Prodrug of boron compound and its use in the treatment of bacterial infection

Abstract

The present application describes prodrugs of antibacterial organic boron compounds of formula I, or salts thereof, pharmaceutical compositions thereof, and methods of use and production thereof. [Chemical 1] TIFF2025520238000026.tif49148

Description

Technical Field

[0001] The present application relates to prodrugs of antibacterial boron organic compounds, pharmaceutical compositions thereof, methods of use thereof, and methods of manufacture thereof.

Background Art

[0002] Due to the increasing drug resistance of bacteria, new antibacterial compounds are needed for the treatment of microbial infections. These new drugs need to have useful activity against major mammalian pathogens including Gram-negative bacteria such as Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae, and major Gram-positive bacteria such as multi-drug resistant staphylococci and streptococci. Drugs that function by new mechanisms of action are particularly advantageous for avoiding undesirable cross-resistance with existing drugs.

[0003] For many patients with bacterial infections, oral formulations are the optimal choice. Oral administration has the excellent advantages of avoiding infections associated with intubation, reducing drug costs, and reducing hidden costs such as the need for healthcare professionals and equipment for intravenous administration of antibiotics compared to the intravenous administration route. Oral administration is particularly important for improving compliance in patients who require long-term treatment.

[0004] Some antibacterial boron organic compounds have been previously described in PCT applications WO2008 / 157726 and WO2010 / 080558 and US application US 2009 / 0227541. So far, such compounds have not been approved for human anti-infective treatment.

[0005] The boron-containing organic compounds (shown below) are described in US Patent Application US 2013 / 0165411. Such compounds are particularly active against Gram-negative bacteria such as Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae. Also, this type of molecule showed good therapeutic effects in a mouse thigh infection model with reduced neutrophils of Pseudomonas aeruginosa after subcutaneous administration. However, no oral formulations of this molecule have been reported so far. In fact, many antibiotics including cephalosporins can only be administered by intravenous injection. Drugs with low oral bioavailability are not suitable for the development of oral drugs because there is insufficient sufficient exposure of the drug. When the oral bioavailability is low, higher doses may be required, which may cause additional side effects.

[0006]

Chemical formula

[0007] There are mainly two ways to improve the oral absorbability of a compound by improving its membrane permeability. One involves changing the chemical structure, and the other involves developing a formulation without changing the molecular structure. The former can be achieved by attaching relatively small structural modifying groups such as alkyl groups or acyl groups to appropriate substituents within the drug such as carboxy groups or amino groups to form prodrugs.

[0008] The preferred compounds provided in the present application are stable in prodrug form before absorption and show better absorption due to their unique prodrug form. These prodrug molecules are rapidly chemically and / or enzymatically converted to the active drug within body compartments such as the intestinal tract, liver, and / or plasma after being administered to a mammal in need of treatment. Such desired conversion to the active drug can occur during and / or after absorption.

[0009] However, it is difficult to develop an ideal prodrug that satisfies all of the above conditions. For example, a prodrug having an ester bond is liable to hydrolysis and may affect the chemical stability before absorption. An amide bond can cause significant changes in physical properties and, as a result, may adversely affect the membrane permeability (such as oral absorption ability). Furthermore, an amide bond is not easily hydrolyzed and may affect the biological conversion of the compound into its active form and the plasma concentration of the active form. Moreover, the enzyme that controls the biotransformation of the prodrug into its active form is substrate-specific, and in particular, the steric hindrance for inserting a substituent for forming the prodrug can block the reaction of the enzyme, making it difficult to predict the pharmacokinetic properties of the prodrug. For these reasons, it is impossible to predict how the prodrug increases the plasma concentration of the active form, whether the prodrug improves the membrane permeability, and / or whether the prodrug is converted into the active form in vivo.

Prior Art Documents

Patent Documents

[0010]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0011] This application describes a novel prodrug of a boron compound having high antibacterial activity against Gram-negative bacteria such as Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae.

[0012] Using animal experiments with the active form and the prodrug as test drugs, it has been found that the prodrug described in this application enhances the in vivo exposure of the corresponding active form.

Means for Solving the Problems

[0013] In one aspect, the present specification provides a compound of Formula I or a pharmaceutically acceptable salt, complex or tautomer thereof,

[0014]

Chemical formula

[0015] wherein, R 1 is selected from the group consisting of H, C 1-24 alkyl-C(=O)-, C 1-24 alkoxy-C(=O)-, C 3-7 cycloalkyl-C(=O)-, heteroalkyl-C(=O)-, aryl-C(=O)-, heteroaryl-C(=O)-, and (5-methyl-1,3-dioxo-2-one-4-yl)methyl, and, R 2 is selected from the group consisting of C 1-24 alkyl-C(=O)-, C 1-24 alkoxy-C(=O)-, C 3-7 cycloalkyl-C(=O)-, heteroalkyl-C(=O)-, aryl-C(=O)-, heteroaryl-C(=O)-, and (5-methyl-1,3-dioxo-2-one-4-yl)methyl, or, R 1 and R 2 together form a heterocyclic group selected from the group consisting of 1,3-dioxane, 2-C 1-6 alkyl-1,3-dioxane, 2,2-di(C 1-6 alkyl)-1,3-dioxane, 2-methyl-1,3-dioxane, 2-aryl-1,3-dioxane, 2-(2-carboxyphenyl)-1,3-dioxane, 2-(4-carboxyphenyl)-1,3-dioxane, or 2-C 1-6 alkylOC(=O)-1,3-dioxane, each of which is optionally substituted with 1 to 4 R 3 s, R 3Each time it appears, it is independently selected from the group consisting of a halogen, a hydroxyl group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, an aryl group, and a heteroaryl group, or when bonded to adjacent carbons, two Rs 3 groups together with the carbon to which they are attached form a fused C3-C6 cycloalkyl group, or when bonded to the same carbon, two Rs 3 groups together with the carbon to which they are attached form a spiro C3-C6 cycloalkyl group, wherein each R 3 is independently optionally substituted with 1 to 3 fluorines, hydroxyl groups or C1-C3 alkyl groups.

