WO2017093593A1 - New family of compounds, method for the production thereof, and uses thereof in the treatment and/or prophylaxis of diseases - Google Patents

New family of compounds, method for the production thereof, and uses thereof in the treatment and/or prophylaxis of diseases Download PDF

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Publication number
WO2017093593A1
WO2017093593A1 PCT/ES2016/070859 ES2016070859W WO2017093593A1 WO 2017093593 A1 WO2017093593 A1 WO 2017093593A1 ES 2016070859 W ES2016070859 W ES 2016070859W WO 2017093593 A1 WO2017093593 A1 WO 2017093593A1
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compound
formula
alkyl
pharmaceutically acceptable
group
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PCT/ES2016/070859
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Spanish (es)
French (fr)
Inventor
Roberto Quesada Pato
Elsa HERNANDO SANTA CRUZ
Ricardo Enrique PÉREZ TOMÁS
Vanessa SOTO CERRATO
Olga L.A. ZEGARRA
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Universidad De Burgos
Universitat De Barcelona
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Publication of WO2017093593A1 publication Critical patent/WO2017093593A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the field of the invention is related to small molecules capable of facilitating the transport of anions through lipid membranes. These molecules are able to replace the lost function in diseases related to deficiencies in the transport of anions at the cellular level.
  • the compounds of the invention are particularly useful in the treatment of diseases such as cystic fibrosis.
  • prodigiosins natural pigments initially isolated from bacteria of the genus Serratia. These naturally occurring alkaloids unit containing 4-methoxy-2,2' -bipirrol and show cytotoxic activities and immunosuppressant (Fürstner, A. Chemistry and Biology of Roseophilin and the prodigiosin Alkaloids: A Survey of the Last Years 2500 Angew . Chem. Int. Ed. 2003, 42, 3582-3603).
  • obatoclax a member of the family of prodiginins with anticancer properties, which is currently in clinical trials
  • GX15- 070 Small molecule obatoclax (GX15- 070) MCL-1 and overcomes MCL-1-mediated resistance to apoptosis antagonists.
  • PNAS, 2007, 104, 19512-19517 A general characteristic of these compounds is the fact that they are cytotoxic even at very low concentrations.
  • some of these compounds facilitate the transport of anions in lipid membranes and this action has been related to their cytotoxicity (D ⁇ az de Gre ⁇ u, B. et al.
  • Cystic fibrosis is a genetic disease that results in a severe reduction in the function of a protein called the transmembrane conductance regulator of the cystic fibrosis ("cystic fibrosis transmembrane conductance regulator", CFTR) that regulates the permeability of anions in the epithelial membranes.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • This condition results in an imbalance in ion transport and a reduced apical secretion of anions.
  • an accumulation of abnormally dense mucus in the lung occurs and this produces recurrent microbial infections that damage lung function and can ultimately lead to death in patients with cystic fibrosis.
  • these patients with cystic fibrosis usually suffer from gastrointestinal problems and pancreatic insufficiency.
  • a corrector for the treatment of cystic fibrosis called kalydeco (ivacaftor) and a combination, called Orkambi (ivacaftor + lumacaftor), of a corrector plus an enhancer is approved in the market.
  • these treatments are aimed at patients with specific mutations and are not of general application for all CF patients.
  • the mechanism of action of these compounds always involves an action on the CFTR protein in such a way that the activity of the protein present in the membrane (enhancer effect) is enhanced or defects that occur in the transit of this protein towards the protein are corrected. plasma membrane in which its action develops (corrective effect).
  • the present invention relates to a compound of formula (I)
  • Ri, R2, R3, 6, R7 and Re are independently selected from the group consisting of: H, OH, halogen, O-Rg, N R10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl,
  • R 4 and R5 are selected from the group consisting of: H, OH, halogen, O-Rg, N R10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl,
  • Rg, R10, and Rn are radicals independently selected from the group consisting of: H, OH, halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl.
  • a preferred embodiment of the invention relates to a pharmaceutically acceptable addition salt and / or solvate of a compound of formula (I) in accordance with the above described.
  • Said pharmaceutically acceptable addition salt and / or solvate is independently selected from the group consisting of: (Z) -5- (1-Butyl-1 H-1, 2,3-) triazol-4-yl) -2 - ((3,5-dimethyl-1 H -pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (la), (Z) -5- (1 Chloride) -octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2- yl) methylene) -3-methoxy-2H-pyrrolium (Ib ), (Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -3-methoxy-2 - ((5-methyl-4- pentyl-1 H-pyrrole- 2-yl) methylene) -2H-pyrrole chloride (le), (Z) -3-methoxy-2
  • Another embodiment of the invention also described relates to a process for obtaining a compound of formula (I), or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, comprising the following steps:
  • a particular embodiment of the invention in turn, described refers to an intermediate of the cycloaddition reaction (a) described above, characterized by being a triazole-pyrrole-carbaldehyde of formula (II) where R 4 and R5 are selected from the group consisting of: H, OH, halogen, O-Rg, N R10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl,
  • R 6 , R 7 and Re are independently selected from the group consisting of: H, OH, halogen, O-Rg, N R10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or hetaryl,
  • Rg, Rio and R11 are radicals independently selected from the group consisting of: H, OH, halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl.
  • Another preferred embodiment of the described invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt or solvate thereof, described above, and at least one pharmaceutically acceptable excipient.
  • Another additional embodiment relates to a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, for use as a medicament, preferably for use in the treatment and / or prophylaxis of diseases derived from anomalous transport of anions at the cellular level, and more preferably for use in the treatment and / or prophylaxis of cystic fibrosis.
  • Another additional embodiment relates to pharmaceutical compositions as described above for use as a medicament, preferably for use in the treatment and / or prophylaxis of diseases derived from the anomalous transport of anions at the cellular level, and more preferably for use in the treatment and / or prophylaxis of cystic fibrosis.
  • a further embodiment includes a method of treatment and / or prophylaxis of diseases, in particular of diseases derived from the anomalous transport of anions at the cellular level, and more preferably of cystic fibrosis, which comprises administering a pharmaceutical composition as described above, wherein said pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I), or of a pharmaceutically acceptable addition salt and / or solvate thereof, as described above.
  • the present invention relates to the compound of formula (I)
  • Ri, R 2 , R3, R-6, R 7 and Rs are independently selected from the group consisting of: H, OH, halogen, O-Rg, NR10R11, COORg, CONR10R11, alkyl, cycloalkyl, alkenyl, alkynyl , aryl, arylalkyl, heterocycle or heteroaryl,
  • R 4 and R5 are selected from the group consisting of: H, OH, halogen, O-Rg, NR10R11, COORg, CONR1 0 R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl,
  • Rg, R10 and Rn are radicals independently selected from the group consisting of: H, OH, halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl.
  • alkyl refers to aliphatic, linear or branched chains, among which are, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, tere-butyl, sec-butyl, pentyl, isopentyl and dodecyl.
  • cycloalkyl refers to cycles of 3 to 6 members, among which are, but are not limited to, cyclobutyl, cyclopentyl and cyclohexyl.
  • alkenyl refers to hydrocarbon groups containing double bonds, among which are, but are not limited to, 2- butenyl, 3- pentenyl and 4-octenyl.
  • alkynyl refers to groups containing triple bonds, among which are, but are not limited to, 2-butynyl and 2-hexinyl.
  • aryl refers to aromatic mono and polycyclic compounds, among which are, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, diphenyl, indenyl, phenanthryl and anthracil.
  • arylalkyl refers to an aliphatic chain in which at least one of the hydrogens has been replaced by an aryl group, as defined above, among those found, but not limited to , benzyl and propylphenyl.
  • heterocycle refers to cyclic compounds of 4 to 6 members containing 1 to 4 heteroatoms such as oxygen, sulfur, nitrogen, among which are, but not limited to, pyrrole, pyridyl, pyridazyl, triazolyl , isoxazolidinyl, furyl, thiophenyl and thiazolyl.
  • heteroaryl is a five to six membered aromatic heteroaryl, monocyclic, or a bicyclic seven to eleven aromatic heteroaryl, which in each case contains 1, 2, 3 or 4 heteroatoms selected, independently from each other, from the group consisting of N, S or O
  • R 7 is independently selected from the group consisting of: H, OH, halogen, O-Rg, NR10R11, COORg, CONR10R11, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl.
  • R 7 is H.
  • Ri is independently selected from the group consisting of: H, OH, halogen, O-Rg, COORg, CONR10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl;
  • R2 is independently selected from the group consisting of: H, OH, halogen,
  • Rs is independently selected from the group consisting of: H, OH, halogen, O-Rg, COORg, CONR10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl;
  • R6 is independently selected from the group consisting of: H, OH, halogen, O-Rg, COORg, CONR10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl;
  • R 8 is independently selected from the group consisting of; H, halogen, O-Rg, NR10R11, COORg, CONR10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl and
  • R 4 and R5 are selected from the group consisting of: H, OH, O-Rg, NR10R11, COORg, CONR10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl. In another particular embodiment Rg is alkyl.
  • Ri is alkyl, and preferably when Ri is alkyl, said alkyl is methyl.
  • R2 is H or alkyl, and preferably when R2 is alkyl, said alkyl is pentyl.
  • R3 is H or alkyl, and preferably when R3 is alkyl, said alkyl is methyl.
  • R 4 and R5 are independently selected from H or ORg.
  • Rg is alkyl, preferably methyl.
  • R 6 is H.
  • R 8 is alkyl, preferably butyl or octyl.
  • R 1 is alkyl
  • R 2 is H or alkyl
  • R 3 is H or alkyl
  • R 4 and R 5 are selected from H or ORg
  • R 6 is H
  • R 7 is H
  • R 8 is alkyl , preferably where R 9 is alkyl.
  • Another embodiment of the invention relates to a pharmaceutically acceptable addition and / or solvate salt of a compound of formula (I) according to the embodiments described above.
  • said pharmaceutically acceptable addition and / or solvate salt is a hydrochloride salt or the mesylate.
  • said pharmaceutically acceptable addition and / or solvate salt is chloride.
  • An embodiment of the invention as described above is a pharmaceutically acceptable addition and / or solvate salt of a compound of formula (I) that is selected from the group consisting of:
  • the process is carried out in two stages from a 5-alkynyl-2H-pyrrole-2-ylidene compound of formula (III).
  • the reaction of this type of compounds of formula (III) with an organic azide R 8 N 3 results in the formation of a 5- (1, 2,3-triazol-4-yl) -1 H-pyrrole-2- carbaldehyde of formula (II).
  • the condensation of this type of compounds of formula (II) with an unsubstituted pyrrole in the alpha position of formula (IV), in the presence of an organic or inorganic acid leads to obtaining the compounds of the invention of formula (I) or of its pharmaceutically acceptable salts and / or solvates.
  • this embodiment of the invention consists in a process for obtaining a compound of formula (I) or its pharmaceutically acceptable salts and / or solvates, comprising:
  • copper mixtures of copper (II) sulphate and sodium ascorbate are acceptable copper catalysts for carrying out the compound of the invention.
  • methanol is preferably used as organic solvents.
  • the compounds of the invention of formula (I) and their pharmaceutically acceptable addition salts and / or solvates are particularly useful as chemotherapeutic agents for the treatment of cystic fibrosis and other diseases derived from the anomalous transport of anions at the cellular level.
  • An embodiment of the present invention is the intermediate of the cycloaddition reaction (a) described in the process of obtaining the compounds of formula (I), characterized by being a triazole-pyrrole-carbaldehyde of formula (II):
  • R 4 and R5 are selected from the group consisting of: H, OH, halogen, O-Rg, N R10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl,
  • R 6 , R 7 and Re are independently selected from the group consisting of: H, OH, halogen, O-Rg, N R10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or hetaryl.
  • Rg, R10 and Rn are radicals independently selected from the group consisting of: H, OH, halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl.
  • R 7 is independently selected from the group consisting of: H, OH, halogen, O-Rg, N R10R11, COORg, CON R10R11, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl.
  • R 7 is H.
  • R6 is independently selected from the group consisting of: H, OH, halogen, O-Rg, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl;
  • Rs are independently selected from the group consisting of; H, halogen, O-Rg, NR10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl and
  • R 4 and R 5 are selected from the group consisting of: H, OH, O-Rg, N R10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl.
  • R 9 is alkyl.
  • An embodiment of the present invention is the intermediate of the cycloaddition reaction (a) described in the process of obtaining the compounds of formula (I), represented by 5- (1-butyl-1 H-1, 2, 3-Triazol-4-yl) -3-methoxy-1 H-pyrrole-2-carbaldehyde of formula (Na):
  • Another embodiment of the present invention is the intermediate of the cycloaddition reaction (a) described in the process of obtaining the compounds of formula (I), represented by 5- (1-octyl-1 H-1, 2, 3-Triazol-4-yl) -3-methoxy-1 H-pyrrole-2-carbaldehyde of formula (llb):
  • An embodiment of the present invention is a pharmaceutical composition comprising a compound of formula (I)
  • Ri, R 2 , R3, R6, R7 and Re are independently selected from the group consisting of: H, OH, halogen, O-Rg, NR10R11, COORg, CONR10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl , arylalkyl, heterocycle or heteroaryl;
  • R 4 and R5 are selected from the group consisting of: H, OH, halogen, O-Rg, NR10R11, COORg, CONR10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl;
  • Rg, R10 and Rn are radicals independently selected from the group consisting of: H, OH, halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl;
  • Another embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (Z) chloride ) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2- yl) methylene) -3-methoxy -2H-pyrrolium (la), (Z) chloride -5- (1-octyl- 1 H- 1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H- pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -3 chloride -methoxy-2 - ((5-methyl-4-pentyl-1 H
  • composition of the present invention comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, is administered by one of the routes of administration selected from the group consisting of : oral, intravenous, muscular and intramuscular route.
  • Another particular embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: chloride of ( Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2- yl) methylene) -3- methoxy-2H-pyrrolium (la), (Z) chloride -5- (1-octyl- 1 H- 1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H -pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) chloride - 3-methoxy-2 - ((5-methyl-4-pentyl-1 H-pyr
  • One embodiment refers to the use of a compound of formula (I) or of a pharmaceutically acceptable addition salt and / or solvate thereof, described above to prepare a medicament.
  • Another embodiment relates to the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, to prepare a medicament.
  • Another embodiment relates to a compound of formula (I) or to a pharmaceutically acceptable addition salt and / or solvate thereof, described above, for use as a medicine.
  • Another embodiment relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or an addition salt and / or a pharmaceutically acceptable solvate thereof, described above, for use as a medicament.
  • An embodiment relates to the use of a compound of formula (I) or of a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: ((Z) -5 chloride - (1 -butyl- 1 H- 1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H- pyrrolium (la), (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrole-2) chloride -yl) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) chloride -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -3-methoxy- 2 - ((5-methyl-4-pentyl-1 H-pyrrol-2-yl)
  • Another embodiment relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (( Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3- methoxy-2H-pyrrolium (la), (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H) chloride -pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) chloride - 3-Methoxy-2 - ((5-methyl-4-pentyl-1 H-pyrrol-2-
  • One embodiment refers to a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (Z) -5- (1 - butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (la) , (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene chloride ) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1 -butyl-1 H-1, 2, 3-triazol-4-yl) -3-methoxy-2 - (( 5-methyl-4-pentyl-1 H-pyrrol-2-yl) methylene) -2H- pyrrolium (le
  • Another embodiment relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (Z) chloride - 5- (1-Butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H -pyrrolium (la), (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrole-) chloride 2- il) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -3-methoxy chloride -2- ((5-methyl-4-pentyl-1 H -pyrrol-2-
  • One embodiment refers to the use of a compound of formula (I) or of a pharmaceutically acceptable addition salt and / or solvate thereof, described above, to prepare a medicament for the treatment and / or prophylaxis of diseases derived from abnormal transport. of anions at the cellular level.
  • cystic fibrosis Best's disease, Bartter's syndrome, chronic obstructive pulmonary disease or congenital mitonia.
  • Another embodiment relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, to prepare a medicament for the treatment and / or prophylaxis of diseases. derived from the anomalous transport of anions at the cellular level.
  • One embodiment refers to a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, for use in the treatment and / or prophylaxis of diseases derived from the anomalous transport of anions at the cellular level. .
  • Another embodiment relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, for use in the treatment and / or prophylaxis of diseases derived from abnormal transport. of anions at the cellular level
  • One embodiment refers to the use of a compound of formula (I) or of a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (Z) -5- chloride (1-Butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (la), (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrole-2-) chloride il) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1 -butyl-1 H-1, 2, 3-triazol-4-yl) -3-methoxy-2 chloride - ((5-methyl-4-pentyl-1 H-pyrrol-2-yl) methylene) -2H
  • Another embodiment relates to the use of a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (Z) chloride ) -5- (1 -butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy -2H-pyrrolium (la), (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-) chloride pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -3 chloride -methoxy- 2 - ((5-methyl-4-pentyl-1 H -pyrrol
  • One embodiment refers to a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (Z) -5- (1 - butyl-1 H-1,2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (la) , (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene chloride ) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1 -butyl-1 H-1, 2, 3-triazol-4-yl) -3-methoxy-2 - (( 5-methyl-4-pentyl-1 H-pyrrol-2-yl) methylene) -2H- pyrrolium (le
  • Another embodiment relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (Z) chloride - 5- (1-Butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H -pyrrolium (la), (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrole-) chloride 2- il) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -3-methoxy chloride -2- ((5-methyl-4-pentyl-1 H -pyrrol-2-
  • An embodiment relates to the use of a compound of formula (I) or of a pharmaceutically acceptable addition salt and / or solvate thereof, described above, to prepare a medicament for the treatment and / or prophylaxis of cystic fibrosis.
  • Another embodiment relates to the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, to prepare a medicament for the treatment and / or prophylaxis of the cystic fibrosis.
  • One embodiment refers to a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, for use in the treatment and / or prophylaxis of cystic fibrosis.
  • Another embodiment relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, for use in the treatment and / or prophylaxis of cystic fibrosis.
