KR101681041B1 - A noble aromatic compound derivatives as a ligand to inactivate err gamma - Google Patents
A noble aromatic compound derivatives as a ligand to inactivate err gamma Download PDFInfo
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- DNRRKNXPALYUTH-UHFFFAOYSA-N COc(cc1)ccc1C(c(cc1)ccc1OC)=C(CCCO)c1cccnc1 Chemical compound COc(cc1)ccc1C(c(cc1)ccc1OC)=C(CCCO)c1cccnc1 DNRRKNXPALYUTH-UHFFFAOYSA-N 0.000 description 2
- MBNWCMBROCPZNI-UHFFFAOYSA-N C[n]1ncc(C(CCCBr)=C(c(cc2)ccc2O)c(cc2)ccc2O)c1 Chemical compound C[n]1ncc(C(CCCBr)=C(c(cc2)ccc2O)c(cc2)ccc2O)c1 MBNWCMBROCPZNI-UHFFFAOYSA-N 0.000 description 2
- KJYZQUMLOWXZKM-HYOGKJQXSA-N CN(C)CCOc(cc1)ccc1/C(/c(cc1)ccc1O)=C(/CCCO)\c1ccc(N2CCOCC2)nc1 Chemical compound CN(C)CCOc(cc1)ccc1/C(/c(cc1)ccc1O)=C(/CCCO)\c1ccc(N2CCOCC2)nc1 KJYZQUMLOWXZKM-HYOGKJQXSA-N 0.000 description 1
- VXKJVHWOGMYDHP-OHYPFYFLSA-N CN(C)CCOc(cc1)ccc1/C(/c(cc1)ccc1O)=C(/CCCO)\c1ccc(cn[n]2C)c2c1 Chemical compound CN(C)CCOc(cc1)ccc1/C(/c(cc1)ccc1O)=C(/CCCO)\c1ccc(cn[n]2C)c2c1 VXKJVHWOGMYDHP-OHYPFYFLSA-N 0.000 description 1
- SGRALQREBIRWKQ-RQZHXJHFSA-N CN(C)CCOc(cc1)ccc1/C(/c(cc1)ccc1O)=C(/CCCOC)\c1ccncc1 Chemical compound CN(C)CCOc(cc1)ccc1/C(/c(cc1)ccc1O)=C(/CCCOC)\c1ccncc1 SGRALQREBIRWKQ-RQZHXJHFSA-N 0.000 description 1
- VQHWPBFJWISGTP-LSDHQDQOSA-N CN(C)CCOc(cc1)ccc1/C(/c(cc1)ccc1O)=C(\CCC(OC)=O)/Br Chemical compound CN(C)CCOc(cc1)ccc1/C(/c(cc1)ccc1O)=C(\CCC(OC)=O)/Br VQHWPBFJWISGTP-LSDHQDQOSA-N 0.000 description 1
- KIZXVYFZCXUWEQ-OWWNRXNESA-N CN(C)CCOc(cc1)ccc1/C(/c(cc1)ccc1O)=C(\CCC(OC)=O)/c1cc2cnccc2cc1 Chemical compound CN(C)CCOc(cc1)ccc1/C(/c(cc1)ccc1O)=C(\CCC(OC)=O)/c1cc2cnccc2cc1 KIZXVYFZCXUWEQ-OWWNRXNESA-N 0.000 description 1
- VXKJVHWOGMYDHP-ORIPQNMZSA-N CN(C)CCOc(cc1)ccc1/C(/c(cc1)ccc1O)=C(\CCCO)/c1ccc(cn[n]2C)c2c1 Chemical compound CN(C)CCOc(cc1)ccc1/C(/c(cc1)ccc1O)=C(\CCCO)/c1ccc(cn[n]2C)c2c1 VXKJVHWOGMYDHP-ORIPQNMZSA-N 0.000 description 1
- TZZWVGSSCXRUKI-ZQHSETAFSA-N CN(C)CCOc(cc1)ccc1/C(/c(cc1)ccc1O)=C(\CCCOC)/c(cc1)ccc1C#N Chemical compound CN(C)CCOc(cc1)ccc1/C(/c(cc1)ccc1O)=C(\CCCOC)/c(cc1)ccc1C#N TZZWVGSSCXRUKI-ZQHSETAFSA-N 0.000 description 1
- YFMLHHYICBILMH-CYYJNZCTSA-N CN(C)CCOc(cc1)ccc1/C(/c(cc1)ccc1O)=C(\CCCOC)/c1cccnc1 Chemical compound CN(C)CCOc(cc1)ccc1/C(/c(cc1)ccc1O)=C(\CCCOC)/c1cccnc1 YFMLHHYICBILMH-CYYJNZCTSA-N 0.000 description 1
- JYPPLMIUNJGKFP-IGCPIRJNSA-N CN(C)CCOc(cc1)ccc1/C(/c(cc1)ccc1O)=C/CCCO Chemical compound CN(C)CCOc(cc1)ccc1/C(/c(cc1)ccc1O)=C/CCCO JYPPLMIUNJGKFP-IGCPIRJNSA-N 0.000 description 1
- VPZDYJDLCDLYAO-UHFFFAOYSA-N COC(CCC(c1ccc2OCCOc2c1)=C(c(cc1)ccc1OC)c(cc1)ccc1OC)=O Chemical compound COC(CCC(c1ccc2OCCOc2c1)=C(c(cc1)ccc1OC)c(cc1)ccc1OC)=O VPZDYJDLCDLYAO-UHFFFAOYSA-N 0.000 description 1
- JEBPPHRHSPCEKF-UHFFFAOYSA-N COC(CCC(c1cccnc1)=C(c(cc1)ccc1OC)c(cc1)ccc1OC)=O Chemical compound COC(CCC(c1cccnc1)=C(c(cc1)ccc1OC)c(cc1)ccc1OC)=O JEBPPHRHSPCEKF-UHFFFAOYSA-N 0.000 description 1
- WCVXKTCZYZCYOG-UHFFFAOYSA-N COCCCC(c1ccncc1)=C(c(cc1)ccc1O)c(cc1)ccc1O Chemical compound COCCCC(c1ccncc1)=C(c(cc1)ccc1O)c(cc1)ccc1O WCVXKTCZYZCYOG-UHFFFAOYSA-N 0.000 description 1
- SXEGUTXRUGXAQR-UHFFFAOYSA-N COc(cc1)ccc1C(c(cc1)ccc1OC)=CCCC(O)=O Chemical compound COc(cc1)ccc1C(c(cc1)ccc1OC)=CCCC(O)=O SXEGUTXRUGXAQR-UHFFFAOYSA-N 0.000 description 1
- KWDOKLDZSPAVSN-UHFFFAOYSA-N C[n]1ncc(C(CCC(OC)=O)=C(c(cc2)ccc2OC)c(cc2)ccc2OC)c1 Chemical compound C[n]1ncc(C(CCC(OC)=O)=C(c(cc2)ccc2OC)c(cc2)ccc2OC)c1 KWDOKLDZSPAVSN-UHFFFAOYSA-N 0.000 description 1
- HAKNGFRWCSSQJZ-UHFFFAOYSA-N Oc(cc1)ccc1C(c(cc1)ccc1O)=C(CCCBr)c1cccnc1 Chemical compound Oc(cc1)ccc1C(c(cc1)ccc1O)=C(CCCBr)c1cccnc1 HAKNGFRWCSSQJZ-UHFFFAOYSA-N 0.000 description 1
- SDUFGYOAGOSQJJ-UHFFFAOYSA-N Oc(cc1)ccc1C(c(cc1)ccc1O)=C(CCCBr)c1ccncc1 Chemical compound Oc(cc1)ccc1C(c(cc1)ccc1O)=C(CCCBr)c1ccncc1 SDUFGYOAGOSQJJ-UHFFFAOYSA-N 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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Abstract
Description
The present invention relates to novel aromatic ring compound derivatives which can act as ERR? (Estrogen related receptor gamma) inactivation ligands and their pharmaceutical uses.
