Sulfamide derivatives for alcohol use disorder

Abstract

The present invention relates to sulfamide derivatives of formula I, wherein the meaning of groups R1 and R2 is indicated in the description, for use to prevent and / or treat alcohol use disorder. The invention also relates to the administration of these derivatives in combination with other drugs and / or ligands. (I)

Description

[0001] SULFAMIDE DERIVATIVES FOR ALCOHOL USE DISORDER

[0002] The present invention relates to sulfonamide derivatives for use in the prevention and / or treatment of alcohol use disorder. The invention also relates to the administration of such derivatives in combination with other drugs and / or ligands.

[0003] STATE OF THE ART

[0004] Alcohol use disorder (AUD) is a chronic and recurring condition affecting millions of people worldwide, with devastating consequences for the physical, mental, and social health of those who suffer from it, as well as for their families and communities. AUD represents a single diagnostic entity that encompasses both alcohol abuse and dependence in the current Diagnostic and Statistical Manual of Mental Disorders (DSM-5, American Psychiatric Association). AUD is a leading cause of ill health in the global population, resulting in three million deaths annually and 132.6 million disability-adjusted life years (DALYs), according to the 2018 World Health Organization (WHO) report (Global status report on alcohol and health 2018. https: / / www.who.int / publications / i / item / 9789241565639).These alarming figures contrast sharply with the insufficient care patients, especially women, receive, due both to the social stigma associated with alcohol abuse and the lack of effective treatments. Alcohol consumption is widespread in our society, and the harm caused by its abuse represents an enormous social and familial burden. According to the latest Survey on Alcohol and Other Drugs in Spain (EDADES Survey 2022, National Drug Plan), 77% of the population between 15 and 64 years of age (82.1% of men and 70.8% of women) has consumed alcohol in the last year, with alcohol being one of the drugs whose consumption begins at the youngest age (16.5 years), along with tobacco.In this regard, more than 73% of Spanish secondary school students between 14-18 years old consume alcohol, 32% exhibit risky or binge drinking, and 25-30% of young people between 16 and 18 years old have been drunk in the last month (National Drug Plan, ESTUDES 2023). Furthermore, according to the ESEMeD-Spain epidemiological study on mental disorders (Haro JM, Palacín C, Vilagut G, Martínez M, Bernal M, Luque I, Codony M, Dolz M, Alonso J; ESEMeD-Spain Group. Prevalence of mental disorders and associated factors: results from the ESEMeD-Spain study, Med Clin (Bare). 2006 Apr 1;126(12):445-51), alcoholism or AUD is one of the most prevalent disorders throughout life in our country, at 3.6%, and is more frequent in men (6.47%) than in women (0.96%).It should be noted that a comma is used to separate the whole number from the decimal.

[0005] Despite being a leading cause of morbidity and mortality, effective therapies for alcohol use disorder (AUD) are limited, and very few medications are available to help combat this devastating chronic condition. The medications developed have been based on scientific studies that have identified pharmacological targets capable of interfering with alcohol seeking and consumption. Many signaling systems have been linked to excessive alcohol consumption, including those related to dopamine, serotonin (5-HT), norepinephrine, glutamate, opioid peptides, nociceptin / orphanin FQ (N / OFQ), corticotropin-releasing hormone (CRH), and glucocorticoids (Koob GF. Alcohol Use Disorder Treatment: Problems and Solutions. Annu Rev Pharmacol Toxicol. 2024 Jan 23;64:255-275).Chronic alcohol consumption results in an imbalance of these brain communication systems, and current approved therapies aim to correct this imbalance, although their efficacy has never exceeded 50% of treated patients. This is the case, for example, with the opioid receptor antagonists nalmefene and naltrexone, or the NMDA glutamate receptor antagonist acamprosate. Therefore, currently approved medications only cover a minority of responding patients, leaving a majority of patients with alcohol use disorder (AUD) who require treatment without access. Thus, the therapeutic and pharmacological management of patients with AUD is a clear and currently unmet medical need.

[0006] Among the multiple molecular signaling systems affected by alcohol, other lipid compounds such as acylethanolamides (N-acylethanolamines) (Rodríguez de Fonseca F, Del Arco I, Bermudez-Silva FJ, Bilbao A, Cippitelli A, Navarro M. The endocannabinoid system: physiology and pharmacology. Alcohol Alcohol. 2005 Jan-Feb;40(1):2-14.) have been shown to be involved in different stages of the alcohol addiction cycle, including intoxication, alcohol-seeking behavior, and relapse after a period of abstinence (Bilbao A, Serrano A, Cippitelli A, Pavón FJ, Giuffrida A, Suárez J, García-Marchena N, Baixeras E, Gómez de Heras R, Orio L, Alén F, Ciccocioppo R, Cravatt BF, Parsons LH, Piomelli D, Rodríguez de Fonseca F. Role of the satiety factor oleoylethanolamide in alcoholism. Addict Biol. 2016 Jul;21(4):859-72).Acylethanolamides are a family of fatty acid derivatives that includes arachidonylethanolamide (AEA, also called anandamide), an agonist of cannabinoid receptors (CB), and oleylethanolamide (OEA), an agonist of peroxisome proliferator-activated receptor alpha (PPARα). These lipids are also involved in anxiety and affective disorders associated with alcohol addiction, alcohol-induced neuroinflammation, or alcohol-related liver disease (Serrano A, Pavón FJ, Buczynski MW, Schlosburg J, Natividad LA, Polis IY, Stouffer DG, Zorrilla EP, Roberto M, Cravatt BF, Martin-Fardon R, Rodríguez de Fonseca F, Parsons LH. Deficient endocannabinoid signaling in the central amygdala contributes to alcohol dependence-related anxiety-like behavior and excessive alcohol intake. Neuropsychopharmacology. 2018 Aug;43(9): 1840-1850).Furthermore, previous genetic studies have identified genetic variants of the genes encoding proteins involved in AEA endocannabinoid signaling, which were associated with TIJA. This finding confirms the important role of acylethanolamides in the initiation and maintenance of pathological alcohol consumption (Hoenicka J, Ponce G, Jiménez-Arhero MA, Ampuero I, Rodríguez-Jiménez R, Rubio G, Aragüés M, Ramos JA, Palomo T. Association in alcoholic patients between psychopathic traits and the additive effect of allelic forms of the CNR1 and FAAH endocannabinoid genes, and the 3' region of the DRD2 gene. Neurotox Res. 2007 Jan;11(1):51-60.).

