JP5255994B2 - Nuclear receptor ligand - Google Patents

Description

  The present invention is a compound that acts as an agonist or antagonist on retinoid X receptor (RXR), which is a nuclear receptor (hereinafter referred to as “rexinoid compound”), and is a heterocyclic ring. The present invention relates to a novel compound which is a nuclear receptor ligand composed of a skeleton. 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 antagonists can also selectively suppress the function of RXR-containing heterodimers. For example, RXR antagonist HX531 can improve insulin resistance and obesity by suppressing the function of PPAR-RXR heterodimer. Therefore, the pharmaceutical application with respect to type II diabetes is anticipated (nonpatent literature 5).

  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 II diabetes model mouse, insulin resistance is improved and a decrease in blood glucose level is observed (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).

RXR agonists and antagonists, that is, rexinoid compounds, are known to have different genes expressed due to differences in molecular structure. As the known rexinoid compound, a compound as shown in FIG. 1 can be mentioned, but a heterocyclic compound type rexinoid closed at an aromatic carboxylic acid site has not been reported. Conventional rexinoid compounds have been applied to pharmaceutical use, but there are some that cause problems such as an increase in blood triglyceride as a side effect. Therefore, development of new rexinoids with different molecular structures is desired. Although a novel rexinoid compound having an alkoxy group has been reported (Patent Document 2), a new compound 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 US Patent No. 5,962,508 International Publication WO2008 / 105386 Pamphlet

  An object of the present invention is to provide a novel rexinoid compound having a structure different from that of a conventional rexinoid compound.

  As a result of intensive research in order to solve the above-mentioned problems, the present inventors have found a novel rexinoid compound that is a complex compound type ring-closed at an aromatic carboxylic acid site and has an appropriate rexinoid activity, and has completed the present invention. did.

（式中、R¹, R²は、各々直鎖アルキル鎖、分枝アルキル鎖、及び分枝アルキル基を有するアルコキシ基から選択され、互いに独立又は閉環しており、その位置は、R³に対し、メタ位若しくはパラ位に位置し、
R³は、水素、アルキル基、アルケニル基、アルキニル基、アルコキシ基、アシル基、アルキルアミノ基、及びアリールアミノ基から選択され、
環A及び環Bは、各々芳香環からなり、
環B及びN-Y-Xで構築される環は、5員環であり、
前記環B及びN-Y-Xで構築される環のうちX-Yは、N=N又はN=C-R⁵ であり、R⁵は、アルキル基、アルケニル基、アルキニル基、置換フェニル基、アルコキシ基及び置換アミノ基から選択され、
Zは、カルボン酸エステル、並びにカルボキシル基、ヒドロキサム酸及びそれらの塩から選択され、Xに対し、メタ位若しくはパラ位に位置する化合物。）
２．下記の一般式IIで表される化合物。
一般式II：

（式中、R³は、水素、アルキル基、アルケニル基、アルキニル基、アルコキシ基、アシル基、アルキルアミノ基、及びアリールアミノ基から選択され、
環B及びN-Y-Xで構築される環は、5員環であり、
前記環B及びN-Y-Xで構築される環のうちX-Yは、N=N又はN=C-R⁵ であり、R⁵は、アルキル基、アルケニル基、アルキニル基、置換フェニル基、アルコキシ基及び置換アミノ基から選択され、
Zは、カルボン酸エステル、並びにカルボキシル基、ヒドロキサム酸及びそれらの塩から選択され、Xに対し、メタ位若しくはパラ位に位置する化合物。）
３．下記の一般式IIIで表される化合物。
一般式III：

（式中、R²は、直鎖アルキル鎖、分枝アルキル鎖、及び分枝アルキル基を有するアルコキシ基から選択され、その位置は、R³に対し、メタ位又はパラ位に位置し、
R³は、水素、アルキル基、アルケニル基、アルキニル基、アルコキシ基、アシル基、アルキルアミノ基、及びアリールアミノ基から選択され、
R⁴Oは、直鎖アルキル又は分枝アルキルを有するアルコキシ基であり、その位置は、R³に対し、R²とは異なるメタ位又はパラ位に位置し、
環B及びN-Y-Xで構築される環は、5員環であり、
前記環B及びN-Y-Xで構築される環のうちX-Yは、N=N又はN=C-R⁵ であり、R⁵は、アルキル基、アルケニル基、アルキニル基、置換フェニル基、アルコキシ基及び置換アミノ基から選択され、
Zは、カルボン酸エステル、並びにカルボキシル基、ヒドロキサム酸及びそれらの塩から選択され、Xに対し、メタ位若しくはパラ位に位置する化合物。）
４．下記の一般式IVで表される、前項２に記載の化合物。
一般式IV：

（式中、R³は、水素、アルキル基、アルケニル基、アルキニル基、アルコキシ基、アシル基、アルキルアミノ基、及びアリールアミノ基から選択され、
R⁵は、アルキル基、アルケニル基、アルキニル基、置換フェニル基、アルコキシ基及び置換アミノ基から選択される化合物。）
５．下記の一般式Vで表される前項４に記載の化合物。
一般式V：

（式中、R³は、水素、アルキル基、アルケニル基、アルキニル基、アルコキシ基、アシル基、アルキルアミノ基、及びアリールアミノ基から選択される化合物。）
６．前項１〜５のいずれか１に記載の化合物を有効成分として含有するRXR受容体タンパク質の転写調節剤。 That is, this invention consists of the following.
1. A compound represented by the following general formula I:
Formula I:

(In the formula, R ¹ and R ² are each selected from a linear alkyl chain, a branched alkyl chain, and an alkoxy group having a branched alkyl group, and are independently or ring-closed with each other, and the position is 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;
Ring A and Ring B are each composed of an aromatic ring,
The ring constructed from ring B and NYX is a 5-membered ring ,
Of the rings constructed of the ring B and NYX, XY is N = N or N = CR ⁵ , and R ⁵ is an alkyl group, an alkenyl group, an alkynyl group, a substituted phenyl group, an alkoxy group, and a substituted amino group. Selected
Z is a carboxylic acid ester and a compound selected from a carboxyl group, hydroxamic acid and salts thereof, and located at the meta position or para position with respect to X. )
2. A compound represented by the following general formula II.
Formula II:

Wherein R ³ is selected from hydrogen, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, acyl groups, alkylamino groups, and arylamino groups;
The ring constructed from ring B and NYX is a 5-membered ring ,
Of the rings constructed of the ring B and NYX, XY is N = N or N = CR ⁵ , and R ⁵ is an alkyl group, an alkenyl group, an alkynyl group, a substituted phenyl group, an alkoxy group, and a substituted amino group. Selected
Z is a carboxylic acid ester and a compound selected from a carboxyl group, hydroxamic acid and salts thereof, and located at the meta position or para position with respect to X. )
3. A compound represented by the following general formula III.
Formula III:

(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 from ring B and NYX is a 5-membered ring ,
Of the rings constructed of the ring B and NYX, XY is N = N or N = CR ⁵ , and R ⁵ is an alkyl group, an alkenyl group, an alkynyl group, a substituted phenyl group, an alkoxy group, and a substituted amino group. Selected
Z is a carboxylic acid ester and a compound selected from a carboxyl group, hydroxamic acid and salts thereof, and located at the meta position or para position with respect to X. )
4). 3. The compound according to item 2 represented by the following general formula IV:
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 ⁵ is a compound selected from an alkyl group, an alkenyl group, an alkynyl group, a substituted phenyl group, an alkoxy group, and a substituted amino group. )
5. 5. The compound according to item 4 represented by general formula V below.
Formula V:

(In the formula, R ³ is a compound selected from hydrogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an acyl group, an alkylamino group, and an arylamino group. )
6). A transcriptional regulator for RXR receptor protein comprising the compound according to any one of items 1 to 5 as an active ingredient.

  Some of the novel rexinoid compounds of the present invention have RXR agonistic properties and some have RXR antagonistic properties. Among the compounds of the present invention, the compound having RXR agonistic activity has a low transcription activation efficiency compared to the activity of LGD1069, which is an existing RXR 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, RXR antagonisticity was observed in other parts of the compounds of the present invention.

（式中、R¹, R²は、各々直鎖アルキル鎖、分枝アルキル鎖、及び分枝アルキル基を有するアルコキシ基から選択され、互いに独立又は閉環しており、その位置は、R³に対し、メタ位若しくはパラ位に位置し、
R³は、水素、アルキル基、アルケニル基、アルキニル基、アルコキシ基、アシル基、アルキルアミノ基、及びアリールアミノ基から選択され、
環A及び環Bは、各々芳香環からなり、
環B及びN-Y-Xで構築される環は、5員環であり、
前記環B及びN-Y-Xで構築される環のうちX-Yは、N=N又はN=C-R⁵ であり、R⁵は、アルキル基、アルケニル基、アルキニル基、置換フェニル基、アルコキシ基及び置換アミノ基から選択され、
Zは、カルボン酸エステル、並びにカルボキシル基、ヒドロキサム酸及びそれらの塩から選択され、Xに対し、メタ位若しくはパラ位に位置する化合物。） The compound of the present invention is represented by the following general formula I.
Formula I:

(In the formula, R ¹ and R ² are each selected from a linear alkyl chain, a branched alkyl chain, and an alkoxy group having a branched alkyl group, and are independently or ring-closed with each other, and the position is 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;
Ring A and Ring B are each composed of an aromatic ring,
The ring constructed from ring B and NYX is a 5-membered ring ,
Of the rings constructed of the ring B and NYX, XY is N = N or N = CR ⁵ , and R ⁵ is an alkyl group, an alkenyl group, an alkynyl group, a substituted phenyl group, an alkoxy group, and a substituted amino group. Selected
Z is a carboxylic acid ester and a compound selected from a carboxyl group, hydroxamic acid and salts thereof, and located at the meta position or para position with respect to X. )

（式中、R³は、水素、アルキル基、アルケニル基、アルキニル基、アルコキシ基、アシル基、アルキルアミノ基、及びアリールアミノ基から選択され、
環B及びN-Y-Xで構築される環は、5員環であり、
前記環B及びN-Y-Xで構築される環のうちX-Yは、N=N又はN=C-R⁵ であり、R⁵は、アルキル基、アルケニル基、アルキニル基、置換フェニル基、アルコキシ基及び置換アミノ基から選択され、
Zは、カルボン酸エステル、並びにカルボキシル基、ヒドロキサム酸及びそれらの塩から選択され、Xに対し、メタ位若しくはパラ位に位置する化合物。） Moreover, the compound of this invention can also be represented by the following general formula II.
Formula II:

Wherein R ³ is selected from hydrogen, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, acyl groups, alkylamino groups, and arylamino groups;
The ring constructed from ring B and NYX is a 5-membered ring ,
Of the rings constructed of the ring B and NYX, XY is N = N or N = CR ⁵ , and R ⁵ is an alkyl group, an alkenyl group, an alkynyl group, a substituted phenyl group, an alkoxy group, and a substituted amino group. Selected
Z is a carboxylic acid ester and a compound selected from a carboxyl group, hydroxamic acid and salts thereof, and located at the meta position or para position with respect to X. )

（式中、R²は、直鎖アルキル鎖、分枝アルキル鎖、及び分枝アルキル基を有するアルコキシ基から選択され、その位置は、R³に対し、メタ位又はパラ位に位置し、
R³は、水素、アルキル基、アルケニル基、アルキニル基、アルコキシ基、アシル基、アルキルアミノ基、及びアリールアミノ基から選択され、
R⁴Oは、直鎖アルキル又は分枝アルキルを有するアルコキシ基であり、その位置は、R³に対し、R²とは異なるメタ位又はパラ位に位置し、
環B及びN-Y-Xで構築される環は、5員環であり、
前記環B及びN-Y-Xで構築される環のうちX-Yは、N=N又はN=C-R⁵ であり、R⁵は、アルキル基、アルケニル基、アルキニル基、置換フェニル基、アルコキシ基及び置換アミノ基から選択され、
Zは、カルボン酸エステル、並びにカルボキシル基、ヒドロキサム酸及びそれらの塩から選択され、Xに対し、メタ位若しくはパラ位に位置する化合物。） Furthermore, the compound of this invention can also be represented by the following general formula III.
Formula III:

(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 from ring B and NYX is a 5-membered ring ,
Of the rings constructed of the ring B and NYX, XY is N = N or N = CR ⁵ , and R ⁵ is an alkyl group, an alkenyl group, an alkynyl group, a substituted phenyl group, an alkoxy group, and a substituted amino group. Selected
Z is a carboxylic acid ester and a compound selected from a carboxyl group, hydroxamic acid and salts thereof, and located at the meta position or para position with respect to X. )

（式中、R³は、水素、アルキル基、アルケニル基、アルキニル基、アルコキシ基、アシル基、アルキルアミノ基、及びアリールアミノ基から選択され、
R⁵は、アルキル基、アルケニル基、アルキニル基、置換フェニル基、アルコキシ基及び置換アミノ基から選択される化合物。 The compound of the present invention is specifically a compound represented by the following general formula IV.
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 ⁵ is a compound selected from an alkyl group, an alkenyl group, an alkynyl group, a substituted phenyl group, an alkoxy group, and a substituted amino group.

