Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/14—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic 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
  • A61P31/04—Antibacterial agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• ESKAPE pathogens Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae/Escherichia coli (Enterobacteriacaea), Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species cause the most hospital-acquired infections and frequently “escape” the action of traditional therapeutics.
• MDR multi-drug resistant
• the World Health Organization issued a list of antibiotic-resistant ‘Priority Pathogens’ in 2017 for which new antibiotics are urgently needed.
• the most critical group of all includes multidrug resistant bacteria that pose a particular threat in hospitals, nursing homes, and among patients whose care requires devices such as ventilators and blood catheters. They include Acinetobacter, Pseudomonas and various Enterobacteriaceae (including Klebsiella, E. coli, Serratia, and Proteus). They can cause severe and often deadly infections such as bloodstream infections and pneumonia.
• the second and third most critical groups list high and medium priority bacteria that are becoming increasingly drug-resistant such as Neisseria gonorrhoeae. Sexually transmitted infections (STIs) caused by the bacteria N.
• STIs sexually transmitted infections
• gonorrhoeae (gonococcal infections) have increased 63% since 2014 and are a cause of sequelae including pelvic inflammatory disease, ectopic pregnancy, and infertility and can facilitate transmission of human immunodeficiency virus (HIV).
• N. gonorrhoeae s ability to acquire antimicrobial resistance influences treatment recommendations and complicates control.
• CDC recommended the combination of ceftriaxone and azithromycin for treatment of uncomplicated gonococcal infections.
• ceftriaxone resistance has led to reevaluation of this recommendation.
• Azithromycin resistance in N. gonorrhoeae is an increasing concern.
• One embodiment provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof as described herein, and a pharmaceutically acceptable vehicle.
• pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof as described herein, one or more (e.g., 1 or 2) antibacterial agents and a pharmaceutically acceptable vehicle.
• One embodiment provides a method of treating or preventing a bacterial infection in an animal (e.g., a mammal such as a human) comprising administering to the animal a compound of formula I or a pharmaceutically acceptable salt thereof as described herein.
• One embodiment provides a method of treating or preventing a bacterial infection in an animal (e.g., a mammal such as a human) comprising administering to the animal a compound of formula I or a pharmaceutically acceptable salt thereof as described herein and one or more (e.g., 1 or 2) antibacterial agents.
• One embodiment provides a method of treating or preventing a bacterial infection in an animal (e.g., a mammal such as a human) comprising administering to the animal in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof as described herein.
• One embodiment provides a method of treating or preventing a bacterial infection in an animal (e.g., a mammal such as a human) infected with bacteria comprising administering to the animal a compound of formula I or a pharmaceutically acceptable salt thereof as described herein.
• an animal e.g., a mammal such as a human
• One embodiment provides a compound of formula I or a pharmaceutically acceptable salt thereof as described herein for use in medical treatment.
• One embodiment provides a compound of formula I or a pharmaceutically acceptable salt thereof as described herein for the prophylactic or therapeutic treatment of a bacterial infection.
• One embodiment provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof as described herein for the preparation of a medicament for the prophylactic or therapeutic treatment of a bacterial infection in an animal.
• One embodiment provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof as described herein for the preparation of a medicament for treating a bacterial infection in an animal (e.g., a mammal such as a human).
• One embodiment provides processes and intermediates disclosed herein that are useful for preparing compounds of formula I or salts thereof.
• One embodiment provides a prodrug of a compound of formula I. DETAILED DESCRIPTION
• halo or halogen is fluoro, chloro, bromo, or iodo. Alkyl, alkenyl and alkoxy, etc.
• (C a -C b )alkyl wherein a and b are integers refers to a straight or branched chain hydrocarbon alkyl radical having from a to b carbon atoms.
• a is 1 and b is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.
• alkenyl refers to alkyl that contains one or more double bonds.
• aryl refers to a single aromatic ring or a multiple condensed ring system wherein the ring atoms are carbon. For example, an aryl group can have 6 to 10 carbon atoms, or 6 to 12 carbon atoms.
• Aryl includes a phenyl radical.
• Aryl also includes multiple condensed ring systems (e.g., ring systems comprising 2 rings) having about 9 to 12 carbon atoms or 9 to 10 carbon atoms in which at least one ring is aromatic. Such multiple condensed ring systems may be optionally substituted with one or more (e.g., 1 or 2) oxo groups on any cycloalkyl portion of the multiple condensed ring system. It is to be understood that the point of attachment of a multiple condensed ring system, as defined above, can be at any position of the ring system including an aryl or a cycloalkyl portion of the ring.