[0007] Based on these discoveries, medicinal chemistry programs have been developed focused on modulating the activity of the cannabinoid receptor type 1 (CB1), the nuclear transcription factors PPARα and PPARγ, and TPRV1. These programs have identified chemical entities as potential candidates for therapeutic use against TIJA, which have been tested in preclinical models, although their efficacy in humans has not yet been studied (Alen F, Decara J, Brunoh G, You ZB, Bühler KM, López-Moreno JA, Cippitelli A, Pavón FJ, Suárez J, Gardner EL, de la Torre R, Ciccocioppo R, Serrano A, Rodríguez de Fonseca F. PPARa / CB1 receptor dual ligands as a novel therapy for alcohol use disorder: Evaluation of a novel oleic acid conjugate in preclinical rat models. Biochem Pharmacol. 2018 Nov; 157:235-243.; Stopponi S, Somaini L, Cippitelli A, Cannella N, Braconi S, Kallupi M, Ruggeh B, Heilig M, Demopulos G, Gaitanahs G, Massi M, Ciccocioppo R.Activation of nuclear PPARγ receptors by the antidiabetic agent pioglitazone suppresses alcohol drinking and relapse to alcohol seeking. Biol Psychiatry. 2011 Apr 1;69(7):642-9.). In particular, some of these products have turned out to be simultaneous ligands for CB1 and PPARα receptors, (W02020 / 030843A2).

[0008] On the other hand, application W02007 / 085469A1 describes sulfonamide derivatives that were described for the treatment of obesity as PPARα agonists.

[0009] Therefore, it would be desirable to have new derivatives that show greater efficacy in TIJA models through positive interaction with the PPARα receptor and the transient receptor potential vanilloid type 1 (TRPV1).

[0010] DESCRIPTION OF THE INVENTION

[0011] The present invention relates to a series of sulfonamide derivatives with combined activity as agonists of the peroxisome proliferator-activated receptor alpha (PPARα) and the transient receptor potential vanilloid type 1 (TRPV1), and which show efficacy for the prevention, relief, improvement and / or treatment of alcohol use disorder (AUD), administered alone or in combination with at least one p-opioid receptor antagonist (MRA) such as nalmefene or naltrexone.

[0012] In one aspect, the present invention relates to a compound of formula I: or a pharmaceutically acceptable salt thereof, where:

[0013] Ri represents C12-C20 alkyl, adamantyl or C12-C20 alkenyl; and

[0014] R2 represents H, C1-C12 alkyl or C1-C12 alkenyl, for use in the prevention and / or treatment of alcohol use disorder and its associated pathologies, preferably where the associated pathologies are selected from alcoholic liver disease, neurological or mental disease, heart disease, and pancreatic disease. In another embodiment, the invention relates to the compound of formula I for the use defined above, wherein the C12-C20 alkenyl group has from 1 to 4 carbon-carbon double bonds in any available position of the chain, preferably from 1 to 3 carbon-carbon double bonds in any available position of the chain, even more preferably 1 or 2 carbon-carbon double bonds in any available position of the chain, and still more preferably 1 carbon-carbon double bond in any available position of the chain.

[0015] In another embodiment, the invention relates to the compound of formula I for the use defined above, wherein the C1-C12 alkenyl group has from 1 to 4 carbon-carbon double bonds in any available position of the chain, preferably from 1 to 3 carbon-carbon double bonds in any available position of the chain, even more preferably 1 or 2 carbon-carbon double bonds in any available position of the chain, and still more preferably 1 carbon-carbon double bond in any available position of the chain.

[0016] In another embodiment, the invention relates to the compound of formula I for the use defined above, where R1 represents stearoyl, oleyl, lauryl, elaidyl, palmityl, adamantil or palmitoleyl, and more preferably where R1 represents oleyl, lauryl, elaidyl, palmityl or adamantil.

[0017] In another embodiment, the invention relates to the compound of formula I for the use defined above, where R1 represents C16-C20 alkyl or C16-C20 alkenyl, preferably where R1 represents C16-C18 alkyl or C16-C20 alkenyl, more preferably where R1 represents stearoyl, oleyl, elaidyl, palmityl or palmitoleyl, and even more preferably where R1 represents stearoyl, oleyl, elaidyl or palmityl.

[0018] In another embodiment, the invention relates to the compound of formula I for the use defined above, wherein R2 represents H or C1-C12 alkyl, preferably where R2 represents H or C1-C5 alkyl, more preferably where R2 represents H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or isopentyl, even more preferably where R2 represents H, propyl, or isopropyl, and still more preferably where R2 represents H or isopropyl. In another embodiment, the invention relates to the compound of formula I for the use defined above, wherein:

[0019] Ri represents C12-C20 alkyl, adamantyl or C12-C20 alkenyl; and

[0020] R2 represents H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl, even more preferably where R2 represents H, propyl or isopropyl, and still more preferably where R2 represents H or propyl.