[0016] In a preferred embodiment of formula I, R 1 and R 2 are both alkyl groups.

[0017] In another preferred embodiment of formula I, R 1 and R 2 are both C1-C6 alkyl-C(=O)-.

[0018] In another aspect, the present specification provides a compound of formula II or a pharmaceutically acceptable salt thereof,

[0019]

Chemical formula

[0020] wherein R 4 is selected from the group consisting of C 1-24 alkoxy-C(=O)-, C 3-7 cycloalkyl-C(=O)-, heteroalkyl-C(=O)-, aryl-C(=O)-, heteroaryl-C(=O)-, and (5-methyl-1,3-dioxo-2-one-4-yl)methyl.

[0021] In another aspect, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, complex or tautomer thereof, and a pharmaceutically acceptable carrier.

[0022] In another aspect, the present application provides a pharmaceutical composition comprising a compound of Formula I or II or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0023] In another aspect, the present application provides a method for treating microbial infections in mammals, which comprises administering to a mammal in need of treatment a therapeutically effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, complex or tautomer thereof. The compound of Formula I or Formula II, or a pharmaceutically acceptable salt, complex or tautomer thereof, can be administered orally, parenterally, transdermally, topically, rectally, or intranasally in the form of a pharmaceutical composition comprising an inhalation solution or powder composition.

[0024] In another aspect, the compound of the present invention or a pharmaceutically acceptable salt, complex or tautomer thereof is administered orally to a mammal in the form of a pharmaceutical composition.

[0025] In another aspect, the present application provides a method for treating Mycobacterium microbial infections in humans or other warm-blooded animals by administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof. The compound of Formula I or Formula II can be administered orally, parenterally, transdermally, topically, rectally, or intranasally in the form of a pharmaceutical composition.

[0026] In another aspect, the present application provides compositions and methods for treating microbial infections caused by microorganisms selected from Gram-negative bacteria including, but not limited to, Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae.

[0027] In one embodiment, the method is used to treat infections of the skin, soft tissue, respiratory system, blood, intraperitoneal cavity, urinary tract, or eye.

[0028] In another aspect, the present application provides novel intermediates and methods for producing the compounds of formula I.

BEST MODE FOR CARRYING OUT THE INVENTION

[0029] Unless otherwise specified, the following terms used in this specification and the claims have the meanings shown below.

[0030] The carbon atom content of various moieties containing hydrocarbons is represented by a prefix indicating the minimum and maximum number of carbon atoms of that moiety, i.e., the prefix C i-j represents a carbon atom moiety from integer "i" to integer "j". For example, C 1-7 The alkyl group means an alkyl group having 1 to 7 (including 1 to 7) carbon atoms.

[0031] The terms "alkyl group", "alkenyl group", etc. mean linear and branched chain groups. However, for individual groups such as "propyl group", only linear chain groups are included, and for branched chain isomers such as "isopropyl group", only branched chain groups are included. Groups such as alkyl groups and alkenyl groups may be substituted with 1, 2 or 3 substituents selected from the group consisting of halogen groups, aryl groups, Het 1 or Het 2 and may be substituted with 1, 2 or 3 substituents selected from the group consisting of. Representative examples include difluoromethyl group, 2-fluoroethyl group, trifluoroethyl group, -CH=CH-aryl group, -CH=CH-Het 1 , -CH2-phenyl group, etc., but are not limited thereto.

[0032] The term cycloalkyl group means a cyclic saturated monovalent hydrocarbon group having 3 to 6 carbon atoms such as cyclopropyl group and cyclohexyl group. The cycloalkyl group may be substituted with 1, 2 or 3 substituents selected from the group consisting of halogen groups, aryl groups, Het 1 or Het 2 and may be substituted with 1, 2 or 3 substituents selected from the group consisting of.

[0033] The term "heteroalkyl" means an alkyl group or cycloalkyl group as defined above having a substituent containing a heteroatom selected from N, O or S(O), where n is an integer from 0 to 2, and the substituents include a hydroxyl group (OH), C n alkoxy group, amino group, thio group (SH), etc. Representative substituents include -NR 1-4 R a R b , -OR a or -S(O) n R c , where R a is H, C 1-4 alkyl group, C 3-6 cycloalkyl group, optionally substituted aryl group, optionally substituted heterocycle, or -COR (where R is C 1-4 alkyl group), R b is H, C 1-4 alkyl group, -SO2R (where R is C 1-4 alkyl group or C 1-4 hydroxyalkyl group), -SO2NRR' (where R and R' are independently of each other H or C 1-4 alkyl group), -CONR'R'' (where R' and R'' are independently of each other H or C 1-4 alkyl group), n is an integer from 0 to 2, and R c is H, C 1-4 alkyl group, C 3-6 cycloalkyl group, optionally substituted aryl group or NR a R b , where R a and R b are as defined above. Representative examples include, but are not limited to, 2-methoxyethyl (-CH2CH2OCH3), 2-hydroxyethyl (-CH2CH2OH), hydroxymethyl (-CH2OH), 2-aminoethyl (-CH2CH2NH2), 2-dimethylaminoethyl (-CH2CH2NHCH3), benzyloxymethyl, thiophen-2-ylthiomethyl, etc.