ERR? Is a human nuclear receptor protein called NR3B3, encoded by the ESRRG gene. ERRγ functions as a constitutive activator in transcription. ERRγ is a member of the nuclear hormone receptor family of steroid hormone receptors, yet physiologically active ligands are not identified and are classified as orphan receptors. ERR? Protein is known to be a major regulator of various genes involved in fatty acid oxidation and mitochondrial biogenesis in the myocardium, and is also known to be involved in glucose production in the liver.
On the other hand, a recent study has shown that (Z) -4- (1- (4- (2- (dimethylamino) ethoxy) phenyl) -5-hydroxy- , A low-molecular organic compound known as GSK5182, acts as a ligand to ERRγ and inhibits the activity of ERRγ, thereby alleviating hyperglycemia and insulin resistance.
The present invention relates to a pharmaceutical composition comprising (Z) -4- (1- (4- (2- (dimethylamino) ethoxy) phenyl) -5-hydroxy-2-phenylpent- To provide novel aromatic ring compounds derived from the parent moiety of the compounds.
The present invention also provides a pharmaceutical composition for preventing or treating metabolic diseases containing the novel aromatic ring compound as an active ingredient.
The present invention also provides an ERR? Activity inhibitor containing the novel aromatic ring compound as an active ingredient.
In order to solve the above-mentioned problems, the present invention provides an aromatic ring compound represented by the following formula (1), a pharmaceutically acceptable salt, hydrate or solvate thereof:
[Chemical Formula 1]
From here,
R 1 is hydroxy, (dimethylamino) ethoxy or methoxy,
R 2 is hydroxy, (dimethylamino) ethoxy or methoxy,
Ar is an aromatic ring, a heteroaromatic ring or a fused aromatic ring substituted with CN-, OH-, OMe-, halogen or alkyl,
X represents methoxy, methyl ester, hydroxy or halogen.
The compound represented by the general formula (1)
Is preferably selected from the group consisting of
The present invention also provides a pharmaceutical composition for the prevention or treatment of metabolic diseases containing the novel aromatic ring compound represented by the above formula (1), a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient.
The metabolic diseases are preferably selected from the group consisting of obesity, diabetes, hyperlipidemia, fatty liver and arteriosclerosis.
The active ingredient may act as a ligand that inhibits the activity of ERRy.
The present invention also provides an ERR gamma activity inhibitor comprising the novel aromatic ring compound represented by the above formula (1), a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient.
The ERR gamma activity inhibitor may be of reagent use.
The novel aromatic ring compound derivatives of the present invention have improved drug stability, pharmacological activity and toxicity compared with the existing GSK5182 compounds, and thus are useful for the prevention or treatment of metabolic diseases such as obesity, diabetes, hyperlipemia, fatty liver and arteriosclerosis There is an excellent effect that can be used.
Hereinafter, the present invention will be described in detail.
The inventors of the present invention have completed the present invention by developing a novel aromatic ring compound derivative having improved drug stability, pharmacological activity and toxicity compared with the GSK5182 compound acting as a ligand capable of inhibiting the activity of ERR ?.
Accordingly, the present invention provides an aromatic ring compound represented by the following formula (1), a pharmaceutically acceptable salt, hydrate or solvate thereof:
[Chemical Formula 1]
From here,
R 1 is hydroxy, (dimethylamino) ethoxy or methoxy,
R 2 is hydroxy, (dimethylamino) ethoxy or methoxy,
Ar is an aromatic ring, a heteroaromatic ring or a fused aromatic ring substituted with CN-, OH-, OMe-, halogen or alkyl,
X represents methoxy, methyl ester, hydroxy or halogen.
The novel compounds according to the invention can be prepared via the route of the following schemes I to IV.
[Reaction Scheme I]
[Reaction Scheme II ]
[Reaction Scheme III ]
[Reaction Scheme IV ]
In a preferred embodiment, each of the novel compounds according to the routes of Schemes I to IV above can be prepared by the following specific processes.
[Process A] Preparation of a compound represented by the formula (2)
(Bromophenylphosphoryl) alkyl acid, which is commonly used, with a ketone compound represented by the formula (1) in the presence of a strong base of NaH. Examples of the aprotic polar solvent used in this step include dimethylsulfoxide. As the ether, tetrahydrofuran is preferable. The reaction temperature may vary depending on the solvent used, but usually it is -10 to 80 ° C, preferably 0 to 25 ° C. The reaction time may vary depending on the reaction temperature and the solvent to be used, but it is generally preferable to carry out the reaction for about 1 hour to 1 day.
[Step B] Preparation of a compound represented by the formula (3)
The alkyl acid compound represented by the general formula (2) can be subjected to a methylation reaction by treatment with dichloro sulfur oxide and methanol which are generally used for the chlorine substitution reaction. The reagents and anhydrous solvent used in this process are methanol. The reaction temperature is dichloro sulfur oxide, the chloro substitution reaction is carried out at 0 ° C, and the methylation reaction is carried out at reflux temperature. The reaction time may vary depending on the reaction temperature, but it is generally preferred to react for about 3 hours.
[Step C] Preparation of a compound represented by the formula (4)
The olefin compound represented by the general formula (3) is treated by treating diborochlorine (II) commonly used in the bromo substitution reaction to carry out a bromination reaction. As the solvent used in this step, an anhydrous organic solvent such as chloroform or dichloromethane is used. The reaction temperature is refluxed at about 80 ° C. The reaction time is usually about 1 day.
[Process D] Preparation of a compound represented by the formula (5)
A brominated compound represented by the formula (4) and an arylborate compound are prepared using a Suzuki coupling reaction under a palladium catalyst which is usually used. As the solvent used in this step, a single water-soluble solvent such as N , N -dimethylformamide, N , N -dimethylacetamide or dimethylsulfoxide is used, or a solvent in which 1 to 10% of water is mixed is used. The most preferred solvent to be used is N , N -dimethylformamide mixed with 1 to 5% water. The base to be used is not particularly limited as long as it does not adversely affect the reaction, and it may be a weak base or a strong base. There is no particular limitation, and examples thereof include alkali metal hydrides such as sodium hydride and barium hydride, alkali metal carbonates such as sodium carbonate, potassium carbonate, potassium hydrogencarbonate, , And alkali metal phosphates such as potassium phosphate. The base to be used is preferably an alkali metal phosphate, more preferably potassium phosphate. The reaction temperature is refluxed at about 80 ° C. The reaction time is usually about 1 day.
[Process E] Preparation of the compound represented by the formula (6)
The ester compound represented by the general formula (5) is prepared by treating LiAlH 4 , which is usually used in the reduction reaction, and reducing it with alcohol. As the anhydrous solvent used in this step, a mixed solvent comprising a single solvent such as diethyl ether, tetrahydrofuran, hexane, heptane and the like and a combination of two or more solvents is used. As the preferable solvent, a polar solvent is preferable, and most preferable is tetrahydrofuran. It is preferable that the reaction is carried out at about 0 ° C and the reaction is usually carried out within 1 hour.
[Step F] Preparation of a compound represented by the formula (7)
The methoxy-protected compound represented by the formula (6) is prepared by treating tribromoboran (BBr 3 ) which is usually used in the dimerization reaction. As the solvent used in this step, an anhydrous organic solvent such as chloroform or dichloromethane is used. The reaction temperature is refluxed at about 80 ° C. The reaction time is usually about 1 day.
[Step G] Preparation of the compound represented by the formula (8)
The bromo compound represented by the general formula (7) is prepared by treating methoxy sodium and methanol, which are usually used in the methoxy substitution reaction, for methylation. The reagents and anhydrous solvent used in this process are methanol. The reaction is preferably carried out at room temperature and is usually carried out for about 3 days.
[Step H] Preparation of a compound represented by the formula (9) and (9 ')
Is prepared by reacting a compound represented by the formula (8) with an alkylhalogen in the presence of a base. As the solvent used in this step, a single water-soluble solvent such as N , N -dimethylformamide, N , N -dimethylacetamide, dimethylsulfoxide or acetone may be used, or a solvent in which 1 to 10% do. The most preferred solvent used is acetone mixed with 1 to 5% water. The base to be used is preferably an alkali metal carbonate, more preferably potassium carbonate. The reflux reaction is carried out at a reaction temperature of about 60 ° C, and it is usually preferable to carry out the reaction for about 4 hours.
