2-indolinone derivatives and uses thereof

Abstract

The present invention relates to the cosmetic use of a compound of formula (I), wherein R1 and R2 may be equal or different and may signify H, an alkyl group with 1-5 carbon atoms, or R1 and R2 are bonded, forming a ring with 4-8 members; n signifies 0, 1, 2, 3 or 4; and R3 is a residue of two condensed rings, which has the meanings indicated in the description.

Description

[0001] 2-INDOLINONE DERIVATIVES AND THEIR USES

[0002] Field of the invention

[0003] The present invention relates to the production of synthetic chemical products for cosmetic, nutraceutical, and therapeutic applications (biomedical sector). Specifically, it falls within the field of the chemical synthesis of new compounds, their cosmetic use for healed wounds, and their therapeutic use in the prevention or treatment of fibrosis (hypertrophic scars or keloids).

[0004] Background

[0005] A scar is the final result of correction that enhances the skin, resulting in a break in its continuity. It may be almost imperceptible or manifest as a mark or scar. Although the epidermis regenerates completely, the integrity of the dermis and appendages is never complete. It is generally replaced by denser fibrous tissue, without appendages and generally with loss of elastic fibers.

[0006] Scars are, therefore, the consequence of the biological process of wound repair. These wounds may have occurred on the skin or on other organs and tissues of the body.

[0007] Normally, scars tend to be well defined, but sometimes fibroblasts and their evolution into myofibroblasts produce excess collagen (type I and III), and this gives rise to pathological scars that range from small textural alterations to hypertrophic and keloid scars.

[0008] Hypertrophic scars do not extend beyond the original wound boundaries. These hypertrophic scars typically reach a certain size and then stabilize or recede.

[0009] Sometimes scars can grow beyond the original injury area and extend into the adjacent dermal tissue.

[0010] Keloids are defined as pathological scars that grow beyond the boundaries of the original lesion. They occur in areas of cutaneous injury and are similar to benign dermal fibroproliferative tumors, without malignant potential. They are characterized by excessive deposition of extracellular components, namely collagen, fibronectin, elastin, proteoglycans, and growth factors. The pathogenesis of keloid formation is complex, involving patient factors such as ethnicity (higher incidence among African Americans, Asian Americans, Latin Americans, and other ethnicities with darker pigmentation), genetics (familial case reports and parallelism in identical twins imply a genetic contribution to the pathophysiology), age, hormones, keloid location, as well as microenvironmental factors such as injury and inflammatory skin conditions.Chronic inflammation is increasingly considered to play a key role in the pathogenesis of keloids.

[0011] Keloids cause cosmetic deformities, and although they may be asymptomatic, they can be itchy or painful. In some cases, they can grow large enough to cause functional limitations, especially when located on flexor surfaces.

[0012] Despite various advances in knowledge, the exact molecular basis of pathological scar formation remains largely unknown. (Limandjaja GC, Niessen FB, Scheper RJ, Gibbs S. The keloid disorder: Heterogeneity, histopathology, mechanisms and models. Front. Cell. Dev. Biol. 2020, 8, 360. DOI: 10.3389 / fcell.2020.00360).

[0013] Evidence to date suggests a longer inflammatory period with immune cell infiltrate present in the scar tissue of keloids, the consequence of which may contribute to increased fibroblast activity with increased and more sustained ECM deposition (Limandjaja GC, van den Broek LJ, Breetveld M, Waaijman T, Monstrey S, de Boer EM, Scheper RJ, Niessen FB, Gibbs S. Characterization of In Vitro Reconstructed Human Normotrophic, Hypertrophic, and Keloid Scar Models, issue Eng. Part C Methods, 2018, 24, 242-253. DOI: 10.1089 / ten.TEC.2017.0464)

[0014] This, in turn, may explain why keloid scars extend beyond the original wound margins, whereas hypertrophic scars, in which the immune cell infiltrate decreases over time, remain within the original wound margins and often regress over time (Brown JJ, Bayat A. Genetic susceptibility to raised dermal scarring. Br. J. Dermatol. 2009, 161 , 8-18. DOI: 10.1111 / j.1365-2133.2009.09258).

[0015] To find better treatments, a better understanding of the mechanism of keloid formation and progression is needed.

[0016] The formation of keloid scars is a serious problem for those who suffer from them, as they cause pain, itching, a burning sensation, peeling, irritation from clothing rubbing against them, or other uncomfortable skin changes. If keloids are located on a joint, movement may be restricted. Additionally, they pose a cosmetic problem, depending on the affected area, and a psychological problem, stemming from both the discomfort and the cosmetic issues. These problems seriously and negatively impact the quality of life of those who suffer from keloid scars, while generating high healthcare costs for health systems, which can range from a few hundred euros for a single spheroid injection to thousands of euros for surgical excision or radiotherapy (Elsaie, ML. Update on management of keloid and hypertrophic scars: A systemic review. J. Cosmet. Dermatol. 2021 , 20, 2729- 2738. DOI: 10.1111 / jocd.14310; Bijlard E, Kouwenberg CA, Timman R, Hovius SE, Busschbach JJ, Mureau MA. Burden of keloid disease: a cross-sectional health-related quality of life assessment. Acta Derm. Venereol. 2017, 97, 225-229. DOI: 10.2340 / 00015555-2498); Kassi K, Kouame K, Kouassi A, et al. Quality of life in black African patients with keloid scars. Dermatol. Reports. 2020, 12, 8312. DOI: 10.4081 / dr.2020.8312; Lu W, Chu H, Zheng X. Effects on quality of life and psychosocial well-being in Chinese patients with keloids. Am. J. Transí. Res. 2021, 13, 1636-1642. PMCID: PMC8014351).

[0017] Document W02008015190 relates to the treatment and prevention of excessive scarring, such as those manifested by keloid and hypertrophic scars, with a composition comprising a moisturizing agent and an anesthetic. The moisturizing agent may include emollients, gelling agents, and humectants.

[0018] Another document related to the treatment of scars is EP2958634B1, which deals with methods and compositions for improving the appearance and formation of scars and specifically discloses compositions comprising a ureido polymer.

[0019] Some 2-indolinone derivatives are known in the therapeutic field, but not their cosmetic use.

[0020] Document CN 108420820 discloses an indolinone derivative, but the object of the invention is the application to combat resistant bacteria.

[0021] Application WO9632380 relates to azaindole-derived compounds useful as tyrosine kinase inhibitors, for use as an anticancer agent or in the treatment of coronary artery disease or the control of angiogenesis.

[0022] A similar use as tyrosine kinase inhibitors is disclosed in WQ0008202 for 3-methylidenyl-2-indolinone derivatives.

[0023] El artículo Molecular Diversity (2021) 25:1051-1075; Structure-activity relationship study of DEL-22379: ERK dimerization inhibitors with increased safety, Yang Yang, ■ Yuanzheng Zhou, Lei Tao, Tao Yang, Yinglan Zhao, Youfu Luo, https: / / doi.org / 10.1007 / s11030-020-10088-0, 2-indolin como inhibidores de ERK.

[0024] El artículo Synthesis of a Dual Functional Anti-MDR Tumor Agent PH 11-7 with Elucidations of Anti-Tumor Effects and Mechanisms', Ye Su1 , Xin Cheng., Yaohong Tan, Yunhui Hu, Yuan Zhou, Juanni Liu, Yuanfu Xu, Yinliang Xie, Caiyun Wang, Yingdai Gao, Jianxiang Wang, Tao Cheng, Chunzheng Yang, Dongsheng Xiong, Hua Miao, PLoS ONE | www.plosone.org 7 March 2012 | Volume 7 | Issue 3 | e32782, se refiere a la síntesis de un agente anti-MDR que es un derivado de 2-indolinona.

[0025] Therefore, it is observed that the state of the art includes some 2-indolinone derivatives and their use in medicine. To date, no cosmetic use for this type of compound has been identified, particularly for skin treatment and, more specifically, for the treatment of healed scars.

[0026] Description

[0027] A first object of the invention relates to the cosmetic use of a compound of formula (I): in which

[0028] Ri and R2 may be the same or different, and may mean H, an alkyl group of 1 to 5 carbon atoms, or R1 and R2 are joined together to form a 4- to 8-membered ring, such as piperidine, n means 0, 1, 2, 3 or 4

[0029] Rs is selected from:

[0030] - indolyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; indolyl substituted by an alkyl group of 1 to 5 carbon atoms at the N atom, which may also be substituted on one carbon by one of the groups mentioned above; - indazolyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0031] - 3-azaindolyl, 4-azaindolyl, 5-azaindolyl, 6-azaindolyl, 7-azaindolyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms,

[0032] - 3-azaindolyl, 4-azaindolyl, 5-azaindolyl, 6-azaindolyl, 7-azaindolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph,

[0033] - benzofuranyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0034] - benzothiazolyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0035] - benzothiophenyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0036] - benzimidazolyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0037] - benzoxazolyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0038] - isobenzoxazolyl unsubstituted or substituted by an alkyl of 1 to 5 carbon atoms, hydroxyl or an alkoxy group of 1 to 5 carbon atoms;

[0039] - unsubstituted quinolinyl or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0040] - isoquinol ini lo unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0041] - imidazo[1,2-a]pyridinyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms,

[0042] - indolizinyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0043] - isothionaphthenyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0044] - isobenzofuranyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - isoindolyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms and

[0045] - isoindolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph.

[0046] The phrase “the N atom, which may also be substituted on a carbon by one of the groups mentioned” in this specification refers to the fact that the N atom in each case may optionally bear a substituent which may be any of those mentioned for any carbon atom of the same group being defined in that section.

[0047] In this specification, when nothing is specified, it should be understood that for any of the compounds that have some type of isomerism, all isomers are included in the formula, and therefore within the scope of the invention.

[0048] According to particular embodiments, in any of the alternatives indicated above for R3, the alkyl group of 1 to 5 carbon atoms, if present, is methyl or ethyl.

[0049] According to particular embodiments, in any of the alternatives indicated above for R3, the alkoxy group of 1 to 5 carbon atoms, if present, is methoxy or ethoxy.

[0050] For any of the alternatives indicated for R3, when no specific position of union to the rest of the molecule is indicated, it must be understood that the radical R3 is joined to the rest of the molecule by any possible position from the chemical point of view, that is, it is joined to the rest of the molecule through any carbon atom or N, as the case may be, that has a hydrogen that can be eliminated.

[0051] According to particular preferred embodiments, R3 is 2-benzoxazolyl.

[0052] According to further particular embodiments, R1 and R2 are joined together to form a piperidinyl moiety.

[0053] According to additional particular embodiments, n= 1 or 2.

