WO2002062337A1

WO2002062337A1 - Thiazolidinediones

Info

Publication number: WO2002062337A1
Application number: PCT/US2001/049118
Authority: WO
Inventors: Dirk A. Heerding
Original assignee: SmithKline Beecham Corp
Current assignee: SmithKline Beecham Corp
Priority date: 2000-12-18
Filing date: 2001-12-17
Publication date: 2002-08-15
Anticipated expiration: 2003-06-18
Also published as: JP2004518697A

Abstract

This invention relates to novel thiazolidinediones and their use as anti-bacterials

Description

THIAZOLIDINEDIONES

FIELD OF THE INVENTION

This invention relates to the use of thiazolidinediones as anti-bacterials.

BACKGROUND OF THE INVENTION

There is a medical need for novel antibiotics and a market opportunity for new antibacterial agents. Thus, the object of this invention is to identify novel compounds having antibiotic activity.

A number of mechanisms are causing an increasing proportion of pathogenic bacteria to become resistant to existing antibiotics. There are now examples of both Gram- positive and Gram-negative infections for which no effective drug treatments are available, making the provision of agents that display novel modes of action, through inhibition of unexploited targets, vital. Effective inhibitors would provide treatment (bacterial eradication and cure of infection) for nosocomial and/or community acquired infections (including respiratory tract infection, urinary tract infection, systemic and soft tissue infections, bone and joint infections, meningitis, endocarditis and STD) caused by Gram- positive and Gram-negative organisms and would not be subject to any currently identified specific resistance mechanisms.

Importantly, it has now been discovered that compounds of the present invention have antibacterial activity and, therefore, may be useful for the treatment of bacterial infections in mammals, particularly in man.

SUMMARY OF THE INVENTION

This invention comprises the use of thiazolidinedione derivatives as antibacterials for the treatment of Gram positive and Gram negative bacterial infections such as respiratory tract infections, urinary tract infections, systemic and soft tissue infections , bone and joint infections, meningitis, endocarditis and sexually transmitted diseases. Other aspects and advantages of the present invention are described further in the following detailed description of the preferred embodiments thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides for a method of treatment of Gram positive and Gram negative bacterial infections such as respiratory tract infections, urinary tract infections, systemic and soft tissue infections , bone and joint infections, meningitis, endocarditis and sexually transmitted diseases which comprises administering to a patient in need thereof, a compound of Formula (I):

(D wherein:

R¹ is independently hydrogen or C 1.3 alkyl;

R.2 is methyl, benzyl, phenyl, napthyl, C2.4 alkenyl, or C2.4 alkynyl, wherein the benzyl, phenyl, and napthyl may be substituted or unsubstituted by one or two halogens or CF₃;

X is O or S; or a pharmaceutically acceptable salt thereof.

Also included in the invention are pharmaceutically acceptable salt complexes.

When used herein, the term "alkyl", includes all straight chain and branched isomers. Representative examples thereof include methyl, ethyl, n-propyl, or wo-propyl.

When used herein, the terms halogen' and lialo' include fluorine, chlorine, bromine and iodine. The compounds of this invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds and diastereomers are contemplated to be within the scope of the present invention.

Some of the compounds of this invention may be crystallized or recrystallized from solvents such as organic solvents. In such cases solvates may be formed. This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.

Since the antibiotic compounds of the invention are intended for use in pharmaceutical compositions it will readily be understood that they are each provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 95% pure, particularly at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably from 10 to 49% of a compound of the formula (I) or salt thereof.

Preferably R¹ is hydrogen or methyl.

Preferably R² is phenyl, (2-propenyl-4-ethoxy)phenyl, 3-(trifluoromethyl)phenyl, 2-,ethoxy- 4-chlorophenyl, 3-chloro-4-methylphenyl, 4-chloronapthyl, 3-trifluoromethyl, 3,4- dichlorophenyl, 3,5-dichlorophenyl or 4-t-butyl-phenyl. Preferably X is O.

