MXPA99009032A - Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of dementia - Google Patents

Abstract

La presente invención se refiere al uso de inhibidores de la enzima 2-ciclooxigenasa o derivados de los mismos, para prevenir y tratar la demencia. En particular, la presente invención describe el método para prevenir y tratar la demencia en un sujeto, en donde el método comprende tratar al sujeto con una cantidad terapéuticamente efectiva de un compuesto de la Fórmula I en donde R2, R3 y R4 son como los definidos en la descripción.

Description

METHOD FOR USING 2-CYCLOOXYGENASE ENZYME INHIBITORS IN THE TREATMENT AND PREVENTION OF DEMENTIA FIELD OF THE INVENTION The present invention belongs to the field of the prevention and treatment of dementia. More specifically, the present invention relates to the use of inhibitors of the enzyme 2-cyclooxygenase or derivatives thereof to prevent and treat Alzheimer's Disease. BACKGROUND OF THE INVENTION Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially the production of PGG2, PGH2 or PGE2, has been a common target of the discovery of anti-inflammatory drugs. However, the common non-spheroidal anti-inflammatory drugs (NSAIDs) that are active to reduce the pain induced by prostaglandins and the swelling associated with the inflammation process, are also active to affect other processes regulated by prostaglandins that are not associated with the inflammation process. Thus, the use of high doses of most common NSAIDs can produce serious side effects, including life-threatening ulcers, which limit REF. 31,474 its therapeutic potential. An alternative to the use of NSAIDs is the use of corticosteroids, which also produce adverse effects, especially when it is a long-term therapy. It has been found that NSAIDs prevent the production of prostaglandins by inhibiting enzymes of the arachidonic acid / prostaglandin pathway in humans, including the enzyme cyclooxygenase (COX). The recent discovery of an inducible enzyme associated with inflammation (termed "cyclooxygenase-2" (COX-2) "or "Prostaglandin G / H synthetase II") provides a viable target of inhibition which more effectively reduces inflammation and produces less drastic side effects. Dementia, characterized by memory loss, confusion and disorientation, is suffered by 50% of the elderly population of North America. Of that number, approximately 60% suffer from progressive mental deterioration known as Alzheimer's Disease. Alzheimer's disease causes the death of brain cells, often beginning in the portion of the brain responsible for memory control. Emergence is usually gradual, then presents symptoms such as loss of short-term memory. In the later stages of the disease, the patient becomes disoriented and eventually becomes unable to take care of himself. U.S. Patent No. 5,192,753 (McGeer et al.) Describes the use of the NSAID indomethacin for the treatment of dementia. International Patent Publication W094 / 13635 (published June 23, 1994) describes the use of specific COX-2 compounds for the treatment of Alzheimer's disease. In International Patent Publication 095/15316 [pyrazol-1-yl] -benzenesulfone idas are described as inhibitors of 2-cyclooxygenase and have shown promise in the treatment of inflammation, arthritis and pain, with minimal side effects in studies preclinical and clinical. However, its use for the treatment of central nervous system disorders, including dementia or specifically for the treatment or prevention of other Alzheimer's diseases, had previously not been described. The present invention relates to the use of 2-cyclooxygenase inhibitors for the treatment and prevention of dementia. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method for the treatment or prevention of dementia in a subject in need of such treatment or prevention, wherein the method comprises administering to the subject a therapeutically effective amount of a dementia inhibitor. -cycloxygenase or a derivative thereof. The term "treatment" includes the partial or total inhibition of dementia, including Alzheimer's disease, vascular dementia, dementia due to multiple infarctions, presenile dementia, alcoholic dementia and senile dementia. The term "prevention" includes either preventing the establishment of clinically evident dementia or preventing the establishment of a preclinically evident stage of dementia in at-risk individuals. This definition also aims to encompass the prevention of the onset of cell death in the brain or to stop or reverse the progression of the symptoms of Alzheimer's disease. This includes prophylactic treatment of those at risk of developing dementia. The phrase "therapeutically effective" is intended to qualify the amount of each agent that will achieve the goal of improving the severity of the disease and the frequency of incidence on the treatment of each agent by themselves, while at the same time avoiding the adverse side effects typically associated with alternative therapies. The term "subject" for the purposes of treatment includes any human or animal subject having any of the known dementias and preferably the subject is a human being. For prevention methods, the subject is any human or animal subject and preferably is a human subject that is at risk of developing dementia. The subject may be at risk due to exposure to head injuries, being exposed to other environmental factors associated with Alzheimer's disease and being genetically predisposed to suffer from dementia. In the above method, dementia includes Alzheimer's disease, vascular dementia, dementia due to multiple infarctions, presenile dementia, alcoholic dementia and senile dementia. Inhibitors of the cyclooxygenase pathway in the metabolism of arachidonic acid to prevent and treat dementia can inhibit enzymatic activity through a variety of mechanisms. By way of example, the inhibitors used in the methods described herein can block the enzyme activity directly by acting as a substrate for the enzyme. The use of selective 2-cyclooxygenase inhibitors is highly advantageous, since they minimize the gastric side effects that may occur with non-selective NSAIDs, especially when prolonged prophylactic treatment is expected.

