Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
  • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
  • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
  • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to novel enzyme inhibitors, more specifically to inhibitors of peptide deformylase useful in the treatment or prevention of infections and other diseases in which peptide deformylases are involved, especially in the treatment of bacterial and parasitic infections. More specifically the invention relates to isoxazoles capable of inhibiting bacterial peptide deformylase, also known as PDF.
• Peptide deformylase (EC 3.4.1.88), also known as PDF, is an enzyme that catalyzes the deformylation of formyl-L-methionyl peptides. PDF removes the formyl group from the /V-terminal Met of newly synthesized proteins, i.e. catalyzes the conversion of formyl-L-methionyl peptide to methionyl peptide (Adams and Capecchi, 1966; Adams, 1968).
• PDF is essential to bacteria, and bacterial peptide deformylase (PDF) is now widely recognised as an attractive target for antibacterial chemotherapy (Giglione et al., 2000; Giglione and Meinnel, 2001 ; Pei 2001 ; Yuan et al., 2001 ; Clements et al., 2002).
• Deformylation is a crucial step in bacterial protein biosynthesis and PDF is an essential ingredient in bacterial growth, with the gene encoding PDF present in all sequenced pathogenic bacterial genomes.
• Novel antibacterial compounds are urgently needed due to the growing resistance exhibited by both Gram-negative and Gram-positive bacteria and other microorganisms.
• Traditional antibiotics have targeted pathways unique to bacterial replication and maintenance. However, new pathways are not being targeted in a manner that outpaces the growth of bacterial resistance. Thus, novel compounds and strategies are greatly needed that can be used to eradicate resistant bacteria.
• the present invention relates to compounds of the general formula (I) wherein R 1 t R 2 , X and Y are as defined in the detailed part of this description.
• the compounds of the invention are useful for the treatment of infections caused by bacteria or parasites. It is especially contemplated that the compounds of the present invention are useful for the treatment of infections fully or partly caused by Gram-positive or Gram-negative bacteria such as Escherichia co//and Staphylococcus aureus or by a parasite such as Plasmodium falciparum.
• peptide deformylase or "PDF” as used herein is intended to mean peptide deformylase (EC 3.4.1.88), also known as PDF, which catalyzes the conversion of the ⁇ Merminal formyl-L-methionyl peptide to met ionyl peptide in newly synthesized proteins.
• treatment is defined as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of a compound of the present invention to prevent the onset of the symptoms or the complications, or alleviating the symptoms or the complications, or eliminating the disease, condition, or disorder.
• C ⁇ -6 alkyl denotes a straight or branched, saturated hydrocarbon chain having from one to six carbon atoms.
• C -6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl , 2-methylbutyl, 3-methylbutyl, n-hexyl, iso-hexyl, 4-methylpentyl, neopentyl, 2,2-dimethylpropyl and the like.
• C 2-6 alkenyl denotes a straight or branched, unsaturated hydrocarbon chain having from two to six carbon atoms and at least one double bond.
• C 2-6 alkenyl groups include, but are not limited to, vinyl, 1- propenyl, allyl, iso-propenyl, n-butenyl, n-pentenyl, n-hexenyl and the like.
• C 1-6 alkoxy in the present context designates a group O-d.6 alkyl used alone or in combination, wherein C -6 alkyl is as defined above.
• linear alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.
• branched alkoxy are iso-propoxy, sec-butoxy, tert-butoxy, iso-pentoxy and iso-hexoxy.
• cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
• aminocarbonylC 1-6 alkyl in the present context designates a group NH-C(0)-C 1-6 alkyl used alone or in combination, wherein C -6 alkyl is as defined above.
• aminocarbonylC 1-6 alkyl grou ps include, but are not limited to, aminocarbonylmethyl and aminocarbonylethyl.
• C 3-10 cycloalkyl denotes a radical of one or more saturated mono-, bi-, tri- or spirocyclic hydrocarbon having from three to ten carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adarnantyl and the like.
• C 3- heterocycloalkyl denotes a radical of a totally saturated heterocycle like a cyclic hydrocarbon containing one or more heteroatoms selected from nitrogen, oxygen and sulphur independently in the cycle.