Preferred compounds are:

5-(3-Phenoxy-benzylidene)-thiazolidine-2,4-dione;

5-(2-Fluoro-5-methoxy-benzylidene)-2-thioxo-thiazolidin-4-one; 5-(3,5-Dimethoxy-benzylidene)-2-thioxo-thiazolidin-4-one;

5-Biphenyl-4-ylmethylene-2-thioxo-thiazolidin-4-one;

5-(4-Methyl-3-nitro-benzylidene)-2-thioxo-thiazolidin-4-one;

5-(3-Bromo-benzylidene)-2-thioxo-thiazolidin-4-one; 5-(3-Methyl-benzylidene)-2-thioxo-thiazolidin-4-one;

5-[3-(3,5-Dichloro-phenoxy)-benzylidene]-thiazolidine-2,4-dione;

5-[3-(3,4-Dichloro-phenoxy)-benzylidene]-2-thioxo-thiazolidin-4-one;

5-(4-Chloro-benzylidene)-thiazolidine-2,4-dione;

5-(4-Methylsulfanyl-benzylidene)-thiazolidine-2,4-dione; 5-(3-Trifluoromethoxy-benzylidene)-thiazolidine-2,4-dione;

5-(3,5-Dichloro-benzylidene)-thiazolidine-2,4-dione;

5-(3-Chloro-4-hydroxy-5-methoxy-benzylidene)-thiazolidine-2,4-dione; and

5-(4'-Chloro-biphenyl-4-ylmethylene)-thiazolidine-2,4-dione.

Methods for preparing compounds of Formula (I) can be found in WO 0018748, EP 343643 and Tetrahedron (2000), 56(26). Compounds of the Formula I are prepared by the method described in Scheme 1.

Scheme 1

(a) piperidine, benzoic acid, toluene, reflux.

Compounds of Formula I can be prepared as shown in Scheme 1. A suitable aldehyde such as 1-Scheme 1 is condensed with thiazolidine-2,4-dione (2-Scheme 1) in an aldol reaction. The condensation is catalyzed using piperidine and benzoic acid and heated in a suitable solvent such as toluene. Other catalysts, such as piperidine or sodium acetate, and other solvents, such as glacial acetic acid, can also be used to carry out this reaction. A representative range of conditions to carry out aldol condensations are listed by March (Advanced Organic Chemistry, Third Edition; Wiley-Interscience: New York, 1985; p 829- 834) and references cited therein.

The compound of this invention may be used as antibacterials for the treatment of Gram positive and Gram negative bacterial infections such as respiratory tract infections, urinary tract infections, systemic and soft tissue infections, bone and joint infections, meningitis, endocarditis and sexually transmitted diseases. Evidence of their activity is demonstrated by the following assay.

Biological Assay: Whole-cell antimicrobial activity was determined by broth microdilution. Test compounds were dissolved in DMSO and diluted 1:10 in water to produce a 256 ug/mL stock solution. Using a 96 well microtitre plate, a Microlab AT Plus 2 (Hamilton Co., Reno, NV) serially diluted 50uL of the stock solution into cation adjusted Mueller Hinton broth.

After the compounds were diluted, a 50 uL aliquot of the test isolate (~1 x 10" cfu/ L) was added to each well of the microtitre plate. The final test concentrations ranged from 0.06 -

64 ug/mL. Inoculated plates were incubated at 35°C in ambient air for 18 to 24 hours. Organisms were selected from the following laboratory strains: S. aureus Oxford, S. aureus WCUH29, E. faecalis 1, E. faecalis 7, H. influenzae, Ql, H. influenzae NEMCl, M. catarrhalis 1502, S. pneumoniae 1629, S. pneumoniae N1387, S. pneumoniae ERY2, E. coli 7623 AcrABEFD⁺ and E. coli 120 AcrAB^". The minimum inhibitory concentration (MIC) was determined as the lowest concentration of compound that inhibited visible growth. Compounds of this invention had at least one MIC of 64ug/mL or less. The compound of Example 9 had the following MICs:

MIC (ug/mL) S. aureus Oxford 4

S. aureus WCUH29 2 H. influenzae Ql 4

H. influenzae NMEC1 16

M. catarrhalis 1502 4

S. pneumoniae ERY2 64

The present invention also provides a pharmaceutical composition that comprises a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof and a pharmaceutically acceptable carrier. The compositions of the invention include those in a form adapted for oral, topical or parenteral use and may be used for the treatment of bacterial infection in mammals including humans.

