WO2017216281A1 - Heterocyclic compounds as antibacterials - Google Patents
Heterocyclic compounds as antibacterials Download PDFInfo
- Publication number
- WO2017216281A1 WO2017216281A1 PCT/EP2017/064652 EP2017064652W WO2017216281A1 WO 2017216281 A1 WO2017216281 A1 WO 2017216281A1 EP 2017064652 W EP2017064652 W EP 2017064652W WO 2017216281 A1 WO2017216281 A1 WO 2017216281A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ring
- compound
- alkyl
- compounds
- optionally substituted
- Prior art date
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- 230000000844 anti-bacterial effect Effects 0.000 title description 5
- 229940088710 antibiotic agent Drugs 0.000 title description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 161
- 201000008827 tuberculosis Diseases 0.000 claims abstract description 47
- 239000003814 drug Substances 0.000 claims abstract description 42
- 238000011282 treatment Methods 0.000 claims abstract description 30
- 125000001424 substituent group Chemical group 0.000 claims description 45
- 125000003118 aryl group Chemical group 0.000 claims description 42
- 125000000217 alkyl group Chemical group 0.000 claims description 37
- 238000002360 preparation method Methods 0.000 claims description 29
- 125000004429 atom Chemical group 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 23
- 125000001072 heteroaryl group Chemical group 0.000 claims description 22
- 125000005843 halogen group Chemical group 0.000 claims description 20
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 125000004122 cyclic group Chemical group 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- 208000035143 Bacterial infection Diseases 0.000 claims description 15
- 125000002619 bicyclic group Chemical group 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 13
- 125000001153 fluoro group Chemical group F* 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 125000005647 linker group Chemical group 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
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- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 230000008878 coupling Effects 0.000 claims description 4
- 238000010168 coupling process Methods 0.000 claims description 4
- 229910052701 rubidium Inorganic materials 0.000 claims description 4
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- 239000000814 tuberculostatic agent Substances 0.000 claims description 3
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229940121383 antituberculosis agent Drugs 0.000 claims 2
- -1 hydrohalic acids Chemical class 0.000 description 42
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- 238000012360 testing method Methods 0.000 description 14
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- 230000000694 effects Effects 0.000 description 11
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 125000002950 monocyclic group Chemical group 0.000 description 10
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- 241000187479 Mycobacterium tuberculosis Species 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 239000000651 prodrug Substances 0.000 description 9
- 229940002612 prodrug Drugs 0.000 description 9
- AEKVBBNGWBBYLL-UHFFFAOYSA-N 4-fluorobenzonitrile Chemical compound FC1=CC=C(C#N)C=C1 AEKVBBNGWBBYLL-UHFFFAOYSA-N 0.000 description 8
- 241000304886 Bacilli Species 0.000 description 8
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- 230000001580 bacterial effect Effects 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 102000018832 Cytochromes Human genes 0.000 description 7
- 108010052832 Cytochromes Proteins 0.000 description 7
- 125000000753 cycloalkyl group Chemical group 0.000 description 7
- 208000027531 mycobacterial infectious disease Diseases 0.000 description 7
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- 239000002904 solvent Substances 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 206010062207 Mycobacterial infection Diseases 0.000 description 6
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- 125000001246 bromo group Chemical group Br* 0.000 description 6
- 125000001309 chloro group Chemical group Cl* 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 239000002054 inoculum Substances 0.000 description 6
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- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
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- 238000005481 NMR spectroscopy Methods 0.000 description 5
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- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
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- 238000004440 column chromatography Methods 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 125000006574 non-aromatic ring group Chemical group 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- JARJBXACNCCARV-UHFFFAOYSA-N 5-fluoro-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole Chemical compound C1NCC2CC(F)CC21 JARJBXACNCCARV-UHFFFAOYSA-N 0.000 description 4
- RJEVOPRUJWDKRJ-UHFFFAOYSA-N 6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane;hydrochloride Chemical compound Cl.C1NCC2C(C(F)(F)F)C21 RJEVOPRUJWDKRJ-UHFFFAOYSA-N 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 4
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 4
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
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- 125000002837 carbocyclic group Chemical group 0.000 description 4
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Classifications
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- 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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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- 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
- A61P31/06—Antibacterial agents for tuberculosis
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Definitions
- the present invention relates to novel compounds.
- the invention also relates to such compounds for use as a pharmaceutical and further for the use in the treatment of bacterial diseases, including diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis.
- Such compounds may work by interfering with ATP synthase in M. tuberculosis, with the inhibition of cytochrome activity as the primary mode of action.
