MXPA98002097A - Beta3 selecti adrenergic agonists - Google Patents

Abstract

The present invention relates to: are in the field of medicine, particularly in the treatment of Type II diabetes and obesity. More specifically, the present invention relates to selective receptor agonists 3 in the treatment of Type II diabetes and obesity. The invention provides compounds and method for treating diabetes that requires the same compound of the formula

Description

BETA-SELECTIVE ADRENERGIC AGONISTS FIELD OF THE INVENTION The present invention is in the field of medicine, particularly in the treatment of Type II diabetes and obesity. More specifically, the present invention relates to selective β3 adrenergic receptor agonists useful in the treatment of Type II diabetes and obesity.

BACKGROUND OF THE INVENTION The current preferred treatment for Type II non-insulin-dependent diabetes as well as obesity is diet and exercise, with reduced sight weight and improved insulin sensitivity. However, according to the patient, it is usually poor. The problem is complicated by the fact that there are currently no approved drugs that adequately treat any type II diabetes or obesity. The invention described herein is directed towards an effective and timely treatment for these serious diseases.

REF: 26996 A therapeutic opportunity that has recently been recognized involves the relationship between the stimulation of the adrenergic receptor and anti-hyperglycemic effects. Compounds that act as β3 receptor agonists have been shown to exhibit a marked effect on serum lipolysis, thermogenesis and glycoside levels in animal models of Type II diabetes (non-insulin dependent). The ß3 receptor, which is found in various types of human tissue including human fat tissue, has approximately 50% homology for the ßi and ß2 receptor subtypes, it is still considerably less abundant. The importance of the ß3 receptor is a relatively recent discovery since the amino acid sequence of the human receptor was only cleared in the late 1980s. A large number of publications have appeared in recent years reporting events in the discovery of agents that stimulate the ß3 receptor . Despite these recent developments, there remains a need to develop a selective β3 receptor agonist which has minimal agonist activity against the ßi and ß2 receptors.

The present invention provides compounds which are selective β3 receptor agonists. As such, the compounds effectively lead to an increase in insulin sensitivity and are useful for treating Type II diabetes and other diseases involved with the β3 receptor, without cardiac or tremor-related side effects.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides compounds of the formula I: wherein: Ri is OH, halo, S02NHR2, C02R2, CONHR2, NHCOR2, -NH (optionally substituted aryl), CF3, or CF2H; Ri 'is H, halo, C alquilo ~C alkyl, OH, S02NHR2, C02R2, CONHR2, NHCOR2, CF3 or CF2H; R2 is H, C? -C4 alkyl, or aryl; R3 is H or C? -C4 alkyl; R is a portion selected from the group consisting of: R5 and R6 are independently Ci-C alkyl; R7 is an optionally substituted heterocycle or a group selected from the group consisting of: is independently H, halo or C 1 -C 4 alkyl R 9 is halo, CN, OR 0, C 4 C 4 alkyl, C 1 -C 4 haloalkyl, C 0 2 R 2, CONRuRi 2, CONH (C 1 -C alkyl or alkoxy of C? -C4), SR2, CSNR2, CSNRnR12, S02R2, S02NRuR12, SOR2, R11R12, aryl, heterocycle, optionally substituted aryl, optionally substituted heterocycle, or C? -C4 alkyl or C2-C alkenyl optionally substituted with CN; Rio is independently C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 8 cycloalkyl, (CH 2) naryl, (CH 2) n-heterocycle, (CH 2) n C 3 -C 7 optionally substituted cycloalkyl, (CH 2) ) n optionally substituted aryl, or (CH2) n optionally substituted heterocycle; R11 and R12 are independently H, C? -C4 alkyl, or combine with the nitrogen to which each is attached to form morpholinyl, piperidinyl, pyrrolidinyl or piperazinyl; Xi is O or S; X2 is absent or a linear or branched alkylene of 1 to 5 carbons; m is 0 or 1; n is 0, 1, 2 or 3; or is 1, 2, 3, 4, 5 or 6; or a pharmaceutically acceptable salt or solvate thereof. The present invention also provides a novel process for making compounds of Formula I.

The compounds of the present invention are selective β3 receptor agonists and as such are useful for treating Type II diabetes and obesity, as well as being useful for stimulating the β3 receptor. Therefore, the present invention also provides methods of treating Type II diabetes and obesity, as well as a method of stimulating the β3 receptor. In addition, the present invention provides the use of compounds of Formula I for treating Type II diabetes and obesity, as well as the use of compounds of Formula I to stimulate the β3 receptor.

DETAILED DESCRIPTION For the purposes of the present invention, as described and claimed herein, the following terms are defined in the following. As they relate to the present invention, the terms in the following can not be interpreted, individually or collectively, to describe chemical structures that are unstable or impossible to construct.

The term "halo" represents fluorine, chlorine, bromine or iodine. The term "C 1 -C 4 alkyl" represents a straight or branched chain alkyl group having from one to four carbon atoms such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec- butyl, t-butyl and the like. A "haloalkyl" is one such as alkyl substituted with one or more haloatoms, preferably one to three haloatoms. An example of a haloalkyl is trifluoromethyl. An "alkoxy" is an alkyl group covalently linked by a -0- bond. The term "linear or branched alkylene of 1 to 5 carbons" represents a linear or branched alkylene portion of one to five carbons. A branched alkylene may have one or more branching points. A linear or branched alkylene of 1 to 5 carbons may optionally be unsaturated at one or more carbons. Thus, a linear or branched alkylene of 1 to 5 carbons includes portions of alkylene, alkenylene and alkylidene of 1 to 5 carbons. Examples include methylene, ethylene, propylene, butylene, -CH (CH3) CH2-, CH (C2H5) CH2-, -CH (CH3) CH (CH3-, -CH2C (CH3) 2", -CH2CH (CH3) CH2 -, -C (CH3) 2CH =, -CH = CHCH2-, -CH = CH-, and the like.

