MXPA06011243A - Therapeutic agents - Google Patents
Therapeutic agentsInfo
- Publication number
- MXPA06011243A MXPA06011243A MXPA/A/2006/011243A MXPA06011243A MXPA06011243A MX PA06011243 A MXPA06011243 A MX PA06011243A MX PA06011243 A MXPA06011243 A MX PA06011243A MX PA06011243 A MXPA06011243 A MX PA06011243A
- Authority
- MX
- Mexico
- Prior art keywords
- carbon atoms
- group
- phenyl
- optionally substituted
- disorders
- Prior art date
Links
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Abstract
The present invention relates to compounds of formula (I) and processes for preparing such compounds, their use in the treatment of obesity, psychiatric and neurological disorders, to methods for their therapeutic use and to pharmaceutical compositions containing them.
Description
THERAPEUTIC AGE
Field of the Invention The present invention relates to certain 1,2-diaryl imidazole-4-carboxamide compounds of Formula I, to processes for the preparation of these compounds, to their use in the treatment of obesity, psychiatric disorders. or neurological, to methods for their therapeutic use, and to pharmaceutical compositions containing them. Background of the Invention It is known that certain modulators of CB | (known as antagonists or inverse agonists) are useful in the treatment of obesity and of psychiatric and neurological disorders (International Publication No. WO01 / 70700 and European Patent Number EP 656354). International Publications Numbers WO04 / 60367 and
WO2004 / 099130 disclose that certain diaryl imidazoles and triazoles are useful as COX-1 inhibitors, useful in the treatment of inflammation. The compounds exemplified in these applications are unknown in the claims of the present invention. The Patent Number DD 140966 discloses that certain anidates of imidazole carboxylic acid are useful as plant growth regulators. The compounds exemplified in this application are unknown in the claims of the present invention. International Publications Nos. WO03 / 007887 and WO03 / 075660 disclose certain 4,5-d -aryl-imidazole-2-carboxamides as modulators of C B |. International Publications Nos. WO03 / 27076 and WO03 / 63781 disclose certain 1,2-diaryl imidazole-4-carboxamides which are modulators of CB |. The compounds exemplified in these applications are unknown in the claims of the present invention. International Publication No. WO03 / 401 07 discloses certain 1,2-diaryl imidazole-4-carboxamides as useful in the treatment of obesity and obesity-related disorders. However, there is a need for CB modulators | with better physicochemical properties and / or properties of DM PK and / or pharmacodynamic properties. Description of the Invention The invention relates to a compound of Formula (I):
and pharmaceutically acceptable salts thereof, wherein: R1 represents: a) an alkoxy group of 1 to 6 carbon atoms optionally substituted by one or more fluoros, b) a group of the formula phenyl- (CH2) pO-, wherein p is 1, 2, or 3, and the phenyl ring is optionally substituted by 1, 2, or 3 groups represented by Z, c) ung rupo R5S (O) 2O or R5S (O) 2N H, wherein R5 represents an alkyl group of 1 to 10 carbon atoms optionally substituted by one or more fluoros, or R 5 represents phenyl or a heteroaryl group, each of which is optionally substituted by 1 2, or 3 groups represented by Z, or d) a group of the formula (R6) 3Si, wherein R6 represents an alkyl group of 1 to 6 carbon atoms, which may be the same or different; Ra represents halogen, an alkyl group of 1 to 3 carbon atoms, or an alkoxy group of 1 to 3 carbon atoms; m is 0, 1, 2, or 3; R 2 represents an alkyl group of 1 to 3 carbon atoms, an alkoxyl group of 1 to 3 carbon atoms, hydroxyl, nitro, cyano, or halogen; n is 0, 1, 2, or 3; R3 represents: a) a group X-Y-N R7R8, wherein X is CO or SO2, Y is absent or represents N H optionally substituted by an alkyl group of 1 to 3 carbon atoms; and R7 and R8 independently represent: an alkyl group of 1 to 6 carbon atoms optionally substituted by 1, 2, or 3 groups represented by W; a cycloalkyl group of 3 to 15 carbon atoms optionally substituted by 1, 2, or 3 groups represented by W; a group (cycloalkyl of 3 to 15 carbon atoms) - alkylene of 1 to 3 carbon atoms optionally substituted by 1, 2, or 3 g groups represented by W; a g rupe - (C H2) r (phenyl) s, where r is 0, 1, 2, 3, or 4, s is 1 when r is 0, or otherwise s is 1 or 2, and groups phenyl are optionally independently substituted by 1, 2, or 3 groups represented by Z; a saturated 5- to 8-membered heterocyclic group containing a nitrogen atom, and optionally one of the following: oxygen, sulfur, or an additional nitrogen atom, wherein the heterocyclic group is optionally substituted by one or more alkyl groups of 1 to 3 carbon atoms, hydroxyl, or benzyl; a group - (CH2) Het, where t is 0, 1, 2, 3, or 4, and the alkylene chain is optionally substituted by one or more alkyl groups of 1 to 3 carbon atoms, and Het represents a group heteroaryl optionally substituted by 1, 2, or 3 groups selected from an alkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, or halogen, wherein the alkyl and alkoxy groups are optionally substituted independently by one or more fluoros; or R7 represents H, and R8 is as defined above; or R7 and R8, together with the nitrogen atom to which they are attached, represent a saturated or partially unsaturated 5- to 8-membered heterocyclic group containing a nitrogen atom and optionally one of the following: oxygen, sulfur, or an atom of additional nitrogen;
wherein the heterocyclic group is optionally substituted by one or more alkyl groups of 1 to 3 carbon, hydroxyl, fluorine, or benzyl atoms; or b) oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidezolyl, triazolyl, tetrazolyl, thienyl, fuleyl, or oxazolinyl, each optionally substituted by 1, 2, or 3 g Z moieties; R4 represents H, an alkyl group of 1 to 6 carbon atoms, an alkoxy group of 1 to 6 carbon atoms, or an alkoxy group of 1 to 6 carbon atoms-alkylene of 1 to 6 carbon atoms, which contains a maximum of 6 carbon atoms, each of which groups is optionally substituted by one or more of fluorine or cyano; Z represents an alkyl group of 1 to 3 carbon atoms, an alkoxy group of 1 to 3 carbon atoms, hydroxyl, halogen, trifluoromethyl, trifluorothiomethyl, difluoro-methoxy, trifluoromethoxy, trifluoromethylsulfonyl, nitro, amino, mono- or di-alkyl of 1 to 3 carbon atoms-amino, alkyl of 1 to 3 carbon atoms-sulfonyl, alkoxy of 1 to 3 carbon atoms -carbonyl, carboxyl, cyano, carbamoyl, mono- or di-alkyl of 1 to 3 carbon atoms-carbamoyl, and acetyl; and W represents hydroxyl, fluorine, an alkyl group of 1 to 3 carbon atoms, an alkoxy group of 1 to 3 carbon atoms, amino, mono- or di-alkyl of 1 to 3 carbon-amino atoms, or an amine heterocyclic selected from morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl, wherein the heterocyclic amine is optionally substituted by an alkyl group of 1 to 3 carbon atoms, or hydroxyl; with the proviso that, when n is 1, then R2 is not methoxy in either the 2-position or the 4-position of the phenyl ring, and with the additional proviso that R1 is not methyl-sulfonyl-amino, methoxy , or CF3O-. In a particular group of compounds of Formula (I):
and pharmaceutically acceptable salts thereof, wherein: R1 represents: a) an alkoxy group of 1 to 6 carbon atoms optionally substituted by one or more fluoros, b) a group of the formula phenyl- (CH2) pO-, where p is 1, 2, or 3, and the phenyl ring is optionally substituted by 1, 2, or 3 groups represented by Z, c) a group R 5 S (O) 2 O or R 5 S (O) 2 N H, wherein R 5 represents an alkyl group of 1 to 6 carbon atoms optionally substituted by one or more fluoros, or R5 represents phenyl or a heteroaryl group, each of which is optionally substituted by 1 2, or 3 groups represented by Z, or d) a group of the formula (R6) 3Si, wherein R6 represents an alkyl group of 1 to 6 carbon atoms, which may be the same or different;
Ra represents halogen, an alkyl group of 1 to 3 carbon atoms, or an alkoxy group of 1 to 3 carbon atoms; m is 0, 1, 2, or 3; R2 represents an alkyl group of 1 to 3 carbon atoms, an alkoxy group of 1 to 3 carbon atoms, hydroxyl, nitro, cyano, or halogen; n is 0, 1, 2, or 3; R3 represents: a) a group X-Y-NR7R8, wherein X is CO or SO2, Y is absent or represents NH optionally substituted by an alkyl group of 1 to 3 carbon atoms; and R7 and R8 independently represent: an alkyl group of 1 to 6 carbon atoms optionally substituted by 1, 2, or 3 groups represented by W; a cycloalkyl group of 3 to 15 carbon atoms optionally substituted by 1, 2, or 3 groups represented by W; a (cycloalkyl of 3 to 15 carbon atoms) -alkylene group of 1 to 3 carbon atoms optionally substituted by 1, 2, or 3 groups represented by W; a group - (CH2) r (phenyl) s, where r is 0, 1, 2, 3, or
4, s is 1 when r is 0, or otherwise s is 1 or 2, and the phenyl groups are optionally independently substituted by 1, 2, or 3 groups represented by Z; a saturated 5- to 8-membered heterocyclic group containing an atom or nitrogen, and optionally one of the following: oxygen, sulfur, or an additional nitrogen atom, wherein the heterocyclic group is optionally substituted by one or more alkyl groups of 1 to 3 carbon atoms, hydroxyl, or benzyl; a g rupe - (C H2) tHet, where t is 0, 1, 2, 3, or 4, and the alkylene chain is optionally substituted by one or more alkyl groups of 1 to 3 carbon atoms, and Het represents a heteroaryl group optionally substituted by 1, 2, or 3 groups selected from an alkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, or halogen; or R7 represents H, and R8 is as defined above; or R7 and R8, together with the nitrogen atom to which they are attached, represent a saturated or partially unsaturated 5- to 8-membered heterocyclic group containing a nitrogen atom and optionally one of the following: oxygen, sulfur, or an atom of additional nitrogen; wherein the heterocyclic group is optionally substituted by one or more alkyl groups of 1 to 3 carbon atoms, hydroxyl, fluorine, or benzyl; or b) oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl, or oxazolinyl, each optionally substituted by 1, 2, or 3 Z groups; R4 represents H, an alkyl group of 1 to 6 carbon atoms, an alkoxy group of 1 to 6 carbon atoms, or an alkoxy group of 1 to 6 carbon atoms-alkylene of 1 to 6 carbon atoms, which contains a maximum of 6 carbon atoms, each of which groups is optionally substituted by one or more of fluorine or cyano; Z represents an alkyl group of 1 to 3 carbon atoms, an alkoxy group of 1 to 3 carbon atoms, hydroxyl, halogen, trifluoromethyl, trifluorothiomethyl, difluoro-methoxy, trifluoromethoxy, trifluoromethylsulfonyl, nitro, amino, mono- or di-alkyl of 1 to 3 carbon atoms-amino, alkyl of 1 to 3 carbon atoms-sulfonyl, alkoxy of 1 to 3 carbon atoms -carbonyl, carboxyl, cyano, carbamoyl, mono- or di-alkyl of 1 to 3 carbon atoms-carbamoyl, and acetyl; and W represents hydroxyl, fluorine, an alkyl group of 1 to 3 carbon atoms, an alkoxy group of 1 to 3 carbon atoms, amino, mono- or di-alkyl of 1 to 3 carbon-amino atoms, or an amine heterocyclic selected from morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl, wherein the heterocyclic amine is optionally substituted by an alkyl group of 1 to 3 carbon atoms, or hydroxyl; with the proviso that, when n is 1, then R2 is not methoxy in either the 2-position or the 4-position of the phenyl ring, and with the additional proviso that R1 is not methyl-sulfonyl-amino, methoxy, or CF3O-.
