WO2015104433A1 - Dérivés de benzo[c][1,2,5]oxadiazol pour le traitement de maladies causées par helicobacter - Google Patents

Dérivés de benzo[c][1,2,5]oxadiazol pour le traitement de maladies causées par helicobacter Download PDF

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WO2015104433A1
WO2015104433A1 PCT/ES2014/070011 ES2014070011W WO2015104433A1 WO 2015104433 A1 WO2015104433 A1 WO 2015104433A1 ES 2014070011 W ES2014070011 W ES 2014070011W WO 2015104433 A1 WO2015104433 A1 WO 2015104433A1
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group
compound
formula
pharmaceutical composition
day
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PCT/ES2014/070011
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English (en)
Spanish (es)
Inventor
Javier Sancho Sanz
Adrián VELÁZQUEZ CAMPOY
Nunilo CREMADES CASASÍN
Mirian ALIAS NIÑO
Juan José GALANO FRUTOS
Eliette Touati
Valérie Michel
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Universidad De Zaragoza
Fundación Agencia Aragonesa Para La Investigación Y Desarrollo
Institut Pasteur
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Priority to PCT/ES2014/070011 priority Critical patent/WO2015104433A1/fr
Publication of WO2015104433A1 publication Critical patent/WO2015104433A1/fr

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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
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K31/433—Thidiazoles
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/12—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to benzo [c] [1, 2,5] oxadiazole derivatives of formula I and their use for the treatment and prevention of diseases caused by Helicobacter, preferably caused by Helicobacter Pylori.
  • the invention relates to a pharmaceutical composition of the compound of formula I and its method of production. STATE OF THE TECHNIQUE
  • H. pylori Helicobacter pylori infection is one of the most frequent chronic diseases today; In fact, this bacterium is colonizing the gastric mucosa of more than 50% of the human population.
  • H. pylori is a gram-negative bacillus that causes chronic gastritis, gastric and duodenal ulcers and is a risk factor in the development of MALT lymphoma and adenocarcinoma (one of the most frequent and lethal types of cancer).
  • the conventional treatment currently used to eradicate Helicobacter pylori infection consists of two broad-spectrum antibiotics and a proton pump inhibitor. Therefore, there is no specific treatment for this condition or especially effective since the number of patients treated successfully does not exceed 80%. In addition, its great mutational variability is causing a decline in the efficacy of conventional treatments due to an increasing increase in resistance to conventional antibiotics.
  • the present invention provides compounds with high activity against bacteria, in particular Gram positive bacteria, such as Helicobacter pylori, Campylobacter jejuni, Staphylococcus epidermidis and Staphylococcus aureus. Therefore, said compounds are useful for the prevention and / or treatment of diseases caused by said bacteria. These compounds act as antibiotics with greater bacteriostatic effect.
  • a first aspect of the invention relates to a compound of formula I:
  • X represents oxygen (O) or sulfur (S), preferably O;
  • Y represents sulfur (S) or NR ', where R' is hydrogen or an alkyl group (C-Ce), preferably R 'is H or methyl (CH3), more preferably Y is S; R1 represents a nitrous group (-NO), an amine group (-NR 3 R ' 3 ) or
  • R 2 represents -OH or aryl group, preferably a phenyl group, where the aryl group, and in particular the phenyl group, is optionally substituted by one or more (ie, one to five when the aryl is a phenyl group) groups -OR 4 , where R 4 represents a hydrogen or a (C1-C6) alkyl group, preferably R 4 is a hydrogen or a methyl; R 3 and R ' 3 , are the same or different and represent H, a -OR group "or a (C1-C6) alkyl group, preferably H, -OR” or a (C1-C3) alkyl group, preferably H, OR "or methyl; where R" represents an H or a (C1-C6) alkyl group, preferably H or (C1-C3) alkyl, preferably H or methyl and
  • n an integer between 1 and 3, preferably 1 or 2.
  • the present invention also relates to pharmaceutically acceptable salts and solvates of the compounds of formula I.
  • Some compounds of formula I may have chiral centers, which may give rise to various stereoisomers.
  • the present invention relates to each of the individual stereoisomers as well as their mixtures.
  • the compounds of formula I are useful for the prevention and / or treatment of diseases caused by bacteria, preferably Gram positive bacteria, for example and not limited to Helicobacter pylori, Campylobacter jejuni, Staphylococcus epidermidis and Staphylococcus aureus.
