WO2015104433A1 - Benzo[c][1,2,5]oxadiazole derivatives for treating diseases caused by helicobacter - Google Patents

Benzo[c][1,2,5]oxadiazole derivatives for treating diseases caused by helicobacter Download PDF

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Publication number
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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Spanish (es)
French (fr)
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/en
Publication of WO2015104433A1 publication Critical patent/WO2015104433A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic 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
    • A61K31/4245Oxadiazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic 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
    • A61K31/433Thidiazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D271/00Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/12Heterocyclic 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
    • YGENERAL 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
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against 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

The invention relates to benzo[c][1,2,5]oxadiazole derivatives, and the use thereof as antibiotics and in particular for the treatment and/or prevention of diseases caused by bacteria, in particular of diseases caused by Helicobacter.

Description

DERIVADOS DE ΒΕΝΖΟΓ01Π.2.51ΟΧΑΡΙΑΖΟί_ PARA EL TRATAMIENTO DE ENFERMEDADES CAUSADAS POR HELICOBATER  DERIVATIVES OF ΒΕΝΖΟΓ01Π.2.51ΟΧΑΡΙΑΖΟί_ FOR THE TREATMENT OF DISEASES CAUSED BY HELICOBATER
La presente invención se refiere a derivados de benzo[c][1 ,2,5]oxadiazol de fórmula I y a su uso para el tratamiento y prevención de enfermedades causadas por Helicobacter, preferiblemente causadas por Helicobacter Pylori. Asimismo, la invención se refiere a una composición farmacéutica del compuesto de fórmula I y a su procedimiento de obtención. ESTADO DE LA TÉCNICA 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. Likewise, the invention relates to a pharmaceutical composition of the compound of formula I and its method of production. STATE OF THE TECHNIQUE
La infección por Helicobacter pylori (H. pylori) es una de las enfermedades crónicas más frecuentes en la actualidad; de hecho, esta bacteria se encuentra colonizando la mucosa gástrica de más del 50% de la población humana. Helicobacter pylori (H. 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 es un bacilo gram-negativo que causa gastritis crónica, úlceras gástricas y duodenales y es factor de riesgo en el desarrollo de linfoma MALT y adenocarcinoma (uno de los tipos de cáncer más frecuente y letal). 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).
El tratamiento convencional utilizado actualmente para erradicar la infección por Helicobacter pylori consiste en dos antibióticos de amplio espectro y un inhibidor de la bomba de protones. Por tanto, no hay un tratamiento específico para esta afección ni especialmente efectivo ya que el número de pacientes tratados con éxito no supera el 80 %. Además, su gran variabilidad mutacional está produciendo un declive de la eficacia de los tratamientos convencionales debido a un aumento creciente de resistencias a antibióticos convencionales. 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.
DESCRIPCIÓN DE LA INVENCIÓN La presente invención proporciona unos compuestos con gran actividad frente a bacterias, en particular bacterias Gram positivas, como por ejemplo Helicobacter pylori, Campylobacter jejuni, Staphylococcus epidermidis and Staphylococcus aureus. Por tanto, dichos compuestos son útiles para la prevención y/o tratamiento de enfermedades causadas por dichas bacterias. Estos compuestos actúan como antibióticos con mayor efecto bacteriostático. DESCRIPTION OF THE INVENTION 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.
Por tanto, un primer aspecto de la invención se refiere a un compuesto de fórmula I: Therefore, a first aspect of the invention relates to a compound of formula I:
Figure imgf000003_0001
Figure imgf000003_0001
donde: where:
X representa oxigeno (O) o azufre (S), preferiblemente O; X represents oxygen (O) or sulfur (S), preferably O;
Y representa azufre (S) o NR', donde R' es hidrógeno o un grupo alquilo (Ci- Ce), preferiblemente R' es H o metilo (CH3), más preferiblemente Y es S; R1 representa un grupo nitroso (-NO), un grupo amina (-NR3R'3) o
Figure imgf000003_0002
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
Figure imgf000003_0002
R2 representa grupo -OH o arilo, preferiblemente un grupo fenilo, donde el grupo arilo, y en particular el grupo fenilo, está opcionalmente sustituido por uno o más (es decir, de uno a cinco cuando el arilo es un grupo fenilo) grupos -OR4, donde R4 representa un hidrógeno o un grupo alquilo (C1-C6), preferiblemente R4 es un hidrógeno o un metilo; R3 y R'3, son iguales o diferentes y representa H, un grupo -OR" o un grupo alquilo (C1 -C6), preferiblemente H, -OR" o un grupo alquilo (C1 -C3), preferiblemente H, OR" o metilo; donde R" represente un H o un grupo alquilo (C1 -C6), preferiblemente H o alquilo (C1-C3), preferiblemente H o metilo y 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 representa un número entero de entre 1 y 3, preferiblemente 1 ó 2. n represents an integer between 1 and 3, preferably 1 or 2.
La presente invención también se refiere a las sales y los solvatos farmacéuticamente aceptables de los compuestos de fórmula I. The present invention also relates to pharmaceutically acceptable salts and solvates of the compounds of formula I.
Algunos compuestos de fórmula I pueden poseer centros quirales, los cuales pueden dar lugar a diversos estereoisómeros. La presente invención se refiere a cada uno de los estereoisómeros individuales así como a sus mezclas. 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.
Además, los compuestos de fórmula I son útiles para la prevención y/o tratamiento de enfermedades causadas por bacterias, preferiblemente bacterias Gram positivas, por ejemplo y sin limitarse a Helicobacter pylori, Campylobacter jejuni, Staphylococcus epidermidis and Staphylococcus aureus. En otra realización preferida los compuestos de fórmula I son útiles para la prevención y/o el tratamiento de enfermedades causadas por bacterias de género Helicobacter, preferiblemente para la prevención y/o tratamiento de enfermedades causadas por Helicobacter pylori. Ejemplos de bacterias Gram positivas, podrían ser bacterias del género Helicobacteri, Campylobacter, Staphylococcus o Staphylococcus, en particular bacterias de la especie Helicobacter pylori, Campylobacter jejuni, Staphylococcus epidermidis o Staphylococcus aureus. Así, otro aspecto de la presente invención se refiere al uso de un compuesto de fórmula I, tal y como se ha definido anteriormente o una sal farmacéuticamente aceptable del mismo, para la elaboración de un medicamento, preferiblemente donde el medicamento es un antibiótico, más preferiblemente donde el medicamento es un antibiótico contra bacterias, preferiblemente bacterias Gram positivas, más preferiblemente bacterias del género Helicobacter, y aún más preferiblemente donde el medicamento es un antibiótico contra Helicobacter Pylori. In addition, 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. In another preferred embodiment 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. Examples of 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. Thus, another aspect of the present invention relates to the use of 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.
Otro aspecto de la presente invención se refiere a una composición farmacéutica que comprende un compuesto de fórmula I tal y como se ha definido anteriormente o una sal farmacéuticamente aceptable del mismo y uno o más excipientes farmacéuticamente aceptables. Another aspect of the present invention relates to 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.
Otro aspecto de la presente invención se refiere al uso de un compuesto de fórmula I tal y como se ha definido anteriormente o de la composición farmacéutica tal y como se ha definido anteriormente, para la elaboración de un medicamento para su uso en el tratamiento y/o prevención de una enfermedad causada por bacterias, preferiblemente bacterias Gram positivas, más preferiblemente por Helicobacter, y más preferiblemente para el tratamiento y/o prevención de una enfermedad causada por Helicobacter pylori, y aún más preferiblemente para el tratamiento y/o la prevención de una enfermedad seleccionada de infección del sistema digestivo, gastritis, gastritis crónica, úlcera péptidica, gástrica y/o duodenal, linfoma gástrico, y en particular linfoma MALT, o cáncer gástrico. 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.
Por "infección del sistema digestivo" se entiende a una infección bacteriana producida en cualquier parte del sistema digestivo (boca, faringe, esófago, estómago, intestino delgado (incluido el duodeno) e intestino grueso), en particular en el estomago y en el intestino delgado y preferiblemente en la infección es una infección gástrica. Tanto el cáncer gástrico como el linfoma gástrico, en particular el linfoma MALT (linfoma de la mucosa asociada al tejido linfoide), son enfermedades que pueden estar causadas por H. pylori, y esta bacteria ha sido clasificada dentro del grupo I de carcinógenos por la Agencia Internacional de Investigación del Cáncer. By "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. Both gastric cancer and gastric lymphoma, particularly MALT lymphoma (lymphoma associated with lymphoid tissue), 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.
En las definiciones anteriores, el término C1 -C6 alquilo, como grupo o parte de un grupo, se considera a un grupo alquilo de cadena lineal o ramificada que contiene de 1 a 6 átomos de carbono e incluye los grupos metilo, etilo, propilo, isopropilo, butilo, isobutilo, sec-butilo, fe/t-butilo, pentilo, entre otros. Más preferiblemente el grupo alquilo contiene de 1 a 3 átomos de carbono y aún más preferiblemente es un grupo metilo o etilo. In the above definitions, the term 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.
Por "arilo" se refiere en la presente invención a una cadena carbocíclica aromática, que tiene de 5 a 12 átomos de carbono, pudiendo ser de anillo único ó múltiple, en este último caso con anillos separados y/o condensados, opcionalmente sustituido por uno o más grupos -OR4, donde R4 está definido anteriormente. Preferiblemente el grupo arilo es un fenilo. By "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. Preferably the aryl group is a phenyl.