[0021] In another embodiment, the invention relates to the compound of formula I for the use defined above, where:

[0022] R1 represents stearoyl, oleyl, lauryl, elaidyl, palmityl, adamantyl or palmitoleyl; and

[0023] R2 represents H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl, even more preferably where R2 represents H, propyl or isopropyl, and still more preferably where R2 represents H or propyl.

[0024] In another embodiment, the invention relates to the compound of formula I for the use defined above, where:

[0025] R1 represents oleyl, lauryl, elaidyl, palmityl or adamantyl; and

[0026] R2 represents H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl, even more preferably where R2 represents H, propyl or isopropyl, and still more preferably where R2 represents H or propyl.

[0027] In another embodiment, the invention relates to the compound of formula I for the use defined above, where:

[0028] R1 represents C16-C20 alkyl or C16-C20 alkenyl, preferably where R1 represents C16-C18 alkyl or C16-C18 alkenyl, more preferably where R1 represents stearoyl, oleyl, elaidyl, palmityl or palmitoleyl, and even more preferably where R1 represents stearoyl, oleyl, elaidyl or palmityl; and

[0029] R2 represents H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl, even more preferably where R2 represents H, propyl or isopropyl, and still more preferably where R2 represents H or propyl.

[0030] In another embodiment, the invention relates to the compound of formula I for the use defined above, where:

[0031] R1 represents oleyl or stearoyl; and

[0032] R2 represents H, propyl, or isopropyl. In another embodiment, the invention relates to the compound of formula I for the use defined above, wherein the compound of formula I is selected from N-oleyl sulfamide (NOS), N-pal methyl sulfamide, and N-elaidi l-N'-propyl sulfamide.

[0033] In another embodiment, the invention relates to the compound of formula I for the use defined above, wherein alcoholic liver disease is selected from steatosis, steatohepatitis, hepatitis, cirrhosis, and liver cancer.

[0034] In another embodiment, the invention relates to the compound of formula I for the use defined above, wherein the neurological or mental disease associated with alcohol use disorder is selected from cognitive impairment, dementia, anxiety, depression, opioid addiction, psychosis, demyelination, and fetal alcohol spectrum syndrome.

[0035] In another embodiment, the invention relates to the compound of formula I for the use defined above, wherein the heart disease associated with alcohol use disorder is selected from dilated cardiomyopathy, ischemic coronary disease, and atherosclerosis.

[0036] In another embodiment, the invention relates to the compound of formula I for the use defined above, wherein the pancreatic disease associated with alcohol use disorder is selected from acute pancreatitis, chronic pancreatitis, and pancreatic cancer.

[0037] The present invention also relates to a pharmaceutical composition comprising a compound of the invention (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. The excipients must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not harmful to the person taking the composition.

[0038] Another aspect of the invention relates to a pharmaceutical composition comprising: a compound of formula I as defined above; one or more p-opioid receptor (MOR) ligands, preferably wherein the p-opioid receptor ligands are selected from nalmefene, naltrexone and / or a mixture thereof; and one or more pharmaceutically acceptable excipients thereof.

[0039] Another aspect of the invention relates to a pharmaceutical composition comprising: the compound of formula I as defined above; one or more drugs selected from acamprosate, topiramate and / or a mixture thereof; and one or more pharmaceutically acceptable excipients thereof.

[0040] Another aspect of the invention relates to a pharmaceutical composition comprising: the compound of formula I as defined above; one or more GLP-1 receptor ligands, and preferably wherein the GLP-1 receptor ligands are selected from liraglutide, semaglutide, dulaglutide and / or a mixture thereof; and one or more pharmaceutically acceptable excipients thereof.

[0041] Another aspect of the present invention relates to a pharmaceutical composition comprising: the compound of formula I as defined above; and one or more p-opioid receptor (MOR) ligands, or one or more GLP-1 receptor ligands, or one or more drugs selected from acamprosate and topiramate, for use as a medicament.

[0042] Another aspect of the present invention relates to a pharmaceutical composition comprising:

[0043] - the compound of formula I as defined above; and

[0044] - another active ingredient selected from one or more p-opioid receptor (MOR) ligands, one or more GLP-1 receptor ligands, one or more drugs selected from acamprosate and topiramate, or any of the above combinations.

[0045] Another aspect of the invention relates to a combined preparation, hereinafter referred to as the combined preparation of the invention, comprising: a compound of formula I as defined above; and another active ingredient selected from the list consisting of one or more p-opioid receptor (MOR) ligands, one or more GLP-1 receptor ligands, one or more drugs selected from acamprosate and topiramate, or any of the above combinations.

[0046] Another aspect relates to the composition or combined preparation of the invention for use as a medicament.

[0047] Another aspect of the invention relates to the composition or combined preparation of the invention for use in the prevention and / or treatment of alcohol use disorder and its associated pathologies, preferably where the associated pathologies are selected from alcoholic liver disease, neurological or mental disease, heart disease, and pancreatic disease.

[0048] In another embodiment, the invention relates to the composition or the combined preparation for the use defined above, wherein alcoholic liver disease is selected from steatosis, steatohepatitis, hepatitis, cirrhosis, and liver cancer.

[0049] In another embodiment, the invention relates to the composition or combined preparation for the use defined above, wherein the neurological or mental disease associated with alcohol use disorder is selected from cognitive impairment, dementia, anxiety, depression, opioid addiction, psychosis, demyelination, and fetal alcohol spectrum syndrome.

