Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
  • C07D277/62—Benzothiazoles
  • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
  • A61P31/06—Antibacterial agents for tuberculosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • 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
  • C07D417/02—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 two hetero rings
  • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to nitrobenzothiazole derivatives, to their preparation and to their therapeutic application.
• the compounds according to the present invention are useful especially in the treatment of tuberculosis.
• Tuberculosis is a disease that is still a threat to global health today. Overall, one-third of the human population is infected with
• tuberculosis Mycobacterium tuberculosis. Despite the fact that treatments exist and that the disease is curable, tuberculosis killed approximately 1.82 million people in 2008, and its overall incidence increases by 1% per year, with a 2008 estimate of 9.4 million. new cases per year of declared disease. Added to this are the difficulties of correct prescription and adherence to treatment protocols, as well as the emergence of multi-resistant M. tuberculosis strains. Drug-drug interactions also interfere with the optimal treatment of AIDS and TB in co-infected patients.
• MDR-TB multi-resistant Strains resistant to at least isoniazid and rifampicin are referred to as “multi-resistant” (MDR-TB). Recently, new strains have appeared that are resistant to a larger number of molecules: those resistant to isoniazid, rifampicin, fluoroquinolones and at least one second-line injectable drug are defined as "ultra-resistant”. -resistant "(XDR-TB).
• rifampicin Another therapeutic disadvantage in the treatment of tuberculosis is the interaction of rifampicin with treatments against HIV (Human Immunodeficiency Virus), which represents an obstacle in the treatment of patients co-infected with tuberculosis and tuberculosis. HIV.
• HIV Human Immunodeficiency Virus
• the current therapeutic recommendations against HIV favor, first-line, triple antiretroviral therapy combining a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) with two nucleoside reverse transcriptase inhibitors (NRTIs). IP and NNRTI are metabolized by CYP3A4. Metabolic interactions between antiretrovirals (ATRV) and some associated drugs have been identified.
• rifampicin a potent inducer of intestinal and hepatic CYP3A4, decreases ATRV concentrations.
• the subject of the present invention is in particular nitrobenzothiazole derivatives, having a bacteriostatic as well as a bactericidal action against strains of Mycobacterium or Corynebacterium susceptible and resistant to first-line antibiotics, their preparation and their therapeutic applications.
• Benzothiazoles have been described in compositions used to repel insects, mites and ticks (WO 99/65886) and as a cell adhesion inhibitor (JP2000086642). Benzothiazoles have also been disclosed in the preparation of immunostimulatory compounds for the treatment of infectious diseases, tumors and immune diseases (JP2000178248).
• Nitrobenzothiazoles have been described as fungicides and bactericides (DE 2136924) and (DE 2136923).
• the subject of the present invention is the compounds corresponding to formula (I):
• Ri represents:
• aryl optionally substituted by one or more groups selected independently from each other from OH, C 1-3 -alkoxy, C 3-6 -heterocycloalkyl, C 1-3- fluoroalkoxy, halogen;
• a heteroaryl optionally substituted with one or more groups independently selected from a C 1-4 alkyl group, a halogen atom;
• C 3-6 heterocycloalkyl optionally substituted with one or more groups independently selected from C 1-3 -alkyl, aryl and aryl-C 1-3 alkyl;
• the compounds of general formula (I) may comprise one or more asymmetric carbons. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention.
• the compounds of general formula (I) can also exist in the form of isomers of rotamer or atropoisomeric type.
• the compounds of formula (I) may also exist in the form of bases or of addition salts with acids or with bases. Such addition salts are part of the invention.
• salts are advantageously prepared with pharmaceutically acceptable acids or bases, but the salts of other acids or bases that are useful, for example, for the purification or separation of the compounds of general formula (I) are also part of the invention.
• the N-oxides of the compounds comprising a tertiary nitrogen atom or nitrogen-containing heteroaryl compounds are also part of the invention with the exception of benzothiazole-N-oxide compounds.
• the compounds of formula (I) according to the present invention also include those in which one or more hydrogen, carbon or halogen atoms, in particular chlorine or fluorine atoms, have been replaced by their radioactive isotopes, for example tritium for replace hydrogen or carbon 14 to replace carbon 12.