• heterocycles include, but are not limited to, pyrrolidine ( -pyrrolidine, 2-pyrrolidine, 3- pyrrolidine, 4-pyrrolidine, 5-pyrrolidine), pyrazolidine (1-pyrazolidine, 2-pyrazolidine, 3- pyrazolidine, 4-pyrazolidine, 5-pyrazolidine), imidazolidine (1-imidazolidine, 2- imidazolidine, 3-imidazolidine, 4-imidazolidine, 5-irmidazolidine), thiazolidine (2- thiazolidine, 3-thiazolidine, 4-thiazolidine, 5-thiazolidine), piperidine (1-piperidine, 2- piperidine, 3-piperidine, 4-piperidine, 5-piperidine, 6-piperidine), piperazine (1- piperolidine ( -pyrrol
• heteroaryl as used herein includes heterocyclic aromatic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulphur such as furyl, thienyl, pyrrolyl, and is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated below.
• Examples include, but are not limited to, phenyl, biphenyl, indenyl, naphthyl (1- naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), phenanthrenyl, fluorenyl, pentalenyl, azulenyl, biphenylenyl, thiophenyl (1 -thienyl, 2-thienyl), furyl (1-furyl, 2- furyl), furanyl, thiophenyl, isoxazolyl, isothiazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, pyranyl, pyridazinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,
• Non-limiting exarnples of partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.
• C 1-6 alkylaryl refers to an aryl group as defined above attached through a C 1-6 alkyl group as defined above having one, two, three, four, five or six carbon atoms.
• C 1-6 alkylheteroaryl refers to a heteroaryl group as defined above attached through a C 1-6 alkyl group as defined above having one, two, three, four, five or six carbon atoms.
• Halogen designates an atom selected from the group consisting of F, CI, Br and I.
• unsubstituted or substituted as used herein means that the groups in question are optionally unsubstituted or substituted with one or more, for example one, two, three or four of the substituents specified.
• the groups in question are substituted with one or more, for example one, two, three or four substituents independently of each other selected from halogen, C 1-6 alkyl, C 3- -
• the substituents may be the same or different.
• a functional group which can be converted to hydrogen in vivo
• Non-limiting examples of such groups are acyl, carbamoyl, monoalkylated carbamoyl, dialkylated carbamoyl, alkoxycarbonyl, alkoxyalkyl groups and the like such as C 1-6 alkylcarbonyl, aroyl, C 1-6 alkylcarbamoyl, di-C 1-6 alkyl-alkylcarbamoyl, C 1-6 alkoxycarbonyl and C 1-6 alkoxy- C 1-6 alkyl.
• diseases and disorders related to peptide deformylase is intended to include any disease or disorder in which an effect, preferably an inhibiting effect, on peptide deformylase is beneficial, especially on the bacterial peptide deformylase.
• IC 50 denotes the concentration required for 50% inhibition of PDF in a binding assay.
• the present invention relates of compounds of the general formula (I)
• X is selected from hydroxy, C 1-6 alkoxy, and -NH-OH
• Y is selected from S, SO, S0 2 and O
• R- 1 is selected from hydrogen, C 1-6 alkyl, C 2 .e alkenyl, C 3-10 cycloalkyl, C 3- heterocycloalkyl, an unsubstituted or substituted C 1-6 alkylaryl group, an unsubstituted or substituted C 1-6 alkylheteroaryl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, wherein a substituted group in connection with Ri is substituted with one, two, three or four substituents independently selected from the group consisting of halogen, C 1-6 alkyl and C 1-6 alkoxy; and R 2 is selected from C 1-6 alkyl, C 3 , 10 cycloalkyl, C 3-7 heterocycloalkyl, an un
• X is hydroxy, methoxy, ethoxy, propoxy or -NH-OH.
• Y is S, SO or S0 2 , more preferably S (sulfur).
• R ⁇ is hydrogen, C 1-6 alkyl, or C 3- ⁇ o cycloalkyl; more preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec. butyl, isobutyl, tert-butyl, pentyl, cyclopentyl or cyclohexyl; or Ri is an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, or R 1 is selected from an unsubstituted or substituted C 1-6 alkylaryl group and an unsubstituted or substituted C ⁇ -6 alkylheteroaryl group.
• R 2 is selected from an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, an unsubstituted or substituted C 1-6 alkylaryl group, and an unsubstituted or substituted C 1-6 alkylheteroaryl group.
• R 2 may also be an unsubstituted or substituted aryl group, or an unsubstituted or substituted phenyl group.