- ATP synthase in M. tuberculosis
- cytochrome activity as the primary mode of action.
- such compounds are antitubercular agents.
- Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), a serious and potentially fatal infection with a world-wide distribution.
- TB tuberculosis
- Estimates from the World Health Organization indicate that more than 8 million people contract TB each year, and 2 million people die from tuberculosis yearly.
- TB cases have grown 20% worldwide with the highest burden in the most impoverished communities. If these trends continue, TB incidence will increase by 41% in the next twenty years.
- tuberculosis agents such as ethambutol, streptomycin, kanamycin, amikacin, capreomycin, ethionamide, cycloserine, ciprofoxacin and ofloxacin are added to the combination therapies.
- agents such as ethambutol, streptomycin, kanamycin, amikacin, capreomycin, ethionamide, cycloserine, ciprofoxacin and ofloxacin are added to the combination therapies.
- MDR-TB multi-drug-resistant strains
- MDR-TB multi-drug-resistant strains
- drug resistant as used hereinbefore or hereinafter is a term well understood by the person skilled in microbiology.
- a drug resistant Mycobacterium is a
- Mycobacterium which is no longer susceptible to at least one previously effective drug; which has developed the ability to withstand antibiotic attack by at least one previously effective drug.
- a drug resistant strain may relay that ability to withstand to its progeny. Said resistance may be due to random genetic mutations in the bacterial cell that alters its sensitivity to a single drug or to different drugs.
- MDR tuberculosis is a specific form of drug resistant tuberculosis due to a bacterium resistant to at least isoniazid and rifampicin (with or without resistance to other drugs), which are at present the two most powerful anti-TB drugs.
- drug resistant includes multi drug resistant.
- the dormant TB can get reactivated to cause disease by several factors like suppression of host immunity by use of immunosuppressive agents like antibodies against tumor necrosis factor a or interferon- ⁇ .
- immunosuppressive agents like antibodies against tumor necrosis factor a or interferon- ⁇ .
- the only prophylactic treatment available for latent TB is two- three months regimens of rifampicin, pyrazinamide.
- the efficacy of the treatment regime is still not clear and furthermore the length of the treatments is an important constrain in resource- limited environments. Hence there is a drastic need to identify new drugs, which can act as chemoprophylatic agents for individuals harboring latent TB bacilli.
- the tubercle bacilli enter healthy individuals by inhalation; they are phagocytosed by the alveolar macrophages of the lungs. This leads to potent immune response and formation of granulomas, which consist of macrophages infected with M. tuberculosis surrounded by T cells. After a period of 6-8 weeks the host immune response cause death of infected cells by necrosis and accumulation of caseous material with certain extracellular bacilli, surrounded by macrophages, epitheloid cells and layers of lymphoid tissue at the periphery. In case of healthy individuals, most of the
- mycobacteria are killed in these environments but a small proportion of bacilli still survive and are thought to exist in a non-replicating, hypometabolic state and are tolerant to killing by anti-TB drugs like isoniazid. These bacilli can remain in the altered physiological environments even for individual's lifetime without showing any clinical symptoms of disease. However, in 10% of the cases these latent bacilli may reactivate to cause disease.
- patho-physiological environment in human lesions namely, reduced oxygen tension, nutrient limitation, and acidic pH.
- Self-medication with antimicrobials is another major factor contributing to resistance.
- Self-medicated antimicrobials may be unnecessary, are often inadequately dosed, or may not contain adequate amounts of active drug.
- Patient compliance with recommended treatment is another major problem. Patients forget to take medication, interrupt their treatment when they begin to feel better, or may be unable to afford a full course, thereby creating an ideal environment for microbes to adapt rather than be killed.
- Anti-infective compounds for treating tuberculosis have been disclosed in e.g.
- the purpose of the present invention is to provide compounds for use in the treatment of bacterial diseases, particularly those diseases caused by pathogenic bacteria such as Mycobacterium tuberculosis (including the latent disease and including drug resistant M. tuberculosis strains).
- Such compounds may also be novel and may act by interfering with ATP synthase in M. tuberculosis, with the inhibition of cytochrome activity being considered the primary mode of action.
