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WO2018021762A1 - Nouveau composé, son procédé de préparation, et composition pharmaceutique le contenant - Google Patents

Nouveau composé, son procédé de préparation, et composition pharmaceutique le contenant Download PDF

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Publication number
WO2018021762A1
WO2018021762A1 PCT/KR2017/007853 KR2017007853W WO2018021762A1 WO 2018021762 A1 WO2018021762 A1 WO 2018021762A1 KR 2017007853 W KR2017007853 W KR 2017007853W WO 2018021762 A1 WO2018021762 A1 WO 2018021762A1
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group
indole
mmol
ethyl
added
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Korean (ko)
Inventor
이인희
김세환
문순영
장정인
강승태
윤현호
이혁주
이재걸
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Hyundai Pharm Co Ltd
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Hyundai Pharm Co Ltd
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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/22—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an aralkyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to a novel compound that binds to a peroxysome proliferator activated receptor (Gamma) but does not act as an agonist, a preparation method thereof, and a pharmaceutical composition comprising the same as an active ingredient.
  • a peroxysome proliferator activated receptor Gamma
  • Diabetes has been treated mainly with the introduction of insulin, but insulin has the trouble of using injections, and simply supplements the insulin that is lacking in the body, and does not solve the fundamental treatment of diabetes.
  • drugs that promote insulin secretion such as sulfonylurea
  • drugs that slowly release glucose stored in the liver such as metformin, which inhibits glycolysis, such as acarbose, which inhibit absorption.
  • Drugs or drugs that enhance the sensitivity of insulin receptors, such as rosiglitazone and pioglitazone, have been developed and sold.
  • Thiazolidinedione (TZD) drugs such as rosiglitazone and pioglitazone, act on the nuclear receptor peroxysome proliferator activated receptor-gamma (hereinafter referred to as 'PPAR ⁇ '). Anti-diabetic effect is shown by increasing the sensitivity of insulin by activating transcription.
  • the thiazolidinedione drug can obtain anti-diabetic effect by increasing the activity of 'PPAR ⁇ ', but also controls the expression of genes causing various side effects, showing side effects such as weight gain, swelling, and bone mineral density, cardiovascular There is a problem that can cause diseases, such as the situation is limited to use in the market. Therefore, two of the three subunits (PPAR- ⁇ / ⁇ or PPAR- ⁇ / ⁇ ) and three (PPAR-) of the PPAR ⁇ partial agonist and PPAR as a solution to address the side effects of the PPAR ⁇ agonist. Drugs that act on ⁇ / ⁇ / ⁇ ) are also being developed, but are not yet on the market due to side effects and safety issues.
  • the present inventors bind to PPAR ⁇ with high affinity, but do not induce gene transcription, thereby not acting as an agonist, blocking phosphorylation by CDK5, improving insulin resistance, and important pharmacology in developing new drugs.
  • PK physical properties
  • Another object of the present invention is to provide a method for preparing the compound.
  • It is another object of the present invention to provide a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof.
  • R 1 to R 4 are the same as or different from each other, and each independently hydrogen, a halogen group, a C 1 to C 10 alkyl group, a C 1 to C 10 alkoxy group and a hetero atom selected from the group consisting of N, O and S Is selected from the group consisting of 5 to 10 heteroaryl group containing one or more ring atoms,
  • R 5 to R 9 are the same as or different from each other, and are each independently selected from the group consisting of hydrogen, a halogen group and a C 1 to C 10 alkoxy group,
  • R 10 is selected from the group consisting of a hydroxyl group, an amino group and a C 1 to C 10 alkoxy group,
  • R 11 is selected from the group consisting of hydrogen, a halogen group, a nitro group, a thiol group, a C 1 to C 10 alkyl group, a C 1 to C 10 alkoxy group, a C 6 to C 10 aryl group and N, O and S Is selected from the group consisting of 5 to 10 heteroaryl groups containing one or more hetero atoms,
  • L is selected from the group consisting of a single bond, an alkylene group of C 1 to C 10 and an arylene group of C 6 to C 10 ,
  • A is selected from the group consisting of O and NR 12 ,
  • R 12 is selected from the group consisting of a hydroxyl group and a C 1 to C 10 alkoxy group
  • the heteroaryl group of 5 to 10, the C 1 to C 10 alkylene group and C 6 to C 10 arylene group of L are each independently halogen, C 1 to C 10 alkyl group and C 1 to C 10 It may be substituted or unsubstituted with one or more substituents selected from the group consisting of alkoxy groups. When the substituents are plural, the plural substituents are the same as or different from each other.
