JP5545614B2 - New substituted biphenylcarboxylic acid derivatives - Google Patents

Description

  The present invention relates to a partial agonist (or partial agonist) or antagonist selective for peroxisome proliferator-activated receptor δ, and further to treatment of diseases and / or the like caused by abnormal regulation of peroxisome proliferator-activated receptor δ and / or Alternatively, the present invention relates to a pharmaceutical or pharmaceutical composition for prevention, and a method for treating and / or preventing a disease or the like caused by abnormal regulation of peroxisome proliferator-activated receptor δ.

Peroxisome proliferator-activated receptor (PPAR, hereinafter referred to as PPAR) is a ligand-dependent transcription factor belonging to the nuclear receptor superfamily, and induces transcription of target genes in a ligand-dependent manner. To do. That is, when a ligand binds to PPAR, PPAR binds to a PPAR response element (PPAR) present in the promoter region of the target gene, and transcription of the target gene is induced.
So far, three types of isoforms (α type, δ type, and γ type) having different tissue distributions have been identified in various animal species including humans. Among these, PPARα is distributed in the liver, kidney, heart, muscle, and the like with high fatty acid catabolism, and is highly expressed particularly in the liver. When transcription of the target gene is induced by PPARα, A decrease in neutral fat, an increase in HDL cholesterol, a decrease in body weight, promotion of angiogenesis, etc. are induced. PPARδ is ubiquitously expressed in tissues in the body, mainly skeletal muscle, and activation of PPARδ leads to catabolism of fatty acids in skeletal muscle, increase in HDL cholesterol, improvement of insulin resistance, suppression of obesity, etc. It has become clear that it is induced (Non-Patent Document 1, Non-Patent Document 2). PPARγ is highly expressed in adipocytes and macrophages, and induces proteins involved in adipocyte differentiation and insulin sensitivity acquisition. Thus, each isoform of PPAR performs various functions in a specific organ or tissue.

  In the cell, PPAR forms a heterodimer with the retinoid X receptor (RXR). This heterodimer binds to a DNA sequence known as the PPAR response element (PPRE) and activates transcription of various genes. In addition, the PPAR / RXR heterodimer incorporates an activation cofactor such as DRIP-205 and SRC-1 to regulate the expression level of mRNA encoded by the target gene.

Each PPAR isoform is expected to contribute to alleviation of various symptoms known as metabolic syndrome, such as improvement of fat metabolism and insulin resistance, by inducing transcription of each target gene. . So-called fibrates such as fenofibrate, bezafibrate and clofibrate are already known as exogenous ligands for PPARα, and so-called thiazolidine-based agents such as troglitazone and pioglitazone are known as exogenous ligands for PPARγ. . In addition to the fibrates and thiazolidines, several compounds targeting each PPAR isoform have been reported (see Patent Documents 1 to 6).
PPARδ is expected to be involved in fat metabolism or cholesterol metabolism. As effective drug candidates targeting δ-type isoforms, for example, L-165041 (Non-Patent Document 3), GW-501516 (Non-Patent Document 1) and the like have been reported so far. It has not yet been approved.

WO01 / 092201 WO00 / 75103 WO2004 / 0567748 WO2004 / 046091 WO03 / 051821 WO02 / 098840

Oliver et al., Proc. Natl. Acad. Sci. USA. 98: 5306-531 2001 Tanaka et al., Proc. Natl. Acad. Sci. USA. 100: 15924-15929 2003 Leibowitz et al., FEBS Lett. 473: 333-336 2000

An object of the present invention is to provide a partial agonist (partial agonist) and / or an antagonist selective for peroxisome proliferator-responsive receptor δ (PPARδ).
Another object of the present invention is to provide a PPARδ transcriptional activator and a PPARδ transcriptional activity inhibitor containing these compounds (partial agonists or antagonists) as active ingredients.
Furthermore, an object of the present invention is to provide a therapeutic and / or prophylactic agent for diseases caused by abnormal PPARδ transcriptional activity (abnormally enhanced or abnormally suppressed transcriptional activity) containing these compounds as active ingredients.

As described above, although it is a PPAR agonist that is attracting attention as a therapeutic agent for metabolic syndrome such as abnormal fat metabolism, there are also problems to be solved. Among existing PPAR agonists (eg, PPARγ agonists), compounds that induce side effects (eg, liver dysfunction, edema, weight gain, etc.) based on their potent agonist activity have been reported (JP 2007- 314464 and the like). Therefore, recently, not only an agonist having full activity against PPAR (full agonist), but also development of an agonist with weak activity (partial agonist, partial agonist) and antagonist has become important.
In view of the above circumstances, the present inventors conducted extensive research and found a compound that exhibits partial agonist and / or antagonist activity selective for PPARδ, and completed the present invention.

That is, the present invention relates to the general formula (1):

[Wherein, R ₁ represents a linear, branched or cyclic hydrocarbon group having 1 to 10 carbon atoms and a methoxyethoxy group, R ₂ represents a hydrogen atom or a halogen atom, and R ₃ represents a straight chain, A branched or cyclic hydrocarbon group having 1 to 10 carbon atoms, a trifluoromethyl group, a phenyl group which may be unsubstituted or substituted, a phenoxy group which may be unsubstituted or substituted, Represents an adamantyl group which may be unsubstituted or substituted, R ₄ represents a hydrogen atom, a halogen atom or a hydrocarbon group having 1 to 10 carbon atoms, and X represents a CH ₂ NHCO group or a CONHCH ₂ group. It is a partial agonist and / or antagonist selective for PPARδ represented by
The present invention also provides a compound represented by the general formula (1):

[Wherein, R ₁ represents a linear, branched or cyclic hydrocarbon group having 1 to 10 carbon atoms and a methoxyethoxy group, R ₂ represents a hydrogen atom or a halogen atom, and R ₃ represents a straight chain, A branched or cyclic hydrocarbon group having 1 to 10 carbon atoms, a trifluoromethyl group, a phenyl group which may be unsubstituted or substituted, a phenoxy group which may be unsubstituted or substituted, Represents an adamantyl group which may be unsubstituted or substituted, R ₄ represents a hydrogen atom, a halogen atom or a hydrocarbon group having 1 to 10 carbon atoms, and X represents a CH ₂ NHCO group or a CONHCH ₂ group. Is a PPARδ transcriptional activator containing a partial agonist selective to PPARδ represented by
Furthermore, the present invention relates to a general formula (1):

[Wherein, R ₁ represents a linear, branched or cyclic hydrocarbon group having 1 to 10 carbon atoms and a methoxyethoxy group, R ₂ represents a hydrogen atom or a halogen atom, and R ₃ represents a straight chain, A branched or cyclic hydrocarbon group having 1 to 10 carbon atoms, a trifluoromethyl group, a phenyl group which may be unsubstituted or substituted, a phenoxy group which may be unsubstituted or substituted, Represents an adamantyl group which may be unsubstituted or substituted, R ₄ represents a hydrogen atom, a halogen atom or a hydrocarbon group having 1 to 10 carbon atoms, and X represents a CH ₂ NHCO group or a CONHCH ₂ group. It is a PPARδ transcriptional activity inhibitor containing an antagonist selective for PPARδ represented by

  The present invention provides antagonists or partial agonists that are selective for PPARδ.

