JP2013177329A - Rxr partial agonist - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound (rexinoid) which is bonded to a retinoid X receptor (RXR) and gives partial agonist action.SOLUTION: There is provided a compound represented by formula (II).

Description

  The present invention is a compound that acts as a partial agonist for retinoid X receptor (RXR), which is a nuclear receptor (hereinafter referred to as “RXR partial agonist”), and has a heterocyclic skeleton. It relates to a novel compound consisting of Furthermore, it relates to its action.

  Nuclear receptors are one of ligand-dependent transcriptional regulators that are responsible for maintaining cell proliferation, immune response, physiological functions such as sugar / lipid metabolism, and homeostasis. The ligand corresponding to the nuclear receptor controls the transcription of the downstream gene. Nuclear receptors are derived from the same primordial gene and form a superfamily.

  Retinoid X receptor (hereinafter abbreviated as “RXR”) is a nuclear ligand that is a ligand-dependent transcription factor that is thought to have 9-cis retinoic acid and docosahexaneenoic acid (DHA) as endogenous ligands. One of the receptors. Its function is exhibited as a homodimer and by forming heterodimers with various nuclear receptors (Non-patent Document 1).

  RXR heterodimer partners include retinoic acid receptor (RAR), which is involved in cell differentiation and proliferation, vitamin D receptor (VDR), which is also involved in cell differentiation, proliferation and bone metabolism, and lipid metabolism. Examples include peroxisome proliferator-responsive receptors (PPAR) and thyroid hormone receptor thyroid hormone receptor (TR). Therefore, the function of RXR and the activity expression of these nuclear receptors are closely related, and an agonist or antagonist that controls RXR function can control the function of these heterodimers. (Non-patent document 2).

For example, the RAR agonist Am80 (generic name: tamibarotene: treatment for relapsed or refractory acute promyelocytic leukemia: 4-[(5,6,7,8-tetrahydro-5,5,8, 8-tetramethyl-2-naphthyl) carbamoyl] benzoic acid: Non-patent document 3) shows almost no cell differentiation-inducing action when present alone at a concentration of 3.3 × 10 ^-10 M, whereas it acts on Am80 and RXR. When a substance is used in combination, the RXR agonist acts as a synergist of Am80, and a significant differentiation inducing action is observed (Non-patent Document 4). Such synergistic effects on nuclear receptor heterodimers by RXR agonists are observed not only on RAR but also on VDR, PPAR, etc. that form heterodimers with RXR. Such a highly lipophilic drug molecule targeting the nuclear receptor can be effective as a synergist that exerts its effect even when the drug is used in a low volume.

  RXR agonists are not limited to actions via the nuclear receptor heterodimer containing RXR. For example, tamoxifen used for breast cancer treatment is an estrogen receptor (ER) that does not form a heterodimer with RXR, but its RXR agonist improves the resistance of estrogen-resistant breast cancer. (Non-Patent Document 6). Furthermore, the carcinogenesis preventing effect by the RXR agonist substance alone or in combination with tamoxifen has been reported (Non-patent Document 7). The effectiveness of RXR agonists in taxol-resistant cancer has also been reported (Non-patent Document 8). In addition, the anti-angiogenic action of RXR agonists has been reported (Non-patent Document 9).

  In addition, the RXR agonist has an interesting physiological activity even when administered alone. For example, it has been reported that when an RXR agonist is administered to a type 2 diabetes model mouse, insulin resistance is improved and blood glucose level is reduced (Non-patent Document 10).

  In addition, since RXR agonists act on the hair root cycle and have a hair-growing action, application as a hair-restoring agent has also been reported (Patent Document 1).

  Known RXR agonists include compounds as shown in FIG. These have been applied to pharmaceutical uses, but an increase in blood triglycerides (TG) can be cited as a common problem with existing RXR agonists (Non-patent Documents 11 and 12). A close examination of these RXR agonists reveals that RXR partial agonists that moderately weaken their effectiveness (RXR full agonists) that can fully activate RXR in common (Non-patent Documents 13 and 14). I have been interested in agonists.

  So far, the RXR partial agonist described in Patent Document 2 and Patent Document 3 has been successfully created. However, the RXR partial agonist described in Patent Document 2 and the RXR partial agonist CBt-PMN described in Patent Document 3 have a high concentration required for RXR activation, and a compound having an effect at a lower concentration is desired.

Science, 290, pp.2140-2144, 2000 Cell, 83, pp.841-850, 1995 AmnoLake Tablets 2mg <Tamivalotene> Nippon Shinyaku sales package insert (prepared in June 2005) Journal of Medicinal Chemistry, 37, pp.1508-1517, 1994 The Journal of Clinical Investigation, 108, pp.1001-1013, 2001 Cancer Research, 58, pp.479-484, 1998 etc. Cancer Letters, 201, pp.17-24, 2003 Clinical Cancer Research, 10, pp8656-8664, 2004 British Journal of Cancer, 94, pp.654-660, 2006 Nature, 386, pp.407-410, 1997 Mol. Pharmacol., 59, pp.170-176, 2001 J. Clin. Oncol., 15, pp.790-795, 1997 J. Med. Chem., 44, 2298-2303, 2001 Med. Chem. Lett., 14, 6117-6122, 2004

US Pat. No. 5,962,508 International Publication No. 2010/098125 JP 2010-1111588 A

  An object of the present invention is to provide a stronger RXR partial agonist than the conventional RXR partial agonist, and further to provide anti-inflammatory, anti-allergic action and the like due to its use.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have developed a novel RXR partial agonist which is a complex compound type having a ring closed at an aromatic carboxylic acid site and has an appropriate rexinoid activity (RXR partial agonist activity). The present invention has been completed.