[Step I] Preparation of the compound represented by the formula (10)
The methoxy protective compound represented by the general formula (4) is prepared by treating tribromoboran (BBr 3 ) generally used in the dimerization reaction. As the solvent used in this step, an anhydrous organic solvent such as chloroform or dichloromethane is used. The reaction temperature is refluxed at about 80 ° C. The reaction time is usually about 1 day.
[Step J] Preparation of a compound represented by the formula (11) and (11 ')
A phenolic compound represented by the formula (10) and an alkyl alcohol are prepared by using a Mitsunobu reaction in the presence of an azodicarboxylate reagent and triphenylphosphine. The anhydrous solvent used in this step is tetrahydrofuran, dioxane, dichloromethane or the like, most preferably dichloromethane. The azodicarboxylate reagent used is DEAD or DIAD. It is advisable to slowly add the nucleophile compound and the alcohol compound after first reacting with triphenylphosphine. The reaction is carried out at room temperature, and it is generally preferred to carry out the reaction for about one day.
[Step K] Preparation of a compound represented by the formula (12) and (12 ')
The brominated compound represented by the general formula (11) and the compound represented by the general formula (11 ') and the arylborate compound are prepared using a Suzuki coupling reaction under a palladium catalyst which is usually used. As the solvent used in this step, a single water-soluble solvent such as N , N -dimethylformamide, N , N -dimethylacetamide or dimethylsulfoxide is used, or a solvent in which 1 to 10% of water is mixed is used. The most preferred solvent to be used is N , N -dimethylformamide mixed with 1 to 5% water. The base to be used is not particularly limited as long as it does not adversely affect the reaction, and it may be a weak base or a strong base. There is no particular limitation, and examples thereof include alkali metal hydrides such as sodium hydride and barium hydride, alkali metal carbonates such as sodium carbonate, potassium carbonate, potassium hydrogencarbonate, , And alkali metal phosphates such as potassium phosphate. The reaction temperature is refluxed at about 80 ° C. The reaction time is usually about 1 day.
[Step L] Preparation of compounds represented by formulas (13) and (13 ')
The ester compound represented by the general formula (12) and the general formula (12 ') is prepared by treating LiAlH 4 , which is usually used in the reduction reaction, with alcohol. As the anhydrous solvent used in this step, a mixed solvent comprising a single solvent such as diethyl ether, tetrahydrofuran, hexane, heptane and the like and a combination of two or more solvents is used. As the preferable solvent, a polar solvent is preferable, and most preferable is tetrahydrofuran. It is preferable that the reaction is carried out at about 0 ° C and the reaction is usually carried out within 1 hour.
[Step M] Preparation of compounds represented by formulas (14-1) and (14-2)
(Trifluoromethyl) sulfinyl) oxy) zinc or an isopropylating agent (bis ((isopropyl) sulfinyl) oxy) zinc, trifluoroacetic acid, (ref. Nature 492 95-99, JACS 2012, 134, 1494-1497). The solvent used in this step is preferably a mixed solvent of dichloromethane and water. Is preferably carried out at room temperature and is usually reacted for about one day.
[Step N] Preparation of a compound represented by the formula (15)
The dimethylamino compound represented by the formula 13'-2 is prepared by reacting 1-chloroethylcarbonochloridate, which is a dimethylation reagent, in the presence of a base. As the anhydrous solvent used in this step, dichloromethane is preferable. The base to be used is preferably an amine base such as N, N -diisopropylamine. The reaction is carried out at about 50 ° C, and it is generally preferable to carry out the reaction for about 1 hour.
Preferable examples of the compound prepared from Processes A to N according to the above Reaction Schemes I to IV are as follows:
The present invention also provides a pharmaceutical composition for the prevention or treatment of metabolic diseases containing the novel aromatic ring compound represented by the above formula (1), a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient.
The metabolic diseases are preferably selected from the group consisting of obesity, diabetes, hyperlipidemia, fatty liver and arteriosclerosis.
The active ingredient may act as a ligand that inhibits the activity of ERRy.
The pharmaceutically acceptable salts of the novel compounds of formula (I) according to the present invention may be prepared by conventional methods in the art. Pharmacologically acceptable salts should be low in toxicity to humans and should not adversely affect the biological activity and physicochemical properties of the parent compound. Free acids that can be used in the preparation of pharmaceutically acceptable salts can be divided into inorganic and organic acids. As the inorganic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid and the like can be used. The organic acid may be selected from the group consisting of acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, Benzoic acid, embonic acid, aspartic acid, glutamic acid and the like can be used. Organic bases that can be used to prepare organic base addition salts include tris (hydroxymethyl) methylamine, dicyclohexylamine, and the like. Amino acids that can be used in the production of amino acid addition bases are natural amino acids such as alanine and glycine.
The novel compounds of formula (I) according to the present invention include all pharmaceutically acceptable salts as well as all hydrates and solvates thereof. The hydrate and the solvate can be obtained by dissolving the novel compound represented by the general formula (1) in a solvent which can be mixed with water such as methanol, ethanol, acetone or 1,4-dioxane, adding a free acid or a free base and then crystallizing or recrystallizing . In such cases, solvates (especially hydrates) may be formed. Thus, the novel compounds of the present invention also include stoichiometric solvates, including hydrates, in addition to varying amounts of water-containing compounds that can be prepared by methods such as lyophilization.
The pharmaceutical composition of the present invention comprises at least one compound selected from the novel compounds represented by the formula (1), the pharmaceutically acceptable salts thereof, the solvates thereof and the hydrates thereof as an active ingredient, For example, tablets, capsules, troches, solutions, suspensions, etc., or parenteral administration preparations by adding an acceptable carrier, adjuvant and excipient in the form of tablets, capsules, have.
The excipient that can be used in the pharmaceutical composition of the present invention may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, . For example, there may be mentioned lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth, Sodium alginate, sodium alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like.
The dose of the compound according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and disease severity of the patient, and is generally 0.01 To 1,000 mg / day, and may be administered once or several times a day at a predetermined time interval according to the judgment of a doctor or pharmacist. However, the dosage may not be limited in any way because it may be increased or decreased depending on route of administration, severity of disease, sex, weight, age, and the like.
The pharmaceutical composition of the present invention can be administered to a subject through various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerebroventricular injections. In the present invention, "administration" means providing a predetermined substance to a patient by any suitable method, and the administration route of the pharmaceutical composition of the present invention is either oral or non-oral May be administered orally. In addition, the pharmaceutical composition of the present invention may be administered using any device capable of delivering an effective ingredient to a target cell.
The "subject" to which the pharmaceutical composition of the present invention is administered is not particularly limited, but may be, for example, a human, a monkey, a cow, a horse, a sheep, a pig, a chicken, a turkey, a quail, a cat, a dog, Or guinea pig, preferably a mammal, more preferably a human.
The present invention also provides an ERR gamma activity inhibitor comprising the novel aromatic ring compound represented by the above formula (1), a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient.
The ERR? Activity inhibitor may be a reagent application, preferably a research reagent application.
In addition to the active ingredient of the present invention, the reagent for research may further include various additives, preservatives, and the like which may be included in conventional reagents.
[ Example ]
BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to preferred embodiments for better understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited thereto.
Particularly, although there are differences in the structure and physical properties of the substituents depending on the kind of substituent, nonetheless, the compounds having substituents not described in the examples among the compounds described in the following claims are also included in the reaction Principles and conditions of the present invention can be applied, and it is therefore obvious that those substituent-containing compounds can be easily carried out based on the common sense in the art based on the disclosure of the examples by those skilled in the art.
Example 1: Preparation of compound 4
1.1. (5,5-b Bis (4-methoxyphenyl) phen -4- Te Noyik Preparation of acid (Compound 2)
NaH (2 g, 50.0 mmol) was added to 50 mL of anhydrous DMSO under nitrogen, followed by stirring at 70 ° C for 1 hour. After the reaction was cooled to 20 캜 or lower, 4- (bromotriphenylphosphoranyl) butanoic acid (8.5 g, 19.8 mmol) was added in portions for 5 minutes. The red solution was stirred at 20 ° C or less for 15 minutes, and then a solution of bis (4-methoxyphenyl) methanone (6 g, 24.8 mmol) dissolved in 33 mL of dry THF was slowly added thereto and reacted at room temperature for 19 hours. After removing the organic layer using dichloromethane and ice water, the water layer was acidified with 12N HCl solution and extracted again into the organic layer. The organic layer was washed with brine, and water was removed with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (MC / MeOH) to obtain 23.1 g (yield: 50%) of the title compound.