（式中、R³は、水素、アルキル基、アルケニル基、アルキニル基、アルコキシ基、アシル基、アルキルアミノ基、及びアリールアミノ基から選択される化合物。 More specifically, the compound of the present invention is represented by the following general formula V.
Formula V:

Wherein R ³ is a compound selected from hydrogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an acyl group, an alkylamino group, and an arylamino group.

  Specifically, among the compounds shown in the following examples, compounds 20a, 20b, 20c, 20d, 21, 22, 23a, 23b, 23c, 23d, 23e, 25a, 25b, 25c, 27a, 27b, 27c, Examples thereof include compounds represented by 29a, 29b, and 29c. Among the compounds of the present invention, RXR agonists include compounds represented by compounds 20a, 20b, 29a and 29b, and preferably compounds represented by 20b and 29b. RXR antagonists include compounds shown in 23a, 23b and 23c.

  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.

  In the present invention, the compound represented by any one of the general formulas I to V has an agonistic or antagonistic action on 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 or suppression of action. Whether the compound of the present invention has an enhancing action or an inhibiting 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.

  Among the compounds of the present invention, a compound having an RXR antagonistic action can be used as a retinoid action inhibitor. Therefore, that is, substances that bind to receptors in the nuclear nucleus / superfamily existing in the cell nucleus and express physiological activity, for example, retinoid compounds containing ATRA, eicosanoids, vitamin D compounds such as vitamin D3 Alternatively, the action of thyroxine or an orphan receptor ligand whose ligand is unknown can be suppressed.

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

  In the present invention, the compound represented by the general formula VI has an action as a histone deacetylase (HDAC) inhibitor in addition to an RXR agonistic action. Therefore, in addition to RXR agonistic action, cell differentiation and apoptosis action based on HDAC inhibition can be expected.

  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, it can be used, for example, as an antiallergic agent, anticancer agent and / or antiinflammatory 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 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 aminoaryl carboxylic acid derivatives, aryl acetic acid derivatives, aryl butyric acid derivatives, aryl carboxylic acids, aryl propionic acid derivatives, pyrazoles, pyrazolones, salicylic acid derivatives, thiazine carboxamides, 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.

[Examples] Synthesis of target compounds (Examples 1 to 11)
FIG. 2 shows a scheme of the production method until intermediates 5a, 5b and 5c in this example are obtained.

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 An intermediate (29 g, 90%) was obtained.

2) Synthesis of intermediate 1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-naphthalene (3a)

  Intermediate 2 (5.7 g, 30 mmol) was dissolved in anhydrous benzene (130 mL), aluminum chloride (0.4 g, 3.1 mmol) was added, and the mixture was heated to reflux for 24 hours. The mixture was poured into 100 mL of ice water and extracted with n-hexane (100 mL × 2). The organic layer was washed with water (100 mL × 2) and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, a colorless oil intermediate (4.3 g, 74%) was obtained by distillation under reduced pressure (127 ° C., 30 mmHg).

¹ H NMR (300 MHz, CDCl3) δ: 7.33-7.11 (m, 4H), 1.69 (s, 4H), 1.28 (s, 12H).

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

  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 at room temperature for 3 hr. 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, CDCl3) 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).

4) Synthesis of intermediate 5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (3c)

  Intermediate 2 was dissolved in anhydrous dichloromethane (20 mL), phenol (3.7 g, 40 mmol) and aluminum chloride (2.7 g, 20 mmol) were added, and the mixture was stirred for 2 hours at room temperature. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 5), the reaction mixture was poured into water (100 mL) and extracted with dichloromethane (50 mL × 2). The organic layer was washed with water (100 mL × 2) and then with anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, recrystallization (ethyl acetate / n-hexane) was performed to obtain an intermediate body (6.8 g, 75%) of colorless needle crystals.

¹ H NMR (300 MHz, CDCl3) δ: 7.16 (d, 1H, J = 8.5 Hz), 6.75 (d, 1H, J = 2.5 Hz), 6.61 (dd, 1H, J = 8.5, 2.5 Hz), 1.66 (s, 4H), 1.26 (s, 6H), 1.24 (s, 6H).

5) Synthesis of intermediate 1,1,4,4-Tetramethyl-6-nitro-1,2,3,4-tetrahydro-naphthalene (4a)

  Concentrated nitric acid (12 mL) and concentrated sulfuric acid (18 mL) were mixed, and while maintaining at −10 ° C., intermediate 3a (11 g, 59 mmol) was added dropwise and stirred for 40 minutes. After confirming the completion of the reaction with a TLC plate (n-hexane), the reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution (100 mL) and extracted with ethyl acetate (50 mL × 4). The organic layer was washed with water (100 mL × 2) and saturated brine (100 mL), and then dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, flash column chromatography (ethyl acetate: n-hexane = 1: 100) was performed to obtain an intermediate (11 g, 83%) of pale yellow crystals.

¹ H NMR (300 MHz, CDCl3) δ: 8.18 (d, 1H, J = 2.5 Hz), 7.95 (dd, 1H, J = 8.5, 2.5 Hz), 7.44 (d, 1H, J = 8.5 Hz), 1.73 (s, 4H), 1.33 (s, 6H), 1.31 (s, 6H).

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

  Intermediate 3b (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, CDCl3) 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).

7) Synthesis of intermediate 5,5,8,8-Tetramethyl-3-nitro-5,6,7,8-tetrahydro-naphthalen-2-ol (4c)

  Intermediate 3c (6.1 g, 30 mmol) was dissolved in acetic anhydride (90 mL), and a mixture of fuming nitric acid (1.3 mL, 30 mmol), acetic anhydride (5.0 mL), and acetic acid (5.0 mL) was added dropwise. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 5), it was poured into water (100 mL), and the precipitated crystals were collected by filtration. The crystals collected by filtration were redissolved in dichloromethane (150 mL), washed with a saturated aqueous sodium hydrogen carbonate solution (100 mL × 2), and then dried over anhydrous magnesium sulfate. After distilling off the solvent, recrystallization was performed with dichloromethane / n-hexane to obtain a yellow crystal intermediate (2.8 g, 37%).

¹ H NMR (300 MHz, CDCl3) δ: 10.27 (s, 1H), 8.02 (s, 1H), 7.05 (s, 1H), 1.69 (s, 4H), 1.29 (s, 12H).

8) Synthesis of intermediate 6-Methoxy-1,1,4,4-tetramethyl-7-nitro-1,2,3,4-tetrahydro-naphthalene (4d)

  Intermediate 4c (250 mg, 1.0 mmol) was dissolved in anhydrous N, N-dimethylformamide (5.0 mL), then iodomethane (93 μL, 1.5 mmol) and potassium carbonate (207 mg, 1.5 mmol) were added, and an argon atmosphere was added. Stir for 3 hours at room temperature. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 5), the reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (20 mL × 2). The organic layer was washed with water (30 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, flash column chromatography (ethyl acetate: n-hexane = 1: 8) was performed to obtain an intermediate (247 mg, 94%) of pale yellow crystals.

¹ H NMR (300 MHz, CDCl3) δ: 7.82 (s, 1H), 6.94 (s, 1H), 3.93 (s, 3H), 1.71 (s, 4H), 1.31 (s, 6H), 1.28 (s, 6H).

9) Synthesis of intermediate 5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (5a)

  Intermediate 4a (4.7 g, 20 mmol) was dissolved in ethyl acetate (20 mL), 10% palladium-activated carbon (catalytic amount) was added, and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 10), Celite filtration was performed. The solvent was distilled off under reduced pressure to obtain a white crystalline intermediate (4.1 g, qy).

¹ H NMR (300 MHz, CDCl3) δ: 7.11 (d, 1H, J = 8.5 Hz), 6.66 (d, 1H, J = 2.5 Hz), 6.54 (dd, 1H, J = 8.5, 2.5 Hz), 3.81 (br s, 2H), 1.65 (s, 4H), 1.25 (s, 6H), 1.23 (s, 6H).

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

  Intermediate 4b (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).

11) Synthesis of intermediate 3-Methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (5c)

  Intermediate 4d (240 mg, 0.90 mmol) was dissolved in ethyl acetate (5.0 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: 3), Celite filtration was performed. The solvent was distilled off under reduced pressure to obtain an intermediate (230 mg, qy.) Of colorless crystals.

¹ H NMR (500 MHz, CDCl3) δ: 6.68 (s, 1H), 6.65 (s, 1H), 3.83 (s, 3H), 1.64 (s, 4H), 1.25 (s, 6H), 1.22 (s, 6H).

The scheme of the production method until obtaining the intermediate 9 in this example is shown in FIG.
12) Synthesis of intermediate 4-Iodo-benzoic acid methyl ester (6)

  4-Iodobenzoic acid (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 hr. 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).

13) Synthesis of intermediate 4-Iodo-3-nitro-benzoic acid methyl ester (7)

  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).

14) Synthesis of intermediate 4-Amino-3-bromo-benzoic acid ethyl ester (8)

  Ethyl 4-aminobenzoate (1.7 g, 10 mmol) was dissolved in chloroform (15 mL), and N-bromosuccinimide (1.8 g, 10 mmol) was added dropwise under ice cooling. After completion of dropping, the mixture was stirred at 5 to 10 ° C. for 4 hours at room temperature. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 3), the precipitate was filtered. The filtrate was washed with water (40 mL) and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, an intermediate (2.5 g, qy) of colorless crystals was obtained.

¹ H NMR (500 MHz, CDCl3) δ: 8.11 (d, 1H, J = 2.0 Hz), 7.79 (dd, 1H, J = 8.0, 2.0 Hz), 6.73 (d, 1H, J = 8.0 Hz), 4.49 (br s, 2H), 4.32 (q, 2H, J = 7.0 Hz), 1.37 (t, 3H, J = 7.0 Hz).

15) Synthesis of intermediate 3-Bromo-4-nitro-benzoic acid ethyl ester (9)

  Hydrogen peroxide (5 mL, 50 mmol) was added to trifluoroacetic acid (40 mL), intermediate 8 (2.2 g, 9 mmol) was added, and the mixture was stirred with heating at 60 ° C. for 1 hr. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 3), the solvent was distilled off under reduced pressure. The residue was poured into 2N aqueous sodium hydroxide solution (100 mL) and extracted with ethyl acetate (70 mL × 2). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (70 mL), and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, an intermediate (2.2 g, 89%) of red crystals was obtained.

¹ H NMR (500 MHz, CDCl3) δ: 8.39 (d, 1H, J = 2.0 Hz), 8.10 (dd, 1H, J = 8.0, 2.0 Hz), 7.84 (d, 1H, J = 8.0 Hz), 4.43 (q, 2H, J = 7.0 Hz), 1.43 (t, 3H, J = 7.0 Hz).

A scheme of the production method until obtaining the intermediate 11 in this example is shown in FIG.
16) Synthesis of intermediate 3-Nitro-4- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -benzoic acid methyl ester (10a)

  Intermediate 5a (810 mg, 4.0 mmol) and Intermediate 7 (1200 mg, 4.0 mmol) were dissolved in anhydrous toluene (25 mL), and (±) -2,2′-bis (diphenylphosphino) -1,1 '-Binaphthyl (190 mg, 0.30 mmol), cesium carbonate (1800 mg, 5.6 mmol) and tris (dibenzylideneacetone) dipalladium (0) (180 mg, 0.20 mmol) were added, and the mixture was heated to reflux for 20 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: 6) was performed to obtain a yellow needle crystal intermediate (1200 mg, 75%).