  • the compounds of formula I are useful for the prevention and / or treatment of diseases caused by bacteria of the genus Helicobacter, preferably for the prevention and / or treatment of diseases caused by Helicobacter pylori.
  • Gram positive bacteria could be bacteria of the genus Helicobacteri, Campylobacter, Staphylococcus or Staphylococcus, in particular bacteria of the species Helicobacter pylori, Campylobacter jejuni, Staphylococcus epidermidis or Staphylococcus aureus.
  • a compound of formula I as defined above or a pharmaceutically acceptable salt thereof, for the preparation of a medicament, preferably where the medicament is an antibiotic, more preferably where the medicament is an antibiotic against bacteria, preferably Gram positive bacteria, more preferably Helicobacter genus bacteria, and even more preferably where the medicament is an antibiotic against Helicobacter Pylori.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I as defined above or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • Another aspect of the present invention relates to the use of a compound of formula I as defined above or of the pharmaceutical composition as defined above, for the preparation of a medicament for use in the treatment and / or prevention of a disease caused by bacteria, preferably Gram positive bacteria, more preferably by Helicobacter, and more preferably for the treatment and / or prevention of a disease caused by Helicobacter pylori, and even more preferably for the treatment and / or prevention of a disease selected from infection of the digestive system, gastritis, chronic gastritis, peptic, gastric and / or duodenal ulcer, gastric lymphoma, and in particular MALT lymphoma, or gastric cancer.
  • a disease caused by bacteria preferably Gram positive bacteria, more preferably by Helicobacter, and more preferably for the treatment and / or prevention of a disease caused by Helicobacter pylori, and even more preferably for the treatment and / or prevention of a disease selected from infection of the digestive system, gastritis, chronic gastritis
  • infection of the digestive system is meant a bacterial infection produced in any part of the digestive system (mouth, pharynx, esophagus, stomach, small intestine (including the duodenum) and large intestine), in particular in the stomach and intestine Thin and preferably in infection is a gastric infection.
  • gastric cancer and gastric lymphoma are diseases that may be caused by H. pylori, and this bacterium has been classified within group I of carcinogens by the International Agency for Research on Cancer.
  • C1-C6 alkyl as a group or part of a group, is considered to be a straight or branched chain alkyl group containing from 1 to 6 carbon atoms and includes the methyl, ethyl, propyl groups, Isopropyl, butyl, isobutyl, sec-butyl, fe / t-butyl, pentyl, among others. More preferably the alkyl group contains 1 to 3 carbon atoms and even more preferably it is a methyl or ethyl group.
  • aryl refers in the present invention to an aromatic carbocyclic chain, having 5 to 12 carbon atoms, being able to be single or multiple ring, in the latter case with separate and / or condensed rings, optionally substituted by one or more groups -OR 4 , where R 4 is defined above.
  • R 4 is defined above.
  • the aryl group is a phenyl.
  • aryl group is a phenyl, this may be substituted by up to 5 groups - OR 4 the same or different, preferably by 1, 2, 3 or 4 substituents, more preferably by 1, 2 or 3 substituents and even more preferably by 1 or 2 substituents, provided that said group has sufficient available positions that can be substituted. If present, said substituents may be the same or different and may be located over any available position.
  • treatment refers to eliminating, reducing or decreasing the cause or effects of a disease.
  • treatment includes, but is not limited to, alleviating, reducing or eliminating one or more symptoms of the disease; reduce the degree of disease, stabilize (i.e., not worsen) the disease status, delay or slow the progression of the disease, relieve or improve the disease status and remit (either total or partial).
  • prevention refers to preventing the onset of the disease that occurs in a patient who is predisposed or has risk factors, but still has no symptoms of the disease. Prevention also includes preventing the recurrence of a disease in a subject who has previously suffered from the disease.
  • the present invention therefore relates to the compounds of formula I as defined above.
  • X is O in the compounds of formula I.
  • Y is S.
  • the compounds are of formula II:
  • R1, R2 and n are defined in the present invention.
  • the invention relates to the compounds of formula I where Ri represents a group -NR 3 R ' 3 . In another embodiment, the invention relates to the compounds of formula I wherein Ri represents a group -S0 2 NR 3 R ' 3 . In another embodiment, the invention relates to the compounds of formula I where Ri represents a -NO group. In another embodiment, the invention relates to the compounds of formula I wherein R 2 represents -OH group.