  • One embodiment refers to the use of a compound of formula (I) or of a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (Z) -5- chloride (1-Butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (la), (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrole-2-) chloride il) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1 -butyl-1 H-1, 2, 3-triazol-4-yl) -3-methoxy-2 chloride - ((5-methyl-4-pentyl-1 H-pyrrol-2-yl) methylene) -2H
  • An embodiment relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (Z) chloride ) -5- (1 -butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy -2H-pyrrolium (la), (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-) chloride pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -3 chloride -methoxy- 2 - ((5-methyl-4-pentyl
  • Another embodiment relates to a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (Z) -5- (1 - butyl-1 H-1,2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (la) , (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene chloride ) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1 -butyl-1 H-1, 2, 3-triazol-4-yl) -3-methoxy-2 - (( 5-methyl-4-pentyl-1 H-pyrrol-2-yl) methylene) -2H- pyrrolium (le
  • Another embodiment relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (Z) chloride - 5- (1-Butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H -pyrrolium (la), (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrole-) chloride 2- il) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -3-methoxy chloride -2- ((5-methyl-4-pentyl-1 H -pyrrol-2-
  • One embodiment relates to a method of treatment and / or prophylaxis of diseases, and in particular of diseases derived from the anomalous transport of anions at the cellular level, which comprises administering to a human subject a pharmaceutical composition comprising a therapeutically effective amount of a compound. of formula (I) or of an addition salt and / or a pharmaceutically acceptable solvate thereof, described above.
  • Another embodiment relates to a method of treatment and / or prophylaxis of cystic fibrosis, which comprises administering to a human subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or of an addition salt and / or a pharmaceutically acceptable solvate thereof, described above.
  • One embodiment relates to a method of treatment and / or prophylaxis of diseases derived from the anomalous transport of anions at the cellular level, which comprises administering to a human subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or of an addition salt and / or a pharmaceutically acceptable solvate thereof, described above, independently selected from the group consisting of: (Z) -5- (1 -butyl-1 H-1, 2,3-triazole chloride) - 4-yl) -2 - ((3,5-dimethyl-1 H -pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (la), (Z) -5- (1-) chloride octyl- 1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (Ib) , (Z) -5-
  • Another embodiment relates to a method of treatment and / or prophylaxis of cystic fibrosis, which comprises administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or of an addition salt and / or a pharmaceutically acceptable solvate thereof, described above selected independently from the group consisting of: (Z) -5- (1 -butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-) chloride pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (la), (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 chloride - ((3,5-Dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1 -butyl-1 H-1, 2,3-triazol-4-
  • One embodiment relates to a method of treatment and / or prophylaxis of cystic fibrosis comprising administering a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, in a concentration of 0 , 1 ⁇ to 50 ⁇ , preferably in a concentration of 15 ⁇ to 40 ⁇ and more preferably, when it comes to combining greater therapeutic efficacy by minimizing the toxicity of the drug administered, when the concentration of the compound of formula (I) or of a Addition salt and / or a pharmaceutically acceptable solvate thereof, described above, to be administered is in the range of 0.1 ⁇ to 20 ⁇ .
  • Figure 1 Fluorescence assay used to measure the activity of the compounds.
  • the panel shows the response of cells incubated for 40 minutes with the compound at various concentrations and in triplicate.
  • the application of Nal induces a reduction in fluorescence, the speed of which depends on the concentration of the compound: 2 ⁇ (light gray), 8.3 ⁇ oscuro (dark gray) and 20 ⁇ (black).
  • FIG. 3 pH dependence of the activity of the compounds la, Ib, le and Id.
  • the figure shows the maximum fluorescence extinction rate (VmEF) of the four compounds (concentration: 20 ⁇ ) at the indicated pH values .
  • VmEF maximum fluorescence extinction rate
  • the response to two pH values of the CFTR protein is also shown, whose activity is stimulated by the application of an agonist that increases intracellular cAMP (forskolin 20 ⁇ ) and an enhancer (genistein 10 ⁇ ).
  • Figure 4 Kinetics of incorporation of the enhancer compound (12 ⁇ ) into the cell membrane. In the continuous presence of the compound in the extracellular solution, the activity of the cell membrane, measured as VmFE, increases with time.
  • Figure 5. Stability of compound le (12 ⁇ ) in the cell membrane. After 45 minutes of incubation, the compound is washed from the extracellular solution to establish its stability in the cell membrane. We see that the activity of the membrane decreases very slowly, leaving more than 85% of the transport after 60 minutes.
  • reaction mixture is diluted with 50 mL of NH4OH, and after 10 minutes it is extracted with Et2 ⁇ D (3 x 25 mL). The organic phase is washed with a saturated NaCl solution (1 x 40 mL), dried over Na2SC1 ⁇ 4 and concentrated under reduced pressure. The solid obtained is recrystallized from a mixture DCM: hexane: Et20 to obtain the Na compound. Yield: 67%.
  • reaction mixture is diluted with 50 ml_ of NH4OH, and after 10 minutes it is extracted with Et2Ü (3 x 25 ml_).
  • the organic phase is washed with a saturated NaCl solution (1 x 40 mL), dried over Na2SC1 ⁇ 4 and concentrated under reduced pressure.
  • the solid obtained is recrystallized from a mixture DCM: hexane: Et20 obtaining compound llb. Yield: 76%.
  • Example 6 Toxicity of the compounds la, Ib, le and Id in different cell lines. The following cell lines were used:
  • MCF-7 human breast adenocarcinoma cells.
  • - MCF-10A normal mammary human epithelium cells.
  • MTT means bromide of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium, blue thiazole.
  • 10x10 3 cells were seeded in 96-well culture plates and after 24 hours they were incubated in the absence (control cells) or in the presence of different concentrations of Ib, le and Id for 24 hours.
  • the FRT (Fisher rat thyroid) cell line a rat thyroid line with stable expression of the yellow fluorescent protein (YFP), was used.
  • the cells are seeded in 96-well plates at a density of 40,000 cells / well.
  • the assay is based on the diverse ability of the chloride (Ch) and iodide (I " ) anions to extinguish the fluorescence of the YFP protein.
  • the cells were seeded in the presence of an extracellular solution with 130 mM NaCI, a condition in which the YFP fluorescence is very bright Under these conditions, the cells were incubated with the various compounds at various concentrations or with dimethyl sulfoxide (DMSO) as a control.
  • DMSO dimethyl sulfoxide
  • the initial fluorescence is recorded with a fluorescence reader and after a few seconds it is added a solution of Nal. If the compound is active, I " is internalized and, competing with Ch for YFP, binds to it and extinguishes fluorescence (Figure 1).
  • the adjustment of the curve to an exponential equation and its successive derivative allows to calculate the maximum rate of extinction of the fluorescence (VmEF) for each concentration and this parameter is a direct indication of the activity of

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Abstract

The invention relates to compounds of formula (I) or addition salts and/or pharmaceutically acceptable solvates thereof, and the pharmaceutical compositions containing same. The invention also relates to a method for producing said compounds of formula (I) or addition salts and/or pharmaceutically acceptable solvates thereof. Finally the invention relates to the use of said compounds of formula (I) or addition salts and/or pharmaceutically acceptable solvates thereof, and of the pharmaceutical compositions containing same for the preparation of a drug. In particular, drugs intended for the treatment and/or prophylaxis of diseases derived from abnormal anion transport at a cellular level and, more specifically, those intended for the treatment and/or prophylaxis of cystic fibrosis.

Description

Una nueva familia de compuestos, procedimiento de obtención de los mismos y sus usos en el tratamiento y/o profilaxis de enfermedades  A new family of compounds, procedure for obtaining them and their uses in the treatment and / or prophylaxis of diseases
CAMPO DE LA INVENCIÓN FIELD OF THE INVENTION
El campo de la invención está relacionado con moléculas pequeñas capaces de facilitar el transporte de aniones a través de membranas lipídicas. Estas moléculas son capaces de suplir la función perdida en enfermedades relacionadas con deficiencias en el transporte de aniones a nivel celular. Los compuestos de la invención son particularmente útiles en el tratamiento de enfermedades como la fibrosis quística. The field of the invention is related to small molecules capable of facilitating the transport of anions through lipid membranes. These molecules are able to replace the lost function in diseases related to deficiencies in the transport of anions at the cellular level. The compounds of the invention are particularly useful in the treatment of diseases such as cystic fibrosis.
ANTECEDENTES DE LA INVENCIÓN BACKGROUND OF THE INVENTION
Los compuestos de la invención no han sido descritos en el estado de la técnica. Hay compuestos relacionados, como las prodigiosinas, unos pigmentos naturales aislados inicialmente de bacterias del género Serratia. Estos alcaloides de origen natural contienen la unidad 4-metoxi-2,2'-bipirrol y muestran actividades citotóxicas e inmunosupresoras (Fürstner, A. Chemistry and Biology of Roseophilin and the Prodigiosin Alkaloids: A Survey of the Last 2500 Years. Angew. Chem. Int. Ed. 2003, 42, 3582 - 3603). También se conocen en el estado de la técnica otros compuestos, como el obatoclax, miembro de la familia de las prodigininas con propiedades anticancerígenas, que actualmente se encuentra en fase de ensayos clínicos (Nguyen, M. et al. Small molecule obatoclax (GX15-070) antagonizes MCL- 1 and overcomes MCL-1-mediated resistance to apoptosis. PNAS, 2007, 104, 19512-19517). Una característica general de estos compuestos es el hecho de que resultan citotóxicos incluso en concentraciones muy bajas. Por otra parte ha sido demostrado que algunos de estos compuestos facilitan el transporte de aniones en membranas lipídicas y esta acción ha sido relacionada con su citotoxicidad (Díaz de Greñu, B. et al. Synthetic Prodiginine Obatoclax (GX15-070) and Related Analogues: Anión Binding, Transmembrane Transport, and Cytotoxicity Properties. Chem. Eur. J., 2011 , 17, 14074-14083). Existen numerosas enfermedades relacionadas con disfunciones de las proteínas de membrana encargadas de facilitar el transporte de iones a través de membranas biológicas o canales iónicos. Estas enfermedades son muy diversas y se agrupan en lo que se conoce como "channelopathies" (F. M. Ashcroft, F. M. From molecule to malady. Nature, 2006, 440, 440-447). El desarrollo de moléculas o compuestos capaces de suplir la actividad de estos canales iónicos, que se encuentra alterada en el caso de estas enfermedades, sería deseable terapéuticamente. La fibrosis quística (CF) es una enfermedad genética que da lugar a una grave reducción de la función de una proteína denominada regulador de la conductancia transmembrana de la fibrosis quística ("cystic fibrosis transmembrane conductance regulator", CFTR) que regula la permeabilidad de aniones en las membranas epiteliales. Esta condición tiene como resultado un desequilibrio en el transporte de iones y una secreción apical de aniones reducida. Como consecuencia se produce una acumulación de moco anormalmente denso en el pulmón y esto produce infecciones microbianas recurrentes que dañan la función pulmonar y pueden conducir en última instancia a la muerte en los pacientes con fibrosis quística. Además estos pacientes con fibrosis quística padecen normalmente problemas gastrointestinales e insuficiencia pancreática. Actualmente no se conoce una cura para esta enfermedad. Además de tratamientos paliativos de los síntomas, en el mercado se encuentra aprobado un corrector para el tratamiento de la fibrosis quística denominado kalydeco (ivacaftor) y una combinación, denominada Orkambi (ivacaftor + lumacaftor), de un corrector más un potenciador. En ambos casos estos tratamientos se dirigen a pacientes con mutaciones específicas y no son de aplicación general para todos los enfermos de CF. El mecanismo de acción de estos compuestos involucra siempre una acción sobre la proteína CFTR de tal manera que se potencia la actividad de la proteína presente en la membrana (efecto potenciador) o bien se corrigen defectos que se producen en el tránsito de esta proteína hacia la membrana plasmáticas en la que se desarrolla su acción (efecto corrector). El desarrollo de fármacos capaces de suplir la función de transporte de la proteína CFTR sería un prometedor agente terapéutico para corregir la reducida conductancia apical de aniones de estas células afectadas por esta enfermedad. En el estado de la técnica no se ha descrito ningún tratamiento que utilice esta estrategia para conseguir una acción terapéutica. Además, a diferencia de los tratamientos actuales, estos compuestos serían capaces de actuar sobre el origen de la enfermedad, siendo potencialmente de aplicación para todos los pacientes de fibrosis quística independientemente de la mutación causante de la misma. The compounds of the invention have not been described in the state of the art. There are related compounds, such as prodigiosins, natural pigments initially isolated from bacteria of the genus Serratia. These naturally occurring alkaloids unit containing 4-methoxy-2,2' -bipirrol and show cytotoxic activities and immunosuppressant (Fürstner, A. Chemistry and Biology of Roseophilin and the prodigiosin Alkaloids: A Survey of the Last Years 2500 Angew . Chem. Int. Ed. 2003, 42, 3582-3603). Other compounds are also known in the state of the art, such as obatoclax, a member of the family of prodiginins with anticancer properties, which is currently in clinical trials (Nguyen, M. et al. Small molecule obatoclax (GX15- 070) MCL-1 and overcomes MCL-1-mediated resistance to apoptosis antagonists. PNAS, 2007, 104, 19512-19517). A general characteristic of these compounds is the fact that they are cytotoxic even at very low concentrations. On the other hand it has been shown that some of these compounds facilitate the transport of anions in lipid membranes and this action has been related to their cytotoxicity (Díaz de Greñu, B. et al. Synthetic Prodiginine Obatoclax (GX15-070) and Related Analogues: Anion Binding, Transmembrane Transport, and Cytotoxicity Properties. Chem. Eur. J., 2011, 17, 14074-14083). There are numerous diseases related to dysfunctions of membrane proteins responsible for facilitating the transport of ions through biological membranes or ion channels. These diseases are very diverse and are grouped into what is known as "channelopathies" (FM Ashcroft, FM From molecule to malady. Nature, 2006, 440, 440-447). The development of molecules or compounds capable of supplying the activity of these ion channels, which is altered in the case of these diseases, would be therapeutically desirable. Cystic fibrosis (CF) is a genetic disease that results in a severe reduction in the function of a protein called the transmembrane conductance regulator of the cystic fibrosis ("cystic fibrosis transmembrane conductance regulator", CFTR) that regulates the permeability of anions in the epithelial membranes. This condition results in an imbalance in ion transport and a reduced apical secretion of anions. As a consequence, an accumulation of abnormally dense mucus in the lung occurs and this produces recurrent microbial infections that damage lung function and can ultimately lead to death in patients with cystic fibrosis. In addition, these patients with cystic fibrosis usually suffer from gastrointestinal problems and pancreatic insufficiency. Currently there is no known cure for this disease. In addition to palliative treatment of symptoms, a corrector for the treatment of cystic fibrosis called kalydeco (ivacaftor) and a combination, called Orkambi (ivacaftor + lumacaftor), of a corrector plus an enhancer is approved in the market. In both cases, these treatments are aimed at patients with specific mutations and are not of general application for all CF patients. The mechanism of action of these compounds always involves an action on the CFTR protein in such a way that the activity of the protein present in the membrane (enhancer effect) is enhanced or defects that occur in the transit of this protein towards the protein are corrected. plasma membrane in which its action develops (corrective effect). The development of drugs capable of supplying the transport function of the CFTR protein would be a promising therapeutic agent to correct the reduced apical conductance of these cells affected by this disease. In the state of the art, no treatment using this strategy to achieve therapeutic action has been described. In addition, unlike current treatments, these compounds would be able to act on the origin of the disease, being potentially applicable to all cystic fibrosis patients regardless of the mutation causing it.
BREVE DESCRIPCION DE LA INVENCION BRIEF DESCRIPTION OF THE INVENTION
La presente invención se refiere a un compuesto de fórmula (I)  The present invention relates to a compound of formula (I)
Figure imgf000003_0001
donde Ri , R2, R3, 6, R7 y Re se seleccionan de forma independiente de entre el grupo formado por: H, OH, halógeno, O-Rg, N R10R11 , COORg, CON R10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo,
Figure imgf000003_0001
where Ri, R2, R3, 6, R7 and Re are independently selected from the group consisting of: H, OH, halogen, O-Rg, N R10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl,
R4 y R5 se seleccionan de entre el grupo formado por: H, OH, halógeno, O-Rg, N R10R11 , COORg, CON R10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, R 4 and R5 are selected from the group consisting of: H, OH, halogen, O-Rg, N R10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl,
y en donde Rg, R10, y Rn son radicales seleccionados de forma independiente de entre el grupo formado por: H, OH, halógeno, alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo. and wherein Rg, R10, and Rn are radicals independently selected from the group consisting of: H, OH, halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl.
Una realización preferente de la invención se refiere a_una sal de adición y/o solvato farmacéuticamente aceptable de un compuesto de formula (I) de acuerdo con lo descrito anteriormente.  A preferred embodiment of the invention relates to a pharmaceutically acceptable addition salt and / or solvate of a compound of formula (I) in accordance with the above described.
Dicha sal de adición y/o solvato farmacéuticamente aceptable, según se describe anteriormente, se selecciona de forma independiente de entre el grupo formado por: Cloruro de (Z)-5-(1-butil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3-metoxi-2H- pirrolio (la), Cloruro de (Z)-5-(1-octil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2- il)metilen)-3-metoxi-2H-pirrolio (Ib), (Z)-5-(1-butil-1 H-1 ,2,3-triazol-4-il)-3-metoxi-2-((5-metil-4- pentil-1 H-pirrol-2-il)metilen)-2H-pirrol cloruro (le), Cloruro de (Z)-3-metoxi-2-((5-metil-4-pentil- 1 H-pirrol-2-il)metilen)-5-(1-octil-1 H-1 ,2,3-triazol-4-il)-2H-pirrolio (Id).  Said pharmaceutically acceptable addition salt and / or solvate, as described above, is independently selected from the group consisting of: (Z) -5- (1-Butyl-1 H-1, 2,3-) triazol-4-yl) -2 - ((3,5-dimethyl-1 H -pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (la), (Z) -5- (1 Chloride) -octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2- yl) methylene) -3-methoxy-2H-pyrrolium (Ib ), (Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -3-methoxy-2 - ((5-methyl-4- pentyl-1 H-pyrrole- 2-yl) methylene) -2H-pyrrole chloride (le), (Z) -3-methoxy-2 - ((5-methyl-4-pentyl-1 H-pyrrole-2-yl) methylene) -5 chloride - (1-octyl-1 H-1, 2,3-triazol-4-yl) -2H-pyrrolium (Id).