That is, this invention consists of the following.
1. Formula I:
(Wherein, R ^1, R ² are each linear alkyl chain, an alkoxy group having a branch alkyl chain, and branched alkyl groups, and independently of each other or closed, its position is in R ³ In contrast, it is located in the meta or para position,
R ³ is selected from hydrogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, acyl group, alkylamino group, and arylamino group;
The ring constructed by NYX is a 5-membered ring, 6-membered ring or 7-membered ring,
When the ring constructed by NYX is a 5-membered ring, XY is selected from N = CR ⁵ and C = CR ⁶ ;
R ⁵ is selected from hydrogen and halogenated alkyl groups;
R ⁶ is selected from hydrogen, alkyl group, halogenated alkyl group, alkenyl group, alkynyl group, substituted phenyl group, alkoxy group and substituted amino group,
Z is selected from carboxylic acid esters and carboxyl groups, hydroxamic acids and their salts. )
The compound shown by.
2. ^2. The compound according to 1 above, wherein R ¹ and R ² are closed to form a 6-membered ring.
3. Formula II:
(Wherein R ³ is selected from an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an acyl group, an alkylamino group, and an arylamino group;
The ring constructed by NYX is a 5-membered ring, 6-membered ring or 7-membered ring,
When the ring constructed by NYX is a 5-membered ring, XY is selected from N = CR ⁵ and C = CR ⁶ ;
R ⁵ is selected from hydrogen and halogenated alkyl groups;
R ⁶ is selected from hydrogen, alkyl group, halogenated alkyl group, alkenyl group, alkynyl group, substituted phenyl group, alkoxy group and substituted amino group,
Z is selected from carboxylic acid esters and carboxyl groups, hydroxamic acids and their salts. )
The compound of said 1 or 2 shown by these.
4). Formula III:
(Wherein R ³ is selected from an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an acyl group, an alkylamino group, and an arylamino group;
R ⁵ is a group selected from hydrogen, a halogenated alkyl group, preferably trifluoromethyl. )
The compound in any one of said 1-3 shown by these.
5. Formula IV:
Wherein R ³ is selected from hydrogen, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, acyl groups, alkylamino groups, and arylamino groups;
R ⁶ is a group selected from hydrogen, a halogenated alkyl group, an alkenyl group, an alkynyl group and an alkoxy group. )
The compound in any one of said 1-3 shown by these.
6). Formula V:
(Wherein R ² is selected from a linear alkyl chain, a branched alkyl chain, and an alkoxy group having a branched alkyl group, and the position thereof is located at the meta position or para position with respect to R ³ ;
R ³ is selected from hydrogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, acyl group, alkylamino group, and arylamino group;
R ⁴ O is an alkoxy group having linear alkyl or branched alkyl, and the position thereof is located at a meta position or a para position different from R ² with respect to R ³ ;
The ring constructed by NYX is a 5-membered ring, 6-membered ring or 7-membered ring,
When the ring constructed by NYX is a 5-membered ring, XY is selected from N = CR ⁵ and C = CR ⁵ and R ⁵ is selected from hydrogen, a halogenated alkyl group, an alkenyl group, an alkynyl group and an alkoxy group. Selected
Z is selected from carboxylic acid esters and carboxyl groups, hydroxamic acids and salts thereof, and is located in the meta position or para position with respect to X. )
The compound shown by.
7). The chemical | medical agent containing the compound of any one of said 1-6 as an active ingredient.
8). 8. The drug according to 7 above, wherein the active ingredient is a transcriptional regulator and a nuclear receptor ligand action regulator.
9. 8. The drug according to 7 above, wherein the drug is an anti-inflammatory agent, an antiallergic agent, an anticancer agent, an antimetabolic syndrome therapeutic agent, and an antidiabetic agent.
10. 10. The drug according to 7 or 9, further comprising an anti-inflammatory agent as an active ingredient.
11. 10. The drug according to 7 or 9, further comprising an antiallergic agent as an active ingredient.
12 10. The drug according to 7 or 9, further comprising an anti-metabolic syndrome agent as an active ingredient.
13. 10. The drug according to 7 or 9 further comprising an antidiabetic agent as an active ingredient.
14 10. The drug according to 7 or 9, further comprising an anticancer drug as an active ingredient.
15. 15. A pharmaceutical composition comprising the drug according to any one of 7 to 14 above and a pharmacologically and pharmaceutically acceptable carrier.

According to the present invention, as an RXR partial (partial) agonist exhibiting excellent RXR activation ability even at a low concentration without causing hepatic hypertrophy and blood triglyceride elevation that have been a problem with existing RXR agonists (full agonists) Useful compounds are obtained.
The compounds according to the present invention are useful for the development of therapeutic agents for diseases for which RXR agonists are effective, particularly for the development of therapeutic agents for intractable autoimmune diseases such as Crohn's disease.

It is a figure which shows the existing RXR agonist. It is a figure which shows the synthetic scheme of the compound of the intermediate body 1-4. FIG. 2 is a diagram showing a synthesis scheme of compounds of intermediates 5 and 6. It is a figure which shows the synthetic scheme of the target compound (Example 1, 7) -12)). It is a figure which shows the synthetic scheme of the target compound (Example 1, 13), 14)). It is a figure which shows the result of the RXR activation test of the target compound. In the figure, 1 indicates compound 12b and 2 indicates compound 15. It is a figure which shows the result of a TPA dermatitis experiment (Experimental example 2). It is a figure which shows the result of TNBS enteritis experiment (Experimental example 3).

  Specifically, among the compounds shown in the following examples, the compounds shown in compounds 12a, 12b and 15 are mentioned, and the compound shown in 12b is preferable.

  In the present invention, the compound represented by any one of the general formulas I to V may be a pharmaceutically acceptable salt. In addition, in the compound of any one of the general formulas I to V or a salt thereof, when there are isomers (for example, optical isomers, geometric isomers and compatible isomers), the present invention includes those isomers. And also solvates, hydrates and crystals of various shapes.

In the present invention, the pharmaceutically acceptable salt includes general pharmacologically and pharmaceutically acceptable salts. Specific examples of such salts are as follows.
Examples of basic addition salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; trimethylamine salts and triethylamine salts; dicyclohexylamine salts and ethanolamines. Aliphatic amine salts such as salts, diethanolamine salts, triethanolamine salts and brocaine salts; Aralkylamine salts such as N, N-dibenzylethylenediamine; and heterocyclic aromatics such as pyridine salts, picoline salts, quinoline salts and isoquinoline salts For example, tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt Quaternary ammonium salts such as tetrabutylammonium salts; arginine; basic amino acid salts such as lysine salt and the like.

  Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, perchlorate; for example, acetate, propionate, lactate, maleate , Organic acid salts such as fumarate, tartrate, malate, citrate and ascorbate; sulfonic acids such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate Salts; for example, acidic amino acids such as aspartate and glutamate.