[0054] According to additional particular embodiments, R1 and R2 are joined together to form a piperidinyl moiety and n=1 or 2.

[0055] According to further particular embodiments, R1 and R2 are joined to form a piperidinyl moiety and n=2, and R3 has any of the meanings given above. According to further particular embodiments, R1 and R2 are joined to form a piperidinyl moiety, n=2, and R3 is selected from 5-methoxy-2-indolyl; 5-hydroxy-2-indolyl; 2-benzothiazolyl, 5-methoxy-1-methyl-2-indolyl; 2-benzofuranyl; 2-benzothiophenyl; 2-benzimidazolyl; 2-methyl-5-benzoxazolyl; 2-methyl-6-benzoxazolyl, and 2-quinolinyl.

[0056] According to additional particular embodiments, R1 and R2 are joined to form a piperidinyl moiety, n=1, and R3 is 2-benzofuranyl.

[0057] According to particularly preferred embodiments, R1 and R2 are joined to form a cycle such as piperidine, n means 2 and R3 is 2-benzoxazolyl:

[0058] In a particular embodiment, the cosmetic use includes the cosmetic treatment of the skin, more specifically healed skin wounds and / or normal skin healing. Normal scars are those that are not aberrant, such as keloid or hypertrophic scars. As used herein, cosmetic use means non-therapeutic use.

[0059] In yet another embodiment, the cosmetic use comprises applying one or more compounds of formula (I) to healed skin wounds, said application being simultaneous or sequential, one compound of formula (I) after another. That is, the cosmetic use may comprise applying a combination of compounds of formula (I).

[0060] In another particular embodiment, the cosmetic use comprises the improvement of the appearance and / or reduction of already formed scars and / or other visible effects of healed wounds, keloids and hypertrophic scars, as well as, for example, the formation of textural alterations in the skin, such as wrinkles.

[0061] In another particular embodiment, the cosmetic use comprises the use of one or more compounds of formula I to increase skin elasticity and / or reduce textural alterations of the skin and / or reduce itching of the skin and / or reduce skin pain by topical administration of said compound to a subject. Said cosmetic use refers to a non-therapeutic use and should be understood to exclude therapeutic uses. A second object of the invention relates to a compound of formula (II): in which:

[0062] Ri and R2 may be the same or different, and may mean H, an alkyl group of 1 to 5 carbon atoms, or R1 and R2 are joined together to form a 4- to 8-membered ring, such as piperidine, n means 0, 1, 2, 3 or 4

[0063] Rs is selected from:

[0064] - one of 2-indolyl, 5-indolyl or 6-indolyl unsubstituted, or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0065] - one of 4-indolyl or 7-indolyl, substituted by a group selected from alkyl of 1 to 5 carbon atoms, hydroxyl and alkoxy of 1 to 5 carbon atoms;

[0066] - 3-indolyl substituted on one of carbons 2, 4, 5, 6 or 7 by a group selected from an alkyl group of 1 to 5 carbon atoms, hydroxyl and alkoxyl group of 1 to 5 carbon atoms

[0067] - 3-indolyl substituted at carbon 5 by a group selected from an alkyl group of 1 to 5 carbon atoms, hydroxyl and alkoxyl group of 2 to 5 carbon atoms;

[0068] - indolyl substituted with an alkyl group of 1 to 5 carbon atoms at the N atom, which may also be substituted on one carbon by one of the groups mentioned above; except for unsubstituted 3-indolyl, where n=2 and R1 and R2 form a piperidinyl moiety;

[0069] - one of 3-indazolyl, 4-indazolyl, 5-indazolyl or 7-indazolyl, unsubstituted or substituted by a group selected from an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; except unsubstituted 5-indazolyl, where n=2 and R1 and R2 form a piperidinyl moiety;- 6-indazolyl substituted by a group selected from an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - a 3-azaindolyl, 4-azaindolyl, 5-azaindolyl, 6-azaindolyl, - 7-aza-2-indolyl, 7-aza-4-indolyl, 7-aza-5-indolyl, 7-aza-6-indolyl radical, unsubstituted,

[0070] - a 3-azaindolyl, 4-azaindolyl, 5-azaindolyl, 6-azaindolyl or 7-azaindolyl radical substituted by a group selected from an alkyl group having 1 to 5 carbon atoms, hydroxyl and alkoxy group having 1 to 5 carbon atoms,

[0071] - a 3-azaindolyl, 4-azaindolyl, 5-azaindolyl, 6-azaindolyl or 7-azaindolyl residue substituted by an alkyl group having 1 to 5 carbon atoms at the N atom, which may also be substituted on one carbon by one of the groups mentioned in the preceding paragraph, except for unsubstituted 7-aza-3-indolyl, in the case where n=2 and R1 and R2 form a piperidinyl residue;

[0072] - one of 2-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl or 6-benzofuranyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0073] - 3-benzofuranyl substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0074] - benzothiazolyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0075] - benzothiophenyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0076] - benzimidazolyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0077] - benzoxazolyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0078] - isobenzoxazolyl unsubstituted or substituted by an alkyl of 1 to 5 carbon atoms, hydroxyl or an alkoxy group of 1 to 5 carbon atoms;

[0079] - one of 1-quinolinyl, 2-quinolinyl, 3-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl or 8-quinolinyl unsubstituted or substituted by a group selected from an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0080] 4-quinolinyl substituted by a group selected from an alkyl group of 1 to 5 carbon atoms, hydroxyl, an alkoxy group of 1 to 5 carbon atoms in position 2, 3, 5, 7 or 8, or alkoxy of 2 to 5 carbon atoms in position 2, 3, 5, 6, 7 or 8;

[0081] - isoquinol inyl unsubstituted or substituted by an alkyl group having 1 to 5 carbon atoms, hydroxyl or alkoxy group having 1 to 5 carbon atoms; - one of 5-imidazo[1,2-a]pyridinyl, 6-imidazo[1,2-a]pyridinyl, 7-imidazo[1,2-a]pyridinyl, or 8-imidazo[1,2-a]pyridinyl, unsubstituted or substituted by an alkyl group having 1 to 5 carbon atoms, hydroxyl or alkoxy group having 1 to 5 carbon atoms,

[0082] - 3-imidazo[1,2-a]pyridinyl substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms,

[0083] - indolizinyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; isothionaphthenyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0084] - isobenzofuranyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0085] - isoindolyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxyl group of 1 to 5 carbon atoms and

[0086] - isoindolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph,

[0087] - 2-quinoxalinyl, 4-quinoxalinyl or 8-quinoxalinyl unsubstituted or substituted by alkyl of 1 to 5 carbon atoms, hydroxyl or alkoxy of 1 to 5 carbon atoms, and

[0088] - 6-quinoxalinyl substituted by alkyl of 1 to 5 carbon atoms, hydroxyl or alkoxy of 1 to 5 carbon atoms.

[0089] According to particular embodiments of formula (II)

[0090] Ri and R2 may be the same or different, and may represent H, an alkyl group of 1 to 5 carbon atoms, or R1 and R2 are joined together to form a 4 to 8 membered ring, such as piperidine, n represents 0, 1, 2, 3 or 4 Rs is selected from:

[0091] - 2-indolyl unsubstituted, or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxyl group of 1 to 5 carbon atoms,

[0092] - 2-indolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph,

[0093] - 4-indolyl substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxyl group of 1 to 5 carbon atoms,

[0094] - 4-indolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph;

[0095] - 5-indolyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms,

[0096] - 5-indolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph;

[0097] - 6-indolyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0098] - 6-indolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph;

[0099] - 7-indolyl substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxyl group of 1 to 5 carbon atoms,

[0100] - 7-indolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph;

[0101] - 3-indolyl substituted by an alkyl of 1 to 5 carbon atoms in position 2, 4, 5, 6 or 7, or substituted by an alkoxyl group of 1 to 5 carbon atoms in position 4, 6 or 7,

[0102] - 3-indolyl substituted by an alkyl group having 1 to 5 carbon atoms at the N atom, which may also be substituted on one carbon by one of the groups mentioned in the preceding paragraph; - a 3-indazolyl, 4-indazolyl, 6-indazolyl or 7-indazolyl radical, unsubstituted or substituted by an alkyl group having 1 to 5 carbon atoms, hydroxyl or alkoxy group having 1 to 5 carbon atoms,

[0103] - a 3-indazolyl, 4-indazolyl, 6-indazolyl or 7-indazolyl residue, substituted by an alkyl group of 1 to 5 carbon atoms on the N atom, and which may also be substituted on one carbon by one of the groups mentioned in the preceding paragraph;

[0104] - 5-indazolyl substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms,

[0105] - 5-indazolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph;

[0106] - a 3-azaindolyl, 4-azaindolyl, 5-azaindolyl or 6-azaindolyl residue, unsubstituted or substituted by an alkyl group having 1 to 5 carbon atoms, hydroxyl or alkoxy group having 1 to 5 carbon atoms,

[0107] - a 3-azaindolyl, 4-azaindolyl, 5-azaindolyl or 6-azaindolyl residue substituted by an alkyl group of 1 to 5 carbon atoms at the N atom, which may also be substituted on one carbon by one of the groups mentioned in the preceding paragraph;

[0108] - 7-aza-2-indolyl, 7-aza-4-indolyl, 7-aza-5-indolyl, 7-aza-6-indolyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy of 1 to

[0109] 5 carbon atoms,

[0110] - 7-aza-2-indolyl, 7-aza-4-indolyl, 7-aza-5-indolyl, 7-aza-6-indolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph,

[0111] - 7-aza-3-indolyl substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms,

[0112] - 7-aza-3-indolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph;

[0113] - one of 2-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl or 6-benzofuranyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0114] - 3-benzofuranyl substituted by an alkyl group having 1 to 5 carbon atoms, hydroxyl or alkoxy group having 1 to 5 carbon atoms; - benzothiazolyl unsubstituted or substituted by an alkyl group having 1 to 5 carbon atoms, hydroxyl or alkoxy group having 1 to 5 carbon atoms;

[0115] - unsubstituted benzimidazolyl or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms,

[0116] - benzoxazolyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0117] - 2-quinolinyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0118] - 3-quinolinyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0119] - 4-quinolinyl substituted by alkyl of 1 to 5 carbon atoms or hydroxyl in position 2, 3, 5, 6, 7 or 8, or by an alkoxy group of 1 to 5 carbon atoms in position 2, 3, 5, 7 or 8;

[0120] - 5-quinolinyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0121] - 6-quinolinyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0122] - 7-quinolinyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0123] - 8-quinolinyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0124] - 1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7- isoquinolinyl, 8-isoquinolinyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms;

[0125] - 2-quinoxalinyl, 4-quinoxalinyl or 8-quinoxalinyl unsubstituted or substituted by alkyl of 1 to 5 carbon atoms, hydroxyl or alkoxy of 1 to 5 carbon atoms, and

[0126] - 6-quinoxalinyl substituted by alkyl of 1 to 5 carbon atoms, hydroxyl or alkoxy of 1 to 5 carbon atoms.