  • the invention relates to the compounds of formula I wherein R 2 represents phenyl group, where the phenyl is optionally substituted by one or more -OR 4 groups, preferably by one or two OR- 4 groups, more preferably by one or two groups -OCH 3 .
  • the invention relates to the compounds of formula I where R 2 represents phenyl group, where the phenyl is optionally substituted by a -OR 4 group, preferably by a -OCH 3 group, more preferably the phenyl group is substituted by at least one group -OR 4 , more preferably it is a position for and even more preferably by a group -OCH 3 .
  • the invention relates to the compounds of formula I wherein R3 and R'3 are the same or different and represent H, more preferably they are the same.
  • the invention relates to the compounds of formula I wherein R3 and R'3, are the same or different and represents (C1-C3) alkyl group, preferably represents a CH3 group.
  • the invention relates to the compounds of formula I wherein R 1 represents a group -NR 3 R ' 3 and R 3 and R' 3, are the same or different and represents H, a (C1-C3) alkyl group or OR group ", where R" is a hydrogen or a (C1-C3) alkyl group.
  • the invention relates to the compounds of formula I where Ri represents an amine group (-NR 3 R ' 3 ) and can be selected from NH 2 , NHOH, N (CH 3 ) 2 , NHOCH 3 , NCH 3 OH or NCH3OCH3.
  • the invention relates to the compounds of formula I where n represents 1 or 2.
  • the invention relates to the compounds of formula II wherein:
  • R1 represents a group -NR 3 R ' 3 ;
  • R 2 represents -OH or phenyl group, where the phenyl is optionally substituted by one or more -OR 4 groups, where R 4 is a (C1-C3) alkyl group, preferably where the phenyl is optionally substituted by one or more groups - OCH 3 ;
  • R3 and R'3 independently represent H, OR "or (C1-C3) alkyl, preferably H, -OCH 3 or -CH 3 ;
  • n 1 to 3, preferably 1 or 2, and more preferably 1.
  • the invention relates to the compounds of formula II wherein:
  • R1 represents a group -NR 3 R ' 3 ;
  • R 2 represents phenyl group, where the phenyl is optionally substituted by one or more -OR 4 groups, preferably where the phenyl is optionally substituted by one or more -OCH 3 groups;
  • R3 and R'3 represent H
  • n 1 to 3, preferably 1 or 2, and more preferably 1.
  • the invention relates to the compounds of formula II wherein:
  • R1 represents a group -NR 3 R ' 3
  • R 2 represents phenyl group, where the phenyl is optionally substituted by one or two -OR 4 alkyl groups, preferably where the phenyl is optionally substituted by one or two -OCH 3 groups;
  • R 3 and R ' 3 represents H
  • n 1 to 3, preferably 1 or 2, and more preferably 1.
  • the invention relates to the compounds of formula II wherein:
  • Ri represents a group -NR 3 R ' 3 ;
  • R 2 represents phenyl group, where the phenyl is optionally substituted by an -OR 4 alkyl group, preferably where the phenyl is optionally substituted by a -OCH 3 group;
  • R 3 and R ' 3 represents H
  • n 1 to 3, preferably 1 or 2, and more preferably 1.
  • the invention relates to the compounds of formula II wherein:
  • Ri represents a group -S0 2 NR 3 R ' 3 ;
  • R 2 represents -OH or phenyl group, where the phenyl is optionally substituted by one or more -OR 4 alkyl groups, preferably where the phenyl is optionally substituted by one or more -OCH 3 groups;
  • R 3 and R ' 3 independently represent H, OR "or (Ci-C 3 ) alkyl, preferably H-OCH 3 or -CH 3 ;
  • n 1 to 3, preferably 1 or 2.
  • the invention relates to the compounds of formula II wherein:
  • R 2 represents -OH group
  • R 3 and R ' 3 independently represent H, OR "or (Ci-C 3 ) alkyl, preferably H-OCH 3 or -CH 3 ;
  • n 1 to 3, preferably 1 or 2, and more preferably 2.
  • the invention relates to the compounds of formula II wherein:
  • Ri represents a group -S0 2 NR 3 R ' 3 ;
  • R 2 represents -OH group
  • R 3 and R ' 3 represents H
  • n 1 to 3, preferably 1 or 2, and more preferably 2.