La expresión "opcionalmente sustituido por uno o más" significa la posibilidad del grupo arilo de estar sustituido por uno o más grupos -OR4, cuando el arilo es un fenilo, este puede estar sustituido hasta por 5 grupos - OR4 iguales o diferente, preferiblemente por 1 , 2, 3 ó 4 sustituyentes, más preferiblemente por 1 , 2 ó 3 sustituyentes y aún más preferiblemente por 1 ó 2 sustituyentes, siempre que dicho grupo disponga de suficientes posiciones disponibles susceptibles de ser sustituidas. Si están presentes, dichos sustituyentes pueden ser iguales o diferentes y pueden estar situados sobre cualquier posición disponible. The expression "optionally substituted by one or more" means the possibility of the aryl group to be substituted by one or more -OR 4 groups, when the aryl 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.
A lo largo de la presente descripción, el término "tratamiento" se refiere a eliminar, reducir o disminuir la causa o efectos de una enfermedad. Para los propósitos de esta invención, tratamiento incluye, aunque sin quedar limitados a los mismos, aliviar, disminuir o eliminar uno o más síntomas de la enfermedad; reducir del grado de enfermedad, estabilizar (es decir, no empeorar) el estado de la enfermedad, retrasar o ralentizar la progresión de la enfermedad, aliviar o mejorar el estado de la enfermedad y remitir (ya sea total o parcial). Throughout the present description, the term "treatment" refers to eliminating, reducing or decreasing the cause or effects of a disease. For the purposes of this invention, 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).
Tal como se utiliza en la presente invención, el término "prevención" se refiere a prevenir la aparición de la enfermedad que se presente en un paciente que está predispuesto o tiene factores de riesgo, pero que todavía no presenta síntomas de la enfermedad. Prevención también incluye prevenir la reaparición de una enfermedad en un sujeto que previamente ha padecido dicha enfermedad. As used in the present invention, the term "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.
La presente invención se refiere, por tanto, a los compuestos de fórmula I según se han definido anteriormente. The present invention therefore relates to the compounds of formula I as defined above.
En una realización preferida, X es O en los compuestos de fórmula I. En otra realización preferida, Y es S. In a preferred embodiment, X is O in the compounds of formula I. In another preferred embodiment, Y is S.
En una realización más preferida, los compuestos son de fórmula II: In a more preferred embodiment, the compounds are of formula II:
Figure imgf000007_0001
Figure imgf000007_0001
II  II
donde R1 , R2 y n están definidos en la presente invención. where R1, R2 and n are defined in the present invention.
En otra realización, la invención se refiere a los compuestos de fórmula I donde Ri representa un grupo -NR3R'3. En otra realización, la invención se refiere a los compuestos de fórmula I donde Ri representa un grupo -S02NR3R'3. En otra realización, la invención se refiere a los compuestos de fórmula I donde Ri representa un grupo -NO. En otra realización, la invención se refiere a los compuestos de fórmula I donde R2 representa grupo -OH. In another embodiment, 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.
En otra realización, la invención se refiere a los compuestos de fórmula I donde R2 representa grupo fenilo, donde el fenilo está opcionalmente sustituido por uno o más grupos -OR4, preferiblemente por uno o dos grupos-OR4, más preferiblemente por uno o dos grupos -OCH3. In another embodiment, 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 .
En otra realización, la invención se refiere a los compuestos de fórmula I donde R2 representa grupo fenilo, donde el fenilo está opcionalmente sustituido por un grupo -OR4,, preferiblemente por un grupo -OCH3, más preferiblemente el grupo fenilo está sustuido por al menos un grupo -OR4, más preferiblemente es posición para y aún más preferiblemente por un grupo -OCH3. En otra realización, la invención se refiere a los compuestos de fórmula I donde R3 y R'3, son iguales o diferentes y representan H, más preferiblemente son iguales. In another embodiment, 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 . In another embodiment, 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.
En otra realización, la invención se refiere a los compuestos de fórmula I donde R3 y R'3, son iguales o diferentes y representa grupo alquilo (C1-C3), preferiblemente representa un grupo CH3. In another embodiment, 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.
En otra realización, la invención se refiere a los compuestos de fórmula I donde R1 representa un grupo -NR3R'3 y R3 y R'3, son iguales o diferentes y representa H, un grupo alquilo (C1-C3) o grupo OR", donde R" es un hidrógeno o un grupo alquilo (C1-C3). En otra realización, la invención se refiere a los compuestos de fórmula I donde Ri representa un grupo amina (-NR3R'3) y se puede seleccionar de entre NH2, NHOH, N(CH3)2, NHOCH3, NCH3OH o NCH3OCH3. En otra realización, la invención se refiere a los compuestos de fórmula I donde n representa 1 ó 2. In another embodiment, 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. In another embodiment, 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. In another embodiment, the invention relates to the compounds of formula I where n represents 1 or 2.
En otra realización, la invención se refiere a los compuestos de fórmula II donde: In another embodiment, the invention relates to the compounds of formula II wherein:
R1 representa un grupo -NR3R'3; R1 represents a group -NR 3 R '3;
R2 representa grupo -OH o fenilo, donde el fenilo está opcionalmente sustituido por uno o más grupos -OR4, donde R4 es un grupo alquilo (C1-C3), preferiblemente donde el fenilo está opcionalmente sustituido por uno o más grupos -OCH3; 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 y R'3 independientemente representan H, OR" o alquilo (C1-C3), preferiblemente H, -OCH3 o -CH3; y R3 and R'3 independently represent H, OR "or (C1-C3) alkyl, preferably H, -OCH 3 or -CH 3 ; and
n representa de 1 a 3, preferiblemente 1 ó 2, y más preferiblemente 1 . n represents 1 to 3, preferably 1 or 2, and more preferably 1.
En otra realización, la invención se refiere a los compuestos de fórmula II donde: In another embodiment, the invention relates to the compounds of formula II wherein:
R1 representa un grupo -NR3R'3; R1 represents a group -NR 3 R '3;
R2 representa grupo fenilo, donde el fenilo está opcionalmente sustituido por uno o más grupos -OR4, preferiblemente donde el fenilo está opcionalmente sustituido por uno o más grupos -OCH3; 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 y R'3 representan H; y R3 and R'3 represent H; Y
n representa de 1 a 3, preferiblemente 1 ó 2, y más preferiblemente 1 . n represents 1 to 3, preferably 1 or 2, and more preferably 1.
En otra realización, la invención se refiere a los compuestos de fórmula II donde: In another embodiment, the invention relates to the compounds of formula II wherein:
R1 representa un grupo -NR3R'3; R2 representa grupo fenilo, donde el fenilo está opcionalmente sustituido por uno o dos grupos -OR4 alquilo, preferiblemente donde el fenilo está opcionalmente sustituido por uno o dos grupos -OCH3; 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;
R3 y R'3 representa H; y R 3 and R ' 3 represents H; Y
n representa de 1 a 3, preferiblemente 1 ó 2, y más preferiblemente 1 . n represents 1 to 3, preferably 1 or 2, and more preferably 1.
En otra realización, la invención se refiere a los compuestos de fórmula II donde: In another embodiment, the invention relates to the compounds of formula II wherein:
Ri representa un grupo -NR3R'3; Ri represents a group -NR 3 R '3;
R2 representa grupo fenilo, donde el fenilo está opcionalmente sustituido por un grupo -OR4 alquilo, preferiblemente donde el fenilo está opcionalmente sustituido por un grupo -OCH3; 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;
R3 y R'3 representa H; y R 3 and R ' 3 represents H; Y
n representa de 1 a 3, preferiblemente 1 ó 2, y más preferiblemente 1 . n represents 1 to 3, preferably 1 or 2, and more preferably 1.
En otra realización, la invención se refiere a los compuestos de fórmula II donde: In another embodiment, the invention relates to the compounds of formula II wherein:
Ri representa un grupo -S02NR3R'3; Ri represents a group -S0 2 NR 3 R '3;
R2 representa grupo -OH o fenilo, donde el fenilo está opcionalmente sustituido por uno o más grupos -OR4 alquilo, preferiblemente donde el fenilo está opcionalmente sustituido por uno o más grupos -OCH3; 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;
R3 y R'3 independientemente representan H, OR" o alquilo (Ci-C3), preferiblemente H -OCH3 o -CH3; y R 3 and R ' 3 independently represent H, OR "or (Ci-C 3 ) alkyl, preferably H-OCH 3 or -CH 3 ; and
n representa de 1 a 3, preferiblemente 1 ó 2. n represents 1 to 3, preferably 1 or 2.
En otra realización, la invención se refiere a los compuestos de fórmula II donde: In another embodiment, the invention relates to the compounds of formula II wherein:
representa un grupo -SO2NR3R'3; represents a group -SO 2 NR 3 R '3;
R2 representa grupo -OH; R 2 represents -OH group;
R3 y R'3 independientemente representan H, OR" o alquilo (Ci-C3), preferiblemente H -OCH3 o -CH3; y R 3 and R ' 3 independently represent H, OR "or (Ci-C 3 ) alkyl, preferably H-OCH 3 or -CH 3 ; and
n representa de 1 a 3, preferiblemente 1 ó 2, y más preferiblemente 2. En otra realización, la invención se refiere a los compuestos de fórmula II donde: n represents 1 to 3, preferably 1 or 2, and more preferably 2. In another embodiment, the invention relates to the compounds of formula II wherein:
Ri representa un grupo -S02NR3R'3; Ri represents a group -S0 2 NR 3 R '3;
R2 representa grupo -OH; R 2 represents -OH group;
R3 y R'3 representa H; y R 3 and R ' 3 represents H; Y
n representa de 1 a 3, preferiblemente 1 ó 2, y más preferiblemente 2. n represents 1 to 3, preferably 1 or 2, and more preferably 2.
