(19)
(11)EP 2 285 802 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
11.11.2015 Bulletin 2015/46

(21)Application number: 09746957.1

(22)Date of filing:  12.05.2009
(51)International Patent Classification (IPC): 
C07D 403/04(2006.01)
C07D 409/06(2006.01)
A61P 31/04(2006.01)
C07D 405/06(2006.01)
A61K 31/4166(2006.01)
(86)International application number:
PCT/US2009/002969
(87)International publication number:
WO 2009/139870 (19.11.2009 Gazette  2009/47)

(54)

OXO-IMIDAZOLYL COMPOUNDS HAVING ANTIBACTERIAL ACTIVITY

OXO-IMIDAZOLYL-VERBINDUNGEN MIT ANTIBAKTERIELLER WIRKUNG

COMPOSÉS OXO-IMIDAZOLYLES PRÉSENTANT UNE ACTIVITÉ ANTIBACTÉRIENNE


(84)Designated Contracting States:
AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK TR

(30)Priority: 12.05.2008 US 127494 P

(43)Date of publication of application:
23.02.2011 Bulletin 2011/08

(73)Proprietors:
  • Astex Pharmaceuticals, Inc.
    Pleasanton, CA 94588 (US)
  • The Rockefeller University
    New York, NY 10065 (US)

(72)Inventors:
  • BEARSS, Dave
    Alpine, UT 84004 (US)
  • VANKAYALAPATI, Hariprasad
    Draper UT 84020 (US)
  • XU, Yong
    Midvale UT 84047 (US)
  • FISCHETTI, Vincent, A.
    West Hempstead NY 11552 (US)
  • STEBBINS, Charles, Erec
    New York NY 10065 (US)

(74)Representative: Boult Wade Tennant 
Verulam Gardens 70 Gray's Inn Road
London WC1X 8BT
London WC1X 8BT (GB)


(56)References cited: : 
EP-A- 0 237 138
FR-A- 2 858 324
WO-A-2005/016227
US-A1- 2004 198 741
  
  • B. BULIC ET. AL.: "Rhodanine-Based Tau Aggregation in Cell Models of Taupathy." ANGEWANDTE CHEMIE, INTERNATIONAL EDITION IN ENGLISH, vol. 46, 2007, pages 9215-9219, XP002537084
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

BACKGROUND OF THE INVENTION



[0001] The present invention is directed to oxo-imidazolyl compounds. In particular, the present invention is directed to oxo-thioxo-imidazolyl compounds useful in the treatment of infectious diseases, including bacterial infections.

[0002] Bacterial infection remains a problem - particularly with each discovered new resistance to existing antibacterial drugs. Thus, there is a continuing need for new compounds that are useful in the treatment of infectious diseases, including bacterial infections.

[0003] There are 2-epimerase enzymes specific either to bacteria or animals that are not utilized by the other. For example, UDP-N-acetylglucosamine 2-epimerase is an important enzyme intermediary used in animal cellular amino sugar metabolism. UDP-N-acetylglucosamine 2-epimerase, however, is not found in bacteria. Instead, UDP-N-acylglucosamine 6-phosphate 2-epimerase is utilized by bacteria. We have identified compounds that inhibit gram-positive-bacteria-specific 2-epimerase enzymes. Accordingly, such compounds have use in disrupting the metabolism of gram positive bacteria without affecting host animals, including humans, that do not utilize the gram-positive-bacteria-specific 2-epimerase.

[0004] International Patent Publication No. WO 2007062078 describes the preparation of amide containing heterocyclic compounds as thrombopoietin activity modulators. International Patent Publication No. WO 2005016227 describes the screening for heparanase-activating proteinases for use in the therapeutic degradation of heparins. U.S. Patent Publication No. 2005042213 describes screening proteases participating in heparanase activation, and pharmaceutical compounds for medical uses. U.S. Patent Publication Nos. 2002052396, 2003195213, and 2004198741 describe rhodanine derivatives, preparation thereof, compositions, and methods for treating or preventing Flaviviridae family viral infections and associated diseases. U.S. Patents 5,998,447 and 6,514,952 describe the preparation of 5-membered-ring heterocycles as inhibitors of leudocyte adhesion and VLA-4 antagonists.

[0005]  E.V. Leshcheva et al., Izvestiya Bysshikh Uchebnykh Zavedenii, Khimiya I Khimicheskaya Teckhnologiya (2003), 46(5), 105-108 describes new functional derivatives of 4,4,6-trimethyl-4H-pyrrolo[3,2,1-I,J]quinolin-1,2-diones. R.T. Pardasani et al., Phosphorus, Sulfur and Silicon and the Related Elements (2002), 177(10), 2435-2443 describes syntheses of indigold dye precursors and bioactive compounds via condensation of 1,2- and 1,4-diones with thiohydantoins. V. Chazeau et al., European Journal of Medicinal Chemistry (1992), 27(6),615-625 describes study of 5-arylidene-2-thiohydantoins with potential immunomodulating and anticancer activities. International Patent Publication No. EP 237138 describes the preparation of heterocyclylidenethiozolidine derivatives as aldose reductase inhibitors and pharmaceutical compositions containing them.M.K. Rout, J. Indian chemical Society (1958), 35, 287-293 describes thiohydantoin derivatives and their use in the estimation of silver, mercury, and copper. A.J. Hill et al., J. Amer. Chem. Soc., (1924), 46, 2806-2810 describes condensation reactions of cyclic ketones: the action of isatin and isatin α-chloride upon certain hydantoins.
FR-A-2, 858, 324 discloses antibiotic compounds based on rhodanine which is substituted by 5-phenyl-2-furylmethlidene.
Angewandte Chemie, International Edition (2007), 46(48), 9215-9219 discloses rhodanine-based tau aggregation inhibitors. These compounds are cytotoxic and their use as antibacterial agents is not suggested.

SUMMARY OF THE INVENTION



[0006] The present invention provides a compound represented by Formula I or II:



or a pharmaceutically acceptable salt thereof, wherein

X, Y, and Z each independently is O, S, or NR4;

A is phenyl or pyridyl;

B is phenyl, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, homopiperazinyl, pyranyl, furyl, 1H-tetrahydropyranyl, tetrahydrofuranyl, thienyl, oxazolyl, isoxazolyl, oxadiazoyl, oxazolinyl, morpholinyl, thiazolyl, thiadiazolyl or thiazolidinyl; wherein for Formula I, A may be halo and B may be CH3 but not at the same time;

R1 in each instance independently is C0-4alkyl;

R2 in each instance independently is C0-4alkyl, C1-4alkoxy, halo, -CF2H, CF3, -OCF3, -SCF3, SF5;

R3 in each instance independently is C0-4alkyl;

R4 in each instance independently is C0-4alkyl, or phenyl, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, homopiperazinyl, pyranyl, furyl, 1H-tetrahydropyranyl, tetrahydrofuranyl, thienyl, oxazolyl, isoxazolyl, oxadiazoyl, oxazolinyl, morpholinyl, thiazolyl, thiadiazolyl or thiazolidinyl;

n is 0, 1, or 2; and

m and mm each independently is 0, 1, 2, 3, 4, or 5.