[0034] The term "halogen" means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0035] The term "aryl group" means a phenyl group, a biphenyl group or a naphthyl group optionally substituted with 1 to 3 substituents independently selected from halogen, -C 1-4 alkyl group, -OH, -OC 1-4 alkyl group, -S(O) n C 1-4 alkyl group (wherein n is 0, 1 or 2), -C 1-4 alkyl NH2, -NHC 1-4 alkyl group, -C(=O)H or -C=N-OR d (wherein R d is H or -C 1-4 alkyl group).

[0036] Het 1 is, each time it appears, independently a 5- or 6-membered C-bonded heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring. Het 2 is, each time it appears, independently a 5- or 6-membered N-bonded heterocyclic ring having 1 to 4 nitrogens in the ring and optionally having 1 oxygen or sulfur in the ring.

[0037] "Optional" or "optionally" means that the event or situation described thereafter may occur but does not necessarily occur, and the description includes both the case where the event or situation occurs and the case where it does not occur. For example, "an aryl group optionally mono- or disubstituted with an alkyl group" means that the alkyl group may or may not be present, and the description includes both the case where the aryl group is mono- or disubstituted with an alkyl group and the case where the aryl group is not substituted with an alkyl group.

[0038] Compounds having the same molecular formula but different in the nature or order of atomic bonds or different in the spatial arrangement of atoms are called "isomers". Isomers different in the spatial arrangement of atoms are called "stereoisomers".

[0039] Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are mirror images that cannot be superimposed on each other are called "enantiomers". For example, if a compound has an asymmetric center, it is bonded to four different groups, and a pair of enantiomers is possible. Enantiomers are characterized by the absolute configuration of their asymmetric center and are described by the (R)- and (S)-stereochemistry rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarization and is designated as dextrorotatory or levorotatory (i.e., the (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal ratios of enantiomers is called a "racemic mixture".

[0040] The compounds described in the present application may have one or more asymmetric centers, and thus such compounds can be produced as individual (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise stated, the description or naming of a particular compound in the specification and claims is intended to include its individual enantiomers and mixtures, racemates or other forms. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition J. March, John Wiley and Sons, New York, 1992).

[0041] "Pharmaceutically acceptable carrier" means a carrier that is generally safe, non-toxic and free of other undesirable biological effects and is useful for preparing pharmaceutical compositions, including carriers useful for veterinary and human pharmaceuticals. The "pharmaceutically acceptable carrier" used in the specification and claims includes one or more such carriers.

[0042] "Pharmaceutically acceptable salt" of a compound means a pharmaceutically usable salt that has the pharmacological activity required of the parent compound. Such salts are (1) Acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc., or (2) Salts formed by substituting acidic protons present in the parent compound with metal ions such as alkali metal ions, alkaline earth metal ions, aluminum ions, etc., or salts formed by blending with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.

[0043] The term "tautomer" means two or more forms or isomers of an organic compound that can be converted into each other by a general chemical reaction called tautomerization, and is usually the same as that described by Smith et al. in Advanced Organic Chemistry. 2001, 5th Ed. NY: Wiley Interscience., p. 1218-1223. The concept of tautomerization is called tautomerism. Tautomerism may involve a change from a ring structure to an open structure, such as the interconversion between the cyclic pyran form and the open-chain form of glucose, for example, as observed, by the formation and cleavage of C-O bonds. The degree of tautomerism is usually affected by solvent effects such as hydration with water and medium acidity. The related processes for cyclic boron compounds may include the formation and cleavage of B-O bonds as follows.

[0044] [Chem.]

[0045] "Treatment" of a disease (1) preventing the disease, i.e., in a mammal that may be exposed to or is susceptible to the disease but has not experienced or manifested the symptoms of the disease, preventing the progression of the clinical symptoms of the disease; (2) suppressing the disease, i.e., arresting or reducing the progression of the disease or its clinical symptoms, or (3) alleviating the disease, i.e., causing regression of the disease or its clinical symptoms.

[0046] "Therapeutically effective amount" means an amount of a compound that, when administered to a mammal for treating a disease, is sufficient to affect the treatment of the disease. The "therapeutically effective amount" varies depending on the compound, the disease and its severity, the age, weight, etc. of the mammal to be treated.

[0047] "Prodrug" means any compound that, when administered to a mammalian subject, releases the active parent drug in vivo by the compounds described in this application. The prodrugs of the compounds of the present invention are prepared by modifying the functional groups present in the compounds of the present invention, and the modification can cleave in vivo to release the parent compound. In some embodiments, the prodrug comprises a compound described in the present invention, wherein the hydroxy, sulfhydryl, amide, or amino group in the compound is bonded to any group that can cleave in vivo to regenerate the free hydroxyl, amide, amide, or sulfhydryl group, respectively.

[0048] The term "mammal" refers to all mammals including humans, domestic animals, and companion animals.

