepsis, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis The law, as well as antibacterial prophylaxis in patients with suppressed immunity, such as patients undergoing cancer chemotherapy, or organ transplantation.

Since the compound of formula (I) is active against Gram-positive and/or Gram-negative bacteria, the compounds of the invention may be used in combination His antibacterial agent is effective against bacterial infections.

Accordingly, the invention also relates to a combination comprising (a) a compound of formula (I), and (b) one or more additional antimicrobial agents, provided that the one or more additional antimicrobial agents are not resistant to mycobacteria Agent.

The invention also relates to a combination comprising (a) a compound of formula (I), and (b) one or more additional antibacterial agents, provided that the one or more additional antibacterial agents are not antimycobacterial agents, Used as a medicine.

The invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier, and a therapeutically effective amount of (a) a compound of formula (I), and (b) one or more other The antibacterial agent, provided that the one or more other antibacterial agents are not antimycobacterial agents.

The invention also relates to the use of a combination or pharmaceutical composition as defined above for the treatment of infections of bacteria, in particular from infections of mycobacteria.

The pharmaceutical composition of the present invention may have a wide variety of pharmaceutical forms suitable for administration, and suitable compositions which can be cited are all compositions which are generally applied for systemic administration of a drug, for the preparation of the present invention. The pharmaceutical composition of the invention, wherein an effective amount of a particular compound, optionally an addition salt form, is used as an active ingredient, and is sufficiently mixed with a pharmaceutically acceptable carrier, which can be regarded as a pharmaceutical preparation to be administered. A variety of types are used, and these pharmaceutical compositions need to be formulated into a single dosage form, particularly for oral administration or parenteral injection, for example, when preparing an oral dosage form composition. Use any conventional pharmaceutical medium, for example, water, glycols, oils, alcohols, etc., for formulating liquid formulations, such as suspensions, thickeners, elixirs, lotions, solutions, etc. ;or It is a solid carrier such as starch, kaolin, diluent, lubricant, binder, disintegrating agent, etc., used for formulating powders, pills, capsules and tablets; for easy administration, tablets and capsules In the most advantageous oral dosage form, in this case, it is clear that a solid pharmaceutical carrier is used. As for the composition that is not used orally, the carrier usually contains sterile water, at least a large part, of course. Including other components, for example, a co-solvent; an injectable solution, a carrier which can be used, for example, a saline solution, a glucose solution or a mixture thereof; an injectable suspension can be a suitable liquid carrier or suspension. The preparation, which is also included, is a solid type, but is converted into a liquid preparation type immediately before use.

Depending on the mode of administration, the pharmaceutical composition preferably comprises from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight of active ingredient, and from 1 to 99.95% by weight, more preferably from 30 to 99.9. % by weight of the pharmaceutically acceptable carrier, all percentages are based on the weight of the total composition.

The weight ratio of the compound of formula (I) to (b) other antibacterial agents in combination may be determined by those of ordinary skill in the art, and the ratio and the correct dose and frequency of administration are determined by the particular formula (I). The compound and other antibacterial agents used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, diet, time of administration, general physiological condition, mode of administration, and individual other medications, etc. These are well known to those of ordinary skill in the art and, in addition, it is clear that the effective daily dose may be reduced or increased depending on the response of the patient being treated and/or the evaluation of the prescribed medication by the physician.

The compound of formula (I) and one or more other antibacterial agents may be combined in a single The formulation of one is formulated in a separate formulation such that it can be administered simultaneously, separately or sequentially, and thus the invention also relates to a product comprising (a) a compound of formula (I), And (b) one or more other antimicrobial agents, provided that one or more of the other antimicrobial agents are not antimycobacterial agents, as a combined preparation for simultaneous, separate or sequential use in the treatment of bacterial infections.

The pharmaceutical composition may further comprise a wide variety of other components known in the art, for example, lubricants, stabilizers, buffers, emulsifiers, viscosity modifiers, surfactants, preservatives, flavors and Colorant.

It is especially advantageous to formulate the above-mentioned pharmaceutical composition into a unit dosage form, which is convenient for administration and to obtain a uniform dosage form. The unit dosage form referred to in the text refers to a unit form which is physically separated and is suitable as a single dose. Each unit contains a predetermined amount of active ingredient, which is calculated and associated with the carrier to produce the desired therapeutic effect. Examples of such unit dosage forms are tablets (including drug core or film ingot), capsules. , pills, powder packs, flat suppositories, injectable solutions or suspensions, and the like, as well as divided multi-formulations thereof, the daily dose of the compound according to the invention, of course, depending on the compound used, the mode of administration, The desired treatment and the disease of the bacteria shown.