The term "2-cyclooxygenase inhibitor" describes a compound capable of inhibiting the enzyme 2-cyclooxygenase without significantly inhibiting 1-cyclooxygenase. Preferably it includes compounds that have an IC50 of 2-cyclooxygenase less than approximately 0.2 μM and also have an inhibition selectivity index of 2-cyclooxygenase on the inhibition of 1-cyclooxygenase, of at least 50 and preferably at least 100. Even more preferably, the compounds have an IC50 of cyclooxygenase 1 greater than about 1 μM and more preferably greater than 10 μM. The method provided herein relates to the use of inhibitors of the enzyme 2-cyclooxygenase or derivatives thereof in the prevention and treatment of dementia. Preferably, the 2-cyclooxygenase inhibitor is selected from the group consisting of compounds of Formula I 2 wherein R is selected from the group consisting of hydride, alkyl, haloalkyl, alkoxycarbonyl, cyano, cyanoalkyl, carboxyl, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, carboxyalkylaminocarbonyl, carboxyalkyl, aralkyloxycarbonylamino nocaxbonyl, aminocarbonylalkyl, alkoxycarbonylcyanoalkenyl and hydroxyalkyl; 3 wherein R is selected from the group consisting of hydride, alkyl, cyano, hydroxyalkyl, cycloalkyl, alkylsulfonyl and halo radicals; and 4 wherein R is selected from the group consisting of aralkenyl, aryl, cycloalkyl, 4-cycloalkenyl and heterocyclic radicals; wherein R is optionally substituted in a substitutable position, with one or more radicals which are selected from the group consisting of halo, thioalkyl, alkylsulfonyl, cyano, nitro, haloalkyl, alkyl, hydroxyl, alkenyl, hydroxyalkyl, carboxyl, cycloalkyl, alkylamino, dialkylamino, alkoxycarbonyl, aminocarbonyl, alkoxy, haloalkoxy, sulfamyl, heterocyclic and amino; or a pharmaceutically acceptable salt or a derivative thereof. A compound of particular interest consists of those compounds of Formula I wherein R is selected from the group consisting of hydride, lower alkyl, lower haloalkyl, lower alkoxycarbonyl, cyano, lower cyanoalkyl, carboxyl, indocarbonyl, lower alkylaminocarbonyl, lower cycloalkylaminocarbonyl, arylaminocarbonyl, carboxyalkylaminocarbonyl lower, aminocarbonylalkyl lower, aralkoxycarbonylalkylaminocarbonyl lower, carboxyalkyl lower, alkoxycarbonylcyanoalkenyl and lower hydroxyalkyl; 3 wherein R is selected from the group consisting of hydride, lower alkyl, cyano, hydroxyalkyl, lower cyanoalkyl, lower alkylsulfonyl 4 and halo radicals; and wherein R is selected from the group consisting of alkenyl, aryl, cycloalkyl, 4-cycloalkenyl and heterocyclic radicals; wherein R is optionally substituted in a substitutable position, with one or more radicals which are selected from the group consisting of halo, lower alkylthio, alkylsulfonyl, cyano, nitro, lower haloalkyl, lower alkyl, hydroxyl, lower alkenyl, hydroxyalkyl, lower radicals, carboxyl, lower cycloalkyl, lower alkylamino, lower dialkylamino, lower alkoxycarbonyl, aminocarbonyl, lower alkoxy, lower haloalkoxy, sulfamyl, 5- or 6-membered heterocyclic and amino; or a pharmaceutically acceptable salt or derivative thereof. A family of specific compounds of particular interest with Formula I, consists of compounds, salts and pharmaceutically acceptable derivatives thereof, which are the following: 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -lH- pyrazol-1-yl] -benzenesulfonamide; 4- [5-phenyl-3- (trifluoromethyl) -IH-pyrazol-1-yl] -benzenesulfonamide; 4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -lH-pyrazol-1-yl] -benzenesulfonamide; 4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -IH-pyrazol-1-yl] -benzenesulfonamide; 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -lH-pyrazol-1-yl] - benzenesulfonamide; 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -IH-pyrazol-1-yl] -benzenesulfonamide; 4- [4-chloro-5- (4-chlorophenyl) -3- (trifluoromethyl) -lH-pyrazol-1-yl] -benzenesulfonamide; 4- [3- (difluoromethyl) -5- (4-methylphenyl) -3- (trifluoromethyl) -lH-pyrazol-1-yl] -benzenesulfonamide; 4- [3- (difluoromethyl) -5-phenyl-lH-pyrazol-1-yl] -benzenesulfonamide; 4- [3- (difluoromethyl) -5- (4-methoxyphenyl) -lH-pyrazol-1-yl] -benzenesulfonamide; 4- [3-cyano-5- (4-fluorophenyl) -1H-pyrazol-1-yl] -benzenesulfonamide; 4- [3- (difluoromethyl) -5- (3-fluoro-4-methoxyphenyl) -1H-pyrazol-1-yl] -benzenesulfonamide; 4- [5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] -benzenesulfonamide; 