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WO2018172925A1 - Inhibiteurs de l'adn gyrase pour le traitement d'infections bactériennes - Google Patents

Inhibiteurs de l'adn gyrase pour le traitement d'infections bactériennes Download PDF

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WO2018172925A1
WO2018172925A1 PCT/IB2018/051848 IB2018051848W WO2018172925A1 WO 2018172925 A1 WO2018172925 A1 WO 2018172925A1 IB 2018051848 W IB2018051848 W IB 2018051848W WO 2018172925 A1 WO2018172925 A1 WO 2018172925A1
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ethyl
piperidin
methyl
reaction
nitrobenzylamino
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Inventor
Chandrasekhar ALAPATI
Ankita BANERJEE
Radha RANGARAJAN
Rajinder Kumar
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VITAS PHARMA RESEARCH PVT Ltd
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VITAS PHARMA RESEARCH PVT Ltd
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    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • C07D471/02—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 two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • 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
    • C07D487/08—Bridged systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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

  • This invention is related to compounds which specifically inhibit bacterial DNA Gyrase for the treatment of bacterial infections.
  • Antibacterial drug resistance is a worldwide problem; new mechanisms of resistance emerge periodically and spread rapidly across the globe.
  • the growing rate of antimicrobial resistance in clinical and non clinical settings poses significant threat to human health and animals, not only in India but also globally (Lancet Infectious Diseases, 9, 228-36, 2009).
  • Each mechanism of resistance renders yet another class of antibiotics ineffective, ultimately resulting in fewer and fewer therapeutic options for patients.
  • WHO now recognizes antimicrobial resistance as one of three greatest threats to human health (Clinical Infectious Diseases 50, 1081-1083, 2010).
  • To address the issue of drug resistance new chemotypes that target critical pathways in bacteria must be developed.
  • DNA Topioisomerases are involved in the transient breaking and rejoining of DNA during replication, transcription and recombination. They are well conserved across the bacterial species and essential for viability. There are two classes of Topoisomerases, depending on whether they introduce single stranded (type 1) or double stranded breaks (type 2). DNA Gyrase and Topo IV are Type 2 Topoisomerases. Gyrase is responsible for the introduction of negative supercoils into DNA to allow fork progression during replication. It is a heterodimer consisting of two subunits of GyrA and two subunits of GyrB (Reviewed in Infectious Disorders - Drug Targets7, 3-9, 2007).
  • Gyrase is a clinically validated target. Inhibitors of this target, the fluoroquinolones have been in use since the 1960s but suffer widespread drug resistance. Despite extensive research, newer generations of fluorquinolones have not overcome resistance effectively. Recently two non-fluoroquinolone inhibitors of Gyrase have been described. One of them is NXL101 and the other is GSK299423. NXL101 belongs to a novel quinoline class with potent activity against gram-positive bacteria, including methicillin-and fluoroquinolone-resistant strains
  • GSK299423 shows potent antibacterial activity against MRSA, fluoroquinolone resistant strains of S. aureus and Gram negatives such as E. coli, H. influenzae, M. catarrhalis and Klebsiella, pneumoniae (Nature, 466, 935-942, 2010;. While the compound potently inhibits DNA Gyrase, it has serious hERG binding liability (BMCL, 21 , 7489-7495, 2011). Similarly, NXL-101 causes QT prolongation, which led to its discontinuation from clinical development (North American Journal of Medical Science, 4, 537-47, 2012). Nevertheless, the target continues to be attractive and novel chemotypes directed against the target will have significant clinical benefits, once proven to be efficacious and safe.
  • Figure 1 discloses time kill kinetics of VT-03 -00061 against MRSA 33591.
  • Figure 2 discloses time kill kinetics of VT-03-00061 against E. coli 25922.