- R 1 represents C e alkyl or hydrogen
- L 1 represents a linker group -C(R a )(R b )-;
- X 1 represents an optional carbocyclic aromatic linker group (which linker group may itself be optionally substituted by one or more substituents selected from fluoro, -OH, -OCi-6 alkyl and Ci- 6 alkyl, wherein the latter two alkyl moieties are themseleves optionally substituted by one or more fluoro atoms); nl and n2 independently represent 0 or 1 (hence, the X a -containing ring may be 3-, 4- or 5-membered, or (when m is 2), 6-membered);
- R a and R b independently represent hydrogen or Ci- 6 alkyl (optionally substituted by one or more fluoro atoms);
- X a represents -C(R al )(R bl ) m - or -N(R c1 )-;
- n 1 or 2;
- each R al and R bl independently represents fluoro, hydrogen or Ci- 6 alkyl
- R cl represents hydrogen or Ci- 6 alkyl
- Q 5 represents one or more independent substituents selected from halo, Ci- 6 alkyl
- -OCi-6 alkyl which latter two alkyl moieties may themselves be optionally substituted by one or more halo, e.g. fluoro, atoms), aryl and heteroaryl (which latter two aromatic groups may themselves be optionally substituted by one or more substituents selected from halo, Ci- 6 alkyl and -OCi- 6 alkyl, which latter two alkyl moieties may themselves be substituted with one or more fluoro atoms);
- ring A is a 5-membered aromatic ring containing at least one heteroatom (preferably containing at least one nitrogen atom);
- ring B is a 5- or 6-membered ring, which may be aromatic or non-aromatic, optionally containing one to four heteroatoms (preferably selected from nitrogen, oxygen and sulfur); either ring A and/or ring B may be optionally substituted by one or more substituents selected from: halo, C e alkyl (optionally substituted by one or more halo, e.g
- salts include acid addition salts and base addition salts.
- Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
- the pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms that the compounds of formula (I) are able to form.
- These pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
- Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic,
- prodrug of a relevant compound of the invention includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)).
- parenteral administration includes all forms of administration other than oral administration.
- Prodrugs of compounds of the invention may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesising the parent compound with a prodrug substituent.
- Prodrugs include compounds of the invention wherein a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group in a compound of the invention is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.
- prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs” p. 1-92, Elesevier, New York-Oxford (1985).
- Positional isomers may also be embraced by the compounds of the invention. All such isomers (e.g. if a compound of the invention incorporates a double bond or a fused ring, the cis- and trans- forms, are embraced) and mixtures thereof are included within the scope of the invention (e.g. single positional isomers and mixtures of positional isomers may be included within the scope of the invention).
- tautomer or tautomeric form
- proton tautomers also known as prototropic tautomers
- Valence tautomers include interconversions by reorganisation of some of the bonding electrons.
- Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional
- the various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
- the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a 'chiral pool' method), by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e.
- a resolution for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person.
- stereoisomers including but not limited to diastereoisomers, enantiomers and atropisomers
- mixtures thereof e.g. racemic mixtures
- stereoisomers are included within the scope of the invention.
- all stereoisomers are contemplated and included as the compounds of the invention.
- stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.
- the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
- the present invention also embraces isotopically- labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention.
- Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, n C, 13 C, 14 C , 13 N, 15 0, 17 0, 18 0, 32 P, 33 P, 35 S, 18 F, 36 C1, 123 I, and 125 I.
- Certain isotopically-labeled compounds of the present invention e.g., those labeled with 3 H and 14 C
- Tritiated ( 3 H) and carbon-14 ( 14 C) isotopes are useful for their ease of preparation and
- isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the
- C 1-q alkyl groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain, and/or cyclic (so forming a C3- q -cycloalkyl group).
- Such cycloalkyl groups may be monocyclic or bicyclic and may further be bridged. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic.
- Such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C 2-q alkenyl or a C 2 _q alkynyl group).
- C 3 - q cycloalkyl groups may be monocyclic or bicyclic alkyl groups, which cycloalkyl groups may further be bridged (so forming, for example, fused ring systems such as three fused cycloalkyl groups).
- Such cycloalkyl groups may be saturated or unsaturated containing one or more double bonds (forming for example a cycloalkenyl group). Substituents may be attached at any point on the cycloalkyl group. Further, where there is a sufficient number (i.e. a minimum of four) such cycloalkyl groups may also be part cyclic.
- halo when used herein, preferably includes fluoro, chloro, bromo and iodo.
- Heterocyclic groups when referred to herein may include aromatic or non-aromatic heterocyclic groups, and hence encompass heterocycloalkyl and hetereoaryl.
- aromatic or non-aromatic 5- or 6-membered rings may be heterocyclic groups (as well as carbocyclic groups) that have 5- or 6-members in the ring.
- Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e.
- heterocycloalkyl groups may also be bridged. Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C 2-q heterocycloalkenyl (where q is the upper limit of the range) group.
- C 2-q heterocycloalkyl groups that may be mentioned include 7-azabicyclo[2.2.1 Jheptanyl, 6-azabicyclo[3.1.1 ]heptanyl, 6-azabicyclo[3.2.1]-octanyl, 8-azabicyclo-[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and
- 1,3-dithiolanyl imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo[2.2.1]- heptanyl, 6-oxabicyclo-[3.2.1]octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, non- aromatic pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl (such as 1,2,3,4-tetrahydropyridyl and 1 ,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholin
- heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in the N- or S- oxidised form. Heterocycloalkyl mentioned herein may be stated to be specifically monocyclic or bicyclic.
- Aryl groups that may be mentioned include C 6 - 2 o, such as C 6-12 (e.g. C 6 -io) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 12 (e.g. 6 and 10) ring carbon atoms, in which at least one ring is aromatic.
- C 6 -io aryl groups include phenyl, naphthyl and the like, such as 1,2,3,4-tetrahydronaphthyl.
- the point of attachment of aryl groups may be via any atom of the ring system. For example, when the aryl group is poly cyclic the point of attachment may be via atom including an atom of a non-aromatic ring.
- aryl groups are polycyclic (e.g. bicyclic or tricyclic), they are preferably linked to the rest of the molecule via an aromatic ring. Most preferred aryl groups that may be mentioned herein are "phenyl”. Unless otherwise specified, the term "heteroaryl” when used herein refers to an aromatic group containing one or more heteroatom(s) (e.g. one to four heteroatoms) preferably selected from N, O and S. Heteroaryl groups include those which have between 5 and 20 members (e.g.
- heteroaryl group may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic (so forming, for example, a mono-, bi-, or tricyclic heteroaromatic group).
- the heteroaryl group is polycyclic the point of attachment may be via any atom including an atom of a non-aromatic ring.
- heteroaryl groups are polycyclic (e.g. bicyclic or tricyclic), they are preferably linked to the rest of the molecule via an aromatic ring.
- Heteroaryl groups that may be mentioned include 3,4-dihydro-lH-isoquinolinyl, 1,3-dihydroisoindolyl, 1,3-dihydroisoindolyl (e.g. 3,4-dihydro-lH-isoquinolin-2-yl, l,3-dihydroisoindol-2-yl, l,3-dihydroisoindol-2-yl; i.e.
- heteroaryl groups that are linked via a non-aromatic ring or, preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzo- dioxolyl (including 1,3-benzodioxolyl), benzofuranyl, benzofurazanyl,
- benzothiadiazolyl including 2,1,3-benzothiadiazolyl
- benzothiazolyl including 2,1,3-benzothiadiazolyl
- benzoxadiazolyl including 2,1,3-benzoxadiazolyl
- benzoxazinyl including 3,4-dihydro-2H-l,4- benzoxazinyl
- benzoxazolyl benzomorpholinyl
- benzoselenadiazolyl including
- tetrahydroisoquinolinyl (including 1,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetra- hydro isoquinolinyl), tetrahydroquinolinyl (including 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thiophenetyl, thienyl, triazolyl (including 1,2,3-triazolyl, 1 ,2,4-triazolyl and 1,3,4-triazolyl) and the like.
- heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
- the point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
- heteroaryl groups that may be mentioned herein are 5- or 6- membered aromatic groups containing 1, 2 or 3 heteroatoms (e.g. preferably selected from nitrogen, oxygen and sulfur). It may be specifically stated that the heteroaryl group is monocyclic or bicyclic. In the case where it is specified that the heteroaryl is bicyclic, then it may consist of a five-, six- or seven-membered monocyclic ring (e.g. a monocyclic heteroaryl ring) fused with another five-, six- or seven-membered ring (e.g. a monocyclic aryl or heteroaryl ring). Heteroatoms that may be mentioned include phosphorus, silicon, boron and, preferably, oxygen, nitrogen and sulfur.
- aromatic groups When “aromatic” groups are referred to herein, they may be aryl or heteroaryl.
- aromatic linker groups When “aromatic linker groups” are referred to herein, they may be aryl or heteroaryl, as defined herein, are preferably monocyclic (but may be polycyclic) and attached to the remainder of the molecule via any possible atoms of that linker group. However, when, specifically carbocylic aromatic linker groups are referred to, then such aromatic groups may not contain a heteroatom, i.e. they may be aryl (but not heteroaryl).
