MXPA01013421A

MXPA01013421A - Therapeutic agents.

Info

Publication number: MXPA01013421A
Application number: MXPA01013421A
Authority: MX
Inventors: Ian Charles Kilpatrick
Original assignee: Knoll Gmbh
Priority date: 1999-06-24
Filing date: 2000-06-16
Publication date: 2002-07-30
Also published as: EP1218008A2; AU6150200A; WO2001000186A3; GB9914743D0; JP2003503343A; WO2001000186A2; CA2376886A1

Abstract

A method of treating obesity and related conditions comprising the administration of a therapeutically effective amount of a compound of formula (I) including pharmaceutically acceptable salts, solvates, racemates, enantiomers, diastereoisomers and mixtures thereof in which: R1 represents H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C1-6alkyl, C1-6alkoxy or C1-6alkanoyl; R2 and R3 independently represent H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C1-6alkyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkylthio, C1-6alkylsulphinyl, C1-6alkylsulphonyl or hydroxy; R4 and R5 independently represent H, C1-6alkyl or R4 and R5 combined together with the carbon atom to which they are attached represent C3-6cycloalkylidene (each alkyl or cycloalkylidene being optionally substituted with one or more of halo, cyano, hydroxy, amino or C1-6alkyl); and R6, R7 and R8 independently represent H, halo, hydroxy, mercapto, nitro, cyano or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino; and any nitrogen atom being optionally substituted with one or more C1-6alkyl): C1-6alkyl, C1-6alkanoyl, C1-6alkoxy, C2-6alkoxycarbonyl, carboxy, C1-6alkanoyloxy, C1-6alkylthio, C1-6alkylsulphinyl, C1-6alkylsulphonyl, C1-6alkylsulphonylamino, sulphamoyl, carbamoyl, C2-6alkylcarbamoyl or C1-6alkanoylamino; to a mammal in need thereof.