  By using a compound of the present invention or a combination of a compound of the present invention and a PPARδ agonist other than the compound of the present invention, the transcriptional activation state of PPARδ can be adjusted to a desired level.

  A preventive or therapeutic agent for metabolic syndrome (for example, diabetes, hyperlipidemia, hypercholesterol (particularly LDL) disease, hypertension, obesity, arteriosclerosis, etc.) comprising the compound of the present invention as an active ingredient. Can provide drugs with fewer side effects.

Compounds of the invention for PPARδ transcriptional activity, 4′-butoxy-3 ′-((2-fluoro-4- (trifluoromethyl) benzamido) methyl) biphenyl-3-carboxylic acid (J87), and 4′-butoxy It is the result of investigating the influence of -3 '-((2-fluoro-4- (trifluoromethyl) benzamido) methyl) biphenyl-4-carboxylic acid (J85). GW is GW-501516 used as a control. Assuming that the maximum activity of GW is 100%, the% of the maximum activity of each compound against GW is shown in the figure.

In the general formula (1), R ₁ is a linear, branched or cyclic hydrocarbon group having 1 to 10 carbon atoms and a methoxyethoxy group, and preferably an n-butyl group. R ₂ is either a hydrogen atom or a halogen atom, preferably a halogen atom, more preferably a fluorine atom. R ₃ has a linear, branched or cyclic hydrocarbon group having 1 to 10 carbon atoms, a trifluoromethyl group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted group. It may be any of a phenoxy group which may be substituted or an adamantyl group which may be unsubstituted or substituted, preferably a trifluoromethyl group or an adamantyl group. R ₄ is any one of a hydrogen atom, a halogen atom, and a hydrocarbon group having 1 to 10 carbon atoms, preferably a methyl group or a fluorine atom. X is either a CH ₂ NHCO group or a CONHCH ₂ group, preferably a CONHCH ₂ group. In the general formula (1), the bonding position of the carboxyl group is not particularly limited, but for example, the 3-position or the 4-position is preferable.

The partial agonist or antagonist selective for PPARδ represented by the general formula (1) is not only a biphenyl-substituted carboxylic acid derivative represented by the general formula (1), but also a salt or a solvate or a hydrate thereof. It may be. The salt of the biphenyl-substituted carboxylic acid derivative is not particularly limited, and is a conventional salt, for example, an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as calcium salt or magnesium salt; aluminum Examples thereof include metal salts such as salts, and preferably pharmaceutically acceptable.
In addition, unless otherwise specified, the biphenyl-substituted carboxylic acid derivative represented by the general formula (1) is a stereoisomer such as a tautomer, a geometric isomer (for example, E-form, Z-form, etc.), enantiomer or the like. Isomers are also included. That is, when the biphenyl-substituted carboxylic acid derivative represented by the general formula (1) contains one or more asymmetric carbons, the stereochemistry of the asymmetric carbon is independently (R). Or (S) isomers and may exist as stereoisomers such as enantiomers or diastereoisomers of the derivatives.
As the active ingredient of the medicament of the present invention, any stereoisomer in a pure form, any mixture of stereoisomers, racemate and the like can be used.

Examples of the partial agonist or antagonist selective to PPARδ in the general formula (1) and salts thereof include, but are not limited to, the following.
4′-butoxy-3 ′-((2-fluoro-4- (trifluoromethyl) benzamido) methyl) biphenyl-4-carboxylic acid and its salt 4′-butoxy-3 ′-((2-fluoro-4- (Trifluoromethyl) benzamido) methyl) biphenyl-3-carboxylic acid and its salt 4′-butoxy-3 ′-((2-fluoro-4- (trifluoromethyl) benzamido) methyl) -2-methylbiphenyl-4 -Carboxylic acid and its salt 4'-butoxy-3 '-((2-fluoro-4- (trifluoromethyl) benzamido) methyl) -2-fluorobiphenyl-4-carboxylic acid and its salt 3'-((2 -Fluoro-4- (trifluoromethyl) benzamido) methyl) 4'-methoxyethoxybiphenyl-3-carboxylic acid and its salts

Among the compounds represented by the general formula (1) of the present invention, R ₁ is a linear, branched or cyclic hydrocarbon group having 1 to 10 carbon atoms, a methoxyethoxy group, and R ₂ is a hydrogen atom or a halogen atom. R ₃ has a linear, branched or cyclic hydrocarbon group having 1 to 10 carbon atoms, a trifluoromethyl group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted group. A phenoxy group which may be substituted, an adamantyl group which may be unsubstituted or substituted, X is a CONHCH ₂ group, and the bonding position of the carboxyl group is the 3rd or 4th position (1a)

[Wherein, R ₁ represents a linear, branched or cyclic hydrocarbon group having 1 to 10 carbon atoms, a methoxyethoxy group, R ₂ represents a hydrogen atom or a halogen atom, and R ₃ represents a linear or branched group. Or a cyclic hydrocarbon group having 1 to 10 carbon atoms, a trifluoromethyl group, an unsubstituted or optionally substituted phenyl group, an unsubstituted or optionally substituted phenoxy group, and unsubstituted Alternatively, it represents an adamantyl group which may have a substituent, and the bonding position of the carboxyl group is the 3-position or 4-position] can be produced by the following method (Scheme 1).

That is, the general formula (1a)

[Wherein, R ₁ represents a linear, branched or cyclic hydrocarbon group having 1 to 10 carbon atoms, a methoxyethoxy group, R ₂ represents a hydrogen atom or a halogen atom, and R ₃ represents a linear or branched group. Or a cyclic hydrocarbon group having 1 to 10 carbon atoms, a trifluoromethyl group, an unsubstituted or optionally substituted phenyl group, an unsubstituted or optionally substituted phenoxy group, and unsubstituted Or an adamantyl group which may have a substituent, and the bonding position of the carboxyl group is the 3-position or 4-position] is methyl 4′-methoxy-3′-formylbiphenyl-4-carboxylate (2) And general formula (7)

[Wherein R ₂ and R ₃ are as described above] (Step I), which is produced by reacting the compound represented by the general formula (3),

[Wherein, R ₂ and R ₃ are as described above] General formula (4) produced by deprotecting the ether part and ester part of the compound represented by (Step II),

[Wherein, R ₂ and R ₃ are as described above] General formula (5) produced by benzyl esterification of the carboxy group of the compound represented by (Step III),

[Wherein R ₂ and R ₃ are as described above] and the general formula (8),

[Wherein R ₁ represents a linear, branched or cyclic hydrocarbon group having 1 to 10 carbon atoms, a methoxyethoxy group, and Y represents a halogen atom] (IV step) General formula (6) obtained by

[Wherein R ₁ , R ₂ , R ₃ are as described above] can be carried out by deprotecting (step V).

