RU2397986C2 - Antibiotics containing borinic acid complexes and methods of obtaining them - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are structure and manufacturing of antibiotics which include borinic acid complexes, in particular derivatives of hydroxyquinoline, imidazole and picolinic acid, together with compositions of said antibiotics and methods of application of antibiotics and compositions as bactericidal and fungicidal preparations as well as therapeutic medications for treatment of diseases caused by bacteria and fungi.

EFFECT: obtaining antibiotics which include borinic acid complexes.

51 cl, 1 ex, 4 tbl

Description

This application claims priority to provisional application US Serial No. 60/434375, filed December 18, 2002, Serial No. 60/436095, filed December 23, 2002, and Serial No. 60/437849, filed January 3, 2003, the essence of which is fully included in this work in as links.

Technical field

This invention relates to the field of antibiotics, in particular to the field of antibacterial and antifungal compounds and their use. Also provided are methods for the preparation and use of these antibiotics and pharmaceutical compositions based on them.

State of the art

One of the hallmarks of the current stage of development of medicine is the reduction in morbidity and mortality associated with bacterial and fungal infections. However, the misuse of antibiotics and the natural selection of infectious bacterial populations have led to the development of different levels of drug resistance in most infectious bacterial agents to most antibiotics. For some cases, such as MRSA (Staphylococcus A Resistance to Various Medicines / Multidrug-Resistant StaphA), there is currently one or only a few effective antibiotics. In addition, the existence of immunodeficiency syndromes leads to the additional occurrence of opportunistic infections, the treatment of which requires intensive use of antibiotics.

Thus, in the field of medicine there is an urgent need for new, more effective antibiotics, especially for the treatment of bacterial infections that are resistant to the use of modern available therapeutic agents.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to compounds having antibiotic activity. The compounds of this invention having antibiotic activity are borinate derivatives, in particular borinic acid complexes, and include compounds such as derivatives of hydroxyquinolines, picolinic acids and imidazoles.

Compounds having antibiotic activity are also presented in the form of pharmaceutical compositions that can be administered to an animal, particularly preferably a human, for treating a disease with a bacterial or fungal etiology or opportunistic infections associated with bacteria or fungi in an animal, particularly preferably in a human , with impaired immunity or a weakened state of health.

In preferred embodiments, the compounds of this invention are compounds whose structure is consistent with Formulas 1 or 2 with the preferred substituents disclosed herein.

The invention also relates to methods for producing compounds having antibiotic activity, to the preparation of pharmaceutical compositions based on them, and to methods for using the indicated antibiotics for therapeutic purposes. Embodiments related to kits and packaging of antibiotics and pharmaceutical compositions of the present invention are also contemplated.

The invention also relates to methods for treating infections, preferably bacterial and / or fungal infections, using compounds having antibiotic activity as disclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to antibiotics, in particular to antibacterial and antifungal compounds useful for the treatment and / or prevention of bacterial infections.

The invention relates to a compound whose structure corresponds to the formula

where B is boron, O is oxygen,

m is 0, 1 or 2,

where R ^∗ and R ^{∗∗ are} each independently selected from substituted or unsubstituted alkyl (C ₁ -C ₄ ), substituted or unsubstituted cycloalkyl (C ₃ -C ₆ ), substituted or unsubstituted vinyl, substituted or unsubstituted alkynyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenyl and substituted or unsubstituted heterocycle,

and where z is 0 or 1, and when z is 1, A represents CH, CR ¹⁰ or N,

and where D represents N, CH or CR ¹² ,

and where E represents H, OH, alkoxy or N- (morpholinyl) ethoxy,

and where r is 1 or 2, and if r is 1, then G represents = O (oxygen with a double bond), and if r is 2, then each G independently represents H, methyl, ethyl or propyl,

where R ^{12 is} selected from (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO ₂ alkyl, SO ₃ H, SC ₃ , CN, halogen, CF ₃ , NO ₂ , NH ₂ , 2 ∗ amino, 3 ∗ - amino, NH ₂ SO ₂ and CONH ₂ ,

and where J represents CR ¹⁰ or N,

and where R ⁹ , R ¹⁰ and R ^{11 are} each independently selected from the group consisting of hydrogen, alkyl, (CH ₂ ) _n OH (n = 1-3), CH ₂ NH ₂ , CH ₂ NH alkyl, CH ₂ N ( alkyl) ₂ , halogen, CHO, CH = NOH, CO ₂ H, CO ₂ -alkyl, S-alkyl, SO ₂ -alkyl, S-aryl, NH ₂ , alkoxy, CF ₃ , СCF ₃ , NO ₂ , СО ₃ H and OH,

including its salts, especially all pharmaceutically acceptable salts.

In a preferred embodiment, in formula 1 or 2, one of R ∗ and R ∗∗ is substituted or unsubstituted alkyl (C ₁ -C ₄ ) or each R ∗ and R ∗∗ is substituted or unsubstituted alkyl (C ₁ -C ₄ )

In a preferred embodiment, in formula 1 or 2, one of R ∗ and R ∗∗ is substituted or unsubstituted cycloalkyl (C ₃ -C ₆ ) or each R ∗ and R ∗∗ is substituted or unsubstituted cycloalkyl (C ₃ -C ₆ )

In a preferred embodiment, in formula 1 or 2, one of R ∗ and R ∗∗ is substituted or unsubstituted vinyl, or each R ∗ and R ∗∗ is substituted or unsubstituted vinyl. In a further preferred embodiment, vinyl corresponds to the formula

in which R ¹ , R ² and R ^{3 are} each independently selected from the group consisting of hydrogen, alkyl, aryl, substituted aryl, benzyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , S-alkyl, S-aryl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen CF ₃ and NO ₂ .

In a preferred embodiment, in formula 1 or 2, one of R ∗ and R ∗∗ is substituted or unsubstituted alkynyl, or each R ∗ and R ∗∗ is substituted or unsubstituted alkynyl. In a further preferred embodiment, alkynyl corresponds to the formula

in which R ^{1 is} selected from the group consisting of hydrogen, alkyl, aryl, substituted aryl, benzyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , S-alkyl, S-aryl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ and NO ₂ .

In a preferred embodiment, in formula 1 or 2, one of R ∗ and R ∗∗ is substituted or unsubstituted phenyl, or each R ∗ and R ∗∗ is substituted or unsubstituted phenyl. In a further preferred embodiment, phenyl corresponds to the formula

in which R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are} each independently selected from the group consisting of hydrogen, alkyl, aryl, substituted aryl, benzyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3) CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , CONH-alkyl, CON (alkyl) ₂ , OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° amino, 3 ° amino, NH ₂ SO ₂ , OCH ₂ CH ₂ NH ₂ , OCH ₂ CH ₂ NH-alkyl, OCH ₂ CH ₂ N (alkyl) ₂ , oxazolidin-2-yl or alkyl substituted oxazolidin-2-yl.

In a preferred embodiment, in formula 1 or 2, one of R ∗ and R ∗∗ is substituted or unsubstituted benzyl, or each R ∗ and R ∗∗ is substituted or unsubstituted benzyl. In a further preferred embodiment, benzyl corresponds to the formula

in which R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are} each independently selected from the group consisting of alkyl, aryl, substituted aryl, benzyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3 ), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , CONH-alkyl, CON (alkyl) ₂ , OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° amino, 3 ° amino, NH ₂ SO ₂ , OCH ₂ CH ₂ NH ₂ , OCH ₂ CH ₂ NH-alkyl, OCH ₂ CH ₂ N (alkyl) ₂ , oxazolmdin-2-yl or alkyl substituted oxazolidin-2-yl.

In a preferred embodiment, in formula 1 or 2, one of R ∗ and R ∗∗ is a substituted or unsubstituted heterocycle, or each R ∗ and R ∗∗ is a substituted or unsubstituted heterocycle. In a further preferred embodiment, the heterocycle corresponds to the formula

where X = CH = CH, N = CH, NR ¹³ (where R ¹³ = H, alkyl, aryl or benzyl), O or S,

and where Y = CH or N,

and where R ¹ and R ^{2 are} each independently selected from the group consisting of hydrogen, alkyl, aryl, substituted aryl, benzyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , 3-alkyl, S-aryl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ and NO ₂ .

The structure of the compounds of this invention also allows interaction with a solvent, which leads to the formation of structures (formulas 1B and 2B) with the inclusion of atoms from the solvent, which is captured by the compound during synthesis or therapeutic use. Thus, such solvent structures can, in particular, integrate into the compounds of the invention between boron and nitrogen atoms, thereby increasing the size of the cycle by one or two atoms in comparison with what is disclosed in the structures of this invention. In the case where the boron-containing cyclic structure of the present invention contains 5 atoms, including, for example, boron, nitrogen, oxygen and 2 carbon atoms, the incorporation of a solvent atom between boron and nitrogen should lead to the formation of a 7-membered ring. For example, the use of hydroxyl- and amine-containing solvents can lead to the formation of structures containing oxygen or nitrogen between boron and nitrogen atoms in the cycle with an increase in its size. Similar structures are specifically contemplated in the present invention, where R ∗∗∗ is H or alkyl.

The terms used in this invention have the following meanings.

The terms “alkyl”, “lower alkyl” and “C ₁ -C ₆ alkyl” in the present invention denote straight or branched chain alkyl groups containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl , sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl.

The terms “alkoxy”, “lower alkoxy” and “C ₁ -C ₆ alkoxy” in the present invention denote straight or branched chain alkoxy groups containing 1 to 6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy , n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy and 3-methylpentoxy.

The term "halogen" in the present invention means fluorine, bromine, chlorine and iodine.

The term "cycloalkyl", for example C ₃ -C ₇ cycloalkyl, in the present invention denotes cycloalkyl groups containing 3-7 atoms, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. In C ₃ -C ₇ cycloalkyl groups, preferably in C ₅ -C ₇ cycloalkyl groups, one or two carbon atoms forming a ring may optionally be substituted with a heteroatom such as sulfur, oxygen or nitrogen. Examples of such groups are piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, perhydroazepinyl, perhydrooxazapinyl, oxepanyl and perhydrooxepanyl. C ₃ and C ₄ cycloalkyl groups with a carbon atom substituted with nitrogen or oxygen include aziridinyl, azetidinyl, oxetanyl and oxiranyl.

The term “aryl” means an aromatic carbocyclic group containing one ring (eg, phenyl), several rings (eg, biphenyl), or polycondensed rings in which at least one ring is aromatic (eg, 1,2,3,4 -tetrahydronaphthyl, naphthyl, antryl or phenanthryl), and which is optionally mono-, di- or trisubstituted, for example, halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl and hydroxy. Preferred aryl groups include phenyl and naphthyl, each of which is optionally substituted as described above.

The term “heteroaryl” means one or more aromatic ring systems consisting of 5-, 6-, or 7-membered rings containing at least one to four heteroatoms selected from nitrogen, oxygen, or sulfur. Such heteroaryl groups include, for example, thienyl, furanyl, thiazolyl, imidazolyl, (from) oxazolyl, pyridyl, pyrimidinyl, (iso) quinolinyl, naphthyridinyl, benzimidazolyl and benzoxazolyl. Preferred heteroaryls are thiazolyl, pyrimidinyl, preferably pyrimidin-2-yl, and pyridyl. Other preferred heteroaryl groups include 1-imidazolyl, 2-thienyl, 1- or 2-quinolinyl, 1- or 2-isoquinolinyl, 1- or 2-tetrahydroisoquinolinyl, 2- or 3-furanyl and 2-tetrahydrofuranyl.

The term "ligand" denotes a nitrogen-containing aromatic system that is capable of forming an inverse donor-acceptor bond with the Lewis acid center of boron and is attached as a fragment of boronate ester. Such ligands are known to those skilled in the art. Examples of their structures are given below.

The compounds of the present invention are involved in the inhibition of key microbial enzymes, such as bacterial DNA methyltransferase (DNA). Many of the compounds disclosed herein are selective microbe methyltransferase inhibitors but do not inhibit mammalian methyltransferases. However, the antibacterial and antifungal activity of the compounds of the invention is not limited to activities related to the inhibition of the specified enzyme, which is not the final effect, essential for the specified therapeutic activity.

This invention also relates to embodiments of the compounds disclosed herein in the form of pharmaceutical compositions. The pharmaceutical compositions of the present invention can be prepared by well-known methods, for example by conventional mixing, dissolving, granulating, drazhirovany, grinding powder, emulsification, encapsulation, inclusion or lyophilization.