Description

THERAPEUTIC AGENTS The present invention relates to 1,4-triazolo [1, 5-a] pyrimidines, which are useful in the treatment and prophylaxis of obesity and related conditions, including disorders in eating, such as bulimia, anorexia, ingestion of snacks and snacks, diabetes mellitus not dependent on insulin, hyperglycemia, hyperlipidemia and tension, and as an aid to stop smoking. The compounds of the formula A: wherein R represents H or optionally substituted alkyl, alkoxy or alkanoyl; R2 and R3 independently represent H or optionally substituted alkyl, alkoxy, alkanoyl, alkylthio, alkylsulfinyl or sulfonyl; R and R5 independently represent H, alkyl or, together with the carbon atom to which they are attached, represent optionally substituted cycloalkui Mdeno; and R6, R7 and R8 independently represent H, halogen, hydroxy, mercapto, cyano or optionally substituted alkyl, alkanoyl, alkoxy, alkoxycarbonyl, carboxy, alkanoyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, sulfamoyl, carbamoyl, alkylcarbamoyl or alkanoylamino, optionally substituted; the processes for its preparation and its use in the treatment and / or prophylaxis of attacks, neurological disorders, such as epilepsy and / or conditions in which there is neurological damage, such as fulminating attacks, brain trauma, skull damage and hemorrhages, are described in WO 95/10521 (Knoll AG). A process for preparing these compounds is described in WO 98/07724 (Knoll AG). The present invention provides a method for treating obesity, comprising administering a therapeutically effective amount of a compound of formula I: including pharmaceutically acceptable salts, solvates, racemates, enantiomers, diastereoisomers, and mixtures thereof, wherein: RT represents H or one of the following groups (optionally substituted with one or more of halogen, cyano, hydroxy or amino): alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or alkanoyl of 1 to 6 carbon atoms; R2 and R3, independently, represent H or one of the following groups (optionally substituted with one or more of halogen, cyano, hydroxy or amino): alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl from 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms in the alkyl, alkylsulfonyl of 1 to 6 carbon atoms in the alkyl or hydroxy; R4 and R5, independently, represent H, alkyl of 1 to 6 carbon atoms, or R4 and R5, combined with the carbon atom to which they are attached, represent cycloalkylidene of 3 to 6 carbon atoms (each alkyl or cycloalkylidene is substituted optionally with one or more of: halogen, cyano, hydroxy, amino or alkyl of the 6 carbon atoms); and Re, R7 and R's, independently, represent H, halogen, hydroxy, mercapto, nitro, cyano or one of the following groups (optionally substituted with one or more of: halogen, cyano, hydroxy or amino, and any nitrogen atom is optionally substituted with one or more of alkyl of 1 to 6 carbon atoms): alkyl of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 atoms of carbon in the alkoxy, carboxy, alkanoyloxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 atoms carbon in the alkyl, sulfamoyl, carbamoyl, alkylcarbamoyl of 2 to 6 carbon atoms in the alkyl or alkanoylamino of 1 to 6 carbon atoms; to a mammal that needs it. It will be understood that any group mentioned herein, which contains a chain of three or more carbon atoms, means a group in which the chain can be straight or branched. For example, an alkyl group may comprise propyl, which includes n-propyl and isopropyl, and butyl, which includes n-butyl, secondary butyl, isobutyl and tertiary butyl. The total number of carbon atoms that is specified herein for certain substituents, for example "from 1 to 6" means an alkyl group having from 1 to 6 carbon atoms. The term "halogen" or "halo", when used herein, means fluorine, chlorine, bromine and iodine. The term "optionally substituted", as used herein, unless immediately followed by a list of substituent groups, means optionally substituted with one or more groups selected from halogen, cyano, hydroxy and amino. When the substituents R6, R7 and R8 of the phenyl ring are different from H, the substituent can replace any H attached to a carbon atom of the ring, and can be located in any of said ring positions, that is, up to three from positions 2, 3, 4 and / or 5. The specific compounds of formula I are: 7- [1- (4-fluorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine , 7- [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (4-bromophenoxy) ethyl] -1, 2 , 4-triazolo [1,5-a] pyrimidine, 7- [1- (4-cyanophenoxy) ethyl] -1, 2,4-triazolo [1,5-a] pyrimidine, 7- [1- (4- trifluoromethylphenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 5-7- [1- (4-methoxyphenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine , 7- [1- (4-trifluoromethoxyphenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (4-acetylphenoxy) ethyl] -1,2,4-triazolo [1,5-ajpyrimidine, 7-. { 1- [4- (methylthio) phenoxy] ethyl} -1,2,4-triazolo [1,5-a] 10 pyrimidine, 7- [1- (4-methylsulfinylphenoxy) ethyl] -1,2,4-triazolo [1,5-a] • pyrimidine, 7- [1- (4-methylsulfonylphenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7-. { 1- [4- (ethylthio) phenoxy] ethyl} -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (3-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1 - (2, 4-d fluorofenoxi) eti I] - 1,2,4-triazolo [1, 5-a] pyrimidine, • 7- [1- (2,4-dichlorophenoxy) ethyl] -1,2 , 4-triazolo [1,5-a] pyrimidine, 20 7- [1- (3,4-dichlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (2-chloro-4-fluorophenoxy) ethyl] -1, 2,4-triazolo [1,5-a] pyrimidine, 7- [1- (4-chlorophenoxy) ethyl] -2-metll-1,2,4 -triazolo [1,5-a] pyrimidine, 7- (4-chlorophenoxymethyl) -1, 2,4-triazolo [1, 5-a] pyrimidine, 7- [1- (4-chlorophenoxy) -1-methylethyl ] -1,2,4-triazolo [1,5-ajpyrimidine, 7- [1- (4-chlorophenoxy) propyl] -1, 2,4-triazolo [1,5-a] pyrimidine, and 7- [1 - (4-chlorophenoxy) ethyl] -1,4,4-triazolo [1,5-a] pyrimidin-5-ol, its stereoisomers and its pharmaceutically acceptable salts. Specific examples of the examples of the stereoisomers of the formula I are: (+) - 7 - [1- (4-fluorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, and (- ) -7- [1 - (4-f luorof enoxi) eti I] - 1, 2, 4-triazolo [1, 5-a] pyrimidine; (+) -7- [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, (-) - 7- [1- (4-chlorophenoxy) ethyl] - 1,2,4-triazolo [1,5-a] pyrimidine; (+) - 7 - [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidin-5-ol, and (-) - 7- [1- ( 4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidin-5-ol, and pharmaceutically acceptable salts thereof. Preferred compounds of the formula I are 7- [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine and 7- [1- (4-chlorophenoxy) ethyl] - 1, 2,4-triazolo [1, 5-a] pyrimidin-5-ol, including the racemates, the enantiomers and their mixtures, and their pharmaceutically acceptable salts. The most preferred compounds of the formula I are (R) -7- [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, and (S) -7- [ 1- (4- • EHMMAttHli chlorophenoxy) ethyl] -1, 2,4-triazolo [1, 5-a] pyrimidine, and its pharmaceutically acceptable salts. A highly preferred compound of the formula I is (R) -7- [1- (4-chlorophenoxy) ethyl] -1,4-triazolo [1,5-a] pyrimidine and its pharmaceutically acceptable salts. The compounds of the formula I can be prepared as described in WO 95/10521 (Knoll AG) and in WO 98/07724 (Knoll AG). The compound of the formula I can be administered in any of the known pharmaceutical dosage forms. The amount of the compound to be administered will depend on several factors, including the age of the patient, the severity of the condition and the past medical history of the patient, and always falls within the sound discretion of the physician administering it; but, in general, it is contemplated that the dose of the compound to be administered is in the range of 0.1 to 1000 mg, preferably 1 to 500 mg per day, administered in one or more doses. Oral dosage forms are the preferred compositions for use in the present invention, and these are the known dosage forms for such administration; for example: tablets, capsules, granules, syrups and aqueous or oily suspensions. The excipients used in the preparation of these compositions are the excipients known in the pharmaceutical field. Tablets can be prepared from a mixture of the active compound with fillers, for example, calcium phosphate; disintegrating agents, for example, corn starch; lubricating agents, for example, magnesium stearate; binders, for example, microcrystalline cellulose or polyvinylpyrrolidone, and other optional ingredients known in the art, to enable tabletting of the mixture, by known methods. If desired, the tablets can be coated using known methods and excipients which can include an enteric coating using, for example, hydroxypropylmethylcellulose phthalate. The tablets can be formulated in a manner known to those skilled in the art, so as to give sustained release of the compounds of the present invention. If desired, said tablets may be provided with enteric coatings, by known methods, for example, by the use of cellulose acetate phthalate. Similarly, capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipients can be prepared by known methods and, if desired, provided with enteric coatings, in a known manner. The contents of the capsule can be formulated using known methods, so as to give sustained release of the active compound. Each of the tablets and capsules may conveniently contain from 1 to 500 mg of the active compound. It is preferred that each of the tablets and capsules contain 5, 10, 15, 20, 25, 30, 50, 100, 250 or 500 mg. Other dosage forms for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium, in the presence of a suspending agent.