[0050] In another embodiment, the invention relates to the composition or the combined preparation for the use defined above, wherein the heart disease associated with alcohol use disorder is selected from dilated cardiomyopathy, ischemic coronary disease, and atherosclerosis.

[0051] In another embodiment, the invention relates to the composition or the combined preparation for the use defined above, wherein the pancreatic disease associated with alcohol use disorder is selected from acute pancreatitis, chronic pancreatitis, and pancreatic cancer.

[0052] The present invention also relates to the salts and solvates of compounds of formula I. Compounds of formula I and their salts may differ in certain physical properties, but are equivalent for the purposes of the invention. All salts of compounds of formula I are included within the scope of the invention.

[0053] The compounds of the present invention can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as solvates. As used herein, the term solvate refers to a complex of variable stoichiometry formed by a solute (a compound of formula I or a salt thereof) and a solvent. Examples of solvents include pharmaceutically acceptable solvents such as water, ethanol, and the like. A complex with water is known as a hydrate. The solvates of the compounds of the invention (or their salts), including hydrates, are included within the scope of the invention.

[0054] Some compounds of the present invention may exist as several diastereomers and / or several optical isomers. Diastereomers can be separated using conventional techniques such as chromatography or fractional crystallization. Optical isomers can be resolved using conventional optical resolution techniques to yield optically pure isomers. This resolution can be performed on chiral synthetic intermediates or on products of formula I. Optically pure isomers can also be obtained individually using enantiospecific syntheses. The present invention covers both individual isomers and mixtures thereof (e.g., racemic mixtures or mixtures of diastereomers), whether obtained by synthesis or by physical mixing.

[0055] The terms “C12-C20 alkyl” and “C1-C12 alkyl”, independently, as a group or part of a group, refer to a linear or branched chain alkyl group, containing 12 to 20 or 1 to 12 carbon atoms respectively.

[0056] The terms “C12-C20 alkenyl” and “C2-C12 alkenyl” independently refer to a linear or branched alkyl chain containing 12 to 20 or 2 to 12 carbon atoms respectively, and containing 1 to 4 carbon-carbon double bonds, preferably 1 to 3 carbon-carbon double bonds, more preferably 1 or 2 carbon-carbon double bonds, and still more preferably 1 carbon-carbon double bond, in any available position of the chain.

[0057] Throughout this description, the term “treatment” refers to eliminating, reducing, or lessening the cause or effects of a disease. For the purposes of this invention, treatment includes, but is not limited to, relieving, lessening, or eliminating one or more symptoms of the disease; reducing the severity of the disease; stabilizing (i.e., not worsening) the disease state; delaying or slowing the progression of the disease; alleviating or improving the disease state; and achieving remission (either total or partial).

[0058] As used in the present invention, the term “prevention” refers to preventing the onset of a disease in a patient who is predisposed or has risk factors, but who does not yet exhibit symptoms of the disease. Prevention also includes preventing the recurrence of a disease in a person who has previously suffered from that disease.

[0059] The term “combined preparation” or “juxtaposition,” as used in this document, means that the components of the combined preparation need not be present as a union, for example, in a true composition, to be available for combined, separate, or sequential application. Thus, the term “juxtaposed” implies that it does not necessarily result in a true combination, given the physical separation of the components.

[0060] Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and / or treatment of alcohol use disorder and its associated pathologies.

[0061] Another aspect of the invention relates to a method for preventing and / or treating alcohol use disorder and its associated pathologies in a subject in need, particularly in humans, comprising administering to said subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. Another aspect of the present invention relates to the use of a pharmaceutical composition or combination preparation comprising: a compound of formula I as defined above or a pharmaceutically acceptable salt thereof; and one or more p-opioid receptor (POR) ligands or one or more GLP-1 receptor ligands or one or more drugs selected from acamprosate and topiramate, for the preparation of a medicament, and preferably for the preparation of a medicament for the prevention and / or treatment of alcohol use disorder and its associated pathologies.

[0062] Another aspect of the invention relates to a method for preventing and / or treating alcohol use disorder and its associated pathologies in a subject in need, especially in humans, comprising administering to said subject an effective amount of a pharmaceutical composition or a combined preparation comprising: a compound of formula I as defined above or a pharmaceutically acceptable salt thereof; and one or more p-opioid receptor (MOR) ligands or one or more GLP-1 receptor ligands or one or more drugs selected from acamprosate and topiramate,

[0063] In the present invention, alcohol use disorder is understood as the official definition contained in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5, published by the American Psychiatric Association).

[0064] According to the DSM-5, alcohol use disorder is characterized by a problematic pattern of alcohol use that leads to clinically significant problems or functional impairment, as evidenced by at least two of the following criteria within a 12-month period:

[0065] - Consumption of alcohol in larger quantities or for a longer period than planned.

[0066] - Persistent desire or unsuccessful efforts to control or reduce alcohol consumption. - A large amount of time spent in activities related to obtaining, consuming, or recovering from the effects of alcohol.

[0067] - Persistent desire or recurrent use of alcohol that results in failure to fulfill important obligations at work, school, or home.

[0068] - Persistence in alcohol consumption despite social or interpersonal problems caused or exacerbated by the effects of alcohol.

[0069] - Abandonment or reduction of important social, occupational, or recreational activities due to alcohol consumption.

[0070] - Alcohol consumption in dangerous situations.

[0071] - Consuming alcohol despite being aware of having a persistent or recurring physical or psychological problem that was probably caused or exacerbated by alcohol.

[0072] Alcohol use disorder is classified into degrees of severity (mild, moderate, and severe) depending on the number of the criteria listed above that are met.