¹ H NMR (500 MHz, CDCl3) δ: 9.77 (br s, 1H), 8.91 (d, 1H, J = 2.0 Hz), 7.94 (dd, 1H, J = 9.0, 2.0 Hz), 7.37 (d, 1H , J = 8.0 Hz), 7.18 (d, 1H, J = 2.0 Hz), 7.16 (d, 1H, J = 9.0 Hz), 7.04 (dd, 1H, J = 8.0, 2.0 Hz), 3.91 (s, 3H ), 1.72 (s, 4H), 1.31 (s, 6H), 1.28 (s, 6H).

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

  Intermediate 5b (650 mg, 3.0 mmol) and Intermediate 7 (920 mg, 3.0 mmol) were dissolved in anhydrous toluene (30 mL), and (±) -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).

18) Intermediate of 4- (3-Methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -3-nitro-benzoic acid methyl ester (10c) Composition

  Intermediate 5c (220 mg, 1.0 mmol) and Intermediate 7 (290 mg, 1.0 mmol) were dissolved in anhydrous toluene (10 mL), and (±) -2,2′-bis (diphenylphosphino) -1,1 '-Binaphthyl (45 mg, 0.072 mmol), cesium carbonate (440 mg, 1.3 mmol) and tris (dibenzylideneacetone) dipalladium (0) (44 mg, 0.048 mmol) were added, and the mixture was heated to reflux for 15 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 (350 mg, 87%).

¹ H NMR (500 MHz, CDCl3) δ: 9.66 (br s, 1H), 8.91 (d, 1H, J = 2.0 Hz), 7.95 (dd, 1H, J = 2.0 Hz), 7.23 (s, 1H), 7.10 (d, 1H, J = 9.0 Hz), 6.88 (s, 1H), 3.91 (s, 3H), 3.82 (s, 3H), 1.71 (s, 4H), 1.32 (s, 6H), 1.26 (s , 6H).

19) Synthesis of intermediate 4-Nitro-3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -benzoic acid ethyl ester (10d)

  Intermediate 5a (150 mg, 0.75 mmol) and Intermediate 9 (210 mg, 0.75 mmol) were dissolved in anhydrous toluene (10 mL), and (±) -2,2′-bis (diphenylphosphino) -1,1 '-Binaphthyl (35 mg, 0.056 mmol), cesium carbonate (340 mg, 1.1 mmol) and tris (dibenzylideneacetone) dipalladium (0) (34 mg, 0.038 mmol) were added, and the mixture was heated to reflux for 30 hours. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 3), 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 (233 mg, 77%).

¹ H NMR (500 MHz, CDCl3) δ: 9.50 (br s, 1H), 8.24 (d, 1H, J = 9.0 Hz), 8.00 (d, 1H, J = 2.0 Hz), 7.35 (d, 1H, J = 8.0 Hz), 7.32 (dd, 1H, J = 9.0, 2.0 Hz), 7.23 (d, 1H, J = 2.5 Hz), 7.02 (dd, 1H, J = 8.0, 2.5 Hz), 4.33 (q, 2H , J = 7.0 Hz), 1.72 (s, 4H), 1.34 (t, 3H, J = 7.0 Hz), 1.31 (s, 6H), 1.30 (s, 6H).

20) Synthesis of intermediate 3-Amino-4- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -benzoic acid methyl ester (11a)

  Intermediate 10a (770 mg, 2.0 mmol) was dissolved in ethyl acetate (10 mL), 10% palladium activated carbon (catalytic amount) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 24 hours. 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 a white crystalline intermediate (644 mg, 91%).

¹ H NMR (300 MHz, CDCl3) δ: 7.48 (m, 2H), 7.23 (d, 1H, J = 8.5 Hz), 7.14 (d, 1H, J = 9.0 Hz), 6.94 (s, 1H), 6.81 (d, 1H, J = 8.5 Hz), 5.52 (s, 1H), 3.87 (s, 3H), 3.57 (br s, 2H), 1.69 (s, 4H), 1.28 (s, 6H), 1.26 (s , 6H).

21) Synthesis of intermediate 3-Amino-4- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -benzoic acid methyl ester (11b)

  Intermediate 10b (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).

22) Intermediate of 3-Amino-4- (3-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -benzoic acid methyl ester (11c) Composition

  Intermediate 10c (340 mg, 0.83 mmol) was dissolved in ethyl acetate (5.0 mL), 10% palladium-activated carbon (catalytic amount) was added, and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 2), celite filtration was performed. The solvent was distilled off under reduced pressure to obtain an intermediate (290 mg, 90%) of colorless crystals.

¹ H NMR (300 MHz, CDCl3) δ: 7.60-7.46 (m, 2H), 7.20 (d, 1H, J = 8.0 Hz), 7.00 (s, 1H), 6.79 (s, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 1.67 (s, 4H), 1.29 (s, 6H), 1.20 (s, 6H).

23) Synthesis of intermediate 4-Amino-3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -benzoic acid ethyl ester (11d)

  Intermediate 10d (230 mg, 0.58 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 for 5 hours under a hydrogen atmosphere. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 3), Celite filtration was performed. The solvent was distilled off under reduced pressure to obtain a pale yellow crystal intermediate (210 mg, qy).

¹ H NMR (500 MHz, CDCl3) δ: 7.83 (d, 1H, J = 2.0 Hz), 7.72 (dd, 1H, J = 8.0, 2.0 Hz), 7.15 (d, 1H, J = 8.0 Hz), 6.76 (d, 1H, J = 8.0 Hz), 6.72 (d, 1H, J = 2.5 Hz), 6.52 (dd, 1H, J = 8.0, 2.5 Hz), 5.05 (br s, 1H), 4.29 (q, 2H , J = 7.0 Hz), 4.16 (br s, 2H), 1.66 (s, 4H), 1.33 (t, 3H, J = 7.0 Hz), 1.25 (s, 6H), 1.24 (s, 6H).

  FIG. 5 shows a scheme of the production method until obtaining the target compound (20a, 20b, 20c, 20d, 21, 22, 23a, 23b, 23c, 23d, 23e) in this example.

24) Synthesis of intermediate 3-Acetylamino-4- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -benzoic acid methyl ester (12a)

  Intermediate 11a (180 mg, 0.50 mmol) was dissolved in acetic acid (5.0 mL), acetic anhydride (0.5 mL) was added, and the mixture was stirred at room temperature for 30 min. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 3), the mixture was poured into 2N aqueous sodium hydroxide solution (50 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (40 mL × 2) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, recrystallization was performed with dichloromethane / n-hexane to obtain an intermediate (180 mg, 90%) of colorless needle crystals.

¹ H NMR (500 MHz, CDCl3) δ: 7.97 (s, 1H), 7.78 (d, 1H, J = 7.75 Hz), 7.23 (d, 1H, J = 8.5 Hz), 6.97 (s, 1H), 6.85 (d, 1H, J = 7.75 Hz), 6.41 (s, 1H), 3.88 (s, 3H), 2.22 (s, 3H), 1.68 (s, 4H), 1.27 (s, 6H), 1.25 (s, 6H).

25) Synthesis of intermediate 3-Acetylamino-4- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -benzoic acid methyl ester (12b)

  Intermediate 12a (150 mg, 0.40 mmol) was dissolved in acetic acid (5.0 mL), acetic anhydride (0.5 mL) was added, and the mixture was stirred at room temperature for 5 min. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 3), the reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution (70 mL) and extracted with ethyl acetate (50 mL × 2). The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution (70 mL) and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, an intermediate (173 mg, qy) of colorless crystals was obtained.

26) Intermediate 3-Acetylamino-4- (3-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -benzoic acid methyl ester (12c) Composition

  Intermediate 11c (130 mg, 0.35 mmol) was dissolved in anhydrous dichloromethane (4.0 mL), acetyl chloride (30 μL, 0.42 mmol), 4-dimethylaminopyridine (43 mg, 0.35 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. Stir. After confirming the completion of the reaction on a TLC plate (ethyl acetate: n-hexane = 1: 2), the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic layer was washed with water (20 mL) and saturated brine (20 mL), and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, flash column chromatography (ethyl acetate: n-hexane = 2: 1) was performed to obtain an intermediate (120 mg, 79%) of colorless crystals.

¹ H NMR (300 MHz, CDCl3) δ: 8.26 (s, 1H), 7.80 (d, 1H, J = 9.0 Hz), 7.27-7.23 (m, 1H), 6.93 (s, 1H), 6.81 (s, 1H), 6.33 (s, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 2.20 (s, 3H), 1.67 (s, 4H), 1.29 (s, 6H), 1.18 (s, 6H ).

27) Synthesis of intermediate 4-Acetylamino-3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -benzoic acid ethyl ester (12d)

  Intermediate 11d (210 mg, 0.57 mmol) was dissolved in acetic acid (5.0 mL), acetic anhydride (0.5 mL) was added, and the mixture was stirred for 5 min at room temperature. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 3), the mixture was poured into 2N aqueous sodium hydroxide solution (60 mL) and extracted with ethyl acetate (40 mL × 2). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL × 2) and saturated brine (40 mL), and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, an intermediate of yellow crystals (180 mg, 76%) was obtained.

¹ H NMR (500 MHz, CDCl3) δ: 8.18 (d, 1H, J = 8.0 Hz), 7.93 (s, 1H), 7.82 (d, 1H, J = 8.5 Hz), 7.81 (s, 1H), 7.17 (d, 1H, J = 8.0 Hz), 6.72 (br s, 1H), 6.54 (d, 1H, J = 8.5 Hz), 5.33 (br s, 1H), 4.33 (q, 2H, J = 7.0 Hz) , 2.13 (s, 3H), 1.67 (s, 4H), 1.35 (t, 3H, J = 7.0 Hz), 1.25 (s, 6H), 1.22 (s, 6H).

28) Synthesis of intermediate 3-Butyrylamino-4- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -benzoic acid methyl ester (13)

  4-Dimethylaminopyridine (49 mg, 0.40 mmol) was dissolved in anhydrous dichloromethane (5.0 mL), butyric acid chloride (42 μL, 0.40 mmol) and intermediate 11b (150 mg, 0.40 mmol) were added in this order, and 40 minutes. Stir at room temperature. After confirming the completion of the reaction on a TLC plate (ethyl acetate: n-hexane = 1: 5), the reaction mixture was poured into a 2N aqueous sodium hydroxide solution (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with water (30 mL) and saturated brine (30 mL), and 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 solid intermediate (170 mg, qy).

¹ H NMR (300 MHz, DMSO-d6) δ: 7.90 (s, 1H), 7.77 (d, 1H, J = 7.0 Hz), 7.14 (s, 1H), 7.03 (s, 1H), 6.97 (d, 1H, J = 9.0 Hz), 3.87 (s, 3H), 2.39 (t, 2H, J = 7.5 Hz), 2.20 (s, 3H), 1.83-1.70 (m, 2H), 1.67 (s, 4H), 1.28 (s, 6H), 1.21 (s, 6H), 1.03 (t, 3H, J = 7.5 Hz).

29) Synthesis of intermediate 3-Hexanoylamino-4- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -benzoic acid methyl ester (14)

  After 4-dimethylaminopyridine (49 mg, 0.40 mmol) was dissolved in anhydrous dichloromethane (5.0 mL), hexanoic acid chloride (56 μL, 0.40 mmol) and intermediate 11b (150 mg, 0.40 mmol) were added in this order. Stir for minutes at room temperature. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 3), the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic layer was washed with water (20 mL) and saturated brine (20 mL), and 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 solid intermediate (180 mg, 98%).

¹ H NMR (300 MHz, CDCl3) δ: 7.91 (d, 1H, J = 1.75 Hz), 7.77 (dd, 1H, J = 8.5, 1.75 Hz), 7.24 (br s, 1H), 7.14 (s, 1H ), 7.03 (s, 1H), 6.97 (d, 1H, J = 8.5 Hz), 6.44 (br s, 1H), 3.87 (s, 3H), 2.40 (t, 2H, J = 7.5 Hz), 2.20 ( s, 3H), 1.73 (t, 2H, J = 7.5 Hz), 1.67 (s, 4H), 1.40-1.35 (m, 4H), 1.28 (s, 6H), 1.21 (s, 6H), 0.91 (t , 3H, J = 7.0 Hz).