"Non-toxic", such as sodium carboxymethylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example, peanut oil The active compound can be formulated to granules with or without additional excipients The granules can be ingested directly by the patient, or they can be added to a suitable liquid carrier (eg, water) before ingestion.The granules can contain disintegrants, for example, an effervescent couple formed by an acid and a salt carbonate or bicarbonate, to facilitate dispersion in the liquid medium The therapeutically active compounds of the formula I can be formulated to a composition that the patient retains in the mouth, so that the active compound is administered through the mucosa. of the mouth 15 The dosage forms suitable for rectal administration are known pharmaceutical forms for said administration, for example, suppositories with bases of cocoa butter or polyethylene glycol. • The dosage forms suitable for parenteral administration are the pharmaceutical forms known for that administration; for example, sterile suspensions or sterile solutions in a suitable solvent. Dosage forms for topical administration may comprise a matrix in which the pharmacologically active compounds of the present invention are dispersed, so that The compounds are kept in contact with the skin, in order to transdermally administer the compounds, and a suitable transdermal composition can be prepared by mixing the pharmaceutically active compound with a topical carrier, such as a mineral oil. petrolatum and / or a wax, for example, paraffin wax or beeswax, together with a potential transdermal accelerator, such as dimethyl sulfoxide or propylene glycol Alternatively the active compounds can be dispersed in a cream, gel or ointment base, The amount of active compound contained in a topical formulation should be such that a therapeutically effective amount of the compound is delivered during the period of time during which the topical formulation is intended to remain on the skin. active of the formula I to a composition that is dispersed as an aerosol inside the cavity oral or nasal ad of the patient. Said aerosols can be administered from a pump package or from a pressure package containing a volatile propellant. The therapeutically active compounds of the formula I, used in the method of the present invention, can also be administered by continuous infusion, either from an external source, for example, by intravenous infusion, or from a source of the compound placed within the body . Internal sources include the implanted reservoirs that contain the compound to be infused, which is released continuously, for example, by osmosis, and the implants that may be: (a) liquids, such as an oily suspension of the compound that is going to to be infused, for example, in the form of a derivative very sparingly soluble in water, such as a dodecanoate salt or a lipophilic ester; or (b) solids, in the form of a support implanted, for example, of a synthetic resin or of a waxy material, for the compound to be infused. The support can be a single body containing the entire compound, or a series of several bodies, each of which contains part of the compound to be supplied. The amount of active compound present in an internal source must be such that a therapeutically effective amount of the compound is delivered over a prolonged period of time. In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example, such as those obtained by grinding with fluid energy. The following in vivo test supports the discovery that the compounds of formula I have efficacy in the treatment of obesity. There is evidence, from preclinical studies, that (R) -7- [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine administered to rodents as a suspension 0.4% of Cellosize in purified water BP, caused reductions, related to the dose, of the food intake of between 5 and 50 mg / kg, per os. -t ^ > A "liL ^ * '--- - - - - ---- - - - - - - - - - - - - - --- ^ lm In continuous series, the animals lost body weight in response to (R) -7- [1- (4-chlorophenoxy) ethyl] -1,4,4-triazolo [1,5-a] pyrimidine (100-300 mg / kg per os in the same suspension as before), Without altering the feed intake of the animals The present invention also comprises a compound of the formula I for use as a medicament The pharmaceutical compositions containing a therapeutically effective amount of a compound of the formula I can be used to treat obesity, eating disorders, such as bulimia, anorexia, snack and snack ingestion, diabetes mellitus not dependent on insulin, hyperglycemia, hyperlipidemia and tension in mammals, particularly in humans, and as an aid to stop smoking in humans. The precise amount of the active compound administered in said treatment will depend on several factorsFor example, the age of the patient, the severity of the condition and the previous medical history, and always within the healthy discretion of the doctor who administers, the amount of active compound administered per day is on the scale of 1 to 1000 mg, preferably 5 to 500 mg, administered in a single dose or in divided doses, one or more times during the day. In another aspect, the present invention provides the use of a compound of the formula I in the manufacture of a medicament for use in the treatment of obesity, eating disorders, such as bulimia, anorexia, ingestion of snacks and ^^ a snacks, diabetes mellitus not dependent on insulin, hyperglycemia, hyperlipidemia and tension, and as an aid to stop smoking. The present invention also provides a method for treating obesity, eating disorders, such as bulimia, anorexia, snack and snack ingestion, non-insulin-dependent diabetes mellitus, hyperglycemia, hyperlipidemia and tension, comprising administration to a patient who in need thereof, of a therapeutically effective amount of a compound of formula I. The present invention also provides a method for reducing the irresistible tendency to smoke in humans, which comprises administering to a patient in need thereof, an amount Therapeutically effective of a compound of formula I. The present invention also provides a method for reducing weight gain after smoking cessation in humans, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the formula I. Additionally, the compounds of the present invention can not be useful in the treatment or prevention of metabolic diseases and the conditions that originate from them, for example, thermogenesis that is not due to exercise activity, and increased metabolic rate. The compounds of the present invention can be useful for preventing cardiovascular diseases, and for reducing the adhesiveness of platelets, for helping to lose weight after pregnancy and for helping to lose weight after quitting. In accordance with the present invention, it is further provided • a method for the treatment of obesity, and the use of a compound of formula I in the manufacture of the medicament for that treatment. The present invention also provides a method for manufacturing a medicament for the prophylaxis of obesity, and the use of a compound of formula I in said manufacture. 10 In an alternative embodiment, the present invention provides a pharmaceutical composition for the treatment and / or prevention of obesity, comprising a therapeutically effective amount of a compound of formula I including enantiomers and pharmaceutically acceptable salts thereof, 15 with a pharmaceutically acceptable diluent or carrier. In an alternative embodiment, the present invention provides a method for prophylaxis of obesity, comprising administering to a mammal in need thereof, of a compound of formula I including enantiomers and their salts 20 pharmaceutically acceptable, together with a pharmaceutically acceptable diluent or carrier. The invention is illustrated by the following examples which are given by way of example only. The final product of each of these examples was characterized by one or more of 25 the following procedures: gas-liquid chromatography, - "" * "- -,, ^ fc '^ .A ^ S chromatography high performance liquid;....... Elemental analysis, nuclear magnetic resonance spectroscopy and infrared spectroscopy of the present compounds is prepared invention as described in WO 95/10521 (Knoll AG) and in WO 98/07724 (Knoll AG), which are incorporated herein by means of this reference.

