Search

EP-4737456-A1 - DERIVATIVES OF IMIDAZO[1,2-A]PYRIDINE WITH ANTI-INFLAMMATORY ACTIVITY

EP4737456A1EP 4737456 A1EP4737456 A1EP 4737456A1EP-4737456-A1

Abstract

The present invention relates to the chemical synthesis and production of compounds derived from Imidazo[1,2-a]pyridine of formula I where R 2 , R 3 , R 5 , R 6 , and R 7 have the meanings indicated in the description, method of obtaining them, as well as their therapeutic use as a pharmaceutical composition for in vitro and in vivo anti-inflammatory use in diseases involving inflammatory and pro-fibrotic processes.

Inventors

  • MARCILLA DÍAZ, Antonio
  • CUMELLA MONTÁNCHEZ, José María
  • DEL POZO LOSADA, Jesús
  • DEL POZO LOSADA, CARLOS
  • Sánchez López, Christian Miquel
  • Sánchez Sancho, Francisco Antonio
  • GARCÍA CSÁKY, Aurelio
  • OLIVER PÉREZ, Eduardo
  • IBÁÑEZ CABEZA. Borja
  • Baquero Gálvez, María Gracia
  • ROSCALES GARCÍA, Silvia

Assignees

  • Universitat de València
  • Consejo Superior de Investigaciones Científicas (CSIC)
  • Universidad Complutense de Madrid (UCM)
  • Centro Nacional de Investigaciones Cardiovasculares Carlos III (F.S.P.)
  • IMHOTECH LABORATORIES, S.L.

Dates

Publication Date
20260506
Application Date
20240626

Claims (20)