  • the invention relates to the compounds of formula II wherein:
  • Ri represents a group -SO 2 NR 3 R ' 3 ;
  • R 2 represents phenyl group, where the phenyl is optionally substituted by one or more -OR 4 alkyl groups, preferably where the phenyl is optionally substituted by one or more -OCH 3 groups;
  • R 3 and R ' 3 independently represent H, OR "or (Ci-C 3 ) alkyl, preferably H-OCH 3 or -CH 3 ;
  • n 1 to 3, preferably 1 or 2, and more preferably 1.
  • the invention relates to the compounds of formula II wherein:
  • Ri represents a group -SO 2 NR 3 R ' 3 ;
  • R 2 represents phenyl group, where the phenyl is optionally substituted by one or more -OR 4 groups, preferably where the phenyl is optionally substituted by one or more -OCH 3 groups;
  • R 3 and R ' 3 independently represent a (Ci-C 3 ) alkyl, preferably preferably -CH 3 ; Y
  • n 1 to 3, preferably 1 or 2, and more preferably 1.
  • the invention relates to the compounds of formula II wherein:
  • Ri represents a group -SO 2 NR 3 R ' 3 ;
  • R 2 represents -OH or phenyl group, where the phenyl is optionally substituted by one or two -OR 4 groups, preferably where the phenyl is optionally substituted by one or two -OCH 3 groups;
  • R3 and R'3 independently represent H or (C1-C3) alkyl, preferably H or -CH 3 ;
  • n 1 to 3, preferably 1 or 2.
  • the invention relates to the compounds of formula II wherein:
  • R1 represents a group -SO 2 NR 3 R ' 3 ;
  • R 2 represents phenyl group, where the phenyl is optionally substituted by one or two -OR 4 groups, preferably where the phenyl is optionally substituted by one or two -OCH 3 groups;
  • R 3 and R ' 3 independently represent H or alkyl (CC 3 ), preferably H or -CH 3 ; Y
  • n 1 to 3, preferably 1 or 2, and more preferably 1.
  • the invention relates to the compounds of formula II wherein:
  • R1 represents a group -SO 2 NR 3 R ' 3 ;
  • R 2 represents phenyl group, where the phenyl is optionally substituted by one or two -OR 4 groups, preferably where the phenyl is optionally substituted by one or two -OCH 3 groups;
  • R 3 and R ' 3 independently represent a (Ci-C 3 ) alkyl, preferably -OCH 3 ; Y
  • n 1 to 3, preferably 1 or 2, and more preferably 1.
  • the invention relates to the compounds of formula II wherein:
  • R1 represents a group -SO 2 NR 3 R ' 3 ;
  • R 2 represents -OH or phenyl group, where the phenyl is optionally substituted by a -OR 4 group, preferably where the phenyl is optionally substituted by a -OCH 3 group;
  • R3 and R'3 independently represent H, OR "or (C1-C3) alkyl, preferably H-OCH 3 or -CH 3 ;
  • n 1 to 3, preferably 1 or 2.
  • the invention relates to the compounds of formula II wherein:
  • R1 represents a group -SO 2 NR 3 R ' 3 ;
  • R 2 represents phenyl group, where the phenyl is optionally substituted by a -OR 4 group, preferably where the phenyl is optionally substituted by a -OCH 3 group;
  • R 3 and R ' 3 independently represent H, OR "or (Ci-C 3 ) alkyl, preferably H-OCH 3 or -CH 3 ;
  • n 1 to 3, preferably 1 or 2, and more preferably 1.
  • the invention relates to the compounds of formula II wherein:
  • R1 represents a group -SO 2 NR 3 R ' 3 ;
  • R 2 represents phenyl group, where the phenyl is optionally substituted by an -OR 4 alkyl group, preferably where the phenyl is optionally substituted by a -OCH 3 group;
  • R 3 and R ' 3 independently represent a (Ci-C 3 ) alkyl, preferably -CH 3 ; Y
  • n 1 to 3, preferably 1 or 2, and more preferably 1.
  • the invention relates to the compound of formula 1:
  • the invention relates to the compound of formula 2
  • the invention relates to the compound of formula 3
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I as defined above or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition further comprises at least one other active ingredient, this active ingredient can be an antacid; another antibiotic, such as but not limited to amoxicillin, metronidazole, clarithromycin or levofloxacin; a proton pump inhibitor, such as but not limited to omeprazole, pantoprazole or rabeprazole; or any of its combinations.