  • Zi, Z 2 , Z 3 are each independently CRi ;
  • Z 4 , Z 5 , Z 6 are each independently selected from a group consisting of N or CRi ;
  • Z 2 and Z 3 together form an optionally substituted saturated or unsaturated 5-6 member ed cyclic ring which contains minimum one heteroatom at bridging or any other position of the ring;
  • Z5 and Z 6 together form an optionally substituted saturated or unsaturated 5-6 member ed cyclic ring which contains minimum one heteroatom at bridging or any other position of the ring;
  • Z 4 and Z 6 directly form a bond in absence of Z5 where its substitution together form an optionally substituted saturated or unsaturated 5-6 membered cyclic ring containing at least one heteroatom at bridging or any other position of the ring;
  • Ri are each independently selected from a group consisting of hydrogen, oxo, cyano, halogen, hydroxyl and Ci-6 alkyl optionally substituted with one or two Ci-6 alkoxy.
  • Ai is selected from a group consisting of -(CR2R3) m -CH 2 - , -CH 2 -(CR 2 R3) m - , -NH- (CR 2 R 3 ) m -CH 2 ,-(CR 2 R 3 ) m -CH 2 -0- and
  • m is 1 or 2;
  • R 2 is selected from a group consisting of hydrogen, halogen, hydroxyl, acyloxy, Ci- 6 alkyl optionally substituted with one or two Ci-6 alkoxy and Ci-6 alkoxy optionally substituted with C 1-6 alky 1
  • R3 is hydrogen
  • G is selected from a group of formulae consisting of Gl, G2, G3, G4, G5, G6, G7, G8, G9 and Gl 0 as provided below
  • a 2 is CR 4 R 5 or is absent; wherein R 4 and R5 are each independently hydrogen or
  • monocyclic aryl and hetero-aryl can be five or six membered ring bearing one or two hetero atom (N, O, S)
  • aryl or hetero aryl ring substituted independently with halogen F, CI, Br
  • the monocyclic or bicyclic aryl or heteroaryl is fused to saturated or unsaturated cyclic ring containing at least one heteroatom selected from the group consisting of oxygen, nitrogen and sulphur which is optionally substituted with halogen, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkyl substituted with Ci-6 alkoxy, Ci-6 alkoxy optionally substituted with Ci-6 alkyl, Ci-4 haloalkoxy, C 1 -4 haloalkyl, C 1 -4 thioalkyl, nitro, cyano, carboxy, C 1 -4 alkylsulfonyl, aminosulfonyl, hydroxyl, amino, aminoalkyl, oxo, hydroxyalkyl, alkynyl, alkylcarbonyl and carbonyl.
  • Zi and Z 3 are each independently selected from a group consisting of CH or N ;
  • Ai is selected from the group consisting of -(CR 2 R 3 ) m -CH 2 - , -CH 2 -(CR 2 R 3 ) m - -NH- (CR 2 R 3 ) m -CH 2 ,-(CR 2 R 3 ) m -CH 2 -0- and
  • m is lor 2
  • R 2 is selected from the group consisting of hydrogen, halogen, acyloxy, Ci- 6 alkyl optionally substituted with one or two Ci_6alkoxy and Ci_6alkoxy optionally substituted with Ci-6 alkyl;
  • R3 is hydrogen
  • a 2 is CR4R5 or is absent; wherein R4 and R5 are each independently hydrogen or
  • VT-03 compounds of the invention show minimal (insignificant) hERG binding activity indicating the advantage of these compounds as against the known compounds in the art (BMCL, 21 , 7489-7495, 2011).
  • VT-03 compounds of formula I of the invention are useful in the treatment of patients suffering from infections caused by Staphylococcus species,
  • Enterococcus species Streptococcus species, Moraxella species, E.coli, Klebsiella species, Pseudomonas species and Acinetobacter species.