Yellow oil; Rf = 0.3 (hexanes / EtOAc 1/2); 1 H NMR (400 MHz, CDCl 3): 7.80 (d, J = 7.6 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 4.19-4.12 (m, 6H), 2.46 (s, 3H) , 1.31 (t, J = 7.4 Hz, 6 H)
1.2. methyl (5,5-b Bis (4-methoxyphenyl) phen -4- (Compound 3) < / RTI > Produce
(5,6-bis (4-methoxyphenyl) phen-4-te novolac acid (9.6 g, 30.7 mmol) was dissolved in 120 mL of carbon tetrachloride under nitrogen and cooled to below 0 ° C. SOCl 2 (4.02 g, 33.8 mmol) was slowly added dropwise, and the mixture was reacted for 3 hours at 70 ° C. When the reaction was completed, the solvent was concentrated under reduced pressure to remove the remaining reagent, and the reaction solution was diluted with ethyl acetate (EtOAc) The organic layer was dried over anhydrous Na 2 SO 4 and filtered. The solvent was distilled under reduced pressure to obtain 39.67 g (yield: 97%) of the desired compound.
Yellow oil; Rf = 0.3 (hexanes / EtOAc 1/2); 1 H NMR (400 MHz, CDCl 3): 7.80 (d, J = 7.6 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 4.19-4.12 (m, 6H), 2.46 (s, 3H) , 1.31 (t, J = 7.4 Hz, 6 H)
1.3. methyl 4- Bromo -5,5- Bis (4-methoxyphenyl) phen -4- Of the compound (4) Produce
Methyl (5,5-bbis (4-methoxyphenyl) phen-4-tneoate (9.67 g, 29.6 mmol) was dissolved in 120 mL of carbon tetrachloride under nitrogen atmosphere and then copper bromide (CuBr 2 16.54 g, 74.1) After the reaction was completed, the solution was filtered through celite, the solvent was concentrated under reduced pressure to remove the remaining reagent, the reaction solution was diluted with ethyl acetate (EtOAc) The organic layer was dried over anhydrous Na 2 SO 4 and filtered. The solvent was distilled under reduced pressure to obtain 11.51 g (yield: 96%) of the target compound.
Yellow oil; Rf = 0.3 (hexanes / EtOAc 1/2); 1 H NMR (400 MHz, CDCl 3): 7.80 (d, J = 7.6 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 4.19-4.12 (m, 6H), 2.46 (s, 3H) , 1.31 (t, J = 7.4 Hz, 6 H)
Example 2: Preparation of compound 5
2.1. methyl 5,5- Bis (4- Methoxyphenyl ) -4- (pyridin-3-yl) phen-4- Tneoate (Compound 5-1)
The compound methyl 4-bromo-5,5-bis (4-methoxyphenyl) phen-4-te nito (0.900 g, 2.22 mmol) synthesized in Example 1 was dissolved in DMF / H 2 O ) Was dissolved in 12.24 mL of a mixed solution and 0.546 g (2.66 mmol) of PdCl 2 (dppf) -CH 2 Cl 2 (0.181 g, 0.22 mmol) and potassium phosphate (1.41 g, , 6.66 mmol) were successively added at room temperature and reacted at 80 ° C for 3 hours. When the reaction was completed, the reaction solution was cooled to room temperature, and the reaction was terminated by using water and ethyl acetate. Ethyl acetate was further added to extract the organic layer. The organic layer was washed with brine, and water was removed with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (MC / MeOH) and Prep-HPLC to obtain the desired compound 740 mg (Yield: 93%).
Yellow oil; Rf = 0.3 (hexanes / EtOAc 1/2); 1 H NMR (400 MHz, CDCl 3): 7.80 (d, J = 7.6 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 4.19-4.12 (m, 6H), 2.46 (s, 3H) , 1.31 (t, J = 7.4 Hz, 6 H)
2.2. Methyl 5 , 5- Bis (4- Methoxyphenyl ) -4- (pyridin-4-yl) phen-4- Tneoate (Compound 5-2)
(Pyridin-4-yl) boronic ester instead of (pyridin-3-yl) boronic ester in Example 2.1 above. 810 mg (yield: 87%) of the desired compound was obtained.
2.3. methyl 4- (4- Cyanophenyl ) -5,5- bis (4- Methoxyphenyl ) Phen-4- Tneoate (Compound 5-3)
In Example 2.1, the same method was used except that (4-cyanophenyl) boronic ester reagent was used instead of (pyridin-3-yl) boronic ester. 850 mg (yield: 90%) of the desired compound was obtained.
2.4. methyl 5,5- Bis (4- Methoxyphenyl ) -4- (1- methyl -1H- Pyrazole -4-yl) phen-4- Tennoi ( Compound 5-4) Produce
In Example 2.1 above, (1-methyl-1H-pyrazol-4-yl) boronic ester reagent was used instead of (pyridin-3-yl) boronic ester and synthesized in the same manner. 650 mg (yield: 72%) of the desired compound was obtained.
2.5. methyl 4- (2,3- Dihydrobenzo [b] [1,4] dioxin -6-yl) -5,5-bis (4- Methoxyphe Yl) phen-4- Tennoite (Compound 5-5)
In Example 2.1, the same method as in Example 2.1 was used instead of (pyridin-3-yl) boronic ester instead of (2,3-dihydrobenzo [b] [1,4] dioxin- . 600 mg (Yield: 59%) of the desired compound was obtained.
Example 3: Preparation of Compound 6
3.1. 5,5- Bis (4- Methoxyphenyl ) -4- (pyridin-3-yl) phen-4-en-1-ol (Compound 6-1)
Methyl 5,5-bis (4-methoxyphenyl) -4- (pyridin-3-yl) phen-4-tneoate (0.740 g, 1.83 mmol) synthesized in Example 2 was dissolved in nitrogen Was dissolved in 12 mL of tetrahydrofuran and then cooled to 0 占 폚 or lower. 1M LAH (2.74 mL, 2.74 mmol) was slowly added dropwise while maintaining the temperature, followed by reaction at 0 ° C for 1 hour. The reaction was terminated by using water, diluted with ethyl acetate (EtOAc), washed with a carbonic acid solution, brine, and the organic layer was dried with anhydrous Na 2 SO 4 and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (MC / MeOH) to obtain the title compound (580 mg, yield: 85%).
Yellow oil; Rf = 0.3 (hexanes / EtOAc 1/2); 1 H NMR (400 MHz, CDCl 3): 7.80 (d, J = 7.6 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 4.19-4.12 (m, 6H), 2.46 (s, 3H) , 1.31 (t, J = 7.4 Hz, 6 H)
3.2. 5,5- Bis (4- Methoxyphenyl ) -4- (pyridin-4-yl) phen-4-en-1-ol (Compound 6-2)
In the same manner as in Example 3.1, using methyl 5,5-bis (4-methoxyphenyl) -4- (pyridin-4-yl) mg (yield: 74%) of the title compound.
3.3. 4- (5-hydroxy-1,1- Bis (4-methoxyphenyl) phen -1-thien-2-yl) Benzonitrile (Compound 6-3)
(4-cyanophenyl) -5,5-bis (4-methoxyphenyl) phen-4-tneoate as a starting compound, the compound 480 mg (Yield: 61%) was obtained.
3.4. 5,5- Bis (4- Methoxyphenyl ) -4- (1- methyl -1H- Pyrazole Yl) phen-4-en-1-ol ( Unity Preparation of water 6-4)
Methyl 5-bis (4-methoxyphenyl) -4- (1-methyl-1H-pyrazol-4-yl) 430 mg (yield: 73%) of the desired compound was obtained as the starting compound.
3.5. 4- (2,3- Dihydrobenzo [b] [1,4] dioxin -6-yl) -5,5- Bis (4-methoxyphenyl) phen 4-en-1-ol (compound 6-5)
The compound 5-5 was obtained in the same manner as in Example 3.1, except that methyl 4- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) Phenyl) phen-4-tneoate as starting compounds, 350 mg (yield: 63%) of the desired compound was obtained.