4- [4-chloro-5-phenyl-lH-pyrazol-1-yl] -benzenesulfonamide; 4- [5- (4-chlorophenyl) -3- (hydroxymethyl) -lH-pyrazol-1-yl] -benzenesulfonamide; and 4- [5- (4- (N, N-dimethylamino) -phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] -benzenesulfonamide; A family of specific compounds of particular particular interest within Formula I, consists of the compounds and pharmaceutically acceptable salts or derivatives thereof which are the following: 4- [5- (4-methylphenyl) -3- (trifluoromethyl) - lH-pyrazol-1-yl] -benzenesulfonamide; 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -lH-pyrazol-1-yl] -benzenesulfonamide; and 4- [5- (3-fluoro-4-methoxyphenyl) -3- (difluoromethyl) -lH-pyrazol-1-yl] -benzenesulfonamide; The term "derivatives" is intended to encompass any compound that is structurally related to 2-cycloxygenase inhibitors or that possesses substantially equivalent biological activity. By way of example, such inhibitors may include, but not be limited to, prodrugs thereof. The compounds used in the methods of the present invention may be present in free base form or in the form of pharmaceutically acceptable addition salts thereof. The term "pharmaceutically acceptable salts" embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not determinant, as long as it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of the compounds of Formula I can be prepared from an inorganic acid or an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric and phosphoric acids. Suitable organic acids can be selected from the group consisting of cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic aliphatic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric acids , citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesyl, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pathothenic, 2-hydroxyethane sulfonic, toluenesulfonic, sulphanilic, cyclohexylaminosulfonic, stearic, algenic, beta-hydroxybutyric, salicylic, galactolic and galacturonic. The pharmaceutically accepted basic addition salts of the compounds of Formula I include metal salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts prepared from N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglimine (N-methylglucamine) and procaine. All these salts can be prepared by conventional methods from the corresponding compound of Formula I, by reacting, for example, the appropriate acid or base with the compound of Formula I. Materials and Methods Hsiao et al. [Science (1996)] has described an Alzheimer model in transgenic mice. Inhibitors of 2-cyclooxygenase must be active at a dose of 20 mg / kg. The active compounds of the present invention can be administered by any route known to those skilled in the art, preferably in the form of a pharmaceutical composition adapted for such a route and in an effective dose for the intended treatment. The active compounds and composition, for example, can be administered orally, intravascularly, intraperitoneally, intranasally, intrabroncheally, subcutaneously, intramuscularly or topically (including aerosol). The administration of the present invention can be carried out either for prevention or for treatment purposes. The methods and compositions used herein may be employed alone or in conjunction with additional therapies known to those skilled in the art, in the prevention or treatment of dementia. Alternatively, the methods and compositions described herein may be used as adjunctive therapy. As an example, the 2-cyclooxygenase inhibitor can be administered alone or in combination with other antineoplastic agents or other growth inhibitory agents or other drugs or nutrients. The term "adjunctive therapy" (or "combination therapy"), to define the use of a 2-cyclooxygenase inhibitory agent and other pharmaceutical agents, encompasses the administration of each agent sequentially in a regimen that will provide beneficial effects. by the use of such a combination of drugs and also encompasses the co-administration of these agents in a substantially simultaneous manner, for example in a single formulation having a fixed ratio of these active ingredients, or in multiple formulations separately for each agent. The present invention also comprises a pharmaceutical composition for the adjunctive prevention and treatment of dementia, comprising a therapeutically effective amount of a compound of Formula I in association with at least