In a particular group of compounds of Formula (I): and pharmaceutically acceptable salts thereof, R represents: a) an alkoxy group of 3 to 6 carbon atoms substituted by one or more fluoros, or b) a group of the phenyl- (CH2) pO- formula, wherein p is 1, 2, or 3, and the phenyl ring is optionally substituted by 1, 2, or 3 groups represented by Z, or c) a group R5S (O) 2O , wherein R5 represents an alkyl group of 1 to 6 carbon atoms optionally substituted by one or more fluoros, or R5 represents phenyl or a heteroaryl group, each of which. which is optionally substituted by 1, 2, or 3 groups represented by Z; Ra represents halogen, an alkyl group of 1 to 3 carbon atoms, or an alkoxy group of 1 to 3 carbon atoms; m is 0, 1, 2, or 3; R2 represents halogen; n is 0, 1, 2, or 3; R3 represents: a) a group X-Y-NR7R8, wherein X is CO; Y is absent or represents optionally substituted N H or an alkyl group of 1 to 3 carbon atoms;
and R7 and R8 independently represent: an alkyl group of 1 to 6 carbon atoms optionally substituted by 1, 2, or 3 groups represented by W; a cycloalkyl group of 3 to 15 carbon atoms optionally substituted by 1, 2, or 3 groups represented by W; a (cycloalkyl of 3 to 15 carbon atoms) - alkylene group of 1 to 3 carbon atoms optionally substituted by 1, 2, or 3 groups represented by W; a group - (CH2) r (phenyl) S1 where r is 0, 1, 2, 3, or 4, s is 1 when r is 0, and otherwise s is 1 or 2, and the phenyl groups are optionally independently substituted by 1, 2, or 3 groups represented by Z; a saturated 5- to 8-membered heterocyclic group containing a nitrogen atom, and optionally one of the following: oxygen, sulfur, or an additional nitrogen atom, wherein the heterocyclic group is optionally substituted by one or more alkyl groups from 1 to 3 carbon atoms, hydroxyl, or benzyl; a group - (CH2) tHet, where t is 0, 1, 2, 3, or 4, and the alkylene chain is optionally substituted by one or more alkyl groups of 1 to 3 carbon atoms, and. Het represents a heteroaryl group optionally substituted by 1, 2, or 3 groups selected from an alkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, or halogen; or R7 represents H, and R8 is as defined above; or R7 and R8, together with the nitrogen atom to which they are attached, represent a 5- to 8-membered saturated or partially unsaturated heterocyclic group containing one nitrogen atom and optionally one of the following: oxygen , sulfur, or an additional nitrogen atom or; wherein the heterocyclic group is optionally substituted by one or more alkyl groups of 1 to 3 carbon, hydroxyl, fluorine, or benzyl atoms; R4 represents H, an alkyl group of 1 to 6 carbon atoms, an alkoxy group of 1 to 6 carbon atoms, or an alkoxy group of 1 to 6 carbon atoms-alkylene of 1 to 6 carbon atoms, containing a maximum of 6 carbon atoms, each of which groups is optionally substituted by one or more of fluorine or cyano;
Z represents an alkyl group of 1 to 3 carbon atoms, an alkoxy group of 1 to 3 carbon atoms, hydroxyl, halogen, trifluoromethyl, trifluorothiomethyl, difluoro-methoxy, trifluoromethoxy, trifluoromethylsulfonyl, nitro, amino, mono- or di-alkyl of 1 to 3 carbon atoms-amino, alkyl of 1 to 3 carbon atoms-sulfonyl, alkoxy of 1 to 3 carbon atoms -carbonyl, carboxyl, cyano, carbamoyl, mono- or di-alkyl of 1 to 3 carbon atoms-carbamoyl, and acetyl; and W represents hydroxyl, fluorine, an alkyl group of 1 to 3 carbon atoms, an alkoxy group of 1 to 3 carbon atoms, amino, mono- or di-alkyl of 1 to 3 carbon-amino atoms, or an amine heterocyclic selected from morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl, wherein the heterocyclic amine is optionally substituted by an alkyl group of 1 to 3 carbon atoms, or hydroxyl. In a particular group of compounds of Formula I, R 1 represents-a group R 5 S (O) 2 O, wherein R 5 represents an alkyl group of 1 to 6 carbon atoms, in particular an alkyl group of 2 to 6 carbon atoms, each optionally substituted by one or more fluoros, and wherein R2, R3, R4, Ra, m, and n are as defined above. In a particular group of compounds of Formula I, R3 represents a group CON H N R7R8, wherein N R7R8 represents piperidino, and R1, R2, R4, Ra, m, and n are as defined above. It will be understood that, when a Z substituent is present in more than one group, or when more than one Z substituent is present in the same group, these substitutions are independently selected and may be the same or different. The same is true for W. In a similar way, when m is 2 or 3, then the Ra groups are independently selected, so that they can be the same or different, and in a similar way, when n is 2 or 3, then the groups R2 are independently selected, such that they may be the same or different. Similarly, when R5 and R7 and / or R8 contain a heteroaryl group, the heteroaryl groups and their optional substituents are independently selected, such that they may be the same or different.
The term "cycloalkyl of 3 to 15 carbon atoms" includes the monocyclic, bicyclic, tricyclic, and spiro systems, for example cyclopentyl, cyclohexyl, and adamantyl. The term "heteroaryl" means an aromatic monocyclic ring of 5, 6, or 7 members, or a 9 or 10 membered bicyclic ring, with up to 5 ring heteroatoms selected from oxygen, nitrogen, and sulfur. Suitable aromatic heteroaryl groups include, for example, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazoyl, ylthiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3 , 5-triazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidodazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinolinyl, or naphthyridinyl. Preferably, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or 1,3,5-triazinyl, and more preferably pyrrolyl, thienyl, imidazolyl, oxazolyl, or pyridyl. Suitable 5- to 8-membered heterocyclic groups saturated or partially unsaturated containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, include, for example, tetrahydrofuranyl, tetrahydropyranyl, 2,3-dihydro-1,3-thiazolyl , 1,3-thiazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-1,4-thiazinyl, 1-oxotetrahydrothienyl, 1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, d ihydropyridinyl , tetrahydropyridinyl, dihydro-pyrimidinyl, or tetrahydro-pyrimidinyl, preferably tetrahydrofuran, tetrahydro-pyranyl, pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl, more preferably tetrahydro-furan-3-yl, tetrahydro -piran-4-yl, pyrrolidin-3-yl, morpholino, piperidino, piperidin-4-yl, or piperazin-1-yl. Suitable g roups where R 1 represents a group R 5 S (O) 2-O, wherein R 5 represents an alkyl group of 1 to 6 carbon atoms optionally substituted by one or more fluoros, include methanesulfonyloxy, ethan sulphonyloxy, n-propylsulphonyloxy, n-butylsulphonyloxy, 3-methyl-butan-1-sulfonyloxy, 3,3-dimethyl-butan-1-sulphonyloxy, fluoro-methyl-sulphonyloxy, difluoromethylsulfonyloxy, trifluoro -methyl-sulfonyloxy, mono-, di-, or tri- (fluoroethyl) -sulfonyloxy, 3,3, 3-trifluoro-propyl-1-sulfonyloxy, or 4,4,4-trifluoro-butyl-1-sulfonyloxy. Suitable groups in which R 1 represents an alkoxy group of. 1 to 6 carbon atoms optionally substituted by one or more fluoros, include butoxyl, pentyloxy, hexyloxy, fluoro-methoxy, difluoro-methoxy, trifluoro-ethoxy, 4,4,4-trifluoro-butoxy, 5,5,5-trifluoro -pentyloxy, and 6,6,6-trifluoromyoxyloyl, The suitable groups wherein R 1 represents a group R 5 S (O) 2 O, wherein R 5 represents phenyl or a heteroaryl group, each of which is optionally substituted by 1, 2, or 3 groups represented by Z, include phenylsulfonyloxy, thienylsulfonyloxy, or pyridylsulfonyloxy, optionally substituted by 1, 2, or 3 groups represented by Z. A particular group of compounds of Formula I is represented by the Formula IA:
wherein R1 is: a) an alkoxy group of 3 to 6 carbon atoms substituted by one or more fluoros, b) a group of the formula phenyl- (CH2) pO-, where p is 1, 2, or 3, and the phenyl ring is optionally substituted by 1, 2, or 3 groups represented by Z, c) a group R5S (O) 2O, wherein R5 represents an alkyl group of 1 to 10 carbon atoms optionally substituted by one or more fluoros, or R5 represents thienyl or pyridyl, each of which is optionally substituted by one or more halogens; R2a represents H or chlorine; R2 represents H or chlorine; R3 represents a group CON H N R7R8, wherein N R7R8 represents piperidino, or R3 represents a group CON R7R8, wherein R7 is H, and R8 is pyridyl optionally substituted by halogen or trifluoromethyl; and R4 represents an alkyl group of 1 to 3 carbon atoms.
Now follow other values of R2a, R2b, R4, R5, R7, and R8 in the compounds of Formula I and Formula IA. It will be understood that these values may be used where appropriate with any of the definitions, claims, or modalities defined hereinabove or hereinbelow. In a particular manner, in the compounds of Formula IA described immediately above, R 1 represents a group R 5 S (O) 2 O, wherein R 5 represents an alkyl group of 2 to 7 carbon atoms optionally substituted by one or more fluorines. In particular, in the compounds of Formula IA described immediately above, R 1 represents a group R 5 S (O) 2 O, wherein R 5 represents 2-thienyl optionally substituted by chloro, or R 5 represents 3-pyridyl. Particularly in the compounds of Formula IA described immediately above, R2a represents chlorine, and R2b represents chlorine. In a particular manner, in the compounds of Formula IA described immediately above,. R3 represents a group CONH NR7R8, wherein N R7R8 represents piperidino. In particular in the compounds of Formula IA described immediately above, R3 represents a group CON R7R8, wherein R7 is H, and R8 is pyridyl optionally substituted by trifluoromethyl. Particularly in the compounds of Formula IA described immediately above, R 4 is methyl. An additional particular group of compounds of Formula I is represented by Formula IA:
wherein R is: a) an alkoxy group of 3 to 6 carbon atoms substituted by one or more fluoros, b) a group of the formula phenyl- (CH2) pO-, where p is 1, 2, or 3, and the phenyl ring is optionally substituted by 1, 2, or 3 groups represented by Z, c) a group R5S (O) 2 O, wherein R5 represents an alkyl group of 1 to 6 carbon atoms optionally substituted by one or more fluoros; R2a represents H or chlorine; R2 represents H or chlorine; R3 represents a group CON H N R7R8, wherein N R7R8 represents piperidino; and R4 represents an alkyl group of 1 to 3 carbon atoms. Now other values of R1 follow in the compounds of Formula I and Formula IA. . It will be understood that these values may be used where appropriate with any of the definitions, claims, or modalities defined hereinbefore or later herein. In a group of compounds of Formula I or Formula IA, R 1 is an alkoxy group of 3 to 6 carbon atoms substituted by one or more fluorines. In a second group of compounds of Formula I or Formula IA, R 1 is an alkoxy group of 4 to 6 carbon atoms optionally substituted by one or more fluoros. In a third group of compounds of Formula I or Formula IA, R 1 is an alkoxy group of 4 to 6 carbon atoms substituted by one or more fluoros. In a fourth group of compounds of Formula I or Formula IA, R1 is a group of phenyl (CH2) pO-, where p is 1, 2, or 3. In a fifth group of compounds of Formula I or of Formula IA, R1 is an RsS (O) 2O group, wherein R5 represents an alkyl group of 1 to 6 carbon atoms optionally substituted by one or more fluoros. In particular, R 1 is 4,4,4-trifluoro-butoxy, n-butylsulfonyloxy, n-propylsulphonyloxy, n-ethyl-sulfonyloxy, benzyloxy, 4,4,4-trifluoro-butyl-T-sulfonyloxy, or 3,3,3-trifluoro-propyl-1-sulfonyloxy. More particularly, R 1 is 4,4,4-trifluoro-butoxy, n-butylsulphonyloxy, n-propylsulphonyloxy, ethyl-sulphonyloxy, or benzyloxy. Another particular of compounds of Formula I is represented by Formula IA:
wherein R is: a) an alkoxy group of 3 to 6 carbon atoms substituted by one or more fluoros, or b) a group of the formula R5S (O) 2O, wherein R5 represents an alkyl group of 1 to 6 atoms carbon optionally substituted by one or more fluoros, or R5 represents phenyl or a heteroaryl group, each of which is optionally substituted by 1, 2, or 3 groups represented by Z; R2a represents chlorine; R2b represents chlorine; R3 represents a group CONHR7R8, wherein NR7R8 represents piperidino; and R4 represents an alkyl group of 1 to 3 carbon atoms. In a particular group of compounds of Formula IA, R 1 represents a group R 5 S (O) 2 O, wherein R 5 represents an alkyl group of 1 to 6 carbon atoms optionally substituted by one or more fluoros; R2a represents chlorine; R2b represents chlorine; R3 represents a group CONHNR7R8, wherein NR7R8 represents piperidino; and R4 represents an alkyl group of 1 to 3 carbon atoms. In a particular group of compounds of Formula IA, R 1 represents an alkoxy group of 4 to 6 carbon atoms optionally substituted by one or more fluoros; R2a represents chlorine; R2b represents chlorine; R3 represents a group CON H N R7R8, wherein N R7R8 represents piperid ino; Y . R4 represents an alkyl group of 1 to 3 carbon atoms. In a particular group of compounds of Formula IA, R 1 represents an alkoxy group of 4 to 6 carbon atoms substituted by one or more fluoros; R2a represents chlorine; R2b represents chlorine; R3 represents a group CONH N R7R8, wherein N R7R8 represents piperidino; and R4 represents an alkyl group of 1 to 3 carbon atoms. "Pharmaceutically acceptable salt", wherein these salts are possible, includes both the pharmaceutically acceptable acid addition and base addition salts. A suitable pharmaceutically acceptable salt of a compound of Formula I is, for example, an acid addition salt of a compound of Formula I which is sufficiently basic, for example an acid addition salt with an inorganic or organic acid. , such as hydrochloric, hydrobromic, sulfuric, trifluoroacetic, citric, or maleic acid; or, for example, a salt of a compound of Formula I which is sufficiently acidic, for example an alkali metal or alkaline earth metal salt, such as a sodium, calcium, or magnesium salt, or an ammonium salt, or a salt with an organic base, such as methyl amine, di-ethyl-amine, trimethyl-amine, piperidine, morpholine, or tris- (2-hydroxy-ethyl) -amine. Throughout the specification and the appended claims, a given chemical formula or name will encompass all stereoisomers and optical isomers and racemates thereof, as well as mixtures in different proportions of the separated enantiomers, wherein such isomers and enantiomers exist , as well as pharmaceutically acceptable salts thereof, and solvates thereof, such as, for example, hydrates. The isomers can be separated using conventional techniques, for example chromatography or fractional crystallization. The enantiomers can be isolated by separation of the racemate, for example by fractional crystallization, resolution, or high performance liquid chromatography. The diastereomers can be isolated by separation of the mixtures of isomers, for example by fractional crystallization, high performance liquid chromatography, or flash chromatography. Alternatively, the stereoisomers can be made by chiral synthesis from the chiral starting materials, under conditions that do not cause racemization or epimerization, or by derivation, with a chiral reagent. All stereoisomers are included within the scope of the invention. All tautomers, when possible, are included within the scope of the invention. The present invention also encompasses compounds that contain one or more isotopes, for example 4C, 11C, or 19F, and their use as isotopically labeled compounds for pharmacological and metabolic studies.