• R 2 is a substituted phenyl group, wherein a substituted phenyl is substituted with one, two, three or four substituents independently selected from methyl, ethyl, n-propyl, butyl, isopropyl, isobutyl, sec-butyl, terf-butyl, fluoro, chloro, bromo, iodo, methoxy, trifluoromethyl, trifluorornethoxy, aminocarbonylmethyl and thiophenyl.
• R 2 is a substituted phenyl group, substituted with one, two, three or four substituents independently selected from chloro, bromo, trifluoromethyl or trifluorornethoxy.
• R 2 group is an unsubstituted or substituded group, wherein the group is selected from biphenyl, diphenyl, naphtyl, benzothiophenylmethyl, thiophenyl- pyrimidinyl, pyridyl, quinolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiophenyl, furanyl, thiadiazolyl and oxadiazolyl.
• R 2 is selected from C 1-6 alkyl, C 3- ⁇ 0 cycloalkyl and C 3-7 heterocycloalkyl.
• Preferred compounds of the invention are:
• the compounds of the invention may exist as geometric isomers or optical isomers or stereoisomers as well as tautomers. Accordingly, the invention includes all geometric isomers and tautomers including mixtures and racemic mixtures of these and a pharmaceutically acceptable salt thereof, especially all R- and S-isomers.
• the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
• Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
• Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
• suitable organic acids include formic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like.
• compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
• metal salts include lithium, sodium, potassium, magnesium salts and the like.
• ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
• Also intended as pharmaceutically acceptable acid addition salts are the hydrates, which the present compounds are able to form.
• the acid addition salts may be obtained as the direct products of compound synthesis.
• the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
• the compounds of the present invention may form solvates with standard low molecular weight solvents using methods well known to the person skilled in the art. Such solvates are also contemplated as being within the scope of the present invention.
• the invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the Formula I. Prodrugs are any covalently bonded compounds, which release the active parent drug according to Formu la I in vivo.
• a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein.
• Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
• both the cis (Z) and trans (E) isomers are within the scope of this invention.
• each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
• Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, (1985).
• the invention also encompasses active metabolites of the present compounds.
• the present invention includes all complexes of the compounds of this invention.
• the compounds of Formula I exhibit an IC 50 value of less than 500 ⁇ M, preferably less than 100 ⁇ M, more preferably less than 50 ⁇ M, even more preferably less than 1 ⁇ M, especially less than 500 nM, particularly less than 100 nM, when subjected to a bacterial PDF assay.
• a compound according to the present invention can be used in medicine, in particular as a protease inhibitor such as a peptide deformylase inh ibitor.
• a compound according to the invention can also be used in the treatment, prophylaxis and/or diagnosis of bacterial infections fully or partly caused by an organism belonging to any of the genera Staphylococcus, Enterococcus, Streptococcus, Haemophilus, Moraxella, Escherichia, Mycobacterium, Mycoplasma, Pseudomonas, Chlamydia, Rickettsia, Klebsiella, Shigella, Salmonella, Bordetella, Clostridium, Helicobacter, Campylobacter, Legionella and Neisseria.
• the compounds of the present invention may be prepared by the methods set forth in the schemes A-E below.
• the general synthetic scheme involves the initial radical bromination of ethyl-5- methylisoxazole-3-carboxylate using N-bromosuccinimide and benzoylperoxide as radical initiator.
• Reaction of the ethyl ester with a methanolic solution of hydroxylamine hydrochloride afforded the desired hydroxamic acid.
• the desired hydroxamic acid is obtained by reaction with a methanolic solution of hydroxylamine hydrochloride.
• Alkylation of the benzylic position can be achieved by treating the intermediate previously obtained (Step 1 , Scheme C) with a suitable base (for example NaH), followed by addition of an electrophile (for example alkyl/benzyl halides).
• a suitable base for example NaH
• an electrophile for example alkyl/benzyl halides
• the desired hydroxamic acid is then obtained by reaction with a methanolic solution of hydroxylamine hydrochloride.
• Acid addition salts of the compounds of Formula I are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form inner salts or zwitterions, which may be acceptable.
• Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine.
• Cations such as Li + , Na + , K + , Ca ++ , Mg ++ and NH 4 + are specific examples of cations present in pharmaceutically acceptable salts.
• Halides, sulfate, phosphate, alkanoates (such as acetate and trifluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts.
• a pharmaceutical composition comprising, as an active ingredient, a compound of the present invention together with a pharmaceutically acceptable carrier or diluent.