Example 4: Preparation of compound 7
4.1. 4,4 '- (5- Bromo -2- (pyridin-3-yl) phen-1-ene- Dill ) Preparation of diphenol (Compound 7-1)
4-methoxyphenyl) -4- (pyridin-3-yl) phen-4-en-1-ol (0.580 g, 1.44 mmol), Compound 6-1 synthesized in Example 3, Was dissolved in 3 mL of dichloromethane under nitrogen and then cooled to 0 ° C or lower. 1M BBr 3 (15.4 mL, 15.4 mmol) was slowly added dropwise while maintaining the temperature, followed by reaction at 40 ° C for 1 day. The reaction solution was cooled to about 0 캜, and the reaction was terminated by using water. The residue obtained by distillation of the solvent under reduced pressure was purified by column chromatography (MC / MeOH) to obtain the target compound 650 mg (Yield: 86%).
4.2. 4,4 '- (5- Bromo -2- (pyridin-4-yl) phen-1-ene- Dill ) Preparation of diphenol (Compound 7-2)
(4-methoxyphenyl) -4- (pyridin-4-yl) phen-4-en-1-ol, which is Compound 6-2, as a starting compound, 717 mg (Yield: 100%) of the compound was obtained.
4.3. 4- (5- Bromo -1,1- Bis (4-hydroxyphenyl) phen -1-thien-2-yl) Benzonitrile (Compound 7-3)
1-Bis (4-methoxyphenyl) phen-1-en-2-yl) benzonitrile, which is Compound 6-3, was used as starting compound in the same manner as in Example 4.1 400 mg (yield: 90%) of the desired compound was obtained.
4.4. 4,4 '- (5- Bromo -2- (1- methyl -1H- Pyrazole Yl) phen-1-ene-l, l- Dill ) Diphenol ( anger Preparation of Compound 7-4)
(4-methoxyphenyl) -4- (1-methyl-1H-pyrazol-4-yl) 470 mg (Yield: 87%) of the title compound was obtained as a starting compound.
4.5. 4,4 '- (5- Bromo -2- (2,3- Dihydrobenzo [b] [1,4] dioxin -6-yl) phen-1-ene-1,1-diyl) diphenol (Compound 7-5)
In the same manner as in Example 4.1, 4- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -5,5-bis (4-methoxyphenyl) ) Phen-4-en-1-ol as starting compounds, 240 mg (yield: 70%) of the desired compound was obtained.
Yellow oil; Rf = 0.3 (hexanes / EtOAc 1/2); 1 H NMR (400 MHz, CDCl 3): 7.80 (d, J = 7.6 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 4.19-4.12 (m, 6H), 2.46 (s, 3H) , 1.31 (t, J = 7.4 Hz, 6 H)
Example 5: Preparation of Compound 8
5.1. 4,4 '- (5- Methoxy -2- (pyridin-3-yl) phen-1-ene- Dill ) Preparation of diphenol (Compound 8-1)
(5-bromo-2- (pyridin-3-yl) phen-1-ylene-1,1-diyl) diphenol (0.650 g, 1.32 mmol) was dissolved in 2 mL of methanol and then cooled to 0 ° C or lower. 5N NaOMe methanol solution (2.64 mL, 13.2 mmol) was slowly added dropwise while maintaining the temperature, followed by reaction at 25 ° C for 3 days. The reaction solution was cooled to about 0 캜, and a small amount of water was added to terminate the reaction. The solution was diluted with methanol, filtered, and the filtrate was distilled under reduced pressure. The resulting residue was purified by column chromatography (MC / MeOH) to obtain 430 mg of the title compound (yield: 90%).
5.2. 4,4 '- (5- Methoxy -2- (pyridin-4-yl) phen-1-ene- Dill ) Diphenol ( Compound 8-2) Manufacturing
(5-bromo-2- (pyridin-4-yl) phen-1-ene-1,1-diyl) diphenol, which is Compound 7-2, was synthesized in the same manner as in Example 5.1, To obtain 510 mg of the title compound (yield: 87%).
5.3. 4- (1,1- Bis (4- Hydroxyphenyl ) -5- Methoxyphen -1-thien-2-yl) Benzonitrile (Compound 8-3)
(5-bromo-1,1-bis (4-hydroxyphenyl) phen-1-en-2-yl) benzonitrile, which is a compound 7-3, 58 mg (Yield: 85%) of the desired compound was obtained.
5.4. 4,4 '- (5- Methoxy -2- (1- methyl -1H- Pyrazole Yl) phen-1-ene-l, l- Dill ) Diphenol ( anger Preparation of the compound 8-4)
(5-bromo-2- (1-methyl-1H-pyrazol-4-yl) Diyl) diphenol as starting compound, 140 mg (yield: 92%) of the desired compound was obtained.
5.5. 4,4 '-( 2- (2,3- Dihydrobenzo [b] [1,4] dioxin -6-yl) -5- Methoxyphen -1-thien-1, 1-diyl) diphenol (Compound 8-5)
B] [l, 4] dioxin-6-yl) pentane (Compound 7-5) was obtained in the same manner as in Example 5.1, -1-thien-1, 1-diyl) diphenol as starting compounds, 80 mg (yield: 72%) of the desired compound was obtained.
Example 6: Preparation of compound 9
6.1. (Z) -4- (1- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -5- Methoxy (Compound 9-1) and (E) -4- (1- (4- (2- (dimethylamino) phen-1- Ethoxy ) Phenyl ) -5-methoxy-2- (pyridin-3-yl) phen-1-en-1-yl) phenol (Compound 9'-
(0.789 g, 5.48 mmol) was dissolved in 80 mL of a mixed solvent of acetone / water (19: 1) and cooled to 0 ° C. Potassium carbonate (1.514 g, 10.96 mmol) Respectively. The mixture was stirred for about 30 minutes while maintaining the temperature. Then, a solution of 4,4'- (5-methoxy-2- (pyridin-3-yl) , 1-diyl) diphenol hydrochloride (1.09 g, 2.74 mmol) was added and the mixture was reacted at 63 ° C for 4 hours. The residue was purified by column chromatography (MC / MeOH) and prep-HPLC to obtain 66 mg of the title compound (yield: 5.6%) and 55 mg (yield: 4.7%) respectively.
6.2. (Z) -4- (1- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -5- Methoxy (Compound 9-2) and (E) -4- (1- (4- (2- (dimethylamino) -2-pyridin- Ethoxy ) Phenyl ) -5-methoxy-2- (pyridin-4-yl) phen-1-en-1-yl) phenol (Compound 9'-
(5-methoxy-2- (pyridin-4-yl) phen-1-ene-1,1-diyl) diphenol, Compound 8-2, was synthesized in the same manner as in Example 6.1, To obtain 22 mg of the title compound (yield: 5.0%) and 22 mg (yield: 5.0%), respectively.
6.3. (Z) -4- (1- (4- (2- (dimethylamino) Ethoxy ) Funnel ) -1- (4- Hydroxyphenyl ) -5- Me 1-en-2-yl) Benzonitrile (Compound 9-3) and (E) -4- (1- (4- (2- (dimethylamino) Et city) Funnel ) -1- (4- Hydroxyphenyl ) -5- Methoxyphen -1-thien-2-yl) Benzonitrile (Compound 9'-3)
(4-hydroxyphenyl) -5-methoxyphen-1-yl) benzonitrile, which is a compound 8-3, was synthesized in the same manner as in Example 6.1, 20 mg (yield: 4.5%) of the aimed compound and 21 mg (yield: 4.7%) respectively.
6.4. (Z) -4- (1- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -5- Methoxy -2- (1- methyl -1H- blood Yl) phen-1-en-1-yl) phenol (Compound 9-4) and (E) -4- (1- (4- (2- Et city) Phenyl ) -5- Methoxy -2- (1- methyl -1H- Pyrazole Yl) phen-1-en-1-yl) phenol (Compound 9'-4)
In the same manner as in Example 6.1, the title compound was obtained from 4,4 '- (5-methoxy-2- (1-methyl-1H-pyrazol- Diyle) diphenol as starting compounds, respectively, to obtain 3.65 mg and 2.55 mg of the desired compound, respectively.