Pharmaceutical compositions for use in accordance with the present invention can be prepared in the usual way using one or more physiologically acceptable carriers, including excipients and auxiliary additives, which facilitate the conversion of the active compounds into preparations intended for pharmaceutical use. The appropriate preparation depends on the chosen route of administration.

Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, hydroxyethanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC- (CH ₂ ) _{n is} CH ₃ , where n is 0-4, and the like. Non-toxic pharmaceutical base addition salts include salts of bases such as sodium, potassium, calcium, ammonium and functional equivalents. A variety of non-toxic pharmaceutically acceptable addition salts will be apparent to those skilled in the art.

For injection, the compounds of this invention can be prepared in the form of appropriate aqueous solutions, such as physiologically compatible buffers, for example, Hanks' solution, Ringer's solution or physiological saline buffer. For transmucosal and transdermal administration, appropriate wetting agents are used in the preparation to overcome the necessary barrier. Such substances are well known in the art.

For oral administration, the compositions can be easily prepared by combining the active compounds with pharmaceutically acceptable excipients well known in the art. With such carriers, compositions of the compounds of the invention can be prepared in the form of tablets, pills, capsules, liquids, gels, syrups, suspensions, suspensions, and the like. for oral administration to a patient in need of treatment. Pharmaceutical preparations for oral administration can be prepared with a solid excipient, optionally grinding the resulting mixture, processing the mixture into granules after adding additional suitable auxiliary components, if desired, to obtain tablets. Suitable excipients are, in particular, excipients such as sugars, including lactose, sucrose, mannitol or sorbitol; fiber preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and / or polyvinylpyrrolidone (PVP). If desired, dispersants, such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate, may be added.

Pharmaceutical preparations that can be administered orally include push-fit capsules made from gelatin, as well as soft fused capsules made from gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules may contain the active ingredients in admixture with an excipient, such as lactose, binders, such as starches, and / or lubricants, such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as non-volatile liquid oils, liquid paraffin or liquid polyethylene glycols. In addition, stabilizers can be added. All preparations for oral administration should have a dosage suitable for such administration. For buccal administration, the preparations may be in the form of tablets or lozenges formulated in the usual manner.

For administration by inhalation, the compositions of the compounds for use in accordance with the present invention are typically supplied by aerosol delivery from pressurized packages or from a nebulizer using a suitable nebulizing aerosol substance, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, a standard dose can be determined if there is a valve for a metered amount. For use in an inhaler, capsules and cartridges of, for example, gelatin, containing a powder mixture of a compound and a suitable powder base, such as lactose or starch, can be prepared.

Compositions of the compounds can be prepared for parenteral administration by injection, for example, bolus injection or continuous infusion. Injectable preparations can be made in unit dosage form, for example, in ampoules or in multi-dose containers, with the addition of a preservative. Such compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous fillers, and may contain adjuvants, such as suspending, stabilizing and / or dispersing agents.

Pharmaceutical preparations for parenteral administration include aqueous solutions of the active compounds in a water-soluble form. In addition, suspensions of the active compounds can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or excipients include fixed oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optional, but the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to create highly concentrated solutions in the preparation. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, for example sterile anti-pyrogenic water, before use. The compounds may also be formulated in rectal formulations, such as suppositories or retention enemas, for example, containing conventional suppository bases, such as cocoa butter or other glycerides.

In addition to the preparations described previously, the compounds can also be prepared as a depot preparation. Such long acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be prepared with suitable polymeric or hydrophobic products (for example, as an emulsion in an acceptable oil) or ion exchange resins or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

The pharmaceutical carrier for the hydrophobic compounds of the present invention is a cosolvent system containing benzyl alcohol, a non-polar surfactant, an immiscible organic polymer, and an aqueous phase. The co-solvent system may be a VPD co-solvent system. VPD is a solution of 3% wt./about. benzyl alcohol, 8% wt./about. non-polar surfactant, polysorbate 80 and 65% wt./about. polyethylene glycol 300, in absolute ethanol. The VPD co-solvent system (VPD: 5W) contains VPD diluted in a 1: 1 ratio with 5% dextrose in aqueous solution. Such a co-solvent system dissolves hydrophobic compounds well and, in itself, has low toxicity when administered systemically. Naturally, the proportions in the system of cosolvents can be significantly changed without violating the characteristics of its solubility and toxicity. In addition, the identity of the co-solvent components can be changed: for example, other low-toxic non-polar non-polar surfactants can be used instead of polysorbate 80; the fractional size of polyethylene glycol can be changed; other biocompatible polymers can replace polyethylene glycol, for example polyvinylpyrrolidone; other sugars or polysaccharides can replace dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be used. Liposomes and emulsions are well known examples of excipients or carriers for the delivery of hydrophobic drugs.

Some organic solvents, such as dimethyl sulfoxide, can also be used, although with some risk due to increased toxicity. Additionally, the compounds can be delivered using a controlled release system of the active substance, such as semipermeable matrices of solid hydrophobic polymers containing a therapeutic agent. Various controlled release materials have been found that are well known to those skilled in the art. Capsules for controlled release, depending on their chemical nature, release compounds over a period of several weeks to 100 days. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies for stabilizing protein and nucleic acid can be applied.

The pharmaceutical compositions may also contain a solid or gel phase of excipients or carriers. Examples of such fillers or carriers include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols.

The compounds of this invention can be presented in the form of salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts can be formed with many acids, including, but not limited to, hydrochloric, sulfuric, acetic, dairy, tartaric, malic, succinic, phosphoric, hydrobromic, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, maleic, hydrogen iodide, alkane, such as acetic, HOOC- (CH ₂ ) _n -CH ₃ , where n is 0-4, and the like. Salts are generally more soluble in aqueous or other protic solvents than the corresponding free base forms. Non-toxic pharmaceutical base addition salts include salts of bases such as sodium, potassium, calcium, ammonium, and the like. A variety of non-toxic pharmaceutically acceptable addition salts will be apparent to those skilled in the art.

The pharmaceutical compositions of the compounds of the present invention can be prepared and administered in various ways, including systemic, local or local administration. Methods of preparation and administration can be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA. The route of administration can be selected with the goal of maximum delivery to the desired target site in the body. Suitable routes of administration may include, for example, oral, rectal, transmucosal, transdermal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injection, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal or intraocular injection.

Alternatively, the compound can be administered in a local rather than systemic manner, for example, by injecting the compound directly into a specific tissue, often using a depot preparation or a drug with controlled release of the active substance.

Pharmaceutical compositions suitable for use in accordance with the present invention include compositions in which the active ingredients are contained in an effective amount to achieve the intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent or ameliorate existing symptoms in a patient to be treated. The determination of effective quantities is the responsibility of qualified specialists in this field, in particular in the framework of the detailed disclosure presented here.

For any compound used according to the method of this invention, the therapeutically effective dose can be initially estimated from cell culture analysis. For example, in animal models, a dose can be formulated to achieve a repeatable concentration range that includes an EC ₅₀ (effective dose for a 50% increase) as determined in cell culture, i.e. the concentration of the tested compound, at which half the maximum inhibition of bacterial cell growth is achieved. Such information can be used to more accurately determine the doses that are applicable to humans.

It should be understood, however, that the specific dose level for any particular patient will depend on many factors, including the nature of the compound, age, body weight, general health, gender, diet, time of administration, route of administration and rate of elimination, combination of drugs, severity a specific disease during therapy and the opinion of the attending physician.

For administration to non-human animals, a drug or pharmaceutical composition containing the drug may be added to the animal’s food or drinking water. It is most convenient to prepare food products and drinking water for an animal with a predetermined dose of the drug, so the animal consumes the appropriate amount of the drug with food. It is also convenient to add the pre-prepared mixture containing the drug to food or drinking water immediately before the animals consume the products.

Preferred compounds of the present invention will have some pharmacological properties. Such properties include, but are not limited to, oral bioavailability, low toxicity, low serum protein binding, and acceptable half-lives in vitro and in vivo. Biological tests can be performed to predict these desired properties. Biological tests conducted to predict bioavailability include transport through intestinal cell monolayers, including Caco-2 cell monolayers. Serum protein binding can be predicted from the albumin binding assay. Such biological tests are described in a review by Oravcova et al. (1996, J. Chromat. B 677: 1-27). The half-life of the compound is inversely proportional to the dosage frequency of the compound. In vitro half-lives of compounds can be predicted from microsomal half-lives, as described in the literature: Kuhnz, Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127).

The toxicity and therapeutic efficacy of the compounds can be established by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by the definition of LD ₅₀ (dose lethal for 50% of the population) and ED ₅₀ (dose therapeutically effective for 50% of the population). The dose ratio characterizing toxic and therapeutic effects is a therapeutic index, and it can be expressed as the ratio between LD ₅₀ and ED ₅₀ . Compounds that have high therapeutic indices are preferred. Data from cell and animal culture tests can be used to determine the dose range for humans. The dosage of such compounds is preferably in the range of circulating concentrations, which include an ED ₅₀ with or without low toxicity. The dose may vary within this range depending on the dosage form and route of administration. The exact technology for the preparation of the drug, the route of administration and the dose can be selected individually by the doctor, taking into account the condition of the patient. (See, for example, Fingi et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch.l, p.1.)

The number of doses and the intervals between them can be set individually to provide such a plasma content of the active substance that is sufficient for the manifestation of a growth-inhibiting effect on bacterial cells. Dosages for an ordinary patient with systemic administration range from 100 to 2000 mg / day. Given the patient’s body surface area, the usual dosages range from 50 to 910 mg / m ² / day. Normal mean plasma levels should be in the range of 0.1-1000 μM. In cases of local administration or selective absorption, the effective local concentration of the compound cannot be related to the plasma concentration.

The compounds of this invention are useful as antibiotics for the treatment of diseases in both animals and humans, including, but not limited to, actinomycosis, anthrax, bacterial dysentery, botulism, brucellosis, cellulitis, cholera, conjunctivitis, cystitis, diphtheria, bacterial endocarditis , epiglottitis, gastroenteritis, glanders, gonorrhea, Legionnaires disease, leptospirosis, septic meningitis, plague, bacterial pneumonia, postpartum sepsis, rheumatic fever, Rocky Mountain spotted fever, scarlet fever, streptococcal fa ringitis, syphilis, tetanus, tuberculosis, tularemia, typhoid fever, typhus and pertussis.

The contents in this application of all articles and reference materials, including patents, are hereby incorporated by reference.

The compounds of this invention include a new class of broad-spectrum antibiotics.

Types of medically important bacteria that are suitable targets for the manifestation of the antibacterial activity of the inhibitors of this invention include gram-positive bacteria including cocci, such as Staphylococcus species and Streptococcus species; acid resistant bacteria, including Mycobacterium species; bacilli, including species of Bacillus, species of Corynebacterium and species of dostr-idlum; filamentous bacteria including Actinomyces spp. and Streptomyces spp.; gram-negative bacteria including cocci, such as Neisseria spp. and Acinetobacter spp.; bacilli such as Pseudomonas spp., Brucella spp., Agrobacterium spp., Bordetella spp., Escherichia spp., Shigella spp., Yersinia spp., Salmonella spp., Klebsiella spp., Enterobacter spp., Haemophilus spp., Pasteurella spp. and Streptobacillus spp. spirochete species, Campylobacter species, Vibrio species; and intracellular bacteria, including Rickettsiae species and Chlamydia species.

Specific bacterial species that are targeted by the antibiotics of this invention include Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pyogenes. Streptococcus agalactiae, Streptococcus pneumoniae, Enterococcus faecalis, Enterococcus Saecium, Bacillus anthracis, Mycobacterium avium, Mycobacterium tuberculosis, Acinetobacter baumannii, Corynebacterium diphtheria, Clostridium perfringens, Clostridium botulinum, Clostridium tetani, Neisseria gonorrhoeae, Neisseria meningitidis, Pseudomonas aeruginosa, Legionella pneumophila, Escherichia coli , Yersinia pestis, Haemophilus influenzae, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Vibrio cholerae. Vibrio parahemolyticus, Trepomena pallidum, Actinomyces Israelii, Rickettsia prowazekii, Rickettsia rickettsii, Chlamydia trachomatis, Chlamydia psittaci, Brucella abortus, Agrobacterium tumefaciens and Francisella tularensis.