The terms used herein have the following meanings alone or in combination with other terms.
“Alkyl” means a linear or branched alkyl group having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc. Can be mentioned. Preferred is alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo Examples include pentyl, tert-pentyl, n-hexyl, and isohexyl. A lower alkyl having 1 to 6 carbon atoms is particularly preferred.

  “Alkenyl” means linear or branched alkenyl having 2 to 20 carbon atoms, preferably 2 to 8 carbon atoms, having one or more double bonds to the above “alkyl”. Examples include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl and the like.

  “Aryl” refers to monocyclic aromatic hydrocarbon groups (phenyl) and polycyclic aromatic hydrocarbon groups (eg 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl). , 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl and the like. Preferable is phenyl or naphthyl (1-naphthyl, 2-naphthyl).

  “Alkynyl” means alkynyl having 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms, having one or more triple bonds in the above alkyl. For example, ethynyl, 1-propynyl, 2-propynyl, 1 -Butynyl, 2-butynyl, 3-butynyl and the like.

“Alkoxy” means a linear or branched (chain) alkoxy group having 1 to 20 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, sec -Butoxy group, tert-butoxy group, pentyloxy group, hexyloxy group, octadecanoxy group, allyloxy group and the like. C ₁ -C ₆ linear or branched lower alkoxy is preferred.

“Acyl” means alkanoyl, aroyl and the like. Examples of the alkanoyl include alkanoyl having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (formyl, acetyl, trifluoroacetyl, propionyl, butyryl, etc.). Examples of aroyl include aroyl having 7 to 15 carbon atoms, and specific examples include benzoyl and naphthoyl.
The “halogenated alkyl” means a group in which one or more hydrogen atoms of the alkyl group are substituted with a halogen atom selected from fluorine, bromine, chlorine and iodine.

  In the present invention, the compound represented by any one of the general formulas I to V has partial agonism for RXR. Since RXR is a nuclear receptor involved in DNA transcription, the compound of the present invention can also be referred to as a transcriptional regulatory compound. In the present specification, the term “modulating action” or an analog thereof should be interpreted in the broadest sense including the enhancement of action. Whether the compound of the present invention has a potentiating action can be easily assayed according to the method specifically shown in the experimental examples of the present specification.

  In the present invention, among the compounds represented by any one of the general formulas I to V, the RXR agonistic substance has a synergist action that remarkably enhances the physiological action of retinoid, such as cell differentiation action and cell inhibition action. Therefore, it can be used as an action enhancer when treating with a pharmaceutical composition containing a retinoid including a retinoic acid or a compound having a retinoic acid-like biological activity (for example, Am80).

  Representative examples of the physiological activity of retinoids include cell differentiation action, cell suppression action, life support action and the like. Retinoids are thought to be useful for the treatment and prevention of vitamin A deficiency, keratosis of epithelial tissues, rheumatism, delayed allergy, bone disease, and leukemia and certain types of cancer. Further, even when no retinoid is administered, the compound of the present invention enhances the action of retinoic acid already present in the living body, and therefore the compound of the present invention itself can be administered.

  The above-mentioned compound is a substance that binds to a nuclear receptor / superfamily receptor present in the nucleus of a cell and expresses biological activity, for example, an active vitamin A metabolite (All-trans Retinoic Acid: ATRA). ) -Containing retinoid compounds, eicosanoids, vitamin D compounds such as vitamin D3, or thyroxine and orphan receptor ligands with unknown ligands can be enhanced or suppressed.

  Therefore, RXR agonistic compounds can be used to regulate the action expression of these physiologically active substances, and abnormalities in biological action involving one or more of the nuclear receptors belonging to the nuclear receptors / superfamily. It can be used for prevention and / or treatment of accompanying diseases.

  Also included within the scope of the present invention are reagents such as reagents and medicaments containing the compound of the present invention as an active ingredient. When used as a pharmaceutical, for example, it can be used as an antiallergic agent, anti-inflammatory agent, antimetabolic syndrome agent, antidiabetic agent and / or anticancer agent.

  When used as a pharmaceutical comprising the compound of the present invention as an active ingredient, the dosage is not particularly limited. For example, when the action of a retinoid is regulated by using a compound containing a retinoid such as retinoic acid as an active ingredient and the compound of the present invention in combination, or without using a medicine containing a retinoid, retinoic acid already present in the living body Appropriate doses can be easily selected for all administration methods, such as when administering the drug of the present invention for the purpose of regulating the action of the drug. For example, in the case of oral administration, the active ingredient can be used in the range of about 0.01 to 1000 mg per adult day. When a drug containing a retinoid as an active ingredient is used in combination with the drug of the present invention, the drug of the present invention can be administered either during the retinoid administration period and / or before or after that period. is there.

  When the agent of the present invention is used as an antiallergic agent, the compound of the present invention is used as an active ingredient, and a known antiallergic agent may be included as an active ingredient. Antiallergic agents include mediator release inhibitors, histamine H1-antagonists, thromboxane inhibitors, leukotriene antagonists, Th2 cytokine inhibitors, etc., specifically, mediator release inhibitors such as sodium cromoglycate Tranilast, histamine H1-antagonist, ketotifen fumarate, azelastine hydrochloride, thromboxane inhibitor, ozagrel hydrochloride (thromboxane A2 synthase inhibitor), seratrodast (thromboxane A2 antagonist), pranluca as leukotriene antagonist And sulatast tosilate as Th2 cytokine inhibitors.

  When the agent of the present invention is used as an anti-metabolic syndrome agent or a therapeutic agent for diabetes, the compound of the present invention described above may be used as an active ingredient, and a known anti-metabolic syndrome agent or therapeutic agent for diabetes may be included as an active ingredient. Antimetabolic syndrome drugs include PPAR activators such as statin anti-hyperlipidemic plasma drugs and fibrate anti-hyperlipidemic plasma drugs, and antidiabetic drugs include sulfonylurea (SU) drugs, phenylalanine derivative drugs, biguanide drugs , Thiazolidinedione derivatives, α-glucosidase inhibitors, DPP-IV inhibitors, insulin preparations and the like.

  When using the chemical | medical agent of this invention as an anticancer agent, besides using the compound of the said this invention as an active ingredient, you may contain a well-known anticancer agent as an active ingredient. Examples of anticancer agents include estrogen antagonistic anti-breast cancer agents and taxane anticancer agents, and specific examples include tamoxifen or taxol.