The "acyl" portion, alone or in combination, is derived from an alkanoic acid containing from one to seven carbon atoms. The term "acyl" also includes portions derived from an arylcarboxylic acid. The term "aryl" represents an optionally substituted or unsubstituted phenyl or naphthyl. The term (CH2) naril is preferably benzyl or phenyl. The term "optionally substituted" as used herein means an optional substitution of one to three, preferably one to two groups independently selected from halo, C? -C haloalkyl, hydroxy, carboxy, tetrazolyl, acyl, COOR2, CONR11R12, CONH (C? -C4 alkoxy), cyano, C? -C alkoxy, C? -C4 alkyl, phenyl, benzyl, nitro, NRnR12, NHCO (C? -C4 alkyl), NHCO (benzyl) , NHCO (phenyl), SR2, S (C-C4 alkyl), OCO (C? -C alkyl), S02 (NR11R12), S02 (C? -C4 alkyl), or S02 (phenyl); with the proviso that such substitution does not totally destroy the biological activity, as defined in this specification. R11 and R12 are independently H, C-C4 alkyl, or combined with the nitrogen to which each is attached to form morpholinyl, piperidinyl, pyrrolidinyl or piperazinyl. The term "heterocycle" means a 5 or 6 membered saturated or unsaturated ring, optionally substituted or unsubstituted, stable, the ring having from one to four heteroatoms which are the same or different and which are selected from the group consisting of sulfur , oxygen and nitrogen; and when the heterocycle contains two adjacent carbon atoms, the adjacent carbon atoms can be structured to form a group of the formula -CH = CH-; with the condition of (1) when the heterocyclic ring contains 5 members, the heteroatoms comprise no more than two sulfur or two oxygen atoms, but not both; and (2) when the heterocyclic ring contains 6 members and is aromatic, sulfur and oxygen are not present. The heterocycle may be attached to any carbon or nitrogen which produces a stable structure. The heterocycle may be optionally substituted. Examples of a heterocycle include pyrazole, pyrazoline, imidazole, isoxazole, triazole, tetrazole, oxazole, 1,3-dioxolone, thiazole, oxadiazole, thiadiazole, pyridine, pyrimidine, piperazine, morpholine, pyrazine, pyrrolidine, piperidine, oxazolidone, oxazolidinedione, imidazolidinone. . The term "leaving group" as used in the specification is understood by those skilled in the art. Generally, a leaving group is any group or atom that increases the electrophilicity of the atom to which it is attached for displacement. Preferred leaving groups are p-nitrobenzene sulfonate, triflate, mesylate, tosylate, imidate, chloride, bromide and iodide. The term "pharmaceutically effective amount", as used herein, represents an amount of a compound of the invention that is capable of stimulating the β3 receptor in mammals. The particular dose of the compound administered according to this invention will, of course, be determined by the particular circumstances surrounding the patient, including the compound administered, the route of administration, the particular condition being treated and similar considerations. The term "dosage unit form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined amount of the active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier . The term "treat", as used herein, describes the administration and care of a patient for the purposes of combating the disease, condition or disorder and includes the administration of a compound of the present invention to prevent the onset of symptoms. or complications, to relieve symptoms or complications, or to eliminate the disease, condition or disorder. The term "selective" means preferential agonism of the β3 receptor on the ßi or β2 receptor agonism. In general, the compounds of the present invention demonstrate at a minimum a doubled differential of twenty (preferably over a 50x differential) at the dose required to behave as a β3 receptor agonist and the dose required for the equal agonism of the βi and ß2 as measured in the Functional Agonist Assay. The compounds demonstrate this differential across the dose range. Thus, selective β3 compounds behave as agonists for the β3 receptor at many reduced concentrations with low toxicity by virtue of their minimal agonism of the other receptors. As previously noted, the present invention provides compounds of Formula I. Preferred compounds are those of Formula la: (la) where is F, OH, -S02NR2, -NHCOR2, or CF2H; R7 is Re is independently H, halo or C 1 -C 4 alkyl; R9 is OR10, tetrazolyl, CONRnR12, or S02NRnR? 2; Rio is (CH2) naril, (CH2) nheterocycle, the aryl or heterocycle is optionally substituted with tetrazolyl, CN, C02R2, CONR11R12, or S02NRnR? 2; R11 and R12 are independently H, C? -C alkyl, or combined with the nitrogen to which each is attached to form morpholinyl, piperidinyl, pyrrolidinyl or piperazinyl; X is alkylene of 1 to 2 carbons; n is 0, 1, 2 or 3; or a pharmaceutically acceptable salt. Other preferred compounds are those of Formula Ib: wherein: Ri is F, -S02NR2, -NHCOR2, or CF2H; R7 is an optionally substituted heterocycle or Rβ is independently H, halo or Cx-C4 alkyl; R9 is OR10, CONR11R12, or S02NR? R? 2; Rio is independently (CH2) narile, (CH2) n-heterocycle, the aryl or heterocycle are optionally substituted with tetrazolyl, CN, CO2R2 / CONR11R12, or SO2NR11R12; R11 and R12 are independently H, C? -C alkyl, or combined with the nitrogen to which each is attached to form morpholinyl, piperidinyl, pyrrolidinyl or piperazinyl; Xi is 0 or S; n is 0, 1, 2 or 3; or is 1, 2, 3, 4, 5 or 6; or a pharmaceutically acceptable salt or solvate thereof. Additional preferred compounds are those of the Formula le: de) wherein: Ri is F, -SO2NR2, -NHCOR2, or CF2H; R9 is OR10, CONR11R12, SO2NR11R12, SOR2, NR11R12, optionally substituted aryl, optionally substituted aryloxy or optionally substituted heterocycle; Rio is (CH) naril, (CH2) nheterocycle, the aryl or heterocycle is optionally substituted with tetrazolyl, CONRnR? 2, or S02NR? R? 2; Rii and R12 are independently H, C? -C4 alkyl, or combined with the nitrogen to which each is attached to form morpholinyl, piperidinyl, pyrrolidinyl or piperazinyl; Xi is 0 or S; m is 0 or 1; n is 0, 1, 2 or 3; or a pharmaceutically acceptable salt or solvate thereof. Particularly preferred compounds are those of Formula la, Ib or le, wherein R9 is CONH2 and OR10, wherein Rio is an optionally substituted aryl, particularly phenyl or optionally substituted heterocycle, particularly pyridine. Additional preferred compounds include the following: (All isomers of :) 5-. { 3- [2-hydroxy-3- (2-fluorophenyloxy) -prop i lami] -2-met ilbutyl} -thiophene-2-sulfonamide (All isomers of :) 5- (2-fluoro-4 -. {3- [2-hydroxy-3- (2-fluorophenyloxy) -2-methylbutyl} - phenyl) - lH-tetrazole (All isomers of :) 4-. { 3- [2-hydroxy-3- (3-hydroxy-phenyloxy) -propylamino] -2-methylbutyl} -benzamide (All isomers of :) 4-. { 3- [2-hydroxy-3- (2-fluorophenyloxy) -propylamino] -2-methylbutyl} -methylbenzamide (All isomers of :) 4-. { 3- [2-hydroxy-3- (3-acetylaminophenyloxy) -propylamino] -2-methylbutyl} -benzamide By virtue of their acidic portions, some of the compounds of Formula I include the pharmaceutically acceptable base addition salts of the mimes. Such salts include those derived from inorganic bases such as ammonium and alkali metal and alkaline earth metal hydroxides, carbonates, bicarbonates and the like, as well as salts derived from basic organic amines such as aliphatic and aromatic amines, aliphatic diamines, hydroxyalkamines and the like. Such bases useful in the preparation of the salts of this invention, thus include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methylamine, diethylamine, ethylenediamine, cyclohexylamine, ethanolamine, and the like.