[0127] For any of the alternatives indicated for R3, when no specific position of union to the rest of the molecule is indicated, it must be understood that the radical R3 is joined to the rest of the molecule by any possible position from the chemical point of view, that is, it is joined to the rest of the molecule through any carbon atom, or N as the case may be, that has a hydrogen that can be eliminated.

[0128] According to particular embodiments R1 and R2 are joined together to form a piperidinyl moiety.

[0129] According to particular realizations n=2.

[0130] According to particular embodiments R1 and R2 are joined together to form a piperidine residue and n=1 or 2.

[0131] According to particular preferred embodiments R3es2-benzoxazolyl.

[0132] According to particular embodiments R1 and R2 are joined to form a piperidine moiety, n=2, R3 is selected from 2-benzofuranyl; 2-benzothiophenyl; 2-benzothiazolyl, 5-methoxy-1-methyl-2-indolyl, 2-benzoxazolyl, 2-methyl-5-benzoxazolyl, 2-methyl-6-benzoxazolyl, 2-benzimidazolyl, and 2-quinolinyl.

[0133] According to particularly preferred embodiments, Ri and R2 are joined to form a cycle such as piperidine, n means 2 and R3 is 2-benzoxazolyl:

[0134] Preferred embodiments relate to the compounds of formula (II):

[0135] - (E)-A / -(3-(benzo[d]oxazol-2-yl-methylene)-2-oxoindolin-5-yl)-3-(pipehdin-1-yl)propan-amide,

[0136] - (E)-N-(3-(benzo[b]furan-2-yl-methylene)-2-oxoindolin-5-yl)-3-(piperidin-1-yl)propanamide,

[0137] - (E)-N-(3-(benzo[b]thiophene-2-yl-methylene)-2-oxendolin-5-yl)-3-(piperidine-1-yl)propanamide, - (Z)-N-(3-((1 H-benzo[d]imidazol-2-yl)methylene-linn-1-2-pyridone)-3-2-oxone il)propanamide,

[0138] - (E / Z)-N-(3-((2-methylbenzo[d]oxazol-5-yl)methylene)-2-oxondolin-5-yl)-3-(piperidin-1- il)propanamide,

[0139] - (E / Z)-N-(3-((2-methylbenzo[d]oxazol-6-yl)methylene)-2-oxondolin-5-yl)-3-(piperidin-1- il)propanamide,

[0140] - (E)-N-(2-oxo-3-(quinolin-2-ylmethylene)indolin-5-yl)-3-(piperidin-1-yl)propanamide or

[0141] - (E)-N-(3-(benzo[b]furan-2-yl)methylene)-2-oxoendolin-5-yl)-3-(piperidin-1-yl)acetamide.

[0142] Compounds of formula (II) can be synthesized by conventional synthesis methods. In addition, the starting products are commercially available compounds: 5-aminooxindole, acryloyl chloride (for n = 2), 2-piperidineacetic acid (for n = 1), piperidine (or secondary amines in general), and aldehydes of formula R3- CHO. The rest of the reagents and solvents used are also commercially available.

[0143] Documents describing such known methods are, for example, the closely related article: Nesi, G.; Sestito, S.; Mey, V.; Ricciardi, S.; Falasca, M.; Danesi, R.; Lapucci, A.; Breschi, MC; Fogli, S.; Rapposelli, S. Synthesis of Novel 3,5-Disubstituted-2-Oxindole Derivatives As Antitumor Agents against Human Nonsmall Cell Lung Cancer. ACS Med. Chem. Lett. 2013, 4 (12), 1137–1141. https: / / doi.org / 10.1021 / ml400162g.

[0144] The compounds of formula II can be obtained by a process comprising: a) converting the 5-aminooxindole of formula (III) in a compound of formula IV in which R1, R2 and n have the meanings given in formula (II), and b) Reaction of the product obtained in a) with a heterocyclic aldehyde of formula R3-CHO, where R3 has the given meaning, in the presence of an acid or a base, to give the compound of formula (II), where R1, R2 and n have the meanings given above for formula (II).

[0145] Ejemplos de agentes de acoplamiento peptídico son carbodiimidas, sales de aminio, uronio, o fosfonio como diciclohexilcarbodiimida (DCC), 1-ethyl-3-(3- dimetilaminopropil)carbodiimida (EDC o EDAC o WSC), hexafluorofosfato de benzotriazol tetrametil uronio (HBTII), hexafluorofosfato de O-(1 H-6-clorobenzotriazol- 1-¡l)-1 ,1 ,3,3-tetrametiluronio (HCTIIO), hexafluorofosfato de benzotriazol-1-il-oxi-tris- (dimetilamino)-fosphonio (BOP), 2-cloro-4,6-dimetoxi-1 ,3,5-triazine (CDMT), cloruro de (clormetilen)dimetiliminio, 1 ,1'-carbonyldiimidazol (GDI), 2,4,6-tripropyl-1, 3, 5, 2,4,6- tr¡oxathfosfohnano-2,4,6-thóx¡do (T3P or PPACA), chlorophosphates de dialquilo, hexafluorophosphate de 7-azabenzotriazol-1-iloxi)tripyrrolidinophosphonio (PyAOP),

[0146] 7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), ethyl cyano(hidroxyimino)acetate-O2]tri-1-pyrrolidinylphosphonium hexafluorophosphate

[0147] (PyOxim), O-[(Ethoxycarbonyl)cyanomethylenamine]-N , N , N', N tetramethyluronium (TOTII) tetrafluoroborate, N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium hexafloronium (TSTII) tetrafluoroborate ,3,3-tetramethyl-2-(4,5,6,7-tetrachloro- 1 ,3-dioxoisoindolin-2-yl)isouronium (CITU), hexafluorophosphate of 1- [bis(dimethylamine)methylene]-1 H-1 ,2,3-HA-Triazolo-3pyridinium[4,5 hexafluorophosphate of (1-cyano-2-ethoxy-2-oxoethyldenaminoxy)dimethylamino-morpholino- carbenium (COMll), among others.The final step - stage b) - is an aldol-type condensation with the corresponding aldehyde, which is documented in the literature (2-lndolone PAK1 inhibitor and application thereof in preparation of antitumor agent CN111675647 A 2020-09-18, Preparation of hydrosoluble 3-arylidene-2-oxyindole tyrosine kinase inhibitors WO9622976 A1 ; Structure-activity relationship study of DEL-22379: ERK dimerization inhibitors with increased safety, Yang, Yang; Zhou, Yuanzheng; Tao, Lei; Yang, Tao; Zhao, Yinglan; et al.; Molecular Diversity (2021), 25(2), 1051-1075). It can be carried out both thermally (as in other examples described in the literature) and by microwave heating. It can also be seen in the “examples” section, as General Method I and General Method II.

[0148] Step a) of the procedure can be carried out according to several alternatives: a.1) A first alternative comprises carrying out a reaction of 5-aminooxindole of formula (III) with an amino acid of formula (V) in which Ri, R2 and n have the meanings given in formula (II), in the presence of a peptide coupling agent, directly obtaining the compound of formula IV: in which R1, R2 and n have the meanings given above for formula (II). a.2) A second alternative for the case where n=2, comprises carrying out a 5-aminooxindole reaction of formula (III) with a compound selected from acid chloride or a mixed anhydride of formula

[0149] VI:

[0150] (nucleophilic or aza-Michael substitution reactions) obtaining the functionalization of the amino group in position 5 of the 5-aminooxindole, that is, obtaining the intermediate of formula VII: and reaction of the intermediate of formula VII with a secondary amine of formula (VIII): in which R1, R2 and n have the meanings given in formula (II), to give the compound of formula IV ((referred to as 1 in the examples section) where Ri, R2 have the meanings given in formula (II) and n=2.

[0151] This variant corresponds to performing a nucleophilic or aza-Michael substitution reaction. An example of this variant in step a) involves using the acid chloride CH2=CH-C(=O)CI to obtain an amide, which is then functionalized, for example, with piperidinyl (for the case where R1 and R2 form piperidinyl) by aza-Michael reaction.

[0152] A third alternative to carry out step a) when n= 1, comprises: a.3) A 5-aminooxindole reaction of formula (III): with a compound selected from:

[0153] - acid chloride or a mixed anhydride of formula (IX): obtaining the functionalization of the amino group in position 5 of 5-aminooxindole, obtaining the intermediate of formula (X): and reaction of the obtained intermediate of formula (X) with a secondary amine of formula (VIII): in which Ri, R2 and n have the meanings given in formula (II), to give the compound of formula (IV): in which R1, R2 have the meanings given in formula (II) and n=1. An example of this variation in step a) comprises using the acid chloride CH2=CH-C(=O)CI to obtain an amide, which is then functionalized, for example, with piperidinyl (for the case where R1 and R2 form piperidinyl) by aza-Michael reaction.

[0154] The general procedure and the variations of step a) are shown in Figure 1.

[0155] Examples of acids that can be used in step b) are: organic acids such as acetic or thiofluoroacetic, or mineral acids such as sulfuric or phosphoric.

[0156] Examples of bases that can be used in step b) are: inorganic bases such as metal hydroxides or carbonates, or organic bases such as secondary or tertiary amines.

[0157] An example of step a) - according to the vahante a.1) - of the procedure in which the reaction of 5-aminooxindole of formula (III) is carried out by means of a peptide coupling type reaction is shown in the following scheme:

[0158] An additional example of step a) of the process in which the reaction of 5-aminooxindole of formula (III) with an acid chloride is carried out is shown below:

[0159] A concrete example of the last stage of the procedure (stage b) is shown in the following diagram:

[0160] The compounds of formula (II) have therapeutic, as well as nutraceutical and cosmetic activity.

[0161] A further object of the invention relates to a compound of formula (I) and / or compound of formula (II) for therapeutic use in cutaneous healing of the skin of a subject.

[0162] The compounds of formula (I) and those of formula (II), which are included in those of formula (I), are also useful in the treatment of fibrosis, hypertrophic scar, keloid, or the prevention of tissue susceptible to developing fibrosis, hypertrophic scar, or keloid, the treatment comprising an improvement in the appearance and / or a substantial reduction in the formation of said scars. Preferably, the scar has formed on a wound.