6.5. (Z) -4- (2- (2,3- Dihydrobenzo [b] [1,4] dioxin -6-yl) -1- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -5- Methoxy -1-yl) phenol (Compound 9-5) and (E) -4- (2- (2,3- Dihydro Benzo [ b] [1,4] dioxine -6-yl) -1- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -5- Methoxy -1-thien-1-yl) phenol (Compound 9'-5)
In the same manner as in Example 6.1, the title compound was obtained as a colorless oil from Compound 8-5, 4,4 '- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -1-thien-1, 1-diyl) diphenol as starting compounds, 3.65 mg and 2.55 mg of the title compound were obtained.
Example 7: Preparation of Compound 10
Methyl 4-bromo-5,5-bis (4-methoxyphenyl) phen-4-tna nito (3.0 g, 7.4 mmol) which was the compound 4 synthesized in Example 1.3 was dissolved in 70 mL of dichloromethane And cooled to -20 占 폚 or lower. 1M BBr 3 (14.8 mL, 14.8 mmol) was slowly added dropwise while maintaining the temperature, followed by reaction at 25 ° C for 3 hours. The reaction solution was cooled to about 0 캜, and the reaction was terminated by using a sodium hydrogencarbonate solution. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (MC / MeOH) to obtain methyl 4-bromo-5,5-bis (4-hydroxyphenyl) g (yield: 81%).
Example 8: Preparation of compound 11 and compound 11 '
After dissolving 2- (dimethylethylamino) ethanol (0.694 g, 7.79 mmol) and triphenylphosphine (2.043 g, 7.79 mmol) in 45 mL of dichloromethane, the reaction mixture was cooled to 0 ° C and then treated with diisopropyl azodicarboxylate , 7.79 mmol) was slowly added dropwise. The mixture was stirred for about 10 minutes while maintaining the temperature, and then methyl 4-bromo-5,5-bis (4-hydroxyphenyl) phen-4-tneoate (2.26 g, 5.99 mmol) was dissolved in 45 mL of dichloromethane and slowly added dropwise, followed by reaction at room temperature for 1 day. The residue obtained by vacuum distillation of the solvent was purified by column chromatography (MC / MeOH) to obtain the target compound 11, methyl (Z) -4-bromo-5- (4- (2- (dimethylamino) ethoxy) phenyl (4- (2- (dimethylamino) ethoxy) phenyl) -5- (4-hydroxyphenyl) (Yield: 24%) of the title compound as a white amorphous solid.
Example 9: Preparation of compounds 12 and 12 '
9.1. methyl (Z / E) -5- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -4,5-bis (4- Hydroxy Phenyl) phen-4- Tennoite (Compound 12-1 / 12'-1)
(E / Z) -4-bromo-5- (4- (2- (dimethylamino) ethoxy) phenyl) -5- (0.238 g, 0.532 mmol) was dissolved in 4 mL of DMF and treated with (4-hydroxyphenyl) boronic ester (0.164 g, 0.745 mmol), PdCl 2 (dppf) -CH 2 Cl 2 (0.043 g, 0.053 mmol) and 2M sodium carbonate solution (0.798 mL, 1.596 mmol) were successively added at room temperature, followed by reaction at 80 ° C for 4 hours. When the reaction was completed, the reaction solution was cooled to room temperature, and the reaction was terminated by using water and ethyl acetate. Ethyl acetate was further added to extract the organic layer. The organic layer was washed with brine, and water was removed with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (MC / MeOH) and Prep-HPLC to obtain 42 mg (yield: 17%) of a mixture of objective compounds 12-1 and 12'-1.
9.2. methyl (Z / E) -5- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -5- (4- Hydroxyphenyl ) -4- (6- Dinky 3-yl) phen-4- Tneoate (Compound 12-2 / 12'-2) of Produce
In Example 9.1, the title compound was synthesized by the same method using (6-hydroxypyridin-3-yl) boronic acid reagent instead of (4-hydroxyphenyl) boronic ester. 72 mg (yield: 37%) of a mixture of objective compound 12-2 and 12-2) was obtained.
9.3. methyl (Z) -5- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -5- (4- Hydroxyphenyl ) -4- (l-methyl-lH- Indazole -6-yl) phen-4- Tennoite (Compound 12-3) and methyl (E) -5- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -5- (4- Hydroxyphenyl ) -4- (1- methyl -1H-indazol-6-yl) phen-4- Tenno It Compound 12'-3) Produce
The title compound was synthesized in the same manner as in Example 9.1 using (1-methyl-1H-indazol-6-yl) boronic acid reagent instead of (4-hydroxyphenyl) boronic ester. 115 mg (yield: 16%) of the desired compound 12-3 and 75 mg (yield: 11%) of the target compound 12'-3 were obtained.
9.4. methyl (Z) -5- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -5- (4- Hydroxyphenyl ) -4- (Ala Isoquinoline -7-yl) phen-4- Tennoite (Compound 12-4) and methyl (E) -5- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -5- (4- Hydroxyphenyl )-4-( Isoquinoline -7-yl) phen-4-tneoate ( anger Preparation of compound 12'-4)
The compound was synthesized in the same manner as in Example 9.1, except that (isoquinolin-7-yl) boronic acid reagent was used instead of (4-hydroxyphenyl) boronic ester. To obtain 22 mg (yield: 10%) of the desired compound 12-4 and 26 mg (yield: 12%) of the target compound 12'-4.
9.5. methyl (Z / E) -5- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -5- (4- Hydroxyphenyl ) -4- (l-methyl-lH-indol-5-yl) Tneoate (compound 12-5 / 12'-5) of Produce
The title compound was synthesized in the same manner as in Example 9.1, except that (1-methyl-1H-indol-5-yl) boronic acid reagent was used instead of (4-hydroxyphenyl) boronic ester. 50 mg (yield: 25%) of a mixture of objective compound 12-5 and 12'-5 was obtained.
9.6. methyl (Z / E) -5- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -5- (4- Hydroxyphenyl ) -4- (6- Reflux 3-yl) phen-4- < / RTI > Tneoate (Compound 12-6 / 12'-6) Produce
The title compound was synthesized in the same manner as in Example 9.1, except that (6- (trifluoromethyl) pyridin-3-yl) boronic acid reagent was used instead of (4-hydroxyphenyl) boronic ester. 33 mg (yield: 14%) of a mixture of objective compound 12-6 and 12'-6 was obtained.
9.7. methyl (Z) -5- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -5- (4- Hydroxyphenyl ) -4- (6- Porinophyre Di-3-yl) phen-4- Tennoite (Compounds 12-7) and methyl (E) -5- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -5- (4- Hydroxyphenyl ) -4- (6- Morpholinopyridine 3-yl) phen-4-tneoate ( Compound 12'-7) Produce
The procedure of Example 9.1 was repeated except that (6-morpholinopyridin-3-yl) boronic ester reagent was used instead of (4-hydroxyphenyl) boronic ester. 13 mg (yield: 6%) of the target compound 12-7 and 14 mg (yield: 7%) of 12'-7 were obtained.
9.8. methyl (Z / E) -5- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -4- (2- Fluoropyridine Yl) -5- (4- Hydroxyphenyl ) Phen-4- (Compound 12-8 / 12'-8) Produce
The compound was synthesized in the same manner as in Example 9.1, except that (2-fluoropyridin-4-yl) boronic acid reagent was used instead of (4-hydroxyphenyl) boronic ester. 35 mg (yield: 20%) of a mixture of objective compound 12-8 and 12'-8 was obtained.
9.9. methyl (Z / E) -5- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -5- (4- Hydroxyphenyl ) -4- ( Lt; RTI ID = 0.0 > [1,2-a] 6-yl) phen-4- (Compound 12-9 / 12'-9) Produce
The title compound was synthesized in the same manner as in Example 9.1, except that (imidazo [1,2-a] pyridin-6-yl) boronic acid reagent was used instead of (4-hydroxyphenyl) boronic ester. 24 mg (yield: 26%) of a mixture of objective compounds 12-9 and 12'-9 was obtained.