  When the agent of the present invention is used as an anti-inflammatory agent, in addition to the compound of the present invention as an active ingredient, a known anti-inflammatory agent may be included as an active ingredient. The anti-inflammatory agent may be steroidal or non-steroidal. Non-steroidal anti-inflammatory agents include aminoarylcarboxylic acid derivatives, arylacetic acid derivatives, arylbutyric acid derivatives, arylcarboxylic acids, arylpropionic acid derivatives, pyrazoles, pyrazolones, salicylic acid derivatives, thiazinecarboxamides, And other types of structures may be selected.

  As the drug of the present invention, one or more substances selected from the compounds represented by the above general formula I may be administered as they are, but preferably contain one or more of the above substances. It is preferable to administer as an oral or parenteral pharmaceutical composition. Oral or parenteral pharmaceutical compositions can be prepared using pharmaceutical additives available to those skilled in the art, that is, pharmacologically and pharmaceutically acceptable carriers. For example, one or more of the above substances can be blended in a medicine containing a retinoid such as retinoic acid as an active ingredient, and used as a pharmaceutical composition in the form of a so-called mixture.

  Examples of the pharmaceutical composition suitable for oral administration include tablets, capsules, powders, fine granules, granules, liquids, and syrups. The pharmaceutical composition suitable for parenteral administration includes For example, injections, drops, suppositories, inhalants, eye drops, nasal drops, ointments, creams, patches and the like can be mentioned. Examples of pharmacologically and pharmaceutically acceptable carriers used in the production of the above pharmaceutical composition include, for example, excipients, disintegrating agents or disintegrating aids, binders, lubricants, coating agents, dyes, Diluents, bases, solubilizers or solubilizers, isotonic agents, pH adjusters, stabilizers, propellants, adhesives, and the like can be mentioned.

  In the examples of the present specification, a method for producing a preferred compound represented by the formula I of the present invention will be specifically described. Any of the compounds included in the scope of the present invention can be produced by appropriately modifying or altering the starting materials and reagents used in these production methods and reaction conditions. The manufacturing method of the compound of this invention is not limited to what was specifically demonstrated by the Example.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the scope of the following examples.

[Example 1] Synthesis of target compound A scheme of a production method until intermediate 5 in this example was obtained is shown in FIG.

1) Synthesis of intermediate 2,5-dichloro-2,5-dimethylhexane (2)

  2,5-Dimethyl-2,5-hexanediol (26 g, 175 mmol) was dissolved in concentrated hydrochloric acid (350 mL) and then vigorously stirred at room temperature for 15 minutes. The resulting precipitate was collected by filtration and then redissolved in dichloromethane (300 mL. The organic layer was washed with water (200 mL × 2) and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, white crystals Intermediate 2 (29 g, 90%) was obtained.

2) Synthesis of intermediate 1,1,4,4,6-Pentamethyl-1,2,3,4-tetrahydro-naphthalene (3)

  Intermediate 2 (18 g, 100 mmol) was dissolved in anhydrous toluene (15 mL), aluminum chloride (1.3 g, 10 mmol) was added, and the mixture was stirred for 3 hours at room temperature. After confirming the completion of the reaction with a TLC plate (n-hexane), the reaction mixture was poured into water (60 mL) and extracted with ethyl acetate (50 mL × 2). The organic layer was washed with water (70 mL × 2) and saturated brine (50 mL), and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, a colorless oil intermediate (18 g, 88%) was obtained by distillation under reduced pressure (133 ° C., 20 mmHg).

¹ H NMR (300 MHz, CDCl ₃ ) δ: 7.20 (d, 1H, J = 8.0 Hz), 7.11 (d, 1H, J = 2.0 Hz), 6.95 (dd, 1H, J = 8.0, 2.0 Hz), 2.30 (s, 3H), 1.67 (s, 4H), 1.27 (s, 6H), 1.26 (s, 6H).

3) Synthesis of intermediate 1,1,4,4,6-Pentamethyl-7-nitro-1,2,3,4-tetrahydro-naphthalene (4)

  Intermediate 3 (4.1 g, 20 mmol) was dissolved in acetic anhydride (20 mL) and added dropwise to concentrated nitric acid (22 mL) while maintaining at −15 ° C. After confirming the completion of the reaction with a TLC plate (n-hexane), the mixture was poured into ice water (100 mL), 2N aqueous sodium hydroxide solution (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic layer was washed with water (100 mL × 2) and saturated brine (100 mL), and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization was performed with ethyl acetate / n-hexane to obtain an intermediate (2.3 g, 46%) of pale yellow plate crystals.

¹ H NMR (300 MHz, CDCl ₃ ) δ: 7.96 (s, 1H), 7.21 (s, 1H), 2.56 (s, 3H), 1.70 (s, 4H), 1.30 (s, 6H), 1.29 (s , 6H).

4) Synthesis of intermediate 3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (5)

  Intermediate 4 (500 mg, 2.0 mmol) was dissolved in ethyl acetate (6.0 mL), 10% palladium activated carbon (catalytic amount) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hr. After confirming the completion of the reaction with a TLC plate (n-hexane), celite filtration was performed. The solvent was distilled off under reduced pressure to obtain an intermediate (410 mg, 95%) of white crystals.

¹ H NMR (500 MHz, CDCl3) δ: 7.04 (s, 1H), 6.96 (s, 1H), 2.29 (s, 3H), 1.65 (s, 4H), 1.25 (s, 6H), 1.24 (s, 6H).

  The scheme of the production method until obtaining the intermediate 8 in this example is shown in FIG.

5) Synthesis of intermediate 4-Iodo-benzoic acid methyl ester (7)

  4-Iodobenzoic acid (6) (5.0 g, 20 mmol) was dissolved in anhydrous methanol, thionyl chloride (2.6 mL, 30 mmol) was added under ice cooling, and the mixture was heated to reflux for 1 hour. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 2), the solvent was distilled off under reduced pressure. The residue was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic layer was washed with water (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, an intermediate (4.8 g, 91%) of colorless crystals was obtained.

¹ H NMR (500 MHz, CDCl3) δ: 7.80 (d, 2H, J = 8.0 Hz), 7.74 (d, 2H, J = 8.0 Hz), 3.91 (s, 3H).