  • the present invention a) synthesizing the compound represented by the formula (2) or 3; b) cyclization of the compound represented by Formula 2 synthesized in step a) in the presence of polyphosphoric acids, or by cyclization of the compound represented by Formula 3 in the presence of acetic acid Synthesizing the compound to be represented; c) synthesizing the compound represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 4 synthesized in step b) with the compound represented by Chemical Formula 5; d) synthesizing a compound represented by the following Chemical Formula 7 by substituting hydrogen bonded to a nitrogen atom of the compound represented by Chemical Formula 6 synthesized in step c); And e) reacting the compound represented by Formula 7 synthesized in step d) with a strong base to synthesize a compound represented by Formula 1 below.
  • R 1 to R 11 , L and A are the same as described above.
  • the present invention provides a pharmaceutical composition for treating metabolic disease comprising the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound represented by Formula 1 according to the present invention binds to PPAR ⁇ with high affinity but does not act as an agent and thus does not induce gene transcription and blocks phosphorylation by CDK5, thereby preventing conventional diabetes mellitus.
  • the occurrence of side effects caused by the drug used for treatment can be minimized. Accordingly, the present invention can provide a pharmaceutical composition that can exhibit an excellent effect in the treatment of PPAR ⁇ related metabolic diseases.
  • 1 is a reference diagram for explaining an experimental example 3 of the present invention.
  • the present invention binds to PPAR ⁇ with high affinity but does not induce gene transcriptional activity and thus does not act as an agonist, and may block phosphorylation by CDK5 to improve insulin resistance, or a pharmaceutical thereof.
  • the compound is represented by the following Chemical Formula 1.
  • R 1 to R 4 are the same as or different from each other, and each independently hydrogen, a halogen group, a C 1 to C 10 alkyl group, a C 1 to C 10 alkoxy group and a hetero atom selected from the group consisting of N, O and S Is selected from the group consisting of 5 to 10 heteroaryl group containing one or more ring atoms,
  • R 5 to R 9 are the same as or different from each other, and are each independently selected from the group consisting of hydrogen, a halogen group and a C 1 to C 10 alkoxy group,
  • R 10 is selected from the group consisting of a hydroxyl group, an amino group and a C 1 to C 10 alkoxy group,
  • R 11 is selected from the group consisting of hydrogen, a halogen group, a nitro group, a thiol group, a C 1 to C 10 alkyl group, a C 1 to C 10 alkoxy group, a C 6 to C 10 aryl group and N, O and S Is selected from the group consisting of 5 to 10 heteroaryl groups containing one or more hetero atoms,
  • L is selected from a single bond, C 1 to C 10 arylene group consisting of an alkyl group and a C 6 to C 10 of,
  • A is selected from the group consisting of O and NR 12 ,
  • R 12 is selected from the group consisting of a hydroxyl group and a C 1 to C 10 alkoxy group
  • the heteroaryl group of 5 to 10, the C 1 to C 10 alkylene group and C 6 to C 10 arylene group of L are each independently halogen, C 1 to C 10 alkyl group and C 1 to C 10 It may be substituted or unsubstituted with one or more substituents selected from the group consisting of alkoxy groups. When the substituents are plural, the plural substituents are the same as or different from each other.
  • the compound represented by Formula 1 is characterized in that an aromatic ring group connected to an indole moiety by a specific substituent, that is, a ketone group or an imino group.
  • a specific substituent that is, a ketone group or an imino group.
  • R 1 to R 4 are each independently selected from the group consisting of hydrogen, a halogen group, a pyridine group, and a trifluoromethyl group (-CF 3 ).
  • R 5 to R 9 it may be selected from the group consisting of each independently hydrogen, a halogen group, a methoxy group (-OCH 3) and trifluoro methoxy group (-OCF 3).
  • R 10 is preferably a hydroxyl group (-OH).
  • the structure represented by * -LR 11 in the formula (1) is preferably selected from the group consisting of the structure represented by the following S1 to S30.
  • Such a compound represented by Formula 1 of the present invention, or a pharmaceutically acceptable salt thereof may be embodied as any one compound selected from the group consisting of Formulas C1 to C77, or a pharmaceutically acceptable salt thereof. It is not limited to these.