[0163] In another particular embodiment, the therapeutic use for skin healing comprises applying one or more compounds of formula I to the open wound before scar formation to promote faster and more effective healing. It can be applied topically directly to the wound site or as part of a bandage placed over the wound.

[0164] As used herein, the term "wound" refers to a type of injury in which the skin is torn, cut, or punctured (open wound), or in which blunt force trauma causes a contusion (closed wound).

[0165] The compounds of formula (I) exhibited potent wound healing activity in vitro against cultured human keratinocytes (scratch assays, also known as wound healing assays). Keratinocytes are the predominant cell type found in the epidermis, the outermost layer of the skin, and play a critical role in wound healing. The keratinocyte scratch assay provides valuable information on the migratory behavior of keratinocytes and their ability to heal wounds. This assay allows the investigation of the underlying mechanisms of cell migration and wound healing in a controlled laboratory setting.In a further embodiment, the compound of formula (I) and / or compound of formula (II) for therapeutic use of cutaneous healing of the skin of a subject is selected from one or more of the group consisting of: (E)- / V-(3-(benzo[d]oxazol-2-yl-methylene)-2-oxoindolin-5-yl)-3-(piperidin-1-yl)propanamide (CMPO), (E)- / V-(3-(benzo[b]thiophen-2-yl-methylene)-2-oxoindolin-5-yl)-3-(piperidin-1-yl)propanamide (CMP2), and.

[0166] (EZZ)-A / -(3-((2-methylbenzo[d]oxazol-6-yl)methylene)-2-oxoindolin-5-yl)-3-(pipehdin-1-yl)propanamide (3f) (CMP5).

[0167] The compounds of the invention also exhibited potent antifibrotic activity in in vitro antiproliferative assays on cultured human fibroblasts. Fibroblasts are connective tissue cells that synthesize and secrete extracellular matrix components, such as collagen, elastin, and glycosaminoglycans. These cells are responsible for the production of new tissue during wound healing and play an important role in the repair of injured tissue. When fibroblasts are overactivated, they can produce and deposit excessive amounts of collagen in the affected tissue. This exaggerated response results in excessive scarring, leading to the formation of hypertrophic scars or keloids.

[0168] The healing and antifibrotic capacity of the compounds of formula (I) is much higher than that disclosed in the state of the art, for compounds such as pirfenidone or tranilast, in in vitro studies carried out with keratinocytes and fibroblasts.

[0169] Hall CL, Wells AR, Leung KP. Pirfenidone reduces profibrotic responses in human dermal myofibroblasts, in vitro. Lab Invest. 2018, 98, 640-655. DOI: 10.1038 / s41374-017-0014-3.

[0170] Mecott-Rivera GÁ, Aguilar-Baqueiro JA, Bracho S, et al. Pirfenidone increases the epithelialization rate of skin graft donor sites. Burns. 2018, 44, 2051-2058. D0l:10.1016 / j. burns.2018.07.007.

[0171] Armendariz-Borunda J, Lyra-Gonzalez I, Medina-Preciado D, Gonzalez-Garcia I, Martinez-Fong D, Miranda RA, Magaña-Castro R, Peña-Santoyo P, Garcia-Rocha S, Bautista CA, Godoy J, Flores-Montana J, Floresvillar-Mosqueda J, Armendariz-Vazquez O, Lucano-LanderosMS, Vazquez-Del Mercado M, Sanchez-Parada MG. A controlled clinical trial with pirfenidone in the treatment of pathological skin scarring caused by burns in pediatric patients. Ann. Plast. Surg. 2012, 68, 22-28.

[0172] DGI:10.1097 / SAP.0b013e31821 b6d08. Pirfenidone, approved in the EU and USA for the oral treatment of idiopathic pulmonary fibrosis, has been used in dermocosmetic formulations for the treatment of keloid scars, having shown relatively low efficacy. Tranilast, an antiallergic approved in 1982 in Japan and South Korea for use in bronchial asthma and hypertrophic scars, has not been effective in the treatment of keloids.

[0173] A further object of the invention relates to a pharmaceutical composition comprising at least one compound of formula I and at least:

[0174] An excipient

[0175] A solvent for therapeutic use in skin healing in a subject.

[0176] Preferably, the compound of formula I is applied together with an aqueous solvent. The solvent can be any non-irritating solvent, such as deionized water and phosphate-buffered saline (PBS), which is acceptable for injection into the scar. In another embodiment, the composition can be a topical composition suitable for dispensing directly onto the skin surface, such as a lotion or cream as described below.

[0177] The compounds of formula I, or pharmaceutical compositions of this invention can be contacted with devices that can be applied to the skin, including hydrogel adhesive bandages, injectable compositions, kits and methods for improving scar and / or keloid formation at a wound site.

[0178] Preferably, when treating a healed and / or closed wound, the compound of formula I or pharmaceutical composition is injected or applied to the scar tissue. Preferably, it will be placed below the stratum corneum, the outermost layer of the skin.

[0179] The solvent of the pharmaceutical composition is selected from suspensions, colloids, hydrogels, and emulsions, for example, water or mixtures of water and propylene glycol. Such pharmaceutical compositions can be prepared as injectables, either as liquid solutions or suspensions. Solid forms suitable for dissolving in a hydrogel or liquid solution, or for suspending in liquid prior to use, can also be prepared. The pharmaceutical composition can also be emulsified.

[0180] The excipients must be pharmaceutically acceptable and compatible with the compound of formula I and in amounts suitable for therapeutic use. Suitable excipients include, for example, dextrose, glycerol, ethanol, or the like, and combinations thereof. In addition, if desired, the composition may contain minor amounts of auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and the like, which enhance the effectiveness of the active ingredient. Details of formulation and administration techniques can be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).

[0181] Unless otherwise indicated, the percentages indicated below are by weight.

[0182] Preferably, the compound of formula I should be present in an amount of about 0.1% to about 100% by weight of the pharmaceutical composition. More preferably, they should be present in the compositions of this invention in an amount of about 0.1% to about 10% by weight of the composition. Even more preferably, they should be present in an amount of about 0.1% to about 5% by weight of the composition. More preferably, they should be present in an amount of about 0.1% to about 0.5% by weight of the composition. Most preferably, they should be present in an amount of between 0.1% and 0.5% by weight of the pharmaceutical composition.

[0183] The pharmaceutical compositions of the invention may be presented in the form of a lotion or liquid that can be applied to the wound surface of the skin. It may also be applied directly to the skin or contained within an adhesive bandage (i.e., the treatment solution is contained within the absorbent portion of the bandage) and placed on the wound surface of the skin. These types of compositions may be more viscous and may be based on a gel or hydrogel composition.

[0184] The compositions of this invention may be formulated into a wide variety of product types, including, but not limited to, liquids, lotions, creams, gels, sticks, sprays, shaving creams, ointments, liquid cleansers, washes, solid bars, shampoos, pastes, powders, mousses, wipes, patches, wound dressings, adhesive bandages, hydrogels, and films. These product types may contain various types of cosmetically acceptable topical carriers, including, but not limited to, solutions, emulsions (e.g., microemulsions and nanoemulsions), gels, solids, and liposomes. The following are non-limiting examples of such carriers.

[0185] The topical compositions of the invention may be formulated as solutions. The solutions preferably contain an aqueous solvent (e.g., from about 50% to about 99.99% or from about 90% to about 99% of a cosmetically acceptable aqueous solvent). A lotion may also be made from such a solution. The lotions preferably contain from about 1% to about 20% (more preferably, from about 5% to about 10%) of an emollient(s) and from about 50% to about 90% (more preferably, from about 60% to about 80%) of water.

[0186] Another type of product that can be formulated from a solution is a cream. A cream preferably contains from about 5% to about 50% (more preferably, from about 10% to about 20%) of an emollient(s) and from about 45% to about 85% (more preferably from about 50% to about 75%) of water.

[0187] Another type of product that can be formulated from a solution is an ointment. An ointment may contain a simple base of animal or vegetable oils or semi-solid hydrocarbons. An ointment may preferably contain between 2% and 10% emollient(s) plus between 0.1% and 2% thickening agent(s).

[0188] Lotions and creams may also be formulated as emulsions. Preferably, such lotions contain between 0.5% and 5% emulsifier(s). Such creams will preferably contain from about 1% to about 20% (more preferably, from about 5% to about 10%) of an emollient(s); from about 20% to about 80% (more preferably, from 30% to about 70%) of water; and from about 1% to about 10% (more preferably, from about 2% to about 5%) of an emulsifier(s).

[0189] The compositions of this invention may be prepared according to those methods and processes known to those skilled in the art, or according to the preparation methods of this invention. For example, water-soluble components such as glycerin, propylene glycol, sorbitol, inorganic base, preservatives, and the like may be dissolved in water, and cellulose-derived polymers may be added to this combination.

[0190] Another preparation method involves mixing all the ingredients into a water-free slurry and then adding the slurry to the water. Preferably, the composition does not contain surfactants, including anionic, cationic, amphoteric, or nonionic surfactants.

[0191] Included in a liquid formation or lotion of the composition may be water, oils, preservatives, emulsifiers, viscosity enhancers, emollients, electrolytes, fragrance, buffers, pH modifiers, skin protectants, metal ion sequestrants and the like.

[0192] Absorbent articles such as bandages can also be used to cover the open wound and administer the compound of formula I or a pharmaceutical composition comprising it. Any absorbent bandage can be used in this invention.

[0193] Typically, bandages have three layers: a skin-facing layer, an absorbent layer, and a top layer facing away from the subject's skin. The bottom layer of the bandage faces the wearer's skin and may be made of an apertured film or other material that does not adhere to the wound but allows the treatment solution to penetrate. The absorbent layer may be made of absorbent fibers and contains the treatment solution. The top layer may also be an apertured film. The top layer may have a smaller open area than the bottom layer; this will prevent unwanted leakage of the treatment solution from the absorbent layer. Bandages may be square, rectangular, round, oval, or triangular in shape. Bandages can generally range from 0.25 mm to 5 mm thick.

[0194] Any of the pharmaceutical compositions indicated above, as well as the formulation in creams, lotions or ointments can be used for the cosmetic use of already healed wounds.

[0195] Brief description of the figures

[0196] Figure 1. General scheme of the procedure for obtaining the compounds of formula (II)

[0197] Figure 2. Photographs of healing using the compound (E)- / V-(3-(benzo[d]oxazol-2-yl-methylene)-2-oxoindolin-5-yl)-3-(pipehdin-1-yl)propan-amide (CMPO) (scratch test) at Days 0, 1 and 3, arranged vertically.