6) Synthesis of intermediate 4-Iodo-3-nitro-benzoic acid methyl ester (8)

  Intermediate 6 (1.3 g, 5.0 mmol) was dissolved in concentrated sulfuric acid (5.0 mL), and a mixed solution of concentrated sulfuric acid (9.0 mL) and concentrated nitric acid (6.0 mL) was added dropwise under ice cooling. After completion of dropping, the temperature was returned to room temperature and stirred for 5 hours. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 5), the reaction mixture was poured into ice water (100 mL) and extracted with ethyl acetate (60 mL × 2). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL × 2) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization from dichloromethane / n-hexane gave an intermediate (1.2 g, 76%) of yellow needle crystals.

¹ H NMR (500 MHz, CDCl3) δ: 8.45 (d, 1H, J = 2.0 Hz), 8.15 (d, 1H, J = 8.0 Hz), 7.88 (dd, 1H, J = 8.0, 2.0 Hz), 3.97 (s, 3H).

  The scheme of the production method until obtaining the target compound 12 in this example is shown in FIG.

7) Synthesis of intermediate 3-Nitro-4- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -benzoic acid methyl ester (9)

  After dissolving Intermediate 5 (650 mg, 3.0 mmol) and Intermediate 8 (920 mg, 3.0 mmol) in anhydrous toluene (30 mL), (±) -2,2′-bis (diphenylphosphino) -1,1 '-Binaphthyl (140 mg, 0.23 mmol), cesium carbonate (1400 mg, 4.2 mmol) and tris (dibenzylideneacetone) dipalladium (0) (140 mg, 0.15 mmol) were added, and the mixture was heated to reflux for 16 hours. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 5), Celite filtration was performed. After evaporation of the solvent under reduced pressure, flash column chromatography (ethyl acetate: n-hexane = 1: 10) was performed to obtain a red solid intermediate (1100 mg, 94%).

¹ H NMR (300 MHz, CDCl3) δ: 9.63 (br s, 1H), 8.93 (d, 1H, J = 2.0 Hz), 7.93 (dd, 1H, J = 9.0, 2.0 Hz), 7.24 (s, 1H ), 7.17 (s, 1H), 6.82 (d, 1H, J = 9.0 Hz), 3.91 (s, 3H), 2.19 (s, 3H), 1.70 (s, 4H), 1.31 (s, 6H), 1.25 (s, 6H).

8) Synthesis of intermediate 3-Amino-4- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -benzoic acid methyl ester (10)

  Intermediate 9 (1100 mg, 2.8 mmol) was dissolved in ethyl acetate (20 mL), 10% palladium activated carbon (catalytic amount) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hr. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 5), Celite filtration was performed. The solvent was distilled off under reduced pressure to obtain an intermediate (1000 mg, 97%) of white crystals.

¹ H NMR (300 MHz, CDCl3) δ: 7.49 (s, 1H), 7.48 (d, 1H, J = 8.0 Hz), 7.13 (s, 1H), 6.86 (s, 1H), 6.83 (d, 1H, J = 8.0 Hz), 5.39 (br s, 1H), 3.87 (s, 3H), 3.55 (br s, 2H), 2.19 (s, 3H), 1.67 (s, 4H), 1.28 (s, 6H), 1.21 (s, 6H).

9) Intermediate 1- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -1H-benzoimidazole-5-carboxylic acid methyl ester (11a) Composition
Intermediate 10 (146.6 mg, 0.4 mmol) was dissolved in formic acid (1.0 mL) and stirred at 100 ° C. for 4 hours. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 1), the mixture was poured into a 2N aqueous sodium hydroxide solution (10 mL) and extracted with ethyl acetate (40 mL × 3). The organic layer was washed with saturated brine (10 mL) and then dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, flash column chromatography (ethyl acetate: n-hexane = 1: 4) was performed to obtain a colorless powdery intermediate (140.4 mg, 93%).

¹ H NMR (300 MHz, CDCl ₃ ) d: 8.61 (d, 1H, J = 2.0 Hz), 8.06 (s, 1H), 8.03 (dd, 1H, J = 9.0, 2.0 Hz), 7.33 (s, 1H ), 7.22 (s, 1H), 7.21 (d, 1H, J = 9.0 Hz), 3.98 (s, 3H), 2.05 (s, 3H), 1.75 (s, 1H), 1.36 (s, 6H), 1.29 (s, 6H).

10) Intermediate 1- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2-trifluoromethyl-1H-benzoimidazole-5-carboxylic acid methyl ester Synthesis of (11b)

Intermediate 10 (520 mg, 1.4 mmol) was dissolved in trifluoroacetic acid (8.0 mL), trifluoroacetic anhydride (1.0 mL, 7.0 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 5), the reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution (30 mL) and extracted with ethyl acetate (50 mL × 3). The organic layer was washed with water (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, flash column chromatography (ethyl acetate: n-hexane = 1: 20) was performed to obtain a white granular intermediate (590 mg, 95%).

¹ H NMR (300 MHz, CDCl ₃ ) δ: 8.68 (d, 1H, J = 1.5 Hz), 8.10 (dd, 1H, J = 9.0, 1.5 Hz), 7.28 (d, 1H, J = 8.5 Hz), 7.20 (s, 1H), 7.12 (dd, 1H, J = 9.0, 0.5 Hz), 3.97 (s, 3H), 1.89 (s, 3H), 1.73 (s, 4H), 1.35 (s, 6H), 1.25 (s, 6H).

11) Synthesis of target compound 1- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -1H-benzoimidazole-5-carboxylic acid (12a)

Intermediate 11a (143.6 mg, 0.40 mmol) was dissolved in methanol (3.0 mL) and tetrahydrofuran (1.0 mL), 2N aqueous sodium hydroxide solution (2.0 mL) was added, and the mixture was stirred at 60 ° C. for 1.5 hours. Stir with heating. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 1), the mixture was neutralized with 2N hydrochloric acid (2.0 mL), poured into water (20 mL), and ethyl acetate (40 mL × 3). Extracted with. The organic layer was washed with saturated brine (20 mL) and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, recrystallization was performed with ethyl acetate / n-hexane to obtain the target compound (108.9 mg, 76%).