[0073] For therapeutic use, the compounds of formula I shall preferably be in a pharmaceutically acceptable or substantially pure form. That is, they shall have a pharmaceutically acceptable level of purity, excluding normal pharmaceutical additives such as diluents and carriers, and not including any material considered toxic, at normal dosage levels. The purity levels for the active ingredient are preferably greater than 50%, more preferably greater than 70%, and more preferably greater than 90%. In a preferred embodiment, they are greater than 95% of the compound of formula I.

[0074] The compounds of formula I for therapeutic use are prepared in solid form or aqueous suspension in a pharmaceutically acceptable diluent. These preparations may be administered by any appropriate route, for which purpose the preparation shall be formulated in the pharmaceutical form suitable for the chosen route of administration. In one particular embodiment, the administration of the compound of formula I provided by this invention is effected orally, topically, rectally, or parenterally (including subcutaneous, intraperitoneal, intradermal, intramuscular, intravenous, etc.). A review of the various pharmaceutical forms for administering medications and the excipients necessary for obtaining them can be found, for example, in the "Treatise on Galenic Pharmacy," C. Faulí i Trillo, 1993, Luzán 5, SA Ediciones, Madrid, and in other common or similar works of the Spanish and United States Pharmacopoeias.

[0075] The compounds of formula I described in the present invention can be used in conjunction with other additional drugs to provide combination therapy. These additional drugs may form part of the same pharmaceutical composition or, alternatively, may be provided as a separate composition for administration concurrently or separately with the pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof.

[0076] Also within the scope of this invention are prodrugs of compounds of formula I. The term “prodrug,” as used herein, includes any compound derived from a compound of formula I, such as esters (including carboxylic acid esters, amino acid esters, phosphate esters, metal salt sulfonate esters, etc.), carbamates, amides, etc., which, when administered to an individual, is capable of providing, directly or indirectly, said compound of formula I to that individual. Advantageously, such a prodrug is a compound that increases the bioavailability of the compound of formula I when administered to an individual or that enhances the release of the compound of formula I into a biological compartment. The nature of the prodrug is not critical, provided that it can be administered to an individual and provides the compound of formula I into a biological compartment of that individual.The preparation of this derivative compound can be carried out using conventional methods known to experts in the field.

[0077] The pharmaceutical composition provided by this invention comprises at least one compound of formula I, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount. In the sense used herein, the term “therapeutically effective amount” refers to the amount of compound calculated to produce the desired effect. The dose of compound of formula I, or a pharmaceutically acceptable salt thereof, to be administered to an individual may vary within a wide range depending on numerous factors, including the characteristics of the compound used. For example, its activity and biological half-life, the concentration of the compound in the pharmaceutical composition, the individual's clinical condition, the severity of the pathology, the chosen dosage form, etc.The pharmaceutical composition provided by this invention can be administered once or more times a day for preventive or therapeutic purposes or, alternatively, other temporal administration guidelines can be followed, not necessarily daily but also on a one-off, weekly, etc. basis.

[0078] Throughout the description and claims, the word "comprises" and its variations are not intended to exclude other technical features, additives, components, or steps. For those skilled in the art, other objects, advantages, and features of the invention will become apparent partly from the description and partly from the practice of the invention. The following examples and figures are provided for illustrative purposes and are not intended to limit the scope of the present invention.

[0079] DESCRIPTION OF THE FIGURES

[0080] Fig. 1. General structure and embodiment examples of sulfonamide derivatives for reducing alcohol consumption. (A) Effects of N-oleyl sulfonamide (NOS) on alcohol self-administration in Wistar rats, the main compound of the present invention. (BC) Effective embodiments on alcohol consumption in the two-bottle test in Wistar rats with different sulfonamide derivatives. (DE) Ineffective embodiments on alcohol consumption in the two-bottle test in Wistar rats with different sulfonamide derivatives. Data are means ± standard error of the mean. (*) P < 0.05 and (**) P < 0.01 compared to the vehicle group.

[0081] Fig. 2. N-oleyl sulfamide (NOS) reduces alcohol self-administration by parenteral and oral routes. (A) Effects of intraperitoneal administration of 0, 3, and 6 mg / kg of NOS on alcohol self-administration in Wistar rats. (B) Effects of oral administration of 3 and 6 mg / kg of NOS on alcohol self-administration in Wistar rats. Data are means ± standard error of the mean. (**) P < 0.01 and (***) P < 0.001 compared with the vehicle group (dose 0); ( # (***) P < 0.05 and (“) P < 0.001 compared with the 3 mg / kg dose group. Fig. 3. N-oleyl sulfamide (NOS) reduces relapse in alcohol consumption induced by alcohol deprivation. Effects of intraperitoneal administration of 6 mg / kg of NOS on alcohol consumption in alcohol-deprived Wistar rats for five days. Data are means ± standard error of the mean. (***) P < 0.001 compared with the vehicle group; ( #) P < 0.05 compared to baseline (BL) of the vehicle group; (*) P < 0.01 compared to baseline (BL) of the NOS group; ( $ ) P < 0.05 compared to alcohol consumption on day 1.

[0082] Fig. 4. N-oleyl sulfamide (NOS) reduces relapse in context-induced alcohol consumption. Effects of intraperitoneal administration of 0, 3, 6, and 10 mg / kg of NOS on alcohol consumption measured in animals with extinction of operant alcohol-seeking behavior. Data are means ± standard error of the mean. (*) P < 0.05 compared to the vehicle group (dose 0); (#*) P < 0.01 compared to baseline extinction value (EXT).

[0083] Fig. 5. N-oleyl sulfamide (NOS) reduces the motivation to consume alcohol in a forward ratio model. Effects of intraperitoneal administration of 6 mg / kg of NOS on the cutoff point of operant alcohol-seeking behavior. Data are means ± standard error of the mean. (***) P < 0.001 compared with the vehicle group (Dose 0).