  1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: R 2 represents H; an aryl, wherein the aryl group is unsubstituted, or substituted with alkyl groups of 1 to 5 carbon atoms, or substituted with a haloalkyl, or substituted with an alkoxy group of 1 to 5 carbon atoms, R 3 represents H; a halogen; a haloalkyl; an alkoxycarbonyl with 2 to 5 carbon atoms; an amino; an aryl or heteroaryl, where the aryl and heteroaryl groups are unsubstituted or are substituted with alkyl groups with 1 to 5 carbon atoms, or with an alkoxycarbonyl of 2 to 5 carbon atoms; R 5 represents H; an alkenyl of 2 to 10 carbon atoms; an alkoxycarbonyl of 2 to 5 carbon atoms; a nitro group; a carboxyl; an alkyl of 1 to 5 carbon atoms unsubstituted or substituted with one or more hydroxy groups; an N-(3-methylene-2-oxoindolin-5-yl)-3-(piperidin-1-yl)propanamide group); or carbaldehyde, R 6 represents a hydrogen atom (H); an unsubstituted alkyl of 1 to 5 carbon atoms; an alkyl group of 1 to 5 carbon atoms substituted with one or more hydroxy groups; an alkoxy group of 1 to 5 carbon atoms; a halogen selected from F, Cl, I; an alkoxycarbonyl (-O-(C=O)-R) where R has 1 to 3 carbon atoms; a nitro grup; an alkenyl of 3 to 10 carbon atoms unsubstituted or substituted; an alkenyl of 2 carbon atoms substituted with a phenyl (styryl); an aryl, wherein the aryl group is unsubstituted or substituted by one or more hydroxyl groups, or substituted with one or more methoxy groups; heteroaryl; or heteroaryl wherein the heteroaryl group is selected from dibenzothiophenyl, a group of formula II, a group of formula III: where D, B, E, G independently represent N, CH, or C-R, where R is unsubstituted alkyl of one to three carbon atoms, unsubstituted aryl, or unsubstituted cycloalkyl, Z represents CH or N, Y represents CH or N, W represents O, S, or NH, R 7 represents a hydrogen atom (H); an unsubstituted aryl group or an aryl group substituted with one or more hydroxy groups, or substituted with one or more methoxy groups; a halogen; an alkenyl of 3 to 10 C atoms, unsubstituted or substituted by an aryl group; an alkenyl of 2 carbon atoms substituted with a phenyl (styryl); an alkoxycarbonyl of 2 to 5 carbon atoms; a heteroaryl group; or heteroaryl where the heteroaryl group is selected from benzothiophenyl, benzofuranyl, benzopyrrolyl; dibenzothiophenyl, a group of formula II and a group of formula III as defined above, - wherein: - at least 3 of the substituents R 2 , R 3 , R 5 , R 6 , and R 7 are simultaneously H, and the position of carbon 8 of the imidazo[1,2a]pyridine structure has no substituents, and - when R 5 is a carbaldehyde, at least one of R 2 , R 3 , R 6 or R 7 is other than H, - when R 6 is an aryl or substituted aryl, R 3 is not a substituted aryl - when R 3 represents an amino group, R 6 does not represent hydrogen - when R 2 represents an unsubstituted aryl, or an aryl substituted with a methyl or methoxy group, at least one of the substituents R 2 , R 3 , R 5 , R 6 , and R 7 is not H - at least one of the groups R 3 , R 5 , R 6 , R 7 is different from H, when R 2 is an unsubstituted aryl, or is an aryl substituted with a halogen, a methyl or a methoxy.
  2. A compound according to claim 1, wherein R 2 represents an aryl substituted with a CF 3 group or with an alkoxy group of 1 to 5 carbon atoms; and preferably, in addition, R 3 and R 5 are simultaneously H.
  3. A compound according to claim 1, wherein: - R 2 represents an aryl substituted with alkoxy of 1 to 5 carbon atoms, and - simultaneously R 6 is: - an alkyl of one to 5 carbon atoms, or - an aryl group substituted with a hydroxyl, and preferably, in addition, R 3 and R 5 are simultaneously H.
  4. A compound according to claim 1, wherein R 2 represents a group selected from aryl substituted with alkoxy of 1 to 5 carbon atoms; and simultaneously R 6 is - alkyl of one to 5 carbon atoms, or - an aryl group substituted with a hydroxyl; and preferably R 3 and R 5 are simultaneously H.
  5. A compound according to claim 1, wherein R 2 represents a phenyl substituted with an alkoxy of 1 to 5 carbon atoms or phenyl substituted with trihalomethyl; and - simultaneously R 7 is a heteroaryl group, preferably 2-benzo[b]furyl; and more preferably, R 3 , R 4 , R 5 , and R 6 are simultaneously H.
  6. A compound according to claim 1, wherein: - R 2 represents aryl substituted with alkoxy of 1 to 5 carbon atoms and R 7 is aryl substituted with hydroxyl or with an alkoxy group of 1 to 5 carbon atoms, or - R 2 represents aryl substituted with alkoxy of 1 to 5 carbon atoms and R 7 represents alkenyl substituted with an aryl group; and preferably, in addition, R 3 and R 5 are simultaneously H.
  7. A compound according to claim 1, wherein R 2 represents an aryl substituted with an alkoxy of 1 to 5 carbon atoms and R 7 is an aryl substituted with a hydroxyl or with an alkoxy group of 1 to 5 carbon atoms or an alkenyl substituted with an aryl group; and preferably, in addition, R 3 and R 5 are simultaneously H.