Due to the basic portion, some of the compounds of Formula I may also exist as pharmaceutically acceptable acid addition salts. Acids commonly employed to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acids, as well as organic acids such as paratoluenesulfonic acid, methanesulfonic, oxalic, parabromophenylsulfonic, carbonic, succinic, citric, benzoic, acetic, and related inorganic and organic acids. Such pharmaceutically acceptable salts, thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, mono-phosphate acid, acid diphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate , isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, 2-butyn-l, 4-dioate, 3-hexin-2, 5-dioate, benzoate, chloro-benzoate, hydroxybenzoate, methoxybenzoate , phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hippurate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propansulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like salts. It is recognized that various stereoisomal forms of the compounds of Formulas I may exist. The compounds can be prepared as racemates and can conveniently be used as such. Therefore, racemates, individual enantiomers, diastereomers or mixtures thereof form part of the present invention. Unless otherwise specified, when a compound is described or referred to in this specification, all racemates, individual enantiomers, diastereomers or mixtures thereof are included in the reference or description. The compounds of Formula I are prepared as described in the following Schemes and Examples.

In Scheme I, Rlf Ri 'and R4 have the same meaning as previously described. The reaction of Scheme I is carried out under conditions appreciated in the art for the amination of epoxides. For example, the epoxide (II) can be combined with the amine (III) in an alcohol, preferably ethanol at room temperature for the reflux temperature of the reaction mixture. Preferably, the reaction is carried out under conditions generally described in At ins et al., Tetrahedron Lett. 2 ^: 2451 (1986). These conditions are included by mixing the reactants in the presence of trimethylsilylacetamide in a polar aprotic solvent such as acetonitrile, dimethylformamide (DMF), acetone, dimethyl sulfoxide (DMSO), dioxane, diethylene glycol ether (diglyme), tetrahydrofuran (THF), or other polar aprotic solvents in which the reactants are soluble. Preferably, the solvent is DMSO. The reaction is carried out at a temperature in the range of about 0 ° C to reflux. The compounds of the present invention can be prepared by a novel combinatorial / parallel synthesis. This synthesis is described in Scheme II.

Formula I (IV) (V) In Scheme II, Ri, Ri ', R2, and R have the same meaning as previously described. The reaction of Scheme II is preferably carried out by adding to a small glass flask: a non-reactive solvent such as methanol, DMF, methylene chloride or acetonitrile, amine (IV), and ketone (V). The solution is allowed to stir during imine formation and is treated with Amberlite IRA400 borohydride resin (Aldrich). The suspension is then stirred an additional 24 hours to effect reduction to the secondary amine. Methylene chloride and benzaldehyde resin bonded with polystyrene (Frechet, JM et al., J. Am Chem. Soc. 9_3: 492 (1971) is added to the small bottle to purify the excess of the initial primary amine material. stirring, preferably overnight The suspension is then filtered through a cotton plug, and the residual solids are rinsed with methanol.The evaporation under a flow of air, followed by drying for several hours at room temperature in an oven vacuum, producing the desired product of sufficient purity A modification of Scheme II is necessary when the amine hydrochloride salt is used.The addition of combined resin base or purification allows the desired reaction to proceed.Imine formation using hydrochloride salts of amine, an aldehyde or ketone, and a combined resin amine base can be carried out using two different resins: poly (4-vinylpyridine), commercially available e Aldrich, and resin (VIII), synthesized by the reaction of Merrifield resin with piperidine (Scheme lia): In Scheme lia, PS is polystyrene. Both of the poly (4-vinylpyridine) and the resin (VIII) promote the formation of imine. Scheme II can also be carried out by the use of traditional techniques. The reductive aminations described in Scheme II are well known in the art. Typically they are made by mixing the starting materials of amine and ketone in a solvent and adding a reducing agent. Solvents typically include lower alcohols, DMF, and the like. A wide variety of reducing agents can be used, most commonly sodium borohydride and sodium cyanoborohydride. The reaction is typically carried out from room temperature to the reflux temperature of the solvent. The products are isolated by techniques well known in the art. Any of the ketone and amino starting materials used in Scheme II can be prepared by techniques recognized and appreciated by one skilled in the art. The synthesis of the additional initial materials is generally described in Schemes III and IV.