• Typical aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like.
• aryl is phenyl or naphthyl.
• heteroaryl refers to a single aromatic ring or a multiple condensed ring system. The term includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the rings. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic.
• Such rings include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl.
• the term also includes multiple condensed ring systems (e.g. ring systems comprising 2 rings) wherein a heteroaryl group, as defined above, can be condensed with one or more heteroaryls (e.g., naphthyridinyl), heterocycles, (e.g., 1, 2, 3, 4-tetrahydronaphthyridinyl), cycloalkyls (e.g., 5,6,7,8-tetrahydroquinolyl) or aryls (e.g. indazolyl) to form a multiple condensed ring system.
• heteroaryls e.g., naphthyridinyl
• heterocycles e.g., 1, 2, 3, 4-tetrahydronaphthyridinyl
• cycloalkyls e.g., 5,6,7,8-
• Such multiple condensed ring systems may be optionally substituted with one or more (e.g., 1 or 2) oxo groups on the cycloalkyl or heterocycle portions of the condensed ring.
• a monocyclic or bicyclic heteroaryl has 5 to 10 ring atoms comprising 1 to 9 carbon atoms and 1 to 4 heteroatoms.
• a monocyclic or bicyclic heteroaryl has 5 to 10 ring atoms comprising 1 to 9 carbon atoms and 1 to 4 heteroatoms wherein at least one ring containing at least one heteroatom is aromatic.
• the point of attachment of a multiple condensed ring system (as defined above for a heteroaryl) can be at any position of the multiple condensed ring system including a heteroaryl, heterocycle, aryl or cycloalkyl portion of the multiple condensed ring system and at any suitable atom of the multiple condensed ring system including a carbon atom and heteroatom (e.g., a nitrogen).
• heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl and thianaphthenyl.
• heterocyclyl or “heterocycle” as used herein refers to a single saturated or partially unsaturated ring containing at least one heteroatom or a multiple ring system wherein at least one ring is saturated or partially unsaturated and contains at least one heteroatom .
• the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) from about 1 to 6 carbon atoms and from about 1 to 3 (e.g., 1, 2 or 3) heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring.
• a monocyclic or bicyclic heterocyclyl has 5 to 10 ring atoms comprising 1 to 9 carbon atoms and 1 to 4 heteroatoms (e.g., 1, 2, 3, or 4) selected from the group consisting of oxygen, nitrogen and sulfur in the ring wherein the at least one ring is saturated or partially unsaturated and includes at least one heteroatom.
• the ring may be substituted with one or more (e.g., 1, 2 or 3) oxo groups and the sulfur and nitrogen atoms may also be present in their oxidized forms.
• Such rings include but are not limited to azetidinyl, tetrahydrofuranyl or piperidinyl.
• heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl and tetrahydrothiopyranyl.
• haloalkyl includes an alkyl group as defined herein that is substituted with one or more (e.g., 1, 2, 3, or 4) halo groups.
• halo alkyl is a “(C 1 -C 6 )haloalkyl”.
• alkoxy refers to an -O-alkyl group.
• cycloalkyl, carbocycle, or carbocyclyl includes saturated and partially unsaturated carbocyclic ring systems.
• the carbocyclyl is a monocyclic carbocyclic ring.
• Such carbocyclyls include “(C 3 -C 7 )carbocyclyl” and “(C 3 -C 8 )cycloalkyl”.
• carbocyclyls include without limitation cyclopropane, cyclobutane, cyclobutene, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane and cycloheptene. Specific values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
• (C 1 -C 6 )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec- butyl, pentyl, 3-pentyl, or hexyl;
• (C 1 -C 6 )alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy;
• (C 3 -C 8 )cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
• (C 1 -C 6 )haloalkyl can be iodomethyl, bromomethyl, chloromethyl, fluoromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2,2,2- trifluoroethyl
• X 1 is CR 3 .
• X 2 is CR 4 .
• X 2 is N.
• a compound of formula I is a compound of formula Ia: or a salt thereof.
• a compound of formula I is a compound of formula Ib: or a salt thereof.
• a compound of formula I is a compound of formula Ic: Ic or a salt thereof.
• Y 3 is CR 7b .