[0084] Fig. 6. N-oleyl sulfamide (NOS) does not reduce sucrose self-administration. Effects of intraperitoneal administration of 0, 3, and 6 mg / kg of NOS on operant self-administration of a 10% sucrose solution. Data are means ± standard error of the mean.

[0085] Fig. 7. The effects of N-oleyl sulfonamide (NOS) on alcohol consumption are reversed by a TRPV1 receptor antagonist. Administration of 10 mg / kg of capsazepine (CZP) blocks the reduction in alcohol self-administration induced by intraperitoneal administration of 6 mg / kg of NOS. Data are means ± standard error of the mean. (**) P < 0.01 compared with the vehicle group (NOS 0 mg / kg + CZP 0 mg / kg); ( # ) P < 0.05 compared to the CZP 10 mg / kg group; ( $(**) P < 0.05 compared with the NOS 6 mg / kg + CZP 10 mg / kg group. Fig. 8. The effects of N-oleyl sulfamide (NOS) on alcohol consumption are synergistic with those of a p-opioid receptor antagonist. Administration of 0.05 mg / kg of nalmefene (NF) potentiates the reduction in alcohol self-administration induced by intraperitoneal administration of 6 mg / kg of NOS. Data are means ± standard error of the mean. (**) P < 0.01 and (***) P < 0.001 compared with the vehicle group (NOS 0 mg / kg + NF 0 mg / kg); ( # ) P < 0.05 compared to the NOS 6 mg / kg + NF 0.05 mg / kg group.

[0086] EXAMPLES

[0087] The invention will then be illustrated by means of tests carried out by the inventors, which demonstrate the effectiveness of the product of the invention.

[0088] Materials and methods

[0089] Animals

[0090] For the alcohol self-administration studies, 48 ​​adult male Wistar rats (8 per group) (Harían, Barcelona, ​​Spain) weighing 375–425 g at the start of the experiments were housed in individually adapted cages on a 12-hour light / dark cycle (12:00 PM to dark) in a room with constant humidity and temperature (23 ± 1 °C). Standard rodent food and water were available ad libitum. The animals were habituated to the housing and handling conditions for two weeks prior to the alcohol self-administration protocol.

[0091] For the alcohol consumption studies using the two bottle choice paradigm, we used male Wistar rats weighing 250 g at the start of the experiments.

[0092] All experimental procedures in animals were carried out in accordance with European Directive 2010 / 63 / EU on the protection of animals used for scientific purposes and with Spanish regulations (Royal Decree 53 / 2013 and Royal Decree 178 / 2004). All protocols were approved by the Research Ethics Committee of the University of Málaga (CEUMA), minimizing potential pain, suffering, or distress according to the recommendations of the three Rs (replacement, reduction, and refinement). Drugs

[0093] Formula I sulfonamide derivatives were synthesized following the description published by Cano et al. (Cano C, Pavón J, Serrano A, Goya P, Paez JA, de Fonseca FR, Macias-Gonzalez M. Novel sulfamide analogs of oleoylethanolamide showing in vivo satiety-inducing actions and PPARα activation. J Med Chem. 2007 Jan 25;50(2):389-93). Capsazepine and nalmefene were obtained from Tocris-Bioscience (Biogen Científica, Madrid, Spain). A fresh solution was prepared daily before administration by dissolving the drugs in a vehicle solution consisting of 1% Tween-80 in 0.9% saline. All compounds were administered at a volume of 2 mL / kg body weight via intraperitoneal (ip) and orally. Different doses of formula I compounds, as well as capsazepine and nalmefene, were selected between 1 and 10 mg / kg (Cano C, Pavón J, Serrano A, Goya P, Paez JA, de Fonseca FR, Macias-Gonzalez M.Novel sulfamide analogs of oleoylethanolamide showing in vivo satiety inducing actions and PPARalpha activation. J Med Chem. 2007 Jan 25;50(2):389- 93.; and Calleja-Conde J, Echeverry-Alzate V, Giné E, Bühler KM, Nadal R, Maldonado R, Rodríguez de Fonseca F, Gual A, López-Moreno JA. Nalmefene is effective at reducing alcohol seeking, treating alcohol-cocaine interactions and reducing alcohol-induced histone deacetylases gene expression in blood. Br J Pharmacol. 2016 Aug;173(16):2490-505).

[0094] Model of alcohol self-administration.

[0095] Groups of animals were trained for self-administration of alcohol as previously described 7 in self-administered operating boxes with an air extractor and sound attenuation (Letica, model LE 850, Panlab, Barcelona, ​​Spain). These operating boxes consisted of cubicles equipped with two retractable levers on each side and a central water tank.

[0096] The location of the active lever was balanced across training sessions to prevent the development of preferences. Pressing the active lever dispensed 0.1 mL of the solution with a 2.5-second delay, while pressing the inactive lever had no effect. All alcohol operant sessions lasted 30 minutes each day for 5 days a week (Monday to Friday), with the animals weighed daily. The number of lever presses in each session was automatically recorded by the computer program. Training was conducted using a modified version of the traditional saccharin-alcohol substitution procedure. 7During the first three days of training, the animals received 0.2% saccharin solution in the receptacle to facilitate the acquisition of a baseline lever pressure level. Thereafter, the following sequence was used at a ratio of 1 (FR1): 0.16% saccharin and 2% alcohol for three sessions; 0.12% saccharin and 4% alcohol for three sessions; 0.08% saccharin and 6% alcohol for four sessions; 0.04% saccharin and 8% alcohol for four sessions; 0.02% saccharin and 10% alcohol; and finally, only 10% alcohol (v / v) for the remaining sessions.