  • another antibiotic such as but not limited to amoxicillin, metronidazole, clarithromycin or levofloxacin
  • a proton pump inhibitor such as but not limited to omeprazole, pantoprazole or rabeprazole; or any of its combinations.
  • the invention relates to a composition in which the compound of formula I is dissolved in oil, preferably in olive oil, to improve the solubility of said compound and, therefore, to improve its effectiveness .
  • oil preferably in olive oil
  • a non-aqueous solvent and more preferably olive oil works as a coadjuvant, as a solvent and / or as a vehicle of the compound of formula I.
  • the solvent is an olive oil
  • the advantages of the composition of The invention increases with increasing benefits of said solvent in the digestive system.
  • the invention relates to the pharmaceutical composition as defined above, where the solvent is a non-aqueous solvent.
  • the invention relates to the pharmaceutical composition as defined above, where the solvent is an oil.
  • the invention relates to the pharmaceutical composition as defined above, where the solvent is olive oil.
  • the invention relates to the pharmaceutical composition as defined above, where the composition is suitable for oral, topical and intravenous administration.
  • the preferred route of administration for the compounds of the invention is the oral route. Therefore, in another embodiment the invention relates to the pharmaceutical composition as defined above, where the composition is suitable for oral administration. Thus, by oral administration, the compounds of the invention act both systemically and topically.
  • Solid compositions for oral administration include tablets, tablets, granules and capsules.
  • the manufacturing method is based on a simple mixture, dry granulation or wet granulation of the active ingredient with excipients.
  • excipients may be, for example, diluents such as lactose, microcrystalline cellulose, mannitol or calcium hydrogen phosphate; binding agents such as starch, gelatin or polyvinylpyrrolidone; disintegrants such as sodium carboxymethyl starch or croscarmellose sodium; and lubricating agents such as magnesium stearate, stearic acid or talc.
  • the tablets may also be coated with suitable excipients and by known techniques in order to delay their disintegration and absorption in the gastrointestinal tract and thus achieve sustained action for a longer period of time, or simply to improve their organoleptic properties or their stability.
  • the active ingredient can also be incorporated by coating on inert pellets by using natural or synthetic film-forming polymers. It is also possible to make soft gelatin capsules, in which the active ingredient is mixed with water or oily medium, for example coconut oil, liquid paraffin or olive oil.
  • Powders and granules can be obtained for the preparation of oral suspensions by adding water, mixing the active ingredient with dispersing or wetting agents; suspending and preservative. Other excipients can also be added, for example sweeteners, flavorings and dyes.
  • Liquid forms for oral administration may include emulsions, solutions, suspensions, syrups and elixirs containing commonly used inert diluents, such as distilled water, ethanol, sorbitol, glycerol, polyethylene glycols (macrogols) and propylene glycol. Such compositions may also contain adjuvants such as wetting, suspending, sweetening, flavoring, preservative and pH regulating agents.
  • the dosage and frequency of the doses will vary depending on the nature and severity of the disease to be treated, the age, the general condition and the weight of the patient, as well as the particular compound administered and the route of administration, among other factors. .
  • an adequate dosage range for a 25 g mouse the dose would be approximately 0.02-0.2 mg / day which would correspond to 56-560 mg / day for a human of a body weight of 70 kg, which can be administered as a single dose or in several doses. Therefore, taking into account the results obtained in the in vivo assays, in another embodiment the invention relates to the pharmaceutical composition as defined above, wherein the compound of formula I is administered at a dose of 0.1 mg. / kg / day at 10 mg / kg / day. In another embodiment the invention relates to the pharmaceutical composition as defined above, wherein the compound of formula I is administered at a dose of 0.15 mg / kg / day at 5 mg / kg / day.
  • the invention relates to the pharmaceutical composition as defined above, wherein the compound of formula I is administered at a dose of 0.2 mg / kg / day at 3 mg / kg / day.
  • the invention relates to the pharmaceutical composition as defined above, where the medicament is administered once a day, twice a day or three times a day. In another embodiment the invention relates to the pharmaceutical composition as defined above, where the medicament is administered once a day or twice a day. In another embodiment the invention relates to the pharmaceutical composition as defined above, where the medicament is administered once daily.
  • the compounds of the present invention may contain one or more basic nitrogen and could therefore form salts with acids, both organic and inorganic.
  • salts include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; and salts with organic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid , glycolic acid, succinic acid and propionic acid, among others.