- substituents e.g. selected from C 1-6 alkyl
- compounds of the invention that are the subject of this invention include those that are stable. That is, compounds of the invention include those that are sufficiently robust to survive isolation from e.g. a reaction mixture to a useful degree of purity.
- R a and R b independently represent hydrogen
- L 1 represents -CH 2 -
- X 1 when X 1 is present, then it represents a carbocyclic aromatic linker group, for example a phenyl group or a bicyclic (carbocyclic) aromatic linker group (in which at least one of the rings of the bicycle is aromatic), for instance such that the bicycle consists of two separate rings fused with each other, in which each ring is 5- or 6-membered so forming a 6,6-, 5,6- or 5,5-fused bicyclic ring), hence including groups such as phenyl, naphthyl (including fully aromatic naphthyl and 1,2,3,4-tetrahydronaphthyl) and the like, so forming e.g. in particular:
- -naphthylene e.g.:
- Such linker groups that X 1 may represent may be optionally substituted (e.g. by one or more substituents selected from fluoro, CH 3 , CF 3 , -OCH 3 and -OCF3). In an embodiment such linker groups that X 1 may represent are unsubstituted.
- Further aspects of the invention (or further aspects of compounds of the invention) that may be mentioned include those in which:
- X a represents -CH 2 - which is substituted (e.g. at the X a position) by one or more (e.g. one or two) Q 5 substituent(s);
- Q 5 represents halo (e.g. fluoro) or C1-3 alkyl (optionally substituted by one or more fluoro atoms).
- nl and n2 both represent 1;
- nl and n2 both represent 0.
- compounds of the invention comprise:
- ring A which is an aromatic ring containing at least one to three (e.g. one or two) heteroatoms, preferably contains at least one nitrogen atom;
- ring B is more preferably also an aromatic ring (e.g. a 5- or especially a 6-membered aromatic ring), preferably containing at least one nitrogen atom. It is preferred that Ring A of the compounds of the invention are represented as follows:
- Monocyclic heteroaryl groups that may be mentioned include 5- or 6-membered rings containing one to four heteroatoms (preferably selected from nitrogen, oxygen and sulfur). It is preferred that Ring B of the compounds of the invention are represented as follows:
- Preferred substituents (when present; e.g such optional substituents may be absent or there may be one) on ring B include C 1-3 alkyl (e.g. methyl) or halo (e.g. bromo or, more preferably, chloro).
- Other preferred substituents on ring B include -OCi- 6 alkyl (e.g. -OCi- 3 alkyl, such as -OCH 3 ).
- Preferred substituents (when present; e.g such optional substituents may be absent or there may be one) on ring B include C 1-3 alkyl (e.g. methyl) or halo (e.g. bromo or, more preferably, chloro). Preferred substituents (when present; preferably, there may be one or two substituents) on ring A include C1-3 alkyl (e.g. methyl or ethyl).
- L 2 represents an aromatic group (e.g. phenyl or pyridyl) and such groups are substituted
- preferred substituents include halo and especially -OC1-3 alkyl (e.g. -O-methyl), where the latter is substituted by fluoro, so forming for example a -OCF3 group.
- Ring A and Ring B may be represented as follows:
- Certain compounds of the invention are mentioned (e.g. hereinbefore) for use in the treatment of tuberculosis. Certain of such compounds mentioned herein may also be novel per se. And certain of such compounds mentioned herein may be novel as medicaments/pharmaceuticals (or novel as a component of a pharmaceutical composition/formulation). Hence, in further aspects of the invention, there is provided the following compounds per se or following compounds for use as
- L 1 represents -CH 2 -
- X a represents -CH 2 - and which is substituted (e.g. at the X a position) by one or two Q 5 substituent(s);
- Q 5 represents halo (e.g. fluoro) or C 1-3 alkyl (optionally substituted by one or more fluoro atoms);
- ring A and ring B together represent a 8 or 9-membered bicyclic ring (ring A is a 5-membered ring and ring B may be a 5 or 6-membered ring, in which both rings are preferably aromatic) containing at least one nitrogen atom (and in a major embodiment, at least one nitogen atom that is common to both rings); optional substituents on ring A and ring B are halo, C1-3 alkyl and -OC1-3 alkyl; and
- ring A and ring B bicycles are represented as defined herein or more particulary as follows:
- the compounds according to the invention have surprisingly been shown to be suitable for the treatment of a bacterial infection including a mycobacterial infection, particularly those diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis (including the latent and drug resistant form thereof).