• This composition may be in unit dosage form and may comprise from about 1 ⁇ g to about 1000 mg such as, e.g., from about 10 ⁇ g to about 500 mg, from about 0.05 to about 100 mg or from about 0.1 to about 50 mg, of the compound of the invention or a pharmaceutically acceptable salt or ester thereof.
• the composition of the invention may be used for oral, nasal, transdermal, pulmonal or parenteral administration. It is contemplated that the pharmaceutical composition of the invention is useful for treatment of bacterial and/or parasitic infections.
• the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in either single or multiple doses. Accordingly, the compounds of Formula I may be used in the manufacture of a medicament.
• the pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques, for example such as those disclosed in Remington (Gennaro and Gen aro (1995)).
• compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral
• compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
• Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
• compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.
• Suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
• a typical oral dosage is in the range of from about 0.001 to about 50 rng/kg body weight per day, preferably from about 0.01 to about 30 mg/kg body weight per day, and more preferred from about 0.05 to about 20 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages.
• the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
• a typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from about 0.05 to about 500 mg, preferably from about 0.05 to about 100 mg, more preferably from about 0.1 to about 50 mg, and more preferred from about 0.5 mg to about 20 mg.
• parenteral routes such as intravenous, intrathecal, intramuscular and similar administration
• typically doses are in the order of about half the dose employed for oral administration.
• the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
• One example is an acid addition salt of a compound having the utility of a free base.
• a compound of the Formula (I) contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the Formula (I) with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids. Representative examples are mentioned above.
• Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.
• solutions of the novel compounds of the Formula (I) in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed.
• aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
• the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
• the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
• Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
• solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose.
• liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water.
• the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
• the pharmaceutical compositions formed by combining the novel compounds of the Formula (I) and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
• the formulations may conveniently be presented in unit dosage form by methods known in the art of
• Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.
• the preparation may be tableted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
• the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
• the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
• a typical tablet which may be prepared by conventional tabletting tecl iniques, may contain: Core: Active compound (free compound or salt) 5.0 mg Lactosum Ph. Eur. 67.8 mg Cellulose, microcryst. (Avicel) 31.4 mg Amberlite 1.0 mg Magnesii stearas q.s. Coating: Hydroxypropyl methylcellulose approx. 9 mg Acylated monoglyceride approx. 0.9 mg
• the pharmaceutical composition of the invention may comprise the compound of the Formula (I) in combination with further pharmacologically active substances such as those described in the foregoing.
• X is selected from hydroxy, C 1-6 alkoxy, and -NH-OH
• Y is selected from S, SO, S0 2 and O;
• R-i is selected from hydrogen, C ⁇ -6 alkyl, C 2 . 6 alkenyl, C 3-10 cycloalkyl, C 3-7 heterocycloalkyl, an unsubstituted or substituted C ⁇ -6 alkylaryl group, an unsubstituted or substituted C 1-6 alkylheteroaryl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, wherein a substituted group in connection with R-i is substituted with one, two, three or four substituents independently selected from the group consisting of halogen, C-,.
• R 2 is selected from C 1-6 alkyl, C 3- ⁇ 0 cycloalkyl, C 3-7 heterocycloalkyl, an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, an unsubstituted or substituted C 1-6 alkylaryl group, or an unsubstituted or substituted C ⁇ -6 alkylheteroaryl group, wherein a substituted group in connection with R 2 is substituted with one, two, three or four substituents independently selected from the group consisting of halogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkoxy, hydroxy, aminocarbonylC 1-6 alkyl, trifluoromethyl, trifluorornethoxy, trifluoromethylthio, heteroaryl, nitro and cyano; may be used for the preparation of a medicament for treatment of bacterial infections.
• the compounds of formula I may be used as protease inhibitors, particularly as inhibitors of metallo proteases, more particularly as inhibitors of peptide deformylase, even more particularly as inhibitors of bacterial peptide deformylase.
• the present invention provides useful compositions and formulations of said compounds, including pharmaceutical compositions and formulations of said compounds.
• the compounds of the present invention may be especially useful for the treatment or prevention of diseases caused by a variety of bacterial or prokaryotic organisms.
• examples include Gram-positive and Gram-negative aerobic and anaerobic bacteria such as, Staphylococci, for example S. aureus and S. epidermidis; Enterococci, for example E. faecium and E. faecalis; Streptococci, for example S. pneumoniae; Haemophilus, for example H. influenzae; Moraxella, for example M. catarrhalis; Escherichia, for example E. coli; Mycobacteria, for example M. tuberculosis and M. ranae; Mycoplasma, for example M.