30) Synthesis of intermediate 3-Benzoylamino-4- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -benzoic acid methyl ester (15a)

  4-Dimethylaminopyridine (37 mg, 0.30 mmol) was dissolved in anhydrous dichloromethane (10 mL), benzoic acid chloride (46 μL, 0.40 mmol) was added, and the mixture was stirred for 5 minutes at room temperature. Then intermediate 11b (110 mg, 0.30 mmol) was added and stirred for 40 minutes at room temperature. After confirming the completion of the reaction on a TLC plate (ethyl acetate: n-hexane = 1: 3), the reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with water (40 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, an orange oil residue (240 mg) was obtained. The residue was used for the next reaction without purification.

31) Intermediate 3- (4-Methyl-benzoylamino) -4- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -benzoic acid methyl ester Synthesis of (15b)

  4-Dimethylaminopyridine (37 mg, 0.30 mmol) was dissolved in anhydrous dichloromethane (10 mL), p-toluic acid chloride (53 μL, 0.40 mmol) was added, and the mixture was stirred for 5 minutes at room temperature. Then intermediate 11b (110 mg, 0.30 mmol) was added and stirred for 40 minutes at room temperature. After confirming the completion of the reaction on a TLC plate (ethyl acetate: n-hexane = 1: 3), the reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with water (40 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, a pale yellow oil residue (180 mg) was obtained. The residue was used for the next reaction without purification.

32) Intermediate 3- (4-Nitro-benzoylamino) -4- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -benzoic acid methyl ester Synthesis of (15c)

  4-Dimethylaminopyridine (37 mg, 0.30 mmol) was dissolved in anhydrous dichloromethane (10 mL), p-nitrobenzoic acid chloride (74 mg, 0.40 mmol) was added, and the mixture was stirred for 5 minutes at room temperature. Then intermediate 11b (110 mg, 0.30 mmol) was added and stirred for 40 minutes at room temperature. After confirming the completion of the reaction on a TLC plate (ethyl acetate: n-hexane = 1: 3), the reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with water (40 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, a residue (210 mg) was obtained. The residue was used for the next reaction without purification.

33) Intermediate 3- (3-Nitro-benzoylamino) -4- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -benzoic acid methyl ester Synthesis of (15d)

  After dissolving 4-dimethylaminopyridine (49 mg, 0.40 mmol) in anhydrous dichloromethane (5.0 mL), m-nitrobenzoic acid chloride (110 mg, 0.60 mmol), intermediate 11b (150 mg, 0.40 mmol) in this order. In addition, the mixture was stirred at room temperature for 20 minutes. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 3), the mixture was poured into 2N aqueous sodium hydroxide solution (50 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with water (30 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, flash column chromatography (ethyl acetate: n-hexane = 1: 6) was performed to obtain an intermediate (210 mg, qy) of yellow crystals.

¹ H NMR (500 MHz, CDCl3) δ: 8.57 (s, 1H), 8.39 (d, 1H, J = 7.0 Hz), 8.31 (s, 1H), 8.04 (d, 1H, J = 7.0 Hz), 7.97 (br s, 1H), 7.85 (dd, 1H, J = 8.5, 2.0 Hz), 7.65 (t, 1H, J = 8.0 Hz), 7.16 (s, 1H), 7.03 (d, 1H, J = 8.5 Hz ), 6.91 (s, 1H), 6.07 (br s, 1H), 3.90 (s, 3H), 2.26 (s, 3H), 1.62 (s, 4H), 1.25 (s, 6H), 1.14 (s, 6H ).

34) Synthesis of intermediate 4- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -3-phenylacetylamino-benzoic acid methyl ester (15e)

  After 4-dimethylaminopyridine (49 mg, 0.40 mmol) was dissolved in anhydrous dichloromethane (10 mL), phenylacetyl chloride (66 μL, 0.50 mmol) and intermediate 11b (150 mg, 0.40 mmol) were added in this order, and the mixture was added for 30 minutes at room temperature. And stirred. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 4), the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with water (30 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, flash column chromatography (ethyl acetate: n-hexane = 1: 4) was performed to obtain colorless crystals (160 mg, 81%).

¹ H NMR (300 MHz, CDCl3) δ: 7.92 (d, 1H, J = 1.75 Hz), 7.74 (dd, 1H, J = 8.5, 1.75 Hz), 7.40-7.23 (m, 6H), 7.13 (s, 1H), 7.06 (s, 1H), 6.94 (d, 1H, J = 8.5 Hz), 6.89 (s, 1H), 3.86 (s, 3H), 3.76 (s, 2H), 2.12 (s, 3H), 1.67 (s, 4H), 1.29 (s, 6H), 1.19 (s, 6H).

35) Intermediate 2-Methyl-1- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -1H-benzimidazole-5-carboxylic acid methyl ester (16a )

  Intermediate 12a (160 mg, 0.40 mmol) was dissolved in anhydrous 1,4-dioxane (5.0 mL), then p-toluenesulfonic acid monohydrate (76 mg, 0.40 mmol), anhydrous pyridine (32 μL, 0.40 mmol) ) And heated to reflux for 5 hours. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 3), the reaction mixture was poured into water (80 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with water (40 mL × 2) and saturated brine (30 mL), and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, recrystallization was performed with dichloromethane / n-hexane to obtain an intermediate (110 mg, 72%) of colorless needle crystals.

¹ H NMR (500 MHz, CDCl3) δ: 8.44 (s, 1H), 7.93 (d, 1H, J = 8.0 Hz), 7.48 (d, 1H, J = 8.0 Hz), 7.26 (s, 1H), 7.17 (d, 1H, J = 8.0 Hz), 7.10 (d, 1H, J = 8.0 Hz), 3.95 (s, 3H), 2.54 (s, 3H), 1.76 (s, 4H), 1.36 (s, 6H) , 1.31 (s, 6H).

36) Intermediate 2-Methyl-1- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -1H-benzimidazole-5-carboxylic acid methyl ester Synthesis of (16b)

  Intermediate 12b (170 mg, 0.40 mmol) was dissolved in anhydrous 1,4-dioxane (5.0 mL), paratoluenesulfonic acid monohydrate (190 mg, 1.0 mmol) was added, and the mixture was heated to reflux for 19 hours. After confirming the completion of the reaction on a TLC plate (ethyl acetate: n-hexane = 1: 2), the reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with water (50 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, a brown solid intermediate (150 mg, 98%) was obtained.

¹ H NMR (300 MHz, CDCl3) δ: 8.46 (d, 1H, J = 1.5 Hz), 7.92 (dd, 1H, J = 8.5, 1.5 Hz), 7.30 (s, 1H), 7.12 (s, 1H) , 6.98 (d, 1H, J = 8.5 Hz), 3.95 (s, 3H), 2.42 (s, 3H), 1.90 (s, 3H), 1.74 (s, 4H), 1.36 (s, 6H), 1.26 ( s, 6H).

37) Intermediate 1- (3-Methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2-methyl-1H-benzimidazole-5-carboxylic acid Synthesis of methyl ester (16c)

  Intermediate 12c (110 mg, 0.27 mmol) was dissolved in acetic acid (5.0 mL) and then heated to reflux for 18 hours. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 2: 1), the solvent was distilled off under reduced pressure, and flash column chromatography (ethyl acetate: n-hexane = 1: 1) was performed to obtain a colorless solid. Intermediate (100 mg, 92%) was obtained.

¹ H NMR (300 MHz, CDCl3) δ: 8.43 (d, 1H, J = 1.5, 0.75 Hz), 7.90 (dd, 1H, J = 8.5, 1.5 Hz), 7.18 (dd, 1H, J = 8.5, 0.75 Hz), 6.97 (s, 1H), 3.94 (s, 3H), 3.72 (s, 3H), 2.46 (s, 3H), 1.77-1.71 (m, 4H), 1.38 (s, 3H), 1.37 (s , 3H), 1.28 (s, 3H), 1.25 (s, 3H).

38) Intermediate 2-Methyl-3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -3H-benzimidazole-5-carboxylic acid ethyl ester (16d )

  Intermediate 12d (180 mg, 0.43 mmol) was dissolved in anhydrous 1,4-dioxane (6.0 mL), paratoluenesulfonic acid monohydrate (190 mg, 1.0 mmol) was added, and the mixture was heated to reflux for 13 hours. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 2), the mixture was poured into a saturated aqueous sodium hydrogen carbonate solution (40 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (40 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, a brown solid intermediate (170 mg, 99%) was obtained.

¹ H NMR (500 MHz, CDCl3) δ: 7.98 (dd, 1H, J = 8.5, 1.5 Hz), 7.91 (d, 1H, J = 1.5 Hz), 7.73 (d, 1H, J = 8.0 Hz), 7.49 (d, 1H, J = 8.5 Hz), 7.26 (d, 1H, J = 2.0 Hz), 7.10 (dd, 1H, J = 8.0, 2.0 Hz), 4.36 (q, 2H, J = 7.0 Hz), 2.56 (s, 3H), 1.77 (s, 4H), 1.38 (t, 3H, J = 7.0 Hz), 1.37 (s, 6H), 1.32 (s, 6H).

39) Intermediate 1- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2-propyl-1H-benzimidazole-5-carboxylic acid methyl ester Synthesis of (17)

  Intermediate 13 (170 mg, 0.39 mmol) was dissolved in acetic acid (5.0 mL) and then heated to reflux for 16 hours. After confirming the completion of the reaction on a TLC plate (ethyl acetate: n-hexane = 1: 3), the solvent was distilled off under reduced pressure, and flash column chromatography (ethyl acetate: n-hexane = 1: 3) was performed. An intermediate (140 mg, 87%) was obtained.

¹ H NMR (500 MHz, CDCl3) δ: 8.51 (d, 1H, J = 1.25 Hz), 7.92 (dd, 1H, J = 8.5, 1.25 Hz), 7.30 (s, 1H), 6.97 (d, 1H, J = 8.5 Hz), 3.95 (s, 3H), 2.76-2.56 (m, 2H), 1.89-1.74 (m, 9H), 1.36 (s, 6H), 1.26 (s, 6H), 0.95 (t, 3H , J = 7.5 Hz).

40) Intermediate 1- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2-pentyl-1H-benzoimidazole-5-carboxylic acid methyl ester Synthesis of (18)

  Intermediate 14 (180 mg, 0.38 mmol) was dissolved in acetic acid (5.0 mL) and then heated to reflux for 13 hours. After confirming the completion of the reaction on a TLC plate (ethyl acetate: n-hexane = 1: 8), the solvent was distilled off under reduced pressure, and flash column chromatography (ethyl acetate: n-hexane = 1: 8) was performed. An intermediate (180 mg, qy) was obtained.

¹ H NMR (500 MHz, CDCl3) δ: 8.49 (d, 1H, J = 1.25 Hz), 7.90 (dd, 1H, J = 8.5, 1.25 Hz), 7.30 (s, 1H), 7.11 (s, 1H) , 6.96 (d, 1H, J = 8.5 Hz), 3.94 (s, 3H), 2.72-2.57 (m, 2H), 1.89 (s, 3H), 1.78-1.70 (m, 6H), 1.36 (s, 6H ), 1.32-1.22 (m, 10H), 0.82 (t, 3H, J = 7.0 Hz).

41) Intermediate 1- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2-phenyl-1H-benzimidazole-5-carboxylic acid methyl ester Synthesis of (19a)

  The crude crystals of intermediate 15a (240 mg) were dissolved in anhydrous 1,4-dioxane (10 mL), paratoluenesulfonic acid monohydrate (190 mg, 1.0 mmol) was added, and the mixture was heated to reflux for 11 hours. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 3), the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with water (40 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, flash column chromatography (ethyl acetate: n-hexane = 1: 4) was performed to obtain a colorless oil intermediate (220 mg, qy).