The present invention also encompasses a composition of Formula I, ie, compounds which are converted to a compound of Formula I in vivo. The following definitions will be applied throughout the specification and the appended claims. Unless otherwise reported or indicated, the term "alkyl" denotes a straight or branched chain alkyl group. Examples of this alkyl group include methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, secondary butyl, and tertiary butyl. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, and tertiary butyl. Unless otherwise reported or indicated, the term "alkoxy" denotes an O-alkyl group, wherein the alkyl group is as defined above. Unless otherwise reported or indicated, the term "halogen" shall mean fluorine, chlorine, bromine, or iodine. The specific compounds of the invention are one or more of the following: 1- (4-benzyloxy-phenyl) -2- (2,4-dichloro-phenyl) -5- piperidin-1-yl-amide methyl-1 H-imidazole-4-carboxylic acid; 4- [2- (2,4-di-chloro-phenyl) -5-methyl-4- (piperidin-1-yl-carbamoyl) -midazol-1-yl] -phenyl-acid ester Ethanesulfonic; Propan-1-sulfonic acid 4- [2- (2,4-dichloro-phenyl) -5-methyl-4- (piperidin-1-yl-carbamoyl) -imidazol-1-yl] -phenyl-ester; 4- [2- (2,4-Dichloro-phenyl) -5-methyl-4- (piperidin-1-yl-carbamoyl) -imidazol-1-yl] -phenyl-ester of butan-1-sulfonic acid; 2- (2,4-Dichloro-phenyl) -5-methyl-1- [4- (4,4,4-trifluoro-butoxy) -phenyl] -1 H- piperidin-1-yl-amide imidazole-4-carboxylic acid; 3,3,3-trifluoride 4- [2- (2,4-dichloro-phenyl) -5-methyl-4- (piperidin-1-yl-carbamoyl) -imidazol-1-yl] -phenyl-ester} -propan-1-sulfonic acid;
4- [2- (2,4-Dichloro-phenyl) -5-methyl-4- (piperidin-1-yl-carbamoyl) -imidazol-1-yl] -phenyl-ester of 4,4,4-trifluoro acid -butan-1-sulfonic; thiophene-2-sulfonate of 4-. { 2- (2,4-dichloro-phenyl) -5-methyl-4- [(piperidin-1-yl-amino) -carbonyl] -1H-imidazol-1-yl} -phenyl; 4- pyridine-3-sulfonate. { 2- (2,4-Dichloro-phenyl) -5-methyl-4 - [(piperidin-1-yl-amino) -carbonyl] -1H-imidazol-1-yl} -phenyl; 4- pyridine-3-sulfonate. { 2- (2,4-dichloro-phenyl) -5- ^ methyl-4 - [(piperidin-1-ylamino) -carbonyl] -1H-imidazol-1-yl} -phenyl; 3-methyl-butan-1-sulfonate of 4-. { 2- (2,4-Dichloro-phenyl) -5-methyl-4 - [(piperidin-1-yl-amino) -carbonyl] -1H-imidazol-1-yl} -phenyl; 3,3-dimethyl-butan-1-sulfonate of 4-. { 2- (2,4-Dichloro-phenyl) -5-methyl-4 - [(piperidin-1-yl-amino) -carbonyl] -1H-imidazol-1-yl} -phenyl; 3,3,3-trifluoro-propane-1-sulfonate from 4- [2- (2,4-difluoro-phenyl) -5-methyl-4- ( { [5- (trifluoro-methyl) -p} Ridin-2-yl] -amino.}. -carbonyl) -1 H -imidazol-1-yl] -phenyl; 3-Methyl-butan-1-sulfonate from 4- [2- (2,4-difluoro-pheyl) -5-methyl-4- ( { [5- (trifluoromethyl) -pyridin-2-yl) ] -amino.}. -carbonyl) -1 H -im id azo 1-1 -i I] -phenyl; and the pharmaceutically acceptable salts thereof.
Methods of Preparation The compounds of the invention can be prepared as illustrated below, according to any of the following methods. However, the invention is not limited to these methods, and the compounds can also be prepared as described for the structurally related compounds in the prior art. The compounds of Formula I, wherein R 1 represents: a) an alkoxy group of 3 to 6 carbon atoms substituted by one or more fluoros, or b) a group of the formula phenyl (CH 2) pO-, wherein p is 1 , 2, or 3, and the phenyl ring is optionally substituted by 1, 2, or 3 groups represented by Z, or c) a group R5S (O) 2O, can be prepared by the reaction of a compound of Formula II :
wherein R2, R3, R4, Ra, m, and n are as defined above, with a group R1 AX, wherein R1 A represents a group such that R1 AO represents R1, and X. represents a leaving group, for example halogen , at a temperature in the range of -25 ° C to 150 ° C, in the presence of an inert solvent, for example dichloromethane, and optionally in the presence of a base, for example triethylamine or pyridine.
The compounds of Formula I, where Ra, R1, R2, R4, m, and n are as defined above, and R3 represents a group XY- N R7R8, where X is CO, and Y, R7 and R8 are as defined above, can be prepared by the reaction of a compound of Formula III:
wherein Ra, R1, Rz, R4, m, and n are as defined above, and R1 0 represents H or an alkyl group of 1 to 6 carbon atoms, with a compound of Formula IV or a salt thereof: R7R8YNH2 IV wherein Y, R7 and R8 are as defined above, in an inert solvent, for example toluene, in the presence of a Lewis acid, for example trimethyl aluminum, at a temperature in the range of -25 ° C to 1 50 ° C, when R 1 0 is an alkyl group of 1 to 6 carbon atoms; or alternatively, when R10 is H, by reacting a compound of Formula I11 with a chlorinating agent, for example oxalyl chloride, and then the acid chloride produced is reacted with an amine of the Formula IV in an inert solvent, for example dichloromethane, in the presence of a base, for example triethylamine, at a temperature in the range of -25 ° C to 1 50 ° C. The compounds of Formula I, wherein Ra, R1, R2, R4, m, and n are as defined above, and R3 represents a group XY-NR7R8, wherein X is SO2, can be prepared by the reaction of a composed of Formula V:
wherein Ra, R1, R2, R4, m, and n are as defined above, and A represents a leaving group, for example halogen, for example chlorine, with a compound of Formula IV, wherein Y, R7, and R8 are as defined above, or a salt thereof, in an inert solvent, for example tetrahydrofuran or dichloromethane, in the presence of a base, for example potassium carbonate, triethylamine, or pyridine, at a temperature in the range of -25 ° C to 150 ° C. The compounds of Formula I, wherein Ra, R2, R3, R4, m, and n are as defined above, and R1 represents a group R5S (O) 2NH, can be prepared by the reaction of a compound of the Formula SAW :
wherein Ra, R2, R3, R4, m, and n are as defined above, with a sulfonation agent of the formula R5SO2L, wherein R5 is as defined above, and L represents a leaving group, for example chlorine, in an inert solvent, for example dichloromethane, in the presence of a base, for example triethylamine, at a temperature in the range of -25 ° C to 150 ° C. It is believed that certain intermediary compounds are novel and form part of the present invention, in particular the compounds of Formula I 1 as defined above, and including each and all of the definitions of R 1 given previously. The compounds of Formulas II, III, V, and VI can be prepared by the general synthetic route shown at the end of the examples, and adaptations thereof, or by analogous methods known to those skilled in the art. It will be appreciated by those skilled in the art that, during the reaction sequence, certain functional groups will require protection by deprotection at an appropriate stage; see "Protective Groups in Organic Synthesis", 3rd Edition (1999) by Greene and Wuts.
Pharmaceutical Preparations The compounds of the invention will normally be administered by the oral, parenteral, intravenous, intramuscular, subcutaneous, or other injectable, buccal, rectal, vaginal, transdermal, and / or nasal routes, and / or by inhalation. , in the form of pharmaceutical preparations comprising the active ingredient a pharmaceutically acceptable addition salt, in a pharmaceutically acceptable dosage form. Depending on the disorder and the patient to be treated, and the route of administration, the compositions may be administered in different doses. Suitable daily doses of the compounds of the invention in the therapeutic treatment of humans are from about 0.001 to 10 milligrams / kilogram of body weight, preferably from 0.01 to 1 milligram / kilogram of body weight. Oral formulations, in particular tablets or capsules, which can be formulated by methods known to those skilled in the art, are preferred to provide the doses of the active compound in the range of 0.5 milligrams to 500 milligrams, for example 1 milligram, 3 milligrams, 5 milligrams, 10 milligrams, 25 milligrams, 50 milligrams, 100 milligrams, and 250 milligrams. In accordance with a further aspect of the invention, there is also provided a pharmaceutical formulation that includes any of the compounds of the invention, or pharmaceutically acceptable derivatives thereof, mixed with adjuvants, d eluents, and / or pharmaceutical carriers. acceptable Pharmacological Properties The compounds of Formula (I) are useful for the treatment of obesity or overweight (for example, to promote weight loss and for the maintenance of weight loss), for the prevention of weight gain ( for example, induced by medication, or subsequent to quitting), for the modulation of appetite and / or satiety, eating disorders (eg, overeating, anorexia, bulimia, and compulsion), cravings (for drugs, tobacco , alcohol, any appetizing macronutrients, or non-essential food items), for the treatment of psychiatric disorders, such as psychotic and / or mood disorders, schizophrenia, and schizoaffective disorder, bipolar disorders, anxiety, anxiety-depressive disorders, depression , mania, obsessive-compulsive disorders, impulse control disorders (eg, Guilles de la Tourette syndrome), attention disorders such as ADD / ADHD, tension, and junk neurological disorders, such as dementia and cognitive and / or memory dysfunction (eg, amnesia, Alzheimer's disease, Pick's dementia, aging dementia, vascular dementia, mild cognitive impairment, cognitive decline related to age, and mild dementia) of aging), neurological and / or neurodegenerative disorders (e.g., multiple sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's chorea, and Alzheimer's disease), disorders related to demyelination, neuroinflammatory disorders (e.g. de G u illain-Barré). Compounds are also potentially useful for the prevention or treatment of addiction and addictive disorders and behaviors (eg, alcohol and / or drug abuse, pathological gambling, cleptomony, drug withdrawal disorders ( for example, abstinence from alcohol with or without perceptual alterations; delirium due to abstinence from alcohol; abstinence of amphetam inas; abstinence from ***e; nicotine withdrawal; abstinence from opioids; abstinence from thirst before, hypnotics, or anxiolytics with or without perceptual alterations; delirium for abstinence from thirst before, hypnotics, or anxiolytics; and symptoms of withdrawal due to other substances), mood induced by alcohol and / or drugs, anxiety and / or sleep disorder with establishment during abstinence, and recurrence to alcohol and / or drugs. The compounds are also potentially useful for the prevention or treatment of neurological disorders, such as dystonias, dyskinesias, akathisia, tremors and spasticity, treatment of vertebral column lesions, neuropathy, migraine, wakefulness disorders, disorders. of sleep (for example, altered sleep architecture, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), pain disorders, cranial trauma. The compounds are also potentially useful for the treatment of still existing cardiovascular disorders (eg, atherosclerosis, arteriosclerosis, angina, abnormal heart rhythms, and arrhythmias, congestive heart failure, coronary artery disease, heart disease, hypertension), for prevention and the treatment of left ventricular hypertrophy, myocardial infarction, transient ischemic attack, peripheral vasculopathy, systemic inflammation of the vasculature, septic shock, embolism, cerebral apoplexy, cerebral infarction, cerebral ischemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhage, disorders metabolic (for example, conditions that show a reduced metabolic activity, or a decrease in the energy expenditure at rest as a percentage of the mass without total fat, diabetes mellitus, dyslipidemia, fatty liver, gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hyperuricacidemia toleration impaired glucose, impaired fasting glucose, insulin resistance, insulin resistance syndrome, metabolic syndrome, syndrome X, hypoventilation syndrome due to obesity (Pickwickian syndrome), type I diabetes, type II diabetes, low levels of high density lipoprotein cholesterol and / or high levels of low density lipoprotein cholesterol, low levels of adiponectin), reproductive and endocrine disorders (eg, treatment of hypogonadism in men, treatment of infertility or as a contraceptive, menstrual abnormalities / emeniopathy , polycystic ovarian disease, sexual and reproductive dysfunction in women and men (erectile dysfunction), subjects deficient in growth hormone, hirsutism in women, short stature normal variant), and diseases related to respiratory systems (eg, asthma and disease) chronic obstructive pulmonary) and gastrointestinal (for example, gastrointestinal mobility or intestinal propulsion, diarrhea, emesis, nausea, gallbladder disease, cholelithiasis, gastro-oesophageal reflux related to obesity, ulcers). The compounds are also potentially useful as agents in the treatment of dermatological disorders, cancers (e.g., colon, rectum, prostate, breast, ovary, endometrium, cervix, gallbladder, bile duct), craniopharyngioma, Prader-Willi syndrome, Turner syndrome, Frohlich syndrome, glaucoma, infectious diseases, urinary tract disorders and inflammatory disorders (for example, arthritis deformans, inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis), and orthopedic disorders. The compounds are also potentially useful as agents in the treatment of achalasia (esophageal). In another aspect, the present invention provides a compound of Formula I as defined above, for use as a medicament. In a further aspect, the present invention provides the use of a compound of Formula I in the preparation of a medicament for the treatment or prophylaxis of obesity or overweight (e.g., promotion of weight loss and maintenance of weight loss), prevention of weight gain (for example, induced by medication or subsequent to quitting), for the modulation of appetite and / or satiety, eating disorders (for example, overeating, anorexia, bulimia, and compulsion), cravings (for drugs, tobacco, alcohol, any appetizing macronutrients, or non-essential food items), for the treatment of psychiatric disorders, such as psychotic and / or mood disorders, schizophrenia and schizoaffective disorder, bipolar disorders, anxiety, anxiety-depressive disorders, depression, mania, obsessive-compulsive disorders, impulse control disorders (for example, Guilles de la Tourette syndrome), attention disorders such as AD / ADHD , tension, and neurological disorders, such as dementia and cognitive and / or memory dysfunction (eg, amnesia, Alzheimer's disease, Pick's dementia, dementia aging, vascular dementia, mild cognitive impairment, cognitive decline related to age, and mild dementia due to aging). neurological and / or neurodegenerative disorders (e.g., multiple sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's chorea, and Alzheimer's disease), disorders related to demyelination, neuroinflammatory disorders (e.g., Guillain-Barré syndrome). In a further aspect, the present invention provides the use of a compound of Formula I in the preparation of a medicament for the treatment or prophylaxis of addiction and addictive disorders and behaviors (eg, alcohol and / or alcohol abuse). drugs, pathologically playing, kleptomania), drug withdrawal disorders (eg, abstinence from alcohol with or without perceptual alterations; delirium due to abstinence from alcohol; abstinence from amphetamines; abstinence from ***e; nicotine withdrawal, opioid withdrawal; abstinence from sedatives, hypnotics or anxiolytics with or without perceptual alterations; delirium for withdrawal of sedatives, hypnotics or anxiolytics; and withdrawal symptoms due to other substances), humor induced by alcohol and / or drugs, anxiety and / or sleep disorder with establishment during abstinence, and recurrence of alcohol and / or drugs. In a further aspect, the present invention provides the use of a compound of Formula I in the preparation of a medicament for the treatment or prophylaxis of neurological dysfunctions, such as dystonias, dyskinesias, akathisia, tremors and spasticity, treatment of lesion of spine, neuropathy, migraine, wakefulness disorders, sleep disorders (eg, altered sleep