Other antibacterial agents which may be used in combination with the compounds of formula (I) of the present invention are known to the art, including antibiotics of beta-nadecylamine, for example, natural penicillins, semisynthetic penicillins, Natural cephalosporins, semi-synthetic cephalosporins, cephamycins, 1-oxacephems, clavulanic acids, penems ), carbapenems, nocardicins, monobactams; tetracyclines, anhydrotetracyclines, anthracyclines; Aminoglycosides; nucleosides, for example, N -nucleosides, C-nucleosides, carbocyclic nucleosides, blasticidin S; macrolacides, For example, a 12-membered ring is a lactone group, a 14-membered ring is a lactone group, a 16-membered ring is a lactone group; an ansamycins; an peptide, for example, Bleomycins, gramicidins, polymyxins, bacitracins, containing lactones Macrocyclic peptide antibiotics, actinomycins, amphomycin, capreomycin, distamycin, enduracidins, mikamycin , neocarzinostatin, stendomycin, viomycin, virginiamycin; cycloheximide; cycloserine; venom Variotin; sarkomycin A; novobiocin; griseofulvin; chloramphenicol; mitomycins; fumagillin Monensins; pyrrolnitrin; fosfomycin; fusidic acid; D-( p -hydroxyphenyl)glycine; D-phenylglycine; Eneidiynes (enediynes).

Definite antibiotics which can be used in combination with the compound of the formula (I) of the present invention are, for example, benzylpenicillin (potassium, pKain, Benzin), phenoxymethyl Penicillin (potassium), phenethicillin potassium, propicillin, carbenicillin (disodium, sodium phenyl, indanyl sodium), sulbenicillin ), ticarcillin disodium, methicillin sodium, oxacillin sodium, cloxacillin sodium, dicloxacillin, flucloxacillin, Ampicillin, mezlocillin, piperacillin sodium, amoxicillin, ciclacillin, hectacillin, sulbactam sodium, salampicillin Hydrochloride), bacampicillin hydrochloride, pivmecillinam, cephalexin, cefaclor, cephaloglycin, cefadroxil , cephradine, cefroxadine, cephapirin sodium, cephalothin sodiu m), cephacetrile sodium, cefsulodin sodium, cephaloridine II, cefazozine, cefoperazone sodium, cefmandole ), vefotiam hydrochloride, cefazolin sodium, ceftizoxime sodium, cefotaxime sodium, cefmenoxime hydrochloride, cefuroxime, ceftriax Ceftriaxone sodium, ceftazidime, cefoxitin, spimezecil sodium (cefmetazole), cefotetan, latamoxef, clavulanic acid, imipenem, aztreonam, tetracycline, chlortetracycline hydrochloride (chlortetracycline hydrochloride), chlortetracycline, oxytetracycline, methacycline, doxycycline, rolitetracycline, minocycline ), daunorubicin hydrochloride, doxorubicin, aclarubicin, kanamycin sulfate, bekanamycin, Tobramycin, gentamycin sulfate, dibekacin, amikacin, micronomicin, ribostamycin , neomycin sulfate, paromomycin sulfate, streptomycin sulfate, dihydrostreptomycin, destomycin A, hygromycin B B), ampoules (a Pramycin), sisomicin, netilmicin sulfate, spectinomycin hydrochloride, astromicin sulfate, validamycin, spring thunder Kasugamycin, polyoxin, blasticidin S, erythromycin, erythromycin estolate, oleandomycin phosphate, Treacetyloleandomycin, columnasamycin, josamycin, spiromycin (spiramycin), tylosin, ivermectin, midecamycin, bleomycin sulfate, peplomycin sulfate, gramicidin S (gramicidin S), polymyxin B, bacitracin, colistin sulfate, colistinmethanesulfonate sodium, enramycin ( Enramycin), mikamycin, virginiamycin, capreomycin sulfate, viomycin, enviomycin, vancomycin, release line Actinomycin D, neocarzinostatin, bestatin, pepstatin, monensin, lasalocid, salinomycin, both sexes Phytomycin B (amphotericin B), nystatin, natamycin, trichomycin, mithramycin, lincomycin, clindamycin (clindamycin), clindamycin palmitate hydroch Loride), containing flavomycin (flavophospholipol), cycloserine, pecilocin, griseofulvin, chloramphenicol, chloramphenicol palmitate, Mitomycin C, pyrrolnitrin, fosfomycin, fusidic acid, bicozamycin, tiamulin, dry worm Siccanin.

Tables 1 to 4 list the compounds of formula (I) according to the invention.

Absolute stereochemistry of the isomerized carbon atoms of some compounds The configuration was not experimentally determined, in which case the first isomer separated was labeled "A" and the second isolated isomer was labeled "B", not Further reference is made to the configuration of true stereochemistry, however, the "A" and "B" isoforms described can be unambiguously identified by experts in the art using known methods (eg, X-ray diffraction). .

If "A" and "B" are stereoisomeric mixtures, they can be separated again, with the first separated division being labeled "A1", "B1", and the second division. The separated persons are labeled as "A2" and "B2", respectively, without reference to the configuration of true stereochemistry, however, the "A1, A2" and "B1, B2" isomer types can be Experts in the art are unambiguously identified using known methods (e.g., X-ray diffraction).

When the compound is labeled "A" or "B" in this context, it means that the compound is a mixture of two mirrors, in which case the compound is labeled "A1", "A2", "B1" or "B2" "At the time, it means that the compound is a mirror image.