The reaction in Step I is carried out in a solvent such as toluene, benzene, acetonitrile, dioxane, N, N-dimethylformamide in the presence of an acid (for example, trifluoroacetic acid or trifluoromethanesulfonic acid) and in the presence of triethylsilane as a reducing agent. Can be implemented. The reaction temperature at this time is usually -20 to 150 ° C, preferably 0 to 100 ° C, and the reaction time is usually 1 to 48 hours, preferably 6 to 24 hours.
The reaction of the second step can be carried out in a solvent such as chloroform, methylene chloride, carbon tetrachloride and the like in the presence of BBr ₃ or BCl ₃ . The reaction temperature at this time is usually −100 to 100 ° C., preferably −80 to 50 ° C., and the reaction time is usually 1 to 72 hours, preferably 6 to 48 hours.
The reaction in Step III can be carried out in a solvent such as chloroform, methylene chloride, acetonitrile, etc., in the presence of cesium fluoride, celite fluoride, or silica gel in the presence of cesium fluoride. The reaction temperature at this time is usually 0 to 150 ° C., preferably the boiling temperature of the solvent, and the reaction time is usually 1 to 48 hours, preferably 3 to 24 hours.
The reaction in the step IV is carried out in a solvent such as N, N-dimethylformamide, DMSO, toluene, benzene, acetonitrile, dioxane and the like, for example, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, potassium carbonate, It can be carried out in the presence of an alkali metal carbonate such as sodium carbonate or cesium carbonate. The reaction temperature at this time is usually -20 to 150 ° C, preferably 0 to 100 ° C, and the reaction time is usually 1 to 48 hours, preferably 6 to 24 hours.
The reaction in Step V is carried out in the presence of a metal catalyst such as palladium-supported activated carbon, platinum-supported activated carbon, platinum oxide, and rhodium-supported alumina in a solvent such as ethanol, methanol, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, and the like. It can be carried out at cm ² to 5 kgf / cm ² . The reaction temperature can be 0 to 100 ° C., preferably room temperature to 80 ° C.

Further, among the compounds represented by the general formula (1) of the present invention, R ₁ is a linear, branched or cyclic hydrocarbon group having 1 to 10 carbon atoms, a methoxyethoxy group, and R ₂ is a hydrogen atom or Halogen atom, R ₃ is a linear, branched or cyclic hydrocarbon group having 1 to 10 carbon atoms, trifluoromethyl group, unsubstituted or substituted phenyl group, unsubstituted or substituted group A phenoxy group which may have a substituent, an adamantyl group which may be unsubstituted or substituted, R ₄ is a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, and X is a CONHCH ₂ group In general formula (1b), the bonding position of the carboxyl group is the 3rd or 4th position

[Wherein, R ₁ is a linear, branched or cyclic hydrocarbon group having 1 to 10 carbon atoms, a methoxyethoxy group, R ₂ is a hydrogen atom or a halogen atom, and R ₃ is a linear, branched or cyclic group. Hydrocarbon group having 1 to 10 carbon atoms, trifluoromethyl group, phenyl group which may be unsubstituted or substituted, phenoxy group which may be unsubstituted or substituted, unsubstituted or substituted An adamantyl group which may have a group; R ₄ is a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms; X is a CONHCH ₂ group; ] Can be produced by the following method (Scheme 2).

That is, the general formula (1b)

[Wherein, R ₁ is a linear, branched or cyclic hydrocarbon group having 1 to 10 carbon atoms, a methoxyethoxy group, R ₂ is a hydrogen atom or a halogen atom, and R ₃ is a linear, branched or cyclic group. Hydrocarbon group having 1 to 10 carbon atoms, trifluoromethyl group, phenyl group which may be unsubstituted or substituted, phenoxy group which may be unsubstituted or substituted, unsubstituted or substituted An adamantyl group which may have a group; R ₄ is a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms; X is a CONHCH ₂ group; ] Is 4-bromophenol (9) and general formula (8),

[Wherein R ₁ represents a linear, branched or cyclic hydrocarbon group having 1 to 10 carbon atoms, a methoxyethoxy group, and Y represents a halogen atom]. General formula (10) obtained by (VI process),

[Wherein R ₁ is as described above] (formula VII) produced by formylation (step VII),

[Wherein R ₁ is as described above] and the general formula (7),

[Wherein R ₂ , R ₃ are as described above] (general formula (12) produced by reacting a compound represented by step VIII),

[Wherein R ₁ , R ₂ , R ₃ are as described above] and a bis (pinacolato) diborane compound (step IX), which is produced by reacting the compound represented by the general formula (13),

[Wherein R ₁ , R ₂ , R ₃ are as described above] and a compound represented by the general formula (15),

[Wherein, R ₄ represents a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, R ₅ represents a hydrogen atom, a hydrocarbon group having 1 to 10 carbon atoms, and Z represents a halogen atom] It can be produced by reacting a compound (Step X). When R ₅ is a hydrocarbon group having 1 to 10 carbon atoms, it can be produced by hydrolyzing the compound of the general formula (14) (step XI).

The reaction in the step VI is carried out in a solvent such as N, N-dimethylformamide, DMSO, toluene, benzene, acetonitrile, dioxane, etc., as a base, for example, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, potassium carbonate, It can be carried out in the presence of an alkali metal carbonate such as sodium carbonate or cesium carbonate. The reaction temperature at this time is usually -20 to 150 ° C, preferably 0 to 100 ° C, and the reaction time is usually 1 to 48 hours, preferably 6 to 24 hours.
The reaction of Step VII can be carried out in a solvent such as chloroform, methylene chloride, carbon tetrachloride, in the presence of dichloromethyl methyl ether, and in the presence of a Lewis acid such as titanium tetrachloride, aluminum chloride, tin tetrachloride. . The reaction temperature at this time is usually −100 to 100 ° C., preferably −50 to 50 ° C., and the reaction time is usually 1 to 72 hours, preferably 6 to 48 hours.
The reaction in the step VIII is a reducing agent in the presence of an acid (for example, trifluoroacetic acid or trifluoromethanesulfonic acid) in a solvent such as toluene, benzene, acetonitrile, dioxane, N, N-dimethylformamide or the like. Can be carried out in the presence of triethylsilane. The reaction temperature at this time is usually -20 to 150 ° C, preferably 0 to 100 ° C, and the reaction time is usually 1 to 48 hours, preferably 6 to 24 hours.
The reaction in Step XI is carried out in a solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, dioxane and the like, in the presence of, for example, potassium acetate, sodium acetate, potassium carbonate, sodium carbonate, dichlorobis (triphenyl). It can be carried out in the presence of palladium such as phosphine) palladium and dichlorobis (tri-O-tolylphosphine) palladium. The reaction temperature is usually −100 to 180 ° C., preferably 0 to 150 ° C., and the reaction time is usually 1 to 48 hours, preferably 6 to 24 hours.
The reaction in Step X is carried out in a single or mixed solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, dioxane, ethanol and the like, for example, presence of potassium acetate, sodium acetate, potassium carbonate, sodium carbonate, etc. The reaction can be carried out in the presence of palladium such as dichlorobis (triphenylphosphine) palladium and dichlorobis (tri-O-tolylphosphine) palladium. The reaction temperature is usually −100 to 180 ° C., preferably 0 to 150 ° C., and the reaction time is usually 1 to 48 hours, preferably 6 to 24 hours.
The reaction of step XI can be carried out under acidic conditions or basic conditions. The acidic conditions can be carried out in a single or mixed acidic solvent such as hydrochloric acid, acetic acid, hydrobromic acid and the like. The reaction temperature is usually 0 to 150 ° C., preferably 20 to 100 ° C., and the reaction time is usually 1 to 48 hours, preferably 6 to 24 hours. As basic conditions, it can implement in the mixed solvent of water and organic solvents, such as methanol, ethanol, and dioxane. The reaction temperature is usually 0 to 120 ° C., preferably the boiling temperature of the solvent, and the reaction time is usually 1 to 48 hours, preferably 6 to 24 hours.