In carrying out the procedures of the present invention, of course, it should be understood that reference is made to specific buffers, media, reagents, cells, culture conditions, and the like. it is not intended to be limited only by them, but should be read in such a way that it includes all related materials that could be considered by an ordinary person skilled in the art as being of interest or significance in the specific context in which such a discussion is given. For example, it is often possible to replace one buffer system or culture medium with another and still obtain similar, if not identical, results. Specialists in this field will have enough knowledge of such systems and methodologies to be able to carry out such replacements without excessive experimentation, which will optimally serve their purposes in applying the methods and techniques disclosed in this paper.

The invention is described in more detail in the following examples, but without limitation only to them. It should be understood that these methods and examples in no way limit the invention to the embodiments described herein, and that other embodiments and applications will undoubtedly be apparent to those skilled in the art.

The compounds of this invention were evaluated for antibacterial activity according to the recommendations and procedures prescribed by the National Committee for Clinical Laboratory Standards (NCCLS) (cf., NCCLS Document M7-A3, 1993 - Antimicrobial Susceptibility Testing).

MIC Definition Protocol

The MIC determination protocol used is as follows:

1. Approximately 2.5 mg of the compounds to be tested were weighed into cryocavities.

2. Stock solutions with a concentration of 5 mg / ml were prepared by adding DMSO to the samples.

3. Working solutions with a concentration of 256 μg / ml were prepared from 5 mg / ml of basic solutions by adding sterile distilled water, respectively.

4. The setup, Beckman 2000 Automated Workstation, was programmed to load 96-well plates with culture media and connections as follows:

- 100 μl of the appropriate medium was added to columns 1-11,

- 200 μl of the appropriate medium was added to column 12,

- 100 μl of a compound of 256 μg / ml of working solution was added to column 1 (one compound per row),

- two serial dilution was carried out from column 1 to 10,

- column 11 served as growth control.

5. A set of 10 organisms was sown from the main vessels stored at -80 ° C and incubated for 24 hours at 34 ° C. The organisms were then reseeded and incubated for 24 hours at 34 ° C.

- The inoculum was first prepared in sterile distilled water to achieve 0.09-0.11 absorption at a wavelength of 620 nm,

- 1/100 dilution was carried out in an appropriate medium,

- 100 μl of medium with the body was added to columns 1-11,

- column 12 served as pure control.

6. Complete 96-well plates were incubated 24 hours at 34 ° C. Data was taken from 96-well plates using a reader, a Beckman Automated Plate Reader, at a wavelength of 650 nm. MICs were determined by calculations including data on growth control (column 11) and net control (column 12).

Borinata complexes

This procedure was applied to obtain the results presented in the tables below. The microbiological data for compounds 10-123 are shown in Tables 1-4 as MIC (minimum inhibitory concentration) with a microgram dimension per ml.

Thus, the invention relates to antibiotics, which are generally referred to as complexes of borinic acid, most preferably are derivatives of substituted borinic acids.

The synthesis of the compounds of this invention was carried out in several ways. Reaction Scheme No. 1 illustrates the synthesis of intermediate boric acids and their subsequent conversion into target complexes of boric acid. When R ∗ and R ∗∗ are identical, then the interaction of two equivalents of aryl magnesium halide (or arylithium) with trialkyl borate followed by acid hydrolysis leads to the desired boric acid 5. When R ∗ and R aryl (dialkoxy) borane (4), heteroaryl (dialkoxy) borane or alkyl (dialkoxy) borane (the alkoxy group contains a methoxy, ethoxy, isopropoxy or propoxy moiety) followed by acid hydrolysis leads to asymmetric borin islotam 6 with excellent yields. In suitable cases, alkylene ethers (3, T = absent, CH ₂ , CMe ₂ ) are reacted with the corresponding organolithium or organomagnesium reagent.

As shown in Scheme 1, boric acid complexes are prepared from boric acid precursors by reaction with 1 equivalent of the desired heterocyclic ligand in suitable solvents (such as ethanol, isopropanol, dioxane, ether, toluene, dimethylformamide, N-methylpyrrolidone or tetrahydrofuran).

Scheme 1

In some cases, the compounds of the invention may contain one or more asymmetric carbon atoms, i.e. the compounds may exist in various stereoisomeric forms. Such compounds may be, for example, racemates or optically active forms. In such situations, individual enantiomers, i.e. optically active forms can be obtained by asymmetric synthesis or separation of racemates. The separation of the racemates can be carried out, for example, by conventional methods, such as crystallization in the presence of a resolving agent or chromatography using, for example, a chiral HPLC column.

Representative compounds of the present invention include, but are not limited to, the compounds disclosed herein and their pharmaceutically acceptable acid and base addition salts. In addition, if the compound of the invention is obtained in the form of an acid addition salt, then the free base can be obtained by alkalizing an acid salt solution. Conversely, if the product is a free base, an addition salt, especially a pharmaceutically acceptable addition salt, can be prepared by dissolving the free base in a suitable organic solvent and treating the resulting solution with acid in accordance with conventional procedures for preparing acid addition salts from base compounds. In a preferred embodiment, the compounds of this invention include any of compounds 10-123 (Tables 1, 2, 3 and 4) and their variants.

Table 1
Data on antibacterial activity against certain gram-positive and gram-negative pathogens Compound R ^∗ R ^∗∗ Ligand S. aureus ATCC 29213 S. epidennidis ATCC 12228 S. pneumoniae ATCC 6301 E. faecalis ATCC 29212 E. faecium CT-26 M.
catarrhalis ATCC 25238 10 3-ClC ₆ H ₄ 3-ClC ₆ H ₄ 8-hydroxyquinoline one 2 2 32 four - eleven 4-Me-3-ClC ₆ H ₃ 4-Me-3-ClC ₆ H ₃ 4-hydroxybenzimidazole 0.125 four - 8 8 - 12 3-ClC ₆ H ₄ 3-ClC ₆ H ₄ 5-fluoro-8-hydroxyquinoline 0.125 2 2 8 four 2 13 3-ClC ₆ H ₄ 3-ClC ₆ H ₄ 5-chloro-8-hydroxyquinoline 0.125 one one 64 2 0.25 fourteen 3-ClC ₆ H ₄ 3-ClC ₆ H ₄ 4-methyl-8-hydroxyquinoline 0.125 one one 64 four 0.5 fifteen 2-F-4-ClC ₆ H ₃ 3-FC ₆ H ₄ 8-hydroxyquinoline 0.125 one 2 16 four 0.5 16 4-Me-3-ClC ₆ H ₃ 4-Me-3-ClC ₆ H ₃ 2-HO ₂ C-4-hydroxy-5,7-dichloroquinoline 0.25 0.5 0.5 0.25 17 3-ClC ₆ H ₄ 3-ClC ₆ H ₄ 2-amino-8-hydroxyquinoline 0.25 2 2 8 8 2 eighteen 3-ClC ₆ H ₄ 3-Cl-4-FC ₆ H ₃ 8-hydroxyquinoline 0.25 one 2 8 four one 19 3-ClC ₆ H ₄ 3-ClC ₆ H ₄ 5-cyano-8-hydroxyquinoline 0.25 2 four 16 four 0.5 twenty 3-ClC ₆ H ₄ 3-Cl-5-FC ₆ H ₃ 8-hydroxyquinoline 0.25 one 2 8 four 2 21 3-ClC ₆ H ₄ 3-FC ₆ N ₄ 5-cyano-8-hydroxyquinoline 0.5 four 2 16 8 0.25 22 3-ClC ₆ H ₄ 3-FC ₆ N ₄ 5-nitro-8-hydroxyquinoline 0.5 four 2 64 16 0.12 23 3-ClC ₆ H ₄ 3-FC ₆ N ₄ 5-chloro-7-chloro-8-hydroxyquinoline 0.5 16 8 64 16 0.12 24 3-ClC ₆ H ₄ 3-FC ₆ N ₄ 5-bromo-7-bromo-8-hydroxyquinoline 0.5 8 8 64 32 0.12 25 3-ClC ₆ H ₄ 3-ClC ₆ H ₄ 2-carboxy-4-hydroxy-8-methoxyquinoline 0.5 8 2 16 16 2 26 3-ClC ₆ H ₄ Me 8-hydroxyquinoline 0.5 one - four four - 27 3-NCC ₆ H ₄ 4-Me-3-ClC ₆ H ₃ 8-hydroxyquinoline 0.5 one one 8 2 one 28 3,4-Cl ₂ C ₆ N _s 3-FC ₆ N ₄ 8-hydroxyquinoline 0.5 one 2 four 2 one 29th 2,4-Cl ₂ C ₆ H ₃ 3-FC ₆ N ₄ 8-hydroxyquinoline 0.5 one 2 8 2 0.5 thirty 3,4-Cl ₂ C ₆ H ₃ 3,4-Cl ₂ C ₆ H ₃ 8-hydroxyquinoline one 0.5 - 2 2 - 31 4-Me-3-ClC ₆ H ₃ 4-Me-3-ClC ₆ H ₃ 2-carboxy-4-hydroxyquinoline one one 2 one 32 3-ClC ₆ H ₄ 3-FC ₆ N ₄ 8-hydroxyquinoline one one one 16 2 2 33 3-Cl-5-FC ₆ H ₃ 3-MeC ₆ H ₄ 8-hydroxyquinoline one one one 8 2 2 34 3-ClC ₆ H ₄ 3-FC ₆ N ₄ 5-fluoro-8-hydroxyquinoline one 2 2 8 four one 35 3-ClC ₆ H ₄ 3-MeSC ₆ H ₄ 5-fluoro-8-hydroxyquinoline one 2 2 8 four 2 36 3-ClC ₆ H ₄ 2-thienyl 8-hydroxyquinoline one one 2 8 2 four 37 3-Me-4-ClC ₆ H ₃ 3-NCC ₆ H ₄ 8-hydroxyquinoline one one one 8 2 one 38 2-FC ₆ H ₄ 3-NCC ₆ H ₄ 8-hydroxyquinoline one one 2 16 2 one 39 3-ClC ₆ H ₄ 3-NCC ₆ H ₄ 8-hydroxyquinoline one one one 8 2 2 40 3-NCC ₆ H ₄ Vinyl 8-hydroxyquinoline one one one 8 2 2 41 3-NCC ₆ H ₄ Ethinyl 8-hydroxyquinoline one one one four 2 one 42 3-FC ₆ N ₄ Ethinyl 8-hydroxyquinoline one one one 8 2 one 43 2-ClC ₆ H ₄ Ethinyl 8-hydroxyquinoline one one one 8 2 one 44 Ethinyl Ethinyl 8-hydroxyquinoline one one one 16 2 0.25 45 3,5-F ₂ C ₆ H ₃ Ethinyl 8-hydroxyquinoline one one one 8 one one 46 3,5-Cl ₂ C ₆ H ₃ Ethinyl 8-hydroxyquinoline one one one four one one 47 3,4-Cl ₂ C ₆ H ₃ Ethinyl 8-hydroxyquinoline one one one 8 2 one 48 3-Cl-4-FC ₆ H ₃ Ethinyl 8-hydroxyquinoline one one one 8 2 2 49 4-ClC ₆ H ₄ 4-ClC ₆ H ₄ 5-chloro-8-hydroxyquinoline 2 one one 16 2 0.25 fifty 4-ClC ₆ H ₄ 4-ClC ₆ H ₄ 8-hydroxyquinoline 2 2 2 four four - 51 3-FC ₆ N ₄ 3-FC ₆ N ₄ 8-hydroxyquinoline 2 one - 8 2 - 52 4-Me-3-ClC ₆ H ₃ 4-Me-3-ClC ₆ H ₃ 8-hydroxyquinoline 2 four - 8 16 - 53 3-NCC ₆ H ₄ 3-NCC ₆ H ₄ 8-hydroxyquinoline 2 2 - 64 four 2 54 4-ClC ₆ H ₄ 4-Cl-3-FC ₆ H ₃ 8-hydroxyquinoline 2 one 2 8 four one