[0049] "Patient" means a mammal including non - primates (such as cows, pigs, horses, cats, dogs, rats, mice, etc.) and primates (such as monkeys such as cynomolgus monkeys, chimpanzees, humans, etc.), or, for example, a human. In some embodiments, the patient is a human.

[0050] The compounds described in this application are usually named according to the IUPAC or CAS naming system. Abbreviations well - known to those skilled in the art (for example, "Ar" representing an aryl group, "Ph" representing a phenyl group, "Me" representing a methyl group, "Et" representing an ethyl group, "h" representing time, "rt" or "r.t." representing room temperature) can be used.

[0051] Exemplary embodiments The specific and preferred values of the groups, substituents, and ranges listed below are for illustrative purposes only and do not exclude other defined values of the groups and substituents or other values within the defined ranges.

[0052] In some preferred compounds described in this application, C 1-4 The alkyl group may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec - butyl, or their isomeric forms.

[0053] In some of the preferred compounds described in the present application, C 3-6 The cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or their isomeric forms.

[0054] In some of the preferred compounds described in the present application, C 1-4 Heteroalkyl may be hydroxymethyl, hydroxyethyl or 2-methoxyethyl.

[0055] In some of the preferred compounds described in the present application, the halogen may be fluorine (F) or chlorine (Cl).

[0056] Preferred groups of the compounds of formula I include the following. That is

[0057]

Chemical formula

[0058] Further preferred groups of the compounds of formula I include the following. That is

[0059]

Chemical formula

[0060] Another preferred group of the compounds of formula I includes the following. That is

[0061]

Chemical formula

[0062] Yet another preferred group of the compounds of formula I includes the following. That is

[0063]

Chemical formula

[0064] In some embodiments, the pharmaceutically acceptable salt of the compound is preferably a hydrochloride salt.

[0065] General synthetic methods In some embodiments, the compounds described in the present application may be prepared according to one or more of the schemes described below. These methods can be used directly or can be modified by a trained chemist to prepare the important intermediates and specific compounds described in the present application.

[0066] Other general methods for preparing some bicyclic boron compounds are described, for example, in US Patent Application Publications US2013 / 016541, US2009 / 0227541, and PCT Patent Application 2010 / 080558.

[0067] It should also be understood that the racemic compounds or intermediates described in the present application can be separated into the desired optically active isomers using conventional means including, but not limited to, chiral liquid chromatography or cocrystallization with chiral auxiliary reagents (e.g., commercially available chiral acids or amines).

[0068] Suitable synthetic sequences can be readily selected according to the specific structures described in the present application and are within the scope of the art known to those practicing organic synthesis, such as methods compiled in available chemical databases such as CAS Scifinder and Elesevier Reaxys. Based on these general methods, the realization of the production of the compounds described in the present application is straightforward and can be carried out within the scope of general expertise. Some of the general synthetic methods for preparing the compounds described in the present application are described in the following Schemes 1-6 (not limiting and used for illustration only).

[0069] The general method for synthesizing the compound of formula I described in the present application is described in General Scheme 1.

[0070] Scheme 1. General synthesis of prodrugs.

[0071] [Chemical formula]

[0072] Non-limiting examples of esterifying agents for the conversion described in (a) include, but are not limited to, acyl chlorides, acid anhydrides, or acids with EDC.

[0073] The deprotecting agent for the conversion described in (b) depends on the protecting group used. For example, in some embodiments, R a and R b are independently selected from H, Bn, Boc, Fmoc, Cbz, etc.

[0074] Other detailed synthetic schemes for synthesizing the specific compounds described in this application are illustrated by the methods described in the following examples.

[0075] Examples The examples described in this application are illustrated by the following examples. These illustrations are for illustrative purposes only and do not limit the scope of the present disclosure. Common abbreviations well known to those skilled in synthetic techniques are used throughout. 1 1H NMR spectra (d, ppm) are recorded on a 300 MHz instrument using DMSO-d6 unless otherwise specified. Mass spectrometry data for the cationization method is provided. Chromatography means silica gel chromatography unless otherwise specified. TLC means thin layer chromatography. HPLC means reverse phase HPLC. Unless otherwise specified, all reagents are commercially available or prepared by conventional methods described in existing literature.

[0076] Example 1 (2S)-3-Acetoxy-1-[[(3S)-3-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[2,1-c][1,2]oxaborol-7-yl]oxy]propan-2-yl acetate hydrochloride

[0077]

Chem.

[0078] The preparation scheme of the compound of Example 1 is as follows.

[0079]

Chem.

[0080] Intermediate 2. Ac2O (32 μL, 0.33 mmol) was added dropwise to a solution of Intermediate 1 (60 mg, 0.26 mmol, prepared as described in US Patent Application US 2013 / 0165411) and pyridine (31 μL, 0.33 mmol) in DCM (2 mL), and the resulting mixture was stirred for 2 hours. After completion of the reaction, the solvent was removed by concentration, and the residue was purified by pre-HPLC to obtain Intermediate 2 (25 mg): MS (m / z): 438 [m+H].