The relative configuration of the compounds of the invention indicated by erythro and threo was determined by auto-NMR, performed on Bruker Avance 400 MHz (samples were dissolved in CDCl3), and the chemical shifts of the largest protons in different stereoisomers were compared. Or by 2D NOESY;-LCMS, on an Applied Biosystems API100 Single quadrupole mass spectrometer, the sample was dissolved in a mixture of acetonitrile/methanol and injected in a Flow Injection Analysis mode using 40V. The declining potential is analyzed in the positive shower; the erythro/threo title is based on the [MH+] ion peak associated with the loss of methanol (generated from the source of the electric sprinkler) Crack), when an ion is produced, the spectrum of the threo compound is greater than that of the erythro compound.

The compounds of the invention are numbered to be identical to the compounds of WO 2004/011436 and can be prepared according to the method disclosed in WO 2004/011436, the "example number" in the table below corresponding to the example number of WO 2004/011436, according to This compound can be prepared by this procedure.

Additional compounds are indicated by letters.

Compounds A, B and C were prepared according to the method disclosed in WO 2004/011436, the following diagram shows the synthesis of compounds A, B and C, example numbers A8, A9, B12 and B13 correspond to the method of WO 2004/011436 .

The intermediate 1 therein was prepared in the same manner as the intermediate 12 of WO 2004/011436, i.e. according to the method of Example A8 of WO 2004/011436, but starting from 1,3-difluorobenzene, yield: 57% of intermediates 1.

Intermediate 2 is used as an intermediate with WO 2004/011436 14 was prepared in the same manner, i.e., according to the method of Example A9 of WO 2004/011436, but starting from Intermediate 1 and reacted with N-ethylbenzylamine, yield: 88% of Intermediate 2.

Compound C was prepared in the following manner: as in the case of Example B12 disclosed in WO 2004/011436, the intermediate 2 was reacted with the intermediate compound 3 of WO 2004/011436, and the residue obtained according to the procedure of B12 (5.4) g), which is a mixture of non-image isomers, which is purified by column chromatography on silica gel (solvent: CH ₂ Cl ₂ /cyclohexane: 60/40), two fractions are collected, and the solvent is removed by evaporation. The second fraction was crystallized from diisopropyl ether to obtain 0.83 g of Compound C (non-Spiegelmer B) (yield: 13%).

The preparation of the compounds A and B is as follows: The residue obtained in the synthesis of the compound C is reacted with 1-chloroethyl chloroformate in the same manner as in the example B13 disclosed in WO 2004/011436, according to an example. The residue obtained by the method of B13 (1.7 g), which is a non-image isomer, was purified by column chromatography on silica gel (solvent: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH; /2/0.1), two fractions were collected, the solvent was removed by evaporation, and the two fractions were separately crystallized from diisopropyl ether to obtain 0.31 g of Compound B (non-Spiegelmer A) (capacity: 27) %) with 0.52 g of Compound A (non-Spiegelmer B) (yield: 45%).

Compound D was prepared according to the method disclosed in WO 2004/011436, and the following is a synthetic method for preparing Compound D, and Example Nos. A9, B12 and B13 correspond to the procedure of WO 2004/011436.

Intermediate 3 was prepared using the same method as Intermediate 14 of WO 2004/011436, ie, according to the method of Example A9 of WO 2004/011436, but starting with 3-chloropropionetone, yield: 98% Intermediate 3.

The preparation of Compound J was carried out as follows: Intermediate 3 was reacted with Compound 3 in the middle of WO 2004/011436 by the same method as Example B12 disclosed in WO 2004/011436, and the obtained residue (4.9 g) was placed in silicone. It was purified by column chromatography (solvent: CH ₂ Cl ₂ ), and a fraction was collected, and the solvent was evaporated to yield: 1.43 g of Compound J as a mixture of non-mironomers.

Compound D was prepared as follows: Residue of Compound J was reacted with 1-chloroethylformate using the same procedure as Example B13 disclosed in WO 2004/011436, and the residue obtained according to the procedure of Example B13 (1.2 g) ), purified by column chromatography on silica gel (dissolved solution: CH ₂ Cl ₂ /CH ₃ OH/NH ₄ OH; 95/5/0.5), two fractions were collected, the solvent was removed by evaporation, and the second was divided into two. Crystallization from isopropyl ether gave 0.08 g of Compound D (non-image isomer B) (yield: 10%).

The preparation of compounds E and F was carried out by using the following procedure to isolate compound 4 (non-image isomer B) of WO 2004/011436 into its mirror image. The final compound 4 (2.5 g) of WO 2004/011436 was separated into its mirror image by column chromatography (solvent: hexane/ethanol 99.95/0.05; column: CHIRACEL OD), and two were collected. A pure fractionation was carried out by evaporation of the solvent, and 0.5 g of Compound E (mirror B1) (melting point 180 ° C) and 0.12 g of Compound F (mirror B2) (melting point 175 ° C) were obtained.