Otra realización de la invención también descrita se refiere a un procedimiento de obtención de un compuesto de fórmula (I), o de una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, que comprende las siguientes etapas:  Another embodiment of the invention also described relates to a process for obtaining a compound of formula (I), or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, comprising the following steps:
(a) la reacción de cicloadición de una azida RsN3 y un compuesto 5-alquinil-2H-pirrol-2- ilideno de fórmula (III), utilizando un catalizador de cobre, para generar un compuesto triazolil-pirrol-carbaldehido de fórmula (II),  (a) the cycloaddition reaction of an RsN3 azide and a 5-alkynyl-2H-pyrrol-2-ylidene compound of formula (III), using a copper catalyst, to generate a triazolyl-pyrrole-carbaldehyde compound of formula (II ),
(b) la condensación del compuesto de fórmula (II) obtenido anteriormente, con un pirrol no sustituido en posición alfa de fórmula (IV), en presencia de una cantidad de ácido y de un disolvente orgánico,  (b) the condensation of the compound of formula (II) obtained above, with an unsubstituted pyrrole in the alpha position of formula (IV), in the presence of an amount of acid and an organic solvent,
(c) la evaporación del disolvente orgánico y la purificación mediante columna cromatográfica del compuesto de fórmula (I).  (c) evaporation of the organic solvent and purification by chromatographic column of the compound of formula (I).
Una realización particular de la invención, a su vez, descrita se refiere a un compuesto intermedio de la reacción de cicloadición (a) descrita anteriormente, caracterizado por ser un triazol-pirrol-carbaldehido de fórmula (II)
Figure imgf000005_0001
donde R4 y R5 se seleccionan de entre el grupo formado por: H, OH, halógeno, O-Rg, N R10R11 , COORg, CON R10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, A particular embodiment of the invention, in turn, described refers to an intermediate of the cycloaddition reaction (a) described above, characterized by being a triazole-pyrrole-carbaldehyde of formula (II)
Figure imgf000005_0001
where R 4 and R5 are selected from the group consisting of: H, OH, halogen, O-Rg, N R10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl,
R6, R7 y Re se seleccionan de forma independiente de entre el grupo formado por: H, OH, halógeno, O-Rg, N R10R11 , COORg, CON R10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo, R 6 , R 7 and Re are independently selected from the group consisting of: H, OH, halogen, O-Rg, N R10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or hetaryl,
y en donde Rg, Rio y R11 son radicales seleccionados de forma independiente de entre el grupo formado por: H, OH, halógeno, alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo. and wherein Rg, Rio and R11 are radicals independently selected from the group consisting of: H, OH, halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl.
Otra realización preferida de la invención descrita se refiere a una composición farmacéutica que comprende un compuesto de formula (I) o una sal de adición o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, y al menos un excipiente farmacéuticamente aceptable. Another preferred embodiment of the described invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt or solvate thereof, described above, and at least one pharmaceutically acceptable excipient.
Otra realización adicional se refiere a un compuesto de fórmula (I) o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, para uso como medicamento, preferiblemente para uso en el tratamiento y/o profilaxis de enfermedades derivadas del transporte anómalo de aniones a nivel celular, y más preferiblemente para uso en el tratamiento y/o profilaxis de la fibrosis quística.  Another additional embodiment relates to a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, for use as a medicament, preferably for use in the treatment and / or prophylaxis of diseases derived from anomalous transport of anions at the cellular level, and more preferably for use in the treatment and / or prophylaxis of cystic fibrosis.
Otra realización adicional se refiere a composiciones farmacéuticas tal como se describe anteriormente para uso como medicamento, preferiblemente para uso en el tratamiento y/o profilaxis de enfermedades derivadas del transporte anómalo de aniones a nivel celular, y más preferiblemente para uso en el tratamiento y/o profilaxis de la fibrosis quística.  Another additional embodiment relates to pharmaceutical compositions as described above for use as a medicament, preferably for use in the treatment and / or prophylaxis of diseases derived from the anomalous transport of anions at the cellular level, and more preferably for use in the treatment and / or prophylaxis of cystic fibrosis.
Finalmente, una realización adicional incluye un método de tratamiento y/o profilaxis de enfermedades, en particular de enfermedades derivadas del transporte anómalo de aniones a nivel celular, y más preferiblemente de la fibrosis quística, que comprende administrar una composición farmacéutica según lo descrito anteriormente, donde dicha composición farmacéutica comprende una cantidad terapéuticamente efectiva de un compuesto de fórmula (I), o de una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, según lo descrito anteriormente. DESCRIPCIÓN DE LA INVENCIÓN Finally, a further embodiment includes a method of treatment and / or prophylaxis of diseases, in particular of diseases derived from the anomalous transport of anions at the cellular level, and more preferably of cystic fibrosis, which comprises administering a pharmaceutical composition as described above, wherein said pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I), or of a pharmaceutically acceptable addition salt and / or solvate thereof, as described above. DESCRIPTION OF THE INVENTION
La presente invención se refiere al compuesto de fórmula (I)  The present invention relates to the compound of formula (I)
Figure imgf000006_0001
Figure imgf000006_0001
donde Ri , R2, R3, R-6, R7 y Rsse seleccionan de forma independiente de entre el grupo formado por: H, OH, halógeno, O-Rg, NR10R11 , COORg, CONR10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo, where Ri, R 2 , R3, R-6, R 7 and Rs are independently selected from the group consisting of: H, OH, halogen, O-Rg, NR10R11, COORg, CONR10R11, alkyl, cycloalkyl, alkenyl, alkynyl , aryl, arylalkyl, heterocycle or heteroaryl,
R4 y R5 se seleccionan de entre el grupo formado por: H, OH, halógeno, O-Rg, NR10R11 , COORg, CONR10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, R 4 and R5 are selected from the group consisting of: H, OH, halogen, O-Rg, NR10R11, COORg, CONR1 0 R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl,
En donde Rg, R10 y Rn son radicales seleccionados de forma independiente de entre el grupo formado por: H, OH, halógeno, alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo.  Wherein Rg, R10 and Rn are radicals independently selected from the group consisting of: H, OH, halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl.
En la presente invención, el término "alquilo" se refiere a cadenas alifáticas, lineales o ramificadas, entre los que se encuentran, pero sin limitarse, metilo, etilo, propilo, isopropilo, butilo, tere-butilo, sec-butilo, pentilo, isopentilo y dodecilo.  In the present invention, the term "alkyl" refers to aliphatic, linear or branched chains, among which are, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, tere-butyl, sec-butyl, pentyl, isopentyl and dodecyl.
En la presente invención, el término "cicloalquilo" se refiere a ciclos de 3 a 6 miembros, entre los que se encuentran, pero sin limitarse, ciclobutil, ciclopentil y ciclohexil. In the present invention, the term "cycloalkyl" refers to cycles of 3 to 6 members, among which are, but are not limited to, cyclobutyl, cyclopentyl and cyclohexyl.
En la presente invención, el término "alquenilo" se refiere a grupos de hidrocarburos conteniendo enlaces dobles, entre los que se encuentran, pero sin limitarse, 2- butenilo, 3- pentenilo y 4-octenilo.  In the present invention, the term "alkenyl" refers to hydrocarbon groups containing double bonds, among which are, but are not limited to, 2- butenyl, 3- pentenyl and 4-octenyl.
En la presente invención, el término "alquinilo" se refiere a grupos conteniendo triples enlaces, entre los que se encuentran, pero sin limitarse, 2-butinilo y 2- hexinilo. In the present invention, the term "alkynyl" refers to groups containing triple bonds, among which are, but are not limited to, 2-butynyl and 2-hexinyl.
En la presente invención, el término "arilo" se refiere a compuestos mono y policíclicos aromáticos, entre los que se encuentran, pero sin limitarse, fenilo, naftilo, tetrahidronaftilo, difenilo, indenilo, fenantrilo y antracilo. En la presente invención, el término "arilalquilo" se refiere a a una cadena alifática en la que al menos uno de los hidrógenos se ha sustituido por un grupo arilo, tal como se ha definido más arriba, entre los que se encuentran, pero sin limitarse, bencilo y propilfenilo. In the present invention, the term "aryl" refers to aromatic mono and polycyclic compounds, among which are, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, diphenyl, indenyl, phenanthryl and anthracil. In the present invention, the term "arylalkyl" refers to an aliphatic chain in which at least one of the hydrogens has been replaced by an aryl group, as defined above, among those found, but not limited to , benzyl and propylphenyl.
En la presente invención, el término "heterociclo" se refiere a compuestos cíclicos de 4 a 6 miembros conteniendo de 1 a 4 heteroátomos como oxígeno, azufre, nitrógeno, entre los que se encuentran, pero sin limitarse, pirrol, piridil, piridazil, triazolil, isoxazolidinil, furil, tiofenil y tiazolil.  In the present invention, the term "heterocycle" refers to cyclic compounds of 4 to 6 members containing 1 to 4 heteroatoms such as oxygen, sulfur, nitrogen, among which are, but not limited to, pyrrole, pyridyl, pyridazyl, triazolyl , isoxazolidinyl, furyl, thiophenyl and thiazolyl.
En la presente invención, el término "hetarilo" es un heteroarilo aromático de cinco a seis miembros, monocíclico, o un heteroarilo aromático de siete a once miembros, bicíclico, que en cada caso contiene 1 , 2, 3 ó 4 heteroátomos seleccionados, independientemente uno de otro, de entre el grupo consistente en N, S u O  In the present invention, the term "heteroaryl" is a five to six membered aromatic heteroaryl, monocyclic, or a bicyclic seven to eleven aromatic heteroaryl, which in each case contains 1, 2, 3 or 4 heteroatoms selected, independently from each other, from the group consisting of N, S or O
En una realización de la invención R7 se selecciona de forma independiente de entre el grupo formado por: H, OH, halógeno, O-Rg, NR10R11 , COORg, CONR10R11 , alquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo. In one embodiment of the invention R 7 is independently selected from the group consisting of: H, OH, halogen, O-Rg, NR10R11, COORg, CONR10R11, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl.
En otra realización preferente R7 es H. In another preferred embodiment R 7 is H.
Una realización particular se refiere al compuesto de formula (I) descrito anteriormente donde:  A particular embodiment refers to the compound of formula (I) described above where:
Ri se selecciona de forma independiente de entre el grupo formado por: H , OH, halógeno, O-Rg, COORg, CONR10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo;  Ri is independently selected from the group consisting of: H, OH, halogen, O-Rg, COORg, CONR10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl;
R2 se selecciona de forma independiente de entre el grupo formado por: H , OH, halógeno, R2 is independently selected from the group consisting of: H, OH, halogen,
O-Rg, COORg, CONR10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo; O-Rg, COORg, CONR10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl;
Rs se selecciona de forma independiente de entre el grupo formado por: H , OH, halógeno, O-Rg, COORg, CONR10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo;  Rs is independently selected from the group consisting of: H, OH, halogen, O-Rg, COORg, CONR10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl;
R6 se selecciona de forma independiente de entre el grupo formado por: H , OH, halógeno, O-Rg, COORg, CONR10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo;  R6 is independently selected from the group consisting of: H, OH, halogen, O-Rg, COORg, CONR10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl;
R8 se selecciona de forma independiente de entre el grupo formado por ; H, halógeno, O- Rg, NR10R11 , COORg, CONR10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo y R 8 is independently selected from the group consisting of; H, halogen, O-Rg, NR10R11, COORg, CONR10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl and
R4 y R5 se seleccionan de entre el grupo formado por: H, OH, O-Rg, NR10R11 , COORg, CONR10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo. En otra realización particular Rg es alquilo. R 4 and R5 are selected from the group consisting of: H, OH, O-Rg, NR10R11, COORg, CONR10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl. In another particular embodiment Rg is alkyl.
En una realización particular de la invención, Ri es alquilo, y preferiblemente cuando Ri es alquilo, dicho alquilo es metilo.  In a particular embodiment of the invention, Ri is alkyl, and preferably when Ri is alkyl, said alkyl is methyl.
En otra realización particular de la invención, R2 es H o alquilo, y preferiblemente cuando R2 es alquilo, dicho alquilo es pentilo.  In another particular embodiment of the invention, R2 is H or alkyl, and preferably when R2 is alkyl, said alkyl is pentyl.
En otra realización de la invención, R3 es H o alquilo, y preferiblemente cuando R3 es alquilo, dicho alquilo es metilo.  In another embodiment of the invention, R3 is H or alkyl, and preferably when R3 is alkyl, said alkyl is methyl.
En otra realización de la invención, R4 y R5 se seleccionan independientemente entre H o ORg.In another embodiment of the invention, R 4 and R5 are independently selected from H or ORg.
En una realización particular de la invención, Rg es alquilo, preferiblemente metilo. In a particular embodiment of the invention, Rg is alkyl, preferably methyl.
En una realización de la invención, R6 es H. In one embodiment of the invention, R 6 is H.
En otra realización de la invención R8 es alquilo, preferiblemente butilo u octilo. In another embodiment of the invention R 8 is alkyl, preferably butyl or octyl.
En una realización preferida de la invención R1 es alquilo, R2 es H o alquilo, R3 es H o alquilo, R4 y R5 se seleccionan entre H o ORg, R6 es H, R7 es H y R8 es alquilo, preferiblemente donde R9 es alquilo. In a preferred embodiment of the invention R 1 is alkyl, R 2 is H or alkyl, R 3 is H or alkyl, R 4 and R 5 are selected from H or ORg, R 6 is H, R 7 is H and R 8 is alkyl , preferably where R 9 is alkyl.
Otra realización de la invención se refiere a una sal de adición y/o solvato farmacéuticamente aceptable de un compuesto de formula (I) de acuerdo con las realizaciones descritas anteriormente. Another embodiment of the invention relates to a pharmaceutically acceptable addition and / or solvate salt of a compound of formula (I) according to the embodiments described above.
En una realización particular de la invención dicha sal de adición y/o solvato farmacéuticamente aceptable es una sal de hidrocloruro o el mesilato.  In a particular embodiment of the invention said pharmaceutically acceptable addition and / or solvate salt is a hydrochloride salt or the mesylate.
En otra realización particular de la invención dicha sal de adición y/o solvato farmacéuticamente aceptable es el cloruro. In another particular embodiment of the invention said pharmaceutically acceptable addition and / or solvate salt is chloride.
Una realización de la invención de acuerdo a lo descrito anteriormente es una sal de adición y/o solvato farmacéuticamente aceptable de un compuesto de fórmula (I) que se selecciona de entre el grupo formado por:  An embodiment of the invention as described above is a pharmaceutically acceptable addition and / or solvate salt of a compound of formula (I) that is selected from the group consisting of:
Cloruro de (Z)-5-(1-butil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3-metoxi- 2H-pirrolio (la), Cloruro de (Z)-5-(1-octil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2- il)metilen)-3-metoxi-2H-pirrolio (Ib), Cloruro de (Z)-5-(1-butil-1 H-1 ,2,3-triazol-4-il)-3-metoxi-2- ((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-2H-pirrolio (le), Cloruro de (Z)-3-metoxi-2-((5-metil-4- pentil-1 H-pirrol-2-il)metilen)-5-(1-octil-1 H-1 ,2,3-triazol-4-il)-2H-pirrolio (Id). (Z) -5- (1-Butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) chloride -3-methoxy-2H-pyrrolium (la), (Z) Chloride -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl -1 H-pyrrol-2- yl) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) Chloride -5- (1-butyl-1 H-1, 2,3-triazol-4- il) -3-methoxy-2- ((5-methyl-4-pentyl-1 H-pyrrol-2-yl) methylene) -2H-pyrrolium (le), (Z) -3-methoxy-2- chloride ((5-methyl-4- pentyl-1 H-pyrrole-2-yl) methylene) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2H-pyrrolium (Id ).
Otra realización de la invención es la ruta sintética preferida para la preparación de los compuestos de la invención y que se ilustra en el siguiente esquema:
Figure imgf000009_0001
Another embodiment of the invention is the preferred synthetic route for the preparation of the compounds of the invention and which is illustrated in the following scheme:
Figure imgf000009_0001
El proceso se realiza en dos etapas a partir de un compuesto 5-alquinil-2H-pirrol-2-ilideno de fórmula (III). La reacción de este tipo de compuestos de fórmula (III) con una azida orgánica R8N3 da lugar a la formación de un 5-(1 ,2,3-triazol-4-il)-1 H-pirrol-2-carbaldehido de fórmula (II). La condensación de este tipo de compuestos de fórmula (II) con un pirrol no sustituido en posición alfa de fórmula (IV), en presencia de un ácido orgánico o inorgánico conduce a la obtención de los compuestos de la invención de fórmula (I) o de sus sales y/o solvatos farmacéuticamente aceptables. The process is carried out in two stages from a 5-alkynyl-2H-pyrrole-2-ylidene compound of formula (III). The reaction of this type of compounds of formula (III) with an organic azide R 8 N 3 results in the formation of a 5- (1, 2,3-triazol-4-yl) -1 H-pyrrole-2- carbaldehyde of formula (II). The condensation of this type of compounds of formula (II) with an unsubstituted pyrrole in the alpha position of formula (IV), in the presence of an organic or inorganic acid leads to obtaining the compounds of the invention of formula (I) or of its pharmaceutically acceptable salts and / or solvates.
Por tanto, esta realización de la invención consiste en un procedimiento de obtención de un compuesto de fórmula (I) o de sus sales y/o solvatos farmacéuticamente aceptables, que comprende:  Therefore, this embodiment of the invention consists in a process for obtaining a compound of formula (I) or its pharmaceutically acceptable salts and / or solvates, comprising:
(a) la reacción de cicloadición de una azida RsN3 y un compuesto 5-alquinil-2H-pirrol-2- ilideno de fórmula (III) utilizando preferentemente un catalizador de cobre para generar un 5-(1 ,2,3-triazol-4-il)-1 H-pirrol-2-carbaldehido de fórmula (II).  (a) the cycloaddition reaction of an RsN3 azide and a 5-alkynyl-2H-pyrrol-2-ylidene compound of formula (III) preferably using a copper catalyst to generate a 5- (1, 2,3-triazole-) 4-yl) -1 H-pyrrole-2-carbaldehyde of formula (II).
(b) Este compuesto de fórmula (II) se condensa con un pirrol no sustituido en posición alfa de fórmula (IV) en presencia de una cantidad de ácido y de un disolvente orgánico. (b) This compound of formula (II) is condensed with an unsubstituted pyrrole in the alpha position of formula (IV) in the presence of an amount of acid and an organic solvent.