[0081] Example 1 Intermediate 2 was dissolved in a dioxane solution of 5M HCl (2 mL) at room temperature, and the resulting mixture was stirred for 1 hour. Then, the mixture was lyophilized to obtain the compound of Example 1 (16.9 mg) as a pale yellow powder. MS (m / z): 338 [M+H]. 11H NMR: (400 MHz, D2O): 7.48 (t, J = 8.0 Hz, 1H); 7.01 (d, J = 7.6 Hz, 1H); 6.92 (dd, J = 12.0, 8.0 Hz, 1H); 5.35 (dd, J = 7.4, 3.0 Hz, 1H); 4.35~4.17 (m, 5H); 3.73~3.60 (m, 1H); 3.56~3.51 (m, 2H); 3.08~3.01 (m, 1H); 1.99 (s, 3H), 1.98 (s, 3H).

[0082] The following compounds were synthesized according to the steps described in Example 2.

[0083] [Table 1A]

[0084] [Table 1B]

[0085] Example 4 [(2S,6S)-2-(Aminomethyl)-4-bora-3,5,8-trioxatricyclo[7.3.1.04,13]trideca-1(12),9(13),10-triene-6-yl]methyl 2-methylpropanoate hydrochloride

[0086] [Chemical Structure]

[0087] The compound of Embodiment 4 was prepared according to the method described in U.S. Patent Application No. 2013 / 0165411.

[0088] Example 5 [(2S,6R)-2-(Aminomethyl)-4-bora-3,5,8-trioxatricyclo[7.3.1.04,13]trideca-1(12),10-diene-6-yl]methanol hydrochloride

[0089] [Chemical formula]

[0090] The compound of Embodiment 5 was prepared according to the method described in U.S. Patent Application No. 2013 / 0165411.

[0091] Example 7 [(2S,6S)-2-(Aminomethyl)-4-bora-3,5,8-trioxatricyclo[7.3.1.04,13]trideca-1(12),9(13),10-triene-6-yl]methyl acetate hydrochloride

[0092] [Chemical formula]

[0093] The compound of Embodiment 7 was prepared according to the method described in U.S. Patent Application No. 2013 / 0165411.

[0094] Example 8 [(2S,6S)-2-(Aminomethyl)-4-bora-3,5,8-trioxatricyclo[7.3.1.04,13]trideca-1(12),9(13),10-triene-6-yl]methyl propionate hydrochloride

[0095] [Chemical formula]

[0096] The compound of Embodiment 8 was prepared according to the method described in U.S. Patent Application No. 2013 / 0165411.

[0097] Utility and Measurement The compounds described in this application are prodrugs and are expected to be converted into the parent boron compounds to exhibit antibacterial effects. The antibacterial activity of the parent boron compounds is disclosed in US Patent Application US 2013 / 0165411. Therefore, the compounds described in this application are useful antibacterial agents and can effectively combat many human and veterinary pathogens, including Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae.

[0098] The in vitro activity of the compounds described in this application can be evaluated by standard test procedures such as the measurement of the minimum inhibitory concentration (MIC) described in, for example, "Approved Standard. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, 3rd ed., 1993" issued by the Clinical and Laboratory Standards Institute in Villanova, Pennsylvania, USA. Low MIC values indicate high antibacterial activity, while high MIC values indicate a decrease in antibacterial activity (in the latter case, high drug concentrations are required to eradicate the pathogen). Generally, an MIC value of ≤ 4 - 8 μg / mL or less indicates the therapeutic effect of the antibacterial agent (i.e., it is suitable for treatment), and an MIC value of ≥ 16 μg / mL indicates that the test compound lacks therapeutically useful activity.

[0099] The useful in vitro activity (efficacy) of the representative compounds described in this application against Mycobacterium such as Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae is shown in the MIC data in Table 2.

[0100] As is clear from the data in Table 2, the reference compound of Example 5 has high activity (MIC range is 2 - 4 μg / mL) against many Gram-negative bacteria (including Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae). As typical of prodrug derivatives, the prodrugs of Example 5, such as the compounds of Examples 2, 3, 4, and 8, are considered to be inactive.

[0101]

Table 2

[0102] In addition to in vitro activity (efficacy is determined as MIC), it is important that the in vivo efficacy or ability to eradicate bacterial pathogens affects the survival of mammals under treatment. As is well known, compounds with similar in vitro antibacterial efficacy (MIC) can exhibit significantly different activities in vivo. Thus, some effective compounds may bring about the desired therapeutic effect, or other ineffective compounds may lack a useful anti-infective effect. This is very important for actual treatment results and is determined by various factors that affect the behavior of the compound in the body, such as absorption, distribution, metabolism, and excretion.

[0103] Furthermore, in vivo activity (or therapeutic effect) is generally the most important activity for prodrug compounds, which are generally inactive in vitro and release the active drug after administration to a mammal in need of treatment.

[0104] To establish the in vivo efficacy of the compounds described in this application, a Pseudomonas aeruginosa mouse lung infection model is performed by administering the test compound in a manner similar to the method described by Andes et al. in Antimicrobial Agents and Chemotherapy, 2002, 46(11), 3484 - 3489. In this model, the greater the decrease in bacterial colony-forming units (CFU), the more favorable the therapeutic effect (more bacterial eradication), and the smaller the decrease in bacterial colony-forming units, the less effective (less bacterial eradication). The in vivo antibacterial effect is also called "efficacy", and the term "potency" is generally used for in vitro activity (represented by MIC).