It's < 3 - a? Na III (IX) (X) ^ HH (XI I) In Scheme III, Xi, Ri 'and Ri are the same as previously defined. Equimolar amounts of the aromatic compound (Compound IX) and (2S) - (+) - glycidyl 3-nitrobenzenesulfonate (Compound X) are dissolved in an inert solvent such as acetone and treated with 1.1 equivalents of a non-reactive acid scavenger , such as K2C03. The suspension is then heated to reflux for 16-20 hours with stirring. The solvent is removed in a vacuum. The residue is divided between chloroform and another organic solvent and water. The organic layer is dried over Na2SO4 and concentrated to give the epoxide (XI) in sufficient purity (>.95%) and performance (85-100%). The epoxide (XI) is dissolved in an alcohol, preferably methanol, and treated with an equivalent of dibenzylamine. The solution is preferably stirred at reflux for three to four hours and then cooled to room temperature. Approximately 10 equivalents of ammonium formate are added to the flask, followed by 10% palladium on carbon, and the suspension is stirred vigorously at reflux for 30-45 minutes. The reaction mixture is then filtered through Celite, concentrated to a minimum volume and treated with 1.1 equivalents of a 1.0 M anhydrous solution of HCl in ether. The solution is concentrated to dryness. The solid residue is triturated with pentane to produce products of sufficient purity (> 97%) and yield (60-100%). If desired, another purification can be carried out by passing over a short plug of silica, eluting with CHC13, then CHCl3 / MeOH 95: 5, then CHCl3 / MeOH / NH OH 25: 5: 1. Alternatively, the epoxide (XI) is treated with a solution of methanol saturated with ammonia gas and stirred at room temperature in a sealed tube for 16 hours. This solution is then evaporated, and the residue is subjected to standard purifications such as column chromatography or recrystallization. The HCl salt is then optionally produced by the addition of HCl gas in ether. The reaction of Scheme III is further described in U.S. Patent 5,012,761 to Beedle et al., And mentioned in the present reference. U.S. Patent 5,013,761 is incorporated herein by reference. Ketone portions used in Scheme II that are either unknown in the art or not commercially available are prepared in accordance with Scheme IV.

Ski IV (xi i i) (XIV) (XV) In Scheme IV, X2, R, R5, Re and R7 are the same as previously defined. Preferably, R 4 is a substituted phenyl. The reaction described in Scheme IV is referred to as a Heck reaction and is described in A.J. Chalk et al., J. Org. Chem. 41: 1206 (1976). The reaction is achieved by treating the compound (XIII) with an arylpalladium reagent. The arylpalladium reagent is generated in situ by treating Compound (XIV) with a palladium-triarylphosphine complex. The reaction is generally carried out under conditions appreciated in the art. Another embodiment of the present invention is a process for preparing a compound of Formula I which comprises: In stage I, it reacts an epoxide of the formula: with an amine of formula B: H2N R «: ni); and in step 2, reacting the product of step 1 to form an acid addition salt. The starting materials for the compounds described in Schemes I, II, III and IV are either commercially available, known in the art, or can be prepared by methods known in the art or described herein. The following examples and preparations are provided primarily to further illustrate the invention. The scope of the invention is not constructed as it consists primarily of the following examples. In the following examples and preparations, melting point, nuclear magnetic resonance spectrum, mass spectrum, high pressure liquid chromatography on silica gel, gas chromatography, N, N-dimethylformamide, palladium on carbon, tetrahydrofuran, ethyl acetate , thin layer chromatography and elemental analysis are abbreviated Pf NMR, MS, CLAP, GC, DMF, Pd / C, THF, EtOAc, CCF and AE respectively. The terms "AE" RMN1"EM" indicate that the data was consistent with the desired structure.

Preparation 1 (S) -3- (2-fluorophenyl) -1,2-epoxypropane A solution of 2-fluorophenol (865 mg, 7.72 moles) and (2S) - (+) - glycidyl-3-nitrobenzenesulfonate (2.0 g, 7.72 mmol) in 50 ml of acetone is treated with 1. 1 equivalent of K2CO3 (1.17 g, 8.5 mmol) and stir at reflux for 18 hours. The suspension is cooled to room temperature, the solids are filtered, and the filtrate is concentrated to dryness. The resulting solids are divided between chloroform and water, and the aqueous layer is extracted once with chloroform. The organic layers are combined and dried over Na 2 SO and concentrated in vacuo for a colorless oil which crystallizes slowly at 0 ° C for 1.11 g (86%) of white needles. TLC (Rf = 0.5, CHC13 and NMR indicates> 95% purity, so the material is used without further purification.

Preparation 2 (S) -3- (2-fluorophenyloxy) -2- hydroxypropylammonium chloride S-3- (2-fluorophenyl) -1,2-epoxypropane (1.08 g, 6.4 mmol) is dissolved in 50 ml of methanol and treated with dibenzylamine (1.23 ml, 6.4 mmol, d = 1026. The mixture is stirred at reflux for 3 hours and then cooled to room temperature A huge excess of ammonium formate (3.0 g, 47.6 mmol) followed by 10% palladium on carbon (350 mg) is added, and the suspension is stirred at reflux for 45 minutes After cooling the suspension, the reaction mixture is filtered through Celite and the filtrate is concentrated in vacuo to a colorless oil.The oil is redissolved in 10 ml of methanol and treated with an anhydrous 1.0 solution. M HCl in ether (7.0 mL, 7 mmol) and reduced in vacuo to dryness The residue is triturated in pentane and the solids are filtered to yield 1.4 g (99%) of a dry white powder.