• pneumoniae Pseudomonas, for example P. aeruginosa; intercellular microbes, for example Chlamydia and Rickettsiae.
• Other examples include Klebsiella pneumoniae, Shigella flexneri, Salmonella typhimuhum, Bordetella pertussis, Clostridia perfringens, Helicobacter pylori, Campylobacter jejuni, Legionella pneumophila and Neisseria gonorrhoeae. It is further contemplated that the compounds of the present invention are useful for the treatment of parasitic infections, for example infections caused by Plasmodium falciparum and the like.
• the present invention relates to a method for the treatment of ailments, the method comprising administering to a subject in need thereof an effective amount of a compound or a composition of this invention.
• an effective amount of a compound or a composition of this invention corresponds to an amount of active ingredient, i.e. active compound or a pharmaceutically acceptable salt or ester thereof, in the range of from about 1 ⁇ g to about 1000 mg such as, e.g., from about 10 ⁇ g to about 500 mg, from about 0.05 to about 100 mg or from about 0.1 to about 50 mg per day.
• the present invention relates to use of a compound of this invention for the preparation of a medicament, preferably a medicament for the treatment of infections caused by Gram-positive or Gram-negative aerobic or anaerobic bacteria, or by parasites.
• the compounds of the present invention are useful for the treatment of parasitic infections, for example infections caused by Plasmodium falciparum and the like.
• an intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients is most effective, although an intramuscular bone injection is also useful.
• the parenteral dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to inhibit PDF.
• the compounds may be administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg/kg/day.
• the precise amount of an inventive compound which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.
• the compounds of this invention may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to inhibit bone resorption or to achieve any other therapeutic indication as disclosed herein.
• a pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 50 mg/kg in a manner consistent with the condition of the patient.
• the oral dose would be about 0.5 to about 20 mg/kg.
• the compounds of the present invention fully or partly inhibit bacterial PDF, and are thus useful for the treatment and/or prevention of a wide variety of conditions and disorders in which inhibition of PDF is beneficial.
• the present invention relates to a compound of the general Formula (I) or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for use as a pharmaceutical composition.
• the invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound of the Formula (I) or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or diluents.
• NMR data were acquired on a Bruker Advance DRX 250.
• CDCI 3 is deuteriochloroform
• DMSO-d 6 is hexadeuteriodimethylsulfoxide
• D 2 0 is deuteriooxide
• acetone-d 6 is hexadeuterioacetone
• CD 3 OD is tetradeuteriomethanol.
• Step 1 Ethyl-5-methylisoxazole-3-carboxylate (6.24 g, 40 mmol) was dissolved in dry CCI (50 mL), and the solution was heated to reflux. A mixture of finely powdered NBS (freshly recrystallized, 7.1 g, 1 mmol) and BPO (freshly recrystallized, 0.5 g, 0.05 mmol) was added in portions over 1 h to the refluxing solution. The mixture was refluxed for 2 h, after which an additional 1.4 g of NBS (0.2 mmol) and 0.5 g of BPO (0.05 mmol) were added in one portion. Refluxing was continued 2 h more.
• Step 2 The product of Step 1 (234 mg, 1 mmol) was dissolved in dry DMF, under argon atmosphere. K 2 C0 3 (138 mg, 1.5 mmol) and a thiol (1.1 mmol) were added, and the mixture was stirred at 60 °C for 1-3 h. The solution was cooled to room temperature, water was added and the mixture was extracted 3 times with EtOAc. The combined organic layers were dried over Na 2 S0 4 , filtered and concentrated to dryness. Purification by flash column chromatography afforded the expected products.
• Step 3 The preparation of NH 2 OK/NH 2 OH solution was performed according to previously reported procedure (Hauser and Renfrow, 1943; Hanessian et al., 2001).
• NH 2 OH ⁇ CI 28 mg, 4 mmol
• MeOH MeOH
• KOH 34 mg, 6 mmol
• MeOH MeOH
• the alkali solution was added in one portion to the hydroxylamine solution, and sudden precipitation of potassium chloride was observed.
• the ethyl ester prepared at Step 2 (1 mmol) dissolved in MeOH (1 mL) was added in one portion to the suspension. Stirring was continued at room temperature for 1-12 h, until all starting material disappeared on TLC. 1 N HCI was added until pH 2, the volume was reduced to 3 mL, and the solution directly purified by preparative HPLC.