• Y 2 is CR 6b .
• a compound of formula I is a compound of formula Id: or a salt thereof.
• a compound of formula I is a compound of formula Ie: or a salt thereof.
• a compound of formula I is a compound of formula If: or a salt thereof.
• a compound of formula I is a compound of formula Ig:
• the compoune of formula I is a compound of formula Ih: or a salt thereof.
• a compound of formula I is a compound of formula Ii: or a salt thereof.
• R 3 is hydrogen.
• R 3 is hydrogen or halo.
• R 4 is hydrogen.
• R 4 is hydrogen or halo
• R 1 R 1 is hydrogen, (C 1 -C 6 )alkyl, or aryl(C 1 -C 6 )alkyl-, wherein the (C 1 -C 6 )alkyl or aryl(C 1 -C 6 )alkyl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) groups independently selected from the group consisting of halo and phenyl , wherein phenyl is optionally substituted with one or more halo, -OH, -NO2, -CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C 1 -C 4 )alkoxy, or (C 1 -C 4 )haloalkoxy.
• one or more e.g., 1, 2, 3, 4, or 5
• groups independently selected from the group consisting of halo and phenyl , wherein phenyl is optionally substituted with one or more halo, -OH,
• R 1 is hydrogen.
• R 2 is hydrogen.
• Z is -N(R c ) 2 .
• Z is -NH 2 .
• R 7b is hydrogen.
• R 6b is hydrogen.
• R 7b is hydrogen or (C 1 -C 6 )alkyl.
• R 6b is hydrogen or (C 1 -C 6 )alkyl.
• R 5a is (C 1 -C 10 )alkenyl, -W-(C 3 -C 7 )carbocyclyl, -W-aryl, or -W- heteroaryl, wherein the (C 1 -C 10 )alkenyl, -W-(C 3 -C 7 )carbocyclyl, -W-aryl, -W-heteroaryl, is optionally substituted with one or more groups independently selected from Q.
• R 5a is (C 1 -C 10 )alkyl, (C 2 -C 10 )alkenyl, -W-(C 3 -C 7 )carbocyclyl, -W- aryl, or -W-heteroaryl, wherein the C 1 -C 10 )alkyl, (C 2 -C 10 )alkenyl, -W-(C 3 -C 7 )carbocyclyl, -W- aryl, or -W-heteroaryl, is optionally substituted with one or more groups independently selected from Q.
• R 5a is (C 2 -C 10 )alkenyl, -W-(C 3 -C 7 )carbocyclyl, -W-aryl, or -W- heteroaryl, wherein the (C 2 -C 10 )alkenyl, -W-(C 3 -C 7 )carbocyclyl, -W-aryl, or -W-heteroaryl, is optionally substituted with one or more groups independently selected from Q.
• R 5a is (C 2 -C 6 )alkenyl, -W-(C 3 -C 7 )carbocyclyl, -W-aryl, or -W- heteroaryl, wherein the (C 2 -C 6 )alkenyl, -W-(C 3 -C 7 )carbocyclyl, -W-aryl, -W-heteroaryl, is optionally substituted with one or more groups independently selected from Q.
• R 5a is (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, -W-(C 3 -C 7 )carbocyclyl, -W-aryl, or -W-heteroaryl, wherein the C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, -W-(C 3 -C 7 )carbocyclyl, -W-aryl, or - W-heteroaryl, is optionally substituted with one or more groups independently selected from Q.
• R 5a is (C 2 -C 6 )alkenyl, -W-(C 3 -C 7 )carbocyclyl, -W-aryl, or -W- heteroaryl, wherein the (C 2 -C 6 )alkenyl, -W-(C 3 -C 7 )carbocyclyl, -W-aryl, or -W-heteroaryl, is optionally substituted with one or more groups independently selected from Q.
• R 5a is:
• R 5a is:
• One embodiment provides the compound:
• One embodiment provides the compound:
• variable groups shown below can represent the final corresponding groups present in a compound of formula I or that these groups can represent groups that can be converted to the final corresponding groups present in a compound of formula I at a convenient point in a synthetic sequence.
• the variable groups can contain one or more protecting groups that can be removed at a convenient point in a synthetic sequence to provide the final corresponding groups in the compound of formula I.
• Schemes 1-3 illustrates a general method for the preparation of compounds of formula I.
• the bacterial infection being treated is a Gram-negative bacterial strain infection.