[0007] The present invention is generally directed to compounds, and pharmaceutical compositions comprising said compounds, where the compounds have the following general structures (I) and (II) below:



including stereoisomers and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4 and X, Y, Z, A and B are defined herein.

[0008] These compounds of the present invention have utility over a broad range of therapeutic applications, and may be used to treat diseases, such as infection, that are mediated at least in part by bacterial 2-epimerase activity. Accordingly, in one aspect of the invention, the compounds described herein are formulated as pharmaceutically compositions for administration to a subject in need thereof.

[0009] Described herein are methods for treating or preventing infection, which method comprises administering to a patient in need of such a treatment and therapeutically effective amount of a compound described herein or a pharmaceutically acceptable composition comprising said compound.

[0010] Also described is a method for inhibiting 2-epimerase activity in a biological sample, which method comprises containing the biological sample with a compound described herein, or a pharmaceutically acceptable composition comprising said compound.

[0011] Further described is a method of inhibiting bacterial 2-epimerase activity in a patient, which method comprises administering to the patient a compound described herein or a pharmaceutically acceptable composition comprising said compound.

[0012] The following compounds are known from various compound libraries:




DETAILED DESCRIPTION OF THE INVENTION



[0013] As described above, there are 2-epimerase enzymes specific either to bacteria or animals that are not utilized by the other. For example, UDP-N-acetylglucosamine 2-epimerase is an important enzyme intermediary used in animal cellular amino sugar metabolism. UDP-N-acetylglucosamine 2-epimerase, however, is not found in bacteria. Instead, UDP-N-acylglucosamine 6-phosphate 2-epimerase is utilized by bacteria.

[0014] The non-hydrolyzing bacterial UDP-N-acetylglucosamine 2-epimerases (epimerase) catalyze the reversible conversion of UDP-N-acetylglucosamine (UDP-GlcNAc) into UDP-N-acetylmannosamine (UDP-ManNAc) (Kawamura et al., J Biol Chem 254(17):8457-8465(1979) and Kawamura et al., J Biol Chem 253(10):3595-3601(1978)). The latter is an intermediate in the biosynthesis of several bacterial cell surface polysaccharides as well as the enterobacterial common antigen (ECA). The enterococcal common antigen is a surface-associated glycolipid common to all members of the enterobacteriacea family (Kuhn et al., FEMS Microbiol Rev 4(3):195-222, 58-464(1988)). The importance of UDP-GlcNAc 2-epimerase in the biosynthesis of polysaccharides in gram-positive bacteria is highlighted by the presence of two functionally redundant copies of these enzymes in species such as Staphyloccocus aureus and Bacillus Anthracis. The bacterial epimerase is related to the bi-functional mammalian UDP-GlcNAc 2-epimerase/ManNAc kinase, a hydrolyzing enzyme that converts UDP-GlcNAc into UDP and ManAc and phophorylates the latter into ManNAc 6-phosphate (Hinderlich et al., J Biol Chem 272(39):24313-24318(1997)). The mammalian enzyme catalyzes the rate-limiting step in sialic acid biosynthesis and is a key regulator of cell surface sialylation in humans (Keppler et al., Science 284(54188):1372-1376(1999)).

[0015] A unique feature of the bacterial epimerases is their allosteric regulation by the substrate UDP-GlcNAc, which acts as an activator. In the absence of this activator, virtually no UDP-ManNAc is epimerized in the reverse reaction (Samuel et al., Biochim Biophys Acta 1700(1):85-91(2004)), but when trace amounts of UDP-GlcNAc are added, the reaction proceeds to its normal equilibrium. This suggests that UDP-GlcNAc is required for the enzyme to acquire a conformation in which it is catalytically competent. This requirement is not found in the mammalian form of the enzyme.

[0016] The present invention is directed to a compound represented by Formula I:

or a pharmaceutically acceptable salt thereof, wherein

X, Y, and Z each independently is O, S, or NR4;

A is phenyl or pyridyl;

B is phenyl, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, homopiperazinyl, pyranyl, furyl, 1H-tetrahydropyranyl, tetrahydrofuranyl, thienyl, oxazolyl, isoxazolyl, oxadiazoyl, oxazolinyl, morpholinyl, thiazolyl, thiadiazolyl or thiazolidinyl; wherein for Formula I, A may be halo and B may be CH3 but not at the same time;

R1 in each instance independently is C0-4alkyl;

R2 in each instance independently is C0-4alkyl, C1-4alkoxy, halo, -CF2H, CF3, -OF3, -SCF3, SF5;

R3 in each instance independently is C0-4alkyl;

R4 in each instance independently is C0-4alkyl, or phenyl, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, homopiperazinyl, pyranyl, furyl, 1H-tetrahydropyranyl, tetrahydrofuranyl, thienyl, oxazolyl, isoxazolyl, oxadiazoyl, oxazolinyl, morpholinyl, thiazolyl, thiadiazolyl or thiazolidinyl;

n is 0, 1, or 2; and

m and mm each independently is 0, 1, 2, 3, 4, or 5.

The present invention also is directed to a compound represented by Formula II:

or a pharmaceutically acceptable salt thereof, wherein

X, Y, and Z each independently is O, S, or NR4;

A is phenyl or pyridyl;

B is phenyl, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, homopiperazinyl, pyranyl, furyl, 1H-tetrahydropyranyl, tetrahydrofuranyl, thienyl, oxazolyl, isoxazolyl, oxadiazoyl, oxazolinyl, morpholinyl, thiazolyl, thiadiazolyl or thiazolidinyl; wherein for Formula I, A may be halo and B may be CH3 but not at the same time;

R1 in each instance independently is C0-4alkyl;

R2 in each instance independently is C0-4alkyl, C1-4alkoxy, halo, -CF2H, CF3, -OCF3, -SCF3, SF5;

R3 in each instance independently is C0-4alkyl;

R4 in each instance independently is C0-4alkyl, or phenyl, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, homopiperazinyl, pyranyl, furyl, 1H-tetrahydropyranyl, tetrahydrofuranyl, thienyl, oxazolyl, isoxazolyl, oxadiazoyl, oxazolinyl, morpholinyl, thiazolyl, thiadiazolyl or thiazolidinyl;

n is 0, 1, or 2; and

m and mm each independently is 0, 1, 2, 3, 4, or 5.



[0017] In one aspect, the present invention is directed to a compound represented by Formula I, wherein Z is O, Y is S, and the other variables are as defined above for Formula I.