[0105] In the case of lung infection in Pseudomonas aeruginosa-infected ICR mice (randomly grouped into groups of 6 mice each), the reference example 5 was orally administered at a dose of 10 mg / kg once a day. Compared with the untreated control group, the reference compound of example 5 showed weak antibacterial efficacy, causing a 0.53 log reduction in CFU in the lungs. As oral prodrugs, the compounds of examples 2 and 8 were also force-fed orally at a dose of 10 mg / kg once a day. The prodrug itself had no antibacterial efficacy but showed good in vivo efficacy. Surprisingly, when administered at 10 mg / kg, the compounds of examples 2 and 8 showed far better effects than the reference compound of example 5, with a 1.77 and 0.82 log reduction in CFU in the lungs. This data strongly supported that the prodrugs of examples 2 and 8 were converted into the reference compound of example 5 after oral administration and exerted antibacterial activity. This data also supported a high conversion rate.

[0106]

Table 3

[0107] To further elucidate the therapeutic potential of drug compounds, pharmacokinetic (PK) data are used to establish important parameters for predicting treatment outcomes, such as the area under the curve (AUC) that monitors the change in drug concentration over time in the whole body. Therefore, a higher AUC value indicates a greater exposure to the drug, which is usually associated with greater therapeutic potential because a larger amount of the drug is available to combat mammalian infections. Conversely, a low AUC value leads to a reduced exposure to the drug under study and a reduced amount of antibiotic available to combat bacterial infections. For this purpose, the compounds described in the present application were tested in an orally administered rat PK model in a manner similar to the method described in the monograph Current Protocols in Pharmacology, 2005, 7.1.1 - 7.1.26, John Wiley & Sons, Inc.

[0108] All compounds were administered to Sprague-Dawley rats by intravenous injection (iv) or forced oral administration (rats were randomly grouped into groups of three). Since the prodrugs were expected to be converted to the parent molecules in vivo, only the parent compound (the compound of Example 5) was measured for all samples. As shown in Table 4, the parent compound of Example 5 has only a low oral bioavailability of 15%. This low bioavailability and low exposure (AUC) and C max are not suitable for development as an oral drug. Very surprisingly, the pharmacokinetic data of the compounds of the present invention showed that at the same dose of 5 mg / kg, the systemic exposure (AUC) and C max were significantly improved. Although the molecular weights of these prodrugs are higher than that of Example 5, the AUCs of Examples 1, 2, 3, 4, 6, 7 and 8 are all significantly higher than that of Example 5. For example, the compound of Example 2 showed an AUC of 2906 ng·h / mL and C ma x of 870 ng / mL. This unexpected result indicates that the exposure was significantly improved by 3.4-fold and C max was improved by 3-fold, which is consistent with the improvement in efficacy shown in Table 3. Due to the introduction of the substructure of the prodrug, the prodrug usually has a larger molecular weight. Therefore, by correcting the AUC with the dose and molecular weight (MW) to obtain the AUC per mole, the efficacy between the prodrugs can be compared. Importantly, compared with the compound of Example 4 previously described in US2013 / 0165411, the compound of Example 2 also showed a significantly higher AUC per mole.

[0109]

Table 4

[0110] In addition, in the lung distribution study conducted in Balb / C mice (3 mice at each time point), the exposure amount in the lung of Example 2 was much higher than the exposure in plasma (evaluated by the area under the concentration-time curve (AUC) in the lung / plasma). As shown in Table 5, the compounds of Example 5 and 2 were intravenously injected and orally administered at 10 mg / kg, respectively. In the analysis of Example 2, the concentrations of the parent compound (Example 5) and the prodrug (Example 2) in plasma and lung were measured. The prodrug (Example 2) was rapidly converted to Example 5, and almost no prodrug was detected in plasma. Compared with the AUC by intravenous injection of Example 5, the oral bioavailability of Example 5 generated in Example 2 was 83.95% in mice. Although the prodrug was rapidly converted, surprisingly, more Example 5 was detected in the lung, and the lung / plasma AUC ratio was 5.24, which was almost 2.2 times the AUC of Example 5 administered by intravenous injection. The high accumulation of the drug in the lung is particularly useful for the treatment of pneumonia, which is consistent with the excellent therapeutic effect of Example 2 in the Pseudomonas aeruginosa mouse lung infection model (Table 3).

[0111]

Table 5

[0112] Such a remarkable increase in in vivo exposure (AUC) in plasma and lung after oral administration of the compound of Example 2 was completely unexpected and very surprising. Other related compounds provided in this application also showed surprising increases in in vivo exposure. Therefore, the pharmacokinetic data in the orally administered rat model of the compound of Example 2 showed that the in vivo exposure and C max were significantly increased compared with the parent compound of Example 5.

[0113] The above complete representative data reveals the surprising excellent therapeutic potential of the compounds described in the present application and has beneficial unexpected advantages in terms of efficacy, effectiveness, and exposure. The significant and surprising increase in the main parameters of the three clearly different antibacterial compounds described in the present application provides significant benefits for the treatment of humans or mammals, including but not limited to convenient long-term oral administration, reduction of effective drug dosage, and reduction of potential side effects.

[0114] Dosage and pharmaceutical formulations Generally, the compounds described in the present application are administered in a therapeutically effective amount by an acceptable mode of administration of the formulations for similar uses. For example, the compounds described in the present application can be administered orally, parenterally, transdermally, topically, rectally, or intranasally. The actual amount of the compound described in the present application (i.e., the active ingredient) depends on many factors such as the severity of the disease to be treated (i.e., the infectious disease), the age and relative health status of the subject, the effect of the compound used, the route and form of administration, and other factors, all of which are within the authority of the attending clinician.