Preparation 3 (S) -3- (2-fluorophenylthio) -2-hydroxypropyl sheet The (2S) - (+) - glycidyl-3-nitrobenzenesulfonate (3.0 g, 11.6 mmol) and potassium carbonate (1.8 g, 13 mmol) in acetone (50 ml) are separated with nitrogen for 5 minutes. 2-Fluorothiophenol (1.5 g, 11.6 mmol) is added and the mixture is stirred at room temperature under a blanket of nitrogen for 4 hours. The acetone is removed and the residue is partitioned between water / ethyl acetate. The organic layer is dried (MgSO) and concentrated to give 1.6 g (75%) of the epoxy intermediate as a colorless oil and used without further purification. The epoxy intermediate (1.2 g, 6.5 mmol) is dissolved in methanol (10 ml) and cooled to 0 ° C using an ice bath. The solution is saturated with ammonia gas and the reaction vessel is sealed and allowed to stir at room temperature for 16 hours. The reaction is opened at 0 ° C and the ammonia is allowed to evaporate before the mixture is concentrated. The residue is purified by flash chromatography on silica gel using 25: 5: 1 CHCl 3: MeOH: NH 4 OH to give 980 mg of a colorless oil (75%) which crystallizes rapidly under vacuum to give a white solid, m.p. 50-53 ° C. NMR EM. AE.

Preparation 4 4- [(2-oxocyclohexyl) methyl] benzonitrile A mixture of methyl cyclohexanone-2-carboxylate (11.0 g, 70 mmol, from Fluka), a-bromo-p-tolunitrile (12.3 g, 63 mmol), potassium carbonate (10.5 g, 76 mmol) in THF (200 ml) is refluxed for 24 hours. The progress of the reaction is followed by CG. The reaction is diluted with water and the THF is removed under reduced pressure. The aqueous portion was extracted with EtOAc, dried (MgSO) to give 19.3 g of a white solid which was 74% pure by gas chromatography. The solid was recrystallized from hexane / EtOAc to give 7.75 g of white crystals that were 100% pure per clg. A second growth of 3.65 g is obtained by adding more hexane to the filtrate. A total of 11.4 g (67%) of 1- [(4-cyanophenyl) methyl] -1-methoxy-carbonyl-2-oxocyclohexane carboxylate is obtained; p.f. 82-84 ° C. NMR EM. Under a blanket of nitrogen, a mixture of 1- [(4-cyanophenyl) methyl] -1-methoxy-carbonyl-2-oxocyclohexane carboxylate (7.6 g, 28 mmol), sodium cyanide (2.1 g, 42 mmol) and DMSO (100 ml) is heated at 115 ° C for 1.5 hours. The progress of the reaction is monitored by cgl. The reaction is cooled and partitioned between water, EtOAc and brine. The organic layer is washed with water and dried (MgSO4). After concentration, the unpurified product is obtained as a brown oil. Purification by means of a filtration cap (200 g of silica gel, 15% EtOAc / hexane) gave 3.3 g (55%) of the product as a colorless oil. NMR EM.

Preparation 5 4 - [(2-oxocyclohexyl) methyl] benzamide A solution of DMSO (20 ml) of the compound of Preparation 28 (2.5 g, 11.7 mmol) is cooled in an ice bath. Solid K2C03 (500 mg) is added followed immediately by 30% H202 (3 ml). After 20 minutes, the TLC (EtOAc / hexane 3/7) shows a trace of the remaining initial material. The ice bath is removed and the reaction is stirred at room temperature for 1 hour. The reaction is diluted with 500 ml of water and the white solid is collected and dried to give 2.44 g (90%) of the desired amide. The product is recrystallized from EtOAc / hexane 1/9 to give 2.02 g of the title product as white crystals, m.p. 167-170 ° C. NMR EM.

Preparation 6 2-tetralone-6-carboxylic acid ethylene ketal The 6-bromo-2-tetralone (2.0 g, 8.89 mmol) is dissolved in toluene (50 ml) and treated with excess ethylene glycol (4.88 ml, 88.9 mmol) and catalytic p-toluenesulfonic acid (15 mg). The solution is stirred at reflux for 16 hours, and the water is removed from the reaction mixture using a Dean-Stark condenser. After cooling to room temperature, the toluene solution is washed with 2 x NaOH IN, 1 x water, 1 x brine, dried over Na 2 SO 4 and concentrated in vacuo to give 2. 23 g (93%) of ethylene ketal of 6-bromo-2-tetralone as a brown oil which is used without further purification. Ethylene ketal of 6-bromo-2-tetralone (2.2 g, 8.15 mmol) is dissolved in anhydrous THF (30 ml), cooled to -78 ° C and treated with tert-butyl-lithium. (12.05 ml, 20.4 mmol, 1.7 M in pentane) under a nitrogen atmosphere. After stirring for 30 minutes, the anhydrous carbon dioxide gas is passed through the reaction mixture for 20 minutes at -78 ° C. The suspension is then allowed to warm to room temperature. The solution is maintained with water and acidified with IN HCl, then 2 x EtOAc is extracted. The organic extracts are washed with brine, dried over Na 2 SO and concentrated in a light brown oil. The oily residue is applied to a column of flash silica chromatography and eluted with 30% -50% EtOAc in hexanes to produce 2-tet ralon-6-carboxylic acid ethylene ketal 1.06 g (55%), a solid which is It crystallizes slowly. NMR E.

Preparation 7 2-Tetralon-6-carboxamide The ethylene ketal of 2-tet ralon-6-carboxylic acid (395 mg, 2.07 mmol) is co-dissolved in CH2C1 (50 ml) with N-hydroxysuccinimide (260 mg, 2.76 mmol) at 0 ° C and treated with a light of 1, 3-dicyclohexylcarbodiimide (502 mg, 2.50 mmol). The mixture is allowed to warm to room temperature for 30 minutes, during which time a fine white precipitate forms. Ammonium chloride (333 mg, 6.23 mmol) and triethylamine (1.58 ml, 12.5 mmol, d = 0.797) are added and the solution is stirred at room temperature for 16 hours. The urea is suspended and the salts are filtered out and the solution is concentrated in a colorless oil. The oil is applied to a column of flash silica chromatography and eluted with 50-100% EtOAc in hexanes to yield 250 mg (64%) of 2-tetralon-6-carboxamide ethylene ketal as a white solid, clean by NMR , CCF. The ethylene ketal of 2-tet ralon-6-carboxamide (250 mg, 1.07 mmol) and catalytic p-toluenesulfonic acid are stirred in acetone (50 ml) at room temperature for 48 hours. The volatile materials are removed and the residue is triturated in ethyl acetate. The solids are filtered, washed and dried to yield 77.5 mg (38%) of 2-Tet ralon-6-carboxamide as a white powder, pure by NMR, TLC. EM.