  • the invention also provides compounds of formula (II) or pharmaceutically acceptable salts thereof:
  • Zi and Z 3 are each independently selected from a group consisting of CH or N ;
  • Ri is independently selected from the group consisting of hydrogen, methoxy, cyano, halogen, hydroxyl, Ci- 6 alkoxy and Ci- 6 alkyl optionally substituted with one or two Ci_6 alkoxy, alkyne, carboxyl, carboxamide;
  • G is Gl, G2 or G3
  • R 2 is selected from the group consisting of
  • VT-03 compounds of Formula II of the invention are useful in the treatment of patients suffering from infections caused by Staphylococcus species, Enterococcus species, Streptococcus species, Moraxella species, E.coli, Mycobacterium species, Neisseria meningitidis, Neisseria
  • the instant invention provides preferred VT-03 compounds of formula I in Table I
  • the instant invention provides preferred VT-03 compounds of formula II II -03 Compounds of the Invention
  • the invention further consists of the following
  • VT-03-00014 Synthesis ofVT-03-00014, VT-03-00017, VT-03-00021, VT-03-00021a, VT-03-00022, VT-03- 00024, VT-03-00026, VT-03-00026a, VT-03-00027, VT-03-00028, VT-03-00030, VT-03- 00031, VT-03-00032, VT-03-00042, VT-03-00043, VT-03-00045, VT-03-00046, VT-03-00048, VT-03-00049, VT-03-00050, VT-03-00051, VT-03-00052, VT-03-00053, VT-03-00054, VT-03- 00055, VT-03-00056, VT-03-00057, VT-03-00058, VT-03-00059, VT-03-00060, VT-
  • a sealed tube was charged with (7-bromoquinoxalin-2(lH)-one (2.2g, 9.82mmol), Zn(CN) 2 (1.72g, 14.73mmol), Pd 2 (dba) 3 (0.896g,0.98mmol), dppf(0.542mg, 0.98mmol), Zn powder(0.126g, 1.96mmol) and DMF(20mL). It was degassed for lOmin with Nitrogen and heated at 90°C for 0.5h. Upon completion, the reaction was diluted with EtOAc and filtered through a celite bed. The filtrate was concentrated.
  • VT-03-00110 (71a) Tert-butyl l-(2-(7-ethynyl-2-oxoquinoxalin-l(2H)-yl)ethyl)piperidin-4-ylcarbamate :-
  • VT-03-00124 - Compound-83c (30mg) was taken in MeOH(6ml) and triturated with 10% Pd-C(50mg) under Hydrogen atmosphere. Upon completion the reaction was filtered through celite bed and concentrated. The crude was triturated with EtOAc to give the required compound VT-03-00124 as a brown solid (7mg).
  • the compounds of the invention are useful for the treatment of infections in subjects, mammals in particular, including humans.
  • the compounds may be used for the treatment of infections of soft tissues, blood, skin, mouth, lungs, respiratory tract, urinary tract and reproductive tract.
  • the compounds of the invention are useful for the treatment of infections caused by microorganisms, such as but not limited to Staphylococcus species such as
  • Staphylococcus aureus Staphylococcus epidermidis, Staphylococcus haemolyticus,
  • Enterococcus species such as Enterococcus faecalis, Enterococcus faecium, Streptococcus species like Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella species, for example Moraxella catarrhalis, E. coli, Mycobacterium species,
  • Neisseria meningitidis Neisseria gonorrhoeae
  • Klebsiella species such as Klebsiella
  • pneumoniae Klebsiella oxytoca
  • Pseudomonas species such as Pseudomonas aeruginosa
  • Acinetobacter species such as Acinetobacter baumannii.
  • the compounds of the present invention are delivered to the subjects by forms suitable for each administration route.
  • the compounds are administered as tablets, capsules, injection, drops, inhaler, ointment, foams suppository.
  • the route of administration is oral, parenteral or topical.
  • Topical or transdermal administration include powders, sprays, ointments, pastes creams, lotions, gels, solutions, patches and inhalants.
  • composition of the present invention is presented in unit dosage form generally in an amount that produces a therapeutic effect in the subject.
  • the compounds of the present invention are administered at a daily dose that is the lowest dose effective to produce a therapeutic effect.
  • the dosage will effect from about 0.0001 to about lOOmg per kg body weight per day.
  • the dosage will range from about 0.001 to 75mg per kg body weight per day and more preferably, the dosage will range from about 0.1 to about 50mg per kg body weight per day.
  • Each unit dose may be, for example, 5, 10, 25, 50, 100, 125, 150, 200 or 250 mg of the compound of the invention.
  • the effective daily dose of the compound is administered as two, three, four or more sub- doses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms.
  • the antibacterial compositions of the present invention may be administered by any method known in the art.