[0097] First, a Formula I product was tested (Figure 1A). The selected doses of N-oleyl sulfonamide (NOS) ranged from 1 to 10 mg / kg, with 6 mg / kg of NOS being the preferred dose for comparison (Figure 1A). The solutions were injected intraperitoneally (ip), 30 minutes before the alcohol self-administration session. After each treatment, the animals rested for a period of 24 hours and then returned to the daily 30-minute alcohol self-administration sessions.

[0098] Alcohol consumption in the two-bottle choice model.

[0099] Voluntary alcohol consumption was assessed using the two-bottle choice test, as previously described. Animals were trained to drink water or a 10% (v / v) alcohol solution for 24 hours daily until a stable baseline consumption level was reached. At that point, rats were divided into different groups (9–10 animals per group) to be treated with vehicle and compounds of formula I at a dose of 6 mg / kg, i.e.: N-palmityl sulfamide (Figure 1B), N-elaidyl-N'-propyl sulfamide (Figure 1C), N-lauryl sulfamide (Figure 1D), and N-adamantyl-N'-propyl sulfamide (Figure 1E).

[0100] Motivational measurement (Self-management break point)

[0101] To measure compulsive alcohol seeking and the effect of NOS (6 mg / kg, ipi), animals trained to self-administer alcohol using a lever (FR1) were subjected to a progressive ratio (PR) reinforcement schedule. The number of lever presses required to obtain the next alcohol reinforcer increased progressively in the following sequence: 1, 1, 2, 2, 3, 3, 4, 4, 5, 5, 7, 7, 9, 9, 11, 11, 13, 13, etc. The last completed ratio (breakpoint) was used as an indicator of alcohol motivation. During the PR trial, only the alcohol lever was available. Sessions lasted 90 minutes or until 15 minutes of non-response had elapsed. The pretreatment time during the PR trial was the same as for the FR1 trial.

[0102] Model of relapse due to alcohol withdrawal

[0103] Rats were trained to self-administer 10% alcohol (v / v). After three days of sessions with a stable baseline response, the rats were alcohol-deprived for five consecutive days (without operant sessions). At the end of the fifth day of the deprivation phase, the rats were divided into four groups and treated with vehicle or NOS (6 mg / kg, i.p.) 30 minutes before the session.

[0104] Relapse model by context (alcohol self-administration)

[0105] 1. Conditioning Phase: Upon completion of the alcohol self-administration procedure, the animals were trained to discriminate between 10% (v / v) alcohol and water in daily 30-minute sessions. Beginning with self-administration training at the 10% alcohol concentration, discriminative stimuli predicting the availability of the alcohol solution versus water were presented during the alcohol and water self-administration sessions, respectively. The discriminative stimulus for alcohol consisted of the odor of an orange extract (S+), while the availability of water (i.e., no reward) was signaled by an anise extract (S-). The olfactory stimuli were generated by placing 6–8 drops of the respective extract on the bed of the operant chamber. In addition, each lever press that resulted in the delivery of the alcohol solution was associated with the chamber being illuminated for 5 seconds (CS+).However, the signal associated with the water sessions was a 5-second (70 dB) tone (CS-). Concurrent with the presentation of these stimuli, a 5-second waiting period was applied, during which responses were recorded, but no reward was given. Olfactory stimuli serving as S+ or S- for alcohol or water availability were introduced 1 minute before lever extension and remained present throughout all 30-minute sessions. The chamber bedding was cleaned between sessions. Rats received only alcohol sessions during the first three days of the conditioning phase; subsequently, alcohol and water sessions were administered randomly throughout the training days, with the condition that all rats received a total of 10 alcohol sessions and 10 water sessions.Extinction phase: After the last day of conditioning, the rats underwent 30-minute extinction sessions for 15 consecutive days. During this phase, the sessions began with lever extension without the presentation of discriminative stimuli. Lever presses activated the delivery mechanism but did not result in the delivery of liquids or the presentation of the contingent response cues (light or tone).

[0106] 3. Reinstatement / Recovery Trial: Reinstatement trials began the day after the last extinction session. This trial lasted 30 minutes under conditions identical to those of the conditioning phase, except that alcohol and water were unavailable. Sessions began with the extension of both levers and the presentation of the paired stimuli S+ for alcohol or S- for water. The discriminative stimulus remained present throughout the session, and responses on the previously active lever recovered the 5-second delivery and presentation mechanism of CS+ in the S+ condition or CS- in the S- condition. Animals were tested under the S+ / CS+ condition on day 1 and under the S- / CS- condition on day 2. Subsequently, reinstatement experiments were conducted every four days (days 6, 10, and 14), in which NOS was administered at different doses 30 minutes before the sessions.The response on the inactive lever was recorded to collect possible non-specific behavioral effects.

[0107] Data analysis

[0108] GraphPad Prism v5.04 (GraphPad Software, San Diego, CA, USA). Data were expressed as means ± standard error. The analysis of the effects on self-administration and alcohol consumption was performed using repeated measures ANOVA, with time and treatment as factors. A p-value less than 0.05 was considered statistically significant.

[0109] Results

[0110] 1. Actions of sulfonamide-derived compounds in alcohol self-administration (Figure 1)

[0111] Starting with compounds of formula I, N-oleyl sulfamide (Figure 1A), N-palmityl sulfamide (Figure 1B), and N-elaidyl-N'-propyl sulfamide (Figure 1C) reduced alcohol self-administration or consumption. Substitution of R1 with a shorter-chain fatty acid (C12:0, lauric acid) reduced its effectiveness (Figure 1D), as did substitution with a bulky linear group such as adamantyl (Figure 1E). The data indicate that C18–C16 is the optimal chain length for R1 in compounds of formula I for reducing alcohol self-administration.