EXAMPLE 1 1 a) .- A mixture of 30.0 g of 2- (4-chlorophenoxy) propionic acid in 300 ml of toluene was added to a solution of 22.0 ml of thionyl chloride and 2 ml of dimethylformamide in 150 ml of toluene, 60-70 ° C, with stirring. The mixture was stirred for 18 hours at 70-80 ° C, and then evaporated under reduced pressure to give the acid chloride. A solution of 23.5 g of Meldrum acid in 90 ml of dichloromethane was cooled to 0-5 ° C under nitrogen and 33 ml of pyridine was added at 0-5 ° C. To this mixture was added a solution of the acid chloride prepared above in 90 ml of dichloromethane, dropwise, keeping the temperature below 5 ° C. The mixture was stirred for one hour at 0-5 ° C and then at room temperature for 18 hours. The mixture was diluted with 150 ml of dichloromethane and washed with 2M hydrochloric acid and then with saturated sodium bicarbonate solution and then with water. The bicarbonate washes were acidified with 5M The hydrochloric acid was extracted and extracted with dichloromethane. These dichloromethane extracts were combined with the original solution in dichloromethane, and dried and evaporated to give the intermediate derivative of Meldrum acid. This derivative was boiled under reflux with 400 ml of methanol for six hours, and then allowed to stand at room temperature for 66 hours with 10 ml of methanolic hydrogen chloride solution. The mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and evaporated under reduced pressure to give an oil which was distilled in high vacuum. The distillate was purified by column chromatography on silica gel, using petroleum ether, p. and. 60-80 ° C / ethyl acetate, 20: 1, as mobile phase, to give methyl 4- (4-chlorophenoxy) -3-oxopentanoate, as an oil. b) 1.87 g of guanidine hydrochloride was added, with stirring, to a solution of 0.41 g of sodium in 15 ml of ethanol. The mixture was stirred for 15 minutes and then a solution of 5.0 g of methyl 4- (4-chlorophenoxy) -3-oxopentanoate in 15 ml of ethanol was added to this mixture. The mixture was stirred and allowed to boil under reflux for 16 hours. The mixture was cooled and then evaporated to dryness under reduced pressure to give a solid. The solid was triturated with 10 ml of water containing 2 ml of glacial acetic acid and 20 ml of dichloromethane for 1 hour, and then filtered. The residue obtained was washed with water and then with dichloromethane, to give 2-amino-4- [1- (4-chlorophenoxy) ethyl-6-hydroxypyrimidine, p. F. 125 ° C. c) .- A mixture of 0.5 g of 2-amino-4- [1- (4-chlorophenoxy) ethyl-6-hydroxypyrimidine, 0.5 ml of dimethylformamide-dimethylacetal and 5 ml of toluene was stirred and left to boil. reflux for 8 hours. The mixture was evaporated for 8 hours. The mixture was allowed to stand at room temperature for 24 hours and then was evaporated to dryness under reduced pressure to give a solid which was triturated with ether and filtered to give the amidine as a solid. d) .- 62 ml of a 60 percent dispersion of sodium hydride in mineral oil was dissolved in 10 ml of methanol, from which the mineral oil had been removed by washing with petroleum) and 0.12 g of hydroxylamine hydrochloride was added. . The mixture was stirred for 5 minutes and then added to the 0.5 g of amidinopyrimidine obtained in c). The mixture was stirred at room temperature for 72 hours and then evaporated to dryness under reduced pressure to give a residue which was washed with water and dried to give formamidoxin. e) .- 5.0 g of the product of d) and 100 g of polyphosphoric acid were stirred and heated in a steam bath for 4 hours. The mixture was allowed to cool to room temperature, then 100 g of ice and 100 ml of ethyl acetate were added. A solution of 110 g of potassium carbonate in a total volume of 100 ml of water was added dropwise over 15 minutes to neutralize the mixture. The mixture was separated and the aqueous layer was extracted with ethyl acetate. The combined layers of ethyl acetate were dried and evaporated to give a solid which was purified by chromatography on ^ waÁia rapid column, on silica, using dichloromethane / methanol (75: 3; as mobile phase, to give 7- [1- (4-chlorophenoxy) ethyl] -1, 2,4-triazolo [1, 5-a] pyrimidin-5-ol, mp 190 ° C.