  • suitable modes of administration include oral, intravenous, intramuscular topical or any other parenteral mode of administration.
  • the present invention is directed to a method of formulating compounds of the present invention in a pharmaceutically acceptable carrier or excipient and may be administered in a wide variety of different dosage forms e.g. tablets, capsules, sprays, creams, lotions, ointments, aqueous suspensions syrups, and the like.
  • a pharmaceutically acceptable carrier or excipient may be administered in a wide variety of different dosage forms e.g. tablets, capsules, sprays, creams, lotions, ointments, aqueous suspensions syrups, and the like.
  • Such carriers may include one or more of solid diluents or fillers, sterile aqueous media, and various nontoxic organic solvents, etc.
  • tablets may contain various excipients such as one or more of microcrystalline cellulose, sodium citrate, calcium carbonate and the like, along with various disintegrants such as starch and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose and the like.
  • solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluents or solvent e.g. as solution in 1, 3 butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils are conventionally employed including synthetic mono or diglycerides.
  • fatty acids such as oleic acid find in the preparation of injectables.
  • aqueous solutions may be suitable for intravenous injection purposes.
  • the oily solutions may be suitable for intra articular, intramuscular, and/or subcutaneous injection purposes.
  • the compounds of the present invention may be administered topically that include transdermal, buccal, or sublingual application.
  • therapeutic compounds may be suitably admixed in a pharmacologically inert topical carrier such as a gel, an ointment, a lotion, and/or a cream.
  • topical carriers may include water, glycerol, alcohol, propylene glycol, fatty alcohols, triglycerides, fatty acid esters, and/or mineral oils.
  • the timing of the administration of the pharmaceutical composition may also be regulated.
  • the compounds may be administered intermittently or by controlled release.
  • an "independently" selected substituent refers to a group of substituents, wherein the substituents may be different.
  • variable "A 2 " for a formula (I) compound indicates that in the absence of the said variable, the adjacent variables on both sides of the absent variable are connected directly together and is synonymous to a single covalent bond For example, in the chain -G-A2-NH-A3-R 6j if A 2 is "absent", then the chain becomes -G-NH-A 3 -R 6 .
  • alkyl refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups and cycloalkyl substituted alkyl groups; wherein the term “cycloalkyl” refers to a saturated or unsaturated monocyclic alkyl ring consisting of 3-8 carbon atoms or a saturated or partially unsaturated bicyclic ring consisting of 9 or 10 carbon atoms.
  • aryl refers to a mono- or bicylic aromatic ring containing optionally substituted carbon atoms.
  • the said term"aryl” can be fused to saturated or unsaturated cyclic ring containing minimum one heteroatom selected from oxygen, nitrogen and sulphur which is optionally substituted.
  • the preferred substituents are alkyl, alkoxy, alkyl optionally substituted with alkoxy, alkoxy optionally substituted with alkyl, carboxy, hydroxyalkyl, hydroxyl, halogen, haloalkyl, alkylthio, alkylsulfonyl, cyano, nitro, alkynyl, amino, aminoalkyl, alkylcarbonyl, aminosulfonyl, oxo, carbomyl, carbonyl, haloalkoxy.
  • heteroaryl refers to an optionally substituted 5- or 6-membered monocyclic hetero aromatic ring or a 9- or 10-membered bicyclic hetero aromatic ring containing minimum one heteroatom which are independently selected from nitrogen, sulphur or oxygen.
  • heteroaryl can be fused to saturated or unsaturated cyclic ring containing minimum one of the said heteroatom which is optionally substituted.
  • the preferred substituents are alkyl, alkoxy, alkyl optionally substituted with alkoxy, alkoxy optionally substituted with alkyl, carboxy, hydroxyalkyl, hydroxyl, halogen, haloalkyl, alkylthio, alkylsulfonyl, cyano, nitro, alkynyl, amino, aminoalkyl, alkylcarbonyl, aminosulfonyl, oxo, carbomyl, carbonyl, haloalkoxy.
  • alkoxy refers to alkyl ether radical, wherein the term “alkyl” is as defined above.
  • amino refers to -NH 2 group.