The preparation of the compound G is as follows: a mixture of the compound 115 of WO 2004/011436 (prepared according to B15 of WO 2004/011436) (0.00028 mol), a pyridine-3-boronic acid and a 1,3-propanediol cyclic ester (0.00055 mol) , Pd[P(Ph ₃ )] ₄ (0.00003 mol) and Na ₂ CO ₃ 2M (0.0011 mol), together in dimethoxyethane (4 ml), stirred at 90 ° C for 1.5 hours, then was poured into water and extracted with CH ₂ Cl _2, the organic layer was separated, dried (MgSO _4), filtered, and solvent was evaporated, the residue was purified by silica gel column chromatography _{(eluent: CH 2 Cl 2 / CH 3} OH 95/5; 5 μm), pure fractionation was collected, and the solvent was evaporated to yield: 0.09 g of Compound G (60%) (melting point 201 ° C).

The preparation of the compound H is as follows: a mixture of the compound 15 of WO 2004/011436 (prepared according to B7 of WO 2004/011436) (0.0009 mol), 2-furan boric acid (0.0018 mol), Pd[P(Ph ₃ )] ₄ (0.00009 mol) with Na ₂ CO ₃ 2M (0.0036 mol) in dimethoxyethane (10 ml), stirred at 90 ° C for 6 hours, then poured into water to CH ₂ Cl _extracted, the organic layer was separated, dried (MgSO _4), filtered, and solvent was removed by evaporation, the residue (0.57 g of) was purified by silica gel column chromatography _{(eluent: CH 2 Cl 2 / CH 3} OH / NH 4 OH 99 /1/0.1; 10 μm), the pure fraction was collected, and the solvent was evaporated to give 0.23 g of the residue, which was crystallized from diisopropyl ether / acetonitrile, and the precipitate was filtered and dried to give: H (15%) (melting point 215 ° C).

Compound I was prepared according to the method disclosed in WO 2004/011436, the following diagram illustrating the synthetic route of Compound I, and the example numbers A10 and B1 are related to the method of WO 2004/011436.

The commercially available 5-ethenyl-1,2-dihydroindole (0.0407 mol) was mixed with dimethylamine hydrochloride (0.0858 mol) in paraformaldehyde (37% aqueous solution, 4 ml). Add HCl / iPrOH (1 ml) and ethanol (100 ml), stir and reflux for 48 hours, remove the solvent by evaporation, the residue is placed in H ₂ O / HCl 3 N / CH ₂ Cl ₂ , and the aqueous layer is alkalized to extracted with CH ₂ Cl _2, the organic layer was separated, dried (MgSO _4), filtered, and solvent was evaporated, the residue was purified (eluent by column chromatography on _{silica: CH 2 Cl 2 / CH 3} OH / NH 4 OH 95/5/0.2; 15-40 μm), the pure fractions were collected, and the solvent was evaporated to yield: 4.9 g of Intermediate 4 (48%).

n- BuLi 1.6 M (0.0102 mol) was added dropwise to a solution of diisopropylamine (0.0091 mol) dissolved in tetrahydrofuran (15 ml) at -20 ° C under -20 ° C. After being stirred for 20 minutes, it was cooled to -70 ° C, and a solution of Intermediate Compound 3 (0.0091 mol) of WO 2004/011436 dissolved in tetrahydrofuran (10 ml) was added dropwise, and the mixture was stirred at -70 ° C for 2 hours. A solution of the intermediate 4 (0.01 mol) of the present invention dissolved in tetrahydrofuran (20 ml) was added dropwise, and the mixture was stirred at -70 ° C for 3 hours, poured into ice water, and extracted with EtOAc. dried (MgSO _4), filtered, and the solvent was removed, the residue (6.5 g) was purified by column chromatography (eluent placed evaporated on _{silica: CH 2 Cl 2 / CH 3} OH / NH 4 OH 99/1 / 0.2; 15-40 μ m), two fractions were obtained, and the solvent was removed by evaporation. The yield was 0.96 g of F1, 0.72 g of F2, and the crystal was precipitated from diethyl ether. The precipitate was filtered off and dried to give: 0.87 g of compound. I (17%).

Method of analysis

The mass of some of the compounds was recorded by LCMS (liquid chromatography mass spectrometry), the methods used are described below, and the data are listed in Table 5 below.

LCMS-method

LCMS analysis was performed on a Kromasil C18 column (Interchim, Montlucon, FR; 5 μm, 4.6 x 150 mm) and analyzed at a flow rate of 1 ml/min (electrospray ionization in positive mode, scan mode from 100 to 900) Amu), using two mobile phases (mobile phase A: 30% 6.5 mM ammonium acetate + 40% acetonitrile + 30% formic acid (2 ml / liter); mobile phase B: 100% acetonitrile) for gradient elution, conditions For: 100% A for 1 minute to 100% B for 4 minutes, 100% B for 5 minutes to 100% A for 3 minutes, and 100% A for 2 minutes for re-leveling.

Pharmacological example Prepare a suspension of bacteria for sensitivity testing:

The bacteria used in this study were grown overnight in a bottle containing 100 ml of Mueller-Hinton Broth (Becton Dickinson-cat. no. 275730) dissolved in sterile deionized water and shaken at 37 ° C. The stock solution (0.5 ml/tube) was stored at -70 °C for use, and the calibration of the bacteria was performed by detecting the TCID ₅₀ in a microtiter plate, where TCID ₅₀ represents _50% of the culture that can increase bacterial growth to the inoculation. % dilution.