(c) El disolvente orgánico se evapora y el compuesto de fórmula (I) deseado se obtiene mediante purificación en columna cromatográfica. (c) The organic solvent is evaporated and the compound of formula (I) desired is obtained by chromatographic column purification.
En la presente invención son catalizadores de cobre aceptables para la realización de la obtención del compuesto de la invención una mezcla de sulfato de cobre (II) y ascorbato sódico.  In the present invention, copper mixtures of copper (II) sulphate and sodium ascorbate are acceptable copper catalysts for carrying out the compound of the invention.
En la presente invención son ácidos aceptables para la realización de la obtención del compuesto de la invención ácido clorhídrico y ácido trifluoroacético.  In the present invention they are acceptable acids for the realization of obtaining the compound of the invention hydrochloric acid and trifluoroacetic acid.
Como disolventes orgánicos se utiliza preferentemente metanol.  As organic solvents, methanol is preferably used.
Los compuestos de la invención de fórmula (I) y sus sales de adición y/o solvatos farmacéuticamente aceptables son particularmente útiles como agentes quimioterapéuticos para el tratamiento de fibrosis quística y de otras enfermedades derivadas del transporte anómalo de aniones a nivel celular. Una realización de la presente invención es el compuesto intermedio de la reacción de cicloadición (a) descrita en el proceso de obtención de los compuestos de fórmula (I), caracterizado por ser un triazol-pirrol-carbaldehido de fórmula (II): The compounds of the invention of formula (I) and their pharmaceutically acceptable addition salts and / or solvates are particularly useful as chemotherapeutic agents for the treatment of cystic fibrosis and other diseases derived from the anomalous transport of anions at the cellular level. An embodiment of the present invention is the intermediate of the cycloaddition reaction (a) described in the process of obtaining the compounds of formula (I), characterized by being a triazole-pyrrole-carbaldehyde of formula (II):
Figure imgf000010_0001
Figure imgf000010_0001
donde R4 y R5 se seleccionan de entre el grupo formado por: H, OH, halógeno, O-Rg, N R10R11 , COORg, CON R10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, where R 4 and R5 are selected from the group consisting of: H, OH, halogen, O-Rg, N R10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl,
R6, R7 y Re se seleccionan de forma independiente de entre el grupo formado por: H, OH, halógeno, O-Rg, N R10R11 , COORg, CON R10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo. R 6 , R 7 and Re are independently selected from the group consisting of: H, OH, halogen, O-Rg, N R10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or hetaryl.
En donde Rg, R10 y Rn son radicales seleccionados de forma independiente de entre el grupo formado por: H, OH, halógeno, alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo.  Wherein Rg, R10 and Rn are radicals independently selected from the group consisting of: H, OH, halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl.
Otra realización de la invención se refiere al compuesto intermedio descrito anteriormente, donde R7 se seleccionan de forma independiente de entre el grupo formado por: H, OH, halógeno, O-Rg, N R10R11 , COORg, CON R10R11 , alquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo. Another embodiment of the invention relates to the intermediate compound described above, where R 7 is independently selected from the group consisting of: H, OH, halogen, O-Rg, N R10R11, COORg, CON R10R11, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl.
En una realización preferida de la invención R7 es H. In a preferred embodiment of the invention R 7 is H.
En otra realización de la invención R6 se selecciona de forma independiente de entre el grupo formado por: H, OH, halógeno, O-Rg, COORg, CON R10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo;  In another embodiment of the invention R6 is independently selected from the group consisting of: H, OH, halogen, O-Rg, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl;
Rs se seleccionan de forma independiente de entre el grupo formado por; H, halógeno, O-Rg, NR10R11 , COORg, CON R10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo y  Rs are independently selected from the group consisting of; H, halogen, O-Rg, NR10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl and
R4 y R5 se seleccionan de entre el grupo formado por: H, OH, O-Rg, N R10R11 , COORg, CON R10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo. R 4 and R 5 are selected from the group consisting of: H, OH, O-Rg, N R10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl.
En otra realización adicional de la invención R9 es alquilo. Una realización de la presente invención es el compuesto intermedio de la reacción de cicloadición (a) descrita en el proceso de obtención de los compuestos de fórmula (I), representado por el 5-(1-butil-1 H-1 ,2,3-triazol-4-il)-3-metoxi-1 H-pirrol-2-carbaldehido de fórmula (Na): In a further embodiment of the invention R 9 is alkyl. An embodiment of the present invention is the intermediate of the cycloaddition reaction (a) described in the process of obtaining the compounds of formula (I), represented by 5- (1-butyl-1 H-1, 2, 3-Triazol-4-yl) -3-methoxy-1 H-pyrrole-2-carbaldehyde of formula (Na):
Figure imgf000011_0001
Figure imgf000011_0001
Otra realización de la presente invención es el compuesto intermedio de la reacción de cicloadición (a) descrita en el proceso de obtención de los compuestos de fórmula (I), representado por el 5-(1-octil-1 H-1 ,2,3-triazol-4-il)-3-metoxi-1 H-pirrol-2-carbaldehido de fórmula (llb): Another embodiment of the present invention is the intermediate of the cycloaddition reaction (a) described in the process of obtaining the compounds of formula (I), represented by 5- (1-octyl-1 H-1, 2, 3-Triazol-4-yl) -3-methoxy-1 H-pyrrole-2-carbaldehyde of formula (llb):
Figure imgf000011_0002
Figure imgf000011_0002
Una realización de la presente invención es una composición farmacéutica que comprende un compuesto de fórmula (I)  An embodiment of the present invention is a pharmaceutical composition comprising a compound of formula (I)
Figure imgf000011_0003
Figure imgf000011_0003
donde Ri , R2, R3, R6, R7 y Re se seleccionan de forma independiente de entre el grupo formado por: H, OH, halógeno, O-Rg, NR10R11 , COORg, CONR10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo; R4 y R5 se seleccionan de entre el grupo formado por: H, OH, halógeno, O-Rg, NR10R11 , COORg, CONR10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo; where Ri, R 2 , R3, R6, R7 and Re are independently selected from the group consisting of: H, OH, halogen, O-Rg, NR10R11, COORg, CONR10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl , arylalkyl, heterocycle or heteroaryl; R 4 and R5 are selected from the group consisting of: H, OH, halogen, O-Rg, NR10R11, COORg, CONR10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl;
en donde Rg, R10 y Rn son radicales seleccionados de forma independiente de entre el grupo formado por: H, OH, halógeno, alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo; wherein Rg, R10 and Rn are radicals independently selected from the group consisting of: H, OH, halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl;
o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, junto con excipientes farmacéuticamente aceptables. or a pharmaceutically acceptable addition salt and / or solvate thereof, together with pharmaceutically acceptable excipients.
Otra realización de la presente invención es una composición farmacéutica que comprende un compuesto de fórmula (I) o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, seleccionado independientemente de entre el grupo formado por: cloruro de (Z)-5-(1-butil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2- il)metilen)-3-metoxi-2H-pirrolio (la), cloruro de (Z)-5-(1 -octil- 1 H- 1 ,2,3-triazol-4-il)-2-((3,5- dimetil-1 H-pirrol-2-il)metilen)-3-metoxi-2H-pirrolio (Ib), cloruro de (Z)-5-(1-butil-1 H-1 ,2,3- triazol-4-il)-3-metoxi-2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-2H-pirrolio (le), cloruro de (Z)- 3-metoxi-2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-5-(1-octil-1 H-1 ,2,3-triazol-4-il)-2H-pirrolio (Id) junto con excipientes farmacéuticamente aceptables.  Another embodiment of the present invention is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (Z) chloride ) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2- yl) methylene) -3-methoxy -2H-pyrrolium (la), (Z) chloride -5- (1-octyl- 1 H- 1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H- pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -3 chloride -methoxy-2 - ((5-methyl-4-pentyl-1 H-pyrrol-2-yl) methylene) -2H-pyrrolium (le), (Z) chloride - 3-methoxy-2 - ((5- methyl-4-pentyl-1 H-pyrrol-2-yl) methylene) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2H-pyrrolium (Id) together with excipients pharmaceutically acceptable.
La composición farmacéutica de la presente invención que comprende un compuesto de fórmula (I) o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, es administrada por una de las vías de administración seleccionadas de entre el grupo compuesto por: vía oral, intravenosa, muscular e intramuscular.  The pharmaceutical composition of the present invention comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, is administered by one of the routes of administration selected from the group consisting of : oral, intravenous, muscular and intramuscular route.
Otra realización particular de la presente invención es una composición farmacéutica que comprende un compuesto de fórmula (I) o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, seleccionado independientemente de entre el grupo formado por: cloruro de (Z)-5-(1-butil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2- il)metilen)-3-metoxi-2H-pirrolio (la), cloruro de (Z)-5-(1 -octil- 1 H- 1 ,2,3-triazol-4-il)-2-((3,5- dimetil-1 H-pirrol-2-il)metilen)-3-metoxi-2H-pirrolio (Ib), cloruro de (Z)-5-(1-butil-1 H-1 ,2,3- triazol-4-il)-3-metoxi-2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-2H-pirrolio (le), cloruro de (Z)- 3-metoxi-2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-5-(1-octil-1 H-1 ,2,3-triazol-4-il)-2H-pirrolio (Id) y que es administrada por una de las vías de administración seleccionadas de entre el grupo compuesto por via oral, intravenosa, muscular e intramuscular.  Another particular embodiment of the present invention is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: chloride of ( Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2- yl) methylene) -3- methoxy-2H-pyrrolium (la), (Z) chloride -5- (1-octyl- 1 H- 1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H -pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) chloride - 3-methoxy-2 - ((5-methyl-4-pentyl-1 H-pyrrol-2-yl) methylene) -2H-pyrrolium (le), (Z) chloride - 3-methoxy-2 - ((5 -methyl-4-pentyl-1 H-pyrrole-2-yl) methylene) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2H-pyrrolium (Id) and that It is administered by one of the administration routes selected from the group consisting of oral, intravenous, muscular and intramuscular route.
Una realización se refiere al uso de un compuesto de fórmula (I) o de una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente para preparar un medicamento. Otra realización se refiere al uso de una composición farmacéutica que comprenda un compuesto de fórmula (I) o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, para preparar un medicamento. One embodiment refers to the use of a compound of formula (I) or of a pharmaceutically acceptable addition salt and / or solvate thereof, described above to prepare a medicament. Another embodiment relates to the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, to prepare a medicament.
Otra realización de refiere a un compuesto de fórmula (I) o a una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, para uso como medicamento.  Another embodiment relates to a compound of formula (I) or to a pharmaceutically acceptable addition salt and / or solvate thereof, described above, for use as a medicine.
Otra realización se refiere a una composición farmacéutica que comprenda un compuesto de fórmula (I) o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, para uso como medicamento.  Another embodiment relates to a pharmaceutical composition comprising a compound of formula (I) or an addition salt and / or a pharmaceutically acceptable solvate thereof, described above, for use as a medicament.
Una realización se refiere al uso de un compuesto de fórmula (I) o de una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, seleccionado independientemente de entre el grupo formado por: (cloruro de (Z)-5-(1 -butil- 1 H- 1 ,2,3-triazol- 4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3-metoxi-2H-pirrolio (la), cloruro de (Z)-5-(1-octil- 1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3-metoxi-2H-pirrolio (Ib), cloruro de (Z)-5-(1-butil-1 H-1 ,2,3-triazol-4-il)-3-metoxi-2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-2H- pirrolio (le), cloruro de (Z)-3-metoxi-2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-5-(1-octil-1 H- 1 ,2,3-triazol-4-il)-2H-pirrolio (Id), para preparar un medicamento. An embodiment relates to the use of a compound of formula (I) or of a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: ((Z) -5 chloride - (1 -butyl- 1 H- 1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H- pyrrolium (la), (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrole-2) chloride -yl) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) chloride -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -3-methoxy- 2 - ((5-methyl-4-pentyl-1 H-pyrrol-2-yl) methylene) -2H- pyrrolium (le), (Z) -3-methoxy-2 - ((5-methyl-4) chloride -pentyl-1 H-pyrrol-2-yl) methylene) -5- (1-octyl-1 H- 1, 2,3-triazol-4-yl) -2H-pyrrolium (Id), to prepare a medicament.
Otra realización se refiere al uso de una composición farmacéutica que comprenda un compuesto de fórmula (I) o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, seleccionado independientemente de entre el grupo formado por: (cloruro de (Z)-5-(1-butil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3- metoxi-2H-pirrolio (la), cloruro de (Z)-5-(1-octil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol- 2-il)metilen)-3-metoxi-2H-pirrolio (Ib), cloruro de (Z)-5-(1-butil-1 H-1 ,2,3-triazol-4-il)-3-metoxi- 2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-2H-pirrolio (le), cloruro de (Z)-3-metoxi-2-((5-metil-4- pentil-1 H-pirrol-2-il)metilen)-5-(1-octil-1 H-1 ,2,3-triazol-4-il)-2H-pirrolio (Id), para preparar un medicamento.  Another embodiment relates to the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (( Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3- methoxy-2H-pyrrolium (la), (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H) chloride -pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) chloride - 3-Methoxy-2 - ((5-methyl-4-pentyl-1 H-pyrrol-2-yl) methylene) -2H-pyrrolium (le), (Z) -3-methoxy-2 - ((5 -methyl-4- pentyl-1 H-pyrrole-2-yl) methylene) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2H-pyrrolium (Id), for Prepare a medication
Una realización se refiere a un compuesto de fórmula (I) o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, seleccionado independientemente de entre el grupo formado por: cloruro de (Z)-5-(1 -butil-1 H-1 ,2,3-triazol- 4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3-metoxi-2H-pirrolio (la), cloruro de (Z)-5-(1-octil- 1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3-metoxi-2H-pirrolio (Ib), cloruro de (Z)-5-(1 -butil-1 H-1 , 2, 3-triazol-4-il)-3-metoxi-2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-2H- pirrolio (le), cloruro de (Z)-3-metoxi-2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-5-(1-octil-1 H- 1 ,2,3-triazol-4-il)-2H-pirrolio (Id), para uso como medicamento. Otra realización se refiere a una composición farmacéutica que comprenda un compuesto de fórmula (I) o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, seleccionado independientemente de entre el grupo formado por: cloruro de (Z)-5-(1-butil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3-metoxi- 2H-pirrolio (la), cloruro de (Z)-5-(1-octil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2- il)metilen)-3-metoxi-2H-pirrolio (Ib), cloruro de (Z)-5-(1-butil-1 H-1 ,2,3-triazol-4-il)-3-metoxi-2- ((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-2H-pirrolio (le), cloruro de (Z)-3-metoxi-2-((5-metil-4- pentil-1 H-pirrol-2-il)metilen)-5-(1-octil-1 H-1 ,2,3-triazol-4-il)-2H-pirrolio (Id), para uso como medicamento. One embodiment refers to a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (Z) -5- (1 - butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (la) , (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene chloride ) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1 -butyl-1 H-1, 2, 3-triazol-4-yl) -3-methoxy-2 - (( 5-methyl-4-pentyl-1 H-pyrrol-2-yl) methylene) -2H- pyrrolium (le), (Z) -3-methoxy-2 - ((5-methyl-4-pentyl-1) chloride H-pyrrol-2-yl) methylene) -5- (1-octyl-1 H- 1, 2,3-triazol-4-yl) -2H-pyrrolium (Id), for use as a medicine. Another embodiment relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (Z) chloride - 5- (1-Butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H -pyrrolium (la), (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrole-) chloride 2- il) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -3-methoxy chloride -2- ((5-methyl-4-pentyl-1 H -pyrrol-2-yl) methylene) -2H-pyrrolium (le), (Z) -3-methoxy-2 - ((5-methyl-) chloride 4- pentyl-1 H-pyrrol-2-yl) methylene) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2H-pyrrolium (Id), for use as a medicine .
Una realización se refiere al uso de un compuesto de fórmula (I) o de una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, para preparar un medicamento destinado al tratamiento y/o profilaxis de enfermedades derivadas del transporte anómalo de aniones a nivel celular. One embodiment refers to the use of a compound of formula (I) or of a pharmaceutically acceptable addition salt and / or solvate thereof, described above, to prepare a medicament for the treatment and / or prophylaxis of diseases derived from abnormal transport. of anions at the cellular level.
Son enfermedades derivadas del transporte anómalo de aniones a nivel celular en el contexto de esta invención la fibrosis quística, la enfermedad de Best, el síndrome de Bartter, la enfermedad pulmonar obstructiva crónica o la mitonia congénita.  Diseases derived from the anomalous transport of anions at the cellular level in the context of this invention are cystic fibrosis, Best's disease, Bartter's syndrome, chronic obstructive pulmonary disease or congenital mitonia.
Otra realización se refiere al uso de una composición farmacéutica que comprenda un compuesto de fórmula (I) o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, para preparar un medicamento destinado al tratamiento y/o profilaxis de enfermedades derivadas del transporte anómalo de aniones a nivel celular. Another embodiment relates to the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, to prepare a medicament for the treatment and / or prophylaxis of diseases. derived from the anomalous transport of anions at the cellular level.
Una realización se refiere a un compuesto de fórmula (I) o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, para uso en el tratamiento y/o profilaxis de enfermedades derivadas del transporte anómalo de aniones a nivel celular.One embodiment refers to a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, for use in the treatment and / or prophylaxis of diseases derived from the anomalous transport of anions at the cellular level. .