[0018] In still another embodiment of this aspect, the present invention is directed to a compound represented by Formula I, wherein Z is O, Y is S, A is phenyl, B is phenyl, and the other variables are as defined above for Formula I.

[0019] In yet still another embodiment of this aspect, the present invention is directed to a compound represented by Formula I, wherein Z is O, Y is S, X is S, and the other variables are as defined above for Formula I.

[0020] In another embodiment of this aspect, the present invention is directed to a compound represented by Formula I, wherein Z is O, Y is S, X is O, and the other variables are as defined above for Formula I.

[0021] In another aspect, the present invention is directed to a compound represented by Formula II, wherein Z is O, Y is S, and the other variables are as defined above for Formula II.

[0022] In another embodiment of this aspect, the present invention is directed to a compound represented by Formula II, wherein Z is O, Y is S, A is phenyl, B is phenyl, and the other variables are as defined above for Formula II.

[0023] As used herein, "C0-4alkyl" is used to mean an alkyl having 0 to 4 carbons - that is, 0, 1, 2, 3, or 4 carbons in a straight or branched configuration. An alkyl having no carbon is hydrogen when the alkyl is a terminal group. An alkyl having no carbon is a direct bond when the alkyl is a bridging (connecting) group.

[0024] As used herein unless otherwise specified, "alkyl", "alkenyl", and "alkynyl" includes straight or branched configurations. Lower alkyls, alkenyls, and alkynyls have 16 carbons. Higher alkyls, alkenyls, and alkynyls have more than 6 carbons.

[0025] As used herein unless otherwise specified, the terms "aryl" and "ar" are well known to chemists and include, for example, phenyl and naphthyl. Phenyl, naphthyl, tolyl, and xylyl are preferred.

[0026] As used herein unless otherwise specified, the terms "hetaryl" or "heteroaryl" are well known to chemists and include, for example, pyridinyl.

[0027] As used herein unless otherwise specified, "hetcyclyl" (also known as "heterocyclyl") is well known to chemists and contains at least one N, S or O hetero-ring atom, and includes saturated, unsaturated, partially saturated, mono or polycyclic (unless specified as single-ringed) hetcyclic groups such as, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, homopiperazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, imidazopyridyl, indazolyl, benzotriazolyl, tetrazolo-pyridazinyl, pyranyl, furyl, 1H-tetrahydropyranyl, tetrahydrofuranyl, thienyl, oxazolyl, isoxazolyl, oxadiazoyl, oxazolinyl, morpholinyl, benzofuranyl, benzoxazolyl, benzoxadiazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, or benzodioxyl and the like.

[0028] As used herein unless otherwise specified, "halogen" is fluorine, chlorine, bromine or iodine.

[0029] The above Formulas I, and II are shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of Formulas I, and II and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

[0030] The invention also encompasses a pharmaceutical composition that is comprised of a compound of Formula I or II in combination with a pharmaceutically acceptable carrier.

[0031] Preferably, the composition is comprised of a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of a compound of Formula I or II as described above (or a pharmaceutically acceptable salt or N-oxide thereof).

[0032] Moreover, within this preferred embodiment, the invention encompasses a pharmaceutical composition for the treatment of disease by the inhibition of bacterial 2-epimerase activity, comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of Formula I or II as described above (or a pharmaceutically acceptable salt or N-oxide thereof).

[0033] The compounds and compositions of the present invention are effective for treating mammals such as, for example, humans.

[0034] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0035] When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, methanesulfonic, and tartaric acids.

[0036] The pharmaceutical compositions of the present invention or used by the methods described herein comprise a compound represented by Formula I, or II (or a pharmaceutically acceptable salt or N-oxide thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0037] In practice, the compounds represented by Formula I, or pharmaceutically acceptable salts or N-oxides thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration. E.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula I, or a pharmaceutically acceptable salt or N-oxide thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.

[0038] Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt or N-oxide of Formula I, or II. The compounds of Formula I or II, or pharmaceutically acceptable salts or N-oxides thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

[0039] The pharmaceutical compositions of this invention include a pharmaceutically acceptable liposomal formulation containing a compound of Formula I or II or a pharmaceutically acceptable salt or N-oxide thereof.

[0040] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0041] In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.

[0042] A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent or other such excipient. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used.

[0043] In hard gelatin capsules, the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. In soft gelatin capsules, the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.

[0044] For example, a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about 1mg to about 2g of the active ingredient, typically 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or 1000mg.

[0045] Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[0046] Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0047] Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I or II of this invention, or a pharmaceutically acceptable salt or N-oxide thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5 wt % to about 10 wt % of the compound, to produce a cream or ointment having a desired consistency.

[0048] Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.

[0049] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described by Formula I or II, or pharmaceutically acceptable salts or N-oxides thereof, may also be prepared in powder or liquid concentrate form.

[0050] Generally, dosage levels on the order of from about 0.01mg/kg to about 150mg/kg of body weight per day are useful in the treatment of bacterially infected conditions, or alternatively about 0.5mg to about 10g per patient per day. For example, bacterially infected patients may be effectively treated by the administration of from about 0.01 to 100mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 7g per patient per day.

[0051] Similarly, infections from Staphylococcus aureus, Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus pneumonia, Streptococcus agalactiae, Group C streptococcus, Group G streptococcus, Enterococcus faecalis, Enterococcus faecium, Bacillus anthracis, Bacillus cereus, Escherichia coli, Pseudomonas areuginosa, Neisseria meningitides, or Neisserin gonorrhoeae may be effectively treated by the administration of from about 0.01 to 100mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 7g per patient per day.

[0052] It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

[0053] The compounds of the present invention, or pharmaceutically acceptable salts or N-oxides thereof, can also be effectively administered in conjunction with other anti-infection therapeutic compounds. For example, antibiotics and antiviral agents can be advantageous co-agents with the compounds of the present invention. Accordingly, the present invention includes compositions comprising the compounds represented by Formula I or II, or a pharmaceutically acceptable salt or N-oxide thereof, and an antibiotic agent or an antiviral inhibiting agent. The amounts of each can be therapeutically effective alone--in which case the additive effects can overcome infections resistant to treatment by monotherapy. The amounts of any can also be subtherapeutic--to minimize adverse effects, particularly in sensitive patients.

[0054] Thus, the compositions of the present invention include a compound according to Formula I or II, or a pharmaceutically acceptable salt or N-oxide thereof, and an antiviral or antibiotic agent.

[0055] The compounds of the present invention, or pharmaceutically acceptable salts or N-oxides thereof, can also be effectively administered in conjunction with other therapeutic compounds, aside from anti-infective agents. For example, therapeutic agents effective to ameliorate adverse side-effects can be advantageous co-agents with the compounds of the present invention.