- the present invention thus also relates to compounds of the invention as defined hereinabove, for use as a medicine, in particular for use as a medicine for the treatment of a bacterial infection including a mycobacterial infection.
- Such compounds of the invention may act by interfering with ATP synthase in M. tuberculosis, with the inhibition of cytochrome activity being the primary mode of action.
- Cytochrome is an essential component of the electron transport chain required for ATP synthesis.
- the present invention also relates to the use of a compound of the invention, as well as any of the pharmaceutical compositions thereof as described hereinafter for the manufacture of a medicament for the treatment of a bacterial infection including a mycobacterial infection.
- the invention provides a method of treating a patient suffering from, or at risk of, a bacterial infection, including a mycobacterial infection, which comprises administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition according to the invention.
- the compounds of the present invention also show activity against resistant bacterial strains.
- the compounds can treat a bacterial infection it is meant that the compounds can treat an infection with one or more bacterial strains.
- the invention also relates to a composition
- a composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to the invention.
- the compounds according to the invention may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs.
- an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a
- compositions are desirable in unitary dosage form suitable, in particular, for administration orally or by parenteral injection.
- any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders,
- the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
- injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
- injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
- solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.
- the pharmaceutical composition will preferably comprise from 0.05 to 99 % by weight, more preferably from 0.1 to 70 % by weight, even more preferably from 0.1 to 50 % by weight of the active ingredient(s), and, from 1 to 99.95 % by weight, more preferably from 30 to 99.9 % by weight, even more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
- the pharmaceutical composition may additionally contain various other ingredients known in the art, for example, a lubricant, stabilising agent, buffering agent, emulsifying agent, viscosity-regulating agent, surfactant, preservative, flavouring or colorant.
- Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required
- Such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
- the daily dosage of the compound according to the invention will, of course, vary with the compound employed, the mode of administration, the treatment desired and the mycobacterial disease indicated. However, in general, satisfactory results will be obtained when the compound according to the invention is administered at a daily dosage not exceeding 1 gram, e.g. in the range from 10 to 50 mg/kg body weight.
- the present invention also relates to a combination of (a) a compound according to the invention, and (b) one or more other antibacterial agents.
- the present invention also relates to a combination of (a) a compound according to the invention, and (b) one or more other antibacterial agents, for use as a medicine.
- the present invention also relates to the use of a combination or pharmaceutical composition as defined directly above for the treatment of a bacterial infection.
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of (a) a compound according to the invention, and (b) one or more other antibacterial agents, is also comprised by the present invention.
- the weight ratio of (a) the compound according to the invention and (b) the other antibacterial agent(s) when given as a combination may be determined by the person skilled in the art.
- Said ratio and the exact dosage and frequency of administration depends on the particular compound according to the invention and the other antibacterial agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration and general physical condition of the particular patient, the mode of administration as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
- a particular weight ratio for the present compound of the invention and another antibacterial agent may range from 1/10 to 10/1, more in particular from 1/5 to 5/1, even more in particular from 1/3 to 3/1.
- the compounds according to the invention and the one or more other antibacterial agents may be combined in a single preparation or they may be formulated in separate preparations so that they can be administered simultaneously, separately or
- the present invention also relates to a product containing (a) a compound according to the invention, and (b) one or more other antibacterial agents, as a combined preparation for simultaneous, separate or sequential use in the treatment of a bacterial infection.
- the other antibacterial agents which may be combined with the compounds of the invention are for example antibacterial agents known in the art.
- the compounds of the invention may be combined with antibacterial agents known to interfere with the respiratory chain of Mycobacterium tuberculosis, including for example direct inhibitors of the ATP synthase (e.g. bedaquiline, bedaquiline fumarate or any other compounds that may have be disclosed in the prior art, e.g.
- quinolones/fluoroquinolones such as for example moxifloxacin, gatifloxacin, ofloxacin, ciprofloxacin, sparfloxacin; macro lides such as for example clarithromycin,
- amoxycillin with clavulanic acid rifamycins; rifabutin; rifapentin; as well as others, which are currently being developed (but may not yet be on the market; see e.g.
- the compounds according to the invention can generally be prepared by a succession of steps, each of which may be known to the skilled person or described herein.