Otra realización se refiere a una composición farmacéutica que comprenda un compuesto de fórmula (I) o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, para uso en el tratamiento y/o profilaxis de enfermedades derivadas del transporte anómalo de aniones a nivel celular Another embodiment relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, for use in the treatment and / or prophylaxis of diseases derived from abnormal transport. of anions at the cellular level
Una realización se refiere al uso de un compuesto de fórmula (I) o de una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, seleccionado independientemente de entre el grupo formado por: cloruro de (Z)-5-(1 -butil-1 H-1 ,2,3-triazol- 4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3-metoxi-2H-pirrolio (la), cloruro de (Z)-5-(1-octil- 1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3-metoxi-2H-pirrolio (Ib), cloruro de (Z)-5-(1 -butil-1 H-1 , 2, 3-triazol-4-il)-3-metoxi-2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-2H- pirrolio (le), cloruro de (Z)-3-metoxi-2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-5-(1-octil-1 H- 1 ,2,3-triazol-4-il)-2H-pirrolio (Id), para preparar un medicamento destinado al tratamiento y/o profilaxis de enfermedades derivadas del transporte anómalo de aniones a nivel celular.One embodiment refers to the use of a compound of formula (I) or of a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (Z) -5- chloride (1-Butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (la), (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrole-2-) chloride il) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1 -butyl-1 H-1, 2, 3-triazol-4-yl) -3-methoxy-2 chloride - ((5-methyl-4-pentyl-1 H-pyrrol-2-yl) methylene) -2H-pyrrolium (le), (Z) -3-methoxy-2 - ((5-methyl-4-) chloride pentyl-1 H-pyrrole-2-yl) methylene) -5- (1-octyl-1 H- 1, 2,3-triazol-4-yl) -2H-pyrrolium (Id), to prepare a medicament for the treatment and / or prophylaxis of diseases derived from the anomalous transport of anions at the cellular level.
Otra realización se refiere al uso de una composición farmacéutica que contenga un compuesto de fórmula (I) o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, seleccionado independientemente de entre el grupo formado por: cloruro de (Z)-5-(1 -butil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3- metoxi-2H-pirrolio (la), cloruro de (Z)-5-(1-octil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol- 2-il)metilen)-3-metoxi-2H-pirrolio (Ib), cloruro de (Z)-5-(1-butil-1 H-1 ,2,3-triazol-4-il)-3-metoxi- 2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-2H-pirrolio (le), cloruro de (Z)-3-metoxi-2-((5-metil-4- pentil-1 H-pirrol-2-il)metilen)-5-(1-octil-1 H-1 ,2,3-triazol-4-il)-2H-pirrolio (Id), para preparar un medicamento destinado al tratamiento y/o profilaxis de enfermedades derivadas del transporte anómalo de aniones a nivel celular. Another embodiment relates to the use of a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (Z) chloride ) -5- (1 -butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy -2H-pyrrolium (la), (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-) chloride pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -3 chloride -methoxy- 2 - ((5-methyl-4-pentyl-1 H -pyrrol-2-yl) methylene) -2H-pyrrolium (le), (Z) -3-methoxy-2 chloride ((5- methyl-4- pentyl-1 H-pyrrole-2-yl) methylene) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2H-pyrrolium (Id), to prepare a medicine intended for the treatment and / or prophylaxis of diseases derived from the anomalous transport of anions at the cellular level.
Una realización se refiere a un compuesto de fórmula (I) o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, seleccionado independientemente de entre el grupo formado por: cloruro de (Z)-5-(1 -butil-1 H-1 , 2, 3-triazol- 4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3-metoxi-2H-pirrolio (la), cloruro de (Z)-5-(1-octil- 1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3-metoxi-2H-pirrolio (Ib), cloruro de (Z)-5-(1 -butil-1 H-1 , 2, 3-triazol-4-il)-3-metoxi-2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-2H- pirrolio (le), cloruro de (Z)-3-metoxi-2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-5-(1-octil-1 H- 1 ,2,3-triazol-4-il)-2H-pirrolio (Id), para uso en el tratamiento y/o profilaxis de enfermedades derivadas del transporte anómalo de aniones a nivel celular.  One embodiment refers to a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (Z) -5- (1 - butyl-1 H-1,2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (la) , (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene chloride ) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1 -butyl-1 H-1, 2, 3-triazol-4-yl) -3-methoxy-2 - (( 5-methyl-4-pentyl-1 H-pyrrol-2-yl) methylene) -2H- pyrrolium (le), (Z) -3-methoxy-2 - ((5-methyl-4-pentyl-1) chloride H-pyrrole-2-yl) methylene) -5- (1-octyl-1 H- 1, 2,3-triazol-4-yl) -2H-pyrrolium (Id), for use in treatment and / or prophylaxis of diseases derived from the anomalous transport of anions at the cellular level.
Otra realización se refiere a una composición farmacéutica que comprenda un compuesto de fórmula (I) o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, seleccionado independientemente de entre el grupo formado por: cloruro de (Z)-5-(1-butil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3-metoxi- 2H-pirrolio (la), cloruro de (Z)-5-(1-octil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2- il)metilen)-3-metoxi-2H-pirrolio (Ib), cloruro de (Z)-5-(1-butil-1 H-1 ,2,3-triazol-4-il)-3-metoxi-2- ((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-2H-pirrolio (le), cloruro de (Z)-3-metoxi-2-((5-metil-4- pentil-1 H-pirrol-2-il)metilen)-5-(1-octil-1 H-1 ,2,3-triazol-4-il)-2H-pirrolio (Id), para uso en el tratamiento y/o profilaxis de enfermedades derivadas del transporte anómalo de aniones a nivel celular.  Another embodiment relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (Z) chloride - 5- (1-Butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H -pyrrolium (la), (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrole-) chloride 2- il) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -3-methoxy chloride -2- ((5-methyl-4-pentyl-1 H -pyrrol-2-yl) methylene) -2H-pyrrolium (le), (Z) -3-methoxy-2 - ((5-methyl-) chloride 4- pentyl-1 H-pyrrol-2-yl) methylene) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2H-pyrrolium (Id), for use in the treatment and / or prophylaxis of diseases derived from the anomalous transport of anions at the cellular level.
Una realización se refiere al uso de un compuesto de fórmula (I) o de una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, para preparar un medicamento destinado al tratamiento y/o profilaxis de la fibrosis quística. Otra realización se refiere al uso de una composición farmacéutica que comprenda un compuesto de fórmula (I) o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, para preparar un medicamento destinado al tratamiento y/o profilaxis de la fibrosis quística. An embodiment relates to the use of a compound of formula (I) or of a pharmaceutically acceptable addition salt and / or solvate thereof, described above, to prepare a medicament for the treatment and / or prophylaxis of cystic fibrosis. Another embodiment relates to the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, to prepare a medicament for the treatment and / or prophylaxis of the cystic fibrosis.
Una realización se refiere a un compuesto de fórmula (I) o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, para uso en el tratamiento y/o profilaxis de la fibrosis quística. One embodiment refers to a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, for use in the treatment and / or prophylaxis of cystic fibrosis.
Otra realización se refiere a una composición farmacéutica que comprenda un compuesto de fórmula (I) o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, para uso en el tratamiento y/o profilaxis de la fibrosis quística.  Another embodiment relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, for use in the treatment and / or prophylaxis of cystic fibrosis.
Una realización se refiere al uso de un compuesto de fórmula (I) o de una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, seleccionado independientemente de entre el grupo formado por: cloruro de (Z)-5-(1 -butil-1 H-1 ,2,3-triazol- 4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3-metoxi-2H-pirrolio (la), cloruro de (Z)-5-(1-octil- 1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3-metoxi-2H-pirrolio (Ib), cloruro de (Z)-5-(1 -butil-1 H-1 , 2, 3-triazol-4-il)-3-metoxi-2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-2H- pirrolio (le), cloruro de (Z)-3-metoxi-2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-5-(1-octil-1 H- 1 ,2,3-triazol-4-il)-2H-pirrolio (Id), para preparar un medicamento destinado al tratamiento y/o profilaxis de la fibrosis quística.  One embodiment refers to the use of a compound of formula (I) or of a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (Z) -5- chloride (1-Butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (la), (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrole-2-) chloride il) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1 -butyl-1 H-1, 2, 3-triazol-4-yl) -3-methoxy-2 chloride - ((5-methyl-4-pentyl-1 H-pyrrol-2-yl) methylene) -2H-pyrrolium (le), (Z) -3-methoxy-2 - ((5-methyl-4-) chloride pentyl-1 H-pyrrol-2-yl) methylene) -5- (1-octyl-1 H- 1, 2,3-triazol-4-yl) -2H-pyrrolium (Id), to prepare a medicament intended for treatment and / or prophylaxis of cystic fibrosis.
Una realización se refiere al uso de una composición farmacéutica que comprenda un compuesto de fórmula (I) o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, seleccionado independientemente de entre el grupo formado por: cloruro de (Z)-5-(1 -butil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3- metoxi-2H-pirrolio (la), cloruro de (Z)-5-(1-octil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol- 2-il)metilen)-3-metoxi-2H-pirrolio (Ib), cloruro de (Z)-5-(1-butil-1 H-1 ,2,3-triazol-4-il)-3-metoxi- 2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-2H-pirrolio (le), cloruro de (Z)-3-metoxi-2-((5-metil-4- pentil-1 H-pirrol-2-il)metilen)-5-(1-octil-1 H-1 ,2,3-triazol-4-il)-2H-pirrolio (Id), para preparar un medicamento destinado al tratamiento y/o profilaxis de la fibrosis quística. An embodiment relates to the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (Z) chloride ) -5- (1 -butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy -2H-pyrrolium (la), (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-) chloride pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -3 chloride -methoxy- 2 - ((5-methyl-4-pentyl-1 H -pyrrol-2-yl) methylene) -2H-pyrrolium (le), (Z) -3-methoxy-2 chloride ((5- methyl-4- pentyl-1 H-pyrrole-2-yl) methylene) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2H-pyrrolium (Id), to prepare a medicine intended for the treatment and / or prophylaxis of cystic fibrosis.
Otra realización se refiere a un compuesto de fórmula (I) o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, seleccionado independientemente de entre el grupo formado por: cloruro de (Z)-5-(1 -butil-1 H-1 , 2, 3-triazol- 4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3-metoxi-2H-pirrolio (la), cloruro de (Z)-5-(1-octil- 1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3-metoxi-2H-pirrolio (Ib), cloruro de (Z)-5-(1 -butil-1 H-1 , 2, 3-triazol-4-il)-3-metoxi-2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-2H- pirrolio (le), cloruro de (Z)-3-metoxi-2-((5-rnetil-4-pentil-1 H-pirrol-2-il)metilen)-5-(1-octil-1 H- 1 ,2,3-triazol-4-il)-2H-pirrolio (Id), para uso en el tratamiento y/o profilaxis de la fibrosis quística.Another embodiment relates to a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (Z) -5- (1 - butyl-1 H-1,2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (la) , (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene chloride ) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1 -butyl-1 H-1, 2, 3-triazol-4-yl) -3-methoxy-2 - (( 5-methyl-4-pentyl-1 H-pyrrol-2-yl) methylene) -2H- pyrrolium (le), (Z) -3-methoxy-2 - ((5-rnetyl-4-pentyl-1 H-pyrrol-2-yl) methylene) -5- (1-octyl-1 H- 1 chloride) , 2,3-triazol-4-yl) -2H-pyrrolium (Id), for use in the treatment and / or prophylaxis of cystic fibrosis.
Otra realización se refiere a una composición farmacéutica que comprenda un compuesto de fórmula (I) o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, seleccionado independientemente de entre el grupo formado por: cloruro de (Z)-5-(1-butil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3-metoxi- 2H-pirrolio (la), cloruro de (Z)-5-(1-octil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2- il)metilen)-3-metoxi-2H-pirrolio (Ib), cloruro de (Z)-5-(1-butil-1 H-1 ,2,3-triazol-4-il)-3-metoxi-2- ((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-2H-pirrolio (le), cloruro de (Z)-3-metoxi-2-((5-metil-4- pentil-1 H-pirrol-2-il)metilen)-5-(1-octil-1 H-1 ,2,3-triazol-4-il)-2H-pirrolio (Id), para uso en el tratamiento y/o profilaxis de la fibrosis quística. Another embodiment relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, independently selected from the group consisting of: (Z) chloride - 5- (1-Butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H -pyrrolium (la), (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrole-) chloride 2- il) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -3-methoxy chloride -2- ((5-methyl-4-pentyl-1 H -pyrrol-2-yl) methylene) -2H-pyrrolium (le), (Z) -3-methoxy-2 - ((5-methyl-) chloride 4- pentyl-1 H-pyrrol-2-yl) methylene) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2H-pyrrolium (Id), for use in the treatment and / or prophylaxis of cystic fibrosis.
Una realización se refiere a un método de tratamiento y/o profilaxis de enfermedades, y en particular de enfermedades derivadas del transporte anómalo de aniones a nivel celular, que comprende administrar a un sujeto humano una composición farmacéutica que comprenda una cantidad terapéuticamente efectiva de un compuesto de fórmula (I) o de una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente.  One embodiment relates to a method of treatment and / or prophylaxis of diseases, and in particular of diseases derived from the anomalous transport of anions at the cellular level, which comprises administering to a human subject a pharmaceutical composition comprising a therapeutically effective amount of a compound. of formula (I) or of an addition salt and / or a pharmaceutically acceptable solvate thereof, described above.
Otra realización se refiere a un método de tratamiento y/o profilaxis de la fibrosis quística, que comprende administrar a un sujeto humano una composición farmacéutica que comprenda una cantidad terapéuticamente efectiva de un compuesto de fórmula (I) o de una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente.  Another embodiment relates to a method of treatment and / or prophylaxis of cystic fibrosis, which comprises administering to a human subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or of an addition salt and / or a pharmaceutically acceptable solvate thereof, described above.
Una realización se refiere a un método de tratamiento y/o profilaxis de enfermedades derivadas del transporte anómalo de aniones a nivel celular, que comprende administrar a un sujeto humano una composición farmacéutica que comprenda una cantidad terapéuticamente efectiva de un compuesto de fórmula (I) o de una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, seleccionado independientemente de entre el grupo formado por: cloruro de (Z)-5-(1 -butil-1 H-1 ,2,3-triazol- 4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3-metoxi-2H-pirrolio (la), cloruro de (Z)-5-(1-octil- 1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3-metoxi-2H-pirrolio (Ib), cloruro de (Z)-5-(1 -butil-1 H-1 , 2, 3-triazol-4-il)-3-metoxi-2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-2H- pirrolio (le), cloruro de (Z)-3-metoxi-2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-5-(1-octil-1 H- 1 ,2,3-triazol-4-il)-2H-pirrolio (Id).  One embodiment relates to a method of treatment and / or prophylaxis of diseases derived from the anomalous transport of anions at the cellular level, which comprises administering to a human subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or of an addition salt and / or a pharmaceutically acceptable solvate thereof, described above, independently selected from the group consisting of: (Z) -5- (1 -butyl-1 H-1, 2,3-triazole chloride) - 4-yl) -2 - ((3,5-dimethyl-1 H -pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (la), (Z) -5- (1-) chloride octyl- 1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (Ib) , (Z) -5- (1-Butyl-1 H-1, 2, 3-triazol-4-yl) -3-methoxy-2 - ((5-methyl-4-pentyl-1 H-pyrrole) chloride -2-yl) methylene) -2H- pyrrolium (le), (Z) -3-methoxy-2 - ((5-methyl-4-pentyl-1 H-pyrrole-2-yl) methylene) -5 chloride - (1-octyl-1 H- 1, 2,3-triazol-4-yl) -2H-pyrrolium (Id).
Otra realización se refiere a un método de tratamiento y/o profilaxis de la fibrosis quística, que comprende administrar a un sujeto una composición farmacéutica que comprenda una cantidad terapéuticamente efectiva de un compuesto de fórmula (I) o de una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente seleccionado independientemente de entre el grupo formado por: cloruro de (Z)-5-(1 -butil-1 H-1 ,2,3-triazol- 4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3-metoxi-2H-pirrolio (la), cloruro de (Z)-5-(1-octil- 1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3-metoxi-2H-pirrolio (Ib), cloruro de (Z)-5-(1 -butil-1 H-1 , 2, 3-triazol-4-il)-3-metoxi-2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-2H- pirrolio (le), cloruro de (Z)-3-metoxi-2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-5-(1-octil-1 H- 1 ,2,3-triazol-4-il)-2H-pirrolio (Id). Another embodiment relates to a method of treatment and / or prophylaxis of cystic fibrosis, which comprises administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or of an addition salt and / or a pharmaceutically acceptable solvate thereof, described above selected independently from the group consisting of: (Z) -5- (1 -butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-) chloride pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (la), (Z) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 chloride - ((3,5-Dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1 -butyl-1 H-1, 2,3-triazol-4-yl) -3-methoxy-2 - ((5-methyl-4-pentyl-1 H-pyrrol-2-yl) methylene) -2H- pyrrolium (le), (Z) chloride ) -3-methoxy-2 - ((5-methyl-4-pentyl-1 H-pyrrol-2-yl) methylene) -5- (1-octyl-1 H- 1, 2,3-triazol-4- il) -2H-pyrrolium (Id).
Una realización se refiere a un método de tratamiento y/o profilaxis de la fibrosis quística que comprenda administrar un compuesto de formula (I) o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, en una concentración de 0, 1 μΜ a 50 μΜ, preferentemente en una concentración de 15 μΜ a 40 μΜ y más preferiblemente, cuando se trata de combinar una mayor eficacia terapéutica minimizando la toxicidad del fármaco administrado, cuando la concentración del compuesto de fórmula (I) o de una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, descritos anteriormente, a administrar se encuentra en el rango de 0,1 μΜ a 20 μΜ.  One embodiment relates to a method of treatment and / or prophylaxis of cystic fibrosis comprising administering a compound of formula (I) or a pharmaceutically acceptable addition salt and / or solvate thereof, described above, in a concentration of 0 , 1 μΜ to 50 μΜ, preferably in a concentration of 15 μΜ to 40 μΜ and more preferably, when it comes to combining greater therapeutic efficacy by minimizing the toxicity of the drug administered, when the concentration of the compound of formula (I) or of a Addition salt and / or a pharmaceutically acceptable solvate thereof, described above, to be administered is in the range of 0.1 μΜ to 20 μΜ.
BREVE DESCRIPCIÓN DE LAS FIGURAS BRIEF DESCRIPTION OF THE FIGURES
Figura 1. Ensayo en fluorescencia usado para medir la actividad de los compuestos. Ejemplo del ensayo usado para determinar la actividad de los compuestos. El panel muestra la respuesta de células incubadas durante 40 minutos con el compuesto le a diversas concentraciones y en triplicado. La aplicación de Nal induce una reducción de la fluorescencia, cuya velocidad depende de la concentración del compuesto: 2μΜ (gris claro), 8.3 μΜ (gris oscuro) y 20 μΜ (negro).  Figure 1. Fluorescence assay used to measure the activity of the compounds. Example of the test used to determine the activity of the compounds. The panel shows the response of cells incubated for 40 minutes with the compound at various concentrations and in triplicate. The application of Nal induces a reduction in fluorescence, the speed of which depends on the concentration of the compound: 2μΜ (light gray), 8.3 μ oscuro (dark gray) and 20 μΜ (black).