  8. A compound according to claim 1, wherein R 2 represents an aryl substituted with an alkoxy of 1 to 5 carbon atoms, R 3 is H, R 6 is H, an alkyl group or an aryl group, and R 7 is H or an aryl substituted with a hydroxyl or with an an alkoxy group of 1 to 5 carbon atoms; and preferably R 3 and R 5 are simultaneously H.
  9. A compound according to claim 1, wherein R 3 is an unsubstituted aryl; and preferably, further, R 2 , R 5 , and R 6 are simultaneously H; and more preferably, further, R 2 , R 5 , R 6 , and R 7 are simultaneously H.
  10. A compound according to claim 1, wherein R 3 represents an unsubstituted aromatic heterocycle, or an aromatic heterocycle substituted with an alkoxycarbonyl group having 2 to 5 carbon atoms; and preferably, in addition, R 2 , R 5 , and R 6 are simultaneously H; and more preferably, in addition, R 2 , R 5 , R 6 , and R 7 are simultaneously H.
  11. A compound according to claim 1, wherein R 3 is a group selected from benzofuranyl, benzothiophenyl, and indole, unsubstituted or substituted with an alkoxycarbonyl group of 2 to 5 carbon atoms; and preferably, furthermore, R 2 , R 5 , and R 6 are simultaneously H; and more preferably, furthermore, R 2 , R 5 , R 6 , and R 7 are simultaneously H.
  12. A compound according to claim 1, wherein R 3 is a group selected from benzofuranyl, benzothiophenyl, and indole, substituted or substituted with an alkoxycarbonyl group of 2 to 5 carbon atoms; and simultaneously, R 7 is a group selected from benzofuranyl, benzothiophenyl, and indole; preferably, R 2 , R 5 , and R 6 are simultaneously H.
  13. A compound according to claim 1, wherein R 5 represents H, an ethoxycarbonyl, a nitro group, a carboxyl, a hydroxymethyl, a carbaldehyde, or an ethoxyl, and preferably, R 2 , R 3 , R 6 , and R 7 are simultaneously H.
  14. A compound according to claim 1, wherein R 6 or R 7 represents a fragment wherein D, B, E, G independently represent CH or C-R, wherein R may be unsubstituted alkyl, unsubstituted aryl, or unsubstituted cycloalkyl, Z represents CH, and W represents O.
  15. A compound according to claim 1, wherein R 6 or R 7 represents a fragment wherein D, B, E, and G independently represent CH, Z represents C, and W represents O.
  16. A compound according to claim 1, wherein R 6 represents an alkyl group of 1 to 5 carbon atoms or an alkoxycarbonyl (-O-(C=O)-R) where R has 1 to 3 carbon atoms, and preferably, in addition, R 2 , R 3 , R 5 , and R 7 are simultaneously H.
  17. A compound according to claim 1, wherein R 7 represents an unsubstituted aryl group, and preferably, furthermore, R 2 , R 3 , R 5 , and R 7 are simultaneously H.
  18. A compound according to claim 1 selected from: - Imidazo[1,2-a]pyridine-5-carboxylic acid (2) - Ethyl imidazo[1,2-a]pyridine-5-carboxylate (3) - 3-Phenylimidazo[1,2-a]pyridine (4) - Imidazo[1,2-a]pyridin-5-ylmethanol (5) - 2-(4-Methoxyphenyl)-6-methylimidazo[1,2-a]pyridine (8) - 4-(Imidazo[1,2-a]pyridin-7-yl)phenol (12) - 4-(2-(4-(Trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-7-yl)phenol (13) - 4-(2-(4-(Trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-6-yl)phenol (15) - 4-(2-(4-Methoxyphenyl)imidazo[1,2-a]pyridin-7-yl)phenol (16) - 4-(2-(4-Methoxyphenyl)imidazo[1,2-a]pyridin-6-yl)phenol (17) - (E)-7-Styrylimidazo[1,2-a]pyridine (19) - (E)-2-(4-Methoxyphenyl)-7-styrylimidazo[1,2-a]pyridine (20) - 7-(3,4-Dimethoxyphenyl)imidazo[1,2-a]pyridine (21) - 6-Iodo-2-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridine (25) - 7-(Benzofuran-2-yl)imidazo[1,2-a]pyridine (26) PS1906 - 4-(Imidazo[1,2-a]pyridin-6-yl)phenol (27) - (E)-6-Styrylimidazo[1,2-a]pyridine (28) - 6-(Benzofuran-2-yl)imidazo[1,2-a]pyridine (29) - 6-(3,4-Dimethoxyphenyl)imidazo[1,2-a]pyridine (30) - Ethyl 5-(imidazo[1,2-a]pyridin-3-yl)-1H-indole-2-carboxylate (31) (PS1801) - 7-(Benzofuran-3-yl)imidazo[1,2-a]pyridine (32) - 6-(Benzofuran-3-yl)imidazo[1,2-a]pyridine (33) - 7-(Furan-3-yl)imidazo[1,2-a]pyridine (34) - 6-(Furan-3-yl)imidazo[1,2-a]pyridine (35) - 7-(Thiophen-3-yl)imidazo[1,2-a]pyridine (36) - 6-(Thiophen-3-yl)imidazo[1,2-a]pyridine (37) - 7-(Pyridin-4-yl)imidazo[1,2-a]pyridine (38) - 6-(Pyridin-4-yl)imidazo[1,2-a]pyridine (39) - 7-(Dibenzothiophen-3-yl)imidazo[1,2-a]pyridine (40) - 6-(Dibenzothiophene-3-yl)imidazo[1,2-a]pyridine (41) - Ethyl 5-(7-(benzofuran-2-yl)-3-imidazo[1,2-a]pyridin)-1H-indole-2-carboxylate, (42) - 2-(4-Methoxyphenyl)-6-iodo-imidazo[1,2-a]pyridine, - N-(3-(imidazo[1,2-a]pyridin-5-ylmethylen)-2-oxoindolin-5-yl)-3-(piperidin-1-yl)propanamide.
  19. A compound according to claim 1, wherein the compound of formula I is selected from
  20. A compound of formula I, defined in any of claims 1 to 17, for use as a medicament.