55 4-Cl-3-FC ₆ H ₃ 4-Cl-3-FC ₆ H ₃ 8-hydroxyquinoline 2 one 2 four 2 four 56 3-MeC ₆ H ₄ 3,5-Cl ₂ C ₆ H ₃ 8-hydroxyquinoline 2 2 2 8 four four 57 4-ClC ₆ H ₄ 4-FC ₆ N ₄ 5-fluoro-8-hydroxyquinoline 2 2 four 16 four one 58 3-ClC ₆ H ₄ 4-FC ₆ N ₄ 5-fluoro-8-hydroxyquinoline 2 2 2 8 four 0.5 59 3-ClC ₆ H ₄ 4-MeSC ₆ H ₄ 8-hydroxyquinoline 2 one one 8 four 2 60 4-ClC ₆ H ₄ 3-MeSC ₆ H ₄ 8-hydroxyquinoline 2 one 2 8 four 2 61 3-ClC ₆ H ₄ cyclopropyl 8-hydroxyquinoline 2 one one 16 2 2 62 4-ClC ₆ H ₄ 3-MeSC ₆ H ₄ 5-fluoro-8-hydroxyquinoline 2 2 2 8 four 2 63 4-ClC ₆ H ₄ 4-MeSC ₆ H ₄ 8-hydroxyquinoline 2 one 2 8 four one 64 4-ClC ₆ H ₄ 4-MeSC ₆ H ₄ 5-fluoro-8-hydroxyquinoline 2 2 four 8 8 one 65 4-ClC ₆ H ₄ 4-Cl-3-HOC ₆ H ₃ 8-hydroxyquinoline 2 2 2 16 four four 66 4-ClC ₆ H ₄ 3-FC ₆ N ₄ 4-methyl-8-hydroxyquinoline 2 one one 64 four 0.5 67 3-ClC ₆ H ₄ 3- (DMISO) C ₆ H ₄ 4-methyl-8-hydroxyquinoline 2 one one 64 four 0.5 68 3-FC ₆ N ₄ 3- (DMISO) C ₆ H ₄ 8-hydroxyquinoline 2 2 16 32 four 0.12 69 3- (DMISO) C ₆ H ₄ cyclopropyl 8-hydroxyquinoline 2 one 2 64 four one 70 3-FC ₆ N ₄ cyclopropyl 8-hydroxyquinoline 2 one one 64 2 0.5 71 3-FC ₆ N ₄ 4-NCC ₆ H ₄ 5-chloro-7-chloro-8-hydroxyquinoline 2 2 8 64 four 0.12 72 3- (DMISO) C ₆ H ₄ 3- (DMISO) C ₆ H ₄ 8-hydroxyquinoline four 2 four 64 four - 73 3- (DMISO) C ₆ H ₄ vinyl 8-hydroxyquinoline 2 one 2 64 8 0.25 74 4-FC ₆ N ₄ 4-NCC ₆ H ₄ 8-hydroxyquinoline 2 one 2 32 2 one 75 3-ClC ₆ H ₄ 3-MeSC ₆ H ₄ 8-hydroxyquinoline 2 one 2 64 four - 76 4-Me-3-ClC ₆ H ₃ 2-thienyl 8-hydroxyquinoline 2 one - 8 four - 77 3-ClC ₆ H ₄ 2-MeC ₆ H ₄ 8-hydroxyquinoline 2 one one 8 four 2 78 3-ClC ₆ H ₄ 2-MeOS ₆ H ₄ 8-hydroxyquinoline 2 one one 8 2 2 79 3-ClC ₆ H ₄ 2-Me-4-ClC ₆ H ₃ 8-hydroxyquinoline 2 2 2 8 four 2 80 4-Cl-3-MeC ₆ H ₃ 4-Cl-3-MeC ₆ H ₃ 8-hydroxyquinoline 2 one 2 four four 2 81 3-ClC ₆ H ₄ 3-Cl-6-MeOS ₆ H ₃ 8-hydroxyquinoline 2 one 2 8 four 2 82 3,5-Cl ₂ C ₆ H ₃ 4- (Me ₂ NC ₂ H ₄ ) OC ₆ H ₄ 8-hydroxyquinoline 2 2 2 8 2 four 83 4-BrC ₆ H ₄ 4- (Ме ₂ НС ₂ Н ₄ ) OS ₆ Н ₄ 8-hydroxyquinoline 2 one 2 four four 2 84 3-ClC ₆ H ₄ 4-F-3-MeC ₆ H ₃ 8-hydroxyquinoline 2 one 2 8 four four 85 3-Me-4-ClC ₆ H ₃ 3-F-4-ClC ₆ H ₃ 8-hydroxyquinoline 2 one 2 four four 2 86 3-FC ₆ N ₄ 4-Cl-3-MeC ₆ H ₃ 8-hydroxyquinoline 2 one 2 8 four 2 87 3-FC ₆ N ₄ 3-F-4-ClC ₆ H ₃ 8-hydroxyquinoline 2 one 2 8 four one 88 3-Cl-6-FC ₆ H ₃ 3-NCC ₆ H ₄ 8-hydroxyquinoline 2 2 2 8 2 2 89 2,5-F ₂ C ₆ H ₃ 3-NCC ₆ H ₄ 8-hydroxyquinoline 2 one one 8 2 2 90 4-F-3-ClC ₆ H ₃ 3-NCC ₆ H ₄ 8-hydroxyquinoline 2 2 one 8 2 2 91 3-Me-4-ClC ₆ H ₃ 4-NCC ₆ H ₄ 8-hydroxyquinoline 2 one 2 8 2 one 92 2,5-F ₂ C ₆ H ₃ 4-NCC ₆ H ₄ 8-hydroxyquinoline 2 one 2 8 four one 93 3-Cl-6-FC ₆ H ₃ 4-NCC ₆ H ₄ 8-hydroxyquinoline 2 one one 8 four one 94 3-Cl-6-MeOS ₆ H ₃ 4-NCC ₆ H ₄ 8-hydroxyquinoline 2 one one 8 four 2 95 4-NCC ₆ H ₄ Ethinyl 8-hydroxyquinoline 2 one 2 8 2 one 96 4-ClC ₆ H ₄ 3,4-F ₂ C ₆ H ₃ 8-hydroxyquinoline 2 one 2 8 2 one 97 4-ClC ₆ H ₄ 4-Me-3-FС ₆ Н ₃ 8-hydroxyquinoline 2 one one 8 2 one 98 4-ClC ₆ H ₄ 3,5-F ₂ C ₆ H ₃ 8-hydroxyquinoline 2 one one 8 four one 99 3-CF ₃ -4-ClC ₆ H ₃ 3-FC ₆ N ₄ 8-hydroxyquinoline 2 one 2 8 2 one one hundred 4-ClC ₆ H ₄ 3-F-5-CF ₃ C ₆ H ₃ 8-hydroxyquinoline 2 one 2 four 2 one Ciprofloxacin 0.125 0.125 0.5 0.5 64 0.125 Kloxacillin 0.125 0.25 0.125 16 64 one Imipenem 0.125 0.125 0.125 one 64 0.125 Ceftriaxone 2 one 0.125 64 64 0.125 Meropenem 0.06 0.06 2 Erythromycin 0.5 0.5 2 Penicillin g 0.5 16 0.125 one 32 0.125 DMISO = 4,4-dimethyloxazolin-2-yl

table 2
Data on antibacterial activity against certain gram-positive and gram-negative pathogens Compound R ^∗ R ^∗∗ Ligand S. aureus ATCC 29213 S. epidennidis ATCC 12228 S. pneumonia ATCC 6301 E. faecalis ATCC 29212 E. faecium CT-26 H. influenzae ATCC 49766 101 3-ClC ₆ H ₄ 3-ClC ₆ H ₄ 1- (2-morpholino-4-yl-ethyl) imidazole acetate 0.12 four 16 64 64 four 102 3-ClC ₆ H ₄ 3-ClC ₆ H ₄ 2-hydroxyisopropyl-3-hydroxypyridine 0.5 one 0.25 64 2 64 103 4-ClC ₆ H ₄ 4-ClC ₆ H ₄ 2-hydroxyisopropyl-3-hydroxypyridine 0.25 0.5 0.5 four one 64 104 3-ClC ₆ H ₄ 4-Me-3-C1C ₆ H ₃ 2-hydroxymethyl-1N-benzylimidazole 0.5 four 16 32 8 105 3-ClC ₆ H ₄ 3-ClC ₆ H ₄ 2-hydroxymethylpyridine 0.125 four four 32 32 four 106 4-Me-3-ClC ₆ H ₃ 4-Me-3-ClC ₆ H ₃ 2-pyridylacetic acid 0.5 four - 64 64 64 107 4-Me-3-ClC ₆ H ₃ 4-Me-3-ClC ₆ H ₃ 3- (2-hydroxyethoxy) picolinic acid 0.125 four 16 8 32 108 4-Me-3-ClC ₆ H ₃ 4-Me-3-ClC ₆ H ₃ 3- (N-morpholinethoxy) picolinic acid 0.25 four four 2 64 109 4-Me-3-ClC ₆ H ₃ 4-Me-3-ClC ₆ H ₃ 3- (OCH ₂ CH ₂ CH ₂ CO ₂ H) picolinic acid one four four 32 16 16 110 4-Me-3-ClC ₆ H ₃ 4-Me-3-ClC ₆ H ₃ 3-carboxypicolinic acid 0.125 four - 8 8 8 111 4-Me-3-ClC ₆ H ₃ 4-Me-3-ClC ₆ H ₃ 3-hydroxypicolinic acid 2 one - 2 2 64 112 4-Me-3-ClC ₆ H ₃ 4-CH ₃ C ₆ H ₄ 3-hydroxypicolinic acid four 2 - four 8 64 113 4-Me-3-ClC ₆ H ₃ phenylethyl 3-hydroxypicolinic acid 0.5 one - 2 64 64 114 3-ClC ₆ H ₄ 3-ClC ₆ H ₄ 3-hydroxypicolinic acid 0.125 8 - 64 64 16 115 4-EtO-3-ClC ₆ H ₃ 4-EtO-3-ClC ₆ H ₃ 3-hydroxypicolinic acid 2 2 one 8 16 64 116 2-Cl-5-Br-6-FC ₆ H ₂ 2-F-4-ClC ₆ H ₃ 3-hydroxypicolinic acid 2 one 0.25 four four 64 117 2-Me-4-ClC ₆ H ₃ 3-ClC ₆ H ₄ 3-hydroxypicolinic acid 2 one 0.5 four four 16 118 2-Me-4-ClC ₆ H ₃ 2-Me-4-ClC ₆ H ₃ 3-hydroxypicolinic acid one 0.25 0.12 one one 16 119 4-Me-3-ClC ₆ H ₃ 4-Me-3-ClC ₆ H ₃ 3-OAc-picolinic acid 2 one - 2 2 64 120 4-Me-3-ClC ₆ H ₃ 4-Me-3-ClC ₆ H ₃ 4-hydroxybenzimidazole 0.125 four - 8 8 121 3-ClC ₆ H ₄ 3-ClC ₆ H ₄ 4-hydroxyethylimidazole 0.125 four 8 32 32 four 122 3-ClC ₆ H ₄ 3-ClC ₆ H ₄ 6-amino-3-hydroxypicolinic acid 0.25 four 16 32 32 8 123 3-ClC ₆ H ₄ 3-ClC ₆ H ₄ imidazoleacetic acid 0.125 2 8 32 32 8 Ceftriaxone 2 one <0.125 64 64 0.12 Ciprofloxacin 0.12 0.12 0.5 0.5 64 0.12 Kloxacillin 0.12 0.25 0.12 16 64 8 Erythromycin 0.5 0.5 - 2 - four Imipenem 0.12 0.12 <0.125 one 64 2 Meropenem 0.06 0.06 - 2 - 0.06 Penicillin g 0.5 16 <0.125 one 32 0.12

Table 3
In vitro antimycobacterial activity M. tuberculosis MIC (mcg / ml) Compound H37Rv ^∗ P2SP1 ^∗∗ P1SP2 ^∗∗ 10 0.387 0.387 0.387 fifty 0.387 0.387 0.387 51 0.387 0.387 0.387 53 0.775 0.775 0.387 55 0.775 0.775 0.387 65 0.775 0.775 0.775 72 0.775 0.775 0.775 75 0.775 0.775 0.775 Isoniacid (INH) <0,062 > 8 > 8 Rifampicin <0.125 16 > 16 Ethambutol <1 8 8 Ethionamide one > 64 32 p-aminosalicylate <0.25 32 16 Ofloxacin four 32 16 Streptomycin <2 <2 <2 Kanamycin <2 <2 <2 Cycloserine 8 8 8 ^∗ Sensitive strain
^∗∗ Multi-drug resistant strain

Table 4
Antifungal activity of selected boric acid complexes Compound C. albicans ATCC 90028 10 2 fifty 2 51 one

52 2 53 one 55 one 65 0.5 72 four 76 2

The present invention also includes acylated prodrugs of the compounds of the invention. Various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable additive salts and acylated prodrugs of the invented compounds will be provided to those skilled in the art.