En otra realización, la invención se refiere a los compuestos de fórmula II donde: In another embodiment, the invention relates to the compounds of formula II wherein:
Ri representa un grupo -SO2NR3R'3; Ri represents a group -SO 2 NR 3 R '3;
R2 representa grupo fenilo, donde el fenilo está opcionalmente sustituido por uno o más grupos -OR4 alquilo, preferiblemente donde el fenilo está opcionalmente sustituido por uno o más grupos -OCH3; 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;
R3 y R'3 independientemente representan H, OR" o alquilo (Ci-C3), preferiblemente H -OCH3 o -CH3; y R 3 and R ' 3 independently represent H, OR "or (Ci-C 3 ) alkyl, preferably H-OCH 3 or -CH 3 ; and
n representa de 1 a 3, preferiblemente 1 ó 2, y más preferiblemente 1 . n represents 1 to 3, preferably 1 or 2, and more preferably 1.
En otra realización, la invención se refiere a los compuestos de fórmula II donde: In another embodiment, the invention relates to the compounds of formula II wherein:
Ri representa un grupo -SO2NR3R'3; Ri represents a group -SO 2 NR 3 R '3;
R2 representa grupo fenilo, donde el fenilo está opcionalmente sustituido por uno o más grupos -OR4, preferiblemente donde el fenilo está opcionalmente sustituido por uno o más grupos -OCH3; 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 y R'3 independientemente representan un alquilo (Ci-C3), preferiblemente preferiblemente -CH3; y R 3 and R ' 3 independently represent a (Ci-C 3 ) alkyl, preferably preferably -CH 3 ; Y
n representa de 1 a 3, preferiblemente 1 ó 2, y más preferiblemente 1 . n represents 1 to 3, preferably 1 or 2, and more preferably 1.
En otra realización, la invención se refiere a los compuestos de fórmula II donde: In another embodiment, the invention relates to the compounds of formula II wherein:
Ri representa un grupo -SO2NR3R'3; R2 representa grupo -OH o fenilo, donde el fenilo está opcionalmente sustituido por uno o dos grupos -OR4, preferiblemente donde el fenilo está opcionalmente sustituido por uno o dos grupos -OCH3; 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 y R'3 independientemente representan H o alquilo (C1-C3), preferiblemente H o -CH3; y R3 and R'3 independently represent H or (C1-C3) alkyl, preferably H or -CH 3 ; Y
n representa de 1 a 3, preferiblemente 1 ó 2. n represents 1 to 3, preferably 1 or 2.
En otra realización, la invención se refiere a los compuestos de fórmula II donde: In another embodiment, the invention relates to the compounds of formula II wherein:
R1 representa un grupo -SO2NR3R'3; R1 represents a group -SO 2 NR 3 R '3;
R2 representa grupo fenilo, donde el fenilo está opcionalmente sustituido por uno o dos grupos -OR4, preferiblemente donde el fenilo está opcionalmente sustituido por uno o dos grupos -OCH3; 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;
R3 y R'3 independientemente representan H o alquilo (C C3), preferiblemente H o -CH3; y R 3 and R ' 3 independently represent H or alkyl (CC 3 ), preferably H or -CH 3 ; Y
n representa de 1 a 3, preferiblemente 1 ó 2, y más preferiblemente 1 . n represents 1 to 3, preferably 1 or 2, and more preferably 1.
En otra realización, la invención se refiere a los compuestos de fórmula II donde: In another embodiment, the invention relates to the compounds of formula II wherein:
R1 representa un grupo -SO2NR3R'3; R1 represents a group -SO 2 NR 3 R '3;
R2 representa grupo fenilo, donde el fenilo está opcionalmente sustituido por uno o dos grupos -OR4, preferiblemente donde el fenilo está opcionalmente sustituido por uno o dos grupos -OCH3; 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;
R3 y R'3 independientemente representan un alquilo (Ci-C3), preferiblemente -OCH3; y R 3 and R ' 3 independently represent a (Ci-C 3 ) alkyl, preferably -OCH 3 ; Y
n representa de 1 a 3, preferiblemente 1 ó 2, y más preferiblemente 1 . n represents 1 to 3, preferably 1 or 2, and more preferably 1.
En otra realización, la invención se refiere a los compuestos de fórmula II donde: In another embodiment, the invention relates to the compounds of formula II wherein:
R1 representa un grupo -SO2NR3R'3; R2 representa grupo -OH o fenilo, donde el fenilo está opcionalmente sustituido por un grupo -OR4, preferiblemente donde el fenilo está opcionalmente sustituido por un grupo -OCH3; 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 y R'3 independientemente representan H, OR" o alquilo (C1-C3), preferiblemente H -OCH3 o -CH3; y R3 and R'3 independently represent H, OR "or (C1-C3) alkyl, preferably H-OCH 3 or -CH 3 ; and
n representa de 1 a 3, preferiblemente 1 ó 2. n represents 1 to 3, preferably 1 or 2.
En otra realización, la invención se refiere a los compuestos de fórmula II donde: In another embodiment, the invention relates to the compounds of formula II wherein:
R1 representa un grupo -SO2NR3R'3; R1 represents a group -SO 2 NR 3 R '3;
R2 representa grupo fenilo, donde el fenilo está opcionalmente sustituido por un grupo -OR4, preferiblemente donde el fenilo está opcionalmente sustituido por un grupo -OCH3; 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;
R3 y R'3 independientemente representan H, OR" o alquilo (Ci-C3), preferiblemente H -OCH3 o -CH3; y R 3 and R ' 3 independently represent H, OR "or (Ci-C 3 ) alkyl, preferably H-OCH 3 or -CH 3 ; and
n representa de 1 a 3, preferiblemente 1 ó 2, y más preferiblemente 1 . n represents 1 to 3, preferably 1 or 2, and more preferably 1.
En otra realización, la invención se refiere a los compuestos de fórmula II donde: In another embodiment, the invention relates to the compounds of formula II wherein:
R1 representa un grupo -SO2NR3R'3; R1 represents a group -SO 2 NR 3 R '3;
R2 representa grupo fenilo, donde el fenilo está opcionalmente sustituido por un grupo -OR4 alquilo, preferiblemente donde el fenilo está opcionalmente sustituido por un grupo -OCH3; 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;
R3 y R'3 independientemente representan un alquilo (Ci-C3), preferiblemente -CH3; y R 3 and R ' 3 independently represent a (Ci-C 3 ) alkyl, preferably -CH 3 ; Y
n representa de 1 a 3, preferiblemente 1 ó 2, y más preferiblemente 1 . n represents 1 to 3, preferably 1 or 2, and more preferably 1.
En otra realización, la invención se refiere al compuesto de fórmula 1 : In another embodiment, the invention relates to the compound of formula 1:
Figure imgf000014_0001
o a una sal del mismo.
Figure imgf000014_0001
or a salt thereof.
otra realización, la invención se refiere al compuesto de fórmula 2  another embodiment, the invention relates to the compound of formula 2
Figure imgf000014_0002
o a una sal del mismo.
Figure imgf000014_0002
or a salt thereof.
otra realización, la invención se refiere al compuesto de fórmula 3 another embodiment, the invention relates to the compound of formula 3
Figure imgf000015_0001
Figure imgf000015_0001
o a una sal del mismo. or a salt thereof.
La presente invención también se refiere a una composición farmacéutica que comprende un compuesto de fórmula I tal y como se ha definido anteriormente o una sal farmacéuticamente aceptable del mismo y uno o más excipientes farmacéuticamente aceptables. The present invention also relates to 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.
Los excipientes deben ser "aceptables" en el sentido de ser compatibles con los demás ingredientes de la composición y de no ser perjudiciales para quién tome dicha composición. Es bastante común para tratar y/o prevenir enfermedades causadas por bacterias la terapia combinada con varios principios activos, por tanto en otra realización de la presente invención, la composición farmacéutica además comprende al menos otro principio activo, este principio activo puede ser un antiácido; otro antibiótico, como por ejemplo pero sin limitarse a amoxicilina, metronidazol, claritromicina o levofloxacina; un inhibidor de bomba de protones, como por ejemplo pero sin limitarse al omeprazol, pantoprazol o rabeprazol; o cualquiera de sus combinaciones. En los ensayos realizados por los autores de la presente invención se ha encontrado de manera sorprendente como el uso de un disolvente no acuoso para los compuestos de la presente invención incrementa su actividad. Por tanto, en una realización particular, la invención se refiere a una composición en la que el compuesto de fórmula I se disuelve en aceite, preferiblemente en aceite de oliva, para mejorar la solubilidad de dicho compuesto y, por tanto, para mejorar su eficacia. De forma que un disolvente no acuoso y más preferiblemente el aceite de oliva funciona como coadjuvante, como disolvente y/o como vehículo del compuesto de fórmula I. Por otro lado, si el disolvente es un aceite de oliva, las ventajas de la composición de la invención aumentan al incrementar los beneficios de dicho disolvente en el sistema digestivo. The excipients must be "acceptable" in the sense of being compatible with the other ingredients of the composition and of not being harmful to who takes said composition. It is quite common to treat and / or prevent diseases caused by bacteria therapy combined with several active ingredients, therefore in another embodiment of the present invention, 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. In the tests carried out by the authors of the present invention it has been surprisingly found how the use of a non-aqueous solvent for the compounds of the present invention increases their activity. Therefore, in a particular embodiment, 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 . So that 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. On the other hand, if 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.
Por tanto, en otra realización la invención se refiere a la composición farmacéutica tal y como se ha definido anteriormente, donde el disolvente es un disolvente no acuoso. Therefore, in another embodiment the invention relates to the pharmaceutical composition as defined above, where the solvent is a non-aqueous solvent.
En otra realización la invención se refiere a la composición farmacéutica tal y como se ha definido anteriormente, donde el disolvente es un aceite. In another embodiment the invention relates to the pharmaceutical composition as defined above, where the solvent is an oil.