Typically, an inoculum size of about 100 TCID ₅₀ is used for the sensitivity test.

Antimicrobial sensitivity test: IC ₉₀ determination Microtitre plate assay

A flat, sterile 96-well plastic microtiter plate filled with 180 μl of sterile deionized water, supplemented with 0.25% BSA, followed by a 45 μl volume of compound stock solution (7.8 x final test concentration) ) To the second column, a series of 5-fold dilutions (45 μl in 180 μl) were prepared directly from column 2 of the microtiter plate to column 11, with untreated control samples (column 1) With the inoculum (column 12), it is included in the microtiter plate. Depending on the type of bacteria, each tank is inoculated with about 10 to 60 CPU bacterial inoculum (100 TCID50, volume 100 μl, at 2.8). In the Mueller-Hinton broth medium of x, add to the columns A to H except the 12th column, add the broth medium of the same volume but without inoculum to columns A to H of column 12, culture at 37 ° C It is cultured for 24 hours under standard air pressure (the incubator has an open air valve and continuous ventilation). After the completion of the culture, the growth of the bacteria is quantified by fluorescence analysis one day after the inoculation, and thus the resazurin ( Resazurin) (0.6 mg/ml) in a volume of 20 μl, added to all 3 hours after inoculation In the trough, the plate was incubated overnight, and the color changed from blue to pink, indicating the growth of bacteria. In a computer-controlled fluorometer (Cytofluor Biosearch), the 530 nm laser wavelength and 590 nm luminescence Fluorescence at wavelengths, the percentage of growth inhibition affected by the compound, calculated according to standard methods, IC ₉₀ (in micrograms per milliliter) is the concentration that inhibits bacterial growth by 90%. The results are shown in Table 6. .

Agar dilution method

The MIC ₉₉ value (the lowest concentration at which 99% inhibits bacterial growth) can be determined according to the NCCLS Standard Method ^* , which is a standard method for the dilution of acacia, which uses Mueller-Hinton.

^* Clinical laboratory standard institute. 2005. Methods for dilution Antimicrobial susceptibility tests for bacteria that grows Aerobically:approved standard -sixth edition

Time kill assays

The bactericidal or bacteriostatic activity of the compound can be determined using a broth microdilution method ^* , measured in a time killing assay, for S. aureus resistant to Staphylococcus aureus and methicillin (methicillin) ( In the time killing analysis of MRSA), the starting inoculum of S.aurues and MRSA was 10 ⁶ CFU/ml, and the concentration of the antibacterial compound used in Muller Hinton broth was 0.1 to 10 times the MIC (ie, in microtiter) The IC ₉₀ tested in the plate), the tank without the antibacterial agent was used as the control group for the growth of the culture, and the plate containing the microorganism and the test compound was cultured at 37 ° C, and after the culture, the culture was carried out at 0, 4, 24, and 48 hours. Samples were removed and serially diluted (10 ^-1 to 10 ^-6 ) in sterile PBS and (200 μl) and placed on Mueller Hinton amaranth. The number of survivors was counted and the plates were incubated at 37 °C. After 24 hours, count the number of colonies produced, plot the relative time of log ₁₀ CFU per ml, and make a killing curve. The effect of sterilization is usually defined as a 3-log ₁₀ reduction in CFU/ml (compared to no For the inoculated control group), It was slow turn potential contamination (carryover) impact, under the Department of the colonies by the highest dilution to lay a series of dilutions and counting the erasing.

^* Zurenko.GE et al. In vitro activilies of U-100592 and U-100766. novel oxazolidinoni; antibacteial agents. Antimicrob. Agents Chemother. 40 , 839-845 (1996).

Determination of intracellular ATP values

To analyze changes in ATP concentration in total cells (using the ATP bioluminescence kit, Roche), the analysis was performed as follows: S. aureus (ATCC29213) stock was grown in 100 ml Mueller Hinton flask and placed in a shaking incubator Incubate at 37 ° C for 24 hours (300 rpm), measure OD ₄₀₅ nm and calculate CFU / ml, and dilute the culture to 1 x 10 ⁶ CFU / ml (final concentration for ATP measurement: 1 x 10 ⁵ CFU / 100 μl/well) and the test compound was added, 0.1 to 10 times the MIC (ie IC ₉₀ measured in the microtiter plate analysis), and the tubes were incubated at 300 rpm and 37 ° C for 0, 30 and 60 minutes. Take 0.6 ml of the bacterial suspension from the snap-cap tube, add to the new 2 ml eppendorf tube, add 0.6 ml of cell lysing agent (Roche kit), vortex at maximum speed, in the chamber Incubate for 5 minutes at room temperature, cool on ice, warm the luminometer to 30 °C (Luminoskan Ascent Labsystems with injector), fill a column (=6 tank) with 100 μl of the same sample, to the syringe system Add 100 μl of luciferin reagent to each tank and measure the cold By 1 second.