Tables 1, 2 and 3 also contain the inhibitory activity of the known antibiotics given at the end of each of the tables.

Examples

Proton NMR was recorded on a Varian AS 400 spectrometer, and chemical shifts are expressed as δ (ppm) relative to the tetramethylsilane region. Mass spectra were determined on a Micromass Quattro II instrument. Example numbers refer to compounds.

The formation of ethylene glycol ester of boronic acid (compound 3 T = absent)

General procedure

Boronic acid was dissolved in anhydrous THF or anhydrous diethyl ether (~ 10 ml / g) in a nitrogen atmosphere. Ethylene glycol (1 molar equivalent) was added to the reaction mixture and the mixture was refluxed for 1 to 4 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure to give ethylene glycol ether as a residue in the form of an oil or a solid. In cases where an oil or solid was obtained which dissolved in hexane, anhydrous hexane was added and removed under reduced pressure. The product was then held for several hours under high vacuum. In cases where a solid insoluble in hexane was obtained, the solid was separated by filtration and washed with cold hexane.

3-cyanophenylboronic acid ethylene glycol ester (3a)

3-Cyanophenylboronic acid (1 g, 6.8 mmol) was dissolved in anhydrous THF (10 ml) in a nitrogen atmosphere. Ethylene glycol (379 μl, 422 mg, 6.8 mmol) was added and the reaction mixture was refluxed for 4 hours, then cooled to room temperature. THF was removed using a rotary evaporator to give a white solid, to which cold hexane was added. The product was separated by filtration to obtain a white solid (1.18 g, quantitative yield). ¹ H-NMR (300.058 MHz, DMSO-d ₆ ) δ ppm 7.92-8.01 (3H, m), 7.50-7.64 (1H, m), 4.35 (4H, s).

Thiophene-3-boronic acid ethylene glycol ester (3b)

Thiophene-3-boronic acid (1 g, 7.8 mmol) was dissolved in anhydrous THF (10 ml) in a nitrogen atmosphere. Ethylene glycol (435 μl, 484 mg, 7.8 mmol) was added and the reaction mixture was refluxed for 1 hour, then cooled to room temperature. THF was removed using a rotary evaporator to give a white solid. Hexane was added, dissolving the solid, and the solvent was removed using a rotary evaporator. The product was placed under high vacuum to give a tan solid (1.17 g, 97%). ¹ H-NMR (300.058 MHz, CDCl ₃ ) δ ppm 7.93 (1H, s), 7.3-7.4 (2H, m), 4.35 (4H, s).

The formation of asymmetric borinic acid (6) from ethylene glycol boronic acid ester

General Procedure A: Grignard Reaction Technique

Boronic acid ethylene glycol ether was dissolved in anhydrous THF (10-20 ml / g) in a nitrogen atmosphere. The solution was cooled to -78 ° C in an acetone / dry ice bath or to 0 ° C in an ice / water bath. Grignard reagent (0.95 to 1.2 molar equivalent) was added dropwise to the cooled solution. The reaction mixture was warmed to room temperature and stirred for 3-18 hours. 6N Hcl (2 ml / g) was added to the mixture, and the solvent was removed in vacuo. The product was extracted with diethyl ether (40 ml / g) and washed with water (3 × equal volume). The organic layer was dried (MgSO ₄ ), filtered and the solvent was removed using a rotary evaporator, obtaining a crude product, which was purified either by column chromatography or used in the next step without purification. Alternative procedure: if the product of boric acid contained a basic group, such as amine or pyridine, then after stirring at room temperature for 3-18 hours, water (2 ml / g) was added and the pH was adjusted to 5-7. The product was extracted with diethyl ether (40 ml / g) and washed with water (3 × equal volume). The organic layer was dried (MgSO ₄ ), filtered and the solvent was removed using a rotary evaporator, obtaining a crude product, which was purified either by column chromatography or used in the next step without purification.

(4-Cyanophenyl) (3-fluorophenyl) boric acid (6a)

4-Cyanophenylboronic acid ethylene glycol ester (500 mg, 2.89 mmol) was dissolved in anhydrous THF under a nitrogen atmosphere. The solution was cooled to −78 ° C. in an acetone / dry ice bath, and 3-fluorophenyl magnesium bromide (1M in THF) (2.74 ml, 2.74 mmol, 0/95 molar equivalent) was added dropwise to the cold solution. The reaction mixture was allowed to slowly warm to room temperature and was stirred for 18 hours. 6N HCl (1 ml) was added to the reaction mixture, which caused turbidity, and the solvent was removed using a rotary evaporator. The product was extracted with diethyl ether (20 ml) and washed with water (3 × 20 ml). The organic layer was dried (MgSO ₄ ), filtered and the solvent was removed using a rotary evaporator, obtaining the crude product as an oily solid. The product was used in the next step without purification.

General Procedure B: Reaction Procedure with (hetero) arylithium

(Hetero) aryl bromide or iodide was dissolved in anhydrous THF (20-30 ml / g) in a nitrogen atmosphere and degassed. The solution was cooled to −78 ° C. in an acetone / dry ice bath, and n-, second-, or tert-butyl lithium in THF or another solvent (1.5-2.4 molar equivalents) was added dropwise to the cooled solution, which usually caused intense yellowing of the solution. Boronic acid ethylene glycol ether (1 molar equivalent) was dissolved in anhydrous THF or diethyl ether (2-5 ml / g) in a nitrogen atmosphere. Ethylene glycol ester of boronic acid in THF was added dropwise to a cooled solution of aryllithium, which usually led to a pale yellow color of the solution. The reaction mixture was warmed to room temperature and stirred for 3-18 hours. 6N Hcl (2-4 ml / g) was added to the mixture, and the solvent was removed in vacuo. The product was extracted with diethyl ether (40 ml / g) and washed with water (3 × equal volume). The organic layer was dried (MgSO ₄ ), filtered and the solvent was removed using a rotary evaporator, obtaining a crude product, which was purified either by column chromatography or used in the next step without purification. Alternative procedure: if the product of boric acid contained a basic group, such as amine or pyridine, then after stirring at room temperature for 3-18 hours, water (2 ml / g) was added and the pH was adjusted to 5-7. The product was extracted with diethyl ether (40 ml / g) and washed with water (3 × equal volume). The organic layer was dried (MgSO ₄ ), filtered and the solvent was removed using a rotary evaporator, obtaining a crude product, which was purified either by column chromatography or used in the next step without purification.

(3-Thiophene) (3-chlorophenyl) boric acid (6b)

3-Chloro-bromobenzene (447 μl, 728 mg, 3.8 mmol) was dissolved in anhydrous THF (15 ml) in a nitrogen atmosphere. The solution was degassed and cooled to −78 ° C. in an acetone / dry ice bath. Tert-butyllithium (1.7 M in THF) (4.47 ml, 7.6 mmol, 2 molar equivalents) was added dropwise to the cooled solution, which caused intense yellowing of the solution. The solution was stirred at -78 ° C and at the same time 3-thiophenboronic acid ethylene glycol ester (586 mg) was dissolved in anhydrous diethyl ether (1 ml). The boronic acid ester solution was then added dropwise to the cooled solution, resulting in a color change of the solution to pale yellow. The reaction mixture was warmed to room temperature and stirred for 18 hours. 6N Hcl (2 ml) was added to the mixture, and the reaction mixture was stirred for 1 hour. The solvent was removed using a rotary evaporator. The product was extracted with diethyl ether (10 ml) and washed with water (2 × 10 ml). The organic layer was dried (MgSO ₄ ), filtered and the solvent was removed using a rotary evaporator, obtaining the crude product as an orange oil. The product was purified by column chromatography using silica gel and hexane: ethyl acetate 5: 1 eluent to give the pure product as a clear oil (614 mg, 73%).

(3-Chlorophenyl) vinyl borinic acid (6c)

The compound was prepared by a method similar to that described for 6b by reacting 3-chlorophenylboronic acid ethylene glycol ester with vinyl lithium.

(3-Fluoro-5-chlorophenyl) ethynylborinic acid (6d)

The compound was prepared in a manner analogous to that described for 6b by reacting 3-fluoro-5-chlorophenylboronic acid ethylene glycol ester with ethynyl lithium.

(4-Methyl-3-chlorophenyl) (2-thienyl) borinic acid (6e)

The compound was prepared in a manner analogous to that described for 6b by reacting 2-thienylboronic acid ethylene glycol ester with 4-methyl-3-chlorophenyl lithium.

(4-Cyanophenyl) ethynylborinic acid (6f)

The compound was prepared in a manner analogous to that described for 6b by reacting 4-cyanophenylboronic acid ethylene glycol ester with ethynyl lithium.

(3-Fluorophenyl) cyclopropylboronic acid (6g)

The compound was prepared in a manner analogous to that described for 6b by reacting 3-fluorophenylboronic acid ethylene glycol ester with cyclopropyl lithium.

(3-Thienyl) methylboric acid (6h)

The compound was prepared by a method similar to that described for 6b by reacting 3-thienylboronic acid ethylene glycol ester with methyl lithium.

(4-Pyridyl) phenylboric acid (6i)

The compound was prepared by a method similar to that described for 6b by reacting phenylboronic acid ethylene glycol ester with 4-pyridyllithium.

(3-Cyanophenyl) (2-fluorophenyl) boric acid (6j)

The compound was prepared in a manner analogous to that described for 6b by reacting 3-cyanophenylboronic acid ethylene glycol ester with 2-fluorophenyl lithium.

The formation of symmetric boric acid (5) by the interaction of organometallic compounds with trialkyl borates

Bis (4-chlorophenyl) boric acid (5a) (Procedure C)

To a cold solution (-78 ° C) of Grimethylborate (0.37 ml) in anhydrous tetrahydrofuran (THF, 25 ml) was added dropwise 4-chlorophenylmagnesium bromide (6.75 ml, 1M solution in ether). The reaction mixture was stirred at -78 ° C for 1 hour and then 18 hours at room temperature. The solvent was removed under reduced pressure. The resulting residue was stirred with 100 ml of ether and 15 ml of 6N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with ether (2 × 100 ml).

The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed to give a light yellowish solid. The product was chromatographed on silica gel (hexane: ether = 1: 1) to give 420 mg of borinic acid. ¹ H-NMR (400 MHz, DOCl ₃ ) δ: 5.84 (s, OH), 7.46 (d, 4H, Ar-H), 7.72 (d, 4H, Ar-H). Bis (3-chloro-4-methylphenyl) boric acid (5b)

The title compound was prepared analogously to the procedure described for 5a by reacting 3-chloro-4-methylphenyl magnesium bromide with trimethyl borate. The product was isolated by silica gel chromatography.

Bis (3-fluoro-4-methylphenyl) boric acid (5c)

The title compound was prepared analogously to the procedure described for 5a by reacting 3-fluoro-4-methyl-phenyl lithium with trimethyl borate. The product was isolated by silica gel chromatography.

Bis (3-chloro-4-methoxyphenyl) boric acid (5d)

The title compound was prepared analogously to the procedure described for 5a by reacting 3-chloro-4-methoxyphenyl lithium with trimethyl borate. The product was isolated by silica gel chromatography.

Bis (3-fluoro-4-methoxyphenyl) borinic acid (5e)

The title compound was prepared analogously to the procedure described for 5a by reacting 3-fluoro-4-methoxyphenyl lithium with trimethyl borate. The product was isolated by silica gel chromatography. The formation of asymmetric boric acid (6) by the interaction of organometallic compounds with alkyl (aryl) dialkoxyboranes

(4-Chlorophenyl) methylboronic acid (6k) (Procedure D)

To 4-chlorophenylmagnesium bromide (5.5 ml, 1M solution in ether) at -78 ° C was added dropwise using a syringe di (isopropoxy) methylborane (1 ml, 0.78 g). The reaction mixture was stirred at -78 ° C for 1 hour and then stirred overnight at ambient temperature. 100 ml of ether and 15 ml of 6N hydrochloric acid were added dropwise to the reaction mixture, and then the mixture was stirred for 1 hour. The organic layer was separated and the aqueous layer was extracted with ether (2 × 100 ml). The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 1.1 g of oil. ¹ H-NMR of the product corresponded to (4-chlorophenyl) methylboric acid.