Further, among the compounds represented by the general formula (1) of the present invention, R ₁ is a linear, branched or cyclic hydrocarbon group having 1 to 10 carbon atoms, a methoxyethoxy group, and R ₂ is a hydrogen atom or Halogen atom, R ₃ is a linear, branched or cyclic hydrocarbon group having 1 to 10 carbon atoms, trifluoromethyl group, unsubstituted or substituted phenyl group, unsubstituted or substituted group A phenoxy group which may have a substituent, an adamantyl group which may be unsubstituted or substituted, R ₄ is a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, X is a CONHCH ₂ group, General formula (1b) in which the carboxyl group is bonded to the 3rd or 4th position

[Wherein, R ₁ is a linear, branched or cyclic hydrocarbon group having 1 to 10 carbon atoms, a methoxyethoxy group, R ₂ is a hydrogen atom or a halogen atom, and R ₃ is a linear, branched or cyclic group. Hydrocarbon group having 1 to 10 carbon atoms, trifluoromethyl group, phenyl group which may be unsubstituted or substituted, phenoxy group which may be unsubstituted or substituted, unsubstituted or substituted An adamantyl group which may have a group, R ₄ is a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, X is a CONHCH ₂ group, and the bonding position of the carboxyl group is the 3rd or 4th position] Can also be produced by the following method (Scheme 3).

That is, the general formula (1b)

[Wherein, R ₁ is a linear, branched or cyclic hydrocarbon group having 1 to 10 carbon atoms, a methoxyethoxy group, R ₂ is a hydrogen atom or a halogen atom, and R ₃ is a linear, branched or cyclic group. Hydrocarbon group having 1 to 10 carbon atoms, trifluoromethyl group, phenyl group which may be unsubstituted or substituted, phenoxy group which may be unsubstituted or substituted, unsubstituted or substituted An adamantyl group which may have a group, R ₄ is a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, X is a CONHCH ₂ group, and the bonding position of the carboxyl group is the 3rd or 4th position] Is the general formula (12),

[Wherein, R ₁ is a linear, branched or cyclic hydrocarbon group having 1 to 10 carbon atoms, a methoxyethoxy group, R ₂ is a hydrogen atom or a halogen atom, and R ₃ is a linear, branched or cyclic group. Hydrocarbon group having 1 to 10 carbon atoms, trifluoromethyl group, phenyl group which may be unsubstituted or substituted, phenoxy group which may be unsubstituted or substituted, unsubstituted or substituted The adamantyl group which may have a group] and the general formula (16),

It can be produced by reacting a compound represented by the formula [wherein R ₄ represents a hydrogen atom, a halogen atom, or a hydrocarbon group having 1 to 10 carbon atoms] (Step XII).

  The reaction in Step XII is carried out in a single or mixed solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, dioxane, ethanol and the like, for example, presence of potassium acetate, sodium acetate, potassium carbonate, sodium carbonate, etc. The reaction can be performed in the presence of palladium such as dichlorobis (triphenylphosphine) palladium and dichlorobis (tri-O-tolylphosphine) palladium. The reaction temperature is usually −100 to 180 ° C., preferably 0 to 150 ° C., and the reaction time is usually 1 to 48 hours, preferably 6 to 24 hours.

According to an embodiment of the present invention, a PPARδ transcription activator comprising a partial agonist (partial agonist) or antagonist selective for PPARδ (an agent that activates (or induces) transcription of a PPARδ target gene) or PPARδ transcription activity An inhibitor (an agent that suppresses transcriptional activation of a PPARδ target gene by an agonist or the like) is provided.
Here, “agonist” refers to a compound that binds to PPARδ and induces transcriptional activation of a target gene by PPARδ. A “partial agonist” (or partial agonist) binds to PPARδ and induces transcriptional activation of a target gene by PPARδ, but is a complete agonist (full agonist; for example, it actually acts as an agonist in vivo. It is a compound with a weaker action than a compound that is In the present specification, the term “partial agonist” refers to a compound whose maximum activity is about several percent to 75%, preferably about 10% to 50% of the maximum activity of GW-501516 known as a full agonist. That is. On the other hand, an “antagonist” is a compound that binds to PPARδ but does not induce transcriptional activity by PPARδ and suppresses activation of PPARδ transcriptional activity by an agonist. As used herein, the term “antagonist” refers to a compound that reduces the activity of a full agonist to, for example, 70% or less, preferably 50% or less, more preferably 30% when a full agonist is present. A compound that decreases below, and even more preferably a compound that decreases below 10%.
Partial agonists also include compounds that act as antagonists when co-existing with other agonists.

  The compound of the present invention can induce the transcription activity of the target gene by PPARδ to a lesser extent than the full agonist. Alternatively, the compound of the present invention can suppress the transcriptional activation of the target gene of PPARδ by a full agonist. Accordingly, PPARδ-related diseases (for example, diabetes, hyperlipidemia, hypercholesterol (especially LDL) disease, hypertension, obesity, arteriosclerosis, etc.) and these diseases are treated using the compound of the present invention as a medicine. When used for the prevention or treatment of symptoms of metabolic syndrome (characterized as an easily evoked condition), the incidence of side effects as expected to be caused by a known full agonist (eg, GW-501516) is reduced. The target disease can be effectively prevented or treated.