- a suitable coupling reagent e.g. 1,1 '- carbonyldiimidazole, N,A ⁇ -dicyclohexylcarbodiimide, 1 -(3-dimethylaminopropyl)- 3-ethylcarbodiimide (or hydrochloride thereof) or N,A ⁇ -disuccinimidyl carbonate
- a suitable base e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyridine, triethylamine, dimethylaminopyridine,
- the carboxylic acid group of the compound of formula (IV) may first be converted under standard conditions to the corresponding acyl chloride (e.g. in the presence of POCb, PCI5, SOCI2 or oxalyl chloride), which acyl chloride is then reacted with a compound of formula (V), for example under similar conditions to those mentioned above;
- LG 2 represents a suitable leaving group, such as iodo, bromo, chloro or a sulfonate group (for example a type of group that may be deployed for a coupling), with a compound of formula (V), wherein the integers are as hereinbefore defined, under standard conditions, for example optionally in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Pd(dba) 2 , Pd(OAc) 2 , Cu, Cu(OAc) 2 , Cul, NiCl 2 or the like, with an optional additive such as Ph 3 P, X-phos or the like, in the presence of an appropriate base (e.g. t-BuONa, or the like) in a suitable solvent (e.g. dioxane or the like) under reaction conditions known to those skilled in the art.
- an appropriate metal catalyst or a salt or complex thereof
- a pinacolato boronate ester group (or may represent iodo, bromo or chloro, provided that the "leaving groups" are mutually compatible), and wherein the reaction may be performed in the presence of a suitable catalyst system, e.g. a metal (or a salt or complex thereof) such as Pd, Cul, Pd/C, PdCl 2 ,
- reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art, such as extraction, crystallization and chromatography. It is further evident that reaction products that exist in more than one enantiomeric form, may be isolated from their mixture by known techniques, in particular preparative chromatography, such as preparative HPLC, chiral
- the starting materials and the intermediates are compounds that are either
- 1,4-dioxane (5 mL) was irradiated under microwave at 110 °C for 1 h under N 2 .
- Compound 3 was prepared in the same way as Compound 2 , starting from 2-ethyl-5H,6H,7H,8H-imidazo[l,2-a]pyridine-3-carboxylic acid CAS [1529528 99-1] and intermediate B ⁇ yielding 0.045 g, 28%.
- Compound 4 was prepared in the same way as Compound 2, starting from intermediate L and intermediate B', yielding 0.031 g, 16%.
- HPLC High Performance Liquid Chromatography
- MS Mass Spectrometer
- tune parameters e.g. scanning range, dwell time
- ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW).
- Data acquisition was performed with appropriate software.
- Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H] + (protonated molecule) and/or [M-H] ⁇ (deprotonated molecule).
- the type of adduct is specified (i.e.
- SQL Single Quadrupole Detector
- RT room temperature
- BEH bridged ethylsiloxane/silica hybrid
- HSS High Strength Silica
- DAD Diode Array Detector
- MSD Mass Selective Detector
- DAD Diode Array Detector
- Untreated control samples with (column 1) and without (column 12) inoculum are included in each microtiter plate.
- the same volume of broth medium without inoculum is added to column 12 in row A to H.
- the cultures are incubated at 37°C for 7 days in a humidified atmosphere (incubator with open air valve and continuous ventilation). On day 7 the bacterial growth is checked visually.
- the 90 % minimal inhibitory concentration (MIC90) is determined as the concentration with no visual bacterial growth.
- Bactericidal or bacteriostatic activity of the compounds can be determined in a time kill assay using the broth dilution method.
- a time kill assay on Mycobacterium tuberculosis strain H37RV
- the starting inoculum of M. tuberculosis is 10 6 CFU / ml in Middlebrook (lx) 7H9 broth.
- the antibacterial compounds are used at the concentration of 0.1 to 10 times the MIC90. Tubes receiving no antibacterial agent constitute the culture growth control.
- the tubes containing the microorganism and the test compounds are incubated at 37 °C.
- TEST 4 (see also test 1 above; in this test a different strain of Mycobacterium tuberculosis strain is employed)
- Compounds of the invention/examples may typically have an IC90 value from 0.01 to 10 ⁇ g/ml.