• radioactive isotopes for example tritium for replace hydrogen or carbon 14 to replace carbon 12.
• Ci-6 represent a linear or branched carbon chain which can have from 1 to 6 carbon atoms
• Co-6 represent a linear or branched carbon chain which may have from 0 to 6 carbon atoms. carbon;
• alkyl represents a saturated, linear or branched aliphatic group; for example, a C 1-6 -alkyl group represents a linear or branched carbon chain of 1 to 6 carbon atoms, especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, butyl, pentyl; when an alkyl group is substituted by one or more halogen atoms or by one or more groups as indicated in the definitions, these substitutions may be borne by the same carbon atom and / or by different carbon atoms;
• cycloalkyl represents a saturated cyclic aliphatic group.
• halogen represents a fluorine, chlorine, bromine or iodine atom
• fluoroalkyl represents an alkyl group in which one or more hydrogen atoms are replaced by a fluorine atom.
• group fluoroalkyl there may be mentioned trifluoromethyl, difluoromethyl, 3,3,3-trifluoropropyl;
• heterocycloalkyl represents a saturated or partially saturated, monocyclic or polycyclic ring, optionally substituted, comprising from 3 to 6 members and one to several heteroatoms such as nitrogen, oxygen or sulfur atoms.
• a heterocycloalkyl may be pyrrolidine, morpholine, piperazine, diazetidine, dihydropyrrolidine, piperidine, azepane, imidazolidine, thiomorpholine, tetrahydropyran, tetrahydrothiopyran, piperazine, diazepane or azabicyclooctane, a tropane, a 3,6-diaza-bicyclo [3.1.0] hexane;
• aryl represents an optionally substituted monocyclic or polycyclic aromatic system comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms. When the system is polycyclic at least one of the rings is aromatic.
• aryl groups there may be mentioned phenyl, naphthyl, indanyl, tetrahydronaphthyl, anthracenyl or azulenyl;
• heteroaryl represents an optionally substituted monocyclic or polycyclic aromatic system comprising from 5 to 14 members, preferably from 5 to 10 members and comprising one to more heteroatoms such as nitrogen, oxygen or sulfur atoms. When the system is polycyclic at least one of the rings is aromatic. Nitrogen atoms can be in the form of N-oxides.
• monocyclic heteroaryls mention may be made of thiazole, thiadiazole, thiophene, imidazole, triazole, tetrazole, pyridine, furan, oxazole, isoxazole, oxadiazole, pyrrole, pyrazole, pyrimidine, pyridazine and pyrazine.
• indole By way of example of polycyclic heteroaryls, mention may be made of indole, benzofuran, benzimidazole, benzothiophene, benzotriazole, benzothiazole, benzoxazole, quinoline, isoquinoline, indazole, quinazoline, phthalazine, quinoxaline, naphthyridine, 2,3-dihydro-1H-indole, 2,3-dihydro-benzofuran, tetrahydroquinoline, tetrahydroisoquinoline or tetrahydroisoquinazoline;
• alkoxy represents a saturated linear or branched aliphatic chain -O-C mn -alkyl group.
• alkoxy groups there may be mentioned methoxy;
• fluoroalkoxy represents an alkoxy group in which one or more hydrogen atoms are replaced by a fluorine atom.
• fluoroalkoxy group mention may be made of the groups -O-CHF 2, -O-CF 3, or -O-CF 2 -CF 3;
• aryloxy is -O-aryl
• heteroaryloxy is -O-heteroaryl
• hydroxyalkyl represents a -C 1 -6-alkyl-OH group.
• a hydroxyalkyl group mention may be made of the -CH 2 -OH group;
• phenyl optionally substituted with one or more groups independently selected from OH, methoxy, morpholine, trifluoromethoxy, chlorine or fluorine;
• a tetrahydropyranyl group, a morpholinyl group, a pyrrolidinyl and thiomorpholinyl group optionally substituted with one or more groups chosen independently of each other from a methyl, phenyl and benzyl group;
• PG group protection group that allows, on the one hand, to protect a reactive function such as a hydroxyl or an amine during a synthesis and on the other hand, to regenerate the reactive function intact at the end of synthesis.
• Examples of protecting groups as well as methods of protection and deprotection are given in "Protective Group in Organic Synthesis", Green et al., 4th Edition, John Wiley & Sons, Inc., New York, 2007.
• GP is understood to mean a group that can be easily cleaved from a molecule by breaking a heterolytic bond, with departure from an electronic pair. This group can thus be easily replaced by another group during a substitution reaction, for example.
• Such leaving groups are, for example, halogens or an activated hydroxy group such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate, etc. Examples of leaving groups as well as references for their preparation are given in "Advanced Organic Chemistry", M. B. Smith and J. March, 6th Edition, Wiley Interscience, 2007, p.496-501.
• the compounds of general formula (I) can be prepared according to the process (route A), characterized in that a compound of formula (II) is reacted:
• R represents a C 1-4 alkyl, with an amine of formula (III):