[0056] Representative EXAMPLES of the present invention are summarized in Table 1 below:

[0057] General synthetic method for FORMULA I:





[0058] To a mixture of oxo-thioxo-imidazolyl compound (1.0eq.) and arylaldehyde (1.0eq.) in acetic acid 5mL is added β-alanine (2.69mg, 0.030mmol) and heat to 170°C for 30min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system.

[0059] General synthetic method for FORMULA II:



[0060] To a mixture of oxo-thioxo-imidazolyl compound (1.0eq.) and indoline-2,3-dione (1.0eq.) in acetic acid, 5mL is added acetic anhydride 0.5mL and heated to 80°C for 2h. The resulting reaction mixture is cooled down and the resulting reaction mixture is concentrated to dry. Purification by column chromatography using MeOH/DCM, 2-7% ration solvent system provided pure product as red solid.
TABLE 1 EXAMPLES:
EX.Formula/MWStructure
1 C20H14BrN3O4S

MW: 472.31
2 C20H13BrClN3O4S

MW: 506.76
3 C23H17ClN2O3S2

MW: 468.04
4 C24H20N2O4S2

MW: 464.09
5 C23H17ClN2O4S

MW: 452.06
6 C23H16Cl2N2O4S

MW: 487.06
7 C23H17BrN2O3S2

MW: 511.99
8 C23H17FN2O3S2

MW: 452.07
9 C23H16BrClN2O4S

MW: 529.97
10 C23H17BrN2O4S

MW: 497.36
11 C23H16BrClN2O3S2

MW: 547.87
12 C24H17F3N2O5S

MW: 502.46
13 C18H14Cl2N2O4S

MW: 425.29
14 C23H17I1N2O4S

MW: 544.36
15 C17H13BrN2O3S2

MW: 437.33
Table 2, Inhibitive activity of SGI compounds on Staphylococcus aureus MRSA and B. Anthracis.
Inhibitive activityConc. µMEX. 1EX. 2EX. 3EX. 4EX. 5EX. 6EX. 7
Anthracis 30 88.02 98.76 100.00 100.00 99.71 96.71 96.71
10 2.50 40.22 100.00 0.00 68.90 99.55 97.71
3   11.29 -5.40 -3.85 4.99 96.18 67.90
MRSA 30 -2.22 93.83 90.97 18.49 86.63 94.51 91.14
10 -8.00 -19.36 -1.47 -13.24 -16.90 98.71 91.14
3   -11.91 -2.94 -2.94 -13.52 -3.72 -19.16
                 
Inhibitive activityConc. µMEX.8EX.9EX.10EX.11EX.12EX.13 
Anthracis 30 98.76 98.08 98.83 94.47 96.58 93.95  
10 6.99 98.08 98.83 8.15 96.69 97.18  
3 0 98.08 72.63 19.46 8.01 4.13  
MRSA 30 46.21 95.65 95.36 -0.89 95.15 92.90  
10 -24.79 95.65 92.50 -7.45 -6.26 4.53  
3 -15.78 17.90 -9.55   -1.32 -2.47  


[0061] Compounds of the claimed can be prepared by the condensation reaction (Knoevenagel reaction) of substituted thiohydantoins with corresponding aldehydes, ketones, or other reactive species. (Londhe, A.; et al., Indian J. Heterocycl. Chem. 2005, 15, 137-140.) The choice of reaction condition is crucial for the condensation reaction. The most frequently used basic condensation conditions are not workable for the preparation because the substituted thiohydantoin is basic liable and it decomposes immediately in basic media and elevated temperature. Therefore, we developed two kinds of reaction conditions which are suitable for substituted thiohydantoin condensation reaction. The starting material thiohydantoin is prepared by the cyclization reaction of efficient thiocarbonyl agent 1,1'-thiocarbonyldiimidazole with dipeptide Gly-DL-Phe. (Charton, J. et al., Bioorg. Med. Chem. Lett. 2005, 15, 4833-4837.) The first method is using acetate anhydride as promoter and the condensation reaction process readily at 80°C for 2h. (Hui, Y.-H. et al., Youji Huaxue 2006, 26, 391-395) The second method is using β-alanine as catalyst, which is a neutral amine acid, and the condensation reaction provided good yield in 30min under microwave irradiation. (Prout, F. S. et al., J. Org. Chem. 1953, 18, 928-33).

EXAMPLES



[0062] EXAMPLE 1: 2-(4-(5-Bromo-2-oxoindolin-3-ylidene)-5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid, SGI-4003.



[0063] Synthesis of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid.



[0064] To a mixture of Gly-DL-Phe (1.0g, 4.50mmol) and DIPEA (2.61g, 20.25mmol) in anhydrous THF 20mL is added 1,1'-thiocarbonyldiimidazole (1.203g, 6.75mmol) and heated to reflux overnight. The resulting reaction mixture is concentrated to dry and the pure product (0.85g, 3.22mmol, yellow solid) is obtained by column chromatography using acetic acid/DCM, 0-5% ration solvent system. Spectral Data: 1H-NMR (CD3OD/300 MHz): 6.45 (m, 5H), 4.80 (dd, J = 11.7, 5.4 Hz, 1H), 3.15 (s, 2H), 2.87 (dd, J = 13.8, 11.4 Hz, 1H), 2.70 (dd, J = 14.4, 5.4 Hz, 1H). MS (ES+, m/z): 265.0 (M++1, 70.0).

[0065] To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.130g, 0.492mol) and 5-bromoindoline-2,3-dione (0.101g, 0.447mmol) in acetic acid 5mL is added acetic anhydride 0.5mL and heated to 80°C for 2h. The resulting reaction mixture is cooled down and the resulting reaction mixture is concentrated to dry. After purification by column chromatography using MeOH/DCM, 2-7% ration solvent system, pure product as red solid EXAMPLE 1 (0.062g, 0.131mmol) is obtained. Spectral Data: 1H-NMR (CD3OD/300 MHz): 8.71 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.20 (m, 5H), 6.80 (d, J = 8.4 Hz, 1H), 5.64 (dd, J = 11.6, 5.6 Hz, 1H), 3.61 (m, J = 14.4, 5.4 Hz, 2H). MS (ES+, m/z): 472.0 (M+, 100.0).

[0066] EXAMPLE 2: 2-(4-(5-Bromo-6-chloro-2-oxoindolin-3-ylidene)-5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid.



[0067] To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.200g, 0.757mmol) and 5-bromo-6-chloro-indoline-2,3-dione (0.179g, 0.688mmol) in acetic acid 5mL is added acetic anhydride 0.5mL and heated to 80°C for 2h. The resulting reaction mixture is cooled down and the resulting reaction mixture is concentrated to dry. After purification by column chromatography using MeOH/DCM, 2-7% ration solvent system, pure product as red solid EX. 2 (0.109g, 0.109mmol) is obtained. Spectral Data: 1H-NMR (CD3OD/300 MHz): 8.94 (d, J = 13.2 Hz, 1H), 7.15 (m, 6H), 5.54 (m, 1H), 3.53 (m, 2H). MS (ES+, m/z): 508.0 (M+, 80.0).