[0198] Figure 3. Western Blot showing the results of reversibility of the fibrotic phenotype: Conditions: (E)-A / -(3-(benzo[d]oxazol-2-yl-methylene)-2-oxoindolin-5-yl)-3-(pipehdin-1-yl)propan-amide (CMPO): Treatment with TGF-pi and (E)-A / -(3-(benzo[d]oxazol-2-¡l-methylene)-2-oxoindolin-5-yl)-3-(pipehdin-1-yl)propan-amide (CMPO); PIR: Treatment with TGF-pi and pirfenidone; TGF-B: Treatment with TGF-pi; Cntl: No treatment EXAMPLES

[0199] MATERIALS AND METHODS

[0200] A. OBTAINING AND CHARACTERIZATION OF CHEMICAL COMPOUNDS

[0201] A. Synthesis of dialkylamino- / V-(2-oxoindolin-5-yl)alkanamides (1)

[0202] (formula IV in the description)

[0203] A1. Synthesis of / V-(2-oxoindolin-5-yl)-2-(piperidin-1 -yl)acetamide (1a).

[0204] To a solution of 5-aminoindolyn-2-one (500 mg, 3.38 mmol) in THF (8 mL), pipeñdinacetic acid (532 mg, 3.72 mmol), (1-cyano-2-ethoxy-2-oxoethylideneamineoxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU, 1840 mg, 4.3 mmol) and N, / V-diisopropylethylamine (DIPEA, 6 mmol, 2.1 mL). The mixture was kept stirring for 48 h. After adding water (10 mL) and ethyl acetate (10 mL), separating the organic phase, extracting the aqueous phase with ethyl acetate (3 x 10 mL), drying the organic phase over MgSO4, filtration, and evaporation of the solvent, a crude product was obtained which was purified by chromatography on a silica gel column using a CHC acetone 8:2 mixture as eluent.

[0205] Colorless oil (572 mg, 62%). 1H-NMR (300 MHz, DMSO-d6) 5 10.28 (s, 1 H), 9.52 (s, 1 H), 7.56 (d, J= 0.7 Hz, 1 H), 7.35 (dd, J = 8.0, 2.0 Hz, 1 H), 6.73 (d, J= 8.4 Hz, 1 H), 3.45(s,2H), 3.03(s,2H), 2.45(m,4H), 1.56(m,4H), 1.41(m,2H) ppm. 13 C-NMR (DMSO- d6, 75 MHz): 5 176.73, 168.5, 139.9, 133.2, 126.6, 119.2, 117.3, 109.3, 63.1, 54.6 (2C), 36.5, 26.0 (2C), 23.9 ppm. MS: m / z [M+H] (C15H20N3O2) = 274. Their data coincide with those previously described in the bibliography. Yang, Y.; Zhou, Y.; Tao, L.; Yang, T.; Zhao, Y.; Luo, Y. Structure-activity relationship study of DEL-22379: ERK dimerization inhibitors with increased safety. Molecular Diversity 2021, 25, 1051–1075.

[0206] A2 Synthesis of / V-(2-oxoindolin-5-yl)-3-(piperidin-1 -yl)propanamide (1 b).

[0207] Method I , 1999 .

[0208] To a solution of 5-aminoindolin-2-one (500 mg, 3.38 mmol) in THF (8 mL) were successively added 3-(piperidin-1-yl)propanoic acid (584 mg, 3.72 mmol), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COM11, 1840 mg, 4.3 mmol) and N, / V-diisopropylethylamine (DIPEA, 6 mmol, 2.1 mL). The mixture was kept under stirring for 48 h. After adding water (10 mL) and ethyl acetate (10 mL), separating the organic phase, extracting the aqueous phase with ethyl acetate (3 x 10 mL), drying the organic phase over MgSCU, filtration, and evaporation of the solvent, a crude product was obtained which was purified by column chromatography on silica gel using a CHC acetone 8:2 mixture as eluent.

[0209] Method II

[0210] To a solution of / V-(2-oxoindol-5-yl)acrylamide (404 mg, 2.0 mmol) in isopropanol (15 mL) was added piperidine (4.5 mmol, 0.44 mL). The mixture was refluxed for 18 h. After evaporation of the solvent in vacuo, the resulting oil was purified by column chromatography on silica gel using a DCM:MeOH 8:2 mixture as eluent. Brown solid (488 mg, 85%). 1 H-NMR (DMSO-d6, 300 MHz): 5 10.28 (s, 1 H), 10.07 (s, 1 H), 7.50 (s, 1 H), 7.32 (dd, J = 8.3, 1.7 Hz, 1 H), 6.73 (d, J = 8.3 Hz, 1 H), 3.45 (s, 2H), 2.72 (m, 2H), 2.52 (m, 6H), 1.61 - 1.51 (m, 4H), 1.44 - 1.37 (m, 2H) ppm. 13 C-NMR (DMSO-d6, 75 MHz): 5 176.2, 169.3, 139.1 , 133.3, 126.0, 118.3, 116.3, 108.8, 54.0, 53.3 (2C), 36.0, 33.2, 24.9 (2C), 23.4 ppm. MS: m / z [M+H] (C16H22N3O2) = 288. Its data are consistent with those previously described in the literature.

[0211] Yao, D.; Ruhan, A.; Jiang, J.; Huang, J.; Wang, J.; Han, W. Design, synthesis and biological evaluation of 2-indolinone derivatives as PAK1 inhibitors in MDA-MB-231 cells. Bioorg. Med. Chem. Lett. 2020, 30, 127355.

[0212] B. Synthesis of derivatives of dialquilamino-A / -(2-oxoindolin-5-yl)-3-alkanamida (formula II)

[0213] Example of general method I to obtain a formula II composition

[0214] In a microwave tube, the corresponding dialkylamino-A / -(2-oxoindolin-5-yl)alkanamide (1 , between 1 and 2 mmol) is dissolved in a polar solvent such as an alcohol of between 1 and 4 carbon atoms (5 - 25 mL), and the corresponding aldehyde (2, between 1 and 3 mmol) and an organic base such as a secondary amine of between 2 and 6 carbon atoms (between 0.25 and 1.5 mmol) are added successively. The tube is sealed, and the mixture is stirred at temperatures between 80 ° C and 150 ° C under microwave irradiation for 5 to 60 min. After this time, the solvent is evaporated in vacuo and the resulting oil is purified by column chromatography. In a microwave tube, the corresponding dialkylamino-A / -(2-oxoindolin-5-yl)alkanamide (1 , 1.5 mmol) was dissolved in absolute EtOH (10 mL), and the corresponding aldehyde (2, 1.60 mmol) and piperidine (44 pL, 0.45 mmol) were added successively. The tube was sealed, and the mixture was stirred at 140 °C under microwave irradiation for 15 min. After this time, the solvent was evaporated in vacuo and the resulting oil was purified by column chromatography using a DCM:MeOH 8:2 mixture as eluent.

[0215] 1 (1.0 equiv) (1.1 equiv)

[0216] General Method II

[0217] To a solution of the corresponding dialkylamino-A / -(2-oxoindolin-5-yl)alkanamide (1 , between 1 and 2 mmol) in a polar solvent such as an alcohol of between 1 and 4 carbon atoms (5 - 25 mL), the corresponding aldehyde (2, between 1 and 3 mmol) and an organic base such as a secondary amine of between 2 and 6 carbon atoms (between 0.25 and 1.5 mmol) are successively added, the reaction being maintained with stirring at temperatures between 20 ° C and 150 ° C for 24 h. After this time, the solvent was evaporated under vacuum and the resulting oil was purified by column chromatography.

[0218] To a solution of the corresponding dialkylamino-A / -(2-oxoindolin-5-yl)alkanamide (1 , 1.5 mmol) in 96% EtOH (20 mL), the corresponding aldehyde (2, 1.60 mmol) and piperidine (83 pL, 0.84 mmol) were successively added, and the reaction was kept stirring at 50 °C for 24 h. After this time, the solvent was evaporated in vacuo and the resulting oil was purified by column chromatography using a DCM:MeOH 8:2 mixture as eluent. (1.1 equiv)

[0219] (E)-A / -(3-(benzo[o0oxazol-2-yl-methylene)-2-oxoindolin-5-yl)-3-(piperidin-1-yl)propanamide (3a) (CMPO)

[0220] Obtained following the general procedure from 1 by benzo[d]oxazole-2-carbaldehyde (2a).

[0221] Red solid (487 mg, 78%). 1H-NMR (MeOH-d4, 300 MHz): 5 9.54 (d, J = 2.0 Hz, 1 Hz), 7.82-7.92 (m, 2H), 7.45-7.58 (m, 3H), 7.44 (s, 1 H), 6.56 (d, J = 8.4 Hz, 3 Hz, 3.5 Hz). J = 6.8 Hz, 2H), 3.27-3.36 (m, 4H), 2.98 (t, J = 6.8 Hz, 2H), 1 .58-1 .92 (m, 4H), 1 .65-1 .81 (m, 2H) ppm. 13 C-NMR (MeOH-d4, 75 MHz): 5 170.8, 170.5, 161.9, 152.2, 143.4, 142.1 , 135.5, 134.6, 128.4, 126.6, 125.3, 12.7, 121.7. 121.5, 118.0, 112.4, 111.2, 54.7 (20), 54.4, 31.4, 24.4 (20), 22.7 ppm. MS: m / z [M+H] (C 24 H 25 N4O3) = 417.

[0222] (E)-A / -(3-(benzo[b]furan-2-yl-methylene)-2-oxoindolin-5-yl)-3-(piperidin-1- yl)propanamide (3b)

[0223] Obtained following the general procedure from 1 by benzo[£>]furan-2- carbaldehyde (2b).

[0224] Brown solid (510 mg, 82%). 1H-NMR (MeOH-d4, 300 MHz): 5 9.34 (s, 1 H), 7.94 (d, J = 8.2 Hz, 1 H), 7.65 (d, J = 7.7 Hz, 1 H), 7.45 (t, J = 7.7 Hz, 1 H), 7.45 (t, J = 7.7 Hz, 1 H), 7.41 (s, 1 H). = 7.4 Hz, 1 H), 7.30 (s, 1 H), 7.14 (d, J = 7.6 Hz, 1 H), 6.75 (d, J = 8.1 Hz, 1 H), 3.52 (t, J = 5.8 Hz, 2H), 3.23-3.41 (m, J = 5.8 Hz, 2H), 3.23-3.41 (m, J = 8.97). Hz, 2H), 1.84-1.97 (m, 4H), 1.64-1.78 (m, 2H) ppm. 13 C-NMR (MeOH-d4, 75 MHz): 5 169.6, 169.6, 157.9, 153.8, 140.3, 134.6, 129.6, 121.9, 119.4, 117.2, 113.8, 110.8, 54.7 (20), 54.6, 31.6, 24.5 (20), 22.8 ppm. MS: m / z [M+H] (C25H26N3O3) = 416.