architecture, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), pain disorders, cranial trauma. In a further aspect, the present invention provides the use of a compound of Formula I in the preparation of a medicament for the treatment or prophylaxis of immune cardiovascular disorders (eg, atherosclerosis, arteriosclerosis, angina pectoris, abnormal heart rhythms, and arrhythmias, congestive heart failure, coronary artery disease, heart disease, hypertension, prevention and treatment of left ventricular hypertrophy, myocardial infarction, transient ischemic attack, peripheral vasculopathy, systemic inflammation of the vasculature, septic shock, embolism, cerebral stroke, cerebral infarction , cerebral ischemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhage, metabolic disorders (for example, conditions that show a reduced metabolic activity or a decrease in the energy expenditure at rest as a percentage of the mass without total fat, diabetes mellitus, dyslipidemia , fatty liver, drop, hi perchesterolemia, hyperlipidemia, hypertriglyceridemia, hyperuricacidemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance, insulin resistance syndrome, metabolic syndrome, syndrome X, hypoventilation syndrome due to obesity (Pickwickian syndrome), type I diabetes , type II diabetes, low levels of high density lipoprotein cholesterol and / or high levels of low density lipoprotein cholesterol, low levels of adiponectin), reproductive and endocrine disorders (eg, treatment of hypogonadism in men, treatment of infertility or as a contraceptive, menstrual abnormalities / emeniopathy, polycystic ovarian disease, sexual and reproductive dysfunction in women and men (erectile dysfunction), subjects deficient in growth hormone, hirsutism in women, short stature normal variant), and diseases related to the systems respiratory (for example, asthma and disease) chronic obstructive pulmonary age) and gastrointestinal (eg, dysfunction of gastrointestinal motility or intestinal propulsion, diarrhea, emesis, nausea, gall bladder disease, cholelithiasis, gastro-esophageal reflux related to obesity, ulcers). In a further aspect, the present invention provides the use of a compound of Formula I in the preparation of a medicament for the treatment or prophylaxis of dermatological disorders, cancers (e.g., colon, rectum, prostate, breast, ovarian, endometrium, cervix, gallbladder, bile duct), craniopharyngioma, Prader-Willi syndrome, Turner syndrome, Frohlich syndrome, glaucoma, infectious diseases, urinary tract disorders and inflammatory disorders (eg, arthritis deformans, inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis), and orthopedic disorders. In a still further aspect, the present invention provides a method, which comprises administering a pharmacologically effective amount of a compound of Formula I to a patient in need thereof, for the prophylaxis or treatment of obesity or overweight (eg, promotion of weight loss and maintenance of weight loss) , prevention of weight gain (for example, induced by medication, or subsequent to quitting), for the modulation of appetite and / or satiety, eating disorders (for example, overeating, anorexia, bulimia, and compulsion) , cravings (for drugs, tobacco, alcohol, any appetizing macronutrients, or non-essential food items), for the treatment of psychiatric disorders, such as psychotic and / or mood disorders, schizophrenia, and schizoaffective disorder, bipolar disorders, anxiety , anxio-depressive disorders, • depression, mania, obsessive-compulsive disorders, impulse control disorders (eg, Guilles de la Tourette syndrome), tr attention disorders such as ADD / ADHD, stress, and neurological disorders, such as dementia and cognitive and / or memory dysfunction (eg, amnesia, Alzheimer's disease, Pick's dementia, dementia due to aging, vascular dementia, mild cognitive impairment , age-related cognitive decline, and mild dementia due to aging), neurological and / or neurodegenerative disorders (e.g., multiple sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's chorea, and Alzheimer's disease), disorders related to demyelination , neuroinflammatory disorders (for example, Guillain-Barré syndrome). In a still further aspect, the present invention provides a method, which comprises administering a pharmacologically effective amount of a compound of the Formula I to a patient in need thereof, for the prophylaxis or treatment of addiction and addictive disorders and behaviors ( for example, alcohol and / or drug abuse, pathological gambling, kleptomania), drug withdrawal disorders (eg, abstinence from alcohol with or without perceptual alterations); delirium due to abstinence from alcohol; abstinence from amphetamines; abstinence from ***e; nicotine withdrawal; abstinence from opioids; abstinence from sedatives, hypnotics, or anxiolytics with or without perceptual alterations; delirium for withdrawal of sedatives, hypnotics, or anxiolytics; and withdrawal symptoms due to other substances), humor induced by alcohol and / or drugs, anxiety and / or sleep disorder with establishment during abstinence, and recurrence of alcohol and / or drugs. In still a further aspect, the present invention provides a method, which comprises administering a pharmacologically effective amount of a compound of Formula I to a patient in need thereof, for the prophylaxis or treatment of neurological dysfunctions, such as dystonias, dyskinesias. , akathisia, tremors and spasticity, treatment of spinal injuries, neuropathy, migraine, wakefulness disorders, sleep disorders (for example, altered sleep architecture, sleep apnea, obstructive sleep apnea, sleep apnea syndrome) , pain disorders, cranial trauma. In a still further aspect, the present invention provides a method, which comprises administering a pharmacologically effective amount of a compound of the Formula I to a patient in need thereof, for the prophylaxis or treatment of immune cardiovascular disorders (e.g. atherosclerosis, arteriosclerosis, angina pectoris, abnormal heart rhythms, and arrhythmias, congestive heart failure, coronary artery disease, heart disease, hypertension, prevention and treatment of left ventricular hypertrophy, myocardial infarction, transient ischemic attack, peripheral vascular disease, systemic inflammation of the vasculature, septic shock, embolism, cerebral apoplexy, cerebral infarction, cerebral ischemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhage, metabolic disorders (for example, conditions that show a reduced metabolic activity, or a decrease in the energy expenditure at rest as a percentage of the mass without total fat, diabetes mellitus, dyslipidemia, fatty liver, gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hyperuricacidemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance, insulin resistance syndrome, metabolic syndrome, X syndrome, hypoventilation syndrome due to obesity (Pickwickian syndrome), type I diabetes, type II diabetes, low levels of high density lipoprotein cholesterol and / or high levels of low density lipoprotein cholesterol, low levels of adiponectin), disorders reproductive and endocrine (for example, treatment of hypogonadism in men, treatment of infertility or as a contraceptive, menstrual abnormalities / emeniopathy, polycystic ovarian disease, sexual and reproductive dysfunction in women and men (erectile dysfunction), subjects deficient in growth hormone, hirsutism in women, short stature normal variant), and diseases related to respiratory systems (eg, asthma and chronic obstructive pulmonary disease) and gastrointestinal (eg, dysfunction of gastrointestinal motility or intestinal propulsion, diarrhea, emesis, nausea, gallbladder disease, cholelithiasis, gastro-intestinal reflux -esophageal related to obesity, ulcers). In a still further aspect, the present invention provides a method, which comprises administering a pharmacologically effective amount of a compound of Formula I to a patient in need thereof, for the prophylaxis or treatment of dermatological disorders, cancers (e.g. of colon, rectum, prostate, breast, ovary, endometrium, cervix, gall bladder, bile duct), craniopharyngioma, Prader-Willi syndrome, Turner syndrome, Frohlich syndrome, glaucoma, infectious diseases, urinary tract disorders, and inflammatory disorders (eg, arthritis deformans, inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis), and orthopedic disorders. The compounds of the present invention are particularly suitable for the treatment of obesity or overweight (e.g., promotion of weight loss and maintenance of weight loss), prevention or reversion of weight gain (e.g., rebound, medication-induced, or subsequent to quitting), for the modulation of appetite and / or satiety, eating disorders (eg, overeating, anorexia, bulimia, and compulsion), cravings (for drugs, tobacco, alcohol, any appetizing macronutrients , and non-essential food items) The compounds of Formula I are useful for the treatment of obesity, psychiatric disorders, such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxiety-depressive disorders, depression, cognitive disorders, memory disorders , obsessive-compulsive disorders, anorexia, bulimia, attention disorders such as ADHD, epilepsy, and related conditions, and trasto neurological disorders, such as dementia, neurological disorders (for example multiple sclerosis), Raynaud's syndrome, Parkinson's disease, Huntington's chorea, and Alzheimer's disease). The compounds are also potentially useful for the treatment of immune, cardiovascular, reproductive, and endocrine disorders, septic shock, and diseases related to the respiratory and gastrointestinal systems (eg, diarrhea). The compounds are also potentially useful as agents in the treatment of indications of prolonged abuse, addiction, and / or recurrence, for example in the treatment of drug dependence (nicotine, ethanol, ***e, opiates, etc.) and / or in the treatment of withdrawal symptoms of drugs (nicotine, ethanol, ***e, opiates, etc.). The compounds can also eliminate the weight gain that normally accompanies quitting. In another aspect, the present invention provides a compound of Formula I as defined above, for use as a medicament. In a further aspect, the present invention provides the use of a compound of Formula I in the preparation of a medicament for the treatment or prophylaxis of obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxiety disorders, depressants, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders such as ADHD, epilepsy, and related conditions, neurological disorders such as dementia, neurological disorders (for example multiple sclerosis), Parkinson's disease, Huntington's disease, and Alzheimer's disease, immune, cardiovascular, reproductive, and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems (eg, diarrhea), and indications of prolonged abuse, addiction, and / or recurrence, for example in the treatment of drug dependence (n icotine, ethanol, ***e, opiates, etc.) and / or the treatment of drug withdrawal symptoms (nicotine, ethanol, ***e, opiates, etc.). In still further aspect, the present invention provides a method for the treatment of obesity, psychiatric disorders, such as psychotic disorders, such as schizophrenia and bipolar disorders, anxiety, anxiety-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders such as ADHD, epilepsy, and related conditions, neurological disorders such as dementia, neurological disorders (for example multiple sclerosis), disease. Parkinson's disease, Huntington's disease, and Alzheimer's disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems (for example, diarrhea), and indications of prolonged abuse, addiction, and / or recurrence, for example for the treatment of drug dependence (nicotine, ethanol, ***e, opiates, etc.), and / or for the treatment of drug withdrawal symptoms (nicotine, ethanol, ***e, opiates, etc.), which comprises administering a pharmacologically effective amount of a compound of Formula I to a patient who need The compounds of the present invention are particularly suitable for the treatment of obesity, for example by reducing appetite and body weight, maintaining weight reduction, and preventing rebound. The compounds of the present invention can also be used to prevent or reverse the weight gain induced by the medication, for example the weight gain caused by the anti-psychotic (neuroleptic) treatments. The compounds of the present invention can also be used to prevent or reverse the weight gain associated with quitting smoking. The compounds of the present invention are suitable for use in the treatment of the above indications in populations of juvenile or adolescent patients. Combination Therapy The compounds of the invention can be combined with another therapeutic agent that is useful in the treatment of obesity, such as other anti-obesity drugs, that affect energy expenditure, glycolysis, gluconeogenesis, glycogenolysis, lipolysis, lipogenesis, absorption of fat, storage of fat, excretion of fat, hunger and / or satiety, and / or the mechanisms of anxiety, appetite / motivation, food intake, or gastrointestinal mobility. The compounds of the invention can be further combined with another therapeutic agent that is useful in the treatment of disorders associated with obesity, such as hypertension, hyperlipidemias, dyslipidemias, diabetes, sleep apnea, asthma, cardiac disorders, atherosclerosis, macro- and micro-vascular, hepatic steatosis, cancer, joint disorders, and gallbladder disorders. For example, a compound of the present invention can be used in combination with another therapeutic agent that lowers blood pressure, or that lowers the LDL: HDL ratio, or an agent that causes a reduction in circulating levels of lipoprotein cholesterol. low density. In patients with diabetes mellitus, the compounds of the invention can also be combined with therapeutic agents used for the treatment of complications related to micro-angiopathies. The compounds of the invention can be used in conjunction with other therapies for the treatment of obesity and its associated complications, the metabolic syndrome, and type 2 diabetes, and these include biguanide drugs, insulin (synthetic insulin analogs), and anti-hyperglycemics oral (these are divided into prandial glucose regulators and alpha-glucosidase inhibitors). In another aspect of the invention, the compound of Formula I, or a pharmaceutically acceptable salt thereof, can be administered in association with a PPAR modulator agent. PPAR modulating agents include, but are not limited to, an alpha and / or gamma agonist of PPAR, or pharmaceutically acceptable salts, solvates, solvates of these salts, or prodrugs thereof. Suitable PPAR alpha and / or gamma agonists, pharmaceutically acceptable salts, solvates, solvates of these salts, or prodrugs thereof, are well known in the art. In addition, the combination of the invention can be used in conjunction with a sulfonyl urea. The present invention also includes a compound of the present invention in combination with a cholesterol reducing agent. The cholesterol lowering agents referred to in this application include, but are not limited to,, inhibitors of HMG-CoA-reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A-reductase). Suitably, the HMG-CoA reductase inhibitor is a statin. In the present application, the term "cholesterol-lowering agent" also includes chemical modifications of HMG-CoA reductase inhibitors, such as esters, prodrugs, and metabolites, whether active or inactive. The present invention also includes a compound of the present invention in combination with an inhibitor of the loyal bile acid transport system (inhibitor of IBAT). The present invention also includes a compound of the present invention in combination with a bile acid binding resin. The present invention also includes a compound of the present invention in combination with a bile acid sequestering agent, for example colestipol or cholestyramine or cholestagel. In accordance with a further aspect of the present invention, a combination treatment is provided, which comprises administering an effective amount of a compound of the Formula I, or a pharmaceutically acceptable salt thereof, optionally together with a diluent or carrier. pharmaceutically acceptable, with the simultaneous administration, in sequence, or separated from one or more of the following agents selected from: a CETP inhibitor (cholesteryl ester transfer protein); an antagonist of cholesterol absorption; an inhibitor of MTP (microsomal transfer protein); a nicotinic acid derivative, including the slow release and combination products; a phytosterol compound; probucol; an anti-coagulant; an omega-3 fatty acid;