  • Some compounds of the present invention may contain one or more acidic protons and therefore may also form salts with bases.
  • salts include: salts with inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminum, zinc, etc .; and salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, / V-methylglucamine, procaine and the like.
  • salts are understood to be those salts that, in medical judgment, are suitable for use in contact with the tissues of humans or other mammals without causing undue toxicity, irritation, allergic response or the like. Salts Pharmaceutically acceptable are widely known to any person skilled in the art.
  • the salts of a compound of formula I can be obtained during the final isolation and purification of the compounds of the invention or they can be prepared by treating a compound of formula I with a sufficient amount of the desired acid or base to give the salt of a conventional form.
  • the salts of the compounds of formula I can in turn be transformed into other salts of compounds of formula I by ion exchange by means of an ion exchange resin.
  • the compounds of the present invention can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as solvates.
  • solvate refers to a complex of variable stoichiometry formed by a solute (a compound of formula I or a salt thereof) and a solvent.
  • solvents include pharmaceutically acceptable solvents such as water, ethanol and the like.
  • a complex with water is known as hydrate.
  • Solvates of the compounds of the invention (or their salts), including hydrates, are included within the scope of the invention.
  • the compounds of formula I can exist in different physical forms, that is to say in amorphous form and crystalline forms. Also, the compounds of the present invention may have the ability to crystallize in more than one way, a characteristic known as polymorphism.
  • the polymorphs can be distinguished by several physical properties well known by the understood in the field such as X-ray diffractograms, melting points or solubility. All physical forms of the compounds of formula I, including all their polymorphic forms (“polymorphs”), are included within the scope of the present invention.
  • Some compounds of the present invention could exist in the form of several diastereoisomers and / or several optical isomers.
  • the diastereoisomers can be separated by conventional techniques such as chromatography or fractional crystallization.
  • Optical isomers can be resolved by using conventional optical resolution techniques, to give optically pure isomers. This resolution can be performed on synthesis intermediates that are chiral or on products of formula I.
  • Optically pure isomers can also be obtained individually using enantiospecific synthesis.
  • the present invention covers both the individual isomers and their mixtures (for example racemic mixtures or mixtures of diastereoisomers), whether they are obtained by synthesis or by physically mixing them.
  • the compounds of formula I can be obtained following the procedures described below. As will be apparent to one skilled in the art, the precise method used for the preparation of a given compound may vary depending on its chemical structure. Also, in some of the procedures detailed below, it may be necessary or convenient to protect reactive or labile groups by conventional protecting groups. Both the nature of such protecting groups and the procedures for their introduction and removal are well known and form part of the prior art (see for example Greene TW and Wuts PGM, "Protective Groups in Organic Synthesis", John Wiley & Sons, 4 to edition, 2007). Whenever a protective group is present, a subsequent deprotection stage will be necessary, which is carried out under the usual conditions in organic synthesis, such as those described in the reference mentioned above.
  • Figure 1 Represents the comparison of the effects of compound E with 5% DMSO as a vehicle and compound 2 with olive oil as a vehicle when treating mice by Helicobacter pylori SS1 (HpSS1) at a dose 1 of 0.02 mg / day and at a dose 2: 0.2 mg / day.
  • HpSS1 Helicobacter pylori SS1
  • EXAMPLE 2 BIOLOGICAL TESTS Reagents and chemical compounds.
  • Coupling constants were indicated in hertz. Coupling patterns were indicated as s (singlet), d (doublet), t (triplet), q (quartet) dd (doublet doublet), m (multiplet), bs (wide singlet). The purity of the compounds was determined by HPLC chromatography that was> 95%, using Waters equipment equipped with a 600-E pump, a 2996 PDA detector, and a 2707 autoloader. The column used was a C18 reverse phase (VYDAC).
  • a preliminary flavodoxin binding assay was carried out to dscartareliminate compounds that did not bind to the target protein. This screening was based on comparing the mean denaturation temperature (Tm) of flavodoxin with that of the protein in the presence of compound. For this, the intrinsic fluorescence of the flavodoxin in the visible was monitored with a FluoDia T70 spectrofluorimeter (excitation at 445 nm and emission at 525 nm) as a function of temperature.