one pharmaceutically acceptable carrier, an adjuvant or a diluent (collectively referred to as "vehicle" materials) and other agents against dementia or other growth inhibitory agents or other drugs or nutrients. For oral administration, the pharmaceutical composition may be in the form, for example, of a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units or dosage forms are capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia gum, corn starch or gelatin; with disintegrating agents such as corn starch, potato starch or sodium carboxymethyl cellulose; and with lubricants such as talc or magnesium stearate. The active ingredient can also be administered by injection in the form of a composition whereinFor example, saline, dextrose or water may be used as a suitable vehicle. For intravenous, intramuscular, subcutaneous or intraperitoneal administration, the compound can be combined with a sterile aqueous solution, which is preferably isotonic with respect to the blood of the recipient. Such formulations can be prepared by dissolving the solid active ingredient in water containing physiologically compatible substances such as sodium chloride, glycine and the like, and having a regulated HP compatible with physiological conditions, to produce an aqueous solution and then said solution is sterilized. The formulations may be present in single-dose or multi-dose containers, such as sealed ampoules or flasks. Formulations suitable for parenteral administration, conveniently comprise a sterile aqueous preparation of the active compound, which is preferably isotonic. The preparations for injection may also be formulated by suspending or emulsifying the compounds in a non-aqueous solvent, such as a vegetable oil, synthetic aliphatic acid glycerides, higher aliphatic acid esters or propylene glycol. Formulations for topical administration include known gels, creams, oils and the like. For aerosol administration, the compounds can be formulated with known aerosol excipients such as saline, and are administered using commercially available nebulizers. The formulation in a source of fatty acid can be used to improve biocompatibility. For rectal administration, the active ingredient can be formulated in suppositories, using bases that are solid at room temperature and that melt or dissolve at body temperature. Commonly used bases include cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights and fatty stress of polyethylene stearate. The dosage form and amount can be easily established with reference to the known central nervous system prophylactic or treatment regimens. The amount of therapeutically active compound that is administered and the dosage regimen for the treatment of a disease with the compounds and / or compositions of the present invention, depends on a variety of factors including the age, weight, sex and medical conditions of the patient. subject, the severity of the disease, the route and frequency of administration and the particular compound employed, as well as the pharmacokinetic properties of the treated individual and, therefore, said amount may vary widely. The dose will generally be lower if the compounds are administered locally rather than systemically, and also if they are administered for prevention rather than treatment. Such treatments can be administered as often as necessary and for the period of time deemed necessary by the doctor treating the patient. Those skilled in the art will note that the dosage regimen or the therapeutically effective amount of the inhibitor to be administered may need to be optimized for each individual. The pharmaceutical compositions may contain the active ingredient in a range of about 0.1 to 2000 mg, preferably in a range of about 0.5 to 500 mg and more preferably between about 1 and 200 mg. A daily dose of about 0.01 to 100 mg / kg of body weight, preferably between about 0.1 and about 50 mg / kg of body weight and more preferably of about 1 to 20 mg / kg of body weight may be appropriate. The daily dose can be administered in one to four doses per day. All of the patents referred to herein are incorporated by reference. Although the present invention has been described with respect to specific embodiments, the details of said embodiments are not considered as limiting. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for la - li. manufacture of the objects to which it refers.