another compound against obesity, for example sibutramine, phentermine, orlistat, bupropion, ephedrine, thyroxine; a compound against hypertension, for example an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, an adrenergic blocker, an alpha-adrenergic blocker, a beta-adrenergic blocker, an alpha / beta-blocker mixed adrenergic, an adrenergic stimulant, a calcium channel blocker, an AT-1 blocker, a saluretic, a diuretic, or a vasodilator; a modulator of melanin concentrating hormone (MCH); an NPY receiver modulator; an orexin receptor modulator; a modulator of phosphoinositide-dependent protein kinase (PDK); or modulators of nuclear receptors, for example LXR,
FXR, RXR, GR, ERRa, ß, PPARa, ß,?, And RORalfa; . an agent modulating the transmission of monoamine, for example a selective serotonin reuptake inhibitor (SSRI), an inhibitor of noradrenaline re-uptake (NARI), an inhibitor of noradrelin-serotonin reuptake ( SNRI), an inhibitor of monoamine oxidase (MAOI), a tricyclic antidepressant agent (TCA), a specific noradrenergic and serotonergic antidepressant (NaSSA); an anti-psychotic agent, for example olanzapine and clozapine; a serotonin receptor modulator;
a leptin modulator / leptin receptor; a ghrelin modulator / ghrelin receptor; a DPP-IV inhibitor; or a pharmaceutically acceptable salt, solvate, solvate of this salt, or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier, to a warm-blooded animal, such as man, in need of such therapeutic treatment. In accordance with a further aspect of the present invention, a continuation treatment comprising administering an effective amount of a compound of the Formula I, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier is provided. , with the simultaneous administration, in sequence, or separated from very low calorie diets (VLCD), or low calorie diets (LCD). Accordingly, in a further feature of the invention, there is provided a method for the treatment of obesity and its associated complications in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to this animal a an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in simultaneous, sequential, or separate administration, with an effective amount of a compound from one of the other classes of compounds described in this section of combination, or a pharmaceutically acceptable salt, solvate, solvate of this salt, or a prodrug thereof. Accordingly, in a further feature of the invention, there is provided a method for the treatment of hyperlipidemic conditions in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to this animal an effective amount of a compound of the Formula I, or a pharmaceutically acceptable salt thereof, in a simultaneous, sequential, or separate administration, with an effective amount of a compound from one of the other classes of compounds described in this combination section, or a pharmaceutically acceptable salt, solvate of this salt, or prodrug thereof. According to a further aspect of the invention, there is provided a pharmaceutical composition, which comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a compound from one of the other classes of compounds described herein. combination section, or a pharmaceutically acceptable salt, solvate, solvate of this salt, or prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier. In accordance with a further aspect of the present invention, a therapeutic kit is provided, which comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a compound from one of the other classes of compounds described in this combination section, or a pharmaceutically acceptable salt. , solvate, solvate of this salt, or prodrug thereof. In accordance with a further aspect of the present invention, there is provided a therapeutic kit, which comprises: a) a compound of the Formula I, or a pharmaceutically acceptable salt thereof, in a first unit dosage form; b) a compound from one of the other classes of compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of this salt, or prodrug thereof, in a second unit dosage form; and c) a container element for containing the first and second dosage forms. In accordance with a further aspect of the present invention there is provided a therapeutic kit, which comprises: a) a compound of the Formula. I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form; b) a compound from one of the other classes of compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of this salt, or prodrug thereof, in a second unit dosage form; and c) a container element for containing the first and second dosage forms. According to another feature of the invention, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of this salt, or prodrug thereof, in the manufacture of a medicament for use in the treatment of obesity and its associated complications in a warm-blooded animal, such as man. In accordance with another feature of the invention, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of this salt, or prodrug thereof, in the manufacture of a medicament for use in the treatment of hyperlipidemic conditions in a warm-blooded animal, such as man. According to a further aspect of the present invention, a combination treatment is provided, which comprises administration of an effective amount of a compound of the
Formula I, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with simultaneous administration, in sequence, or separated from an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of this salt, or prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier, to a warm-blooded animal, such as man, in need of such therapeutic treatment. Additionally, a compound of the invention can also be combined with therapeutic agents that are useful in the treatment of disorders or conditions associated with obesity (such as type 2 diabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, coronary heart disease, nonalcoholic steatohepatitis, osteoarthritis, and some cancers), and psychiatric and neurological conditions. It will be understood that there are medically accepted definitions of obesity and overweight. A patient can be identified, for example, by measuring the body mass index (BMI), which is calculated by dividing the weight in kilograms by height in meters squared, and comparing the result with the definitions. Pharmacological Activity The compounds of the present invention are active against the receptor product of the CB1 gene. The affinity of the compounds of the invention for central cannabinoid receptors can be demonstrated in the methods described in Devane et al., Molecular Pharmacology, 1988, 34, 605, or those described in International Publication Number WO01 / 70700 or European Patent Number. EP 656354. In an alternative manner, the test can be carried out as follows. 10 micrograms of membranes prepared from cells stably transfected with the CB1 gene, were suspended in 200 microliters of 100 mM NaCl, 5 mM MgCl2, 1 mM EDTA, 50 mM HEPES (pH 7.4), 1 mM DTT, 0.1 BSA percent, and 100 μM GDP. To this was added an EC80 concentration of the agonist (CP55940), the required concentration of the test compound, and.0.1 μCi of [35S] -GTPyS. The reaction was allowed to proceed at 30 ° C for 45 minutes. The samples were then transferred to GF / B filters using a cell harvester, and washed with wash buffer (50 mM Tris (pH 7.4), 5 mM MgCl 2, 50 mM NaCl). The filters were then covered with scintillant, and counted to determine the amount of [35S] -GTPyS retained by the filter. The activity is measured in the absence of all ligands (minimal activity) or in the presence of an EC80 concentration of CP55940 (maximum activity). These activities are established as 0 percent and 100 percent activity, respectively. At different concentrations of the novel ligand, the activity is calculated as a percentage of the maximum activity, and plotted. The data is adjusted using the equation y = A + ((BA) / 1 + ((C / x) UD)), and the IC50 value is determined as the concentration required to give the maximum average inhibition of GTP? S binding the conditions used.
The compounds of the present invention are active at the CB1 receptor (IC50 < 1 micromolar). More preferably, the compounds have an IC50 < 200 nanomolar. For example, the IC50 of Example 1 is 18 nM, and of Example 2 is 28 nM. It is believed that the compounds of the invention are selective antagonists of CB1, or inverse agonists of CB1. The potency, selectivity profile, and propensity for side effects may limit the clinical utility of the compounds known hitherto with alleged CB1 inverse antagonist / antagonist properties. In this aspect, the pre-clinical evaluation of the compounds of the present invention in models of the gastrointestinal and / or cardiovascular function, indicates that they offer significant advantages, comparing with the antagonist / inverse agonist agents of
Reference CB1 representative. The compounds of the present invention may provide additional benefits in terms of potency, selectivity profile, bioavailability, half-life in plasma, permeability of the blood-brain membrane, plasma protein binding (eg, increasing the free fraction of the drug), or solubility, comparing with the representative reference CB1 inverse antagonist / antagonist agents. The utility of the compounds of the present invention in the treatment of obesity and related conditions is demonstrated by a decrease in body weight in obese mice induced by cafeteria diet. The female C57B1 / 6J mice were given access to the calorie-dense "cafeteria" diet taste (soft chocolate / cocoa-type pastes, chocolate, fatty cheese, and nugats), and standard laboratory food for 8 to 10 weeks . The compounds to be tested were then administered systemically (intravenously, intraperitoneally, subcutaneously, or orally) once a day for a minimum of 5 days, and the body weights of the mice were monitored on a daily basis. The simultaneous assessment of adiposity was carried out by means of DEXA images at the baseline and at the end of the study. Blood sampling was also carried out to test changes in plasma markers related to obesity. Examples Abbreviations DMF Dimethyl formamide. DEA Diethyl-amine. EtOAc Ethyl acetate. THF - Tetrahydrofuran. TLC Thin layer chromatography. Triplet. s Singlete. d Doublet. q Quartet. quint Quintet. m Multiplete.
br Am plío, bs Singlete ample, d m Doblete de m ultiplete. bt Triplet wide. dd Doublet doublet. General Experimental Procedures The mass spectra were recorded either in a Micromass ZQ single quadrupole mass spectrometer, or in a Micromass LCZ single quadrupole mass spectrometer, both equipped with a pneumatically assisted electrospray interface (liquid chromatography- mass spectroscopy). The measurements of 1 H RM N were carried out in a Varian Mercury 300 or in a Varian I nova 500, operating at frequencies of 1 H of 300 and 500 M Hz, respectively. Chemical changes are given in parts per million with CDCI3 as the internal standard. CDCI3 is used as the solvent for nuclear magnetic resonance, unless otherwise reported. The purification was carried out on a high performance liquid chromatography of semi-preparation, with a fraction collector triggered by the mass, the mass spectrometer of a single quadrupole Shimadzu QP 8000 with the C8 column of 19x100 millimeters. The mobile phase used was, if not otherwise reported, acetonitrile and regulator (N H4Ac 0.1 M: acetonitrile, 95: 5). For the isolation of the isomers, a Kromasil CN E9344 column (250 x 20 m ID diameter) was used. Heptane: ethyl acetate: D EA, 95: 5: 0.1 was used as the mobile phase (1 m illiliter / m in uto). Fractions were collected using an ultraviolet detector (330 nanometers). Examples of the invention Example 1 Step 1 N- (4-benzyloxy-phenyl) -2,4-dichloro-benzamidine 4-benzyloxy-aniline hydrochloride (5.0 grams, 21.2 millimoles) was added dropwise to a solution of ethyl magnesium bromide (44.5 milliliters, 1 M in tetrahydrofuran, 44.5 millimoles) in 25 milliliters of dry tetrahydrofuran under a nitrogen atmosphere. After stirring for 20 minutes, a solution of 2,4-dichloro-benzonitrile (3.65 grams, 21.2 millimoles) in 25 milliliters of tetrahydrofuran was added. The reaction mixture was stirred for 20 hours at room temperature. Water (50 milliliters) was carefully added. Extraction with EtOAc (100 milliliters, twice), drying (Na2SO4), filtration, and evaporation to dryness, afforded 7.7 grams (98 percent) of the title compound. Step 2: Ethyl-1-acid ester (4-benzyloxy-phenD-2- (2, 4-dichloro-phenyl) -5-methyl-1 H-imidazole-4-carboxylic acid To the N- (4-benzyloxy-phenyl) -2,4-dichloro-benzamidine of Example 1, step 1 (6.88 grams, 1 8.5 millimoles) dissolved in 50 milliliters of tetrahydrofuran, potassium carbonate (2.56 grams, 18.5 millimoles) was added, and the suspension was stirred for 10 minutes. Ethyl 3-bromo-2-oxobutanoate (4.65 grams, 22.2 mmol) was added dropwise over 1 hour, and the mixture was stirred for 66 hours at room temperature. The solution was filtered and evaporated to dryness. The residue was dissolved in acetic acid, and refluxed for 1 hour. The mixture was cooled to room temperature, 100 milliliters of water was added, and the product was extracted with EtOAc (200 milliliters, twice). The combined organic phases were washed with saturated sodium hydrogen carbonate, dried (Na2SO), filtered, and concentrated. Flash chromatography (silica, hexane: EtOAc, 70:30, 60:40) afforded 5.75 grams (65 percent) of the title compound as a pale yellow solid. 1 H NMR (CDC): d 7.5-7.2 (8H, m), 7.1-6.9 (4H, m), 5.1 (2H, s), 4.5 (2H, q), 2.5 (3H, s), 1.5 (3H, t). MS m / z 504 (M + Na), 985 (2 M + Na). Step 3 1- (4-Benzyl-oxo-phenyl) -2- (2,4-dichloro-phenyl) -5-methyl-1 H-imidazole-4-carboxylic acid To a suspension of the ethyl ester of acid 1 - (4-benzyloxy-phenyl) -2- (2,4-dichloro-phenyl) -5-methyl-1H-imidazole-4-carboxylic acid of Example 1, step 2 (3.62 grams, 7.5 mmol) in 60 milliliters of methanol, potassium hydroxide (4.05 grams, 72 mmol) in water (20 milliliters) was added, and the reaction mixture was refluxed for 2 hours. The mixture was cooled to room temperature, acidified to a pH of about 2 with 1M HCl, and extracted with ethyl acetate (200 milliliters, twice). The combined organic phases were dried (Na2SO4), filtered, and concentrated to give 3.38 grams (99 percent) of the title compound. Step 4 1- (4-Benzyloxy-phenyl-2- (2,4-dichloro-phenyp-5-methyl-1H-imidazo [4-carboxylic acid] 1-4-benzyloxy-phenyl-4-carboxylic acid A solution of acid 1- ( 4-benzyloxy-phenyl) -2- (2,4-dichloro-phenyl) -5-methyl-1H-imidazole-4-carboxylic acid from Example 1, step 3 (3.38 grams, 7.5 mmol) in 60 milliliters of CH 2 Cl 2, three drops of dimethylformamide were added, followed by oxalyl chloride (1.3 milliliters, 14.9 mmol) .The mixture was refluxed for 2 hours, cooled to room temperature, and evaporated to dryness. milliliters of CH2Cl2, and cooled to 0 ° C. Triethylamine (2.1 milliliters, 14.9 millimoles) was added, followed by 1-amino-piperidine (0.9 milliliters, 8.2 millimoles), and the mixture was stirred at room temperature for 2 hours. Water (300 milliliters) was added, the mixture was extracted with CH2CI2 (100 milliliters, three times), dried (Na2SO4), filtered, and concentrated.Short evaporation chromatography (silica, hexane: EtOAc, :2, EtOAc) provided 2.94 grams (74 percent) of the title compound as a white solid. 1 H NMR (CDCl 3): d 7.5-7.2 (8H, m), 7.1-6.9 (4H, m), 5.1 (2H, s), 3.0-2.7 (4H, m), 2.5 (3H, s), 1.9- 1.7 (4H, m), 1.6-1.4 (2H, m). MS m / z 558 (M + Na). HPLC: 96.5%.