As an active ingredient of the medicament of the present invention, in addition to the compound represented by the general formula (1), physiologically acceptable salts thereof may be used. Examples of the salt include alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, and calcium; ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris ( A salt of an amine such as hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, L-glucamine; or lysine; Salts with basic amino acids such as δ-hydroxylysine and arginine can be formed. If basic groups are present, salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; methanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, acetic acid, propionate, tartaric acid , Fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, salicylic acid and other organic acids Salts; or salts with acidic amino acids such as aspartic acid and glutamic acid.
Furthermore, a solvate or hydrate of the compound represented by the general formula (1) or a salt thereof can also be used as the active ingredient of the medicament of the present invention.

  The medicament of the present invention may be administered with an active ingredient compound represented by the general formula (1) and a pharmacologically acceptable salt thereof, or a solvate thereof or a hydrate thereof. However, in general, it is desirable to administer in the form of a pharmaceutical composition containing the above-mentioned substance, which is an active ingredient, and one or more pharmaceutical additives. As the active ingredient of the medicament of the present invention, two or more of the above substances can be used in combination, and the above pharmaceutical composition includes diabetes, hyperlipidemia, high cholesterol (particularly LDL) disease, hypertension. It is also possible to formulate other known active ingredients for the prevention or treatment of symptoms of metabolic syndrome characterized by obesity, arteriosclerosis and the like, and conditions that are likely to cause these diseases.

  The type of pharmaceutical composition is not particularly limited, and dosage forms include tablets, capsules, granules, powders, syrups, suspensions, suppositories, ointments, creams, gels, patches, inhalants, An injection agent etc. are mentioned. These preparations are prepared according to a conventional method. In the case of a liquid preparation, it may be dissolved or suspended in water or other appropriate solvent at the time of use. Tablets and granules may be coated by a known method. In the case of injection, it is prepared by dissolving the compound of the present invention in water, but it may be dissolved in physiological saline or glucose solution as necessary, and a buffer or preservative may be added. Good. It is provided in any dosage form for oral or parenteral administration. For example, a pharmaceutical composition for oral administration in the form of granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions or liquids, for intravenous administration, for intramuscular administration, Alternatively, it can be prepared as a pharmaceutical composition for parenteral administration in the form of injections, drops, transdermal absorbents, transmucosal absorbents, nasal drops, inhalants, suppositories, etc. for subcutaneous administration. Injections, infusions, and the like can be prepared as powdered dosage forms such as freeze-dried forms, and can be used by dissolving in an appropriate aqueous medium such as physiological saline at the time of use. It is also possible to administer a sustained release preparation coated with a polymer directly into the brain.

  A person skilled in the art can appropriately select the type of pharmaceutical additive used for the production of the pharmaceutical composition, the ratio of the pharmaceutical additive to the active ingredient, or the method for producing the pharmaceutical composition depending on the form of the composition. It is. As the additive for preparation, an inorganic or organic substance, or a solid or liquid substance can be used, and generally it can be blended in an amount of 1 to 90% by weight based on the weight of the active ingredient. Specifically, examples of such substances are lactose, glucose, mannitol, dextrin, cyclodextrin, starch, sucrose, magnesium aluminate metasilicate, synthetic aluminum silicate, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium , Ion exchange resin, methylcellulose, gelatin, gum arabic, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, tragacanth, bentonite, bee gum, titanium oxide, sorbitan fatty acid ester, Sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin, polyso Bate, macrogol, vegetable oils, waxes, liquid paraffin, white petrolatum, fluorocarbons, nonionic surfactants, propylene glycol, water and the like.

  In order to produce a solid preparation for oral administration, an active ingredient and excipient components such as lactose, starch, crystalline cellulose, calcium lactate, anhydrous silicic acid and the like are mixed to form a powder, or if necessary, sucrose, Add a binder such as hydroxypropylcellulose and polyvinylpyrrolidone, a disintegrant such as carboxymethylcellulose and carboxymethylcellulose calcium, and wet or dry granulate to form granules. In order to produce tablets, these powders and granules may be tableted as they are or after adding a lubricant such as magnesium stearate or talc. These granules or tablets may be coated with an enteric solvent base such as hydroxypropylmethylcellulose phthalate or methacrylic acid-methyl methacrylate polymer and coated with an enteric solvent preparation or ethylcellulose, carnauba wax, hardened oil, etc. to form a sustained preparation. it can. In order to produce capsules, powders or granules are filled into hard capsules, or active ingredients are dissolved as they are or dissolved in glycerin, polyethylene glycol, sesame oil, olive oil, etc., and then coated with a gelatin film to form soft capsules. Can do.

  In order to produce injections, active ingredients such as hydrochloric acid, sodium hydroxide, lactose, lactic acid, sodium, sodium monohydrogen phosphate, sodium dihydrogen phosphate, etc. Dissolve in distilled water for injection together with an isotonic agent, filter aseptically and fill into ampoules, or add mannitol, dextrin, cyclodextrin, gelatin, etc. . In addition, reticine, polysorbate 80, polyoxyethylene hydrogenated castor oil, etc. may be added to the active ingredient and emulsified in water to give an emulsion for injection.

  To produce a rectal dosage form, the active ingredient is moistened with a suppository base material such as cacao butter, fatty acid tri, di- and monoglycerides, polyethylene glycol, etc., dissolved, poured into a mold and cooled, or the active ingredient is made of polyethylene. What is necessary is just to coat | cover with a gelatin film | membrane after melt | dissolving in glycol, soybean oil, etc.

  In order to produce an external preparation for skin, the active ingredient is added to white petrolatum, beeswax, liquid paraffin, polyethylene glycol, etc., and if necessary, moistened and kneaded to make an ointment, or rosin, alkyl acrylate polymer After being kneaded with an adhesive such as polyalkyl, it is spread on a non-woven fabric such as polyalkyl to obtain a tape.

  The dose and frequency of administration of the medicament of the present invention are not particularly limited, and conditions such as prevention and / or progression of the disease to be treated and / or purpose of treatment, type of disease, patient weight and age, severity of the disease, etc. Depending on the situation, it is possible to make an appropriate selection based on the judgment of the doctor. In general, the dose per day for an adult is about 0.01 to 1000 mg (weight of active ingredient), and can be administered once or several times a day or every few days. it can. When used as an injection, daily doses of 0.001 to 100 mg (active ingredient weight) are preferably administered continuously or intermittently to adults.

  The medicament of the present invention can be prepared as a sustained-release preparation such as a delivery system encapsulated in implantable tablets and microcapsules using a carrier that can prevent immediate removal from the body. As the carrier, for example, biodegradable and biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoester, and polylactic acid can be used. Such materials can be readily prepared by those skilled in the art. Liposome suspensions can also be used as pharmaceutically acceptable carriers. Useful liposomes are prepared as a lipid composition comprising, but not limited to, phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanol (PEG-PE) through a filter of appropriate pore size to obtain a size suitable for use, and reverse phase. Purified by evaporation.