En otra realización la invención se refiere a la composición farmacéutica tal y como se ha definido anteriormente, donde el disolvente es aceite de oliva. In another embodiment the invention relates to the pharmaceutical composition as defined above, where the solvent is olive oil.
En otra realización la invención se refiere a la composición farmacéutica tal y como se ha definido anteriormente, donde la composición es adecuada para administración oral, tópica e intravenosa. In another embodiment the invention relates to the pharmaceutical composition as defined above, where the composition is suitable for oral, topical and intravenous administration.
Como se demuestra en los ensayos, la vía de administración preferida para los compuestos de la invención es la vía oral. Por tanto, en otra realización la invención se refiere a la composición farmacéutica tal y como se ha definido anteriormente, donde la composición es adecuada para administración oral. Así pues, mediante la administración vía oral, los compuestos de la invención actúan tanto por vía sistémica como por vía tópica. As demonstrated in the assays, 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.
Las composiciones sólidas para la administración oral incluyen tabletas, comprimidos, granulados y cápsulas. En cualquier caso el método de fabricación está basado en una mezcla simple, granulación seca o granulación húmeda del principio activo con excipientes. Estos excipientes pueden ser, por ejemplo, diluyentes tales como lactosa, celulosa microcristalina, manitol o hidrogenofosfato cálcico; agentes aglutinantes como por ejemplo almidón, gelatina o polivinilpirrolidona; disgregantes como carboximetilalmidón sódico o croscarmelosa sódica; y agentes lubricantes como por ejemplo estearato magnésico, ácido esteárico o talco. Los comprimidos pueden ser además recubiertos con excipientes adecuados y mediante técnicas conocidas con el objeto de retrasar su disgregación y absorción en el tracto gastrointestinal y así conseguir una acción sostenida durante un mayor período de tiempo, o simplemente para mejorar sus propiedades organolépticas o su estabilidad. El principio activo puede también ser incorporado por recubrimiento sobre pellets inertes mediante el uso de polímeros filmógenos naturales o sintéticos. También es posible la realización de cápsulas de gelatina blanda, en las que el principio activo se mezcla con agua o con medio oleoso, por ejemplo aceite de coco, parafina líquida o aceite de oliva. Solid compositions for oral administration include tablets, tablets, granules and capsules. In any case, the manufacturing method is based on a simple mixture, dry granulation or wet granulation of the active ingredient with excipients. These 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.
Se pueden obtener polvos y granulados para la preparación de suspensiones orales mediante la adición de agua, mezclando el principio activo con agentes dispersantes o humectantes; suspensantes y conservantes. También pueden añadirse otros excipientes, por ejemplo edulcorantes, aromatizantes y colorantes. Como formas líquidas para la administración oral se pueden incluir emulsiones, soluciones, suspensiones, jarabes y elixires que contienen diluyentes inertes comúnmente utilizados, tales como agua destilada, etanol, sorbitol, glicerol, polietilenglicoles (macrogoles) y propilénglicol. Dichas composiciones pueden también contener coadyuvantes como agentes humectantes, suspensantes, edulcorantes, aromatizantes, conservantes y reguladores de pH. 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.
La dosificación y la frecuencia de las dosis variarán en función de la naturaleza y gravedad de la enfermedad a tratar, la edad, la condición general y el peso del paciente, así como también del compuesto particular administrado y la vía de administración, entre otros factores. A título de ejemplo, un rango adecuado de dosificación para un ratón de 25 g la dosis sería de aproximadamente 0,02-0,2 mg/día lo que correspondería a 56-560 mg/día para un humano de un peso corporal de 70 kg, que puede administrarse como dosis única o en varias tomas. Por tanto, teniendo en cuenta los resultados obtenido en los ensayos in vivo, en otra realización la invención se refiere a la composición farmacéutica tal y como se ha definido anteriormente, donde el compuesto de fórmula I se administra a una dosis de 0,1 mg/kg/día a 10 mg/kg/día. En otra realización la invención se refiere a la composición farmacéutica tal y como se ha definido anteriormente, donde el compuesto de fórmula I se administra a una dosis de 0,15 mg/kg/día a 5 mg/kg/día. 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. . By way of example, 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.
En otra realización la invención se refiere a la composición farmacéutica tal y como se ha definido anteriormente, donde el compuesto de fórmula I se administra a una dosis de 0,2 mg/kg/día a 3 mg/kg/día. 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 0.2 mg / kg / day at 3 mg / kg / day.
En otra realización la invención se refiere a la composición farmacéutica tal y como se ha definido anteriormente, donde el medicamento se administra una vez al día, dos veces al día o tres veces al día. En otra realización la invención se refiere a la composición farmacéutica tal y como se ha definido anteriormente, donde el medicamento se administra una vez al día o dos veces al día. En otra realización la invención se refiere a la composición farmacéutica tal y como se ha definido anteriormente, donde el medicamento se administra una vez al día. In another embodiment 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.
Los compuestos de la presente invención pueden contener uno o más nitrógenos básicos y podrían por tanto formar sales con ácidos, tanto orgánicos como inorgánicos. Ejemplos de dichas sales incluyen: sales con ácidos inorgánicos como ácido clorhídrico, ácido bromhídrico, ácido yodhídrico, ácido nítrico, ácido perclórico, ácido sulfúrico o ácido fosfórico; y sales con ácidos orgánicos, como ácido metanosulfónico, ácido trifluorometanosulfónico, ácido etanosulfónico, ácido bencenosulfónico, ácido p-toluenosulfónico, ácido fumárico, ácido oxálico, ácido acético, ácido maleico, ácido ascórbico, ácido cítrico, ácido láctico, ácido tartárico, ácido malónico, ácido glicólico, ácido succínico y ácido propiónico, entre otros. Algunos compuestos de la presente invención podrían contener uno o más protones ácidos y por tanto podrían formar también sales con bases. Ejemplos de dichas sales incluyen: sales con cationes inorgánicos como sodio, potasio, calcio, magnesio, litio, aluminio, zinc, etc.; y sales formadas con aminas farmacéuticamente aceptables como amoníaco, alquilaminas, hidroxialquilaminas, lisina, arginina, /V-metilglucamina, procaína y similares. The compounds of the present invention may contain one or more basic nitrogen and could therefore form salts with acids, both organic and inorganic. Examples of such 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. Examples of such 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.
No hay limitación en el tipo de sal que se puede utilizar, con la condición de que cuando se usen con fines terapéuticos sean farmacéuticamente aceptables. Se entiende por sales farmacéuticamente aceptables aquellas sales que, a criterio médico, son adecuadas para el uso en contacto con los tejidos de seres humanos u otros mamíferos sin provocar una toxicidad indebida, irritación, respuesta alérgica o similar. Las sales farmacéuticamente aceptables son ampliamente conocidas por cualquier experto en la materia. There is no limitation on the type of salt that can be used, provided that when used for therapeutic purposes they are pharmaceutically acceptable. Pharmaceutically acceptable 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.
Las sales de un compuesto de fórmula I pueden obtenerse durante el aislamiento final y purificación de los compuestos de la invención o bien pueden prepararse por tratamiento de un compuesto de fórmula I con una cantidad suficiente del ácido o la base deseados para dar la sal de una forma convencional. Las sales de los compuestos de fórmula I se pueden transformar a su vez en otras sales de compuestos de fórmula I por intercambio de iones mediante una resina de intercambio iónico. 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.
Los compuestos de fórmula I y sus sales pueden diferir en ciertas propiedades físicas, pero son equivalentes a efectos de la invención. Todas las sales de los compuestos de fórmula I quedan incluidas dentro del ámbito de la invención. The compounds of formula I and their salts may differ in certain physical properties, but are equivalent for the purposes of the invention. All salts of the compounds of formula I are included within the scope of the invention.
Los compuestos de la presente invención pueden formar complejos con disolventes en los que se hacen reaccionar o desde los que se hacen precipitar o cristalizar. Estos complejos se conocen como solvatos. Tal como se utiliza aquí, el término solvato se refiere a un complejo de estequiometría variable formado por un soluto (un compuesto de fórmula I o una sal del mismo) y un disolvente. Ejemplos de disolventes incluyen los disolventes farmacéuticamente aceptables como agua, etanol y similares. Un complejo con agua se conoce como hidrato. Los solvatos de los compuestos de la invención (o sus sales), incluyendo hidratos, quedan incluidos dentro del ámbito de la invención. 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. As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (a compound of formula I or a salt thereof) and a solvent. Examples of 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.
Los compuestos de fórmula I pueden existir en diferentes formas físicas, es decir en forma amorfa y formas cristalinas. Asimismo, los compuestos de la presente invención pueden tener la capacidad de cristalizar de más de una forma, una característica que se conoce como polimorfismo. Los polimorfos se pueden diferenciar por varias propiedades físicas bien conocidas por los entendidos en la materia como por ejemplo sus difractogramas de rayos X, puntos de fusión o solubilidad. Todas las formas físicas de los compuestos de fórmula I, incluyendo todas sus formas polimórficas ("polimorfos"), quedan incluidas dentro del ámbito de la presente invención. 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.
Algunos compuestos de la presente invención podrían existir en forma de varios diastereoisómeros y/o varios isómeros ópticos. Los diastereoisómeros pueden separarse mediante técnicas convencionales como la cromatografía o la cristalización fraccionada. Los isómeros ópticos pueden ser resueltos mediante el uso de técnicas convencionales de resolución óptica, para dar los isómeros ópticamente puros. Esta resolución puede realizarse sobre los intermedios de síntesis que sean quirales o bien sobre los productos de fórmula I. Los isómeros ópticamente puros también pueden ser obtenidos individualmente empleando síntesis enantioespecíficas. La presente invención cubre tanto los isómeros individuales como sus mezclas (por ejemplo mezclas racémicas o mezclas de diastereoisómeros), tanto si se obtienen por síntesis como mezclándolos físicamente. 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.