Example 2 Step 1 2- (2,4-dichloro-phenyl) -1- (4-hydroxy-phen-D-5-methyl-1H-imidazole-4-piperidin-1-yl-amide) carboxylic acid 1- (4-Benzyloxy-phenyl) -2- (2,4-dichloro-phenyl) -5-methyl-1H-imidazole-4-carboxylic acid piperidin-1-yl-amide of Example 1, step 4 (2.78 grams, 5.2 mmol) was dissolved in 80 milliliters of CH 2 Cl 2, and cooled to 0 ° C. A solution of boron tribromide (1M in CH 2 Cl 2, 10.4 milliliters, 10.4 mmol) was added dropwise, and the mixture of The reaction was stirred at room temperature for 1 hour Water (200 milliliters) was added, and the solution was extracted with EtOAc (200 milliliters, three times) The combined organic phases were dried (Na2SO4), filtered, and concentrated. Flash chromatography (silica, hexane: EtOAc, 1: 3, EtOAc) afforded 1.34 grams (58 percent) of the title compound as a white solid.1H NMR (CDCl3): d 8.6 (1H, bs), 7.4 -7.1 (3H, m), 7.0-6.9 (4H, m), 3.0-2.8 (4H, m), 2.5 (3H, s), 1 .8-1.6 (4H, m), 1.5-1.3 (2H, m). Step 2 4-f 2- (2,4-Dichloro-phenyl) -5-methyl-4- (p1-perid-1-yl-carbamoyl) -imidazole-1-ill-phenyl-ester of ethanesulfonic acid . A solution of the 2- (2,4-dichloro-phenyl) -1- (4-hydroxy-phenyl) -5-methyl-1H-imidazole-4-carboxylic acid piperidin-1-yl-amide of Example 2 , step 1 (321 milligrams, 0.72 millimoles) in 10 milliliters of CH2CI2, cooled to 0 ° C. Triethylamine (101 microliters, 0.72 mmol) was added, followed by ethansulfonyl chloride (69 microliters, 0.72 mmol), and the reaction mixture was stirred at room temperature overnight. Water was added, the mixture was extracted with CH2Cl2 (20 milliliters, three times), dried (Na2SO4), filtered, and concentrated. Flash chromatography (silica, hexane: EtOAc, 1: 3) gave 230 milligrams (60 percent) of the title compound as a white solid. 1 H NMR (CDCl 3): d 7.9 (1 H, broad s), 7.4-7.1 (7 H, m), 3.3 (2 H, q), 3.0-2.8 (4 H, m), 2.5 (3 H, s), 1.9-1.7 (4H, m), 1.5 (3H, t), 1.5-1.4 (2H, m). MS m / z 560 (M + Na). HPLC: 97.0%. EXAMPLE 3 4-α2- (2,4-dichloro-phenyl) -5-methyl-4- (piperidin-1-yl-carbamoyl) -imidazol-1-yl-phenyl-ester of propan- 1-sulfonic One. 2- (2,4-dichloro-phenyl) -1- (4-hydroxy-phenyl) -5-methyl-1H-imidazole-4-carboxylic acid piperidin-1-yl-amide solution of Example 2, step 1 (320 milligrams, 0.72 millimoles) in 10 milliliters of CH2CI2, cooled to 0 ° C. Triethylamine (100 microliters, 0.72 mmol) was added, followed by 1-propan-sulfonyl chloride (81 microliters, 0.72 mmol), and the reaction mixture was stirred at room temperature overnight. Water was added, the mixture was extracted with CH2Cl2 (20 milliliters, three times), dried (Na2SO4), filtered, and concentrated. Flash chromatography (silica, hexane: EtOAc, 1: 2) afforded 220 milligrams (56 percent) of the title compound as a white solid. H NMR (CDCl 3): d 7.9 (1H, broad s), 7.4-7.1 (7H, m), 3.3 (2H, m), 3.0-2.8 (4H, m), 2.5 (3H, s), 2.1-1.9 (2H, m), 1.9-1.7 (4H, m), 1.5-1.4
(2H, m), 1.2 (3H, t). , MS m / z 574 (M + Na). HPLC: 97.0%. Example 4 4-22- (2,4-dichloro-phenyl) -5-methyl-4- (piperidin-1-yl-carbamoyl) -imidazole-1-yl-phenyl ester of butan-1-sulfonic acid A solution of the 2- (2,4-dichloro-phenyl) -1- (4-hydroxy-phenyl) -5-methyl-1H-imidazole-4-carboxylic acid piperidin-1-yl-amide of Example
2, step 1 (320 milligrams, 0.72 millimoles) in 10 milliliters of CH2Cl2, cooled to 0 ° C. Triethylamine (100 microliters, 0.72 mmol) was added, followed by 1-butan-sulfonyl chloride (93 microliters,
0. 72 mmol), and the reaction mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with CH2Cl2 (20 milliliters, three times), dried (Na2SO4), filtered, and concentrated. Flash chromatography (silica, hexane: EtOAc, 1: 2) afforded 230 milligrams (57 percent) of the title compound as a white solid. 1 H NMR (CDCl 3): d 7.9 (1H, .bs), 7.4-7.1 (7H,), 3.3 (2H, m), 3.0-2.8
(4H, m), 2.5 (3H, s), 2.1-1.9 (2H, m), 1.9-1.7 (4H, m), 1.6-1.4 (4H, m), 1.0 (3H, t). MS m / z 588 (M + Na). HPLC: 96.0%. EXAMPLE 5 2- (2,4-Dichloro-phenyl) -5-methyl-1-y4- (4.4.4-trifluoro-butoxy) -phenn-1 H-imidazole acid piperidin-1-yl-amide -4-carboxylic 1-iodo-4,4,4-trifluoro-butane (376 milligrams, 1.58 millimoles) was added dropwise to a suspension of piperidin-1-yl-amide of 2- (2,4-dichloro) phenyl) -1 - (4-hydroxy-phenyl) -5-methyl-1H-imidazole-4-carboxylic acid of Example 2, step 1 (351 milligrams, 0.79 millimoles) and K2CO3 (218 milligrams, 1.58 millimoles) in 50 milliliters of acetone. The reaction mixture was refluxed overnight, cooled, and filtered, and concentrated. Flash chromatography (silica, hexane: EtOAc, 1: 2) afforded 200 milligrams (46 percent) of the title compound as a white solid. 1 H NMR (CDCl 3): d 8.0 (1 H, broad s), 7.4-7.2 (3 H, m), 7.1-7.0 (2 H, m), 6.9-6.8 (2 H, m), 4.1-4.0 (2 H, m) , 3.0-2.90 (4H, m), 2.5-2.2 (5H, m), 2.2-2.0 (2H, m), 1.9-1.7 (4H, m), 1.6-1.4 (2H, m). MS m / z 578 (M + Na). HPLC: 99.4%. Example 6 4-r2- (2,4-D-chloro-phenyl) -5-methyl-4- (piperidin-1-yl-carbamoyl) -imidazole-1-yl-phenyl-ester of 3,3,3-trifluoro acid -propan-1-sulfonic acid 2- (2,4-dichloro-phenyl) -1- (4-hydroxy-phenyl) -5-methyl-1H-imidazole-4- piperidin-1-yl-amide carboxyl of Example 2, step 1 (0.89 grams, 2.00 mmol) was dissolved in dichloromethane (20 milliliters), cooled to 0 ° C, and triethylamine (0.35 milliliters, 2.4 mmol) was added, followed by 3,3,3-trifluoro-propane-sulfonyl chloride (prepared by a method analogous to that described in International Publication Number WO00 / 010968 for the butyl homologue) (0.35 milliliters, 2.40 millimoles). The reaction mixture was stirred at room temperature overnight. The fjna layer chromatography showed remaining starting material, and thus, another portion of triethylamine and 3,3,3-trifluoro-propanesulfonyl chloride was added, and the reaction mixture was stirred for an additional 2 hours. . Water was added, and the product was extracted with dichloromethane. dried (Na2SO4), filtered, and concentrated. Flash chromatography (hexane: EtOAc, 1: 3-EtOAc), followed by recrystallization (hexane.EtOAc), gave 700 milligrams (59 percent) of the title compound as a colorless solid. 1 H NMR (CDCl 3): d 7.40-7.10 (8H, m), 3.60-3.43 (2H, m), 3.02-2.70 (6H, m), 2.50 (3H, s), 1.92-1.70 (4H, m), 1.57-1.40 (2H, m). MS m / z 627 (M + Na). HPLC: 97.8%. Example 7 4-r2- (2,4-dichloro-phenyl) -5-methyl-4- (piperidin-1-yl-carbamoyl) -imidazol-1-p-phenyl ester of 4,4 acid, 4-trifluoro-butan-1-sulfonic acid 2- (2,4-dichloro-phenyl) -1- (4-hydroxy-phenyl) -5-methyl-1H-imidazole-4-piperidin-1-yl-amide -carboxylic of Example 2, step 1
(0.49 grams, 1.20 millimoles) was dissolved in diclot-methane (20 milliliters), cooled to 0 ° C, and triethylamine (0.67 milliliters,
4. 8 mmol), followed by 4,4,4-trifluoro-butan-1-sulfonyl chloride (prepared as described in International Publication Number WO00 / 010968) (0.38 grams, 1.80 mmol).