9.10. methyl (Z / E) -5- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -5- (4- Hydroxyphenyl ) -4- (pyridin-3-yl) phen-4- Tennoite (Compound 12-10 / 12'-10)
In Example 9.1, the title compound was synthesized by the same method using (pyridin-3-yl) boronic acid reagent instead of (4-hydroxyphenyl) boronic ester. 21 mg (yield: 12%) of the desired compound 12-10 was obtained, and 18 mg (yield: 10%) of the desired compound 12'-10 was obtained.
Example 10: Preparation of compounds 13 and 13 '
10.1. (Z) -4,4 '- (1- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -5- Hydroxyphen (E) -4- (1- (4- (2- (dimethylamino) -1- Ethoxy ) Phenyl ) -5- Hi (Compound 13-2) and (Z) -4- (1- (4- (2- (dimethylamino) phenoxy) Ethoxy ) Phenyl) -5- Hydroxyphen -1-thien-1-yl) phenol (Compound 13'-1)
(Z / E) -5- (4- (2- (dimethylamino) ethoxy) phenyl) -4,5-bis (4- Phenoxy) phen-4-tneoate (0.042 g, 0.09 mmol) was dissolved in tetrahydrofuran (4 mL) under nitrogen, followed by cooling to 0 占 폚 or lower. 1M LAH (0.54 mL, 0.54 mmol) was slowly added dropwise while maintaining the temperature, followed by reaction at 0 ° C for 1 hour. The reaction was terminated by using water, diluted with ethyl acetate (EtOAc), washed with a carbonic acid solution, brine, and the organic layer was dried with anhydrous Na 2 SO 4 and filtered. The residue obtained by distilling off the solvent under reduced pressure was purified by prep-HPLC to obtain 11.9 mg (yield: 30.5%) of the desired compound 13-1, 56.7 mg (yield: 21.8%) of 13-2 and 57.5 mg Yield: 24.3%).
Yellow oil; Rf = 0.3 (hexanes / EtOAc 1/2); 1 H NMR (400 MHz, CDCl 3): 7.80 (d, J = 7.6 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 4.19-4.12 (m, 6H), 2.46 (s, 3H) , 1.31 (t, J = 7.4 Hz, 6 H)
10.2. (Z) -4- (1- (4- (2- (dimethylamino) Ethoxy ) Phenyl (Compound 13-3) and (Z) -5- (1- (4- (2-methoxyphenyl) (2- (dimethylamino) Ethoxy ) Phenyl ) -5-hydroxy-1- (4- Hydroxyphenyl ) Phen-1-thien-2-yl) pyridin-2-ol (Compound 13-4)
(Z / E) -5- (4- (2- (dimethylamino) ethoxy) phenyl) -5- (4-hydroxyphenyl) propanoate was obtained in the same manner as in Example 10.1. ) -4- (6-methoxypyridin-3-yl) phen-4-enoate as starting compounds, 15 mg of 13-3 and 14 mg of 13-4 were obtained.
10.3. (Z) -4- (1- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -5-hydroxy y-2- (1- methyl (1- (4- (2- (dimethylamino) -1H-indazol-6-yl) Ethoxy ) Phenyl ) -5-hydroxy y-2- (1- methyl -1H- Indazole -6-yl) phen-1-en-1-yl) phenol (Compound 13'-2)
(Z) -5- (4- (2- (dimethylamino) ethoxy) phenyl) -5- (4-hydroxyphenyl) -4- (E) -5- (4- (2- (dimethylamino) ethoxy) phenyl) -5-methyl-1H- (Yield: 80%), 13 (3-hydroxyphenyl) -4- (1-methyl-1H-indazol- -2 > was obtained (yield: 40%).
10.4. (Z) -4- (1- (4- (2- (dimethylamino) Ethoxy ) Phenyl (Compound 13-6) and (E) -4- (1- (4- (2- (2-hydroxyphenyl) (Dimethylamino) Et city) Phenyl ) -5-hydroxy-2- (isoquinolin-7-yl) phen-1-en-1-yl) phenol (Compound 13'-
(Z) -5- (4- (2- (dimethylamino) ethoxy) phenyl) -5- (4-hydroxyphenyl) -4- Quinolin-7-yl) phen-4-enoate and compound 12'-4 Methyl (E) -5- (4- (2- (dimethylamino) ethoxy) phenyl) -5- (4- (Yield: 15%) of 13-6 and 7.7 mg (yield: 31%) of 13'-3 as starting compounds, respectively .
10.5. (Z) -4- (1- (4- (2- (dimethylamino) Ethoxy ) Phenyl) -5-hydroxy-2- (1- methyl -1H-indol-5-yl) phen-1-en-1-yl) phenol (Compound 13-7)
(Z) -5- (4- (2- (dimethylamino) ethoxy) phenyl) -5- (4- hydroxyphenyl) -4- Methyl-1H-indol-5-yl) phen-4-enoate was used as starting compound to obtain 2.6 mg (yield: 5.6%) of compound 13-7.
10.6. (E) -4- (1- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -5-hydroxy-2- (6- ( triple Yl) phen-1-en-1-yl) phenol (Compound 13'-4)
(Z) -5- (4- (2- (dimethylamino) ethoxy) phenyl) -5- (4-hydroxyphenyl) -4- - (trifluoromethyl) pyridin-3-yl) phen-4-enoate as starting compounds, 7.7 mg of the desired compound 13-4 was obtained.
10.7. (Z) -4- (1- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -5-hydroxy-2- (6- Morpholi 1- (4- (2- (dimethylamino) ethoxy) -phenol (Compound 13-8) and (E) -4- Phenyl ) -5-hydroxy-2- (6- Morpholinopyridine Yl) phen-1-en-1-yl) phenol (Compound 13'-5)
(Z) -5- (4- (2- (dimethylamino) ethoxy) phenyl) -5- (4-hydroxyphenyl) -4- (Morpholinopyridin-3-yl) phen-4-enoate and compound 12'-7 methyl (E) -5- (4- (2- (dimethylamino) ethoxy) phenyl) -5- (Yield: 57%) of the target compound 13-8, 8.8 mg (yield: 57%) of 13-5 as starting compounds, respectively, (Yield: 65%).
10.8. (Z / E) -4- (1- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -2- (2- Fluoropyridine Yl) -5- Hydroxyphen -1-thien-1-yl) phenol (Compound 13-9 / 13'-6)
(Z / E) -5- (4- (2- (dimethylamino) ethoxy) phenyl) -4- (2-fluoropyridine -4-yl) -5- (4-hydroxyphenyl) phen-4-enoate as a starting compound, 7.7 mg of a mixture of the target compound 13-9 / 13-6 in a ratio of 6: 4 was obtained.
10.9. (Z) -4- (1- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -5-hydroxy-2- ( already article[ 1,2-a] pyridine Yl) phenol (Compound 13-10) and (E) -4- (1- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -5-hydroxy-2- ( Imidazo [l, 2-a] pyridine -6-yl) phen-1-en-1-yl) phenol (Compound 13'-7)
(Z) -5- (4- (2- (dimethylamino) ethoxy) phenyl) -5- (4-hydroxyphenyl) -4- (Yield: 44%) of the target compound 13-10 and 10 mg (yield: 44%) of 13'-7 as starting compounds, using a mixture of 2- : 25%).
10.10. (Z) -4- (1- (4- (2- (dimethylamino) Ethoxy ) Phenyl (Compound 13-11) and (E) -4- (1- (4- (2- (2-pyridyl) Dimethylamino) Ethoxy ) Phenyl) -5-hydroxy-2- (pyridin-3-yl) phen-1-en-1-yl) phenol (Compound 13'-
(Z / E) -5- (4- (2- (dimethylamino) ethoxy) phenyl) -5- (4-hydroxyphenyl) 10% yield (yield: 44%) of the target compound 13-11 and 10 mg (yield: 25%) of 13'-8 as starting compounds, respectively, ).