BSU 43639 refers to Bacillus subtilis (ATCC43639); ECO 25922 refers to Escherichia coli (ATCC25922); EFA 14506 refers to Enterococcus faecalis (ATCC14506); EFA 29212 refers to Enterococcus faecalis (ATCC29212); LMO 49594 refers to Listeria monocytogenes (ATCC49594); PAE 27853 refers to Pseudomonas aeruginosa (ATCC27853); SMU 33402 refers to Streptococcus mutans (ATCC33402); SPN 6305 refers to Streptococcus pneumoniae (ATCC6305); SPY 8668 refers to Streptococcus mutans (ATCC8668); STA 43300 refers to Staphylococcus aureus (ATCC43300); STA 25923 Is Staphylococcus aureus (ATCC25923); STA 29213 refers to Staphylococcus aureus (ATCC29213); STA RMETH refers to methicillin-resistant Staphylococcus aureus (MRSA) (a kind from University The clinical isolate of the Antwerp, ATCC refers to the American type tissue culture.

Claims (39)

A use of a compound for the manufacture of a medicament for the treatment of a bacterial infection caused by staphylococci, enterococci or streptococci, which is a compound of the formula a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof, wherein R ¹ is hydrogen, halo, polyhalogenated C _1-6 alkyl, C _1-6 alkane a group, a hydroxy C _1-6 alkyl group, a C _1-6 alkyl oxygen, Ar or Het; p is an integer equal to 1 or 2; R ² is a C _1-6 alkyl oxygen, a C _1-6 alkyl oxygen C _1-6 alkyloxy or C _1-6 alkylthio; R ³ is C _1-6 alkyl, Ar, Het or Het ¹ ; R ⁴ and R ⁵ are each independently hydrogen, C _1-6 alkyl or benzene a methyl group; or R ⁴ and R ^{5 together} with the N atom to which they are attached form a group selected from the group consisting of pyrrolidinyl, 2-pyrroline, 3-pyrroline, pyrrolyl, imidazolidinyl, pyrazole Pyridyl, 2-imidazolinyl, 2-pyrazolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridyl, piperidine Base Base, pyrimidinyl, pyridyl Base, three a morpholino group and a thiomorpholinyl group, which may optionally have a C _1-6 alkyl group, a halogen group, a polyhalogen C _1-6 alkyl group, a hydroxyl group, a hydroxy C _1-6 alkyl group, or a C _1-6 group. Alkyloxy, amine, mono- or di-(C _1-6 alkyl)amine, C _1-6 alkyl sulfide, C _1-6 alkyloxy C _1-6 alkyl, C _1-6 alkane Substituted with a C _1-6 alkyl or pyrimidinyl group; R ⁶ is hydrogen, halo, polyhalogenated C _1-6 alkyl, C _1-6 alkyl, C _1-6 alkyloxy, C ₆ alkyl sulphide Or two adjacent R ⁶ groups may together form a divalent group of the formula -CH=CH-CH=CH-; r is an integer equal to 1 or 2, R ⁷ is hydrogen, C _1-6 alkyl, Ar , Het or Het ¹ ; Ar is a carbocyclic ring selected from the group consisting of phenyl, naphthyl, anthracenyl, 1,2-dihydro-indenyl, tetrahydronaphthyl, each carbocyclic ring may be 1, 2 or 3 as needed Substituted by a substituent, each substituent is independently selected from the group consisting of hydroxyl, halo, cyano, nitro, amine, mono- or di-(C _1-6 alkyl)amine, C _1-6 Alkyl, polyhalogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkyloxy, polyhalogenated C _1-6 alkyloxy, C _1-6 alkyloxy C _1-6 alkane , carboxy, C _1-6 alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono - or di - (C _1-6 alkyl) aminocarbonyl ; Het is a monocyclic heterocycle selected from the following: N- phenoxy-piperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, Azolyl, different Azyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridyl Base and 嗒 Each monocyclic heterocyclic ring may be substituted with 1, 2 or 3 substituents, each of which is independently selected from the group consisting of halo, hydroxy, C _1-6 alkyl, polyhalogen C _1-6 Alkyl, hydroxy C _1-6 alkyl, C _1-6 alkyloxy, C _1-6 alkyloxy C _1-6 alkyl or Ar-C(=O)-; Het ¹ is selected from the following Cyclic heterocycle: quinolinyl, quin Polinyl, fluorenyl, benzimidazolyl, benzo Azolyl, benzopyrene Azolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo[1,4] Octyl or benzo[1,3] Each of the bicyclic heterocyclic rings may be substituted with 1, 2 or 3 substituents, each of which is independently selected from the group consisting of halo, hydroxy, C _1-6 alkyl, polyhalogen C _1-6 An alkyl group, a hydroxy C _1-6 alkyl group, a C _1-6 alkyloxy group, a C _1-6 alkyloxy C _1-6 alkyl group or Ar-C(=O)-; and the limitation is that the compound is not Is (αS,βR)-6-bromo-(-[2-(dimethylamino)ethyl]-2-methoxy-(-1-naphthyl-(-phenyl-3-quinolineethanol) a pharmaceutically acceptable acid or base addition salt or an N-oxide type thereof. The use according to the first aspect of the patent application, wherein R ¹ is hydrogen, a halogen group, a polyhalogen C _1-6 alkyl group, a C _1-6 alkyl group, Ar or Het; and R ³ is Ar, Het or Het ¹ , Ar It is a carbocyclic ring selected from the group consisting of phenyl, naphthyl, anthryl