  • Tm mean denaturation temperature
  • the dissociation constants of the complexes were determined at 25 ° C by isothermal titration calorimetry (ITC) using a calorimeter VP-ITC (MicroCal, GE Healthcare). Degassed solutions of flavodoxin 20 ⁇ were titrated with concentrated inhibitor coloutions (around 500 ⁇ ) dissolved in the same tamoon (50 mM EPPS, pH 9.0, and 5% DMSO), and the heats associated with each injection were adjusted accordingly a stoichiometry of 1: 1 for the complex formed.
  • ITC isothermal titration calorimetry
  • VP-ITC MicroCal, GE Healthcare
  • MICs Minimum inhibitory concentrations.
  • the strains Hp strains 26695 and Hp1061 were grown as described in St Maurice, M .; Cremades, N .; Croxen, M. A .; Sisson, G .; Sancho, J .; Hoffman, P. S. Flavodoxin: quinone reduce (FqrB): a redox partner of pyruvate: ferredoxin oxidoreductase that reversibly couples pyruvate oxidation to NADPH production in Helicobacter pylori and Campylobacter jejuni. J. Bacteriol. 2007, 189, 4764-4773. For microdilution determinations, 96-well round-bottom plates were used.
  • MCCsV Minimum cytotoxic concentrations
  • HeLa cells were cultured in complete medium (500 mL of Eagle medium: P04-03591 from Ibian Technologies plus 50 mL of fetal bovine serum plus 5.5 mL of antibiotic containing 550,000 units of penicillin and 550,000 ⁇ g streptomycin) with phenol red using 96-well plates (with 30,000 cells in 100 ⁇ in each well) to which volumes of 1 ⁇ of compound dissolved in DMSO were added at final concentrations of 0.1, 0, 25, 0.5, 1, 10, 25, 50, 75 and 100 ⁇ To the control wells was added 1 ⁇ of DMSO The plates were incubated at 37 ° C for 24 h and centrifuged.The medium was replaced by 100 ⁇ .
  • complete medium 500 mL of Eagle medium: P04-03591 from Ibian Technologies plus 50 mL of fetal bovine serum plus 5.5 mL of antibiotic containing 550,000 units of penicillin and 550,000 ⁇ g streptomycin
  • Table 1 shows the results of the previous tests for the compounds of formula 1, 2 and 3 compared to the results obtained for compound E.

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Abstract

La présente invention concerne des dérivés de benzo[c][1,2,5]oxadiazol, ainsi que leur utilisation en tant qu'antibiotiques et, plus particulièrement, dans le traitement et/ou la prévention de maladies causées par des bactéries, spécifiquement, des maladies causées par Helicobacter.
PCT/ES2014/070011 2014-01-09 2014-01-09 Dérivés de benzo[c][1,2,5]oxadiazol pour le traitement de maladies causées par helicobacter WO2015104433A1 (fr)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
ES2796148A1 (es) * 2019-05-21 2020-11-25 Univ Zaragoza Compuestos para el tratamiento de enfermedades causadas por Helicobacter

Citations (1)

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US20100063296A1 (en) * 2007-03-02 2010-03-11 Javier Sancho Sanz Composition for treating infectious diseases caused by helicobacter

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US20100063296A1 (en) * 2007-03-02 2010-03-11 Javier Sancho Sanz Composition for treating infectious diseases caused by helicobacter

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Title
GALANO JUAN J ET AL.: "Improved Flavodoxin Inhibitors with Potential Therapeutic Effects against Helicobacter pylori Infection", JOURNAL OF MEDICINAL CHEMISTRY, vol. 56, no. 15, 31 July 2013 (2013-07-31), pages 6248 - 6258 *
KESSLER U ET AL.: "Discovery and synthesis of novel benzofurazan derivatives as inhibitors of influenza A virus.", BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS 20131015, vol. 23, no. 20, 15 October 2013 (2013-10-15), pages 5575 - 5577 *
PAGANO M ET AL.: "The fight against the influenza A virus H1N1: Synthesis, molecular modeling, and biological evaluation of benzofurazan derivatives as viral RNA polymerase inhibitors.", CHEMMEDCHEM 2014, vol. 9, no. 1, 31 December 2013 (2013-12-31), pages 129 - 150 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2796148A1 (es) * 2019-05-21 2020-11-25 Univ Zaragoza Compuestos para el tratamiento de enfermedades causadas por Helicobacter
WO2020234424A1 (fr) 2019-05-21 2020-11-26 Universidad De Zaragoza Benzo [c] [1,2,5] oxadiazole pour le traitement de maladies provoquées par helicobacter

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