  • aminoalkyl refers to -NH(alkyl) or -N(alkyl)(alkyl) group wherein the term “alkyl” is as defined above.
  • halogen refers to F, CI, Br or I.
  • haloalkyl refers to an "alkyl” group substituted with one or more halogen wherein the terms “alkyl” and “halogen” are as defined above.
  • haloalkoxy refers to an "alkoxy” group substituted with at least one "halogen” wherein the terms “alkoxy” and “halogen” are as defined above.
  • hydroxyl refers to -OH group.
  • hydroxyalkyl refers to an alkyl group which is substituted with one or more, preferably one
  • nitro refers to -N0 2 group.
  • cyano refers to -CN group.
  • thiol or "thio” refers to -SH group.
  • alkyl sulfonyloxy refers to -OS0 2 — alkyl group wherein the term “alkyl” is as defined above.
  • aryloxy refers to aryl ether radical, wherein the term “aryl” is as defined above.
  • thioalkyl or "alkylthio” refers to -S-alkyl radical wherein the term “alkyl” is as defined above.
  • arylthio refers to -S-aryl radical wherein the term “aryl” is as defined above.
  • acylthio refers to -S-acyl radical wherein the term “acyl” is as defined above.
  • heterocyclylthio refers to -S-heterocyclyl radical wherein the term “heterocyclyl” is as defined herein.
  • heterocyclyloxy refers to -O-heterocyclyl radical wherein the term “heterocyclyl” is as defined herein.
  • heterocyclic or “heterocyclyl” as used above includes optionally substituted aromatic and non-aromatic, single and fused, mono- or bicyclic rings suitably containing minimum one heteroatom selected from oxygen, nitrogen and sulphur, which rings may be optionally C- substituted.
  • the preferred substituents are alkyl, alkoxy, alkyl optionally substituted with alkoxy, alkoxy optionally substituted with alkyl, carboxy, hydroxyalkyl, hydroxyl, halogen, haloalkyl, alkylthio, alkylsulfonyl, cyano, nitro, alkynyl, amino, aminoalkyl, alkylcarbonyl, aminosulfonyl, oxo, carbomyl, carbonyl, haloalkoxy.
  • containing at least one heteroatom refers to at least one carbon atom of the ring being replaced by a heteroatom selected from oxygen, nitrogen and sulphur.
  • the compounds of present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention is inclusive of all possible enantiomers and diastereomers in pure or substantially pure form and mixtures of two or more stereoisomers in ratios that are effective. This means that the compounds of present invention may exist both as levorotatory and as dextrorotatory, in the form of racemates and in the form of two enantiomers.
  • the compounds of present invention are capable of forming both pharmaceutically acceptable salts. Examples of salts include but not restricted to metals or amines such as alkali and alkaline earth metals or organic amines.
  • acids for salt formation include but is not limited to hydrochloric, sulphuric, phosphoric, acetic, citric, oxalic, malonic, salicyclic, malic, fumaric, succinic, ascorbic and the likes thereof.
  • the compound of the present invention can exist as unsolvated or solvated forms including hydrated forms.
  • the compounds detailed in the present disclosure are capable of forming pharmaceutically acceptable prodrugs.
  • Prodrugs are covalently bonded carriers that release the active compound internally after administration to the subject.
  • the present invention provides pharmaceutical compositions comprising an effective amount of compound of Formula (I), prodrugs, tautomeric forms, stereoisomers, optical isomers, pharmaceutically acceptable salts, solvates, polymorphs, analogs or derivatives thereof with pharmaceutically acceptable carriers.
  • Example 2 MICs against Fluoroquinolone resistant strains
  • the activity of compounds was evaluated in an in vitro Gyrase assay using recombinant Gyrase protein as per the instructions of the assay kit (Inspiralis).
  • the assay measures the ability of E.coli Gyrase to convert relaxed plasmid DNA into the supercoiled form.
  • the enzyme is incubated with the substrate (relaxed DNA) in the presence and absence of compounds for 1 hour at 37 ° C and the DNA is run on a gel at low voltage for several hours. The gel is then stained with Ethidium bromide and DNA in the different forms is quantified using DNA imaging and quantification software (Image Lab). The activity of the enzyme is proportional to the amount of supercoiled form detected.