Los compuestos de fórmula I pueden obtenerse siguiendo los procedimientos descritos a continuación. Como será evidente para un experto en la materia, el método preciso utilizado para la preparación de un compuesto dado puede variar en función de su estructura química. Asimismo, en alguno de los procedimientos que se detallan a continuación puede ser necesario o conveniente proteger los grupos reactivos o lábiles mediante grupos protectores convencionales. Tanto la naturaleza de dichos grupos protectores como los procedimientos para su introducción y eliminación son bien conocidos y forman parte del estado de la técnica (véase por ejemplo Greene T.W. y Wuts P.G.M, "Protective Groups in Organic Synthesis", John Wiley & Sons, 4a edición, 2007). Siempre que esté presente algún grupo protector, será necesaria una posterior etapa de desprotección, que se realiza en las condiciones habituales en síntesis orgánica, como las descritas en la referencia mencionada más arriba. A lo largo de la descripción y las reivindicaciones la palabra "comprende" y sus variantes no pretenden excluir otras características técnicas, aditivos, componentes o pasos. Para los expertos en la materia, otros objetos, ventajas y características de la invención se desprenderán en parte de la descripción y en parte de la práctica de la invención. Los siguientes ejemplos y figuras se proporcionan a modo de ilustración, y no se pretende que sean limitativos de la presente invención. 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. Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. The following examples and figures are provided by way of illustration, and are not intended to be limiting of the present invention.
BREVE DESCRIPCIÓN DE LAS FIGURAS BRIEF DESCRIPTION OF THE FIGURES
Figura 1 : Representa la comparativa de los efectos del compuesto E con DMSO al 5% como vehículo y del compuesto 2 con aceite de oliva como vehículo al tratar ratones por Helicobacter pylori SS1 (HpSS1 ) a una dosis 1 de 0,02 mg/día y a una dosis 2: 0,2 mg/día. 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.
EJEMPLOS EXAMPLES
A continuación se ilustrará la invención mediante unos ensayos realizados por los inventores, que pone de manifiesto la efectividad de los compuestos de fórmula I. The invention will now be illustrated by tests carried out by the inventors, which demonstrates the effectiveness of the compounds of formula I.
Ejemplo 1 : Síntesis de los compuestos de fórmula 1 , 2 y 3 Example 1: Synthesis of the compounds of formula 1, 2 and 3
Síntesis del compuesto 1 Synthesis of compound 1
Figure imgf000022_0001
Figure imgf000022_0001
A B 1 AB 1
Figure imgf000023_0001
Figure imgf000023_0001
0,05 moles de cloruro de sulfonilo C se añaden gota a gota a una disolución acuosa de amoniaco en continua agitación (45ml_). La mezcla resultante se calienta a 100°C y se deja enfriar hasta que alcanza la temperatura ambiente. El producto (A) se recristaliza en agua (46% rendimiento). 0.05 moles of sulfonyl chloride C are added dropwise to an aqueous solution of ammonia under continuous stirring (45ml_). The resulting mixture is heated to 100 ° C and allowed to cool until it reaches room temperature. The product (A) is recrystallized from water (46% yield).
12 mmoles de B y 15 mmoles de NaHC03 se añaden a una disolución de A (4 mmoles) en acetonitrilo (25 mL) en continua agitación. La mezcla se mantiene a temperatura ambiente y con agitación hasta que, por cromatografía de capa fina (TLC), se comprueba la desaparición completa de A (24 h). A continuación se elimina el disolvente a presión reducida y el residuo se trata con agua (500mL), se filtra, se lava con agua y se seca a vacío. El compuesto I se recristaliza en metanol (57% rendimiento). 12 mmol of B and 15 mmol of NaHC03 are added to a solution of A (4 mmol) in acetonitrile (25 mL) with continuous stirring. The mixture is kept at room temperature and with stirring until, by thin layer chromatography (TLC), the complete disappearance of A (24 h) is checked. The solvent is then removed under reduced pressure and the residue is treated with water (500mL), filtered, washed with water and dried under vacuum. Compound I is recrystallized from methanol (57% yield).
1 :1H-NMR (400 MHz, DMSO-d6): δ: 3,74 (s, 3H), 4,55 (s, 2H), 6,92 (m, 2H), 7,42 (m, 2H), 7,56 (d, J = 9,6 Hz, 1 H), 7,83 (bs, 2H), 7,90 (d, J = 10 Hz, 1 H). 1: 1 H-NMR (400 MHz, DMSO-d6): δ: 3.74 (s, 3H), 4.55 (s, 2H), 6.92 (m, 2H), 7.42 (m, 2H), 7.56 (d, J = 9.6 Hz, 1 H), 7.83 (bs, 2H), 7.90 (d, J = 10 Hz, 1 H).
Síntesis del compuesto 2 Synthesis of compound 2
Figure imgf000023_0002
Figure imgf000023_0002
D 2 Preparación de Fe activado: 10 mL de ácido clorhídrico concentrado se añaden lentamente y con agitación a 50 gramos de Fe (40 mesh), con cuidado de mantener la mezcla en baño de hielo para evitar que el calor generado sea excesivo. Una vez terminada la adición, dejar agitar a temperatura ambiente con continua agitación, para evitar que el Fe se apelmace. Dejar secar completamente antes de ser usado. D 2 Preparation of activated Fe: 10 mL of concentrated hydrochloric acid are added slowly and with stirring to 50 grams of Fe (40 mesh), being careful to keep the mixture in an ice bath to avoid excessive heat generated. Once the addition is finished, allow stirring at room temperature with continuous stirring, to prevent Fe from caking. Let dry completely before being used.
5 gramos de D se disuelven en una mezcla de metanol y diclorometano, con agitación vigorosa. Antes de añadir el hierro activado, la disolución se calienta hasta casi ebullición. A continuación el hierro activado es añadido y se mantiene la agitación y el reflujo durante 30 minutos. Seguidamente, 1 mL de agua se añade lentamente a la mezcla de reacción. Pequeños volúmenes de agua son añadidos poco a poco y a lo largo de un período de 6 horas, de tal forma que al final, 20 mL de agua hayan sido añadidos. Por último, se mantiene el reflujo durante 1 hora más. Para aislar 2, la mezcla de reacción se filtra y el sólido obtenido se extrae 3 veces con tolueno caliente. Los extractos se añaden al filtrado original y se elimina el disolvente a presión reducida. El sólido obtenido se recristaliza en tolueno para obtener 2 (46% rendimiento). 5 grams of D are dissolved in a mixture of methanol and dichloromethane, with vigorous stirring. Before adding the activated iron, the solution is heated until almost boiling. The activated iron is then added and stirring and refluxing is maintained for 30 minutes. Next, 1 mL of water is slowly added to the reaction mixture. Small volumes of water are added little by little and over a period of 6 hours, so that in the end, 20 mL of water has been added. Finally, reflux is maintained for another 1 hour. To isolate 2, the reaction mixture is filtered and the solid obtained is extracted 3 times with hot toluene. The extracts are added to the original filtrate and the solvent is removed under reduced pressure. The solid obtained is recrystallized from toluene to obtain 2 (46% yield).
2: 1H-NMR (400 MHz, CDCI3): δ: 3,78 (s, 3H), 4,18 (s, 2H), 4,63 (bs, 2H), 6,23 (d, J = 9,6 Hz, 1 H), 6,77 (m, 2H), 7,1 1 (m,3H). 2: 1 H-NMR (400 MHz, CDCI3): δ: 3.78 (s, 3H), 4.18 (s, 2H), 4.63 (bs, 2H), 6.23 (d, J = 9.6 Hz, 1 H), 6.77 (m, 2H), 7.1 1 (m, 3H).
Síntesis del compuesto 3 Synthesis of compound 3
Figure imgf000024_0001
Figure imgf000024_0001
A 3 10 mmoles de 2-mercaptoetanol se añaden a una mezcla en agitación de KOH (10 mmoles) en 30ml_ de etanol y A (4,5 mmoles) en 5 ml_ de DMF. Esta mezcla se calienta a 65°C durante 10 horas y a continuación se enfría hasta temperatura ambiente. La mezcla se filtra y el sólido (3) se recristaliza en etanol (89% rendimiento). To 3 10 mmol of 2-mercaptoethanol are added to a stirring mixture of KOH (10 mmol) in 30 ml of ethanol and A (4.5 mmol) in 5 ml of DMF. This mixture is heated at 65 ° C for 10 hours and then cooled to room temperature. The mixture is filtered and the solid (3) is recrystallized from ethanol (89% yield).
3: 1H-NMR (400 MHz, DMSO-d6): δ: 3,39 (t, J = 8 Hz, 2H), 3,76 (q, J = 7,2 Hz, 2H), 7,51 (d, J = 10 Hz, 1 H), 7,82 (bs, 2H), 7,90 (d, J = 10 Hz, 1 H). 3: 1 H-NMR (400 MHz, DMSO-d6): δ: 3.39 (t, J = 8 Hz, 2H), 3.76 (q, J = 7.2 Hz, 2H), 7.51 (d, J = 10 Hz, 1 H), 7.82 (bs, 2H), 7.90 (d, J = 10 Hz, 1 H).
EJEMPLO 2: ENSAYOS BIOLOGICOS Reactivos v compuestos químicos. EXAMPLE 2: BIOLOGICAL TESTS Reagents and chemical compounds.