The medicament of the present invention can be included as a pharmaceutical composition in the form of a kit together with instructions for administration in a container or pack. When the pharmaceutical composition of the present invention is supplied as a kit, different components of the composition are packaged in separate containers and mixed immediately before use. The reason why the components are packaged separately in this way is to enable long-term storage without losing the function of the active component.
Reagents contained in the kit are supplied in a container in which the constituents maintain the activity effectively for a long period of time, are not adsorbed by the material of the container, and do not undergo alteration. For example, a sealed glass ampoule includes a buffer packaged under a neutral and non-reactive gas such as nitrogen gas. Ampoules are composed of glass, polycarbonate, organic polymers such as polystyrene, ceramics, metals, or any other suitable material commonly used to hold reagents. Other examples of suitable containers include simple bottles made from similar materials such as ampoules, and packaging materials that are internally lined with foil such as aluminum or alloy. Containers also include test tubes, vials, flasks, bottles, syringes, or the like.

  The kit also includes instructions for use. Instructions for using this kit are printed on paper or other materials and / or electrical or electromagnetic such as floppy disk, CD-ROM, DVD-ROM, Zip disk, video tape, audio tape, etc. May be supplied as a readable medium. Detailed instructions for use may be actually attached to the kit, or may be posted on a website designated by the manufacturer or distributor of the kit or notified by e-mail or the like.

Furthermore, the present invention includes diseases that occur due to abnormal PPARδ transcriptional activity (eg, diabetes, hyperlipidemia, high cholesterol (particularly LDL) disease, hypertension, obesity, arteriosclerosis, and Metabolic syndrome), which is characterized as a condition prone to causing these diseases, is included.
Here, “treatment” means to prevent or alleviate the progression and worsening of a disease state in a mammal suffering from a disease or the like that develops due to an abnormality in PPARδ transcriptional activity. And treatment aimed at preventing or mitigating exacerbations.
In addition, “prevention” means to prevent in advance the onset or illness of a mammal that is likely to suffer from a disease or the like that develops due to abnormal PPARδ transcriptional activity. It is a treatment aimed at preventing the onset of various symptoms.

  “Mammal” to be treated means any animal classified as a mammal, and is not particularly limited. For example, in addition to humans, pet animals such as dogs, cats, rabbits, cows, pigs, sheep , Livestock animals such as horses. Particularly preferred “mammals” are humans.

  Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the examples.

[Synthesis Example 1] 4′-butoxy-3 ′-((2-fluoro-4- (trifluoromethyl) benzamido) methyl) -2-methylbiphenyl-4-carboxylic acid (17)


Compound 18 (145 mg, 0.323 mmol), bis (pinacolato) diboron (120 mg, 0.473 mmol), (Ph ₃ P) ₂ PdCl ₂ (18 mg, 0.0398 mmol) and KOAc (140 mg, 1.43 mmol) were added to dioxane ( 3 mL) and stirred at 100 ° C. for 3 hours. The reaction was diluted with ethyl acetate and water and extracted with ethyl acetate. The organic layer was dried over MgSO ₄ , concentrated, and purified by silica gel chromatography (hexane / ethyl acetate = 10/1) to obtain Compound 19 (139 mg, 0.281 mmol, 87%).

¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.24 (t, J = 7.9 Hz, 1H), 7.78 (d, J = 1.4 Hz, 1H), 7.74 (dd, J = 8.0, 1.4 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.37 (d, J = 11.6 Hz, 1H), 7.31 (m, 1H), 6.89 (d, J = 8.0 Hz, 1H), 4.69 (d, J = 4.9 Hz, 2H), 4.06 (t, J = 6.7 Hz, 2H), 1.82 (m, 2H), 1.50 (m, 2H), 1.32 (s, 12H), 0.97 (t, J = 7.6 Hz, 3H); MS (FAB) 495 (M) ⁺
Compound 19 (132 mg, 0.266 mmol) and methyl 4-bromo-3-methylbenzoate (110 mg, 0.480 mmol) were dissolved in DME (3 mL), ethanol (2 mL) and 2M aqueous Na ₂ CO ₃ solution (Ph Treated with ₃ P) ₂ PdCl ₂ (35 mg, 0.049 mmol) and stirred at 60 ° C. for 5 h. The reaction was diluted with ethyl acetate, quenched with brine and extracted with ethyl acetate. The organic layer was dried over MgSO ₄ , concentrated, and purified by silica gel chromatography (hexane / ethyl acetate = 10/1) to obtain Compound 20 (111 mg, 0.214 mmol, 81%).

¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.25 (t, J = 7.6 Hz, 1H), 7.93 (s, 1H), 7.86 (dd, J = 7.9, 1.8 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.42 (m, 1H), 7.39 (d, J = 11.6 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.27 (m, 1H), 7.23 (dd, J = 8.3, 2.2 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 4.73 (d, J = 5.5 Hz, 2H), 4.10 (t, J = 6.7 Hz, 2H), 3.92 (s, 3H ), 2.32 (s, 3H), 1.86 (m, 2H), 1.55 (m, 2H), 1.01 (t, J = 7.6 Hz, 3H); MS (FAB) 517 (M) ⁺

Compound 20 (32.1 mg, 62.0 μmol) was dissolved in 6N aqueous HCl (3 mL) and acetic acid (8 mL), and the mixture was stirred at 100 ° C. for 2 hr. The reaction was poured into water and the resulting precipitate was passed through a filter to give the title compound (4′-butoxy-3 ′-((2-fluoro-4- (trifluoromethyl) benzamido) methyl) -2-methylbiphenyl- 4-carboxylic acid) was obtained as a white solid (30.1 mg, 59.8 μmol, 96%).
mp. 240-241 ° C;
¹ H-NMR (500 MHz, DMSO) 12.88 (s, 1H), 8.94 (t, J = 5.9 Hz, 1H), 7.84-7.77 (m, 4H), 7.66 (d, J = 7.9 Hz, 1H), 7.28-7.25 (m, 3H), 7.08 (m, 1H), 4.50 (d, J = 5.9 Hz, 2H), 4.07 (t, J = 6.1 Hz, 2H), 2.28 (s, 3H), 1.76 (m , 2H), 1.50 (m, 2H), 0.95 (t, J = 7.6 Hz, 3H);
MS (FAB) 504 (M + H) ⁺

Synthesis Example 2 4′-Butoxy-3 ′-((2-fluoro-4- (trifluoromethyl) benzamido) methyl) -2-fluorobiphenyl-4-carboxylic acid (21)

In the same manner as in the synthesis of Compound 17, the title compound (4′-butoxy-3 ′-((2-fluoro-4- (trifluoromethyl) benzamido) methyl) -2-fluorobiphenyl-4-carboxylic acid) is colorless. Obtained as an individual.
Yield 71%
mp. 219-221 ° C;
¹ H-NMR (500 MHz, DMSO) δ 13.25 (s, 1H), 8.96 (t, J = 5.7 Hz, 1H), 7.83-7.78 (m, 3H), 7.72 (dd, J = 11.3, 1.5 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.52-7.49 (m, 2H), 7.14 (d, J = 9.2 Hz, 1H), 4.51 ( d, J = 5.7 Hz, 2H), 4.09 (t, J = 6.1 Hz, 2H), 1.76 (m, 2H), 1.49 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H);
MS (FAB) 508 (M + H) ⁺