and tetrahydronaphthyl. Each carbocyclic ring may be substituted with 1, 2 or 3 substituents, each of which is independently selected from the group consisting of: Hydroxy, halo, cyano, nitro, amine, mono- or di-(C _1-6 alkyl)amine, C _1-6 alkyl, polyhalo C _1-6 alkyl, hydroxy C _{1- 6} alkyl, C _1-6 alkyl oxygen, polyhalogen C _1-6 alkyl oxygen, C _1-6 alkyl oxygen C _1-6 alkyl, carboxyl, C _1-6 alkyloxycarbonyl, aminocarbonyl , morpholinyl and mono- or di(C _1-6 alkyl)aminocarbonyl. According to the use of the first or second aspect of the patent application, wherein the compound of the formula (I) is a compound of the formula A pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof. The use of the compound of the formula (I) or (Ia) according to the above formula, wherein the compound of the formula (I) or (Ia) is a compound of the formula A pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof. The use according to claim 1 or 2, wherein R ¹ is hydrogen; C _1-6 alkyl; halo; hydroxy C _1-6 alkyl; C _1-6 alkyl oxygen; Base; or Het. The use according to item 5 of the scope of the patent application, wherein R ¹ is hydrogen, a halogen group, a phenyl group or Het which may be optionally substituted. The use according to item 6 of the patent application, wherein R ¹ is hydrogen, a halogen group or a phenyl group which may optionally be substituted. The use according to item 7 of the patent application, wherein R ¹ is a halogen group. The use according to claim 1 or 2, wherein R ² is C _1-6 alkyl oxygen or C _1-6 alkyl sulfur. The use according to the first aspect of the patent application, wherein R ³ is C _1-6 alkyl, Ar or Het. The use according to claim 10, wherein R ³ is Ar or Het. The use according to the first aspect of the patent application, wherein R ³ is Ar or Het1. Use according to the scope of claim 10, 11 or 12, wherein R ³ is Ar. The use according to claim 13 wherein R ³ is a phenyl group which may optionally be substituted or a naphthyl group which may be substituted. The use according to claim 1 or 2, wherein R ⁴ and R ⁵ are each independently hydrogen, C _1-6 alkyl or benzyl. The use according to claim 15 wherein R ⁴ and R ⁵ are each independently hydrogen or C _1-6 alkyl. The use according to claim 1 or 2, wherein R ⁴ and R ^{5 together} with the N to which they are attached form a group selected from the group consisting of pyrrolidinyl, 2-pyrroline, 3-pyrroline, pyrrole , imidazolidinyl, pyrazolyl, 2-imidazolinyl, 2-pyrazolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridyl, piperidine Base Base, pyrimidinyl, pyridyl Base, three a morpholino group and a thiomorpholinyl group, which may optionally have a C _1-6 alkyl group, a halogen group, a polyhalogen C _1-6 alkyl group, a hydroxyl group, a hydroxy C _1-6 alkyl group, or a C _1-6 group. Alkyloxy, amine, mono- or di-(C _1-6 alkyl)amine, C _1-6 alkyl sulfide, C _1-6 alkyloxy C _1-6 alkyl, C _1-6 alkane Substituted with a C _1-6 alkyl or pyrimidinyl group. The use according to claim 17, wherein R ⁴ and R ^{5 together} with the N to which they are attached form a group selected from the group consisting of pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and piperidin. Pyridyl, pyridyl, piperidine Base Base, pyrimidinyl, pyridyl Base, three a morpholino group and a thiomorpholinyl group, which may optionally have a C _1-6 alkyl group, a halogen group, a polyhalogen C _1-6 alkyl group, a hydroxyl group, a hydroxy C _1-6 alkyl group, or a C _1-6 group. Alkyloxy, amine, mono- or di-(C _1-6 alkyl)amine, C _1-6 alkyl sulfide, C _1-6 alkyloxy C _1-6 alkyl, C _1-6 alkane Substituted with a C _1-6 alkyl or pyrimidinyl group. The use according to the first aspect of the patent application, wherein R ⁶ is hydrogen, a halogen group, a polyhalogen C _1-6 alkyl group, or a C _1-6 alkyl group; or two adjacent R ⁶ groups may together form the following formula The divalent group -CH=CH-CH=CH-. According to the use of the first aspect of the patent application, wherein R ⁶ is hydrogen, halo, C _1-6 alkyl, C _1-6 alkyloxy, or two adjacent R ⁶ groups may together form the following formula The group -CH=CH-CH=CH-. Use according to claim 19 or 20, wherein R ⁶ is hydrogen or a halogen group. Use according to claim 1 or 2 wherein R ⁷ is hydrogen. The use according to claim 1 or 2, wherein r is an integer equal to one. The use according to claim 1 or 2, wherein p is an integer equal to one. According to the use of the third item of the patent application, but the limitation is that when one of R ¹ is a C _1-6 alkyl group, the other R ¹ substituent is selected from the group consisting of: a halogen group, a polyhalogenated C _1-6 alkane