¹ H NMR (500 MHz, CDCl3) δ: 8.61 (s, 1H), 8.11 (d, 2H, J = 8.0 Hz), 7.98 (d, 1H, J = 8.5 Hz), 7.62-7.29 (m, 5H) , 7.56 (d, 2H, J = 8.0 Hz), 7.28 (s, 1H), 7.12 (s, 1H), 7.08 (d, 1H, J = 8.5 Hz), 3.97 (s, 3H), 1.85 (s, 3H), 1.72-1.69 (m, 4H), 1.34 (s, 3H), 1.33 (s, 3H), 1.23 (s, 3H), 1.07 (s, 3H).

42) Intermediate 1- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2-p-tolyl-1H-benzimidazole-5-carboxylic acid Synthesis of methyl ester (19b)

  The crude crystals of intermediate 15b (180 mg) were dissolved in anhydrous 1,4-dioxane (10 mL), paratoluenesulfonic acid monohydrate (190 mg, 1.0 mmol) was added, and the mixture was heated to reflux for 3 hours. After confirming the completion of the reaction on a TLC plate (ethyl acetate: n-hexane = 1: 3), the reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with water (40 mL) and saturated brine (30 mL), and 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 oil intermediate (160 mg, qy).

¹ H NMR (500 MHz, CDCl3) δ: 8.58 (s, 1H), 7.99 (d, 2H, J = 8.0 Hz), 7.95 (d, 1H, J = 8.5 Hz), 7.46 (d, 2H, J = 8.0 Hz), 7.15 (s, 1H), 7.09 (s, 1H), 7.05 (d, 1H, J = 8.5 Hz), 3.96 (s, 3H), 2.33 (s, 3H), 1.82 (s, 3H) , 1.73-1.69 (s, 4H), 1.34 (s, 3H), 1.33 (s, 3H), 1.24 (s, 3H), 1.11 (s, 3H).

43) Intermediate 2- (4-Nitro-phenyl) -1- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -1H-benzimidazole- Synthesis of 5-carboxylic acid methyl ester (19c)

  The crude crystals of intermediate 15c (210 mg) were dissolved in anhydrous 1,4-dioxane (10 mL), paratoluenesulfonic acid monohydrate (190 mg, 1.0 mmol) was added, and the mixture was heated to reflux for 3 hours. After confirming the completion of the reaction on a TLC plate (ethyl acetate: n-hexane = 1: 3), the reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with water (40 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, flash column chromatography (ethyl acetate: n-hexane = 1: 4) was performed to obtain a colorless oil intermediate (100 mg, 65%).

¹ H NMR (500 MHz, CDCl3) δ: 8.63 (d, 1H, J = 1.0 Hz), 8.14 (d, 2H, J = 9.0 Hz), 8.02 (dd, 1H, J = 8.5, 1.0 Hz), 7.77 (d, 2H, J = 9.0 Hz), 7.30 (s, 1H), 7.15 (s, 1H) 7.11 (d, 1H, J = 8.5 Hz), 3.98 (s, 3H), 1.84 (s, 3H), 1.75-1.72 (m, 4H), 1.36 (s, 3H), 1.36 (s, 3H), 1.25 (s, 3H), 1.11 (s, 3H).

44) Intermediate 2- (3-Nitro-phenyl) -1- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -1H-benzimidazole- Synthesis of 5-carboxylic acid methyl ester (19d)

  Intermediate 15d (205 mg, 0.40 mmol) was dissolved in acetic acid (5.0 mL) and then heated to reflux for 13 hours. After confirming the completion of the reaction on a TLC plate (ethyl acetate: n-hexane = 1: 3), the solvent was distilled off under reduced pressure, and flash column chromatography (ethyl acetate: n-hexane = 1: 5) was performed. An intermediate (190 mg, 94%) was obtained.

¹ H NMR (300 MHz, CDCl3) δ: 8.63 (dd, 1H, J = 1.5, 0.5 Hz), 8.30 (dd, 1H, J = 8.0, 1.5 Hz), 8.24-8.18 (m, 1H), 8.08 ( t, 1H, J = 1.75 Hz), 8.03 (dd, 1H, J = 8.5, 1.75 Hz), 7.57 (t, 1H, J = 8.0 Hz), 7.32 (s, 1H), 7.24 (s, 1H), 7.16 (d, 1H, J = 8.5 Hz), 3.98 (s, 3H), 1.82 (s, 3H), 1.75 (s, 4H), 1.36 (s, 3H), 1.35 (s, 3H), 1.26 (s , 3H), 1.15 (s, 3H).

45) Intermediate 2-Benzyl-1- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -1H-benzimidazole-5-carboxylic acid methyl ester Synthesis of (19e)

  Intermediate 15e (150 mg, 0.32 mmol) was dissolved in acetic acid (5.0 mL) and then heated to reflux for 12 hours. After confirming the completion of the reaction on a TLC plate (ethyl acetate: n-hexane = 1: 3), the solvent was distilled off under reduced pressure, and flash column chromatography (ethyl acetate: n-hexane = 1: 5) was performed. An intermediate (130 mg, 87%) was obtained.

¹ H NMR (300 MHz, CDCl3) δ: 8.58 (s, 1H), 7.95 (dd, 1H, J = 8.5, 1.5 Hz), 7.19 (s, 1H), 7.14-7.10 (m, 3H), 7.01 ( d, 1H, J = 2.5 Hz), 6.98 (s, 1H), 6.93-6.90 (m, 2H), 4.16 (s, 2H), 3.96 (s, 3H), 1.73 (s, 4H), 1.35 (s , 6H), 1.20 (s, 6H).

(Example 1) Target compound 2-Methyl-1- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -1H-benzimidazole-5-carboxylic acid ( 20a)

  Intermediate 16a (75 mg, 0.20 mmol) was dissolved in methanol (4.0 mL), 2N aqueous sodium hydroxide solution (4.0 mL) was added, and the mixture was stirred with heating at 60 ° C. for 15 min. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 1), the reaction mixture was poured into 2N hydrochloric acid (30 mL) and extracted with ethyl acetate (20 mL × 2). The organic layer was washed with water (30 mL × 2) and saturated brine (20 mL), and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization was performed with methanol to obtain the objective compound (8 mg, 11%) as colorless needle crystals.

Mp> 295 ° C; ¹ H NMR (500 MHz, DMSO-d6) δ: 12.71 (br s, 1H), 8.19 (s, 1H), 7.83 (d, 1H, J = 8.5 Hz), 7.58 (d, 1H , J = 8.5 HZ), 7.51 (s, 1H), 7.29 (d, 1H, J = 8.0 Hz), 7.18 (s, 1H), 2.47 (s, 3H), 1.71 (s, 4H), 1.33 (s , 6H), 1.29 (s, 6H); IR (KBr): v = 2960 (OH), 1698 (CO) cm ^-1 ; FAB-MS m / e: 363 [M + H] ⁺ ; Anal. Calcd for C ₂₃ H ₂₆ N ₂ O ₂・ 5 / 3H ₂ O: C, 70.38; H, 7.53; N, 7.14.Found: C, 70.61; H, 7.27; N, 6.97.

Example 2 Target Compound 2-Methyl-1- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -1H-benzimidazole-5-carboxylic acid Synthesis of acid (20b)

  Intermediate 16b (150 mg, 0.38 mmol) was dissolved in methanol (10 mL), 2N aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred with heating at 60 ° C. for 20 min. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 1), the mixture was poured into 2N hydrochloric acid (20 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with water (40 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization was performed with ethyl acetate / n-hexane to obtain the target compound (84 mg, 58%) as a colorless powder.

Mp 295.0 ° C; ¹ H NMR (300 MHz, DMSO-d6) δ: 12.71 (br s, 1H), 8.20 (s, 1H), 7.81 (d, 1H, J = 8.5 Hz), 7.47 (s, 1H) , 7.36 (s, 1H), 6.94 (d, 1H, J = 8.5 Hz), 2.32 (s, 3H), 1.85 (s, 3H), 1.69 (s, 4H), 1.33 (s, 6H), 1.25 ( s, 3H), 1.24 (s, 3H); IR (KBr): v = 2957-2925 (OH), 1701 (CO) cm ^-1 ; FAB-MS m / e: 377 [M + H] ⁺ ; Anal Calcd for C ₂₄ H ₂₈ N ₂ O ₂ 1 / 4H ₂ O: C, 75.66; H, 7.54; N, 7.35. Found: C, 75.70; H, 7.42; N, 7.36.

Example 3 Target Compound 1- (3-Methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2-methyl-1H-benzimidazole-5 Synthesis of -carboxylic acid (20c)

  Intermediate 16c (98 mg, 0.24 mmol) was dissolved in methanol (2.0 mL), 2N aqueous sodium hydroxide solution (2.0 mL) was added, and the mixture was stirred with heating at 60 ° C. for 1 hr. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 3: 1), the pH was adjusted to 6 with 2N hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layer was washed with water (20 mL) and saturated brine (20 mL), and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, recrystallization was performed with methanol to obtain the objective compound (62 mg, 66%) as colorless plate crystals.

¹ H NMR (300 MHz, DMSO-d6) δ: 8.16 (d, 1H, J = 0.75 Hz), 7.79 (dd, 1H, J = 8.5, 0.75 Hz), 7.41 (s, 1H), 7.17 (s, 1H), 6.98 (d, 1H, J = 8.5 Hz), 3.72 (s, 3H), 2.34 (s, 3H), 1.69 (m, 4H), 1.36 (s, 6H), 1.25 (s, 3H), 1.24 (s, 3H).

(Example 4) Target compound 2-Methyl-3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -3H-benzimidazole-5-carboxylic acid ( 20d)

  Intermediate 16d (160 mg, 0.41 mmol) was dissolved in ethanol (4.0 mL), 2N aqueous sodium hydroxide solution (4.0 mL) was added, and the mixture was stirred with heating at 60 ° C. for 10 min. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 2), the mixture was poured into 2N hydrochloric acid (4.0 mL) and extracted with ethyl acetate (20 mL × 2). The organic layer was washed with saturated brine (20 mL) and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the objective compound (140 mg, 92%) was obtained as a colorless powder.

Mp 290.0-290.5 ° C; ¹ H NMR (300 MHz, DMSO-d6) δ: 12.89 (br s, 1H), 7.83 (dd, 1H, J = 8.5, 1.5 Hz), 7.68 (d, 1H, J = 1.5 Hz), 7.67 (d, 1H, J = 8.5 Hz), 7.61 (d, 1H, J = 8.5 Hz), 7.53 (d, 1H, J = 2.0 Hz), 7.31 (dd, 1H, J = 8.5, 2.0 Hz), 1.72 (s, 4H), 1.34 (s, 6H), 1.30 (s, 6H); IR (KBr): v = 2960-2928 (OH), 1699 (CO) cm ^-1 ; FAB-MS m / e:. 363 [M + H] +; Anal Calcd for C 23 H 26 N 2 O 2 · 1 / 3H 2 O:. C, 74.37; H, 7.33; N, 7.54 Found: C, 74.58; H, 7.26; N, 7.60.

(Example 5) Target compound 1- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2-propyl-1H-benzimidazole-5-carboxylic acid Synthesis of acid (21)

  Intermediate 17 (140 mg, 0.33 mmol) was dissolved in methanol (2.0 mL) and tetrahydrofuran (2.0 mL), 2N aqueous sodium hydroxide solution (4.0 mL) was added, and the mixture was heated with stirring at 60 ° C. for 45 min. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 1), the pH was adjusted to 6 with 2N hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layer was washed with water (20 mL) and saturated brine (20 mL), and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization was performed with dichloromethane / methanol to obtain the target compound (43 mg, 32%) as colorless plate crystals.

¹ H NMR (300 MHz, DMSO-d6) δ: 8.22 (d, 1H, J = 1.25 Hz), 7.80 (dd, 1H, J = 8.5, 1.25 Hz), 7.45 (s, 1H), 7.31 (s, 1H), 6.93 (d, 1H, J = 8.5 Hz), 2.59-2.54 (m, 2H), 1.84 (s, 3H), 1.76-1.70 (m, 6H), 1.33 (s, 6H), 1.24 (s , 6H), 0.89 (t, 3H, J = 7.5 Hz).