  • the compound represented by the formula (1) of the present invention is used in the form of a pharmaceutically acceptable salt, it is preferable that it is in the form of an acid addition salt formed by a pharmaceutically acceptable free acid.
  • the acid used in the preparation of the acid addition salt is not particularly limited, but hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, dicarboxylate, phenyl-substituted alkanoate, hydroxy alkano Eate, alkanedioate, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, or fumaric acid.
  • the method for preparing the acid addition salt is not particularly limited, but the compound represented by Chemical Formula 1 is dissolved in an organic solvent (for example, methanol, ethanol, acetone, methylene chloride, acetonitrile, etc.), and the organic or inorganic acid is dissolved.
  • the precipitate formed by addition can be prepared by filtration and drying, or by drying the organic solvent and excess acid under reduced pressure and then drying.
  • the present invention provides a method for preparing a compound represented by Chemical Formula 1, which will be described in detail below.
  • a compound represented by the following Chemical Formula 2 or 3 is synthesized.
  • the method for synthesizing the compound represented by the following Chemical Formula 2 or 3 is not particularly limited as long as it is known in the art, and the raw material is added to an organic solvent (for example, acetate, alcohol, ether) and 5 at room temperature. After the reaction for 15 hours to dry and filtered it can be synthesized.
  • an organic solvent for example, acetate, alcohol, ether
  • the compound represented by Formula 2 synthesized above is cyclized in the presence of polyphosphoric acids, or the compound represented by Formula 3 synthesized above is cyclized in the presence of acetic acid
  • the compound represented by it is synthesize
  • the compound represented by the formula (6) is synthesized by reacting the compound represented by the formula (4) synthesized above with the compound represented by the formula (5).
  • Synthesis of the compound represented by Formula 6 is carried out by drying the compound and the compound represented by Formula 4 and Formula 5 into an organic solvent (for example, dichloromethane) and reacted for 10 to 15 hours, followed by drying and filtration Can be synthesized. Catalysts such as aluminum chloride may also be used to facilitate the synthesis process.
  • the compound represented by the following formula (7) is synthesized by substituting hydrogen bonded to the nitrogen atom of the compound represented by the formula (6). That is, hydrogen bonded to the nitrogen atom present in the indole moiety is substituted with a substituent represented by * -LR 11 .
  • the method for substituting the hydrogen with a substituent represented by * -LR 11 is not particularly limited as long as it is a method known in the art.
  • the compound represented by Chemical Formula 1 is synthesized by reacting the compound represented by Chemical Formula 7 synthesized above with a strong base. Specifically, the compound represented by Chemical Formula 7 is dissolved in an organic solvent (eg, tetrahydrofuran, methanol, etc.), reacted with a strong base (eg, sodium hydroxide, etc.) for 30 minutes to 2 hours, and then dried. And it can be synthesized through a process of filtration.
  • an organic solvent eg, tetrahydrofuran, methanol, etc.
  • a strong base eg, sodium hydroxide, etc.
  • the present invention provides a pharmaceutical composition for treating metabolic disease associated with PPAR ⁇ containing the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition of the present invention binds to PPAR ⁇ with high affinity, does not act as an agonist, and thus does not induce gene transcription, and can block phosphorylation of the amino acid at position 273 of serine of PPAR ⁇ by CDK5, It does not cause side effects and can be effective in treating metabolic diseases.
  • the side effects may include weight gain, edema, impairment of bone growth or formation, or cardiac hypertrophy.
  • metabolic diseases associated with phosphorylation of PPAR ⁇ by CDK5 include diabetes, insulin resistance, impaired glucose tolerance, pre-diabetes, hyperglycemia, and hyperinsulinemia ( hyperinsulinemia, obesity or inflammation.
  • compositions of the present invention may be formulated and used in oral or parenteral dosage forms.
  • Formulations for oral administration include tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), glidants (e.g., silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols) It may contain.
  • Lactose dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine
  • glidants e.g., silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols
  • the parenteral administration may be a method of injecting into the body by subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.
  • Such a pharmaceutical composition of the present invention is preferably used to adjust the dosage according to the age, weight, sex, dosage form, health condition and degree of disease of the patient.
  • a target compound was obtained in the same manner as in Example 1, except that (3-chlorophenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in ⁇ Step 4>. .
  • Example 2 The same procedure as in Example 1 was performed except that (4- (tert-butyl) phenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in ⁇ Step 4>. The compound was obtained.