The antibiotic compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibiotics.

The composition may be formulated for administration by any route, such as oral, topical or parenteral, especially oral. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

The topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams. The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1 % up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.

Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.

Suppositories will contain conventional suppository bases, e.g. cocoa butter or other glyceride.

For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. The solution preferably contains a buffer (such as phosphate) to keep the pH in the range of about 3.5 to 7. DMSO or alcoholic solvents may also be present (at concentrations such as 0.01 to 10 mL/liter) to aid solubility and penetration of the compound of Formula (I). Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. The compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient. The dosage as employed for adult human treatment will preferably range from 1 to 140 mg kg of body weight, depending on the route and frequency of administration.

No unacceptable toxicological effects are expected when a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof is administered in the above-mentioned dosage range. The compounds of formula (I) may be the sole therapeutic agent in the compositions of the invention or a combination with other antibiotics or compounds which enhance the antibacterial activity of a compound of formula (I) may be employed.

The antibiotic compounds of the present invention are active against a wide range of organisms including both Gram-negative organisms such as Escherichia coli, Haemophilus influenzae and Moraxella catarrhalis and Gram-positive organisms such as Staphylococcus aureus, Streptococcus pneumoniae and Enterococcus faecalis, including isolates resistant to existing antibiotics.

The following Examples are illustrative but not limiting embodiments of the present invention. Example 1

Preparation of 5-(4-benzyloxy-benzyl)-thiazolidine-2,4-dione

Prepared according to Giles et al. (Tetrahedron, 2000, 56(26), 4531-4537)

Example 2

Preparation of 5-Fl-(4-methoxyphenyl)-ethylidene1-2-thioxo-thiazolidin-4-one

Prepared according to Esswein et al. (WO 0018748, 2000). Example 3

Preparation of 5-(3-methoxy-benzylidene)-thiazolidine-2,4-dione

Prepared according to Cetenko et al. (EP 343643, 1989).

Example 4

Preparation of 5-(3-phenoxy-benzylidene)-thiazolidine-2.4-dione

3-Phenoxybenzaldehyde (1 eq), thiazolidine-2,4-dione (1 eq), piperidine (0.1 eq) and benzoic acid (0.1 eq) are combined in toluene and heated to reflux. After 18h, the resulting precipitate is collected, washed with toluene and dried under vacuum to give the desired compound. MS (ES+) m/z 298.2 (M+H+)

Example 5

Preparation of 5-(3-hydroxy-5-methoxy-benzylidene)-thiazolidine-2,4-dione

In a manner analogous to the preparation of Example 4, 3-hydroxy-5- methoxybenzaldehyde and thiazolidine-2,4-dione gave the desired compound.

Example 6

Preparation of 5-(4-allyloxy-benzylidene)-thiazolidine-2,4-dione

In a manner analogous to the preparation of Example 4, 4-allyloxybenzaldehyde and thiazolidine-2,4-dione gave the desired compound.

Example 7 - Example 34

The following examples were prepared in a manner analogous to the preparation of Example 4.

Example 35 Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.

Tablets/In gredients Per Tablet 1.Active ingredient 40 mg (Cpd of Formula I)

2.Corn Starch 20 mg

3.Alginic acid 20 mg

4.Sodium Alginate 20 mg 5.Mg stearate 1.3 mg

2.3 mg

Procedure for tablets:

Step 1: Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable mixer/blender. Step 2: Add sufficient water portion-wise to the blend from Step 1 with careful mixing after each addition. Such additions of water and mixing until the mass is of a consistency to permit its conversion to wet granules.