The reaction mixture was stirred at room temperature for 3 hours. Thin layer chromatography showed remaining starting material, and another portion of triethylamine and 4,4,4-trifluorobutan-1-sulfonyl chloride was added, and the reaction mixture was stirred overnight. Water was added, the product was extracted with dichloromethane, dried (Na2SO), filtered, and concentrated. Flash chromatography (hexane: EtOAc, 1: 3-EtOAc), followed by recrystallization (hexane: EtOAc), afforded 0.45 grams (61 percent) of the title compound as a colorless solid. 1 H NMR (CDCl 3): d 7.35-7.19 (8H, m), 3.40 (2H, m), 3.05-2.90 (4H, m), 2.78-2.20 (7H, sym), 1.92-1.70 (4H, m), 1.57-1.40 (2H, m). MS m / z 641 (M + Na). HPLC: 98.6%. Example 8 4-f2- (2,4-dichloro-phenyl) -5-methyl-4-y (p -peridin-1-ylamino) -carbonip-1 H-imidazole-1-thiophene-2-sulphonate -il} -phenyl The 2- (2, 4-dichloro-phenyl) -1- (4-hydroxy-phenyl) -5-methyl-N-piperidin-1-1,1-H-imidazole-4-carboxamide, prepared as described in Example 2, step 1 (100 milligrams, 0.22 millimoles), and triethylamine (0.31 milliliters, 2.25 millimoles) in dichloromethane (2.5 milliliters), were cooled to -78 ° C. 2-Thiophenesulfonyl chloride (287 milligrams, 1.57 millimoles) dissolved in dichloromethane (2.5 milliliters) was carefully added to the reaction mixture. The resulting mixture was stirred at -78 ° C for 1 hour, and at room temperature overnight. Water was added to the reaction, the phases were separated, and the organic phase was washed with water and dried. The solvent was removed under reduced pressure, and separation by high performance liquid chromatography of preparation gave the title compound (110 milligrams, 83 percent) as a solid. 1 H NMR (400 MHz): d 7.89 (s, NH), 7.75-7.74 (m, 1H), 7.55-7.54 (m, 1H), 7.35-7.34 (m, 1H), 7.30-7.25 (m, 2H) , 7.13-7.11 (m, 1H), 7.07 (d, 4H), 2.90-2.86 (m, 4H), 1.80-1.75 (m, 4H), 1.48-1.42 (m, 2H). MS m / z 591 (M + H) +. Example 9 Pyridine-3-sulfonate of 4-. { 2- (2,4-dichloro-phenyl) -5-methyl-4-f (piperidin-1-yl-amino) -carbonyl-1H-imidazol-1-yl) -phenyl 2- (2,4-dichloro) phenyl) -1- (4-hydroxy-phenyl) -5-methyl-N-piperidin-1-yl-1H-imidazole-4-carboxamide prepared as described in Example 2, step 1 (100 milligrams, 0.22 millimoles), and triethylamine (0.31 milliliters, 2.25 millimoles) in dichloromethane (5.0 milliliters), were cooled to -78 ° C. 3-pyridine sulfonyl chloride (144 milligrams, 0.67 millimole) was added in small portions to the reaction mixture. The resulting mixture was stirred at -78 ° C for 1 hour, and at room temperature overnight. Water was added to the reaction, the phases were separated, and the organic phase was washed with water and dried. The solvent was removed under reduced pressure, and separation by high performance liquid chromatography of preparation gave the title compound (110 milligrams, 84 percent) as a solid. 1 H NMR (400 MHz): d 8.96 (s, 1 H), 8.92 (s, 1 H), 8.09-8.06 (m, 1 H), 7.89 (s, 1 H), 7.51-7.49 (m, 1 H), 7.36 (d , 1H), 7.30-7.25 (m, 2H), 7.06 (s, 4H), 2.88-2.84 (m, 4H), 2.48 (s, 3H), 1.79-1.74 (m, 4H), 1.47-1.41 (m , 2H). MS m / z 586 (M + H) +. EXAMPLE 10 5-Chloro-thiophene-2-sulfonatide of 4-f2- (2,4-dichloro-phenyl) -5-methyl-4-r (piperidin-1-yl-amine) -carboniH-1 H- imidazol-1-yl) -pheni! or 2- (2,4-dichloro-phenyl) -1- (4-hydroxy-phenyl) -5-methyl-N-piperidin-1-l-1H-imidazole -4-carboxamide prepared as described in Example 2, step 1 (100 milligrams, 0.22 millimole), and triethylamine (0.16 milliliter, 1.12 millimole) in dichloromethane (.2.5 milliliter), were cooled to -78 ° C. Chloro-thiophene-2-sulfonyl chloride (244 milligrams, 1.12 mmol) in dichloromethane (2.5 milliliters) was carefully added to the reaction mixture. The resulting mixture was stirred at -78 ° C for 1 hour, and at room temperature overnight. Water was added to the reaction, the phases were separated, and the organic phase was washed with water and dried. The solvent was removed under reduced pressure, and separation by high performance liquid chromatography of preparation gave the title compound (84 milligrams, 60 percent) as a solid. 1 H NMR (400 MHz): d 7.90 (s, NH), 7.34-7.26 (m, 4H), 7.10 (d, 4H), 6.96 (d, 1H), 2.88-2.85 (m, 4H), 2.49 (s) , 3H), 1.79-1.74 (m, 4H), 1.47-1.42 (m, 2H). MS m / z 625 (M + H) +. Example 11 3-Methyl-butan-1-sulfonate of 4-f2- (2,4-dichloro-phenyl) -5-methyl-4-y (piperidin-1-yl-amino) -carboniH-1H-imidazole-1 -yl) -phenyl The 2- (2,4-d-ro-phenyl I) - 1- (4-hydroxy-phenyl) -5-methyl-Np-peridin-1-yl-1H-imidazole-4 -carboxamide prepared as described in Example 2, step 1 (50 milligrams, 0.11 mmol) was dissolved in dichloromethane (3.0 milliliters), cooled to 0 ° C, and triethylamine (20 microliters) was added to the mixture. , 0.13 millimoles). The resulting mixture was cooled to -78 ° C, and 3-methyl-butan-1-sulfonyl chloride (23 milligrams, 0.13 mmol) was added carefully. The reaction was stirred at -78 ° C for 1.5 hours. Water was added to the reaction, the product was extracted with dichloromethane, and dried. The solvent was removed under reduced pressure, and separation by high performance liquid chromatography of preparation gave the title compound (46 milligrams, 71 percent) as a solid. 1 H NMR (400 MHz): d 7.86 (s, NH), 7.30-7.20 (m, 5H), 7.12-7.09 (m, 2H), 3.26-3.22 (m, 2H), 2.86-2.80 (m, 4H) , 2.46 (s, 3H), 1.86-1.80 (m, 3H), 1.77-1.69 (m, 4H), 1.45-1.37 (m, 2H), 0.93 (d, 6H). MS m / z 579 (M + H) +. EXAMPLE 12 3.3-Di-methyl-bu-tan-1-sulfonate of 4-f2- (2,4-d! C! Gold-pheni!) - 5-methyl-4-r (piperidin-1-yl-amino) ) -carboniH-1H-imidazo! -1-yl) -phenyl The 2- (2,4-dichloro-phenyl) -1- (4-hydroxy-phenyl) -5-methyl-N-piperidin-1-yl- 1 H-imidazole-4-carboxamide prepared as described in Example 2, step 1 (50 milligrams, 0.11 mmol), dissolved in dichloromethane (3.0 milliliters), cooled to 0 ° C, and added to the triethylamine mixture (20 microliters, 0.13 mmol). The resulting mixture was cooled to -78 ° C, and 3,3-dimethyl-butan-1-sulfonyl chloride (25 milligrams, 0.13 mmol) was added carefully. The reaction was stirred at -78 ° C for 2 hours. Water was added to the reaction, the product was extracted with dichloromethane, and dried. The solvent was removed under reduced pressure, and separation by high performance liquid chromatography of preparation gave the title compound (46 milligrams, 69 percent) as a solid.
1 H NMR (400 MHz): d 7.85 (s, NH), 7.30-7.20 (m, 5H), 7.1 3-7.09 (m, 2H), 3.24-3.1 8 (m, 2H), 2.86-2.81 (m , 4H), 2.46 (s, 3H), 1 .86-1.80 (m, 2H), 1 .76-1 .69 (m, 5H), 1 .44-1 .37 (m, 2H), 0.92 (s, 9H). MS m / z 593 (M + H) +. EXAMPLE 13 Step 1: 1-r4- (Benzyloxy) -phenyl-2- (2,4-dichloro-phenyl) -5-methyl-N-r5- (trifluoro-methyl) -pyridin-2 - n-1 H -amidazole-4-carboxamide The 2-amino-5- (trifluoromethyl) -pyridine (404 milligrams, 2.49 mmol) was dissolved in dichloromethane (2.5 milliliters) under argon, and added carefully trimethylaluminum (1.25 milliliters, 2.0M in toluene, 2.5 millimoles) for 5 minutes. The solution was stirred at room temperature for 1.5 hours, and as a result, a 0.66M solution of an amidation reagent was obtained. 3.75 milliliters (2.5 millimoles) of this delivery solution was added to 1 - [4- (benzyloxy) -phenyl] -2- (2,4-dichloro-phenyl) -5-methyl-1 H-imidazole-4-carboxylate of ethyl, prepared as described in Example 1, step 2 (400 milligrams, 0.83 mmol), and the reaction solution was stirred at 45 ° C overnight. The reaction solution was cooled to 0 ° C, and quenched with HCl (aqueous, 2M, 7.5 milliliters). The mixture was diluted with dichloromethane, and neutralized by the addition of KOH (aqueous, 2M). The organic phase was separated, and the aqueous phase was further extracted with dichloromethane. The collected organic phases were washed with H2O before being dried with Na2SO4. The solvent was removed under reduced pressure, and purification by high performance yield liquid chromatography gave the title compound (319 milligrams, 64 percent) as a solid. 1 H NMR (400 MHz): d 9.89 (s, NH), 8.54 (s, 1H), 8.50 (d, 1H), 7.92-7.88 (m, 1H), 7.40-7.33 (m, 5H), 7.27-7.20. (m, 3H), 7.03-6.91 (m, 4H), 5.02 (s, 2H), 2.50 (s, 3H). MS m / z 597 (M + H) +. Step 2: 2- (2,4-dichloro-phenyl) -1- (4-hydroxy-phenyl) -5-methyl-N-r5- (trifluoro-met-P-pyridin-2-iH-1 H-imidazole -4-carboxamide 1- [4- (benzyloxy) -phenyl] -2- (2,4-dichloro-phenyl) -5-methyl-N- [5- (tri- fluoro-methyl) -pyridin-2 -yl] -1H-imidazole-4-carboxamide (319 milligrams, 0.53 mmol) was dissolved in hydrogen bromide (7.5 milliliters, 4.1M in acetic acid, 30.75 mmol), and the reaction mixture was stirred at room temperature for 4 hours The acetic acid was co-evaporated with ethanol, the residue was neutralized with ammonia, and dissolved in methanol, purification by flash chromatography gave the title compound (266 milligrams, 98 percent). 400 MHz): d 10.36 (s, NH, OH), 10.09 (s, NH, OH),
8. 89 (s, 1H), 8.69 (d, 1H), 8.48-8.43 (m, 1H), 7.87-7.80 (m, 2H), 7.67 (d, 1H), 7.41 (d, 2H), 7.06 (d, 2H), 2.65 (s, 3H). MS m / z 507 (M + H) +.
Step 3: 3,3-Trifluoro-propan-1-sulfonate of 4-r 2 - (2,4-dichloro-phenyl) -5-methyl-4- ( { R 5 - (trifluoromethyl) -pyridin -2-iH-amino) -carbonyl) -1H-imidazol-1-ill-phenyl 2-82,4-dichloro-phenyl) -1- (4-hydroxy-phenyl) -5-methyl-N- [5- (trifluoromethyl) -pyridin-2-yl] -1H-imidazole-4-carboxamide (136 milligrams, 0.27 mmol) and triethylamine (40 microliters, 0.32 mmol) in dichloromethane (4.0 milliliters), cooled to -78 ° C. 3,3,3-Trifluoro-propane-1-sulfonyl chloride (63 milligrams, 0.32 mmol) was carefully added to the reaction mixture. The resulting mixture was stirred at -78 ° C for 1 hour, and then allowed to reach room temperature. Water was added to the reaction, and the phases were separated. The organic phase was washed with NaHCO 3, brine, and dried with Na 2 SO 4. The solvent was removed under reduced pressure, and separation by high performance liquid chromatography of preparation gave the title compound (88 milligrams, 49 percent) as a solid. 1 H NMR (400 MHz): d 9.87 (s, NH), 8.55 (s, 1 H), 8.49 (d, 1 H), 7.93-7.89 (m, 1 H), 7.34-7.18 (m, 7 H), 3.53 (m , 2H), 2.85-2.73 (m, 2H), 2.54 (m, 3H). MS m / z 667 (M + H) +. EXAMPLE 14 3-Methyl-1-bu-1-sulfonate of 4-α- 2- (2,4-dichloro-phenyl) -5-methyl-4- ( { F5- (trifluoro-methyl) -pyridin- 2-iH-amino) -carbonyl) -1 H-imidazol-1-ill-phenyl The 2- (2, 4-dichloro-phenyl) -1- (4-hydroxy-phenyl) -5-methyl-N- [5- (trifluoromethyl) -pyridin-2-yl] -1H-imidazole-4-carboxamide prepared as described in Example 13, step 3 (139 milligrams, 0.27 millimoles) and triethylamine (46 microliters, 0.33 millimoles) in dichloromethane (4.0 milliliters), were cooled to -78 ° C. 3-Methyl-butan-1-sulfonyl chloride (56 milligrams, 0.33 millimoles) was carefully added to the reaction mixture. The resulting mixture was stirred at -78 ° C for 1 hour, and then allowed to reach room temperature. Water was added to the reaction, and the phases were separated. The organic phase was washed with NaHCO3, brine, and dried with Na2SO4. The solvent was removed under reduced pressure, and separation by high performance liquid chromatography of preparation gave the title compound (81 milligrams, 46 percent) as a solid. 1 H NMR (400 MHz): d 9.87 (s, NH), 8.55 (s, 1H), 8.49 (d, 1H), 7.93-7.89 (m, 1H), 7.34-7.14 (m, 7H), 3.29-3.24 (m, 2H), 2.53 (s, 3H), 1.88-1.81 (m, 2H), 1.79-1.69 (m, 1H), 0.95 (d, 6H). MS m / z 641 (M + H) +. General Synthetic Route
Claims (10)
1 . A compound of Formula (I): and pharmaceutically acceptable salts thereof, wherein: R1 represents: a) an alkoxy group of 1 to 6 carbon atoms optionally substituted by one or more fluoros, b) a group of the formula phenyl- (CH2) pO-, wherein p is 1, 2, or 3, and the phenyl ring is optionally substituted by 1, 2, or 3 groups represented by Z, c) a group R5S (O) 2O or R5S (O) 2NH, wherein R5 represents an alkyl group of 1 to 10 carbon atoms optionally substituted by one or more fluoros, or R5 represents phenyl or a heteroaryl group , each of which is optionally substituted by 1 2, or 3 groups represented by Z, or d) a group of the formula (R6) 3, wherein R6 represents an alkyl group of 1 to 6 carbon atoms, which it can be the same or different; Ra represents halogen, an alkyl group of 1 to 3 carbon atoms, or an alkoxy group of 1 to 3 carbon atoms; m is 0, 1, 2, or 3; R2 represents an alkyl group of 1 to 3 carbon atoms, an alkoxy group of 1 to 3 carbon atoms, hydroxyl, nitro, cyano, or halogen; n is 0, 1, 2, or 3; R3 represents: a) a group X-Y-N R7R8, wherein X is CO or SO2, Y is absent or represents N H optionally substituted by an alkyl group of 1 to 3 carbon atoms; and R7 and R8 independently represent: an alkyl group of 1 to 6 carbon atoms optionally substituted by 1, 2, or 3 groups represented by W; a cycloalkyl group of 3 to 15 carbon atoms optionally substituted by 1, 2, or 3 groups represented by W; a group (cycloalkyl of 3 to 15 carbon atoms) -alkylene of 1 to 3 carbon atoms optionally substituted by 1, 2, or 3 groups represented by W; a g rupe - (CH2) r (phenyl) s, where r is 0, 1, 2, 3, or 4, s is 1 when r is 0, or otherwise s is 1 or 2, and phenyl groups they are optionally independently substituted by 1, 2, or 3 groups represented by Z; a saturated 5- to 8-membered heterocyclic group containing a nitrogen atom, and optionally one of the following: oxygen, sulfur, or an additional nitrogen atom, wherein the heterocyclic group is optionally substituted by one or more alkyl groups of 1 to 3 carbon atoms, hydroxyl, or benzyl; a group - (CH2) tHet, where t is 0, 1, 2, 3, or 4, and the alkyl chain is optionally substituted by one or more alkyl groups of 1 to 3 carbon atoms, and H et represents a heteroaryl group optionally substituted by 1, 2, or 3 g groups selected from an alkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, or halogen, wherein the alkyl and alkoxy groups are optionally independently substituted by one or more fluoros; or R7 represents H, and R8 is as defined above; or R7 and R8, together with the nitrogen atom to which they are attached, represent a saturated or partially unsaturated 5- to 8-membered heterocyclic group containing a nitrogen atom and optionally one of the following: oxygen, sulfur, or an atom of additional nitrogen; wherein the heterocyclic group is optionally substituted by one or more alkyl groups of 1 to 3 carbon atoms, hydroxyl, fluorine, or benzyl; or b) oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl, or oxazolinyl, each optionally substituted by 1, 2, or 3 Z groups; R 4 represents H, an alkyl group of 1 to 6 carbon atoms, an alkoxy group of 1 to 6 carbon atoms, or an alkoxy group of 1 to 6 carbon atoms-alkylene of 1 to 6 carbon atoms, which contains a maximum of 6 carbon atoms, each of which groups is optionally substituted by one or more of fluorine or cyano; Z represents an alkyl group of 1 to 3 carbon atoms, an alkoxy group of 1 to 3 carbon atoms, hydroxyl, halogen, trifluoromethyl, trifluorothiomethyl, difluoro-ethoxy, trifluoromethoxy, trifluoromethyl. -sulphonyl, nitro, amino, mono- or di-alkyl of 1 to 3 carbon-amino atoms, alkyl of 1 to 3 carbon-sulfonyl atoms, alkoxy of 1 to 3 carbon-carbonyl atoms, carboxyl , cyano, carbamoyl, mono- or di-alkyl of 1 to 3 carbon atoms-carbam or Ilo, and acetyl; and W represents hydroxyl, fluorine, an alkyl group of 1 to 3 carbon atoms, an alkoxy group of 1 to 3 carbon atoms, amino, m ono- or di-alkyl of 1 to 3 carbon atoms or-am or a heterocyclic amine selected from morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl, wherein the heterocyclic amine is optionally substituted by an alkyl group of 1 to 3 carbon atoms, or hydroxyl; with the proviso that, when n is 1, then R2 is not methoxy in either the 2-position or the 4-position of the phenyl ring, and with the additional proviso that R1 is not methyl-sulfonyl-amino, methoxy, or CF3O-.