(4-Fluorophenyl) methylboric acid (6m)

The title compound was prepared analogously to the procedure described for 6k by reacting 4-fluorophenyl magnesium bromide with di (isopropoxy) methyl borane. The product was isolated by silica gel chromatography.

(4-Biphenyl) methylboric acid (6n)

The title compound was prepared analogously to the method described for 6k by reacting 4-biphenyllithium with di (isopropoxy) methylborane. The product was isolated by silica gel chromatography.

(3-Chloro-4-methylphenyl) methylboric acid (6 °)

The title compound was prepared analogously to the method described for 6k by reacting 3-chloro-4-methylphenyllithium with di (isopropoxy) methylborane. The product was isolated by silica gel chromatography.

(3-Chloro-4-methoxyphenyl) methylboric acid (6p)

The title compound was prepared analogously to the method described for 6k by reacting 3-chloro-4-methoxyphenyl lithium with di (isopropoxy) methylborane. The product was isolated by silica gel chromatography.

(4-Dimethylaminophenyl) methylboronic acid (6q)

The title compound was prepared analogously to the method described for 6k by reacting 4-dimethylaminophenyl lithium with di (isopropoxy) methylborane. The product was isolated by silica gel chromatography.

(3-Chloro-4-dimethylaminophenyl) vinyl borinic acid (6r)

The title compound was prepared analogously to the method described for 6k by reacting 3-chloro-4-dimethylaminophenyl lithium with di (butoxyvinyl) borane. The product was isolated by silica gel chromatography.

Bis (3-chlorophenyl) borinic acid ester and

4- (hydroxyethyl) imidazole (121)

To a solution of bis (3-chlorophenyl) borinic acid (0.4 g, 1.428 mmol) in ethanol (10 ml) was added 4- (hydroxyethyl) imidazole hydrochloride (0.191 g, 1.428 mmol) and sodium bicarbonate (0.180 g, 2.143 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The salt was removed by filtration. The filtrate was concentrated, treated with hexane, and the product was obtained as a solid, which was separated by filtration (450 mg, 84.9%).

Bis (4-chlorophenyl) borinic acid ester and

4- (hydroxymethyl) imidazole (126)

The title compound was prepared analogously to the method of Example 121 by reacting bis (4-chlorophenyl) borinic acid with 4- (hydroxymethyl) imidazole hydrochloride. The product was obtained as white crystals.

Bis (3-chloro-4-methylphenyl) borinic acid ester and 1-benzyl-4-

(hydroxymethyl) imidazole (127)

To a solution of 1-benzyl-4- (hydroxymethyl) imidazole (96 mg, 0.521 mmol) in methanol (5 ml) was added bis (3-chloro-4-methylphenyl) boric acid (121 mg, 0.521 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was treated with hexane, which led to the formation of a solid. The precipitate was separated by filtration, washed with hexane and a product was obtained (193 g, 83%). ¹ H-NMR (CDCl ₃ ) δ: 2.3 (s, 6H, 2XCH ₃ ), 4.8 (br s, 2H, CH ₂ ), 5.1 (br s, 2H, CH ₂ ), 6.9-7.4 (complex, 13H, Ar-H); MS (EC ⁺ ) m / z) 448.78, MF (MF) C ₂₅ H ₂₃ BCl ₂ N ₂ O.

Bis (3-chloro-4-methylphenyl) borinic acid ester and 1-methyl-2-

(hydroxymethyl) imidazole (128)

The title compound was prepared analogously to the method of Example 127 by reacting bis (3-chloro-4-methylphenyl) borinic acid with 1-methyl-2- (hydroxymethyl) imidazole hydrochloride. The product was obtained as white crystals.

Bis (3-chloro-4-methylphenyl) borinic acid ester and 1-ethyl-2-

(hydroxymethyl) imidazole (129)

The title compound was prepared analogously to the method of Example 127 by reacting bis (3-chloro-4-methylphenyl) borinic acid with 1-ethyl-2- (hydroxymethyl) imidazole hydrochloride. The product was obtained as white crystals.

Bis (3-chloro-4-methylphenyl) borinic acid ester and 1-methyl-4-

(hydroxymethyl) imidazole (130)

The title compound was prepared analogously to the method of Example 127 by reacting bis (3-chloro-4-methylphenyl) borinic acid with 1-methyl-4- (hydroxymethyl) imidazole hydrochloride. The product was obtained as white crystals.

Bis (3-chloro-4-methylphenyl) borinic acid 2-pyridylethyl ether (131)

The title compound was prepared analogously to the method of Example 121 by reacting bis (3-chloro-4-methylphenyl) borinic acid with 2-pyridylethanol. The product was obtained as white crystals.

Bis (4-chlorophenyl) borinic acid 2-pyridylmethyl ester (132)

The title compound was obtained analogously to the method of Example 121 by reacting bis (4-chlorophenyl) borinic acid with 2-pyridylmethanol. The product was obtained as white crystals.

Bis (4-fluorophenyl) borinic acid 2-pyridylmethyl ester (133)

The title compound was prepared analogously to the method of Example 121 by reacting bis (4-fluorophenyl) borinic acid with 2-pyridylmethanol. The product was obtained as white crystals.

Hydroxyquinoline Derivatives

Bis (3-chlorophenyl) borinic acid ester and 8-hydroxyquinoline (10)

A solution of bis (3-chlorophenyl) borinic acid (0.18 g) in ethanol (1 ml) and 8-hydroxyquinoline (0.105 g) was stirred at 5 ° C. The reaction mixture was then stirred at ambient temperature, and a yellow precipitate formed. The reaction mixture was stirred for an additional 4 hours. The product was isolated by filtration, washed with hexane, dried in air and 160 mg of complex was obtained.

Bis (3-chlorophenyl) borinic acid ester and 5-fluoro-8-hydroxyquinoline (12)

The title compound was prepared analogously to the method of Example 10 by reacting bis (3-chlorophenyl) borinic acid with 5-fluoro-8-hydroxyquinoline. The product was obtained as yellow crystals.

Bis (3-chlorophenyl) borinic acid ester and 5-chloro-8-hydroxyquinoline (13)

The title compound was prepared analogously to the method of Example 10 by reacting bis (3-chlorophenyl) borinic acid with 5-chloro-8-hydroxyquinoline. The product was obtained as yellow crystals.

Bis (3-chlorophenyl) borinic acid ester and 5-cyano-8-hydroxyquinoline (19)

The title compound was prepared analogously to the method of Example 10 by reacting bis (3-chlorophenyl) borinic acid with 5-cyano-8-hydroxyquinoline. The product was obtained as yellow crystals.

An ester of (2-thienyl) methylboric acid and 8-hydroxyquinoline (26)

The title compound was prepared analogously to the method of Example 10 by reacting (2-thienyl) methylborinic acid with 8-hydroxyquinoline. The product was obtained as yellow crystals.

Ether of (3-chlorophenyl) (2-thienyl) borinic acid and 8-hydroxyquinoline (36)

The title compound was prepared analogously to the method of Example 10 by reacting (3-chlorophenyl) (2-thienyl) borinic acid with 8-hydroxyquinoline. The product was obtained as yellow crystals.

An ester of (3-cyanophenyl) vinyl borinic acid and 8-hydroxyquinoline (40)

The title compound was prepared analogously to the method of Example 10 by reacting (3-cyanophenyl) vinyl borinic acid with 8-hydroxyquinoline. The product was obtained as yellow crystals.

The ester of (2-chlorophenyl) ethynylborinic acid and 8-hydroxyquinoline (43)

The title compound was prepared analogously to the method of Example 10 by reacting (2-chlorophenyl) ethynylborinic acid with 8-hydroxyquinoline. The product was obtained as yellow crystals.

Bis (ethynyl) borinic acid ester and 8-hydroxyquinoline (44) (XXI)

The title compound was prepared analogously to the method of Example 10 by reacting bis (ethynyl) borinic acid with 8-hydroxyquinoline. The product was obtained as pale yellow crystals.

An ester of (3-fluorophenyl) cyclopropylborinic acid and 8-hydroxyquinoline (70)

The title compound was prepared analogously to the method of Example 10 by reacting (3-fluorophenyl) cyclopropylboronic acid with 8-hydroxyquinoline. The product was obtained as pale yellow crystals.

In a preferred embodiment, the present invention includes all compounds specifically listed herein, their pharmaceutically acceptable salts and compositions of any of these compounds, in those cases where they contain a pharmaceutically acceptable carrier. Most preferred are compounds having the structure of any of the compounds listed in tables 1, 2, 3 or 4, especially compounds 10-108, compounds 111-112 or compounds 116-120. In such compounds, a ligand, as described elsewhere herein, is attached to boron via said reactive groups.

The present invention also relates to a method for treating diseases caused by microbes when they infect a patient and / or preventing such infection in a patient at risk of infection, to a method that comprises administering to said patient a therapeutically effective amount of any of the compounds of this invention, preferably one or more of listed in tables 1-4. In one aspect, the compounds of the invention exhibit antibacterial (i.e., bactericidal) and antifungal (i.e., fungicidal) activity.

In a preferred embodiment, the microbe is a bacterium, preferably gram-positive, wherein said gram-positive bacterium belongs to the group comprising Staphylococcus species, Streptococcus species, Bacillus species, Mycobacterium species, Corynebacterium species, Clostridium species, Actinomyces species, Enterococcus species and Streptomyces species.

In another preferred embodiment of the method, the bacterium is a gram-negative bacterium, preferably selected from the group comprising Acinetobacter species, Neisseria species, Pseudomonas species, Brucella species, Agrobacterium species, Bordetella species, Escherichia species, Shigella species, Yersinia species, Salmonella species, species Klebsiella, Enterobacter spp., Haemophilus spp., Pasteurella spp., Streptobacillus spp., Spirochete spp., Campylobacter spp., Vibrio spp. And Helicobacter spp.

In a most preferred embodiment of the present invention, the bacterium is selected from the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pyogenes, Streptococcus agalactiae. Streptococcus pneumoniae, Enterococcus faecalis, Enterococcus faecium. Bacillus anthracis, Mycobacterium avium, Mycobacterium tuberculosis, Acinetobacter baumannii, Corynebacterium diphtheria, Clostridium perfringens, Clostridium botulinum, Clostridium tetani, Neisseria gonorrhoeae, Neisseria meningitidis, Pseudomonas aeruginosa, Legionella pneumophila, Escherichia coli, Yersinia pestis, Haemophilus influenzae, Helicobacter pylori, Campylobacter fetus Campylobacter jejuni. Vibrio cholerae. Vibrio parahemolyticus, Trepomena pallidum, Actinomyces israelii, Rickettsia prowazekii, Rickettsia rickettsii, Chlamydia trachomatis, Chlamydia psittaci, Brucella abortus, Agrobacterium tumefaciens and Francisella tularensis.