¹ H NMR (300 MHz, CDCl ₃ ) d: 8.76 (d, 1H, J = 2.0 Hz), 8.17 (s, 1H), 8.11 (dd, 1H, J = 8.0, 2.0 Hz), 7.33 (s, 1H ), 7.27 (d, 1H, J = 8.0 Hz), 7.26 (s, 1H), 7.23 (s, 1H), 2.06 (s, 3H), 1.74 (s, 1H), 1.36 (s, 6H), 1.29 (s, 6H); FAB- MS m / z:.. 363 [M + H] +; Anal Calcd for C 23 H 26 N 2 O 2 1 / 4EtOAc: C, 74.97; H, 7.34; N, 7.29. Found: C, 75.06; H, 7.74; N, 7.74.

12) Target compound 1- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2-trifluoromethyl-1H-benzoimidazole-5-carboxylic acid (12b )

Intermediate 11b (50 mg, 0.11 mmol) was dissolved in methanol (1.0 mL) and tetrahydrofuran (2.0 mL), 2N aqueous sodium hydroxide solution (1.0 mL) was added, and the mixture was heated with stirring at 60 ° C. for 1 hr. After confirming the completion of the reaction on a TLC plate (ethyl acetate: n-hexane = 2: 1), the reaction mixture was poured into 2N hydrochloric acid (2.0 mL) and extracted with ethyl acetate (40 mL × 3). The organic layer was washed with saturated brine (10 mL) and water (10 mL), and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, flash column chromatography (dichloromethane: methanol = 50: 1) and recrystallization from ethyl acetate / n-hexane gave the target compound (21 mg, 43%).

¹ H NMR (300 MHz, CDCl ₃ ) δ: 8.75 (d, 1H, J = 1.5 Hz), 8.15 (dd, 1H, J = 8.5, 1.5 Hz), 7.30 (s, 1H), 7.21 (s, 1H ), 7.15 (d, 1H, J = 9.5 Hz), 1.91 (s, 3H), 1.74 (s, 4H), 1.36 (s, 6H), 1.25 (s, 6H); FAB-MS m / e: 431 [M + H] +; Anal. Calcd for C ₂₄ H ₂₅ F ₃ N ₂ O ₂ : C, 66.96; H, 5.85; N, 6.51. Found: C, 6.93; H, 6.11; N, 6.41.

  The scheme of the production method until obtaining the target compound 12 in this example is shown in FIG.

13) Intermediate 1- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -1H-indole-5-carboxylic acid methyl ester (14) Composition

  Intermediate 13 (1.0 g, 3.6 mmol), methyl indole-5-carboxylate (520 mg, 3.0 mmol), tripotassium phosphate (1.3 g, 6.3 mmol), copper (I) iodide (28 mg) 0.15 mmol), N, N′-dimethylethylenediamine (0.065 mL), potassium iodide (600 mg, 3.6 mmol) were dissolved in anhydrous toluene (4.0 mL), and the mixture was irradiated at 160 ° C. under microwave irradiation at 2.degree. The mixture was heated and stirred for 5 hours. After confirming the progress of the reaction on a TLC plate (ethyl acetate: n-hexane = 1: 10), the reaction was returned to room temperature, filtered through Celite, and flash column chromatography (ethyl acetate: n-hexane = 1: 40) was performed. An intermediate (89 mg, 7.9%) of colorless crystals was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ: 8.47 (d, 1H, J = 1.5 Hz), 7.88 (dd, 1H, J = 9.0, 1.5 Hz), 7.29-7.23 (m, 3H), 7.10 (d , 1H, J = 9.0 Hz), 6.75 (d, 1H, J = 3.0 Hz), 3.94 (s, 3H), 2.00 (s, 3H), 1.73 (s, 4H), 1.35 (s, 6H), 1.27 (s, 6H).

14) Synthesis of the target 1- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -1H-indole-5-carboxylic acid (15)

  Intermediate 14 (66 mg, 0.18 mmol) was dissolved in methanol (2.0 mL) and tetrahydrofuran (1.0 mL), 2N aqueous sodium hydroxide solution (2.0 mL) was added, and the mixture was stirred with heating at 60 ° C. for 80 min. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 10: 1), the mixture was poured into 2N hydrochloric acid (2.0 mL) and water (20 mL), and extracted with ethyl acetate (40 mL × 3). The organic layer was washed with saturated brine (20 mL) and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product (58 mg, 92%) as a colorless powder.

¹ H NMR (300 MHz, CDCl ₃ ) δ: 8.58 (d, 1H, J = 1.0 Hz), 7.96 (d, 1H, J = 8.5, 1.5 Hz), 7.31-7.25 (m, 3H), 7.14 (d , 1H, J = 8.5 Hz), 6.80 (d, 1H, J = 3.0 Hz), 2.02 (s, 3H), 1.75 (s, 4H), 1.47 (s, 6H), 1.27 (s, 6H); FAB -MS m / e: 362 [M + H] +.

[Experiment 1] RXR activity evaluation

1) Measurement principle Since many nuclear receptors are transcription factors involved in transcriptional regulation, a reporter gene assay is performed as a means for measuring transcription activity. An RXR receptor protein expression plasmid and a reporter plasmid are introduced into cells such as COS-1 cells and HeLa cells to overexpress a fusion protein. When the RXR agonist (ligand) binds to the receptor, transcription occurs in a ligand-dependent manner, a downstream fusion protein is generated, and downstream luciferase production begins. RXR agonist activity was measured by measuring the luciferase activity.

2) Host cell culture Dulbecco's modified Eagle MEM medium (DMEM) was used as a cell growth medium. First, 4.75 g of DMEM powder was dissolved in 500 mL of ultrapure water (produced with Milli-Q ^(R) ), sterilized by high-pressure heat (121 ° C, 20 minutes), then returned to room temperature. Add activated fetal bovine serum (FBS) to 10% (v / v), add 10 mL of high pressure heat-sterilized 10% NaHCO3, and then add 0.292 g of L-glutamine to 8 mL of ultrapure water. The dissolved one was prepared by adding after filtration sterilization.

For the passage of each cell, remove the culture supernatant of cells cultured in a 100 mm culture dish, collect the cells by trypsin treatment, centrifuge at 4 ° C, 1000 rpm for 3 minutes, and then add the growth medium to disperse the cells. Then, 15 mL of a growth medium in which cells were dispersed in a 100 mm culture dish was added, and cultured in the presence of 37 ° C. and 5% CO ₂ .
Transformation was performed using Effectene ^™ Transection Reagent (QIAGEN). LGD1069 was used as a positive control for RXR, TIPP-703 was used as a positive control for PPAR, and carba-T0901317 was used as a positive control for LXR. These were counted in the plates to be assayed as DMSO-dissolved stock solutions.