[0115] Data obtained from cell culture assays and animal studies can be used to prepare a series of dosages for administration to humans. The dosage of such a compound is preferably within a circulating concentration range that includes little or no toxicity, i.e., the ED 50 The dosage can vary within this range depending on the dosage form used and the route of administration used. For any of the compounds used in the methods described in the present application, the therapeutically effective amount can be initially estimated from cell culture assays. The dosage can be prepared in an animal model to be within the circulating plasma concentration range that includes the IC 50 (i.e., the concentration of the test compound that achieves half of the maximum suppression of symptoms). Such information can be used to more accurately determine the useful dosage for humans. The levels in plasma can be measured, for example, by high performance liquid chromatography.

[0116] When used as a medicine, the compounds described in this application are usually administered in the form of a pharmaceutical composition. These compounds can be administered by various routes including oral administration, parenteral administration, transdermal administration, topical administration, rectal administration and intranasal administration.

[0117] These compounds are effective both as injection compositions and oral compositions. Such compositions are prepared by methods well known in the pharmaceutical art and contain at least one active compound.

[0118] This application further describes a pharmaceutical composition containing one or more compounds described in this application and a pharmaceutically acceptable carrier as active ingredients. When preparing the compositions described in this application, the active ingredient is generally mixed with an excipient, diluted with an excipient, or enclosed in a carrier such that it can be in the form of a capsule, sachet, paper or other container. When the excipient is used as a diluent, it may be a solid, semi-solid or liquid material that functions as a medium, carrier or vehicle for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, troches, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid or liquid media), for example ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders.

[0119] When preparing the formulation, it may be necessary to grind the active compound to provide an appropriate particle size before combining it with other ingredients. If the active compound is substantially insoluble, it is usually ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size is usually adjusted by grinding to provide a substantially uniform distribution in the formulation, for example about 40 mesh.

[0120] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. Formulations may further include lubricants such as talc, magnesium stearate, mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl and propyl hydroxybenzoate esters, sweetening agents, and flavoring agents. The compositions described herein can be prepared by employing procedures known to those skilled in the art to provide an active ingredient that is released rapidly, sustainably, or with a delay after administration to a patient.

[0121] The amount of the active ingredient (i.e., the compounds described in the present application) in the pharmaceutical composition and its unit dosage forms can vary or be adjusted widely depending on the specific application, the potency of the specific compound, and the desired concentration.

[0122] The composition is preferably formulated in the form of unit dosage forms, and each dosage contains from about 5 to about 100 mg, more generally from about 10 to about 30 mg, of the active ingredient. The term "unit dosage form" means a physically discrete unit suitable as a unit dose for human subjects and other mammals, and each unit contains a predetermined amount of the active substance calculated in combination with a suitable pharmaceutical excipient to produce the desired therapeutic effect. Preferably, the compounds described in the present application are about 20% or less, more preferably about 15% or less, by weight of the pharmaceutical composition, and the remainder is a pharmaceutically inert carrier.

[0123] The active compound is effective over a wide range of dosage ranges and is generally administered in a pharmaceutically or therapeutically effective amount. However, it should be understood that the actual amount of the compound administered will be determined by the physician according to the circumstances to be treated, the severity of the bacterial infection being treated, the selected route of administration, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and other circumstances not included but relevant.

[0124] In the therapeutic use for treating or combating bacterial infections in warm-blooded animals, the compound or its pharmaceutical composition can be administered orally, topically, transdermally and / or parenterally in a certain dose to achieve and maintain a certain concentration, i.e., a certain dose, or the blood level of the active ingredient in the animal to be treated, which would be antibacterial effective. Generally, the dose of such antibacterial or therapeutically active ingredient of the active ingredient (i.e., the effective dose) is in the range of about 0.1 mg / kg to about 100 mg / kg body weight per day, more preferably in the range of about 1.0 mg / kg to about 50 mg / kg body weight per day.

[0125] To prepare a solid composition such as a tablet, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compounds described in the present application. When these preformulation compositions are called homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, and the composition can be easily subdivided into equivalent unit dosage forms such as tablets, pills, capsules. Next, this solid preformulation is subdivided into unit dosage forms of the above type containing, for example, from 0.1 to about 500 mg of the active ingredient described in the present application.

[0126] The tablets or pills described in the present application can be formulated by coating or other methods to provide a dosage form with the advantage of extended action. For example, the tablets or pills may contain an internal dosage component and an external dosage component, the latter being in the form of an envelope covering the former. These two components can be separated by an enteric dissolution layer that resists disintegration in the stomach and allows the internal component to enter the duodenum completely or be released slowly. Such enteric layers or coatings can use, for example, a plurality of materials including a plurality of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

[0127] Liquid forms that can incorporate the compositions described in the present application for oral or injectable administration include aqueous solutions, properly flavored syrups, aqueous or oil suspensions, and emulsions flavored with edible oils such as corn oil, cottonseed oil, sesame oil, coconut oil or peanut oil, and elixirs and similar pharmaceutical carriers.