Claims (51)

1. The compound of structural formula 2

where B is boron,
O is oxygen,
m is 0, 1 or 2,
R * and R ** are each independently selected from unsubstituted alkyl (C ₁ -C ₄ ), unsubstituted cycloalkyl (C ₃ -C ₆ ),

where R ¹ , R ² and R ^{3 are} each independently selected from the group consisting of hydrogen, alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , S-alkyl, S-phenyl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ and NO ₂ ;

where R1 is selected from the group consisting of hydrogen, alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , S-alkyl, S-phenyl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ and NO ₂ ;

where R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are} each independently selected from the group consisting of hydrogen, alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , CONHalkyl, CON (alkyl) ₂ , OH, alkoxy, phenyloxy, SH, S -alkyl, S-phenyl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° amino, 3 ° amino, NH ₂ SO ₂ , OCH ₂ CH ₂ NH ₂ , OCH ₂ CH ₂ NH alkyl, OCH ₂ CH ₂ N (alkyl) ₂ , oxazolidin-2-yl or an alkyl substituted oxazolidin-2-yl;

where R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are} each independently selected from the group consisting of alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3) , CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , CONH alkyl, CON (alkyl) ₂ , OH, alkoxy, phenyloxy, SH, S-alkyl , S-phenyl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° amino, 3 ° amino, NH ₂ SO ₂ , OCH ₂ CH ₂ NH ₂ , OCH ₂ CH ₂ NH alkyl, OCH ₂ CH ₂ N (alkyl) ₂ , oxazolidin-2-yl or an alkyl-substituted oxazolidin-2-yl; and

or

where X is selected from CH = CH, N = CH, NR ¹³ , O or S, R ^{13 is} selected from H, alkyl, phenyl or benzyl,
and where R ¹ and R ^{2 are} each independently selected from the group consisting of hydrogen, alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , S-alkyl, S-phenyl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ and NO ₂ ,
and where Y is selected from CH or N;
and where z is 1, and when z is 1, A represents CH, CR ¹⁰ or N, and
where D represents N, CH or CR ¹² ,
and where E represents H, OH, alkoxy, COOH, COOalkyl or N- (morpholinyl) ethoxy,
and where r is 1, and if r is 1, then G represents = O (oxygen with a double bond)
where R ^{12 is} selected from (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , OH, alkoxy, phenyloxy, SH, S-alkyl, S-phenyl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° amino, 3 ° - amino, NH ₂ SO ₂ and CONH ₂ ,
and where R ⁹ and R ^{10 are} each independently selected from the group consisting of hydrogen, alkyl, (CH ₂ ) _n OH (n = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH alkyl, CH ₂ N (alkyl) ₂ , halogen, CHO, CH = NOH, CO ₂ H, CO ₂ -alkyl, S-alkyl, SO ₂ -alkyl, S-phenyl, NH ₂ , alkoxy, CF ₃ , SCF ₃ , NO ₂ , SO ₃ H and OH ,
provided that the compound is not selected from

,

and

,
or its salt or adduct of a compound of the specified formula with a solvent,
and wherein said substituted benzyl has the structure

in which R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are} each independently selected from the group consisting of alkyl, phenyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , CONH alkyl, CON (alkyl) ₂ , OH, alkoxy, phenyloxy, SH, S-alkyl, S-phenyl , SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° amino, 3 ° amino, NH ₂ SO ₂ , OCH ₂ CH ₂ NH ₂ , OCH ₂ CH ₂ NH alkyl, OCH ₂ CH ₂ N (alkyl) ₂ , oxazolidin-2-yl or alkyl substituted oxazolidin-2-yl; and
said substituted phenyl has the structure

in which R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are} each independently selected from the group consisting of hydrogen, alkyl, phenyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , CONH alkyl, CON (alkyl) ₂ , OH, alkoxy, phenyloxy, SH, S-alkyl, S -phenyl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° amino, 3 ° amino, NH ₂ SO ₂ , OCH ₂ CH ₂ NH ₂ , OCH ₂ CH ₂ NH ₂ alkyl, OCH ₂ CH ₂ N (alkyl) ₂ , oxazolidin-2-yl or alkyl substituted oxazolidin-2-yl. 2. The compound according to claim 1, where at least one of R * and R ** corresponds to the formula

in which R ¹ , R ² and R ^{3 are} each independently selected from the group consisting of hydrogen, alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , S-alkyl, S-phenyl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen CF ₃ and NO ₂ ;
and wherein said substituted benzyl has the structure

in which R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are} each independently selected from the group consisting of alkyl, phenyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , CONHalkyl, CON (alkyl) ₂ , OH, alkoxy, phenyloxy, SH, S-alkyl, S-phenyl , SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° amino, 3 ° amino, NH ₂ SO ₂ , OCH ₂ CH ₂ NH ₂ , OCH ₂ CH ₂ NH alkyl, OCH ₂ CH ₂ N (alkyl) ₂ , oxazolidin-2-yl or alkyl substituted oxazolidin-2-yl; and
said substituted phenyl has the structure

in which R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are} each independently selected from the group consisting of hydrogen, alkyl, phenyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , CONH alkyl, CON (alkyl) ₂ , OH, alkoxy, phenyloxy, SH, S-alkyl, S phenyl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° amino, 3 ° amino, NH ₂ SO ₂ , OCH ₂ CH ₂ NH ₂ , OCH ₂ CH ₂ NH alkyl, OCH ₂ CH ₂ N (alkyl) ₂ , oxazolidin-2-yl or alkyl substituted oxazolidin-2-yl. 3. The compound according to claim 1, where at least one of R * and R ** corresponds to the formula

in which R ^{1 is} selected from the group consisting of hydrogen, alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH alkyl CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , S-alkyl, S-phenyl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ and NO ₂ ;
and wherein said substituted benzyl has the structure

in which R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are} each independently selected from the group consisting of alkyl, phenyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , CONH alkyl, CON (alkyl) ₂ , OH, alkoxy, phenyloxy, SH, S-alkyl, S-phenyl , SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° amino, 3 ° amino, NH ₂ SO ₂ , OCH ₂ CH ₂ NH ₂ , OCH ₂ CH ₂ NH alkyl, OCH ₂ CH ₂ N (alkyl) ₂ , oxazolidin-2-yl or alkyl substituted oxazolidin-2-yl; and
said substituted phenyl has the structure

in which R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are} each independently selected from the group consisting of hydrogen, alkyl, phenyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , CONH alkyl, CON (alkyl) ₂ , OH, alkoxy, phenyloxy, SH, S-alkyl, S phenyl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° amino, 3 ° amino, NH ₂ SO ₂ , OCH ₂ CH ₂ NH ₂ , OCH ₂ CH ₂ NH alkyl, OCH ₂ CH ₂ N (alkyl) ₂ , oxazolidin-2-yl or alkyl substituted oxazolidin-2-yl. 4. The compound according to claim 1, where at least one of R * and R ** corresponds to the formula

in which R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are} each independently selected from the group consisting of hydrogen, alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , CONNalkyl, CON (alkyl) ₂ , OH, alkoxy, phenyloxy, SH, S-alkyl, S-phenyl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° amino, 3 ° amino, NH ₂ SO ₂ , OCH ₂ CH ₂ NH ₂ , OCH ₂ CH ₂ Nalkyl, OCH ₂ CH ₂ N (alkyl) ₂ , oxazolidin-2-yl or alkyl substituted oxazolidin-2-yl;
and wherein said substituted benzyl has the structure

in which R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are} each independently selected from the group consisting of alkyl, phenyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , CONH alkyl, CON (alkyl) ₂ , OH, alkoxy, phenyloxy, SH, S-alkyl, S-phenyl , SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° amino, 3 ° amino, NH ₂ SO ₂ , OCH ₂ CH ₂ NH ₂ , OCH ₂ CH ₂ NH alkyl, OCH ₂ CH ₂ N (alkyl) ₂ , oxazolidin-2-yl or alkyl substituted oxazolidin-2-yl; and
said substituted phenyl has the structure

in which R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are} each independently selected from the group consisting of hydrogen, alkyl, phenyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , CONH alkyl, CON (alkyl) ₂ , OH, alkoxy, phenyloxy, SH, S-alkyl, S -phenyl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° amino, 3 ° amino, NH ₂ SO ₂ , OCH ₂ CH ₂ NH ₂ , OCH ₂ CH ₂ NH alkyl, OCH ₂ CH ₂ N (alkyl) ₂ , oxazolidin-2-yl or alkyl substituted oxazolidin-2-yl. 5. The compound according to claim 1, where at least one of R * and R ** corresponds to the formula

in which R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are} each independently selected from the group consisting of alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3 ), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , CONH alkyl, CON (alkyl) ₂ , OH, alkoxy, phenyloxy, SH, S- alkyl, S-phenyl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° amino, 3 ° amino, NH ₂ SO ₂ , OCH ₂ CH ₂ NH ₂ , OCH ₂ CH ₂ NH alkyl, OCH ₂ CH ₂ N (alkyl) ₂ , oxazolidin-2-yl or alkyl substituted oxazolidin-2-yl;
and wherein said substituted benzyl has the structure

in which R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are} each independently selected from the group consisting of alkyl, phenyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , CONHalkyl, CON (alkyl) ₂ , OH, alkoxy, phenyloxy, SH, S-alkyl, S-phenyl , SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° amino, 3 ° amino, NH ₂ SO ₂ , OCH ₂ CH ₂ NH ₂ , OCH ₂ CH ₂ Nalkyl, OCH ₂ CH ₂ N (alkyl) ₂ , oxazolidin-2-yl or alkyl substituted oxazolidin-2-yl; and
said substituted phenyl has the structure

in which R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are} each independently selected from the group consisting of hydrogen, alkyl, phenyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , CONH alkyl, CON (alkyl) ₂ , OH, alkoxy, phenyloxy, SH, S-alkyl, S phenyl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , NH ₃ , 2 ° amino, 3 ° amino, NH ₂ SO ₂ , OCH ₂ CH ₂ NH ₂ , OCH ₂ CH ₂ NH alkyl, OCH ₂ CH ₂ N (alkyl) ₂ , oxazolidin-2-yl or alkyl substituted oxazolidin-2-yl. 6. The compound according to claim 1, where at least one of R * and R ** corresponds to the formula

or

where X = CH = CH, N = CH, NR ¹³ (where R ¹³ = H, alkyl, phenyl or benzyl), O or S,
and where Y = CH or N,
and where R ¹ and R ^{2 are} each independently selected from the group consisting of hydrogen, alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , S-alkyl, S-phenyl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ and NO ₂ ;
and wherein said substituted benzyl has the structure

in which R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are} each independently selected from the group consisting of alkyl, phenyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , CONH alkyl, CON (alkyl) ₂ , OH, alkoxy, phenyloxy, SH, S-alkyl, S-phenyl , SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° amino, 3 ° amino, NH ₂ SO ₂ , OCH ₂ CH ₂ NH ₂ , OCH ₂ CH ₂ NH alkyl, OCH ₂ CH ₂ N (alkyl) ₂ , oxazolidin-2-yl or alkyl substituted oxazolidin-2-yl; and
said substituted phenyl has the structure