[0225] (E)-A / -(3-(benzo[b]thiophen-2-yl-methylene)-2-oxoindolin-5-yl)-3-(piperidin-1- yljpropanamide (3c) (CMP2)

[0226] Obtained following the general method from 1 by benzo[£>]thiophene-2-carbaldehyde (2c).

[0227] Orange solid (556 mg, 86%). 1H-NMR (MeOH-d4, 300 MHz): 5 8.73 (, J = 1.7 Hz, 1 H), 7.91 (m, 3H), 7.89 (s), 7.39–7.50 (m, 3H), 6.90 (d, J = 8.3 Hz, 1 H,), 3.45 (t, J = 6.8 Hz, 2H), 3.27–3.36 (m, 4H), 2.92 (t, J = 6.8 Hz, 2H), 1.81–1.95 (m, 4H), 1.61–1.78 (m, 2H) ppm. 13 C-NMR (MeOH-d4, 75 MHz): 5 171.9, 169.9, 146.4, 143.2, 140.7, 140.5, 138.5, 133.0, 125.9, 123.4, 122.6, 117.6, 111.3, 54.6 (20), 54.3, 31.3, 24.4 (20), 22.7 ppm. MS: m / z [M+H](C25H26N3O2S)=432.

[0228] (Z)-A / -(3-((1H-benzo[c / ]imidazol-2-yl)methylene)-2-oxoindolin-5-yl)-3-(piperidin-1- yljpropanamide (3d)

[0229] Obtained following the general procedure from 1 by 1 / 7-benzo[d]¡m¡dazole-2- carbaldehyde (2d).

[0230] Orange solid (556 mg, 68%). 1H-NMR (MeOH-d4, 300 MHz): 5 7.94 (d, J = 1.9 Hz, 1 H), 7.65-7.73 (m, 2H), 7.58 (s, 1 H), 7.44 (dd, J = 8.5, 1.9 Hz, 1 H), 7.33 (7.3 H), 7.3 (Hz). 6.88 (d, J = 8.4 Hz, 1 H), 3.30 (t, J = 7.2 Hz, 2H), 3.04-3.20 (m, 4H, H-29), 2.84 (t, J = 7.2 Hz, 2H), 1.78-1.90 (m, 4.2 Hz, 2H), 2H) ppm. 13 C-NMR (MeOH-d4, 75 MHz): 5 170.5, 170.3, 149.3, 139.2, 139.1 , 134.8, 134.8, 129.7, 125.1 , 124.0, 124.0, 123.6, 123.6 123.6, 114.1 , 114.1 , 111.5, 54.7 (2C), 54.5, 32.0, 24.8 (2C), 23.2 ppm. MS: m / z [M+H] (C 24 H 26 N5O2) = 416.

[0231] (E / Z)-A / -(3-((2-methylbenzo[o[]oxazol-5-yl)methylene)-2-oxoindolin-5-yl)-3-(piperidin-1- yl)propanamide (3e)

[0232] Obtained following the general method from 1 by 2-methylbenzo[d]oxazole-5- carbaldehyde (2e).

[0233] E / Z isomer mixture, 70:30. Brown solid (477 mg, 74%). Isomer E, majority: 1H-RMN (MeOH-d4, 300 MHz): 5 7.97 (d, J = 2.0 Hz), 7.90 (s, 1 H), 7.82 (s, 1 H), 7.72- 7.76 (m, 2H), 7.42 (dd, J = 8.4, 2.0 Hz, 1 H), 6.88 (d, J = 8.4 Hz, 1 H), 2.87 (t, J = 6.9 Hz, 2H), 2.63-2.73 (m, 4H), 2,70 (s, 3H), 2.59 (t, J = 6.9 Hz, 2H), 1.59-1.69 (m, 4H), 1.47 - 1.57 (m, 2H) ppm. 13 C-RMN (MeOH-d4, 75 MHz): 5 170.7, 170.2, 166.6, 151.0, 142.2, 139.0, 136.8, 132.7, 131.5, 127.8, 126.1 , 122.2, 121.3, 118.9, 115.2, 111.2, 109.9, 53.9, 53.5 (2C), 32.2, 24.7 (2C), 23.1 , 13.0 ppm. Isómero Z, minoritario: 1 H-RMN (MeOH-d4, 300 MHz): 5 9.08 (s, 1 H), 8.00-8.03 (m, 1 H), 7.93-7.95 (d, J = 2.0 Hz 1 H), 7.77 (s, 1 H), 7.63 (d, J = 8.3 Hz, 1 H), 7.28 (dd, J = 8.3, 2.0 Hz, 1 H), 6.83 (d, J = 8.3 Hz, 1 H), 3.15 (t, J = 6.7 Hz, 2H), 2.99 (t, J = 6.7 Hz, 2H), 2.91-3.07 (m, 4H), 2.69 (s, 3H), 1.69-1.80 (m, 4H), 1.59 - 1.67 (m, 2H) ppm. 13C-NMR (MeOH-d4, 75 MHz): 5 170.6, 168.3, 166.5, 142.7, 140.2, 137.3, 137.1 , 132.8, 131.0, 129.8, 122.1 , 11.1, 1.1.8. 117.8, 113.2, 112.2, 109.3, 54.0 (2C), 53.6, 32.3, 23.8 (2C), 22.4, 13.0 ppm. MS: m / z [M+H] (C 25 H 27 H4O3) = 431.

[0234] (E / Z)-A / -(3-((2-methylbenzo[o[]oxazol-6-yl)methylene)-2-oxoindolin-5-yl)-3-(piperidin-1- yl)propanamide (3f) (CMP5)

[0235] Obtained following the general method from 1 by 2-methylbenzo[d]oxazole-6- carbaldehyde (2f).

[0236] E / Z isomer mixture, 75:25. Brown solid (406 mg, 63%). E isomer, majority: 1 H-NMR (MeOH-d4, 300 MHz): 5 8.04 (d, J = 2.1 Hz), 7.96 (s, 1 H), 7.84 (s, 1 H), 7.70- 7.73 (m, 2H), 7.93 (dd, J, 1 Hz, 2.1 Hz). 6.89 (d, J = 8.5 Hz, 1 H), 3.30 (t, J = 7.0 Hz, 2H), 3.06-3.19 (m, 4H), 2.80 (t, J = 7.0 Hz, 2H), 2.70 (s, 3H, HR), 1.72 (m, 2H) ppm. 13C-NMR (MeOH-d4, 75 MHz): 5 170.3, 168.8, 151.6, 141.4, 139.1 , 137.0, 132.6, 131.1 , 127.6, 126.6, 122.0, 121.4, 121.6, 121.9. 115.2, 110.7, 109.9, 53.2 (2C), 53.0, 30.2, 23.3 (2C), 21 .7, 12.9 ppm. Z isomer, minority: 1 H-NMR (MeOH-d4, 300 MHz): 5 8.85 (s, 1 Hz), 8.20 (dd, J = 8.8, 1.7 Hz, 1 H), 7.95 (s, 1 H), 7.75 (s, 1 H), 7.60 (d, J = 8.5 Hz, 1 Hz, 7 = 32 Hz). 8.4, 2.1 Hz, 1 H), 6.82 (d, J = 8.4 Hz, 1 H), 3.40 (t, J = 7.0 Hz, 2H), 3.15-3.26 (m, 4H), 2.92 (t, J = 7.0 Hz, 2H), 2.92 (t, J = 7.0 Hz, 2H), (m, 4H), 1.60 - 1.72 (m, 2H) ppm. 13 C-NMR (MeOH-d4, 75 MHz): 5 168.8, 166.0, 152.1 , 141.6, 140.9, 137.4, 132.2, 132.6, 129.8, 126.2, 125.4, 12.0, 121.0, 121.4. 117.3, 112.0, 109.7, 109.3, 53.3, 53.2 (2C), 30.4, 23.3 (2C), 21.8, 12.9 ppm. MS: m / z [M+H] (C 25 H 27 H4O3) = 431.

[0237] (E)-A / -(2-oxo-3-(quinolin-2-ylmethylene)indolin-5-yl)-3-(piperidin-1-yl)propanamide (3g)

[0238] Obtained following the general method starting from 1 by quinolin-2-carbaldehyde (2g).

[0239] Red solid (556 mg, 87%). 1 H-RMN (MeOH-d4, 300 MHz): 5 9.42 (d, J = 2.2 Hz, 1 H), 8.48 (d, J = 8.4 Hz, 1 H), 8.42 (d, J = 8.5 Hz, 1 H), 7.98 (H 7, J. = 81), 7.98. 7.0, 1.5 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.82 (s), 7.68 (dt, J = 7.0, 1.2 Hz, 1 H), 7.32 (dd, J = 8.3, 2.2 ( H3 ,6 Hz. 1 = 1 H), 3.47 (t, J = 6.6 Hz, 2H), 3.28-3.34 (m, 4H), 2.92 (t, J = 6.6 Hz, 2H), 1.78-1.92 (m, 4H), 1 .60-1 ,786(ppm, 2H). 13 C-NMR (MeOH-d4, 75 MHz): 5 172.1 , 169.8, 155.0, 149.5, 141.7, 138.3, 136.0, 133.7, 132.2, 131.29 , 120.9. 125.8, 125.0, 123.4, 122.3, 117.6, 110.9, 54.6 (2C), 54.4, 31.2, 24.4 (2C), 22.7 ppm. MS: m / z [M+H] (C26H27N4O2) = 427.

[0240] (E)- / V-(3-(benzo[b]furan-2-yl)methylene)-2-oxondolin-5-yl)-3-(piperidin-1-yl)acetamide

[0241] (3h)

[0242] Obtained following the general method from 1a and benzo[£>]furan-2-carbaldehyde (2b).

[0243] Red solid (505 mg, 84%). 1 H-NMR (dmso-d6, 300 MHz): 5 10.5 (s, 1 H), 9.70 (s, 1 H), 9.42 (s, 1 H), 8.01 (d, H = 8.4 Hz, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 7.66 (s, 1 H), 7.54 (t, J = 7.8 Hz, 1 H), 7.49 (s, 1 H), 7.38 - 7.28 (m, 2H), 6.83 (d, J = 8.3 Hz, 1 H), 3.14 (s, 2H), 2.53 (m, 4H), 1.63 - 1.57 (m, 4H), 1.44 - 1.43 (m, 2H) ppm. 13C-NMR (dmso-d6, 75 MHz): 169.5, 168.7, 156.2, 152.8, 139.6, 133.4, 128.4, 127.6, 126.1, 124.4, 122.7, 122.0, 121.4, 120.1, 118.0, 116.4, 112.5, 110.1, 63.1, 54.6 (2C), 26.0 (2C), 24.0 ppm. MS: m / z [M+H] (C24H24N3O3) = 402.