  • Example 8 In vivo activity in the systemic infection model against S.aureus (MRSA ATCC 33591)
  • the activity of compounds was evaluated in an in vitro Gyrase supercoiling assay using ciprofloxacin resistant recombinant Gyrase protein (with mutation S83L) as per the instructions of the assay kit (Inspiralis).
  • the enzyme is incubated with the substrate (relaxed DNA) in the presence and absence of compounds for 1 hour at 37 ° C and the DNA is run on a gel at low voltage for several hours.
  • the amount of supercoiled DNA is quantified using DNA imaging and quantification software (Image Lab). The activity of the enzyme is proportional to the amount of supercoiled form detected.
  • VT-03 compounds (of Formula II) to bind the hERG channel
  • membranes expressing the hERGchannel were incubated with radiolabeled Astemizole and displacement of the labeled ligand in the presence of compounds was measured.
  • the table below shows IC 50 concentrations. The compounds show no significant hERG binding activity up to the highest concentration tested.

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Abstract

La présente invention concerne des composés qui sont des inhibiteurs spécifiques de l'ADN Gyrase et peuvent être utilisés pour le traitement d'infections du tractus respiratoire.
PCT/IB2018/051848 2017-03-23 2018-03-20 Inhibiteurs de l'adn gyrase pour le traitement d'infections bactériennes Ceased WO2018172925A1 (fr)

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WO2019145919A1 (fr) 2018-01-29 2019-08-01 Cadila Healthcare Limited Composés hétérocycliques utiles en tant qu'agents antibactériens
US11618751B1 (en) 2022-03-25 2023-04-04 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives
JP2023551272A (ja) * 2020-11-26 2023-12-07 エルジー・ケム・リミテッド ジアシルグリセロールキナーゼ阻害剤としての複素環化合物及びその用途
US12281112B2 (en) 2021-04-07 2025-04-22 Ventus Therapeutics U.S., Inc. Compounds for inhibiting NLRP3 and uses thereof
US12312351B2 (en) 2022-10-31 2025-05-27 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors
US12441728B2 (en) 2023-10-04 2025-10-14 Ventus Therapeutics U.S., Inc. Pyridazine compounds for inhibiting NLRP3

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019145919A1 (fr) 2018-01-29 2019-08-01 Cadila Healthcare Limited Composés hétérocycliques utiles en tant qu'agents antibactériens
JP2023551272A (ja) * 2020-11-26 2023-12-07 エルジー・ケム・リミテッド ジアシルグリセロールキナーゼ阻害剤としての複素環化合物及びその用途
JP7604067B2 (ja) 2020-11-26 2024-12-23 エルジー・ケム・リミテッド ジアシルグリセロールキナーゼ阻害剤としての複素環化合物及びその用途
US12312350B2 (en) 2021-04-07 2025-05-27 Ventus Therapeutics U.S., Inc. Compounds for inhibiting NLRP3 and uses thereof
US12410167B2 (en) 2021-04-07 2025-09-09 Ventus Therapeutics U.S., Inc. Pyridazine compounds for inhibiting NLRP3
US12351578B2 (en) 2021-04-07 2025-07-08 Ventus Therapeutics U.S., Inc. Compounds for inhibiting NLRP3 and uses thereof
US12281112B2 (en) 2021-04-07 2025-04-22 Ventus Therapeutics U.S., Inc. Compounds for inhibiting NLRP3 and uses thereof
US12168657B2 (en) 2022-03-25 2024-12-17 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives
US12195460B2 (en) 2022-03-25 2025-01-14 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors
US11618751B1 (en) 2022-03-25 2023-04-04 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives
US12312351B2 (en) 2022-10-31 2025-05-27 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors
US12331048B2 (en) 2022-10-31 2025-06-17 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors
US12398136B2 (en) 2022-10-31 2025-08-26 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors
US12441728B2 (en) 2023-10-04 2025-10-14 Ventus Therapeutics U.S., Inc. Pyridazine compounds for inhibiting NLRP3

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