[0068] EXAMPLE 3: 2-(4-((5-(4-Chlorophenyl)thiophen-2-yl)methylene)-5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid.



[0069] To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.080g, 0.304mmol) and 5-(4-chorophenyl)thiophene-2-carbaldehyde (0.068g, 0.304mmol) in acetic acid 5mL is added β-alanine (2.7mg, 0.030mmol) and heat to 170°C for 30min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.110g, 0.235 mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CD3OD/300 MHz): 7.66 (dd, J = 8.7, 1.5 Hz, 2H), 7.50 (dm, J = 12.6 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.18 (m, 5H), 6.69 (s, 1H), 5.65 (dd, J = 12.0, 4.5 Hz, 1H), 3.68 (dd, J = 13.8, 12.0 Hz, 1H), 3.51 (dd, J = 14.4, 4.5 Hz, 1H). MS (ES+, m/z): 469.5 (M++1, 30.0).

[0070] EXAMPLE 4: 2-(4-((5-(4-Methoxyphenyl)thiophen-2-yl)methylene)-5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid



[0071] To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.080g, 0.303mmol) and 5-(4-methoxylphenyl)thiophene-2-carbaldehyde (0.066g, 0.303mmol) in acetic acid 5mL is added β-alanine (2.69mg, 0.030mmol) and heat to 170oC for 30min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.075g, 0.162mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CD3OD/300 MHz): 7.62 (m, 2H), 7.45 (m, 1H), 7.33 (m, 5H), 7.27 (d, J = 13.2 Hz, 1H), 6.94 (d, J = 6.9 Hz, 2H), 6.70 (s, 1H), 5.50 (m, 1H), 3.82 (s, 3H), 3.53 (m, 2H). MS (ES+, m/z): 465.1 (M++1, 20.0).

[0072] EXAMPLE 5: 2-(4-((5-(4-Chlorophenyl)furan-2-yl)methylene)-5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid



[0073] To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.080g, 0.304mmol) and 5-(4-chorophenyl)thiophene-2-carbaldehyde (0.063g, 0.304mmol) in acetic acid 5mL is added β-alanine (2.7mg, 0.030mmol) and heat to 170°C for 30min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.038g, 0.084mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CD3OD/300 MHz): 7.81 (dm, J = 9.0 Hz, 2H), 7.41 (dm, J = 9.3 Hz, 2H), 7.14 (m, 5H), 6.98 (s, 2H), 6.42 (s, 1H), 5.51 (d, J = 8.7 Hz, 1H), 3.75 (dd, J = 11.7, 11.0 Hz, 1H), 3.55 (dd, J = 15.3, 3.9 Hz, 1H). MS (ES-, m/z): 451.1 (M--1, 100.0).

[0074] EXAMPLE 6: 2-(4-((5-(3,4-Dichlorophenyl)furan-2-yl)methylene)-5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid



[0075] To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.055g, 0.207mmol) and 5-(3,4-dichloro-phenyl)thiophene-2-carbaldehyde (0.050g, 0.207mmol) in acetic acid 5mL is added β-alanine (1.8mg, 0.021mmol) and heat to 170°C for 30min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.060g, 0.123mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CDCl3/CD3OD/300 MHz): 7.84 (d, J = 2.1 Hz, 1H), 7.60 (dd, J = 8.7, 2.4 Hz, 1H), 7.44 (d, J = 2.7 Hz, 1H), 7.17 (m, 6H), 6.85 (m, 1H), 6.42 (s, 1H), 5.61 (dd, J = 11.1, 5.4 Hz, 1H), 3.66 (m, 1H), 3.53 (m, 1H). MS (ES-, m/z): 585.3 (M-, 100.0).

[0076] EXAMPLE 6E: (E)-2-(4-((5-(3,4-dichlorophenyl)furan-2-yl)methylene)-5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid

[0077] To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.110g, 0.416mmol) and 5-(3,4-dichloro-phenyl)thiophene-2-carbaldehyde (0.100g, 0.416mmol) in acetic acid 10mL is added β-alanine (1.8mg, 0.021mmol) and heat to 80°C for 16h. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.070g, 0.144mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. The product is further purified by recryatallization in hexane and DCM mixture and got pure E-isomer. 1H-NMR (CDCl3/CD3OD/300 MHz): 7.84 (d, J = 2.1 Hz, 1H), 7.60 (dd, J = 8.7, 2.4 Hz, 1H), 7.44 (d, J = 2.7 Hz, 1H), 7.17 (m, 6H), 6.85 (m, 1H), 6.42 (s, 1H), 5.61 (dd, J = 11.1, 5.4 Hz, 1H), 3.66 (dd, J = 14.1, 12.6 Hz, 1H), 3.53 (dd, J = 14.1, 5.1 Hz, 1H). MS (ES-, m/z): 585.3 (M-, 100.0).

[0078] EXAMPLE 7: 2-(4-((5-(4-Bromophenyl)thiophen-2-yl)methylene)-5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid



[0079] To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.100g, 0.378mmol) and 5-(4-bromophenyl)thiophene-2-carbaldehyde (0.101g, 0.378mmol) in acetic acid 5mL is added β-alanine (3.37mg, 0.038mmol) and heat to 170°C for 30min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.120g, 0.234mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CD3OD/300 MHz): 7.84 (m, 1H), 7.63 (m, 1H), 7.50 (m, 3H), 7.15 (m, 6H), 6.69 (s, 1H), 5.66 (dd, J = 11.4, 5.1 Hz, 1H), 3.69 (dd, J = 14.4, 12.0 Hz, 1H), 3.51 (dd, J = 10.5, 5.1 Hz, 1H). MS (ES+, m/z): 511.3 (M--1, 100.0).

[0080] EXAMPLE 8: 2-(4-((5-(4-Fluorophenyl)thiophen-2-yl)methylene)-5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid



[0081] To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.100g, 0.378mmol) and 5-(4-fluorophenyl)thiophene-2-carbaldehyde (0.078g, 0.378mmol) in acetic acid 5mL is added β-alanine (3.37mg, 0.038mmol) and heat to 170°C for 30min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.125g, 0.276mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CD3OD/300 MHz): 7.71 (m, 2H), 7.52 (d, J = 4.5 Hz, 1H), 7.43 (d, J = 4.5 Hz, 1H), 7.16 (m, 7H), 6.69 (s, 1H), 5.66 (dd, J = 11.4, 5.1 Hz, 1H), 3.69 (dd, J = 14.4, 11.7 Hz, 1H), 3.51 (dd, J = 10.5, 5.1 Hz, 1H). MS (ES-, m/z): 451.4 (M--1, 45.0).