  • Example 2 The same procedure as in Example 1 was carried out except that (3,4-difluorophenyl) boronic acid was used instead of 4- (chloroophenyl) boronic acid used in ⁇ Step 4>. The compound was obtained.
  • Example 2 The same procedure as in Example 1 was carried out except that (3- (methylthio) phenyl) boronic acid was used instead of 4- (chloroophenyl) boronic acid used in ⁇ Step 4>. The compound was obtained.
  • Example 2 The same procedure as in Example 1 was performed except for using (3- (trifluoromethoxy) phenyl) boronic acid instead of 4- (chlorofluorophenyl) boronic acid used in ⁇ Step 4>. To obtain the target compound.
  • Example 2 The same procedure as in Example 1 was performed except for using (3- (trifluoromethyl) phenyl) boronic acid instead of 4- (chlorofluorophenyl) boronic acid used in ⁇ Step 4>. The desired compound was obtained.
  • the target compound was obtained in the same manner as in Example 1, except that (meth-toluyl) boronic acid was used instead of 4- (chloroophenyl) boronic acid used in ⁇ Step 4>.
  • a target compound was obtained in the same manner as in Example 9, except that (3-methoxyphenyl) boronic acid acid was used instead of 4- (chlorophenyl) boronic acid acid used in ⁇ Step 4>. .
  • Example 9 The same procedure as in Example 9 was carried out except that (4- (tert-butyl) phenyl) boronic acid was used instead of 4- (chloroophenyl) boronic acid used in ⁇ Step 4>. The compound was obtained.
  • Example 9 The same procedure as in Example 9 was carried out except that (3- (trifluoromethoxy) phenyl) boronic acid was used instead of 4- (chlorofluorophenyl) boronic acid used in ⁇ Step 4>. To obtain the target compound.
  • Example 9 The same procedure as in Example 9 was carried out except for using (4- (methylthio) phenyl) boronic acid instead of 4- (chloroophenyl) boronic acid used in ⁇ Step 4>. The compound was obtained.
  • Example 9 The same procedure as in Example 9 was performed except for using (4- (trifluoromethyl) phenyl) boronic acid instead of 4- (chlorofluorophenyl) boronic acid used in ⁇ Step 4>. The desired compound was obtained.
  • a target compound was obtained in the same manner as in Example 9, except that (4-bromophenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in ⁇ Step 4>. .
  • a target compound was obtained in the same manner as in Example 9, except that (quinolin-3-yl) boronic acid was used instead of 4- (chloroophenyl) boronic acid used in ⁇ Step 4>. .
  • the target compound was obtained in the same manner as in Example 9, except that (para-toluyl) boronic acid was used instead of 4- (chloroophenyl) boronic acid used in ⁇ Step 4>.
  • Example 9 The same procedure as in Example 9 was carried out except that (3-fluoro-4-methoxyphenyl) boronic acid was used instead of 4- (chlorofluoro) boronic acid used in ⁇ Step 4>. To obtain the target compound.
  • a target compound was obtained by the same procedure as in Example 19, except that (3-chlorophenyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in ⁇ Step 4>.
  • (3-chlorophenyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in ⁇ Step 4>.
  • Example 19 The same procedure as in Example 19 was carried out except for using (4- (methylthio) phenyl) boronic acid instead of (4-chlorophenyl) boronic acid used in ⁇ Step 4>. The compound was obtained.
  • Example 19 The same procedure as in Example 19 was carried out except that (4- (trifluoromethoxy) phenyl) boronic acid was used instead of the (4-chlorophenyl) boronic acid used in ⁇ Step 4>. To obtain the target compound.
  • Example 19 The same procedure as in Example 19 was carried out except for using (3- (methylthio) phenyl) boronic acid instead of (4-chlorophenyl) boronic acid used in ⁇ Step 4>. The compound was obtained.
  • Example 19 The same procedure as in Example 19 was carried out except that (3-fluoro-4-methylphenyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in ⁇ Step 4>. The compound was obtained.
  • Example 19 The same procedure as in Example 19 was carried out except that (3,4,5-trifluorophenyl) boronic acid was used instead of the (4-chlorophenyl) boronic acid used in ⁇ Step 4>. To obtain the target compound.
  • Example 19 The same procedure as in Example 19 was carried out except for using (3,5-difluorophenyl) boronic acid instead of (4-chlorophenyl) boronic acid used in ⁇ Step 4>. The compound was obtained.