Todos los reactivos y productos químicos que se obtuvieron de suministradores comerciales se usaron sin purificación adicional. Los espectros de 1 H RMN y 19F RMN de los compuestos sintetizados se adquirieron a temperatura ambiente a 400 y a 376 MHz, respectivamente, usando una sonda de 5 mm. Los desplazamientos químicos (δ) se indicaron en partes por millón respecto al tetrametilsilano con la resonancia del solvente como estándar interno.  All reagents and chemicals that were obtained from commercial suppliers were used without further purification. The 1 H NMR and 19 F NMR spectra of the synthesized compounds were acquired at room temperature at 400 and 376 MHz, respectively, using a 5 mm probe. Chemical shifts (δ) were indicated in parts per million with respect to tetramethylsilane with solvent resonance as internal standard.
Las constantes de acoplamiento (J) se indicaron en hertzios. Los patrones de acoplamiento se indicaron como s (singlete), d (doblete), t(triplete), q (cuartete) dd (doblete de dobletes),m (multiplete), bs (singlete ancho). La pureza de los compuestos se determinó por cromatografía HPLC que era >95%, usando usando un equipo Waters equipado con una bomba 600-E, un detector 2996 PDA , y un autocargador 2707. La columna utilizada fue una de fase reversa C18 (VYDAC 238TP C18 5 Mm, 4,6 mm 250 mm) y se empleó un gradiente lineal de tampón B (100% en 40 min) partiendo de 100% tampón A (tampón A: 0,1 % TFA en H20, tampón B: 0,085% TFA en CH3CN/H20, 95:5 v/v) con un flujo de 1 mL/min. La flavodoxina de H. pylori se expresó en E. coli y se purificó como se indica en Cremades, N.; Bueno, M.; Toja, M.; Sancho, J. Towards a new therapeutic target: Helicobacter pylori flavodoxin. Biophys. Chem. 2005, 1 15, 267-276. La concentración de proteína se determinó por absorbancia del cofactor FMN a 452 nm usando un coeficiente de extinción de 10 650 M"1 cm"1. Coupling constants (J) 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). 238TP C18 5 mm, 4.6 mm 250 mm) and a linear gradient of buffer B (100% in 40 min) was used starting from 100% buffer A (buffer A: 0.1% TFA in H20, buffer B: 0.085 % TFA in CH3CN / H20, 95: 5 v / v) with a flow of 1 mL / min. H. pylori flavodoxin it was expressed in E. coli and purified as indicated in Cremades, N .; Well, M .; Toja, M .; Sancho, J. Towards a new therapeutic target: Helicobacter pylori flavodoxin. Biophys Chem. 2005, 1 15, 267-276. The protein concentration was determined by absorbance of the FMN cofactor at 452 nm using an extinction coefficient of 10 650 M "1 cm " 1 .
Ensayo preliminar de unión a la flavodoxina de Helicobacter pylori (Hp). Preliminary test for binding to the flavodoxin of Helicobacter pylori (Hp).
Para alguno de los candidatos a inhibidor se llevó a cabo un ensayo preliminar de unión a flavodoxina para dscartareliminar compuestos que no se unieran a la proteína diana. Este cribado se basó en comparar la temperatura de desnaturalización media (Tm) de flavodoxina con la de la proteína en presencia de compuesto. Para ello la fluorescencia intrínseca de la flavodoxina en el visible se monitorizó con un espectrofluorímetro FluoDia T70 (excitación a 445 nm y emisión a 525 nm) como función de la temperatura. El cofactor de flavodoxina, FMN, fuertemente amortiguado por la apoproteína, es liberado según la flavodoxina se despliega, dando lugar a un gran aumento en la emisión de fluorescencia (ver Cremades, N.; Velazquez-Campoy, A.; Freiré, E.; Sancho, J. The flavodoxin from Helicobacter pylori: structural determinants of thermostability and FMN cofactor binding. Biochemistry 2008, 47, 627-639). Las curvas de desnaturalización térmica se analilzaron usando software propio y las Tm aparentes se calcularon como en Cremades, N.; Velazquez-Campoy, A.; Martinez-Julvez, M.; Neira, J. L.; Perez-Dorado, I.; Hermoso, J.; Jiménez, P.; Lanas, A.; Hoffman, P. S.; Sancho, J. Discovery of specific flavodoxin inhibitors as potential therapeutic agents against Helicobacter pylori infection. ACS Chem. Biol. 2009, 4, 928-938. Sólo los compuestos que elevaron la Tm de la proteína en, al menos, 2 desviaciones estándar de la Tm media de controles de poteína sin compuesto fueron ensayadas en adelante. Afinidad de los complejos entre flavodoxina de Hp y candidatos a inhibidores. Las constantes de disociación de los complejos se determinaron a 25 °C por calorimetría de titulación isoterma (ITC) utilizando un calorímetro VP-ITC (MicroCal, GE Healthcare). Disoluciones degaseadas de flavodoxina 20 μΜ se titularon con coluciones concentradas de inhibidores (alrededor de 500 μΜ) disueltos en el mismo tamoón (50 mM EPPS, pH 9,0, y 5% DMSO), y los calores asociados con cada inyección se ajustaron asuminedo una estequiometría de 1 :1 para el complejo formado. For one of the inhibitor candidates, 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. The cofactor of flavodoxin, FMN, strongly buffered by apoprotein, is released as flavodoxin is deployed, resulting in a large increase in fluorescence emission (see Cremades, N .; Velazquez-Campoy, A .; Freiré, E. ; Sancho, J. The flavodoxin from Helicobacter pylori: structural determinants of thermostability and FMN cofactor binding. Biochemistry 2008, 47, 627-639). Thermal denaturation curves were analyzed using proprietary software and apparent Tm were calculated as in Cremades, N .; Velazquez-Campoy, A .; Martinez-Julvez, M .; Neira, JL; Perez-Dorado, I .; Beautiful, J .; Jiménez, P .; The NASA.; Hoffman, PS; Sancho, J. Discovery of specific flavodoxin inhibitors as potential therapeutic agents against Helicobacter pylori infection. ACS Chem. Biol. 2009, 4, 928-938. Only compounds that raised the Tm of the protein by at least 2 standard deviations from the mean Tm of potent controls without compound were tested hereinafter. Complexity affinity between Hp flavodoxin and inhibitor candidates. 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 μΜ were titrated with concentrated inhibitor coloutions (around 500 μΜ) 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.
Concentraciones mínimas inhibitoria (MICs). Las cepas Hp strains 26695 y Hp1061 se cultivaron como está descrito en St Maurice, M.; Cremades, N.; Croxen, M. A.; Sisson, G.; Sancho, J.; Hoffman, P. S. Flavodoxin:quinone reducíase (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. Para las determinaciones por microdilución se utilizaron placas de 96 pocilios de fondo redondo. El cultivo bacteriano y la dilución subsiguiente a OD660nm de 0,01 antes de mezclar con concentraciones apropiadas de compuesto a ensayar se llevaron a cabo como se ha descrito en Cremades, N.; Velazquez-Campoy, A.; Martinez-Julvez, M.; Neira, J. L.; Perez-Dorado, I.; Hermoso, J.; Jiménez, P.; Lanas, A.; Hoffman, P. S.; Sancho, J. Discovery of specific flavodoxin inhibitors as potential therapeutic agents against Helicobacter pylori infection. ACS Chem. Biol. 2009, 4, 928-938. El DMSO presente en el ensayo (<3% v/v) no fue nocivo para las células. Las placas se agitaron en condiciones microaeróbicas durante 28 h. La menor concentración de compuesto que inhibió completamente el crecicmiento de Hp se registró como la MIC del compuesto. Minimum inhibitory concentrations (MICs). 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. Bacterial culture and subsequent dilution to OD660 nm of 0.01 before mixing with appropriate concentrations of compound to be tested were carried out as described in Cremades, N .; Velazquez-Campoy, A .; Martinez-Julvez, M .; Neira, J. L .; Perez-Dorado, I .; Beautiful, J .; Jiménez, P .; The NASA.; Hoffman, P. S .; Sancho, J. Discovery of specific flavodoxin inhibitors as potential therapeutic agents against Helicobacter pylori infection. ACS Chem. Biol. 2009, 4, 928-938. The DMSO present in the assay (<3% v / v) was not harmful to the cells. The plates were shaken under microaerobic conditions for 28 h. The lowest concentration of compound that completely inhibited the growth of Hp was recorded as the MIC of the compound.
Ensayos bactericidas. La actividad bactericida de los compuestos para células de Hp (cepas 26695 y Hp1061 ) cultivadas en medios basados en Brucella suplementados con 7,5% de suero fetal bovino se determinó como se ha descrito16. Las bacterias dse diluyeron a OD660nm = 0,1 en 3 mL de medio suplementado con 2% suero de bovino recién nacido, y el volúmen apropiado de compuesto a ensayar se añadió a una concentración final de 2 x MIC. Alícuotas del medio se recogieron a distintos tiempos, se centrifugaron, se resuspendieron en medio y se platearon en Brucella agar suplementado con 7,5% de suero para la determinación de las cuentas viables. La actividad bactericida se calculó comparando con el control de DMSO. Bactericidal assays The bactericidal activity of the compounds for Hp cells (strains 26695 and Hp1061) grown in Brucella-based media supplemented with 7.5% fetal bovine serum was determined as described16. The bacteria were diluted to OD660nm = 0.1 in 3 mL of medium supplemented with 2% newborn bovine serum, and the appropriate volume of compound to be tested was added to a final concentration of 2 x MIC. Aliquots of the medium were collected at different times, they centrifuged, resuspended in medium and plated in Brucella agar supplemented with 7.5% serum for determination of viable counts. Bactericidal activity was calculated compared to the DMSO control.