EXAMPLE A The use of the compounds of the present invention in the manufacture of pharmaceutical compositions is illustrated by the following description. In this description, the term "active compound" denotes any compound of the invention but, in particular, any compound that is the final product of one of the preceding examples. a) .- Capsules In the preparation of capsules 10 parts by weight of active compound and 240 parts by weight of lactose are disaggregated, and then mixed. Hard gelatin capsules are filled with the mixture, and each capsule contains a unit dose or part of a unit dose of the active compound. b) .- Tablets Tablets are prepared from the following ingredients: Parts by weight. Active compound 10 - ~ ** ** ** ** fe * - Lactose 190 Corn starch 22 Polyvinylpyrrolidone 10 Magnesium stearate 3 The active compound, lactose and some of the starch are disaggregated, mixed and the resulting mixture is granulated with a solution of the polyvinylpyrrolidone in ethanol The dry granulate is mixed with the magnesium stearate and the rest of the starch, then the mixture is compressed in a forming machine. 10 tablets to give tablets, each of which contains a unit dose, or a part of a unit dose of the active compound. c) Enteric coated tablets Tablets are prepared by the method described in (b) above. Enteric-coated tablets are coated in a conventional manner, using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethano-dichloromethane (1: 1). d) .- Suppositories 20 In the preparation of suppositories 100 parts by weight of active compound are incorporated in 1300 parts by weight of a suppository base formed by triglyceride and the mixture is formed into suppositories, each of which contains a therapeutically amount effective of the active ingredient. 25 É & iÉÉTÉ & üüb