  • a target compound was obtained in the same manner as in Example 19, except that (4-bromophenyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in ⁇ Step 4>. .
  • Example 19 The same procedure as in Example 19 was carried out except for using (4- (trifluoromethyl) phenyl) boronic acid instead of (4-chlorophenyl) boronic acid used in ⁇ Step 4>. The desired compound was obtained.
  • the target compound was obtained in the same manner as in Example 19, except that (pyridin-4-yl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in ⁇ Step 4>. .
  • a target compound was obtained in the same manner as in Example 19, except that (3-fluorophenyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in ⁇ Step 4>. .
  • a target compound was obtained in the same manner as in Example 19, except that (quinolin-3-yl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in ⁇ Step 4>. .
  • a target compound was obtained in the same manner as in Example 19, except that (3-methoxyphenyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in ⁇ Step 4>. .
  • a target compound was obtained in the same manner as in Example 19, except that (4-methoxyphenyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in ⁇ Step 4>. .
  • a target compound was obtained in the same manner as in Example 19, except for using (para-toluyl) boronic acid instead of (4-chlorophenyl) boronic acid used in ⁇ Step 4>.
  • Example 19 The same procedure as in Example 19 was carried out except for using (3- (trifluoromethyl) phenyl) boronic acid instead of (4-chlorophenyl) boronic acid used in ⁇ Step 4>. The desired compound was obtained.
  • Example 19 The same procedure as in Example 19 was carried out except that (3-fluoro-4-methoxyphenyl) boronic acid was used instead of the (4-chlorophenyl) boronic acid used in ⁇ Step 4>. To obtain the target compound.
  • Example 19 The same procedure as in Example 19 was carried out except that (3- (trifluoromethoxy) phenyl) boronic acid was used in place of the (4-chlorophenyl) boronic acid used in ⁇ Step 4>. To obtain the target compound.
  • a target compound was obtained in the same manner as in Example 19, except that (4-nitrophenyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in ⁇ Step 4>. .
  • a target compound was obtained in the same manner as in Example 19, except that (4-fluorophenyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in ⁇ Step 4>. .
  • Example 40 The same procedure as in Example 40 was carried out except that (4- (tert-butyl) phenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in ⁇ Step 4>. The compound was obtained.
  • a target compound was obtained in the same manner as in Example 40, except that (3-fluorophenyl) boronic acid was used instead of 4- (chlorofluoro) boronic acid used in ⁇ Step 4>. .
  • a target compound was obtained in the same manner as in Example 40, except that (4-bromophenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in ⁇ Step 4>. .
  • Example 40 The same procedure as in Example 40 was carried out except that (3- (methylthio) phenyl) boronic acid was used instead of 4- (chloroophenyl) boronic acid used in ⁇ Step 4>. The compound was obtained.
  • Example 40 The same procedure as in Example 40 was carried out except that (4- (methylthio) phenyl) boronic acid was used instead of 4- (chloroophenyl) boronic acid used in ⁇ Step 4>. The compound was obtained.
  • a target compound was obtained in the same manner as in Example 48, except that (4-chlorophenyl) boronic acid was used instead of 3- (chlorophenyl) boronic acid used in ⁇ Step 4>. .
  • ethyl-3-benzoyl-1- (4- (chlorophenyl) -6- (trifluoromethyl) -1H-indole-2-carboxylate synthesized in step ⁇ 4> (92 mg, 0.46 mmol) was added and dissolved by addition of tetrahydrofuran (1 mL) and methanol (1 mL), then 1N sodium hydroxide (0.45 ml, 5 vol) was added and stirred for 1 hour. After completion of the reaction, the mixture was concentrated and adjusted to pH 5 using 2N-HCl, after which the organic layer was separated using ethyl acetate and water, and then water contained in the organic layer was removed with magnesium sulfate.
  • a target compound was obtained in the same manner as in Example 49, except for using (3-chlorophenyl) boronic acid instead of 4- (chlorophenyl) boronic acid used in ⁇ Step 4>. .
  • a target compound was obtained in the same manner as in Example 51, except for using (3-methoxyphenyl) boronic acid instead of (3-chlorophenyl) boronic acid used in ⁇ Step 2>. .
  • Example 53 The same procedure as in Example 53 was carried out except for using (4- (tert-butyl) phenyl) boronic acid instead of (3-chlorophenyl) boronic acid used in ⁇ Step 2>. The compound was obtained.