Base, C _1-6 alkyl, Ar or Het. The use according to claim 1 or 2, wherein the bacterial infection is a Gram-positive bacterial infection. Use according to the scope of claim 1 wherein R ¹ is hydrogen; C _1-6 alkyl; halo; hydroxy C _1-6 alkyl; C _1-6 alkyl oxygen; phenyl; _{a 1-6} alkyl-substituted furyl group; or a pyridyl group; R ² is a C _1-6 alkyl group; a C _1-6 alkyl group; or a C _1-6 alkyl group C _1-6 alkyl group; ³ is a phenyl group which may be optionally substituted with 1 or 2 halo groups; a naphthyl group which may be substituted with 1 or 2 halo groups or a C _1-6 alkyl group as desired; a thienyl group; substituted by Ar-C(=O) Piperidinyl; 2,3-dihydrobenzo[1,4] Octyl; benzo[1,3] Methoxy; fluorenyl; furyl; or C _1-6 alkyl; R ⁴ and R ⁵ are each independently hydrogen; C _1-6 alkyl; benzyl; or R ⁴ and R ⁵ are attached to the attached N Forming a group selected from the group consisting of imidazolyl; pyridyl substituted by C _1-6 alkyl a group substituted with a C _1-6 alkyl group a group substituted with a pyrimidinyl group Piperidinyl; piperidinyl substituted by dimethylamino; thiomorpholinyl; morpholinyl; pyrrolidinyl; or triazolyl; R ⁶ is hydrogen; halo; C _1-6 alkyl The C _1-6 alkyl oxygen or two adjacent R ⁶ groups may together form a divalent group of the formula -CH=CH-CH=CH-; R ⁷ is hydrogen. According to the use of the first aspect of the patent application, the limitation is that when R ³ is Ar, Het or Het ¹ , then R ¹ is a hydroxy C _1-6 alkyl group or a C _1-6 alkyl oxygen. Use according to the scope of claim 28, wherein R ¹ is halo, hydroxy C _1-6 alkyl or C _1-6 alkyl oxygen; R ² is C _1-6 alkyl oxygen; R ³ is C _{1- 6} alkyl, phenyl or naphthyl; R ⁴ and R ⁵ are C _1-6 alkyl; R ⁶ is hydrogen; R ⁷ is hydrogen; p is 1; r is 1. The use according to the first aspect of the patent application, wherein the compound of the formula (I) is selected from the following compounds a pharmaceutically acceptable acid or base addition salt or an N-oxide thereof, and wherein: (A) or (B) indicates that the compound is a mixture of two mirror image isomers and (A) is isolated first (B) the second; (A1), (A2), (B1) and (B2) indicate that the compound is a mirror image isomer; (A1) and (A2) represent the first and second from (A), respectively. And (B1) and (B2) represent the first and second parts of (B). A composition comprising (a) a compound of formula (I) as defined in any one of claims 1 to 30, and (b) one or more other antibacterial agents, wherein the composition is for use in therapy Bacterial infection caused by staphylococcus, enterococci or streptococci. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a medically effective amount as an active ingredient (a) a compound of formula (I) as defined in any one of claims 1 to 30 of the patent application, b) one or more other antibacterial agents, wherein the composition is for treating a bacterial infection caused by Staphylococcus, Enterococcus or Streptococcus. a compound as defined in claims 1 to 30 for use in the treatment of staphylococci, enterococci or chains Bacterial infection caused by cocci. A product comprising (a) a compound of formula (I) as defined in any one of claims 1 to 30, and (b) one or more other antibacterial agents, but the limitation is the one or A variety of antibacterial agents are not antimycobacterial agents, which are combined preparations for simultaneous, separate or sequential use in the treatment of bacterial infections caused by staphylococci, enterococci or streptococci. A compound of formula (I), wherein the compound is selected from the group consisting of: a pharmaceutically acceptable acid or base addition salt or an N-oxide thereof, and wherein: (A) or (B) indicates that the compound is a mixture of two mirror image isomers and (A) is isolated first (B) the second; (A1), (A2), (B1) and (B2) indicate that the compound is a mirror image isomer; (A1) and (A2) represent the first and second from (A), respectively. And (B1) and (B2) represent the first and second parts of (B). The use according to claim 1 or 2, wherein the bacterial infection is Staphylococcus, Enterococcus or Streptococcus infection. According to the use of claim 1 or 2, the bacterial infection is methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative staphylococci (MRCNS), anti-penicillin pneumococci or multiple resistance Enterococcus faecium infection. According to the application of the scope of claim 37, the bacterial infection is Staphylococcus aureus or Streptococcus pneumoniae infection. According to the use of claim 38, the bacterial infection is an infection with methicillin-resistant Staphylococcus aureus (MRSA).