Example 11: Preparation of compound 14
11.1. (Z) -4- (1- (4- (2- (dimethylamino) Ethoxy ) -3- ( Trifluoromethyl ) Phenyl ) -5-methoxy-2- (pyridin-3-yl) phen-1-en-1-yl) phenol (Compound 14-1)
(Z) -4- (1- (4- (2- (dimethylamino) ethoxy) phenyl) -5-methoxy-2- (pyridin- (Trifluoromethyl) sulfinyl) oxy) zinc (0.127 g, 0.284 mmol) was dissolved in dichloromethane / water (2.5: 1) Dissolved in 3.5 mL of the mixed solution, and then cooled to 0 ° C or lower. (0.012 mL, 0.154 mmol) and a 70% aqueous solution of tert-butylhydroperoxide (0.064 mL, 0.461 mmol) were added in this order, followed by reaction at room temperature for 1 day. After diluting with dichloromethane, washing with sodium bicarbonate solution, brine, the organic layer was dried with anhydrous Na 2 SO 4 and filtered. The residue obtained by distilling off the solvent under reduced pressure was purified by prep-HPLC to obtain 5.4 mg (yield: 7.0%) of the desired compound 14-1.
11.2. (Z) -4- (1- (4- (2- (dimethylamino) Ethoxy ) Phenyl ) -2- (6- Isopropylpyridine Yl) -5- Methoxyphen -1-thien-1-yl) phenol (Compound 14-2)
In Example 11.1, bis ((isopropylsulfinyl) oxy) zinc reagent was used instead of bis ((trifluoromethyl) sulfinyl) oxy) zinc to synthesize the same. 2.7 mg (Yield: 4.4%) of the desired compound 14-2 was obtained.
Example 12: Preparation of compound 15
(E) -4- (1- (4- (2- (dimethylamino) ethoxy) phenyl) -5-hydroxy-2- 1-yl) phenol (0.033 g, 0.070 mmol) and N, N-diisopropylethylamine (0.073 mL, 0.420 mmol) were dissolved in 3 mL of dichloromethane And then cooled to 0 ° C or less. 1-chloroethylcarbonochloridate (0.046 mL, 0.420 mmol) was added to the reaction mixture. The mixture was reacted at room temperature for 0 to 15 minutes and at 45 ° C for 1 hour. Thereafter, the solvent was distilled off under reduced pressure, methanol was added to the remaining residue, and the reaction was further carried out at 70 ° C for 1 hour. After diluting with dichloromethane, washing with sodium bicarbonate solution, brine, the organic layer was dried with anhydrous Na 2 SO 4 and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by prep-HPLC to obtain the target compound 15 (E) -4- (5-hydroxy-2- (1 -methyl-1 H-indazol- (Yield: 14.0%) of (4- (2- (methoxyamino) ethoxy) phenyl) phen-1-en-1-yl) phenol.
Comparative Example
1-en-1-yl) phenol (GSK5182) was used as a comparative compound, Was used for comparison with the derivatized compound synthesized according to < RTI ID = 0.0 >
Experimental Example
1. Experimental Method
1.1. ERR? , ERRα , ERRβ , ERα binding assay
1.1.1. ERR gamma binding assay (inverse agonist assay)
The inhibitor to be tested was placed in a 384-well plate, starting at a final concentration of 10 μM, and sequentially diluted to a two-fold concentration. GST-conjugated ERR gamma LBD (ligand-binding domain) was added to give a final concentration of 5 nM. Fluorcien-conjugated coacitivator PGC1a and Tb-a-GST antibody were added to give 500 nM and 5 nM, respectively. After all the reagents were added, the reaction was allowed to proceed for 1 hour at 20 ° C with gently shaking, and the binding activity was measured by TR-FRET method. That is, the excitation was performed at 340 nm, and the emission values were measured at 495 nm and 520 nm, respectively. The results were analyzed using a measurement value of 490 nm / 520 nm. The analysis program was Prism 6.
1.1.2. ERR alpha / ERR beta / ER alpha binding assay (Selectivity test)
ERR alpha binding assay used ERR alpha LBD with GST, and all other methods were the same as ERR gamma binding assay.
ERR beta binding assay was performed using ERR alpha LBD conjugated with GST to a final concentration of 10 nM and fluorescence-conjugated coacitivator PGC1a to 250 nM. All other methods were identical to the ERR gamma binding assay.
ER alpha binding assay was performed by adding ER alpha LBD (ligand-binding domain) conjugated with GST to a 384-well plate containing inhibitor to a final concentration of 7.3 nM. A final concentration of 4 nM was added to each of 250 nM and 5 nM of each of the fluorescence-conjugated coac- tivator PGC1a and Tb-a-GST antibody, and the agonist beta-estradiol. All subsequent experiments were identical to the ERR gamma binding assay.
1.2. ERR γ inverse agonist functional assay
AD293 was cultured in a 24 well plate for 24 hours using a DMEM High glucose (Hyclone, USA) medium supplemented with 0.5% FBS at a concentration of 9 × 10 4 cells / well. The cells were treated with DMEM high glucose medium supplemented with 10% FBS and treated with the Trans IT-LT1 transfection reagent (Mirus, USA), pCMX-Gal4-ERRγ, pFR-luciferase reporter plasmid and pCMV- Time. The luciferase activity assay and the β-gal assay were performed on the lysate obtained after the treatment of the drug for 24 hours. All results were derived from more than three independent and repeated experiments.
1.3. in vitro ADME / Tox evaluation
1.3.1. CYP450 Activity inhibition assessment
(Phenacetin 50 μM, Diclofenac 10 μM, S-mephenytoin 100 μM, Dextromethorphan 5 μM, and Midazolam®) were mixed with human liver microsomes (0.25 mg / ml) and 0.1 M phosphate buffer 2.5 μM) and 5 compounds were added at concentrations of 0 and 10 μM, respectively. The cells were preincubated at 37 ° C for 5 minutes, added with NADPH generation system solution, and cultured at 37 ° C for 15 minutes. The reaction was then terminated by adding an acetonitrile solution containing an internal standard (terfenadine) and centrifuging for 5 minutes at 14,000 rpm at 4 ° C. The supernatant was then injected into the LC-MS / MS system, Metabolites were simultaneously analyzed to evaluate the inhibitory activity of the drug metabolizing enzyme by five kinds of compounds.
1.3.2. Microsomal Stability assessment
Four kinds of liver microsomes (Human, Dog, Rat, Mouse 0.5 mg / ml) and 0.1 M phosphate buffer solution (pH 7.4) were added at a concentration of 1 μM and preincubated at 37 ° C for 5 minutes. NADPH regeneration system solution was added and incubated at 37 ° C for 30 minutes. To terminate the reaction, an acetonitrile solution containing an internal standard (chlorpropamide) was added, centrifuged for 5 minutes at 14,000 rpm at 4 ° C, and the supernatant was injected into the LC-MS / The metabolic stability of the five compounds was evaluated by analysis.
1.3.3. hERG channel coupling Low performance evaluation
As a positive control, E-4031 (effective IC50: 10-90 nM) compound was diluted stepwise with 3-fold, mixed with a membrane containing a hERG channel prepared beforehand and a fluorescent tracer and reacted for about 4 hours. Was measured to obtain IC 50 . Fluorescence intensities (Excitation at 530 nm, Emission at 590 nm) were measured at the 16-point dilution stepwise for the submitted test compounds and compared with the DMSO solvent control.
hERG Fluorescence Polarization Assay (Invitrogen: PV5365) kit was used.
2. Experimental results
The experimental results obtained by the experimental method according to Item 1 of the Experimental Example are shown in the following Tables 1 and 2.
[Table 1]
A = [single IC 50 < 1 [mu] M]
B = [1 μM <single IC 50 <10 μM]
C = [single IC 50 ≥ 10 μM]
+ = [a single% value ≤ 10%]
++ = [10% <a single% value <50%]
+++ = [a single% value ≥ 50%]
[Table 2]
A = [single IC 50 < 1 [mu] M]
B = [1 μM <single IC 50 <10 μM]
C = [single IC 50 ≥ 10 μM]
+ = [a single% value ≤ 10%]
++ = [10% <a single% value <50%]
+++ = [a single% value ≥ 50%]
Claims (7)
Wherein the active ingredient acts as a ligand which inhibits the activity of ERR? (Estrogen related receptor gamma).
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| US4897490A (en) | 1987-02-25 | 1990-01-30 | Bristol-Meyers Company | Antihypercholesterolemic tetrazole compounds |
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| JPH08268949A (en) * | 1995-03-29 | 1996-10-15 | Eisai Co Ltd | Diphenylmethylene derivative |
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