in which R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 are} each independently selected from the group consisting of hydrogen, alkyl, phenyl, substituted benzyl, (CH ₂ ) _k OH (where k = 1, 2 or 3), CH ₂ NH ₂ , CH ₂ NH-alkyl, CH ₂ N (alkyl) ₂ , CO ₂ H, CO ₂ alkyl, CONH ₂ , CONH alkyl, CON (alkyl) ₂ , OH, alkoxy, phenyloxy, SH, S-alkyl, S phenyl, SO ₂ alkyl, SO ₃ H, SCF ₃ , CN, halogen, CF ₃ , NO ₂ , NH ₂ , 2 ° amino, 3 ° amino, NH ₂ SO ₂ , OCH ₂ CH ₂ NH ₂ , OCH NNalkil ₂ CH _2, OCH ₂ CH ₂ N (alkyl) _2, oxazolidin-2-yl, or alkyl substituted oxazolidin-2-yl. 7. The compound according to claim 1, where R ⁹ represents H; m represents 0; A represents CH; D represents CH; E represents OH; R * is selected from 4-Me-3-ClC ₆ H ₃ , 3-ClC ₆ H ₄ , 4-EtO-3-ClC ₆ H ₃ , 2-Cl-5-Br-6-F-C ₆ H ₂ , 2-Me-4-ClC ₆ H ₃ ; and R ** is selected from 4-Me-3-ClC ₆ H ₃ , 4-Me-C ₆ H ₄ ; phenylethyl; 3-ClC ₆ H ₄ , 4-EtO-3-ClC ₆ H ₃ , 2-F-4-ClC ₆ H ₃ , 2-Me-4-ClC ₆ H ₃ . 8. The compound according to claim 1, where R ⁹ represents H; m represents 0; A represents CH; D represents CH; E represents OH;
when R * is 4-Me-3-ClC ₆ H ₃ , R ** is selected from 4-Me-3-ClC ₆ H ₃ , 4-Me-C ₆ H ₄ ; phenethyl;
when R * is 3-ClC ₆ H ₄ , R ** is 3-ClC ₆ H ₄ ;
when R * is 4-EtO-3-ClC ₆ H ₃ , R ** is 4-EtO-3-ClC ₆ H ₃ ;
when R * is 2-Cl-5-Br-6-FC ₆ H ₂ , R ** is 2-F-4-ClC ₆ H ₃ ; and
when R * is 2-Me-4-ClC ₆ H ₃ , R ** is selected from 3-ClC ₆ H ₄ and 2-Me-4-ClC ₆ H ₃ . 9. The compound according to claim 1, where R ⁹ represents H; m represents 0; A represents CH; D represents CH; E represents OH; R * represents 4-Me-3-ClC ₆ H ₃ ; R ** is 4-Me-3-ClC ₆ H ₃ . 10. The compound according to claim 1, where R ⁹ represents H; m represents 0; A represents CH; D represents CH; E represents OH; R * represents 2-Me-4-ClC ₆ H ₃ ; R ** is 2-Me-4-ClC ₆ H ₃ . 11. The compound according to claim 1, where R ⁹ represents H; m represents 0; A represents CH; D represents CH; E represents 2-hydroxyethoxy, N-morpholinyl ethoxy, OCH ₂ CH ₂ CH ₂ COOH, COOH or OAc; R * represents 4-Me-3-ClC ₆ H ₃ ; R ** is 4-Me-3-ClC ₆ H ₃ . 12. The compound according to claim 1, where R ⁹ represents H; m represents 1; A represents CH; D represents CH; E represents H; R * represents 4-Me-3-ClC ₆ H ₃ and R ** represents 4-Me-3-ClC ₆ H ₃ . 13. The compound according to claim 1, where the solvent in the composition of the adduct with the solvent is selected from a hydroxyl solvent and an amino solvent. 14. A compound selected from a complex of bis (3-chloro-4-methylphenyl) borinic acid with 3- (2-hydroxyethoxy) picolinic acid (107), a complex of bis (3-chloro-4-methylphenyl) borinic acid with 3- ( N-morpholinyl ethoxy) picolinic acid (108), a complex of bis (3-chloro-4-methylphenyl) borinic acid with 3- (OCH ₂ CH ₂ CH ₂ CO ₂ H) picolinic acid (109), a complex of bis (3-chloro- 4-methylphenyl) boric acid with 3-carboxypicolinic acid (110), a complex of bis (3-chloro-4-methylphenyl) borinic acid with 3-hydroxypicolinic acid (111), a complex of 3-chloro-4-methylphenyl, 4-methylphenyl- borinovo acids with 3-hydroxypicolinic acid (112), a complex of 3-chloro-4-methylphenyl, phenylethyl-borinic acid with 3-hydroxypicolinic acid (113), a complex of bis (3-chlorophenyl) borinic acid with 3-hydroxypicolinic acid (114), complex of bis (3-chloro-4-ethoxyphenyl) borinic acid with 3-hydroxypicolinic acid (115), complex of 5-bromo-2-chloro-6-fluorophenyl-4-chloro-2-fluorophenylborinic acid with 3-hydroxypicolinic acid (116 ), a complex of 4-chloro-2-methylphenyl-3-chlorophenylborinic acid with 3-hydroxypicolinic acid (117), a complex of bis (4-chloro-2-methylpheny k) boric acid with 3-hydroxypicolinic acid (118), a complex of bis (3-chloro-4-methylphenyl) boric acid with 3-OAc-picolinic acid (119), and a complex of bis (3-chlorophenyl) borinic acid with 6-amino -3-hydroxypicolinic acid (122) and their salts and adducts with a solvent. 15. A compound selected from a complex of bis (3-chlorophenyl) borinic acid with 1- (2-morpholino-4-yl-ethyl) -imidazole acetate (101), a complex of bis (3-chlorophenyl) borinic acid with 2- (hydroxyisopropyl) -3 -hydroxypyridine (102), a complex of bis (4-chlorophenyl) borinic acid with 2- (hydroxyisopropyl) -3-hydroxypyridine (103), a complex of bis (4-methyl-3-chlorophenyl) borinic acid with 2-hydroxymethyl-1N-benzylimidazole (104), a complex of bis (3-chlorophenyl) borinic acid with 2- (hydroxymethyl) pyridine (105), bis (3-chloro-4-methylphenyl) boric acid ester and 4- (hydroxy) benzimidazole (120), bis (3-chlorophenyl) borinic acid ester and 4- (hydroxyethyl) imidazole (121), a complex of bis (3-chlorophenyl) borinic acid with 6-amino-3-hydroxypicolinate (122), a complex of bis (3-chlorophenyl) borinic acid with imidazole acetate (123), bis (4-chlorophenyl) boric acid ester and 4- (hydroxymethyl) imidazole (126), bis (3-chloro-4-methylphenyl) boric acid ester and 1-benzyl-4- (hydroxymethyl) - imidazole (127), bis (3-chloro-4-methylphenyl) borinic acid ester and 1-methyl-2- (hydroxymethyl) imidazole (128), bis (3-chloro-4-methylphenyl) borinic acid ester and 1-ethyl -2- (hydroxymethyl) -imidazole (129), bis (3-chloro-4-methylphenyl) borinic acid ester and 1-methyl-4- (hydroxymethyl) imidazole (130), a complex of bis (3-chloro-4-methylphenyl) boric acid with 2-pyridylethanol (131), a complex of bis (4-chlorophenyl) borinic acid with 2-pyridylmethanol (132), a complex of bis (4-fluorophenyl) borinic acid with 2-pyridylmethanol (133) and their salts and solvent adducts. 16. The compound according to any one of claims 1, 7-12, 15, having the following structure:

where R *** is selected from H and alkyl. 17. A pharmaceutical composition having antibacterial activity, containing a compound according to any one of claims 1, 9, 14 or 15 or a salt thereof in a pharmaceutically acceptable carrier. 18. The composition according to p. 17 in a form selected from a tablet, pill, capsule, liquid, gel, syrup, suspension and suspension. 19. The composition according to 17, which further comprises an excipient selected from sugar, a fiber preparation and a dispersant. 20. The composition according to claim 19, in which the specified sugar is selected from lactose, sucrose, mannitol and sorbitol. 21. The composition of claim 19, wherein said fiber preparation is selected from corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and polyvinylpyrrolidone. 22. The composition according to claim 19, in which the dispersing agent is selected from agar, alginic acid and its salts. 23. The composition according to 17, in which the carrier is contained in a solid phase or gel phase. 24. The composition according to item 23, in which the carrier is selected from calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives, gelatin and polyethylene glycol. 25. The composition of claim 17, wherein the salt of said compound is a salt formed with a pharmaceutically compatible acid or base. 26. The composition according A.25, in which the pharmaceutically compatible salt is formed with an acid selected from hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, phosphoric, hydrobromic, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric , benzoic, citric, maleic, hydroiodic and alkanoic acids. 27. The composition according to p, in which the alkanoic acid forming the salt has the formula HOOC- (CH ₂ ) _n -CH ₃ where n is an integer from 0 to 4. 28. The composition of claim 25, wherein the pharmaceutically compatible salt formed with the base is selected from sodium, potassium, calcium, and ammonium salts. 29. A method of treating a disease caused by microbes in a patient affected by it, comprising administering to said patient a therapeutically effective amount of a compound according to any one of claims 1, 9, 14 or 15. 30. The method according to clause 29, wherein said microbe is a bacterium. 31. The method of claim 30, wherein said bacterium is a gram-positive bacterium. 32. The method of claim 31, wherein said gram-positive bacterium is selected from the group comprising Staphylococcus spp., Streptococcus spp., Bacillus spp., Mycobacterium spp., Corynebacterium spp., Clostridium spp., Actinomyces spp., Enterococcus spp. And Streptomyces spp. 33. The method of claim 30, wherein said bacterium is a gram-negative bacterium. 34. The method according to claim 33, wherein said gram-negative bacterium is selected from the group comprising Acinetobacter species, Neisseria species, Pseudomonas species, Brucella species, Agrobacterium species, Bordetella species, Escherichia species, Shigella species, Yersinia species, Salmonella species, species Klebsiella, Enterobacter spp., Haemophillus spp., Pasteurella spp., Streptobacillus spp., Spirochete spp., Campylobacter spp., Vibrio spp. And Helicobacter spp. 35. The method of claim 30, wherein said bacterium is selected from the group comprising Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, Enterococcus faecalis, Enterococcus la. Bacillus anthracis, Mycobacterium avium, Mycobacterium tuberculosis, Acinetobacter baumanii, Corynebacterium diphtheria, Clostridium perfringens, Clostridium botulinum, Clostridium tetani, Neisseria gonorrhoeae, Neisseria meningitidis, Pseudomonas aeruginosa, Legionella pneumophila, Escherichia coli, Yersinia pestis, Haemophilus influenzae, Helicobacter pylori, Campylobacter fetus Campylobacter jejuni. Vibrio cholerae. Vibrio parahemolyticus, Trepomena pallidum, Actinomyces israelii, Rickettsia prowazekii, Rickettsia rickettsii, Chlamydia trachomatis, Chlamydia psittaci, Brucella abortus, Agrobacterium tumefaciens and Francisella tularensis. 36. The method according to clause 29, wherein said disease is selected from actinomycosis, anthrax, bacterial dysentery, botulism, brucellosis, cellulitis, cholera, conjunctivitis, cystitis, diphtheria, bacterial endocarditis, epiglottitis, gastroenteritis, glanders, gonorrhea, disease ” ", leptospirosis, septic meningitis, plague, bacterial pneumonia, postpartum sepsis, rheumatic fever, Rocky Mountain spotted fever, scarlet fever, streptococcal pharyngitis, syphilis, tetanus, tuberculosis, tularemia, typhoid fever, rash typhoid and whooping cough. 37. A method of treating a disease caused by fungi or yeast in a patient affected by it, comprising administering to said patient a therapeutically effective amount of a compound according to any one of claims 1, 9, 14 or 15. 38. A method of killing a microorganism or inhibiting the growth of a microorganism, comprising contacting said microorganism with a compound selected from compounds according to any one of claims 1, 9, 14 or 15. 39. The method of claim 38, wherein said compound is used in a therapeutically effective amount. 40. The method of claim 38, wherein said microorganism is a bacterium. 41. The method of claim 40, wherein said bacterium is a gram-positive bacterium. 42. The method according to paragraph 41, wherein said gram-positive bacterium is selected from the group comprising Staphylococcus spp., Streptococcus spp., Bacillus spp., Mycobacterium spp., Corynebacterium spp., Clostridium spp., Actinomyces spp., Enterococcus spp. And Streptomyces spp. 43. The method of claim 40, wherein said bacterium is a gram-negative bacterium. 44. The method according to item 43, wherein said gram-negative bacterium is selected from the group comprising Acinetobacter species, Neisseria species, Pseudomonas species, Brucella species, Agrobacterium species, Bordetella species, Escherichia species, Shigella species, Yersinia species, Salmonella species, Klebsiella species , Enterobacter spp., Haemophilus spp., Pasteurella spp., Streptobacillus spp., Spirochet spp., Campylobacter spp., Vibrio spp. and Helicobacter spp. 45. The method of claim 40, wherein said bacterium is selected from the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pyogenes, Streptococcus agalactiae. Streptococcus pneumoniae, Enterococcus faecalis, Enterococcus faecium, Bacillus anthracis, Mycobacterium avium, Mycobacterium tuberculosis, Acinetobacter baumanii, Corynebacterium diphtheria, Clostridium perfringens, Clostridium botulinum, Clostridium tetani, Neisseria gonorrhoeae, Neisseria meningitidis, Pseudomonas aeruginosa, Legionella pneumophila, Escherichia coli, Yersinia pestis , Haemophilus influenzae, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni. Vibrio cholerae. Vibrio parahemolyticus, Trepomena pallidum, Actinomyces israelii, Rickettsia prowazekii, Rickettsia rikettsii, Chlamydia trachomatis, Chlamydia psittaci, Brucella abortus, Agrobacterium tumefaciens and Francisella tularensis. 46. The method according to § 38, wherein said microorganism is a fungus or yeast. 47. The method of claim 46, wherein said yeast is selected from the group consisting of Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis and Candida parapsilosis. 48. The method of claim 46, wherein said fungus is selected from the group consisting of Aspergilius species, Trichophyton species, Microsporum species, Cryptococcus neoformans, Blastomyces dermatitidis, Coccidiodes immitis, Histoplasma capsulatum and Paracoccidioies brasiliensis. 49. The method according to paragraph 41, wherein said gram-positive bacterium is selected from Staphylococcus species, Streptococcus species, Bacillus species, Clostridium species and Enterococcus species. 50. The method of claim 49, wherein said gram-positive bacterium belongs to the species Staphylococcus aureus. 51. The method of claim 50, wherein said gram-positive bacterium belongs to the species Staphylococcus aureus.