[0082] EXAMPLE 9: (E)-2-(4-((5-(4-bromo-3-chlorophenyl)furan-2-yl)methylene)-5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid



[0083] To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.045g, 0.175mmol) and 5-(4-bromo-3-chloro-phenyl)thiophene-2-carbaldehyde (0.050g, 0.175mmol) in acetic acid 5mL is added β-alanine (1.6mg, 0.018mmol) and heat to 170°C for 30min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.075g, 0.141mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system.

[0084] EXAMPLE 10: (E)-2-(4-((5-(4-bromophenyl)furan-2-yl)methylene)-5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid



[0085] To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.053g, 0.199mmol) and 5-(4-bromophenyl)thiophene-2-carbaldehyde (0.050g, 0.199mmol) in acetic acid 5mL is added β-alanine (1.8mg, 0.020mmol) and heat to 170°C for 30min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.060g, 0.120mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CD3OD/300 MHz): 7.83 (dm, J = 9.0 Hz, 2H), 7.44 (dm, J = 9.3 Hz, 2H), 7.17 (m, 5H), 7.03 (s, 2H), 6.47 (s, 1H), 5.64 (d, J = 8.7 Hz, 1H), 3.69 (m, 1H), 3.49 (m, 1H). MS (ES-, m/z): 495.2 (M-, 80.0).

[0086] EXAMPLE 11:



[0087] (2-(4-Bromo-3-chlorophenyl)thiophene: INT-4027.



[0088] To a mixture of 1-bromo-2-chloro-4-iodobenzene (2.0g, 6.30mmol) in dioxane 30mL, 2-tributylstannyl thiophene (2.352g, 6.30mmol), and 5% equivalent of Pd(PPh3)4 (0.364g, 0.315mmol) is refluxed under nitrogen for 5h. After cooling and evaporation of the solvent, the residue is dissolved in EtOAc 50mL. 10% KF 30mL is added and the solution is stirred at r.t. for 30min. The resultant precipitate is removed by filtration. The solution is washed with water 20mL x 3, and dried with Na2SO4 and concentrated. The pure product (1.2g, 4.39mmol, white solid) is obtained by column chromatography using EtOAc/Hexane, 1-3% ration solvent system. 1H-NMR (CDCl3/300 MHz): 7.74 (d, J = 2.1 Hz, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.37 (m, 3H), 7.14 (m, 1H). MS (ES-, m/z): 529.2 (M+-Br, 20.0).

[0089] 2-(4-bromo-3-chlorophenyl)thiophene: INT-4028.



[0090] To a solution of DMF 1.2mL and 1,2-dichloroethane 5mL is slowly added a solution of POCl3 (0.68mL, 7.3mmol) in 1,2-dichloroethane 5mL with stirring over 20min at 0-5°C. To the reaction mixture is slowly added a solution of INT-4027 (1.0g, 3.66mmol) in 1,2-dichloroethane 5mL over 10min below 10°C, and the mixture is stirred under reflux for 17h. The resulting solution is poured into chilled 50% KOH (10mL) and extracted with ethyl acetate. The extract is washed successively with 5% HCl, water, and brine, and dried over MgSO4. The ethyl acetate solution is evaporated under reduced pressure to give a residue, which is purified by column chromatography using EtOAc/Hexane, 1-3% ration solvent system. The pure product (0.710g, 2.35mmol, white solid) is obtained. 1H-NMR (CDCl3/300 MHz): 9.96 (s, 1H), 7.81 (d, J = 2.7 Hz, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.46 (m, 2H). MS (ES-, m/z): 301.1 (M++1, 20.0).

[0091] (E)-2-(4-((5-(4-bromo-3-chlorophenyl)thiophen-2-yl)methylene)-5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid, EXAMPLE 11



[0092] To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.044g, 0.175mmol) and 5-(4-bromo-3-chloro-phenyl)thiophene-2-carbaldehyde (0.050g, 0.166mmol) in acetic acid 5mL is added β-alanine (1.6mg, 0.018mmol) and heat to 170°C for 30min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.075g, 0.141mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CDCl3/300 MHz): 9.88 (br, 1H), 8.92 (br, 1H), 7.65 (m, 2H), 7.31 (m, 8H), 6.85 (s, 1H), 5.76 (dd, J = 11.1, 5.4 Hz, 1H), 3.70 (m, 2H). MS (ES-, m/z): 545.2 (M-, 100.0).

[0093] EXAMPLE 12: 2-(4-((5-(4-Trifluoromethoxyphenyl)thiophen-2-yl)methylene)-5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid



[0094] To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.031g, 0.117mmol) and 5-(4-trifluoromethoxy-phenyl)thiophene-2-carbaldehyde (0.030g, 0.117mmol) in acetic acid 5mL is added β-alanine (1.042mg, 0.012mmol) and heat to 170°C for 30min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.035g, 0.069mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CD3OD/300 MHz): 7.91 (m, 2H), 7.32 (d, J = 9.0 Hz, 2H), 7.14 (m, 5H), 7.02 (m, 2H), 6.47 (s, 1H), 5.64 (dd, J = 11.1, 5.4 Hz, 1H), 3.70 (dd, J = 14.1, 12.6 Hz, 1H), 3.53 (dd, J = 14.1, 5.1 Hz, 1H). MS (ES-, m/z): 501.4 (M-, 100.0).

[0095] EXAMPLE 13: 2-(4-((5-(3,4-Dichlorophenyl)furan-2-yl)methylene)-5-oxo-2-thioxoimidazolidin-1-yl)butanoic acid



[0096] To a mixture of 2-(2-aminoacetamido)butanoic acid (0.5g, 3.12mmol) and DIPEA (1.812g, 14.05mmol) in anhydrous THF 10mL is added 1,1'-thiocarbonyldiimidazole (0.834g, 4.68mmol) and heated to reflux overnight. The resulting reaction mixture is concentrated to dry and the pure product 2-(5-oxo-2-thioxoimidazolidin-1-yl)butanoic acid (0.24g, 1.187mmol, yellow solid) is obtained by column chromatography using acetic acid/DCM, 0-5% ration solvent system. 1H-NMR (CD3OD/300 MHz): 5.21 (dd, J = 10.5, 5.1 Hz, 1H), 4.09 (d, J = 5.4 Hz, 2H), 2.25 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H). MS (ES+, m/z): 200.9 (M-, 100.0).

[0097] To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)butanoic acid (0.130g, 0.643mmol) and 5-(3,4-dichloro-phenyl)thiophene-2-carbaldehyde (0.155g, 0.643mmol) in acetic acid 5mL is added β-alanine (5.72mg, 0.064mmol) and heat to 170°C for 30min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.060g, 0.141mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CD3OD/300 MHz): 7.97 (d, J = 2.1 Hz, 1H), 7.68 (dd, J = 8.4, 2.1 Hz, 1H), 7.49 (d, J = 4.8 Hz, 1H), 7.02 (m, 2H), 6.48 (s, 1H), 5.31 (dd, J = 11.1, 5.4 Hz, 1H), 2.32 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H). MS (ES-, m/z): 423.3 (M-, 100.0).