Concentraciones citotóxicas mínimas (MCCsV La toxicidad de los compuestos hacia las células HeLa se determinó por el método XTT usando el Kit II de proliferación celular (Roche), que detecta la actividad de la deshidrogenasa por reducción de una sal de tetrazolio. Todos los experimentos se realizaron dos veces por triplicado. Las células HeLa fueron cultivadas en medio completo (500 mL de medio de Eagle: P04-03591 de Ibian Technologies más 50 mL de suero fetal bovino más 5,5 mL de antibiótico que contiene 550 000 unidades de penicilina y 550 000 μg de estreptomicina) con rojo fenol utilizando placas de 96 pocilios (con 30 000 células en 100 μί en cada pocilio) a las que se añadieron volúmenes de 1 μί de compuesto disuelto en DMSO a concentraciones finales de 0,1 , 0,25, 0,5, 1 , 10, 25, 50, 75 y 100 μΜ. A los pocilios control se agregó 1 μί de DMSO. Las placas se incubaron a 37 ° C durante 24 h y fueron centrifugadas. El medio fue reemplazado por 100 μί. de medio fresco sin rojo de fenol, y 50 μί de mezcla XTT-PMS (50 μί de XTT + 1 μί de PMS) se agregaron a cada pocilio. Las placas se incubaron durante 4 h a 37 °C, y se registró la absorbancia a 450 y 500 nm enun lector de ELISA. La viabilidad celular se calculó como se ha explicado (ver López, L. C; Dos-Reis, S.; Espargaro, A.; Carrodeguas, J. A.; Maddelein, M. L.; Ventura, S.; Sancho, J. Discovery of novel inhibitors of amyloid beta-peptide 1 -42 aggregation. J. Med. Chem. 2012, 55, 9521 -9530). Minimum cytotoxic concentrations (MCCsV) The toxicity of the compounds to HeLa cells was determined by the XTT method using Cell Proliferation Kit II (Roche), which detects dehydrogenase activity by reducing a tetrazolium salt. performed twice in triplicate 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 μg streptomycin) with phenol red using 96-well plates (with 30,000 cells in 100 μί in each well) to which volumes of 1 μί of compound dissolved in DMSO were added at final concentrations of 0.1, 0, 25, 0.5, 1, 10, 25, 50, 75 and 100 μΜ To the control wells was added 1 μί of DMSO The plates were incubated at 37 ° C for 24 h and centrifuged.The medium was replaced by 100 μί. of m Fresh edio without phenol red, and 50 μί of XTT-PMS mixture (50 μί of XTT + 1 μί of PMS) were added to each well. The plates were incubated for 4 h at 37 ° C, and the absorbance at 450 and 500 nm was recorded in an ELISA reader. Cell viability was calculated as explained (see López, L. C; Dos-Reis, S .; Espargaro, A .; Carrodeguas, JA; Maddelein, ML; Ventura, S .; Sancho, J. Discovery of novel inhibitors of amyloid beta-peptide 1 -42 aggregation. J. Med. Chem. 2012, 55, 9521-9530).
A continuación en la tabla 1 se muestran los resultados de los ensayos anteriores para los compuestos de fórmula 1 , 2 y 3 comparados con los resultados obtenidos para el compuesto E. 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.
Tabla 1 : Compuesto Kd MIC (μΜ) MCC (μΜ) IT Table 1 : Compound K d MIC (μΜ) MCC (μΜ) IT
Figure imgf000029_0001
Figure imgf000029_0001
Comparando los resultados de E frente a los resultados de 1 , 2 y 3, se puede observar que el reemplazamiento del grupo nitro por un grupo sulfonamida (1) mejoró la afinidad (menor Kd), bajó la toxicidad (mayor MCC) y mejoró ligeramente la inhibición (MIC), dando lugar a un mejor índice Terapéutico (IT) de 0,6. El reemplazamiento del grupo nitro por un grupo amino (2) disminuyó la afinidad (mayor Kd), no modificó la inhibición y redujo marcadamente la toxicidad, lo que dio lugar a un IT de 12. Además se analizó una versión corta de 3 en la que el grupo nitro fue reemplazado por un grupo sulfonamida y el grupo p-metoxifenilo fue reemplazado por un grupo hidroximetilo. Este compuesto puede unir aún flavodoxina y muestra una baja toxicidad. Comparing the results of E against the results of 1, 2 and 3, it can be seen that replacing the nitro group with a sulfonamide group (1) improved affinity (lower Kd), lowered toxicity (higher MCC) and slightly improved inhibition (MIC), resulting in a better Therapeutic Index (IT) of 0.6. The replacement of the nitro group with an amino group (2) decreased affinity (higher Kd), did not modify the inhibition and markedly reduced toxicity, which resulted in an IT of 12. In addition, a short version of 3 was analyzed in the that the nitro group was replaced by a sulfonamide group and the p-methoxyphenyl group was replaced by a hydroxymethyl group. This compound can still bind flavodoxin and shows low toxicity.
ENSAYOS IN VIVO DEL COMPUESTO 2 Resultados de la colonización de ratones (Figura 1 ): IN VIVO TESTS OF COMPOUND 2 Results of the colonization of mice (Figure 1):
dosis 1 : 0,02 mg/Día dose 1: 0.02 mg / day
dosis 2: 0,2 mg/Día dose 2: 0.2 mg / day
Los efectos del compuesto E se comparan con el grupo de ratones infectados con Hp y tratados con el vehículo: DMSO 5%.  The effects of compound E are compared with the group of mice infected with Hp and treated with the vehicle: 5% DMSO.
Los efectos del compuesto 2 se comparan al grupo de ratones infectados con Hp y tratados con el vehículo: aceite de oliva.  The effects of compound 2 are compared to the group of mice infected with Hp and treated with the vehicle: olive oil.
En comparación con ratones infectados por HpSS1 , la presencia de DMSO 5% parece inhibir ligeramente la colonización gástrica sin alcanzar significación estadística, mientras que la presencia de aceite de oliva no tiene ningún efecto.  Compared to mice infected with HpSS1, the presence of 5% DMSO seems to slightly inhibit gastric colonization without reaching statistical significance, while the presence of olive oil has no effect.
El compuesto E a la dosis 1 inhibe ligeramente la colonización gástrica por Hp (p = 0,044). En este grupo 2/7 ratones no fueron colonizados.  Compound E at dose 1 slightly inhibits gastric colonization by Hp (p = 0.044). In this group 2/7 mice were not colonized.
El compuesto 2 a la dosis 2 condujo a niveles medios de colonización 50 veces menores que los mostrados por los ratones infectados que recibieron simplemente el aceite de oliva (p = 0,0012). En ese grupo, 2/7 ratones no fueron colonizados. Compound 2 at dose 2 led to average colonization levels 50 times lower than those shown by infected mice that simply received olive oil (p = 0.0012). In that group, 2/7 mice were not colonized.

Claims

REIVINDICACIONES
1 . Un compuesto de fórmula I: 1 . A compound of formula I:
Figure imgf000031_0001
Figure imgf000031_0001
I o una sal farmacéuticamente aceptable del mismo, donde: I or a pharmaceutically acceptable salt thereof, where:
X representa oxigeno (O) o azufre (S); X represents oxygen (O) or sulfur (S);
Y representa azufre (S) o NR', donde R' es hidrógeno o un grupo alquilo (Ci-C6) Y represents sulfur (S) or NR', where R' is hydrogen or an alkyl group (Ci-C 6 )
Ri representa un grupo nitroso (-NO), un grupo amina (-NR3R'3) o
Figure imgf000031_0002
Ri represents a nitrous group (-NO), an amine group (-NR 3 R' 3 ) or
Figure imgf000031_0002
R2 representa grupo -OH o arilo, donde el grupo arilo está opcionalmente sustituido por uno o más grupos -OR4, donde R4 representa un hidrógeno o un grupo alquilo (Ci-Ce); R 2 represents -OH or aryl group, where the aryl group is optionally substituted by one or more -OR 4 groups, where R 4 represents a hydrogen or an alkyl group (Ci-Ce);
R3 y R'3, son iguales o diferentes y representa H, un grupo -OR" o un grupo alquilo (C1-C6); donde R" represente un H o un grupo alquilo (d- c6) y R3 and R'3 are the same or different and represent H, an -OR" group or an alkyl group (C1-C6); where R" represents an H or an alkyl group (d-c 6 ) and
n representa de 1 a 3. n represents 1 to 3.
2. El compuesto según la reivindicación 1 , donde X es O. 2. The compound according to claim 1, where X is O.
3. El compuesto según cualquiera de las reivindicaciones 1 ó 2, donde Y es S, NH o NCH3. 3. The compound according to any of claims 1 or 2, where Y is S, NH or NCH 3 .
4. El compuesto según la reivindicación 3, donde Y es S. 4. The compound according to claim 3, where Y is S.
5. El compuesto según cualquiera de las reivindicaciones 1 a 4, donde Ri representa un grupo -NR3R'3 o NO; donde R3 y R'3 están descritos en la reivindicación 1 . 5. The compound according to any of claims 1 to 4, where Ri represents a -NR 3 R' 3 or NO group; where R 3 and R' 3 are described in claim 1.
6. El compuesto según la reivindicación 5, donde Ri representa un grupo -NR3R'3. 6. The compound according to claim 5, where Ri represents a -NR 3 R' 3 group.
7. El compuesto según cualquiera de las reivindicaciones 1 a 6, donde R3 y R'3 son iguales o diferentes y representan H, un grupo alquilo (Ci-C3) o un grupo OR", donde R" es un hidrógeno o un grupo alquilo (Ci-C3). 7. The compound according to any of claims 1 to 6, where R 3 and R' 3 are the same or different and represent H, an alkyl group (Ci-C 3 ) or an OR group", where R" is a hydrogen or an alkyl group (Ci-C 3 ).