Claims

1. - A method for treating obesity and related conditions, characterized in that it comprises the administration of • a therapeutically effective amount of a compound of formula I: including its pharmaceutically acceptable salts, solvates, racemates, enantiomers, diestereoisomers, and mixtures thereof; wherein: Ri represents H or one of the following groups (optionally substituted with one or more of halogen, cyano, hydroxy or amino): • alkyl of 1 to 6 carbon atoms, alkoxyl of 1 to 6 carbon atoms or alkanoyl of 1 to 6 carbon atoms; R2 and R3, independently, represent H or one of the following groups (optionally substituted with one or more of halogen, cyano, hydroxy or amino): alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl from 1 to 6 carbon atoms, alkylthio from 1 to 6 carbon atoms, alkylsulfinyl from 1 to 6 carbon atoms "ÜWtaifiiMM MMü carbon in the alkyl, alkylsulfonyl of 1 to 6 carbon atoms in the alkyl or hydroxy; R4 and R5, independently, represent H, alkyl of 1 to 6 carbon atoms, or R4 and R5, combined with the carbon atom to which they are attached, represent cycloalkylidene of 3 to 6 carbon atoms (each alkyl or cycloalkylidene is optionally substituted with one or more of: halogen, cyano, hydroxy, amino or alkyl of 1 to 6 carbon atoms); and Rβ, R7 and Rs, independently, represent H, halogen, hydroxy, Mercapto, nitro, cyano or one of the following groups (optionally substituted with one or more of: halogen, cyano, hydroxy or amino, and any nitrogen atom is optionally substituted with one or more of alkyl of 1 to 6 carbon atoms ): alkyl of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkoxy of 15 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms in the alkoxy, carboxy, alkanoyloxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyl from 1 to 6 carbon atoms, • Alkylsulfonylamino of 1 to 6 carbon atoms in the alkyl, Sulphamoyl, carbamoyl, alkylcarbamoyl of 2 to 6 carbon atoms in the alkyl or alkanoylamino of 1 to 6 carbon atoms; to a mammal that needs it.

2. The use of a compound of the formula I according to claim 1, in the manufacture of the 25 medicine for the prevention or treatment of obesity, or MMtfÜM ^^ HI of related conditions.

3. A pharmaceutical composition for the treatment and / or prevention of obesity and related conditions, characterized in that it comprises an effective therapeutically effective amount of a compound of the formula I, as described in claim 1, together with a pharmaceutically acceptable diluent or carrier.

4. A method according to claim 1, a use according to claim 2 or a composition according to claim 3, further characterized in that the compound is selected from: • 7- [1- (4-fluorophenoxy) ) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine , 7- [1- (4-bromophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 15 7- [1- (4-cyanophenoxy) ethyl] -1,2,4- triazolo [1,5-a] pyrimidine, 7- [1- (4-trifluoromethylphenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (4-methoxyphenoxy) ethyl] ] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (4-trifluoromethoxyphenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, • 7- [1- (4-acetylphenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7-. { 1- [4- (methylthio) phenoxy] ethyl} -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (4-methylsulfinylphenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (4-methylsulfonylphenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7-. { 1- [4- (ethylthio) phenoxy] ethyl} -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (3-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 25 7- [ 1- (2,4-difluorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, ^ G ^ ^ | ^ 7- [1 - (2,4-di chlorofenoxi) ethyl] -1, 2,4-triazolo [1,5-a] pyrimidine, 7- [1- (3,4- dichlorophenoxy) ethyl] -1, 2,4-triazolo [1,5-a] pyrimidine, 7- [1- (2-chloro-4-fluorophenoxy) ethyl] -1, 2,4-triazolo [1,5- a] pyrimidine, 7- [1- (4-chlorophenoxy) ethyl] -2-methyl-1,2,4-triazolo [1,5-a] pyrimidine, • 5-7- (4-chlorophenoxymethyl) -1,2 , 4-triazolo [1,5-a] pyrimidine, 7- [1- (4-chlorophenoxy) -1-methylethyl] -1,2,4-triazolo [1,5-a] pyrimidine, 7- [1- (4-chlorophenoxy) propyl] -1,2,4-triazolo [1,5-a] pyrimidine, and 7- [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5- a] pyrimidin-5-ol.