Preparation 8 2 -Tet ralón- 6-morfol inamida The 2-tetralon-6-carboxylic ethylene ketal (395 mg, 2.07 mmol) is co-dissolved in CH2CI2 (50 ml) with N-hydroxysuccinimide (260 mg, 2.76 mmol) at 0 ° C and treated with a light excess of 1, 3-dicyclohexyl-carbodiimide (502 mg, 2.50 mmol). The mixture is allowed to warm to room temperature for 30 minutes, during which time a fine white precipitate forms. Morpholine (0.91 ml, 10.4 mmol, d = 0.998) is added and the solution is stirred at room temperature for 16 hours. The urea is suspended, filtered off and the solution concentrated in vacuo for a colorless oil. The oil is applied to a silica flash chromatography column and eluted with 50-100% EtOAc in hexanes to yield 323 mg (51%) of 2-Tet ralon-6-morpholinamide ethylene ketal as a slowly crystallizing solid. , clean by NMR, CCF. The ethylene ketal of 2-Tet ralon-6-morpholinemide (323 mg, 1.06 mmol) and catalytic p-toluenesulfonic acid are stirred in acetone (50 ml) at room temperature for 48 hours. The CCF indicates an ethylene ketal mixture of 2 -tetralon-6-morpholineamide and the desired product, so the solution is heated to reflux for 16 hours. Volatile materials are removed in vacuo and the residue is applied to a silica flash chromatography column and eluted with 50-100% EtOAc in hexanes to yield 27 mg (10%) of 2-tetralon-6-morpholineamide, a solid that crystallizes slowly, pure by NMR, CCF. EM.

Preparation 9 5- [2-Fluoro-4- (2-met-il-3-oxobuti-1) -phenyl] -tetrazole The 4-bromo-2-fluorobenzonitrile (5.3 g, 26.5 mmol) and 3-methi 1-3-buten-2-ol (3.5 g, 40 mmol) are dissolved in N-met ilpyrrolidinone (30 ml) and treated with catalytic palladium diacetate (115 mg, 0.5 mmol), t ris- (o-tol il) -phosphine (300 mg, 1.0 mmol), and NaHCO 3 (2.7 g, 32 mmol). The mixture is stirred at 120 ° C for one hour. The solution is cooled to room temperature and partitioned between H20 / ethyl acetate, dried (MgSO) and concentrated in vacuo. The residue is applied to a column of silica chromatography and eluted with hexane / ethyl acetate 4: 1 to yield 2.3 g of a light yellow oil (43%). The oil (1.3 g, 6.3 mmol) is dissolved in DMF (30 ml) and treated with sodium azide (455 mg, 7 mmol) and ammonium chloride (375 mg, 7 mmol) and stirred at 90 ° C for 16 hours. The reaction mixture is concentrated in vacuo and partitioned between 3N NaOH / diethyl ether. The aqueous layer is acidified with concentrated HCl and cooled, and then extracted with diethyl ether, dried (MgSO 4), and concentrated in a light brown oil. The residue is applied to a column of silica chromatography and eluted with CHCl3 / MeOH / NH4OH 25: 5: 1 to yield 140 mg of a white solid (9%).

Preparation 10 5- (2-methyl-3-oxobutyl) -thiophen-2-sulfonamide The 5-bromot iofen-2-sulfonamide (5.2 g, 21.5 mmol) and 3-met il-3-buten-2-ol (2.8 g, 32.2 mmol) are dissolved in N-met ilpyrrolidinone (40 ml) and treated with catalytic palladium diacetate (96 mg, 0.43 mmol), tris- (o-tolyl) -phosphine (262 mg, 0.86 mmol) and NaHCO 3 (2.2 g, 25.8 mmol). The mixture is stirred at 160 ° C for 48 hours. The CCF indicated in the reaction was approximately completed at that time. The solution is cooled to room temperature and partitioned between H2? / Ethyl acetate, dried (MgSO.sub.4) and concentrated in a dark brown oil. The residue is applied to a column of silica chromatography and eluted with hexane / ethyl acetate 2: 3 to yield 220 mg of a light brown oil (4.1%).

Preparation 11 4- (2-met il-3-oxobutyl) benzamide CONHj The 4-bromobenzonitrile (9.1 g, 50 mmol) and 3-met il-3-buten-2-ol (6.5 g, 75 mmol) are dissolved in N-met i lpyrrolidinone (40 ml) and treated with palladium diacetate. catalytic (225 mg, 1.0 mmol), tris- (o-tolyl) -phosphine (610 mg, 2.0 mmol), and NaHCO3 (5.0 g, 60 mmol). The mixture is stirred at 120 ° C for three hours. The solution is cooled to room temperature and divided between H20 / ethyl acetate, it is dried (MgSO4) and concentrated in a vacuum. The residue is applied to a column of silica chromatography and eluted with hexane / ethyl acetate 3: 1 to yield 6.2 g of a light yellow oil (66%). The oil (4.6 g, 24.6 mmol) is dissolved in DMSO (20 ml) and treated with K2C03 (1.0 g) and H202 (6 ml, 30% w / w) and stirred at 0 ° C for 10 minutes. The reaction mixture is diluted with 500 ml of water and saturated with NaCl, and then extracted with ethyl acetate. The organic extracts are dried (MgSO 4), and concentrated in vacuo to a white solid. The solid is recrystallized from ethyl acetate / hexane 1: 1 to yield 3.22 g of a white solid (64%).