Figura 2. Dosis-respuesta de los compuestos la, Ib, le e Id. La velocidad máxima de extinción de la fluorescencia (VmEF) se obtiene de experimentos como los del ejemplo mostrado en la figura 1.  Figure 2. Dose-response of compounds la, Ib, le and Id. The maximum rate of fluorescence extinction (VmEF) is obtained from experiments such as the example shown in Figure 1.
Figura 3. Dependencia del pH de la actividad de los compuestos la, Ib, le y Id. La figura muestra la velocidad máxima de extinción de la fluorescencia (VmEF) de los cuatro compuestos (concentración: 20 μΜ) a los valores de pH indicados. Como comparación se muestra también la respuesta a dos valores de pH de la proteína CFTR, cuya actividad es estimulada por la aplicación de un agonista que aumentan el cAMP intracelular (forskolina 20 μΜ) y de un potenciador (genisteina 10 μΜ).  Figure 3. pH dependence of the activity of the compounds la, Ib, le and Id. The figure shows the maximum fluorescence extinction rate (VmEF) of the four compounds (concentration: 20 μΜ) at the indicated pH values . As a comparison, the response to two pH values of the CFTR protein is also shown, whose activity is stimulated by the application of an agonist that increases intracellular cAMP (forskolin 20 μΜ) and an enhancer (genistein 10 μΜ).
Figura 4. Cinética de incorporación del compuesto le potenciador (12 μΜ) en la membrana celular. En la presencia continua del compuesto en la solución extracelular, la actividad de le en la membrana celular, medida como VmFE, aumenta con el tiempo. Figura 5. Estabilidad del compuesto le (12 μΜ) en la membrana celular. Después de 45 minutos de incubación, el compuesto le es lavado de la solución extracelular para establecer cuál es su estabilidad en la membrana de las células. Vemos que la actividad de le en la membrana disminuye muy lentamente, quedando más del 85% del transporte después de 60 minutos. Figure 4. Kinetics of incorporation of the enhancer compound (12 μΜ) into the cell membrane. In the continuous presence of the compound in the extracellular solution, the activity of the cell membrane, measured as VmFE, increases with time. Figure 5. Stability of compound le (12 μΜ) in the cell membrane. After 45 minutes of incubation, the compound is washed from the extracellular solution to establish its stability in the cell membrane. We see that the activity of the membrane decreases very slowly, leaving more than 85% of the transport after 60 minutes.
EJEMPLOS EXAMPLES
Ejemplo 1. Síntesis de compuestos intermedios Na y llb.  Example 1. Synthesis of intermediate compounds Na and llb.
Figure imgf000019_0001
Figure imgf000019_0001
5-(1-butil-1 H-1 ,2,3-triazol-4-il)-3-metoxi-1 H-pirrol-2-carbaldehido (lia). A una mezcla del alquino III (204 mg, 1 mmol) y 1-butanoazida (99 mg, 1 mmol) disuelta en tBuOH (4 mL) y agua (2 mL) se le añaden CuS04 (0.2 equiv., disuelto en 2 mL de agua), K2CO3 (1 equiv.) y ascorbato de sodio (0.4 equiv.). La mezcla resultante se agita durante 3 días vigorosamente a temperatura ambiente. Posteriormente la mezcla de reacción se diluye con 50 mL de NH4OH, y tras 10 minutos se extrae con Et2<D (3 x 25 mL). La fase orgánica es lavada con una disolución saturada de NaCI (1 x 40 mL), secada sobre Na2SC¼ y concentrada a presión reducida. El sólido obtenido se recristaliza en una mezcla DCM:hexano:Et20 obteniéndose el compuesto Na. Rendimiento: 67%. 1 H NMR (300 MHz, CDCI3): δ = 10.76 (s, 1 H), 9.51 (s, 1 H), 8.26 (s, 1 H), 6.37 (s, 1 H), 4.42 (t, J = 7.2 Hz, 2H), 3.92 (s, 3H, OCH3), 1.99-1.87 (m, 2H), 1.47-1.33 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCI3): δ = 174.44 (CHO), 159.79 (C), 140.01 (C), 131.72 (C), 121.25 (CH), 1 19.10 (C), 93.55 (CH), 58.23 (OCH3), 50.42 (CH2), 32.31 (CH2), 19.80 (CH2), 13.58 (CH3); HRMS (El) m/z [M]+ calculado para [C12H16N402] 248.1273; encontrado: 248.1282. 5- (1-Butyl-1 H-1, 2,3-triazol-4-yl) -3-methoxy-1 H-pyrrol-2-carbaldehyde (lia). To a mixture of the alkyne III (204 mg, 1 mmol) and 1-butanoazide (99 mg, 1 mmol) dissolved in tBuOH (4 mL) and water (2 mL) are added CuS04 (0.2 equiv., Dissolved in 2 mL of water), K2CO 3 (1 equiv.) and sodium ascorbate (0.4 equiv.). The resulting mixture is stirred vigorously for 3 days at room temperature. Subsequently, the reaction mixture is diluted with 50 mL of NH4OH, and after 10 minutes it is extracted with Et2 <D (3 x 25 mL). The organic phase is washed with a saturated NaCl solution (1 x 40 mL), dried over Na2SC¼ and concentrated under reduced pressure. The solid obtained is recrystallized from a mixture DCM: hexane: Et20 to obtain the Na compound. Yield: 67%. 1 H NMR (300 MHz, CDCI3): δ = 10.76 (s, 1 H), 9.51 (s, 1 H), 8.26 (s, 1 H), 6.37 (s, 1 H), 4.42 (t, J = 7.2 Hz, 2H), 3.92 (s, 3H, OCH3), 1.99-1.87 (m, 2H), 1.47-1.33 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCI3): δ = 174.44 (CHO), 159.79 (C), 140.01 (C), 131.72 (C), 121.25 (CH), 1 19.10 (C), 93.55 (CH), 58.23 (OCH3 ), 50.42 (CH2), 32.31 (CH2), 19.80 (CH2), 13.58 (CH3); HRMS (El) m / z [M] + calculated for [C12H16N402] 248.1273; Found: 248.1282.
Figure imgf000019_0002
Figure imgf000019_0002
5-(1-octil-1 H-1,2,3-triazol-4-il)-3-metoxi-1 H-pirrol-2-carbaldehido (llb). A una mezcla del alquino III (204 mg, 1 mmol) y 1-octanoazida (155 mg, 1 mmol) disuelta en tBuOH (4 mL) y agua (2 mL) se le añaden CuS04 (0.2 equiv., disuelto en 2 mL de agua), K2CO3 (1 equiv.) y ascorbato de sodio (0.4 equiv.). La mezcla resultante se agita durante 3 días vigorosamente a temperatura ambiente. Posteriormente la mezcla de reacción se diluye con 50 ml_ de NH4OH, y tras 10 minutos se extrae con Et2Ü (3 x 25 ml_). La fase orgánica es lavada con una disolución saturada de NaCI (1 x 40 mL), secada sobre Na2SC¼ y concentrada a presión reducida. El sólido obtenido se recristaliza en una mezcla DCM:hexano:Et20 obteniéndose el compuesto llb. Rendimiento: 76 %. 1 H NMR (300 MHz, CDCI3): δ = 1 1.21 (s, 1 H), 9.49 (s, 1 H), 8.43 (s, 1 H), 6.44 (s, 1 H), 4.40 (t, J = 6.3 Hz, 2H), 3.92 (s, 3H, OCH3), 2.09-1.78 (m, 2H), 1.47-1.1 1 (m, 10H), 0.86 (t, J = 6.4 Hz, 3H); 13C NMR (75 MHz, CDCI3): δ = 174.31 (CHO), 160.04 (C), 140.02 (C), 132.12 (C), 121.42 (CH), 1 19.13 (C), 93.56 (CH), 58.19 (OCH3), 50.69 (CH2), 31.83 (CH2), 30.34 (CH2), 29.17 (CH2), 29.08 (CH2), 26.57 (CH2), 22.71 (CH2), 14.18 (CH3). HRMS (El) m/z [M]+ calculado para [C16H24N402] 304.1899; 5- (1-Octyl-1 H-1,2,3-triazol-4-yl) -3-methoxy-1 H-pyrrol-2-carbaldehyde (llb). To a mixture of the alkyne III (204 mg, 1 mmol) and 1-octanoazide (155 mg, 1 mmol) dissolved in tBuOH (4 mL) and water (2 mL) are added CuS04 (0.2 equiv., Dissolved in 2 mL of water), K2CO3 (1 equiv.) and sodium ascorbate (0.4 equiv.). The resulting mixture is stirred vigorously for 3 days at room temperature. Subsequently, the reaction mixture is diluted with 50 ml_ of NH4OH, and after 10 minutes it is extracted with Et2Ü (3 x 25 ml_). The organic phase is washed with a saturated NaCl solution (1 x 40 mL), dried over Na2SC¼ and concentrated under reduced pressure. The solid obtained is recrystallized from a mixture DCM: hexane: Et20 obtaining compound llb. Yield: 76%. 1 H NMR (300 MHz, CDCI3): δ = 1 1.21 (s, 1 H), 9.49 (s, 1 H), 8.43 (s, 1 H), 6.44 (s, 1 H), 4.40 (t, J = 6.3 Hz, 2H), 3.92 (s, 3H, OCH3), 2.09-1.78 (m, 2H), 1.47-1.1 1 (m, 10H), 0.86 (t, J = 6.4 Hz, 3H); 13C NMR (75 MHz, CDCI3): δ = 174.31 (CHO), 160.04 (C), 140.02 (C), 132.12 (C), 121.42 (CH), 1 19.13 (C), 93.56 (CH), 58.19 (OCH3 ), 50.69 (CH2), 31.83 (CH2), 30.34 (CH2), 29.17 (CH2), 29.08 (CH2), 26.57 (CH2), 22.71 (CH2), 14.18 (CH3). HRMS (El) m / z [M] + calculated for [C16H24N402] 304.1899;
Ejemplo 2: Síntesis del compuesto la representado por la fórmula: Example 2: Synthesis of the compound represented by the formula:
Figure imgf000020_0001
Figure imgf000020_0001
Cloruro de (Z)-5-(1-butil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3- metoxi-2H-pirrolio (la). Una mezcla del carbaldehido Na (1 equiv, 0.3 mmol) y 2,4-dimetilpirrol (2 equiv, 0.6 mmol) se disuelve en 5 mL de MeOH bajo atmósfera de nitrógeno a temperatura ambiente. Sobre esto se añade HCI disuelto en MeOH (2 equiv, 0.6 mmol) gota a gota en 15 minutos. Una vez que una placa de TLC muestra que el material de partida se ha consumido el disolvente es evaporado a presión reducida. El residuo resultante se purifica mediante columna cromatográfica en óxido de aluminio (hexane/AcOEt 3: 1) obteniéndose el compuesto la. Rendimiento 66 %. 1 H NMR (300 MHz, CDCI3): δ = 13.55 (s, 1 H), 13.24 (s, 1 H), 9.69 (s, 1 H), 7.24 (s, 1 H), 6.66 (d, J = 1.3 Hz, 1 H), 6.12 (s, 1 H), 4.44 (t, J = 7.2 Hz, 2H), 4.02 (s, 3H, OCH3), 2.60 (s, 3H), 2.32 (s, 3H), 2.0-1.91 (m, 2H), 1.44-1.32 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCI3): δ = 165.61 (C), 153.52 (C), 145.58 (C), 144.73 (C), 138.54 (C), 126.60 (CH), 126.43 (C), 119.16 (C), 117.19 (CH), 116.91 (CH), 94.58 (CH), 58.99 (OCH3), 50.60 (CH2), 32.17 (CH2), 19.77 (CH2), 14.41 (CH3), 13.54 (CH3), 12.17 (CH3). HRMS (El) m/z [M]+ calculado para [C18H23N50] 325.1903; encontrado: 325.1913. Ejemplo 3: Síntesis del compuesto Ib representado por la fórmula: (Z) -5- (1-Butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) chloride -3- methoxy-2H-pyrrolium (la). A mixture of carbaldehyde Na (1 equiv, 0.3 mmol) and 2,4-dimethylpyrrole (2 equiv, 0.6 mmol) is dissolved in 5 mL of MeOH under a nitrogen atmosphere at room temperature. On this, HCI dissolved in MeOH (2 equiv, 0.6 mmol) is added dropwise in 15 minutes. Once a TLC plate shows that the starting material has been consumed the solvent is evaporated under reduced pressure. The resulting residue is purified by chromatographic column on aluminum oxide (hexane / AcOEt 3: 1) to obtain compound la. 66% yield. 1 H NMR (300 MHz, CDCI 3 ): δ = 13.55 (s, 1 H), 13.24 (s, 1 H), 9.69 (s, 1 H), 7.24 (s, 1 H), 6.66 (d, J = 1.3 Hz, 1 H), 6.12 (s, 1 H), 4.44 (t, J = 7.2 Hz, 2H), 4.02 (s, 3H, OCH3), 2.60 (s, 3H), 2.32 (s, 3H) , 2.0-1.91 (m, 2H), 1.44-1.32 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCI3): δ = 165.61 (C), 153.52 (C), 145.58 (C), 144.73 (C), 138.54 (C), 126.60 (CH), 126.43 (C), 119.16 (C) , 117.19 (CH), 116.91 (CH), 94.58 (CH), 58.99 (OCH3), 50.60 (CH2), 32.17 (CH2), 19.77 (CH2), 14.41 (CH3), 13.54 (CH3), 12.17 (CH3) . HRMS (El) m / z [M] + calculated for [C18H23N50] 325.1903; Found: 325.1913. Example 3: Synthesis of compound Ib represented by the formula:
Figure imgf000021_0001
Figure imgf000021_0001
Cloruro de (Z)-5-(1 -octil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3- metoxi-2H-pirrolio (Ib). Una mezcla del carbaldehido llb (1 equiv, 0.3 mmol) y 2,4-dimetilpirrol (2 equiv, 0.6 mmol) se disuelve en 5 mL de MeOH bajo atmósfera de nitrógeno a temperatura ambiente. Sobre esto se añade HCI disuelto en MeOH (2 equiv, 0.6 mmol) gota a gota en 15 minutos. Una vez que una placa de TLC muestra que el material de partida se ha consumido el disolvente es evaporado a presión reducida. El residuo resultante se purifica mediante columna cromatográfica en óxido de aluminio (hexane/AcOEt 3: 1) obteniéndose el compuesto Ib. Rendimiento 60 %. 1 H NMR (300 MHz, CDCI3): δ = 13.58 (s, 1 H), 13.29 (s, 1 H), 9.69 (s, 1 H), 7.26 (s, 1 H), 6.69 (s, 1 H), 6.13 (s, 1 H), 4.43 (t, J = 7.3 Hz, 2H), 4.04 (s, 3H, OCH3), 2.62 (s, 3H), 2.34 (s, 3H), 2.03-1.89 (m, 2H), 1.42-1.16 (m, 10H), 0.86 (t, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCI3): δ = 165.65 (C), 153.55 (C), 145.67 (C), 144.74 (C), 138.59 (C), 126.62 (CH), 126.48 (C), 1 19.23 (C), 117.24 (CH), 116.94 (CH), 94.64 (CH), 59.02 (OCH3), 50.97 (CH2), 31.84 (CH2), 30.34 (CH2), 29.18 (CH2), 29.08 (CH2), 26.58 (CH2), 22.73 (CH2), 14.46 (CH3), 14.21 (CH3), 12.20 (CH3). HRMS (El) m/z [M]+ calculado para [C22H31 N50] 381.2529; encontrado: 381.2524. (Z) -5- (1-Octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) chloride -3- methoxy-2H-pyrrolium (Ib). A mixture of carbaldehyde llb (1 equiv, 0.3 mmol) and 2,4-dimethylpyrrole (2 equiv, 0.6 mmol) is dissolved in 5 mL of MeOH under a nitrogen atmosphere at room temperature. On this, HCI dissolved in MeOH (2 equiv, 0.6 mmol) is added dropwise in 15 minutes. Once a TLC plate shows that the starting material has been consumed the solvent is evaporated under reduced pressure. The resulting residue is purified by chromatographic column on aluminum oxide (hexane / AcOEt 3: 1) to obtain compound Ib. 60% yield. 1 H NMR (300 MHz, CDCI3): δ = 13.58 (s, 1 H), 13.29 (s, 1 H), 9.69 (s, 1 H), 7.26 (s, 1 H), 6.69 (s, 1 H ), 6.13 (s, 1 H), 4.43 (t, J = 7.3 Hz, 2H), 4.04 (s, 3H, OCH3), 2.62 (s, 3H), 2.34 (s, 3H), 2.03-1.89 (m , 2H), 1.42-1.16 (m, 10H), 0.86 (t, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCI3): δ = 165.65 (C), 153.55 (C), 145.67 (C), 144.74 (C), 138.59 (C), 126.62 (CH), 126.48 (C), 1 19.23 (C ), 117.24 (CH), 116.94 (CH), 94.64 (CH), 59.02 (OCH3), 50.97 (CH2), 31.84 (CH2), 30.34 (CH2), 29.18 (CH2), 29.08 (CH2), 26.58 (CH2 ), 22.73 (CH2), 14.46 (CH3), 14.21 (CH3), 12.20 (CH3). HRMS (El) m / z [M] + calculated for [C22H31 N50] 381.2529; Found: 381.2524.
Ejemplo 4: Síntesis del compuesto I ^representado por la fórmula:  Example 4: Synthesis of compound I ^ represented by the formula:
Figure imgf000021_0002
Cloruro de (Z)-5-(1 -butil-1 H-1 ,2,3-triazol-4-il)-3-metoxi-2-((5-metil-4-pentil-1 H-pirrol-2- il)metilen)-2H-pirrolio (le).
Figure imgf000021_0002
Chloride (Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -3-methoxy-2 - ((5-methyl-4-pentyl-1 H-pyrrole- 2- il) methylene) -2H-pyrrolium (le).