  • Example 55 The same procedure as in Example 55 was carried out except that (3-methylthiophenyl) boronic acid was used instead of (4-methylthiophenyl) boronic acid used in ⁇ Step 4>. Got.
  • a target compound was obtained in the same manner as in Example 55 except for using (4-fluorophenyl) boronic acid instead of (4-methylthiophenyl) boronic acid used in ⁇ Step 4>. .
  • Example 58 The same procedure as in Example 58 was performed except for using (4-trifluoromethoxyphenyl) boronic acid instead of (4-methylthiophenyl) boronic acid used in ⁇ Step 4>. The desired compound was obtained.
  • Example 58 The same procedure as in Example 58 was carried out except that (3-methylthiophenyl) boronic acid was used instead of (4-methylthiophenyl) boronic acid used in ⁇ Step 4>. Got.
  • a target compound was obtained in the same manner as in Example 61, except that (3-fluorophenyl) boronic acid was used instead of (4-fluorophenyl) boronic acid used in ⁇ Step 4>. .
  • a target compound was obtained by the same procedure as in Example 61, except that (3-chlorophenyl) boronic acid was used instead of (4-fluorophenyl) boronic acid used in ⁇ Step 4>. It was.
  • the target compound was obtained in the same manner as in Example 64, except that (meth-toluyl) boronic acid was used instead of (3-methylphenyl) boronic acid used in ⁇ Step 4>.
  • the target compound was obtained in the same manner as in Example 64, except that (4-methoxyphenyl) boronic acid was used instead of (3-methylphenyl) boronic acid used in ⁇ Step 4>.
  • 6-chloro-3- (4-chlorobenzoyl) -1- (4-chlorophenyl) -1H-indole-2-carboxylic acid (50 synthesized in step 5) was used. mg, 0.1124 mmol) and ethanol (1.0 ml) were added and reacted. Next, hydroxylamine hydrochloride (12 mg, 0.1686 mmol) and sodium acetate (18.4 mg, 0.2248 mmol) were added, the mixture was stirred under reflux for 5 hours, the temperature was lowered to room temperature, and the reaction solution was concentrated.
  • 6-chloro-3- (4-chlorobenzoyl) -1- (4-chlorophenyl) -1H-indole-2-carboxylic acid (30) synthesized in ⁇ Step 5> above (30) mg, 0.0675 mmol) and ethanol (0.5 ml) were added and dissolved.
  • methylhydroxylamine hydrochloride (8.5 mg, 0.1012 mmol) and sodium sulfate (19.2 mg, 0.1350 mmol) were added and stirred under reflux, and then the temperature was lowered to room temperature and the reaction solution was concentrated.
  • Example 70 The same procedure as in Example 70 was carried out except that 1- (bromomethyl) -3-methoxybenzene was used instead of 1- (bromomethyl) -4-chlorobenzene used in ⁇ Step 4>. To give the desired compound.
  • Example 70 The same procedure as in Example 70 was repeated except that 1- (bromomethyl) -2-chlorobenzene was used instead of 1- (bromomethyl) -4-chlorobenzene used in ⁇ Step 4>. To give the desired compound.
  • Example 70 The same procedure as in Example 70 was carried out except that 3- (bromomethyl) pyididine was used instead of 1- (bromomethyl) -4-chlorobenzene used in ⁇ Step 4>. Got.
  • Example 1 except that 1- (bromomethyl) -3- (trifluoromethoxy) benzene was used instead of 1- (bromomethyl) -4-chlorobenzene used in ⁇ Step 4>. The same procedure as in 70 was carried out to obtain the target compound.
  • Time-Resolved Fluorescence (RFU) mode in Flexstation 3 (Molecular Devices), excitation1 340 nm, emission1 518 nm, excitation2 340 nm, emission2 488 nm, integration delay 50 us
  • the fluorescence values were read under the integration 400 us condition.
  • Experimental results were calculated using the 518 nm RFUs / 488 nm RFUs ratio value. Specifically, the binding activity of each compound relative to the vehicle (binding activity) was calculated by the formula [100%-each compound ratio / vehicle ratio].