[Synthesis Example 3] 4'-butoxy-3 '-((2-fluoro-4- (trifluoromethyl) benzamido) methyl) biphenyl-4-carboxylic acid (22)

Compound 19 (60 mg, 0.13 mmol) and methyl 4-carboxyphenylboronic acid (50 mg, 0.30 mmol) were dissolved in DME (6 mL), ethanol (4 mL) and 2M aqueous Na ₂ CO ₃ solution (Ph ₃ P ) ₂ PdCl ₂ (10 mg, 0.014 mmol) and stirred at 50 ° C. for 5 hours. The reaction was diluted with ethyl acetate, quenched with brine and extracted with ethyl acetate. The organic layer was dried over MgSO ₄ , concentrated, and purified by silica gel chromatography (hexane / ethyl acetate = 3/1) to give the title compound (4′-butoxy-3 ′-((2-fluoro-4- (tri Fluoromethyl) benzamido) methyl) biphenyl-4-carboxylic acid) (30 mg, 0.061 mmol, 47%) was obtained as a white solid.
mp. 263-265 ° C;
¹ H-NMR (500 MHz, DMSO xd ₆ ) δ 8.96 (t, J = 5.7 Hz, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.83 (m, 2H), 7.71 (d, J = 8.5 Hz, 2H), 7.69-7.62 (m, 3H), 7.12 (d, J = 9.2 Hz, 1H), 4.52 (d, J = 5.7 Hz, 2H), 4.08 (t, J = 6.1 Hz, 2H) , 1.75 (m, 2H), 1.49 (m, 2H), 0.95 (t, J = 7.6 Hz, 3H);
MS (FAB) 490 (M + H) ⁺

Synthesis Example 4 4′-Butoxy-3 ′-((2-fluoro-4- (trifluoromethyl) benzamido) methyl) biphenyl-3-carboxylic acid (23)

The title compound (4′-butoxy-3 ′-((2-fluoro-4- (trifluoromethyl) benzamido) methyl) biphenyl-3-carboxylic acid) was obtained by a method similar to the synthesis of compound 22.
67%;
mp. 263-265 ° C;
¹ H-NMR (500 MHz, DMSO) δ 8.28 (t, J = 1.8 Hz, 1H), 8.26 (t, J = 7.9 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.79 (d , J = 7.9 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.56-7.50 (m, 3H), 7.42 (m, 1H), 7.40 (d, J = 11.6 Hz, 1H), 6.99 (d, J = 7.9 Hz, 1H), 4.76 (d, J = 5.5 Hz, 2H), 4.11 (t, J = 6.7 Hz, 2H), 1.87 (m, 2H), 1.55 (m, 2H), 1.01 (t, J = 7.6 Hz, 3H); MS (FAB) 490 (M + H) ⁺

Synthesis Example 5 3 ′-((2-Fluoro-4- (trifluoromethyl) benzamido) methyl) 4′-methoxyethoxybiphenyl-3-carboxylic acid (24)

Synthesis of methyl 3 '-((2-fluoro-4- (trifluoromethyl) benzamido) methyl) -4'-methoxybiphenyl-4-carboxylate (25)

Methyl 3′-formyl-4′-methoxybiphenyl-4-carboxylate (1.08 g, 4.00 mmol), 2-fluoro-4-trifluoromethylbenzamide (1.66 g, 8.01 mmol), toluene (30 mL) Were added trifluoroacetic acid (0.5 mL) and triethylsilane (0.5 mL), and the mixture was heated to reflux for 24 hours. The reaction mixture was concentrated, poured into water, and extracted with ethyl acetate. The organic layer was dried over MgSO ₄ , concentrated, and purified by silica gel chromatography (hexane / ethyl acetate = 5/1 to 3/1) to give compound 25 (1.35 g, 73%) as a white solid.
¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.25 (t, J = 7.9 Hz, 1H), 8.07 (d, J = 7.9 Hz, 2H), 7.64 (d, J = 1.8 Hz, 1H), 7.62 ( d, J = 7.9 Hz, 2H), 7.57 (dd, J = 8.5, 1.8 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.42 (m, 1H), 7.39 (d, J = 11.6 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 4.74 (d, J = 5.5 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H);
MS (FAB) 461 (M) ⁺

Synthesis of 3 ′-((2-fluoro-4- (trifluoromethyl) benzamido) methyl) -4′-hydroxybiphenyl-4-carboxylic acid (26)

Compound 25 (1.15 g, 2.49 mmol) and dichloromethane (80 mL) were mixed and cooled to -78? C. A dichloromethane solution (10 mmol) of 1 mol / L boron tribromide was added, stirred for 3 hours, and returned to room temperature. Saturated brine was added to the reaction mixture, and the mixture was extracted with dichloromethane and ethyl acetate. The organic layer was dried over MgSO ₄ , concentrated, and purified by silica gel chromatography (hexane / ethyl acetate = 2/1 to 0/1) to give compound 26 (880 mg, 82%) as a white solid.
¹ H-NMR (500 MHz, DMSO) δ 9.96 (s, 1H), 8.99 (t, J = 5.5 Hz, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.84-7.81 (m, 2H) , 7.68-7.66 (m, 3H), 7.59 (d, J = 2.4 Hz, 1H), 7.50 (dd, J = 8.5, 2.4 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 4.49 ( d, J = 5.5 Hz, 2H);
MS (FAB) 434 (M + H) ⁺

Synthesis of 3 ′-((2-fluoro-4- (trifluoromethyl) benzamido) methyl) -4′-hydroxybiphenyl-4-carboxylic acid benzyl ester (27)

Compound (26) (396 mg, 0.914 mmol) and acetonitrile (80 mL) were mixed. CsF-Celite (0.36 g) and benzyl bromide (0.66 g, 3.9 mmol) were added, and the mixture was heated to reflux for 5 hours. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography (hexane / ethyl acetate = 5/1 to 2/1) to obtain Compound 27 (353 mg 74%) as a white solid.
¹ H-NMR (500 MHz, CDCl ₃ ) δ 9.25 (s, 1H), 8.29 (t, J = 8.2 Hz, 1H), 8.11 (d, J = 8.2 Hz, 2H), 7.64 (m, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.2 Hz, 1H), 7.52 (dd, J = 8.5, 2.4 Hz, 1H), 7.47-7.34 (m, 7H), 7.06 (d , J = 8.5 Hz, 1H), 5.38 (s, 2H), 4.67 (d, J = 6.1 Hz, 2H);
MS (FAB) 524 (M + H) ⁺ ;