[0098] EXAMPLE 14:



[0099] To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.050g, 0.189mmol) and 5-(4-iodo-phenyl)thiophene-2-carbaldehyde (0.059g, 0.189mmol) in acetic acid 5mL is added β-alanine (1.68mg, 0.019mmol) and heat to 170°C for 30min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.085g, 0.125mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CD3OD/300 MHz): 7.72 (m, 2H), 7.49 (m, J = 9.0 Hz, 2H), 7.18 (m, 5H), 7.89 (m, 2H), 6.45 (s, 1H), 5.62 (dd, J = 11.1, 5.4 Hz, 1H), 3.69 (dd, J = 14.1, 12.6 Hz, 1H), 3.53 (dd, J = 14.1, 5.1 Hz, 1H). MS (ES-, m/z): 560.0 (M-, 100.0).

Fischetti Lab Protocol for Epimerase Inhibitor Growth Curves



[0100] All compounds are solubilized at a stock concentration of 5mM in DMSO. They are sonicated in a sonicating water bath for 2 bursts of 10s in order to break up the clumps. All compounds are treated similarly, regardless of clumping state, to ensure proper solubilization. Some compounds are sonicated more if necessary.

[0101] Since 3% DMSO is tolerable for most Gram+ strains, that is the concentration used in our assay. Therefore, stock inhibitor compounds are diluted 1:5 (1mM), 1:15 (0.3333mM), and 1:50 (0.1mM). Upon addition of [6µL inhibitor + 95µL BHI] followed by + 100µL cells (at the beginning of the growth assay), the final concentrations become 30µM, 10µM, and 3µM.

[0102] Currently, two strains are used for each growth assay: B. anthracis ΔSterne, and Staphylococcus aureus MRSA. Cells are inoculated from a single colony and then grown overnight for 16h in BHI shaking at 150rpm at 30°C. These are inoculated 1:100 into 25mL BHI in a 125mL flask, and grown for 3.5h under the same conditions.

[0103] OD600 of the exponential culture is then normalized to 0.220, and 100µL of this is added to each well containing 100µL [6µL epimerase inhibitor compounds or DMSO alone + 95µL BHI]. A typical 96-well plate layout is used. The plate is inserted into a SpectraMax 96-well plate reader set at 25°C. The OD600 is measured every 2min with 40s of shaking in between readings. The assay is monitored in this manner for 16h, but sometimes for up to 20h. Data is collected with SoftMaxPro software, and exported to Microsoft Excel for analysis.

[0104] The cells reach stationary phase typically at 40,000s, so data is assessed at this point. The kinetic reading can help identify aberrations in the data (cell clumping, bubbles, etc.). The final results are expressed as % inhibition. This is achieved after subtracting the media background from all points, and then determining the percent of growth inhibition using this formula:




Claims

1. A compound represented by Formula I or II:



or a pharmaceutically acceptable salt thereof, wherein

X, Y, and Z each independently is O, S, or NR4;

A is phenyl or pyridyl;

B is phenyl, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, homopiperazinyl, pyranyl, furyl, 1H-tetrahydropyranyl, tetrahydrofuranyl, thienyl, oxazolyl, isoxazolyl, oxadiazoyl, oxazolinyl, morpholinyl, thiazolyl, thiadiazolyl or thiazolidinyl; wherein for Formula I, A may be halo and B may be CH3 but not at the same time;

R1 in each instance independently is C0-4alkyl;

R2 in each instance independently is C0-4alkyl, C1-4alkoxy, halo, -CF2H, CF3, -OCF3, -SCF3, SF5;

R3 in each instance independently is C0-4alkyl;

R4 in each instance independently is C0-4alkyl, or phenyl, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, homopiperazinyl, pyranyl, furyl, 1H-tetrahydropyranyl, tetrahydrofuranyl, thienyl, oxazolyl, isoxazolyl, oxadiazoyl, oxazolinyl, morpholinyl, thiazolyl, thiadiazolyl or thiazolidinyl;

n is 0, 1, or 2; and

m and mm each independently is 0, 1, 2, 3, 4, or 5.


 
2. The compound according to Formula I of claim 1, wherein Z is O, and Y is S.
 
3. The compound according to claim 2, wherein X is S.
 
4. The compound according to claim 2, wherein X is O.
 
5. The compound according to Formula II of claim 1, wherein Z is O, and Y is S.
 
6. The compound according to any one of claims 2, 3, 4, or 5, wherein A is phenyl, and B is phenyl.
 
7. The compound according to claim 1 consisting of



or a pharmaceutically acceptable salt thereof.
 
8. The compound according to claim 1 consisting of

or a pharmaceutically acceptable salt thereof.
 
9. The compound according to claim 1 consisting of

or a pharmaceutically acceptable salt thereof.
 
10. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.
 
11. A kit for treating a 2-epimerase-mediated disease comprising a therapeutically effective amount of a composition of claim 10.
 
12. The kit of claim 11, wherein the 2-epimerase-mediated disease is an infection.
 
13. A kit for treating infections from Staphylococcus aureus, Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus pneumonia, Streptococcus agalactiae, Group C streptococcus, Group G streptococcus, Enterococcus faecalis, Enterococcus faecium, Bacillus anthracis, Bacillus cereus, Escherichia coli, Pseudomonas areuginosa, Neisseria meningitides, or Neisseria gonorrhoeae comprising a therapeutically effective amount of a compound according to claim 1.
 


Ansprüche

1. Verbindung dargestellt durch die Formel I oder II:



oder ein pharmazeutisch annehmbares Salz davon, wobei

X, Y und Z jeweils unabhängig O, S oder NR4 ist;

A Phenyl oder Pyridyl ist;

B Phenyl, Pyrrolyl, Pyrrolinyl, Imidazolyl, Pyrazolyl, Pyridyl, Pyrimidinyl, Pyrazinyl, Pyridazinyl, Triazolyl, Tetrazolyl, Pyrrolidinyl, Imidazolidinyl, Piperidyl, Piperazinyl, Homopiperazinyl, Pyranyl, Furyl, 1 H-Tetrahydropyranyl, Tetrahydrofuranyl, Thienyl, Oxazolyl, Isoxazolyl, Oxadiazoyl, Oxazolinyl, Morpholinyl, Thiazolyl, Thiadiazolyl oder Thiazolidinyl ist; wobei für Formel I, A Halogen sein kann und B CH3 sein kann, aber nicht gleichzeitig;

R1 in jedem Fall unabhängig C0-4-Alkyl ist;