Una mezcla del carbaldehido Na (1 equiv, 0.3 mmol) y 2-metil-3-pentilpirrol (2 equiv, 0.6 mmol) se disuelve en 5 mL de MeOH bajo atmósfera de nitrógeno a temperatura ambiente. Sobre esto se añade HCI disuelto en MeOH (2 equiv, 0.6 mmol) gota a gota en 15 minutos. Una vez que una placa de TLC muestra que el material de partida se ha consumido el disolvente es evaporado a presión reducida. El residuo resultante se purifica mediante columna cromatográfica en óxido de aluminio (hexane/AcOEt 3:1) obteniéndose el compuesto le. Rendimiento: 57 %. 1 H NMR (300 MHz, CDCI3): δ = 13.77 (s, 1 H), 13.29 (s, 1 H), 9.70 (s, 1 H), 7.18 (s, 1 H), 6.82 (d, J = 2.0 Hz, 1 H), 6.68 (d, J = 1.8 Hz, 1 H), 4.45 (t, J = 7.3 Hz, 2H), 4.03 (s, 3H, OCH3), 2.60 (s, 3H), 2.40 (t, J = 7.6 Hz, 2H), 2.02-1.91 (m, 2H), 1.60-1.49 (m, 2H), 1.44- 1.28 (m, 6H), 0.97 (t, J = 7.4 Hz, 3H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCI3): δ = 165.76 (C), 152.78 (C), 145.75 (C), 138.43 (C), 131.51 (CH), 131.07 (C), 126.61 (CH), 126.46 (C), 1 19.91 (CH), 1 19.68 (C), 94.57 (CH), 58.99 (OCH3), 50.56 (CH2), 32.11 (CH2), 31.43 (CH2), 29.48 (CH2), 25.36 (CH2), 22.51 (CH2), 19.72 (CH2), 14.07 (CH3), 13.49 (CH3), 12.81 (CH3). HRMS (El) m/z [M]+ calculado para [C22H31 N50] 381.2529; encontrado: 381.2524.  A mixture of carbaldehyde Na (1 equiv, 0.3 mmol) and 2-methyl-3-pentylpyrrole (2 equiv, 0.6 mmol) is dissolved in 5 mL of MeOH under a nitrogen atmosphere at room temperature. On this, HCI dissolved in MeOH (2 equiv, 0.6 mmol) is added dropwise in 15 minutes. Once a TLC plate shows that the starting material has been consumed the solvent is evaporated under reduced pressure. The resulting residue is purified by chromatographic column in aluminum oxide (hexane / AcOEt 3: 1) to obtain compound le. Yield: 57%. 1 H NMR (300 MHz, CDCI3): δ = 13.77 (s, 1 H), 13.29 (s, 1 H), 9.70 (s, 1 H), 7.18 (s, 1 H), 6.82 (d, J = 2.0 Hz, 1 H), 6.68 (d, J = 1.8 Hz, 1 H), 4.45 (t, J = 7.3 Hz, 2H), 4.03 (s, 3H, OCH3), 2.60 (s, 3H), 2.40 ( t, J = 7.6 Hz, 2H), 2.02-1.91 (m, 2H), 1.60-1.49 (m, 2H), 1.44-1.28 (m, 6H), 0.97 (t, J = 7.4 Hz, 3H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCI3): δ = 165.76 (C), 152.78 (C), 145.75 (C), 138.43 (C), 131.51 (CH), 131.07 (C), 126.61 (CH), 126.46 (C) , 1 19.91 (CH), 1 19.68 (C), 94.57 (CH), 58.99 (OCH3), 50.56 (CH2), 32.11 (CH2), 31.43 (CH2), 29.48 (CH2), 25.36 (CH2), 22.51 ( CH2), 19.72 (CH2), 14.07 (CH3), 13.49 (CH3), 12.81 (CH3). HRMS (El) m / z [M] + calculated for [C22H31 N50] 381.2529; Found: 381.2524.
Ejemplo 5: Síntesis del compuesto Idjepresentado por la fórmula: Example 5: Synthesis of compound Idpresented by the formula:
Figure imgf000022_0001
Figure imgf000022_0001
Cloruro de (Z)-3-metoxi-2-((5-metil-4-pentil-1 H-pirrol-2-il)m  (Z) -3-Methoxy-2 - ((5-methyl-4-pentyl-1 H-pyrrole-2-yl) m chloride
triazol-4-il)-2H-pirrolio (Id). Una mezcla del carbaldehido llb (1 equiv, 0.3 mmol) y 2-metil-3- pentilpirrol (2 equiv, 0.6 mmol) se disuelve en 5 mL de MeOH bajo atmósfera de nitrógeno a temperatura ambiente. Sobre esto se añade HCI disuelto en MeOH (2 equiv, 0.6 mmol) gota a gota en 15 minutos. Una vez que una placa de TLC muestra que el material de partida se ha consumido el disolvente es evaporado a presión reducida. El residuo resultante se purifica mediante columna cromatográfica en óxido de aluminio (hexane/AcOEt 3: 1) obteniéndose el compuesto Ib. Rendimiento 63 %. 1 H NMR (300 MHz, CDCI3): δ = 13.73 (s, 1 H), 13.26 (s, 1 H), 9.66 (s, 1 H), 7.14 (s, 1 H), 6.79 (s, 1 H), 6.64 (s, 1 H), 4.41 (t, J = 7.3 Hz, 2H), 3.99 (s, 3H, OCH3), 2.56 (s, 3H), 2.37 (t, J = 7.6 Hz, 2H), 2.02-1.87 (m, 2H), 1.59-1.46 (m, 2H), 1.35-1.15 (m, 14H), 0.85 (dt, J = 6.8, 6.9 Hz, 6H). 13C NMR (75 MHz, CDCI3): δ = 165.84 (C), 152.86 (C), 145.86 (C), 138.52 (C), 131.57 (CH), 131.15 (C), 126.65 (CH), 126.53 (C), 120.00 (CH), 119.77 (C), 94.66 (CH), 59.05 (0CH3), 50.96 (CH2), 31.82 (CH2), 31.50 (CH2), 30.31 (CH2), 29.57 (CH2), 29.17 (CH2), 29.06 (CH2), 26.57 (CH2), 25.44 (CH2), 22.71 (CH2), 22.59 (CH2), 14.19 (CH3), 14.15 (CH3), 12.90 (CH3). HRMS (El) m/z [M]+ calculado para [C26H39N50] 437.3155; encontrado: 437.3159. triazol-4-yl) -2H-pyrrolium (Id). A mixture of carbaldehyde llb (1 equiv, 0.3 mmol) and 2-methyl-3- pentylpyrrole (2 equiv, 0.6 mmol) is dissolved in 5 mL of MeOH under a nitrogen atmosphere at room temperature. On this, HCI dissolved in MeOH (2 equiv, 0.6 mmol) is added dropwise in 15 minutes. Once a TLC plate shows that the starting material has been consumed the solvent is evaporated under reduced pressure. The resulting residue is purified by chromatographic column on aluminum oxide (hexane / AcOEt 3: 1) to obtain compound Ib. Yield 63%. 1 H NMR (300 MHz, CDCI3): δ = 13.73 (s, 1 H), 13.26 (s, 1 H), 9.66 (s, 1 H), 7.14 (s, 1 H), 6.79 (s, 1 H ), 6.64 (s, 1 H), 4.41 (t, J = 7.3 Hz, 2H), 3.99 (s, 3H, OCH3), 2.56 (s, 3H), 2.37 (t, J = 7.6 Hz, 2H), 2.02-1.87 (m, 2H), 1.59-1.46 (m, 2H), 1.35-1.15 (m, 14H), 0.85 (dt, J = 6.8, 6.9 Hz, 6H). 13C NMR (75 MHz, CDCI3): δ = 165.84 (C), 152.86 (C), 145.86 (C), 138.52 (C), 131.57 (CH), 131.15 (C), 126.65 (CH), 126.53 (C) , 120.00 (CH), 119.77 (C), 94.66 (CH), 59.05 (0CH3), 50.96 (CH2), 31.82 (CH2), 31.50 (CH2), 30.31 (CH2), 29.57 (CH2), 29.17 (CH2) , 29.06 (CH2), 26.57 (CH2), 25.44 (CH2), 22.71 (CH2), 22.59 (CH2), 14.19 (CH3), 14.15 (CH3), 12.90 (CH3). HRMS (El) m / z [M] + calculated for [C26H39N50] 437.3155; Found: 437.3159.
Ejemplo 6. Toxicidad de los compuestos la, Ib, le y Id en distintas líneas celulares. Se utilizaron las siguientes líneas celulares: Example 6. Toxicity of the compounds la, Ib, le and Id in different cell lines. The following cell lines were used:
- MCF-7: células de adenocarcinoma de mama humano.  - MCF-7: human breast adenocarcinoma cells.
- A549: células de adenocarcinoma de pulmón humano.  - A549: human lung adenocarcinoma cells.
- MCF-10A: células de epitelio humano mamario normal.  - MCF-10A: normal mammary human epithelium cells.
El efecto de los derivados la, Ib, le y Id en la viabilidad de diferentes líneas celulares cancerosas (MCF-7 y A459) y líneas celulares no cancerosas (MCF-10A) fue determinado por el ensayo del MTT, donde MTT significa bromuro de 3-(4,5-dimetiltiazol-2-il)-2,5- difeniltetrazolio, tiazol azul. En este ensayo, 10x103 células fueron sembradas en placas de cultivo de 96 pocilios y tras 24 horas fueron incubadas en ausencia (células control) o en presencia de distintas concentraciones de la, Ib, le y Id durante 24 horas. Posteriormente, se añadió 10 μΜ de MTT durante 4 horas y las absorbancias fueron medidas en un espectrofotómetro a una longitud de 570 nm. Estos ensayos permitieron calcular las concentraciones necesarias para disminuir el 50% de la viabilidad celular. Este valor, IC50, se recoge en la siguiente tabla. The effect of derivatives la, Ib, le and Id on the viability of different cancer cell lines (MCF-7 and A459) and non-cancer cell lines (MCF-10A) was determined by the MTT assay, where MTT means bromide of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium, blue thiazole. In this test, 10x10 3 cells were seeded in 96-well culture plates and after 24 hours they were incubated in the absence (control cells) or in the presence of different concentrations of Ib, le and Id for 24 hours. Subsequently, 10 μΜ of MTT was added for 4 hours and the absorbances were measured in a spectrophotometer at a length of 570 nm. These tests allowed calculating the concentrations necessary to decrease 50% of cell viability. This value, IC50, is collected in the following table.
ICso (μΜ) ICso (μΜ) ICso (μΜ)  ICso (μΜ) ICso (μΜ) ICso (μΜ)
Compuesto  Compound
MCF-7 A549 MCF-10A  MCF-7 A549 MCF-10A
Ta 00 92.70 ± 3.54 79.92 ± 9.74  Ta 00 92.70 ± 3.54 79.92 ± 9.74
Ib >100 >100 >100  Ib> 100> 100> 100
le 46.62 ± 7.35 34.99 ± 1 1.49 31.16 ± 1.58  le 46.62 ± 7.35 34.99 ± 1 1.49 31.16 ± 1.58
Id 33.86 ± 16.12 54.32 ± 15.45 32.96 ± 5.99 Los resultados indican una citotoxicidad de baja a muy moderada de estos compuestos. Todos los ensayos de transporte de aniones en células han sido realizados a concentraciones inferiores a las indicadas, de tal manera que la viabilidad de las células no está comprometida en esas condiciones. Ejemplo 7: Medidas funcionales de la capacidad de transportar aniones de los compuestos la, Ib, le y Id. Id 33.86 ± 16.12 54.32 ± 15.45 32.96 ± 5.99 The results indicate a low to very moderate cytotoxicity of these compounds. All cell anion transport assays have been performed at concentrations below those indicated, such that the viability of the cells is not compromised under those conditions. Example 7: Functional measures of the ability to transport anions of compounds la, Ib, le and Id.
Células:  Cells:
Se utilizó la línea celular FRT (Fisher rat thyroid), una línea de tiroides de rata con expresión estable de la proteína fluorescente amarilla (YFP). Las células se siembran en placas de 96 pocilios a una densidad de 40,000 células/pocilio.  The FRT (Fisher rat thyroid) cell line, a rat thyroid line with stable expression of the yellow fluorescent protein (YFP), was used. The cells are seeded in 96-well plates at a density of 40,000 cells / well.
El método:  The method:
El ensayo se basa en la diversa capacidad de los aniones cloruro (Ch) y ioduro (I") de extinguir la fluorescencia de la proteína YFP. Las células fueron sembradas en presencia de una solución extracelular con 130 mM NaCI, condición en la cual la fluorescencia de la YFP es muy brillante. En estas condiciones, las células fueron incubadas con los diversos compuestos a diversas concentraciones o con dimetil sulfóxido (DMSO) como control. Se registra la fluorescencia inicial con un lector de fluorescencia y luego de pocos segundos se agrega una solución de Nal. Si el compuesto es activo, el I" se internaliza y, compitiendo con el Ch por la YFP, se une a ésta y extingue la fluorescencia (Figura 1). El ajuste de la curva a una ecuación exponencial y su sucesiva derivada permite calcular la velocidad máxima de extinción de la fluorescencia (VmEF) para cada concentración y este parámetro es una indicación directa de la actividad del compuesto. The assay is based on the diverse ability of the chloride (Ch) and iodide (I " ) anions to extinguish the fluorescence of the YFP protein. The cells were seeded in the presence of an extracellular solution with 130 mM NaCI, a condition in which the YFP fluorescence is very bright Under these conditions, the cells were incubated with the various compounds at various concentrations or with dimethyl sulfoxide (DMSO) as a control.The initial fluorescence is recorded with a fluorescence reader and after a few seconds it is added a solution of Nal. If the compound is active, I " is internalized and, competing with Ch for YFP, binds to it and extinguishes fluorescence (Figure 1). The adjustment of the curve to an exponential equation and its successive derivative allows to calculate the maximum rate of extinction of the fluorescence (VmEF) for each concentration and this parameter is a direct indication of the activity of the compound.
Resultados:  Results:
La VmEF para cada concentración permite reconstruir una curva dosis-respuesta (Figura 2) y obtener los siguientes valores de EC50: la > 40 μΜ; Ib = 21.83 ± 2.74; le = 17.05 ± 1.30; Id = 24.88 ± 3.28. Estos ensayos muestran que las concentraciones que permiten obtener el 50% de actividad son inferiores a las concentraciones para reducir la viabilidad del 50%, en especial para los compuestos Ib y le. The VmEF for each concentration allows to reconstruct a dose-response curve (Figure 2) and obtain the following EC50 values:> 40 μΜ; Ib = 21.83 ± 2.74; le = 17.05 ± 1.30; Id = 24.88 ± 3.28. These tests show that the concentrations that allow 50% activity to be obtained are lower than the concentrations to reduce the viability of 50%, especially for compounds Ib and le.
Sucesivamente se estableció si la actividad de transporte de estos compuestos variaba con el pH. Para esto se usaron soluciones de Nal tamponadas a pH 7.3, 6.9, 6.6 y 6.2 (Figura 3). Los resultados indican que los compuestos Ib, le y Id presentan una actividad que depende netamente del pH. Para el compuesto la, se nota que la actividad es muy baja y no es significativamente diversa a los diversos valores de pH. Es interesante notar que si bien a pH 7.3 la actividad de estos compuestos es muy inferior a la de la proteína CFTR, incluida en la figura como comparación, a valores de pH más ácidos la actividad más elevada de los compuestos se acerca mucho a la de la CFTR. Estos resultados sugieren que en condiciones de inflamación como las descritas en las vías aéreas de los pacientes con fibrosis quística, donde el pH es más ácido que en condiciones normales, los compuestos tienen una actividad 2-3 veces mayor que aquella medida a pH 7.3. It was subsequently established if the transport activity of these compounds varied with the pH. For this, buffered Nal solutions were used at pH 7.3, 6.9, 6.6 and 6.2 (Figure 3). The results indicate that the compounds Ib, le and Id have an activity that clearly depends on the pH. For compound la, it is noted that the activity is very low and is not significantly diverse at the various pH values. It is interesting to note that although at pH 7.3 the activity of these compounds is much lower than that of the CFTR protein, included in the figure as a comparison, at more acidic pH values the higher activity of the compounds is very close to that of the CFTR. These results suggest that in conditions of inflammation such as those described in the airways of patients with cystic fibrosis, where the pH is more acidic than in normal conditions, the compounds have an activity 2-3 times greater than that measured at pH 7.3.
Otra información importante era establecer la cinética de incorporación en la membrana de este tipo de compuestos. Para eso fue seleccionado el compuesto le (12 μΜ) pues su mayor actividad permite un mejor seguimiento temporal.  Another important information was to establish the kinetics of incorporation in the membrane of this type of compounds. For this, the compound le (12 μΜ) was selected because its greater activity allows a better temporary follow-up.
Los datos obtenidos indican que la actividad de le aumenta muy rápidamente al inicio, por lo que a 2 minutos de incubación el transporte corresponde al 50% de la actividad final (Figura 4). La actividad de transporte continúa aumentando más lentamente en los siguientes 30 minutos hasta llegar a un valor más o menos constante.  The data obtained indicate that the activity increases very quickly at the beginning, so that after 2 minutes of incubation the transport corresponds to 50% of the final activity (Figure 4). Transport activity continues to increase more slowly in the next 30 minutes until it reaches a more or less constant value.
Determinación de la estabilidad de los compuestos en la membrana celular. Para obtener esta información, las células fueron incubadas durante 45 minutos con el compuesto le (12 μΜ) y luego el compuesto fue lavado de la solución extracelular y la actividad fue medida cada dos minutos durante 60 minutos (Figura 5). Los resultados muestran que la actividad de transporte disminuye muy lentamente, de manera que después de 1 hora aún se detecta más del 85% de la actividad inicial.  Determination of the stability of the compounds in the cell membrane. To obtain this information, the cells were incubated for 45 minutes with the compound le (12 μΜ) and then the compound was washed from the extracellular solution and the activity was measured every two minutes for 60 minutes (Figure 5). The results show that the transport activity decreases very slowly, so that after 1 hour more than 85% of the initial activity is still detected.