[0244] C. In vitro healing activity on cultured human keratinocytes.

[0245] The experimental protocol was carried out according to the scientific article:

[0246] Pastar I, Stojadinovic O, Yin NC, Ramirez H, Nusbaum AG, Sawaya A, Patel SB, Khalid L, Isseroff RR, Tomic-Canic M. Epithelialization in wound healing: a comprehensive review. Adv Wound Care (NewRochelle) 2014;3(7):445-64. DOI: 10.1089 / wound.2013.0473

[0247] If HaCat cells appeared in plates of 24 pocilios at a density of 100,000 cells in DMEM with 1 g / l of glucose (Gibco, Fisher Scientific) supplemented with 10% fetal bovine serum (FBS), penicilin and streptomycin (at least 100 g per 1), and cultured at 37°C, 5% CO2 until confluent to form a monolayer adherent to the well wall. The medium was then removed and a scratch (wound) was made in the cultured keratinocyte monolayer using a sterile 100 pL pipette tip, thus creating a space (scratch) in the cell layer. Cells were then washed twice with PBS and 100 pL of DMEM in 1 g / L glucose, supplemented with penicillin and streptomycin (100 pg mL -1 ) without FBS. Cells were treated with compounds of formula I at a final concentration of 10 pg mi' 1. Images of the scratch were obtained by microscopy immediately after wound creation (time zero), and at regular intervals thereafter, using an Eclipse TE2000-S inverted microscope (Nikon) coupled to a Nikon F-601 camera, at 40x magnification. The extent of wound closure was quantified by manually measuring the distance between scratch edges. The percentage of wound closure was calculated by comparing the initial scratch width with the width at each time point. Migration was determined by measuring the total wound height at 0, 24, 48, and 72 hours, using Imaged software (NIH). Measurements at day 0 were considered as 0% wound healing Table 1.

[0248] Table 1: Wound closure test

[0249] As can be seen, the compounds (E)-A / -(3-(benzo[b]thiophen-2-yl-methylene)-2- oxoindolin-5-yl)-3-(piperidin-1-yl)propanamide (CMP2) and (EZZ)- / V-(3-((2-methylbenzo[c]oxazol-6-yl)methylene)-2-oxoindolin-5-yl)-3-(piperidin-1-yl)propanamide (CMP5) of the present invention have a wound closure activity superior to pirfenidone (PIR), a commercial compound used as a positive control.

[0250] Additionally, the control of fibroblast activation by the compounds of the invention reduces the excessive amount of collagen, thereby helping to improve the aesthetic appearance of scars.

[0251] Analogously to the results with the compounds (E)- / V-(3-(benzo[b]thiophen-2-yl-methylene)-2-oxoindolin-5-yl)-3-(piperidin-1-yl)propanamide (3c) (CMP2) and (EZZ)- / V-(3-((2-methylbenzo[c]oxazol-6-yl)methylene)-2-oxoindolin-5-yl)-3-(piperidin-1-yl)propanamide (CMP5), a wound closure test was performed with (E)-A / -(3-(benzo[d]oxazol-2-yl-methylene)-2-oxoindolin-5-yl)-3-(piperidin-1-yl)propanamide (CMP0), Fig. 2 shows the photographs of the experiment. On day zero, the wound surface area in all wells was 100% as a control, with no product added. The wound size on subsequent days (x) was calculated according to the equation:

[0252] % wound, day x = (day x / day 0 * 100)

[0253] The results show a wound percentage of 51% after 1 day, and 13% after 3 days when applying (E)- / V-(3-(benzo[d]oxazol-2-yl-methylene)-2-oxoindolin-5-yl)-3-(piperidin-yl)propanamide (CMPO). A reduction of almost 90% of the initial size at 72 hr. As can be seen (E)- / V-(3-(benzo[d]oxazol-2-¡l-methylen)-2-oxo¡ndolin- 5-yl)-3-(piperidin-1-yl)propanamide (CMPO) presents better characteristics than (E)-N- (3-(benzo[b]thiophen-2-yl-methylene)-2-oxoindolin-5-yl)-3-(piperidin-1-yl)propanamide (3c) (CMP2) and (EZZ)- / V-(3-((2-methylbenzo[c]oxazol-6-yl)methylene)-2-oxoindolin-5-yl)-3-(piperidin- 1-¡l)propanamide (CMP5).

[0254] D. Determination of the inhibitory activity of a-SMA: Fibrotic phenotype reversibility assay

[0255] Alpha-smooth muscle actin (α-SMA) is a protein expressed in cells called myofibroblasts, which play a key role in wound healing and tissue repair.

[0256] Myofibroblasts express α-SMA, which allows them to generate contractile force, similar to smooth muscle cells. This ability is essential for reducing the size of wounds by approximating the edges. Myofibroblasts produce large amounts of collagen and other extracellular matrix components that help repair damaged tissue. Under normal conditions, myofibroblasts appear during the final stages of wound healing. Their main function is to contract the wound to reduce the affected area and produce the extracellular matrix that will serve as the basis for tissue regeneration.

[0257] However, when their activity is not properly regulated, they can contribute to pathological wound healing. α-SMA expression is a key marker of myofibroblasts. α-SMA is a critical protein for myofibroblast function during wound healing, but its overactivation is associated with pathological processes such as keloids. To induce the fibrotic phenotype, primary human fibroblasts (PromoCell, C-12302) were seeded at a density of 75,000 cells / p60 and treated for 72 hours with TGF-β (Transforming Growth Factor beta 1) at a concentration of 1 ng / ml. In order to analyze the potential to reverse this phenotype, cells were treated with Pirfenidone (100 uM) and (E)-A / -(3-(benzo[d]oxazol-2-¡l-methylene)-2- oxoindolin-5-yl)-3-(piperidin-1-yl)propan-amide (CMP0) (3a) (3uM) for another 72h.To assess both the induction of the fibrotic phenotype with TGF-β and the ability of the drugs to reverse it, levels of the CISMA protein, a widely used biomarker for this purpose, were analyzed. To do this, total protein was extracted from fibroblasts using RIPA lysis buffer, and 25 μg of each sample was analyzed by Western blotting. Specific immunodetection of the protein was achieved with the primary antibody anti-α-SMA (GTX100034, GeneTex, 1:1500 dilution). The chemoluminescent signal was obtained using a secondary antibody conjugated to horseradish peroxidase (anti-Rabbit-HRP, Sigma-Aldrich, A0545) and a luminol-based substrate (Thermo Scientific, 32106).

[0258] The results in Fig. 3 show a significant reduction of α-SMA in (E)- / V-(3-(benzo[d]oxazol-2-yl-methylene)-2-oxoindolin-5-yl)-3-(pipehdin-1-yl)propan-amide (CMP0) with respect to the TGF-pi condition, with a greater effect than in Pirfenidone, indicating that (E)-A / -(3-(benzo[d]oxazol-2-yl-methylene)-2-oxoindolin-5-yl)-3-(pipehdin-1-yl)propan-amide (CMP0) (3a) has the ability to reverse the fibrotic phenotype and that this ability is superior to that of Pirfenidone.

Claims

MODIFIED CLAIMS received by the International Bureau on June 18, 2025 (18.06.2025) 1. Cosmetic use of a compound of formula (I): in which: Ri and R2 can be the same or different, and can mean H, an alkyl group of 1 to 5 carbon atoms, or R1 and R2 are joined together to form a 4 to 8 membered ring, n means 0, 1, 2, 3 or 4 Rs is selected from: - indolyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; indolyl substituted by an alkyl group of 1 to 5 carbon atoms at the N atom, which may also be substituted on one carbon by one of the groups mentioned above; - indazolyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - a 3-azaindolyl, 4-azaindolyl, 5-azaindolyl, 6-azaindolyl or 7-azaindolyl residue, unsubstituted or substituted by an alkyl group having 1 to 5 carbon atoms, hydroxyl or alkoxy group having 1 to 5 carbon atoms, - a 3-azaindolyl, 4-azaindolyl, 5-azaindolyl, 6-azaindolyl or 7-azaindolyl residue substituted by an alkyl group having 1 to 5 carbon atoms at the N atom, which may also be substituted on one carbon by one of the groups mentioned in the preceding paragraph, - benzofuranyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - benzothiazolyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - benzothiophenyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - benzimidazolyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - benzoxazolyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - isobenzoxazolyl unsubstituted or substituted by an alkyl of 1 to 5 carbon atoms, hydroxyl or an alkoxy group of 1 to 5 carbon atoms; - unsubstituted quinolinyl or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - isoquinol inyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - imidazo[1,2-a]pyridinyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms. - indolizinyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - isothionaphthenyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - isobenzofuranyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms: - isoindolyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxyl group of 1 to 5 carbon atoms and - isoindolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph.

2. Cosmetic use according to claim 1, wherein, in formula (I), Ri and R2 are joined together to form a piperidinyl moiety.

3. Cosmetic use according to claim 1, wherein, in formula (I), n= 1 or 2.

4. Cosmetic use according to claim 1, wherein, in formula (I), Ri and R2 are joined together to form a piperidinyl moiety and n=1 or 2.

5. Cosmetic use according to claim 1, wherein, in formula (I), R3 is 2-benzoxazolyl.

6. Cosmetic use according to claim 1, wherein, in formula (I), R1 and R2 are joined together to form a piperidinyl residue and n=2, and Rs is selected from: - indolyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; indolyl substituted by an alkyl group of 1 to 5 carbon atoms at the N atom, which may also be substituted on one carbon by one of the groups mentioned above; - indazolyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - a 3-azaindolyl, 4-azaindolyl, 5-azaindolyl, 6-azaindolyl or 7-azaindolyl residue, unsubstituted or substituted by an alkyl group having 1 to 5 carbon atoms, hydroxyl or alkoxy group having 1 to 5 carbon atoms, - a 3-azaindolyl, 4-azaindolyl, 5-azaindolyl, 6-azaindolyl or 7-azaindolyl residue substituted by an alkyl group having 1 to 5 carbon atoms at the N atom, which may also be substituted on one carbon by one of the groups mentioned in the preceding paragraph; - benzofuranyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - benzothiazolyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - benzothiophenyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - benzimidazolyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - benzoxazolyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - isobenzoxazolyl unsubstituted or substituted by an alkyl of 1 to 5 carbon atoms, hydroxyl or an alkoxy group of 1 to 5 carbon atoms; - unsubstituted quinolinyl or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - isoquinol inyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - imidazo[1,2-a]pyridinyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - indolizinyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; isothionaphthenyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - isobenzofuranyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxyl group of 1 to 5 carbon atoms and - isoindolyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxyl group of 1 to 5 carbon atoms and - isoindolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph.