2. A compound as claimed in claim 1, wherein: R1 represents: a) an alkoxy group of 3 to 6 carbon atoms substituted by one or more fluoros, or b) a group of the formula phenyl- (CH2) ) pO-, where p is 1, 2, or 3, and the phenyl ring is optionally substituted by 1, 2, or 3 groups represented by Z, or c) a group R5S (O) 2O, wherein R5 represents an alkyl group of 1 to 6 carbon atoms optionally substituted by one or more fluoros, or R5 represents phenyl or a heteroaryl group, each of which is optionally substituted by 1, 2, or 3 groups represented by Z; Ra represents halogen, an alkyl group of 1 to 3 carbon atoms, or an alkoxy group of 1 to 3 carbon atoms; m is 0, 1, 2, or 3; R2 represents halogen; n is 0, 1, 2, or 3; R3 represents: a) a group X-Y-NR7R8, wherein X is CO; Y is absent or represents N H optionally substituted by an alkyl group of 1 to 3 carbon atoms; and R7 and R8 independently represent: an alkyl group of 1 to 6 carbon atoms optionally substituted by 1, 2, or 3 groups represented by W; a cycloalkyl group of 3 to 15 carbon atoms optionally substituted by 1, 2, or 3 groups represented by W; a group (cycloalkyl of 3 to 15 carbon atoms) -alkylene of 1 to 3 carbon atoms optionally substituted by 1, 2, or 3 groups represented by W; a group - (CH2) r (phenyl) s, wherein r is 0, 1, 2, 3, or 4, s is 1 when r is 0, and otherwise s is 1 or 2, and the phenyl groups are optionally independently substituted by 1, 2, or 3 g quotas represented by Z; a 5- to 8-membered saturated heterocyclic group containing one nitrogen atom, and optionally one of the following: oxygen, sulfur, or an additional nitrogen atom, wherein the heterocyclic group is optionally replaced by one or more groups of 1 to 3 carbon atoms, hydroxyl, or benzyl; a group - (CH2) tH.et, where t is 0, 1, 2, 3, or 4, and the alkylene chain is optionally substituted by one or more alkyl groups of 1 to 3 carbon atoms, and Het represents a heteroaryl group optionally substituted by 1, 2, or 3 groups selected from an alkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, or halogen; or R7 represents H, and R8 is as defined above; or R7 and R8, together with the nitrogen atom to which they are attached, represent a saturated or partially unsaturated 5- to 8-membered heterocyclic group containing a nitrogen atom and optionally one of the following: oxygen, sulfur, or an atom of additional nitrogen; wherein the heterocyclic group is optionally substituted by one or more alkyl groups of 1 to 3 carbon atoms, hydroxyl, fluorine, or benzyl; R4 represents H, an alkyl group of 1 to 6 carbon atoms, an alkoxy group of 1 to 6 carbon atoms, or an alkoxy group of 1 to 6 carbon atoms-alkylene of 1 to 6 carbon atoms, containing a maximum of 6 carbon atoms, each of which groups is optionally substituted by one or more of fluorine or cyano; Z represents an alkyl group of 1 to 3 carbon atoms, an alkoxy group of 1 to 3 carbon atoms, hydroxyl, halogen, trifluoromethyl, trifluorothiomethyl, difluoro-methoxy, trifluoromethoxy, trifluoromethylsulfonyl, nitro, amino, mono- or di-alkyl of 1 to 3 carbon atoms-amino, alkyl of 1 to 3 carbon atoms-sulfonyl, alkoxy of 1 to 3 carbon atoms -carbonyl, carboxyl, cyano, carbamoyl, mono- or di-alkyl of 1 to 3 carbon atoms-carbamoyl, and acetyl; and W represents hydroxyl, fluorine, an alkyl group of 1 to 3 carbon atoms, an alkoxy group of 1 to 3 carbon atoms, amino, mono- or di-alkyl of 1 to 3 carbon-amino atoms, or an amine heterocyclic selected from morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl, wherein the heterocyclic amine is optionally substituted by an alkyl group of 1 to 3 carbon atoms, or hydroxyl.
3. A compound of Formula I, as represented by Formula IA: where R 1 is: a) an alkoxy group of 3 to 6 carbon atoms substituted by one or more fluoros, b) a group of the phenyl- (CH 2) pO- form, where p is 1, 2, or 3, and the phenyl ring is optionally substituted by 1, 2, or 3 groups represented by Z, c) a group R 5 S (O) 2 O, wherein R 5 represents an alkyl group of 1 to 10 carbon atoms optionally substituted by one or more fluoros, or R5 represents thienyl or pyridyl, each of which is optionally substituted by one or more halogens; R2a represents H or chlorine; R2b represents H or chlorine; R3 represents a group CON H NR7R8, wherein N R7R8 represents piperidino, or R3 represents a group CON R7R8, wherein R7 is H, and R8 is pyridyl optionally substituted by halogen or trifluoromethyl; and R4 represents an alkyl group of 1 to 3 carbon atoms.
4. A compound of Formula I, as represented by Formula IA: wherein R1 is: a) an alkoxy group of 3 to 6 carbon atoms substituted by one or more fluoros, b) a group of the phenyl- (CH2) pO-, wherein p is 1, 2, or 3, and the phenyl ring is optionally substituted by 1, 2, or 3 groups represented by Z, c) a group R 5 S (O) 2 O, wherein R 5 represents an alkyl group of 1 to 6 carbon atoms optionally substituted by one or more fluoros; R2a represents H or chlorine; R represents H or chlorine; R3 represents a group CONHNR7R8, wherein N R7R8 represents piperidino; and R4 represents an alkyl group of 1 to 3 carbon atoms.
5. A compound of Formula I, as represented by Formula IA: wherein R1 is: a) an alkoxy group of 3 to 6 carbon atoms substituted by one or more fluoros, or b) a group of the formula R5S (O) 2O, wherein R5 represents an alkyl group of 1 to 6 atoms carbon optionally substituted by one or more fluoros, or R5 represents phenyl or a heteroaryl group, each of which is optionally substituted by 1, 2, or 3 groups represented by Z; R2a represents chlorine; R2b represents chlorine; R3 represents a group CON HR7R8, wherein NR7R8 represents piperidino; and R4 represents an alkyl group of 1 to 3 carbon atoms.
6. A compound according to any of the preceding claims, wherein: R1 represents a group R5S (O) 2O, wherein R5 represents an alkyl group of 1 to 6 carbon atoms optionally substituted by one or more fluoros.
7. A compound according to any of claims 1 to 5, wherein R1 is an alkoxy group of 4 to 6 carbon atoms substituted by one or more fluoros.
8. A compound according to any of claims 1 to 5, wherein R is a group of the formula phenyl (CH2) pO-, wherein p is 1, 2, or 3.
9. A compound according to any of claims 1 to 3, wherein R3 represents a group CONHNR7R8, wherein N R7R8 represents piperidino.
10. A compound according to any one of the preceding claims, wherein R4 represents an alkyl group of 1 to 6 carbon atoms. eleven . A compound selected from one or more of the following: 1- (4-benzyloxy-phenyl) -2- (2,4-dichloro-phenyl) -5-methyl-1H piperidin-1-yl-amide -imidazole-4-carboxylic acid; 4- [2- (2,4-Dichloro-phenyl) -5-methyl-4- (piperidin-1-yl-carbamoyl) -imidazol-1-yl] -phenyl ester of ethanesulfonic acid; 4- [2- (2,4-d-ro-phenyl) -5-m-ethyl-4- (piperidin-1-yl-carbamoyl) -imidazol-1-yl] -phenyl-ester of propan-1 acid sulfonic; 4- [2- (2,4-Dichloro-phenyl) -5-methyl-4- (piperidin-1-yl-carbamoyl) -imidazol-1-yl] -phenyl ester of butan-1-sulfonic acid; 2- (2,4-Dichloro-phenyl) -5-methyl-1- [4- (4,4,4-trifluoro-butoxy) -phenyl] -1H-imidazole-4-piperidin-1-yl-amide -carboxylic; 4- [2- (2,4-dichloro-phenyl) -5-methyl-4- (piperidin-1-yl-carbamoyl) -imidazol-1-yl] -phenyl-ester of the 3,3,3-trifluoro-propane-1-sulfonic acid; 4- [2- (2,4-d-ro-phenyl) -5-methyl-4- (piperidin-1-yl-carbam or I) -imidazol-1-yl] -phenyl-ester ester. 4,4,4-trifluoro-butan-1-sulfonic acid; thiophene-2-sulfonate of 4-. { 2- (2,4-dichloro-phenyl) -5-methyl-4- [(piperidin-1-yl-amino) -carbonyl] -1H-imidazol-1-yl} -phenyl; 4- pyridine-3-sulfonate. { 2- (2,4-Dichloro-phenyl) -5-methyl-4 - [(piperidin-1-yl-amino) -carbonyl] -1H-imidazol-1-yl} -phenyl; 4- pyridine-3-sulfonate. { 2- (2,4-Dichloro-phenyl) -5-methyl-4 - [(piperidin-1-yl-amino) -carbonyl] -1 H -imidazol-1-yl} -phenyl; 3-meti.l-butan-1-sulphonate of 4-. { 2- (2,4-Dichloro-phenyl) -5-methyl-4 - [(piperidin-1-yl-amino) -carbonyl] -1 H -imidazol-1-yl} -phenyl; 3,3-Di-ethyl-butan-1-sulfonate of 4-. { 2- (2,4-Dichloro-phenyl) -5-methyl-4 - [(piperidin-1-yl-amino) -carbonyl] -1 H -imidazol-1-yl} -phenyl; 4- [2- (2,4-difluoro-phenyl) -5- m ethyl-4- ( { [5- (trifluoromethyl) -pyridin 3,3,3-trifluoro-propane-1-sulfonate] -2-il] -am ino.}. -carbonyl) -1 H -imidazol-1-yl] -phenyl; 3-m-ethyl-butan-1-sulfonate of 4- [2- (2,4-d -ifluoro-phenyl) -5-methyl-4- ( { [5- (trifluoromethyl) -pyridin-2- il] -a ino.}. -carbonyl) -1 H -im idazol-1-yl] -phenyl; and the pharmaceutically acceptable salts of the same. 12. A compound of Formula I, as claimed in any of claims 1 to 11, for use as a medicament. 13. A pharmaceutical formulation, which comprises a compound of Formula I according to any of claims 1 to 11, and a pharmaceutically acceptable adjuvant, diluent, or vehicle. 14. The use of a compound of Formula I according to any of claims 1 to 1, in the preparation of a medicament for the treatment or prophylaxis of obesity, psychiatric disorders such as psychotic disorders, schizophrenia and bipolar disorders, anxiety, anxiety-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders, epilepsy, and related conditions, and neurological disorders, such as dementia, neurological disorders, Parkinson's disease , Huntington's chorea, and Alzheimer's disease, immune, cardiovascular, reproductive, and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems, and indications for prolonged abuse, addiction, and / or recurrence. 15. A method for the treatment of obesity, psychiatric disorders such as psychotic disorders, schizophrenia and bipolar disorders, anxiety, anxiety-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention, epilepsy, and related conditions, and neurological disorders, such as dementia, neurological disorders, Parkinson's disease, Huntington's chorea, and Alzheimer's disease, immune, cardiovascular, reproductive, and endocrine disorders, septic shock, system-related diseases respiratory and gastrointestinal, and indications for prolonged abuse, addiction, and / or recurrence, which comprises administering a pharmacologically effective amount of a compound of Formula I according to any of claims 1 to 11, to a patient who need 16. A compound as defined in any of claims 1 to 11, for use in the treatment of obesity. 17. A process for the preparation of a compound according to any of claims 1 to 11, which comprises reacting a compound of Formula II: wherein R2, R3, R4, Ra, m, and n are as defined above, with a group R1A-X, wherein R1A represents a group such that R1AO represents R1, and X represents a leaving group, at a temperature in the range of -25 ° C to 150 ° C, in the presence of a solvent inert, and optionally in the presence of a base.
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