Claims (14)

1. REVINDICATIONS Having described the invention as an antecedent, the content of the following claims is claimed as property: 1. The use of a compound of Formula I
2. characterized in that R is selected from the group consisting of hydride, alkyl, haloalkyl, alkoxycarbonyl, cyano, cyanoalkyl, carboxyl, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, carboxyalkylaminocarbonyl, carboxyalkyl, aralkoxycarbonylalkylaminocarbonyl ^, alkoxycarbonylcyanoalkyl, and hydroxyalkyl; wherein R is selected from the group consisting of hydride, alkyl, cyano, hydroxyalkyl, cycloalkyl, alkylsulfonyl and halo radicals; and wherein R is selected from the group consisting of aralkenyl, aryl, cycloalkyl, cycloalkenyl and heterocyclic radicals; wherein R is optionally substituted in a substitutable position, with one or more radicals which are selected from the group consisting of halo, thioalkyl, alkylsulfonyl, cyano, nitro, haloalkyl, alkyl, hydroxyl, alkenyl, hydroxyalkyl, carboxyl, cycloalkyl, alkylamino, dialkylamino, alkoxycarbonyl, aminocarbonyl, alkoxy, haloalkoxy, sulfamyl, heterocyclic and amino; or a pharmaceutically acceptable salt or derivative thereof, for preparing a medicament for the treatment of a dementia in a subject. The use according to claim 2 1, characterized in that R is selected from the group consisting of hydride, alkyl of 1 to 10 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms , cyano, cyanoalkyl of 1 to 6 carbon atoms, carboxyl, aminocarbonyl, N-alkylaminocarbonyl of 1 to 6 carbon atoms, cycloalkylaminocarbonyl of 3 to 7 carbon atoms, arylaminocarbonyl, carboxy (alkylaminocarbonyl of 1 to 6 carbon atoms) , aryl- (alkoxycarbonylalkylaminocarbonyl of 1 to 6 carbon atoms), carboxy- (alkyl of 1 to 6 carbon atoms), alkoxycarbonyl- cyanoalkenyl of 1 to 6 carbon atoms and hydroxyalkyl of 1 to 6 carbon atoms; 3 wherein R is selected from the group consisting of hydride radicals, alkyl of 1 to 10 carbon atoms, cyano, hydroxyalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms carbon and halo; and wherein R is selected from the group consisting of aralkenyl, aryl, cycloalkyl, cycloalkenyl and heterocyclic radicals; wherein R is optionally substituted in a substitutable position with one or more radicals that are selected from the group consisting of halo, thioalkyl radicals of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, cyano, nitro, haloalkyl from 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, hydroxyl, alkenyl of 2 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, carboxyl, cycloalkyl of 3 to 7 carbon atoms, N- alkylamino of 1 to 6 carbon atoms, di-N-alkylamino of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, aminocarbonyl, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms , sulfamyl, 5- or 6-membered heterocyclic and amino; or a pharmaceutically acceptable salt or derivative thereof.