- Compounds of the invention/examples for example when tested in Test 1 or Test 2 described above, may typically have a pICso from 3 to 10 (e.g. from 4.0 to 9.0, such as from 5.0 to 8.0)
- Compounds of the examples were tested in Test 1 described above (in section "Pharmacological Examples") and the following results were obtained:
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JP2018565675A JP2019518046A (ja) | 2016-06-16 | 2017-06-15 | 抗菌薬としての複素環式化合物 |
MX2018015656A MX2018015656A (es) | 2016-06-16 | 2017-06-15 | Compuestos heterociclicos como antibacterianos. |
US16/309,725 US11179396B2 (en) | 2016-06-16 | 2017-06-15 | Heterocyclic compounds as antibacterials |
BR112018076126-5A BR112018076126A2 (pt) | 2016-06-16 | 2017-06-15 | compostos heterocíclicos como antibacterianos |
EA201990043A EA201990043A1 (ru) | 2016-06-16 | 2017-06-15 | Антибактериальные соединения |
KR1020197000960A KR20190017948A (ko) | 2016-06-16 | 2017-06-15 | 항균제로서의 헤테로고리 화합물 |
CN201780037229.4A CN109476657A (zh) | 2016-06-16 | 2017-06-15 | 作为抗细菌剂的杂环化合物 |
CA3026010A CA3026010A1 (en) | 2016-06-16 | 2017-06-15 | Heterocyclic compounds as antibacterials |
AU2017286368A AU2017286368B2 (en) | 2016-06-16 | 2017-06-15 | Heterocyclic compounds as antibacterials |
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US10364232B2 (en) | 2015-07-02 | 2019-07-30 | Janssen Sciences Ireland Uc | Antibacterial compounds |
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WO2021048342A1 (en) | 2019-09-13 | 2021-03-18 | Janssen Sciences Ireland Unlimited Company | Antibacterial compounds |
WO2021063914A1 (en) | 2019-09-30 | 2021-04-08 | Janssen Sciences Ireland Unlimited Company | 4-quinolinone antibacterial compounds |
WO2021063915A1 (en) | 2019-09-30 | 2021-04-08 | Janssen Sciences Ireland Unlimited Company | Antibacterial compounds |
US11179396B2 (en) | 2016-06-16 | 2021-11-23 | Janssen Sciences Ireland Uc | Heterocyclic compounds as antibacterials |
US11224596B2 (en) | 2017-03-01 | 2022-01-18 | Janssen Sciences Ireland Unlimited Company | PZA and cytochrome bc1 inhibitor combination treatment |
KR20220062021A (ko) | 2019-09-10 | 2022-05-13 | 시오노기 앤드 컴파니, 리미티드 | 미코박테리아 감염에 유용한 벤질 아민 함유 5,6-헤테로방향족 화합물 |
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WO2022214519A1 (en) | 2021-04-07 | 2022-10-13 | Janssen Sciences Ireland Unlimited Company | Antibacterial compounds |
WO2022214520A1 (en) | 2021-04-07 | 2022-10-13 | Janssen Sciences Ireland Unlimited Company | Antibacterial compounds |
US11529341B2 (en) | 2018-03-13 | 2022-12-20 | Jubilant Prodel LLC | Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation |
US11629135B2 (en) | 2017-11-06 | 2023-04-18 | Jubilant Prodell Llc | Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation |
WO2023073090A1 (en) | 2021-10-28 | 2023-05-04 | Janssen Sciences Ireland Unlimited Company | Imidazopyridine amides and related compounds for use in the treatment of bacterial infections |
EP4034106A4 (en) * | 2019-09-26 | 2023-10-25 | The Global Alliance for TB Drug Development, Inc. | THIAZOLE CARBOXAMIDE COMPOUNDS AND THEIR USE FOR THE TREATMENT OF MYCOBACTERIAL INFECTIONS |
US11833156B2 (en) | 2017-09-22 | 2023-12-05 | Jubilant Epipad LLC | Heterocyclic compounds as pad inhibitors |
WO2024089170A1 (en) | 2022-10-27 | 2024-05-02 | Janssen Sciences Ireland Unlimited Company | Antibacterial compounds |
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WO2024089170A1 (en) | 2022-10-27 | 2024-05-02 | Janssen Sciences Ireland Unlimited Company | Antibacterial compounds |
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EA201990043A1 (ru) | 2019-05-31 |
US11179396B2 (en) | 2021-11-23 |
EP3472158A1 (en) | 2019-04-24 |
JP2019518046A (ja) | 2019-06-27 |
US20190134046A1 (en) | 2019-05-09 |
CA3026010A1 (en) | 2017-12-21 |
AU2017286368A1 (en) | 2018-12-06 |
KR20190017948A (ko) | 2019-02-20 |
CN109476657A (zh) | 2019-03-15 |
MA45377A (fr) | 2019-04-24 |
BR112018076126A2 (pt) | 2019-03-26 |
MX2018015656A (es) | 2019-03-14 |
AU2017286368B2 (en) | 2021-02-25 |
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