7. Cosmetic use according to claim 1, wherein, in formula (I), Ri and R2 are linked forming a piperidinyl moiety, n=2, R3 is selected from 5-methoxy¡-2-indolyl; 5-hydroxy-2-indolyl; 2-benzothiazolyl, 5-methoxy-1-methyl-2-idol; 2- benzofuranyl; 2-benzothiophenyl; 2-benzimidazolyl; 2-methyl-5-benzoxazolyl; 2-methyl-6-benzoxazolyl and 2-quinolinyl.

8. Cosmetic use according to claim 1, wherein, in formula (I), R1 and R2 are joined together to form a piperidine ring, n means 2 and R3 is 2-benzoxazolyl:

9. Cosmetic use according to any one of the preceding claims on the skin, 10. Cosmetic use according to any one of the preceding claims on healed skin wounds.

11. A compound of formula (II): in which Ri and R2 may be the same or different, and may mean H, an alkyl group of 1 to 5 carbon atoms, or R1 and R2 are joined together to form a 4 to 8 membered ring, n means 0, 1, 2, 3 or 4, Rs is selected from: - one of 2-indolyl, 5-indolyl or 6-indolyl unsubstituted, or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - one of 4-indolyl or 7-indolyl, substituted by a group selected from alkyl of 1 to 5 carbon atoms, hydroxyl and alkoxy of 1 to 5 carbon atoms; - 3-indolyl substituted on one of carbons 2, 4, 6 or 7 by a group selected from an alkyl group of 1 to 5 carbon atoms, hydroxyl and alkoxyl group of 1 to 5 carbon atoms; - 3-indolyl substituted at carbon 5 by a group selected from an alkyl group of 1 to 5 carbon atoms, hydroxyl and alkoxyl of 2 to 5 carbon atoms; - indolyl substituted with an alkyl group of 1 to 5 carbon atoms at the N atom, which may also be substituted on one carbon by one of the groups mentioned above; except for unsubstituted 3-indolyl, where n=2 and R1 and R2 form a piperidinyl moiety; - one of 3-indazolyl, 4-indazolyl, 5-indazolyl or 7-indazolyl, unsubstituted or substituted by a group selected from an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; except unsubstituted 5-indazolyl, in the case of that n=2 and Ri and R2 form a piperidinyl moiety;- 6-indazolyl substituted by a group selected from an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - a 3-azaindolyl, 4-azaindolyl, 5-azaindolyl, 6-azaindolyl, - 7-aza-2-indolyl, 7-aza-4-indolyl, 7-aza-5-indolyl, 7-aza-6-indolyl radical, unsubstituted, - a 3-azaindolyl, 4-azaindolyl, 5-azaindolyl, 6-azaindolyl or 7-azaindolyl radical substituted by a group selected from an alkyl group having 1 to 5 carbon atoms, hydroxyl and alkoxy group having 1 to 5 carbon atoms, - a 3-azaindolyl, 4-azaindolyl, 5-azaindolyl, 6-azaindolyl or 7-azaindolyl residue substituted by an alkyl group having 1 to 5 carbon atoms at the N atom, which may also be substituted on one carbon by one of the groups mentioned in the preceding paragraph, except for unsubstituted 7-aza-3-indolyl, in the case where n=2 and R1 and R2 form a piperidinyl residue; - one of 2-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl or 6-benzofuranyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - 3-benzofuranyl substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - benzothiazolyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - benzothiophenyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - benzimidazolyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - benzoxazolyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - isobenzoxazolyl unsubstituted or substituted by an alkyl of 1 to 5 carbon atoms, hydroxyl or an alkoxy group of 1 to 5 carbon atoms; - one of 1-quinolinyl, 2-quinolinyl, 3-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl or 8-quinolinyl unsubstituted or substituted by a group selected from an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; 4-quinolinyl substituted by a group selected from an alkyl group of 1 to 5 carbon atoms, hydroxyl, an alkoxy group of 1 to 5 carbon atoms in position 2, 3, 5, 7 or 8, or alkoxy of 2 to 5 carbon atoms in position 2, 3, 5, 6, 7 or 8; - isoquinol inyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - one of 5-imidazo[1,2-a]pyridinyl, 6-imidazo[1,2-a]pyridinyl, 7-imidazo[1,2-a]pyridinyl, or 8-imidazo[1,2-a]pyridinyl, unsubstituted, or substituted by an alkyl group having 1 to 5 carbon atoms, hydroxyl or alkoxy group having 1 to 5 carbon atoms, - 3-imidazo[1,2-a]pyridinyl substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxyl group of 1 to 5 carbon atoms, - indolizinyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; isothionaphthenyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - isobenzofuranyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - isoindolyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxyl group of 1 to 5 carbon atoms and - isoindolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph; - 2-quinoxalinyl, 4-quinoxalinyl or 8-quinoxalinyl unsubstituted or substituted by alkyl of 1 to 5 carbon atoms, hydroxyl or alkoxy of 1 to 5 carbon atoms, and - 6-quinoxalinyl substituted by alkyl of 1 to 5 carbon atoms, hydroxyl or alkoxy of 1 to 5 carbon atoms.

12. A compound according to claim 11, wherein Rs is selected from: - 2-indolyl unsubstituted, or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxyl group of 1 to 5 carbon atoms, - 2-indolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph, - 4-indolyl substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxyl group of 1 to 5 carbon atoms, - 4-indolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph; - 5-indolyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms, - 5-indolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph; - 6-indolyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - 6-indolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph; - 7-indolyl substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxyl group of 1 to 5 carbon atoms, - 7-indolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph; - 3-indolyl substituted by an alkyl of 1 to 5 carbon atoms in position 2, 4, 5, 6 or 7, or substituted by an alkoxyl group of 1 to 5 carbon atoms in position 4, 6 or 7, - 3-indolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph; - a 3-indazolyl, 4-indazolyl, 6-indazolyl or 7-indazolyl residue, unsubstituted or substituted by an alkyl group having 1 to 5 carbon atoms, hydroxyl or alkoxy group having 1 to 5 carbon atoms, - a 3-indazolyl, 4-indazolyl, 6-indazolyl or 7-indazolyl residue, substituted by an alkyl group of 1 to 5 carbon atoms on the N atom, and which may also be substituted on one carbon by one of the groups mentioned in the preceding paragraph; - 5-indazolyl substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms, - 5-indazolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph; - a 3-azaindolyl, 4-azaindolyl, 5-azaindolyl or 6-azaindolyl residue, unsubstituted or substituted by an alkyl group having 1 to 5 carbon atoms, hydroxyl or alkoxy group having 1 to 5 carbon atoms, - a 3-azaindolyl, 4-azaindolyl, 5-azaindolyl or 6-azaindolyl residue substituted by an alkyl group of 1 to 5 carbon atoms at the N atom, which may also be substituted on one carbon by one of the groups mentioned in the preceding paragraph; - 7-aza-2-indolyl, 7-aza-4-indolyl, 7-aza-5-indolyl, 7-aza-6-indolyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms, - 7-aza-2-indolyl, 7-aza-4-indolyl, 7-aza-5-indolyl, 7-aza-6-indolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph, - 7-aza-3-indolyl substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxyl group of 1 to 5 carbon atoms, - 7-aza-3-indolyl substituted with an alkyl group of 1 to 5 carbon atoms on the N atom, which may also be substituted on one carbon by one of the groups mentioned in the previous paragraph; - one of 2-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl or 6-benzofuranyl, unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - 3-benzofuranyl substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - benzothiazolyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - unsubstituted benzimidazolyl or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms, - benzoxazolyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - 2-quinolinyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - 3-quinolinyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - 4-quinolinyl substituted by alkyl of 1 to 5 carbon atoms or hydroxyl in position 2, 3, 5, 6, 7 or 8, or by an alkoxyl group of 1 to 5 carbon atoms in position 2, 3, 5, 7 or 8; - 5-quinolinyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - 6-quinolinyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - 7-quinolinyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - 8-quinolinyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - 1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7- isoquinolinyl, 8-isoquinolinyl unsubstituted or substituted by an alkyl group of 1 to 5 carbon atoms, hydroxyl or alkoxy group of 1 to 5 carbon atoms; - 2-quinoxalinyl, 4-quinoxalinyl or 8-quinoxalinyl unsubstituted or substituted by alkyl of 1 to 5 carbon atoms, hydroxyl or alkoxy of 1 to 5 carbon atoms, and - 6-quinoxalinyl substituted by alkyl of 1 to 5 carbon atoms, hydroxyl or alkoxy of 1 to 5 carbon atoms.

13. A compound according to claim 11 or 12, wherein Ri and R2 are linked to form a piperidine moiety.

14. A compound according to claim 11, wherein n=2.

15. A compound according to claim 11 or 12, wherein R1 and R2 are joined to form a piperidine moiety and n=1 or 2.

16. A compound according to claim 11 or 12, wherein R3 is 2-benzoxazole.

17. A compound according to claim 11, wherein R1 and R2 are joined to form a piperidine moiety, n= 1 or 2, R3 is selected from 2-benzofuran; 2- benzothiophene; 2-benzothiazole, 5-methoxy-1-methyl-2-indole, 2-benzoxazole, 2-methyl-5-benzoxazole, 2-methyl-6-benzoxazole and 2-quinoline.

18. A compound according to claim 11, wherein Ri and R2 are linked to form piperidine, n means 2 and R3 is 2-benzoxazole.

19. A compound of formula (I) and / or compound of formula (II) for therapeutic use in the treatment of skin healing of a subject's skin. 60 Declaration pursuant to Article 19(1) PCT Ref.: PCT / ES2024 / 070745 deposited on November 27, 2024 Priority: Application in Spain P202330984 of November 27, 2023 Title: "2-INDOLINONE DERIVATIVES AND THEIR USES" Applicant: Complutense University of Madrid and University of Valencia N / Ref.: 2024_129 WO Madrid, June 18, 2025 With regard to the international application mentioned in the reference, it is declared that the following claims have been modified pursuant to Article 19 of the PCT in light of the International Search Report: - In claim 11, the alternative that the group R3 is a 3-indolyl radical substituted at carbon number 5 with alkoxy groups of 1 carbon atom has been eliminated. Any modifications to the description that are necessary to adapt it to the modified claims will be made in the national phase. Sénida Cueto Industrial Property Agent European Patent Attorney

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