[0128] Compositions for inhalation or insufflation include pharmaceutically acceptable solutions and suspensions, aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may include the appropriate pharmaceutically acceptable excipients described above. Preferably, the compositions are administered via the oral or nasal respiratory route to achieve local or systemic effects. Preferably, the compositions in pharmaceutically acceptable solvents can be nebulized using an inert gas. The nebulized solution can be directly inhaled from the nebulizer device, and the nebulizer device can be connected to a face mask tent or an intermittent positive pressure breathing apparatus. The solution, suspension or powder composition can be administered from a device that delivers the formulation in an appropriate manner, preferably orally or intranasally.

[0129] Another preferred formulation used in the methods described in the present application is a transdermal delivery device ("patch"). Such transdermal patches can be used to continuously or discontinuously infuse the compounds described in the present application in a controlled amount. The structure and use of transdermal patches for delivering pharmaceutical formulations are well known in the art. See, for example, U.S. Patent 5,023,252, published June 11, 1991, which is incorporated herein by reference. Such patches can be configured for continuous, pulsatile, or on-demand delivery of the pharmaceutical formulation.

[0130] In general, it is desirable or necessary to introduce pharmaceutical compositions directly or indirectly into the brain. Direct techniques typically involve placing a drug delivery catheter in the host's ventricular system to bypass the blood-brain barrier. U.S. Patent 5,011,472 describes such implantable delivery systems for delivering biological agents to specific anatomical regions of the body, which patent is incorporated herein by reference.

[0131] In generally preferred indirect techniques, it is common to prepare compositions that convert hydrophilic drugs into lipophilic drugs to provide drug latency. Latency is generally achieved by blocking hydroxyl, carbonyl, sulfate, and primary amine groups present on the drug, making the drug more soluble in lipids and more easily transported across the blood-brain barrier. Alternatively, delivery of hydrophilic drugs can be enhanced by injecting an intravascular hypertonic solution that can transiently open the blood-brain barrier.

[0132] Other suitable formulations of the compounds described in this application are described in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th Edition (1985).

[0133] As described above, the compounds described in this application are suitable for the various drug delivery systems described above. Further, to improve the in vivo serum half-life of the administered compound, the compound can be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques for extending the serum half-life of the compound can be employed. For the preparation of liposomes, various methods can be used as described, for example, in U.S. Patents 4,235,871, 4,501,728, and 4,837,028 to Szoka et al., each of which is incorporated herein by reference.

[0134] As described above, the compounds administered to a patient are in the form of the pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques or can be sterile filtered. The resulting aqueous solutions can be used as packaged or can be lyophilized, and the lyophilized formulations can also be used in combination with a sterile aqueous carrier prior to administration. The pH of the compound formulations is typically from 3 to 11, more preferably from 5 to 9, and most preferably from 7 to 8. It should be understood that the use of some of the excipients, carriers, or stabilizers described above may result in the formation of pharmaceutical salts.

[0135] The disclosures of each patent, patent application, and publication (e.g., periodicals, articles, and / or textbooks) cited in this application are hereby incorporated by reference in their entirety into this specification. Further, as used in this specification and the appended claims, singular articles such as "a," "an," and "one" are intended to mean either the singular or the plural. This application describes embodiments in connection with preferred aspects, but those skilled in the art, after reading the foregoing, can affect changes, equivalent alternatives, and other types of changes to the embodiments described in this application. Each of the above aspects can include or incorporate such changes or aspects disclosed with respect to any or all of the other aspects. The description of the present invention is not limited to the specific aspects described herein, but is intended as a single illustration of the various aspects provided by the present invention. Without departing from the spirit and scope of this application, many modifications and changes can be made to this application, which can be easily conceived by those skilled in the art. In addition to the methods recited in the present invention, functionally equivalent methods within the scope of this specification can be easily conceived by those skilled in the art from the foregoing description. It should be understood that this specification is not limited to specific methods, reagents, process conditions, materials, etc., and it is natural that these methods, reagents, and materials can vary. It should also be understood that the terms used in this application are used only to describe specific aspects and are not intended to be limiting. Therefore, this specification should be regarded as illustrative.

Claims

【Request Item 1】 【Chemistry 1】 or a pharmaceutically acceptable salt, complex or tautomer thereof.

2. 2. The compound of claim 1, or a pharmaceutically acceptable salt, complex, or tautomer thereof, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, complex or tautomer thereof, for use in the treatment of a microbial infection in a mammal.

4. 4. The compound of claim 3, or a pharmaceutically acceptable salt, complex, or tautomer thereof, wherein the compound, or a pharmaceutically acceptable salt, complex, or tautomer thereof, is administered orally, parenterally, transdermally, topically, rectally, or intranasally to a mammal in the form of a pharmaceutical composition.

5. 5. The compound of claim 4, or a pharmaceutically acceptable salt, complex, or tautomer thereof, wherein the compound, or a pharmaceutically acceptable salt, complex, or tautomer thereof, is orally administered to a mammal in the form of a pharmaceutical composition.

6. 4. The compound of claim 3, or a pharmaceutically acceptable salt, complex, or tautomer thereof, wherein the microbial infection is caused by a Gram-negative bacterium selected from Pseudomonas aeruginosa, Acinetobacter bowmannii, Escherichia coli, and Klebsiella pneumoniae.

7. 4. The compound of claim 3, or a pharmaceutically acceptable salt, complex or tautomer thereof, wherein the infection is a skin, soft tissue, respiratory, blood, intraperitoneal, urinary or ocular infection.

8. 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or 2, or a pharmaceutically acceptable salt, complex or tautomer thereof, and a pharmaceutically acceptable carrier.

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