• R 1 is as defined for the compounds of formula (I).
• reaction is optionally carried out in the presence of a mineral or organic base in the case where the secondary amine of formula (III) is in the form of acid salt (for example hydrochloride) in a polar solvent such as alcohol, DMF or DMSO and at a temperature between 5 ° C and 100 ° C.
• a mineral or organic base for example hydrochloride
• a polar solvent such as alcohol, DMF or DMSO
• the reaction is preferably carried out in MeOH at RT with optionally triethylamine.
• the compounds of formula (I) can be prepared according to the process characterized in that a reduction reaction of the compounds of formula (IV) having a benzothiazole N-oxide ring is carried out:
• R 1 is as defined for the compounds of formula (I).
• the reaction is preferably carried out using a trivalent phosphorus reagent such as triethyl phosphite in an alcohol such as ethanol (Wagner et al., Chem., Ber., 1973, 106, 640-654).
• a trivalent phosphorus reagent such as triethyl phosphite in an alcohol such as ethanol (Wagner et al., Chem., Ber., 1973, 106, 640-654).
• R represents a C 1-4 alkyl
• the reaction is carried out using a trivalent phosphorus reagent such as triethylphosphite in an alcohol such as ethanol (Wagner et al., Chem., Ber., 1973, 106, 640-654).
• a trivalent phosphorus reagent such as triethylphosphite in an alcohol such as ethanol (Wagner et al., Chem., Ber., 1973, 106, 640-654).
• the compounds of formula (IV) having a benzothiazole N-oxide ring in which R 1 is as defined for the compounds of formula (I) are obtained by reaction of the corresponding N-oxide derivatives of formula (V) in which R represents a Ci is alkylated with an amine of formula (III) in which R 1 is as defined for the compounds of formula (I).
• the reaction is carried out between 5 and 100 ° C, in a polar solvent such as an alcohol, DMF or DMSO, optionally in the presence of a mineral or organic base in the case where the secondary amine of formula (III ) is in the form of acid salt (for example hydrochloride).
• a polar solvent such as an alcohol, DMF or DMSO
• a mineral or organic base in the case where the secondary amine of formula (III ) is in the form of acid salt (for example hydrochloride).
• the reaction is preferably carried out in MeOH at RT in the presence optionally of triethylamine.
• GP represents a leaving group, preferably a halogen.
• the reactions are monitored by thin layer chromatography (silica gel 60F254, Merck) with 254nM UV detection or by spraying a solution of Draggendorff reagent / AcOH / H 2 O / EtOH: 2/3/10/10 or by spraying a solution of ninhydrin 0.5% / n-butanol (Prolabo) followed by heating to ⁇ 100 ° C.
• the solvents are removed on a rotary evaporator under reduced pressure at 40.degree.
• the LCMS analytical characteristics of the products are the ratio m / z of the ion (M + H) + or ion (M ⁇ H) ⁇ and the retention time (tr) of the corresponding peak, observed in UV most often at 220nm and expressed in minutes.
• a suspension of 0.5 g (1.12 mmol) of the compound obtained in the preceding step in 7 ml of ethanol is added dropwise to 0.22 ml (1.26 mmol) of triethyl phosphite.
• the reaction mixture is then stirred at 70 ° C. for 2 hours and then cooled to RT.
• the precipitate obtained is rinsed with petroleum ether.
• the expected product is obtained in the form of trifluoroacetate.
• the first line (“salt") of each box represents the state of the compound: "/" for a compound in free base form and "TFA" for a compound in the form of trifluoroacetic acid salt.
• the second and third lines of each box indicate the LCMS characteristics in parentheses using the methods A, B or C used as described above.
• the fourth line indicates the melting point with the letter symbolizing the measuring device in parentheses: K for the Koffler bench and M for the Mettler-Toledo FP62.
• Alamar blue is a colorimetric test which makes it possible to determine the MIC (minimum inhibitory concentration) of anti-bacterials.
• Alamar blue is a redox indicator that changes from blue to pink in case of bacterial growth. Resazurin (blue and non-fluorescent) is reduced to resorufin (pink and fluorescent) by live bacteria. The reading of the plate is therefore visual or by fluorescence measurement. The fluorescence intensity is proportional to the number of living bacteria.
• Table II illustrates the activities of some examples of compounds on the growth of Mycobacterium tuberculosis.
• the compounds according to the invention namely the compounds corresponding to formula (I), have moreover good microbiological properties and are particularly suitable for use in the preparation of medicaments, particularly narrow-spectrum antibiotics for the treatment and / or prevention of tuberculosis.
• antibiotics have antimicrobial action against M. tuberculosis for the treatment and / or prevention of tuberculosis.
• the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid or base of the compound of formula ( I).