The following compounds are prepared in a manner analogous to the schemes and / or preparations described herein or by techniques appreciated in the art: Example 1 A 5x8 grid of small vials with a 4 ml screw cap is available. 33 μmol of ketone is added to each of the rows of small vials in the grid (of preparations 4-34, or commercially available), one ketone per row, as a stock solution in methanol (0.5M, 65 μl). If the solubility was a problem, acetonitrile / methanol or DMF is used. 50 μmoles is added to each column of small vials in the grid of amine hydrochloride, an amine hydrochloride (or amine) (from preparations 2, 3, 36-41 or commercially available) per column, as a stock solution in methanol (0.5M, 100 μl). Then resin VIII is added to each small bottle (18-20 mg), 1.01 meq / g, 70-90μeq of base). Teflon line caps are then placed in each small vial. The suspensions are then stirred for 24 hours, at which time each small vial is treated with approximately 30 mg (2.5 mmol of resin BH - / g, 75 μmol) of borohydride resin Amberlite IRA400 (Aldrich Chemical). The lids are placed, and the small bottles are shaken for an additional 24 hours, then 150 μl of methylene chloride and 40 mg (1 mmol / g of resin, 0.4 mmoles) benzaldehyde resin bound with polystyrene (Fechet, JM; Schuerch, CJ Am. Chem. Soc. 1971,! 9_3, 492.) to purify the excess of the initial material from the primary amine are added to the small bottles, and the suspension is stirred for 1 day. Each small bottle is then filtered through a cotton plug. The residual resin is washed with three small portions of methanol (approximately 200 μl). The resulting solutions are then treated with 20 μl of concentrated HCl (120 μmoles) to ensure the formation of the HCl salt of the amine product, then each small vial is diluted to a volume of about 4 ml, and 1 ml of each solution is transferred. to a small bottle with a tared screw cap of 4 ml. This solution is allowed to evaporate in a fume hood under a current of air until dry, then it is placed in an empty oven for 24 hours at room temperature. The resulting residues are then weighed and directly subjected to testing with no other purification. The volume of the material (75%) was evaporated in a similar way. The following matrices are listed in the additional examples 2-81. These compounds are prepared using combinatorial / parallel techniques according to the present invention. All the reaction conditions are the same from plate to plate and in substantial accordance with Scheme 2 and Example 1. The framework for each plate was the same and is represented in the upper corner of the 5x8 matrix. The variable functional groups are illustrated in the rows and columns. The ketones and amines represented on each plate are prepared according to the schemes and preparations described herein or by techniques known in the art.

As previously observed, the compounds of the present invention are selective, potent, β3-adrenergic receptor agonists. This pharmacologically activity is determined in the ß3 functional agonist assay. ß3 Functional Agonist Assay Cell Lines The hß2 DNA is expressed from a plasmid 57537 obtained from the American Type Culture Collection. The hßi and hß2 adrenergic receptors are cloned from human genomic libraries using the polymerase chain reaction method with degenerate probes. All long receivers are cloned, expressed and sequenced to verify identity according to published sequences (hßi- T. Frielle et al (1993) Molecular Pharmacology 44: 264-270). These receptors were then expressed in the DXB-11 variant of the CHO cells using a tetrahydrofolate reductase restoration and hygromycin resistance vector. The β3 receptor in the rat expressing the CHO cell line is known in the art. Mol. Pharm., Vol 40, pp. 895-99 (1991). CHO cells are cultured in 10% dialyzed FBS / DMEM high glucose / 0.1% proline.

CAMP assay Cell membranes from the previous cell line are harvested using 25 mM hypotonic hepes (pH 7.4), lmM EDTA, 20 μg / ml leupeptin, 1 mM PMSF buffer with scrap followed by differential centrifugation. Membranes are incubated in 25 mM Tris (pH 7.6), 0.2% BSA, 2.6 mM Mg, 0.8 mM ATP, 0.1 mM GTP, 5 mM creatine phosphate, 50 U / ml creatine kinase, 0.2 mM IBMX at 32 ° C. Agonists were added and the incubation is continued for 15 minutes. The produced cAMP was assayed using an immuno assay method with fluorescent indicator body. Intact cell assays were performed using suspended cells removed from the culture flasks by trypsin treatment. The cells were preincubated with 0.5 mM IBMX at 37 ° C. Agonists were added and the incubation is continued for 15 minutes. Incubation is stopped by heating the suspension in boiling water. The cAMP or cGMP in these and the single incubations were tested by RIA (Amersham). The compounds of the invention are β3 receptor agonists. Isoproterenol is accepted in the art as a selective β3 agonist and is widely used as a comparator in the evaluation of the activity of the compounds. See Trends in Pharm. Sci. 15: 3 (1994). In the ß3 Functional Agonist assay, the compounds showed at least 30%, preferably 50% and more preferably over 85% response of isoproterenols at a single dose of 50 μmol. The dose response titers in the described agonists reveal the CE5o values of < 10 μM, preferably < 1 mM. In the functional assay, the dose titration provides an EC50 for isoproterenol of 1.1 + 0.5 m. When shielding against the ßi and ß2 receptors in the functional assay, dose titration experiments indicate that stimulation of the receptor with the compounds of the invention is greatly reduced or not observed. This is defined by measuring the intrinsic activity (maximum response achieved) compared to isoproterenol. The claimed compounds of Formula I are selective β3 receptor agonists and have an intrinsic activity of < 3% response of isoproterenol. In this way, the compounds of the invention are selective β3 adrenergic receptor agonists. It has been shown that in order to play a role as β3 agonists, the compounds are useful under the conditions of treatment in a mammal. The preferred mammal of treatment is a human. The relationship between β3 receptor modulation and the treatment of diseases, such as Type II diabetes and obesity, as established in the technique. Other conditions recognized in the art include: asthma, depression and gastro-intestinal disorders such as gastrointestinal motility. In this way, the present compounds are useful in the treatment of inflammatory bowel disease (Crohn's disease or ulcerative colitis), bowel irritation syndrome, rapid emptying syndrome due to nonspecific diarrhea, asthma and depression. In the treatment of non-human mammals, the compounds of the present invention are useful for increasing weight gain and / or improving feed utilization efficiency and / or increasing non-fat body mass and / or decreasing the mortality rate in childbirth and increase the post / natal survival rate. The compounds of Formula I are preferably formulated before administration. Therefore, yet another embodiment of the present invention is a pharmaceutical formulation comprising a compound of Formula I and one or more pharmaceutically acceptable carriers, diluent or excipients. The present pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it can be a solid, semi-solid or liquid material, which acts as a vehicle, excipient or medium for the active ingredient. In this way, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, seals, elixirs, suspensions, emulsions, solutions, syrups, aerosol (as a solid or in a liquid medium), soft gelatin capsules and hard, suppositories, sterile injectable solutions and sterile packaged powders. Some examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, aqueous syrup, methylcellulose, methyl and propylhydroxybenzoates, talc, magnesium stearate and mineral oil. The formulations may additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preservatives, sweetening agents or flavoring agents. The compositions of the invention can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient. The compositions are preferably formulated in a dosage unit form, each dose containing from about 0.1 to about 500 mg, preferably from about 5 to about 200 mg, of the active ingredient. However, it will be understood that the therapeutic dose administered will be determined by the physician in light of the relevant circumstances including the condition to be treated, the choice of the compound to be administered and the chosen route of administration, and therefore, the ranges of prior doses do not attempt to limit the scope of the invention in any way. The compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, topical, intravenous, intramuscular, or intranasal. For all indications, a typical daily dose will contain from about 0.05 mg / kg to about 20 mg / kg of the active compound of this invention. Preferred daily doses will be from about 0.1 to about 10 mg / kg, ideally from about 0.1 to about 5 mg / kg. However, for topical administration, a typical dose is from about 1 to about 500 μg of the compound per cm 2 of an affected tissue. Preferably, the applied amount of the compound will be in the range of about 30 to about 300 μg / cm2, more preferably, about 50 to about 200 μg / cm2 and more preferably, about 60 to about 100 μg / cm2. The following formulation example is illustrative only and is not intended to limit the scope of the invention in any way.