[0112] 2. Comparison of the intraperitoneal and oral routes in NOS (Figure 2)

[0113] Both NOS administration via i (3, 6 and 10 mg / kg, Figure 2A) and oral administration (3 and 6 mg / kg, Figure 2B) reduced alcohol self-administration, indicating that these sulfonamide derivatives are active via both oral routes.

[0114] 3. NOS reduces relapse by exposure in the alcohol withdrawal test (Figure 3). Administration of 6 mg / kg of NOS via IP significantly reduced the expected increase in alcohol consumption after a 5-day interruption of alcohol self-administration (Figure 3). This effect indicates that NOS reduces relapse associated with re-exposure to alcohol after a period of abstinence.

[0115] 4. NOS reduces relapse by context (Figure 4)

[0116] Treatment with 6 mg / kg of NOS via IP prior to exposure of the animals to the self-administration context significantly reduced context-related relapse, indicating that these sulfonamide-derived compounds could be used to reduce habitual alcohol consumption associated with specific events and places.

[0117] 5. NOS actions against alcohol-seeking motivation (Figure 5)

[0118] To measure alcohol-seeking motivation, a reinforcement test with PR was performed, and the breakpoint was determined. Treatment with 6 mg / kg of NOS via intraperitoneal injection reduced the alcohol self-administration breakpoint, indicating that it exerts a robust effect on motivational circuits, reducing the hedonic value of alcohol.

[0119] 6. NOS actions are selective (Figure 6)

[0120] Administration of 3 and 6 mg / kg of NOS via intraperitoneal injection did not affect the consumption of 10% sucrose, indicating a selectivity of this sulfonamide derivative for alcohol and not for other similar caloric molecules. 7. The actions of NOS can be blocked with a TRPV1 receptor antagonist (Figure 7)

[0121] The TRPV1 receptor antagonist capsazepine was able to prevent the reduction in alcohol self-administration observed in animals treated with 6 mg / kg of NOS. These results implicate the TRPV1 receptor as one of the targets of NOS action.

[0122] 8. The actions of NOS are additive to those of a p-opioid receptor antagonist (Figure 8). Nalmefene, a MOR receptor antagonist used clinically to reduce alcohol consumption, and NOS were able to reduce alcohol self-administration in Wistar rats. Furthermore, the combination of both was even more effective than either drug alone, indicating a synergistic effect in reducing alcohol consumption.

Claims

CLAIMS 1.- A compound of formula I: I or a pharmaceutically acceptable salt thereof, where: Ri represents C12-C20 alkyl, adamantyl or C12-C20 alkenyl; and R2 represents H, C1-C12 alkyl or C1-C12 alkenyl, for use in the prevention and / or treatment of alcohol use disorder and its associated pathologies, where the associated pathologies are selected from alcoholic liver disease, neurological or mental disease, heart disease and pancreatic disease. 2.- The compound of formula I for use according to claim 1, where R1 represents C16-C18 alkyl or C16-C18 alkenyl. 3.- The compound of formula I for use according to any of claims 1-2, where R1 represents stearoyl, oleyl, elaidyl, palmitil or palmitoleyl. 4.- The compound of formula I for use according to any of claims 1-3, where R2 represents H or C1-C12 alkyl. 5.- The compound of formula I for use according to any of claims 1-4, where R2 represents H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl.

6. The compound of formula I for use according to claim 1, wherein the compound of formula I is selected from N-oleyl sulfamide (NOS), N-palmityl sulfamide and N-elaidyl-N'-propyl sulfamide. 7.- A pharmaceutical composition or a combined preparation comprising: a compound of formula I according to any of claims 1 to 6; one or more p-opioid receptor ligands, or one or more GLP-1 receptor ligands, or one or more drugs selected from acamprosate and topiramate, and one or more pharmaceutically acceptable excipients thereof. 8.- The pharmaceutical composition or combined preparation according to claim 7, wherein the p-opioid receptor ligands are selected from nalmefene, naltrexone and / or a mixture thereof.

9. The pharmaceutical composition or combination preparation according to any of claims 7-8, wherein the GLP-1 receptor ligands are selected from liraglutide, semaglutide, dulaglutide and / or a mixture thereof.

10. The pharmaceutical composition or combined preparation according to any of claims 7-9, for use as a medicinal product.

11. The pharmaceutical composition or combined preparation according to any of claims 7-9, for use in the prevention and / or treatment of alcohol use disorder and its associated pathologies, wherein the associated pathologies are selected from alcoholic liver disease, neurological or mental disease, heart disease and pancreatic disease.

12. The compound of formula I, the pharmaceutical composition or the combined preparation for use according to any of the preceding claims, wherein alcoholic liver disease is selected from steatosis, steatohepatitis, cirrhosis and liver cancer.

13. The compound of formula I, the pharmaceutical composition or the combined preparation for use according to any of the preceding claims, wherein the neurological or mental disease is selected from cognitive impairment, dementia, anxiety, depression, opioid addiction, psychosis, demyelination and fetal alcohol spectrum syndrome.

14. The compound of formula I, the pharmaceutical composition or the combined preparation for use according to any of the preceding claims, wherein the disease Cardiac selection includes dilated cardiomyopathy, ischemic coronary artery disease, and atherosclerosis.

15. The compound of formula I, the pharmaceutical composition or the combined preparation for use according to any of the preceding claims, wherein the pancreatic disease is selected from acute pancreatitis, chronic pancreatitis and pancreatic cancer.

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