Claims

REIVINDICACIONES
Un compuesto de fórmula (I):  A compound of formula (I):
Figure imgf000026_0001
Figure imgf000026_0001
donde Ri , R2, R3, R6, R7 y Re se seleccionan de forma independiente de entre el grupo formado por: H , OH , halógeno, O-Rg, N R10R11 , COORg, CON R10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo, where Ri, R 2 , R3, R6, R7 and Re are independently selected from the group consisting of: H, OH, halogen, O-Rg, N R10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl , aryl, arylalkyl, heterocycle or heteroaryl,
R4 y R5 se seleccionan de entre el grupo formado por: H , OH , halógeno, O-Rg, N R10R11 , COORg, CON R10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, R 4 and R5 are selected from the group consisting of: H, OH, halogen, O-Rg, N R10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl,
y en donde Rg, R10, y Rn son radicales seleccionados de forma independiente de entre el grupo formado por: H , OH , halógeno, alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo. and wherein Rg, R10, and Rn are radicals independently selected from the group consisting of: H, OH, halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl.
Un compuesto según la reivindicación 1 donde R7 se selecciona de forma independiente de entre el grupo formado por: H , OH , halógeno, O-Rg, N R10R11 , COORg, CON R10R11 , alquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo. A compound according to claim 1 wherein R 7 is independently selected from the group consisting of: H, OH, halogen, O-Rg, N R10R11, COORg, CON R10R11, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or hetaryl.
Un compuesto según cualquiera de las reivindicaciones 1 o 2 donde R7 es H . A compound according to any one of claims 1 or 2 wherein R 7 is H.
Un compuesto según cualquiera de las reivindicaciones 1 a 3 donde A compound according to any one of claims 1 to 3 wherein
R1 se selecciona de forma independiente de entre el grupo formado por: H , OH , halógeno, O-Rg, COORg, CON R10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo; R1 is independently selected from the group consisting of: H, OH, halogen, O-Rg, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl;
R2 se selecciona de forma independiente de entre el grupo formado por: H , OH , halógeno, O-Rg, COORg, CON R10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo; R 2 is independently selected from the group consisting of: H, OH, halogen, O-Rg, COORg, CON R 10 R 11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl;
Rs se selecciona de forma independiente de entre el grupo formado por: H , OH , halógeno, O-Rg, COORg, CON R10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo; R6 se selecciona de forma independiente de entre el grupo formado por: H, OH, halógeno, O-Rg, COORg, CONR10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo; Rs is independently selected from the group consisting of: H, OH, halogen, O-Rg, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl; R6 is independently selected from the group consisting of: H, OH, halogen, O-Rg, COORg, CONR10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl;
Rs se selecciona de forma independiente de entre el grupo formado por; H, halógeno, O- Rg, NR10R11 , COORg, CONR10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo y  Rs is independently selected from the group consisting of; H, halogen, O-Rg, NR10R11, COORg, CONR10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl and
R4 y R5 se seleccionan de entre el grupo formado por: H, OH, O-Rg, NR10R11 , COORg, CON R10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo. R 4 and R5 are selected from the group consisting of: H, OH, O-Rg, NR10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl.
Un compuesto según cualquiera de las reivindicaciones 1 a 4 donde Rg es alquilo. A compound according to any one of claims 1 to 4 wherein Rg is alkyl.
Una sal de adición y/o solvato farmacéuticamente aceptable de un compuesto de formula (I) según cualquiera de las reivindicaciones 1 a 5. A pharmaceutically acceptable addition and / or solvate salt of a compound of formula (I) according to any one of claims 1 to 5.
Una sal de adición y/o solvato farmacéuticamente aceptable según la reivindicación 6, donde dicha sal de adición y/o solvato farmacéuticamente aceptable es una sal de hidrocloruro o un mesilato. A pharmaceutically acceptable addition and / or solvate salt according to claim 6, wherein said pharmaceutically acceptable addition and / or solvate salt is a hydrochloride salt or a mesylate.
Una sal de adición y/o solvato farmacéuticamente aceptable según cualquiera de las reivindicaciones 6 o 7, que se selecciona de forma independiente de entre el grupo formado por: A pharmaceutically acceptable addition and / or solvate salt according to any of claims 6 or 7, which is independently selected from the group consisting of:
Cloruro de (Z)-5-(1-butil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3- metoxi-2H-pirrolio (la), Cloruro de (Z)-5-(1-octil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H- pirrol-2-il)metilen)-3-metoxi-2H-pirrolio (Ib), (Z)-5-(1-butil-1 H-1 ,2,3-triazol-4-il)-3-metoxi-2- ((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-2H-pirrol cloruro (le), Cloruro de (Z)-3-metoxi-2-((5- metil-4-pentil-1 H-pirrol-2-il)metilen)-5-(1-octil-1 H-1 ,2,3-triazol-4-il)-2H-pirrolio (Id).  (Z) -5- (1-Butyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) chloride -3- methoxy-2H-pyrrolium (la), (Z) Chloride -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl -1 H- pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (Ib), (Z) -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -3-methoxy-2- ((5-methyl-4-pentyl-1 H-pyrrol-2-yl) methylene) -2H-pyrrole chloride (le), (Z) -3-methoxy-2- chloride ( (5- methyl-4-pentyl-1 H-pyrrol-2-yl) methylene) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -2H-pyrrolium (Id) .
Procedimiento de obtención de un compuesto de fórmula (I), según cualquiera de las reivindicaciones 1 a 5, o de una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, según cualquiera de las reivindicaciones 6 a 8, que comprende las siguientes etapas: Process for obtaining a compound of formula (I), according to any one of claims 1 to 5, or a pharmaceutically acceptable addition salt and / or solvate thereof, according to any one of claims 6 to 8, comprising the following stages:
(a) la reacción de cicloadición de una azida RsN3 y un compuesto 5-alquinil-2H-pirrol-2- ilideno de fórmula (I I I), utilizando un catalizador de cobre, para generar un compuesto triazolil-pirrol-carbaldehido de fórmula (II);  (a) the cycloaddition reaction of an RsN3 azide and a 5-alkynyl-2H-pyrrol-2-ylidene compound of formula (III), using a copper catalyst, to generate a triazolyl-pyrrole-carbaldehyde compound of formula (II );
(b) la condensación del compuesto de fórmula (I I) obtenido anteriormente, con un pirrol no sustituido en posición alfa de fórmula (IV), en presencia de una cantidad de ácido y de un disolvente orgánico; (c) la evaporación del disolvente orgánico y la purificación mediante columna cromatográfica del compuesto de fórmula (I). (b) the condensation of the compound of formula (II) obtained above, with an unsubstituted pyrrole in the alpha position of formula (IV), in the presence of an amount of acid and an organic solvent; (c) evaporation of the organic solvent and purification by chromatographic column of the compound of formula (I).
10. Composición farmacéutica que comprende un compuesto de formula (I), según cualquiera de las reivindicaciones 1 a 5, o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, según cualquiera de las reivindicaciones 6 a 8 y al menos un excipiente farmacéuticamente aceptable. 10. Pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable addition salt and / or solvate thereof, according to any of claims 6 to 8 and at least one pharmaceutically acceptable excipient.
11. Composición farmacéutica según la reivindicación 10 caracterizada por que la sal del compuesto de formula (I) se selecciona de forma independiente de entre el grupo formado por: Cloruro de (Z)-5-(1-butil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H-pirrol-2-il)metilen)-3- metoxi-2H-pirrolio (la), Cloruro de (Z)-5-(1-octil-1 H-1 ,2,3-triazol-4-il)-2-((3,5-dimetil-1 H- pirrol-2-il)metilen)-3-metoxi-2H-pirrolio (Ib), Cloruro de (Z)-5-(1-butil-1 H-1 ,2,3-triazol-4-il)- 3-metoxi-2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-2H-pirrolio (le), Cloruro de (Z)-3- metoxi-2-((5-metil-4-pentil-1 H-pirrol-2-il)metilen)-5-(1-octil-1 H-1 ,2,3-triazol-4-il^ 11. Pharmaceutical composition according to claim 10 characterized in that the salt of the compound of formula (I) is independently selected from the group consisting of: (Z) -5- (1-Butyl-1 H-1 Chloride), 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H-pyrrol-2-yl) methylene) -3-methoxy-2H-pyrrolium (la), (Z) Chloride - 5- (1-Octyl-1 H-1, 2,3-triazol-4-yl) -2 - ((3,5-dimethyl-1 H- pyrrol-2-yl) methylene) -3-methoxy-2H -pyrrolium (Ib), (Z) Chloride -5- (1-butyl-1 H-1, 2,3-triazol-4-yl) - 3-methoxy-2 - ((5-methyl-4-pentyl) -1 H-pyrrol-2-yl) methylene) -2H-pyrrolium (le), (Z) -3-methoxy-2 - ((5-methyl-4-pentyl-1 H-pyrrole-2-yl) ) methylene) -5- (1-octyl-1 H-1, 2,3-triazol-4-yl ^
(Id).  (Id)
12. Uso de un compuesto de fórmula (I), según cualquiera de las reivindicaciones 1 a 5, o de una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, según cualquiera de las reivindicaciones 6 a 8, para preparar un medicamento. 12. Use of a compound of formula (I), according to any one of claims 1 to 5, or of a pharmaceutically acceptable addition salt and / or solvate thereof, according to any of claims 6 to 8, to prepare a medicament .
13. Uso de un compuesto de fórmula (I), según cualquiera de las reivindicaciones 1 a 5, o de una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, según cualquiera de las reivindicaciones 6 a 8, para preparar un medicamento destinado al tratamiento y/o profilaxis de enfermedades derivadas del transporte anómalo de aniones a nivel celular. 13. Use of a compound of formula (I), according to any of claims 1 to 5, or of a pharmaceutically acceptable addition salt and / or solvate thereof, according to any of claims 6 to 8, to prepare a medicament intended for the treatment and / or prophylaxis of diseases derived from the anomalous transport of anions at the cellular level.
14. Uso de un compuesto de fórmula (I), según cualquiera de las reivindicaciones 1 a 5, o de una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, según cualquiera de las reivindicaciones 6 a 8, para preparar un medicamento destinado al tratamiento y/o profilaxis de la fibrosis quística. 14. Use of a compound of formula (I), according to any one of claims 1 to 5, or of a pharmaceutically acceptable addition salt and / or solvate thereof, according to any of claims 6 to 8, to prepare a medicament intended for the treatment and / or prophylaxis of cystic fibrosis.
15. Un compuesto de fórmula (I), según cualquiera de las reivindicaciones 1 a 5, o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, según cualquiera de las reivindicaciones 6 a 8, para uso como medicamento. 15. A compound of formula (I), according to any one of claims 1 to 5, or a pharmaceutically acceptable addition salt and / or solvate thereof, according to any of claims 6 to 8, for use as a medicament.
16. Un compuesto de fórmula (I), según cualquiera de las reivindicaciones 1 a 5, o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, según cualquiera de las reivindicaciones 6 a 8, para uso en el tratamiento y/o profilaxis de enfermedades derivadas del transporte anómalo de aniones a nivel celular. 16. A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable addition salt and / or solvate thereof, according to any of the claims 6 to 8, for use in the treatment and / or prophylaxis of diseases derived from the anomalous transport of anions at the cellular level.
17. Un compuesto de fórmula (I), según cualquiera de las reivindicaciones 1 a 5, o una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, según cualquiera de las reivindicaciones 6 a 8, para uso en el tratamiento y/o profilaxis de la fibrosis quística. 17. A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable addition salt and / or solvate thereof, according to any of claims 6 to 8, for use in the treatment and / or prophylaxis of cystic fibrosis.
18. Una composición farmacéutica, según cualquiera de las reivindicaciones 10 o 11 , para uso como medicamento. 18. A pharmaceutical composition according to any of claims 10 or 11, for use as a medicament.
19. Una composición farmacéutica, según cualquiera de las reivindicaciones 10 o 11 , para uso en el tratamiento y/o profilaxis de enfermedades derivadas del transporte anómalo de aniones a nivel celular. 19. A pharmaceutical composition according to any of claims 10 or 11, for use in the treatment and / or prophylaxis of diseases derived from the anomalous transport of anions at the cellular level.
20. Una composición farmacéutica, según cualquiera de las reivindicaciones 10 o 11 , para uso en el tratamiento y/o profilaxis de la fibrosis quística. 20. A pharmaceutical composition according to any of claims 10 or 11, for use in the treatment and / or prophylaxis of cystic fibrosis.
21. Método de tratamiento y/o profilaxis de enfermedades que comprende administrar una composición farmacéutica según cualquiera de las reivindicaciones 10 o 11 , donde dicha composición farmacéutica comprende una cantidad terapéuticamente efectiva de un compuesto de fórmula (I) según cualquiera de las reivindicaciones 1 a 5, o de una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, según cualquiera de las reivindicaciones 6 a 8. 21. Method of treatment and / or prophylaxis of diseases comprising administering a pharmaceutical composition according to any of claims 10 or 11, wherein said pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I) according to any of claims 1 to 5, or an addition salt and / or a pharmaceutically acceptable solvate thereof, according to any one of claims 6 to 8.
22. Método de tratamiento y/o profilaxis de enfermedades derivadas del transporte anómalo de aniones a nivel celular que comprende administrar una composición farmacéutica según cualquiera de las reivindicaciones 10 o 1 1 , donde dicha composición farmacéutica comprende una cantidad terapéuticamente efectiva de un compuesto de fórmula (I) según cualquiera de las reivindicaciones 1 a 5, o de una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, según cualquiera de las reivindicaciones 6 a 8. 23. Método de tratamiento y/o profilaxis de la fibrosis quística que comprende administrar una composición farmacéutica según cualquiera de las reivindicaciones 10 o 11 , donde dicha composición farmacéutica comprende una cantidad terapéuticamente efectiva de un compuesto de fórmula (I) según cualquiera de las reivindicaciones 1 a 5, o de una sal de adición y/o un solvato farmacéuticamente aceptable del mismo, según cualquiera de las reivindicaciones 6 a 8. 22. Method of treatment and / or prophylaxis of diseases derived from the anomalous transport of anions at the cellular level comprising administering a pharmaceutical composition according to any one of claims 10 or 1, wherein said pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 5, or of a pharmaceutically acceptable addition salt and / or solvate thereof, according to any of claims 6 to 8. 23. Method of treatment and / or prophylaxis of cystic fibrosis which comprises administering a pharmaceutical composition according to any one of claims 10 or 11, wherein said pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 5, or of an addition salt and / or a pharmaceutically acceptable solvate thereof, according to any of claims 6 to 8.
24. Compuesto intermedio de la reacción de cicloadición (a) del procedimiento de la reivindicación 9, caracteriz hido de fórmula (II) 24. Intermediate of the cycloaddition reaction (a) of the process of claim 9, hybrid character of formula (II)
Figure imgf000030_0001
Figure imgf000030_0001
donde R4 y R5 se seleccionan de entre el grupo formado por: H , OH , halógeno, O-Rg, N R10R11 , COORg, CON R10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo,where R 4 and R5 are selected from the group consisting of: H, OH, halogen, O-Rg, N R10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl,
R6, R7 y Re se seleccionan de forma independiente de entre el grupo formado por: H , OH , halógeno, O-Rg, N R10R11 , COORg, CON R10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo, R 6 , R 7 and Re are independently selected from the group consisting of: H, OH, halogen, O-Rg, N R10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or hetaryl,
y en donde Rg, Rio y R11 son radicales seleccionados de forma independiente de entre el grupo formado por: H , OH , halógeno, alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo.  and wherein Rg, Rio and R11 are radicals independently selected from the group consisting of: H, OH, halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl.
25. Un compuesto intermedio según la reivindicación 24 donde R7 se selecciona de forma independiente de entre el grupo formado por: H , OH , halógeno, O-Rg, NR10R11 , COORg, CON R10R11 , alquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo. 26. Un compuesto intermedio según cualquiera de las reivindicaciones 24 o 25 donde R7 es H . 25. An intermediate compound according to claim 24 wherein R 7 is independently selected from the group consisting of: H, OH, halogen, O-Rg, NR10R11, COORg, CON R10R11, alkyl, alkenyl, alkynyl, aryl, arylalkyl , heterocycle or heteroaryl. 26. An intermediate compound according to any of claims 24 or 25 wherein R 7 is H.
27. Un compuesto intermedio según cualquiera de las reivindicaciones 24 a 26 donde 27. An intermediate compound according to any of claims 24 to 26 wherein
R6 se selecciona de forma independiente de entre el grupo formado por: H , OH , halógeno, O-Rg, COORg, CON R10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo;  R6 is independently selected from the group consisting of: H, OH, halogen, O-Rg, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl;
R8 se selecciona de forma independiente de entre el grupo formado por ; H , halógeno, O- R9, N R10R11 , COORg, CON R10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo, heterociclo o hetarilo y R 8 is independently selected from the group consisting of; H, halogen, O- R 9 , N R10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle or heteroaryl and
R4 y R5 se seleccionan de entre el grupo formado por: H , OH , O-Rg, N R10R11 , COORg, CON R10R11 , alquilo, cicloalquilo, alquenilo, alquinilo, arilo, arilalquilo. R 4 and R 5 are selected from the group consisting of: H, OH, O-Rg, N R10R11, COORg, CON R10R11, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl.
28. Un compuesto intermedio según cualquiera de las reivindicaciones 24 a 27 donde Rg alquilo. 28. An intermediate compound according to any of claims 24 to 27 wherein Rg alkyl.
29. Un compuesto intermedio según la reivindicación 24, donde dicho compuesto es 5-(1-butil- 1 H-1 ,2,3-triazol-4-il)-3-metoxi-1 H-pirrol-2-carbaldehido de fórmula (Na): 29. An intermediate compound according to claim 24, wherein said compound is 5- (1-butyl-1 H-1, 2,3-triazol-4-yl) -3-methoxy-1 H-pyrrol-2-carbaldehyde of formula (Na):
Figure imgf000031_0001
Figure imgf000031_0001
30. Un compuesto intermedio según la reivindicación 24, donde dicho compuesto es 5-(1-octil- 1 H-1 ,2,3-triazol-4-il)-3-metoxi-1 H-pirrol-2-carbaldehido de fórmula (llb):  30. An intermediate compound according to claim 24, wherein said compound is 5- (1-octyl-1 H-1, 2,3-triazol-4-yl) -3-methoxy-1 H-pyrrol-2-carbaldehyde of formula (llb):
Figure imgf000031_0002
Figure imgf000031_0002
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