• Examples 1-18 were prepared by following the General Method A.
• Examples 19-32 were prepared by following the General Method B. General Method C (Scheme C).
• Step 1 Intermediates obtained from Step 2, General Method A (1 mmol), were dissolved in dry DCM, and m-CPBA (690 mg, 2.5 mmol) was added in one portion. Stirring was continued at room temperature for 1-3 h, until total conversion to the di- oxidized product (monitored by TLC and ES-MS). More DCM was added, the organic phase was extracted 3 times with an aq. solution of Na 2 C0 3 and once with water, dried over Na 2 S0 4 , filtered and concentrated to dryness. Purification by flash column chromatography or by recrystallization from heptane/EtOAc afforded the expected products.
• Step 2 Same procedure as in Step 3, General Method A.
• Step 1 Intermediates obtained from Step 2, General Method A (1 mmol) were dissolved in glacial AcOH (8 mL) and NaB0 3 ⁇ 2 0 (229 mg, 1.5 mmol) was added in one portion. Stirring was continued at room temperature for 1-3 h, monitoring the reaction by ES-MS and TLC. A saturated solution of NaCI was added, extracted 3 times with EtOAc. The collected organic layers were dried over Na 2 S0 4 , filtered and concentrated to dryness. Purification by flash column chromatography afforded the expected products.
• Step 2 Same procedure as in Step 3, General Method A.
• Example 38 was prepared by following the General Method D.
• Step 1 Intermediates obtained from Step 1 , General Method C (0.5 mmol), were dissolved in THF (5 mL), cooled to -30 °C and NaH (0.6 mmol) was added in one portion. After stirring at low temperature for 15 min, an electrophile (1.5 mmol, for example Mel, EtBr, /-PrBr) was slowly added to the solution. After stirring at low temperature for 15-30 minutes, the cooling bath was removed and the solution was allowed to warm to room temperature. Stirring was continued at room temperature for 1-2 h. Water was added, the mixture extracted 3 times with EtOAc, dried over Na 2 S0 , filtered and concentrated to dryness. Purification by flash column chromatography (heptane/EtOAc) or HPLC afforded the expected product.
• Step 2 Same procedure as in Step 3, General Method A.
• the compounds of this invention may be tested in the following biological assay in order to determine the concentration of compound (IC50) required for exhibiting the desired pharmacological effect.
• PDF Peptide Deformylase
• Bovine serum albumin Catalase Fluka, cat no. 60640
• TNBS Fluorescent Base
• 2,4,6-trinitrobenzene sulfonic acid 2,4,6-trinitrobenzene sulfonic acid.
• the IC 50 value of a compound of the invention as a bacterial PDF inhibitor was determined using the following assay.
• Assay buffer 0.1 M MOPS pH was adjusted to 7.2 with NaOH, containing 0.25 M NaCI,
• E.coli enzyme (2.5 mg/ml) 10 ⁇ l + 290 ⁇ l Assay buffer, 1 ⁇ l per ml enzyme mix.
• TNBS solution Freshly dilute 1 M TNBS stock solution diluted 1:10 with water.
• Buffer C 0.5 M borate buffer adjusted to pH 9.5 with NaOH.
• Buffer D 0.2 ml of freshly prepared 0.5 M Na 2 S0 3 was mixed with 9.8 mL of 0.5M NaH 2 P0 4 .
• Inhibitor solution 2 mM Sodium 4-(hydroxymercurio) benzoate in assay buffer.
• Compound mix Compound of formula I dissolved in DMSO in a 10 mg/mL stock solution. Further dilutions were made in DMSO in the concentration range between 0.05 to 100 mM.
• the assay was performed in a 96 Microtiter plate containing test compound. To each well containing test compound mix was added 75 microliter of enzyme mix followed by the addition of 25 microliter of substrate mix. The resulting mix was incubated for 30 minutes at room temperature with shaking. TNBS solution (50 microliter/well) was added and the resulting mixture was incubated for 15 minutes under shaking. Buffer C was then added (20 microliter/well). After incubating at room temperature for 15 minutes under shaking, buffer D was added (50 microliter/well). The optical diffraction was then measured at 420 nm, thereby determining the IC 50 value.
• Gennaro A. R.; Gennaro A. L. Remington, The Science and Practice of Pharmacy, 19th ed., Mack Publishing Co., Easton, Pa., 1995.

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