Synthesis of 3 '-((2-fluoro-4- (trifluoromethyl) benzamido) methyl) 4'-methoxyethoxybiphenyl-3-carboxylic acid benzyl ester (28)

Compound (27) (30.2 mg, 57.7 μmol), methoxyethoxy chloride (20 mg, 0.21 mmol), anhydrous potassium carbonate (10 mg) and DMF (1 mL) were mixed, and the mixture was heated and stirred at 80 ° C. for 2 hours. . The reaction mixture was poured into saturated brine and extracted with dichloromethane. The organic layer was dried over MgSO ₄ , concentrated and purified by silica gel chromatography (hexane / ethyl acetate = 5/1 to 2/1) to give compound 28 (30.5 mg, 91%) as a white solid.
¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.15 (t, J = 7.9 Hz, 1H), 8.11 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 2.4 Hz, 1H), 7.62 ( d, J = 8.5 Hz, 2H), 7.55-7.34 (m, 9H), 6.99 (d, J = 8.5 Hz, 1H), 5.38 (s, 2H), 4.75 (d, J = 4.9 Hz, 2H), 4.24 (t, J = 4.7 Hz, 2H), 3.79 (t, J = 4.7 Hz, 2H), 3.35 (s, 3H);
MS (FAB) 582 (M + H) ⁺

Synthesis of 3 ′-((2-fluoro-4- (trifluoromethyl) benzamido) methyl) 4′-methoxyethoxybiphenyl-3-carboxylic acid (24)

Compound 28 (30.5 mg, 52.4 μmol), 10% Pd—C (20 mg) and AcOEt (5 mL) were mixed and subjected to catalytic reduction for 1 hour at room temperature and normal pressure. The reaction was filtered through celite and concentrated to give the title compound (3 ′-((2-fluoro-4- (trifluoromethyl) benzamido) methyl) 4′-methoxyethoxybiphenyl-3-carboxylic acid) (21.0 mg , 82%) was obtained as a white solid.
¹ H-NMR (500 MHz, DMSO) δ 2.92 (s, 1H), 8.94 (t, J = 5.5 Hz, 1H), 7.99 (d, J = 7.9 Hz, 2H), 7.86-7.81 (m, 2H) , 7.73-7.64 (m, 5H), 7.14 (d, J = 8.5 Hz, 1H), 4.53 (d, J = 5.5 Hz, 2H), 4.21 (t, J = 4.0 Hz, 2H), 3.72 (t, J = 4.0 Hz, 2H), 3.31 (s, 3H);
MS (FAB) 492 (M + H) ⁺

[Experimental Example] Effect of PPARδ on Transcriptional Activity Human fetal kidney-derived cell HEK-293 confluently cultured in Dulbecco's modified Eagle's medium (10% FCS) was diluted to 1/6, and 100 μL was seeded in a 96-well plate, Culture was performed. The next day, while stirring a 14 mL tube containing phosphate buffer (70 μL) by vortex, various prepared plasmids (receptor plasmids expressing chimeric proteins of GAL4 DNA binding region and human PPARδ ligand binding region, reporter plasmid (luciferase assay) ), Β-galactosidase plasmid (for internal standard)) solution (70 μL) was added dropwise. After 20 minutes, 10 μL each was added to a 96-well plate while vortexing. After culturing the 96-well plate for about 8 hours, compound (GW-501516 (control as a full agonist), compound 22 (4′-butoxy-3 ′-((2-fluoro-4- (trifluoromethyl) benzamide)) Methyl) biphenyl-4-carboxylic acid), compound 23 (4′-butoxy-3 ′-((2-fluoro-4- (trifluoromethyl) benzamido) methyl) biphenyl-3-carboxylic acid)) 25 μL was added to each well and cultured overnight.
After the culture, luciferase activity and β-galactosidase activity were measured according to a conventional method. A value obtained by dividing the obtained luciferase activity by β-galactosidase activity was defined as RLU (Relativistic Light Unit).

As a result of activity measurement, it was found that the maximum activity of Compound 23 was about 50% of the maximum activity of GW-501516, which is a full agonist, and Compound 22 was about 10%. It was also revealed that when Compound 23 or Compound 22 was added in the presence of GW-501516, the maximum activity decreased in a concentration-dependent manner (that is, Compound 23 and Compound 22 also exhibited antagonist activity).
Compound 17 (4′-butoxy-3 ′-((2-fluoro-4- (trifluoromethyl) benzamido) methyl) -2-methylbiphenyl-4-carboxylic acid) and compound 21 (4′-butoxy-3 ′ -((2-Fluoro-4- (trifluoromethyl) benzamido) methyl) biphenyl-4-carboxylic acid), like Compound 22, exhibits a maximum activity of about 10% of the maximum activity of GW-501516. Also showed antagonist activity.
Furthermore, Compound 17, Compound 21, _{EC 50} for PPARδ compounds 22 and compound 23, respectively, 11 nM, 53 nm, were 170nM and 29 nM.
From the above, it has been clarified that the compound of the present invention has an activity as a partial agonist and acts as an antagonist when it coexists with a full agonist.

  The compounds of the present invention have activity as PPARδ partial agonists or antagonists. Therefore, a medicine containing these compounds as an active ingredient is expected to exhibit a medicinal effect that avoids side effects that may be caused by a full agonist of PPARδ.

Claims (4)

General formula (1):
[Wherein, R ₁ represents a linear, branched or cyclic hydrocarbon group having 1 to 10 carbon atoms and a methoxyethoxy group, R ₂ represents a fluorine atom bonded to the 2-position, and R ₃ represents the 4-position. a trifluoromethyl group bound to Table by _{R 4} represents a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, a carboxyl group is bonded to the 4-position, X represents a ₂ group CONHCH] Biphenyl-substituted carboxylic acid derivatives or salts thereof, or solvates or hydrates thereof. The biphenyl-substituted carboxylic acid derivative or a salt thereof, or a solvate or a hydrate thereof according to claim 1, wherein R ₁ is an n-butyl group . The biphenyl-substituted carboxylic acid derivative or a salt thereof, or a solvate or a hydrate thereof according to claim 1 or 2, wherein R ₄ is a hydrogen atom or a methyl group . The compound represented by the general formula (1) is 4′-butoxy-3 ′-((2-fluoro-4- (trifluoromethyl) benzamido) methyl) biphenyl-4-carboxylic acid, 4′-butoxy-3. '-((2-Fluoro-4- (trifluoromethyl) benzamido) methyl) -2-methylbiphenyl-4-carboxylic acid, 4'-butoxy-3'-((2-fluoro-4- (trifluoromethyl The biphenyl-substituted carboxylic acid derivative or a salt thereof, or a solvate or a hydrate thereof according to claim 1, which is any one of :)) benzamido) methyl) -2-fluorobiphenyl-4-carboxylic acid.