3. 3. The use according to claim 2, characterized in that the compound is selected from the compounds and their pharmaceutically acceptable salts of the group consisting of 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -IH- pyrazol-1-yl] -benzenesulfonamide; 4- [5-phenyl-3- (trifluoromethyl) -lH-pyrazol-1-yl] -benzenesulfonamide; 4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -lH-pyrazol-1-yl] -benzenesulfonamide; 4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -lH-pyrazol-1-yl] -benzenesulfonamide; 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -lH-pyrazol-1-yl] -benzenesulfonamide; 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -lH-pyrazol-1-yl] -benzenesulfonamide; 4- [4-chloro-5- (4-chlorophenyl) -3- (trifluoromethyl) -lH-pyrazol-1-yl] -benzenesulfonamide; 4- [3- (difluoromethyl) -5- (4-methylphenyl) -lH-pyrazol-1-yl] -benzenesulfonamide; 4- [3- (difluoromethyl) -5-phenyl-lH-pyrazol-1-yl] -benzenesulfonamide; 4- [3- (difluoromethyl) -5- (4-methoxyphenyl) -lH-pyrazol-1-yl] -benzenesulfonamide; 4- [3-cyano-5- (4-fluorophenyl) -1H-pyrazol-1-yl] -benzenesulfonamide; 4- [3- (difluoromethyl) -5- (3-fluoro-4-methoxyphenyl) -1H-pyrazol-1-yl] -benzenesulfonamide; 4- [5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] -benzenesulfonamide;

   4- [4-chloro-5-phenyl-lH-pyrazol-1-yl] -benzenesulfonamide; 4- [5- (4-chlorophenyl) -3- (hydroxymethyl) -IH-pyrazol-1-yl] -benzenesulfonamide; and 4- [5- (4- (N, N-dimethylamino) -phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] -benzenesulfonamide.
4. 4. The use according to claim 2, characterized in that the compound is 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -lH-pyrazol-1-yl] -benzenesulfonamide, or a pharmaceutically acceptable salt thereof. same.
5. 5. The use according to claim 2, characterized in that the compound is 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -lH-pyrazol-1-yl] -benzenesulfonamide, or a pharmaceutically acceptable salt of the same.
6. 6. The use according to claim 2, characterized in that the compound is 4- [5- (3-fluoro-4-methoxyphenyl) -3- (difluoromethyl) -lH-pyrazol-1-yl] -benzenesulfonamide, or a pharmaceutically acceptable salt thereof.
7. The use according to claim 1, characterized in that the dementia is selected from the group consisting of Alzheimer's disease, vascular dementia, dementia by multiple infarctions, presenile dementia, alcoholic dementia and senile dementia.
8. 8. The use according to claim 7, characterized in that the dementia is Alzheimer's disease.
9. 9. The use of a compound of Formula I

   characterized in that R is selected from the group consisting of hydride, alkyl, haloalkyl, alkoxycarbonyl, cyano, cyanoalkyl, carboxyl, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, carboxyalkylaminocarbonyl, carboxyalkyl, aralkoxycarbonylalkylaminocarbonyl, aminocarbonylalkyl, alkoxycarbonylcyanoalkenyl and hydroxyalkyl; wherein R is selected from the group consisting of hydride, alkyl, cyano, hydroxyalkyl, cycloalkyl, alkylsulfonyl and halo radicals; and wherein R is selected from the group consisting of aralkenyl, aryl, cycloalkyl, cycloalkenyl and heterocyclic radicals; wherein R is optionally substituted in a substitutable position, with one or more radicals which are selected from the group consisting of halo, thioalkyl, alkylsulfonyl, cyano, nitro, haloalkyl, alkyl, hydroxyl, alkenyl, hydroxyalkyl, carboxyl, cycloalkyl, alkylamino , dialkylamino, alkoxycarbonyl, aminocarbonyl, alkoxy, haloalkoxy, sulfayl, heterocyclic and amino; or a pharmaceutically acceptable salt or derivative thereof, for preparing a medicament for the prevention of a dementia which is selected from the group consisting of Alzheimer's disease, vascular dementia, dementia for multiple infarctions, presenile dementia, alcoholic dementia and senile dementia. The use