R2 in jedem Fall unabhängig C0-4-Alkyl, C1-4-Alkoxy, Halogen, -CF2H, CF3,-OCF3, -SCF3, SF5 ist;

R3 in jedem Fall unabhängig C0-4-Alkyl ist;

R4 in jedem Fall unabhängig C0-4-Alkyl oder Phenyl, Pyrrolyl, Pyrrolinyl, Imidazolyl, Pyrazolyl, Pyridyl, Pyrimidinyl, Pyrazinyl, Pyridazinyl, Triazolyl, Tetrazolyl, Pyrrolidinyl, Imidazolidinyl, Piperidyl, Piperazinyl, Homopiperazinyl, Pyranyl, Furyl, 1 H-Tetrahydropyranyl, Tetrahydrofuranyl, Thienyl, Oxazolyl, Isoxazolyl, Oxadiazoyl, Oxazolinyl, Morpholinyl, Thiazolyl, Thiadiazolyl oder Thiazolidinyl ist;

n 0, 1 oder 2 ist; und

m und mm jeweils unabhängig 0, 1, 2, 3, 4 oder 5 ist.


 
2. Verbindung nach Formel I von Anspruch 1, wobei Z O ist und Y S ist.
 
3. Verbindung nach Anspruch 2, wobei X S ist.
 
4. Verbindung nach Anspruch 2, wobei X O ist.
 
5. Verbindung nach Formel II von Anspruch 1, wobei Z O ist und Y S ist.
 
6. Verbindung nach einem der Ansprüche 2, 3, 4 oder 5, wobei A Phenyl und B Phenyl ist.
 
7. Verbindung nach Anspruch 1 bestehend aus



oder aus einem pharmazeutisch annehmbaren Salz davon.
 
8. Verbindung nach Anspruch 1 bestehend aus

oder einem pharmazeutisch annehmbaren Salz davon.
 
9. Verbindung nach Anspruch 1 bestehend aus

oder einem pharmazeutisch annehmbaren Salz davon.
 
10. Zusammensetzung, welche eine Verbindung nach Anspruch 1 und einen pharmazeutisch annehmbaren Hilfsstoff umfasst.
 
11. Kit zur Behandlung einer 2-Epimerase-vermittelten Erkrankung, umfassend eine therapeutisch wirksame Menge einer Zusammensetzung nach Anspruch 10.
 
12. Kit nach Anspruch 11, wobei die 2-Epimerase-vermittelten Erkrankung eine Infektion ist.
 
13. Kit zur Behandlung von Infektionen von Staphylococcus aureus, Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus pneumonia, Streptococcus agalactiae, Gruppe C Streptococcus, Gruppe G Streptococcus, Enterococcus faecalis, Enterococcus faecium, Bacillus anthracis, Bacillus cereus, Escherichia coli, Pseudomonas areuginosa, Neisseria meningitides oder Neisseria gonorrhoeae, umfassend eine therapeutisch wirksame Menge einer Verbindung nach Anspruch 1.
 


Revendications

1. Composé représenté par la formule I ou II :



ou un de ses sels pharmaceutiquement acceptables, formule dans laquelle :

X, Y et Z représente chacun indépendamment O, S ou un groupe NR4 ;

A représente un groupe phényle ou pyridyle ;

B représente un groupe phényle, pyrrolyle, pyrrolinyle, imidazoylyle, pyrazolyle, pyridyle, pyrimidinyle, pyrazinyle, pyridazinyle, triazolyle, tétrazolyle, pyrrolidinyle, imidazolidinyle, pipéridyle, pipérazinyle, homopipérazinyle, pyrannyle, furyle, 1H-tétrahydropyrannyle, tétrahydrofurannyle, thiényle, oxazolyle, isoxazolyle, oxadiazolyle, oxazolinyle, morpholinyle, thiazolyle, thiadiazolyle ou thiazolidinyle ; où, pour la formule I, A peut représenter un groupe halogéno et B peut représenter un groupe CH3, mais pas en même temps ;

R1 représente dans chaque cas indépendamment un groupe alkyle en C0 à C4 ;

R2 représente dans chaque cas indépendamment un groupe alkyle en C0 à C4, alkoxy en C1 à C4, halogéno, -CF2H, CF3, -OCF3, -SCF3 ou SF5 ;

R3 représente dans chaque cas indépendamment un groupe alkyle en C0 à C4 ;

R4 représente dans chaque cas indépendamment un groupe alkyle en C0 à C4, ou un groupe phényle, pyrrolyle, pyrrolinyle, imidazolyle, pyrazolyle, pyridyle, pyrimidinyle, pyrazinyle, pyridazinyle, triazolyle, tétrazolyle, pyrrolidinyle, imidazolidinyle, pipéridyle, pipérazinyle, homopipérazinyle, pyrannyle, furyle, 1H-tétrahydropyrannyle, tétrahydrofurannyle, thiényle, oxazolyle, isoxazolyle, oxadiazolyle, oxazolinyle, morpholinyle, thiazolyle, thiadiazolyle ou thiazolidinyle ;

n est égal à 0, 1 ou 2 ; et

m et mm sont chacun égaux indépendamment à 0, 1, 2, 3, 4 ou 5.


 
2. Composé de formule I suivant la revendication 1, dans lequel Z représente O et Y représente Z.
 
3. Composé suivant la revendication 2, dans lequel X représente S.
 
4. Composé suivant la revendication 2, dans lequel X représente O.
 
5. Composé de formule II suivant la revendication 1, dans lequel Z représente O et Y représente S.
 
6. Composé suivant l'une quelconque des revendications 2, 3, 4 ou 5, dans lequel A représente un groupe phényle et B représente un groupe phényle.
 
7. Composé suivant la revendication 1, consistant en :



ou un de ses sels pharmaceutiquement acceptables.
 
8. Composé suivant la revendication 1, consistant en :

ou un de ses sels pharmaceutiquement acceptables.
 
9. Composé suivant la revendication 1, consistant en :

ou un de ses sels pharmaceutiquement acceptables.
 
10. Composition comprenant un composé suivant la revendication 1 et un excipient pharmaceutiquement acceptable.
 
11. Kit pour traiter une maladie à médiation par la 2-épimérase, comprenant une quantité thérapeutiquement efficace d'une composition de la revendication 10.
 
12. Kit suivant la revendication 11, la maladie à médiation par la 2-épimérase étant une infection.
 
13. Kit pour traiter des affections par Staphylococcus aureus, Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus agalactiae, un Streptococcus du Groupe C, un Streptococcus du Groupe G, Enterococcus faecalis, Enterococcus faecium, Bacillus anthracis, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Neisseria meningitidis ou Neisseria gonorrhoeae, comprenant une quantité thérapeutiquement efficace d'un composé suivant la revendication 1.
 






Cited references

REFERENCES CITED IN THE DESCRIPTION



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Patent documents cited in the description




Non-patent literature cited in the description