(Example 6) Target compound 1- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2-pentyl-1H-benzimidazole-5-carboxylic acid Synthesis of acid (22)

  Intermediate 18 (180 mg, 0.39 mmol) was dissolved in methanol (2.0 mL) and tetrahydrofuran (2.0 mL), 2N aqueous sodium hydroxide solution (4.0 mL) was added, and the mixture was heated with stirring at 60 ° C. for 1 hr. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 2), the mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate (40 mL × 3). The organic layer was washed with water (40 mL) and saturated brine (40 mL), and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization was performed with dichloromethane / n-hexane to obtain the objective compound (100 mg, 60%) as colorless needle crystals.

¹ H NMR (300 MHz, DMSO-d6) δ: 8.22 (d, 1H, J = 1.0 Hz), 7.81 (dd, 1H, J = 8.5, 1.0 Hz), 7.46 (s, 1H), 7.33 (s, 1H), 6.95 (d, 1H, J = 8.5 Hz), 2.68-2.55 (m, 2H), 1.84 (s, 3H), 1.69-1.58 (m, 6H), 1.33 (s, 3H), 1.32 (s , 3H), 1.24-1.16 (m, 10H), 0.76 (t, 3H, J = 7.0 Hz).

(Example 7) Target compound 1- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2-phenyl-1H-benzimidazole-5-carboxylic acid Synthesis of acid (23a)

  Intermediate 19a (214 mg, 0.30 mmol) was dissolved in methanol (10 mL), 2N aqueous sodium hydroxide solution (6.0 mL) was added, and the mixture was stirred with heating at 60 ° C. for 5 min. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 1), the mixture was poured into 1N hydrochloric acid (30 mL) and extracted with ethyl acetate (25 mL × 2). The organic layer was washed with water (40 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization was performed with dichloromethane / n-hexane to obtain the target compound (96 mg, 73%) as a colorless powder.

¹ H NMR (300 MHz, DMSO-d6) δ: 12.81 (br s, 1H), 8.36 (s, 1H), 7.90 (dd, 1H, J = 8.5, 1.0 Hz), 7.53 (s, 1H), 7.51 (s, 1H), 7.42-7.32 (m, 5H), 7.08 (d, 1H, J = 8.5 Hz), 1.78 (s, 3H), 1.66 (s, 4H), 1.31 (s, 3H), 1.30 ( s, 3H), 1.21 (s, 3H), 1.06 (s, 3H).

(Example 8) Target compound 1- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2-p-tolyl-1H-benzimidazole-5 Synthesis of -carboxylic acid (23b)

  Intermediate 19b (160 mg, 0.30 mmol) was dissolved in methanol (10 mL), 2N aqueous sodium hydroxide solution (6.0 mL) was added, and the mixture was stirred with heating at 60 ° C. for 5 min. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 1), the mixture was poured into 1N hydrochloric acid (30 mL) and extracted with ethyl acetate (25 mL × 2). The organic layer was washed with water (40 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, recrystallization was performed with dichloromethane / n-hexane to obtain the target compound (99 mg, 73%) as a colorless powder.

¹ H NMR (300 MHz, DMSO-d6) δ: 12.80 (br s, 1H), 8.34 (d, 1H, J = 1.0 Hz), 7.88 (dd, 1H, J = 8.5, 1.0 Hz), 7.42 (d , 2H, J = 8.5 Hz), 7.40 (s, 2H), 7.15 (d, 2H, J = 8.5 Hz), 7.04 (d, 1H, J = 8.5 Hz), 2.29 (s, 3H), 1.72 (s , 3H), 1.68 (s, 4H), 1.31 (s, 6H), 1.23 (s, 3H), 1.11 (s, 3H).

(Example 9) Target compound 2- (4-Nitro-phenyl) -1- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -1H of 2-benzimidazole-5-carboxylic acid (23c)

  Intermediate 19c (95 mg, 0.19 mmol) was dissolved in methanol (10 mL), 2N aqueous sodium hydroxide solution (6.0 mL) was added, and the mixture was stirred with heating at 60 ° C. for 5 min. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 1), the mixture was poured into 1N hydrochloric acid (30 mL) and extracted with ethyl acetate (25 mL × 2). The organic layer was washed with water (40 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization was performed with dichloromethane / n-hexane to obtain the target compound (86 mg, 93%) as a colorless powder.

¹ H NMR (300 MHz, DMSO-d6) δ: 12.88 (br s, 1H), 8.42 (d, 1H, J = 1.0 Hz), 8.22 (d, 2H, J = 9.0 Hz), 7.95 (dd, 1H , J = 8.5, 1.0 Hz), 7.77 (d, 2H, J = 9.0 Hz), 7.45 (s, 1H), 7.44 (s, 1H), 7.14 (d, 1H, J = 8.5 Hz), 1.81 (s , 3H), 1.67 (s, 4H), 1.32 (s, 3H), 1.32 (s, 3H), 1.22 (s, 3H), 1.07 (s, 3H).

Example 10 Target compound 2- (3-Nitro-phenyl) -1- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -1H of 2-benzimidazole-5-carboxylic acid (23d)

  Intermediate 19d (180 mg, 0.37 mmol) was dissolved in methanol (2.0 mL) and tetrahydrofuran (2.0 mL), 2N aqueous sodium hydroxide solution (4.0 mL) was added, and the mixture was stirred with heating at 60 ° C. for 2 hr. 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 and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with water (30 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, recrystallization was performed with dichloromethane / n-hexane to obtain the target compound (100 mg, 57%) as white needle crystals.

¹ H NMR (300 MHz, DMSO-d6) δ: 8.41 (d, 1H, J = 1.0 Hz), 8.26 (dd, 1H, J = 8.0, 2.0 Hz), 8.21 (d, 1H, J = 8.0 Hz) , 7.99 (t, 1H, J = 2.0 Hz), 7.94 (dd, 1H, J = 8.5, 1.0 Hz), 7.72 (t, 1H, J = 8.0 Hz), 7.47 (s, 1H), 7.46 (s, 1H), 7.17 (d, 1H, J = 8.5 Hz), 1.79 (s, 3H), 1.68 (s, 4H), 1.33 (s, 3H), 1.31 (s, 3H), 1.22 (s, 3H), 1.07 (s, 3H).

Example 11 Target Compound 2-Benzyl-1- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -1H-benzimidazole-5-carboxylic acid Synthesis of acid (23e)

  Intermediate 19e (130 mg, 0.27 mmol) was dissolved in methanol (2.0 mL) and tetrahydrofuran (2.0 mL), 2N aqueous sodium hydroxide solution (4.0 mL) was added, and the mixture was heated with stirring at 60 ° C. for 2 hr. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 2), it was poured into 2N hydrochloric acid (1.5 mL), saturated aqueous ammonium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). did. The organic layer was washed with water (20 mL) and saturated brine (20 mL), and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization was performed with dichloromethane / methanol to obtain the objective compound (100 mg, 82%) as colorless cubic crystals.

¹ H NMR (300 MHz, DMSO-d6) δ: 8.25 (dd, 1H, J = 1.0 Hz), 7.81 (dd, 1H, J = 8.5, 1.0 Hz), 7.29 (s, 1H), 7.24 (s, 1H), 7.15-7.11 (m, 3H), 6.95 (d, 1H, J = 8.5 Hz), 6.88-6.85 (m, 2H), 4.04 (s, 2H), 1.69 (s, 3H), 1.52 (s , 4H), 1.32 (s, 6H), 1.20 (s, 6H).

[Examples] Synthesis of target compounds (Examples 12 to 14)
FIG. 6 shows a scheme of the production method until obtaining the target compound (25a, 25b, 25c) in this example.

1) Intermediate 2-Oxo-1- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2,3-dihydro-1H-benzimidazole-5- Synthesis of carboxylic acid methyl ester (24a)

  Intermediate 11a (180 mg, 0.50 mmol) and triethylamine (70 μL, 0.50 mmol) were dissolved in 1,2-dichloroethane (5.0 mL), then triphosgene (59 mg, 0.20 mmol) was added dropwise under an argon atmosphere. The mixture was heated to reflux for 7 hours. After confirming the completion of the reaction on a TLC plate (ethyl acetate: n-hexane = 1: 3), the reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with water (40 mL × 2) and saturated brine (30 mL), and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization was performed with dichloromethane / n-hexane to obtain an intermediate (160 mg, 86%) of light pink needle crystals.

¹ H NMR (500 MHz, CDCl3) δ: 8.83 (s, 1H), 7.82 (d, 1H, J = 8.0 Hz), 7.81 (s, 1H), 7.47 (d, 1H, J = 8.0 Hz), 7.40 (s, 1H), 7.28 (d, 1H, J = 8.0 Hz), 7.05 (d, 1H, J = 8.0 Hz), 3.92 (s, 3H), 1.74 (s, 4H), 1.33 (s, 6H) , 1.32 (s, 6H).

2) Intermediate 2-Oxo-1- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2,3-dihydro-1H-benzimidazole- Synthesis of 5-carboxylic acid methyl ester (24b)

  Intermediate 11b (110 mg, 0.30 mmol) was dissolved in 1,2-dichloroethane (6.0 mL), then triethylamine (70 μL, 0.50 mmol) and triphosgene (59 mg, 0.20 mmol) were added, and 19 g under argon atmosphere was added. Heated to reflux for hours. After confirming the completion of the reaction on a TLC plate (ethyl acetate: n-hexane = 1: 3), the reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with water (60 mL) and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, an intermediate (130 mg, qy) of pale yellow crystals was obtained.

¹ H NMR (300 MHz, DMSO-d6) δ: 11.35 (s, 1H), 7.67 (dd, 1H, J = 8.0, 1.5 Hz), 7.60 (d, 1H, J = 1.5 Hz), 7.39 (s, 1H), 7.27 (s, 1H), 6.66 (d, 1H, J = 8.0 Hz), 3.86 (s, 3H), 2.00 (s, 3H), 1.68 (s, 4H), 1.31 (s, 3H), 1.30 (s, 3H), 1.23 (s, 3H), 1.23 (s, 3H).

3) Intermediate 2-Oxo-3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2,3-dihydro-1H-benzimidazole-5- Synthesis of carboxylic acid ethyl ester (24c)

  Intermediate 11c (120 mg, 0.30 mmol) was dissolved in 1,2-dichloroethane (6.0 mL), triethylamine (70 μL, 0.50 mmol) and triphosgene (59 mg, 0.20 mmol) were added, and the mixture was added under argon atmosphere. Heated to reflux for hours. After confirming the completion of the reaction on a TLC plate (ethyl acetate: n-hexane = 1: 2), the reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with water (50 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization was performed with ethyl acetate / n-hexane to obtain a light brown crystal intermediate (98 mg, 75%).

¹ H NMR (300 MHz, DMSO-d6) δ: 11.56 (br s, 1H), 7.75 (dd, 1H, J = 8.0, 1.5 Hz), 7.53 (d, 1H, J = 8.5 Hz), 7.49 (d , 1H, J = 1.5 Hz), 7.46 (d, 1H, J = 2.5 Hz), 7.28 (dd, 1H, J = 8.5, 2.5 Hz), 7.17 (d, 1H, J = 8.0 Hz), 4.25 (q , 2H, J = 7.0 Hz), 1.70 (s, 4H), 1.31 (s, 6H), 1.29 (s, 6H), 1.27 (t, 3H, J = 7.0 Hz).

(Example 12) Target compound 2-Oxo-1- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2,3-dihydro-1H-benzimidazole Synthesis of -5-carboxylic acid (25a)

  Intermediate 24a (76 mg, 0.20 mmol) was dissolved in methanol (5.0 mL), 2N aqueous sodium hydroxide solution (5.0 mL) was added, and the mixture was stirred with heating at 60 ° C. for 15 min. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 1), the mixture was poured into 2N hydrochloric acid (30 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with water (40 mL × 2) and saturated brine (30 mL), and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, recrystallization was performed with methanol to obtain the target compound (42 mg, 58%) as a colorless powder.