8. El compuesto según cualquiera de las reivindicaciones 1 a 7, donde Ri se selecciona entre NH2, NHOH, N(CH3)2, NHOCH3, NCH3OH o NCH3OCH3. 8. The compound according to any of claims 1 to 7, where Ri is selected from NH 2 , NHOH, N(CH 3 ) 2 , NHOCH 3 , NCH 3 OH or NCH 3 OCH 3 .
9. El compuesto según cualquiera de las reivindicaciones 1 a 4, donde Ri representa un grupo -SO2NR3R'3, donde R3 y R'3 están descritos en la reivindicación 1 . 9. The compound according to any of claims 1 to 4, where Ri represents a group -SO 2 NR 3 R' 3 , where R 3 and R' 3 are described in claim 1.
10. El compuesto según la reivindicación 9, donde R3 y R'3 son iguales o diferentes y representan H o un grupo alquilo (Ci-C3). 10. The compound according to claim 9, wherein R 3 and R' 3 are the same or different and represent H or an alkyl group (Ci-C 3 ).
1 1 . El compuesto según cualquiera de las reivindicaciones 1 a 10, donde R2 representa grupo -OH. eleven . The compound according to any of claims 1 to 10, where R 2 represents -OH group.
12. El compuesto según cualquiera de las reivindicaciones 1 a 10, donde R2 representa grupo fenilo, donde el fenilo está opcionalmente sustituido por uno o más grupos OR4, donde R representa un hidrógeno o un grupo alquilo (C1 -C6). 12. The compound according to any of claims 1 to 10, where R 2 represents phenyl group, where phenyl is optionally substituted by one or more OR 4 groups, where R represents a hydrogen or a (C1 -C6) alkyl group.
13. El compuesto según cualquiera de las reivindicaciones 1 a 10, donde R2 representa grupo fenilo está opcionalmente sustituido por uno o dos grupos OR4, donde R4 representa un hidrógeno o un grupo alquilo (d- C6). 13. The compound according to any of claims 1 to 10, where R2 represents phenyl group is optionally substituted by one or two OR 4 groups, where R 4 represents a hydrogen or a (d-C 6 ) alkyl group.
14. El compuesto según cualquiera de las reivindicaciones 1 a 10, donde R2 representa grupo fenilo está opcionalmente sustituido por uno grupo OR , donde R representa un hidrógeno o un grupo alquilo (C1-C6). 14. The compound according to any of claims 1 to 10, where R2 represents a phenyl group and is optionally substituted by an OR group, where R represents a hydrogen or a (C1-C6) alkyl group.
15. El compuesto según cualquiera de las reivindicaciones 12 a 14, donde R4 es un metilo. 15. The compound according to any of claims 12 to 14, where R 4 is a methyl.
16. El compuesto según cualquiera de las reivindicaciones 1 a 15, donde n representa 1 ó 2. 16. The compound according to any of claims 1 to 15, where n represents 1 or 2.
17. El compuesto según la reivindicación 16, donde n representa 1 . 17. The compound according to claim 16, where n represents 1.
18. El compuesto según la reivindicación 1 , seleccionado de un compuesto de fórmula 1 18. The compound according to claim 1, selected from a compound of formula 1
Figure imgf000033_0001
Figure imgf000033_0001
19. El compuesto según la reivindicación 1 , seleccionado de un compuesto de fórmula 19. The compound according to claim 1, selected from a compound of formula
Figure imgf000034_0001
Figure imgf000034_0001
. El compuesto según la reivindicación 1 , seleccionado de un compuesto de fórmula 3: . The compound according to claim 1, selected from a compound of formula 3:
Figure imgf000034_0002
Figure imgf000034_0002
21 . Uso de un compuesto de fórmula I, descrito en cualquiera twenty-one . Use of a compound of formula I, described in any
reivindicaciones 1 a 20, para la elaboración de un medicamento. claims 1 to 20, for the preparation of a medicine.
. El uso según la reivindicación 21 , donde el medicamento antibiótico. . The use according to claim 21, wherein the antibiotic medicine.
23. El uso según cualquiera de las reivindicaciones 21 ó 22, donde el medicamento es un antibiótico contra bacterias Gram positivas, preferiblemente contra Helicobacter. 23. The use according to any of claims 21 or 22, wherein the medicament is an antibiotic against Gram positive bacteria, preferably against Helicobacter.
24. El uso según cualquiera de las reivindicaciones 21 a 23, donde el medicamento es un antibiótico contra Helicobacter Pylori. 24. The use according to any of claims 21 to 23, wherein the medicine is an antibiotic against Helicobacter Pylori.
25. Una composición farmacéutica que comprende un compuesto de fórmula I descrito en cualquiera de las reivindicaciones 1 a 20 y uno o más excipientes farmacéuticamente aceptables. 25. A pharmaceutical composition comprising a compound of formula I described in any of claims 1 to 20 and one or more pharmaceutically acceptable excipients.
26. La composición farmacéutica según la reivindicación 25, donde el disolvente es un disolvente no acuoso. 26. The pharmaceutical composition according to claim 25, wherein the solvent is a non-aqueous solvent.
27. La composición farmacéutica según la reivindicación 26, donde el disolvente es un aceite. 27. The pharmaceutical composition according to claim 26, wherein the solvent is an oil.
28. La composición farmacéutica según la reivindicación 27, donde el disolvente es aceite de oliva. 28. The pharmaceutical composition according to claim 27, wherein the solvent is olive oil.
29. La composición farmacéutica según cualquiera de las reivindicaciones 25 a 28, donde la composición está en forma adecuada para su administración oral, tópica e intravenosa. 29. The pharmaceutical composition according to any of claims 25 to 28, wherein the composition is in a form suitable for oral, topical and intravenous administration.
30. La composición farmacéutica según la reivindicación 29, donde la composición está en forma adecuada para su administración oral. 30. The pharmaceutical composition according to claim 29, wherein the composition is in a form suitable for oral administration.
31 . La composición farmacéutica según cualquiera de las reivindicaciones 25 a 30, donde el compuesto de fórmula I se encuentra para su administración a una dosis de 0, 1 mg/kg/día a 10 mg/kg/día. 31. The pharmaceutical composition according to any of claims 25 to 30, wherein the compound of formula I is for administration at a dose of 0.1 mg/kg/day to 10 mg/kg/day.
32. La composición farmacéutica según la reivindicación 31 , donde el compuesto de fórmula I se encuentra para su administración a una dosis de 0,15 mg/kg/día a 5 mg/kg/día. 32. The pharmaceutical composition according to claim 31, wherein the compound of formula I is for administration at a dose of 0.15 mg/kg/day to 5 mg/kg/day.
33. La composición farmacéutica según la reivindicación 32, donde el compuesto de fórmula I se encuentra para su administración a una dosis de 0,2 mg/kg/día a 3 mg/kg/día. 33. The pharmaceutical composition according to claim 32, wherein the compound of formula I is for administration at a dose of 0.2 mg/kg/day to 3 mg/kg/day.
34. La composición farmacéutica según cualquiera de las reivindicaciones 31 a 33, donde el medicamento se encuentra a una dosis adecuada para su administración una vez al día, dos veces al día o tres veces al día. 34. The pharmaceutical composition according to any of claims 31 to 33, wherein the medication is at a dose suitable for administration once a day, twice a day or three times a day.
35. La composición farmacéutica según la reivindicación 34, donde el medicamento se encuentra a una dosis adecuada para su administración una o dos veces al día. 35. The pharmaceutical composition according to claim 34, wherein the medication is at a dose suitable for administration once or twice a day.
36. La composición farmacéutica según la reivindicación 35, donde el medicamento se encuentra a una dosis adecuada para su administración una vez al día. 36. The pharmaceutical composition according to claim 35, wherein the medication is at a dose suitable for administration once a day.
37. La composición farmacéutica según cualquiera de las reivindicaciones 25 a 36, donde dicha composición es un antibiótico. 37. The pharmaceutical composition according to any of claims 25 to 36, wherein said composition is an antibiotic.
38. La composición farmacética según cualquiera de las reivindicaciones 25 a 37, donde además comprende otro principio activo. 38. The pharmaceutical composition according to any of claims 25 to 37, where it also comprises another active ingredient.
39. Uso de un compuesto de fórmula I descrito en cualquiera de las reivindicaciones 1 a 20 o de la composición farmacéutica definida en cualquiera de las reivindicaciones 25 a 38, para la elaboración de un medicamento para su uso en el tratamiento y/o prevención de una enfermedad causada por bacterias. 39. Use of a compound of formula I described in any of claims 1 to 20 or of the pharmaceutical composition defined in any of claims 25 to 38, for the preparation of a medicine for use in the treatment and/or prevention of a disease caused by bacteria.
40. El uso según la reivindicación 39, donde las bacterias son bacterias Gram positivas. 40. The use according to claim 39, wherein the bacteria are Gram positive bacteria.
41 . El uso según cualquiera de las reivindicaciones 39 o 40, donde las bacterias son del género Helicobacter. 41. The use according to any of claims 39 or 40, where the bacteria are of the Helicobacter genus.
42. El uso según la reivindicación 41 , las bacterias son de la especie Helicobacter pylori. 42. The use according to claim 41, the bacteria are of the Helicobacter pylori species.
43. El uso según cualquiera de las reivindicaciones 39 a 42, donde la enfermedad se selecciona de infección en el sistema digestivo (boca, faringe, esófago, estómago, intestino delgado (incluido el duodeno) e intestino grueso), en particular infección gástrica, gastritis, gastritis crónica, úlcera peptídica, gástrica y/o duodenal, linfoma o cáncer gástrico 43. The use according to any of claims 39 to 42, wherein the disease is selected from infection in the digestive system (mouth, pharynx, esophagus, stomach, small intestine (including duodenum) and large intestine), in particular gastric infection, gastritis, chronic gastritis, peptide, gastric and/or duodenal ulcer, lymphoma or gastric cancer
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