• the Gram-negative bacterial strain is selected from the group consisting of Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Acinetobacter lwoffi, Actinobacillus actinomycetemcomitans, Aeromonas hydrophilia, Aggregatibacter actinomycetemcomitans, Agrobacterium tumefaciens, Bacteroides distasonis, Bacteroides eggerthii, Bacteroides forsythus, Bacteroides fragilis, Bacteroides ovalus, Bacteroides splanchnicus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Bordetella bronchiseptica, Bordetella parapertussis, Bordetella pertussis,
• the bacterial infection being treated is a Gram-positive bacterial strain infection.
• the Gram-positive bacterial strain is selected from the group consisting of Actinomyces naeslundii, Actinomyces viscosus, Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Corynebacterium diphtheriae, Corynebacterium ulcerans, Enterococcus faecalis, Enterococcus faecium, Micrococcus luteus, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Mycobacterium tuberculosis, Propionibacterium acnes, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus hyicus, Staphylococcus intermedius, Staphylococc
• compositions can, if desired, also contain other active therapeutic agents, such as a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an anti-cancer, an antimicrobial (for example, an aminoglycoside, an antifungal, an antiparasitic, an antiviral, a carbapenem, a cephalosporin (e.g., cefepime), a fluoroquinolone, a macrolide, a penicillin, a sulfonamide, a tetracycline, another antimicrobial), an anti-psoriatic, a corticosteriod, an anabolic steroid, a diabetes-related agent, a mineral, a nutritional, a thyroid agent, a vitamin, a calcium-related hormone, an antidiarrheal, an anti-tussive, an anti-
• the antibacterial agent is selected from quinolones, tetracyclines, glycopeptides, aminoglycosides, E-lactams, rifamycins, macrolides, ketolides, oxazolidinones, coumermycins, and chloramphenicol. It will be appreciated that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism.
• the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.
• optically active forms for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.
• the compound (or composition thereof) may be at least 51% the absolute stereoisomer depicted. In another embodiment, the compound (or composition thereof) may be at least 60% the absolute stereoisomer depicted. In another embodiment, the compound (or composition thereof) may be at least 80% the absolute stereoisomer depicted. In another embodiment, the compound (or composition thereof) may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound (or composition thereof) may be at least 95 the absolute stereoisomer depicted.
• the present invention encompasses all tautomeric forms of a compound of formula I as well as mixtures thereof that can exist in equilibrium with non-charged and charged entities depending upon pH, which possess the useful properties described herein
• a salt of a compound of formula I can be useful as an intermediate for isolating or purifying a compound of formula I.
• administration of a compound of formula I as a pharmaceutically acceptable acid or base salt may be appropriate.
• Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, fumarate, benzoate, ascorbate, ⁇ -ketoglutarate, and ⁇ -glycerophosphate.
• Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts. Salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording the corresponding anion.
• Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
• Pharmaceutically suitable counterions include pharmaceutically suitable cations and pharmaceutically suitable anions that are well known in the art. Examples of pharmaceutically suitable anions include, but are not limited to those described above (e.g. physiologically acceptable anions) including Cl-, Br-, I-, CH 3 SO 3 -, H 2 PO 4 -, CF 3 SO 3 -, p-CH 3 C 6 H 4 SO 3 -, citrate, tartrate, phosphate, malate, fumarate, formate, or acetate.
• a compound of the invention comprising a counterion can be converted to a compound of the invention comprising a different counterion.
• Such a conversion can be accomplished using a variety of well-known techniques and materials including but not limited to ion exchange resins, ion exchange chromatography and selective crystallization.
• the compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
• the compounds can be formulated as a solid dosage form with or without an enteric coating.
• the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent, excipient or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient’s diet.
• a pharmaceutically acceptable vehicle such as an inert diluent, excipient or an assimilable edible carrier.
• the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
• Such compositions and preparations should contain at least 0.1% of active compound.
• compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 90% of the weight of a given unit dosage form.
• the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
• the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
• binders such as gum tragacanth, acacia, corn starch or gelatin
• excipients such as dicalcium phosphate
• a disintegrating agent such as
• the unit dosage form When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
• the active compound may be incorporated into sustained-release preparations, particles, and devices.
• the active compound may also be administered intravenously or intramuscularly by infusion or injection.
• Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
• Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
• the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
• the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
• the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
• the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
• the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
• Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
• the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
• the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
• Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, nanoparticles, and the like.
• Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
• Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
• the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
• Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
• Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No.4,938,949.
• the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
• a suitable dose will be in the range of from about 1 to about 500 mg/kg, e.g., from about 5 to about 400 mg/kg of body weight per day, such as 1 to about 250 mg per kilogram body weight of the recipient per day.
• the compound is conveniently formulated in unit dosage form; for example, containing 5 to 500 mg, 10 to 400 mg, or 5 to 100 mg of active ingredient per unit dosage form.
• the invention provides a composition comprising a compound of the invention formulated in such a unit dosage form.
• the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
• the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
• Co-administration of a compound disclosed herein with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more other active therapeutic agents, such that therapeutically effective amounts of disclosed herein and one or more other active therapeutic agents are both present in the body of the patient.
• the ability of a compound disclosed herein to inhibit a N. gonorrhoeae growth is shown in Table 1 and can be determined using a method as described in Example 34. Table 1
• the requisite intermediate was prepared as follows: 2-cyano-1-(1H-indol-4-yl)guanidine To a solution of 4-aminoindole (5.29 g, 40 mmol) in methanol (150 mL) was added HCl solution (4 M in dioxane, 12.5 mL, 50 mmol) at r.t. slowly. The reaction mixture was stirred at r.t. for 10 min then the solvent was removed in vacuo. The residue was dissolved in DMF (60 mL) and sodium dicyanamide (8.90 g, 100 mmol) was added at r.t. The reaction mixture was heated at 45 o C overnight. Then DMF was removed in vacuo.
• the requisite intermediate was prepared as follows: 2-cyano-1-(2-methyl-1H-indol-4-yl)guanidine To a solution of 4-aminoindole (0.83 g, 5.7 mmol) in methanol (30 mL) was added HCl solution (4 M in dioxane, 1.7 mL, 6.8 mmol) at r.t. slowly. The reaction mixture was stirred at r.t. for 5 min then the solvent was removed in vacuo. The residue was dissolved in DMF (12 mL) and sodium dicyanamide (1.26 g, 14.2 mmol) was added at r.t. The reaction mixture was heated at 45 o C overnight. Then DMF was removed in vacuo.
• Example 1 describes a representative synthesis using the general procedure described in the paragraph above.
• Example 1. Preparation of 7-benzyl-7H-pyrrolo[2,3-h]quinazoline-2,4-diamine.
• reaction mixture was stirred at r.t. for 3 hours, then treated with water and extracted with DCM, washed with water, brine and dried. After concentration it was purified by column chromatography on silica gel using EtOAc in hexane as eluents to give the product as a white powder (100 mg, 90% yield).
• CLSI Clinical and Laboratory Standards Institute
• a 96-well plate containing TH broth with 2-fold serial dilution of compounds was inoculated with log- phase bacterial at 2.5x10 7 CFU/mL. The final volume in each well was 200 ⁇ L. Each compound was tested in duplicate.
• the microtiter plates were incubated in an anaerobic environment for 24 hours at 37 °C using the candle jar technique.
• MIC assays for various Gram-negative and Gram-positive strains were conducted in accordance with the CLSI guidelines for broth microdilution.
• a 96-well plate containing CAMH broth with 2-fold serial dilution of compounds was inoculated with log-phase bacterial at 5x10 5 CFU/mL. The final volume in each well was 100 ⁇ L. Each compound was tested in duplicate.
• the microtiter plates were incubated in an aerobic environment for 18 hours at 37 °C.
• the bacterial growth was tested by reading the plate with a SpectraMax iD5 plate reader (Molecular Devices, Inc.) at 600 nm.
• the MIC was defined as the lowest compound concentration that inhibited bacteria growth.
• the following Gram-negative and Gram-positive strains were used in the aerobic MIC procedure: P. aeruginosa ATCC 27853 A. baumannii ATCC 19606 E. coli ATCC 25922 E. coli W4573 E. coli N43 K. pneumoniae ATCC 10031 K. pneumoniae ATCC 13883 S. sonnei ATCC 29930 P. mirabilis ATCC 29906 Methicillin-susceptible S. aureus (MSSA) ATCC 19636 Methicillin-resistant S.
• MSSA Methicillin-susceptible S. aureus
• MRSA aureus ATCC 33951
• Compound X a compound of formula I
• the tablets can optionally comprise an enteric coating.

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