3) Measurement of transcriptional activity (Day 1) COS-1 cells were seeded in a 60 mm culture dish with 5 mL of growth medium together with 50 × 10 ⁴ cells and cultured overnight.
(Day 2) Transformation was performed by a lipofection method using Effectene ^™ Transection Reagent (QIAGEN).
(Day 3) After 16 to 18 hours, the culture supernatant is removed, and the cells are collected by trypsin treatment. After centrifugation at 4 ° C. and 1000 rpm for 3 minutes, the growth medium is added to disperse the cells, and 2.0 × 10 6 It seed | inoculated to 96 well white plate so that it might become ⁴ cells / well. Thereafter, each compound was added so that the DMSO concentration was 1% or less.
(Day 4) After 24 hours, 25 μL of the supernatant was used for SEAP measurement, and the remaining cell solution was used for luciferase activity measurement.

SEAP measurement was performed according to the method described in Methods in molecular biology, 63, pp. 49-60, 1997 / BD Great EscAPe SEAP User manual (BD bioscience).
Specifically, it measured by the following method. 25 μL of dilution buffer was added to 25 μL of the supernatant on day 4, and incubated at 65 ° C. for 30 minutes. After returning to room temperature, assay buffer (7 μL), 10 × MUP (0.3 μL), and dilution buffer (2.7 μL) were added, and incubated at room temperature in the dark for 60 minutes. Thereafter, the fluorescence intensity was measured with an excitation wavelength of 360 nm and a fluorescence wavelength of 465 nm using a microplate reader (Infinite ^™ (infinite) 200, manufactured by TECAN).

The assay buffer was prepared by the following method. L-homoarginine (0.45 g) and magnesium chloride (0.02 g) were dissolved in 50 mL of ultrapure water (produced with Milli-Q ^(R) ), and diethanolamine (21 mL) was added. Then, after adjusting the pH to 9.8 with hydrochloric acid, the volume was adjusted to 100 mL with ultrapure water and stored at 4 ° C.

The dilution buffer was prepared by the following method. Sodium chloride (4.38 g) and Tris Base (2.42 g) were dissolved in 90 mL of ultrapure water (produced with Milli-Q ^(R)) . Thereafter, the pH was adjusted to 7.2 with hydrochloric acid to prepare a 5-fold dilution buffer, which was stored at 4 ° C. Dilution buffer was prepared by diluting it 5-fold immediately before use.

4-Methylumbelliferyl phosphate was dissolved in ultrapure water (produced with Milli-Q ^(R) ) to a concentration of 25 mM and stored at -20 ° C. to make 10 · MUP.

Luciferase activity using the 96-well white plate manufactured by NUNC, luminescent substrate ^{(Steady-Glo (R) Luciferase} Assay System, Promega Corp.) emission intensity of the reaction product a microplate reader with (Infinite ^TM (infinite) 200, manufactured by TECAN).

  The measurement results were obtained by reacting 1 μM of positive control (LGD1069 described in Non-patent document 15 for RXR, TIPP-703 described in Non-patent document 16 for PPAR, and carba-T0901317 described in Non-patent document 17 for LXR). The transcriptional activity was 1 and the relative activity was examined.

Non-Patent Document 15: Cancer Res. 1996, 56, 5566.
Non-Patent Document 16: Bioorg. Med. Chem. Lett., 2008, 18, 4525.
Non-Patent Document 17: Heterocycles, 2008, 76, 137.

4) Measurement results The above measurement results are shown in Table 1 and FIG.

Table 1 shows the transcriptional activation ability for each RXR subtype of compounds 1 and 2.

CBt-PMN is a compound described in Patent Document 3.

[Experiment 2] Evaluation of drug efficacy in TPA-induced mouse dermatitis 1) Model creation method
1. Seven-week-old male ICR mice were purchased, and 5 mice per group were used per compound.
2. A 0.03% acetone solution of Phorbol 12-myristate 13-acetate (TPA) was prepared.
The left ear of the mouse was used as the inflammation-inducing group, and the right ear was used as the unsensitized part.
3. For the test compound, a 5 mM solution was prepared in acetone.
4. Before TPA treatment, thickness gauge (Dial thickness gauge 0.01mm type)
-PEACOCK Co., Ltd. Ozaki Manufacturing Co., Ltd .: G-1A) was used to measure the thickness of both ears.
5. After measuring the thickness of both ears, 10 µL of TPA or acetone was applied to each ear.
6. After 1 hour of treatment in step 4, add an acetone solution of the test compound prepared in step 3 to each ear.
10 μL per side was applied.
7. 5 and 6 were repeated for 4 days.
8. The day after the work in 7, measure the thickness of both ears using a thickness gauge, euthanize with ether, then cut the ears and sample with 6 mm trepan (Azuwan). The mass of this was measured. The cut ears were stored for PCR measurement and tissue section preparation.

2) Evaluation method
1. Efficacy was evaluated by measuring the thickness of ear thickening and the mass of ear sampled after 4 days of treatment.

3) Measurement results The measurement results are shown in FIG.