Step 3: The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen. Step 4: The wet granules are then dried in an oven at 140°F (60°C) until dry.

Step 5: The dry granules are lubricated with ingredient No. 5.

Step 6: The lubricated granules are compressed on a suitable tablet press.

Inhalant Formulation A compound of Formula I, (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.

Parenteral Formulation

A pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of Formula I in polyethylene glycol with heating. This solution is then diluted with water for injections Ph Eur. (to 100 ml). The solution is then sterilized by filtration through a 0.22 micron membrane filter and sealed in sterile containers.

The above specification and Examples fully disclose how to make and use the compounds of the present invention. However, the present invention is not limited to the particular embodiments described hereinabove, but includes all modifications thereof within the scope of the following claims. The various references to journals, patents and other publications which are cited herein comprise the state of the art and are incorporated herein by reference as though fully set forth.

Claims

What is claimed is:

1. A method of treatment of Gram positive and Gram negative bacterial infections which comprises administering to a patient in need thereof, a compound of Formula (I):

(I) wherein:

R¹ is independently hydrogen or C1-.3 alkyl;

R^ is methyl, benzyl, phenyl, C2_4 alkenyl, or C2- alkynyl, wherein the benzyl, phenyl, and napthyl may be substituted or unsubstituted by one or two halogens or CF3;

X is O or S; or a pharmaceutically acceptable salt thereof.

2. A method according to claim 1 wherein: X is O or S;

R¹ is Me or H; and R² is phenyl, (2-propenyl-4-ethoxy)phenyl, 3-(trifluoromethyl)phenyl, 2-ethoxy-4- chlorophenyl, 3-chloro-4-methylphenyl, 4-chloronapthyl, 3-trifluoromethyl, 3,4- dichlorophenyl, 3,5-dichlorophenyl or 4-t-butyl-phenyl.

3. A method according to Claim 1 wherein the compound is chosen from the group consisting of:

5-(3-Phenoxy-benzylidene)-thiazolidine-2,4-dione; 5-(2-Fluoro-5-methoxy-benzylidene)-2-thioxo-thiazolidin-4-one; 5-(3,5-Dimethoxy-benzylidene)-2-thioxo-thiazolidin-4-one; 5-Biphenyl-4-ylmethylene-2-thioxo-thiazolidin-4-one; 5-(4-Methyl-3-nitro-benzylidene)-2-thioxo-thiazolidin-4-one; 5-(4-Methyl-3-nitro-benzylidene)-2-thioxo-thiazolidin-4-one; 5-(3-Bromo-benzylidene)-2-thioxo-thiazolidin-4-one; 5-(3-Methyl-benzylidene)-2-thioxo-thiazolidin-4-one; 5-[3-(3,5-Dichloro-phenoxy)-benzylidene]-thiazolidine-2,4-dione; 5-[3-(3,4-Dichloro-phenoxy)-benzylidene]-2-thioxo-thiazolidin-4-one; 5-(4-Chloro-benzylidene)-thiazolidine-2,4-dione;

5-(4-Methylsulfanyl-benzylidene)-thiazolidine-2,4-dione; 5-(3-Trifluoromethoxy-benzylidene)-thiazolidine-2,4-dione; 5-(3,5-Dichloro-benzylidene)-thiazolidine-2,4-dione; 5-(3-Chloro-4-hydroxy-5-methoxy-benzylidene)-thiazolidine-2,4-dione; and 5-(4'-Chloro-biphenyl-4-ylmethylene)-thiazolidine-2,4-dione.

4. A method according to Claim 1 wherein the gram positive or gram negative bacterial infection is chosen from: respiratory tract infections, urinary tract infections, systemic and soft tissue infections , bone and joint infections, meningitis, endocarditis and sexually transmitted diseases.