Formulation 1 Hard gelatin capsules are prepared using the following ingredients: Amount (mg / capsule) 4- (3- [2-hydroxy-3- (3-hydroxyphenyloxy) -propylamino] -2-methyl-butyl ester} benzamide starch, dry 425 magnesium stearate 10 Total 460 mg The above ingredients are mixed and filled in Hard gelatine capsules in amounts of 460 mg The preferred, main and modes of operation of the present invention have been described in the above specification The invention which is intended to be protected herein, however, is not for be constructed as limiting for the particular forms described, as they are to be considered as sufficiently illustrative as restrictive Variations and changes may be made by those skilled in the art without departing from the spirit of the invention.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (10)

1. A compound of the Formula (I) characterized in that: Ri is OH, halo, S02NHR2, C02R2, CONHR2, NHCOR2, -NH (optionally substituted aryl), CF3, or CF2H; Ri 'is H, halo, C? -C4 alkyl, OH, S02NHR2, C02R, CONHR2, NHCOR2, CF3 or CF2H; R2 is H, C1-C4 alkyl, or aryl; R3 is H or C? -C4 alkyl; R is a portion selected from the group consisting of: R. R6 are independently alkyl of C1-C4; R7 is an optionally substituted heterocycle or a group selected from the group consisting of: R? is independently H, halo or C? -C4 alkyl; R9 is halo, CN, ORio, C? -C4 alkyl, C? -C4 haloalkyl, C02R2, CONRnR? 2 CONH (C1-C4 alkyl or C1-C4 alkoxy), SR2, CSNR2, CSNRnR? 2, S02R2, SO2NR11R12, SOR2, R11R12 aryl, heterocycle, optionally substituted aryl, optionally substituted heterocycle, or C1-C4 alkyl or C2-C4 alkenyl optionally substituted with CN; Rio is independently C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 8 cycloalkyl, (CH 2) naryl, (CH 2) nheterocycle, (CH 2) n C 3 -C 7 cycloalkyl optionally substituted, (CH 2) n optionally substituted aryl, or (CH) n optionally substituted heterocycle; Rn and R12 are independently H, C1-C4 alkyl, or combine with the nitrogen to which each is attached to form morpholinyl, piperidinyl, pyrrolidinyl or piperazinyl; Xi is 0 or S; X2 is absent or a linear or branched alkylene of 1 to 5 carbons; m is 0 or 1; n is 0, 1, 2 or 3; or is 1, 2, 3, 4, 5 or 6; or a pharmaceutically acceptable salt or solvate thereof.

2. A compound according to claim 1, characterized in that Ri is halo, CF3, CONHR2, or NH (optionally substituted aryl); and R4 is

3. A compound according to claim 2, characterized in that R7 is 9 R9 is halo, CN, ORio, C02R2, CONRnR? 2, SR2, SO2R2 SO2NR11R12, SOR2, or NR11R12.

4. A compound according to claim 3, characterized in that R7 is

R9 is halo, CN, or ORio-5. A compound according to any of claims 1 to 4 for use as a pharmacist.

6. A compound according to any of claims 1 to 4 for use in the treatment of Type II diabetes.

7. A compound according to any of claims 1 to 4 for use in the treatment of obesity.

8. A compound according to any of claims 1 to 4 for use in the β3 receptor agonism.

9. A pharmaceutical formulation characterized in that it comprises as an active ingredient a compound according to any of claims 1 to 4, associated with one or more pharmaceutically acceptable carriers, excipients or diluents.

10. A process for preparing a compound of Formula I, characterized in that it comprises: in step 1, reacting an epoxide of the formula: with an amine of the formula (B) H2N R4 (III) and in step 2, reacting the product of step 1 to form an acid addition salt.