• These drugs are used therapeutically, especially in the treatment and / or prevention of tuberculosis.
• the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.
• These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt of said compound, as well as at least one pharmaceutically acceptable excipient.
• excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
• compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration the active ingredient of formula (I) above or its salt can be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for prophylaxis (to be adapted case by case) or the treatment of the disorders or diseases above.
• Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
• oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions
• sublingual, oral, intratracheal intraocular, intranasal forms of administration by inhalation
• topical, transdermal, subcutaneous, intramuscular or intravenous administration forms rectal administration forms and implants.
• the compounds according to the invention can be used in creams, gels, ointments or lotions.
• a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:
• the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.
• the present invention also relates to the use of the compounds of formula (I), or a pharmaceutically acceptable salt thereof or hydrates or solvates (to be adapted case by case), for the treatment and / or the prevention of bacterial infections due to mycobacteria such as M. smegmatis, M. phlei, or other microorganisms such as Nocardia brasiliensis, Nocardia absessus or Corynebacterium diphtheria, for example.
• mycobacteria such as M. smegmatis, M. phlei, or other microorganisms such as Nocardia brasiliensis, Nocardia absessus or Corynebacterium diphtheria, for example.
• one of the aspects of the invention relates to the use of the compounds of formula (I) or a pharmaceutically acceptable salt thereof or hydrates or solvates (to be adapted case by case) for the treatment and / or prevention infectious diseases such as tuberculosis, leprosy, nocardiosis, diphtheria, mycobacterial pulmonary infection, cutaneous mycobacterial infection, atypical mycobacterial infection and mycobacteriosis.
• infectious diseases such as tuberculosis, leprosy, nocardiosis, diphtheria, mycobacterial pulmonary infection, cutaneous mycobacterial infection, atypical mycobacterial infection and mycobacteriosis.
• tuberculosis includes infections caused by bacilli of the tuberculosis complex (M. tuberculosis, M. bovis and M. africanum) which are all pathogenic to humans.
• Pulmonary tuberculosis is by far the most common and the most widespread; these are tuberculosis of the lung, larynx, trachea and bronchi, tuberculosis of the intrathoracic lymph nodes, respiratory tuberculosis of pleura, primary respiratory tuberculosis and any other respiratory tuberculosis.
• tuberculosis and extrapulmonary tuberculosis tuberculosis of the nervous system such as tuberculous meningitis, tuberculous leptomeningitis, brain tuberculomas and other nervous system tuberculosis, or bone or bone tuberculosis.
• tuberculosis of the genitourinary system peripheral lymphadenopathic tuberculosis, intestinal tuberculosis, peritoneal and / or mesenteric glands, cutaneous tuberculosis and subcutaneous tissue, tuberculosis of the eye, ear, or adrenal glands, as well as disseminated tuberculosis.
• leprosy includes infections caused by Mycobacterium leprae: indeterminate leprosy, tuberculoid leprosy, borderline leprosy, tuberculoid borderline leprosy, lepromatous leprosy, and other forms of leprosy.
• diphtheria includes pharyngeal diphtheria, nasopharyngeal diphtheria, cutaneous diphtheria, and other forms of diphtheria.
• nocardiosis includes pulmonary nocardiosis, cutaneous nocardiosis, and other forms of nocardiosis.
• the present invention also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound of formula (I).

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Communicable Diseases (AREA)
• Oncology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pulmonology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Thiazole And Isothizaole Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

Priority Applications (3)

Applications Claiming Priority (2)

Publications (1)

Family

ID=43498537

Family Applications (1)

Country Status (5)

Cited By (2)

Families Citing this family (2)

Citations (8)

Family Cites Families (1)

• 2010
  • 2010-11-22 FR FR1059602A patent/FR2967672B1/fr not_active Expired - Fee Related
• 2011
  • 2011-11-18 EP EP11796759.6A patent/EP2643307B1/fr active Active
  • 2011-11-18 WO PCT/FR2011/052699 patent/WO2012069743A1/fr not_active Ceased
  • 2011-11-18 US US13/988,868 patent/US8993561B2/en not_active Expired - Fee Related
  • 2011-11-18 JP JP2013539319A patent/JP5876885B2/ja not_active Expired - Fee Related

Patent Citations (8)

Non-Patent Citations (8)

Also Published As

Similar Documents

Legal Events