according to claim 2, characterized in that R is selected from the group consisting of hydride, alkyl of 1 to 10 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms , cyano, cyanoalkyl of 1 to 6 carbon atoms, carboxyl, aminocarbonyl, N-alkylaminocarbonyl of 1 to 6 carbon atoms, cycloalkylaminocarbonyl of 3 to 7 carbon atoms, arylaminocarbonyl, carboxy (alkylaminocarbonyl of 1 to 6 carbon atoms) , aryl- (alkoxycarbonylalkylaminocarbonyl of 1 to 6 carbon atoms), carboxy- (alkyl of 1 to 6 carbon atoms), alkoxycarbonyl- cyanoalkenyl of 1 to 6 carbon atoms and hydroxyalkyl of 1 to 6 carbon atoms;

   wherein R is selected from the group consisting of hydride radicals, alkyl of 1 to 10 carbon atoms, cyano, hydroxyalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkylsulfonyl of the ß carbon atoms and halo; and wherein R is selected from the group consisting of aralkenyl, aryl, cycloalkyl, cycloalkenyl and heterocyclic radicals; wherein R is optionally substituted in a substitutable position with one or more radicals which are selected from the group consisting of halo, thioalkyl radicals of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, cyano, nitro, haloalkyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, hydroxyl, alkenyl of 2 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, carboxyl, cycloalkyl of 3 to 7 carbon atoms, N-alkylamino of 1 to 6 carbon atoms, di-N-alkylamino of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, aminocarbonyl, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, sulfamyl, 5- or 6-membered heterocyclic and amino; or a pharmaceutically acceptable salt or derivative thereof. 11. The use according to claim 10, characterized in that the compound is selected from the compounds and their pharmaceutically acceptable salts of the group consisting of 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -IH- pyrazol-1-yl] -benzenesulfonamide; 4- [5-phenyl-3- (trifluoromethyl) -lH-pyrazol-1-yl] -benzenesulfonamide; 4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -lH-pyrazol-1-yl] -benzenesulfonamide; 4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -lH-pyrazol-1-yl] -benzenesulfonamide; 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -lH-pyrazol-1-yl] -benzenesulfonamide; 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -lH-pyrazol-1-yl] -benzenesulfonamide; 4- [4-chloro-5- (4-chlorophenyl) -3- (trifluoromethyl) -IH-pyrazol-1-yl] -benzenesulfonamide; 4- [3- (difluoromethyl) -5- (4-methylphenyl) -lH-pyrazol-1-yl] -benzenesulfonamide; 4- [3- (difluoromethyl) -5-phenyl-lH-pyrazol-1-yl] -benzenesulfonamide; 4- [3- (difluoromethyl) -5- (4-methoxyphenyl) -lH-pyrazol-1-yl] -benzenesulfonamide; 4- [3-cyano-5- (4-fluorophenyl) -1H-pyrazol-1-yl] -benzenesulfonamide; 4- [3- (difluoromethyl) -5- (3-fluoro-4-methoxyphenyl) -1H-pyrazol-1-yl] -benzenesulfonamide;

   4- [5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] -benzenesulfonamide; 4- [4-chloro-5-phenyl-lH-pyrazol-1-yl] -benzenesulfonamide; 4- [5- (4-chlorophenyl) -3- (hydroxymethyl) -lH-pyrazol-1-yl] -benzenesulfonamide; and 4- [5- (4- (N, N-dimethylamino) -phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] -benzenesulfonamide; 12. The use according to claim 10, characterized in that the compound is 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -lH-pyrazol-1-yl] -benzenesulfonamide, or a pharmaceutically acceptable salt of the same. 13. The use according to claim 10, characterized in that the compound is 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -lH-pyrazol-1-yl] -benzenesulfonamide, or a pharmaceutically acceptable salt thereof. same. 14. The use according to claim 10, characterized in that the compound is 4- [5- (3-fluoro-4-methoxyphenyl) -3- (difluoromethyl) -IH-pyrazol-1-yl] -benzenesulfonamide, or a pharmaceutically acceptable salt thereof.