Mp> 295 ° C; ¹ H NMR (300 MHz, DMSO-d6) δ: 12.75 (br s, 1H), 11.38 (s, 1H), 7.73 (d, 1H, J = 8.0 Hz), 7.64 (s, 1H ), 7.56 (d, 1H, J = 8.5 Hz), 7.49 (d, 1H, J = 2.0 Hz), 7.31 (dd, 1H, J = 8.5, 2.0 Hz), 7.03 (d, 1H, J = 8.0 Hz) ), 1.75 (s, 4H), 1.36 (s, 6H), 1.33 (s, 6H); IR (KBr): v = 3350 (NH), 2960-2925 (OH), 1716 (CO), 1606 (CO ) cm ^-1 ; FAB-MS m / e: 365 [M + H] ⁺ ; Anal. Calcd for C ₂₂ H ₂₄ N ₂ O ₃・ 1 / 3H ₂ O: C, 71.33; H, 6.71; N, 7.56 Found: C, 71.24; H, 6.61; N, 7.36.

(Example 13) Target compound 2-Oxo-1- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2,3-dihydro-1H of 2-benzimidazole-5-carboxylic acid (25b)

  Intermediate 24b (120 mg, 0.31 mmol) was dissolved in methanol (10 mL), 2N aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred with heating at 60 ° C. for 20 min. After confirming the completion of the reaction on a TLC plate (ethyl acetate: n-hexane = 1: 1), the reaction mixture was poured into 1N hydrochloric acid (20 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with water (40 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, recrystallization was performed with methanol to obtain the target compound (45 mg, 38%) as a colorless powder.

Mp> 295 ° C; ¹ H NMR (300 MHz, DMSO-d6) δ: 12.69 (br s, 1H), 11.29 (s, 1H), 7.64 (dd, 1H, J = 8.0, 1.5 Hz), 7.59 (d , 1H, J = 1.5 Hz), 7.39 (s, 1H), 7.26 (s, 1H), 6.63 (d, 1H, J = 8.0 Hz), 2.01 (s, 3H), 1.68 (s, 4H), 1.31 (s, 6H), 1.30 (s, 3H), 1.24 (s, 3H), 1.23 (s, 3H); IR (KBr): v = 2959-2926 (OH), 1712 (CO), 1685 (CO) cm ^-1 ; FAB-MS m / e: 379 [M + H] ⁺ ; Anal.Calcd for C ₂₃ H ₂₆ N ₂ O ₃・ 1 / 4H ₂ O: C, 72.13; H, 6.97; N, 7.31. Found: C, 72.40; H, 7.05; N, 7.18.

(Example 14) Objective compound 2-Oxo-3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2,3-dihydro-1H-benzimidazole Synthesis of -5-carboxylic acid (25c)

  Intermediate 24c (95 mg, 0.24 mmol) was dissolved in ethanol (5.0 mL), 2N aqueous sodium hydroxide solution (5.0 mL) was added, and the mixture was stirred with heating at 60 ° C. for 40 min. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 2: 3), the reaction mixture was poured into water (40 mL) and 2N hydrochloric acid (5.0 mL), and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with water (50 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, flash column chromatography (ethyl acetate: n-hexane = 2: 3) was performed to obtain the target compound (83 mg, 94%) as a colorless powder.

Mp> 295 ° C; ¹ H NMR (300 MHz, DMSO-d6) δ: 12.66 (br s, 1H), 11.49 (br s, 1H), 7.72 (dd, 1H, J = 8.0, 1.5 Hz), 7.53 ( d, 1H, J = 8.5 Hz), 7.44 (d, 1H, J = 2.0 Hz), 7.44 (d, 1H, J = 1.5 Hz), 7.26 (dd, 1H, J = 8.5, 2.0 Hz), 7.14 ( d, 1H, J = 8.0 Hz), 1.70 (s, 4H), 1.31 (s, 6H), 1.28 (s, 6H); IR (KBr): v = 3071 (NH), 2960-2861 (OH), 1682 (CO), 1608 (CO) cm ^-1 ; FAB-MS m / e: 365 [M + H] ⁺ ; Anal. Calcd for C ₂₂ H ₂₄ N ₂ O ₃ : C, 71.33; H, 6.71; N , 7.56. Found: C, 71.18; H, 6.62; N, 7.51.

[Examples] Synthesis of target compounds (Examples 15 to 17)
FIG. 7 shows a scheme of the production method until obtaining the target compound (27a, 27b, 27c) in this example.

1) Intermediate 1- (5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-benzimidazole-5- Synthesis of carboxylic acid methyl ester (26a)

  Intermediate 11a (210 mg, 0.60 mmol) was dissolved in anhydrous N, N-dimethylformamide (6.0 mL) and then carbon disulfide (360 μL, 6.0 mmol), 1,8-diazabicyclo [5,4,0]. -7-undecene (90 μL, 0.60 mmol) was added, and the mixture was heated and stirred at 60 ° C. for 15 hours under an argon atmosphere. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 3), the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with water (40 mL × 2) and saturated brine (30 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 (190 mg, 81%) of pale brown needle crystals.

¹ H NMR (500 MHz, CDCl3) δ: 10.29 (br s, 1H), 7.93 (s, 1H), 7.89 (d, 1H, J = 8.5 Hz), 7.51 (d, 1H, J = 8.5 Hz), 7.44 (d, 1H, J = 2.0 Hz), 7.28 (dd, 1H, J = 8.0, 2.0 Hz), 7.03 (d, 1H, J = 8.0 Hz), 3.94 (s, 3H), 1.75 (s, 4H ), 1.36 (s, 6H), 1.32 (s, 6H).

2) Intermediate 1- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-benzimidazole- Synthesis of 5-carboxylic acid methyl ester (26b)

  Intermediate 11b (110 mg, 0.30 mmol) was dissolved in carbon tetrachloride (5.0 mL), and then carbon disulfide (180 μL, 3.0 mmol), 1,8-diazabicyclo [5,4,0] -7-undecene. (45 μL, 0.30 mmol) was added, and the mixture was heated and stirred at 70 ° C. for 2 hours under an argon atmosphere. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 2), the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with water (50 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, recrystallization was performed with ethyl acetate / n-hexane to obtain a light yellow oil intermediate (130 mg, qy).

¹ H NMR (300 MHz, CDCl3) δ: 10.41 (br s, 1H), 7.95 (d, 1H, J = 1.5 Hz), 7.88 (dd, 1H, J = 8.5, 1.5 Hz), 7.32 (s, 1H ), 7.19 (s, 1H), 6.78 (d, 1H, J = 8.5 Hz), 3.94 (s, 3H), 2.06 (s, 3H), 1.73 (s, 3H), 1.36 (s, 3H), 1.34 (s, 3H), 1.30 (s, 3H), 1.26 (s, 3H).

3) Intermediate 3- (5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-benzimidazole-5- Synthesis of carboxylic acid ethyl ester (26c)

  Intermediate 11c (120 mg, 0.30 mmol) was dissolved in carbon tetrachloride (5.0 mL), and then carbon disulfide (180 μL, 3.0 mmol), 1,8-diazabicyclo [5,4,0] -7-undecene. (45 μL, 0.30 mmol) was added, and the mixture was heated and stirred at 60 ° C. for 19 hours under an argon atmosphere. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 2), the reaction mixture was poured into water (40 mL) and extracted with dichloromethane (30 mL × 2). The organic layer was washed with water (40 mL) and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, flash column chromatography (ethyl acetate: n-hexane = 1: 3) was performed to obtain a light orange solid intermediate (110 mg, 82%).

¹ H NMR (300 MHz, CDCl3) δ: 10.44 (br s, 1H), 7.97 (dd, 1H, J = 8.5, 1.5 Hz), 7.74 (d, 1H, J = 1.5 Hz), 7.51 (d, 1H , J = 8.5 Hz), 7.45 (d, 1H, J = 2.5 Hz), 7.33 (dd, 1H, J = 8.5, 2.5 Hz), 7.27 (d, 1H, J = 8.5 Hz), 4.35 (q, 2H , J = 7.0 Hz), 1.76 (s, 4H), 1.36 (t, 3H, J = 7.0 Hz), 1.36 (s, 6H), 1.33 (s, 6H).

Example 15 Target Compound 1- (5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-benzimidazole Synthesis of -5-carboxylic acid (27a)

  Intermediate 26a (79 mg, 0.20 mmol) was dissolved in methanol (3.0 mL), 2N aqueous sodium hydroxide solution (3.0 mL) was added, and the mixture was stirred with heating at 60 ° C. for 15 min. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 1), the reaction mixture was poured into 2N hydrochloric acid (30 mL) and extracted with ethyl acetate (20 mL × 2). The organic layer was washed with water (30 mL × 2) and saturated brine (30 mL), and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, recrystallization was performed with methanol to obtain the target compound (51 mg, 67%) as colorless needle crystals.

Mp> 295 ° C; ¹ H NMR (500 MHz, DMSO-d6) δ: 13.19 (br s, 1H), 12.89 (br s, 1H), 7.77 (d, 1H, J = 8.5 Hz), 7.74 (s, 1H), 7.55 (d, 1H, J = 8.5 Hz), 7.48 (s, 1H), 7.27 (d, 1H, J = 8.5 Hz), 6.95 (d, 1H, J = 8.5 Hz), 1.71 (s, 4H), 1.33 (s, 6H), 1.28 (s, 6H);; IR (KBr): v = 3231 (NH), 2962-2859 (OH), 1688 (CO) cm ^-1 ; FAB-MS m / e: 381 [M + H] ⁺ ; Anal. Calcd for C ₂₂ H ₂₄ N ₂ O ₂ S1 / 2H ₂ O: C, 66.30; H, 6.58; N, 7.03. Found: C, 66.27; H, 6.70; N, 6.69.

(Example 16) Target compound 1- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2-thioxo-2,3-dihydro-1H of 2-benzimidazole-5-carboxylic acid (27b)

  Intermediate 26b (130 mg, 0.30 mmol) was dissolved in methanol (3.0 mL), 2N aqueous sodium hydroxide solution (3.0 mL) was added, and the mixture was stirred with heating at 60 ° C. for 10 min. After confirming the completion of the reaction on a TLC plate (ethyl acetate: n-hexane = 1: 1), the reaction mixture was poured into 1N hydrochloric acid (20 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with water (40 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, recrystallization was performed with ethyl acetate / n-hexane to obtain the target compound (90 mg, 76%) as pale yellow needle crystals.

Mp> 295.0 ° C; ¹ H NMR (300 MHz, DMSO-d6) δ: 13.20 (br s, 1H), 12.91 (br s, 1H), 7.76 (dd, 1H, J = 8.5, 1.5 Hz), 7.75 ( d, 1H, J = 1.5 Hz), 7.41 (s, 1H), 7.24 (s, 1H), 6.68 (d, 1H, J = 8.5 Hz), 1.95 (s, 3H), 1.68 (s, 4H), 1.33 (s, 3H), 1.32 (s, 3H), 1.23 (s, 3H), 1.23 (s, 3H); IR (KBr): v = 3056 (NH), 2962-2923 (OH), 1693 (CO ) cm ^-1 ; FAB-MS m / e: 395 [M + H] ⁺ ; Anal. Calcd for C ₂₃ H ₂₆ N ₂ O ₂ S ・ 1 / 2H ₂ O: C, 68.48; H, 6.74; N, 6.94. Found: C, 68.39; H, 6.63; N, 6.82.

Example 17 Target Compound 3- (5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-benzimidazole Synthesis of -5-carboxylic acid (27c)

  Intermediate 26c (110 mg, 0.27 mmol) was dissolved in methanol (5.0 mL), 2N aqueous sodium hydroxide solution (5.0 mL) was added, and the mixture was stirred with heating at 60 ° C. for 30 min. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 1), it was poured into water (30 mL) and 2N hydrochloric acid (5.0 mL), and extracted with ethyl acetate (20 mL × 2). The organic layer was washed with water (30 mL) and saturated brine (20 mL), and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the target compound (95 mg, 93%) was obtained as a pale pink powder.

Mp> 295 ° C; ¹ H NMR (300 MHz, DMSO-d6) δ: 13.29 (br s, 1H), 12.95 (br s, 1H), 7.85 (dd, 1H, J = 8.5, 1.5 Hz), 7.58 ( d, 1H, J = 8.5 Hz), 7.51 (d, 1H, J = 1.5 Hz), 7.39 (d, 1H, J = 1.5 Hz), 7.31 (dd, 1H, J = 8.5, 1.5 Hz), 7.30 ( d, 1H, J = 8.5 Hz), 1.71 (s, 4H), 1.34 (s, 6H), 1.28 (s, 6H); IR (KBr): v = 3041 (NH), 2959-2926 (OH), 1692 (CO) cm ^-1 ; FAB-MS m / e: 381 [M + H] ⁺ ; Anal. Calcd for C ₂₂ H ₂₄ N ₂ O ₂ S: C, 69.44; H, 6.36; N, 7.36. : C, 69.15; H, 6.44; N, 7.20.