  • PPAR ⁇ Peroxisome proliferator activated receptor-Gamma
  • HEK293 cells were plated at 5 ⁇ 10 4 in 24-well plates (SPL, 30024). HEK293 cells were transfected with PPPAR (PPAR Response Element) as FuGENE HD (Promega, E2312). 24 hours after transduction, the compounds of Examples 1 to 77 and the compounds of Comparative Examples 1 to 3 were treated for 24 hours by concentration. After 24 hours of treatment, cells were collected to calculate the activity of the reporter gene assay and the Luciferase assay. In this case, the reporter gene analysis was performed using a Dual Reporter gene assay kit (Promega, E1980), and the activity of the luciferase assay was calculated by normalizing renilla activity.
  • PPPAR PPAR Response Element
  • FuGENE HD FuGENE HD
  • the compound of the present invention has excellent activity of binding to PPAR ⁇ .
  • the binding activity level indicates the presence or absence of binding, and is not directly related to pharmacological activity. Further, the compounds of the present invention do not induce the transcriptional activity of PPAR ⁇ , while the compounds of the comparative examples can be seen to induce the transcriptional activity of PPAR ⁇ .
  • PPAR ⁇ -Ligand binding domain human recombinant (Cayman, 10007941) 0.43 mg, CDK5 / p35 active (millipore, 14-477) 100 ng, 10-fold kinase buffer (CellSignaling, 9802S) and DW
  • the premix was prepared to have a final volume of 36 ⁇ l of data warehousing (premix was prepared on ice and stored in ice). 2 ⁇ l of each compound was mixed in 36 ⁇ l of the premix and reacted for 10 minutes on ice. Then, 2 ⁇ l of ATP 10 mM (2 ⁇ l of DW for negative control) was added and reacted for 15 minutes in a 37 ° C. water bath.
  • hypoglycemic effect of the pharmaceutical compositions containing the compounds of Examples 1, 2, 19, and 20 and the compound of Comparative Example 1 at 10 mg / kg concentration were evaluated by the following method, and the results are shown in Table 2 below. It was.
  • DIO mice with group separation completed were administered a pharmaceutical composition for each group for one week at each dose.
  • IPGTT Intraperitoneal Glucose Tolerance Test
  • DIO mice to which each pharmaceutical composition was administered for 1 week were orally administered 1 g / kg of glucose, and the blood glucose was measured by Accu-chek active strip (Roche diagnostic Co.) by puncture of the microvenous veins. At this time, the measurement time was -30 minutes, 0 minutes, 20 minutes, 40 minutes, 60 minutes and 120 minutes based on the glucose administration time, and the values measured in each group were averaged.
  • DIO mice that terminated the administration of each pharmaceutical composition were fasted over-night.
  • blood glucose of DIO mice was measured by Accu-chek active strip (Roche diagnostic Co.) and recorded as fasting blood glucose, and then the values measured in each group were averaged.
  • DIO mice that terminated the administration of each pharmaceutical composition were fasted over-night.
  • about 50 ⁇ l of blood was drawn through the capillary (KIMBLE CHASE, USA) of DIO mice by orbital blood collection, and blood was centrifuged at 3600 rpm for 10 minutes to separate plasma. Thereafter, insulin was measured using an insulin ELISA kit (Miobs, Japan), and then averaged values measured in each group.
  • the pharmaceutical compositions containing the compounds of Examples 1, 2, 19, and 20 exhibited equivalent or more blood glucose reductions compared to the pharmaceutical compositions containing the compounds of Comparative Example 1, confirming that the effect was excellent. Can be.

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Abstract

La présente invention concerne un nouveau composé inhibant la phosphorylation de PPARγ médiée par CDK5, son procédé de préparation et une composition pharmaceutique le contenant. Le nouveau composé de la présente invention se lie à PPARγ avec une affinité élevée mais n'induit pas d'activité transcriptionnelle de manière à ne pas agir comme un agoniste, ne provoque pas d'effets secondaires d'un anti-diabétique classique en bloquant l'activité de phosphorylation de CDK5, et a des propriétés pharmacologiques améliorées. Par conséquent, une composition pharmaceutique contenant le composé de la présente invention en tant qu'ingrédient actif peut être utilisée dans le traitement de maladies métaboliques associées à PPARγ.
PCT/KR2017/007853 2016-07-26 2017-07-20 Nouveau composé, son procédé de préparation, et composition pharmaceutique le contenant Ceased WO2018021762A1 (fr)

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KR20250079420A (ko) 2023-11-27 2025-06-04 울산과학기술원 Ppp3r1을 유효성분으로 포함하는 대사성 질환 예방 또는 치료용 약학적 조성물

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