[Experimental Example 3] Evaluation of drug efficacy in 2,4,6-trinitrobenzenesulfonic acid (TNBS) -induced mouse enteritis 1) Method for creating a model Non-patent document 18 was used as a reference.
1. Purchase 7-week-old (18-20 g body weight) female BALB / c mice, one per group
Five animals were used.
2. A 5% TNBS aqueous solution (Sigma) was diluted 5-fold with acetone to prepare a TNBS solution for pretreatment.
3. Using a clipper under diethyl ether anesthesia, place the mouse back 1.5 x 1.5 cm ²
She shave. After shaving, group by weight and use the 200 µL pipetman at the shaved place to prepare 150 µL of the pretreatment TNBS solution prepared in 2 per animal.
It was applied. For the normal group, an acetone-water solution was applied.
4. Five days after TNBS presensitization, the animals were again divided into groups according to body weight (5 animals per group).
5. The body weight was measured daily for 7 days from this day, and then a CMC solution of the compound was orally administered using a stomach tube. The compound was administered at 30 mg / kg per animal.
The compound to be administered was prepared by dissolving in ethanol at a final concentration of 1% and suspending in 0.5% carboxymethylcellulose (CMC) solution. Compound preparation
The test was performed at a volume of 10 mL / kg.
6. On the second day from the start of oral administration, a TNBS solution for intestinal injection was prepared. This is 5% TNBS aqueous solution
(Sigma) was diluted with purified water and ethanol to make a 2% TNBS solution. At this time, ethanol was adjusted to 50% of the total amount.
7. On the third day after the start of oral administration, 100 µL of the TNBS solution prepared in 6 was applied to the TNBS presensitized group under isoflurane anesthesia using a catheter. In the TNBS presensitization untreated group, 50% ethanol was injected into the intestine.
8. Four days after rectal administration of TNBS, after weighing, mice were euthanized with diethyl ether and dissected. The fasting of the previous day was not performed. Remove the large intestine,
After the measurement of the large intestine, a part was stored for PCR measurement and preparation of tissue sections.

Non-Patent Document 18: Nature Protocol 2007, 2, 541.

2) Evaluation method The drug efficacy was evaluated based on the suppression of the body weight phenomenon from the start of TNBS intestinal injection and the length of the large intestine sampled by dissection.

3) Measurement results The measurement results are shown in FIG.

  All animal experiments were conducted after examination by the Okayama University Animal Experiment Committee.

  As described above in detail, among the compounds of the present invention, the compound having RXR partial agonist activity has a lower transcriptional activation ability than the activity of NEt-TMN, which is an existing RXR complete agonist. This can be said to indicate RXR partial agonist activity, and since RXR activity is not extremely activated, appropriate application of RXR can be expected. In addition, some of the compounds of the present invention showed a remarkable anti-inflammatory effect in TPA-induced dermatitis and TNBS-induced enteritis. Moreover, since the compound of this invention can anticipate the effect | action as an active ingredient of an anticancer agent, an anti-inflammatory agent, and an antiallergy, it can be utilized as such a pharmaceutical. It can also be used as a biochemical test reagent.

Claims (15)

Formula I:
(Wherein, R ^1, R ² are each linear alkyl chain, an alkoxy group having a branch alkyl chain, and branched alkyl groups, and independently of each other or closed, its position is in R ³ In contrast, it is located in the meta or para position,
R ³ is selected from hydrogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, acyl group, alkylamino group, and arylamino group;
The ring constructed by NYX is a 5-membered ring, 6-membered ring or 7-membered ring,
When the ring constructed by NYX is a 5-membered ring, XY is selected from N = CR ⁵ and C = CR ⁶ ;
R ⁵ is selected from hydrogen and halogenated alkyl groups;
R ⁶ is selected from hydrogen, alkyl group, halogenated alkyl group, alkenyl group, alkynyl group, substituted phenyl group, alkoxy group and substituted amino group,
Z is selected from carboxylic acid esters and carboxyl groups, hydroxamic acids and their salts. )
The compound shown by. The compound according to claim ^1, wherein R ¹ and R ² are closed to form a 6-membered ring. Formula II:
(Wherein R ³ is selected from an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an acyl group, an alkylamino group, and an arylamino group;
The ring constructed by NYX is a 5-membered ring, 6-membered ring or 7-membered ring,
When the ring constructed by NYX is a 5-membered ring, XY is selected from N = CR ⁵ and C = CR ⁶ ;
R ⁵ is selected from hydrogen and halogenated alkyl groups;
R ⁶ is selected from hydrogen, alkyl group, halogenated alkyl group, alkenyl group, alkynyl group, substituted phenyl group, alkoxy group and substituted amino group,
Z is selected from carboxylic acid esters and carboxyl groups, hydroxamic acids and their salts. )
The compound of Claim 1 or 2 shown by these. Formula III:
(Wherein R ³ is selected from an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an acyl group, an alkylamino group, and an arylamino group;
R ⁵ is a group selected from hydrogen, a halogenated alkyl group, preferably trifluoromethyl. )
The compound in any one of Claims 1-3 shown by these. Formula IV:
Wherein R ³ is selected from hydrogen, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, acyl groups, alkylamino groups, and arylamino groups;
R ⁶ is a group selected from hydrogen, a halogenated alkyl group, an alkenyl group, an alkynyl group and an alkoxy group. )
The compound in any one of Claims 1-3 shown by these. Formula V:
(Wherein R ² is selected from a linear alkyl chain, a branched alkyl chain, and an alkoxy group having a branched alkyl group, and the position thereof is located at the meta position or para position with respect to R ³ ;
R ³ is selected from hydrogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, acyl group, alkylamino group, and arylamino group;
R ⁴ O is an alkoxy group having linear alkyl or branched alkyl, and the position thereof is located at a meta position or a para position different from R ² with respect to R ³ ;
The ring constructed by NYX is a 5-membered ring, 6-membered ring or 7-membered ring,
When the ring constructed by NYX is a 5-membered ring, XY is selected from N = CR ⁵ and C = CR ⁵ and R ⁵ is selected from hydrogen, a halogenated alkyl group, an alkenyl group, an alkynyl group and an alkoxy group. Selected
Z is selected from carboxylic acid esters and carboxyl groups, hydroxamic acids and salts thereof, and is located in the meta position or para position with respect to X. )
The compound shown by. The chemical | medical agent containing the compound of any one of Claims 1-6 as an active ingredient. The drug according to claim 7, wherein the active ingredient is a transcriptional regulator and a nuclear receptor ligand action regulator. The drug according to claim 7, wherein the drug is an anti-inflammatory agent, an antiallergic agent, an anticancer agent, an antimetabolic syndrome therapeutic agent, or an antidiabetic agent. The drug according to claim 7 or 9, further comprising an anti-inflammatory agent as an active ingredient. The drug according to claim 7 or 9, further comprising an antiallergic agent as an active ingredient. The drug according to claim 7 or 9, further comprising an anti-metabolic syndrome agent as an active ingredient. The drug according to claim 7 or 9, further comprising an antidiabetic agent as an active ingredient. The drug according to claim 7 or 9, further comprising an anticancer drug as an active ingredient. A pharmaceutical composition comprising the drug according to any one of claims 7 to 14 and a pharmacologically and pharmaceutically acceptable carrier.