5. A method according to claim 1, a Use according to claim 2 or a composition according to claim 3, further characterized in that • the compound is selected from: (+) - 7 - [1- (4-fluorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, and (-) - 7- [1- (4-fluorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine; 15 (+) - 7 - [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine, (-) - 7- [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidine; (+) -7- [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidin-5-ol, and (-) - 7- [1- (4- chlorophenoxy) ethyl] -1,2,4-triazolo [1,5-a] pyrimidin-5-ol.

6. A method according to claim 1, a Use according to claim 2 or a composition according to claim 3, further characterized in that the compound is selected from d: 7- [1- (4-chlorophenoxy) ethyl] -1, 2,4-triazolo [1, 5-a] pyrimidine and 7- [1- (4-chlorophenoxy) ethyl] -1,2,4-triazolo [1,5- a] pyrimidin-5-ol, including their racemates, their enantiomers and their 25 mixtures, and their pharmaceutically acceptable salts.

7. - A method according to claim 1, a use according to claim 2 or a composition according to claim 3, further characterized in that the compound is selected from (R) -7- [1 - (4-chlorophenoxy) ethyl] -1, 2,4- • triazolo [1, 5-a] pyrimidine and its pharmaceutically acceptable salts.

8. A method according to any of claims 1, 4, 5, 6, or 7, further characterized in that the related condition is selected from eating disorders such as bulimia, anorexia, ingestion of snacks and 10 snacks, diabetes mellitus not dependent on insulin, hyperglycemia, hyperlipidemia and tension. • SUMMARY A method for treating obesity and related conditions is described, which comprises the administration of a therapeutically effective amount of a compound of the formula (II) including pharmaceutically acceptable salts, solvates, racemates, enantiomers, diastereoisomers and mixtures thereof, wherein : R ^ represents H or one of the following groups (optionally substituted with one or more of halogen, cyano, hydroxy or amino); alkyl of 1 to 5 carbon atoms, alkoxy of 1 to 6 carbon atoms or alkanoyl of 1 to 6 carbon atoms; R3 and R5 independently represent H or one of the following groups (optionally substituted with one or more of halogen, cyano, hydroxy or amino); alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms or hydroxy; R and R5 independently represent H, alkyl of 1 to 6 carbon atoms or R4 and R5 combined together with the carbon atom to which they are attached represent cycloalkylidene of 1 to 6 carbon atoms (each alkyl or cycloalkylidene being optionally substituted with one or more of halogen, cyano, hydroxy, amino or alkyl of 1 to 6 carbon atoms); and R6, R7 and Rs independently represent H, halogen, hydroxy, mercapto, nitro, cyano or one of the following groups (optionally - - ** »> - * • * '- • HHlMliÉÍMIhá? It is substituted with one or more of halogen, cyano, hydroxy or amino; and any nitrogen atom being optionally substituted with one or more of alkyl of 1 to 6 carbon atoms); alkyl of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms, carboxy, alkanoyloxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, sulfamoyl, carbamoyl, alkylcarbamoyl of 2 to 6 carbon atoms or alkanoylamino of 1 to 6 carbon atoms; for a mammal with the need for it. MhilferiMlkaAriUaiMI ^ H ^^ IMiMWH--