[Examples] Synthesis of target compounds (Examples 18 to 20)
FIG. 8 shows a scheme of the production method until obtaining the target compound (29a, 29b, 29c) in this example.

1) Synthesis of intermediate 1- (5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -1H-benzotriazole-5-carboxylic acid methyl ester (28a)

  Intermediate 11a (180 mg, 0.50 mmol) was dissolved in tetrahydrofuran (3.0 mL), and a solution obtained by diluting concentrated sulfuric acid (1.0 mL) in water (10 mL) was added dropwise. Thereafter, a 0.7 M aqueous sodium nitrite solution (1.0 mL) was added dropwise while maintaining the temperature at 0 ° C., and the mixture was stirred for 15 minutes. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 2), the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with water (40 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, flash column chromatography (ethyl acetate: n-hexane = 1: 3) was performed to obtain an orange solid intermediate (180 mg, 99%).

¹ H NMR (300 MHz, CDCl3) δ: 8.87 (s, 1H), 8.23 (d, 1H, J = 8.5 Hz), 7.73 (d, 1H, J = 8.5 Hz), 7.67 (d, 1H, J = 2.0 Hz), 7.55 (d, 1H, J = 8.5 Hz), 7.49 (dd, 1H, J = 8.5, 2.0 Hz), 4.00 (s, 3H), 1.77 (s, 4H), 1.36 (s, 12H) .

2) Intermediate 1- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -1H-benzotriazole-5-carboxylic acid methyl ester (28b) Composition

  Intermediate 11b (150 mg, 0.40 mmol) was dissolved in tetrahydrofuran (2.0 mL), and a solution obtained by diluting concentrated sulfuric acid (1.0 mL) in water (10 mL) was added dropwise. Thereafter, a 0.6 M sodium nitrite aqueous solution (1.0 mL) was added dropwise while maintaining the temperature at 0 ° C., and the mixture was stirred for 90 minutes. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 2), the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (40 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, flash column chromatography (ethyl acetate: n-hexane = 1: 3) was performed to obtain an orange solid intermediate (140 mg, 91%).

¹ H NMR (500 MHz, CDCl3) δ: 8.87 (d, 1H, J = 1.5 Hz), 8.19 (dd, 1H, J = 8.5, 1.5 Hz), 7.40 (d, 1H, J = 8.5 Hz), 7.35 (s, 1H), 7.29 (s, 1H), 4.00 (s, 3H), 2.07 (s, 3H), 1.75 (s, 4H), 1.36 (s, 6H), 1.29 (s, 6H).

3) Synthesis of intermediate 3- (5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -3H-benzotriazole-5-carboxylic acid ethyl ester (28c)

  Intermediate 11c (150 mg, 0.40 mmol) was dissolved in tetrahydrofuran (2.0 mL), and a solution obtained by diluting concentrated sulfuric acid (1.0 mL) in water (10 mL) was added dropwise. Thereafter, a 0.6 M aqueous sodium nitrite solution (1.0 mL) was added dropwise while maintaining the temperature at 0 ° C., and the mixture was stirred for 35 minutes. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 2), the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (40 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, flash column chromatography (ethyl acetate: n-hexane = 1: 2) was performed to obtain a red solid intermediate (130 mg, 83%).

¹ H NMR (500 MHz, CDCl3) δ: 8.47 (d, 1H, J = 1.5 Hz), 8.17 (d, 1H, J = 9.0 Hz), 8.10 (dd, 1H, J = 9.0, 1.5 Hz), 7.89 (d, 1H, J = 2.0 Hz), 7.56 (d, 1H, J = 8.5 Hz), 7.52 (dd, 1H, J = 8.5, 2.0 Hz), 4.44 (q, 2H, J = 7.0 Hz), 1.78 (s, 4H), 1.54 (s, 6H), 1.43 (t, 3H, J = 7.0 Hz), 1.38 (s, 6H).

Example 18 Synthesis of target compound 1- (5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -1H-benzotriazole-5-carboxylic acid (29a)

  Intermediate 28a (180 mg, 0.48 mmol) was dissolved in methanol (10 mL), 2N aqueous sodium hydroxide solution (8.0 mL) was added, and the mixture was stirred with heating at 60 ° C. for 20 min. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 2), the reaction mixture was poured into 1N hydrochloric acid (20 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with water (40 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the target compound (170 mg, qy) was obtained as an orange solid.

Mp 260.0-261.0 ° C; 1H NMR (300 MHz, DMSO-d6) δ: 13.39 (br s, 1H), 8.72 (d, 1H, J = 1.5 Hz), 8.19 (dd, 1H, J = 9.0, 1.5 Hz ), 7.90 (d, 1H, J = 9.0 Hz), 7.77 (d, 1H, J = 2.0 Hz), 7.67 (d, 1H, J = 8.5 Hz), 7.60 (dd, 1H, J = 8.5, 2.0 Hz) ), 1.73 (s, 4H), 1.34 (s, 12H); IR (KBr): v = 2961-2933 (OH), 1713 (CO) cm ^-1 ; FAB-MS m / e: 350 (M + H ] ⁺ ; Anal. Calcd for C ₃₃ H ₃₆ N ₂ O ₄ S ・ 1 / 3H ₂ O: C, 70.96; H, 6.71; N, 11.82. Found: C, 71.20; H, 6.73; N, 11.71.

Example 19 Objective Compound 1- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -1H-benzotriazole-5-carboxylic acid (29b) Synthesis of

  Intermediate 28b (140 mg, 0.36 mmol) was dissolved in methanol (6.0 mL), 2N aqueous sodium hydroxide solution (6.0 mL) was added, and the mixture was stirred with heating at 60 ° C. for 5 min. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 2), the mixture was poured into 1N hydrochloric acid (12 mL) and extracted with ethyl acetate (20 mL × 2). The organic layer was washed with water (20 mL) and saturated brine (20 mL), and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the target compound (95 mg, 93%) as white needle crystals was obtained.

Mp 238.0-239.0 ° C; ¹ H NMR (300 MHz, DMSO-d6) δ: 13.26 (br s, 1H), 8.72 (d, 1H, J = 1.5 Hz), 8.14 (dd, 1H, J = 8.5, 1.5 Hz), 7.56 (d, 1H, J = 8.5 Hz), 7.52 (s, 1H), 7.49 (s, 1H), 2.00 (s, 3H), 1.71 (s, 4H), 1.34 (s, 6H), 1.27 (s, 6H); IR (KBr): v = 2961 (OH), 1714 (CO) cm ^-1 ; FAB-MS m / e: 364 [M + H] ⁺ ; Anal. Calcd for C ₂₂ H ₂₅ N ₃ O ₂ : C, 72.70; H, 6.93; N, 11.56. Found: C, 72.55; H, 6.97; N, 11.54.

Example 20 Synthesis of target compound 3- (5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -3H-benzotriazole-5-carboxylic acid (29c)

  Intermediate 28c (120 mg, 0.32 mmol) was dissolved in ethanol (6.0 mL), 2N aqueous sodium hydroxide solution (6.0 mL) was added, and the mixture was stirred with heating at 60 ° C. for 15 min. After confirming the completion of the reaction with a TLC plate (ethyl acetate: n-hexane = 1: 2), the reaction mixture was poured into 1N hydrochloric acid (12 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was washed with water (40 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the target compound (100 mg, 90%) of pale pink needle crystals was obtained.

Mp 234.0-235.0 ° C; ¹ H NMR (300 MHz, DMSO-d6) δ: 13.45 (br s, 1H), 8.31 (d, 1H, J = 1.0 Hz), 8.28 (d, 1H, J = 8.5 Hz) , 8.04 (dd, 1H, J = 8.5, 1.0 Hz), 7.79 (d, 1H, J = 2.0 Hz), 7.69 (d, 1H, J = 8.5 Hz), 7.61 (dd, 1H, J = 8.5, 2.0 Hz), 1.74 (s, 4H), 1.34 (s, 12H); IR (KBr): v = 2960-2921 (OH), 1684 (CO) cm ^-1 ; FAB-MS m / e: 350 (M + H] ⁺ ; Anal. Calcd for C ₂₁ H ₂₃ N ₃ O ₂ 1 / 5H ₂ O: C, 71.45; H, 6.68; N, 11.90. Found: C, 71.64; H, 6.72; N, 11.76.

[Experimental example] 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 the transcriptional 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, 9.5 g of DMEM powder was dissolved in 1 L of ultrapure water (produced by Milli-Q ^(R) ), sterilized by high-pressure heat (121 ° C, 15 minutes), returned to room temperature, Add activated fetal bovine serum (FBS) to 10% (v / v), add 10 mL of 10% NaHCO ₃ sterilized by high-pressure heat, and then add 10 mL of L-glutamine after filter sterilization. Prepared.

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. 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 15 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 at an excitation wavelength of 360 nm and a fluorescence wavelength of 460 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).

4) Measurement results The above measurement results are shown in Tables 1 to 3 below.

Table 1 shows the results of measuring the transcriptional activity of the RXR receptor protein by measuring the luciferase activity which is a reporter protein for each target compound. As a result of the measurement, the relative activity was examined by setting the transcriptional activity when LGD1069, which is a positive control of RXR, was reacted at 1 μM to 100%. As a result, transcriptional activity was observed for compounds 20a, 29a, 20b, and 29b.

Table 2 shows the concentration (EC ₅₀ ) and E _max (biological activity) (%) that give half of the maximum transcriptional activation ability of 20b and 29b that showed particularly strong transcriptional activity. E _max (biological activity) (%) indicates the relative maximum transcriptional activation ability when LGD1069 (1 μM) is 100%.

Table 3 shows the results of measuring the transcriptional activity of RXR receptor protein for 23a, 23b, and 23c by measuring the luciferase activity that is the reporter protein. As a result of the measurement, the relative activity was examined by setting the transcriptional activity when LGD1069, which is a positive control of RXR, was reacted at 1 μM to 100%.

  As described above in detail, among the compounds of the present invention, the compound having RXR agonistic activity has a lower transcriptional activation ability than the activity of LGD1069, which is an existing RXR 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, RXR antagonisticity was observed in other parts of the compounds of the present invention. RXR forms heterodimers with various nuclear receptors, and is involved in the transcriptional regulation of DNA. Appropriate synergistic or antagonistic effects are exerted on nuclear receptors such as PPAR, which are attracting attention as development targets. 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.

It is a figure which shows the existing rexinoid compound. It is a figure which shows the synthetic scheme of the compound of the intermediate bodies 1-5. It is a figure which shows the synthetic scheme of the compound of the intermediate bodies 6-9. It is a figure which shows the synthetic scheme of the compound of the intermediate bodies 10-11. It is a figure which shows the synthetic scheme of the target compound (Examples 1-10). It is a figure which shows the synthetic scheme of the target compound (Examples 11-13). It is a figure which shows the synthetic scheme of the target compound (Examples 14-16). It is a figure which shows the synthetic scheme of the target compound (Examples 17-19).

Claims (4)

A compound represented by the following general formula II.
Formula II:

Wherein R ³ is hydrogen or an alkyl group,
XY in NYX is N = N or N = CR ⁵ , R ⁵ is an alkyl group, a phenyl group or a substituted phenyl group,
Z is a compound selected from a carboxylic acid ester, a carboxyl group and a salt thereof , and located in the para position with respect to N. ) Represented by the general formula IV below, compounds of claim 1.
Formula IV:

(Wherein R ³ is hydrogen or a methyl group,
R ⁵ is a methyl group, a methylphenyl group or a nitrophenyl group. ) The compound of Claim 2 represented by the following general formula V.
Formula V:

(In the formula, R ³ is hydrogen or a methyl group. ) A transcriptional regulator for RXR receptor protein comprising the compound according to any one of claims 1 to 3 as an active ingredient.

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