Description

FIELD OF THE INVENTION The present invention relates to the production of synthetic chemicals for cosmetic, nutraceutical and therapeutic applications (Biomedical sector). It falls within the field of preparing new compounds through the chemical synthesis of imidazo[1,2-a]pyridine derivatives using Suzuki coupling and heterocyclisation reactions, with potent anti-inflammatory activity in vitro in cell cultures and in vivo in mouse models. BACKGROUND OF THE INVENTION Inflammation is a normal response of the immune system to infection. However, when allowed to continue unchecked, it can result in autoimmune or autoinflammatory disorders, neurodegenerative diseases, or even cancer. The growing understanding that chronic inflammation is crucial in many diseases opens up new ways for treatment. A variety of safe and effective anti-inflammatory agents are currently available, including aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), with many more drugs in development. An effective anti-inflammatory drug should be able to inhibit the development of inflammation without interfering with normal homeostasis. Anti-inflammatory drugs typically inhibit cyclooxygenases (COX), which are involved in the biosynthesis of prostaglandins that promote inflammation. Conventional NSAIDs are associated with gastric and renal side effects, as they inhibit both constitutive COX-1 and inducible COX-2. Most selective COX-2 inhibitors (COXIBs) lack gastric side effects but are associated with cardiac side effects with long-term use. On the other hand, excess reactive oxygen species (ROS) in the body cause oxidative stress, which damages the p53 protein and poly (ADP-ribosyl)ation (PARP), which, in turn, triggers the activation of proteases (calpains), protein degradation, and disruption of mitochondrial functions, which reduces ATP levels and ultimately leads to cell necrosis. ROS dysregulation can cause cellular dysfunction that results in the development of many diseases such as cancers, cardiovascular diseases, strokes, and ultimately death. Current approaches to overcoming inflammation include the use of immuno-selective anti-inflammatory derivatives, selective glucocorticoid receptor agonists, statins, histone deacetylase inhibitors, PPAR agonists, resolvins and proteins, and TNFα inhibitors, among others. Transforming growth factor-beta (TGFβ) is a crucial agent in immune system homeostasis, involved, among other things, in inflammatory cell migration, growth inhibition, invasion, epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) remodelling, and immunosuppression. However, although it is normally dynamically regulated and involved in maintaining tissue homeostasis, TGFβ is often chronically overexpressed in different pathologies, such as cancer, fibrosis, and inflammation. The TGFβ signalling pathway has become a popular target for drug development. Furthermore, TGFβ is the most potent profibrogenic cytokine, and its expression is increased in almost all fibrotic diseases. There is growing evidence that reactive oxygen species (ROS) modulate TGFβ signalling through different pathways. In particular, TGFβ1 increases ROS production and suppresses antioxidant enzymes, leading to a redox imbalance. ROS, in turn, induce/activate TGFβ1 and mediate many of the fibrogenic effects of TGFβ. In this regard, compounds that selectively inhibit TGFβ receptors could have the potential to inhibit the inflammatory response and be developed for therapeutic applications in the treatment of fibrosis, late-stage carcinogenesis, atherosclerosis, and excessive scarring diseases in which TGFβ activity has been implicated in the signalling pathway. Inhibition of TGFβ is capable of reducing perivascular inflammation, thereby slowing disease progression. In this regard, deficiency of its receptor ALK5 is capable of inhibiting macrophage-mediated inflammation. In turn, the TGFβ/ALK5 pathway has been proposed as a therapeutic target capable of restoring sensitivity to the anti-inflammatory activity of corticosteroids in inflammation caused by respiratory viral infections. In most cells, TGFβ sends signals through the combination of TGFβR-II and ALK5. ALK5 is a tyrosine kinase that is the type I receptor for tumour growth factor beta (TGFβ-I) and has been described as a mediator in the inflammatory response, an inducer of fibrosis of various origins, and a promoter of cell survival, migration, differentiation and proliferation, related to various pathologies, including tumour processes. In fact, Alk5 inhibition has a clear inhibitory effect on the inflammatory response, promoting the anti-inflammatory response in human macrophages. Alk5 inhibition is referred to in Ling LE, Lee WC. Tgf-beta type I receptor (Alk5) kinase inhibitors in oncology. Curr Pharm Biotechnol. 2011 Dec;12(12):2190-202. https://doi.org/10.2174/138920111798808257. On the other hand, it has recently been reported that targeting the TGFβ/Smad signalling